FN Thomson Reuters Web of Science™ VR 1.0 PT J CA Comm Infect Dis TI Recommended Childhood Immunization Schedule - United States, January-December 2000 SO PEDIATRICS LA English DT Article C1 Comm Infect Dis, Elk Grove Village, IL 60007 USA. Red Book, New York, NY 10019 USA. Pediat Practice Act Grp, Elk Grove Village, IL 60007 USA. Amer Thorac Soc, New York, NY 10019 USA. Canadian Paediat Soc, Ottawa, ON, Canada. Ctr Dis Control & Prevent, Atlanta, GA USA. US FDA, Rockville, MD 20857 USA. NIH, Bethesda, MD 20892 USA. Natl Vaccine Program Off, Rockville, MD USA. RP Comm Infect Dis, Elk Grove Village, IL 60007 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD JAN PY 2000 VL 105 IS 1 BP 148 EP 151 PG 4 WC Pediatrics SC Pediatrics GA 273KL UT WOS:000084706400026 ER PT J AU Pichichero, ME Edwards, KM Anderson, EL Rennels, MB Englund, JA Yerg, DE Blackwelder, WC Jansen, DL Meade, BD AF Pichichero, ME Edwards, KM Anderson, EL Rennels, MB Englund, JA Yerg, DE Blackwelder, WC Jansen, DL Meade, BD TI Safety and immunogenicity of six acellular pertussis vaccines and one whole-cell pertussis vaccine given as a fifth dose in four- to six-year-old children SO PEDIATRICS LA English DT Article DE acellular; adverse reactions; antibody; diphtheria-tetanus-pertussis vaccine; pertussis vaccine; whole cell; whooping cough ID LINKED IMMUNOSORBENT-ASSAY; TOXIN NEUTRALIZATION TEST; ADVERSE REACTIONS; HUMAN-SERA; IMMUNIZATIONS; ANTITOXIN; ELISA AB Objective. To evaluate the safety and immunogenicity of 6 different acellular pertussis vaccines combined with diphtheria and tetanus toxoids (DTaP) and with 1 licensed whole-cell pertussis vaccine (DTwP) as a fifth dose in children who had previously received the same DTaP, a different DTaP, or DTwP as primary and fourth-dose vaccinations. Methods. Healthy 4- to 6-year-old children were enrolled at 5 National Institute of Allergy and Infectious Diseases Vaccine Treatment and Evaluation Units to receive a fifth dose of a DTaP or DTwP vaccine. All had been randomly assigned to receive 3 primary doses of DTaP or DTwP at 2, 4, and 6 months and a fourth-dose booster at 15 to 20 months of age as part of earlier National Institutes of Health multicenter acellular pertussis vaccine trials. Parents recorded the occurrence and magnitude of fever, irritability, and injection site redness, swelling, and pain for 3 days after vaccination. Sera obtained before and 1 month after the booster vaccination were analyzed by enzyme-linked immunosorbent assay for antibody to pertussis toxin, filamentous hemagglutinin, fimbriae, pertactin, and diphtheria and tetanus toxoid. Safety and/or immunogenicity data are reported for 317 children who received DTaP and 10 children who received DTwP. Results. Fever and moderate or severe irritability were uncommon following the fifth dose of DTaP vaccine and were generally less frequent than following the fourth dose. However, for the DTaP vaccine groups, redness, swelling, and pain increased in prevalence compared with the fourth dose. The time course and frequency of reactions following DTaP vaccination were generally similar in children who received the same DTaP, a different DTaP, or DTwP for previous doses in the 5- dose series. No significant differences among the DTaP vaccines were detected in the occurrence of reactions, but the statistical power to detect differences was limited by sample size. Significant increases in antibodies directed against the included antigens were observed for all DTaP vaccines in paired pre- and post-fifth dose sera. Post-fifth dose antibody concentrations differed significantly among the DTaP vaccines. Some children in the study showed an antibody response to an antigen not reported to be in the DTaP vaccine. Conclusion. All the studied DTaP vaccines performed similarly with regard to reactions, whether given as a fifth sequential dose of the same vaccine, a mix of different DTaP vaccines in the 5-dose sequence, or after 3 DTwP and 1 DTaP vaccinations. Large injection site reactions occurred more frequently after the fifth dose of DTaP than after the previous 4 doses. A fifth dose of all DTaP vaccines induced an antibody response to those antigens contained in the vaccine. No DTaP was consistently most or least reactogenic or immunogenic. C1 Univ Rochester, Med Ctr, Dept Microbiol & Immunol, Sch Med, Rochester, NY 14642 USA. Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37212 USA. St Louis Univ, Sch Med, Dept Med, St Louis, MO 63104 USA. Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. Baylor Coll Med, Dept Microbiol, Houston, TX 77030 USA. Baylor Coll Med, Dept Immunol, Houston, TX 77030 USA. Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. NIAID, Div Microbiol & Infect Dis, Bethesda, MD 20892 USA. Ctr Biol Evaluat & Res, Div Bacterial Prod, Rockville, MD USA. RP Pichichero, ME (reprint author), Univ Rochester, Med Ctr, Dept Microbiol & Immunol, Sch Med, 601 Elmwood Ave,POB 672, Rochester, NY 14642 USA. FU NIAID NIH HHS [N01-AI05051, N01-AI02645, N01-AI05049] NR 22 TC 42 Z9 42 U1 0 U2 2 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JAN PY 2000 VL 105 IS 1 BP art. no. EP e11 DI 10.1542/peds.105.1.e11 PG 8 WC Pediatrics SC Pediatrics GA 273KL UT WOS:000084706400038 PM 10617748 ER PT J AU Rennels, MB Deloria, MA Pichichero, ME Losonsky, GA Englund, JA Meade, BD Anderson, EL Steinhoff, MC Edwards, KM AF Rennels, MB Deloria, MA Pichichero, ME Losonsky, GA Englund, JA Meade, BD Anderson, EL Steinhoff, MC Edwards, KM TI Extensive swelling after booster doses of acellular pertussis-tetanus-diphtheria vaccines SO PEDIATRICS LA English DT Article; Proceedings Paper CT Meeting of the Academic-Pediatric-Societies CY MAY 03, 1998 CL NEW ORLEANS, LOUISIANA SP Acad Pediat Societies DE pertussis; reactions; vaccine; diphtheria; toxoid ID WHOLE-CELL; ADVERSE REACTIONS; CHILDREN; IMMUNOGENICITY; IMMUNIZATION; TOXOIDS; JAPAN; REACTOGENICITY; VACCINATION; RESPONSES AB Background. Diphtheria and tetanus toxoid combined with acellular pertussis (DTaP) vaccines are less reactogenic than diphtheria and tetanus toxoid combined with whole cell pertussis (DTwP) vaccines. However, local reactions increase in rate and severity with each successive DTaP dose, and swelling of the entire injected limb has been reported after booster doses. Methods. We reviewed reports of swelling of the entire thigh or upper arm after the fourth and fifth dose, respectively, of DTaP vaccines administered in the National Institutes of Health multicenter comparative DTaP studies. Relationships were explored among reports of severe swelling, rates of other reactions, quantity of vaccine contents, and prevaccination and postvaccination antibody levels to pertussis toxin, tetanus toxin, and diphtheria toxin. Results. Entire thigh swelling was an unsolicited reaction reported in 20 (2%) of the 1015 children who received 4 consecutive doses of the same DTaP vaccine. The reaction was associated with 9 of the 12 DTaP vaccines evaluated. Although there were no reports of swelling of the entire upper arm in 121 children given a fifth dose of the same DTaP, 4 (2.7%) of 146 recipients of 5 doses of a mixed schedule of DTaP vaccines experienced such swelling. Rates of other reactions were higher in children with entire thigh swelling than in those without. Of the children with entire thigh swelling, 60% had local pain, and 60% had erythema. All swelling subsided spontaneously without sequelae. There was a significant linear association between the rates of entire thigh swelling after dose 4 and diphtheria toxoid content in the DTaP products. Lesser degrees of swelling (> 50 mm but less than entire limb) correlated with pertussis toxoid content after dose 4 and aluminum content after dose 5. No relationship was established between levels of serum antibody to diphtheria, tetanus, or pertussis toxin and rates of swelling of the whole thigh. Conclusions. Booster doses of DTaP vaccines can cause entire limb swelling, which is usually associated with redness and pain. Our data suggest that this extensive swelling reaction may be more common with vaccines containing high diphtheria toxoid content. C1 Univ Maryland, Sch Med, Baltimore, MD 21201 USA. NIAID, NIH, Bethesda, MD 20892 USA. Univ Rochester, Sch Med, Rochester, NY USA. Baylor Coll Med, Houston, TX 77030 USA. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. Johns Hopkins Sch Publ Hlth, Baltimore, MD USA. St Louis Univ, Sch Med, St Louis, MO USA. Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. RP Rennels, MB (reprint author), 22 S Greene St, Baltimore, MD 21201 USA. FU NIAID NIH HHS [N01-AI15096, N01-AI02645, N01-AI05049] NR 27 TC 81 Z9 81 U1 1 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JAN PY 2000 VL 105 IS 1 BP art. no. EP e12 DI 10.1542/peds.105.1.e12 PG 6 WC Pediatrics SC Pediatrics GA 273KL UT WOS:000084706400039 PM 10617749 ER PT J AU Rich, KC Fowler, MG Mofenson, LM Abboud, R Pitt, J Diaz, C Hanson, IC Cooper, E Mendez, H AF Rich, KC Fowler, MG Mofenson, LM Abboud, R Pitt, J Diaz, C Hanson, IC Cooper, E Mendez, H CA Women Infants Transmission Study G TI Maternal and infant factors predicting disease progression in human immunodeficiency virus type 1-infected infants SO PEDIATRICS LA English DT Article DE human immunodeficiency virus type 1; infant; maternal; disease progression ID VITAMIN-A-DEFICIENCY; INFECTED INFANTS; P24 ANTIGENEMIA; CLINICAL-TRIALS; HIV-INFECTION; CHILDREN; TRANSMISSION; AIDS; MORTALITY; MOTHERS AB Background. Infants with perinatally acquired human immunodeficiency virus type 1 (HIV-1) infection have widely variable courses. Previous studies showed that a number of maternal and infant factors, when analyzed separately, are associated with infant HIV-1 disease progression. In this study, clincal, virologic, and immunologic characteristics in the mothers and infants were examined together to determine the predictors of disease progression by 18 months of age and the associations with rapid progression during the first 6 months of life. Methods. One hundred twenty-two HIV-1-infected women whose infants were HIV-1 infected were identified from the Women and Infants Transmission Study (WITS) cohort. WITS is a longitudinal natural history study of perinatal HIV-1 infection carried out in 6 sites in the continental United States and in Puerto Rico. The women were enrolled during pregnancy and their infants were enrolled at the time of delivery and followed prospectively by a standardized protocol. Virologic and immunologic studies were performed in laboratories certified by National Institutes of Health-sponsored quality assurance programs. Maternal factors in pregnancy were used as potential predictors of infant disease progression (progression to Centers for Disease Control and Prevention [CDC] Clinical Class C disease or death by 18 months of age) or as correlates of progression at <6 months of age. Infant factors defined during the first 6 months of life were used as potential predictors of progression during 6 to 18 months of age and as correlates of progression at <6 months of age. Results. Progression by 18 months of age occurred in 32% of infants and by 6 months of age in 15%. Maternal characteristics that, by univariate analysis, were significant predictors of infant disease progression by 18 months of age were elevated viral load, depressed CD4(+)%, and depressed vitamin A. CD8(+)%, CD8(+) activation markers, zidovudine (ZDV) use, hard drug use, and gestational age at delivery were not. When examined in a combined multivariate analysis of maternal characteristics, only vitamin A concentration independently predicted infant progression. Infant characteristics during the first 6 months of life that, by univariate analysis, were associated with disease progression included elevated mean viral load at 1 to 6 months of age, depressed CD4(+)%, CDC Clinical Disease Category B, and growth delay. Early HIV-1 culture positivity (< 48 hours), CD8(+)%, CD8(+) activation markers, and ZDV use during the first month of life did not predict progression. Multivariate analysis of infant characteristics showed that the only independent predictors were progression to CDC Category B by 6 months of age (odds ratio [OR], 5.80) and mean viral load from 1 to 6 months of age (OR, 1.99). The final combined maternal and infant analysis included the significant maternal and infant characteristics in a multivariate analysis. It showed that factors independently predicting infant progression by 18 months of age were progression to CDC Category B by 6 months of age (OR, 5.80) and elevated mean HIV-1 RNA copy number at 1 to 6 months of age (OR, 1.99). The characteristics associated with rapid progression to CDC Category C disease or death by 6 months of age were also examined. The only maternal characteristic associated with progression by 6 months in multivariate analysis was low maternal CD4(+)%. The infant characteristics associated with progression by 6 months of age in multivariate analysis were depressed mean CD4(+)% from birth through 2 months and the presence of lymphadenopathy, hepatomegaly, or splenomegaly by 3 months. Infant ZDV use was not assocciated with rapid progression. Conclusion. The strongest predictors of progression by 18 months are the presence of moderate clinical symptoms and elevated RNA copy number in the infants in the first 6 months of life. In contrast, progression by 6 months is associated with maternal and infant immune suppression, and the presence of infant clinical symptoms. The difference suggests that the key pathogenetic mechanisms responsible for progression may vary with age. These observations help provide direction for future pathogenesis research and assist in clinical care. C1 Univ Illinois, Dept Pediat, Chicago, IL 60612 USA. NIAID, Bethesda, MD 20892 USA. NICHHD, Bethesda, MD 20892 USA. New England Res Inst, Watertown, MA 02172 USA. Columbia Univ, Coll Phys & Surg, New York, NY USA. Univ Puerto Rico, San Juan, PR 00936 USA. Baylor Coll Med, Houston, TX 77030 USA. Boston City Hosp, Boston, MA 02118 USA. SUNY Hlth Sci Ctr, Brooklyn, NY 11203 USA. RP Rich, KC (reprint author), Univ Illinois, Dept Pediat, M-C 856,840 S Wood St, Chicago, IL 60612 USA. FU NIAID NIH HHS [U01 AI 34858, UO1 AI 34852, U01 AI 34856] NR 33 TC 32 Z9 33 U1 0 U2 2 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JAN PY 2000 VL 105 IS 1 AR e8 DI 10.1542/peds.105.1.e8 PG 6 WC Pediatrics SC Pediatrics GA 273KL UT WOS:000084706400035 PM 10617745 ER PT J AU Shearer, WT Lipshultz, SE Easley, KA McIntosh, K Pitt, J Quinn, TC Kattan, M Goldfarb, J Cooper, E Bryson, Y Kovacs, A Bricker, JT Peavy, H Mellins, RB AF Shearer, WT Lipshultz, SE Easley, KA McIntosh, K Pitt, J Quinn, TC Kattan, M Goldfarb, J Cooper, E Bryson, Y Kovacs, A Bricker, JT Peavy, H Mellins, RB CA Natl Heart Lung Blood Inst TI Alterations in cardiac and pulmonary function in pediatric rapid human immunodeficiency virus type 1 disease progressors SO PEDIATRICS LA English DT Article DE human immunodeficiency virus infections; human immunodeficiency virus type 1; child; infant; newborn; diseases; disease progression; cohort studies; lung; heart ID HIV-INFECTION; VIRAL LOAD; CHILDREN; MULTICENTER; SURVIVAL; INFANTS; LIFE; RNA AB Objective. Infants with human immunodeficiency virus type 1 (HIV- 1) can be divided into rapid progressors (RPs) and non-rapid progressors (non-RPs) based on symptoms and immunologic status, but detailed information about cardiac and pulmonary function in RP and non-RP children needs to be adequately described. Methodology. Cardiac, pulmonary, and immunologic data and HIV- 1 RNA burden were periodically measured in 3 groups: group I, 205 vertically infected children enrolled from 1990 to 1994 and followed through 1996; group II, a prospectively studied cohort enrolled at birth that included 93 infected (group IIa); and 463 noninfected infants (group IIb). Results. Mean respiratory rates were generally higher in group IIa RP than non-RP children throughout the period of follow-up, achieving statistical signifance at 1 month, 12 months, 24 months, 30 months, and 48 months of follow-up. Non-RP and group IIb (HIV-uninfected children) had similar mean respiratory rates from birth to 5 years of age. Significant differences in mean respiratory rates were found between group I RP and non-RP at 7 age intervals over the first 6 years of life. Mean respiratory rates were higher in RP than in non-RP at <1 year, 2.0 years, 2.5 years, 3.0 years, 3.5 years, 4.0 years, and 6.0 years of age. Mean heart rates in group IIa RP, non-RP, and group IIb differed at every age. Rapid progressors had higher mean heart rates than non-RP at all ages through 24 months. Mean heart rates at 30 months through 60 months of age were similar for RP and non-RP children. Non-RP children had higher mean heart rates than did group IIb at 8 months, 24 months, 36 months, 42 months, 48 months, 54 months, and 60 months of age. In group I, RP had higher mean heart rates than non-RP at 2.0 years, 2.5 years, 3.0 years, and 4.0 years of age. After 4 years of age, the non-RP and RP had similar mean heart rates. Mean fractional shortening differed between the 3 group II subsets (RP, non-RP, and IIb) at 4, 8, 12, 16, and 20 months of age. Although mean fractional shortening was lower in RP than in non-RP in group II at all time points between 1 and 20 months, the mean fractional shortening was significantly lower in RP only at 8 months when restricting the statistical comparisons to the 2 HIV-infected groups (RP and non-RP). Mean fractional shortening increased in the first 8 months of life followed by a gradual decline through 5 years of age among group IIb children. No significant differences among the 3 groups in mean fractional shortening were detected after 20 months of age. In group I, differences between RP and non-RP in mean fractional shortening were detected at 1.5, 2.0, 2.5, and 3.0 years of age. After 3 years of age, group means for fractional shortening in RP and non-RP did not differ. Because of the limited data from the first months of the group I patients, it could not be determined whether this group experienced the gradual early rise in mean fractional shortening seen in the group II infants. In group IIa, RP had more clinical (eg, oxygen saturation <96%) and chest radiographic abnormalities (eg, cardiomegaly) at 18 months of life. RP also had significantly higher 5-year cumulative mortality than non-RP, higher HIV-1 viral burdens than non-RP, and lower CD8(+) T-cell counts. Conclusions. Rapid disease progression in HIV-1-infected infants is associated with significant alterations in heart and lung function: increased respiratory rate, increased heart rate, and decreased fractional shortening. The same children exhibited the anticipated significantly increased 5-year cumulative mortality, increased serum HIV-1 RNA load, and decreased CD8(+) (cytotoxic) T-cell counts. Measurements of cardiopulmonary function in HIV-1-infected children seem to be useful in the total assessment of HIV-1 disease progression. C1 Texas Childrens Hosp, Dept Allergy & Immunol, Houston, TX 77030 USA. Baylor Coll Med, Houston, TX 77030 USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Columbia Univ, Sch Med, New York, NY USA. Presbyterian Hosp, New York, NY USA. NIAID, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD USA. Mt Sinai Sch Med, New York, NY USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Boston Med Ctr, Boston, MA USA. Univ Calif Los Angeles, Med Ctr, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. Univ So Calif, Sch Med, Los Angeles, CA USA. NHLBI, Bethesda, MD 20892 USA. RP Shearer, WT (reprint author), Texas Childrens Hosp, Dept Allergy & Immunol, 6621 Fannin St MC 1-3291, Houston, TX 77030 USA. RI Easley, Kirk/K-6910-2015 OI Easley, Kirk/0000-0003-4419-2617 FU NCRR NIH HHS [M01 RR000645, M01 RR002172, M01 RR000865, M01 RR000043, K01 RR000188, M01 RR000071, M01 RR000188, M01 RR000533]; NHLBI NIH HHS [N01-HR-96037,, N01-HR-96038, N01 HR096037, N01-HR-96039] NR 22 TC 12 Z9 13 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JAN PY 2000 VL 105 IS 1 AR e9 DI 10.1542/peds.105.1.e9 PG 8 WC Pediatrics SC Pediatrics GA 273KL UT WOS:000084706400036 PM 10617746 ER PT J AU Moody, TW Coy, D Cuttitta, F Montuenga, LM AF Moody, TW Coy, D Cuttitta, F Montuenga, LM TI Proadrenomedullin NH2-terminal 20 peptide (PAMP) and adrenomedullin bind to teratocarcinoma cells SO PEPTIDES LA English DT Article DE PAMP; adrenomedullin; receptors; cAMP; c-fos mRNA; growth ID GENE-RELATED PEPTIDE; AUTOCRINE GROWTH-FACTOR; N-TERMINAL-20 PEPTIDE; HYPOTENSIVE PEPTIDE; RETINOIC ACID; VASCULAR BED; HUMAN TISSUE; CYCLIC-AMP; CALCITONIN; RECEPTOR AB Proadrenomedullin NH2-terminal 20 peptide (PAMP) and adrenomedullin (ADM) bind to teratocarcinoma cells. The effects of PAMP and ADM on teratocarcinoma cells were investigated. I-125-PAMP bound to PA 1 cells with moderate affinity (K-d = 110 nM) to a single class of sites (B-max = 110 000/cell). Specific I-125-PAMP binding was inhibited by PAMP (IC50 of 100 nM) but not ADM, calcitonin gene-related peptide (CGRP), or amylin. Specific I-125-ADM binding was inhibited with high affinity by ADM, CGRP, and CGRP(8-37) (IC50 values of 10, 10, and 15 nM respectively) but not PAMP or amylin. ADM elevated cAMP (ED50 value of 100 nM), whereas PAMP had no effect on basal cAMP but inhibited the increase in cAMP caused by 10 nM ADM. Also, the increase in cAMP caused by ADM was inhibited CGRP(8-37), suggesting that ADM is binding to CGRP receptors. ADM (100 nM) stimulated transiently c-fos mRNA, whereas PAMP (1000 nM) had little effect; however, PAMP inhibited the increase in c-fos mRNA caused by ADM. ADM stimulated [H-3]thymidine uptake into PAI cells, whereas PAMP inhibited the increase in thymidine uptake caused by ADM. These results indicate that ADM and PAMP are both biologically active in teratocarcinoma cells. Published by Elsevier Science Inc. C1 NCI, Med Branch, Dept Cell & Canc Biol, Rockville, MD 20850 USA. Tulane Univ, Sch Med, Dept Med, Peptide Res Lab, New Orleans, LA 70112 USA. Univ Navarra, Dept Histol & Pathol, E-31080 Pamplona, Spain. RP Moody, TW (reprint author), NCI, Med Branch, Dept Cell & Canc Biol, Rockville, MD 20850 USA. FU NIDDK NIH HHS [DK36107] NR 42 TC 20 Z9 23 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD JAN PY 2000 VL 21 IS 1 BP 101 EP 107 DI 10.1016/S0196-9781(99)00178-3 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 291LH UT WOS:000085735300013 PM 10704725 ER PT B AU Gao, Y Yao, ZJ Voigt, D Luo, JH Yang, DJ Burke, TR AF Gao, Y Yao, ZJ Voigt, D Luo, JH Yang, DJ Burke, TR BE Fields, GB Tam, JP Barany, G TI Novel phosphotyrosyl mimetics for the preparation of potent small molecule Grb2 SH2 domain inhibitors SO PEPTIDES FOR THE NEW MILLENNIUM LA English DT Proceedings Paper CT 16th American Peptide Symposium CY JUN 26-JUL 01, 1999 CL MINNEAPOLIS, MN SP Amer Peptide Soc ID BINDING C1 NCI, Div Basic Sci, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RP Gao, Y (reprint author), NCI, Div Basic Sci, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RI Burke, Terrence/N-2601-2014; Yao, Zhu-Jun/E-7635-2015 NR 5 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS BN 0-7923-6445-7 PY 2000 BP 566 EP 567 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BR58X UT WOS:000166856900223 ER PT B AU Long, YQ Lung, FDT Voigt, JH Yao, ZJ Burke, TR Yang, DJ Luo, JH Guo, RB King, CR Roller, PP AF Long, YQ Lung, FDT Voigt, JH Yao, ZJ Burke, TR Yang, DJ Luo, JH Guo, RB King, CR Roller, PP BE Fields, GB Tam, JP Barany, G TI High affinity nonphosphorylated cyclic peptide inhibitors of Grb2-SH2/growth factor receptor interactions SO PEPTIDES FOR THE NEW MILLENNIUM LA English DT Proceedings Paper CT 16th American Peptide Symposium CY JUN 26-JUL 01, 1999 CL MINNEAPOLIS, MN SP Amer Peptide Soc ID GRB2 SH2 DOMAIN; BINDING C1 NCI, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RP Long, YQ (reprint author), NCI, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RI Burke, Terrence/N-2601-2014; Yao, Zhu-Jun/E-7635-2015 NR 8 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS BN 0-7923-6445-7 PY 2000 BP 568 EP 570 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BR58X UT WOS:000166856900224 ER PT B AU Yao, ZJ Barchi, JJ Burke, TR AF Yao, ZJ Barchi, JJ Burke, TR BE Fields, GB Tam, JP Barany, G TI Design and synthesis of a new tyrosine analog having chi(1) and chi(2) angles constrained to values observed for an SH2 domain-bound phosphotyrosyl residue SO PEPTIDES FOR THE NEW MILLENNIUM LA English DT Proceedings Paper CT 16th American Peptide Symposium CY JUN 26-JUL 01, 1999 CL MINNEAPOLIS, MN SP Amer Peptide Soc ID SRC HOMOLOGY-2 DOMAIN C1 NCI, Div Basic Sci, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RP Yao, ZJ (reprint author), NCI, Div Basic Sci, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RI Barchi Jr., Joseph/N-3784-2014; Burke, Terrence/N-2601-2014; Yao, Zhu-Jun/E-7635-2015 NR 3 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS BN 0-7923-6445-7 PY 2000 BP 576 EP 578 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BR58X UT WOS:000166856900227 ER PT J AU Jeffcoat, MK Lewis, CE Reddy, MS Wang, CY Redford, M AF Jeffcoat, MK Lewis, CE Reddy, MS Wang, CY Redford, M TI Post-menopausal bone loss and its relationship to oral bone loss SO PERIODONTOLOGY 2000 LA English DT Article ID ESTROGEN REPLACEMENT THERAPY; PERIODONTAL-DISEASE; ALVEOLAR BONE; HIP FRACTURE; TOOTH LOSS; POSTMENOPAUSAL WOMEN; INCREASED RISK; ELDERLY WOMEN; SKELETAL BONE; OSTEOPOROSIS C1 Univ Alabama, Sch Dent, Dept Periodont, Birmingham, AL 35294 USA. Univ Alabama, Sch Med, Dept Med, Div Prevent Med, Birmingham, AL 35294 USA. NIDCR, NIH, Bethesda, MD USA. Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. RP Jeffcoat, MK (reprint author), Univ Alabama, Sch Dent, Dept Periodont, Birmingham, AL 35294 USA. NR 52 TC 66 Z9 67 U1 0 U2 3 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0906-6713 J9 PERIODONTOL 2000 JI Periodontol. 2000 PY 2000 VL 23 BP 94 EP 102 DI 10.1034/j.1600-0757.2000.2230109.x PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 315CZ UT WOS:000087096200009 PM 11276771 ER PT J AU Glavac, D Ravnik-Glavac, M Potocnik, U Dean, M Wine, J AF Glavac, D Ravnik-Glavac, M Potocnik, U Dean, M Wine, J TI Screening methods for cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in non-human primates SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Article; Proceedings Paper CT Life Sciences Conference 1998 Signalling Concepts in Life Sciences CY SEP 19-24, 1998 CL GOZD MARTULJEK, SLOVENIA DE non-isotopic conformation analysis; mutation detection; CFFR gene; animal model; gene therapy ID GENOMIC DNA-SEQUENCE AB We report here a comparison of isotopic and non-isotopic conformation analysis approach, for screening genomic DNA for coding variations In the cystic fibrosis transmembrane conductance regulator (CFTR) gene. A large pool of non-human primates was tested in order to detect naturally occuring CFTR carriers, for future testing of gene therapy of cystic fibrosis. We screened 25 of 27 CFTR exons in over 1,000 animals. We have detected numerous missense mutations and single nucleotide polymorphisms. We found that both methods are highly efficient for detection of variations in DNA sequence, but the non-radioactive approach is faster, less expensive and in some Gases more sensitive. C1 Univ Ljubljana, Fac Med, Inst Pathol, Genet Mol Lab, SI-1000 Ljubljana, Slovenia. Univ Ljubljana, Fac Med, Inst Biochem, SI-1000 Ljubljana, Slovenia. NCI, NIH, Lab Genom Divers, Bethesda, MD 20892 USA. Stanford Univ, Cyst Fibrosis Res Lab, Stanford, CA 94305 USA. RP Glavac, D (reprint author), Univ Ljubljana, Fac Med, Inst Pathol, Genet Mol Lab, Korytkova 2, SI-1000 Ljubljana, Slovenia. RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 NR 6 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0031-6768 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PY 2000 VL 439 IS 3 SU S BP R12 EP R13 DI 10.1007/s004240000072 PG 2 WC Physiology SC Physiology GA 271BG UT WOS:000084572000005 PM 27757673 ER PT J AU Ravnik-Glavac, M Dean, M di Sant'Agnese, P Chernick, M Kozelj, M Krizman, I Glavac, D AF Ravnik-Glavac, M Dean, M di Sant'Agnese, P Chernick, M Kozelj, M Krizman, I Glavac, D TI Evidence that hereditary pancreatitis is genetically heterogeneous disorder SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Article; Proceedings Paper CT Life Sciences Conference 1998 Signalling Concepts in Life Sciences CY SEP 19-24, 1998 CL GOZD MARTULJEK, SLOVENIA DE hereditary pancreatitis; cationic trypsinogen gene mutations; cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations; genetic heterogeneity ID CYSTIC-FIBROSIS GENE; CATIONIC TRYPSINOGEN GENE; DNA-SEQUENCE; MUTATIONS; IDENTIFICATION; FORMS AB Hereditary pancreatitis (HP) is an autosomal dominant disorder characterized by recurrent acute attacks of severe abdominal pain with an onset in early childhood. Many HP patients progress to complicated chronic pancreatitis and/or pancreatic cancer. Initially, a single mutation R117H in the cationic trypsinogen gene was detected in all affected members of five unrelated HP families. Further studies identified a second mutation (N21L) in two HP families without the R117H mutation. Before the association between cationic trypsinogen and HP was found, we detected a cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation (L327R) in all affected individuals of a family with HP. We therefore performed a mutational analysis for R117H and N21L in cationic trypsinogen in this and three additional unrelated families with HP. The R117H mutation was detected in all 9 affected members of three HP families and in 3 asymptomatic but at-risk relatives. However, neither the R117H nor the N21L mutation in the cationic trypsinogen were found in the HP family with the L327R alteration in CFTR. The L327R allele segregates with the disease within this HP family and was not detected on 360 unrelated Caucasian non-CF chromosomes. Although close to 800 different mutations have been detected in the CF gene of cystic fibrosis patients, L327R is a new alteration, not yet reported in connection with CF. The results of this study indicate that the CFTR gene may play a role in the etiology of minority of cases with HP and suggest that hereditary pancreatitis is genetically heterogeneous disease. C1 Univ Ljubljana, Fac Med, Inst Biochem, SI-1000 Ljubljana, Slovenia. Univ Ljubljana, Fac Med, Inst Pathol, Genet Mol Lab, SI-1000 Ljubljana, Slovenia. NCI, NIH, Lab Genom Divers, Bethesda, MD 20892 USA. NIDDKD, NIH, Pediat Metab Branch, Bethesda, MD 20892 USA. Univ Ljubljana, Med Ctr, Dept Gastroenterol, SI-1000 Ljubljana, Slovenia. RP Ravnik-Glavac, M (reprint author), Univ Ljubljana, Fac Med, Inst Biochem, Vrazov Trg 2, SI-1000 Ljubljana, Slovenia. RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 NR 18 TC 10 Z9 10 U1 0 U2 2 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0031-6768 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PY 2000 VL 439 IS 3 SU S BP R50 EP R52 DI 10.1007/s004240000088 PG 3 WC Physiology SC Physiology GA 271BG UT WOS:000084572000021 PM 27757658 ER PT J AU Ravnik-Glavac, M Dean, M Glavac, D AF Ravnik-Glavac, M Dean, M Glavac, D TI Study of mutant and polyvariant mutant CFTR genes in patients with congenital absence of the vas deferens SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Article; Proceedings Paper CT Life Sciences Conference 1998 Signalling Concepts in Life Sciences CY SEP 19-24, 1998 CL GOZD MARTULJEK, SLOVENIA DE cystic fibrosis transmembrane conductance; regulator; cystic fibrosis; congenital bilateral absence of the vas defrens; CFTR gene mutations; polyvariant CFTR genes ID CYSTIC-FIBROSIS GENE; BILATERAL ABSENCE; POLYMORPHISM; MUTATIONS AB Congenital bilateral absence of the vas deferens (CBAVD) is a form of male infertility in which mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been identified. Cystic fibrosis patients have mutations in both alleles of the gene while most CBAVD patients have mutations in only one allele. Frequently, the second CFTR allele is not mutant but polyvariant. We have studied CFTR gene mutations and polyvariant allele (TG)m(T)n in intron 8 in 37 patients with CBAVD. Ten (27%) compound heterozygotes and 16 (43.3%) heterozygotes have been detected, while no alteration have been found in the coding and intronic bounderies regions in 11 (29.7%) patients. DeltaF508 was the most frequent mutation present in 15/74 (20.3%) alleles. Additional mutant alleles include: R117H (6.8%), R75Q (5.4%), D1270N (2.7%) and G576A (2.7%). We identified in total 14 different mutations and mutant variants, of which one E804V has not been reported previously. Of 37 alleles with not detectable alteration in the coding or splice site regions the (TG)12(T)5 allele has been found in 14 (37.8%) genes. If we consider that (TG)12(T)5 is believed per se to be a highly penetrant pathogenic allele connected with CBAVD, we have detected a disease-causing alterations in 49/74 (66.2%) CFTR alleles of CBAVD patients. These results are extremely important for genetic counseling of couples indicated for in vitro fertilization. C1 Univ Ljubljana, Fac Med, Inst Biochem, SI-1000 Ljubljana, Slovenia. Univ Ljubljana, Fac Med, Inst Pathol, Genet Mol Lab, SI-1000 Ljubljana, Slovenia. NCI, NIH, Lab Genom Divers, Bethesda, MD 20892 USA. RP Ravnik-Glavac, M (reprint author), Univ Ljubljana, Fac Med, Inst Biochem, Vrazov Trg 2, SI-1000 Ljubljana, Slovenia. RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 NR 9 TC 7 Z9 7 U1 0 U2 2 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0031-6768 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PY 2000 VL 439 IS 3 SU S BP R53 EP R55 DI 10.1007/s004240000089 PG 3 WC Physiology SC Physiology GA 271BG UT WOS:000084572000022 PM 27757657 ER PT J AU Kimura, S Gonzalez, F AF Kimura, S Gonzalez, F TI Applications of genetically manipulated mice in pharmacogenetics and pharmacogenomics SO PHARMACOLOGY LA English DT Article DE cytochrome P450; xenobiotic-metabolizing enzymes; gene knockout mouse; transgenic mouse; pharmacogenetics; pharmacogenomics ID ACETAMINOPHEN HEPATOTOXICITY; HYDROCARBON METABOLISM; CYTOCHROME P4501A2; EPOXIDE HYDROLASE; DRUG OXIDATION; CELL-LINE; TOXICITY; CANCER; RAT; ACTIVATION AB Gene knockout mice have proven to be very useful in understanding the role of xenobiotic-metabolizing enzymes in chemical toxicity and carcinogenesis, The combination of gene knockout technology with transgenic mouse technology should provide more versatile and suitable animal models to study the risks of chemical exposures in humans in terms of toxicity and carcinogenesis, as well as development and design of new therapeutic drugs, Recent studies using genetically manipulated mice are summarized. Copyright (C) 2000 S. Karger AG. Basel. C1 NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Kimura, S (reprint author), NCI, Lab Metab, NIH, Bldg 37,Rm 3E24,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 36 TC 10 Z9 11 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0031-7012 J9 PHARMACOLOGY JI Pharmacology PY 2000 VL 61 IS 3 BP 147 EP 153 DI 10.1159/000028395 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 357KM UT WOS:000089499200005 PM 10971200 ER PT J AU Schindler, CW Thorndike, EB Ma, JD Goldberg, SR AF Schindler, CW Thorndike, EB Ma, JD Goldberg, SR TI Conditioned suppression with cocaine as the unconditioned stimulus SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE cocaine; conditioned suppression; classical conditioning; interstimulus interval; rats ID SELF-ADMINISTERED COCAINE; INHIBITION; DRUGS; RATS AB A conditioned-suppression procedure was used to study drug conditioning using cocaine as the unconditioned stimulus (UCS). Rats were first trained to nose poke for food-reinforcement during daily 60-min sessions. At least 1 week following jugular vein catheterization, a 5-min tone-light compound stimulus was presented 30 min into the food-reinforcement session. Two minutes after the onset of the stimulus, either 0 (saline), 1.0, 3.0 or 5.6 mg/kg cocaine, was administered IV to separate groups of rats. For another group, the stimulus was presented, and the 5.6 mg/kg dose of cocaine was injected in an unpaired fashion (i.e., at different times). After 5 days of training a test was given with the tone-light stimulus presented alone. No disruption of responding during the tone-light stimulus was observed in the saline and 1.0 mg/kg cocaine groups or for the unpaired group. When the tone-light stimulus was paired with 5.6 mg/kg cocaine; however, it produced nearly a 50% reduction in responding, which then gradually extinguished when the stimulus was presented alone for 5 days. The 3.0 mg/kg cocaine group produced intermediate suppression. When the tone-light compound stimulus was shortened to 70 s and the interstimulus interval (ISI) was 0, 30, or 60 s in three separate groups of rats, the most robust conditioned suppression was observed at the 60 s ISI. Therefore, the conditioned suppression procedure, using 3.0 or 5.6 mg/kg IV cocaine doses as the UCS, produced robust conditioning effects comparable to other drugs and more conventional reinforcers. The conditioned suppression procedure may be a useful model for studying the classically conditioned effects of cocaine. (C) 1999 Elsevier Science Inc. C1 NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, NIH,Intramural Res Program, Baltimore, MD 21224 USA. RP Schindler, CW (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, NIH,Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 32 TC 10 Z9 10 U1 3 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD JAN PY 2000 VL 65 IS 1 BP 83 EP 89 DI 10.1016/S0091-3057(99)00176-8 PG 7 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 268BP UT WOS:000084394700014 PM 10638640 ER PT J AU Chou, JY AF Chou, JY TI Molecular genetics of hepatic methionine adenosyltransferase deficiency SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE methionine adenosyltransferase I/III deficiency; S-adenosylmethionine; genetic mutations; autosomal recessive or dominant inheritance ID S-ADENOSYLMETHIONINE SYNTHETASE; ISOLATED PERSISTENT HYPERMETHIONINEMIA; DOMINANT INHERITANCE; INBORN ERROR; 2A GENE; CLONING; EXPRESSION; LIVER; DEMYELINATION; MECHANISMS AB Hepatic methionine adenosyltransferase (MAT) deficiency is caused by mutations in the human MA nil gene that abolish or reduce hepatic MAT activity that catalyzes the synthesis of S-adenosylmethionine from methionine and ATP. This genetic disorder is characterized by isolated persistent hypermethioninemia in the absence of cystathionine P-synthase deficiency, tyrosinemia, or liver disease. Depending on the nature of the genetic defect, hepatic MAT deficiency can be transmitted either as an autosomal recessive or dominant trait. Genetic analyses have revealed that mutations identified in the MATIA gene only partially inactivate enzymatic activity, which is consistent with the fact that most hepatic MAT-deficient individuals are clinically well. Two hypermethioninemic individuals with null MA TIA mutations have developed neurological problems, including brain demyelination, although this correlation is by no means absolute. Presently, it is recommended that a DNA-based diagnosis should be performed for isolated hypermethioninemic individuals with unusually high plasma methionine levels to assess if therapy aimed at the prevention of neurological manifestations is warranted. Published 1999 by Elsevier Science Inc. All rights reserved. C1 NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Chou, JY (reprint author), NICHHD, Heritable Disorders Branch, NIH, Bldg 10,Room 9S241, Bethesda, MD 20892 USA. NR 38 TC 12 Z9 12 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD JAN PY 2000 VL 85 IS 1 BP 1 EP 9 DI 10.1016/S0163-7258(99)00047-9 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 266RN UT WOS:000084313900001 PM 10674710 ER PT J AU Paruszewski, R Rostafinska-Suchar, G Strupinska, M Winiecka, I Stables, JP AF Paruszewski, R Rostafinska-Suchar, G Strupinska, M Winiecka, I Stables, JP TI Synthesis and anticonvulsant activity of some amino acid derivatives - Part 3: Derivatives of Ala, Arg, Tzl, Gly and (chi)Abu(3) SO PHARMAZIE LA English DT Article; Proceedings Paper CT 13th International Congress of Pharmacology CY JUL 26-31, 1998 CL MUNICH, GERMANY AB Ten amino acid derivatives as antagonists of the excitatory amino acid (EAA) receptor and anticonvulsant activity have been designed. Five of these compounds supposed to show rather strong and five of them rather weak action as it was expected on the base of their hydrophobicity, All the compounds were synthesized and then evaluated in mice in the maximal electroshock seizure (MES) test, the subcutaneous Metrasol seizure threshold (scMet) test and the rotorod neurotoxicity (Tox) test. Four of the obtained componds have shown high activity (three received class I and one class II) and six were classified in class III according to the classification of the Anticonvulsant Screening Project (ASP) of the Antiepileptic Drug Development Program (ADDP) of NINDS, One of the compounds classified in class I (10) was tested quantitatively following i.p. administration in mice. It has a MES ED50 = 29.05 b.w. and protective index (PI) of 3.77. C1 Med Univ, Dept Drug Chem, Warsaw, Poland. NINDS, Div Convuls Dev & Neuromuscular Disorders, NIH, Bethesda, MD 20892 USA. RP Paruszewski, R (reprint author), Ul Banacha 1, PL-02097 Warsaw, Poland. NR 10 TC 10 Z9 11 U1 0 U2 3 PU GOVI-VERLAG GMBH PI ESCHBORN PA PHARMAZEUTISCHER VERLAG GINNHEIMER STRASSE 26, D-65760 ESCHBORN, GERMANY SN 0031-7144 J9 PHARMAZIE JI Pharmazie PD JAN PY 2000 VL 55 IS 1 BP 27 EP 30 PG 4 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 276HJ UT WOS:000084871800006 PM 10683867 ER PT J AU Nedvidkova, J Pacak, K Haluzik, M Nedvidek, J AF Nedvidkova, J Pacak, K Haluzik, M Nedvidek, J TI The regulation of adenohypophyseal prolactin secretion: Effect of triiodothyronine and methylene blue on estrogenized rat adenohypophysis SO PHYSIOLOGICAL RESEARCH LA English DT Review DE estrogen; thyroid hormone; methylene blue; catecholamines; dopamine receptors; NO; prolactin ID ANTERIOR-PITUITARY; GONADOTROPIN-SECRETION; MESSENGER-RNA; FEMALE RAT; RECEPTORS; ESTRADIOL; HORMONE; ACID; CANNABINOIDS; EXPRESSION AB Estrogens and thyroid hormones contribute importantly to cell proliferation and tumor transformation in the pituitary gland. We found that methylene blue antagonized estrogen-promoted adenohypophyseal enlargement and the enhancement of prolactin secretion. The purpose of the present article is to provide a review about neurotransmitters and their receptors involved in estrogen-induced anterior pituitary growth and in the antagonistic effects of triiodothyronine (T3) and methylene blue (MB). Central dopaminergic and noradrenergic systems are the most important factors regulating pituitary growth and function. Recently nitric oxide (NO) was added to the list of the neurotransmitters and neuropeptides involved in the control of the anterior pituitary secretion. Our data suggest that estrogen-induced anterior pituitary growth is associated with decreased synthesis and metabolism of central catecholamines, reduction of adenohypophyseal beta-adrenergic receptors and increase of dopamine DA-2 receptors. We found that the treatment with T3 or MB prevented both estrogen-induced catecholaminergic inhibition and dopamine DA-2 receptor increment in the anterior pituitary. In contrast to T3, MB given alone also slightly decreased the anterior pituitary weight. Serum levels and anterior pituitary content of prolactin were increased after treatment with estradiol benzoate (EB), whereas T3 or MB partially attenuated prolactin hypersecretion after estrogen administration. This is in accord with the attenuation of EB-induced inhibition of dopaminergic system by T3 and MB. MB given in combination with EB also partially attenuated EB-promoted rise of adenohypohyseal NO synthase activity which plays an important role in the regulation of prolactin secretion. Further studies on central catecholaminergic systems, pituitary receptors, the nitrergic system and mechanisms of intracellular signal transduction are necessary for better understanding of pituitary tumor transformation and possibly for the discovery of new approaches towards treating patients with these diseases. C1 Inst Endocrinol, Prague 1, Czech Republic. NINDS, NIH, Bethesda, MD 20892 USA. Charles Univ, Fac Med 1, Prague, Czech Republic. Acad Sci Czech Republ, Inst Physiol, Prague, Czech Republic. RP Nedvidkova, J (reprint author), Inst Endocrinol, Narodni Trida 8, Prague 1, Czech Republic. NR 36 TC 3 Z9 3 U1 0 U2 0 PU ACAD SCIENCES CZECH REPUBLIC, INST PHYSIOLOGY PI PRAGUE 4 PA VIDENSKA 1083, PRAGUE 4 142 20, CZECH REPUBLIC SN 0862-8408 J9 PHYSIOL RES JI Physiol. Res. PY 2000 VL 49 SU 1 BP S27 EP S35 PG 9 WC Physiology SC Physiology GA 325PW UT WOS:000087685700007 PM 10984069 ER PT J AU Pacak, K AF Pacak, K TI Stressor-specific activation of the hypothalamic-pituitary-adrenocortical axis SO PHYSIOLOGICAL RESEARCH LA English DT Review DE norepinephrine; ACTH; corticosterone; microdialysis; paraventricular nucleus; immobilization; cold; pain; hemorrhage; hypoglycemia ID CORTICOTROPIN-RELEASING-FACTOR; INDUCED NOREPINEPHRINE RELEASE; RAT MEDULLA-OBLONGATA; PARAVENTRICULAR NUCLEUS; BRAIN-STEM; MESSENGER-RNA; IMMUNOREACTIVE NEURONS; IMMOBILIZATION STRESS; SUPRAOPTIC NUCLEI; VASOPRESSIN AB New information has accrued from in vivo microdialysis studies about stress-related changes in norepinephrine concentrations in extracellular fluid of the paraventricular nucleus (PVN) and the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Our data on the effects of lower brainstem hemisections show that paraventricular noradrenergic terminals are derived mainly from medullary A1 and A2 catecholaminergic cells. The activation of these cells contributes importantly to stress-induced noradrenergic activation in the paraventricular nucleus of conscious animals. The results from brainstem hemisection experiments also indicate that baseline levels and immobilization-induced increments in corticotropin-releasing hormone (CRH) mRNA expression in the PVN depend on ipsilaterally ascending medullary tract. Thus, the prevalent: concept that stress-induced noradrenergic activation of the HPA axis depends mainly on activation of locus ceruleus noradrenergic neurons requires re-evaluation. Our new stress concepts favor stressor-specific activation of the HPA axis. The present data also suggest the existence of stressor-specific central pathways that differentially participate in the regulation of sympathoneuronal and adrenomedullary outflows as well as of the activity of the HPA axis. Furthermore, the results are inconsistent with a founding tenet of Selye's stress theory, the doctrine of nonspecificity, which defines stress as the nonspecific response of the body to any demand, We expect that future studies in this area will focus on further examination of the notion of stressor-specific patterns of central neurotransmitter release and elucidate the genetic bases of these patterns. C1 NINDS, CNS, CNB, DIR,NIH, Bethesda, MD 20892 USA. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), NINDS, CNS, CNB, DIR,NIH, Bldg 10,Room 6N252,10 Ctr Dr MSC-1620, Bethesda, MD 20892 USA. NR 34 TC 53 Z9 55 U1 2 U2 4 PU ACAD SCIENCES CZECH REPUBLIC, INST PHYSIOLOGY PI PRAGUE 4 PA VIDENSKA 1083, PRAGUE 4 142 20, CZECH REPUBLIC SN 0862-8408 J9 PHYSIOL RES JI Physiol. Res. PY 2000 VL 49 SU 1 BP S11 EP S17 PG 7 WC Physiology SC Physiology GA 325PW UT WOS:000087685700005 PM 10984067 ER PT J AU Hearing, VJ AF Hearing, VJ TI The melanosome: The perfect model for cellular responses to the environment SO PIGMENT CELL RESEARCH LA English DT Article; Proceedings Paper CT 17th International Pigment Cell Conference (IPCC) CY OCT 30-NOV 03, 1999 CL NAGOYA, JAPAN DE melanin; pigmentation; photoabsorption; melanoma ID MELANOCYTE-STIMULATING-HORMONE; TYROSINASE-RELATED PROTEIN-1; AGOUTI SIGNAL PROTEIN; MIGRATION INHIBITORY FACTOR; COAT-COLOR MUTANTS; MURINE MELANOCYTES; IN-VIVO; ENDOPLASMIC-RETICULUM; METASTATIC MELANOMA; CYTOPLASMIC TAIL AB Melanocytes play critical roles in mammals, including the regulation of constitutive pigmentation in the skin, hair, and eyes, in embryological development, and in photoprotection from ionizing radiation. The pigments themselves, possibly due to the inherent cytotoxic properties of their precursors, are synthesized and deposited within membrane-bound organelles known as melanosomes, However, the structure of melanosomes, and thus their characteristic properties, varies widely, from relatively disorganized, poorly pigmented pheomelanosomes to highly structured, melanized eumelanosomes. Melanocytes respond to various physiological stimuli, such as melanocyte-stimulating hormone (MSH), agouti signal protein (ASP), endothelins and/or ultra violet light (UVL) by highly complex intracellular signaling mechanisms that can elicit dramatic changes in melanosome and melanocyte morphology. MSH and UVL stimulate transcription of melanogenic genes that elicit dramatic increases in the amount of eumelanins produced, whereas ASP serves as an antagonist of MSH and inhibits the transcription of those same genes. Recent studies have shown that melanocyte-specific transcription factors, such as MITF, play important roles in these responses, but ubiquitous transcription factors, such as ITF2 and E2A, are also involved. Virtually all known intracellular signaling pathways affect one or more parameters of pigmentation, and it is clear that both melanocyte-specific and basic housekeeping processes are affected by such modulation. The properties of melanins, including their photoprotective function, may be optimized by such stimulatory responses. Studies targeted at elucidating the regulatory mechanisms involved and the functional changes that result demonstrate that the melanosome is the perfect model to study such biological response mechanisms. C1 NCI, Pigment Cell Biol Sect, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hearing, VJ (reprint author), NCI, Pigment Cell Biol Sect, Cell Biol Lab, NIH, Room 1B25,Bldg 37, Bethesda, MD 20892 USA. NR 79 TC 77 Z9 80 U1 3 U2 13 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0893-5785 J9 PIGM CELL RES JI Pigm. Cell. Res. PY 2000 VL 13 SU 8 BP 23 EP 34 DI 10.1034/j.1600-0749.13.s8.7.x PG 12 WC Cell Biology; Dermatology SC Cell Biology; Dermatology GA 361GA UT WOS:000089714000006 PM 11041354 ER PT J AU Abdel-Malek, Z Scott, MC Suzuki, I Tada, A Im, S Lamoreux, L Ito, S Barsh, G Hearing, VJ AF Abdel-Malek, Z Scott, MC Suzuki, I Tada, A Im, S Lamoreux, L Ito, S Barsh, G Hearing, VJ TI The melanocortin-1 receptor is a key regulator of human cutaneous pigmentation SO PIGMENT CELL RESEARCH LA English DT Article; Proceedings Paper CT 17th International Pigment Cell Conference (IPCC) CY OCT 30-NOV 03, 1999 CL NAGOYA, JAPAN DE melanocortin 1 receptor; human melanocytes; ultraviolet radiation; melanocortins; agouti signaling protein; eumelanin; pheomelanin ID MELANOCYTE-STIMULATING-HORMONE; CULTURED HUMAN MELANOCYTES; MOUSE AGOUTI GENE; MOLECULAR-CLONING; RED HAIR; INDUCED MELANOGENESIS; HUMAN KERATINOCYTES; HUMAN EPIDERMIS; ULTRAVIOLET-B; HUMAN HOMOLOG AB The cloning and characterization of the human melanocortin-1 receptor (MC1R) and the demonstration that normal human melanocytes respond to the melanocortins, alpha-melanocyte stimulating hormone (alpha-MSH) and adrenocorticotrophic hormone (ACTH), with increased proliferation and eumelanogenesis had put an end to a long-standing controversy about the role of melanocortins in regulating human cutaneous pigmentation. We have shown that alpha-MSH and ACTH bind the human MC1R with equal affinity, and are equipotent in their mitogenic and melanogenic effects on human melanocytes. We also showed that the activation of the MC1R is important for the melanogenic response of human melanocytes to ultraviolet radiation (UVR). The MC1R is also the principal mediator of the inhibitory effects of agouti signaling protein (ASP) on melanogenesis. Expression of the MC1R is subject to regulation by its own ligands alpha-MSH and ACTH, as well as by UVR and endothelin-1. Recent studies that we conducted on the expression of MC1R variants by human melanocytes and the implications of these variants on the function of the MC1R revealed the following. Human melanocytes homozygous for Arg160Trp mutation in the MC1R demonstrated a significantly reduced response to alpha-MSH. Also, this culture responded poorly to ASP and exhibited an exaggerated cytotoxic response to UVR. Another culture, which was homozygous for Val92Met mutation in the MC1R, demonstrated a normal response to alpha-MSH. Heterozygous mutations that are frequently expressed in various melanocyte cultures did not disrupt MC1R function. These results begin to elucidate the significance of MC1R variants in the function of the receptor. Our data emphasize the significance of a normally functioning MC1R in the response of melanocytes to melanocortins. ASP, and UVR. C1 Univ Cincinnati, Dept Dermatol, Cincinnati, OH 45267 USA. POLA Labs, Yokohama, Kanagawa 244, Japan. Texas A&M Univ, College Stn, TX 77843 USA. Fujita Hlth Univ, Toyoake, Aichi, Japan. Stanford Univ, Stanford, CA 94305 USA. NCI, Bethesda, MD 20892 USA. RP Abdel-Malek, Z (reprint author), Univ Cincinnati, Dept Dermatol, POB 670592, Cincinnati, OH 45267 USA. FU NIEHS NIH HHS [R01 ES06882, R01 ES09116] NR 67 TC 75 Z9 78 U1 0 U2 2 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0893-5785 J9 PIGM CELL RES JI Pigm. Cell. Res. PY 2000 VL 13 SU 8 BP 156 EP 162 DI 10.1034/j.1600-0749.13.s8.28.x PG 7 WC Cell Biology; Dermatology SC Cell Biology; Dermatology GA 361GA UT WOS:000089714000027 PM 11041375 ER PT J AU Harvey, RG Zhang, FJ Dipple, A Weiss, MA AF Harvey, RG Zhang, FJ Dipple, A Weiss, MA TI Synthesis of adducts of PAH diol epoxide metabolites in p53 tumor suppressor gene sites SO POLYCYCLIC AROMATIC COMPOUNDS LA English DT Article; Proceedings Paper CT 17th International Symposium on Polycyclic AromatiC Compounds (ISPAC 17) CY OCT 25-29, 1999 CL BORDEAUX, FRANCE SP Int Soc Polycycl Aromat Compounds, Univ Boreeaux I, CNRS DE benzo[a]pyrene diol epoxide; p53 gene adducts ID OLIGONUCLEOTIDE ADDUCTS; SEQUENCE CONTEXT; DNA; DEOXYGUANOSINE; NUCLEOSIDE; MUTATIONS; BINDING AB The synthesis, structures, and mutagenic properties of benzo[a]pyrene-deoxyadenosine adducts in a sequence context related to the p53 gene are described. C1 Univ Chicago, Ben May Inst Canc Res, Chicago, IL 60637 USA. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. Case Western Reserve Univ, Sch Med, Cleveland, OH 44106 USA. RP Harvey, RG (reprint author), Univ Chicago, Ben May Inst Canc Res, Chicago, IL 60637 USA. NR 20 TC 0 Z9 0 U1 0 U2 0 PU GORDON BREACH SCI PUBL LTD PI READING PA C/O STBS LTD, PO BOX 90, READING RG1 8JL, BERKS, ENGLAND SN 1040-6638 J9 POLYCYCL AROMAT COMP JI Polycycl. Aromat. Compd. PY 2000 VL 21 IS 1-4 BP 11 EP 23 DI 10.1080/10406630008028519 PG 13 WC Chemistry, Organic SC Chemistry GA 388TP UT WOS:000166199400003 ER PT J AU Whalen, D Doan, L Poulose, B Friedman, S Gold, A Sangaiah, R Ramesha, AR Sayer, JM Jerina, DM AF Whalen, D Doan, L Poulose, B Friedman, S Gold, A Sangaiah, R Ramesha, AR Sayer, JM Jerina, DM TI Mechanisms of solution reactions of cyclopenta[cd]pyrene oxide and acenaphthylene oxide SO POLYCYCLIC AROMATIC COMPOUNDS LA English DT Article; Proceedings Paper CT 17th International Symposium on Polycyclic AromatiC Compounds (ISPAC 17) CY OCT 25-29, 1999 CL BORDEAUX, FRANCE SP Int Soc Polycycl Aromat Compounds, Univ Boreeaux I, CNRS DE cyclopenta-fused epoxides; hydrolysis; mechanisms ID POLYCYCLIC AROMATIC-HYDROCARBONS; EPOXIDE; ACID; BENZOPYRENE; HYDROLYSIS AB Rates and products of the acid-catalyzed and spontaneous reactions of cyclopenta[cd]pyrene oxide (2) and acenaphthalene oxide (3) in 1:3 dioxane-water and water, respectively, have been determined. Both 2 and 3 undergo acid-catalyzed hydrolyses to yield cis diol as the major product, and undergo spontaneous reactions to yield predominantly ketone products. The mechanisms of these reactions are discussed. C1 Univ Maryland, Dept Biochem & Chem, Baltimore, MD 21250 USA. Univ N Carolina, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Whalen, D (reprint author), Univ Maryland, Dept Biochem & Chem, Baltimore, MD 21250 USA. NR 17 TC 3 Z9 3 U1 0 U2 0 PU GORDON BREACH SCI PUBL LTD PI READING PA C/O STBS LTD, PO BOX 90, READING RG1 8JL, BERKS, ENGLAND SN 1040-6638 J9 POLYCYCL AROMAT COMP JI Polycycl. Aromat. Compd. PY 2000 VL 21 IS 1-4 BP 43 EP 52 DI 10.1080/10406630008028522 PG 10 WC Chemistry, Organic SC Chemistry GA 388TP UT WOS:000166199400006 ER PT J AU Jerina, DM Sayer, JM Kroth, H Kohlhagen, G Laco, GS Pommier, Y AF Jerina, DM Sayer, JM Kroth, H Kohlhagen, G Laco, GS Pommier, Y TI Bay-region diol epoxides of benzo[a]pyrene are stealth poisons of topoisomerase I SO POLYCYCLIC AROMATIC COMPOUNDS LA English DT Article; Proceedings Paper CT 17th International Symposium on Polycyclic AromatiC Compounds (ISPAC 17) CY OCT 25-29, 1999 CL BORDEAUX, FRANCE SP Int Soc Polycycl Aromat Compounds, Univ Boreeaux I, CNRS DE topoisomerase I; benzo[a]pyrene 7,8-diol 9,10-epoxides; DNA adducts ID DNA; MECHANISM; COMPLEXES; SEQUENCE; COVALENT; ADDUCTS AB Topoisomerase I transiently cleaves one strand of duplex DNA to relieve torsional strain during enzymatic processing events such as transcription and replication. Thus, topoisomerase I is an important target for anti-tumor drugs. We have examined the effects of cis- and trans-opened (+)-(7R,8S,9S, 10R)- and (-)-(7S,8R,9R,10S)benzo[a]pyrene 7,8-diol 9,10-epoxide adducts at the exocyclic amino groups of the purine bases at or near a known cleavage site in a 22-mer DNA duplex. The dG adducts lie in the minor groove either upstream or downstream from the modified base, and the dA adducts are intercalated at either side of the modified base. Thus four distinct structural motifs were available for study. The dG adducts inhibit cleavage at the normal site with resultant remote cleavages being observed. In contrast, three of the four dA adducts examined appear to be initially invisible to the enzyme since they allow the normal cleavage to occur, but they prevent subsequent religation and thus act as topoisomerase "stealth poisons". C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Lab, Div Basic Sci, Bethesda, MD 20892 USA. RP Jerina, DM (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NR 14 TC 0 Z9 0 U1 0 U2 0 PU GORDON BREACH SCI PUBL LTD PI READING PA C/O STBS LTD, PO BOX 90, READING RG1 8JL, BERKS, ENGLAND SN 1040-6638 J9 POLYCYCL AROMAT COMP JI Polycycl. Aromat. Compd. PY 2000 VL 21 IS 1-4 BP 53 EP 62 DI 10.1080/10406630008028523 PG 10 WC Chemistry, Organic SC Chemistry GA 388TP UT WOS:000166199400007 ER PT J AU Ponten, I Page, JE Dipple, A Kumar, S Sayer, JM Yagi, H Pilcher, A Jerina, DM AF Ponten, I Page, JE Dipple, A Kumar, S Sayer, JM Yagi, H Pilcher, A Jerina, DM TI Effect of structure and sequence on mutations induced by diol epoxide-DNA abducts in an E-coli-M13 vector system SO POLYCYCLIC AROMATIC COMPOUNDS LA English DT Article; Proceedings Paper CT 17th International Symposium on Polycyclic AromatiC Compounds (ISPAC 17) CY OCT 25-29, 1999 CL BORDEAUX, FRANCE SP Int Soc Polycycl Aromat Compounds, Univ Boreeaux I, CNRS DE benzo[a]pyrene; benzo[c]phenanthrene; diol epoxides; oligonucleotide adducts; mutagenesis; M13 ID SITE-SPECIFIC MUTATION; DEOXYADENOSINE ADDUCTS; POLYMERASES AB The effects of two DNA sequence contexts on the mutagenic response to dG and dA adducts derived from the optically active 7,8-diol 9,10-epoxides of benzo[a]pyrene (BaP DEs) and 3,4-diol 1,2-epoxides of benzo[c]phenanthrene (BcPh DEs) were examined. On replication of the adduct-containing, single-stranded vector M13mp7L2 in E. coli SMH77, frequencies of substitution mutations ranging from 0.05% to 68% were observed. In general, the highest mutational frequencies were observed for BaP DE-dA adducts at the central position in a similar to TAG similar to sequence. The BaP DE adducts showed no relationship between stereochemistry and mutagenic response. In contrast, mutagenicity of the BcPh DE-dA adducts in the similar to TAG similar to sequence depended strongly on the configuration at C-l, the site of attachment of the hydrocarbon to the purine. In this sequence, BcPh DE-dA adducts with 1R configuration were 16-600 times less mutagenic than those with 1S configuration. C1 NCI, Frederick Canc Res & Dev Ctr, Chem Carcinogenesis Lab, Frederick, MD 21702 USA. SUNY Coll Buffalo, Great Lakes Ctr, Buffalo, NY 14222 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Ponten, I (reprint author), NCI, Frederick Canc Res & Dev Ctr, Chem Carcinogenesis Lab, Frederick, MD 21702 USA. NR 16 TC 1 Z9 1 U1 0 U2 2 PU GORDON BREACH SCI PUBL LTD PI READING PA C/O STBS LTD, PO BOX 90, READING RG1 8JL, BERKS, ENGLAND SN 1040-6638 J9 POLYCYCL AROMAT COMP JI Polycycl. Aromat. Compd. PY 2000 VL 21 IS 1-4 BP 63 EP 72 DI 10.1080/10406630008028524 PG 10 WC Chemistry, Organic SC Chemistry GA 388TP UT WOS:000166199400008 ER PT J AU Jerina, DM AF Jerina, DM TI From arene oxides to diol epoxides and DNA SO POLYCYCLIC AROMATIC COMPOUNDS LA English DT Article; Proceedings Paper CT 17th International Symposium on Polycyclic AromatiC Compounds (ISPAC 17) CY OCT 25-29, 1999 CL BORDEAUX, FRANCE SP Int Soc Polycycl Aromat Compounds, Univ Boreeaux I, CNRS DE polycyclic aromatic hydrocarbons; carcinogenicity; NIH; Shift; arene oxides; diol epoxides; bay-region theory; DNA adducts; conformation and configuration of PAH metabolites ID POLYCYCLIC AROMATIC-HYDROCARBONS; BENZOPYRENE 7,8-DIOL 9,10-EPOXIDES; RAS CODON-61 SEQUENCE; DG MISMATCH OPPOSITE; CARCINOGEN BENZOPYRENE; K-REGION; DEOXYRIBONUCLEIC-ACID; SOLUTION CONFORMATION; CATALYZED HYDROLYSIS; N-6-AMINO GROUP AB Although the polycyclic aromatic hydrocarbons (PAH) are structurally less complex compared to many other compounds with high biological activity, their metabolism, the chemical reactivity of their metabolites, and the mutagenicity and tumorigenicity of these metabolites have stimulated intensive research into their mechanisms of action. The present report focuses on our contributions to the identification of bay-region and fjord-region diol epoxides as ultimate carcinogens of the PAH and describes some of the remarkable stereochemical control involved in their synthesis, metabolic formation, and expression of tumorigenic activity. C1 NIDDKD, Sect Oxidat Mech, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Jerina, DM (reprint author), NIDDKD, Sect Oxidat Mech, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NR 65 TC 3 Z9 3 U1 0 U2 4 PU GORDON BREACH SCI PUBL LTD PI READING PA C/O STBS LTD, PO BOX 90, READING RG1 8JL, BERKS, ENGLAND SN 1040-6638 J9 POLYCYCL AROMAT COMP JI Polycycl. Aromat. Compd. PY 2000 VL 19 IS 1-4 BP 5 EP 36 DI 10.1080/10406630008034720 PG 32 WC Chemistry, Organic SC Chemistry GA 388TK UT WOS:000166199000003 ER PT J AU Song, LL Myers, SR Lantvit, D Lubet, RA Steele, VE Kelloff, GJ Moon, RC Pezzuto, JM AF Song, LL Myers, SR Lantvit, D Lubet, RA Steele, VE Kelloff, GJ Moon, RC Pezzuto, JM TI Chemoprevention of DMBA-induced mammary carcinogenesis: Relationship between induction of phase II enzymes, effects on dmba-induced hemoglobin adducts and decreases in mammary tumor multiplicity SO POLYCYCLIC AROMATIC COMPOUNDS LA English DT Article DE DMBA; carcinogens; hemoglobin; biomarkers; tumors; antioxidants ID BUTYLATED HYDROXYANISOLE; 7,12-DIMETHYLBENZANTHRACENE; ETHOXYQUIN; METABOLISM; RATS; DNA; 7,12-DIMETHYLBENZ(A)ANTHRACENE; HEPATOCARCINOGENESIS; ANTIOXIDANTS; AFLATOXIN-B1 AB The chemopreventive potential of 1,2-dithiole-3-thione, ethoxyquin, butylated hydroxanisole (BHA) and beta -naphthoflavone (BNF) was investigated in the 7,12-dimethylbenz(a)anthracene (DMBA) rat mammary tumor model. Female Sprague-Dawley rats received a single dose of DMBA (15 mg) at 50 days of age. Chemopreventive agents were administered via the diet, beginning one week prior to DMBA dosing and continuing until one week following DMBA. Tumor latency, multiplicity and incidence were not affected by BHA (2.5 or 5.0 g/kg diet), but administration of low or high doses of beta -napthflavone (1.65 and 3.3 g/kg diet), or high doses of ethoxyquin (5.0 g/kg diet) or 1,2-dithiole-3-thione (0.6 g/kg diet), effectively inhibited ail parameters of tumorigenesis. It is presumed that many of these agents which decrease the tumorigenicity act by altering the metabolism of the carcinogen resulting in diminished numbers of reactive ultimate carcinogens. We examined both for the induction of enzymes that might alter carcinogen metabolism as well as alterations in levels of DMBA adducts to hemoglobin. A strong correlation was observed between the effect of these agents on carcinogenesis and the induction of phase II enzymes (quinone reductase and glutathione S-transferase) and glutathione in the mammary gland. We also examined the effects of BNF; 1,2-dithiol-3-thione and BHA on formation of hemoglobin adducts by DMBA. Similarly to the results on carcinogenesis the relative efficacy of compounds in inhibiting DMBA adduct formation and DMBA induced mammary tumorigenesis was BNF > 1,2 Dithiolthione much greater than BHA. These results support the hypothesis that these agents work by altering metabolism of DMBA to reactive intermediates but further offer the possibility that modulation of hemoglobin adducts may serve as a surrogate marker of efficacy. C1 Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. Univ Illinois, Coll Pharm, Program Collaborat Res Pharmaceut Sci, Chicago, IL 60612 USA. Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, Chicago, IL 60612 USA. Univ Illinois, Coll Med, Dept Surg Oncol, Chicago, IL 60612 USA. NCI, Chemoprevent Branch, Div Canc Prevent & Control, Bethesda, MD 20892 USA. RP Myers, SR (reprint author), Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. NR 26 TC 1 Z9 1 U1 0 U2 0 PU GORDON BREACH SCI PUBL LTD PI READING PA C/O STBS LTD, PO BOX 90, READING RG1 8JL, BERKS, ENGLAND SN 1040-6638 J9 POLYCYCL AROMAT COMP JI Polycycl. Aromat. Compd. PY 2000 VL 18 IS 2 BP 193 EP 210 DI 10.1080/10406630008028145 PG 18 WC Chemistry, Organic SC Chemistry GA 388TG UT WOS:000166198700006 ER PT J AU Kim, SS Yoo, YM Shin, JS Jeong, KS AF Kim, SS Yoo, YM Shin, JS Jeong, KS TI Blood compatibility of polyurethane-poly(vinyl alcohol) polymer blends SO POLYMER-KOREA LA Korean DT Article DE blood compatibility; PU/PVA blend; PU; PVA AB The blood compatibilities of PU/PVA polymer blends with different mixing ratios were evaluated using various methods, such as fibrinogen adsorption, plasma recalcification time, platelet adhesion, whole blood clotting time and complement activation. In addition, PVA on the surface of the polymer blends was crosslinked by glutaraldehyde to restrain the mobility of PVA molecules for characterizing the effect of PVA in the polymer blends on blood compatibility. The fibrinogen adsorption on the polymer blends decreased with the increase of PVA amount in the polymer blends. The plasma recalcification times of the polymer blends with 10-50 wt% PVA were longer than those of PU, WA, and polymer blends with higher amount of WA. The morphological changes and adhesion of platelets on the polymer blends with 30-50 wt% PVA were less than those on the other materials. The blood clotting times and complement activation on the polymer blends with 30-50 wt% PVA were reduced, compared to the other materials. On the other hand, the blood compatibility of the crosslinked polymer blends was relatively decreased compared to the non-crosslinked ones. According to these experimental results, the blood compatibility of the polymer blends with 30-50 wt% PVA was better than that of the other materials and such a blood compatibility of the polymer blends might be related to the mobility of PVA, molecules on the surface. C1 Korea Res Inst Chem Technol, Adv Mat Div, Taejon 305600, South Korea. Chungbuk Natl Univ, Dept Chem, Cheongju 361763, Chungbuk, South Korea. NIAAA, Lab Membrane Biochem & Biophys, Bethesda, MD 20892 USA. RP Kim, SS (reprint author), Korea Res Inst Chem Technol, Adv Mat Div, Taejon 305600, South Korea. NR 12 TC 1 Z9 1 U1 0 U2 1 PU POLYMER SOC KOREA PI SEOUL PA ROOM 601, HATCHON BUILDING, 831 YEOKSAM-DONG, KANGNAM-KU, SEOUL 135-792, SOUTH KOREA SN 0379-153X J9 POLYM-KOREA JI Polym.-Korea PD JAN PY 2000 VL 24 IS 1 BP 82 EP 89 PG 8 WC Polymer Science SC Polymer Science GA 281UK UT WOS:000085179000011 ER PT B AU Steele, VE Boone, CW Wargovich, MJ McKee, K Sharma, S Wilkinson, BP Wyatt, HP Gao, P Kelloff, GJ AF Steele, VE Boone, CW Wargovich, MJ McKee, K Sharma, S Wilkinson, BP Wyatt, HP Gao, P Kelloff, GJ BE Cheze, C Vercauteren, J Verpoorte, R TI Polyphenols and cancer prevention SO POLYPHENOLS, WINE AND HEALTH SE PROCEEDINGS OF THE PHYTOCHEMICAL SOCIETY OF EUROPE LA English DT Proceedings Paper CT Polyphenols, Wine and Health Symposium CY APR 14-16, 1999 CL UNIV VICTOR SEGALEN BORDEAUX 2, BORDEAUX, FRANCE SP Phytochem Soc Europe, Conseil Reg Aquitaine, Conseil Gen Gironde, Mairie Bordeaux, Chateau Smith Haut Lafitte, Lab Caudalie, ONIVins, Ferco, La Fiee Lois, Inst Francais Nutrit, Randox Labs Ltd HO UNIV VICTOR SEGALEN BORDEAUX 2 ID EPIDERMAL ORNITHINE DECARBOXYLASE; CHEMOPREVENTIVE AGENTS; TUMOR PROMOTION; DRUG DEVELOPMENT; ELLAGIC ACID; COLON-CANCER; CARCINOGENESIS; QUERCETIN; TUMORIGENESIS; RESVERATROL C1 NCI, DCP, Chemoprevent Branch, Rockville, MD 20852 USA. RP Steele, VE (reprint author), NCI, DCP, Chemoprevent Branch, 6130 Execut Blvd, Rockville, MD 20852 USA. NR 42 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS BN 0-7923-6735-9 J9 PR PHYT SOC PY 2000 VL 48 BP 177 EP 190 PG 14 WC Food Science & Technology; Public, Environmental & Occupational Health SC Food Science & Technology; Public, Environmental & Occupational Health GA BS31H UT WOS:000169430000009 ER PT S AU Eckelman, WC AF Eckelman, WC BE Tamaki, N Tsukamoto, E Kuge, Y Katoh, C Morita, K TI The importance of receptor ligand subtype selectivity for diagnosis and drug development SO POSITRON EMISSION TOMOGRAPHY IN THE MILLENNIUM SE INTERNATIONAL CONGRESS SERIES LA English DT Proceedings Paper CT International Positron Emission Tomography Symposium (PET) CY SEP 24-26, 1999 CL SAPPORO, JAPAN DE muscarinic; pharmaceuticals; serotonin ID ALZHEIMERS-DISEASE; RAT-BRAIN; BINDING; INVIVO; DEMENTIA AB The general hypothesis is that subtype selective ligands will be more effective in studying biochemistry in vivo than the more nonselective radiotracers used to date. We have tested this hypothesis in two areas of receptor binding radiotracers the muscarinic receptor and the serotonin receptor. Based on encouraging in vitro data indicating M2 subtype selectivity, we have synthesized, radiolabeled with F-18, and evaluated 3-(3-(3-fluoropropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methyl pyridine [FP-TZTP] for muscarinic subtype selectivity in vivo. Serotonin receptors, specifically the 5-HT1A subtype, have been implicated in anxiety, dementia, schizophrenia, and depression. We have synthesized and evaluated two fluorinated derivatives of WAY 100635, N-{2-[4-(2-methoxyphenyl)-piperazino]ethyl}-N-(2-pyridyl) cyclohexanecarboxamide using various acids in place of the cyclohexanecarboxylic acid. The two acids are 4-fluoro-3-methylbenzoic acid (MeFB) and trans 4-fluorocyclohexanecarboxylic acid (FC). All three subtype selective radiopharmaceuticals can be used for detecting changes in subtype receptor concentrations and for screening pharmaceuticals. C1 NIH, Ctr Clin, Chief PET Dept, Bethesda, MD 20892 USA. RP Eckelman, WC (reprint author), NIH, Ctr Clin, Chief PET Dept, Bldg 10,Room 1C495,10 Ctr Dr,MSC 1180, Bethesda, MD 20892 USA. NR 17 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0531-5131 BN 0-444-50385-4 J9 INT CONGR SER PY 2000 VL 1197 BP 291 EP 296 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA BQ34G UT WOS:000088052500035 ER PT J AU Martynov, A Schepkina, J Chestkov, V Radko, SP Kolosova, I Chrambach, A AF Martynov, A Schepkina, J Chestkov, V Radko, SP Kolosova, I Chrambach, A TI Towards a quantitative free flow electrophoresis and its application to particle size separations SO PREPARATIVE BIOCHEMISTRY & BIOTECHNOLOGY LA English DT Article ID CAPILLARY-ZONE-ELECTROPHORESIS; POLYACRYLAMIDE AB The possibility to quantify free-flow electrophoresis (FFE) data was explored in application to 6 negatively charged polystyrene size standards in the size range of 73 to 762 nm diameter. Peak fraction numbers in FFE were shown to be proportional to mobilities of the particles, determined by capillary zone electrophoresis in the identical buffer. Standard deviations of peak fraction numbers demonstrate a high degree of intra-experimental reproducibility while inter-experimentally, a variability of 1 to 5 peak fraction numbers within 28 fractions was found. A relative mobility (R-f) scale for peak identification in FFE based on the free mobility of the dye, SPADNS, allowed for the utilization of the entire electrophoretic migration path but failed to improve the precision of fraction numbers in view of the substantial zone spreading of the dye. Mobility differences between particles increased upon lowering the ionic strength of the electrophoretic buffer. Peak width increased with particle size in inverse relation to ionic strength. C1 NICHHD, Macromol Anal Sect, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. Russian Acad Med Sci, Med Genet Res Ctr, Dept Biotechnol, Moscow, Russia. RP Martynov, A (reprint author), NICHHD, Macromol Anal Sect, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. NR 11 TC 1 Z9 1 U1 1 U2 1 PU MARCEL DEKKER INC PI NEW YORK PA 270 MADISON AVE, NEW YORK, NY 10016 USA SN 1082-6068 J9 PREP BIOCHEM BIOTECH JI Prep. Biochem. Biotechnol. PY 2000 VL 30 IS 4 BP 331 EP 341 DI 10.1080/10826060008544972 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 370GV UT WOS:000165115900007 PM 11065278 ER PT S AU Read, JS AF Read, JS BE Ammann, AJ Rubinstein, A TI Cesarean section delivery to prevent vertical transmission of human immunodeficiency virus type 1 - Associated risks and other considerations SO PREVENTION AND TREATMENT OF HIV INFECTION IN INFANTS AND CHILDREN SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 2nd Conference on Global Strategies for the Prevention of HIV Transmission from Mothers to Infants CY SEP 01-06, 1999 CL MONTREAL, CANADA SP Glaxo Welcome ID TO-CHILD TRANSMISSION; PERINATAL TRANSMISSION; COST-EFFECTIVENESS; HIV-1; COMPLICATIONS; INFECTION; WOMEN AB Delivery by elective cesarean section (ECS), cesarean section prior to labor and rupture of membranes, is associated with a lower rate of vertical transmission of HIV compared with other modes of delivery. The efficacy of ECS among women receiving combination antiretroviral therapy or among women with low viral loads is unknown. In assessing the possible utility of ECS as an intervention to decrease vertical transmission in the United States and other countries, the potential risks associated with operative delivery as well as other considerations should also be addressed. Although cesarean section delivery is associated with an increased rate of postpartum morbidity compared with vaginal delivery in the general population, operative delivery performed emergently carries a higher risk of complications than scheduled or elective procedures. Analyses of the risk of postpartum morbidity according to mode of delivery among HIV-infected women have been performed in the Women and Infants Transmission Study (WITS), the largest database in North America with relevant data, as well as other, smaller databases. These analyses suggest a similar pattern to that observed in the general population. In addition to quantifying the incidence of postpartum morbidity events, it is also important to distinguish between minor and major morbidity. Neonatal morbidity related to ECS is generally due to iatrogenic, preterm birth, that is, situations where the gestational age is not accurately assessed prior to delivery. Occupationally acquired HIV infection related to obstetric procedures is a possibility, although risk related to mode of delivery is unknown. The results of economic analyses of ECS compared to vaginal delivery in the US indicate that ECS is a cost-effective intervention in preventing vertical transmission of HIV among women who refrain from breastfeeding. However, more precise estimates of the risk of vertical transmission among women receiving combination antiretroviral therapy and of the potential risks of maternal and pediatric adverse events related to receipt of such therapy are needed. In summary, the benefit of ECS must be weighed against potential risks, and issues such as cost-effectiveness also should be taken into consideration. C1 NICHHD, PAMA Branch, NICHD, NIH, Bethesda, MD 20892 USA. RP Read, JS (reprint author), NICHHD, PAMA Branch, NICHD, NIH, Execut Bldg,Room 4B11F,6100 Execut Blvd MSC 7510, Bethesda, MD 20892 USA. NR 20 TC 6 Z9 8 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-267-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 918 BP 115 EP 121 PG 7 WC Infectious Diseases; Multidisciplinary Sciences; Pediatrics SC Infectious Diseases; Science & Technology - Other Topics; Pediatrics GA BT09V UT WOS:000171939500014 PM 11131694 ER PT S AU Nathanson, N Eisinger, RW AF Nathanson, N Eisinger, RW BE Ammann, AJ Rubinstein, A TI Future directions for NIH-supported pediatric AIDS research SO PREVENTION AND TREATMENT OF HIV INFECTION IN INFANTS AND CHILDREN SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 2nd Conference on Global Strategies for the Prevention of HIV Transmission from Mothers to Infants CY SEP 01-06, 1999 CL MONTREAL, CANADA SP Glaxo Welcome ID TRANSMISSION AB The Office of AIDS Research (OAR) at the National Institutes of Health (NIH) is responsible for the coordination of AIDS research. In June 1999, the OAR, in conjunction with the NIH Institutes and Centers, initiated a review of NIH-sponsored pediatric AIDS research. This article discusses a number of important priorities for future clinical research in NIH-sponsored pediatric AIDS in both developed and developing countries. These have the potential to significantly prevent perinatal transmission, reduce adolescent infections, and impact treatment of pediatric infections. C1 US Dept HHS, NIH, Off AIDS Res, Bethesda, MD 20892 USA. RP Nathanson, N (reprint author), US Dept HHS, NIH, Off AIDS Res, Bldg 2,Room 4W02,2 Ctr Dr, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-267-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 918 BP 195 EP 200 PG 6 WC Infectious Diseases; Multidisciplinary Sciences; Pediatrics SC Infectious Diseases; Science & Technology - Other Topics; Pediatrics GA BT09V UT WOS:000171939500024 PM 11131705 ER PT S AU Dominguez, K Bertolli, J Fowler, M Peters, V Ortiz, I Melville, S Rakusan, T Frederick, T Hsu, H D'Almada, P Maldonado, Y Wilfert, C AF Dominguez, K Bertolli, J Fowler, M Peters, V Ortiz, I Melville, S Rakusan, T Frederick, T Hsu, H D'Almada, P Maldonado, Y Wilfert, C CA PSD Consortium Perinatal Safety Review Working Gr BE Ammann, AJ Rubinstein, A TI Lack of definitive severe mitochondrial signs and symptoms among deceased HIV-uninfected and HIV-indeterminate children <= 5 years of age, pediatric spectrum of HIV disease project (PSD), USA SO PREVENTION AND TREATMENT OF HIV INFECTION IN INFANTS AND CHILDREN SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 2nd Conference on Global Strategies for the Prevention of HIV Transmission from Mothers to Infants CY SEP 01-06, 1999 CL MONTREAL, CANADA SP Glaxo Welcome ID HUMAN-IMMUNODEFICIENCY-VIRUS AB Background: In response to recent reports of mitochondrial dysfunction in HIV-uninfected infants exposed to antiretroviral (ARV) prophylaxis., the Perinatal Safety Review Working Group reviewed deaths in five large HIV-exposed perinatal cohorts in the United States to determine if similar cases of severe mitochondrial toxicity could be detected. We describe the results of this review for the PSD cohort. Methods: Hospitalization, clinic and death records for deceased HIV-uninfected and HIV-indeterminate children who were less than 5 years of age were reviewed. Standard definitions were used to classify HIV infection status and the likelihood that signs and symptoms were related to mitochondrial dysfunction. Children were classified as having signs and symptoms that were considered (1) unrelated, (2) unlikely, (3) consistent with, or (4) likely related to mitochondrial disease. SIDS deaths were put into a separate category. Results: 8,465 of 13,125 HIV-exposed children were either HIV-uninfected or HIV-indeterminate. Among the 84 deaths in the subgroup of 8,465 children, 9 were considered in Class 2 (unlikely), 4 were considered in Class 3 (consistent with), and none were considered in Class 4 (likely). 