FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Hoare, SRJ De Vries, G Usdin, TB AF Hoare, SRJ De Vries, G Usdin, TB TI Measurement of agonist and antagonist ligand-binding parameters at the human parathyroid hormone type 1 receptor: Evaluation of receptor states and modulation by guanine nucleotide SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID TERNARY COMPLEX MODEL; ADENYLATE-CYCLASE; (PTH)/PTH-RELATED PEPTIDE; G-PROTEINS; CALCITONIN; PTH; IDENTIFICATION; LINKING; ANALOGS; BONE AB Determination of ligand-binding constants for parathyroid hormone (PTH) receptors has been hampered by a lack of suitable experimental systems and mechanistic models for data analysis. In this study, ligand binding to the cloned human PTH-1 receptor was measured using membrane-based radioligand-binding assays. Guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) (10 mu M) reduced binding of agonist radioligands [I-125]rPTH(1-34) and [I-125]PTHrP(1-36) but only to a limited extent (by 29 +/- 5 and 42 +/- 3%, respectively). Radiolabeled agonist dissociation was described by three and two phases in the absence and presence of GTP gamma S, respectively. GTP gamma S treatment removed a pseudoirreversible binding phase. Inhibition of radiolabeled antagonist ([I-125]bPTH(3-34)) binding was measured using a 90-min incubation, which allowed binding of ligands to closely approach the asymptotic maximum. Agonist/[I-125]bPTH(3-34) displacement curves were fitted best by assuming two independent affinity states, both in the presence and absence of GTP gamma S. After a 3-h incubation, binding of PTH agonists in the presence of GTP gamma S was described by a single affinity state, indicating the presence of slow components in the binding reaction. Antagonist binding was described by a single affinity state and was not significantly affected by GTP gamma S. The data were used to evaluate potential receptor-binding models. Although other models could not be excluded, all of the observations could be explained by assuming two binding sites on the receptor that recognize two corresponding sites on agonist ligands, Using the model, it was possible to estimate receptor-ligand-binding constants and to propose a direct method for identifying ligands that interact with a putative antagonist binding region of the receptor. C1 NIMH, Cell Biol Unit, Genet Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Math Res Branch, NIH, Bethesda, MD 20892 USA. RP Room 3DO6,Bldg 36,36 Convent Dr, Bethesda, MD 20892 USA. EM usdin@codon.nih.gov NR 36 TC 19 Z9 19 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUN PY 1999 VL 289 IS 3 BP 1323 EP 1333 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 199GA UT WOS:000080471300020 PM 10336523 ER PT J AU Jones, HE Bigelow, GE Preston, KL AF Jones, HE Bigelow, GE Preston, KL TI Assessment of opioid partial agonist activity with a three-choice hydromorphone dose-discrimination procedure SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID DRUG DISCRIMINATION; ANTAGONIST OPIOIDS; STIMULUS PROPERTIES; INTRINSIC EFFICACY; DEPENDENT HUMANS; MU-OPIOIDS; MORPHINE; SALINE; RECEPTOR; BUTORPHANOL AB The discriminative stimulus and subjective effects of opioid mixed agonist-antagonists were assessed in volunteer nondependent heroin users trained in a three-choice drug discrimination procedure to discriminate among the effects of i.m. administration of 2 ml of saline, 1 mg of hydromorphone, and 4 mg of hydromorphone (a morphine-like mu agonist). Other subjective, behavioral, and physiological measures were concurrently collected. The discrimination was readily learned by six of the eight subjects. After training, generalization curves were determined for the following i.m. drug conditions: hydromorphone (0.375-4.0 mg), pentazocine (7.5-60 mg), butorphanol (0.75-6 mg), nalbuphine (3-24 mg), and buprenorphine (0.075-0.6 mg), All five of the test drugs were discriminated significantly or showed trends toward being discriminated as hydromorphone 1 mg-like at one or more dose levels. Hydromorphone showed an inverted U-shaped dose-effect function on the hydromorphone 1 mg-like discrimination. Subjective effect measures produced clearer differentiation among the test drugs than did drug discrimination performance. The present results differ from those of a previous study that observed a close relationship between the results of the discrimination measure and subjective effect measures. The previous study used similar methods and test drugs but different training drugs (e.g., 3 mg of hydromorphone versus 6 mg of butorphanol versus saline), It appears that both the sensitivity of drug discrimination performance to between-drug differences and the relationship between discriminative and subjective effects depends upon the specific discrimination that is trained (e.g., two-choice or three-choice), The present high dose-low dose-saline discrimination procedure appears useful for assessing partial agonist activity. The present data are consistent with partial agonist activity for pentazocine, butorphanol, nalbuphine, and buprenorphine. C1 Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. RP Preston, KL (reprint author), NIDA, Clin Trials Sect, Addict Res Ctr, NIH,Intramural Res Program, POB 5180, Baltimore, MD 21224 USA. RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 FU NIDA NIH HHS [T32-DA07209, R01 DA04089, K05-DA00050] NR 37 TC 17 Z9 17 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUN PY 1999 VL 289 IS 3 BP 1350 EP 1361 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 199GA UT WOS:000080471300023 PM 10336526 ER PT J AU Vandivier, RW Eidsath, A Banks, SM Preas, HL Leighton, SB Godin, PJ Suffredini, AF Danner, RL AF Vandivier, RW Eidsath, A Banks, SM Preas, HL Leighton, SB Godin, PJ Suffredini, AF Danner, RL TI Down-regulation of nitric oxide production by ibuprofen in human volunteers SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID ENDOTOXIN-SHOCK; CARDIOVASCULAR-RESPONSE; INTRAVENOUS ENDOTOXIN; SYNTHASE ACTIVITY; SEPTIC SHOCK; EXHALED AIR; IN-VIVO; INDUCTION; EXPRESSION; ASPIRIN AB Ibuprofen has been shown in vitro to modulate production of nitric oxide (NO), a mediator of sepsis-induced hypotension. We sought to determine whether ibuprofen alters NO production and, thereby, vascular tone, in normal and endotoxin-challenged volunteers. Techniques for detecting NO were validated in 17 subjects infused with sodium nitroprusside, a NO donor. Then, endotoxin (4 ng/kg) or saline (vehicle alone) was administered in a single-blinded, crossover design to 12 other subjects randomized to receive either ibuprofen (2400 mg p.o.) or a placebo. Endotoxin decreased mean arterial pressure (MAP; P = .002) and increased alveolar NO flow rates (P = .04) and urinary excretion of nitrite and nitrate (P = .07). In both endotoxemic and normal subjects, ibuprofen blunted the small fall in MAP associated with bed rest (P = .005) and decreased alveolar NO flow rates (P = .03) and urinary excretion of nitrite and nitrate (P = .02). However, ibuprofen had no effect on the decrease in MAP caused by endotoxin, although it blocked NO production to the point of disrupting the normal relationship between increases in exhaled NO flow rate and decreases in MAP (P = .002). These are the first in vivo data to demonstrate that ibuprofen down-regulates NO in humans. Ibuprofen impaired the NO response to bed rest, producing a small rise in blood pressure. Although ibuprofen also interfered with the ability of endotoxin to induce NO production, it had no effect on the fall in blood pressure, suggesting that the hemodynamic response to endotoxin is not completely dependent on NO under these conditions. C1 NIH, Dept Crit Care Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NIH, Biomed Engn & Instrumentat Program, Off Res Serv, Bethesda, MD 20892 USA. RP Danner, RL (reprint author), NIH, Dept Crit Care Med, Warren G Magnuson Clin Ctr, Bldg 10,Room 7D43, Bethesda, MD 20892 USA. NR 42 TC 30 Z9 32 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUN PY 1999 VL 289 IS 3 BP 1398 EP 1403 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 199GA UT WOS:000080471300029 PM 10336532 ER PT J AU McGowan, MH Russell, P Carper, DA Lichtstein, D AF McGowan, MH Russell, P Carper, DA Lichtstein, D TI Na+, K+-ATPase inhibitors down-regulate gene expression of the intracellular signaling protein 14-3-3 in rat lens SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID DIGITALIS-LIKE COMPOUNDS; BOVINE ADRENOCORTICAL-CELLS; CARDIAC MYOCYTES; ENDOGENOUS OUABAIN; RESPONSE GENES; SODIUM-PUMP; KINASE-C; IDENTIFICATION; 14-3-3-PROTEINS; HYPOTHALAMUS AB To identify genes that are differentially expressed by Naf, K+-ATPase inhibitors, we used the differential display technique to compare mRNA expression patterns in rat lens. Lenses were treated with 10 mu M ouabain, bufalin, or 19-norbufalin derivative for 24 h and were compared with control lenses. Differential display analysis revealed that one of the downregulated genes was 14-3-3 theta. Down-regulation was confirmed by Northern blot and by reverse transcription-polymerase chain reaction analysis. Reverse transcription-polymerase chain reaction of additional 14-3-3 isoforms revealed that the eta and gamma isoforms of 14-3-3 are also down-regulated by ouabain, bufalin, and 19-norbufalin derivative, whereas the zeta isoform is downregulated only by bufalin. Down-regulation of the 14-3-3 isoforms occurred without a significant change in gamma-crystallin gene expression. These results demonstrate that one of the consequences of Na+, K+-ATPase inhibition by exogenous or endogenous inhibitors is the down-regulation of mRNA transcripts encoding several isoforms of 14-3-3. Because the 14-3-3 proteins are multifunctional regulatory proteins, the reduction in the abundance of various isoforms will have profound effects on cell function. C1 Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Physiol, IL-91120 Jerusalem, Israel. NEI, Lab Mechanisms Ocular Dis, Bethesda, MD USA. RP Lichtstein, D (reprint author), Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Physiol, POB 12272, IL-91120 Jerusalem, Israel. NR 42 TC 20 Z9 20 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUN PY 1999 VL 289 IS 3 BP 1559 EP 1563 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 199GA UT WOS:000080471300050 PM 10336553 ER PT J AU Kaste, LM Drury, TF Horowitz, AM Beltran, E AF Kaste, LM Drury, TF Horowitz, AM Beltran, E TI An evaluation of NHANES III estimates of early childhood caries SO JOURNAL OF PUBLIC HEALTH DENTISTRY LA English DT Article DE early childhood caries; dental caries; infant; prevalence; United States; Mexican-American; National Health and Nutrition Examination Survey III; NHANES III; estimates ID HEALTH; ISSUES AB Objectives: The purposes of this study were to estimate and evaluate the prevalence for the United States of early childhood caries (ECC) among children 12 to 23 months of age. Methods: The 1988-94 National Health and Nutrition Examination Survey (NHANES III) public-use data set was analyzed using SUDAAN. Two ECC case definitions were used. Definition #1 was restricted to the caries score called by the examiner. Definition #2 liberally included children identified by definition #1 and those possibly having questionable caries scores. Results: The NHANES III six-year prevalence estimates of caries in the maxillary anterior incisors of children 12 to 23 months of age were 1.0 percent for definition #1 and 1.7 percent for definition #2. Mexican-American and economically disadvantaged children were disproportionally represented with ECC. Conclusions: The prevalence of ECC among children 12 to 23 months of age is barely detectable at the national level. Alternative study designs and improved case definitions are needed for further advances in ECC. C1 Med Univ S Carolina, Coll Dent Med, Dept Stomatol, Div Dent Publ Hlth & Oral Epidemiol, Charleston, SC 29425 USA. Med Univ S Carolina, Coll Med, Dept Biometry & Epidemiol, Charleston, SC 29425 USA. Med Univ S Carolina, Ctr Hlth Care Res, Charleston, SC 29425 USA. NIDCR, Hlth Policy Anal & Dev Branch, Bethesda, MD USA. Ctr Dis Control & Prevent, Surveillance Invest Res Branch, Atlanta, GA USA. RP Kaste, LM (reprint author), Med Univ S Carolina, Coll Dent Med, Dept Stomatol, Div Dent Publ Hlth & Oral Epidemiol, 173 Ashley Ave,POB 250507, Charleston, SC 29425 USA. NR 8 TC 32 Z9 34 U1 2 U2 2 PU AAPHD NATIONAL OFFICE PI PORTLAND PA 3760 SW LYLE COURT, PORTLAND, OR 97221 USA SN 0022-4006 J9 J PUBLIC HEALTH DENT JI J. Public Health Dent. PD SUM PY 1999 VL 59 IS 3 BP 198 EP 200 DI 10.1111/j.1752-7325.1999.tb03269.x PG 3 WC Dentistry, Oral Surgery & Medicine; Public, Environmental & Occupational Health SC Dentistry, Oral Surgery & Medicine; Public, Environmental & Occupational Health GA 253KE UT WOS:000083555100008 PM 10649592 ER PT J AU Martens, PB Pillemer, SR Jacobsson, LTH O'Fallon, WM Matteson, EL AF Martens, PB Pillemer, SR Jacobsson, LTH O'Fallon, WM Matteson, EL TI Survivorship in a population based cohort of patients with Sjogren's syndrome, 1976-1992 SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE Sjogren's syndrome; mortality; epidemiology ID LYMPHOPROLIFERATION; EPIDEMIOLOGY; LYMPHOMA AB Objective, Sjogren's syndrome (SS) has been associated with development of lymphoid malignancies and other significant medical complications, but the effect of SS on survival in a population based sample has not been reported. We analyzed survival in an incidence cohort of patients diagnosed with SS in residents of Olmsted County, Minnesota, USA, between 1976 and 1992. Methods, All records of physician diagnosed SS were reviewed, as well as all records from patients diagnosed with xerostomia and keratoconjunctivitis sicca, and records of patients with rheumatoid arthritis (RA) and systemic lupus erythematosus. The case definition for SS required 2 of 3 criteria: keratoconjunctivitis sicca, xerostomia, or serologic abnormality. Confounding illnesses were excluded. All patients were white. Results. Of the 74 cases of SS identified, 50 (67%) had primary SS and 24 (33%) secondary SS, An average of 7.2 years of followup was available for patients with primary SS and 9.9 years for patients with secondary SS. Compared with the general population, patients with SS had increased mortality (p = 0.04). When patients with primary and secondary SS were studied separately, increased mortality was found in patients with secondary SS (p < 0.005) but not primary SS (p = 0.86). Conclusion. In this population based cohort, patients with primary SS did not have increased mortality. However, mortality may have been increased in patients with secondary SS, the majority of whom had RA. C1 Mayo Clin & Mayo Grad Sch Med, Div Rheumatol, Rochester, MN 55901 USA. Mayo Clin & Mayo Grad Sch Med, Dept Hlth Sci Res, Rochester, MN 55901 USA. NIDR, Bethesda, MD 20892 USA. Univ Lund, Malmo, Sweden. RP Matteson, EL (reprint author), Mayo Clin & Mayo Fdn, Div Rheumatol, 200 1st St SW, Rochester, MN 55905 USA. FU NCRR NIH HHS [RR-00585] NR 20 TC 40 Z9 41 U1 2 U2 2 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD JUN PY 1999 VL 26 IS 6 BP 1296 EP 1300 PG 5 WC Rheumatology SC Rheumatology GA 202HM UT WOS:000080646300016 PM 10381046 ER PT J AU Rost, K Fortney, J Zhang, ML Smith, J Smith, GR AF Rost, K Fortney, J Zhang, ML Smith, J Smith, GR TI Treatment of depression in rural Arkansas: Policy implications for improving care SO JOURNAL OF RURAL HEALTH LA English DT Article ID MAJOR DEPRESSION; MEDICAL OUTCOMES; OUTPATIENTS; DISORDERS; SYMPTOMS AB Policy-makers have long suspected that greater barriers to care result in depressed rural residents being less likely to receive high-qualify treatment. This study recruited 470 depressed community residents in a 1992 telephone survey, followed 95 percent of them through one year, and abstracted additional data on their health care utilization from insurance claims, medical and pharmacy records. Bivariate and multivariate models demonstrated that during the year following the baseline there were no significant rural-urban differences in the rate (probability of any outpatient depression treatment), type (probability of receiving general medical depression care only), or quality (completion of guideline-concordant acute-stage care) of outpatient depression treatment. Annual expenditures for outpatient depression treatment were lower for rural subjects compared with their urban counterparts. Rural subjects had 3.05 times the odds of being admitted to a hospital for physical problems and 3.06 times the odds of being admitted to a hospital for mental health problems during the year following baseline compared with urban subjects. Cost-offset analyses demonstrate that every dollar invested in depression treatment was associated with a $2.61 decrease in the cost of treating physical problems in depressed rural residents. Limited insurance coverage and limited availability of services were the most significant barriers to speciality and general medical outpatient treatment for depression in both rural and urban residents. More than 80 percent of depressed residents in both rural and urban areas visited a primary care provider during the year following baseline. The potential cost offset of depression treatment in rural populations plus the improvement in productivity observed in both rural and urban populations indicate that it may be economically possible to improve quality of care for depression without bankrupting an already strained health care budget. C1 Univ Arkansas Med Sci, Ctr Rural Mental Healthcare Res, Dept Psychiat, Little Rock, AR 72204 USA. NIMH, Ctr Mental Hlth Serv Res, Bethesda, MD 20892 USA. Merck, Rahway, NJ USA. RP Rost, K (reprint author), Univ Arkansas Med Sci, Ctr Rural Mental Healthcare Res, Dept Psychiat, 5800 W 10th St,Suite 605, Little Rock, AR 72204 USA. FU NIMH NIH HHS [MH49116, MH53629, MH54444, MH55297] NR 23 TC 25 Z9 25 U1 0 U2 0 PU NATL RURAL HEALTH ASSOC PI KANSAS CITY PA ONE WEST ARMOUR BLVD, STE 301, KANSAS CITY, MO 64111 USA SN 0890-765X J9 J RURAL HEALTH JI J. Rural Health PD SUM PY 1999 VL 15 IS 3 BP 308 EP 315 DI 10.1111/j.1748-0361.1999.tb00752.x PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 407NY UT WOS:000167278700004 PM 11942563 ER PT J AU Klimes-Dougan, B Free, K Ronsaville, D Stilwell, J Welsh, CJ Radke-Yarrow, M AF Klimes-Dougan, B Free, K Ronsaville, D Stilwell, J Welsh, CJ Radke-Yarrow, M TI Suicidal ideation and attempts: A longitudinal investigation of children of depressed and well mothers SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE suicide; development; childhood; adolescence ID MULTIPLE SOURCES; AFFECTIVELY ILL; RISK-FACTORS; PARENTS; PSYCHOPATHOLOGY; BEHAVIOR; ADOLESCENTS; STRATEGIES; SEVERITY; DISORDER AB Objective: This study uses a prospective longitudinal design to examine suicidality (ideation, plans, attempts, and completions) in children and adolescents, to compare suicidality in the offspring of depressed and well mothers, and to identify correlates and predictors of suicidality. Method: Two children (n = 192) from each of the families in an ongoing longitudinal study of the offspring of mothers with major depressive disorder (n = 42), with bipolar disorder (n = 26), or without past or current psychiatric diagnosis (n = 30) were studied. Assessment of suicidality, based on diagnostic interviews, was made when the younger of the sibling pairs were approximately 6, 9, and 14 years of age and older siblings were approximately 6, 9, 13, and 18 years of age. Results: Children of depressed mothers were more likely to report suicidal thoughts or behaviors than were children of well mothers (particularly the older sibling cohort). Developmental trajectories of suicidality differed for offspring of mothers with major depressive disorder and bipolar disorder. Links were found between lifetime reports of suicidality and the adolescent's mood problems (e.g., hypomanic behavior), coping strategies, and parental rejection. Also, child's and mother's suicidality were related. Conclusions: These findings have implications for planning interventions targeted at preventing suicide in youth. C1 NIMH, Sect Dev Psychopathol, Bethesda, MD 20892 USA. RP Klimes-Dougan, B (reprint author), NIMH, Sect Dev Psychopathol, Bldg 15K,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 46 TC 47 Z9 49 U1 3 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD JUN PY 1999 VL 38 IS 6 BP 651 EP 659 DI 10.1097/00004583-199906000-00011 PG 9 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 200UQ UT WOS:000080558800011 PM 10361782 ER PT J AU Kandel, DB Johnson, JG Bird, HR Weissman, MM Goodman, SH Lahey, BB Regier, DA Schwab-Stone, ME AF Kandel, DB Johnson, JG Bird, HR Weissman, MM Goodman, SH Lahey, BB Regier, DA Schwab-Stone, ME TI Psychiatric comorbidity among adolescents with substance use disorders: Findings from the MECA study SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE adolescents; psychiatric comorbidity; substance use disorders ID MENTAL-DISORDERS; DRUG-ABUSE; TREATMENT CLIENTS; DEPRESSION; ALCOHOL; CHILD; PSYCHOPATHOLOGY; EPIDEMIOLOGY; PREVALENCE; COOCCURRENCE AB Objective: To investigate the extent to which adolescents in the community with current substance use disorders (SUD) experience co-occurring psychiatric disorders. Method: Diagnostic data were obtained from probability samples of 401 children and adolescents, aged 14 to 17 years, and their mothers/caretakers, who participated in the Methods for the Epidemiology of Child and Adolescent Mental Disorders (MECA) Study. Results: The rates of mood and disruptive behavior disorders are much higher among adolescents with current SUD than among adolescents without SUD. Comparison with adult samples suggests that the rates of current comorbidity of SUD with psychiatric disorders are the same among adolescents as adults, and lower for lifetime disruptive disorders/antisocial personality disorder among adolescents than adults. Conclusions: The high rate of coexisting psychiatric disorders among adolescents with SUD in the community needs to be taken into account in prevention and treatment programs. C1 Columbia Univ, New York, NY 10032 USA. New York State Psychiat Inst, New York, NY 10032 USA. Emory Univ, Atlanta, GA 30322 USA. Univ Chicago, Chicago, IL 60637 USA. NIMH, Rockville, MD 20857 USA. Yale Univ, New Haven, CT USA. RP Kandel, DB (reprint author), Columbia Univ, 1051 Riverside Rd,Unit 20, New York, NY 10032 USA. OI Weissman, Myrna/0000-0003-3490-3075 FU NIDA NIH HHS [DA0008]; NIMH NIH HHS [MH 43878-06, MH30906] NR 40 TC 146 Z9 149 U1 10 U2 23 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD JUN PY 1999 VL 38 IS 6 BP 693 EP 699 DI 10.1097/00004583-199906000-00016 PG 7 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 200UQ UT WOS:000080558800016 PM 10361787 ER PT J AU Sheps, DS McMahon, RP Light, KC Maixner, W Pepine, CJ Cohen, JD Goldberg, AD Bonsall, R Carney, R Stone, PH Sheffield, D Kaufmann, PG AF Sheps, DS McMahon, RP Light, KC Maixner, W Pepine, CJ Cohen, JD Goldberg, AD Bonsall, R Carney, R Stone, PH Sheffield, D Kaufmann, PG CA PIMI Investigators TI Low hot pain threshold predicts shorter time to exercise-induced angina: Results from the psychophysiological investigations of myocardial ischemia (PIMI) study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID CORONARY-ARTERY DISEASE; ST-SEGMENT DEPRESSION; PLASMA BETA-ENDORPHIN; MENTAL STRESS; SILENT; PECTORIS; PERCEPTION; RESPONSES; NALOXONE; EXPERIENCE AB OBJECTIVES The purpose of this study was to test whether cutaneous thermal pain thresholds are related to anginal pain perception. BACKGROUND Few ischemic episodes are associated with angina; symptoms have been related to pain perception thresholds. METHODS A total of 196 patients with documented coronary artery disease underwent bicycle exercise testing and thermal pain testing. The Marstock test of cutaneous sensory perception was administered at baseline after 30 min of rest on two days and after exercise and mental stress. Resting hot pain thresholds (HPTs) were averaged for the two baseline visits and divided into two groups: 1) average HPT <41 degrees C, and 2) average HPT greater than or equal to 41 degrees C, to be clearly indicative of abnormal hypersensitivity to noxious heat. RESULTS Patients with HPT <41 degrees C had significantly shorter time to angina onset on exercise testing than patients with HPT <41 degrees C (p < 0.04, log rank test). Heart rates, systolic blood pressure and rate-pressure product at peak exercise were not different for the two groups. Resting plasma beta-endorphin levels were significantly higher in the HPT <41 degrees C group (5.9 +/- 3.7 pmol/liter vs. 4.7 +/- 2.8 pmol/liter, p = 0.02). Using a Cox proportional hazards model, patients with HPT <41 degrees C had an increased risk of angina (p = 0.03, rate ratio = 2.0). These differences persisted after adjustment for age, gender, depression, anxiety and history of diabetes or hypertension (p < 0.01). CONCLUSIONS Occurrence of angina and timing of angina onset on an exercise test are related to overall hot pirin sensory perception. The mechanism of this relationship requires further study. (C) 1999 by the American College of Cardiology. C1 E Tennessee State Univ, Johnson City, TN 37614 USA. Maryland Med Res Inst, Baltimore, MD USA. Univ N Carolina, Chapel Hill, NC USA. Univ Florida, Gainesville, FL USA. St Louis Univ, Med Ctr, St Louis, MO USA. Henry Ford Hosp, Detroit, MI 48202 USA. Emory Univ, Sch Med, Atlanta, GA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NHLBI, Bethesda, MD 20892 USA. RP Sheps, DS (reprint author), 2 Profess Pk Dr,Suite 15, Johnson City, TN 37604 USA. RI McMahon, Robert/C-5462-2009; OI Sheffield, David/0000-0001-9121-1783 FU NHLBI NIH HHS [HV 18114, HV 18119, HV 18120] NR 39 TC 16 Z9 17 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN PY 1999 VL 33 IS 7 BP 1855 EP 1862 DI 10.1016/S0735-1097(99)00099-6 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 210UM UT WOS:000081123100006 PM 10362185 ER PT J AU Vasan, RS Larson, MG Benjamin, EJ Evans, JC Reiss, CK Levy, D AF Vasan, RS Larson, MG Benjamin, EJ Evans, JC Reiss, CK Levy, D TI Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction - Prevalence and mortality in a population-based cohort SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID SYSTOLIC FUNCTION; AORTIC-STENOSIS; SEX-DIFFERENCES; CARDIAC ADAPTATION; IMPROVING SURVIVAL; GENDER DIFFERENCES; UNITED-STATES; AGE; ECHOCARDIOGRAPHY; FRAMINGHAM AB OBJECTIVES The purpose of this study was to assess the relative proportions of normal versus impaired left ventricular (LV) systolic function among persons with congestive heart failure (CHF) in the community and to compare their long-term mortality during follow-up. BACKGROUND Several hospital-based investigations have reported that a high proportion of subjects with CHF have normal LV systolic function. The prevalence and prognosis of CHF with normal LV systolic function in the community are not known. METHODS We evaluated the echocardiograms of 73 Framingham Heart Study subjects with CHF (33 women, 40 men, mean age 73 years) and 146 age- and gender-matched control subjects (nested case-control study). Impaired LV systolic function was defined as an LV ejection fraction (LVEF) <0.50. RESULTS Thirty-seven CHF cases (51%) had a normal LVEF; 36 (49%) had a reduced LVEF. Women predominated in the former group (65%), whereas men constituted 75% or the latter group. During a median follow-up of 6.2 years, CHF cases with normal LVEF experienced an annual mortality of 8.7% versus 3.0% for matched control subjects (adjusted hazards ratio = 4.06, 95% confidence interval 1.61 to 10.26). Congestive heart failure cases with reduced LVEF had an annual mortality of 18.9% versus 4.1% for matched control subjects (adjusted hazards ratio = 4.31, 95% confidence interval 1.98 to 9.36). CONCLUSIONS Normal LV systolic function is often found in persons with CHF in the community and is in more common in women than in men. Although CHF cases with normal LVEF have a lower mortality risk than cases with reduced LVEF, they have a fourfold mortality risk compared with control subjects who are free of CHF. 1999 by the American College of Cardiology. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. Harvard Univ, Sch Med, Beth Israel Hosp, Div Cardiol, Boston, MA USA. Harvard Univ, Sch Med, Beth Israel Hosp, Div Clin Epidemiol, Boston, MA USA. Boston Med Ctr, Cardiol Sect, Boston, MA USA. Boston Univ, Sch Med, Dept Epidemiol & Prevent Med, Boston, MA 02118 USA. Barnes Hosp, St Louis, MO 63110 USA. NHLBI, Bethesda, MD 20892 USA. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, 5 Thurber St, Framingham, MA 01702 USA. OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [N0I-HC-38038]; NINDS NIH HHS [2-ROI-NS-17950-11] NR 59 TC 801 Z9 840 U1 0 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN PY 1999 VL 33 IS 7 BP 1948 EP 1955 DI 10.1016/S0735-1097(99)00118-7 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 210UM UT WOS:000081123100019 PM 10362198 ER PT J AU Burklow, TR Moak, JP Bailey, JJ Makhlouf, FT AF Burklow, TR Moak, JP Bailey, JJ Makhlouf, FT TI Neurally mediated cardiac syncope: Autonomic modulation after normal saline infusion SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID HEART-RATE-VARIABILITY; POWER SPECTRAL-ANALYSIS; UNEXPLAINED SYNCOPE; NEUROCARDIOGENIC SYNCOPE; YOUNG-PATIENTS; UPRIGHT TILT; UP TILT; CHILDREN; MANAGEMENT; COMPONENTS AB OBJECTIVES This study assessed the heart variability response to orhtostatic stress before and after normal saline administration BACKGROUND The efficacy of sodium chloride and mineralocortoid in the treatment of neurally mediated cardiac syncope is attributed to intravascular volume expansion; however, their modulation of autonomic nervous system activity has not been evaluated. MEHTODS Heart rate variability analysis was perio,med on 12 adolescents with a history of syncope or presyncope (mean age 15.2 +/- 0.7 years) during tilt table testing. Subjects were upright 80 degrees for 30 min or until syncope After normal saline administration, the patient was returned upright for 30 min. Heart rate variability analysis data were analyzed by an autoregression model (Burg method). RESUTLS All subjects reproducibly developed syncope during control tilt table testing; median time to syncope was 9.4 +/- 2.1 min. After normal saline infusion, none of the subjects developed syncope after 30 min upright. In the control tilt, there was an initial increase followed by a progressive decrease in low frequency power until syncope. Repeat tilt after normal saline administration demonstrates that low frequency power increased but; the magnitude of initial change was blunted when compared with control. In addition, low frequency power increased during normal saline tilt sequence compared with the control tilt, during which it decreased, CONCLUSIONS Normal saline blunted low frequency power stimulation and prevented paradoxical low withdrawal. Increasing intravascular volume with saline alters autonomic responses syncope (C) 1999 by the American College of Cardiology. C1 Childrens Natl Med Ctr, Dept Cardiol, Washington, DC 20010 USA. NIH, Ctr Informat Technol, Bethesda, MD USA. American Univ, Dept Stat, Washington, DC 20016 USA. RP Moak, JP (reprint author), Childrens Natl Med Ctr, Dept Cardiol, 111 Michigan Ave NW, Washington, DC 20010 USA. NR 44 TC 16 Z9 17 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN PY 1999 VL 33 IS 7 BP 2059 EP 2066 DI 10.1016/S0735-1097(99)00133-3 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 210UM UT WOS:000081123100035 PM 10362214 ER PT J AU Sher, L AF Sher, L TI Seasonal distribution of myocardial infarction and seasonal mood changes SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Letter C1 NIMH, Sect Biol Rhythms, Bethesda, MD 20892 USA. RP Sher, L (reprint author), NIMH, Sect Biol Rhythms, Bethesda, MD 20892 USA. NR 12 TC 11 Z9 11 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN PY 1999 VL 33 IS 7 BP 2088 EP 2089 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 210UM UT WOS:000081123100045 PM 10362222 ER PT J AU Pihlstrom, BL Hargreaves, KM Bouwsma, OJ Myers, WR Goodale, MB Doyle, MJ AF Pihlstrom, BL Hargreaves, KM Bouwsma, OJ Myers, WR Goodale, MB Doyle, MJ TI Pain after periodontal scaling and root planing SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article ID PERCEPTION AB Background. Although periodontal scaling and root planing, or SRP, is one of the most common procedures used in dental practice, there is little information available about the degree of postprocedural pain associated with it. The authors under-took this study to document the intensity and duration of pain after SRP with a view toward helping practitioners and their patients manage postprocedural discomfort. Methods. Using the Heft-Parker self-assessment pain scale, 52 adults with moderate periodontitis evaluated their pain before and after SRP conducted with local anesthetic. Results. After SRP, 28 percent of all :patients reported faint-to-weak pain, 18 percent experienced weak-to-mild pain, 28 percent experienced mild-to-moderate pain, 8 percent had moderate-to-strong pain and 8 percent reported strong-to-intense pain. The average time to onset of maximum pain was approximately three hours after SRP, and the average duration of mild or greater pain was about six hours. Upon awakening the morning alter SRP, subjects found that pain had returned to pre-SRP levels. Overall, 23 percent of all patients reported self-medicating with analgesics to relieve postprocedural pain. Women self-medicated earlier (P < .05) and more often than men (43 percent vs. 10 percent; P < .05). Conclusions. Patients experienced significant duration and magnitude of pain after SRP. This pain peaked between two and eight hours after SRP, lasted about six hours, and returned to pre-SRP levels by the morning after the procedure. Almost 25 percent of all patients self-medicated to relieve pain after SRP, and women took analgesic medication earlier and more often than men. Clinical Implications. Practitioners should consider using appropriate analgesic drugs to alleviate mild-to-moderate pain after SRP. On the basis of this study, it would appear that an analgesic that has a peak effect two to eight hours after the completion of SRP would be the most appropriate medication. Moreover, it is unlikely that analgesic medication would be needed by most patients beyond the day on which SRP was performed. C1 Univ Minnesota, Sch Dent, Natl Inst Dent & Craniofacial Res, Oral Hlth Clin Res Ctr,NIH, Minneapolis, MN 55455 USA. Univ Texas, Hlth Sci Ctr, Dept Pharmacol, San Antonio, TX USA. Univ Texas, Hlth Sci Ctr, Dept Endodont, San Antonio, TX USA. Procter & Gamble Co, Regulatory & Clin Dev, Worldwide Clin Invest, Mason, OH USA. Procter & Gamble Co, Dept Biometr & Stat Sci, Mason, OH USA. Procter & Gamble Co, Procter & Gamble Worldwide, Hlth Care Res & Dev, Mason, OH USA. RP Pihlstrom, BL (reprint author), Univ Minnesota, Sch Dent, Natl Inst Dent & Craniofacial Res, Oral Hlth Clin Res Ctr,NIH, 515 Delaware St SE, Minneapolis, MN 55455 USA. RI Hargreaves, Kenneth/F-5308-2010 FU NIDCR NIH HHS [DE09737] NR 13 TC 21 Z9 22 U1 0 U2 1 PU AMER DENTAL ASSN PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD JUN PY 1999 VL 130 IS 6 BP 801 EP 807 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 204FR UT WOS:000080753900014 PM 10377637 ER PT J AU Donly, KJ Segura, A Wefel, JS Hogan, MM AF Donly, KJ Segura, A Wefel, JS Hogan, MM TI Evaluating the effects of fluoride-releasing dental materials on adjacent interproximal caries SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article ID IONOMER RESTORATIVE MATERIALS; GLASS-IONOMER; ENAMEL REMINERALIZATION; PRIMARY MOLARS; SHORT-TERM; AMALGAM RESTORATIONS; CLINICAL-EVALUATION; FILLING MATERIALS; TEETH ADJACENT; MODEL AB Background. The authors examined several restorative materials to evaluate their ability to inhibit demineralization and enhance remineralization of incipient carious lesions on the interproximal enamel of teeth adjacent to those restored with the materials. Methods. Twenty-one subjects in need of a crown on a mandibular molar and a Class II inlay on an adjacent tooth took part in this six-phase study. Artificial enamel lesions were created and positioned within the interproximal portion of a crown. Lesions were photographed with polarized light microscopy and characterized before and after 30-day intraoral exposures. Each phase included the placement of a new section in the crown model and a new Class II inlay restorative material in the adjacent tooth. Results. Results demonstrated that nonfluoridated resin composite, fluoridated resin composite and resin-modified glass ionomer restorative materials, when placed in subjects who brushed with a fluoridated dentifrice, demonstrated significantly (P <.05) less enamel demineralization than the nonfluoridated resin composite control placed in subjects who brushed with a nonfluoridated dentifrice. The resin-modified glass ionomer cement, however, even when brushed with a nonfluoridated dentifrice, exhibited significantly (P <.05) less demineralization than the nonfluoridated resin composite control brushed with a nonfluoridated dentifrice. Conclusions. Resin-modified glass ionomer cement appears to significantly inhibit demineralization of interproximal enamel of teeth adjacent to those restored with the material. Clinical Implications. Resin-modified glass ionomer cement restorations can enhance prevention of enamel demineralization on adjacent teeth. C1 Univ Texas, Hlth Sci Ctr, Sch Dent, San Antonio, TX 78284 USA. Univ Iowa, Coll Dent, Dept Pediat Dent, Iowa City, IA 52242 USA. Univ Iowa, Coll Dent, Ctr Clin Studies, Iowa City, IA 52242 USA. Univ Iowa, Coll Dent, Dows Inst Dent Res, Iowa City, IA 52242 USA. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Donly, KJ (reprint author), Univ Texas, Hlth Sci Ctr, Sch Dent, 7703 Floyd Curl Dr, San Antonio, TX 78284 USA. FU NIDCR NIH HHS [P50 DE11134] NR 87 TC 45 Z9 45 U1 0 U2 1 PU AMER DENTAL ASSN PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD JUN PY 1999 VL 130 IS 6 BP 817 EP 825 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 204FR UT WOS:000080753900016 PM 10377639 ER PT J AU Slavkin, HC AF Slavkin, HC TI Learning, immunology and allergic responses SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article ID HYPERSENSITIVITY C1 Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. RP Slavkin, HC (reprint author), Natl Inst Dent & Craniofacial Res, 31 Ctr Dr,MSC 2290,Bldg 31,Room 2C39, Bethesda, MD 20892 USA. NR 13 TC 1 Z9 1 U1 0 U2 0 PU AMER DENTAL ASSN PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD JUN PY 1999 VL 130 IS 6 BP 863 EP 867 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 204FR UT WOS:000080753900023 PM 10377646 ER PT J AU Ferrucci, L Harris, TB Guralnik, JM Tracy, RP Corti, MC Cohen, HJ Penninx, B Pahor, M Wallace, R Havlik, RJ AF Ferrucci, L Harris, TB Guralnik, JM Tracy, RP Corti, MC Cohen, HJ Penninx, B Pahor, M Wallace, R Havlik, RJ TI Serum IL-6 level and the development of disability in older persons SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE IL-6; disability; inflammation; aging ID C-REACTIVE PROTEIN; CORONARY HEART-DISEASE; ACUTE-PHASE PROTEINS; CARDIOVASCULAR-DISEASE; RHEUMATOID-ARTHRITIS; ELDERLY SUBJECTS; UNSTABLE ANGINA; RISK-FACTORS; PLASMA IL-6; INTERLEUKIN-6 AB BACKGROUND: The serum concentration of interleukin 6 (IL-6), a cytokine that plays a central role in inflammation, increases with age. Because inflammation is a component of many age-associated chronic diseases, which often cause disability, high circulating levels of IL-6 may contribute to functional decline in old age. We tested the hypothesis that high levels of IL-6 predict future disability in older persons who are not disabled. METHODS: Participants at the sixth annual follow-up of the Iowa site of the Established Populations for Epidemiologic Studies of the Elderly aged 71 years or older were considered eligible for this study if they had no disability in regard to mobility or in selected activities of daily living (ADL), and they were re-interviewed 4 years later. Incident cases of mobility-disability and of ADL-disability were identified based on responses at the follow-up interview. Measures of IL-6 were obtained from specimens collected at baseline from the 283 participants who developed any disability and from 350 participants selected randomly (46.9%) from those who continued to be non-disabled. FINDINGS: Participants in the highest IL-6 tertile were 1.76 (95% CI, 1.17-2.64) times more likely to develop at least mobility-disability and 1.62 (95% CI, 1.02-2.60) times more likely to develop mobility plus ADL-disability compared with to the lowest IL-6 tertile. The strength of this association was almost unchanged after adjusting for multiple confounders. The increased risk of mobility-disability over the full spectrum of IL-6 concentration was nonlinear, with the risk rising rapidly beyond plasma levels of 2.5 pg/mL. INTERPRETATION: Higher circulating levels of IL-6 predict disability onset in older persons. This may be attributable to a direct effect of IL-6 on muscle atrophy and/or to the pathophysiologic role played by IL-6 in specific diseases. C1 INRCA, Natl Res Inst, Dept Geriatr, Florence, Italy. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. Univ Vermont, Dept Pathol, Lab Clin Biochem Res, Colchester, VT USA. Univ Padua, Inst Internal Med, Padua, Italy. VA Med Ctr, Durham, NC USA. Duke Univ, Sch Med, Durham, NC USA. Univ Tennessee, Med Grp, Dept Prevent Med, Memphis, TN USA. Univ Iowa, Coll Med, Iowa City, IA USA. RP Ferrucci, L (reprint author), NIA, Epidemiol Demog & Biometry Program, 7201 Wisconsin Ave,Gateway Bldg,Suite 3C-309, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [R01 HL 46696]; NIA NIH HHS [AG-0-2106] NR 46 TC 460 Z9 465 U1 0 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUN PY 1999 VL 47 IS 6 BP 639 EP 646 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 202VE UT WOS:000080672200001 PM 10366160 ER PT J AU Simonsick, EM Guralnik, JM Fried, LP AF Simonsick, EM Guralnik, JM Fried, LP TI Who walks? Factors associated with walking behavior in disabled older women with and without self-reported walking difficulty SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE disability; walking; aged; women ID BODY-MASS INDEX; TIME PHYSICAL-ACTIVITY; WEIGHT CHANGE; NHANES-I; HEALTH; ADULTS; EXERCISE; DISABILITY; FEAR; RISK AB OBJECTIVES: To determine how severity of walking difficulty and sociodemographic, psychosocial, and health-related factors influence walking behavior in disabled older women. DESIGN: Cross-sectional analyses of baseline data from the Women's Health and Aging Study (WHAS). SETTING: hn urban community encompassing 12 contiguous zip code areas in the eastern portion of Baltimore City and part of Baltimore County, il Maryland. PARTICIPANTS: A total of 920 moderately to severely disabled community-resident women, aged 65 years and older, identified from an age-stratified random sample of Medicare beneficiaries. MEASUREMENTS: Walking behavior was defined as minutes walked for exercise and total blocks walked per week. Independent variables included self-reported walking difficulty, sociodemographic factors, psychological status (depression, mastery, anxiety, and cognition), and health-related factors (falls and fear of falling, fatigue, vision and balance problems, weight, smoking, and cane use). RESULTS: Walking at least 8 blocks per week was strongly negatively related to severity of walking difficulty. Independent of difficulty level, older age, black race, fatigue, obesity, and cane use were also negatively associated with walking; living alone and high mastery had a positive association with walking. CONCLUSIONS: Even among functionally limited women, sociocultural, psychological, and health-related factors were independently associated with walking behavior. Thus, programs aimed at improving walking ability need to address these factors in addition to walking difficulties to maximize participation and compliance. C1 NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. Johns Hopkins Univ, Inst Med, Baltimore, MD USA. RP Simonsick, EM (reprint author), NIA, Epidemiol Demog & Biometry Program, 7201 Wisconsin Ave,Suite 3C-309, Bethesda, MD 20892 USA. NR 54 TC 64 Z9 64 U1 3 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUN PY 1999 VL 47 IS 6 BP 672 EP 680 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 202VE UT WOS:000080672200006 PM 10366165 ER PT J AU Scuteri, A Di Bernardo, MG De Propris, AM Marigliano, V AF Scuteri, A Di Bernardo, MG De Propris, AM Marigliano, V TI Insulin effects on the left ventricle in older hypertensive subjects SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE insulin; older; hypertension; left ventricular mass; left ventricular function ID GLUCOSE-INTOLERANCE; BLOOD-PRESSURE; METABOLISM; MASS; DETERMINANT; HYPERTROPHY; RESISTANCE; HEART; AGE AB BACKGROUND: To evaluate the effects of hyperinsulinemia on left ventricular (LV) structure and function in older hypertensive subjects METHODS: Thirty-seven hypertensive subjects (17 men/20 women) aged 50 to 80, were studied. LV mass were evaluated echocardiographically according to the Penn convention. A 75-g oral glucose tolerance test (OGTT) was performed after overnight fasting, and both blood glucose and insulin concentrations were assayed at 0, 30, 60, 90, 120, and 180 minutes. Comparison between groups was performed by analysis of variance. A P value of .05 was considered statistically significant. RESULTS: When the hypertensive patients were divided into two groups according to the median value of 2-hour post-loading plasma insulin, there was no difference in blood pressure levels between the groups. However, hyperinsulinemic hypertensive subjects had an increased LV mass (P < .05), mean wall thickness, and interventricular septum thickness (P < .05 for both parameters) and had better systolic function-ejection and shortening fractions (P < .0001 for both indices). CONCLUSIONS: Hyperinsulinemia may be associated with increased left ventricular mass and with a better systolic performance in older hypertensive subjects. C1 Univ La Sapienza, Policlin Umberto I, Cattedra Gerontol & Geriatria, Med Clin 1, Rome, Italy. RP Scuteri, A (reprint author), NIA, NIH, Cardiovasc Sci Lab, 5600 Nathan Shock Dr,3B10, Baltimore, MD 21224 USA. NR 28 TC 2 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUN PY 1999 VL 47 IS 6 BP 727 EP 729 PG 3 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 202VE UT WOS:000080672200016 PM 10366175 ER PT J AU Humphrey, SM AF Humphrey, SM TI Automatic indexing of documents from journal descriptors: A preliminary investigation SO JOURNAL OF THE AMERICAN SOCIETY FOR INFORMATION SCIENCE LA English DT Article ID VOCABULARY; RETRIEVAL; WORLD AB A new, fully automated approach for indexing documents is presented based on associating textwords in a training set of bibliographic citations with the indexing of journals. This journal-level indexing is in the form of a consistent, timely set of journal descriptors (JDs) indexing the individual journals themselves, This indexing is maintained in journal records in a serials authority database. The advantage of this novel approach is that the training set does not depend on previous manual indexing of hundreds of thousands of documents (i.e., any such indexing already in the training set is not used), but rather the relatively small intellectual effort of indexing at the journal level, usually a matter of a few thousand unique journals for which retrospective indexing to maintain consistency and currency may be feasible, If successful, JD indexing would provide topical categorization of documents outside the training set, i.e., journal articles, monographs, WEB documents, reports from the grey literature, etc., and therefore be applied in searching, Because JDs are quite general, corresponding to subject domains, their most probable use would be for improving or refining search results. C1 Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. RP Humphrey, SM (reprint author), Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. FU Intramural NIH HHS [NIH0010104141] NR 25 TC 14 Z9 14 U1 0 U2 2 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0002-8231 J9 J AM SOC INFORM SCI JI J. Am. Soc. Inf. Sci. PD JUN PY 1999 VL 50 IS 8 BP 661 EP 674 DI 10.1002/(SICI)1097-4571(1999)50:8<661::AID-ASI4>3.0.CO;2-R PG 14 WC Computer Science, Information Systems; Information Science & Library Science SC Computer Science; Information Science & Library Science GA 196WR UT WOS:000080331300003 PM 21712970 ER PT J AU Walenga, JM Hoppensteadt, D Pifarre, R Cressman, MD Hunninghake, DB Fox, NL Terrin, ML Probstfield, JL AF Walenga, JM Hoppensteadt, D Pifarre, R Cressman, MD Hunninghake, DB Fox, NL Terrin, ML Probstfield, JL CA Post CABG Studies Investigators TI Hemostatic effects of 1 mg daily warfarin on post CABG patients SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Article DE warfarin; CABG; coronary bypass graft; restenosis; thrombosis ID PLASMINOGEN-ACTIVATOR INHIBITOR; AORTOCORONARY BYPASS-SURGERY; CORONARY-ARTERY DISEASE; FIXED MINIDOSE WARFARIN; ISCHEMIC-HEART-DISEASE; MYOCARDIAL-INFARCTION; FACTOR-VII; ANTICOAGULANT TREATMENT; ORAL ANTICOAGULATION; VENOUS THROMBOSIS AB Although coronary bypass graft surgery has increased the survival and quality of life of many individuals, patients remain at risk of restenosis and thrombotic occlusion of the coronary arteries and bypass grafts. In the screening period for participation in the multicenter Post Coronary Artery Bypass Graft (Post CABG) trial, the effects of 1 mg daily warfarin were evaluated using paired patient samples collected prior to and after at least 21 days of treatment. In stable patients (n = 40; 39 males 1 female; 51-74 years old) who previously had undergone coronary artery revascularization (1-10 years), no alterations in prothrombin time, international normalized ratio (INR), prothrombin fragment 1.2, or the hemostatic risk factors factor VII antigen and coagulant activity, von Willebrand's factor, fibrinogen, tPA, or PAI-1 were associated with the 1 mg daily warfarin treatment. The observations reported here supported the Post CABG Studies Steering Committee decision to treat patients with 1-4 mg warfarin daily adjusted to achieve INRs not to exceed 2.0 consistent with low-intensity therapy. C1 Loyola Univ, Med Ctr, Dept Pathol, Maywood, IL 60153 USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Univ Minnesota, Minneapolis, MN USA. Maryland Med Res Inst, Baltimore, MD USA. NHLBI, Bethesda, MD 20892 USA. RP Walenga, JM (reprint author), Loyola Univ, Med Ctr, Dept Pathol, 2160 S 1st Ave, Maywood, IL 60153 USA. NR 33 TC 4 Z9 4 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 JUN PY 1999 VL 7 IS 3 BP 313 EP 318 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 211LY UT WOS:000081163600011 PM 10373714 ER PT J AU Champion, HC Bivalacqua, TJ Wang, R Kadowitz, PJ Keefer, LK Saavedra, JE Hrabie, JA Doherty, PC Hellstrom, WJG AF Champion, HC Bivalacqua, TJ Wang, R Kadowitz, PJ Keefer, LK Saavedra, JE Hrabie, JA Doherty, PC Hellstrom, WJG TI Induction of penile erection by intracavernosal and transurethral administration of novel nitric oxide donors in the cat SO JOURNAL OF UROLOGY LA English DT Article DE penile erection; novel nitric oxide donors; diazeniumdiolates; transurethral; intracavernosal ID ALPROSTADIL; DYSFUNCTION; IMPOTENCE; LINSIDOMINE; PHYSIOLOGY; COMPLEXES; THERAPY; RELEASE; MEN AB Purpose: The effects of novel nitric oxide (NO) donors administered intracavernosally and transurethrally on erectile function in the anesthetized cat were evaluated. Materials and Methods: In pentobarbital-anesthetized cats, increases in intracavernosal pressure, penile length, and duration of erectile response were determined after intracavernosal and transurethral injections of novel NO donors (MAHMA/NO, PAPA/NO, DEA/NO, PIPERAZI/NO and PROLI/NO). All parameters were measured after administration of NO donors intracavernosally via a 30-gauge needle and urethrally via a Jelco i.v. catheter in a volume of 200 mu l. Systemic arterial pressure was also assessed in these experiments. All NO donors were compared with a triple-drug control combination comprised of papaverine (1.65 mg.), prostaglandin E-1 (0.5 mu g.), and phentolamine (25 mu g.). Results: MAHMA/NO, PAPA/NO, DEA/NO, PIPERAZI/NO and PROLI/NO induced dose dependent increases in intracavernosal pressure and penile length (p <0.05) when administered intracavernosally. The increases in cavernosal pressure and penile length were comparable to those observed with the triple-drug control combination. The maximum increase in cavernosal pressure in response to PROLI/NO and PAPA/NO was associated with no significant change in systemic arterial pressure. Transurethral administration of PROLI/NO and PIPERAZI/NO induced dose-dependent increases in cavernosal pressure and penile length (p <0.05). The response was similar to that of the triple-drug control combination, except that transurethral PROLI/NO and PIPERAZI/NO had no significant effect on systemic blood pressure. Conclusions: NO donors caused dose-dependent increases in cavernosal pressure when administered intracavernosally and transurethrally. These data suggest further exploration of the use of NO donors for the treatment of erectile dysfunction. C1 Tulane Univ, Sch Med, Dept Urol SL42, New Orleans, LA 70112 USA. Tulane Univ, Sch Med, Dept Pharmacol, New Orleans, LA 70112 USA. NCI, Comparat Carcinogenesis Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. NCI, SAIC Fredrick, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. VIVUS Inc, Mt View, CA USA. RP Hellstrom, WJG (reprint author), Tulane Univ, Sch Med, Dept Urol SL42, 1430 Tulane Ave, New Orleans, LA 70112 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU NCI NIH HHS [N01-CO-56000] NR 26 TC 21 Z9 21 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JUN PY 1999 VL 161 IS 6 BP 2013 EP 2019 DI 10.1016/S0022-5347(05)68875-1 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 194PJ UT WOS:000080202500084 PM 10332492 ER PT J AU Korte, T Ludwig, K Booy, FP Blumenthal, R Herrmann, A AF Korte, T Ludwig, K Booy, FP Blumenthal, R Herrmann, A TI Conformational intermediates and fusion activity of influenza virus hemagglutinin SO JOURNAL OF VIROLOGY LA English DT Article ID VESICULAR STOMATITIS-VIRUS; MEDIATED MEMBRANE-FUSION; LOW-PH; ENVELOPE GLYCOPROTEIN; BIOLOGICAL-MEMBRANES; FUSOGENIC ACTIVITY; KINETICS; ENHANCEMENT; FLUORESCENCE; PRETREATMENT AB Three strains of influenza virus (H1, H2, and H3) exhibited similar characteristics in the ability of their hemagglutinin (HA) to induce membrane fusion, but the HAs differed in their susceptibility to inactivation. The extent of inactivation depended on the pH of preincubation and was lowest for A/Japan (H2 subtype), in agreement with previous studies (A, Purl, F. Booy, R. W. Doms, J, M, White, and R. Blumenthal, J, Virol, 64:3824-3832, 1990), While significant inactivation of X31 (H3 subtype) was observed at 37 degrees C at pH values corresponding to the maximum of fusion (about pH 5.0), no inactivation was seen at preincubation pH values 0.2 to 0.4 pH units higher. Surprisingly, low-pH preincubation under those conditions enhanced the fusion rates and extents of A/Japan as well as those of X31, For A/PR 8/34 (H1 subtype), neither a shift of the pH (to >5.0) nor a decrease of the temperature to 20 degrees C was sufficient to prevent inactivation, We provide evidence that the activated HA is a conformational intermediate distinct from the native structure and from the final structure associated with the conformational change of HA, which is implicated by the high-resolution structure of the soluble trimeric fragment TBHA2 (P, A. Bullough, F, M. Hughson, J, J, Skehel, and D. C. Wiley, Nature 371.:37-43, 1994). C1 Humboldt Univ, Inst Biol Biophys, Math Nat Wissensch Fak 1, D-10115 Berlin, Germany. NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, NIH, Frederick, MD 21702 USA. NIAMSD, NIH, Bethesda, MD 20892 USA. RP Blumenthal, R (reprint author), Humboldt Univ, Inst Biol Biophys, Math Nat Wissensch Fak 1, Invalidenstr 43, D-10115 Berlin, Germany. NR 39 TC 63 Z9 64 U1 1 U2 6 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 JUN PY 1999 VL 73 IS 6 BP 4567 EP 4574 PG 8 WC Virology SC Virology GA 195UW UT WOS:000080271400006 PM 10233915 ER PT J AU Williams, O Wolffe, EJ Weisberg, AS Merchlinsky, M AF Williams, O Wolffe, EJ Weisberg, AS Merchlinsky, M TI Vaccinia virus WR gene A5L is required for morphogenesis of mature virions SO JOURNAL OF VIROLOGY LA English DT Article ID MOLECULAR-WEIGHT PRECURSOR; COLI LAC REPRESSOR; EARLY TRANSCRIPTION; ESCHERICHIA-COLI; STRUCTURAL POLYPEPTIDE; PROTEOLYTIC MATURATION; EXTRACELLULAR VIRUS; ENVELOPE FORMATION; CORE PROTEINS; DNA-SEQUENCE AB The vaccinia virus WR A5L open reading frame (corresponding to open reading frame A4L in vaccinia virus Copenhagen) encodes an immunodominant late protein found in the core of the vaccinia virion. To investigate the role of this protein in vaccinia virus replication,,ve have constructed a recombinant virus, vA5Li, in which the endogenous gene has been deleted and an inducible copy of the A5 gene dependent on isopropyl-beta-D-thiogalactopyranoside (IPTG) for expression has been inserted into the genome. In the absence of inducer, the yield of infectious virus was dramatically reduced. However, DNA synthesis and processing, viral protein expression (except for A5), and early stages in virion formation were indistinguishable from the analogous steps in a normal infection. Electron microscopy revealed that the major vaccinia virus structural form present in cells infected with vA5Li in the absence of inducer was immature virions. Viral particles were purified from vA5Li-infected cells in the presence and absence of inducer. Both particles contained viral DNA and the full complement of viral proteins, except for A5, which was missing from particles prepared in the absence of inducer. The particles prepared in the presence of IPTG were more infectious than those prepared in its absence. The A5 protein appears to be required for the immature virion to form the brick-shaped intracellular mature virion. C1 US FDA, Ctr Biol Evaluat & Res, Viral Dis Lab, Rockville, MD 20852 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Merchlinsky, M (reprint author), US FDA, Ctr Biol Evaluat & Res, Viral Dis Lab, HFM-457,1401 Rockville Pike, Rockville, MD 20852 USA. NR 57 TC 24 Z9 24 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 1999 VL 73 IS 6 BP 4590 EP 4599 PG 10 WC Virology SC Virology GA 195UW UT WOS:000080271400009 PM 10233918 ER PT J AU Kiernan, RE Ono, A Freed, EO AF Kiernan, RE Ono, A Freed, EO TI Reversion of a human immunodeficiency virus type 1 matrix mutation affecting Gag membrane binding, endogenous reverse transcriptase activity, and virus infectivity SO JOURNAL OF VIROLOGY LA English DT Article ID LIFE-CYCLE; ENVELOPE GLYCOPROTEIN; VIF PROTEIN; PARTICLE-PRODUCTION; PLASMA-MEMBRANE; CORE STRUCTURES; MATURE VIRIONS; EARLY STEPS; ASSOCIATION; REPLICATION AB We previously characterized mutations in the human immunodeficiency virus type 1 matrix (MA) protein that displayed reduced infectivity in single-round assays, defects in the stable synthesis of viral DNA In infected cells, and impaired endogenous reverse transcriptase activity. The mutants, which contained substitutions in a highly conserved Leu at MA amino acid 20, also increased binding of Gag to membrane. To elucidate further the role of MA in the virus replication cycle, we have characterized a viral revertant of an amino acid 20 mutant (20LK), The revertant virus, which replicates with essentially wild-type kinetics in H9 cells, contains second-site compensatory changes at MA amino acids 73 (E-->K) and 82 (A-->T), while retaining the original 20LK mutation. Single-cycle infectivity assays, performed with luciferase-expressing viruses, show that the 20LK/73EK/82AT triple mutant displays markedly improved infectivity relative to the original 20LK mutant. The stable synthesis of viral DNA in infected cells is also significantly increased compared with that of 20LK DNA, Furthermore, activity of revertant virions in endogenous reverse transcriptase assays is restored to near-wild-type-levels. Interestingly, although 20LK/73EK/82AT reverses the defects in replication kinetics, postentry events, and endogenous reverse transcriptase activity induced by the 20LK mutation, the reversion does not affect the 20LK-imposed increase in Gag membrane binding. Mutants containing single and double amino acid substitutions were constructed, and their growth kinetics were examined. Only virus containing all three changes (20LK/73EK/82AT) grew with significantly accelerated kinetics; 73EK, 73EK/82AT, and 20LK/82AT mutants displayed pronounced defects in virus particle production. Viral core-like complexes were isolated by sucrose density gradient centrifugation of detergent-treated virions. Intriguingly, the protein composition of wild-type and mutant detergent-resistant complexes differed markedly. In wild-type and 20LK; complexes, MA was removed following detergent solubilization of the viral membrane. In contrast, in revertant preparations, the majority of MA cosedimented with the detergent-resistant complex. These results suggest that the 20LK/73EK/82AT mutations induced a significant alteration in MA-MA or Il ZA-core interactions. C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Freed, EO (reprint author), NIAID, Mol Microbiol Lab, NIH, Bldg 4,Rm 307, Bethesda, MD 20892 USA. NR 53 TC 21 Z9 21 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 JUN PY 1999 VL 73 IS 6 BP 4728 EP 4737 PG 10 WC Virology SC Virology GA 195UW UT WOS:000080271400024 PM 10233933 ER PT J AU Wu, TY Guo, JH Bess, J Henderson, LE Levin, JG AF Wu, TY Guo, JH Bess, J Henderson, LE Levin, JG TI Molecular requirements for human immunodeficiency virus type 1 plus-strand transfer: Analysis in reconstituted and endogenous reverse transcription systems SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; HIV-1 NUCLEOCAPSID PROTEIN; RNASE-H ACTIVITY; HAMMERHEAD RIBOZYME CATALYSIS; DNA-SYNTHESIS; IN-VITRO; DISPLACEMENT SYNTHESIS; POLYPURINE TRACT; VIRAL-DNA; ESCHERICHIA-COLI AB We have developed a reconstituted system which models the events associated with human immunodeficiency virus type 1 (HIV-1) plus-strand transfer. These events include synthesis of plus-strand strong-stop DNA [(+) SSDNA] from a minus strand DNA donor template covalently attached to human tRNA(3)(Lys), tRNA primer removal, and annealing of (+) SSDNA to the minus-strand DNA acceptor template. Termination of (+) SSDNA synthesis at the methyl A (nucleotide 58) near the 3' end of tRNA(3)(Lys) reconstitutes the 18-nucleotide primer binding site (PBS). Analysis of (+) SSDNA synthesis in vitro and in HIV-1 endogenous reactions indicated another major termination site: the pseudouridine at nucleotide 55. In certain HIV-1 strains, complementarity between nucleotides 56 to 58 and the first three bases downstream of the PBS could allow all of the (+) SSDNA products to be productively transferred. Undermodification of the tRNA may be responsible for termination beyond the methyl A. In studies of tRNA removal, we find that initial cleavage of the 3' rA by RNase H is not sufficient to achieve successful strand transfer. The RNA-DNA hybrid formed by the penultimate 17 bases of tRNA still annealed to (+) SSDNA must also be destabilized. This can occur by removal of additional 3'-terminal bases by RNase H (added either in cis or trans). Alternatively, the nucleic acid chaperone activity of nucleocapsid protein (NC) can catalyze this destabilization. NC stimulates annealing of the complementary PBS sequences in (+) SSDNA and the acceptor DNA template. Reverse transcriptase also pro motes annealing but to a lesser extent than NC. C1 NICHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC, AIDS Vaccine Program, Frederick, MD 21702 USA. RP Levin, JG (reprint author), NICHD, Mol Genet Lab, NIH, Bldg 6B,Room 216, Bethesda, MD 20892 USA. RI Bess, Jr., Julian/B-5343-2012 FU NCI NIH HHS [N01-CO-56000] NR 79 TC 65 Z9 66 U1 1 U2 4 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 JUN PY 1999 VL 73 IS 6 BP 4794 EP 4805 PG 12 WC Virology SC Virology GA 195UW UT WOS:000080271400031 PM 10233940 ER PT J AU Johnson, RP Lifson, JD Czajak, SC Cole, KS Manson, KH Glickman, R Yang, J Montefiori, DC Montelaro, R Wyand, MS Desrosiers, RC AF Johnson, RP Lifson, JD Czajak, SC Cole, KS Manson, KH Glickman, R Yang, J Montefiori, DC Montelaro, R Wyand, MS Desrosiers, RC TI Highly attenuated vaccine strains of simian immunodeficiency virus protect against vaginal challenge: Inverse relationship of degree of protection with level of attenuation SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNE-RESPONSES; RHESUS MACAQUES; SIV INFECTION; NEF GENE; T-CELLS; LIVE; ENVELOPE; REPLICATION; INDUCTION; DELETION AB Three different deletion mutants of simian immunodeficiency virus (SIV) that vary in their levels of attenuation were tested for the ability to protect against mucosal challenge with pathogenic SIV. Four female rhesus monkeys were vaccinated by intravenous inoculation with SIVmac239 Delta 3, four with SIVmac239 Delta 3X, and four with SIVmac239 Delta 4. These three vaccine strains exhibit increasing levels of attenuation: Delta 3 < Delta 3X < Delta 4. The vaccinated monkeys were challenged by vaginal exposure to uncloned, pathogenic SIVmac251 at 61 weeks after the time of vaccination. On the basis of viral RNA loads in plasma, cell-associated virus loads in peripheral blood, and CD4 cell counts, strong protective effects were observed in all three groups of vaccinated monkeys. However, the degree of protection correlated inversely with the level of attenuation; the least-attenuated strain, SIVmac239 Delta 3, gave the greatest protection. One monkey in the Delta 3X group and two in the Delta 4 group clearly became superinfected by the challenge virus, but these animals had levels of SIV RNA in plasma that were considerably lower than those of naive animals that were challenged in parallel. Protection against vaginal challenge appears easier to achieve than protection against intravenous challenge, since four other SIVmac239 Delta 4-vaccinated monkeys showed no protection, when challenged intravenously with a much lower inoculum of the same challenge virus stock Protection against vaginal challenge in the Delta 4-vaccinated group occurred in the absence of detectable serum neutralizing activities and appeared to be associated with the development of an early SIV-specific cytotoxic-T-lymphocyte response. Our results demonstrate that mucosal protection can be achieved by systemic immunization with the highly attenuated SIVmac239 Delta 4 more than 1 year prior to the time of challenge. C1 Harvard Univ, New England Reg Primate Res Ctr, Sch Med, Southborough, MA 01772 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. Univ Pittsburgh, Sch Med, Dept Mol Genet & Biochem, Pittsburgh, PA 15261 USA. Primedica, Worcester, MA 01608 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. RP Desrosiers, RC (reprint author), Harvard Univ, New England Reg Primate Res Ctr, Sch Med, 1 Pine Hill Dr,POB 9102, Southborough, MA 01772 USA. FU NCRR NIH HHS [K26 RR000168, P51 RR000168]; NIAID NIH HHS [AI35365, AI43044, AI43075, P01 AI028243, P01 AI035365, T32 AI007487, U01 AI035365] NR 34 TC 186 Z9 189 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 JUN PY 1999 VL 73 IS 6 BP 4952 EP 4961 PG 10 WC Virology SC Virology GA 195UW UT WOS:000080271400048 PM 10233957 ER PT J AU Juhasz, K Murphy, BR Collins, PL AF Juhasz, K Murphy, BR Collins, PL TI The major attenuating mutations of the respiratory syncytial virus vaccine candidate cpts530/1009 specify temperature-sensitive defects in transcription and replication and a non-temperature-sensitive alteration in mRNA termination SO JOURNAL OF VIROLOGY LA English DT Article ID SERONEGATIVE CHIMPANZEES; MESSENGER-RNA; M2 GENE; RSV; IMMUNIZATION; SUBSTITUTION; EXPRESSION; MUTANTS; PROTEIN AB The live-attenuated respiratory syncytial virus vaccine candidate cpts530/1009 was previously shown to contain two separate amino acid changes in the L protein, mutations 530 and 1009 (Phe-521-->Leu and Met-1169-->Val, respectively, according to the amino acid sequence of the L protein). Each mutation independently specifies temperature-sensitive (ts) and attenuation phenotypes. In this study, we examined the effects of these mutations on transcription and RNA replication, using complete infectious recombinant virus as well as a plasmid-based minireplicon system, the latter under conditions in which effects on replication and transcription are uncoupled. In comparison with recombinant wild-type virus, the 530 and 1009 viruses were partially restricted at 37 degrees C for RNA replication, mRNA synthesis, and virus growth. The 1009 virus was partially restricted for RNA synthesis and virus growth even at 32 degrees C, which suggested that the 1009 mutation has a non-ts component in addition to the fs component. Interestingly, the synthesis of polycistronic readthrough mRNAs was elevated 1.6- to 3.8-fold for the 1009 virus, and this defect was non-ts, Studies with the minigenome system showed that the 530 and 1009 mutations each directly affect both replication and transcription, that the effect on replication was marginally greater than on transcription for the 530 mutation, and that the increase in readthrough mRNA associated with the 1009 mutation also was observed with the minigenome system. 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. NR 22 TC 17 Z9 17 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 JUN PY 1999 VL 73 IS 6 BP 5176 EP 5180 PG 5 WC Virology SC Virology GA 195UW UT WOS:000080271400075 PM 10233984 ER PT J AU Mann, EA McClean, MD Gurevich-Uvena, J Barkmeier, J McKenzie-Garner, P Paffrath, J Patow, C AF Mann, EA McClean, MD Gurevich-Uvena, J Barkmeier, J McKenzie-Garner, P Paffrath, J Patow, C TI The effects of excessive vocalization on acoustic and videostroboscopic measures of vocal fold condition SO JOURNAL OF VOICE LA English DT Article DE vocal abuse; videostroboscopy; perturbation; vocal fold AB Although dysphonia is a recognized consequence of acute vocal abuse, associated changes in vocal fold appearance and function are not well understood. To document these presumed effects of vocal abuse, audio recordings of sustained vowel production were obtained from 42 drill sergeants daily during the first 6 days of a vocally demanding training exercise. Acoustic analysis showed abnormal levels of jitter and shimmer on Day 1 in 16 of the 42 subjects. Considering only the 26 subjects who showed normal voice acoustics on Day 1, the median levels of jitter and shimmer varied little over the course of training, and significant increases in jitter and shimmer were not seen during the study period. However, the distributions for both jitter and shimmer became more positively skewed and showed a greater number of positive outliers over the course of training. This trend was attributed to 11 subjects who showed two or more instances of abnormal voice acoustics over Days 2 through 6. Laryngeal videostroboscopic recordings of sustained vowel production also were obtained prior to and following training. Perceptual ratings of these recordings by 2 observers revealed significant increases in vocal fold edema, erythema, and edge irregularity, and decreases in vocal fold mucosal wave and amplitude of excursion following the 5-day training period. In,general, there was considerable intersubject variability in the extent of acoustic and videostroboscopic effects over the course of training. Of the two types of data, videostroboscopy appears to provide a more sensitive indication of the effects of excessive vocalization. C1 Walter Reed Army Med Ctr, Div Otolaryngol Head & Neck Surg, Dept Surg, Washington, DC 20307 USA. Natl Inst Deafness & Other Commun Disorders, Bethesda, MD USA. Johns Hopkins Bayview Med Ctr, Baltimore, MD USA. RP Mann, EA (reprint author), Walter Reed Army Med Ctr, Div Otolaryngol Head & Neck Surg, Dept Surg, Washington, DC 20307 USA. NR 10 TC 20 Z9 20 U1 0 U2 1 PU SINGULAR PUBLISHING GROUP INC PI SAN DIEGO PA 401 WEST A ST, STE 325, SAN DIEGO, CA 92101-7904 USA SN 0892-1997 J9 J VOICE JI J. Voice PD JUN PY 1999 VL 13 IS 2 BP 294 EP 302 DI 10.1016/S0892-1997(99)80035-6 PG 9 WC Otorhinolaryngology SC Otorhinolaryngology GA 216YR UT WOS:000081472500017 PM 10442762 ER PT J AU Endicott, J Amsterdam, J Eriksson, E Frank, E Freeman, E Hirschfeld, R Ling, F Parry, B Pearlstein, T Rosenbaum, J Rubinow, D Schmidt, P Severino, S Steiner, M Stewart, DE Thys-Jacobs, S AF Endicott, J Amsterdam, J Eriksson, E Frank, E Freeman, E Hirschfeld, R Ling, F Parry, B Pearlstein, T Rosenbaum, J Rubinow, D Schmidt, P Severino, S Steiner, M Stewart, DE Thys-Jacobs, S TI Is premenstrual dysphoric disorder a distinct clinical entity? SO JOURNAL OF WOMENS HEALTH & GENDER-BASED MEDICINE LA English DT Article ID PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND TRIAL; SERTRALINE TREATMENT; FLUOXETINE TREATMENT; MAJOR DEPRESSION; HORMONE AGONIST; MENSTRUAL-CYCLE; SYMPTOMS; WOMEN; CLOMIPRAMINE AB Does the evidence now available support the concept of premenstrual dysphoric disorder (PMDD) as a distinct clinical disorder such that the relative safety and efficacy of potential treatment can be evaluated? In a roundtable discussion of this question, a wealth of information was reviewed by a panel of experts. The key characteristics of PMDD, with clear onset and offset of symptoms closely linked to the menstrual cycle and the prominence of symptoms of anger, irritability, and internal tension, were contrasted with those of known mood and anxiety disorders. PMDD displays a distinct clinical picture that, in the absence of treatment, is remarkably stable from cycle to cycle and over time. Effective treatment of PMDD can be accomplished with serotinergic agents. At least 60% of patients respond to selective serotonin reuptake inhibitors (SSRIs). In comparison with other disorders, PMDD symptoms respond to low doses of SSRIs and to intermittent dosing. Normal functioning of the hypothalamic-pituitary-adrenal (HPA) axis, biologic characteristics generally related to the serotonin system, and a genetic component unrelated to major depression are further features of PMDD that separate it from other affective (mood) disorders. Based on this evidence, the consensus of the group was that PMDD is a distinct clinical entity. Potential treatments for this disorder can now be evaluated on this basis to meet the clear need for effective therapy. C1 Columbia Univ, Coll Phys & Surg, New York, NY 10032 USA. Univ Penn, Philadelphia, PA 19104 USA. Univ Gothenburg, Gothenburg, Sweden. Western Psychiat Inst & Clin, Pittsburgh, PA USA. Univ Texas, Galveston, TX 77550 USA. Univ Tennessee, Memphis, TN USA. Univ Calif San Diego, San Diego, CA 92103 USA. Butler Hosp, Providence, RI 02906 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NIMH, Bethesda, MD 20892 USA. Univ New Mexico, Albuquerque, NM 87131 USA. McMaster Univ, St Josephs Hosp, Hamilton, ON L8S 4L8, Canada. Univ Toronto, Toronto Hosp, Toronto, ON, Canada. St Lukes Roosevelt Ctr, New York, NY USA. RP Endicott, J (reprint author), Columbia Univ, Coll Phys & Surg, 722 W 168th St, New York, NY 10032 USA. RI Stewart, Donna Eileen/J-2844-2016 OI Stewart, Donna Eileen/0000-0002-8157-7746 NR 81 TC 107 Z9 108 U1 1 U2 10 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1524-6094 J9 J WOMEN HEALTH GEN-B JI J. WOMENS HEALTH GENDER-BASED MED. PD JUN PY 1999 VL 8 IS 5 BP 663 EP 679 DI 10.1089/jwh.1.1999.8.663 PG 17 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 230ZQ UT WOS:000082281900020 PM 10839653 ER PT J AU Gracely, RH AF Gracely, RH TI Placebos: Ruse, potentiator or powerful therapeutic tool? SO JOURNAL OF WOMENS HEALTH & GENDER-BASED MEDICINE LA English DT Meeting Abstract C1 NIDCR, Clin Measurement & Mechanisms Unit, PNMB, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1524-6094 J9 J WOMEN HEALTH GEN-B JI J. WOMENS HEALTH GENDER-BASED MED. PD JUN PY 1999 VL 8 IS 5 BP 700 EP 700 PG 1 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 230ZQ UT WOS:000082281900046 ER PT J AU Maddox, YT AF Maddox, YT TI Fostering international women's health research SO JOURNAL OF WOMENS HEALTH & GENDER-BASED MEDICINE LA English DT Meeting Abstract C1 NICHHD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1524-6094 J9 J WOMEN HEALTH GEN-B JI J. WOMENS HEALTH GENDER-BASED MED. PD JUN PY 1999 VL 8 IS 5 BP 700 EP 700 PG 1 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 230ZQ UT WOS:000082281900045 ER PT J AU Dorn, LD Nottelmann, ED Susman, EJ Inoff-Germain, G Cutler, GB Chrousos, GP AF Dorn, LD Nottelmann, ED Susman, EJ Inoff-Germain, G Cutler, GB Chrousos, GP TI Variability in hormone concentrations and self-reported menstrual histories in young adolescents: Menarche as an integral part of a developmental process SO JOURNAL OF YOUTH AND ADOLESCENCE LA English DT Article ID CHRONOLOGIC AGE; MOOD DISORDERS; PUBERTAL STAGE; GIRLS; CYCLE; ACCURACY; RECALL; GONADOTROPINS; PATTERNS; BEHAVIOR AB Menarche has been considered a marker for examining interindividual differences in biobehavioral development and for separating pubertal development into 2 stages. The purpose of this study was (1) to compare hormone concentrations in pre- and postmenarcheal girls to determine whether they fit a continuous or dichotomous model of pubertal development surrounding menarche; and (2) to address methodological issues of variability in self-reports of menstrual histories and reliability in reporting age at menarche. Girls (N = 52) ages 9 to 14 years were enrolled in a longitudinal study. Blood was drawn for hormone concentrations. Menstrual-cycle information was collected by questionnaire and oral report. Discrepancies in reporting of age at menarche ranged from 0 to 18 months and variability was noted in length of cycle. There was great overlap in hormones between pre- and postmenarcheal categories. Future studies might consider menarche as the culmination of underlying developmental processes rather than as a discrete event Limitations of each measure of puberty should be considered by investigators conducting biobehavioral studies of adolescents. C1 Univ Pittsburgh, Sch Nursing, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Dept Psychiat, Sch Med, Pittsburgh, PA 15261 USA. NIMH, Depress & Anxiety Program, Dev Psychopathol Branch, Bethesda, MD 20892 USA. Natl Inst Hlth, Pediat Endocrinol Training Program, Bethesda, MD USA. Eli Lilly & Co, Growth & Recovery Res & Clin Invest, Indianapolis, IN 46285 USA. Penn State Univ, University Pk, PA 16802 USA. RP Dorn, LD (reprint author), Univ Pittsburgh, Sch Nursing, 3500 Victoria St,440 Victoria Bldg, Pittsburgh, PA 15261 USA. NR 51 TC 13 Z9 13 U1 1 U2 3 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0047-2891 J9 J YOUTH ADOLESCENCE JI J. Youth Adolesc. PD JUN PY 1999 VL 28 IS 3 BP 283 EP 304 DI 10.1023/A:1021680726753 PG 22 WC Psychology, Developmental SC Psychology GA 218AE UT WOS:000081530500001 ER PT J AU Sharp, RR Barrett, JC AF Sharp, RR Barrett, JC TI The environmental genome project and bioethics SO KENNEDY INSTITUTE OF ETHICS JOURNAL LA English DT Article ID INFORMED CONSENT; GENETIC RESEARCH; TISSUE SAMPLES; CANCER; INSTITUTE; DISEASE; ISSUES; LEGAL C1 NIEHS, Div Intramural Res, NIH, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Sharp, RR (reprint author), NIEHS, Div Intramural Res, NIH, Mol Carcinogenesis Lab, POB 12233, Res Triangle Pk, NC 27709 USA. NR 57 TC 6 Z9 6 U1 1 U2 3 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4319 USA SN 1054-6863 J9 KENNEDY INST ETHIC J JI Kennedy Inst. Ethics J. PD JUN PY 1999 VL 9 IS 2 BP 175 EP 188 DI 10.1353/ken.1999.0014 PG 14 WC Ethics; Philosophy; Social Issues SC Social Sciences - Other Topics; Philosophy; Social Issues GA 241QX UT WOS:000082895000006 PM 11657327 ER PT J AU Hugo, CPM Pichler, RP Schulze-Lohoff, E Prols, F Adler, S Krutsch, HC Murphy-Ullrich, JE Couser, WG Roberts, DD Johnson, RJ AF Hugo, CPM Pichler, RP Schulze-Lohoff, E Prols, F Adler, S Krutsch, HC Murphy-Ullrich, JE Couser, WG Roberts, DD Johnson, RJ TI Thrombospondin peptides are potent inhibitors of mesangial and glomerular endothelial cell proliferation in vitro and in vivo SO KIDNEY INTERNATIONAL LA English DT Article DE thrombospondin; inflammation; mesangial cells; glomerular endothelial cells; cell proliferation; proteinuria; microaneurysm ID GROWTH-FACTOR-BETA; EXPERIMENTAL MESANGIOPROLIFERATIVE GLOMERULONEPHRITIS; SMOOTH MUSCLE ACTIN; MONOCLONAL-ANTIBODY; HEPARIN-BINDING; I REPEATS; RAT; ADHESION; PROGRESSION; ACTIVATION AB Background. Thrombospondin 1 (TSP1), a multifunctional, matricellular glycoprotein, is expressed de novo in many inflammatory disease processes, including glomerular disease. Short peptide fragments derived from the type I properdin repeats of the TSP1 molecule mimic anti-angiogenic and/or transforming growth factor-p (TGF-P)-activating properties of the whole TSP1. glycoprotein. We investigated the effects of D-reverse peptides derived from the type I domain of TSP1 in experimental mesangial proliferative glomerulonephritis in the rat (anti-Thy1 model), as well as their effects on cultured mesangial and glomerular endothelial cells. Methods. Effects of TSP peptides on proliferation of mesangial or glomerular endothelial cells in culture after growth arrest or growth factor stimulation (fibroblast growth factor-2, platelet-derived growth factor-BE, 10% fetal calf serum) were measured by [(3)H]thymidine incorporation assay. Adhesion of rat mesangial cells (MCs) to a TSP-peptide matrix was assayed using an attachment-hexosaminidase assay. TSP peptides were intraperitoneally injected daily in rats that had received an intravenous injection of polyclonal anti-Thy1 antibody to induce mesangial proliferative glomerulonephritis. On biopsies from days 2, 5, and 8 of anti-Thy1 disease, mesangial and glomerular endothelial proliferation, matrix expansion, mesangial activation, and microaneurysm formation were assessed. Functional parameters such as blood pressure and proteinuria were also measured. Results. An 18-amino acid peptide (type I peptide) with antiangiogenic and TGF-P-activating sequences decreased mesangial and glomerular endothelial cell proliferation in vitro and in vivo and reduced microaneurysm formation and proteinuria in experimental glomerulonephritis. Analogues lacking the TGF-P-activating sequence mimicked most effects of the type I peptide. The mechanism of action of these peptides may include antagonism of fibroblast growth factor-2 and alteration of MC adhesion. The TGF-P-activating sequence alone did not have significant effects on mesangial or glomerular endothelial cells in vitro or in experimental kidney disease in vivo. Conclusion. Peptides from TSP1 may be promising therapeutics in treating glomerular disease with mesangial and endothelial cell injury. C1 Univ Erlangen Nurnberg, Div Nephrol, D-91054 Erlangen, Germany. Univ Vienna, Div Nephrol, Vienna, Austria. New York Med Coll, Dept Med, Div Nephrol, Valhalla, NY 10595 USA. NCI, Pathol Lab, Biochem Pathol Sect, NIH, Bethesda, MD 20892 USA. Univ Alabama, Dept Pathol, Div Mol & Cellular Pathol, Birmingham, AL 35294 USA. Univ Washington, Dept Med, Div Nephrol, Seattle, WA 98195 USA. RP Hugo, CPM (reprint author), Univ Erlangen Nurnberg, Div Nephrol, Loschgestr 8, D-91054 Erlangen, Germany. EM mfm444@remail.uni-erlangen.de RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU NHLBI NIH HHS [HL-18645]; NIDDK NIH HHS [DK-02142, DK-43422] NR 36 TC 21 Z9 21 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JUN PY 1999 VL 55 IS 6 BP 2236 EP 2249 DI 10.1046/j.1523-1755.1999.00459.x PG 14 WC Urology & Nephrology SC Urology & Nephrology GA 199TX UT WOS:000080500400009 PM 10354272 ER PT J AU Hawkins, J AF Hawkins, J TI On the right track SO LAB ANIMAL LA English DT Editorial Material C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Hawkins, J (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD JUN PY 1999 VL 28 IS 6 BP 19 EP 19 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA 206DZ UT WOS:000080863200005 ER PT J AU Davis, JA Paylor, R McDonald, MP Libbey, M Ligler, A Bryant, K Crawley, JN AF Davis, JA Paylor, R McDonald, MP Libbey, M Ligler, A Bryant, K Crawley, JN TI Behavioral effects of ivermectin in mice SO LABORATORY ANIMAL SCIENCE LA English DT Article ID BLOOD-BRAIN-BARRIER; PINWORMS SYPHACIA-OBVELATA; ORAL ANTHELMINTIC THERAPY; P-GLYCOPROTEIN; STARTLE-RESPONSE; EFFECTIVE ERADICATION; LABORATORY MICE; BREEDING COLONY; RATS; RABBITS AB Background and Purpose: Ivermectin is a common anthelmintic drug, widely used in laboratory rodents for treatment of pinworm and mite infestations. We evaluated the action of ivermectin on sensitive behavioral tasks in mice during treatment for mites within a barrier facility. Methods: A total of 21 (5 males, 16 females) mice (129/SvEv) were used for measuring body weight, open field locomotor activity, and rotarod motor coordination. For acoustic startle and prepulse inhibition, 20 C57BL/6J and 29 AKR/J mice were studied. For the Morris water task, the same 20 C57BL/6J mice were studied. Ivermectin (0.08% sheep drench) was administered in the drinking water of the home cage for 8 weeks. Control groups received normal tap water in identical bottles. Results: Ivermectin did not affect general health, body weight, motor coordination, swimming behavior, or spatial learning in several inbred strains of mice. However, it induced a small but significant effect on some sensitive behaviors. Conclusions: A cautious approach to initiating ivermectin treatment in mice should be used for sensitive behavioral experiments. C1 NINDS, Anim Hlth Care Sect, NIH, Bethesda, MD 20892 USA. NIMH, Sect Behav Neuropharmacol, Expt Therapeut Branch, NIH, Bethesda, MD USA. RP Davis, JA (reprint author), NINDS, Anim Hlth Care Sect, NIH, Bldg 35,Room B125, Bethesda, MD 20892 USA. NR 51 TC 29 Z9 29 U1 2 U2 6 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 0023-6764 J9 LAB ANIM SCI JI Lab. Anim. Sci. PD JUN PY 1999 VL 49 IS 3 BP 288 EP 296 PG 9 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 207QJ UT WOS:000080947300011 PM 10403444 ER PT J AU Kim, CN Bhalla, K Kreitman, RJ Willingham, MC Hall, P Tagge, EP Jia, T Frankel, AE AF Kim, CN Bhalla, K Kreitman, RJ Willingham, MC Hall, P Tagge, EP Jia, T Frankel, AE TI Diphtheria toxin fused to granulocyte-macrophage colony-stimulating factor and Ara-C exert synergistic toxicity against human AML HL-60 cells SO LEUKEMIA RESEARCH LA English DT Article DE diphtheria toxin; GMCSF receptor; myeloid leukemia cells; Ara-C ID ACUTE MYELOID-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; CYTOCHROME-C; PROTEASE ACTIVITY; DRUG-RESISTANCE; FUSION-PROTEIN; APOPTOSIS; BCL-2; OVEREXPRESSION; MODULATION AB Human granulocyte-macrophage colony-stimulating factor fused to truncated diphtheria toxin (DT388-GM-CSF) sensitized wild-type and Bcl2-overexpressing HL60 human leukemia cells to intoxication by Ara-C based on proliferation and clonogenic assays. The toxin/drug combination showed dramatic synergistic toxicity with combination indices of < 0.1. Synergy was not seen with two other protein synthesis inhibiting drugs-ricin and cycloheximide nor with GMCSF alone. No changes in Ara-C incorporation into cellular DNA or cell cycle occupancy were seen. As compared to exposure to DT388-GM-CSF or Ara-C alone, co-treatment produced significant increases in cytosolic accumulation of cytochrome c, a higher percentage of cells with loss of mitochondrial membrane potential and an increase in reactive oxygen species and morphologic changes of apoptosis, and a greater induction of poly(ADP-ribose) polymerase (PARP) and DNA fragmentation factor 45 (DFF45) cleavage activities of caspase 3. Co-treatment did not significantly alter BcI2, Bcl-x(L), Bax or Fas receptor (FasR), but modestly increased Fas ligand (FasL) protein. These finding suggest that co-treatment with DT388-GM-CSF may lead to a lowered apoptotic threshold and clonogenic survival of human AML blasts due to Ara-C. These observations also suggest that clinical trials of combination therapy may be warranted in patients with AML. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 Wake Forest Univ, Sch Med, Dept Canc Biol, Winston Salem, NC 27157 USA. Wake Forest Univ, Sch Med, Dept Pathol, Winston Salem, NC 27157 USA. Emory Univ, Sch Med, Div Hematol Oncol, Atlanta, GA USA. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Med Univ S Carolina, Dept Pharmaceut Sci, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Surg, Charleston, SC 29425 USA. RP Frankel, AE (reprint author), Wake Forest Univ, Sch Med, Dept Canc Biol, Med Ctr Dr, Winston Salem, NC 27157 USA. FU NCI NIH HHS [CA56613, CA63382, CA76178] NR 50 TC 23 Z9 25 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD JUN PY 1999 VL 23 IS 6 BP 527 EP 538 DI 10.1016/S0145-2126(99)00039-9 PG 12 WC Oncology; Hematology SC Oncology; Hematology GA 199VC UT WOS:000080503900002 PM 10374846 ER PT J AU Guru, SC Crabtree, JS Brown, KD Dunn, KJ Manickam, P Prasad, NB Wangsa, D Burns, AL Spiegel, AM Marx, SJ Pavan, WJ Collins, FS Chandrasekharappa, SC AF Guru, SC Crabtree, JS Brown, KD Dunn, KJ Manickam, P Prasad, NB Wangsa, D Burns, AL Spiegel, AM Marx, SJ Pavan, WJ Collins, FS Chandrasekharappa, SC TI Isolation, genomic organization, and expression analysis of Men1, the murine homolog of the MEN1 gene SO MAMMALIAN GENOME LA English DT Article ID ENDOCRINE; REGION AB The mouse homolog of the human MEN1 gene, which is defective in a dominant familial cancer syndrome, multiple endocrine neoplasia type 1 (MEN1), has been identified and characterized. The mouse Men1 transcript contains an open reading frame encoding a protein of 611 amino acids which has 97% identity and 98% similarity to human menin. Sequence of the entire Menl gene (9.3 kb) was assembled, revealing 10 exons, with exon I being non-coding; a polymorphic tetranucleotide repeat was located in the 5'- flanking: region. The exon-intron organization and the size of the coding exons 2-9 were well conserved between the human and mouse genes. Fluorescence in situ hybridization localized the Men1 gene to mouse Chromosome (Chr) 19, a region known to be syntenic to human Chr 11q13, the locus for the MEN1 gene. Northern analysis indicated two messages-2.7 kb and 3.1 kb-expressed in all stages of the embryo analyzed and in all eight adult tissues tested. The larger transcript differs from the smaller by the inclusion of an unspliced intron I. Whole-mount in situ hybridization of 10.5-day and 11.5-day embryos showed ubiquitous expression of Men1 RNA. Western analysis with antibodies raised against a conserved C-terminal peptide identified an approximately 67-kDa protein in the lysates of adult mouse brain, kidney, liver, pancreas, and spleen tissues, consistent with the size of human menin. The levels of mouse menin do not appear to fluctuate during the cell cycle. C1 Natl Human Genome Res Inst, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Chandrasekharappa, SC (reprint author), Natl Human Genome Res Inst, Genet & Mol Biol Branch, NIH, Bldg 49,Room 3E-13,49 Convent Dr, Bethesda, MD 20892 USA. NR 13 TC 41 Z9 43 U1 0 U2 1 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0938-8990 J9 MAMM GENOME JI Mamm. Genome PD JUN PY 1999 VL 10 IS 6 BP 592 EP 596 DI 10.1007/s003359901051 PG 5 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 197UD UT WOS:000080383300013 PM 10341092 ER PT J AU Kobayashi, S Satomura, K Levsky, JM Sreenath, T Wistow, GJ Semba, I Shum, L Slavkin, HC Kulkarni, AB AF Kobayashi, S Satomura, K Levsky, JM Sreenath, T Wistow, GJ Semba, I Shum, L Slavkin, HC Kulkarni, AB TI Expression pattern of macrophage migration inhibitory factor during embryogenesis SO MECHANISMS OF DEVELOPMENT LA English DT Article DE macrophage migration inhibitory factor; cytokine; embryogenesis ID FACTOR MIF; IDENTIFICATION; LOCALIZATION; CELLS AB Although macrophage migration inhibitory factor (MIF) was originally identified as a lymphokine that inhibits the migration of macrophages, its ubiquitous expression suggests it may have a role beyond the immune system. Here we report a detailed characterization of MIF expression during mouse embryogenesis. The MIF expression pattern was found to parallel tissues specification and organogenesis. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 Funct Genom Unit, Bethesda, MD 20892 USA. Gene Targeting Facil, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, Rockville, MD 20852 USA. NEI, Sect Mol Struct & Funct, Bethesda, MD 20892 USA. NIAMSD, Craniofacial Dev Sect, NIH, Bethesda, MD 20892 USA. RP Kulkarni, AB (reprint author), Funct Genom Unit, Bethesda, MD 20892 USA. NR 10 TC 28 Z9 28 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD JUN PY 1999 VL 84 IS 1-2 BP 153 EP 156 DI 10.1016/S0925-4773(99)00057-X PG 4 WC Developmental Biology SC Developmental Biology GA 218PA UT WOS:000081559900016 PM 10473131 ER PT J AU Merrill, RM Brown, ML Potosky, AL Riley, G Taplin, SH Barlow, W Fireman, BH AF Merrill, RM Brown, ML Potosky, AL Riley, G Taplin, SH Barlow, W Fireman, BH TI Survival and treatment for colorectal cancer medicare patients in two group staff health maintenance organizations and the fee-for-service setting SO MEDICAL CARE RESEARCH AND REVIEW LA English DT Article ID FECAL-OCCULT-BLOOD; FLUOROURACIL PLUS LEVAMISOLE; BREAST-CANCER; MANAGED CARE; SCREENING SIGMOIDOSCOPY; ADJUVANT THERAPY; COLON-CANCER; MORTALITY; OUTCOMES; QUALITY AB The current study compares treatment use and long-term survival in colorectal cancer patients between Medicare beneficiaries enrolled in two large prepaid group/study health maintenance organizations (HMOs) and the fee-for-service (FFS) setting. The study is based on 15,352 colorectal cancer cases diagnosed between 1985 and 1992 and followed through 1995. Survival differences between the HMO and FFS cases were assessed using Cox regression. Treatment differences were evaluated using logistic regression. HMO cases had a lower overall mortality than did FFS cases but not a significantly lower colorectal cancer-specific mortality. Use of surgical resection was similar between HMO and FFS cases. However, rectal cancer cases in the HMOs were more likely to receive postsurgical radiation therapy than FFS cases. Superior overall survival in the HMOs may be the result of increased colorectal cancer screening, greater use of adjuvant therapies, and selection of healthier individuals. C1 Brigham Young Univ, Provo, UT 84602 USA. NCI, Bethesda, MD 20892 USA. US Hlth Care Financing Adm, Baltimore, MD 21207 USA. RP Merrill, RM (reprint author), Brigham Young Univ, Provo, UT 84602 USA. NR 63 TC 29 Z9 30 U1 2 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1077-5587 J9 MED CARE RES REV JI Med. Care Res. Rev. PD JUN PY 1999 VL 56 IS 2 BP 177 EP 196 PG 20 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 206GA UT WOS:000080867900004 PM 10373723 ER PT J AU Boni, R Vortmeyer, AO Huang, S Burg, G Hofbauer, G Zhuang, Z AF Boni, R Vortmeyer, AO Huang, S Burg, G Hofbauer, G Zhuang, Z TI Mutation analysis of the MEN1 tumour suppressor gene in malignant melanoma SO MELANOMA RESEARCH LA English DT Article DE genetic mutation; malignant melanoma; MEN1; tumour suppressor gene ID ENDOCRINE NEOPLASIA TYPE-1; ANGIOFIBROMAS AB During the initiation and progression of malignant melanoma a series of genetic events accumulate, including alterations of chromosome 11q. Recently, an important tumour suppressor gene, the multiple endocrine neoplasia type 1 (MEN1) gene, has been mapped on 11q13 and has been cloned. To assess whether the MEN1 region is involved in tumour initiation and progression, we analysed 23 primary cutaneous melanomas and 17 metastases for loss of heterozygosity (LOH) using two informative polymorphic markers closely linked to the MEN1 gene (PYGM and D11S449). To search for mutations within the gene, single-strand conformation polymorphism (SSCP) analysis was performed using 13 primer sets with designed intronic sequences to amplify the MEN1 coding sequence exons 2 to 10. None of the cases showed LOH at the MEN1 gene locus. By SSCP analysis, no aberrant bands were identified on exons 3 to 10, Analysis of exon 2 revealed the presence of aberrant bands in two of the analysed melanomas. Sequencing analysis revealed a genetic polymorphism at S145S (AGC-->ACT) in both sections. None of the cases analysed showed MEN1 gene mutations. This study represents the first genetic analysis of the MEN1 gene in sporadic melanomas, our data demonstrate no evidence of deletion or mutation of the MEN1 gene in primary or metastatic melanoma. Therefore, MEN1 gene alterations appear not to be associated with tumorigenesis of malignant melanoma, The MEN1 gene appears to be a highly specific tumour suppressor gene only involving tumours within the spectrum of MEN1 disease. (C) 1999 Lippincott Williams & Wilkins. C1 Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Boni, R (reprint author), Univ Zurich Hosp, Dept Dermatol, Gloriastr 31, CH-8091 Zurich, Switzerland. RI Hofbauer, Gunther/B-2671-2010 OI Hofbauer, Gunther/0000-0003-0542-7989 NR 13 TC 8 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0960-8931 J9 MELANOMA RES JI Melanoma Res. PD JUN PY 1999 VL 9 IS 3 BP 249 EP 252 PG 4 WC Oncology; Dermatology; Medicine, Research & Experimental SC Oncology; Dermatology; Research & Experimental Medicine GA 224WZ UT WOS:000081924100006 PM 10465580 ER PT J AU Wynn, TA AF Wynn, TA TI Immune deviation as a strategy for schistosomiasis vaccines designed to prevent infection and egg-induced immunopathology SO MICROBES AND INFECTION LA English DT Article ID NITRIC-OXIDE SYNTHASE; GRANULOMA-FORMATION; IFN-GAMMA; MURINE SCHISTOSOMIASIS; MANSONI CERCARIAE; TNF-ALPHA; T-CELLS; IRRADIATED CERCARIAE; PROTECTIVE IMMUNITY; MONOCLONAL-ANTIBODY C1 NIAID, Schistosomiasis Immunol & Pathol Unit, Immunobiol Sect, Lab Parasit Dis,NIH, Bethesda, MD 20892 USA. RP Wynn, TA (reprint author), NIAID, Schistosomiasis Immunol & Pathol Unit, Immunobiol Sect, Lab Parasit Dis,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RI Wynn, Thomas/C-2797-2011 NR 74 TC 12 Z9 18 U1 0 U2 0 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS CEDEX 15 PA 23 RUE LINOIS, 75724 PARIS CEDEX 15, FRANCE SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD JUN PY 1999 VL 1 IS 7 BP 525 EP 534 DI 10.1016/S1286-4579(99)80092-6 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 212YE UT WOS:000081244600008 PM 10603569 ER PT J AU Klein, DL AF Klein, DL TI Pneumococcal disease and the role of conjugate vaccines SO MICROBIAL DRUG RESISTANCE-MECHANISMS EPIDEMIOLOGY AND DISEASE LA English DT Article ID MEMBRANE PROTEIN COMPLEX; RESISTANT STREPTOCOCCUS-PNEUMONIAE; OTITIS-MEDIA; ANTIBODY-RESPONSE; UNITED-STATES; CHILDREN; CARRIAGE; IMMUNOGENICITY; INFECTIONS; PREVENTION C1 NIAID, Resp Dis Branch, DMID, NIH, Bethesda, MD 20892 USA. RP Klein, DL (reprint author), NIAID, Resp Dis Branch, DMID, NIH, 6700-B Rockledge Dr,Room 3130, Bethesda, MD 20892 USA. NR 61 TC 29 Z9 35 U1 1 U2 2 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1076-6294 J9 MICROB DRUG RESIST JI Microb. Drug Resist.-Mechan. Epidemiol. Dis. PD SUM PY 1999 VL 5 IS 2 BP 147 EP 157 DI 10.1089/mdr.1999.5.147 PG 11 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA 216DG UT WOS:000081425500008 PM 10432276 ER PT J AU Okayama, N Grisham, MB Kevil, CG Eppihimer, LA Wink, DA Alexander, JS AF Okayama, N Grisham, MB Kevil, CG Eppihimer, LA Wink, DA Alexander, JS TI Effect of reactive oxygen metabolites on endothelial permeability: Role of nitric oxide and iron SO MICROCIRCULATION LA English DT Article DE superoxide; hydrogen peroxide; xanthine; xanthine oxidase; nitric oxide synthase ID XANTHINE OXIDASE; CULTURED ENDOTHELIUM; LEUKOCYTE ADHESION; CELL INJURY; SUPEROXIDE; PEROXYNITRITE; OXIDATION; CONTRIBUTES; DYSFUNCTION; INHIBITION AB Objective: We evaluated the effects of the xanthine oxidase (XO)-derived reactive oxygen metabolites on the permeability of bovine pulmonary artery-endothelial monolayers and examined how iron and nitric oxide (NO) participate in these changes in permeability. Methods: Permeability was measured using a cell-column chromatographic method in which monolayers were exposed to combinations of agents. Results: Exposure of monolayers to a superoxide/peroxide generator, xanthine (X, 0.1 mM)/XO (25 mU/mL), increases solute permeability after 10 minutes, but the same dose of either X or XO alone did not. Exposure of monolayers to peroxide (0.1 mM) also increased permeability, but only after 70 minutes. This X/XO permeability was attenuated by either by either catalase, superoxide dismutase, methionine (1 mM), an oxy-radical scavenger, or desferrioxamine (0.1 mM), an iron chelator. Spermine NONOate (SNO), an NO donor, attenuated X/XO permeability at 0.1 mM, but this protection was not significant at 0.01 or 1 mM. Spermine NONOate (0.1 mM) did not alter the permeability produced by 0.1 mM peroxide. L-N-5-(1-iminoethyl)-ornithine (10 mu M), an NO synthase inhibitor, completely blocked peroxide-, and partially attenuated X/XO-mediated permeability. However, 3-morphosynodiomine (SIN-1, 1 mM) plus catalase (1,000 U/mL), a peroxynitrite generator, did not alter permeability. Conclusions: Xanthine/Xanthine Oxidase permeability involves peroxide, superoxide, oxy-radicals, and iron. Endogenous NO may regulate peroxide-, but not superoxide-mediated permeability. The protective effects of exogenous NO on the X/XO permeability may represent interactions between superoxide, peroxide, and cell surface-bound iron. C1 Louisiana State Univ, Med Ctr, Dept Mol & Cellular Physiol, Shreveport, LA 71130 USA. Natl Canc Inst, Dept Radiat Biol, Bethesda, MD USA. RP Alexander, JS (reprint author), Louisiana State Univ, Med Ctr, Dept Mol & Cellular Physiol, 1501 Kings Highway, Shreveport, LA 71130 USA. RI Kevil, Christopher/G-9318-2011 FU NHLBI NIH HHS [HL 47615]; NIDDK NIH HHS [DK 43785] NR 37 TC 13 Z9 14 U1 0 U2 3 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1073-9688 J9 MICROCIRCULATION JI Microcirculation PD JUN PY 1999 VL 6 IS 2 BP 107 EP 116 DI 10.1038/sj.mn.7300039 PG 10 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 209DA UT WOS:000081031400003 PM 10466113 ER PT J AU Strouboulis, J Damjanovski, S Vermaak, D Meric, F Wolffe, AP AF Strouboulis, J Damjanovski, S Vermaak, D Meric, F Wolffe, AP TI Transcriptional repression by XPc1, a new polycomb homolog in Xenopus laevis embryos, is independent of histone deacetylase SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID POSITION-EFFECT VARIEGATION; FISSION YEAST CENTROMERES; DROSOPHILA HOMEOTIC GENES; MATERNAL MESSENGER-RNA; PROMOTER IN-VIVO; GROUP PROTEINS; CHROMATIN STRUCTURE; HSP70 PROMOTER; CAENORHABDITIS-ELEGANS; REGULATORY ELEMENTS AB The Polycomb group (Pc-G) genes encode proteins that assemble into complexes implicated in the epigenttic maintenance of heritable patterns of expression of developmental genes, a function largely conserved from Drosophila to mammals and plants. The Pc-G is thought to act at the chromatin level to silence expression of target genes; however, little is known about the molecular basis of this repression. In keeping with the evidence that Pc-G homologs in higher vertebrates exist in related pairs, we report here the isolation of XPc1, a second Polycomb homolog in Xenopus laevis. We show that XPc1 message is maternally deposited in a translationally masked form in Xenopus oocytes, with XPc1 protein first appearing in embryonic nuclei shortly after the blastula stage. XPc1 acts as a transcriptional repressor in vivo when tethered to a promoter in Xenopus embryos. We find that XPc1-mediated repression can be only partially alleviated by an increase in transcription factor dosage and that inhibition of deacetylase activity by trichostatin A treatment has no effect on XPc1 repression, suggesting that histone deacetylation does not form the basis for Pc-G-mediated repression in our assay. 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 96 TC 26 Z9 26 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 JUN PY 1999 VL 19 IS 6 BP 3958 EP 3968 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 198GX UT WOS:000080416100004 PM 10330136 ER PT J AU Carrodeguas, JA Kobayashi, R Lim, SE Copeland, WC Bogenhagen, DF AF Carrodeguas, JA Kobayashi, R Lim, SE Copeland, WC Bogenhagen, DF TI The accessory subunit of Xenopus laevis mitochondrial DNA polymerase gamma increases processivity of the catalytic subunit of human DNA polymerase gamma and is related to class II aminoacyl-tRNA synthetases SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TRANSFER-RNA SYNTHETASE; ESCHERICHIA-COLI; SACCHAROMYCES-CEREVISIAE; YEAST MITOCHONDRIAL; DROSOPHILA EMBRYOS; BINDING-PROTEIN; CONFERS PROCESSIVITY; THERMUS-THERMOPHILUS; CLONING; BACTERIOPHAGE-T7 AB Peptide sequences obtained from the accessory subunit of Xenopus laevis mitochondrial DNA (mtDNA) polymerase gamma (pol gamma) were used to clone the cDNA encoding this protein. Amino-terminal sequencing of the mitochondrial protein indicated the presence of a 44-amino-acid mitochondrial targeting sequence, leaving a predicted mature protein with 419 amino acids and a molecular mass of 47.3 kDa. This protein is associated with the larger, catalytic subunit in preparations of active mtDNA polymerase, The small subunit exhibits homology to its human, mouse, and Drosophila counterparts. Interestingly, significant homology to glycyl-tRNA synthetases from prokaryotic organisms reveals a likely evolutionary relationship. Since attempts to produce an enzymatically active recombinant catalytic subunit of Xenopus DNA poly have not been successful, we tested the effects of adding the small subunit of the Xenopus enzyme to the catalytic subunit of human DNA pol gamma purified from baculovirus-infected insect cells. These experiments provide the first functional evidence that the small subunit of DNA pol gamma stimulates processive DNA synthesis by the human catalytic subunit under physiological salt conditions. C1 SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USA. Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Bogenhagen, DF (reprint author), SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USA. RI Carrodeguas, Jose/L-7334-2014 OI Carrodeguas, Jose/0000-0003-0062-1029 FU NIGMS NIH HHS [GM29681, R01 GM029681]; PHS HHS [P01-04068] NR 34 TC 78 Z9 80 U1 0 U2 3 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 JUN PY 1999 VL 19 IS 6 BP 4039 EP 4046 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 198GX UT WOS:000080416100012 PM 10330144 ER PT J AU Le Gallic, L Sgouras, D Beal, G Mavrothalassitis, G AF Le Gallic, L Sgouras, D Beal, G Mavrothalassitis, G TI Transcriptional repressor ERF is a Ras/mitogen-activated protein kinase target that regulates cellular proliferation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SIGNAL-TRANSDUCTION PATHWAY; TERNARY COMPLEX FACTORS; ETS DOMAIN PROTEIN; MAP KINASE; NUCLEOCYTOPLASMIC TRANSPORT; GENE-EXPRESSION; UV-LIGHT; HA-RAS; PHOSPHORYLATION; MITOGEN AB A limited number of transcription factors have been suggested to be regulated directly by Erks within the Rasimitogen-activated protein kinase signaling pathway. In this paper we demonstrate that ERF, a ubiquitously expressed transcriptional repressor that belongs to the Ets family, is physically associated with and phosphorylated in vitro and in vivo by Erks, This phosphorylation determines the ERF subcellular localization. Upon mitogenic stimulation, ERF is immediately phosphorylated and exported to the cytoplasm, The export is blocked by specific Erk inhibitors and is abolished when residues undergoing phosphorylation are mutated to alanine. Upon growth factor deprivation, ERF is rapidly dephosphorylated and transported back into the nucleus. Phosphorylation-defective ERF mutations suppress Ras-induced tumorigenicity and arrest the cells at the G(0)/G(1) phase of the cell cycle. Our findings strongly suggest that ERF may be important in the control of cellular proliferation during the G(0)/G(1) transition and that it may be one of the effecters in the mammalian Ras signaling pathway. C1 FORTH, IMBB, Heraklion 71409, Crete, Greece. Univ Crete, Sch Med, Heraklion 71409, Crete, Greece. NCI, Mol Oncol Lab, SAIC, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, Lab Cellular Biochem, SAIC, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Mavrothalassitis, G (reprint author), FORTH, IMBB, Heraklion 71409, Crete, Greece. RI Sgouras, Dionyssios Nicholas/D-9943-2012 OI Sgouras, Dionyssios Nicholas/0000-0003-0975-2607 NR 59 TC 57 Z9 59 U1 0 U2 4 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 JUN PY 1999 VL 19 IS 6 BP 4121 EP 4133 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 198GX UT WOS:000080416100020 PM 10330152 ER PT J AU Calvo, O Cuesta, R Anderson, J Gutierrez, N Garcia-Barrio, MT Hinnebusch, AG Tamame, M AF Calvo, O Cuesta, R Anderson, J Gutierrez, N Garcia-Barrio, MT Hinnebusch, AG Tamame, M TI GCD14p, a repressor of GCN4 translation, cooperates with Gcd10p and Lhp1p in the maturation of initiator methionyl-tRNA in Saccharomyces cerevisiae SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID NUCLEOTIDE EXCHANGE FACTOR; NUCLEAR RNASE-P; AMINO-ACID BIOSYNTHESIS; FACTOR-II; COMPLEX-FORMATION; ESCHERICHIA-COLI; GENE DISRUPTION; SHUTTLE VECTORS; BINDING PROTEIN; FACTOR EIF2B AB Gcd10p and Gcd14p were first identified genetically as repressors of GCN4 mRNA translation in Saccharomyces cerevisiae. Recent findings indicate that Gcd10p and Gcd14p reside in a nuclear complex required for the presence of 1-methyladenosine in tRNAs, Here we show that Gcd14p is an essential protein with predicted binding motifs for S-adenosylmethionine, consistent with a direct function in tRNA methylation. Two different gcd14 mutants exhibit defects in cell growth and accumulate high levels of initiator methionyl-tRNA (tRNA(i)(Met)) precursors containing 5' and 3' extensions, suggesting a defect in processing of the primary transcript. Dosage suppressors of grd10 mutations, encoding tRN(i)(Met) (hcIMT1 to hcIMT4; he indicates that the gene is carried on a high-copy-number plasmid) or a homologue of human La protein implicated in tRNA 3'-end formation (hcLHP1), also suppressed gcd14 mutations. In fact, the lethality of a GCD14 deletion was suppressed by hcIMT4, indicating that the essential function of Gcd14p is required for biogenesis of tRNA(i)(Met). A mutation in GCD10 or deletion of LHP1 exacerbated the defects in cell growth and expression of mature tRNA(i)(Met) in gcd14 mutants, consistent with functional interactions between Gcd14p, Gcd10p, and Lhp1p in vivo. Surprisingly, the amounts of NME1 and RPR1, the RNA components of RNases P and MRP, were substantially lower in gcd14 lhp1::LEU2 double mutants than in the corresponding single mutants, whereas 5S rRNA was present at wild-type levels. Our findings suggest that Gcd14p and Lhp1p cooperate in the maturation of a subset of RNA polymerase III transcripts. C1 Univ Salamanca, CSIC, Inst Microbiol Bioquim, Salamanca 37007, Spain. NICHHD, Sect Mol Genet Lower Eukaryotes, Mol Genet Lab, Bethesda, MD 20892 USA. RP Univ Salamanca, CSIC, Inst Microbiol Bioquim, Edificio Dept Biol,Campus Miguel de Unamuno, Salamanca 37007, Spain. EM tamame@gugu.usal.es NR 65 TC 42 Z9 44 U1 2 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 1999 VL 19 IS 6 BP 4167 EP 4181 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 198GX UT WOS:000080416100025 PM 10330157 ER PT J AU Marinissen, MJ Chiariello, M Pallante, M Gutkind, JS AF Marinissen, MJ Chiariello, M Pallante, M Gutkind, JS TI A network of mitogen-activated protein kinases links G protein-coupled receptors to the c-jun promoter: a role for c-Jun NH2-terminal kinase, p38s, and extracellular signal-regulated kinase 5 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID EPIDERMAL GROWTH-FACTOR; NIH 3T3 CELLS; TRANSCRIPTION FACTOR MEF2C; ENHANCER-BINDING-FACTOR; MAP KINASE; TRANSDUCTION PATHWAY; CELLULAR STRESSES; INDEPENDENT PATHWAY; CYCLE PROGRESSION; DNA INTERACTIONS AB The expression of the c-jun proto-oncogene is rapidly induced in response to mitogens acting on a large variety of cell surface receptors, The resulting functional activity of c-Jun proteins appears to be critical for cell proliferation. Recently, we have shown that a large family of G protein-coupled receptors (GPCRs), represented by the mi muscarinic receptor, can initiate intracellular signaling cascades that result in the activation of mitogen-activated protein kinases (MAPK) and c-Jun NH2-terminal kinases (JNK) and that the activation of JNK but not of MAPK correlated with a remarkable increase in the expression of c-jun mRNA, Subsequently, however, we obtained evidence that GPCRs can potently stimulate the activity of the c-jun promoter through MEF2 transcription factors, which do not act downstream from JNK. In view of these observations, we set out to investigate further the nature of the signaling pathway linking GPCRs to the c-jun promoter. Utilizing NIH 3T3 cells, we found that GPCRs can activate the c-jun promoter in a JNK-independent manner. Additionally, we demonstrated that these GPCRs can elevate the activity of novel members of the MAPK family, including ERK5, p38 alpha, p38 gamma, and p38 delta, and that the activation of certain kinases acting downstream from MEK5 (ERK5) and MKK6 (p38 alpha and p38 gamma) is necessary to fully activate the c-jun promoter. Moreover, in addition to JNK, ERK5, p38 alpha, and p38 gamma were found to stimulate the c-jun promoter by acting on distinct responsive elements. Taken together, these results suggest that the pathway linking GPCRs to the c-jun promoter involves the integration of numerous signals transduced by a highly complex network of MAPK, rather than resulting from the stimulation of a single linear protein kinase cascade. Furthermore, our findings suggest that each signaling pathway affects one or more regulatory elements on the c-jun promoter and that the transcriptional response most likely results from the temporal integration of each of these biochemical routes. C1 Natl Inst Dent & Cranofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Gutkind, JS (reprint author), Natl Inst Dent & Cranofacial Res, Oral & Pharyngeal Canc Branch, NIH, 9000 Rockville Pike,Bldg 30,Room 212, Bethesda, MD 20892 USA. RI Gutkind, J. Silvio/A-1053-2009; Chiariello, Mario/O-3642-2014 OI Chiariello, Mario/0000-0001-8434-5177 NR 77 TC 177 Z9 180 U1 0 U2 3 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 JUN PY 1999 VL 19 IS 6 BP 4289 EP 4301 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 198GX UT WOS:000080416100038 PM 10330170 ER PT J AU Lai, WS Carballo, E Strum, JR Kennington, EA Phillips, RS Blackshear, PJ AF Lai, WS Carballo, E Strum, JR Kennington, EA Phillips, RS Blackshear, PJ TI Evidence that tristetraprolin binds to AU-rich elements and promotes the deadenylation and destabilization of tumor necrosis factor alpha mRNA SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID FINGER TRANSCRIPTION FACTOR; 3' UNTRANSLATED REGION; PRIMARY RESPONSE GENE; MESSENGER-RNA; 3'-UNTRANSLATED REGION; NUCLEOTIDE-SEQUENCE; TRANSGENIC MICE; C-ELEGANS; PROTEIN; CELLS AB Mice deficient in tristetraprolin (TTP), the prototype of a family of CCCH zinc finger proteins, develop an inflammatory syndrome mediated by excess tumor necrosis factor alpha (TNF-alpha). Macrophages derived from these mice oversecrete TNF-alpha, by a mechanism that involves stabilization of TNF-alpha mRNA, and TTP can bind directly to the AU-rich element (ARE) in TNF-alpha mRNA (E. Carballo, W. S. Lai, and P. J. Blackshear, Science 281:1001-1005, 1998), We show here that TTP binding to the TNF-alpha ARE is dependent upon the integrity of both zinc fingers, since mutation of a single cysteine residue in either zinc finger to arginine severely attenuated the binding of TTP to the TNF-alpha ARE. In intact cells, TTP at low expression levels promoted a decrease in size of the TNF-alpha mRNA as well as a decrease in its amount; at higher expression levels, the shift to a smaller TNF-alpha mRNA size persisted, while the accumulation of this smaller species increased. RNase H experiments indicated that the shift to a smaller size was due to TTP-promoted deadenylation of TNF-alpha mRNA. This CCCH protein is likely to be important in the deadenylation and degradation of TNF-alpha mRNA and perhaps other ARE-containing mRNAs, both in normal physiology and in certain pathological conditions. C1 A2 05 NIEHS, Off Clin Res, Res Triangle Pk, NC 27709 USA. A2 05 NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. RP A2 05 NIEHS, Off Clin Res, 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM black009@niehs.nih.gov NR 52 TC 511 Z9 518 U1 3 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 1999 VL 19 IS 6 BP 4311 EP 4323 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 198GX UT WOS:000080416100040 PM 10330172 ER PT J AU Maddelein, ML Wickner, RB AF Maddelein, ML Wickner, RB TI Two prion-inducing regions of Ure2p are nonoverlapping SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID YEAST SACCHAROMYCES-CEREVISIAE; SUP35 PROTEIN; IN-VITRO; SCRAPIE PRION; GENE; PROPAGATION; DETERMINANT; PSI(+); INCOMPATIBILITY; IDENTIFICATION AB Ure2p of Saccharomyces cerevisiae normally functions in blocking utilization of a poor nitrogen source when a good nitrogen source is available. The non-Mendelian genetic element [URE3] is a prion (infectious protein) form of Ure2p, so that overexpression of Ure2p induces the de novo appearance of infectious [URE3]. Earlier studies defined a prion domain comprising Ure2p residues 1 to 64 and a nitrogen regulation domain included in residues 66 to 354. We find that deletion of individual runs of asparagine within the prion domain reduce prion-inducing activity. Although residues 1 to 64 are sufficient for prion induction, the fragment from residues 1 to 80 is a more efficient inducer of [URE3]. In frame deletion of a region around residue 224 does not affect nitrogen regulation but does eliminate prion induction by the remainder of Ure2p. Larger deletions removing the region around residue 224 and more of the C-terminal part of Ure2p restore prion-inducing ability. A fragment of Ure2p lacking the original prion domain does not induce [URE3], but surprisingly, further deletion of residues 151 to 157 and 348 to 354 leaves a fragment that can do so. The region from 66 to 80 and the region around residue 224 are both necessary for this second prion-inducing activity. Thus, each of two nonoverlapping parts of Ure2p is sufficient to induce the appearance of the [URE3] prion. C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP NIDDKD, Lab Biochem & Genet, NIH, Bldg 8,Room 225,8 Ctr Dr MSC 0830, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov RI MADDELEIN, Marie-Lise/G-5395-2010 NR 50 TC 83 Z9 83 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 1999 VL 19 IS 6 BP 4516 EP 4524 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 198GX UT WOS:000080416100058 PM 10330190 ER PT J AU Owshalimpur, D Kelley, MJ AF Owshalimpur, D Kelley, MJ TI Genomic structure of the EPHA1 receptor tyrosine kinase gene SO MOLECULAR AND CELLULAR PROBES LA English DT Article DE exon; intron; mutation; evolution; genomic structure ID FAMILY; PROTOONCOGENE; MUTATIONS; FORMS AB Some receptor tyrosine kinase genes are mutated in inherited and somatically acquired human cancers. To permit mutational analysis, the complete genomic structure of the human EPHA1 gene on chromosome 7q34 was determined and oligonucleotide pairs were designed to amplify coding regions. The gene contains 18 exons, two more than the related tyrosine kinase, EPHB2. Presumed sequencing errors in the published cDNA sequence of EPHA1 were identified in exons 10 and 11. Availability of this information will facilitate mutational analysis of EPHA1. C1 NCI, Lung Canc Biol Sec, Bethesda, MD 20889 USA. RP Kelley, MJ (reprint author), Duke Univ, VA Hosp, 508 Fulton St, Durham, NC 27705 USA. OI Kelley, Michael/0000-0001-9523-6080 NR 10 TC 5 Z9 9 U1 0 U2 0 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0890-8508 J9 MOL CELL PROBE JI Mol. Cell. Probes PD JUN PY 1999 VL 13 IS 3 BP 169 EP 173 DI 10.1006/mcpr.1999.0228 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology GA 210RG UT WOS:000081118000001 PM 10369740 ER PT J AU Zhang, JZ AF Zhang, JZ TI Performance of likelihood ratio tests of evolutionary hypotheses under inadequate substitution models SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE likelihood ratio test; substitution models; molecular clock; transition transversion bias; rate variation among sites; molecular evolution ID MAXIMUM-LIKELIHOOD; PHYLOGENETIC ANALYSIS; STATISTICAL TESTS; DNA-SEQUENCES; SITES; INFERENCE; GENES; TREES; RATES AB In recent years, likelihood ratio tests (LRTs) based on DNA and protein sequence data have been proposed for testing various evolutionary hypotheses. Because conducting an LRT requires an evolutionary model of nucleotide or amino acid substitution, which is almost always unknown, it becomes important to investigate the robustness of LRTs to violations of assumptions of these evolutionary models. Computer simulation was used to examine performance of LRTs of the molecular clock, transition/transversion bias, and among-site rate variation under different substitution models. The results showed that when correct models are used, LRTs perform quite well even when the DNA sequences are as shea as 300 nt. However, LRTs were found to be biased under incorrect models. The extent of bias varies considerably, depending on the hypotheses tested, the substitution models assumed, and the lengths of the sequences used, among other things. A preliminary simulation study also suggests that LRTs based on parametric bootstrapping may be more sensitive to substitution models than are standard LRTs. When an assumed substitution model is grossly wrong and a more realistic model is available, LRTs can often reject the wrong model; thus, the performance of LRTs may be improved by using a more appropriate model. On the other hand, many factors of molecular evolution have not been considered in any substitution models so far built, and the possibility of an influence of this negligence on LRTs is often overlooked. The dependence of LRTs on substitution models calls for caution in interpreting test results and highlights the importance of clarifying the substitution patterns of genes and proteins and building more realistic models. C1 Penn State Univ, Inst Mol Evolutionary Genet, University Pk, PA 16802 USA. Penn State Univ, Dept Biol, University Pk, PA 16802 USA. RP Zhang, JZ (reprint author), NIAID, Host Def Lab, NIH, 9000 Rockville Pike,Bldg 10,Room 11N104, Bethesda, MD 20892 USA. NR 32 TC 41 Z9 41 U1 0 U2 0 PU SOC MOLECULAR BIOLOGY EVOLUTION PI LAWRENCE PA PO BOX 1897, LAWRENCE, KS 66044-8897 USA SN 0737-4038 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD JUN PY 1999 VL 16 IS 6 BP 868 EP 875 PG 8 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 203ZL UT WOS:000080738400016 PM 10368963 ER PT J AU Goldsworthy, SM Stockton, PS Trempus, CS Foley, JF Maronpot, RR AF Goldsworthy, SM Stockton, PS Trempus, CS Foley, JF Maronpot, RR TI Effects of fixation on RNA extraction and amplification from laser capture microdissected tissue SO MOLECULAR CARCINOGENESIS LA English DT Article DE PixCell; reverse transcription-polymerase chain reaction; beta(2)-microglobulin; glyceraldehyde-3-phosphate dehydrogenase; TaqMan ID POLYMERASE CHAIN-REACTION; PARAFFIN-EMBEDDED TISSUE; PCR AMPLIFICATION; MESSENGER-RNA; HYBRIDIZATION; TIME AB One of the key end points for understanding the molecular basis of carcinogenesis is the quantitation of gene expression in specific cell populations. Microdissection techniques allow extraction of morphologically distinct cells for molecular analysis. A recent advance in microdissection uses the PixCell laser capture microdissection (LCM) system, which allows for precise removal of pure cell populations from morphologically preserved tissue sections. The objective of this study was to determine the optimal fixation protocol for analyzing RNA from tissue samples using LCM. Optimal fixation must provide acceptable morphology, allow proper laser capture of selected cells, and preserve the integrity of mRNA. We evaluated the effects of both cross-linking and precipitive-type fixatives on frozen and paraffin-embedded mouse liver tissue. For assessment of the quality of the mRNA in LCM samples generated from various fixed tissues, reverse transcription-polymerase chain reaction (RT-PCR)-amplified mouse liver beta(2)-microglobulin mRNA was detected with ethidium bromide. We also examined mouse glyceraldehyde-3-phosphate-dehydrogenase by using the fluorogenic TaqMan system for real-time quantitative detection of RT-PCR products. Frozen tissues yielded more RT-PCR product than did paraffin-embedded tissues. In both frozen and paraffin-embedded tissues, differences were observed between the fixatives. Precipitive fixatives, such as ethanol and acetone, consistently produced more RT-PCR amplification product than did cross-linking fixatives such as formalin. Optimal fixation protocols for LCM analysis will facilitate the examination of gene expression in specific cell populations, accelerating investigations of the molecular differences responsible for the phenotypic changes observed during carcinogenesis. Published 1999 Wiley-Liss, Inc.dagger. C1 NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. Pathol Associates Int, Durham, NC USA. NIEHS, Lab Environm Carcinogenesis & Mutagenesis, Res Triangle Pk, NC 27709 USA. RP Goldsworthy, SM (reprint author), NIEHS, Lab Expt Pathol, Bldg 101,MC C2-01, Res Triangle Pk, NC 27709 USA. NR 20 TC 248 Z9 268 U1 0 U2 7 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD JUN PY 1999 VL 25 IS 2 BP 86 EP 91 DI 10.1002/(SICI)1098-2744(199906)25:2<86::AID-MC2>3.0.CO;2-4 PG 6 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 201ZR UT WOS:000080628100001 PM 10365909 ER PT J AU Misteli, T Spector, DL AF Misteli, T Spector, DL TI RNA polymerase II targets pre-mRNA splicing factors to transcription sites in vivo SO MOLECULAR CELL LA English DT Article ID C-TERMINAL DOMAIN; XENOPUS OOCYTE NUCLEI; MESSENGER-RNA; CAPPING ENZYME; LARGEST SUBUNIT; SR PROTEINS; NASCENT TRANSCRIPTS; CONDITIONAL MUTANTS; IN-VIVO; COMPLEX AB Biochemical evidence indicates that pre-mRNA splicing factors physically interact with the C-terminal domain of tt le largest subunit of RNA polymerase II. We have investigated the in vivo function of this interaction. In mammalian cells, truncation of the CTD of RNA pol II LS prevents the targeting of the splicing machinery to a transcription site. In the absence of the CID, pre-mRNA splicing is severely reduced. The presence of unspliced RNA alone is not sufficient for the accumulation of splicing factors at the transcription site, nor for its efficient splicing. Our results demonstrate a critical role for the CTD of RNA pol II LS in the intranuclear targeting of splicing factors to transcription sites in vivo. C1 NCI, NIH, Bethesda, MD 20892 USA. Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. FU NIGMS NIH HHS [GM42694] NR 66 TC 222 Z9 226 U1 1 U2 2 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 JUN PY 1999 VL 3 IS 6 BP 697 EP 705 DI 10.1016/S1097-2765(01)80002-2 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 210UN UT WOS:000081123200002 PM 10394358 ER PT J AU Arora, KK Chung, HO Catt, KJ AF Arora, KK Chung, HO Catt, KJ TI Influence of a species-specific extracellular amino acid on expression and function of the human gonadotropin-releasing hormone receptor SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID 2ND INTRACELLULAR LOOP; SIGNAL-TRANSDUCTION; INTERNALIZATION; MUTATIONS; LIGAND AB The mammalian GnRH receptor is an atypical G protein-coupled receptor which lacks the C-terminal cytoplasmic tail that is present in all other seven-transmembrane domain receptors. The mouse and rat GnRH receptors contain 327 amino acids, whereas human, sheep, and bovine receptors have an additional residue in the second extracellular loop at position 191. Another notable species difference is that human receptors undergo agonist-induced internalization much more rapidly than the mouse receptor. In this report, the role of the additional amino acid (Lys191) in GnRH receptor function was studied in transiently expressed mutant and wild-type human and mouse GnRH receptors. Deletion of Lys191 from the human GnRH receptor caused a 4-fold increase in receptor expression in COS-1 and HEK 293 cells and a modest increase in binding affinity. The magnitude of the agonist-induced inositol phosphate response mediated by the Delta K191 human receptor was similar to that of the wild-type receptor, but the EC50 was decreased by about 5-fold. In addition, the rate of internalization of the Delta K191 human receptor was significantly reduced and was similar to that of the mouse receptor. In contrast to these effects of deletion of Lys191, its replacement by Arg, Glu, Gln, or Ala caused no significant change in receptor expression or function. These findings demonstrate that a specific residue in the extracellular region of the human GnRH receptor is a significant determinant of receptor expression, agonist-induced activation, and internalization. C1 NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Catt, KJ (reprint author), NICHHD, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Room 6A36, Bethesda, MD 20892 USA. NR 13 TC 40 Z9 40 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 JUN PY 1999 VL 13 IS 6 BP 890 EP 896 DI 10.1210/me.13.6.890 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 202UE UT WOS:000080669900012 PM 10379888 ER PT J AU Ferreira, H Seppala, R Pinto, R Huizing, M Martins, E Braga, AC Gomes, L Krasnewich, DM Miranda, MCS Gahl, WA AF Ferreira, H Seppala, R Pinto, R Huizing, M Martins, E Braga, AC Gomes, L Krasnewich, DM Miranda, MCS Gahl, WA TI Sialuria in a Portuguese girl: Clinical, biochemical, and molecular characteristics SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE sialuria; UDP-GlcNAc 2-epimerase; sialic acid; feedback inhibition; allosterism ID N-ACETYLNEURAMINIC ACID; BIFUNCTIONAL ENZYME CATALYZES; FIRST 2 STEPS; SIALIC-ACID; RAT-LIVER; 2-EPIMERASE/N-ACETYLMANNOSAMINE KINASE; SALLA DISEASE; FIBROBLASTS; BIOSYNTHESIS; METABOLISM AB Sialuria, a disorder of sialic acid (NeuAc) metabolism characterized by increased free NeuAc in the cytoplasm of cells, is due to failure of CMP-Neu5Ac to feedback inhibit UDP-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase. We now describe the fifth patient in the world with sialuria, a 7-year-old Portuguese girl with developmental delay, hepatomegaly, coarse facies, and urinary excretion of 19 mu mol of free NeuAc/mg creatinine, The patient's fibroblasts stored excess free NeuAc in the cytosolic fraction, and fibroblast UDP-GlcNAc 2-epimerase activity was only 26% inhibited by 100 mu M CMP-Neu5Ac (normal, 79%). The patient's UDP-GlcNAc 2-epimerase gene displayed an R266Q mutation in only one allele, consistent with known sialuria mutations and with the proposed dominant nature of this disorder. Extensive description of sialuria patients will help to define the clinical and biochemical spectrum of this disease. (C) 1999 Academic Press. C1 Hosp Maria Pia, Dept Pediat, Porto, Portugal. NICHHD, Sect Human Biochem Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. Inst Med Genet, Jacinto Magalhaes, P-4150 Porto, Portugal. Natl Human Genome Res Inst, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Ferreira, H (reprint author), Hosp Maria Pia, Dept Pediat, Porto, Portugal. RI sa Miranda, Maria Clara/K-3920-2013 OI sa Miranda, Maria Clara/0000-0003-0123-5525 NR 22 TC 11 Z9 12 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JUN PY 1999 VL 67 IS 2 BP 131 EP 137 DI 10.1006/mgme.1999.2852 PG 7 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 208XG UT WOS:000081016700006 PM 10356312 ER PT J AU Shields, MJ Hodgson, W Ribaudo, RK AF Shields, MJ Hodgson, W Ribaudo, RK TI Differential association of beta(2)-microglobulin mutants with MHC class I heavy chains and structural analysis demonstrate allele-specific interactions SO MOLECULAR IMMUNOLOGY LA English DT Article DE beta(2)-microglobulin; MHC; molecular modeling ID MAJOR-HISTOCOMPATIBILITY-COMPLEX; 2.4 ANGSTROM RESOLUTION; 3-DIMENSIONAL STRUCTURE; PEPTIDE BINDING; CRYSTAL-STRUCTURE; MONOCLONAL-ANTIBODIES; VIRAL PEPTIDES; CELL BIOLOGY; T-CELL; MOLECULES AB Dynamic interactions between major histocompatibility complex (MHC) class I heavy chains and beta(2)-microglobulin (beta(2)m) play a critical role in their stability on the cell surface, and their ability to present peptide antigens to CD8(+) T-cells, A cursory review of protein sequence homologies and three-dimensional crystal structures of MHC complexes might indicate very similar modes of interaction between the heavy and light chains. In this report, a panel of human beta(2)m mutants was screened to probe the interactions of beta(2)m with the murine MHC molecules H-2K(b), -D-b, -K-d, -L-d, and -D-d. Binding experiments coupled with analyses of existing three-dimensional crystal structures demonstrate allelic differences in their interaction with beta(2)m A comprehensive analysis of the existing murine MHC structures indicates a conformational flexibility on the part of murine beta(2)m that is not present in beta(2)m of the human structures. This flexibility is in a region directly interacting with the heavy chain and may relate to its lower affinity for murine heavy chains relative to human beta(2)m. This defined panel of pam mutants of differing affinity may also be useful for subsequent studies of thymic selection, T-cell recognition, and more refined algorithms for protein structure prediction. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. RP Shields, MJ (reprint author), 8507 Capricorn Way 80, San Diego, CA 92126 USA. NR 46 TC 15 Z9 15 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD JUN PY 1999 VL 36 IS 9 BP 561 EP 573 DI 10.1016/S0161-5890(99)00077-2 PG 13 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 229MF UT WOS:000082197800001 PM 10499810 ER PT J AU Glover, RE Ivy, ED Orringer, EP Maeda, H Mason, RP AF Glover, RE Ivy, ED Orringer, EP Maeda, H Mason, RP TI Detection of nitrosyl hemoglobin in venous blood in the treatment of sickle cell anemia with hydroxyurea SO MOLECULAR PHARMACOLOGY LA English DT Article ID ELECTRON-PARAMAGNETIC-RESONANCE; NITRIC-OXIDE; PLATELET ACTIVATION; RIBONUCLEOTIDE REDUCTASE; ENDOTHELIAL-CELLS; STEADY-STATE; IN-VITRO; DISEASE; ERYTHROCYTES; RATS AB The clinical efficacy of hydroxyurea (HU) in the treatment of sickle cell anemia has mainly been attributed to increased levels of fetal hemoglobin (HbF), which reduces the tendency for sickle hemoglobin to polymerize, thereby reducing the frequency of the vaso-occlusive phenomena associated with the disease. However, benefits from HU treatment in patients have been reported in advance of increased HbF levels. Thus, it has been suggested that other hydroxyurea-dependent mechanisms may, in part, account for its clinical efficacy. We have previously demonstrated that HU is metabolized in rats to release nitric oxide and, therefore, postulated the same to occur in humans. However, to our knowledge, evidence of nitric oxide production from HU metabolism in humans has yet to be demonstrated. Here we report that oral administration of HU for the treatment of sickle cell anemia produced detectable nitrosyl hemoglobin. The nitrosyl hemoglobin complex could be detected as early as 30 min after administration and persisted up to 4 h. Our observations support the hypothesis that the ability of HU to ease the vaso-occlusive phenomena may, in part, be attributed to vasodilation and/or decreased platelet activation induced by HU-derived nitric oxide well in advance of increased HbF levels. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dept Med, Chapel Hill, NC USA. Kumamoto Univ Med, Dept Microbiol, Kumamoto, Japan. RP Glover, RE (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 40 TC 85 Z9 88 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 JUN PY 1999 VL 55 IS 6 BP 1006 EP 1010 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 200KX UT WOS:000080540100007 PM 10347241 ER PT J AU Donovan, PJ Smith, GT AF Donovan, PJ Smith, GT TI Cell sensitivity to transplacental mutagenesis by N-ethyl-N-nitrosourea is greatest during early gestation in the Syrian hamster SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE 6-thioguanine; diphtheria toxin; N-ethyl-N-nitrosourea; mutation; fetus; embryo ID ETHYLNITROSOUREA; MOUSE; DNA; CARCINOGENESIS; TERATOGENESIS; GASTRULATION; ELIMINATION; MECHANISMS; TISSUES; MICE AB The extremely high rate of cell division that occurs during early embryogenesis is hypothesized to predispose to high rates of mutation after chemical exposure, We tested this supposition experimentally. To probe the variation in susceptibility to mutation induction as a function of gestation stage, somatic cells of the developing Syrian hamster were isolated after transplacental treatment with N-ethyl-N-nitrosourea (ENU), Mutants were quantified using either 6-thioguanine (6-TG) or diphtheria toxin (DT) as selective agents. Several different approaches were used. In one, three litters were exposed on each gestation day and fetuses were removed on day 13. Maximum fetal sensitivity to ENU's genotoxic action was noted when treatment was at days 8 and 9, fewer mutants being obtained with earlier and later exposures. To compensate for the low numbers of target cells early in gestation, this experiment was repeated using larger numbers of litters exposed at the earlier time points, and the highest mutation frequency was now found to occur after treatment on gestation days 6 and 7, In the second approach, mutations were quantified in cells harvested 24 h after transplacental ENU exposure. Hen again, embryos exposed at earlier times of gestation were more susceptible than those treated at later periods. Based on the total cell numbers in embryos and fetuses at each gestation day, we conclude that mutation frequency is maximal on day 6, corresponding to the primitive streak stage with extremely high rates of cell division. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NCI, Comparat Carcinogenesis Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Donovan, PJ (reprint author), NCI, Comparat Carcinogenesis Lab, Frederick Canc Res & Dev Ctr, Rm 205E, Frederick, MD 21702 USA. NR 46 TC 11 Z9 11 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JUN 1 PY 1999 VL 427 IS 1 BP 47 EP 58 DI 10.1016/S0027-5107(99)00086-X PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 209WB UT WOS:000081071600006 PM 10354501 ER PT J AU Donovan, PJ AF Donovan, PJ TI Cell sensitivity to transplacental carcinogenesis by N-ethyl-N-nitrosourea is greatest in early post-implantation development SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE N-ethyl-N-nitrosouea; tumor; embryo; fetus ID 1-ETHYL-1-NITROSOUREA; PROLIFERATION; INITIATION; MICE; DNA AB In a clear demonstration of the changing sensitivity of the developing mammal to transplacental carcinogenesis, Ivankovic and Druckrey [S. Ivankovic, ii. Druckrey, Transplacentare Erzeugung maligner Tumoren des Nervensystem: I.;Athyl-nitroso-harnstoff (ANH) an ED IX-Ratten, Z. Krebsforsch. 71 (1968) 320-360] exposed pregnant ED IX rats to a pulse of N-ethyl-N-nitrosourea (ENU), a reactive carcinogen with a half-life of 20 min. No tumors were seen with ENU exposure before gestation day 12, but the multiplicity of neurogenic tumors increased steadily thereafter and was greatest with treatment on day 30, followed by a decline in sensitivity for the last three days of gestation. Similarly, a transplacental study of ENU in the Syrian hamster [B.A. Diwan, S. Rehm, J.M. Rice, Age- and dose-dependent transplacental carcinogenesis by N-nitrosoethylurea in Syrian golden hamsters, J. Cancer Res. Clin. Oncol. 122 (1996) 643-652] found that the numbers of tumors induced were greatest after exposure of late fetal stages. While these observations suggested that embryonic cells are refractory to carcinogenesis, an alternative explanation could be that a significant tumor yield was not observed because too few target cells were present in the embryo. I have resolved this issue by combining these published data with others on the numbers of neuroectodermal cells in the developing ED IX rat brain [R. Miiller, M.F. Rajewsky, Elimination of O-6-ethylguanine from the DNA of brain, liver, and other rat tissues exposed to ethylnitrosourea at different stages of prenatal development? Cancer Res. 43 (1983) 2897-2904] and total cell counts of successive developmental stages of the Syrian hamster fetus [P.J. Donovan, G.T. Smith, Cell sensitivity to transplacental mutagenesis by N-ethyl-N-nitrosourea is greatest during early gestation in the Syrian hamster, Mutation Res., 1999, this issue], allowing the risk per cell at different stages of gestation to be calculated. Sensitivity to carcinogenesis was found to be greatest early in gestation and to decrease as gestation proceeds. For the rat model, tumor frequency per cell changed from 1.3 X 10(-6) at day 12 exposure to 2.6 x 10(-6) at day 23 exposure, a 50-fold decrease. For the hamster model, the tumor-initiation rate decreased 1250-fold from 1.2 X 10(-5) at day 7 exposure to 9.6 X 10(-9) at day 13 exposure. Thus, two independent experiments with different rodent species demonstrate that sensitivity of individual cells to damage leading to transplacental carcinogenesis is greatest in the early fetus and lessens markedly as gestation proceeds, in parallel with changing sensitivity to mutation (Donovan et al,, Mutat. Res., this issue). (C) 1999 Elsevier Science B.V,All rights reserved. C1 NCI, Comparat Carcinogenesis Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Donovan, PJ (reprint author), NCI, Comparat Carcinogenesis Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NR 14 TC 3 Z9 3 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 1 PY 1999 VL 427 IS 1 BP 59 EP 63 PG 5 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 209WB UT WOS:000081071600007 PM 10354502 ER PT J AU Lyman, CA Navarro, E Garrett, KF Roberts, DD Pizzo, PA Walsh, TJ AF Lyman, CA Navarro, E Garrett, KF Roberts, DD Pizzo, PA Walsh, TJ TI Adherence of Candida albicans to bladder mucosa: development and application of a tissue explant assay SO MYCOSES LA English DT Article DE Candida; adherence; uroepithelium; tissue explant assay ID HUMAN EPITHELIAL-CELLS; ENDOTHELIAL-CELLS; PATHOGENICITY; PATHOGENESIS; STRAINS; ATTACHMENT; MECHANISMS; INVITRO AB In order to study the interactions between Candida species and uroepithelial tissue, a tissue explant assay was developed using bladder mucosa harvested from New Zealand white rabbits. Blastoconidia of Candida albicans, Candida tropicalis and Candida glabrata attached to the uroepithelial tissue in similar quantities. However? there was significantly more adherence to the uroepithelium by pre-germinated C. albicans compared with C. albicans blastoconidia. Furthermore, the amount of uroepithelial tissue injury was directly related to the length of exposure of the tissue to Candida. Thus, this tissue explant assay may provide a useful method for investigating properties related to fungal adherence to transitional uroepithelium and organism-mediated tissue injury. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Lyman, CA (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bldg 10,Room 13N240, Bethesda, MD 20892 USA. RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 NR 24 TC 3 Z9 8 U1 0 U2 0 PU BLACKWELL WISSENSCHAFTS-VERLAG GMBH PI BERLIN PA KURFURSTENDAMM 57, D-10707 BERLIN, GERMANY SN 0933-7407 J9 MYCOSES JI Mycoses PD JUN PY 1999 VL 42 IS 4 BP 255 EP 259 PG 5 WC Dermatology; Mycology SC Dermatology; Mycology GA 217JF UT WOS:000081495700005 PM 10424092 ER PT J AU Alayash, AI AF Alayash, AI TI Hemoglobin-based blood substitutes: oxygen carriers, pressor agents, or oxidants? SO NATURE BIOTECHNOLOGY LA English DT Review DE blood substitutes; blood pressure; oxidants ID CROSS-LINKED HEMOGLOBIN; CELL-FREE HEMOGLOBIN; NITRIC-OXIDE; FREE-RADICALS; EFFICACY; POLYMERIZATION; METHEMOGLOBIN; MECHANISMS; FAILURE AB Hemoglobin-based blood substitutes are being developed as oxygen-carrying agents for the prevention of ischemic tissue damage and hypovolemic (low blood volume) shock. The ability of cell-free hemoglobin blood substitutes to affect vascular tone through the removal of nitric oxide has also prompted an evaluation of their usefulness for maintaining blood pressure in critically ill patients. Before the clinical potential of these substitutes can be fully realized, however, concerns remain as to the intrinsic toxicity of the hemoglobin molecule, particularly the interference of the heme prosthetic group with the tissue oxidant/antioxidant balance. This review provides some insights into the complex redox chemistry of hemoglobin and places an emphasis on how current knowledge may be exploited both to selectively enhance/suppress specific chemical reaction pathway(s) and to ultimately design safer hemoglobin-based therapeutics. C1 US FDA, Lab Plasma Derivat, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Alayash, AI (reprint author), US FDA, Lab Plasma Derivat, Ctr Biol Evaluat & Res, NIH Campus,Bldg 29,Room 112,8800 Rockville Pike, Bethesda, MD 20892 USA. NR 53 TC 149 Z9 152 U1 0 U2 18 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD JUN PY 1999 VL 17 IS 6 BP 545 EP 549 DI 10.1038/9849 PG 5 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 203PR UT WOS:000080716500024 PM 10385317 ER PT J AU Chowdhury, PS Pastan, I AF Chowdhury, PS Pastan, I TI Improving antibody affinity by mimicking somatic hypermutation in vitro SO NATURE BIOTECHNOLOGY LA English DT Article DE phage display; single-chain antibody; hot spots; affinity improvement ID SINGLE-CHAIN FV; PHAGE DISPLAY; RECOMBINANT IMMUNOTOXIN; PSEUDOMONAS EXOTOXIN; ANTITUMOR-ACTIVITY; BREAST-CANCER; MATURATION; SELECTION; MUTATION; MUTAGENESIS AB In vivo affinity maturation of antibodies involves mutation of hot spots in the DNA encoding the variable regions. We have used this information to develop a strategy to improve antibody affinity in vitro using phage display technology. In our experiment with the antimesothelin scFv, SS(scFv), we identified DNA sequences in the variable regions that are naturally prone to hypermutations, selected a few hot spots encoding nonconserved amino acids, and introduced random mutations to make libraries with a size requirement between 10(3) and 10(4) independent clones. Fanning of the hot spot libraries yielded several mutants with a 15- to 55-fold increase in affinity compared with a single clone with a fourfold increased affinity from a library in which mutagenesis was done outside the hot spots. The strategy should be generally applicable for the rapid isolation of higher-affinity mutants of Fvs, Fabs, and other recombinant antibodies from antibody phage libraries that are small in size. C1 NCI, Mol Biol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Div Basic Sci, NIH, Bldg 37,Room 4E16, Bethesda, MD 20892 USA. NR 38 TC 172 Z9 184 U1 1 U2 8 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD JUN PY 1999 VL 17 IS 6 BP 568 EP 572 PG 5 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 203PR UT WOS:000080716500028 PM 10385321 ER PT J AU Biesecker, BB Marteau, TM AF Biesecker, BB Marteau, TM TI The future of genetic counselling: an international perspective SO NATURE GENETICS LA English DT Article ID UNITED-KINGDOM; PRENATAL-DIAGNOSIS; FETAL-ABNORMALITY; CLINICAL-PRACTICE; CYSTIC-FIBROSIS; SERVICES; ATTITUDES; WOMEN; ECONOMICS; PROVIDERS AB The focus of clinical genetics, and thus genetic counselling, is forecast to expand from the diagnosis and prediction of rare, often untreatable conditions, to the prediction of common, often treatable or preventable conditions'. Whether this evolution is likely to proceed rapidly or at a pace that permits sensible integration of molecular genetic tools is unknown and a source of debate(2,3) . It is clear, however, that genetic discoveries will modify the way in which disease and risk are conceptualized. Here, we predict how genetic counselling, specifically for more common diseases, might be provided in the decades to come. We envisage an expansion of professional roles and expertise for many health care providers and highlight the need for counselling practices to become more evidence based. Although we support an evidentiary-based approach to the integration of genetic testing into practice, genetic advance is unlikely to occur in an orderly and standardized manner within countries, much less among different countries and health care systems(4). Geneticists will become increasingly involved in professional education and policy-making regarding genetic testing and screening programs. C1 Natl Human Genome Res Inst, Med Genet Branch, NIH, Bethesda, MD USA. United Med & Dent Sch Guys & St Thomas, Psychol & Genet Res Grp, London SE1 7EH, England. RP Biesecker, BB (reprint author), Natl Human Genome Res Inst, Med Genet Branch, NIH, Bethesda, MD USA. OI Marteau, Theresa/0000-0003-3025-1129 NR 68 TC 56 Z9 56 U1 1 U2 5 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUN PY 1999 VL 22 IS 2 BP 133 EP 137 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 202YX UT WOS:000080680900016 ER PT J AU Hacia, JG Fan, JB Ryder, O Jin, L Edgemon, K Ghandour, G Mayer, RA Sun, B Hsie, L Robbins, CM Brody, LC Wang, D Lander, ES Lipshutz, R Fodor, SPA Collins, FS AF Hacia, JG Fan, JB Ryder, O Jin, L Edgemon, K Ghandour, G Mayer, RA Sun, B Hsie, L Robbins, CM Brody, LC Wang, D Lander, ES Lipshutz, R Fodor, SPA Collins, FS TI Determination of ancestral alleles for human single-nucleotide polymorphisms using high-density oligonucleotide arrays SO NATURE GENETICS LA English DT Article ID HUMAN-EVOLUTION; GENE; CHIMPANZEE; DIVERSITY; PRIMATES; SEQUENCES; LINKAGE; NUCLEAR; REGION; GENOME AB Here we report the application of high-density oligonucleotide array (DNA chip)-based analysis to determine the distant history of single nucleotide polymorphisms (SNPs) in current human populations. We analysed orthologues for 397 human SNP sites (identified in CEPH:pedigrees from Amish, Venezuelan and Utah populations(1)) from 23 common chimpanzee, 19 pygmy chimpanzee and 11 gorilla genomic DNA samples. From this data we determined 214 proposed ancestral alleles (the sequence found in the last common ancestor of humans and chimpanzees). In a diverse human population set, we found that SNP alleles with higher frequencies were more likely to be ancestral than less frequently occurring alleles, There were, however, exceptions. We also found three shared human/pygmy chimpanzee polymorphisms, all involving CpG dinucleotides, and two shared human/gorilla polymorphisms, one involving a CpG dinucleotide. We demonstrate that mi;microarray-based assays allow rapid comparative sequence analysis of intra- and interspecies genetic variation. C1 Natl Human Genome Res Inst, Bethesda, MD 20892 USA. Affymetrix, Santa Clara, CA 95051 USA. Zool Soc San Diego, Ctr Reprod Endangered Species, San Diego, CA 92112 USA. Fudan Univ, Inst Genet, Shanghai 200433, Peoples R China. Univ Texas, Inst Human Genet, Houston, TX 77225 USA. Whitehead Inst Biomed Res, Cambridge Ctr 9, Cambridge, MA 02142 USA. RP Collins, FS (reprint author), Natl Human Genome Res Inst, Bldg 49-3A14, Bethesda, MD 20892 USA. RI MOE Key Lab at Fudan University, Contemp Anthropology/A-1772-2010; Jin, Li/C-1468-2009; OI Jin, Li/0000-0002-4546-2415; Sun, Bryan/0000-0002-0740-0125 FU NHGRI NIH HHS [5POLHGO1323-03] NR 28 TC 273 Z9 291 U1 4 U2 18 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUN PY 1999 VL 22 IS 2 BP 164 EP 167 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 202YX UT WOS:000080680900021 PM 10369258 ER PT J AU Wallis, DE Roessler, E Hehr, U Nanni, L Wiltshire, T Richieri-Costa, A Gillessen-Kaesbach, G Zackai, EH Rommens, J Muenke, M AF Wallis, DE Roessler, E Hehr, U Nanni, L Wiltshire, T Richieri-Costa, A Gillessen-Kaesbach, G Zackai, EH Rommens, J Muenke, M TI Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly SO NATURE GENETICS LA English DT Article ID SINE OCULIS; VISUAL-SYSTEM; PERSPECTIVES; EXPRESSION AB Holoprosencephaly (HPE) is a common, severe malformation of the brain that involves separation of the central nervous system into left and right halves. Mild HPE can consist of signs such as a single central incisor, hypotelorism microcephaly, or other craniofacial findings that can be present with or without associated brain malformations(1-3). The aetiology of HPE is extremely:heterogeneous, with the proposed participation of a minimum of 12 HPE-associated genetic loci as well as the:causal. involvement of specific teratogens acting: at the earliest stages of neurulation(4). The HPE2 locus was recently characterized as a 1-Mb interval on human chromosome 2p21 that contained a gene associated with HPE: A minimal critical region was defined by a set of six overlapping deletions and three clustered translocations in HPE patients(5). We:describe here the isolation and characterization of the human homeobox-containing SIX3 gene from the HPE2 minimal critical region (MCR). We show that at least 2 of the HPE-associated translocation :breakpoints in 2p21 are less than 200 kb from the 5' end of SIX3. Mutational analysis has identified four different mutations in the homeodomain of SIX3 that are predicted to interfere with transcriptional activation and are associated with HPE, We propose that SIX3 is the HPE2 gene, essential for the development of the anterior neural plate and eye in humans. C1 Univ Penn, Sch Med, Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Childrens Hosp Philadelphia, Dept Genet, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Childrens Hosp Philadelphia, Dept Neurol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. Natl Human Genome Res Inst, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Halle Wittenberg, Dept Human Genet, Halle, Germany. Univ San Paulo, Dept Clin Genet, Bauru, SP, Brazil. Univ Essen Gesamthsch, Dept Human Genet, Essen, Germany. Univ Toronto, Hosp Sick Children, Dept Genet, Program Genet & Genomic Biol, Toronto, ON M5G 1X8, Canada. RP Muenke, M (reprint author), Univ Penn, Sch Med, Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. RI Richieri-Costa, Antonio/B-2514-2013 FU NICHD NIH HHS [HD28732, HD29862] NR 20 TC 177 Z9 180 U1 2 U2 8 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUN PY 1999 VL 22 IS 2 BP 196 EP 198 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 202YX UT WOS:000080680900029 PM 10369266 ER PT J AU Margolis, L Grivel, JC AF Margolis, L Grivel, JC TI Cytokine modulation of HIV-1 chemokine receptor expression SO NATURE MEDICINE LA English DT Letter ID LYMPHOID-TISSUE; IMMUNODEFICIENCY C1 NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Margolis, L (reprint author), NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. NR 6 TC 1 Z9 1 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUN PY 1999 VL 5 IS 6 BP 592 EP 593 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 205LR UT WOS:000080823300003 ER PT J AU Matzinger, P AF Matzinger, P TI Graft tolerance: A duel of two signals SO NATURE MEDICINE LA English DT Editorial Material ID CD40; CELL C1 NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Matzinger, P (reprint author), NIAID, Cellular & Mol Immunol Lab, NIH, Bldg 4,Room 11, Bethesda, MD 20892 USA. NR 6 TC 17 Z9 17 U1 0 U2 2 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUN PY 1999 VL 5 IS 6 BP 616 EP 617 DI 10.1038/9458 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 205LR UT WOS:000080823300024 PM 10371494 ER PT J AU Chun, TW Engel, D Mizell, SB Hallahan, CW Fischette, M Park, S Davey, RT Dybul, M Kovacs, JA Metcalf, JA Mican, JM Berrey, MM Corey, L Lane, HC Fauci, AS AF Chun, TW Engel, D Mizell, SB Hallahan, CW Fischette, M Park, S Davey, RT Dybul, M Kovacs, JA Metcalf, JA Mican, JM Berrey, MM Corey, L Lane, HC Fauci, AS TI Effect of interleukin-2 on the pool of latently infected, resting CD4(+) T cells in HIV-1-infected patients receiving highly active anti-retroviral therapy SO NATURE MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIRETROVIRAL THERAPY; CONTROLLED TRIAL; HIV ERADICATION; CANCER-PATIENTS; COMBINATION; VIREMIA; REPLICATION; INDIVIDUALS; ACTIVATION AB The size of the pool of resting CD4(+) T cells containing replication-competent HIV in the blood of patients receiving intermittent interleukin (IL)-2 plus highly active anti-retroviral therapy (HAART) was significantly lower than that of patients receiving HAART alone. Virus could not be isolated from the peripheral blood CD4(+) T cells in three patients receiving IL-2 plus HAART, despite the fact that large numbers of resting CD4(+) T cells were cultured. Lymph node biopsies were done in two of these three patients and virus could not be isolated. These results indicate that the intermittent administration of IL-2 with continuous HAART may lead to a substantial reduction in the pool of resting CD4(+) T cells that contain replication-competent HIV. C1 NIAID, Natl Inst Hlth, Immunoregulat Lab, Bethesda, MD 20892 USA. NCI, Natl Inst Hlth, Pathol Lab, Bethesda, MD 20892 USA. Univ So Calif, Sch Med, Div Biometry, Dept Prevent Med, Los Angeles, CA 90033 USA. Univ Washington, Dept Med & Lab Med, Seattle, WA 98104 USA. Fred Hutchinson Canc Res Ctr, Program Infect Dis, Seattle, WA 98104 USA. RP Chun, TW (reprint author), NIAID, Natl Inst Hlth, Immunoregulat Lab, Bethesda, MD 20892 USA. NR 31 TC 298 Z9 306 U1 0 U2 2 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUN PY 1999 VL 5 IS 6 BP 651 EP 655 DI 10.1038/9498 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 205LR UT WOS:000080823300033 PM 10371503 ER PT J AU Richmond, BJ Hertz, JA Gawne, TJ AF Richmond, BJ Hertz, JA Gawne, TJ TI The relation between V1 neuronal responses and eye movement-like stimulus presentations SO NEUROCOMPUTING LA English DT Article AB Primates normally make 2-3 saccadic eye movements/s to explore the environment. To investigate how these eye movements might influence visual responses, we compared the dynamics of stimuli arriving on V1 complex cell receptive fields by switching stimuli in sequence while a monkey fixated to the responses occurring when the stimulus appears clue to saccadic eye movements. During the image sequences, information was greater when each image remained on the receptive fields longer, up to 200 ms; information was greatest when there was a gap of 50 ms between images. Responses were more variable when the image appeared due to a saccadic eye movement. The amount of stimulus-related information was lower in the early phase of the post-saccadic time, but increased during the post-saccadic fixation, so that after 400 ms there was almost as much stimulus-related information available as during the image switching. Eye position showed much larger variability after saccades, with the variability decreasing over 350-400 ms to reach the level seen during long fixations. The dynamics of information accumulation in V1 complex cells appear to be well matched to the manner in which the environment is normally viewed. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. NORDITA, DK-2100 Copenhagen, Denmark. Univ Alabama, Sch Optometry, Dept Physiol Opt, Birmingham, AL 35294 USA. RP Richmond, BJ (reprint author), NIMH, Neuropsychol Lab, Bldg 49,Room 1B80, Bethesda, MD 20892 USA. NR 4 TC 18 Z9 18 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-2312 J9 NEUROCOMPUTING JI Neurocomputing PD JUN PY 1999 VL 26-7 BP 247 EP 254 DI 10.1016/S0925-2312(99)00018-1 PG 8 WC Computer Science, Artificial Intelligence SC Computer Science GA 216UK UT WOS:000081462700033 ER PT J AU Tabak, J Senn, W O'Donovan, MJ Rinzel, J AF Tabak, J Senn, W O'Donovan, MJ Rinzel, J TI Comparison of two models for pattern generation based on synaptic depression SO NEUROCOMPUTING LA English DT Article DE spontaneous activity; synaptic depression; excitatory network; connectivity ID ANTAGONISTS AB Previously, we developed two similar 3-variable models to explain the pattern of spontaneous rhythmic activity generated by the spinal cord of chick embryo. The models differ in the implementation of a slow depression variable, but each produces patterns of activity that qualitatively resemble experimental recordings. For both models, the ratio inter-episode interval/episode duration (i/d ratio) was too small compared to experiments. The introduction of a parameter representing the connectivity of the network has different effects on each model, therefore allowing them to be distinguished experimentally. Also, the model that seems to better satisfy experimental constraints is able to generate a large i/d ratio. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NINDS, Neural Control Lab, Bethesda, MD 20892 USA. Univ Bern, Inst Informat & Appl Math, CH-3012 Bern, Switzerland. NYU, Ctr Neural Sci, New York, NY 10003 USA. RP Tabak, J (reprint author), NINDS, Neural Control Lab, Bldg 49,Rm 3A50,NIH Campus, Bethesda, MD 20892 USA. RI tabak, joel/K-1549-2013; Senn, Walter/D-6308-2014; o'donovan, michael/A-2357-2015 OI Senn, Walter/0000-0003-3622-0497; o'donovan, michael/0000-0003-2487-7547 NR 5 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-2312 J9 NEUROCOMPUTING JI Neurocomputing PD JUN PY 1999 VL 26-7 BP 551 EP 556 DI 10.1016/S0925-2312(99)00032-6 PG 6 WC Computer Science, Artificial Intelligence SC Computer Science GA 216UK UT WOS:000081462700073 ER PT J AU O'Brien, RJ Xu, DS Petralia, RS Steward, O Huganir, RL Worley, P AF O'Brien, RJ Xu, DS Petralia, RS Steward, O Huganir, RL Worley, P TI Synaptic clustering of AMPA receptors by the extracellular immediate-early gene product Narp SO NEURON LA English DT Article ID C-REACTIVE PROTEIN; METABOTROPIC GLUTAMATE RECEPTORS; ACUTE-PHASE PROTEINS; AMYLOID-P COMPONENT; RAT CEREBRAL-CORTEX; EXCITATORY SYNAPSES; POSTSYNAPTIC SITES; HIPPOCAMPAL-NEURONS; COMPLEMENT-SYSTEM; MESSENGER-RNA AB Narp (neuronal activity-regulated pentraxin) is a secreted immediate-early gene (IEG) regulated by synaptic activity in brain. In this study, we demonstrate that Narp possesses several properties that make it likely to play a key role in excitatory synaptogenesis. Narp is shown to be selectively enriched at excitatory synapses on neurons from both the hippocampus and spinal cord. Overexpression of recombinant Narp increases the number of excitatory but not inhibitory synapses in cultured spinal neurons. In transfected HEK 293T cells, Narp interacts with itself, forming large surface clusters that coaggregate AMPA receptor subunits. Moreover, Narp-expressing HEK 293T cells can induce the aggregation of neuronal AMPA receptors. These studies support a model in which Narp functions as an extracellular aggregating factor for AMPA receptors. C1 Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. Natl Inst Deafness & Commun Disorders, NIH, Neurochem Lab, Bethesda, MD 20892 USA. Univ Virginia, Dept Neurosci, Charlottesville, VA 22908 USA. RP Worley, P (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. OI Steward, Oswald/0000-0001-7069-8756 FU NIMH NIH HHS [R01MH53608]; NINDS NIH HHS [K08NS01652, R01NS36715] NR 58 TC 270 Z9 280 U1 1 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JUN PY 1999 VL 23 IS 2 BP 309 EP 323 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 212LR UT WOS:000081218600016 PM 10399937 ER PT J AU Sharifi, N Ament, M Brennan, MB Hochgeschwender, U AF Sharifi, N Ament, M Brennan, MB Hochgeschwender, U TI Isolation and characterization of the mouse homolog of the preprodynorphin (Pdyn) gene SO NEUROPEPTIDES LA English DT Article ID RAT PRODYNORPHIN GENE; MESSENGER-RNA; FQ PRECURSOR; EXPRESSION; NOCICEPTIN; DYNORPHIN; SEQUENCE; RECEPTOR; CLONING; BRAIN AB We have isolated and sequenced the mouse preprodynorphin gene (Pdyn). The Pdyn gene can encode for six biologically active dynorphin peptides. The predicted mouse preprodynorphin has 90%, 67%, and 66% identity with the predicted rat, porcine, and human preprodynorphins, respectively. Using an RT-PCR technique, we show that the Pdyn gene starts being expressed at embryonic day 12.5, with a steep increase of expression by embryonic day 14.5; in the adult mouse it is expressed in the brain, but not in liver, heart, spleen, or kidney. C1 Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. NIMH, NSB, Mol Genet Unit, Bethesda, MD 20892 USA. Eleanor Roosevelt Inst, Denver, CO USA. RP Hochgeschwender, U (reprint author), Oklahoma Med Res Fdn, 825 NE 13th St,MS 49, Oklahoma City, OK 73104 USA. NR 17 TC 12 Z9 13 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 0143-4179 J9 NEUROPEPTIDES JI Neuropeptides PD JUN PY 1999 VL 33 IS 3 BP 236 EP 238 DI 10.1054/npep.1999.0023 PG 3 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 226AJ UT WOS:000081997900007 PM 10657497 ER PT J AU Azari, NP Knorr, U Arnold, S Antke, C Ebner, A Niemann, H Pettigrew, KD Witte, OW Seitz, RJ AF Azari, NP Knorr, U Arnold, S Antke, C Ebner, A Niemann, H Pettigrew, KD Witte, OW Seitz, RJ TI Reorganized cerebral metabolic interactions in temporal lobe epilepsy SO NEUROPSYCHOLOGIA LA English DT Article DE brain; functional imaging; glucose metabolism; language; principal component analysis; epilepsy ID POSITRON EMISSION TOMOGRAPHY; INTERICTAL GLUCOSE HYPOMETABOLISM; MEMORY FUNCTION; F-18 FLUORODEOXYGLUCOSE; PARTIAL SEIZURES; VERBAL MEMORY; BRAIN; LANGUAGE; MRI; NETWORKS AB Patients with left temporal lobe epilepsy demonstrate language impairments that are not well understood. To explore abnormal patterns of brain functional connections with respect to language processing, we applied a principal component analysis to resting regional cerebral metabolic data obtained with positron emission tomography in patients with right- and left-sided temporal lobe epilepsy and controls. Two principal components were expressed differentially among the groups. One principal component comprised a pattern of metabolic interactions involving left inferior frontal and left superior temporal regions-corresponding to Broca's and Wernicke's areas, respectively-and right mesial temporal cortex and right thalamus. Functional couplings between these brain regions were abnormally enhanced in the left-sided epilepsy patients. The right thalamic-left superior temporal coupling was also abnormally enhanced in the right-sided epilepsy patients, but differentially from that in the left-sided patients. The other principal component was characterized by a pattern of metabolic interactions involving right and left mid prefrontal and right superior temporal cortex. Although both the right- and left-sided epilepsy patients showed decreased functional couplings between left mid prefrontal and the other brain regions, a weaker right-left mid prefrontal coupling in the left-sided epilepsy patients best distinguished them from the right-sided patients. The two mutually independent, abnormal metabolic patterns each predicted verbal intelligence deficits in the patients. The findings suggest a site-dependent reorganization of two independent, language-subserving pathways in temporal lobe epilepsy. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 Univ Dusseldorf, Dept Neurol, D-4000 Dusseldorf, Germany. Univ Frankfurt, Dept Neurol, D-6000 Frankfurt, Germany. Bethel Epilepsy Ctr, Bielefeld, Germany. NIMH, NIH, Bethesda, MD 20892 USA. RP Seitz, RJ (reprint author), Univ Dusseldorf, Dept Neurol, D-4000 Dusseldorf, Germany. EM seitz@neurologie.uni-duesseldorf.de NR 73 TC 12 Z9 12 U1 0 U2 3 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 JUN PY 1999 VL 37 IS 6 BP 625 EP 636 DI 10.1016/S0028-3932(98)00130-4 PG 12 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 201QC UT WOS:000080605600001 PM 10390024 ER PT J AU Bartzokis, G Beckson, M Newton, T Mandelkern, M Mintz, J Foster, JA Ling, W Bridge, TP AF Bartzokis, G Beckson, M Newton, T Mandelkern, M Mintz, J Foster, JA Ling, W Bridge, TP TI Selegiline effects on cocaine-induced changes in medial temporal lobe metabolism and subjective ratings of euphoria SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE cocaine; selegiline; PET; MRI; hippocampus; amygdala; euphoria ID L-DEPRENYL SELEGILINE; CEREBRAL BLOOD-FLOW; ACETYLCHOLINE-RELEASE; HUMAN BRAIN; MAO-B; HIPPOCAMPUS; DOPAMINE; DEPENDENCE; AMYGDALA; RAT AB To test the effect of selegiline, aspecific monoamine oxidase-B (MAO-B)inhibitor, on the cerebral metabolic and euphorigenic effects of cocaine in experienced users, eight cocaine-dependent (CD) subjects were evaluated using a within-subjects design. Each subject participated in two pairs of [F-18]-fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans (baseline scan followed 24 h Inter by a second scan obtained in conjunction with a 40-mg cocaine infusion) performed before and after a 1-week period of daily treatment with 10 mg selegiline administered orally. The hippocampus and amygdala were evaluated because of their hypothesized involvement in the addiction process, and the thalamus teas evaluated as a comparison region. Following 7 days of selegiline treatment, the magnitude of the subjective euphoria ("high") produced by cocaine infusion was reduced by 40% (cocaine by selegiline interaction F = 7.15, df = 1,22, p = .014). Selegiline treatment also altered glucose utilization (normalized against whole brain counts) in the two limbic regions, but not the thalamus. In the amygdala, the effects of cocaine differed, depending upon whether or not patients were being treated with selegiline (cocaine by selegiline interaction F = 4.67, df = 1,19.8, p = .043). A different effect was observed in the hippocampus, where selegiline treatment decreased metabolic activity irrespective of whether cocaine was given (main effect F = 7.70, df = 1,20, p = .012). The concomitant changes in both the subjective experience of the "high" and normalized amygdala glucose utilization after selegiline treatment, suggest that a relationship exists between cocaine-induced euphoria and limbic metabolism. The data suggest that selegiline may be a useful adjunct in the treatment of cocaine dependence. (C) 1999 American College of Neuropsychopharmacology. Published by Elsevier Science Inc. C1 N Little Rock VA Med Ctr NLR, Psychiat Serv, Little Rock, AR 72114 USA. Univ Arkansas Med Sci, Dept Psychiat, Little Rock, AR 72205 USA. W Los Angeles Vet Affairs Med Ctr, Psychiat Serv, Los Angeles, CA 90073 USA. W Los Angeles Vet Affairs Med Ctr, Res Serv, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA 90074 USA. W Los Angeles Vet Affairs Med Ctr, Nucl Med Serv, Los Angeles, CA 90073 USA. Univ Calif Irvine, Dept Phys, Irvine, CA 92697 USA. NIDA, Med Dev Div, Rockville, MD 20857 USA. RP Bartzokis, G (reprint author), N Little Rock VA Med Ctr NLR, Psychiat Serv, 2200 Ft Roots Dr,Bldg 170,116A, Little Rock, AR 72114 USA. RI Bartzokis, George/K-2409-2013; OI newton, thomas/0000-0002-3198-5901 FU NIDA NIH HHS [1YO1 DA 50038] NR 43 TC 38 Z9 40 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 JUN PY 1999 VL 20 IS 6 BP 582 EP 590 DI 10.1016/S0893-133X(98)00092-X PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 191TN UT WOS:000080037800007 PM 10327427 ER PT J AU Lawler, CP Prioleau, C Lewis, MM Mak, C Jiang, D Schetz, JA Gonzalez, AM Sibley, DR Mailman, RB AF Lawler, CP Prioleau, C Lewis, MM Mak, C Jiang, D Schetz, JA Gonzalez, AM Sibley, DR Mailman, RB TI Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE antipsychotic; dopamine receptors; aripiprazole; adenylyl cyclase; functional selectivity; CHO cells; C-6 cells; schizophrenia ID UNDERLYING AUTORECEPTOR SELECTIVITY; QUINOLINONE DERIVATIVE OPC-14597; VENTRAL TEGMENTAL AREA; MOLECULAR-CLONING; D-2 RECEPTORS; HIGH-AFFINITY; DIFFERENTIAL EXPRESSION; SPLICE VARIANTS; MESSENGER-RNA; D2 RECEPTORS AB OPC-14597 {aripiprazole; 7-(4-(4-(2,3-dichlorophenyl)-1-piperazinyl)butyloxy)-3,4-dihydro-2 (1H)-quinolinone} is a novel candidate antipsychotic that has high affinity for striatal dopamine D-2-like receptors, but causes few extrapyramidal effects. These studies characterized the molecular pharmacology of OPC-14597, DM-2451 (its major rodent metabolite), and the related quinolinone derivative OPC-4392 at each of the cloned dopamine receptors, and at serotonin 5HT(6) and 5HT(7) receptors. All three compounds exhibited highest affinity for D-2L and D-2S receptors relative to the other cloned receptors examined. Both OPC-4392 and OPC-14597 demonstrated dual agonist/antagonist actions at D-2L receptors, although the metabolite DM-1451 behaved as a. pure antagonist. These data suggest that clinical atypicality can occur with drugs that exhibit selectivity for D-2L/D-2S rather than D-3 or D-4 receptors, and raise the possibility that the unusual profile of OPC-14597 in vivo (presynaptic agonist and postsynaptic antagonist) may reflect different functional consequences of this compound interacting with a single dopamine receptor subtype (D-2) in distinct cellular locales. (C) 1999 American College of Neuropsychopharmacology. Published by Elsevier Science Inc. C1 Univ N Carolina, Sch Med, UNC Neurosci Ctr, Dept Neurobiol, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Med, Dept Psychiat, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Med, Dept Med Chem, Chapel Hill, NC 27599 USA. NINDS, Mol Neuropharmacol Sect, Bethesda, MD 20892 USA. RP Lawler, CP (reprint author), Univ N Carolina, Sch Med, UNC Neurosci Ctr, Dept Neurobiol, CB 7250, Chapel Hill, NC 27599 USA. OI Mailman, Richard/0000-0003-1353-2738 FU NIMH NIH HHS [MH33127, MH40537, MH53356] NR 79 TC 279 Z9 291 U1 6 U2 15 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 JUN PY 1999 VL 20 IS 6 BP 612 EP 627 DI 10.1016/S0893-133X(98)00099-2 PG 16 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 191TN UT WOS:000080037800010 PM 10327430 ER PT J AU Spring, KR AF Spring, KR TI Epithelial fluid transport - A century of investigation SO NEWS IN PHYSIOLOGICAL SCIENCES LA English DT Article ID CELL EPITHELIUM; WATER AB Our current understanding of the mechanism of fluid transport by epithelia relies upon mathematical models der eloped 30 years ago to explain the mechanism of solute-solvent coupling and the pathways taken by water across an epithelium. The validity of these models is reconsidered in light of recent findings, and it is concluded that a simple three-compartment model system is adequate to explain fluid absorption and secretion by epithelia. C1 NHLBI, Sect Transport Physiol, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Spring, KR (reprint author), NHLBI, Sect Transport Physiol, Kidney & Electrolyte Metab Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 13 TC 50 Z9 50 U1 0 U2 0 PU NEWS IN PHYSIOLOGICAL SCIENCES PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0886-1714 J9 NEWS PHYSIOL SCI JI News Physiol. Sci. PD JUN PY 1999 VL 14 BP 92 EP 98 PG 7 WC Physiology SC Physiology GA 209TY UT WOS:000081066000002 ER PT J AU Wells, DJ AF Wells, DJ TI Tdd-4, a DNA transposon of Dictyostelium that encodes proteins similar to LTR retroelement integrases SO NUCLEIC ACIDS RESEARCH LA English DT Article ID MESSENGER-RNA INTRONS; SACCHAROMYCES-CEREVISIAE; RETROVIRAL INTEGRASES; HIV-1 INTEGRASE; BINDING DOMAIN; DISCOIDEUM; SEQUENCES; RETROTRANSPOSON; INVITRO; GENES AB Tdd-4 is the first DNA transposon to be isolated from Dictyostelium discoideum, This element was isolated by insertion into a target plasmid, Two classes of elements were identified which include a 3.8 kb version and a 3.4 kb deleted version. Sequence analysis reveals that the 145 bp inverted terminal repeats contain the 5'-TG...CA-3' conserved terminal dinucleotides found in prokaryotic transposons and integrated LTR retroelement DNA sequences. Tdd-4 open reading frames are assembled by removal of six introns, introns 1-5 conform to the GT-AG rule, whereas intron 6 appears to be an AT-AA intron, Also, intron 6 undergoes an alternative 5' splicing reaction. The alternatively spliced region encodes 15 tandem SPXX repeats that are proposed to function as a DNA binding motif, By analogy to other transposons that encode two proteins from the same gene, the full-length Tdd-4 protein is the putative transposase and the truncated Tdd-4 protein is the putative transposition inhibitor. Protein database searches demonstrate Tdd-4 encoded proteins are unique for a DNA element by containing similarities to retroviral/retrotransposon integrases. The putative Tdd-4 transposase contains the same structural relationship as integrases by possessing an N-terminal HHCC motif, a central DDE motif and a C-terminal DNA-binding domain composed of the SPXX motif. C1 Utah State Univ, Dept Biol, Program Mol Biol, Logan, UT 84322 USA. RP Wells, DJ (reprint author), NIAID, Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM dwells@atlas.niaid.nih.gov NR 64 TC 11 Z9 11 U1 0 U2 0 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 1 PY 1999 VL 27 IS 11 BP 2408 EP 2415 DI 10.1093/nar/27.11.2408 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 202XU UT WOS:000080678100024 PM 10325432 ER PT J AU Winters, TA Russell, PS Kohli, M Dar, ME Neumann, RD Jorgensen, TJ AF Winters, TA Russell, PS Kohli, M Dar, ME Neumann, RD Jorgensen, TJ TI Determination of human DNA polymerase utilization for the repair of a model ionizing radiation-induced DNA strand break lesion in a defined vector substrate SO NUCLEIC ACIDS RESEARCH LA English DT Article ID BASE-EXCISION-REPAIR; CELL NUCLEAR ANTIGEN; HUMAN APURINIC/APYRIMIDINIC ENDONUCLEASE; HUMAN APURINIC ENDONUCLEASE; LIGASE-III; MAMMALIAN-CELLS; BINDING ACTIVITY; XRCC1 PROTEIN; BOVINE TESTIS; SITE REPAIR AB Human DNA polymerase and DNA ligase utilization for the repair of a major class of ionizing radiation-induced DNA lesion [DNA single-strand breaks containing 3'-phosphoglycolate (3'-PG)] was examined using a novel, chemically defined vector substrate containing a single, site-specific 3'-PG single-strand break lesion. In addition, the major human AP endonuclease, HAP1 (also known as APE1, APEX, Ref-1), was tested to determine if it was involved in initiating repair of 3'-PG-containing single-strand break lesions. DNA polymerase beta was found to be the primary polymerase responsible for nucleotide incorporation at the lesion site following excision of the 3'-PG blocking group. However, DNA polymerase delta/epsilon was also capable of nucleotide incorporation at the lesion site following 3'-PG excision, In addition, repair reactions catalyzed by DNA polymerase beta were found to be most effective in the presence of DNA ligase III, while those catalyzed by DNA polymerase delta/epsilon appeared to be more effective in the presence of DNA ligase I. Also, it was demonstrated that the repair initiating 3'-PG excision reaction was not dependent upon HAP1 activity, as judged by inhibition of HAP1 with neutralizing HAP1-specific polyclonal antibody. C1 Georgetown Univ, Med Ctr, Div Radiat Res, Dept Radiat Med, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Dept Biochem, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Vincent T Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. NIH, Warren G Magnuson Clin Ctr, Dept Nucl Med, Bethesda, MD 20892 USA. RP Jorgensen, TJ (reprint author), Georgetown Univ, Med Ctr, Div Radiat Res, Dept Radiat Med, TRB E212A,3970 Reservoir Rd NW, Washington, DC 20007 USA. EM jogensent@odrge.odr.georgetown.edu NR 59 TC 28 Z9 28 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUN 1 PY 1999 VL 27 IS 11 BP 2423 EP 2433 DI 10.1093/nar/27.11.2423 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 202XU UT WOS:000080678100026 PM 10325434 ER PT J AU Overpeck, MD Hediger, ML Zhang, J Trumble, AC Klebanoff, MA AF Overpeck, MD Hediger, ML Zhang, J Trumble, AC Klebanoff, MA TI Birth weight for gestational age of Mexican American infants born in the United States SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID NUTRITION-EXAMINATION-SURVEY; FETAL GROWTH; WOMEN; ENVIRONMENT; PREVALENCE; POPULATION; PREGNANCY; HEALTH AB Objective: To develop a reference for birth weight for gestational age to identify Mexican American infants born in the United States who are small or large for gestational age. Methods: Reference percentiles were developed for Mexican American and non-Hispanic white births, using national vital statistics from 1992-1994 for Mexican Americans (n = 1,197,916) and 1994 for non-Hispanic whites (n = 2,238,457). Birth weights and gestation from the last menstrual period were taken from birth certificates. Smoothed curves were fit, using unweighted fourth-degree polynomial equations, for the tenth, 50th, and 90th percentiles by gender and parity. Results: Mexican American infants were heavier than non-Hispanic white infants between 30 and 37 weeks' gestation for all parities and both genders. However, at term there was consistent crossover. Non-Hispanic white infants were heavier at or after 37 through 42 weeks' gestation, whereas the growth of Mexican American infants appeared to slow. Beginning at 37 weeks, the differences in weights of infants of primiparas increased to more than 100 g by 40 weeks; the differences were only slightly less for infants of multiparas. Conclusion: Given differences in distribution of birth weights for gestational age between Mexican Americans and non-Hispanic whites, the ability to recognize fetal growth restriction (FGR) or excessive growth is questionable. These data provide a reference for Mexican Americans for clinical use and for future studies in identifying infants at risk for FGR or overgrowth. (Obstet Gynecol 1999;93:943-7.) C1 NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. RP Overpeck, MD (reprint author), NICHHD, Div Epidemiol, NIH, Bldg 6100,Room 7B03,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 26 TC 58 Z9 60 U1 1 U2 1 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 JUN PY 1999 VL 93 IS 6 BP 943 EP 947 DI 10.1016/S0029-7844(98)00553-5 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 201FG UT WOS:000080583900010 PM 10362159 ER PT J AU Conley, BA Smiley, JK Cheson, BD AF Conley, BA Smiley, JK Cheson, BD TI Clinical trials - Referral resource SO ONCOLOGY-NEW YORK LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Conley, BA (reprint author), NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD JUN PY 1999 VL 13 IS 6 BP 814 EP 814 PG 1 WC Oncology SC Oncology GA 368QC UT WOS:000090128200011 PM 10378219 ER PT J AU O'Connell, AC Torske, KR AF O'Connell, AC Torske, KR TI Primary failure of tooth eruption - A unique case SO ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY AND ENDODONTICS LA English DT Article ID RETINAL-PIGMENT EPITHELIUM; CLEIDOCRANIAL DYSPLASIA; DENTAL FOLLICLE; MODALITY; TEETH AB Primary failure of tooth eruption rarely occurs. This case represents a rare clinical situation and appears to reflect a generalized disturbance in the eruptive process, inasmuch as (1) deciduous and permanent dentition are affected, (2) incisors, molars, and premolars are involved in all quadrants, (3) skeletal and craniofacial growth are within normal limits, and (4) no systemic/genetic anomalies were detected. This is the first such case reported in the literature; diagnosis and management are discussed. C1 NIDR, Clin Res Ctr, Clin Res Core, NIH, Bethesda, MD 20892 USA. Natl Naval Dent Ctr, Naval Dent Sch, Bethesda, MD USA. RP O'Connell, AC (reprint author), NIDR, Clin Res Ctr, Clin Res Core, NIH, Bldg 10,Rm 1N113, Bethesda, MD 20892 USA. OI O'Connell, Anne C/0000-0002-1495-3983 NR 26 TC 8 Z9 10 U1 0 U2 1 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 1079-2104 J9 ORAL SURG ORAL MED O JI Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. PD JUN PY 1999 VL 87 IS 6 BP 714 EP 720 DI 10.1016/S1079-2104(99)70167-8 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 206RJ UT WOS:000080892800021 PM 10397664 ER PT J AU Rimer, BK Conaway, M Lyna, P Glassman, B Yarnall, KSH Lipkus, I Barber, LT AF Rimer, BK Conaway, M Lyna, P Glassman, B Yarnall, KSH Lipkus, I Barber, LT TI The impact of tailored interventions on a community health center population SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE cancer screening; tailored interventions ID CANCER SCREENING PRACTICES; VIETNAMESE-AMERICAN WOMEN; CERVICAL-CANCER; PRIMARY-CARE; PROMOTE MAMMOGRAPHY; PATIENT REMINDERS; OLDER WOMEN; BREAST; METAANALYSIS; PHYSICIAN AB We conducted a 4-year randomized study in a community health center that serves primarily low income Blacks in Durham, North Carolina. Patients (1318 at baseline) were assigned randomly to one of three study groups: provider prompting intervention alone, provider prompting and tailored print materials or the previous group and tailored telephone counseling. The purpose of the study was to determine whether increasingly intensive, tailored print and telephone interventions also were increasingly effective in promoting adherence to mammograms, Pap tests and overall cancer screening compliance. Thus, the combination of tailored print interventions (print and telephone) should have bean more effective than the provider prompting intervention alone, or the print intervention and prompting combination. This is one of the few studies to examine a measure of overall cancer screening compliance and to assess the benefit of combinations of tailored interventions in promoting adherence to cancer screening. Patients gave extremely high ratings to the interventions. At the bivariate level, we found a significant effect of the most intensive group (provider prompting intervention, tailored print communications and tailored telephone counseling) on Pap test compliance (P = 0.05) and borderline significance at the multivariate level (P = 0.06) as well on overall screening compliance (P = 0.06). There was not a significant effect on mammography, probably because a majority of the patients were receiving regular mammograms. We also found some important subgroup differences. For example, a larger proportion of women reported Pap tests in the tailored print and counseling group when they believed the materials were 'meant for me.' These results show that a combination of tailored interventions may have potential for reaching the women who have too often been labeled the 'hard to reach.' (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 NCI, Bethesda, MD 20892 USA. Univ Virginia, Hlth Sci Ctr, Sch Med, Dept Environm Hlth Sci, Charlottesville, VA 22908 USA. Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. NCI, NIH, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Dept Psychiat, Durham, NC 27710 USA. Lincoln Community Hlth Ctr, Durham, NC 27707 USA. RP Rimer, BK (reprint author), NCI, 6130 Execut Blvd,Room 242, Bethesda, MD 20892 USA. FU NCI NIH HHS [5RO1CA 59734-04] NR 69 TC 82 Z9 83 U1 1 U2 6 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD JUN PY 1999 VL 37 IS 2 BP 125 EP 140 DI 10.1016/S0738-3991(98)00122-0 PG 16 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 212VL UT WOS:000081238300004 PM 14528540 ER PT J AU Schmidt, LA Fox, NA Sternberg, EM Gold, PW Smith, CC Schulkin, J AF Schmidt, LA Fox, NA Sternberg, EM Gold, PW Smith, CC Schulkin, J TI Adrenocortical reactivity and social competence in seven year-olds SO PERSONALITY AND INDIVIDUAL DIFFERENCES LA English DT Article; Proceedings Paper CT National-Institute-of-Mental-Health Conference for Advancing Research on Developmental Plasticity CY MAY 12-15, 1996 CL CHANTILLY, VIRGINIA SP NIMH DE social competence; self-presentation; salivary cortisol; children ID BIOCHEMICAL MANIFESTATIONS; BEHAVIORAL-INHIBITION; STRESS; NEUROBIOLOGY; ACTIVATION; DEPRESSION; ATTACHMENT; CHILDREN AB We examined temporal changes in salivary cortisol in response to a peer self-presentation task in a group of seven year-olds, some of whom scored high, average, and low on the Harter (1983) Perceived Social Competence Scale, Salivary cortisol was measured pre-task, and 20 and 35 min post-task. We found a significant relation between individual differences in perceived social competence and salivary cortisol reactivity in response to the task. Children who perceived themselves as socially competent exhibited a significantly greater decrease in salivary cortisol from 20 to 35 min following the task compared with children who self-reported a relatively lower degree of social competence. We speculate on the meaning of salivary cortisol changes in children's socio-emotional development. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 McMaster Univ, Dept Psychol, Hamilton, ON L8S 4K1, Canada. Univ Maryland, Inst Child Study, College Pk, MD 20742 USA. NIMH, Clin Neuroendocrinol Branch, Neuroendocrine Immunol & Behav Unit, Bethesda, MD 20892 USA. NIMH, Clin Neuroendocrinol Branch, Neurosci Behav Unit, Bethesda, MD 20892 USA. RP Schmidt, LA (reprint author), McMaster Univ, Dept Psychol, Hamilton, ON L8S 4K1, Canada. NR 16 TC 29 Z9 30 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0191-8869 J9 PERS INDIV DIFFER JI Pers. Individ. Differ. PD JUN PY 1999 VL 26 IS 6 BP 977 EP 985 PG 9 WC Psychology, Social SC Psychology GA 192YF UT WOS:000080106800001 ER PT J AU Long, RM AF Long, RM TI Learning the system: Changes pending in peer review and around the NIH SO PHARMACEUTICAL RESEARCH LA English DT News Item C1 NIGMS, Pharmacol & Physiol Sci Branch, Pharmacol Physiol & Biol Chem Div, NIH, Bethesda, MD USA. RP Long, RM (reprint author), NIGMS, Pharmacol & Physiol Sci Branch, Pharmacol Physiol & Biol Chem Div, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 J9 PHARMACEUT RES JI Pharm. Res. PD JUN PY 1999 VL 16 IS 6 BP 783 EP 784 PG 2 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 208KD UT WOS:000080989200001 PM 10397594 ER PT J AU Chen, GF Tang, YM Green, B Lin, DX Guengerich, FP Daly, AK Caporaso, NE Kadlubar, FF AF Chen, GF Tang, YM Green, B Lin, DX Guengerich, FP Daly, AK Caporaso, NE Kadlubar, FF TI Low frequency of CYP2A6 gene polymorphism as revealed by a one-step polymerase chain reaction method SO PHARMACOGENETICS LA English DT Article DE genetic polymorphism; restriction fragment length polymorphism; DNA sequencing; cytochrome P450 ID HUMAN LIVER-MICROSOMES; CYTOCHROME-P450 2A6 CYP2A6; COUMARIN 7-HYDROXYLATION; 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE; IDENTIFICATION; ACTIVATION; ENZYMES AB Human cytochrome P450 2A6 (CYP2A6) has been shown to metabolically activate carcinogens and mutagens, Genetic polymorphisms for CYP2A6 have been reported previously in different ethnic groups using a two-step polymerase chain reaction (PCR) method to identify CYP2A6*1, CYP2A6*2 and CYP2A6*3. Moreover, a new truncated allele has been recently identified in a Japanese population. We report here a one-step PCR amplification of the CYP2A6 gene from human genomic DNA and the detection of intact CYP2A6 alleles by restriction enzyme digestion. The diagnostic exon (exon 3) of the CYP2A6 gene was amplified from human genomic DNA with a primer pair. The forward primer is unique to the CYP2A6 gene, which eliminates previous problems in amplifying two highly homologous CYP2A genes, CYP2A7 and CYP2A13, in humans. The resulting PCR products (214 bp) were digested with XcmI or DdeI to detect the presence of CYP2A6*2 or CYP2A6*3 alleles, respectively. The allelic frequencies for CYP2A6*2 were 2.3% (n = 320) in the Caucasian and 0.7% (n = 71) in the Chinese populations, respectively, CYP2A6*3 allelic frequency in the Chinese population was 0.7%; while no CYP2A6*3 allele was detected in the Caucasian population, The allelic frequencies are relatively low and the reason for this discrepancy between different methods is discussed. Pharmacogenetics 9:327-332 (C) 1999 Lippincott Williams & Wilkins. C1 Natl Ctr Toxicol Res, Div Mol Epidemiol, Jefferson, AR 72079 USA. Chinese Acad Med Sci, Inst Canc, Dept Chem Etiol & Carcinogenesis, Beijing 100021, Peoples R China. Beijing Union Med Coll, Beijing, Peoples R China. Vanderbilt Univ, Ctr Mol Toxicol, Dept Biochem, Nashville, TN USA. Univ Newcastle Upon Tyne, Sch Med, Dept Pharmacol Sci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. Natl Canc Inst, Genet Epidemiol Branch, Bethesda, MD USA. RP Kadlubar, FF (reprint author), Natl Ctr Toxicol Res, Div Mol Epidemiol, 3900 NCTR Dr Jefferson, Jefferson, AR 72079 USA. RI Daly, Ann/H-3144-2011 OI Daly, Ann/0000-0002-7321-0629 NR 17 TC 42 Z9 46 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0960-314X J9 PHARMACOGENETICS JI Pharmacogenetics PD JUN PY 1999 VL 9 IS 3 BP 327 EP 332 DI 10.1097/00008571-199906000-00007 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 222AU UT WOS:000081760700007 PM 10471064 ER PT J AU Katoh, T Inatomi, H Yang, MH Kawamoto, T Matsumoto, T Bell, DA AF Katoh, T Inatomi, H Yang, MH Kawamoto, T Matsumoto, T Bell, DA TI Arylamine N-acetyltransferase 1 (NAT1) and 2 (NAT2) genes and risk of urothelial transitional cell carcinoma among Japanese SO PHARMACOGENETICS LA English DT Article DE N-acetyltransferase 1; N-acetyltransferase 2; polymorphism; urothelial cancer ID BLADDER-CANCER; N-ACETYLTRANSFERASE-1 NAT1; POLYMORPHISMS; ACETYLATION; ASSOCIATION; EXPRESSION; EXPOSURE; SMOKING; ALLELE C1 Univ Occupat & Environm Hlth, Sch Hlth Sci, Dept Hlth Informat Sci, Kitakyushu, Fukuoka 807, Japan. Univ Occupat & Environm Hlth, Sch Med, Dept Environm Hlth, Kitakyushu, Fukuoka 807, Japan. Natl Inst Environm Hlth Sci, Lab Computat Biol & Risk Assessment, Res Triangle Pk, NC USA. RP Katoh, T (reprint author), Univ Occupat & Environm Hlth, Sch Hlth Sci, Dept Hlth Informat Sci, Kitakyushu, Fukuoka 807, Japan. NR 17 TC 26 Z9 27 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0960-314X J9 PHARMACOGENETICS JI Pharmacogenetics PD JUN PY 1999 VL 9 IS 3 BP 401 EP 404 DI 10.1097/00008571-199906000-00017 PG 4 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 222AU UT WOS:000081760700017 PM 10471074 ER PT J AU Szallasi, A Blumberg, PM AF Szallasi, A Blumberg, PM TI Vanilloid (capsaicin) receptors and mechanisms SO PHARMACOLOGICAL REVIEWS LA English DT Review ID DORSAL-ROOT GANGLION; PRIMARY SENSORY NEURONS; NERVE GROWTH-FACTOR; H-3 RESINIFERATOXIN BINDING; GENE-RELATED PEPTIDE; PROTEIN-KINASE-C; SPINOTHALAMIC TRACT NEURONS; RAT SPINAL-CORD; PRIMARY AFFERENT NEURONS; INDUCED SECONDARY HYPERALGESIA C1 NCI, Mol Mechanisms Tumor Promot Sect, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD USA. RP Szallasi, A (reprint author), St Louis Univ, Dept Pathol, 1402 S Grand Blvd, St Louis, MO 63104 USA. EM arpads@thalamus.wustl.edu NR 604 TC 1282 Z9 1325 U1 10 U2 52 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0031-6997 EI 1521-0081 J9 PHARMACOL REV JI Pharmacol. Rev. PD JUN PY 1999 VL 51 IS 2 BP 159 EP 211 PG 53 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 204GN UT WOS:000080755900002 PM 10353985 ER PT J AU Toscano, JP Nikolaitchik, AV Yourd, E Keefer, LK AF Toscano, JP Nikolaitchik, AV Yourd, E Keefer, LK TI Time-resolved IR studies of potential nitric oxide-releasing agents. SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Meeting Abstract C1 Johns Hopkins Univ, Dept Chem, Baltimore, MD 21218 USA. NCI, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 1999 VL 69 SI SI BP 13S EP 14S PG 2 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 220KB UT WOS:000081663200041 ER PT J AU Khan, SG Schneider, TD Kraemer, KH AF Khan, SG Schneider, TD Kraemer, KH TI Splice mutations in xeroderma pigmentosum group C cells SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 1999 VL 69 SI SI BP 31S EP 31S PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 220KB UT WOS:000081663200089 ER PT J AU Emmert, S Kobayashi, N Khan, SG Kraemer, KH AF Emmert, S Kobayashi, N Khan, SG Kraemer, KH TI The xeroderma pigmentosum group C gene induces preferential repair of cyclobutane pyrimidine dimers. SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 1999 VL 69 SI SI BP 41S EP 41S PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 220KB UT WOS:000081663200123 ER PT J AU Reszka, KJ Ortwerth, BJ Chignell, CF Dillon, J AF Reszka, KJ Ortwerth, BJ Chignell, CF Dillon, J TI Photoreactivity of human lens proteins: EPR and spin trapping investigations. SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Meeting Abstract C1 Columbia Univ, Dept Ophthalmol, New York, NY 10032 USA. Univ Missouri, Mason Inst Visual Sci, Columbia, MO 65212 USA. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 1999 VL 69 SI SI BP 42S EP 42S PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 220KB UT WOS:000081663200125 ER PT J AU Roberts, JE Wang, RH Tan, IP Datillo, M Chignell, CF AF Roberts, JE Wang, RH Tan, IP Datillo, M Chignell, CF TI Hypericin (active ingredient in St. John's Wort) photooxidation of lens proteins. SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Meeting Abstract C1 Fordham Univ, New York, NY 10023 USA. NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 1999 VL 69 SI SI BP 42S EP 42S PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 220KB UT WOS:000081663200126 ER PT J AU Fornace, AJ AF Fornace, AJ TI Regulation of UV-responsive genes by p53-dependent and independent signalling mechanisms. SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Meeting Abstract ID TUMOR-SUPPRESSOR P53; INDUCTION; GADD45; APOPTOSIS; BAX C1 NCI, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NR 11 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 1999 VL 69 SI SI BP 44S EP 44S PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 220KB UT WOS:000081663200131 ER PT J AU Subramaniam, S Henderson, R AF Subramaniam, S Henderson, R TI Structural basis of proton transport by bacteriorhodopsin SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Meeting Abstract C1 MRC, Mol Biol Lab, Cambridge, England. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 JUN PY 1999 VL 69 SI SI BP 46S EP 46S PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 220KB UT WOS:000081663200135 ER PT J AU Miyoshi, N Takeshita, T Misik, V Riesz, P AF Miyoshi, N Takeshita, T Misik, V Riesz, P TI Monomerization of photosensitizers by ultrasound irradiation in surfactant micellar solutions. SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Meeting Abstract C1 Fukui Med Univ, Fac Med, Dept Pathol, Matsuoka, Fukui 9101193, Japan. Hamamtsu Photon KK, Syst Div, Hamamatsu, Shizuoka 43131, Japan. NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 1999 VL 69 SI SI BP 83S EP 84S PG 2 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 220KB UT WOS:000081663200251 ER PT J AU Sandvik, SL Bilski, P Martinez, LJ Sik, RH Chignell, CF AF Sandvik, SL Bilski, P Martinez, LJ Sik, RH Chignell, CF TI Photophysics of fluorinated quinolones. SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Meeting Abstract C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 2 Z9 2 U1 0 U2 1 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 JUN PY 1999 VL 69 SI SI BP 83S EP 83S PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 220KB UT WOS:000081663200249 ER PT J AU Bilski, P Li, M Chignell, CF AF Bilski, P Li, M Chignell, CF TI Antioxidant properties and phototoxicity of herbal components and extracts: Determination by singlet oxygen phosphorescence. SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Meeting Abstract C1 NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 1999 VL 69 SI SI BP 84S EP 84S PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 220KB UT WOS:000081663200253 ER PT J AU Hawkins, ME Moser, AM Patel, M Balis, FM AF Hawkins, ME Moser, AM Patel, M Balis, FM TI Use of 3-methyl isoxanthopterin (3-MI) a fluorescent guanosine analog, in a coupled, single step real time assay for O-6-alkyl transferase (AT). SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Meeting Abstract C1 NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. Childrens Canc Ctr, San Antonio, TX 78229 USA. RI MOSER, ASHER/F-1873-2012 NR 0 TC 0 Z9 0 U1 1 U2 2 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 JUN PY 1999 VL 69 SI SI BP 85S EP 86S PG 2 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 220KB UT WOS:000081663200257 ER PT J AU Kukielczak, B Sik, RH Chignell, CF AF Kukielczak, B Sik, RH Chignell, CF TI Effect of magnetite particles on merocyanine 540 (MC540) phototoxicity in human erythrocytes and L1210 cells. SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Meeting Abstract C1 NIEHS, LPC, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 1999 VL 69 SI SI BP 86S EP 86S PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 220KB UT WOS:000081663200258 ER PT J AU Haoudi, A Cannon, RE Mason, JM AF Haoudi, A Cannon, RE Mason, JM TI The transposition of the human LINE-1 is enhanced in UV-induced skin cancer cell lines. SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Meeting Abstract C1 NIEHS, Genet Mol Lab, Lab Environm Carcinogenesis & Mutagenesis, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 1999 VL 69 SI SI BP 87S EP 88S PG 2 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 220KB UT WOS:000081663200264 ER PT J AU Ehrenshaft, M Daub, ME Jenns, AE Chung, KR Bilski, P Li, M Chignell, CF AF Ehrenshaft, M Daub, ME Jenns, AE Chung, KR Bilski, P Li, M Chignell, CF TI The singlet oxygen resistance gene SOR1 and vitamin B6; An unexpected connection SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Meeting Abstract C1 N Carolina State Univ, Dept Plant Pathol, Raleigh, NC 27695 USA. N Carolina State Univ, Dept Chem, Raleigh, NC 27695 USA. NIEHS, Lab Pharmocol & Chem, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 JUN PY 1999 VL 69 SI SI BP 95S EP 95S PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 220KB UT WOS:000081663200289 ER PT J AU Bilski, P McDevitt, T Chignell, CF AF Bilski, P McDevitt, T Chignell, CF TI Merocyanine 540 solubilized as an ion pair with cationic surfactant in nonpolar solvents: Spectral and photochemical properties SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID SINGLET OXYGEN PRODUCTION; ABSORPTION-SPECTRA; MOLECULAR-OXYGEN; OPTICAL PROBES; QUANTUM YIELDS; ROSE-BENGAL; MEMBRANE; PHOTOSENSITIZATION; LIPOSOMES; PHOTOISOMERIZATION AB Merocyanine 540 (MC) is an anionic dye that is used to photopurge the bone marrow of leukemia cells. Under these conditions it is localized mostly in cell membranes, which may affect its photochemical reactivity, We investigated the photochemistry of MC dissolved as a hydrophobic ion pair with a hexadecyltrioctadecylammonium cation in cyclohexane, trimethylpentane and toluene as well as in propylene carbonate, CH3CN, C2H5OH and D2O, In organic solvents, the absorption and fluorescence spectra of MC were strongly red-shifted compared with aqueous solutions. The fluorescence was also more intense despite aggregation that occurred in some solvents. Aggregation strongly affects the spectral and photochemical properties of MC, especially in aliphatic hydrocarbons in which distinctive H-type aggregates are formed. Hydrophobic MC is a moderate photosensitizer of singlet molecular oxygen (O-1(2)), The following values for O-1(2) quantum yields were calculated based on O-1(2) phosphorescence relative to O-1(2) generation by Rose Bengal: similar to 0.12 in trimethylpenthane, similar to 0.13 in cyclohexane, 0.045 in EtOH, 0.039 in toluene, 0.007 in CH2CN and similar to 3 x 10(-4) in D2O, The H-aggregates of MC in cyclohexane and trimethylpentane are better O-1(2) producers than monomeric MC. The above O-1(2) quantum yields are corrected for self-quenching because MC is an efficient O-1(2) quencher (17 x 10(7) M-1 s(-1) in CH2CN, 6.8 x 10(7) M-1 s(-1) in D2O, 5.2 x 10(7) M-1 s(-1) in EtOH, and 1.4 x 10(7) M-1 s(-1) in toluene), Merocyanine undergoes photodegradation, a solvent-dependent process that proceeds faster when the dye is aggregated. The initial photodegradation rate is much slower in organic solvents than in water, but photodegradation products accumulated during longer irradiation may increase the rate in most solvents. Higher photostability and better photosensitization by MC in hydrophobic nonpolar solvents suggest that the killing of leukemia cells via a photodynamic mechanism may operate mostly in cell membranes. In contrast, any cytotoxic products from photodecomposition may be important in hydrophilic cell compartments. Our data show the spectral and photochemical properties of MC in a pure hydrophobic environment. C1 NIEHS, Environm Toxicol Program, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Bilski, P (reprint author), NIEHS, Environm Toxicol Program, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 32 TC 15 Z9 16 U1 0 U2 5 PU AMER SOC PHOTOBIOLOGY PI AUGUSTA PA BIOTECH PARK, 1021 15TH ST, SUITE 9, AUGUSTA, GA 30901-3158 USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD JUN PY 1999 VL 69 IS 6 BP 671 EP 676 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 207XK UT WOS:000080960900008 PM 10378005 ER PT J AU Knutson, B Burgdorf, J Panksepp, J AF Knutson, B Burgdorf, J Panksepp, J TI High-frequency ultrasonic vocalizations index conditioned pharmacological reward in rats SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE reward; vocalization; rat; amphetamine; morphine ID PLACE; AMPHETAMINE; VALIDATION; WITHDRAWAL; RECEPTORS AB We have proposed that short (<0.5 s), high-frequency (similar to 50 kHz) ultrasonic vocalizations ("50-kHz USVs") index a positive affective state in adult rats, because they occur prior to rewarding social interactions (i.e., rough-and-tumble play, sex). To evaluate this hypothesis in the case of nonsocial stimuli, we examined whether rats would make increased 50-kHz USVs in places associated with the administration of rewarding pharmacological compounds [i.e, amphetamine (AMPH) and morphine (MORPH)]. In Experiment 1, rats made a greater percentage of 50-kHz USVs on the AMPH-paired side of a two-compartment chamber than on the vehicle-paired side, even after statistical correction for place preference. In Experiment 2, rats made a higher percentage of 50-kHz USVs on the MORPH-paired side than on the vehicle-paired side, despite nonsignificant place preference. These findings support the hypothesis that 50-kHz USVs mark a positive affective state in rats and introduce a novel and rapid marker of pharmacological reward. (C) 1999 Elsevier Science Inc. C1 NIAAA, Clin Studies Lab, Bethesda, MD 20892 USA. Bowling Green State Univ, Dept Psychol, Bowling Green, OH 43402 USA. RP Knutson, B (reprint author), NIAAA, Clin Studies Lab, Mail Stop 1610,Bldg 10,Rm 6S240, Bethesda, MD 20892 USA. EM knutson@odin.niaaa.nih.gov OI Knutson, Brian/0000-0002-7669-426X FU NICHD NIH HHS [HD30387]; NIMH NIH HHS [MH18931] NR 27 TC 119 Z9 123 U1 2 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD JUN PY 1999 VL 66 IS 4 BP 639 EP 643 DI 10.1016/S0031-9384(98)00337-0 PG 5 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 203AN UT WOS:000080685000013 PM 10386908 ER PT J AU Prevost, M Kocher, JP AF Prevost, M Kocher, JP TI Structural characterization by computer experiments of the lipid-free LDL-receptor-binding domain of apolipoprotein E SO PROTEIN ENGINEERING LA English DT Article DE apoE-RBD; LDL-receptor binding domain; four-helix bundle; Molecular Dynamics; protein packing ID CAVITY FORMATION; CYTOCHROME-C; LIQUID WATER; SECONDARY STRUCTURE; MOLECULAR-DYNAMICS; FREE-ENERGY; PROTEIN; SIMULATIONS; INTERMEDIATE; RECOGNITION AB The structure and dynamics of the lipid-free LDL-receptor-binding domain of apolipoprotein E (apoE-RBD) has been investigated by Molecular Dynamics Simulations. ApoE-RBD in its monomeric lipid-free form is a singular four-helix bundle made up of four elongated amphipathic helices. Analysis of one 1.5 ns molecular dynamics trajectory of apoE-RBD performed in water indicates that the lipid-free domain adopts a structure that exhibits characteristics found in native proteins: it has very stable helices and presents a compact structure. Yet its interior exhibits a larger number of transient atomic-size cavities relative to that found in other proteins of similar size and its apolar side chains are more mobile. The latter features distinguish the elongated four-helix bundle as a slightly disordered structure, which shows a structural likeness with some de novo designed four-helix bundle proteins and shares with the latter a leucine-rich residue composition. We anticipate that these unique properties compared with other native helix bundles may be related to the postulated ability of apoE-RBD to undergo an opening of its bundle upon interaction with phospholipids. The distribution of empty cavities computed along the trajectory in the interface regions between the different pairs of helices reveals that the tertiary contacts in one of the interfaces are weaker suggesting that this particular interface could be more easily ruptured upon lipid association. C1 Free Univ Brussels, B-1050 Brussels, Belgium. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Prevost, M (reprint author), Free Univ Brussels, CP 165-64,Av F Roosevelt, B-1050 Brussels, Belgium. NR 33 TC 3 Z9 3 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0269-2139 J9 PROTEIN ENG JI Protein Eng. PD JUN PY 1999 VL 12 IS 6 BP 475 EP 483 DI 10.1093/protein/12.6.475 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 220GX UT WOS:000081657500007 PM 10388844 ER PT J AU Tcherkasskaya, O Ptitsyn, OB AF Tcherkasskaya, O Ptitsyn, OB TI Direct energy transfer to study the 3D structure of non-native proteins: AGH complex in molten globule state of apomyoglobin SO PROTEIN ENGINEERING LA English DT Article DE apomyoglobin; direct energy transfer; fluorescence; molten globule ID HORSE HEART METMYOGLOBIN; TRYPTOPHANYL FLUORESCENCE; 3-DIMENSIONAL STRUCTURE; ALPHA-LACTALBUMIN; CYTOCHROME-C; EXCHANGE; NMR; RESOLUTION AB The direct energy transfer technique was modified and applied to probe the relative localization of apomyoglobin A-, G- and H-helixes, which are partly protected from deuterium exchange in the equilibrium molten globule state and in the molten globule-like kinetic intermediate. The non-radiative transfer of tryptophan electronic energy to 3-nitrotyrosine was studied in different conformational states of apomyoglobin (native, molten globule, unfolded) and interpreted in terms of average distances between groups of the protein chain. The experimental data show that the distance between the middle of A-helix and the N-terminus of G-helix as well as the distance between the middle of the A-helix and the C-terminus of the H-helix in the molten globule state are close to those in the native state. This is a strong argument in favor of similarity of the overall architecture of the molten globule and native states. C1 NCI, Lab Expt & Computat Biol, NIH, Bethesda, MD 20892 USA. Russian Acad Sci, Inst Macromol Cpds, St Petersburg 199004, Russia. Russian Acad Sci, Inst Prot Res, Pushchino 142292, Moscow Region, Russia. RP Tcherkasskaya, O (reprint author), NCI, Lab Expt & Computat Biol, NIH, Bethesda, MD 20892 USA. NR 35 TC 18 Z9 19 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0269-2139 J9 PROTEIN ENG JI Protein Eng. PD JUN PY 1999 VL 12 IS 6 BP 485 EP 490 DI 10.1093/protein/12.6.485 PG 6 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 220GX UT WOS:000081657500008 PM 10388845 ER PT J AU Frankel, AE Ramage, J Latimer, A Feely, T Delatte, S Hall, P Tagge, E Kreitman, R Willingham, M AF Frankel, AE Ramage, J Latimer, A Feely, T Delatte, S Hall, P Tagge, E Kreitman, R Willingham, M TI High-level expression and purification of the recombinant diphtheria fusion toxin DTGM for PHASE I clinical trials SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article ID COLONY-STIMULATING FACTOR; ACUTE MYELOID-LEUKEMIA; BINDING DOMAIN SUBSTITUTION; RICIN-A-CHAIN; GENETIC CONSTRUCTION; DIFFERENTIATION ANTIGEN; PSEUDOMONAS EXOTOXIN; ESCHERICHIA-COLI; FACTOR-RECEPTOR; SINGLE-CHAIN AB A genetically engineered fusion toxin targeted-to acute myeloid leukemic (AML) blasts was designed with the first 388 amino acid residues of diphtheria toxin with an H-M linker fused to human granulocyte-macrophage colony-stimulating factor. The cDNA was subcloned in the pRK bacterial expression plasmid and used to transform BL21 (DE3) Escherichia coli harboring pUBS500 plasmid. Transformants were grown in Superbroth and induced with IPTG. Inclusion bodies were isolated, washed, and denatured in guanidine hydrochloride with dithioerythritol. Recombinant protein was refolded by diluting 100-fold in cold buffer with arginine and oxidized glutathione. After dialysis, purified protein was obtained after anion-exchange, size exclusion on FPLC, and polymixin B affinity chromatography. The final material was filter sterilized, aseptically vialed, and stored at -80 degrees C. Fifty-four 3-liter bacterial culture preparations were made and pooled into 27 batches. The final product was characterized by Coomassie Plus protein assay, Coomassie-stained SDS-PAGE, limulus amebocyte lysate endotoxin assay,human AML HL60 cell cytotoxicity assay, HPLC TSR3000, N-terminal sequencing, E. coli DNA contamination, C57BL6 mouse toxicity, and immunohistochemistry. Yields were 23 mg/liter bacterial culture of denatured fusion toxin. After refolding and chromatography, final yields were 24 +/- 4% or 5 mg/liter. Vialed product was sterile and 1.7 +/- 0.4 mg/ml in PBS. Purity by SDS-PAGE was 99 +/- 1%. Aggregates by HPLC were <1%. Potency revealed a 24-h IC50 of 2.7 +/- 0.5 pM on HL60 cells. Endotoxin levels were 1 eu/mg. The N-terminal sequence was confirmed, and E. coli DNA was <113 pg/mg. The LD10 in mice was 110 mu g/kg/day x 5. There was no evidence of loss of solubility, proteolysis, aggregation, or loss of potency over 3 months at -80 and -20 degrees C. Further, the drug was stable at 4, 25, and 37 degrees C in human serum for 48 h. Drug reacted only with human monocytes, granulocytes, and myeloid precursors in frozen human tissue sections by immunohistochemistry. The synthesis of this protein drug should be useful for production for clinical phase I/II clinical trials and may be suitable for other diphtheria fusion toxins indicated for clinical development. This is the! first report of the scaleup of a recombinant fusion toxin for clinical trials. (C) 1999 Academic Press. C1 Wake Forest Univ, Sch Med, Dept Canc Biol, Winston Salem, NC 27157 USA. Wake Forest Univ, Sch Med, Dept Pathol, Winston Salem, NC 27157 USA. Med Univ S Carolina, Dept Surg, Charleston, SC 29425 USA. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Med Univ S Carolina, Dept Pharm, Charleston, SC 29425 USA. RP Frankel, AE (reprint author), Wake Forest Univ, Sch Med, Dept Canc Biol, Hanes 4046,Med Ctr Blvd, Winston Salem, NC 27157 USA. FU NHLBI NIH HHS [NIHR0176738] NR 39 TC 31 Z9 33 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD JUN PY 1999 VL 16 IS 1 BP 190 EP 201 DI 10.1006/prep.1999.1071 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 200VT UT WOS:000080561300024 PM 10336877 ER PT J AU Tsai, CJ Kumar, S Ma, BY Nussinov, R AF Tsai, CJ Kumar, S Ma, BY Nussinov, R TI Folding funnels, binding funnels, and protein function SO PROTEIN SCIENCE LA English DT Review DE binding funnels; conformational ensembles; energy landscape; folding funnels; function; misfolding ID ENERGY LANDSCAPES; KINETICS; INTERFACES; DOMAIN; RECOGNITION; MECHANISM; EVOLUTION; DOCKING; MODEL; COMPLEMENTATION AB Folding funnels have been the focus of considerable attention during the last few years. These have mostly been discussed in the general context of the theory of protein folding. Here we extend the utility of the concept of folding funnels, relating them to biological mechanisms and function. In particular, here we describe the shape of the funnels in light of protein synthesis and folding; flexibility, conformational diversity, and binding mechanisms; and the associated binding funnels, illustrating the multiple routes and the range of complexed conformers. Specifically, the walls of the folding funnels, their crevices, and bumps are related to the complexity of protein folding, and hence to sequential vs, nonsequential folding. Whereas the former is more frequently observed in eukaryotic proteins, where the rate of protein synthesis is slower, the latter is more frequent in prokaryotes, with faster translation rates. The bottoms of the funnels reflect the extent of the flexibility of the proteins. Rugged floors imply a range of conformational isomers, which may be close on the energy landscape. Rather than undergoing an induced fit binding mechanism, the conformational ensembles around the rugged bottoms argue that the conformers, which are most complementary to the ligand, will bind to it with the equilibrium shifting in their favor. Furthermore, depending on the extent of the ruggedness, or of the smoothness with only a few minima, we may infer nonspecific, broad range vs. specific binding. In particular, folding and binding are similar processes, with similar underlying principles. Hence, the shape of the folding funnel of the monomer enables making reasonable guesses regarding the shape of the corresponding binding funnel. Proteins having a broad range of binding, such as proteolytic enzymes or relatively nonspecific endonucleases, may be expected to have not only rugged floors in their folding funnels, but their binding funnels will also behave similarly, with a range of complexed conformations. Hence, knowledge of the shape of the folding funnels is biologically very useful. The converse also holds: If kinetic and thermodynamic data are available, hints regarding the role of the protein and its binding selectivity may be obtained. Thus, the utility of the concept of the funnel carries over to the origin of the protein and to its function. C1 NCI, Lab Expt & Comp Biol, SAIC, Intramural Res Support Program, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Fac Med, Sackler Inst Mol med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Lab Expt & Comp Biol, SAIC, Intramural Res Support Program, Bldg 469,Room 151, Frederick, MD 21702 USA. RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU NCI NIH HHS [N01-CO-56000] NR 66 TC 420 Z9 425 U1 4 U2 52 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD JUN PY 1999 VL 8 IS 6 BP 1181 EP 1190 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 203KE UT WOS:000080706200003 PM 10386868 ER PT J AU Enoch, MA Goldman, D AF Enoch, MA Goldman, D TI Genetics of alcoholism and substance abuse SO PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Article ID MICE LACKING; DRUG-ABUSE; DEPENDENCE; DOPAMINE; COCAINE; GENES; ASSOCIATION; INHERITANCE; DISORDERS; RECEPTORS AB Twin studies have demonstrated that addictive disorders are genetically and environmentally influenced. Our knowledge of behavioral differences predisposing to addiction is advancing rapidly, particularly in alcoholism but also in the other addictions, through studies on animals and humans. Recently, linkage analyses in humans and rodents have pointed to genomic regions harboring genes which influence addiction or drug-associated behaviors. There is increasing evidence that the addictions have common as well as distinct neurobiological pathways. These advances in the understanding of the genetics of addictive disorders should facilitate the development of specific pharmacotherapies and the more accurate targeting of therapies using molecular diagnostic approaches. C1 NIAAA, NIH, DICBR, Neurogenet Lab LNG, Bethesda, MD 20892 USA. RP Enoch, MA (reprint author), NIAAA, NIH, DICBR, Neurogenet Lab LNG, 12420 Parklawn Dr,Pk 5 Bldg,Room 451,MSC 8110, Bethesda, MD 20892 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 34 TC 46 Z9 46 U1 4 U2 6 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0193-953X J9 PSYCHIAT CLIN N AM JI Psychiatr. Clin. North Amer. PD JUN PY 1999 VL 22 IS 2 BP 289 EP + DI 10.1016/S0193-953X(05)70077-0 PG 12 WC Psychiatry SC Psychiatry GA 205VV UT WOS:000080842000006 PM 10385934 ER PT J AU Wise, RA AF Wise, RA TI Cognitive factors in addiction and nucleus accumbens function: Some hints from rodent models SO PSYCHOBIOLOGY LA English DT Review ID BRAIN-STIMULATION REWARD; VENTRAL TEGMENTAL AREA; FREELY MOVING RATS; SELF-ADMINISTRATION BEHAVIOR; OPPONENT-PROCESS THEORY; FOOD-DEPRIVED RATS; DOPAMINE NEURONS; INTRAVENOUS COCAINE; 6-HYDROXYDOPAMINE LESIONS; MONKEY MIDBRAIN AB Elevation of extracellular dopamine levels in the nucleus accumbens is important for both the initiation and the maintenance of cocaine and heroin seeking in animal models. Nucleus accumbens neurons fire in response to both the receipt and the expectancy of reward. The learning of drug self-administration habits depends critically on the ability of the animal to learn associations between rewards and their environmental predictors, and such learning does not occur in accumbens-compromised animals. Reward-associated stimuli are also critical for the initiation of drug taking following periods of abstinence in trained animals. Reward-associated stimuli are also important in maintaining continued responding for these drugs, although once extracellular dopamine levels have become elevated by initial drug intake, subsequent drug self-administration becomes increasingly dominated by pharmacological factors, at least in rodent models. Initially rewarding drug injections appear to lose their rewarding effectiveness when dopamine concentration in the nucleus accumbens is elevated above some satiating level. When dopamine is depleted or dopamine function is impaired, the probability of response initiation decreases; rats do not appear to self-medicate depression of the reward system as humans have been suggested to do. This presumed difference between the two species may reflect cognitive functions unique to humans, such as insight gained from the observation of others and response biases conferred through language and culture. Thus, although they inform us regarding some cognitive factors in addiction and nucleus accumbens function, our animal models may inform us minimally about cognitive factors that are of major significance in humans. C1 NIDA, Behav Neurosci Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Wise, RA (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Wise, Roy/A-6465-2012 NR 115 TC 16 Z9 16 U1 3 U2 8 PU PSYCHONOMIC SOC INC PI AUSTIN PA 1710 FORTVIEW RD, AUSTIN, TX 78704 USA SN 0889-6313 J9 PSYCHOBIOLOGY JI Psychobiology PD JUN PY 1999 VL 27 IS 2 BP 300 EP 310 PG 11 WC Psychology; Psychology, Multidisciplinary SC Psychology GA 219BQ UT WOS:000081588400015 ER PT J AU Maki, PM Zonderman, AB Weingartner, H AF Maki, PM Zonderman, AB Weingartner, H TI Age differences in implicit memory: Fragmented object identification and category exemplar generation SO PSYCHOLOGY AND AGING LA English DT Article ID FRONTAL-LOBE FUNCTIONS; EXPLICIT MEMORY; ALZHEIMERS-DISEASE; DIVIDED ATTENTION; HYPERACTIVE-CHILDREN; OLDER ADULTS; CUED-RECALL; TESTS; DISSOCIATION; YOUNG AB In a cross-sectional study of 164 participants aged 21 to 91, the authors examined age differences on two implicit tests, fragmented object identification (FOI) and category exemplar generation (CEG), and on tests of explicit memory, attention, and verbal fluency. FOI results revealed impaired perceptual skill learning in those over 60 and a decrease in perceptual priming across young, middle-aged, and older groups. CEG priming was impaired in those over 80. Regression analysis revealed explicit contamination of priming on both the FOI and CEG tests. Across the three implicit measures, age accounted for 4 to, 13% of the variance when explicit memory was controlled. Semantic fluency predicted CEG priming, suggesting possible frontal lobe involvement on the test. Altogether, results indicate that age has a small but reliable influence on implicit memory. C1 NIA, Gerontol Res Ctr, Lab Personal & Cognit, Baltimore, MD 21224 USA. NIAAA, Div Intramural Clin & Biol Res, Rockville, MD 20852 USA. RP Maki, PM (reprint author), NIA, Gerontol Res Ctr, Lab Personal & Cognit, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Zonderman, Alan B/0000-0002-6523-4778 NR 49 TC 35 Z9 35 U1 0 U2 1 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0882-7974 J9 PSYCHOL AGING JI Psychol. Aging PD JUN PY 1999 VL 14 IS 2 BP 284 EP 294 DI 10.1037/0882-7974.14.2.284 PG 11 WC Gerontology; Psychology, Developmental SC Geriatrics & Gerontology; Psychology GA 209KA UT WOS:000081045700009 PM 10403715 ER PT J AU Schenk, S Partridge, B Shippenberg, TS AF Schenk, S Partridge, B Shippenberg, TS TI U69593, a kappa-opioid agonist, decreases cocaine self-administration and decreases cocaine-produced drug-seeking SO PSYCHOPHARMACOLOGY LA English DT Article DE cocaine; self-administration; U69593; kappa-opioid; drug abuse; relapse ID FREELY MOVING RATS; RECEPTOR AGONISTS; DOPAMINE RELEASE; BEHAVIORAL SENSITIZATION; NUCLEUS-ACCUMBENS; RHESUS-MONKEYS; STIMULUS; MORPHINE; NEURONS; REINSTATEMENT AB Rationale: Previous research has shown that kappa-opioid receptor agonists decrease intravenous cocaine self-administration. These agents also block the development of sensitization that occurs following repeated exposure to cocaine, which is thought to be important in the maintenance and reinstatement of compulsive drug-seeking behavior. Objectives: This study was designed to determine the effects of the kappa-opioid receptor agonist, U69593, on the maintenance of cocaine self-administration and on the ability of a priming injection of cocaine to reinitiate drug-seeking. Methods: During daily test sessions, the dose-effect curve (0.015-1.0 mg/kg per infusion) was obtained by either repeatedly reducing the cocaine dose from a starting dose of 1.0 mg/kg per infusion or by repeatedly doubling the cocaine dose from a starting dose of 0.015 mg/kg per infusion. The effect of U69593 (0.0 or 0.32 mg/kg) on responding reinforced by different cocaine doses was determined. The effect of U69593 on the reinstatement of extinguished cocaine-taking behavior was measured in other groups. Results: U69593 decreased responding maintained by low doses of cocaine, regardless of whether cocaine doses were presented in an ascending or descending order. Responding maintained by high doses was unaffected. In animals which received pretreatment with U69593, the priming effects of cocaine were significantly attenuated. The effects of U69593 were specific, since amphetamine-induced cocaine-seeking was not altered by prior administration of U69593. Conclusions: These findings demonstrate that U69593 attenuates cocaine self-administration and the reinstatement of drug-taking behavior which occurs in response to experimenter-administered cocaine. It is suggested that U69593 may decrease low dose cocaine self-administration by decreasing the priming effects of cocaine. C1 Texas A&M Univ, Dept Psychol, College Stn, TX 77843 USA. NIDA, Integrat Neurosci Unit, Behav Neurosci Lab, Baltimore, MD 21224 USA. RP Schenk, S (reprint author), Texas A&M Univ, Dept Psychol, College Stn, TX 77843 USA. FU NIDA NIH HHS [DA 10084] NR 45 TC 128 Z9 129 U1 0 U2 5 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUN PY 1999 VL 144 IS 4 BP 339 EP 346 DI 10.1007/s002130051016 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 212VX UT WOS:000081239300005 PM 10435406 ER PT J AU Leshner, AI AF Leshner, AI TI HIV prevention with drug-using populations current status and future prospects - Preface SO PUBLIC HEALTH LA English DT Editorial Material C1 NIDA, NIH, Lexington, KY 40583 USA. RP Leshner, AI (reprint author), NIDA, NIH, Lexington, KY 40583 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0033-3506 J9 PUBLIC HEALTH JI Public Health PD JUN PY 1999 VL 113 SU 1 BP 1 EP 3 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 211TJ UT WOS:000081177700001 ER PT J AU Needle, RH Coyle, SL Normand, J Lambert, E Cesari, H AF Needle, RH Coyle, SL Normand, J Lambert, E Cesari, H TI HIV prevention with drug-using populations - Current status and future prospects: Introduction and overview SO PUBLIC HEALTH LA English DT Editorial Material ID OUT-OF-TREATMENT; IMMUNODEFICIENCY-VIRUS SEROCONVERSION; ABUSE TREATMENT; UNITED-STATES; RISK BEHAVIOR; HEPATITIS-B; FOLLOW-UP; AIDS; USERS; EDUCATION C1 Natl Inst Drug Abuse, Div Epidemiol & Prevent Res, Rockville, MD 20857 USA. Natl Inst Drug Abuse, Community Res Branch, Rockville, MD 20857 USA. Natl Inst Drug Abuse, Epidemiol & Appl Sci Review Branch, Off Extramural Program Review, Rockville, MD 20857 USA. RP Needle, RH (reprint author), Natl Inst Drug Abuse, Div Epidemiol & Prevent Res, Parklawn Bldg,Room 9A-42,5600 Fishers Lane, Rockville, MD 20857 USA. NR 66 TC 0 Z9 0 U1 0 U2 1 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0033-3506 J9 PUBLIC HEALTH JI Public Health PD JUN PY 1999 VL 113 SU 1 BP 4 EP 18 PG 15 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 211TJ UT WOS:000081177700002 ER PT J AU Coyle, SL Needle, RH Normand, J AF Coyle, SL Needle, RH Normand, J TI Outreach-based HIV prevention for injecting drug users: A review of published outcome data SO PUBLIC HEALTH LA English DT Article; Proceedings Paper CT Research Synthesis Symposium on the Prevention of HIV in Drug Abusers CY AUG 03-05, 1997 CL FLAGSTAFF, AZ ID RISK BEHAVIORS; COMMUNITY OUTREACH; PUERTO-RICO; SAN-JUAN; INTERVENTION; AIDS; PROGRAM; EFFICACY; WOMEN; POPULATIONS AB Objectives. Over the past decade, a body of observational research has accrued about the effects of outreach-based human immunodeficiency virus (HIV) interventions for drug users, The authors reviewed the findings related to postintervention behavior changes and integrated findings across studies to provide the best estimate of program impact, Methods. The authors conducted a computerized literature search to locate published accounts of HIV intervention effects on drug users, Thirty-six publications covered outreach-based HIV risk reduction interventions for out-of-treatment injecting drug users (IDUs) and reported intervention effects on HIV-related behaviors or HIV seroincidence. Two-thirds of the publications reported that participation in street-based outreach interventions was followed with office-based HIV testing and counseling, The authors described the theoretical underpinnings of outreach intervention components, the content of the interventions, and the outcome measures that investigators used most frequently The authors also described and critiqued the evaluation study designs that were in place. Because most of the evaluations were based on pretest and posttest measures of behavior rather than on controlled studies, results were examined with respect to accepted criteria for attributing intervention causality, that is, the plausibility of cause and effect, correct temporal sequence, consistency of findings across reports, strength of associations observed, specificity of associations, and dose-response relationships between interventions and observed outcomes. Results. The majority of the published evaluations showed that IDUs in a variety of places and time periods changed their baseline drug-related and sex-related risk behaviors following their participation in an outreach-based HIV risk reduction intervention. More specifically, the publications indicated that IDUs regularly reported significant follow-up reductions in drug injection, multiperson reuse of syringes and needles, multiperson reuse of other injection equipment (cookers, cotton, rinse water), and crack use. The studies also showed significant intervention effects in promoting entry into drug treatment and increasing needle disinfection. Although drug users also significantly reduced sex-related risks and increased condom use, the majority still practiced unsafe sex. One quasi experimental study found that reductions in injection risks led to significantly reduced HIV seroincidence among outreach participants. Few investigators looked at dosage effects, but two reports suggested that the longer the exposure to outreach-based interventions, the greater the reductions in drug injection frequency. Conclusions. Accumulated evidence from observational and quasi-experimental studies strongly indicate that outreach-based interventions have been effective in reaching out-of-treatment IDUs, providing the means for behavior change and inducing behavior change in the desired direction. The findings provide sound evidence that participation in outreach-based prevention programs can lead to lower HIV incidence rates among program participants. C1 NIDA, Off Extramural Program Review, Rockville, MD 20857 USA. NIDA, Clin Epidemiol & Appl Sci Review Branch, Off Extramural Program Review, Rockville, MD 20857 USA. RP Coyle, SL (reprint author), NIDA, Off Extramural Program Review, Parklawn Bldg,Room 10-42,5600 Fishers Lane, Rockville, MD 20857 USA. EM sc91m@nih.gov NR 48 TC 1 Z9 1 U1 1 U2 2 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0033-3506 J9 PUBLIC HEALTH JI Public Health PD JUN PY 1999 VL 113 SU 1 BP 19 EP 30 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 211TJ UT WOS:000081177700003 ER PT J AU Sloboda, Z AF Sloboda, Z TI What we have learned from research about the prevention of HIV transmission among drug abusers SO PUBLIC HEALTH LA English DT Article; Proceedings Paper CT Research Synthesis Symposium on the Prevention of HIV in Drug Abusers CY AUG 03-05, 1997 CL FLAGSTAFF, ARIZONA AB Objective. After more than 10 years of experience conducting behavioral change interventions and with accumulated research results, several emergent principles have been identified for the effective prevention of HIV transmission among drug abusers, In August 1997, a symposium was held in Flagstaff, Arizona, to achieve two major purposes: (I)to synthesize the findings from HIV prevention research conducted to date for interventions targeting drug abusers and (2) to extract a preliminary set of prevention principles that could be linked to effectiveness across at least two or more studies. This chapter summarizes the key findings of that symposium. Methods. Major findings were abstracted From the conclusion sections of the presentations and from the chapters included in this special volume. Many consistencies regarding intervention approaches across studies were noted, These findings are discussed under the following headings: General Observations, Engagement, Multiple Interventions, Intervention Issues, Methodological Issues, and Translation from Research to Practice. Suggested areas for further research are also presented and discussed. Results. Ten principles that have implications for HIV prevention interventions emerged from this preliminary review of the research. These principles engage drug users into the intervention; specify target behaviors and attitudes for intervention: suggest settings to optimize outreach; and recommend booster approaches to reinforce knowledge, skills, and attitudes learned through the intervention. Conclusions. The drug abuse community is threatened by the incursion of HIV and by the hepatitis viruses A, B, and C. The same behaviors are involved in transmitting all of these viruses. The first. generation of research to assess the impact of a variety of interventions delivered among drug abusers to prevent HIV has shown consistently favorable findings, proving that drug abusers can be helped to change their risky drug-using behaviors and, to a lesser extent, their risky sexual behaviors. The need to translate these: findings for community practitioners is heightened by the devastating impact of HIV and AIDS. C1 Natl Inst Drug Abuse, Div Epidemiol & Prevent Res, Rockville, MD 20857 USA. Natl Inst Drug Abuse, Div Clin Res, Prevent Res Branch, Rockville, MD 20857 USA. RP Sloboda, Z (reprint author), Natl Inst Drug Abuse, Div Epidemiol & Prevent Res, Parklawn Bldg,Room 9A-53,5600 Fishers Lane, Rockville, MD 20857 USA. NR 22 TC 0 Z9 0 U1 1 U2 1 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0033-3506 J9 PUBLIC HEALTH JI Public Health PD JUN PY 1999 VL 113 SU 1 BP 194 EP 204 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 211TJ UT WOS:000081177700021 ER PT J AU Harden, VA AF Harden, VA TI Museum exhibit standards: Do historians really want them? SO PUBLIC HISTORIAN LA English DT Article ID PUBLIC HISTORY C1 Natl Inst Hlth, Washington, DC USA. RP Harden, VA (reprint author), Natl Inst Hlth, Washington, DC USA. NR 18 TC 0 Z9 0 U1 0 U2 0 PU UNIV CALIF PRESS PI BERKELEY PA JOURNALS DEPT 2120 BERKELEY WAY, BERKELEY, CA 94720 USA SN 0272-3433 J9 PUBL HISTORIAN JI Public Hist. PD SUM PY 1999 VL 21 IS 3 BP 91 EP 109 PG 19 WC History SC History GA 225WJ UT WOS:000081988700011 ER PT J AU Knebel, AR Leidy, NK Sherman, S AF Knebel, AR Leidy, NK Sherman, S TI Health related quality of life and disease severity in patients with alpha-1 antitrypsin deficiency SO QUALITY OF LIFE RESEARCH LA English DT Article DE dyspnea; functional status; health outcome assessment; pulmonary emphysema; symptoms ID OBSTRUCTIVE PULMONARY-DISEASE; RANDOMIZED CONTROLLED TRIAL; OF-LIFE; ALPHA-1-ANTITRYPSIN DEFICIENCY; RESPIRATORY REHABILITATION; EXERCISE CAPACITY; LUNG-FUNCTION; DYSPNEA; EMPHYSEMA; IMPACT AB Study question: To describe health-related quality of life (HRQL) in individuals with alpha-1 antitrypsin (AAT) deficiency, examine the cross-sectional relationship between disease severity and HRQL, and explore changes in lung function and HRQL over time in a subset of these individuals. Material/Methods: Forty-five adults with AAT deficiency and moderate to severe emphysema completed the Chronic Respiratory Disease Questionnaire (CRQ), six-minute walk distance (6-MWD) and pulmonary function tests (PFTs). Twenty of the 45 were followed for two additional years with repeated measurements of CRQ and PFTs. Results: The mean +/- SD age was 49 +/- 8 years. Initial CRQ subscale scores were: dyspnea 17.5 +/- 4.3; fatigue 17.0 +/- 5.46; emotional function 33.1 +/- 8.67; and mastery 21.7 +/- 4.65. No relationship was found between percent predicted forced expiratory volume in one second (FEV1%) and CRQ score; 6 MWD and fatigue correlated significantly (r = 0.32, p < 0.05). Repeated PFT and CRQ measurements in 20 subjects showed statistically significant declines in FEV1 and slow vital capacity (SVC), but no change in CRQ scores. Conclusions: Results suggest persons with AAT deficiency face challenges to HRQL that are similar to older adults with chronic pulmonary disease. Further research is needed on the nature of the relationship between disease severity and HRQL in this population. C1 NIH, Ctr Clin, Dept Nursing, Bethesda, MD 20892 USA. MEDTAP Int, Bethesda, MD USA. Natl Inst Nursing Res, Div Intramural Res, Bethesda, MD USA. RP Knebel, AR (reprint author), NIH, Ctr Clin, Dept Nursing, Bldg 10 Room 2C206,10 Ctr DR MSC 1506, Bethesda, MD 20892 USA. NR 30 TC 12 Z9 12 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0962-9343 J9 QUAL LIFE RES JI Qual. Life Res. PD JUN PY 1999 VL 8 IS 4 BP 385 EP 391 DI 10.1023/A:1008945316646 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 222TC UT WOS:000081800000012 PM 10472171 ER PT J AU Orel, SG Kay, N Reynolds, C Sullivan, DC AF Orel, SG Kay, N Reynolds, C Sullivan, DC TI BI-RADS categorization as a predictor of malignancy SO RADIOLOGY LA English DT Article; Proceedings Paper CT 83rd Scientific Assembly and Annual Meeting of the Radiological-Society-of-North-America CY NOV 30-DEC 05, 1997 CL CHICAGO, ILLINOIS SP Radiol Soc N Amer DE breast, biopsy; breast neoplasms, localization; breast neoplasms, radiography ID PROBABLY BENIGN LESIONS; MAMMOGRAPHIC FOLLOW-UP; SUSPICION; BIOPSY AB PURPOSE: To determine the positive predictive value (PPV) of the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) categories 0, 2, 3, 4, and 5 by using BI-RADS terminology and by auditing data on needle localizations. MATERIALS AND METHODS: Between April 1991 and December 1996, 1,400 mammographically guided needle localizations were performed in 1,109 patients. Information entered into the mammographic database included where the initial mammography was performed (inside vs outside the institution), BI-RADS category, mammographic finding, and histopathologic findings. A recorded recommendation was available for 1,312;localizations in 1,097 patients who composed the study population. who composed the study population RESULTS: The 1,312 localizations yielded 449 (34%) cancers (139 [31%] were ductal carcinoma in situ [DCIS]; 310 [69%] were invasive cancers) and 863 (66%) benign lesions. There were 15 (1%) category 0 lesions; the PPV was 13% (two of 15 lesions). There were 50 (4%) category 2 lesions; the PPV was 0% (0 of40 lesions). There were 141 (1 1%) category 3 lesions; the PPV was 2%(three of 141 lesions). The three cancers in this group were all non-comedotype DCIS. There were 936 (71%) category 4 lesions; the PPV was 30% (279 of 936 lesions). There were 170 (13%) category 5 lesions; the PPV was 97% (165 of 1 70 lesions). CONCLUSION: Placing mammographic lesions into BI-RADS categories is useful for predicting the presence of malignancy. Perhaps, most important, a lesion placed into BI-RADS category 3 is highly predictive of-benignity ty, and short-term interval follow-up as an alternative to biopsy would decrease the number of biopsies performed in benign lesions. C1 Univ Penn, Med Ctr, Dept Radiol, Philadelphia, PA 19104 USA. Mayo Clin, Div Anat Pathol, Rochester, MN USA. NCI, Rockville, MD USA. RP Orel, SG (reprint author), Univ Penn, Med Ctr, Dept Radiol, 3400 Spruce St, Philadelphia, PA 19104 USA. NR 14 TC 170 Z9 199 U1 0 U2 5 PU RADIOLOGICAL SOC NORTH AMER PI EASTON PA 20TH AND NORTHAMPTON STS, EASTON, PA 18042 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUN PY 1999 VL 211 IS 3 BP 845 EP 850 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 198VY UT WOS:000080446000037 PM 10352614 ER PT J AU Baker, LC Brown, ML AF Baker, LC Brown, ML TI Managed care, consolidation among health care providers, and health care: evidence from mammography SO RAND JOURNAL OF ECONOMICS LA English DT Article ID HOSPITAL COST INFLATION; SCREENING MAMMOGRAPHY; MAINTENANCE ORGANIZATION; UNITED-STATES; HMO PENETRATION; NATIONAL SURVEY; BREAST-CANCER; IMPACT; MARKET; PRICE AB We discuss the effects of managed care on the structure of the health care delivery system, focusing on managed-care-induced consolidation among health care providers. We empirically investigate the relationship between HMO market share and mammography providers. We find evidence of consolidation: increases in HMO activity are associated with reductions in the number of mammography providers and with increases in the number of services produced by remaining providers. We also find that increases in HMO market share are associated with reductions in costs for mammography and with increases in waiting times for appointments, but not with worse health outcomes. C1 Stanford Univ, Stanford, CA 94305 USA. NBER, Cambridge, MA 02138 USA. NCI, Bethesda, MD 20892 USA. RP Baker, LC (reprint author), Stanford Univ, Stanford, CA 94305 USA. OI Baker, Laurence/0000-0001-5032-794X NR 48 TC 46 Z9 46 U1 1 U2 6 PU RAND PI LAWRENCE PA 810 EAST 10TH ST, LAWRENCE, KS 66044 USA SN 0741-6261 J9 RAND J ECON JI Rand J. Econ. PD SUM PY 1999 VL 30 IS 2 BP 351 EP U2 DI 10.2307/2556084 PG 25 WC Economics SC Business & Economics GA 205VJ UT WOS:000080841000009 PM 10558503 ER PT J AU Dichter, JR Lundgren, JD Nielsen, TL Jensen, BN Schattenkerk, J Benfield, TL Lawrence, M Shelhamer, J AF Dichter, JR Lundgren, JD Nielsen, TL Jensen, BN Schattenkerk, J Benfield, TL Lawrence, M Shelhamer, J TI Pneumocystis carinii pneumonia in HIV-infected patients: effect of steroid therapy on surfactant level SO RESPIRATORY MEDICINE LA English DT Article ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; PULMONARY SURFACTANT; VIRUS INFECTION; LUNG-DISEASE; PROTEIN-A; AIDS; CORTICOSTEROIDS; ABNORMALITIES; PHOSPHOLIPIDS; ALPHA AB Previous studies have suggested alterations in pulmonary surfactant lipid in the setting of Pneumocystis carinii pneumonia in HIV-infected patients. Because pulmonary surfactant lipid is composed of a variety of lipid products and because other phospholipids might be present in bronchoalveolar lavage (BAL) lipid determinations, a single molecular species of phospholipid which comprises a substantial portion of the surfactant lipid fraction, dipalmitoyl phosphatidylcholine (DPPC), was measured by capillary column gas chromatography in BAL samples taken at the time of the diagnosis of P. carinii pneumonia, and 10 days after treatment for P. carinii pneumonia. DPPC was measured at day 0 and day 10 in seven patients who had been randomized to receive methylprednisolone adjuvant therapy for P. carinii pneumonia and in six patients who had been randomized to not receive methylprednisolone therapy. The level of DPPC in BAL from all patients at day 0 was 0.49 +/- 0.06 mu g ml(-1) BAL. This level is significantly lower that the level of DPPC determined in BAL from five normal volunteers 2.48 +/- 0.40 mu g ml(-1). At day 0, the BAL level of DPPC in patients treated with methylprednisolone was not different from the BAL level of DPPC in patients not treated with methylprednisolone. By day 10 of therapy for P. carinii pneumonia, BAL levels of DPPC in all patients had increased to 1.05 +/- 0.19 mu g ml(-1) BAL. At day 10 DPPC levels in the methylprednisolone treated group were not different from the group not treated with methylprednisolone. We conclude that in HIV-infected patients, lung surfactant lipid is reduced in the setting of P. carinii pneumonia. The lipid levels return toward normal levels with treatment. Adjuvant therapy with corticosteroids does not alter the rate of recovery of surfactant lipid levels at least after 10 days of therapy. C1 NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. Univ Copenhagen, Dept Infect Dis, Hvidovre, Denmark. Univ Copenhagen, Hvidovre Hosp, DK-2650 Hvidovre, Denmark. Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. RP Shelhamer, J (reprint author), NIH, Ctr Clin, Dept Crit Care Med, Bldg 10,Room 7-D-43, Bethesda, MD 20892 USA. OI Lundgren, Jens/0000-0001-8901-7850 NR 29 TC 2 Z9 2 U1 0 U2 2 PU W B SAUNDERS CO LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0954-6111 J9 RESP MED JI Respir. Med. PD JUN PY 1999 VL 93 IS 6 BP 373 EP 378 DI 10.1053/rmed.1999.0581 PG 6 WC Cardiac & Cardiovascular Systems; Respiratory System SC Cardiovascular System & Cardiology; Respiratory System GA 204WG UT WOS:000080795000001 PM 10464817 ER PT J AU Harik-Khan, R Wise, RA Lou, C Morrell, CH Brant, LJ Fozard, JL AF Harik-Khan, R Wise, RA Lou, C Morrell, CH Brant, LJ Fozard, JL TI The effect of gestational parity on FEV1 in a group of healthy volunteer women SO RESPIRATORY MEDICINE LA English DT Article ID PULMONARY-FUNCTION; FOLLOW-UP; PREGNANCY; RISK; DECLINE; DISEASE; LUNG AB In the past, studies utilizing within-subject comparisons of small groups of pregnant women showed that forced expiratory volume in is (FEV1) remained essentially unchanged during pregnancy. However, one of the findings from an epidemiological study was that women with greater number of children experienced a faster decline of FEV1. The aim of this study was to examine the effect of parity on FEV1 in a group of healthy volunteer women. To this end, cross-sectional multiple regression analyses of data from 397 healthy women participants in the Baltimore Longitudinal Study of Aging (BLSA) with a mean (range) age of 47.7 (18-92) years were performed. Similar analyses were done using the younger (50 years or less) and the older (>50 years) subgroups. After controlling for age, height, weight, and smoking, parity as a dichotomous variable was associated with a higher FEV1 in women of child-bearing age (0.1391; P=0.02) but not in the older women. There was a modest link with the number of children (P=0.05), with the first child possibly having the greatest effect on FEV1. We could not account for the effect of parity on FEV1 by the educational level, occupation, health status of the women, or by the presence of a cohort effect. Thus the nulliparous state is associated with lower FEV1 in this group of healthy adult women of child-bearing age. C1 NIA, Clin Invest Lab, Intramural Res Program, Gerontol Res Ctr, Baltimore, MD 21224 USA. Johns Hopkins Sch Med, Dept Med, Baltimore, MD 21205 USA. Shanghai Inst Planned Parenthood Res, Shanghai 200032, Peoples R China. Loyola Coll, Dept Math Sci, Baltimore, MD 21210 USA. NIA, Res Resources Branch, Intramural Res Program, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Harik-Khan, R (reprint author), NIA, Clin Invest Lab, Intramural Res Program, Gerontol Res Ctr, 5600 Nathan Shock Dr,Box 06, Baltimore, MD 21224 USA. RI Fozard, James Leonard/B-3660-2009; OI Wise, Robert/0000-0002-8353-2349 NR 20 TC 9 Z9 9 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0954-6111 J9 RESP MED JI Respir. Med. PD JUN PY 1999 VL 93 IS 6 BP 382 EP 388 DI 10.1053/rmed.1999.0572 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System SC Cardiovascular System & Cardiology; Respiratory System GA 204WG UT WOS:000080795000003 PM 10464819 ER PT J AU Petralia, SA Vena, JE Freudenheim, JL Dosemeci, M Michalek, A Goldberg, MS Brasure, J Graham, S AF Petralia, SA Vena, JE Freudenheim, JL Dosemeci, M Michalek, A Goldberg, MS Brasure, J Graham, S TI Risk of premenopausal breast cancer in association with occupational exposure to polycyclic aromatic hydrocarbons and benzene SO SCANDINAVIAN JOURNAL OF WORK ENVIRONMENT & HEALTH LA English DT Article DE benzene; breast cancer; estrogen receptor; occupational exposures; polycyclic aromatic hydrocarcarbons; women ID CIGARETTE-SMOKING; ORGANIC-SOLVENTS; WORKERS; MORTALITY; COHORT; WOMEN; HYPOTHESIS; MATRIX; TISSUE; DAMAGE AB Objectives This study examined the relationship between risk of premenopausal breast cancer and occupational exposure to benzene and polycyclic aromatic hydrocarbons (PAH) and whether the proposed relationship between PAH and breast cancer differed by tumor estrogen receptor (ER) status. Methods In a case-referent study of premenopausal breast cancer, occupational histories and other information were obtained through interviews, and job-exposure matrices were used to assess exposure to PAH and benzene. Results A dose-response relationship for the probability of exposure to benzene [low: odds ratio (OR) 1.64, 95% confidence interval(95% CI) 0.64-4.21;high: OR 1.95, 95% CI 1.14-3.33) and to PAH (low: OR 1.56, 95% CI 0.78-3.12; high: OR 2.40, 95% CI 0.96-6.01). Risk increased with duration of exposure to benzene, but not to PAH. A dose-response relationship was not evident for the intensity of exposure to benzene or to PAH. When analyses were stratified by tumor ER status, PAH exposure was related to a greater increase in the risk of ER-positive (OR 2.27, 95% CI 1.14-4.54) than ER-negative (OR 1.12, 95% CI 0.47-2.64) breast cancer. Risk of ER-positive, but not ER-negative, tumors increased with the probability of exposure to PAH. Conclusions The findings suggest an association between risk and occupational exposure to benzene. Although it was difficult to study PAH independently of benzene, there was some suggestion of an association between PAH exposure and ER-positive tumors. These data should be interpreted with caution because of the limitations of this study, including low-response rates and small numbers of exposed persons. C1 NCI, Occupat Epidemiol Branch, Bethesda, MD 20892 USA. SUNY Buffalo, Sch Med & Biomed Sci, Dept Social & Prevent Med, Buffalo, NY 14260 USA. Univ Quebec, Inst Armand Frappier, Montreal, PQ H3C 3P8, Canada. McGill Univ, Dept Epidemiol & Biostat, Dept Occupat Hlth, Montreal, PQ, Canada. RP Petralia, SA (reprint author), NCI, Occupat Epidemiol Branch, Execut Plaza S,Rm 8110,6120 Execut Blvd, Bethesda, MD 20892 USA. NR 29 TC 42 Z9 44 U1 1 U2 3 PU SCAND J WORK ENV HEALTH PI HELSINKI PA TOPELIUKSENKATU 41A, SF-00250 HELSINKI, FINLAND SN 0355-3140 J9 SCAND J WORK ENV HEA JI Scand. J. Work Environ. Health PD JUN PY 1999 VL 25 IS 3 BP 215 EP 221 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 219CD UT WOS:000081589600005 PM 10450771 ER PT J AU DeGraba, TJ Hallenbeck, JM Pettigrew, KD Dutka, AJ Kelly, BJ AF DeGraba, TJ Hallenbeck, JM Pettigrew, KD Dutka, AJ Kelly, BJ TI Progression in acute stroke - Value of the initial NIH Stroke Scale score on patient stratification in future trials SO STROKE LA English DT Article DE outcome; stroke assessment; stroke, acute ID ACUTE ISCHEMIC STROKE; SYSTEM CEREBRAL INFARCTION; PROFILE CLINICAL COURSE; SPONTANEOUS IMPROVEMENT; PROGNOSIS; SERIAL AB Background and Purpose-The objective was to determine the occurrence of neurological changes during the first 48 hours after acute stroke as it relates to initial stroke severity, Methods The National Institutes of Health Stroke Scale (NIHSS) was performed serially for the first 48 hours on 127 consecutive ischemic stroke patients (129 strokes) admitted to the neuroscience intensive care unit. Incidence of stroke progression (a greater than or equal to 3-point increase on the NIHSS) was recorded and analysis performed to determine its association with initial stroke severity and other demographic and physiological variables, Deficit resolution by 48 hours, defined as an NIHSS score of 0 or 1, measured the frequency of functional recovery predicted by the initial deficit, Results-Overall progression was noted in 31% of events (40/129). Applying Bayes' solution to the observed frequency of worsening, the greatest likelihood of predicting future patient progression occurs with stratification at NIHSS scores of less than or equal to 7 and >7. Patients with an initial NIHSS of less than or equal to 7 experienced a 14.8% (13/88) worsening rate versus a those with a score of >7 with a 65.9% (27/41) worsening rate (P<0.000005). Forty-five percent (40/88) of those with an initial score of less than or equal to 7 were functionally normal at 48 hours, whereas only 2.4% (1/41) of those with scores of >7 returned to a normal examination within this period (chi(2), P<0.000005). Conclusions-This study suggests that the early clinical course of the neurological deficit after acute stroke is dependent on the initial stroke severity and that a dichotomy in early outcome exists surrounding an initial NIHSS score of 7. These findings may have significant implications for the design and patient stratification in treatment protocols with respect to primary clinical outcome. C1 NINDS, Clin Stroke Res Unit, Stroke Branch, NIH, Bethesda, MD 20892 USA. USN, Med Ctr, Dept Neurol, Bethesda, MD 20814 USA. NIMH, NIH, Bethesda, MD 20892 USA. Natl Naval Med Ctr, Dept Crit Care Med, Bethesda, MD USA. RP DeGraba, TJ (reprint author), NINDS, Clin Stroke Res Unit, Stroke Branch, NIH, 36 Convent Dr MSC 4128,Bldg 36 Rm 4A-03, Bethesda, MD 20892 USA. NR 24 TC 140 Z9 150 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUN PY 1999 VL 30 IS 6 BP 1208 EP 1212 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 201CX UT WOS:000080578100009 PM 10356101 ER PT J AU Yamada, S Iacono, RP Mandybur, GT Anton, R Lonser, R Yamada, S Haugen, GE AF Yamada, S Iacono, RP Mandybur, GT Anton, R Lonser, R Yamada, S Haugen, GE TI Endoscopic procedures for resection of arteriovenous malformations SO SURGICAL NEUROLOGY LA English DT Article DE endoscopy; arteriovenous malformation; functional area; intraventricular AVM AB BACKGROUND Resection of arteriovenous malformations (AVMs), particularly those located in functional areas, requires precision. To enhance that precision, endoscope-assisted microsurgery has been employed at Loma Linda University. METHODS Twenty-five consecutive cases of AVM were treated microsurgically with endoscopic assistance. Patients were divided into two groups: (1) those having AVMs in functional areas, and (2) those whose AVMs extended into the ventricle, either in the trigonal area or the capsulocaudatothalamic area. The endoscope was inserted into the subarachnoid space to interrupt communicating venules around the major draining vein and into the cleavage developed between the AVM venous loops and surrounding brain tissue as shunting arterioles and communicating venules were interrupted. For surgery of intraventricular AVMs, the curved endoscope was inserted into the ventricle, providing visualization of the AVM core, which was dissected from the ventricular side. RESULTS AVMs were totally resected in all cases except for two patients with capsulocaudatothalamic AVMs, which were decreased in size sufficiently to receive radiosurgery. CONCLUSION Endoscope-assisted microsurgery enhances magnification, illumination, and technical precision while the surgeon is dissecting the AVM cope vessels and while operating on AVMs extending into the ventricle. (C) 1999 by Elsevier Science Inc. C1 Loma Linda Univ, Sch Med, Div Neurosurg, Loma Linda, CA USA. Univ Mississippi, Med Ctr, Dept Neurosurg, Jackson, MS 39216 USA. NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Nippon Med Sch, Dept Neurosurg, Tokyo 113, Japan. RP Yamada, S (reprint author), 11234 Anderson St,Room 2539, Loma Linda, CA 92354 USA. NR 12 TC 6 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 0090-3019 J9 SURG NEUROL JI Surg. Neurol. PD JUN PY 1999 VL 51 IS 6 BP 641 EP 649 DI 10.1016/S0090-3019(99)00021-X PG 9 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 203HK UT WOS:000080702300021 PM 10369233 ER PT J AU Grasso, YZ Kim, MR Faiman, C Kohn, LD Tahara, K Gupta, MK AF Grasso, YZ Kim, MR Faiman, C Kohn, LD Tahara, K Gupta, MK TI Epitope heterogeneity of thyrotropin receptor-blocking antibodies in graves' patients as detected with wild-type versus chimeric thyrotropin receptors SO THYROID LA English DT Article ID THYROID-STIMULATING ANTIBODIES; IDIOPATHIC MYXEDEMA PATIENTS; TSH-RECEPTOR; TRANSIENT HYPOTHYROIDISM; GONADOTROPIN RECEPTORS; IMMUNOGLOBULIN-G; AUTOANTIBODIES; DISEASE; CELLS; SERA AB The stable transfectants of wild-type (W25) and mutant thyrotropin-receptor (TSH-R) allow detection of the bioactivities of TSH-R antibodies in Graves' patients. A mutant Chinese hamster ovary (CHO) cell line (Mcl+2) transfected with a chimeric construct, where residues 8 to 165 of the TSH-R are replaced with residues 10 to 166 of the lutropin/choriogonadotropin (LH/CGR) receptor, lacks the cyclic adenosine monophosphate (cAMP) response to most thyrotropin stimulating antibodies (TSAb), yet retains the response to TSH and acquires the response to LH/CG. We compared Mc1+2 cells with wild-type W25 cells for their ability to detect TSAb as well as thyrotropin-blocking antibodies (TBAb) in Graves' sera. Eighteen normal and 39 Graves' sera were tested for TSAb and TBAb levels by in vitro bioassays using W25 and Mc1+2 cells. In addition, these sera were also tested for thyrotropin-binding inhibitory activity (TBII) by a radioreceptor assay. Eighteen (47%) Graves' sera had TBAb activity measured with W25 cells but not with Mc1+2 cells. These TBAbs were, therefore, a population of antibodies with functional epitopes on the N-terminus of the extracellular domain. This TBAb activity by W25 cells exhibited a high degree of correlation with TBII levels by a radioreceptor assay (r = 0.70, p = 0.001). Ten (25.6%) Graves' sera had positive TBAb activity in both W25 and Mc1+2 cells; moreover, their activity in both assays was similar (r = 0.83, P < 0.001). The TBAb activity in these sera, however, did not correlate with TBII activity. Eleven (28%) Graves' sera had no TBAb activity. Overall, thyroid-stimulating antibodies were detected in 87% and 28% of the 39 Graves' sera by W25 and Mc1+2 cells, respectively. Thus, using the 2 cell lines, at least 2 distinct populations of TBAbs were detected. One is detected in a similar fashion by both W25 and Mc1+2 cell lines and likely interacts with the epitopes residing in the unaltered C-terminus of the TSH-R. The other is reactive in W25 cells only, indicating the loss of TBAb epitope in the chimeric receptor located in the N-terminus of the TSH-R. Furthermore, our results indicate that the TBAb binding epitope in 8-165 residues of the native TSH-R is highly associated with TBII activity in Graves' disease. These results indicate that patients with Graves' disease harbor TBAbs with epitope heterogeneity and favor the notion that there are different sites and mechanisms by which TBAbs act in Graves' patients. It remains to be determined whether or not TBAb subtyping will have a useful predictive role in the management of patients with Graves' disease. C1 Cleveland Clin Fdn, Dept Clin Pathol, Cleveland, OH 44195 USA. Cleveland Clin Fdn, Dept Endocrinol, Cleveland, OH 44195 USA. NIDDK, Bethesda, MD USA. RP Gupta, MK (reprint author), Cleveland Clin Fdn, Dept Clin Pathol, 9500 Euclid Ave,L11, Cleveland, OH 44195 USA. NR 27 TC 25 Z9 26 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1050-7256 J9 THYROID JI Thyroid PD JUN PY 1999 VL 9 IS 6 BP 531 EP 537 DI 10.1089/thy.1999.9.531 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 210VA UT WOS:000081124300003 PM 10411114 ER PT J AU Park, ES You, SH Kim, H Kwon, OY Ro, HK Cho, BY Taniguchi, SI Kohn, LD Shong, M AF Park, ES You, SH Kim, H Kwon, OY Ro, HK Cho, BY Taniguchi, SI Kohn, LD Shong, M TI Hormone-dependent regulation of intercellular adhesion molecule-1 gene expression: Cloning and analysis of 5 '-regulatory region of rat intercellular adhesion molecule-1 gene in FRTL-5 rat thyroid cells SO THYROID LA English DT Article ID TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; THYROTROPIN RECEPTOR; GRAVES-DISEASE; TNF-ALPHA; SERINE PHOSPHORYLATION; FUNCTIONAL-ANALYSIS; EPITHELIAL-CELLS; INTERFERON-GAMMA; PHOSPHOLIPASE-C AB Intercellular adhesion molecule-1 (ICAM-1) has been suggested to play an important role in the perpetuation of autoimmune thyroid disease. To clarify the regulation of ICAM-1 gene in thyroid cells, we investigated ICAM-I expression in the FRTL-5 thyroid cell model and defined several elements in the 5'-regulatory region that are important for transcriptional regulation of the rat ICAM-1 gene. Cells maintained in medium with 5% serum but without hydrocortisone, insulin, and thyrotropin (TSH) express the highest levels of ICAM-1 RNA. TSH/forskolin downregulate ICAM-I RNA levels independent of the presence or absence of hydrocortisone or insulin. Moreover, TSH/forskolin decrease ICAM-1 RNA levels that are maximally induced by two cytokines: 100 ng/mL tumor necrosis factor-alpha (TNF-alpha or 100 U/ml interferon-gamma(IFN-gamma). The effect of TSH/forskolin, as well as TNF-alpha and IFN-gamma, on ICAM-1 RNA levels is transcriptional. Thus, we cloned a 1.8-kb fragment of the 5'-flanking region of the rat ICAM-1 gene, upstream of the translational start site, and showed that TNF-alpha or IFN-gamma caused a 3.5- and greater than 12-fold increase respectively, in its promoter activity, when linked to a luciferase reporter gene and stably transfected into FRTL-5 cells. TSH or forskolin, in contrast, halved the activity of the full length chimera within 24 hours and significantly suppressed the TNF-alpha and IFN-gamma-induced increase (>50%; p < 0.02). Using 5'-deletion mutants, we located the element important for the TNF-alpha effect between -431 and -175 bp; we additionally show that deletion of a NF-KB core element within this region, TTGGAAATTC (-240 to -230 bp), causes the loss of TNF-alpha inducibility. The effect of IFN-gamma could be localized between -175 bp and -97 bp from the start of translation. This region contains 2 regulatory elements known to be involved in IFN-gamma action in other eukaryotic cells, an IFN-gamma activated site (GAS), -138 to -128 bp, and Spl site, -112 to -108 bp. Deletion of the 10 bp GAS sequence resulted in the complete loss of IFN-gamma induction of pCAM-175 promoter activity. TSH and forskolin action was also mapped between -175 bp and -97 bp from the start of translation. The mutant construct, pCAM-175delGAS mut1, which has no GAS sequence, exhibited no TSH-mediated suppression of promoter activity. We thus show that TSH/cAMP can downregulate ICAM-1 gene expression and inhibit the activity of cytokines (TNF-alpha and IFN-gamma) to increase ICAM-1 gene expression in FRTL-5 thyroid cells. We also localized elements on the 5'-flanking region of ICAM-I important for these actions. We propose that this TSH/cyclic adenosine monophosphate (cAMP) action is a component of the mechanism to preserve self-tolerance of the thyroid during hormone-induced growth and function of the gland, and it may attenuate cytokine action during inflammatory reactions. C1 Chungnam Natl Univ, Sch Med, Dept Internal Med, Chung Ku, Taejon 301040, South Korea. Chungnam Natl Univ, Sch Med, Dept Anat, Taejon, South Korea. Seoul Natl Univ, Sch Med, Dept Internal Med, Seoul, South Korea. NIDDK, Sect Cell Regulat, Metab Dis Branch, NIH, Baltimore, MD USA. RP Shong, M (reprint author), Chungnam Natl Univ, Sch Med, Dept Internal Med, Chung Ku, 640 Daesadong, Taejon 301040, South Korea. NR 64 TC 11 Z9 13 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1050-7256 J9 THYROID JI Thyroid PD JUN PY 1999 VL 9 IS 6 BP 601 EP 612 DI 10.1089/thy.1999.9.601 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 210VA UT WOS:000081124300013 PM 10411124 ER PT J AU Sesso, A Fujiwara, DT Jaeger, M Jaeger, R Li, TC Monteiro, MMT Correa, H Ferreira, MA Schumacher, RI Belisario, J Kachar, B Chen, EJ AF Sesso, A Fujiwara, DT Jaeger, M Jaeger, R Li, TC Monteiro, MMT Correa, H Ferreira, MA Schumacher, RI Belisario, J Kachar, B Chen, EJ TI Structural elements common to mitosis and apoptosis SO TISSUE & CELL LA English DT Article; Proceedings Paper CT Joint Meeting of the Brazilian-Society-of-Electron-Microscopy-and-Microanalysis / Brazilian-Cell-Biology-Society CY DEC, 1998 CL SAO PAULO, BRAZIL SP Brazilian Soc Electron Microscopy & Microanal, Brazilian Cell Biol Soc DE mistosis; apoptosis; nuclear envelope; Golgi ID PROGRAMMED CELL-DEATH; GOLGI-APPARATUS; ACINAR-CELLS; ACTIVATION; INDUCTION; PANCREAS; KINASE; PHASE; RATS AB Both mitotic and apoptotic cells display hypercondensation of the chromatin and loss of the nuclear envelope (Lazebnik et at., 1993). Herein, we describe a third similarity between the two processes. We have observed, initially in apoptotic cells of the PC-12 lineage clusters of 40-60 (similar to 50) nm vesicles adjoined by a minor contingent of tubule vesicular elements of 100-200 nm which are indistinguishable from their vesicular counterparts in mitotic PC-12 cells. The clusters of similar to 50 nm vesicles were subsequently observed in all studied rat tissue cells in apoptosis (plasma cells and macrophages, secretory epithelial cells from pancreatic acini, ventral lobe of prostate and mammary gland). Clusters of similar to 50 nm vesicles comparable to those of the PC-12 cells were found in HeLa cells treated with human alfa TNF, in WEHI-3 cells exposed to VM 26 (a teneposide) (Sesso et at., 1997) and in HL-60 cells treated with thapsigargin, PC-12 and HeLa cells affixed to coverslips were double labelled and examined with the fluorescence microscope to reveal simultaneously the disposition of the chromatin with Hoechst stain and the distribution of the fluorescence of Golgi or of Golgi-associated proteins. A common pattern of fluorescence was observed in a minor proportion of apoptotic cells using three different antibodies used. The label frequently appeared as finely dispersed granules in the cytoplasm. In some apoptotic cells, relatively coarse granules were observed. This pattern of label distribution is compatible with the disposition of vesicular clusters we have encountered in apoptotic PC-12 cells sectioned serially or semi serially. In such sections of both mitotic and apoptotic PC-12 cells, we noticed that the conglomerates of 50 nm vesicles were frequently associated with cisternae of the rough ER. Vesicles of similar size were also noted pinching off from the extremities of Golgi cisternae reduced in size, These cisternae diminish in length and width when they are in the process of disassembling at the very beginning of mitosis and in apoptosis. C1 Fac Med Sao Paulo, Lab Mol Pathol, BR-01246903 Sao Paulo, Brazil. Univ Sao Paulo, Inst Chem, BR-05508 Sao Paulo, Brazil. Univ Sao Paulo, Fac Dent, BR-05508 Sao Paulo, Brazil. NIDCD, NIH, Bethesda, MD 20205 USA. Butantan Inst, Sao Paulo, Brazil. RP Sesso, A (reprint author), Fac Med Sao Paulo, Lab Mol Pathol, Av Dr Arnnaldo 455, BR-01246903 Sao Paulo, Brazil. RI Marques, Marcia/F-3780-2012; Jaeger, Ruy/G-8230-2011 OI Marques, Marcia/0000-0002-9398-1252; NR 29 TC 48 Z9 51 U1 0 U2 5 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0040-8166 J9 TISSUE CELL JI Tissue Cell PD JUN PY 1999 VL 31 IS 3 BP 357 EP 371 DI 10.1054/tice.1999.0042 PG 15 WC Anatomy & Morphology; Cell Biology SC Anatomy & Morphology; Cell Biology GA 226LN UT WOS:000082021600015 PM 10481307 ER PT J AU Spalding, JW French, JE Tice, RR Furedi-Machacek, M Haseman, JK Tennant, RW AF Spalding, JW French, JE Tice, RR Furedi-Machacek, M Haseman, JK Tennant, RW TI Development of a transgenic mouse model for carcinogenesis bioassays: Evaluation of chemically induced skin tumors in Tg.AC mice SO TOXICOLOGICAL SCIENCES LA English DT Article DE Tg.AC transgenic mice; chemical carcinogens; carcinogen bioassay; skin cancer ID HA-RAS GENE; PAPILLOMA DEVELOPMENT; EXPRESSION; TUMORIGENESIS; ASSOCIATION; INITIATION; PROMOTION AB Transgenic rodent models have emerged as potentially useful tools in the assessment of drug and chemical safety. The transgenic Tg.AC mouse carries an inducible v-Ha-ras oncogene that imparts the characteristic of genetically initiated skin to these animals, The induction of epidermal papillomas in the area of topically applied chemical agents, for duration of not more than 26 weeks, acts as a reporter phenotype that defines the activity of the test article. We describe here the activity of six chemicals that have been previously characterized for activity in the standard 2-year bioassay conducted by the National Toxicology Program (NTP). Homozygous female Tg.AC mice were treated with benzene (BZ), benzethonium chloride (BZTC), o-benzyl-p-chlorophenol (BCP), 2-chloroethanol (2-CE), lauric acid diethanolamine (LADA) and triethanolamine (TEA), BZ and LADA induced skin papillomas in a dose-dependent manner, while BCP induced papillomas only at the highest dose. BZTC, 2-CE, and TEA exhibited no activity. The correspondence of chemical activity in Tg.AC mice with that in the 2-year bioassay was high. A comparison of responsiveness to BZ and LADA was made between hemizygous and homozygous female Tg.AC mice. Both genotypes appear to be equally sensitive to maximum doses of active compounds. The results reported here indicate that the Tg.AC transgenic mouse model can discriminate between carcinogens and noncarcinogens and that both mutagenic and nonmutagenic chemicals can be detected. These studies provide support for the adjunctive use of the Tg.AC transgenic mouse skin tumor model in drug and chemical safety assessment and for the prediction of the carcinogenic potential of chemicals. C1 NIEHS, Lab Environm Carcinogenesis & Mutagenesis, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Biostat Branch, Res Triangle Pk, NC 27709 USA. Integrated Syst Lab, Res Triangle Pk, NC 27709 USA. RP Spalding, JW (reprint author), NIEHS, Lab Environm Carcinogenesis & Mutagenesis, POB 12233,MD F1-05, Res Triangle Pk, NC 27709 USA. NR 45 TC 37 Z9 38 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JUN PY 1999 VL 49 IS 2 BP 241 EP 254 DI 10.1093/toxsci/49.2.241 PG 14 WC Toxicology SC Toxicology GA 251PY UT WOS:000083455100011 PM 10416269 ER PT J AU Moser, VC AF Moser, VC TI Comparison of aldicarb and methamidophos neurotoxicity at different ages in the rat: Behavioral and biochemical parameters SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE aldicarb; methamidophos; age; sensitive populations; neurobehavior; cholinesterase; rat ID NEUROBEHAVIORAL SCREENING BATTERY; FUNCTIONAL OBSERVATIONAL BATTERY; NICOTINIC ACETYLCHOLINE-RECEPTOR; ORGANOPHOSPHORUS COMPOUNDS; ORGANO-PHOSPHATE; CHOLINESTERASE-INHIBITORS; CARBAMATE INSECTICIDE; MUSCARINIC RECEPTORS; ESTERASE-ACTIVITIES; ORAL CHLORPYRIFOS AB Young organisms are often more sensitive to the toxic effects of pesticides, and this finding has spurred research on further characterization of this susceptibility. The neurotoxic effects of cholinesterase (ChE)-inhibiting pesticides are of particular concern for human health risk assessment due to the widespread exposure potential in children. This study evaluated age-related differences in susceptibility for a carbamate (aldicarb) and an organophosphorus pesticide (methamidophos). Comparisons were made between preweanling (Postnatal Day 17, PND17), postweanling (PND27), and adult (similar to PND70) male and female rats. All were acute studies using oral administration. Sensitivity was quantified by (1) determination of maximally-tolerated doses (MTDs); (2) measurement of brain and blood ChE inhibition; and (3) neurobehavioral evaluation using end points known to be sensitive indicators of exposure to anticholinesterases. MTD data showed that preweanling rats were twice as sensitive as adults to aldicarb, but there was no differential sensitivity to methamidophos. The dose- response data for brain ChE inhibition followed a similar pattern of age-related differences, and similar levels of inhibition were measured at the MTD regardless of age. Dose-response and time course studies of neurobehavioral end points indicated that differential effects due to age depend on the behavioral end point examined. Following aldicarb administration, the dose-response curves for a few end points overlapped; however, the young rats otherwise showed fewer signs of toxicity than did the adults despite similar levels of brain ChE inhibition. Motor activity assessment showed that aldicarb did not produce any activity depression in PND17 rats, whereas the data for the PND27 and adult rats overlapped. With methamidophos, the dose-response curves for most end points for preweanling and adult rats were quite similar. Aldicarb-induced ChE inhibition was readily reversible in all age groups, whereas with methamidophos, enzyme activity recovered more rapidly in the young. Most behavioral alterations had recovered by 24 h with either pesticide. The results of these studies indicate that (1) ChE-inhibiting pesticides are not all the same regarding relative sensitivity of the young; (2) age-related differences were reflected in both the MTDs and degree of ChE inhibition; and (3) age-related differences in neurobehavioral measures depended on the pesticide and on the end points examined. C1 NIEHS, Div Neurotoxicol, US EPA, Res Triangle Pk, NC 27709 USA. RP Moser, VC (reprint author), NIEHS, Div Neurotoxicol, US EPA, Res Triangle Pk, NC 27709 USA. NR 71 TC 43 Z9 44 U1 0 U2 5 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 JUN 1 PY 1999 VL 157 IS 2 BP 94 EP 106 DI 10.1006/taap.1999.8675 PG 13 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 207AC UT WOS:000080912300002 PM 10366542 ER PT J AU Fan, QR Mosyak, L Garboczi, DN Winter, CC Wagtmann, N Long, EO Wiley, DC AF Fan, QR Mosyak, L Garboczi, DN Winter, CC Wagtmann, N Long, EO Wiley, DC TI Structure of a human natural killer cell inhibitory receptor SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 1st International Conference on HLA-G CY JUL 06-07, 1998 CL PARIS, FRANCE ID HLA-C; DIRECT BINDING; COMPLEX; SUPERFAMILY; HORMONE; LYSIS C1 Harvard Univ, Howard Hughes Med Inst, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Wiley, DC (reprint author), Harvard Univ, Howard Hughes Med Inst, Dept Mol & Cellular Biol, 7 Divin Ave, Cambridge, MA 02138 USA. NR 13 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0041-1345 J9 TRANSPLANT P JI Transplant. Proc. PD JUN PY 1999 VL 31 IS 4 BP 1871 EP 1872 DI 10.1016/S0041-1345(99)00193-1 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 204JR UT WOS:000080761400037 PM 10371978 ER PT J AU Bravo, NR AF Bravo, NR TI Careers-perspective interview - Norka Ruiz Bravo SO TRENDS IN CELL BIOLOGY LA English DT Editorial Material C1 NCI, Div Canc Biol, NIH, Bethesda, MD 20892 USA. RP Bravo, NR (reprint author), NCI, Div Canc Biol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD JUN PY 1999 VL 9 IS 6 BP 245 EP 245 PG 1 WC Cell Biology SC Cell Biology GA 221ZX UT WOS:000081758700009 ER PT J AU Sheng, HZ Westphal, H AF Sheng, HZ Westphal, H TI Early steps in pituitary organogenesis SO TRENDS IN GENETICS LA English DT Review ID ANTERIOR NEURAL PLATE; HOMEOBOX GENE LHX3; HOMEODOMAIN FACTOR; CELL-DIFFERENTIATION; RATHKES POUCH; MOUSE; PIT-1; LIM; FGF8; MESENCHYME AB Significant advances have been made in defining the transcription cascade that is responsible for the early steps of pituitary formation and the environmental signals that induce, pattern and specify the pituitary gland and its cell types. It is now possible to outline the molecular mechanisms underlying the formation of the pituitary gland, as well as the initial development of organ-specific cell types. C1 NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Sheng, HZ (reprint author), NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. NR 36 TC 93 Z9 94 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD JUN PY 1999 VL 15 IS 6 BP 236 EP 240 DI 10.1016/S0168-9525(99)01742-4 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 215KD UT WOS:000081380100011 PM 10354584 ER PT J AU Reddy, PH Williams, M Tagle, DA AF Reddy, PH Williams, M Tagle, DA TI Recent advances in understanding the pathogenesis of Huntington's disease SO TRENDS IN NEUROSCIENCES LA English DT Article ID NEURONAL INTRANUCLEAR INCLUSIONS; CAG REPEAT; TRANSGENIC MICE; PALLIDOLUYSIAN ATROPHY; NEUROLOGICAL PHENOTYPE; TRINUCLEOTIDE REPEATS; EMBRYONIC LETHALITY; GLUTAMINE REPEATS; MURINE HUNTINGTIN; EXPANDING WORLD AB Huntington's disease (HD) is an autosomal, dominantly inherited neurodegenerative disorder that is characterized by abnormal involuntary. movements (chorea), intellectual impairment and selective neuronal loss. The expansion of a polymorphic trinucleotide repeat (the sequence CAG that codes for glutamine) to a length that exceeds 40 repeat units in exon I of the gene, HD, correlates with the onset and progression of the disease. The protein encoded by HD, huntingtin, is normally localized in the cytoplasm, whereas the mutant protein is also found in the nucleus, suggesting that its translocation to this site is important for the pathogenesis of HD. Although several proteins that interact with huntingtin have been identified in vitro, the significance of these interactions with the mutant protein in the pathogenesis of HD has yet to be determined. Recent progress in the development of cellular and animal models for the disease have provided invaluable insights and resources for studying the disease mechanisms underlying HD, and will be useful for screening and evaluating possible therapeutic strategies. C1 Natl Ctr Human Genome Inst, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Reddy, PH (reprint author), Natl Ctr Human Genome Inst, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. NR 70 TC 128 Z9 133 U1 1 U2 7 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD JUN PY 1999 VL 22 IS 6 BP 248 EP 255 DI 10.1016/S0166-2236(99)01415-0 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 215JF UT WOS:000081378000003 PM 10354600 ER PT J AU Murphy, DL Wichems, C Li, Q Heils, A AF Murphy, DL Wichems, C Li, Q Heils, A TI Molecular manipulations as tools for enhancing our understanding of 5-HT neurotransmission SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID RECEPTOR MUTANT MICE; TRANSPORTER KNOCKOUT MICE; MONOAMINE-OXIDASE-A; AGGRESSIVE-BEHAVIOR; BRAIN-SEROTONIN; TRANSGENIC MICE; DEFICIENT MICE; 5-HYDROXYTRYPTAMINE(1B) RECEPTORS; M-CHLOROPHENYLPIPERAZINE; SOMATOSENSORY CORTEX AB A developing trend in exploring the sites at which drugs act is to use molecular rather than chemical agents to alter receptors, intracellular signalling mechanisms or gene expression. The 5-HT neurotransmission system is targeted by drugs useful in many behavioural disorders, including anxiety, depression, psychosis and eating disorders. It also regulates many physiological functions and provides some examples of the potential use of these new molecular approaches. This article reviews the progress made in the molecular manipulation of 5-HT receptors and discusses the potential of such tools for the treatment of diseases associated with the 5-HT transmission system. C1 NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. RP Murphy, DL (reprint author), NIMH, Clin Sci Lab, Bldg 10,Room 3D41,10 Ctr Dr,MSC 1264, Bethesda, MD 20892 USA. NR 82 TC 52 Z9 52 U1 4 U2 6 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD JUN PY 1999 VL 20 IS 6 BP 246 EP 252 DI 10.1016/S0165-6147(99)01325-5 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 215KH UT WOS:000081380500004 PM 10366867 ER PT J AU Krivanek, O Leapman, R Sarikaya, M AF Krivanek, O Leapman, R Sarikaya, M TI Proceedings of the International Workshop towards Atomic Resolution Analysis - Port Ludlow, Washington, USA, 6-11 September 1998 - Part 1: Techniques and instrumentation - Foreword SO ULTRAMICROSCOPY LA English DT Editorial Material C1 Univ Washington, Seattle, WA 98195 USA. NIH, Bethesda, MD 20892 USA. RP Krivanek, O (reprint author), Univ Washington, Seattle, WA 98195 USA. NR 0 TC 6 Z9 6 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3991 J9 ULTRAMICROSCOPY JI Ultramicroscopy PD JUN PY 1999 VL 78 IS 1-4 BP IX EP IX PG 1 WC Microscopy SC Microscopy GA 206PC UT WOS:000080887400001 ER PT J AU Leapman, RD Rizzo, NW AF Leapman, RD Rizzo, NW TI Towards single atom analysis of biological structures SO ULTRAMICROSCOPY LA English DT Article; Proceedings Paper CT International Workshop Towards Atomic Resolution Analysis (TARA) CY SEP 06-11, 1998 CL PORT LUDLOW, WASHINGTON SP Gatan, Hitachi, JEOL, LEO, Philips, FEI DE electron energy loss spectroscopy (EELS); scanning transmission electron microscopy (STEM); spectrum-imaging; compositional mapping; detection limits; phosphorus; DNA; tobacco mosaic virus ID ELECTRON-ENERGY-LOSS; LOSS SPECTROSCOPY; SPATIAL-RESOLUTION; ELEMENTAL ANALYSIS; CROSS-SECTIONS; MICROANALYSIS; EELS; SPECTROMETER; ORGANIZATION; MICROSCOPY AB Mapping single atoms in biological structures is now becoming within the reach of analytical electron microscopy. Electron energy-loss spectroscopy (EELS) in the field-emission scanning transmission electron microscope (STEM) provides a particularly high sensitivity for detecting the biologically important element, phosphorus. Imaging can be performed at low dose with dark-field STEM prior to analysis at high dose, so that structures of macromolecular assemblies can be correlated with the numbers of specific atoms that they contain. Measurements confirm theoretical predictions that single atom detection requires a nanometer-sized probe. Although phosphorus atoms may have moved several nanometers from their original positions by beam-induced structural degradation at the high required dose of similar to 10(9) e/nm(2), damaged molecules are nevertheless stable enough to be analyzed at 1 or 2 nm resolution. Such analyses can only be achieved by means of spectrum-imaging with correction for specimen drift. Optimal strategies for mapping small numbers of phosphorus atoms have been investigated using well-characterized specimens of DNA plasmids and tobacco mosaic virus. Published by Elsevier Science B.V. C1 NIH, Bioengn & Phys Sci Program, ORS, Bethesda, MD 20892 USA. RP Leapman, RD (reprint author), NIH, Bioengn & Phys Sci Program, ORS, Bldg 10, Bethesda, MD 20892 USA. NR 32 TC 37 Z9 38 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3991 J9 ULTRAMICROSCOPY JI Ultramicroscopy PD JUN PY 1999 VL 78 IS 1-4 BP 251 EP 268 DI 10.1016/S0304-3991(99)00031-5 PG 18 WC Microscopy SC Microscopy GA 206PC UT WOS:000080887400023 PM 10389278 ER PT J AU Varma, A Kwon-Chung, KJ AF Varma, A Kwon-Chung, KJ TI Characterization of the Glyceraldehyde-3-phosphate Gene and the use of its promoter for heterologous expression in Cryptococcus neoformans, a human pathogen SO GENE LA English DT Article DE gene expression; GPD; hygromycin; plasmid; transformation ID SCHIZOPHYLLUM-COMMUNE; DEHYDROGENASE; VIRULENCE; IDENTIFICATION; SYSTEM; YEAST; DNA AB The GPD gene encoding glyceraldehyde-3-phosphate dehydrogenase was isolated from Cryptococcus neoformans, a heterobasidiomycetous yeast that is pathogenic to humans. The gene contains 11 introns, differing from the conserved intron positions found in the GPD genes of Basidiomycetes. The predicted amino-acid sequence of this gene is extremely similar to that reported from GPD proteins of other basidiomycetes. The promoter region of the C. neoformans GPD gene was similar to those of other basidiomycetes. Plasmid constructs containing up to 1600 base pairs upstream of the native GPD open reading frame were used to express either the native URA5 gene in a ura5 mutant or the heterologous hphI gene (a bacterial gene that confers resistance to the aminoglycoside hygromycin) in a wild-type strain of C. neoformans. Transformation frequencies resulting from the plasmid-borne Gpd(p):: URA5 gene were at levels similar to those of the native URA5, which suggested that all the sequences necessary for proper expression were present. Transformation frequencies using the Gpd(p)::hphI gene constructs were poor. However, addition of DNA sequences flanking the 3'-end of an native C. neoformans gene significantly improved the transformation frequencies resulting from the expression of the heterologous hphI gene. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIAID, Clin Invest Lab, Mol Microbiol Sect, NIH, Bethesda, MD 20892 USA. RP Kwon-Chung, KJ (reprint author), NIAID, Clin Invest Lab, Mol Microbiol Sect, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 20 TC 22 Z9 24 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD MAY 31 PY 1999 VL 232 IS 2 BP 155 EP 163 DI 10.1016/S0378-1119(99)00132-8 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 204XC UT WOS:000080789800002 PM 10352226 ER PT J AU Burbelo, PD Kozak, CA Finegold, AA Hall, A Pirone, DM AF Burbelo, PD Kozak, CA Finegold, AA Hall, A Pirone, DM TI Cloning, central nervous system expression and chromosomal mapping of the mouse PAK-1 and PAK-3 genes SO GENE LA English DT Article DE Cdc42; kinase signaling; Rac; Rho GTPases ID ACTIVATED PROTEIN-KINASE; LINKED MENTAL-RETARDATION; ACTIN ORGANIZATION; MOLECULAR-CLONING; TARGET PROTEINS; RAC GTPASE; CDC42; CELL; TRANSFORMATION; MEMBRANE AB Two cDNAs encoding PAK kinases were isolated from a mouse embryo library by screening with a PCR-generated probe derived from the kinase domain of a rat PAK kinase. These cDNAs, designated PAK-1 and PAK-3? encode mouse PAK kinases of 545 and 544 amino acids, respectively. Both proteins possess an N-terminal Cdc42/Rac interacting binding domain (CRIB) and a C-terminal serine/threonine kinase domain. Comparison of the two mouse PAK kinases revealed that the proteins show 87% amino acid identity. Northern analysis of a multiple mouse tissue blot with a PAK-1 probe detected a 3.0 kb transcript that was almost exclusively expressed in the brain and spinal cord compared to other tissues such as lung, liver and kidney. A similar pattern of central nervous system tissue expression of PAK-3 transcripts of 3.6 and 8 kb was also observed. Analysis of two multilocus genetic crosses localized Pak1 and Pak3 to a position on chromosome 7 and X, respectively. The high level of PAK-1 and PAK-3 kinase expression in the mouse brain and spinal cord suggests a potentially important role for these kinases in the control of the cellular architecture and/or signaling in the central nervous system. (C) 1999 Published by Elsevier Science B.V. All rights reserved. C1 Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. NIDR, Pain & Neurosensory Mechanisms Branch, NIH, Bethesda, MD 20892 USA. Univ London Univ Coll, Dept Biochem, MRC, Mol Cell Biol Lab, London WC1E 6BT, England. RP Burbelo, PD (reprint author), Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. RI Burbelo, Peter/B-1027-2009 FU NCI NIH HHS [R29-CA77459-01] NR 26 TC 12 Z9 15 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD MAY 31 PY 1999 VL 232 IS 2 BP 209 EP 215 DI 10.1016/S0378-1119(99)00110-9 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 204XC UT WOS:000080789800008 PM 10352232 ER PT J AU Olsen, JH McLaughlin, JK Nyren, O Mellemkjaer, L Lipworth, L Blot, WJ Fraumeni, JF AF Olsen, JH McLaughlin, JK Nyren, O Mellemkjaer, L Lipworth, L Blot, WJ Fraumeni, JF TI Hip and knee implantations among patients with osteoarthritis and risk of cancer: A record-linkage study from Denmark SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID ORTHOPEDIC PROSTHESES; JOINT REPLACEMENT; MALIGNANCY AB A nationwide cohort study of hip and knee replacement patients in Denmark was undertaken to assess any carcinogenic potential of these implants. A cohort of 22,997 osteoarthritis patients who received hip replacements and of 4,771 osteoarthritis patients who received knee replacements during the period 1977 through 1989 were identified using the nationwide Danish Hospital Discharge Registry. These patients were followed for cancer occurrence through 1993, using the Danish Cancer Registry. There was no overall excess of cancer in either the hip implant cohort [standardized incidence ratio (SIR) = 0.94; 95% confidence interval (CI) = 0.91-0.98] or the knee implant cohort (SIR = 0.97; 95% CI = 0.89-1.06). The risk reduction in both groups of patients reflected for the most part reduced risks for cancers of the respiratory system and the digestive tract, particularly stomach cancer (SIR = 0.69; 95% CI = 0.50-0.81 for hip replacement patients; SIR = 0.46; 95% CI = 0.20-0.91 for knee replacement patients). Elevated risks were observed for melanoma of the skin in both groups of patients. There was no clear excess risk for lymphohematopoietic cancers or malignant neoplasms of the bone or connective tissue among implant patients in either implant group. Contrary to an earlier study in Sweden, we did not find an excess risk for kidney or prostate cancers. In summary, these nationwide results indicate no overall cancer hazard among hip and knee implant patients, but limited follow-up warrants continued surveillance of individuals undergoing these increasingly common surgical procedures. (C) 1999 Wiley-Liss, Inc. C1 Danish Canc Soc, Inst Canc Epidemiol, DK-2100 Copenhagen, Denmark. Int Epidemiol Inst, Rockville, MD USA. Karolinska Inst, Dept Med Epidemiol, Stockholm, Sweden. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Olsen, JH (reprint author), Danish Canc Soc, Inst Canc Epidemiol, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. NR 24 TC 27 Z9 27 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAY 31 PY 1999 VL 81 IS 5 BP 719 EP 722 DI 10.1002/(SICI)1097-0215(19990531)81:5<719::AID-IJC8>3.0.CO;2-D PG 4 WC Oncology SC Oncology GA 191TR UT WOS:000080038100008 PM 10328222 ER PT J AU Bonifacino, JS Dell'Angelica, EC AF Bonifacino, JS Dell'Angelica, EC TI Molecular bases for the recognition of tyrosine-based sorting signals SO JOURNAL OF CELL BIOLOGY LA English DT Review ID CLATHRIN-ASSOCIATED PROTEINS; FACTOR-II RECEPTOR; ADAPTER-COMPLEX; MEDIUM CHAINS; CYTOPLASMIC TAIL; COATED PITS; MDCK CELLS; MOTIF; ENDOCYTOSIS; INTERNALIZATION C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bldg 18T,Room 101, Bethesda, MD 20892 USA. OI Bonifacino, Juan S./0000-0002-5673-6370 NR 42 TC 334 Z9 338 U1 1 U2 7 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD MAY 31 PY 1999 VL 145 IS 5 BP 923 EP 926 DI 10.1083/jcb.145.5.923 PG 4 WC Cell Biology SC Cell Biology GA 203ZH UT WOS:000080738100001 PM 10352010 ER PT J AU Jefferson, TO Rabinovich, R Tuomilehto, J AF Jefferson, TO Rabinovich, R Tuomilehto, J TI Vaccines and their real or perceived adverse effects - Authors' conclusions are at odds with investigators' SO BRITISH MEDICAL JOURNAL LA English DT Letter C1 Cochrane Ctr, Oxford OX2 7LG, England. NIAID, Clin & Regulatory Affairs Branch, Div Microbiol & Infect Dis, Bethesda, MD 20892 USA. Natl Publ Hlth Inst, Diabet & Genet Epidemiol Unit, SF-00300 Helsinki, Finland. RP Jefferson, TO (reprint author), Cochrane Ctr, Oxford OX2 7LG, England. NR 6 TC 1 Z9 1 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-8138 J9 BRIT MED J JI Br. Med. J. PD MAY 29 PY 1999 VL 318 IS 7196 BP 1487 EP 1487 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 202TL UT WOS:000080668200047 PM 10346786 ER PT J AU Stewart, P AF Stewart, P TI Exposure assessment in community-based epidemiological studies SO LANCET LA English DT Editorial Material C1 NCI, Occupat Epidemiol Branch, Rockville, MD 20892 USA. RP Stewart, P (reprint author), NCI, Occupat Epidemiol Branch, Rockville, MD 20892 USA. NR 4 TC 6 Z9 6 U1 0 U2 1 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD MAY 29 PY 1999 VL 353 IS 9167 BP 1816 EP 1817 DI 10.1016/S0140-6736(99)90075-2 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 202TG UT WOS:000080667800006 PM 10359403 ER PT J AU Olivero, OA Shearer, GM Chougnet, CA Kovacs, AAS Landay, AL Baker, R Stek, AM Khoury, MM Proia, LA Kessler, HA Sha, BE Tarone, RE Poirier, MC AF Olivero, OA Shearer, GM Chougnet, CA Kovacs, AAS Landay, AL Baker, R Stek, AM Khoury, MM Proia, LA Kessler, HA Sha, BE Tarone, RE Poirier, MC TI Incorporation of zidovudine into leukocyte DNA from HIV-1-positive adults and pregnant women, and cord blood from infants exposed in utero SO AIDS LA English DT Article DE AIDS; 3 ' azido-3 '-deoxythymidine; HIV-1; peripheral blood mononuclear cells; radioimmunoassay ID IMMUNODEFICIENCY-VIRUS TYPE-1; ANTIRETROVIRAL THERAPY; 3'-AZIDO-2',3'-DIDEOXYTHYMIDINE AZT; HIV-INFECTION; MICE; TRANSMISSION; LYMPHOMA AB Objective: The nucleoside analog 3'-azido-3'-deoxythymidine (ZDV) has widespread clinical use but also is carcinogenic in newborn mice exposed to the drug in utero and becomes incorporated into newborn mouse DNA. This pilot study was designed to determine ZDV incorporation into human blood cell DNA from adults and newborn infants. Design: in this prospective cohort study, peripheral brood mononuclear cells (PBMC) were obtained from 28 non-pregnant adults and 12 pregnant women given ZDV therapy, six non-pregnant adults with no exposure to ZDV, and six non-pregnant adults who last received ZDV greater than or equal to 6 months previously. In addition, cord blood leukocytes were obtained from 22 infants of HIV-1-positive, ZDV-exposed women and from 12 infants unexposed to ZDV. There were 11 mother-infant pairs involving HIV-1-positive women. Methods: DNA was extracted from PBMC obtained from non-pregnant HIV-1-positive adults taking ZDV, pregnant HIV-1-positive women given ZDV during pregnancy, and from adults not taking ZDV. Cord blood leukocytes were examined from infants exposed to ZDV in utero and from unexposed controls. DNA samples were assayed for ZDV incorporation by anti-ZDV radioimmunoassay (RIA). Results: The majority (76%) of samples from ZDV-exposed individuals, pregnant women (8 of 12), non-pregnant adults (24 of 28), or infants at delivery (15 of 22), had detectable ZDV-DNA levels. The range of positive values far ZDV-treated adults and infants was 25-544 and 22-452 molecules ZDV/10(6) nucleotides, respectively. Analysis of 11 mother-infant pairs showed variable ZDV-DNA incorporation in both, with no correlation by pair or by duration of drug treatment during pregnancy. Two of the 24 samples from individuals designated as controls were positive by anti-ZDV RIA. The 20-fold range for ZDV-DNA values in both adults and infants suggested large interindividual differences in ZDV phosphorylation. Conclusions: Incorporation of ZDV into DNA was detected in most of the samples from ZDV-exposed adults and infants. Therefore, the biologic significance of ZDV-DNA damage and potential subsequent events, such as mutagenicity, should be Further investigated in large cohorts of HIV-positive individuals. The interindividual variability of ZDV incorporation into DNA in humans is considerable and consistent with reported variability in the formation of the ZDV-trisphosphate, (C) 1999 Lippincott Williams & Wilkins. C1 NCI, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Univ So Calif, Sch Med, Comprehens Maternal Child HIV Management & Res Ct, Los Angeles, CA 90033 USA. Rush Presbyterian St Lukes Med Ctr, Dept Med, Chicago, IL 60612 USA. Rush Presbyterian St Lukes Med Ctr, Dept Immunol Microbiol, Chicago, IL 60612 USA. Fairfax Inova Hosp, Dept Neonatol, Falls Church, VA 22046 USA. NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. RP Olivero, OA (reprint author), NCI, Div Basic Sci, NIH, Bldg 37,Rm 2A01,NIH37 Convent Dr,MSC-4255, Bethesda, MD 20892 USA. FU NCRR NIH HHS [M01RR-43] NR 28 TC 93 Z9 95 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAY 28 PY 1999 VL 13 IS 8 BP 919 EP 925 DI 10.1097/00002030-199905280-00007 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 199VG UT WOS:000080504300007 PM 10371172 ER PT J AU Moriuchi, H Moriuchi, M AF Moriuchi, H Moriuchi, M TI Dichotomous effects of macrophage-derived chemokine on HIV infection SO AIDS LA English DT Letter ID T-CELLS; BETA-CHEMOKINES; REPLICATION; RANTES; MDC; MIP-1-BETA; ACTIVATION; RECEPTOR; STRAINS; ENHANCE C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Moriuchi, H (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 16 TC 8 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAY 28 PY 1999 VL 13 IS 8 BP 994 EP 996 DI 10.1097/00002030-199905280-00019 PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 199VG UT WOS:000080504300019 PM 10371184 ER PT J AU Misra, S Hurley, JH AF Misra, S Hurley, JH TI Crystal structure of a phosphatidylinositol 3-phosphate-specific membrane-targeting motif, the FYVE domain of Vps27p SO CELL LA English DT Article ID PROTEIN-KINASE-C; BINDING DOMAIN; X-RAY; DIFFRACTION DATA; PHOSPHOLIPASE-C; NMR STRUCTURE; FINGERS; REFINEMENT; PTDINS(3)P; COMPLEX AB Phosphatidylinositol 3-phosphate regulates membrane trafficking and signaling pathways by interacting with the FYVE domains of target proteins. The 1.15 Angstrom structure of the Vps27p FYVE domain reveals two antiparallel beta sheets and an alpha helix stabilized by two Zn2+-binding clusters. The core secondary structures are similar to a rabphilin-3A Zn2+-binding domain and to the C1 and LIM domains. Phosphatidylinositol 3-phosphate binds to a pocket formed by the (R/K)(R/K)HHCR motif. A lattice contact shows how anionic ligands can interact with the phosphatidylinositol 3-phosphate-binding site. The tip of the FYVE domain has basic and hydrophobic surfaces positioned so that nonspecific interactions with the phospholipid bilayer can abet specific binding to phosphatidylinositol 3-phosphate. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. OI Misra, Saurav/0000-0002-1385-8554 NR 64 TC 180 Z9 182 U1 2 U2 8 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD MAY 28 PY 1999 VL 97 IS 5 BP 657 EP 666 DI 10.1016/S0092-8674(00)80776-X PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 202VD UT WOS:000080672100014 PM 10367894 ER PT J AU Lopez-Hernandez, E Santos, E AF Lopez-Hernandez, E Santos, E TI Oncogenic Ras-induced germinal vesicle breakdown is independent of phosphatidylinositol 3-kinase in Xenopus oocytes SO FEBS LETTERS LA English DT Article DE Ras; phosphatidylinositol 3-kinase; germinal vesicle breakdown; Xenopus oocyte; insulin; signal transduction ID INSULIN-RECEPTOR SUBSTRATE-1; MEIOTIC MATURATION; PROTEIN-KINASE; GLUCOSE-TRANSPORT; SH2 DOMAINS; MAP KINASE; PHOSPHOINOSITIDE 3-KINASE; SIGNALING PATHWAYS; IN-VITRO; ACTIVATION AB A number of reports have identified phosphatidylinositol 3-kinase as a downstream effector of Ras in various cellular settings, in contrast to others supporting the notion that phosphatidylinositol 3-kinase acts upstream of Ras. Here, we used Xenopus oocytes, a model of Ras-mediated cell cycle progression (G2/M transition) to analyze the contribution of phosphatidylinositol 3-kinase to insulin/Ras-dependent signaling pathways leading to germinal vesicle breakdown and to ascertain whether phosphatidylinositol 3-kinase acts upstream or downstream of Ras in those signaling pathways. We analyzed the process of meiotic maturation induced by progesterone, insulin or micro-injected oncogenic Ras (Lys12) proteins in the presence and absence of specific inhibitors of phosphatidylinositol 3-kinase activity. As expected, the progesterone-induced maturation was independent of phosphatidylinositol 3-kinase since similar rates of germinal vesicle breakdown were produced by the hormone in the presence and absence of wortmannin and LY294002. In contrast, insulin-induced germinal vesicle breakdown was completely blocked by pre-incubation with the inhibitors prior to insulin treatment. Interestingly, similar rates of germinal vesicle breakdown were obtained in Ras (Lys12)-injected oocytes, independently of whether or not they had been pre-treated with phosphatidylinositol 3-kinase inhibitors. The effect of wortmannin or LY294002 on MAPK and Akt activation by progesterone, insulin or Ras was also analyzed. Whereas insulin activated those kinases in a phosphatidylinositol 3-kinase-dependent manner, progesterone and Ras were able to activate those kinases in the absence of phosphatidylinositol 3-kinase activity. Since Ras is a necessary and sufficient downstream component of insulin signaling pathways leading to germinal vesicle breakdown, these observations demonstrate that phosphatidylinositol 3-kinase is not a downstream effector of Ras in insulin/Ras-dependent signaling pathways leading to entry into the M phase in Xenopus oocytes. (C) 1999 Federation of European Biochemical Societies. C1 NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Santos, E (reprint author), NCI, Cellular & Mol Biol Lab, NIH, Bldg 37,Room 1C27, Bethesda, MD 20892 USA. NR 58 TC 22 Z9 22 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD MAY 28 PY 1999 VL 451 IS 3 BP 284 EP 288 DI 10.1016/S0014-5793(99)00595-5 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 203JE UT WOS:000080704000015 PM 10371206 ER PT J AU Boix, E Nikolovski, Z Moiseyev, GP Rosenberg, HF Cuchillo, CM Nogues, MV AF Boix, E Nikolovski, Z Moiseyev, GP Rosenberg, HF Cuchillo, CM Nogues, MV TI Kinetic and product distribution analysis of human eosinophil cationic protein indicates a subsite arrangement that favors exonuclease-type activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BOVINE PANCREATIC RIBONUCLEASE; SITE-DIRECTED MUTAGENESIS; CRYSTAL-STRUCTURE; CATALYTIC PROPERTIES; SECONDARY STRUCTURE; MASS-SPECTROMETRY; MOLECULAR-CLONING; GRANULE PROTEINS; BINDING SUBSITES; NEUROTOXIN AB With the use of a high yield prokaryotic expression system, large amounts of human eosinophil cationic protein (ECP) have been obtained. This has allowed a thorough kinetic study of the ribonuclease activity of this protein. The catalytic efficiencies for oligouridylic acids of the type (Up)(n)U>p, mononucleotides U>p and C>p, and dinucleoside monophosphates CpA, UpA, and UpG have been interpreted by the specific subsites distribution in ECP, The distribution of products derived from digestion of high molecular mass substrates, such as poly(U) and poly(C), by ECP was compared with that of RNase A The characteristic cleavage pattern of polynucleotides by ECP suggests that an exonuclease-like mechanism is predominantly favored in comparison to the endonuclease catalytic mechanism of RNase A. Comparative molecular modeling with bovine pancreatic RNase A-substrate analog crystal complexes revealed important differences in the subsite structure, whereas the secondary phosphate-binding site (p(2)) is lacking, the secondary base subsite (B-2) is severely impaired, and there are new interactions at the p(o), B-o, and p(-1) sites, located upstream of the P-O-5' cleavable phosphodiester bond, that are not found in RNase A. The differences in the multisubsites structure could explain the reduced catalytic efficiency of ECP and the shift from an endonuclease to an exonuclease-type mechanism. C1 Univ Autonoma Barcelona, Dept Bioquim & Biol Mol, Fac Ciencies, Bellaterra 08193, Spain. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Nogues, MV (reprint author), Univ Autonoma Barcelona, Dept Bioquim & Biol Mol, Fac Ciencies, Bellaterra 08193, Spain. RI Boix, Ester/B-9038-2012; Nogues, Victoria/H-6100-2015 OI Boix, Ester/0000-0003-1790-2142; Nogues, Victoria/0000-0002-7104-0961 NR 68 TC 62 Z9 62 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 28 PY 1999 VL 274 IS 22 BP 15605 EP 15614 DI 10.1074/jbc.274.22.15605 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 200VE UT WOS:000080560100046 PM 10336457 ER PT J AU Efrati, E Tocco, G Eritja, R Wilson, SH Goodman, MF AF Efrati, E Tocco, G Eritja, R Wilson, SH Goodman, MF TI "Action-at-a-distance" mutagenesis - 8-oxo-7,8-dihydro-2 '-deoxyguanosine causes base substitution errors at neighboring template sites when copied by DNA polymerase beta SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ESCHERICHIA-COLI; 8-HYDROXYGUANINE 7,8-DIHYDRO-8-OXOGUANINE; NUCLEOSIDE TRIPHOSPHATASE; MUTT PROTEIN; REPLICATION; INSERTION; FIDELITY; EXCISION; LESION; REPAIR AB 8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG), a common oxidative DNA lesion, favors a syn-conformation in DNA, enabling formation of stable 8-oxo-dG A base mispairs resulting in G.C --> T.A transversion mutations. When human DNA polymerase (pol) beta was used to copy a short single-stranded gap containing a site-directed 8-oxo-dG lesion, incorporation of dAMP opposite 8-oxo-dG was slightly favored over dCMP depending on "downstream" sequence context. Unexpectedly, however, a significant increase in dCMP A and dGMP A mispairs was also observed at the "upstream" 3'-template site adjacent to the lesion. Errors at these undamaged template sites occurred in four sequence contexts with both gapped and primed single-stranded DNA templates, but not when pol alpha replaced pol beta. Error rates at sites adjacent to 8-oxo-dG were roughly 1% of the values opposite 8-oxo-dG:, potentially generating tandem mutations during in vivo short-gap repair synthesis by pol beta, When 8-oxo-dG was replaced with 8-bromo-2'-deoxyguanosine, incorporation of dCMP was strongly favored by both enzymes, with no detectable misincorporation occurring at neighboring template sites. C1 Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA. Univ So Calif, Dept Chem, Hedco Mol Biol Labs, Los Angeles, CA 90089 USA. European Mol Biol Org, D-69012 Heidelberg, Germany. NIEHS, Res Triangle Pk, NC 27709 USA. RP Goodman, MF (reprint author), Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA. RI eritja, ramon/B-5613-2008 OI eritja, ramon/0000-0001-5383-9334 FU NIGMS NIH HHS [GM21422] NR 31 TC 56 Z9 62 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 28 PY 1999 VL 274 IS 22 BP 15920 EP 15926 DI 10.1074/jbc.274.22.15920 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 200VE UT WOS:000080560100087 PM 10336498 ER PT J AU Mulligan-Kehoe, MJ Russo, A AF Mulligan-Kehoe, MJ Russo, A TI Inhibition of cytoplasmic antigen, glucose-6-phosphate dehydrogenase, by V-H-C(H)1, an intracellular Fd fragment antibody derived from a semisynthetic Fd fragment phage display library SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE phage display; Fd fragment; random CDRIII library; intracellular inactivation; proteasomal degradation ID CHAIN VARIABLE FRAGMENTS; VIRAL LIFE-CYCLE; ESCHERICHIA-COLI; MONOCLONAL-ANTIBODIES; REVERSE-TRANSCRIPTASE; FILAMENTOUS PHAGE; HIV-1 INFECTION; GENE SEGMENTS; IN-VITRO; EXPRESSION AB A library of Fd fragment antibody binding proteins was created by random mutation of 15 nucleotides within the CDRIII region of the immunoglobulin heavy chain gene and displayed as Fd coat protein fusion constructs of M13 phage. The library was screened for those V-H binding sites that bound glucose-6-phosphate dehydrogenase (G6PD). One isolate (DH27(bp)) inhibited G6PD activity by 85%. The DH27(bp) gene was reengineered, placed in a eukaryotic expression vector having an isopropyl-beta-delta-thiogalactopyranoside (IPTG) inducible promoter, and transfected and then expressed in Chinese hamster V79 cells. G6PD activity was completely inhibited. Removal of IPTG reverted the cell to full G6PD activity: The intracellular dynamics of the G6PD/DH27(bp) complex showed that when the proteasomes of cells expressing DH27(bp) were inhibited (N-acetyl-Leu-Leu-norleucinal or lactacystin) G6PD activity increased. Metabolic labelling of newly synthesized IPTG-induced proteins during/absence of proteasomal inhibitors showed that both G6PD and DH27(bp) are signaled for degradation when the intracellular complex is formed, furthermore, semi-quantitative RT/PCR demonstrated that GGPD mRNA is upregulated over the time course of G6PD inactivation by DH27(bp) Fd binding protein. These effects were not observed in those cells expressing a non-mutated Fd (UMHC) or in IPTG-treated non-transduced V79 cells. Our results demonstrate that an Fd-based intracellular binding protein can find and disable the function of a specific intracellular target and once the Fd expression is repressed the activity of intracellular targeted protein can revert to normal. (C) 1999 Academic Press. C1 NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. Dartmouth Coll, Dartmouth Med Sch, Dept Surg, Hanover, NH 03756 USA. RP Mulligan-Kehoe, MJ (reprint author), NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. EM mary.j.mulligan-kehoe@dartmouth.edu NR 75 TC 3 Z9 4 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD MAY 28 PY 1999 VL 289 IS 1 BP 41 EP 55 DI 10.1006/jmbi.1999.2749 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 205JZ UT WOS:000080818700005 PM 10339404 ER PT J AU Dauter, Z Dauter, M de La Fortelle, E Bricogne, G Sheldrick, GM AF Dauter, Z Dauter, M de La Fortelle, E Bricogne, G Sheldrick, GM TI Can anomalous signal of sulfur become a tool for solving protein crystal structures? SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE anomalous scattering of sulfur and chlorine; single wavelength; phasing; lysozyme ID REFINEMENT; SCATTERING; LYSOZYME AB A general method for solving the phase problem from native crystals of macromolecules has long eluded structural biology. For well diffracting crystals this goal can now be achieved, as is shown here, thanks to modern data collection techniques and new statistical phasing algorithms. Using solely a native crystal of tetragonal hen egg-white lysozyme, a protein of 14 kDa molecular mass, it was possible to detect the positions of the ten sulfur and seven chlorine atoms from their anomalous signal, and proceed from there to obtain an electron-density map of very high quality. (C) 1999 Academic Press. C1 Natl Canc Inst, Frederick & Brookhaven Natl Lab, Upton, NY 11973 USA. MRC, Mol Biol Lab, Cambridge CB2 2QH, England. Lab Utilisat Rayonnement Electromagnet, F-91405 Orsay, France. Univ Gottingen, Inst Anorgan Chem, D-37077 Gottingen, Germany. RP Dauter, Z (reprint author), Natl Canc Inst, Frederick & Brookhaven Natl Lab, Bldg 725A-X9, Upton, NY 11973 USA. EM daute@bnl.gov NR 21 TC 184 Z9 187 U1 0 U2 4 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAY 28 PY 1999 VL 289 IS 1 BP 83 EP 92 DI 10.1006/jmbi.1999.2743 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 205JZ UT WOS:000080818700008 PM 10339407 ER PT J AU Dauter, Z Dauter, N AF Dauter, Z Dauter, N TI Anomalous signal of solvent bromides used for phasing of lysozyme SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE anomalous scattering; single wavelength; solvent bromide ions; phasing; lysozyme ID EGG-WHITE LYSOZYME; SCATTERING; REFINEMENT; RESOLUTION; PROTEIN; CRYSTALLOGRAPHY; ANGSTROM; SNB AB The anomalous signal of bromide ions, present in the crystal structure of tetragonal hen egg-white lysozyme through the substitution of NaCl by NaBr in the crystallization medium, was used for phasing of X-ray data collected to 1.7 Angstrom resolution with a wavelength near the absorption edge of bromine. Phasing of a single wavelength data set, based purely on anomalous delta f " contribution, led to easily interpretable electron density, equivalent to the complete multiwavelength anonalous dispersion phasing based on four-wavelength data. The classic small-structure direct methods program SHELXS run against all anomalous differences gave a successful solution of six highest peaks corresponding to six bromide ions in the structure with data limited up to a resolution of 3.5 Angstrom. Interpretable maps were obtained at a resolution up to 3.0 Angstrom using programs MLPHARE and DM. Bromide ions occupy well ordered positions at the protein surface. Phasing based on the single wavelength signal of anomalous scatterers introduced into the ordered solvent shell can be proposed as a tool for solving structures of well diffracting crystals. (C) 1999 Academic Press. C1 Natl Canc Inst, Frederick & Brookhaven Natl Lab, Upton, NY 11973 USA. RP Dauter, Z (reprint author), Natl Canc Inst, Frederick & Brookhaven Natl Lab, NSLS Bldg 725A-X9, Upton, NY 11973 USA. NR 23 TC 67 Z9 67 U1 0 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 MAY 28 PY 1999 VL 289 IS 1 BP 93 EP 101 DI 10.1006/jmbi.1999.2744 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 205JZ UT WOS:000080818700009 PM 10339408 ER PT J AU Chen, XJ Tanner, K Levine, JD AF Chen, XJ Tanner, K Levine, JD TI Mechanical sensitization of cutaneous C-fiber nociceptors by prostaglandin E-2 in the rat SO NEUROSCIENCE LETTERS LA English DT Article DE primary afferent nociceptor; mechanical hyperalgesia; pain ID ASPIRIN-LIKE DRUGS; HAIRY SKIN; INVITRO; BRADYKININ; AFFERENTS; RECEPTORS; CHEMOSENSITIVITY; HYPERALGESIA AB While it is generally assumed that nociceptor sensitization underlies peripheral hyperalgesia, there is disagreement regarding the ability of inflammatory mediators to sensitize nociceptors to mechanical stimuli. In this in vivo electrophysiological study, mechanical threshold and response to sustained threshold and sustained suprathreshold mechanical stimuli were measured before and after intradermal administration of prostaglandin E-2 (PGE(2)) into the receptive field of cutaneous C-fiber nociceptors in the rat. PGE(2) produced a decrease in mechanical threshold and an increase in response to sustained threshold but not sustained suprathreshold mechanical stimulation. These data suggest that while inflammatory mediators produce a decrease in mechanical threshold and/or an increase in number of action potentials to sustained threshold stimuli, they do not increase the maximal response to mechanical stimuli in C-fiber nociceptors. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Calif San Francisco, Div Neurosci, Dept Anat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Oral & Maxillofacial Surg, San Francisco, CA 94143 USA. RP Levine, JD (reprint author), Univ Calif San Francisco, Pain Ctr, NIH, Box 0440,C-521, San Francisco, CA 94143 USA. FU NINDS NIH HHS [NS21647] NR 20 TC 39 Z9 40 U1 0 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD MAY 28 PY 1999 VL 267 IS 2 BP 105 EP 108 DI 10.1016/S0304-3940(99)00345-6 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 200GM UT WOS:000080531300008 PM 10400223 ER PT J AU Lemstra, AW Metman, LV Lee, JI Dougherty, PM Lenz, FA AF Lemstra, AW Metman, LV Lee, JI Dougherty, PM Lenz, FA TI Tremor-frequency (3-6 Hz) activity in the sensorimotor arm representation of the internal segment of the globus pallidus in patients with Parkinson's disease SO NEUROSCIENCE LETTERS LA English DT Article DE globus pallidus; Parkinson's disease; tremor; tremor-related activity; central pattern generator; neurophysiology ID THALAMIC NUCLEAR GROUP; SINGLE-UNIT ANALYSIS; MPTP MODEL; NEURONS; CELLS AB Neurons in the internal segment of the globus pallidus (GPi) oscillate at approximately the frequency of parkinsonian tremor. However, the correlation of that activity with tremor has not previously been studied. We now describe the relationship between single neuron activity in the arm sensorimotor portion of GPi and upper extremity tremor in patients with Parkinson's disease. There was a significant concentration of power in the tremor-frequency range (3-6 Hz) for 11/44 GPi neurons. However, pallidal tremor-frequency activity correlated significantly with electromyogram (EMG) activity during tremor for only a single GPi neuron. These data are most consistent with the hypothesis that the output of neurons in GPi is transformed in thalamus by a non-linear mechanism, before transmission via the cortex to the spinal motorneurons that drive movement. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 Johns Hopkins Univ, Dept Neurosurg, Baltimore, MD 21287 USA. NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Lenz, FA (reprint author), Johns Hopkins Univ, Dept Neurosurg, Meyer Bldg 7-113,600 N Wolfe St, Baltimore, MD 21287 USA. OI Dougherty, Patrick/0000-0002-2177-2734 FU NINDS NIH HHS [K08 NS01384, NS28598, P01 NS32386-PROJECT 1] NR 18 TC 36 Z9 39 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 MAY 28 PY 1999 VL 267 IS 2 BP 129 EP 132 DI 10.1016/S0304-3940(99)00343-2 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 200GM UT WOS:000080531300014 PM 10400229 ER PT J AU Rosenthal, NE AF Rosenthal, NE TI Malignant sadness - The anatomy of depression SO SCIENCE LA English DT Book Review C1 NIMH, NIH, Bethesda, MD 20892 USA. RP Rosenthal, NE (reprint author), NIMH, NIH, Bldg 10,Room 3S-231,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 3 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 MAY 28 PY 1999 VL 284 IS 5419 BP 1474 EP 1474 DI 10.1126/science.284.5419.1474 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200PD UT WOS:000080548100022 ER PT J AU Zimmerberg, J AF Zimmerberg, J TI Virology - Hole-istic medicine SO SCIENCE LA English DT Editorial Material ID PROTEIN SECRETION SYSTEMS; ESCHERICHIA-COLI; MEMBRANE; CHANNELS C1 NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Zimmerberg, J (reprint author), NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. NR 13 TC 4 Z9 4 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 MAY 28 PY 1999 VL 284 IS 5419 BP 1475 EP + DI 10.1126/science.284.5419.1475 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200PD UT WOS:000080548100023 PM 10383325 ER PT J AU Frank, S Kohler, U Schackert, G Schackert, HK AF Frank, S Kohler, U Schackert, G Schackert, HK TI Expression of TRAIL and its receptors in human brain tumors (vol 257, pg 454, 1999) SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Correction C1 Tech Univ Dresden, Dept Surg Res, D-8027 Dresden, Germany. Tech Univ Dresden, Dept Neurosurg, D-8027 Dresden, Germany. RP Frank, S (reprint author), NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bldg 10,Room 4N 244, Bethesda, MD 20892 USA. NR 1 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 27 PY 1999 VL 259 IS 1 BP 230 EP 230 DI 10.1006/bbrc.1999.0755 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 201KG UT WOS:000080593500041 ER PT J AU Mozes, MM Hodics, T Kopp, JB AF Mozes, MM Hodics, T Kopp, JB TI Isoform specificity of commercially-available anti-TGF-beta antibodies SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE TGF-beta; monoclonal antibodies; polyclonal antibodies; Western blot analysis ID GROWTH-FACTOR-BETA AB The transforming growth factor-beta (TGF-beta) cytokine family has important and complex effects on many biologic processes. Mammals have three TGF-beta isoforms which differ in their primary amino acid sequence, receptor binding characteristics, distribution, and function. Characterization of TGF-beta production and localization is critically dependent upon appropriate reagents, including antibodies. We have analyzed the isoform specificity of eight commercially-available TGF-beta antibodies, including one monoclonal antibody and seven polyclonal antibodies. We carried out semi-quantitative Western blot analysis using recombinant TGF-beta 1, beta 2, and beta 3 as targets. We found that sensitivity and isoform specificity are dependent in part upon the presence or absence of reducing conditions. The antibodies tested showed a broad range of sensitivity, with an ability to detect 50 pg to 20 ng. Cross-reactivity with another, incorrect isoform was seen with several antibodies, and ranged from 0.2% to 42%. Nevertheless, we identified TGF-beta antibodies directed against each isoform which provide moderate-to-high sensitivity and specificity when used in Western blot analysis. These results may have relevance for investigators who wish to detect particular TGF-beta isoforms with techniques other than Western blot analysis, particularly when these techniques involve denatured proteins. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIDDK, Kidney Dis Sect, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. Semmelweis Univ, Sch Med, Inst Pathophysiol, Budapest, Hungary. RP Kopp, JB (reprint author), NIDDK, Kidney Dis Sect, Metab Dis Branch, NIH, 10-3N116, Bethesda, MD 20892 USA. RI Mozes, Miklos/E-9003-2011 NR 5 TC 8 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD MAY 27 PY 1999 VL 225 IS 1-2 BP 87 EP 93 DI 10.1016/S0022-1759(99)00031-9 PG 7 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 199XX UT WOS:000080510300009 PM 10365785 ER PT J AU Hildesheim, A McShane, LM Schiffman, M Bratti, MC Rodriguez, AC Herrero, R Morera, LA Cardenas, F Saxon, L Bowman, FP Crowley-Nowick, PA AF Hildesheim, A McShane, LM Schiffman, M Bratti, MC Rodriguez, AC Herrero, R Morera, LA Cardenas, F Saxon, L Bowman, FP Crowley-Nowick, PA TI Cytokine and immunoglobulin concentrations in cervical secretions: reproducibility of the Weck-cel collection instrument and correlates of immune measures SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE mucosal immunology; cytokines; immunoglobulin; genital tract ID HUMAN PAPILLOMAVIRUS; GENITAL-TRACT; ANTIBODY-RESPONSES; VAGINAL SECRETIONS; HPV VACCINE; VIRUS; DISEASE; WOMEN; LYMPHOCYTES; SUBCLASSES AB Elucidation of local immune response at the cervix is important for understanding and evaluating STD vaccine approaches currently being proposed. However, no well-validated method exists for the collection of cervical secretions for evaluation of cervical immune response. The purpose of this study was to determine the reproducibility of the Weck-cel sponge used to collect cervical secretions for immunological assessment. Additionally, it was possible to examine correlates of immunity as part of our investigation. Two cervical secretion specimens were collected sequentially from each of 120 women using Weck-cel sponges. Cervical secretions were collected prior to Pap smear sampling to avoid blood contamination, At the laboratory, the duplicate specimens were weighed and tested in replicate wells to determine the concentration of two cytokines (IL-10 and IL-12) and two immunoglobulin isotypes (IgG and IgA). IL-12, total IgG, and total IgA showed a strong correlation between samples from the same woman ranging from 0.78 to 0.84. Kappa coefficients obtained after categorizing assay results ranged from 0.62 to 0.67. Variance components analysis suggested that 69% to 85% of the variance observed was accounted for by between-women variance, with the remaining variability attributed to variation between samples collected from the same woman. IL-10 results were less reproducible than those obtained from the other assays examined, suggesting problems with the assay used to measure this cytokine rather than with the Weck-cel sampling instrument. Various factors were found to significantly correlate with cytokine and immunoglobulin measures at the cervix. Age and reproductive status were associated with all four immune measures; women over 50 years of age and those who were postmenopausal had increased concentrations of IL-10, IL-12, IgG, and IgA. Hemoglobin concentrations were positively correlated with IgG and IL-10 concentrations, but not with IgA or IL-12 concentrations, suggesting local production of IgA and IL-12. The concentration of all immune measures decreased with increasing volume of collection. No significant association was observed between time from collection to freezing of specimens and concentrations of cytokines or immunoglobulins. Overall, our data suggest that measurement of immunological parameters in cervical secretions collected using Weck-cel sponges are reproducible. In addition, various correlates of cytokine and immunoglobulin concentrations were identified. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NCI, Interdisciplinary Studies Sect, Environm Epidemiol Branch, DCEG, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, DCTD, Bethesda, MD USA. Minist Hlth, San Jose, Costa Rica. Int Agcy Res Canc, Unit Field & Intervent Studies, F-69372 Lyon, France. Informat Management Serv, Rockville, MD USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol,Fearing Res Lab, Boston, MA USA. RP Hildesheim, A (reprint author), NCI, Interdisciplinary Studies Sect, Environm Epidemiol Branch, DCEG, 6130 Execut Blvd,EPN 443, Bethesda, MD 20892 USA. NR 34 TC 37 Z9 38 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD MAY 27 PY 1999 VL 225 IS 1-2 BP 131 EP 143 DI 10.1016/S0022-1759(99)00037-X PG 13 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 199XX UT WOS:000080510300014 PM 10365790 ER PT J AU Johnson, RT Gibbs, CJ AF Johnson, RT Gibbs, CJ TI Creutzfeldt-Jakob disease - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Johns Hopkins Hosp, Baltimore, MD 21287 USA. NIH, Bethesda, MD 20892 USA. RP Johnson, RT (reprint author), Johns Hopkins Hosp, Baltimore, MD 21287 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 27 PY 1999 VL 340 IS 21 BP 1689 EP 1689 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 199QY UT WOS:000080494200030 ER PT J AU Unger, T Sionov, RV Moallem, E Yee, CL Howley, PM Oren, M Haupt, Y AF Unger, T Sionov, RV Moallem, E Yee, CL Howley, PM Oren, M Haupt, Y TI Mutations in serines 15 and 20 of human p53 impair its apoptotic activity SO ONCOGENE LA English DT Article DE serine; phosphorylation; p53; transactivation; apoptosis ID CASEIN KINASE-II; CELL-CYCLE PROGRESSION; DNA-BINDING FUNCTION; PHOSPHORYLATION SITE; WILD-TYPE; TRANSACTIVATION DOMAIN; C-JUN; PROTEIN; GENE; MDM2 AB Phosphorylation of the p53 tumor suppressor protein is likely to play an important role in regulating its activity, To study the regulatory role of potential phosphorylation sites within the N-terminal transactivation domain of human p53 (hp53), a series of p53 serine mutants were evaluated for transcriptional transactivation and sequence specific DNA binding. The role of these mutations in regulating p53-mediated growth suppression and programmed cell death,vas examined. This mutational analysis comprised serine residues located at positions 6, 9, 15, 20, 33 and 37 of human p53. Substitution of serine for alanine, either at individual residues or at all sis residues together, did not affect the suppression of cell growth and cell transformation, or the ability to bind DNA specifically and to transactivate different promoters, nor did it alter p53 expression, However, the ability of p53 to induce apoptosis was impaired by specific serine substitutions. Mutations in all sis N-terminal serines together reduced the apoptotic activity of p53 in H1299 cells by 50%, Analysis of individual mutants revealed that mutations in serine 15 and 20 are primarily responsible for this impairment. Our results suggest that these serines play a role in the regulation of p53-mediated apoptosis. C1 Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. Hebrew Univ Jerusalem, Hadassah Med Sch, Lautenberg Ctr Gen & Tumor Immunol, IL-91120 Jerusalem, Israel. NCI, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Unger, T (reprint author), Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. NR 58 TC 161 Z9 162 U1 2 U2 9 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 27 PY 1999 VL 18 IS 21 BP 3205 EP 3212 DI 10.1038/sj.onc.1202656 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 200DF UT WOS:000080523800003 PM 10359526 ER PT J AU Straus, SE McKenzie, R Demitrack, MA AF Straus, SE McKenzie, R Demitrack, MA TI Low-dose hydrocortisone for chronic fatigue syndrome - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NIAID, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. RP Straus, SE (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 26 PY 1999 VL 281 IS 20 BP 1888 EP 1889 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 198ME UT WOS:000080427300015 ER PT J AU Bristol, JA Schlom, J Abrams, SI AF Bristol, JA Schlom, J Abrams, SI TI Persistence, immune specificity, and functional ability of murine mutant ras epitope-specific CD4(+) and CD8(+) T lymphocytes following in vivo adoptive transfer SO CELLULAR IMMUNOLOGY LA English DT Article ID METASTATIC MELANOMA; CELL THERAPY; TUMOR-CELLS; IN-VIVO; IMMUNOTHERAPY; VACCINE; INTERLEUKIN-2; ACTIVATION; MUTATIONS; CANCER AB Adoptive T-cell transfer has been shown to be a potentially effective strategy for cellular immunotherapy in some murine models of disease. However, several issues remain unresolved regarding some of the basic features involved in effective adoptive transfer, such as the influence of specific peptide antigen (Ag) boost after T-cell transfer, the addition of IL-2 post-T-cell transfer, the trafficking of transferred T cells to lymphoid and nonlymphoid tissues, and the functional stability of recoverable CD4(+) and CD8(+) T cells. We investigated several of these parameters, particularly as they relate to the persistence and maintenance of effector functions of murine CD4(+) and/or CD8(+) T lymphocytes after adoptive cellular transfer into partially gamma-irradiated syngeneic hosts. Our laboratory previously identified murine (H-2(d)) immunogenic CD4(+) and CD8(+) T-cell peptide epitopes reflecting codon 12 ras mutations as tumor-specific Ag. Therefore, the model system chosen here employed epitope-specific MHC class IT-restricted CD4(+) T cells and MHC class I-restricted CD8(+) T cells produced from previously immunized BALB/c mice. Between 2 and 7 days after T-cell transfer, recipient mice received various combinations of peptide boosts and/or IL-2 treatments. At different times after the T-cell transfer, spleen and lung tissues were analyzed phenotypically to monitor the persistence of the immune T cells and functionally (via proliferation or cytotoxicity assays) to assess the maintenance of peptide specificity. The results showed that immune donor T lymphocytes (uncultured immune T cells or cloned T cells) were recover able from the spleens and lungs of recipient mice after transfer. The recovery of Ag-specific T-cell responses was greatest from recipient mice that received peptide boosts and IL-2 treatment. However, mice that received a peptide boost without IL-2 treatment responded nearly as well, which suggested that including a peptide boost after T-cell transfer was more obligatory than exogenous IL-2 treatment to sustain adoptively transferred T cells in vivo. Ag specific T-cell responses were weak in mice that either received IL-2 alone or did not receive the cognate peptide boost after T-cell transfer. The T-cell clones were also monitored by flow cytometry or RT-PCR based on expression of the T-cell receptor V beta-chain, which was previously characterized. Ag-specific T cells were recovered from both spleens and lungs of recipient mice, demonstrating that the T-cell clones could localize to both lymphoid and nonlymphoid tissues. This study demonstrates that both uncultured and in vitro-cloned T lymphocytes can migrate to lymphoid tissues and nonlymphoid (e.g., lung) tissues in recipient hosts and that their functional activities can be maintained at these sites after transfer, if they are exposed to peptide Ag in vivo. C1 NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, NIH, Bldg 10,Room 8B-07, Bethesda, MD 20892 USA. NR 22 TC 14 Z9 14 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0008-8749 J9 CELL IMMUNOL JI Cell. Immunol. PD MAY 25 PY 1999 VL 194 IS 1 BP 78 EP 89 DI 10.1006/cimm.1999.1489 PG 12 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 209BZ UT WOS:000081028700010 PM 10357883 ER PT J AU Wang, YQ He, HY Zigler, JS Iwata, T Ibaraki, N Reddy, VN Carper, D AF Wang, YQ He, HY Zigler, JS Iwata, T Ibaraki, N Reddy, VN Carper, D TI bFGF suppresses serum-deprivation-induced apoptosis in a human lens epithelial cell line SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE apoptosis; bcl-2; bFGF; lens; serum deprivation ID FIBROBLAST GROWTH-FACTOR; INTERNUCLEOSOMAL FRAGMENTATION; MOUSE LENS; BASIC FGF; C-MYC; BCL-2; EXPRESSION; DEATH; DIFFERENTIATION; DNA AB There is increasing evidence that basic fibroblast growth factor (bFGF) plays an important role in cell proliferation, differentiation, and survival in various systems. In the eye, although a truncated, dominant negative bFGF receptor in transgenic mice induced defective lens development and caused lens fiber cells to display characteristics of apoptosis, there is little direct evidence of the effect of bFGF on lens epithelial cell apoptosis. Our study examines the effects of bFGF on programmed cell death induced by serum deprivation using a human lens epithelial cell line, Cells supplemented with 20% fetal bovine serum were used as normal controls. Over a period of 7 days, the addition of 100 ng/ml bFGF effectively suppressed serum-deprived apoptosis. The expression of gamma-crystallin and major intrinsic protein, which are markers of lens cell differentiation, was not detected, Also there was no significant difference in cell proliferation between serum-deprived cells with or without bFGF. ICE (caspase-1) was expressed under both the conditions, but the level of expression between the two groups was not substantially different, bcl-2 and c-myc were upregulated only in bFGF-treated cells. Thus we speculate that the inhibitory effect of bFGF on apoptosis is through the upregulation of the inhibitor of apoptosis, instead of downregulation of the initiator. This effect appears to be independent of lens cell differentiation and proliferation, (C) 1999 Academic Press. C1 NEI, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Michigan, Sch Med, Kellogg Eye Ctr, Ann Arbor, MI 48105 USA. Nippon Med Sch, Dept Ophthalmol, Tokyo 113, Japan. RP Carper, D (reprint author), NEI, NIH, Bldg 6,Room 232,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 46 TC 26 Z9 28 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 MAY 25 PY 1999 VL 249 IS 1 BP 123 EP 130 DI 10.1006/excr.1999.4450 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 201LE UT WOS:000080595600013 PM 10328960 ER PT J AU Wolffe, AP Jones, PL Wade, PA AF Wolffe, AP Jones, PL Wade, PA TI DNA demethylation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID MOUSE EMBRYO; 5-METHYLCYTOSINE-DNA GLYCOSYLASE; CHROMATIN STRUCTURE; METHYLATED DNA; GENE; METHYLTRANSFERASE; CYTOSINE; TRANSCRIPTION; MECHANISM; IDENTIFICATION C1 NICHHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. RP Wolffe, AP (reprint author), NICHHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. NR 53 TC 120 Z9 124 U1 1 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 25 PY 1999 VL 96 IS 11 BP 5894 EP 5896 DI 10.1073/pnas.96.11.5894 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200ER UT WOS:000080527100002 PM 10339513 ER PT J AU Eaton, WA AF Eaton, WA TI Searching for "downhill scenarios" in protein folding SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID ENERGY LANDSCAPE; KINETICS; PERSPECTIVE; PATHWAYS; MODEL; DIFFUSION; DYNAMICS; FUNNELS C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Eaton, WA (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. NR 39 TC 84 Z9 85 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 MAY 25 PY 1999 VL 96 IS 11 BP 5897 EP 5899 DI 10.1073/pnas.96.11.5897 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200ER UT WOS:000080527100003 PM 10339514 ER PT J AU van Melderen, L Gottesman, S AF van Melderen, L Gottesman, S TI Substrate sequestration by a proteolytically inactive Lon mutant SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE SulA; RcsA; serine protease; ATPase; protease La ID ATP-DEPENDENT PROTEASE; HEAT-SHOCK PROTEIN; DIVISION INHIBITOR SULA; ESCHERICHIA-COLI K-12; CELL-DIVISION; MYXOCOCCUS-XANTHUS; CLP PROTEASE; SPECIFICITY COMPONENT; NUCLEOTIDE-SEQUENCE; MOLECULAR CHAPERONE AB Lon protein of Escherichia coli is an ATP-dependent protease responsible for the rapid turnover of both abnormal and naturally unstable proteins, including SulA, a cell division inhibitor made after DNA damage, and RcsA, a positive regulator of transcription. Lon is a multimer of identical 94-kDa subunits, each containing a consensus ATPase motif and a serine active site, We found that overexpressing Lon, which is mutated for the serine active site (LonS679A) and is therefore devoid of proteolytic activity, unexpectedly led to complementation of the UV sensitivity and capsule overproduction of a ion deletion mutant. SulA was not degraded by LonS679A, but rather was completely protected by the Lon mutant from degradation by other cellular proteases. We interpret these results to mean that the mutant LonS679A binds but does not degrade Lon substrates, resulting in sequestration of the substrate proteins and interference with their activities, resulting in apparent complementation. Lon that carried a mutation in the consensus ATPase site, either with or without the active site serine, was no longer able to complement a Delta lon mutant, These in vivo results suggest that the pathway of degradation by Lon couples ATP-dependent unfolding with movement of the substrate into protected chambers within Lon, where it is held until degradation proceeds, In the absence of degradation the substrate remains sequestered. Comparison of our results with those from a number of other systems suggest that proteins related to the regulatory portions of energy-dependent proteases act as energy-dependent sequestration proteins. C1 NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, Bldg 37,Room 2E18,37 Covent Dr,MSC4255, Bethesda, MD 20892 USA. NR 61 TC 36 Z9 36 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 MAY 25 PY 1999 VL 96 IS 11 BP 6064 EP 6071 DI 10.1073/pnas.96.11.6064 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200ER UT WOS:000080527100031 PM 10339542 ER PT J AU Aslund, F Zheng, M Beckwith, J Storz, G AF Aslund, F Zheng, M Beckwith, J Storz, G TI Regulation of the OxyR transcription factor by hydrogen peroxide and the cellular thiol - disulfide status SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ESCHERICHIA-COLI; OXIDATIVE STRESS; NADH PEROXIDASE; THIOREDOXIN; GLUTATHIONE; GLUTAREDOXIN-1; CYTOPLASM; REGULON; FORMS; GENES AB The Escherichia coli transcription factor OxyR is activated by the formation of an intramolecular disulfide bond and subsequently is deactivated by enzymatic reduction of the disulfide bond. Here we show that OxyR can be activated by two possible pathways. In mutants defective in the cellular disulfide-reducing systems, OxyR is constitutively activated by a change in the thiol-disulfide redox status in the absence of added oxidants. In wild-type cells, OxyR is activated by hydrogen peroxide. By monitoring the presence of the OxyR disulfide bond after exposure to hydrogen peroxide in vivo and in vitro, we also show that the kinetics of OxyR oxidation by low concentrations of hydrogen peroxide is significantly faster than the kinetics of OxyR reduction, allowing for transient activation in an overall reducing environment. We propose that the activity of OxyR in vivo is determined by the balance between hydrogen peroxide levels and the cellular redox environment. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. RP Storz, G (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. OI Storz, Gisela/0000-0001-6698-1241 FU NIGMS NIH HHS [GM41883, GM55090, R01 GM041883, R01 GM055090] NR 21 TC 333 Z9 346 U1 0 U2 16 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 25 PY 1999 VL 96 IS 11 BP 6161 EP 6165 DI 10.1073/pnas.96.11.6161 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200ER UT WOS:000080527100047 PM 10339558 ER PT J AU Idris, AH Smith, HRC Mason, LH Ortaldo, JR Scalzo, AA Yokoyama, WM AF Idris, AH Smith, HRC Mason, LH Ortaldo, JR Scalzo, AA Yokoyama, WM TI The natural killer gene complex genetic locus Chok encodes Ly-49D, a target recognition receptor that activates natural killing SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE natural killer cell; cytotoxicity; tumor ID CLASS-I MHC; NK CELLS; HLA-E; INHIBITORY RECEPTORS; MOUSE; MOLECULE; FAMILY; CHROMOSOME-6; CD94/NKG2A; DAP12 AB Previously, we established that natural killer (NK) cells from C57BL/6 (B6), but not BALB/c, mice lysed Chinese hamster ovary (CHO) cells, and we mapped the locus that determines this differential CHO-killing capacity to the NK gene complex on chromosome 6. The localization of Chok in the NK gene complex suggested that it may encode either an activating or an inhibitory receptor. Here, results from a lectin-facilitated lysis assay predicted that Chok is an activating B6 NK receptor. Therefore, we immunized BALB/c mice with NK cells from BALB.B6-Cmv1(r) congenic mice and generated a mAb, designated 4E4, that blocked B6-mediated CHO lysis. mAb 4E4 also redirected lysis of Daudi targets, indicating its reactivity with an activating NK cell receptor. Furthermore, only the 4E4(+) B6 NK cell subset mediated CHO killing, and this lysis was abrogated by preincubation with mAb 4E4. Flow cytometric analysis indicated that mAb 4E4 specifically reacts with Ly-49D but not Ly-49A, B, C, E, G, H, or I transfectants. Finally, gene transfer of Ly-49D(B6) into BALB/c NR cells conferred cytotoxic capacity against CHO cells, thus establishing that the Ly-49D receptor is sufficient to activate NK cells to lyse this target. Hence, Ly-49D is the Chok gene product and is a mouse NK cell receptor capable of directly triggering natural killing. C1 Washington Univ, Sch Med, Howard Hughes Med Inst, St Louis, MO 63110 USA. Mt Sinai Sch Med, Immunobiol Ctr, New York, NY 10029 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Univ Western Australia, Queen Elizabeth II Med Ctr, Dept Microbiol, Nedlands, WA 6907, Australia. RP Yokoyama, WM (reprint author), Washington Univ, Sch Med, Howard Hughes Med Inst, St Louis, MO 63110 USA. NR 43 TC 78 Z9 78 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 MAY 25 PY 1999 VL 96 IS 11 BP 6330 EP 6335 DI 10.1073/pnas.96.11.6330 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200ER UT WOS:000080527100076 PM 10339587 ER PT J AU Jeyakumar, M Butters, TD Cortina-Borja, M Hunnam, V Proia, RL Perry, VH Dwek, RA Platt, FM AF Jeyakumar, M Butters, TD Cortina-Borja, M Hunnam, V Proia, RL Perry, VH Dwek, RA Platt, FM TI Delayed symptom onset and increased life expectancy in Sandhoff disease mice treated with N-butyldeoxynojirimycin SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID BONE-MARROW TRANSPLANTATION; LYSOSOMAL STORAGE DISEASES; GAUCHER-DISEASE; TAY-SACHS; GLYCOLIPID BIOSYNTHESIS; GANGLIOSIDE METABOLISM; MOUSE MODELS; THERAPY; INHIBITOR; CELL AB Sandhoff disease is a neurodegenerative disorder resulting from the autosomal recessive inheritance of mutations in the HEXB gene, which encodes the P-subunit of P-hexosaminidase, G(M2) ganglioside fails to be degraded and accumulates within lysosomes in cells of the periphery and the central nervous system (CNS), There are currently no therapies for the glycosphingolipid lysosomal storage diseases that involve CNS pathology, including the G(M2) gangliosidoses. One strategy for treating this and related diseases is substrate deprivation, This would utilize an inhibitor of glycosphingolipid biosynthesis to balance synthesis with the impaired rate of catabolism, thus preventing storage, One such inhibitor is N-butyldeoxynojirimycin, which currently is in clinical trials for the potential treatment of type 1 Gaucher disease, a related disease that involves glycosphingolipid storage in peripheral tissues, but not in the CNS, In this study, we have evaluated whether this drug also could be applied to the treatment of diseases with CNS storage and pathology. We therefore have treated a mouse model of Sandhoff disease with the inhibitor N-butyldeoxynojirimycin. The treated mice have delayed symptom onset, reduced storage in the brain and peripheral tissues, and increased life expectancy. Substrate deprivation therefore offers a potentially general therapy for this family of lysosomal storage diseases, including those with CNS disease. C1 Univ Oxford, Dept Biochem, Glycobiol Inst, Oxford OX1 3QU, England. NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. Univ Oxford, Dept Stat, Oxford OX1 3TG, England. Univ Oxford, Dept Pharmacol, Oxford OX1 3QT, England. RP Platt, FM (reprint author), Univ Oxford, Dept Biochem, Glycobiol Inst, S Parks Rd, Oxford OX1 3QU, England. RI Cortina Borja, Mario/A-3847-2009; Platt, Frances/G-1004-2010; Proia, Richard/A-7908-2012 NR 21 TC 170 Z9 175 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 MAY 25 PY 1999 VL 96 IS 11 BP 6388 EP 6393 DI 10.1073/pnas.96.11.6388 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200ER UT WOS:000080527100086 PM 10339597 ER PT J AU Ohshima, T Schiffmann, R Murray, GJ Kopp, J Quirk, JM Stahl, S Chan, CC Zerfas, P Tao-Cheng, JH Ward, JM Brady, RO Kulkarni, AB AF Ohshima, T Schiffmann, R Murray, GJ Kopp, J Quirk, JM Stahl, S Chan, CC Zerfas, P Tao-Cheng, JH Ward, JM Brady, RO Kulkarni, AB TI Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ALPHA-GALACTOSIDASE-A; GENE; EXPRESSION; THERAPY; CELLS AB Fabry disease is an X-linked metabolic disorder caused by a deficiency of cu-galactosidase A (alpha-Gal A). The enzyme defect leads to the systemic accumulation of glycosphingolipids with Lu-galactosyl moieties consisting predominantly of globotriaosylceramide (Gb3). In patients with this disorder, glycolipid deposition in endothelial cells leads to renal failure and cardiac and cerebrovascular disease. Recently, we generated alpha-Gal A gene knockout mouse lines and described the phenotype of 10-week-old mice. In the present study, we characterize the progression of the disease with aging and explore the effects of bone marrow transplantation (BMT) on the phenotype. Histopathological analysis of alpha-Gal A-/0 mice revealed subclinical lesions in the Kupffer cells in the liver and macrophages in the skin with no gross lesions in the endothelial cells. Gb3 accumulation and pathological lesions in the affected organs increased with age. Treatment with BMT from the wild-type mice resulted in the clearance of accumulated Gb3 in the liver, spleen, and heart with concomitant elevation of alpha-Gal A activity. These findings suggest that BMT may have a potential role in the management of patients with Fabry disease. C1 Natl Inst Dent & Craniofacial Res, Funct Genomics Unit, NIH, Bethesda, MD 20892 USA. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD USA. NIDDK, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NINDS, Electron Microscope Facil, NIH, Bethesda, MD 20892 USA. NCI, Vet & Tumor Pathol Sect, Off Lab Anim Sci, NIH, Frederick, MD 21702 USA. RP Kulkarni, AB (reprint author), Natl Inst Dent & Craniofacial Res, Funct Genomics Unit, NIH, Bldg 30,Room 529,30 Convent Dr, Bethesda, MD 20892 USA. OI Kopp, Jeffrey/0000-0001-9052-186X NR 17 TC 67 Z9 73 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 MAY 25 PY 1999 VL 96 IS 11 BP 6423 EP 6427 DI 10.1073/pnas.96.11.6423 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200ER UT WOS:000080527100092 PM 10339603 ER PT J AU Burg, MB Peters, EM Bohren, KM Gabbay, KH AF Burg, MB Peters, EM Bohren, KM Gabbay, KH TI Factors affecting counteraction by methylamines of urea effects on aldose reductase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TRIMETHYLAMINE-N-OXIDE; ENZYME; OSMOLYTE; SOLUTES; PROTEIN; SITE AB The concentration of urea in renal medullary cells is high enough to affect enzymes seriously by reducing V-max or raising K-m, yet the cells survive and function, The usual explanation is that the methylamines found in the renal medulla, namely glycerophosphocholine and betaine, have actions opposite to those of urea and thus counteract its effects. However, urea and methylamines have the similar (not counteracting) effects of reducing both the K-m and V-max of aldose reductase (EC 1.1.1.21), an enzyme whose function is important in renal medullas. Therefore, we examined factors that might determine whether counteraction occurs, namely different combinations of assay conditions (pH and salt concentration), methylamines (glycerophosphocholine, betaine, and trimethylamine N-oxide), substrates (DL-glyceraldehyde and D-xylose), and a mutation in recombinant aldose reductase protein (C298A), We find that V-max of both wild-type and C298A mutant generally is reduced by urea and/or the methylamines. However, the effects on K-m are much more complex, varying widely with the combination of conditions. At one extreme, we find a reduction of K-m of wild-type enzyme by urea and/or methylamines that is partially additive, whereas at the other extreme we find that urea raises K-m for D-xylose of the C298A mutant, betaine lowers the K-m, and the two counteract in a classical fashion so that at a 2:1 molar ratio of betaine to urea there is no net effect. We conclude that counteraction of urea effects on enzymes by methylamines can depend on ion concentration, pH, the specific methylamine and substrate, and identity of even a single amino acid in the enzyme. C1 NHLBI, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. Baylor Coll Med, Dept Cell Biol, Houston, TX 77030 USA. RP Burg, MB (reprint author), NHLBI, NIH, Bldg 10,Room 6N260, Bethesda, MD 20892 USA. NR 16 TC 28 Z9 28 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 25 PY 1999 VL 96 IS 11 BP 6517 EP 6522 DI 10.1073/pnas.96.11.6517 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200ER UT WOS:000080527100109 PM 10339620 ER PT J AU Bostom, AG Silbershatz, H Rosenberg, IH Selhub, J D'Agostino, RB Wolf, PA Jacques, PF Wilson, PWF AF Bostom, AG Silbershatz, H Rosenberg, IH Selhub, J D'Agostino, RB Wolf, PA Jacques, PF Wilson, PWF TI Nonfasting plasma total homocysteine levels and all-cause and cardiovascular disease mortality in elderly Framingham men and women SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID CORONARY-ARTERY DISEASE; VASCULAR-DISEASE; NATURAL-HISTORY; RISK FACTOR; HYPERHOMOCYSTEINEMIA; HOMOCYSTINURIA AB Background: Elevated fasting total homocysteine (tHcy) levels were recently shown to confer an independent risk for all-cause and cardiovascular disease (CVD) mortality among selected Norwegian patients with confirmed coronary heart disease. We examined whether elevated fasting plasma tHcy levels were predictive of all-cause and CVD mortality in a large, population-based sample of elderly US women and men. Methods: Nonfasting plasma tHcy levels were determined in 1933 elderly participants (mean age, 70 +/- 7 years; 58.9% women) from the original Framingham Study cohort, examined between 1979 and 1982, with follow-up through 1992. Unadjusted and adjusted (ie, for age, sex, diabetes, smoking, systolic blood pressure, total and high-density lipoprotein cholesterol, and creatinine) relative risk estimates (with 95% confidence intervals [CIs]) for total and CVD mortality were generated by proportional hazards modeling, with tHcy levels (quartiles) as the independent variable. Results: There were 653 total deaths and 244 CVD deaths during a median follow-up of 10.0 years. Proportional hazards modeling revealed that tHcy levels of 14.26 mu mol/L or greater (the upper quartile), vs less than 14.26 mu mol/L (the lower three quartiles), were associated with relative risk estimates of 2.18 (95% CI, 1.86-2.56) and 2.17 (95% CI, 1.68-2.82) for all-cause and CVD mortality, respectively. The relative risk estimates after adjustment for age, sex, systolic blood pressure, diabetes, smoking, and total and high-density lipoprotein cholesterol levels attenuated these associations, but they remained significant: 1.54 (95% CI, 1.31-1.82) for all-cause mortality; 1.52 (95%;, CI, 1.16-1.98) for CVD mortality. Conclusion: Elevated nonfasting plasma tHcy levels are independently associated with increased rates of all-cause and CVD mortality in the elderly. C1 Mem Hosp Rhode Isl, Div Gen Internal Med, Pawtucket, RI 02860 USA. Tufts Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA USA. Boston Univ, Dept Math, Boston, MA 02215 USA. NHLBI, Framingham Study, Framingham, MA USA. RP Bostom, AG (reprint author), Mem Hosp Rhode Isl, Div Gen Internal Med, 111 Brewster St, Pawtucket, RI 02860 USA. FU NHLBI NIH HHS [N01-HC-38038, R01-HL-40423-05]; NINDS NIH HHS [2-RO1-NS-17950-12] NR 22 TC 221 Z9 235 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD MAY 24 PY 1999 VL 159 IS 10 BP 1077 EP 1080 DI 10.1001/archinte.159.10.1077 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 196GL UT WOS:000080300600007 PM 10335684 ER PT J AU Wilson, PWF Kannel, WB Silbershatz, H D'Agostino, RB AF Wilson, PWF Kannel, WB Silbershatz, H D'Agostino, RB TI Clustering of metabolic factors and coronary heart disease SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID INSULIN-RESISTANCE SYNDROME; CARDIOVASCULAR RISK-FACTORS; GLUCOSE-TOLERANCE; HDL-CHOLESTEROL; BLOOD-PRESSURE; YOUNG FINNS; PLASMA; TRIGLYCERIDE; SENSITIVITY; POPULATION AB Background: The degree of clustering for common metabolic coronary disease risk factors is not well known, the antecedents of clustering are not well studied, and the impact of such clusters on coronary risk has not been assessed systematically. Methods: Prospective community sample of 2406 men and 2569 women aged 18 to 74 years at baseline. The 6 metabolically linked risk factors considered were the lowest sex-specific quintile of high-density lipoprotein cholesterol and the highest quintiles of body mass index, systolic blood pressure, triglycerides, glucose, and serum total cholesterol. Results: At baseline the risk factor sum, represented as integer values, ranged from 0 to 6, and clusters of 3 or more risk factors occurred at twice the rate predicted by chance. After adjustment for age and obesity level, a 2.25-kg (5-lb) weight increase over 16 years was associated with an increased risk factor sum in men (+20%; P = .002) and women (+37%; P<.001), and a 2.25-kg weight loss was associated with a decreased risk factor sum in men (-48%; P<.001) and women (-40%; P<.001). Clusters of 3 or more risk factors were associated with a 2.39 (95% confidence interval, 1.56-3.36) and 5.90 (95% confidence interval, 2.54-13.73) times greater risk of coronary heart disease in men and women, respectively (both P<.001). Conclusions: Atherogenic risk factor clustering is common in both sexes, worsens with weight gain, and is associated with greatly increased risk of coronary disease risk in both sexes. C1 NHLBI, Framingham Heart Study, Framingham, MA 01701 USA. Boston Univ, Sch Med, Framingham Heart Study, Boston, MA 02215 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. RP Wilson, PWF (reprint author), NHLBI, Framingham Heart Study, 5 Thurber St, Framingham, MA 01701 USA. FU NHLBI NIH HHS [N01-HC-38038] NR 36 TC 382 Z9 414 U1 3 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD MAY 24 PY 1999 VL 159 IS 10 BP 1104 EP 1109 DI 10.1001/archinte.159.10.1104 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 196GL UT WOS:000080300600011 PM 10335688 ER PT J AU Hanson, LC Earp, JA Garrett, J Menon, M Danis, M AF Hanson, LC Earp, JA Garrett, J Menon, M Danis, M TI Community physicians who provide terminal care SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT 21st Annual Meeting of the Society-of-General-Internal-Medicine CY APR 25, 1998 CL CHICAGO, ILLINOIS SP Soc Gen Internal Med ID LIFE-SUSTAINING CARE; ADVANCE DIRECTIVES; FAMILY MEMBERS; ILL PATIENTS; END; EXPERIENCE; DECISIONS; SUPPORT AB Background: Most dying patients are treated by physicians in community practice, yet studies of terminal care rarely include these physicians. Objective: To examine the frequency of life-sustaining treatment use and describe what factors influence physicians' treatment decisions in community-based practices. Methods: Family members and treating physicians for decedents 65 years and older who died of cancer, congestive heart failure, chronic lung disease, cirrhosis, or stroke completed interviews about end-of-life care in community settings. Results: Eighty percent of eligible family and 68.8% of eligible physicians participated (N = 165). Most physicians were trained in primary care and 85.4% were primary care physicians for the decedents. Physicians typically knew the decedent a year or more (68.9%), and 93.3%;, treated them for at least 1 month before death. In their last month of life, 2.4% of decedents received cardiopulmonary resuscitation, 5.5% received ventilatory support, and 34.1% received hospice care. Family recalled a discussion of treatment options in 78.2% of deaths. Most discussions (72.1%) took place a month or more before death. Place of death, cancer, and having a living will were independent predictors of less aggressive treatment before death. Physicians believed that advanced planning and good relationships were the major determinants of good decision making. Conclusions: Community physicians use few life-sustaining treatments for dying patients. Treatment decisions are made in the context of long-term primary care relationships, and living wills influence treatment decisions. The choice to remain in community settings with a familiar physician may influence the dying experience. C1 Univ N Carolina, Div Gen Internal Med, Chapel Hill, NC USA. Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. Natl Inst Hlth, Clin Bioeth Dept, Bethesda, MD USA. RP Hanson, LC (reprint author), Univ N Carolina, Div Gen Med, CB 7110, Chapel Hill, NC 27599 USA. NR 25 TC 24 Z9 24 U1 1 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD MAY 24 PY 1999 VL 159 IS 10 BP 1133 EP 1138 DI 10.1001/archinte.159.10.1133 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 196GL UT WOS:000080300600015 PM 10335692 ER PT J AU Robinson, D AF Robinson, D TI NIH funding SO SCIENTIST LA English DT Letter C1 NHLBI, Vasc Res Program, Sheperdstown, WV 25443 USA. RP Robinson, D (reprint author), NHLBI, Vasc Res Program, Sheperdstown, WV 25443 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU SCIENTIST INC PI PHILADELPHIA PA 3600 MARKET ST SUITE 450, PHILADELPHIA, PA 19104 USA SN 0890-3670 J9 SCIENTIST JI Scientist PD MAY 24 PY 1999 VL 13 IS 11 BP 12 EP 12 PG 1 WC Information Science & Library Science; Multidisciplinary Sciences SC Information Science & Library Science; Science & Technology - Other Topics GA 199KX UT WOS:000080481700011 ER PT J AU Hoff, R McNamara, J AF Hoff, R McNamara, J TI Therapeutic vaccines for preventing AIDS: their use with HAART SO LANCET LA English DT Editorial Material ID VIRUS TYPE-1 INFECTION; HIV-1 INFECTION; IMMUNODEFICIENCY; VACCINATION; SAFETY; TRIAL C1 NIAID, Vaccine & Prevent Res Program, NIH, Bethesda, MD 20892 USA. NIAID, Therapeut Res Program, Div Aids, NIH, Bethesda, MD 20892 USA. RP Hoff, R (reprint author), NIAID, Vaccine & Prevent Res Program, NIH, Bethesda, MD 20892 USA. NR 14 TC 8 Z9 8 U1 0 U2 1 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD MAY 22 PY 1999 VL 353 IS 9166 BP 1723 EP 1724 DI 10.1016/S0140-6736(99)90025-9 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 202TF UT WOS:000080667700003 PM 10347978 ER PT J AU Baird, DD Wilcox, AJ Kramer, MS AF Baird, DD Wilcox, AJ Kramer, MS TI Why might infertile couples have problem pregnancies? SO LANCET LA English DT Editorial Material ID TIME; IVF C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. McGill Univ, Dept Paediat, Montreal, PQ, Canada. McGill Univ, Dept Epidemiol, Montreal, PQ, Canada. RP Baird, DD (reprint author), NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. OI Wilcox, Allen/0000-0002-3376-1311; Baird, Donna/0000-0002-5544-2653 NR 19 TC 24 Z9 25 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD MAY 22 PY 1999 VL 353 IS 9166 BP 1724 EP 1725 DI 10.1016/S0140-6736(99)90050-8 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 202TF UT WOS:000080667700004 PM 10347979 ER PT J AU Tsao, LI Cadet, JL Su, TP AF Tsao, LI Cadet, JL Su, TP TI Reversal by [D-Ala(2),D-Leu(5)]enkephalin of the dopamine transporter loss caused by methamphetamine SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE DADLE ([D-Ala(2),D-Leu(5)]enkephalin); methamphetamine; neurotoxicity AB A single administration of 40 mg/kg (i.p.) of methamphetamine caused a loss of dopamine transporter in the striatum of albino Swiss (CD-1) mouse for at least 3 weeks. The administration of a single dose of [D-Ala(2),D-Leu(5)]enkephalin (DADLE) (18 mg/kg, i.p.), given at day 14 after the administration of methamphetamine, caused a significant, transient restoration of dopamine transporter level in the striatum. These results suggest that delta-opioid peptide DADLE is able to reverse the neuronal damage caused by methamphetamine. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIDA, Intramural Res Program, Mol Neuropsychiat Sect, NIH, Baltimore, MD 21224 USA. RP Su, TP (reprint author), NIDA, Intramural Res Program, Mol Neuropsychiat Sect, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 8 TC 8 Z9 9 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD MAY 21 PY 1999 VL 372 IS 3 BP R5 EP R7 DI 10.1016/S0014-2999(99)00240-X PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 204KB UT WOS:000080762500018 PM 10395030 ER PT J AU Hoffmann, C Moro, S Nicholas, RA Harden, TK Jacobson, KA AF Hoffmann, C Moro, S Nicholas, RA Harden, TK Jacobson, KA TI The role of amino acids in extracellular loops of the human P2Y(1) receptor in surface expression and activation processes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID THYROTROPIN-RELEASING-HORMONE; PROTEIN-COUPLED RECEPTORS; SITE-DIRECTED MUTAGENESIS; ANGIOTENSIN-II; ANTAGONIST BINDING; PEPTIDE BINDING; LIGAND-BINDING; P-2Y-PURINOCEPTOR AGONISTS; MUTATIONAL ANALYSIS; RESIDUES AB The P2Y(1) receptor is a membrane-bound G protein-coupled receptor stimulated by adenine nucleotides, Using alanine scanning mutagenesis, the role in receptor activation of charged amino acids (Asp, Glu, Lys, and Arg) and cysteines in the extracellular loops (EL) of the human P2Y(1) receptor has been investigated. The mutant receptors were expressed in COS-7 cells and measured for stimulation of phospholipase C induced by the potent agonist 2-methylthioadenosine-5'-diphosphate (2-MeSADP), In addition to single point mutations, all receptors carried the hemagglutinin epitope at the N-terminus for detection of cell-surface expression. The C124A and C202A mutations, located near the exofacial end of transmembrane helix 3 and in EL2, respectively, ablated phospholipase C stimulation by less than or equal to 100 mu M 2-MeSADP, Surface enzyme-linked immunosorbent assay detection of both mutant receptors showed <10% expression, suggesting that a critical disulfide bridge between EL2 and the upper part of transmembrane 3, as found in many other G protein coupled receptors, is required for proper trafficking of the P2Y(1) receptor to the cell surface. In contrast, the C42A and C296A mutant receptors (located in the N-terminal domain and EL3) were activated by 2-MeSADP, but the EC50 values were > 1000-fold greater than for the wild-type receptor. The double mutant receptor C42A/C296A exhibited no additive shift in the concentration-response curve for 2-MeSADP, These data suggest that Cys(42) and Cys(296) form another disulfide bridge in the extracellular region, which is critical for activation. Replacement of charged amino acids produced only minor changes in receptor activation, with two remarkable exceptions. The E209A mutant receptor (EL2) exhibited a >1000-fold shift in EC,,, However, if Glu(209) were substituted with amino acids capable of hydrogen bonding (Asp, Gin, or Arg), the mutant receptors responded like the wild-type receptor. Arg(287) in EL3 was impaired similarly to Glu(209) when substituted by alanine. Substitution of Arg287 by lysine, another positively charged residue, failed to fully restore wild-type activity. C1 NIDDK, Bioorgan Chem Lab, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. RP Jacobson, KA (reprint author), NIDDK, Bioorgan Chem Lab, Mol Recognit Sect, NIH, Bldg 8A,Rm B1A-17, Bethesda, MD 20892 USA. RI Moro, Stefano/A-2979-2012; Jacobson, Kenneth/A-1530-2009 OI Moro, Stefano/0000-0002-7514-3802; Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031116-20, Z99 DK999999] NR 45 TC 99 Z9 100 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 21 PY 1999 VL 274 IS 21 BP 14639 EP 14647 DI 10.1074/jbc.274.21.14639 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 225MK UT WOS:000081965200022 PM 10329657 ER PT J AU Manthey, D Bukauskas, F Lee, CG Kozak, CA Willecke, K AF Manthey, D Bukauskas, F Lee, CG Kozak, CA Willecke, K TI Molecular cloning and functional expression of the mouse gap junction gene connexin-57 in human HeLa cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHROMOSOMAL ASSIGNMENTS; CHANNELS; PROTEINS; FAMILY; PH; HYBRIDIZATION; SEQUENCE; PAIRS; BRAIN; CDNA AB A new mouse connexin gene has been isolated that codes for a connexin protein of 505 amino acid residues. Based on the predicted molecular mass of 57.115 kDa, it has been designated connexin-57. Similar to most other mouse connexin genes, the coding region of connexin-57 is not interrupted by introns and exists in the mouse genome as a single-copy gene. Within the connexin family, this new gene shows highest sequence identity to porcine connexin-60 in the Lu group of connexins. The connexin-57 gene was mapped to a position on mouse chromosome 4, 30 centimorgans proximal to a cluster of previously mapped connexin genes. Low levels of connexin-57 mRNA were detected in skin, heart, kidney, testis, ovary, intestine, and in the mouse embryo after 8 days post coitum, but expression was not detected in brain, sciatic nerve or liver. In order to analyze gene function, the connexin-57 coding region was expressed by transfection in human HeLa cells, where it restored homotypic intercellular transfer of microinjected neurobiotin. Heterotypic transfer was observed between HeLa connexin-57 transfectants and HeLa cells, expressing murine connexin-83, -37, or -30.3. Double whole-cell voltage clamp analyses revealed that HeLa-connexin-57 transfectants expressed about 10 times more channels than parental HeLa cells. Voltage gating by transjunctional and transmembrane voltages as well as unitary conductance (similar to 27 picosiemens) were different from intrinsic connexin channels in parental HeLa cells. C1 Univ Bonn, Genet Inst, D-53117 Bonn, Germany. Yeshiva Univ Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10461 USA. Kaunas Med Univ, Lab Excitable Struct, Kaunas, Lithuania. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Willecke, K (reprint author), Univ Bonn, Genet Inst, Romerstr 164, D-53117 Bonn, Germany. NR 53 TC 76 Z9 79 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 21 PY 1999 VL 274 IS 21 BP 14716 EP 14723 DI 10.1074/jbc.274.21.14716 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 225MK UT WOS:000081965200032 PM 10329667 ER PT J AU Herold, J Siddell, SG Gorbalenya, AE AF Herold, J Siddell, SG Gorbalenya, AE TI A human RNA viral cysteine proteinase that depends upon a unique Zn2+-binding finger connecting the two domains of a papain-like fold SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AMINO-ACID SEQUENCE; HEPATITIS-C VIRUS; INFECTIOUS-BRONCHITIS VIRUS; ZINC-CONTAINING ENZYME; P-28 CLEAVAGE SITE; CRYSTAL-STRUCTURE; MURINE CORONAVIRUS; BLEOMYCIN HYDROLASE; SECONDARY STRUCTURE; BINDING SITE AB A cysteine proteinase, papain-like proteinase (PL1pro), of the human coronavirus 229E (HCoV) regulates the expression of the replicase polyproteins, pp1a and ppa1ab, by cleavage between Gly(111) and Asn(112), far upstream of its own catalytic residue Cys(1054). In this report, using bioinformatics tools, we predict that, unlike its distant cellular homologues, HCoV PL1pro and its coronaviral relatives have a poorly conserved Zn2+ finger connecting the left and right hand domains of a papain-like fold. Optical emission spectrometry has been used to confirm the presence of Zn2+ in a purified and proteolytically active form of the HCoV PL1pro fused with the Escherichia coli maltose-binding protein. In denaturation/renaturation experiments using the recombinant protein, its activity was shown to be strongly dependent upon Zn2+, which could be partly substituted by Co2+ during renaturation, The reconstituted, Zn2+-containing PL1pro was not sensitive to 1,10-phenanthroline, and the Zn2+-depleted protein was not reactivated by adding Zn2+ after renaturation. Consistent with the proposed essential structural role of Zn2+, PL1pro was selectively inactivated by mutations in the Zn2+ finger including replacements of any of four conserved Cys residues predicted to co-ordinate Zn2+. The unique domain organization of HCoV PL1pro provides a potential framework for regulatory processes and may be indicative of a nonproteolytic activity of this enzyme. C1 NCI, Frederick Canc Res & Dev Ctr, Adv Biomed Comp Ctr, SAIC,NIH, Frederick, MD 21702 USA. Univ Wurzburg, Inst Immunol & Virol, D-97078 Wurzburg, Germany. Leiden Univ, Ctr Med, NL-2300 RC Leiden, Netherlands. Russian Acad Med Sci, Inst Poliomyelitis & Viral Encephalitis, Moscow 142782, Russia. RP Gorbalenya, AE (reprint author), NCI, Frederick Canc Res & Dev Ctr, Adv Biomed Comp Ctr, SAIC,NIH, 430 Miller Dr,Rm 235, Frederick, MD 21702 USA. RI Gorbalenya, Alexander/J-4818-2012 OI Gorbalenya, Alexander/0000-0002-4967-7341 FU NCI NIH HHS [N01-CO-56000] NR 86 TC 49 Z9 52 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 21 PY 1999 VL 274 IS 21 BP 14918 EP 14925 DI 10.1074/jbc.274.21.14918 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 225MK UT WOS:000081965200057 PM 10329692 ER PT J AU Xu, P Jacobs, AR Taylor, SI AF Xu, P Jacobs, AR Taylor, SI TI Interaction of insulin receptor substrate 3 with insulin receptor, insulin receptor-related receptor, insulin-like growth factor-1 receptor, and downstream signaling proteins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOSPHOTYROSINE-DEPENDENT INTERACTION; PLECKSTRIN HOMOLOGY DOMAIN; TANDEM SH2 DOMAINS; PHOSPHATIDYLINOSITOL 3-KINASE; HEPATOMA-CELLS; SH2-CONTAINING PROTEIN; TYROSINE-PHOSPHATASE; DOCKING PROTEIN; 2-HYBRID SYSTEM; RAT ADIPOCYTES AB Insulin receptor substrates (IRS) mediate biological actions of insulin, growth factors, and cytokines. All four mammalian IRS proteins contain pleckstrin homology (PH) and phosphotyrosine binding (PTB) domains at their N termini. However, the molecules diverge in their C-terminal sequences. IRS3 is considerably shorter than IRS1, IRS2, and IRS4, and is predicted to interact with a distinct group of downstream signaling molecules. In the present study, we investigated interactions of IRS3 with various signaling molecules. The PTB domain of mIRS3 is necessary and sufficient for binding to the juxtamembrane NPXpY motif of the insulin receptor in the yeast two-hybrid system. This interaction is stronger if the PH domain or the C-terminal phosphorylation domain is retained in the construct. As determined in a modified yeast two-hybrid system, mIRS3 bound strongly to the p85 subunit of phosphatidylinositol 3-kinase. Although high affinity interaction required the presence of at least two of the four YXXM motifs in mIRS3, there was not a requirement for specific YXXM motifs. mIRS3 also bound to SHP2, Grb2, Nck, and Shc, but less strongly than to p85. Studies in COS-7 cells demonstrated that deletion of either the PH or the PTB domain abolished insulin-stimulated phosphorylation of mIRS3. Insulin stimulation promoted the association of mIRS3 with p85, SHP2, Nck, and Shc. Despite weak association between mIRS3 and Grb2, this interaction was not increased by insulin, and may not be mediated by the SH2 domain of Grb2. Thus, in contrast to other IRS proteins, mIRS3 appears to have greater specificity for activation of the phosphatidylinositol 3-kinase pathway rather than the Grb2/Ras pathway. C1 NIDDK, Diabet Branch, NIH, Bethesda, MD 20892 USA. George Washington Univ, Grad Program Genet, Washington, DC 20052 USA. RP NIDDK, Diabet Branch, NIH, Bldg 10,Rm 9S-213, Bethesda, MD 20892 USA. EM simeon_taylor@nih.gov NR 49 TC 38 Z9 39 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 21 PY 1999 VL 274 IS 21 BP 15262 EP 15270 DI 10.1074/jbc.274.21.15262 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 225MK UT WOS:000081965200101 PM 10329736 ER PT J AU Asermely, KE Sterling, GH McCafferty, MR O'Neill, JJ AF Asermely, KE Sterling, GH McCafferty, MR O'Neill, JJ TI Accelerated communication - Synaptophysin is phosphorylated in rat cortical synaptosomes treated with botulinum toxin A SO LIFE SCIENCES LA English DT Article DE botulinum toxin; acetylcholine; synaptophysin; protein phosphorylation; exocytosis; vesicle ID SYNAPTIC VESICLE MEMBRANE; AFFINITY CHOLINE UPTAKE; PHARMACOLOGICAL CHARACTERIZATION; CLOSTRIDIAL NEUROTOXINS; PROTEIN-PHOSPHORYLATION; FUSION COMPLEX; ACETYLCHOLINE; CALCIUM; INHIBITION; TRANSPORT AB Phosphorylation and dephosphorylation of neuronal proteins have been implicated in regulation of synaptic transmission. Studies were performed to determine if synaptophysin was phosphorylated or dephosphorylated during exposure of synaptosomes to botulinum toxin A (BoTX/A). Cholinergic-enriched synaptosomes were preincubated in the presence of H-3-choline to label newly synthesized acetylcholine (H-3-ACh). This was followed by incubation with low or high potassium to stimulate release of newly synthesized 3H-ACh. BoTX/A inhibited total Ach release by 15-19% and inhibited release of newly synthesized H-3-ACh by 35%. A 165% increase in synaptophysin phosphorylation occurred in a dose-dependent manner over a range of doses (0.2 nM, 2 nM, 20 nM, 100 nM) of BoTX/A. When 4-Aminopyridine was added to synaptosomes that were BoTX/A treated, synaptophysin was dephosphorylated to control levels. Synaptosomes incubated with BoTX/A exhibited an inhibition of potassium stimulated ACh release and an increase in synaptophysin phosphorylation. Synaptophysin phosphorylation may be involved in inhibition of acetylcholine release. (C) 1999 Elsevier Science Inc. C1 Temple Univ, Sch Med, Dept Pharmacol, Philadelphia, PA 19140 USA. RP Asermely, KE (reprint author), NINDS, NIH, Bldg 36,Room 5D-06 36 Convent Dr, Bethesda, MD 20892 USA. NR 42 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 0024-3205 J9 LIFE SCI JI Life Sci. PD MAY 21 PY 1999 VL 64 IS 26 BP PL297 EP PL303 DI 10.1016/S0024-3205(99)00212-X PG 7 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 201FT UT WOS:000080584900013 PM 10403513 ER PT J AU Feng, ZH Chang, RCC Bing, GY Hudson, P Tiao, NY Jin, L Hong, JS AF Feng, ZH Chang, RCC Bing, GY Hudson, P Tiao, NY Jin, L Hong, JS TI Long-term increase of Sp-1 transcription factors in the hippocampus after kainic acid treatment SO MOLECULAR BRAIN RESEARCH LA English DT Article DE hippocampus; kainic acid; mossy fiber sprouting; temporal lobe epilepsy; transcription factor ID PREPROENKEPHALIN MESSENGER-RNA; FOS-RELATED ANTIGEN; RAT HIPPOCAMPUS; DENTATE GYRUS; MOSSY FIBERS; TREATED RATS; CPG ISLAND; FACTOR SP1; GENE; BRAIN AB Systemic administration of kainic acid (KA), a glutamate receptor agonist, causes robust seizures and has been used as an excellent rodent model for human temporal lobe epilepsy. Recently, we have demonstrated that a single injection of KA increases the steady-state levels of proenkephalin (PENK) mRNA in the rat hippocampus for at least one year. However, the molecular mechanisms underlying this long-term increase in PENK mRNA levels have not been clearly defined. To determine the possible involvement of the Sp-l transcription factors in this regulation, electrophoresis mobility-shift assays were used to study the expression of Sp-l factors in the hippocampus after KA treatment. The results showed that then are long-lasting increases in Sp-l DNA-binding activity. The Sp-l DNA-binding complexes were only competed by the non-radioactive Sp-l element and not by ENKCRE2, AP-I or CRE elements, indicating the specificity of Sp-l DNA-binding activity. Since the expression of Sp-l parallels the time course of long-lasting increase in the expression of PENK mRNA and mossy fiber sprouting after KA treatment, we hypothesize that the increase in Sp-l activity may be associated with the long-term changes in the plasticity of hippocampal function after KA-induced seizures. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Feng, ZH (reprint author), NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, POB 12233,MD F1-01, Res Triangle Pk, NC 27709 USA. RI Chang, Raymond Chuen-Chung/C-1107-2009; OI Chang, Raymond Chuen-Chung/0000-0001-8538-7993; Bing, Guoying/0000-0003-0609-8152 NR 36 TC 18 Z9 18 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 MAY 21 PY 1999 VL 69 IS 1 BP 144 EP 148 DI 10.1016/S0169-328X(99)00099-6 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 201CM UT WOS:000080577100015 ER PT J AU Wang, RF Wang, X Atwood, AC Topalian, SL Rosenberg, SA AF Wang, RF Wang, X Atwood, AC Topalian, SL Rosenberg, SA TI Cloning genes encoding MHC class II-restricted antigens: Mutated CDC27 as a tumor antigen SO SCIENCE LA English DT Article ID T-CELL RESPONSES; HLA-DM; INFILTRATING LYMPHOCYTES; HUMAN-MELANOMA; HUMAN HOMOLOG; BETA-CATENIN; KAPPA-B; IDENTIFICATION; PROTEINS; COMPLEX AB In an effort to identify tumor-specific antigens recognized by CD4(+) T cells, an approach was developed that allows the screening of an invariant chain-complementary DNA fusion library in a genetically engineered cell line expressing the essential components of the major histocompatibility complex (MHC) class II processing and presentation pathway. This Led to the identification of a mutated form of human CDC27, which gave rise to an HLA-DR4-restricted melanoma antigen, A mutated form of triosephosphate isomerase, isolated by a biochemical method, was also identified as an HLA-DR1-restricted antigen. Thus, this approach may be generally applicable to the identification of antigens recognized by CD4(+) T cells, which could aid the development of strategies for the treatment of patients with cancer, autoimmune diseases, or infectious diseases. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Wang, RF (reprint author), NCI, Surg Branch, NIH, Bldg 10-2B42,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 47 TC 206 Z9 212 U1 0 U2 4 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD MAY 21 PY 1999 VL 284 IS 5418 BP 1351 EP 1354 DI 10.1126/science.284.5418.1351 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 198NN UT WOS:000080430600051 PM 10334988 ER PT J AU Fan, S Wang, JA Yuan, R Ma, Y Meng, Q Erdos, MR Pestell, RG Yuan, F Auborn, KJ Goldberg, ID Rosen, EM AF Fan, S Wang, JA Yuan, R Ma, Y Meng, Q Erdos, MR Pestell, RG Yuan, F Auborn, KJ Goldberg, ID Rosen, EM TI BRCA1 inhibition of estrogen receptor signaling in transfected cells SO SCIENCE LA English DT Article ID TUMOR-SUPPRESSOR; TRANSCRIPTIONAL ACTIVATION; NUCLEAR RECEPTORS; DNA-DAMAGE; GENE BRCA1; PROLIFERATION; CANCER; DIFFERENTIATION; EXPRESSION; BREAST AB Mutations of the breast cancer susceptibility gene BRCA1 confer increased risk for breast, ovarian, and prostatic cancers, but it is not clear why the mutations are associated with these particular tumor types. In transient transfection assays, BRCA1 was found to inhibit signaling by the Ligand-activated estrogen receptor (ER-alpha) through the estrogen-responsive enhancer element and to block the transcriptional activation function AF-2 of ER-alpha. These results raise the possibility that wild-type BRCA1 suppresses estrogen-dependent transcriptional pathways related to mammary epithelial cell proliferation and that Loss of this ability contributes to tumorigenesis. C1 Albert Einstein Coll Med, Long Isl Jewish Med Ctr, Dept Radiat Oncol, New Hyde Park, NY 11040 USA. Albert Einstein Coll Med, Long Isl Jewish Med Ctr, Dept Otolaryngol, New Hyde Park, NY 11040 USA. N Shore Univ Hosp, NSUH LIJ Hlth Syst, Dept Radiat Oncol, Manhasset, NY 11030 USA. NIH, Genet & Mol Biol Branch, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Dev, Bronx, NY 10461 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Mol Biol, Bronx, NY 10461 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA. RP Fan, S (reprint author), Albert Einstein Coll Med, Long Isl Jewish Med Ctr, Dept Radiat Oncol, Long Isl Campus,270-05 76th Ave, New Hyde Park, NY 11040 USA. FU NCI NIH HHS [R01-CA75503]; NIEHS NIH HHS [R01-ES09169] NR 22 TC 337 Z9 361 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 MAY 21 PY 1999 VL 284 IS 5418 BP 1354 EP 1356 DI 10.1126/science.284.5418.1354 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 198NN UT WOS:000080430600052 PM 10334989 ER PT J AU Dittmer, U Hasenkrug, KJ AF Dittmer, U Hasenkrug, KJ TI Alternative interpretation of lymphocyte depletion studies using monoclonal antibodies in animals previously vaccinated with attenuated retroviral vaccines SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Letter ID PROTECTION; MECHANISMS C1 NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Dittmer, U (reprint author), NIAID, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 5 TC 5 Z9 5 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD MAY 20 PY 1999 VL 15 IS 8 BP 785 EP 785 DI 10.1089/088922299310881 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 198FV UT WOS:000080413200011 PM 10357475 ER PT J AU Medin, JA Takenaka, T Carpentier, S Garcia, V Basile, JP Segui, B Andrieu-Abadie, N Auge, N Salvayre, R Levade, T AF Medin, JA Takenaka, T Carpentier, S Garcia, V Basile, JP Segui, B Andrieu-Abadie, N Auge, N Salvayre, R Levade, T TI Retrovirus-mediated correction of the metabolic defect in cultured Farber disease cells SO HUMAN GENE THERAPY LA English DT Article ID HUMAN ACID CERAMIDASE; LYSOSOMAL STORAGE; SIGNAL-TRANSDUCTION; SKIN FIBROBLASTS; GENE-TRANSFER; SPHINGOMYELIN; VECTOR; VII; EXPRESSION; DEFICIENCY AB Farber disease is a rare severe lysosomal storage disorder due to a deficient activity of the enzyme acid ceramidase (AC), Patients have granulomas along with lipid-laden macrophages that accumulate in a number of tissues, leading to multiple diverse clinical symptoms. There is no therapy for the disorder and most patients succumb to the disease in early childhood. The severity of the disease progression seems to correlate with the amount of the accumulated ceramide substrate. Since the cDNA for human AC has been elucidated we sought to establish if genetic transfer of this sequence would lead to enzymatic and, especially, functional correction of the catabolic defect in Farber patient cells. To do this, a novel amphotropic recombinant retrovirus was constructed that engineers transfer of the human AC cDNA, On infection of patient fibroblasts, AC enzyme activity in cell extracts was completely restored. Further, substrate-loading assays of intact living cells showed a fully normalized catabolism of lysosomal ceramide, Lastly, as reported for some other corrected enzymatic defects of lysosomes, metabolic cooperativity was seen, in that functionally corrected patient fibroblasts secreted AC that was taken up through the mannose 6-phosphate receptor and used by uncorrected fibroblasts as well as recipient Farber lymphoblastoid cells. This overall transduction and uptake scenario for Farber disease allows future treatment of this severe disorder to be envisioned using gene transfer approaches. C1 Univ Illinois, Hematol Oncol Sect, MBRB, Dept Med, Chicago, IL 60607 USA. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. CHU Rangueil, U466, Lab Biochim Malad Metab, Inst Louis Bugnard,INSERM, F-31403 Toulouse, France. RP Medin, JA (reprint author), Univ Illinois, Hematol Oncol Sect, MBRB, Dept Med, Room 3150,900 S Ashland Ave, Chicago, IL 60607 USA. RI Andrieu-Abadie, Nathalie/N-6793-2013; Segui, Bruno/O-8957-2014; Levade, Thierry/O-8948-2014 OI Andrieu-Abadie, Nathalie/0000-0003-2698-1970; Segui, Bruno/0000-0002-6119-1889; NR 44 TC 20 Z9 20 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 MAY 20 PY 1999 VL 10 IS 8 BP 1321 EP 1329 DI 10.1089/10430349950018003 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 199QQ UT WOS:000080493500007 PM 10365663 ER PT J AU Cushman, M Insaf, S Paul, G Ruell, JA De Clercq, E Schols, D Pannecouque, C Witvrouw, M Schaeffer, CA Turpin, JA Williamson, K Rice, WG AF Cushman, M Insaf, S Paul, G Ruell, JA De Clercq, E Schols, D Pannecouque, C Witvrouw, M Schaeffer, CA Turpin, JA Williamson, K Rice, WG TI Extension of the polyanionic cosalane pharmacophore as a strategy for increasing anti-HIV potency SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; AURINTRICARBOXYLIC ACID ATA; MOLECULAR-WEIGHT; HUMAN CD4; ANALOGS; REPLICATION; INHIBITION; SERIES; AGENT; SITE AB The anti-HIV agent cosalane inhibits both the binding of gp120 to CD4 as well as an undefined postattachment event prior to reverse transcription. Several cosalane analogues having an extended polyanionic "pharmacophore" were designed based on a hypothetical model of the binding of cosalane to CD4. The analogues were synthesized, and a number of them displayed anti-HIV activity. One of the new analogues was found to possess enhanced potency as an anti-HIV agent relative to cosalane itself. Although the new analogues inhibited both HIV-1 and HTV-2, they were more potent as inhibitors of HIV-1 than HIV-2. Mechanism of action studies indicated that the most potent of the new analogues inhibited fusion of the viral envelope with the cell membrane at lower concentrations than it inhibited attachment, suggesting inhibition of fusion as the primary mechanism of action. C1 Purdue Univ, Sch Pharm & Pharmacal Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. Katholieke Univ Leuven, Rega Inst Med Res, B-3000 Louvain, Belgium. NCI, Frederick Canc Res & Dev Ctr, Lab Antiviral Drug Mechanisms, SAIC Frederick, Frederick, MD 21702 USA. RP Cushman, M (reprint author), Purdue Univ, Sch Pharm & Pharmacal Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. FU NIAID NIH HHS [N01-AI-36624] NR 29 TC 16 Z9 16 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 MAY 20 PY 1999 VL 42 IS 10 BP 1767 EP 1777 DI 10.1021/jm980727m PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 198QH UT WOS:000080435100010 PM 10346929 ER PT J AU Yu, QS Holloway, HW Utsuki, T Brossi, A Greig, NH AF Yu, QS Holloway, HW Utsuki, T Brossi, A Greig, NH TI Synthesis of novel phenserine-based-selective inhibitors of butyrylcholinesterase for Alzheimer's disease SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ANTICHOLINESTERASE ACTIVITIES; CARBAMATE ANALOGS; ANTIPODAL ISOMERS; HUPERZINE-A; ACETYLCHOLINESTERASE; CHOLINESTERASES; PHYSOSTIGMINE; GENES; RING AB Four novel analogues (8-11) of cymserine (2) were synthesized by methods similar to those recently developed for the total syntheses of N-8-norphenserine (Yu, Q. S.; et al. J. Med. Chem. 1997, 40, 2895-2901) and N-1,N-8-bisnorphenserine (Yu, Q. S.; et al. J. Med. Chem. 1998, 41, 2371-2379). As our structure-activity studies predicted, these compounds are highly potent and selective inhibitors of human butyryleholinesterase (BChE) and will test the novel hypothesis that BChE inhibitors are useful in the treatment of Alzheimer's disease. In a similar manner, the same modifications that provided BChE selectivity were applied to the acetylcholinesterase (AChE)-selective inhibitor, tolserine (5), to provide the novel tolserine analogues 12-15. As predicted, these modifications altered the AChE-selective action of tolserine (5) to favor a lack of cholinesterase enzyme subtype selectivity. C1 NIA, Lab Cellular & Mol Biol, 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, Lab Cellular & Mol Biol, Gerontol Res Ctr 4E02, Intramural Res Program,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 29 TC 121 Z9 123 U1 3 U2 14 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 MAY 20 PY 1999 VL 42 IS 10 BP 1855 EP 1861 DI 10.1021/jm980459s PG 7 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 198QH UT WOS:000080435100020 PM 10346939 ER PT J AU Lee, SH Shiao, YH Plisov, SY Kasprzak, KS AF Lee, SH Shiao, YH Plisov, SY Kasprzak, KS TI Nickel(II) acetate-treated Chinese hamster ovary cells differentially express vimentin, hSNF2H homologue, and h ferritin SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID INTERMEDIATE FILAMENTS; CHROMATIN; CARCINOGENS; MECHANISM; MODEL; RATS; RNA AB In probing the possible non-genotoxic molecular mechanism(s) of nickel(II)-induced carcinogenesis, we performed a non-radioactive mRNA differential display analysis for nickel(II) acetate-treated Chinese hamster ovary cells (CHO-K1-BH4), Three out of thirty differentially expressed cDNAs had sequences highly similar to known genes. Down-regulation of vimentin and a hSNF2H homologue and up-regulation of ferritin heavy chain were confirmed by Northern blot analysis, The expression of these mRNAs was time- and nickel(II) concentration-dependent. For vimentin, the decrease in mRNA level was concurrent with a decrease in the protein level. For ferritin, the increase in mRNA had no effect on the protein level. Dysregulation of these gene products signifies their involvement in the epigenetic effects of carcinogenic nickel(II) compounds. C1 NCI, Comparat Carcinogenesis Lab, Frederick Canc Res & Dev Ctr, NIH, Frederick, MD 21702 USA. RP Lee, SH (reprint author), NCI, Comparat Carcinogenesis Lab, Frederick Canc Res & Dev Ctr, NIH, Bldg 538,Room 205, Frederick, MD 21702 USA. NR 19 TC 12 Z9 14 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 19 PY 1999 VL 258 IS 3 BP 592 EP 595 DI 10.1006/bbrc.1999.0692 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 201LK UT WOS:000080596100017 PM 10329430 ER PT J AU Stauber, RH Shen, RL Palm, G Tarasova, NI AF Stauber, RH Shen, RL Palm, G Tarasova, NI TI Direct visualization of HIV-1 entry: Mechanisms and role of cell surface receptors SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; GREEN FLUORESCENT PROTEIN; T-CELLS; MICROSCOPIC ANALYSIS; ENDOCYTIC PATHWAY; ENVELOPED VIRUSES; INFLUENZA-VIRUS; LIVING CELLS; INFECTION; FUSION AB Highly fluorescent virions of T- and M-tropic HIV-1 strains were obtained by incorporation of the viral accessory protein Vpr, fused to the green fluorescent protein, in trans. The fluorescent virions displayed normal morphology, were infectious, and could be used for direct visualization of HIV-1 attachment and trafficking in various cell lines. More than 90% of the viral particles were found to enter the cells by direct membrane fusion in T-cells, CD4+ HeLa cells, and macrophages, Visualizing HIV-1 attachment and entry in the absence or presence of CD4 and/or the appropriate coreceptors indicated that CD4 is the major receptor for virus attachment in the case of JR-CSF and NL-4-3 HIV-1 isolates; however, the coreceptors are required for membrane fusion. Internalization of the coreceptor CXCR4 inhibited entry, but did not prevent virus binding suggesting that transient downregulation of the coreceptor(s) may not be the most efficient way of blocking HIV infection in vivo. (C) 1999 Academic Press. C1 NCI, Mol Aspects Drug Design Sect, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA. NCI, Human Retrovirus Sect, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA. NCI, Prot Struct Sect, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA. RP Tarasova, NI (reprint author), NCI, Mol Aspects Drug Design Sect, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA. RI Shen, Rulong/E-4079-2011; OI Stauber, Roland/0000-0002-1341-4523 NR 50 TC 22 Z9 22 U1 1 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 19 PY 1999 VL 258 IS 3 BP 695 EP 702 DI 10.1006/bbrc.1999.0511 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 201LK UT WOS:000080596100036 PM 10329448 ER PT J AU Frederikse, PH Farnsworth, P Zigler, JS AF Frederikse, PH Farnsworth, P Zigler, JS TI Thiamine deficiency in vivo produces fiber cell degeneration in mouse lenses SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID AMYLOID PRECURSOR PROTEIN; VULNERABLE BRAIN-REGIONS; EXPRESSION; OPACITIES; BETA; IMMUNOREACTIVITY; PRESENILIN-1; DISEASE; PLASMA AB Thiamine (Vitamin B1) is a co-factor for enzymes key in bridging aerobic and anaerobic metabolism. One such enzyme, transketolase, catalyzes two of three reactions for entry into the pentose-phosphate pathway, a major source of chemical reducing power. Thus, thiamine deprivation (TD) is considered a classic model of systemic oxidative stress and is linked with degenerative diseases. TD in mice and rats produces neurodegeneration with Alzheimer's disease characteristics. Age-related disease of the lens, commonly cataract, is also linked with thiamine and oxidative stress. To test the effects of TD on mice, we used a previously defined protocol involving a thiamine free diet and a thiamine antagonist. After 12 days, lens fiber cell degeneration was observed primarily along the lens posterior beneath the intact capsule. These regions exhibited a localized increased expression of Alzheimer precursor protein, A beta peptides, and presenilin 1. These data indicate that TD in mice produces fiber cell degeneration and suggest common mechanisms for TD-induced lens fiber and neuronal cell degeneration. (C) 1999 Academic Press. C1 NEI, Lab Mechanisms Ocular Dis, NIH, Bethesda, MD 20892 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Physiol & Pharmacol, Newark, NJ 07103 USA. RP Frederikse, PH (reprint author), NEI, Lab Mechanisms Ocular Dis, NIH, Bldg 6,Room 237, Bethesda, MD 20892 USA. NR 20 TC 23 Z9 27 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 19 PY 1999 VL 258 IS 3 BP 703 EP 707 DI 10.1006/bbrc.1999.0560 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 201LK UT WOS:000080596100037 PM 10329449 ER PT J AU Ottiger, M Bax, A AF Ottiger, M Bax, A TI How tetrahedral are methyl groups in proteins? A liquid crystal NMR study SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID NUCLEAR MAGNETIC-RESONANCE; HIGH-RESOLUTION NMR; DIPOLAR COUPLINGS; HUMAN UBIQUITIN; STAPHYLOCOCCAL NUCLEASE; ORIENTED MACROMOLECULES; PHOSPHOLIPID MICELLES; RELAXATION; C-13; DYNAMICS AB A small degree. of protein alignment with an external magnetic field can be obtained in a dilute aqueous liquid crystalline solution of dimyristoylphosphatidylcholine (DMPC) and dihexanoylphosphatidylcholine (DHPC). It is demonstrated that residual one-bond C-13-C-13 and C-13-H-1 dipolar couplings of methyl groups in weakly aligned human ubiquitin can be measured with high accuracy. Experimentally, the ratio between C-13-H-1 and C-13-C-13 dipolar, couplings is found to be -3.17 +/- 0.03. Assuming a static conformation of the methyl group, rapidly spinning about its 3-fold symmetry axis, this ratio corresponds to an average C-C-H bond angle of 110.9 +/- 1 degrees,which is larger than the ideal tetrahedral value of 109.5 degrees. Data indicate that the geometry of the various methyl groups is quite uniform, but that small (less than or equal to 1 degrees) deviations between the C-C vector and the axis connecting the methyl carbon to the geometric center of the three methyl protons may occur. The largest outlier is found for Ala(46), which has a positive phi backbone angle, causing its methyl group to be within van der Waals contact of the preceding carbonyl oxygen. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NR 53 TC 42 Z9 42 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD MAY 19 PY 1999 VL 121 IS 19 BP 4690 EP 4695 DI 10.1021/ja984484z PG 6 WC Chemistry, Multidisciplinary SC Chemistry GA 198MP UT WOS:000080428200019 ER PT J AU Feuer, EJ Sheinfeld, J Bosl, GJ AF Feuer, EJ Sheinfeld, J Bosl, GJ TI Does size matter? Association between number of patients treated and patient outcome in metastatic testicular cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID HOSPITAL VOLUME; SURVIVAL; CHEMOTHERAPY; BREAKTHROUGH; VINBLASTINE; BLEOMYCIN; IMPACT; TUMOR C1 NCI, Div Canc Control & Poplat Sci, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Dept Surg, Urol Serv, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. RP Feuer, EJ (reprint author), NCI, Div Canc Control & Poplat Sci, Execut Plaza N,Rm 313,MSC 7344, Bethesda, MD 20892 USA. NR 13 TC 17 Z9 17 U1 0 U2 1 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 19 PY 1999 VL 91 IS 10 BP 816 EP 818 DI 10.1093/jnci/91.10.816 PG 3 WC Oncology SC Oncology GA 196HM UT WOS:000080303000001 PM 10340895 ER PT J AU Brown, ML AF Brown, ML TI Cancer patient care in clinical trials sponsored by the National Cancer Institute: What does it cost? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID MANAGED CARE C1 NCI, Appl Res Branch, Canc Surveillance Res Program, Div Canc Control & Populat,NIH, Bethesda, MD 20892 USA. RP Brown, ML (reprint author), NCI, Appl Res Branch, Canc Surveillance Res Program, Div Canc Control & Populat,NIH, Execut Plaza N,Rm 313, Bethesda, MD 20892 USA. NR 8 TC 11 Z9 11 U1 0 U2 0 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 19 PY 1999 VL 91 IS 10 BP 818 EP 819 DI 10.1093/jnci/91.10.818 PG 2 WC Oncology SC Oncology GA 196HM UT WOS:000080303000002 PM 10340896 ER PT J AU Dey, S Hafkemeyer, P Pastan, I Gottesman, MM AF Dey, S Hafkemeyer, P Pastan, I Gottesman, MM TI A single amino acid residue contributes to distinct mechanisms of inhibition of the human multidrug transporter by stereoisomers of the dopamine receptor antagonist flupentixol SO BIOCHEMISTRY LA English DT Article ID HUMAN P-GLYCOPROTEIN; BACTERIOPHAGE-T7 RNA-POLYMERASE; TRANSIENT-EXPRESSION SYSTEM; VACCINIA VIRUS; MONOCLONAL-ANTIBODIES; SUBSTRATE-SPECIFICITY; RESISTANCE; CELLS; DRUGS; BINDING AB Both cis and trans isomers of the dopamine receptor antagonist flupentixol inhibit drug transport and reverse drug resistance mediated by the human multidrug transporter P-glycoprotein (Pgp) with a stereoselective potency. The rate of ATP hydrolysis by Pgp and photoaffinity labeling of Pgp with the substrate analogue [I-125]iodoarylazidoprazosin ([I-125]IAAP) are modulated by each isomer in an opposite manner, suggesting different mechanisms for the inhibitory effect on drug transport. In this study we demonstrate that substitution of a single phenylalanine residue at position 983 (F983) with alanine (F983A) in putative transmembrane (TM) region 12 selectively affects inhibition of Pgp-mediated drug transport by both isomers of flupentixol. In F983A the stimulatory effect of cis(Z)-flupentixol and the inhibitory effect of trans(E)-flupentixol on ATP hydrolysis and [I-125]IAAP labeling were significantly altered. This indicates that F983 contributes to inhibition of drug transport by both isomers of flupentixol and plays an important role in stimulation and inhibition of ATP hydrolysis and [I-125]IAAP labeling by cis(Z)- and trans(E)-flupentixol, respectively. The near-wild-type level of drug transport by the F983A Pgp mutant dissociates susceptibility to inhibition by flupentixol from drug translocation, indicating the allosteric nature of the flupentixol interaction. The inhibitory effects of cyclosporin A on drug transport, drug-stimulated ATP hydrolysis, and [I-125]IAAP labeling as well as the stimulatory effect of verapamil on ATP hydrolysis by Pgp were minimally affected by substitution of F983, suggesting no global alteration in the structural and functional integrity of the mutant. Taken together, our data suggest that distinct mechanisms of inhibition of Pgp-mediated drug transport by the cia and trans isomers of flupentixol are mediated through a common site of interaction. C1 NCI, Cell Biol Lab, Bethesda, MD 20892 USA. NCI, Mol Biol Lab, Div Basic Sci, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, 37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. NR 43 TC 46 Z9 47 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 18 PY 1999 VL 38 IS 20 BP 6630 EP 6639 DI 10.1021/bi983038l PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 201KJ UT WOS:000080593700030 PM 10350482 ER PT J AU Barrett, WC DeGnore, JP Konig, S Fales, HM Keng, YF Zhang, ZY Yim, MB Chock, PB AF Barrett, WC DeGnore, JP Konig, S Fales, HM Keng, YF Zhang, ZY Yim, MB Chock, PB TI Regulation of PTP1B via glutathionylation of the active site cysteine 215 SO BIOCHEMISTRY LA English DT Article ID PROTEIN-TYROSINE PHOSPHATASES; EPIDERMAL GROWTH-FACTOR; HYDROGEN-PEROXIDE; SULFENIC ACID; GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; REVERSIBLE INACTIVATION; MASS-SPECTROMETRY; OXIDATIVE STRESS; S-THIOLATION; CELLS AB The reversible regulation of protein tyrosine phosphatase is an important mechanism in processing signal transduction and regulating cell cycle. Recent reports have shown that the active site cysteine residue, Cys215, can be reversibly oxidized to a cysteine sulfenic derivative (Denu and Tanner, 1998; Lee et al., 1998). We propose an additional modification that has implications for the in vivo regulation of protein tyrosine phosphatase 1B (PTP1B, EC 3.1.3.48): the glutathionylation of Cys215 to a mixed protein disulfide. Treatment of PTP1B with diamide and reduced glutathione or with only glutathione disulfide (GSSG) results in a modification detected by mass spectrometry in which the cysteine residues are oxidized to mixed disulfides with glutathione. The activity is recovered by the addition of dithiothreitol, presumably by reducing the cysteine disulfides. In addition, inactivated PTP1B is reactivated enzymatically by the glutathione-specific dethiolase enzyme thioltransferase (glutaredoxin), indicating that the inactivated form of the phosphatase is a glutathionyl mixed disulfide. The cysteine sulfenic derivative can easily oxidize to its irreversible sulfinic and sulfonic forms and hinder the regulatory efficiency if it is not converted to a more stable and reversible end product such as a glutathionyl derivative. Glutathionylation of the cysteine sulfenic derivative will prevent the enzyme from further oxidation to its irreversible forms, and constitutes an efficient regulatory mechanism. C1 NHLBI, Biochem Lab, Metab Regulat Sect, NIH, Bethesda, MD 20892 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA. RP Chock, PB (reprint author), NHLBI, Biochem Lab, Metab Regulat Sect, NIH, Bldg 3,Room 204, Bethesda, MD 20892 USA. RI Konig, Simone/B-6504-2008 OI Konig, Simone/0000-0003-0672-7246 FU NCI NIH HHS [CA 69202] NR 37 TC 343 Z9 352 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 MAY 18 PY 1999 VL 38 IS 20 BP 6699 EP 6705 DI 10.1021/bi990240v PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 201KJ UT WOS:000080593700037 PM 10350489 ER PT J AU Cocco, L Rubbini, S Manzoli, L Billi, AM Faenza, I Peruzzi, D Matteucci, A Artico, M Gilmour, RS Rhee, SG AF Cocco, L Rubbini, S Manzoli, L Billi, AM Faenza, I Peruzzi, D Matteucci, A Artico, M Gilmour, RS Rhee, SG TI Inositides in the nucleus: presence and characterisation of the isozymes of phospholipase beta family in NIH 3T3 cells SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS LA English DT Article DE inositide; nucleus; phospholipase C; isozyme; phosphatidylinositol 4,5-bisphosphate ID FRIEND-CELLS; C BETA(1); DIFFERENTIATION; LOCALIZATION; DIACYLGLYCEROL; PLC-BETA(1); STIMULATION; RECEPTOR; KINASE; CYCLE AB Previous reports from our laboratories and others have hinted that the nucleus is a site for an autonomous signalling system acting through the activation of the inositol lipid cycle. Among phospholipases (PLC) it has been shown previously that PLC beta(1) is specifically localised in the nucleus as well as at the plasma membrane. Using NIH 3T3 cells, it has been possible to obtain, with two purification strategies, in the presence of in the absence of Nonidet P-40, both intact nuclei still maintaining the outer membrane and nuclei completely stripped of their envelope. In these nuclei, we show that not only PLC beta(1) is present, but also PLC beta(2), PLC beta(3) and PLC beta(4). The more abounding isoform is PLC beta(1) followed by PLC beta(3), PLC beta(2) and PLC beta(4), respectively. All the isoforms are enriched in nuclear preparations free from nuclear envelope and cytoplasmatic debris, indicating that the actual localisation of the PLC beta isozymes is in the inner nuclear compartment. (C) 1999 Published by Elsevier Science B.V. All rights reserved. C1 Univ Bologna, Inst Human Anat, I-40126 Bologna, Italy. Ist Ortoped Rizzoli, CNR, Cytomorphol Inst, I-40136 Bologna, Italy. Ist Ortoped Rizzoli, CNR, Lab Cell Biol & Electron Microscopy, I-40136 Bologna, Italy. Univ Auckland, Sch Med, Dept Mol Med, Auckland, New Zealand. NHLBI, Lab Cell Signalling, NIH, Bethesda, MD 20892 USA. RP Cocco, L (reprint author), Univ Bologna, Inst Human Anat, I-40126 Bologna, Italy. NR 20 TC 26 Z9 26 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-1981 J9 BBA-MOL CELL BIOL L JI BBA-Mol. Cell. Biol. Lipids PD MAY 18 PY 1999 VL 1438 IS 2 BP 295 EP 299 DI 10.1016/S1388-1981(99)00061-X PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 198FE UT WOS:000080411400014 PM 10320812 ER PT J AU Zinovieva, RD Piatigorsky, J Tomarev, SI AF Zinovieva, RD Piatigorsky, J Tomarev, SI TI O-crystallin, arginine kinase and ferritin from the octopus lens SO BIOCHIMICA ET BIOPHYSICA ACTA-PROTEIN STRUCTURE AND MOLECULAR ENZYMOLOGY LA English DT Article DE crystallin; octopus; lens; ferritin; phosphatidylethanolamine-binding protein ID AMINO-ACID-SEQUENCE; PHOSPHATIDYLETHANOLAMINE-BINDING PROTEIN; GLUTATHIONE-S-TRANSFERASE; MESSENGER-RNA; DETOXIFICATION ENZYMES; SCHISTOSOMA-MANSONI; BOVINE BRAIN; EXPRESSION; RECRUITMENT; SQUID AB Three proteins have been identified in the eye lens of the octopus, Octopus dofleini. A 22 kDa protein comprising 3-5% of the soluble protein of the lens is 35-43% identical to a family of phosphatidylethanolamine-binding proteins of vertebrates. Other members of this family include the immunodominant antigen of the filarial parasite, Onchocerca volvulus, putative odorant-binding proteins of Drosophila and a protein with unknown function of Caenorhabditis elegans. We have called this protein O-crystallin on the basis of its abundance in the transparent lens. O-Crystallin mRNA was detected only in the lens. Two tryptic peptides of another octopus lens protein, less abundant than O-crystallin, showed 80% identity to arginine kinase of invertebrates, a relative of creatine kinase of vertebrates. Finally, ferritin cDNA was isolated as an abundant cDNA from the octopus lens library. Northern blots showed that ferritin mRNA is not lens-specific. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Tomarev, SI (reprint author), NEI, Mol & Dev Biol Lab, NIH, Bldg 6,Room 2A04,6 Ctr Dr MSC 2730, Bethesda, MD 20892 USA. NR 37 TC 5 Z9 5 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4838 J9 BBA-PROTEIN STRUCT M JI Biochim. Biophys. Acta-Protein Struct. Molec. Enzym. PD MAY 18 PY 1999 VL 1431 IS 2 BP 512 EP 517 DI 10.1016/S0167-4838(99)00066-7 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 203CR UT WOS:000080690500023 PM 10350626 ER PT J AU Johansson, M Elam, M Rundqvist, B Eisenhofer, G Herlitz, H Lambert, G Friberg, P AF Johansson, M Elam, M Rundqvist, B Eisenhofer, G Herlitz, H Lambert, G Friberg, P TI Increased sympathetic nerve activity in renovascular hypertension SO CIRCULATION LA English DT Article DE hypertension; nervous system, sympathetic; renin ID ANGIOTENSIN-II; SODIUM RESTRICTION; PLASMA; HUMANS; SURVIVAL; DISEASE; RELEASE AB Background-increased sympathetic nerve activity may contribute to the progression of renovascular hypertension. Because previous results have been inconclusive, we investigated whether renovascular hypertensives show increased total and regional sympathetic nerve activity. Methods and Results-Sixty-five patients underwent renal angiography and measurements of plasma renin activity and angiotensin II in conjunction with estimation of sympathetic nerve activity by means of radiotracer dilution and intraneural recordings of muscle sympathetic nerve activity (MSNA), Age-matched healthy subjects (n=15) were examined for comparison. Total body norepinephrine (NE) spillover, an index of overall sympathetic nerve activity, was increased by 100% and MSNA by 60% in the hypertensive patients compared with healthy subjects (P<0.01 for both). A subgroup of 24 patients with well-defined renovascular hypertension (cured or improved hypertension after renal angioplasty) showed similar increases in total body NE spillover compared with the group at large. Patients with arterial plasma renin activity and angiotensin II levels above median had higher values for total body NE spillover than patients below median (P<0.01). Conclusions-This study unequivocally demonstrates elevated sympathetic nerve activity in patients with renovascular hypertension. The adrenergic overactivity may contribute to the blood pressure elevation and perhaps also to the high cardiovascular mortality in renovascular hypertension. C1 Univ Gothenburg, Sahlgrens Univ Hosp, Dept Clin Physiol, SE-41345 Gothenburg, Sweden. Univ Gothenburg, Sahlgrens Univ Hosp, Dept Clin Neurophysiol, SE-41345 Gothenburg, Sweden. Univ Gothenburg, Sahlgrens Univ Hosp, Dept Cardiol, SE-41345 Gothenburg, Sweden. Univ Gothenburg, Sahlgrens Univ Hosp, Dept Nephrol, SE-41345 Gothenburg, Sweden. NINDS GE, Bethesda, MD 20892 USA. RP Friberg, P (reprint author), Univ Gothenburg, Sahlgrens Univ Hosp, Dept Clin Physiol, SE-41345 Gothenburg, Sweden. RI Lambert, Gavin/E-7384-2010 OI Lambert, Gavin/0000-0003-0315-645X NR 31 TC 109 Z9 110 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 18 PY 1999 VL 99 IS 19 BP 2537 EP 2542 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 195VF UT WOS:000080272300008 PM 10330385 ER PT J AU Ma, DW Wang, GQ Wang, SM Kozikowski, AP Lewin, NE Blumberg, PM AF Ma, DW Wang, GQ Wang, SM Kozikowski, AP Lewin, NE Blumberg, PM TI Synthesis and protein kinase C binding activity of benzolactam-V7 SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID ALPHA-AMINO-ACIDS; TUMOR PROMOTERS; INDOLACTAM-V; TELEOCIDINS; CLARIFICATION; NITRATION; MIMICS; DOMAIN; DELTA; ILV AB Benzolactam-V7 (3a), a simplified analogues of (-)-indolactam-V with twist-form conformation, was synthesized and evaluated as a new protein kinase C modulator. Both 3a and its-7-substituted analogue 3c showed weak binding activity to displace PDBU binding from recombinant PKC alpha. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 Georgetown Univ, Med Ctr, Inst Cognit & Computat Sci, Drug Discovery Lab, Washington, DC 20007 USA. Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Bioorgan & Nat Prod Chem, Shanghai 200032, Peoples R China. NCI, Bethesda, MD 20892 USA. RP Ma, DW (reprint author), Georgetown Univ, Med Ctr, Inst Cognit & Computat Sci, Drug Discovery Lab, 3970 Reservoir Rd NW, Washington, DC 20007 USA. NR 13 TC 19 Z9 19 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD MAY 17 PY 1999 VL 9 IS 10 BP 1371 EP 1374 DI 10.1016/S0960-894X(99)00207-3 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 198ZH UT WOS:000080454300007 PM 10360738 ER PT J AU Shibata, MA Liu, ML Knudson, MC Shibata, E Yoshidome, K Bandey, T Korsmeyer, SJ Green, JE AF Shibata, MA Liu, ML Knudson, MC Shibata, E Yoshidome, K Bandey, T Korsmeyer, SJ Green, JE TI Haploid loss of bax leads to accelerated mammary tumor development in C3(1)/SV40-TAg transgenic mice: reduction in protective apoptotic response at the preneoplastic stage SO EMBO JOURNAL LA English DT Article DE apoptosis; bax; cell death; mammary gland; transgenic mice; tumor progression ID PROGRAMMED CELL-DEATH; BCL-2 HOMOLOG BAK; IN-VIVO; IMMUNOHISTOCHEMICAL ANALYSIS; SUPPRESSOR P53; E1B 19K; GENE; EXPRESSION; PROTEIN; ADENOCARCINOMA AB The dramatic increase in apoptosis observed during the development of preneoplastic mammary lesions is associated with a significant elevation in Bax expression in C3(1)/SV40 large T antigen (TAg) transgenic mice. The significance of Bax expression during tumor progression in vivo was studied by generating double-transgenic mice carrying the C3(1)/TAg transgene and mutant alleles for bax, C3(1)/TAg transgenic mice carrying mutant bax alleles exhibited accelerated rates of tumor growth, increased tumor numbers, larger tumor mass and decreased survival rates compared with mice carrying wild-type bax. Accelerated tumorigenesis associated with the bax(+/-) genotype did not require the loss of function of the second bax allele. Thus, haploid insufficiency of bax is enough to accelerate tumor progression, suggesting that the protective effect of Bax is dose-dependent. While levels of apoptosis in the preneoplastic lesions, but not carcinomas, were reduced in bax(+/-) or bax(-/-) mice compared with bax(+/+) mice, rates of cellular proliferation in mammary lesions were similar among all bax genotypes. These data demonstrate that bax is a critical suppressor of mammary tumor progression at the stage of preneoplastic mammary lesion development through the upregulation of apoptosis, but that this protective effect is lost during the transition from preneoplasia to invasive carcinoma. C1 NCI, Lab Cell Regulat & Carcinogenesis, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Harvard Univ, Dana Farber Canc Inst, Boston, MA 02115 USA. SAIC, Frederick, MD USA. RP Green, JE (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NR 29 TC 93 Z9 94 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD MAY 17 PY 1999 VL 18 IS 10 BP 2692 EP 2701 DI 10.1093/emboj/18.10.2692 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 201KK UT WOS:000080593800003 PM 10329616 ER PT J AU Blystone, SD Slater, SE Williams, MP Crow, MT Brown, EJ AF Blystone, SD Slater, SE Williams, MP Crow, MT Brown, EJ TI A molecular mechanism of integrin crosstalk: alpha(v)beta(3) suppression of calcium/calmodulin-dependent protein kinase II regulates alpha(5)beta(1) function SO JOURNAL OF CELL BIOLOGY LA English DT Article DE integrin; vitronectin; kinase; crosstalk; signaling ID FUNCTION-ASSOCIATED ANTIGEN-1; CYTOPLASMIC DOMAIN; SMOOTH-MUSCLE; CELL-MIGRATION; T-CELLS; RECEPTOR; FIBRONECTIN; ACTIVATION; COMPLEX; BINDING AB Many cells express more than one integrin receptor for extracellular matrix, and in vivo these receptors map be simultaneously engaged. Ligation of one integrin may influence the behavior of others on the cell, a phenomenon we have called integrin crosstalk. Ligation of the integrin alpha(v)beta(3) inhibits both phagocytosis and migration mediated by alpha(5)beta(1) on the same cell, and the beta(3) cytoplasmic tail is necessary and sufficient for this regulation of alpha(5)beta(1) Ligation of alpha(5)beta(1) activates the calcium- and calmodulin-dependent protein kinase II (CamKII). This activation is required for alpha(5)beta(1)-mediated phagocytosis and migration. Simultaneous ligation of alpha(v)beta(3) or expression of a chimeric molecule with a free pg cytoplasmic tail prevents alpha(5)beta(1)-mediated activation of CamKII. Expression of a constitutively active CamKII restores alpha(5)beta(1) functions blocked by alpha(v)beta(3)-initiated integrin crosstalk. Thus. alpha(v)beta(3) inhibition of alpha(5)beta(1) activation of CamKII is required for its role in integrin crosstalk. Structure-function analysis of the beta 3 cytoplasmic tail demonstrates a requirement fur Ser752 in beta(3)-mediated suppression of CamKII activation, while crosstalk is independent of Tyr747 and Tyr759, implicating Ser752, but not beta(3) tyrosine phosphorylation in initiation of the alpha(v)beta(3) Signal for integrin crosstalk. C1 SUNY Hlth Sci Ctr, Dept Anat & Cell Biol, Syracuse, NY 13210 USA. Washington Univ, Sch Med, Dept Med, Div Infect Dis, St Louis, MO 63110 USA. NIA, Vasc Biol Unit, Cardiovasc Sci Lab, Gerontol Res Ctr,NIH, Baltimore, MD 21224 USA. Univ Calif San Francisco, Program Microbiol Pathogenesis & Host Def, San Francisco, CA 94143 USA. RP Blystone, SD (reprint author), SUNY Hlth Sci Ctr, Dept Anat & Cell Biol, 750 E Adams St, Syracuse, NY 13210 USA. FU NIAID NIH HHS [R01 AI024674, AI08990-02, AI24674, R37 AI024674]; NIGMS NIH HHS [GM38330, R01 GM038330] NR 26 TC 97 Z9 97 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD MAY 17 PY 1999 VL 145 IS 4 BP 889 EP 897 DI 10.1083/jcb.145.4.889 PG 9 WC Cell Biology SC Cell Biology GA 198EL UT WOS:000080409700019 PM 10330414 ER PT J AU Tonnetti, L Veri, MC Bonvini, E D'Adamio, L AF Tonnetti, L Veri, MC Bonvini, E D'Adamio, L TI A role for neutral sphingomyelinase-mediated ceramide production in T cell receptor-induced apoptosis and mitogen-activated protein kinase-mediated signal transduction SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE neutral sphingomyelinase; ceramide; T cell receptor; signaling; activation; apoptosis ID MAJOR HISTOCOMPATIBILITY COMPLEX; NEGATIVE SELECTION; TRANSGENIC MICE; PHOSPHOLIPASE C-GAMMA-1; CLONAL ELIMINATION; ANTIGEN RECEPTOR; SELF-TOLERANCE; ENTEROTOXIN-B; THYMOCYTES; DEATH AB Studying apoptosis induced by T cell receptor (TCR) cross-linking in the T cell hybridoma, 3DO, we found both neutral sphingomyelinase activation and production of ceramide upon receptor engagement. Pharmacological inhibition of ceramide production by the fungal toxin, fumonisin B1, impaired TCR-induced interleukin (IL)-2 production and programmed cell death. Addition of either exogenous ceramide or bacterial sphingomyelinase reconstituted both responses. Moreover, specific inactivation of neutral sphingomyelinase by antisense RNA inhibited IL-2 production and mitogen-activated protein kinase activation after TCR triggering. These results suggest that ceramide production by activation of neutral sphingomyelinase is an essential component of the TCR signaling machinery. C1 NIAID, Tcell Apoptosis Unit, Lab Cell & Mol Immunol, NIH, Bethesda, MD 20892 USA. Ctr Biol Evaluat & Res, Div Monoclonal Antibodies, Immunobiol Lab, Bethesda, MD 20892 USA. RP NIAID, Tcell Apoptosis Unit, Lab Cell & Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ldadamio@atlas.niaid.nih.gov NR 48 TC 68 Z9 69 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD MAY 17 PY 1999 VL 189 IS 10 BP 1581 EP 1589 DI 10.1084/jem.189.10.1581 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 198TT UT WOS:000080440900007 PM 10330437 ER PT J AU Wang, RF Wang, X Rosenberg, SA AF Wang, RF Wang, X Rosenberg, SA TI Identification of a novel major histocompatibility complex class II-restricted tumor antigen resulting from a chromosomal rearrangement recognized by CD4(+) T cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE melanoma antigens; fusion proteins; antitumor immunity; immunotherapy; chromosomal rearrangement ID INVARIANT CHAIN; LDL RECEPTOR; FAMILIAL HYPERCHOLESTEROLEMIA; AUTOIMMUNE ENCEPHALOMYELITIS; TRANSGENIC MICE; MESSENGER-RNA; HLA-DR; PEPTIDE; PROTEIN; LYMPHOCYTES AB CD4(+) T cells play an important role in antitumor immune responses and autoimmune and infectious diseases. Although many major histocompatibility complex (MHC) class I-restricted tumor antigens have been identified in the last few years, little is known about MHC class II-restricted human tumor antigens recognized by CD4(+) T cells. Here, we describe the identification of a novel melanoma antigen recognized by an human histocompatibility leukocyte antigen (HLA)-DR1-restricted CD4(+) tumor-infiltrating lymphocyte (TIL)1363 using a genetic cloning approach. DNA sequencing analysis indicated that this was a fusion gene generated by a low density lipid receptor (LDI-R) gene in the 5' end fused to a GDP-L-fucose:beta-D-galactoside 2-alpha-L-fucosyltransferase (FUT) in an antisense orientation in the 3' end. The fusion gene encoded the first five ligand binding repeats of LDLR in the NH2 terminus followed by a new polypeptide translated in frame with LDLR from the FUT gene in an antisense direction. Southern blot analysis showed that chromosomal DNA rearrangements occurred in the 1363mel cell line. Northern blot analysis detected two fusion RNA transcripts present only in the autologous 1363mel, but not in other cell lines or normal tissues tested. Two minimal pep tides were identified from the COOH terminus of the fusion protein. This represents the first demonstration that a fusion protein resulting from a chromosomal rearrangement in tumor cells serves as an immune target recognized by CD4(+) T cells. C1 NCI, NIH, Surg Branch, Bethesda, MD 20892 USA. RP Wang, RF (reprint author), NCI, NIH, Surg Branch, Bldg 10-Rm 2B08, Bethesda, MD 20892 USA. NR 38 TC 105 Z9 106 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD MAY 17 PY 1999 VL 189 IS 10 BP 1659 EP 1667 DI 10.1084/jem.189.10.1659 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 198TT UT WOS:000080440900015 PM 10330445 ER PT J AU Emanuel, EJ AF Emanuel, EJ TI Death's door - The end of euthanasia? SO NEW REPUBLIC LA English DT Article C1 NIH, Dept Clin Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Emanuel, EJ (reprint author), NIH, Dept Clin Bioeth, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NEW REPUBLIC INC PI WASHINGTON PA 1220 19TH ST NW SUITE 600, WASHINGTON, DC 20036 USA SN 0028-6583 J9 NEW REPUBLIC JI New Repub. PD MAY 17 PY 1999 VL 220 IS 20 BP 15 EP 16 PG 2 WC Political Science SC Government & Law GA 192UA UT WOS:000080096900011 PM 11789546 ER PT J AU Kornyshev, AA Leikin, S AF Kornyshev, AA Leikin, S TI Electrostatic zipper motif for DNA aggregation SO PHYSICAL REVIEW LETTERS LA English DT Article ID DEBYE-HUCKEL THEORY; POLYELECTROLYTE SOLUTIONS; RODLIKE POLYELECTROLYTES; HELICAL MACROMOLECULES; RAMAN-SPECTROSCOPY; CONDENSATION; ATTRACTION; FORCES; FLUCTUATIONS; COUNTERIONS AB Counterion specificity of DNA condensation is rationalized from a theory of electrostatic interaction between helical molecules that accounts for different charge distribution patterns. an axial charge separation due to ion binding in helical grooves allows close approach of opposite charges along the DNA-DNA contact and forms an electrostatic "zipper" that "fastens" the molecules together. Predictions of the theory are in agreement with experimental data. C1 Univ Calif Santa Barbara, Inst Theoret Phys, Santa Barbara, CA 93106 USA. Res Ctr Julich, D-52425 Julich, Germany. NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. RP Leikin, S (reprint author), NICHD, LPSB, NIH, Bldg 12A,Rm 2041, Bethesda, MD 20892 USA. RI Leikin, Sergey/A-5518-2008; Kornyshev, Alexei/C-3404-2008 OI Leikin, Sergey/0000-0001-7095-0739; NR 28 TC 162 Z9 162 U1 0 U2 10 PU AMERICAN PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 J9 PHYS REV LETT JI Phys. Rev. Lett. PD MAY 17 PY 1999 VL 82 IS 20 BP 4138 EP 4141 DI 10.1103/PhysRevLett.82.4138 PG 4 WC Physics, Multidisciplinary SC Physics GA 196QW UT WOS:000080319900054 ER PT J AU Blum, A Porat, R Rosenschein, U Keren, G Roth, A Laniado, S Miller, H AF Blum, A Porat, R Rosenschein, U Keren, G Roth, A Laniado, S Miller, H TI Clinical and inflammatory effects of dietary L-arginine in patients with intractable angina pectoris SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY-ARTERY DISEASE; HYPERCHOLESTEROLEMIC HUMANS; ENDOTHELIAL DYSFUNCTION; MONONUCLEAR-CELLS; MICROCIRCULATION; INHIBITION; ALPHA AB We evaluated the effects of oral L-arginine on the clinical outcome and the inflammatory markers of patients with intractable angina pectoris. Our findings demonstrated a significant clinical improvement in 7 of 10 patients, which was associated with a significant decrease in cell adhesion molecule and proinflammatory cytokine levels. Dietary L-arginine may have clinical beneficial effects in patients with intractable angina pectoris, and may have anti-inflammatory properties. C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. Tel Aviv Sourasky Med Ctr, Dept Cardiol, Tel Aviv, Israel. Tel Aviv Univ, IL-69978 Tel Aviv, Israel. RP Blum, A (reprint author), NHLBI, Cardiol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 20 TC 33 Z9 33 U1 0 U2 2 PU EXCERPTA MEDICA INC PI NEW YORK PA 245 WEST 17TH STREET, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAY 15 PY 1999 VL 83 IS 10 BP 1488 EP + DI 10.1016/S0002-9149(99)00129-0 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 193ZR UT WOS:000080168100014 PM 10335768 ER PT J AU Ward, MH Lopez-Carrillo, L AF Ward, MH Lopez-Carrillo, L TI Dietary factors and the risk of gastric cancer in Mexico City SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE case-control studies; diet; stomach neoplasms ID STOMACH-CANCER; POPULATION; EPIDEMIOLOGY; CONSUMPTION; SPAIN AB Dietary factors play an important role in gastric cancer risk but have not been investigated extensively in Mexico. The authors conducted a population-based case-control study of gastric cancer in the Mexico City, Mexico, metropolitan area in 1989-1990, A total of 220 patients with histologically confirmed gastric adenocarcinomas were interviewed. Controls were an age-stratified random sample of residents of the Mexico City metropolitan area. The dietary questionnaire was a 70-item semiquantitative food frequency adapted for the Mexican diet. Odds ratios were calculated for quartiles of consumption of food groups and were adjusted for age, gender, calories, chili pepper intake, cigarette smoking, socioeconomic status, added salt, and history of peptic ulcer disease. There was approximately a threefold increased risk of gastric cancer for frequent consumption (highest quartile) of both fresh meat (odds ratio (OR) = 3.1) and processed meat (OR = 3.2), Odds ratios were also significantly elevated for frequent consumption of dairy products (OR = 2.7) and fish (OR = 2.2). The authors observed a decreasing gradient of risk with increasing frequency of vegetable consumption due to a significant inverse trend for the yellow and orange vegetables. High intake of citrus fruits showed a slight inverse association. Consumption of salty snacks more than twice per month was associated with an 80 percent increased risk, and there was a significant positive trend, These findings are consistent with many studies around the world that indicate important roles for salt, processed meats, and vegetable consumption in gastric cancer risk. C1 Inst Nacl Salud Publ, Cuernavaca 62508, Morelos, Mexico. NCI, Div Canc Epidemiol & Genet, Occupat Epidemiol Branch, Bethesda, MD USA. RP Lopez-Carrillo, L (reprint author), Inst Nacl Salud Publ, Av Univ 655,Col Sta Maria Ahuacatitlan, Cuernavaca 62508, Morelos, Mexico. NR 31 TC 85 Z9 90 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 MAY 15 PY 1999 VL 149 IS 10 BP 925 EP 932 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 196JL UT WOS:000080305200005 PM 10342801 ER PT J AU Hanus, LO Fales, HM Spande, TF Basile, AS AF Hanus, LO Fales, HM Spande, TF Basile, AS TI A gas chromatographic-mass spectral assay for the quantitative determination of oleamide in biological fluids SO ANALYTICAL BIOCHEMISTRY LA English DT Article ID FATTY-ACID AMIDES; PROTEIN KINASE-C; MOLECULAR CHARACTERIZATION; BRAIN LIPIDS; INDUCE SLEEP; RECEPTOR AB Oleamide is a putative endogenous sleep-inducing lipid which potently enhances currents mediated by GABA(A) and serotonin receptors, While a quantitative assay would aid in determining the role of oleamide in physiological processes, most of the available assays are lacking in sensitivity. We now describe a quantitative assay for measuring low nanogram amounts of oleamide in biological fluids using GC/MS in the selective ion-monitoring mode. The internal standard (C-13(18) oleamide) was added to known concentrations of oleamide, which were converted to the N-trimethylsilyl or N-tert-butyldimethylsilyl derivatives before analysis by GC/MS, yielding linear calibration curves over the range of 1-25 ng of oleamide when monitoring the m/z 338/356 fragments. Using this technique, oleamide levels were determined following solvent extraction of normal rat cerebrospinal fluid and plasma to be 44 and 9.9 ng/ml, respectively. This technique constitutes a sensitive and reliable method for determining low nanogram quantities of oleamide in biological fluids. C1 NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Basile, AS (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bldg 8,Room 1A15,MSC 0826, Bethesda, MD 20892 USA. NR 27 TC 27 Z9 28 U1 1 U2 4 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD MAY 15 PY 1999 VL 270 IS 1 BP 159 EP 166 DI 10.1006/abio.1999.4083 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 198UG UT WOS:000080442200021 PM 10328778 ER PT J AU Rana, TM Jeang, KT AF Rana, TM Jeang, KT TI Biochemical and functional interactions between HIV-1 Tat protein and TAR RNA SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; LONG TERMINAL REPEAT; TRANSCRIPTION ELONGATION-FACTOR; CREB-BINDING-PROTEIN; NF-KAPPA-B; TYPE-1 TAT; POLYMERASE-II; IN-VITRO; MAJOR GROOVE; HISTONE ACETYLTRANSFERASES AB HIV-1 trans-activator of transcription (Tat) is an unusual transcriptional activator in being an RNA-binding protein rather than a DNA-binding protein. Recent findings have greatly advanced our understanding of the transcriptional function(s) of this protein. Here we review how Tat interacts with trans-activation responsive RNA and how this interaction contributes to transcription. We discuss the biological implications of recent studies showing an association of Tat with cellular kinases(s) and protein acetylases. Evidence for nontranscriptional activities of the Tat protein is also summarized. (C) 1999 Academic Press. C1 Robert Wood Johnson Rutgers Med Sch, Dept Pharmacol, Piscataway, NJ 08854 USA. NIH, Mol Microbiol Lab, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), Robert Wood Johnson Rutgers Med Sch, Dept Pharmacol, 675 Hoes Lane, Piscataway, NJ 08854 USA. RI Jeang, Kuan-Teh/A-2424-2008 FU FIC NIH HHS [TW 00702]; NIAID NIH HHS [AI 43198, AI 41404] NR 95 TC 138 Z9 142 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD MAY 15 PY 1999 VL 365 IS 2 BP 175 EP 185 DI 10.1006/abbi.1999.1206 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 201FR UT WOS:000080584800001 PM 10328810 ER PT J AU Marsh, JW AF Marsh, JW TI The numerous effector functions of Nef SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Review ID IMMUNODEFICIENCY-VIRUS TYPE-1; LONG TERMINAL REPEAT; CD4 DOWN-REGULATION; HUMAN T-CELLS; CYTOTOXIC LYMPHOCYTE-T; THREONINE PROTEIN-KINASE; CELLULAR SERINE KINASE; PROVIRAL DNA-SYNTHESIS; TUMOR-NECROSIS-FACTOR; CLASS-I MOLECULES C1 NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Marsh, JW (reprint author), NIMH, Mol Biol Lab, Bldg 36,Rm 1B08,36 Convent Dr,MSC 4034, Bethesda, MD 20892 USA. NR 149 TC 30 Z9 31 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD MAY 15 PY 1999 VL 365 IS 2 BP 192 EP 198 DI 10.1006/abbi.1999.1208 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 201FR UT WOS:000080584800003 PM 10328812 ER PT J AU Lee, YB Joe, YA Wolff, EC Dimitriadis, EK Park, MH AF Lee, YB Joe, YA Wolff, EC Dimitriadis, EK Park, MH TI Complex formation between deoxyhypusine synthase and its protein substrate, the eukaryotic translation initiation factor 5A (elF5A) precursor SO BIOCHEMICAL JOURNAL LA English DT Article DE equilibrium ultracentrifugation; hypusine; protein-protein interactions; tetrameric enzyme ID YEAST SACCHAROMYCES-CEREVISIAE; HYPUSINE-CONTAINING PROTEIN; CELL VIABILITY; AFFINITY-CHROMATOGRAPHY; ANGSTROM RESOLUTION; BLOOD-COAGULATION; SITES REACTIVITY; BINDING; PURIFICATION; ENZYME AB Deoxyhypusine synthase catalyses the first step in the posttranslational synthesis of hypusine [N-6-(4-amino-2-hydroxybutyl) lysine] in a single cellular protein, the precursor of eukaryotic initiation factor 5A (eIF5A). Deoxyhypusine synthase exists as a tetramer with four potential active sites. The formation of a stable complex between human deoxyhypusine synthase and its protein substrate, human recombinant eIF5A precursor (ec-eIF5A), was examined by affinity chromatography using polyhistidine-tagged (His Tag) ec-eIF5A, by a gel mobility-shift method, and by analytical ultracentrifugation, Deoxyhypusine synthase was selectively retained by His Tag-ec-eIF5A immobilized on a resin. The complex of deoxyhypusine synthase and ec-eIF5A was separated from the free enzyme and protein substrate by electrophoresis under non-denaturing conditions. The stoichiometry of the two components in the complex was estimated to be 1 deoxyhypusine synthase tetramer to 1 ec-eIF5A monomer by N-terminal amino acid sequencing of the complex. Equilibrium ultracentrifugation data further supported this 1:1 ratio and indicated a very strong interaction of the enzyme with ec-eIF5A (K-d less than or equal to 0.5 nM). Formation of the complex was not dependent on NAD(+) or spermidine and occurred at pH 7.0-9.2. An enzyme-product complex, as well as the deoxyhypusine-containing product (modified ec-eIF5A), was also detected at pH 7.0-9.2 in a complete reaction mixture containing 1 mM spermidine. C1 Natl Inst Dent & Craniofacial Res, NIH, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. NIH, Bioengn & Phys Sci Program, Bethesda, MD 20892 USA. Catholic Univ Korea, Canc Res Inst, Catholic Res Inst Med Sci, Seoul 137040, South Korea. RP Park, MH (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Oral & Pharyngeal Canc Branch, Bldg 30,Room 211, Bethesda, MD 20892 USA. NR 47 TC 26 Z9 29 U1 0 U2 1 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD MAY 15 PY 1999 VL 340 BP 273 EP 281 DI 10.1042/0264-6021:3400273 PN 1 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 199VT UT WOS:000080505300033 PM 10229683 ER PT J AU De Bellis, MD Keshavan, MS Clark, DB Casey, BJ Giedd, JN Boring, AM Frustaci, K Ryan, ND AF De Bellis, MD Keshavan, MS Clark, DB Casey, BJ Giedd, JN Boring, AM Frustaci, K Ryan, ND TI Developmental traumatology Part II: Brain development SO BIOLOGICAL PSYCHIATRY LA English DT Article DE posttraumatic Stress Disorder (PTSD); child maltreatment; neurodevelopment; corpus callosum; hippocampus; intracranial volume ID POSTTRAUMATIC-STRESS-DISORDER; SCHOOL-AGE-CHILDREN; SEXUALLY ABUSED GIRLS; HUMAN CORPUS-CALLOSUM; HIPPOCAMPAL VOLUME; VENTRICULAR ENLARGEMENT; MALTREATED CHILDREN; MEMORY DYSFUNCTION; PREFRONTAL CORTEX; COMBAT VETERANS AB Background: Previous investigations suggest that maltreated children with a diagnosis of posttraumatic stress disorder (PTSD) evidence alterations of biological stress systems. Increased levels of catecholaminergic neurotransmitters and steroid hormones during traumatic experiences in childhood could conceivably adversely affect brain development. Methods: In this study, 44 maltreated children and adolescents with PTSD and 61 matched controls underwent comprehensive psychiatric and neuropsychological assessments and an anatomical magnetic resonance imaging (MRI) brain scan. Results: PTSD subjects had smaller intracranial and cerebral volumes than marched controls, The total midsagittal area of corpus callosum and middle and posterior regions remained smaller; while right, left, and total lateral ventricles were proportionally larger than controls, after adjustment for intracranial volume. Brain volume robustly and positively correlated with age of onset of PTSD trauma and negatively correlated with duration of abuse. Symptoms of intrusive thoughts, avoidance, hyperarousal or dissociation correlated positively with ventricular volume, and negatively with brain volume and total corpus callosum and regional measures, Significant gender by diagnosis effect revealed greater corpus callosum al-ea reduction in maltreated males with PTSD and a trend for greater cerebral volume reduction than maltreated females with PTSD. The predicted decrease in hippocampal volume seen in adult PTSD was not seen in these subjects. Conclusions: These data suggest that the overwhelming stress of maltreatment experiences in childhood is associated with adverse brain development. Biol Psychiatry 1999;45:1271-1284 (C) 1999 Society of Biological Psychiatry. C1 Univ Pittsburgh, Med Ctr, Western Psychiat Inst & Clin, Dev Traumatol Lab, Pittsburgh, PA 15213 USA. NIMH, Bethesda, MD 20892 USA. RP De Bellis, MD (reprint author), Univ Pittsburgh, Med Ctr, Western Psychiat Inst & Clin, Dev Traumatol Lab, 3811 OHara St, Pittsburgh, PA 15213 USA. RI Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 FU NIMH NIH HHS [MH 41712, MH01180, MH43687] NR 96 TC 515 Z9 520 U1 12 U2 52 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 MAY 15 PY 1999 VL 45 IS 10 BP 1271 EP 1284 DI 10.1016/S0006-3223(99)00045-1 PG 14 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 198FJ UT WOS:000080411800004 PM 10349033 ER PT J AU Helmkamp, CE Bigelow, LB Paltan-Ortiz, JD Torrey, EF Kleinman, JE Herman, MM AF Helmkamp, CE Bigelow, LB Paltan-Ortiz, JD Torrey, EF Kleinman, JE Herman, MM TI Evaluation of superior vermal Purkinje cell placement in mental illness SO BIOLOGICAL PSYCHIATRY LA English DT Article DE cerebellar vermis; Purkinje cells; schizophrenia; bipolar illness; alcoholism; neurodevelopment ID CEREBELLAR ATROPHY; SCHIZOPHRENIC-PATIENTS; COMPUTED-TOMOGRAPHY; AUTISM; PATHOLOGY; BRAIN AB Background: A number of neuroimaging and neuropathological studies have reported abnormalities in the cerebellar vermis in schizophrenia and bipolar disorder In an effort to further understand vermal abnormalities in mental illness, we have analyzed ectopic placement of Purkinje-like cells. Methods: The superior cerebellar vermis was evaluated in 39 cases of severe mental illness [schizophrenia (n = 12), bipolar disease (n = 12), and depression (n = IS)]. We also examined 9 subjects with polysubstance abuse and IS normal controls. All normally placed Purkinje cells and displaced Purkinje-like cells (i.e., in the internal granule layer and intrafoliar white matter) were counted in the same foliar field. The ratio of displaced Purkinje-like cells to total Purkinje cells and Purkinje cell density were calculated. Results: No significant difference in the ratio of displaced to normally placed Purkinje cells or in Purkinje cell density between groups of subjects was found. Conclusions: Our study does not support a hypothesis of abnormalities of Purkinje cell migration or other events related to their displacement as a basis for the vermal abnormalities reported previously in schizophrenia and bipolar disorder. Biol Psychiatry 1999;45:1370-1375 (C) 1999 Society of Biological Psychiatry. C1 St Elizabeth Hosp, Ctr Neurosci, NIMH, Clin Brain Disorders Branch, Washington, DC 20032 USA. RP Herman, MM (reprint author), NIMH, CBDB, Sect Neuropathol, NIH, Bldg 36,Room 3A24,36 Convent Dr,MSC 4091, Bethesda, MD 20892 USA. NR 35 TC 8 Z9 8 U1 3 U2 3 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 MAY 15 PY 1999 VL 45 IS 10 BP 1370 EP 1375 DI 10.1016/S0006-3223(98)00153-X PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 198FJ UT WOS:000080411800014 PM 10349043 ER PT J AU Miller, LL Korn, EL Stevens, DS Janik, JE Gause, BL Kopp, WC Holmlund, JT Curti, BD Sznol, M Smith, JW Urba, WJ Donegan, SE Watson, TM Longo, DL AF Miller, LL Korn, EL Stevens, DS Janik, JE Gause, BL Kopp, WC Holmlund, JT Curti, BD Sznol, M Smith, JW Urba, WJ Donegan, SE Watson, TM Longo, DL TI Abrogation of the hematological and biological activities of the interleukin-3/granulocyte-macrophage colony-stimulating factor fusion protein PIXY321 by neutralizing anti-PIXY321 antibodies in cancer patients receiving high-dose carboplatin SO BLOOD LA English DT Article; Proceedings Paper CT 15th Annual Meeting of the American-Society-of-Clinical-Oncology CY 1996 CL ORLANDO, FLORIDA SP Amer Soc Clin Oncol ID RECOMBINANT HUMAN INTERLEUKIN-3; BONE-MARROW TRANSPLANTATION; PHASE-I TRIAL; OVARIAN-CANCER; CYCLOPHOSPHAMIDE CHEMOTHERAPY; ADVANCED MALIGNANCY; FACTOR AUGMENTS; BREAST-CANCER; CARCINOMA; COMBINATION AB This dose-escalation study was performed to evaluate the hematologic activity, biological effects, immunogenicity, and toxicity of PIXY321 (an interleukin-3/granulocyte-macrophage colony-stimulating factor fusion protein) administered after high-dose carboplatin (CBDCA) treatment. Patients with advanced cancers received CBDCA at 800 mg/m(2) intravenously on day 0 of repeated 28-day cycles. In part A of the study, patients were treated with CBDCA alone during cycle 1 and then received PIXY321 on days 1 through 18 of cycle 2 and later cycles. In part B, patients received 18 days of PIXY321 beginning on day 1 of all CBDCA cycles, including cycle 1. PIXY321 was administered subcutaneously in 2 divided doses. Total doses of 135, 250, 500, 750, and 1,000 mu g/m(2)/d were administered to successive cohorts of 3 to 6 patients in part: A. In part B, patient groups received PIXY321 doses of 750, 1,000, and 1,250 mu g/m(2)/d. The hematologic effects of PIXY321 were assessed in the first 2 cycles of therapy Anti-PIXY321 antibody formation was assessed by enzyme-linked immunosorbent assay (ELISA) and neutralization assay. Of the 49 patients enrolled, 31 were fully evaluable for hematologic efficacy. When comparing the first B cycle (cycle B-1; with PIXY321) with the first A cycle (cycle A-1; without PIXY321), the fusion protein had no significant effect on platelet nadirs or duration of platelets less than 20,000/mu L but was able to speed the time of recovery of platelet counts to 100,000/mu L (15 v 20 days; P = .01) Significant improvements in neutrophil nadir and duration of ANC less than 500 were observed In cycles A-2 and B-l (with PIXY321) as compared with cycle A-1 (without PIXY321). Initial PIXY321 prophylaxis (cycle A-2 and cycle B-1), enhanced the recovery of ANC to greater than 1,500/mu L by an average of at least 8 days as compared with cycle A-1 (without PIXY321; P less than or equal to .004). However, positive PIXY321 hematologic effects were lost in the second course of PIXY321 among patients treated in part B, ELISA analysis showed that 92% of patients had developed neutralizing anti-PIXY321 antibodies by the completion of 2 PIXY321-containing cycles. The incidental action of PIXY321 to depress serum cholesterol levels was also abrogated during cycle B-2. We conclude that PIXY321 was active in speeding hematologic recovery but that neutralizing anti-PIXY321 antibody formation suppressed the hematologic and biochemical effects by the second cycle of PIXY321 administration. The immunogenicity of this fusion protein provides a cautionary warning that clinical development of bioengineered human molecules requires thorough testing for immune neutralization. This is a US government work. There are no restrictions on its use. C1 NCI, Frederick Canc Res & Dev Ctr, Biol Response Modifiers Program, Frederick, MD 21702 USA. NCI, Biometr Res Branch, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. SAIC Frederick, Clin Serv Program, Frederick, MD USA. Immunex Res & Dev Corp, Seattle, WA 98101 USA. RP Miller, LL (reprint author), Pharmacia & Upjohn Inc, Mail Code 7216-298-163,7000 Portage Rd, Kalamazoo, MI 49001 USA. NR 48 TC 22 Z9 28 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1200 19TH ST, NW, STE 300, WASHINGTON, DC 20036-2422 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 15 PY 1999 VL 93 IS 10 BP 3250 EP 3258 PG 9 WC Hematology SC Hematology GA 194JY UT WOS:000080190100010 PM 10233876 ER PT J AU Zheng, TZ Holford, TR Mayne, ST Owens, PH Ward, B Carter, D Dubrow, R Zahm, SH Boyle, P Tessari, J AF Zheng, TZ Holford, TR Mayne, ST Owens, PH Ward, B Carter, D Dubrow, R Zahm, SH Boyle, P Tessari, J TI beta-benzene hexachloride in breast adipose tissue and risk of breast carcinoma SO CANCER LA English DT Article DE beta-benzene hexachloride; breast carcinoma; case-control; environment; epidemiology ID POLYCHLORINATED BIPHENYL RESIDUES; CANCER RISK; SERUM; HEXACHLOROCYCLOHEXANE; EPIDEMIOLOGY; PESTICIDES; CELLS; WOMEN AB BACKGROUND. Epidemiologic studies have recently related benzene hexachloride (BHC) to breast carcinoma risk. Experimental studies have also shown that beta-BHC is weakly estrogenic, hence supporting the alleged association. By directly comparing beta-BHC levels in breast adipose tissue from incident breast carcinoma cases and controls, this study examined the hypothesis that exposure to beta-BHC increases the risk of breast carcinoma in females. METHODS, A total of 490 Connecticut women (304 cases and 186 controls) were enrolled in the study during the period 1994-1997. Cases were patients ages 40-79 years with histologically confirmed incident primary breast carcinoma. Controls were patients with histologically confirmed incident benign breast disease. Breast adipose tissue was collected and analyzed for BHC isomers. A linear logistic regression model was used to adjust for potential confounders in estimating the association of exposure with disease. RESULTS. No significant differences in breast adipose tissue levels of beta-BHC were observed between the cases and their controls overall, nor by menopausal status or estrogen and progesterone receptor status of the breast carcinoma cases. A nonsignificant reduced risk was observed among all subjects and among pre- and postmenopausal women when the highest quartile was compared with the lowest. Parous women with higher beta-BHC levels, regardless of lactation status, had a nonsignificantly reduced breast carcinoma risk, whereas a nonsignificantly increased risk was observed among nulliparous women with higher beta-BHC levels, based on very few study subjects. CONCLUSIONS. The results of this study do not support the hypothesis that increasing adipose tissue levels of beta-BHC are associated with an increased risk of breast carcinoma in females. Cancer 1999;85:2212-8, (C) 1999 American Cancer Society. C1 Yale Univ, Sch Med, New Haven, CT USA. Ctr Canc, New Haven, CT USA. NCI, NIH, Bethesda, MD 20892 USA. European Inst Oncol, Milan, Italy. Colorado State Univ, Ft Collins, CO 80523 USA. RP Zheng, TZ (reprint author), 129 Church St,Suite 700, New Haven, CT 06510 USA. RI Zahm, Shelia/B-5025-2015; Boyle, Peter/A-4402-2014 OI Boyle, Peter/0000-0001-6251-0610 NR 25 TC 19 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 0008-543X J9 CANCER JI Cancer PD MAY 15 PY 1999 VL 85 IS 10 BP 2212 EP 2218 DI 10.1002/(SICI)1097-0142(19990515)85:10<2212::AID-CNCR16>3.0.CO;2-F PG 7 WC Oncology SC Oncology GA 193PH UT WOS:000080144900016 PM 10326700 ER PT J AU Spiro, TP Gerson, SL Liu, LL Majka, S Haaga, J Hoppel, CL Ingalls, ST Pluda, JM Willson, JKV AF Spiro, TP Gerson, SL Liu, LL Majka, S Haaga, J Hoppel, CL Ingalls, ST Pluda, JM Willson, JKV TI O-6-benzylguanine: A clinical trial establishing the biochemical modulatory dose in tumor tissue for alkyltransferase-directrd DNA repair SO CANCER RESEARCH LA English DT Article ID MAMMALIAN O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; O6-METHYLGUANINE-DNA METHYLTRANSFERASE ACTIVITY; PERFORMANCE LIQUID-CHROMATOGRAPHY; O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; NITROSOUREA RESISTANCE; HUMAN-LYMPHOCYTES; ALKYLATING-AGENTS; HUMAN PLASMA; DEPLETION; SENSITIVITY AB Early phase evaluation of anticancer drugs has traditionally used toxicity (usually hematological) rather than efficacy end points to establish appropriate dosing schedules, To establish a biochemical efficacy end point for overcoming alkylguanine DNA alkyltransferase (AGT)-mediated tumor cell resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea. we performed a novel dose escalation clinical trial for the AGT-depleting agent O-6-benzylguanine (BG). The dose of BG required to deplete AGT to undetectable levels (BMDT) in sequential computed tomography-guided tumor tissue biopsies before BG and 18 h after BG was determined. Thirty patients received doses of BG ranging from 10 to 120 mg/m(2). In tumor tissue, AGT depletion >86% of baseline was demonstrated at all doses tested. Residual tumor AGT activity, present 18 h after BC doses of 10-80 mg/m(2), was eliminated at the 120 mg/m(2) dose and is thus the BMDT of BG, BG pharmacokinetics are characterized by the rapid, dose-independent clearance of BG from plasma, Metabolism of BG to its biologically active metabolite, 8-oxo-benzylguanine (8-oxo-BG), was found. The t(1/2) of 8-oxo-BG is longer than BG, Plasma concentrations of 8-oxo-BG well above 200 ng/ml 18 h after the end of the BG infusion a ere observed at the highest dose levels tested and appeared to correlate with depiction of AGT activity to undetectable levels in tumor tissue. AGT activity in peripheral blood mononuclear cells at baseline did not correlate with tumor tissue AGT activity, Depletion of AGT activity to undetectable levels in peripheral blood mononuclear cells occurred at lower doses and was not a reliable predictor for tumor tissue depletion. No serious side effects were observed with administration of BG alone or in combination with 13 mg/m(2) 1,3-bis(2-chloroethyl)-1-nitrosourea. This is the first clinical study in which biochemical analyses from pre- and posttreatment tumor biopsies have been used as an efficacy end point for the clinical development of an anticancer agent. From our tumor tissue biopsy data, we have established that a BG dose of 120 mg/m(2) infused over 1 h should be used in Phase II clinical trials. C1 Case Western Reserve Univ, Sch Med BRB, Div Hematol Oncol, Dept Med, Cleveland, OH 44106 USA. Case Western Reserve Univ, Dept Pharmacol, Cleveland, OH 44106 USA. Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. Case Western Reserve Univ, Dept Radiol, Cleveland, OH 44106 USA. Univ Hosp Cleveland, Ireland Canc Ctr, Cleveland, OH 44106 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20852 USA. Louis Stokes Cleveland Dept Vet Affairs Med Ctr, Cleveland, OH 44106 USA. RP Spiro, TP (reprint author), Case Western Reserve Univ, Sch Med BRB, Div Hematol Oncol, Dept Med, 10900 Euclid Ave, Cleveland, OH 44106 USA. FU NCI NIH HHS [1 R01 CA 75518, 2 UO1 CA 62502]; NCRR NIH HHS [M01 RR-00080-36] NR 48 TC 123 Z9 125 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 1999 VL 59 IS 10 BP 2402 EP 2410 PG 9 WC Oncology SC Oncology GA 198ER UT WOS:000080410200027 PM 10344750 ER PT J AU Tatusova, TA Madden, TL AF Tatusova, TA Madden, TL TI BLAST 2 SEQUENCES, a new tool for comparing protein and nucleotide sequences SO FEMS MICROBIOLOGY LETTERS LA English DT Article DE algorithm; sequence alignment; software ID SEARCH; STATISTICS AB 'BLAST 2 SEQUENCES', a new BLAST-based tool for aligning two protein or nucleotide sequences, is described. While the standard BLAST program is widely used to search for homologous sequences in nucleotide and protein databases, one often needs to compare only two sequences that are already known to be homologous, coming from related species or, e.g. different isolates of the same virus. In such cases searching the entire database would be unnecessarily time-consuming. 'BLAST 2 SEQUENCES' utilizes the BLAST algorithm for pairwise DNA-DNA or protein-protein sequence comparison. A World Wide Web version of the program can be used interactively at the NCBI WWW site (http://www.ncbi.nlm.nih.gov/gorf/bl2.html). The resulting alignments are presented in both graphical and text form. The variants of the program for PC (Windows), Mac and several UNIX-based platforms can be downloaded from the NCBI FTP site (ftp://ncbi.nlm.nih.gov). (C) 1999 Published by Elsevier Science B.V. All rights reserved. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Tatusova, TA (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. NR 11 TC 1309 Z9 1346 U1 1 U2 34 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1097 J9 FEMS MICROBIOL LETT JI FEMS Microbiol. Lett. PD MAY 15 PY 1999 VL 174 IS 2 BP 247 EP 250 DI 10.1016/S0378-1097(99)00149-4 PG 4 WC Microbiology SC Microbiology GA 195BV UT WOS:000080230000006 PM 10339815 ER PT J AU Johansson, KE Tully, JG Bolske, G Pettersson, B AF Johansson, KE Tully, JG Bolske, G Pettersson, B TI Mycoplasma cavipharyngis and Mycoplasma fastidiosum, the closest relatives to Eperythrozoon spp. and Haemobartonella spp. SO FEMS MICROBIOLOGY LETTERS LA English DT Article DE Eperythrozoon; Haemobartonella; mollicutes; Mycoplasma cavipharyngis; Mycoplasma fastidiosum; phylogeny; pneumoniae group; rickettsia; 16S rRNA ID RIBOSOMAL-RNA; PHYLOGENY; CLUSTER; SEQUENCES AB The 16S rRNA gene sequences of Mycoplasma cavipharyngis and Mycoplasma fastidiosum have been determined. Phylogenetic analysis showed that these species formed a new cluster within the so-called pneumoniae group of the mollicutes (class Mollicutes). This fluster will be referred to as the M. fastidiosum cluster. Interestingly, the M. fastidiosum cluster formed a sister lineage to the haemotrophic bacteria, Eperythrozoon spp. and Haemobartonella spp. The two latter genera, formerly classified as rickettsias, formed a stable phylogenetic entity in the tree as judged from branch lengths, bootstrap values and sequence signatures. Thus, the members of the M. fastidiosum cluster are the closest known relatives to the haemotrophic bacteria. Our data strongly support that the haemotrophic bacteria should be reclassified to reflect their actual phylogenetic affiliation. (C) 1999 Federation of European Microbiological Societies. Published by Elsevier Science B.V. Ail rights reserved. C1 Natl Vet Inst, Dept Bacteriol, S-75007 Uppsala, Sweden. NIAID, Mycoplasma Sect, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Royal Inst Technol, Dept Biotechnol, S-10044 Stockholm, Sweden. RP Johansson, KE (reprint author), Natl Vet Inst, Dept Bacteriol, POB 7073, S-75007 Uppsala, Sweden. NR 15 TC 31 Z9 34 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1097 J9 FEMS MICROBIOL LETT JI FEMS Microbiol. Lett. PD MAY 15 PY 1999 VL 174 IS 2 BP 321 EP 326 DI 10.1016/S0378-1097(99)00159-7 PG 6 WC Microbiology SC Microbiology GA 195BV UT WOS:000080230000016 PM 10339825 ER PT J AU Geanacopoulos, M Vasmatzis, G Lewis, DEA Roy, S Lee, B Adhya, S AF Geanacopoulos, M Vasmatzis, G Lewis, DEA Roy, S Lee, B Adhya, S TI GalR mutants defective in repressosome formation SO GENES & DEVELOPMENT LA English DT Article DE repressosome; transcription; galR mutants; protein-protein interactions; DNA looping; GalR; repression ID ESCHERICHIA-COLI; DNA; BINDING; ELEMENTS; PROMOTER; INVITRO; ALPHA; HU AB Transcription repression of the galactose operon of Escherichia coli requires (1) the binding of the GalR repressor to tandem operators flanking the promoters, (2) the binding of histone-like protein, HU, to a site between the GalR-binding sites, and (3) negatively supercoiled DNA. Under these conditions, protein-protein interactions mediate the formation of a nucleoprotein complex in the form of a DNA loop, which we have termed a repressosome. To analyze the structure of the repressosome, we have screened and isolated galR mutants in which single amino acid substitutions in GalR lead to defects in loop formation while the protein's operator-binding activity is retained. The mutant proteins were purified and their properties confirmed in vitro. We verified that in the case of the two stronger mutations, the proteins had secondary structures that were identical to that of wild-type GalR as reflected by circular dichroism spectroscopy. Homology-based modeling of GalR by use of the crystal structures of PurR and LacI has enabled us to place the three sites of mutation in a structural context. They occur in the carboxy-terminal subdomain of the GalR core, are surface exposed, and, therefore, may be involved in protein-protein interactions. On the basis of our model of GalR and its structural alignment with LacI and PurR, we have identified additional residues, the substitution of which leads to a specific defect in repression by looping. The effects of the mutations are the same in the presence of HMG-17, a eukaryotic protein unrelated to HU, which can also mediate GalR-dependent repression of the gal promoter. This observation suggests that the mutations define sites of GalR-GalR interaction rather than HU-GalR interaction in the repressosome. 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. NR 31 TC 30 Z9 30 U1 0 U2 1 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 MAY 15 PY 1999 VL 13 IS 10 BP 1251 EP 1262 DI 10.1101/gad.13.10.1251 PG 12 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 202PE UT WOS:000080660700005 PM 10346814 ER PT J AU Paull, TT Gellert, M AF Paull, TT Gellert, M TI Nbs1 potentiates ATP-driven DNA unwinding and endonuclease cleavage by the Mre11/Rad50 complex SO GENES & DEVELOPMENT LA English DT Article DE Nijmegen breakage syndrome; Mre11/Rad50 protein; ATP binding; DNA unwinding ID STRAND-BREAK REPAIR; END-JOINING REPAIR; SACCHAROMYCES-CEREVISIAE; V(D)J RECOMBINATION; MEIOTIC RECOMBINATION; ESCHERICHIA-COLI; CELL-CYCLE; NONHOMOLOGOUS RECOMBINATION; ILLEGITIMATE RECOMBINATION; HUMAN MRE11 AB The Nijmegen breakage syndrome gene product (Nbs1) was shown recently to associate in vivo with the Mre11 and Rad50 proteins, which play pivotal roles in eukaryotic DNA double-strand break repair, meiotic recombination, and telomere maintenance. We show in this work that the triple complex of recombinant Nbs1, Mre11, and Rad50 proteins binds cooperatively to DNA and forms a distinct protein-DNA species. The Mre11/Rad50/Nbs1 complex displays several enzymatic activities that are not seen without Nbs1, including partial unwinding of a DNA duplex and efficient cleavage of fully paired hairpins. Unwinding and hairpin cleavage are both increased by the presence of ATP. On nonhairpin DNA ends, ATP controls a switch in endonuclease specificity that allows Mre11/Rad50/Nbs1 to cleave a 3'-protruding strand at a double-/single-strand transition. Mutational analysis demonstrates that Rad50 is responsible for ATP binding by the complex, but the ATP-dependent activities are expressed only with Nbs1 present. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gellert, M (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 65 TC 378 Z9 390 U1 0 U2 6 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 MAY 15 PY 1999 VL 13 IS 10 BP 1276 EP 1288 DI 10.1101/gad.13.10.1276 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 202PE UT WOS:000080660700007 PM 10346816 ER PT J AU Brinkmann, U Brinkmann, E Bera, TK Wellmann, A Pastan, I AF Brinkmann, U Brinkmann, E Bera, TK Wellmann, A Pastan, I TI Tissue-specific alternative splicing of the CSE1L/CAS (cellular apoptosis susceptibility) gene SO GENOMICS LA English DT Article ID CHROMOSOME SEGREGATION; NUCLEAR-LOCALIZATION; BREAST-CANCER; HUMAN HOMOLOG; CAS PROTEIN; CELLS; CSE1; BINDING; PROLIFERATION; EXPRESSION AB CSE1L/CAS (CAS) is a nuclear transport factor that plays a role in proliferation and apoptosis. The CAS gene consists of 25 exons. mRNA homologous over its entire length to the yeast homologue CSE1 is the predominant transcript in proliferating tissues. Additional mRNAs are generated by alternative splicing in a tissue-specific manner. An extended 3'-end is found in fetal and adult brain, A mRNA containing the 5'-end of CAS up to position 690 and an alternative 3'-end is expressed in trachea and encodes a truncated Ran-binding domain. Fetal liver expresses a mRNA with deletions of a central portion of CAS and additional sequences encoded by the last intron, SW480 colon cancer cells express another similar to 1500-base mRNA. Western blot analyses of various human tissues and immunohistology of mouse embryos show a correlation of CAS transcripts and CAS protein in different tissues, CAS isoforms may control nuclear transport of tissue-specific proteins. C1 NCI, Mol Biol Lab, DBS, NIH, Bethesda, MD 20892 USA. RP Brinkmann, U (reprint author), Epidauros Biotechnol, Am Neuland 1, D-82347 Bernried, Germany. NR 24 TC 7 Z9 8 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD MAY 15 PY 1999 VL 58 IS 1 BP 41 EP 49 DI 10.1006/geno.1998.5700 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 203KJ UT WOS:000080706600006 PM 10331944 ER PT J AU Moreira, EF Jaworski, CJ Rodriguez, IR AF Moreira, EF Jaworski, CJ Rodriguez, IR TI Cloning of a novel member of the reticulon gene family (RTN3): Gene structure and chromosomal localization to 11q13 SO GENOMICS LA English DT Article ID NEUROENDOCRINE-SPECIFIC PROTEIN; CELL LUNG-CANCER; SUBCELLULAR-LOCALIZATION; GENOMIC ORGANIZATION; ENCODING RETICULONS; NSP-A; EXPRESSION; IDENTIFICATION; MARKERS AB A novel member of the neuron-specific protein (NSP) or newly named reticulon (RTN) gene family was isolated during a subtraction cloning between macula and peripheral retina. The mRNA for this NSP/RTN-like gene is approximately threefold more abundant in macula than in peripheral retina. The cDNA is 2527 bp long and contains an open reading frame of 236 amino acids. The deduced peptide shows a strong similarity to the NSP/RTN and tropomyosin-like gene families but it is clearly a novel member. The gene contains seven exons and spans more than 15 kb. The gene was localized to chromosome 11q13 between markers D11S4535 and D11S4627 using somatic cell hybrid panels. Southern blot analysis identified the presence of a pseudogene(s) that was subsequently localized to chromosome 4. Multitissue Northern blot analysis found this gene to be widely expressed in human tissues with the highest expression in the brain. We are calling this gene RTN3 to reflect the newly proposed nomenclature. (C) 1999 Academic Press. C1 NEI, NIH, Retinal Cell & Mol Biol Lab, Bethesda, MD 20892 USA. RP Rodriguez, IR (reprint author), NEI, NIH, Retinal Cell & Mol Biol Lab, 6 Ctr Dr,MSC 2740,Bldg 6,Room 304, Bethesda, MD 20892 USA. NR 25 TC 65 Z9 67 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD MAY 15 PY 1999 VL 58 IS 1 BP 73 EP 81 DI 10.1006/geno.1999.5807 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 203KJ UT WOS:000080706600009 PM 10331947 ER PT J AU Hashimoto, H Nishino, A Shintani, N Hagihara, N Copeland, NG Jenkins, NA Yamamoto, K Matsuda, T Ishihara, T Nagata, S Baba, A AF Hashimoto, H Nishino, A Shintani, N Hagihara, N Copeland, NG Jenkins, NA Yamamoto, K Matsuda, T Ishihara, T Nagata, S Baba, A TI Genomic organization and chromosomal location of the mouse vasoactive intestinal polypeptide 1(VPAC(1)) receptor SO GENOMICS LA English DT Article ID CYCLASE-ACTIVATING POLYPEPTIDE; TISSUE DISTRIBUTION; PACAP GENE; PEPTIDE; EXPRESSION; LOCALIZATION; CLONING; MAP; VIP AB The gene encoding the mouse vasoactive intestinal polypeptide type 1 (VPAC(1)) receptor was cloned, and its structural organization was determined. The gene (Vipr1) is more than 16 kb in length and is divided into 13 exons. The 5'-flanking region is highly GC-rich and lacks an apparent TATA box, but contains a CCAAT box, three potential Spl-binding sites, and two potential AP-a-binding sites. Promoter analysis of the 5'-flanking region of Vipr1 using a luciferase gene reporter system revealed that the isolated 5'-flanking region has functional promoter activity. The mouse Vipr1 gene is encoded by a single gene, which was mapped to the distal region of mouse chromosome 9. This region is syntenic with human chromosome 3p, where the human VPAC(1) receptor gene has been mapped. (C) 1999 Academic Press. C1 Osaka Univ, Grad Sch Pharmaceut Sci, Mol Neuropharmacol Lab, Suita, Osaka 5650871, Japan. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Mammalian Genet Lab, Frederick, MD 21702 USA. Natl Inst Genet, Struct Biol Ctr, Shizuoka 4118540, Japan. Osaka Univ, Sch Med, Dept Genet, Suita, Osaka 5650871, Japan. RP Baba, A (reprint author), Osaka Univ, Grad Sch Pharmaceut Sci, Mol Neuropharmacol Lab, 1-6 Yamadaoka, Suita, Osaka 5650871, Japan. RI Hashimoto, Hitoshi/D-1209-2010; Shintani, Norihito/D-5860-2014 OI Hashimoto, Hitoshi/0000-0001-6548-4016; Shintani, Norihito/0000-0002-7850-9064 NR 23 TC 19 Z9 22 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD MAY 15 PY 1999 VL 58 IS 1 BP 90 EP 93 DI 10.1006/geno.1999.5805 PG 4 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 203KJ UT WOS:000080706600011 PM 10331949 ER PT J AU Bronte, V Chappell, DB Apolloni, E Cabrelle, K Wang, M Hwu, P Restifo, NP AF Bronte, V Chappell, DB Apolloni, E Cabrelle, K Wang, M Hwu, P Restifo, NP TI Unopposed production of granulocyte-macrophage colony-stimulating factor by tumors inhibits CD8(+) T cell responses by dysregulating antigen-presenting cell maturation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RECOMBINANT ANTICANCER VACCINES; CSF GENE-EXPRESSION; DENDRITIC CELLS; BONE-MARROW; ANTITUMOR IMMUNITY; GM-CSF; INDUCED APOPTOSIS; IMMUNIZATION; LYMPHOCYTES; LIGAND AB Tumor cells gene-modified to produce GM-CSF potently stimulate antitumor immune responses, in part, by causing the growth and differentiation of deudritic cells (DC), However, GM-CSF-modified tumor cells must be gamma-irradiated or they will grow progressively, killing the host. We observed that 23 of 75 (31%) human tumor lines and two commonly used mouse tumor lines spontaneously produced GM-CSF, In mice, chronic GM-CSF production by tumors suppressed Ag-specific CD8(+) T cell responses, Interestingly, an inhibitory population of adherent CD11b(Mac-1)/Gr-1 double-positive cells caused the observed impairment of CD8(+) T cell function upon direct cell-to cell contact. The inhibitory cells were positive for some markers associated with Ag presenting cells, like F4/80, but were negative for markers associated with fully mature DC like DEC205, B7.2, and MHC class II. We have previously reported that a similar or identical population of inhibitory "immature" APC was elicited after immunization with powerful recombinant immunogens, We show here that these inhibitory cells can be elicited by the administration of recombinant GM-CSF alone, and, furthermore, that they can be differentiated ex vivo into "mature" APC by the addition of IL-4 and GM-CSF, Thus, tumors may be able to escape from immune detection by producing "unopposed" GM-CSF, thereby disrupting the balance of cytokines needed for the maturation of fully functional DC. Further, CD11b/Gr-1 double-positive cells may function as "inhibitory" APC under the influence of GM-CSF alone. C1 Dept Oncol & Surg Sci, Padua, Italy. NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20814 USA. NIH, Surg Branch, Bethesda, MD 20892 USA. RP Restifo, NP (reprint author), Bldg 10,Room 2B42, Bethesda, MD 20892 USA. RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 BC010763-01, Z99 CA999999] NR 62 TC 255 Z9 263 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 1999 VL 162 IS 10 BP 5728 EP 5737 PG 10 WC Immunology SC Immunology GA 195FP UT WOS:000080240200012 PM 10229805 ER PT J AU Su, SB Gao, JL Gong, WH Dunlop, NM Murphy, PM Oppenheim, JJ Wang, JM AF Su, SB Gao, JL Gong, WH Dunlop, NM Murphy, PM Oppenheim, JJ Wang, JM TI T21/DP107, a synthetic leucine zipper-like domain of the HIV-1 envelope gp41, attracts and activates human phagocytes by using G-protein-coupled formyl peptide receptors SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; LIPOXIN A(4) RECEPTOR; SERUM AMYLOID-A; CHEMOATTRACTANT RECEPTORS; CHEMOTACTIC RECEPTOR; HUMAN MONOCYTES; STABLE ANALOGS; FORMYLPEPTIDE; GLYCOPROTEIN; NEUTROPHILS AB A leucine zipper-like domain, T21/DP107, located in the amino terminus of the ectodomain of gp41, is crucial to the formation of fusogenic configuration of the HIV-1 envelope protein gp41. We report that the synthetic T21/DP107 segment is a potent stimulant of migration and calcium mobilization in human monocytes and neutrophils, The activity of T21/DP107 on phagocytes was pertussis toxin-sensitive, suggesting this peptide uses Gi-coupled seven-transmembrane receptor(s), Since the bacterial chemotactic peptide fMLP partially desensitized the calcium-mobilizing activity of T21/DP107 in phagocytes, we postulated that T21/DP107 might preferentially use a lower affinity fMLP receptor. By using cells transfected to express cloned prototype chemotactic N-formyl peptide receptor (FPR) or its variant, FPR-like 1 (FPRL1), we demonstrate that T21/DP107 activates both receptors but has a much higher efficacy for FPRL1, In addition, T21/DP107 at nM concentrations induced migration of FPRL1-transfected human embryonic kidney 293 cells. In contrast, fMLP did not induce significant chemotaxis of the same cells at a concentration as high as 50 mu M Although a lipid metabolite, lipoxin A4, was a high-affinity ligand for FPRL1, it was not reported to induce Ca2+ mobilization or chemotaxis in FPRL1-transfected cells. Therefore, T21/DP107 is a first chemotactic peptide agonist identified thus far for FPRL1. Our results suggest that this peptide domain of the HIV-1 gp41 may have the potential to activate host innate immune response by interacting with FPR and FPRL1 on phagocytes. C1 NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Mol Immunoregulat Lab, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp, Intramural Res Support Program, Frederick, MD 21702 USA. NIH, NIAID, Host Def Lab, Bethesda, MD 20892 USA. RP Wang, JM (reprint author), NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Mol Immunoregulat Lab, Bldg 560,Room 31-19, Frederick, MD 21702 USA. NR 53 TC 73 Z9 78 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 1999 VL 162 IS 10 BP 5924 EP 5930 PG 7 WC Immunology SC Immunology GA 195FP UT WOS:000080240200036 PM 10229829 ER PT J AU Moriuchi, M Moriuchi, H Margolis, DM Fauci, AS AF Moriuchi, M Moriuchi, H Margolis, DM Fauci, AS TI USF/c-Myc enhances, while Yin-Yang 1 suppresses, the promoter activity of CXCR4, a coreceptor for HIV-1 entry SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CELLULAR TRANSCRIPTION FACTOR; CHEMOKINE RECEPTOR CXCR4; LONG TERMINAL REPEAT; CYCLOPHILIN-A; FUSION COFACTOR; T-LYMPHOCYTES; TROPIC HIV-1; PROTEIN; CLONING AB Transcription factors USF1 and USF2 up-regulate gene expression (i.e., HIV-1 long terminal repeats) via interaction with an E box on their target promoters, which is also a binding site for c-Myc. The c-Myc oncoprotein is important in control of cellular proliferation and differentiation, while Yin-Yang 1 (YY1) has been shown to control the expression of a number of cellular and viral genes. These two proteins physically interact with each other and mutually inhibit their respective biological functions, In this study, we show that USF/c-Myc up-regulates, while YY1 down-regulates the promoter activity of CXCR4, a coreceptor for T cell-tropic HIV-1 entry. We have identified an E box around -260 and a YY1 binding site around -300 relative to the transcription start site. Mutation of the E box abolished USF/c-Myc-mediated up-regulation of CXCR4 promoter activity, and mutation of the YY1 binding site was associated with unresponsiveness to YY1-mediated inhibition, These data suggest that USF/c-Myc and YY1 may play an important role in the HIV-l-replicative cycle, by modulating both the viral fusion/entry process and viral expression. C1 NIH, NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. RP Moriuchi, H (reprint author), Nagasaki Univ, Sch Med, Dept Pediat, 1-7-1 Sakamoto, Nagasaki 8528501, Japan. OI Margolis, David/0000-0001-5714-0002 NR 43 TC 54 Z9 54 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 1999 VL 162 IS 10 BP 5986 EP 5992 PG 7 WC Immunology SC Immunology GA 195FP UT WOS:000080240200044 PM 10229837 ER PT J AU Hogaboam, CM Gallinat, CS Taub, DD Strieter, RM Kunkel, SL Lukacs, NW AF Hogaboam, CM Gallinat, CS Taub, DD Strieter, RM Kunkel, SL Lukacs, NW TI Immunomodulatory role of C10 chemokine in a murine model of allergic bronchopulmonary aspergillosis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INDUCED AIRWAY HYPERREACTIVITY; FUNCTIONAL-CHARACTERIZATION; EOSINOPHIL CHEMOATTRACTANT; BRONCHOALVEOLAR LAVAGE; EXPRESSION PATTERN; MOLECULAR-CLONING; ENDOTHELIAL-CELLS; LUNG FIBROBLASTS; FIBROTIC LUNG; MAST-CELLS AB The immunomodulatory role of the chemokine C10 was explored in allergic airway responses during experimental allergic bronchopulmonary aspergillosis (ABPA), The intratracheal delivery of Asperigillus fumigatus Ag into A. fumigatus-sensitized mice resulted in significantly increased levels of C10 within the bronchoalveolar lavage, and these levels peaked at 48 h after A, fumigatus challenge. In addition, C10 levels in BAL samples were greater than 5-fold higher than levels of other chemokines such as monocyte-chemoattractant protein-1, eotaxin, and macrophage-inflammatory protein-1 alpha. From in vitro studies, it was evident that major pulmonary sources of CIO may have included alveolar macrophages, lung fibroblasts, and vascular smooth muscle cells. Experimental ABPA was associated with severe peribronchial eosinophilia, bronchial hyperresponsiveness, and augmented IL-13 and IgE levels. The immunoneutralization of C10 with polyclonal anti-C10 antiserum 2 h before the intratracheal A. fumigatus challenge significantly reduced the airway inflammation and hyperresponsiveness in this model of ABPA, but had no effect on IL-10 nor IgE levels, Taken together, these data suggest that C10 has a unique role in the progression of experimental ABPA. C1 Univ Michigan, Sch Med, Dept Pathol, Div Pulm & Crit Care, Ann Arbor, MI 48109 USA. Univ Michigan, Sch Med, Dept Internal Med, Div Pulm & Crit Care, Ann Arbor, MI 48109 USA. NIA, NIH, Baltimore, MD 21224 USA. RP Hogaboam, CM (reprint author), Univ Michigan, Sch Med, Dept Pathol, Div Pulm & Crit Care, 1301 Catherine Rd, Ann Arbor, MI 48109 USA. RI Gallinat, Chad/E-7561-2010 FU NHLBI NIH HHS [HL31963, HL35276]; NIOSH CDC HHS [15POHL56402] NR 53 TC 58 Z9 61 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 1999 VL 162 IS 10 BP 6071 EP 6079 PG 9 WC Immunology SC Immunology GA 195FP UT WOS:000080240200055 PM 10229848 ER PT J AU Noben-Trauth, N Paul, WE Sacks, DL AF Noben-Trauth, N Paul, WE Sacks, DL TI IL-4-and IL-4 receptor-deficient BALB/c mice reveal differences in susceptibility to Leishmania major parasite substrains SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TH1 IMMUNE-RESPONSE; T-CELL SUBSETS; INTERFERON-GAMMA; INTERLEUKIN-13 RECEPTOR; IFN-GAMMA; INTERLEUKIN-4-DEFICIENT MICE; MURINE LEISHMANIASIS; PROTECTIVE IMMUNITY; MONOCLONAL-ANTIBODY; ALPHA CHAIN AB Using genetically pure BALB/c mice deficient in IL-4 (IL-4(-/-)) or IL-4 receptor cu-chain (IL-4R alpha(-/-)), we have observed different disease outcomes to Leishmania major infection depending on the parasite substrain, Infection with L. major LV39 caused progressive, nonhealing ulcers and uncontrolled parasite growth in both IL-4(-/-) and IL-4Ra(-/-) mice, In contrast, infection with L, major IR173 was partially controlled in IL-4(-/-) mice but efficiently controlled in IL-4R alpha(-/-) mice. Both IL-4(-/-) and IL-4R alpha(-/-) mice infected with either substrain displayed reduced Th2 responses. Surprisingly, IFN-gamma secretion was not up-regulated in the mutant mice, even in the IL-4R alpha(-/-) mice, which were resistant to L, major IR173. The lack of increased IFN-gamma production suggests that cytokine cross-regulation may not be operating in this model and that the effective ratios of Th1/Th2 cytokines become more indicative of disease outcome. The partial vs complete resistance to IR173 in IL-4(-/-) or IL-4R alpha(-/-) mice implies that, in addition to IL-4, IL-13 may be involved in disease progression during L, major infection. The results with LV39 infection indicate that yet another unidentified factor is capable of causing susceptibility to L. major in the absence of IL-4 or IL-4 signaling. C1 NIAID, Immunol Lab, NIH, Rockville, MD 20852 USA. NIAID, Parasitol Lab, NIH, Rockville, MD 20852 USA. RP Noben-Trauth, N (reprint author), NIAID, Immunol Lab, NIH, Twinbrook 2,Room 125,12441 Parklawn Dr, Rockville, MD 20852 USA. NR 55 TC 110 Z9 111 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 1999 VL 162 IS 10 BP 6132 EP 6140 PG 9 WC Immunology SC Immunology GA 195FP UT WOS:000080240200063 PM 10229856 ER PT J AU Scala, G Chen, XN Liu, WM Telles, JN Cohen, OJ Vaccarezza, M Igarashi, T Fauci, AS AF Scala, G Chen, XN Liu, WM Telles, JN Cohen, OJ Vaccarezza, M Igarashi, T Fauci, AS TI Selection of HIV-specific immunogenic epitopes by screening random peptide libraries with HIV-1-Positive sera SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; GP120 ENVELOPE GLYCOPROTEIN; HUMAN MONOCLONAL-ANTIBODY; NEUTRALIZING ANTIBODIES; DISCONTINUOUS EPITOPES; PASSIVE-IMMUNIZATION; FILAMENTOUS PHAGE; TYPE-1; INFECTION; MIMOTOPES AB Efforts to develop a protective HIV-1 vaccine have been hindered by difficulties in identifying epitopes capable of inducing broad neutralizing Ab responses. In fact, the high mutation rate occurring in HIV-1 envelope proteins and the complex structure of gp120 as an oligomer associated with gp41 result in a high degree of antigenic polymorphism. To overcome these obstacles, we screened random peptide libraries using sera from HIV-infected subjects to identify antigenic and immunogenic mimics of HIV-1 epitopes, After extensive counterscreening with HIV-negative sera, we isolated peptides specifically recognized by Abs from HIV-1-infected individuals. These peptides behaved as antigenic mimics of linear or conformational HIV-1 epitopes generated in vivo in infected subjects. Consistent with these findings, sera of simian HIV-infected monkeys also recognized the HIV-specific epitopes, The selected peptides were immunogenic in mice, where they elicited HIV-specific Abs that effectively neutralized HIV-1 isolates. These results demonstrate that pools of HIV-1 mimotopes can be selected from combinatorial peptide libraries by taking advantage of the HIV-specific Ab repertoire induced by the natural infection. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. Univ Catanzaro, Dipartimento Med Sperimentale & Clin, Catanzaro, Italy. RP Scala, G (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Room 6A08,10 Ctr Dr, Bethesda, MD 20892 USA. RI SCALA, GIUSEPPE/A-3280-2009; OI VACCAREZZA, Mauro/0000-0003-3060-318X NR 38 TC 77 Z9 88 U1 1 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 1999 VL 162 IS 10 BP 6155 EP 6161 PG 7 WC Immunology SC Immunology GA 195FP UT WOS:000080240200066 PM 10229859 ER PT J AU Ensoli, F Fiorelli, V DeCristofaro, M Muratori, DS Novi, A Vannelli, B Thiele, CJ Luzi, G Aiuti, F AF Ensoli, F Fiorelli, V DeCristofaro, M Muratori, DS Novi, A Vannelli, B Thiele, CJ Luzi, G Aiuti, F TI Inflammatory cytokines and HIV-1-associated neurodegeneration: Oncostatin-M produced by mononuclear cells from HIV-1-infected individuals induces apoptosis of primary neurons SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CENTRAL-NERVOUS-SYSTEM; IMMUNE-DEFICIENCY-SYNDROME; AIDS-KAPOSIS SARCOMA; HIV-1 GENE-EXPRESSION; CEREBROSPINAL-FLUID; GROWTH-FACTOR; QUINOLINIC ACID; TRANSGENIC MICE; SPINDLE CELLS AB Neurologic abnormalities are common in HIV-1-infected patients and often represent the dominant clinical manifestation of pediatric AIDS. The neurological dysfunction has been directly related to CNS invasion by HIV-1 that is principally, if not exclusively, supported by blood-derived monocytes/macrophages and lymphocytes, By using primary long term cultures of human fetal sensory neurons as well as sympathetic precursors-like neuronal cells, we determined that blood-derived mononuclear cells from HIV-1-infected individuals spontaneously release soluble mediators that can potently inhibit the growth and survival of developing neurons as well as the viability of postmitotic neuronal cells by inducing apoptotic cell death. Analysis of the cytokines produced by lymphomonocytic cells, HIV-1 infected or activated, indicated that oncostatin M (oncM) is a major mediator of these effects. Since low TGF-beta 1 concentrations were capable of enhancing oncM-mediated neuronal alterations, our data indicate that by acting in concert with other cytokines, oncM may induce neuronal demise in both the developing and the mature brain. Thus, this cytokine may contribute to the setting of the neuronal cell damage observed in HN-l-infected individuals. C1 Univ Rome La Sapienza, Dept Allergy & Clin Immunol, I-00185 Rome, Italy. Univ Florence, Dept Anat & Histol, Florence, Italy. NCI, Dept Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Ensoli, F (reprint author), Univ Rome La Sapienza, Dept Allergy & Clin Immunol, Viale Univ, I-00185 Rome, Italy. NR 70 TC 48 Z9 51 U1 1 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 MAY 15 PY 1999 VL 162 IS 10 BP 6268 EP 6277 PG 10 WC Immunology SC Immunology GA 195FP UT WOS:000080240200081 PM 10229874 ER PT J AU Rodgers, JR Levitt, JM Cresswell, P Lindahl, KF Mathis, D Monaco, JT Singer, DS Ploegh, HL Bryant, PW AF Rodgers, JR Levitt, JM Cresswell, P Lindahl, KF Mathis, D Monaco, JT Singer, DS Ploegh, HL Bryant, PW TI A nomenclature solution to mouse MHC confusion SO JOURNAL OF IMMUNOLOGY LA English DT Letter ID GENES C1 Baylor Coll Med, Dept Microbiol & Immunol, Houston, TX 77030 USA. Yale Univ, New Haven, CT 06520 USA. SW Texas State Univ, San Marcos, TX USA. Univ Strasbourg 1, F-67070 Strasbourg, France. Univ Cincinnati, Cincinnati, OH 45221 USA. NIH, Bethesda, MD USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Rodgers, JR (reprint author), Baylor Coll Med, Dept Microbiol & Immunol, Houston, TX 77030 USA. NR 5 TC 5 Z9 5 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 1999 VL 162 IS 10 BP 6294 EP 6294 PG 1 WC Immunology SC Immunology GA 195FP UT WOS:000080240200084 PM 10375304 ER PT J AU Roche, KW Ly, CD Petralia, RS Wang, YX McGee, AW Bredt, DS Wenthold, RJ AF Roche, KW Ly, CD Petralia, RS Wang, YX McGee, AW Bredt, DS Wenthold, RJ TI Postsynaptic density-93 interacts with the delta 2 glutamate receptor subunit at parallel fiber synapses SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CEREBELLAR PURKINJE-CELLS; TUMOR-SUPPRESSOR PROTEIN; NITRIC-OXIDE SYNTHASE; LONG-TERM DEPRESSION; RAT-BRAIN; CLUSTERING ACTIVITY; GUANYLATE KINASES; COCHLEAR NUCLEUS; K+ CHANNELS; PSD-95 AB The glutamate receptor subunit delta 2 has a unique distribution at the parallel fiber-Purkinje cell synapse of the cerebellum, which is developmentally regulated such that delta 2 occurs at both parallel fiber synapses and climbing fiber synapses early in development but is restricted to parallel fiber synapses in adult animals. To identify proteins that might be involved in the trafficking or docking of delta 2 receptors, we screened a yeast two-hybrid library with the cytosolic C terminus of delta 2 and isolated a member of the postsynaptic density (PSD)-95 family of proteins, which are known to interact with the extreme C termini of NMDA receptors. We find that delta 2 binds specifically to PSD-93, which is enriched in Purkinje cells. In addition, PSD-93 clusters delta 2 when they are coexpressed in heterologous cells, and clustering is disrupted by point mutations of delta 2 that disrupt the delta 2-PSD-93 interaction. Ultrastructural localization of PSD-93 and delta 2 shows they are colocalized at parallel fiber synapses; however, PSD-93 also is present at climbing fiber synapses of the adult rat, where delta 2 is not found, indicating that the presence of PSD-93 alone is not sufficient for determining the synaptic expression of delta 2. C1 Natl Ins tDeafness & Other Commun Disorders, Neurochem Lab, NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, Sch Med, Dept Physiol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Med, Program Biomed Sci, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Med, Neurosci Program, San Francisco, CA 94143 USA. RP Roche, KW (reprint author), Natl Ins tDeafness & Other Commun Disorders, Neurochem Lab, NIH, Bldg 36,Room 5D08, Bethesda, MD 20892 USA. OI Roche, Katherine/0000-0001-7282-6539 FU NIGMS NIH HHS [GM36017] NR 41 TC 77 Z9 82 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 15 PY 1999 VL 19 IS 10 BP 3926 EP 3934 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 193XE UT WOS:000080162400028 PM 10234023 ER PT J AU Qin, ZH Chen, RW Wang, YM Nakai, M Chuang, DM Chase, TN AF Qin, ZH Chen, RW Wang, YM Nakai, M Chuang, DM Chase, TN TI Nuclear factor kappa B nuclear translocation upregulates c-Myc and p53 expression during NMDA receptor-mediated apoptosis in rat striatum SO JOURNAL OF NEUROSCIENCE LA English DT Article DE transcription factor; NF-kappa B; quinolinic acid; tumor suppressor gene; apoptosis; Huntington 's disease ID INDUCED CELL-DEATH; METHYL-D-ASPARTATE; TRANSCRIPTION FACTOR; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; TUMOR-SUPPRESSOR; PRIMARY NEURONS; IN-VITRO; ACTIVATION; BRAIN AB Nuclear factor kappa B (NF-kappa B) appears to participate in the excitotoxin-induced apoptosis of striatal medium spiny neurons. To elucidate molecular mechanisms by which this transcription factor contributes to NMDA receptor-triggered apoptotic cascades in vivo, rats were given the NMDA receptor agonist quinolinic acid (QA) by intrastriatal infusion, and the role of NF-kappa B in the induction of apoptosis-related genes and gene products was evaluated. QA administration induced time-dependent NF-kappa B nuclear translocation. The nuclear NF-kappa B protein after QA treatment was comprised mainly of p65 and c-Rel subunits as detected by gel supershift assay. Levels of c-Myc and p53 mRNA and protein were markedly increased at the time of QA-induced NF-kappa B nuclear translocation. Immunohistochemical analysis showed that c-Myc and p53 induction occurred in the excitotoxin-sensitive medium-sized striatal neurons. NF-kappa B nuclear translocation was blocked in a dose-dependent manner by the cell-permeable recombinant peptide NF-kappa B SN50, but not by the NF-kappa B SN50 control peptide. NF-kappa B SN50 significantly inhibited the QA-induced elevation in levels of c-Myc and p53 mRNA and protein. Pretreatment or posttreatment with NF-kappa B SN50, but not the control peptide, also substantially reduced the intensity of QA-induced internucleosomal DNA fragmentation. The results suggest that NF-kappa B may promote an apoptotic response in striatal medium-sized neurons to excitotoxic insult through upregulation of c-Myc and p53. This study also provides evidence indicating an unique signaling pathway from the cytoplasm to the nucleus, which regulates p53 and c-Myc levels in these neurons during apoptosis. C1 NINCDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. NIMH, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Chase, TN (reprint author), NINCDS, Expt Therapeut Branch, NIH, Bldg 10,Room 5C103,10 Ctr Dr,MSC 1406, Bethesda, MD 20892 USA. NR 64 TC 199 Z9 208 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 15 PY 1999 VL 19 IS 10 BP 4023 EP 4033 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 193XE UT WOS:000080162400036 PM 10234031 ER PT J AU Green, PG Dahlqvist, SR Isenberg, WM Strausbaugh, HJ Miao, FJP Levine, JD AF Green, PG Dahlqvist, SR Isenberg, WM Strausbaugh, HJ Miao, FJP Levine, JD TI Sex steroid regulation of the inflammatory response: Sympathoadrenal dependence in the female rat SO JOURNAL OF NEUROSCIENCE LA English DT Article DE plasma extravasation; inflammation; sex differences; estrogen; testosterone; estrogen receptor; sympathoadrenal axis; hypothalamic-pituitary adrenal axis ID PITUITARY-ADRENAL AXIS; INDUCED PLASMA EXTRAVASATION; FEEDBACK NEUROENDOCRINE CONTROL; WALL INDUCED POLYARTHRITIS; ADJUVANT-INDUCED ARTHRITIS; COLLAGEN-INDUCED ARTHRITIS; SUSCEPTIBLE LEWIS RATS; RHEUMATOID-ARTHRITIS; NERVOUS-SYSTEM; KNEE-JOINT AB To investigate the role of sex steroids in sex differences in the response of rats to the potent inflammatory mediator bradykinin (BK), we evaluated the effect of sex steroid manipulation on the magnitude of BK-induced synovial plasma extravasation (PE). The magnitude of BK-induced PE is markedly less in females. Ovariectomy of female rats increased BK-induced PE, and administration of 17 beta-estradiol to ovariectomized female rats reconstituted the female phenotype. Castration in male rats decreased BK-induced PE, and administration of testosterone or its nonmetabolizable analog dihydrotestosterone reconstituted the male phenotype. The results of these experiments strongly support the role of both male and female sex steroids in sex differences in the inflammatory response. Because the stress axes are sexually dimorphic and are important in the regulation of the inflammatory response, we evaluated the contribution of the hypothalamic-pituitary-adrenal and the sympathoadrenal axes to sex differences in BK-induced PE. Neither hypophysectomy nor inhibition of corticosteroid synthesis affected BK-induced PE in female or male rats. Adrenal denervation in females produced the same magnitude increase in BK-induced PE as adrenalectomy or ovariectomy, suggesting that the adrenal medullary factor(s) in females may account for the female sex steroid effect on BK-induced PE. Furthermore, we have demonstrated that in female but not male rats, estrogen receptor a! immunoreactivity is present on medullary but not cortical cells in the adrenal gland. These data suggest that regulation of the inflammatory response by female sex steroids is strongly dependent on the sympathoadrenal axis, possibly by its action on estrogen receptors on adrenal medullary cells. C1 Univ Calif San Francisco, NIH, Pain Ctr, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Oral & Maxillofacial Surg, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Div Neurosci, San Francisco, CA 94143 USA. Univ Umea Hosp, Dept Rheumatol, SE-90185 Umea, Sweden. RP Green, PG (reprint author), Univ Calif San Francisco, NIH, Pain Ctr, C-522,Box 0440, San Francisco, CA 94143 USA. RI Green, Paul/C-5943-2011 FU NINR NIH HHS [NR12773] NR 77 TC 53 Z9 53 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 15 PY 1999 VL 19 IS 10 BP 4082 EP 4089 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 193XE UT WOS:000080162400041 PM 10234036 ER PT J AU Poulaki, V Benekou, A Bozas, E Bolaris, S Stylianopoulou, F AF Poulaki, V Benekou, A Bozas, E Bolaris, S Stylianopoulou, F TI P53 expression and regulation by NMDA receptors in the developing rat brain SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE p53; development; brain; NMDA receptors ID CELL-DEATH; DNA FRAGMENTATION; NERVOUS-SYSTEM; MESSENGER-RNA; GENE-EXPRESSION; IN-VIVO; APOPTOSIS; PROTEIN; EMBRYOGENESIS; PATHWAYS AB The p53 tumor suppressor gene, which is considered the guardian of the genome, encodes a phosphoprotein, which is a sequence-specific transcriptional activator or repressor of target genes, The role of p53 in developmental processes has not been studied extensively, although its expression appears to undergo temporal and spatial changes during prenatal and postnatal development, In the present study, we assessed the levels of p53 mRNA and protein in the developing rat brain and its relation to developmental cell death. Furthermore, we investigated the potential role of n-methyl-d-aspartate (NMDA) receptors in regulating p53 expression, since these receptors are involved in the control of cell death. We found that p53 mRNA and protein were detectable in the rat brain throughout perinatal development, In embryos, p53 immunoreactivity was mainly localized in the nuclei of neuroepithelial cells, with a maximum in staining at embryonic day (E)12, In the neuroepithelium, we also found significant numbers of TdT-mediated dUTP nick end labeling (TUNEL)-positive cells, both in dividing periventricular cells and in migrating neurons, In neonates, immediately after birth there was a reduction in the number of apoptotic cells, which then increased to reach a maximum at postnatal day (P)5, Postnatally, apoptotic as well as p53-positive cells were detected in most brain areas, P53 immunoreactivity was also highest on P5, In most cells, p53 immunoreactivity and the TUNEL signal colocalized, P53 immunoreactivity as well as the number of TUNEL- positive cells were dramatically decreased in the brains of newborns treated with MK-801, an NMDA receptor antagonist, Our results show that p53 is involved in the control of developmental cell death, and that NMDA receptors play a regulatory role in the expression of the p53 gene, and thus in apoptosis occurring in the developing rat brain, J, Neurosci, Res, 56:427-440, 1999, (C) 1999 Wiley-Liss, Inc. C1 Univ Athens, Fac Nursing, Lab Biol Biochem, Athens, Greece. NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Poulaki, V (reprint author), Bldg 10,Room 2A10,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 33 TC 17 Z9 17 U1 2 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD MAY 15 PY 1999 VL 56 IS 4 BP 427 EP 440 DI 10.1002/(SICI)1097-4547(19990515)56:4<427::AID-JNR10>3.0.CO;2-J PG 14 WC Neurosciences SC Neurosciences & Neurology GA 191PV UT WOS:000080031500010 PM 10340750 ER PT J AU Schmidt, MI Duncan, BB Sharrett, AR Lindberg, G Savage, PJ Offenbacher, S Azambuja, MI Tracy, RP Heiss, G AF Schmidt, MI Duncan, BB Sharrett, AR Lindberg, G Savage, PJ Offenbacher, S Azambuja, MI Tracy, RP Heiss, G CA ARIC Investigators TI Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study SO LANCET LA English DT Article ID INDUCED INSULIN-RESISTANCE; NECROSIS-FACTOR-ALPHA; INNATE IMMUNE-SYSTEM; CARDIOVASCULAR-DISEASE; OBESITY; ASSOCIATION; EXPRESSION; LEPTIN; NIDDM AB Background Type 2 diabetes mellitus and atherosclerotic cardiovascular disease have common antecedents. Since markers of inflammation predict coronary heart disease and are raised in patients with type 2 diabetes, we investigated whether they predict whether people will develop type 2 diabetes. Methods 12 330 men and women, aged 45-64 years, were followed up for a mean of 7 years. We analysed the association between different markers of acute inflammation and subsequent diagnosis of diabetes. In a subgroup of 610 individuals selected originally for an unrelated atherosclerosis case-control study, we also investigated diabetes associations with total sialic acid and orosomucoid, haptoglobin, and alpha(1)-antitrypsin. Findings 1335 individuals had a new diagnosis of diabetes. Adjusted odds ratios for developing diabetes for quartile extremes were 1.9 (95% CI 1.6-2.3) for raised white-cell count, 1.3 (1.0-1.5) for low serum albumin, and 1.2 (1.0-1.5) for raised fibrinogen. In the subgroup analysis, individuals with concentrations of orosomucoid and sialic acid of more than the median had odds ratios of 7.9 (2.6-23.7) and 3.7 (1.4-9.8), respectively. Adjustment for body-mass index and waist-to-hip ratio lessened the associations; those for white-cell count (1.5 [1.3-1.8]), orosomucoid (7.1 [2.1-23.7]), and sialic acid (2.8 [1.0-8.1]) remained significant. Interpretation Markers of inflammation are associated with the development of diabetes in middle-aged adults. Although autoimmunity may partly explain these associations, they probably reflect the pathogenesis of type 2 diabetes. C1 UFRGS, Sch Med, Dept Social Med, BR-90035003 Porto Alegre, RS, Brazil. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. Univ N Carolina, Sch Dent, Dent Res Ctr, Chapel Hill, NC USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Malmo Hosp, NEPI Fdn, Malmo, Sweden. Univ Vermont, Dept Pathol & Biochem, Colchester, VT USA. RP Schmidt, MI (reprint author), UFRGS, Sch Med, Dept Social Med, Rua Barcelos 2600-414, BR-90035003 Porto Alegre, RS, Brazil. FU NHLBI NIH HHS [N01-HC-55016, N01-HC-55015, N01-HC-55018] NR 30 TC 575 Z9 600 U1 4 U2 16 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD MAY 15 PY 1999 VL 353 IS 9165 BP 1649 EP 1652 DI 10.1016/S0140-6736(99)01046-6 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 198DT UT WOS:000080408000008 PM 10335783 ER PT J AU Ohta, K Wu, TC Lichten, M Shibata, T AF Ohta, K Wu, TC Lichten, M Shibata, T TI Competitive inactivation of a double-strand DNA break site involves parallel suppression of meiosis-induced changes in chromatin configuration SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RECOMBINATION HOT-SPOT; YEAST SACCHAROMYCES-CEREVISIAE; NUCLEASE-HYPERSENSITIVE SITES; MEIOTIC GENE CONVERSION; TRANSCRIPTION; HOTSPOTS; REPAIR; TRANS; MRE11; CIS AB In Saccharomyces cerevisiae, DNA double-strand breaks (DSBs) initiate meiotic recombination at open sites in chromatin, which display a meiosis-specific increase in micrococcal nuclease (MNase) sensitivity. The arg4 promoter contains such a DSB site. When arg4 sequences are placed in a pBR322-derived insert at HIS4 (his4::arg4), the presence of strong DSB sites in pBR322 sequences leads to an almost complete loss of breaks from the insert-borne arg4 promoter region. Most of the MNase-sensitive sites occurred at similar positions in insert-borne and in normal ARG4 sequences, indicating that hotspot inactivation is not a consequence of changes in nucleosome positioning, However, a meiosis-specific increase in MNase hypersensitivity was no longer detected at the inactive insert-borne arg4 DSB site. Elimination of pBR322 sequences restored DSBs to the insert-borne arg4 promoter region and also restored the meiotic induction of MNase hypersensitivity. Thus, the meiotic induction of MNase hypersensitivity at the DSB sites is suppressed and activated in parallel to DSBs themselves, without changes in the underlying DNA sequence or nucleosome positioning. We suggest that meiosis-specific changes in chromatin at a DSB site area signal reflecting a pivotal step in DSB formation. C1 RIKEN, Inst Phys & Chem Res, Cellular & Mol Biol Lab, Wako, Saitama 3510198, Japan. NCI, Div Basic Sci, Biochem Lab, Bethesda, MD 20892 USA. RP Ohta, K (reprint author), RIKEN, Inst Phys & Chem Res, Cellular & Mol Biol Lab, Wako, Saitama 3510198, Japan. RI Lichten, Michael/C-5795-2013 OI Lichten, Michael/0000-0001-9707-2956 NR 29 TC 18 Z9 20 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 MAY 15 PY 1999 VL 27 IS 10 BP 2175 EP 2180 DI 10.1093/nar/27.10.2175 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 198NY UT WOS:000080431800014 PM 10219090 ER PT J AU Walchle, C Diwan, BA Shiao, YH Calvert, RJ AF Walchle, C Diwan, BA Shiao, YH Calvert, RJ TI Microsatellite instability is infrequent in azoxymethane-induced rat intestinal tumors: An assessment by capillary electrophoresis SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article; Proceedings Paper CT 89th Annual Meeting of the American-Association-for-Cancer-Research CY MAR 27-APR 01, 1998 CL NEW ORLEANS, LOUISIANA SP Amer Assoc Canc Res DE rat; colon cancer; microsatellite instability; azoxymethane; intestinal tumor; capillary electrophoresis ID P53 GENE-MUTATIONS; COLORECTAL-CANCER; MISMATCH REPAIR; METHYLAZOXYMETHANOL ACETATE; COLON CARCINOGENESIS; F344 RATS; 1,2-DIMETHYLHYDRAZINE; DNA; CELL; INVOLVEMENT AB A rat model of colon cancer in which tumors are induced by azoxymethane (AOM) is frequently used to study putative environmental agents that may modify the risk of human colon cancer development. In order to evaluate the usefulness of this model for human risk assessment, a comparison of the molecular changes associated with tumorigenesis in the rat model with those in human colon cancer is desirable. Microsatellite instability (MSI), an alteration in length of short repetitive DNA sequences associated with defective DNA mismatch repair, is an important molecular characteristic of many human colon tumors. Intestinal tumors were induced in male Fischer 344 rats injected with 15 mg/kg body wt AOM in four weekly doses. Thirteen intestinal tumors were examined for MSI at 10 different microsatellite loci, using a capillary electrophoresis (CE) method for accurate assessment of DNA length. This method was shown to have a resolution of 1 bp for a 140-bp PCR product and to be capable of detecting one mutant sequence within a background of 10 wild-type sequences. The CE method also readily distinguished a known MSI-positive human tumor sample from its matching control sample. Among the 13 rat intestinal tumors examined, only one had MSI, which was present at only a single locus. We conclude that, unlike sporadic human colon tumors in which 15-30% of tumors have MSI (usually at multiple loci), MSI is very rare in AOM-induced rat intestinal tumors. C1 NCI, Comparat Carcinogenesis Lab, Div Basic Sci, Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA. NCI, Intramural Res Support Program, SAIC Frederick, Ft Detrick, MD 21702 USA. US FDA, Off Special Nutr, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. RP Walchle, C (reprint author), NCI, Comparat Carcinogenesis Lab, Div Basic Sci, Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA. FU NCI NIH HHS [N01-CO-5600] NR 39 TC 8 Z9 8 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD MAY 15 PY 1999 VL 157 IS 1 BP 9 EP 15 DI 10.1006/taap.1999.8662 PG 7 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 201DQ UT WOS:000080580100002 PM 10329502 ER PT J AU Knechtle, SJ Fechner, JH Dong, YC Hong, X Tsuchida, M Brunner, K Neville, D Hamawy, M AF Knechtle, SJ Fechner, JH Dong, YC Hong, X Tsuchida, M Brunner, K Neville, D Hamawy, M TI Central tolerance is not a significant mechanism for prolonged allograft survival in anti-CD3 immunotoxin treated monkeys SO TRANSPLANTATION LA English DT Meeting Abstract C1 NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. Univ Wisconsin, Dept Surg, Madison, WI 53706 USA. RI Fechner, John/C-5962-2016 OI Fechner, John/0000-0002-8220-7237 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD MAY 15 PY 1999 VL 67 IS 9 MA 59 BP S557 EP S557 DI 10.1097/00007890-199905150-00084 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 201YD UT WOS:000080624100079 ER PT J AU Ricciardi, R Quarfordt, SH Saavedra, JE Keefer, LK Foley, DP Wheeler, SA Meyer, WC AF Ricciardi, R Quarfordt, SH Saavedra, JE Keefer, LK Foley, DP Wheeler, SA Meyer, WC TI VPYRRO/NO, a selective nitric oxide donor to the liver, improves hepatic hemodynamics and function. SO TRANSPLANTATION LA English DT Meeting Abstract C1 Univ Massachusetts, Sch Med, Dept Surg, Worcester, MA USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD MAY 15 PY 1999 VL 67 IS 9 MA 432 BP S650 EP S650 DI 10.1097/00007890-199905150-00455 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 201YD UT WOS:000080624100450 ER PT J AU Thomas, J Thomas, F Eckhoff, D Contreras, J Haisch, C Neville, D AF Thomas, J Thomas, F Eckhoff, D Contreras, J Haisch, C Neville, D TI Immune studies of primate functional tolerance (FnTOL) SO TRANSPLANTATION LA English DT Meeting Abstract C1 Univ Alabama, Tuscaloosa, AL 35487 USA. E Carolina Univ, Greenville, NC 27858 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD MAY 15 PY 1999 VL 67 IS 9 MA 57 BP S557 EP S557 DI 10.1097/00007890-199905150-00082 PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 201YD UT WOS:000080624100077 ER PT J AU Di Sioudi, BD Miller, CE Lai, KH Grimsley, JK Wild, JR AF Di Sioudi, BD Miller, CE Lai, KH Grimsley, JK Wild, JR TI Rational design of organophosphorus hydrolase for altered substrate specificities SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article; Proceedings Paper CT 3th International Meeting on Esterases Reacting with Organophosphorus Compounds CY APR 15-18, 1998 CL INTER UNVI CTR, DUBROVNIK, CROATIA SP INst Med Res & Occupat Hlth, Minist Sci & Technol Republ Croatia, Minist Def Republ Croatia, Us Army Med Res & Mat Command, Assoc European Toxicol & Sci Toxicol, Netherlands & Novartis Crop Protect AG HO INTER UNVI CTR DE organophosphorus hydrolase; phosphotriesterase; protein engineering; neurotoxin degradation; organophosphates; detoxification ID PSEUDOMONAS-DIMINUTA MG; BINUCLEAR METAL CENTER; HYDROLYZING ENZYME; 3-DIMENSIONAL STRUCTURE; NERVE AGENTS; IMMOBILIZED PHOSPHOTRIESTERASE; BACTERIAL PHOSPHOTRIESTERASE; STREPTOMYCES-LIVIDANS; NUCLEOTIDE-SEQUENCE; FLAVOBACTERIUM SP AB Organophosphorus hydrolase (OPH) is a bacterial enzyme that hydrolyzes a broad variety of OP neurotoxins, including chemical warfare agents and many widely used pesticides. OPH has extremely high hydrolytic efficiency with different phosphotriester and phophothiolester pesticides (k(cat) = 50-15000 s(-1)) as well as phosphorofluorates such as DFP and the chemical warfare agents sarin and soman (k(cat) = 50-11000 s(-1)). In contrast, the enzyme has much lower catalytic capabilities for phosphonothioate neurotoxins such as acephate or the chemical warfare agent VX [O-ethyl S-(2-diisopropyl aminoethyl) methylphosphonothioate] (k(cat) = 0.3-20 s(-1)). Different metal-associated forms of the enzyme have demonstrated varying hydrolytic capabilities for each of the OP neurotoxins, and the activity of OPH (Co2+) is consistently higher than that of OPH (Zn2+) by five- to 20-fold. Protein engineering strategies have exploited these metal-induced catalytic differences, and other slight modifications to the opd gene have resulted in significant enhancement of the rates of detoxification of the thioate pesticides and chemical warfare agents. In order to develop practical applications of OPH, other experiments have focused on improvement of enzyme production, localization, stability, and shelf-life, as well as efficient catalysis of substrates of interest. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA. NIDDK, NIH, Bethesda, MD 20892 USA. Christ Hosp & Med Ctr, Dept Internal Med, Oak Lawn, IL 60463 USA. RP Wild, JR (reprint author), Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA. EM wild@bioch.tamu.edu FU NIEHS NIH HHS [2 T32 ES07273-06] NR 57 TC 39 Z9 41 U1 5 U2 17 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD MAY 14 PY 1999 VL 119 BP 211 EP 223 DI 10.1016/S0009-2797(99)00030-7 PG 13 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 211WG UT WOS:000081184400023 PM 10421455 ER PT J AU Vila-Petroff, MG Younes, A Egan, J Lakatta, EG Sollott, SJ AF Vila-Petroff, MG Younes, A Egan, J Lakatta, EG Sollott, SJ TI Activation of distinct cAMP-dependent and cGMP-dependent pathways by nitric oxide in cardiac myocytes SO CIRCULATION RESEARCH LA English DT Article DE nitric oxide signaling; cGMP; cAMP; contractility; cardiac myocyte ID CYCLIC ADENOSINE-MONOPHOSPHATE; PROTEIN-KINASE; CA2+ CURRENT; MYOCARDIAL-CONTRACTION; VENTRICULAR MYOCYTES; SIGNAL TRANSDUCTION; GUANYLYL CYCLASE; PAPILLARY-MUSCLE; CELL-FUNCTION; GMP AB Nitric oxide (NO) donors were recently shown to produce biphasic contractile effects in cardiac tissue, with augmentation at low NO levels and depression at high NO levels. We examined the subcellular mechanisms involved in the opposing effects of NO on cardiac contraction and investigated whether NO-modulates contraction exclusively via guanylyl cyclase (GC) activation or whether some contribution occurs via cGMP/PKG-independent mechanisms, in indo 1-loaded adult cardiac myocytes. Whereas a high concentration of the NO donor S-nitroso-N-acetylpenicillamine (SNAP, 100 mu mol/L) significantly attenuated contraction amplitude by 24.4+/-4.5% (without changing the Ca2+ transient or total cAMP), a low concentration of SNAP (1 mu mol/L) significantly increased contraction amplitude (38 +/- 10%), Ca2+ transient (26+/-10%), and cAMP levels (from 6.2 to 8.5 pmol/mg of protein). The negative contractile response of 100 mu mol/L SNAP was completely abolished in the presence of the specific blocker of PKG KT 5823 (1 mu mol/L); the positive contractile response of 1 mu mol/L SNAP persisted, despite the presence of the selective inhibitor of GC 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 mu mol/L) alone, but was completely abolished in the presence of ODQ plus the specific inhibitory cAMP analog Rp-8-CPT-cAMPS (100 mu mol/L), as well as by the NO scavenger oxyhemoglobin. Parallel experiments in cell suspensions showed significant increases in adenylyl cyclase (AC) activity at low concentrations (0.1 to 1 mu mol/L) of SNAP (AC, 18% to 20% above basal activity). We conclude that NO can regulate both AC and GC in cardiac myocytes. High levels of NO induce large increases in cGMP and a negative inotropic effect mediated by a PKG-dependent reduction in myofilament responsiveness to Ca2+. Low levels of NO increase cAMP, at least in part, by a novel cGMP-independent activation of AC and induce a positive contractile response. C1 NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Intramural Res Program, Baltimore, MD 21224 USA. NIA, Clin Invest Lab, Intramural Res Program, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Intramural Res Program, Box 13,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM sollotts@grc.nia.nih..gov NR 59 TC 189 Z9 193 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD MAY 14 PY 1999 VL 84 IS 9 BP 1020 EP 1031 PG 12 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 199WJ UT WOS:000080506800006 PM 10325239 ER PT J AU Dianov, GL Prasad, R Wilson, SH Bohr, VA AF Dianov, GL Prasad, R Wilson, SH Bohr, VA TI Role of DNA polymerase beta in the excision step of long patch mammalian base excision repair SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL NUCLEAR ANTIGEN; BOVINE TESTIS; SITE REPAIR; PATHWAY; REQUIREMENT; BINDING; EXTRACT AB The two base excision repair (BER) subpathways in mammalian cells are characterized by the number of nucleotides synthesized into the excision patch. They are the "single-nucleotide" BER pathway and the "long patch" (several nucleotides incorporated) BER pathway. Both of these subpathways involve excision of a damaged base and/or nearby nucleotides and DNA synthesis to fill the excision gap Whereas DNA polymerase beta (pol beta) is known to participate in the single-nucleotide BER pathway, the identity of polymerases involved in long patch BER has remained unclear. By analyzing products of long patch excision generated during BER of a uracil-containing DNA substrate in mammalian cell extracts we find that long patch excision depends on pol beta. We show that the excision of the characteristic 5'-deoxyribose phosphate containing oligonucleotide (dRP-oligo) is deficient in extracts from pol beta null cells and is rescued by addition of purified pol beta. Also, pol beta-neutralizing antibody inhibits release of the dRP-oligo in wild-type cell extracts, and the addition of pol beta after inhibition with antibody completely restores the excision reaction. The results indicate that pol beta plays an essential role in long patch BER by conducting strand displacement synthesis and controlling the size of the excised flap. C1 NIA, NIH, Baltimore, MD 21224 USA. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Dianov, GL (reprint author), NIA, NIH, Baltimore, MD 21224 USA. NR 22 TC 183 Z9 191 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 14 PY 1999 VL 274 IS 20 BP 13741 EP 13743 DI 10.1074/jbc.274.20.13741 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 196RW UT WOS:000080322200004 PM 10318775 ER PT J AU Pan, CJ Lin, BC Chou, JY AF Pan, CJ Lin, BC Chou, JY TI Transmembrane topology of human glucose 6-phosphate transporter SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GLYCOGEN-STORAGE-DISEASE; PUTATIVE GLUCOSE-6-PHOSPHATE TRANSLOCASE; ASPARAGINE-LINKED OLIGOSACCHARIDES; ENDOPLASMIC-RETICULUM; ESCHERICHIA-COLI; CHROMOSOME 11Q23; GENE; PROTEIN; IB; PHOSPHATE AB Glycogen storage disease type 1b is caused by a deficiency in a glucose 6-phosphate transporter (G6PT) that translocates glucose 6-phosphate from the cytoplasm to the endoplasmic reticulum lumen where the active site of glucose 6-phosphatase is situated. Using amino- and carboxyl-terminal tagged G6PT, we demonstrate that proteolytic digestion of intact microsomes resulted in the cleavage of both tags, indicating that both termini of G6PT face the cytoplasm. This is consistent with ten and twelve transmembrane domain models for G6PT predicted by hydropathy analyses. A region of G6PT corresponding to amino acid residues 50-71, which constitute a transmembrane segment in the twelve-domain model, are situated in a 51-residue luminal loop in the ten-domain model. To determine which of these two models is correct, we generated two G6PT mutants, T53N and S55N, that created a potential Asn-linked glycosylation site at residues 53-55 ((NSS)-S-53) Or 55-57 (N(55)QS), respectively. (NSS)-S-53 Or N(55)QS would be glycosylated only if it is situated in a luminal loop larger than 33 residues as predicted by the ten-domain model. Whereas wild-type G6PT is not a glycoprotein, both T53N and S55N mutants are glycosylated, strongly supporting the ten-helical model for G6PT. C1 NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Chou, JY (reprint author), NICHHD, Heritable Disorders Branch, NIH, Bldg 10,Rm 9S241, Bethesda, MD 20892 USA. EM chou@helix.nih.gov RI Lin, Baochuan/A-8390-2009 OI Lin, Baochuan/0000-0002-9484-0785 NR 29 TC 55 Z9 57 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 14 PY 1999 VL 274 IS 20 BP 13865 EP 13869 DI 10.1074/jbc.274.20.13865 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 196RW UT WOS:000080322200023 PM 10318794 ER PT J AU Sekiya, F Bae, YS Jhon, DY Hwang, SC Rhee, SG AF Sekiya, F Bae, YS Jhon, DY Hwang, SC Rhee, SG TI AHNAK, a protein that binds and activates phospholipase C-gamma 1 in the presence of arachidonic acid SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN GENE AHNAK; STIMULATES PHOSPHOINOSITIDE HYDROLYSIS; PLACENTAL-LACTOGEN RELEASE; C-GAMMA; TAU-PROTEIN; PLASMA-MEMBRANE; KINASE-C; IN-SITU; CA-2+; CELLS AB We have recently shown that phospholipase C-gamma (PLC-gamma) is activated by tau, a neuronal cell-specific microtubule-associated protein, in the presence of arachidonic acid, We now report that non-neuronal tissues also contain a protein that can activate PLC-gamma in the presence of arachidonic acid. Purification of this activator from bovine lung cytosol yielded several proteins with apparent molecular sizes of 70-130 kDa. They were identified as fragments derived from an unusually large protein (similar to 700 kDa) named AHNAK, which comprises about 30 repeated motifs each 128 amino acids in length. Two AHNAK fragments containing one and four of the repeated motifs, respectively, were expressed as glutathione S-transferase fusion proteins. Both recombinant proteins activated PLC-gamma 1 at nanomolar concentrations in the presence of arachidonic acid, suggesting that an intact AHNAK molecule contains multiple sites for PLC-gamma activation. The role of arachidonic acid was to promote a physical interaction between AHNAK and PLC-gamma 1, and the activation by AHNAK and arachidonic acid was mainly attributable to reduction in the enzyme's apparent K-m toward the substrate phosphatidylinositol 4,5-bisphosphate. Our results suggest that arachidonic acid liberated by phospholipase A(2) can act as an additional trigger for PLC-gamma activation, constituting an alternative mechanism that is independent of tyrosine phosphorylation. 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. OI Hwang, Sung Chul/0000-0003-2401-619X NR 39 TC 56 Z9 56 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 14 PY 1999 VL 274 IS 20 BP 13900 EP 13907 DI 10.1074/jbc.274.20.13900 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 196RW UT WOS:000080322200028 PM 10318799 ER PT J AU Gupta, D Wang, QL Vinson, C Dziarski, R AF Gupta, D Wang, QL Vinson, C Dziarski, R TI Bacterial peptidoglycan induces CD14-dependent activation of transcription factors CREB ATF and AP-1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NECROSIS-FACTOR-ALPHA; SIGNAL-REGULATED KINASE; LPS-BINDING-PROTEIN; LIPOPOLYSACCHARIDE LPS; SOLUBLE PEPTIDOGLYCAN; MONOCYTIC CELLS; CROSS-LINKING; C-JUN; CD14; GENE AB Peptidoglycan (PGN), the major cell wall component of Gram-positive bacteria, induces secretion of cytokines in macrophages through CD14, the pattern recognition receptor that binds lipopolysaccharide and other microbial products. To begin to elucidate the mechanisms that regulate the transcription of cytokine genes, we wanted to determine which transcription factors are activated by PGN in mouse RAW264.7 and human THP-1 macrophage cells. Our results demonstrated that: (i) PGN induced phosphorylation of the transcription factors ATF-1 and CREB; (ii) ATF-1 and CREB bound DNA asa dimer and induced transcriptional activation of a CRE reporter plasmid, which was inhibited by dominant negative CREB and ATF-1; (iii) PGN induced phosphorylation of c-Jun, protein synthesis of JunB and c-Fos, and transcriptional activation of the AP-1 reporter plasmid, which was inhibited by dominant negative c-Fos; and (iv) PGN-induced activation of CREB/ATF and AP-1 was mediated through CD14. This is the first study to demonstrate activation of CREB/ATF and AP-1 transcription factors by PGN or by any other component of Gram-positive bacteria. C1 Indiana Univ, Sch Med, NW Ctr Med Educ, Gary, IN 46408 USA. NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Gupta, D (reprint author), Indiana Univ, Sch Med, NW Ctr Med Educ, 3400 Broadway, Gary, IN 46408 USA. FU NIAID NIH HHS [AI28797] NR 39 TC 59 Z9 60 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 14 PY 1999 VL 274 IS 20 BP 14012 EP 14020 DI 10.1074/jbc.274.20.14012 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 196RW UT WOS:000080322200043 PM 10318814 ER PT J AU Standaert, ML Bandyopadhyay, G Sajan, MP Cong, L Quon, MJ Farese, RV AF Standaert, ML Bandyopadhyay, G Sajan, MP Cong, L Quon, MJ Farese, RV TI Okadaic acid activates atypical protein kinase C (zeta/lambda) in rat and 3T3/L1 adipocytes - An apparent requirement for activation of GLUT4 translocation and glucose transport SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INSULIN-STIMULATED GLUCOSE; GLUCOSE-TRANSPORTER-4 TRANSLOCATION; PHOSPHATIDYLINOSITOL 3-KINASE; 3T3-L1 ADIPOCYTES; POTENTIAL ROLE; AKT; CELLS; ZETA; ALPHA; PDK1 AB Okadaic acid, an inhibitor of protein phosphatases 1 and 2A, is known to provoke insulin-like effects on GLUT4 translocation and glucose transport, but the underlying mechanism is obscure. Presently, we found in both rat adipocytes and 3T3/L1 adipocytes that okadaic acid provoked partial insulin-like increases in glucose transport, which were inhibited by phosphatidylinositol (PI) 3-kinase inhibitors, wortmannin and LY294002, and inhibitors of atypical protein kinase C (PKC) isoforms, zeta and lambda. Moreover, in both cell types, okadaic acid provoked increases in the activity of immunoprecipitable PRC-zeta/lambda by a PI 3-kinase-dependent mechanism. In keeping with apparent PI 3-kinase dependence of stimulatory effects of okadaic acid on glucose transport and PKC-zeta/lambda activity, okadaic acid provoked insulin-like increases in membrane PI 3-kinase activity in rat adipocytes; the mechanism for PI 3-kinase activation was uncertain, however, because it was not apparent in phosphotyrosine immunoprecipitates. Of further note, okadaic acid provoked partial insulin-like increases in the translocation of hemagglutinin antigen-tagged GLUT4 to the plasma membrane in transiently transfected rat adipocytes, and these stimulatory effects on hemagglutinin antigen-tagged GLUT4 translocation were inhibited by eo-expression of kinase;inactive forms of PRC-zeta and PKC-lambda. but not by a double mutant (T308A, 5473A), activation-resistant form of protein kinase B, Our findings suggest that, as with insulin, PI 3-kinase-dependent atypical PKCs, zeta and lambda, are required for okadaic acid-induced increases in GLUT4 translocation and glucose transport in rat adipocytes and 3T3/L1 adipocytes. C1 Univ S Florida, Coll Med, Dept Internal Med, Tampa, FL 33612 USA. NHLBI, Hypertens Endocrine Branch, NIH, Bethesda, MD 20892 USA. RP Farese, RV (reprint author), JA Haley VA Hosp, Res Serv VAR 151, 13000 Bruce B Downs Blvd, Tampa, FL 33612 USA. RI Quon, Michael/B-1970-2008; Farese, Robert/B-3605-2015 FU NIDDK NIH HHS [2R01DK38079-09A1, R01 DK065969] NR 20 TC 54 Z9 57 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 MAY 14 PY 1999 VL 274 IS 20 BP 14074 EP 14078 DI 10.1074/jbc.274.20.14074 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 196RW UT WOS:000080322200051 PM 10318822 ER PT J AU Dhavan, GM Lapham, J Yang, SW Crothers, DM AF Dhavan, GM Lapham, J Yang, SW Crothers, DM TI Decreased imino proton exchange and base-pair opening in the IHF-DNA complex measured by NMR SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE DNA; imino proton; NMR; proton exchange rates; base-pair opening ID INTEGRATION HOST FACTOR; ESCHERICHIA-COLI; SPIN-ECHO; PROTEIN; SPECTROSCOPY; KINETICS; REPLICATION; OLIGONUCLEOTIDES; SEQUENCE; ELEMENTS AB Integration Host Factor, IHF, is an E. coli DNA binding protein that imposes a substantial bend on DNA. Previous footprinting studies and bending assays have characterized several recognition sequences in the bacterial and lambda phage genome as unique in the way they are bound by II-IF. We have chosen one of the lambda phage sites, H1, for study because it presents a small yet sequence-specific substrate for NMR analysis of the complex. A 19 base-pair duplex, H19, corresponding to the recognition sequence at the H1 site was constructed by isotopically labeling one of the strands with N-15. (H-1, N-15) heteronuclear NMR experiments aided in assigning the imino proton resonances of the DNA alone and in complex with IHF. The NMR results are consistent with a mode of binding observed in the recent crystal structure of IHF bound to another of its sites from the lambda phage genome. Additionally, the dramatic change that IHF imposes on the imino proton chemical shifts is indicative of a severe deviation from canonical B-DNA structure. In order to understand the dynamic properties of the DNA in the complex with IHF, the exchange rates of the imino protons with the solvent have been measured for H19 with and without IHF bound. A drastic reduction in exchange is observed for the imino protons in the IHF bound DNA. In the DNA-protein complex, groups of adjacent base-pair exchange at the same rate, and appear to close more slowly than the rate of imino proton exchange with bulk water, since their exchange rate is independent of catalyst concentration. We infer that segments of the double helix as large as 6 bp open in a cooperative process, and remain open much longer than is typical for opening fluctuations in naked duplex DNA. We discuss these results in terms of the specific protein-DNA contacts observed in the crystal structure. (C) 1999 Academic Press. C1 Yale Univ, Dept Chem, New Haven, CT 06511 USA. Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06511 USA. NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Crothers, DM (reprint author), Yale Univ, Dept Chem, New Haven, CT 06511 USA. NR 33 TC 24 Z9 24 U1 0 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 MAY 14 PY 1999 VL 288 IS 4 BP 659 EP 671 DI 10.1006/jmbi.1999.2690 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 198EJ UT WOS:000080409500014 PM 10329171 ER PT J AU Zhao, YU Sheng, HZ Amini, R Grinberg, A Lee, E Huang, SP Taira, M Westphal, H AF Zhao, YU Sheng, HZ Amini, R Grinberg, A Lee, E Huang, SP Taira, M Westphal, H TI Control of hippocampal morphogenesis and neuronal differentiation by the LIM homeobox gene Lhx5 SO SCIENCE LA English DT Article ID EMBRYONIC CEREBRAL-CORTEX; DENTATE GYRUS; C-ELEGANS; MICE; EXPRESSION; FOREBRAIN; HOMEODOMAIN; MULTIPLE; REELER; CELLS AB The mammalian hippocampus contains the neural circuitry that is crucial for cognitive functions such as Learning and memory. The development of such circuitry is dependent on the generation and correct placement of the appropriate number and types of neurons. Mice Lacking function of the LIM homeobox gene Lhx5 showed a defect in hippocampus development. Hippocampal neural precursor cells were specified and proliferated, but many of them failed to either exit the cell cycle or to differentiate and migrate properly. Lhx5 is therefore essential for the regulation of precursor cell proliferation and the control of neuronal differentiation and migration during hippocampal development. C1 NICHHD, Lab Mammalian Genes & Dev, Bethesda, MD 20892 USA. NICHHD, Genet Mol Lab, Bethesda, MD 20892 USA. RP Westphal, H (reprint author), NICHHD, Lab Mammalian Genes & Dev, Bethesda, MD 20892 USA. NR 35 TC 107 Z9 112 U1 1 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD MAY 14 PY 1999 VL 284 IS 5417 BP 1155 EP 1158 DI 10.1126/science.284.5417.1155 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 197HJ UT WOS:000080359100033 PM 10325223 ER PT J AU Linders, JTM Flippen-Anderson, JL George, CF Rice, KC AF Linders, JTM Flippen-Anderson, JL George, CF Rice, KC TI An expedient synthesis of 9-keto-2-methyl-5-(dimethoxyphenyl)morphans SO TETRAHEDRON LETTERS LA English DT Article DE Thorpe-Ziegler reaction; alkylation; phenylmorphans ID RECEPTOR SUBTYPE SELECTIVITY; AMINATION AB An expedient synthesis of ortho-methoxy substituted 9-keto-5-phenylmorphans has been developed, featuring a Thorpe-Zieger cyclization to construct the substituted 2-phenylcyclohexanone intermediate. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 NIDDKD, Med Chem Lab, NIH, Bethesda, MD 20892 USA. USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. RP Linders, JTM (reprint author), Janssen Res Fdn, Dept Med Chem, Turnhoutseweg 30, B-2340 Beerse, Belgium. NR 19 TC 7 Z9 7 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD MAY 14 PY 1999 VL 40 IS 20 BP 3905 EP 3908 DI 10.1016/S0040-4039(99)00566-3 PG 4 WC Chemistry, Organic SC Chemistry GA 193HV UT WOS:000080130600024 ER PT J AU Brewer, HB AF Brewer, HB TI Hypertriglyceridemia: Changes in the plasma lipoproteins associated with an increased risk of cardiovascular disease SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article; Proceedings Paper CT Meeting on Clinical Significance and Management of Hypertriglyceridemia CY NOV 09, 1998 CL DALLAS, TEXAS ID LOW-DENSITY-LIPOPROTEIN; CORONARY-ARTERY DISEASE; TRIGLYCERIDE-RICH LIPOPROTEINS; APOLIPOPROTEIN-C-III; RECEPTOR-RELATED PROTEIN; ISCHEMIC-HEART-DISEASE; AVERAGE CHOLESTEROL LEVELS; HEPATIC LIPASE ACTIVITY; MIDDLE-AGED MEN; APO A-I AB There is a growing body of evidence from epidemiologic, clinical, and laboratory data that indicates that elevated triglyceride levels are an independent risk fact tor for cardiovascular disease. identification and quantification of atherogenic lipoproteins in patients with hypertriglyceridemia are important steps in the prevention of cardiovascular disease. Increased levels of apoC-III, apoC-I, or apoA-II on the apoB-containing lipoproteins may alter lipoprotein metabolism and result in the accumulation of atherogenic remnants, Hypertriglyceridemic patients at risk for cardiovascular disease often develop a lipoprotein profile characterized by elevated triglyceride, dense LDL, and low HDL cholesterol, Understanding that each of these factors contributes separately to the patient's risk of cardiovascular disease can help physicians provide patients with more effective risk-reduction programs for cardiovascular disease. (C) 1999 by Excerpta Medica, Inc. C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Brewer, HB (reprint author), NHLBI, NIH, Bldg 10,Room 7N115,10 Ctr Dr,MSC 1666, Bethesda, MD 20892 USA. NR 116 TC 52 Z9 55 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 245 WEST 17TH STREET, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAY 13 PY 1999 VL 83 IS 9B SI SI BP 3F EP 12F PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 197EY UT WOS:000080353100002 PM 10357568 ER PT J AU Koechlin, E Basso, G Pietrini, P Panzer, S Grafman, J AF Koechlin, E Basso, G Pietrini, P Panzer, S Grafman, J TI The role of the anterior prefrontal cortex in human cognition SO NATURE LA English DT Article ID WORKING-MEMORY; EPISODIC MEMORY; RETRIEVAL; RECOGNITION; ACTIVATION; SYSTEM; BRAIN; TASK AB Complex problem-solving and planning involve the most anterior part of the frontal lobes including the fronto-polar prefrontal cortex (FPPC)(1-6), which is especially well developed in humans compared with other primates(7,8). The specific role of this region in human cognition, however, is poorly understood. Here we show using functional magnetic resonance imaging, that bilateral regions in the FPPC alone are selectively activated when subjects have to keep in mind a main goal while performing concurrent (sub)goals. Neither keeping in mind a goal over time (working memory) nor successively allocating attentional resources between alternative goals (dual-task performance) could by themselves activate these regions. Our results indicate that the FPPC selectively mediates the human ability to hold in mind goals while exploring and processing secondary goals, a process generally required in planning and reasoning. C1 NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. RP Grafman, J (reprint author), NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. EM jgr@box-j.nih.gov RI Basso, Gianpaolo/A-9208-2012; Koechlin, Etienne/E-5061-2016; OI Basso, Gianpaolo/0000-0002-6245-9402; Grafman, Jordan H./0000-0001-8645-4457 NR 27 TC 567 Z9 575 U1 5 U2 32 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAY 13 PY 1999 VL 399 IS 6732 BP 148 EP 151 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 196XU UT WOS:000080335700049 PM 10335843 ER PT J AU Jacques, PF Selhub, J Bostom, AG Wilson, PWF Rosenberg, IH AF Jacques, PF Selhub, J Bostom, AG Wilson, PWF Rosenberg, IH TI The effect of folic acid fortification on plasma folate and total homocysteine concentrations SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID NEURAL-TUBE DEFECTS; CORONARY HEART-DISEASE; SERUM TOTAL HOMOCYSTEINE; MYOCARDIAL-INFARCTION; VASCULAR-DISEASE; RISK FACTOR; MICROBIOLOGICAL ASSAY; LACTOBACILLUS-CASEI; SUPPLEMENTATION; PREVENTION AB Background In 1996, the Food and Drug Administration issued a regulation requiring all enriched grain products to be fortified with folic acid to reduce the risk of neural-tube defects in newborns. Fortification (140 mu g per 100 g) began in 1996, and the process was essentially complete by mid-1997. Methods To assess the effect of folic acid fortification on folate status, we measured plasma folate and total homocysteine concentrations (a sensitive marker of folate status) using blood samples from the fifth examination (January 1991 to December 1994) of the Framingham Offspring Study cohort for baseline values and the sixth examination (January 1995 to August 1998) for follow-up values. We divided the cohort into two groups on the basis of the date of their follow-up examination: the study group consisted of 350 subjects who were seen after fortification (September 1997 to March 1998), and the control group consisted of 756 subjects who were seen before fortification (January 1995 to September 1996). Results Among the subjects in the study group who did not use vitamin supplements, the mean folate concentrations increased from 4.6 to 10.0 ng per milliliter (11 to 23 nmol per liter) (P<0.001) from the baseline visit to the follow-up visit, and the prevalence of low folate concentrations (<3 ng per milliliter [7 nmol per liter]) decreased from 22.0 to 1.7 percent (P< 0.001). The mean total homocysteine concentration decreased from 10.1 to 9.4 mu mol per liter during this period (P<0.001), and the prevalence of high homocysteine concentrations (>13 mu mol per liter) decreased from 18.7 to 9.8 percent (P<0.001). In the control group, there were no statistically significant changes in concentrations of folate or homocysteine. Conclusions The fortification of enriched grain products with folic acid was associated with a substantial improvement in folate status in a population of middle-aged and older adults. (N Engl J Med 1999;340:1449-54.) (C) 1999, Massachusetts Medical Society. C1 Tufts Univ, USDA, Jean Mayer Human Nutr Res Ctr Aging, Boston, MA 02111 USA. Mem Hosp Rhode Isl, Div Gen Internal Med, Providence, RI USA. NHLBI, Framingham Heart Study, Framingham, MA USA. RP Rosenberg, IH (reprint author), Tufts Univ, USDA, Jean Mayer Human Nutr Res Ctr Aging, 711 Washington St, Boston, MA 02111 USA. FU NHLBI NIH HHS [N01-HC-38038] NR 42 TC 745 Z9 762 U1 1 U2 22 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 13 PY 1999 VL 340 IS 19 BP 1449 EP 1454 DI 10.1056/NEJM199905133401901 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 194MT UT WOS:000080198700001 PM 10320382 ER PT J AU Fananapazir, L AF Fananapazir, L TI Advances in molecular genetics and management of hypertrophic cardiomyopathy SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HEAVY-CHAIN GENE; BETA-CARDIAC MYOSIN; OBSTRUCTIVE CARDIOMYOPATHY; SKELETAL-MUSCLE; SUDDEN-DEATH; MUTATIONS; EXPRESSION; REDUCTION; DISTINCT; DISEASE C1 NHLBI, Sect Clin electrophysiol & Inherited Cardiac Dis, Cardiol Branch, NIH, Bethesda, MD 20892 USA. RP Fananapazir, L (reprint author), NHLBI, Sect Clin electrophysiol & Inherited Cardiac Dis, Cardiol Branch, NIH, Bldg 10,Room 7B14,10 Ctr Dr,MSC 1650, Bethesda, MD 20892 USA. NR 37 TC 29 Z9 41 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 MAY 12 PY 1999 VL 281 IS 18 BP 1746 EP 1752 DI 10.1001/jama.281.18.1746 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 193WR UT WOS:000080161200033 PM 10328076 ER PT J AU Tedeschi, G Bonavita, S Banerjee, TK Virta, A Schiffmann, R AF Tedeschi, G Bonavita, S Banerjee, TK Virta, A Schiffmann, R TI Diffuse central neuronal involvement in Fabry disease - A proton MRS imaging study SO NEUROLOGY LA English DT Article ID MAGNETIC-RESONANCE SPECTROSCOPY; N-ACETYLASPARTATE; RAT-BRAIN; DEGENERATION; STROKE AB Background: The in vivo determination of parenchymal involvement is important to evaluate disease burden. Proton MRS imaging (H-1-MRSI) permits simultaneous measurement of N-acetylaspartate (NA), a putative neuron-specific molecule, choline-containing compounds, creatine-phosphocreatine, and lactate from four 15-mm slices divided into 0.84-mL single-volume elements. Objective: To assess the cortical and subcortical neuropathology in Fabry disease (FD). Methods: Regions of interest (ROIs) were selected from several cortical and subcortical locations in nine FD patients. Mean ROI metabolite ratios were compared with control values. Results: FD patients showed a widespread pattern of cortical and subcortical NA reduction. Seven patients showed discrete MRI abnormalities consisting of white matter hyperintensities or basal ganglia infarcts. Conclusions: We found diffuse neuronal involvement in FD extending beyond the areas of MRI-visible cerebrovascular abnormalities. H-1-MRSI may become useful in therapeutic trials. C1 NINDS, Neuroimaging Branch, NIH, Bethesda, MD 20892 USA. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Tedeschi, G (reprint author), Univ Naples 2, Inst Neurol Sci, Via Pansini 5, I-80131 Naples, Italy. NR 28 TC 37 Z9 39 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAY 12 PY 1999 VL 52 IS 8 BP 1663 EP 1667 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 195DJ UT WOS:000080233600028 PM 10331696 ER PT J AU Luo, G Herrera, AH Horowits, R AF Luo, G Herrera, AH Horowits, R TI Molecular interactions of N-RAP, a nebulin-related protein of striated muscle myotendon junctions and intercalated disks SO BIOCHEMISTRY LA English DT Article ID F-ACTIN-BINDING; INTRAMOLECULAR ASSOCIATION; VINCULIN-BINDING; FOCAL ADHESIONS; SKELETAL-MUSCLE; ACIDIC PHOSPHOLIPIDS; THIN-FILAMENTS; TALIN-BINDING; TAIL DOMAINS; LIM DOMAIN AB N-RAP is a recently discovered muscle-specific protein that is concentrated at the myotendon junctions in skeletal muscle and at the intercalated disks in cardiac muscle. The C-terminal half of N-RAP contains a region with sequence homology to nebulin, while a LIM domain is found at its N-terminus. N-RAP is hypothesized to perform an anchoring function, linking the terminal actin filaments of myofibrils to protein complexes located beneath the sarcolemma. We used a solid-phase assay to screen myofibrillar and junctional proteins for binding to several recombinant fragments of N-RAP; including the nebulin-like super repeat region (N-RAP-SR), the N-terminal half including the LIM domain (N-RAP-NH), and the region of N-RAP between the super repeat region and the LIM domain (N-RAP-IB). Actin is the only myofibrillar protein tested that exhibits specific binding to N-RAP, with high-affinity binding to N-RAP super repeats, and 10-fold weaker binding to N-RAP-IB. In contrast, myosin, isolated myosin heads, tropomyosin, and troponin exhibited no specific interaction with N-RAP domains. A recombinant fragment corresponding to the C-terminal one-fourth of vinculin also binds specifically to N-RAP super repeats, while no specific N-RAP binding activity was observed for other regions of the vinculin molecule. Finally, talin binds with high affinity to the LIM domain of N-RAP. These results support our hypothesis that N-RAP is part of a complex of proteins that anchors the terminal actin filaments of the myofibril to the membrane, and functions in transmitting tension from the myofibrils to the extracellular matrix. C1 NIAMSD, Phys Biol Lab, NIH, Bethesda, MD 20892 USA. RP Horowits, R (reprint author), NIAMSD, Phys Biol Lab, NIH, Bldg 6,Room 408,MSC 2755, Bethesda, MD 20892 USA. NR 47 TC 39 Z9 42 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 11 PY 1999 VL 38 IS 19 BP 6135 EP 6143 DI 10.1021/bi982395t PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 199TW UT WOS:000080500300020 PM 10320340 ER PT J AU Cullinane, C Mazur, SJ Essigmann, JM Phillips, DR Bohr, VA AF Cullinane, C Mazur, SJ Essigmann, JM Phillips, DR Bohr, VA TI Inhibition of RNA polymerase II transcription in human cell extracts by cisplatin DNA damage SO BIOCHEMISTRY LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; ANTITUMOR DRUG CIS-DIAMMINEDICHLOROPLATINUM(II); INTERSTRAND CROSS-LINKS; UPSTREAM BINDING-FACTOR; IN-VITRO; INVITRO TRANSCRIPTION; XERODERMA-PIGMENTOSUM; ALKYLATING-AGENTS; SEQUENCE CONTEXT; PROTEIN COMPLEX AB The anticancer drug cisplatin induces a spectrum of lesions in DNA. The effect of such DNA damage on transcription by RNA polymerase II (RNA pol II) in human cell extracts was investigated at the level of initiation and elongation. RNA pol II transcription directed from the adenovirus major late promoter was inhibited following treatment of the promoter-containing template with increasing concentrations of cisplatin. Furthermore, transcription from an undamaged promoter fragment was depleted in the presence of increasing amounts of cisplatin DNA damage on an exogenous plasmid, suggesting such damage may hijack an essential factor for transcription initiation. The effect of cisplatin damage on RNA pol II elongation was investigated using site-specifically-placed cisplatin adducts. The GTG adduct was an effective block to RNA pol II elongation, inhibiting the polymerase by 80%. In contrast, RNA pol II completely bypassed the cisplatin GG intrastrand adduct. These studies suggest that the inhibition of RNA pol II transcription observed following the treatment of cells with cisplatin is likely to reflect the combined effects of DNA damage at the level of both transcription initiation and elongation. C1 NIA, Mol Genet Lab, Baltimore, MD 21224 USA. La Trobe Univ, Dept Biochem, Bundoora, Vic 3083, Australia. MIT, Dept Chem, Cambridge, MA 02139 USA. MIT, Div Bioengn & Environm Hlth, Cambridge, MA 02139 USA. RP Bohr, VA (reprint author), NIA, Mol Genet Lab, Baltimore, MD 21224 USA. NR 56 TC 64 Z9 66 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 11 PY 1999 VL 38 IS 19 BP 6204 EP 6212 DI 10.1021/bi982685+ PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 199TW UT WOS:000080500300029 PM 10320349 ER PT J AU Koenig, BW Ferretti, JA Gawrisch, K AF Koenig, BW Ferretti, JA Gawrisch, K TI Site-specific deuterium order parameters and membrane-bound behavior of a peptide fragment from the intracellular domain of HIV-1 gp41 SO BIOCHEMISTRY LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; PROTEIN SECONDARY STRUCTURE; CHEMICAL-SHIFT INDEX; X-RAY-DIFFRACTION; ENVELOPE GLYCOPROTEIN; TRANSMEMBRANE PROTEIN; LIPID BILAYERS; NMR-SPECTRA; ANTIBACTERIAL PEPTIDES; PHOSPHOLIPID BILAYER AB The behavior of the cytolytic peptide fragment 828-848 (P828) from the carboxy-terminus of the envelope glycoprotein gp41 of HIV-1 in membranes was investigated by solid-state H-2 NMR on P828 with the selectively deuterated isoleucines I-3, I-13, I-16, and I-20. The quadrupole splittings of the I-3 side chain show significant sensitivity to the main phase-transition temperature of the lipid, consistent with partial penetration of the N-terminal peptide region into the hydrophobic core of the membrane. In contrast, the quadrupole splittings of I-13, I-16, and I-20 are in agreement with a location of the C-terminal portion of the peptide near the lipid/water interface. The perturbation of the bilayer by the peptide was studied by H-2 NMR on sn-1 chain deuterated 1-stearoyl-2-oleoyl-sn-glycero-3-phosphoserine membranes. Peptide incorporation results in a significant reduction of lipid chain order toward the bilayer center, but only a modest reduction near the lipid glycerol. These observations suggest a penetration of the partially structured peptide backbone into the membrane/water interface region that reduces lateral packing density and decreases order in the hydrophobic core. In addition, the structure of the peptide was investigated free in water and bound to SDS micelles by high-resolution NMR. P828 is unstructured in water but exists in a flexible partially helical conformation when bound to negatively charged liposomes or micelles. The flexible helix covers the first 14 residues of the peptide, whereas the C-terminus of the peptide, where three of the six positively charged arginine residues are located, appears to be unstructured. The peptide-induced changes in lipid chain order profiles indicate that membrane curvature stress is the driving force for the cytolytic behavior of P828. C1 NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Gawrisch, K (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, 12420 Parklawn Dr,Room 158, Rockville, MD 20852 USA. RI Koenig, Bernd/B-4315-2008 OI Koenig, Bernd/0000-0002-5300-6276 NR 67 TC 43 Z9 43 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 11 PY 1999 VL 38 IS 19 BP 6327 EP 6334 DI 10.1021/bi982800g PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 199TW UT WOS:000080500300043 PM 10320363 ER PT J AU Kuschel, M Zhou, YY Spurgeon, HA Bartel, S Karczewski, P Zhang, SJ Krause, EG Lakatta, EG Xiao, RP AF Kuschel, M Zhou, YY Spurgeon, HA Bartel, S Karczewski, P Zhang, SJ Krause, EG Lakatta, EG Xiao, RP TI beta(2)-adrenergic cAMP signaling is uncoupled from phosphorylation of cytoplasmic proteins in canine heart SO CIRCULATION LA English DT Article DE receptors, adrenergic, beta; contractility; relaxation; phospholamban; troponin I ID PHOSPHOLAMBAN PHOSPHORYLATION; CALCIUM CHANNELS; AUTORADIOGRAPHIC LOCALIZATION; BETA-ADRENOCEPTORS; ADENYLATE-CYCLASE; CARDIAC MYOCYTES; CA2+ CURRENT; CYCLIC-AMP; TROPONIN-I; STIMULATION AB Background-Recent studies of beta-adrenergic receptor (beta-AR) subtype signaling in in vitro preparations have raised doubts as to whether the cAMP/protein kinase A (PKA) signaling is activated in the same manner in response to beta(2)-AR versus beta(1)-AR stimulation. Methods and Results-The present study compared, in the intact dog, the magnitude and characteristics of chronotropic, inotropic, and lusitropic effects of cAMP accumulation, PKA activation, and PKA-dependent phosphorylation of key effector proteins in response to beta-AR subtype stimulation. In addition, many of these parameters and L-type Ca2+ current (I-Ca) were also measured in single canine ventricular myocytes. The results indicate that although the cAMP/PKA-dependent phosphorylation cascade activated by beta(1)-AR stimulation could explain the resultant modulation of cardiac function, substantial beta(1)-AR-mediated chronotropic, inotropic, and lusitropic responses occurred in the absence of PKA activation and phosphorylation of nonsarcolemmal proteins, including phospholamban, troponin I-Ca C protein, and glycogen phosphorylase kinase. However, in single canine myocytes, we found that beta(2)-AR-stimulated increases in both I-Ca and contraction were abolished by PKA inhibition. Thus, the beta(2)-AR-directed cAMP/PKA signaling modulates sarcolemmal L-type Ca2+ channels but does not regulate PKA-dependent phosphorylation of cytoplasmic proteins. Conclusions-These results indicate that the dissociation of beta(2)-AR signaling from cAMP regulatory systems is only apparent and that beta(2)-AR-stimulated cAMP/PKA signaling is uncoupled from phosphorylation of nonsarcolemmal regulatory proteins involved in excitation-contraction coupling. C1 NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. Max Delbruck Ctr Mol Med, Berlin, Germany. RP Xiao, RP (reprint author), NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 37 TC 80 Z9 86 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 11 PY 1999 VL 99 IS 18 BP 2458 EP 2465 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 193NR UT WOS:000080143300019 PM 10318670 ER PT J AU Koshinuma, M Tajima, K Nakamura, A Gershfeld, NL AF Koshinuma, M Tajima, K Nakamura, A Gershfeld, NL TI Influence of surface charge and hydrocarbon chain length on the sponge-vesicle transformation of an ionized phospholipid SO LANGMUIR LA English DT Article ID AIR-WATER-INTERFACE; THERMODYNAMIC PROPERTIES; BILAYER; TEMPERATURE; STATE AB The influence of charge density and hydrocarbon chain length on the sponge-vesicle transformation of two bilayer-forming ionic phospholipids, the sodium salts of dilauroyl- and dimyristoylphosphatidylglycerol (NaDLPG and NaDMPG), was examined by measuring the solution properties of the lipids in water. The phase diagrams of these compounds in water indicate they undergo a transformation from a transparent, jelly-like sponge phase to unilamellar vesicles at a critical temperature T*; for NaDLPG T* = 19 degrees C, and for NaDMPG T* = 31.6 degrees C. At T > T* multilamellar vesicles form. The Krafft temperature for NaDLPG is similar to 5 degrees C, just above, T-m, the gel-liquid crystal transition temperature, and for NaDMPG it is similar to 32 degrees C, slightly higher than T*. For both lipids, the charge density of the equilibrium monolayers at the air/water interface decreases dramatically as T increases and approaches T*. This effect is attributed to hydrolysis of the phosphate moiety of the lipid. Changes in solubility consistent with a decrease in bilayer charge density at T* are also observed. The transformation from the sponge phase to vesicles at T* is a structural response to the change in bilayer charge density. The results emphasize the importance of bilayer-localized chemical reactions in the transformation of the sponge state to vesicles. C1 NIAMSD, NIH, Bethesda, MD 20892 USA. RP Gershfeld, NL (reprint author), NIAMSD, NIH, Bldg 6,Room 139, Bethesda, MD 20892 USA. EM ngo@cu.nih.gov NR 19 TC 11 Z9 11 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD MAY 11 PY 1999 VL 15 IS 10 BP 3430 EP 3436 DI 10.1021/la981200f PG 7 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 197DT UT WOS:000080349900009 ER PT J AU Basanez, G Nechushtan, A Drozhinin, O Chanturiya, A Choe, E Tutt, S Wood, KA Hsu, YT Zimmerberg, J Youle, RJ AF Basanez, G Nechushtan, A Drozhinin, O Chanturiya, A Choe, E Tutt, S Wood, KA Hsu, YT Zimmerberg, J Youle, RJ TI Bax, but not Bcl-x(L), decreases the lifetime of planar phospholipid bilayer membranes at subnanomolar concentrations SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PROGRAMMED CELL-DEATH; CYTOCHROME-C; PERMEABILITY TRANSITION; ION-CHANNEL; BCL-2; MITOCHONDRIA; APOPTOSIS; RELEASE; PROTEIN; SURVIVAL AB Release of proteins through the outer mitochondrial membrane can be a critical step in apoptosis, and the localization of apoptosis-regulating Bcl-2 family members there suggests they control this process. We used planar phospholipid membranes to test the effect of full-length Bax and Bcl-x(L) synthesized in vitro and native Bax purified from bovine thymocytes. Instead of forming pores with reproducible conductance levels expected for ionic channels, Bax, but not Bcl-xL, created arbitrary and continuously variable changes in membrane permeability and decreased the stability of the membrane, regardless of whether the source of the protein was synthetic or native, This breakdown of the membrane permeability barrier and destabilization of the bilayer was quantified by using membrane lifetime measurements. Bax decreased membrane lifetime in a voltage- and concentration-dependent manner. Bcl-x(L) did not protect against Bax-induced membrane destabilization, supporting the idea that these two proteins function independently. Corresponding to a physical theory for lipidic pore formation, Bax potently diminished the linear tension of the membrane (i.e., the energy required to form the edge of a new pore). We suggest that Bax acts directly by destabilizing the lipid bilayer structure of the outer mitochondrial membrane, promoting the formation of a pore-the apoptotic pore-large enough to allow mitochondrial proteins such as cytochrome c to be released into the cytosol, Bax could then enter and permeabilize the inner mitochondrial membrane through the same hole. C1 NICHHD, Lab Cellular & Mol Biophys, Bethesda, MD 20892 USA. NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Zimmerberg, J (reprint author), NICHHD, Lab Cellular & Mol Biophys, Bethesda, MD 20892 USA. RI Basanez, Gorka/L-9509-2014 OI Basanez, Gorka/0000-0002-7475-7861 NR 35 TC 208 Z9 211 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 MAY 11 PY 1999 VL 96 IS 10 BP 5492 EP 5497 DI 10.1073/pnas.96.10.5492 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 195JG UT WOS:000080246500033 PM 10318911 ER PT J AU Detera-Wadleigh, SD Badner, JA Berrettini, WH Yoshikawa, T Goldin, LR Turner, G Rollins, DY Moses, T Sanders, AR Karkera, JD Esterling, LE Zeng, J Ferraro, TN Guroff, JJ Kazuba, D Maxwell, ME Nurnberger, JI Gershon, ES AF Detera-Wadleigh, SD Badner, JA Berrettini, WH Yoshikawa, T Goldin, LR Turner, G Rollins, DY Moses, T Sanders, AR Karkera, JD Esterling, LE Zeng, J Ferraro, TN Guroff, JJ Kazuba, D Maxwell, ME Nurnberger, JI Gershon, ES TI A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CONTROLLED FAMILY; LINKAGE ANALYSIS; CHROMOSOME-18; SCHIZOPHRENIA; PEDIGREES; ILLNESS; INHERITANCE; ASSOCIATION; PSYCHOSES; TRAITS AB Bipolar disorder is a severe mental illness characterized by mood swings of elation and depression. Family, twin, and adoption studies suggest a complex genetic etiology that may involve multiple susceptibility genes and an environmental component. To identify chromosomal loci contributing to vulnerability, we have conducted a genome-wide scan on approximate to 396 individuals from 22 multiplex pedigrees by using 607 microsatellite markers. Multipoint nonparametric analysis detected the strongest evidence for linkage at 13q32 with a maximal logarithm of odds (lod) score of 3.5 (P = 0.000028) under a phenotype model that included bipolar I, bipolar II with major depression, schizoaffective disorder, and recurrent unipolar disorder, Suggestive linkage was found on 1q31-q32 (lod = 2.67; P = 0.00022) and 18p11.2 (lod = 2.32; P = 0.00054), Recent reports have linked schizophrenia to 13q32 and 18p11.2. Our genome scan identified other interesting regions, 7q31 (lod = 2.08; P = 0.00099) and 22q11-q13 (lod = 2.1; P = 0.00094), and also confirmed reported linkages on 4p16, 12q23-q24, and 21q22. By comprehensive screening of the entire genome, we detected unreported loci for bipolar disorder, found support for proposed linkages, and gained evidence for the overlap of susceptibility regions for bipolar disorder and schizophrenia. C1 NIMH, Clin Neurogenet Branch, NIH, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. Univ Penn, Dept Psychiat, Ctr Neurobiol & Behav, Philadelphia, PA 19104 USA. Indiana Univ, Indianapolis, IN 46202 USA. RP Detera-Wadleigh, SD (reprint author), NIMH, Clin Neurogenet Branch, NIH, Bethesda, MD 20892 USA. OI Nurnberger, John/0000-0002-7674-1767 NR 41 TC 344 Z9 349 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 11 PY 1999 VL 96 IS 10 BP 5604 EP 5609 DI 10.1073/pnas.96.10.5604 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 195JG UT WOS:000080246500053 PM 10318931 ER PT J AU He, XS Rehermann, B Lopez-Labrador, FX Boisvert, J Cheung, R Mumm, J Wedemeyer, H Berenguer, M Wright, TL Davis, MM Greenberg, HB AF He, XS Rehermann, B Lopez-Labrador, FX Boisvert, J Cheung, R Mumm, J Wedemeyer, H Berenguer, M Wright, TL Davis, MM Greenberg, HB TI Quantitative analysis of hepatitis C virus-specific CD8(+) T cells in peripheral blood and liver using peptide-MHC tetramers SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID FLOW-CYTOMETRY; B VIRUS; LYMPHOCYTE RESPONSIVENESS; DIRECT VISUALIZATION; MONOCLONAL-ANTIBODY; VIRAL-HEPATITIS; INFECTION; RESPONSES; HETEROGENEITY; ACTIVATION AB It is believed that the hepatitis C virus (HCV)-specific CD8(+) cytotoxic T lymphocytes (CTLs) play a role in the development of liver cell injury and in the clearance of the virus. To develop a direct binding assay for HCV-specific CTLs, we generated two peptide-MHC tetramers by using the recombinant HLA A2.1 molecule and AZ-restricted T cell epitopes of the HCV NS3 protein, With these reagents we are able to detect specific CD8(+) cells in the blood of 15 of 20 HLA-A2(+), HCV-infected patients, at a frequency ranging from 0.01% to 1.2% of peripheral CD8(+) T cells. Phenotypic analysis of these specific cells indicated that there is a significant variation in the expression of the CD45 isoforms and CD27 in different patients, A 6-hour incubation of one patient's blood with NS3 peptides resulted in the activation of the epitope-specific CD8(+) cells, as indicated by their expression of CD69 and IFN-gamma. We also detected NS3-specific CD8(+) T cells in the intrahepatic lymphocyte population isolated from liver biopsies of two HCV-infected patients. The frequency of these specific CD8(+) cells in the liver was 1-2%, at least 30-fold higher than in the peripheral blood. All of the intrahepatic NS3-specific CD8(+) T cells were CD69(+), suggesting that they were activated CTLs, Direct quantitation and characterization of HCV-specific CTLs should extend our understanding of the immunopathogenesis and the mechanism of clearance or persistence of HCV. C1 Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA. NIDDKD, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94121 USA. RP He, XS (reprint author), Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. FU NIAID NIH HHS [N01AI40034]; NIGMS NIH HHS [GM07276, T32 GM007276] NR 39 TC 331 Z9 344 U1 1 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 11 PY 1999 VL 96 IS 10 BP 5692 EP 5697 DI 10.1073/pnas.96.10.5692 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 195JG UT WOS:000080246500068 PM 10318946 ER PT J AU Zimmer, A Zimmer, AM Hohmann, AG Herkenham, M Bonner, TI AF Zimmer, A Zimmer, AM Hohmann, AG Herkenham, M Bonner, TI TI Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SIGNAL-TRANSDUCTION; MOLECULAR-CLONING; MOUSE-BRAIN; RAT-BRAIN; EXPRESSION; PHARMACOLOGY; BINDING; AGONIST; CELLS; LOCALIZATION AB Delta(9)-Tetrahyhrocannabinol (Delta(9)-THC), the major psychoactive ingredient in preparations of Cannabis sativa (marijuana, hashish), elicits central nervous system (CNS) responses, including cognitive alterations and euphoria. These responses account for the abuse potential of cannabis, while other effects such as analgesia suggest potential medicinal applications. To study the role of the major known target of cannabinoids in the CNS, the CBI cannabinoid receptor, we have produced a mouse strain with a disrupted CB1 gene. CB1 knockout mice appeared healthy and fertile, but they had a significantly increased mortality rate. They also displayed reduced locomotor activity, increased ring catalepsy, and hypoalgesia in hotplate and formalin tests. Delta(9)-THC-induced ring-catalepsy, hypomobility, and hypothermia were completely absent in CBI mutant mice. In contrast, rye still found Delta(9)-THC-induced analgesia in the tail-flick test and other behavioral (licking of the abdomen) and physiological (diarrhea) responses after Delta(9)-THC administration. Thus, most, but not all, CNS effects of Delta(9)-THC are mediated by the CB1 receptor. C1 NIMH, Genet Lab, Bethesda, MD 20892 USA. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Zimmer, A (reprint author), NIMH, Genet Lab, Bldg 36,Room 3D06, Bethesda, MD 20892 USA. RI Zimmer, Andreas/B-8357-2009; OI Herkenham, Miles/0000-0003-2228-4238 NR 51 TC 669 Z9 686 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 MAY 11 PY 1999 VL 96 IS 10 BP 5780 EP 5785 DI 10.1073/pnas.96.10.5780 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 195JG UT WOS:000080246500083 PM 10318961 ER PT J AU Steiner, H Bonner, TI Zimmer, AM Kitai, ST Zimmer, A AF Steiner, H Bonner, TI Zimmer, AM Kitai, ST Zimmer, A TI Altered gene expression in striatal projection neurons in CB1 cannabinoid receptor knockout mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RAT-BRAIN; ENDOGENOUS LIGAND; DOPAMINE NEURONS; MESSENGER-RNA; ANANDAMIDE; LOCALIZATION; DYNORPHIN; BINDING AB The basal ganglia, a brain structure critical for sensorimotor and motivational aspects of behavior, contain very high levels of CB1 cannabinoid receptors, These receptors are activated by endogenous lipophilic ligands, and they are thought to mediate behavioral effects of cannabinoid drugs. To evaluate the role of the endogenous cannabinoid system in the regulation of basal ganglia pathways, we have investigated the effects of targeted deletion of CB1 receptors on gene expression of various neuropeptides and transmitter-related enzymes in basal ganglia neurons. Mice without CB1 receptors are extremely hypoactive in a test for exploratory behavior (open-field test), showing markedly reduced locomotion and rearing. These CB1 mutants display significantly increased levels of substance P, dynorphin, enkephalin, and GAD 67 mRNAs in neurons of the two output pathways of the striatum that project to the substantia nigra and the globus pallidus. Our findings demonstrate that elimination of CB1 receptors results in behavioral abnormalities and functional reorganization of the basal ganglia. C1 NIMH, Genet Lab, Bethesda, MD 20892 USA. Univ Tennessee, Dept Anat & Neurobiol, Coll Med, Memphis, TN 38163 USA. RP Zimmer, A (reprint author), NIMH, Genet Lab, Bldg 36,Room 3D-06, Bethesda, MD 20892 USA. RI Zimmer, Andreas/B-8357-2009 FU NIDA NIH HHS [R29 DA011261, DA11261, R01 DA011261]; NINDS NIH HHS [NS20702, NS26473, R01 NS020702] NR 34 TC 91 Z9 92 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 MAY 11 PY 1999 VL 96 IS 10 BP 5786 EP 5790 DI 10.1073/pnas.96.10.5786 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 195JG UT WOS:000080246500084 PM 10318962 ER PT J AU Yasui, M Kwon, TH Knepper, MA Nielsen, S Agre, P AF Yasui, M Kwon, TH Knepper, MA Nielsen, S Agre, P TI Aquaporin-6: An intracellular vesicle water channel protein in renal epithelia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RAT-KIDNEY; MEMBRANE; CLONING; CHIP28; EXPRESSION; CELLS; FAMILY AB All characterized mammalian aquaporins (AQPs) are localized to plasma membranes where they function chiefly to mediate water transport across cells, Here we show that AQP6 is localized exclusively in intracellular membranes in renal epithelia, By using a polyclonal antibody to the C terminus of AQP6, immunoblots revealed a major 30-kDa band in membranes from rat renal cortex and medulla, Endoglycosidase treatment demonstrated presence of an intracellular high mannose glycan on each subunit, Sequential ultracentrifugation of rat kidney homogenates confirmed that AQP6 resides predominantly in vesicular fractions, and immunohistochemical and immunoelectron microscopic studies confirmed that >98% of AQP6 is located in intracellular membrane vesicles. In glomeruli, AQP6 is present in membrane vesicles within podocyte cell bodies and foot processes. In proximal tubules, AQP6 is also abundant in membrane vesicles within the subapical compartment of segment 2 and segment 3 cells, but was not detected in the brush border or basolateral membranes. In collecting duct, AQP6 resides in intracellular membrane vesicles in apical, mid, and basolateral cytoplasm of type A intercalated cells, but was not observed in the plasma membrane. Unlike other members of the AQP family, the unique distribution in intracellular membrane vesicles in multiple types of renal epithelia indicates that AQP6 is not simply involved in transcellular fluid absorption. Moreover, our studies predict that AQP6 participates in distinct physiological functions such as glomerular filtration, tubular endocytosis, and acid-base metabolism. C1 Univ Aarhus, Dept Cell Biol, DK-8000 Aarhus C, Denmark. Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Nielsen, S (reprint author), Univ Aarhus, Dept Cell Biol, DK-8000 Aarhus C, Denmark. RI Yasui, Masato/L-3312-2013 FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 26 TC 155 Z9 163 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 11 PY 1999 VL 96 IS 10 BP 5808 EP 5813 DI 10.1073/pnas.96.10.5808 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 195JG UT WOS:000080246500088 PM 10318966 ER PT J AU Xu, RH Lechleider, RJ Shih, HM Hao, CF Sredni, D Roberts, AB Kung, HF AF Xu, RH Lechleider, RJ Shih, HM Hao, CF Sredni, D Roberts, AB Kung, HF TI Functional analysis of human Smad1: Role of the amino-terminal domain SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID TGF-BETA SUPERFAMILY; NEURAL INDUCTION; SIGNAL-TRANSDUCTION; VENTRAL MESODERM; TUMOR-SUPPRESSOR; XENOPUS ECTODERM; ACTS DOWNSTREAM; IN-VIVO; RECEPTOR; PROTEINS AB The signals originating from transforming growth factor beta/activin/bone morphogenetic proteins (BMPs) are transduced by a set of evolutionarily conserved family of Smad proteins which, upon activation, directly translocate to the nucleus where they may activate transcription. Smad proteins of different species contain conserved amino- (N) and carboxy- (C) terminal domains separated by a proline-rich linker. Human, Drosophila, and Xenopus Smad1 all have been shown to mediate the biological effects of BMP-4 in Xenopus embryos. We have investigated the functional domains of human Smad1 (hSmad1) using the Xenopus embryo system. Dorsal injection of hSmad1 RNA into the 4-cell-stage embryos results in embryonic ventralization. Since the C-terminus of Smads has been shown to mediate the transcriptional activity, whereas this activity is masked by the presence of the N-terminus, we tested the effect of a hSmad1 construct lacking the C-terminal domain [hSmad1(N)] in the Xenopus embryo system. Surprisingly, we found that hSmad1(N) not only synergizes with hSmad1 in embryonic ventralization, but induces ventralization by itself. Ectopic expression of a dominant negative BMP receptor (DN-BR) as well as neural inducers noggin and chordin induce neurogenesis in the animal cap, which is inhibited by co-expression of either hSmad1 or hSmad1(N). Ventral expression of DN-BR induces formation of a second body axis at tailbud stage, which is also prevented by hSmad1 and hSmad1(N). It has recently been reported that calmodulin interacts with the N-terminal domain of Smad proteins. We demonstrate that the ventralizing activity of hSmad1 and hSmad1(N) is markedly inhibited by calmodulin. Thus, calmodulin acts as a Smad1 inhibitor. A model is proposed to accomodate these findings. (C) 1999 Academic Press. C1 NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res Support Programs, Frederick, MD 21702 USA. NCI, Chemoprevent Lab, Bethesda, MD 20814 USA. Natl Hlth Res Inst, Div Mol & Genom Med, Taipei, Taiwan. NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Lab Biochem Physiol, Frederick, MD 21702 USA. Bar Ilan Univ, Interdisciplinary Dept, IL-52900 Ramat Gan, Israel. Univ Hong Kong, Inst Mol Biol, Pokfulam, Hong Kong. RP Xu, RH (reprint author), NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res Support Programs, Frederick, MD 21702 USA. RI Xu, Ren-He/M-3125-2016 FU NCI NIH HHS [N01-CO-56000] NR 54 TC 10 Z9 10 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 10 PY 1999 VL 258 IS 2 BP 366 EP 373 DI 10.1006/bbrc.1999.0598 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 199VH UT WOS:000080504400025 PM 10329393 ER PT J AU Vogel, K Roche, PA AF Vogel, K Roche, PA TI SNAP-23 and SNAP-25 are palmitoylated in vivo SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID SYNAPTOSOMAL-ASSOCIATED PROTEIN; TRANSPORT AB The neuronal presynaptic membrane t-SNARE complex consists of the transmembrane protein syntaxin with the palmitoylated protein SNAP-25. In nonneuronal tissues, SNAP-23 replaces SNAP-25 in the t-SNARE complex, although the mechanism of membrane anchoring of SNAP-23 has not been determined. We now report that like SNAP-25, SNAP-23 is palmitoylated in vivo on one or more cysteine residues present in a central "palmitoylation domain." Interestingly, SNAP-23 is palmitoylated less well than SNAP-25, and in vivo binding studies indicate a correlation between the extent of palmitoylation and the ability of SNAP-23 or SNAP-25 to bind to syntaxin in vivo. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Roche, PA (reprint author), Bldg 10,Room 4B36, Bethesda, MD 20892 USA. NR 17 TC 67 Z9 69 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 10 PY 1999 VL 258 IS 2 BP 407 EP 410 DI 10.1006/bbrc.1999.0652 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 199VH UT WOS:000080504400032 PM 10329400 ER PT J AU Lee, MK Heaton, J Cho, MW AF Lee, MK Heaton, J Cho, MW TI Identification of determinants of interaction between CXCR4 and gp120 of a dual-tropic HIV-1(DH12) isolate SO VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ENVELOPE V3 LOOP; T-CELL-LINE; CHEMOKINE RECEPTORS; HIV-1 ENTRY; EXTRACELLULAR DOMAINS; CORECEPTOR ACTIVITY; FUSION COFACTORS; DISTINCT CCR5; AIDS RESEARCH AB Using a panel of chimeric viruses and their chimeric envelope glycoproteins, we have previously reported that the V1/V2 or the V3 regions of a dual-tropic primary human immunodeficiency virus type 1 (HIV-1) isolate (HIV-1(DH12)) could individually confer CXCR4 usage when introduced into the backbone of a macrophage-tropic (M-tropic) virus isolate (HIV-1(ADS)). In this study, chimeric CXCR4-CXCR2 chemokine receptors were employed to identify the determinants involved in the interaction between CXCR4 and the dual-tropic HIV-1(DH12) gp120. Our results indicate that (i) HIV-1(DH12) gp120 interacts primarily with the extracellular domains I (El) and 2 (E2) of CXCR4, (ii) the V1/V2 and the V3 regions interact with different domains of CXCR4, and (iii) the V1/V2 region plays a more critical role in the interaction between CXCR4 and HIV-1(DH12) gp120. Combining our data and those of others suggests that the pattern of CXCR4 usage is highly dependent on HIV-1 isolates. In addition, an M-tropic virus may evolve to become dual-tropic by first acquiring the ability to interact with CXCR4 through the V1/V2 region of gp120. C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Cho, MW (reprint author), NIAID, Mol Microbiol Lab, NIH, 9000 Rockville Pike,Bldg 4,Room 339, Bethesda, MD 20892 USA. NR 49 TC 19 Z9 19 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 MAY 10 PY 1999 VL 257 IS 2 BP 290 EP 296 DI 10.1006/viro.1999.9686 PG 7 WC Virology SC Virology GA 198ZL UT WOS:000080454600003 PM 10329539 ER PT J AU Xiang, Y Moss, B AF Xiang, Y Moss, B TI Identification of human and mouse homologs of the MC51L-53L-54L family of secreted glycoproteins encoded by the molluscum contagiosum poxvirus SO VIROLOGY LA English DT Article ID VIRUS; RECEPTORS; PROTEINS; APOPTOSIS; GENOME AB Molluscum contagiosum virus (MCV) is a human poxvirus that produces small, benign skin tumors primarily in young children and encodes proteins that modulate the host immune response. The MC51L, MC53L, and MC54L open reading frames of MCV have significant amino acid sequence similarities and related proteins are encoded by other poxviruses. These three MCV genes were individually expressed in mammalian cells as glycosylated and secreted proteins. A database search detected partial sequences of homologous human and mouse cDNAs; determination of the complete sequences confirmed the homology and indicated potential signal peptides and N-glycosylation sites as well as a pattern of cysteines that are conserved in the viral proteins. The human gene, which was mapped to chromosome 11q13, was highly expressed in spleen and lymph nodes, suggesting an immune modulatory role. The latter finding is consistent with a recent report (Novick at ai., 1999, immunity 10, 127-136) that the human protein binds IL-18, suggesting an anti-inflammatory role for the poxvirus homologs. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. NR 20 TC 39 Z9 40 U1 0 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAY 10 PY 1999 VL 257 IS 2 BP 297 EP 302 DI 10.1006/viro.1999.9676 PG 6 WC Virology SC Virology GA 198ZL UT WOS:000080454600004 PM 10329540 ER PT J AU Qiu, JM Brown, KE AF Qiu, JM Brown, KE TI A 110-kDa nuclear shuttle protein, nucleolin, specifically binds to adeno-associated virus type 2 (AAV-2) capsid SO VIROLOGY LA English DT Article DE nucleolin; adeno-associated virus 2 (AAV-2); binding ID NUCLEOTIDE-SEQUENCE; MINUTE VIRUS; MICE DNA; CELLS; IDENTIFICATION; RNA; SURFACE; ACID; LOCALIZATION; PURIFICATION AB A 110-kDa protein was copurified with adeno-associated virus type 2 (AAV-2) virions after CsCl density gradient isopycnic centrifugation. Amino acid sequence of peptides derived from this protein after tryptic digestion, monoclonal antibody production, and Western blot analysis showed that the copurified protein was the major nucleolar phosphoprotein, human nucleolin. Virus overlay assays demonstrated that AAV-2 capsid specifically bound to the human nucleolin, and immunoprecipitation studies confirmed the in vitro binding of nucleolin and intact AAV-2 capsids but not denatured viral proteins. Double-immunofluorescence staining of infected cells showed that AAV capsid and nucleolin were colocalized in both cytoplasm and nucleus. In addition, when cytoplasmic and nuclear fractions were extracted from AAV-infected KB cells at different time points postinfection, immunoprecipitation data and Western blotting showed that AAV capsid formation and nucleolin interact specifically and share their subcellular localization in infected cells. With the known functions of nucleolin in the synthesis of rRNA and ribosome assembly, binding to single-stranded DNA, and acting as a shuttle between cytoplasm and nucleolus, our data showing that AAV-2 capsid binds specifically to nucleolin both in vitro and in vivo suggest a key role of nucleolin in AAV-2 replication, particularly in capsid assembly. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Qiu, JM (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Room 7C218,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 43 TC 44 Z9 44 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 MAY 10 PY 1999 VL 257 IS 2 BP 373 EP 382 DI 10.1006/viro.1999.9664 PG 10 WC Virology SC Virology GA 198ZL UT WOS:000080454600012 PM 10329548 ER PT J AU Berezhkovskii, AM Szabo, A Weiss, GH AF Berezhkovskii, AM Szabo, A Weiss, GH TI Theory of single-molecule fluorescence spectroscopy of two-state systems SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article AB We derive an explicit expression for the probability density of the amplitudes of the biexponential fluorescence decay of a two-state system observed in single-molecule experiments of finite duration T. The shape of the probability density of the amplitudes depends on (k(1) + k(2))T, where the k(i) are the interconversion rate constants. It approaches a delta function in the limit T --> infinity. When the interconversion rates in the ground and excited states differ, the single-molecule and bulk experiments will give different results even in the limit of infinite duration of the experiment. (C) 1999 American Institute of Physics. [S0021-9606(99)00318-9]. C1 NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. LY Karpov Phys Chem Res Inst, Moscow 103064, Russia. NIDDK, Chem Phys Lab, Bethesda, MD 20892 USA. RP Berezhkovskii, AM (reprint author), NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. RI Szabo, Attila/H-3867-2012 NR 9 TC 76 Z9 77 U1 1 U2 6 PU AMER INST PHYSICS PI WOODBURY PA CIRCULATION FULFILLMENT DIV, 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2999 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD MAY 8 PY 1999 VL 110 IS 18 BP 9145 EP 9150 DI 10.1063/1.478836 PG 6 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 192HU UT WOS:000080073200035 ER PT J AU Zhang, LJ Kim, M Choi, YH Goemans, B Yeung, C Hu, ZY Zhan, SL Seth, P Helman, LJ AF Zhang, LJ Kim, M Choi, YH Goemans, B Yeung, C Hu, ZY Zhan, SL Seth, P Helman, LJ TI Diminished G(1) checkpoint after gamma-irradiation and altered cell cycle regulation by insulin-like growth factor II overexpression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INHIBITOR P21 GENE; NIH 3T3 CELLS; P53-INDEPENDENT EXPRESSION; DEPENDENT KINASES; PHASE-TRANSITION; PROTEIN-KINASES; CANCER CELLS; D1; PROGRESSION; DIFFERENTIATION AB High levels of insulin-like growth factor II (IGFII) mRNA expression are detected in many human tumors of different origins including rhabdomyosarcoma, a tumor of skeletal muscle origin. To investigate the role of IGFII in tumorigenesis, we have compared the mouse myoblast cell line C2C12-2.7, which was stably transfected with human IGFII cDNA and expressed high and constant amounts of IGFII, to a control cell line C2C12-1.1, A rhabdomyosarcoma cell line, RH30, which expresses high levels of IGFII and contains mutated p53, was also used in these studies. IGFII overexpression in mouse myoblast C2C12 cells causes a reduced cycling time and higher growth rate. After gamma-irradiation treatment, C2C12-1.1 cells were arrested mainly in G(0)/G(1) phase. However, C2C12-2.7 and RH30 cells went through a very short G(1) phase and then were arrested in an extended G(2)/M phase. To verify further the effect of IGFII on the cell cycle, we developed a Chinese hamster ovary (CHO) cell line with tetracycline-controlled IGFII expression. We found that CHO cells with high expression of IGFII have a shortened cycling time and a diminished G(1) checkpoint after treatment with methylmethane sulfonate (MMS), a DNA base-damaging agent, when compared with CHO cells with very low IGFII expression, It was also found that IGFII overexpression in C2C12 cells was associated with increases in cyclin D1, p21, and p53 protein levels, as well as mitogen-activated protein kinase activity, These studies suggest that IGFII overexpression shortens cell cycling time and diminishes the G(1) checkpoint after DNA damage despite an intact p53/p21 induction. In addition, IGFII overexpression is also associated with multiple changes in the levels and activities of cell cycle regulatory components following gamma-irradiation, Taken together, these changes may contribute to the high growth rate and genetic alterations that occur during tumorigenesis. C1 NCI, Mol Oncol Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Med Breast Canc Sect, NIH, Bethesda, MD 20892 USA. NCI, Cell Signalling & Oncogenesis Sect, NIH, Bethesda, MD 20892 USA. NIDDK, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. RP Helman, LJ (reprint author), NCI, Mol Oncol Sect, Pediat Oncol Branch, NIH, Bldg 10,Rm 13N240, Bethesda, MD 20892 USA. NR 57 TC 18 Z9 18 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 7 PY 1999 VL 274 IS 19 BP 13118 EP 13126 DI 10.1074/jbc.274.19.13118 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 194NL UT WOS:000080200400027 PM 10224065 ER PT J AU Yang, F Bewley, CA Louis, JM Gustafson, KR Boyd, MR Gronenborn, AM Clore, GM Wlodawer, A AF Yang, F Bewley, CA Louis, JM Gustafson, KR Boyd, MR Gronenborn, AM Clore, GM Wlodawer, A TI Crystal structure of cyanovirin-N, a potent HIV-inactivating protein, shows unexpected domain swapping SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE human immunodeficiency virus; virucides; cyanovirin-N; domain swapping; protein structure ID MACROMOLECULAR STRUCTURE DETERMINATION; NMR; RESOLUTION; CRYSTALLOGRAPHY; CYANOBACTERIUM; REFINEMENT; MECHANISM; DIFFUSION; MODE AB The crystal structure of cyanovirin-N (CV-N), a protein with potent antiviral activity, was solved at 1.5 Angstrom resolution by molecular replacement using as the search model the solution structure previously determined by NMR. The crystals belong to the space group P3(2)21 with one monomer of CV-N in each asymmetric unit. The primary structure of CV-N contains 101 residues organized in two domains, A (residues 1 to 50) and B (residues 51 to 101), with a high degree of internal sequence and structural similarity. We found that under the conditions of the crystallographic experiments (low pH and 26 % isopropanol), two symmetrically related monomers form a dimer by domain swapping, such that domain A of one monomer interacts with domain B' of its crystallographic symmetry mate and vice versa. Because the two swapped domains are distant from each other, domain swapping does not result in additional intramolecular interactions. Even though one of the protein sample solutions that was used for crystallization clearly contained 100% monomeric CV-N molecules, as judged by various methods, we were only able to obtain crystals containing domain-swapped dimers. With the exception of the unexpected phenomenon of domain swapping, the crystal structure of CV-N is very similar to the NMR structure, with a root-mean-square deviation of 0.55 Angstrom for the main-chain atoms, the best agreement reported to date for structures solved using both techniques. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Macromol Struct Lab, Frederick, MD 21702 USA. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NCI, Lab Drug Discovery Res & Dev DTP, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Wlodawer, A (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Macromol Struct Lab, Frederick, MD 21702 USA. RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 NR 32 TC 121 Z9 127 U1 1 U2 9 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 MAY 7 PY 1999 VL 288 IS 3 BP 403 EP 412 DI 10.1006/jmbi.1999.2693 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 194QG UT WOS:000080204600008 PM 10329150 ER PT J AU Segel, DJ Bachmann, A Hofrichter, J Hodgson, KO Doniach, S Kiefhaber, T AF Segel, DJ Bachmann, A Hofrichter, J Hodgson, KO Doniach, S Kiefhaber, T TI Characterization of transient intermediates in lysozyme folding with time-resolved small-angle X-ray scattering SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE SAXS; protein folding; folding intermediates; folding kinetics; lysozyme ID EGG-WHITE LYSOZYME; HEN LYSOZYME; ALPHA-LACTALBUMIN; KINETICS; STATES; DIFFRACTION; PROTEINS; PATHWAY AB We have used synchrotron radiation, together with stopped-flow and continuous-flow mixing techniques to monitor refolding of lysozyme at pH 5.2. From data measured at times which range from 14 ms to two seconds, we can monitor changes in the size, the shape and the pair distribution function of the polypeptide chain during the folding process. Comparison of the results with the properties of native and GdmCl-unfolded lysozyme shows that a major chain collapse occurs in the deadtime of mixing. During this process about 50 % of the change in radius of gyration between the unfolded protein and the native state occurs and the polypeptide chain adopts a globular shape. Time-resolved fluorescence spectra of this collapsed state suggest that the hydrophobic sidechains are still highly solvent accessible. A subsequently formed intermediate with helical structure in the cc-domain is nearly identical in size and shape with native lysozyme and has a solvent-inaccessible hydrophobic core. Despite its native-like properties, this intermediate is only slightly more stable (Delta G(0) = - 4 kJ/mol) than the collapsed state and still much less stable than native lysozyme (Delta Delta G(0) = 36 kJ/mol) at 20 degrees C. (C) 1999 Academic Press. C1 Stanford Univ, Dept Phys, Stanford, CA 94305 USA. Univ Basel, Dept Biophys Chem, Biozentrum, CH-4056 Basel, Switzerland. NIH, Chem Phys Lab, Bethesda, MD 20892 USA. Stanford Univ, Dept Chem, Stanford, CA 94305 USA. Stanford Synchrotron Radiat Lab, Stanford, CA 94309 USA. RP Doniach, S (reprint author), Stanford Univ, Dept Phys, Stanford, CA 94305 USA. RI Kiefhaber, Thomas/A-3028-2010 NR 30 TC 134 Z9 136 U1 3 U2 21 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 MAY 7 PY 1999 VL 288 IS 3 BP 489 EP 499 DI 10.1006/jmbi.1999.2703 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 194QG UT WOS:000080204600014 PM 10329156 ER PT J AU Aringer, M Cheng, A Nelson, JW Chen, M Sudarshan, C Zhou, YJ O'Shea, JJ AF Aringer, M Cheng, A Nelson, JW Chen, M Sudarshan, C Zhou, YJ O'Shea, JJ TI Janus kinases and their role in growth and disease SO LIFE SCIENCES LA English DT Review DE interferons; interleukins; cytokine receptors; signal transduction; Janus kinases ID SEVERE COMBINED IMMUNODEFICIENCY; PROTEIN-TYROSINE KINASES; RECEPTOR-GAMMA-CHAIN; SIGNAL-TRANSDUCTION PATHWAY; JAK-STAT PATHWAY; HUMAN B-CELLS; DEFECTIVE LYMPHOID DEVELOPMENT; MICE LACKING JAK3; T-CELLS; INTERFERON-ALPHA/BETA AB Janus kinases (JAK) play a crucial role in the initial steps of cytokine signaling. Each of the four members (JAK1, JAK2, JAK3, TYK2) of this non-receptor tyrosine kinase family is indispensable for the effects of distinct cytokines. Moreover, recent reports have added to our knowledge on their highly specific functions: JAK3 knockout mice and JAK3 deficient patients cannot signal through the interleukin-2,4,7,9, or 15 receptors and suffer from severe combined immunodeficiency (SCID). JAK1 and JAK2 knockout mice do not survive, their cells again showing distinct patterns of cytokine signaling deficits. At the other end of the spectrum, JAK fusion proteins have been shown to play a role in leukemias. In addition, a new class of JAK-specific inhibitors was described by several groups, the CIS/SOCS/Jab family. This review on the rapidly growing field focuses on JAK function and regulation, and on their emerging role in development and human disease. C1 NIAMSD, Lymphocyte Biol Sect, Arthrit & Rheumatism Branch,Howard Hughes Med Ins, NIH,Natl Inst Hlth Res Scholars Program, Bethesda, MD 20892 USA. RP O'Shea, JJ (reprint author), NIAMSD, Lymphocyte Biol Sect, Arthrit & Rheumatism Branch,Howard Hughes Med Ins, NIH,Natl Inst Hlth Res Scholars Program, 10 Ctr Dr,MSC 1820, Bethesda, MD 20892 USA. NR 110 TC 47 Z9 49 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD MAY 7 PY 1999 VL 64 IS 24 BP 2173 EP 2186 DI 10.1016/S0024-3205(98)00538-4 PG 14 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 196TE UT WOS:000080323000001 PM 10374907 ER PT J AU Liu, D Smith, CL Barone, FC Ellison, JA Lysko, PG Li, K Simpson, IA AF Liu, D Smith, CL Barone, FC Ellison, JA Lysko, PG Li, K Simpson, IA TI Astrocytic demise precedes delayed neuronal death in focal ischemic rat brain SO MOLECULAR BRAIN RESEARCH LA English DT Article DE cerebral ischemia; astroglia; neuronal death; GFAP and GLUT3 mRNA ID CEREBRAL-ARTERY OCCLUSION; FIBRILLARY ACIDIC PROTEIN; FORUM POSITION PAPER; DNA FRAGMENTATION; HYPOXIA-ISCHEMIA; GLOBAL-ISCHEMIA; APOPTOSIS; OLIGODENDROCYTES; GLUTATHIONE; EXPRESSION AB Active neuronal-glial interaction is important in the maintenance of brain homeostasis and is vital for neuronal survival following brain injury. The time course of post-ischemic astroglial dysfunction and neuronal death was studied in the spontaneously hypertensive rat (SHR) brain following permanent middle cerebral artery occlusion (MCAO). In situ hybridization with S-35-labeled riboprobes for GFAP and GLUT3 was used to monitor mRNA expression in glia and neurons. Astrocytic proteins GFAP, vimentin, S100, Glutathione-S-Transferase Y-b (GST Y-b) and neuronal protein TG2 were detected by immunofluorescence. Cells were co-stained with in situ end labeling (ISEL) to detect DNA fragmentation, a hallmark of cell death. GFAP mRNA expression declined rapidly in the ischemic region of the cortex and was almost absent by 12 h. Immunohistochemical studies revealed a parallel decline in the corresponding protein: a reduction in GFAP staining was apparent in the infarct after 3 h and by 24 h, there was essentially no remaining GFAP. Three other glial proteins (vimentin, S100 and GST Y-b) disappeared from infarct over a similar time course. A few ISEL positive cells were observed in the infarct at 6 h, but maximal detection was not seen until 24-48 h. Most of the ISEL-positive cells were neurons, identified by co-staining with the neuronal marker TG2. Few cells expressing GFAP or other glial markers were positive at any time point. Neuronal GLUT3 mRNA declined more slowly than GFAP mRNA in the ischemic core and disappeared during the period of neuronal death. Concurrent with the loss of GFAP mRNA and protein expression in the infarct, there was a rapid rise in GFAP mRNA in the peri-infarct region of ipsilateral hemisphere and proximal region of the contralateral hemisphere. This was followed by the enhanced GFAP protein expression characteristic of reactive astrocytes, but over a significantly slower time course. These studies show that MCAO leads to a rapid decline of GFAP mRNA and glial proteins, which appears to precede the decline in neuronal mRNA and neuronal death within the infarct. Early astroglial dysfunction may play a critical role in determining the outcome of acute hypoxic-ischemic injury by compromising neuronal-glial interactions. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIDDK, EDMNS, DB, NIH, Bethesda, MD 20892 USA. NINDS, NIH, Bethesda, MD 20892 USA. SmithKline Beecham Pharmaceut, King Of Prussia, PA 19406 USA. Hershey Med Ctr, Hershey, PA 17033 USA. RP Simpson, IA (reprint author), NIDDK, EDMNS, DB, NIH, Rm 5N102,Bldg 10,10 Ctr Dr,MSC 1420, Bethesda, MD 20892 USA. NR 39 TC 83 Z9 86 U1 1 U2 4 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 MAY 7 PY 1999 VL 68 IS 1-2 BP 29 EP 41 DI 10.1016/S0169-328X(99)00063-7 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 197JB UT WOS:000080360700004 ER PT J AU Ma, XM Aguilera, G AF Ma, XM Aguilera, G TI Transcriptional responses of the vasopressin and corticotropin-releasing hormone genes to acute and repeated intraperitoneal hypertonic saline injection in rats SO MOLECULAR BRAIN RESEARCH LA English DT Article DE corticotropin releasing hormone; vasopressin; hypothalamic paraventricular nucleus; heteronuclear RNA; stress ID PITUITARY-ADRENAL AXIS; RECEPTOR MESSENGER-RNA; ARGININE-VASOPRESSIN; GLUCOCORTICOID RECEPTOR; PARAVENTRICULAR NUCLEUS; CHRONIC STRESS; HETERONUCLEAR RNA; RAPID CHANGES; NEUROSECRETORY NEURONS; IMMOBILIZATION STRESS AB The contribution of corticotropin releasing hormone (CRH) and vasopressin (VP) to the adaptation of ACTH responses to chronic stress was studied by analysis of CRH and VP expression in the hypothalamic paraventricular nucleus (PVN) of rats receiving acute or chronic i.p. hypertonic saline injection (ipHS), a stress model in which the HPA axis is not desensitized after repeated stimulation. Repeated ipHS for 14 days had no effect on CRH hnRNA levels but increased CRH mRNA levels by 42.2%. Parallel with preserved plasma corticosterone responses to repeated ipHS, CRH hnRNA responses and CRH mRNA response to the last injection in repeatedly stressed rats were identical to those in naive rats (8.6-fold increase by 15 min, returning to basal level by 1 h). Parvocellular VP hnRNA responses to a single ipHS were slower and more prolonged than for CRH(7.1-, 11.5-, 9.8- and 4.6-fold by 1, 2, 4 and 6 h), and VP mRNA levels increased by 4 h and remained elevated 12 h later. Parvocellular VP hnRNA was at basal levels after 14 days ipHS, but VP mRNA levels remained elevated as during acute stimulation. Despite high basal mRNA levels, VP hnRNA responses to the last repeated ipHS were minor, suggesting increases in mRNA stability. This study shows that conserved pituitary ACTH responsiveness to a homotypical repeated stress is associated with the ability of parvocellular PVN neurons to increase CRH transcription after repeated stimulation. (C) 1999 Published by Elsevier Science B.V. All rights reserved. C1 NICHHD, Dev Endocrinol Branch, Sect Endocrine Physiol, NIH, Bethesda, MD 20892 USA. RP Aguilera, G (reprint author), NICHHD, Dev Endocrinol Branch, Sect Endocrine Physiol, NIH, Bldg 10,Room 10N262, Bethesda, MD 20892 USA. NR 43 TC 50 Z9 51 U1 0 U2 2 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 MAY 7 PY 1999 VL 68 IS 1-2 BP 129 EP 140 DI 10.1016/S0169-328X(99)00080-7 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 197JB UT WOS:000080360700013 ER PT J AU Brady, LS Herkenham, M Rothman, RB Partilla, JS Konig, M Zimmer, AM Zimmer, A AF Brady, LS Herkenham, M Rothman, RB Partilla, JS Konig, M Zimmer, AM Zimmer, A TI Region-specific up-regulation of opioid receptor binding in enkephalin knockout mice SO MOLECULAR BRAIN RESEARCH LA English DT Article DE opioid receptor; enkephalin; knockout; amygdala; hypothalamus; autoradiography ID CHRONIC NALTREXONE TREATMENT; RAT-BRAIN; OPIATE RECEPTORS; PEPTIDES; SITES; PROENKEPHALIN; LIGANDS; ANALOGS; MOUSE AB Mn and delta opioid receptors were labeled in enkephalin knockout mice by quantitative autoradiography. Discrete, large increases (100-300%) were found in limbic forebrain structures for mu binding and striatum and pallidum for delta binding. The up-regulation of opioid receptors may reflect a form of 'denervation supersensitivity.' The receptor up-regulation in limbic areas is consistent with the increased emotional and aggressive behaviors observed in the enkephalin knockout mice. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIMH, Intramural Res Program, Funct Neuroanat Sect, Bethesda, MD 20892 USA. NIMH, Intramural Res Program, Genet Lab, Bethesda, MD 20892 USA. NIDA, Div Intramural Res, Clin Psychopharmacol Sect, Baltimore, MD 21224 USA. RP Herkenham, M (reprint author), NIMH, Intramural Res Program, Funct Neuroanat Sect, Bethesda, MD 20892 USA. RI Zimmer, Andreas/B-8357-2009; OI Herkenham, Miles/0000-0003-2228-4238 NR 22 TC 38 Z9 38 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 MAY 7 PY 1999 VL 68 IS 1-2 BP 193 EP 197 DI 10.1016/S0169-328X(99)00090-X PG 5 WC Neurosciences SC Neurosciences & Neurology GA 197JB UT WOS:000080360700021 ER PT J AU Kalab, P Pu, RT Dasso, M AF Kalab, P Pu, RT Dasso, M TI The Ran GTPase regulates mitotic spindle assembly SO CURRENT BIOLOGY LA English DT Article ID NUCLEAR-PROTEIN IMPORT; GAMMA-TUBULIN; IN-VITRO; FORM; RCC1 AB Ran is an abundant nuclear GTPase with a clear role in nuclear transport during interphase [1] but with roles in mitotic regulation that are less well understood [2], The nucleotide-binding state of Ran is regulated by a GTPase activating protein, RanGAP1, and by a guanine nucleotide exchange factor, RCC1, Ran also interacts with a guanine nucleotide dissociation inhibitor, RanBP1, RanBP1 has a high affinity for GTP-bound Ran, and it acts as a cofactor for RanGAP1, increasing the rate of GAP-mediated GTP hydrolysis on Ran approximately tenfold [3]. RanBP1 levels oscillate during the cell cycle [4], and increased concentrations of RanBP1 prolong mitosis in mammalian cells [4] and in Xenopus egg extracts (our unpublished observations). We investigated how increased concentrations of RanBP1 disturb mitosis, We found that spindle assembly is dramatically disrupted when exogenous RanBP1 is added to M phase Xenopus egg extracts. We present evidence that the role of Ran in spindle assembly is independent of nuclear transport and is probably mediated through changes in microtubule dynamics. C1 NICHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. RP Dasso, M (reprint author), NICHD, Mol Embryol Lab, NIH, Bldg 18,Room 106, Bethesda, MD 20892 USA. RI Kalab, Petr/B-2478-2009; OI Dasso, Mary/0000-0002-5410-1371 NR 16 TC 236 Z9 243 U1 0 U2 4 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD MAY 6 PY 1999 VL 9 IS 9 BP 481 EP 484 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 195DB UT WOS:000080232900016 PM 10322113 ER PT J AU Lang, LX Jagoda, E Schmall, B Vuong, BK Adams, HR Nelson, DL Carson, RE Eckelman, WC AF Lang, LX Jagoda, E Schmall, B Vuong, BK Adams, HR Nelson, DL Carson, RE Eckelman, WC TI Development of fluorine-18-labeled 5-HT1A antagonists SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID IN-VIVO; RECEPTOR ANTAGONIST; H-3 WAY-100635; RAT-BRAIN; P-MPPI; PET; BINDING; RADIOLIGAND; DELINEATION; LIGAND AB We have synthesized five fluorinated derivatives of WAY 100635, N-{2-[4-(2-methoxyphenyl)piperazino]ethyl)-N-(2-pyridyl)cyclohexanecarboxamide (4a), using various acids in place of the cyclohexanecarboxylic acid (CHCA, 2a) in the reaction scheme. The five acids are 4-fluorobenzoic acid (FB, 2b), 4-fluoro-3-methylbenzoic acid (MeFB, 2c), trans-4-fluorocyclohexanecarboxylic acid (FC, 2d), 4-(fluoromethyl)benzoic acid (FMeB, 2e), and 3-nitro-4-(fluoromethyl)benzoic acid (NFMeB, 2f) (see Scheme 1). These compounds were radiolabeled with fluorine-18, and their biological properties were evaluated in rats and compared with those of [C-11]carbonyl WAY 100635 ([carbonyl-C-11]4a), [Carbonyl-C-11]4a cleared the brain with a biological half-life averaging 41 min. The metabolite-corrected blood radioactivity had a half-life of 29 min. [F-18]FCWAY ([F-18]4d) gave half-lives and intercepts comparable to [carbonyl-C-11]4a in the brain, but the blood clearance was faster. [F-18]FBWAY ([F-18]4b) showed an early rapid net efflux from the whole brain, clearing with a biological half-life of 35 min. The metabolite-corrected blood half-life was 41 min. The comparable whole brain and blood half-lives for Me[F-18]FBWAY ([F-18]4c) were 16 and 18 min, respectively. For each compound, the corresponding carboxylic acid was identified as a major metabolite in blood. Fluoride was also found after injection of [F-18]4d. However, for all compounds there was a good correlation (R > 0.97) between the differential uptake ratio (DUR, (%ID/g) x body weight (g)/100) in individual rat brain regions at 30 min after injection and the concentration of receptors as determined by in vitro quantitative autoradiography in rat. Specific binding ratios [region of interest (ROI)/ cerebellum-1] in control studies for cortex (Ctx) and hippocampus (H) were higher for [carbonyl-C-11]4a and [F-18]4d compared to [F-18]4b and [F-18]4c. [F-18]4d has similar pharmacokinetic properties and comparable specific binding ratios to [carbonyl-11C]4a. Fifty nanomoles of 4a blocked only 30% of the specific binding of [F-18]4d, while complete blockade was obtained from co-injection of 200 nmol of 4a (H/Cb-1 from 17.2 to 0.6). [F-18]4b and [F-18]4c showed lower specific binding ratios than [carbonyl-C-11]4a and [F-18]4d. [F-18]4c was superior to [F-18]4b since its specific binding was more readily blocked by 4a. These studies suggest that [F-18]4c should be a useful compound to assess dynamic changes in serotonin levels while [F-18]4d, with its high contrast and F-18 label, should provide better statistics and quantification for static measurement of 5-HT1A receptor distribution. C1 NIH, Ctr Clin, Positron Emiss Tomog Dept, Bethesda, MD 20892 USA. Eli Lilly & Co, Indianapolis, IN 46285 USA. RP Lang, LX (reprint author), NIH, Ctr Clin, Positron Emiss Tomog Dept, Bldg 10,10 Ctr Dr,Rm 1C497,MSC1180, Bethesda, MD 20892 USA. RI Carson, Richard/H-3250-2011 OI Carson, Richard/0000-0002-9338-7966 FU NIMH NIH HHS [N01MH2003] NR 31 TC 88 Z9 88 U1 1 U2 4 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 MAY 6 PY 1999 VL 42 IS 9 BP 1576 EP 1586 DI 10.1021/jm980456f PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 193XP UT WOS:000080163300009 PM 10229627 ER PT J AU Meier, C Knispel, T Marquez, VE Siddiqui, MA De Clercq, E Balzarini, J AF Meier, C Knispel, T Marquez, VE Siddiqui, MA De Clercq, E Balzarini, J TI cycloSal-pronucleotides of 2 '-fluoro-ara- and 2 '-fluoro-ribo-2 ',3 '-dideoxyadenosine as a strategy to bypass a metabolic blockade SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE NUCLEOSIDE MONOPHOSPHATES; HUMAN LYMPHOID-CELLS; 2',3'-DIDEOXYNUCLEOSIDE ANALOGS; CELLULAR PHARMACOLOGY; PARTITION-COEFFICIENT; ADENOSINE-DEAMINASE; MITOCHONDRIAL-DNA; PRO-NUCLEOTIDES; RETENTION TIME AB Novel, lipophilic cycloSal triesters 4a-c and 5a-c were synthesized, respectively, from the ara- and ribo-configurated 2'-fluorinated-2',3'-dideoxyadenosines 2 and 3. The cycloSal phosphotriesters were used as tools to study the effects of the two different sugar pucker conformations induced by two opposite configurations of the fluorine substituent at C2' of the dideoxyribose moiety. F-ara-ddA (2) is known to be an active anti-HIV agent, whereas the ribo-analogue 3 is inactive. Hydrolysis studies with the triester precursors 4a-c and 5a-c showed selective formation of the monophosphates of 2 and 3. The lipophilicity of the triester prodrugs was considerably increased by the cycloSal mask with respect to ddA (1), F-ara-ddA (2), and F-ribo-ddA (3). Phosphotriesters 4 and 5 proved to be completely resistant to ADA and AMPDA deamination. In parallel experiments, ribo-nucleoside 3 showed a 50-fold faster deamination rate relative to the ara-analogue 2. Against HIV in CEM cells, the phosphotriesters 4 proved to be 10-fold more potent than the parent nucleoside 2. Furthermore, the prodrugs 4 were active against MSV-induced transformation of C3H/3T3 fibroblasts, while 2 was inactive. More interestingly, the ribo-configurated phosphotriesters 5, prepared from the inactive F-ribo-ddA (3), showed a level of anti-HIV activity that was even higher than that of F-ara-ddA (2). Our findings clearly prove that the application of the cycloSal-pronucleotide concept to F-ribo-ddA (3) overcomes a metabolic blockade in the formation of the corresponding monophosphate. C1 Univ Wurzburg, Inst Organ Chem, D-97074 Wurzburg, Germany. Katholieke Univ Leuven, Rega Inst Med Res, B-3000 Louvain, Belgium. NCI, NIH, Bethesda, MD 20892 USA. RP Meier, C (reprint author), Univ Hamburg, Inst Organ Chem, Martin Luther King 6, D-20146 Hamburg, Germany. NR 54 TC 54 Z9 56 U1 0 U2 9 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 MAY 6 PY 1999 VL 42 IS 9 BP 1615 EP 1624 DI 10.1021/jm981097r PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 193XP UT WOS:000080163300012 PM 10229630 ER PT J AU Nandanan, E Camaioni, E Jang, SY Kim, YC Cristalli, G Herdewijn, P Secrist, JA Tiwari, KN Mohanram, A Harden, TK Boyer, JL Jacobson, KA AF Nandanan, E Camaioni, E Jang, SY Kim, YC Cristalli, G Herdewijn, P Secrist, JA Tiwari, KN Mohanram, A Harden, TK Boyer, JL Jacobson, KA TI Structure-activity relationships of bisphosphate nucleotide derivatives as P2Y(1) receptor antagonists and partial agonists SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ACID RELATED-COMPOUNDS; PHOSPHOLIPASE-C; P-2Y-PURINOCEPTOR AGONISTS; POTENT ANTAGONISTS; PURINE NUCLEOSIDES; ADENYLYL-CYCLASE; ADENOSINE; IDENTIFICATION; CLONING; ACTIVATION AB The P2Y(1) receptor is present in the heart, in skeletal and various smooth muscles, and in platelets, where its activation is linked to aggregation. Adenosine 3',5'- and 2',5'-bisphosphates have been identified as selective antagonists at the P2Y1 receptor (Boyer et al. Mel. Pharmacol. 1996, 50, 1323-1329) and have been modified structurally to increase receptor affinity (Camaioni et al. J. Med. Chem. 1998, 41, 183-190). We have extended the structure-activity relationships to a new series of deoxyadenosine bisphosphates with substitutions in the adenine base, ribose moiety, and phosphate groups. The activity of each analogue at P2Y1 receptors was determined by measuring its capacity to stimulate phospholipase C in turkey erythrocyte membranes (agonist effect) and to inhibit phospholipase C stimulation elicited by 10 nM 2-(methylthio)adenosine 5'-diphosphate (antagonist effect). 2'-Deoxyadenosine bisphosphate analogues containing halo, amino, and thioether groups at the 2-position of the adenine ring were more potent P2Y1 receptor antagonists than analogues containing various heteroatom substitutions at the 8-position. An N-6-methyl-2-chloro analogue, 6, was a full antagonist and displayed an IC50 Of 206 nM. Similarly, N-6-methyl-2-alkylthio derivatives 10, 14, and 15 were nearly full antagonists of IC50 0.5 mu M. On the ribose moiety, 2'-hydroxy,4'-thio, carbocyclic, and six-membered anhydrohexitol ring modifications have been prepared and resulted in enhanced agonist properties. The 1,5-anhydrohexitol analogue 36 was a pure agonist with an EC50 Of 3 mu M, i.e., similar in potency to ATP. 5'-Phosphate groups have been modified in the form of triphosphate, methyl phosphate, and cyclic 3',5'-diphosphate derivatives. The carbocyclic analogue had enhanced agonist efficacy, and the 5'-O-phosphonylmethyl modification was tolerated, suggesting that deviations from the nucleotide structure may result in improved utility as pharmacological probes. The N-6-methoxy modification eliminated receptor affinity. Pyrimidine nucleoside 3',5'-bisphosphate derivatives were inactive as agonists or antagonists at P2Y receptor subtypes. C1 NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. So Res Inst, Organ Chem Res Dept, Birmingham, AL 35255 USA. Univ Camerino, Dipartimento Sci Chim, I-62032 Camerino, Italy. Katholieke Univ Leuven, Rega Inst Med Res, B-3000 Louvain, Belgium. 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; Erathodiyil, Nandanan/A-8333-2010; OI Jacobson, Kenneth/0000-0001-8104-1493; Camaioni, Emidio/0000-0002-8529-0849 FU NHLBI NIH HHS [HL54889]; NIGMS NIH HHS [GM38213] NR 39 TC 56 Z9 56 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAY 6 PY 1999 VL 42 IS 9 BP 1625 EP 1638 DI 10.1021/jm980657j PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 193XP UT WOS:000080163300013 PM 10229631 ER PT J AU Coop, A Rothman, RB Dersch, C Partilla, J Porreca, F Davis, P Jacobson, AE Rice, KC AF Coop, A Rothman, RB Dersch, C Partilla, J Porreca, F Davis, P Jacobson, AE Rice, KC TI delta opioid affinity and selectivity of 4-hydroxy-3-methoxyindolomorphinan analogues related to naltrindole SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MESSAGE-ADDRESS CONCEPT; RECEPTOR AGONIST; IMMUNE-SYSTEM; ANTAGONISTS; BINDING; CELLS; PEPTIDES; MOIETY; MOUSE; RAT AB To investigate the effect of the introduction of a 4-phenolic substituent on the delta opioid affinity and selectivity of the indolomorphinans, a range of 4-phenolic analogues of naltrindole were prepared and evaluated in in vitro assays. Although the majority of the ligands displayed poor affinity for all three opioid receptors (mu, kappa, delta), 17-cyclopropylmethyl-6,7-didehydro-4-hydroxy-3-methoxy-6,7:2',3'-indolomorphinan (13) was an exception, displaying excellent delta binding selectivity (delta K-i = 7 nM, mu/delta = 1900, mu/kappa = 1130). GTP-gamma-S functional assays showed 13 to be a selective delta antagonist, albeit with lower potency than naltrindole. Although the reason for the unique profile of 13 could not be determined, these results validate our approach of introducing groups into the indolomorphinans that are known to reduce mu activity, to obtain increased delta selectivity. C1 NIDDK, Med Chem Lab, NIH, Bethesda, MD 20892 USA. NIDA, Addict Res Ctr, Clin Psychopharmacol Sect, Baltimore, MD 21224 USA. Univ Arizona, Hlth Sci Ctr, Dept Pharmacol, Tucson, AZ 85724 USA. RP Rice, KC (reprint author), NIDDK, Med Chem Lab, NIH, Bldg 8,Room B1-23, Bethesda, MD 20892 USA. NR 54 TC 34 Z9 34 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 MAY 6 PY 1999 VL 42 IS 9 BP 1673 EP 1679 DI 10.1021/jm9807003 PG 7 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 193XP UT WOS:000080163300018 PM 10229636 ER PT J AU Zhan, QM Antinore, MJ Wang, XW Carrier, F Smith, ML Harris, CC Forance, AJ AF Zhan, QM Antinore, MJ Wang, XW Carrier, F Smith, ML Harris, CC Forance, AJ TI Association with Cdc2 and inhibition of Cdc2/cyclin B1 kinase activity by the p53-regulated protein Gadd45 SO ONCOGENE LA English DT Article DE g2 checkpoint; UV radiation; Cdc2; cyclin B1; Gadd45 ID CELL-CYCLE CHECKPOINTS; IONIZING-RADIATION; GROWTH ARREST; G(2) DELAY; HELA-CELLS; P53; G(1); PROGRESSION; IRRADIATION; DISRUPTION AB Recently Gadd45, a p53-regulated stress protein, has been implicated in the activation of a G2/M checkpoint after damage by UV radiation and alkylating agents, While inhibitory phosphorylation of Cdc2 and suppression of cyclin B1 levels are known to be involved in GZ delays after genotoxic stress, Gadd45 has non been found to directly inhibit the activity of Cdc2/Cyclin B1 complex, while it had no appreciable effect on Cdk2/ Cyclin E activity even at very high levels of Gadd45, In contrast, p21(Cip1/Waf1) is an universal cdk/cyclin inhibitor and inhibited both of the cyclin complexes tested here, Gadd45 was also able to physically interact with Cdc2, but not Cyclin B1, Addition of Gadd45 to immunoprecipitated Cdc2/Cyclin B1 in vitro led to a dissociation of this complex, and thus may represent a new checkpoint mechanism whereby Cdc2/Cyclin B1 can be inhibited, With the use of an antisense approach, reduced Gadd45 expression attenuated the suppression of Cdc2/Cyclin B1 activity in UV-irradiated human cells. Taken together, these results implicate Gadd45 in the control of G2/M cell cycle progression after certain stresses. C1 NCI, Biol Chem Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NCI, Human Carcinogenesis Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Forance, AJ (reprint author), NCI, Biol Chem Lab, Div Basic Sci, NIH, Bldg 37,Room 5C09, Bethesda, MD 20892 USA. RI Carrier, France/C-3063-2008; Wang, Xin/B-6162-2009; Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X NR 34 TC 330 Z9 344 U1 0 U2 13 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 6 PY 1999 VL 18 IS 18 BP 2892 EP 2900 DI 10.1038/sj.onc.1202667 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 193FK UT WOS:000080125100012 PM 10362260 ER PT J AU Noronha, SB Wagner, LW Matheson, NH Shiloach, J AF Noronha, SB Wagner, LW Matheson, NH Shiloach, J TI Use of an ethanol sensor for feedback control of growth and expression of TBV25H in Saccharomyces cerevisiae SO BIOTECHNOLOGY AND BIOENGINEERING LA English DT Article DE ethanol; sensor; ADH2; TBV25H; Saccharomyces; malaria ID METHANOL CONCENTRATION; PICHIA-PASTORIS; TRANSMISSION; YEAST; CULTURE; GLUCOSE AB A process for production of a malaria transmission blocking vaccine candidate under the control of the ADH2 promoter in Saccharomyces cerevisiae was developed. Monitoring and controlling the ethanol concentration during the process is essential for successful expression of the recombinant protein. A simple sensor accomplishing this task has been developed, the principle of its operation is the following: air-flow through silicone tubing submerged in the media picks up ethanol, which is detected by an alcohol sensor that relays a signal to a controller regulating the amount of ethanol added to the culture. The sensor was used successfully in high cell density cultures of various scales. (C) 1999 John Wiley & Sons, Inc. Biotechnol Bioeng 63: 285-289, 1999. C1 NIDDK, Biotechnol Unit, LCDB, NIH, Bethesda, MD 20892 USA. Dupont Co, Cent Res & Dev, Newark, DE 19714 USA. RP Shiloach, J (reprint author), NIDDK, Biotechnol Unit, LCDB, NIH, Bethesda, MD 20892 USA. NR 12 TC 5 Z9 5 U1 0 U2 3 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0006-3592 J9 BIOTECHNOL BIOENG JI Biotechnol. Bioeng. PD MAY 5 PY 1999 VL 63 IS 3 BP 285 EP 289 PG 5 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 176FE UT WOS:000079140000004 PM 10099607 ER PT J AU Chow, WH Devesa, SS Warren, JL Fraumeni, JF AF Chow, WH Devesa, SS Warren, JL Fraumeni, JF TI Rising incidence of renal cell cancer in the United States SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HYPERTENSION; CARCINOMA; OBESITY; TRENDS AB Context Clinical surveys have revealed that incidental detection of renal cell carcinoma is rising because of increased use of imaging procedures. Objective To examine incidence, mortality, and survival trends of renal cell and renal pelvis cancers by age, sex, race, and tumor stage at diagnosis, Design Calculation of age-adjusted incidence and mortality rates, along with 5-year relative survival rates, using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. Setting and Participants Patients diagnosed as having kidney cancer from 1975 through 1995 in the 9 geographic areas covered by tumor registries in the SEER program, which represent about 10% of the US population. Main Outcome Measures Incidence, mortality, and 5-year relative survival rates by time periods, Results The age-adjusted incidence rates for renal cell carcinoma between 1975 and 1995 for white men, white women, black men, and black women were 9.6, 4.4, 11.1, and 4.9 per 100 000 person-years, respectively. The corresponding rates for renal pelvis cancer were 1.5, 0.7, 0.8, and 0.5 per 100 000 person-years, Renal cell cancer incidence rates increased steadily between 1975 and 1995, by 2.3% annually among white men, 3.1% among white women, 3.9% among black men, and 4.3% among black women. Increases were greatest for localized tumors but were also seen for more advanced and unstaged tumors. In contrast, the incidence rates for renal pelvis cancer declined among white men and remained stable among white women and blacks. Although 5-year relative survival rates for patients with renal cell cancer improved among whites but not among blacks, kidney cancer mortality rates increased in all race and sex groups. Conclusions Increasing detection of presymptomatic tumors by imaging procedures, such as ultrasonography, computed tomography, and magnetic resonance imaging, does not fully explain the upward incidence trends of renal cell carcinoma. Other factors may be contributing to the rapidly increasing incidence of renal cell cancer in the United States, particularly among blacks. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Chow, WH (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8100, Bethesda, MD 20892 USA. NR 21 TC 947 Z9 976 U1 2 U2 12 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 5 PY 1999 VL 281 IS 17 BP 1628 EP 1631 DI 10.1001/jama.281.17.1628 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 191MJ UT WOS:000080025900028 PM 10235157 ER PT J AU de Alba, E Baber, JL Tjandra, N AF de Alba, E Baber, JL Tjandra, N TI The use of residual dipolar coupling in concert with backbone relaxation rates to identify conformational exchange by NMR SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ROTATIONAL DIFFUSION ANISOTROPY; LIQUID-CRYSTALLINE MEDIUM; HETERONUCLEAR NMR; HUMAN UBIQUITIN; N-15; SPECTROSCOPY; DYNAMICS; PROTEINS; MACROMOLECULES; MOTIONS C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Tjandra, N (reprint author), NHLBI, Biophys Chem Lab, NIH, Bldg 3, Bethesda, MD 20892 USA. NR 19 TC 51 Z9 51 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD MAY 5 PY 1999 VL 121 IS 17 BP 4282 EP 4283 DI 10.1021/ja990062t PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 196HN UT WOS:000080303100025 ER PT J AU Hoover, RN AF Hoover, RN TI Dioxin dilemmas SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID MORTALITY; WORKERS; COHORT C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Hoover, RN (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Execut Plaza S,Rm 8094, Bethesda, MD 20892 USA. NR 11 TC 2 Z9 2 U1 0 U2 0 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 5 PY 1999 VL 91 IS 9 BP 745 EP 746 DI 10.1093/jnci/91.9.745 PG 2 WC Oncology SC Oncology GA 193ND UT WOS:000080142100002 PM 10328098 ER PT J AU Devesa, SS Fraumeni, JF AF Devesa, SS Fraumeni, JF TI The rising incidence of gastric cardia cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID GASTROESOPHAGEAL REFLUX DISEASE; HELICOBACTER-PYLORI INFECTION; UNITED-STATES; SOCIOECONOMIC-FACTORS; MEDICAL CONDITIONS; ESOPHAGEAL CANCER; MORTALITY TRENDS; RISK-FACTORS; ADENOCARCINOMA; CARCINOMA C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Devesa, SS (reprint author), NIH, Execut Plaza S,Rm 8048, Bethesda, MD 20892 USA. NR 41 TC 92 Z9 98 U1 1 U2 2 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 5 PY 1999 VL 91 IS 9 BP 747 EP 749 DI 10.1093/jnci/91.9.747 PG 3 WC Oncology SC Oncology GA 193ND UT WOS:000080142100003 PM 10328099 ER PT J AU Swisher, SG Roth, JA Nemunaitis, J Lawrence, DD Kemp, BL Carrasco, CH Connors, DG El-Naggar, AK Fossella, F Glisson, BS Hong, WK Khuri, FR Kurie, JM Lee, JJ Lee, JS Mack, M Merritt, JA Nguyen, DM Nesbitt, JC Perez-Soler, R Pisters, KMW Putnam, JB Richli, WR Savin, M Schrump, DS Shin, DM Shulkin, A Walsh, GL Wait, J Weill, D Waugh, MKA AF Swisher, SG Roth, JA Nemunaitis, J Lawrence, DD Kemp, BL Carrasco, CH Connors, DG El-Naggar, AK Fossella, F Glisson, BS Hong, WK Khuri, FR Kurie, JM Lee, JJ Lee, JS Mack, M Merritt, JA Nguyen, DM Nesbitt, JC Perez-Soler, R Pisters, KMW Putnam, JB Richli, WR Savin, M Schrump, DS Shin, DM Shulkin, A Walsh, GL Wait, J Weill, D Waugh, MKA TI Adenovirus-mediated p53 gene transfer in advanced non-small-cell lung cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID WILD-TYPE P53; RECOMBINANT ADENOVIRUS; IN-VITRO; EXPRESSION VECTOR; INHIBITS GROWTH; CYCLE CONTROL; PHASE-I; APOPTOSIS; THERAPY; EFFICACY AB Background: Preclinical studies in animal models have demonstrated tumor regression following intratumoral administration of an adenovirus vector containing wild-type p53 complementary DNA (Ad-p53). Therefore, in a phase I clinical trial, we administered Ad-p53 to 28 patients with nonsmall-cell lung cancer (NSCLC) whose cancers had progressed on conventional treatments. Methods: Patients received up to six, monthly intratumoral injections of Ad-p53 by use of computed tomography- guided percutaneous fine-needle injection (23 patients) or bronchoscopy (five patients). The doses ranged from 10(6) plaque-forming units (PFU) to 10(11) PFU. Results: Polymerase chain reaction (PCR) analysis showed the presence of adenovirus vector DNA in 18 (86%) of 21 patients with evaluable posttreatment biopsy specimens; vector-specific p53 messenger RNA was detected by means of reverse transcription-PCR analysis in 12 (46%) of 26 patients. Apoptosis (programmed cell death) was demonstrated by increased terminal deoxynucleotide transferase-mediated biotin uridine triphosphate nick-end labeling (TUNEL) staining in posttreatment biopsy specimens from 11 patients. Vector-related toxicity was minimal (National Cancer Institute's Common Toxicity Criteria: grade 3 = one patient; grade 4 = no patients) in 84 courses of treatment, despite repeated injections (up to six) in 23 patients. Therapeutic activity in 25 evaluable patients included partial responses in two patients (8%) and disease stabilization (range, 2-14 months) in 16 patients (64%); the remaining seven patients (28%) exhibited disease progression. Conclusions: Repeated intratumoral injections of Ad-p53 appear to be well tolerated, result in transgene expression of wild-type p53, and seem to mediate antitumor activity in a subset of patients with advanced NSCLC. C1 Univ Texas, Dept Thorac & Cardiovasc Surg, MD Anderson Cancer Ctr, Sect Thorac Mol Oncol, Houston, TX 77030 USA. Univ Texas, MD Anderson Cancer Ctr, Dept Diagnost Imaging, Houston, TX 77030 USA. Univ Texas, MD Anderson Cancer Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA. Univ Texas, MD Anderson Cancer Ctr, Dept Biomath, Houston, TX 77030 USA. Univ Texas, MD Anderson Cancer Ctr, Dept Pathol, Houston, TX 77030 USA. Baylor Univ, Med Ctr, PRN Res Inc, Houston, TX 77030 USA. Introgen Therapeut Inc, Houston, TX USA. Med City Dallas Hosp, Dallas, TX USA. CV Associates, Nashville, TN USA. NCI, Bethesda, MD 20892 USA. RP Swisher, SG (reprint author), Univ Texas, Dept Thorac & Cardiovasc Surg, MD Anderson Cancer Ctr, Sect Thorac Mol Oncol, 1515 Holcombe Blvd,Box 109, Houston, TX 77030 USA. RI Ray, Dana/C-3470-2013; Shin, Dong Moon/G-9649-2013 FU NCI NIH HHS [P50CA70907, R01CA45187, CA16672] NR 40 TC 350 Z9 377 U1 3 U2 16 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 5 PY 1999 VL 91 IS 9 BP 763 EP 771 DI 10.1093/jnci/91.9.763 PG 9 WC Oncology SC Oncology GA 193ND UT WOS:000080142100010 PM 10328106 ER PT J AU Penninx, BWJH Guralnik, JM AF Penninx, BWJH Guralnik, JM TI Depression as a risk factor for cancer: Renewing a debate on the psychobiology of disease - Reply SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 Free Univ Amsterdam, Inst Res Extramural Med, NL-1081 BT Amsterdam, Netherlands. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. RP Penninx, BWJH (reprint author), Free Univ Amsterdam, Inst Res Extramural Med, VD Boechorstststr 7, NL-1081 BT Amsterdam, Netherlands. NR 0 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 MAY 5 PY 1999 VL 91 IS 9 BP 804 EP 804 PG 1 WC Oncology SC Oncology GA 193ND UT WOS:000080142100021 ER PT J AU Bornstein, SR Stratakis, CA Chrousos, GP AF Bornstein, SR Stratakis, CA Chrousos, GP TI Adrenocortical tumors: Recent advances in basic concepts and clinical management SO ANNALS OF INTERNAL MEDICINE LA English DT Review ID GLUCOCORTICOID-REMEDIABLE ALDOSTERONISM; ENDOCRINE NEOPLASIA TYPE-1; DISCOVERED ADRENAL MASSES; GROWTH-FACTOR-II; COMPARATIVE GENOMIC HYBRIDIZATION; GASTRIC-INHIBITORY POLYPEPTIDE; DEPENDENT CUSHINGS-SYNDROME; HYPERALDOSTERONISM TYPE-II; ITALIAN STUDY-GROUP; LAPAROSCOPIC ADRENALECTOMY AB Adrenocortical masses are among the most common tumors in humans. However, only a small proportion of these tumors cause endocrine diseases (such as primary hyperaldosteronism, hypercortisolism, hyperandrogenism, or hyperestrogenism), and less than 1% are malignant. In recent years, several of the molecular and cellular mechanisms involved in adrenal tumorigenesis have been unraveled. As a result, alterations in intercellular communication, local production of growth factors and cytokines, and aberrant expression of ectopic receptors on adrenal tumor cells have been implicated in adrenal cell growth, hyperplasia, tumor formation, and autonomous hormone production. Genetic and chromosomal abnormalities, including several chromosomal loci and the genes coding for p53, p57, and insulin-like growth factor II, have been reported in adrenal tumors. In addition, chromosomal markers have been identified in several familial syndromes associated with adrenal tumors; these include menin, which is responsible for multiple endocrine neoplasia type I, and the hybrid gene that causes glucocorticoid-remediable hyperaldosteronism. Algorithms for endocrine testing and imaging procedures are now available to codify screening for, confirmation of, and differentiation of causes of primary hyperaldosteronism and the Cushing syndrome. Improved radiologic, computerized radiologic, and magnetic resonance imaging techniques, as well as selective catheterization studies, are useful in localizing adrenal tumors and in distinguishing between benign and malignant lesions and between functional and nonfunctional nodules. Finally, recent refinements in the field of minimally invasive general surgery have made laparoscopic adrenalectomy the method of choice for removing adrenal tumors; this type of surgery allows shorter hospital stays, lower morbidity rates, and faster recovery. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Bornstein, SR (reprint author), NICHHD, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N 262,10 Ctr Dr,MSC 1862, Bethesda, MD 20892 USA. NR 143 TC 118 Z9 126 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 MAY 4 PY 1999 VL 130 IS 9 BP 759 EP 771 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 192DE UT WOS:000080062300008 PM 10357696 ER PT J AU Garant, MJ Kole, S Maksimova, EM Bernier, M AF Garant, MJ Kole, S Maksimova, EM Bernier, M TI Reversible change in thiol redox status of the insulin receptor alpha-subunit in intact cells SO BIOCHEMISTRY LA English DT Article ID CLASS-I DISULFIDES; SIGNAL-TRANSDUCTION; TYROSINE KINASE; RAT ADIPOCYTES; SULFHYDRYL-GROUPS; N-ACETYLCYSTEINE; BETA-SUBUNIT; GLUTATHIONE; AGENTS; BONDS AB In this study, we used maleimidobutyrylbiocytin to examine possible alteration that may occur in the redox state of the insulin receptor (IR) sulfhydryl groups in response to reduced glutathione (GSH) or N-acetyl-L-cysteine (NAC). Short-term treatment of intact cells expressing large numbers of IR with GSH or NAC led to a rapid and reversible reduction of IR alpha-subunit disulfides, without affecting the receptor beta-subunit thiol reactivity. The overall integrity of the oligomeric structure of IR was maintained, indicating that neither class I nor class II disulfides were targeted by these agents. Similar findings were obtained in cells transfected with IR mutants lacking cysteine(524), one of the class I disulfides that link the two IR alpha-subunits. Membrane-associated thiols did not participate in GSH- or NAC-mediated reduction of IR alpha-subunit disulfides. No difference in insulin binding was observed in GSH-treated cells; however, ligand-mediated increases in IR autophosphorylation, tyrosine phosphorylation of cellular substrates, and dual phosphorylation of the downstream target mitogen-activated protein kinase were inhibited at concentrations of GSH (10 mM or greater) that yielded a significant increase in IR alpha-subunit thiol reactivity. GSH did not affect IR signaling in the absence of insulin. Our results provide the first evidence that the IR alpha-subunit contains a select group of disulfides whose redox status can be rapidly altered by the reducing agents GSH and NAC. C1 NIA, Diabet Sect, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. RP Bernier, M (reprint author), NIA, Diabet Sect, Clin Invest Lab, NIH, 5600 Nathan Shock Dr,Box 23, Baltimore, MD 21224 USA. OI Bernier, Michel/0000-0002-5948-368X NR 46 TC 16 Z9 17 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 4 PY 1999 VL 38 IS 18 BP 5896 EP 5904 DI 10.1021/bi982844p PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 193YP UT WOS:000080165600026 PM 10231542 ER PT J AU Xie, L Li, WX Rhodes, T White, H Schoenberg, M AF Xie, L Li, WX Rhodes, T White, H Schoenberg, M TI Transient kinetic analysis of N-phenylmaleimide-reacted myosin subfragment-1 SO BIOCHEMISTRY LA English DT Article ID ADENOSINE-TRIPHOSPHATE HYDROLYSIS; NUCLEOTIDE BINDING; MECHANISM; ACTOMYOSIN; ACTIN; COMPLEX; ATPASE; FIBERS; STATES AB Alkylation of myosin's Cys-707 (SH1) and Cys-697 (SH2) has profound consequences for myosin's ability to interact with actin and hydrolyze MgATP. Pre-steady-state measurements of myosin-S1 alkylated at SH1 and SH2 by N-phenylmaleimide (NPM) in the presence of ATP were taken to identify the steps of the reaction that are altered. It was found that the rate constant most affected by this modification is the apparent rate of the ATP hydrolysis step. This rate constant is reduced 20000-fold, an effect comparable in magnitude to the effect of the same modification on the binding of MgATP to S1 or acto-S1 [Xie, L., and Schoenberg, M. (1998) Biochemistry 37, 8048]. In contrast, the rate constants of phosphate release and dissociation of acto-S1 by ATP were reduced <20-fold. For unmodified S1, the enhancement of fluorescence seen after addition of ATP had the same rate constant as the ATP hydrolysis step (S1.ATP double left right arrow S1.ADP/P-i) measured by single-turnover experiments in a quench-flow experiment. This is consistent with results previously observed [Johnson, K. A., and Taylor, E. W. (1978) Biochemistry 17, 3432]. However, NPM-modified S1 exhibited virtually no fluorescence enhancement upon ATP binding. This provides further evidence that M.ATP is the predominant intermediate of NPM-S1-catalyzed ATP hydrolysis. C1 NIAMSD, NIH, Bethesda, MD 20892 USA. Eastern Virginia Med Sch, Dept Pharmacol Physiol & Biochem, Norfolk, VA 23507 USA. RP Schoenberg, M (reprint author), NIAMSD, NIH, Bldg 6,Rm 408, Bethesda, MD 20892 USA. NR 22 TC 5 Z9 5 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 MAY 4 PY 1999 VL 38 IS 18 BP 5925 EP 5931 DI 10.1021/bi981778o PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 193YP UT WOS:000080165600030 PM 10231546 ER PT J AU Singh, JP Larson, MG O'Donnell, CJ Tsuji, H Evans, JC Levy, D AF Singh, JP Larson, MG O'Donnell, CJ Tsuji, H Evans, JC Levy, D TI Heritability of heart rate variability - The Framingham Heart Study SO CIRCULATION LA English DT Article DE heart rate; genetics; epidemiology ID RESPIRATORY SINUS ARRHYTHMIA; FREQUENCY-DOMAIN; MORTALITY; DISEASE; RISK AB Background-There is evolving evidence that heart rate (HR) is genetically determined. Heart rate variability (HRV) measured by power spectral analysis provides quantitative phenotypic markers of autonomic nervous system activity. Reported determinants of HR and HRV only partially explain their variability in the population. The purpose of this study was to assess the heritability of HR and HRV and estimate the contribution of genetic factors to their variance. Methods and Results-Subjects who underwent ambulatory recordings at a routine examination were eligible; subjects with congestive heart failure, coronary artery disease, diabetes mellitus, and those taking cardioactive medications were excluded. We analyzed high-frequency power, low-frequency power, very low-frequency power, total power, low-frequency/high-frequency ratio, and the standard deviation of normal R-R intervals from 2-hour continuous ECG recordings. Heritability analysis was done by studying correlations between siblings (n = 682, in 291 sibships, 517 pairs) and between spouse pairs (n = 206 pairs) after adjusting for important covariates. Results from separate models were combined to estimate the components of variance attributable to measured covariates, additive genetic effects (heritability), and household effects. After adjusting for covariates, the correlations were consistently higher among siblings (0.21 to 0.26) compared with spouses (0.01 to 0.19). The measured covariates in general accounted for 13% to 40% of the total phenotypic variance, whereas genetic factors accounted for 13% to 23% of the variation among HR and HRV measures. Conclusions-Heritable factors may explain a substantial proportion of the variance in HR and HRV. These results highlight the contribution of genetic versus environmental factors to autonomic nervous system activity. C1 Framingham Heart Dis Epidemiol Study, NHLBI, Framingham, MA 01702 USA. NHLBI, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Div Epidemiol & Prevent Med, Boston, MA 02118 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Unit, Boston, MA USA. Harvard Univ, Beth Israel Hosp, Sch Med, Div Cardiol, Boston, MA 02215 USA. Harvard Univ, Beth Israel Hosp, Sch Med, Div Clin Epidemiol, Boston, MA 02215 USA. Kansai Med Univ, Osaka, Japan. RP Levy, D (reprint author), Framingham Heart Dis Epidemiol Study, NHLBI, 5 Thurber St, Framingham, MA 01702 USA. NR 24 TC 131 Z9 135 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 4 PY 1999 VL 99 IS 17 BP 2251 EP 2254 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 191CW UT WOS:000080004900006 PM 10226089 ER PT J AU Nechushtan, A Smith, CL Hsu, YT Youle, RJ AF Nechushtan, A Smith, CL Hsu, YT Youle, RJ TI Conformation of the Bax C-terminus regulates subcellular location and cell death SO EMBO JOURNAL LA English DT Article DE apoptosis; Bcl-2; GFP; mitochondria; point mutations ID BCL-X-L; ENDOPLASMIC-RETICULUM; APOPTOSIS; PHOSPHORYLATION; PROTEIN; HETERODIMERIZES; MITOCHONDRIA; DIMERIZATION; SURVIVAL; BCL-X(L) AB Bax, a pro-apoptotic member of the Bcl-2 family, translocates from the cytosol to the mitochondria during programmed cell death. We report here that both gain-of-function and loss-of-function mutations can be achieved by altering a single amino acid in the Bax hydrophobic C-terminus, The properly mutated C-terminus of Bax can target a non-relevant protein to the mitochondria, showing that specific conformations of this domain alone allow mitochondrial docking. These data along with N-terminus epitope exposure experiments suggest that the C- and the N-termini interact and that upon triggering of apoptosis, Bax changes conformation, exposing these two domains to insert into the mitochondria and regulate the cell death machinery. C1 NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Light Microscopy Facil, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Youle, RJ (reprint author), NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NR 31 TC 539 Z9 548 U1 1 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD MAY 4 PY 1999 VL 18 IS 9 BP 2330 EP 2341 DI 10.1093/emboj/18.9.2330 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 195LE UT WOS:000080251600003 PM 10228148 ER PT J AU Cutler, ML Shupert, WL Schlom, J Kantor, J AF Cutler, ML Shupert, WL Schlom, J Kantor, J TI Low-level transforming activity of an activated Ras gene under the control of a vaccinia virus p40 promoter is abrogated by truncation of the Ras cDNA SO VACCINE LA English DT Article ID CELL RESPONSES; T-LYMPHOCYTES; EXPRESSION; PEPTIDE; IDENTIFICATION; EPITOPES; PROTEIN; VECTORS; CD4(+); IMMUNIZATION AB Many human cancers have been shown to contain activated forms of the Ras proto-oncogene. Mutations comprising amino acid changes at codons 12, 13 and 61 therefore represent unique targets for cancer immunotherapy. Recombinant Vaccinia viruses encoding point mutated Rns oncogenes have raised issues concerning the safety and transforming ability of these recombinant vaccines. Vaccinia virus, a representative of the orthopox virus genus, is a large DNA virus that is cytopathogenic and that replicates in the cytoplasm of the infected cell. However, it remains unclear whether orthopox viruses are capable of genetic interactions with infected cells. Our studies show that DNA isolated from cells infected with a recombinant Vaccinia virus expressing mutated Ras constituted a poor reagent for transfection into NIH3T3 cells for transformation analysis. Stable integration of a recombinant Vaccinia virus expressing mutant Ras DNA was not detected in recipient cells. This study also demonstrates that the crossover plasmids used to generate the recombinant virus where the activated Ras gene is under the control of a Vaccinia virus early promoter had low but detectable transforming efficiency in the NIH3T3 transformation assay. Analysis of the transfected cells indicated that Ras transcription was initiated upstream of the Vaccinia virus promoter. The introduction of wobble mutations as well as the truncation of the Pas protein removed the transforming capabilities of the crossover vector. This study demonstrates the potential problems and solutions in the use of point mutated oncogenes in live vectors for cancer vaccine development. Published by Elsevier Science Ltd. C1 NCI, NIH, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, NIH, Tumor Immunol & Biol Lab, 10 Ctr Dr,Bldg 10,Room 8 B07, Bethesda, MD 20892 USA. NR 37 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD MAY 4 PY 1999 VL 17 IS 18 BP 2275 EP 2283 DI 10.1016/S0264-410X(98)00479-4 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 193QA UT WOS:000080146500008 PM 10403595 ER PT J AU Dawson, DA AF Dawson, DA TI Alternative definitions of high risk for impaired driving: the overlap of high volume, frequent heavy drinking and alcohol dependence SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE ethanol intake; driving; heavy drinking days ID PREVENTIVE PARADOX; CONSUMPTION; POPULATION; STRATEGIES; PREVALENCE AB This paper examines the distributions of past-year volume of ethanol intake, frequency of drinking 5 + drinks and alcohol dependence in a representative sample of 18352 U.S. current drinkers aged 18 years or over. Within categories defined by these three partially overlapping domains, it presents rates of self-perceived impaired driving, i.e. driving after having had too much to drink, in the year preceding interview. High volume drinkers, those with an average daily ethanol intake of 1 ounce or more, composed 19.7% of current drinkers and accounted for 66.5% of all reported ethanol consumption, 72.6% of all heavy drinking days, 49.2% of all alcohol dependence and 62.8% of all impaired driving incidents. Frequent heavy drinkers, those who drank 5 + drinks at least once a week, composed 12.3% of current drinkers and accounted for 42.9% of all reported ethanol consumption, 81.9% of all heavy drinking days, 40% of all alcohol dependence and 57% of all impaired driving incidents. Drinkers with DSM-IV alcohol dependence composed 9.9% of current drinkers and accounted for 28.9% of all reported ethanol consumption, 37% of all heavy drinking days and 56.9% of all impaired driving incidents. The overlap of these three high risk groups, each of which bad a probability of at least one impaired driving incident per year, was far from complete. Of individuals who met any of these criteria for high risk drinking (i.e. high volume, frequent heavy drinking or dependence), more than half met only one criterion and only one in seven met all three. The group that did meet all three criteria had such a high rate of impaired driving incidents, an average of 5.14/year, that it accounted for 36.4% of all such incidents despite making up only 3.8% of all current drinkers. The results are discussed in terms of their implications for targeting prevention and intervention efforts, e.g. whether targeting one problematic aspect of drinking behavior will reach drinkers with other types of problem behaviors as well. (C) 1999 Published by Elsevier Science Ireland Ltd. All rights reserved. C1 NIAAA, NIH, Bethesda, MD 20892 USA. RP Dawson, DA (reprint author), NIAAA, NIH, 6000 Execut Blvd,MSC 7003,Willco Bldg,Suite 514, Bethesda, MD 20892 USA. NR 32 TC 21 Z9 21 U1 0 U2 2 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 MAY 3 PY 1999 VL 54 IS 3 BP 219 EP 228 DI 10.1016/S0376-8716(98)00165-3 PG 10 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 191KB UT WOS:000080020600004 PM 10372795 ER PT J AU Metzger, H Chen, HX Goldstein, B Haleem-Smith, H Inman, JK Peirce, M Torigoe, C Vonakis, B Wofsy, C AF Metzger, H Chen, HX Goldstein, B Haleem-Smith, H Inman, JK Peirce, M Torigoe, C Vonakis, B Wofsy, C TI A quantitative approach to signal transduction SO IMMUNOLOGY LETTERS LA English DT Article; Proceedings Paper CT 10th Symposium on Signals and Signal Processing in the Immune System CY SEP 13-17, 1998 CL BALATONOSZOD, HUNGARY DE IgE receptor; tyrosine phosphorylation; membrane receptors ID AFFINITY IGE RECEPTOR; PROTEIN-TYROSINE PHOSPHATASES; IMMUNOGLOBULIN-E; KINASE; CELLS; PHOSPHORYLATION; AGGREGATION; MECHANISM; ASSOCIATION; SYK AB The high affinity receptor for IgE (Fc epsilon RI), is one of a family of immunoreceptors whose antigen-induced clustering leads to a variety of cellular responses. The signaling pathways are enormously complex but by focusing on only the most initial steps, it is now possible to sketch plausible molecular models that relate the interaction of multivalent antigens with the receptor-bound IgE to the earliest cellular events. In this paper, we describe how we have combined quantitative experimentation and mathematical modeling to probe this system further. We also discuss some of the formidable challenges that remain before we can claim reasonably complete understanding of even these early events. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIAMS, Arthritis & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. Univ Calif Los Alamos Natl Lab, Los Alamos, NM USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. Univ New Mexico, Dept Math, Albuquerque, NM 87131 USA. RP Metzger, H (reprint author), NIAMS, Arthritis & Rheumatism Branch, NIH, Bldg 10,Room 9N-228,10 Ctr Dr MSC 1820, Bethesda, MD 20892 USA. NR 28 TC 8 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2478 J9 IMMUNOL LETT JI Immunol. Lett. PD MAY 3 PY 1999 VL 68 IS 1 BP 53 EP 57 DI 10.1016/S0165-2478(99)00030-9 PG 5 WC Immunology SC Immunology GA 206BG UT WOS:000080855700008 PM 10397156 ER PT J AU Tortorella, D Story, CM Huppa, JB Wiertz, EJHJ Jones, TR Bacik, I Bennink, JR Yewdell, JW Ploegh, HL AF Tortorella, D Story, CM Huppa, JB Wiertz, EJHJ Jones, TR Bacik, I Bennink, JR Yewdell, JW Ploegh, HL TI Dislocation of type I membrane proteins from the ER to the cytosol is sensitive to changes in redox potential (vol 142, pg 365, 1998) SO JOURNAL OF CELL BIOLOGY LA English DT Correction C1 Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Natl Inst Publ Hlth & Environm, RIVM, NL-3720 BA Bilthoven, Netherlands. Wyeth Ayerst Res, Infect Dis Sect, Dept Biol Mol, Pearl River, NY 10965 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Tortorella, D (reprint author), Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RI yewdell, jyewdell@nih.gov/A-1702-2012 NR 1 TC 0 Z9 0 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD MAY 3 PY 1999 VL 145 IS 3 BP 643 EP 643 PG 1 WC Cell Biology SC Cell Biology GA 194PW UT WOS:000080203600020 ER PT J AU Muraro, PA Martin, R Lassmann, H Gambi, D AF Muraro, PA Martin, R Lassmann, H Gambi, D TI Plaques, T cells and beyond: report on an international meeting on the immunological basis of multiple sclerosis held at the University of Chieti, Italy SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE multiple sclerosis; T lymphocytes; myelin basic protein; experimental allergic encephalomyelitis C1 Univ G DAnnunzio, Sch Med, Dept Oncol & Neurosci, Neurol Clin, I-66013 Chieti, Italy. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Univ Vienna, Inst Neurol, A-1090 Vienna, Austria. RP Gambi, D (reprint author), Univ G DAnnunzio, Sch Med, Dept Oncol & Neurosci, Neurol Clin, Via Vestini, I-66013 Chieti, Italy. OI Muraro, Paolo/0000-0002-3822-1218 NR 0 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD MAY 3 PY 1999 VL 96 IS 2 BP 251 EP 254 DI 10.1016/S0165-5728(99)00028-4 PG 4 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 197BG UT WOS:000080344300015 PM 10337925 ER PT J AU Weisner, C Kaskutas, LA Hilton, ME Barile, AL AF Weisner, C Kaskutas, LA Hilton, ME Barile, AL TI 'When you were drinking' vs. 'in the past 12 months': the impact of using different time frames in clinical and general populations SO ADDICTION LA English DT Article; Proceedings Paper CT 124th Annual Meeting of the American-Public-Health-Association CY NOV 17-21, 1996 CL NEW YORK, NEW YORK SP Amer Public Hlth Assoc ID ALCOHOL-CONSUMPTION AB Aim. Different time frames have been used to ask about drinking in clinical and general populations. Surveys of clinical populations have asked about the quantity and frequency of drinking within the context of "when you were drinking". In general population surveys, the customary practice has been to ask about a period of time such as "the last 12 months". This paper compares answers to questions about drinking using bath time frames. Design. Bivariate chi-squares and multi-variate logistic regression analyses were used to compare consumption estimates across the two time frames for different demographic and drinking categories of respondents. Setting and participants. In-person interviews were conducted with general population (N = 3069) and representative treatment samples (N = 381) in a northern California county. Measurements. Respondents were asked about their drinking within the context of "the East 12 months" and only "when you were drinking". Findings. There were no meaningful differences in aggregate measures of drinking based on the time frame of assessment in either sample. Drinking five or more drinks weekly was a significant predictor of consistent reporting of frequency of drinking among the clinical sample, and of reporting inconsistent frequency of drinking 12 or more drinks among the general population. Being female or being age 46 or over also was predictive of a "consistent" response in the general population for drinking 12 or more drinks; while being 46 or older, married, and white was predictive of consistent responses for drinking to intoxication in that population. Conclusions. Survey respondents do not average their drinking across a 12-month time frame that includes periods of abstinence; rather, they appear to answer only for the periods they were drinking. C1 Inst Publ Hlth, Alcohol Res Grp, Berkeley, CA 94709 USA. Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. NIAAA, Div Clin & Prevent Res, Berkeley, CA USA. RP Weisner, C (reprint author), Inst Publ Hlth, Alcohol Res Grp, 2000 Hearst Ave,Suite 300, Berkeley, CA 94709 USA. NR 11 TC 7 Z9 7 U1 0 U2 0 PU CARFAX PUBLISHING PI BASINGSTOKE PA RANKINE RD, BASINGSTOKE RG24 8PR, HANTS, ENGLAND SN 0965-2140 J9 ADDICTION JI Addiction PD MAY PY 1999 VL 94 IS 5 BP 731 EP 736 DI 10.1046/j.1360-0443.1999.94573111.x PG 6 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 199VA UT WOS:000080503700014 PM 10563038 ER PT J AU Higley, JD Bennett, AJ AF Higley, JD Bennett, AJ TI Central nervous system serotonin and personality as variables contributing to excessive alcohol consumption in non-human primates SO ALCOHOL AND ALCOHOLISM LA English DT Article; Proceedings Paper CT Markku Linnoila Memorial Symposium on Personality-Biological Interactions in Alcoholism, at the 9th Congress of the ISBRA CY JUN 27-JUL 02, 1998 CL COPENHAGEN, DENMARK SP Int Soc Biomed Res Alcoholism ID FLUID 5-HYDROXYINDOLEACETIC ACID; MONKEYS MACACA-MULATTA; OBSESSIVE-COMPULSIVE DISORDER; DISRUPTIVE BEHAVIOR DISORDERS; DIMINISHED SOCIAL COMPETENCE; BIOGENIC-AMINE METABOLISM; CSF 5-HIAA CONCENTRATIONS; CEREBROSPINAL-FLUID; RHESUS-MONKEYS; VERVET MONKEYS AB Non-human primates will readily consume an alcohol solution for its reinforcing effects when such a solution is palatable, with some subjects consuming alcohol to excess. In this review, we discuss variables that contribute to high alcohol consumption and the behaviours that are correlated with it in a non-human primate model. Developmental and behavioural correlates of central nervous system (CNS) serotonergic activity, as measured by concentrations of the serotonin metabolite 5-hydroxyindol-3-ylacetic acid (5-HIAA) in the cerebrospinal fluid (CSF), were used to investigate neurogenetic influences on alcohol consumption, as well as personality traits that characterize excessive alcohol intake. Interindividual differences in CSF 5-HIAA concentrations were shown to have trait-like qualities, and with stable inter-individual differences across time and settings. Research has shown numerous similarities between human and non-human primates with respect to Type I- and II-like alcohol abuse and their associated behaviours. In the present series of studies, features characteristic of Type I alcohol misuse, such as high levels of anxiety, hypothalamic-pituitary-adrenal output, and situational stress predicted high alcohol intake. Primates with low CSF 5-HIAA concentrations also exhibited behaviours characteristic of Type II alcohol abuse. Principal among the traits that these subjects exhibited were deficits in impulse control. For example, subjects with low CSF 5-HIAA concentrations engaged in spontaneous behaviours that bring reinforcement but placed them at risk, such as entering food baited traps, jumping from dangerous heights to get from one tree to another, and consuming large amounts of alcohol. They can be characterized by other Type II-like deficits, such as impaired social competence, social alienation, and unrestrained, violent aggression. Non-human primates with low CSF 5-HIAA concentrations also exhibited high intrinsic tolerance following modest intakes of alcohol, and high rates of aggression during intoxication. High preferences for sweet solutions were shown to predict excessive alcohol consumption. Maternal and paternal genetic influences played major roles in producing low CNS serotonin function and excessive alcohol consumption. These genetic influences on serotonin function were exacerbated by early rearing experiences, particularly parental deprivation. C1 NIAAA, Clin Studies Lab, Primate Unit, DICBR, Poolesville, MD 20837 USA. RP Higley, JD (reprint author), NIH, Anim Ctr, Bldg 112,POB 529, Poolesville, MD 20837 USA. NR 141 TC 66 Z9 68 U1 6 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0735-0414 J9 ALCOHOL ALCOHOLISM JI Alcohol Alcohol. PD MAY-JUN PY 1999 VL 34 IS 3 BP 402 EP 418 DI 10.1093/alcalc/34.3.402 PG 17 WC Substance Abuse SC Substance Abuse GA 226CK UT WOS:000082002600017 PM 10414617 ER PT J AU Purohit, V AF Purohit, V TI Symposium: Alcohol-induced hepatic fibrosis: Mechanisms - Introduction to the Symposium SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Editorial Material C1 NIAAA, Biomed Res Branch, Div Basic Res, NIH, Bethesda, MD 20892 USA. RP Purohit, V (reprint author), NIAAA, Biomed Res Branch, Div Basic Res, NIH, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 1999 VL 23 IS 5 BP 901 EP 903 DI 10.1111/j.1530-0277.1999.tb04200.x PG 3 WC Substance Abuse SC Substance Abuse GA 201DG UT WOS:000080579200021 ER PT J AU Lauer, MS Larson, MG Evans, JC Levy, D AF Lauer, MS Larson, MG Evans, JC Levy, D TI Association of left, ventricular dilatation and hypertrophy with chronotropic incompetence in the Framingham Heart Study SO AMERICAN HEART JOURNAL LA English DT Article ID EXERCISE; DISEASE; IMPACT; MASS AB Background Chronotropic incompetence and left ventricular (LV) dilatation have both been shown to be markers of an adverse cardiovascular prognosis. Chronotropic incompetence has been described in patients with symptomatic LV dilatation and dysfunction, but the effect of asymptomatic LV dilatation and hypertrophy on exercise heart rate response has not been well characterized. Methods and Results Members of the Framingham Offspring Study underwent M-mode echocardiography and graded exercise testing as part of a routine evaluation. Subjects receiving beta-blockers and digitalis and subjects with preexisting coronary heart disease, heart failure, and baseline ST-segment abnormalities were excluded. Chronotropic incompetence was assessed in 2 ways: (1) failure to achieve an age-predicted target heart rate and (2) a low chronotropic index, a measure of heart rate response that takes into account effects of age, resting heart rate, and physical Fitness. Echocardiographic variables studied included LV diastolic and systolic dimensions, LV wall thickness, LV mass, and fractional shortening. There were 1414 men and 1601 women eligible for analyses; failure to reach target heart rate occurred in 20%; of men and 23% of women; a low chronotropic index was noted in 14% of men and 12% of women. In unadjusted categorical analyses, an abnormally high LV mass, as defined by exceeding the 90th percentile predicted value of a healthy reference group, was associated with Failure to achieve target heart rate in men (31% vs 18%, odds ratio [OR] 2.05, 95% confidence interval [Cl] 1.49 to 2.83) and women (3.4% vs 20%, OR 2.09, 95% Cl 1.63 to 2.69). Similarly, an abnormally high IV mass was predictive of a low chronotropic index in men (18% vs 13%, OR 1.47 95% Cl 1.01 to 2.14) and women (17% vs 10%, OR 1.78, 95% Cl 1.29 to 2.45). When considered as a continuous variable, LV diastolic dimension predicted failure to achieve target heart rate in men (ageadjusted OR For 1 SD increase 1.30, 95% Cl 1.00 to 1.33) and in women (age-adjusted OR 1.30, 95% CI 1.12 to 1.50). Similarly, LV diastolic dimension predicted low chronotropic index in men (age-adjusted OR 1.22, 95% Cl 1.05 to 1.42) and in women (age-adjusted OR 1.18, 95% Cl 1.01 to 1.39). After also adjusting for resting blood pressure, physical activity, and other potential confounders, LV mass, when considered as a continuous variable, remained predictive of failure to achieve target heart rate in men (adjusted OR 1.23, 95% Cl 1.06 to 1.42) and a low chronotropic index in men (adjusted OR 1.26, 95% Cl 1.06 to 1.49). Among women, LV diastolic dimension predicted failure to achieve target heart rate (adjusted OR 1.27 95% Cl 1.12 to 1.45) and low chronotropic index (adjusted OR 1.18, 95% Cl 1.01 to 1.39), whereas in men it predicted low chronotropic index (adjusted OR 1.22, 95% Cl 1.04 to 1.42). Conclusions In this asymptomotic, population-based cohort, chronotropic incompetence was predicted by increased LV mass and cavity size; among men, it was also predicted by depressed systolic function. C1 Cleveland Clin Fdn, Dept Cardiol, Sect Heart Failure & Transplantat, Cleveland, OH 44195 USA. NHLBI, Framingham Heart Study, NIH, Inst Blood, Framingham, MA USA. Boston Univ, Sch Med, Dept Prevent Med & Epidemiol, Boston, MA USA. RP Lauer, MS (reprint author), Cleveland Clin Fdn, Dept Cardiol, Sect Heart Failure & Transplantat, 9500 Euclid Ave, Cleveland, OH 44195 USA. RI Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 FU NHLBI NIH HHS [N01-HC-38038] NR 23 TC 32 Z9 32 U1 0 U2 0 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD MAY PY 1999 VL 137 IS 5 BP 903 EP 909 DI 10.1016/S0002-8703(99)70415-1 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 194AY UT WOS:000080171000022 PM 10220640 ER PT J AU Hesdorffer, DC Melton, LJ Malkasian, GD Atkinson, EJ Brinton, LA O'Fallon, WM AF Hesdorffer, DC Melton, LJ Malkasian, GD Atkinson, EJ Brinton, LA O'Fallon, WM TI Hip fractures among infertile women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cohort studies; hip fractures; infertility; menstrual cycle; menstruation disorders ID BONE-MINERAL DENSITY; MIDDLE-AGED WOMEN; RISK-FACTORS; OSTEOPOROTIC FRACTURES; PERIMENOPAUSAL WOMEN; REPRODUCTIVE FACTORS; MASS; HISTORY; PREMENOPAUSAL; EPIDEMIOLOGY AB A retrospective cohort study was conducted in a population-based inception cohort of 1,157 Olmsted County, Minnesota, women with infertility (failure to conceive after 1 year despite intercourse without contraception) that was first diagnosed at the Mayo Clinic (Rochester, Minnesota) between 1935 and 1964. In this relatively young cohort, 31 hip fractures were observed during 35,849 person-years of follow-up; 36.5 had been expected (standardized incidence ratio = 0.85, 95% confidence interval 0.58-1.20), Standardized incidence ratios did not differ by type or cause of infertility. The data suggested that women with consistently irregular menses may have a greater risk of hip fracture. This finding should be confirmed by additional studies with longer follow-up periods and with assessment of other fracture outcomes. C1 Mayo Clin & Mayo Fdn, Dept Hlth Sci Res, Clin Epidemiol Sect, Rochester, MN 55905 USA. Columbia Univ Coll Phys & Surg, Gertrude H Sergievsky Ctr, New York, NY 10032 USA. Mayo Clin & Mayo Fdn, Dept Obstet & Gynecol, Rochester, MN 55905 USA. NCI, Environm Epidemiol Branch, Bethesda, MD 20892 USA. RP Melton, LJ (reprint author), Mayo Clin & Mayo Fdn, Dept Hlth Sci Res, Clin Epidemiol Sect, 200 1st St SW, Rochester, MN 55905 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 FU NIA NIH HHS [AG04875]; NIAMS NIH HHS [AR30582] NR 28 TC 7 Z9 7 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 MAY 1 PY 1999 VL 149 IS 9 BP 810 EP 813 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 190FW UT WOS:000079952900004 PM 10221317 ER PT J AU Sharrett, AR Sorlie, PD Chambless, LE Folsom, AR Hutchinson, RG Heiss, G Szklo, M AF Sharrett, AR Sorlie, PD Chambless, LE Folsom, AR Hutchinson, RG Heiss, G Szklo, M TI Relative importance of various risk factors for asymptomatic carotid atherosclerosis versus coronary heart disease incidence - The atherosclerosis risk in communities study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE atherosclerosis; carotid artery diseases; coronary disease; prospective studies; risk factors ID MIDDLE-AGED MEN; IMPROVED LIPOLYTIC EFFICIENCY; RETINYL PALMITATE RESPONSES; LOW-DENSITY-LIPOPROTEIN; POSTPRANDIAL TRIGLYCERIDE; ARTERY DISEASE; FACTOR-VII; ENZYMATIC DETERMINATION; PLASMA-LEVELS; PATHOGENESIS AB Major risk factors for coronary heart disease are also associated with early carotid artery thickening, but no studies have yet examined patterns of risk factors to see whether they differ for the two outcomes. Assuming similar pathogenesis for both coronary and carotid atherosclerosis, one could interpret risk factor pattern differences as relating to differences in staging, i.e., early atheroma versus later stenotic or occlusive atherothrombosis. This study included 12,193 Atherosclerosis Risk in Communities Study participants aged 45-64 years who were free of clinical cardiovascular disease in 1987-1989, in whom 420 myocardial infarctions or coronary heart disease deaths occurred over the next 6 years. Plasma low density lipoprotein cholesterol, systolic blood pressure, and smoking were major risk factors for both outcomes. Compared with these factors, triglycerides and high density lipoprotein (HDL) cholesterol were associated only weakly with carotid atherosclerosis but were associated strongly with coronary heart disease incidence. No other risk factors, including those associated with diabetes mellitus, hemostasis, and inflammation, differed in their relative contribution to the two outcomes. These results suggest that the high triglyceride-low HDL cholesterol pattern is involved in the transition from atheroma to atherothrombosis, and that control of this pattern may be important in persons with detectable subclinical disease. C1 NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ N Carolina, Sch Publ Hlth, Dept Biostat, Chapel Hill, NC USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Sharrett, AR (reprint author), NHLBI, Div Epidemiol & Clin Applicat, 2 Rockledge Ctr,MSC 7934,6701 Rockledge Dr,Room 8, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [N01-HC55016, N01-HC55015, N01-HC55018] NR 37 TC 66 Z9 67 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 MAY 1 PY 1999 VL 149 IS 9 BP 843 EP 852 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 190FW UT WOS:000079952900008 PM 10221321 ER PT J AU Harris, TB Ferrucci, L Tracy, RP Corti, MC Wacholder, S Ettinger, WH Heimovitz, H Cohen, HJ Wallace, R AF Harris, TB Ferrucci, L Tracy, RP Corti, MC Wacholder, S Ettinger, WH Heimovitz, H Cohen, HJ Wallace, R TI Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly SO AMERICAN JOURNAL OF MEDICINE LA English DT Article ID CORONARY HEART-DISEASE; SERUM AMYLOID-A; CARDIOVASCULAR-DISEASE; UNSTABLE ANGINA; RISK-FACTORS; PLASMA IL-6; HEALTHY-MEN; INFLAMMATION; METHODOLOGY; VARIABILITY AB PURPOSE: To investigate whether interleukin-6 and C-reactive protein levels predict all-cause and cause-specific mortality in a population-based sample of nondisabled older people. SUBJECTS AND METHODS: A sample of 1,293 healthy, nondisabled participants in the Iowa 65+ Rural Health Study was followed prospectively for a mean of 4.6 years. Plasma interleukin-6 and C-reactive protein levels were measured in specimens obtained from 1987 to 1989. RESULTS: Higher interleukin-6 levels were associated with a twofold greater risk of death [relative risk (RR) for the highest quartile (greater than or equal to 3.19 pg/mL) compared with the lowest quartile of 1.9 [95% confidence interval, CI, 1.2 to 3.11]. Higher C-reactive protein levels (greater than or equal to 2.78 mg/L) were also associated with increased risk (RR = 1.6; CI, 1.0 to 2.6). Subjects with elevation of both interleukin-6 and C-reactive protein levels were 2.6 times more likely (CI, 1.6 to 4.3) to die during follow-up than those with low levels of both measurements. Similar results were found for cardiovascular and noncardiovascular causes of death, as well as when subjects were stratified by sex, smoking status, and prior cardiovascular disease, and for both early (<2.3 years) and later follow-up. Results were independent of age, sex, body mass index, and history of smoking, diabetes, and cardiovascular disease, as well as known indicators of inflammation including fibrinogen and albumin levels and white blood cell count. CONCLUSIONS: Higher circulating levels of interleukin-6 and C-reactive protein were associated with mortality in this population-based sample of healthy older persons. These measures may be useful for identification of high-risk subgroups for anti-inflammatory interventions. (C) 1999 by Excerpta Medica, Inc. C1 NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. Natl REs Inst INRCA, Florence, Italy. Univ Vermont, Burlington, VT USA. Univ Padua, Padua, Italy. NCI, Bethesda, MD 20892 USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. Sytel, Bethesda, MD USA. Duke Univ, Sch Med, Durham, NC USA. Univ Iowa, Coll Med, Iowa City, IA USA. RP Harris, TB (reprint author), NIA, Epidemiol Demog & Biometry Program, Gateway Bldg,Room 3C-309,7201 Wisconsin Ave, Bethesda, MD 20892 USA. FU NIA NIH HHS [AG-0-2106] NR 36 TC 927 Z9 958 U1 4 U2 20 PU EXCERPTA MEDICA INC PI NEW YORK PA 245 WEST 17TH STREET, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD MAY PY 1999 VL 106 IS 5 BP 506 EP 512 DI 10.1016/S0002-9343(99)00066-2 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 194YA UT WOS:000080221300003 PM 10335721 ER PT J AU Garcia-Closas, M Herrero, R Bratti, C Hildesheim, A Sherman, ME Morera, LA Schiffman, M AF Garcia-Closas, M Herrero, R Bratti, C Hildesheim, A Sherman, ME Morera, LA Schiffman, M TI Epidemiologic determinants of vaginal pH SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE aging; bacterial vaginosis; cervical neoplasia; menopause; vaginal pH ID POST-MENOPAUSAL WOMEN; BACTERIAL VAGINOSIS; CERVICAL-CANCER; POSTMENOPAUSE; CYTOLOGY AB OBJECTIVES: This study was undertaken to evaluate the relationship between vaginal pH and factors related to cervical cancer. STUDY DESIGN: In a population-based sample of 9161 women from Guanacaste Province in Costa Pica women were categorized into 2 groups, those with vaginal pH in the reference range (4.0-4.5) and those with elevated vaginal pH (5.0-5.5). Odds ratios were used to estimate the relationship between elevated pH and its potential determinants. RESULTS: Aging was strongly associated with increasing vaginal pH, starting at around 45 years of age and continuing into old age. Menopause was responsible for an additional 1.7-fold increase in the odds of having an elevated pH (odds ratio 1.7, 95% confidence interval 1.4-2.0). Human papillomavirus infection and cervical intraepithelial neoplasia were not associated with changes in pH. CONCLUSIONS: Our data indicate that vaginal pH is strongly related to age and to menopausal status and thus could be a marker of age-related hormonal changes. Elevated pH does not appear to be associated with risk of high-grade intraepithelial neoplasia among women infected with human papillomavirus. C1 NCI, EEB, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20892 USA. Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. Int Agcy Res Canc, F-69372 Lyon, France. RP Garcia-Closas, M (reprint author), NCI, EEB, Div Canc Epidemiol & Genet, NIH, Execut Plaza S,Room 7076,6120 Execut Blvd, Rockville, MD 20892 USA. RI Garcia-Closas, Montserrat /F-3871-2015 OI Garcia-Closas, Montserrat /0000-0003-1033-2650 NR 26 TC 26 Z9 26 U1 0 U2 1 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAY PY 1999 VL 180 IS 5 BP 1060 EP 1066 DI 10.1016/S0002-9378(99)70595-8 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 201PB UT WOS:000080603000003 PM 10329856 ER PT J AU Andrews, WW Tsao, J Goldenberg, RL Hauth, JC Mercer, B Iams, J Meis, P Moawad, A Das, A Van Dorsten, PJ Caritis, SN Thurnau, G Miodovnik, M Roberts, J McNellis, D AF Andrews, WW Tsao, J Goldenberg, RL Hauth, JC Mercer, B Iams, J Meis, P Moawad, A Das, A Van Dorsten, PJ Caritis, SN Thurnau, G Miodovnik, M Roberts, J McNellis, D TI The Preterm Prediction Study: Failure of midtrimester cervical sialidase level elevation to predict subsequent spontaneous preterm birth SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE bacterial vaginosis; genital tract infection; neuraminidase; prematurity; preterm birth; sialidase ID BACTERIAL VAGINOSIS; GARDNERELLA-VAGINALIS; FETAL FIBRONECTIN; CONTROLLED TRIAL; METRONIDAZOLE; NEURAMINIDASE; WOMEN; INFECTIONS; MICROFLORA; PREGNANCY AB OBJECTIVE: Our objective was to determine any associations among midtrimester cervical fluid sialidase activity, bacterial vaginosis, and subsequent spontaneous preterm birth. STUDY DESIGN: In this nested case-control study all patients (n=126) with spontaneous preterm birth at <35 weeks' gestation and selected control subjects delivered at greater than or equal to 37 weeks' gestation (n=126, matched for race, parity, and center) were derived from women enrolled in the multicenter National institute of Child Health and Human Development Preterm Prediction Study. Sialidase activity and presence of bacterial vaginosis according to Gram stain were determined in cervical swabs and vaginal smears, respectively, obtained at 22 weeks' to 24 weeks 6 days' gestation. RESULTS: The mean +/- SD sialidase activities were similar in case patients and control subjects (0.64 +/- 1.60 vs 0.41 +/- 0.94 nmol . mL(-1) . min(-1), P=.21). Neither sialidase activity above the 90th percentile (10.3% vs 9.5%, P=.8) nor sialidase activity above the 95th percentile (7.9% vs 4.8%, P=.3) of control specimens (>1.43 and >2.23 nmol . mL(-1) . min(-1), respectively) was associated with spontaneous preterm birth. The frequency of combinations of bacterial vaginosis and elevated sialidase activity was similar (P greater than or equal to.63 with either cutoff) in case patients and control subjects. Sialidase activity was significantly higher among women with bacterial vaginosis than among those without bacterial vaginosis (1.35 +/- 1.87 vs 0.03 +/- 0.14 nmol . mL(-1) . min(-1), P<.0001). CONCLUSIONS: Elevated cervical fluid sialidase activity at 22 to 24 weeks' gestation did not distinguish women at increased risk for spontaneous preterm birth, nor did it discriminate a subgroup of patients who had bacterial vaginosis associated with spontaneous preterm birth. C1 Univ Alabama, NICHHD, Maternal Fetal Med Unit Network, Birmingham, AL USA. Univ Alabama, Dept Microbiol, Birmingham, AL USA. RP Andrews, WW (reprint author), Univ Alabama, Dept Obstet & Gynecol, 618 South 20th St, Birmingham, AL 35233 USA. OI caritis, steve/0000-0002-2169-0712 NR 23 TC 22 Z9 23 U1 0 U2 2 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAY PY 1999 VL 180 IS 5 BP 1151 EP 1154 DI 10.1016/S0002-9378(99)70609-5 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 201PB UT WOS:000080603000017 PM 10329870 ER PT J AU Whitcup, SM Ferris, FL AF Whitcup, SM Ferris, FL TI New corticosteroids for the treatment of ocular inflammation SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Editorial Material ID LOTEPREDNOL ETABONATE; EFFICACY; UVEITIS; SAFETY C1 NEI, NIH, Bethesda, MD 20892 USA. RP Whitcup, SM (reprint author), NEI, NIH, 10 Ctr Dr,Bldg 10,Room 10S221, Bethesda, MD 20892 USA. NR 9 TC 11 Z9 11 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD MAY PY 1999 VL 127 IS 5 BP 597 EP 599 PG 3 WC Ophthalmology SC Ophthalmology GA 194DN UT WOS:000080177000015 PM 10334354 ER PT J AU Battey, JF AF Battey, JF TI News from the National Institute on Deafness and other Communication Disorders SO AMERICAN JOURNAL OF OTOLOGY LA English DT Article C1 Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. RP Battey, JF (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0192-9763 J9 AM J OTOL JI Am. J. Otol. PD MAY PY 1999 VL 20 IS 3 BP 297 EP 298 PG 2 WC Otorhinolaryngology SC Otorhinolaryngology GA 192QZ UT WOS:000080091600003 PM 10337967 ER PT J AU Cooper, RA Quatrano, LA Stanhope, SJ Cavanagh, PR Miller, F Kerrigan, DC Esquenazi, A Harris, GF Winters, LM AF Cooper, RA Quatrano, LA Stanhope, SJ Cavanagh, PR Miller, F Kerrigan, DC Esquenazi, A Harris, GF Winters, LM TI Gait analysis in rehabilitation medicine - A brief report SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article DE gait analysis; motion analysis; research priorities; rehabilitation AB Gait analysis can be a powerful tool for rehabilitation research and clinical practice. However, there has been little coordinated effort to set goals for the application of gait analysis in rehabilitation. Therefore, a priority setting process was engaged to obtain the opinions of a diverse pool of experts related to human motion analysis. The primary goal of this process was to develop priorities for future research, development, and standardization in gait analysis. A multistep approach was used that included expert testimony, group discussions, individually developed priorities, and a ranking process. Several important priorities emerged from this activity. The highest priority was assigned to research on the efficacy, outcomes, and cost-effectiveness of gait analysis. C1 NICHHD, Natl Ctr Med Rehab Res, NIH, Rockville, MD USA. Univ Pittsburgh, Dept Rehabil Sci & Technol, Pittsburgh, PA USA. Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA. Univ Pittsburgh, Div Phys Med & Rehabil, Pittsburgh, PA USA. NIH, Biomech Lab, Dept Rehabil Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD USA. Penn State Univ, Ctr Locomot Studies, University Pk, PA 16802 USA. Alfred I Dupont Inst, Wilmington, DE USA. Harvard Med Sch, Spaulding Rehabil Hosp, Boston, MA USA. Temple Univ Hosp, Moss Rehabil Hosp, Philadelphia, PA 19140 USA. Shriners Hosp Crippled Children, Pediat Mot Anal & Gait Lab, Chicago, IL USA. Catholic Univ Amer, Dept Biomed Engn, Washington, DC 20064 USA. RP Cooper, RA (reprint author), Human Engn Res Labs, 7180 Highland Dr, Pittsburgh, PA 15206 USA. NR 1 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-9115 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD MAY-JUN PY 1999 VL 78 IS 3 BP 278 EP 280 DI 10.1097/00002060-199905000-00019 PG 3 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 196DP UT WOS:000080294000013 PM 10340426 ER PT J AU Ginis, I Schweizer, U Brenner, M Liu, J Azzam, N Spatz, M Hallenbeck, JM AF Ginis, I Schweizer, U Brenner, M Liu, J Azzam, N Spatz, M Hallenbeck, JM TI TNF-alpha pretreatment prevents subsequent activation of cultured brain cells with TNF-alpha and hypoxia via ceramide SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE ceramide; intercellular adhesion molecule-1; astrocytes; brain endothelial cells; ischemic tolerance; tumor necrosis factor-alpha ID TUMOR-NECROSIS-FACTOR; STRESS-INDUCED APOPTOSIS; FACTOR KAPPA-B; ENDOTHELIAL-CELLS; PROTEIN-KINASE; SPHINGOMYELIN PATHWAY; ISCHEMIA-REPERFUSION; OXIDATIVE STRESS; RAT; INJURY AB We have developed a cellular model in which cultured astrocytes and brain capillary endothelial cells preconditioned with tumor necrosis factor-alpha (TNF-alpha) fail to upregulate intercellular adhesion molecule-1 (ICAM-1) protein (80%, inhibition) and mRNA (30% inhibition) when challenged with TNF-alpha or exposed to hypoxia. Inasmuch as ceramide is known to mediate some of the effects of TNF-alpha, its levels were measured at various times after the TNF-alpha preconditioning. We present evidence for the first time that, in normal brain cells, TNF-alpha pretreatment causes a biphasic increase of ceramide levels: an early peak at 15-20 min, when ceramide levels increased 1.9-fold in astrocytes and 2.7-fold in rat brain capillary endothelial cells, and a delayed 2- to 3-fold ceramide increase that occurs 18-24 h after addition of TNF-alpha. The following findings indicate that the delayed ceramide accumulation results in cell unresponsiveness to TNF-alpha: 1) coincident timing of the ceramide peak and the tolerance period, 2) mimicking of preconditioning by addition of exogenous ceramide, and 3) attenuation of preconditioning by fumonisin B-1, an inhibitor of ceramide synthesis. In contrast to observations in transformed cell lines, the delayed ceramide increase was transient and did not induce apoptosis in brain cells. C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. RP Ginis, I (reprint author), NINDS, Stroke Branch, NIH, Bldg 36,Rm 4A03, Bethesda, MD 20892 USA. EM ginis@codon.nih.gov RI Schweizer, Ulrich/E-8105-2013 NR 55 TC 54 Z9 55 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD MAY PY 1999 VL 276 IS 5 BP C1171 EP C1183 PG 13 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 195HR UT WOS:000080245000022 PM 10329967 ER PT J AU Youngren, JF Goldfine, ID Pratley, RE AF Youngren, JF Goldfine, ID Pratley, RE TI Insulin receptor autophosphorylation in cultured myoblasts correlates to glucose disposal in Pima Indians SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE insulin receptor tyrosine kinase; insulin resistance ID HUMAN SKELETAL-MUSCLE; DEPENDENT DIABETES-MELLITUS; TYROSINE-KINASE-ACTIVITY; OBESE SUBJECTS; CELL-CULTURES; RESISTANCE; NIDDM AB In a previous study [Youngren, J. F., I. D. Goldfire, and R. E. Pratley. Am. J. Physiol. 273 (Endocrinol. Metab. 36): E276-E283, 1997] of skeletal muscle biopsies from insulin-resistant, nondiabetic Pima Indians, we demonstrated that diminished insulin receptor (IR) autophosphorylation correlated with in vivo insulin resistance. In the present study, to determine whether decreased IR function is a primary trait of muscle, and not secondary to an altered in vivo environment, we cultured myoblasts from 17 nondiabetic Pima Indians in whom insulin-stimulated glucose disposal (M) was measured during hyperinsulinemic-euglycemic glucose clamps. Myoblast IR autophosphorylation was determined by a highly sensitive ELISA. IR autophosphorylation directly correlated with M (r = 0.56, P = 0.02) and inversely correlated with the fasting plasma insulin (r = -0.58, P < 0.05). The relationship between M and IR autophosphorylation remained significant after M was adjusted for the effects of percent body fat (partial r = 0.53, P < 0.04). The relationship between insulin resistance and the capacity for myoblast IR autophosphorylation in nondiabetic Pima Indians suggests that variations in IR-signaling capacity may be intrinsic characteristics of muscle that contribute to the genetic component determining insulin action in this population. C1 Univ Calif San Francisco, Div Diabet & Endocrine Res, Mt Zion Med Ctr, Dept Med, San Francisco, CA 94143 USA. NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. RP Youngren, JF (reprint author), Univ Calif San Francisco, Div Diabet & Endocrine Res, Mt Zion Med Ctr, Dept Med, Box 1616, San Francisco, CA 94143 USA. EM drjack@itsa.ucsf.edu FU NIDDK NIH HHS [DK-44834] NR 23 TC 15 Z9 15 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD MAY PY 1999 VL 276 IS 5 BP E990 EP E994 PG 5 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 194ZF UT WOS:000080224100022 PM 10329994 ER PT J AU Iwasaki, A Kelsall, BL AF Iwasaki, A Kelsall, BL TI Mucosal immunity and inflammation I. Mucosal dendritic cells: their specialized role in initiating T cell responses SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE type 1 T helper cell; type 2 T helper cell; interleukin-12; interleukin-10; interleukin-4 ID ORAL TOLERANCE; PEYERS PATCH; IFN-GAMMA; TH2 CELLS; MICE; IMMUNIZATION; EXPRESSION; EPITHELIUM; INFECTION; APOPTOSIS AB Dendritic cells (DCs) are the most competent antigen-presenting cells known for the induction of primary T cell responses. Functional studies of tissue-resident DCs have been impaired by the rarity of these cells in any given organ. Recent development of isolation procedures allowing extraction of highly purified fresh DC populations has made it possible to study mucosal DCs in distinct mucosa-associated lymphoid tissues. Here, we discuss several recent studies by us and others that describe the tissue-specific phenotype and function of mucosal DCs and speculate on the mechanism by which the resident DCs regulate tissue-specific T cell responses. C1 NIAID, Clin Invest Lab, Mucosal Immun Sect, NIH, Bethesda, MD 20892 USA. RP Kelsall, BL (reprint author), NIAID, Clin Invest Lab, Mucosal Immun Sect, NIH, Bldg 10,Room 11N238,10 Ctr Dr, Bethesda, MD 20892 USA. EM kelsall@nih.gov NR 24 TC 75 Z9 76 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD MAY PY 1999 VL 276 IS 5 BP G1074 EP G1078 PG 5 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 197BH UT WOS:000080344400002 PM 10329996 ER PT J AU Warburton, D Zhao, JS Berberich, MA Bernfield, M AF Warburton, D Zhao, JS Berberich, MA Bernfield, M TI Molecular embryology of the lung: then, now, and in the future SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE sprouty; branchless; breathless; vascular endothelial growth factor; hepatocyte forkhead homologue; surfactant protein A; pulmonary neuroendocrine cells; Notch; laminin ID ACID RECEPTORS RARS; SP-A GENE; BRANCHING MORPHOGENESIS; EMBRYONIC LUNG; SONIC HEDGEHOG; RETINOIC ACID; MOUSE LUNG; MICE LACKING; TRANSFORMING GROWTH-FACTOR-BETA-1; EPITHELIAL DIFFERENTIATION AB Complementary molecular and genetic approaches are yielding information about gain-versus loss-of-function phenotypes of specific genes and gene families in the embryonic, fetal, neonatal, and adult lungs. New insights are being derived from the conservation of function between genes regulating branching morphogenesis of the respiratory organs in Drosophila and in the mammalian lung. The function of specific morphogenetic genes in the lung are now placed in context with pattern-forming functions in other, better understood morphogenetic fields such as the limb bud. Initiation of lung morphogenesis from the floor of the primitive foregut requires coordinated transcriptional activation and repression involving hepatocyte nuclear factor-3 beta, Sonic hedgehog, patched, Gli2, and Gli3 as well as Nkx2.1. Subsequent inductive events require epithelial-mesenchymal interaction mediated by specific fibroblast growth factor ligand-receptor signaling as well as modulation by other peptide growth factors including epidermal growth factor, platelet-derived growth factor-A and transforming growth factor-beta and by extracellular matrix components. A scientific rationale for developing new therapeutic approaches to urgent questions of human pulmonary health such as bronchopulmonary dysplasia is beginning to emerge from work in this field. C1 Childrens Hosp Los Angeles, Res Inst, Dev Biol Program, Los Angeles, CA 90027 USA. Childrens Hosp Los Angeles, Res Inst, Dept Surg, Los Angeles, CA 90027 USA. Univ So Calif, Sch Med, Ctr Craniofacial Mol Biol, Los Angeles, CA 90027 USA. Univ So Calif, Sch Dent, Los Angeles, CA 90027 USA. NHLBI, Div Lung Dis, Dev Biol & Pediat Grp, NIH, Bethesda, MD 20892 USA. Harvard Univ, Childrens Hosp, Sch Med, Div Dev & Newborn Biol, Boston, MA 02115 USA. RP Warburton, D (reprint author), Childrens Hosp Los Angeles, Res Inst, Dev Biol Program, 4650 Sunset Blvd,MS 35, Los Angeles, CA 90027 USA. NR 57 TC 67 Z9 68 U1 0 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD MAY PY 1999 VL 276 IS 5 BP L697 EP L704 PG 8 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 194ZD UT WOS:000080223900002 PM 10330024 ER PT J AU Traynor, T Yang, TX Huang, YNG Krege, JH Briggs, JP Smithies, O Schnermann, J AF Traynor, T Yang, TX Huang, YNG Krege, JH Briggs, JP Smithies, O Schnermann, J TI Tubuloglomerular feedback in ACE-deficient mice SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE transgenic mouse; gene knockout; micropuncture; angiotensin converting enzyme; stop-flow pressure ID ANGIOTENSIN-CONVERTING ENZYME; BLOOD-PRESSURE; CARDIOVASCULAR HOMEOSTASIS; FILTRATION-RATE; HENLE FLOW; INHIBITION; PLASMA; GENE; DETERMINANTS; FERTILITY AB In these experiments, we used a strain of angiotensin converting enzyme (ACE) germline null mutant mice, generated by J. H. Krege and co-workers (J. H. Krege, S. W. M. John, L. L. Langenbach, J. B. Hodgin, J. R. Hagaman, E. S. Bachman, J. C. Jennette, D.A. O'Brien, and O. Smithies. Nature 375: 146-148, 1995), to examine the effect of chronic ACE deficiency on the magnitude of tubuloglomerular feedback (TGF) responses; The genotype was determined by PCR on DNA extracted from the tail and was verified after each experiment by assessment of the blood pressure response to an injection of ANG I. To assess TGF responsiveness, we determined the change in stop-flow pressure (P(SF)) caused by increasing NaCl concentration at the macula densa by using micropuncture techniques. When loop of Henle flow rate was increased from 0 to 40 nl/min, P(SF) fell from a mean of 42.3 +/- 1.95 to 33.6 +/- 2.09 mmHg (n = 6, P = 0.005) in wild-type mice (+/+), fell from 40.6 +/- 2.35 to 38.6 +/- 1.93 mmHg in heterozygous (+/-) mice (n = 7, P = 0.014), and did not change in homozygous ACE (-/-) mice [36.7 +/- 2.02 mmHg vs. 36.4 +/- 2.01 mmHg; n = 4, P = not significant (NS)]. During an infusion of ANG II at a dose that did not significantly elevate blood pressure (70 ng.kg(-1).min(-1)), TGF response magnitude (P(SF0) - P(SF40)) increased from 6.5 +/- 1.4 to 9.8 +/- 1.19 mmHg in +/+ (P = 0.006); from 1.14 +/- 0.42 to 4.6 +/- 1.3 mmHg in +/- (P = 0.016),and from 0.42 +/- 0.25 to 4.02 +/- 1.06 in -/- mice (P = 0.05). Absence of TGF responses in ACE null mutant mice and restoration of near-normal responses during an acute infusion of ANG II supports previous conclusions that ANG II is an essential component in the signal transmission pathway that links the macula densa with the glomerular vascular pole. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. Univ Michigan, Dept Physiol, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ N Carolina, Dept Pathol, Chapel Hill, NC 27599 USA. Guilford Med Associates, Greensboro, NC 27405 USA. RP Schnermann, J (reprint author), NIDDKD, NIH, Bldg 10,Room 4D 51,10 Ctr Dr,MSC 1370, Bethesda, MD 20892 USA. EM JurgenS@intra.niddk.nih.gov RI Briggs, Josephine/B-9394-2009 OI Briggs, Josephine/0000-0003-0798-1190 FU NHLBI NIH HHS [HL-49277]; NIDDK NIH HHS [DK-40042, DK-37448] NR 29 TC 34 Z9 34 U1 1 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 MAY PY 1999 VL 276 IS 5 BP F751 EP F757 PG 7 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 194YY UT WOS:000080223400012 PM 10330057 ER PT J AU Raczynski, JM Finnegan, JR Zapka, JG Meischke, H Meshack, A Stone, EJ Bracht, N Sellers, DE Daya, M Robbins, M McAlister, A Simons-Morton, D AF Raczynski, JM Finnegan, JR Zapka, JG Meischke, H Meshack, A Stone, EJ Bracht, N Sellers, DE Daya, M Robbins, M McAlister, A Simons-Morton, D TI REACT theory-based intervention to reduce treatment-seeking delay for acute myocardial infarction SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Review DE coronary artery disease; acute myocardial infarction; treatment-seeking delay; community trial ID CORONARY HEART-DISEASE; NORTH KARELIA PROJECT; PREHOSPITAL DELAY; THROMBOLYTIC THERAPY; RISK-FACTORS; COMMUNITY INTERVENTION; IMMEDIATE ANGIOPLASTY; HOSPITAL ARRIVAL; CHEST PAIN; CARE UNIT AB Coronary heart disease (CHD) remains the leading cause of mortality in the U.S. Innovations in reperfusion therapies can potentially reduce CHD morbidity and mortality associated with acute myocardial infarction (AMI) when treatment is initiated within the first few hours of symptom onset. However, delay in seeking treatment for AMI is unacceptably lengthy, resulting in most patients being ineligible for reperfusion therapies. The Rapid Early Action for Coronary Treatment (REACT) Trial is a four-year, 20-community, randomized trial tc, design and test the effectiveness of a multi-component intervention to reduce patient delay fbr hospital care-seeking for AMI symptoms. This manuscript describes the development and content of the theoretically-based REACT intervention and summarizes: (1) the research literature used to inform the intervention; (2) the behavioral theories used to guide the development, implementation, and evaluation of the intervention; (3) the formative research undertaken to understand better decision-making processes as well as barriers and facilitators to seeking medical care as perceived by AMI patients, their families, and medical professionals; (4) the intervention design issues that were addressed; (5) the synthesis of data sources in developing the core message content; (6) the conceptualization for determining the intervention target audiences and associated intervention components and strategies, their integration with guiding theoretical approaches and implementation theories for the study, and a description of major intervention materials developed to implement the intervention; and (7) the focus of the outcome, impact, and process measurement based on the intervention components and theories on which they were developed. (C) 1999 American Journal of Preventive Medicine. C1 Univ Alabama, Ctr Hlth Promot, Birmingham, AL 35294 USA. Univ Alabama, Dept Med, Birmingham, AL 35294 USA. Univ Alabama, Dept Hlth Behav, Birmingham, AL 35294 USA. Univ Minnesota, Sch Publ Hlth, Dept Epidemiol, Minneapolis, MN USA. Univ Massachusetts, Ctr Med, Div Prevent & Behav Med, Worcester, MA 01605 USA. King Cty EMS, Seattle, WA USA. Univ Texas, Sch Publ Hlth, Houston, TX USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. New England Res Inst, Watertown, MA 02172 USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. Univ Rhode Isl, Kingston, RI 02881 USA. RP Raczynski, JM (reprint author), Univ Alabama, Ctr Hlth Promot, 215 Ryals Bldg, Birmingham, AL 35294 USA. FU NHLBI NIH HHS [U01-HL-53412, U01-HL-53141, U01-HL-53149] NR 70 TC 26 Z9 27 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD MAY PY 1999 VL 16 IS 4 BP 325 EP 334 DI 10.1016/S0749-3797(99)00023-9 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 198MG UT WOS:000080427500011 PM 10493291 ER PT J AU Hser, YI Joshi, V Anglin, MD Fletcher, B AF Hser, YI Joshi, V Anglin, MD Fletcher, B TI Predicting posttreatment cocaine abstinence for first-time admissions and treatment repeaters SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID DRUG-ABUSE TREATMENT; FOLLOW-UP OUTCOMES; TREATMENT CAREERS; DATOS; CLIENTS; CRACK; BEHAVIORS; RETENTION; SPENT AB Objectives. This study examined client and program characteristics that predict posttreatment cocaine abstinence among cocaine abusers with different treatment histories. Methods. Cocaine abusers (n = 507) treated in 18 residential programs were interviewed at intake and 1-year follow-up as part of the nationwide Drug Abuse Treatment Outcome Study (DATOS) Program directors provided the program-level data in a mail survey. We applied the hierarchical linear modeling approach for the analysis. Results. No prior treatment and longer retention in DATOS programs were positive predictors of posttreatment abstinence. The interactive effect of these 2 variables was also significantly positive. Programs that offered legal services and included recovering staff increased their clients' likelihood of cocaine abstinence. Crack use at both the client and program level predicted negative impact. None of the program variables assessed differentially affected the outcomes of first-timers and repeaters. Conclusions. Although treatment repeaters were relatively difficult to treat, their likelihood of achieving abstinence was similar to that of first-timers if they were retained in treatment for a sufficient time. First-timers and repeaters responded similarly to the treatment program characteristics examined. The treatment and policy implications of these findings are discussed. C1 Univ Calif Los Angeles, Inst Neuropsychiat, Los Angeles, CA 90025 USA. NIDA, Bethesda, MD USA. RP Hser, YI (reprint author), Univ Calif Los Angeles, Drug Abuse Res Ctr, 1640 S Sepulveda Blvd,Suite 200, Los Angeles, CA 90025 USA. FU NIDA NIH HHS [K02-DA00139, K02-DA00146, U01-DA10378] NR 27 TC 49 Z9 51 U1 1 U2 2 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAY PY 1999 VL 89 IS 5 BP 666 EP 671 DI 10.2105/AJPH.89.5.666 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 189RL UT WOS:000079919600004 PM 10224976 ER PT J AU Svikis, DS Pickens, RW Schweitzer, W Johnson, E Haug, N AF Svikis, DS Pickens, RW Schweitzer, W Johnson, E Haug, N TI Weekly patterns of drug treatment attendance SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID DISABILITY BENEFITS; COCAINE DEPENDENCE; MENTAL-ILLNESS; SUBSTANCE-ABUSE; PAYMENTS; ABSTINENCE; ALCOHOL; REINFORCEMENT; RECIPIENTS; INCENTIVES AB Objectives. This study examined weekly patterns of drug treatment attendance in relation to date of welfare payment receipt and reason for treatment absence. Methods. Treatment attendance by Medicaid-eligible pregnant women who were drug dependent was examined by calendar week over a 29-month period. Results. Time series analyses showed that attendance was lower during week 1 than week 4. Drug use was the most frequently reported reason for treatment absence during week 1 (25%) but was not reported as a reason during week 3. Conclusion. Drug-dependent out-patients had increased absences associated with illicit drug use during the first week of the month when welfare payments were received. The generalizability of the findings is unknown. C1 Johns Hopkins Bayview Med Ctr, Ctr Addict & Pregnancy, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. NIDA, Intramural Res Program, Baltimore, MD USA. Henry Ford Hlth Sci Ctr, Detroit, MI USA. RP Svikis, DS (reprint author), Johns Hopkins Bayview Med Ctr, Ctr Addict & Pregnancy, D-4-E,4940 Eastern Ave, Baltimore, MD 21224 USA. FU NIDA NIH HHS [P50 DA 09258] NR 34 TC 3 Z9 3 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAY PY 1999 VL 89 IS 5 BP 752 EP 755 DI 10.2105/AJPH.89.5.752 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 189RL UT WOS:000079919600017 PM 10224989 ER PT J AU Gladwin, MT Schechter, AN Shelhamer, JH Ognibene, FP AF Gladwin, MT Schechter, AN Shelhamer, JH Ognibene, FP TI The acute chest syndrome in sickle cell disease - Possible role of nitric oxide in its pathophysiology and treatment SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article ID RED-BLOOD-CELLS; HYPOXIC PULMONARY VASOCONSTRICTION; RESPIRATORY-DISTRESS SYNDROME; ISOLATED RAT LUNGS; ENDOTHELIAL-CELLS; ERYTHROCYTE ADHERENCE; S-NITROSOHEMOGLOBIN; VASCULAR REACTIVITY; PULSE OXIMETRY; RIB INFARCTS C1 NIDDKD, Dept Crit Care Med, Warren G Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. RP Gladwin, MT (reprint author), NIDDKD, Dept Crit Care Med, Warren G Magnuson Clin Ctr, NIH, Bldg 10,Room 7D43, Bethesda, MD 20892 USA. OI Schechter, Alan N/0000-0002-5235-9408 NR 87 TC 46 Z9 46 U1 0 U2 1 PU AMER LUNG ASSOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAY PY 1999 VL 159 IS 5 BP 1368 EP 1376 PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 196GU UT WOS:000080301300002 PM 10228097 ER PT J AU Karzai, W von Specht, BU Parent, C Haberstroh, J Wollersen, K Natanson, C Banks, SM Eichacker, PQ AF Karzai, W von Specht, BU Parent, C Haberstroh, J Wollersen, K Natanson, C Banks, SM Eichacker, PQ TI G-CSF during Escherichia coli versus Staphylococcus aureus pneumonia in rats has fundamentally different and opposite effects SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article ID COLONY-STIMULATING FACTOR; TUMOR-NECROSIS-FACTOR; ACUTE LUNG INJURY; SEPTIC SHOCK; GUINEA-PIGS; VASCULAR-PERMEABILITY; IMPROVES SURVIVAL; HUMAN NEUTROPHILS; FACTOR-ALPHA; RG-CSF AB We investigated if bacteria type alters outcome with prophylactic granulocyte colony stimulating factor (G-CSF) therapy during pneumonia. Rats received G-CSF or placebo daily for 6 d and after the third dose were intrabronchially inoculated with either Escherichia coli or Staphylococcus aureus. Without G-CSF, E. coli and S. aureus produced similar (p = NS) mortality rates (36 versus 38%) and serial changes in mean circulating neutrophil counts (CNC), but differing mean (+/-SE) tumor necrosis factor (TNF) levels (E. coli, 259 +/- 104 versus S. aureus, 51 +/- 17 pg/ml, p = 0.01). G-CSF prior to bacteria increased mean CNC more than six times compared with placebo (p = 0.001). However, with G-CSF in the first 6 h after E. coli, there was a greater than 20-fold decrease in mean (+/- SE) CNC (x 10(3)/mm(3)) to below placebo (0.5 +/- 0.1 versus 0.8 +/- 0.1), whereas with G-CSF after S. aureus, there was only a fivefold decrease in mean CNC and CNC were greater than placebo (1.8 +/- 0.2 versus 0.8 +/- 0.1) (E. coli versus S. aureus decrease in CNC with G-CSF, p = 0 001). With E. coli, G-CSF worsened oxygenation and increased bacteremia and mortality, whereas with S. aureus, C-CSF improved oxygenation and decreased bacteremia and mortality (G-CSF therapy, E. coli versus 5. aureus, p = 0.03, 0.05, and 0.001, respectively). Thus, during S. aureus pneumonia with low TNF levels, G-CSF increased CNC and bacterial clearance, resulting in less pulmonary injury and decreased death. During E. coli pneumonia with high TNF levels, G-CSF paradoxically decreased CNC, resulting in impaired bacterial clearance and worsened pulmonary injury and death. Bacterial species and the associated inflammatory mediator response can alter outcome with prophylactic C-CSF therapy during pneumonia. C1 Univ Hosp, Dept Anesthesiol, Freiburg, Germany. Univ Hosp, Dept Surg Res, Freiburg, Germany. NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Karzai, W (reprint author), Univ Hosp, Dept Anesthesiol, D-07740 Jena, Germany. NR 36 TC 53 Z9 56 U1 0 U2 0 PU AMER LUNG ASSOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAY PY 1999 VL 159 IS 5 BP 1377 EP 1382 PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 196GU UT WOS:000080301300003 PM 10228098 ER PT J AU Hamid, QA Wenzel, SE Hauk, PJ Tsicopoulos, A Wallaert, B Lafitte, JJ Chrousos, GP Szefler, SJ Leung, DYM AF Hamid, QA Wenzel, SE Hauk, PJ Tsicopoulos, A Wallaert, B Lafitte, JJ Chrousos, GP Szefler, SJ Leung, DYM TI Increased glucocorticoid receptor beta in airway cells of glucocorticoid-insensitive asthma SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article ID STEROID-RESISTANT ASTHMA; INCREASED EXPRESSION; BINDING; INVITRO; ISOFORM AB Glucocorticoid (GC)-insensitive asthma is a challenging clinical problem that can be associated with life-threatening disease progression. The molecular basis of GC insensitivity is unknown. Alternative splicing of the GC receptor (GCR) pre-mRNA generates a second GCR, termed GCR beta, which does not bind GC but antagonizes the transactivating activity of the classic GCR. Thus increased expression of GCR beta could account for glucocorticoid insensitivity. Bronchoalveolar ravage (BAL) cells and peripheral blood mononuclear cells (PBMC) were examined for GCR beta immunoreactivity using a GCR beta-specific antibody by immunohistochemical staining. Cell localization of GCR beta expression was performed using a double immunostaining technique. Patients with GC-insensitive asthma expressed a significantly higher number of GCR beta-immunoreactive cells in their BAL and peripheral blood than GC-sensitive asthmatics or normal control subjects. Furthermore, GCR beta expression in GC-insensitive asthma was particularly high in airway T cells, which are thought to play a major role in the pathogenesis of asthma. We also examined the expression of GCR beta in specimens from the airways of patients with chronic bronchitis. In chronic bronchitis, few cells were GCR beta-positive and their numbers did not differ significantly from normal control subjects. We conclude that GC-insensitive asthma is associated with increased expression of GCR beta in airway T cells. C1 Natl Jewish Med & Res Ctr, Div Allergy Immunol, Denver, CO 80206 USA. Natl Jewish Med & Res Ctr, Div Pulm Med, Denver, CO 80206 USA. Natl Jewish Med & Res Ctr, Div Clin Pharmacol, Denver, CO 80206 USA. Univ Colorado, Hlth Sci Ctr, Dept Pediat, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Dept Med, Denver, CO 80262 USA. NIH, Dev Endocrinol Branch, Bethesda, MD 20892 USA. McGill Univ, Meakins Christie Labs, Montreal, PQ, Canada. McGill Univ, Dept Pathol, Montreal, PQ, Canada. Inst Pasteur, F-59019 Lille, France. RP Leung, DYM (reprint author), Natl Jewish Med & Res Ctr, Div Allergy Immunol, 1400 Jackson St,Room K926, Denver, CO 80206 USA. FU NHLBI NIH HHS [HL 37260, HL36577]; NIAMS NIH HHS [AR41256] NR 17 TC 194 Z9 204 U1 2 U2 10 PU AMER LUNG ASSOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAY PY 1999 VL 159 IS 5 BP 1600 EP 1604 PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 196GU UT WOS:000080301300038 PM 10228133 ER PT J AU Watson, ML White, AM Campbell, EM Smith, AW Uddin, J Yoshimura, T Westwick, J AF Watson, ML White, AM Campbell, EM Smith, AW Uddin, J Yoshimura, T Westwick, J TI Anti-inflammatory actions of interleukin-13 - Suppression of tumor necrosis factor-alpha and antigen-induced leukocyte accumulation in the guinea pig lung SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article ID SMOOTH-MUSCLE CELLS; ALLERGIC AIRWAY INFLAMMATION; BRONCHOALVEOLAR LAVAGE FLUID; HUMAN ENDOTHELIAL-CELLS; EOSINOPHIL RECRUITMENT; T-CELLS; TISSUE EOSINOPHILIA; RECEPTOR ANTAGONIST; CYTOKINE PRODUCTION; EPITHELIAL-CELLS AB The Th-2 cytokine interleukin (IL)-13 is believed to play an important role in the development of allergy, although it has also been ascribed anti-inflammatory roles in several experimental models. In this study, we have examined the effects of human recombinant IL-13 on eosinophilic lung inflammation in the guinea pig. IL-13 (1 to 100 ng, given by intratracheal instillation) did not elicit airway eosinophil recruitment. A pronounced accumulation of eosinophils, as well as monocyte/macrophages, was elicited by intratracheal instillation of guinea pig tumor necrosis factor alpha (gpTNF-alpha). Intratracheal administration of IL-13 (1 to 100 ng) given immediately prior to exposure to gpTNF-alpha resulted in a dose-related suppression of eosinophil and monocyte/macrophage accumulation in the airways, as assessed by bronchoalveolar lavage (BAL) and eosinophil peroxidase activity in whole-lung homogenates. IL-13 treatment also reduced BAL fluid (BALF) leukocyte accumulation induced by subsequent aerosol antigen challenge of sensitized guinea pigs. Antigen challenge also resulted in elevated levels of immunoreactive eotaxin and eosinophil-stimulating activity in BALF, although only the latter was reduced significantly by IL-13 instillation prior to challenge. In contrast to the suppressive effects of IL-13, instillation of human recombinant IL-4 (100 ng) alone elicited an increase in BALF monocyte/macrophage numbers, and IL-4 was unable to inhibit gpTNF-alpha-induced leukocyte accumulation. Hence, IL-13 (but not human IL-4) exhibits an anti-inflammatory action in the airways of gpTNF-alpha- or antigen-challenged guinea pigs, by mechanisms that may involve the decreased generation of eosinophil-stimulating activity in the airways. C1 Univ Bath, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England. Natl Heart & Lung Inst, Imperial Coll Sch Med, London, England. NCI, Immunopathol Lab, Frederick Canc Res & Dev Ctr, Frederick, MD USA. RP Watson, ML (reprint author), Univ Bath, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England. FU Wellcome Trust NR 53 TC 23 Z9 24 U1 0 U2 1 PU AMER LUNG ASSOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD MAY PY 1999 VL 20 IS 5 BP 1007 EP 1012 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 197WJ UT WOS:000080388900019 PM 10226071 ER PT J AU Avila, NA Shawker, TS Jones, JV Cutler, GB Merke, DP AF Avila, NA Shawker, TS Jones, JV Cutler, GB Merke, DP TI Testicular adrenal rest tissue in congenital adrenal hyperplasia: Serial sonographic and clinical findings SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article ID ADRENOGENITAL SYNDROME; MASSES; TUMOR; ASSOCIATION; US AB OBJECTIVE. The purpose of this study was to describe the serial sonographic findings and clinical and laboratory data obtained during follow-up of patients with congenital adrenal hyperplasia in whom testicular adrenal rest tissue develops. MATERIALS AND METHODS. We retrospectively reviewed testicular sonography and laboratory data for 12 patients with congenital adrenal hyperplasia who also had intratesticular masses consistent with adrenal rest tissue. The studies were done during follow-up that ranged from 7 months to 10 years. RESULTS. During follow-up of 11 of the 12 patients after the initial sonographic diagnosis, the testicular adrenal rest tissue either remained stable in size (n = 1), grew larger or smaller (n = 9), disappeared (n = 4), or reappeared after disappearing (n = 3). In one patient, the testicular adrenal rest tissue grew very rapidly in a 1-month interval. Discordant changes in the testicular adrenal rest tissue were noted in 10 patients with bilateral masses. We found no relationship between the change in size of the masses and clinical control (based on 17-hydroxyprogesterone level) at the time of sonography. CONCLUSION. In patients with congenital adrenal hyperplasia who have testicular masses detected sonographically, testicular adrenal rest tissue is the most Likely diagnosis. Testicular adrenal rest tissue may remain stable in size, grow larger or smaller, or disappear during sonographic follow-up. The change in size may be marked, may occur very rapidly, and, in our study cohort, was not related to short-term clinical control based on 17-hydroxyprogesterone level at the time of sonography. C1 NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Nursing, Bethesda, MD 20892 USA. Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN 46285 USA. NICHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Avila, NA (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bldg 10,Rm 1C660,10 Ctr Dr,MSC 1182, Bethesda, MD 20892 USA. NR 12 TC 38 Z9 42 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD MAY PY 1999 VL 172 IS 5 BP 1235 EP 1238 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 189RM UT WOS:000079919700013 PM 10227495 ER PT J AU Fritsch, M Jaffe, ES Griffin, C Camacho, J Raffeld, M Kingma, DW AF Fritsch, M Jaffe, ES Griffin, C Camacho, J Raffeld, M Kingma, DW TI Lymphoproliferative disorder of fetal origin presenting as oligohydramnios SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE lymphoproliferative disease; Epstein-Barr virus; placenta; in situ hybridization ID EPSTEIN-BARR-VIRUS; NON-HODGKINS-LYMPHOMA; CELL LYMPHOMA; PREGNANCY; DISEASE; PLACENTA; IMMUNODEFICIENCIES; TUMORS AB Lymphoma involving the placenta or fetus remains a very rare event. All cases reported to date have shown the lymphoma cells to be of maternal origin in that the tumor cells have preferentially involved the intervillous spares with sparing of the villi and fetal circulation. We report a novel case of a monoclonal primary placental Epstein-Barr virus (EBV)associated B-cell lymphoma of fetal origin. The placenta of a 20-week stillborn fetus born to a 19-year-old gravida 1 para 0 woman, presenting with oligohydramnios, showed a large cell infiltrate confined within villi and sparing the intervillous spaces, indicative of preferential involvement of the fetal circulation. Necropsy did not show any other site of involvement by malignant lymphoma or other abnormalities. Immunophenotypic studies showed the tumor cells to be of B-cell phenotype with a relatively high proliferation rate. EBV EBER1 RNA was identified in more than 95% of tumor cells, and polymerase chain reaction studies showed EBV EBNA1 strain type A and wildtype EBV LMP 1. Analysis of the immunoglobulin heavy chain by polymerase chain reaction showed a monoclonal B-cell population. In situ hybridization studies using a commercially available probe directed at repeated sequences on the human Y chromosome showed a single intense signal within trophoblastic epithelium and lymphoma cells, indicative of male origin. The mother remains in good health ii months after delivery. C1 NCI, Pathol Lab, Hematopathol Sect, NIH, Bethesda, MD 20892 USA. Johns Hopkins Hosp, Dept Pathol, Baltimore, MD 21287 USA. Cooper Hosp Univ Med Ctr, Dept Pathol, Camden, NJ 08103 USA. RP Kingma, DW (reprint author), NCI, Pathol Lab, Hematopathol Sect, NIH, Bldg 10,Room 2N202,10 Ctr Dr,MSC-1500, Bethesda, MD 20892 USA. NR 33 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD MAY PY 1999 VL 23 IS 5 BP 595 EP 601 DI 10.1097/00000478-199905000-00015 PG 7 WC Pathology; Surgery SC Pathology; Surgery GA 194EB UT WOS:000080178200015 PM 10328093 ER PT J AU Fetsch, PA Marincola, FM Abati, A AF Fetsch, PA Marincola, FM Abati, A TI The new melanoma markers: MART-1 and melan-A (the NIH experience) SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Letter ID METASTATIC MELANOMA; MALIGNANT-MELANOMA; IN-VIVO; EXPRESSION; ANTIBODY; LESIONS; IMMUNOTHERAPY; ANTIGENS; HLA-A2; GP100 C1 NCI, Cytopathol Sect, NIH, Bethesda, MD 20892 USA. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Fetsch, PA (reprint author), NCI, Cytopathol Sect, NIH, Bethesda, MD 20892 USA. NR 25 TC 37 Z9 37 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD MAY PY 1999 VL 23 IS 5 BP 607 EP 609 DI 10.1097/00000478-199905000-00017 PG 3 WC Pathology; Surgery SC Pathology; Surgery GA 194EB UT WOS:000080178200017 PM 10328095 ER PT J AU Gopinath, R Hanna, LE Kumaraswami, V Pillai, SVP Kavitha, V Vijayasekaran, V Rajasekharan, A Nutman, TB AF Gopinath, R Hanna, LE Kumaraswami, V Pillai, SVP Kavitha, V Vijayasekaran, V Rajasekharan, A Nutman, TB TI Long-term persistence of cellular hyporesponsiveness to filarial antigens after clearance of microfilaremia SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID HUMAN LYMPHATIC FILARIASIS; PARASITE-SPECIFIC ANERGY; IMMUNE-RESPONSES; BANCROFTIAN FILARIASIS; ONCHOCERCA-VOLVULUS; CYTOKINE PRODUCTION; BRUGIA-MALAYI; DIETHYLCARBAMAZINE TREATMENT; INTERLEUKIN-10 PRODUCTION; IMMUNOLOGICAL REACTIVITY AB The persistence of parasite-specific cellular hyporespensiveness after clearance of blood microfilariae (mf) was studied in 18 individuals who had been treated with a single dose of ivermectin diethylcarbamazine, or a combination 2-3 years previously and who had initially cleared their parasitemia. At recruitment: into the present study, 50% were again mf+ and 50% remained mf-. There were no significant differences between the mf+ and mf- groups in the amount of interferon-gamma (IFN-gamma) produced by peripheral blood mononuclear cells in response to adult or microfilarial antigens, although IFN-gamma production in response to purified protein derivative was greater in the mf+ group (geometric mean [gm] = 3,791 pg/ml; P = 0.02) than in the mf- group (gm = 600 pg/ml). These data suggest that although microfilaremic individuals may temporarily regain the ability to produce IFN-gamma to parasite antigens post-treatment, they subsequently revert to a state of hyporesponsiveness to mf-containing antigens that appears to be independent of the recurrence of microfilaremia and the response to nonparasite antigens. C1 NIAID, Parasit Dis Lab, Helminth Immunol Sect, NIH, Bethesda, MD 20892 USA. Govt Gen Hosp, Madras, Tamil Nadu, India. TB Res Ctr, Madras, Tamil Nadu, India. RP Gopinath, R (reprint author), NIAID, Parasit Dis Lab, Helminth Immunol Sect, NIH, Bldg 4,Room 126, Bethesda, MD 20892 USA. NR 39 TC 16 Z9 16 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DRIVE SUITE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD MAY PY 1999 VL 60 IS 5 BP 848 EP 853 PG 6 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 198TE UT WOS:000080439600023 PM 10344663 ER PT J AU Ellsworth, DL Manolio, TA AF Ellsworth, DL Manolio, TA TI The emerging importance of genetics in epidemiologic research III. Bioinformatics and statistical genetic methods SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE molecular epidemiology; epidemiologic methods; bioinformatics; computational biology; genetic linkage; statistical genetics ID CONVERTING-ENZYME GENE; SINGLE-NUCLEOTIDE POLYMORPHISMS; QUANTITATIVE TRAIT LOCI; DISCORDANT SIB PAIRS; LINKAGE ANALYSIS; METHYLENETETRAHYDROFOLATE REDUCTASE; ENVIRONMENTAL-INFLUENCES; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; SEGREGATION ANALYSIS AB PURPOSE: To outline potential benefits of integrating recent developments in bioinformatics and statistical genetics with traditional epidemiologic studies to localize genes influencing complex phenotypes and examine genetic effects on disease susceptibility. METHODS: An overview of bioinformatic and statistical approaches for localizing disease-susceptibility genes as well as challenges associated with identifying functional DNA variants and context-dependent genetic effects concludes this three-part series on the importance of genetics in epidemiologic research. RESULTS: Rapidly evolving bioinformatic and statistical methods are providing invaluable information on newly-discovered genes and molecular variation influencing human diseases that is readily available to epidemiologic researchers. CONCLUSIONS: Integrating bioinformatics and molecular biotechnology with epidemiologic methods of assessing disease risk is rapidly expanding our ability to identify genetic influences on complex human diseases. These technological advances are likely to have a profound impact on current knowledge of complex disease etiology, and may reveal novel approaches to disease treatment and prevention. C1 NHLBI, Div Epidemiol & Clin Applicat, Epidemiol & Biometry Program, NIH, Bethesda, MD 20892 USA. RP Ellsworth, DL (reprint author), NHLBI, Div Epidemiol & Clin Applicat, Epidemiol & Biometry Program, NIH, 6701 Routledge Dr,MSC 7934, Bethesda, MD 20892 USA. NR 78 TC 20 Z9 20 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD MAY PY 1999 VL 9 IS 4 BP 207 EP 224 DI 10.1016/S1047-2797(99)00007-1 PG 18 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 192CX UT WOS:000080061600001 PM 10332927 ER PT J AU Breslow, RA Wideroff, L Graubard, BI Erwin, D Reichman, ME Ziegler, RG Ballard-Barbash, R AF Breslow, RA Wideroff, L Graubard, BI Erwin, D Reichman, ME Ziegler, RG Ballard-Barbash, R TI Alcohol and prostate cancer in the NHANES I epidemiologic follow-up study SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE alcohol; prostate cancer; Cohort study ID RISK-FACTORS; SAMPLING DESIGN; UNITED-STATES; MEN; CONSUMPTION; DIET; POPULATION; SMOKING; NUTRITION; ETHANOL AB PURPOSE: We prospectively investigated the association between alcohol consumption and prostate cancer In the Epidemiologic Followup Study (NHEFS) of the first National Health and Nutrition Examination Survey (NHANES I). METHODS: There were two cohorts: 1) Cohort I, followed from baseline (1971-15) through 1992, included 5766 men ages 25-74 years (median follow-up = 17 years); and 2) Cohort II, followed from the first follow-up round for Cohort I (1982-84) through 1992, included the 3868 men in Cohort I free of prostate cancer in 1982-84 (median follow-up = 9 years). Alcohol consumption was assessed at baseline as usual consumption, and at follow-up as usual consumption and as distant past consumption at. the ages of 25, 35, 45, and 55. RESULTS: There were 252 incident cases of prostate cancer. Consistent with most previous studies, we found no significant associations between usual total alcohol consumption and prostate cancer in Cohorts I or II If, = non significant (NS)I, except for a significant inverse association at the heaviest level of drinking in Cohort II [relative risk (RR) = 0.23, 95% confidence interval (CI) = 0.06-0.95]. Further study of heavy drinkers in Cohort II revealed significant inverse associations between distant past heavy drinking (defined as > 25 drinks/week)and prostate cancer at age 25 (RR = 0.20, 95% CI = 0.06-0.63), age 35 (RR = 0.30, 95% CI = 0.12-0.77), and age 45(RR = 0.39, 95% CI = 0.17-0.93), but not at: age 55 (RR = 0.43, 95% CI = 0.17-1.10). CONCLUSIONS: These results suggest that it may be important to consider distant past alcohol consumption in etiologic studies of prostate cancer. However, our results were based on small numbers of cases who were heavy drinkers and require replication. C1 NCI, Appl Res Branch, Div Canc Prevent & Control, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Biostat Branch, Bethesda, MD 20892 USA. Informat Management Serv, Rockville, MD USA. ROW Associates, Rockville, MD USA. RP Breslow, RA (reprint author), Ctr Dis Control & Prevent, 4770 Buford Hwy,MS k-55, Atlanta, GA 30341 USA. RI Hernandez, Jessica/G-6527-2011 NR 70 TC 35 Z9 36 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD MAY PY 1999 VL 9 IS 4 BP 254 EP 261 DI 10.1016/S1047-2797(98)00071-4 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 192CX UT WOS:000080061600005 PM 10332931 ER PT J AU Gran, B Hemmer, B Vergelli, M McFarland, HF Martin, R AF Gran, B Hemmer, B Vergelli, M McFarland, HF Martin, R TI Molecular mimicry and multiple sclerosis: Degenerate T-Cell recognition and the induction of autoimmunity SO ANNALS OF NEUROLOGY LA English DT Article ID MYELIN BASIC-PROTEIN; PEPTIDE COMBINATORIAL LIBRARIES; DIFFERENTIAL-AVIDITY MODEL; CENTRAL-NERVOUS-SYSTEM; TOLERANCE INDUCTION; HEALTHY-INDIVIDUALS; POSITIVE SELECTION; THYMIC EXPRESSION; CROSS-REACTIVITY; TRANSGENIC MICE AB Various mechanisms have been proposed for the initiation of autoimmune responses by autoreactive T-cell clones. One of these, the molecular mimicry hypothesis, postulates that myelin-reactive T-cell clones are activated by foreign antigens. Until recently, sequence homology between self- and foreign antigens was considered necessary for cross-recognition to occur in multiple sclerosis. This article reviews current progress in T-cell receptor immunology that led to modify this view and proposes a role for degenerate T-cell antigen recognition in the induction of autoimmunity. C1 NINDS, Cellular Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Univ Marburg, Dept Neurol, Clin Neuroimmunol Grp, Marburg, Germany. Univ Florence, Dept Neurol & Psychiat Sci, Florence, Italy. RP Martin, R (reprint author), NINDS, Cellular Immunol Sect, Neuroimmunol Branch, NIH, Bldg 10,Room 5B-16,10 Ctr Dr MSC 1400, Bethesda, MD 20892 USA. RI Gran, Bruno/A-2288-2013 OI Gran, Bruno/0000-0001-6384-2342 NR 93 TC 74 Z9 78 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD MAY PY 1999 VL 45 IS 5 BP 559 EP 567 DI 10.1002/1531-8249(199905)45:5<559::AID-ANA3>3.0.CO;2-Q PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 192DG UT WOS:000080062500003 PM 10319877 ER PT J AU Hunter, KE Blaxton, TA Bookheimer, SY Figlozzi, C Gaillard, WD Grandin, C Anyanwu, A Theodore, WH AF Hunter, KE Blaxton, TA Bookheimer, SY Figlozzi, C Gaillard, WD Grandin, C Anyanwu, A Theodore, WH TI O-15 water positron emission tomography in language localization: A study comparing positron emission tomography visual and computerized region of interest analysis with the Wada Test SO ANNALS OF NEUROLOGY LA English DT Article ID FUNCTIONAL MRI; INDIVIDUAL VARIABILITY; CORTICAL LOCALIZATION; DOMINANCE; AREAS; LATERALIZATION; EPILEPSY; CHILDREN; ANATOMY; PET AB We compared O-15 water positron emission tomography (PET) auditory and visual confrontational naming activation with an intracarotid amobarbital (Amytal) injection procedure (IAP) for language lateralization in 12 patients with intractable epilepsy. PET scans were evaluated by three raters experienced in functional imaging as well. as by a region of interest (ROI) approach. Compared with IAP, raters' positive predictive value for language lateralization ranged from 88 to 91%. ROI analysis had a positive predictive value of 80%. Six patients had surgery; 1 with right-sided IAP language dominance but left-sided PET activation had dysphasia for 6 months after left temporal lobectomy. C1 NINCDS, Clin Epilepsy Sect, NIH, Epilepsy Res Branch, Bethesda, MD 20892 USA. RP Theodore, WH (reprint author), NINCDS, Clin Epilepsy Sect, NIH, Epilepsy Res Branch, Bldg 10,Room 5N-250, Bethesda, MD 20892 USA. NR 20 TC 54 Z9 54 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD MAY PY 1999 VL 45 IS 5 BP 662 EP 665 DI 10.1002/1531-8249(199905)45:5<662::AID-ANA17>3.0.CO;2-A PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 192DG UT WOS:000080062500017 PM 10319891 ER PT J AU Sivakumar, K Sambuughin, N Selenge, B Nagle, JW Baasanjav, D Hudson, LD Goldfarb, LG AF Sivakumar, K Sambuughin, N Selenge, B Nagle, JW Baasanjav, D Hudson, LD Goldfarb, LG TI Novel exon 3B proteolipid protein gene mutation causing late-onset spastic paraplegia type 2 with variable penetrance in female family members SO ANNALS OF NEUROLOGY LA English DT Article ID PELIZAEUS-MERZBACHER-DISEASE; NONSENSE MUTATION; PLP; HETEROGENEITY; MYELIN; LOCUS AB Spastic paraplegia type 2 (SPG2) is allelic to Pelizaeus-Merzbacher disease (PMD), with both conditions resulting from mutations in the proteolipid protein gene (PLP). We report an SPG2 family in which 3 male members and a heterozygous female member were affected with spastic paraplegia characterized by relatively late onset and mild clinical manifestations. A unique H147Y mutation in exon 3B of the PLP altering the proteolipid protein (PLP) but not the alternatively spliced DM20 isoform was identified as the cause of this distinct disease phenotype. Cellular pathology studies of SPG2 mutations offer an explanation for the paradoxical finding that mutations associated with the mildest phenotype in male family members also affect female carriers. C1 NINDS, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Basic Neurosci Program, NIH, Bethesda, MD 20892 USA. NINDS, Lab Dev Neurogenet, NIH, Bethesda, MD 20892 USA. Barrow Neurol Inst, Phoenix, AZ 85013 USA. Mongolian Natl Inst Hlth, Ulaanbaatar, Mongol Peo Rep. RP Goldfarb, LG (reprint author), NINDS, Med Neurol Branch, NIH, Bldg 10,Room 4B37,10 Ctr Dr, Bethesda, MD 20892 USA. NR 19 TC 20 Z9 22 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD MAY PY 1999 VL 45 IS 5 BP 680 EP 683 DI 10.1002/1531-8249(199905)45:5<680::AID-ANA23>3.0.CO;2-H PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 192DG UT WOS:000080062500023 PM 10319897 ER PT J AU Vey, N Kantarjian, H Tran, H Beran, M O'Brien, S Bivins, C Giles, F Cortes, J Cheson, B Arbuck, S Estey, E AF Vey, N Kantarjian, H Tran, H Beran, M O'Brien, S Bivins, C Giles, F Cortes, J Cheson, B Arbuck, S Estey, E TI Phase I and pharmacologic study of 9-aminocamptothecin colloidal dispersion formulation in patients with refractory or relapsed acute leukemia SO ANNALS OF ONCOLOGY LA English DT Article DE acute leukemia; 9-aminocamptothecin; phase I clinical trial; topoisomerase I inhibitors ID MYELOGENOUS LEUKEMIA; CAMPTOTHECIN; CANCER; XENOGRAFTS; TOPOTECAN; INHIBITOR; INFUSION; DESIGN; TRIALS; MODEL AB Purpose: Topoisomerase I inhibitors have shown promising anti leukemic activity in acute myelogenous leukemia (AML) and myelodysplastic syndrome. In this phase I study, we investigated the toxicity profile, pharmacokinetics, and activity of a prolonged continuous infusion schedule of the colloidal dispersion formulation of 9-amino-camptothecin (9-AC/CD) in patients with acute leukemia. Patients and methods: Patients with refractory or relapsed AML, acute lymphocytic leukemia (ALL) or chronic myelogenous leukemia in blastic phase (CML-BP) were included in the study. Eligibility criteria were age greater than 15 years, performance status of 2 or better, creatinine < 1.5 mg/dl, and bilirubin < 1.5 mg/dl. 9-AC/CD was given as a continuous intravenous infusion over seven days every three to four weeks. The starting dose was 0.2 mg/m(2)/d (1.4 mg/m(2)/course). Courses were given every three to four weeks according to toxicity and anti leukemic efficacy. This phase I study used the classical 3 + 3 design. The dose was escalated by 50% until grade 1 toxicity was observed, and then by 30% to 35% until the dose limiting toxicity was defined. At the maximal tolerated dose (MTD), 8 to 10 patients were planned to be treated to better define the toxicity and early-activity profiles. Results: Thirty-nine patients (AML thirty-six patients; ALL two patients; CML-BP one patient), median age 56 years, were treated. Severe mucositis was the dose limiting toxicity; it occurred in three of six patients treated at a dose of 1.6 mg/m(2)/d. The MTD was defined as 1.4 mg/m(2)/day by the phase I design. Upon expansion of the number of patients, 3 of 10 patients had grade 4 mucositis and 1 of 10 patients had grade 3 diarrhea. Nausea and vomiting were uncommon. No complete or partial remission was observed in 37 evaluable patients. However, 9-AC/CD exhibited antileukemic activity, as reflected by the finding of marrow hypoplasia on day 14 in 46% of the patients. Average steady-state concentration of 9-AC lactone was close to 10 nmol/l, and the of 9-AC lactone area under curve (AUC) was 1409 +/- 705 nmol/l.hr. Conclusion: The MTD of 9-AC/CD given as a seven-day continuous infusion was 1.4 mg/m(2)/d (9.8 mg/m(2)/course) in patients with acute leukemia. This represents three to fourfold dose escalation compared with the MTD of 9-AC given as shorter continuous infusion (three days) in patients with solid tumors. Future studies will determine the activity of prolonged administration of 9-AC/CD in patients with better prognosis acute leukemia. C1 Univ Texas, MD Anderson Canc Ctr, Leukemia Dept, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Pharmacol, Houston, TX 77030 USA. NCI, Bethesda, MD 20892 USA. RP Kantarjian, H (reprint author), Univ Texas, MD Anderson Canc Ctr, Leukemia Dept, Box 61,1515 Holcombe Blvd, Houston, TX 77030 USA. NR 25 TC 16 Z9 17 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD MAY PY 1999 VL 10 IS 5 BP 577 EP 583 DI 10.1023/A:1026406920321 PG 7 WC Oncology SC Oncology GA 203RC UT WOS:000080719800018 PM 10416008 ER PT J AU Sandor, V Reed, E Sarosy, G Middleton, LP Davis, P Kohn, E AF Sandor, V Reed, E Sarosy, G Middleton, LP Davis, P Kohn, E TI Synchronous inflammatory breast cancer and advanced ovarian carcinoma: A case with prolonged disease-free survival SO ANNALS OF ONCOLOGY LA English DT Article DE breast cancer; cisplatin; ovarian cancer; paclitaxel ID SUSCEPTIBILITY GENE; CYCLOPHOSPHAMIDE; PACLITAXEL; DIAGNOSIS; CISPLATIN; BRCA1 AB Despite the known association of these malignancies, the incidence of a synchronous presentation of breast and ovarian cancer is low, and the current literature does not address an approach to this clinical problem directly. We report a greater than 2.5 year disease-free survival in a patient treated for synchronous stage IIIB inflammatory breast cancer and stage IIIC epithelial ovarian cancer. The prolonged disease-free survival in our case may provide some guidance in this unusual clinical situation. C1 NCI, Med Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Kohn, E (reprint author), NCI, Med Branch, NIH, 10 Ctr Dr,MSC 1500,Bldg 10,Room 2A33, Bethesda, MD 20892 USA. NR 18 TC 0 Z9 1 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD MAY PY 1999 VL 10 IS 5 BP 585 EP 588 DI 10.1023/A:1008239124657 PG 4 WC Oncology SC Oncology GA 203RC UT WOS:000080719800019 PM 10416009 ER PT J AU Boons, CW AF Boons, CW TI Can breast cancer be prevented? SO ANNALS OF SAUDI MEDICINE LA English DT Letter C1 NCI, Chemoprevent Branch, NIH, Rockville, MD 20852 USA. RP Boons, CW (reprint author), NCI, Chemoprevent Branch, NIH, EPN 201,6130 Execut Blvd, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU K FAISAL SPEC HOSP RES CENTRE PI RIYADH PA PUBLICATIONS OFFICE PO BOX 3354, RIYADH 11211, SAUDI ARABIA SN 0256-4947 J9 ANN SAUDI MED JI Ann. Saudi Med. PD MAY PY 1999 VL 19 IS 3 BP 276 EP 276 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 231RN UT WOS:000082324100026 PM 17283476 ER PT J AU Balasundaram, D Tabor, CW Tabor, H AF Balasundaram, D Tabor, CW Tabor, H TI Sensitivity of spermidine-deficient Saccharomyces cerevisiae to paromomycin SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID PHENOTYPIC SUPPRESSION; REQUIREMENT; GROWTH AB Spermidine-deficient Saccharomyces cerevisiae cells are much more sensitive to paromomycin than nondeficient cells, resulting in cessation of growth and cell death. C1 NIDDK, NIH, Bethesda, MD 20892 USA. RP Tabor, H (reprint author), NIDDK, NIH, Bldg 8,Room 225, Bethesda, MD 20892 USA. NR 9 TC 5 Z9 5 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 MAY PY 1999 VL 43 IS 5 BP 1314 EP 1316 PG 3 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 191RJ UT WOS:000080035100058 PM 10223963 ER PT J AU Buckheit, RW Russell, JD Pallansch, LA Driscoll, JS AF Buckheit, RW Russell, JD Pallansch, LA Driscoll, JS TI Anti-human immunodeficiency virus type 1 (HIV-1) activity of 2 '-fluoro-2 ',3 '-dideoxyarabinosyladenine (F-ddA) used in combination with other mechanistically diverse inhibitors of HIV-1 replication SO ANTIVIRAL CHEMISTRY & CHEMOTHERAPY LA English DT Article DE nucleoside analogue; combination efficacy ID REVERSE-TRANSCRIPTASE INHIBITOR; RESISTANT; INFECTION; 2'-BETA-FLUORO-2',3'-DIDEOXYADENOSINE; POTENT; PLASMA AB 2'-Fluoro-2'3'-dideoxyarabinosyladenine (F-ddA), a nucleoside reverse transcriptase inhibitor of human immunodeficiency virus (HIV) replication, is currently being evaluated in clinical trials. Future monotherapy for the treatment of HIV is unlikely owing to the rapid emergence of drug-resistant viruses, so F-ddA was evaluated in combination with a variety of mechanistically diverse inhibitors of HIV replication. Such in vitro studies provide insights into whether certain drug combinations yield synergistic antiviral activity or, more importantly, antagonistic antiviral activity or synergistic cytotoxicity. F-ddA exhibited synergistic antiviral interactions with representatives of each of the major classes of anti-HIV compounds, including other nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors. Greatest levels of synergistic interaction were detected when F-ddA was used in combination with the non-nucleoside compounds nevirapine and costatolide, the nucleoside analogues AZT, ddC and 3TC and the protease inhibitors ritonavir and nelfinavir. No evidence of either combination toxicity or antagonistic antiviral activity was detected with any of the tested compounds. C1 So Res Inst, Dept Microbiol Res, Frederick, MD 21701 USA. NCI, Med Chem Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Buckheit, RW (reprint author), So Res Inst, Dept Microbiol Res, 431 Aviat Way, Frederick, MD 21701 USA. NR 16 TC 4 Z9 4 U1 0 U2 0 PU INT MEDICAL PRESS PI LONDON PA 125 HIGH HOLBORN, LONDON WC1V 6QA, ENGLAND SN 0956-3202 J9 ANTIVIR CHEM CHEMOTH JI Antivir. Chem. Chemother. PD MAY PY 1999 VL 10 IS 3 BP 115 EP 119 PG 5 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Virology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Virology GA 204VL UT WOS:000080785300002 PM 10431610 ER PT J AU Qoronfleh, MW AF Qoronfleh, MW TI Dissolved oxygen concentration affects the accumulation of HIV-1 recombinant proteins in Escherichia coli SO APPLIED BIOCHEMISTRY AND BIOTECHNOLOGY LA English DT Article DE dissolved oxygen; HIV-1 proteins; recombinant proteins; Escherichia coli; heterologous gene expression ID CELL-DENSITY FERMENTATION; FED-BATCH CULTURES; AEROBIC REGULATION; GENE-EXPRESSION; GROWTH-RATE; INDUCTION; PROTEASE; PLASMID; FNR; DEHYDROGENASE AB A central problem in aerobic growth of any culture is the maintenance of dissolved oxygen concentration (DOC) above growth-limiting levels especially in high-cell density fermentations that are usually of the fed-batch type Fermenter studies have been conducted to determine the influence of DOC on the production of heterologous proteins in Escherichia coli. The results demonstrated that there is a significant degree of product-to-product variation in the response of heterologous protein accumulation to DOC. For translational fusions of the human immunodeficiency virus-1 (HIV-1) proteins p24Gag and Env41, the imposition of a dissolved oxygen (DO) limitation resulted in 100 and 15% increases in the respective product yields. On the other hand, the imposition of a DO limitation had no effect on the production of a similar translational fusion of the HIV-1 protein p55Gag, and a large negative effect on the production of an influenza protein (C13). The stimulatory effects of DOC on p24Gag production were investigated further. The results of my studies suggested that the stimulatory effect observed at reduced agitation rates on p24Gag accumulation was owing to an oxygen effect and not a shear effect. Furthermore, the results of my investigations indicated that the effect a DOC had on the production of p24Gag was strongly influenced by the cell density at which the culture was induced. C1 NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Struct Biochem Program, Frederick, MD 21702 USA. RP Qoronfleh, MW (reprint author), NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Struct Biochem Program, Frederick, MD 21702 USA. NR 42 TC 5 Z9 5 U1 2 U2 7 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0273-2289 J9 APPL BIOCHEM BIOTECH JI Appl. Biochem. Biotechnol. PD MAY PY 1999 VL 80 IS 2 BP 107 EP 120 DI 10.1385/ABAB:80:2:107 PG 14 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 218BM UT WOS:000081533400002 PM 10436915 ER PT J AU Jourd'heuil, D Miranda, KM Kim, SM Espey, MG Vodovotz, Y Laroux, S Mai, CT Miles, AM Grisham, MB Wink, DA AF Jourd'heuil, D Miranda, KM Kim, SM Espey, MG Vodovotz, Y Laroux, S Mai, CT Miles, AM Grisham, MB Wink, DA TI The oxidative and nitrosative chemistry of the nitric oxide superoxide reaction in the presence of bicarbonate SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article ID CARBON-DIOXIDE; PEROXYNITRITE CAUSES; TYROSINE NITRATION; LIPID-PEROXIDATION; NO; PH; INSIGHTS; KINETICS; INJURY; OXYGEN AB The primary product of the interaction between nitric oxide (NO) and superoxide (O-2(-)) is peroxynitrite (ONOO-), which is capable of either oxidizing or nitrating various biological substrates. However, it has been shown that excess NO or O-2(-) can further react with ONOO- to form species which mediate nitrosation, Subsequently, the controlled equilibrium between nitrosative and oxidative chemistry is critically dependent on the flux of NO and O-2(-). Since ONOO- reacts not only with NO and O-2(-) but also with CO2, the effects of bicarbonate (HCO3-) on the biphasic oxidation profile of dihydrorhodamine-123 (DHR) and on the nitrosation of both 2,3-diaminonaphthalene and reduced glutathione were examined. Nitric oxide and O-2(-) were formed with DEA/NO [NaEt2NN(O)NO] and xanthine oxidase, respectively. The presence of HCO3- did not alter either the oxidation profile of DHR with varying radical concentrations or the affinity of DHR for the oxidative species. This suggests that the presence of CO2 does not affect the scavenging of ONOO- by either NO or O-2(-). However, an increase in the rate of DHR oxidation by ONOO- in the presence of HCO3- suggests that a CO2-ONOO- adduct does play a role in the interaction of NO or O-2(-) with a product derived from ONOO-. Further examination of the chemistry revealed that the intermediate that reacts with NO is neither ONOO- nor cis-HOONO. It was concluded that NO reacts with both trans-HOONO and a CO2 adduct of ONOO- to form nitrosating species which have similar oxidation chemistry and reactivity with O-2(-) and NO. (C) 1999 Academic Press. C1 NCI, Radiat Biol Branch, Tumor Biol Sect, Bethesda, MD 20892 USA. Louisiana State Univ, Med Ctr, Dept Cellular & Mol Physiol, Shreveport, LA 71130 USA. Grambling State Univ, Dept Chem, Grambling, LA 71245 USA. RP Wink, DA (reprint author), NCI, Radiat Biol Branch, Tumor Biol Sect, Bldg 10,Room B3-B69, Bethesda, MD 20892 USA. RI Miranda, Katrina/B-7823-2009 FU NIDDK NIH HHS [DK 43785] NR 32 TC 58 Z9 59 U1 0 U2 4 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD MAY 1 PY 1999 VL 365 IS 1 BP 92 EP 100 DI 10.1006/abbi.1999.1143 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 192CA UT WOS:000080059600012 PM 10222043 ER PT J AU Espeland, MA Whelton, PK Kostis, JB Bahnson, JL Ettinger, WH Cutler, JA Appel, LJ Kumanyika, S Farmer, D Elam, J Wilson, AC Applegate, WB AF Espeland, MA Whelton, PK Kostis, JB Bahnson, JL Ettinger, WH Cutler, JA Appel, LJ Kumanyika, S Farmer, D Elam, J Wilson, AC Applegate, WB CA TONE Cooperative Res Gr TI Predictors and mediators of successful long-term withdrawal from antihypertensive medications SO ARCHIVES OF FAMILY MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED TRIAL; ELDERLY TONE; NONPHARMACOLOGIC INTERVENTIONS; MYOCARDIAL-INFARCTION; CROSS-VALIDATION; BLOOD-PRESSURE; UNITED-STATES; HYPERTENSION; THERAPY; REGRESSION AB Background: National guidelines recommend consideration of step down or withdrawal of medication in patients with well-controlled hypertension, but knowledge of factors that predict or mediate success in achieving this goal is limited. Objective: To identify patient characteristics associated with success, in controlling blood pressure (BP) after withdrawal of antihypertensive medication. Design: The Trial of Nonpharmacologic Interventions in the Elderly tested whether lifestyle interventions designed to promote weight loss or a reduced intake of sodium, alone or in combination, provided satisfactory BP control among elderly patients (aged 60-80 years) with hypertension after withdrawal from antihypertensive drug therapy. Participants were observed for 15 to 36 months after attempted drug withdrawal. Main Outcome Measures: Trial end points were defined by (1) a sustained BP of 150/90 mm Hg or higher, (2) a clinical cardiovascular event, or (3),a decision by participants or their personal physicians to resume BP medication. Results: Proportional hazards regression analyses indicated that the hazard (+/-SE) of experiencing an end point among persons assigned to active interventions wa 75% +/- 9% (weight loss); 68% +/- 7% (sodium reduction), and 55% +/- 7% (combined weight loss/sodium reduction) that of the hazard for those assigned to usual care. Lower baseline systolic BP (P<.001), fewer years since diagnosis of hypertension (P<.001), fewer years of antihypertensive treatment (P<.001), and no history of cardiovascular disease(P=.01) were important predictors of maintaining successful nonpharmacological BP control throughout follow-up, based on logistic regression analysis. Age, ethnicity, baseline level of physical activity, baseline weight, medication class, smoking status, and alcohol intake were not statistically significant predictors. During follow-up, the extent of weight loss (P =.001) and urinary sodium excretion (P =.04) were associated with a reduction in the risk of trial end points in a graded fashion. Conclusions: Withdrawal from antihypertensive medication is most likely to be successful in patients with well- controlled hypertension who have been recently (within 5 years) diagnosed or treated, and who adhere to lifestyle interventions involving weight loss and sodium reduction. More than 80% of these patients may have suer cess in medication withdrawal for longer than 1 year. C1 Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Biostat Sect, Winston Salem, NC 27157 USA. Wake Forest Univ, Sch Med, Dept Med, Winston Salem, NC 27157 USA. Tulane Univ, Sch Publ Hlth & Trop Med, New Orleans, LA USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Med, New Brunswick, NJ 08903 USA. NHLBI, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Univ Illinois, Dept Human Nutr & Dietet, Chicago, IL USA. Univ Tennessee, Dept Med, Memphis, TN 38104 USA. RP Espeland, MA (reprint author), Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Biostat Sect, Med Ctr Blvd, Winston Salem, NC 27157 USA. FU NHLBI NIH HHS [R01 HL-48642, R01 HL-09771]; NIA NIH HHS [R01 AG-09799] NR 39 TC 35 Z9 36 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 1063-3987 J9 ARCH FAM MED JI Arch. Fam. Med. PD MAY-JUN PY 1999 VL 8 IS 3 BP 228 EP 236 DI 10.1001/archfami.8.3.228 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 195UA UT WOS:000080269500012 PM 10333818 ER PT J AU Chan, CC Vortmeyer, AO Chew, EY Green, WR Matteson, DM Shen, DF Linehan, WM Lubensky, IA Zhuang, ZP AF Chan, CC Vortmeyer, AO Chew, EY Green, WR Matteson, DM Shen, DF Linehan, WM Lubensky, IA Zhuang, ZP TI VHL gene deletion and enhanced VEGF gene expression detected in the stromal cells of retinal angioma SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID TUMOR-SUPPRESSOR GENE; ENDOTHELIAL GROWTH-FACTOR; HIPPEL-LINDAU-DISEASE; CENTRAL-NERVOUS-SYSTEM; RENAL-CARCINOMA; UP-REGULATION; HEMANGIOBLASTOMAS; PRODUCT; HETEROZYGOSITY; MUTATIONS AB Objectives: Retinal angioma frequently occurs in von Hippel-Lindau (VHL) disease. However, VHL gene alterations have not been documented in retinal angiomas. Methods: Using tissue microdissection and polymerase chain reaction amplification, we have analyzed 7 retinal angiomas associated with VHL disease for loss of heterozygosity of the VHL gene. Tn addition, vascular endothelial growth factor expression was evaluated in these tumors by immunohistochemistry and in situ hybridization. Results: All 6 informative retinal angiomas showed loss of heterozygosity of the VHL gene. Loss of heterozygosity was detected in vacuolated "stromal" cells, but not in vascular cells or reactive glial tissue. Vascular endothelial growth factor protein and messenger RNA were also present in vacuolated "stromal" cells. Conclusions: These findings suggest that vacuolated "stromal" cells represent the true neoplastic component in retinal angioma. These cells express vascular endothelial growth factor and therefore may be responsible for abundant neovascularization of retinal angioma. C1 NEI, NIH, Immunol Lab, Bethesda, MD 20892 USA. NEI, Clin Trials Branch, Bethesda, MD USA. NCI, NIH, Pathol Lab, Bethesda, MD 20892 USA. NCI, NIH, Urol Oncol Branch, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Wilmer Ophthalmol Inst, Lab Eye Pathol, Baltimore, MD 21205 USA. RP Chan, CC (reprint author), NEI, NIH, Immunol Lab, Bldg 10,Room 10N103,10 Ctr Dr, Bethesda, MD 20892 USA. NR 44 TC 70 Z9 72 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD MAY PY 1999 VL 117 IS 5 BP 625 EP 630 PG 6 WC Ophthalmology SC Ophthalmology GA 194QF UT WOS:000080204500007 PM 10326959 ER PT J AU Ferris, FL Davis, MD AF Ferris, FL Davis, MD TI Treating 20/20 eyes with diabetic macular edema SO ARCHIVES OF OPHTHALMOLOGY LA English DT Editorial Material C1 NEI, Bethesda, MD 20892 USA. RP Ferris, FL (reprint author), NEI, Bldg 31,Room 6A-52,31 Ctr Dr,MSC 2510, Bethesda, MD 20892 USA. EM RickFerris@nei.nih.gov NR 2 TC 9 Z9 9 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0003-9950 EI 1538-3601 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD MAY PY 1999 VL 117 IS 5 BP 675 EP 676 PG 2 WC Ophthalmology SC Ophthalmology GA 194QF UT WOS:000080204500017 PM 10326969 ER PT J AU Fox, PC Brennan, M Di Sun, P AF Fox, PC Brennan, M Di Sun, P TI Cytokine expression in human labial minor salivary gland epithelial cells in health and disease SO ARCHIVES OF ORAL BIOLOGY LA English DT Article DE minor salivary glands; cytokines; Sjogren's syndrome ID PRIMARY SJOGRENS-SYNDROME; AUTOIMMUNE EXOCRINOPATHY; MECHANISMS AB Microdissection of biopsy material from labial minor salivary glands followed by RT-PCR demonstrates extensive production of cytokines IL-2, IL-6, IL-10, TNF-alpha, TGF-beta, and IFN-gamma in both normal glands and in glands affected by Sjogren's syndrome. Continuation of these studies should expand our knowledge of normal salivary gland function and the pathogenis of Sjogren'syndrome. C1 NIDR, Clin Invest Sect, Gene Therapy & Therapeut Branch, Bethesda, MD 20892 USA. RP Fox, PC (reprint author), NIDR, Clin Invest Sect, Gene Therapy & Therapeut Branch, Bethesda, MD 20892 USA. NR 16 TC 16 Z9 16 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0003-9969 J9 ARCH ORAL BIOL JI Arch. Oral Biol. PD MAY PY 1999 VL 44 SU 1 BP S49 EP S52 DI 10.1016/S0003-9969(99)00050-3 PG 4 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 209DT UT WOS:000081033500010 PM 10414856 ER PT J AU Turner, RJ Paulais, M Valdez, II Evans, RL Fox, PC AF Turner, RJ Paulais, M Valdez, II Evans, RL Fox, PC TI Ion transport and signalling in human labial glands SO ARCHIVES OF ORAL BIOLOGY LA English DT Article DE minor salivary glands; fluid secretion; stimulus-secretion coupling ID PAROTID ACINAR-CELLS; CYTOSOLIC FREE CALCIUM; MINOR SALIVARY-GLANDS; MUSCARINIC STIMULATION; FLUID SECRETION; CL--HCO3 EXCHANGE; NA+/H+ EXCHANGE; UP-REGULATION; RAT; CL AB Recent reports characterizing the physiological properties of normal human labial acini are reviewed with particular emphasis on mechanisms related to fluid secretion. In contrast to the salivary glands of several experimental animals, human labial acinar cells do not appear to have al-adrenergic receptors, substance P peptidergic receptors, or significant levels of Cl-/HCO3- exchange. Nor do they appear to secrete HCO3- in response to Ca2+ mobilizing stimuli. The data presently available indicates that fluid secretion by these glands is mainly under muscarinic control and is due to acinar Cl- secretion driven by a basolateral Na+-K+-2Cl(-) cotransporter. C1 Natl Inst Dent Res, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Turner, RJ (reprint author), Natl Inst Dent Res, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RI Paulais, Marc/E-5623-2017 NR 35 TC 8 Z9 8 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0003-9969 J9 ARCH ORAL BIOL JI Arch. Oral Biol. PD MAY PY 1999 VL 44 SU 1 BP S15 EP S19 DI 10.1016/S0003-9969(99)00044-8 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 209DT UT WOS:000081033500004 PM 10414850 ER PT J AU Chima, SC Agostini, HT Ryschkewitsch, CF Lucas, SB Stoner, GL AF Chima, SC Agostini, HT Ryschkewitsch, CF Lucas, SB Stoner, GL TI Progressive multifocal leukoencephalopathy and JC virus genotypes in west African patients with acquired immunodeficiency syndrome - A pathologic and DNA sequence analysis of 4 cases SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID HUMAN POLYOMAVIRUS JC; COMPLETE GENOMES; INSITU HYBRIDIZATION; SYNDROME AIDS; PML; HIV; BRAIN; IMMUNOHISTOCHEMISTRY; EPIDEMIOLOGY; AMERICANS AB Objective-Progressive multifocal leukoencephalopathy is caused by polyomavirus JC in immunosuppressed patients. IC virus genotypes are identified by sequence analysis of the viral genome. Despite the prevalence of acquired immunodeficiency syndrome in sub-Saharan Africa, few cases of progressive multifocal leukoencephalopathy have been reported from this region. Here we describe 4 African cases and provide an analysis of viral genotypes. Methods.-Immunohistochemical staining by labeled streptavidin-biotin for capsid protein antigen was performed on all cases. Polymerase chain reaction amplification of viral genomic DNA was followed by direct cycle sequencing. Results.-JC virus type 3 was identified in 2 cases, and type 6 was isolated in 1 case. The viral regulatory region from 1 case showed an uncommon rearrangement pattern. Conclusions.-Progressive multifocal leukoencephalopathy in West African patients with acquired immunodeficiency syndrome is caused by African genotypes of JC virus (types 3 and 6). The prevalence of disease in this autopsy series from sub-Saharan Africa (1.5%) was less than has been reported from Europe and the United States (4% to 10%) and may be partly due to biological differences in JC virus genotypes. Further studies will be needed to confirm this observation. C1 NINDS, Neurotoxicol Sect, NIH, Bethesda, MD 20892 USA. UMDS, Guys & St thomas Med & Dent Sch, Dept Histopathol, St Thomas Hosp, London, England. Univ Freiburg, Dept Ophthalmol, Freiburg, Germany. RP Stoner, GL (reprint author), NINDS, Neurotoxicol Sect, NIH, Bldg 36,Room 4A-27, Bethesda, MD 20892 USA. RI Chima, Sylvester Chidi/N-5564-2013 NR 45 TC 8 Z9 9 U1 0 U2 3 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD MAY PY 1999 VL 123 IS 5 BP 395 EP 403 PG 9 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 194BW UT WOS:000080173100008 PM 10235497 ER PT J AU Deitz, J Quatrano, L Peckham, PH Bach-Y-Rita, P Cooper, LD Joe, J AF Deitz, J Quatrano, L Peckham, PH Bach-Y-Rita, P Cooper, LD Joe, J TI The grant portfolio of the National Center for Medical Rehabilitation Research: The first five years SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article AB Objective: To relate grant funding activities of the National Center for Medical Rehabilitation Research (NCMRR) with the Center's mission, priorities, and terminology for disability classification. Study Design: Retrospective review by the National Advisory Board on Medical Rehabilitation Research (NABMRR). Data: Abstracts of 153 research proposals and one contract funded by the NCMRR from 1992 through 1996. Method: A six-member research group participated in the development of a rating form and related instructions used to evaluate each abstract. The form was piloted and revised, and interrater agreement was monitored. Results: Funded proposals reflected each of the NCMRR priorities evaluated, with the highest proportion in the areas of assistive technology and whole body system, and the lowest in the area of behavioral adaptation. Although some proposals were funded in each of the domains of the disability classification system, proportionately fewer addressed the domains of disability and societal limitations. Findings also indicated that few funded proposals addressed more than one domain in the disability classification system and that most abstracts did not address consumers' perspectives an quality of life. Recommendations: The NABMRR recommended that the NCMRR (1) encourage more research in the areas of disability and societal limitations and in behavioral adaptation, (2) examine funded proposals in light of a recent Institute of Medicine report, and (3) explore quality-of-life measurements, Further, members of the rehabilitation community are encouraged to e-mail their responses to this review to NCMRR staff at [1q2n@nih.govA] and to suggest areas of research emphasis. (C) 1999 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation. C1 Univ Washington, Dept Rehabil Med 356490, Seattle, WA 98195 USA. NICHHD, Natl Ctr Med Rehabil Res, NIH, Bethesda, MD 20892 USA. Case Western Reserve Univ, Dept Biomed Engn, Cleveland, OH 44106 USA. Cleveland Vet Affairs Med Ctr, Cleveland, OH USA. Univ Wisconsin, Sch Med, Dept Rehabil Med, Madison, WI USA. Natl Multiple Sclerosis Soc, New York, NY USA. Univ Arizona, Coll Med, Tucson, AZ USA. RP Deitz, J (reprint author), Univ Washington, Dept Rehabil Med 356490, Seattle, WA 98195 USA. NR 7 TC 2 Z9 2 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 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD MAY PY 1999 VL 80 IS 5 BP 481 EP 484 DI 10.1016/S0003-9993(99)90185-5 PG 4 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 194BF UT WOS:000080171700002 PM 10326907 ER PT J AU Ehrlich, HP Keefer, KA Myers, RL Passaniti, A AF Ehrlich, HP Keefer, KA Myers, RL Passaniti, A TI Vanadate and the absence of myofibroblasts in wound contraction SO ARCHIVES OF SURGERY LA English DT Article ID SMOOTH MUSCLE ACTIN; ROUS-SARCOMA VIRUS; TYROSINE PHOSPHORYLATION; FOCAL ADHESION; CELL LOCOMOTION; CROSS-TALK; COLLAGEN; PROTEIN; KINASE; FIBROBLASTS AB Hypothesis: Fibroblasts, not myofibroblasts, are responsible for wound contraction. Only myofibroblasts express a smooth muscle actin for which vanadate blocks its expression. Wound contraction in vanadate-treated rats will proceed normally in the absence of myofibroblasts. Design: Laboratory study using rats. Methods: Wound healing in rats receiving vanadate parenterally, an inhibitor of tyrosine phosphate phosphatases, was investigated. For 21 days, treated rats received drinking water containing vanadate, 0.2 mg/mL, in isotonic sodium chloride solution, and the control rats received isotonic sodium chloride solution alone. On day 7, 4 square, full-excision wounds were made dorsally and measured, then 2 polyvinyl alcohol sponges were placed ventrally in subcutaneous pockets. Results: After 2 weeks, the wound area in the rats receiving vanadate measured 7.1+/-1.8 U (mean+/-SD), and the wound area in the control rats measured 7.2 +/- 2.2 U. The control rats' granulation tissue (GT) had myofibroblasts, or alpha-smooth muscle (alpha-SM) actin-positive fibroblasts, whereas the vanadate-treated group's fibroblasts were devoid of alpha-SM actin. By Western blot analysis, GT homogenates in the vanadate-treated group contained less alpha-SM actin. By electron microscopy, control rats' GT showed classic myofibroblast populations, and the collagen fiber bundles were randomly organized. In contrast, the wounds in the vanadate-treated group showed unencumbered fibroblast populations and neatly ordered, parallel collagen fiber bundles. By polarized light microscopy, the GT of the vanadate-treated group displayed orderly collagen fiber bundles. Conclusions: The differentiation of fibroblasts into myofibroblasts requires the dephosphorylation of selected tyrosine phosphate residues. In the absence of myofibroblasts, the rate of rat wound contraction is normal, and collagen fiber bundles have a more orderly arrangement. Myofibroblasts are not required for wound contraction. C1 Penn State Univ, Milton S Hershey Med Ctr, Dept Surg, Coll Med,Div Plast Surg, Hershey, PA 17033 USA. Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Anat & Neurosci, Hershey, PA 17033 USA. NIA, Biol Chem Lab, Baltimore, MD 21224 USA. RP Ehrlich, HP (reprint author), Penn State Univ, Milton S Hershey Med Ctr, Dept Surg, Coll Med,Div Plast Surg, Mail Code H113,500 Univ Dr, Hershey, PA 17033 USA. NR 22 TC 48 Z9 49 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0004-0010 J9 ARCH SURG-CHICAGO JI Arch. Surg. PD MAY PY 1999 VL 134 IS 5 BP 494 EP 501 DI 10.1001/archsurg.134.5.494 PG 8 WC Surgery SC Surgery GA 194BZ UT WOS:000080173400007 PM 10323421 ER PT J AU Hashiramoto, A Sano, H Maekawa, T Kawahito, Y Kimura, S Kusaka, Y Wilder, RL Kato, H Kondo, M Nakajima, H AF Hashiramoto, A Sano, H Maekawa, T Kawahito, Y Kimura, S Kusaka, Y Wilder, RL Kato, H Kondo, M Nakajima, H TI C-myc antisense oligodeoxynucleotides can induce apoptosis and down-regulate fas expression in rheumatoid synoviocytes SO ARTHRITIS AND RHEUMATISM LA English DT Article ID GROWTH-FACTOR-BETA; CELL-DEATH; ARTHRITIS SYNOVIUM; PROLIFERATION; FIBROBLASTS; PROTOONCOGENE; LOCALIZATION; INVOLVEMENT; INHIBITION; PROTEIN AB Objective. To investigate the role of c-myc in the pathogenesis of rheumatoid arthritis (RA) and the mechanism of synovial apoptosis. Methods. Using cultured human synoviocytes from patients with RA and c-myc antisense oligodeoxynucleotides (AS ODN), we examined the inhibition of cell proliferation by the MTI assay and the induction of apoptosis with TUNEL staining and fluorescence microscopy, In addition, the effect of c-myc on downregulation of Fas expression was analyzed by now cytometry, cytotoxicity assay, and reverse transcriptase-polymerase chain reaction. Results. Treatment with c-myc AS ODN induced inhibition of cell proliferation, along with downregulation of c-Myc protein and c-myc messenger RNA (mRNA) expression. The morphologic changes of synovial cell death were typical of apoptosis. In addition, c-myc AS ODN treatment down-regulated expression of Fas mRNA but not Fas antigen. Analysis of the involvement of the caspase cascade revealed that the cytotoxic activity of c-myc AS ODN was completely blocked by inhibitors of both caspase 1 (YVAD-FMK) and caspase 3 (DEVD-FMK). Conclusion. Our results strongly suggest that c-myc AS ODN might be a useful therapeutic tool in RA and clarify that cell death by c-myc AS ODN is induced through the caspase cascade, similar to Fas-induced apoptosis, In addition, combination therapy with anti-Fas antibody and c-myc AS ODN reduced Fas-dependent cytotoxicity. C1 Kyoto Prefectural Univ Med, Dept Internal Med 1, Kamigyo Ku, Kyoto 60208566, Japan. Univ Tokyo, Tokyo, Japan. NIAMSD, NIH, Bethesda, MD 20892 USA. RP Sano, H (reprint author), Kyoto Prefectural Univ Med, Dept Internal Med 1, Kamigyo Ku, 465 Kajii-cho, Kyoto 60208566, Japan. NR 41 TC 41 Z9 44 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD MAY PY 1999 VL 42 IS 5 BP 954 EP 962 DI 10.1002/1529-0131(199905)42:5<954::AID-ANR14>3.0.CO;2-J PG 9 WC Rheumatology SC Rheumatology GA 193MP UT WOS:000080140400014 PM 10323451 ER PT J AU Cid, MC Hernandez-Rodriguez, J Robert, J del Rio, A Casademont, J Coll-Vinent, B Grau, JM Kleinman, HK Urbano-Marquez, A Cardellach, F AF Cid, MC Hernandez-Rodriguez, J Robert, J del Rio, A Casademont, J Coll-Vinent, B Grau, JM Kleinman, HK Urbano-Marquez, A Cardellach, F TI Interferon-alpha may exacerbate cryoglobulinemia-related ischemic manifestations - An adverse effect potentially related to its anti-angiogenic activity SO ARTHRITIS AND RHEUMATISM LA English DT Article; Proceedings Paper CT Meeting of the British-Society-of-Rheumatology CY APR, 1998 CL BRIGHTON, ENGLAND SP British Soc Rheumatol ID HEPATITIS-C VIRUS; MIXED CRYOGLOBULINEMIA; ALFA-2A THERAPY; EXPRESSION; INHIBITION; INFECTION; GROWTH AB The discovery of the strong association between hepatitis C virus (HCV) infection and the development of mixed cryoglobulinemia has motivated active testing of antiviral-directed alternative therapies. Several trials have demonstrated that classic cryoglobulinemia-associated manifestations improve with interferon-alpha (IFN alpha) treatment. Herein we report on 3 HCV-infected patients with severe cryoglobulinemia-related ischemic manifestations who were closely followed up during IFN alpha therapy. Clinical evaluations with special attention to ischemic lesions, liver function tests, and cryocrit determinations were serially performed. In addition to prednisone and immunosuppressive agents, the patients received IFN alpha at 3 x 10(6) units, 3 times per week for 2 months, 3 months, and 4 months, respectively. In all 3 patients, systemic features improved, liver function results returned to normal, and cryocrit values decreased. However, ischemic lesions became less vascularized and ischemia progressed, leading to transmetatarsal and subcondylar amputation, respectively; in 2 of the patients and fingertip necrosis and ulcer enlargement in the third. Skin biopsies performed before IFN alpha therapy and after 2 months of IFN alpha therapy in the third patient showed a significant decrease in subepidermal microvessels. When IFNa was discontinued, the lesions finally healed. Cryoglobulinemia-related ischemic lesions may worsen during IFN alpha treatment, presumably through a decrease in inflammation-induced angiogenesis, The anti-angiogenic activity of IFN alpha may delay the appropriate healing of ischemic lesions. C1 Univ Barcelona, Barcelona, Spain. NIDR, NIH, Bethesda, MD 20892 USA. RP Cid, MC (reprint author), Hosp Clin, Dept Internal Med, Villarroel 170, Barcelona, Spain. RI Casademont, Jordi/A-6828-2010; OI Casademont, Jordi/0000-0002-8100-1827; Cid Xutgla, Maria Cinta/0000-0002-4730-0938 NR 15 TC 43 Z9 43 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD MAY PY 1999 VL 42 IS 5 BP 1051 EP 1055 DI 10.1002/1529-0131(199905)42:5<1051::AID-ANR26>3.0.CO;2-Q PG 5 WC Rheumatology SC Rheumatology GA 193MP UT WOS:000080140400026 PM 10323463 ER PT J AU Ludlow, CL Hang, C Bielamowicz, S Choyke, P Hampshire, V Selbie, WS AF Ludlow, CL Hang, C Bielamowicz, S Choyke, P Hampshire, V Selbie, WS TI Three-dimensional changes in the upper airway during neuromuscular stimulation of laryngeal muscles SO ARTIFICIAL ORGANS LA English DT Article; Proceedings Paper CT 6th Vienna International Workshop on Functional Electrostimulation CY SEP 22-24, 1998 CL VIENNA, AUSTRIA DE thyroarytenoid; dysphagia; voice; glottis; airway; vocal folds; larynx; swallowing AB During swallowing, airway protection depends upon adequate glottal closure and laryngeal elevation to prevent the entry of substances into the airway. Three-dimensional changes in the upper airway during laryngeal muscle stimulation in a canine model were quantified in animals implanted with Peterson type stimulating electrodes in the inferior and superior portions of the thyroarytenoid muscle, together with a reference electrode. Computer tomography scanning was performed on an IMATRON scanner with a 3 mm slice thickness advanced at overlapping 1 mm increments. Stimulation of the thyroarytenoid muscle produced adductions of the vocal fold towards the midline and changes in the supraglottic region as well as the glottis; the glottic wall was compressed medially above and below the glottis. These results suggest that chronic neuromuscular stimulation can effect glottic protection by reducing the glottal opening and may be beneficial for patients with central control disorders affecting airway protection during swallowing. C1 NIDCD, Voice & Speech Sect, NIH, Bethesda, MD 20892 USA. NIH, Dept Radiol, Ctr Clin, Bethesda, MD 20892 USA. NIH, Vet Resources Program, Bethesda, MD 20892 USA. RP Ludlow, CL (reprint author), NIDCD, Voice & Speech Sect, NIH, Bldg 10,Rm 5D,3810 Ctr Dr,MSC 1416, Bethesda, MD 20892 USA. OI Ludlow, Christy/0000-0002-2015-6171 FU NIDCD NIH HHS [Z01 DC 00004] NR 5 TC 4 Z9 4 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0160-564X J9 ARTIF ORGANS JI Artif. Organs PD MAY PY 1999 VL 23 IS 5 BP 463 EP 465 DI 10.1046/j.1525-1594.1999.06364.x PG 3 WC Engineering, Biomedical; Transplantation SC Engineering; Transplantation GA 201NX UT WOS:000080602600022 PM 10378944 ER PT J AU Baker, P Benoit, R Bibel, DJ Brock, T Chung, KT Domer, J Eveleigh, D Faison, B Isenberg, H Jannasch, H Lederberg, J Schaechter, M Schmidt, M Silver, S Summer, W Whitt, D AF Baker, P Benoit, R Bibel, DJ Brock, T Chung, KT Domer, J Eveleigh, D Faison, B Isenberg, H Jannasch, H Lederberg, J Schaechter, M Schmidt, M Silver, S Summer, W Whitt, D TI Microbiology's fifty most significant events during the past 125 years ... SO ASM NEWS LA English DT Article C1 NIAID, Bethesda, MD 20892 USA. Virginia Polytech Inst & State Univ, Blacksburg, VA 24061 USA. Elie Metchnikoff Mem Lib, San Francisco, CA USA. Univ Wisconsin, Madison, WI 53706 USA. Univ Memphis, Memphis, TN 38152 USA. Appalachian State Univ, Boone, NC 28608 USA. Rutgers State Univ, New Brunswick, NJ 08903 USA. Oak Ridge Natl Lab, Oak Ridge, TN USA. Long Isl Jewish Med Ctr, New Hyde Park, NY 11042 USA. Woods Hole Oceanog Inst, Woods Hole, MA 02543 USA. Rockefeller Univ, New York, NY 10021 USA. San Diego State Univ, San Diego, CA 92182 USA. Med Univ S Carolina, Charleston, SC 29425 USA. Univ Illinois, Coll Med, Chicago, IL USA. Yale Univ, New Haven, CT USA. Univ Illinois, Urbana, IL 61801 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0044-7897 J9 ASM NEWS JI ASM News PD MAY PY 1999 VL 65 IS 5 BP U7 EP + PG 10 WC Microbiology SC Microbiology GA 196HY UT WOS:000080304000011 ER PT J AU Brewer, HB AF Brewer, HB TI New insights into the role of HDL in reverse cholesterol transport and atherosclerosis SO ATHEROSCLEROSIS LA English DT Meeting Abstract C1 NHLBI, Mol Dis Branch, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD MAY PY 1999 VL 144 SU 1 BP 6 EP 6 DI 10.1016/S0021-9150(99)80014-8 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 203BM UT WOS:000080687500015 ER PT J AU Santamarina-Fojo, S Amar, M Haudenschild, C Dugi, K Brewer, HB AF Santamarina-Fojo, S Amar, M Haudenschild, C Dugi, K Brewer, HB TI Role of hepatic lipase in lipoprotein metabolism and atherosclerosis SO ATHEROSCLEROSIS LA English DT Meeting Abstract C1 NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD MAY PY 1999 VL 144 SU 1 BP 84 EP 84 DI 10.1016/S0021-9150(99)80322-0 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 203BM UT WOS:000080687500323 ER PT J AU Santamarina-Fojo, S Hoeg, J Vaisman, B Amar, M Foger, B Brousseau, M Koch, C Paigen, B Marcovina, S Brewer, HB AF Santamarina-Fojo, S Hoeg, J Vaisman, B Amar, M Foger, B Brousseau, M Koch, C Paigen, B Marcovina, S Brewer, HB TI LCAT overexpression in different animal models: Modulation of atherosclerosis by CETP, HL and APOA-I SO ATHEROSCLEROSIS LA English DT Meeting Abstract C1 NHLBI, NIH, Bethesda, MD 20892 USA. Jackson Lab, Bar Harbor, ME 04609 USA. Univ Washington, Seattle, WA 98195 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD MAY PY 1999 VL 144 SU 1 BP 164 EP 165 DI 10.1016/S0021-9150(99)80628-5 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 203BM UT WOS:000080687500630 ER PT J AU Brewer, HB AF Brewer, HB TI The role of apolipoproteins, receptors, and enzymes in genetic models of hdl metabolism and atherosclerosis SO ATHEROSCLEROSIS LA English DT Meeting Abstract C1 NHLBI, Mol Dis Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD MAY PY 1999 VL 144 SU 1 BP 165 EP 165 DI 10.1016/S0021-9150(99)80631-5 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 203BM UT WOS:000080687500633 ER PT J AU Brozinick, JT Reynolds, TH Dean, D Cartee, G Cushman, SW AF Brozinick, JT Reynolds, TH Dean, D Cartee, G Cushman, SW TI 1-[N,O-bis-(5-isoquinolinesulphonyl)-N-methyl-L-tyrosyl]-4-phenylpiperaz ine (KN-62), an inhibitor of calcium-dependent camodulin protein kinase II, inhibits both insulin- and hypoxia-stimulated glucose transport in skeletal muscle SO BIOCHEMICAL JOURNAL LA English DT Article DE akt kinase; GLUT4; photolabelling; PI 3-kinase ID ISOLATED-TISSUES; CELL-MEMBRANES; CALMODULIN ANTAGONIST; SIGNALING PATHWAYS; GLYCOGEN-SYNTHASE; HEXOSE-TRANSPORT; ENDOSOME FUSION; RAT; TRANSLOCATION; GLUT4 AB Previous studies have indicated a role for calmodulin in hypoxia- and insulin-stimulated glucose transport. However, since calmodulin interacts with multiple protein targets, it is unknown which of these targets is involved in the regulation of glucose transport. In the present study, we have used the calcium-dependent calmodulin protein kinase II (CAMKII) inhibitor 1-[N,O-bis-(5-isoquinolinesulphonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN-62) to investigate the possible role of this enzyme in the regulation of glucose transport in isolated rat soleus and epitrochlearis muscles. KN-62 did not affect basal 2-deoxyglucose transport, but it did inhibit both insulin- and hypoxia-stimulated glucose transport activity by 46 and 40% respectively, 1-[N,O-Bis-(1,5-isoquinolinesulphonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN-04), a structural analogue of KN-62 that does not inhibit CAMKII, had no effect on hypoxia- or insulin-stimulated glucose transport. Accordingly, KN-62 decreased the stimulated cell-surface GLUT4 labelling by a similar extent as the inhibition of glucose transport (insulin, 49% and hypoxia, 54 %). Additional experiments showed that KN-62 also inhibited insulin- and hypoxia-stimulated transport by 37 and 40 % respectively in isolated rat epitrochlearis (a fast-twitch muscle), indicating that the effect of KN-62 was not limited to the slow-twitch fibres of the soleus. The inhibitory effect of KN-62 on hypoxia-stimulated glucose transport appears to be specific to CAMKII, since KN-62 did not inhibit hypoxia-stimulated Ca-45 efflux from muscles pre-loaded with Ca-45, or hypoxia-stimulated glycogen breakdown. Additionally, KN-62 affected neither insulin-stimulated phosphoinositide 3-kinase nor Akt activity, suggesting that the effects of KN-62 are not due to nonspecific effects of this inhibitor on these regions of the insulin-signalling cascade. The results of the present study suggest that CAMKII might have a distinct role in insulin- and hypoxia-stimulated glucose transport, possibly in the vesicular trafficking of GLUT4. C1 DB NIDDK, Expt Diabet Metab & Nutr Sect, NIH, Bethesda, MD 20892 USA. Univ Wisconsin, Biodynam Lab, Madison, WI 53706 USA. RP Brozinick, JT (reprint author), DB NIDDK, Expt Diabet Metab & Nutr Sect, NIH, Bethesda, MD 20892 USA. OI Cartee, Gregory/0000-0001-5311-1722 NR 52 TC 37 Z9 37 U1 0 U2 1 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD MAY 1 PY 1999 VL 339 BP 533 EP 540 DI 10.1042/0264-6021:3390533 PN 3 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 196PG UT WOS:000080316300008 PM 10215590 ER PT J AU Benvenga, S Robbins, J AF Benvenga, S Robbins, J TI Altered thyroid hormone binding to plasma lipoproteins in the syndrome of resistance to thyroid hormones SO BIOCHIMIE LA English DT Article DE thyroid hormone binding; thyroid hormone resistance; serum lipoproteins ID LOW-DENSITY LIPOPROTEIN; KINDREDS; RECEPTOR; TRIIODOTHYRONINE; HYPOTHYROIDISM; MUTATION AB Lipoproteins, especially HDL, are carriers of a small fraction of the thyroid hormones in plasma and participate in the intracellular transport of T4. In previous work we showed that a brief period of hypothyroidism alters the hormone distribution among the lipoproteins, causing a decrease in VLDL and LDL binding despite a relative increase in VLDL and LDL cholesterol, an increase in HDL binding, and a reversal of T4 and T3 binding to the smallest HDL size subgroup. The present study of three patients with thyroid hormone resistance and largely compensated hypothyroidism showed thyroid hormone distribution that differed markedly from both normal and hypothyroid subjects. The most striking difference was a much lower binding of both T4 and T3 to HDL and a much higher binding to LDL. If confirmed in a larger group of patients, this might serve as a marker for thyroid hormone resistance. (C) Societe francaise de biochimie et biologie moleculaire / Elsevier, Paris. C1 NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. Univ Messina, Sch Med, Cattedra Endocrinol, I-98125 Messina, Italy. RP Robbins, J (reprint author), NIDDK, Genet & Biochem Branch, NIH, Bldg 10,Room 6C201, Bethesda, MD 20892 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS CEDEX 15 PA 23 RUE LINOIS, 75724 PARIS CEDEX 15, FRANCE SN 0300-9084 J9 BIOCHIMIE JI Biochimie PD MAY PY 1999 VL 81 IS 5 BP 545 EP 548 DI 10.1016/S0300-9084(99)80108-4 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 208WB UT WOS:000081013900019 PM 10403188 ER PT J AU Kim, IS Yoo, TM Kobayashi, H Kim, M Le, N Wang, Q Pastan, I Carrasquillo, JA Paik, CH AF Kim, IS Yoo, TM Kobayashi, H Kim, M Le, N Wang, Q Pastan, I Carrasquillo, JA Paik, CH TI Chemical modification to reduce renal uptake of disulfide-bonded variable region fragment of anti-Tac monoclonal antibody labeled with Tc-99m SO BIOCONJUGATE CHEMISTRY LA English DT Article ID SOLUBLE INTERLEUKIN-2 RECEPTOR; STABILIZED FV FRAGMENT; HAIRY-CELL LEUKEMIA; SOMATOSTATIN ANALOG; BIODISTRIBUTION; DISEASE; INFUSION; BINDING; MICE; FAB' AB The anti-Tac disulfide-bonded variable region fragment (dsFv) is a genetically engineered, 25 kDa, murine monoclonal antibody fragment that recognizes the alpha subunit of the interleukin-2 receptor (IL-2R alpha). The dsFv radiolabeled with the tetrafluorophenyl ester (TFP) of [Tc-99m]mercaptoacetyltriglycine ([Tc-99m]MAG3-TFP) showed rapid tumor uptake and fast blood clearance in mice, resulting in high tumor-to-nontumor background ratios. However, its high renal uptake was a problem. In this study, we tested the effect of lowering the isoelectric point (pI) of dsFv to <9.3 on renal and tumor uptake. To lower the pi, dsFv was acylated simultaneously with both [Tc-99m]MAG3-TFP and TFP-glycolate. The acylation of dsFv decreased its pi and its immunoreactivity inversely proportional to the molar ratio of TFP-glycolate to dsFv, whereas the conjugation of [Tc-99m]MAG3-TFP alone did not. When biodistribution studies were performed in nude mice, the effect of the lowered pi was reflected primarily in decreased kidney uptake and whole-body retention, with its highest effect seen at the earliest time point (15 min) after injection. In tumor-bearing nude mice, glycolated [Tc-99m]MAG3-dsFv with a pi range of 4.9 to 6.5 accumulated selectively into IL-2 receptor-positive SP2/Tac tumor similar to that of the control [I-125]dsFv labeled by the Iodo-Gen method, whereas its renal uptake was 25% of [I-125]dsFv at 15 min. At 90 min, the ratios of tumor to receptor-negative SP2/0 tumor, liver, kidney, stomach, and blood had peaked at 10.9, 8.5, 0.3, 5.0, and 6.2, respectively, for the glycolated [Tc-99m]MAG3-dsFv. The corresponding ratios for [125I]dsFv were 3.7, 5.0, 0.1, 1.5, and 2.1, respectively. C1 NCI, Dept Nucl Med, Warren G Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Paik, CH (reprint author), NCI, Dept Nucl Med, Warren G Magnuson Clin Ctr, NIH, Bldg 21,Room 136, Bethesda, MD 20892 USA. RI Carrasquillo, Jorge/E-7120-2010; OI Carrasquillo, Jorge/0000-0002-8513-5734 NR 29 TC 20 Z9 22 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD MAY-JUN PY 1999 VL 10 IS 3 BP 447 EP 453 DI 10.1021/bc980129m PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 200RD UT WOS:000080553100019 PM 10346877 ER PT J AU Mertz, EL Krishtalik, LI AF Mertz, EL Krishtalik, LI TI Free energy of charge transfer and intraprotein electric field: method of calculation depends on the charge state of protein at a given structure SO BIOELECTROCHEMISTRY AND BIOENERGETICS LA English DT Article; Proceedings Paper CT Symposium on Electromagnetic Fields in Biological Systems CY SEP 13-16, 1998 CL PRAGUE, CZECH REPUBLIC SP Int Union Radio Sci, Int Commiss K DE activation energy; dielectric polarization; optical and static; electric field; electron transfer; electrostatic interaction; proteins; electrostatics of ID REORGANIZATION ENERGY; DIELECTRIC-PROPERTIES; CYTOCHROME-C; ELECTROSTATICS; DYNAMICS; COMPLEX AB Free energy of charge transfer presents a basic characteristic of reactions such as protonation, oxido-reduction and similar. Evaluation of this quantity requires calculation of charging energy. Proteins are structured dielectrics, and a consistent incorporation of their structure into calculation of intraprotein electric field results in expression for charging energy of an active group in protein, which is essentially different from that for a simple dielectric. An algorithm for semi-continuum calculation of relevant free energies is described. First of the two components of charging energy in protein, energy of the medium response to charge redistribution in reactants, should be always calculated as the charging energy by the charge redistribution using the static dielectric constant of protein. The second term is interaction energy of the charge redistribution with the 'frozen' electric field of the system before reaction. Charges of protein groups, at which the protein structure has been determined, are often different from those before reaction of charge transfer, so is the corresponding intraprotein field. The field is expressed through either both the optical and static dielectric constants of protein or only optical one depending on whether the charges of protein groups before reaction and upon. structural analysis are the same or not. Proper allowance for difference in charges of reacting groups before reaction and upon structural analysis of protein is thermodynamically necessary and quantitatively important. The expression for activation free energy for charge transfer in proteins is derived in the form presenting explicitly an invariant contribution of protein structure. (C) 1999 Elsevier Science S.A. All rights reserved. C1 Russian Acad Sci, AN Frumkin Electrochem Inst, Moscow 117071, Russia. NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. RP Krishtalik, LI (reprint author), Russian Acad Sci, AN Frumkin Electrochem Inst, Leninskij Prosp 31, Moscow 117071, Russia. NR 17 TC 9 Z9 9 U1 0 U2 0 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 0302-4598 J9 BIOELECTROCH BIOENER JI Bioelectrochem. Bioenerg. PD MAY PY 1999 VL 48 IS 2 BP 397 EP 405 DI 10.1016/S0302-4598(99)00021-5 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 199NB UT WOS:000080487600024 PM 10379560 ER PT J AU Ferlanti, ES Ryan, JF Makalowska, I Baxevanis, AD AF Ferlanti, ES Ryan, JF Makalowska, I Baxevanis, AD TI WebBLAST 2.0: an integrated solution for organizing and analyzing sequence data SO BIOINFORMATICS LA English DT Article ID TOOL AB WebBLAST is a suite of programs intended to assist in organizing sequencing data and to provide first-pass sequence analysis in an automated fashion. Data processing is fully automated, with end-users being presented both graphical and tabular summaries of data that can be viewed using any Web browser. C1 Natl Human Genome Res Inst, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Ferlanti, ES (reprint author), Natl Human Genome Res Inst, Genome Technol Branch, NIH, Bldg 49,Room 2C-76, Bethesda, MD 20892 USA. NR 9 TC 11 Z9 11 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD MAY PY 1999 VL 15 IS 5 BP 422 EP 423 DI 10.1093/bioinformatics/15.5.422 PG 2 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 212RN UT WOS:000081230200010 PM 10366662 ER PT J AU Schapiro, MB Berman, KF Alexander, GE Weinberger, DR Rapoport, SI AF Schapiro, MB Berman, KF Alexander, GE Weinberger, DR Rapoport, SI TI Regional cerebral blood flow in Down syndrome adults during the Wisconsin Card Sorting Test: Exploring cognitive activation in the context of poor performance SO BIOLOGICAL PSYCHIATRY LA English DT Article DE schizophrenia; frontal lobe; Down syndrome; brain activation; mental retardation; cerebral blood flow ID DORSOLATERAL PREFRONTAL CORTEX; POSITRON-EMISSION TOMOGRAPHY; PHYSIOLOGICAL DYSFUNCTION; HUNTINGTONS-DISEASE; GLUCOSE-UTILIZATION; SCHIZOPHRENIA; MODULATION; MECHANISM; PATTERN; RATES AB Background: Prior studies have indicated abnormal frontal lobes in Down syndrome (DS). The Wisconsin Card Sorting Test (WCST) has been used during functional brain imaging studies to activate the prefrontal cortex, Whether this activation is dependent on successful performance remains unclear To determine frontal lobe regional cerebral blood flow (rCBF) response in DS and to further understand the effect of performance on rCBF during the WCST, we studied DS adults who perform poorly on this task. Methods: Initial slope (IS), an rCBF index, was measured,vith the (133)Xe inhalation technique during a Numbers Matching Control Task and the WCST. Ten healthy DS subjects (mean age 28.3 years) and 20 sex-matched healthy volunteers (mean age 28.7 years) were examined. Results: Performance of DS subjects was markedly impaired compared to controls. Both DS and control subjects significantly increased prefrontal IS indices compared to the control task during the WCST. Conclusions: Prefrontal activation in DS during the WCST rt as not related to performance of that task but may reflect engagement of some components involved in the task, arch as effort. Further, these results show that failure to activate prefrontal cortex during WCST in schizophrenia is unlikely to be due to poor performance alone. (C) 1999 Society of Biological Psychiatry. C1 NIA, Neurosci Lab, Sect Brain Aging & Dementia, Ctr Clin, Bethesda, MD 20892 USA. NIMH, St Elizabeths Hosp, Ctr Neurosci, Intramural Res Program, Washington, DC 20032 USA. RP Schapiro, MB (reprint author), NIA, Neurosci Lab, Sect Brain Aging & Dementia, Ctr Clin, Bldg 10,Rm 6C414, Bethesda, MD 20892 USA. NR 33 TC 7 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 1999 VL 45 IS 9 BP 1190 EP 1196 DI 10.1016/S0006-3223(98)00051-1 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 194RT UT WOS:000080207900012 PM 10331111 ER PT J AU Bartzokis, G Beckson, M Hance, DB Lu, PH Foster, JA Mintz, J Ling, W Bridge, P AF Bartzokis, G Beckson, M Hance, DB Lu, PH Foster, JA Mintz, J Ling, W Bridge, P TI Magnetic resonance imaging evidence of "silent" cerebrovascular toxicity in cocaine dependence SO BIOLOGICAL PSYCHIATRY LA English DT Article DE magnetic resonance imaging; cocaine; hyperintense lesions; aging ID MIDDLE CEREBRAL-ARTERY; POSITRON EMISSION TOMOGRAPHY; NEUROVASCULAR COMPLICATIONS; BLOOD-FLOW; ALKALOIDAL COCAINE; LACUNAR INFARCTS; CRACK COCAINE; YOUNG-ADULTS; BRAIN; STROKE AB Background: Cocaine and its metabolites can produce vasospasm. Cocaine-dependent (CD) patients are at increased risk for stroke, and a high frequency of brain perfusion defects has been observed in clinically asymptomatic CD subjects, This is the first controlled magnetic resonance imaging (MRI) study of clinically asymptomatic CD subjects. Methods: Two age-matched groups of male subjects (61 CD and 57 control) participated in the study, Subjects with a history of neurologic symptoms or major medical or neurologic illness, such as hypertension, diabetes, or significant head trauma, were excluded The severity of hyperintense lesions observed on T2-weighted MRI images were rated on a O-3-point scale by an experienced radiologist who was blind to all clinical data. Ratings of 3 were felt to be significant indicators of a possible disease process and were used in the data analysis, three regions were separately rated: the cerebral white matter, subinsular white matter, and subcortical gray matter (basal ganglia and thalamus region). Results: Despite the exclusion criteria minimizing risk factors for cerebrovascular events, 17 of the 61 (27.9%) CD subjects and 4 of 57 (7%) of the control subjects had severe hyperintense lesions suggestive of subclinical or "silent" anoxic vascular events. Significant group differences were observed in the two white matter regions but not in the subcortical gray matter region. The risk of severe white matter lesions in the CD group increased with age, reaching 50% in the oldest age quartile (46-58 years), and this increase was not related to the number of years cocaine was used. Conclusions: The data suggest that asymptomatic CD patients are a heterogeneous population with a significantly increased age-related risk of white matter neuro-vascular toxicity, Premature neurovascular damage may impact treatment outcomes and, as the CD population ages, may manifest as an increased incidence of cognitive deficits, (C) 1999 Society of Biological Psychiatry. C1 N Little Rock VA Med Ctr, Psychiat Serv, N Little Rock, AR 72114 USA. Univ Arkansas Med Sci, Dept Psychiat, Little Rock, AR 72205 USA. W Los Angeles Vet Affairs Med Ctr, Psychiat Serv, Los Angeles, CA USA. Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. Univ Calif Los Angeles, Dept Radiol, Los Angeles, CA USA. NIDA, Med Dev Div, Rockville, MD USA. RP Bartzokis, G (reprint author), N Little Rock VA Med Ctr, Psychiat Serv, 116 NLR,2200 Fort Roots Dr Bldg,170, N Little Rock, AR 72114 USA. RI Bartzokis, George/K-2409-2013 FU NIDA NIH HHS [1YO1 DA 50038] NR 74 TC 41 Z9 41 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 1999 VL 45 IS 9 BP 1203 EP 1211 DI 10.1016/S0006-3223(98)00228-5 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 194RT UT WOS:000080207900014 PM 10331113 ER PT J AU Saroff, HA Kiefer, JE AF Saroff, HA Kiefer, JE TI The legacies of Langmuir, Ising, and Pauling: Ligand binding and the helix-coil transition SO BIOPOLYMERS LA English DT Article DE interactions; cooperativity; one-dimensional lattice theory ID PARAMETERS; PROTEIN; SITES AB Multiple, independent sires or domains behave, on chemical change, in a manner predicted by Langmuir. Distortions of this behavior have been attributed to interactions between the domains, which vary with the progress of the changes occurring at the sires or domains. The two main models for nearest neighbor interactions perturbing the Langmuir prediction for independent domains are those of Ising and Pauling. If we designate the initial site as (-) and the changed site as (+), then the Langmuir requirement for independence of sites yields a set of nearest neighbor interactions such that the (- -), (- +), (+ -), and (+ +) interactions are all identical. This identity is usually characterized as "no interactions. " Ising, in dealing with electron pairs, invoked nearest neighbor interactions such that the interactions of the (- -) pairs equaled those of the (+ +) pairs, but with the (- +) and (+ -) pairs differing from the reference (- -)pair. Pauling, on the other hand postulated that only the (- -) and (+ +) pairs interacted differently. A dichotomy has arisen in the application of these Two models, with some investigators ignoring or overlooking one of the models. We explore these models, alone and combined, with exact partition functions generated in reasonable computer times for hundreds of sites employing our combinatorial algorithm. (C) 1999 John Wiley & Sons, Inc. C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. NIH, Phys Sci Lab, Div Comp Res & Technol, Bethesda, MD 20892 USA. RP Saroff, HA (reprint author), NIDDKD, Lab Biochem & Genet, NIH, Bldg 8,Room 218, Bethesda, MD 20892 USA. NR 17 TC 9 Z9 9 U1 1 U2 3 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0006-3525 J9 BIOPOLYMERS JI Biopolymers PD MAY PY 1999 VL 49 IS 6 BP 425 EP 440 DI 10.1002/(SICI)1097-0282(199905)49:6<425::AID-BIP1>3.0.CO;2-3 PG 16 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 180GU UT WOS:000079378400001 PM 10193190 ER PT J AU Gonzalez, P Zigler, JS Epstein, DL Borras, T AF Gonzalez, P Zigler, JS Epstein, DL Borras, T TI Identification and isolation of differentially expressed genes front very small tissue samples SO BIOTECHNIQUES LA English DT Article ID QUANTITATIVE HYBRIDIZATION; TRABECULAR MESHWORK; MICROARRAY; PATTERNS; SCALE AB Identification of differentially expressed genes from tissue samples weighing only a few milligrams has remained a major challenge. Here, we describe a novel and simple strategy that rises standard molecular biology equipment and commercially available kits. The approach combines isolation of total RNA by silica-gel binding, reverse transcription using anchored modified, 5' end enhancers oligonucleotides, exponential amplification of the single-stranded cDNA and hybridization to high-density cDNA filter arrays. The method was tested by comparing genes expressed on freshly isolated human trabecular meshwork tissue with those expressed in corresponding primary cells at third passage. Validation,cas achieved by using two biological properties: (i) hybridization, to identify the differentially expressed genes, and (ii) PCR amplification, to confirm their distinct expression. The strategy presented allows the identification of differentially expressed genes and/or uncharacterized expressed sequence tags (ESTs) in very small tissue samples, including those from clinical specimens. C1 Duke Univ, Med Ctr, Durham, NC 27710 USA. NEI, NIH, Bethesda, MD 20892 USA. RP Gonzalez, P (reprint author), Duke Univ, Med Ctr, Wadsworth Bldg,Erwin Rd,Box 3802, Durham, NC 27710 USA. FU NEI NIH HHS [EY01894, EY11906] NR 15 TC 35 Z9 37 U1 0 U2 0 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD MAY PY 1999 VL 26 IS 5 BP 884 EP + PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 196TC UT WOS:000080322800016 PM 10337481 ER PT J AU Nilsson, G Mikovits, JA Metcalfe, DD Taub, DD AF Nilsson, G Mikovits, JA Metcalfe, DD Taub, DD TI Mast cell migratory response to interleukin-8 is mediated through interaction with chemokine receptor CXCR2/interleukin-8RB SO BLOOD LA English DT Article ID NEUTROPHIL-ACTIVATING PEPTIDE-2; CHEMOTACTIC FACTOR; T-LYMPHOCYTES; SIGNAL-TRANSDUCTION; EXPRESSION; CYTOKINES; CHEMOATTRACTANT; MECHANISM; CLONING; BETA AB To explore the role of chemokines in mast cell chemotaxis and accumulation at sites of inflammation, we first investigated the response of human mast cells to 18 different chemokines by induction of intracellular calcium mobilization in the human mast cell line, HMC-1. Only a subgroup of CXC chemokines defined by the conserved sequence motif glutamic acid-leucine-arginine (ELR) tripeptide motif, which included interleukin-8 (IL-8), growth-regulated oncogene alpha (GRO alpha), neutrophil-activating peptide-2 (NAP-2), and epithelial cell-derived neutrophil activating peptide-78 (ENA-78), induced calcium flux in the cells. These observations suggested that the receptor CXCR2 (IL-8RB) should be expressed on the surface of these cells. Using the RNAse protection assay, CXCR2 mRNA, but not CXCR1 (IL-8RA) mRNA expression was detected in HMC-1 cells. Flow cytometry analysis documented the surface expression of CXCR2. A binding analysis performed with I-125-IL-8 determined that there were approximately 3,600 high affinity IL-8 binding sites per HMC-1 cell, with a calculated kd of 1.2 to 2 nmol/L. The activity of this receptor was further explored using IL-8, which was found to induce dose-dependent chemotactic and haptotactic responses in both HMC-1 cells and in vitro cultured human cord blood-derived mast cells. These results show the expression of functional CXCR2 receptors on the surface of human mast cells, which may play an important role in mast cell recruitment during the genesis of an inflammatory response. (C) 1999 by The American Society of Hematology. C1 Uppsala Univ, Dept Genet & Pathol, Unit Pathol, S-75185 Uppsala, Sweden. NCI, Frederick Canc Res & Dev Program, Sci Applicat Int Corp, Frederick, MD USA. NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. NIA, Clin Immunol Sect, Immunol Lab, NIH, Baltimore, MD USA. RP Nilsson, G (reprint author), Uppsala Univ, Dept Genet & Pathol, Unit Pathol, S-75185 Uppsala, Sweden. NR 34 TC 81 Z9 82 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1200 19TH ST, NW, STE 300, WASHINGTON, DC 20036-2422 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 1 PY 1999 VL 93 IS 9 BP 2791 EP 2797 PG 7 WC Hematology SC Hematology GA 190UZ UT WOS:000079984800005 PM 10216072 ER PT J AU Zeichner, SL Palumbo, P Feng, YR Xiao, XD Gee, D Sleasman, J Goodenow, R Biggar, R Dimitrov, D AF Zeichner, SL Palumbo, P Feng, YR Xiao, XD Gee, D Sleasman, J Goodenow, R Biggar, R Dimitrov, D TI Rapid telomere shortening in children SO BLOOD LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; BLOOD LYMPHOCYTE SUBPOPULATIONS; AGE-RELATED-CHANGES; HIV-1 INFECTION; HUMAN FIBROBLASTS; INFANTS; TYPE-1; LENGTH; CD4(+); RNA AB Telomere shortening may reflect the total number of divisions experienced by a somatic cell and is associated with replicative senescence. We found that the average rate of telomere shortening in peripheral blood mononuclear cells (PBMCs) obtained longitudinally from nine different infants during the first 3 years of life (270 bp per year) is more than fourfold higher than in adults and does not correlate with telomerase activity, These results show that the rate of telomere loss changes during ontogeny, suggesting the existence of periods of accelerated cell division, Because human immunodeficiency virus (HIV) preferentially infects actively dividing cells, our observation suggesting accelerated cell division in children may provide an explanation for some of the distinctive pathogenic features of the HIV disease in infants, including higher viral loads and more rapid progression to acquired immunodeficiency syndrome (AIDS). This is a US government work. There are no restrictions on its use. C1 NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Pediat, Newark, NJ 07103 USA. NCI, Lab Expt & Computat Biol, Frederick, MD USA. Univ Florida, Dept Pediat, Gainesville, FL USA. NCI, Viral Epidemiol Branch, Bethesda, MD 20892 USA. RP Zeichner, SL (reprint author), NCI, HIV & AIDS Malignancy Branch, NIH, Bldg 10,Room 13N240, Bethesda, MD 20892 USA. NR 30 TC 100 Z9 101 U1 1 U2 8 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1200 19TH ST, NW, STE 300, WASHINGTON, DC 20036-2422 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 1 PY 1999 VL 93 IS 9 BP 2824 EP 2830 PG 7 WC Hematology SC Hematology GA 190UZ UT WOS:000079984800009 PM 10216076 ER PT J AU Kockx, M Gervois, PP Poulain, P Derudas, B Peters, JM Gonzalez, FJ Princen, HMG Kooistra, T Staels, B AF Kockx, M Gervois, PP Poulain, P Derudas, B Peters, JM Gonzalez, FJ Princen, HMG Kooistra, T Staels, B TI Fibrates suppress fibrinogen gene expression in rodents via activation of the peroxisome proliferator-activated receptor-alpha SO BLOOD LA English DT Article ID CORONARY HEART-DISEASE; PPAR-GAMMA ACTIVATORS; LIPOPROTEIN METABOLISM; RESPONSE ELEMENT; FATTY-ACIDS; PROMOTER; MICE; RAT; HYPERCHOLESTEROLEMIA; HEPATOCYTES AB Plasma fibrinogen levels have been identified as an important risk factor for cardiovascular diseases. Among the few compounds known to lower circulating fibrinogen levels in humans are certain fibrates. We have studied the regulation of fibrinogen gene expression by fibrates in rodents. Treatment of adult male rats with fenofibrate (0.5% [wt/wt] in the diet) for 7 days decreased hepatic A alpha-, B beta-, and gamma-chain mRNA levels to 52% +/- 7%, 46% +/- 8%, and 81% +/- 19% of control values, respectively. In parallel, plasma fibrinogen concentrations were decreased to 63% +/- 7% of controls. The suppression of fibrinogen expression was dose-dependent and was already evident after 1 day at the highest dose of fenofibrate tested (0.5% [wt/wt]). Nuclear run-on experiments showed that the decrease in fibrinogen expression after fenofibrate occurred at the transcriptional level, as exemplified for the gene for the A alpha-chain. Other fibrates tested showed similar effects on fibrinogen expression and transcription. The effect of fibrates is specific for peroxisome proliferator-activated receptor-alpha (PPAR alpha) because a high-affinity ligand for PPAR gamma, the thiazolidinedione BRL 49653, lowered triglyceride levels, but was unable to suppress fibrinogen expression. Direct evidence for the involvement of PPAR alpha in the suppression of fibrinogen by fibrates was obtained using PPAR alpha-null (-/-) mice, Compared with (+/+) mice, plasma fibrinogen levels in (-/-) mice were significantly higher (3.20 +/- 0.48 v 2.67 +/- 0.42 g/L). Also, hepatic fibrinogen A alpha-chain mRNA levels were 25% +/- 11% higher in the (-/-) mice. On treatment with 0.2% (wt/wt) fenofibrate, a significant decrease in plasma fibrinogen to 77% +/- 10% of control levels and in hepatic fibrinogen A alpha-chain mRNA levels to 65% +/- 12% of control levels was seen in (+/+) mice, but not in (-/-) mice. These studies show that PPAR alpha regulates basal levels of plasma fibrinogen and establish that fibrate-suppressed expression of fibrinogen in rodents is mediated through PPAR alpha. (C) 1999 by The American Society of Hematology. C1 TNO Prevent & Hlth, Gaubius Lab, NL-2301 CE Leiden, Netherlands. Inst Pasteur, INSERM, U325, Dept Atherosclerose, F-59019 Lille, France. Univ Lille 2, Fac Pharm, Lille, France. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Kooistra, T (reprint author), TNO Prevent & Hlth, Gaubius Lab, POB 2215, NL-2301 CE Leiden, Netherlands. RI Peters, Jeffrey/D-8847-2011; Staels, Bart/N-9497-2016 OI Staels, Bart/0000-0002-3784-1503 NR 45 TC 105 Z9 109 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1200 19TH ST, NW, STE 300, WASHINGTON, DC 20036-2422 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 1 PY 1999 VL 93 IS 9 BP 2991 EP 2998 PG 8 WC Hematology SC Hematology GA 190UZ UT WOS:000079984800028 PM 10216095 ER PT J AU Hirano, A Longo, DL Taub, DD Ferris, DK Young, LS Eliopoulos, AG Agathanggelou, A Cullen, N Macartney, J Fanslow, WC Murphy, WJ AF Hirano, A Longo, DL Taub, DD Ferris, DK Young, LS Eliopoulos, AG Agathanggelou, A Cullen, N Macartney, J Fanslow, WC Murphy, WJ TI Inhibition of human breast carcinoma growth by a soluble recombinant human CD40 ligand SO BLOOD LA English DT Article ID IN-VIVO; CELLS; EXPRESSION; ACTIVATION; CYTOKINES; STIMULATION; ANTIBODIES; RECEPTOR; MICE AB CD40 is present on B cells, monocytes, dendritic cells, and endothelial cells, as well as a variety of neoplastic cell types, including carcinomas. CD40 stimulation by an antibody has previously been demonstrated to induce activation-induced cell death in aggressive histology human B-cell lymphoma cell lines. Therefore, we wanted to assess the effects of a recombinant soluble human CD40 ligand (srhCD40L) on human breast carcinoma cell lines. Human breast carcinoma cell lines were examined for CD40 expression by flow cytometry, CD40 expression could be detected on several human breast cancer cell lines and this could be augmented with interferon-gamma. The cell lines were then incubated with a srhCD40L to assess effects on in vitro growth. srhCD40L significantly inhibited the proliferation of the CD40(+) human breast cancer cell lines. This inhibition could also be augmented with interferon-gamma. Viability was also affected and this was shown to be due to increased apoptosis of the cell lines in response to the ligand. Treatment of tumor-bearing mice was then performed to assess the in vivo efficacy of the ligand. Treatment of tumor-bearing SCID mice with the ligand resulted in significant increases in survival. Thus, CD40 stimulation by its ligand directly inhibits human breast carcinoma cells in vitro and in vivo. These results suggest that srhCD40L may be of clinical use to inhibit human breast carcinoma growth. C1 Sci Applicat Int Corp, Intramural Res Support Program, Frederick, MD USA. NCI, Lab Leukocyte Biol, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. NIA, Baltimore, MD 21224 USA. Univ Birmingham, Sch Med, Inst Canc Studies, Birmingham, W Midlands, England. Walsgrave Gen Hosp, Dept Histopathol, Coventry CV2 2DY, W Midlands, England. Immunex Inc, Seattle, WA USA. RP Murphy, WJ (reprint author), Sci Applicat Int Corp, Intramural Res Support Program, Bldg 567,Room 210, Frederick, MD USA. RI Young, Lawrence/B-7213-2009 OI Young, Lawrence/0000-0003-3919-4298 FU NCI NIH HHS [N01-CO-56000] NR 21 TC 115 Z9 118 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1200 19TH ST, NW, STE 300, WASHINGTON, DC 20036-2422 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 1 PY 1999 VL 93 IS 9 BP 2999 EP 3007 PG 9 WC Hematology SC Hematology GA 190UZ UT WOS:000079984800029 PM 10216096 ER PT J AU Lekstrom-Himes, J Xanthopoulos, KG AF Lekstrom-Himes, J Xanthopoulos, KG TI CCAAT/enhancer binding protein epsilon is critical for effective neutrophil-mediated response to inflammatory challenge SO BLOOD LA English DT Article ID TUMOR-NECROSIS-FACTOR; COLONY-STIMULATING FACTOR; CHRONIC GRANULOMATOUS-DISEASE; IL-1 RECEPTOR ANTAGONIST; FACTOR-ALPHA; DNA-BINDING; DEFICIENT MICE; C/EBP-EPSILON; L-SELECTIN; GRANULE DEFICIENCY AB Targeted mutation of CCAAT/enhancer binding protein (C/EBP) epsilon in mice results in early death, primarily due to spontaneous infection with Pseudomonas aeruginosa. Functional analysis of C/EBP epsilon-deficient neutrophils, in an in vivo model of peritoneal inflammation, shows multiple defects. Reduction of phagocytotic killing by C/EBP epsilon-deficient neutrophils is a result of decreased uptake of opsonized bacteria as well as little to no expression of secondary granule proteins. Abnormalities in neutrophil migration detected in a chemical peritonitis model are likely secondary to abnormal CD11b integrin and L-selectin expression on C/EBP epsilon-deficient neutrophils, Alterations in neutrophil cytokine expression in response to inflammation show decreased levels of interleukin-1 receptor antagonist (IL-1Ra) and increased levels of tumor necrosis factor-alpha (TNF-alpha) expression by C/EBP epsilon-deficient neutrophils, Additionally, TNF-alpha expression is increased in nonactivated, circulating C/EBP epsilon-deficient neutrophils, Overall, C/EBP epsilon-deficient neutrophils are severely functionally impaired, evoking an abnormal microenvironment, which may contribute to the loss of normal responses to inflammatory stimuli. Similarities between the C/EBP epsilon-deficient mouse model and the human disease, specific granule deficiency, will be discussed. C1 NIH, Natl Human Genome Res Inst, Clin Gene Therapy Branch, Bethesda, MD USA. RP Lekstrom-Himes, J (reprint author), 10 Ctr Dr,11N120, Bethesda, MD 20892 USA. NR 54 TC 71 Z9 73 U1 3 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1200 19TH ST, NW, STE 300, WASHINGTON, DC 20036-2422 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 1 PY 1999 VL 93 IS 9 BP 3096 EP 3105 PG 10 WC Hematology SC Hematology GA 190UZ UT WOS:000079984800040 PM 10216107 ER PT J AU Prakasam, G Yeh, JK Chen, MM Castro-Magana, M Liang, CT Aloia, JF AF Prakasam, G Yeh, JK Chen, MM Castro-Magana, M Liang, CT Aloia, JF TI Effects of growth hormone and testosterone on cortical bone formation and bone density in aged orchiectomized rats SO BONE LA English DT Article DE androgen, male; aging; osteoporosis; bone histomorphometry; hormone therapy ID MINERAL DENSITY; TREADMILL EXERCISE; GONADAL-FUNCTION; GH DEFICIENCY; FEMALE RATS; FACTOR-I; OSTEOPOROSIS; ANDROGEN; HISTOMORPHOMETRY; THERAPY AB Osteoporosis in men is a disease that is increasing in incidence, and with an increasing elderly population it poses a serious health problem. Since both testosterone (T) and growth hormone (GH) have an anabolic effect on bone and both decrease with aging, we were prompted to test whether the administration of these hormones in combination would increase bone mass in orchiectomized (orx) senile rats more than administration of either agent alone. Twenty-month-old male Wistar rats were divided into five groups with seven animals each: (a) age-matched intact control, (b) orx, (c) orx+GH (2.5 mg/kg/day), (d) orx+T [10 mg/kg, subcutaneous (s.c.), injection given twice a week], and (e) orx+GH+T. Testosterone and GH were given subcutaneously for 4 weeks. Bone histomorphometry of the tibial shaft showed that the orx group had lower cortical bone area than the intact control group, The decrease in cortical bone area was due to increased intracortical porosis as well as decreased periosteal bone formation rate (BFR), Administration of T to the orx animals prevented the development of the porosis and the decrease in periosteal BFR, The bone mineral content (BMC) and bone mineral density (BMD) of the Femur as tested by dual-energy X-ray absorptiometry were significantly higher in the orx+T than in the orx group and were not significantly different from that of the intact control group. Administration of On to the orx rats increased periosteal BFR significantly; however, the BMC and BMD measured were not increased significantly in comparison to the orx group. When On and T were combined in treatment, the cortical bone area, periosteal BFR, and femoral BMD were all significantly higher than that of the orx and even higher than the intact control rats. Two-way analysis of variance shows that the individual effect of On and T treatment on the periosteal BFR and cortical bone area was significant. The effect of T, but not GH, on femoral BMC and BMD was also significant; however, there is no synergistic interaction between the two treatments. Four weeks of orx with or without GH or T administration had no significant effect on tibial metaphyseal cancellous bone volume, In conclusion, this short-term study suggests that the combined intervention of On and T in androgen-deficient aged male rats may have an independent effect in preventing osteopenia, The significant effect of GH+T may be attributed to the prevention of intracortical porosis, and an increase in periosteal bone formation and cortical bone mass, (C) 1999 by Elsevier Science Inc. All rights reserved. C1 Winthrop Univ Hosp, Dept Med, Metab Lab, Mineola, NY 11501 USA. Winthrop Univ Hosp, Dept Pediat, Div Pediat Endocrinol, Mineola, NY 11501 USA. SUNY Stony Brook, Hlth Sci Ctr, Stony Brook, NY 11794 USA. NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Yeh, JK (reprint author), Winthrop Univ Hosp, Dept Med, Metab Lab, Mineola, NY 11501 USA. NR 43 TC 61 Z9 64 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 8756-3282 J9 BONE JI Bone PD MAY PY 1999 VL 24 IS 5 BP 491 EP 497 DI 10.1016/S8756-3282(99)00018-6 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 190GN UT WOS:000079954600007 PM 10321909 ER PT J AU Selleri, C Maciejewski, JP De Rosa, G Raiola, A Risitano, AM Picardi, M Pezzullo, L Luciano, L Ricci, P Varriale, G Della Cioppa, P Del Vecchio, L Rotoli, B AF Selleri, C Maciejewski, JP De Rosa, G Raiola, A Risitano, AM Picardi, M Pezzullo, L Luciano, L Ricci, P Varriale, G Della Cioppa, P Del Vecchio, L Rotoli, B TI Long-lasting decrease of marrow and circulating long-term culture initiating cells after allogeneic bone marrow transplant SO BONE MARROW TRANSPLANTATION LA English DT Article DE CD34(+); LTC-IC; BMT ID HEMATOPOIETIC STEM-CELLS; SEVERE APLASTIC-ANEMIA; PERIPHERAL-BLOOD; PROGENITOR CELLS; IN-VIVO; MYELOABLATIVE THERAPY; POPULATION FOLLOW; SELF-RENEWAL; CFU-GM; ENGRAFTMENT AB We investigated bone marrow (BM) and circulating (PB) hematopoietic progenitor cells in 37 normal donors and in 25 patients 1 to 8 years after successful allogeneic bone marrow transplant, At the time of testing, transplanted patients had normal blood counts and bone marrow cellularity. By flow cytometry, BM CD34(+) cells were found to be three- to four-fold decreased in transplanted patients compared to normal donors, while the number of PB CD34(+) cells was the same as in normal donors. Using a methylcellulose colony assay, primary BM colony-forming cells (CFU-GM) were decreased 2.1-fold, whereas PB CFU-GM were only marginally decreased, In a long-term culture initiating cell (LTC-IC) assay, an eight-fold decrease of early progenitor cells was observed in the marrow of transplanted patients compared to normal donors, and a five-fold decrease was documented in peripheral blood. We found that the BM LTC-IC cell number correlated with concurrently determined BM CD34(+) cells and committed progenitor cell number (measured as CFU-GM) and with PB LTC-IC number, but not with PB CFU-GM and CD34(+) cells. We conclude that marrow and circulating early stem cell compartments, as measured by the LTC-IC assay, are greatly and permanently depressed following bone marrow transplant, The correlation between BM and PB LTC-IC indicates that the enumeration of circulating LTC-IC can be used as a measure of the stem cell compartment in the bone marrow after transplant. It seems that the deficiency of the most immature progenitor cells persists forever after successful bone marrow transplant; this means that a complete hematopoietic reconstitution can be sustained by a reduced stem cell pool. C1 Univ Naples Federico II, Sch Med, Div Hematol, I-80131 Naples, Italy. Cardarelli Hosp, Serv Immunohematol, Naples, Italy. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Selleri, C (reprint author), Univ Naples Federico II, Sch Med, Div Hematol, Via S Pansini 5, I-80131 Naples, Italy. OI PICARDI, Marco/0000-0001-8508-2524 NR 34 TC 28 Z9 28 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAY PY 1999 VL 23 IS 10 BP 1029 EP 1037 DI 10.1038/sj.bmt.1701759 PG 9 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 200TW UT WOS:000080557000009 PM 10373069 ER PT J AU Andres, FG Mima, T Schulman, AE Dichgans, J Hallett, M Gerloff, C AF Andres, FG Mima, T Schulman, AE Dichgans, J Hallett, M Gerloff, C TI Functional coupling of human cortical sensorimotor areas during bimanual skill acquisition SO BRAIN LA English DT Article DE bimanual movement; motor learning; EEG; coherence; mapping ID SUPPLEMENTARY MOTOR AREA; EVENT-RELATED DESYNCHRONIZATION; PACED FINGER MOVEMENTS; INTERHEMISPHERIC EEG COHERENCE; POSITRON EMISSION TOMOGRAPHY; CEREBRAL-ARTERY INFARCTION; INTERNATIONAL 10-20 SYSTEM; CORPUS-CALLOSUM; SPONTANEOUS OSCILLATIONS; PHYSIOLOGICAL TREMOR AB Bimanual co-ordination of skilled finger movements is a high-level capability of the human motor system and virtually always requires training. Little is known about the physiological processes underlying successful bimanual performance and skill acquisition, In the present study, we used task-related coherence (TRCoh) and task-related power (TRPow) analysis of multichannel surface EEG to investigate the functional coupling and regional activation of human sensorimotor regions during bimanual skill acquisition. We focused on changes in interhemispheric coupling associated with bimanual learning. TRCoh and TRPow were estimated during the fusion of two overlearned unimanual finger-tapping sequences into one novel bimanual sequence, before and after a 30-min training period in 18 normal volunteers. Control experiments included learning and repetition of complex and simple unimanual finger sequences. The main finding was a significant increase in interhemispheric TRCoh selectively in the early learning stage (P < 0.0001), Interhemispheric TRCoh was also present during the unimanual control tasks, but with lower magnitude, even if learning was involved. Training improved bimanual sequence performance (from 58.3 +/- 24.1 to 83.7 +/- 15.3 % correct sequences). After training, interhemispheric (bimanual) TRCoh decreased again, thereby approaching levels similar to those in the unimanual controls. We propose that the initial increase in TRCoh reflects changes in interhemispheric communication that are specifically related to bimanual learning and may be relayed through the corpus callosum, The present data might also offer a neurophysiological explanation for the clinical observation that patients with lesions of the corpus callosum may show deficits in the acquisition of novel bimanual tasks but not necessarily in the execution of previously learned bimanual activities. C1 NIH, Human Motor Control Sect, Bethesda, MD 20892 USA. NINDS, Biometry & Field Study Branch, Bethesda, MD 20892 USA. Univ Tubingen, Neurol Klin, D-7400 Tubingen, Germany. RP Gerloff, C (reprint author), NIH, Human Motor Control Sect, Room 5N-226,Bldg 10,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. OI Mima, Tatsuya/0000-0001-7787-4855 NR 93 TC 183 Z9 183 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD MAY PY 1999 VL 122 BP 855 EP 870 DI 10.1093/brain/122.5.855 PN 5 PG 16 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 200FB UT WOS:000080528000007 PM 10355671 ER PT J AU Esposito, G Kirkby, BS Van Horn, JD Ellmore, TM Berman, KF AF Esposito, G Kirkby, BS Van Horn, JD Ellmore, TM Berman, KF TI Context-dependent, neural system-specific neurophysiological concomitants of ageing: mapping PET correlates during cognitive activation SO BRAIN LA English DT Article DE ageing; brain activation; cognition; frontal lobe; PET ID CEREBRAL BLOOD-FLOW; POSITRON-EMISSION TOMOGRAPHY; PROGRESSIVE MATRICES TEST; HUMAN EXTRASTRIATE CORTEX; WORKING-MEMORY TASKS; CARD SORTING TEST; PREFRONTAL CORTEX; SELECTIVE ATTENTION; RISK-FACTORS; DOPAMINE AB We used PET to explore the neurophysiological changes that accompany cognitive disability in ageing, with a focus on the frontal lobe. Absolute regional cerebral blood flow (rCBF) was measured in 41 healthy volunteers, evenly distributed across an age range of 18-80 years, during two task paradigms: (i) the Wisconsin Card Sorting Test (WCST), which depends heavily on working memory and is particularly sensitive to dysfunction of the dorsolateral prefrontal cortex (DLPFC); and (ii) Raven's Progressive Matrices (RPM), which may also have a working memory component, but depends more on visuo-spatial processing and is most sensitive to dysfunction of postrolandic regions. We used voxel-wise correlational mapping to determine age-related changes in WCST and RPM activation and developed a method to quantitate and localize statistical differences between the correlation maps for the two task paradigms. Because both WCST and RPM performance declined with age, as expected, correlational analyses were performed with and without partialling out the effect of task performance. Task-specific reductions of rCBF activation with age were found in the DLPFC during the WCST and in portions of the inferolateral temporal cortex involved in visuo-spatial processing during the RPM. We also found reduced ability to suppress rCBF in the right hippocampal region during the WCST and in mesial and polar portions of the prefrontal cortex during both task conditions. Task-dependent alterations with age in the relationship between the DLPFC and the hippocampus were also documented; because the collective pattern of changes in the hippocampal-DLPFC relationship with ageing was opposite to that seen in a previous study using dextroamphetamine, we postulated a dopaminergic mechanism. These results indicate that, despite some cognitive overlap between the two tasks and the age-related cognitive decline in both, many of the changes in rCBF activation with age were task-specific, reflecting functional alteration of the different neural circuits normally engaged by young subjects during the WCST and RPM. Reduced activation of areas critical for task performance i.e. the DLPFC during the WCST and posterior visual association areas of the inferolateral temporal cortex during the (RPM), in conjunction with the inability to suppress areas normally not involved in task performance (i.e. the left hippocampal region during the WCST and mesial polar prefrontal cortex during both the WCST and RPM), suggest that, overall, reduced ability to focus neural activity may be impaired in older subjects. The context dependency of the age-related changes is most consistent with systems failure and disordered connectivity. C1 NIH, Bethesda, MD 20892 USA. NIMH, Unit Integrat Neuroimaging, Clin Brain Disorders Branch, Intramural Res Program, Bethesda, MD 20892 USA. RP Berman, KF (reprint author), NIH, Bldg 10,Room 4C101,9000 Rockville Pike, Bethesda, MD 20892 USA. EM bermank@dirpc.nimh.nih.gov OI Ellmore, Timothy/0000-0001-6125-0044 NR 88 TC 140 Z9 145 U1 2 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD MAY PY 1999 VL 122 BP 963 EP 979 DI 10.1093/brain/122.5.963 PN 5 PG 17 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 200FB UT WOS:000080528000015 PM 10355679 ER PT J AU Tjurmina, OA Goldstein, DS Palkovits, M Kopin, IJ AF Tjurmina, OA Goldstein, DS Palkovits, M Kopin, IJ TI alpha(2)-adrenoceptor-mediated restraint of norepinephrine synthesis, release, and turnover during immobilization in rats SO BRAIN RESEARCH LA English DT Article DE immobilization; microdialysis; norepinephrine; paraventricular nucleus; yohimbine ID HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; SYMPATHETIC-NERVE ACTIVITY; IN-VIVO MICRODIALYSIS; NORADRENALINE RELEASE; BRAIN-STEM; PHYSIOLOGICAL SIGNIFICANCE; I1-IMIDAZOLINE SITES; VASOPRESSIN RELEASE; MONOAMINE-OXIDASE; CONSCIOUS RATS AB Stress-related release of norepinephrine (NE) in the brain and periphery probably underlies several neuroendocrine and neurocirculatory responses. NE might influence its own synthesis, release, and turnover, by negative feedback regulation via alpha(2)-adrenoceptors. We examined central and peripheral noradrenergic function by measuring concentrations of NE, dihydroxyphenylglycol (DHPG), and dihydroxyphenylacetic acid (DOPAC) in hypothalamic paraventricular nucleus (PVN) microdialysate and arterial plasma simultaneously during immobilization (IMMO) in conscious rats. The alpha(2)-adrenoceptor antagonist yohimbine (YOH) was injected i.p. or perfused locally into the PVN via the microdialysis probe. The i.p. YOH increased plasma NE, epinephrine (EPI), DHPG, dihydroxyphenylalanine, and DOPAC levels by 4.3, 7.3, 2.5, 0.6 and 1.8-fold and PVN microdialysate NE, DHPG, and DOPAC by 1.2, 0.6 and 0.5-fold. The i.p. YOH also enhanced effects of IMMO on plasma and microdialysate NE, DHPG, and DOPAC. YOH delivered via the PVN microdialysis probe did not affect microdialysate or plasma levels of the analytes at baseline and only slightly augmented microdialysate NE responses to IMMO. The results indicate that alpha(2)-adrenoceptors tonically restrain NE synthesis, release, and turnover in sympathetic nerves and limit IMMO-induced peripheral noradrenergic activation. In the PVN, alpha(2)-adrenoceptors do not appear to contribute to these processes tonically and exert relatively little restraint on IMMO-induced local noradrenergic activation. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIMH, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NINDS, Clin Neurosci Branch, NIH, Bethesda, MD 20892 USA. RP Tjurmina, OA (reprint author), NIMH, Clin Sci Lab, NIH, Bldg 10,Rm 3D41,10 Ctr Dr,MSC-1264, Bethesda, MD 20892 USA. RI Palkovits, Miklos/F-2707-2013 NR 59 TC 24 Z9 24 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAY 1 PY 1999 VL 826 IS 2 BP 243 EP 252 DI 10.1016/S0006-8993(99)01281-0 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 192BF UT WOS:000080057100010 PM 10224302 ER PT J AU Leung, LK Wang, TTY AF Leung, LK Wang, TTY TI Differential effects of chemotherapeutic agents on the Bcl-2/Bax apoptosis pathway in human breast cancer cell line MCF-7 SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE apoptosis; Bax; Bcl-2; breast; chemotherapy; estradiol ID C-MYC EXPRESSION; TUMOR-CELLS; DNA FRAGMENTATION; PROTEIN FAMILY; GROWTH ARREST; DEATH; DOXORUBICIN; ACTIVATION; INDUCTION; MECHANISM AB The present study explored the effects of three commonly used chemotherapeutic agents on the Bcl-2/Bax apoptosis pathway and the interaction of these chemotherapeutic drugs with the estradiol-mediated regulation of this pathway. Our results showed that: (1) Treatment of MCF-7 cells with Adriamycin resulted in time- and concentration-dependent decreases in Bcl-2 and increases in Bax mRNA and protein levels. (2) Camptothecin elicited similar trends on Bcl-2 and Bax as Adriamycin, while etoposide, at 50-100 fold (1-5 mu M) the effective concentration of Adriamycin and camptothecin, only resulted in an increase in Bax mRNA levels. (3) Adriamycin and camptothecin, but not etoposide, were effective in suppressing estradiol-stimulated increases in Bcl-2 mRNA levels. Our study provides evidence that the Bcl-2/Bax apoptosis pathway may be differentially regulated by chemotherapeutic agents. In addition, interaction between these agents and estradiol on the Bcl-2/Bax apoptosis pathway may also exist. C1 NCI, Basic Res Lab, Frederick Canc Res & Dev Ctr, NIH, Frederick, MD 21702 USA. RP Wang, TTY (reprint author), NCI, Basic Res Lab, Frederick Canc Res & Dev Ctr, NIH, Bldg 560-12-05,POB B, Frederick, MD 21702 USA. RI Leung, Lai/C-6511-2013; LEUNG, Lai K./E-6314-2011 OI Leung, Lai/0000-0002-7781-3099; LEUNG, Lai K./0000-0002-7781-3099 NR 25 TC 34 Z9 50 U1 0 U2 5 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD MAY PY 1999 VL 55 IS 1 BP 73 EP 83 DI 10.1023/A:1006190802590 PG 11 WC Oncology SC Oncology GA 213KM UT WOS:000081271800008 PM 10472781 ER PT J AU Nakashima, R Fujita, M Enomoto, T Haba, T Yoshino, K Wada, H Kurachi, H Sasaki, N Wakasa, K Inoue, M Buzard, G Murata, Y AF Nakashima, R Fujita, M Enomoto, T Haba, T Yoshino, K Wada, H Kurachi, H Sasaki, N Wakasa, K Inoue, M Buzard, G Murata, Y TI Alteration of p16 and p15 genes in human uterine tumours SO BRITISH JOURNAL OF CANCER LA English DT Article DE p16; p15; cervical carcinoma; endometrial carcinoma; methylation; immunohistochemistry ID HUMAN-PAPILLOMAVIRUS INFECTION; PRIMARY CERVICAL-CARCINOMA; HUMAN CANCERS; CELL-LINES; GROWTH SUPPRESSION; BASE SUBSTITUTIONS; CDKN2; MTS1; METHYLATION; P15(INK4B) AB The roles of the p16 and p15 inhibitor of cyclin-dependent kinase tumour suppressor genes were examined in human uterine cervical and endometrial cancers. p16 mRNA, examined by reverse transcription polymerase chain reaction (RT-PCR), was significantly reduced in five of 19 (26%) cervical and four of 25 (16%) endometrial tumours. Reduced expression of p16 protein, detected by immunohistochemistry, occurred even more frequently, in nine of 33 (27%) cervical and seven of 37 (19%) endometrial tumours. Hypermethylation of a site within the 5'-CpG island of the p16 gene was detected in only one of 32 (3%) cervical tumours and none of 26 endometrial tumours. Homozygous p16gene deletion, evaluated by differential PCR analysis, was found in four of 40 (10%) cervical tumours and one of 38 (3%) endometrial tumours. Homozygous deletion of p15 was found in three of 40 (846) cervical tumours and one of 38 (3%) endometrial tumours. PCR-SSCP (single-strand conformation polymorphism) analysis detected point mutations in the p16 gene in six (8%) of 78 uterine tumours (four of 40 (10%) cervical tumours and two of 38 (5%) endometrial tumours). Three were mis-sense mutations, one in codon 74 (CTG-->ATG) and one in codon 129 (ACC-->ATC), both in cervical carcinomas, and the other was in codon 127 (GGG-->GAG) in an endometrial carcinoma. There was one non-sense mutation, in codon 50 (CGA-->TGA), in an endometrial carcinoma. The remaining two were silent somatic cell mutations, both in cervical carcinomas, resulting in no amino acid change. These observations suggest that inactivation of the p16 gene, either by homologous deletion, mutation or loss of expression, occurs in a subset of uterine tumours. C1 Osaka Univ, Fac Med, Dept Obstet & Gynecol, Osaka 5650871, Japan. Osaka City Univ Hosp, Dept Pathol, Abeno Ku, Osaka 5450051, Japan. Kanazawa Univ, Fac Med, Dept Obstet & Gynecol, Kanazawa, Ishikawa 9200934, Japan. NCI, Intramural Res Support Program, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Enomoto, T (reprint author), Osaka Univ, Fac Med, Dept Obstet & Gynecol, 2-2 Yamadaoka, Osaka 5650871, Japan. FU NCI NIH HHS [N01-CO-56000] NR 34 TC 68 Z9 71 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 MAY PY 1999 VL 80 IS 3-4 BP 458 EP 467 DI 10.1038/sj.bjc.6690379 PG 10 WC Oncology SC Oncology GA 191NR UT WOS:000080028900023 PM 10408854 ER PT J AU Liscia, DS Morizio, R Venesio, T Palenzona, C Donadio, M Callahan, R AF Liscia, DS Morizio, R Venesio, T Palenzona, C Donadio, M Callahan, R TI Prognostic significance of loss of heterozygosity at loci on chromosome 17p13.3-ter in sporadic breast cancer is evidence for a putative tumour suppressor gene SO BRITISH JOURNAL OF CANCER LA English DT Article DE breast cancer; chromosome 17p13.3; LOH; survival ID BAND 17P13.3; P53 GENE; PROTEIN; 17P; CARCINOMAS; MUTATIONS; REGION; CELLS; ABR AB Several studies indicate that the short arm of chromosome 17 is one of the most frequently altered regions in sporadic breast carcinomas (45-60%). In the present report the 17p13.3-ter locus in tumour DNA of breast cancer patients, along with their matching normal lymphocyte DNA, have been mapped with four markers (D17S5, D17S379, ABR and D17S34), spanning nearly 3 cM of the telomer. Sixty-five of 143 heterozygous tumours had lost at least one of the markers at the minimum region of loss (45%). High levels of loss of these distal markers on 17p13.3 are independent of TP53 mutations and are associated with tumour cell proliferation. A follow-up period of over 7 years demonstrates that loss of these markers correlates both with disease-free (P = 0.004) and overall survival (P = 0.007). In addition we show that for disease-free survival the prognostic power of this genetic alteration is second only to axillary lymph node involvement (3.1 vs 6.3 relative risk), and is a better predictor than the mutational status of TP53 (1.6 relative risk). Our results are further evidence of the presence, within the region, of at least a second tumour suppressor gene distal to TP53, that might be targeted by deletions. C1 Dipartimento Oncol ASL1, Serv Anat Patol, I-10123 Turin, Italy. Natl Canc Inst, LTIB, Oncogenet Sect, Bethesda, MD USA. RP Liscia, DS (reprint author), Dipartimento Oncol ASL1, Serv Anat Patol, Via Cavour 31, I-10123 Turin, Italy. NR 28 TC 17 Z9 17 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 MAY PY 1999 VL 80 IS 5-6 BP 821 EP 826 DI 10.1038/sj.bjc.6690427 PG 6 WC Oncology SC Oncology GA 192CB UT WOS:000080059700024 PM 10360661 ER PT J AU Tracy, TS Korzekwa, KR Gonzalez, FJ Wainer, IW AF Tracy, TS Korzekwa, KR Gonzalez, FJ Wainer, IW TI Cytochrome P450 isoforms involved in metabolism of the enantiomers of verapamil and norverapamil SO BRITISH JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE cytochrome P450; enantiomer; metabolism; norverapamil; verapamil ID 1ST-PASS METABOLISM; EXPRESSION; BIOAVAILABILITY; CYCLOSPORINE; ERYTHROMYCIN; MICROSOMES; INDUCTION; OXIDATION; RIFAMPIN; HUMANS AB Aims The present study was conducted to evaluate metabolism of the enantiomers of verapamil and norverapamil using a broad range of cytochrome P450 isoforms and measure the kinetic parameters of these processes. Methods Cytochrome P450 cDNA-expressed cells and microsomes from a P450-expressed lymphoblastoid cell line were incubated with 40 mu M concentrations of R- or S-verapamil and R- or S-norverapamil and metabolite formation measured by h.p.l.c. as an initial screening. Those isoforms exhibiting substantial activity were then studied over a range of substrate concentrations (2.5-450 mu M) to estimate the kinetic parameters for metabolite formation. Results P450s 3A4, 3A5, 2C8 and to a minor extent 2E1 were involved in the metabolism of the enantiomers of verapamil. Estimated K-m values for the production of D-617 and norverapamil by P450s 3A4 and 3A5 were similar (range = 60-127 mu M) regardless of the enantiomer of verapamil studied while the V-max estimates were also similar (range = 4-8 pmol min(-1) pmol(-1) P450). Only nominal production of D-620 by these isoforms was noted. Interestingly, P450 2C8 readily metabolized both S- and R-verapamil to D-617, norverapamil and PR-22 with only slightly higher K-m values than noted for P450s 3A4 and 3A5. However, the V-max estimates for P450 2C8 metabolism of S- and R-verapamil were in general greater (range = 8-15 pmol min(-1) pmol(-1) P450) than those noted for P450 s 3A4 and 3A5 with preference noted for metabolism of the S-enantiomer. Similarly, P450 s 3A4, 3A5 and 2C8 also mediated the metabolism of the enantiomers of norverapamil with minor contributions by P450 s 2D6 and 2E1. P450s 3A4 and 3A5 readily formed the D-620 metabolite with generally a lower K-m and higher V-max for S-norverapamil than for the R-enantiomer. In contrast, P450 2C8 produced both the D-620 and PR-22 metabolites from the enantiomers of norverapamil, again with stereoselective preference seen for the S-enantiomer. Conclusions These results confirm that P450s 3A4, 3A5 and 2C8 play a major role in verapamil metabolism and demonstrate that norverapamil can also be further metabolized by the P450s. C1 W Virginia Univ, Sch Pharm, Dept Basic Pharmaceut Sci, Morgantown, WV 26506 USA. Univ Pittsburgh, Ctr Clin Pharmacol, Pittsburgh, PA USA. NCI, NIH, Bethesda, MD 20892 USA. McGill Univ, Dept Oncol, Pharmacokinet Div, Montreal, PQ, Canada. RP Tracy, TS (reprint author), W Virginia Univ, Sch Pharm, Dept Basic Pharmaceut Sci, HSN POB 9530, Morgantown, WV 26506 USA. NR 19 TC 123 Z9 125 U1 2 U2 4 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0306-5251 J9 BRIT J CLIN PHARMACO JI Br. J. Clin. Pharmacol. PD MAY PY 1999 VL 47 IS 5 BP 545 EP 552 DI 10.1046/j.1365-2125.1999.00923.x PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 194JU UT WOS:000080189700010 PM 10336579 ER PT J AU Liu, WL Wang, M Tang, DC Ding, I Rodgers, GP AF Liu, WL Wang, M Tang, DC Ding, I Rodgers, GP TI Thrombopoietin has a differentiative effect on late-stage human erythropoiesis SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE EPO; TPO; c-Mpl; erythropoiesis; glycophorin A ID C-MPL LIGAND; RECOMBINANT HUMAN THROMBOPOIETIN; HEMATOPOIETIC STEM-CELLS; EARLY-ACTING CYTOKINES; ERYTHROID PROGENITORS; IN-VITRO; MULTIPOTENTIAL PROGENITORS; ENHANCES PROLIFERATION; LIQUID CULTURE; RECEPTOR AB To further explore the mechanism of the effect of thrombopoietin (TPO) on erythropoiesis, we used a two-phase culture system to investigate the effect of TPO on late-stage human erythroid lineage differentiation. In serum-free suspension and semisolid cultures of human peripheral blood derived erythroid progenitors, TPO alone did not produce benzidine-positive cells, However, in serum-containing culture, TPO alone stimulated erythroid cell proliferation and differentiation, demonstrated by erythroid colony formation, production of benzidine-positive cells and haemoglobin (Hb) synthesis. Monoclonal anti-human erythropoietin antibody and anti-human erythropoietin receptor antibody completely abrogated the erythroid differentiative ability of TPO in the serum-containing systems. This implied that binding of EPO and EPO-R was essential for erythropoiesis and the resultant signal transduction may be augmented by the signals emanating from TPO-c-Mp interaction. Experiment of withdrawal of TPO further demonstrated the involvement of TPO in late-stage erythropoiesis. RT-PCR results showed that there was EPO-R but not c-Mpl expression on developing erythroblasts induced by TPO in serum-containing system. Our results establish that TPO affects not only the proliferation of erythroid progenitors but also the differentiation of erythroid progenitors to mature erythroid cells. C1 NIDDK, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Rodgers, GP (reprint author), NIDDK, Mol & Clin Hematol Branch, NIH, Bldg 10,Room 9N119, Bethesda, MD 20892 USA. NR 36 TC 18 Z9 18 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 MAY PY 1999 VL 105 IS 2 BP 459 EP 469 DI 10.1046/j.1365-2141.1999.01343.x PG 11 WC Hematology SC Hematology GA 201XC UT WOS:000080621300024 PM 10233422 ER PT J AU Fisher, B AF Fisher, B TI Highlights from recent National Surgical Adjuvant Breast and Bowel Project studies in the treatment and prevention of breast cancer SO CA-A CANCER JOURNAL FOR CLINICIANS LA English DT Article ID RANDOMIZED CLINICAL-TRIAL; CARCINOMA-IN-SITU; RECEPTOR-NEGATIVE TUMORS; PREOPERATIVE CHEMOTHERAPY; SEQUENTIAL METHOTREXATE; RADICAL MASTECTOMY; RADIATION-THERAPY; PROGNOSTIC INDEX; POSITIVE TUMORS; TAMOXIFEN AB Findings from major National Surgical Adjuvant Breast and Bowel Project studies in women with breast cancer and negative axillary nodes are reported and discussed. Results of the B-13 and B-19 studies demonstrated that systemic chemotherapy (either with methotrexate and sequentially administered fluorouracil followed by leucovorin, or with cyclophosphamide plus methotrexate and fluorouracil) increased overall disease-free survival in women 49 years of age or younger, as well as in those 50 years old or older. Women older than 50 also experienced a survival advantage with chemotherapy. Moreover, women who received systemic chemotherapy after lumpectomy plus radiation therapy were significantly less likely to develop an ipsilateral recurrence of tumor. The B-14 study established the benefit of tamoxifen. When chemotherapy was added to tamoxifen in the B-20 trial there was an increased benefit. The B-18 trial demonstrated that the outcome of patients who received preoperative chemotherapy was comparable to that of patients who received the same therapy postoperatively. Moreover, results suggested that breast tumor response to preoperative chemotherapy correlated with outcome. Also, larger tumors were sufficiently downstaged by preoperative chemotherapy to permit lumpectomy rather than mastectomy. The B-17 study in women with ductal carcinoma in situ concluded that radiation therapy should follow lumpectomy in women with localized, mammographically detected lesions. The P-1 Breast Cancer Prevention trial showed that tamoxifen was effective in significantly reducing the incidence of both invasive and noninvasive breast tumors in women at high risk for the disease. Although many questions remain, and a new study, P-2, has been designed to compare tamoxifen and raloxifene, it is appropriate to offer tamoxifen to women who are similar to those in the P-2 study and who may benefit from it. C1 Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Allegheny Univ Hlth Sci, Pittsburgh, PA USA. RP Fisher, B (reprint author), Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. FU NCI NIH HHS [U10-CA-69974, U10-CA-37377] NR 28 TC 41 Z9 41 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0007-9235 J9 CA-CANCER J CLIN JI CA-Cancer J. Clin. PD MAY-JUN PY 1999 VL 49 IS 3 BP 159 EP 177 DI 10.3322/canjclin.49.3.159 PG 19 WC Oncology SC Oncology GA 194UY UT WOS:000080213500004 PM 10445015 ER PT J AU Cheng, L Bostwick, DG Li, G Wang, QH Hu, N Vortmeyer, AO Zhuang, ZP AF Cheng, L Bostwick, DG Li, G Wang, QH Hu, N Vortmeyer, AO Zhuang, ZP TI Allelic imbalance in the clonal evolution of prostate carcinoma SO CANCER LA English DT Article DE prostate; metastases; allelic imbalance; microdissection; progression ID IN-SITU HYBRIDIZATION; HUMAN BREAST-CANCER; INTRAEPITHELIAL NEOPLASIA; CHROMOSOMAL-ANOMALIES; INDEPENDENT ORIGIN; HETEROGENEITY; ADENOCARCINOMA; 8P12-21 AB BACKGROUND. To understand better the genetic basis of the clonal evolution of prostate carcinoma, the authors analyzed the pattern of allelic loss in 25 matched primary and metastatic prostate tumors. METHODS. Twenty-five cases were selected from the surgical pathology files of the Mayo Clinic from patients who had undergone radical retropubic prostatectomy and bilateral lymphadenectomy between 1987-1991. All patients had regional lymph node metastases at the time of surgery. DNA samples for the analysis of allelic loss pattern were prepared from primary tumors and matched synchronous lymph node metastases by tissue microdissection. The oligonucleotide primer pairs for the microsatellite DNA markers were D8S133, D8S136, D8S137, ANK1 on chromosome 8p12-21, LPLTET on chromosome 8p22, and D17S855 (intragenic to the BRCA1 gene) on chromosome 17q21. One case was not informative at any of the loci tested and was excluded from further analysis. RESULTS. The overall frequency of allelic imbalance was 79% in primary tumors and 88% in paired metastases. Of 24 informative cases, 14 patients (58%) showed the same pattern of allelic loss or retention in matched primary and metastatic tumors at all marker locus; discordant allelic loss was observed in the remaining 10 patients (42%). Four patients showed loss of the same allele at one or more marker loci in both primary and metastatic tumors, but discordant allelic loss was observed at other marker loci. Five patients showed allelic loss in at least one genetic marker in the metastatic tumor but not in its matched primary tumor. Five patients displayed loss of one allele at one or more marker loci in a primary tumor but not in the matched metastases. There was no significant difference in the frequency of allelic imbalance between primary and met astatic tumors at any marker analyzed (P > 0.05). CONCLUSIONS. These data suggest that different patterns of allelic deletion may be acquired during cancer progression to metastases. The differences in genetic composition between primary prostate carcinoma and its metastases may be related to intrinsic cancer heterogeneity, overall genetic instability, and clonal divergence. (C) 1999 American Cancer Society. C1 Indiana Univ, Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA. Mayo Clin & Mayo Fdn, Dept Lab Med & Pathol, Rochester, MN 55905 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Cheng, L (reprint author), Indiana Univ, Sch Med, Dept Pathol & Lab Med, UH 3465,550 N Univ Blvd, Indianapolis, IN 46202 USA. NR 21 TC 45 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 0008-543X J9 CANCER JI Cancer PD MAY 1 PY 1999 VL 85 IS 9 BP 2017 EP 2022 DI 10.1002/(SICI)1097-0142(19990501)85:9<2017::AID-CNCR20>3.0.CO;2-V PG 6 WC Oncology SC Oncology GA 190AK UT WOS:000079939200020 PM 10223244 ER PT J AU Hjalmars, U Kulldorff, M Wahlqvist, Y Lannering, B AF Hjalmars, U Kulldorff, M Wahlqvist, Y Lannering, B TI Increased incidence rates but no space-time clustering of childhood astrocytoma in Sweden, 1973-1992 - A population-based study of pediatric brain tumors SO CANCER LA English DT Article DE childhood brain tumors; astrocytoma; primitive neuroectodermal tumor medulloblastoma; ependymoma; epidemiology; incidence trends; cluster analysis; geographic information systems; spatial scan statistic; Knox test ID LEUKEMIA CLUSTERS; CANCER INCIDENCE; GREAT-BRITAIN; RISK-FACTORS; EPIDEMIOLOGY; CHILDREN; GLIOMA AB BACKGROUND. Incidence patterns, trends, and spatial and/or temporal clustering of childhood brain tumors were analyzed in the population-based national cancer registry of Sweden. METHODS. Temporal trends were analyzed by a logistic regression procedure in which the average annual percentages of change in incidence rates and the corresponding 95% confidence intervals (CIs) were calculated. Spatial and/or temporal clustering were investigated by using a geographic information system and analyzed with a modified version of the Knox test and a spatial scan statistic. RESULTS. Primary brain tumors in 1223 children ages 0-15 years were registered during 1973-1992. In 80% of cases, the tumor was classified as malignant. Conclusive histopathology was classified in 1142 cases. The age-adjusted incidence rate for all subtypes of brain tumors was 35.9 cases per million children, and for malignant brain tumors 28.6. A statistically significant increasing temporal trend was observed for the group of malignant brain tumors as a whole (P = 0.0001) and the astrocytoma subgroup (P = 0.0001). The annual average increases were 2.6% (95% CI = 1.5-3.8) and 3.0%, respectively (95% CI = 1.6-4.4). The increase in astrocytoma cases was significantly larger for girls than for boys (P = 0.021) and was most striking for girls ages 6-15 years, with an annual average increase of 4.7%. Rates had not increased for the primitive neuroectodermal tumor (PNET)/medulloblastoma or ependymoma subgroups. The geographic distribution of astrocytoma cases was homogenous. No statistically significant space-time interaction or local clusters in space and/or time were found for astrocytomas only or when astrocytomas were grouped with PNETs/medulloblastomas and ependymomas. CONCLUSIONS. The results show statistically increased incidence rates of childhood astroglial tumors, predominantly for girls, in Sweden during the period 1973-1992, but no clustering in space or time. (C) 1999 American Cancer Society. C1 Ostersunds Hosp, Dept Pediat, S-83183 Ostersund, Sweden. NCI, Biometry Branch, Dept Canc Prevent, Bethesda, MD 20892 USA. Karolinska Hosp, Pediat Canc Unit, S-10401 Stockholm, Sweden. Univ Gothenburg, Dept Pediat, Gothenburg, Sweden. RP Hjalmars, U (reprint author), Ostersunds Hosp, Dept Pediat, S-83183 Ostersund, Sweden. RI Kulldorff, Martin/H-4282-2011; OI Kulldorff, Martin/0000-0002-5284-2993 NR 32 TC 62 Z9 62 U1 1 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER JI Cancer PD MAY 1 PY 1999 VL 85 IS 9 BP 2077 EP 2090 DI 10.1002/(SICI)1097-0142(19990501)85:9<2077::AID-CNCR27>3.3.CO;2-W PG 14 WC Oncology SC Oncology GA 190AK UT WOS:000079939200027 PM 10223251 ER PT J AU Dixon, SC Kruger, EA Bauer, KS Figg, WD AF Dixon, SC Kruger, EA Bauer, KS Figg, WD TI Thalidomide up-regulates prostate-specific antigen secretion from LNCaP cells SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article; Proceedings Paper CT 14th Bristol-Myers-Squibb Nagoya International Cancer Treatment Symposium on the Challenges in Cancer Metastasis CY SEP 11-12, 1998 CL NAGOYA, JAPAN SP Bristol Myers Squibb DE thalidomide; PSA; LNCaP cells; PC-3 cells; cDNA array ID PERFORMANCE LIQUID-CHROMATOGRAPHY; NECROSIS-FACTOR-ALPHA; IMMUNE-SYSTEM; INTEGRIN RECEPTORS; BLOOD-CELLS; ANGIOGENESIS; DISEASE AB Thalidomide has been shown to have species- and metabolic-dependent antiangiogenic activity in vitro and in vivo, suggesting its potential in treating human angiogenesis-dependent pathologies such as solid tumors. Based on promising preclinical studies, thalidomide has entered phase II clinical trials for prostate, brain, breast cancer, and Kaposi's sarcoma. However, the antiangiogenic mechanism of action is largely unresolved, as are its effects on tumor-associated gene expression, cytokine secretion, etc. We have investigated the effects of thalidomide on: 1) the secretion of prostate-specific antigen (PSA) in a human androgen-dependent prostate cell line; 2) growth and viability of human prostate cells; and 3) differential gene expression profiles of thalidomide-treated vs untreated human prostate cells. A human androgen-dependent prostate carcinoma cell line (LNCaP) and a human androgen-independent prostate carcinoma cell line (PC-3) were incubated with thalidomide 0.6, 6, or 60 mu g/mL for 5-6 days. Secreted PSA from LNCaP cells was measured using a commercial enzyme-linked immunosorbant assay. Cell viability studies were conducted in both LNCaP and PC-3 cells using the same thalidomide concentrations. Furthermore, the differential gene expression of thalidomide-treated LNCaP cells was compared to that of untreated control cells using a commercially available human cancer cDNA expression array system. Thalidomide-treated LNCaP cells demonstrated increased PSA/cell levels at all concentrations tested compared to untreated control cells. Thalidomide demonstrated a cytostatic effect in LNCaP cells but had no appreciable effect on PC-3 cell viability compared to untreated control cells. Comparison of cDNA expression arrays hybridized with thalidomide-treated LNCaP cDNA probes suggests that thalidomide may up- or downregulate expression of angiogenesis-related genes, i.e., vitronectin, but these differential effects require further verification. Thalidomide over a range of doses has demonstrated nontoxic, cytostatic activity in LNCaP cells and significant upregulation of LNCaP cell PSA secretion in vitro. Furthermore, preliminary data from cDNA nucleic acid arrays of thalidomide-treated LNCaP cells suggest that thalidomide upregulates a potential angiogenic modulatory protein, the vitronectin precursor, which may eventually link thalidomide's antiangiogenic activity with modulation of angiogenic vascular integrin pathways. 