97% of those children who received ARV prophylaxis received zidovudine alone. None of the HIV-uninfected deaths were classified in 2, 3, or 4; and only one of these was exposed to ARV prophylaxis. Among the 3 HIV-indeterminate children who were classified in 3 (consistent with), 2 had no or unknown ARV exposure before 1994 when use of ZDV prophylaxis became the standard of care. Both HIV-uninfected and HIV-indeterminate children with ARV exposure or unknown exposure had lower mortality rates than children without ARV exposure. Conclusion: Monoprophylaxis with ZDV was not associated with higher death rates in the cohort of 8,465 children or with any findings likely consistent with mitochondrial dysfunction among the 85 deaths. Ongoing monitoring of drug safety in large multi-site prospective cohort studies of HIV-exposed children is essential in the era of highly active antiretroviral therapy. C1 Ctr Dis Control & Prevent, Mother Child Transmiss Pediat & Adolescent Studie, Epidemiol Branch, Div HIV AIDS Prevent, Atlanta, GA 30333 USA. New York City Dept Hlth, Off AIDS Surveillance, New York, NY 10012 USA. Puerto Rico Dept Hlth, AIDS Surveillance Program, Rio Piedras, PR 00921 USA. Texas Dept Hlth, Div HIV AIDS, Austin, TX 78756 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. Los Angeles Cty Dept Hlth Serv, Pediat AIDS Surveillance Study, Los Angeles, CA 90012 USA. State Labs Inst, Pediat AIDS Surveillance Project, Boston, MA 02130 USA. Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. Duke Univ, Med Ctr, Durham, NC 27710 USA. Harvard Univ, Sch Med, Childrens Hosp, Boston, MA 02115 USA. NIAID, Pediat Med Branch, Div Aids, NIH, Bethesda, MD 20892 USA. Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. Bristol Myers Squibb Pharmaceut Res Inst, Wallingford, CT USA. Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. Clin Trials & Surveys Corp, Baltimore, MD USA. Glaxo Wellcome Res & Dev Ltd, Res Triangle Pk, NC USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Pediat, Newark, NJ 07103 USA. Univ So Calif, Keck Sch Med, Los Angeles, CA USA. Childrens Hosp, Los Angeles, CA 90027 USA. NICHHD, Pediat Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD 20892 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Pediat, Newark, NJ 07103 USA. Ctr Dis Control & Prevent, Stat & Data Management Branch, Div HIV AIDS Prevent, Atlanta, GA 30333 USA. Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. NIAID, Pediat Med Branch, Div Aids, NIH, Bethesda, MD 20892 USA. US FDA, CDER, Div Antiviral Drug Prod, Rockville, MD 20857 USA. RP Dominguez, K (reprint author), Ctr Dis Control & Prevent, Mother Child Transmiss Pediat & Adolescent Studie, Epidemiol Branch, Div HIV AIDS Prevent, 1600 Clifton Rd,Mailstop E-45, Atlanta, GA 30333 USA. OI Mofenson, Lynne/0000-0002-2818-9808 NR 7 TC 32 Z9 33 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-267-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 918 BP 236 EP 246 PG 11 WC Infectious Diseases; Multidisciplinary Sciences; Pediatrics SC Infectious Diseases; Science & Technology - Other Topics; Pediatrics GA BT09V UT WOS:000171939500028 PM 11131710 ER PT S AU Olivero, OA Shearer, GM Chougnet, CA Kovacs, AAS Baker, R Stek, AM Khoury, MM Poirier, MC AF Olivero, OA Shearer, GM Chougnet, CA Kovacs, AAS Baker, R Stek, AM Khoury, MM Poirier, MC BE Ammann, AJ Rubinstein, A TI Incorporation of zidovudine into cord blood DNA of infants and peripheral blood DNA of their HIV-1-positive mothers SO PREVENTION AND TREATMENT OF HIV INFECTION IN INFANTS AND CHILDREN SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 2nd Conference on Global Strategies for the Prevention of HIV Transmission from Mothers to Infants CY SEP 01-06, 1999 CL MONTREAL, CANADA SP Glaxo Welcome ID IMMUNODEFICIENCY-VIRUS TYPE-1; EXPOSED IN-UTERO; 3'-AZIDO-2',3'-DIDEOXYTHYMIDINE AZT; MUTANT FREQUENCY; CELL-LINE; 3'-AZIDO-3'-DEOXYTHYMIDINE; MICE; TRANSMISSION; GENOTOXICITY; MUTATIONS AB The nucleoside analogue 3'-azido-3'-deoxythymidine (AZT) is a weak carcinogen in adult female mice and a moderately strong carcinogen in the offspring of female mice given the drug during gestation. In addition, incorporation of AZT into DNA was observed in multiple organs of transplacentally exposed newborn mice. Here we investigate the incorporation of AZT into peripheral leukocyte DNA of HIV-1-positive adult pregnant women given AZT for variable times during gestation and cord blood of infants exposed to AZT in utero. The length of treatment varied between 10 days and 9 months. High molecular weight DNA was extracted from maternal peripheral blood mono. nuclear cells (PBMC) and infant cord blood. A specific AZT-DNA radioimmunoassay was used to determine the amount of AZT incorporated into leukocyte DNA. Incorporation of AZT into DNA ranged up to 183.3 and 344.5 molecules of AZT/10(6) nucleotides in the mothers and infants, respectively, and was detected in about 70 % of samples. Therefore, AZT-induced mutagenic events are possible in the majority of adults and infants. No correlation was found between level of incorporation and length of AZT treatment, suggesting that the differences observed among the individuals arise from variability in AZT metabolism. These data support previous observations that a high degree of interindividual variability in AZT phosphorylation occurs in primates. C1 NCI, NIH, Div Basic Sci, Bethesda, MD 20892 USA. Univ So Calif, Sch Med, Comprehens Maternal Child HIV Managment & Res Ctr, Los Angeles, CA 90033 USA. Fairfax Hosp, Dept Neonatol, Falls Church, VA 22046 USA. RP Poirier, MC (reprint author), NCI, NIH, Div Basic Sci, Bldg 37,Rm 2A03,MSC-4255,37 Convent Dr, Bethesda, MD 20892 USA. NR 21 TC 20 Z9 20 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-267-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 918 BP 262 EP 268 PG 7 WC Infectious Diseases; Multidisciplinary Sciences; Pediatrics SC Infectious Diseases; Science & Technology - Other Topics; Pediatrics GA BT09V UT WOS:000171939500030 PM 11131712 ER PT S AU Gerschenson, M Poirier, MC AF Gerschenson, M Poirier, MC BE Ammann, AJ Rubinstein, A TI Fetal patas monkeys sustain mitochondrial toxicity as a result of in utero zidovudine exposure SO PREVENTION AND TREATMENT OF HIV INFECTION IN INFANTS AND CHILDREN SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 2nd Conference on Global Strategies for the Prevention of HIV Transmission from Mothers to Infants CY SEP 01-06, 1999 CL MONTREAL, CANADA SP Glaxo Welcome ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIRETROVIRAL NUCLEOSIDE ANALOGS; INDUCED MYOPATHY; IN-UTERO; DNA; AZT; DYSFUNCTION; 3'-AZIDO-3'-DEOXYTHYMIDINE; DEPLETION; DISORDER AB Mitochondrial toxicity was examined in near-term fetuses of pregnant Erythrocebus patas monkeys given human equivalent doses of 3'-azido-3'deoxythymidine (AZT) during the second half of gestation. Pregnant monkeys were dosed daily with 10 or 40 mg AZT, equivalent to about 21 % and 86 % of the daily AZT dose (500 mg) given to HIV-1-positive pregnant women to prevent maternal-fetal virus transmission. The fetal tissues examined include heart and skeletal muscle, which have high energy requirements, and placenta, which is less dependent on mitochondrial integrity. Slot blot quantitation of mitochondrial DNA (mtDNA) levels showed dose-dependent depletion in heart, skeletal muscle, and placenta from AZT-exposed fetuses compared to unexposed controls. Furthermore, mtDNA degradation, observed by Southern blot analysis, appeared more extensive in AZT-exposed tissues compared to unexposed controls. Mitochondrial functional integrity, as determined by oxidative phosphorylation (OXPHOS) enzyme assays, was also examined in heart, skeletal muscle, and placenta. All three tissues showed strong dose-related decreases in Complex I. In placenta, dose-related increases for Complexes II and IV and a decrease for Complex III were observed. Dose-related increases for Complexes II and IV observed in heart and skeletal muscle have been reported.(1) The increase in Complex IV (cytochrome c oxidase) activity in heart and skeletal muscle tissue from patas fetuses exposed to 40 mg AZT/day has been confirmed here by histochemical staining. Overall, data demonstrate that mitochondrial toxicity, evidenced by depletion in mtDNA and OXPROS enzyme abnormalities, is manifested similarly in heart, skeletal muscle, and placenta of AZT-exposed monkey fetuses. It is therefore possible that the placenta, which is a readily accessible tissue, might be an indicator of potential mitochondrial toxicity in human pregnancies involving nucleoside analog drug exposure. C1 NCI, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Poirier, MC (reprint author), NCI, Div Basic Sci, NIH, 37 Convent Dr,Rm 2A05, Bethesda, MD 20892 USA. NR 33 TC 34 Z9 34 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-267-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 918 BP 269 EP 281 PG 13 WC Infectious Diseases; Multidisciplinary Sciences; Pediatrics SC Infectious Diseases; Science & Technology - Other Topics; Pediatrics GA BT09V UT WOS:000171939500031 PM 11131713 ER PT S AU Gonzalez, CE Samakoses, R Boler, AM Hill, S Wood, LV AF Gonzalez, CE Samakoses, R Boler, AM Hill, S Wood, LV BE Ammann, AJ Rubinstein, A TI Lymphoid interstitial pneumonitis in pediatric AIDS - Natural history of the disease SO PREVENTION AND TREATMENT OF HIV INFECTION IN INFANTS AND CHILDREN SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 2nd Conference on Global Strategies for the Prevention of HIV Transmission from Mothers to Infants CY SEP 01-06, 1999 CL MONTREAL, CANADA SP Glaxo Welcome ID CHILDREN; INFECTION; HIV C1 NCI, HIV AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. Pramongkutklao Coll Med, Bangkok, Thailand. NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Gonzalez, CE (reprint author), Childrens Natl Med Ctr, Pediat Med Suite 3-5-600,111 Michigan Ave NW, Washington, DC 20010 USA. NR 12 TC 6 Z9 6 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-267-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 918 BP 358 EP 361 PG 4 WC Infectious Diseases; Multidisciplinary Sciences; Pediatrics SC Infectious Diseases; Science & Technology - Other Topics; Pediatrics GA BT09V UT WOS:000171939500040 PM 11131724 ER PT S AU Gonzalez, CE Adde, M Taylor, P Wood, LV Magrath, I AF Gonzalez, CE Adde, M Taylor, P Wood, LV Magrath, I BE Ammann, AJ Rubinstein, A TI Impact of chemotherapy for AIDS-related malignancies in pediatric HIV disease SO PREVENTION AND TREATMENT OF HIV INFECTION IN INFANTS AND CHILDREN SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 2nd Conference on Global Strategies for the Prevention of HIV Transmission from Mothers to Infants CY SEP 01-06, 1999 CL MONTREAL, CANADA SP Glaxo Welcome ID INFECTION; CHILDREN C1 NCI, HIV AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Gonzalez, CE (reprint author), Childrens Natl Med Ctr, Suite 3-5-600,111 Michigan Ave NW, Washington, DC 20010 USA. NR 9 TC 2 Z9 3 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-267-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 918 BP 362 EP 366 PG 5 WC Infectious Diseases; Multidisciplinary Sciences; Pediatrics SC Infectious Diseases; Science & Technology - Other Topics; Pediatrics GA BT09V UT WOS:000171939500041 PM 11131726 ER PT B AU Demaimay, R Chesebro, B Caughey, B AF Demaimay, R Chesebro, B Caughey, B BE Groschup, MH Kretzschmar, HA TI Inhibition of formation of protease-resistant prion protein by Trypan Blue, Sirius Red and other Congo Red analogs SO PRION DISEASES: DIAGNOSIS AND PATHOGENESIS LA English DT Proceedings Paper CT Symposium on the Characterization and Diagnosis of Prion Diseases CY SEP 23-25, 1999 CL TUBINGEN, GERMANY ID TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES; SCRAPIE-INFECTED HAMSTERS; INCUBATION PERIOD; PRP ACCUMULATION; AMPHOTERICIN-B; MOUSE; PHTHALOCYANINES; REPLICATION; PORPHYRINS; DELAYS AB Five compounds related to Congo Red were found to inhibit generation of protease-resistant prion protein in a cell-free system. In this assay Trypan Blue, Evans Blue, Sirius Red F3B, Primuline and Thioffavin-S were all more inhibitory than Congo Red itself. In scrapie-infected mouse neuroblastoma cells one compound, Sirius Red F3B, was capable of blocking the formation of protease-resistant prion protein to a similar extent as Congo Red; however, the other four compounds were less effective. Some of these compounds should be considered for testing in TSE disease models in live animals. C1 NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Chesebro, B (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 20 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG WIEN PI VIENNA PA SACHSENPLATZ 4-6, A-1201 VIENNA, AUSTRIA BN 3-211-83530-X PY 2000 BP 277 EP 283 PG 7 WC Infectious Diseases; Clinical Neurology SC Infectious Diseases; Neurosciences & Neurology GA BR80T UT WOS:000167603200026 ER PT B AU Chernomordik, VV Hattery, D Gandjbakhche, AH AF Chernomordik, VV Hattery, D Gandjbakhche, AH BE Gandjbakhiche, AH TI Quantitative optical Imaging using random walk theory SO PROCEEDINGS OF INTER-INSTITUTE WORKSHOP ON IN VIVO OPTICAL IMAGING AT THE NIH LA English DT Proceedings Paper CT 1st Inter-Institute Workshop on In Vivo Optical Imaging CY SEP 16-17, 1999 CL NIH, BETHESDA, MD SP NICHHD, NCI, NHLBI, NINDS, Off Res Woman Hlth, Opt Soc Amer, Hamamatsu, ISS Inc, Zeiss HO NIH ID TIME-DOMAIN; CONTRAST FUNCTIONS; SCATTERING; ABSORPTION; MEDICINE AB The robustness of a random walk model that uses time-dependent contrast functions to quantify the cross-section and the corrected scattering and absorption coefficients of optically abnormal targets from time-of-flight (TOF) data obtained in time-resolved transillumination experiments is successfully analyzed. Several independent sets of experimental TOF data are used to show that the random walk methodology is able to quantify the size and optical properties of embedded targets with an error less than or equal to25%. The underlying theoretical assumptions of the model are tested. Finally, the effect of lateral boundaries on time-resolved measurements of light transmitted through slabs of finite thickness is considered within the framework of a random walk model. C1 NICHHD, NIH, Lab Integrat & Med Biophys, Unit Biomed Stochast Phys, Bethesda, MD 20892 USA. RP Chernomordik, VV (reprint author), NICHHD, NIH, Lab Integrat & Med Biophys, Unit Biomed Stochast Phys, Bethesda, MD 20892 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU OPTICAL SOC AMERICA PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA BN 1-55752-653-2 PY 2000 BP 188 EP 193 PG 6 WC Engineering, Biomedical; Microscopy; Optics; Spectroscopy SC Engineering; Microscopy; Optics; Spectroscopy GA BT68M UT WOS:000173724500032 ER PT S AU Andreucci, L Anselmi, R Bisi, F Bevegni, M AF Andreucci, L Anselmi, R Bisi, F Bevegni, M BE Enderle, JD TI EvTool: a quantitative and radiobiological RTP evaluation system. SO PROCEEDINGS OF THE 22ND ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY, VOLS 1-4 SE PROCEEDINGS OF ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY LA English DT Proceedings Paper CT 22nd Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society CY JUL 23-28, 2000 CL CHICAGO, IL SP IEEE, Engn Med & Biol Soc, Amer Assoc Physicists Med, Amer Inst Med & Biol Engn, Int Union Phys & Engn Sci Med, Int Federat Med & Biol Engn, Int Org Med Phys C1 Natl Canc Inst, Biophys Lab, Genoa, Italy. RP Andreucci, L (reprint author), Natl Canc Inst, Biophys Lab, Genoa, Italy. NR 1 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1094-687X BN 0-7803-6466-X J9 P ANN INT IEEE EMBS PY 2000 VL 22 BP 880 EP 881 PN 1-4 PG 2 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BR59S UT WOS:000166896300246 ER PT B AU Gracely, RH AF Gracely, RH BE Devor, M Rowbotham, MC WiesenfeldHallin, Z TI Charisma and the art of healing: Can nonspecific factors be enough? SO PROCEEDINGS OF THE 9TH WORLD CONGRESS ON PAIN SE PROGRESS IN PAIN RESEARCH AND MANAGEMENT LA English DT Proceedings Paper CT 9th World Congress on Pain CY AUG 22-27, 1999 CL VIENNA, AUSTRIA SP Allergan, ASTA Medica AG, Boots Hlthcare Int, Endo Pharmaceut Inc, Grunenthal GmbH, Janssen Pharmaceutica, Medtron Inc, Menarini Int, Neurex Corp, Novartis, Parke Davis, Pfizer Pharmaceut, Procter & Gamble Co, Purdue Pharma LP, UPSA Labs, UPSA Pain Inst ID EXERCISE-INDUCED ASTHMA; PERCEPTUAL CHARACTERISTICS; PLACEBO; PAIN; ACUPUNCTURE; THERAPY C1 NIDCR, CMMU, PNMB, NIH, Bethesda, MD 20892 USA. RP Gracely, RH (reprint author), NIDCR, CMMU, PNMB, NIH, 10-1N-103D, Bethesda, MD 20892 USA. NR 83 TC 8 Z9 8 U1 1 U2 1 PU INT ASSOC STUDY PAIN (IASP) PRESS PI SEATTLE PA 909 NE 43RD ST, SUITE 304, SEATTLE, WA 98105 USA BN 0-931092-31-0 J9 PROG PAIN RES MANAG PY 2000 VL 16 BP 1045 EP 1067 PG 23 WC Medicine, General & Internal; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA BQ56W UT WOS:000088785400099 ER PT B AU Chadwick, RS Manoussaki, D AF Chadwick, RS Manoussaki, D BE Wada, H Takasaka, T Ikeda, K Koike, T TI Geometric wave amplification in a helicoidal version of the classical model of cochlear mechanics SO PROCEEDINGS OF THE INTERNATIONAL SYMPOSIUM ON RECENT DEVELOPMENTS IN AUDITORY MECHANICS LA English DT Proceedings Paper CT International Symposium on Recent Developments in Auditory Mechanics CY JUL 25-30, 1999 CL SENDAI, JAPAN SP Japan Soc Promot Sci, Aoba Fdn Promot Engn, Charitable Trust Ono Res Fund Acoust, Inoue Fdn Sci, Mikiya Sci & Technol Fdn, Osaka Pharmaceut Manufacturers Assoc, Pharmaceut Manufacturers Assoc Tokyo, Aloka Co Ltd, Aoba Sci Co Ltd, Asahi Co Ltd, Chemie Co Ltd, Dana Japan Co Ltd, Dowa Min Co Ltd, Honda Motor Co Ltd, J Morita MFG Corp, Kawasaki Steel Corp, Machida Endoscope Co Ltd, Nihon Cochlear Co Ltd, Nihon Kohden Corp, Toshiba Corp, Toyota Motor Corp AB Recently we developed a helicoidal box model of the cochlea [1] to address the hypothesis that coiling may have a functional significance. In that study we introduced nonorthogonal helicoidal coordinates, and introduced the WKB expansion to treat wave propagation in a slowly-varying geometry, and then numerically computed the fluid motion in a plane containing the modiolar axis using finite differences. We showed that coiling reduces the inertial impedance to fluid motion induced by the traveling wave. Since the effect was greatest at the apex, we suggested that the characteristic snail-like shape of the mammalian cochlea could increase the low frequency response of the cochlear partition. Here we study a simplified model where radial derivatives are neglected, which is a helicoidal version of what de Beer refers to as a "two dimensional classical model" of cochlear mechanics [2]. The eikonal equation, which determines the local wavenumber, and the transport equation, which determines the amplitude of the wave, can be analytically obtained for our simplified system. We find that spiraling inward from base to apex geometrically amplifies the wave in proportion to the inverse of the square root of the distance from the modiolar axis to the basilar membrane centerline. C1 NIDCD, Sect Auditory Mech, NIH, Bethesda, MD 20892 USA. RP Chadwick, RS (reprint author), NIDCD, Sect Auditory Mech, NIH, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA PO BOX 128 FARRER RD, SINGAPORE 9128, SINGAPORE BN 981-02-4170-4 PY 2000 BP 195 EP 201 PG 7 WC Acoustics; Engineering, Biomedical; Otorhinolaryngology SC Acoustics; Engineering; Otorhinolaryngology GA BS15Z UT WOS:000168874500028 ER PT B AU Iwasa, KH Adachi, M AF Iwasa, KH Adachi, M BE Wada, H Takasaka, T Ikeda, K Koike, T TI Membrane motor of the outer hair cell SO PROCEEDINGS OF THE INTERNATIONAL SYMPOSIUM ON RECENT DEVELOPMENTS IN AUDITORY MECHANICS LA English DT Proceedings Paper CT International Symposium on Recent Developments in Auditory Mechanics CY JUL 25-30, 1999 CL SENDAI, JAPAN SP Japan Soc Promot Sci, Aoba Fdn Promot Engn, Charitable Trust Ono Res Fund Acoust, Inoue Fdn Sci, Mikiya Sci & Technol Fdn, Osaka Pharmaceut Manufacturers Assoc, Pharmaceut Manufacturers Assoc Tokyo, Aloka Co Ltd, Aoba Sci Co Ltd, Asahi Co Ltd, Chemie Co Ltd, Dana Japan Co Ltd, Dowa Min Co Ltd, Honda Motor Co Ltd, J Morita MFG Corp, Kawasaki Steel Corp, Machida Endoscope Co Ltd, Nihon Cochlear Co Ltd, Nihon Kohden Corp, Toshiba Corp, Toyota Motor Corp ID CAPACITANCE; MOTILITY AB The mechanism of voltage-dependent motility of the outer hair cell appears unique among biological motility in that it depends on electrical energy. Here we provide evidence that charge transfer measured as nonlinear capacitance and area changes of the outer hair cell membrane are tightly coupled. We digested the interior of the hair cell with trypsin and inflated the cell into a sphere with a patch pipette. If the cell is fully inflated, a membrane area constraint can be imposed on the cell by applying a short voltage waveform not to allow volume changes. This condition significantly reduced the nonlinear capacitance of the cell, indicating reduced charge transfer. By reducing pressure applied to the pipette, the nonlinear capacitance recovered. Increasing the duration of the waveform and thereby allowing changes in the cell volume also increased the nonlinear capacitance. Thus membrane area constraint and reduction in charge transfer are tightly Linked. Since the cells we examined were internally digested, our results also show that the motile element likely resides in the plasma membrane. C1 NIH, NIDCD, LCB, Biophys Sect, Bethesda, MD 20892 USA. RP Iwasa, KH (reprint author), NIH, NIDCD, LCB, Biophys Sect, Bldg 10,9 Ctr Dr,MSC 0922, Bethesda, MD 20892 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA PO BOX 128 FARRER RD, SINGAPORE 9128, SINGAPORE BN 981-02-4170-4 PY 2000 BP 275 EP 280 PG 6 WC Acoustics; Engineering, Biomedical; Otorhinolaryngology SC Acoustics; Engineering; Otorhinolaryngology GA BS15Z UT WOS:000168874500039 ER PT B AU Dong, XX Ehrenstein, D Iwasa, KH AF Dong, XX Ehrenstein, D Iwasa, KH BE Wada, H Takasaka, T Ikeda, K Koike, T TI Frequency dependence of the membrane capacitance and current noise spectrum SO PROCEEDINGS OF THE INTERNATIONAL SYMPOSIUM ON RECENT DEVELOPMENTS IN AUDITORY MECHANICS LA English DT Proceedings Paper CT International Symposium on Recent Developments in Auditory Mechanics CY JUL 25-30, 1999 CL SENDAI, JAPAN SP Japan Soc Promot Sci, Aoba Fdn Promot Engn, Charitable Trust Ono Res Fund Acoust, Inoue Fdn Sci, Mikiya Sci & Technol Fdn, Osaka Pharmaceut Manufacturers Assoc, Pharmaceut Manufacturers Assoc Tokyo, Aloka Co Ltd, Aoba Sci Co Ltd, Asahi Co Ltd, Chemie Co Ltd, Dana Japan Co Ltd, Dowa Min Co Ltd, Honda Motor Co Ltd, J Morita MFG Corp, Kawasaki Steel Corp, Machida Endoscope Co Ltd, Nihon Cochlear Co Ltd, Nihon Kohden Corp, Toshiba Corp, Toyota Motor Corp ID OUTER HAIR-CELLS; COCHLEAR AMPLIFIER; MOTOR AB It has been shown that the membrane motor of the outer hair cell uses energy obtained by transfer of charge across the membrane. To study the kinetics of motor associated charge transfer across the membrane, we observed the power spectrum of current noise and the frequency dependence of the membrane capacitance from giant patches formed on the lateral membrane of the outer hair cell. The noise spectrum was inverse Lorentzian and the capacitance had Lorentzian frequency dependence as theoretically expected. The characteristic frequency for the capacitance was about 10 kHz and the one for current noise was somewhat higher. The magnitudes of noise, however, was larger than the theoretical prediction based on the capacitance data. This result appears to indicate that different mechanical constraints affected the two quantities monitored. C1 NIH, NIDCD, LCB, Biophys Sect, Bethesda, MD 20892 USA. RP Dong, XX (reprint author), NIH, NIDCD, LCB, Biophys Sect, Bldg 10, Bethesda, MD 20892 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA PO BOX 128 FARRER RD, SINGAPORE 9128, SINGAPORE BN 981-02-4170-4 PY 2000 BP 337 EP 343 PG 7 WC Acoustics; Engineering, Biomedical; Otorhinolaryngology SC Acoustics; Engineering; Otorhinolaryngology GA BS15Z UT WOS:000168874500048 ER PT J AU Zlatanova, J Lindsay, SM Leuba, SH AF Zlatanova, J Lindsay, SM Leuba, SH TI Single molecule force spectroscopy in biology using the atomic force microscope SO PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY LA English DT Review DE atomic force microscopy; DNA stretching; intermolecular interactions; intramolecular interactions; protein unfolding; single molecule force spectroscopy ID TITIN IMMUNOGLOBULIN DOMAINS; SCANNING PROBE MICROSCOPY; DNA-MOLECULES; MECHANICAL MEASUREMENTS; COMPLEMENTARY STRANDS; SPRING CONSTANTS; ADHESION FORCES; ELASTICITY; CANTILEVERS; LIGAND AB The importance of forces in biology has been recognized for quite a while but only in the past decade have we acquired instrumentation and methodology to directly measure interactive forces at the level of single biological macromolecules and/or their complexes. This review focuses on force measurements performed with the atomic force microscope. A general introduction to the principle of action is followed by review of the types of interactions being studied, describing the main results and discussing the biological implications. Published by Elsevier Science Ltd. C1 Argonne Natl Lab, Biochip Technol Ctr, Argonne, IL 60439 USA. Arizona State Univ, Dept Phys & Astron, Tempe, AZ 85287 USA. NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Zlatanova, J (reprint author), Polytech Univ, Dept Chem Engn Chem & Mat Sci, 6 Metrotech Ctr, Brooklyn, NY 11201 USA. RI Zlatanova, Jordanka/B-3273-2009 NR 110 TC 256 Z9 265 U1 5 U2 78 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0079-6107 J9 PROG BIOPHYS MOL BIO JI Prog. Biophys. Mol. Biol. PY 2000 VL 74 IS 1-2 BP 37 EP 61 DI 10.1016/S0079-6107(00)00014-6 PG 25 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 386AU UT WOS:000166038600003 PM 11106806 ER PT S AU Presciuttini, S Casarino, L Verdiani, S Mannucci, A Peirano, L Bailey-Wilson, JE De Stefano, F AF Presciuttini, S Casarino, L Verdiani, S Mannucci, A Peirano, L Bailey-Wilson, JE De Stefano, F BE Sensabaugh, GF Lincoln, PJ Olaisen, B TI Distributions of the number of alleles identical by state (IBS), summed over several loci, among full-sib pairs and unrelated individuals SO PROGRESS IN FORENSIC GENETICS 8 SE INTERNATIONAL CONGRESS SERIES LA English DT Proceedings Paper CT 18th Congress of the International-Society-for-Forensic-Haemogenetics (ISFH) CY AUG 17-21, 1999 CL SAN FRANCISCO, CA SP Calif Assoc Criminlists, Amer Assoc Blood Banks, PE Appl Biosyst, Hitachi Genet Syst, Promega Corp, Int Soc Forens Haemogenet AB Starting from the distribution of the total number of IBS alleles in a sample of 80 full-sib Fairs typed with 13 markers, we show that the power of discrimination between siblings and pairs of unrelated individuals is fairly high at reasonable significance levels. C1 IDRB, Natl Human Genome Res Inst, Baltimore, MD USA. RP Presciuttini, S (reprint author), IDRB, Natl Human Genome Res Inst, Baltimore, MD USA. NR 3 TC 0 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0531-5131 BN 0-444-50303-X J9 INT CONGR SER PY 2000 IS 1193 BP 88 EP 90 PG 3 WC Genetics & Heredity; Medicine, Legal SC Genetics & Heredity; Legal Medicine GA BP92T UT WOS:000086639200024 ER PT J AU Jetten, AM Suter, U AF Jetten, AM Suter, U TI The peripheral myelin protein 22 and epithelial membrane protein family SO PROGRESS IN NUCLEIC ACID RESEARCH AND MOLECULAR BIOLOGY, VOL 64 SE PROGRESS IN NUCLEIC ACID RESEARCH AND MOLECULAR BIOLOGY LA English DT Review ID MARIE-TOOTH-DISEASE; TREMBLER-J MOUSE; ONION BULB NEUROPATHY; HEREDITARY DEMYELINATING NEUROPATHY; OLIGODENDROCYTE-SPECIFIC PROTEIN; CELL AXON INTERACTIONS; PMP22 POINT MUTATIONS; ARREST-SPECIFIC GENES; FRAME-SHIFT MUTATION; SCHWANN-CELLS C1 NIEHS, Cell Biol Sect, Pulm Pathobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. ETH Honggerberg, Inst Cell Biol, CH-8093 Zurich, Switzerland. RP Jetten, AM (reprint author), NIEHS, Cell Biol Sect, Pulm Pathobiol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Suter, Ueli/A-1624-2010; OI Jetten, Anton/0000-0003-0954-4445 NR 204 TC 69 Z9 75 U1 2 U2 8 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0079-6603 J9 PROG NUCLEIC ACID RE PY 2000 VL 64 BP 97 EP 129 DI 10.1016/S0079-6603(00)64003-5 PG 33 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BQ12Z UT WOS:000087255500003 PM 10697408 ER PT J AU Furano, AV AF Furano, AV TI The biological properties and evolutionary dynamics of mammalian LINE-1 retrotransposons SO PROGRESS IN NUCLEIC ACID RESEARCH AND MOLECULAR BIOLOGY, VOL 64 SE PROGRESS IN NUCLEIC ACID RESEARCH AND MOLECULAR BIOLOGY LA English DT Review ID INTERSPERSED REPEATED DNA; OPEN READING FRAME; EMBRYONAL CARCINOMA-CELLS; HUMAN L1 TRANSPOSON; RNA-POLYMERASE-II; REVERSE-TRANSCRIPTASE; MOUSE LINE-1; RIBONUCLEOPROTEIN-PARTICLES; MESSENGER-RNA; NONHOMOLOGOUS RECOMBINATION C1 NIDDKD, Sect Genom Struct & Funct, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. RP Furano, AV (reprint author), NIDDKD, Sect Genom Struct & Funct, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. NR 168 TC 104 Z9 107 U1 1 U2 5 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0079-6603 J9 PROG NUCLEIC ACID RE PY 2000 VL 64 BP 255 EP 294 DI 10.1016/S0079-6603(00)64007-2 PG 40 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BQ12Z UT WOS:000087255500007 PM 10697412 ER PT S AU Zeiger, E AF Zeiger, E BE Balls, M VanZeller, AM Halder, ME TI Current strategies for detecting carcinogens by using genetic toxicity tests SO PROGRESS IN THE REDUCTION, REFINEMENT AND REPLACEMENT OF ANIMAL EXPERIMENTATION SE DEVELOPMENTS IN ANIMAL AND VETERINARY SCIENCES LA English DT Proceedings Paper CT 3rd World Congress on Alternatives and Animal Use in the Life Science CY AUG 29-SEP 02, 1999 CL BOLOGNA, ITALY SP Colgate Palmolive Co, European Commiss, Environm DIrector Gen, European Commiss, Joint Res Ctr, Toiletry & Perfumery Assoc, European Cosmet, Gillette Co, Glaxo Wellcome, Int Fdn Eth Res, Kimberly Clark Corp, L Oreal, Procter & Gamble Co, Unilever Res, Utrecht Congress ID HAMSTER OVARY CELLS; SHORT-TERM TESTS; RODENT CARCINOGENICITY; MUTAGENESIS ASSAY; CHEMICALS; GUIDELINES; NONCARCINOGENS; SYSTEM AB Testing strategies for using genetic toxicity tests to identify potential carcinogens vary among countries, but contain the same basic core tests. The Salmonella mutagenicity test is a component of all testing schemes. In vitro mammalian cell tests are used for measuring the induction of chromosome aberrations and gene mutations, and rodent tests are used to confirm the results of in vitro tests and to make the link to in vivo events. It is generally considered that test batteries are more predictive of carcinogenicity than are the individual tests in the battery. The use of these tests was encouraged by early reports suggesting high degrees of association between mutagenicity and non-mutagenicity in the Salmonella and other genetic toxicity tests, and carcinogenicity or non-carcinogenicity in rodents. The US National Toxicology Program has performed Salmonella mutagenicity, chromosome aberration, mouse lymphoma cell mutation, rodent bone-marrow micronucleus and rodent carcinogenicity tests on a large number of diverse chemicals. These results were used to determine whether the data affirm the routine use of these tests for screening or identifying carcinogens in support of administrative or regulatory decisions. A positive Salmonella test was most predictive of carcinogenicity. Positive responses in the other in vitro or in vivo tests alone, or in a test battery, did not increase the probability that the chemical was a carcinogen, and negative responses did not diminish the implications of the positive Salmonella response. It is concluded that much of the required genetic toxicity testing for identifying potential carcinogens is unnecessary. C1 NIEHS, Environm Toxicol Program EC14, Res Triangle Pk, NC 27709 USA. RP Zeiger, E (reprint author), NIEHS, Environm Toxicol Program EC14, POB 12233, Res Triangle Pk, NC 27709 USA. NR 33 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-5168 BN 0-444-50529-6 J9 DEV AN VET PY 2000 VL 31 BP 113 EP 122 PN A & B PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA BS42Q UT WOS:000169797500012 ER PT S AU Stokes, W Hill, R AF Stokes, W Hill, R BE Balls, M VanZeller, AM Halder, ME TI The role of the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) in the evaluation of new toxicological testing methods SO PROGRESS IN THE REDUCTION, REFINEMENT AND REPLACEMENT OF ANIMAL EXPERIMENTATION SE DEVELOPMENTS IN ANIMAL AND VETERINARY SCIENCES LA English DT Proceedings Paper CT 3rd World Congress on Alternatives and Animal Use in the Life Science CY AUG 29-SEP 02, 1999 CL BOLOGNA, ITALY SP Colgate Palmolive Co, European Commiss, Environm DIrector Gen, European Commiss, Joint Res Ctr, Toiletry & Perfumery Assoc, European Cosmet, Gillette Co, Glaxo Wellcome, Int Fdn Eth Res, Kimberly Clark Corp, L Oreal, Procter & Gamble Co, Unilever Res, Utrecht Congress ID WORKSHOP AB New toxicological test methods offer the potential benefits of improved safety assessments, cost and time savings. and/or the refinement, reduction, and replacement of animal use. Before new test methods are used to generate information to support regulatory decisions, validation studies must be conducted to determine their performance characteristics, limitations, and usefulness for specific proposed uses. The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) and the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) were recently established by the US government to work with test developers and federal agencies to facilitate the evaluation and adoption of new test methods. Test developers are encouraged to interact with ICCVAM/NICEATM throughout test method development, prevalidation, and validation to maximise the likelihood of generating information needed by agencies to assess the usefulness and limitations of new test methods. Test method submission guidelines have been established to assist developers in designing validation studies and test method protocols that will adequately address established validation criteria. Following validation, ICCVAM and NICEATM coordinate the independent peer review of test methods by an independent international panel of expert scientists. The review process allows the participation of interested parties through public meetings and the opportunity for public comments. Test method peer review reports and ICCVAM recommendations are then provided to federal agencies, where they are considered for regulatory acceptance. The development, validation. and acceptance of new methods is expected to provide enhanced protection of public health and the environment, and to benefit animal welfare through the refinement, reduction, and replacement of animal use. C1 NIEHS, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Stokes, W (reprint author), NIEHS, Environm Toxicol Program, POB 12233,Mail Code EC-17, Res Triangle Pk, NC 27709 USA. NR 13 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-5168 BN 0-444-50529-6 J9 DEV AN VET PY 2000 VL 31 BP 385 EP 394 PN A & B PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA BS42Q UT WOS:000169797500037 ER PT S AU Chhabra, RS Haseman, JK Bucher, JR AF Chhabra, RS Haseman, JK Bucher, JR BE Balls, M VanZeller, AM Halder, ME TI Cost and animal use reduction analysis: review of the National Toxicology Program 14-day toxicity study database SO PROGRESS IN THE REDUCTION, REFINEMENT AND REPLACEMENT OF ANIMAL EXPERIMENTATION SE DEVELOPMENTS IN ANIMAL AND VETERINARY SCIENCES LA English DT Proceedings Paper CT 3rd World Congress on Alternatives and Animal Use in the Life Science CY AUG 29-SEP 02, 1999 CL BOLOGNA, ITALY SP Colgate Palmolive Co, European Commiss, Environm DIrector Gen, European Commiss, Joint Res Ctr, Toiletry & Perfumery Assoc, European Cosmet, Gillette Co, Glaxo Wellcome, Int Fdn Eth Res, Kimberly Clark Corp, L Oreal, Procter & Gamble Co, Unilever Res, Utrecht Congress AB The toxicological and carcinogenic potential of chemicals is usually determined through a sequence of acute, 14-day, 90-day and 2-year studies in rats and mice of both sexes. The National Toxicology Program does not conduct acute toxicity studies. Dose levels for 14-day toxicity studies are typically estimated from information in the literature, if available. The toxicology information obtained from 14-day studies is used in the selection of doses for 90-day studies. The usual protocol for 14-day studies includes six groups (five treatment and one control) of animals of each species and sex, with five animals per dose group, resulting in the use of 120 animals per study. Usually, the dose levels are spaced by a multiple of two. The NTP has studied more than 500 chemicals for general toxicity and carcinogenicity. A sample of 60 studies from this database were analysed to determine whether a wider spacing (three-fold versus two-fold) between dose levels in 90-day studies would eliminate the need for a preceding 14-day study. The derivation of maximum tolerated dose or minimum toxic dose (MTD) for chronic toxicity and carcinogenicity studies was used as an endpoint for this analysis. The results of the analysis suggest that the NTP need not perform 14-day studies routinely, and should instead proceed directly to 90-day studies by using a three-fold spacing of the dose groups. This modification in the experimental design would result in a reduction of animal use, and in costs, and in the time required to perform carcinogenesis studies. C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Chhabra, RS (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 7 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-5168 BN 0-444-50529-6 J9 DEV AN VET PY 2000 VL 31 BP 829 EP 834 PN A & B PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA BS42Q UT WOS:000169797500078 ER PT S AU Stokes, WS AF Stokes, WS BE Balls, M VanZeller, AM Halder, ME TI Humane endpoints for laboratory animals used in toxicity testing SO PROGRESS IN THE REDUCTION, REFINEMENT AND REPLACEMENT OF ANIMAL EXPERIMENTATION SE DEVELOPMENTS IN ANIMAL AND VETERINARY SCIENCES LA English DT Proceedings Paper CT 3rd World Congress on Alternatives and Animal Use in the Life Science CY AUG 29-SEP 02, 1999 CL BOLOGNA, ITALY SP Colgate Palmolive Co, European Commiss, Environm DIrector Gen, European Commiss, Joint Res Ctr, Toiletry & Perfumery Assoc, European Cosmet, Gillette Co, Glaxo Wellcome, Int Fdn Eth Res, Kimberly Clark Corp, L Oreal, Procter & Gamble Co, Unilever Res, Utrecht Congress ID END-POINT AB Toxicity testing is conducted to identify potential adverse health effects or to demonstrate the safety of new chemicals and products, thereby providing the basis for safeguarding human and animal health. In acute and chronic toxicity studies using animals, toxic effects are often accompanied by clinical signs of pain or distress. In recent years, there have been significant efforts to identify humane endpoints for toxicity studies that can be used as criteria for ending a test procedure to avoid or terminate pain and distress. New and revised test methods and approaches that incorporate humane endpoints are being considered and adopted by national and international regulatory testing authorities. Prerequisites for the adoption of new and revised methods are a determination that the methods have been adequately validated, and that they will provide equivalent or better information for use in risk assessment. This paper reviews current endpoints used in toxicity testing and describes a systematic approach for developing and validating new endpoints. Humane endpoints incorporated into ocular irritation and dermal hypersensitivity test methods are also presented. Further progress in eliminating pain and distress in toxicity testing is expected, as advances in science and technology are incorporated into research and testing strategies. C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Stokes, WS (reprint author), NIEHS, Mail Code EC-17,POB 12233, Res Triangle Pk, NC 27709 USA. NR 31 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-5168 BN 0-444-50529-6 J9 DEV AN VET PY 2000 VL 31 BP 897 EP 906 PN A & B PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA BS42Q UT WOS:000169797500086 ER PT S AU Shelby, MD AF Shelby, MD BE Balls, M VanZeller, AM Halder, ME TI Will routine testing of endocrine disrupters merely provide data which cannot be interpreted? SO PROGRESS IN THE REDUCTION, REFINEMENT AND REPLACEMENT OF ANIMAL EXPERIMENTATION SE DEVELOPMENTS IN ANIMAL AND VETERINARY SCIENCES LA English DT Proceedings Paper CT 3rd World Congress on Alternatives and Animal Use in the Life Science CY AUG 29-SEP 02, 1999 CL BOLOGNA, ITALY SP Colgate Palmolive Co, European Commiss, Environm DIrector Gen, European Commiss, Joint Res Ctr, Toiletry & Perfumery Assoc, European Cosmet, Gillette Co, Glaxo Wellcome, Int Fdn Eth Res, Kimberly Clark Corp, L Oreal, Procter & Gamble Co, Unilever Res, Utrecht Congress C1 NIEHS, Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Shelby, MD (reprint author), NIEHS, Toxicol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-5168 BN 0-444-50529-6 J9 DEV AN VET PY 2000 VL 31 BP 1611 EP 1611 PN A & B PG 1 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA BS42Q UT WOS:000169797500167 ER PT J AU Klein, EA Thompson, IM Lippman, SM Goodman, PJ Albanes, D Taylor, PR Coltman, C AF Klein, EA Thompson, IM Lippman, SM Goodman, PJ Albanes, D Taylor, PR Coltman, C TI SELECT: the selenium and vitamin E cancer prevention trial: Rationale and design SO PROSTATE CANCER AND PROSTATIC DISEASES LA English DT Review DE prostate cancer; chemoprevention; selenium; vitamin E ID KINASE-C ACTIVITY; PROSTATE-CANCER; ALPHA-TOCOPHEROL; SUBSEQUENT RISK; SERUM SELENIUM; BETA-CAROTENE; FINNISH MEN; CELLS; CARCINOMA; SUPPLEMENTATION AB Prostate cancer is the commonest non-skin malignancy in the United States and has a substantial mortality rate despite the use of PSA-based screening. Furthermore, therapy for prostate cancer by surgery, radiotherapy or hormonal manipulation carries a significant risk of treatment-related morbidity. Recent analysis of secondary endpoints of several large-scale randomized prospective clinical trials for other malignancies has suggested that selenium or vitamin E may result in a decreased incidence and mortality from prostate cancer. In vitro and preclinical studies of these antioxidants support this hypothesis. This review outlines the rationale and design of SELECT, the Selenium and Vitamin E Cancer Prevention Trial, designed to test the hypothesis that selenium or vitamin E alone or in combination can reduce the clinical incidence of prostate cancer in a population-based cohort of men at risk. SELECT is a phase III, randomized, double-blinded, prospective, 2 x 2 factorial clinical trial which will randomize 32,400 healthy men with normal DRE and serum PSA to one of four study arms: selenium alone, vitamin E alone, selenium + vitamin E, or placebo. Study agents will be taken orally for a minimum of 7 and maximum of 12 y with assessments of general health, incident prostate cancer and toxicity performed at 12 month intervals. Under the assumptions described, the detectable risk reduction is 25% for an effective single agent relative to placebo, with an additional 25% reduction for the combination relative to an effective single agent. The estimated power for the comparison of a single agent vs placebo is 96% and the power for the comparison of an effective single agent vs combination is 89%. Secondary endpoints will include prostate cancer-free survival, all-cause mortality, and the incidence and mortality of other cancers and diseases potentially impacted by the chronic use of selenium and vitamin E. Other trial objectives will include periodic quality of life assessments, assessment of serum micronutrient levels and prostate cancer risk, and studies of the evaluation of biological and genetic markers with the risk of prostate cancer. C1 Cleveland Clin Fdn, Dept Urol, Sect Urol Oncol, Cleveland, OH 44195 USA. Univ Texas, Hlth Sci Ctr, Div Urol, San Antonio, TX 78285 USA. Univ Texas, MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA. Fred Hutchinson Canc Res Ctr, SW Oncol Grp Stat Ctr, Seattle, WA 98104 USA. Natl Canc Inst, Canc Prevent Studies Branch, Div Clin Sci, Washington, DC USA. SW Oncol Grp, San Antonio, TX USA. RP Cleveland Clin Fdn, Dept Urol, Sect Urol Oncol, 9500 Euclid Ave,A100, Cleveland, OH 44195 USA. EM kleine@ccf.org RI Albanes, Demetrius/B-9749-2015 NR 57 TC 70 Z9 73 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1365-7852 EI 1476-5608 J9 PROSTATE CANCER P D JI Prostate Cancer Prostatic Dis. PY 2000 VL 3 IS 3 BP 145 EP 151 DI 10.1038/sj.pcan.4500412 PG 7 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 382QQ UT WOS:000165834100003 ER PT J AU Kumar, S Ma, BY Tsai, CJ Sinha, N Nussinov, R AF Kumar, S Ma, BY Tsai, CJ Sinha, N Nussinov, R TI Folding and binding cascades: Dynamic landscapes and population shifts SO PROTEIN SCIENCE LA English DT Review DE allostery; binding; biological pathways; conformational ensembles; dynamic landscapes; folding; funnels; induced conformational change ID DOMAIN; PROTEINS; TRANSITIONS; CHAPERONES; ANTIBODIES; EVOLUTION; LEVINTHAL; PATHWAYS; INSIGHTS; DOCKING AB Whereas previously we have successfully utilized the folding funnels concept to rationalize binding mechanisms (Ma B, Kumar S, Tsai CJ, Nussinov R, 1999, Protein Eng 12:713-720) and to describe binding (Tsai CJ, Kumar S, Ma B, Nussinov R, 1999, Protein Sci 8:1181-1190), here we further extend the concept of folding funnels, illustrating its utility in explaining enzyme pathways, multimolecular associations, and allostery. This extension is based on the recognition that funnels are not stationary; rather, they are dynamic, depending on thr physical or binding conditions (Tsai CJ, Ma B, Nussinov R, 1999, PI-oc Natl Acad Sci USA 96:9970-9972). Different binding states change the surrounding environment of proteins. The changed environment is in turn expressed in shifted energy landscapes, with different shapes and distributions of populations of conformers. Hence, the function of a protein and its properties are not only decided by the static folded three-dimensional structure; they are determined by the distribution of its conformational substates, and in particular, by the redistributions of the populations under different environments. That is, protein function derives from its dynamic energy landscape, caused by changes in its surroundings. C1 NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, 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, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, Intramural Res Support Program, Bldg 469,Rm 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 58 TC 414 Z9 417 U1 2 U2 47 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 JAN PY 2000 VL 9 IS 1 BP 10 EP 19 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 279KG UT WOS:000085042500002 PM 10739242 ER PT J AU Horita, DA Zhang, WX Smithgall, TE Gmeiner, WH Byrd, RA AF Horita, DA Zhang, WX Smithgall, TE Gmeiner, WH Byrd, RA TI Dynamics of the Hck-SH3 domain: Comparison of experiment with multiple molecular dynamics simulations SO PROTEIN SCIENCE LA English DT Article DE N-15 relaxation; conformational sampling; molecular dynamics simulations; order parameters; SH3 domain ID MODEL-FREE APPROACH; MAGNETIC-RESONANCE RELAXATION; N-15 NMR RELAXATION; BINDING; PROTEINS; MACROMOLECULES; SPECTROSCOPY; WATER; SITE; HCK AB Molecular dynamics calculations provide a method by which the dynamic properties of molecules can be explored over timescales and at a level of detail that cannot be obtained experimentally from NMR or X-ray analyses. Recent work (Philippopoulos M, Mandel AM, Palmer AG III, Lim C, 1997, Proteins 25:481-493) has indicated that the accuracy of these simulations is high, as measured by the correspondence of parameters extracted from these calculations to those determined through experimental means. Here, we investigate the dynamic behavior of the Src homology 3 (SH3) domain of hematopoietic cell kinase (Hck) via N-15 backbone relaxation NMR studies and a set of four independent 4 ns solvated molecular dynamics calculations. We also find that molecular dynamics simulations accurately reproduce fast motion dynamics as estimated from generalized order parameter (S-2) analysis for regions of the protein that have experimentally well-defined coordinates (i.e., stable secondary structural elements). However, for regions where the coordinates are not well defined, as indicated by high local root-mean-square deviations among NMR-determined structural family members or high B-factors/low electron density in X-ray crystallography determined structures, the parameters calculated from a short to moderate length (less than 5-10 ns) molecular dynamics trajectory are dependent on the particular coordinates chosen as a starting point for the simulation. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. RP Byrd, RA (reprint author), NCI, Frederick Canc Res & Dev Ctr, Struct Biophys Lab, Program Struct Biol, Bldg 538,POB B, Frederick, MD 21702 USA. RI Byrd, R. Andrew/F-8042-2015; OI Byrd, R. Andrew/0000-0003-3625-4232; Horita, David/0000-0002-9563-107X FU NCI NIH HHS [CA81398, P30 CA036727, R01 CA060612] NR 32 TC 28 Z9 28 U1 1 U2 4 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 JAN PY 2000 VL 9 IS 1 BP 95 EP 103 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 279KG UT WOS:000085042500011 PM 10739251 ER PT J AU Wang, YX Jacob, J Wingfield, PT Palmer, I Stahl, SJ Kaufman, JD Huang, PL Huang, PL Lee-Huang, S Torchia, DA AF Wang, YX Jacob, J Wingfield, PT Palmer, I Stahl, SJ Kaufman, JD Huang, PL Huang, PL Lee-Huang, S Torchia, DA TI Anti-HIV and anti-tumor protein MAP30, a 30 kDa single-strand type-I RIP, shares similar secondary structure and beta-sheet topology with the A chain of ricin, a type-II RIP SO PROTEIN SCIENCE LA English DT Article DE anti-cancer; anti-HIV; NMR; RIP proteins; secondary structure ID CHEMICAL-SHIFTS; REPLICATION; INHIBITION; INFECTION; C-13; NMR AB MAP30 is a 30 kDa single-stranded, type-I ribosome inactivating protein (RIP) possessing anti-tumor and anti-HIV activities. It binds both ribusomal RNA and the HIV-I long-terminal repeat DNA. To understand the structural basis for MAP30 activities, we undertook the study of MAP30 by solution NMR spectroscopy. We report nearly complete H-1, C-13, and N-15 chemical shift assignments of its 263 amino acids. Based upon an analysis of secondary C-13 chemical shifts, (3)J(HNHA) coupling constants, hydrogen exchange data, and nuclear Overhauser effect patterns, we find that the secondary structure and P-sheet topology of MAP30 are very similar to those of the ricin A chain, a subunit of the well-known type-II RIP, even though two proteins display distinct activities. we therefore suggest that MAP30 and ricin A chain share a similar three-dimensional fold, and that the reported functional differences between two proteins arise primarily from differences in local three-dimensional structure and other structural properties such as surface electrostatic potentials. C1 OD NIDCR, Struct Mol Biol Unit, Mol Struct Biol Core, NIH, Bethesda, MD 20892 USA. NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. NYU, Sch Med, Dept Biochem, New York, NY 10016 USA. RP Torchia, DA (reprint author), OD NIDCR, Struct Mol Biol Unit, Mol Struct Biol Core, NIH, Bldg 30,Rm 106, Bethesda, MD 20892 USA. FU NIAID NIH HHS [R01 AI31343]; NINDS NIH HHS [R01 NS033335] NR 18 TC 21 Z9 27 U1 0 U2 5 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 JAN PY 2000 VL 9 IS 1 BP 138 EP 144 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 279KG UT WOS:000085042500016 PM 10739256 ER PT J AU Bai, YW AF Bai, YW TI Kinetic evidence of an on-pathway intermediate in the folding of lysozyme SO PROTEIN SCIENCE LA English DT Article DE hen egg white lysozyme; off-pathway intermediate; on-pathway intermediate; protein folding pathway ID HEN LYSOZYME; PROTEIN; UREA AB By means of a kinetic test, it was demonstrated that one of the folding intermediates (I-alpha) of hen lysozyme with alpha-domain folded and beta-domain unfolded is on the folding pathway under the classical definition. I-alpha folds to the native (N) state directly (unfolded (U) double left right arrow I-alpha double left right arrow N) without having to unfold to U and then refold to N through alternative folding pathways as in I-alpha double left right arrow U double left right arrow N. C1 NCI, Biochem Lab, Bethesda, MD 20850 USA. RP Bai, YW (reprint author), NCI, Biochem Lab, NIH Bldg 37,Room 4A-01, Bethesda, MD 20850 USA. NR 16 TC 16 Z9 16 U1 1 U2 1 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 JAN PY 2000 VL 9 IS 1 BP 194 EP 196 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 279KG UT WOS:000085042500022 PM 10739262 ER PT J AU Li, M Morris, GM Lee, T Laco, GS Wong, CH Olson, AJ Elder, JH Wlodawer, A Gustchina, A AF Li, M Morris, GM Lee, T Laco, GS Wong, CH Olson, AJ Elder, JH Wlodawer, A Gustchina, A TI Structural studies of FIV and HIV-1 proteases complexed with all efficient inhibitor of FIV protease SO PROTEINS-STRUCTURE FUNCTION AND GENETICS LA English DT Article DE enzymes; drug design; inhibition constant; structure comparison; AIDS ID FELINE IMMUNODEFICIENCY VIRUS; INTERVENTION STRATEGIES; NUCLEOTIDE-SEQUENCE; CROSS-RESISTANCE; DRUG DESIGN; AIDS VIRUS; TYPE-1; MODEL; CAT; PROTEINASE AB Three forms of feline immunodeficiency virus protease (FIV PR), the wild type (wt) and two single point mutants, V59I and Q99V, as well as human immunodeficiency virus type 1 protease (HIV-1 PR), were cocrystallized with the C2-symmetric inhibitor, TL-3, The mutants of FIV PR were designed to replace residues involved in enzyme-ligand interactions by the corresponding HIV-1 PR residues at the structurally equivalent position. TL-3 shows decreased (improved) inhibition constants with these FIV PR mutants relative to wt FIV PR. Despite similar modes of binding of the inhibitor to all PRs (from P3 to P3'), small differences are evident in the conformation of the Phe side chains of TL-3 at the P1 and P1' positions in the complexes with the mutated FIV PRs, The differences mimick the observed binding of TL-3 in HIV-1 PR and correlate with a significant improvement in the inhibition constants of TL-3 with the two mutant FIV PRs, Large differences between the HIV-1 and FIV PR complexes are evident in the binding modes of the carboxybenzyl groups of TL-3 at P4 and P4', In HIV-1 PR:TL-3, these groups bind over the flap region, whereas in the FIV PR complexes, the rings are located along the major axis of the active site. A significant difference in the location of the flaps in this region of the HIV-1 and FIV PRs correlates with the observed conformational changes in the binding mode of the peptidomimetic inhibitor at the P4 and P4' positions. These findings provide a structural explanation of the observed K-i values for TL-3 with the different PRs and will further assist in the development of improved inhibitors. Proteins 2000;38:29-40, Published 2000 Wiley-Liss, Inc.dagger C1 NCI, Macromol Struct Lab, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, Intramural Res Support Program, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. RP Gustchina, A (reprint author), NCI, Macromol Struct Lab, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. FU NIAID NIH HHS [R01AI40882]; NIGMS NIH HHS [P01GM48870] NR 41 TC 24 Z9 24 U1 0 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-3585 J9 PROTEINS JI Proteins PD JAN 1 PY 2000 VL 38 IS 1 BP 29 EP 40 DI 10.1002/(SICI)1097-0134(20000101)38:1<29::AID-PROT4>3.0.CO;2-N PG 12 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 269NN UT WOS:000084484600004 PM 10651036 ER PT J AU Miller, KA Witkin, JM Ungard, JT Gasior, M AF Miller, KA Witkin, JM Ungard, JT Gasior, M TI Pharmacological and behavioral characterization of cocaine-kindled seizures in mice SO PSYCHOPHARMACOLOGY LA English DT Article; Proceedings Paper CT 1999 Experimental Biology Meeting CY APR 17-21, 1999 CL WASHINGTON, D.C. DE cocaine; seizures; kindling; locomotor activity; methamphetamine; mice ID SENSITIZATION; METHAMPHETAMINE; SENSITIVITY; STIMULATION; RECEPTORS; ABUSE; DRUG; RAT AB Rationale: Convulsions associated with cocaine toxicity are a serious aspect of cocaine-related emergency room incidents. Seizures can result from a single high dose of cocaine, and evidence is accumulating that correlates repetitive administration of sub-convulsive doses of cocaine with a decreased seizure threshold, a phenomenon known as pharmcological kindling. A murine model of cocaine kindling has not been characterized. Objectives: To determine the necessary and sufficient conditions for generating increased sensitivity to the convulsive and lethal effects of cocaine and to characterize some of the basic pharmacological and behavioral consequences of this phenomenon in mice. Methods: Male, Swiss-Webster mice were given repeated injections of cocaine. Results: Daily administration of 60 mg/kg cocaine produced robust kindling: significant leftward shifts in the dose-effect curves for seizures were observed in cocaine-kindled mice. Cocaine kindling was enduring as these left shifts persisted for at least 20 days, indicating possible permanent synaptic changes. Induction of convulsions per se, utilizing 75 mg/kg cocaine. was not sufficient to engender kindling with a non-optimal dose (40 mg/kg). However, administration of a non-kindling dose of cocaine (40 mg/kg) for as few as four occasions produced increased seizure sensitivity to a 60-mg/kg cocaine challenge. The lethal potencies of cocaine and methamphetamine were significantly increased in cocaine-kindled mice. The baseline locomotor activity of kindled mice was not different from that of non-kindled mice. However, challenge doses of cocaine revealed significant differences in the vertically directed activity of kindled versus non-kindled mice. Conclusions: Overall, this study provides a description of important parameters for a model of cocaine kindling in mice that may be useful for the elucidation of mechanisms responsible for the long-term changes in sensitivity to cocaine and the discovery of novel pharmacological treatments. C1 NIDA, Drug Dev Grp, Addict Res Ctr, Baltimore, MD 21224 USA. RP Gasior, M (reprint author), NIDA, Drug Dev Grp, Addict Res Ctr, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 44 TC 19 Z9 19 U1 1 U2 3 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JAN PY 2000 VL 148 IS 1 BP 74 EP 82 DI 10.1007/s002130050027 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 277KW UT WOS:000084933600012 PM 10663420 ER PT J AU Katz, JL Izenwasser, S Terry, P AF Katz, JL Izenwasser, S Terry, P TI Relationships among dopamine transporter affinities and cocaine-like discriminative-stimulus effects SO PSYCHOPHARMACOLOGY LA English DT Article DE cocaine; binding; dopamine transporter; behavior; discriminative-stimulus effect; high-affinity site; low-affinity site ID NONHUMAN-PRIMATES; UPTAKE SITES; BEHAVIORAL PHARMACOLOGY; CAUDATE-PUTAMEN; BINDING-SITES; WIN 35,428; ANALOGS; INHIBITORS; DRUGS; HETEROGENEITY AB Rationale: The discriminative-stimulus effects of cocaine have been reported to be mediated by indirect agonist actions initiated by the blockade of dopamine uptake, and the potencies of drugs that have discriminative-stimulus effects like cocaine an directly related to their dopamine transporter binding affinities. The binding to the dopamine transporter by cocaine and many of its analogs has been reported to fit better using a two-site model than a one-site model. Objectives: The present study examined the relationship among binding affinities of dopamine uptake inhibitors at these two sites and their potencies to produce discriminative-stimulus effects. Methods: The inhibition constants (K-i values) were derived for unlabeled dopamine uptake inhibitors for displacement of [H-3]WIN 35,428 from rat caudate putamen membranes. These K-i values were related to the ED50 values obtained in rats trained to discriminate 10 mg/kg cocaine from saline injections under a fixed-ratio 20 schedule of food reinforcement. Results: Among the dopamine uptake inhibitors studied, the binding data for eight compounds (WIN 35,428, nomifensine, WIN 35,981, WIN 35,065-2, methylphenidate, cocaine, cocaethylene, and bupropion) were better fit by a two-site model than a one-site model. The data for the remaining eleven compounds (RTI-31, RTI-55, RTI-121, RTI-32, LU19-005, BTCP, GBR12909, GBR12935, mazindol, LU17-133, and EXP561) were better fit by a one-site model. Of the drugs that were fit best by a two-site model, there was a higher correlation among the K-i values for the high-affinity site and the ED50 values (R-2=0.655; P=0.015) than there was for the low-affinity site (R-2=0.543; P=0.037). Of the remaining drugs, there was a high correlation among the K-i values and the ED50 values for the discriminative-stimulus effects (R-2=0.523; P=0.012). Conclusions: These data suggest that the discriminative-stimulus effects of cocaine are more closely related to actions mediated by high-affinity binding to the dopamine transporter than they are to actions mediated by the low-affinity site. The further assessment of the respective contributions of high- and low-affinity binding to the behavioral effects of cocaine will be greatly enhanced with the development of pharmacological tools that have a high degree of selectivity for one of these components. C1 NIDA, Psychobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Univ Birmingham, Dept Psychol, Birmingham, W Midlands, England. RP Katz, JL (reprint author), NIDA, Psychobiol Sect, Intramural Res Program, NIH, POB 5180, Baltimore, MD 21224 USA. RI Izenwasser, Sari/G-9193-2012; OI Katz, Jonathan/0000-0002-1068-1159 NR 41 TC 51 Z9 51 U1 1 U2 2 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JAN PY 2000 VL 148 IS 1 BP 90 EP 98 DI 10.1007/s002130050029 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 277KW UT WOS:000084933600014 PM 10663422 ER PT J AU Jones, HE Herning, RI Cadet, JL Griffiths, RR AF Jones, HE Herning, RI Cadet, JL Griffiths, RR TI Caffeine withdrawal increases cerebral blood flow velocity and alters quantitative electroencephalography (EEG) activity SO PSYCHOPHARMACOLOGY LA English DT Article DE cerebral blood flow velocity; EEG; caffeine; withdrawal; physical dependence; human ID DEPENDENCE; TOMOGRAPHY; VOLUNTEERS; NICOTINE; HUMANS AB Rationale: Cessation of daily caffeine consumption produces a withdrawal syndrome comprised of subjective symptoms and functional impairment. Few controlled studies have examined the physiological effects of caffeine withdrawal. Objective: The present study examined the effect of caffeine withdrawal on cerebral blood flow velocity and quantitative EEG. Methods: Ten volunteers reporting moderate caffeine intake (mean 333 mg/day) participated in this double-blind study. Subjects completed several tests when maintaining their normal diet (baseline period) and during two 1-day periods during which they consumed caffeine-free diets and received capsules containing placebo (placebo test session) or caffeine (caffeine test session) in amounts equal to their baseline daily caffeine consumption. Blood flow velocity was determined for four arteries: right and left middle (MCA), and right and left anterior (ACA) cerebral arteries using pulsed transcranial Doppler sonography. EEG was recorded for 3 min from eight scalp sites while subjects sat, with eyes closed, in a sound-attenuated electronically shielded chamber. Subjective effects were assessed with questionnaires. Results: Results showed an effect of the placebo (21-h withdrawal) condition compared to the caffeine condition. Placebo significantly increased the mean velocity, systolic velocity and diastolic velocity (cm/s) in all four cerebral arteries. In the MCA, the pulsatility index was significantly decreased following placebo. Placebo significantly increased EEG theta power. Placebo also produces subjective effect changes, including increases in heavy feelings in arms and legs and decreases in ability to concentrate. The caffeine and baseline conditions produced similar results on both the physiological and subjective measures, Conclusion: Cessation of daily caffeine consumption produced changes in cerebral blood flow velocity and quantitative EEG. These changes may be related to classic caffeine withdrawal symptoms of headache, drowsiness and decreased alertness. C1 Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21224 USA. NIDA, Mol Neuropsychiat Sect, Div Intramural Res, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21224 USA. RP Griffiths, RR (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, 5510 Nathan Shock Dr, Baltimore, MD 21224 USA. FU NIDA NIH HHS [R01 DA-03890, T32-DA07209] NR 36 TC 29 Z9 29 U1 3 U2 6 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JAN PY 2000 VL 147 IS 4 BP 371 EP 377 DI 10.1007/s002130050005 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 275WF UT WOS:000084842600005 PM 10672630 ER PT J AU Woolverton, WL Rowlett, JK Wilcox, KM Paul, IA Kline, RH Newman, AH Katz, JL AF Woolverton, WL Rowlett, JK Wilcox, KM Paul, IA Kline, RH Newman, AH Katz, JL TI 3 '- and 4 '-chloro-substituted analogs of benztropine: intravenous self-administration and in vitro radioligand binding studies in rhesus monkeys SO PSYCHOPHARMACOLOGY LA English DT Article DE drug abuse; stimulant; cocaine; dopamine; monoamine transport; self-administration; rhesus monkey ID DOPAMINE UPTAKE INHIBITORS; NONHUMAN-PRIMATES; COCAINE RECEPTORS; UPTAKE SITES; RAT-BRAIN; TRANSPORTER; DRUGS; ABUSE; REINFORCEMENT; PHARMACOLOGY AB Rationale: The reinforcing effects of many psychomotor stimulants have been related to increased dopaminergic neurotransmission. Drugs that block dopamine (DA) uptake have generally been found to function as positive reinforcers. Benztropine (BZT) and several of its halogenated analogs have previously been characterized as potent DA-uptake inhibitors with behavioral profiles that indicate diminished psychomotor stimulant effects relative to cocaine. Objectives: The present experiments were designed to examine, in rhesus monkeys, the reinforcing effects of the DA-uptake inhibitor BZT and two chloro-analogs 3'-C1-BZT and 4'-Cl-BZT, and to compare self-administration and binding profiles. Methods: Four rhesus monkeys self-administered cocaine i.v. under a fixed-ratio 10 (FRIO) schedule until stable responding was established. Saline, and various doses of cocaine, BZT, and the BZT analogs were then made available for self-administration. Binding of these compounds to monoaminergic and cholinergic sites in monkey brain were determined using standard radioligand binding techniques. Results: Self-administration was maintained by both 3'-C1-BZT and 4'-Cl-BZT, but not by BZT. Results suggested that 3'-Cl-BZT and 4'-Cl-BZT were weak positive reinforcers. BZT and analogs bound DA transporters (DAT) with affinities higher than that of cocaine and had affinity for muscarinic binding sites. Conclusions: Surprisingly, high affinity at DATs was associated with weak or no reinforcing effects. The mechanism(s) that may underlie this dissociation between DAT actions and reinfurcino effects remains to be established. These data support the proposal that a lead for the discovery of a pharmacotherapeutic agent for cocaine abuse may come from this group of compounds. C1 Univ Mississippi, Med Ctr, Dept Psychiat & Human Behav, Jackson, MS 39216 USA. Natl Inst Drug Abuse, Psychobiol Sect, NIH, Div Intramural Res, Baltimore, MD 21224 USA. RP Woolverton, WL (reprint author), Univ Mississippi, Med Ctr, Dept Psychiat & Human Behav, 2500 N State St, Jackson, MS 39216 USA. OI Katz, Jonathan/0000-0002-1068-1159 FU NIDA NIH HHS [DA-00161, DA-10352] NR 53 TC 41 Z9 41 U1 1 U2 1 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JAN PY 2000 VL 147 IS 4 BP 426 EP 435 DI 10.1007/s002130050012 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 275WF UT WOS:000084842600012 PM 10672637 ER PT J AU Kaufman, P AF Kaufman, P TI Multi-center clinical trials: Past lessons and future directions SO PSYCHOSOMATIC MEDICINE LA English DT Meeting Abstract C1 NHLBI, Washington, DC 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 0033-3174 J9 PSYCHOSOM MED JI Psychosom. Med. PD JAN-FEB PY 2000 VL 62 IS 1 MA 1493 BP 129 EP 129 PG 1 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 286BM UT WOS:000085423800180 ER PT J AU Lerner, DM Schuetz, L Holland, S Rubinov, DR Rosenstein, DL AF Lerner, DM Schuetz, L Holland, S Rubinov, DR Rosenstein, DL TI Low-dose risperidone for the irritable medically ill patient SO PSYCHOSOMATICS LA English DT Article ID DOUBLE-BLIND; DEPRESSION; DISORDER; TRIAL C1 NIMH, Psychiat Consultat Liaison Serv, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Rosenstein, DL (reprint author), NIMH, Psychiat Consultat Liaison Serv, Off Clin Director, NIH, 10 Ctr Dr,MSC 1276,Room 3N238, Bethesda, MD 20892 USA. NR 16 TC 2 Z9 2 U1 0 U2 2 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD JAN-FEB PY 2000 VL 41 IS 1 BP 69 EP 71 PG 3 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 277CF UT WOS:000084914600011 PM 10665272 ER PT J AU Costantini, M Balzi, D Garronec, E Orlandini, C Parodi, S Vercelli, M Bruzzi, P AF Costantini, M Balzi, D Garronec, E Orlandini, C Parodi, S Vercelli, M Bruzzi, P TI Geographical variations of place of death among Italian communities suggest an inappropriate hospital use in the terminal phase of cancer disease SO PUBLIC HEALTH LA English DT Article DE hospital use; place of death; terminal care; cancer ID SOUTH-AUSTRALIA; LAST YEAR; MEDICAL-CARE; LIFE; HOME; SERVICES; LIKELIHOOD; HEALTH; TRENDS; JAPAN AB This study aimed to assess geographic variations of place of death among Italian communities, to investigate the determinants of home death, and to examine trends in the proportion of home deaths over a period of 8 y. A cross-sectional analysis was performed on 13 provinces from two Italian regions (Liguria and Toscana), and the geographic variations and determinants of home death were studied for the 17 597 residents, who died of cancer in 1991. Trends for both the regions of the proportion of home deaths were examined for the period 1987 and 1995. A remarkable heterogeneity in the observed proportion of home deaths among the 13 provinces was observed, ranging between 31.4 and 40.4% in Liguria and between 37.7 and 73.3% in Toscana. The estimated proportion of home deaths after adjustment for age, gender, marital status, education, place of birth, characteristics of the living an:a, and cancer site remained substantially the same. The proportion of home deaths significantly increased with increasing age, and years of education. It was higher among females, married and widowed patients, native patients, and for residents in a semiurban or rural areas. A significant decrease in the percentage of patients who died at home between 1987 and 1995 in both regions was observed. The wide geographical and social differences observed between and within the communities for the frequency of home deaths are not explained by the distribution of known determinants, and possibly suggest patterns of inappropriate hospital admissions in the terminal phase of disease. C1 Natl Canc Inst, Unit Clin Epidemiol & Trials, I-16132 Genoa, Italy. Careggi Hosp, Epidemiol Unit, Florence, Italy. Natl Canc Inst, Canc Registry Sect, Genoa, Italy. Univ Genoa, Genoa, Italy. RP Costantini, M (reprint author), Natl Canc Inst, Unit Clin Epidemiol & Trials, L R Benzi 10, I-16132 Genoa, Italy. RI costantini, massimo/G-1443-2012; OI costantini, massimo/0000-0002-5293-7079; Bruzzi, Paolo/0000-0002-7874-2077; Vercelli, Marina/0000-0002-9757-2616 NR 45 TC 43 Z9 44 U1 2 U2 6 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0033-3506 J9 PUBLIC HEALTH JI Public Health PD JAN PY 2000 VL 114 IS 1 BP 15 EP 20 DI 10.1016/S0033-3506(00)00302-4 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 301RP UT WOS:000086324300004 PM 10787020 ER PT J AU Kiebert, G Wait, S Bernhard, J Bezjak, A Cella, D Day, R Houghton, J Moinpour, C Scott, C Stephens, R AF Kiebert, G Wait, S Bernhard, J Bezjak, A Cella, D Day, R Houghton, J Moinpour, C Scott, C Stephens, R TI Practice and policy of measuring quality of life and health economics in cancer clinical trials: A survey among co-operative trial groups SO QUALITY OF LIFE RESEARCH LA English DT Article DE cancer; co-operative group; health economics; randomized controlled clinical trials; quality of life AB Background: Co-operative groups have played an important role in the advance of health-related quality of life (HRQL) research. However, definitions of the concept, criteria for selection of existing instruments and methods for data collection and interpretation remain poorly defined in the literature. A survey was conducted amongst the major cancer co-operative groups in order to gain a better understanding of their current policy and processes to ensure optimal HRQL data collection within cancer clinical trials. The topic of health economics was similarly addressed. Methods: A written questionnaire was addressed to 16 major European and North American cancer co-operative groups. Eleven groups responded (response rate: 69%), however, one group could not provide information for the survey, thus ten questionnaires were available for analysis. Results: The results from this survey among co-operative groups show that HRQL (more than health economics) is recognized as an important, although usually secondary, outcome measure in oncology trials. On the whole, co-operative groups have a rather flexible policy towards the inclusion of HRQL (and HE) into their clinical trials, and practice is very much on a case-by-case basis, but use standard practice guidelines and internal procedures is to ensure well-defined study protocols and enhance good quality studies. C1 MEDTAP Int, London, England. Novartis Pharma, Qual Life Taskforce Oncol, Basel, Switzerland. Swiss Grp Clin Canc Res, Bern, Switzerland. Int Breast Canc Study Grp, Bern, Switzerland. Natl Canc Inst Canada, Clin Trials Grp, Toronto, ON, Canada. Eastern Cooperat Oncol Grp, Evanston, IL USA. Gynecol Oncol Grp, Evanston, IL USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Canc Res Council, London, England. UCL, Canc Trials Ctr, London, England. SW Oncol Grp, Seattle, WA USA. Radiat Therapy Oncol Grp, Philadelphia, PA USA. MRC, Clin Trial Unit, London, England. RP Kiebert, G (reprint author), MEDTAP Int, London, England. NR 9 TC 6 Z9 6 U1 0 U2 1 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. PY 2000 VL 9 IS 10 BP 1073 EP 1080 DI 10.1023/A:1016658004947 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 426NJ UT WOS:000168355000001 PM 11401040 ER PT J AU Littlefield, LG McFee, AF Sayer, AM O'Neill, JP Kleinerman, RA Maor, MH AF Littlefield, LG McFee, AF Sayer, AM O'Neill, JP Kleinerman, RA Maor, MH TI Induction and persistence of chromosome aberrations in human lymphocytes exposed to neutrons in vitro or in vivo: Implications of findings in 'retrospective' biological dosimetry SO RADIATION PROTECTION DOSIMETRY LA English DT Article; Proceedings Paper CT Workshop on Fluorescence in Situ Hybridisation (Fish) Biological Dosimetry CY APR 30-MAY 01, 1999 CL SITGES, SPAIN SP Natl Radiol Protect Board, Westlakes Res Inst, Nat Ctr Environm & Hlth (GSF), Radiat & Nuclear Safety Authority (STUK), Bundesamt Strahlenschutz (Bfs), IPSN, Univ Liege, Univ Leiden, Univ Basque Country ID ACCIDENTAL RADIATION EXPOSURE; IN-SITU HYBRIDIZATION; TRANSLOCATIONS; IRRADIATION; FREQUENCY; WORKERS; FISH AB The induction and persistence were evaluated of chromosome aberrations in lymphocytes exposed in vitro to highly efficient 1 MeV monoenergetic neutrons and in patients who received fast neutrons as therapy for tumours. For the in vitro studies, lymphocytes were exposed to various doses of neutrons and cultured for one or 20 cell cycles. Aberrations were quantified in painted chromosome pairs 1, 2, or 4. These 1 MeV neutrons were highly efficient in inducing aberrations, and dicentrics as well as one-way and two-way translocations increased as a linear function of dose. About 30% of the aberrant metaphases displayed complex aberrations. After multiple inr vitro cell divisions, Virtually all asymmetrical aberrations had been eliminated from the cell population, and the frequency of one-way translocations was reduced dramatically. In contrast, most two-way translocations apparently survived through multiple cell divisions and still displayed excellent correlation with dose after 20 cell cycles. Classical methods were used to evaluate persistence of aberrations in patients who received fractionated neutron therapy to rumours located in many different sites. Neutron induced dicentrics and rings disappeared from the peripheral circulation within the first three years after exposure, while translocations persisted for more than 17 y. However, considerable variability in numbers of aberrations were observed between patients who had received similar 'average bone marrow doses'. Results of these studies are discussed in relation to the possible use of translocations as retrospective dosemeters in persons exposed to radiation many years ago. C1 Oak Ridge Inst Sci & Educ, Basic & Appl Res Program, Oak Ridge, TN 37830 USA. Univ Vermont, Genet Lab, Burlington, VT 05401 USA. NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Littlefield, LG (reprint author), Oak Ridge Inst Sci & Educ, Basic & Appl Res Program, Oak Ridge, TN 37830 USA. OI Kleinerman, Ruth/0000-0001-7415-2478 NR 24 TC 15 Z9 15 U1 0 U2 1 PU NUCLEAR TECHNOLOGY PUBL PI ASHFORD PA PO BOX 7, ASHFORD TN23 1YW, KENT, ENGLAND SN 0144-8420 J9 RADIAT PROT DOSIM JI Radiat. Prot. Dosim. PY 2000 VL 88 IS 1 BP 59 EP 68 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 314CA UT WOS:000087035500009 ER PT J AU Soyland, C Hassfjell, SP Steen, HB AF Soyland, C Hassfjell, SP Steen, HB TI A new alpha-particle irradiator with absolute dosimetric determination SO RADIATION RESEARCH LA English DT Article ID MAMMALIAN-CELLS; SINGLE; MICROBEAM; SYSTEM; RADON; RADIOBIOLOGY; EXPOSURE; DESIGN AB A new experimental setup for uniform alpha-particle irradiation of cells in vitro is described. The alpha-particle irradiator is based on a radioactive Pb-212/Bi-212 source. In the experimental setup proposed, cells are grown directly on a polylysine-coated track-etch material that forms the base of custom-made cell dishes. Alpha-particle irradiation is done through the base of the dish, Immediately prior to irradiation, the cell dish is scanned under a microscope, and images of cells with the corresponding coordinates are saved, After irradiation and after the biological end point under study has been determined, the cell dish is etched to develop alpha-particle tracks in the dish base. A microscope image series of alpha-particle track images is obtained by accurately revisiting every original (preirradiation) cell position in the track-etched dish, The number of alpha-particle traversals of each individual cell is scored by mapping images of alpha-particle tracks onto the images of cells recorded prior to irradiation. The uncertainty of the alpha-particle hit determination is 0.9 mu m. The procedure described thus presents a method for radiobiological experiments with absolute, rather than statistical, cell dosimetry, (C) 2000 by Radiation Research Society. C1 Norwegian Radium Hosp, Dept Biophys, N-0310 Oslo, Norway. Univ Oslo, Dept Chem, N-0315 Oslo, Norway. RP Soyland, C (reprint author), NCI, Radioimmune & Inorgan Chem Sect, ROBDCS, NIH, Bldg 10,Room B3B69, Bethesda, MD 20892 USA. NR 23 TC 23 Z9 23 U1 1 U2 1 PU RADIATION RESEARCH SOC PI OAK BROOK PA 2021 SPRING RD, STE 600, OAK BROOK, IL 60521 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD JAN PY 2000 VL 153 IS 1 BP 9 EP 15 DI 10.1667/0033-7587(2000)153[0009:ANAPIW]2.0.CO;2 PG 7 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 270WT UT WOS:000084560700002 PM 10630972 ER PT B AU Mitchell, JB Cook, JA Stein, W Coffin, D Espey, MG Miranda, KM Wink, DA AF Mitchell, JB Cook, JA Stein, W Coffin, D Espey, MG Miranda, KM Wink, DA BE Moriaty, M Edington, M Mothersill, C Ward, JF Seymour, C Fry, RJM TI Is there a role for nitric oxide in cancer treatment? SO RADIATION RESEARCH, VOL 2, CONGRESS PROCEEDINGS LA English DT Proceedings Paper CT 11th International Congress of Radiation Research CY JUL 18-23, 1999 CL DUBLIN, IRELAND ID GROWTH; RADIOSENSITIZATION; CYTOTOXICITY; METASTASIS; TUMORS; CELLS C1 NCI, Div Clin Sci, Radiat biol Branch, Bethesda, MD 20892 USA. RP Mitchell, JB (reprint author), NCI, Div Clin Sci, Radiat biol Branch, Bethesda, MD 20892 USA. NR 13 TC 0 Z9 0 U1 0 U2 0 PU ALLEN PRESS INC PI LAWRENCE PA 1041 NEW HAMPSHIRE ST, LAWRENCE, KS 66044 USA BN 1-891276-14-X PY 2000 BP 618 EP 621 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA BR30V UT WOS:000166083700150 ER PT B AU Lubin, JH AF Lubin, JH BE Moriaty, M Edington, M Mothersill, C Ward, JF Seymour, C Fry, RJM TI Radon in houses and risk of lung cancer: Direct evidence far a significant association SO RADIATION RESEARCH, VOL 2, CONGRESS PROCEEDINGS LA English DT Proceedings Paper CT 11th International Congress of Radiation Research CY JUL 18-23, 1999 CL DUBLIN, IRELAND ID RESIDENTIAL RADON; INDOOR RADON; EXPOSURE C1 NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Lubin, JH (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, EPS 8042,6120 Execut Blvd, Bethesda, MD 20892 USA. NR 11 TC 0 Z9 0 U1 0 U2 0 PU ALLEN PRESS INC PI LAWRENCE PA 1041 NEW HAMPSHIRE ST, LAWRENCE, KS 66044 USA BN 1-891276-14-X PY 2000 BP 777 EP 779 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA BR30V UT WOS:000166083700186 ER PT J AU Choyke, PL Doppman, JL AF Choyke, PL Doppman, JL TI Case 18: Adrenocorticotropic hormone-dependent Cushing syndrome SO RADIOLOGY LA English DT Article DE adrenal gland, abnormalities; adrenal gland, CT; adrenal gland, neoplasms; Cushing syndrome; diagnosis please; hormones; pituitary, MR; pituitary, neoplasms ID ADRENAL-HYPERPLASIA; DISEASE; DIAGNOSIS C1 NIH, Dept Diagnost Radiol, Imaging Sci Program, Ctr Clin, Bethesda, MD 20892 USA. RP Choyke, PL (reprint author), NIH, Dept Diagnost Radiol, Imaging Sci Program, Ctr Clin, Bldg 10,Rm 1C660,10 Ctr Dr,MSC 1182, Bethesda, MD 20892 USA. NR 14 TC 1 Z9 1 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMER PI EASTON PA 20TH AND NORTHAMPTON STS, EASTON, PA 18042 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JAN PY 2000 VL 214 IS 1 BP 195 EP 198 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 268LD UT WOS:000084414400031 PM 10644123 ER PT J AU Foo, TKF Ho, VB Hood, MN AF Foo, TKF Ho, VB Hood, MN TI Vessel tracking: Prospective adjustment of section-selective MR angiographic locations for improved coronary artery visualization over the cardiac cycle SO RADIOLOGY LA English DT Article DE coronary vessels, MR; magnetic resonance (MR), motion; correction; magnetic resonance (MR), vascular studies ID BREATH-HOLD; NAVIGATOR-ECHO AB To follow the motion of the coronary artery in magnetic resonance angiography, the authors evaluated vessel tracking, a method for prospective adjustment of the section location as a function of the delay from the cardiac trigger. In 10 volunteers and four patients, this method allowed the vessel to be maintained in the plane of acquisition throughout the cardiac cycle. With a single-phase multisection sequence, vessel-tracking acquisitions had an efficiency of 0.68 +/- 0.04 for both the right and left coronary arteries compared with 0.19 +/- 0.03 for a non-vessel-tracking acquisition (P <.001). C1 Johns Hopkins Hosp, GE Med Syst, Appl Sci Lab, Baltimore, MD 21287 USA. Uniformed Serv Univ Hlth Sci, Dept Radiol, Bethesda, MD 20814 USA. NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. RP Foo, TKF (reprint author), Johns Hopkins Hosp, GE Med Syst, Appl Sci Lab, Room 110-MRI,600 N Wolfe St, Baltimore, MD 21287 USA. NR 17 TC 12 Z9 12 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMER PI EASTON PA 20TH AND NORTHAMPTON STS, EASTON, PA 18042 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JAN PY 2000 VL 214 IS 1 BP 283 EP 289 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 268LD UT WOS:000084414400046 PM 10644138 ER PT S AU Gilbert, DL AF Gilbert, DL BE Chiueh, CC TI Fifty years of radical ideas SO REACTIVE OXYGEN SPECIES: FROM RADIATION TO MOLECULAR BIOLOGY: A FESTSCHRIFT IN HONOR OF DANIEL L GILBERT SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Symposium on Reactive Oxygen Species from Radiation to Molecular Biology in honor of Daniel L Gilbert CY JUL 02, 1998 CL NIH, ROS INTEREST GRP, BETHESDA, MARYLAND SP NIH Labs, Oxygen Club HO NIH, ROS INTEREST GRP ID SYNAPTIC TRANSMISSION; PATHOGENESIS; AMYLOIDOSIS; MICROGLIA; PEPTIDES AB My role in the free radical theory of oxygen toxicity is discussed. Rebeca Gerschman and I published several papers on this subject. This sparked my interest in geochemistry and I developed the idea that oxygen was the best qualified biological potential energy source for the following reasons: great abundance, easily accessible, possession of a high thermodynamic potential, and its slow reaction rate. Ionization radiation can be viewed as a catalyst for reactive oxygen species since a killing dose imparts an infinitesimal small amount of energy. Next, Carol A. Colton and I showed that in the mammalian brain that stimulated microglia produce the superoxide radical anion and its implications in Alzheimer's disease is discussed. More recently, I have become interested in the role of sulfhydryl groups in transcription factors. C1 NINDS, Unit React Oxygen Species, BNP, NIH, Bethesda, MD 20892 USA. RP Gilbert, DL (reprint author), NINDS, Unit React Oxygen Species, BNP, NIH, Bethesda, MD 20892 USA. NR 38 TC 30 Z9 31 U1 0 U2 3 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-238-X J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 899 BP 1 EP 14 PG 14 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BQ52C UT WOS:000088609100001 PM 10863525 ER PT S AU Mitchell, JB Russo, A Kuppusamy, P Krishna, MC AF Mitchell, JB Russo, A Kuppusamy, P Krishna, MC BE Chiueh, CC TI Radiation, radicals, and images SO REACTIVE OXYGEN SPECIES: FROM RADIATION TO MOLECULAR BIOLOGY: A FESTSCHRIFT IN HONOR OF DANIEL L GILBERT SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Symposium on Reactive Oxygen Species from Radiation to Molecular Biology in honor of Daniel L Gilbert CY JUL 02, 1998 CL NIH, ROS INTEREST GRP, BETHESDA, MARYLAND SP NIH Labs, Oxygen Club HO NIH, ROS INTEREST GRP ID SUPEROXIDE-DISMUTASE; CHROMOSOME-ABERRATIONS; RADIOPROTECTION; NITROXIDES; TEMPOL; METABOLISM; OXYGENATION; PROTECTION; INHIBITION; HYPOXIA AB Nitroxide stable free radicals exhibit varied chemical and biological properties. Their biological applications have been greatly expanded over the past few years. Not only have they been shown to exhibit potent antioxidant and radioprotective properties, but also they can serve as in vivo functional imaging probes that non-invasively report on the oxygen status and redox properties of tissue, which may have utility in clinical biomedical research. C1 NCI, Radiat Biol Branch, Div Clin Sci, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, EPR Ctr, Baltimore, MD USA. RP Mitchell, JB (reprint author), NCI, Radiat Biol Branch, Div Clin Sci, Bldg 10,Room B3-B69, Bethesda, MD 20892 USA. NR 51 TC 43 Z9 44 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-238-X J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 899 BP 28 EP 43 PG 16 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BQ52C UT WOS:000088609100003 PM 10863527 ER PT S AU McKinney, LC Aquilla, EM Coffin, D Wink, DA Vodovotz, Y AF McKinney, LC Aquilla, EM Coffin, D Wink, DA Vodovotz, Y BE Chiueh, CC TI Ionizing radiation potentiates the induction of nitric oxide synthase by interferon-gamma and/or lipopolysaccharide in murine macrophage cell lines - Role of tumor necrosis factor-alpha SO REACTIVE OXYGEN SPECIES: FROM RADIATION TO MOLECULAR BIOLOGY: A FESTSCHRIFT IN HONOR OF DANIEL L GILBERT SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Symposium on Reactive Oxygen Species from Radiation to Molecular Biology in honor of Daniel L Gilbert CY JUL 02, 1998 CL NIH, ROS INTEREST GRP, BETHESDA, MARYLAND SP NIH Labs, Oxygen Club HO NIH, ROS INTEREST GRP ID PERITONEAL-MACROPHAGES; NO PRODUCTION; IRRADIATION; RELEASE; NITRATE AB Macrophages respond to infection or injury by changing from a "resting" cellular phenotype to an "activated" state defined by the expression of various cytotoxic effector functions. Regulation of the transition from a resting to an activated state is effected by cytokine and/or pathogenic signals. Some signals do not directly induce activation, but instead "prime" the macrophage to respond more vigorously to a second signal. One example of this priming phenomenon involves induction of nitric oxide (NO) synthesis by the enzyme nitric oxide synthase (NOS2), Our experiments indicate that low doses (1-5 Gy) of ionizing radiation can enhance the induction of enzymatically active NOS2 by IFN-gamma or LPS in J774.1 and RAW264.7 murine macrophage cell lines, Radiation alone did not produce this induction, rather, it was effective as a priming signal; cells exposed to radiation produced more NO when a second signal, either IFN-gamma or LPS, was applied 24 h later. C1 Armed Forces Radiobiol Res Inst, Dept Radiat Pathophysiol & Toxicol, Bethesda, MD 20889 USA. NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. RP McKinney, LC (reprint author), Armed Forces Radiobiol Res Inst, Dept Radiat Pathophysiol & Toxicol, Bethesda, MD 20889 USA. NR 19 TC 15 Z9 15 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-238-X J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 899 BP 61 EP 68 PG 8 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BQ52C UT WOS:000088609100005 PM 10863529 ER PT S AU Yim, MB Kang, SO Chock, PB AF Yim, MB Kang, SO Chock, PB BE Chiueh, CC TI Enzyme-like activity of glycated cross-linked proteins in free radical generation SO REACTIVE OXYGEN SPECIES: FROM RADIATION TO MOLECULAR BIOLOGY: A FESTSCHRIFT IN HONOR OF DANIEL L GILBERT SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Symposium on Reactive Oxygen Species from Radiation to Molecular Biology in honor of Daniel L Gilbert CY JUL 02, 1998 CL NIH, ROS INTEREST GRP, BETHESDA, MARYLAND SP NIH Labs, Oxygen Club HO NIH, ROS INTEREST GRP ID HUMAN LENS PROTEINS; PHYSIOLOGICAL CONDITIONS; END-PRODUCTS; AUTOXIDATIVE GLYCOSYLATION; DIABETIC COMPLICATIONS; HYDROGEN-PEROXIDE; GLYOXALASE SYSTEM; MAILLARD REACTION; OXIDANT STRESS; HUMAN COLLAGEN AB The structure and property of cross-linked amino acids and proteins produced by a three- carbon alpha-dicarbonyl methylglyoxal in glycation reaction were investigated. Our results showed that these reactions generated yellow fluorescent products and several free radical species. From the reaction with alanine, three types of free radicals were identified by EPR spectroscopy: 1) the cross-linked radical cation, methylglyoxal diaklylimine cation radical; 2) the methylglyoxal radical anion as the counterion; 3) the superoxide radical anion produced only in the presence of oxygen. Glycation of bovine serum albumin by methylglyoxal also generated the protein-bound, cross-linked free radical, probably the cation radical of the cross-linked Schiff base as observed with alanine. The glycated protein reduced ferricytochrome c to ferrocytochrome c in the absence of oxygen or added metal ions. This reduction of cytochrome c was accompanied by a large increase in the amplitude of the electron paramagnetic resonance signal originated from the protein-bound free radical. In addition, the glycated protein catalyzed the oxidation of ascorbate in the presence of oxygen while the protein-free radical signal disappeared. These results indicate that glycation of protein generates active centers for catalyzing one-electron oxidation-reduction reactions. This active center, which exhibits enzyme-like character, was suggested to be the cross-linked Schiff base/the cross linked Schiff base radical cation of the protein, It mimics the characteristics of metal-catalyzed oxidation system. These results together indicate that glycated proteins accumulated in vivo provide stable active-sites for catalyzing the formation of free radicals. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. Seoul Natl Univ, Res Ctr Mol Microbiol, Seoul 151742, South Korea. Seoul Natl Univ, Coll Nat Sci, Dept Microbiol, Biophys Lab, Seoul 151742, South Korea. RP Yim, MB (reprint author), NHLBI, Biochem Lab, NIH, Bldg 3, Bethesda, MD 20892 USA. NR 41 TC 18 Z9 19 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-238-X J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 899 BP 168 EP 181 PG 14 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BQ52C UT WOS:000088609100014 PM 10863538 ER PT S AU Hanbauer, I Scortegagna, M AF Hanbauer, I Scortegagna, M BE Chiueh, CC TI Molecular markers of oxidative stress vulnerability SO REACTIVE OXYGEN SPECIES: FROM RADIATION TO MOLECULAR BIOLOGY: A FESTSCHRIFT IN HONOR OF DANIEL L GILBERT SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Symposium on Reactive Oxygen Species from Radiation to Molecular Biology in honor of Daniel L Gilbert CY JUL 02, 1998 CL NIH, ROS INTEREST GRP, BETHESDA, MARYLAND SP NIH Labs, Oxygen Club HO NIH, ROS INTEREST GRP ID METALLOTHIONEIN-I GENE; HUMAN CHROMOSOME-21; TRISOMY-16 MOUSE; RESPONSE ELEMENT; INDUCTION; EXPRESSION; TRANSCRIPTION; ACTIVATION; DISMUTASE; REGION AB In astrocyte primary cultures of trisomy 16 mice, an animal model for Down's syndrome, protein oxidation was 50 % higher than in diploid littermates. Exposure to 10 mu M H2O2 Or 50 phl kainic acid incremented protein oxidation in trisomic but not in diploid cultures, Studies on stress response genes showed that metallothionein (MT) level was 2-3 times higher in trisomy 16 than in diploid cultures. Kainic acid or H2O2 exposure increased the MT protein level in diploid cultures but failed to increase it in trisomy 16 mouse beyond its elevated basal level. The reduced responsiveness of MT to simulated oxidative stress may result in insufficient removal of ROS, which could partially explain the further increase of protein oxidation in trisomy 16 cultures, In contrast, Pb exposure increased MT in trisomy 16 and diploid primary cultures to a similar extent. The similar metal responsiveness of MT in both phenotypes indicated that MT in trisomic glial cultures was not yet maximally stimulated. The flawed redox sensitivity in trisomy 16 mouse suggests possible alterations in the binding activity of ROS-sensitive transcription factors on the MT promoter. C1 NHLBI, Lab Mol Immunol, Bethesda, MD 20892 USA. RP Hanbauer, I (reprint author), NHLBI, Lab Mol Immunol, Bldg 10, Bethesda, MD 20892 USA. NR 39 TC 5 Z9 5 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-238-X J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 899 BP 182 EP 190 PG 9 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BQ52C UT WOS:000088609100015 PM 10863539 ER PT S AU Stadtman, ER Levine, RL AF Stadtman, ER Levine, RL BE Chiueh, CC TI Protein oxidation SO REACTIVE OXYGEN SPECIES: FROM RADIATION TO MOLECULAR BIOLOGY: A FESTSCHRIFT IN HONOR OF DANIEL L GILBERT SE Annals of the New York Academy of Sciences LA English DT Article; Proceedings Paper CT Symposium on Reactive Oxygen Species from Radiation to Molecular Biology in honor of Daniel L Gilbert CY JUL 02, 1998 CL NIH, ROS INTEREST GRP, BETHESDA, MD SP NIH Labs, Oxygen Club HO NIH, ROS INTEREST GRP ID METAL-CATALYZED OXIDATION; AMINO-ACID-RESIDUES; COLI GLUTAMINE-SYNTHETASE; MIXED-FUNCTION OXIDATION; FREE-RADICAL GENERATION; AGE-RELATED-CHANGES; ALZHEIMER-DISEASE; LIPID-PEROXIDATION; CARBON-DIOXIDE; RAT-LIVER AB The oxidative modification of proteins by reactive species, especially reactive oxygen species, Is implicated in the etiology or progression of a panoply of disorders and diseases. These reactive species form through a large number of physiological and non-physiological reactions. An increase in the rate of their production or a decrease in their rate of scavenging will increase the oxidative modification of cellular molecules, including proteins. For the most part, oxidatively modified proteins are not repaired and must be removed by proteolytic degradation, and a decrease In the efficiency of proteolysis will cause an increase in the cellular content of oxidatively modified proteins. The level of these modified molecules can be quantitated by measurement of the protein carbonyl content, which has been shown to increase in a variety of diseases and processes, most notably during aging. Accumulation of modified proteins disrupts cellular function either by loss of catalytic and structural integrity or by interruption of regulatory pathways. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Stadtman, ER (reprint author), NHLBI, Biochem Lab, NIH, Bldg 3,Room 222,MSC 0342, Bethesda, MD 20892 USA. EM erstadtman@nih.gov RI Levine, Rodney/D-9885-2011 NR 126 TC 631 Z9 671 U1 7 U2 42 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-239-8 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 899 BP 191 EP 208 PG 18 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BQ52C UT WOS:000088609100016 PM 10863540 ER PT S AU Espey, MG Miranda, KM Feelisch, M Fukuto, J Grisham, MB Vitek, MP Wink, DA AF Espey, MG Miranda, KM Feelisch, M Fukuto, J Grisham, MB Vitek, MP Wink, DA BE Chiueh, CC TI Mechanisms of cell death governed by the balance between nitrosative and oxidative stress SO REACTIVE OXYGEN SPECIES: FROM RADIATION TO MOLECULAR BIOLOGY: A FESTSCHRIFT IN HONOR OF DANIEL L GILBERT SE Annals of the New York Academy of Sciences LA English DT Article; Proceedings Paper CT Symposium on Reactive Oxygen Species from Radiation to Molecular Biology in honor of Daniel L Gilbert CY JUL 02, 1998 CL NIH, ROS INTEREST GRP, BETHESDA, MD SP NIH Labs, Oxygen Club HO NIH, ROS INTEREST GRP ID LOW-DENSITY-LIPOPROTEIN; WOODCHUCK HEPATITIS-VIRUS; NITRIC-OXIDE PROTECTS; HYDROGEN-PEROXIDE; L-ARGININE; NITRATE BIOSYNTHESIS; SUPEROXIDE-DISMUTASE; ESCHERICHIA-COLI; NITROGEN-DIOXIDE; CHEMICAL BIOLOGY AB Many cellular functions in physiology are regulated by the direct interaction of NO with target biomolecules, In many pathophysiologic and toxicologic mechanisms, NO first reacts with oxygen, superoxide or other nitrogen oxides to subsequently elicit indirect effects. The balance between nitrosative stress and oxidative stress within a specific biological compartment can determine whether the presence of NO will be ultimately deleterious or beneficial, Nitrosative stress can be defined primarily through reactions mediated by N(2)O(3), a reactive nitrogen oxide species generated by high fluxes of NO in an aerobic environment. In contrast, oxidative stress is mediated primarily by superoxide and peroxides, In addition to reactive oxygen species, several reactive nitrogen oxide species such as peroxynitrite, nitroxyl, and nitrogen dioxide can also impose oxidative stress to a cell. We here describe how the mechanisms of cell death are interwoven in the balance between the different chemical intermediates involved in nitrosative and oxidative stress. C1 NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. UCL, Wolfson Inst Biomed Res, London W1P 9LN, England. Univ Calif Los Angeles, Dept Pharmacol, Los Angeles, CA 90095 USA. Louisiana State Univ, Med Ctr, Dept Mol & Cellular Physiol, Shreveport, LA 71130 USA. Duke Univ, Med Ctr, Div Neurol, Durham, NC 27710 USA. RP Espey, MG (reprint author), NCI, Radiat Biol Branch, NIH, Bldg 10,Room B3-B69, Bethesda, MD 20892 USA. EM SP@nih.gov RI Miranda, Katrina/B-7823-2009; Feelisch, Martin/C-3042-2008 OI Feelisch, Martin/0000-0003-2320-1158 NR 70 TC 66 Z9 77 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-239-8 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 899 BP 209 EP 221 PG 13 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BQ52C UT WOS:000088609100017 PM 10863541 ER PT S AU Rauhala, P Chiueh, CC AF Rauhala, P Chiueh, CC BE Chiueh, CC TI Effects of atypical antioxidative agents, S-nitrosoglutathione and manganese, on brain lipid peroxidation induced by iron leaking from tissue disruption SO REACTIVE OXYGEN SPECIES: FROM RADIATION TO MOLECULAR BIOLOGY: A FESTSCHRIFT IN HONOR OF DANIEL L GILBERT SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Symposium on Reactive Oxygen Species from Radiation to Molecular Biology in honor of Daniel L Gilbert CY JUL 02, 1998 CL NIH, ROS INTEREST GRP, BETHESDA, MARYLAND SP NIH Labs, Oxygen Club HO NIH, ROS INTEREST GRP ID NITRIC-OXIDE PROTECTS; OXIDATIVE STRESS; DOPAMINE NEURONS; IN-VITRO; NEUROBLASTOMA-CELLS; ALZHEIMERS-DISEASE; RADICAL FORMATION; CELLULAR-DAMAGE; CARBON-DIOXIDE; FATTY-ACIDS AB A fluorescent assay of brain lipid peroxidation was used for screening new antioxidants for the prevention of neurodegeneration caused by free radicals, Incubation of rat brain homogenates led to a temperature dependent increase in production of fluorescent adducts of peroxidized polyunsaturated fatty acids; it was inhibited completely by lowering the incubation temperature to 4 degrees C, This tissue disruption-induced brain lipid peroxidation at 37 degrees C was blocked by deferoxamine (IC50 = 0.3 mu M) and EDTA; it was augmented by adding submicromolar iron and hemoglobin, Ferrous ion's prooxidative activities were five times more potent than ferric ion. Micromolar manganese completely inhibited lipid peroxidation, confirming earlier unexpected in vivo reports, Trolox and vitamin C suppressed brain lipid peroxidation with IC50 values of 20 and 500 mu M, respectively, U-78517F was approximately 20 times more potent than Trolox, 17 beta-Estradiol, hydralazine, S-nitrosoglutathione and 3-hydroxybenzylhydrazine were as potent as Trolox, Melatonin, glutathione, alpha-lipoic acid and l-deprenyl were about 20 times less potent than Trolox, Surprisingly, N-tert-butyl-alpha-phenylnitrone was a weak antioxidant, Furthermore, this procedure can also detect pro-oxidative side effects of vitamin C, oxidized glutathione, penicillamine and Angeli's salt, The present results obtained from this selective fluorescent assay are consistent with earlier reports that iron complexes promote while manganese inhibits brain lipid peroxidation caused by cell disruption. S-Nitrosoglutathione, melatonin, 17 beta-estradiol, and manganese have been successfully tested in cell/animal models for their potential neuroprotective effects, In conclusion, monitoring fluorescent adducts of peroxidizing polyunsaturated fatty acids in brain homogenates is a simple, quantitative method for studying iron-dependent brain lipid peroxidation and for screening of potential neuroprotective antioxidants in both in vitro and in vivo preparations. C1 NIMH, Unit Neurodegenerat & Neuroprotect, Clin Sci Lab, Ctr Clin,NIH, Bethesda, MD 20892 USA. Univ Helsinki, Dept Pharmacol & Toxicol, Inst Biomed, FIN-00170 Helsinki, Finland. RP Chiueh, CC (reprint author), NIMH, Unit Neurodegenerat & Neuroprotect, Clin Sci Lab, Ctr Clin,NIH, 10-3D-41, Bethesda, MD 20892 USA. OI Rauhala, Pekka/0000-0003-2036-3522 NR 61 TC 27 Z9 28 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-238-X J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 899 BP 238 EP 254 PG 17 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BQ52C UT WOS:000088609100019 PM 10863543 ER PT S AU Wu, RM Chen, RC Chiueh, CC AF Wu, RM Chen, RC Chiueh, CC BE Chiueh, CC TI Effect of MAO-B inhibitors on MPP+ toxicity in vivo SO REACTIVE OXYGEN SPECIES: FROM RADIATION TO MOLECULAR BIOLOGY: A FESTSCHRIFT IN HONOR OF DANIEL L GILBERT SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Symposium on Reactive Oxygen Species from Radiation to Molecular Biology in honor of Daniel L Gilbert CY JUL 02, 1998 CL NIH, ROS INTEREST GRP, BETHESDA, MARYLAND SP NIH Labs, Oxygen Club HO NIH, ROS INTEREST GRP ID HYDROXYL RADICAL FORMATION; PARKINSONS-DISEASE; MONOAMINE-OXIDASE; L-DEPRENYL; SUPEROXIDE-DISMUTASE; NEURONS; NEUROTOXICITY; SELEGILINE; (-)-DEPRENYL; PROTECTION AB l-Deprenyl (Selegiline), a selective and irreversible type B monoamine oxidase inhibitor, has been used as an adjunct to levodopa therapy in Parkinson's disease, Recently, it Is proposed as a putative neuroprotective agent in delaying the progression of cell death based on its capability of reducing the oxidative stress derived from the MAO-B dependent metabolism of dopamine, and blocking the development of MPTP-parkinsonism, However, a variety of experimental models suggest that l-deprenyl provides neuroprotection through multiple modes of mechanism other than the inhibition of MAO-B, We have previously shown that l-deprenyl protects midbrain dopamine neurons from MPP+ toxicity by a novel antioxidant effect. hi the present study we examined whether the protection against MPP+ toxicity is also shared by other reversible or irreversible MAO-B inhibitors including (+)-deprenyl, Ro16-6491 acid pargyline, Our data show that non of these MAO-B inhibitors changes the dopamine loss in the striatum induced by intranigral injection of MPP+, Our result suggests that l-deprenyl may possess a unique neuroprotective action on nigral neuron against MPP+ toxicity independent of the MAO-B inhibition. C1 Natl Taiwan Univ Hosp, Dept Neurol, Coll Med, Taipei 100, Taiwan. En Chu Kong Hosp, Dept Neurol, Taipei, Taiwan. NIMH, Unit Neurotoxicol & Neuroprotect, Clin Sci Lab, Ctr Clin,NIH, Bethesda, MD USA. RP Wu, RM (reprint author), Natl Taiwan Univ Hosp, Dept Neurol, Coll Med, 7 Chuang Shan S Rd, Taipei 100, Taiwan. OI Wu, Ruey-Meei/0000-0002-4947-5467 NR 36 TC 28 Z9 31 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-238-X J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 899 BP 255 EP 261 PG 7 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BQ52C UT WOS:000088609100020 PM 10863544 ER PT S AU Hampson, AJ Grimaldi, M Lolic, M Wink, D Rosenthal, R Axelrod, J AF Hampson, AJ Grimaldi, M Lolic, M Wink, D Rosenthal, R Axelrod, J BE Chiueh, CC TI Neuroprotective antioxidants from marijuana SO REACTIVE OXYGEN SPECIES: FROM RADIATION TO MOLECULAR BIOLOGY: A FESTSCHRIFT IN HONOR OF DANIEL L GILBERT SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Symposium on Reactive Oxygen Species from Radiation to Molecular Biology in honor of Daniel L Gilbert CY JUL 02, 1998 CL NIH, ROS INTEREST GRP, BETHESDA, MARYLAND SP NIH Labs, Oxygen Club HO NIH, ROS INTEREST GRP ID CEREBELLAR GRANULE NEURONS; RECEPTOR; CANNABINOIDS; CANNABIDIOL; ANANDAMIDE; BRAIN; DEATH; MICE AB Cannabidiol and other cannabinoids were examined as neuroprotectants in rat cortical neuron cultures exposed to toxic levels of the neurotransmitter, glutamate, The psychotropic cannabinoid receptor agonist Delta(9)-tetrahydrocannabinol (THC) and cannabidiol, (a non-psychoactive constituent of marijuana), both reduced NMDA, AMPA and kainate receptor mediated neurotoxicities. Neuroprotection was not affected by cannabinoid receptor antagonist, indicating a (cannabinoid) receptor-independent mechanism of action. Glutamate toxicity can be reduced by antioxidants. Using cyclic voltametry and a fenton reaction based system, it was demonstrated that Cannabidiol, THC and other cannabinoids are potent antioxidants. As evidence that cannabinoids can act as an antioxidants In neuronal cultures, cannabidiol was demonstrated to reduce hydroperoxide toxicity in neurons. In a head to head trial of the abilities of various antioxidants to prevent glutamate toxicity, cannabidiol mas superior to both ol-tocopherol and ascorbate In protective capacity, Recent preliminary studies in a rat model of focal cerebral ischemia suggest that cannabidiol may be at least as effective in vivo as seen in these in vitro studies. C1 NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. NINDS, Lab Adapt Syst, Bethesda, MD 20892 USA. George Washington Univ, Dept Emergency Med, Washington, DC 20052 USA. NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. RP Hampson, AJ (reprint author), Cortex Pharmaceut Inc, 15231 Barranca Pkwy, Irvine, CA 92618 USA. OI Grimaldi, Maurizio/0000-0002-7331-7055 NR 17 TC 106 Z9 109 U1 2 U2 12 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-238-X J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 899 BP 274 EP 282 PG 9 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BQ52C UT WOS:000088609100022 PM 10863546 ER PT S AU Ehrenstein, G Galdzicki, Z Lange, GD AF Ehrenstein, G Galdzicki, Z Lange, GD BE Chiueh, CC TI A positive-feedback model for the loss of acetylcholine in Alzheimer's disease SO REACTIVE OXYGEN SPECIES: FROM RADIATION TO MOLECULAR BIOLOGY: A FESTSCHRIFT IN HONOR OF DANIEL L GILBERT SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Symposium on Reactive Oxygen Species from Radiation to Molecular Biology in honor of Daniel L Gilbert CY JUL 02, 1998 CL NIH, ROS INTEREST GRP, BETHESDA, MARYLAND SP NIH Labs, Oxygen Club HO NIH, ROS INTEREST GRP ID GROWTH-FACTOR RECEPTOR; POSSIBLE MECHANISM; BASAL FOREBRAIN; NITRIC-OXIDE; BETA; APOPTOSIS; PROTEIN; PRECURSOR; NEURONS; CELLS AB We describe a two-component positive-feedback system that could account for the large reduction of acetylcholine that is characteristic of patients with Alzheimer's disease (AD). One component is beta-amyloid-induced apoptosis of cholinergic cells, leading to a decrease in acetylcholine. The other component is an increase in the concentration of beta-amyloid in response to a decrease in acetylcholine, We describe each mechanism with a differential equation, and then solve the two equations numerically. The solution provides a description of the time course of the reduction of acetylcholine in AD patients that is consistent with epidemiological data. This model may also provide an explanation for the significant, but lesser, decrease of other neurotransmitters that is characteristic of AD. C1 NINDS, Biophys Sect, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Physiol, Bethesda, MD 20814 USA. NINDS, Instrumentat & Comp Sect, Bethesda, MD 20892 USA. RP Ehrenstein, G (reprint author), NINDS, Biophys Sect, Bethesda, MD 20892 USA. NR 30 TC 5 Z9 5 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-238-X J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 899 BP 283 EP 291 PG 9 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BQ52C UT WOS:000088609100023 PM 10863547 ER PT S AU Colton, CA Chernyshev, ON Gilbert, DL Vitek, MP AF Colton, CA Chernyshev, ON Gilbert, DL Vitek, MP BE Chiueh, CC TI Microglial contribution to oxidative stress in Alzheimer's disease SO REACTIVE OXYGEN SPECIES: FROM RADIATION TO MOLECULAR BIOLOGY: A FESTSCHRIFT IN HONOR OF DANIEL L GILBERT SE Annals of the New York Academy of Sciences LA English DT Article; Proceedings Paper CT Symposium on Reactive Oxygen Species from Radiation to Molecular Biology in honor of Daniel L Gilbert CY JUL 02, 1998 CL NIH, ROS INTEREST GRP, BETHESDA, MD SP NIH Labs, Oxygen Club HO NIH, ROS INTEREST GRP ID NITRIC-OXIDE PRODUCTION; AMYLOID-BETA-PROTEIN; MACROPHAGE ACTIVATION; BRAIN MACROPHAGES; LIPID-PEROXIDATION; SUPEROXIDE ANIONS; END-PRODUCTS; CELLS; MECHANISM; PEPTIDE AB Microglia are the CNS macrophage and are a primary cellular component of plaques in Alzheimer's disease (AD) that may contribute to the oxidative stress associated with chronic neurodegeneration. We now report that superoxide anion production in microglia or macrophages from 3 different species is increased by long term exposure (24 hours) to A beta peptides, Since A beta competes for the uptake of opsonized latex beads and for the production of superoxide anion by opsonized zymosan, a likely site of action are membrane receptors associated with the uptake of opsonized particles or fibers. The neurotoxic fibrillar peptides A beta (1-42) and human amylin increase radical production whereas a non-toxic, non-fibrillar peptide, rat amylin, does not. We also report that the effect of A beta peptides on superoxide anion production is not associated with a concomitant increase in nitric oxide (NO) production in either human monocyte derived macrophages (MDM) or hamster microglia from primary cultures. Since NO is known to protect membrane lipids and scavenge superoxide anion, the lack of A beta-mediated induction of NO production in human microglia and macrophages may be as deleterious as the overproduction of superoxide anion induced by chronic exposure to A beta peptides. C1 Georgetown Univ, Med Ctr, Dept Physiol, Washington, DC 20007 USA. NINDS, Biophys Sect, Unit React Oxygen Species, NIH, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Dept Neurol, Durham, NC USA. RP Colton, CA (reprint author), Georgetown Univ, Med Ctr, Dept Physiol, 3900 Reservoir Rd NW, Washington, DC 20007 USA. EM glia01@aol.com FU NIA NIH HHS [AG 12851, AG 15609]; NINDS NIH HHS [NS36718] NR 69 TC 65 Z9 70 U1 0 U2 5 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-239-8 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 899 BP 292 EP 307 PG 16 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BQ52C UT WOS:000088609100024 PM 10863548 ER PT S AU Misik, V Riesz, P AF Misik, V Riesz, P BE Chiueh, CC TI Free radical intermediates in sonodynamic therapy SO REACTIVE OXYGEN SPECIES: FROM RADIATION TO MOLECULAR BIOLOGY: A FESTSCHRIFT IN HONOR OF DANIEL L GILBERT SE Annals of the New York Academy of Sciences LA English DT Article; Proceedings Paper CT Symposium on Reactive Oxygen Species from Radiation to Molecular Biology in honor of Daniel L Gilbert CY JUL 02, 1998 CL NIH, ROS INTEREST GRP, BETHESDA, MD SP NIH Labs, Oxygen Club HO NIH, ROS INTEREST GRP ID PORPHYRIN ANALOG ATX-70; IN-VITRO; AQUEOUS-SOLUTIONS; LEUKEMIA-CELLS; ULTRASOUND; CAVITATION; ENHANCEMENT; N,N-DIMETHYLFORMAMIDE; SONOLUMINESCENCE; TEMPERATURE AB Current understanding of the mechanism of sonodynamic action (i.e. the ultrasound-dependent enhancement of the cytotoxic action of certain drugs - sonosensitizers) with potential applications for cancer therapy is presented. The experimental evidence suggests that sonosensitization is due to the chemical activation of sonosensitizers inside or in the close vicinity of hot collapsing cavitation bubbles to form sensitizer-derived free radicals either by direct pyrolysis or due to reactions with . H and . OH radicals, formed by pyrolysis of water, These free radicals (mostly carbon-centered) react with oxygen to form peroxyl and alkoxyl radicals. Unlike . OH and . H, which are also formed by pyrolysis inside cavitation bubbles, the reactivity of alkoxyl and peroxyl radicals with organic components dissolved in biological media Is lower and hence have higher probability of reaching critical cellular sites. Sonodynamic therapy appears to be a promising modality for cancer treatment since ultrasound ran penetrate deep within the tissue and can be focused in a small region of tumor to chemically activate relatively non-toxic molecules (e.g. porphyrins) thus minimizing undesirable side effects. C1 NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. Slovak Acad Sci, Inst Expt Pharmacol, Bratislava 84216, Slovakia. RP Riesz, P (reprint author), NCI, Radiat Biol Branch, NIH, Bldg 10,Room B3-B69, Bethesda, MD 20892 USA. EM sono@helix.nih.gov NR 37 TC 88 Z9 104 U1 2 U2 14 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-239-8 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 899 BP 335 EP 348 PG 14 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BQ52C UT WOS:000088609100027 PM 10863551 ER PT S AU Speir, E AF Speir, E BE Chiueh, CC TI Cytomegalovirus gene regulation by reactive oxygen species - Agents in atherosclerosis SO REACTIVE OXYGEN SPECIES: FROM RADIATION TO MOLECULAR BIOLOGY: A FESTSCHRIFT IN HONOR OF DANIEL L GILBERT SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Symposium on Reactive Oxygen Species from Radiation to Molecular Biology in honor of Daniel L Gilbert CY JUL 02, 1998 CL NIH, ROS INTEREST GRP, BETHESDA, MARYLAND SP NIH Labs, Oxygen Club HO NIH, ROS INTEREST GRP ID NF-KAPPA-B; SMOOTH-MUSCLE CELLS; XANTHINE-OXIDASE; EXPRESSION; VIRUS; SUPEROXIDE; ACTIVATION; INFECTION; ATHEROGENESIS; GENERATION AB Oxidative stress Is implicated in the pathogenesis of atherosclerosis, and of viral infections caused by sendai virus, influenza and HIV. Vascular oxidative stress is due to inflammatory and immune responses of vascular cells, and to reperfusion after recanalization of blocked arteries. Because human cytomegalovirus (CMV) may contribute to atherogenesis by several mechanisms, and coronary artery smooth nuscle cells (SMC) are permissive for the virus, we examined CMV interactions with SMC, Infection causes generation of intracellular reactive oxygen species (ROS) which activate NF-kappa B, a cellular transcription factor. NF-kappa B mediates expression of the CMV promoter and of genes involved in the immune and inflammatory responses, Antioxidants or aspirin inhibit ROS, NF-kappa B and CMV. C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. RP Speir, E (reprint author), NHLBI, Cardiol Branch, NIH, 10-7B 15,10 Ctr Dr,MSC 1650, Bethesda, MD 20892 USA. NR 34 TC 28 Z9 35 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-238-X J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 899 BP 363 EP 374 PG 12 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BQ52C UT WOS:000088609100029 PM 10863553 ER PT S AU Luo, YQ Roth, GS AF Luo, YQ Roth, GS BE Chiueh, CC TI Dopamine stimulates astrocytic C6-D2L cells via tyrosine kinase and p38 MAPK activation SO REACTIVE OXYGEN SPECIES: FROM RADIATION TO MOLECULAR BIOLOGY: A FESTSCHRIFT IN HONOR OF DANIEL L GILBERT SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Symposium on Reactive Oxygen Species from Radiation to Molecular Biology in honor of Daniel L Gilbert CY JUL 02, 1998 CL NIH, ROS INTEREST GRP, BETHESDA, MARYLAND SP NIH Labs, Oxygen Club HO NIH, ROS INTEREST GRP ID FIBRILLARY ACIDIC PROTEIN; RECEPTOR MESSENGER-RNA; INTRASTRIATAL INJECTION; SUBSTANTIA-NIGRA; RAT STRIATUM; BRAIN INJURY; OXIDATION; APOPTOSIS; ISCHEMIA; MICRODIALYSIS C1 NIA, Gerontol Res Ctr, Mol Physiol & Genet Sect, Baltimore, MD 21224 USA. RP Luo, YQ (reprint author), NIA, Gerontol Res Ctr, Mol Physiol & Genet Sect, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 33 TC 0 Z9 0 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-238-X J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 899 BP 392 EP 398 PG 7 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BQ52C UT WOS:000088609100031 PM 10863555 ER PT S AU Stadtman, TC AF Stadtman, TC BE Chiueh, CC TI Selenium biochemistry - Mammalian selenoenzymes SO REACTIVE OXYGEN SPECIES: FROM RADIATION TO MOLECULAR BIOLOGY: A FESTSCHRIFT IN HONOR OF DANIEL L GILBERT SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Symposium on Reactive Oxygen Species from Radiation to Molecular Biology in honor of Daniel L Gilbert CY JUL 02, 1998 CL NIH, ROS INTEREST GRP, BETHESDA, MARYLAND SP NIH Labs, Oxygen Club HO NIH, ROS INTEREST GRP ID CONTAINING THIOREDOXIN REDUCTASE; CLOSTRIDIAL GLYCINE REDUCTASE; LUNG ADENOCARCINOMA CELLS; GLUTATHIONE-PEROXIDASE; HELA-CELLS; SELENOCYSTEINE; SELENOPROTEIN; PROTEIN; PURIFICATION; DEIODINASE C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Stadtman, TC (reprint author), NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NR 23 TC 63 Z9 63 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-238-X J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 899 BP 399 EP 402 PG 4 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BQ52C UT WOS:000088609100032 PM 10863556 ER PT J AU Sullivan, DM Finkel, T AF Sullivan, DM Finkel, T TI Expression of Rho GTPases using adenovirus vectors SO REGULATORS AND EFFECTORS OF SMALL GTPASES, PT D SE METHODS IN ENZYMOLOGY LA English DT Review ID PATHWAY; RAC1; SYSTEM; TYPE-5; DNA C1 NHLBI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Sullivan, DM (reprint author), NHLBI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 17 TC 3 Z9 3 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2000 VL 325 BP 303 EP 314 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA BR04L UT WOS:000165500200027 PM 11036613 ER PT J AU Li, QDQ Ding, L Reed, E AF Li, QDQ Ding, L Reed, E TI Proteasome inhibition suppresses cisplatin-dependent ERCC-1 mRNA expression in human ovarian tumor cells SO RESEARCH COMMUNICATIONS IN MOLECULAR PATHOLOGY AND PHARMACOLOGY LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; MESSENGER-RNA EXPRESSION; CATHEPSIN-B ACTIVITY; DNA-REPAIR; ANTICANCER CHEMOTHERAPY; CARCINOMA CELLS; CANCER PATIENTS; THP-1 CELLS; GENE ERCC-1; TRANSCRIPTION AB One of the major problems with ovarian cancer treatment is the clinical development of resistance to cisplatin. Considerable efforts have been directed toward the identification of biological and pharmacological agents that would reverse drug resistance to cisplatin. ALLnL is an inhibitor of the proteasome that can inhibit the ubiquitin-proteasome pathway, which plays an essential role in many processes in cell life. We have recently shown that ALLnL, at concentrations that do not appear harmful, has significantly enhanced DNA platination and decreased DNA repair of cisplatin-DNA adducts in human A2780/CP70 ovarian carcinoma cells. These activities of proteasome inhibition were also associated with substantially increased cisplatin toxicity in these cells. In this communication, we demonstrate that treatment of A2780/CP70 cells with ALLnL blocks cisplatin-induced ERCC-1 mRNA expression in a concentration- and time-dependent manner, as measured by Northern blot analysis. In addition, we showed that the cisplatin-dependent increase in steady-state levels of ERCC-1 mRNA was prevented by pretreatment with lactacystin, a potent and specific inhibitor of proteasome. These results suggest that the effect of proteasome inhibition on cisplatin cytotoxicity, DNA platination, and DNA repair of cisplatin adducts in ovarian cancer cells may be through down-regulating ERCC-1 expression. C1 NCI, Med Ovarian Canc Sect, Dept Dev Therapeut, Med Branch,Div Clin Sci,NIH, Bethesda, MD 20892 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Li, QDQ (reprint author), Univ Maryland, Sch Med, BRB, Room 12-042,655 W Baltimore St, Baltimore, MD 21201 USA. NR 40 TC 11 Z9 11 U1 0 U2 0 PU P J D PUBLICATIONS LTD PI WESTBURY PA PO BOX 966, WESTBURY, NY 11590 USA SN 1078-0297 J9 RES COMMUN MOL PATH JI Res. Commun. Mol. Pathol. Pharmacol. PY 2000 VL 107 IS 5-6 BP 387 EP 396 PG 10 WC Biochemistry & Molecular Biology; Pathology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pathology; Pharmacology & Pharmacy GA 477JZ UT WOS:000171281600005 PM 11589365 ER PT B AU Fauci, AS AF Fauci, AS BE Girard, M Dodet, B TI Host factors in the pathogenesis of HIV disease SO RETROVIRUSES OF HUMAN AIDS AND RELATED ANIMAL DISEASES LA English DT Proceedings Paper CT 12th Cent Gardes Meeting on Retroviruses of Human Aids and Related Animal Diseases CY OCT 25-27, 1999 CL PARIS, FRANCE ID CD4(+) T-CELLS; REPLICATION; CYTOKINES C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU EDITIONS SCIENTIFIQUES ET MEDICALES ELSEVIER PI PARIS PA 23, RUE LINOIS, 75724 PARIS, FRANCE BN 2-84299-173-7 PY 2000 BP 65 EP 67 PG 3 WC Immunology; Infectious Diseases; Medicine, Research & Experimental; Virology SC Immunology; Infectious Diseases; Research & Experimental Medicine; Virology GA BP90T UT WOS:000086564300014 ER PT B AU Moss, B AF Moss, B BE Girard, M Dodet, B TI Protein and recombinant MVA immunization and challenge studies with SHIV 89.6 SO RETROVIRUSES OF HUMAN AIDS AND RELATED ANIMAL DISEASES LA English DT Proceedings Paper CT 12th Cent Gardes Meeting on Retroviruses of Human Aids and Related Animal Diseases CY OCT 25-27, 1999 CL PARIS, FRANCE ID IMMUNODEFICIENCY-VIRUS; RHESUS-MONKEYS; VACCINIA C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU EDITIONS SCIENTIFIQUES ET MEDICALES ELSEVIER PI PARIS PA 23, RUE LINOIS, 75724 PARIS, FRANCE BN 2-84299-173-7 PY 2000 BP 105 EP 107 PG 3 WC Immunology; Infectious Diseases; Medicine, Research & Experimental; Virology SC Immunology; Infectious Diseases; Research & Experimental Medicine; Virology GA BP90T UT WOS:000086564300025 ER PT B AU Nabel, GJ AF Nabel, GJ BE Girard, M Dodet, B TI AIDS vaccines: Challenges and opportunities SO RETROVIRUSES OF HUMAN AIDS AND RELATED ANIMAL DISEASES LA English DT Proceedings Paper CT 12th Cent Gardes Meeting on Retroviruses of Human Aids and Related Animal Diseases CY OCT 25-27, 1999 CL PARIS, FRANCE ID IMMUNODEFICIENCY-VIRUS TYPE-1; DNA VACCINATION; IMMUNE-RESPONSES; HIV TYPE-1; PROTECTIVE IMMUNITY; ANTIBODY-RESPONSES; INFECTION; TRIAL; MICE; IMMUNIZATION C1 NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Nabel, GJ (reprint author), NIH, Vaccine Res Ctr, Bldg 10, Bethesda, MD 20892 USA. NR 39 TC 0 Z9 0 U1 0 U2 0 PU EDITIONS SCIENTIFIQUES ET MEDICALES ELSEVIER PI PARIS PA 23, RUE LINOIS, 75724 PARIS, FRANCE BN 2-84299-173-7 PY 2000 BP 127 EP 131 PG 5 WC Immunology; Infectious Diseases; Medicine, Research & Experimental; Virology SC Immunology; Infectious Diseases; Research & Experimental Medicine; Virology GA BP90T UT WOS:000086564300030 ER PT B AU Arthur, LO AF Arthur, LO BE Girard, M Dodet, B TI Inactivated SIV vaccine: Protection from pathogenic challenge SO RETROVIRUSES OF HUMAN AIDS AND RELATED ANIMAL DISEASES LA English DT Proceedings Paper CT 12th Cent Gardes Meeting on Retroviruses of Human Aids and Related Animal Diseases CY OCT 25-27, 1999 CL PARIS, FRANCE C1 NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, AVP, Frederick, MD 21701 USA. RP Arthur, LO (reprint author), NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, AVP, Frederick, MD 21701 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU EDITIONS SCIENTIFIQUES ET MEDICALES ELSEVIER PI PARIS PA 23, RUE LINOIS, 75724 PARIS, FRANCE BN 2-84299-173-7 PY 2000 BP 145 EP 146 PG 2 WC Immunology; Infectious Diseases; Medicine, Research & Experimental; Virology SC Immunology; Infectious Diseases; Research & Experimental Medicine; Virology GA BP90T UT WOS:000086564300033 ER PT B AU Johnston, MI AF Johnston, MI BE Girard, M Dodet, B TI AIDS vaccine development: Status and future directions SO RETROVIRUSES OF HUMAN AIDS AND RELATED ANIMAL DISEASES LA English DT Proceedings Paper CT 12th Cent Gardes Meeting on Retroviruses of Human Aids and Related Animal Diseases CY OCT 25-27, 1999 CL PARIS, FRANCE C1 NIAID, NIH, Bethesda, MA USA. RP Johnston, MI (reprint author), NIAID, NIH, Bethesda, MA USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU EDITIONS SCIENTIFIQUES ET MEDICALES ELSEVIER PI PARIS PA 23, RUE LINOIS, 75724 PARIS, FRANCE BN 2-84299-173-7 PY 2000 BP 161 EP 163 PG 3 WC Immunology; Infectious Diseases; Medicine, Research & Experimental; Virology SC Immunology; Infectious Diseases; Research & Experimental Medicine; Virology GA BP90T UT WOS:000086564300037 ER PT B AU Franchini, G AF Franchini, G BE Girard, M Dodet, B TI Modeling early intervention with antiviral therapy and therapeutic immunization in the SIV251 macaque model SO RETROVIRUSES OF HUMAN AIDS AND RELATED ANIMAL DISEASES LA English DT Proceedings Paper CT 12th Cent Gardes Meeting on Retroviruses of Human Aids and Related Animal Diseases CY OCT 25-27, 1999 CL PARIS, FRANCE ID ACTIVE ANTIRETROVIRAL THERAPY; RHESUS MACAQUES; PROTECTION; HIV-1; CHALLENGE; INFECTION C1 NCI, Basic Res Lab, Sect Anim Models & Retroviral Vaccines, Bethesda, MD 20892 USA. RP Franchini, G (reprint author), NCI, Basic Res Lab, Sect Anim Models & Retroviral Vaccines, Bethesda, MD 20892 USA. NR 13 TC 0 Z9 0 U1 0 U2 0 PU EDITIONS SCIENTIFIQUES ET MEDICALES ELSEVIER PI PARIS PA 23, RUE LINOIS, 75724 PARIS, FRANCE BN 2-84299-173-7 PY 2000 BP 185 EP 192 PG 8 WC Immunology; Infectious Diseases; Medicine, Research & Experimental; Virology SC Immunology; Infectious Diseases; Research & Experimental Medicine; Virology GA BP90T UT WOS:000086564300044 ER PT S AU Pearson, JL AF Pearson, JL BE Maris, RW Canetto, SS McIntosh, JL Silverman, MM TI Suicidal behavior in later life - Research update SO REVIEW OF SUICIDOLOGY, 2000 SE REVIEW OF SUICIDOLOGY LA English DT Proceedings Paper CT Annual Preconference Workshop on Suicide Update 1997 CY APR 23, 1997 CL MEMPHIS, TN SP Amer Assoc Suicidol ID DELIBERATE SELF-HARM; TERM CARE FACILITIES; PSYCHOLOGICAL AUTOPSY; FOLLOW-UP; PSYCHIATRIC OUTPATIENTS; AFFECTIVE-DISORDERS; EVENTUAL SUICIDE; MAJOR DEPRESSION; SEX-DIFFERENCES; AGE-DIFFERENCES C1 NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. NR 133 TC 1 Z9 1 U1 8 U2 8 PU GUILFORD PRESS PI NEW YORK PA 72 SPRING ST, NEW YORK, NY 10012 USA SN 1092-2199 BN 1-57230-503-7 J9 REV SUICIDOL PY 2000 BP 202 EP 225 PG 24 WC Psychiatry; Psychology, Multidisciplinary; Social Work SC Psychiatry; Psychology; Social Work GA BP69Y UT WOS:000085884800010 ER PT J AU Bostwick, DG Montironi, R Sesterhenn, IA AF Bostwick, DG Montironi, R Sesterhenn, IA TI Diagnosis of prostatic intraepithelial neoplasia - Prostate Working Group 1 Consensus report SO SCANDINAVIAN JOURNAL OF UROLOGY AND NEPHROLOGY LA English DT Article; Proceedings Paper CT Consensus Conference on Public Health and Clinical Significance of Premalignant Alterations in the Genito-Urinary Tract CY JUN 08-10, 2000 CL STOCKHOLM, SWEDEN SP European Commiss, Europe Against Canc DE androgen ablation; atypical adenomatous hyperplasia; cancer; prostate; prostatic intraepithelial neoplasia; prostatic neoplasms; radiation therapy ID ATYPICAL ADENOMATOUS HYPERPLASIA; DUCT-ACINAR DYSPLASIA; IN-SITU HYBRIDIZATION; RADICAL PROSTATECTOMY; CHROMOSOMAL-ANOMALIES; CLINICAL-SIGNIFICANCE; PREMALIGNANT LESION; TELOMERASE ACTIVITY; ANDROGEN ABLATION; CARCINOMA AB High-grade prostatic intraepithelial neoplasia (PIN) is the most likely precursor of prostatic carcinoma. PIN has a high predictive value as a marker for carcinoma, and its identification in biopsy specimens warrants repeat biopsy for concurrent or subsequent carcinoma. The only methods of detection are biopsy and transurethral resection; PIN does not significantly elevate serum PSA concentration or its derivatives, nor does it induce a palpable mass, and cannot be detected by ultrasound. Androgen deprivation therapy decreases the prevalence and extent of PIN, suggesting that this form of treatment may play a role in chemoprevention. Radiation therapy is also associated with a decreased incidence of PIN. C1 Virginia Urol Ctr, Bostwick Labs, Richmond, VA 23294 USA. NCI, Urol Oncol Div, Bethesda, MD 20892 USA. Univ Virginia, Charlottesville, VA 22903 USA. Univ Ancona, Sch Med, Dept Pathol, I-60128 Torrette Di Ancona, Italy. Univ Hosp Lab, I-60128 Torrette Di Ancona, Italy. Armed Forces Inst Pathol, Div Genitourinary Pathol, Washington, DC 20306 USA. RP Bostwick, DG (reprint author), Virginia Urol Ctr, Bostwick Labs, 9351 W Broad St, Richmond, VA 23294 USA. NR 51 TC 3 Z9 3 U1 0 U2 0 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0036-5599 J9 SCAND J UROL NEPHROL JI Scand. J. Urol. Nephrol. PY 2000 VL 34 SU 205 BP 3 EP 10 DI 10.1080/003655900750169266 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 377RA UT WOS:000165526100004 ER PT J AU Fenton, WS Schooler, NR AF Fenton, WS Schooler, NR TI Editors' introduction: Evidence based psychosocial treatment for schizophrenia SO SCHIZOPHRENIA BULLETIN LA English DT Editorial Material DE schizophrenia; psychosocial treatment; evidence-based medicine; psychotherapy; family therapy; serious mental illness AB Current recommendations for evidence-based schizophrenia treatment support a comprehensive, individualized approach that integrates advances in psychopharmacology with psychosocial strategies for disease management. In this issue of the Schizophrenia Bulletin, me invited clinician investigators to summarize new empirical data concerning the efficacy of psychosocial interventions that target common and particularly problematic aspects of schizophrenia. A rich formulary of psychosocial interventions with demonstrated efficacy is now available. With new neuroleptic medications, these interventions should define the current standard of care for schizophrenia. C1 NIMH, Div Mental Disorders Behav Res & AIDS, NIH, Bethesda, MD 20892 USA. Hillside Hosp, N Shore Long Isl Jewish Hlth Syst, Glen Oaks, NY 11004 USA. RP Fenton, WS (reprint author), NIMH, Ctr Neurosci, 6001 Execut Blvd,Room 6216,MSC 9621, Bethesda, MD 20892 USA. NR 16 TC 27 Z9 31 U1 2 U2 4 PU US GOVERNMENT PRINTING OFFICE PI WASHINGTON PA SUPERINTENDENT DOCUMENTS,, WASHINGTON, DC 20402-9325 USA SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PY 2000 VL 26 IS 1 BP 1 EP 3 PG 3 WC Psychiatry SC Psychiatry GA 299EM UT WOS:000086183200002 PM 10755666 ER PT J AU Heinssen, RK Liberman, RP Kopelowicz, A AF Heinssen, RK Liberman, RP Kopelowicz, A TI Psychosocial skills training for schizophrenia: Lessons from the laboratory SO SCHIZOPHRENIA BULLETIN LA English DT Article DE schizophrenia; psychosocial rehabilitation; skills training; social skills training; behavior therapy; cognitive disorders; cognitive techniques ID SEVERE MENTAL-ILLNESS; PROBLEM-SOLVING SKILLS; QUALITY-OF-LIFE; SOCIAL SKILLS; COGNITIVE DEFICITS; PSYCHIATRIC REHABILITATION; BIOBEHAVIORAL TREATMENT; NEGATIVE SYMPTOMS; MANAGEMENT MODULE; SELF-MANAGEMENT AB A large body of research supports the efficacy of psychosocial treatments for schizophrenia, particularly learning-based therapies. The Schizophrenia Patient Outcomes Research Team recommended that cognitive-behavioral therapies be used in schizophrenia, and skills training was included in the practice guideline for treating patients with schizophrenia published by the American Psychiatric Association. This article provides an updated review of empirical studies of psychosocial skills training, showing its value in treating patients with schizophrenia as well as its broader clinical effectiveness. Data supporting the efficacy of psychosocial skills training continue to accumulate. Such programs should continue to be included in best practices guidelines and treatment recommendations for schizophrenia. Future clinical service research could be directed toward integration of skills training with other psychosocial treatment methods. C1 NIMH, Adherence & Behav Change Res Program, Div Mental Disorders Behav Res & AIDS, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Ctr Res Treatment & Rehabil Psychosis, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90024 USA. San Fernando Mental Hlth Ctr, Mission Hills, CA USA. RP Heinssen, RK (reprint author), NIMH, Adherence & Behav Change Res Program, Div Mental Disorders Behav Res & AIDS, 6001 Execut Blvd,Rm 6190,MSC 9615, Bethesda, MD 20892 USA. OI kopelowicz, alex/0000-0002-1728-4105 NR 98 TC 112 Z9 115 U1 3 U2 7 PU US GOVERNMENT PRINTING OFFICE PI WASHINGTON PA SUPERINTENDENT DOCUMENTS,, WASHINGTON, DC 20402-9325 USA SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PY 2000 VL 26 IS 1 BP 21 EP 46 PG 26 WC Psychiatry SC Psychiatry GA 299EM UT WOS:000086183200004 PM 10755668 ER PT J AU Fenton, WS AF Fenton, WS TI Evolving perspectives on individual psychotherapy for schizophrenia SO SCHIZOPHRENIA BULLETIN LA English DT Review DE schizophrenia; psychotherapy; randomized clinical trials; psychosocial treatment; evidence-based medicine; treatment outcome ID RANDOMIZED CONTROLLED TRIAL; COGNITIVE-BEHAVIORAL THERAPY; RESIDUAL PSYCHOTIC SYMPTOMS; TERM FOLLOW-UP; PERSONAL THERAPY; RELAPSE RATES; SUPPORTIVE PSYCHOTHERAPY; PSYCHOSOCIAL TREATMENT; 3-YEAR TRIALS; DRUG AB Some form of individual psychotherapy, in combination with the prescription of antipsychotic medications, is likely the most common treatment for patients with schizophrenia. In the absence of empirical data supporting the efficacy of a particular approach, psychotherapy has often been guided by ideology and deference to authority. In recent years, a reformulation of schizophrenia as a disorder requiring individualized, comprehensive treatment has allowed the development and empirical testing of new targeted and illness-phase-specific individual psychotherapies. This report reviews randomized clinical trials that have evaluated individual psychotherapy of schizophrenia in the context of changing contemporaneous beliefs about the disorder's etiology and treatment. A general approach to individual treatment, termed "flexible psychotherapy," derived from historical approaches but consistent with available clinical and research perspectives, is outlined. C1 NIMH, Ctr Neurosci, Div Mental Disorders Behav Res & AIDS, NIH, Bethesda, MD 20892 USA. RP Fenton, WS (reprint author), NIMH, Ctr Neurosci, Div Mental Disorders Behav Res & AIDS, NIH, 6001 Execut Blvd,Room 6216,MSC 9621, Bethesda, MD 20892 USA. NR 129 TC 36 Z9 37 U1 4 U2 5 PU US GOVERNMENT PRINTING OFFICE PI WASHINGTON PA SUPERINTENDENT DOCUMENTS,, WASHINGTON, DC 20402-9325 USA SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PY 2000 VL 26 IS 1 BP 47 EP 72 PG 26 WC Psychiatry SC Psychiatry GA 299EM UT WOS:000086183200005 PM 10755669 ER PT J AU Schooler, NR Fenton, WS AF Schooler, NR Fenton, WS TI Editors' concluding remarks: Psychosocial treatment: More than compassion and common sense? SO SCHIZOPHRENIA BULLETIN LA English DT Editorial Material ID PRINCIPLES; IMPROVE C1 Hillside Hosp, Div N Shore Long Isl Jewish Hlth Syst, Glen Oaks, NY 11004 USA. NIMH, NIH, Div Mental Disorders Behav Res & AIDS, Bethesda, MD 20892 USA. RP Schooler, NR (reprint author), Hillside Hosp, Div N Shore Long Isl Jewish Hlth Syst, 75-59 263rd St, Glen Oaks, NY 11004 USA. NR 14 TC 1 Z9 1 U1 3 U2 3 PU US GOVERNMENT PRINTING OFFICE PI WASHINGTON PA SUPERINTENDENT DOCUMENTS,, WASHINGTON, DC 20402-9325 USA SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PY 2000 VL 26 IS 1 BP 153 EP 155 PG 3 WC Psychiatry SC Psychiatry GA 299EM UT WOS:000086183200013 PM 10755677 ER PT J AU Greenblat, L AF Greenblat, L TI First person account: Understanding health as a continuum SO SCHIZOPHRENIA BULLETIN LA English DT Article C1 Johns Hopkins Univ, Baltimore, MD 21218 USA. RP Greenblat, L (reprint author), NIMH, Schizophrenia Bulletin, 6001 Execut Blvd,Rm 8184,MSC 9663, Bethesda, MD 20892 USA. NR 0 TC 8 Z9 8 U1 0 U2 0 PU US GOVERNMENT PRINTING OFFICE PI WASHINGTON PA SUPERINTENDENT DOCUMENTS,, WASHINGTON, DC 20402-9325 USA SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PY 2000 VL 26 IS 1 BP 243 EP 245 PG 3 WC Psychiatry SC Psychiatry GA 299EM UT WOS:000086183200022 PM 10755685 ER PT J AU Wyatt, RJ Susser, ES AF Wyatt, RJ Susser, ES TI Editors' introduction: US birth cohort studies of schizophrenia: A sea change SO SCHIZOPHRENIA BULLETIN LA English DT Editorial Material ID ADULT SCHIZOPHRENIA; RISK C1 NIMH, NIH, Neuropsychiat Branch, Bethesda, MD 20892 USA. Columbia Univ, Joseph L Mailman Sch Publ Hlth, Div Epidemiol, New York, NY 10027 USA. Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, Div Epidemiol Brain Disorders, New York, NY 10032 USA. RP Wyatt, RJ (reprint author), NIMH, NIH, Neuropsychiat Branch, Bldg 15K,Rm 203C,15 North Dr, Bethesda, MD 20892 USA. NR 9 TC 5 Z9 5 U1 1 U2 1 PU US GOVERNMENT PRINTING OFFICE PI WASHINGTON PA SUPERINTENDENT DOCUMENTS,, WASHINGTON, DC 20402-9325 USA SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PY 2000 VL 26 IS 2 BP 255 EP 256 PG 2 WC Psychiatry SC Psychiatry GA 326YV UT WOS:000087765600002 PM 10885628 ER PT J AU Susser, ES Schaefer, CA Brown, AS Begg, MD Wyatt, RJ AF Susser, ES Schaefer, CA Brown, AS Begg, MD Wyatt, RJ TI The design of the prenatal determinants of schizophrenia study SO SCHIZOPHRENIA BULLETIN LA English DT Article DE schizophrenia; epidemiology; prenatal ID BIRTH COHORT; ADULT SCHIZOPHRENIA; RISK; COMPLICATIONS; PREGNANCY; DELIVERY; EXPOSURE AB This paper describes the Prenatal Determinants of Schizophrenia (PDS) Study; three companion papers report the first results. The PDS Study was designed to study early antecedents of schizophrenia in a birth cohort of 1959-1967 for whom a wealth of archived prenatal data-including maternal sera-was available, Making use of the registries of a health plan into which the cohort was born, we ascertained and then diagnosed 71 cases of schizophrenia and spectrum disorders in the cohort. We describe herein the available prenatal data, the process of case diagnosis, and the strategies used to analyze prenatal determinants of schizophrenia in this cohort. Data are presented that bear on the main sources of potential bias and are important to understanding the strengths and limitations of this unique data set. C1 Columbia Univ, Joseph L Mailman Sch Publ HLth, Div Epidemiol, New York, NY 10032 USA. Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, Div Epidemiol Brain Disorders, New York, NY 10032 USA. Columbia Univ, Joseph L Mailman Sch Publ HLth, Clin Publ Hlth Biostat, New York, NY 10032 USA. Kaiser Permanente Res Div, Oakland, CA USA. NIMH, Neuropsychiat Branch, Bethesda, MD 20892 USA. RP Susser, ES (reprint author), Columbia Univ, Joseph L Mailman Sch Publ HLth, Div Epidemiol, 600 W 168th St,PH18-119, New York, NY 10032 USA. EM ess8@columbia.edu FU NIMH NIH HHS [1R01MH-53147, 5P20MH-50727, IK20MH 01206] NR 37 TC 68 Z9 68 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PY 2000 VL 26 IS 2 BP 257 EP 273 PG 17 WC Psychiatry SC Psychiatry GA 326YV UT WOS:000087765600003 PM 10885629 ER PT J AU Schaefer, CA Brown, AS Wyatt, RJ Kline, J Begg, MD Bresnahan, MA Susser, ES AF Schaefer, CA Brown, AS Wyatt, RJ Kline, J Begg, MD Bresnahan, MA Susser, ES TI Maternal prepregnant body mass and risk of schizophrenia in adult offspring SO SCHIZOPHRENIA BULLETIN LA English DT Article DE prenatal risk factors; maternal body mass index; birth cohort ID NEURAL-TUBE DEFECTS; OBSTETRIC COMPLICATIONS; WEIGHT-GAIN; DIABETIC MOTHERS; METHYLENETETRAHYDROFOLATE REDUCTASE; CONGENITAL-MALFORMATIONS; UNITED-STATES; OBESE WOMEN; PERINATAL COMPLICATIONS; CESAREAN DELIVERY AB This study examined the relation between maternal prepregnant body mass index (BMI) and development of schizophrenia and schizophrenia spectrum disorders in adult offspring from the Prenatal Determinants of Schizophrenia Study, The study drew on a previously studied cohort of births occurring between 1959 and 1967 to women enrolled in a prepaid health plan. Computerized treatment registries were used to identify possible cases of schizophrenia and spectrum disorders in adult offspring belonging to the health plan from 1981 to 1997, Diagnostic interviews and medical record reviews resulted in diagnosis of 63 cases of schizophrenia and spectrum disorders; these cases and 6,570 unrelated and unaffected cohort members whose mothers also had prepregnancy measures of BMI comprised the sample for analyses. High (greater than or equal to 30.0), compared with average (20.0-26.9), maternal prepregnant BMI (kg/m(2)) was significantly associated with schizophrenia and spectrum disorders in the adult offspring (relative risk [RR] = 2.9; 95% confidence interval [CI] 1.3-6.6), independently of maternal age, parity, race, education, or cigarette smoking during pregnancy. Low (less than or equal to 19.9) maternal BMI was not associated with schizophrenia and spectrum disorders (RR = 1.2; 95% CI 0.64-2.2), Future studies of this cohort will examine factors that may help explain the relationship of high maternal prepregnant BMI with schizophrenia, including nutritional and metabolic factors, toxic exposures, and obstetrical complications. C1 Kaiser Permanente Med Care Program, Div Res, Oakland, CA 94611 USA. Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, New York, NY 10032 USA. NIMH, Neuropsychiat Branch, Bethesda, MD 20892 USA. Columbia Univ, Gertrude H Sergievsky Ctr, New York, NY 10027 USA. Columbia Univ, Joseph J Mailman Sch Publ Hlth, Clin Publ Hlth Biostat, New York, NY 10027 USA. Columbia Univ, Joseph J Mailman Sch Publ Hlth, Div Epidemiol, New York, NY 10027 USA. Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, Div Epidemiol Brain Disorders, New York, NY 10032 USA. RP Schaefer, CA (reprint author), Kaiser Permanente Med Care Program, Div Res, 3505 Broadway, Oakland, CA 94611 USA. EM CAS@dor.kaiser.org FU NIMH NIH HHS [R01-MH-53147] NR 81 TC 48 Z9 48 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PY 2000 VL 26 IS 2 BP 275 EP 286 PG 12 WC Psychiatry SC Psychiatry GA 326YV UT WOS:000087765600004 PM 10885630 ER PT J AU Brown, AS Schaefer, CA Wyatt, RJ Goetz, R Begg, MD Gorman, JM Susser, ES AF Brown, AS Schaefer, CA Wyatt, RJ Goetz, R Begg, MD Gorman, JM Susser, ES TI Maternal exposure to respiratory infections and adult schizophrenia spectrum disorders: A prospective birth cohort study SO SCHIZOPHRENIA BULLETIN LA English DT Article DE birth cohort; prenatal; reproductive outcomes; respiratory; schizophrenia ID NEURAL-TUBE DEFECTS; IN-UTERO EXPOSURE; PRENATAL EXPOSURE; INFLUENZA EPIDEMICS; FOLLOW-UP; DISEASES; COMPLICATIONS; PREGNANCY; CYTOKINES; DELIVERY AB We sought to examine the relationship between maternal exposure to adult respiratory infections and schizophrenia spectrum disorder (SSD) in the Prenatal Determinants of Schizophrenia (PDS) Study, a large birth cohort investigation. Previous work suggests that second trimester exposure to respiratory infection may be a risk factor for SSD. We therefore examined whether this class of infection was associated with adult SSD. For this purpose, we capitalized on several design advantages of the PDS Study, including a comprehensive, prospective data base on physician-diagnosed infections and a continuous followup in which diagnoses of SSD were made, in the majority, by face-to-face interview. Second trimester exposure to respiratory infections was associated with a significantly increased risk of SSD, adjusting for maternal smoking, education, and race (rate ratio [RR] = 2.13 [1.05-4.35], chi(2) = 4.36, df = 1, p = 0.04); no associations were shown for first trimester and third trimester exposure to these respiratory infections. These findings support-and extend-previous studies suggesting that second trimester respiratory infections are risk factors for SSD. This study therefore has implications toward uncovering the etiology of schizophrenia and developing preventive strategies. C1 Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, New York, NY 10032 USA. Kaiser Permanente Med Care Program, Div Res, Oakland, CA 94611 USA. NIMH, Neuropsychiat Branch, Bethesda, MD 20892 USA. Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, Dept Psychiat, New York, NY 10032 USA. Columbia Univ, Joseph L Mailman Sch Publ Hlth, Clin Publ Hlth Biostat, New York, NY USA. Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, Chair Res, New York, NY 10032 USA. Columbia Univ, Joseph L Mailman Sch Publ Hlth, Div Epidemiol, New York, NY 10027 USA. Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, Div Epidemiol Brain Disorders, New York, NY 10032 USA. RP Brown, AS (reprint author), Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, 1051 Riverside Dr,Unit 2, New York, NY 10032 USA. FU NIMH NIH HHS [5P20MH-50727, 1-R01MH-53147, 1K20MH-01206] NR 40 TC 145 Z9 150 U1 4 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PY 2000 VL 26 IS 2 BP 287 EP 295 PG 9 WC Psychiatry SC Psychiatry GA 326YV UT WOS:000087765600005 PM 10885631 ER PT J AU Bresnahan, MA Brown, AS Schaefer, CA Begg, MD Wyatt, RJ Susser, ES AF Bresnahan, MA Brown, AS Schaefer, CA Begg, MD Wyatt, RJ Susser, ES TI Incidence and cumulative risk of treated schizophrenia in the prenatal determinants of schizophrenia study SO SCHIZOPHRENIA BULLETIN LA English DT Article DE schizophrenia; incidence; cumulative risk ID BIRTH COHORT; GENDER DIFFERENCES; AGE AB The present study uses data from the Prenatal Determinants of Schizophrenia (PDS) Study to derive age- and sex-specific estimates of incidence and cumulative risk for DSM-IV schizophrenia. Although not designed as an incidence study, the PDS Study uses both a well-defined population under continuous followup and DSM-IV diagnoses, The originating cohort mas established in Alameda County, California, during 1959-1967 and yielded 12,094 cohort members followed from 1981 to 1997 during the principal ages at risk for schizophrenia. Survival analytic techniques showed that schizophrenia incidence rates per 10,000 person-gears for men mere 9.4 for ages 15-19; 5.6 for ages 20-24; 3.3 for ages 25-29; and 0.9 for ages 30-34, Schizophrenia incidence rates per 10,000 person-years for women mere 1.6 for ages 15-19; 1.3 for ages 20-24; and 4.1 for ages 25-29, The cumulative risk for schizophrenia by age 38 mas 0.93 percent for men and 0.35 percent for women. These estimates of incidence rates and risk mere higher than those in traditional incidence studies but similar to recent findings in other cohorts. Possible explanations for the apparently high rates of disorder include chance, design effects, and true variation in risk over time and place. C1 Columbia Univ, Joseph L Mailman Sch Publ Hlth, Div Epidemiol, New York, NY 10032 USA. Kaiser Permanente Med Care Program, Div Res, Oakland, CA 94611 USA. Columbia Univ, Joseph L Mailman Sch Publ Hlth, Clin Publ Hlth, New York, NY 10027 USA. NIMH, Neuropsychiat Branch, Bethesda, MD 20892 USA. Columbia Univ, Joseph L Mailman Sch Publ Hlth, Div Epidemiol, New York, NY 10027 USA. Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, Div Epidemiol Brain Disorders, New York, NY 10032 USA. RP Bresnahan, MA (reprint author), Columbia Univ, Joseph L Mailman Sch Publ Hlth, Div Epidemiol, 600 W 168th St,PH18-302, New York, NY 10032 USA. FU NIMH NIH HHS [5P20MH-50727, 1R01MH-53147, IK20MH-01206] NR 33 TC 23 Z9 23 U1 1 U2 4 PU US GOVERNMENT PRINTING OFFICE PI WASHINGTON PA SUPERINTENDENT DOCUMENTS,, WASHINGTON, DC 20402-9325 USA SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PY 2000 VL 26 IS 2 BP 297 EP 308 PG 12 WC Psychiatry SC Psychiatry GA 326YV UT WOS:000087765600006 PM 10885632 ER PT J AU Campbell, T AF Campbell, T TI First person account: Falling on the pavement SO SCHIZOPHRENIA BULLETIN LA English DT Article AB The article that follows is part of the Schizophrenia Bulletin's ongoing First Person Account series, We hope that mental health professionals-the Bulletin's primary audience-will take this opportunity to learn about the issues and difficulties confronted by consumers of mental health care. In addition, we hope that these accounts will give patients and families a better sense of not being alone in confronting the problems that can be anticipated by persons with serious emotional difficulties. We welcome other contributions from patients, ex-patients, or family members. Our major editorial requirement is that such contributions be clearly written and organized, and that a novel or unique aspect of schizophrenia be described, with special emphasis on points that will be important for professionals. Clinicians who see articulate patients with experiences they believe should be shared might encourage these patients to submit their articles to Schizophrenia Bulletin, First Person Accounts, EEI Communications, 66 Canal Center Plaza, Suite 200. C1 NIMH, Schizophrenia Bulletin, Bethesda, MD 20892 USA. RP Campbell, T (reprint author), NIMH, Schizophrenia Bulletin, 6001 Execut Blvd,Rm 8184, Bethesda, MD 20892 USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU US GOVERNMENT PRINTING OFFICE PI WASHINGTON PA SUPERINTENDENT DOCUMENTS,, WASHINGTON, DC 20402-9325 USA SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PY 2000 VL 26 IS 2 BP 507 EP 509 PG 3 WC Psychiatry SC Psychiatry GA 326YV UT WOS:000087765600021 PM 10885647 ER PT J AU Lebowitz, BD Pearson, JL AF Lebowitz, BD Pearson, JL TI Intervention research in psychosis: Prevention trials SO SCHIZOPHRENIA BULLETIN LA English DT Article DE mental disorders; prevention; treatment; rehabilitation; geriatrics ID TARDIVE-DYSKINESIA; ALZHEIMER-DISEASE; VITAMIN-E; SCHIZOPHRENIA; DISORDERS; FAMILY; RISK AB Prevention trials have not been a central focus in mental health research in general and in the psychoses in particular. In this article we provide the basis for development of a model for prevention trials, define the parameters of the model, and provide some illustrative examples. The article expands upon traditional approaches to prevention by incorporating perspectives from the fields of treatment and services research. Approaches to prevention are based upon models of etiology, pathophysiology, and risk. A number of barriers to the development of a major emphasis on prevention are identified, and those that are embedded in the infrastructure of the field are highlighted. C1 NIMH, Adult & Geriatr Treatment & Prevent Intervent Res, Bethesda, MD 20892 USA. NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. RP Lebowitz, BD (reprint author), NIMH, Adult & Geriatr Treatment & Prevent Intervent Res, 6001 Execut Blvd,Rm 7160,MSC 9635, Bethesda, MD 20892 USA. NR 23 TC 7 Z9 7 U1 0 U2 0 PU US GOVERNMENT PRINTING OFFICE PI WASHINGTON PA SUPERINTENDENT DOCUMENTS,, WASHINGTON, DC 20402-9325 USA SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PY 2000 VL 26 IS 3 BP 543 EP 549 PG 7 WC Psychiatry SC Psychiatry GA 350JT UT WOS:000089098100006 PM 10993395 ER PT J AU Mirsky, AF Bieliauskas, LA French, LM Van Kammen, DP Jonsson, E Sedvall, G AF Mirsky, AF Bieliauskas, LA French, LM Van Kammen, DP Jonsson, E Sedvall, G TI A 39-year followup of the Genain quadruplets SO SCHIZOPHRENIA BULLETIN LA English DT Article DE schizophrenia; neuropsychology; multiple births; aging ID SCHIZOPHRENIC-PATIENTS; ABNORMALITIES; PERFORMANCE; ATTENTION AB The Genains, a unique group of monozygotic female quadruplets, all developed a schizophrenic disorder by age 24, They have been studied since the 1950s, because of the rarity of this occurrence (estimated to be one in 1.5 billion) and because their illnesses varied in severity, The identical inheritance would tend to rule out genetic differences as the cause of the neuropsychological differences; however, we cannot disentangle the effects of early brain injury and harsh punitive treatment as factors accounting for the differences in the severity of their disorders. We conducted neuropsychological examinations of the Genains at age 66, compared their test profiles, and contrasted certain test scores at 66 with those at ages 27 and 51, Test results indicate generally stable (or even improved) performance over time and support the notion that cognitive decline is not a degenerative process in schizophrenia. The Genains remind us of the exquisite interaction among variables that must be understood before additional, satisfactory progress can be made in preventing the development and predicting the course of schizophrenia. C1 NIMH, Lab Brain & Cognit, Sect Clin & Expt Neuropsychol, Bethesda, MD 20892 USA. Univ Michigan, Hosp Med, Dept Psychiat, Neuropsychol Program, Ann Arbor, MI 48109 USA. RWJ Pharmaceut Res Inst, Raritan, NJ USA. Karolinska Hosp, Psychiat Sect, Dept Clin Neurosci, S-10401 Stockholm, Sweden. RP Mirsky, AF (reprint author), NIMH, Lab Brain & Cognit, Sect Clin & Expt Neuropsychol, Bldg 15K,MSC 2668,15 N Dr, Bethesda, MD 20892 USA. NR 36 TC 3 Z9 6 U1 0 U2 6 PU US GOVERNMENT PRINTING OFFICE PI WASHINGTON PA SUPERINTENDENT DOCUMENTS,, WASHINGTON, DC 20402-9325 USA SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PY 2000 VL 26 IS 3 BP 699 EP 708 PG 10 WC Psychiatry SC Psychiatry GA 350JT UT WOS:000089098100018 PM 10993407 ER PT J AU Chovil, I AF Chovil, I TI First person account: I and I, dancing fool, challenge you the world to a duel SO SCHIZOPHRENIA BULLETIN LA English DT Article AB The article that follows is part of the Schizophrenia Bulletin's ongoing First Person Account series. We hope that mental health professionals-the Bulletin's primary audience-will take this opportunity to learn about the issues and difficulties confronted by consumers of mental health care. In addition, we hope that these accounts will give patients and families a better sense of not being alone in confronting the problems that can be anticipated by persons with serious emotional difficulties. We welcome other contributions from patients, ex-patients, or family members. Our major editorial requirement is that such contributions be clearly written and organized, and that a novel or unique aspect of schizophrenia be described, with special emphasis on points that will be important for professionals. Clinicians who see articulate patients with experiences they believe should be shared might encourage these patients to submit their articles to Schizophrenia Bulletin, First Person Accounts, EEI Communications, 66 Canal Center Plaza, Suite 200, Alexandria, VA 22314.