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 5A01,10 Ctr Dr, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 35 TC 24 Z9 25 U1 0 U2 2 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD MAY PY 1999 VL 43 SU S BP S78 EP S84 DI 10.1007/s002800051103 PG 7 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 202DJ UT WOS:000080636600014 PM 10357564 ER PT J AU Kleiner, DE Stetler-Stevenson, WG AF Kleiner, DE Stetler-Stevenson, WG TI Matrix metalloproteinases and metastasis SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article; Proceedings Paper CT 14th Bristol-Myers-Squibb Nagoya International Cancer Treatment Symposium on the Challenges in Cancer Metastasis CY SEP 11-12, 1998 CL NAGOYA, JAPAN SP Bristol Myers Squibb DE matrix metalloproteinases; metastasis ID BASEMENT-MEMBRANE COLLAGEN; SOYBEAN LEAF METALLOPROTEINASE; HUMAN FIBROBLAST COLLAGENASE; RAT BLADDER-CARCINOMA; IV COLLAGENASE; TISSUE INHIBITOR; TUMOR INVASION; HUMAN GENE; EXTRACELLULAR-MATRIX; TRANSMEMBRANE DOMAIN AB Metastatic disease is responsible for the majority of cancer-related deaths, either directly due to tumor involvement of critical organs or indirectly due to complications of therapy to control tumor growth and spread. An understanding of the mechanisms of tumor cell invasion and metastasis may be important for devising therapies aimed at preventing tumor cell spread. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endoproteinases whose enzymatic activity is directed against components of the extracellular matrix (ECM). In humans, 16 members of this family have been identified by cloning and sequencing. These proteinases are linked by a core of common domain structures and by their relationship to a family of proteinase inhibitors called the tissue inhibitors of metalloproteinases (TIMPs). Four members of the TIMP family have been cloned and sequenced in humans and they inhibit MMPs by forming tight-binding, noncovalent associations with the active site of the MMPs. MMPs facilitate tumor cell invasion and metastasis by at least three distinct mechanisms. First, proteinase action removes physical barriers to invasion through degradation of ECM macromolecules such as collagens, laminins, and proteoglycans. This has been demonstrated in vitro through the use of chemoinvasion assays and in vivo by the presence of active MMPs at the invasive front of tumors. Second, MMPs have the ability to modulate cell adhesion. For cells to move through the ECM, they must be able to form new cell-matrix and cell-cell attachments and break existing ones. Using a cell transfection system that altered the ratio of MMP-2 to TIMP-2 we have demonstrated significant variation in the adhesive phenotype of tumor cells. Finally, MMPs may act on ECM components or other proteins to uncover hidden biologic activities. For example, the angiogenesis inhibitor angiostatin may be produced from plasminogen by MMP action and laminin-5 is specifically degraded by MMP-2 to produce a soluble chemotactic fragment. Thus MMPs play multiple key roles in facilitating the metastasis of tumor cells. Therapies designed to interfere with specific MMP actions may be useful in the control of metastatic disease. C1 NCI, Pathol Lab, Div Clin Sci, Bethesda, MD 20892 USA. RP Kleiner, DE (reprint author), NCI, Pathol Lab, Div Clin Sci, Bldg 10,Room 2N212, Bethesda, MD 20892 USA. RI Stetler-Stevenson, William/H-6956-2012 OI Stetler-Stevenson, William/0000-0002-5500-5808 NR 67 TC 268 Z9 316 U1 0 U2 11 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD MAY PY 1999 VL 43 SU S BP S42 EP S51 DI 10.1007/s002800051097 PG 10 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 202DJ UT WOS:000080636600008 PM 10357558 ER PT J AU Zheng, TZ Holford, TR Mayne, ST Tessari, J Owens, PH Zahm, SH Zhang, B Dubrow, R Ward, B Carter, D Boyle, P AF Zheng, TZ Holford, TR Mayne, ST Tessari, J Owens, PH Zahm, SH Zhang, B Dubrow, R Ward, B Carter, D Boyle, P TI Environmental exposure to hexachlorobenzene (HCB) and risk of female breast cancer in Connecticut SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID POLYCHLORINATED BIPHENYL CONGENERS; ORGANOCHLORINE EXPOSURE; ADIPOSE-TISSUE; SERUM; RESIDUES; WOMEN; PESTICIDES; TOXICITY; PLASMA; MEXICO AB Earlier studies have provided inconclusive results relating hexachlorobenzene (HCB), an organochlorine fungicide, to female breast cancer risk, The current study, with a total of 304 breast cancer cases and 186 controls recruited in Connecticut between 1994 and 1997, examined the association by directly comparing breast adipose tissue levels of HCB between incident breast cancer cases and noncancer controls. The cases and controls were patients who had breast biopsies or surgery at the Yale-New Haven Hospital (New Haven, CT) and histologically diagnosed either as breast cancer or benign breast disease. Information on major known or suspected risk factors for breast cancer was obtained through in-person interview by trained interviewers. No significant difference in mean breast adipose tissue levels of HCB was observed between breast cancer patients (21.0 ppb) and controls (19.1 ppb) in this large case-control study. The risk also did not vary significantly by menopausal status, estrogen or progesterone receptor status of the breast cancer cases, breast cancer histology, stage of diagnosis, or type of benign breast disease. Among parous women who reported ever breast feeding, an odds ratio (OR) of 0.5 [95% confidence interval (CI), 0.2-1.4] was observed when the highest quartile was compared with the lowest quartile, However, no association was observed among parous women who reported never breast feeding (OR = 0.7; 95% CI, 0.3-1.7 for the fourth quartile), For nulliparous women, the adjusted OR was 2.1 (95% CI, 0.5-8.8) for the third tertile when compared with the lowest based on few subjects. Therefore, our study does not support a positive association between environmental exposure to HCB and risk of breast cancer. C1 Yale Univ, Sch Med, New Haven, CT 06520 USA. Colorado State Univ, Ft Collins, CO 80523 USA. NCI, Bethesda, MD 20892 USA. European Inst Oncol, Milan, Italy. McGill Univ, Montreal, PQ H3A 1A2, Canada. RP Zheng, TZ (reprint author), 129 Church St,Suite 700, New Haven, CT 06510 USA. RI Boyle, Peter/A-4380-2014; Zahm, Shelia/B-5025-2015 OI Boyle, Peter/0000-0001-6251-0610; FU NCI NIH HHS [CA-62986] NR 34 TC 33 Z9 34 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 1999 VL 8 IS 5 BP 407 EP 411 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 196GJ UT WOS:000080300400002 PM 10350435 ER PT J AU Gammon, MD Hibshoosh, H Terry, MB Bose, S Schoenberg, JB Brinton, LA Bernstein, JL Thompson, WD AF Gammon, MD Hibshoosh, H Terry, MB Bose, S Schoenberg, JB Brinton, LA Bernstein, JL Thompson, WD TI Oral contraceptive use and other risk factors in relation to HER-2/neu overexpression in breast cancer among young women SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID PROGNOSTIC FACTORS; HORMONE RECEPTORS; ONCOGENE; EXPRESSION; AMPLIFICATION; NEU; PROLIFERATION; CARCINOMAS; TUMOR; P53 AB This study was undertaken to explore whether the incidence of breast tumors that overexpress HER-2/neu protein product (HER-2/neu+) is more strongly associated with oral contraceptives (OCs) and other factors than is the incidence of tumors that do not (HER-2/neu-), In a population-based sample of women <45 years, 42.9% (159 of 371) of in situ and invasive breast cancer cases were HER-2/neu+ as assessed by immunohistochemistry in archived tissue, Polytomous logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for HER-2/neu+ and HER-2/neu- breast cancer, as compared with 462 population-based controls, in relation to OCs and other factors. The ratio of the ORs (HER-2/neu+ versus HER-2/neu- tumors) was used as an indicator of heterogeneity in risk, There was little heterogeneity in risk for OC use of 6 months or more by HER-2/neu status (age-adjusted ratio of ORs, 1.29; 95% CI, 0.83-2.00). Among early pill users (less than or equal to 18 years of age) heterogeneity was apparent (2.39; 95% CI, 1.08-5.30), which was attenuated in a multivariate model (1.99; 95% CI, 0.87-4.54); among cases with estrogen receptor-negative tumors, heterogeneity increased to 5-fold. For other risk factors, there was no marked heterogeneity between + and - tumors for HER-2/neu, In summary, the incidence of breast cancer among younger women in relation to OC use at an early age varied with HER-2/neu status, with the odds ratio for + tumors twice that for - tumors. C1 Columbia Univ, Joseph L Mailman Sch Publ Hlth, Div Epidemiol, New York, NY 10032 USA. Columbia Univ Coll Phys & Surg, Dept Pathol, New York, NY 10032 USA. New Jersey State Dept Hlth & Senior Serv, Appl Canc Epidemiol Program, Trenton, NJ 08625 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. CUNY, Mt Sinai Med Ctr, Dept Community & Prevent Med, New York, NY 10029 USA. Univ So Maine, Dept Appl Sci Med, Portland, ME 04103 USA. RP Gammon, MD (reprint author), Columbia Univ, Joseph L Mailman Sch Publ Hlth, Div Epidemiol, 622 W 168th St,PH18, New York, NY 10032 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 FU NCI NIH HHS [1R21CA S66224] NR 24 TC 14 Z9 14 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 1999 VL 8 IS 5 BP 413 EP 419 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 196GJ UT WOS:000080300400003 PM 10350436 ER PT J AU Steele, VE Holmes, CA Hawk, ET Kopelovich, L Lubet, RA Crowell, JA Sigman, CC Kelloff, GJ AF Steele, VE Holmes, CA Hawk, ET Kopelovich, L Lubet, RA Crowell, JA Sigman, CC Kelloff, GJ TI Lipoxygenase inhibitors as potential cancer chemopreventives SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Review ID EPIDERMAL GROWTH-FACTOR; PROTEIN-KINASE-C; METHYL-N-NITROSOUREA; ARACHIDONIC-ACID METABOLISM; LEUKOTRIENE BIOSYNTHESIS INHIBITOR; HUMAN PROSTATE-CANCER; PERITONEAL POLYMORPHONUCLEAR LEUKOCYTES; 5-LIPOXYGENASE ACTIVATING PROTEIN; RECOMBINANT HUMAN 5-LIPOXYGENASE; EICOSANOID SYNTHESIS INHIBITORS AB Mounting evidence suggests that lipoxygenase (LO)-catalyzed products have a profound influence on the development and progression of human cancers. Compared with normal tissues, significantly elevated levels of LO metabolites have been found in lung, prostate, breast, colon, and skin cancer cells, as well as in cells from patients with both acute and chronic leukemias. LO-mediated products elicit diverse biological activities needed for neoplastic cell growth, influencing growth factor and transcription factor activation, oncogene induction, stimulation of tumor cell adhesion, and regulation of apoptotic cell death. Agents that block LO-catalyzed activity mag be effective in preventing cancer by interfering with signaling events needed for tumor growth. In fact, in a few studies, LO inhibitors have prevented carcinogen-induced lung adenomas and rat mammary gland cancers. During the past 10 years, pharmacological agents that specifically inhibit the LO-mediated signaling pathways are now commercially available to treat inflammatory diseases such as asthma, arthritis, and psoriasis, These well-characterized agents, representing two general drug effect mechanisms, are considered good candidates for clinical chemoprevention studies. One mechanism is inhibition of LO activity (5-LO and associated enzymes, or 12-LO); the second is leukotriene receptor antagonism. Although the receptor antagonists have high potential in treating asthma and other diseases where drug effects are clearly mediated by the leukotriene receptors, enzyme activity inhibitors may be better candidates for chemopreventive intervention, because inhibition of these enzymes directly reduces fatty acid metabolite production, with concomitant damping of the associated inflammatory, proliferative, and metastatic activities that contribute to carcinogenesis. However, because receptor antagonists have aerosol formulations and possible antiproliferative activity, they may also have potential, particularly in the lung, where topical application of such formulations is feasible. C1 NCI, Div Canc Prevent, Chemoprevent Branch, Bethesda, MD 20892 USA. CCS Associates, Mountain View, CA 94043 USA. RP NCI, Div Canc Prevent, Chemoprevent Branch, EPN 201E,MSC 7322,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 244 TC 204 Z9 210 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 1999 VL 8 IS 5 BP 467 EP 483 PG 17 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 196GJ UT WOS:000080300400011 PM 10350444 ER PT J AU Keck, CL Zimonjic, DB Yuan, BZ Thorgeirsson, SS Popescu, NC AF Keck, CL Zimonjic, DB Yuan, BZ Thorgeirsson, SS Popescu, NC TI Nonrandom breakpoints of unbalanced chromosome translocations in human hepatocellular carcinoma cell lines SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID TUMOR-SUPPRESSOR GENES; IN-SITU HYBRIDIZATION; HEPATITIS-B VIRUS; MOLECULAR CYTOGENETICS; HUMAN CANCER; 1P36 REGION; FHIT GENE; NEUROBLASTOMA; ABERRATIONS; HETEROZYGOSITY AB In the search for specific chromosomal alterations in human hepatocellular carcinomas (HCC), we analyzed two new HCC cell lines and identified nonrandom changes by combined G-banding and fluorescence in situ hybridization (FISH). Cell line 7703 was established from an HCC deriving from a patient in the Qidong region of China, where the incidence of HCC is very high and is associated with hepatitis-B virus infection and exposure to aflatoxin. This line has a highly rearranged karyotype eliciting complex rearrangements involving the majority of chromosomes. The second line, SK-Hep-1, derived from a liver adenocarcinoma, is less heterogeneous, having few altered chromosomes. We have characterized the majority of structural and numerical alterations and identified in both lines unbalanced translocations with the breakpoints nonrandomly involving regions 1p36 and 3p14 and gain of chromosome 6p and 8q. While gain of 6p and 8q are recurrent in HCC, translocations of 1p and 3p are described for the first time. Damage and recombination at the breakpoint sites on chromosomes 1 and 3 might have resulted in activation of proto-oncogene, formation of new oncogenic chimeric genes, or loss of tumor suppressor genes. Published by Elsevier Science Inc. C1 NCI, Div Basic Sci, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Popescu, NC (reprint author), NCI, Div Basic Sci, Expt Carcinogenesis Lab, Bldg 37,Room 3C28,37 Convent Dr MSC4255, Bethesda, MD 20892 USA. NR 53 TC 20 Z9 21 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 MAY PY 1999 VL 111 IS 1 BP 37 EP 44 DI 10.1016/S0165-4608(98)00210-6 PG 8 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 191VZ UT WOS:000080043400007 PM 10326589 ER PT J AU Karkera, JD Balan, KV Yoshikawa, T Lipman, TO Korman, L Sharma, A Patterson, RH Sani, N Detera-Wadleigh, SD Wadleigh, RG AF Karkera, JD Balan, KV Yoshikawa, T Lipman, TO Korman, L Sharma, A Patterson, RH Sani, N Detera-Wadleigh, SD Wadleigh, RG TI Systematic screening of chromosome 18 for loss of heterozygosity in esophageal squamous cell carcinoma SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID TUMOR-SUPPRESSOR GENE; FRAGILE SITES; MAJOR CANCERS; ALLELIC LOSS; DPC4 GENE; SHORT ARM; DELETION; IDENTIFICATION; ALLELOTYPE; BREAST AB Esophageal cancer ranks among the 10 most common cancers in the world, and is almost uniformly fatal. The genetic events leading to the development of esophageal carcinoma are not well established. To identify genomic regions involved in esophageal carcinogenesis, we performed a systematic screening for loss of heterozygosity (LOH) in 24 samples of squamous cell carcinomas, initially focusing the analysis on chromosome 18. Thirteen short tandem repeat markers spanning 18p and 18q were used. We found a broad peak of LOH spanning 18p11.2 and 18q21.1 with the most frequent LOH (72%) at D18S978 on 18q12.2, which coincides with a known fragile site FRA18A. This region is 4 cM proximal to known tumor suppressor genes and therefore suggests file possible existence of a yet undiscovered tumor suppressor gene. (C) Elsevier Science Inc., 1999. All rights reserved. C1 Vet Affairs Med Ctr, Med Oncol Sect, Washington, DC 20422 USA. Vet Affairs Med Ctr, Gastroenterol Sect, Washington, DC 20422 USA. Vet Affairs Med Ctr, Pathol & Lab Med Serv, Washington, DC 20422 USA. NIMH, Clin Neurogenet Branch, Unit Gene Mapping & Express, NIH, Bethesda, MD 20892 USA. Howard Univ, Dept Biol, Washington, DC 20059 USA. George Washington Univ, Med Ctr, Dept Pathol, Washington, DC 20037 USA. RP Wadleigh, RG (reprint author), Vet Affairs Med Ctr, Med Oncol Sect, 50 Irving St NW, Washington, DC 20422 USA. NR 34 TC 8 Z9 9 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 MAY PY 1999 VL 111 IS 1 BP 81 EP 86 DI 10.1016/S0165-4608(98)00225-8 PG 6 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 191VZ UT WOS:000080043400014 PM 10326596 ER PT J AU Lin, EM Aikin, JL Good, BC AF Lin, EM Aikin, JL Good, BC TI Premature menopause after cancer treatment SO CANCER PRACTICE LA English DT Article DE chemotherapy; estrogen deficiency; menopause, premature; radiation therapy ID ESTROGEN REPLACEMENT THERAPY; CORONARY HEART-DISEASE; HOT FLASHES; POSTMENOPAUSAL WOMEN; BREAST-CANCER; OVARIAN TRANSPOSITION; VASOMOTOR SYMPTOMS; FERTILITY; CHEMOTHERAPY; SURVIVORS AB PURPOSE: The purpose of this report is to examine the impact that cancer therapies have on ovarian function. OVERVIEW: symptoms of and conditions due to estrogen deficiency after cancer therapy are described and interventions are proposed. The consequences of short-term as well as prolonged estrogen deficiency-including vasomotor instability, infertility, genitourinary atrophy , coronary artery disease, and osteoporosis-are discussed. CLINICAL IMPLICATIONS: Symptoms and conditions associated with premature menopause may cause additional stress for women who undergo cancer therapy knowledge about what happens to these women can enable healthcare providers to help them make decisions about cancer treatment, engage in self-care activities, and explore options for preserving fertility. C1 Univ Virginia, Ctr Canc, Charlottesville, VA 22908 USA. Natl Surg Adjuvant Breast & Bowel Project, Clin Coordinating Sect, Pittsburgh, PA USA. Virginia Commonwealth Univ, Richmond, VA 23284 USA. RP Lin, EM (reprint author), 3334 Marsden Point, Keswick, VA 22947 USA. NR 75 TC 13 Z9 13 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1065-4704 J9 CANCER PRACT JI Cancer Pract. PD MAY-JUN PY 1999 VL 7 IS 3 BP 114 EP 121 PG 8 WC Oncology; Health Care Sciences & Services; Nursing SC Oncology; Health Care Sciences & Services; Nursing GA 197AB UT WOS:000080341500003 ER PT J AU Koyani, S AF Koyani, S TI Cancer survivorship information resources from the US government SO CANCER PRACTICE LA English DT Editorial Material C1 Natl Canc Inst, Off Canc Informat Commun & Educ, Patient Educ Branch, Bethesda, MD 20892 USA. RP Koyani, S (reprint author), Natl Canc Inst, Off Canc Informat Commun & Educ, Patient Educ Branch, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1065-4704 J9 CANCER PRACT JI Cancer Pract. PD MAY-JUN PY 1999 VL 7 IS 3 BP 154 EP 156 DI 10.1046/j.1523-5394.1999.73010.x PG 3 WC Oncology; Health Care Sciences & Services; Nursing SC Oncology; Health Care Sciences & Services; Nursing GA 197AB UT WOS:000080341500009 PM 10352079 ER PT J AU Weinberg, WC Fernandez-Salas, E Morgan, DL Shalizi, A Mirosh, E Stanulis, E Deng, CX Hennings, H Yuspa, SH AF Weinberg, WC Fernandez-Salas, E Morgan, DL Shalizi, A Mirosh, E Stanulis, E Deng, CX Hennings, H Yuspa, SH TI Genetic deletion of p21(WAF1) enhances papilloma formation but not malignant conversion in experimental mouse skin carcinogenesis SO CANCER RESEARCH LA English DT Article ID CYCLE INHIBITOR CIP1/WAF1; TERMINAL DIFFERENTIATION; EPIDERMAL-CELLS; DNA-DAMAGE; P53 LOSS; MICE; GROWTH; P21(CIP1/WAF1); PROGRESSION; KERATINOCYTES AB Tumor suppression by p53 is believed to reside in its ability to regulate gene transcription, including up-regulation of p21(WAF1). In p53(-/-) mice, chemical- or oncogene-induced skin tumors undergo accelerated malignant conversion, To determine the contribution of the p21(WAF1) gene product to epidermal carcinogenesis, animals +/+, +/-, and -/- for a null mutation in the p21(WAF1) gene were treated once with 25 nmol 7,12-dimethylbenz[a]anthracene, followed by 5 mu g of TPA two times/week for 20 weeks. Papilloma frequency was higher in the p21(WAF1)-deficient mice. However, the frequency of malignant conversion was similar among all three genotypes, After TPA treatment, all genotypes developed epidermal hyperplasia, although the labeling index was lower in p21(WAF1) (-/-) epidermis compared with p21(WAF1) (+/+), Furthermore, the expression of differentiation markers was the same across genotypes in untreated or TPA-treated epidermis, Similar frequencies of malignant conversion were also observed in an in vitro assay. Thus, p21(WAT1) suppresses early stages of papilloma formation but not malignant progression in mouse skin carcinogenesis, and decreased levels of p21(WAF1) do not account for the enhanced malignant conversion of p53 null epidermal tumors. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. NIDDKD, Biochem & Metab Lab, NIH, Bethesda, MD 20892 USA. ROW Sci Inc, Rockville, MD 20878 USA. NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Weinberg, WC (reprint author), NIDCR, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,MSC4340,Bldg 30,Room 211, Bethesda, MD 20892 USA. RI Weinberg, Wendy/A-8920-2009; deng, chuxia/N-6713-2016 NR 28 TC 56 Z9 57 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 1 PY 1999 VL 59 IS 9 BP 2050 EP 2054 PG 5 WC Oncology SC Oncology GA 192EW UT WOS:000080066300008 PM 10232585 ER PT J AU Vodovotz, Y Chesler, L Chong, HY Kim, SJ Simpson, JT DeGraff, W Cox, GW Roberts, AB Wink, DA Barcellos-Hoff, MH AF Vodovotz, Y Chesler, L Chong, HY Kim, SJ Simpson, JT DeGraff, W Cox, GW Roberts, AB Wink, DA Barcellos-Hoff, MH TI Regulation of transforming growth factor beta 1 by nitric oxide SO CANCER RESEARCH LA English DT Article ID CEREBRAL ENDOTHELIAL-CELLS; COLON CANCER LINES; MURINE MACROPHAGES; TUMOR-CELLS; TGF-BETA; FACTOR-ALPHA; TNF-ALPHA; RIBONUCLEOTIDE REDUCTASE; MOUSE MACROPHAGES; IL-8 EXPRESSION AB Many tumor cells or their secreted products suppress the function of tumor-infiltrating macrophages, Tumor cells often produce abundant transforming growth factor beta 1 (TGF-beta 1), which in addition to other immunosuppressive actions suppresses the inducible isoform of NO synthase, TGF-beta 1 is secreted in a latent form, which consists of TGF-beta 1 noncovalently associated with latency-associated peptide (LAP) and which can be activated efficiently by exposure to reactive oxygen species, Coculture of the human lung adenocarcinoma cell line A549 and ANA-1 macrophages activated with IFN-gamma plus lipopolysaccharide resulted in increased synthesis and activation of latent TGF-beta 1 protein by both A549 and ANA-1 cells, whereas unstimulated cultures of either cell type alone expressed only latent TGF-beta 1, We investigated whether exposure of tumor cells to NO influences the production, activation, or activity of TGF-beta 1. A549 human lung adenocarcinoma cells exposed to the chemical NO donor diethylamine-NONOate showed increased immunoreactivity of cell-associated latent and active TGF-beta 1 in a time- and dose-dependent fashion at 24-48 h after treatment. Exposure of latent TGF-beta 1 to solution sources of NO neither led to recombinant latent TGF-beta 1 activation nor modified recombinant TGF-beta 1 activity. A novel mechanism was observed, however: treatment of recombinant LAP with NO resulted in its nitrosylation and interfered with its ability to neutralize active TGF-beta 1, These results provide the first evidence that nitrosative stress influences the regulation of TGF-beta 1 and raise the possibility that NO production may augment TGP-beta 1 activity by modifying a naturally occurring neutralizing peptide. C1 NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. Univ Calif Berkeley, Lawrence Berkeley Lab, Div Life Sci, Berkeley, CA 94720 USA. NIMH, Lab Neurotoxicol, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD 20814 USA. RP Vodovotz, Y (reprint author), Cardiovasc Res Fdn, 110 Irving St NW,Suite 4B-1, Washington, DC 20010 USA. NR 78 TC 107 Z9 116 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 1 PY 1999 VL 59 IS 9 BP 2142 EP 2149 PG 8 WC Oncology SC Oncology GA 192EW UT WOS:000080066300024 PM 10232601 ER PT J AU Hong, SH Avis, I Vos, MD Martinez, A Treston, AM Mulshine, JL AF Hong, SH Avis, I Vos, MD Martinez, A Treston, AM Mulshine, JL TI Relationship of arachidonic acid metabolizing enzyme expression in epithelial cancer cell lines to the growth effect of selective biochemical inhibitors SO CANCER RESEARCH LA English DT Article ID NORDIHYDROGUAIARETIC ACID; LUNG-CANCER; IN-VITRO; CYCLOOXYGENASE-2; 12-LIPOXYGENASE; 5-LIPOXYGENASE; PROSTAGLANDINS; CARCINOGENESIS; LIPOXYGENASES; EICOSANOIDS AB Arachidonic acid (AA) metabolizing enzymes are emerging as significant mediators of growth stimulation for epithelial cells. The relative contribution of the various family members of AA metabolizing enzymes to epithelial cancer cell growth is not known. To study this question, we first analyzed a series of epithelial cancer cells to establish the relative frequency of expression for the various enzymes, We analyzed the expression of five AA metabolizing enzymes as well as 5-lipoxygenase activating protein (FLAP) in a panel of human epithelial cancer cell lines (n = 20) using reverse transcription-PCR. From this analysis, we found that cyclooxygenase-l (COX-1), 5-lipoxygenase (5-LOX), and FLAP were universally expressed in all cancer cell lines tested. For the remaining enzymes, the expression of COX-2, 12-LOX, and 15-LOX varied among cell lines, 60, 35, and 90%, respectively. Although the pattern of expression varied among the different cell types, all of the enzymes were expressed in all major cancer histologies. Using a panel of selective biochemical AA metabolizing enzyme inhibitors, we then evaluated the effect of these agents on cell lines with known expression status for the AA metabolizing enzymes, For the enzymes that were not universally expressed, growth inhibition by selective biochemical inhibitors did not closely correlate with the expression status of specific enzymes (P > 0.05), For the universally expressed enzymes, the LOX inhibitors were more potent growth inhibitors than the COX inhibitors. The frequent expression of the AA metabolizing enzymes suggests that AA metabolism pathway may be modulated in response to xenobiotic exposure during carcinogenesis. Although establishing a priori AA metabolizing enzyme status was not consistently informative about what AA metabolizing enzyme inhibition would be most growth inhibitory, the frequent inhibition of many epithelial cancers by these biochemical inhibitors opens a new avenue for cancer therapy and intervention in carcinogenesis. C1 NCI, Intervent Sect, Cell & Canc Biol Dept, Med Branch,Div Clin Sci, Bethesda, MD 20892 USA. RP Mulshine, JL (reprint author), NCI, Intervent Sect, Cell & Canc Biol Dept, Med Branch,Div Clin Sci, Bldg 10-12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Martinez, Alfredo/A-3077-2013 OI Martinez, Alfredo/0000-0003-4882-4044 NR 36 TC 120 Z9 129 U1 2 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 MAY 1 PY 1999 VL 59 IS 9 BP 2223 EP 2228 PG 6 WC Oncology SC Oncology GA 192EW UT WOS:000080066300035 PM 10232612 ER PT J AU Xu, LX Flynn, BJ Ungar, S Pass, HI Linnainmaa, K Mattson, K Gerwin, BI AF Xu, LX Flynn, BJ Ungar, S Pass, HI Linnainmaa, K Mattson, K Gerwin, BI TI Asbestos induction of extended lifespan in normal human mesothelial cells: interindividual susceptibility and SV40 T antigen SO CARCINOGENESIS LA English DT Article ID MAMMARY EPITHELIAL-CELLS; GROWTH-FACTOR-RECEPTOR; MALIGNANT MESOTHELIOMA; IN-VITRO; CROCIDOLITE ASBESTOS; P16(INK4) EXPRESSION; HUMAN CANCER; DNA-SYNTHESIS; LUNG INJURY; P53 AB Normal human mesothelial cells from individual donors were studied for susceptibility to asbestos-induction of apoptosis and generation of an extended lifespan population. Such populations were generated after death of the majority of cells and arose from a subset of mesothelial cultures (4/16) whereas fibroblastic cells (5/5) did not develop extended lifespan populations after asbestos exposure. All mesothelial cultures were examined for the presence of SV40 T antigen to obtain information on (i) the presence of SV40 T antigen expression in normal human mesothelial cells and (ii) the relationship between generation of an extended lifespan population and expression of SV40 T antigen. Immunostaining for SV40 T antigen was positive in 2/38 normal human mesothelial cultures. These cultures also had elevated p53 expression, However, the two isolates expressing SV40 T antigen did not exhibit enhanced proliferative potential or develop an extended lifespan population. asbestos-generated extended lifespan populations were specifically resistant to asbestos-mediated but not to a-Fas-induced apoptosis, Deletion of p16(Ink4a) was shown in 70% of tumor samples. All mesothelioma cell lines examined showed homozygous deletion of this locus which extended to exon 1 beta, Extended lifespan cultures were examined for expression of p16(Ink4a) to establish whether deletion was an early response to asbestos exposure, During their rapid growth phase, extended lifespan cultures showed decreased expression of p16(Ink4a) relative to untreated cultures, but methylation was not observed, and p16(Ink4a) expression became elevated when cells entered culture crisis. These data extend the earlier observation that asbestos can generate extended lifespan populations, providing data on frequency and cell type specificity. In addition, this report shows that generation of such populations does not require expression of SV40 T antigen. Extended lifespan cells could represent a population expressing early changes critical for mesothelioma development. Further study of these populations could identify such changes. C1 NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. Karmanos Canc Inst, Aerodigest Program, Detroit, MI 48201 USA. Inst Occupat Hlth, SF-00250 Helsinki, Finland. Univ Helsinki, Dept Pulm Med, FIN-00290 Helsinki, Finland. RP Gerwin, BI (reprint author), NCI, Human Carcinogenesis Lab, Bldg 37, Bethesda, MD 20892 USA. NR 69 TC 21 Z9 21 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD MAY PY 1999 VL 20 IS 5 BP 773 EP 783 DI 10.1093/carcin/20.5.773 PG 11 WC Oncology SC Oncology GA 191KY UT WOS:000080022700005 PM 10334193 ER PT J AU Lemmer, ER Hall, PD Omori, N Omori, M Shephard, EG Gelderblom, WCA Cruse, JP Barnard, RA Marasas, WFO Kirsch, RE Thorgeirsson, SS AF Lemmer, ER Hall, PD Omori, N Omori, M Shephard, EG Gelderblom, WCA Cruse, JP Barnard, RA Marasas, WFO Kirsch, RE Thorgeirsson, SS TI Histopathology and gene expression changes in rat liver during feeding of fumonisin B(1), a carcinogenic mycotoxin produced by Fusarium moniliforme SO CARCINOGENESIS LA English DT Article ID GROWTH-FACTOR-ALPHA; STEM-CELL COMPARTMENT; C-MYC; OVAL CELLS; HEPATOCELLULAR-CARCINOMA; ESOPHAGEAL CANCER; HEPATOCARCINOGENESIS; REGENERATION; HEPATOCYTES; APOPTOSIS AB Fumonisin B(1) (FB(1)) is a carcinogenic mycotoxin produced by the fungus Fusarium moniliforme in corn. Feeding of FB(1) to rats causes acute liver injury, chronic liver injury progressing to cirrhosis, and sometimes terminates in hepatocellular carcinoma or cholangiocarcinoma. This study describes the histolopathology and changes in gene expression in the rat liver during short-term feeding of FB(1). Male Fischer rats were fed either FB(1) 250 mg/kg or control diet, and were killed weekly for 5 weeks. FB(1) caused a predominantly zone 3 'toxic' liver injury, with hepatocyte death due to necrosis and apoptosis, Hepatocyte injury and death were mirrored by hepatic stellate cell proliferation and marked fibrosis, with progressive disturbance of architecture and formation of regenerative nodules, Despite ongoing hepatocyte mitotic activity, oval cell proliferation was noted from week 2, glutathione S-transferase pi-positive hepatic foci and nodules developed and, at later time points, oval cells were noted inside some of the 'atypical' nodules, Northern blot (mRNA) analysis of liver specimens from weeks 3 to 5 showed a progressive increase in gene expression for alpha-fetoprotein, hepatocyte growth factor, transforming growth factor alpha (TGF-alpha) and especially TGF-beta 1 and c-myc, Immunostaining with LC(1-30) antibody demonstrated a progressive increase in expression of mature TGF-beta 1 protein by hepatocytes over the 5 week feeding period. The overexpression of TGF-beta 1 may be causally related to the prominent apoptosis and fibrosis seen with FB(1)-induced liver injury. Increased expression of c-myc may be involved in the cancer promoting effects of FB(1). C1 Univ Cape Town, MRC, Liver Res Ctr, ZA-7925 Cape Town, South Africa. Univ Cape Town, Dept Anat Pathol, ZA-7925 Cape Town, South Africa. Flinders Univ S Australia, Dept Anat Pathol, Bedford Pk, SA 5042, Australia. S African MRC, Programme Mycotoxins & Expt Carcinogenesis, ZA-7505 Tygerberg, South Africa. NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Shephard, EG (reprint author), Univ Cape Town, MRC, Liver Res Ctr, ZA-7925 Cape Town, South Africa. EM enid@liver.uct.ac.za NR 56 TC 50 Z9 53 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD MAY PY 1999 VL 20 IS 5 BP 817 EP 824 DI 10.1093/carcin/20.5.817 PG 8 WC Oncology SC Oncology GA 191KY UT WOS:000080022700011 PM 10334199 ER PT J AU Melnick, RL Sills, RC Portier, CJ Roycroft, JH Chou, BJ Grumbein, SL Miller, RA AF Melnick, RL Sills, RC Portier, CJ Roycroft, JH Chou, BJ Grumbein, SL Miller, RA TI Multiple organ carcinogenicity of inhaled chloroprene (2-chloro-1,3-butadiene) in F344/N rats and B6C3F(1) mice and comparison of dose-response with 1,3-butadiene in mice SO CARCINOGENESIS LA English DT Article ID NATIONAL-TOXICOLOGY-PROGRAM; INHALATION EXPOSURE; MUTAGENICITY; CHLORIDE; ISOPRENE; TOXICITY; CHEMICALS; INFECTION; MORTALITY; PRODUCTS AB Chloroprene (2-chloro-1,3-butadiene) is a high production chemical used almost exclusively in the production of polychloroprene (neoprene) elastomer. Because of its structural similarity to 1,3-butadiene, a trans-species carcinogen, inhalation studies were performed with chloroprene to evaluate its carcinogenic potential in rats and mice. Groups of 50 male and female F344/N rats and 50 male and female B6C3F(1) mice were exposed to 0, 12.8, 32 or 80 p.p.m. chloroprene (6 h/day, 5 days/week) for 2 years. Under these conditions, chloroprene was carcinogenic to the oral cavity, thyroid gland, lung, kidney and mammary gland of rats, and to the lung, circulatory system (hemangiomas and hemangiosarcomas), Harderian gland, kidney, forestomach, liver, mammary gland, skin, mesentery and Zymbal's gland of mice. Survival adjusted tumor rates in mice were fit to a Weibull model for estimation of the shape of the dose-response curves, estimation of ED10 values (the estimated exposure concentration associated with an increased cancer risk of 10%) and comparison of these parameters with those for 1,3-butadiene. Butadiene has been identified as a potent carcinogen in mice and has been associated with increased risk of lymphatic and hematopoietic cancer in exposed workers. Shape parameter values for most of the neoplastic effects of chloroprene and 1,3-butadiene were consistent with linear or supralinear responses in the area near the lowest tested exposures. The most potent carcinogenic effect of 1,3-butadiene was the induction of lung neoplasms in female mice, which had an ED10 value of 0.3 p.p.m. Since the ED10 value for that same response in chloroprene exposed mice was also 0.3 p.p.m., we conclude that the carcinogenic potency of chloroprene in mice is similar to that of 1,3-butadiene. Cancer potency of chloroprene is greater in the mouse lung than in the rat lung, but greater in the rat kidney than in the mouse kidney and nearly equivalent in the mammary gland of each species. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Pacific NW Lab, Richland, WA 99352 USA. RP Melnick, RL (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. RI Portier, Christopher/A-3160-2010 OI Portier, Christopher/0000-0002-0954-0279 NR 49 TC 26 Z9 26 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD MAY PY 1999 VL 20 IS 5 BP 867 EP 878 DI 10.1093/carcin/20.5.867 PG 12 WC Oncology SC Oncology GA 191KY UT WOS:000080022700017 PM 10334205 ER PT J AU Bednarek, A Shilkaitis, A Green, A Lubet, R Kelloff, G Christov, K Aldaz, CM AF Bednarek, A Shilkaitis, A Green, A Lubet, R Kelloff, G Christov, K Aldaz, CM TI Suppression of cell proliferation and telomerase activity in 4-(hydroxyphenyl)retinamide-treated mammary tumors SO CARCINOGENESIS LA English DT Article ID BREAST-CANCER; RAT; N-(4-HYDROXYPHENYL)RETINAMIDE; DIFFERENTIATION; TISSUES; AGENTS AB The detection of telomerase activity has been proposed as a biomarker of breast cancer development and progression. In this study, we used cell proliferation and telomerase in MNU (N-methyl-N-nitrosourea)-induced mammary carcinomas as targets for assessing the response of tumor cells to 4-(hydroxyphenyl)retinamide (4-HPR), a known inhibitor of mammary carcinogenesis in animal models and premenopausal women, In mammary tumors of rats treated for 1, 2, 4 or 6 weeks with 4-HPR, we observed that telomerase activity decreased progressively with the extension of 4-HPR administration. A marked reduction in telomerase activity was already observed by 2 weeks after treatment and the lowest level was found at 6 weeks after initiation of 4-HPR treatment, The changes in telomerase activity were preceded and accompanied by a significant decrease in the percentage of proliferating cells as evaluated by 5-bromodeoxyuridine (BrdU)-labeling. However, when the values of telomerase activity in the individual tumors were compared with the percentage of proliferating cells, no significant correlation was found. These data suggest that the decreased telomerase activity in the animals treated with 4-HPR is not a simple consequence of the changes in cell proliferation, but a more complex phenomenon involving different cellular mechanisms and pathways. The time-dependent and consistent decrease of telomerase activity in the tumors treated with 4-HPR suggests that, in addition to the percentage of proliferating cells, telomerase activity could also be used as an endpoint in breast cancer chemotherapy studies. C1 Univ Illinois, Dept Surg Oncol, Chicago, IL 60612 USA. Univ Texas, MD Anderson Canc Ctr, Dept Carcinogenesis, Smithville, TX 78957 USA. NCI, DCPC, Rockville, MD 20852 USA. RP Christov, K (reprint author), Univ Illinois, Dept Surg Oncol, 840 S Wood St,M-C 820, Chicago, IL 60612 USA. RI Bednarek, Andrzej/S-9664-2016 FU NCI NIH HHS [N01-CN-55179-MAO] NR 24 TC 25 Z9 25 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 MAY PY 1999 VL 20 IS 5 BP 879 EP 883 DI 10.1093/carcin/20.5.879 PG 5 WC Oncology SC Oncology GA 191KY UT WOS:000080022700018 PM 10334206 ER PT J AU Liang, R Senturker, S Shi, XL Bal, W Dizdaroglu, M Kasprzak, KS AF Liang, R Senturker, S Shi, XL Bal, W Dizdaroglu, M Kasprzak, KS TI Effects of Ni(II) and Cu(II) on DNA interaction with the N-terminal sequence of human protamine P2: enhancement of binding and mediation of oxidative DNA strand scission and base damage SO CARCINOGENESIS LA English DT Article ID DILUTION MASS-SPECTROMETRY; QUANTITATIVE-DETERMINATION; HYDROGEN-PEROXIDE; NICKEL(II); COPPER(II); CHROMATIN; EXPOSURE; IONS; MICE; HP2 AB Epidemiological evidence suggests that certain paternal exposures to metals may increase the risk of cancer in the progeny. This effect may be associated with promutagenic damage to the sperm DNA, The latter is packed with protamines which might sequester carcinogenic metals and moderate the damage. Human protamine P2 has an amino acid motif at its N-terminus that can serve as a heavy metal trap, especially for Ni(II) and Cu(II), We have synthesized a pentadecapeptide modeling this motif, Arg-Thr-His-Gly-Gln-Ser-His-Tyr-Arg-Arg-His-Cys-Ser-Arg-amide (HP2(1-15)) and described its complexes with Ni(II) and Cu(II), including their capacity to mediate oxidative DNA degradation [Bal et al, (1997) Chern. Res. Toxicol,, 10, 906-914 and 915-921], In the present study, effects of HP21-15 On NI(II)- and Cu(II)-mediated DNA oxidation by H(2)O(2) at pH 7.4 were investigated in more detail using the circular plasmid pUC19 DNA as a target, and the single/double-strand breaks and production of oxidized DNA bases, as end points. Ni(II) alone was found to promote oxidative DNA strand scission (mostly single strand breaks) and base damage, while Cu(LI) alone produced the same effects, but to a much greater extent. Both metals were relatively more damaging to the pyrimidine bases than to purine bases. HP2(1-15) fended to increase the Ni(H)/H(2)O(2)-induced DNA breakage. In sharp contrast, the destruction of DNA strands by Cu(II)/H(2)O(2) was almost completely prevented by HP2(1-15). The effect of HP21-15 On the oxidative DNA base damage varied from a limited enhancement (5-hydroxyhydantoin and thymine glycol) to slight suppression (5-hydroxycytosine, 5-hydroxyuracil, 8-oxoguanine, 8-oxoadenine, 2-hydroxyadenine, fapyguanine and fapyadenine) toward Ni(II)/H(2)O(2). HP2(1-15) strongly suppressed the oxidative activity of Cu(II)/H(2)O(2) in regard to all bases in DNA, Consistently with the above, the electron spin resonance/spin trap measurements revealed greater and more persistent generation of OH and O(2)(-).-like oxidants from H(2)O(2) by the Ni(II)-HP2(1-15) complex than by the Cu(II)-HP2(1-15) complex (no O(2)(-). was detected). Both complexes were also found to bind to DNA more strongly than HP2(1-15) alone. The results indicate that protamine P2 is capable of binding Ni(II) and Cu(II) and, in this way, attenuating the mediation of oxidative DNA damage by Cu(II), but not Ni(II), The effects found may be mechanistically involved in the reproductive toxicity and carcinogenicity of metals. C1 NCI, Comparat Carcinogenesis Lab, FCRDC, Frederick, MD 21702 USA. Natl Inst Stand & Technol, Chem Sci & Technol Lab, Gaithersburg, MD 20899 USA. NIOSH, Morgantown, WV 26505 USA. Wroclaw B Beirut Univ, Fac Chem, PL-50383 Wroclaw, Poland. RP Kasprzak, KS (reprint author), NCI, Comparat Carcinogenesis Lab, FCRDC, Frederick, MD 21702 USA. EM kasprkaz@mail.ncifcrf.gov RI Shi, Xianglin/B-8588-2012 NR 24 TC 59 Z9 61 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD MAY PY 1999 VL 20 IS 5 BP 893 EP 898 DI 10.1093/carcin/20.5.893 PG 6 WC Oncology SC Oncology GA 191KY UT WOS:000080022700020 PM 10334208 ER PT J AU Boorman, GA Anderson, LE Morris, JE Sasser, LB Mann, PC Grumbein, SL Hailey, JR McNally, A Sills, RC Haseman, JK AF Boorman, GA Anderson, LE Morris, JE Sasser, LB Mann, PC Grumbein, SL Hailey, JR McNally, A Sills, RC Haseman, JK TI Effect of 26 week magnetic field exposures in a DMBA initiation-promotion mammary gland model in Sprague-Dawley rats SO CARCINOGENESIS LA English DT Article ID BREAST-CANCER; ELECTROMAGNETIC-FIELDS; FEMALE RATS; CARCINOGENICITY; 50-HZ; TUMORIGENESIS; MORTALITY; WORKERS AB Several studies have suggested that exposure to 50 Hz magnetic fields promote chemically induced breast cancer in rats. Groups of 100 female Sprague-Dawley rats were initiated with a single 10 mg gavage dose of 7,12-dimethylbenz[a]anthracene (DMBA) at 50 days of age followed by exposure to ambient fields (sham exposed), 50 Hz magnetic fields at either 1 or 5 Gauss (G) field intensity or 60 Hz fields at 1 G for 18.5 h/day, 7 days/week for 26 weeks. A vehicle control group without DMBA was included. Rats were palpated weekly for the presence of tumors. There was no effect of magnetic field exposure on body weight gains or the time of appearance of mammary tumors, At the end of 26 weeks, the animals were killed and the mammary tumors counted and measured. Mammary gland masses found grossly were examined histologically, The mammary gland carcinoma incidence was 96, 90, 95 and 85% (P < 0.05, decrease) for the DMBA controls, 1 G 50 Hz, 5 G 50 Hz and 1 G 60 Hz groups, respectively. The total numbers of carcinomas were 649, 494 (P < 0.05, decrease), 547 and 433 (P < 0.05, decrease) for the DMBA controls, 1 G 50 Hz, 5 G 50 Hz and 1 G 60 Hz groups, respectively. The number of fibroadenomas varied from 276 to 319, with the lowest number in the 1 G 60 Hz exposure group. Measurement of the tumors revealed no difference in tumor size between groups. In this breast cancer initiation-promotion study in female Sprague-Dawley rats, there was no evidence that 50 or 60 Hz magnetic fields promoted breast cancer under the conditions of this assay. This study does not support the hypothesis that magnetic field exposure can promote breast cancer in this rat model. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Pacific NW Lab, Richland, WA 99352 USA. Expt Pathol Lab, Res Triangle Pk, NC 27709 USA. RP Boorman, GA (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. FU NIEHS NIH HHS [N01-ES-65397] NR 26 TC 28 Z9 29 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD MAY PY 1999 VL 20 IS 5 BP 899 EP 904 DI 10.1093/carcin/20.5.899 PG 6 WC Oncology SC Oncology GA 191KY UT WOS:000080022700021 PM 10334209 ER PT J AU Schulze, K Heineman, FW Schultheiss, HP Balaban, RS AF Schulze, K Heineman, FW Schultheiss, HP Balaban, RS TI Impairment of myocardial calcium homeostasis by antibodies against the adenine nucleotide translocator SO CELL CALCIUM LA English DT Article ID RAT VENTRICULAR MYOCYTES; PERFUSED RABBIT HEARTS; ADP-ATP CARRIER; DILATED CARDIOMYOPATHY; CARDIAC MYOCYTES; INTRACELLULAR CALCIUM; CYTOSOLIC CALCIUM; ENERGY-METABOLISM; ADP/ATP CARRIER; AUTO-ANTIGEN AB The adenine nucleotide translocator (ANT) is an autoantigen in myocarditis and dilated cardiomyopathy. Carrier-specific antibodies impair myocardial energy metabolism and heart function. They cross-react with a myolemmal calcium channel and alter calcium fluxes in isolated myocytes. To test whether antibodies against the ANT can alter calcium homeostasis in intact hearts, guinea pigs were immunized with the carrier protein and their isolated hearts loaded with the intracellular calcium indicator INDO-1. The diastolic and systolic ratios of fluorescence signals at 410 nm and 510 nm (emission wavelengths of the calcium-bound and calcium-free indicator), 'd-s410/510', were measured by excitation at 364 nm. This index of the transient calcium concentration associated with the contraction cycle correlated with the external heart work (EHW) in non-immunized controls, EHW of immunized animals was lower (76+/-62 vs 153+/-47 mJ/g/min in controls, p<0.005) and the amplitude of d-s410/510 was elevated (27.6+/-4.1% of the average ratio of the whole heart cycle vs 21.7+/-1.2% in controls, p<0.005) and essentially independent of EHW. Isoproterenol stimulation increased EHW in ail hearts but d-s410/510 was hightened in control hearts, only. Thus, a disorder between cytosolic calcium transients and work was recorded in hearts from guinea pigs immunized with the ANT. It may contribute to an immunopathic mechanism of heart failure subsequent to myocarditis. C1 Free Univ Berlin, Klinikum Benjamin Franklin, Med Klin Kardiol 2, Dept Cardiol, D-12200 Berlin, Germany. NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. RP Schulze, K (reprint author), Free Univ Berlin, Klinikum Benjamin Franklin, Med Klin Kardiol 2, Dept Cardiol, Hindenburgdamm 30, D-12200 Berlin, Germany. RI Balaban, Robert/A-7459-2009 OI Balaban, Robert/0000-0003-4086-0948 NR 46 TC 15 Z9 16 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 MAY PY 1999 VL 25 IS 5 BP 361 EP 370 DI 10.1054/ceca.1999.0039 PG 10 WC Cell Biology SC Cell Biology GA 221CC UT WOS:000081705600004 PM 10463100 ER PT J AU Jiang, D Zheng, LX Lenardo, MJ AF Jiang, D Zheng, LX Lenardo, MJ TI Caspases in T-cell receptor-induced thymocyte apoptosis SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE apoptosis; caspase; thymic selection ID INTERLEUKIN-1-BETA CONVERTING-ENZYME; FAS-MEDIATED APOPTOSIS; INDUCED NEGATIVE SELECTION; IL-1-BETA-CONVERTING ENZYME; INHIBITS APOPTOSIS; CYSTEINE PROTEASE; SIGNALING COMPLEX; FAMILY PROTEASES; MICE DEFICIENT; ICE-LIKE AB Apoptosis eliminates inappropriate or autoreactive T lymphocytes during thymic development. Intracellular mediators involved in T-cell receptor (TCR)-mediated apoptosis in developing thymocytes during negative selection are therefore of great interest. Caspases, cysteine proteases that mediate mature T-cell apoptosis, have been implicated in thymocyte cell death, but their regulation is not understood. We examined caspase activities in distinct thymocyte subpopulations that represent different stages of T-cell development. We found caspase activity in CD4(+)CD8(+) double positive (DP) thymocytes, where selection involving apoptosis occurs. Earlier and later thymocyte stages exhibited no caspase activity. Only certain caspases, such as caspase-3 and caspase-8-like proteases, but not caspase-1, are active in DP thymocytes in vivo and can be activated when DP thymocytes are induced to undergo apoptosis in vitro by TCR-crosslinking. Thus, specific caspases appear to be developmentally regulated in thymocytes. C1 NIAID, Mol Dev Immune Syst Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Lenardo, MJ (reprint author), NIAID, Mol Dev Immune Syst Sect, Immunol Lab, NIH, 10 Ctr Dr,MSC 1892,Bldg 10,Room 11D09, Bethesda, MD 20892 USA. NR 35 TC 28 Z9 28 U1 1 U2 1 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD MAY PY 1999 VL 6 IS 5 BP 402 EP 411 DI 10.1038/sj.cdd.4400513 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 195VH UT WOS:000080272500005 PM 10381640 ER PT J AU He, HC Wang, XT Gorospe, M Holbrook, NJ Trush, MA AF He, HC Wang, XT Gorospe, M Holbrook, NJ Trush, MA TI Phorbol ester-induced mononuclear cell differentiation is blocked by the mitogen-activated protein kinase kinase (MEK) inhibitor PD98059 SO CELL GROWTH & DIFFERENTIATION LA English DT Article ID SIGNAL-TRANSDUCTION PATHWAYS; MYELOBLASTIC-LEUKEMIA CELLS; MAP KINASE; C-JUN; HL-60 CELLS; MONOCYTIC DIFFERENTIATION; CHEMI-LUMINESCENCE; MAMMALIAN-CELLS; PHOSPHORYLATION; RAF-1 AB The purpose of this study was to evaluate whether the mitogen-activated protein kinase (MAPK) signaling pathway contributes to 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mononuclear differentiation in the human myeloblastic leukemia ML-1 cells. Upon TPA treatment, the activity of ERK1 and ERK2 rapidly increased, with maximal induction between 1 and 3 h, while ERK2 protein levels remained constant, The activity of JNK1 was also significantly induced, with JNK1 protein levels increasing moderately during exposure to TPA. Treatment of cells with PD98059, a specific inhibitor of mitogen-activated protein kinase kinase (MEK), inhibited TPA-induced ERK2 activity. Furthermore, PD98059 completely blocked the TPA-induced differentiation of ML-1 cells, as assessed by a number of features associated with mononuclear differentiation including changes in morphology, nonspecific esterase activity, phagocytic ability, NADPH oxidase activity, mitochondrial respiration, and c-jun mRNA inducibility. We conclude that activation of the MEK/ERK signaling pathway is necessary for TPA-induced mononuclear cell differentiation. C1 Johns Hopkins Univ, Dept Environm Hlth Sci, Sch Hyg & Publ Hlth, Div Toxicol Sci, Baltimore, MD 21205 USA. NIA, Gene Express & Aging Sect, NIH, Baltimore, MD 21224 USA. RP Trush, MA (reprint author), Johns Hopkins Univ, Dept Environm Hlth Sci, Sch Hyg & Publ Hlth, Div Toxicol Sci, 615 N Wolfe St, Baltimore, MD 21205 USA. FU NIEHS NIH HHS [ES07141, ES08078, ES03760] NR 65 TC 40 Z9 43 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1044-9523 J9 CELL GROWTH DIFFER JI Cell Growth Differ. PD MAY PY 1999 VL 10 IS 5 BP 307 EP 315 PG 9 WC Cell Biology SC Cell Biology GA 199UF UT WOS:000080501200003 PM 10359012 ER PT J AU Mukherjee, AB Kundu, GC Mantile-Selvaggi, G Yuan, CJ Mandal, AK Chattopadhyay, S Zheng, F Pattabiraman, N Zhang, Z AF Mukherjee, AB Kundu, GC Mantile-Selvaggi, G Yuan, CJ Mandal, AK Chattopadhyay, S Zheng, F Pattabiraman, N Zhang, Z TI Uteroglobin: a novel cytokine? SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE blastokinin; uteroglobin; CC10; ECM; fibronectin; PLA(2); receptor; cytokine ID AMINO-ACID-SEQUENCE; RECOMBINANT HUMAN UTEROGLOBIN; CELL 10-KDA PROTEIN; ANTIINFLAMMATORY PEPTIDES ANTIFLAMMINS; PHOSPHOLIPASE-A2 INHIBITORY PROTEIN; PROGESTERONE-BINDING PROTEIN; PLATELET-ACTIVATING-FACTOR; TISSUE-SPECIFIC EXPRESSION; REGULATED MAMMALIAN GENE; RABBIT UTEROGLOBIN AB Blastokinin or uteroglobin (UG) is a steroid-inducible, evolutionarily conserved, multifunctional protein secreted by the mucosal epithelia of virtually all mammals. It is present in the blood and in other body fluids including urine. An antigen immunoreactive to UG antibody is also detectable in the mucosal epithelia of all vertebrates. UG-binding proteins (putative receptor), expressed on several normal and cancer cell types, have been characterized. The human UG gene is mapped to chromosome 11q(12.2-13.1), a region that is frequently rearranged or deleted in many cancers. The generation of UG knockout mice revealed that disruption of this gene causes: (i) severe renal disease due to an abnormal deposition of fibronectin and collagen in the glomeruli; (ii) predisposition to a high incidence of malignancies; and (iii) a lack of polychlorinated biphenyl binding and increased oxygen toxicity in the lungs. The mechanism(s) of UG action is likely to be even more complex as it also functions via a putative receptor-mediated pathway that has not yet been clearly defined. Molecular characterization of the UG receptor and signal transduction via this receptor pathway may show that this protein belongs to a novel cytokine/chemokine family. C1 NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. NCI, Frederick Biomed Supercomp Ctr, SAIC, FCRDC, Frederick, MD 21702 USA. RP Mukherjee, AB (reprint author), NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bldg 10,Room 9S241, Bethesda, MD 20892 USA. NR 178 TC 102 Z9 110 U1 0 U2 0 PU BIRKHAUSER VERLAG AG PI BASEL PA VIADUKSTRASSE 40-44, PO BOX 133, CH-4010 BASEL, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD MAY PY 1999 VL 55 IS 5 BP 771 EP 787 DI 10.1007/s000180050331 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 202GF UT WOS:000080643200006 PM 10379362 ER PT J AU Liu, KL Miles, HT Howard, FB Frazier, J Sasisekharan, V AF Liu, KL Miles, HT Howard, FB Frazier, J Sasisekharan, V TI Parallel DNA constrained by "CC+ clamps" SO CHEMICAL RESEARCH IN CHINESE UNIVERSITIES LA English DT Article DE parallel DNA helices; reverse Watson-Crick pairing; CC+ base pair; oligonucleotide ID STRANDED DNA; BASE-PAIRS; DUPLEX; HELIX AB Parallel DNA helices with reverse Watson-Crick pairing have been described in several papers. It has been pointed out, however, that the parallel structures may also be in equilibrium with antiparallel Watson-Crick helices due to their closely similar properties. To avoid the problem we have prepared and characterized DNA helices which are constrained to possess parallel polarity by two dC residues, or "CC+ clamps", at both the ends of AT oligomer chains. The residues are hemiprotonated below neutral pH, forming two stable CC+ base pairs with three hydrogen bonds at each end of the helix. The physical properties of these constructs can then be used to calibrate those of duplexes having the same sequences but lacking the terminal C residues. Though recent studies indicate that dC acid self-structures are four-stranded with intercalated bases, gel electrophoresis indicates that these structures are not present in the molecules described here. C1 NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 13 TC 0 Z9 0 U1 0 U2 0 PU HIGHER EDUCATION PRESS PI BEIJING PA SHATANHOU ST 55, BEIJING 100009, PEOPLES R CHINA SN 1005-9040 J9 CHEM RES CHINESE U JI Chem. Res. Chin. Univ. PD MAY PY 1999 VL 15 IS 2 BP 134 EP 139 PG 6 WC Chemistry, Multidisciplinary SC Chemistry GA 204RE UT WOS:000080777300008 ER PT J AU Agarwal, R Coffing, SL Baird, WM Harvey, RG Dipple, A AF Agarwal, R Coffing, SL Baird, WM Harvey, RG Dipple, A TI Metabolic activation of 4H-cyclopenta[def]chrysene in human mammary carcinoma MCF-7 cell cultures SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID POLYCYCLIC AROMATIC-HYDROCARBONS; TUMOR-INITIATING ACTIVITY; REGION DIOL-EPOXIDES; MAJOR DNA-ADDUCTS; FEMALE CD RATS; MOUSE SKIN; FJORD REGION; LINE MCF-7; BENZOPHENANTHRENE; BINDING AB The tumor initiating activities of 4H-cyclopenta[def]chrysene (C[def]C) and its two putative reactive metabolites. trans-1,2-dihydroxy-anti-3,3a-epoxy-1,2,3,3a-tetrahydro-4H-cyclopenta [def]chrysene (C[def]C-3,3a-DE) and trans-6,7-dihydroxy-anti-8,9-epoxy-6,7,8,9-tetrahydro-4H-cyclopenta[def]chrysene (C[def]C-8,9-DE), were evaluated previously in mice [Amin, S., et al. (1995) Carcinogenesis 16, 2813-2817]. C[def]C-3,3a-DE was the more active inducer of lung tumors and elicited twice as many tumors as C[def]C-8,9-DE. In this study, the route of metabolism of C[def]C to DNA-reactive metabolites in the human mammary carcinoma cell line (MCF-7) was investigated using the P-32-postlabeling assay. The results show that metabolic activation to DNA-binding species proceeds through the formation of both trans-1,2-dihydrodiol and trans-6,7-dihydrodiol metabolites of C[def]C. At a 1 mu M dose, adducts from the methylene-bridged (C[def]C-3,3a-DE) and bay region (C[def]C-8,9-DE) dihydrodiol epoxides were detected in comparable amounts. In contrast, the majority of the postlabeled adducts recovered from cells exposed to a 10 mu M dose were derived from the bay region dihydrodiol epoxide, C[def]C-8,9-DE. Using markers from reactions of the dihydrodiol epoxides with deoxyguanosine 3'-phosphate and deoxyadenosine 3'-phosphate, it was shown that the major radioactive spots formed with both anti-C[def]C-3,3a-DE and anti-C[def]C-8,9-DE chromatographed with deoxyguanosine adduct markers. Thus, the human cells used in these studies can activate C[def]C to carcinogenic metabolites. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. Purdue Univ, Ctr Canc, W Lafayette, IN 47907 USA. Univ Chicago, Ben May Inst, Chicago, IL 60637 USA. RP Agarwal, R (reprint author), NCI, Expt Carcinogenesis Lab, Bldg 37,Room 3C28, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA 67937, CA 40228] NR 32 TC 0 Z9 0 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 MAY PY 1999 VL 12 IS 5 BP 437 EP 441 DI 10.1021/tx980258r PG 5 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 197YM UT WOS:000080394200007 PM 10328754 ER PT J AU Fann, YC Metosh-Dickey, CA Winston, GW Sygula, A Rao, DNR Kadiiska, MB Mason, RP AF Fann, YC Metosh-Dickey, CA Winston, GW Sygula, A Rao, DNR Kadiiska, MB Mason, RP TI Enzymatic and nonenzymatic production of free radicals from the carcinogens 4-nitroquinoline N-oxide and 4-hydroxylaminoquinoline N-oxide SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID PURIFIED NAD(P)H-QUINONE OXIDOREDUCTASE; HYPERFINE COUPLING-CONSTANT; NADPH-DEPENDENT PRODUCTION; RAT-LIVER; SPIN-DENSITIES; OXY RADICALS; ROW ATOMS; MUTAGENICITY; REDUCTION; NITROREDUCTASE AB The anion radicals of 4-nitroquinoline N-oxide (4-NQO) and 4-nitrosoquinoline N-oxide (4-NOO) carcinogens were detected and characterized by electron spin resonance (ESR) spectroscopy. The structures of the radical intermediates were examined by density functional theory (DFT) at the level of hybrid unrestricted uBecke3LYP. The formation of superoxide anion radical catalyzed by flavin-containing enzymes such as cytochrome P450 reductase or xanthine oxidase in the presence of 4-NQO or 4-nitroquinoline N-oxide was studied by spin-trapping experiments. In this case, the ESR signal of the 5,5-dimethyl-1-pyrroline N-oxide (DMPO)-superoxide radical adduct was observed, and its formation was inhibited by superoxide dismutase (SOD), No ESR signal was detected when the two-electron-transferring flavoenzyme DT-diaphorase (NADPH-quinone oxidoreductase) was used. The above is consistent with a one-electron reduction in the metabolism of these nitro compounds to anion free radicals by various flavoenzyme reductases. C1 NIEHS, Lab Pharmacol & Chem, Informat Technol Support Serv, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Pharmacol & Chem, Free Rad Metabolite Sect, NIH, Res Triangle Pk, NC 27709 USA. Adv BioSyst, Baton Rouge, LA 70802 USA. Louisiana State Univ, Dept Chem, Baton Rouge, LA 70803 USA. N Carolina State Univ, Dept Toxicol, Raleigh, NC 27695 USA. RP Fann, YC (reprint author), NIEHS, Lab Pharmacol & Chem, Informat Technol Support Serv, NIH, 111 TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. NR 65 TC 18 Z9 19 U1 0 U2 4 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 MAY PY 1999 VL 12 IS 5 BP 450 EP 458 DI 10.1021/tx980238p PG 9 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 197YM UT WOS:000080394200009 PM 10328756 ER PT J AU Schubert, D Tziatzios, C Schuck, P Schubert, US AF Schubert, D Tziatzios, C Schuck, P Schubert, US TI Characterizing the solution properties of supramolecular systems by analytical ultracentrifugation SO CHEMISTRY-A EUROPEAN JOURNAL LA English DT Article DE analytical methods; analytical ultracentrifugation; association in solution; supramolecular chemistry ID COORDINATION ARRAYS; MASS-SPECTROMETRY; LAMM EQUATION; SEDIMENTATION; COMPLEXES AB Analytical ultracentrifugation is the study of the movement or the local distribution of dissolved supra- or macromolecular particles under the influence of centrifugal force, by measuring and evaluating concentration-versus-radius distributions in the sample. This paper describes application of the method to the determination of the state of association of supramolecular compounds in solution. Both principles and experimental techniques are considered and applied to a special metal coordination array. Those methods analyzing the "transient" sedimentation patterns, namely, sedimentation velocity experiments and the "approach to equilibrium", can yield information on aggregate size within less than approximately 3 h. In particular, by the approach to equilibrium method (Archibald method) the average molar mass of the dissolved compound can be determined within about 30 min. Sedimentation equilibrium analysis can yield the percentage of the different aggregates present and, for reversibly associating systems, association constants. C1 Univ Frankfurt Klinikum, Inst Biophys, D-60590 Frankfurt, Germany. NIH, BEPS, ORS, Bethesda, MD 20892 USA. Tech Univ Munich, Lehrstuhl Makromol Stoffe, D-85747 Garching, Germany. RP Schubert, D (reprint author), Univ Frankfurt Klinikum, Inst Biophys, Theodor Stern Kai 7,Haus 74, D-60590 Frankfurt, Germany. RI Schubert, Ulrich/B-5777-2009; OI Schubert, Ulrich/0000-0003-4978-4670; Schuck, Peter/0000-0002-8859-6966 NR 40 TC 36 Z9 36 U1 0 U2 2 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0947-6539 J9 CHEM-EUR J JI Chem.-Eur. J. PD MAY PY 1999 VL 5 IS 5 BP 1377 EP 1383 DI 10.1002/(SICI)1521-3765(19990503)5:5<1377::AID-CHEM1377>3.0.CO;2-H PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA 194UQ UT WOS:000080212600002 ER PT J AU Sarafianos, SG Das, K Ding, JP Boyer, PL Hughes, SH Arnold, E AF Sarafianos, SG Das, K Ding, JP Boyer, PL Hughes, SH Arnold, E TI Touching the heart of HIV-1 drug resistance: the fingers close down on the dNTP at the polymerase active site SO CHEMISTRY & BIOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HIGH-LEVEL RESISTANCE; DNA TEMPLATE-PRIMER; DOUBLE-STRANDED DNA; I KLENOW FRAGMENT; REVERSE-TRANSCRIPTASE; ANGSTROM RESOLUTION; NONNUCLEOSIDE INHIBITORS; KINETIC MECHANISM; CRYSTAL-STRUCTURE AB Comparison of the recently solved structure of HIV-1 reverse transcriptase (RT)-DNA-dNTP ternary complex with the previously solved structure of RT-DNA binary complex suggests mechanisms by which the HIV-1 RT becomes resistant to nucleoside-analog inhibitors, drugs currently used in the treatment of AIDS. C1 Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. Rutgers State Univ, Dept Chem, Piscataway, NJ 08854 USA. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. RP Arnold, E (reprint author), Rutgers State Univ, Ctr Adv Biotechnol & Med, 679 Hoes Lane, Piscataway, NJ 08854 USA. OI Sarafianos, Stefan G/0000-0002-5840-154X NR 68 TC 58 Z9 60 U1 0 U2 2 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD MAY PY 1999 VL 6 IS 5 BP R137 EP R146 DI 10.1016/S1074-5521(99)80071-4 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 240VA UT WOS:000082846400002 PM 10322129 ER PT J AU Hastings, PD Rubin, KH AF Hastings, PD Rubin, KH TI Predicting mothers' beliefs about preschool-aged children's social behavior: Evidence for maternal attitudes moderating child effects SO CHILD DEVELOPMENT LA English DT Article ID PSYCHOLOGICAL CONTROL; ATTACHMENT SECURITY; MIDDLE CHILDHOOD; ATTRIBUTIONS; PARENT; BOYS; AGGRESSION; SOCIALIZATION; WITHDRAWAL; STABILITY AB Maternal beliefs about children's social behavior may be important contributors to socialization and development, but little is known about how such beliefs form. Transactional models suggest that children's characteristics may influence parents. At 2 years of age, the shy and aggressive behaviors of 65 toddlers (28 females) were observed during interactions with an unfamiliar peer; as well, mothers described the extent to which they advocated protective and authoritarian childrearing attitudes. These variables were used to predict mothers emotions, attributions, parenting goals, and socialization strategies in response to vignettes depicting aggressive and withdrawn child behaviors 2 years later. Most child effects were moderated by maternal attitudes or gender effects. Authoritarian mothers of aggressive toddlers were most likely to report high control and anger, to blame their children for aggression, and to focus on obtaining compliance rather than teaching skills to their children. Protective mothers reported that they would use warmth and involvement to comfort withdrawn children, especially their daughters. C1 NIMH, Sect Dev Psychopathol, NIH, Bethesda, MD 20892 USA. Univ Maryland, College Pk, MD 20742 USA. RP Hastings, PD (reprint author), NIMH, Sect Dev Psychopathol, NIH, 15 N Dr,Bldg 15-K,Room 202-A, Bethesda, MD 20892 USA. EM Paul_D_Hastings@nih.gov NR 75 TC 76 Z9 76 U1 0 U2 14 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0009-3920 J9 CHILD DEV JI Child Dev. PD MAY-JUN PY 1999 VL 70 IS 3 BP 722 EP 741 DI 10.1111/1467-8624.00052 PG 20 WC Psychology, Educational; Psychology, Developmental SC Psychology GA 202BN UT WOS:000080632400015 PM 10368918 ER PT J AU Moens, PB Tarsounas, M Morita, T Habu, T Rottinghaus, ST Freire, R Jackson, SP Barlow, C Wynshaw-Boris, A AF Moens, PB Tarsounas, M Morita, T Habu, T Rottinghaus, ST Freire, R Jackson, SP Barlow, C Wynshaw-Boris, A TI The association of ATR protein with mouse meiotic chromosome cores SO CHROMOSOMA LA English DT Article ID SACCHAROMYCES-CEREVISIAE; CHECKPOINT CONTROL; RECOMBINATION; MEIOSIS; DMC1; HOMOLOGS; SYNAPSIS; LOCALIZATION; DEFICIENT; COMPLEXES AB The ATR (ataxia telangiectasia- and RAD3-related) protein is present on meiotic prophase chromosome cores and paired cores (synaptonemal complexes, SCs). Its striking characteristic is that the protein forms dense aggregates on the cores and SCs of the last chromosomes to pair at the zygotene-pachytene transition. It would appear that the ATR protein either signals delays in pairing or it is directly involved in the completion of the pairing phase. Atm-deficient spermatocytes, which are defective in the chromosome pairing phase, accumulate large amounts of ATR. The behaviour of ATR at meiotic prophase sets it apart from the distribution of the RAD51/DMC1 recombinase complex and our electron microscope observations confirm that they do not co-localize. We failed to detect ATM in association with cores/SCs and we have reported elsewhere that RAD1 protein does not co-localize with DMC1 foci. The expectation that putative DNA-damage checkpoint proteins, ATR, ATM and RAD1, are associated with RAD51/DMC1 recombination sites where DNA breaks are expected to be present, is therefore not supported by our observations. C1 York Univ, Dept Biol, N York, ON M3J 1P3, Canada. Osaka Univ, Dept Mol Embryol, Suita, Osaka 565, Japan. Wellcome CRC Inst, Cambridge CB2 1QR, England. NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Moens, PB (reprint author), York Univ, Dept Biol, 4700 Keele St, N York, ON M3J 1P3, Canada. RI Dry, Kate/I-2328-2014 FU Wellcome Trust NR 24 TC 71 Z9 74 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0009-5915 J9 CHROMOSOMA JI Chromosoma PD MAY PY 1999 VL 108 IS 2 BP 95 EP 102 DI 10.1007/s004120050356 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 196GM UT WOS:000080300700003 PM 10382071 ER PT J AU Kayastha, S Freedman, AN Piver, MS Mukkamalla, J Romero-Guittierez, M Werness, BA AF Kayastha, S Freedman, AN Piver, MS Mukkamalla, J Romero-Guittierez, M Werness, BA TI Expression of the hyaluronan receptor, CD44S, in epithelial ovarian cancer is an independent predictor of survival SO CLINICAL CANCER RESEARCH LA English DT Article ID BREAST-CANCER; VARIANT EXPRESSION; OVEREXPRESSION; CARCINOMA; BINDING; CELLS; RHAMM; ACID AB Most ovarian carcinomas present at advanced stage, principally as the result of dissemination to peritoneal sites. Standard CD44 (CD44S) is the principal receptor for hyaluronic acid, and in vitro and animal studies have suggested that the attachment of ovarian carcinoma cells to the peritoneal mesothelium involves the interaction between CD44S on ovarian carcinoma cells and hyaluronic acid on mesothelial surfaces. We, therefore, analyzed a series of ovarian carcinomas for the expression of CD44S by immunohistochemistry to see whether expression of this receptor by tumor cells correlated with clinicopathological factors and measures of patient outcome. Fifty-six fixed, paraffin-embedded primary epithelial ovarian tumors were immuno-stained with antibody to CD44S, Membrane staining was considered positive, and results were correlated,vith stage, grade, age, histology, and survival. Twenty-two (39%) tumors were positive for CD44S, There was no correlation between CD44 expression and histological type, grade, age, or stage. However, CD44 expression was significantly associated with survival in both univariate (P = 0.003) and multivariate (P = 0.006) analyses. These results support a role for CD44S expression in the spread of ovarian epithelial cancer and suggest that expression of this molecule is a significant independent predictor of survival in women with this disease. C1 Roswell Pk Canc Inst, Div Pathol, Buffalo, NY 14263 USA. Roswell Pk Canc Inst, Dept Gynecol Oncol, Buffalo, NY 14263 USA. NCI, Appl Res Branch, Bethesda, MD 20892 USA. RP Werness, BA (reprint author), Univ Cincinnati, Med Ctr, Dept Pathol, 231 Bethesda Ave, Cincinnati, OH 45267 USA. NR 25 TC 40 Z9 43 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAY PY 1999 VL 5 IS 5 BP 1073 EP 1076 PG 4 WC Oncology SC Oncology GA 200FE UT WOS:000080528300016 PM 10353740 ER PT J AU Chae, JJ Kim, SH Kim, UK Han, KH Kim, HS Kastner, DL Namkoong, Y Park, YB Lee, CC AF Chae, JJ Kim, SH Kim, UK Han, KH Kim, HS Kastner, DL Namkoong, Y Park, YB Lee, CC TI Three novel small deletion mutations of the LDL receptor gene in Korean patients with familial hypercholesterolemia SO CLINICAL GENETICS LA English DT Article DE FH; LDL receptor gene; SSCP; three small deletion mutations ID FRAMESHIFT MUTATIONS; RFLP; DNA; POLYMORPHISM; SEQUENCE; DISEASE; MUTAGENESIS; MECHANISMS; NONSENSE; SOFTWARE AB The low-density lipoprotein (LDL) receptor gene from 80 unrelated Korean patients with familial hypercholesterolemia (FH) was analyzed to screen for small structural rearrangements that could not be detected by Southern blot hybridization. Three different small deletions were detected in exon 11 of 3 FH patients and were characterized by DNA sequence analysis. Of them two mutations are in-frame 36-bp (FH 1) and 9-bp (FH 34) deletions that result in the loss of twelve amino acids (from Met(510) to Ile(521)) and three amino acids (Thr(513), Asp(514) and Trps(515)), respectively. Both mutations are located in the third of the five YWTD motifs of the LDL receptor gene. The third mutation (FH 400) is a 2-bp deletion that shifts the translational reading frame and results bp deletion can be explained by the formation of a hairpin-loop structure mediated by inverted repeat sequences. On the other hand, the mechanism responsible for the 9- and the 2-bp deletions is probably strand-slippage mispairing mediated by short direct repeats. All of these three deletions are novel mutations. Each of the three deletions was detected only in a single pedigree out of 80 FH families analyzed. C1 Seoul Natl Univ, Coll Nat Sci, Dept Biol, Seoul 151742, South Korea. Seoul Natl Univ, Dept Mol Biol, Seoul 151742, South Korea. NIAMSD, Arthrit & Rheumatism Branch, Bethesda, MD 20892 USA. Seoul Natl Univ, SRC Cell Differentiat, Seoul 151742, South Korea. Seoul Natl Univ Hosp, Dept Internal Med, Seoul 110744, South Korea. Kangnung Natl Univ, Dept Biol, Kangnung, South Korea. RP Lee, CC (reprint author), Seoul Natl Univ, Coll Nat Sci, Dept Biol, Seoul 151742, South Korea. RI Kim, Hyo Soo/J-2753-2012 NR 34 TC 6 Z9 6 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 MAY PY 1999 VL 55 IS 5 BP 325 EP 331 DI 10.1034/j.1399-0004.1999.550505.x PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 214EP UT WOS:000081315900006 PM 10422802 ER PT J AU Lefkowitz, DL Gelderman, MP Fuhrmann, SR Graham, S Starnes, JD Lefkowitz, SS Bollen, A Moguilevsky, N AF Lefkowitz, DL Gelderman, MP Fuhrmann, SR Graham, S Starnes, JD Lefkowitz, SS Bollen, A Moguilevsky, N TI Neutrophilic myeloperoxidase-macrophage interactions perpetuate chronic inflammation associated with experimental arthritis SO CLINICAL IMMUNOLOGY LA English DT Article DE myeloperoxidase; arthritis; macrophage; neutrophil ID HUMAN RECOMBINANT MYELOPEROXIDASE; NECROSIS-FACTOR-ALPHA; GROWTH-FACTOR-BETA; RHEUMATOID-ARTHRITIS; SYNOVIAL TISSUES; MANNOSE RECEPTOR; CANDIDA-ALBICANS; PHAGOCYTOSIS; ADHESION; CELLS AB Rheumatoid arthritis is a systemic disease of unknown etiology. The purpose of this stud was to elucidate an unrecognized interaction between neutrophilic myeloperoxidase (MPO) and macrophages (M phi) which could perpetuate the inflammatory response associated with arthritis. A monoarticular arthritis was induced by intra-articular injection of group A streptococcus cell wall fragments (PG-APS) into the ankle joint of female Lewis rats. After swelling/erythema subsided, joints were reinjected with either recombinant MPO or enzymatically inactive MPO (iMPO). Joint measurements were made daily and arthritis was confirmed by histology. Neither iMPO nor MPO could initiate "clinical" arthritis, however, either form of the enzyme injected after PG-APS induced a dose-independent increase in erythema and swelling. Mannans, which bloc the binding of MPO to Mo, ablated clinical symptoms. Also, the presence of tumor necrosis factor alpha was observed only in diseased joints using immunocytochemistry. (C) 1999 Academic Press. C1 Texas Tech Univ, Lubbock, TX 79409 USA. NIH, Bethesda, MD 20931 USA. Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. Free Univ Brussels, Nivelles, Belgium. RP Lefkowitz, DL (reprint author), Texas Tech Univ, Lubbock, TX 79409 USA. NR 45 TC 40 Z9 42 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD MAY PY 1999 VL 91 IS 2 BP 145 EP 155 DI 10.1006/clim.1999.4696 PG 11 WC Immunology SC Immunology GA 216UJ UT WOS:000081462600004 PM 10227806 ER PT J AU Egwuagu, CE Mahdi, RM Chan, CC Sztein, J Li, WM Smith, JA Chepelinsky, AB AF Egwuagu, CE Mahdi, RM Chan, CC Sztein, J Li, WM Smith, JA Chepelinsky, AB TI Expression of interferon-gamma in the lens exacerbates anterior uveitis and induces retinal degenerative changes in transgenic Lewis rats SO CLINICAL IMMUNOLOGY LA English DT Article DE uveitis; retinal degeneration; apoptosis; interferon-gamma; transgenic rat ID TRANSCRIPTION FACTOR IRF-2; ENDOTOXIN-INDUCED UVEITIS; PIGMENT EPITHELIAL-CELLS; HLA-DR ANTIGEN; IFN-GAMMA; CRYSTALLIN GENE; RETINITIS PIGMENTOSA; ECTOPIC EXPRESSION; MULTIPLE-SCLEROSIS; MICE AB Interferon-gamma (IFN-gamma) is a pleiotropic cytokine that has been implicated in immunopathogenic mechanisms of a number of inflammatory diseases of autoimmune or infectious disease etiology. However, its exact role is still a matter of debate. In experimental mouse models, IFN-gamma has been shown to exacerbate autoimmune thyroiditis, insulin-dependent diabetes mellitus, and autoimmune neuritis while it confers protection against experimental allergic encephalomyelitis and experimental uveitis. In this study, we generated transgenic rats with constitutive expression of IFN-gamma in the eye to study its paracrine effects and to investigate whether local production of IFN-gamma also confers protection against uveitis in the rate species. We show here that chronic exposure of ocular cells to IFN-gamma results in apoptotic death of retinal ganglion cells, development of chronic choroiditis, formation of retinal in-foldings, and activation of proinflammatory genes. In contrast to its protective systemic effect in the mouse, constitutive secretion of IFN-gamma in the rat eye was found to predispose the development of severe anterior uveitis and induction of retinal degenerative processes that impair visual acuity. Our data underscore the danger in extrapolation of cytokine effects in the mouse to humans without corroborating evidence in other species. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Egwuagu, CE (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Room 10N116, Bethesda, MD 20892 USA. RI Sztein, Jorge/B-7165-2012 NR 52 TC 15 Z9 15 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD MAY PY 1999 VL 91 IS 2 BP 196 EP 205 DI 10.1006/clim.1999.4701 PG 10 WC Immunology SC Immunology GA 216UJ UT WOS:000081462600010 PM 10227812 ER PT J AU Frucht, DM Sandberg, DI Brown, MR Gerstberger, SM Holland, SM AF Frucht, DM Sandberg, DI Brown, MR Gerstberger, SM Holland, SM TI IL-12 independent costimulation pathways for interferon-gamma production in familial dissemination Mycobacterium avium complex infection SO CLINICAL IMMUNOLOGY LA English DT Article ID CD40-CD40 LIGAND INTERACTION; CELL-MEDIATED-IMMUNITY; HUMAN T-CELLS; CD40 LIGAND; RECEPTOR DEFICIENCY; CYTOKINE PRODUCTION; LEISHMANIA-MAJOR; CALMETTE-GUERIN; HUMAN MONOCYTES; SOLUBLE CD23 AB We have described previously a family with an apparent genetic susceptibility to disseminated Mycobacterium avium complex infection and an underlying defect in IL-12 regulation leading to abnormally low interferon-gamma production. Their T cells appear to act normally when in the presence of normal accessory cells. Cell-to-cell contact was necessary for normal monocytes to complement the familial patient mono defect, suggesting the familial defect in interferon-gamma costimulation involves pathways requiring cell surface molecule interactions. In an effort to better characterize the abnormality in these patients, we examined the role of known costimulatory molecules in residual costimulation by patient PBMC compared to normals. Whereas normals utilized CD40/CD40L interactions and IL-12 production for optimal inteferon-gamma costimulation in PHA-stimulated cocultures, familial patient interferon-gamma production was low and unaffected by their blockade. CD86 blockade caused a greater than 50% reduction in both normal and familial patient interferon-gamma production, implying that a majority of residual familial patient costimulation required this pathway. Furthermore, selected myelomonocytic cell lines (K562 and THP1) acted as potent accessory cells for interferon-gamma production by familial patient and normal T cells, largely independent of IL-12 production. However, CD86 blockade of K562 cell/familial cell cocultures resulted in less than a 20% reduction in interferon-gamma production, indicating that familial patient cells respond to IL-12- and Cd86-independent costimulatory signals for interferon-gamma as well. Thus, we demonstrate that the familial defect also involves interferon-gamma costimulation pathways requiring both CD40/CD40L interaction and IL-12 production, while residual pathways remain that allow low-level interferon-gamma production. Familial Mycobacer avium patient monocytes and certain myelonocytic cell lines can be exploited to investigate IL-12-independent costimulation for interferon-gamma production. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. NIH, Dept Clin Pathol, Ctr Clin, Bethesda, MD 20892 USA. RP Frucht, DM (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Room 11N103,10 Ctr Dr,MSC 1886 Bethesda, Bethesda, MD 20892 USA. NR 34 TC 26 Z9 26 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD MAY PY 1999 VL 91 IS 2 BP 234 EP 241 DI 10.1006/clim.1999.4688 PG 8 WC Immunology SC Immunology GA 216UJ UT WOS:000081462600014 PM 10227816 ER PT J AU Karp, CL Neva, FA AF Karp, CL Neva, FA TI Tropical infectious diseases in human immunodeficiency virus-infected patients SO CLINICAL INFECTIOUS DISEASES LA English DT Review ID PENICILLIUM-MARNEFFEI INFECTION; AMPHOTERICIN-B AMBISOME; VISCERAL LEISHMANIASIS; HIV-INFECTION; CHAGAS-DISEASE; T-CELL; STRONGYLOIDES-STERCORALIS; OPPORTUNISTIC INFECTIONS; HUMAN EHRLICHIOSIS; PLACENTAL MALARIA C1 Johns Hopkins Univ, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Baltimore, MD USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Karp, CL (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Div Infect Dis, 1830 E Monument St,Room 455, Baltimore, MD 21205 USA. NR 120 TC 37 Z9 39 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY PY 1999 VL 28 IS 5 BP 947 EP 963 DI 10.1086/514745 PG 17 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 190HB UT WOS:000079955800001 PM 10452619 ER PT J AU Rodrigue, SW Rosenthal, DI Barton, NW Zurakowski, D Mankin, HJ AF Rodrigue, SW Rosenthal, DI Barton, NW Zurakowski, D Mankin, HJ TI Risk factors for osteonecrosis in patients with type 1 Gaucher's disease SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID MACROPHAGE-TARGETED GLUCOCEREBROSIDASE; ENZYME REPLACEMENT THERAPY; SKELETAL COMPLICATIONS; BONE; MARROW AB This study investigated 51 patients with Type 1 Gaucher's disease clinically and radiographically for the presence of osteonecrosis, Twenty-five female and 26 male patients with a mean age of 37 years were evaluated retrospectively for osteonecrosis of the proximal and distal femur, proximal tibia, and proximal humerus, All patients were examined before enzyme replacement therapy. Gender, age at diagnosis, prior splenectomy, hematocrit, platelet count, acid phosphatase level, radiographs of the long bones, and magnetic resonance quantitative chemical shift imaging of the spine were analyzed to see if any of these values or findings were associated with the presence of osteonecrosis, Splenectomy was an independent risk factor for the presence of osteonecrosis in three of the four major sites and was a multivariate risk factor for osteonecrosis of the proximal femur and tibia. Male gender was the other significant multivariate risk factor for osteonecrosis of the humerus and distal femur when all sites were taken into account. C1 Massachusetts Gen Hosp, Orthopaed Serv, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Childrens Hosp, Dept Radiol, Cambridge, MA 02138 USA. NIH, Inst Neurol Disorders & Stroke, Ctr Clin, Washington, DC USA. RP Mankin, HJ (reprint author), Massachusetts Gen Hosp, Orthopaed Serv, Boston, MA 02114 USA. NR 34 TC 31 Z9 31 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD MAY PY 1999 IS 362 BP 201 EP 207 PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 195AW UT WOS:000080227800030 PM 10335299 ER PT J AU Neuhaus, IM Schwartz, PJ Turner, EH Feldman-Naim, S Matthews, JR Lam, G Rosenthal, NE AF Neuhaus, IM Schwartz, PJ Turner, EH Feldman-Naim, S Matthews, JR Lam, G Rosenthal, NE TI Gender differences in glycosylated hemoglobin levels in seasonal affective disorder patients and controls SO COMPREHENSIVE PSYCHIATRY LA English DT Article ID DEPRESSION; PROLACTIN; UNIPOLAR; BEHAVIOR; MOOD AB Seasonal affective disorder (SAD) has been shown to manifest different symptoms in female and male patients. Specifically, women with SAD have been shown to have greater increases in overeating, weight gain, and increased sleep as compared with their male counterparts. Given these dietary changes, we predicted that female SAD patients would exhibit increased glycosylated hemoglobin (HbA(1)) levels, indicative of chronically elevated glucose levels. Twenty-two patients (15 women and seven men) and matched controls were enrolled during the winter season and tested for HbA(1) levels. A three-way analysis of variance (ANOVA; gender x group x season) was insignificant and the result was a negative study. After the initial hypothesis was rejected, we undertook a posthoc analysis of the data, from which emerged that in winter, women patients had higher HbA1 levels as compared with matched controls. As our original hypothesis was rejected, we cannot accept the results of the post-hoc study. However, numerous other studies have demonstrated that female and male SAD patients differ in their pathophysiology, and are suggestive that in future analyses ought to consider analyzing subjects separately across gender. Copyright (C) 1999 by W.B. Saunders Company. C1 NIMH, Clin Psychobiol Branch, Bethesda, MD 20892 USA. RP Rosenthal, NE (reprint author), NIMH, Clin Psychobiol Branch, Bldg 10,Room 4S-239,10 Ctr Dr, Bethesda, MD 20892 USA. RI Turner, Erick/A-4848-2008 OI Turner, Erick/0000-0002-3522-3357 NR 20 TC 2 Z9 2 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 0010-440X J9 COMPR PSYCHIAT JI Compr. Psychiat. PD MAY-JUN PY 1999 VL 40 IS 3 BP 234 EP 237 DI 10.1016/S0010-440X(99)90010-X PG 4 WC Psychiatry SC Psychiatry GA 198YE UT WOS:000080451400011 PM 10360621 ER PT J AU St Clair, MB Sowers, AL Davis, JA Rhodes, LL AF St Clair, MB Sowers, AL Davis, JA Rhodes, LL TI Urinary bladder catheterization of female mice and rats SO CONTEMPORARY TOPICS IN LABORATORY ANIMAL SCIENCE LA English DT Article AB Catheterization of the urinary bladder of rats and mice is necessary for a variety of clinical and experimental reasons. The anatomy of the female mouse and rat is unique in that the urinary orifice is external and just anterior to the vaginal opening. This characteristic makes the bladder of these species easier to catheterize than that of other species. Methods cited in the literature do not adequately describe techniques that facilitate ease of urinary bladder catheterization (1). We describe a simple technique for urinary catheterization in adult female mice and rats. C1 NINDS, Anim Hlth Care Sect, NIH, Bethesda, MD 20892 USA. NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP St Clair, MB (reprint author), NINDS, Anim Hlth Care Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 4 TC 6 Z9 6 U1 1 U2 4 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1060-0558 J9 CONTEMP TOP LAB ANIM JI Contemp. Top. Lab. Anim. Sci. PD MAY PY 1999 VL 38 IS 3 BP 78 EP 79 PG 2 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 198MJ UT WOS:000080427700006 PM 12086430 ER PT J AU Krebsbach, PH Kuznetsov, SA Bianco, P Robey, PG AF Krebsbach, PH Kuznetsov, SA Bianco, P Robey, PG TI Bone marrow stromal cells: Characterization and clinical application SO CRITICAL REVIEWS IN ORAL BIOLOGY & MEDICINE LA English DT Review DE bone marrow stromal cells; osteoprogenitor cells; transplantation; bone regeneration ID FIBROBLAST GROWTH-FACTOR; MESENCHYMAL STEM-CELLS; MICRO-ENVIRONMENT TRANSFER; COLONY-FORMING CELLS; WESTEN-BAINTON CELLS; EX-VIVO EXPANSION; IN-VIVO; PROGENITOR CELLS; HOST ORIGIN; OSTEOGENIC DIFFERENTIATION AB The bone marrow stroma consists of a heterogeneous population of cells that provide the structural and physiological support for hematopoietic cells. Additionally, the bone marrow stroma contains cells with a stem-cell-like character that allows them to differentiate into bone, cartilage, adipocytes, and hematopoietic supporting tissues. Several experimental approaches have been used to characterize the development and Functional nature of these cells in vivo and their differentiating potential in vitro. In vivo, presumptive osteogenic precursors have been identified by morphologic and immunohistochemical methods. In culture, the stromal cells can be separated from hematopoietic cells by their differential adhesion to tissue culture plastic and their prolonged proliferative potential. In cultures generated from single-cell suspensions of marrow, bone marrow stromal cells grow in colonies, each derived From a single precursor cell termed the colony-forming unit-fibroblast. Culture methods have been developed to expand marrow stromal cells derived From human, mouse, and other species. Under appropriate conditions, these cells are capable of Forming new bone after in vivo transplantation. Various methods of cultivation and transplantation conditions have been studied and found to have substantial influence on the transplantation outcome. The finding that bone marrow stromal cells can be manipulated in vitro and subsequently form bone in vivo provides a powerful new model system for studying the basic biology of bone and for generating models for therapeutic strategies aimed at regenerating skeletal elements. C1 Univ Michigan, Sch Dent, Dept Oral Med Pathol & Oncol, Ann Arbor, MI 48109 USA. Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. Univ Aquila, Dipartimento Med Sperimentale, I-67100 Laquila, Italy. RP Krebsbach, PH (reprint author), Univ Michigan, Sch Dent, Dept Oral Med Pathol & Oncol, Ann Arbor, MI 48109 USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 95 TC 165 Z9 175 U1 0 U2 17 PU INT AMER ASSOC DENTAL RESEARCH PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 1045-4411 J9 CRIT REV ORAL BIOL M JI Crit. Rev. Oral Biol. Med. PD MAY PY 1999 VL 10 IS 2 BP 165 EP 181 PG 17 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 257UE UT WOS:000083799700004 PM 10759420 ER PT J AU McCann, UD Ricaurte, GA AF McCann, UD Ricaurte, GA TI Neuropathology of cocaine abuse SO CURRENT OPINION IN PSYCHIATRY LA English DT Article ID BRAIN; ADDICTION; USERS; AMPHETAMINE; VASCULITIS; ABSTINENCE; INDUCTION; PERFUSION; PROTEINS; HUMANS AB The effects of cocaine abuse on brain structure and function are numerous, Some of these effects, such as catastrophic cerebrovascular incidents, are clearly neuropathological. Others, such as persistent perfusion deficits and changes in cerebral glucose utilization, await further functional definition. More recent findings of increases in dopamine transporter density and gene induction may be neuropathologic, but could represent neuroadaptive responses to cocaine's acute actions of cocaine, manifestations of the reinforcing properties of cocaine or epiphenomena of addiction. Recent technical advances directed at bridging the gap between preclinical and clinical studies hold significant promise for advancing our understanding regarding the neuropathology of cocaine abuse and addiction. Curr Opin Psychiatry 12:277-280. (C) 1999 Lippincott Williams & Wilkins. C1 NIMH, Biol Psychiat Branch, Intramural Res Program, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Dept Neurol & Psychiat, Baltimore, MD 21205 USA. RP Ricaurte, GA (reprint author), Johns Hopkins Bayview Med Ctr, Dept Neurol, 5501 Bayview Circle, Baltimore, MD 21224 USA. NR 30 TC 3 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0951-7367 J9 CURR OPIN PSYCHIATR JI Curr. Opin. Psychiatr. PD MAY PY 1999 VL 12 IS 3 BP 277 EP 280 DI 10.1097/00001504-199905000-00003 PG 4 WC Psychiatry SC Psychiatry GA 267ET UT WOS:000084344700003 ER PT J AU Minoo, P Su, GS Drum, H Bringas, P Kimura, S AF Minoo, P Su, GS Drum, H Bringas, P Kimura, S TI Defects in tracheoesophageal and lung morphogenesis in Nkx2.1(-/-) mouse embryos SO DEVELOPMENTAL BIOLOGY LA English DT Article ID THYROID TRANSCRIPTION FACTOR-1; ENDOTHELIAL GROWTH-FACTOR; ENHANCER-BINDING PROTEIN; CELL-DIFFERENTIATION; GENE-EXPRESSION; DNA-BINDING; FACTOR-I; C GENE; TTF-1; EPITHELIUM AB NKX2.1 is a homeodomain transcriptional factor expressed in thyroid, lung, and parts of the brain. We demonstrate that septation of the anterior foregut along the dorsoventral axis, into distinct tracheal and esophageal structures, is blocked in mouse embryos carrying a homozygous targeted disruption of the Nkx2.1 locus. This is consistent with the loss of Nkx2.1 expression, which defines the dorsoventral boundary within the anterior foregut in wild-type E9 embryos. Failure in septation between the trachea and the esophagus in Nkx2.1(-/-) mice leads to the formation of a common lumen that connects the pharynx-to the stomach, serving both as trachea and as esophagus, similar in phenotype to a human pathologic condition termed tracheoesophageal fistula. The main-stem bronchi bifurcate from this common structure and connect to profoundly hypoplastic lungs. The mutant lungs fail to undergo normal branching embryogenesis, consist of highly dilated sacs that are not capable of sustaining normal gas exchange functions, and lead to immediate postnatal death. In situ hybridization suggests reduced Bmp-4 expression in the mutant lung epithelium, providing a possible mechanistic clue for impaired branching. Functional deletion of Nkx2.1 blocks pulmonary-specific epithelial cell differentiation marked by the absence of pulmonary surfactant protein gene expression. Altered expression of temporally regulated genes such as Vegf demonstrates that the lung in Nkx2.1(-/-) mutant embryos is arrested at early pseudoglandular (E11-E15) stage. These results demonstrate a critical role for Nkx2.1 in morphogenesis of the anterior foregut and the lung as well as in differentiation of pulmonary epithelial cells. (C) 1999 Academic Press. C1 Univ So Calif, Sch Med, Womens & Childrens Hosp, Dept Pediat, Los Angeles, CA 90033 USA. Univ So Calif, Sch Med, Ctr Craniofacial Mol Biol, Los Angeles, CA 90033 USA. Univ So Calif, Sch Dent, Ctr Craniofacial Mol Biol, Los Angeles, CA 90033 USA. Univ So Calif, Sch Dent, Womens & Childrens Hosp, Dept Pediat, Los Angeles, CA 90033 USA. NCI, Lab Metab, Bethesda, MD 20892 USA. RP Minoo, P (reprint author), Univ So Calif, Sch Med, Womens & Childrens Hosp, Dept Pediat, Los Angeles, CA 90033 USA. FU NHLBI NIH HHS [HL56590] NR 32 TC 232 Z9 235 U1 0 U2 6 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 MAY 1 PY 1999 VL 209 IS 1 BP 60 EP 71 DI 10.1006/dbio.1999.9234 PG 12 WC Developmental Biology SC Developmental Biology GA 189UK UT WOS:000079924400006 PM 10208743 ER PT J AU Weinstein, BM AF Weinstein, BM TI What guides early embryonic blood vessel formation? SO DEVELOPMENTAL DYNAMICS LA English DT Review DE blood vessels; angiogenesis; vasculogenesis; axial vessels; dorsal aorta; VEGF; ephrin; Xenopus; zebrafish ID VASCULAR DEVELOPMENT; CARDIOVASCULAR-SYSTEM; ENDOTHELIAL-CELLS; VEGF-C; ZEBRAFISH; VASCULOGENESIS; EXPRESSION; MOUSE; GENE; DIFFERENTIATION AB Survival of vertebrate embryos depends on their ability to assemble a correctly patterned, integrated network: of blood vessels to supply oxygen and nutrients to developing tissues. The arrangement of larger caliber intraembryonic vessels, specification of arterial-venous identity, and proper placement of major branch points and arterial-venous connections are all precisely determined, A number of recent studies in both mammalian and nonmammalian vertebrate species, reviewed here, have now begun to reveal the major role played by genetically predetermined extrinsic cues in guiding the formation of early embryonic blood vessels and determining the global pattern of the vasculature. (C) 1999 Wiley-Liss,Inc. C1 NICHD, NIH, Mol Genet Lab, Bethesda, MD 20892 USA. RP Weinstein, BM (reprint author), NICHD, NIH, Mol Genet Lab, Bldg 6B,Room 309,6 Ctr Dr, Bethesda, MD 20892 USA. FU NICHD NIH HHS [ZO1-HD01011-02] NR 49 TC 67 Z9 69 U1 0 U2 12 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD MAY PY 1999 VL 215 IS 1 BP 2 EP 11 DI 10.1002/(SICI)1097-0177(199905)215:1<2::AID-DVDY2>3.0.CO;2-U PG 10 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 193QZ UT WOS:000080149100002 PM 10340752 ER PT J AU Cepeda, C Li, Z Cromwell, HC Altemus, KL Crawford, CA Nansen, EA Ariano, MA Sibley, DR Peacock, WJ Mathern, GW Levine, MS AF Cepeda, C Li, Z Cromwell, HC Altemus, KL Crawford, CA Nansen, EA Ariano, MA Sibley, DR Peacock, WJ Mathern, GW Levine, MS TI Electrophysiological and morphological analyses of cortical neurons obtained from children with catastrophic epilepsy: Dopamine receptor modulation of glutamatergic responses SO DEVELOPMENTAL NEUROSCIENCE LA English DT Article DE glutamate; dopamine receptors; epilepsy; electrophysiology; immunohistochemistry ID RAT PREFRONTAL CORTEX; HUMAN CEREBRAL-CORTEX; NEOSTRIATAL NEURONS; IN-VITRO; D-3 RECEPTOR; IONTOPHORETIC APPLICATION; NEUROMODULATORY ACTIONS; D2-DOPAMINE RECEPTORS; INHIBITORY INFLUENCE; PYRAMIDAL NEURONS AB The present study examined the electrophysiological effects produced by activation of specific dopamine (DA) receptors and the distribution of DA receptor subtypes and glutamate receptor subunits [N-methyl-D-aspartate (NMDAR1) and GluR1] in cortical tissue samples obtained from children (ages 3 months to 16 years) undergoing epilepsy surgery. DA receptor activation produced differential effects depending on the receptor subtype that was activated. D1 receptor family agonists generally enhanced cortical excitability and favored the emergence of epileptogenic activity. In contrast, D2 receptor family agonists had more variable effects on cortical excitability and the expression of epileptiform discharges. Activation of D1 or D2 receptors decreased the amplitude of non-NMDA-mediated excitatory postsynaptic potentials. In contrast, DA and D1 agonists increased the amplitude of NMDA-mediated potentials. Immunohistochemical analysis showed that the DA receptor subtypes and glutamate receptor subunits examined were present in all cortical layers and areas throughout development. Whole-cell voltage clamp recordings of pyramidal neurons visualized with differential interference contrast optics and infrared videomicroscopy indicated that these neurons displayed a persistent Na+ current, followed by an outward current. DA reduced the outward current but had little effect on the persistent Na+ current. These results suggest a dual role for DA's actions in the human cerebral cortex. Activation of D2 receptors or antagonism of D1 receptors may help control seizures in children. Copyright (C) 1999 S. Karger AG, Basel. C1 Univ Calif Los Angeles, Sch Med, Mental Retardat Res Ctr, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Div Neurosurg, Los Angeles, CA 90024 USA. Chicago Med Sch, N Chicago, IL USA. NINDS, ETB, Bethesda, MD 20892 USA. RP Levine, MS (reprint author), Univ Calif Los Angeles, Sch Med, Mental Retardat Res Ctr, 760 Westwood Plaza,Room 58-258 NPI, Los Angeles, CA 90024 USA. RI Crawford, cynthia/G-2603-2012; OI Cromwell, Howard/0000-0003-0464-7082 FU NINDS NIH HHS [NS 32277, NS 28383, NS 38992] NR 71 TC 32 Z9 32 U1 0 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0378-5866 J9 DEV NEUROSCI-BASEL JI Dev. Neurosci. PD MAY-OCT PY 1999 VL 21 IS 3-5 BP 223 EP 235 DI 10.1159/000017402 PG 13 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 262GM UT WOS:000084057600009 PM 10575246 ER PT J AU Smith, NL Heckbert, SR Bittner, VA Savage, PJ Barzilay, JI Dobs, AS Psaty, BM AF Smith, NL Heckbert, SR Bittner, VA Savage, PJ Barzilay, JI Dobs, AS Psaty, BM TI Antidiabetic treatment trends in a cohort of elderly people with diabetes - The Cardiovascular Health Study, 1989-1997 SO DIABETES CARE LA English DT Article ID IMPAIRED GLUCOSE-TOLERANCE; GLYCEMIC CONTROL; MELLITUS; INSULIN; COMPLICATIONS; TROGLITAZONE; PREVALENCE; POPULATION; EFFICACY; THERAPY AB OBJECTIVE - This study characterizes the pharmaceutical treatment of type 2 diabetes from 1989-1990 to 1996-1997 in an elderly cohort. RESEARCH DESIGN AND METHODS - A total of 5,888 adults aged greater than or equal to 65 years were recruited and attended a baseline clinic visit in 1989-1990 (n = 5,201, original cohort) or 1992-1993 (n = 687, African-American [new] cohort) as participants of the Cardiovascular Health Study Fasting serum glucose (FSG) was measured at baseline. Medication use was ascertained by drug inventory at all annual clinic visits. Diabetes was defined at baseline as insulin or oral hypoglycemic agent (OHA) use eras having an FSG greater than or equal to 7.0 mmol/l (126 mg/dl), the current consensus definition of diabetes. RESULTS - A total of 387 (7%) original (FSG = 9.8 mmol/l [177 mg/dl]) and 115 (17%) new (FSG = 10.6 mmol/l [191 mg/dl]) cohort members had pharmacologically treated diabetes at baseline. Among those in the original and in the new cohorts who survived follow-up, respectively, OHA use decreased from 80 to 48% (P < 0.001) and from 67 to 50% (P < 0.003) and insulin use increased from 20 to 33% (P = 0.001) and from 33 to 37% (P = 0.603). There were 396 (8%) original (FSG = 8.8 mmol/l [159 mg/dl]) and 45 (7%) new (FSG = 10.0 mmol/l [181 mg/dl]) cohort members with diabetes untreated at baseline. Among them, respectively, OHA use reached 38 and 30% and insulin use reached 6 and 16% in 1996-1997. CONCLUSIONS - Diabetes was common in this elderly cohort, and >80% of treated patients with diabetes at baseline were not achieving fasting glucose goals of less than or equal to 6.7 mmol/l (120 mg/dl). Many untreated at baseline remained untreated after 7 years of follow-up. C1 Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98101 USA. Univ Washington, Dept Hlth Serv, Seattle, WA 98101 USA. Emory Univ, Sch Med, Div Endocrinol, Atlanta, GA USA. Univ Alabama, Dept Med, Birmingham, AL 35294 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Smith, NL (reprint author), Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Metropolitan Pk,East Tower,Suite 1360,1730 Minor, Seattle, WA 98101 USA. FU NHLBI NIH HHS [N01-HC-85080, N01-HC-85079, N01-HC-85081] NR 27 TC 20 Z9 21 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAY PY 1999 VL 22 IS 5 BP 736 EP 742 DI 10.2337/diacare.22.5.736 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 192WP UT WOS:000080102900014 PM 10332674 ER PT J AU Duncan, BB Schmidt, MI Offenbacher, S Wu, KK Savage, PJ Heiss, G AF Duncan, BB Schmidt, MI Offenbacher, S Wu, KK Savage, PJ Heiss, G CA ARIC Investigators TI Factor VIII and other hemostasis variables are related to incident diabetes in adults - The Atherosclerosis Risk in Communities (ARIC) study SO DIABETES CARE LA English DT Article; Proceedings Paper CT 58th Annual Meeting of the American-Diabetes-Association CY JUN 13-16, 1998 CL CHICAGO, ILLINOIS SP Amer Diabet Assoc ID TUMOR-NECROSIS-FACTOR; VON-WILLEBRAND-FACTOR; INDUCED INSULIN-RESISTANCE; FACTOR-ALPHA; CARDIOVASCULAR-DISEASE; SKELETAL-MUSCLE; GLUCOSE-UPTAKE; BLOOD-FLOW; IN-VIVO; ADIPOSE-TISSUE AB OBJECTIVE - Our objective was to evaluate whether selected hemostasis variables, some of which may reflect inflammation or endothelial dysfunction, are independently associated with the development of diabetes. RESEARCH DESIGN AND METHODS - We studied a biethnic cohort of 12,330 men and women, 45-64 years of age, of the Atherosclerosis Risk in Communities Study. New cases of diabetes were diagnosed by a reported physician diagnosis, hypoglycemic medication use, or a casual or fasting serum glucose level of greater than or equal to 11.1 or greater than or equal to 7 mmol/l, respectively. RESULTS - Over an average follow-up of 7 years, 1,335 new cases of diabetes were detected. The odds ratios (4th versus Ist quartile) of developing diabetes, adjusted by logistic regression for age, sex, race, study center, family history of diabetes, fasting glucose, physical activity and smoking, were 1.2 (95% CI 1.0-1.5) for fibrinogen and 1.4 (1.1-1.6) for factor VII. Associations for factor VIII, von Willebrand factor, and activated partial thromboplastin time were found to be 1.8 (1.3-2.3), 1.4 (1.1-1.8), and 0.63 (0.49-0.82), respectively in women. Although further adjustment for BMI and waist-to-hip ratio diminished the relationships, a highly statistically significant association (P = 0.001) remained for factor VIII (1.6 [1.2-2.1]) in women. CONCLUSIONS - Factor VIII and other hemostasis variables are associated with the development of diabetes in middle-aged adults. These findings support a role for inflammation and, particularly in women, endothelial dysfunction in the pathogenesis of type 2 diabetes. C1 Univ Fed Rio Grande Sul, Sch Med, Dept Social Med, BR-90035003 Porto Alegre, RS, Brazil. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. Univ N Carolina, Sch Dent, Dent Res Ctr, Chapel Hill, NC USA. Univ Texas, Sch Med, Div Hematol, Houston, TX USA. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. RP Duncan, BB (reprint author), Univ Fed Rio Grande Sul, Sch Med, Dept Social Med, R Ramiro Barcelos 2600-414, BR-90035003 Porto Alegre, RS, Brazil. RI Wu, Kenneth Kun-Yu/B-1070-2010 FU NHLBI NIH HHS [N01-HC-55015, N01-HC-55016, N01-HC-55018] NR 52 TC 72 Z9 75 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAY PY 1999 VL 22 IS 5 BP 767 EP 772 DI 10.2337/diacare.22.5.767 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 192WP UT WOS:000080102900019 PM 10332679 ER PT J AU Silver, K Walston, J Yang, YF Pratley, R Ravussin, E Raben, N Shuldiner, AR AF Silver, K Walston, J Yang, YF Pratley, R Ravussin, E Raben, N Shuldiner, AR TI Molecular scanning of the beta-3-adrenergic receptor gene in Pima Indians and Caucasians SO DIABETES-METABOLISM RESEARCH AND REVIEWS LA English DT Article DE beta-3-adrenergic receptor; insulin resistance; Type 2 diabetes mellitus; obesity; genetics ID DEPENDENT DIABETES-MELLITUS; BETA(3)-ADRENERGIC RECEPTOR; TRP64ARG MUTATION; INSULIN-RESISTANCE; JAPANESE SUBJECTS; ADIPOSE-TISSUE; OBESE SUBJECTS; MESSENGER-RNA; WEIGHT; POLYMORPHISM AB Background The beta-3-adrenergic receptor (beta 3AR) stimulates lipolysis and thermogenesis in adipocytes. The Trp64Arg beta 3AR variant is associated in some, but not all, studies with an earlier onset of Type 2 diabetes mellitus and features of the insulin resistance syndrome. Functional studies as to the role of the Trp64Arg variant have been inconclusive. Earlier studies screened the beta 3AR gene in only ten obese, diabetic Pima Indians. Potentially another yet to be identified polymorphism in the beta 3AR gene in linkage disequilibrium with the Trp64Arg polymorphism could explain the findings in the association and functional studies. Methods We scanned the beta 3AR gene in 20 diabetic Pima subjects and 20 Caucasian subjects using single stranded conformational polymorphism (SSCP) analysis. Variants were sequenced using dideoxy sequence analysis and further characterized using allele specific oligonucleotide hybridization (ASO) and RNA template specific-polymerase chain reaction (RS-PCR) assays. Results We found a guanine to thymidine substitution in the first intron, 14 bases from the splice donor site in both groups. In virtually all subjects, only two haplotypes were detected, Trp64/g1856 and Arg64/t1856, indicating that the g1856t polymorphism is in linkage disequilibrium with the Trp64Arg polymorphism. The g1856t substitution introduces a new consensus splice donor site which, if used, would encode a truncated protein. RNA levels of the two beta 3AR alleles were approximately equal in omental adipose tissue of heterozygotes. No aberrantly spliced beta 3AR mRNA was detected, indicating that the new consensus splice donor site is not used in vivo. Conclusion The g1856t polymorphism is in linkage disequilibrium with the Trp64Arg variant, but does not appear to have a functional role. Copyright (C) 1999 John Wiley & Sons, Ltd. C1 Univ Maryland, Sch Med, Div Diabet Obes & Nutr, Baltimore, MD 21201 USA. Baltimore Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Div Endocrinol & Metab, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Div Gerontol & Geriatr Med, Baltimore, MD USA. NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. NIAMSD, Arthritis & Rheumatism Branch, Bethesda, MD 20892 USA. RP Silver, K (reprint author), Univ Maryland, Sch Med, Div Diabet Obes & Nutr, 725 W Lombard St,Room S-415, Baltimore, MD 21201 USA. FU NCRR NIH HHS [3-M01-RR2719-11S3]; NIDDK NIH HHS [R01 DK49692, 1F32DK09340-01] NR 35 TC 3 Z9 3 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 1520-7552 J9 DIABETES-METAB RES JI Diabetes-Metab. Res. Rev. PD MAY-JUN PY 1999 VL 15 IS 3 BP 175 EP 180 DI 10.1002/(SICI)1520-7560(199905/06)15:3<175::AID-DMRR34>3.0.CO;2-Y PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 218WW UT WOS:000081576900002 PM 10441039 ER PT J AU Simsir, A Fetsch, P Stetler-Stevenson, M Abati, A AF Simsir, A Fetsch, P Stetler-Stevenson, M Abati, A TI Immunophenotypic analysis of non-Hodgkin's lymphomas in cytologic specimens: A correlative study of immunocytochemical and flow cytometric techniques SO DIAGNOSTIC CYTOPATHOLOGY LA English DT Article DE cytology; fine-needle aspiration; immunophenotype; flow cytometry; immunocytochemistry ID FINE-NEEDLE ASPIRATION; CELL LYMPHOMA; MALIGNANT-LYMPHOMA; DIAGNOSIS; CLASSIFICATION; EFFUSIONS AB Most Non-Hodgkin's lymphomas(NHL) can be accurately diagnosed and classified based on morphologic and immunophenotypic findings on cytologic specimens. Immunophenotyping can be accomplished via immunocytochemistry (IC) or flow cytometry (FC). We reviewed our experience with 98 cytology specimens (70 fine-needle aspirates [FNA] and 28 effusions) that were submitted for immunophenotyping utilizing both IC and FC between January 1992 and December 1997 for the diagnosis of NHL. Eighty-five percent of the cases were immunophenotyped by both techniques. Among these there were only two discrepancies between IC and FC, yielding a 98% correlation rate. Of the 98 cases, 11% could nor be immunophenotyped by FC and 4% could not be immunophenotyped by IC. The advantage of IC is the preservation of cytomorphology, which results in the requirement for a lower number of neoplastic cells and a limited, targeted panel of antibodies. This is especially useful in predominantly necrotic lymphomas in which only a few well-preserved neoplastic cells may he present, rendering the specimen inadequate for immunophenotyping by FC. The advantages of FC are in the detection of A small population of monoclonal cells in a background of reactive cells (particularly useful in effusion samples in which the predominant cell population is often reactive T lymphocytes), increased diagnostic precision through evaluation of objective parameters, and the use of multiple markers with dual labelling. We conclude that IC and FC are both excellent methods for immunophenotyping of cytology specimens and can be used interchangeably depending oil the institutional expertise and availability. Diagn. Cytopathol. 1999;20:278-284. Published 1999 Wiley-Liss, Inc. C1 NCI, Pathol Lab, Sect Cytopathol, NIH, Bethesda, MD 20892 USA. RP Abati, A (reprint author), NCI, Pathol Lab, Sect Cytopathol, NIH, 10 Ctr Dr,Bldg 10,Room 2A19, Bethesda, MD 20892 USA. NR 20 TC 35 Z9 37 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 8755-1039 J9 DIAGN CYTOPATHOL JI Diagn. Cytopathol. PD MAY PY 1999 VL 20 IS 5 BP 278 EP 284 DI 10.1002/(SICI)1097-0339(199905)20:5<278::AID-DC6>3.0.CO;2-W PG 7 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 190WJ UT WOS:000079988000006 PM 10319228 ER PT J AU Jacobson, KA Ijzerman, AP Linden, J AF Jacobson, KA Ijzerman, AP Linden, J TI 1,3-dialkylxanthine derivatives having high potency as antagonists at human A(2B) adenosine receptors SO DRUG DEVELOPMENT RESEARCH LA English DT Article DE G protein-coupled receptors; radioligand; alkylxanthines; structure-activity relationships; purines; cyclic AMP ID INTESTINAL EPITHELIA; MOLECULAR-CLONING; A(3) RECEPTOR; MAST-CELLS; RAT-BRAIN; AGONISTS; RELEASE; ANALOGS; ALKYLXANTHINES; DEGRANULATION AB The structure-activity relationships (SAR) of alkylxanthine derivatives as antagonists at the recombinant human adenosine receptors were explored in order to identify selective antagonists of A(2B) receptors. The effects of lengthening alkyl substituents from methyl to butyl at 1- and 3-positions and additional substitution at the 7- and 8-positions were probed. Ki values, determined in competition binding in membranes of HEK-293 cells expressing A(2B) receptors using I-125-ABOPX (T-125-3-(4-amino-3-iodobenzyl)-8-(phenyl -4-oxyacetate)-1-propylxanthine), were approximately 10 to 100 nM for 8-phenylxanthine functionalized congeners. Xanthines containing 8-aryl, 8-alkyl, and 8-cycloalkyl substituents, derivatives of XCC (8-[4-[[carboxy]methyl]oxylphenyl]-1,3-dipropylxanthine) and XAC (8-[4-[[[[(2-aminoethyl)amino]carbonyl]methyl]oxy]phenyl]-1,3-dipropylxanthine), containing various ester and amide groups, including L- and D-amino acid conjugates, were included. Enprofylline was 2-fold more potent than theophylline in A(2B) receptor binding, and the 2-thio modification was not tolerated. Among the most potent derivatives examined were XCC, its hydrazide and aminoethyl and fluoroethyl amide derivatives, XAC, N-hydroxyethy-XAC, and the L-citrulline and D-p-aminophenylalanine conjugates of XAC. An N-hydroxysuccinimide ester of XCC (XCC-NHS, MRS 1204) bound to A2B receptors with a Ki of 9.75 nM and was the most selective (at least 20-fold) in this series. In a functional assay of recombinant human A2B receptors, four of these potent xanthines were shown to fully antagonize the effects of NECA-induced stimulation of cyclic AMP accumulation. Published 1999 Wiley-Liss, Inc. C1 NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Leiden Amsterdam Ctr Drug Res, Div Med Chem, Leiden, Netherlands. Univ Virginia, Dept Internal Med & Mol Physiol & Biol Phys, Charlottesville, VA USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 44 TC 56 Z9 58 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 0272-4391 J9 DRUG DEVELOP RES JI Drug Dev. Res. PD MAY PY 1999 VL 47 IS 1 BP 45 EP 53 DI 10.1002/(SICI)1098-2299(199905)47:1<45::AID-DDR6>3.0.CO;2-U PG 9 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 208YB UT WOS:000081019100006 ER PT J AU Liang, L Zhou, T Jiang, J Pierce, JH Gustafson, TA Frank, SJ AF Liang, L Zhou, T Jiang, J Pierce, JH Gustafson, TA Frank, SJ TI Insulin receptor substrate-1 enhances growth hormone induced proliferations SO ENDOCRINOLOGY LA English DT Article ID JAK2 TYROSINE KINASE; PHOSPHOTYROSINE INTERACTION DOMAIN; PLECKSTRIN HOMOLOGY DOMAIN; ACTIVATED PROTEIN-KINASE; HEMATOPOIETIC-CELLS; SH2 DOMAINS; SIGNAL-TRANSDUCTION; CYTOPLASMIC DOMAIN; 3T3-L1 ADIPOCYTES; INTERFERON-GAMMA AB GH exerts a variety of metabolic and growth-promoting effects. GH induces activation of the GH receptor (GHR)-associated cytoplasmic tyrosine kinase, JAK2, resulting in tyrosine phosphorylation of the GHR and activation of STAT (signal transducer and activator of transcription), Ras-mitogen-activated protein kinase, and phosphoinositol 3-kinase signaling pathways, among others. GH-stimulated tyrosine phosphorylation of insulin receptor substrate (IRS) proteins has been demonstrated in vitro and in vivo. IRS-1 is a multiply phosphorylated cytoplasmic docking protein involved in metabolic and proliferative signaling by insulin, IL4, and other cytokines, but the physiological role of IRS-1 in GH signaling is unknown. In this study, as noted by others, we detected in murine 3T3-F442A preadipocytes GH-dependent tyrosine phosphorylation of IRS-1 and specific GH-induced coimmunoprecipitation with JAK2 of a tyrosine phosphoprotein consistent with IRS-1. We further examined this interaction by in vitro affinity precipitation experiments with glutathione-S-transferase fusion proteins incorporating regions of rat IRS-l and, as a source of JAK2, extracts of 3T3-F442A cells. Fusion proteins containing amino-terminal regions of IRS-I that include the pleckstrin homology, phosphotyrosine-binding, and Shc and IRS-1 NPXY-binding domains, but not those containing other IRS-1 regions or glutathione-S-transferase alone, bound JAK2 from cell extracts. Tyrosine-phosphorylated JAK2 resulting from GH stimulation was included in the amino-terminal IRS-1 fusion precipitates; however, neither tyrosine phosphorylation of JAK2 nor treatment of cells with GH before extraction was necessary for the specific JAK2-IRS-1 interaction to be detected. In contrast, in this assay, specific insulin receptor association with the IRS-1 phosphotyrosine-binding, and Shc and IRS-I NPXY-binding domains was insulin and phosphotyrosine dependent, as previously shown. To test for significance of IRS-1 with regard to GH signaling, IRS- and GHR-deficient 32D cells were stably reconstituted with the rabbit (r) GHR, either alone (32D-rGHR) or with IRS-1 (32D-rGHR-IRS-1). As assayed by three independent methods. GH induced proliferation in 32D-rGHR cells, even in the absence of transfected IRS-I. Notably, however, GH-induced proliferation was markedly enhanced in cells expressing IRS-I. Similarly, GH-induced mitogen-activated protein kinase activation was significantly augmented in IRS-l-expressing cells relative to that in cells harboring no IRS-1. These results indicate that IRS-1 enhances GH-induced proliferative signaling. C1 Univ Alabama Birmingham, Dev Res & Endocrinol Branch, Univ Alabama Stn, Dept Med,Div Endocrinol & Metab, Birmingham, AL 35294 USA. Univ Alabama Birmingham, Dept Med, Div Rheumatol, Birmingham, AL 35294 USA. Univ Alabama Birmingham, Dept Cell Biol, Birmingham, AL 35294 USA. Vet Affairs Med Ctr, Birmingham, AL 35294 USA. NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Metabolex Inc, Hayward, CA 94545 USA. RP Frank, SJ (reprint author), Univ Alabama Birmingham, Dev Res & Endocrinol Branch, Univ Alabama Stn, Dept Med,Div Endocrinol & Metab, Room 756, Birmingham, AL 35294 USA. EM frank@endo.dom.uab.edu FU NIDDK NIH HHS [DK46395] NR 71 TC 38 Z9 38 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD MAY PY 1999 VL 140 IS 5 BP 1972 EP 1983 DI 10.1210/en.140.5.1972 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 187RP UT WOS:000079801200003 PM 10218944 ER PT J AU Jayadev, S Smith, RD Jagadeesh, G Baukal, AJ Hunyady, L Catt, KJ AF Jayadev, S Smith, RD Jagadeesh, G Baukal, AJ Hunyady, L Catt, KJ TI N-linked glycosylation is required for optimal AT(1a) angotensin receptor expression in COS-7 cells SO ENDOCRINOLOGY LA English DT Article ID SITE-DIRECTED MUTAGENESIS; AGONIST-INDUCED PHOSPHORYLATION; ADRENAL GLOMERULOSA CELLS; ANGIOTENSIN-II RECEPTOR; LIGAND-BINDING; HORMONE RECEPTOR; OLIGOSACCHARIDES; IDENTIFICATION; MEMBRANE; RESIDUES AB The nature and role of glycosylation in AT, angiotensin receptor (AT(1)-R) function were investigated by expressing glycosylation-deficient influenza hemagglutinin (HA) epitope-tagged rat AT(1a)-Rs (HA-AT(1a)-Rs) in COS-7 cells. All three asparagine residues (Asn(4), Asn(176) Asn(188)) contained within consensus sites for N-linked glycosylation could be glycosylated in Cos-7 cells and appeared to be glycosylated on the endogenous AT(1)-R in bovine adrenal glomerulosa cells. Heterogeneity of glycosylation at each site accounted for the broad migration pattern of the AT(1)-R in SDS-PAGE. Mutation at each glycosylation site, either alone or in combination, had little effect on Ligand binding parameters (although the N4K mutant had higher affinity) or signaling activity. However, an increasing number of mutated glycosylation sites was associated with decreasing cell surface receptor expression, which was minimal for the unglycosylated N4K/N176Q/N188Q receptor. Decreased surface expression of mutant HA-AT(1a)-Rs was correlated with decreased total cell receptor content as revealed by immunoblotting with an anti-HA antibody. These findings suggest that glycosylation enhances receptor stability, possibly by protecting nascent receptors from proteolytic degradation. C1 NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. US FDA, CDER, Div Cardiorenal Prod, Rockville, MD 20857 USA. Semmelweis Univ, Dept Physiol, H-1088 Budapest, Hungary. RP Catt, KJ (reprint author), NICHHD, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Room 6A-36,49 Convent Dr, Bethesda, MD 20892 USA. EM catt@helix.nih.gov RI Jagadeesh, Gowraganahalli/G-6408-2010 NR 28 TC 37 Z9 37 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD MAY PY 1999 VL 140 IS 5 BP 2010 EP 2017 DI 10.1210/en.140.5.2010 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 187RP UT WOS:000079801200008 PM 10218949 ER PT J AU DeVito, M Biegel, L Brouwer, A Brown, S Brucker-Davis, F Cheek, AO Christensen, R Colborn, T Cooke, P Crissman, J Crofton, K Doerge, D Gray, E Hauser, P Hurley, P Kohn, M Lazar, J McMaster, S McClain, M McConnell, E Meier, C Miller, R Tietge, J Tyl, R AF DeVito, M Biegel, L Brouwer, A Brown, S Brucker-Davis, F Cheek, AO Christensen, R Colborn, T Cooke, P Crissman, J Crofton, K Doerge, D Gray, E Hauser, P Hurley, P Kohn, M Lazar, J McMaster, S McClain, M McConnell, E Meier, C Miller, R Tietge, J Tyl, R TI Screening methods for thyroid hormone disruptors SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review DE developmental toxicity; endocrine disruptors; neurobehavioral toxicity; screens; thyroid hormone; thyroid hormone receptors ID RETINOID-X-RECEPTOR; SPERM PRODUCTION; POLYCHLORINATED-BIPHENYLS; NEONATAL-HYPOTHYROIDISM; BRAIN-DEVELOPMENT; RISK ASSESSMENT; HEPATIC NUCLEI; RAT FETUS; THYROXINE; BINDING AB The U.S. Congress has passed legislation requiring the EPA to implement screening tests for identifying endocrine-disrupting chemicals. A series of workshops was sponsored by the EPA, the Chemical Manufacturers Association, and the World Wildlife Fund; one workshop focused on screens for chemicals that alter thyroid hormone function and homeostasis. participants at this meeting identified and examined methods to detect alterations in thyroid hormone synthesis, transport, and catabolism. In addition, some methods to detect chemicals that bind to the thyroid hormone receptors acting as either agonists or antagonists were also identified. Screening methods used in mammals as well as other vertebrate classes were examined. There was a general consensus that all known chemicals which interfere with thyroid hormone function and homeostasis act by either inhibiting synthesis, altering serum transport proteins, or by increasing catabolism of thyroid hormones. There are no direct data to support the assertion that certain environmental chemicals bind and activate the thyroid hormone receptors; further research is indicated. In light of this, screening methods should reflect known mechanisms of action. Most methods examined, albeit useful for mechanistic studies, were thought to be too specific and therefore would not be applicable for broad-based screening. Determination of serum thyroid hormone concentrations following chemical exposure in rodents was thought to be a reasonable initial screen. Concurrent histologic evaluation of the thyroid would strengthen this screen. Similar methods in teleosts may be useful as screens, but would require indicators of tissue production of thyroid hormones. The use of tadpole metamorphosis as a screen may also be useful; however, this method requires validation and standardization prior to use as a broad-based screen. C1 US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. Haskell Lab Ind Med, Newark, DE 19714 USA. Wageningen Univ Agr, Dept Toxicol, Wageningen, Netherlands. Natl Water Res Inst, Burlington, ON, Canada. World Wildlife Fund, Washington, DC 20037 USA. Tulane Univ, Med Ctr, Ctr Bioenvironm Res, New Orleans, LA 70112 USA. Bayer Corp, Agr Div Toxicol, Stillwell, KS 66085 USA. Univ Illinois, Coll Vet Med, Urbana, IL 61801 USA. Dow Chem Co, Midland, MI 48674 USA. Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. Vet Adm Med Ctr, Psychiat Serv, Baltimore, MD 21218 USA. US EPA, Off Pesticide Prevent & Tox Res, Washington, DC 20460 USA. Hoffmann La Roche Inc, Preclin Dev Adm, Nutley, NJ 07110 USA. Hoffmann La Roche Inc, Preclin Dev Adm, Raleigh, NC 27613 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Genet, Boston, MA 02115 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP DeVito, M (reprint author), US EPA, Natl Hlth & Environm Effects Res Lab, MD-74, Res Triangle Pk, NC 27711 USA. RI Crofton, Kevin/J-4798-2015; OI Crofton, Kevin/0000-0003-1749-9971; gray jr, leon earl/0000-0002-1111-4754 NR 107 TC 125 Z9 131 U1 0 U2 11 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD MAY PY 1999 VL 107 IS 5 BP 407 EP 415 DI 10.2307/3434545 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 195BF UT WOS:000080228700025 PM 10210697 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 EPIDEMIOLOGY LA English DT Article DE menstrual cycles; menarche; gravidity; parity; spontaneous abortion; ischemic heart disease; myocardial infarction ID MYOCARDIAL-INFARCTION; FOLLOW-UP; WOMEN; HISTORY; AGE; ASSOCIATION; MENOPAUSE AB The role of hormones in ischemic heart disease is of considerable interest, but limited data are available pertaining to risk factors associated with endogenous hormones. We examined the association between menstrual and reproductive factors and ischemic heart disease in a cohort of 867 white, college-educated women who prospectively recorded menstrual cycle data for at least 5 years from their early 20s through their menopause. Ischemic heart disease history was obtained from a self-administered (N = 714) or proxy-administered (N = 153) questionnaire completed at a mean age of 73 years. The analysis included 44,899 person-years of follow-up and 45 cases of myocardial infarction, angioplasty, heart bypass surgery, or ischemic heart disease-related mortality. Ischemic heart disease risk decreased with increasing age at menarche (age-adjusted RR 0.76 per year, 95% CI = 0.60-0.95). Considering menstrual cycle characteristics ages 28-32, there was little overall association with length, variability, or bleeding duration. Ischemic heart disease risk increased with later age at first birth (age adjusted RR 2.90 for ages 33-43 compared with 25-29) and later age at last birth (age adjusted RR 3.79 for ages greater than or equal to 40 compared with 35-39), but there was little association with high parity. C1 NIEHS, Epidemiol Branch A3 05, Res Triangle Pk, NC 27709 USA. GlaxoWellcome, Worldwide Epidemiol Dept, Res Triangle Pk, NC USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Cooper, GS (reprint author), NIEHS, Epidemiol Branch A3 05, POB 12233, Res Triangle Pk, NC 27709 USA. OI Baird, Donna/0000-0002-5544-2653; Sandler, Dale/0000-0002-6776-0018 FU NCRR NIH HHS [M01-RR00064] NR 22 TC 58 Z9 59 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD MAY PY 1999 VL 10 IS 3 BP 255 EP 259 DI 10.1097/00001648-199905000-00011 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 189EM UT WOS:000079891400011 PM 10230834 ER PT J AU Hoppin, JA Tolbert, PE Flanders, WD Zhang, RH Daniels, DS Ragsdale, BD Brann, EA AF Hoppin, JA Tolbert, PE Flanders, WD Zhang, RH Daniels, DS Ragsdale, BD Brann, EA TI Occupational risk factors for sarcoma subtypes SO EPIDEMIOLOGY LA English DT Article DE soft tissue sarcoma; skeletal sarcoma; occupational exposures; herbicides; chlorophenol; woodworking ID SOFT-TISSUE SARCOMA; OIL REFINERY WORKERS; MORTALITY FOLLOW-UP; CANCER MORTALITY; CHLOROPHENOL EXPOSURE; COHORT; 2,3,7,8-TETRACHLORODIBENZO-PARA-DIOXIN; HERBICIDES; INDUSTRY; UNION AB Herbicides, chlorophenols, and other occupational exposures are suspected risk factors for soft-tissue sarcoma, but the epidemiologic evidence is inconsistent. Given that soft tissue sarcomas represent a heterogeneous mix of cancer subtypes and that these subtypes have different disease patterns by race, sex, and age at diagnosis, studying all soft tissue sarcomas combined may mask subtype-specific associations. Using the Selected Cancers Study, a large population-based case-control study of sarcoma conducted among U.S. men aged 30 to 60 in 1984 to 1988, we explored the occupational risk factors for soft-tissue sarcoma subtypes and skeletal sarcoma. The analysis included 251 living sarcoma cases (48 dermatofibrosarcoma protuberans, 32 malignant fibrohistiocytic sarcoma, 67 leiomyosarcoma, 53 liposarcoma, and 51 skeletal sarcoma) and 1908 living controls. Exact conditional logistic regression models suggested patterns of subtype specificity for occupational exposures. Self-reported herbicide use was associated with malignant fibrohistiocytic sarcoma (OR = 2.9, 95% CI = 1.1-7.3). We found elevated risks for chlorophenol exposure and cutting oil exposure and malignant fibrohistiocytic sarcoma and leiomyosarcoma. We found no occupational risk factor for liposarcoma. Polytomous regression models identified different odds ratios across subtypes for plywood exposure and exposure to wood and saw dust. Although exploratory, this analysis suggests that occupational risk factors for sarcoma are not uniform across subtypes. C1 Emory Univ, Rollins Sch Publ Hlth, Dept Environm & Occupat Hlth, Atlanta, GA 30322 USA. Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. Emory Univ, Rollins Sch Publ Hlth, Dept Biostat, Atlanta, GA 30322 USA. Arizona State Univ, Dept Anthropol, Tempe, AZ 85287 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. RP Hoppin, JA (reprint author), NIEHS, Epidemiol Branch, MDA3-05,POB 12233, Res Triangle Pk, NC 27709 USA. RI Tolbert, Paige/A-5676-2015 FU NCI NIH HHS [1R29CA63622-01A1] NR 34 TC 23 Z9 23 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD MAY PY 1999 VL 10 IS 3 BP 300 EP 306 DI 10.1097/00001648-199905000-00019 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 189EM UT WOS:000079891400019 PM 10230842 ER PT J AU Kulldorff, H Graubard, B Velie, E AF Kulldorff, H Graubard, B Velie, E TI The P-value and P-value function SO EPIDEMIOLOGY LA English DT Letter C1 Univ Connecticut, Sch Med, Dept Community Med & Hlth Care, Div Biostat, Farmington, CT 06030 USA. NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Kulldorff, H (reprint author), Univ Connecticut, Sch Med, Dept Community Med & Hlth Care, Div Biostat, MC 6205,263 Farmington Ave, Farmington, CT 06030 USA. NR 2 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD MAY PY 1999 VL 10 IS 3 BP 345 EP 346 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 189EM UT WOS:000079891400027 ER PT J AU Hoover, DM Schalk-Hihi, C Chou, CC Menon, S Wlodawer, A Zdanov, A AF Hoover, DM Schalk-Hihi, C Chou, CC Menon, S Wlodawer, A Zdanov, A TI Purification of receptor complexes of interleukin-10 - Stoichiometry and the importance of deglycosylation in their crystallization SO EUROPEAN JOURNAL OF BIOCHEMISTRY LA English DT Article DE interleukin-10; cytokines; structure; crystallization; glycosylation ID HIGH-AFFINITY RECEPTOR; IFN-GAMMA RECEPTOR; CRYSTAL-STRUCTURE; INTERFERON-GAMMA; EXTRACELLULAR DOMAIN; ANGSTROM RESOLUTION; IL-10 RECEPTOR; EXPRESSION; HOMOLOGY; BINDING AB Interleukin-10 (IL-10) is a pleiotropic immunosuppressive cytokine that has a wide range of effects in controlling inflammatory responses. Viral IL-10 (vIL-10) is a homologue of human IL-IO (hIL-10) produced by Epstein-Barr virus (EBV). Both hIL-10 and vIL-10 bind to the soluble extracellular fragment of the cytokine receptor IL-10R1 (shIL-10R1). The stoichiometry of the vIL-10: shIL-10R1 complex has been found to be the same as hIL-10 : shIL-10R1, with two vIL-10 dimers binding to four shIL-10R1 monomers. Complexes of both hIL-10 and vIL-10 with glycosylated shIL-10R1 could not be crystallized. Controlled deglycosylation using peptide: N-glycosidase F and endo-beta-N-acetylglucosaminidase F-3 resulted in the formation of crystals of both hIL-10 : shIL-10R1 and vIL-10 : shIL-10R1 complexes, indicating that the difficulty in the crystal formation was largely due to the presence of complex carbohydrate side chains. The availability of the structure of the ligand-receptor complexes should facilitate our understanding of the basis of the interaction between IL-10 and the IL-10 receptor. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Macromol Struct Lab, Frederick, MD 21702 USA. Schering Plough Res Inst, Kenilworth, NJ USA. DNAX Res Inst Mol & Cellular Biol Inc, Dept Mol Biol, Palo Alto, CA 94304 USA. RP Zdanov, A (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Macromol Struct Lab, Frederick, MD 21702 USA. NR 28 TC 11 Z9 11 U1 0 U2 5 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0014-2956 J9 EUR J BIOCHEM JI Eur. J. Biochem. PD MAY PY 1999 VL 262 IS 1 BP 134 EP 141 DI 10.1046/j.1432-1327.1999.00363.x PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 201GX UT WOS:000080588000018 PM 10231374 ER PT J AU Li, BS Veeranna Gu, JG Grant, P Pant, HC AF Li, BS Veeranna Gu, JG Grant, P Pant, HC TI Activation of mitogen-activated protein kinases (Erk1 and Erk2) cascade results in phosphorylation of NF-M tail domains in transfected NIH 3T3 cells SO EUROPEAN JOURNAL OF BIOCHEMISTRY LA English DT Article DE protein kinase; neurofilament; phosphorylation ID AMYOTROPHIC LATERAL SCLEROSIS; HEAVY NEUROFILAMENT SUBUNIT; CYCLIN-DEPENDENT KINASE-5; EPIDERMAL GROWTH-FACTOR; SIGNAL-REGULATED KINASE; MAP KINASE; NERVOUS-SYSTEM; CELLULAR PHOSPHORYLATION; MAMMALIAN NEUROFILAMENTS; ALZHEIMERS-DISEASE AB Neurofilaments (NFs) are neuron-specific intermediate filaments, and are the major cytoskeletal component in large myelinated axons. Lysine-serine-proline (KSP) repeats in the tail domains of high molecular weight NF proteins (NF-M and NF-H) are extensively phosphorylated in vivo in the axon. This phosphorylation in the tail domain has been postulated to play an important role in mediating neuron-specific properties, including axonal caliber and conduction velocity. Recent studies have shown that the mitogen-activated protein kinases (extracellular signal-regulated kinases, Erk1 and Erk2) phosphorylate KSP motifs in peptide substrates derived from the NF-M and NF-H tail domains in vitro. However, it is not clear whether activation of the mitogen activated protein (MAP) kinase pathway is able to phosphorylate these domains in vivo. To answer this question, a constitutively active form of mitogen-activated Erk activating kinase (MEK1) was cotransfected with an NF-M expression construct into NIH 3T3 cells. The activated mutant, but not the dominant negative mutant, induced phosphorylation of NF-M. In addition, it was shown that epidermal growth factor, which induces the MAP kinase cascade in NIH 3T3 cells, also activated endogenous Erk1 and Erk2 and NF-M tail domain phosphorylation in the transfected cells. These results present direct evidence that in-vivo activation of Erk1 and Erk2 is sufficient for NF-M tail domain phosphorylation in transfected cells. C1 NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. NIDR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. RP Pant, HC (reprint author), NINDS, Neurochem Lab, NIH, Bldg 36,Rm 4D20,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 66 TC 53 Z9 54 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0014-2956 J9 EUR J BIOCHEM JI Eur. J. Biochem. PD MAY PY 1999 VL 262 IS 1 BP 211 EP 217 DI 10.1046/j.1432-1327.1999.00372.x PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 201GX UT WOS:000080588000027 PM 10231383 ER PT J AU Stone, DL van Diggelen, OP de Klerk, JBC Gaillard, JLJ Niermeijer, MF Willemsen, R Tayebi, N Sidransky, E AF Stone, DL van Diggelen, OP de Klerk, JBC Gaillard, JLJ Niermeijer, MF Willemsen, R Tayebi, N Sidransky, E TI Is the perinatal lethal form of Gaucher disease more common than classic type 2 Gaucher disease? SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE Gaucher disease; lysosomal storage disorder; hydrops fetalis; collodion baby; mutation analysis ID GLUCOCEREBROSIDASE GENE; TARGETED DISRUPTION; MOUSE MODEL; MUTATION AB In recent years there has been increased recognition of a severe perinatal lethal form of Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase. We previously reported a case of severe type 2 Gaucher disease which was seen in a medical center in Rotterdam and now present three new cases fi om two other families seen at the same center. Mutational analyses of these cases revealed two novel mutations, H311R and V398F, located in exons 8 and 9, respectively. The identification of four cases of lethal type 2 Gaucher disease in a single center seems to be a function of increased awareness of this phenotype, rather than of geographic clustering. The actual incidence of lethal type 2 Gaucher disease may be underestimated, as many cases may have been misclassified as collodion babies or hydrops of unknown cause. C1 NIMH, Clin Neurosci Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Erasmus Univ, Univ Hosp, Dept Clin Genet, Rotterdam, Netherlands. Erasmus Univ, Univ Hosp, Dept Pediat, Rotterdam, Netherlands. St Clara Hosp, Dept Clin Pathol, Rotterdam, Netherlands. RP Sidransky, E (reprint author), NIMH, Clin Neurosci Branch, Intramural Res Program, NIH, Bldg 49,Room B1EE16,49 Convent Dr MSC 4405, Bethesda, MD 20892 USA. NR 14 TC 28 Z9 31 U1 0 U2 1 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1018-4813 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD MAY-JUN PY 1999 VL 7 IS 4 BP 505 EP 509 DI 10.1038/sj.ejhg.5200315 PG 5 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 204QL UT WOS:000080775600014 PM 10352942 ER PT J AU Inoue, J Cui, YS Rodriguez, L Chen, Z Kador, PF AF Inoue, J Cui, YS Rodriguez, L Chen, Z Kador, PF TI Synthesis and aldose reductase inhibitory activities of novel dibenzocycloheptenone derivatives SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE dibenzocycloheptenone; aldose reductase inhibitor; diabetic complications ID DIABETIC COMPLICATIONS; ESCHERICHIA-COLI; PURIFICATION AB A number of dibenzocycloheptenone derivatives, a novel series of aldose reductase inhibitors, were synthesized and evaluated in vitro for their ability to inhibit rat lens aldose reductase enzyme. The design of these ARIs was based on previously published pharmacophore requirements. The most active compound in this series was a spirosuccinimide derivative, spiro{2,8-dihydroxy-5H-dibenzo[a, d]cycloheptene-5,3'-pyrrolidine}-2',5'-dione 11, having an IC50 of 3.0 mu M (C) Elsevier, Paris. C1 Senju Pharmaceut Co Ltd, Kobe Creat Ctr, Chem Lab, Nishi Ku, Kobe, Hyogo 6512241, Japan. NEI, Lab Ocular Therapeut, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. RP Cui, YS (reprint author), Senju Pharmaceut Co Ltd, Kobe Creat Ctr, Chem Lab, Nishi Ku, 1-5-4 Murotani, Kobe, Hyogo 6512241, Japan. NR 17 TC 6 Z9 6 U1 0 U2 0 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS CEDEX 15 PA 23 RUE LINOIS, 75724 PARIS CEDEX 15, FRANCE SN 0223-5234 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD MAY PY 1999 VL 34 IS 5 BP 399 EP 404 DI 10.1016/S0223-5234(99)80089-0 PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 234MN UT WOS:000082488600004 ER PT J AU Ebert, AD Hopp, HSG Entezami, M Runkel, S Weitzel, HK AF Ebert, AD Hopp, HSG Entezami, M Runkel, S Weitzel, HK TI Acute onset of blindness during labor: report of a case of transient cortical blindness in association with HELLP syndrome SO EUROPEAN JOURNAL OF OBSTETRICS GYNECOLOGY AND REPRODUCTIVE BIOLOGY LA English DT Article DE cortical blindness; labour; HELLP syndrome ID PRE-ECLAMPSIA; PREECLAMPSIA AB The coincidence of HELLP syndrome and cortical blindness is an uncommon but very dramatic event, for the patient as well as the obstetrician. This report describes the first case of HELLP-syndrome-associated cortical blindness occuring suddenly in the third stage of labour. There were only modest correlates of cortical blindness in cerebral CT, MRI and angiography findings, but no signs of a posterior leucoencephalopathy syndrome. Mother and baby were discharged from hospital to outpatient care in good health on the 12th day. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 Free Univ Berlin, Med Ctr Benjamin Franklin, Dept Obstet & Gynecol, Div Obstet, D-1000 Berlin, Germany. Free Univ Berlin, Med Ctr Benjamin Franklin, Dept Obstet & Gynecol, Div Ultrasound, D-1000 Berlin, Germany. RP Ebert, AD (reprint author), NIH, Bldg 10,Room 5B39,10 Ctr Dr MSC 1750, Bethesda, MD 20892 USA. NR 12 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0301-2115 J9 EUR J OBSTET GYN R B JI Eur. J. Obstet. Gynecol. Reprod. Biol. PD MAY PY 1999 VL 84 IS 1 BP 111 EP 113 DI 10.1016/S0301-2115(98)00300-5 PG 3 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 204KF UT WOS:000080762900024 PM 10413240 ER PT J AU Callicott, JH Weinberger, DR AF Callicott, JH Weinberger, DR TI Neuropsychiatric dynamics: the study of mental illness using functional magnetic resonance imaging SO EUROPEAN JOURNAL OF RADIOLOGY LA English DT Review DE fMRI; functional magnetic resonance imaging; neuroimaging; psychiatric dynamics ID CEREBRAL BLOOD-FLOW; CHRONIC-SCHIZOPHRENIC PATIENTS; DORSOLATERAL PREFRONTAL CORTEX; POSITRON-EMISSION TOMOGRAPHY; WORKING-MEMORY TASK; HUMAN BRAIN ACTIVITY; VERBAL FLUENCY TASK; STIMULUS RATE; AUDITORY HALLUCINATIONS; SENSORY STIMULATION AB Functional magnetic resonance imaging (fMRI) is poised to make significant contributions to the study of neuropsychiatric illnesses. Whatever neural pathology attends such illnesses has proven subtle at best. By identifying predictable, regionally specific deficits in brain function, fMRI can suggest brain regions for detailed cellular analyses, provide valuable in vivo data regarding effective connectivity, provide a means to model the effects of various drug challenge paradigms, and characterize intermediate phenotypes in the search for the genes underlying mental illness. Nonetheless, as promising as fMRI appears to be in terms of its relative safety, repeatability, ability to generate individual brain maps and widespread availability, it is still subject to a number of unresolved conceptual conundrums inherited from earlier neuroimaging work. For example, functional neuroimaging has not generated any pathognomic findings in mental illness, has not established a clear link between neurophysiology and observable behavior, and has not resolved the potential confounds of medication. In this article, we will review the relevant historical background preceding fMRI, address methodological considerations in fMRI, and summarize recent fMRI findings in psychiatry. Finally, fMRI is being used to simplify the complex genetics of neuropsychiatric illness by generating quantitative and qualitative brain phenotypes. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 NIMH, Intramural Res Program, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Callicott, JH (reprint author), NIMH, Intramural Res Program, Clin Brain Disorders Branch, NIH, 10 Ctr Dr,Rm 4s237B, Bethesda, MD 20892 USA. OI Callicott, Joseph/0000-0003-1298-3334 NR 103 TC 22 Z9 24 U1 4 U2 7 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0720-048X J9 EUR J RADIOL JI Eur. J. Radiol. PD MAY PY 1999 VL 30 IS 2 BP 95 EP 104 DI 10.1016/S0720-048X(99)00048-0 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 208YY UT WOS:000081021100003 PM 10401590 ER PT J AU Mattay, VS Weinberger, DR AF Mattay, VS Weinberger, DR TI Organization of the human motor system as studied by functional magnetic resonance imaging SO EUROPEAN JOURNAL OF RADIOLOGY LA English DT Article DE BOLD fMRI; functional MRI; motor abnormalities; neuroimaging ID POSITRON EMISSION TOMOGRAPHY; CEREBRAL BLOOD-FLOW; REGIONAL BRAIN ACTIVITY; CORTICAL AREAS; BASAL GANGLIA; SENSORIMOTOR CORTEX; PARKINSONS-DISEASE; FINGER MOVEMENTS; SENSORY STIMULATION; VOLUNTARY MOVEMENTS AB Blood oxygenation level dependent functional magnetic resonance imaging (BOLD fMRI), because of its superior resolution and unlimited repeatability, can be particularly useful in studying functional aspects of the human motor system, especially plasticity, and somatotopic and temporal organization. In this survey, while describing studies that have reliably used BOLD fMRI to examine these aspects of the motor system, we also discuss studies that investigate the neural substrates underlying motor skill acquisition, motor imagery, production of motor sequences; effect of rate and force of movement on brain activation and hemispheric control of motor function. In the clinical realm, in addition to the presurgical evaluation of neurosurgical patients, BOLD fMRI has been used to explore the mechanisms underlying motor abnormalities in patients with neuropsychiatric disorders and the mechanisms underlying reorganization or plasticity of the motor system following a cerebral insult. (C) 1999 Published by Elsevier Science Ireland Ltd. All rights reserved. C1 NIMH, Intramural Res Program, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Mattay, VS (reprint author), NIMH, Intramural Res Program, Clin Brain Disorders Branch, NIH, 10 Ctr Dr,Room 3C-101, Bethesda, MD 20892 USA. NR 99 TC 39 Z9 42 U1 2 U2 5 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0720-048X J9 EUR J RADIOL JI Eur. J. Radiol. PD MAY PY 1999 VL 30 IS 2 BP 105 EP 114 DI 10.1016/S0720-048X(99)00049-2 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 208YY UT WOS:000081021100004 PM 10401591 ER PT J AU Bertolino, A Weinberger, DR AF Bertolino, A Weinberger, DR TI Proton magnetic resonance spectroscopy in schizophrenia SO EUROPEAN JOURNAL OF RADIOLOGY LA English DT Article DE magnetic resonance spectroscopy; schizophrenia; spectral localization ID N-ACETYL ASPARTATE; IN-VIVO; CHEMICAL PATHOLOGY; PREFRONTAL CORTEX; FRONTAL LOBES; BASAL GANGLIA; H-1 MRS; ACETYLASPARTATE; BRAIN; DYSFUNCTION AB Proton magnetic resonance spectroscopy (MRS) has become an important tool to study in vivo certain biochemical aspects of brain disorders. In the last decade this technique has been applied to the in vivo investigation of pathophysiological aspects of psychiatric disorders, extending knowledge of the related brain alterations. This review will focus on providing some background to clarify technical and biochemical issues and it will describe the studies that have been performed in schizophrenia. The results will be framed in a more general context to highlight what we have learned and what remains to be understood from the application of this technique to schizophrenia. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 NIMH, Intramural Res Program, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Weinberger, DR (reprint author), NIMH, Intramural Res Program, Clin Brain Disorders Branch, NIH, 10 Ctr Dr Room 4S235 MSC 1379, Bethesda, MD 20892 USA. NR 55 TC 35 Z9 37 U1 3 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0720-048X J9 EUR J RADIOL JI Eur. J. Radiol. PD MAY PY 1999 VL 30 IS 2 BP 132 EP 141 DI 10.1016/S0720-048X(99)00052-2 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 208YY UT WOS:000081021100007 PM 10401594 ER PT J AU Kelloff, GJ Lieberman, R Steele, VE Boone, CW Lubet, RA Kopelovitch, L Malone, WA Crowell, JA Sigman, CC AF Kelloff, GJ Lieberman, R Steele, VE Boone, CW Lubet, RA Kopelovitch, L Malone, WA Crowell, JA Sigman, CC TI Chemoprevention of prostate cancer: Concepts and strategies SO EUROPEAN UROLOGY LA English DT Article; Proceedings Paper CT Symposium on Strategies for the Chemoprevention of Prostate Cancer CY OCT 29-31, 1998 CL BRUSSELS, BELGIUM DE prostate; chemoprevention; drug development ID INTRAEPITHELIAL NEOPLASIA; SELENIUM SUPPLEMENTATION; PREVENTION TRIAL; CLINICAL-TRIALS; CARCINOMA; LESIONS; HEAD; NECK AB Chemoprevention is the administration of agents to prevent induction and inhibit or delay progression of cancers. for prostate, as for other cancer targets, successful chemopreventive strategies require well-characterized agents, suitable cohorts, and reliable intermediate biomarkers of cancer for evaluating chemopreventive efficacy. Agent requirements are experimental or epidemiological data showing chemopreventive efficacy, safety on chronic administration, and a mechanistic rationale for the observed chemopreventive activity. On this basis, promising chemopreventive drugs in prostate include retinoids, antiandrogens, antiestrogens, steroid aromatase inhibitors, 5 alpha-reductase inhibitors, vitamins D and E, selenium, lycopene, and 2-difluoromethylornithine. Phase II trials are critical for evaluating chemopreventive efficacy. Cohorts in these trials should be suitable for measuring the chemopreventive activity of the agent and the intermediate biomarkers chosen as endpoints. Many cohorts proposed for phase II trials are patients with previous cancers or premalignant lesions. For such patients, trials should be conducted within the context of standard treatment. Two cohorts currently used in phase II prostate cancer chemoprevention trials are patients with PIN and patients scheduled for prostate cancer surgery. Biomarkers should fit expected biological mechanisms, be assayed reliably and quantitatively, measured easily, and correlate to decreased cancer incidence. Protocols for adequately sampling tissue are essential. Changes in PIN provide prostate biomarkers with the ability to be quantified and a high correlation to cancer. PIN measurements include nuclear polymorphism, nucleolar size and number of nucleoli/nuclei, and DNA ploidy. Other potentially useful biomarkers are associated with cellular proliferation kinetics (e.g. PCNA and apoptosis), differentiation (e.g. blood group antigens, vimentin), genetic damage (e.g. LOH on chromosome 8), signal transduction (e.g. TGF alpha, TGF beta, IGF-I, c-erbB-2 expression), angiogenesis, and biochemical changes (e.g. PSA levels). C1 NCI, Chemoprevent Branch, US Dept HHS,Div Canc Prevent, NIH, Bethesda, MD 20892 USA. CCS Associates, Mt View, CA USA. RP Kelloff, GJ (reprint author), NCI, Chemoprevent Branch, US Dept HHS,Div Canc Prevent, NIH, Bethesda, MD 20892 USA. NR 38 TC 85 Z9 86 U1 0 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0302-2838 J9 EUR UROL JI Eur. Urol. PD MAY-JUN PY 1999 VL 35 IS 5-6 BP 342 EP 350 DI 10.1159/000019906 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 198BA UT WOS:000080400800002 PM 10325487 ER PT J AU Urban, D Myers, R Manne, U Weiss, H Mohler, J Perkins, D Markiewicz, M Lieberman, R Kelloff, G Marshall, M Grizzle, W AF Urban, D Myers, R Manne, U Weiss, H Mohler, J Perkins, D Markiewicz, M Lieberman, R Kelloff, G Marshall, M Grizzle, W TI Evaluation of biomarker modulation by fenretinide in prostate cancer patients SO EUROPEAN UROLOGY LA English DT Article; Proceedings Paper CT Symposium on Strategies for the Chemoprevention of Prostate Cancer CY OCT 29-31, 1998 CL BRUSSELS, BELGIUM DE prostate cancer; chemoprevention; (4-hydroxyphenyl)retinamide; fenretinide; surrogate endpoint biomarker ID EPIDERMAL GROWTH-FACTOR; TUMOR-ASSOCIATED GLYCOPROTEIN-72; FACTOR RECEPTOR; INTRAEPITHELIAL NEOPLASIA; P53 PROTEIN; IMMUNOHISTOCHEMICAL DETECTION; CHEMOPREVENTION AGENTS; FACTOR-ALPHA; EXPRESSION; ADENOCARCINOMA AB An NCI-sponsored, phase II trial of N-(4-hydroxyphenyl)retinamide (4-HPR) in patients with organ-confined prostate cancer in the period prior to radical prostatectomy was carried out. Thirty-seven men with the histologic diagnosis of prostate cancer planning to have radical prostatectomy entered the study after informed consent and were given 4-HPR (or matching placebo) as a single daily dose (two 100-mg capsules of 4-HPR or two capsules of placebo daily) for 3 weeks prior to surgery. Four men dropped out for unrelated reasons. Thirty-three men completed the study. At the time of surgery, repeat biopsies of the prostate were performed to study the effects of the drug on potential surrogate endpoint biomarkers (SEBs) of malignancy within the tissue. The panel of potential SEBs of malignancy include p53, cytomorphometric indices, ploidy, PNCA, erbB-2, erbB-3, EGF receptor, TGF-alpha tumor-associated glycoprotein-72, fatty acid synthetase and Lewis Y antigen. Twenty-three patients had matching pre- and posttherapy lesions and were considered informative. Results from the patients indicate significant differential expression of biomarkers in pretreatment specimens of uninvolved prostatic tissue (normal-appearing epithelia) prostatic intraepithelial neoplasia (PIN) and prostate cancer. The mean erbB-2 expression was 0.58 in uninvolved vs. 1.04 in PIN (p = 0.002); while the mean erbB-2 expression was 1.35 in prostate cancer (p = 0.0007, uninvolved vs. prostate cancer). A similar pattern of increased biomarker expression between uninvolved and PIN or prostate cancer tissues can be observed for EGF receptor (mean = 1.21, 1.87 and 1.76 for uninvolved, PIN and prostate cancer, respectively) and erbB-3 (mean = 0.81, 1.59 and 1.30 for uninvolved, PIN and prostate cancer, respectively). There were no statistically significant differences in biomarkers observed in the 4-HPR-treated patients when compared with placebo-treated control patients. There was a posttreatment up-regulation of biomarkers observed in both groups of patients. This observation is most likely explained by an effect due to the diagnostic sextant biopsy equally affecting both groups of patients. Results from this study do not demonstrate a chemoprevention effect of 4-HPR on tissue-based SEBs at the dose given. C1 Univ Alabama, Dept Surg, Div Urol, Birmingham, AL 35294 USA. Univ N Carolina, Chapel Hill, NC USA. NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. RP Urban, D (reprint author), Univ Alabama, Dept Surg, Div Urol, MEB 603, Birmingham, AL 35294 USA. RI Manne, Upender/D-5613-2009 FU NCI NIH HHS [N01CN35577-01] NR 52 TC 29 Z9 29 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0302-2838 J9 EUR UROL JI Eur. Urol. PD MAY-JUN PY 1999 VL 35 IS 5-6 BP 429 EP 438 DI 10.1159/000019875 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 198BA UT WOS:000080400800016 PM 10325501 ER PT J AU Danilkovitch, A Skeel, A Leonard, EJ AF Danilkovitch, A Skeel, A Leonard, EJ TI Macrophage stimulating protein-induced epithelial cell adhesion is mediated by a PI3-K-dependent, but FAK-independent mechanism SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE MSP; adhesion; epithelial cells; integrins; PI3-K; FAK ID RECEPTOR TYROSINE KINASE; HEPATOCYTE GROWTH-FACTOR; SMOOTH-MUSCLE CELLS; PDGF-BETA-RECEPTORS; PHOSPHATIDYLINOSITOL 3-KINASE; PHOSPHOINOSITIDE 3-KINASE; ALPHA-V-BETA-3 INTEGRIN; PROTEOLYTIC CLEAVAGE; SIGNAL-TRANSDUCTION; FOCAL ADHESIONS AB Macrophage stimulating protein (MSP) is a growth and motility factor that mediates its activity via the RON/STK receptor tyrosine kinase. MSP promotes integrin-dependent epithelial cell migration, which suggests that MSP may regulate integrin receptor functions. Integrins are cell surface receptors for extracellular matrix. Epithelial cell adhesion and motility are mediated by integrins. We studied the enhancement by MSP of cell. adhesion and the molecular mechanisms mediating this effect. MSP decreased the time required for adhesion of 293 and RE7 epithelial cells to substrates coated with collagen or fibronectin. Prevention of adhesion by an RGD-containing peptide showed that the cell-substrate interaction was mediated by integrins. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PIS-K), blocked MSP-dependent adhesion, which shows that PI3-K is in the MSP-induced adhesion pathway. MSP also affected focal adhesion kinase (FAR) which is important for some types of cell adhesion and motility. Although MSP caused PI3-K-independent tyrosine phosphorylation and activation of FAK, experiments with dominant-negative FAK constructs showed that FAK does not mediate the effects of MSP on cell adhesion or motility. Thus PIS-K, but not FAK, mediates MSP-induced integrin-dependent adhesion of epithelial cells. Also, we found ligand-independent association between RON and beta 1 integrin, which is additional evidence for a relationship between these two receptor systems. C1 NCI, Frederick Canc Res & Dev Ctr, Immunobiol Lab, Frederick, MD 21702 USA. RP Danilkovitch, A (reprint author), NCI, Frederick Canc Res & Dev Ctr, Immunobiol Lab, Bldg 560,Room 12-46, Frederick, MD 21702 USA. NR 61 TC 28 Z9 29 U1 0 U2 1 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 MAY 1 PY 1999 VL 248 IS 2 BP 575 EP 582 DI 10.1006/excr.1999.4429 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 194CV UT WOS:000080175300024 PM 10222149 ER PT J AU Sato, S Sugiyama, K Lee, YS Kador, PF AF Sato, S Sugiyama, K Lee, YS Kador, PF TI Prevention of naphthalene-1,2-dihydrodiol-induced lens protein modifications by structurally diverse aldose reductase inhibitors SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE naphthalene; cataract; aldose reductase; rat; lens ID NAPHTHALENE CATARACT; ALDEHYDE REDUCTASE; DIHYDRODIOL DEHYDROGENASES; RAT LENS; IDENTIFICATION; METABOLISM; INVITRO; MODEL AB The effects of aldose reductase inhibitors on lens protein modifications induced by naphthalene-1,2-dihydrodiol were investigated in vitro to confirm the role of aldose reductase on naphthalene cataract formation. HPLC analysis of naphthalene-1,2-dihydrodiol incubated with aldose reductase and NAD(+) indicated the formation of a metabolite peak corresponding to 1,2-naphthoquinone. Soluble proteins from rat lenses prepared by gel filtration of crude lens extracts through Sephadex PD-10, incubated with naphthalene-1,2-dihydrodiol in the presence of NAD+ displayed an absorbance co 450 nm and their spectra were essentially identical to those of 1,2-naphthoquinone-protein adducts. Similar spectra were also obtained from proteins isolated from the intact rat lens after in vitro incubation in medium containing naphthalene-1,2-dihydrodiol. The spectra obtained from lens proteins incubated with 1,2-dihydroxynaphthalene were distinct from those of either naphthalene-1,2-dihydrodiol or 1,2-naphthoquinone. Aldose reductase inhibitors possessing either hydantoin or carboxylic acid groups prevented protein modification induced by naphthalene-1,2-dihydrodiol but not protein modification induced by 1,2-dihydroxynaphthalene or 1,2-naphthoquinone. Therefore, the metabolite formed from naphthalene-1,2-dihydrodiol by aldose reductase is 1,2-naphthoquinone. Lens proteins modified by naphthalene-1,2-dihydrodiol appear essentially identical to protein adducts formed with 1,2-naphthoquinone and their formation can be prevented by both hydantoin and carboxylic acid containing aldose reductase inhibitors. C1 NEI, Lab Ocular Therapeut, NIH, Bethesda, MD 20892 USA. RP Sato, S (reprint author), NEI, Lab Ocular Therapeut, NIH, Bldg 10,Rm 10B09,10 Ctr Dr,MSC 1850, Bethesda, MD 20892 USA. NR 23 TC 10 Z9 10 U1 0 U2 3 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 J9 EXP EYE RES JI Exp. Eye Res. PD MAY PY 1999 VL 68 IS 5 BP 601 EP 608 DI 10.1006/exer.1998.0644 PG 8 WC Ophthalmology SC Ophthalmology GA 196MY UT WOS:000080313200010 PM 10328974 ER PT J AU Woody, MA Welniak, LA Sun, R Tian, ZG Henry, M Richards, S Raziuddin, A Longo, DL Murphy, WJ AF Woody, MA Welniak, LA Sun, R Tian, ZG Henry, M Richards, S Raziuddin, A Longo, DL Murphy, WJ TI Prolactin exerts hematopoietic growth-promoting effects in vivo and partially counteracts myelosuppression by azidothymidine SO EXPERIMENTAL HEMATOLOGY LA English DT Article DE prolactin; hematopoiesis; myeloid progenitors; neuroendocrine hormone ID COLONY-STIMULATING FACTOR; AIDS-RELATED COMPLEX; BONE-MARROW; IN-VITRO; HYPOPHYSECTOMIZED RATS; PROGENITOR CELLS; BREAST-CANCER; LYMPHOCYTE-T; DWARF MICE; HORMONE AB Prolactin (PRL) is a neuroendocrine hormone that influences immune and hematopoietic development, The mechanism of action of this hormone in vivo remains unclear; therefore, we assessed the effects of PRL on hematopoiesis in vivo and in vitro. Normal resting mice were treated with 0, 1, 10, or 100 mu g of recombinant human prolactin (rhPRL) for 4 consecutive days and euthanized on the fifth day for analysis of myeloid and erythroid progenitors in the bone marrow and spleen. Both frequencies and absolute numbers of splenic colony-forming unit granulocyte-macrophage (CFU-GM) and burst-forming unit-erythroid (BFU-e) were significantly increased in mice receiving rhPRL compared to the controls that had received saline only. Bone marrow cellularities were not significantly affected by any dose of rhPRL, but the absolute numbers and frequencies of bone marrow CFU-GM and BFU-e were augmented by rhPRL. These results suggest that rhPRL can promote hematopoiesis in vivo, Because rhPRL augments myeloid development in vivo, we examined the potential of the hormone to reverse the anemia and myelosuppression induced by azidothymidine (AZT), Mice were given rhPRL injections concurrent with 2.5 mg/mL AZT in drinking water, rhPRL partially restored hematocrits in the animals after 2 weeks of treatment and increased CFU-GM and BFU-e in both spleens and bone marrow, The experiments with AZT and rhPRL support the conclusion that the hormone increases myeloid and erythroid progenitor numbers in vivo, and they suggest that the hormone is clinically useful in reversing myelosuppression induced by AZT or other myeloablative therapies, (C) 1999 International Society for Experimental Hematology, Published by Elsevier Science Inc. C1 NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Lab Leukocyte Biol, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. NIA, Baltimore, MD 21224 USA. Genzyme Corp, Framingham, MA 01701 USA. RP Murphy, WJ (reprint author), NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Lab Leukocyte Biol, Bldg 567,Room 210, Frederick, MD 21702 USA. RI Tian, Zhigang/J-3512-2013 FU NCI NIH HHS [N01-CO-56000] NR 42 TC 32 Z9 34 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD MAY PY 1999 VL 27 IS 5 BP 811 EP 816 DI 10.1016/S0301-472X(99)00019-3 PG 6 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 196LZ UT WOS:000080311000005 PM 10340396 ER PT J AU Yu, JM Emmons, RVB Hanazono, Y Sellers, S Young, NS Dunbar, CE AF Yu, JM Emmons, RVB Hanazono, Y Sellers, S Young, NS Dunbar, CE TI Expression of interferon-gamma by stromal cells inhibits murine long-term repopulating hematopoietic stem cell activity SO EXPERIMENTAL HEMATOLOGY LA English DT Article DE aplastic anemia; hematopoiesis; bone marrow; animal models; bone marrow failure ID ACQUIRED APLASTIC-ANEMIA; MEDIATED GENE-TRANSFER; BONE-MARROW; COMPETITIVE REPOPULATION; THERAPY; CULTURE; GROWTH; ALPHA; MICROENVIRONMENT; INTERLEUKIN-3 AB Several lines of evidence suggest that overexpression of interferon gamma (IFN-gamma) in the marrow microenvironment may play a role in the pathogenesis of marrow suppression in aplastic anemia. We previously showed that overexpression of IFN-gamma by marrow stromal cells inhibits human long-term culture initiating fell activity assayed in vitro to a much greater degree than the addition of soluble IFN-gamma. The effect of IFN-gamma on true repopulating stem cells assayed in vivo has not been studied previously, We compared the effect of co-culture of murine marrow cells in the presence of stromal cells transduced with a retroviral vector expressing murine IFN-gamma vs stromal cells transduced with a control neo vector, Using a murine congenic competitive repopulation assay, there was significantly less long-term repopulating stem cell activity remaining after culture on mIFN-gamma-expressing stroma as compared to control stroma, We also investigated the effect of directly transducing murine hone marrow cells with the mIFN-gamma or control vector, Marrow cells transduced with either vector were transplanted into W/W-v recipient mice. The percentage of vector-containing cells in the mIFN-gamma mice was significantly lower than in the control mice, suggesting that mIFN-gamma-transduced primitive cells may not have survived culture, or that mIFN-gamma directly decreases gene transfer into repopulating cells, Despite no significant differences in white or red blood cells in the mice transplanted with the mIFN-gamma-transduced cells, the number of bone marrow colony-forming unit-C 16 weeks after transplantation was significantly lower in the IFN-gamma group. These data indicate that ectopic or overexpression of mIFN-gamma, especially by marrow microenvironmental elements, may have a marked effect on primitive hematopoiesis as assayed in vivo. Published by Elsevier Science Inc. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Dunbar, CE (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Room 7C 103, Bethesda, MD 20892 USA. NR 35 TC 17 Z9 20 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD MAY PY 1999 VL 27 IS 5 BP 895 EP 903 DI 10.1016/S0301-472X(99)00009-0 PG 9 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 196LZ UT WOS:000080311000015 PM 10340406 ER PT J AU Schoenfeld, P Guyatt, G Hamilton, F Laine, L Cook, D Bjorkman, D Morgan, D Peterson, W AF Schoenfeld, P Guyatt, G Hamilton, F Laine, L Cook, D Bjorkman, D Morgan, D Peterson, W CA Evidence Based Gasteroenterology Steering TI An evidence-based approach to gastroenterology diagnosis SO GASTROENTEROLOGY LA English DT Article ID IRON-DEFICIENCY; CHOLANGIOPANCREATOGRAPHY; CHOLEDOCHOLITHIASIS; CHOLANGIOGRAPHY; ACCURACY; TESTS C1 NIDDKD, Digest Dis Program, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. Natl Naval Med Ctr, Div Gastroenterol, Bethesda, MD USA. McMaster Univ, Sch Med, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada. Univ So Calif, Sch Med, Div Gastrointestinal & Liver Dis, Los Angeles, CA 90033 USA. Univ Utah, Med Ctr, Div Gastroenterol, Salt Lake City, UT USA. McMaster Univ, Med Ctr, Div Gastroenterol, Hamilton, ON, Canada. Univ Texas, SW Med Sch, Dallas, TX 75230 USA. Vet Adm Med Ctr, Med Serv, Dallas, TX 75216 USA. RP Hamilton, F (reprint author), NIDDKD, Digest Dis Program, Div Digest Dis & Nutr, NIH, Natcher Bldg,Room 6AN-12B,45 Ctr Dr,MSC 6600, Bethesda, MD 20892 USA. NR 21 TC 24 Z9 24 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 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAY PY 1999 VL 116 IS 5 BP 1230 EP 1237 DI 10.1016/S0016-5085(99)70026-0 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 190DY UT WOS:000079947900029 PM 10220515 ER PT J AU Harari, OA Wickham, TJ Stocker, CJ Kovesdi, I Segal, DM Huehns, TY Sarraf, C Haskard, DO AF Harari, OA Wickham, TJ Stocker, CJ Kovesdi, I Segal, DM Huehns, TY Sarraf, C Haskard, DO TI Targeting an adenoviral gene vector to cytokine-activated vascular endothelium via E-selectin SO GENE THERAPY LA English DT Article DE gene therapy; adenovirus; inflammation; endothelium; E-selectin ID INFLAMMATORY BOWEL-DISEASE; RADIOLABELED MONOCLONAL-ANTIBODY; LEUKOCYTE ADHESION MOLECULE-1; SMOOTH-MUSCLE CELLS; IN-VIVO; RHEUMATOID-ARTHRITIS; FIBER KNOB; EXPRESSION; INVIVO; IMMUNOLOCALIZATION AB We have aimed at selective gene delivery to vascular endothelial cells (EC) at sites of inflammation, by targeting E-selectin, a surface adhesion molecule that is only expressed by activated EC. An anti-E-selectin mAb, 1.2B6, was complexed with the adenovirus vector AdZ.FLAG (expressing the FLAG peptide) by conjugating it to an anti-FLAG mAb. Gene transduction of cultured EC was increased 20-fold compared with AdZ.FLAG complexed with a control bsAb providing EC were activated by cytokines. The anti-E-selectin-complexed vector transduced 29 +/- 9% of intimal EC in segments of pig aorta cultured with cytokines ex vivo, compared with less than 0.1% transduced with the control construct (P < 0.05). This strategy could be developed to target endothelium in inflamation with genes capable of modifying the inflammatory response. C1 Natl Heart & Lung Inst, BHF, Cardiovasc Med Unit, London, England. Univ London Imperial Coll Sci Technol & Med, Sch Med, Hammersmith Hosp, Dept Histopathol, London, England. Genvec Inc, Rockville, MD USA. NCI, Expt Immunol, Bethesda, MD 20892 USA. RP Haskard, DO (reprint author), Univ London Imperial Coll Sci Technol & Med, Sch Med, BHF, Cardiovasc Med Unit, Du Cane Rd, London W12 0NN, England. FU Wellcome Trust NR 50 TC 50 Z9 54 U1 0 U2 2 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD MAY PY 1999 VL 6 IS 5 BP 801 EP 807 DI 10.1038/sj.gt.3300898 PG 7 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 194HN UT WOS:000080186700013 PM 10505104 ER PT J AU Gaynes, BN Magruder, KM Burns, BJ Wagner, HR Yarnall, KSH Broadhead, WE AF Gaynes, BN Magruder, KM Burns, BJ Wagner, HR Yarnall, KSH Broadhead, WE TI Does a coexisting anxiety disorder predict persistence of depressive illness in primary care patients with major depression? SO GENERAL HOSPITAL PSYCHIATRY LA English DT Article ID AVOIDANT PERSONALITY-DISORDER; GENERALIZED SOCIAL PHOBIA; DIAGNOSTIC INTERVIEW SCHEDULE; PSYCHIATRIC-DISORDERS; PANIC DISORDER; MEDICAL-CARE; UNITED-STATES; CO-MORBIDITY; HEALTH-CARE; OUTCOMES AB We assessed whether a coexisting anxiety disorder predicts risk for persistent depression in primary care patients with major depression at baseline. Patients with major depression were identified in a 12-month prospective cohort study at a University-based family practice clinic. Presence of an anxiety disorder and other potential prognostic factors were measured at baseline. Persistent depressive illness (major depression, minor depression, or dysthymia) was determined at 12 months. Of 85 patients with major depression at baseline, 43 had coexisting anxiety disorder (38 with social phobia). The risk for persistent depression at 12 months was 44% greater [Risk Ratio (RR) = 1.44, 95% confidence interval (CI) 1.02-2.04] in those with coexisting anxiety. This risk persisted in stratified analysis controlling for other prognostic factors. Patients with coexisting anxiety had greater mean depressive severity [repeated measures analysis of variance (ANOVA), p < 0.04] and total disability days (54.9 vs 19.8, p < 0.02) over the 12-month study. Patients with social phobia had similar increased risk for persistent depression (RR = 1.40, 95% CI 0.98-2.00). A coexisting anxiety disorder indicates risk for persistent depression irt primary cave patients with major depression. Social phobia may be important to recognize in these patients. Identifying anxiety disorders can help primary care clinicians target patients needing more aggressive treatment for depression. (C) 1999 Elsevier Science Inc. C1 Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA. Duke Univ, Med Ctr, NIMH, Durham, NC 27706 USA. Duke Univ, Med Ctr, Dept Psychiat, Durham, NC 27706 USA. Duke Univ, Dept Community & Family Med, Med Ctr, Durham, NC 27706 USA. RP Gaynes, BN (reprint author), Univ N Carolina, Dept Psychiat, CB 7160, Chapel Hill, NC 27599 USA. OI Gaynes, Bradley/0000-0002-8283-5030 FU NIMH NIH HHS [R01 MH45750] NR 62 TC 74 Z9 74 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0163-8343 J9 GEN HOSP PSYCHIAT JI Gen. Hosp. Psych. PD MAY-JUN PY 1999 VL 21 IS 3 BP 158 EP 167 DI 10.1016/S0163-8343(99)00005-5 PG 10 WC Psychiatry SC Psychiatry GA 206GK UT WOS:000080868800004 PM 10378109 ER PT J AU Taetle, R Aickin, M Panda, L Emerson, L Roe, D Thompson, F Davis, L Trent, L Alberts, D AF Taetle, R Aickin, M Panda, L Emerson, L Roe, D Thompson, F Davis, L Trent, L Alberts, D TI Chromosome abnormalities in ovarian adenocarcinoma: II. Prognostic impact of nonrandom chromosome abnormalities in 244 cases SO GENES CHROMOSOMES & CANCER LA English DT Article ID REQUIRING PROLONGED OBSERVATION; CANCER; GENE; ABERRATIONS; REARRANGEMENTS; EXPRESSION; CARCINOMA; NEOPLASIA; TUMORS; TUMORIGENICITY AB In a large series of ovarian carcinomas from 244 patients, 134 cases had chromosome rearrangements. We showed before that the pattern of chromosome breakpoints involved 21 separate chromosome regions nonrandomly and, in 90% of cases with breaks, the breakpoints occurred within 13 commonly involved regions. Log-rank and proportional hazards regression analyses showed that the aggregate presence of a chromosome breakpoint in any of 21 nonrandomly involved regions and breaks in 9 distinct regions (1p1, 1q2, 1p3, 3p1, 6p2, 11p1, 11q1, 12q2, and 13p1) were associated with reduced patient survival. Breakpoints in other areas of the genome, including other nonrandomly involved regions, were not associated with decreased survival. Because many cases had breakpoints in more than one nonrandomly involved region, proportional hazards regression was also used to analyze for effects of each nonrandomly involved region, controlling for effects of other regions. With this approach, only breakpoints within 1p1 and 3p1 retained independent, deleterious effects on survival. Similarly, when nonrandomly involved regions were entered into a proportional hazards model containing clinical variables associated with altered patient survival (tumor grade, tumor stage, and residual disease >1 cm after resection), only 1p1 (P = 0.007) and 3p1 (P = 0.04) were associated with independent, negative effects on survival. These studies demonstrate that chromosome breakpoints within specific, nonrandomly involved chromosome regions are associated with impaired survival in ovarian cancers. Regions 1p1 and 3p1 are identified as areas of particular significance and are appropriate targets for analytical techniques such as SAGE and microarray analysis. Genes Chromosomes Cancer 25:46-52, 1999. (C) 1999 Wiley-Liss, Inc. C1 Arizona Canc Ctr, Tucson, AZ 85724 USA. Univ Arizona, Dept Med, Tucson, AZ USA. Univ Arizona, Dept Pathol, Tucson, AZ USA. Natl Human Genome Res Inst, Canc Genet Lab, Bethesda, MD USA. RP Taetle, R (reprint author), Arizona Canc Ctr, 1515 N Campbell Ave, Tucson, AZ 85724 USA. FU NCI NIH HHS [CA41183, CA23074]; NIEHS NIH HHS [NIH-ES-95-32] NR 36 TC 23 Z9 23 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD MAY PY 1999 VL 25 IS 1 BP 46 EP 52 DI 10.1002/(SICI)1098-2264(199905)25:1<46::AID-GCC7>3.0.CO;2-O PG 7 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 183VU UT WOS:000079575500007 PM 10221339 ER PT J AU Padilla-Nash, HM Nash, WG Padilla, GM Roberson, KM Robertson, CN Macville, M Schrock, E Ried, T AF Padilla-Nash, HM Nash, WG Padilla, GM Roberson, KM Robertson, CN Macville, M Schrock, E Ried, T TI Molecular cytogenetic analysis of the bladder carcinoma cell line BK-10 by spectral karyotyping SO GENES CHROMOSOMES & CANCER LA English DT Article ID CHROMOSOMES; CANCER AB The bladder cancer cell line BK-10 was established from a grade III-IV transitional cell carcinoma (TCC). BK-10 is near-tetraploid (+/-4n) and consists of two subclones with 20-25 structural aberrations. Here we report the cytogenetic analysis of BK-10 by G-banding, spectral karyotyping (SKY), and FISH. SKY refers to the hybridization of 24 differentially labeled chromosome painting probes and the simultaneous visualization of all human chromosomes using spectral imaging. SKY enabled us to confirm 12 markers in BK-10 previously described by G-banding, redefine 11 aberrations, and detect 4 hidden chromosomal rearrangements, 2 of which had been identified as normal or deleted copies of chromosome 20 and 1 as a normal chromosome 3. Twenty out of 21 translocations identified were unbalanced. FISH analysis of BK-10 using chromosome arm-specific paints, centromere probes, and oncogene/tumor suppressor gene-specific probes revealed a deletion of CDKN2A (p16) in all copies of chromosome 9, a low-level amplification of MYC (five copies), and loss of one copy of TP53; detected the presence of the Y chromosome in a hidden translocation; and detected four copies of ERBB-2. A probe set for BCR and ABL verified breakpoints for all translocations involving chromosomes 9 and 22. A new karyotype presentation, "SKY-gram," is introduced by combining data from G-banding, SKY, and FISH analysis. This study demonstrates the approach of combining molecular cytogenetic techniques to characterize fully the multiple complex chromosomal rearrangements found in the bladder cancer cell line BK-10, and to refine the chromosomal breakpoints for all translocations. Genes Chromosomes Cancer 25:53-59, 1999 Published 1999 Wiley-Liss, Inc.double dagger C1 Natl Human Genome Res Inst, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. H&W Cytogenet Serv Inc, Lovettsville, VA USA. Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Surg, Div Urol, Durham, NC 27710 USA. RP Padilla-Nash, HM (reprint author), Natl Human Genome Res Inst, Genome Technol Branch, NIH, 49 Convent Dr,Bldg 49,Room 4C-36, Bethesda, MD 20892 USA. FU PHS HHS [ASI95128] NR 12 TC 31 Z9 31 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD MAY PY 1999 VL 25 IS 1 BP 53 EP 59 DI 10.1002/(SICI)1098-2264(199905)25:1<53::AID-GCC8>3.0.CO;2-T PG 7 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 183VU UT WOS:000079575500008 PM 10221340 ER PT J AU Tran, HT Degtyareva, NP Gordenin, DA Resnick, MA AF Tran, HT Degtyareva, NP Gordenin, DA Resnick, MA TI Genetic factors affecting the impact of DNA polymerase delta proofreading activity on mutation avoidance in yeast SO GENETICS LA English DT Article ID 5' EXONUCLEASE ACTIVITY; SACCHAROMYCES-CEREVISIAE; ESCHERICHIA-COLI; MISMATCH REPAIR; REPLICATION ERRORS; REPETITIVE DNA; HUMAN CANCERS; EPSILON; SUBUNIT; INSTABILITY AB Base selectivity, proofreading, and postreplication mismatch repair are important for replication fidelity. Because proofreading plays an important role in error correction, we have investigated factors that influence its impact in the yeast Saccharomyces cerevisiae. We have utilized a sensitive mutation detection system based on homonucleotide runs of 4 to 14 bases to examine the impact of DNA polymerase delta proofreading on mutation avoidance. The contribution of DNA polymerase delta proofreading on error avoidance was found to be similar to that of DNA polymerase epsilon proofreading in short homonucleotide runs (A(4) and A(5)) but much greater than the contribution of DNA polymerase epsilon proofreading in longer runs. We have identified an intraprotein interaction affecting mutation prevention that results from mutations in the replication and the proofreading regions, resulting in an antimutator phenotype relative to a proofreading defect. Finally, a diploid strain with a defect in DNA polymerase delta proofreading exhibits a higher mutation rate than a haploid strain. We suggest that in the diploid population of proofreading defective cells there exists a transiently hypermutable fraction that would be inviable if cells were haploids. C1 St Petersburg State Univ, Dept Genet, St Petersburg 19034, Russia. NIEHS, Mol Genet Lab, Chromosome Stabil Grp, Res Triangle Pk, NC 27709 USA. RP Resnick, MA (reprint author), NIEHS, Mol Genet Lab, Chromosome Stabil Grp, POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 49 TC 38 Z9 38 U1 0 U2 3 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD MAY PY 1999 VL 152 IS 1 BP 47 EP 59 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 194XB UT WOS:000080219100005 PM 10224242 ER PT J AU Hammell, AB Taylor, RC Peltz, SW Dinman, JD AF Hammell, AB Taylor, RC Peltz, SW Dinman, JD TI Identification of putative programmed-1 ribosomal frameshift signals in large DNA databases SO GENOME RESEARCH LA English DT Article ID ORNITHINE DECARBOXYLASE ANTIZYME; ROUS-SARCOMA VIRUS; RELEASE FACTOR-II; MESSENGER-RNA TURNOVER; POL FUSION PROTEIN; SACCHAROMYCES-CEREVISIAE; IMMUNODEFICIENCY-VIRUS; MUTATIONAL ANALYSIS; LEUKEMIA-VIRUS; GAMMA-SUBUNIT AB The cis-acting elements that promote efficient ribosomal frameshifting in the -1 (5') direction have been well characterized in several viral systems. Results from many studies have convincingly demonstrated that the basic molecular mechanisms governing programmed -1 ribosomal frameshifting are almost identical from yeast to humans. We are interested in testing the hypothesis that programmed -1 ribosomal frameshifting can be used to control cellular gene expression. Toward this end, a computer program was designed to search large DNA databases for consensus -1 ribosomal frameshift signals. The results demonstrated that consensus programmed -1 ribosomal frameshift signals can be identified in a substantial number of chromosomally encoded mRNAs and that they occur with frequencies from two- to sixfold greater than random in all of the databases searched. A preliminary survey of the databases resulting from the computer searches found that consensus frameshift signals are present in at least 21 homologous genes From different species, 2 of which are nearly identical, suggesting evolutionary conservation of function. We show that four previously described missense alleles of genes that are linked to human diseases would disrupt putative programmed -1 ribosomal frameshift signals, suggesting that the Frameshift signal may be involved in the normal expression of these genes. We also demonstrate that signals Found in the yeast RAS1 and the human CCR5 genes were able to promote significant levels of programmed -1 ribosomal frameshifting. The significance of these frameshifting signals in controlling gene expression is not known, however. C1 Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Mol Genet & Microbiol, Piscataway, NJ 08854 USA. Rutgers UMDNJ, Grad Programs Mol Biosci, Piscataway, NJ 08854 USA. NCI, Mol Stat & Bioinformat Sect, Biometr Res Branch, Canc Therapy Evaluat Program,DCTD, Bethesda, MD 20892 USA. RP Dinman, JD (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Mol Genet & Microbiol, Piscataway, NJ 08854 USA. OI Dinman, Jonathan/0000-0002-2402-9698 FU NIAID NIH HHS [T32 AI007403, T32 AI07403-07]; NIGMS NIH HHS [R01 GM48631, R01 GM048631, R01 GM058859, R01 GM58859, R21 GM068123] NR 73 TC 52 Z9 54 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD MAY PY 1999 VL 9 IS 5 BP 417 EP 427 PG 11 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 197CW UT WOS:000080347900004 PM 10330121 ER PT J AU DeSilva, U Massa, H Trask, BJ Green, ED AF DeSilva, U Massa, H Trask, BJ Green, ED TI Comparative mapping of the region of human chromosome 7 deleted in Williams syndrome SO GENOME RESEARCH LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; LARGE-INSERT CLONES; BEUREN-SYNDROME; HUMAN GENE; GENOMIC ORGANIZATION; HEMIZYGOTIC DELETION; 7Q11.23 DELETIONS; COMMON DELETION; CELL-NUCLEI; HUMAN DNA AB Williams syndrome (WS) is a complex developmental disorder resulting from the deletion of a large (similar to 1.5-2 Mb) segment of human chromosome 7q11.23. Physical mapping studies have revealed that this deleted region, which contains a number of known genes, is flanked by several large, nearly identical blocks of DNA. The presence of such highly related DNA segments in close physical proximity to one another has hampered efforts to elucidate the precise long-range organization of this segment of chromosome 7. To gain insight about the structure and evolutionary origins of this important and complex genomic region, we have constructed a fully contiguous bacterial artificial chromosome (BAC) and Pi-derived artificial chromosome (PAC) contig map encompassing the corresponding region on mouse chromosome 5. In contrast to the difficulties encountered in constructing a clone-based physical map of the human WS region, the BAC/PAC-based map of the mouse WS region was straightforward to construct, with no evidence of large duplicated segments, such as those encountered in the human WS region. To confirm this difference, representative human and mouse BACs were used as probes For performing fluorescence in situ hybridization (FISH) to metaphase and interphase chromosomes. Human BACs derived from the nonunique portion of the WS region hybridized to multiple, closely spaced regions on human chromosome 7q11.23. In contrast, corresponding mouse BACs hybridized to a single site on mouse chromosome 5. Furthermore, FISH analysis revealed the presence of duplicated segments within the WS region of various nonhuman primates (chimpanzee, gorilla, orangutan, and gibbon). Hybridization was also noted at the genomic locations corresponding to human chromosome 7p22 and 7q22 in human, chimpanzee, and gorilla, but not in the other animal species examined. Together, these results indicate that the WS region is associated with large, duplicated blocks of DNA on human chromosome 7q11.23 as well as the corresponding genomic regions of other nonhuman primates. However, such duplications are not present in the mouse. C1 NIH, Genome Technol Branch, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. Univ Washington, Dept Mol Biotechnol, Seattle, WA 98195 USA. RP Trask, BJ (reprint author), NIH, Genome Technol Branch, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. FU NIGMS NIH HHS [GM57070, R01 GM057070] NR 46 TC 53 Z9 54 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD MAY PY 1999 VL 9 IS 5 BP 428 EP 436 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 197CW UT WOS:000080347900005 PM 10330122 ER PT J AU Butler, RN August, P Ferdinand, KC Phillips, RA Roccella, EJ AF Butler, RN August, P Ferdinand, KC Phillips, RA Roccella, EJ TI Hypertension: Therapeutic approach to weight loss, exercise, and salt intake - Part two of a roundtable discussion SO GERIATRICS LA English DT Editorial Material ID PHYSICAL-FITNESS; BLOOD-PRESSURE; TABLE AB Ideal body weight is difficult to achieve, but losing 10 lbs may be beneficial in controlling high blood pressure. Patients are more likely to exercise if they enjoy the activity, establish a routine, and exercise with a friend. Older Americans consume a lot of processed foods, the source of 80% of dietary salt. Most older African-Americans, especially those with obesity and type 2 diabetes, are salt-sensitive. Four steps to successful patient education are: 1) tell patients their blood pressure readings; 2) tell them about their medications and potential side effects; 3) provide culturally-sensitive printed materials; 4) use video tapes to educate all new patients and those with compliance problems. C1 Mt Sinai Med Ctr, Dept Geriatr & Adult Dev, New York, NY 10029 USA. Int Longev Ctr, New York, NY USA. Cornell Univ Med Coll, New York, NY USA. Cornell Univ, Med Ctr, New York Hosp, Div Hypertens, New York, NY 10021 USA. Xavier Univ, Coll Pharm, New Orleans, LA 70125 USA. Heartbeats Life Ctr, New Orleans, LA USA. Mt Sinai Sch Med, New York, NY USA. Mt Sinai Med Ctr, Hypertens Program, Zena & Michael A Wiener Cardiovasc Inst, New York, NY 10029 USA. Mt Sinai Med Ctr, Cardiac Hlth Program, Zena & Michael A Wiener Cardiovasc Inst, New York, NY 10029 USA. NHLBI, Natl High Blood Pressure Educ Program, NIH, Bethesda, MD USA. RP Butler, RN (reprint author), Mt Sinai Med Ctr, Dept Geriatr & Adult Dev, New York, NY 10029 USA. NR 10 TC 3 Z9 3 U1 1 U2 3 PU ADVANSTAR COMMUNICATIONS PI DULUTH PA 131 W FIRST ST, DULUTH, MN 55802 USA SN 0016-867X J9 GERIATRICS JI Geriatrics PD MAY PY 1999 VL 54 IS 5 BP 42 EP + PG 7 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 195BY UT WOS:000080230300007 PM 10365185 ER PT J AU Vionnet, J Concepcion, N Warner, T Zapata, G Hanover, J Vann, WF AF Vionnet, J Concepcion, N Warner, T Zapata, G Hanover, J Vann, WF TI Purification of CMP-N-acetylneuraminic acid synthetase from bovine anterior pituitary glands SO GLYCOBIOLOGY LA English DT Article DE CMP-sialic acid synthetase; enzyme purification; pituitary glands; sialic acid metabolism ID CYTIDINE-5'-MONOPHOSPHOSIALATE SYNTHASE; GROUP-B; NUCLEAR; PROTEINS; LIVER; ACETYLGLUCOSAMINE; LOCALIZATION; PEPTIDE; CLONING AB CMP-beta-N-acetylneuraminic acid (CMP-neuNAc) is the substrate for the sialylation of glycoconjugates by sialyltransferases in microbes and higher eukaryotes. CMP-neuNAc synthetase catalyzes the formation of this substrate, CMP-neuNAc, from CTP and neuNAc. In this report we describe the purification of CMP-neuNAc synthetase from bovine anterior pituitary glands. The enzyme was purified by ion exchange, gel filtration, and affinity chromatography, The protein was homogeneous on SDS-PAGE with a molecular weight of 52 kDa, a subunit size similar to that of the E.coli K1 (48.6 kDa), The identity of the 52 kDa protein band was confirmed by native gel electrophoresis in that the position of the enzyme activity in gel slices coincided with the position of major bands in the stained gel. Photoaffinity labeling with I-125-ASA-CDP ethanolamine resulted in the modification of a 52 kDa polypeptide that was partially protected against modification by the substrate CTP, Enzyme activity in crude fractions could be adsorbed onto an immunoadsorbent prepared from antibody against the purified 52 kDa protein. Taken together these data suggest that the 52 kDa polypeptide purified by this procedure described in this report is indeed CMP-neuNAc synthetase. The active enzyme chromatographed on a gel filtration column at 158 kDa suggesting it exists in its native form as an oligomer. C1 US FDA, CBER, OVRR, Div Bacterial Prod,Lab Bacterial Toxins, Bethesda, MD 20892 USA. US FDA, CBER, OVRR, Div Bacterial Prod,Lab Bacterial Polysaccharides, Bethesda, MD 20892 USA. Genentech Inc, S San Francisco, CA 94080 USA. NIDDKD, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Vann, WF (reprint author), US FDA, CBER, OVRR, Div Bacterial Prod,Lab Bacterial Toxins, 8800 Rockville Pike, Bethesda, MD 20892 USA. NR 26 TC 10 Z9 10 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD MAY PY 1999 VL 9 IS 5 BP 481 EP 487 DI 10.1093/glycob/9.5.481 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 191YL UT WOS:000080049700006 PM 10207180 ER PT J AU Kurc, M Farina, M Lins, U Kachar, B AF Kurc, M Farina, M Lins, U Kachar, B TI Structural basis for mechanical transduction in the frog vestibular sensory apparatus: III. The organization of the otoconial mass SO HEARING RESEARCH LA English DT Article DE electron microscopy; freeze-etching; otoconium; vestibular system; otolithic membrane; mechanical transduction; frog vestibular sensory organ ID CALCITE; AMPHIBIANS; ARAGONITE; OTOLITHS; PROTEIN; NEWT AB The saccule and the utricle of the vestibular system detect linear acceleration and gravity. Sensory transduction in these organs depends on myriads of calcium carbonate crystals of high specific gravity, called otoconia, embedded in a filament matrix that overlies the sensory epithelium. The coexistence of hard crystals and slender filaments in this complex extracellular matrix makes it difficult to analyze by conventional electron microscopy. We have now examined this structure in the bullfrog saccule using the quick-freeze, deep-etch replica technique. The otoconia in their typical aragonite polymorph shape exhibit smooth surfaces and are embedded in a loose matrix made of two types of filaments. The regular surface of the otoconia forms a natural smooth background against which we could observe with unprecedented detail the network organization and substructure of the filaments. One type of filament is 8 nm in diameter, while the other, which has a characteristic beaded appearance, is 15 nm in diameter. Both types of filaments either make lateral connections with or end directly on the surface of the otoconia. A consistent observation was the presence of short filaments that directly cross-link adjacent otoconia. Very few otoconia were fractured in an orientation that would allow the study of their internal architecture. These otoconia presented a typical conchoidal cleavage of aragonite. Although crystallites were not clearly apparent, thin lamellar microstructures appeared oriented both perpendicularly and longitudinally to the major otoconial axis. This structural study establishes a framework for the identification of the molecular components present in this unique extracellular matrix and may also help elucidate their role in mechanical transduction. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Natl Inst Deafness & Other Commun Disorders, Lab Cellular Biol, NIH, Bethesda, MD 20892 USA. Fed Univ Rio De Janeiro, Inst Ciencias Biomed, Dept Anat, Lab Biomineralizacao, BR-21941590 Rio De Janeiro, Brazil. Fed Univ Rio De Janeiro, Inst Microbiol Prof Paulo de Goes, Setor Microscopia Eletron, BR-21941590 Rio De Janeiro, Brazil. Fed Univ Rio De Janeiro, Inst Microbiol Prof Paulo de Goes, Dept Microbiol Geral, BR-21941590 Rio De Janeiro, Brazil. RP Kachar, B (reprint author), Natl Inst Deafness & Other Commun Disorders, Lab Cellular Biol, NIH, Bldg 36 Rm 5D-15, Bethesda, MD 20892 USA. RI Farina, Marcos/I-3744-2014; Lins, Ulysses/N-7282-2015 OI Lins, Ulysses/0000-0002-1786-1144 NR 23 TC 5 Z9 5 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 J9 HEARING RES JI Hear. Res. PD MAY PY 1999 VL 131 IS 1-2 BP 11 EP 21 DI 10.1016/S0378-5955(99)00007-6 PG 11 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 194JG UT WOS:000080188600002 PM 10355600 ER PT J AU Riker, A Bartlett, D AF Riker, A Bartlett, D TI Pancreaticoduodenectomy for chronic pancreatitis: A case report and literature review SO HEPATO-GASTROENTEROLOGY LA English DT Review DE pancreaticoduodenectomy; pancreatitis; surgery; CA 19-9; malignancy ID OBSTRUCTIVE PANCREATITIS; BILIARY; DRAINAGE; SURGERY; PANCREATICOJEJUNOSTOMY; EXPERIENCE; RESECTION; CANCER AB This is a case report of a patient with chronic pancreatitis who presented with biliary, duodenal and portal vein obstruction, a mass in the head of the pancreas, and a CA 19-9 level of 372 U/ml. Thus, the concern was raised as to the possibility of pancreatic cancer in this patient. We discuss the difficulties in the diagnosis of pancreatic cancer in patients with chronic pancreatitis and the treatment options available for patients with chronic pancreatitis where the significant findings involve the head of the pancreas. Finally, a brief review is given describing the pertinent literature on the surgical treatment of chronic pancreatitis and the current indications of pancreaticoduodenectomy for chronic pancreatitis. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP NCI, Surg Branch, NIH, Bldg 10,Room 2B07, Bethesda, MD 20892 USA. EM David_Bartlett@nih.gov RI Riker, Adam/A-6065-2011 NR 21 TC 1 Z9 1 U1 0 U2 0 PU H G E UPDATE MEDICAL PUBLISHING S A PI ATHENS PA PO BOX 17257, ATHENS GR-10024, GREECE SN 0172-6390 J9 HEPATO-GASTROENTEROL JI Hepato-Gastroenterol. PD MAY-JUN PY 1999 VL 46 IS 27 BP 2005 EP 2010 PG 6 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 215TH UT WOS:000081398700104 PM 10430385 ER PT J AU Lorenz, MGO Kantor, JA Schlom, J Hodge, JW AF Lorenz, MGO Kantor, JA Schlom, J Hodge, JW TI Anti-tumor immunity elicited by a recombinant vaccinia virus expressing CD70 (CD27L) SO HUMAN GENE THERAPY LA English DT Article ID T-CELL ACTIVATION; COSTIMULATORY MOLECULE B7; ANTITUMOR IMMUNITY; CANCER VACCINES; CD40 LIGAND; MURINE CD70; REJECTION; INDUCTION; RESPONSES; GENE AB CD70, a ligand of the T cell costimulatory receptor CD27, is expressed mainly on activated B cells and has been shown to increase cytotoxic activity and proliferation of preferentially unprimed T cells, Reported herein is the construction of a recombinant vaccinia virus encoding CD70 (designated rV-CD70) and a demonstration of its biological effect on naive T cells in vitro and in vivo, In a whole tumor cell vaccine model, the growth of CD70-negative murine colon adenocarcinoma (MC38) tumor cells infected with rV-CD70 (multiplicity of infection [MOI] of 0.1) and transplanted into syngeneic C57BL/6 mice was inhibited completely while control tumors infected with wild-type vaccinia grew rapidly and killed mice within 3-5 weeks, Tumor-free mice previously immunized with rV-CD70-infected tumors were partially protected against rechallenge with wild-type tumors, demonstrating the induction of systemic anti-tumor immunity, In addition, immunization of C57BL/6 mice with rV-CD70 admired with vaccinia virus encoding carcinoembryonic antigen (rV-CEA) was superior to treatment with rV-CEA alone in inducing CEA-specific lymphoproliferative T cell responses and reducing growth of murine colon carcinomas transduced with CEA, These studies demonstrate for the first time the potential utility of a recombinant vaccinia virus expressing CD70 to enhance T cell responses and mediate anti-tumor immunity. C1 NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, NIH, 10 Ctr Dr,Room 8B07, Bethesda, MD 20892 USA. RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 NR 39 TC 46 Z9 49 U1 0 U2 1 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 MAY 1 PY 1999 VL 10 IS 7 BP 1095 EP 1103 DI 10.1089/10430349950018094 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 193EE UT WOS:000080122300002 PM 10340542 ER PT J AU Wahlfors, JJ Morgan, RA AF Wahlfors, JJ Morgan, RA TI Production of minigene-containing retroviral vectors using an alphavirus/retrovirus hybrid vector system SO HUMAN GENE THERAPY LA English DT Article ID HUMAN FACTOR-IX; BETA-GLOBIN GENE; NUCLEOSIDE PHOSPHORYLASE GENE; HUMAN FACTOR-VIII; TRANSGENIC MICE; EXPRESSION VECTORS; THERAPY; CELLS; HEMOPHILIA; PROMOTER AB In an attempt to increase the synthesis of human clotting factors VIII and IX in transduced cells, optimized expression cassettes containing genomic genelike elements (minigenes) were assembled. Plasmid DNA containing factor VIII or factor IX minigenes and driven by three human cellular promoters (albumin, factor IX, PGK) or the strong viral promoter RSV-LTR were electroporated into TE671 and HepG2 cell lines, and clotting factor levels were determined by ELISA, In comparison with a parallel transfection of MLV-LTR-promoted retroviral vector plasmid DNAs, the PGK- and RSV-LTR-promoted minigene constructs produced equal or greater amounts of clotting factor proteins. A factor IX minigene cassette was cloned into the retrovirus-based gene transfer vector LN tin both forward and reverse orientations) and the minigene vector was introduced into the Phoenix retroviral packaging cell line. Analysis of neo(r) cells demonstrated that insertion of a factor IX minigene into the retroviral vector LN resulted in rearrangement of the factor IX sequence and loss of factor IX expression in the Phoenix packaging cell line, The same factor IX minigene was then inserted into an alphavirus/retrovirus hybrid vector that facilitates the synthesis of retroviral vector RNA in the cytoplasm of cells. Alphavirus/retrovirus virions were produced and used to transduce the Phoenix retroviral vector packaging cell line. The cytoplasmically produced factor IX minigene-containing retroviral vectors were collected and used to transduce TE671 cells. Analysis of transduced cells demonstrated stable transfer of the minigene and expression of factor IX. C1 Natl Human Genome Res Inst, Clin Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. RP Morgan, RA (reprint author), Natl Human Genome Res Inst, Clin Gene Therapy Branch, NIH, 10 Ctr Dr,Bldg 10,Rm 10C103, Bethesda, MD 20892 USA. NR 28 TC 12 Z9 14 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 MAY 1 PY 1999 VL 10 IS 7 BP 1197 EP 1206 DI 10.1089/10430349950018184 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 193EE UT WOS:000080122300011 PM 10340551 ER PT J AU Finegold, AA Mannes, AJ Iadarola, MJ AF Finegold, AA Mannes, AJ Iadarola, MJ TI A paracrine paradigm for in vivo gene therapy in the central nervous system: Treatment of chronic pain SO HUMAN GENE THERAPY LA English DT Article ID BETA-ENDORPHIN; CEREBROSPINAL-FLUID; SPINAL-CORD; RECOMBINANT ADENOVIRUS; CELLS; RAT; VECTORS; BRAIN; EXPRESSION; DISEASES AB A limitation of current gene therapy efforts aimed at central nervous system disorders concerns distribution of vectors on direct injection into neural tissue. Here we have circumvented this problem by transferring genes to the meninges surrounding the spinal cord, achieving an in vivo gene transfer paradigm for treating chronic pain. The therapeutic vector consisted of a recombinant adenovirus encoding a secreted form of the potent endogenous opioid beta-endorphin. In an inflammation model of persistent pain, administration of the vector into the cerebrospinal fluid (CSF) surrounding the spinal cord transduced meningeal pia mater cells. The resulting increase in beta-endorphin secretion attenuated inflammatory hyperalgesia, yet had no effect on basal nociceptive responses. This demonstration of a gene transfer approach to pain treatment can be generalized to neurodegenerative disorcers in which broad spatial distribution of therapeutic effect is critical. C1 NIDCR, Pain & Neurosensory Mechanisms Branch, NIH, Bethesda, MD 20892 USA. Univ Penn, Dept Anesthesiol, Philadelphia, PA 19104 USA. RP Iadarola, MJ (reprint author), NIDCR, Pain & Neurosensory Mechanisms Branch, NIH, Bldg 49,Room 1A11,49 Convent Dr,MSC 4410, Bethesda, MD 20892 USA. OI Mannes, Andrew/0000-0001-5834-5667 NR 37 TC 68 Z9 77 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 MAY 1 PY 1999 VL 10 IS 7 BP 1251 EP 1257 DI 10.1089/10430349950018238 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 193EE UT WOS:000080122300016 PM 10340556 ER PT J AU Cornejo-Roldan, LR Roessler, E Muenke, M AF Cornejo-Roldan, LR Roessler, E Muenke, M TI Analysis of the mutational spectrum of the FGFR2 gene in Pfeiffer syndrome SO HUMAN GENETICS LA English DT Article ID FIBROBLAST GROWTH-FACTORS; FACTOR RECEPTOR-2 GENE; CROUZON-SYNDROME; CRANIOSYNOSTOSIS SYNDROMES; IDENTICAL MUTATIONS; SYNDROME TYPE-2; POINT MUTATION; JACKSON-WEISS; EXON-IIIA; PHENOTYPES AB Pfeiffer syndrome (PS) is one of the classical craniosynostosis syndromes correlated with specific mutations in the human fibroblast growth factor receptor (FGFR) genes, FGFR1 and FGFR2. In this study, we set out to examine the exons in FGFR2 most commonly associated with mutations in PS, exons IIIa and IIIc, in a panel of 78 unrelated individuals with PS by the most sensitive method (direct DNA sequencing). We have identified a total of 18 different mutations among 40 patients; eight of these mutations have not been previously described. The mutational spectrum displays a non-random character with the frequent involvement of cysteine codons. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Penn, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, 10 Ctr Dr,MSC 1852,Bldg 10,10C101, Bethesda, MD 20892 USA. FU NICHD NIH HHS [HD28732, HD29862] NR 39 TC 33 Z9 36 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD MAY PY 1999 VL 104 IS 5 BP 425 EP 431 DI 10.1007/s004390050979 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 208MA UT WOS:000080994100011 PM 10394936 ER PT J AU Allikmets, R Raskind, WH Hutchinson, A Schueck, ND Dean, M Koeller, DM AF Allikmets, R Raskind, WH Hutchinson, A Schueck, ND Dean, M Koeller, DM TI Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A) SO HUMAN MOLECULAR GENETICS LA English DT Article ID EXPRESSED SEQUENCE TAGS; RETINITIS-PIGMENTOSA; FRIEDREICHS-ATAXIA; POINT MUTATIONS; YEAST; IDENTIFICATION; DEFICIENCY; FRATAXIN; HOMOLOG; CLONING AB X-linked sideroblastic anemia and ataxia (XLSA/A) is a recessive disorder characterized by an infantile to early childhood onset of non-progressive cerebellar ataxia and mild anemia with hypochromia and microcytosis. A gene encoding an ATP-binding cassette (ABC) transporter was mapped to Xq13, a region previously shown by linkage analysis to harbor the XLSA/A gene. This gene, ABC7, is an ortholog of the yeast ATM1 gene whose product localizes to the mitochondrial inner membrane and is involved in iron homeostasis. The full-length ABC7 cDNA was cloned and the entire coding region screened for mutations in a kindred in which five male members manifested XLSA/A. An I400M variant was identified in a predicted transmembrane segment of the ABC7 gene in patients with XLSA/A. The mutation was shown to segregate with the disease in the family and was not detected in at least 600 chromosomes of general population controls. Introduction of the corresponding mutation into the Saccharomyces cerevisiae ATM1 gene resulted in a partial loss of function of the yeast Atm1 protein. In addition, the human wild-type ABC7 protein was able to complement ATM1 deletion in yeast. These data indicate that ABC7 is the causal gene of XLSA/A and that XLSA/A is a mitochondrial disease caused by a mutation in the nuclear genome. C1 NCI, Lab Genom Divers, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. Univ Colorado, Hlth Sci Ctr, Dept Cell & Struct Biol, Denver, CO 80262 USA. Univ Colorado, Hlth Sci Ctr, Dept Pediat, Denver, CO 80262 USA. RP Dean, M (reprint author), NCI, Lab Genom Divers, Frederick Canc Res & Dev Ctr, Bldg 560,Room 21-18, Frederick, MD 21702 USA. RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 FU NCI NIH HHS [N01-CO-56000, R01 CA16448] NR 42 TC 251 Z9 258 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAY PY 1999 VL 8 IS 5 BP 743 EP 749 DI 10.1093/hmg/8.5.743 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 192ZG UT WOS:000080109200003 PM 10196363 ER PT J AU Nardo, CJ Chambless, LE Light, KC Rosamond, WD Sharrett, AR Tell, GS Heiss, G AF Nardo, CJ Chambless, LE Light, KC Rosamond, WD Sharrett, AR Tell, GS Heiss, G TI Descriptive epidemiology of blood pressure response to change in body position - The ARIC study SO HYPERTENSION LA English DT Article DE blood pressure; cardiovascular reactivity; epidemiology ID CARDIOVASCULAR REACTIVITY; POSTURAL HYPOTENSION; ORTHOSTATIC HYPOTENSION; BAROREFLEX SENSITIVITY; HYPERTENSIVE SUBJECTS; AGE; STRESS; RESPONSIVENESS; RACE; TILT AB The epidemiology of a common measure of cardiovascular reactivity, the change in systolic blood pressure (Delta SBP) from the supine to the standing position, is described in a cohort of 13 340 men and women aged 45 to 65 years enrolled in the Atherosclerosis Risk in Communities (ARIC) Study. The distribution of Delta SBP was found to be symmetrical and unimodal, with a mean value near zero (-0.45 mm Hg), The range of Delta SBP was from -63.2 to 54.3 mm Hg, and the standard deviation was 10.8. Stratification of Delta SBP by race and gender shows a slight shift in distribution toward higher values for black men and women. Delta SBP was categorized into deciles. Participants in the top 30% and bottom 30% of the distribution were compared with individuals in the middle 40% of the distribution, who had little or no change in SEP on standing. Participants in the bottom 30% (ie, SEP decreased on standing) were significantly older, had a greater prevalence of hypertension and peripheral vascular disease, had higher values of SEP, and had more cigarette-years of smoking. Among participants in the top 30% (ie, SEP increased on standing), a significantly larger proportion were black, mean seated SEP was higher, and the predicted risk of developing coronary heart disease after 8 years was greater. The response of SEP to change in posture showed considerable variability in a population sample of middle-aged adults. Cardiovascular morbidity, sociodemographic factors, and cigarette smoking were associated with the magnitude and direction of the postural change. C1 Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27514 USA. Univ N Carolina, Sch Publ Hlth, Collaborat Studies Coordinating Ctr, Chapel Hill, NC 27514 USA. Univ N Carolina, Sch Med, Dept Psychiat, Chapel Hill, NC 27514 USA. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Bergen, Norway. RP Heiss, G (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Suite 306,NationsBank Plaza,137 E Franklin St, Chapel Hill, NC 27514 USA. RI Tell, Grethe/G-5639-2015 OI Tell, Grethe/0000-0003-1386-1638 FU NHLBI NIH HHS [N01-HC-55015, N01-HC-55016, N01-HC-55018] NR 35 TC 58 Z9 63 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD MAY PY 1999 VL 33 IS 5 BP 1123 EP 1129 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 199MD UT WOS:000080485100006 PM 10334798 ER PT J AU Summers, RM AF Summers, RM TI Virtual bronchoscopy using VRML SO IEEE COMPUTER GRAPHICS AND APPLICATIONS LA English DT Article C1 NIH, Bethesda, MD 20892 USA. RP Summers, RM (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 5 TC 2 Z9 2 U1 0 U2 0 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1314 USA SN 0272-1716 J9 IEEE COMPUT GRAPH JI IEEE Comput. Graph. Appl. PD MAY-JUN PY 1999 VL 19 IS 3 BP 27 EP 29 PG 3 WC Computer Science, Software Engineering SC Computer Science GA 189LQ UT WOS:000079906800008 ER PT J AU Zhu, Q Sullivan, D Chance, B Dambro, T AF Zhu, Q Sullivan, D Chance, B Dambro, T TI Combined ultrasound and near infrared diffused light imaging in a test object SO IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL LA English DT Article ID FREQUENCY-DOMAIN; OPTICAL-PROPERTIES; SCATTERING MEDIA; BREAST; SONOGRAPHY; MIGRATION; LESIONS; BENIGN AB We have investigated the use of combining near infrared (NIR) diffuse light and ultrasound imaging methods to increase the detection sensitivity and to reduce the false alarm rate in small target detection. A line-of-sight optical projection through a test object is identified from an amplitude null and a sharp phase transition produced by diffusive waves originating from two in-phase (initial phase 0 degrees) and out-of-phase (initial phase 180 degrees) light emitting diode sources. This line-of-sight is scanned across a scattering phantom. A complete ultrasound B-scan image is recorded at each projected line in the optical scan. Each acoustic image plane is bisected by the optical beam path and lies in the optical scan plane. The scattering phantom simulates acoustic and optical properties of homogeneous tissue. A single small cylinder-like object simulating some acoustic and optical breast tumor properties is inserted at various places in the scattering phantom. With this single object, the optical scanning identifies the line-of-sight passing through the simulated tumor quite well. Most of these simulated tumors were at or below the threshold for acoustic detection and were not seen consistently with unguided ultrasound. For tests in which a target was apparently detected optically, the selected line-of-sight was indicated in each of three adjacent ultrasound images. Two radiologist observers were statistically more accurate (83%) in identifying the target location on the optically-selected ultrasound images than in the unmarked images (52%). That is, in these single-targets of homogeneous scattering background, the optical technique usually provided the correct line-of-sight, and ultrasound generally showed the location along that line. C1 Univ Connecticut, Dept Elect & Syst Engn, Storrs, CT 06269 USA. NCI, EPN, Diagnost Imaging Program, Rockville, MD 20892 USA. Univ Penn, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. Womens Imaging Ctr Delaware, Newark, DE 19806 USA. RP Zhu, Q (reprint author), Univ Connecticut, Dept Elect & Syst Engn, Storrs, CT 06269 USA. EM zhu@engr.uconn.edu NR 36 TC 12 Z9 12 U1 0 U2 0 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0885-3010 J9 IEEE T ULTRASON FERR JI IEEE Trans. Ultrason. Ferroelectr. Freq. Control PD MAY PY 1999 VL 46 IS 3 BP 665 EP 678 DI 10.1109/58.764853 PG 14 WC Acoustics; Engineering, Electrical & Electronic SC Acoustics; Engineering GA 196WW UT WOS:000080331700021 PM 18238467 ER PT J AU Kim, MG Chen, C Lyu, MS Cho, EG Park, D Kozak, C Schwartz, RH AF Kim, MG Chen, C Lyu, MS Cho, EG Park, D Kozak, C Schwartz, RH TI Cloning and chromosomal mapping of a gene isolated from thymic stromal cells encoding a new mouse type II membrane serine protease, epithin, containing four LDL receptor modules and two CUB domains SO IMMUNOGENETICS LA English DT Article DE thymic stroma; serine protease; CUB domain; LDLR domain; type II membrane protein ID DIFFERENTIATION; LYMPHOCYTES; RECOMBINATION; SEQUENCES; SELECTION; SEGMENTS; MUTANT; DEFECT; MICE; LINE AB We cloned and sequenced a mouse gene encoding a new type of membrane bound serine protease (epithin) containing a multidomain structure. The initial cDNA clone was found previously in a polymerase chain reaction (PCR)-based subtractive library generated from fetal thymic stromal cells. and the message was shown to be highly expressed in a thymic epithelial nurse cell line. A clone isolated from a severe combined immunodeficiency (SCID) thymus library and extended to its full length at the 5' end with the RACE technique contains an open reading frame of 902 amino acids. Based on the sequence of this clone, the predicted protein structure is a type II membrane protein with a C-terminal serine protease domain linked to the membrane by four low density Lipoprotein receptor modules and two CUB domains. High message expression by northern blotting was detected in intestine, kidney, lung, SCID, and Rag-2(-/-) thymus, and 2-deoxyguanosine-treated fetal thymic rudiment, but not in skeletal muscle, liver, heart, testis, and brain. Sorted MHC class II+ and II- fetal thymic stromal cells were positive for expression by reverse transcriptase-PCR, whereas CD45(+) thymocytes were not. Tnt: gene was found in chicken and multiple mammalian species under low stringency Southern hybridization conditions. Under high stringency conditions, only a single gene per haploid genome was identified in the mouse. This gene, Prss14 (protease, serine, 14), was mapped to mouse chromosome 9 and is closely linked to the Fli1 (Friend leukemia integration 1) gene. C1 NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. Seoul Natl Univ, Dept Biol Mol, Seoul, South Korea. RP Schwartz, RH (reprint author), NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. NR 33 TC 103 Z9 108 U1 1 U2 7 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0093-7711 J9 IMMUNOGENETICS JI Immunogenetics PD MAY PY 1999 VL 49 IS 5 BP 420 EP 428 DI 10.1007/s002510050515 PG 9 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 188WG UT WOS:000079871800007 PM 10199918 ER PT J AU Gentry-Weeks, CR Karkhoff-Schweizer, R Pikis, A Estay, M Keith, JM AF Gentry-Weeks, CR Karkhoff-Schweizer, R Pikis, A Estay, M Keith, JM TI Survival of Enterococcus faecalis in mouse peritoneal macrophages SO INFECTION AND IMMUNITY LA English DT Article ID STREPTOCOCCUS-FAECALIS; LISTERIA-MONOCYTOGENES; SALMONELLA-TYPHIMURIUM; INTRACELLULAR SURVIVAL; MURINE MACROPHAGES; GENETIC-ANALYSIS; PLASMID; HEMOLYSIN; ENDOCARDITIS; BACTEREMIA AB Enterococcus faecalis was tested for the ability to persist in mouse peritoneal macrophages in two separate studies. In the first study, the intracellular survival of serum-passaged E. faecalis 418 and two isogenic mutants [cytolytic strain FA2-2(pAM714) and non-cytolytic strain FA2-2(pAM771)] was compared with that of Escherichia coli DH5 alpha by infecting BALB/c mice intraperitoneally and then monitoring the survival of the bacteria within lavaged peritoneal macrophages over a 72-h period. All E. faccalis isolates were serum passaged to enhance the production of cytolysin. E. faecalis 418, FA2-2(pAM714), and FA2-2(pAM771) survived at a significantly higher level (P = 0.0001) than did E. coli DH5 alpha at 24, 48, and 72 h. Internalized E. faecalis 418, FA2-2(pAM714), and FA2-2(pAM771) decreased 10-, 55-, and 31-fold, respectively, over the 72-h infection period, while internalized E. coli DH5 alpha decreased 20,542-fold. The difference in the rate of survival of E. faecalis strains and E. coli DH5 alpha was most prominent between 6 and 48 h postinfection (P = 0.0001); however, no significant difference in killing was observed between 48 and 72 h postinfection. In the second study, additional E. faccalis strains from clinical sources, including DS16C2, MGH-2, OG1X, and the cytolytic strain FA2-2(pAM714), were compared with the nonpathogenic gram-positive bacterium, Lactococcus lactis K1, for the ability to survive in mouse peritoneal macrophages. In these experiments, the E. faccalis strains and L. lactis K1 were grown in brain heart infusion (BHI) broth to ensure that there were equal quantities of injected bacteria. E. faecalis FA2-2(pAM714), DS16C2, MGH-2, and OG1X survived significantly better (P < 0.0001) than did L. lactis K1 at each time point. L. lactis K1 was rapidly destroyed by the macrophages, and by 24 h postinfection, viable L. lactis could not be recovered. E. faecalis FA2-2(pAM714), DS16C2, MGH-2, and OG1X declined at an equivalent rate over the 72-h infection period, and there was no significant difference in survival or rate of decline among the strains. E. faecalis FA2-2(pAM714), MGH-2, DS16C2, and OG1X exhibited an overall decrease of 25-, 55-, 186-, and 129-fold respectively, between 6 and 72 h postinfection. The overall reduction by 1.3 to 2.27 log units is slightly higher than that seen for serum-passaged E. faecalis strains and may be attributable to the higher level of uptake of serum-passaged E. faccalis than of E. faecalis grown in BHI broth. Electron microscopy of infected macrophages revealed that E. faecalis 418 was present within an intact phagocytic vacuole at 6 h postinfection but that by 24 h the infected macrophages were disorganized, the vacuolar membrane was degraded, and the bacterial cells had entered the cytoplasm. Macrophage destruction occurred by 48 h, and the bacteria were released. In conclusion, the results of these experiments indicate that E. faecalis can persist for an extended period in mouse peritoneal macrophages. C1 Colorado State Univ, Dept Microbiol, Ft Collins, CO 80523 USA. Natl Inst Dent & Craniofacial Res, Vaccine & Therapeut Dev Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD USA. Childrens Natl Med Ctr, Dept Infect Dis, Washington, DC 20010 USA. RP Gentry-Weeks, CR (reprint author), Colorado State Univ, Dept Microbiol, Ft Collins, CO 80523 USA. RI Karkhoff-Schweizer, RoxAnn/E-5177-2017 NR 53 TC 59 Z9 61 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD MAY PY 1999 VL 67 IS 5 BP 2160 EP 2165 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 189MQ UT WOS:000079909300016 PM 10225869 ER PT J AU Cheever, AW Poindexter, RW Wynn, TA AF Cheever, AW Poindexter, RW Wynn, TA TI Egg laying is delayed but worm fecundity is normal in SCID mice infected with Schistosoma japonicum and S-mansoni with or without recombinant tumor necrosis factor alpha treatment SO INFECTION AND IMMUNITY LA English DT Article ID GRANULOMA-FORMATION; MURINE SCHISTOSOMIASIS; IMMUNOSUPPRESSED MICE; TH2 CELLS; T-CELLS; EXCRETION; PATHOLOGY; ANTIGEN AB Mice with severe combined immunodeficiency (SCID mice) lack functional B and T cells. Egg laying by Schistosoma mansoni and S. japonicum was delayed in SCID mice, but in a matter of weeks worm fecundity was equivalent to that in intact mice. SCID mice formed smaller hepatic granulomas and showed less fibrosis than did intact mice, The reduction in egg-associated pathology in SCID mice correlated with marked reductions in interleukin-4 (IL-4), IL-5, IL-13, and gamma interferon mRNA expression in the liver. S, mansoni infections were frequently lethal for SCID mice infected for more than 9 weeks, while S. japonicum-infected SCID mice died at the same rate as infected intact mice. We were unable to affect hepatic granuloma formation or egg laying by worms in SCID mice by administration of recombinant murine tumor necrosis factor alpha (TNF-alpha). In fact, SCID and BALB/c mice appeared to express nearly equivalent levels of TNF-alpha mRNA in their granulomatous tissues, suggesting that there is little or no deficit in TNF-alpha expression in infected SCID mice. The data indicate that TNF-alpha may be in large part derived from a non-T-cell source. Together, these findings provide little evidence that TNF-alpha alone can reconstitute early fecundity, granuloma formation, or hepatic fibrosis in schistosome-infected SCID mice. C1 NIAID, Parasit Dis Lab, Immunobiol Sect, NIH, Bethesda, MD 20892 USA. Inst Biomed Res, Rockville, MD USA. RP Wynn, TA (reprint author), NIH, Bldg 4,Rm 126, Bethesda, MD 20892 USA. RI Wynn, Thomas/C-2797-2011 NR 21 TC 52 Z9 53 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD MAY PY 1999 VL 67 IS 5 BP 2201 EP 2208 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 189MQ UT WOS:000079909300022 PM 10225875 ER PT J AU Wright, AC Powell, JL Tanner, MK Ensor, LA Karpas, AB Morris, JG Sztein, MB AF Wright, AC Powell, JL Tanner, MK Ensor, LA Karpas, AB Morris, JG Sztein, MB TI Differential expression of Vibrio vulnificus capsular polysaccharide SO INFECTION AND IMMUNITY LA English DT Article ID GROUP-B STREPTOCOCCI; TETANUS TOXOID CONJUGATE; INFLUENZAE TYPE-B; NEISSERIA-MENINGITIDIS; MONOCLONAL-ANTIBODIES; ESCHERICHIA-COLI; VIRULENCE; STRAINS; HETEROGENEITY; EFFICACY AB Vibrio vulnificus is a human pathogen whose virulence has been associated with the expression of capsular polysaccharide (CPS). Multiple CPS types have been described; however, virulence does not appear to correlate with a particular CPS composition. Reversible-phase variation for opaque and translucent colony morphologies is characterized by changes in CPS expression, as suggested by electron microscopy of cells stained nonspecifically with ruthenium red. Isolates with opaque colony morphologies are virulent and appear to be more thickly encapsulated than naturally occurring translucent-phase variants, which have reduced, patchy, or absent CPS, Previously, we have shown that the virulence of translucent-phase variants was intermediate between opaque-phase variants and acapsular transposon mutants, suggesting a correlation between virulence and the amount of CPS expressed, In the present study, CPS expression of phase variants and genetically defined mutants of V. vulnificus M06-24/O was examined by using a CPS-specific monoclonal antibody with an enzyme-linked immunosorbent assay, flow cytometry, and immunoelectron microscopy. Semiquantitative analyses of CPS expression correlated well among these assays, confirming that the translucent-phase variant was intermediate in CPS expression and retained type I CPS-specific epitopes, Cell surface expression of CPS varied with the growth phase, increasing during logarithmic growth and declining in stationary culture. Significantly greater CPS expression (P = 0.026) was observed for cells grown at 30 degrees C than for those at 37 degrees C. These studies confirm that phase variation and virulence in V. vulnificus correlate with the amount of CPS expressed and demonstrate the fluidity of bacterial polysaccharide expression in response to environmental conditions. C1 Univ Maryland, Inst Biotechnol, Ctr Marine Biotechnol, Baltimore, MD 21202 USA. Univ Maryland, Sch Med, Vet Affairs Med Ctr, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. NICHHD, NIH, Bethesda, MD 20892 USA. RP Wright, AC (reprint author), Univ Maryland, Inst Biotechnol, Ctr Marine Biotechnol, 701 E Pratt St, Baltimore, MD 21202 USA. NR 42 TC 54 Z9 56 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD MAY PY 1999 VL 67 IS 5 BP 2250 EP 2257 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 189MQ UT WOS:000079909300028 PM 10225881 ER PT J AU Clemans, DL Kolenbrander, PE Debabov, DV Zhang, QY Lunsford, RD Sakone, H Whittaker, CJ Heaton, MP Neuhaus, FC AF Clemans, DL Kolenbrander, PE Debabov, DV Zhang, QY Lunsford, RD Sakone, H Whittaker, CJ Heaton, MP Neuhaus, FC TI Insertional inactivation of genes responsible for the D-alanylation of lipoteichoic acid in Streptococcus gordonii DL1 (Challis) affects intrageneric coaggregations SO INFECTION AND IMMUNITY LA English DT Article ID GRAM-POSITIVE BACTERIA; WALL TEICHOIC-ACID; BACILLUS-SUBTILIS; LACTOBACILLUS-CASEI; D-ALANINE; ORAL BACTERIA; VIRIDANS STREPTOCOCCI; ESCHERICHIA-COLI; CARRIER PROTEIN; EXPRESSION AB Most human oral viridans streptococci participate in intrageneric coaggregations, the cell-to-cell adherence among genetically distinct streptococci, Two genes relevant to these intrageneric coaggregations were identified by transposon Tn916 mutagenesis of Streptococcus gordonii DL1 (Challis), A 626-bp sequence flanking the left end of the transposon was homologous to dltA and dltB of Lactobacillus rhamnosus ATCC 7469 (formerly called Lactobacillus casei). A 60-kb probe based on this Banking sequence was used to Identify the homologous DNA in a fosmid library of S. gordonii DL1. This DNA encoded D-alanine-D-alanyl carrier protein ligase that was expressed in Escherichia coli from the fosmid clone. The cloned streptococcal dltA was disrupted by inserting an ermAM cassette, and then it was linearized and transformed into S. gordonii DL1 for allelic replacement. Erythromycin-resistant transformants containing a single insertion in dltA exhibited a loss of D-alanyl esters in lipoteichoic acid (LTA) and a loss of intrageneric coaggregation, This phenotype was correlated with the loss of a 100-kDa surface protein reported previously to be involved in mediating intrageneric coaggregation (C. J. Whittaker, D. L. Clemans, and P. E. Kolenbrander, Infect. Immun, 64:4137-4142, 1996). The mutants retained the parental ability to participate in intergeneric coaggregation with human oral actinomyces, indicating the specificity of the mutation in altering intrageneric coaggregations. The mutants were altered morphologically and exhibited aberrant cell septa in a variety of pleomorphs. The natural DNA transformation frequency was reduced 10-fold in these mutants. Southern analysis of chromosomal DNAs from various streptococcal species with the dltA probe revealed the presence of this gene in most viridans streptococci, Thus, it is hypothesized that D-alanyl LTA may provide binding sites for the putative 100-kDa)a adhesin and scaffolding for the proper presentation of this adhesin to mediate intrageneric coaggregation. C1 NIDCR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. Northwestern Univ, Dept Biochem Mol Biol & Cell Biol, Evanston, IL 60208 USA. RP Kolenbrander, PE (reprint author), NIDCR, Oral Infect & Immun Branch, NIH, Bldg 30,30 Convent Dr,MSC 4350, Bethesda, MD 20892 USA. FU NIGMS NIH HHS [R01 GM51623] NR 68 TC 46 Z9 47 U1 2 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD MAY PY 1999 VL 67 IS 5 BP 2464 EP 2474 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 189MQ UT WOS:000079909300056 PM 10225909 ER PT J AU Kotake, S Schumacher, HR Arayssi, TK Gerard, HC Branigan, PJ Hudson, AP Yarboro, CH Klippel, JH Wilder, RL AF Kotake, S Schumacher, HR Arayssi, TK Gerard, HC Branigan, PJ Hudson, AP Yarboro, CH Klippel, JH Wilder, RL TI Gamma interferon and interleukin-10 gene expression in synovial tissues from patients with early stages of Chlamydia-associated arthritis and undifferentiated oligoarthritis and from healthy volunteers SO INFECTION AND IMMUNITY LA English DT Article ID REACTIVE ARTHRITIS; REITERS-SYNDROME; TRACHOMATIS; INFECTION; ANTIGEN; INHIBITION; CELLS AB Genetically determined differences in interleukin-10 (IL-10) and gamma interferon (IFN-gamma) responses in mice correlate viith clearance of Chlamydia pneumonitis infection. We measured the synovial expression of IL-10 and IFN-gamma and additional cytokine genes in patients who had recent onset Chlamydia-associated arthritis (Chl-AA). IL-IO and IFN-gamma mRNA were relatively abundant in recent-onset Chl-AA. C1 NIAMSD, ARB, NIH, Bethesda, MD 20892 USA. MCP Hahnemann Sch Med, Dept Vet Affairs Med Ctr, Philadelphia, PA USA. Med Coll Penn & Hahnemann Univ, Dept Microbiol & Immunol, Philadelphia, PA USA. Wayne State Univ, Sch Med, Dept Immunol & Microbiol, Detroit, MI 48201 USA. RP Wilder, RL (reprint author), NIAMSD, ARB, NIH, 10 Ctr Dr,MSC 1820,Bldg 10,Rm 9N228, Bethesda, MD 20892 USA. OI Arayssi, Thurayya/0000-0003-2469-0272 FU NIAMS NIH HHS [AR-42541, R01 AR042541] NR 23 TC 27 Z9 28 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD MAY PY 1999 VL 67 IS 5 BP 2682 EP 2686 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 189MQ UT WOS:000079909300090 PM 10225943 ER PT J AU Brunell, PA Wood, D AF Brunell, PA Wood, D TI Varicella serological status of healthcare workers as a guide to whom to test or immunize SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID SUSCEPTIBILITY AB Only 1.6% of 1,331 hospital workers were seronegative for varicella-zoster virus (VZV), including 8.7% of those with a negative history and 0.5% of those with a positive history. Seronegativity was inversely related to age but unrelated to job category, exposure at work to VZV, country of origin, race, or gender. C1 Univ Calif Los Angeles, Sch Med, Ahmanson Pediat Ctr, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Cedars Sinai Med Ctr, Los Angeles, CA USA. Shriners Hosp Crippled Children, Tampa, FL 33612 USA. RP Brunell, PA (reprint author), NIAID, Clin Invest Lab, NIH, Bldg 10,Rm 11N228,10 Ctr Dr, Bethesda, MD 20892 USA. NR 9 TC 12 Z9 12 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0899-823X J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD MAY PY 1999 VL 20 IS 5 BP 355 EP 357 DI 10.1086/501635 PG 3 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 197EG UT WOS:000080351200023 PM 10349958 ER PT J AU Lanzaro, GC Lopes, AHCS Ribeiro, JMC Shoemaker, CB Warburg, A Soares, M Titus, RG AF Lanzaro, GC Lopes, AHCS Ribeiro, JMC Shoemaker, CB Warburg, A Soares, M Titus, RG TI Variation in the salivary peptide, maxadilan, from species in the Lutzomyia longipalpis complex SO INSECT MOLECULAR BIOLOGY LA English DT Article DE maxadilan; population genetics; saliva; vasodilator ID SAND FLY SALIVA; ANTIGENIC DETERMINANTS; VASODILATORY PEPTIDE; PREDICTION; INFECTION; RECEPTOR; GLANDS AB Maxadilan is an approximately 7 kDa peptide that occurs in the saliva of the sand fly Lutzomyia longipalpis. This peptide is a potent vasodilator and may also have immunomodulatory effects related to the pathogenesis of leishmanial infections. Variation in the primary DNA and inferred amino acid sequence of maxadilan is reported. Differences were found within and among natural field populations as well as among sibling species. Extensive amino acid sequence differentiation, up to 23%, was observed among maxadilan from different populations. This is a remarkable degree of polymorphism considering the small size of this peptide. The vasodilatory activity of maxadilan was equivalent among recombinant maxadilan variants. All maxadilan variants induce interleukin-6. Predicted secondary structure and hydrophobicity plots suggest that these characteristics are conserved among variant peptides. However, profiles based on the antigenic index do differ among peptides. C1 Univ Texas, Med Branch, Dept Pathol, Galveston, TX 77555 USA. Univ Texas, Med Branch, Ctr Trop Dis, Galveston, TX 77555 USA. Fed Univ Rio De Janeiro, Inst Microbiol, BR-21941590 Rio De Janeiro, Brazil. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Publ Hlth, Dept Trop Publ Hlth, Boston, MA 02115 USA. Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Parasitol, IL-91120 Jerusalem, Israel. Fdn Oswaldo Cruz, Ctr Pesquisas Goncalo Moniz, Lab Patol & Biol Celular, Salvador, BA, Brazil. Colorado State Univ, Coll Vet Med & Biomed Sci, Dept Pathol, Ft Collins, CO 80523 USA. RP Lanzaro, GC (reprint author), Univ Texas, Med Branch, Dept Pathol, 301 Univ Blvd, Galveston, TX 77555 USA. OI Ribeiro, Jose/0000-0002-9107-0818 FU NIAID NIH HHS [AI 27511, AI39540] NR 25 TC 57 Z9 58 U1 0 U2 2 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0962-1075 J9 INSECT MOL BIOL JI Insect Mol. Biol. PD MAY PY 1999 VL 8 IS 2 BP 267 EP 275 DI 10.1046/j.1365-2583.1999.820267.x PG 9 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 201ZZ UT WOS:000080628800013 PM 10380110 ER PT J AU Striegel-Moore, RH Morrison, JA Schreiber, G Schumann, BC Crawford, PB Obarzanek, E AF Striegel-Moore, RH Morrison, JA Schreiber, G Schumann, BC Crawford, PB Obarzanek, E TI Emotion-induced eating and sucrose intake in children: The NHLBI growth and health study SO INTERNATIONAL JOURNAL OF EATING DISORDERS LA English DT Article DE emotion-induced eating; obesity; food intake; race differences ID BULIMIA NERVOSA; OBESITY; GIRLS; 9-YEAR-OLD; DISORDER; BEHAVIOR AB Objective: Emotion-induced eating has been implicated as a risk factor for the development of. obesity, yet no research has been done on emotion-induced eating in children. The National Heart, Lung, and Blood institute Growth and Health Study (NGHS) a multicenter collaborative study of risk factors for obesity, developed an instrument for measuring emotion-induced eating in children and tested hypotheses regarding the association of emotion-induced eating with food intake and adiposity in preadolescent children. Method: Subjects were 1,213 black girls and 1,166 white girls who were 9 and 10 at study entry. Baseline data were utilized in this report. Girls were assessed by trained female health examiners who recorded height, weight, and indices of sexual maturation. Girls kept a 3-day food diary. Dietary data were coded and analyzed for total caloric and macro nutrient intake. A measure of emotion-induced eating was derived from seven questions about eating in response to emotions (Cronbach's alpha = .78). Results: Black girls had significantly higher emotion-induced eating scores than white girls (10.8 vs. 9.7, P < .0001). For white girls, but not for black girls, emotion-induced eating was associated with increased intake of sucrose. In both races, a modest inverse association was found between body mass index and emotion-induced eating. Discussion: Prospective studies are needed to explore further the role of emotion-induced eating and food intake and the role of emotion-induced eating in the development of obesity. (C) 1999 by John Wiley & Sons, Inc. C1 Wesleyan Univ, Dept Psychol, Middletown, CT 06459 USA. Childrens Hosp, Med Ctr, Div Cardiol, Cincinnati, OH USA. WESTAT Inc, Rockville, MD 20850 USA. Maryland Med Res Inst, Baltimore, MD USA. Univ Calif Berkeley, Dept Publ Hlth, Berkeley, CA 94720 USA. NHLBI, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Striegel-Moore, RH (reprint author), Wesleyan Univ, Dept Psychol, 207 High St, Middletown, CT 06459 USA. EM rstriegel@Wesleyan.edu FU NHLBI NIH HHS [N0-HC-55023-26] NR 26 TC 23 Z9 23 U1 1 U2 4 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0276-3478 J9 INT J EAT DISORDER JI Int. J. Eating Disord. PD MAY PY 1999 VL 25 IS 4 BP 389 EP 398 DI 10.1002/(SICI)1098-108X(199905)25:4<389::AID-EAT3>3.0.CO;2-4 PG 10 WC Psychology, Clinical; Nutrition & Dietetics; Psychiatry; Psychology SC Psychology; Nutrition & Dietetics; Psychiatry GA 182KH UT WOS:000079497800003 PM 10202649 ER PT J AU Offord, EA Sharif, NA Mace, K Tromvoukis, Y Spillare, EA Avanti, O Howe, WE Pfeifer, AMA AF Offord, EA Sharif, NA Mace, K Tromvoukis, Y Spillare, EA Avanti, O Howe, WE Pfeifer, AMA TI Immortalized human corneal epithelial cells for ocular toxicity and inflammation studies SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID GLUTATHIONE S-TRANSFERASES; CONTACT-LENS MODEL; GENE-EXPRESSION; MESSENGER-RNA; IN-VITRO; ACID; EYE; RECEPTOR; VIMENTIN; KERATINOCYTES AB PURPOSE. To develop a metabolically competent, human immortalized corneal epithelial cell Line for use in toxicity and inflammation studies. METHODS. Primary corneal epithelial cells (P-CEPT) were immortalized by a recombinant simian virus (SV)40 T antigen retroviral vector defective for viral replication. The cells were grown in serum-free medium with the addition of bovine pituitary extract, cloned at passage 15 and one of the best-growing clones, CEPI-17-CL4, was extensively characterized for differentiation and metabolic characteristics of the human corneal epithelium. Methods used were immunostaining, reverse transcription-polymerase chain reaction (RT-PCR), northern blot analysis, and enzyme assays. RESULTS. The CEPI-17-CL4 cells showed a typical cobblestone morphology, grew to more than 200 passages and expressed the SV40 T antigen in the nucleus of every cell. Immunofluorescence staining for CEPI-17-CL4 cells was strongly positive for keratins (K)8, K18, and K19 and vimentin; weakly positive for K3, K13, and K17; and negative for K4, K7, and K14. Expression of cytokines (interleukin [IL]-1 alpha, IL-1 beta, IL-6, IL-8, tumor necrosis factor-cr, and IL-ra), growth factors (transforming growth factor [TGF]-alpha, epidermal growth factors [EGF], EGF receptor [EGFR], TGF-beta(1), TGF-beta(2), and platelet-derived growth factor-beta) and cytochrome P450 enzymes (1A1, 2C, 2E1, and 3A5) was similar in CEPI-17-CL4 cells and human corneal epithelial samples obtained in biopsy. The CEPI-17-CL4 cells were metabolically competent for enzymes glutathione S-transferase, quinone reductase, aflatoxin aldehyde reductase, glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase. CONCLUSIONS. The CEPI-17-CL4 cells are truly immortal and express an extensive array of cytokines, growth factors, and metabolic enzymes that resemble the original tissue. These characteristics, which remain stable up to high passage, will allow reproducible, mechanistic studies on toxicity inflammation, and wound healing. C1 Nestle Res Ctr, CH-1000 Lausanne 26, Switzerland. Alcon Labs Inc, Ft Worth, TX 76101 USA. NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Offord, EA (reprint author), Nestle Res Ctr, POB 44, CH-1000 Lausanne 26, Switzerland. NR 49 TC 76 Z9 78 U1 1 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAY PY 1999 VL 40 IS 6 BP 1091 EP 1101 PG 11 WC Ophthalmology SC Ophthalmology GA 192ER UT WOS:000080065900008 PM 10235542 ER PT J AU Silver, PB Tarrant, TK Chan, CC Wiggert, B Caspi, RR AF Silver, PB Tarrant, TK Chan, CC Wiggert, B Caspi, RR TI Mice deficient in inducible nitric oxide synthase are susceptible to experimental autoimmune uveoretinitis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; INDUCTION; UVEITIS; AMINOGUANIDINE; INHIBITOR; LACKING AB PURPOSE. Nitric oxide (NO) is an important mediator of inflammatory tissue damage. The present study addresses the question whether inducible nitric oxide synthase (iNOS), and consequently the ability to upregulate NO, is required to effect the pathogenesis of experimental autoimmune uveoretinitis (EAU) in mice. METHODS. Mice with a homologous disruption of the iNOS gene (iNOS KO) were evaluated for their ability to develop EAU and associated cellular responses after immunization with the interphotoreceptor retinoid-binding protein. EAU Nas determined by histopathology 21 days after uveitogenic immunization, and antigen-specific cellular responses were assessed by delayed type hypersensitivity and lymphocyte proliferation. RESULTS. iNOS knockout (iNOS RO) mice developed EAU with scores similar to wild-type mice and exhibited good cellular responses to the immunizing antigen. CONCLUSIONS. A functional iNOS gene is not necessary for EAU pathogenesis. Therefore, upregulation of NO is not required to mediate autoimmune tissue damage in the eye. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Caspi, RR (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Room 10N222,10 Ctr Dr,MSC 1857, Bethesda, MD 20892 USA. NR 17 TC 6 Z9 7 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAY PY 1999 VL 40 IS 6 BP 1280 EP 1284 PG 5 WC Ophthalmology SC Ophthalmology GA 192ER UT WOS:000080065900032 PM 10235566 ER PT J AU Bettelheim, FA Zigler, JS AF Bettelheim, FA Zigler, JS TI Pressure-induced syneretic response in rhesus monkey lenses SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID LIGHT-SCATTERING; RAT LENSES; AGE; WATER; STATE AB PURPOSE. TO investigate the effect of pressure on the freezable and nonfreezable water content of the lens. METHODS. Excised rhesus monkey lenses in tissue culture media were subjected to three different hydrostatic pressures (2 arm, 1 atm, and 0.03 atm) for 24 hours. Then while still under the experimental pressure, the vessels were cooled in dry ice-acetone until the lenses were frozen. While the lenses were kept frozen, nuclear and cortical samples were dissected, enclosed in a sample pan, and weighed. Differential scanning calorimetry (DSC) measurements were performed between -30 degrees C and 30 degrees C. Total water content of each lens sample was obtained by thermogravimetric analysis at 105 degrees C. The non freezable water content was obtained by subtracting the freezable water content calculated from the DSC data from the total water content. RESULTS. The total water content of the lenses did not change significantly as a function of pressure applied. This was true both for cortical and for nuclear sections. The freezable water content increased as the pressure decreased both in cortex and nucleus. Similarly, the freezable water/nonfreezable water ratio also decreased with increasing pressure. CONCLUSIONS. External hydrostatic pressure would generate II influx of water into the lens. To alleviate this diluting tendency and to prevent turbidity as a result of dilution, the lens must effect an osmotic pressure change equivalent to the applied pressure. Change in the osmotic pressure is caused by changing the activity of the water (i.e., converting free water to bound water). This is a reversible and energetically the least expensive response. The release of bound water from the hydration layers of macromolecules and its conversion to free water in condensed systems are known as syneresis. In the lens decreasing pressures induce syneresis as demonstrated by the increase in freezable water content and the freezable water/nonfreezable water ratio. Such a response may be operative also in accommodating lenses. C1 Adelphi Univ, Dept Chem, Garden City, NY 11530 USA. NEI, Lab Mechanism Ocular Dis, NIH, Bethesda, MD 20892 USA. RP Bettelheim, FA (reprint author), Adelphi Univ, Dept Chem, Garden City, NY 11530 USA. FU NEI NIH HHS [EY-12496] NR 20 TC 6 Z9 6 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAY PY 1999 VL 40 IS 6 BP 1285 EP 1288 PG 4 WC Ophthalmology SC Ophthalmology GA 192ER UT WOS:000080065900033 PM 10235567 ER PT J AU Petty, BG Black, JR Hendrix, CW Lewis, LD Basiakos, Y Feinberg, J Pattison, DG Hafner, R AF Petty, BG Black, JR Hendrix, CW Lewis, LD Basiakos, Y Feinberg, J Pattison, DG Hafner, R TI Escalating multiple-dose safety and tolerance study of oral WR 6026 in HIV-infected subjects: AIDS clinical trials group 173 SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; WR 6026; safety; tolerance; Pneumocystis carinii pneumonia ID PNEUMOCYSTIS-CARINII PNEUMONIA; ACQUIRED IMMUNODEFICIENCY SYNDROME; TRIMETHOPRIM-SULFAMETHOXAZOLE; CLINDAMYCIN-PRIMAQUINE; RANDOMIZED TRIAL; DOUBLE-BLIND; THERAPY; PROPHYLAXIS; MODERATE; 8-AMINOQUINOLINES AB WR 6026 is an 8-aminoquinoline with activity against Pneumocystis carinii in vitro and in an animal model of P. carinii pneumonia that has predicted the clinical utility of related compounds. This study was conducted to assess the safety and tolerance of WR 6026 given once daily for 21 days to HIV-infected subjects with CD4 counts <500 cells/mu l. This double-blind, placebo-controlled study employed WR 6026 doses starting at 30 mg once daily and increasing to 60, 90, 120, or 150 mg once daily. Weekly visits for clinical and laboratory monitoring were conducted. Forty-nine study subjects, including 25 subjects with CD4 counts <200 cells/mu l and 12 subjects with CD4 counts <100 cells/mu l, entered the study. The maximum tolerated dose was 120 mg/day. Dose-limiting methemoglobinemia >20%) was seen in 3 of 6 study subjects who received 150 mg/day for greater than or equal to 19 days. Methemoglobin level was correlated with peak plasma WR 6026 concentrations. Three other study subjects developed skin rashes that may have been drug-related, and two developed asymptomatic serum triglyceride levels >1000 mg/dl. We conclude that WR 6026 is well tolerated at doses up to 120 mg/day for 21 days in HN-infected volunteers including those with CD4 counts <200 cells/mu l. Methemoglobinemia appears to be the primary dose-limiting toxicity. C1 Johns Hopkins Univ, Sch Med, Div Clin Pharmacol, Baltimore, MD USA. Indiana Univ, Indianapolis, IN 46204 USA. Wilford Hall USAF Med Ctr, Dept Infect Dis, Lackland AFB, TX 78236 USA. Mil Med Consortium Appl Retroviral Res, Lackland AFB, TX USA. NIAID, Div Aids, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Div Infect Dis, Baltimore, MD 21205 USA. RP Petty, BG (reprint author), Johns Hopkins Hosp, Div Clin Pharmacol, 600 N Wolfe St,Osler 527, Baltimore, MD 21287 USA. RI Hendrix, Craig/G-4182-2014 OI Hendrix, Craig/0000-0002-5696-8665 FU NCRR NIH HHS [M01RR00750, 5M01RR00722, RR-00035] NR 22 TC 5 Z9 7 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-9450 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. PD MAY 1 PY 1999 VL 21 IS 1 BP 26 EP 32 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 191QA UT WOS:000080032000004 PM 10235511 ER PT J AU Massad, LS Riester, KA Anastos, KM Fruchter, RG Palefsky, JM Burk, RD Burns, D Greenblatt, RM Muderspach, LI Miotti, P AF Massad, LS Riester, KA Anastos, KM Fruchter, RG Palefsky, JM Burk, RD Burns, D Greenblatt, RM Muderspach, LI Miotti, P CA Women's Interagcy HIV Study Grp TI Prevalence and predictors of squamous cell abnormalities in Papanicolaou smears from women infected with HIV-1 SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article; Proceedings Paper CT 5th Conference on Retroviruses and Opportunistic Infections CY FEB 01-05, 1998 CL CHICAGO, IL DE HIV; cytology; screening; squamous intraepithelial lesion ID HUMAN-IMMUNODEFICIENCY-VIRUS; CERVICAL INTRAEPITHELIAL NEOPLASIA; HUMAN-PAPILLOMAVIRUS INFECTION; RISK-FACTORS; COLPOSCOPY; CANCER; POPULATION; MANAGEMENT; DYSPLASIA; LESIONS AB Cervical neoplasia occurs with increased frequency among women infected with HIV-1. Objective: To characterize prevalence of and risk factors for abnormal cervical cytology among women with HIV and to compare them to uninfected women. Methods: Baseline cervical cytology was obtained from 1713 women seropositive for HIV and 482 at-risk control women who were enrolled in the Women's Interagency HIV Study, a multicenter prospective cohort study conducted in six U.S. cities. Associations with sociodemographic, medical, and sexual variables were assessed by Fisher's exact test, Mantel extension test, and logistic regression analysis. Results: Cervical cytology was abnormal in 38.3% of HIV-infected women (atypical squamous cells of uncertain significance [ASCUS] 20.9%, low-grade squamous cells of uncertain significance [LSIL] 14.9%, high-grade squamous cells of uncertain significance [HSIL] 2.3%, cancer 0.2%) and 16.2% of HIV-uninfected women (ASCUS 12.7%, LSIL 2.3%, HSIL 1.2%, cancer 0.0%). Risk factors for any abnormal cytology in multivariate analysis included HIV infection, CD4 cell count, HIV RNA level, detection of human papillomavirus (HPV), a prior history of abnormal cytology, employment, and number of male sex partners within 6 months of enrollment. Prior abortion was associated with a decreased risk of cytologic abnormality. Conclusions: Cervical cytologic abnormalities were frequent among women infected with HIV, although high-grade changes were found in only 2.5%. Factors linked to sexual and reproductive history, HPV infection, and HIV disease all influenced risk. C1 Cook Cty Hosp, Dept Obstet & Gynecol, Div Gynecol Oncol, Chicago, IL 60612 USA. Rush Med Coll, Chicago, IL 60612 USA. New England Res Inst, Watertown, MA 02172 USA. Montefiore Med Ctr, Bronx, NY 10467 USA. SUNY Brooklyn, Dept Obstet & Gynecol, Brooklyn, NY USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA. NICHHD, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA USA. Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA USA. Univ So Calif, Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90033 USA. NIAID, Div Aids, Bethesda, MD 20892 USA. RP Massad, LS (reprint author), Cook Cty Hosp, Dept Obstet & Gynecol, Div Gynecol Oncol, Chicago, IL 60612 USA. EM lsmassad@ameritech.net FU NIAID NIH HHS [U01-AI-31834, U01-AI-34994, U01-AI-35004] NR 46 TC 119 Z9 127 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. PD MAY 1 PY 1999 VL 21 IS 1 BP 33 EP 41 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 191QA UT WOS:000080032000005 PM 10235512 ER PT J AU Raine, TR Jenkins, R Aarons, SJ Woodward, K Fairfax, JL El-Khorazaty, MN Herman, A AF Raine, TR Jenkins, R Aarons, SJ Woodward, K Fairfax, JL El-Khorazaty, MN Herman, A TI Sociodemographic correlates of virginity in seventh-grade black and Latino students SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE adolescents; minorities; risk factors; risk behaviors; sexual activity; virginity; gender differences ID HIGH-SCHOOL STUDENTS; SEXUAL-BEHAVIOR; CIGARETTE-SMOKING; AFRICAN-AMERICANS; FAMILY-STRUCTURE; US ADOLESCENTS; RISK BEHAVIORS; HEALTH RISK; INTERCOURSE; INITIATION AB Purpose: To examine rates of virginity in seventh-grade black and Latino students and assess the extent to which various sociodemographic factors are correlated with virginity. Methods: A total of 523 seventh-grade students from five junior high schools and one middle school in the District of Columbia completed an anonymous self-administered questionnaire. Students responded to questions about age at first intercourse, demographics, grades, educational expectations, and risk behaviors. Multivariate analysis was used to determine the independent strength of the association of these variables with virginity. Results: Eighty-one percent of girls and 44% of boys reported never having had sexual intercourse, i.e., being virgins. Black and Latino students were equally as likely to report being virgins. Younger age and absence of other risk behaviors, including smoking and alcohol use, were associated with virginity for males and females. For boys, reporting high academic achievement and living with both parents was significantly correlated with virginity and appeared to be protective. Conclusions: Although prevalent particularly in seventh-grade black and Latino boys, sexual activity was clearly associated with other risk behaviors in both boys and girls. Sociodemographic correlates of virginity were gender-specific. School-based efforts to delay the onset of initiation of sexual activity in high-risk populations should be targeted at boys 12 years and younger with interventions which are gender-specific. This study underscores a need to examine correlates of virginity to generate practical approaches to prevention of early sexual activity. (C) Society for Adolescent Medicine, 1999. C1 Georgetown Univ, Ctr Med, Dept Gynecol & Obstet, Washington, DC USA. Howard Univ, Coll Med, Dept Pediat & Child Hlth, Washington, DC USA. Childrens Natl Med Ctr, Div Adolescent & Young Adult Med, Washington, DC 20010 USA. Dist Columbia Publ Sch, Comprehens Sch Hlth Program, Washington, DC USA. Res Triangle Inst, Rockville, MD USA. Natl Inst Child Hlth & Human Dev, Rockville, MD USA. RP Raine, TR (reprint author), Univ Calif San Francisco, San Francisco Gen Hosp, Dept Obstet Gynecol & Reprod Hlth Sci, Ward 6D,1001 Potrero Ave, San Francisco, CA 94110 USA. FU NICHD NIH HHS [U18-HD30458, U18-HD30447, U18-HD30450] NR 32 TC 36 Z9 37 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD MAY PY 1999 VL 24 IS 5 BP 304 EP 312 DI 10.1016/S1054-139X(98)00109-8 PG 9 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 192AY UT WOS:000080056400003 PM 10331836 ER PT J AU Siegel, RM Fleisher, TA AF Siegel, RM Fleisher, TA TI The role of Fas and related death receptors in autoimmune and other disease states SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Review DE Fas; APO-1; CD95; autoimmune lymphoproliferative syndrome; autoimmunity; therapy; lymphocytes; apoptosis ID DOMAIN-CONTAINING RECEPTOR; TUMOR-NECROSIS-FACTOR; INDUCED CELL-DEATH; SYSTEMIC LUPUS-ERYTHEMATOSUS; LIGAND-INDUCED APOPTOSIS; CONFER IMMUNE PRIVILEGE; MATURE T-LYMPHOCYTES; LYMPHOPROLIFERATIVE SYNDROME; DENDRITIC CELLS; B-CELLS AB The Pas receptor, also known as APO-1 or CD95, has emerged as a hey initiator of apoptotic programmed cell death in a variety of cell types. CD4(+) T cells are unique in their ability to commit "suicide" by stimulating their own Pas receptors with secreted or membrane-bound Pas ligand. This takes place in the setting of repeated stimulation with T-cell antigens and is thought to be a mechanism for controlling the expansion of T cells during viral infections and autoimmune disease states. T cells can also trigger apoptosis in B cells, macrophages, and other cell types through Pas ligand, These interactions negatively regulate the immune system but can also contribute to immunopathology, as occurs in Pas-mediated damage of target tissues in hepatitis and other organ-specific autoimmune diseases. The dual role of Pas in the immune response complicates the understanding of its role in disease states and may limit its potential as a therapeutic target, Despite the many roles of Pas in immunoregulation, findings in experimental mouse strains and human patients with genetic deficiencies in the Pas pathway have shown that the main result of disrupting this pathway in vivo is systemic autoimmunity and a predisposition toward lymphoid malignancies. The role of Pas in various cell types and the lessons we have learned from Fas-deficient patients with the autoimmune lymphoproliferative syndrome will be discussed. C1 NIAID, Immunol Lab, Bethesda, MD 20892 USA. NIH, Dept Clin Pathol, Ctr Clin, Bethesda, MD 20892 USA. RP Fleisher, TA (reprint author), Bldg 10,Rm 2C306,10 Ctr Dr,Msc 1508, Bethesda, MD 20892 USA. RI Siegel, Richard/C-7592-2009 OI Siegel, Richard/0000-0001-5953-9893 NR 100 TC 41 Z9 42 U1 0 U2 0 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAY PY 1999 VL 103 IS 5 BP 729 EP 738 DI 10.1016/S0091-6749(99)70412-4 PN 1 PG 10 WC Allergy; Immunology SC Allergy; Immunology GA 199FP UT WOS:000080470200002 PM 10329802 ER PT J AU Groves, FD Zhang, LA Chang, YS Ross, PF Casper, H Norred, WP You, WC Fraumeni, JF AF Groves, FD Zhang, LA Chang, YS Ross, PF Casper, H Norred, WP You, WC Fraumeni, JF TI Fusarium mycotoxins in corn and corn products in a high-risk area for gastric cancer in Shandong Province, China SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID FREE SPHINGOID BASES; CUT RAT-LIVER; FUMONISIN B-1; SLICES AB Consumption of fermented, but not unfermented, corn pancakes has been linked with elevated stomach cancer mortality rates in rural Linqu County in Shandong Province, China. Previous surveys of fungal contamination of corn in China have detected fumonisins, which are mycotoxins produced by Fusarium moniliforme. To determine whether mycotoxins might account for the increased risk of cancer among those consuming fermented pancakes, we obtained specimens of corn, cornmeal, unfermented and fermented pancake batter, and cooked fermented pancakes from each of 16 households in Linqu County for analysis by the U.S. Department of Agriculture, Fumonisins B-1, B-2, and B-3 were detected (greater than or equal to 0.5 mu g/g) in 19, 25, and 6% of the corn specimens, respectively, as well as in various corn products, No type A trichothecenes were detected; however, the type B trichothecenes deoxynivalenol and 15-acetyldeoxynivalenol were detected (greater than or equal to 0.5 mu g/g) in 58 and 17% of the corn specimens, respectively, and zearalenone was detected (greater than or equal to 0.5 mu/g) in 15% of the cornmeal specimens. The mycotoxins were detected only at low levels (< 10 mu g/g), which did not increase with fermentation. These findings do not support the hypothesis that mycotoxin contamination increases the risk of gastric cancer among those who consume fermented Chinese pancakes. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Beijing Inst Canc Res, Beijing 100034, Peoples R China. Anim & Plant Hlth Inspect Serv, USDA, Natl Vet Serv Labs, Ames, IA 50010 USA. N Dakota State Univ, Dept Vet & Microbiol Sci, Fargo, ND 58105 USA. ARS, USDA, Russell Res Ctr, Athens, GA 30604 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 11 TC 36 Z9 41 U1 0 U2 2 PU AOAC INT PI GAITHERSBURG PA 481 N FREDRICK AVE, STE 500, GAITHERSBURG, MD 20877-2504 USA SN 1060-3271 EI 1944-7922 J9 J AOAC INT JI J. AOAC Int. PD MAY-JUN PY 1999 VL 82 IS 3 BP 657 EP 662 PG 6 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA 201NJ UT WOS:000080601400012 PM 10367384 ER PT J AU Frank, SM Raja, SN Bulcao, CF Goldstein, DS AF Frank, SM Raja, SN Bulcao, CF Goldstein, DS TI Relative contribution of core and cutaneous temperatures to thermal comfort and autonomic responses in humans SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE adrenergic; epinephrine; hypothermia; metabolism; norepinephrine; thermal comfort; thermoregulation; vasoconstriction ID RANDOMIZED CLINICAL-TRIAL; SKIN BLOOD-FLOW; THERMOREGULATORY RESPONSES; BODY; HYPOTHERMIA; SENSITIVITY AB Subjective thermal comfort plays a critical role in body temperature regulation since this represents the primary stimulus for behavioral thermoregulation. Although both core (T-c) and skin-surface (T-sk) temperatures are known afferent inputs to the thermoregulatory system, the relative contributions of T-c and T-sk to thermal comfort are unknown. We independently altered T-c and T-sk in human subjects while measuring thermal comfort, vasomotor changes, metabolic heat production, and systemic catecholaminergic responses. Multiple linear regression was used to determine the relative T-c/T-sk contribution to thermal comfort and the autonomic thermoregulatory responses, by using the ratio of regression coefficients for T-c and T-sk. The T-c/T-sk contribution ratio was relatively lower for thermal comfort (1:1) than for vasomotor changes (3:1; P = 0.008), metabolic heat production (3.6:1; P = 0.001), norepinephrine (1.8:1; P = 0.03), and epinephrine (3:1; P = 0.006) responses. Thus T-c and T-sk contribute about equally toward thermal comfort, whereas T-c predominates in regulation of the autonomic and metabolic responses. C1 Johns Hopkins Med Inst, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21287 USA. McGill Univ, Sch Med, Montreal, PQ H3G 1A4, Canada. NINDS, Clin Neurosci Branch, Clin Neurochem Sect, NIH, Bethesda, MD 20892 USA. RP Frank, SM (reprint author), Johns Hopkins Med Inst, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21287 USA. OI Yang, Shuman/0000-0002-9638-0890 FU NINDS NIH HHS [NS-26363]; PHS HHS [5MO1R00052] NR 32 TC 141 Z9 142 U1 2 U2 20 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD MAY PY 1999 VL 86 IS 5 BP 1588 EP 1593 PG 6 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 195FV UT WOS:000080240700020 PM 10233122 ER PT J AU Taft-Benz, SA Schaaper, RM AF Taft-Benz, SA Schaaper, RM TI The C-terminal domain of DnaQ contains the polymerase binding site SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ESCHERICHIA-COLI; III HOLOENZYME; SALMONELLA-TYPHIMURIUM; WILD-TYPE; SUBUNIT; MUTANTS; EXONUCLEASE; REPLICATION; DELETIONS; PROTEINS AB The Escherichia coli dnaQ gene encodes the 3'-->5' exonucleolytic proofreading (epsilon) subunit of DNA polymerase III (PoI III). Genetic analysis of dnaQ mutants has suggested that epsilon might consist of two domains, an N-terminal domain containing the exonuclease and a C-terminal domain essential for binding the polymerase (or) subunit. We have created truncated forms of dnaQ resulting in epsilon subunits that contain either the N-terminal or the C-terminal domain. Using the yeast two-hybrid system, we analyzed the interactions of the single-domain epsilon subunits with the alpha and theta subunits of the Pol III core. The DnaQ991 protein, consisting of the N-terminal 186 amino acids, was defective in binding to the cw subunit while retaining normal binding to the theta subunit. In contrast, the N Delta 186 protein, consisting of the C-terminal 57 amino acids, exhibited normal binding to the alpha subunit but was defective in binding to the theta subunit. A strain carrying the dnaQ991 allele exhibited a strong, recessive mutator phenotype, as expected from a defective alpha binding mutant. The data are consistent with the existence of two functional domains in epsilon, with the C-terminal domain responsible for polymerase binding. C1 NIEHS, Genet Mol Lab, Res Triangle Pk, NC 27709 USA. RP Schaaper, RM (reprint author), NIEHS, Genet Mol Lab, POB 12233,MC E3-01, Res Triangle Pk, NC 27709 USA. NR 24 TC 29 Z9 29 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD MAY PY 1999 VL 181 IS 9 BP 2963 EP 2965 PG 3 WC Microbiology SC Microbiology GA 205LB UT WOS:000080821600044 PM 10217794 ER PT J AU Bebenek, A Smith, LA Drake, JW AF Bebenek, A Smith, LA Drake, JW TI Bacteriophage T4 rnh (RNase H) null mutations: Effects on spontaneous mutation and epistatic interaction with rII mutations SO JOURNAL OF BACTERIOLOGY LA English DT Article ID FLAP ENDONUCLEASE; DNA; TOPOISOMERASE; REPLICATION; EXONUCLEASE; MUTANTS; PROTEINS; BINDING; HOTSPOT; REPAIR AB The bacteriophage T4 mh gene encodes T4 RNase H, a relative of a family of flap endonucleases. T4 mh null mutations reduce burst sizes, increase sensitivity to DNA damage, and increase the frequency of acriflavin resistance (Ac-r) mutations. Because mutations in the related Saccharomyces cerevisiae RAD27 gene display a remarkable duplication mutator phenotype, we further explored the impact of mh mutations upon the mutation process. We observed that most Ac-r mutants in an rnh(+) strain contain ac mutations, whereas only roughly half of the Ac-r mutants detected in an rnh Delta strain bear ac mutations. In contrast to the mutational specificity displayed by most mutators, the DNA alterations of ac mutations arising in rnh Delta and rnh(+) backgrounds are indistinguishable. Thus, the increase in Ac-r mutants in an rnh Delta background is probably not due to a mutator effect. This conclusion is supported by the lack of increase in the frequency of rI mutations in an rnh Delta background. In a screen that detects mutations at both the rI locus and the much larger rII locus, the r frequency was severalfold lower in an rnh Delta background. This decrease was due to the phenotype of mh rII double mutants, which display an r(+) plaque morphology but retain the characteristic inability of rII mutants to grow on lambda lysogens. Finally, we summarize those aspects of T4 forward-mutation systems which are relevant to optimal choices for investigating quantitative and qualitative aspects of the mutation process. C1 NIEHS, Lab Mol Genet E3 01, Res Triangle Pk, NC 27709 USA. RP Drake, JW (reprint author), NIEHS, Lab Mol Genet E3 01, POB 12233, Res Triangle Pk, NC 27709 USA. NR 32 TC 4 Z9 4 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD MAY PY 1999 VL 181 IS 10 BP 3123 EP 3128 PG 6 WC Microbiology SC Microbiology GA 197AQ UT WOS:000080342800017 PM 10322013 ER EF