-The Editors. C1 NIMH, Bethesda, MD 20892 USA. RP Chovil, I (reprint author), NIMH, 6001 Execut Blvd,Rm 8184,MSC 9663, Bethesda, MD 20892 USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU US GOVERNMENT PRINTING OFFICE PI WASHINGTON PA SUPERINTENDENT DOCUMENTS,, WASHINGTON, DC 20402-9325 USA SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PY 2000 VL 26 IS 3 BP 745 EP 747 PG 3 WC Psychiatry SC Psychiatry GA 350JT UT WOS:000089098100022 PM 10993411 ER PT J AU Aldridge, SL AF Aldridge, SL TI First person account: How the first wave of deinstitutionalization saved my mother from the "snake pit" SO SCHIZOPHRENIA BULLETIN LA English DT Article AB The article that follows is part of the Schizophrenia Bulletin's ongoing First Person Account series, We hope that mental health professionals-the Bulletin's primary audience-will take this opportunity to learn about the issues and difficulties confronted by consumers of mental health care. In addition, we hope that these accounts will give patients and families a better sense of not being alone in confronting the problems that can be anticipated by persons with serious emotional difficulties. We welcome other contributions from patients, ex-patients, or family members, Our major editorial requirement is that such contributions be clearly written and organized, and that a novel or unique aspect of schizophrenia be described, with special emphasis on points that will be important for professionals. Clinicians who see articulate patients with experiences they believe should be shared might encourage these patients to submit their articles to Schizophrenia Bulletin, First Person Accounts, EEI Communications, 66 Canal Center Plaza, Suite 200, Alexandria, VA 22314.-The Editors. C1 NIMH, Schizophrenia Bulletin, Bethesda, MD 20892 USA. RP Aldridge, SL (reprint author), NIMH, Schizophrenia Bulletin, 6001 Execut Blvd,Rm 8184,MSC 9663, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU US GOVERNMENT PRINTING OFFICE PI WASHINGTON PA SUPERINTENDENT DOCUMENTS,, WASHINGTON, DC 20402-9325 USA SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PY 2000 VL 26 IS 4 BP 933 EP 938 PG 6 WC Psychiatry SC Psychiatry GA 376UD UT WOS:000165474400016 PM 11087025 ER PT B AU Baldwin, W AF Baldwin, W BE Stone, AA Turkkan, JS Bachrach, CA Jobe, JB Kurtzman, HS Cain, VS TI Information no one else knows: The value of self-report SO SCIENCE OF SELF-REPORT: IMPLICATIONS FOR RESEARCH AND PRACTICE LA English DT Proceedings Paper CT Conference on the Science of Self-Report - Implications for Research and Practice CY NOV 07, 1996-NOV 08, 1997 CL NIH, BETHESDA, MD SP Off Behav & Social Sci Res HO NIH C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 24 Z9 24 U1 1 U2 2 PU LAWRENCE ERLBAUM ASSOC PUBL PI MAHWAH PA 10 INDUSTRIAL AVE, MAHWAH, NJ 07430 USA BN 0-8058-2990-3 PY 2000 BP 3 EP 7 PG 5 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychology; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychology; Biomedical Social Sciences GA BN85K UT WOS:000083193900001 ER PT J AU Young, NS AF Young, NS TI Hematopoietic cell destruction by immune mechanisms in acquired aplastic anemia SO SEMINARS IN HEMATOLOGY LA English DT Article ID BONE-MARROW TRANSPLANTATION; PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; NECROSIS-FACTOR-ALPHA; T-CELLS; INTERFERON-GAMMA; PROGENITOR CELLS; MYELODYSPLASTIC SYNDROME; PERIPHERAL-BLOOD; STEM-CELLS; IMMUNOSUPPRESSIVE THERAPY C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Young, NS (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Room 7C103, Bethesda, MD 20892 USA. NR 92 TC 91 Z9 115 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD JAN PY 2000 VL 37 IS 1 BP 3 EP 14 DI 10.1016/S0037-1963(00)90026-X PG 12 WC Hematology SC Hematology GA 282JP UT WOS:000085215100003 PM 10676907 ER PT J AU Barrett, J Saunthararajah, Y Molldrem, J AF Barrett, J Saunthararajah, Y Molldrem, J TI Myelodysplastic syndrome and aplastic anemia: Distinct entities or diseases linked by a common pathophysiology? SO SEMINARS IN HEMATOLOGY LA English DT Article ID PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; COLONY-STIMULATING FACTOR; HEMATOPOIETIC PROGENITOR CELLS; NECROSIS-FACTOR-ALPHA; LOW-DOSE CYCLOSPORINE; BONE-MARROW FAILURE; PERIPHERAL-BLOOD; ANTITHYMOCYTE GLOBULIN; ANTILYMPHOCYTE GLOBULIN; CLONAL HEMATOPOIESIS C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Bone Marrow Transplant Unit, Houston, TX 77030 USA. RP Barrett, J (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 96 TC 124 Z9 133 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD JAN PY 2000 VL 37 IS 1 BP 15 EP 29 PG 15 WC Hematology SC Hematology GA 282JP UT WOS:000085215100004 PM 10676908 ER PT J AU Frickhofen, N Rosenfeld, SJ AF Frickhofen, N Rosenfeld, SJ TI Immunosuppressive treatment of aplastic anemia with antithymocyte globulin and cyclosporine SO SEMINARS IN HEMATOLOGY LA English DT Article ID BONE-MARROW TRANSPLANTATION; SAA WORKING PARTY; PROSPECTIVE RANDOMIZED TRIAL; COLONY-STIMULATING FACTOR; ANTILYMPHOCYTE GLOBULIN; THYMOCYTE GLOBULIN; LYMPHOCYTE GLOBULIN; THERAPY; METHYLPREDNISOLONE; ANDROGENS C1 Dr Horst Schmidt Kliniken GmbH, Dept Med Hematol Oncol 3, D-65199 Wiesbaden, Germany. NHLBI, Hematol Branch, Bethesda, MD 20892 USA. RP Frickhofen, N (reprint author), Dr Horst Schmidt Kliniken GmbH, Dept Med Hematol Oncol 3, D-65199 Wiesbaden, Germany. NR 58 TC 76 Z9 87 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD JAN PY 2000 VL 37 IS 1 BP 56 EP 68 DI 10.1016/S0037-1963(00)90030-1 PG 13 WC Hematology SC Hematology GA 282JP UT WOS:000085215100007 PM 10676911 ER PT J AU Tisdale, JF Dunn, DE Maciejewski, J AF Tisdale, JF Dunn, DE Maciejewski, J TI Cyclophosphamide and other new agents for the treatment of severe aplastic anemia SO SEMINARS IN HEMATOLOGY LA English DT Article ID BONE-MARROW TRANSPLANTATION; HIGH-DOSE CYCLOPHOSPHAMIDE; POLYCLONAL ANTITHYMOCYTE GLOBULIN; MULTIPLE-SCLEROSIS PATIENTS; IGE ANTIBODY-RESPONSES; NECROSIS-FACTOR-ALPHA; SAA WORKING PARTY; RANDOMIZED TRIAL; THYMOCYTE GLOBULIN; INTERFERON-GAMMA C1 NIDDKD, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. Univ Utah, Div Hematol, Salt Lake City, UT USA. RP Tisdale, JF (reprint author), NIDDKD, Mol & Clin Hematol Branch, NIH, Bldg 10,Room 9N116,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 79 TC 17 Z9 19 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD JAN PY 2000 VL 37 IS 1 BP 102 EP 109 DI 10.1016/S0037-1963(00)90034-9 PG 8 WC Hematology SC Hematology GA 282JP UT WOS:000085215100011 PM 10676915 ER PT J AU Alter, HJ Seeff, LB AF Alter, HJ Seeff, LB TI Recovery, persistence, and sequelae in hepatitis C virus infection: A perspective on long-term outcome SO SEMINARS IN LIVER DISEASE LA English DT Review DE HCV; chronic hepatitis; fibrosis; cirrhosis ID NON-B-HEPATITIS; POST-TRANSFUSION HEPATITIS; HEPATOCELLULAR-CARCINOMA; NON-A; UNITED-STATES; FOLLOW-UP; NATURAL-HISTORY; LIVER-DISEASE; POSTTRANSFUSION HEPATITIS; NEUTRALIZING ANTIBODIES AB Hepatitis C has emerged in recent years as the most common basis for liver disease in the United States, having infected an estimated 3.9 million people in this country and an estimated 170 million worldwide. Currently, it is the predominant reason for undergoing liver transplantation. The disease it causes is characterized by silent onset in most infected individuals, a high rate of viral persistence, and the potential for development of ever-worsening chronic liver disease, ranging from chronic hepatitis to cirrhosis and occasionally to hepatocellular carcinoma. Such progression, when it occurs, is also most commonly a silent process that may take 20-40, and occasionally even more, years to reach its endpoint. Because of these characteristics, it has been exceedingly difficult to accurately assess the natural history. Efforts to accomplish this have consisted of retrospective, prospective, and cohort studies. The most concerning data have derived from the retrospective study approach, generally performed at tertiary referral centers. Because these centers commonly attract persons with existing chronic liver disease, they have tended to describe a high rate of progression to cirrhosis and cancer This "referral bias" is avoided in the prospective and cohort study approach, and data derived from these studies indicate a lower rate of progression and a correspondingly higher rate of either recovery or minimal liver disease. In this review, we briefly describe potential mechanisms of viral persistence; present detailed information on outcomes that have derived from retrospective, prospective, and cohort studies, involving both adults and children; examine the data regarding progression of fibrosis and of progression to hepatocellular carcinoma; consider cofactors that might enhance liver disease progression; and report the emerging data that suggest that spontaneous viral clearance may be higher than is currently believed. We conclude with the view that severe, life-threatening, progressive liver disease clearly occurs in a sizable minority (perhaps 30%) of chronically infected persons but speculate that fibrosis progression is neither linear or inevitable and hence that most hepatitis C virus carriers will have either a stable nonprogressive course or such indolent progression that they will die from an unrelated disease before the severe sequelae of hepatitis C become manifest or will have a sustained "curative" response to therapy. Although this view provides reasonable hope to the hepatitis C virus-infected individual, it does not deny the enormous burden this infection presents as the result of its high prevalence and global distribution. The sheer magnitude of the infected population will result in a large number with severe life-threatening liver disease even if the proportion of inferred individuals that develop progressive disease is relatively small. C1 NIDDK, Dept Transfus Med, Warren Grant Magnuson Clin Ctr, NIH, Bethesda, MD 20894 USA. NIDDK, Sect Digest Dis & Nutr, NIH, Bethesda, MD 20894 USA. RP Alter, HJ (reprint author), NIDDK, Dept Transfus Med, Warren Grant Magnuson Clin Ctr, NIH, Bldg 10,Rm 1C-711,10 Ctr Dr,MSC 1184, Bethesda, MD 20894 USA. NR 80 TC 511 Z9 539 U1 4 U2 24 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0272-8087 J9 SEMIN LIVER DIS JI Semin. Liver Dis. PY 2000 VL 20 IS 1 BP 17 EP 35 DI 10.1055/s-2000-9505 PG 19 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 330WL UT WOS:000087984100004 PM 10895429 ER PT J AU Farci, P Purcell, RH AF Farci, P Purcell, RH TI Clinical significance of hepatitis C virus genotypes and quasispecies SO SEMINARS IN LIVER DISEASE LA English DT Review DE hepatitis C virus; generic variability; genotypes; quasispecies; clinical implications ID BLOOD MONONUCLEAR-CELLS; CHRONIC LIVER-DISEASE; QUASI-SPECIES HETEROGENEITY; INTERFERON-ALPHA THERAPY; NON-B-HEPATITIS; SENSITIVITY-DETERMINING REGION; HUMAN-IMMUNODEFICIENCY-VIRUS; ENVELOPE GLYCOPROTEIN GP70; T-LYMPHOCYTE RESPONSE; MAJOR GENETIC GROUPS AB Hepatitis C virus (HCV) is a major cause of morbidity and mortality worldwide, The infection becomes chronic in about 85% of infected individuals, in the face of a strong humoral and cellular immune response. One of the most important features of HCV is its high degree of genetic variability, which is due to the inherent low-fidelity of the viral replication machinery As a consequence, HCV circulates in vivo as a population of divergent, albeit closely related genomes exhibiting a distribution that follows the model referred To as a quasispecies. The generic variability of HCV is complex and has been classified into four hierarchical strata: genotypes, subgenotypes, isolates, and quasispecies. Over the past few years, an extraordinary interest has been focused on the biologic and clinical implications of the genetic variability of HCV. Although there is consensus that the genotypes may influence the out come of antiviral therapy their clinical significance in the natural history of the disease, as well as in transmission, infectivity, and pathogenesis of HCV infection, remains elusive. Conversely, evidence has accumulated that the quasispecies nature of HCV provides a large reservoir of biologically different viral variants that may have important clinical implications for viral persistence by immune escape mechanisms, for the generation of antiviral drug resistance, and for the development of an effective vaccine, This article reviews the state of the art on the biologic and clinical implications of the genetic variability of HCV. C1 Univ Cagliari, Dept Med Sci, I-09124 Cagliari, Italy. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Farci, P (reprint author), Univ Cagliari, Dept Med Sci, Via S Giorgio 12, I-09124 Cagliari, Italy. NR 237 TC 143 Z9 156 U1 2 U2 8 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0272-8087 J9 SEMIN LIVER DIS JI Semin. Liver Dis. PY 2000 VL 20 IS 1 BP 103 EP 126 PG 24 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 330WL UT WOS:000087984100010 PM 10895435 ER PT J AU Rehermann, B AF Rehermann, B TI Interaction between the hepatitis C virus and the immune system SO SEMINARS IN LIVER DISEASE LA English DT Review DE liver; hepatitis C; T cell; cytotoxic; immune response ID CD8(+) T-CELLS; PKR PROTEIN-KINASE; INFECTIOUS MOLECULAR CLONE; LYMPHOTOXIN-BETA RECEPTOR; NONSTRUCTURAL 5A PROTEIN; INTERFERON-ALPHA THERAPY; BLOOD MONONUCLEAR-CELLS; NON-B HEPATITIS; CORE PROTEIN; HYPERVARIABLE REGION-1 AB The hepatitis C virus (HCV) causes a wide spectrum of liver diseases ranging from symptomatic of asymptomatic acute infection with self-limited disease to persistent infection with chronic active hepatitis and an increased risk of liver cirrhosis and hepatocellular carcinoma. The outcome of HCV infection (i.e., viral clearance or persistence) and the manifestation and degree of liver disease is the result of complicated interactions between the virus and the immune response of the host. Remarkably, most de novo HCV infections are clinically inapparent and characterized by a high incidence (70%) of chronically evolving hepatitis, which suggests that HCV may have evolved strategies to not induce, overcome, or evade efficient immune responses of the host. This may be a multifactorial process, influenced by viral tissue tropism, replication, sequence variation and by functional alteration of infected cells. The interaction between HCV and the specific humoral and cellular immune response of the host, the role of the liver as the primary site of viral replication, the target of the host's immune response, and potential mechanisms of viral escape are discussed. C1 NIDDK, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. RP Rehermann, B (reprint author), NIDDK, Liver Dis Sect, NIH, Bldg 10,Room 9B16,10 Ctr Dr, Bethesda, MD 20892 USA. NR 187 TC 106 Z9 111 U1 2 U2 3 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0272-8087 J9 SEMIN LIVER DIS JI Semin. Liver Dis. PY 2000 VL 20 IS 2 BP 127 EP 141 DI 10.1055/s-2000-9946 PG 15 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 342FR UT WOS:000088635000001 PM 10946419 ER PT J AU Lechmann, M Liang, TJ AF Lechmann, M Liang, TJ TI Vaccine development for hepatitis C SO SEMINARS IN LIVER DISEASE LA English DT Review DE recombinant subunit vaccine; immune response; cytotoxic T cell; T helper cell; antibody; protective immunity ID VIRUS-LIKE PARTICLES; CYTOTOXIC T-LYMPHOCYTES; DNA-BASED IMMUNIZATION; CELLULAR IMMUNE-RESPONSES; ENVELOPE E2 PROTEIN; BORNE ENCEPHALITIS-VIRUS; STIMULATING FACTOR GENE; EXPRESSING CD40 LIGAND; HIGH-LEVEL EXPRESSION; HYPERVARIABLE REGION-1 AB Given the global disease burden and public health impact of hepatitis C, the development of an effective vaccine is of paramount importance. However, many challenging obstacles loom ahead of this goal. The hepatitis C virus (HCV), being an RNA virus, can mutate rapidly in adaptation to the environment, thus contributing to the high sequence divergence of multiple viral isolates in the world. The highest heterogeneity has been found in the hypervariable region of the envelope glycoprotein 2, which contains a principal neutralization epitope. HCV also causes persistent infection in a high percentage of immunocompetent hosts despite active immune response. The lack of an efficient tissue culture system for propagating HCV and testing neutralizing antibodies adds further complexity to the task of vaccine development. The immunologic correlates associated with disease progression or protection are yet to be defined, but recent studies suggest that a vigorous multispecific cellular immune response is important in the resolution of infection. Induction of high-titer, long-lasting, and cross-reactive antienvelope antibodies and a vigorous multispecific cellular immune response that includes both helper and cytotoxic T lymphocytes may be necessary for an effective vaccine. Several promising approaches have been used to develop an HCV vaccine. Novel vaccine candidates based on molecular technology such as recombinant proteins, peptides, viruslike particles, naked DNA, and recombinant viruses are being explored. The final vaccine product may require multiple components that target various aspects of protective immunity. Finally, sterilizing immunity may not be necessary if a vaccine can be developed to prevent chronic infection, which is the major cause of morbidity and mortality from this disease. C1 NIDDK, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. RP Liang, TJ (reprint author), NIDDK, Liver Dis Sect, NIH, 10 Ctr Dr,Rm 9B16, Bethesda, MD 20892 USA. NR 125 TC 56 Z9 58 U1 0 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0272-8087 J9 SEMIN LIVER DIS JI Semin. Liver Dis. PY 2000 VL 20 IS 2 BP 211 EP 226 DI 10.1055/s-2000-9947 PG 16 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 342FR UT WOS:000088635000007 PM 10946425 ER PT J AU Balow, JE Boumpas, DT Austin, HA AF Balow, JE Boumpas, DT Austin, HA TI New prospects for treatment of lupus nephritis SO SEMINARS IN NEPHROLOGY LA English DT Review ID STEM-CELL TRANSPLANTATION; AUTOIMMUNE-DISEASE; MURINE LUPUS; MYCOPHENOLATE MOFETIL; CONTROLLED TRIAL; T-CELLS; CYCLOPHOSPHAMIDE THERAPY; PULSE CYCLOPHOSPHAMIDE; GLOMERULAR-DISEASE; CD40 LIGAND C1 NIH, Bethesda, MD 20892 USA. RP Balow, JE (reprint author), NIH, Bldg 10,Rm 9N-222, Bethesda, MD 20892 USA. NR 81 TC 17 Z9 19 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9295 J9 SEMIN NEPHROL JI Semin. Nephrol. PD JAN PY 2000 VL 20 IS 1 BP 32 EP 39 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 275AM UT WOS:000084797300004 PM 10651216 ER PT B AU Motta, L Molina, F Santi, L AF Motta, L Molina, F Santi, L BE Moller, DPF TI SOS - an Oncology site through the third millenium SO SIMULATION IN INDUSTRY'2000 LA English DT Proceedings Paper CT 12th European Simulation Symposium (ESS 2000) CY SEP 28-30, 2000 CL UNIV HAMBURG, HAMBURG, GERMANY SP Soc Comp Simulat Int, ASIM, Arbeitsgemeinsch Simulat, Chinese Assoc Syst Simulat, Czech & Slovak Simulat Soc, Federat European Simulat Soc, Hungarian Simulat Soc, Japan Soc Simulat Technol, Latvian Simulat Soc, Turkish Simulat Soc HO UNIV HAMBURG DE HTML; oncology; telemedicine; telepathology; teleconsulting; web-based ID INTERNET; INFORMATION; WORLD; GUIDE AB The SOS Server owes its name to the telematics service originally created in 1994 to assist the European cancer research community, the Sustaining Oncology Studies Europe Information Resource - SOS Europe. Since then, the scope of services offered by SOS has evolved, reaching the point that, as with the multifaceted discipline of oncology itself, it has now developed into clearinghouse of valuable information for bench researchers, clinicians, nurses, welfare workers and administrative personnel, be they strictly dedicated to oncology or related biomedical disciplines. The SOS Server is structured into two distinct, yet complementary and interlaced, sites: SOS Europe which, as mentioned, aims to fullfil cancer information retrieval needs on a global scale, and its "sister" site, SOS Italia which, although mirroring to a great extent its counterpart, is more than a mere translation of SOS Europe. Indeed, SOS Italia - in concert with the Network of Italian Comprehensive Cancer Centers is currently pending evaluation by the Italian Ministry of Health for formal recognition as FOCAL POINT for the coordination of WWW-based information and services of relevance to the Italian cancer research community. C1 Natl Canc Inst, Telemat & Bioinformat Module, I-16132 Genoa, Italy. RP Motta, L (reprint author), Natl Canc Inst, Telemat & Bioinformat Module, Largo Rosanna Benzi 10, I-16132 Genoa, Italy. NR 17 TC 0 Z9 0 U1 0 U2 0 PU SOC COMPUTER SIMULATION PI SAN DIEGO PA PO BOX 17900, SAN DIEGO, CA 92177 USA BN 1-56555-190-7 PY 2000 BP 682 EP 685 PG 4 WC Computer Science, Interdisciplinary Applications; Computer Science, Software Engineering; Operations Research & Management Science SC Computer Science; Operations Research & Management Science GA BQ96P UT WOS:000165164100115 ER PT J AU Dadachova, E AF Dadachova, E TI Spectroscopic determination of chelator content in antibody-chelator conjugates - UV/Vis, fluorescence, and MALDI-TOF MS studies SO SPECTROSCOPY LA English DT Article ID MONOCLONAL-ANTIBODIES; TUMOR; LOCALIZATION; STABILITY; PROTEINS; AGENTS; DTPA; RADIOPHARMACEUTICALS; RADIOIMMUNOTHERAPY; BIODISTRIBUTION AB The increasing use of monoclonal antibody-bifunctional chelator conjugates in clinical practice has created the need for quality control procedures providing relatively simple and reliable determination of the chelator-to-protein (C/P) ratio. Spectroscopic methods offer a valuable alternative to the use of radioactive isotopes for this purpose. This article discusses the application of UV/Vis spectrophotometry, fluorescence spectroscopy, and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) for the quality control of MAb-chelator conjugates. C1 NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Dadachova, E (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RI Dadachova, Ekaterina/I-7838-2013 NR 39 TC 1 Z9 1 U1 0 U2 3 PU ADVANSTAR COMMUNICATIONS PI DULUTH PA 131 W FIRST ST, DULUTH, MN 55802 USA SN 0887-6703 J9 SPECTROSCOPY JI Spectroscopy PD JAN PY 2000 VL 15 IS 1 BP 26 EP + PG 6 WC Spectroscopy SC Spectroscopy GA 305BY UT WOS:000086520000002 ER PT J AU Liu, B Hannun, YA AF Liu, B Hannun, YA TI Purification of rat brain membrane neutral sphingomyelinase SO SPHINGOLIPID METABOLISM AND CELL SIGNALING, PT A SE METHODS IN ENZYMOLOGY LA English DT Review ID CERAMIDE C1 NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Liu, B (reprint author), NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, POB 12233, Res Triangle Pk, NC 27709 USA. NR 5 TC 11 Z9 11 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2000 VL 311 BP 156 EP 164 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BP55U UT WOS:000085491100017 PM 10563320 ER PT J AU Liu, B Hannun, YA AF Liu, B Hannun, YA TI Sphingomyelinase assay using radiolabeled substrate SO SPHINGOLIPID METABOLISM AND CELL SIGNALING, PT A SE METHODS IN ENZYMOLOGY LA English DT Review ID NEUTRAL SPHINGOMYELINASE; PURIFICATION; CERAMIDE; SIGNAL C1 NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Liu, B (reprint author), NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, POB 12233, Res Triangle Pk, NC 27709 USA. NR 9 TC 36 Z9 36 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2000 VL 311 BP 164 EP 167 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BP55U UT WOS:000085491100018 PM 10563321 ER PT J AU Edsall, L Vann, L Milstien, S Spiegel, S AF Edsall, L Vann, L Milstien, S Spiegel, S TI Enzymatic method for measurement of sphingosine 1-phosphate SO SPHINGOLIPID METABOLISM AND CELL SIGNALING, PT B SE METHODS IN ENZYMOLOGY LA English DT Review ID RADIOACTIVE ACETIC-ANHYDRIDE; PROGRAMMED CELL-DEATH; NEURITE RETRACTION; SURFACE-RECEPTOR; CALCIUM MOBILIZATION; EXTRACELLULAR ACTION; SIGNAL-TRANSDUCTION; CULTURED-CELLS; SPHINGOSINE-1-PHOSPHATE; KINASE C1 NIMH, Lab Mol & Cellular Regulat, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20007 USA. RP Edsall, L (reprint author), NIMH, Lab Mol & Cellular Regulat, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA61774]; NIGMS NIH HHS [GM43880] NR 38 TC 13 Z9 13 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2000 VL 312 BP 9 EP 16 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BR44K UT WOS:000166426900002 PM 11070858 ER PT J AU Mackall, CL AF Mackall, CL TI T-cell immunodeficiency following cytotoxic antineoplastic therapy: A review (Reprinted from The Oncologist, vol 4, pg 370-378, 1999) SO STEM CELLS LA English DT Reprint DE immunodeficiency; thymus; T cells; immune reconstitution ID BONE-MARROW TRANSPLANTATION; PNEUMOCYSTIS-CARINII PNEUMONIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; SIMPLEX VIRUS-INFECTION; INTENSIVE CHEMOTHERAPY; ACYCLOVIR PROPHYLAXIS; LYMPHOCYTE SUBSETS; DOUBLE-BLIND; CANCER; REGENERATION AB Although cancer itself is immunosuppressive, cytotoxic antineoplastic therapy is the primary contributor to the clinical immunodeficiency observed in cancer patients. The immunodeficiency induced by cytotoxic antineoplastic therapy is primarily related to T-cell depletion, with CD4 depletion generally more severe than CD8 depletion, Myeloablative therapy, dose-intensive alkylating agents, purine nucleoside analogs, and corticosteroids substantially increase the risk of therapy-induced immunosuppression, Restoration of T-cell populations following cytotoxic antineoplastic therapy is a complex process. Efficient recovery of CD4(+) T cell populations requires thymic-dependent pathways which undergo an age-dependent decline resulting in prolonged CD4 T-cell depletion in adults following T-cell-depleting therapy. Total CD8(+) T-cell numbers recover in both children and adults relatively quickly post-therapy; however, CD8(+) subset disruptions often remain for a prolonged period. The clinical management of patients with therapy-induced T-cell depletion involves the maintenance of a high index of suspicion for opportunistic pathogens, irradiation of blood products, prophylaxis for viral infections, and reimmunization in selected clinical circumstances. Future research avenues include efforts to rapidly rebuild immunity following cytotoxic antineoplastic therapy so that immune-based therapies may be utilized immediately following cytotoxic therapy to target minimal residual neoplastic disease. C1 NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Mackall, CL (reprint author), NCI, Pediat Oncol Branch, Bldg 10,Rm 13N240,10 Ctr Dr,MSC 1928, Bethesda, MD 20892 USA. NR 70 TC 113 Z9 119 U1 1 U2 3 PU ALPHAMED PRESS PI MIAMISBURG PA ONE PRESTIGE PLACE, STE 290, MIAMISBURG, OH 45342-3758 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PY 2000 VL 18 IS 1 BP 10 EP 18 DI 10.1634/stemcells.18-1-10 PG 9 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 278PL UT WOS:000084998100002 PM 10661568 ER PT J AU Schwartz, GN Kammula, U Warren, MK Park, MK Yan, XY Marincola, FM Gress, RE AF Schwartz, GN Kammula, U Warren, MK Park, MK Yan, XY Marincola, FM Gress, RE TI Thrombopoietin and chemokine mRNA expression in patient post-chemotherapy and in vitro cytokine-treated marrow stromal cell layers SO STEM CELLS LA English DT Article DE quantitative RT-PCR; marrow stromal layers; microenvironment; TaqMan; chemokines; thrombopoietin; insulin-like growth factors ID HUMAN BONE-MARROW; MYELOID PROGENITOR CELLS; MESSENGER-RNA EXPRESSION; PRIMITIVE HEMATOPOIETIC PROGENITORS; LONG-TERM CULTURES; GROWTH-FACTOR-II; GENE-EXPRESSION; NEGATIVE REGULATORS; LIQUID CULTURE; IN-VITRO AB CD34(+) cells and megakaryocyte progenitors were lower in marrow from patients after hematological recovery from the first cycle of 5-fluorouracil, leucovorin, adriamycin, cyclophosphamide (FLAC) chemotherapy plus PIXY321 (GM-CSF/interleukin 3; IL-3 hybrid) than in FLAG + GM-CSF or pre-FLAC marrows, Marrow stromal layers, an in vitro model of the marrow microenvironment. express a combination of stimulatory and inhibitory factors that modulate hematopoietic progenitor cell proliferation and differentiation, The TaqMan assay and quantitative reverse transcriptase-polymerase chain reaction were used to measure monocyte chemoattractant protein-1 (MCP-1). melanoma stimulatory growth activity. and monokine inducible by interferon-gamma (Mig) (inhibitory. chemokines for primitive or megakaryocyte progenitors) mRNA levels in in vitro PIXY and GM-CSF-treated and patient post-FLAC marrow stromal layers, Chemokine mRNA was increased after in vitro GM-CSF and to a lesser extent after PIXY treatment. MCP-1 mRNA levels were Fivefold higher in FLAG + PIXY than in FLAC + GM-CSF layers, and Mig mRNA was elevated in FLAG + GM-CSF layers. Thrombopoietin (TPO), insulin-like growth factor I (TGF-I), and IGF-II (stimulatory factors) for primitive and megakaryocyte progenitors mRNA were also measured. TPO mRNA levels were 30% lower in GR-CSF and PIXY-pretreated than in control layers with no decrease in IGF mRNA, TPO mRNA in stromal layers of patients who developed grade 3 thrombocytopenia (platelets < 20 x 10(9)/l) during the third cycle of FLAC was only 24% of levels in stromal layers of marrow from other post-FLAG patients, Results demonstrate that patient and in vitro treatment had modulatory effects on TPO and chemokine mRNA expression in marrow stromal layers. C1 NCI, Dept Expt Transplantat & Immunol, Med Branch, Bethesda, MD 20892 USA. NCI, Surg Branch, Bethesda, MD 20892 USA. Poiet Technol Inc, Gaithersburg, MD USA. NIAID, Clin Invest Lab, Bethesda, MD 20892 USA. RP Schwartz, GN (reprint author), NCI, Dept Expt Transplantat & Immunol, Med Branch, Bldg 10,Room 12N226, Bethesda, MD 20892 USA. NR 49 TC 7 Z9 7 U1 0 U2 3 PU ALPHAMED PRESS PI MIAMISBURG PA ONE PRESTIGE PLACE, STE 290, MIAMISBURG, OH 45342-3758 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PY 2000 VL 18 IS 5 BP 331 EP 342 DI 10.1634/stemcells.18-5-331 PG 12 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 355XR UT WOS:000089414300005 PM 11007917 ER PT S AU Long, LR Thoma, GR AF Long, LR Thoma, GR BE Yeung, MM Yeo, BL Bouman, CA TI Indexing of image content in spine x-rays SO STORAGE AND RETRIEVAL FOR MEDIA DATABASES 2000 SE PROCEEDINGS OF THE SOCIETY OF PHOTO-OPTICAL INSTRUMENTATION ENGINEERS (SPIE) LA English DT Proceedings Paper CT Conference on Storage and Retrieval for Media Databases 2000 CY JAN 26-28, 2000 CL SAN JOSE, CA SP SPIE, Soc Imaging Sci & Technol DE biomedical image analysis; NLM; NIH; digital x-ray image; Chow-Kaneko algorithm ID VERTEBRAL MORPHOMETRY AB This paper presents work toward indexing the image content in a collection of 17,000 cervical spine and lumbar spine images, for purposes of public dissemination by such systems as the Web-based Medical Information System (WebMIRS). These images were collected as part of a national health survey and to date no radiological or quantitative content has been derived from the images, except for our work, described in this paper. Practical considerations, primarily of labor cost, make the job of deriving radiological interpretations or quantitative anatomical measures by manual methods very difficult. For this reason, the acquisition of content information by automated means, or even by semi-automated means, which require human interaction, but significantly reduce the required labor, are very important. This field is not in an advanced state of development, and the results we present are necessarily work in progress. C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Long, LR (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. NR 8 TC 2 Z9 2 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 0-8194-3590-2 J9 P SOC PHOTO-OPT INS PY 2000 VL 3972 BP 55 EP 63 PG 9 WC Computer Science, Artificial Intelligence; Computer Science, Information Systems; Optics SC Computer Science; Optics GA BP40E UT WOS:000085028500006 ER PT J AU Furuya, K Takeda, H Azhar, S DeGraba, TJ Rothlein, R Hugli, TE del Zoppo, CJ Hallenbeck, JM AF Furuya, K Takeda, H Azhar, S DeGraba, TJ Rothlein, R Hugli, TE del Zoppo, CJ Hallenbeck, JM TI Some potentially harmful side effects of anti-ICAM-1 antibody administration in preclinical animal studies of stroke SO STROKE LA English DT Meeting Abstract C1 NINDS, Bethesda, MD 20892 USA. Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA. Scripps Res Inst, La Jolla, CA USA. NR 0 TC 3 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2000 VL 31 IS 1 MA 11 BP 277 EP 277 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 271HX UT WOS:000084589100069 ER PT J AU Worrall, BB Azhar, S DeGraba, TJ AF Worrall, BB Azhar, S DeGraba, TJ TI IL-1ra polymorphisms and symptomatic carotid atherosclerosis SO STROKE LA English DT Meeting Abstract C1 Univ Virginia, Charlottesville, VA USA. NIH, Stroke Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2000 VL 31 IS 1 MA 28 BP 280 EP 280 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 271HX UT WOS:000084589100086 ER PT J AU Warach, SJ Sabounjian, LAA AF Warach, SJ Sabounjian, LAA TI ECCO 2000 study of citicoline for treatment of acute ischemic stroke: Effects on infarct volumes measured by MRI SO STROKE LA English DT Meeting Abstract C1 NINDS, Bethesda, MD 20892 USA. Interneuron Pharmaceut Inc, Lexington, MA USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2000 VL 31 IS 1 MA 42 BP 283 EP 283 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 271HX UT WOS:000084589100100 ER PT J AU Baird, AE Janket, SJ Eichbaum, Q Chaves, C Silver, B Caplan, L Edelman, R Steven, W AF Baird, AE Janket, SJ Eichbaum, Q Chaves, C Silver, B Caplan, L Edelman, R Steven, W TI Prognostic value of diffusion-weighted imaging in acute stroke SO STROKE LA English DT Meeting Abstract C1 Beth Israel Deaconess Med Ctr, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Univ Western Ontario, London, ON, Canada. NINDS, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2000 VL 31 IS 1 MA 60 BP 286 EP 286 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 271HX UT WOS:000084589100117 ER PT J AU Gammans, RE Harnett, K Sabounjain, LA Warach, SJ AF Gammans, RE Harnett, K Sabounjain, LA Warach, SJ TI Progression of human infarct by DW- and perfusion-MRI and the time window for acute stroke intervention SO STROKE LA English DT Meeting Abstract C1 Interneuron Pharmaceut Inc, Lexington, MA USA. NINDS, Rockville, MD 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 0039-2499 J9 STROKE JI Stroke PD JAN PY 2000 VL 31 IS 1 MA 58 BP 286 EP 286 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 271HX UT WOS:000084589100115 ER PT J AU Lyden, PD Lu, M Jackson, CM Marler, J Kothari, R Brott, T Zivin, JA AF Lyden, PD Lu, M Jackson, CM Marler, J Kothari, R Brott, T Zivin, JA TI Underlying structure of the NIH stroke scale: Results of a factor analysis SO STROKE LA English DT Meeting Abstract C1 Univ Calif San Diego, San Diego, CA 92103 USA. Henry Ford Hlth Syst, Detroit, MI USA. Univ Calif San Diego, La Jolla, CA 92093 USA. NINDS, Bethesda, MD 20892 USA. Univ Cincinnati, Med Ctr, Cincinnati, OH 45267 USA. Mayo Clin Jacksonville, Jacksonville, FL 32224 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2000 VL 31 IS 1 MA P56 BP 307 EP 307 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 271HX UT WOS:000084589100222 ER PT J AU Azhar, S Labiche, RL Nyquist, PA DeGraba, TJ AF Azhar, S Labiche, RL Nyquist, PA DeGraba, TJ TI Tumor necrosis factor gene polymorphism in carotid artery atherosclerosis SO STROKE LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 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 0039-2499 J9 STROKE JI Stroke PD JAN PY 2000 VL 31 IS 1 MA P97 BP 316 EP 316 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 271HX UT WOS:000084589100262 ER PT J AU Llinas, RH Schlaug, G Chaves, C Staroselskaya, I Warach, SJ Caplan, LR AF Llinas, RH Schlaug, G Chaves, C Staroselskaya, I Warach, SJ Caplan, LR TI Diffusion weighted magnetic resonance imaging in posterior circulation stroke SO STROKE LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Boston, MA USA. NINDS, 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 0039-2499 J9 STROKE JI Stroke PD JAN PY 2000 VL 31 IS 1 MA P152 BP 327 EP 327 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 271HX UT WOS:000084589100317 ER PT J AU Schlaug, G Llinas, R Linfante, I Starolselskaja, I Caplan, LR Edelman, RR Warach, S AF Schlaug, G Llinas, R Linfante, I Starolselskaja, I Caplan, LR Edelman, RR Warach, S TI Characterizing brain tissue at risk for infarction SO STROKE LA English DT Meeting Abstract C1 Beth Israel Deaconess Med Ctr, Boston, MA USA. NINDS, 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 0039-2499 J9 STROKE JI Stroke PD JAN PY 2000 VL 31 IS 1 MA P165 BP 330 EP 330 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 271HX UT WOS:000084589100330 ER PT J AU Bremner, JD Horti, A Staib, LH Zea-Ponce, Y Soufer, R Charney, DS Baldwin, R AF Bremner, JD Horti, A Staib, LH Zea-Ponce, Y Soufer, R Charney, DS Baldwin, R TI Kinetic modeling of benzodiazepine receptor binding with PET and high specific activity [C-11]Iomazenil in healthy human subjects SO SYNAPSE LA English DT Article DE PET; iomazenil; modeling; neuroimaging; benzodiazepines ID POSITRON EMISSION TOMOGRAPHY; HUMAN-BRAIN; C-11 FLUMAZENIL; I-123 IOMAZENIL; QUANTITATIVE-EVALUATION; COMPARTMENTAL ANALYSIS; SPECT MEASUREMENT; RO 15-1788; INVIVO; IODINE-123-IOMAZENIL AB Quantitation of the PET benzodiazepine receptor antagonist, [C-11]Iomazenil, using low specific activity radioligand was recently described. The purpose of this study was to quantitate benzodiazepine receptor binding in human subjects using PET and high specific activity [C-11]Iomazenil. Six healthy human subjects underwent PET imaging following a bolus injection of high specific activity (>100 Ci/mmol) [C-11]iomazenil. Arterial samples were collected at multiple time points after injection for measurement of unmetabolized total and nonprotein-bound parent compound in plasma. Time activity curves of radioligand concentration in brain and plasma were analyzed using two and three compartment model. Kinetic rate constants of transfer of radioligand between plasma, nonspecifically bound brain tissue, and specifically bound brain tissue compartments were fitted to the model. Values for fitted kinetic rate constants were used in the calculation of measures of benzodiazepine receptor binding, including binding potential (the ratio of receptor density to affinity), and product of BP and the fraction of free nonprotein-bound parent compound (V-3'). Use of the three compartment model improved the goodness of fit in comparison to the two compartment model. Values for kinetic rate constants and measures. of benzodiazepine receptor binding, including BP and V-3', were similar to results obtained with the SPECT radioligand [I-123]iomazenil, and a prior report with low specific activity [C-11]Iomazenil. Kinetic modeling using the three compartment model with PET and high specific activity [C-11]Iomazenil provides a reliable measure of benzodiazepine receptor binding. Synapse 35:68-77, 2000. Published 2000 Wiley-Liss, Inc.dagger C1 Yale Univ, Sch Med, Dept Diagnost Radiol, New Haven, CT 06250 USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06250 USA. Yale VA PET Ctr, W Haven, CT 06250 USA. VA Connecticut Healthcare Syst, Natl Ctr PTSD, New Haven, CT USA. NIDA, Brain Imaging Ctr, Intramural Res Program, Baltimore, MD 21224 USA. RP Bremner, JD (reprint author), VA Connecticut Healthcare Syst, Yale VA PET Ctr 115A, 950 Campbell Ave, W Haven, CT 06516 USA. RI Bremner, James/B-1632-2013; OI Staib, Lawrence/0000-0002-9516-5136 NR 38 TC 6 Z9 6 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD JAN PY 2000 VL 35 IS 1 BP 68 EP 77 DI 10.1002/(SICI)1098-2396(200001)35:1<68::AID-SYN9>3.0.CO;2-H PG 10 WC Neurosciences SC Neurosciences & Neurology GA 262QM UT WOS:000084078000009 PM 10579810 ER PT J AU Gao, Y Burke, TR AF Gao, Y Burke, TR TI Stereoselective preparation of L-4-(2 '-malonyl)phenylalanine suitably protected for Fmoc-based synthesis of potent signal transduction inhibitory ligands SO SYNLETT LA English DT Article DE phosphotyrosine mimetic; stereoselective; amino acid analogue; SH2 domain ID SOLID-PHASE SYNTHESIS; AMINO-ACIDS; PEPTIDES; L-O-(2-MALONYL)TYROSINE; PHOSPHOTYROSINE AB Preparation is reported of N-Fmoc 4-(2'-(di-tert-butylmalonyl))-L-phenylalanine. a useful reagent for the synthesis of signal transduction-directed ligands containing p-(2'-malonyl)phenylalanine (pmF). one of the most potent pTyr mimetics yet described for the inhibition of Grb2 SH2 domain binding. An important aspect of the current synthetic approach, is the introduction of chirality using the Williams auxiliary, benzyl (2R,3S)-(-)-6-oxo-2,3- diphenyl-4-morpholinecarboxylate. C1 NCI, Med Chem Lab, Div Basic Sci, NIH, Bethesda, MD 20817 USA. RP Burke, TR (reprint author), NCI, Med Chem Lab, Div Basic Sci, NIH, Blg 37,Rm 5C06, Bethesda, MD 20817 USA. RI Burke, Terrence/N-2601-2014 NR 15 TC 19 Z9 19 U1 0 U2 2 PU GEORG THIEME VERLAG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0936-5214 J9 SYNLETT JI Synlett PD JAN PY 2000 IS 1 BP 134 EP 136 PG 3 WC Chemistry, Organic SC Chemistry GA 305TK UT WOS:000086556300041 ER PT J AU Kim, YC Jacobson, KA AF Kim, YC Jacobson, KA TI Versatile synthesis of 6-alkyl and aryl substituted pyridoxal derivatives SO SYNTHESIS-STUTTGART LA English DT Article DE pyridoxal; 6-substitution; P2 receptors; Grignard reaction; Heck reaction; protecting groups; deprotection; N-oxides; heterocycles ID REGIOSELECTIVE SYNTHESIS AB A versatile and convenient procedure for the functional derivatization with carbon substituents at the 6-position of pyridoxal using a Grignard reaction upon a protected N-isobutoxycarbony-loxypyridoxal chloride and Heck reactions with protected 6-vinylpyridoxal has been developed. C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 9 TC 6 Z9 6 U1 0 U2 1 PU GEORG THIEME VERLAG PI STUTTGART PA P O BOX 30 11 20, D-70451 STUTTGART, GERMANY SN 0039-7881 J9 SYNTHESIS-STUTTGART JI Synthesis PD JAN PY 2000 IS 1 BP 119 EP 122 PG 4 WC Chemistry, Organic SC Chemistry GA 280HT UT WOS:000085097000015 ER PT J AU Wang, H Miao, ZW Lai, LH Xu, XJ AF Wang, H Miao, ZW Lai, LH Xu, XJ TI An efficient procedure for cleavage of T-butyl protected cysteine in solid phase peptide synthesis SO SYNTHETIC COMMUNICATIONS LA English DT Article ID ACID AB In the Fmoc-strategy of solid phase peptide synthesis, 1M trimethylsilyl bromide-thioanisole/trifluoroacetic acid in the presence of 1,2-ethanedithiol as scavenger was found to be an efficient deprotecting procedure for a full cleavage and side chains deprotection of the peptide resin involving t-butyl protected cysteine. In addition, selective deprotection of the peptide resin containing protected cysteine was also described based on this method. C1 Peking Univ, Inst Phys Chem, Beijing 100871, Peoples R China. RP Wang, H (reprint author), NIAMS, NIH, Bldg 6,Room 130, Bethesda, MD 20892 USA. NR 10 TC 1 Z9 1 U1 1 U2 5 PU MARCEL DEKKER INC PI NEW YORK PA 270 MADISON AVE, NEW YORK, NY 10016 USA SN 0039-7911 J9 SYNTHETIC COMMUN JI Synth. Commun. PY 2000 VL 30 IS 4 BP 727 EP 735 DI 10.1080/00397910008087375 PG 9 WC Chemistry, Organic SC Chemistry GA 290UY UT WOS:000085697300017 ER PT B AU Eddy, EM Willis, WD Miki, K Mori, C AF Eddy, EM Willis, WD Miki, K Mori, C BE Goldberg, E TI HSP70 chaperones in spermatogenesis SO TESTIS: FROM STEM CELL TO SPERM FUNCTION SE SERONO SYMPOSIA, USA LA English DT Proceedings Paper CT XVth Testis Workshop on the Testis - From Stem Cell to Sperm Function CY APR 07-10, 1999 CL LOUISVILLE, KY SP Serono Symposia USA Inc ID HEAT-SHOCK-PROTEIN; GERM-CELL APOPTOSIS; MEIOTIC PROPHASE; MOUSE SPERMATOGENESIS; SYNAPTONEMAL COMPLEX; MOLECULAR CHAPERONES; GENE-EXPRESSION; CDC2 PROTEIN; DROSOPHILA; MEIOSIS C1 NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Eddy, EM (reprint author), NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. NR 51 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 0-387-95024-9 J9 SERONO SYMP PY 2000 BP 133 EP 142 PG 6 WC Reproductive Biology SC Reproductive Biology GA BQ84K UT WOS:000089810900012 ER PT S AU Hodge, JW Schlom, J AF Hodge, JW Schlom, J BE Walden, P Sterry, W Hennekes, H TI Costimulatory molecules in vaccine design SO THERAPEUTIC VACCINATION STRATEGIES SE ERNST SCHERING RESEARCH FOUNDATION WORKSHOP LA English DT Proceedings Paper CT 30th Ernst-Schering-Research-Foundation Workshop CY MAY, 1999 CL BERLIN, GERMANY SP Ernst Schering Res Fdn ID T-CELL ACTIVATION; ANTITUMOR IMMUNITY; CARCINOEMBRYONIC ANTIGEN; SERONEGATIVE ADULTS; CYTOLYTIC ACTIVITY; RECOMBINANT GP160; POXVIRUS VECTOR; CTLA-4 BLOCKADE; LYMPHOCYTE-T; DOUBLE-BLIND C1 NCI, Tumor Immunol & Biol Branch, NIH, Bethesda, MD 20879 USA. RP Hodge, JW (reprint author), NCI, Tumor Immunol & Biol Branch, NIH, Bldg 10,Room 5B38, Bethesda, MD 20879 USA. RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 NR 62 TC 2 Z9 3 U1 0 U2 0 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0947-6075 BN 3-540-67298-2 J9 E SCHERING RES FDN W PY 2000 VL 30 BP 23 EP 52 PG 30 WC Oncology; Immunology; Medicine, Research & Experimental; Pharmacology & Pharmacy SC Oncology; Immunology; Research & Experimental Medicine; Pharmacology & Pharmacy GA BQ90X UT WOS:000090025700003 ER PT B AU Birkedal-Hansen, H Bodden, MK Caterina, NCM Windsor, LJ Netzel-Arnett, S Engler, JA AF Birkedal-Hansen, H Bodden, MK Caterina, NCM Windsor, LJ Netzel-Arnett, S Engler, JA BE Hawkes, SP Edwards, DR Khokha, R TI Overview of TIMP structure/function relationships SO TISSUE INHIBITORS OF METALLOPROTEINASES IN DEVELOPMENT AND DISEASE, PROCEEDINGS LA English DT Proceedings Paper CT Conference on Tissue Inhibitors of Metalloproteinases in Development and Disease CY SEP 25-29, 1996 CL BANFF, CANADA SP NIH, Alberta Heritage Fdn Med Res, Roche Pharmaceut, Alberta Canc Board, Univ Calgary, Amgen, Natl Canc Inst Canada, Ciba Geigy, London Reg Canc Ctr, Canadian Life Technologies, Celltech, British Biotech Pharmaceut, Agouron Pharmaceut ID C-TERMINAL DOMAIN; TISSUE INHIBITOR; IV COLLAGENASE; GELATINASE-A; MATRIX METALLOPROTEINASES; COMPLEX-FORMATION; ACTIVE-SITE; ACTIVATION; CATALYSIS; BINDING AB TIMPs bind reversibly to active ("switch-open" or proteolytically truncated) forms of MMPs with which they form inhibited, bimolecular, non-covalent complexes. Kinetic studies suggest that TIMP binding is slow, tight (K-D = 0.1-10 nM) and biphasic, i.e. an initial binding phase is followed by "tightening" or "rearrangement" of the complex. In addition, TTMP-1 and TIMP-2 exhibit apparently distinct binding activities toward the "switch-closed" forms of Gel A and Gel B. Modeling of peptide competition data obtained with peptides modeled after TIMP-1, based on the NMR structure of the NH2-terminal domain of TIMP-2, shows that competing peptides occupy two continguous patches (foot-prints), one on either side of the molecule. The VIRAK sequence plays a unique role in that it tunnels through the molecule and forms part of both putative binding patches. Site-directed mutagenesis experiments suggest that single residue replacements (even within binding patches) do not abrogate binding activity. Replacement of disulfide bonds, on the other hand, more profoundly affect TIMP function. Replacement of C1/C70 generates a completely inactive mutant whereas replacement of C3/C99 yields a mutant with approximate to 50% of wildtype activity as measured by active site titration. C1 NIDR, NIH, Bethesda, MD 20892 USA. RP Birkedal-Hansen, H (reprint author), NIDR, NIH, Bethesda, MD 20892 USA. NR 20 TC 0 Z9 0 U1 0 U2 0 PU HARWOOD ACADEMIC PUBL GMBH PI CHUR PA POSTSTRASSE 22, 7000 CHUR, SWITZERLAND BN 90-5702-599-X PY 2000 BP 45 EP 49 PG 5 WC Biochemistry & Molecular Biology; Biology; Medicine, General & Internal SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; General & Internal Medicine GA BQ54N UT WOS:000088719200005 ER PT B AU Stetler-Stevenson, M Lim, M Mansoor, A Stetler-Stevenson, WG AF Stetler-Stevenson, M Lim, M Mansoor, A Stetler-Stevenson, WG BE Hawkes, SP Edwards, DR Khokha, R TI TIMP-1 and TIMP-2: Restricted expression in normal and neoplastic lymphoid cells SO TISSUE INHIBITORS OF METALLOPROTEINASES IN DEVELOPMENT AND DISEASE, PROCEEDINGS LA English DT Proceedings Paper CT Conference on Tissue Inhibitors of Metalloproteinases in Development and Disease CY SEP 25-29, 1996 CL BANFF, CANADA SP NIH, Alberta Heritage Fdn Med Res, Roche Pharmaceut, Alberta Canc Board, Univ Calgary, Amgen, Natl Canc Inst Canada, Ciba Geigy, London Reg Canc Ctr, Canadian Life Technologies, Celltech, British Biotech Pharmaceut, Agouron Pharmaceut ID ERYTHROID-POTENTIATING ACTIVITY; GROWTH-PROMOTING ACTIVITY; TISSUE INHIBITOR; IV COLLAGENASE; EXTRACELLULAR-MATRIX; METALLOPROTEINASES-1 TIMP-1; INVASION; METASTASIS; COMPLEX AB We have examined the expression of TIMP-1 mRNA in lymphoid tissue and found it is not expressed by neoplastic T-cell lines, low grade B-cell lymphoma cell lines or isolated peripheral blood B-cells. TIMP-1 is expressed by isolated tonsillar B-cells (from hyperplastic tonsils) and some high grade Burkitt cell lines. TIMP-2 mRNA expression was restricted to tissues containing cells of T-lineage. The highest levels of TIMP-2 expression were found in neoplastic T-cell lines. Lower levels of TIMP-2 were found in normal peripheral blood T-cells and hyperplastic tonsillar tissue. In all cases of mRNA detection, functional TIMP protein was observed using reverse zymography. TIMP expression correlates with cell lineage in that TIMP-1 is primarily observed in B-cells and TIMP-2 is restricted to T-cells. C1 NCI, Flow Cytometry Unit, Hematopathol Sect, Bethesda, MD 20892 USA. RP Stetler-Stevenson, M (reprint author), NCI, Flow Cytometry Unit, Hematopathol Sect, Bethesda, MD 20892 USA. RI Stetler-Stevenson, William/H-6956-2012 OI Stetler-Stevenson, William/0000-0002-5500-5808 NR 23 TC 0 Z9 0 U1 0 U2 0 PU HARWOOD ACADEMIC PUBL GMBH PI CHUR PA POSTSTRASSE 22, 7000 CHUR, SWITZERLAND BN 90-5702-599-X PY 2000 BP 79 EP 83 PG 5 WC Biochemistry & Molecular Biology; Biology; Medicine, General & Internal SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; General & Internal Medicine GA BQ54N UT WOS:000088719200009 ER PT J AU Orleans, CT Boyd, NR Noll, E Crosette, L Glassman, B AF Orleans, CT Boyd, NR Noll, E Crosette, L Glassman, B TI Computer tailored intervention for older smokers using transdermal nicotine SO TOBACCO CONTROL LA English DT Article; Proceedings Paper CT 2nd Annual Addressing Tobacco in Managed Care National Conference CY JAN 31-FEB 02, 1999 CL SAN DIEGO, CALIFORNIA SP Amer Assoc Hlth Plan, Address Tobacco Managed Care Natl Techn Assistance Off Partners, Alliance Commun Hlth Plans C1 Robert Wood Johnson Fdn, Princeton, NJ 08543 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. NCI, Bethesda, MD 20892 USA. RP Orleans, CT (reprint author), Robert Wood Johnson Fdn, Coll Rd E, Princeton, NJ 08543 USA. NR 5 TC 7 Z9 7 U1 1 U2 1 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0964-4563 J9 TOB CONTROL JI Tob. Control PY 2000 VL 9 SU 1 BP 53 EP 53 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 292NB UT WOS:000085800100019 ER PT J AU Morgan, GD AF Morgan, GD TI Tobacco control research in managed care: opportunities at the National Cancer Institute SO TOBACCO CONTROL LA English DT Article; Proceedings Paper CT 2nd Annual Addressing Tobacco in Managed Care National Conference CY JAN 31-FEB 02, 1999 CL SAN DIEGO, CALIFORNIA SP Amer Assoc Hlth Plan, Address Tobacco Managed Care Natl Techn Assistance Off Partners, Alliance Commun Hlth Plans C1 NCI, Tobacco Control Res Branch, Behav Res Program, Bethesda, MD 20892 USA. RP Morgan, GD (reprint author), NCI, Tobacco Control Res Branch, Behav Res Program, Execut Plaza N,Room 241,6130 Execut Blvd,MSC 7337, Bethesda, MD 20892 USA. NR 2 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 0964-4563 J9 TOB CONTROL JI Tob. Control PY 2000 VL 9 SU 1 BP 75 EP 75 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 292NB UT WOS:000085800100034 ER PT J AU Benowitz, NL Dempsey, DA Goldenberg, RL Hughes, JR Dolan-Mullen, P Ogburn, PL Oncken, C Orleans, CT Slotkin, TA Whiteside, HP Yaffe, S AF Benowitz, NL Dempsey, DA Goldenberg, RL Hughes, JR Dolan-Mullen, P Ogburn, PL Oncken, C Orleans, CT Slotkin, TA Whiteside, HP Yaffe, S TI The use of pharmacotherapies for smoking cessation during pregnancy SO TOBACCO CONTROL LA English DT Editorial Material ID NICOTINE REPLACEMENT THERAPY; TRANSDERMAL NICOTINE; FETAL; SMOKERS C1 Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Biopharmaceut Sci, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. Univ Alabama, Dept Obstet & Gynecol, Smoke Free Families Program, Birmingham, AL 35294 USA. Univ Vermont, Dept Psychiat, Burlington, VT USA. Univ Texas, Hlth Sci Ctr, Sch Publ Hlth, Ctr Hlth Promot Res & Prevent, Houston, TX USA. Mayo Clin & Mayo Fdn, Mayo Med Sch, Dept Obstet & Gynecol, Rochester, MN 55905 USA. Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT USA. Robert Wood Johnson Fdn, Res & Evaluat Unit, Princeton, NJ 08540 USA. Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC USA. NICHHD, Ctr Res Mothers & Children, Bethesda, MD 20892 USA. RP Whiteside, HP (reprint author), Univ Alabama, Sch Med, Dept Obstet & Gynecol, Smoke Free Families Natl Program Off, 320 CIRC,1530 3rd Ave S, Birmingham, AL 35294 USA. NR 20 TC 44 Z9 45 U1 1 U2 2 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0964-4563 J9 TOB CONTROL JI Tob. Control PY 2000 VL 9 SU 3 BP 91 EP 94 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 357VA UT WOS:000089520400025 ER PT J AU Sills, RC Valentine, WM Moser, V Graham, DG Morgan, DL AF Sills, RC Valentine, WM Moser, V Graham, DG Morgan, DL TI Characterization of carbon disulfide neurotoxicity in C57BL6 mice: Behavioral, morphologic, and molecular effects SO TOXICOLOGIC PATHOLOGY LA English DT Article DE peripheral neuropathy; functional observational battery; cross-licking spectrin; neurofilament proteins; carbon disulfide; axonal swelling; C57BL6 mice ID FUNCTIONAL OBSERVATIONAL BATTERY; IN-VIVO; ERYTHROCYTE SPECTRIN; RATS; N,N-DIETHYLDITHIOCARBAMATE; INTOXICATION; RELEASE AB Female C57BL6 mice were exposed to 0 or 800 ppm carbon disulfide (CS2). 6 h/d, 5 d/wk for 20 weeks. The neurologic function of all mice was assessed once at the end of exposures using a functional observational battery. General health effects included a decrease in body weight gain, piloerection, hunched body posture, and ptosis. Treatment-related effects included altered gait (uncoordinated placement of hind limbs and ataxia) and impaired function on an inverted screen test. In addition, rearing and locomotor movement were decreased in treated mice. Focal to multifocal axonal swelling was seen predominantly in the muscular branch of the posterior tibial nerve, and occasionally giant axonal swelling was detected in the lumbar segment of the spinal cord. Electron microscopic examination revealed swollen axons with massive accumulation of neurofilament proteins within the axoplasm. Covalent crosslinking of erythrocyte spectrin (surrogate protein to neurofilament protein) was demonstrated in mice exposed to CS2 but not in mice receiving filtered air. These data provide supportive evidence that covalent cross-linking of neurofilament proteins is a significant feature of the axonal swellings in mice produced by inhalation exposure to CS2. C1 NIEHS, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Sills, RC (reprint author), NIEHS, Environm Toxicol Program, MD B3-08,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 26 TC 23 Z9 23 U1 0 U2 2 PU SOC TOXICOLOGIC PATHOLOGISTS PI MT ROYAL PA 19 MANTUA RD, MT ROYAL, NJ 08061 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JAN-FEB PY 2000 VL 28 IS 1 BP 142 EP 148 DI 10.1177/019262330002800118 PG 7 WC Pathology; Toxicology SC Pathology; Toxicology GA 279HV UT WOS:000085039100018 PM 10669001 ER PT J AU Takayama, S Renwick, AG Johansson, SL Thorgeirsson, UP Tsutsumi, M Dalgard, DW Sieber, SM AF Takayama, S Renwick, AG Johansson, SL Thorgeirsson, UP Tsutsumi, M Dalgard, DW Sieber, SM TI Long-term toxicity and carcinogenicity study of cyclamate in nonhuman primates SO TOXICOLOGICAL SCIENCES LA English DT Article DE cyclamate; primates; carcinogen; toxicity; testicular abnormalities; malignancies; spermatogenesis ID CYCLOHEXYLAMINE; METABOLISM; RATS; PHARMACOKINETICS; SACCHARIN; MICE AB Twenty-one monkeys (cynomolgus, rhesus, African green) were fed cyclamate (100 mg/kg and 500 mg/kg) in the diet five times per week from a few days after birth and continuing for up to 24 years. Malignant tumors were diagnosed in three 24-year-old cyclamate monkeys; these were metastatic colon carcinoma (rhesus; 500 mg/kg), metastatic hepatocellular carcinoma (cynomolgus; 500 mg/kg), and a small, well differentiated adenocarcinoma of the prostate (cynomolgus; 100 mg/kg), Benign tumors were found at necropsy in three females; these were adenoma of the thyroid gland (rhesus; 100 mg/kg) and two cases of leiomyoma of the uterus (rhesus; 100 mg/kg and 500 mg/kg). No tumors were detected in an age-matched control group of 16 monkeys. Examination of the testes revealed complete testicular atrophy in one of the old cyclamate monkeys, and focal germ cell aplasia (Sertoli-only tubules) in two other cyclamate monkeys. Focal spermatogenic interruption (maturation arrest) at various germ cell levels mixed with normal spermatogenesis was observed in both the cyclamate-treated and the control monkeys, all of which were over 20 years old. Measurements of terminal cyclohexylamine concentrations showed that three of the males dosed with cyclamate at 500 mg/kg were high converters, with plasma concentrations comparable to the levels that produce testicular atrophy in rats. However, only one of the three high converters showed histologic evidence of irregular spermatogenesis. The overall conclusion is that the testicular abnormalities and the sporadic cases of different malignancies found after more than 20 years of dosing do not provide clear evidence of a toxic or carcinogenic effect of sodium cyclamate in monkeys. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, Div Basic Sci, Bethesda, MD 20892 USA. Univ Southampton, Clin Pharmacol Grp, Southampton SO16 7PX, Hants, England. Univ Nebraska, Dept Pathol & Microbiol, Omaha, NE 68182 USA. Univ Nebraska, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68182 USA. Nara Med Univ, Kashihara, Nara 634, Japan. Covance Labs Amer Inc, Vienna, VA 22182 USA. NCI, Off Director, Bethesda, MD 20892 USA. RP Thorgeirsson, UP (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, Div Basic Sci, Bldg 37,Room 2D02, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-BC-40510, CA325B] NR 29 TC 18 Z9 24 U1 1 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JAN PY 2000 VL 53 IS 1 BP 33 EP 39 DI 10.1093/toxsci/53.1.33 PG 7 WC Toxicology SC Toxicology GA 273TK UT WOS:000084723400005 PM 10653518 ER PT J AU Davis, MA Flaws, JA Young, M Collins, K Colburn, NH AF Davis, MA Flaws, JA Young, M Collins, K Colburn, NH TI Effect of ceramide on intracellular glutathione determines apoptotic or necrotic cell death of JB6 tumor cells SO TOXICOLOGICAL SCIENCES LA English DT Article; Proceedings Paper CT 88th Annual Meeting of the American-Association-for-Cancer-Research CY APR 12-16, 1997 CL SAN DIEGO, CALIFORNIA SP Amer Assoc Canc Res DE epidermal cells; cell death; ceramide; glutathione; apoptosis ID FACTOR-KAPPA-B; STRESS-INDUCED APOPTOSIS; NECROSIS-FACTOR; SPHINGOMYELIN PATHWAY; SIGNAL-TRANSDUCTION; TNF-ALPHA; ACTIVATION; GENERATION; TRANSLOCATION; REQUIREMENT AB Selective induction of cell death is a means to remove unwanted cell populations from a tissue or organ. Understanding the signaling events responsible for mediating cell death by cytokines, such as tumor necrosis factor-alpha (TNF alpha) are key to the development of pharmacologic inducers of this response. Ceramide has been implicated as a secondary messenger for TNF alpha-induced cell death, but many of the intracellular effects of ceramide are not fully understood. Recent reports suggest that ceramide signaling may involve oxidative stress. To explore the relationship between TNF sensitivity and ceramide signaling, two genetic variants of mouse JB6 RT101 epidermal tumor cells, one resistant and one sensitive to TNF alpha- induced cytotoxicity, were treated with C-2-ceramide. Treatment with 20 mu M ceramide induced apoptosis and this was quickly followed by oncotic necrosis in the TNF alpha-sensitive JB6 (TNFs) cells. The same concentration of ceramide induced apoptosis, but not oncotic necrosis of the TNF alpha resistant JB6 (TNFr) cells. The basal level of glutathione was significantly higher in TNFr cells than in TNFs cells. Treatment with 20 mu M ceramide decreased cellular glutathione in TNFs cells by 50%, in contrast to an insignificant decrease in the TNFr cells. A significant increase in reactive oxygen was noted in TNFs cells treated with 10 or 20 mu M ceramide, Furthermore, pretreatment with the antioxidant N-acetylcysteine or with glutathione monoethylester delayed the onset of ceramide-induced oncotic necrosis, but did not inhibit apoptosis. Our results suggest that the severity of the decrease in glutathione appears to determine whether cells undergo just apoptosis or also oncotic necrosis, They also suggest that ceramide-induced oncotic necrosis is modulated by a decline in cellular glutathione and an elevation of reactive oxygen. These results suggest that a decrease in cellular redox potential determines susceptibility to ceramide-dependent killing pathways. C1 Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Epidemiol Prevent Med, Baltimore, MD 21201 USA. NCI, Lab Biochem Physiol, Frederick, MD 21701 USA. RP Davis, MA (reprint author), Univ Maryland, Sch Med, Dept Pathol, 10 S Pine St, Baltimore, MD 21201 USA. NR 32 TC 31 Z9 35 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 JAN PY 2000 VL 53 IS 1 BP 48 EP 55 DI 10.1093/toxsci/53.1.48 PG 8 WC Toxicology SC Toxicology GA 273TK UT WOS:000084723400007 PM 10653520 ER PT J AU Fonger, GC Stroup, D Thomas, PL Wexler, P AF Fonger, GC Stroup, D Thomas, PL Wexler, P TI TOXNET: A computerized collection of toxicological and environmental health information SO TOXICOLOGY AND INDUSTRIAL HEALTH LA English DT Article DE environmental health information; toxic substances; toxicology information; TOXNET AB The Toxicology and Environmental Health Information Program, managed by the National Library of Medicine's Division of Specialized Information Services, provides access to a number of online bibliographic and factual computer files concerned with the toxicology, safety and handling, and environmental fate of chemicals, along with other files that cover genetic toxicology, developmental and reproductive toxicology, mutagenesis, carcinogenesis and toxic chemical releases. C1 Natl Lib Med, Div Specialized Informat Serv, Toxicol & Environm Hlth Informat Program, Bethesda, MD 20894 USA. RP Fonger, GC (reprint author), Natl Lib Med, Div Specialized Informat Serv, Toxicol & Environm Hlth Informat Program, Bldg 38A-3S316,8600 Rockville Pike, Bethesda, MD 20894 USA. NR 1 TC 11 Z9 14 U1 0 U2 0 PU STOCKTON PRESS PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0748-2337 J9 TOXICOL IND HEALTH JI Toxicol. Ind. Health PD JAN PY 2000 VL 16 IS 1 BP 4 EP 6 DI 10.1177/074823370001600101 PG 3 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA 309CZ UT WOS:000086751200001 PM 10798381 ER PT J AU Howell, MD Manetz, TS Meade, BJ AF Howell, MD Manetz, TS Meade, BJ TI Comparison of murine assays for the identification of chemical sensitizers SO TOXICOLOGY METHODS LA English DT Article DE B220; contact hypersensitivity; flow cytometry; IgE; LLNA; MEST ID LYMPH-NODE ASSAY; SWELLING TEST MEST; CONTACT ALLERGENS; MICE; 2,4-DINITROCHLOROBENZENE; VALIDATION; EXPOSURE AB Efforts are under way, to develop a phenotypic analysis assay capable of identifying and differentiating chemicals with the potential to induce irritation and IgE-mediated and T-cell-mediated sensitization. These studies compare results obtained with the irritancy/phenotypic analysis assay to those obtained in, the mouse ear-swelling test (MEST) and the local lymph node assay (LLNA). Female BALB/c mice (5 animals per group) were exposed topically to the human sensitizers 2,4-dinitrochlorobenzene (DNCB) anal potassium dichromate (PDC) as well as the irritant methyl salicylate (MSC), following the protocol for each assay. DNCB was identified as a sensitizer in the LLNA and phenotypic analysis assay at concentrations as low 0.25%. In the MEST DNCB was considered positive in concentrations as lour as 0.01 and 0.05% at the 24- and 48-h measurements of the MEST respectively. PDC tested positive as a sensitizer in the LLNA and the phenotypic analysis assay at concentrations as low as 0.25 and 0.1%, respectively. In the MEST, PDC was negative at the 24-h time point and tested positive only at the 48-h measurement at the highest concentration tested, 0.5%. Both DNCB and PDC induced an elevation in total serum IgE at the 0.5% concentrations. MSC was negative for sensitizing potential at all concentrations tested in all four assays. Phenotypic analysis of lymph node cells removed from animals dosed with the three chemicals gave results similar to the LLNA, but had the advantage of detecting chemicals with the capacity to induce an increase in the IgE(+) cell population. C1 W Virginia Univ, Dept Microbiol & Immunol, Morgantown, WV 26506 USA. NIOSH, Agr & Immunotoxicol Grp, Morgantown, WV USA. NIAMSD, Arthrit & Rheumatism Branch, Rockville, MD USA. RP Meade, BJ (reprint author), MS 4050,1095 Willowdale Rd, Morgantown, WV 26505 USA. NR 31 TC 6 Z9 6 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI LONDON PA 11 NEW FETTER LANE, LONDON EC4P 4EE, ENGLAND SN 1051-7235 J9 TOXICOL METHOD JI Toxicol. Method. PD JAN-MAR PY 2000 VL 10 IS 1 BP 1 EP 15 PG 15 WC Toxicology SC Toxicology GA 288FG UT WOS:000085551300001 ER PT B AU Stadtman, TC AF Stadtman, TC BE Roussel, AM Anderson, RA Favrier, AE TI Some functions of the essential trace element, selenium SO TRACE ELEMENTS IN MAN AND ANIMALS 10 LA English DT Proceedings Paper CT 10th International Symposium on Trace Elements in Man and Animals (TEMA 10) CY MAY 02-07, 1999 CL EVIAN LES BAINS, FRANCE SP Activat Lab, Albion Labs Inc, AMBI Nutr Co, Astra Calve, Banque Populaire Dauphine & Alpes Sud, Beghin Meiji Ind, Candia Cedillac SA, Co Des Salins Midi & Des Salines Est, Diepal-nsa, Estee Lauder Co, Ingen Inter Genet Techn, INRA, Labcatal SA, Lab Boiron, Lab CCD, Lab Des Granions, Lab Randox, Lab Richelet, Lab Robapharm Pierre Fabre Medicament, Lab Roche Nicholas SA, Mairie Grenoble, Micromass UK Ltd, Nestle Res Ctr, Nicomed AS SERO, Perkin Elmer SA, Pharma N, Roche Diagnost SA, Selenium Tellurium Dev Assoc Inc, Univ Joseph Fourier, Reg Rhone Alpes, SA Eaux Minerales Evian, US Borax Inc ID HUMAN THIOREDOXIN REDUCTASE; SELENOCYSTEINE-CONTAINING ENZYME; CLOSTRIDIAL GLYCINE REDUCTASE; LUNG ADENOCARCINOMA CELLS; SELD GENE-PRODUCT; ESCHERICHIA-COLI; SELENOPHOSPHATE SYNTHETASE; GLUTATHIONE-PEROXIDASE; FORMATE DEHYDROGENASE; NUCLEOTIDE-SEQUENCE C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Stadtman, TC (reprint author), NHLBI, Biochem Lab, NIH, Bldg 3,Room 106,MSC 0320 Ctr Dr, Bethesda, MD 20892 USA. NR 59 TC 0 Z9 0 U1 0 U2 3 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA BN 0-306-46378-4 PY 2000 BP 831 EP 836 PG 6 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA BR11V UT WOS:000165695000267 ER PT J AU Haxby, JV Ishai, A Chao, LL Ungerleider, LG Martin, A AF Haxby, JV Ishai, A Chao, LL Ungerleider, LG Martin, A TI Object-form topology in the ventral temporal lobe - Response to I. Gauthier (2000) SO TRENDS IN COGNITIVE SCIENCES LA English DT Editorial Material ID CORTEX C1 NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Haxby, JV (reprint author), NIMH, Lab Brain & Cognit, Bldg 10,Room 4C104, Bethesda, MD 20892 USA. RI martin, alex/B-6176-2009 NR 13 TC 36 Z9 36 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1364-6613 J9 TRENDS COGN SCI JI TRENDS COGN. SCI. PD JAN PY 2000 VL 4 IS 1 BP 3 EP 4 DI 10.1016/S1364-6613(99)01423-0 PG 2 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 270PK UT WOS:000084544500002 ER PT J AU O'Brien, SJ AF O'Brien, SJ TI Adaptive cycles: parasites selectively reduce inbreeding in Soay sheep SO TRENDS IN ECOLOGY & EVOLUTION LA English DT Editorial Material ID MAJOR HISTOCOMPATIBILITY COMPLEX; INFECTION C1 NCI, Lab Genom Divers, Frederick, MD 21702 USA. RP O'Brien, SJ (reprint author), NCI, Lab Genom Divers, Frederick, MD 21702 USA. NR 11 TC 13 Z9 14 U1 0 U2 6 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0169-5347 J9 TRENDS ECOL EVOL JI Trends Ecol. Evol. PD JAN PY 2000 VL 15 IS 1 BP 7 EP 9 DI 10.1016/S0169-5347(99)01773-5 PG 3 WC Ecology; Evolutionary Biology; Genetics & Heredity SC Environmental Sciences & Ecology; Evolutionary Biology; Genetics & Heredity GA 287UP UT WOS:000085525100004 ER PT J AU Pruitt, KD Katz, KS Sicotte, H Maglott, DR AF Pruitt, KD Katz, KS Sicotte, H Maglott, DR TI Introducing RefSeq and LocusLink: curated human genome resources at the NCBI SO TRENDS IN GENETICS LA English DT Editorial Material ID HUMAN GENES; DATABASE C1 Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Pruitt, KD (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bldg 38A,Room 8N805, Bethesda, MD 20894 USA. NR 8 TC 168 Z9 176 U1 0 U2 1 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD JAN PY 2000 VL 16 IS 1 BP 44 EP 47 DI 10.1016/S0168-9525(99)01882-X PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 349EW UT WOS:000089031500011 PM 10637631 ER PT J AU Masison, DC AF Masison, DC TI Expanding the prion model for the yeast [PSI+] element SO TRENDS IN MICROBIOLOGY LA English DT Editorial Material ID SACCHAROMYCES-CEREVISIAE; SUP35 PROTEIN; IN-VITRO; PROPAGATION; DETERMINANT; PSI(+); GENE; MUTATION; SCRAPIE; PRP C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Masison, DC (reprint author), NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. NR 17 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0966-842X J9 TRENDS MICROBIOL JI Trends Microbiol. PD JAN PY 2000 VL 8 IS 1 BP 1 EP 2 DI 10.1016/S0966-842X(99)01651-0 PG 2 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 301XP UT WOS:000086336100001 PM 10637632 ER PT J AU Taylor, SI AF Taylor, SI TI Rational design of peptide agonists of cell-surface receptors SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Editorial Material ID EXTRACELLULAR DOMAIN; COMPLEX; INSULIN; INTERNALIZATION C1 NIDDK, Diabet Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Taylor, SI (reprint author), NIDDK, Diabet Branch, Div Intramural Res, NIH, Bldg 10, Room 9S-213,10 Ctr Dr, Bethesda, MD 20892 USA. NR 8 TC 2 Z9 2 U1 1 U2 1 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 JAN PY 2000 VL 21 IS 1 BP 9 EP 10 DI 10.1016/S0165-6147(99)01414-5 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 271HZ UT WOS:000084589300002 PM 10637647 ER PT B AU Fuhrman, S Wen, XL Michaels, GS Somogyi, R AF Fuhrman, S Wen, XL Michaels, GS Somogyi, R BE BarYam, Y TI Genetic network inference SO UNIFYING THEMES IN COMPLEX SYSTEMS SE NEW ENGLAND COMPLEX SYSTEMS INSTITUTE SERIES ON COMPLEXITY LA English DT Proceedings Paper CT 2nd International Conference on Complex Systems CY OCT 25-30, 1998 CL NEW ENGLAND COMPLEX SYST INST, NASHUA, NH SP Oxford Univ Press, Natl Sci Fdn, Coopers & Lybrand Consulting, McKinsey & Co, Addison Wesley Longman Publisher, John Benjamin Publisher, Santa Fe Inst, Soc Chaos Theory Psychol & Life Sci, Boston Univ, Coll Engn HO NEW ENGLAND COMPLEX SYST INST AB Development may be conceptualized as the dynamic output of a genetic program. We have applied this analogy experimentally by using reverse transcription-coupled polymerase chain reaction (RT-PCR) to measure the expression (mRNA) of large numbers of genes over the course of central nervous system (CNS) development. We have determined mRNA expression at nine developmental time points for 65 genes in rat cervical spinal cord and hippocampus. Clustering these temporal gene expression patterns using the euclidean distance measure revealed groups of genes which may share inputs. We found that these 65 genes expressed in spinal cord and hippocampus-two distantly related CNS regions-cluster into a small number of basic temporal expression patterns, and that the majority of genes assayed are at least moderately similar in their individual temporal expression patterns when the two regions are compared. This finding suggests the existence of a basic neural genetic program, common to all CNS regions. The collection of temporal gene expression patterns and development of computational methods, such as clustering and reverse engineering algorithms for analyzing these data, may provide new hypotheses concerning the study of development, tissue regeneration and cancer. C1 NINDS, Mol Physiol CNS Dev, LNP, NIH, Bethesda, MD 20892 USA. RP Fuhrman, S (reprint author), NINDS, Mol Physiol CNS Dev, LNP, NIH, 36-2C02, Bethesda, MD 20892 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU PERSEUS PUBLISHING PI CAMBRIDGE PA 11 CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA BN 0-7382-0049-2 J9 NEW ENGL COMPL SYST PY 2000 BP 199 EP 208 PG 10 WC Mathematics, Applied SC Mathematics GA BP77W UT WOS:000086160100019 ER PT B AU Somogyi, R AF Somogyi, R BE BarYam, Y TI Many to one mappings as a basis for life SO UNIFYING THEMES IN COMPLEX SYSTEMS SE NEW ENGLAND COMPLEX SYSTEMS INSTITUTE SERIES ON COMPLEXITY LA English DT Proceedings Paper CT 2nd International Conference on Complex Systems CY OCT 25-30, 1998 CL NEW ENGLAND COMPLEX SYST INST, NASHUA, NH SP Oxford Univ Press, Natl Sci Fdn, Coopers & Lybrand Consulting, McKinsey & Co, Addison Wesley Longman Publisher, John Benjamin Publisher, Santa Fe Inst, Soc Chaos Theory Psychol & Life Sci, Boston Univ, Coll Engn HO NEW ENGLAND COMPLEX SYST INST C1 NINDS, LNP, NIH, Bethesda, MD 20892 USA. RP Somogyi, R (reprint author), NINDS, LNP, NIH, 36-2C02, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 U1 0 U2 1 PU PERSEUS PUBLISHING PI CAMBRIDGE PA 11 CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA BN 0-7382-0049-2 J9 NEW ENGL COMPL SYST PY 2000 BP 503 EP 512 PG 10 WC Mathematics, Applied SC Mathematics GA BP77W UT WOS:000086160100042 ER PT S AU Bezrukov, SM Vodyanoy, I AF Bezrukov, SM Vodyanoy, I BE Abbott, D Kish, LB TI In search for a possible statistical basis of Stochastic Resonance SO UNSOLVED PROBLEMS OF NOISE AND FLUCTUATIONS SE AIP CONFERENCE PROCEEDINGS LA English DT Proceedings Paper CT 2nd International Conference on Unsolved Problems of Noise and Fluctuations (UPoN 99) CY JUL 12-15, 1999 CL ADELAIDE, AUSTRALIA SP IEEE Electron Devoces Soc, Inst Phys, US Off Naval Res, USAF Res Labs, Ctr Biomed Engn, Adelaide, Natl Inst Theoret Phys, Dept Ind Sci & Resources Australia, Defence Sci & Technol Org, Inst Engineers, Australia ID ION CHANNELS; NOISE AB Stochastic Resonance (SR) is a phenomenon of enhancing the information content at the system output by adding noise to the input signal. Originally, SR was shown in dynamical systems ranging from glaciers to superconducting junctions. Later it was found to occur in non-dynamical systems with and without thresholds. Now a growing number of publications report SR practically everywhere: in meteorology, sociology, finance, psyche-physics, electrophysiology, chemistry, etc. We seek a general statistical mechanism which would capture and, thus, explain the essence of SR independently of the system where it is found. Though, at present, this problem is far from solved, we think that the doubly-stochastic Poisson process approach described here represents a significant step toward such a generalization. Using this approach, we show that, in contrast to the current point of view, an activation barrier is not a necessary prerequisite of a Stochastic Resonator. C1 NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. RP Bezrukov, SM (reprint author), NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. NR 11 TC 0 Z9 0 U1 0 U2 0 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 0094-243X BN 1-56396-826-6 J9 AIP CONF PROC PY 2000 VL 511 BP 169 EP 178 PG 10 WC Physics, Applied SC Physics GA BP98J UT WOS:000086805200019 ER PT B AU Anselmi, R Andreucci, L Bisi, F Bevegni, M AF Anselmi, R Andreucci, L Bisi, F Bevegni, M BE Schlegel, W Bortfeld, T TI Implementation of EvTool, a quantitative and radiobiological evaluation system, in a commercial RTPS. SO USE OF COMPUTERS IN RADIATION THERAPY LA English DT Proceedings Paper CT 13th International Conference on the Use of Computers in Radiation Therapy CY MAY 22-25, 2000 CL HEIDELBERG, GERMANY SP Direx Syst GmbH, Gammex RMI GmbH, MDS Nordion Therapy Syst, Multidata Syst Duetschland GmbH, Phys Med & Biol, Siemens Med Technik, Varian Med Syst Int AG C1 Natl Canc Inst, Biophys Lab, I-16132 Genoa, Italy. RP Anselmi, R (reprint author), Natl Canc Inst, Biophys Lab, Lgo R Benzi 10, I-16132 Genoa, Italy. NR 1 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY BN 3-540-67176-5 PY 2000 BP 249 EP 249 PG 1 WC Computer Science, Interdisciplinary Applications; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Radiology, Nuclear Medicine & Medical Imaging GA BQ45R UT WOS:000088386600094 ER PT S AU Pattabiraman, N Matthews, JH Ward, KB Mantile-Selvaggi, G Miele, L Mukherjee, AB AF Pattabiraman, N Matthews, JH Ward, KB Mantile-Selvaggi, G Miele, L Mukherjee, AB BE Mukherjee, AB Chilton, BS TI Crystal structure analysis of recombinant human uteroglobin and molecular modeling of ligand binding SO UTEROGLOBIN/CLARA CELL PROTEIN FAMILY SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on Uteroglobin/Calra Cell Protein Family CY APR 14-16, 2000 CL BETHESDA, MARYLAND SP NICHHD, NHLBI, New York Acad Sci ID IMMUNOGLOBULIN-A NEPHROPATHY; CELL 10-KDA PROTEIN; PHOSPHOLIPASE-A2 ACTIVITY; SECONDARY STRUCTURE; RABBIT UTEROGLOBIN; GENE-EXPRESSION; KDA PROTEIN; PROGESTERONE; REFINEMENT; RESOLUTION AB Uteroglobin, a steroid-inducible, cytokine-like, secreted protein with immunomodulatory properties, has been reported to bind progesterone, polychlorinated biphenyls (PCB), and retinol. Structural studies may delineate whether binding of ligands is a likely physiological function of human uteroglobin (hUG). We report a refined crystal structure of uncomplexed recombinant hUG (rhUG) at 2.5-Angstrom, resolution and the results of our molecular modeling studies of ligand binding to the central hydrophobic cavity of rhUG. The crystal structure of rhUG is very similar to that of reported crystal structures of uteroglobins. Using molecular modeling techniques, the three ligands-PCB, progesterone, and retinol-were docked into the hydrophobic cavity of the dimer structure of rhUG. We undocked the progesterone ligand by pulling the ligand from the cavity into the solvent From our modeling and undocking studies of progesterone, it is clear that these types of hydrophobic ligands could slip into the cavity between helix-3 and helix-3' of the dimer instead of between helix-1 and helix-4 of the monomer, as proposed earlier. Our results suggest that at least one of the physiological functions of UG is to bind to hydrophobic ligands, such as progesterone and retinol. C1 USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Pattabiraman, N (reprint author), NCI, Adv Biomed Comp Ctr, SAIC, 430 Miller Dr, Frederick, MD 21702 USA. NR 48 TC 18 Z9 19 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-293-2 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 923 BP 113 EP 127 PG 15 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BT10P UT WOS:000171966400009 PM 11193750 ER PT S AU Chan, CC Tuaillon, N Li, Q Shen, DF AF Chan, CC Tuaillon, N Li, Q Shen, DF BE Mukherjee, AB Chilton, BS TI Therapeutic applications of antiflammin peptides in experimental ocular inflammation SO UTEROGLOBIN/CLARA CELL PROTEIN FAMILY SE Annals of the New York Academy of Sciences LA English DT Article; Proceedings Paper CT Conference on Uteroglobin/Clara Cell Protein Family CY APR 14-16, 2000 CL BETHESDA, MD SP NICHHD, NHLBI, New York Acad Sci ID ENDOTOXIN-INDUCED UVEITIS; COMPOUND 48/80-INDUCED CONJUNCTIVITIS; ANTIINFLAMMATORY PEPTIDES; INTERLEUKIN-6; PHOSPHOLIPASE-A2; CHEMOTAXIS; INHIBITORS; INJURY; MOUSE; RATS AB Antiflammins are synthetic peptides derived from the region of highest local similarity between uteroglobulin and lipocortin. These peptides have shown anti-inflammatory activity on carrageenan-induced rat footpad edema. They are potent inhibitors for phospholipase A(2) activation both in vitro and in vivo. Previously, we have demonstrated the effectiveness of topical antiflammins in suppressing acute ocular inflammation and allergic response in rodent endotoxin-induced uveitis and murine allergic conjunctivitis. The mechanisms by which antiflammins protect against inflammation and allergy in these ocular models may involve inhibition of phospholipase A2 and inducible nitric oxide synthase (MOS) as well as the production of proinflammatory cytokine, interleukin-6. C1 NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Wilmer Ophthalmol Inst, Baltimore, MD 21218 USA. RP Chan, CC (reprint author), NEI, Immunopathol Sect, Immunol Lab, NIH, 10 Ctr Dr,Bldg 10,Room 10N103, Bethesda, MD 20892 USA. EM ccc@helix.nih.gov NR 22 TC 10 Z9 11 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-293-2 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 923 BP 141 EP 146 PG 6 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BT10P UT WOS:000171966400011 PM 11193752 ER PT S AU Cowan, MJ Huang, X Yao, XL Shelhamer, JH AF Cowan, MJ Huang, X Yao, XL Shelhamer, JH BE Mukherjee, AB Chilton, BS TI Tumor necrosis factor alpha stimulation of human Clara cell secretory protein production by human airway epithelial cells SO UTEROGLOBIN/CLARA CELL PROTEIN FAMILY SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on Uteroglobin/Calra Cell Protein Family CY APR 14-16, 2000 CL BETHESDA, MARYLAND SP NICHHD, NHLBI, New York Acad Sci ID GENE-EXPRESSION; SIGNAL-TRANSDUCTION; POLYCHLORINATED-BIPHENYLS; PHOSPHOLIPASE-A2 ACTIVITY; BINDING-PROTEIN; ACTIVATION; CORTICOSTEROIDS; UTEROGLOBIN; RECEPTOR; KINASE AB Clara cell secretory protein (CCSP) or uteroglobin/CC10 is a product of epithelial cells in a variety of organs including the lung. CCSP has antiinflammatory properties and may act as an inhibitor of secretory phospholipase A(2)'s. Tumor necrosis factor alpha (TNT-alpha) is capable of inducing the expression of gene products including a variety of cytokines and chemokines in the airway epithelium that may upregulate the airway inflammatory response. Therefore, it was of interest to determine whether this proinflammatory cytokine might also induce the production of a counterregulatory protein such as CCSP, which might modulate the inflammatory response in the airway. Normal human tracheobronchial epithelial cells in primary culture and a human bronchial epithelial cell line (BEAS-2B) were studied. CCSP mRNA levels in BEAS-2B cells were detected by ribonuclease protection assay. CCSP mRNA levels increased in response to TNF-alpha (20 ng/mL) stimulation after 8-36 h, with the peak increase at 18 h. Immunoblotting of CCSP released from BEAS-2B cells Into the culture media demonstrated that TNF-alpha induced the synthesis and secretion of CCSP over 8 to 18 h. Similarly, TNF stimulated the release of CCSP from human tracheobronchial epithelial cells in primary culture at 8 and 18 h. The CCSP reporter gene including 801 bases 5' of the transcription start site did not increase transcriptional activity in response to TNF-alpha stimulation. A CCSP mRNA half-life assay indicated that TNF-alpha induced increases in CCSP mRNA at least in part at a posttranscriptional level. Therefore, TNF-alpha induces airway epithelial cell expression of human CCSP and may modulate airway inflammatory responses in this manner. C1 NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Shelhamer, JH (reprint author), NIH, Ctr Clin, Dept Crit Care Med, Bldg 10,Room 7-D-43, Bethesda, MD 20892 USA. NR 33 TC 10 Z9 11 U1 1 U2 4 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-293-2 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 923 BP 193 EP 201 PG 9 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BT10P UT WOS:000171966400016 PM 11193757 ER PT S AU Zhang, ZJ Kundu, GC Zheng, F Yuan, CJ Lee, E Westphal, H Ward, J DeMayo, F Mukherjee, AB AF Zhang, ZJ Kundu, GC Zheng, F Yuan, CJ Lee, E Westphal, H Ward, J DeMayo, F Mukherjee, AB BE Mukherjee, AB Chilton, BS TI Insight into the physiological function(s) of uteroglobin by gene-knockout and antisense-transgenic approaches SO UTEROGLOBIN/CLARA CELL PROTEIN FAMILY SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on Uteroglobin/Calra Cell Protein Family CY APR 14-16, 2000 CL BETHESDA, MARYLAND SP NICHHD, NHLBI, New York Acad Sci ID IMMUNOGLOBULIN-A NEPHROPATHY; HUMAN MESANGIAL CELLS; IGA NEPHROPATHY; PHOSPHOLIPASE-A2 ACTIVITY; GROWTH-FACTOR; CANCER-CELLS; FIBRONECTIN; BINDING; MICE; PROTEIN AB To determine the physiological function(s) of uteroglobin (UG), a steroid-inducible, homodimeric, secreted protein, we have generated trans. genic mice that either are completely UG-deficient due to UG gene-knockout (UG-KO) or are partially UG-deficient due to the expression of UG antisense RNA (UG-AS). Both the UG-KO and UG-AS mice develop immunoglobulin A (IgA) nephropathy (IgAN), characterized by microhematuria, albuminuria, and renal glomerular deposition of IgA, fibronectin (Fn), collagen, and C3 complement. This phenotype of both UG-KO and UG-AS mice is virtually identical to that of human IgAN, the most common primary glomerulopathy worldwide. The molecular mechanism by which UG prevents this disease in mice appears to center around UG's interaction with Fn. Since Fn, IgA, and UG are present in circulation and high plasma levels of IgA-Fn complex have been reported in human IgAN, we sought to determine whether UG interacts with Fn and prevents Fn-Fn and/or IgA-Fn interactions, essential for abnormal tissue deposition of Fn and IgA. Our coimmunoprecipitation studies uncovered the formation of Fn-UG heteromers in vitro and these heteromers are detectable in the plasma of normal mice, but not UG-KO mice. Further, high plasma levels of IgA-Fn complex, a characteristic of human IgAN patients, were also found in UG-KO mice. Finally, coadministration of UG + Fn or UG + IgA to UG-KO mice prevented glomerular deposition of Fn and IgA, respectively. Our results define a possible molecular mechanism of IgAN and provide insight into at least one important physiological function of UG in maintaining normal renal function in mice. C1 NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Lab Mammalian Genet & Dev, NIH, Bethesda, MD 20892 USA. NCI, Vet & Tumor Pathol Sect, Off Lab Anim Sci, NIH, Frederick, MD 21702 USA. Baylor Coll Med, Dept Cell Biol, Houston, TX 77030 USA. RP Mukherjee, AB (reprint author), NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bldg 10,Room 9S241, Bethesda, MD 20892 USA. NR 35 TC 17 Z9 18 U1 0 U2 6 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-293-2 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 923 BP 210 EP 233 PG 24 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BT10P UT WOS:000171966400018 PM 11193759 ER PT S AU Kundu, GC Zhang, ZJ Mantile-Selvaggi, G Mandal, A Yuan, CJ Mukherjee, AB AF Kundu, GC Zhang, ZJ Mantile-Selvaggi, G Mandal, A Yuan, CJ Mukherjee, AB BE Mukherjee, AB Chilton, BS TI Uteroglobin binding proteins: Regulation of cellular motility and invasion in normal and cancer cells SO UTEROGLOBIN/CLARA CELL PROTEIN FAMILY SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on Uteroglobin/Calra Cell Protein Family CY APR 14-16, 2000 CL BETHESDA, MARYLAND SP NICHHD, NHLBI, New York Acad Sci ID EXTRACELLULAR-MATRIX INVASION; RABBIT UTEROGLOBIN; URINE PROTEIN-1; GENE-EXPRESSION; 10-KD PROTEIN; PURIFICATION; FIBRONECTIN; PROLACTIN; REGION; ACID AB Uteroglobin (UG) is a multifunctional, secreted protein with antiinflammatory and antichemotactic properties. While its anti-inflammatory effects, in part, stem from the inhibition of soluble phospholipase A(2) (sPLA(2)) activity, the mechanism(s) of its antichemotactic effects is not clearly understood. Although specific binding of UG on microsomal and plasma membranes has been reported recently, how this binding affects cellular function is not clear. Here, we report that recombinant human UG (hUG) binds to both normal and cancer cells with high affinity (20-35 nM, respectively) and specificity. Affinity cross-Iinking studies revealed that I-125-hUG binds to the NIH 3T3 cell surface with two proteins of apparent molecular masses of 190 and 49 kDa, respectively. UG affinity chromatography yielded similar results. While both the 190- and 49-kDa proteins were expressed in the heart, liver, and spleen, the lung and trachea expressed only the 190-kDa protein. Some cancer cells (e.g., mastocytoma, sarcoma, and lymphoma) expressed both the 190- and 49-kDa proteins. Further, using functional assays, we found that UG dramatically suppressed the motility and extracellular matrix invasion of both NIH 3T3 and some cancer cells. In order to further characterize the anti-ECM-invasive properties of UG, we induced expression of hUG into cancer cell lines derived from organs that, under physiological circumstances, secrete UG at a high level. Interestingly, it has been reported that a high percentage of the adeno. carcinomas arising from the same organs fail to express UG. Our results on induced hUG expression in these cells show that inhibition of motility and ECM invasion requires the expression of both UG and its binding proteins. Taken together, our data define receptor-mediated functions of UG in which this protein regulates vital cellular functions by both autocrine and paracrine pathways. C1 NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Kundu, GC (reprint author), Natl Ctr Cell Sci, NCCS Complex, Pune 411007, Maharashtra, India. NR 35 TC 10 Z9 11 U1 1 U2 3 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-293-2 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 923 BP 234 EP 248 PG 15 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BT10P UT WOS:000171966400019 PM 11193760 ER PT S AU Linnoila, RI Szabo, E Demayo, F Witschi, H Sabourin, C Malkinson, A AF Linnoila, RI Szabo, E Demayo, F Witschi, H Sabourin, C Malkinson, A BE Mukherjee, AB Chilton, BS TI The role of CC10 in pulmonary carcinogenesis: From a marker to tumor suppression SO UTEROGLOBIN/CLARA CELL PROTEIN FAMILY SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on Uteroglobin/Calra Cell Protein Family CY APR 14-16, 2000 CL BETHESDA, MARYLAND SP NICHHD, NHLBI, New York Acad Sci ID CLARA CELL ANTIGEN; LUNG-CANCER; NEUROENDOCRINE DIFFERENTIATION; CLINICOPATHOLOGICAL FEATURES; BRONCHIOLAR EPITHELIUM; TRANSGENIC MICE; MESSENGER-RNA; RETINOIC ACID; NONSMALL CELL; HAMSTER LUNG AB CC10 is infrequently expressed in human non-small cell lung cancers (NSCLCs), despite being abundantly produced by progenitor cells for normal and neoplastic epithelium. Many abnormalities in the surrounding lung associated with field carcinogenesis, which reflect prolonged exposure to such carcinogens as tobacco smoke, also revealed altered expression of CC10. Exposure of hamsters and mice to the tobacco-specific carcinogen NNK led to reduced CC10 expression, which was partially reversible. Overexpression of CC10 in immortalized bronchial epithelial cells delayed the induction of anchorage-independent growth in response to NNK. The data suggest that downregulation of CC10 contributes to carcinogenesis because CC10 antagonizes the neoplastic phenotype. C1 NCI, Cell & Canc Biol Dept, Med Branch, Div Clin Sci,NIH, Rockville, MD 20850 USA. Baylor Coll Med, Houston, TX 77030 USA. Univ Calif Davis, Davis, CA 95616 USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Colorado, Denver, CO 80262 USA. RP Linnoila, RI (reprint author), NCI, Cell & Canc Biol Dept, Med Branch, Div Clin Sci,NIH, 9610 Med Ctr Dr,Suite 300, Rockville, MD 20850 USA. NR 60 TC 38 Z9 42 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-293-2 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 923 BP 249 EP 267 PG 19 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BT10P UT WOS:000171966400020 PM 11193761 ER PT S AU Choi, M Zhang, ZJ Ten Kate, LP Collee, JM Gerritsen, J Mukherjee, AB AF Choi, M Zhang, ZJ Ten Kate, LP Collee, JM Gerritsen, J Mukherjee, AB BE Mukherjee, AB Chilton, BS TI Human uteroglobin gene polymorphisms and genetic susceptibility to asthma SO UTEROGLOBIN/CLARA CELL PROTEIN FAMILY SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on Uteroglobin/Calra Cell Protein Family CY APR 14-16, 2000 CL BETHESDA, MARYLAND SP NICHHD, NHLBI, New York Acad Sci ID NEPHROPATHY; PROTEIN C1 NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. Vrije Univ Amsterdam, Med Ctr, Dept Clin & Human Genet, Amsterdam, Netherlands. Beatrix Childrens Hosp, Dept Pediat Pulmonol, Groningen, Netherlands. RP Choi, M (reprint author), NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. NR 17 TC 8 Z9 8 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-293-2 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 923 BP 303 EP 306 PG 4 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BT10P UT WOS:000171966400024 PM 11193766 ER PT S AU Chowdhury, B Mantile-Selvaggi, G Kundu, GC Miele, L Cordella-Miele, E Zhang, ZJ Mukherjee, AB AF Chowdhury, B Mantile-Selvaggi, G Kundu, GC Miele, L Cordella-Miele, E Zhang, ZJ Mukherjee, AB BE Mukherjee, AB Chilton, BS TI Amino acid residues in alpha-helix-3 of human uteroglobin are critical for its phospholipase A(2) inhibitory activity SO UTEROGLOBIN/CLARA CELL PROTEIN FAMILY SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on Uteroglobin/Calra Cell Protein Family CY APR 14-16, 2000 CL BETHESDA, MARYLAND SP NICHHD, NHLBI, New York Acad Sci ID CELL 10-KDA PROTEIN; TISSUE-SPECIFIC EXPRESSION; RABBIT UTEROGLOBIN; QUATERNARY STRUCTURE; BINDING; GENE; CLONING; REGION; PURIFICATION; LOCALIZATION C1 NICHHD, Sect Dev Genet, Human Genet Branch, NIH, Bethesda, MD 20892 USA. RP Chowdhury, B (reprint author), NICHHD, Sect Dev Genet, Human Genet Branch, NIH, Bethesda, MD 20892 USA. NR 37 TC 3 Z9 3 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-293-2 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 923 BP 307 EP 311 PG 5 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BT10P UT WOS:000171966400025 PM 11193767 ER PT S AU Momeda, K Zhang, ZJ Mukherjee, AB Dhanireddy, R AF Momeda, K Zhang, ZJ Mukherjee, AB Dhanireddy, R BE Mukherjee, AB Chilton, BS TI A novel in situ method of SV40 transfection for the establishment of immortal pulmonary alveolar type II cell lines SO UTEROGLOBIN/CLARA CELL PROTEIN FAMILY SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on Uteroglobin/Calra Cell Protein Family CY APR 14-16, 2000 CL BETHESDA, MARYLAND SP NICHHD, NHLBI, New York Acad Sci ID LUNG DEVELOPMENT; GENE-EXPRESSION; PROTEIN; UTEROGLOBIN; PROLACTIN; RABBITS C1 Georgetown Univ, Sch Med, Dept Pediat, Div Neonatol, Washington, DC 20007 USA. NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Dhanireddy, R (reprint author), Louisiana State Univ, Med Ctr, Dept Pediat, Div Neonatol, Shreveport, LA 71105 USA. RI Dhanireddy, Ramasubbareddy/I-3699-2016 OI Dhanireddy, Ramasubbareddy/0000-0002-8787-6499 NR 15 TC 0 Z9 0 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-293-2 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 923 BP 325 EP 331 PG 7 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BT10P UT WOS:000171966400029 PM 11193771 ER PT S AU Klug, J Beier, HM Bernard, A Chilton, BS Fleming, TP Lehrer, RI Miele, L Pattabiraman, N Singh, G AF Klug, J Beier, HM Bernard, A Chilton, BS Fleming, TP Lehrer, RI Miele, L Pattabiraman, N Singh, G BE Mukherjee, AB Chilton, BS TI Uteroglobin/Clara cell 10-kDa family of proteins: Nomenclature committee report SO UTEROGLOBIN/CLARA CELL PROTEIN FAMILY SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on Uteroglobin/Calra Cell Protein Family CY APR 14-16, 2000 CL BETHESDA, MARYLAND SP NICHHD, NHLBI, New York Acad Sci ID RAT VENTRAL PROSTATE; AMINO-ACID-SEQUENCE; 10 KDA PROTEIN; RABBIT UTEROGLOBIN; SECRETORY PROTEIN; BINDING-PROTEIN; HORMONAL-REGULATION; GENE FAMILY; CLONING; EXPRESSION C1 Univ Marburg, Inst Mol Biol & Tumorforsch, D-30533 Marburg, Germany. Rhein Westfal TH Aachen, Dept Anat & Reprod Biol, D-52057 Aachen, Germany. Univ Catholique Louvain, Fac Med, Unit Ind Toxicol & Occupat Med, B-1200 Brussels, Belgium. Texas Tech Univ, Hlth Sci Ctr, Dept Cell Biol & Biochem, Lubbock, TX 79430 USA. Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Inst Mol Biol, Los Angeles, CA 90095 USA. Loyola Univ, Med Ctr, Dept Pathol, Maywood, IL 60153 USA. Loyola Univ, Med Ctr, Cardinal Bernardin Canc Ctr, Maywood, IL 60153 USA. NCI, Frederick Canc Res & Dev Ctr, Adv Biomed Comp Ctr, SAIC, Frederick, MD 21702 USA. Vet Adm Med Ctr, Pittsburgh, PA 15240 USA. Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15240 USA. RP Klug, J (reprint author), Univ Marburg, Inst Mol Biol & Tumorforsch, Emil Mannkopff Str 2, D-30533 Marburg, Germany. RI BERNARD, Alfred/A-6511-2010 OI BERNARD, Alfred/0000-0003-3171-3743 NR 45 TC 98 Z9 101 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-293-2 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 923 BP 348 EP 354 PG 7 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA BT10P UT WOS:000171966400035 PM 11193777 ER PT S AU Hampel, H Teipel, SJ Alexander, GE Horwitz, B Pietrini, P Hippius, H Moller, HJ Schapiro, MB Rapoport, SI AF Hampel, H Teipel, SJ Alexander, GE Horwitz, B Pietrini, P Hippius, H Moller, HJ Schapiro, MB Rapoport, SI BE Kalaria, RN Ince, P TI Corpus callosum measurement as an in vivo indicator for neocortical neuronal integrity, but not white matter pathology, in Alzheimer's disease SO VASCULAR FACTORS IN ALZHEIMER'S DISEASE SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on Vascular Factors in Alzheimers Disease CY MAY 25-28, 1999 CL NEWCASTLE TYNE, ENGLAND SP Bayer AG, Eisai Ltd, GJ Livanos Trust, Alzheimers Report, Hoechst Marrion Roussel, Janssen Pharmaceut, Novartis Pharma AG, Parke Davis, Pfizer Inc, SmithKline Beecham Pharmaceut, Zeneca, Med Res Council, Inst Brain & Blood Vessels, Akita, Inst Hlth Elderly, Univ Newcastle Upon Tyne ID POSITRON EMISSION TOMOGRAPHY; NEUROFIBRILLARY TANGLES; MULTIPLE-SCLEROSIS; MONOCLONAL-ANTIBODY; RISK-FACTORS; BRAIN MR; ATROPHY; DEMENTIA; LESIONS; HYPERINTENSITIES C1 Univ Munich, Dept Psychiat, Dementia & Neuroimaging Sect, D-80336 Munich, Germany. NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. RP Hampel, H (reprint author), Univ Munich, Dept Psychiat, Dementia & Neuroimaging Sect, Nussbaumstr 7, D-80336 Munich, Germany. NR 44 TC 15 Z9 15 U1 0 U2 3 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-251-7 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 903 BP 470 EP 476 DI 10.1111/j.1749-6632.2000.tb06401.x PG 7 WC Multidisciplinary Sciences; Clinical Neurology; Peripheral Vascular Disease SC Science & Technology - Other Topics; Neurosciences & Neurology; Cardiovascular System & Cardiology GA BQ26Z UT WOS:000087756800060 PM 10818540 ER PT J AU McDowell, JH Nawrocki, JP Hargrave, PA AF McDowell, JH Nawrocki, JP Hargrave, PA TI Isolation of isoelectric species of phosphorylated rhodopsin SO VERTEBRATE PHOTOTRANSDUCTION AND THE VISUAL CYCLE, PART A SE METHODS IN ENZYMOLOGY LA English DT Review ID AFFINITY-CHROMATOGRAPHY; LIGHT; DEPHOSPHORYLATION; ARRESTIN; SITES C1 Univ Florida, Dept Ophthalmol, Gainesville, FL 32610 USA. NIDDKD, Bioorgan Chem Lab, Bethesda, MD 20892 USA. Univ Florida, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. RP McDowell, JH (reprint author), Univ Florida, Dept Ophthalmol, Gainesville, FL 32610 USA. FU NEI NIH HHS [EY06626, EY06625] NR 17 TC 2 Z9 2 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2000 VL 315 BP 70 EP 76 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BQ69G UT WOS:000089206300005 PM 10736694 ER PT J AU Redmond, TM Hamel, CP AF Redmond, TM Hamel, CP TI Genetic analysis of RPE65: From human disease to mouse model SO VERTEBRATE PHOTOTRANSDUCTION AND THE VISUAL CYCLE, PT B SE METHODS IN ENZYMOLOGY LA English DT Review ID RETINAL-PIGMENT EPITHELIUM; LEBERS CONGENITAL AMAUROSIS; BINDING PROTEIN; RETINITIS-PIGMENTOSA; MONOCLONAL-ANTIBODIES; MICROSOMAL PROTEIN; MEMBRANE-RECEPTOR; MESSENGER-RNA; VITAMIN-A; MUTATIONS C1 NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. INSERM, U254, F-34090 Montpellier, France. RP Redmond, TM (reprint author), NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. OI Redmond, T. Michael/0000-0002-1813-5291 NR 45 TC 47 Z9 48 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2000 VL 316 BP 705 EP 724 PG 20 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BQ22M UT WOS:000087601700046 PM 10800710 ER PT J AU Race, RE AF Race, RE TI The trouble with transmissible degenerative encephalopathy agents SO VETERINARY JOURNAL LA English DT Editorial Material C1 NIAID, Rocky Mt Lab, Hamilton, MT 59840 USA. RP Race, RE (reprint author), NIAID, Rocky Mt Lab, 903 S 4th St, Hamilton, MT 59840 USA. NR 2 TC 1 Z9 1 U1 0 U2 0 PU BAILLIERE TINDALL PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1090-0233 J9 VET J JI Vet. J. PD JAN PY 2000 VL 159 IS 1 BP 3 EP 4 DI 10.1053/tvjl.1999.0431 PG 2 WC Veterinary Sciences SC Veterinary Sciences GA 280DZ UT WOS:000085088100002 PM 10640405 ER PT S AU Moody, TW Walters, J Casibang, M Zia, F Gozes, Y AF Moody, TW Walters, J Casibang, M Zia, F Gozes, Y BE Fahrenkrug, J Said, SI TI VPAC(1) receptors and lung cancer SO VIP, PACAP, GLUCAGON, AND RELATED PEPTIDES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 4th International Symposium on VIP, PACAP, GLUCAGON, and Related Peptides CY SEP 02-04, 1999 CL ELSINORE, DENMARK SP Amersham Pharmacia Biotech, ASTRA AB, BACHEM AG, Biotechnol Ctr Cellular Commun, Clinalfa AG, Danish Canc Fdn, Eli Lilly Danmark AS, Euro Diagnost, Fujifilm Sverige AB, Interneuron Pharmaceut Inc, Novex Kem En Tec AS, Leica, Neurosci Pharmabiotec, Neosystem SA, NOVO Nordist AS, Roche Molec Biochem, Schering AG, Sigma Genosys Ltd, Danish Med Res Council, Plasmid Fdn ID CELL-LINES; PEPTIDE; CARCINOMA; GROWTH; TUMORS; VIP; LOCALIZATION; ANTAGONIST AB VIP/PACAP are autocrine growth factors for lung cancer. VIP and/or PACAP mRNA is present in most lung cancer cell lines examined. Although mRNA for VPAC(2)-R is not common, VPAC(1)-R and PACT-R mRNA is present in many, lung cancer cell lines. I-125-VIP binds with high affinity to lung cancer cells and specific I-125-VIP binding is inhibited with high affinity by (Lys(15), Arg(16), Leu(27))VIP1-7 GRF8-27, the VPAC(1)-R specific agonist, but not by Ro25-1553(18), the VPAC(2)-R specific agonist. VIP elevates cAMP and increases c-fos gene expression. The increase in cAMP and c-fos mRNA caused by VIP is inhibited by SN(VII). (SH)VH inhibited the proliferation of NCI-H1299 cells in the MTT assay, which is based on cytotoxicity. In a recent cell line screen, (SN)VH inhibited the growth of 51 of 56 cancer cell lines including leukemia, lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, breast cancer, and prostate cancer (T. Moody, unpublished). It remains to be determined if (SN)VH will be useful for treatment of a wide variety of cancers. C1 NCI, Med Branch, Cell & Canc Biol Dept, Rockville, MD 20850 USA. George Washington Univ, Med Ctr, Dept Microbiol, Washington, DC 20037 USA. Israel Inst Biol Res, IL-70450 Ness Ziona, Israel. RP Moody, TW (reprint author), NCI, Med Branch, Cell & Canc Biol Dept, Bldg KWC,Rm 300,9610 Med Ctr Dr, Rockville, MD 20850 USA. NR 23 TC 20 Z9 20 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-273-8 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 921 BP 26 EP 32 PG 7 WC Biochemistry & Molecular Biology; Gastroenterology & Hepatology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Gastroenterology & Hepatology; Science & Technology - Other Topics GA BT09Y UT WOS:000171939800002 PM 11193832 ER PT S AU Thakur, ML Marcus, CS Saeed, S Pallela, V Minami, C Diggles, L Pham, HL Ahdoot, R Kalinowski, EA Moody, T AF Thakur, ML Marcus, CS Saeed, S Pallela, V Minami, C Diggles, L Pham, HL Ahdoot, R Kalinowski, EA Moody, T BE Fahrenkrug, J Said, SI TI Imaging tumors in humans with Tc-99m-VIP SO VIP, PACAP, GLUCAGON, AND RELATED PEPTIDES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 4th International Symposium on VIP, PACAP, GLUCAGON, and Related Peptides CY SEP 02-04, 1999 CL ELSINORE, DENMARK SP Amersham Pharmacia Biotech, ASTRA AB, BACHEM AG, Biotechnol Ctr Cellular Commun, Clinalfa AG, Danish Canc Fdn, Eli Lilly Danmark AS, Euro Diagnost, Fujifilm Sverige AB, Interneuron Pharmaceut Inc, Novex Kem En Tec AS, Leica, Neurosci Pharmabiotec, Neosystem SA, NOVO Nordist AS, Roche Molec Biochem, Schering AG, Sigma Genosys Ltd, Danish Med Res Council, Plasmid Fdn ID SCINTIGRAPHY; RECEPTORS AB Vasoactive intestinal peptide (VIP) was modified at the C terminus with a spacer and four amino acids to serve as a chelating moiety. The modified peptide, TP 3654, was labeled with Tc-99m and evaluated in normal volunteers, as well as in patients with a history of cancer. Renal clearance (67%) was the primary route of excretion, with approximately 20% of the radioactivity clearing through the hepatobiliary system. No adverse reaction was noted in any of the subjects and all, except one small, of the known lesions as seen by CT, MRI, Tc-99m-MIBI, or mammography were correctly identified within a few minutes of an i.v. injection of approximately 10 mCi of Tc-99m-TP 3654 (specific activity 11.3 x 10(3) Ci/m mol). The scans were in concordance in nine patients. In the remaining two, one with a visible mass in the neck from high grade spindle cell sarcoma and the other with a palpable mass in a breast from ductal epithelial hyperplasia, were localized only with Tc-99m-TP 3654, but not with Tc-99m-MIBI. Both malignancies are known to express VIP receptors. The VIP analog promises to be a nontoxic and reliable agent for imaging cancers in humans that express VIP receptors. C1 Thomas Jefferson Univ, Philadelphia, PA 19107 USA. Univ Calif Los Angeles, Harbor Med Ctr, Torrance, CA 90509 USA. NCI, Rockville, MD 20850 USA. RP Thakur, ML (reprint author), Thomas Jefferson Univ, 1020 Locust St, Philadelphia, PA 19107 USA. NR 8 TC 26 Z9 27 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-273-8 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 921 BP 37 EP 44 PG 8 WC Biochemistry & Molecular Biology; Gastroenterology & Hepatology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Gastroenterology & Hepatology; Science & Technology - Other Topics GA BT09Y UT WOS:000171939800004 PM 11193855 ER PT S AU Brenneman, DE Hauser, J Spong, CY Phillips, TM AF Brenneman, DE Hauser, J Spong, CY Phillips, TM BE Fahrenkrug, J Said, SI TI Chemokines released from astroglia by vasoactive intestinal peptide - Mechanism of neuroprotection from HIV envelope protein toxicity SO VIP, PACAP, GLUCAGON, AND RELATED PEPTIDES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 4th International Symposium on VIP, PACAP, GLUCAGON, and Related Peptides CY SEP 02-04, 1999 CL ELSINORE, DENMARK SP Amersham Pharmacia Biotech, ASTRA AB, BACHEM AG, Biotechnol Ctr Cellular Commun, Clinalfa AG, Danish Canc Fdn, Eli Lilly Danmark AS, Euro Diagnost, Fujifilm Sverige AB, Interneuron Pharmaceut Inc, Novex Kem En Tec AS, Leica, Neurosci Pharmabiotec, Neosystem SA, NOVO Nordist AS, Roche Molec Biochem, Schering AG, Sigma Genosys Ltd, Danish Med Res Council, Plasmid Fdn ID COAT PROTEIN; CELL-CULTURES; HUMAN NEURONS; GP120; INFECTION; NEUROTOXICITY; RECEPTORS; EXPRESSION; APOPTOSIS; CCR3 C1 NICHHD, SDMP, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. George Washington Univ, Med Ctr, Dept Med, Immunochem Lab, Washington, DC 20037 USA. RP Brenneman, DE (reprint author), NICHHD, SDMP, Dev Neurobiol Lab, NIH, Bldg 49,Room 5A38, Bethesda, MD 20892 USA. NR 21 TC 20 Z9 20 U1 1 U2 3 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-273-8 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 921 BP 109 EP 114 PG 6 WC Biochemistry & Molecular Biology; Gastroenterology & Hepatology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Gastroenterology & Hepatology; Science & Technology - Other Topics GA BT09Y UT WOS:000171939800011 PM 11193813 ER PT S AU Gozes, I Zamostiano, R Pinhasov, A Bassan, M Giladi, E Steingart, RA Brenneman, DE AF Gozes, I Zamostiano, R Pinhasov, A Bassan, M Giladi, E Steingart, RA Brenneman, DE BE Fahrenkrug, J Said, SI TI A novel VIP responsive gene - Activity dependent neuroprotective protein SO VIP, PACAP, GLUCAGON, AND RELATED PEPTIDES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 4th International Symposium on VIP, PACAP, GLUCAGON, and Related Peptides CY SEP 02-04, 1999 CL ELSINORE, DENMARK SP Amersham Pharmacia Biotech, ASTRA AB, BACHEM AG, Biotechnol Ctr Cellular Commun, Clinalfa AG, Danish Canc Fdn, Eli Lilly Danmark AS, Euro Diagnost, Fujifilm Sverige AB, Interneuron Pharmaceut Inc, Novex Kem En Tec AS, Leica, Neurosci Pharmabiotec, Neosystem SA, NOVO Nordist AS, Roche Molec Biochem, Schering AG, Sigma Genosys Ltd, Danish Med Res Council, Plasmid Fdn ID VASOACTIVE-INTESTINAL-PEPTIDE; NEUROTROPHIC FACTOR; NEURONAL SURVIVAL; SEQUENCE; IDENTIFICATION; SPECIFICITY; ASTROCYTES; SECRETION; DEATH AB Activity dependent neuroprotective protein (ADNP, 828 amino acids, pI 5.99) is a glial-derived protein that contains a femtomolar active neuroprotective peptide, NAPVSIPQ (NAP). VIP induces a two- to threefold increase in ADNP mRNA in astrocytes, suggesting that ADNP is a VIP-responsive gene. ADNP is widely distributed in the mouse hippocampus, cerebellum, and cerebral cortex. VIP has been shown to possess neuroprotective activity that may be exerted through the activation of glial proteins. We suggest that ADNP may be part of the VIP protection pathway through the femtomolar-acting NAP and through putative interaction with other macromolecules. C1 Tel Aviv Univ, Sackler Fac Med, Dept Clin Biochem, IL-69978 Tel Aviv, Israel. NICHHD, Sect Mol & Dev Pharmacol, LDN, NIH, Bethesda, MD 20892 USA. RP Gozes, I (reprint author), Tel Aviv Univ, Sackler Fac Med, Dept Clin Biochem, IL-69978 Tel Aviv, Israel. NR 21 TC 28 Z9 31 U1 1 U2 5 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-273-8 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 921 BP 115 EP 118 PG 4 WC Biochemistry & Molecular Biology; Gastroenterology & Hepatology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Gastroenterology & Hepatology; Science & Technology - Other Topics GA BT09Y UT WOS:000171939800012 PM 11193814 ER PT S AU Grimaldi, M Cavallaro, S AF Grimaldi, M Cavallaro, S BE Fahrenkrug, J Said, SI TI Expression and coupling of PACAP/VIP receptors in cortical neurons and type I astrocytes SO VIP, PACAP, GLUCAGON, AND RELATED PEPTIDES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 4th International Symposium on VIP, PACAP, GLUCAGON, and Related Peptides CY SEP 02-04, 1999 CL ELSINORE, DENMARK SP Amersham Pharmacia Biotech, ASTRA AB, BACHEM AG, Biotechnol Ctr Cellular Commun, Clinalfa AG, Danish Canc Fdn, Eli Lilly Danmark AS, Euro Diagnost, Fujifilm Sverige AB, Interneuron Pharmaceut Inc, Novex Kem En Tec AS, Leica, Neurosci Pharmabiotec, Neosystem SA, NOVO Nordist AS, Roche Molec Biochem, Schering AG, Sigma Genosys Ltd, Danish Med Res Council, Plasmid Fdn ID CYCLASE-ACTIVATING POLYPEPTIDE; VASOACTIVE-INTESTINAL-PEPTIDE; ADENYLATE-CYCLASE; CELLS C1 CNR, IBFSNC, Inst Bioimaging & Pathophysiol Cent Nervour Syst, I-95123 Catania, Italy. NINCDS, Lab Adapt Syst, NIH, Bethesda, MD 20892 USA. IRCCS, Oasi Inst Res Mental Retardat & Brain Aging, Troina, EN, Italy. RP Cavallaro, S (reprint author), CNR, IBFSNC, Inst Bioimaging & Pathophysiol Cent Nervour Syst, Piazza Roma,2, I-95123 Catania, Italy. RI Cavallaro, Sebastiano/F-3104-2010; OI Cavallaro, Sebastiano/0000-0001-7590-1792; Grimaldi, Maurizio/0000-0002-7331-7055 NR 13 TC 6 Z9 6 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-273-8 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 921 BP 312 EP 316 PG 5 WC Biochemistry & Molecular Biology; Gastroenterology & Hepatology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Gastroenterology & Hepatology; Science & Technology - Other Topics GA BT09Y UT WOS:000171939800039 PM 11193842 ER PT J AU Hardegen, NJ Toro, LA Muller, J Wahl, LM Hewlett, IK Dhawan, S AF Hardegen, NJ Toro, LA Muller, J Wahl, LM Hewlett, IK Dhawan, S TI HIV-1 infects and alters immune function of a monocyte subset expressing low CD14 surface phenotype SO VIRAL IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MONONUCLEAR PHAGOCYTES; MACROPHAGE; DIFFERENTIATION; PATHOGENESIS; CELLS; RECEPTOR AB Monocytes represent a leukocyte subset that express high levels of CD14 on their surface (CD14-high), These cells play a critical role in the pathogenesis of HIV-1 infection. In the present study, we have identified a monocyte subset expressing an extremely low level of CD14 (CD14-low), and examined their susceptibility to HIV-1 infection. Phenotypic analysis by flow cytometry of these cells revealed a low level of CD4, but the absence of CD3, CD14, CD19, and CD83 surface markers. Both CD14-low and CD14-high cell populations expressed CD13 and CD33 markers on their surface, suggesting these cells to be of myeloid origin, Morphologically, CD14-low cells were indistinguishable from CD14-high cells. CD14-low cells were susceptible to infection with a monocytotropic strain of HIV-1 (HIVADA) However, like CD14-high monocytes, CD14-low cells could not be productively infected with a T cell tropic strain of HIV-1 (H9/HTLVIIIB) Similar to CD14-high monocytes, CD14-low cells were capable of inducing antigen-stimulated CD4(+) T-cell proliferation. HIV-1 infection substantially reduced their ability to induce antigen-stimulated T-cell proliferation. These data indicate that CD14-low cells belong to the monocyte lineage and may play an important role in the immunopathogenesis of HIV-1 infection. C1 US FDA, Immunopathogenesis Sect, Mol Virol Lab,Ctr Biol Evaluat & Res, Div Transfus Transmitted Dis, Rockville, MD 20852 USA. Nat Inst Dent & Craniofacial Res, Immunopathol Sect, NIH, Bethesda, MD USA. EntreMed Inc, Rockville, MD USA. US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. RP Dhawan, S (reprint author), US FDA, Immunopathogenesis Sect, Mol Virol Lab,Ctr Biol Evaluat & Res, Div Transfus Transmitted Dis, 1401 Rockville Pike,HFM-315, Rockville, MD 20852 USA. NR 23 TC 1 Z9 1 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0882-8245 J9 VIRAL IMMUNOL JI Viral Immunol. PY 2000 VL 13 IS 1 BP 19 EP 26 DI 10.1089/vim.2000.13.19 PG 8 WC Immunology; Virology SC Immunology; Virology GA 293RF UT WOS:000085866300005 PM 10733165 ER PT J AU Cermelli, C Jacobson, S AF Cermelli, C Jacobson, S TI Viruses and multiple sclerosis SO VIRAL IMMUNOLOGY LA English DT Review ID EPSTEIN-BARR-VIRUS; HUMAN HERPESVIRUS-6 INFECTION; POLYMERASE-CHAIN-REACTION; CENTRAL-NERVOUS-SYSTEM; VARICELLA-ZOSTER VIRUS; MYELIN BASIC-PROTEIN; NEUROLOGICAL DISEASE; MOLECULAR MIMICRY; MARROW TRANSPLANTATION; DEMYELINATING DISEASE AB Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system whose cause is still unknown, Many findings suggest an infectious etiology or, at least, that infectious agents in association with host genetic factors may play a role in the pathogenesis of this disease. Accumulating data, including animal models, human models of virus induced demyelination, epidemiologic, and laboratory findings, demonstrate that viruses and host genetic factors can interact to cause immune-mediated demyelination, While many viruses have been postulated as a possible cause of MS, to date, no "MS virus" has been definitively shown to be associated with this disease. Alternatively, ubiquitous viruses are being considered as the environmental "triggers" that have been postulated to be involved in the MS disease process. We will focus on recent studies with human herpesvirus 6 and MS as how a common virus may be associated with this disorder in a subset of infected individuals. C1 NINDS, Viral Immunol Sect, NIH, Bethesda, MD 20892 USA. Univ Modena & Reggio Emilia, Dept Hyg Microbiol & Biostat, Modena, Italy. RP Jacobson, S (reprint author), NINDS, Viral Immunol Sect, NIH, Bldg 10,Room 5B-16, Bethesda, MD 20892 USA. RI Cermelli, Claudio/L-1501-2016 OI Cermelli, Claudio/0000-0003-3396-0000 NR 108 TC 38 Z9 38 U1 0 U2 3 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0882-8245 J9 VIRAL IMMUNOL JI Viral Immunol. PY 2000 VL 13 IS 3 BP 255 EP 267 DI 10.1089/08828240050144590 PG 13 WC Immunology; Virology SC Immunology; Virology GA 358EZ UT WOS:000089545900002 PM 11016591 ER PT J AU Kusunoki, M Gottlieb, J Goldberg, ME AF Kusunoki, M Gottlieb, J Goldberg, ME TI The lateral intraparietal area as a salience map: the representation of abrupt onset, stimulus motion, and task relevance SO VISION RESEARCH LA English DT Article; Proceedings Paper CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) CY MAY 09-14, 1999 CL FT LAUDERDALE, FL SP Assoc Res Vis & Ophthalmol, Natl Hlth Public Serv Award, Childrens Hosp, Res Fdn DE parietal; saccade; monkey; attention; salience ID TEMPORAL VISUAL AREA; PARIETAL CORTEX; FUNCTIONAL-PROPERTIES; SINGLE NEURONS; MACAQUE MONKEY; EYE; LESIONS AB Neurons in the lateral intraparietal area (LIP) of the monkey represent salient stimuli. They respond to recently flashed stimuli that enter their receptive fields by virtue of saccades better than they respond to stable, behaviorally irrelevant stimuli brought into their receptive fields by saccades. They respond transiently to abrupt motion onsets, but have no directional selectivity. They respond to stable stimuli that are the targets for saccadic eye movements, but far less before the same saccades without stimuli. LIP is important in the attentional mechanisms preceding the choice of saccade target rather than in the intention to generate the saccade itself. (C) Published by Elsevier Science Ltd. All rights reserved. C1 NEI, Sensorimotor Res Lab, Bethesda, MD 20892 USA. UCL, London, England. Georgetown Univ, Sch Med, Dept Neurol, Washington, DC USA. RP NEI, Sensorimotor Res Lab, 49 Convent Dr,Room 2A-50, Bethesda, MD 20892 USA. EM meg@1sr.nei.nih.gov NR 25 TC 134 Z9 134 U1 3 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 EI 1878-5646 J9 VISION RES JI Vision Res. PY 2000 VL 40 IS 10-12 BP 1459 EP 1468 DI 10.1016/S0042-6989(99)00212-6 PG 10 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 313VZ UT WOS:000087021100019 PM 10788652 ER PT J AU Gulnik, S Erickson, JW Xie, D AF Gulnik, S Erickson, JW Xie, D TI HIV protease: Enzyme function and drug resistance SO VITAMINS AND HORMONES - ADVANCES IN RESEARCH AND APPLICATIONS, VOL 58 SE VITAMINS AND HORMONES-ADVANCES IN RESEARCH AND APPLICATIONS LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; ORALLY BIOAVAILABLE INHIBITOR; CYCLIC UREA INHIBITORS; BINDING FREE-ENERGIES; IN-VITRO SELECTION; TYPE-1 PROTEASE; RETROVIRAL PROTEASES; CROSS-RESISTANCE; ESCHERICHIA-COLI; ACTIVE-SITE C1 NCI, Struct Biochem Program, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Gulnik, S (reprint author), NCI, Struct Biochem Program, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 168 TC 25 Z9 26 U1 0 U2 4 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0083-6729 J9 VITAM HORM PY 2000 VL 58 BP 213 EP 256 DI 10.1016/S0083-6729(00)58026-1 PG 44 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA BP76E UT WOS:000086093400008 PM 10668400 ER PT J AU Wolffe, AP Collingwood, TN Li, Q Yee, J Urnov, F Shi, YB AF Wolffe, AP Collingwood, TN Li, Q Yee, J Urnov, F Shi, YB TI Thyroid hormone receptor, v-ErbA, and chromatin SO VITAMINS AND HORMONES - ADVANCES IN RESEARCH AND APPLICATIONS, VOL 58 SE VITAMINS AND HORMONES-ADVANCES IN RESEARCH AND APPLICATIONS LA English DT Review ID RETINOIC-ACID RECEPTOR; TRANSCRIPTION FACTOR ACCESS; LIGAND-BINDING DOMAIN; TUMOR VIRUS PROMOTER; GLUCOCORTICOID RESPONSE ELEMENT; AVIAN ERYTHROBLASTOSIS VIRUS; ACTIVATION FUNCTION AF-2; LINKING NUMBER CHANGE; YEAST PHO5 PROMOTER; LINKER HISTONES B4 C1 NICHHD, Mol Embryol Lab, Bethesda, MD 20892 USA. RP Wolffe, AP (reprint author), NICHHD, Mol Embryol Lab, Bethesda, MD 20892 USA. NR 196 TC 18 Z9 18 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0083-6729 J9 VITAM HORM PY 2000 VL 58 BP 449 EP 492 DI 10.1016/S0083-6729(00)58033-9 PG 44 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA BP76E UT WOS:000086093400015 PM 10668407 ER PT J AU Engelfriet, CP Reesink, HW Blajchman, MA Muylle, L Kjeldsen-Kragh, J Kekomaki, R Yomtovian, R Hocker, P Stiegler, G Klein, HG Soldan, K Barbara, J Slopecki, A Robinson, A Seyfried, H AF Engelfriet, CP Reesink, HW Blajchman, MA Muylle, L Kjeldsen-Kragh, J Kekomaki, R Yomtovian, R Hocker, P Stiegler, G Klein, HG Soldan, K Barbara, J Slopecki, A Robinson, A Seyfried, H TI Bacterial contamination of blood components SO VOX SANGUINIS LA English DT Editorial Material ID TRANSFUSION; IDENTIFICATION; SURVEILLANCE; PLATELETS C1 Sanquin Blood Provis Fdn, Cent Lab Blood Transfus, NL-1006 AC Amsterdam, Netherlands. Sanquin Blood Provis Fdn, Blood Bank Noord Holland, NL-1006 AC Amsterdam, Netherlands. McMaster Univ, Med Ctr, Dept Pathol & Mol Med, Hamilton, ON L8N 3Z5, Canada. Rode Kruis Vlaanderen, Dienst Bloed, B-1050 Brussels, Belgium. Ullevaal Univ Hosp, Dept Immunol & Transfus Med, N-0407 Oslo, Norway. Finnish Red Cross, Blood Transfus Serv, FIN-00310 Helsinki, Finland. Univ Hosp Cleveland, Bloodbank, Cleveland, OH 44106 USA. Allgemeines Krankenhaus Stadt Wien, Univ Klin Blutgrp Serol & Transfus Med, Klin Abt Transfus Med, A-1090 Vienna, Austria. NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Natl Blood Author, Watford WD1 1QH, England. Inst Haematol & Blood Transfus, PL-00957 Warsaw, Poland. RP Engelfriet, CP (reprint author), Sanquin Blood Provis Fdn, Cent Lab Blood Transfus, POB 9137, NL-1006 AC Amsterdam, Netherlands. RI Kjeldsen-Kragh, Jens/A-4472-2008 NR 16 TC 43 Z9 46 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0042-9007 J9 VOX SANG JI Vox Sang. PY 2000 VL 78 IS 1 BP 59 EP 67 DI 10.1046/j.1423-0410.2000.78100591.x PG 9 WC Hematology SC Hematology GA 296GF UT WOS:000086015500011 PM 10729814 ER PT J AU Britton, JA Gammon, MD Kelsey, JL Brogan, DJ Coates, RJ Schoenberg, JB Potischman, N Swanson, CA Stanford, JL AF Britton, JA Gammon, MD Kelsey, JL Brogan, DJ Coates, RJ Schoenberg, JB Potischman, N Swanson, CA Stanford, JL TI Characteristics associated with recent recreational exercise among women 20 to 44 years of age SO WOMEN & HEALTH LA English DT Article DE physical activity; exercise; women ID TIME PHYSICAL-ACTIVITY; HORMONE REPLACEMENT THERAPY; BREAST-CANCER RISK; HEALTH BEHAVIORS; UNITED-STATES; POPULATION; PREVALENCE; PATTERNS; TRENDS AB Data on 1,501 control women from a multi-center, population-based, case-control study of breast cancer were used to examine characteristics associated with; recreational exercise during the year prior to the interview among women 20 to 44 years of age. In a univariate analysis, higher levels of recreational exercise were associated with: higher education; higher family income; white race; previous participation in recreational exercise above the median level at ages 12 to 13 and at age 20; being nulliparous; ever lactating; being a never or past smoker; having a low current Quetelet's index (QI: weight in kilograms divided by height in meters squared); and living in Atlanta or Seattle (compared to New Jersey). In a multiple linear regression model, independent predictors of higher levels of recreational exercise were: participation in higher levels of exercise at 20 years of age; having a low current QI; and never having smoked. Though all women should be encouraged to participate in exercise, these findings identity subgroups of women that may need targeting when developing exercise intervention programs. C1 Columbia Univ, Joseph L Mailman Sch Publ Hlth, Div Epidemiol, New York, NY 10032 USA. Stanford Univ, Dept Hlth Res & Policy, Div Epidemiol, Stanford, CA 94305 USA. Emory Univ, Rollins Sch Publ Hlth, Dept Biostat, Atlanta, GA 30322 USA. Ctr Dis Control, Div Canc Prevent & Control, Atlanta, GA 30341 USA. New Jersey Dept Hlth & Senior Serv, Canc Epidemiol Serv, Trenton, NJ 08625 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. RP Britton, JA (reprint author), Mt Sinai Sch Med, Div Environm Hlth Sci, 1 Gustave L Levy Pl,Box 1057, New York, NY 10029 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 32 TC 10 Z9 10 U1 0 U2 0 PU HAWORTH PRESS INC PI BINGHAMTON PA 10 ALICE ST, BINGHAMTON, NY 13904-1580 USA SN 0363-0242 J9 WOMEN HEALTH JI Women Health PY 2000 VL 31 IS 2-3 BP 81 EP 96 PG 16 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA 415ZR UT WOS:000167753900004 PM 11289687 ER PT J AU Lichtenstein, B Nansel, TR AF Lichtenstein, B Nansel, TR TI Women's douching practices and related attitudes: Findings from four focus groups (conducted for the Longitudinal Study of Vaginal Flora) SO WOMEN & HEALTH LA English DT Article DE douching; hygiene; attitudes; health behavior; qualitative methods ID PELVIC INFLAMMATORY DISEASE; RISK FACTOR; INFECTION; AGE AB Purpose: Vaginal douching is a common hygiene practice for many U.S. women, but is associated with several health risks. Little is known about the beliefs and attitudes that promote and maintain douching practices. This qualitative study, consisting of four focus groups of 31 southern women, was conducted to gather in-depth information about attitudes and beliefs associated with douching. The focus groups consisted of separate groups of low-income and middle-income Caucasian and African-American women. Results. The African-Americans and low-income Caucasians were more likely to douche than middle-income Caucasians. The participants reported douching after menstruation, after sexual intercourse, and at other times for cleanliness and odor control. Concern about odor and cleanliness was a recurrent theme, and douching was represented as an expected and necessary part of feminine: hygiene. Several socioeconomic: and racial differences were observed in douching practices and attitudes. Conclusions: This study provides preliminary information about women's douching practices and attitudes that may inform practitioners educational efforts and future research. C1 Univ Alabama, Dept Sociol, Birmingham, AL 35294 USA. NICHHD, Dept Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. RP Lichtenstein, B (reprint author), Univ Alabama, Dept Sociol, 237 Ullman W Bldg,1212 Univ Blvd, Birmingham, AL 35294 USA. OI Nansel, Tonja/0000-0002-8298-7595 FU NICHD NIH HHS [N01-HD-8-3293] NR 20 TC 27 Z9 28 U1 1 U2 4 PU HAWORTH PRESS INC PI BINGHAMTON PA 10 ALICE ST, BINGHAMTON, NY 13904-1580 USA SN 0363-0242 J9 WOMEN HEALTH JI Women Health PY 2000 VL 31 IS 2-3 BP 117 EP 131 PG 15 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA 415ZR UT WOS:000167753900006 PM 11289682 ER PT B AU Piver, WT AF Piver, WT BE Shen, S TI Estimating the impacts of climate change on human health SO WORLD RESOURCE REVIEW, VOL 12, NOS 2-4: GLOBAL WARMING SCIENCE & POLICY, PTS 1-3 SE GLOBAL WARMING INTERNATIONAL CENTER MONOGRAPH SERIES LA English DT Proceedings Paper CT 11th International Conference on Global Warming Science and Policy CY APR 26-28, 2000 CL BOSTON, MA DE human health; climate change; daily maximum temperature ID POLLUTION C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Piver, WT (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 7 TC 0 Z9 0 U1 0 U2 1 PU SUPCON INTERNATIONAL PI WOODRIDGE PA PO BOX 5275, WOODRIDGE, IL 60517-0275 USA J9 GLOB WARM INT CTR M PY 2000 BP 428 EP 434 PG 7 WC Environmental Sciences; Meteorology & Atmospheric Sciences SC Environmental Sciences & Ecology; Meteorology & Atmospheric Sciences GA BX57T UT WOS:000185752400012 ER PT S AU Creatsas, G Mastorakos, G Chrousos, GP AF Creatsas, G Mastorakos, G Chrousos, GP BE Creatsas, G Mastorakos, G Chrousos, GP TI Introduction: Setting reproductive health priorities to meet the needs of the new millennium SO YOUNG WOMAN AT THE RISE OF THE 21ST CENTURY: GYNECOLOGICAL AND REPRODUCTIVE ISSUES IN HEALTH AND DISEASE SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Editorial Material CT Conference on the Young Woman at the Rise of the 21st Century - Gynecological and Reproductive Issues in Health and Disease CY NOV 18-21, 1998 CL ATHENS, GREECE SP Univ Athens, 2nd Dept Obstet & Gynecol, Hellen Soc Pediat & Adolescent Gynecol, Int Federat Pediat & Adolescent Gynecol C1 Univ Athens, Dept Obstet & Gynecol 2, GR-10679 Athens, Greece. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD USA. RP Creatsas, G (reprint author), 9 Kanari Str, Athens 10671, Greece. NR 4 TC 1 Z9 1 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-226-6 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 900 BP XIII EP XV PG 3 WC Multidisciplinary Sciences; Obstetrics & Gynecology SC Science & Technology - Other Topics; Obstetrics & Gynecology GA BQ26Y UT WOS:000087754500001 PM 10818385 ER PT S AU Kalantaridou, SN Chrousos, GP AF Kalantaridou, SN Chrousos, GP BE Creatsas, G Mastorakos, G Chrousos, GP TI Molecular defects causing ovarian dysfunction SO YOUNG WOMAN AT THE RISE OF THE 21ST CENTURY: GYNECOLOGICAL AND REPRODUCTIVE ISSUES IN HEALTH AND DISEASE SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on the Young Woman at the Rise of the 21st Century - Gynecological and Reproductive Issues in Health and Disease CY NOV 18-21, 1998 CL ATHENS, GREECE SP Univ Athens, 2nd Dept Obstet & Gynecol, Hellen Soc Pediat & Adolescent Gynecol, Int Federat Pediat & Adolescent Gynecol ID FOLLICLE-STIMULATING-HORMONE; LUTEINIZING-HORMONE; RECEPTOR GENE; BETA-SUBUNIT; X-CHROMOSOME; FAILURE; MUTATIONS; HYPOGONADISM; AMENORRHEA; ADHESION AB The functions of the hypothalamic-pituitary ovarian and -adrenal axes are intertwined, and molecular defects in either axis may cause ovarian dysfunction, Advances in molecular genetics have allowed new insights into the pathophysiology of ovarian disorders. Specific gene mutations causing delayed puberty and/or ovarian failure, and heterosexual or isosexual precocious puberty have recently been described, The molecular insights gained into ovarian dysfunction have already led to rational therapies for some of these conditions. C1 NICHHD, Dev Endocrinol Branch, Sect Womens Hlth Res, NIH, Bethesda, MD 20892 USA. NICHHD, Sect Pediat Endocrinol, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Chrousos, GP (reprint author), NIH, Bldg 10,Room 9D42,10 Ctr Dr,MSC 1583, Bethesda, MD 20892 USA. NR 30 TC 1 Z9 1 U1 0 U2 3 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-226-6 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 900 BP 40 EP 45 PG 6 WC Multidisciplinary Sciences; Obstetrics & Gynecology SC Science & Technology - Other Topics; Obstetrics & Gynecology GA BQ26Y UT WOS:000087754500006 PM 10818390 ER PT S AU Kalantaridou, SN Nelson, LM AF Kalantaridou, SN Nelson, LM BE Creatsas, G Mastorakos, G Chrousos, GP TI Premature ovarian failure is not premature menopause SO YOUNG WOMAN AT THE RISE OF THE 21ST CENTURY: GYNECOLOGICAL AND REPRODUCTIVE ISSUES IN HEALTH AND DISEASE SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on the Young Woman at the Rise of the 21st Century - Gynecological and Reproductive Issues in Health and Disease CY NOV 18-21, 1998 CL ATHENS, GREECE SP Univ Athens, 2nd Dept Obstet & Gynecol, Hellen Soc Pediat & Adolescent Gynecol, Int Federat Pediat & Adolescent Gynecol ID FOLLICLE-STIMULATING-HORMONE; YOUNG-WOMEN; AUTOIMMUNE OOPHORITIS; SPONTANEOUS PREGNANCY; NATURAL MENOPAUSE; RECEPTOR GENE; BETA-SUBUNIT; AMENORRHEA; PATIENT; ASSOCIATION AB Normal menopause occurs at an average age of 50 and results from ovarian follicle depletion. Normal menopause is an irreversible condition, whereas premature ovarian failure is characterized by intermittent ovarian function in half of these young women. These young women produce estrogen intermittently and sometimes even ovulate despite the presence of high gonadotropin levels. Indeed, pregnancy has occurred after a diagnosis of premature ovarian failure. On pelvic ultrasound examination, follicles were equally likely to be detected in patients more than 6 years after a diagnosis of premature ovarian failure as in patients less than 6 years after the diagnosis. Thus, the probability of detecting a follicle appears to remain stable during the normal reproductive lifespan of these young women. Indeed, pregnancy was reported in a 44-year-old woman 16 years after a diagnosis of premature ovarian failure, No treatment to restore fertility in patients with premature ovarian failure has proved to be safe and effective in prospective controlled studies, Theoretically, these unproved therapies might even prevent one of these spontaneous pregnancies from occurring. C1 NICHHD, Dev Endocrinol Branch, Sect Womens Hlth Res, NIH, Bethesda, MD 20892 USA. RP Nelson, LM (reprint author), NICHHD, Dev Endocrinol Branch, Sect Womens Hlth Res, NIH, Bldg 10,Room 10N262,10 Ctr Dr MSC 1862, Bethesda, MD 20892 USA. NR 57 TC 40 Z9 47 U1 0 U2 1 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-226-6 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 900 BP 393 EP 402 PG 10 WC Multidisciplinary Sciences; Obstetrics & Gynecology SC Science & Technology - Other Topics; Obstetrics & Gynecology GA BQ26Y UT WOS:000087754500043 PM 10818427 ER PT J AU Bornstein, SR Ehrhart-Bornstein, M AF Bornstein, SR Ehrhart-Bornstein, M TI Basic and clinical aspects of intraadrenal regulation of steroidogenesis SO ZEITSCHRIFT FUR RHEUMATOLOGIE LA English DT Article; Proceedings Paper CT 2nd Bad Nauheim Conference on Rheumatology CY OCT, 1999 CL BAD NAUHEIM, GERMANY DE adrenal; steroidogenesis; paracrine regulation; clinical aspects ID IMMUNE-ENDOCRINE INTERACTION; TUMOR-NECROSIS-FACTOR; HUMAN ADRENAL-CORTEX; CLASS-II EXPRESSION; CUSHINGS-SYNDROME; GENE-EXPRESSION; GROWTH-FACTOR; ADRENOCORTICAL-CELLS; CORTICAL-CELLS; FACTOR-ALPHA AB The adrenal gland combines essential components of the autonomic nervous system and the PIPA axis in close contact. From morphological analyses employing immunohistochemistry, in situ hybridization, the novel technique of laser capture microdissection, and electron microscopy, it has been has shown that the chromaffin cells of the adrenal medulla and the steroid-producing cells of the adrenal cortex are extensively intermingled and functionally interrelated. In in vitro studies, a variety of regulatory factors produced and released by the adrenal medulla were identified as playing an important role in modulating adrenocortical function. An isolated adrenocortical cell deprived of its tissue integrity, input from the nervous system, or intercellular communication with chromaffin, vascular, and immune cells of the adrenal gland, loses its normal capacity to produce glucocorticolds and to adequately respond to the homeostatic challenges of stress. Adrenocortical cells in co-culture with chromaffin cells produced ten times more glucocorticoids than the same number of pure adrenocortical cells and demonstrated marked up-regulation in the mRNA expression of cytochrome p450 enzymes and STAR in the co-culture, while this expression was downregulated in isolated cells. Transgenic animal models of over-expression or deletion of enzymes involved in catecholamine synthesis, as well as of altered function of components of the HPA axis, provide evidence that the mutual interdependence of the sympatho-adrenal system and the HPA axis at the level of the adrenal gland is of physiologic relevance in vivo. Alterations in intercellular communications, local production of neuropeptides, growth factors and cytokines, and aberrant expression of ectopic receptors on adrenal cells have been implicated in adrenal cell growth, development, hyperplasia, tumor formation, autonomous hormone production, and autoimmune disease. Moreover, we described a direct cellular interaction of lymphocytes with adrenal cells as a novel non-cytokine mediated mechanism of immune endocrine interactions. Highlighting the importance of the extra-pituitary mechanisms of adrenocortical regulation, be them neural or immune, is a worthwhile starring point for a more complete analysis of the human stress system in vivo. C1 NICHD, PREB, NIH, Bethesda, MD 20892 USA. RP Bornstein, SR (reprint author), NICHD, PREB, NIH, Bldg 10,Rm 10D42,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 49 TC 12 Z9 12 U1 0 U2 0 PU DR DIETRICH STEINKOPFF VERLAG PI DARMSTADT PA PLATZ DER DEUTSCHEN EINHEIT 25, D-64293 DARMSTADT, GERMANY SN 0340-1855 J9 Z RHEUMATOL JI Z. Rheumatol. PY 2000 VL 59 SU 2 BP 12 EP 17 PG 6 WC Rheumatology SC Rheumatology GA 375WM UT WOS:000165424300006 ER PT J AU Shen, TJ Ikonomi, P Smith, R Noguchi, CT Ho, C AF Shen, TJ Ikonomi, P Smith, R Noguchi, CT Ho, C TI Multi-ribozyme targeting of human alpha-globin gene expression SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Article; Proceedings Paper CT 17th International Congress of Biochemistry and Molecular Biology / American-Society-for-Biochemistry-and-Molecular-Biology CY AUG 24-29, 1997 CL SAN FRANCISCO, CALIFORNIA SP Amer Soc Biochem & Molec Biol DE ribozyme; multi-ribozyme; gene therapy; alpha-globin mRNA; K562 cells ID SICKLE-CELL DISEASE; HEMATOPOIETIC-CELLS; THERAPEUTIC AGENTS; MESSENGER-RNA; VIRUS; THALASSEMIA; ERYTHROCYTES; INHIBITION; HEMOGLOBIN; MODEL AB One approach to gene therapy for the treatment of hemoglobinopathies has been focused on increasing normal globin gene expression. However, because of the high concentration of hemoglobin in the red blood cell (32-34 g/dl), merely introducing the normal globin gene may not be enough to counteract, the effect of an abnormal globin. We propose that in addition to strategies to add normal (beta)- or (gamma)-globin production sickle erythrocytes, a decrease in overall hemoglobin concentration would further decrease the polymerization potential and should be considered with other gene therapy approaches. Ribozymes offer the potential to target a selected gene product. A model system has been set up using the human (alpha)-globin gene for specific gene suppression by ribozymes by cleaving (alpha)-globin mRNA transcripts. Ribozymes, specifically targeted to five different sites in the 5' portion of human (alpha)-globin mRNA, have been designed and tested in vitro. Cleavage of P-32-labeled (alpha)-globin mRNA by these ribozymes has been observed in vitro and the highest level of activity has been found for a multi-ribozyme combining all five ribozymes. The multi-ribozyme gene along with promoters with varying activities in erythroid cells was transfected into human erythroleukemia K562 cells. The multi-ribozyme gene, under the control of human (alpha)2-globin promoter alone and combined with the locus control region enhancer, caused a decrease in the level of or globin mRNA of 50-75% compared to the control, determined by RNase protection and by real-time quantitative PCR. The decrease in (alpha)-globin transcripts has been found to be correlated with expression of the multi-ribozyme in a dose-dependent manner and does not appear to be mediated by an antisense effect. These results suggest that the multi-ribozyme may be useful in gene therapy as an effective suppressor of a specific globin gene. C1 Carnegie Mellon Univ, Dept Biol Sci, Pittsburgh, PA 15213 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Ho, C (reprint author), Carnegie Mellon Univ, Dept Biol Sci, 4400 5th Ave, Pittsburgh, PA 15213 USA. RI Ho, Chien/O-6112-2016 OI Ho, Chien/0000-0002-4094-9232 FU NHLBI NIH HHS [HL-24525] NR 27 TC 4 Z9 4 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD DEC 31 PY 1999 VL 25 IS 24 BP 361 EP 373 DI 10.1006/bcmd.1999.0266 PG 13 WC Hematology SC Hematology GA 273VF UT WOS:000084728000001 PM 10660485 ER PT J AU Koshimizu, T Koshimizu, M Stojilkovic, SS AF Koshimizu, T Koshimizu, M Stojilkovic, SS TI Contributions of the C-terminal domain to the control of P2X receptor desensitization SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GATED ION CHANNELS; P-2X RECEPTOR; EXTRACELLULAR ATP; SENSORY NEURONS; BRAIN; EXPRESSION; SEQUENCES; FAMILY AB The P2X purinergic receptor channels (P2XRs) differ among themselves with respect to the rates of desensitization during prolonged agonist stimulation. Here we studied the desensitization of recombinant channels by monitoring the changes in intracellular free Ca2+ concentration in cells stimulated with ATP, the native and common agonist for all P2XRs. The focus in our investigations was on the relevance of the P2XR C terminus in controlling receptor desensitization. When expressed in GT1 cells, the P2XRs desensitized with rates characteristic to each receptor subtype: P2X(1)R = P2X(3)R > P2X(2b)R > P2X(4)R > P2X(2a)R > P2X(7)R. A slow desensitizing pattern of P2X(2a)R was mimicked partially by P2X(3)R and fully by P2X(4)R when the six-amino acid sequences of these channels located in the cytoplasmic C terminus were substituted with the corresponding arginine 371 to proline 376 sequence of P2X(2a)R. Changing the total net charge in the six amino acids of P2X(4)R to a more positive direction also slowed the receptor desensitization. On the other hand, substitution of arginine 371-proline 376 sequence of P2X(2a)R with the corresponding sequences of P2X(1)R, P2X(3)R, and P2X(4)R increased the rate of receptor desensitization. Furthermore, heterologous polymerization of wild-type P2X(2a)R and mutant P2X(3)R having the C-terminal six amino acids of P2X(2a)R at its analogous position resulted in a functional channel whose desensitization was significantly delayed. These results suggest that composition of the C-terminal six-amino acid sequence and its electrostatic force influence the rate of receptor desensitization. C1 NICHD, Sect Cellular Signaling, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP NICHD, Sect Cellular Signaling, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Rm 6A-36,49 Convent Dr, Bethesda, MD 20892 USA. EM stankos@helix.nih.gov OI Koshimizu, Taka-aki/0000-0001-5292-7535 NR 30 TC 58 Z9 58 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 31 PY 1999 VL 274 IS 53 BP 37651 EP 37657 DI 10.1074/jbc.274.53.37651 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 270GW UT WOS:000084528000021 PM 10608821 ER PT J AU Lebel, M Spillare, EA Harris, CC Leder, P AF Lebel, M Spillare, EA Harris, CC Leder, P TI The Werner syndrome gene product co-purifies with the DNA replication complex and interacts with PCNA and topoisomerase I SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL NUCLEAR ANTIGEN; ESCHERICHIA-COLI; POLY(ADP-RIBOSE) POLYMERASE; SYNDROME PROTEIN; HELICASE; HOMOLOG; SGS1; RECQ; HYBRIDIZATION; CLONING AB Werner syndrome (WS) is a recessive disorder characterized by genomic instability and by the premature onset of a number of age-related diseases. To understand the molecular basis of this disease, we deleted a segment of the murine Wrn gene and created Wrn-deficient embryonic stem (ES) cells. At the molecular level, wild type-but not mutant-WS protein co-purifies through a series of centrifugation, chromatography, and sucrose gradient steps with the well characterized 17 S multiprotein DNA replication complex. Furthermore, wild type WS protein co-immunoprecipitates with a prominent component of the multiprotein replication complex, proliferating cell nuclear antigen (PCNA), In vitro studies also indicate that PCNA binds to a region in the N terminus portion of the WS protein containing a potential 3'-5' exonuclease domain. Finally, human WS protein also co-immunoprecipitates with both PCNA and topoisomerase I. These results suggest that the WS protein interacts with several components of the DNA replication fork. C1 Harvard Univ, Sch Med, Howard Hughes Med Inst, Dept Genet, Boston, MA 02115 USA. Howard Hughes Med Inst, Boston, MA 02115 USA. NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Leder, P (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Dept Genet, 200 Longwood Ave, Boston, MA 02115 USA. NR 37 TC 179 Z9 181 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 31 PY 1999 VL 274 IS 53 BP 37795 EP 37799 DI 10.1074/jbc.274.53.37795 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 270GW UT WOS:000084528000041 PM 10608841 ER PT J AU Forlino, A Porter, FD Lee, EJ Westphal, H Marini, JC AF Forlino, A Porter, FD Lee, EJ Westphal, H Marini, JC TI Use of the Cre/lox recombination system to develop a non-lethal knock-in murine model for osteogenesis imperfecta with an alpha 1(I) G349C substitution - Variability in phenotype in BrtlIV mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PRO-ALPHA-1(I) COLLAGEN GENE; TRIPLE-HELICAL DOMAIN; GLYCINE SUBSTITUTIONS; PATERNAL MOSAICISM; TRANSGENIC MICE; CRE RECOMBINASE; MUTATIONS; COL1A1; PROCOLLAGEN; SERINE AB We utilized the Cre/lox recombination system to develop the first knock-in murine model for osteogenesis imperfecta (OI). The moderately severe OI phenotype was obtained from an alpha 1(I) Gly(349) --> CyS substitution in type I collagen, reproducing the mutation in a type IV OI child. We introduced four single nucleotide (nt) changes into murine collal exon 23: the disease causing G --> T transversion (nt 1546), an adjacent G --> T change (nt 1551) to generate a GUC ribozyme cleavage site, and two transversions (nt 1567 C --> A and nt 1569 C --> G;) to cause a Leu --> Met substitution, We also introduced a 3.2-kilobase pair transcription/translation stop cassette in intron 22, flanked by directly repeating lox recombination sites. After homologous recombination in ES cells, two male chimeras were obtained, Chimeras were mated with transgenic females expressing Cre recombinase to remove the stop cassette from a portion of the progeny's cells. To generate mice with full expression of the Gly(349) --> CYS mutation, these offspring were then mated with wild-type females. Skeletal staining and bone histology of the F2 revealed a classical OI phenotype with deformity, fragility, osteoporosis and disorganized trabecular structure. We designate these mice Brt1IV (Brittle IV). Brt1IV mice have phenotypic variability ranging from perinatal lethality to long term survival with reproductive success. The phenotypic variability is not associated with differences in expression levels of the mutant allele in total RNA derived from tissue extracts. Expression of the mutant protein is also equivalent in different phenotypes. Thus, these mice are an excellent model for delineation of the modifying factors postulated to affect human OI phenotypes. In addition, we generated knock-in mice carrying an "intronic" inclusion by mating chimeras with wild-type females. Alternative splicing involving the stop cassette results in retention of non-collagenous sequences. These mice reproduce the lethal phenotype of similar human mutations and are designated BrtIII. C1 NICHD, SCTD, HDB, NIH, Bethesda, MD 20892 USA. NICHD, Lab Mammalian genet & Dev, NIH, Bethesda, MD 20892 USA. RP Marini, JC (reprint author), NICHD, SCTD, HDB, NIH, Bldg 10,Rm 9S241,10 Ctr Dr,MSC-1830, Bethesda, MD 20892 USA. RI Forlino, Antonella/H-5385-2015 OI Forlino, Antonella/0000-0002-6385-1182 NR 36 TC 77 Z9 79 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 31 PY 1999 VL 274 IS 53 BP 37923 EP 37931 DI 10.1074/jbc.274.53.37923 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 270GW UT WOS:000084528000059 PM 10608859 ER PT J AU Tang, PZ Tsai-Morris, CH Dufau, ML AF Tang, PZ Tsai-Morris, CH Dufau, ML TI A novel gonadotropin-regulated testicular RNA helicase - A new member of the DEAD-box family SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HORMONE RECEPTOR GENE; RAT LEYDIG-CELL; MESSENGER-RNA; CHORIONIC-GONADOTROPIN; PROTEIN; TRANSLATION; INITIATION; DESENSITIZATION; STEROIDOGENESIS; TESTIS AB A gonadotropin-regulated testicular RNA helicase (GRTH) was identified and characterized GRTH cloned from rat Leydig cell, mouse testis, and human testis cDNA Libraries is a novel member of the DEAD-box protein family. GRTH is transcriptionally up-regulated by chorionic gonadotropin via cyclic AMP-induced androgen formation in the Leydig cell. It has ATPase and RNA helicase activities and increases translation in vitro. This helicase is highly expressed in rat, mouse, and human testes and weakly expressed in the pituitary and hypothalamus. GRTH is produced in both somatic (Leydig. cells) and germinal (meiotic spermatocytes and round haploid spermatids) cells and is developmentally regulated. GRTH predominantly localized in the cytoplasm may function as a translational activator. This novel helicase could be relevant to the control of steroidogenesis and the paracrine regulation of androgen-dependent spermatogenesis in the testis. C1 NICHHD, Sect Mol Endocrinol, NIH, Bethesda, MD 20892 USA. NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Dufau, ML (reprint author), NICHHD, Sect Mol Endocrinol, NIH, Bldg 49,Rm 6A36,49 Convent Dr MSC 4510, Bethesda, MD 20892 USA. NR 39 TC 44 Z9 48 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 DEC 31 PY 1999 VL 274 IS 53 BP 37932 EP 37940 DI 10.1074/jbc.274.53.37932 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 270GW UT WOS:000084528000060 PM 10608860 ER PT J AU Lim, SE Longley, MJ Copeland, WC AF Lim, SE Longley, MJ Copeland, WC TI The mitochondrial p55 accessory subunit of human DNA polymerase gamma enhances DNA binding, promotes processive DNA synthesis, and confers N-ethylmaleimide resistance SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SUBSTRATE-SPECIFICITY; DROSOPHILA EMBRYOS; CATALYTIC SUBUNIT; IDENTIFICATION; PURIFICATION; REPLICATION; BACTERIOPHAGE-T7; EXONUCLEASE; PROTEIN; EXCISION AB Human DNA polymerase gamma is composed of a 140-kDa catalytic subunit and a smaller accessory protein variously reported to be 43-54 kDa. Immunoblot analysis of the purified, heterodimeric native human polymerase gamma complex identified the accessory subunit as 55 kDa, We isolated the full-length cDNA encoding a 55-kDa polypeptide, expressed the cDNA in Escherichia coli and purified the 55-kDa protein to homogeneity, Recombinant Hp55 forms a high affinity, salt-stable complex with Hp140 during protein affinity chromatography. Immunoprecipitation, gel filtration, and sedimentation analyses revealed a 190-kDa complex indicative of a native heterodimer, Reconstitution of Hp140 Hp55 raises the salt optimum of Hp140, stimulates the polymerase and exonuclease activities, and increases the processivity of the enzyme by several 100-fold. Similar to Hp140, isolated Hp55 binds DNA with moderate strength and was a specificity for double-stranded primer-template DNA. However, Hp140 Hp55 has a surprisingly high affinity for DNA, and kinetic analyses indicate Hp55 enhances the affinity of Hp140 for primer termini by 2 orders of magnitude. Thus the enhanced DNA binding caused by Hp55 is the basis for the salt tolerance and high processivity characteristic of DNA polymerase gamma, Observation of native DNA polymerase gamma both as an Hp140 monomer and as a heterodimer with Hp55 supports the notion that the two forms act in mitochondrial DNA repair and replication. Additionally, association of Hp55 with Hp140 protects the polymerase from inhibition by N-ethylmaleimide. C1 NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Copeland, WC (reprint author), NIEHS, Mol Genet Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 31 TC 142 Z9 145 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 DEC 31 PY 1999 VL 274 IS 53 BP 38197 EP 38203 DI 10.1074/jbc.274.53.38197 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 270GW UT WOS:000084528000093 PM 10608893 ER PT J AU Allen, DD Smith, QR AF Allen, DD Smith, QR TI Blood-brain barrier choline transport in the senescent rat SO NEUROSCIENCE LETTERS LA English DT Article DE choline; blood-brain barrier; transporter; aging; acetylcholine; hemicholinium-3; cerebrovascular ID CEREBROVASCULAR TRANSPORT; PERFUSION TECHNIQUE; NEURONS; SYSTEM AB Choline is an important membrane phospholipid constituent and a neurotransmitter precursor that is minimally synthesized in brain. The long-term maintenance of brain choline concentration is dependent on uptake from plasma, which occurs via saturable transporter at the blood-brain barrier. Previous studies have suggested that brain choline uptake declined with age. To reevaluate this, brain choline uptake in 3, 12, 24, and 28-month-old Fischer-344 rats was evaluated using the in situ brain perfusion technique. Minimal differences were found with uptake parameters differing by similar to 10% between aged and adult rats for tracer levels while similar trends were observed at higher choline concentrations. Further, estimated V-max and K-m values differed by <30% between the groups. The results suggest that blood-brain barrier choline uptake changes minimally with aging in the rat. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 Texas Tech Univ, Hlth Sci Ctr, Sch Pharm, Dept Pharmaceut Sci, Amarillo, TX 79106 USA. NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. RP Allen, DD (reprint author), Texas Tech Univ, Hlth Sci Ctr, Sch Pharm, Dept Pharmaceut Sci, 1300 S Coulter Dr, Amarillo, TX 79106 USA. NR 19 TC 15 Z9 15 U1 1 U2 3 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 DEC 31 PY 1999 VL 277 IS 3 BP 198 EP 202 DI 10.1016/S0304-3940(99)00869-1 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 268GF UT WOS:000084405400015 PM 10626847 ER PT J AU Sassaman, MB Panico, M Schmall, B Eckelman, WC AF Sassaman, MB Panico, M Schmall, B Eckelman, WC TI [C-11]diazepam synthesis: N-[C-11]methylation of desmethyldiazepam is facilitated by utilization of a preformed sodium salt/benzo-15-crown-5 complex SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Article DE diazepam; desmethyldiazepam; benzodiazepine; benzo-15-crown-5 AB The use of a preformed desmethyldiazepam sodium salt/ benzo-15-crown-5 complex in aprotic media allows for rapid and clean[C-11]methylation without contamination and loss of activity due to alkylation of solvent residues and other dissolved basic-nucleophilic material. C1 NIH, PET Dept, Warren C Magnuson Clin Ctr, Bethesda, MD 20892 USA. CNR, Ctr Med Nucl, I-80131 Naples, Italy. RP Sassaman, MB (reprint author), NIH, PET Dept, Warren C Magnuson Clin Ctr, Bldg 10, Bethesda, MD 20892 USA. NR 4 TC 4 Z9 4 U1 2 U2 3 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0362-4803 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD DEC 30 PY 1999 VL 42 IS 13 BP 1229 EP 1233 DI 10.1002/(SICI)1099-1344(19991230)42:13<1229::AID-JLCR278>3.3.CO;2-J PG 5 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 266PL UT WOS:000084308300001 ER PT J AU Zhang, XY Rice, KC Calderon, SN Kayakiri, H Smith, L Coop, A Jacobson, AE Rothman, RB Davis, P Dersch, CM Porreca, F AF Zhang, XY Rice, KC Calderon, SN Kayakiri, H Smith, L Coop, A Jacobson, AE Rothman, RB Davis, P Dersch, CM Porreca, F TI Probes for narcotic receptor mediated phenomena. 26. Synthesis and biological evaluation of diarylmethylpiperazines and diarylmethylpiperidines as novel, nonpeptidic delta opioid receptor ligands SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID (+)-4-<(ALPHA-R)-ALPHA-((2S,5R)-4-ALLYL-2,5-DIMETHYL-1-PIPERAZINYL)-3-ME THOXYBE.; AGONIST BW373U86; RHESUS-MONKEYS; BINDING-SITE; IN-VITRO; PEPTIDES; AFFINITY; ANTINOCICEPTION; MODULATION; MORPHINE AB We recently reported (+)-4-[(alpha R)-alpha-{(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl}-3-methoxybenzyl]-N,N-diethylbenzamide (1b, SNC80) as a novel nonpeptidic delta receptor agonist and explored the structure-activity relationships (SAR) of a series of related derivatives. We have found that delta binding activities and selectivity showed little change when the S-methoxy group in Ib was removed or replaced by the other substituents, whereas the N,N-diethylbenzamide group is important for interaction with the delta receptor. Extensive modification of the piperazine nucleus led to the synthesis of a new series of N,N-diethyl(alpha-piperazinylbenzyl)benzamides (2, 3 a-e), N,N- diethyl(alpha-piperidinyl or piperidinylidenebenzyl)benzamides (4a, 5a-c, 6a-b), and related derivatives (4b, 7a-c). Several compounds (2, 3a, 3e, 6a) strongly bound to the delta receptor with K(i) values in the low nanomolar range. On the other hand, the binding affinities of these compounds for the mu and kappa receptors were negligible, indicating excellent delta opioid receptor subtype selectivity. The two nitrogen atoms on the piperazine nucleus showed different SAR in the interaction of this series of compounds at the delta receptor. Nitrogen N(4) appears to be an important structural element and is essential for electrostatic interaction, while N(1) seems to be unnecessary for recognition at the delta receptor. C1 NIDDKD, Med Chem Lab, NIH, Bethesda, MD 20892 USA. Natl Inst Drug Abuse, Addict Res Ctr, Clin Psychopharmacol Sect, Baltimore, MD 21224 USA. Univ Arizona, Coll Med, Dept Pharmacol, Tucson, AZ 85724 USA. RP Rice, KC (reprint author), NIDDKD, Med Chem Lab, NIH, Bldg 8,Room B1-23, Bethesda, MD 20892 USA. NR 40 TC 17 Z9 17 U1 0 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 DEC 30 PY 1999 VL 42 IS 26 BP 5455 EP 5463 DI 10.1021/jm9903895 PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 272FN UT WOS:000084640000014 PM 10639287 ER PT J AU Pieters, L Van Dyck, S Gao, M Bai, RL Hamel, E Vlietinck, A Lemiere, G AF Pieters, L Van Dyck, S Gao, M Bai, RL Hamel, E Vlietinck, A Lemiere, G TI Synthesis and biological evaluation of dihydrobenzofuran lignans and related compounds as potential antitumor agents that inhibit tubulin polymerization SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ANTIMITOTIC AGENTS; CYTOTOXICITY; NEOLIGNANS; CELLS AB A series of 19 related dihydrobenzofuran lignans and benzofurans was obtained by a biomimetic reaction sequence involving oxidative dimerization of p-coumaric, caffeic, or ferulic acid methyl esters, followed by derivatization reactions. All compounds were evaluated for potential anticancer activity in an in vitro human disease-oriented tumor cell line screening panel that consisted of 60 human tumor cell lines arranged in nine subpanels, representing diverse histologies. Leukemia and breast cancer cell lines were relatively more sensitive to these agents than were the other cell lines. Compounds 2c and 2d, but especially 2b (methyl (E)-3-[2-(3,4-dihydroxyphenyl)-7-hydroxy-3-methoxycarbonyl-2,3-dihydro-1-benzofuran-5-yl]prop-2-enoate), the dimerization product of caffeic acid methyl ester, containing a 3',4'-dihydroxyphenyl moiety and a hydroxyl group in position 7 of the dihydrobenzofuran ring, showed promising activity. The average GI(50) value (the molar drug concentration required for 50% growth inhibition) of 2b was 0.3 mu M. Against three breast cancer cell Lines, 2b had a GI(50) value of <10 nhl. Methylation, reduction of the double bond of the C-3-side chain, reduction of the methoxycarbonyl functionalities to primary alcohols, or oxidation of the dihydrobenzofuran ring to a benzofuran system resulted in a decrease or loss of cytotoxic activity. Compound 2b inhibited mitosis at micromolar concentrations in cell culture through a relatively weak interaction at the colchicine binding site of tubulin. In vitro it inhibited tubulin polymerization by 50% at a concentration of 13 +/- 1 mu M. The 2R,3R-enantiomer of 2b was twice as active as the racemic mixture, while the 2S,3S-enantiomer had minimal activity as an inhibitor of tubulin polymerization. These dihydrobenzofuran lignans (2-phenyl-dihydrobenzofuran derivatives) constitute a new group of antimitotic and potential antitumor agents that inhibit tubulin polymerization. C1 Univ Antwerp, Dept Pharmaceut Sci, B-2020 Antwerp, Belgium. Sci Applicat Int Corp, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program,Div Canc Treatment & Diag, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Univ Antwerp, Dept Chem, B-2020 Antwerp, Belgium. RP Pieters, L (reprint author), Univ Antwerp, Dept Pharmaceut Sci, B-2020 Antwerp, Belgium. RI Pieters, Luc/P-5820-2016; Gao, Mei/A-9223-2011 OI Pieters, Luc/0000-0002-8288-4254; NR 20 TC 115 Z9 126 U1 10 U2 29 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 DEC 30 PY 1999 VL 42 IS 26 BP 5475 EP 5481 DI 10.1021/jm990251m PG 7 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 272FN UT WOS:000084640000016 PM 10639289 ER PT J AU Norton, JA Gibril, F Jensen, RT AF Norton, JA Gibril, F Jensen, RT TI Surgery to cure the Zollinger-Ellison syndrome. Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID GASTRINOMA; RESECTION C1 Univ Calif San Francisco, San Francisco, CA 94121 USA. NIDDKD, Bethesda, MD 20892 USA. RP Norton, JA (reprint author), Univ Calif San Francisco, San Francisco, CA 94121 USA. NR 5 TC 3 Z9 3 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 30 PY 1999 VL 341 IS 27 BP 2096 EP 2097 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 271BR UT WOS:000084573300019 ER PT J AU Gail, MH AF Gail, MH TI Some of Nathan Mantel's contributions to epidemiology SO STATISTICS IN MEDICINE LA English DT Article ID MANTEL-HAENSZEL ESTIMATOR; RELATIVE EFFICIENCY; STATISTICS; TESTS; NUMBER; MODELS AB Nathan Mantel's many contributions to epidemiology grew out of his role as a statistical consultant and collaborator. His abilities to understand scientific issues, appreciate their subtleties, and produce simple, compelling analyses were remarkable. Several of the procedures he developed to meet consulting needs remain widely used by statisticians and other researchers. Examples are presented to illustrate his approach and intuitive brilliance, including work on the evaluation of diagnostic tests, the Mantel-Haenszel procedure and its extensions, the use of a prospective logistic risk model to analyse case-control data, a method for evaluating aggregation of cancer disease sites in pairs of diseased relatives, and methods for detecting clustering of disease and temporal-spatial association of diseased cases. Published in 1999 by John Wiley & Sons, Ltd. This article is a US Government work and is in the public domain in the United States. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Gail, MH (reprint author), NCI, Div Canc Epidemiol & Genet, Execut Plaza S,Room 8032,6120 Execut Blvd,MSC 724, Bethesda, MD 20892 USA. NR 53 TC 2 Z9 2 U1 2 U2 4 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD DEC 30 PY 1999 VL 18 IS 24 BP 3389 EP 3400 DI 10.1002/(SICI)1097-0258(19991230)18:24<3389::AID-SIM458>3.0.CO;2-# PG 12 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 273PQ UT WOS:000084716400004 PM 10611613 ER PT J AU Buyse, M George, SL Evans, S Geller, NL Ranstam, J Scherrer, B Lesaffre, E Murray, G Edler, L Hutton, J Colton, T Lachenbruch, P Verma, BL AF Buyse, M George, SL Evans, S Geller, NL Ranstam, J Scherrer, B Lesaffre, E Murray, G Edler, L Hutton, J Colton, T Lachenbruch, P Verma, BL CA ISCB Subcommittee Fraud TI The role of biostatistics in the prevention, detection and treatment of fraud in clinical trials SO STATISTICS IN MEDICINE LA English DT Article; Proceedings Paper CT Joint Meeting of the International-Society-for-Clinical-Biostatistics/Society-for-Clinical-Tr ials CY JUL 07-10, 1997 CL BOSTON, MA SP Int Soc Clin Biostatist, Soc Clin Trial ID PUBLISHING SENSITIVE DATA; BREAST-CANCER TRIALS; SCIENTIFIC MISCONDUCT; ELIGIBILITY CRITERIA; MEDICAL-RESEARCH; DIGIT PHENOMENON; INTEGRITY; SCIENCE; QUALITY; DISTRIBUTIONS AB Recent cases of fraud in clinical trials have attracted considerable media attention, but relatively little reaction from the biostatistical community. In this paper we argue that biostatisticians should be involved in preventing fraud las well as unintentional errors), detecting it, and quantifying its impact on the outcome of clinical trials. We use the term 'fraud' specifically to refer to data fabrication (making up data values) and falsification (changing data values), Reported cases of such fraud involve cheating on inclusion criteria so that ineligible patients can enter the trial, and fabricating data so that no requested data are missing. Such types of fraud are partially preventable through a simplification of the eligibility criteria and through a reduction in the amount of data requested. These two measures are feasible and desirable in a surprisingly large number of clinical trials, and neither of them in any way jeopardizes the validity of the trial results. With regards to detection of fraud, a brute force approach has traditionally been used, whereby the participating centres undergo extensive monitoring involving up to 100 per cent verification of their case records. The cost-effectiveness of this approach seems highly debatable, since one could implement quality control through random sampling schemes, as is done in fields other than clinical medicine. Moreover, there are statistical techniques available (but insufficiently used) to detect 'strange' patterns in the data including, but no limited to, techniques for studying outliers, inliers, overdispersion, underdispersion and correlations or lack thereof. These techniques all rest upon the premise that it is quite difficult to invent plausible data, particularly highly dimensional multivariate data. The multicentric nature of clinical trials also offers an opportunity to check the plausibility of the data submitted by one centre by comparing them with the data from all other centres. Finally, with fraud detected, it is essential to quantify its likely impact upon the outcome of the clinical trial. Many instances of fraud in clinical trials, although morally reprehensible, have a negligible impact on the trial's scientific conclusions. Copyright (C) 1999 John Wiley & Sons, Ltd. C1 Int Inst Drug Dev, B-1050 Brussels, Belgium. Limburgs Univ Ctr, Diepenbeek, Belgium. Duke Univ, Med Ctr, Durham, NC USA. Med Control Agcy, London, England. NHLBI, Off Biostat Res, Bethesda, MD USA. Lund Univ, Lund, Sweden. Inst Rech Jouveinal, Fresnes, France. Univ Hosp St Raphael, Biostat Ctr Clin Trials, B-3000 Louvain, Belgium. Univ Edinburgh, Med Stat Unit, Edinburgh EH8 9YL, Midlothian, Scotland. German Canc Res Ctr, Dept Biostat, D-6900 Heidelberg, Germany. Newcastle Univ, Dept Math & Stat, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA USA. US FDA, Rockville, MD 20857 USA. Med Coll & Hosp, Jhansi, Uttar Pradesh, India. RP Int Inst Drug Dev, 430 Ave Louise B14, B-1050 Brussels, Belgium. EM mbuyse@id2.be RI Ranstam, Jonas/A-4386-2009 OI Ranstam, Jonas/0000-0002-8287-7273 NR 115 TC 84 Z9 84 U1 3 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD DEC 30 PY 1999 VL 18 IS 24 BP 3435 EP 3451 DI 10.1002/(SICI)1097-0258(19991230)18:24<3435::AID-SIM365>3.3.CO;2-F PG 17 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 273PQ UT WOS:000084716400008 PM 10611617 ER PT J AU Wittes, J Schabenberger, O Zucker, D Brittain, E Proschan, M AF Wittes, J Schabenberger, O Zucker, D Brittain, E Proschan, M TI Internal pilot studies I: Type I error rate of the naive t-test SO STATISTICS IN MEDICINE LA English DT Article ID CLINICAL-TRIALS; DESIGN; SIZE AB When sample size is recalculated using unblinded interim data, use of the usual t-test at the end of a study may lead to an elevated type I error rate. This paper describes a numerical quadrature investigation to calculate the true probability of rejection as a function of the time of the recalculation, the magnitude of the detectable treatment effect, and the ratio of the guessed to the true variance, We consider both 'restricted' designs, those that require final sample size at least as large as the originally calculated size, and 'unrestricted' designs, those that permit smaller final sample sizes than originally calculated, Our results indicate that the bias in the type I error rate is often negligible, especially in restricted designs, Some sets of parameters, however, induce non-trivial bias in the unrestricted design, Copyright (C) 1999 John Wiley & Sons, Ltd. C1 Stat Collaborat Inc, Washington, DC 20036 USA. Michigan State Univ, Dept Crop & Soil Sci, E Lansing, MI 48824 USA. Hebrew Univ Jerusalem, Dept Stat, IL-91905 Jerusalem, Israel. Potomac Biostat Inc, Potomac, MD 20854 USA. NHLBI, Rockledge Ctr 2, Bethesda, MD 20892 USA. RP Wittes, J (reprint author), Stat Collaborat Inc, 1710 Rhode Isl Ave,Suite 200, Washington, DC 20036 USA. FU NCRR NIH HHS [1R43-RR08524-01]; PHS HHS [2R44-4408254-02] NR 14 TC 65 Z9 66 U1 0 U2 2 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD DEC 30 PY 1999 VL 18 IS 24 BP 3481 EP 3491 DI 10.1002/(SICI)1097-0258(19991230)18:24<3481::AID-SIM301>3.0.CO;2-C PG 11 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 273PQ UT WOS:000084716400011 PM 10611620 ER PT J AU Ahsan, N Hricik, D Matas, A Rose, S Tomlanovich, S Wilkinson, A Ewell, M McIntosh, M Stablein, D Hodge, E Hayes, D Gores, P Cohen, D Gonwa, T Brinler, K Harland, R Neylan, J Pescovitz, M Wynn, J Ahsan, N Yang, HC Bennett, W Copley, J Wilkinson, A Dunn, J Tomlanovich, S Chan, L Bertolatus, JA Weir, M Mendez, R Pirsch, J Helderman, JH AF Ahsan, N Hricik, D Matas, A Rose, S Tomlanovich, S Wilkinson, A Ewell, M McIntosh, M Stablein, D Hodge, E Hayes, D Gores, P Cohen, D Gonwa, T Brinler, K Harland, R Neylan, J Pescovitz, M Wynn, J Ahsan, N Yang, HC Bennett, W Copley, J Wilkinson, A Dunn, J Tomlanovich, S Chan, L Bertolatus, JA Weir, M Mendez, R Pirsch, J Helderman, JH CA Steroid Withdrawal Study Grp TI Prednisone withdrawal in kidney transplant recipients on cyclosporine and mycophenolate mofetil - A prospective randomized study SO TRANSPLANTATION LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Society-of-Transplantation CY MAY 15-19, 1999 CL CHICAGO, ILLINOIS SP Amer Soc Transplantat ID RENAL-ALLOGRAFT RECIPIENTS; STEROID WITHDRAWAL; CONTROLLED TRIAL; AZATHIOPRINE; REJECTION; THERAPY; IMMUNOSUPPRESSION; CESSATION; METHYLPREDNISOLONE; CLASSIFICATION AB Background. Prospective randomized trials have shown a reduced rate of acute rejection (AR) in mycophenolate mofetil-treated kidney transplant recipients. We hypothesized that this increased protection from AR could allow successful prednisone (P) withdrawal in cyclosporine/mycophenolate mofetil/P-treated recipients. Methods. A multicenter, prospective, randomized, double-blind trial of P withdrawal at 3 months posttransplant was initiated. Entry criteria were: primary transplant, adult, no AR by 90 days, mycophenolate mofetil dose greater than or equal to 2 g/day, cyclosporine dose=5-15 mg/kg/day, P dose=10-15 mg/day, Study participants were randomized to have P tapered over 8 weeks (beginning at 3 months posttransplant) to 0 vs. 10 mg/day, Prestudy power analysis determined 500 recipients should be randomized for 80% statistical power to test equivalence of the primary endpoint, AR, or treatment failure at 1 year posttransplant, By design, the study was to be stopped if interim data precluded reaching equivalence. An established data safety monitoring board monitored the study. Results, After 266 patients were enrolled, the patient enrollment was stopped (after safety monitoring board review) because of excess rejection in the P withdrawal group, The Kaplan-Meier estimate of the cumulative incidence of rejection or treatment failure within 1 year posttransplant (+/-95% confidence interval) for the maintenance group was 9.8% (4.4%; treatment failure, 14.9%); for the withdrawal group, 30.8% (21.0%; 39.3%). Treatment differences in the distribution of time to event were highly significant (P=0.0007). Of note, risk was higher in blacks (39.6%) versus nonblacks (16.0%) (P<0.001). At 1 year posttransplant, there was no difference between groups in patient or graft survival, For the patients with functioning grafts at 6 months posttransplant, withdrawal patients had lower cholesterol (P=0.0005), had higher creatinine (P=0.03), and were less likely to use antihypertensives (P=0.001). These differences persist to 1 yr posttransplant. Conclusions. We conclude that for recipients on cyclosporine/mycophenolate mofetil/P with no AR at 90 days, the chance of developing subsequent AR is small; if P is tapered and withdrawn, the risk increases (but the majority remain free of acute and chronic rejection). After withdrawal, the risk of AR is different for blacks versus nonblacks, Withdrawal patients had a lower cholesterol level and less need for antihypertensives. C1 Univ Minnesota, Dept Surg, Minneapolis, MN 55455 USA. Milton S Hershey Med Ctr, Hershey, PA USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. NIAID, Bethesda, MD USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Calif Los Angeles, Los Angeles, CA 90024 USA. Roche Labs, Nutley, NJ USA. Carolinas Med Ctr, Charlotte, NC USA. Columbia Presbyterian Univ, New York, NY USA. Dallas Nephrol, Dallas, TX USA. Duke Univ, Med Ctr, Durham, NC USA. Emory Univ, Atlanta, GA 30322 USA. Indiana Univ, Bloomington, IN 47405 USA. Med Coll Georgia, Augusta, GA 30912 USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. Alton Ochsner Med Fdn & Ochsner Clin, New Orleans, LA 70121 USA. Univ Calif San Diego, La Jolla, CA 92093 USA. Univ Colorado, Boulder, CO 80309 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Iowa, Iowa City, IA 52242 USA. Univ Maryland Hosp, Baltimore, MD 21201 USA. Univ So Calif, Los Angeles, CA 90089 USA. Univ Wisconsin, Madison, WI 53706 USA. Vanderbilt Univ, Nashville, TN USA. RP Matas, A (reprint author), Univ Minnesota, Dept Surg, Box 328 Mayo,420 Delaware St SE, Minneapolis, MN 55455 USA. NR 51 TC 211 Z9 216 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD DEC 27 PY 1999 VL 68 IS 12 BP 1865 EP 1874 PG 10 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 271UM UT WOS:000084612000009 PM 10628766 ER PT J AU Kim, YO Koh, HJ Kim, SH Jo, SH Huh, JW Jeong, KS Lee, IJ Song, BJ Huh, TL AF Kim, YO Koh, HJ Kim, SH Jo, SH Huh, JW Jeong, KS Lee, IJ Song, BJ Huh, TL TI Identification and functional characterization of a novel, tissue-specific NAD(+)-dependent isocitrate dehydrogenase beta subunit isoform SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PRE-MESSENGER-RNA; SACCHAROMYCES-CEREVISIAE; OLIGONUCLEOTIDE PROBES; BINDING-SITES; BOVINE HEART; FATTY-ACIDS; PIG; PROTEIN; CLONING; PURIFICATION AB To understand the interactions and functional role of each of the three mitochondrial NAD(+)-dependent isocitrate dehydrogenase (IDH) subunits (alpha, beta, and gamma), we have characterized human cDNAs encoding two beta isoforms (beta(1) and beta(2)) and the gamma subunit. Analysis of deduced amino acid sequences revealed that beta(1) and beta(2) encode 349 and 354 amino acids, respectively, and the two isoforms only differ in the most carboxyl 28 amino acids. The gamma cDNA encodes 354 amino acids and is almost identical to monkey IDH gamma. Northern analyses revealed that the smaller beta(2) transcript (1.3 kilobases) is primarily expressed in heart and skeletal muscle, whereas the larger beta(1) mRNA (1.6 kilobases) is prevalent in nonmuscle tissues. Sequence analysis of the IDH beta gene indicates that the difference in the C-terminal 28 amino acids between beta(1) and beta(2) proteins results from alternative splicing of a single transcript. Among the various combinations of human IDH subunits co-expressed in bacteria, alpha beta gamma, alpha beta, and alpha gamma combinations exhibited significant amounts of IDH activity, whereas subunits produced alone and beta gamma showed no detectable activity. These data suggest that the alpha is the catalytic subunit and that at least one of the other two subunits plays an essential supporting role for activity. Substitution of beta(1) with beta(2) in the co-expression system lowered the pH optimum for IDH activity from 8.0 to 7.6. This difference in optimal pH was analogous to what was observed in mouse kidney and brain (beta(1) prevalent; optimal pH 8.0) versus heart (beta(2) prevalent; pH 7.6) mitochondria, Experiments with a specially designed splicing reporter constrdct stably transfected into HT1080 cells indicate that acidic conditions favor a splicing pattern responsible for the muscle- and heart-specific beta(2) isoform. Taken together, these data indicate a regulatory role of IDH beta isoforms in determining the pH optimum for IDH activity through the tissue-specific alternative splicing. C1 Kyungpook Natl Univ, Coll Nat Sci, Dept Genet Engn, Taegu 702701, South Korea. Korea Green Cross Corp, Cent Res Inst, Yongin, South Korea. NIAAA, Lab Membrane Biochem & Biophys, Rockville, MD 20852 USA. RP Huh, TL (reprint author), Kyungpook Natl Univ, Coll Nat Sci, Dept Genet Engn, Taegu 702701, South Korea. NR 41 TC 29 Z9 34 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 24 PY 1999 VL 274 IS 52 BP 36866 EP 36875 DI 10.1074/jbc.274.52.36866 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 267WR UT WOS:000084382700009 PM 10601238 ER PT J AU Foger, B Chase, M Amar, MJ Vaisman, BL Shamburek, RD Paigen, B Furchart-Najib, J Paiz, JA Koch, CA Hoyt, RF Brewer, HB Santamarina-Fojo, S AF Foger, B Chase, M Amar, MJ Vaisman, BL Shamburek, RD Paigen, B Furchart-Najib, J Paiz, JA Koch, CA Hoyt, RF Brewer, HB Santamarina-Fojo, S TI Cholesteryl ester transfer protein corrects dysfunctional high density lipoproteins and reduces aortic atherosclerosis in lecithin cholesterol acyltransferase transgenic mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID APOLIPOPROTEIN-A-I; DIET-INDUCED ATHEROSCLEROSIS; HUMAN ADENOVIRUS TYPE-5; OXIDATIVE MODIFICATION; EARLY ATHEROGENESIS; HEPATIC LIPASE; HEART-DISEASE; HUMAN-PLASMA; EXPRESSION; GENE AB Expression of human lecithin cholesterol acyltransferase (LCAT) in mice (LCAT-Tg) leads to increased high density lipoprotein (HDL) cholesterol levels but paradoxically, enhanced atherosclerosis, We have hypothesized that the absence of cholesteryl ester transfer protein (CETP) in LCAT-Tg mice facilitates the accumulation of dysfunctional HDL leading to impaired reverse cholesterol transport and the development of a pro-atherogenic state. To test this hypothesis we crossbred LCAT-Tg with CETP-Tg mice. On both regular chow and high fat, high cholesterol diets, expression of CETP in LCAT-Tg mice reduced total cholesterol (-39% and -13%, respectively; p < 0.05), reflecting a decrease in HDL cholesterol levels. CETP normalized both the plasma clearance of [H-3]cholesteryl esters ([H-3]CE) from HDL (fractional catabolic rate in days(-1): LCAT-Tg = 3.7 +/- 0.34, LCATxCETP-Tg = 6.1 +/- 0.16, and controls = 6.4 +/- 0.16) as well as the liver uptake of [H-3]CE from HDL (LCAT-Tg = 36%, LCATxCETP-Tg = 65%, and controls = 63%) in LCAT Tg mice. On the pro-atherogenic diet the mean aortic lesion area was reduced by 41% in LCATx- CETP-Tg (21.2 +/- 2.0 mu m(2) x 10(3)) compared with LCAT-Tg mice (35.7 +/- 2.0 mu m(2) x 10(3); p < 0.001), Adenovirus-mediated expression of scavenger receptor class B (SR-BI) failed to normalize the plasma clearance and liver up take of [H-3]CE from LCAT-Tg HDL, Thus, the ability of SR-BI to facilitate the selective uptake of CE from LCAT-Tg HDL is impaired, indicating a potential mechanism leading to impaired reverse cholesterol transport and atherosclerosis in these animals. We conclude that CETP expression reduces atherosclerosis in LCAT-Tg mice by restoring the functional properties of LCAT-Tg mouse HDL and promoting the hepatic uptake of HDL CE. These findings provide definitive in vivo evidence supporting the proposed anti-atherogenic role of CETP in facilitating HDL-mediated reverse cholesterol transport and demonstrate that CETP expression is beneficial in pro-atherogenic states that result from impaired reverse cholesterol transport. C1 NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Lab Anim Med Surg, NIH, Bethesda, MD 20892 USA. Jackson Lab, Bar Harbor, ME 04609 USA. Inst Pasteur, Fac Pharm, INSERM, U325, F-59019 Lille, France. RP Santamarina-Fojo, S (reprint author), NHLBI, Mol Dis Branch, NIH, Bldg 10,Rm 7N115,10 Ctr Dr,MSC 1666, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [HL 32087, HL 30086] NR 69 TC 157 Z9 165 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 DEC 24 PY 1999 VL 274 IS 52 BP 36912 EP 36920 DI 10.1074/jbc.274.52.36912 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 267WR UT WOS:000084382700015 PM 10601244 ER PT J AU Wang, QMJ Bhattacharyya, D Garfield, S Nacro, K Marquez, VE Blumberg, PM AF Wang, QMJ Bhattacharyya, D Garfield, S Nacro, K Marquez, VE Blumberg, PM TI Differential localization of protein kinase C delta by phorbol esters and related compounds using a fusion protein with green fluorescent protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NONPROMOTING 12-DEOXYPHORBOL 13-ESTERS; NIH 3T3 FIBROBLASTS; CD-1 MOUSE SKIN; 12-MYRISTATE 13-ACETATE; LIVING CELLS; BINDING; BRYOSTATIN; DOMAINS; TRANSLOCATION; ISOZYMES AB Enzyme localization often plays a controlling role in determining its activity and specificity. Protein kinase C (PKC) has long been known to translocate in response to physiological stimuli as well as to exogenous ligands such as the phorbol esters, We report here that different phorbol derivatives and related ligands, selected for differences in chemical structure and profile of biological activity, induce distinct patterns of redistribution of PKC delta, Localization of a PKC delta-green fluorescent protein (GFP) fusion construct was monitored in living Chinese hamster ovary cells as a function of ligand, concentration, and time using confocal laser scanning microscopy, delta-PKC-GFP was expressed predominantly in the cytoplasm, with some in the nucleus and perinuclear region. Phorbol 12-myristate 13-acetate (PMA) induced plasma membrane translocation followed by slower nuclear membrane translocation. As the concentration of PMA increased, the proportion of nuclear to plasma membrane localization increased markedly. In contrast to PMA, bryostatin 1, a unique activator of PKC that induces a subset of PIMA mediated responses while antagonizing others, at all doses induced almost exclusively nuclear membrane translocation, Like PMA, the complete tumor promoter 12-deoxyphorbol 13-tetradecanoate induced plasma membrane and slower nuclear membrane translocation, whereas the inhibitor of tumor promotion 12-deoxyphorbol 13-phenylacetate, which differs only in its side chain, induced a distinctive distribution of PKC delta-GFP, Finally, the novel constrained diacylglycerol derivative B8-DL-B8 induced a slow Golgi localization. We speculate that differential control of PRC delta localization may provide an interesting strategy for producing ligands with differential biological consequences. C1 NCI, Mol Mechanisms Tumor Promot Sect, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. NCI, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RP Blumberg, PM (reprint author), NCI, Mol Mechanisms Tumor Promot Sect, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bldg 37,Rm 3A01,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM blumberp@dc37a.nci.nih.gov RI Wang, Qiming/B-6064-2012 NR 42 TC 148 Z9 148 U1 0 U2 3 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 DEC 24 PY 1999 VL 274 IS 52 BP 37233 EP 37239 DI 10.1074/jbc.274.52.37233 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 267WR UT WOS:000084382700058 PM 10601287 ER PT J AU Kim, HP Roe, JH Chock, PB Yim, MB AF Kim, HP Roe, JH Chock, PB Yim, MB TI Transcriptional activation of the human manganese superoxide dismutase gene mediated by tetradecanoylphorbol acetate SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; SIGNAL TRANSDUCTION PATHWAYS; PROTEIN-KINASE-C; CYCLIC-AMP; PHORBOL ESTER; MNSOD GENE; SELECTIVE INHIBITOR; OXIDASE ACTIVATION; BINDING-PROTEINS AB Transcriptional activation of human manganese superoxide dismutase (MnSOD) mRNA induced by a phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), was examined to identify the responsive transcriptional regulator. The effect of various deletions and mutations within the 5'-flanking region of the human MnSOD gene promoter was evaluated using the luciferase reporter system in A549 human lung carcinoma cells. Deletion of a region between -1292 and -1202 nucleotides upstream of the transcription start site abolished TPA-responsive induction, whereas deletion of the putative binding sequence for NF-kappa B or AP-1 did not. The region between -1292 and -1202 contains a cAMP-responsive element-like sequence, TGACGTCT, which we identified as the manganese Superoxide dismutase TPA-responsive element, MSTRE. Site-specific mutation of the MSTRE abolished the TPA-responsive induction, validating the critical role of this sequence. We detected specific MSTRE activity from nuclear extracts and demonstrated by antibody supershift assay that this activity is closely related to CREB-1/ATF-1. TPA treatment rap idly induced phosphorylation of the CREB-1/ATF-1-like factor via the protein kinase C pathway. These results led us to conclude that the human MnSOD gene having the promoter construct used in this study is induced by TPA via activation of a CREB-1/ATF-1-like factor and not via either NF-kappa B or AP-1, In addition, we found that this induction was blocked by inhibitors of flavoproteins and NADPH oxidases, indicating involvement of enhanced generation of superoxide radical anion as an upstream signal. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. Seoul Natl Univ, Coll Nat Sci, Dept Microbiol, Seoul 151742, South Korea. Seoul Natl Univ, Res Ctr Mol Microbiol, Seoul 151742, South Korea. RP Yim, MB (reprint author), NHLBI, Biochem Lab, NIH, Bldg 3,Rm 202,3 Ctr Dr,MSC-0342, Bethesda, MD 20892 USA. NR 57 TC 66 Z9 69 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 DEC 24 PY 1999 VL 274 IS 52 BP 37455 EP 37460 DI 10.1074/jbc.274.52.37455 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 267WR UT WOS:000084382700090 PM 10601319 ER PT J AU Bell, DW Varley, JM Szydlo, TE Kang, DH Wahrer, DCR Shannon, KE Lubratovich, M Verselis, SJ Isselbacher, KJ Fraumeni, JF Birch, JM Li, FP Garber, JE Haber, DA AF Bell, DW Varley, JM Szydlo, TE Kang, DH Wahrer, DCR Shannon, KE Lubratovich, M Verselis, SJ Isselbacher, KJ Fraumeni, JF Birch, JM Li, FP Garber, JE Haber, DA TI Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome SO SCIENCE LA English DT Article ID DNA-DAMAGE CHECKPOINT; FISSION YEAST; PROTEIN-KINASE; HUMAN CANCERS; CELL-CYCLE; S-PHASE; ANTICANCER AGENTS; MISMATCH REPAIR; P53 MUTATIONS; PATHWAY AB The hCHK2 gene encodes the human homolog of the yeast Cds1 and Rad53 G(2) checkpoint kinases, whose activation in response to DNA damage prevents cellular entry into mitosis. Here, it is shown that heterozygous germ Line mutations in hCHK2 occur in Li-Fraumeni syndrome, a highly penetrant Familiar cancer phenotype usually associated with inherited mutations in the TP53 gene. These observations suggest that hCHK2 is a tumor suppressor gene conferring predisposition to sarcoma, breast cancer, and brain tumors, and they also provide a link between the central role of p53 inactivation in human cancer and the well-defined G(2) checkpoint in yeast. C1 Massachusetts Gen Hosp, Ctr Canc Risk Anal, Charlestown, MA 02139 USA. Harvard Univ, Sch Med, Charlestown, MA 02139 USA. Paterson Inst Canc Res, Canc Res Campaign, Dept Canc Genet, Manchester M20 4BX, Lancs, England. Harvard Univ, Sch Med, Boston, MA 02114 USA. Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02114 USA. NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Royal Manchester Childrens Hosp, Canc Res Campaign, Paediat & Familial Canc Res Grp, Manchester M27 1HA, Lancs, England. RP Haber, DA (reprint author), Massachusetts Gen Hosp, Ctr Canc Risk Anal, Bldg 149, Charlestown, MA 02139 USA. NR 55 TC 612 Z9 624 U1 1 U2 8 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 DEC 24 PY 1999 VL 286 IS 5449 BP 2528 EP 2531 DI 10.1126/science.286.5449.2528 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 268RQ UT WOS:000084429700056 PM 10617473 ER PT J AU Santoro, F Kennedy, PE Locatelli, G Malnati, MS Berger, EA Lusso, P AF Santoro, F Kennedy, PE Locatelli, G Malnati, MS Berger, EA Lusso, P TI CD46 is a cellular receptor for human herpesvirus 6 SO CELL LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; COFACTOR PROTEIN CD46; ACCELERATING FACTOR CD55; MEASLES-VIRUS; MARROW TRANSPLANTATION; FATAL ENCEPHALITIS; EXANTHEM-SUBITUM; DOWN-REGULATION; VARIANT-A; INFECTION AB Human herpesvirus 6 (HHV-6) is the etiologic agent of exanthema subitum, causes opportunistic infections in immunocompromised patients, and has been implicated in multiple sclerosis and in the progression of AIDS. Here, we show that the two major HHV-6 subgroups (A and B) use human CD46 as a cellular receptor. Downregulation of surface CD46 was documented during the course of HHV-6 infection. Both acute infection and cell fusion mediated by HHV-6 were specifically inhibited by a monoclonal antibody to CD46; fusion was also blocked by soluble CD46. Nonhuman cells that were resistant to HHV-6 fusion and entry became susceptible upon expression of recombinant human CD46. The use of a ubiquitous immunoregulatory receptor opens novel perspectives for understanding the tropism and pathogenicity of HHV-6. C1 San Raffaele Sci Inst, DIBIT, Unit Human Virol, I-20132 Milan, Italy. Univ Bologna, Dept Clin & Expt Med, I-40138 Bologna, Italy. NIAID, Viral Dis Lab, Bethesda, MD 20894 USA. RP Lusso, P (reprint author), San Raffaele Sci Inst, DIBIT, Unit Human Virol, I-20132 Milan, Italy. NR 60 TC 318 Z9 336 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD DEC 23 PY 1999 VL 99 IS 7 BP 817 EP 827 DI 10.1016/S0092-8674(00)81678-5 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 269QC UT WOS:000084488200014 PM 10619434 ER PT J AU Gruschus, JM Kuki, A AF Gruschus, JM Kuki, A TI Ellipsoidal delocalization of tunneling electrons in long-range electron transfer proteins SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID CYTOCHROME-C PEROXIDASE; BIOLOGICAL MOLECULES; COMPLEXES AB A formulation of long-range electronic coupling in electron transfer proteins based on the wave function tails of the donor and acceptor states is presented. These wave function tails, calculated by the IAL Hamiltonian method for cytochrome c and cytochrome c peroxidase, decay exponentially with distance and have falloff rates in the experimentally observed range. Analytical derivatives of the electronic coupling energy with regard to the energies and interactions of the orbitals of the intervening medium provide a detailed picture of the region of the protein important in the electron transfer process. These electronic coupling energy derivatives are calculated for the long-range zinc porphyrin to ruthenium coupling in ruthenated cytochrome c. The region of importance for long-range electron transfer is demonstrated mathematically to approximate an ellipsoid of revolution with the donor and acceptor as foci, The ellipsoidal region has the interesting feature that its minor axis grows as the square root of the donor-acceptor distance in the Limit of long-range electron transfer. C1 NIH, Biophys Chem Lab, NHLBI, Bethesda, MD 20892 USA. Alanex Corp, San Diego, CA 92121 USA. RP Gruschus, JM (reprint author), NIH, Biophys Chem Lab, NHLBI, Bldg 10, Bethesda, MD 20892 USA. NR 32 TC 16 Z9 16 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1089-5647 J9 J PHYS CHEM B JI J. Phys. Chem. B PD DEC 23 PY 1999 VL 103 IS 51 BP 11407 EP 11414 DI 10.1021/jp9925280 PG 8 WC Chemistry, Physical SC Chemistry GA 271NY UT WOS:000084601400024 ER PT J AU Friborg, J Kong, WP Hottiger, MO Nabel, GJ AF Friborg, J Kong, WP Hottiger, MO Nabel, GJ TI p53 inhibition by the LANA protein of KSHV protects against cell death SO NATURE LA English DT Article ID SARCOMA-ASSOCIATED HERPESVIRUS; HUMAN PAPILLOMAVIRUS TYPE-16; KAPOSIS-SARCOMA; TRANSCRIPTIONAL ACTIVATION; DNA-SEQUENCES; NUCLEAR ANTIGEN; EXPRESSION; HUMAN-HERPESVIRUS-8; IDENTIFICATION; COACTIVATORS AB Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus 8, has been implicated in the development of Kaposi's sarcoma (KS) and several B-cen lymphoproliferative diseases(1-3) Most cells in lesions derived from these malignancies are latently infected, and different viral gene products have been identified in association with lytic or latent infection by KSHV4,5. The latency-associated nuclear antigen (LANA), encoded by open reading frame 73 of the KSHV genome, is a highly immunogenic protein that is expressed predominantly during viral latency, in most KS spindle cells and in cell lines established from body-cavity-based lymphomas(6,7). Antibodies to LANA can be detected in a high percentage of HIV-infected individuals who subsequently develop KS8,9, although its role in disease pathogenesis is not completely understood. p53 is a potent transcriptional regulator of cell growth whose induction leads either to cell-cycle arrest or apoptosis. Loss of p53 function correlates with cell transformation and oncogenesis(10,11), and several viral oncoproteins interact with p53 and modulate its biological activity(12-13). Here we show that LANA interacts with the tumour suppressor protein p53 and represses its transcriptional activity. This viral gene product further inhibits the ability of p53 to induce cell death. We propose that LANA contributes to viral persistence and oncogenesis in KS through its ability to promote cell survival by altering p53 function. C1 NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Nabel, GJ (reprint author), NIH, Vaccine Res Ctr, 40 Convent Dr,MSC 3005, Bethesda, MD 20892 USA. RI Hottiger, Michael/J-7747-2013 OI Hottiger, Michael/0000-0002-7323-2270 NR 30 TC 455 Z9 471 U1 3 U2 10 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD DEC 23 PY 1999 VL 402 IS 6764 BP 889 EP 894 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 269ML UT WOS:000084482000036 PM 10622254 ER PT J AU Fanos, JH Mackintosh, MA AF Fanos, JH Mackintosh, MA TI Never again joy without sorrow: The effect on parents of a child with ataxia-telangiectasia SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE ataxia-telangiectasia; parents; family dynamics; genetic testing; genetic counseling ID DUCHENNE MUSCULAR-DYSTROPHY; FRAGILE-X-SYNDROME; CYSTIC-FIBROSIS; PSYCHOLOGICAL-ASPECTS; HUNTINGTON DISEASE; BREAST-CANCER; ATM MUTATIONS; FAMILIES; GENE; HETEROZYGOTES AB The purpose of this study was to explore the impact of having a child with ataxia-telangiectasia (A-T) as well as to assess parental understanding of the genetics of A-T and attitudes toward carrier testing. Sixty-eight parents of individuals with A-T were interviewed. Ninety percent of the parents correctly believed if there is a child with A-T, both are obligate heterozygotes. Only 9% knew each well sib had a two-thirds chance of being a carrier. Eighty-four percent would have their unaffected child tested for carrier status prior to age 18 years. Eighty-two percent believed heterozygosity is associated with increased health risks. We offer the following recommendations. 1) Physicians must realize that communicating the possibility of early death is difficult; parents need guidelines so they know what to expect, but diagnosis should not be a death sentence. Clinicians should stress individual variations in expression of the disorder and offer hope for future progress in treatment. 2) Parents underestimated carrier risks for the well sib and the frequency of carrier status in the general population. Although these distortions are self-protective, they interfere with transmission of accurate genetic information to their children. Parents should be referred to genetic counseling. 3) Psychological counseling should be offered to families at the time of diagnosis so parents can support each other, the affected, and unaffected offspring. Am. J. Med. Genet. 87:413-419, 1999. (C) 1999 Wiley-Liss, Inc. C1 Natl Human Genome Res Inst, Med Genet Branch, NIH, Bethesda, MD USA. Calif Pacific Med Ctr, Dept Pediat, San Francisco, CA 94115 USA. Calif Pacific Med Ctr, Dept Med, San Francisco, CA 94115 USA. Calif Pacific Med Ctr, Dept Psychiat, San Francisco, CA 94115 USA. San Jose State Univ, San Jose, CA 95192 USA. RP Fanos, JH (reprint author), Calif Pacific Med Ctr, Res Inst, 2340 Clay St, San Francisco, CA 94115 USA. OI Mackintosh, Margaret-Anne/0000-0002-2725-3177 NR 45 TC 22 Z9 22 U1 2 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD DEC 22 PY 1999 VL 87 IS 5 BP 413 EP 419 DI 10.1002/(SICI)1096-8628(19991222)87:5<413::AID-AJMG8>3.0.CO;2-X PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 267AN UT WOS:000084332600008 PM 10594880 ER PT J AU Fanos, JH AF Fanos, JH TI "My crooked vision": The well sib views ataxia-telangiectasia SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE ataxia-telangiectasia; sibs; genetic testing; genetic counseling; family dynamics ID BREAST-CANCER; FAMILIES; GENE; HETEROZYGOTES; PRODUCT AB The ataxia-telangiectasia gene (designated ATM) has been identified by positional cloning. Retrospective studies in cystic fibrosis (CF) have shown that the illness and death of a sib have far-reaching ramifications on the surviving sib's life. However, there have been no studies on sibs of children and adults with ataxia-telangiectasia (A-T), Thirty-five sibs from 24 families, including 26 adults and 9 adolescents, were drawn from the University of California, Los Angeles; the A-T Clinical Center at the Johns Hopkins University School of Medicine; and the A-T Children's Project Interviews indicated that, unlike CF, the visibility of A-T caused less resentment of time or attention given to the affected, less guilt, and less identification or idealization of the affected, but more embarrassment and shame. It may be said that, unlike CF, the dynamic is one of burden rather than trauma. The specific phenotypic expression of a genetic illness predisposes the way in which the well sib will encounter problems. In A-T affected families, one must help families locate caregiving resources so they will not burden their well children; sibs need heap with managing feelings of embarrassment and shame. Geneticists must be alert to understanding characteristic differences of disorders they encounter in order to offer the most appropriate support to affected families. Am. J. Med. Genet. 87:420-425, 1999. (C) 1999 WiIey-Liss, Inc. C1 Calif Pacific Med Ctr, Dept Pediat, San Francisco, CA 94115 USA. Calif Pacific Med Ctr, Dept Med, San Francisco, CA 94115 USA. Calif Pacific Med Ctr, Dept Psychiat, San Francisco, CA 94115 USA. Natl Human Genome Res Inst, Med Genet Branch, NIH, Bethesda, MD USA. RP Fanos, JH (reprint author), Calif Pacific Med Ctr, Res Inst, 2340 Clay St, San Francisco, CA 94115 USA. NR 49 TC 14 Z9 15 U1 1 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD DEC 22 PY 1999 VL 87 IS 5 BP 420 EP 425 DI 10.1002/(SICI)1096-8628(19991222)87:5<420::AID-AJMG9>3.0.CO;2-U PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 267AN UT WOS:000084332600009 PM 10594881 ER PT J AU Goldsmith, MF Straus, SE Kupfer, C Lenfant, C Collins, F Hodes, RJ Gordis, E Fauci, AS Alexander, D Battey, JF Slavkin, HC Leshner, AI Olden, K Hyman, SE Fischbach, GD AF Goldsmith, MF Straus, SE Kupfer, C Lenfant, C Collins, F Hodes, RJ Gordis, E Fauci, AS Alexander, D Battey, JF Slavkin, HC Leshner, AI Olden, K Hyman, SE Fischbach, GD TI 2020 vision: NIH heads foresee the future SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article C1 NIH, Bethesda, MD 20892 USA. NIH, Nat Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. NEI, NIH, Bethesda, MD 20892 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, NIH, Bethesda, MD USA. NIA, NIH, Bethesda, MD 20892 USA. NIAAA, NIH, Bethesda, MD USA. NIAID, NIH, Bethesda, MD 20892 USA. NICHHD, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. NIDA, NIH, Bethesda, MD USA. NIEHS, NIH, Bethesda, MD USA. NIMH, NIH, Bethesda, MD 20892 USA. NINDS, NIH, Bethesda, MD 20892 USA. RP Goldsmith, MF (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 8 Z9 8 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 DEC 22 PY 1999 VL 282 IS 24 BP 2287 EP 2290 DI 10.1001/jama.282.24.2287 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 265TK UT WOS:000084261700002 PM 10612308 ER PT J AU Fananapazir, L AF Fananapazir, L TI Hypertrophic cardiomyopathy - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NIH, Bethesda, MD 20892 USA. RP Fananapazir, L (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 7 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 DEC 22 PY 1999 VL 282 IS 24 BP 2303 EP 2303 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 265TK UT WOS:000084261700021 ER PT J AU Topol, IA Tawa, GJ Burt, SK Rashin, AA AF Topol, IA Tawa, GJ Burt, SK Rashin, AA TI On the structure and thermodynamics of solvated monoatomic ions using a hybrid solvation model SO JOURNAL OF CHEMICAL PHYSICS LA English DT Review ID MOLECULAR-DYNAMICS SIMULATIONS; ELECTRONIC-STRUCTURE CALCULATIONS; LINEAR SCALING COMPUTATION; DENSITY-FUNCTIONAL THEORY; FLUORIDE WATER CLUSTERS; HYDRATION FREE-ENERGIES; BOUNDARY ELEMENT METHOD; AB-INITIO CALCULATIONS; AQUEOUS SOLVATION; CONTINUUM MODEL AB The hydration free energies relative to that of the proton are calculated for a representative set of monatomic ions Z(+/-). These include cationic forms of the alkali earth elements Li, Na, and K, and anionic forms of the halogens F, Cl, and Br. In the current model the relative ion hydration free energy is defined as Delta[Delta G(hyd)(Z(+/-))]=G(Z(+/-)[H(2)O](n)(aq))-G(H(+)[H(2)O](n)(aq))-G(Z(+/-)(gas))-G(H(+)(gas)), where the solvated ions are represented by ion-water clusters coupled to a dielectric continuum using a self-consistent reaction field cycle. An investigation of the behavior of Delta[Delta G(hyd)(Z(+/-))] as the number of explicit waters of hydration is increased reveals convergence by n=4. This convergence indicates that the free energy change for the addition of water to a solvated proton-water complex is the same as the free energy change associated with the addition of water to a solvated Z(+/-)-water complex. This is true as long as there are four explicitly solvating waters associated with the ion. This convergence is independent of the type of monatomic ion studied and it occurs before the first hydration shell of the ions (typically greater than or equal to 6) is satisfied. Structural analysis of the ion-water clusters reveals that the waters within the cluster are more likely to form hydrogen bonds with themselves when clustering around anions than when clustering around cations. This suggests that for small ion-water clusters, anions are more likely to be externally solvated than cations. (C) 1999 American Institute of Physics. [S0021-9606(99)51048-9]. C1 NCI, Adv Biomed Comp Ctr, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. BioChemComp Inc, Teaneck, NJ 07666 USA. RP Topol, IA (reprint author), NCI, Adv Biomed Comp Ctr, SAIC Frederick, Frederick Canc Res & Dev Ctr, POB B, Frederick, MD 21702 USA. EM topol@ncifcrf.gov NR 121 TC 107 Z9 107 U1 2 U2 18 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD DEC 22 PY 1999 VL 111 IS 24 BP 10998 EP 11014 DI 10.1063/1.480486 PG 17 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 265KB UT WOS:000084242200034 ER PT J AU Berezhkovskii, AM Bicout, DJ Weiss, GH AF Berezhkovskii, AM Bicout, DJ Weiss, GH TI Collision model for activated rate processes: turnover behavior of the rate constant SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID CONDENSED PHASES; KRAMERS PROBLEM; DYNAMICS; RELAXATION; KINETICS; FREEDOM AB A theory of reaction rates is developed on the basis of the Bhatnagar-Gross-Krook model, which assumes instantaneous Maxwellization of the particle velocity at each collision. This model may be regarded as an alternative to the Kramers model for reaction dynamics in the condensed phase. The main results are two expressions for the rate constant for single- and double-well potentials. These cover the entire range of collision frequency. These expressions predict a turnover of the rate constant as a function of the collision frequency, analogous to the Kramers-Mel'nikov-Meshkov solution for the rate constant in the Kramers model. In contrast to the prediction for the Kramers model, the maximal value of the rate constant is noticeably below the TST estimate even for so high a barrier as 30k(B)T. This is a consequence of two facts: (1) The rate constant grows slowly from zero at small collision frequencies. (2) In addition, the rate of growth increases weakly with the barrier height, Delta U, as ln(Delta U/k(B)T). Simulated results indicate good agreement with the theory. (C) 1999 American Institute of Physics. [S0021-9606(99)51448-7]. C1 NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NCI, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. LY Karpov Phys Chem Res Inst, Moscow 103064, Russia. RP Berezhkovskii, AM (reprint author), NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. EM ghw@helix.nih.gov NR 31 TC 7 Z9 7 U1 0 U2 2 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD DEC 22 PY 1999 VL 111 IS 24 BP 11050 EP 11059 DI 10.1063/1.480464 PG 10 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 265KB UT WOS:000084242200039 ER PT J AU Sprengelmeyer, R Young, AW Schroeder, U Grossenbacher, PG Federlein, J Buttner, T Przuntek, H AF Sprengelmeyer, R Young, AW Schroeder, U Grossenbacher, PG Federlein, J Buttner, T Przuntek, H TI Knowing no fear SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE amygdala; facial expression; emotion recognition; basic emotions; fear ID EMOTIONAL FACIAL EXPRESSIONS; HUMAN AMYGDALA; VOCAL EXPRESSIONS; RECOGNITION; DISGUST; DAMAGE; LESIONS AB People with brain injuries involving the amygdala are often poor at recognizing facial expressions of fear, but the extent to which this impairment compromises other signals of the emotion of fear has not been clearly established. We investigated N.M.., a person with bilateral amygdala damage and a left thalamic lesion! who was impaired at recognizing fear from facial expressions. N.M, showed an equivalent deficit affecting fear recognition from body postures and emotional sounds. His deficit of fear recognition was not linked to evidence of any problem in recognizing anger (a common feature in other reports), but for his everyday experience of emotion N.M. reported reduced anger and fear compared with neurologically normal controls. These findings show a specific deficit compromising the recognition of the emotion of fear from a wide range of social signals, and suggest a possible relationship of this type of impairment with alterations of emotional experience. C1 Ruhr Univ Bochum, Neurol Klin, D-44791 Bochum, Germany. Univ York, Dept Psychol, York YO10 5DD, N Yorkshire, England. NIMH, Bethesda, MD 20892 USA. RP Sprengelmeyer, R (reprint author), Ruhr Univ Bochum, Neurol Klin, Gudrunstr 56, D-44791 Bochum, Germany. EM reiner.sprengelmeyer@ruhr-uni-bochum.de RI Young, Andy/G-2189-2011 OI Young, Andy/0000-0002-1202-6297 NR 26 TC 123 Z9 125 U1 2 U2 25 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8452 J9 P ROY SOC B-BIOL SCI JI Proc. R. Soc. B-Biol. Sci. PD DEC 22 PY 1999 VL 266 IS 1437 BP 2451 EP 2456 PG 6 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA 272ZW UT WOS:000084682200001 PM 10693814 ER PT J AU Rhee, S Han, ZJ Liu, KL Miles, HT Davies, DR AF Rhee, S Han, ZJ Liu, KL Miles, HT Davies, DR TI Structure of a triple helical DNA with a triplex-duplex junction SO BIOCHEMISTRY LA English DT Article ID BINDING PROTEIN; HUMAN-CELLS; HYDRATION AB Extended purine sequences on a DNA strand can lead to the formation of tripler DNA in which the third strand runs parallel to the purine strand. Tripler DNA structures have been proposed to play a role in gene expression and recombination and also have potential application as antisense inhibitors of gene expression. Tripler structures have been studied in solution by NMR, but have hitherto resisted attempts at crystallization. Here, we report a novel design of DNA sequences, which allows the first. crystallographic study of DNA segment containing triplexes and its junction with a duplex. In the 1.8 Angstrom, resolution structure, the sugar-phosphate backbone of the third strand is parallel to the purine-rich strand. The bases of the third strand associate with the Watson and Crick duplex via Hoogsteen-type interactions, resulting in three consecutive C+. GC, BU ABU (BU = 5-bromouracil), and C+. GC triplets. The overall conformation of the DNA tripler has some similarity to the B-form, but is distinct from both A- and B-forms. There are large changes in the phosphate backbone torsion angles (particularly gamma) of the purine strand, probably due to the electrostatic interactions between the phosphate groups and the protonated cytosine. These changes narrow the minor groove width of the purine-Hoogsteen strands and may represent sequence-specific structural variations of the DNA tripler. C1 NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Davies, DR (reprint author), NIDDK, Mol Biol Lab, NIH, Bldg 5,Room 338, Bethesda, MD 20892 USA. NR 31 TC 48 Z9 49 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD DEC 21 PY 1999 VL 38 IS 51 BP 16810 EP 16815 DI 10.1021/bi991811m PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 270YC UT WOS:000084563900011 PM 10606513 ER PT J AU Basson, CT Casey, M Mah, C AF Basson, CT Casey, M Mah, C TI Carney complex - Response SO CIRCULATION LA English DT Letter C1 Cornell Univ, Weill Med Coll, Dept Med, Div Cardiol, New York, NY 10021 USA. MeritCare Heart Serv, Fargo, ND USA. NICHD, Bethesda, MD USA. Ctr Arthritis & Rheumat Dis, Virginia Beach, VA USA. Childrens Hosp, Dept Genet, Boston, MA 02115 USA. Royal Victoria Hosp, Dept Dermatol, Belfast BT12 6BA, Antrim, North Ireland. Queens Univ, Dept Med Genet, Belfast, Antrim, North Ireland. Mayo Clin, Dept Pathol, Rochester, MN USA. RP Basson, CT (reprint author), Cornell Univ, Weill Med Coll, Dept Med, Div Cardiol, New York, NY 10021 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD DEC 21 PY 1999 VL 100 IS 25 BP E150 EP E150 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 268AL UT WOS:000084391400045 ER PT J AU Blum, B AF Blum, B TI Anti-CMV antibodies and coronary artery disease SO CIRCULATION LA English DT Letter C1 NIH, Cardiol Branch, Bethesda, MD 20892 USA. RP Blum, B (reprint author), NIH, Cardiol Branch, Bldg 10, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD DEC 21 PY 1999 VL 100 IS 25 BP E138 EP E138 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 268AL UT WOS:000084391400025 ER PT J AU Nieto, FJ Szklo, M Sorlie, PD AF Nieto, FJ Szklo, M Sorlie, PD TI Cytomegalovirus infection and coronary heart disease SO CIRCULATION LA English DT Letter ID ATHEROSCLEROSIS C1 Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD 21218 USA. NHLBI, Bethesda, MD 20892 USA. RP Nieto, FJ (reprint author), Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD 21218 USA. NR 5 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD DEC 21 PY 1999 VL 100 IS 25 BP E139 EP E139 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 268AL UT WOS:000084391400026 PM 10604906 ER PT J AU Putney, JW AF Putney, JW TI TRP, inositol 1,4,5-trisphosphate receptors, and capacitative calcium entry SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID PDZ-DOMAIN PROTEIN; CHANNELS; RELEASE; INFLUX; INAD C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 30 TC 129 Z9 129 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 DEC 21 PY 1999 VL 96 IS 26 BP 14669 EP 14671 DI 10.1073/pnas.96.26.14669 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 267TM UT WOS:000084375400001 PM 10611268 ER PT J AU Glick, A Popescu, N Alexander, V Ueno, H Bottinger, E Yuspa, SH AF Glick, A Popescu, N Alexander, V Ueno, H Bottinger, E Yuspa, SH TI Defects in transforming growth factor-beta signaling cooperate with a Ras oncogene to cause vapid aneuploidy and malignant transformation of mouse keratinocytes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CELL-CYCLE CONTROL; TGF-BETA; SKIN TUMORS; II RECEPTOR; TERMINAL DIFFERENTIATION; GENETIC CHANGES; CANCER CELLS; HIGH-RISK; EXPRESSION; PROGRESSION AB Genetic inactivation of the transforming growth factor-beta (TGF-beta) signaling pathway can accelerate tumor progression in the mouse epidermal model of multistage carcinogenesis. By using an in vitro model of keratinocyte transformation that parallels in vivo malignant conversion to squamous cell carcinoma, we show that v-ras(Ha) transduced primary TGF-beta 1-/- keratinocytes and keratinocytes expressing a TGF-beta type II dominant-negative receptor transgene have significantly higher frequencies of spontaneous transformation than control genotypes, Malignant transformation in the TGF-beta 1-/- keratinocytes is preceded by aneuploidy and accumulation of chromosomal aberrations. Similarly, transient inactivation of TGF-beta signaling with a type II dominant-negative receptor adenovirus causes rapid changes in ploidy, Exogenous TGF-beta 1 can suppress aneuploidy, chromosome breaks, and malignant transformation of the TGF-beta 1-/- keratinocytes at concentrations that do not significantly arrest cell proliferation. These results point to genomic instability as a mechanism by which defects in TGF-beta signaling could accelerate tumor progression in mouse multistage carcinogenesis. C1 NCI, Lab Cellular Carcinogenesis & Tumor Promot, Bethesda, MD 20892 USA. NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. Kyushu Univ, Sch Med, Dept Cardiol, Fukuoka 8128582, Japan. Yeshiva Univ Albert Einstein Coll Med, Bronx, NY 10461 USA. RP Glick, A (reprint author), NCI, Lab Cellular Carcinogenesis & Tumor Promot, Bldg 37 3B-19, Bethesda, MD 20892 USA. FU NIDDK NIH HHS [R01 DK056077] NR 49 TC 48 Z9 52 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 DEC 21 PY 1999 VL 96 IS 26 BP 14949 EP 14954 DI 10.1073/pnas.96.26.14949 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 267TM UT WOS:000084375400051 PM 10611318 ER PT J AU Zhao, YG Guo, YJ Tomac, AC Taylor, NR Grinberg, A Lee, EJ Huang, SP Westphal, H AF Zhao, YG Guo, YJ Tomac, AC Taylor, NR Grinberg, A Lee, EJ Huang, SP Westphal, H TI Isolated cleft palate in mice with a targeted mutation of the LIM homeobox gene Lhx8 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GAMMA-AMINOBUTYRIC-ACID; HOMEOTIC TRANSFORMATION; HOMEODOMAIN PROTEINS; BETA-3 SUBUNIT; NEURAL CREST; MOUSE MODEL; C-ELEGANS; DROSOPHILA; ASSOCIATION; FOREBRAIN AB Formation of the mammalian secondary palate is a highly regulated and complex process whose impairment often results in cleft palate, a common birth defect in both humans and animals. Loss-of-function analysis has linked a growing number of genes to this process. Here we report that Lhx8, a recently identified LIM homeobox gene, is expressed in the mesenchyme of the mouse palatal structures throughout their development. To test the function of Lhx8 in vivo, we generated a mutant mouse with a targeted deletion of the Lhx8 gene. Our analysis of the mutant animals revealed a crucial role for Lhx8 in palatogenesis. In Lhx8 homozygous mutant embryos, the bilateral primordial palatal shelves formed and elevated normally, but they often failed to make contact and to fuse properly, resulting in a cleft secondary palate. Because development of other craniofacial structures appeared normal, the impaired palatal formation in Lhx8-mutant mice was most likely caused by an intrinsic primary defect in the mesenchyme of the palatal shelves. The cleft palate phenotype observed in Lhx8-mutant mice suggests that Lhx8 is a candidate gene for the isolated nonsyndromic form of cleft palate in humans. C1 NICHHD, Lab Mammalian Genes & Dev, Bethesda, MD 20892 USA. RP Westphal, H (reprint author), NICHHD, Lab Mammalian Genes & Dev, Bethesda, MD 20892 USA. NR 49 TC 92 Z9 98 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 DEC 21 PY 1999 VL 96 IS 26 BP 15002 EP 15006 DI 10.1073/pnas.96.26.15002 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 267TM UT WOS:000084375400060 PM 10611327 ER PT J AU Kwon, ED Foster, BA Hurwitz, AA Madias, C Allison, JP Greenberg, NM Burg, MB AF Kwon, ED Foster, BA Hurwitz, AA Madias, C Allison, JP Greenberg, NM Burg, MB TI Elimination of residual metastatic prostate cancer after surgery and adjunctive cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade immunotherapy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RENAL-CELL CARCINOMA; RECEPTOR ZETA-CHAIN; TUMOR; EXPRESSION; ADENOCARCINOMA; RESPONSES; DISEASE; MOUSE AB Cancer relapse after surgery is a common occurrence, most frequently resulting from the outgrowth of minimal residual disease in the form of metastases. We examined the effectiveness of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade as an adjunctive immunotherapy to reduce metastatic relapse after primary prostate tumor resection, For these studies, we developed a murine model in which overt metastatic outgrowth of TRAMP-C2 (C2) prostate cancer ensues after complete primary tumor resection. Metastatic relapse in this model occurs reliably and principally within the draining lymph nodes in close proximity to the primary tumor, arising from established metastases present at the time of surgery. Using this model, we demonstrate that adjunctive CTLA-4 blockade administered immediately after primary tumor resection reduces metastatic relapse from 97.4 to 44%, Consistent with this, lymph nodes obtained 2 weeks after treatment reveal marked destruction or complete elimination of C2 metastases in 60% of mice receiving adjunctive anti-CTLA-4 whereas 100% of control antibody-treated mice demonstrate progressive CZ lymph node replacement. Our study demonstrates the potential of adjunctive CTLA-4 blockade immunotherapy to reduce cancer relapse emanating from minimal residual metastatic disease and may have broader implications for improving the capability of immunotherapy by combining such forms of therapy with other cytoreductive measures including surgery. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Dept Cell Biol, Houston, TX 77030 USA. Univ Calif Berkeley, Canc Res Lab, Berkeley, CA 94720 USA. Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA. RP Kwon, ED (reprint author), Loyola Univ, Med Ctr, Cardinal Bernardin Canc Ctr, Dept Urol, Room 202, Maywood, IL 60153 USA. FU NCI NIH HHS [CA82185, CA58204, CA64851, P50 CA058204, R01 CA064851, R01 CA073747] NR 25 TC 145 Z9 148 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 DEC 21 PY 1999 VL 96 IS 26 BP 15074 EP 15079 DI 10.1073/pnas.96.26.15074 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 267TM UT WOS:000084375400073 PM 10611340 ER PT J AU Davey, RT Bhat, N Yoder, C Chun, TW Metcalf, JA Dewar, R Natarajan, V Lempicki, RA Adelsberger, JW Millers, KD Kovacs, JA Polis, MA Walker, RE Falloon, L Masur, H Gee, D Baseler, M Dimitrov, DS Fauci, AS Lane, HC AF Davey, RT Bhat, N Yoder, C Chun, TW Metcalf, JA Dewar, R Natarajan, V Lempicki, RA Adelsberger, JW Millers, KD Kovacs, JA Polis, MA Walker, RE Falloon, L Masur, H Gee, D Baseler, M Dimitrov, DS Fauci, AS Lane, HC TI HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE HIV-1 infection; antiretroviral drugs; viral load; relapse; CD4 ID INDUCTION THERAPY; INFECTION; REPLICATION; RESERVOIR; INDINAVIR; RECOVERY; VIREMIA AB Identifying the immunologic and virologic consequences of discontinuing antiretroviral therapy in HIV-infected patients is of major importance in developing long-term treatment strategies for patients with HIV-1 infection, We designed a trial to characterize these parameters after interruption of highly active antiretroviral therapy (HAART) in patients who had maintained prolonged viral suppression on antiretroviral drugs. Eighteen patients with CD4(+) T cell counts greater than or equal to 350 cells/mu l and viral load below the limits of detection for greater than or equal to 1 year while on HAART were enrolled prospectively in a trial in which HAART was discontinued. Twelve of these patients had received prior IL-2 therapy and had low frequencies of resting, latently infected CD4 cells. Viral load relapse to >50 copies/ml occurred in all 18 patients independent of prior IL-2 treatment, beginning most commonly during weeks 2-3 after cessation of HAART. The mean relapse rate constant was 0.45 (0.20 log(10) copies) day(-1), which was very similar to the mean viral clearance rate constant after drug resumption of 0.35 (0.15 log(10) copies) day(-1) (P = 0.28), One patient experienced a relapse delay to week 7. All patients except one experienced a relapse burden to > 5,000 RNA copies/ml, Ex vivo labeling with BrdUrd showed that CD4 and CD8 cell turnover increased after withdrawal of HAART and correlated with viral load whereas lymphocyte turnover decreased after reinitiation of drug treatment. Virologic relapse occurs rapidly in patients who discontinue suppressive drug therapy, even in patients with a markedly diminished pool of resting, latently infected CD4(+) T cells. C1 NIAID, NIH, Bethesda, MD 20892 USA. NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. Sci Applicat Int Corp, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, NIH, Frederick, MD 21702 USA. RP Davey, RT (reprint author), NIAID, NIH, Bldg 10,Room 11C-103, Bethesda, MD 20892 USA. RI Lempicki, Richard/E-1844-2012; OI Lempicki, Richard/0000-0002-7059-409X; Polis, Michael/0000-0002-9151-2268 NR 31 TC 384 Z9 388 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 DEC 21 PY 1999 VL 96 IS 26 BP 15109 EP 15114 DI 10.1073/pnas.96.26.15109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 267TM UT WOS:000084375400079 PM 10611346 ER PT J AU Karas, RH Hodgin, JB Kwoun, M Krege, JH Aronovitz, M Mackey, W Gustafsson, JA Korach, KS Smithies, O Mendelsohn, ME AF Karas, RH Hodgin, JB Kwoun, M Krege, JH Aronovitz, M Mackey, W Gustafsson, JA Korach, KS Smithies, O Mendelsohn, ME TI Estrogen inhibits the vascular injury response in estrogen receptor beta-deficient female mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE 17 beta-estradiol; vascular smooth muscle ID ATHEROSCLEROTIC CORONARY-ARTERIES; CELLS IN-VITRO; ER-BETA; POSTMENOPAUSAL WOMEN; DIFFERENTIAL RESPONSE; 17-BETA ESTRADIOL; ENDOTHELIAL-CELLS; CAROTID-ARTERY; MESSENGER-RNA; NITRIC-OXIDE AB The protective effects of estrogen in the cardiovascular system result from both systemic effects and direct actions of the hormone on the vasculature. Two estrogen receptors have been identified, ER alpha and ER beta. We demonstrated previously that estrogen inhibits the response to vascular injury in both wild-type and ER alpha-deficient mice, and that ER beta is expressed in the blood vessels of each, suggesting a role for ER beta in the vascular protective effects of estrogen. In the present study, we examined the effect of estrogen administration on mouse carotid arterial injury in ER beta-deficient mice. Surprisingly, in ovariectomized female wild-type and ER beta knockout mice, 17 beta-estradiol markedly and equally inhibited the increase in vascular medial area and the proliferation of vascular smooth muscle cells after vascular injury, These data demonstrate that ER beta is not required for estrogen-mediated inhibition of the response to vascular injury, and suggest that either of the two known estrogen receptors is sufficient to protect against vascular injury, or that another unidentified estrogen receptor mediates the vascular protective effects of estrogen. C1 New England Med Ctr Hosp Inc, Mol Cardiol Res Inst, Boston, MA 02111 USA. Tufts Univ, Sch Med, Dept Med, Boston, MA 02111 USA. Tufts Univ, Sch Med, Dept Vasc Surg, Boston, MA 02111 USA. Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27709 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Karolinska Inst, Dept Med Nutr, S-14186 Huddinge, Sweden. RP Mendelsohn, ME (reprint author), New England Med Ctr Hosp Inc, Mol Cardiol Res Inst, 750 Washington St,80, Boston, MA 02111 USA. OI Korach, Kenneth/0000-0002-7765-418X FU NHLBI NIH HHS [R01 HL56069, HL59953, R01 HL056069, R01 HL061298, R01 HL61298] NR 41 TC 203 Z9 207 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 DEC 21 PY 1999 VL 96 IS 26 BP 15133 EP 15136 DI 10.1073/pnas.96.26.15133 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 267TM UT WOS:000084375400083 PM 10611350 ER PT J AU Charlab, R Valenzuela, JG Rowton, ED Ribeiro, JMC AF Charlab, R Valenzuela, JG Rowton, ED Ribeiro, JMC TI Toward an understanding of the biochemical and pharmacological complexity of the saliva of a hematophagous sand fly Lutzomyia longipalpis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PHLEBOTOMUS-PAPATASI DIPTERA; MOLECULAR-CLONING; AEDES-AEGYPTI; EXPRESSION; PROTEIN; VENOM; 5'-NUCLEOTIDASE; IDENTIFICATION; LEISHMANIASIS; ANTAGONISTS AB The saliva of blood-sucking arthropods contains powerful pharmacologically active substances and may be a vaccine target against some vector-borne diseases. Subtractive cloning combined with biochemical approaches was used to discover activities in the salivary glands of the hematophagous fly Lutzomyia longipalpis. Sequences of nine full-length cDNA clones were obtained, five of which are possibly associated with blood-meal acquisition, each having cDNA similarity to: (i) the bed bug Cimex lectularius apyrase, (ii) a 5'-nucleotidase/phosphodiesterase, (iii) a hyaluronidase, (iv) a protein containing a carbohydrate-recognition domain (CRD), and (v) a RGD-containing peptide with no significant matches to known proteins in the BLAST databases. Following these findings, we observed that the salivary apyrase activity of L. longipalpis is indeed similar to that of Cimex apyrase in its metal requirements. The predicted isoelectric point of the putative apyrase matches the Value found for Lutzomyia salivary apyrase, A 5'-nucleotidase, as well as hyaluronidase activity, was found in the salivary glands, and the CRD-containing cDNA matches the N-terminal sequence of the HPLC-purified salivary anticlotting protein. A cDNA similar to alpha-amylase was discovered and salivary enzymatic activity demonstrated for the first time in a bloodsucking arthropod. Full-length clones were also found coding for three proteins of unknown function matching, respectively, the N-terminal sequence of an abundant salivary protein, having similarity to the CAP superfamily of proteins and the Drosophila yellow protein. Finally, two partial sequences are reported that match possible housekeeping genes. Subtractive cloning will considerably enhance efforts to unravel the salivary pharmacopeia of blood-sucking arthropods. C1 NIAID, Sect Med Entomol, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Walter Reed Army Inst Res, Dept Entomol, Washington, DC 20307 USA. RP Ribeiro, JMC (reprint author), NIAID, Sect Med Entomol, Parasit Dis Lab, NIH, Bldg 4,Room 126,4 Ctr Dr,MSC 0425, Bethesda, MD 20892 USA. RI Rowton, Edgar/A-1975-2011; Rowton, Edgar/A-4474-2012; OI Rowton, Edgar/0000-0002-1979-1485; Ribeiro, Jose/0000-0002-9107-0818 NR 41 TC 162 Z9 167 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 21 PY 1999 VL 96 IS 26 BP 15155 EP 15160 DI 10.1073/pnas.96.26.15155 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 267TM UT WOS:000084375400087 PM 10611354 ER PT J AU Lyons, WE Mamounas, LA Ricaurte, GA Coppola, V Reid, SW Bora, SH Wihler, C Koliatsos, VE Tessarollo, L AF Lyons, WE Mamounas, LA Ricaurte, GA Coppola, V Reid, SW Bora, SH Wihler, C Koliatsos, VE Tessarollo, L TI Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID D-FENFLURAMINE; SPINAL-CORD; ADULT-RAT; RECEPTORS; BDNF; EXPRESSION; BEHAVIOR; FLUOXETINE; FOREBRAIN; PROMOTES AB Brain-derived neurotrophic factor (BDNF) has trophic effects on serotonergic (5-HT) neurons in the central nervous system. However, the role of endogenous BDNF in the development and function of these neurons has not been established in vivo because of the early postnatal lethality of BDNF null mice. In the present study, we use heterozygous BDNF+/- mice that have a normal life span and show that these animals develop enhanced intermale aggressiveness and hyperphagia accompanied by significant weight gain in early adulthood; these behavioral abnormalities are known to correlate with 5-HT dysfunction. Forebrain 5-HT levels and fiber density in BDNF+/- mice are normal at an early age but undergo premature age-associated decrements. However, young adult BDNF+/- mice show a blunted c-fos induction by the specific serotonin releaser-uptake inhibitor dexfenfluramine and alterations in the expression of several 5-HT receptors in the cortex, hippocampus, and hypothalamus. The heightened aggressiveness can be ameliorated by the selective serotonin reuptake inhibitor fluoxetine. Our results indicate that endogenous BDNF is critical for the normal development and function of central 5-HT neurons and for the elaboration of behaviors that depend on these nerve cells. Therefore, BDNF+/- mice may provide a useful model to study human psychiatric disorders attributed to dysfunction of serotonergic neurons. C1 NCI, Neurol Dev Grp, Adv Biosci Labs, Basic Res Program,Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Div Neuropathol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. RP Mamounas, LA (reprint author), NCI, Neurol Dev Grp, Adv Biosci Labs, Basic Res Program,Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RI Coppola, Vincenzo/E-2917-2011 OI Coppola, Vincenzo/0000-0001-6163-1779 FU NIMH NIH HHS [F32 MH085433, R29MH85433]; NINDS NIH HHS [F32 NS010580, NS 10580] NR 43 TC 539 Z9 542 U1 2 U2 11 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 DEC 21 PY 1999 VL 96 IS 26 BP 15239 EP 15244 DI 10.1073/pnas.96.26.15239 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 267TM UT WOS:000084375400102 PM 10611369 ER PT J AU Jun, K Piedras-Renteria, ES Smith, SM Wheeler, DB Lee, SB Lee, TG Chin, HM Adams, ME Scheller, RH Tsien, RW Shin, HS AF Jun, K Piedras-Renteria, ES Smith, SM Wheeler, DB Lee, SB Lee, TG Chin, HM Adams, ME Scheller, RH Tsien, RW Shin, HS TI Ablation of P/Q-type Ca2+ channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the alpha(1A)-subunit SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID FAMILIAL HEMIPLEGIC MIGRAINE; ACTIVATED CALCIUM CHANNELS; CEREBELLAR PURKINJE-CELLS; P-TYPE; FUNCTIONAL DIVERSITY; TRANSMITTER RELEASE; MUTANT MICE; NEURONS; EXPRESSION; SUBUNIT AB The Ca2+ channel alpha(1A)-subunit is a voltage-gated, pore-forming membrane protein positioned at the intersection of two important lines of research: one exploring the diversity of Ca2+ channels and their physiological roles, and the other pursuing mechanisms of ataxia, dystonia, epilepsy, and migraine. alpha(1A)-Subunits are thought to support both P- and Q-type Ca2+ channel currents, but the most direct test, a null mutant, has not been described, nor is it known which changes in neurotransmission might arise from elimination of the predominant Ca2+ delivery system at excitatory nerve terminals. We generated alpha(1A)-deficient mice (alpha(1A)(-/-)) and found that they developed a rapidly progressive neurological deficit with specific characteristics of ataxia and dystonia before dying approximate to 3-4 weeks after birth. P-type currents in Purkinje neurons and P- and Q-type currents in cerebellar granule cells were eliminated completely whereas other Ca2+ channel types, including those involved in triggering transmitter release, also underwent concomitant changes in density. Synaptic transmission in alpha(1A)(-/-) hippocampal slices persisted despite the lack of P/Q-type channels but showed enhanced reliance on N-type and R-type Ca2+ entry. The alpha(1A)(-/-) mice provide a starting point for unraveling neuropathological mechanisms of human diseases generated by mutations in alpha(1A). C1 Pohang Univ Sci & Technol, Natl Creat Res Initiat Ctr Calcum & Learning, Pohang 790784, South Korea. Pohang Univ Sci & Technol, Dept Life Sci, Pohang 790784, South Korea. Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Howard Hughes Med Inst, Stanford, CA 94305 USA. NIH, Genet Res Branch, Div Neurosci & Basic Behav Sci, Bethesda, MD 20892 USA. Univ Calif Riverside, Dept Entomol, Riverside, CA 92521 USA. Univ Calif Riverside, Dept Neurosci, Riverside, CA 92521 USA. RP Shin, HS (reprint author), Pohang Univ Sci & Technol, Natl Creat Res Initiat Ctr Calcum & Learning, Pohang 790784, South Korea. NR 52 TC 302 Z9 312 U1 2 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 21 PY 1999 VL 96 IS 26 BP 15245 EP 15250 DI 10.1073/pnas.96.26.15245 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 267TM UT WOS:000084375400103 PM 10611370 ER PT J AU Bulte, JWM Zhang, SC van Gelderen, P Herynek, V Jordan, EK Duncan, ID Frank, JA AF Bulte, JWM Zhang, SC van Gelderen, P Herynek, V Jordan, EK Duncan, ID Frank, JA TI Neurotransplantation of magnetically labeled oligodendrocyte progenitors: Magnetic resonance tracking of cell migration and myelination SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; SUPERPARAMAGNETIC IRON-OXIDE; BLOOD-BRAIN-BARRIER; TRANSFERRIN RECEPTOR; NEURAL TRANSPLANTS; PARKINSONS-DISEASE; RAT-BRAIN; T-CELLS; MR; ANTIBODY AB Demyelination is a common pathological finding in human neurological diseases and frequently persists as a result of failure of endogenous repair. Transplanted oligodendrocytes and their precursor cells can (re)myelinate axons, raising the possibility of therapeutic intervention. The migratory capacity of transplanted cells is of key importance in determining the extent of (re)myelination and can, at present, be evaluated only by using invasive and irreversible procedures. We have exploited the transferrin receptor as an efficient intracellular delivery device for magnetic nanoparticles, and transplanted tagged oligodendrocyte progenitor cells into the spinal cord of myelin-deficient rats. Cell migration could be easily detected by using three-dimensional magnetic resonance microscopy, with a close correlation between the areas of contrast enhancement and the achieved extent of myelination. The present results demonstrate that magnetic resonance tracking of transplanted oligodendrocyte progenitors is feasible; this technique has the potential to be easily extended to other neurotransplantation studies involving different precursor cell types. C1 NINDS, Lab Diagnost Radiol Res, Ctr Clin, NIH, Bethesda, MD 20892 USA. NINDS, In Vivo NMR Ctr, NIH, Bethesda, MD 20892 USA. NINDS, Neuroimaging Branch, NIH, Bethesda, MD 20892 USA. Univ Wisconsin, Sch Vet Med, Dept Med Sci, Madison, WI 53706 USA. RP Bulte, JWM (reprint author), NINDS, Lab Diagnost Radiol Res, Ctr Clin, NIH, Bldg 10,Room B1256,10 Ctr Dr,MSC 1074, Bethesda, MD 20892 USA. RI Bulte, Jeff/A-3240-2008 OI Bulte, Jeff/0000-0003-1202-1610 FU NINDS NIH HHS [NS 33710] NR 42 TC 416 Z9 441 U1 2 U2 21 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 21 PY 1999 VL 96 IS 26 BP 15256 EP 15261 DI 10.1073/pnas.96.26.15256 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 267TM UT WOS:000084375400105 PM 10611372 ER PT J AU Coop, A Pinto, J Wang, LJ McCullough, K Rothman, RB Dersch, C Jacobson, AE Rice, KC AF Coop, A Pinto, J Wang, LJ McCullough, K Rothman, RB Dersch, C Jacobson, AE Rice, KC TI Delta opioid binding selectivity of 3-ether analogs of naltrindole SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID ANTAGONISTS; AGONIST; LIGANDS AB Masking of the 3-phenol of naltrindole as a range of ethers caused a decrease in binding affinity at all three opiate receptors (mu, kappa, delta), however for the methyl ether, the reduction in affinity at both mu and kappa was greater than at delta, thereby increasing delta binding selectivity. (C) 1999 Published by Elsevier Science Ltd. C1 NIDDKD, Med Chem Lab, Bethesda, MD 20892 USA. Natl Inst Drug Abuse, Addict Res Ctr, Clin Psychopharmacol Sect, Baltimore, MD 21224 USA. RP Rice, KC (reprint author), NIDDKD, Med Chem Lab, Bldg 8,Rm B1-23, Bethesda, MD 20892 USA. NR 12 TC 9 Z9 9 U1 0 U2 0 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 DEC 20 PY 1999 VL 9 IS 24 BP 3435 EP 3438 DI 10.1016/S0960-894X(99)00622-8 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 265WK UT WOS:000084268900010 PM 10617086 ER PT J AU Chiu, NM Wang, B Kerksiek, KM Kurlander, R Pamer, EG Wang, CR AF Chiu, NM Wang, B Kerksiek, KM Kurlander, R Pamer, EG Wang, CR TI The selection of M3-restricted T cells is dependent on M3 expression and presentation of N-formylated peptides in the thymus SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE major histocompatibility complex; thymic selection; cytotoxic T cell; transgenic mice; T cell receptor ID CLASS-IB MOLECULE; POSITIVE SELECTION; HISTOCOMPATIBILITY ANTIGEN; RECEPTOR GENES; H2-M3; BINDING; MOUSE; MICE; IDENTIFICATION; SPECIFICITY AB The major histocompatibility complex (MHC) class Ib molecule H2-M3 binds N-formylated peptides from mitochondria and bacteria. To explore the role of MS expression and peptide supply in positive and negative selection, we generated transgenic mice expressing an M3-restricted TCR-alpha/beta from a CD8(+) T cell hybridoma (D7) specific for a listerial peptide (LemA). Development of M3-restricted transgenic T cells is impaired in both beta 2-microglobulin-deficient and transporter associated with antigen processing (TAP)-deficient mice, but is not diminished by changes in the H-2 haplotype. Maturation of M3/LemA-specific CD8(+) single positive cells in fetal thymic organ culture was sensitive to M3 expression levels as determined by antibody blocking and use of the castaneus mutant allele of M3. positive selection was rescued in TAP(-/-) lobes by nonagonist mitochondrial and bacterial peptides, whereas LemA and a partial agonist variant caused negative selection. Thus, MS-restricted CD8(+) T cells are positively and negatively selected by M3, with no contribution from the more abundant class Ia molecules. These results demonstrate that class Ib molecules can function in thymic education like class Ia molecules, despite limited ligand diversity and low levels of expression. C1 Univ Chicago, Gwen Knapp Ctr Lupus & Immunol Res, Comm Immunol, Chicago, IL 60637 USA. Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. Yale Univ, Infect Dis Sect, New Haven, CT 06520 USA. Yale Univ, Immunobiol Sect, New Haven, CT 06520 USA. NIH, Dept Clin Pathol, Ctr Clin, Bethesda, MD 20892 USA. RP Wang, CR (reprint author), Univ Chicago, Gwen Knapp Ctr Lupus & Immunol Res, Comm Immunol, 924 E 57th St, Chicago, IL 60637 USA. FU NIAID NIH HHS [R01 AI040310, R29 AI040310, R29 AI040310-05, AI40310]; NIMH NIH HHS [K08 MH090397] NR 49 TC 33 Z9 33 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD DEC 20 PY 1999 VL 190 IS 12 BP 1869 EP 1878 DI 10.1084/jem.190.12.1869 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 268MC UT WOS:000084419300015 PM 10601361 ER PT J AU Huang, Y Simons, SS AF Huang, Y Simons, SS TI Functional analysis of R651 mutations in the putative helix 6 of rat glucocorticoid receptors SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE glucocorticoid receptors; helix 6; R651 mutations; ligand volume; TAT GRE; MMTV ID LIGAND-BINDING DOMAIN; NUCLEAR HORMONE RECEPTORS; CARBOXYL-TERMINAL REGIONS; TUMOR VIRUS PROMOTER; ESTROGEN-RECEPTOR; STEROID-BINDING; TRANSCRIPTIONAL ACTIVATION; CONFORMATIONAL-CHANGES; RESPONSE ELEMENTS; CRYSTAL-STRUCTURE AB Trypsin digestion of steroid-free, but not steroid-bound, rat glucocorticoid receptor (GR) has recently been reported to occur at arginine-651 (R651). This residue is close to the affinity labeled Cys-656 and thus could be a sensitive probe of steroid binding. This hypothesis is supported by the current model of the GR ligand binding domain (LBD), which is based on the X-ray structures of several related receptor LBDs and places R651 in the middle of the putative alpha-helix 6 (649-EQRMS-653 of rat GR), close to the bound steroid. To test this model, R651, which could be involved in hydrophilic and/or hydrogen bonding, was mutated to alanine (A), which favors alpha-helices, the helix breakers proline (P) and glycine (G), or tryptophan (W). All receptors were expressed at about the same level, as determined by Western blots, but the cell-free binding activity of R651P was reduced twofold. The cell-free binding: affinities were all within a factor of 10 of wild type receptors. Whole cell biological activity with transiently transfected receptors was determined with a variety of GR: agonists (dexamethasone and deacylcortivazol) or antagonists (dexamethasone mesylate, RU486, and progesterone). Reporters containing both simple (GRE) and complex (MMTV) enhancers were used to test for alterations in GR interactions with enhancer/promoter complexes. Surprisingly, no correlation was observed between biological activity and ability to preserve alpha-helical structures for each point mutation. Finally, similar trypsin digestion patterns indicated no major differences in the tertiary structure of the mutant receptors. Collectively, these results argue that the polar/ionizable residue R651 is not required: for GR activity and is not part of an alpha-helix in the steroid-free or bound GR. The effect of these mutations on GR structure and activity may result from a cascade of initially smaller perturbations. These LED alterations were the most varied for interactions with deacylcortivazol and RU 486, which have recently been predicted to be sub-optimal binders due to their large size. However, further analyses of ligand size versus affinity suggest that there is no narrowly defined optimal size for ligand binding, although larger ligands may be more sensitive to modifications of LED structure. Finally, the changes in GR activity with the various mutations seem to result from altered LED interactions with common, as opposed to enhancer specific, transcription factors. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 NIDDK, Steroid Hermones Sect, LMCB, NIH, Bethesda, MD 20892 USA. RP Simons, SS (reprint author), NIDDK, Steroid Hermones Sect, LMCB, NIH, Bldg 8,Room B2A-07, Bethesda, MD 20892 USA. NR 77 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD DEC 20 PY 1999 VL 158 IS 1-2 BP 117 EP 130 DI 10.1016/S0303-7207(99)00171-9 PG 14 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 263VP UT WOS:000084146200015 PM 10630412 ER PT J AU Heinz, A Weingartner, H George, D Hommer, D Wolkowitz, OM Linnoila, M AF Heinz, A Weingartner, H George, D Hommer, D Wolkowitz, OM Linnoila, M TI Severity of depression in abstinent alcoholics is associated with monoamine metabolites and dehydroepiandrosterone-sulfate concentrations SO PSYCHIATRY RESEARCH LA English DT Article DE depression; alcoholism; neurosteroids; detoxification stress; cortisol; DHEA-S ID HEALTHY CONTROL SUBJECTS; CEREBROSPINAL-FLUID; PANIC DISORDER; 5-HYDROXYINDOLEACETIC ACID; MAJOR DEPRESSION; CORTISOL; WITHDRAWAL; SEROTONIN; DHEA; RAT AB Depressed mood increases the relapse risk of abstinent alcoholics; its neurobiological correlates may include reduced serotonin and norepinephrine turnover rates and increased cortisol concentrations during detoxification stress. Neurosteroids such as dehydroepiandrosterone and its sulfate (DHEA and DHEA-S) may antagonize cortisol action and may have mood-elevating effects on their own. We measured severity of depression with Beck's Depression Inventory (BDI) and Hamilton's Depression Rating Scale (HDRS), plasma concentrations of cortisol, DHEA and DHEA-S, and CSF concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and the dopamine metabolite homovanillic acid (HVA) in 21 abstinent alcoholics after 4 weeks of abstinence and in 11 age-matched healthy control subjects. Only CSF MHPG concentrations were reduced in alcoholics compared to control subjects (41.4 +/- 6.6 vs. 53.3 +- 8.6 pmol/ml). Self-rated depression was significantly correlated with CSF MHPG (Spearman's R = + 0.57, P < 0.01), CSF 5-HLAA (R = + 0.51, P < 0.05) and plasma cortisol concentrations (R = + 0.50, P < 0.05). Negative correlations were found between DHEA-S concentrations and both self-rated depression (R = -0.45, P < 0.05) and observer-rated depression (R = - 0.55, P < 0.05). The ratio of DHEA-S to cortisol serum concentrations was also negatively correlated with depression (BDI: R = -0.55, P < 0.01; HDRS: R = - 0.63, P < 0.005). Anxiety (Spielberger's State Anxiety Scale) was only associated with CSF MHPG concentrations (R = + 0.58, P < 0.01). Our findings point to the importance of noradrenergic dysfunction in the pathogenesis of depression among abstinent alcoholics and indicate that their mood states may also be modulated by a low DHEA-S to cortisol ratio, hypothetically indicative of IOW stress protection capacities. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Heidelberg, Cent Inst Mental Hlth, Dept Addict Behav & Addict Med, D-68159 Mannheim, Germany. Univ Calif San Francisco, San Francisco, CA 94143 USA. NIAAA, Bethesda, MD 20892 USA. RP Heinz, A (reprint author), Univ Heidelberg, Cent Inst Mental Hlth, Dept Addict Behav & Addict Med, J5, D-68159 Mannheim, Germany. NR 67 TC 34 Z9 36 U1 2 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD DEC 20 PY 1999 VL 89 IS 2 BP 97 EP 106 DI 10.1016/S0165-1781(99)00099-2 PG 10 WC Psychiatry SC Psychiatry GA 273UP UT WOS:000084726300002 PM 10646828 ER PT J AU Drew, KL Osborne, PG Frerichs, KU Hu, Y Koren, RE Hallenbeck, JM Rice, ME AF Drew, KL Osborne, PG Frerichs, KU Hu, Y Koren, RE Hallenbeck, JM Rice, ME TI Ascorbate and glutathione regulation in hibernating ground squirrels SO BRAIN RESEARCH LA English DT Article DE ascorbic acid; ischemia; oxidative stress; torpor; arctic ground squirrel; 13-lined ground squirrel ID CEREBRAL-ISCHEMIA; ENDOTHELIAL-CELLS; INDUCED INJURY; ACID; BRAIN; TEMPERATURE; INHIBITION; SUPPRESSION; METABOLISM; TOLERANCE AB Ground squirrels withstand up to 90% reductions in cerebral blood flow during hibernation as well as rapid reperfusion upon periodic arousals from torpor. Metabolic suppression likely plays a primary adaptive role which allows hibernating species to tolerate such phenomena. However, several other aspects of hibernation physiology are also consistent with tolerance to dramatic fluctuations in cerebral blood flow, suggesting that multiple neuroprotective adaptations may work in concert during hibernation. The purpose of the present work, was to study the dynamics of the low molecular weight antioxidants, ascorbate and glutathione (GSH), during hibernation. Alterations in concentrations of ascorbate during hibernation and arousal in two species of hibernating ground squirrels suggest that it in concentrations of ascorbate during hibernation and arousal in two species of hibernating ground squirrels suggest that it could play a protective role during hibernation or arousal. Samples were collected during the hibernation season from arctic ground squirrels (AGS: Spermophilus parryii) and 13-lined ground squirrels (TLS; S. tridecemlineatus) during prolonged torpor and in squirrels that did not hibernate or had not been hibernating for several weeks. We determined antioxidant levels in plasma, cerebrospinal fluid (CSF), and in frontal cortex, hippocampus and cerebellum using high-performance liquid chromatography (HPLC). Plasma ascorbate concentrations increased dramatically (3-4-fold) in both species during hibernation and rapidly returned to prehibernation levels upon arousal. By contrast, plasma GSH concentrations fell slightly or remained stable during hibernation. Ascorbate levels in the CSF doubled in hibernating AGS (not determined in TLS), while brain ascorbate content fell slightly (10-15%) in both species. Substantial increases in plasma and CSF ascorbate concentrations suggest that this antioxidant could play a protective role during hibernation and reperfusion upon arousal from hibernation. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Univ Alaska, Inst Arctic Biol, Fairbanks, AK 99775 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Neurosurg, Boston, MA 02115 USA. NINDS, NIH, Stroke Branch, Bethesda, MD 20892 USA. NYU Med Ctr, Dept Physiol, New York, NY 10016 USA. NYU Med Ctr, Dept Neurosci & Neurosurg, New York, NY 10016 USA. RP Drew, KL (reprint author), Univ Alaska, Inst Arctic Biol, POB 757000, Fairbanks, AK 99775 USA. RI Drew, Kelly/B-7995-2013 FU NINDS NIH HHS [NS-34115] NR 43 TC 45 Z9 46 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD DEC 18 PY 1999 VL 851 IS 1-2 BP 1 EP 8 DI 10.1016/S0006-8993(99)01969-1 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 269XA UT WOS:000084501700001 PM 10642822 ER PT J AU Backman, C Perlmann, T Wallen, A Hoffer, BJ Morales, M AF Backman, C Perlmann, T Wallen, A Hoffer, BJ Morales, M TI A selective group of dopaminergic neurons express Nurr1 in the adult mouse brain SO BRAIN RESEARCH LA English DT Article DE Nurr1; tyrosine hydroxylase; brain; dopamine; distribution ID CENTRAL-NERVOUS-SYSTEM; RAT MEDULLA-OBLONGATA; DORSAL MOTOR NUCLEUS; TYROSINE-HYDROXYLASE; CELL-BODIES; NGFI-B; RECEPTORS; GENE; MICE; TRANSCRIPTION AB Nurr1, an orphan receptor of the nuclear receptor superfamily, is widely expressed in the central nervous system (CNS) including brain regions where dopaminergic neurons are abundant. Recent analyses of Nurr1 null mutant mice have shown that Nurr1 is essential for the development and survival of midbrain dopaminergic neurons. However, other dopaminergic neuronal populations do not seem to be affected by ablation of the Nurr1 gene. The purpose of the present study was to investigate the degree of co-existence of Nurr1 mRNA and tyrosine hydroxylase (TH) immunoreactivity in the brain of adult mice to better characterize the selective effects of Nurr1 on catecholaminergic neurons. Our results indicate that the majority of TH-immunoreactive neurons in the substantia nigra (SN; 96%), ventral tegmental area (VTA; 95%), retrorubral field (91%), olfactory bulb (85%), linear nucleus raphe (91%) and central grey (61%) express Nurr1, In contrast, dopaminergic cells of the paraventricular and periventricular hypothalamic nucleus showed only a few Nurr1/TH double labeled neurons, while TH-immunoreactive neurons in the arcuate nucleus and zona incerta did not express Nurr1 mRNA. Nurr1 expression was also excluded from (nor)adrenergic neurons of the brainstem. In conclusion, Nurr1 transcripts were not found in all CNS catecholaminergic neurons. Nurr1 expression was confined to periglomerular and midbrain dopaminergic neurons. These results suggest that within the adult mouse brain, Nurr1 may participate in dopaminergic functions of the olfactory bulb and midbrain. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIDA, Cellular Neurobiol Dept, NIH, Baltimore, MD 21224 USA. Karolinska Inst, Ludwig Inst Canc Res, S-17177 Stockholm, Sweden. RP Backman, C (reprint author), NIDA, Cellular Neurobiol Dept, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI backman, cristina/C-1276-2013; Wallen-Mackenzie, Asa/B-9105-2017 OI Wallen-Mackenzie, Asa/0000-0002-8713-070X NR 21 TC 75 Z9 82 U1 2 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD DEC 18 PY 1999 VL 851 IS 1-2 BP 125 EP 132 DI 10.1016/S0006-8993(99)02149-6 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 269XA UT WOS:000084501700014 PM 10642835 ER PT J AU Deng, XL Cadet, JL AF Deng, XL Cadet, JL TI Methamphetamine administration causes overexpression of nNOS in the mouse striatum SO BRAIN RESEARCH LA English DT Article DE methamphetamine; neurotoxicity; nitric oxide synthase ID NITRIC-OXIDE SYNTHASE; INDUCED NEUROTOXICITY; GLUTAMATE; MICE; 7-NITROINDAZOLE; INHIBITOR; NEURONS AB The accumulated evidence suggests that the overproduction of nitric oxide (NO) is involved in methamphetamine (METH)-induced neurotoxicity. Using NADPH-diaphorase histochemistry, neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) antibody immunohistochemistry, the possible overexpression of nNOS and iNOS was investigated in the brains of mice treated with METH. The number of positive cells or the density of positive fibers was assessed at 1 h, 24 h and 1 week after METH injections. There were no clear positive iNOS cells and fibers demonstrated in the brains of mice after METH treatment. In contrast, METH caused marked increases in nNOS in the striatum and hippocampus at 1 and 24 h post-treatment. The nNOS expression normalized by I week. There were no statistical changes in nNOS expression in the frontal cortex, the cerebellar cortex, nor in the substantia nigra. These results provide further support for the idea that NO is involved in the neurotoxic effects of METH. (C) 1999 Published by Elsevier Science B.V. All rights reserved. C1 NIDA, Mol Neuropsychiat Sect, NIH, IRP,Addict Res Ctr, Baltimore, MD 21224 USA. RP Cadet, JL (reprint author), NIDA, Mol Neuropsychiat Sect, NIH, IRP,Addict Res Ctr, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 16 TC 56 Z9 58 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD DEC 18 PY 1999 VL 851 IS 1-2 BP 254 EP 257 DI 10.1016/S0006-8993(99)02087-9 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 269XA UT WOS:000084501700031 PM 10642852 ER PT J AU Foley, D AF Foley, D TI Sorting out sleep in patients with Alzheimer's disease SO LANCET LA English DT Editorial Material C1 NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. RP Foley, D (reprint author), NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. NR 12 TC 5 Z9 5 U1 2 U2 2 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD DEC 18 PY 1999 VL 354 IS 9196 BP 2098 EP 2099 DI 10.1016/S0140-6736(99)00413-4 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 266UG UT WOS:000084318200006 PM 10609812 ER PT J AU Kuznetsova, N Leikin, S AF Kuznetsova, N Leikin, S TI Does the triple helical domain of type I collagen encode molecular recognition and fiber assembly while telopeptides serve as catalytic domains? Effect of proteolytic cleavage on fibrillogenesis and on collagen-collagen interaction in fibers SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID X-RAY-DIFFRACTION; FIBRIL FORMATION; INVITRO; FORCES; SEQUENCE; DRIVEN; CHAIN; CDNA AB Over the last several decades, it has been established that proteolytic removal of short, non-helical terminal peptides (telopeptides) from type I collagen significantly alters the kinetics of in vitro fibrillogenesis. However, it has also been observed that the protein is still capable of forming fibers even after complete removal of telopeptides. This study focuses on the characterization of this fibrillogenesis competency of collagen, We have combined traditional kinetic and thermodynamic assays of fibrillogenesis efficacy with direct measurements of interaction between collagen molecules in fibers by osmotic stress and x-ray diffraction. We found that telopeptide cleavage by pepsin or by up to 20 h of Pronase treatment altered fiber assembly kinetics, but the same fraction of the protein still assembled into fibers. Small-angle x-ray diffraction showed that these fibers have normal, native-like D-stagger. Force measurements indicated that collagen-collagen interactions in fibers were not affected by either pepsin or Pronase treatment, In contrast, prolonged (>20 h) Pronase treatment resulted in cleavage of the triple helical domain as indicated by SDS-polyacrylamide gel electrophoresis. The triple-helix cleavage correlated with the observed decrease in the fraction of protein capable of forming fibers and with the measured loss of attraction between helices in fibers, These data suggest that telopeptides play a catalytic role, whereas the information necessary for proper molecular recognition and fiber assembly is encoded in the triple helical domain of collagen. C1 NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. RP Leikin, S (reprint author), NICHD, Lab Phys & Struct Biol, NIH, Bldg 12A,Rm 2041, Bethesda, MD 20892 USA. RI Leikin, Sergey/A-5518-2008 OI Leikin, Sergey/0000-0001-7095-0739 NR 36 TC 75 Z9 75 U1 1 U2 12 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 DEC 17 PY 1999 VL 274 IS 51 BP 36083 EP 36088 DI 10.1074/jbc.274.51.36083 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 266AV UT WOS:000084279200009 PM 10593890 ER PT J AU Yates, PA Burman, RW Mummaneni, P Krussel, S Turker, MS AF Yates, PA Burman, RW Mummaneni, P Krussel, S Turker, MS TI Tandem B1 elements located in a mouse methylation center provide a target for de novo DNA methylation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CYTOSINE METHYLATION; DENOVO METHYLATION; CELLS; GENE; SEQUENCES; REPEATS; PATTERNS; UPSTREAM; REGIONS; LOCUS AB A cis-acting methylation center that signals de novo DNA methylation is located upstream of the mouse Aprt gene. In the current study, two approaches were taken to determine if tandem B1 repetitive elements found at the 3' end of the methylation center contribute to the methylation signal. First, bisulfite genomic sequencing demonstrated that CpG sites within the B1 elements were methylated at relative levels of 43% in embryonal stem cells deficient for the maintenance DNA methyltransferase when compared with wild type embryonal stem cells. Second, the ability of the BI elements to signal de novo methylation upon stable transfection into mouse embryonal carcinoma cells was examined, This approach demonstrated that the B1 elements were methylated de novo to a high level in the embryonal carcinoma cells and that the B1 elements acted synergistically, The results from these experiments provide strong evidence that the tandem B1 repetitive elements provide a significant fraction of the methylation center signal. By extension, they also support the hypothesis that one role for DNA methylation in mammals is to protect the genome from expression and transposition of parasitic elements. C1 Oregon Hlth Sci Univ, Ctr Res Occupat & Environm Toxicol, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA. NICHD, Sect Neuroendocrinol, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Turker, MS (reprint author), Oregon Hlth Sci Univ, Ctr Res Occupat & Environm Toxicol, L606,3181 SW Sam Jackson Pk Rd, Portland, OR 97201 USA. FU PHS HHS [T32] NR 32 TC 66 Z9 69 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 DEC 17 PY 1999 VL 274 IS 51 BP 36357 EP 36361 DI 10.1074/jbc.274.51.36357 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 266AV UT WOS:000084279200047 PM 10593928 ER PT J AU Ro, HS Miles, EW AF Ro, HS Miles, EW TI Structure and function of the tryptophan synthase alpha(2)beta(2) complex - Roles of beta subunit histidine 86 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AMINO-ACID AMINOTRANSFERASE; D-SERINE DEHYDRATASE; INDUCED CONFORMATIONAL-CHANGES; NUCLEAR MAGNETIC-RESONANCE; ESCHERICHIA-COLI; PYRIDOXAL 5'-PHOSPHATE; SALMONELLA-TYPHIMURIUM; CRYSTAL-STRUCTURES; INTERSUBUNIT COMMUNICATION; CATALYTIC MECHANISM AB To probe the structural and functional roles of active-site residues in the tryptophan synthase alpha(2)beta(2) complex from Salmonella typhimurium, we have determined the effects of mutation of His(86) in the beta subunit. His(86) is located adjacent to beta subunit Lys(87), which forms an internal aldimine with the pyridoxal phosphate and catalyzes the abstraction of the alpha-proton of L-serine. The replacement of His(86) by leucine (H86L) weakened pyridoxal phosphate binding similar to 20-fold and abolished the circular dichroism signals of the bound coenzyme and of a reaction intermediate. Correlation of these results with previous crystal structures indicates that beta-His(86) plays a structural role in binding pyridoxal phosphate and in stabilizing the correct orientation of pyridoxal phosphate in the active site of the beta subunit. The H86L mutation also altered the pH profiles of absorbance and fluorescence signals and shifted the pH optimum for the synthesis of L-tryptophan from pH 7.5 to 8.8. We propose that the interaction of His(86) with the phosphate of pyridoxal phosphate and with Lys(87) lowers the pK(a) of Lys(87) in the wild-type alpha(2)beta(2) complex and thereby facilitates catalysis by Lys(87) in the physiological pH range. C1 NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Miles, EW (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bldg 8,Rm 225,8 Ctr Dr,MSC 0830, Bethesda, MD 20892 USA. EM EdithM@intra.niddk.nih.gov NR 56 TC 7 Z9 7 U1 0 U2 6 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 DEC 17 PY 1999 VL 274 IS 51 BP 36439 EP 36445 DI 10.1074/jbc.274.51.36439 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 266AV UT WOS:000084279200059 PM 10593940 ER PT J AU Fernandez-Salas, E Sagar, M Cheng, C Yuspa, SH Weinberg, WC AF Fernandez-Salas, E Sagar, M Cheng, C Yuspa, SH Weinberg, WC TI p53 and tumor necrosis factor alpha regulate the expression of a mitochondrial chloride channel protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EPIDERMAL-KERATINOCYTES; MOLECULAR-CLONING; INDUCED APOPTOSIS; SKIN-CANCER; CELL-LINES; P64; ONCOGENE; GROWTH; PROGRESSION; DATABASE AB A novel chloride intracellular channel (CLIC) gene, clone mc3s5/mtCLIC, has been identified from differential display analysis of differentiating mouse keratinocytes from p53+/+ and p53-/- mice. The 4.2-kilobase pair cDNA contains an open reading frame of 762 base pairs encoding a 253-amino acid protein with two putative transmembrane domains. mc3s5/mtCLIC protein shares extensive homology with a family of intracellular organelle chloride channels but is the first shown to be differentially regulated. mc3s5/mtCLIC mRNA is expressed to the greatest extent in vivo in heart, lung, liver, kidney, and skin, with reduced levels in some organs from p53-/- mice, mc3s5/mtCLIC mRNA and protein are higher in p53+/+ compared with p53-/- basal keratinocytes in culture, and both increase in differentiating keratinocytes independent of genotype. Overexpression of p53 in keratinocytes induces mc3s5/mtCLIC mRNA and protein. Exogenous human recombinant tumor necrosis factor alpha also up-regulates mc3s5/mtCLIC mRNA and protein in keratinocytes, Subcellular fractionation of keratinocytes indicates that both the green fluorescent protein-mc3s5 fusion protein and the endogenous mc3s5/mtCLIC are localized to the cytoplasm and mitochondria. Similarly, mc3s5/mtCLIC was localized to mitochondria and cytoplasmic fractions of rat liver homogenates. Furthermore, mc3s5/mtCLIC colocalized with cytochrome oxidase in keratinocyte mitochondria by immunofluorescence and was also detected in the cytoplasmic compartment. Sucrose gradient-purified mitochondria from rat liver confirmed this mitochondrial localization. This represents the first report of localization of a CLIC type chloride channel in mitochondria and the first indication that expression of an organellular chloride channel can be regulated by p53 and tumor necrosis factor alpha. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Fernandez-Salas, E (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, 37 Convent Dr,MSC 4255,Bldg 37,Rm 3B16, Bethesda, MD 20892 USA. RI Weinberg, Wendy/A-8920-2009 NR 44 TC 96 Z9 99 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 DEC 17 PY 1999 VL 274 IS 51 BP 36488 EP 36497 DI 10.1074/jbc.274.51.36488 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 266AV UT WOS:000084279200065 PM 10593946 ER PT J AU Giannoukos, G Silverstein, AM Pratt, WB Simons, SS AF Giannoukos, G Silverstein, AM Pratt, WB Simons, SS TI The seven amino acids (547-553) of rat glucocorticoid receptor required for steroid and hsp90 binding contain a functionally independent LXXLL motif that is critical for steroid binding SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEAT-SHOCK-PROTEIN; CARBOXYL-TERMINAL REGIONS; NUCLEAR-RECEPTOR; ANDROGEN RECEPTOR; PROGESTERONE-RECEPTOR; MOLECULAR CHAPERONES; RETINOIC ACID; DOMAIN; ACTIVATION; CELLS AB Hsp90 association with glucocorticoid receptors (GRs) is required for steroid binding. We recently reported that seven amino acids (547-553) overlapping the aminoterminal end of the rat GR ligand-binding domain are necessary for hsp90 binding, and consequently steroid binding. The role of a LXXLL motif at the COOH terminus of this sequence has now been analyzed by determining the properties of Leu to Ser mutations in full-length GR and glutathione S-transferase chimeras. Surprisingly, these mutations decreased steroid binding capacity without altering receptor levels, steroid binding affinity, or hsp90 binding. Single mutations in the context of the full-length receptor did not affect the transcriptional activity but the double mutant (L550S/L553S) was virtually inactive. This biological inactivity was found to be due to an increased rate of steroid dissociation from the activated mutant complex, These results, coupled with those from trypsin digestion studies, suggest a model in which the GR ligand-binding domain is viewed as having a "hinged pocket," with the hinge being in the region of the trypsin digestion site at Arg(651). The pocket would normally be kept shut via the intramolecular interactions of the LXXLL motif at amino acids 550-554 acting as a hydrophobic clasp. C1 NIDDK, LMCB, Steroid Hormones Sect, NIH, Bethesda, MD 20892 USA. Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA. RP Simons, SS (reprint author), NIDDK, LMCB, Steroid Hormones Sect, NIH, Bldg 8,Rm B2A-07, Bethesda, MD 20892 USA. FU NIDDK NIH HHS [DK31573] NR 57 TC 40 Z9 41 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 DEC 17 PY 1999 VL 274 IS 51 BP 36527 EP 36536 DI 10.1074/jbc.274.51.36527 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 266AV UT WOS:000084279200070 PM 10593951 ER PT J AU Cristofari, G Gabus, C Ficheux, D Bona, M Le Grice, SFJ Darlix, JL AF Cristofari, G Gabus, C Ficheux, D Bona, M Le Grice, SFJ Darlix, JL TI Characterization of active reverse transcriptase and nucleoprotein complexes of the yeast retrotransposon Ty3 in vitro SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HIV-1 NUCLEOCAPSID PROTEIN; RNA ANNEALING ACTIVITIES; PROVIRAL DNA-SYNTHESIS; TERMINAL ZINC-FINGER; PRIMER-BINDING-SITE; IN-VITRO; STRAND TRANSFER; VIRUS; NCP7; RECOMBINATION AB Human immunodeficiency virus (HIV) and the distantly related yeast Ty3 retrotransposon encode reverse transcriptase (RT) and a nucleic acid-binding protein designated nucleocapsid protein (NCp) with either one or two zinc fingers, required for HIV-1 replication and Ty3 transposition, respectively. In vitro binding of HIV-1 NCp7 to viral 5' RNA and primer tRNA(3)(Lys) catalyzes formation of nucleoprotein complexes resembling the virion nucleocapsid. Nucleocapsid complex formation functions in viral RNA dimerization and tRNA annealing to the primer binding site (PBS). RT is recruited in these nucleoprotein complexes and synthesizes minus-strand cDNA initiated at the PBS. Recent results on yeast Ty3 have shown that the homologous NCp9 promotes annealing of primer tRNA(i)(Met) to a 5'-3' bipartite PBS, allowing RNA:tRNA dimer formation and initiation of cDNA synthesis at the 5' PBS (1), To compare specific cDNA synthesis in a retrotransposon and HIV-1, we have established a Ty3 model system comprising Ty3 RNA with the 5'-3' PBS, primer tRNA(i)(Met), NCp9, and for the first time, highly purified Ty3 RT. Here we report that Ty3 RT is as active as retroviral HIV-1 or murine leukemia virus RT using a synthetic template-primer system, Moreover, and in contrast to what was found with retroviral RTs, retrotransposon Ty3 RT was unable to direct cDNA synthesis by self-priming. We also show that Ty3 nucleoprotein complexes were formed in vitro and that the N terminus of NCp9, but not the zinc finger, is required for complex formation, tRNA annealing to the PBS, RNA dimerization, and primer tRNA-directed cDNA synthesis by Ty3 RT. These results indicate that NCp9 chaperones bona fide cDNA synthesis by RT in the yeast Ty3 retrotransposon, as illustrated for NCp7 in HIV-1, reinforcing the notion that Ty3 NCp9 is an ancestor of HIV-1 NCp7. C1 Ecole Normale Super Lyon, INSERM, LaboRetro, Unite Virol Humaine,U412, F-69364 Lyon 07, France. Inst Biol & Chim Prot, F-69367 Lyon, France. NCI, Frederick Canc Res & Dev Ctr, HIV Drug Resistance Program, Div Basic Sci,NIH, Frederick, MD 21702 USA. RP Darlix, JL (reprint author), Ecole Normale Super Lyon, INSERM, LaboRetro, Unite Virol Humaine,U412, 46 Allee Italie, F-69364 Lyon 07, France. RI Cristofari, Gael/A-2831-2011 OI Cristofari, Gael/0000-0001-5620-3091 FU NIAID NIH HHS [AI31147] NR 41 TC 23 Z9 25 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 DEC 17 PY 1999 VL 274 IS 51 BP 36643 EP 36648 DI 10.1074/jbc.274.51.36643 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 266AV UT WOS:000084279200086 PM 10593967 ER PT J AU Yahiro, K Niidome, T Kimura, M Hatakeyama, T Aoyagi, H Kurazono, H Imagawa, K Wada, A Moss, J Hirayama, T AF Yahiro, K Niidome, T Kimura, M Hatakeyama, T Aoyagi, H Kurazono, H Imagawa, K Wada, A Moss, J Hirayama, T TI Activation of Helicobacter pylori VacA toxin by alkaline or acid conditions increases its binding to a 250-kDa receptor protein-tyrosine phosphatase beta SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID VACUOLATING CYTOTOXIN; LECTIN; CELLS; GASTRITIS; DISEASE; UREASE; ZETA; PH AB Helicobacter pylori, a Gram-negative gastric bacterium, secretes VacA, a cytotoxin that causes vacuolar degeneration of susceptible cells. Velocity sedimentation analysis showed that treatment of VacA at alkaline pH led to disassembly of VacA oligomers, an observation reported previously for acid-treated VacA, Exposure of VacA to acid or alkali increased its binding to AZ-521 cells, as shown by indirect immunofluorescence and flow cytometry, Moreover, immunoprecipitates with polyclonal antibodies against VacA from AZ-521 cells previously exposed to acid- or alkali-treated VacA had a 250-kDa glycoprotein containing galactose-beta(1-3)-N-acetylgalactosamine and galactose-beta(1-4)-N-acetylglucosamine, p250, purified by chromatography on peanut agglutinin affinity and Superose 6 columns, contained N-terminal and internal amino acid sequences of YRQQRKLVEEIGWSYT and LIIQDHILEATQDDY, respectively. These sequences are identical to those of a receptor protein-tyrosine phosphatase (RPTP beta/PTP zeta); in agreement, p250 reacted with anti-human RPTP beta monoclonal antibody. Immunoprecipitation with antihuman RPTP beta antibody of solubilized membrane preparations previously incubated with VacA or heat-inactivated VacA demonstrated that RPTP beta bound native, but not denatured, VacA. Acidic and alkaline treatments were associated with activation of VacA and increased binding to the cell surface RPTP beta. C1 Nagasaki Univ, Inst Trop Med, Dept Bacteriol, Nagasaki 8528523, Japan. Nagasaki Univ, Fac Engn, Dept Appl Chem, Nagasaki 8528523, Japan. Univ Tsukuba, Dept Microbiol, Inst Basic Med Sci, Tsukuba, Ibaraki 3050006, Japan. Otsuka Pharmaceut Co Ltd, Tokushima 7710192, Japan. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Hirayama, T (reprint author), Nagasaki Univ, Inst Trop Med, Dept Bacteriol, Nagasaki 8528523, Japan. RI Niidome, Takuro/F-1508-2010; OI Niidome, Takuro/0000-0002-8070-8708; Hatakeyama, Tomomitsu/0000-0002-9505-1980 NR 31 TC 124 Z9 134 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 17 PY 1999 VL 274 IS 51 BP 36693 EP 36699 DI 10.1074/jbc.274.51.36693 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 266AV UT WOS:000084279200093 PM 10593974 ER PT J AU Kroog, GS Jian, XY Chen, L Northup, JK Battey, JF AF Kroog, GS Jian, XY Chen, L Northup, JK Battey, JF TI Phosphorylation uncouples the gastrin-releasing peptide receptor from G(q) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BETA-ADRENERGIC-RECEPTOR; MUSCARINIC CHOLINERGIC RECEPTORS; PROTEIN-KINASE-C; SF9 INSECT CELLS; BETA-2-ADRENERGIC RECEPTOR; DEPENDENT PHOSPHORYLATION; BOMBESIN RECEPTORS; 48-KDA PROTEIN; LIGAND-BINDING; ARRESTIN AB Previous work on the desensitization of G protein-coupled receptors has focused on the role of arrestin binding following receptor phosphorylation. We have examined the hypothesis that phosphorylation alone contributes to desensitization. In this study we demonstrate that for the G(q)-coupled gastrin-releasing peptide receptor (GRP-R), phosphorylation by GRK2 to a stoichiometry of similar to 1 mol PO(4)/mol GRP-R is sufficient in the absence of arrestin to reduce the rate of receptor catalyzed G protein activation by approximately 80%. Furthermore, GRP-Rs exposed in vivo to agonist are rapidly phosphorylated to a similar stoichiometry and are desensitized to a similar degree. Finally, the molecular mechanism for both in vitro GRK2-induced and in vivo agonist-induced desensitization is primarily a decrease in the maximum velocity (V(max)) for the catalysis of guanine nucleotide exchange by the GRP-R rather than a change in the affinity of the receptor for the alpha(q) or beta(gamma) subunits. Based on these results, we suggest that, for some G protein-coupled receptors, phosphorylation has a role in desensitization that is independent of arrestin. C1 NIDCD, Mol Biol Lab, NIH, Rockville, MD 20850 USA. NIDCD, Lab Cellular Biol, NIH, Rockville, MD 20850 USA. RP Battey, JF (reprint author), NIDCD, Mol Biol Lab, NIH, 5 Res Ct, Rockville, MD 20850 USA. EM batteyj@nidcd.nih.gov NR 44 TC 12 Z9 12 U1 0 U2 3 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 DEC 17 PY 1999 VL 274 IS 51 BP 36700 EP 36706 DI 10.1074/jbc.274.51.36700 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 266AV UT WOS:000084279200094 PM 10593975 ER PT J AU Gao, HQ Sarafianos, SG Arnold, E Hughes, SH AF Gao, HQ Sarafianos, SG Arnold, E Hughes, SH TI Similarities and differences in the RNase H activities of human immunodeficiency virus type 1 reverse transcriptase and moloney murine leukemia virus reverse transcriptase SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE retroviruses; reverse transcriptase; RNase H; HIV-1; MLV ID DOUBLE-STRANDED DNA; ANGSTROM RESOLUTION; HIV-1 RT; POLYMERASE; DOMAIN; MUTATIONS; PURIFICATION; MUTAGENESIS; EXPRESSION; MECHANISM AB Retroviral revXerse transcriptases (RTs) have an associated RNase Fl activity that can cleave RNA-DNA duplexes with considerable precision. We believe that the structure of the RNA-DNA duplexes in the context of RT determines the specificity of RNase Fl cleavage. To test this idea, we treated three related groups of synthetic RNA-DNA hybrids with either Moloney murine leukemia virus (MLV) RT or human immunodeficiency virus type 1 (HIV-1) RT. All of the hybrids were prepared using the same 81-base RNA template. The first series of RNase Fl substrates was prepared with complementary DNA oligonucleotides of different lengths, ranging from 6 to 20 nucleotides, all of which shared a common 5' end and were successively shorter at their 3' ends. The second series of oligonucleotides had a common 3' end but shorter 5' ends. The DNA oligonucleotides in the third series were all 20 bases long but had non-complementary stretches at either the 5' end, 3' end, or both ends. Several themes have emerged from the experiments with these RNA-DNA duplexes. (1) Both HIV-1 RT and MLV RT cleave fairly efficiently if the duplex region is at least eight bases long, but not if it is shorter. (2) Although, under the conditions we have used, both enzymes require the substrate to have a region of RNA-DNA duplex, both MLV RT and HIV-1 RT can cleave RNA outside the region that is part of the RNA-DNA duplex. (3) The polymerase domain of HIV-1 RT uses certain mismatched segments of RNA-DNA to position the enzyme for RNase Fl cleavage, whereas the polymerase domain of MLV RT does not use the same mismatched segments to define the position for RNase H cleavage. (4) For HIV-1 RT, a mismatched region near the RNase H domain can interfere with RNase Fl cleavage; cleavage is usually (but not always) more efficient if the mismatched segment is deleted. These results are discussed in regard to the structure of HIV-1 RT and the differences between HIV-1 RT and MLV RT. C1 NCI, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. Rutgers State Univ, Dept Chem, Piscataway, NJ 08854 USA. RP Hughes, SH (reprint author), NCI, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, POB B, Frederick, MD 21702 USA. OI Sarafianos, Stefan G/0000-0002-5840-154X FU NIAID NIH HHS [AI09578, AI27690] NR 33 TC 23 Z9 23 U1 0 U2 0 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 DEC 17 PY 1999 VL 294 IS 5 BP 1097 EP 1113 DI 10.1006/jmbi.1999.3325 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 271MB UT WOS:000084596800004 PM 10600369 ER PT J AU Buch, KBN Padberg, F Nolde, T Teipel, SJ Stubner, S Haslinger, A Schwarz, MJ Sunderland, T Arai, H Rapoport, SI Moller, HJ Hampel, H AF Buch, KBN Padberg, F Nolde, T Teipel, SJ Stubner, S Haslinger, A Schwarz, MJ Sunderland, T Arai, H Rapoport, SI Moller, HJ Hampel, H TI Cerebrospinal fluid tau protein shows a better discrimination in young old (< 70 years) than in old old patients with Alzheimer's disease compared with controls SO NEUROSCIENCE LETTERS LA English DT Article DE tau-protein; cerebrospinal fluid; age; diagnosis; discriminative power; Alzheimer's disease; major depression ID CLINICAL-DIAGNOSIS; A-BETA-1-42(43); MARKER AB Tau protein is consistently reported to be elevated in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD). CSF tau alone, however, is not a clinically useful diagnostic marker due to its relatively low diagnostic specificity. Therefore, efforts are under way to combine tau measurements with other criteria in order to improve diagnostic applicability. We investigated whether age could serve as an useful criterion to increase diagnostic accuracy. CSF levels of tau were measured in young old (<70 years) and old old (greater than or equal to 70 years) patients with probable AD, elderly patients with major depression (MD), and age-matched healthy controls (HC). In AD patients, CSF tau levels were significantly elevated compared with MD patients and HC (P < 0.001). Based on a previously established cut-off of 260 pg/ml, the discriminative power was higher in the young old than in the old old subjects. Similarly, receiver operating characteristics analysis revealed a statistically significant higher correct classification rate in the young old. Our findings indicate that the discriminative power of CSF tau is higher in the young than in the old old. We suggest that the effect of age should be considered in studies investigating CSF tau as a diagnostic marker for neurodegenerative disorders. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Munich, Dept Psychiat, Geriatr Psychiat Branch, Dementia Res Sect & Memory Clin, D-80336 Munich, Germany. NIMH, NIH, Geriatr Psychiat Branch, Bethesda, MD 20892 USA. Tohoku Univ, Sch Med, Dept Geriatr Med, Aoba Ku, Sendai, Miyagi 98077, Japan. NIA, NIH, Neurosci Lab, Bethesda, MD 20892 USA. RP Buch, KBN (reprint author), Univ Munich, Dept Psychiat, Geriatr Psychiat Branch, Dementia Res Sect & Memory Clin, Nussbaumstr 7, D-80336 Munich, Germany. EM katharina.buerger@psy.med.uni-muench-en.de NR 20 TC 22 Z9 22 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD DEC 17 PY 1999 VL 277 IS 1 BP 21 EP 24 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 267EV UT WOS:000084345000006 ER PT J AU Couse, JF Hewitt, SC Bunch, DO Sar, M Walker, VR Davis, BJ Korach, KS AF Couse, JF Hewitt, SC Bunch, DO Sar, M Walker, VR Davis, BJ Korach, KS TI Postnatal sex reversal of the ovaries in mice lacking estrogen receptors alpha and beta SO SCIENCE LA English DT Article ID MULLERIAN-INHIBITING SUBSTANCE; TARGETED DISRUPTION; SERTOLI CELLS; MOUSE; GENE; EXPRESSION; HORMONE; DIFFERENTIATION; TESTIS; DIETHYLSTILBESTROL AB Mice lacking estrogen receptors alpha and beta were generated to clarify the roles of each receptor in the physiology of estrogen target tissues. Both sexes of alpha beta estrogen receptor knockout (alpha beta ERKO) mutants exhibit normal reproductive tract development but are infertile. Ovaries of adult alpha beta ERKO females exhibit follicle transdifferentiation to structures resembling seminiferous tubules of the testis, including Sertoli-like cells and expression of Mullerian inhibiting substance, sulfated glycoprotein-2, and Sox9, Therefore, Loss of both receptors Leads to an ovarian phenotype that is distinct from that of the individual ERKO mutants, which indicates that both receptors are required for the maintenance of germ and somatic cells in the postnatal ovary. C1 NIEHS, Receptor Biol Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, NIH, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dept Cell Biol, Reprod Biol Lab, Chapel Hill, NC 27599 USA. Chem Ind Inst Toxicol, Res Triangle Pk, NC 27709 USA. RP Korach, KS (reprint author), NIEHS, Receptor Biol Sect, Reprod & Dev Toxicol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. OI Korach, Kenneth/0000-0002-7765-418X NR 28 TC 369 Z9 384 U1 1 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 DEC 17 PY 1999 VL 286 IS 5448 BP 2328 EP 2331 DI 10.1126/science.286.5448.2328 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 266UK UT WOS:000084318500057 PM 10600740 ER PT J AU Ponting, CP AF Ponting, CP TI Chlamydial homologues of the MACPF (MAC/peforin) domain SO CURRENT BIOLOGY LA English DT Letter ID PROTEIN-SYNTHESIS; HUMAN-COMPLEMENT; PSI-BLAST; TRACHOMATIS; DATABASES; INCLUSION; PERFORIN; SEQUENCE; TOOL C1 NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20814 USA. RP Ponting, CP (reprint author), Univ Oxford, Dept Human Anim & Genet, MRC, Funct Genet Unit, S Parks Rd, Oxford OX1 3QX, England. NR 26 TC 49 Z9 49 U1 0 U2 1 PU CURRENT BIOLOGY LTD PI LONDON PA 34-42 CLEVELAND STREET, LONDON W1P 6LE, ENGLAND SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD DEC 16 PY 1999 VL 9 IS 24 BP R911 EP R913 DI 10.1016/S0960-9822(00)80102-5 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 267WT UT WOS:000084382800005 PM 10608922 ER PT J AU Monti, P Inga, A Scott, G Aprile, A Campomenosi, P Menichini, P Ottaggio, L Viaggi, S Abbondandolo, A Burns, PA Fronza, G AF Monti, P Inga, A Scott, G Aprile, A Campomenosi, P Menichini, P Ottaggio, L Viaggi, S Abbondandolo, A Burns, PA Fronza, G TI 5-Methylcytosine at HpaII sites in p53 is not hypermutable after UVC irradiation SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE ultraviolet light; 5-methylcytosine; p53; molecular epidemiology ID SKIN-CANCER; PYRIMIDINE DIMERS; MOLECULAR EPIDEMIOLOGY; CYTOSINE METHYLATION; MUTATIONAL SPECTRUM; INDUCED MUTAGENESIS; CYCLOBUTANE DIMERS; ULTRAVIOLET-LIGHT; FUNCTIONAL ASSAY; CELL-LINES AB Using a yeast based p53 functional assay we previous:ly demonstrated that the WC-induced p53 mutation spectrum appears to be indistinguishable from the one observed in Non Melanoma Skin Cancer (NMSC). However, position 742 (codon 248, CpG site) represented the major hot spot in NMSC but was not found mutated in the yeast system. In order to determine whether UVC-induced mutagenic events may be facilitated at methylated cytosine (5mC), a yeast expression vector harbouring a human wild-type p53 cDNA (pLS76) was methylated in vitro by HpaII methylase. Methylation induced 98% protection to HpaII endonuclease. Unmethylated and methylated pLS76 vectors were then UVC irradiated (lambda(max): 254nm) and transfected into a yeast strain containing the ADE2 gene regulated by a p53-responsive promoter. The results revealed that: (i) 5mC at HpaII sites did not cause any difference in the UVC-induced survival and/or mutagenicity; (ii) none of the 20 mutants derived from methylated pLS76 showed p53 mutations targeted at HpaII sites; (iii) the UVC-induced p53 mutation spectra derived from methylated and unmethylated pLS76 were indistinguishable not only when classes of mutations and hot spots were concerned, but also when compared through a rigorous statistical test to estimate their relatedness (P = 0.85); (iv) the presence of 5mC did not increase the formation of photo-lesions at codon 248, as determined by using a stop polymerase assay. Although based on a limited number of mutants, these results suggest that the mere presence of 5mC at position 742 does not cause a dramatic increase of its mutability after UVC irradiation. We propose that position 742 is a hot spot in NMSC either because of mutagenic events at 5mC caused by other UV components of solar light and/or because not all the NMSC are directly correlated with UV mutagenesis hut may have a "spontaneous" origin. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Natl Canc Inst, IST, Mutagenesis Lab, I-16132 Genoa, Italy. Univ Leeds, Sch Med, Leeds LS2 9JT, W Yorkshire, England. Univ Genoa, Dept Oncol Biol & Genet, I-16132 Genoa, Italy. RP Fronza, G (reprint author), Natl Canc Inst, IST, Mutagenesis Lab, Largo R Benzi, I-16132 Genoa, Italy. RI Campomenosi, Paola/C-9729-2011; OI Campomenosi, Paola/0000-0002-8853-1134 NR 37 TC 5 Z9 6 U1 0 U2 2 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 DEC 16 PY 1999 VL 431 IS 1 BP 93 EP 103 DI 10.1016/S0027-5107(99)00187-6 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 274WG UT WOS:000084787600010 PM 10656489 ER PT J AU Chen, GQ Cui, CH Mayer, ML Gouaux, E AF Chen, GQ Cui, CH Mayer, ML Gouaux, E TI Functional characterization of a potassium-selective prokaryotic glutamate receptor SO NATURE LA English DT Article ID ACID-BINDING PROTEINS; AMPA RECEPTORS; EXPRESSION; CHANNELS; FAMILY; DESENSITIZATION; CONDUCTION; SEQUENCE; MUTATION; KAINATE AB Ion channels are molecular pores that facilitate the passage of ions across cell membranes and participate in a range of biological processes, from excitatory signal transmission in the mammalian nervous system to the modulation of swimming behaviour in the protozoan Paramecium(1). Two particularly important families of ion channels are ionotropic glutamate receptors (GluRs)(2) and potassium channels(3,4). GluRs are permeable to Na+, K+ and Ca2+ are gated by glutamate, and have previously been found only in eukaryotes(2), In contrast, potassium channels are selective for K+, are gated by a range of stimuli, and are found in both prokaryotes and eukaryotes(3,4). Here we report the discovery and functional characterization of GluR0 from Synechocystis PCC 6803, which is the first GluR found in a prokaryote. GluR0 binds glutamate, forms potassium-selective channels and is related in amino-acid sequence to both eukaryotic GluRs and potassium channels. On the basis of amino-acid sequence and functional relationships between GluR0 and eukaryotic GluRs, we propose that a prokaryotic GluR was the precursor to eukaryotic GluRs. GluR0 provides evidence for the missing link between potassium channels and GluRs, and we suggest that their ion channels have a similar architecture, that GluRs are tetramers and that the gating mechanisms of GluRs and potassium channels have some essential features in common. C1 Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. NICHHD, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. RP Gouaux, E (reprint author), Columbia Univ, Dept Biochem & Mol Biophys, 630 W 168th St, New York, NY 10032 USA. RI Mayer, Mark/H-5500-2013 NR 30 TC 239 Z9 251 U1 1 U2 8 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD DEC 16 PY 1999 VL 402 IS 6763 BP 817 EP 821 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 266ZQ UT WOS:000084330500067 PM 10617203 ER PT J AU Lo, EJ Green, PG Miao, FJP Relchling, DB Levine, JD AF Lo, EJ Green, PG Miao, FJP Relchling, DB Levine, JD TI Bradykinin-induced neurogenic migration of neutrophils into the rat knee joint SO NEUROREPORT LA English DT Article DE inflammation; plasma extravasation; platelet activating factor; polymorphonuclear leukocytes; sympathetic post-ganglionic neurons; synovium ID PLASMA EXTRAVASATION; POLYMORPHONUCLEAR LEUKOCYTES; VASCULAR-PERMEABILITY; INFLAMMATION; ADENOSINE; PROSTAGLANDINS; HYPERALGESIA; INVOLVEMENT; RELEASE; CELLS AB THIS study examined the dependence of neurogenic and non-neurogenic synovial plasma extravasation on neutrophils. Perfusion of bradykinin into the knee joint produced both a rapid increase in the magnitude of plasma extravasation and a significant increase in number of neutrophils in the synovium. Both bradykinin-induced plasma extravasation and neutrophil accumulation were dependent on sympathetic post-ganglionic neuron terminals, since both were blocked in sympathectomized rats. Platelet activating factor, which produces plasma extravasation independent of sympathetic neurons, did not increase the number of neutrophils in the synovium. These findings support the suggestion that bradykinin acts on sympathetic nerve terminals in the knee leading to attraction of neutrophils, which promotes plasma extravasation. (C) 1999 Lippincott Williams & Wilkins. C1 Univ Calif San Francisco, NIH, Pain Ctr, San Francisco, CA 94143 USA. RP Levine, JD (reprint author), Univ Calif San Francisco, NIH, Pain Ctr, 521 Parnassus Ave, San Francisco, CA 94143 USA. RI Green, Paul/C-5943-2011 FU NIADDK NIH HHS [AM32634] NR 28 TC 12 Z9 12 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD DEC 16 PY 1999 VL 10 IS 18 BP 3821 EP 3824 DI 10.1097/00001756-199912160-00018 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 266MB UT WOS:000084302800020 PM 10716216 ER PT J AU Rintala, J Seemann, R Chandrasekaran, K Rosenberger, TA Chang, L Contreras, MA Rapoport, SI Chang, MCJ AF Rintala, J Seemann, R Chandrasekaran, K Rosenberger, TA Chang, L Contreras, MA Rapoport, SI Chang, MCJ TI 85 kDa cytosolic phospholipase A2 is a target for chronic lithium in rat brain SO NEUROREPORT LA English DT Article DE brain; chronic lithium; phospholipids; signal transduction ID SIGNAL-TRANSDUCTION; CEREBRAL-CORTEX; A(2) ACTIVITY; ACID; MYOINOSITOL; EXPRESSION; CLONING; GENE; GTP AB THE mechanism by which chronic lithium exerts its therapeutic effect in brains of bipolar patients is not known. One possibility, suggested by our demonstration in the rat brain, is that chronic lithium inhibits turnover of arachidonic acid (AA) by reducing the activity of an AA-specific phospholipase A2 (PLA2). To test this further, mRNA levels of two AA-specific PLA2s, cytosolic PLA2 (cPLA2) type IV and intracellular PLA2 (iPLA2) type VIII, and protein level of cPLA2 were quantified in the brain of rats given lithium for 6 weeks. Chronic lithium markedly reduced brain mRNA and protein level of cPLA2, but had no effect on mRNA level of iPLA2. These results suggest that the final common path effect of chronic lithium administration is to reduce turnover of AA in brain by down-regulating cPLA2. (C) 1999 Lippincott Williams & Wilkins. C1 NIA, Sect Brain Physiol & Metabol, NIH, Bethesda, MD 20892 USA. Univ Maryland, Dept Anesthesiol, Sch Med, Teaching Facil, Baltimore, MD 21201 USA. RP Rintala, J (reprint author), NIA, Sect Brain Physiol & Metabol, NIH, Bldg 10,Rm 6C103,10 Ctr Dr,MSC 1582, Bethesda, MD 20892 USA. NR 24 TC 98 Z9 102 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD DEC 16 PY 1999 VL 10 IS 18 BP 3887 EP 3890 DI 10.1097/00001756-199912160-00030 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 266MB UT WOS:000084302800032 PM 10716228 ER PT J AU Starr, SE Fletcher, CV Spector, SA Yong, FH Fenton, T Brundage, RC Manion, D Ruiz, NM Gersten, M Becker, M McNamara, J Mofenson, LM AF Starr, SE Fletcher, CV Spector, SA Yong, FH Fenton, T Brundage, RC Manion, D Ruiz, NM Gersten, M Becker, M McNamara, J Mofenson, LM CA Pediat AIDS Clinical Trials Grp 38 TI Combination therapy with efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors in children infected with human immunodeficiency virus type 1 SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID DIDANOSINE; ZIDOVUDINE; INDINAVIR; GROWTH AB Background: Consistent long-term viral suppression has been difficult to achieve in children with human immunodeficiency virus type 1 (HIV-1) infection. We tested the safety and antiviral efficacy of a novel combination consisting of efavirenz, nelfinavir, and one or more nucleoside reverse-transcriptase inhibitors in 57 children previously treated with only nucleoside reverse-transcriptase inhibitors. Methods: The children were monitored for 48 weeks after the initiation of therapy. We assessed plasma concentrations of efavirenz and nelfinavir, plasma HIV-1 RNA levels, and lymphocyte subpopulations. Results: At base line, the 57 HIV-1-infected children (age range, 3.8 to 16.8 years) had a median of 699 CD4 cells per cubic millimeter and 10,000 copies of HIV-1 RNA per milliliter of plasma. The most common treatment-related effects of at least moderate severity were rash (in 30 percent of children), diarrhea (in 18 percent), neutropenia (in 12 percent), and biochemical abnormalities (in 12 percent). Serious side effects were uncommon. The mean values for the area under the curve for efavirenz and nelfinavir corresponded to expected values. In an intention-to-treat analysis, 76 percent of children had plasma HIV-1 RNA levels of less than 400 copies per milliliter after 48 weeks of therapy and 63 percent had levels of less than 50 copies per milliliter. A high plasma HIV-1 RNA level at base line significantly decreased the likelihood that plasma levels of HIV-1 RNA would become undetectable during treatment. Conclusions: In HIV-1-infected children who were previously treated with nucleoside reverse-transcriptase inhibitors, the combination of efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors was generally well tolerated and had a potent and sustained antiviral effect. (N Engl J Med 1999;341:1874-81.) (C)1999, Massachusetts Medical Society. C1 Childrens Hosp Philadelphia, Div Infect Dis & Immunol, Philadelphia, PA 19104 USA. Univ Minnesota, Minneapolis, MN USA. Univ San Diego, San Diego, CA 92110 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Frontier Sci & Technol Res Fdn, Brookline, MA USA. Dupont Merck Pharmaceut Co, Wilmington, DE 19880 USA. Agourou Pharmaceut, La Jolla, CA USA. NIAID, Rockville, MD USA. NICHHD, Rockville, MD USA. RP Starr, SE (reprint author), Childrens Hosp Philadelphia, Div Infect Dis & Immunol, 34th St & Civic Ctr blvd, Philadelphia, PA 19104 USA. OI Mofenson, Lynne/0000-0002-2818-9808 FU NIAID NIH HHS [AI33835, AI41110] NR 24 TC 175 Z9 175 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 16 PY 1999 VL 341 IS 25 BP 1874 EP 1881 DI 10.1056/NEJM199912163412502 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 264XZ UT WOS:000084210200002 PM 10601506 ER PT J AU Schmidt, MA Ohazama, CJ Agyeman, KO Freidlin, RZ Jones, M Laurienzo, JM Brenneman, CL Arai, AE von Ramm, OT Panza, JA AF Schmidt, MA Ohazama, CJ Agyeman, KO Freidlin, RZ Jones, M Laurienzo, JM Brenneman, CL Arai, AE von Ramm, OT Panza, JA TI Real-time three-dimensional echocardiography for measurement of left ventricular volumes SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID 3-DIMENSIONAL ECHOCARDIOGRAPHY; MYOCARDIAL-INFARCTION; RECONSTRUCTION; MASS; VALIDATION; IMAGES; SYSTEM AB Left ventricular (LV) volumes are important prognostic indexes in patients with heart disease. Although several methods can evaluate LV volumes, most have important intrinsic limitations. Rear-time 3-dimensional echocardiography (RT3D echo) is a navel technique capable of instantaneous acquisition of volumetric images, The purpose of this study was to validate LV volume calculations with RT3D echo and to determine their usefulness in cardiac patients. To this end, 4 normal subjects and 21 cardiac patients underwent magnetic resonance Imaging (MRI) and RT3D echo on the same day, A strong correlation was found between LV volumes calculated with MRI and with RT3D echo (r = 0.91; y = 20.1 + 0.71x; SEE 28 ml). LV volumes obtained with MRI were greater than those obtained with RT3D echo (126 +/- 83 vs 110 +/- 65 ml; p = 0.002), probably due to the fact that heart rate during MRI acquisition was lower than that during RTSD echo examination (62 +/- 11 vs 79 +/- 16 beats/min; p = 0.0001). Analysis of intra- and interobserver variability showed strong indexes of agreement in the measurement of LV volumes with RT3D echo. Thus, LV volume measurements with RT3D echo are accurate and reproducible, This technique expands the use of ultrasound for the noninvasive evaluation of cardiac patients and provides a new tool for the investigational study of cardiovascular disease, (C) 1999 by Excerpta Medica, Inc. C1 NHLBI, Cardiol Branch, Cardiac Energet Lab, Ctr Informat Technol, Bethesda, MD USA. NHLBI, Lab Anim Med & Surg, Ctr Informat Technol, Bethesda, MD USA. Duke Univ, Engineer Res Ctr, Durham, NC USA. RP Panza, JA (reprint author), NIH, Bldg 10,Room 7B-15, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [HL-58104] NR 25 TC 88 Z9 103 U1 0 U2 3 PU EXCERPTA MEDICA INC PI NEW YORK PA 245 WEST 17TH STREET, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD DEC 15 PY 1999 VL 84 IS 12 BP 1434 EP 1439 DI 10.1016/S0002-9149(99)00591-3 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 263WG UT WOS:000084147800013 PM 10606118 ER PT J AU Piscitelli, SC AF Piscitelli, SC TI Update on the treatment of neutropenia in HIV-infected patients - Introduction SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Editorial Material ID FILGRASTIM C1 Warren G Magnuson Clin Ctr, Clin Pharmacokinet Lab, NIH, Bethesda, MD 20892 USA. RP Piscitelli, SC (reprint author), Warren G Magnuson Clin Ctr, Clin Pharmacokinet Lab, NIH, Bldg 10,Room 1N257, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD DEC 15 PY 1999 VL 56 SU 5 BP S3 EP S4 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 268AF UT WOS:000084390900001 PM 10613379 ER PT J AU Cervenakova, L Buetefisch, C Lee, HS Taller, I Stone, G Gibbs, CJ Brown, P Hallett, M Goldfarb, LG AF Cervenakova, L Buetefisch, C Lee, HS Taller, I Stone, G Gibbs, CJ Brown, P Hallett, M Goldfarb, LG TI Novel PRNP sequence variant associated with familial encephalopathy SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE PRNP gene; point mutation; Creutzfeldt-Jakob disease; Gerstmann-Straussler-Scheinker disease; human spongiform encephalopathy; prion disease ID STRAUSSLER-SCHEINKER-DISEASE; CREUTZFELDT-JAKOB DISEASE; PRION PROTEIN; SPONGIFORM ENCEPHALOPATHY; NEUROFIBRILLARY TANGLES; SERIES AB Human transmissible spongiform encephalopathies (TSEs) are a group of chronic progressive neurodegenerative disorders that may be hereditary, infectious, or sporadic. Hereditary TSEs are associated with mutations in the PRNP gene on chromosome 20p12-pter. We report on a family in which seven patients developed limb and truncal ataxia, dysarthria, myoclonic jerks, and cognitive decline. The age of onset in the 30s, 40s, or 50s, prolonged disease duration, cerebellar atrophy on imaging, and the presence of synchronic periodic discharges on electroencephalogram suggested a familial encephalopathy resembling Gerstmann-Straussler-Scheinker disease. A novel H187R mutation has been identified in affected, but not in unaffected, family members or unrelated controls suggesting a pathogenic role for this mutation. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88: 653-656, 1999. Published 1999 Wiley-Liss, Inc.dagger C1 NINDS, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Cent Nervous Syst Studies Lab, NIH, Bethesda, MD 20892 USA. Amer Red Cross, Jerome H Holland Lab, Rockville, MD USA. RP Goldfarb, LG (reprint author), NINDS, Med Neurol Branch, NIH, Bldg 10,Room 5N226,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. NR 20 TC 28 Z9 31 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD DEC 15 PY 1999 VL 88 IS 6 BP 653 EP 656 DI 10.1002/(SICI)1096-8628(19991215)88:6<653::AID-AJMG14>3.0.CO;2-E PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 261KE UT WOS:000084007700014 PM 10581485 ER PT J AU Kempner, ES AF Kempner, ES TI Advances in radiation target analysis SO ANALYTICAL BIOCHEMISTRY LA English DT Review ID MOLECULAR-WEIGHT; ENERGY-TRANSFER; BINDING-SITES; TEMPERATURE-DEPENDENCE; SARCOPLASMIC-RETICULUM; INACTIVATION ANALYSIS; REGULATORY PROTEINS; IONIZING-RADIATION; MEMBRANE-PROTEINS; PUMP PROTEIN C1 NIAMSD, Phys Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kempner, ES (reprint author), NIAMSD, Phys Biol Lab, NIH, Bethesda, MD 20892 USA. NR 62 TC 13 Z9 13 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 EI 1096-0309 J9 ANAL BIOCHEM JI Anal. Biochem. PD DEC 15 PY 1999 VL 276 IS 2 BP 113 EP 123 DI 10.1006/abio.1999.4362 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 266DC UT WOS:000084284500002 PM 10603233 ER PT J AU Kitazume, E Higashiyama, T Sato, N Kanetomo, M Tajima, T Kobayashi, S Ito, Y AF Kitazume, E Higashiyama, T Sato, N Kanetomo, M Tajima, T Kobayashi, S Ito, Y TI On-line microextraction of metal traces for subsequent determination by plasma atomic emission spectrometry using pH peak focusing countercurrent chromatography SO ANALYTICAL CHEMISTRY LA English DT Article ID INDUCTIVELY-COUPLED PLASMA; HEAVY-METALS; SEPARATION; EXTRACTION; PHASE AB Metal ions were highly efficiently enriched by pH peak focusing high-speed countercurrent chromatography. The peak intensity for a 10-mL standard sample in the effluent stream was increased over 100-fold compared to conventional plasma atomic emission spectrometry, Ca, Cd, Cu, Mg, Mn, Ni, and Zn are chromatographically extracted in a basic organic stationary phase containing a complex-forming reagent such as bis(2-ethylhexyl) phosphoric acid, After the sample solution is introduced into the column, metal ions remain around the sharp pH border formed between acidic and basic zones, moving toward the column outlet. Enriched metal ions are finally eluted with the sharp pH border as a highly concentrated peak into a volume of less than 100 mu L. We evaluated this method for concentration efficiency in trace determination in tap water using different column diameters. C1 Iwate Univ, Fac Humanities & Social Sci, Morioka, Iwate 0208550, Japan. Hitachi Ltd, Cent Res Lab, Kokubunji, Tokyo 1858601, Japan. Hitachi Tokyo Elect Co, Kokubunji, Tokyo 1858601, Japan. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Kitazume, E (reprint author), Iwate Univ, Fac Humanities & Social Sci, Morioka, Iwate 0208550, Japan. NR 13 TC 8 Z9 8 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD DEC 15 PY 1999 VL 71 IS 24 BP 5515 EP 5521 DI 10.1021/ac990074x PG 7 WC Chemistry, Analytical SC Chemistry GA 265MV UT WOS:000084248700009 PM 10624157 ER PT J AU Lou, YC Lung, FDT Pai, MT Tzeng, SR Wei, SY Roller, PP Cheng, JW AF Lou, YC Lung, FDT Pai, MT Tzeng, SR Wei, SY Roller, PP Cheng, JW TI Solution structure and dynamics of G1TE, a nonphosphorylated cyclic peptide inhibitor for the Grb2 SH2 domain SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE nuclear magnetic resonance; solution structure; signal transduction; drug design ID FK506 BINDING-PROTEIN; N-15 NMR RELAXATION; SIGNAL-TRANSDUCTION; NUCLEOTIDE EXCHANGE; BACKBONE DYNAMICS; HETERONUCLEAR NMR; LIGAND-BINDING; RAS; RECEPTOR; ADAPTER AB The solution structure and dynamics of G1TE, a nonphosphorylated cyclic peptide inhibitor for the Grb2 SH2 domain, was determined using two-dimensional NMR and simulated annealing methods. G1TE consists of 10 amino acids and a C-terminal Cys cyclized through its side-chain sulfur atom by a thioether linkage to its N terminus. The results indicate that G1TE assumes a circle-like shape in solution in which all the side chains are protruding outside, and none of the residues are involved in intramolecular hydrogen bonding. The average root-mean-square deviations were found to be 0.41 +/- 0.11 Angstrom for the backbone heavy atoms C, C alpha, and N, and 1.03 +/- 0.14 Angstrom for all heavy atoms in a family of 10 structures. N-15 relaxation measurements indicate that G1TE has rather restricted dynamics in the fast time scale within its backbone. However, residues Tyr3, Val6, and Gly7 may be involved in a possible conformational exchange. The structural comparison between G1TE in solution and the BCR-Abl phosphopeptide bound to Grb2 SH2 domain revealed that G1TE may form a larger circle-like binding surface than the BCR-Abl phosphopeptide in the bound form. Also, the restricted backbone dynamics of G1TE may result in a reduced loss of entropy and can compensate for the absence of a phosphate group at the Tyr3 position. These structural and dynamic properties of G1TE may provide a molecular basis for understanding its interactions with the Grb2 SH2 domain. (C) 1999 Academic Press. C1 Natl Tsing Hua Univ, Dept Life Sci, Div Struct Biol & Biomed Sci, Hsinchu 300, Taiwan. China Med Coll, Dept Nutr, Taichung 400, Taiwan. NCI, Med Chem Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Cheng, JW (reprint author), Natl Tsing Hua Univ, Dept Life Sci, Div Struct Biol & Biomed Sci, Hsinchu 300, Taiwan. NR 39 TC 15 Z9 15 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 DEC 15 PY 1999 VL 372 IS 2 BP 309 EP 314 DI 10.1006/abbi.1999.1513 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 271JX UT WOS:000084591400012 PM 10600169 ER PT J AU Miyamoto, S Safer, B AF Miyamoto, S Safer, B TI Immunosuppressants FK506 and rapamycin have different effects on the biosynthesis of cytoplasmic actin during the early period of T cell activation SO BIOCHEMICAL JOURNAL LA English DT Article DE ionomycin; lymphocytes; phorbol myristate acetate; protein synthesis; signalling ID MESSENGER-RNA; LYMPHOCYTE-T; SIGNAL-TRANSDUCTION; CYCLOSPORINE-A; PHORBOL ESTER; BETA-ACTIN; TRANSLATION INITIATION; CYTOSKELETAL ACTIN; CALCIUM IONOPHORES; GENE-EXPRESSION AB FK506 and rapamycin are immunosuppressants that interfere with T cell activation. FK506 inhibits early events of T cell activation such as the induction of cytokine transcription, whereas rapamycin inhibits later interleukin 2 signalling events. However, both reagents either directly or indirectly reduce protein synthesis. Therefore a kinetic study was conducted in human primary T lymphocytes examining increased synthesis of proteins stimulated by either ionomycin+phorbol myristate acetate (PMA) or PMA alone. Three patterns of protein expression were observed. Synthesis of one group of proteins had enhanced synthesis with FK506, but reduced synthesis with rapamycin. A second group had reduced synthesis with rapamycin and either no change or a slight reduction with FK506 and a third group had reduction with both FK506 and rapamycin. One major protein of the first group, p42, had a rapid increase in synthesis that decreased by 8 h. Its synthesis was strongly enhanced by FK506, but reduced by rapamycin after ionomycin + PMA stimulation. In contrast, this protein was strongly induced by PMA alone in these cells and not affected by FK506 treatment, but still reduced by rapamycin, p42 was identified as cytoplasmic actin. mRNA levels of both gamma- and beta-actin were found to be enhanced with FK506 treatment suggesting that regulation of actin was at a transcriptional or post-transcriptional level. Results with actinomycin D indicated that FK506 is regulating actin biosynthesis at the post-transcriptional level. Rapamycin, however, appeared to be operating at the level of translation. C1 NHLBI, Mol Hematol Branch, Sect Prot & RNA Biosynth, Bethesda, MD 20892 USA. RP Miyamoto, S (reprint author), Univ Calif Davis, Sch Med, Dept Biol Chem, 4422 Tupper Hall, Davis, CA 95616 USA. NR 36 TC 10 Z9 10 U1 0 U2 0 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD DEC 15 PY 1999 VL 344 BP 803 EP 812 DI 10.1042/0264-6021:3440803 PN 3 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 273BW UT WOS:000084688200020 PM 10585867 ER PT J AU Reischl, IG Coward, WR Church, MK AF Reischl, IG Coward, WR Church, MK TI Molecular consequences of human mast cell activation following immunoglobulin E-high-affinity immunoglobulin E receptor (IgE-Fc epsilon RI) interaction SO BIOCHEMICAL PHARMACOLOGY LA English DT Review DE mast cell; Fc epsilon RI; IgE; signal transduction; MAP kinase; inositol phosphate; sphingosine ID PROTEIN-KINASE-C; CYTOSOLIC PHOSPHOLIPASE A(2); BASOPHILIC LEUKEMIA-CELLS; ANTIGEN-PRESENTING CELLS; TUMOR-NECROSIS-FACTOR; TYROSINE PHOSPHORYLATION; RBL-2H3 CELLS; T-CELLS; NUCLEAR FACTOR; MEDIATED DEGRANULATION AB The cross-linking by immunoglobulin E of its high-affinity receptor, Fc epsilon RI, on mast cells initiates a complex series of biochemical events leading to degranulation and the synthesis and secretion of eicosanoids and cytokines through the action of transcription factors, such as nuclear factor-kappa B. The initial activation involves the phosphorylation of Fc epsilon RI beta- and gamma-subunits through the actions of the tyrosine kinases lyn and syk. For the purposes of description, the subsequent events may be grouped in three cascades characterized by the key proteins involved. First, the phospholipase C-inositol phosphate cascade activates protein kinase C and is largely responsible for calcium mobilization and influx. Second, activation of Ras and Raf via mitogen-activated protein kinase causes the production of arachidonic acid metabolites. Third, the generation of sphingosine and sphingosine-1-phosphate occurs through activation of sphingomyelinase. While the early signaling events tend to be specific for the cited cascades, there is an increasing overlap of activated proteins with the downstream propagation of the signal. It is the balanced interaction between these proteins that culminates in degranulation, synthesis, and release of eicosanoids and cytokines. (C) 1999 Elsevier Science Inc. C1 Southampton Gen Hosp, Southampton SO16 6YD, Hants, England. RP Reischl, IG (reprint author), NIH, 9000 Rockville Pike,Bldg 10,Room 9N256, Bethesda, MD 20814 USA. NR 114 TC 41 Z9 45 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD DEC 15 PY 1999 VL 58 IS 12 BP 1841 EP 1850 DI 10.1016/S0006-2952(99)00226-9 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 260WM UT WOS:000083976500001 PM 10591138 ER PT J AU Chariot, A Gielen, J Merville, MP Bours, V AF Chariot, A Gielen, J Merville, MP Bours, V TI The homeodomain-containing proteins - An update on their interacting partners SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE transcription; homeodomain; HOX genes; cofactor; CBP; NF-kappa B; acetylation ID NF-KAPPA-B; DNA-BINDING SPECIFICITIES; HOX PROTEINS; TRANSCRIPTION FACTORS; PBX PROTEINS; HISTONE ACETYLTRANSFERASES; MOLECULAR-CLONING; MYELOID-LEUKEMIA; HOMEOBOX GENES; DROSOPHILA AB Homeodomain-containing proteins are transcription regulators controlling the coordinated expression of genes involved in development, differentiation, and cellular transformation. They share a highly conserved 60-amino-acid region (the "homeodomain"), which allows them to bind DNA and modulate the expression of multiple target genes, whose identities remain largely unknown. Although each HOX gene product exhibits in vivo specificity, they harbor very similar DNA-binding affinities in vitro, suggesting that other mechanisms such as protein-protein interactions are critical to modulate their function. In this commentary, we describe the proteins that can interact with the HOX gene products, including newly identified partners such as CREB binding protein and the NF-kappa B/I kappa B-alpha proteins. We also outline the molecular programs that are regulated by the transcriptional complexes involving the HOX gene produces and where new pharmacological tools could find interesting targets. (C) 1999 Elsevier Science Inc. C1 Univ Liege, Lab Med Chem & Med Oncol, Liege, Belgium. RP Chariot, A (reprint author), NIAID, Immunoregulat Lab, NIH, Room 11B17,Bldg 10, Bethesda, MD 20892 USA. NR 81 TC 32 Z9 33 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD DEC 15 PY 1999 VL 58 IS 12 BP 1851 EP 1857 DI 10.1016/S0006-2952(99)00234-8 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 260WM UT WOS:000083976500002 PM 10591139 ER PT J AU Kedjouar, B Daunes, S Vilner, BJ Bowen, WD Klaebe, A Faye, JC Poirot, M AF Kedjouar, B Daunes, S Vilner, BJ Bowen, WD Klaebe, A Faye, JC Poirot, M TI Structural similitudes between cytotoxic antiestrogen-binding site (AEBS) ligands and cytotoxic sigma receptor ligands. Evidence for a relationship between cytotoxicity and affinity for AEBS or sigma-2 receptor but not for sigma-1 receptor SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE AEBS; sigma receptors; tamoxifen; diphenylmethane; BD1008; cytotoxicity ID PROTEIN-KINASE-C; RAT-LIVER; CELL-PROLIFERATION; MELANOMA-CELLS; BREAST-CANCER; HISTAMINE; POTENT; INHIBITION; TAMOXIFEN; LINES AB 1-Benzyl-4-(N-2-pyrrotidinylethoxy)benzene (PBPE) is a cyto toxic derivative of the antitumoral drug tamoxifen. PBPE binds with high affinity and specificity to the microsomal antiestrogen-binding site (AEBS). PBPE, as well as some other high-affinity AEBS ligands, shares structural features with high-affinity and selective sigma receptor ligands in the N-(arylethyl)-N-alkyl-2-(1-pyrrolidinyl)ethylamine class, such as BD1008, which are cytotoxic against tumoral cells. Based on these structural and pharmacological similitudes, we set out to examine whether AEBS and sigma receptors could be related binding sites. We showed that BD1008 had a high affinity for AEBS. However, prototypical sigma receptor ligands were very low-affinity competitors on AEBS. Surprisingly, AEBS ligands displayed a high affinity for sigma-1 and sigma-2 receptor subtypes, showing that AEBS and sigma receptor-binding sites were not mutually exchangeable. Moreover, phenytoin, which is an allosteric modulator of sigma-1 receptor, was a competitive inhibitor of [H-3]tamoxifen on AEBS. These results suggest that the tamoxifen-binding site on AEBS and the sigma ligand-binding site on sigma receptors were not identical but. related entities. We also showed here that the high-affinity and specific AEBS ligands also bound sigma receptors with high affinity. Moreover, the compounds that were capable of displacing tamoxifen from AEBS were cytotoxic against tumoral cells but not against the AEBS-deficient cell line Rtx-6. These results confirm that AEBS and sigma receptors might belong to the same family of proteins, and that the tamoxifen-binding site might be involved in the cytotoxicity of AEBS ligands and some classes of sigma compounds. (C) 1999 Elsevier Science Inc. C1 CHU Rangueil, Inst Louis Bugnard, INSERM U397, Lab Endocrinol & Cellular Commun, F-31403 Toulouse 4, France. NIDDKD, Unit Receptor Biochem & Pharmacol, Med Chem Lab, NIH, Bethesda, MD 20892 USA. Univ Toulouse 3, IMRPC, UMR CNRS 5623, Biol Organ Chem Grp, F-31062 Toulouse, France. RP Poirot, M (reprint author), CHU Rangueil, Inst Louis Bugnard, INSERM U397, Lab Endocrinol & Cellular Commun, F-31403 Toulouse 4, France. RI Poirot, Marc/K-3551-2012 OI Poirot, Marc/0000-0002-5711-6624 NR 41 TC 20 Z9 20 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD DEC 15 PY 1999 VL 58 IS 12 BP 1927 EP 1939 DI 10.1016/S0006-2952(99)00285-3 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 260WM UT WOS:000083976500010 PM 10591147 ER PT J AU Kimbrell, TA Little, JT Dunn, RT Frye, MA Greenberg, BD Wassermann, EM Repella, JD Danielson, AL Willis, MW Benson, BE Speer, AM Osuch, E George, MS Post, RM AF Kimbrell, TA Little, JT Dunn, RT Frye, MA Greenberg, BD Wassermann, EM Repella, JD Danielson, AL Willis, MW Benson, BE Speer, AM Osuch, E George, MS Post, RM TI Frequency dependence of antidepressant response to left prefrontal repetitive transcranial magnetic stimulation (rTMS) as a function of baseline cerebral glucose metabolism SO BIOLOGICAL PSYCHIATRY LA English DT Article DE transcranial stimulation; depression; PET; metabolism ID HUMAN MOTOR CORTEX; POSTTRAUMATIC-STRESS-DISORDER; POSITRON EMISSION TOMOGRAPHY; SYNAPTIC PLASTICITY; CLINICAL-EVALUATION; SLEEP-DEPRIVATION; MAJOR DEPRESSION; HUMAN-BRAIN; BLOOD-FLOW; PET IMAGES AB Background: Recent studies suggest that both high frequency (10-20 Hz) and low frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) have an antidepressant effect in some individuals, Electrophysiologic data indicate that high frequency rTMS enhances neuronal firing efficacy and that low frequency rTMS has the opposite effect. Methods: We investigated the antidepressant effects of 10 daily left prefrontal I Hz versus 20 Hz rTMS with the hypothesis that within a given subject, antidepressant response would differ by frequency and vary as a function of baseline cerebral glucose metabolism, After baseline PET scans utilizing [F-18]-Fluorodeoxyglucose, thirteen subjects participated in a randomized crossover trial of 2 weeks of 20 Hz paired with 2 weeks I Hz or placebo rTMS, Results: We found a negative correlation between degree of antidepressant response after I Hz compared to 20 Hz rTMS (r = -0.797, p < .004), Additionally, better response to 20 Hz was associated with the degree of baseline hypometabolism, whereas response to 1 Hz rTMS tended to be associated with baseline hypermetabolism. Conclusions: These preliminary results suggest that anti-depressant response to rTMS might vary as a function of stimulation frequency and may depend on pretreatment cerebral metabolism. Further studies combining rTMS and functional neuroimaging are needed. Biol Psychiatry 1999;46:1603-1613 (C) 1999 Society of Biological Psychiatry. C1 NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. NINDS, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. Univ Arkansas, Dept Psychiat, Little Rock, AR 72204 USA. Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. Med Univ S Carolina, Dept Psychiat Radiol & Neurol, Charleston, SC 29425 USA. RP Post, RM (reprint author), NIMH, Biol Psychiat Branch, 10 Ctr Dr,MSC-1272, Bethesda, MD 20892 USA. RI Osuch, Elizabeth/B-5009-2015 OI Osuch, Elizabeth/0000-0001-5946-1862 NR 63 TC 200 Z9 206 U1 4 U2 9 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 DEC 15 PY 1999 VL 46 IS 12 BP 1603 EP 1613 DI 10.1016/S0006-3223(99)00195-X PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 267BU UT WOS:000084335400002 PM 10624541 ER PT J AU Lozier, JN Metzger, ME Donahue, RE Morgan, RA AF Lozier, JN Metzger, ME Donahue, RE Morgan, RA TI Adenovirus-mediated expression of human coagulation factor IX in the rhesus macaque is associated with dose-limiting toxicity SO BLOOD LA English DT Article; Proceedings Paper CT 40th Annual Meeting of the American-Society-of-Hematology CY DEC 04-08, 1998 CL MIAMI BEACH, FLORIDA SP Amer Soc Hematol ID VIVO GENE-THERAPY; HEMOPHILIA-B DOGS; IN-VIVO; IMMUNE-RESPONSES; NONHUMAN-PRIMATES; VIRAL-ANTIGENS; MOUSE-LIVER; VECTORS; MICE; RECOMBINANT AB We used a first-generation adenovirus vector (AVC3FIX5) to assess whether human factor IX could be expressed and detected in the rhesus macaque, which we have shown does not make high-titer antibodies to human factor IX protein. Three animals received 1 x 10(10) to 1 x 10(11) plaque-forming units per kilogram by intravenous injection. Human factor IX was present within 24 hours of vector administration and peaked 4 days later at 4,000 ng/mL in the high-dose recipient, and lower levels were seen in the intermediate-dose recipient. No human factor IX was detected in the low-dose recipient's plasma. Serum cytokine analysis and early hypoferremia suggested a dose-dependent acute-phase response to the vector. Human factor IX was detectable in rhesus plasma for 2 to 3 weeks for the high- and intermediate-dose recipients, but disappeared concomitant with high-titer antihuman factor IX antibody development. There was substantial, dose-dependent, dose-limiting liver toxicity that was manifest as elevated serum transaminase levels, hyperbilirubinemia, hypoalbuminemia, and prolongation of clotting times. Of particular interest was prolongation of the thrombin clotting time, an indicator of decreased fibrinogen or fibrinogen dysfunction, All evidence of liver toxicity resolved except for persistent hypofibrinogenemia in the high-dose recipient, indicating possible permanent liver damage. Our data suggest a narrow therapeutic window for first-generation adenovirus-mediated gene transfer. The development of antihuman factor IX antibodies and abnormalities of fibrinogen in the rhesus macaque is of concern for application of adenovirus (or other viral) vectors to hemophilia gene therapy. C1 Natl Human Genome Res Inst, Clin Gene Therapy Branch, Bethesda, MD USA. NHLBI, Hematol Branch, Rockville, MD USA. RP Morgan, RA (reprint author), Bldg 10,Room 10C103,10 Ctr Dr, Bethesda, MD 20892 USA. NR 38 TC 93 Z9 93 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 DEC 15 PY 1999 VL 94 IS 12 BP 3968 EP 3975 PG 8 WC Hematology SC Hematology GA 263TD UT WOS:000084140600002 PM 10590040 ER PT J AU Gross, BS Wilde, JI Quek, L Chapel, H Nelson, DL Watson, SP AF Gross, BS Wilde, JI Quek, L Chapel, H Nelson, DL Watson, SP TI Regulation and function of WASp in platelets by the collagen receptor, glycoprotein VI SO BLOOD LA English DT Article ID WISKOTT-ALDRICH-SYNDROME; ACTIN-DEPOLYMERIZING PROTEIN; SRC HOMOLOGY-3 DOMAINS; TYROSINE PHOSPHORYLATION; KINASE INHIBITOR; CELL ACTIVATION; T-CELL; N-WASP; EXPRESSION; GENE AB Aldrich syndrome (WAS) is an X-linked recessive disorder associated with abnormalities in platelets and lymphocytes giving rise to thrombocytopenia and immunodeficiency. WAS is caused by a mutation in the gene encoding the cytoskeletal protein (WASp). Despite its importance, the role of WASp in platelet function is not established. WASp was recently shown to undergo tyrosine phosphorylation in platelets after activation by collagen, suggesting that it may play a selective role in activation by the adhesion molecule. In the present study, we show that WASp is heavily tyrosine phosphorylated by a collagen-related peptide (CRP) that binds to the collagen receptor glycoprotein (GP) VI, but not to the integrin alpha 2 beta 1. Tyrosine phosphorylation of WASp was blocked by Src family kinase inhibitors and reduced by treatment with wortmannin and in patients with X-linked agammaglobulinemia (XLA), a condition caused by a lack of functional expression of Btk, This indicates that Src kinases, phosphatidylinositol 3-kinase (PI 3-kinase), and Btk all contribute to the regulation of tyrosine phosphorylation of WASp. The functional importance of WASp was investigated in 2 WAS brothers who show no detectable expression of WASp. Platelet aggregation and secretion from dense granules induced by CRP and thrombin was slightly enhanced in the WAS platelets relative to controls. Furthermore, there was no apparent difference in morphology in WAS platelets after stimulation by these agonists, These observations suggest that WASp does not play a critical role in intracellular signaling downstream of tyrosine kinase-linked and G protein-coupled receptors in platelets. (C) 1999 by The American Society of Hematology. C1 Univ Oxford, Dept Pharmacol, Oxford OX1 3QT, England. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. John Radcliffe Hosp, Dept Immunol, Oxford OX3 9DU, England. RP Watson, SP (reprint author), Univ Oxford, Dept Pharmacol, Mansfield Rd, Oxford OX1 3QT, England. RI Watson, Stephen/Q-6292-2016 OI Watson, Stephen/0000-0002-7846-7423 FU Wellcome Trust NR 51 TC 53 Z9 54 U1 0 U2 1 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 DEC 15 PY 1999 VL 94 IS 12 BP 4166 EP 4176 PG 11 WC Hematology SC Hematology GA 263TD UT WOS:000084140600023 PM 10590061 ER PT J AU Egeler, RM Favara, BE van Meurs, M Laman, JD Claassen, E AF Egeler, RM Favara, BE van Meurs, M Laman, JD Claassen, E TI Differential in situ cytokine profiles of langerhans-like cells and T cells in Langerhans cell histiocytosis: Abundant expression of cytokines relevant to disease and treatment SO BLOOD LA English DT Article ID COLONY-STIMULATING FACTOR; TUMOR-NECROSIS-FACTOR; DENDRITIC CELLS; TNF-ALPHA; GM-CSF; 2-CHLORODEOXYADENOSINE; CULTURE; THERAPY; GROWTH; CD40 AB The pathogenesis of Langerhans cell histiocytosis (LCH) remains poorly understood. To further elucidate LCH pathogenesis, we analyzed the expression of 10 cytokines relevant to cellular recruitment and activation at the protein level in 14 patients and identified the lesional cells responsible for cytokine production in situ by immunohistochemistry. The cytokines investigated included the hematopoietic growth factors interleukin-3 (IL-3), IL-7, and granulocyte-macrophage colony-stimulating factor (GM-CSF); the lymphocyte regulatory cytokines IL-2, IL-4, and IL-10; the inflammatory regulators IL-1 alpha and tumor necrosis factor-alpha (TNF-or); and the effector cell-activating cytokines IL-5 and interferon-gamma (IFN-gamma). In all specimens, CD1a(+) histiocytes (LCH cells) and CD3(+) T cells produced large amounts of cytokines, creating a true cytokine storm. IL-2, IL-4, IL-5, and TNF-or were produced exclusively by T cells, whereas only IL-2 was produced by LCH cells. Equal numbers of LCH cells, T cells, and macrophages produced GM-CSF and IFN-gamma. Equal numbers of LCH cells and macrophages produced IL-10, whereas IL-3 was produced by T cells and macrophages. IL-7 was only produced by macrophages. Eosinophils, present in some specimens, were partially responsible for the production of IL-5, IFN-gamma, GM-CSF, IL-10, IL-3, and IL-7. Expression of all cytokines, abundant in most biopsies, was irrespective of age, gender, or site of biopsy. These findings emphasize the role of T cells in LCH. The juxtaposition of T cells and LCH cells suggests that both cells interact in a cytokine amplification cascade, resulting from stimulation of autocrine and paracrine stimulatory loops. This cascade can be linked directly to the development of LCH through recruitment, maturation, and proliferation of LCH cells. The cytokines studied are known to be involved in the development of other characteristic features of LCH, such as fibrosis, necrosis, and osteolysis. (C) 1999 by The American Society of Hematology. C1 Univ Calgary, So Alberta Childrens Canc Program, Alberta Childrens Hosp, Tom Baker Canc Ctr,Dept Oncol & Pediat, Calgary, AB T2T 5C7, Canada. Erasmus Univ, Sophia Childrens Hosp, Dept Pediat Oncol, Rotterdam, Netherlands. Erasmus Univ, Dept Immunol, Rotterdam, Netherlands. NIH, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT USA. Univ Utah, Dept Pathol, Salt Lake City, UT USA. ID DLO Inst Anim Sci & Hlth, Dept Immunol, Lelystad, Netherlands. RP Egeler, RM (reprint author), Univ Calgary, So Alberta Childrens Canc Program, Alberta Childrens Hosp, Tom Baker Canc Ctr,Dept Oncol & Pediat, 1820 Richmond Rd SW, Calgary, AB T2T 5C7, Canada. NR 42 TC 163 Z9 168 U1 0 U2 4 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 DEC 15 PY 1999 VL 94 IS 12 BP 4195 EP 4201 PG 7 WC Hematology SC Hematology GA 263TD UT WOS:000084140600026 PM 10590064 ER PT J AU Lehrnbecher, T Foster, CB Zhu, SX Leitman, SF Goldin, LR Huppi, K Chanock, SJ AF Lehrnbecher, T Foster, CB Zhu, SX Leitman, SF Goldin, LR Huppi, K Chanock, SJ TI Variant genotypes of the low-affinity Fc gamma receptors in two control populations and a review of low-affinity Fc gamma receptor polymorphisms in control and disease populations SO BLOOD LA English DT Article ID HEPARIN-INDUCED THROMBOCYTOPENIA; SYSTEMIC LUPUS-ERYTHEMATOSUS; LIGAND-BINDING POLYMORPHISM; SINGLE AMINO-ACID; HUMAN T-CELLS; RIIA POLYMORPHISM; HUMAN-NEUTROPHILS; HUMAN IGG2; FUNCTIONAL POLYMORPHISM; MONOCLONAL-ANTIBODIES AB Fc gamma-receptors (Fc gamma R) provide a critical link between humoral and cellular immunity. The genes of the low-affinity receptors for IgG and their isoforms, namely, Fc gamma RIIa, Fc gamma RIIb, Fc gamma RIIIa, Fc gamma RIIIb, and SH-Fc gamma RIIIb, are located in close proximity on chromosome 1q22. Variant alleles may differ in biologic activity and a number of studies have reported the frequencies of variant Fc gamma R alleles in both disease and control populations. No large study has evaluated the possibility of a nonrandom distribution of variant genotypes. We analyzed 395 normal individuals (172 African Americans [AA] and 223 Caucasians [CA]) at the following loci: Fc gamma RIIa, Fc gamma RIIIa, and Fc gamma RIIIb, including the SH-Fc gamma RIIIb. The genotypic distributions of Fc gamma RIIa, Fc gamma RIIIa, and Fc gamma RIIIb conform to the Hardy-Weinberg law in each group. There was no strong evidence that combinations of 2-locus genotypes of the 3 loci deviated from random distributions in these healthy control populations. The distribution of SH-Fc gamma RIIIb is underrepresented in CA compared with AA (P < .0001) controls. A previously reported variant Fc gamma RIIb was not detected in 70 normal individuals, indicating that this allele, if it exists, is very rare (<1%). In conclusion, we present data that should serve as the foundation for the interpretation of association studies involving multiple variant alleles of the low-affinity Fc gamma R. (C) 1999 by The American Society of Hematology. C1 NCI, Genet Lab, Immunocompromised Host Sect, Pediat Oncol Branch,NIH, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. RP Chanock, SJ (reprint author), NCI, Genet Lab, Immunocompromised Host Sect, Pediat Oncol Branch,NIH, Bldg 10,Room 13N240, Bethesda, MD 20892 USA. NR 67 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 DEC 15 PY 1999 VL 94 IS 12 BP 4220 EP 4232 PG 13 WC Hematology SC Hematology GA 263TD UT WOS:000084140600029 PM 10590067 ER PT J AU Albores-Saavedra, J Henson, DE AF Albores-Saavedra, J Henson, DE TI Pyloric gland metaplasia with perineural invasion of the gallbladder - A lesion that can be confused with adenocarcinoma SO CANCER LA English DT Article DE gallbladder; pyloric gland metaplasia; perineural invasion; intraneural invasion ID CROHNS-DISEASE; CARCINOMA; PANCREAS; DUCTS AB BACKGROUND. Metaplastic pyloric glands have been described in a variety of organs including the gallbladder, in which they can extend into the muscular wall and serosa. METHODS. Clinical, histologic, and immunohistochemical features of four cases of gallbladder florid pyloric gland metaplasia with perineural and intraneural invasion are analyzed. RESULTS. The patients with pyloric gland metaplasia and perineural and intraneural invasion were all females ages 57-72 years. A preoperative diagnosis of chronic cholecystitis and cholelithiasis was made for all four patients, but a histologic diagnosis of adenocarcinoma was made for two patients and entertained in two others. Macroscopically the gallbladders showed changes usually associated with chronic cholecystitis. No intraluminal masses were observed in any of the gallbladders. The characteristic microscopic features included florid pyloric gland metaplasia, proliferation of medium-sized nerve trunks more prominent in the muscular layer and serosa, and perineural and intraneural invasion by the metaplastic glands lined by cytologically bland cuboidal or columnar mucin-containing cells. At last follow-up all patients were alive and symptom free 1-7 years after laparoscopic cholecystectomy. CONCLUSIONS. Pyloric gland metaplasia of the gallbladder should be added to the long and increasing list of benign epithelial proliferations that are associated with perineural and intraneural invasion. This lesion should not be mistaken for adenocarcinoma of the gallbladder, a misinterpretation that may have serious therapeutic implications. The pathogenesis of this phenomenon is unknown. (C) 1999 American Cancer Society. C1 Univ Texas, SW Med Ctr, Dept Pathol, Div Anat Pathol, Dallas, TX 75235 USA. NCI, Canc Biomarkers Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. RP Albores-Saavedra, J (reprint author), Univ Texas, SW Med Ctr, Dept Pathol, Div Anat Pathol, 5323 Harry Hines Blvd, Dallas, TX 75235 USA. NR 20 TC 12 Z9 13 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 DEC 15 PY 1999 VL 86 IS 12 BP 2625 EP 2631 DI 10.1002/(SICI)1097-0142(19991215)86:12<2625::AID-CNCR6>3.0.CO;2-D PG 7 WC Oncology SC Oncology GA 266WB UT WOS:000084322300006 PM 10594857 ER PT J AU Koo, HM McWilliams, MJ Alvord, WG Woude, GFV AF Koo, HM McWilliams, MJ Alvord, WG Woude, GFV TI Ras oncogene-induced sensitization to 1-beta-D-arabinofuranosylcytosine SO CANCER RESEARCH LA English DT Article ID DEPENDENT PROTEIN-KINASES; ANTICANCER DRUG SCREEN; ACUTE MYELOID-LEUKEMIA; TUMOR-CELL LINES; CYCLIN-A; INDUCED APOPTOSIS; ACTIVATED RAS; MUTATIONS; CANCER; OVEREXPRESSION AB Human tumor cells containing ras oncogenes display enhanced sensitivity to 1-beta-D-arabinofuranosylcytosine (Ara-C) and other deoxycytidine analogues (H-M. Koo, et al., Cancer Res., 56: 5211-5216, 1996). Human tumor cell lines with or without a ras oncogene as well as a pair of isogenic cell lines with one containing an activated ras oncogene were used to study the basis for differential sensitivity. We found that human tumor cells containing ras oncogenes upon entry into the S phase of the cell cycle underwent apoptosis in response to Ara-C treatment. By contrast, human tumor cells harboring wild-type ras alleles were only delayed in the S phase when exposed to Ara-C. Thus, the ras oncogene specifically renders human cells more sensitive to Ara-C by preventing S-phase arrest. This may occur by the ras oncogene compromising an S-phase checkpoint. C1 NCI, Frederick Canc Res & Dev Ctr, Adv Biosci Labs, Basic Res Program, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Data Management Serv, Frederick, MD 21702 USA. NCI, Div Basic Sci, NIH, Frederick, MD 21702 USA. RP Woude, GFV (reprint author), Van Andel Res Inst, 201 Monroe Ave NW,Suite 400, Grand Rapids, MI 49503 USA. NR 23 TC 24 Z9 26 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 DEC 15 PY 1999 VL 59 IS 24 BP 6057 EP 6062 PG 6 WC Oncology SC Oncology GA 270HT UT WOS:000084530400009 PM 10626790 ER PT J AU Waheed, I Guo, ZS Chen, GA Weiser, TS Nguyen, DM Schrump, DS AF Waheed, I Guo, ZS Chen, GA Weiser, TS Nguyen, DM Schrump, DS TI Antisense to SV40 early gene region induces growth arrest and apoptosis in T-antigen-positive human pleural mesothelioma cells SO CANCER RESEARCH LA English DT Article ID HUMAN-MALIGNANT MESOTHELIOMAS; TUMOR-SUPPRESSOR; DNA-SEQUENCES; CYCLIN D1; SIMIAN-VIRUS-40; P53; PROMOTER; EXPRESSION; TRANSFORMATION; INHIBITION AB Although SV40 oncoproteins have been detected in malignant pleural mesotheliomas (MPMs), their role in the pathogenesis and clinical behavior of these neoplasms remains controversial. In the present study, we sought to define the relevance of SV40 T/t antigen expression in established human mesothelioma cell lines deficient for p16(INK4a) as well as ARF expression, SV40 early region sequences were readily detected in genomic DNA isolated from pleural mesothelioma lines; however, levels of SV40 T/t antigen expression were highly variable in these cells. An adenoviral vector expressing an antisense transcript to SV40 early region inhibited T antigen expression and mediated significant growth inhibition and apoptosis in T-antigen-positive mesothelioma cells and SV40-transformed COS-7 cells. Abrogation of T/t antigen expression coincided with enhanced p21/WAF-1 expression, suggesting that restoration of p53-mediated pathways may have contributed to the growth inhibition and apoptosis induced by the antisense construct. These effects were mt observed after similar treatment of mesothelioma or lung cancer cells containing no SV40 DNA sequences. Collectively, these data suggest that SV40 oncoproteins contribute to the malignant phenotype of pleural mesotheliomas and indicate that interventions designed to abrogate their expression may be efficacious in the treatment of individuals with these neoplasms. C1 NCI, Thorac Oncol Sect, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Schrump, DS (reprint author), NCI, Thorac Oncol Sect, Surg Branch, NIH, Bldg 10,Room 2B07,10 Ctr Dr MSC 1502, Bethesda, MD 20892 USA. NR 42 TC 63 Z9 64 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 1999 VL 59 IS 24 BP 6068 EP 6073 PG 6 WC Oncology SC Oncology GA 270HT UT WOS:000084530400011 PM 10626792 ER PT J AU Devereux, TR Horikawa, I Anna, CH Annab, LA Afshari, CA Barrett, JC AF Devereux, TR Horikawa, I Anna, CH Annab, LA Afshari, CA Barrett, JC TI DNA methylation analysis of the promoter region of the human telomerase reverse transcriptase (hTERT) gene SO CANCER RESEARCH LA English DT Article ID CATALYTIC SUBUNIT; ISLAND AB The promoter of the hTERT gene encoding the catalytic subunit of telomerase was recently cloned and has a dense CG-rich CpG island, suggesting a role for methylation in regulation of hTERT expression. In this study, we have initiated the analysis of the regulation of hTERT expression by examining the methylation status of up to 72 CpG sites extending from 500 bases upstream of the transcriptional start site of the hTERT gene into the first exon in 37 cell lines. These cell lines represent a variety of cell and tissue types, including normal, immortalized, and cancer cell Lines from lung, breast, and other tissues. Using bisulfite genomic sequencing, we did not find a generalized pattern of site-specific or region-specific methylation that correlated with expression of the hTERT gene: most of the hTERT-negative normal cells and about one-third of the hTERT-expressing cell lines had the unmethylated/hypomethylated promoter, whereas the other hTERT-expressing cell lines showed partial or total methylation of the promoter. The promoter of one hTERT-negative fibroblast cell line, SUSM-1, was methylated at all sites examined. Treatment of SUSM-1 cells with the demethylating agent 5-aza-2'-deoxycytidine and the histone deacetylase inhibitor trichostatin A induced the cells to express hTERT, suggesting a potential role for DNA methylation and/or histone deacetylation in negative regulation of hTERT. This study indicates that there are multiple levels of regulation of hTERT expression in CpG island methylation-dependent and -independent manners. C1 NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Devereux, TR (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, Mail Drop D4-04,POB 12233, Res Triangle Pk, NC 27709 USA. NR 14 TC 154 Z9 163 U1 1 U2 6 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 1999 VL 59 IS 24 BP 6087 EP 6090 PG 4 WC Oncology SC Oncology GA 270HT UT WOS:000084530400014 PM 10626795 ER PT J AU Lorenzo, PS Bogi, K Hughes, KM Beheshti, M Bhattacharyya, D Garfield, SH Pettit, GR Blumberg, PM AF Lorenzo, PS Bogi, K Hughes, KM Beheshti, M Bhattacharyya, D Garfield, SH Pettit, GR Blumberg, PM TI Differential roles of the tandem C1 domains of protein kinase C delta in the biphasic down-regulation induced by bryostatin 1 SO CANCER RESEARCH LA English DT Article ID PHORBOL ESTER BINDING; PROTEOLYTIC ACTIVATION; SIGNAL-TRANSDUCTION; MOUSE KERATINOCYTES; CELL-PROLIFERATION; IN-VIVO; ISOZYMES; TRANSLOCATION; DEGRADATION; CALCIUM AB Bryostatin 1 (Bryo), currently in clinical trials, has been shown to induce a biphasic concentration-response curve for down-regulating protein kinase C (PKC) delta, with protection of the enzyme from down-regulation at high Bryo doses. In our ongoing studies to identify the basis for this unique behavior of PKC delta, we examined the participation of the two ligand binding sites (C1a and C1b) in the regulatory domain of the enzyme. Three mutants of PKC delta prepared by introducing a point mutation in either C1a or C1b or both C1a and C1b were overexpressed in NM 3T3 cells. All of the constructs retained a biphasic response to down-regulation assessed after 24-h treatment with Bryo. However, the roles of the individual C1 domains were different for the two phases of the response. For down-regulation, both the C1a and the C1b mutants displayed equivalent 3-4-fold reductions in their affinities for the ligand. For protection from down-regulation, a reduced protection was observed for the C1a mutant, which showed a broader biphasic curve compared with those for wild-type PKC delta and the C1b mutant. Like wild-type PKC delta, all of the mutants showed the same subcellular partitioning of the protected enzyme to the particulate fraction of the cells, arguing against changes in sensitivity to Bryo due to differences in localization. Likewise, relatively similar patterns of localization were observed using green fluorescent protein-PKC delta constructs. We conclude that the C1 domains of PKC delta do not have equivalent roles in inducing protection against Bryo-induced down-regulation. The Cia domain plays a critical role in conferring the degree of protection at high concentrations of Bryo. Elucidation of the differential effect of Bryo on PKC delta may suggest strategies for the design of novel ligands with Bryo-like activities. C1 NCI, Mol Mech Tumor Promot Sect, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. Arizona State Univ, Canc Res Inst, Tempe, AZ 85287 USA. RP Blumberg, PM (reprint author), NCI, Mol Mech Tumor Promot Sect, Cellular Carcinogenesis & Tumor Promot Lab, Bldg 37,Room 3A01,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM blumberp@dc37a.nci.nih.gov NR 41 TC 31 Z9 32 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 1999 VL 59 IS 24 BP 6137 EP 6144 PG 8 WC Oncology SC Oncology GA 270HT UT WOS:000084530400023 PM 10626804 ER PT J AU Nishimura, MI Avichezer, D Custer, MC Lee, CS Chen, C Parkhurst, MR Diamond, RA Robbins, PF Schwartzentruber, DJ Rosenberg, SA AF Nishimura, MI Avichezer, D Custer, MC Lee, CS Chen, C Parkhurst, MR Diamond, RA Robbins, PF Schwartzentruber, DJ Rosenberg, SA TI MHC class I-restricted recognition of a melanoma antigen by a human CD4(+) tumor infiltrating lymphocyte SO CANCER RESEARCH LA English DT Article ID T-CELL RECEPTOR; MAJOR HISTOCOMPATIBILITY COMPLEX; POSITIVE SELECTION; MOLECULAR MIMICRY; BINDING-SITE; IDENTIFICATION; SPECIFICITY; EXPRESSION; PEPTIDES; TYROSINASE AB It is generally considered that MNC class I-restricted antigens are recognized by CD8(+) T cells, whereas MBC class II-restricted antigens are recognized by CD4(+) T cells, In the present study, we report an MHC class I-restricted CD4(+) T cell isolated from the tumor infiltrating lymphocytes (TILs) of a patient with metastatic melanoma, TIL 1383 I recognized HLA-A2(+) melanoma cell lines but not autologous transformed B cells or fibroblasts, The antigen recognized by TIL 1383 I was tyrosinase, and the epitope was the 368-376 peptide. Antibody blocking assays confirmed that TIL 1383 I was MHC class I restricted, and the CD4 and CD8 coreceptors did not contribute significantly to antigen recognition, TIL 1383 I was weakly cytolytic and secreted cytokines in a pattern consistent with it being a T-h1 cell, The avidity of TIL 1383 I for peptide pulsed targets is 10-100-fold lower than most melanoma-reactive CD8(+) T cell clones. These CD4(+) T cells may represent a relatively rare population of T cells that express a T-cell receptor capable of cross-reacting with an MHC class I/peptide complex with sufficient affinity to allow triggering in the absence of the CD4 coreceptor. C1 NCI, Surg Branch, Bethesda, MD 20892 USA. CALTECH, Div Biol, Pasadena, CA 91125 USA. RP Nishimura, MI (reprint author), NCI, Surg Branch, Bldg 10-2B06,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 66 TC 56 Z9 56 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 1999 VL 59 IS 24 BP 6230 EP 6238 PG 9 WC Oncology SC Oncology GA 270HT UT WOS:000084530400036 PM 10626817 ER PT J AU McClanahan, J Fukushima, PI Stetler-Stevenson, M AF McClanahan, J Fukushima, PI Stetler-Stevenson, M TI Increased peripheral blood gamma delta T-cells in patients with lymphoid neoplasia: A diagnostic dilemma in flow cytometry SO CYTOMETRY LA English DT Article DE gamma delta T-cells; immunophenotype; non-Hodgkin's lymphoma ID RECEPTOR; LOCALIZATION; RECOGNITION; EXPRESSION; SUBSET; SYSTEM AB We have observed increased numbers of non-neoplastic gamma delta-T-cells in the peripheral blood of a series of patients with non-Hodgkin's lymphoma not of gamma delta-T-cell origin. The majority of normal gamma delta-T-cells are negative for surface CD4 and CD8 and a subpopulation does not express CD5, two immunophenotypic findings strongly suggestive of neoplasia in alpha beta T-cells. In addition, they express cytotoxic T-cell/Natural killer cell antigens. In this study, up to 22% of PBLs were CD4 and CD8 negative gamma delta-T-cells and up to 33% PBLs were CD5 negative gamma delta-T-cells, In addition, as high as 42% of PBLS were gamma delta-T-cells expressing cytotoxic T-cell/Natural killer cell antigens, suggestive of a large granular lymphoproliferative disorder. Failure to recognize that these are normal gamma delta-T-cells could lead to the erroneous diagnosis of peripheral blood involvement with a T-cell neoplasm, especially in the setting of a history of non-Hodgkin's lymphoma. Cytometry (Comm. Clin. Cytometry) 38:280-285, 1999. Published 1999 Wiley-Liss, Inc.dagger C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Stetler-Stevenson, M (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Room 2N-108, Bethesda, MD 20892 USA. NR 13 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 0196-4763 J9 CYTOMETRY JI Cytometry PD DEC 15 PY 1999 VL 38 IS 6 BP 280 EP 285 DI 10.1002/(SICI)1097-0320(19991215)38:6<280::AID-CYTO4>3.0.CO;2-G PG 6 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 267WP UT WOS:000084382500004 PM 10589043 ER PT J AU Theis, K Chen, PJ Skorvaga, M Van Houten, B Kisker, C AF Theis, K Chen, PJ Skorvaga, M Van Houten, B Kisker, C TI Crystal structure of UvrB, a DNA helicase adapted for nucleotide excision repair SO EMBO JOURNAL LA English DT Article DE crystallography; DNA damage; helicase; nucleotide excision repair; UvrB ID COLI UVRABC ENDONUCLEASE; ESCHERICHIA-COLI; (A)BC EXCINUCLEASE; PROTEIN COMPLEX; PREINCISION COMPLEX; CATALYTIC SITE; ACTIVE-SITE; 5' INCISION; DAMAGED DNA; BINDING AB Nucleotide excision repair (NER) is a highly conserved DNA repair mechanism. NER systems recognize the damaged DNA strand, cleave it on both sides of the lesion, remove and newly synthesize the fragment. UvrB is a central component of the bacterial NER system participating in damage recognition, strand excision and repair synthesis, We have solved the crystal structure of UvrB in the apo and the ATP-bound forms. UvrB contains two domains related in structure to helicases, and two additional domains unique to repair proteins. The structure contains all elements of an intact helicase, and is evidence that UvrB utilizes ATP hydrolysis to move along the DNA to probe for damage. The location of conserved residues and structural comparisons allow us to predict the path of the DNA and suggest that the tight preincision complex of UvrB and the damaged DNA is formed by insertion of a flexible beta-hairpin between the two DNA strands. C1 SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USA. NIEHS, Genet Mol Lab, NIH, Res Triangle Pk, NC 27709 USA. Slovak Acad Sci, Canc Res Inst, Dept Mol Genet, Bratislava 83391, Slovakia. RP Kisker, C (reprint author), SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USA. NR 56 TC 141 Z9 142 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD DEC 15 PY 1999 VL 18 IS 24 BP 6899 EP 6907 DI 10.1093/emboj/18.24.6899 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 270KE UT WOS:000084533900005 PM 10601012 ER PT J AU Herbst, R Zhang, XL Qin, J Simon, MA AF Herbst, R Zhang, XL Qin, J Simon, MA TI Recruitment of the protein tyrosine phosphatase CSW by DOS is an essential step during signaling by the Sevenless receptor tyrosine kinase SO EMBO JOURNAL LA English DT Article DE corkscrew; Daughter of Sevenless; protein tyrosine phosphatase; Sevenless; signal transduction ID DEVELOPING DROSOPHILA EYE; PHOSPHOTYROSINE PHOSPHATASE; PHOSPHORYLATION SITES; ADAPTER PROTEIN; INSULIN; CORKSCREW; TRANSDUCTION; ACTIVATION; CELLS; IRS-1 AB The pleckstrin homology (PH) domain-containing protein Daughter of Sevenless (DOS) is an essential component of the Sevenless receptor tyrosine kinase (SEV) signaling cascade, which specifies R7 photoreceptor development in the Drosophila eye. Previous results have suggested that DOS becomes tyrosine phosphorylated during SEV signaling and collaborates with the protein tyrosine phosphatase CSW, We have investigated this possibility by identifying tyrosine residues 801 and 854 of DOS as the phosphorylated binding sites for the CSW SH2 domains. We show that these sites become phosphorylated in response to SEV activation and that phosphorylation of both sites is required to allow CSW to bind DOS. Mutant DOS proteins in which either Y801 or Y854 of DOS has been changed to phenylalanine are unable to function during signaling by SEV and other receptor tyrosine kinases, In contrast, we find that a mutant DOS protein in which all tyrosine phosphorylation sites except Y801 and Y854 have been removed is able effectively to provide DOS function during SEV signaling and to rescue the lethality associated with dos loss-of-function mutations. These results indicate that a primary role for DOS during signaling by SEV and other receptor tyrosine kinases is to become phosphorylated at Y801 and Y854 and then recruit CSW. C1 Stanford Univ, Dept Biol Sci, Stanford, CA 94305 USA. DNAX Res Inst Mol & Cellular Biol Inc, Palo Alto, CA 94304 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Simon, MA (reprint author), Stanford Univ, Dept Biol Sci, Stanford, CA 94305 USA. FU NEI NIH HHS [R01EY9845] NR 38 TC 35 Z9 36 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD DEC 15 PY 1999 VL 18 IS 24 BP 6950 EP 6961 DI 10.1093/emboj/18.24.6950 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 270KE UT WOS:000084533900010 PM 10601017 ER PT J AU Zhang, JM Zhao, XH Wei, Q Paterson, BM AF Zhang, JM Zhao, XH Wei, Q Paterson, BM TI Direct inhibition of G(1) cdk kinase activity by MyoD promotes myoblast cell cycle withdrawal and terminal differentiation SO EMBO JOURNAL LA English DT Article DE cell cycle; G(1) cdks; MyoD; myogenesis ID RETINOBLASTOMA GENE-PRODUCT; LOOP-HELIX REGULATORS; SKELETAL-MUSCLE; MYOGENIC DIFFERENTIATION; PROLIFERATING MYOBLASTS; DIRECT BINDING; EXPRESSION; PROTEIN; PHOSPHORYLATION; FAMILY AB MyoD has been proposed to facilitate terminal myoblast differentiation by binding to and inhibiting phosphorylation of the retinoblastoma protein (pRb). Here we show that MyoD can interact with cyclin-dependent kinase 4 (cdk4) through a conserved 15 amino acid (aa) domain in the C-terminus of MyoD. MyoD, its C-terminus lacking the basic helix-loop-helix (bHLH) domain, or the 15 aa cdk4-binding domain all inhibit the cdk4-dependent phosphorylation of pRb in vitro. Cellular expression of full-length MyoD or fusion proteins containing either the C-terminus or just the 15 aa cdk4-binding domain of MyoD inhibit cell growth and pRb phosphorylation in vivo. The minimal cdk4-binding domain of MyoD fused to GFP can also induce differentiation of C2C12 muscle cells in growth medium. The defective myogenic phenotype in MyoD-negative BC3H1 cells can be rescued completely only when MyoD contains the cdk4-binding domain. We propose that a regulatory checkpoint in the terminal cell cycle arrest of the myoblast during differentiation involves the modulation of the cyclin D cdk-dependent phosphorylation of pRb through the opposing effects of cyclin D1 and MyoD. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Paterson, BM (reprint author), NCI, Biochem Lab, NIH, Bldg 37 Room 4A21,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 66 TC 81 Z9 83 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD DEC 15 PY 1999 VL 18 IS 24 BP 6983 EP 6993 DI 10.1093/emboj/18.24.6983 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 270KE UT WOS:000084533900013 PM 10601020 ER PT J AU Hurlin, PJ Steingrimsson, E Copeland, NG Jenkins, NA Eisenman, RN AF Hurlin, PJ Steingrimsson, E Copeland, NG Jenkins, NA Eisenman, RN TI Mga, a dual-specificity transcription factor that interacts with Max and contains a T-domain DNA-binding motif SO EMBO JOURNAL LA English DT Article DE Brachyury; Max; mesoderm; Mga; Tbx ID HOLT-ORAM SYNDROME; MESODERM FORMATION; BOX GENE; C-MYC; XENOPUS EMBRYOS; REPRESSOR SIN3; MOUSE EMBRYOS; MESSENGER-RNA; BRACHYURY; PROTEIN AB The basic-helix-loop-helix-leucine zipper (bHLHZip) proteins Myc, Mad and Mnt are part of a transcription activation/repression system involved in the regulation of cell proliferation, The function of these proteins as transcription factors is mediated by heterodimerization with the small bHLHZip protein Max, which is required for their specific DNA binding to E-box sequences. We have identified a novel Max-interacting protein, Mga, which contains a Myc-like bHLHZip motif, but otherwise shows no relationship with Mac or other Max-interacting proteins, Like Myc, Mad and Mnt proteins, Mga requires heterodimerization with Max for binding to the preferred Myc-Max-binding site CACGTG, In addition to the bHLHZip domain, Mga contains a second DNA-binding domain: the T-box or T-domain, The T-domain is a highly conserved DNA-binding motif originally defined in Brachyury and characteristic of the Tbx family of transcription factors. Mga binds the preferred Brachyury-binding sequence and represses transcription of reporter genes containing promoter-proximal Brachyury-binding sites. Surprisingly, Mga is converted to a transcription activator of both Myc-Max and Brachyury site-containing reporters in a Max-dependent manner. Our results suggest that Mga functions as a dual-specificity transcription factor that regulates the expression of both Max-network and T-box family target genes. C1 Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA. NCI, Mammalian Genet Lab, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Hurlin, PJ (reprint author), Shriners Hosp Crippled Children, Rm 610,3101 SW Sam Jackson Pk Rd, Portland, OR 97201 USA. FU NCI NIH HHS [CA20525] NR 49 TC 78 Z9 81 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 DEC 15 PY 1999 VL 18 IS 24 BP 7019 EP 7028 DI 10.1093/emboj/18.24.7019 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 270KE UT WOS:000084533900017 PM 10601024 ER PT J AU Rybak, SM Newton, DL AF Rybak, SM Newton, DL TI Natural and engineered cytotoxic ribonucleases: Therapeutic potential SO EXPERIMENTAL CELL RESEARCH LA English DT Review ID BOVINE SEMINAL RIBONUCLEASE; EOSINOPHIL-DERIVED NEUROTOXIN; CATIONIC PROTEINS INVITRO; RANA-CATESBEIANA LECTIN; HUMAN CARCINOMA-CELLS; AMINO-ACID-SEQUENCE; ANTITUMOR ACTION; MONOCLONAL-ANTIBODIES; P-30 PROTEIN; SCHISTOSOMA-MANSONI C1 NCI, Frederick Canc Res & Dev Ctr, Dev Therapeut Program, Div Canc Treatment & Diag,SAIC Frederick, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21702 USA. RP Rybak, SM (reprint author), NCI, Frederick Canc Res & Dev Ctr, Dev Therapeut Program, Div Canc Treatment & Diag,SAIC Frederick, Bldg 567,Room 152, Frederick, MD 21702 USA. NR 126 TC 82 Z9 83 U1 0 U2 2 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 DEC 15 PY 1999 VL 253 IS 2 BP 325 EP 335 DI 10.1006/excr.1999.4718 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 266ZW UT WOS:000084331000008 PM 10585255 ER PT J AU Heanue, TA Reshef, R Davis, RJ Mardon, G Oliver, G Tomarev, S Lassar, AB Tabin, CJ AF Heanue, TA Reshef, R Davis, RJ Mardon, G Oliver, G Tomarev, S Lassar, AB Tabin, CJ TI Synergistic regulation of vertebrate muscle development by Dach2, Eya2, and Six1, homologs of genes required for Drosophila eye formation SO GENES & DEVELOPMENT LA English DT Article DE Dach2; Eya2; Six1; Pax3; myogenesis; dachshund; somite development ID SINE OCULIS; SKI PROTOONCOGENE; PARAXIAL MESODERM; PAX-3 EXPRESSION; SKELETAL-MUSCLE; PRECURSOR CELLS; SONIC-HEDGEHOG; EYELESS GENE; COMPOUND EYE; ABSENT GENE AB We have identified a novel vertebrate homolog of the Drosophila gene dachshund, Dachshund2 (Dach2). Dach2 is expressed in the developing somite prior to any myogenic genes with an expression profile similar to Pax3, a gene previously shown to induce muscle differentiation. Pax3 and Dach2 participate in a positive regulatory feedback loop, analogous to a feedback loop that exists in Drosophila between the Pax gene eyeless (a Pax6 homolog) and the Drosophila dachshund gene. Although Dach2 alone is unable to induce myogenesis, Dach2 can synergize with Eya2 (a vertebrate homolog of the Drosophila gene eyes absent) to regulate myogenic differentiation. Moreover, Eya2 can also synergize with Six1 (a vertebrate homolog of the Drosophila gene sine oculis) to regulate myogenesis. This synergistic regulation of muscle development by Dach2 with Eya2 and Eya2 with Six1 parallels the synergistic regulation of Drosophila eye formation by dachshund with eyes absent and eyes absent with sine oculis. This synergistic regulation is explained by direct physical interactions between Dach2 and Eya2, and Eya2 and Six1 proteins, analogous to interactions observed between the Drosophila proteins. This study reveals a new layer of regulation in the process of myogenic specification in the somites. Moreover, we show that the Pax, Dach, Eya, and Six genetic network has been conserved across species. However, this genetic network has been used in a novel developmental context, myogenesis rather than eye development, and has been expanded to include gene family members that are not directly homologous, for example Pax3 instead of Pax6. C1 Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biochem & Mol Biol, Boston, MA 02115 USA. Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. St Jude Childrens Res Hosp, Dept Genet, Memphis, TN 38105 USA. NEI, NIH, Bethesda, MD 20892 USA. RP Tabin, CJ (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. FU NEI NIH HHS [EY12162, R01 EY012162]; NIGMS NIH HHS [GM58462, R01 GM058462] NR 72 TC 262 Z9 265 U1 0 U2 4 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 DEC 15 PY 1999 VL 13 IS 24 BP 3231 EP 3243 DI 10.1101/gad.13.24.3231 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 273RD UT WOS:000084719900008 PM 10617572 ER PT J AU Gecz, J Barnett, S Liu, JJ Hollway, G Donnelly, A Eyre, H Eshkevari, HS Baltazar, R Grunn, A Nagaraja, R Gilliam, C Peltonen, L Sutherland, GR Baron, M Mulley, JC AF Gecz, J Barnett, S Liu, JJ Hollway, G Donnelly, A Eyre, H Eshkevari, HS Baltazar, R Grunn, A Nagaraja, R Gilliam, C Peltonen, L Sutherland, GR Baron, M Mulley, JC TI Characterization of the human glutamate receptor subunit 3 gene (GRIA3), a candidate for bipolar disorder and nonspecific X-linked mental retardation SO GENOMICS LA English DT Article ID MANIC-DEPRESSIVE ILLNESS; CENTRAL-NERVOUS-SYSTEM; LOCALIZATION; LINKAGE; MAP; IDENTIFICATION; GENOME; FMR2; SCHIZOPHRENIA; CHROMOSOME-14 AB The X-chromosome breakpoint in a female patient with a balanced translocation t(X;12)(q24;q15), bipolar affective disorder and mental retardation was mapped within the glutamate receptor 3 (GRIA3) gene by fluorescence in situ hybridization. The GRIA3 cDNA of 5894 bp was cloned, and the gene structure and pattern of expression were determined. The most abundant GRIA3 transcript is composed of 17 exons, An. additional 5 exons (2a, 2b, 5a, 5b, and 5c) from the 5' end of the GRIA3 open reading frame were identified by EST analysis (ESTs AI379066 and AA947914), Two new polymorphic microsatellite repeats, (TC)(n=12-26) and (AC)(n=15-19) were identified within GRIA3 5' and 3'UTRs. No mutations were detected in families segregating disorders mapping across GRIA3, one with X-linked bipolar affective disorder (BP) and one with a nonspecific X-linked mental retardation (MRX27). To assess the possibility of the involvement of the GRIA3 gene in familial cases of complex BP, a large set of 373 individuals from 40 pedigrees segregating BP were genotyped using closely linked (DXS1001) and intragenic (DXS1212 and GRIA3 3' UTR (AC)(n))) GRIA3 STR markers. No evidence of linkage was found by parametric Lod score analysis (the highest Lod score was 0.3 at DXS1212, using the dominant transmission model) or by affected sib-pair analysis. (C) 1999 Academic Press. C1 Womens & Childrens Hosp, Dept Cytogenet & Mol Genet, Ctr Med Genet, N Adelaide, SA 5006, Australia. Womens & Childrens Hosp, Dept Psychol Med, N Adelaide, SA 5006, Australia. Univ Adelaide, Dept Paediat, Adelaide, SA, Australia. Univ Adelaide, Dept Genet, Adelaide, SA, Australia. Columbia Univ, Dept Psychiat, New York, NY 10032 USA. Columbia Univ, Columbia Genome Ctr, New York, NY 10032 USA. NIA, Genet Lab, Baltimore, MD 21224 USA. Univ Calif Los Angeles, Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. RP Gecz, J (reprint author), Womens & Childrens Hosp, Dept Cytogenet & Mol Genet, Ctr Med Genet, 72 King William Rd, N Adelaide, SA 5006, Australia. RI Hollway, Georgina/E-6764-2010; Sutherland, Grant/D-2606-2012 FU NIMH NIH HHS [MH00176, MH42535, MH43979] NR 64 TC 46 Z9 49 U1 2 U2 4 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 DEC 15 PY 1999 VL 62 IS 3 BP 356 EP 368 DI 10.1006/geno.1999.6032 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 280EN UT WOS:000085089400005 PM 10644433 ER PT J AU Poirier, MC Patterson, TA Slikker, W Olivero, OA AF Poirier, MC Patterson, TA Slikker, W Olivero, OA TI Incorporation of 3 '-azido-3 '-deoxythymidine (AZT) into fetal DNA and fetal tissue distribution of drug after infusion of pregnant late-term rhesus macaques with a human-equivalent AZT dose SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE transplacental; zidovudine; monkey; DNA incorporation; pharmacokinetics ID HUMAN-IMMUNODEFICIENCY-VIRUS; MATERNAL VIRAL LOAD; ZIDOVUDINE PHARMACOKINETICS; TRANSPLACENTAL TRANSFER; TRANSMISSION; MICE; 3'-AZIDO-2',3'-DIDEOXYTHYMIDINE; AZIDOTHYMIDINE; INFANTS; MICRONUCLEI AB In the United States, the nucleoside analogue drug 3'-azido-3'-deoxythymidine (AZT; also called zidovudine or ZDV) is given to most pregnant women who produce a positive test result for HIV-1. To investigate transplacental distribution and genotoxicity of AZT, near-term pregnant rhesus (Macaca mulatta) monkeys and their fetuses were studied. Four pregnant monkeys were continuously infused with 8 mg AZT/kg body weight for the 4 hours just prior to hysterotomy at term. This short-term AZT exposure resulted in AZT incorporation into DNA of fetal liver, lung, heart, skeletal muscle, brain, testis, and placenta, which varied between 29 and 1944 molecules of AZT/10(6) nucleotides. In contrast, values for AZT and combined metabolites, determined by radioactivity, varied between 0.94 and 5.20 mu g AZT equivalents/g tissue. A fifth animal, (H076), was infused with 17.3 mg AZT/kg body weight for similar to 3 hours, followed by 1 hour without drug before hysterotomy. Similar to the 4 other monkeys, variable levels of AZT (16-147 molecules of AZT/10(6) nucleotides) were incorporated into organ DNA of H076, whereas organ tissues contained less-variable levels of AZT and metabolites (0.86-2.05 mu g AZT equivalents/g tissue). For H076, at hysterotomy 1 hour after discontinuation of drug, values for AZT and the 3'-azido-3'-deoxythymidine-beta-D-glucuronide (AZTG) in fetal blood and amniotic fluid were twofold and threefold higher than those in maternal blood. Most AZT pharmacokinetic parameters in the fifth monkey were similar to those previously reported for the first 4 monkeys and those observed in a similar study of pregnant women. These data show that a short-term AZT infusion in pregnant rhesus monkeys, which have similar AZT pharmacokinetics to those present in a pregnant human, results in incorporation of drug into the DNA of placenta and most fetal organs. Data imply that the human fetus may also be subject to incorporation of AZT into DNA even after short-term AZT infusion to the mother just before delivery. C1 NCI, Div Basic Sci, NIH, Bethesda, MD 20892 USA. US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, Jefferson, AR 72079 USA. RP Poirier, MC (reprint author), NCI, Div Basic Sci, NIH, Bldg 37,Room 2A05,37 Convent Dr,MSC-4255, Bethesda, MD 20892 USA. FU NIEHS NIH HHS [Y01-ES-10187] NR 33 TC 43 Z9 43 U1 0 U2 2 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 DEC 15 PY 1999 VL 22 IS 5 BP 477 EP 483 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 284MR UT WOS:000085336600008 PM 10961609 ER PT J AU Wilson, DB Pinilla, C Wilson, DH Schroder, K Boggiano, C Judkowski, V Kaye, J Hemmer, B Martin, R Houghten, RA AF Wilson, DB Pinilla, C Wilson, DH Schroder, K Boggiano, C Judkowski, V Kaye, J Hemmer, B Martin, R Houghten, RA TI Immunogenicity. I. Use of peptide libraries to identify epitopes that activate clonotypic CD4(+) T cells and induce T cell responses to native peptide ligands SO JOURNAL OF IMMUNOLOGY LA English DT Article ID COMBINATORIAL LIBRARIES; ANTIGEN RECOGNITION; RECEPTOR; BINDING; SPECIFICITY; MOLECULES; CLONE; IDENTIFICATION; REQUIREMENTS; DEGENERACY AB Recent studies have demonstrated the utility of synthetic combinatorial libraries for the rapid identification of peptide ligands that stimulate clonotypic populations of T cells. Here we screen a decapeptide combinatorial library arranged in a positional scanning format with two different clonotypic populations of CD4(+) T cells to identify peptide epitopes that stimulate proliferative responses by these T cells in vitro, An extensive collection of mimic peptide sequences was synthesized and used to explore the fine specificity of TCR/peptide/MHC interactions. We also demonstrate that many of these deduced ligands are not only effective immunogens in vivo, but are capable of inducing T cell responses to the original native ligands used to generate the clones. These results have significant implications for considerations of T cell specificity and the design of peptide vaccines for infectious disease and cancer using clinically relevant T cell clones of unknown specificity. C1 Torrey Pines Inst Mol Studies, San Diego, CA 92121 USA. Scripps Res Inst, La Jolla, CA 92037 USA. NINDS, NIH, Bethesda, MD 20892 USA. RP Wilson, DB (reprint author), Torrey Pines Inst Mol Studies, 3550 Gen Atom Court, San Diego, CA 92121 USA. FU NCI NIH HHS [CA-78040]; NIAID NIH HHS [AI-31231, AI-22519] NR 24 TC 50 Z9 50 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 1999 VL 163 IS 12 BP 6424 EP 6434 PG 11 WC Immunology SC Immunology GA 263PJ UT WOS:000084134200010 PM 10586032 ER PT J AU Kuprash, DV Alimzhanov, MB Tumanov, AV Anderson, AO Pfeffer, K Nedospasov, SA AF Kuprash, DV Alimzhanov, MB Tumanov, AV Anderson, AO Pfeffer, K Nedospasov, SA TI TNF and lymphotoxin beta cooperate in the maintenance of secondary lymphoid tissue microarchitecture but not in the development of lymph nodes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; ALPHA-DEFICIENT MICE; ORGAN DEVELOPMENT; ABNORMAL-DEVELOPMENT; RECEPTOR; ORGANOGENESIS; INFLAMMATION; CYTOKINE; MEMBER; MOUSE AB Inactivation of genes encoding members of TNF and TNF receptor families reveal their divergent roles in the formation and function of secondary lymphoid organs. Most lymphotoxin alpha (lt alpha)- and all lymphotoxin beta receptor (lt beta)-deficient mice are completely devoid of lymph nodes (LNs); however, most lymphotoxin beta (lt beta)-deficient mice develop mesenteric LNs, Tnf- and tnfrp55-deficient mice develop a complete set of LNs, while lt beta/tnfrp55 double-deficient mice lack all LNs, demonstrating cooperation between LT beta and TNFRp55 in LN development. Now we report that lt beta/tnf double-deficient mice develop the same set of mucosal LNs as do lt beta-deficient mice, suggesting that ligands other than TNF signal through TNFRp55 during LN development, These LNs retain distinct T and B cells areas; however, they lack follicular dendritic cell networks. Structures resembling germinal centers can be found in the LNs from immunized lt beta-deficient mice but not in lt beta/tnf double-deficient mice. Additionally, stromal components of the spleen and LNs appear to be more severely disturbed in lt beta/tnf double-deficient mice as compared with lt beta-deficient mice. We conclude that LT beta and TNF cooperate in the establishment of the correct microarchitecture of lymphoid organs. C1 Russian Acad Sci, Engelhardt Inst Mol Biol, Lab Mol Immunol, Moscow 117984, Russia. Moscow State Univ, Belozersky Inst Physicochem Biol, Moscow, Russia. NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Mol Immunoregulat Lab, Frederick, MD 21702 USA. Sci Applicat Int Corp, Intramural Res Support Program, Frederick, MD USA. Tech Univ Munich, Inst Med Microbiol Immunol & Hyg, D-8000 Munich, Germany. Univ Cologne, Inst Genet, Cologne, Germany. USA, Med Res Inst Infect Dis, Dept Clin Pathol, Frederick, MD 21702 USA. RP Kuprash, DV (reprint author), Russian Acad Sci, Engelhardt Inst Mol Biol, Lab Mol Immunol, 32 Vavilov St, Moscow 117984, Russia. RI Nedospasov, Sergei/J-5936-2013; Nedospasov, Sergei/L-1990-2015; Kuprash, Dmitry/O-4899-2015; Nedospasov, Sergei/Q-7319-2016 OI Kuprash, Dmitry/0000-0002-1488-4148; FU NCI NIH HHS [N01-CO-56000] NR 45 TC 59 Z9 60 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 DEC 15 PY 1999 VL 163 IS 12 BP 6575 EP 6580 PG 6 WC Immunology SC Immunology GA 263PJ UT WOS:000084134200029 PM 10586051 ER PT J AU Poljak, L Carlson, L Cunningham, K Kosco-Vilbois, MH Siebenlist, U AF Poljak, L Carlson, L Cunningham, K Kosco-Vilbois, MH Siebenlist, U TI Distinct activities of p52/NF-kappa B required for proper secondary lymphoid organ microarchitecture: Functions enhanced by Bcl-3 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NF-KAPPA-B; FOLLICULAR DENDRITIC CELLS; GERMINAL CENTER REACTIONS; LYMPHOTOXIN-ALPHA; SPLENIC MICROARCHITECTURE; IMMUNE-RESPONSES; TRANSCRIPTION FACTORS; TARGETED DISRUPTION; DEFICIENT MICE; TNF RECEPTOR AB Mice rendered deficient in p52, a subunit of NF-kappa B, or in Bcl-3, an I kappa B-related regulator that associates with p52 homodimers, share defects in the microarchitecture of secondary lymphoid organs. The mutant mice are impaired in formation of B cell follicles and are unable to form proper follicular dendritic cell (FDC) networks upon antigenic challenge. The defects in formation of B cell follicles may be attributed, at least in part, to impaired production of the B lymphocyte chemoattractant (BLC) chemokine, possibly a result of defective FDCs, The p52- and Bcl-3-deficient mice exhibit additional defects within the splenic marginal zone, including reduced numbers of metallophilic macrophages, reduced deposition of the laminin-beta 2 chain and impaired expression of a mucosal addressin marker on sinus-lining cells. Whereas p52-deficient mice are severely defective in all of these aspects, Bcl-3-deficient mice are only partially defective. We determined that FDCs or other non-hemopoietic cells that underlie FDCs are intrinsically impaired in p52-deficient mice. Adoptive transfers of wild-type bone marrow into p52-deficient mice failed to restore FDC networks or follicles. The transfers did restore metallophilic macrophages to the marginal zone, however. Together, the results suggest that p52 carries out functions essential for a proper splenic microarchitecture in both hemopoietic and non-hemopoietic cells and that Bcl-3 is important in enhancing these essential activities of p52. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Serono Pharmaceut Res Inst, Geneva, Switzerland. RP Siebenlist, U (reprint author), NIAID, Immunoregulat Lab, NIH, 10 Ctr Dr,MSC 1876,Bldg 10,Room 11B16, Bethesda, MD 20892 USA. NR 43 TC 57 Z9 59 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 DEC 15 PY 1999 VL 163 IS 12 BP 6581 EP 6588 PG 8 WC Immunology SC Immunology GA 263PJ UT WOS:000084134200030 PM 10586052 ER PT J AU Powell, JD Lerner, CG Ewoldt, GR Schwartz, RH AF Powell, JD Lerner, CG Ewoldt, GR Schwartz, RH TI The-180 site of the IL-2 promoter is the target of CREB/CREM binding in T cell anergy SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD28 RESPONSE ELEMENT; GENE-EXPRESSION; PROTEIN-KINASE; CLONAL ANERGY; AP-1 SITES; INTERLEUKIN-2 PRODUCTION; TRANSCRIPTION FACTOR; REGULATORY ELEMENT; ANTIGEN RECEPTOR; LYMPHOCYTES-T AB Anergic T cells display a marked decrease in their ability to produce IL-2 even in the presence of optimal TCR and costimulatory signals. Using IL-2 enhancer/promoter-driven reporter constructs, we have previously identified a region that appears to be a target for cis transcriptional repression in anergy. This region of the promoter, which shares partial homology with a consensus AP-l-binding sequence, is located about -180 bp from the transcriptional start site. In the present study, we demonstrate that cAMP response element-binding protein/cAMP response element modulator (CREB/CREM), activating transcription factor-2/c-Jun, and Jun-Jun/Oct complexes bind to this site. However, the induction of anergy by prolonged stimulation through the TCR led to an increase in binding of only the CREB/CREM complex. Furthermore, the level of binding of this complex appeared to be up-regulated in both resting and restimulated anergic T cells. Finally, an IL-2 promoter-driven reporter construct that contained a mutation that specifically reduced the binding of the CREB/CREM complex displayed a decreased ability to be affected by anergy, while a construct that contained a mutation that decreased the binding of the Jun-Jun/Oct complex was still susceptible to anergy, These findings suggest that the -180 region of the IL-2 promoter is the target of a CREB/CREM transcriptional inhibitor that contributes to the repression of IL-2 production in T cell anergy. C1 NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Powell, JD (reprint author), NIAID, Cellular & Mol Immunol Lab, NIH, Bldg 4,Room 111, Bethesda, MD 20892 USA. NR 44 TC 101 Z9 106 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 DEC 15 PY 1999 VL 163 IS 12 BP 6631 EP 6639 PG 9 WC Immunology SC Immunology GA 263PJ UT WOS:000084134200036 PM 10586058 ER PT J AU Kurlander, RJ Chao, E Fields, J Nataraj, C AF Kurlander, RJ Chao, E Fields, J Nataraj, C TI The adjacent flanking region plays a critical role in facilitating the presentation of the Listeria monocytogenes product lemA to H2 M3(wt)-restricted, peptide-specific murine CD8 cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RESTRICTED EPITOPE PRESENTATION; CLASS-I PRESENTATION; EXOGENOUS SOLUBLE-ANTIGEN; B SURFACE-ANTIGEN; T-CELLS; MHC PRESENTATION; CTL RESPONSES; PARTICULATE ANTIGENS; COMPLEX; MOLECULES AB Mice infected with Listeria monocytogenes (LM) generate CD8 effecters specific for f-MIGWII, the amino terminus of the bacterial product lemA presented by the class Ib MHC molecule H2 M3(wt). lemA has several distinctive properties: 1) it is readily presented as an exogenous Ag in the absence of bacterial infection; 2) it is processed by a TAP-independent pathway, which is sensitive to chloroquine, pepstatin, and brefeldin; and 3) the immunogenic portion of the molecule is extremely resistant to proteolytic degradation even by proteinase K, To assess the structural basis for these findings, we expressed a truncated variant (t-lemA) containing the amino-terminal hexapeptide and the subsequent 27 amino acids linked to a histidine tail in Escherichia coli, and purified the product by affinity chromatography. Purified t-lemA could be presented to f-MIGWII-specific effecters by macrophages and fibroblasts at 1-10 nM. Unlike f-MIGWII, which binds directly to H2 M3(wt), t-lemA required processing by a chloroquine-, pepstatin-, and brefeldin-sensitive pathway, Brefeldin sensitivity often implies endogenous processing in the cytoplasm, but several lines of evidence suggest translocation to the cytoplasm and proteosomal degradation are not critical for t-lemA presentation. Unlike f-MIGWII, t-lemA was profoundly resistant to proteinase K, and, using S-35-labeled t-lemA, we could identify the region from position 1 to similar to 30 as the protease-resistant element. Thus, the hydrophobic peptide sequence following f-MIGMII can account for the unusual properties of lemA noted above. Analogous modification could be used to alter the properties of other peptide Ags presented by class I MHC products. C1 NIH, Ctr Clin, Dept Clin Pathol, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. RP Kurlander, RJ (reprint author), NIH, Ctr Clin, Dept Clin Pathol, Bldg 10,Room 2C-390,10 Ctr Dr, Bethesda, MD 20892 USA. NR 48 TC 5 Z9 5 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 DEC 15 PY 1999 VL 163 IS 12 BP 6741 EP 6747 PG 7 WC Immunology SC Immunology GA 263PJ UT WOS:000084134200050 PM 10586072 ER PT J AU Le, YY Gong, WH Li, BQ Dunlop, NM Shen, WP Su, SB Ye, RD Wang, JM AF Le, YY Gong, WH Li, BQ Dunlop, NM Shen, WP Su, SB Ye, RD Wang, JM TI Utilization of two seven-transmembrane, G protein-coupled receptors, formyl peptide receptor-like 1 and formyl peptide receptor, by the synthetic hexapeptide WKYMVm for human phagocyte activation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LIPOXIN A(4) RECEPTOR; SERUM AMYLOID-A; PHOSPHOINOSITIDE HYDROLYSIS; HUMAN MONOCYTES; CHEMOATTRACTANT RECEPTORS; CHEMOTACTIC RECEPTOR; HUMAN NEUTROPHILS; STABLE ANALOGS; IDENTIFICATION; LEUKOCYTES AB Trp-Lys-Tyr-Val-D-Met (WKYMVm) is a synthetic leukocyte-activating peptide postulated to use seven-transmembrane, G protein-coupled receptor(s), In the study to characterize the receptor(s) for WKYMVm, we found that this peptide induced marked chemotaxis and calcium flux in human phagocytes, The signaling induced by WKYMVm in phagocytes was attenuated by high concentrations of the bacterial chemotactic peptide fMLP, suggesting that WKYMVm might use receptor(s) for fMLP. This hypothesis was tested by using cells over expressing genes encoding two seven-transmembrane receptors, formyl peptide receptor (FPR) and formyl peptide receptor-like 1 (FPRL1), which are with high and low affinity for fMLP, respectively. Both FPR- and FPRL1-expressing cells mobilized calcium in response to picomolar concentrations of WKYMVm, While FPRL1-expressing cells migrated to picomolar concentrations of WKYMVm, nanomolar concentrations of the peptide were required to induce migration of FPR-expressing cells. In contrast, fMLP elicited both calcium flux and chemotaxis only in FPR-expressing cells with an efficacy comparable with WKYMVm, Thus, WKYMVm uses both FPR and FPRL1 to stimulate phagocytes with a markedly higher efficacy for FPRL1, Our study suggests that FPR and FPRL1 in phagocytes react to a broad spectrum of agonists and WKYMVm as a remarkably potent agonist provides a valuable tool for studying leukocyte signaling via these receptors. C1 Natl Canc Inst, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Div Basic Sci, Frederick, MD 21702 USA. Sci Applicat Int Corp, Intramural Res Support Program, Frederick, MD 21702 USA. Univ Illinois, Dept Pharmacol, Chicago, IL 60612 USA. RP Wang, JM (reprint author), NCI, FCRDC, Bldg 560,Room 31-40, Frederick, MD 21702 USA. RI Ye, Richard/O-5223-2016 OI Ye, Richard/0000-0002-2164-5620 NR 41 TC 148 Z9 150 U1 1 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 DEC 15 PY 1999 VL 163 IS 12 BP 6777 EP 6784 PG 8 WC Immunology SC Immunology GA 263PJ UT WOS:000084134200055 PM 10586077 ER PT J AU Kammula, US Lee, KH Riker, AI Wang, E Ohnmacht, GA Rosenberg, SA Marincola, FM AF Kammula, US Lee, KH Riker, AI Wang, E Ohnmacht, GA Rosenberg, SA Marincola, FM TI Functional analysis of antigen-specific T lymphocytes by serial measurement of gene expression in peripheral blood mononuclear cells and tumor specimens SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INFILTRATING LYMPHOCYTES; METASTATIC MELANOMA; IDENTIFICATION; PEPTIDE; ENHANCEMENT; VACCINE; PCR AB The cloning of cancer Ags recognized by T cells has provided potentially new tools to enhance immunity against metastatic cancer. The biological monitoring of effective immunization has, however, remained a dilemma. We describe here a sensitive molecular quantitation methodology that allows analysis of in vivo immune response to vaccination. Metastatic melanoma patients were immunized with a synthetically modified peptide epitope (209-2M) from the melanoma self-Ag gp100, Using serial gene expression analysis, we report functional evidence of vaccine-induced CTL reactivity in fresh cells obtained directly from the peripheral blood of postimmunized patients. Further, we demonstrate in vivo localization of vaccine-induced immune response within the tumor microenvironment, The results of these molecular assays provide direct evidence that peptide immunization in humans can result in tumor-specific CTL that localize to metastatic sites. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. NCI, Dept Transfus Med, Ctr Clin, NIH, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), NCI, Surg Branch, NIH, Bldg 10,Room 2B42,10 Ctr Dr,MSC 1502, Bethesda, MD 20892 USA. NR 23 TC 164 Z9 169 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 DEC 15 PY 1999 VL 163 IS 12 BP 6867 EP 6875 PG 9 WC Immunology SC Immunology GA 263PJ UT WOS:000084134200066 PM 10586088 ER PT J AU Ralston, E Lu, ZM Ploug, T AF Ralston, E Lu, ZM Ploug, T TI The organization of the Golgi complex and microtubules in skeletal muscle is fiber type-dependent SO JOURNAL OF NEUROSCIENCE LA English DT Article DE acetylcholine receptor; endoplasmic reticulum; flexor digitorum brevis; Golgi complex; neuromuscular junction; red gastrocnemius; trans-Golgi network; tensor fascia latae ID FIBROBLAST GROWTH-FACTOR; MEMBRANE SIALOGLYCOPROTEIN; SARCOPLASMIC-RETICULUM; ENDOPLASMIC-RETICULUM; ORGANIZING CENTERS; MEDIAL CISTERNAE; MESSENGER-RNA; APPARATUS; RAT; EXPRESSION AB Skeletal muscle has a nonconventional Golgi complex (GC), the organization of which has been a subject of controversy in the past. We have now examined the distribution of the GC by immunofluorescence and immunogold electron microscopy in whole fibers from different rat muscles, both innervated and experimentally denervated. The total number of GC elements, small polarized stacks of cisternae, is quite similar in all fibers, but their intracellular distribution is fiber type-dependent. Thus, in slow-twitch, type I fibers, similar to 75 of all GC elements are located within 1 mu m from the plasma membrane, and each nucleus is surrounded by a belt of GC elements. In contrast, in the fast-twitch type IIB fibers, most GC elements are in the fiber core, and most nuclei only have GC elements at their poles. Intermediate, type IIA fibers also have an intermediate distribution of GC elements. Interestingly, the distribution of microtubules, with which GC elements colocalize, is fiber type-dependent as well. At the neuromuscular junction, the distribution of GC elements and microtubules is independent of fiber type, and junctional nuclei are surrounded by GC elements in all fibers. After denervation of the hindlimb muscles, GC elements as well as microtubules converge toward a common pattern, that of the slow-twitch fibers, in all fibers. Our data suggest that innervation regulates the distribution of microtubules, which in turn organize the Golgi complex according to muscle fiber type. C1 NINCDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. Univ Copenhagen, Panum Inst, Dept Med Physiol, Copenhagen Muscle Res Ctr, DK-2200 Copenhagen, Denmark. RP Ralston, E (reprint author), NINCDS, Neurobiol Lab, NIH, Bldg 36,Room 2A 21, Bethesda, MD 20892 USA. NR 47 TC 44 Z9 47 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD DEC 15 PY 1999 VL 19 IS 24 BP 10694 EP 10705 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 267AU UT WOS:000084333100017 PM 10594053 ER PT J AU Kocsis, E Kessel, M DeMoll, E Grahame, DA AF Kocsis, E Kessel, M DeMoll, E Grahame, DA TI Structure of the Ni/Fe-S protein subcomponent of the acetyl-CoA decarbonylase/synthase complex from Methanosarcina thermophila at 26-angstrom resolution SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE acetyl-CoA decarbonylase/synthase; Archaea; CO dehydrogenase; coenzyme A; electron microscopy; methanogens; multienzyme complex; three-dimensional reconstruction ID CARBON-MONOXIDE DEHYDROGENASE; TRANSMISSION ELECTRON-MICROSCOPY; ENZYME COMPLEX; METHANOTHRIX-SOEHNGENII; 3-DIMENSIONAL RECONSTRUCTION; BIOLOGICAL MACROMOLECULES; CRYOELECTRON MICROSCOPY; PARAMAGNETIC CENTERS; RIBOSOMAL-SUBUNITS; METAL CENTERS AB The acetyl-CoA decarbonylase/synthase (ACDS) complex is responsible for synthesis and cleavage of acetyl-CoA in methanogens, The complex is composed of five different subunits, with a probable stoichiometry of alpha(8)beta(8)gamma(8)delta(8)epsilon(8). The native molecular mass of a subcomponent of the ACDS complex from Methanosarcina thermophila, the Ni/Fe-S protein containing the 90-kDa alpha and 19-kDa epsilon subunits, was determined by scanning transmission electron microscopy. A value of 218.6 +/- 19.6 kDa (n = 566) was obtained, thus establishing that the oligomeric structure of this subcomponent is alpha(2)epsilon(2). The three-dimensional structure of alpha(2)epsilon(2) was determined at 26-Angstrom resolution by analysis of a large number of electron microscopic images of negatively stained, randomly oriented particles. The alpha(2)epsilon(2) subcomponent has a globular appearance, 110 Angstrom in diameter, and consists of two large, hemisphere-like masses that surround a hollow internal cavity. The two large masses are connected along one face by a bridge-like structure and have relatively less protein density joining them at other positions. The internal cavity has four main openings to the outside, one of which is directly adjacent to the bridge, The results are consistent with a structure in which the large hemispheric masses are assigned to the two alpha subunits, with epsilon(2) as the bridge forming a structural link between them. The structure of the alpha(2)epsilon(2) subcomponent is discussed in connection with biochemical data from gel filtration, crosslinking, and dissociation experiments and in the context of its function as a major component of the ACDS complex. (C) 1999 Academic Press. C1 Uniformed Serv Univ Hlth Sci, Dept Biochem & Mol Biol, Bethesda, MD 20814 USA. NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. Univ Kentucky, Albert B Chandler Med Ctr, Dept Microbiol & Immunol, Lexington, KY 40536 USA. RP Grahame, DA (reprint author), Uniformed Serv Univ Hlth Sci, Dept Biochem & Mol Biol, Bethesda, MD 20814 USA. FU NCRR NIH HHS [P41-RR01777] NR 36 TC 15 Z9 18 U1 1 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD DEC 15 PY 1999 VL 128 IS 2 BP 165 EP 174 DI 10.1006/jsbi.1999.4163 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 273GV UT WOS:000084700300004 PM 10600570 ER PT J AU Ishima, R Louis, JM Torchia, DA AF Ishima, R Louis, JM Torchia, DA TI Transverse C-13 relaxation of CHD2 methyl isotopmers to detect slow conformational changes of protein side chains SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID NMR-SPECTROSCOPY; PERDEUTERATED PROTEINS; HIV-1 PROTEASE; DYNAMICS; INHIBITOR; RESIDUES; MOTIONS; TIMES; H-1 C1 Natl Inst Dent & Craniofacial Res, Struct Mol Biol Unit, NIH, Bethesda, MD 20892 USA. NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Torchia, DA (reprint author), Natl Inst Dent & Craniofacial Res, Struct Mol Biol Unit, NIH, Bethesda, MD 20892 USA. NR 23 TC 64 Z9 66 U1 0 U2 11 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 DEC 15 PY 1999 VL 121 IS 49 BP 11589 EP 11590 DI 10.1021/ja992836b PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 266NT UT WOS:000084306600047 ER PT J AU Broder, CC Earl, PL AF Broder, CC Earl, PL TI Recombinant vaccinia viruses - Design, generation, and isolation SO MOLECULAR BIOTECHNOLOGY LA English DT Article DE vaccinia virus; biotechnology/methods; proteins/biosynthesis; genetic vectors; recombinant proteins; gene expression; recombination; selection/genetics; transfection ID HOST-RANGE SELECTION; BACTERIOPHAGE-T7 RNA-POLYMERASE; DOMINANT SELECTABLE MARKER; ATTENUATED MVA STRAIN; FOREIGN GENES; ENVELOPE GLYCOPROTEIN; ESCHERICHIA-COLI; EXPRESSION VECTOR; LAC REPRESSOR; REGULATED EXPRESSION AB The technologies of recombinant gene expression have greatly enhanced the structural and functional analyses of genetic elements and proteins. Vaccinia virus, a large double-stranded DNA virus and the prototypic and best characterized member of the poxvirus family, has been an instrumental tool among these technologies and the recombinant vaccinia virus system has been widely employed to express genes from eukaryotic, prokaryotic, and viral origins Vaccinia virus is also the prototype live viral vaccine and serves as the basis for well established viral vectors which have been successfully evaluated as human and animal vaccines for infectious diseases and as anticancer vaccines in a variety of animal model systems. Vaccinia virus technology has also been instrumental in a number of unique applications, from the discovery of new viral receptors to the synthesis and assembly of other viruses in culture. Here we provide a simple and detailed outline of the processes involved in the generation of a typical recombinant vaccinia virus, along with an up to date review of relevant literature. C1 Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. NR 98 TC 16 Z9 17 U1 1 U2 9 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1073-6085 J9 MOL BIOTECHNOL JI Mol. Biotechnol. PD DEC 15 PY 1999 VL 13 IS 3 BP 223 EP 245 DI 10.1385/MB:13:3:223 PG 23 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 290LN UT WOS:000085677900005 PM 10934535 ER PT J AU Shi, HP Zhang, ZP Wang, X Liu, SG Teng, CT AF Shi, HP Zhang, ZP Wang, X Liu, SG Teng, CT TI Isolation and characterization of a gene encoding human Kruppel-like factor 5 (IKLF): binding to the CAAT/GT box of the mouse lactoferrin gene promoter SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ZINC-FINGER PROTEIN; EPIDERMAL GROWTH-FACTOR; TRANSCRIPTIONAL ACTIVATION DOMAIN; MULTIGENE FAMILY; GASTRIN PROMOTER; NUCLEAR PROTEINS; DNA; IDENTIFICATION; ELEMENT; REGION AB The mouse lactoferrin gene promoter includes a CAAT/GT box, GGGCAATAGGGTGGGGCCAGCCC, which functions as the epidermal growth factor response element (EGFRE) in human endometrial carcinoma RL95-2 cells (RL95), A positive clone, EGFREB, of 2575 bp length, was isolated from an expression library of RL95 cells with a multimer of the EGFRE sequence. In this work, we have identified that EGFREB encodes the C-terminus of Kruppel-like factor 5 (KLF5), This mRNA is most abundant in human colon and small intestine. A full-length cDNA clone was isolated from a human colon library using EGFREB as the hybridization probe. The full-length cDNA consists of 3336 bp with a 302 bp 5'-UTR, a 1663 bp 3'-UTR, and a 1371 bp sequence coding for a 457 amino acid polypeptide, Based on its tissue distribution and sequence homology to the mouse IKLF, we renamed this protein IKLF, DNase I footprinting and electrophoresis mobility shift assay confirmed the binding of IKLF to the EGFRE. The human IKLF gene spans >20 kb in length and is organized into four exons, whose intron/exon junctions follow the GT/AG rule. The three zinc fingers are encoded by three exons, Nuclear localization of IKLF was demonstrated by green fluorescence protein (GFP)-tagged IKLF in transfection experiments and western analysis. Overexpression of IKLF in RL95 cells represses the activity of reporter constructs containing the CAAT/GT box of the mouse lactoferrin gene. These findings imply that IKLF is a nuclear transcription factor that binds to the CAAT/GT box, and functions as a modulator of the mouse lactoferrin gene promoter activity. C1 NIEHS, Gene Regulat Grp, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Teng, CT (reprint author), NIEHS, Gene Regulat Grp, Reprod & Dev Toxicol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 48 TC 53 Z9 54 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 DEC 15 PY 1999 VL 27 IS 24 BP 4807 EP 4815 DI 10.1093/nar/27.24.4807 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 270QN UT WOS:000084547200018 PM 10572182 ER PT J AU Pickle, LW Mungiole, M Jones, GK White, AA AF Pickle, LW Mungiole, M Jones, GK White, AA TI Exploring spatial patterns of mortality: The new Atlas of United States Mortality SO STATISTICS IN MEDICINE LA English DT Article ID LUNG-CANCER RISK; STATISTICAL MAPS; NEW-JERSEY; EMPLOYMENT; OCCUPATION; PERCEPTION AB The National Center for Health Statistics, CDC, has produced an Atlas of United States Mortality which includes maps of rates for the leading causes of death in the United States for the period 1988-1992. As part of this project, many aspects of statistical mapping have been re-examined to maximize the atlas's effectiveness in conveying accurate mortality patterns to epidemiologists and public health practitioners. Because recent cognitive research demonstrated that no one map style is optimal for answering many different map questions, maps and graphs of several different mortality statistics are included for each cause of death. New mixed effects models were developed to provide predicted rates and improved variance estimates. Results from these models were smoothed using a weighted head-banging algorithm to produce maps of general spatial trends free of background noise. Maps of White female lung cancer rates from the new atlas are presented here to illustrate how this innovative combination of maps and graphs permits greater exploration of the underlying mortality data than is possible from previous single-map atlas designs. Published in 1999 by John Wiley & Sons, Ltd. This article is a U.S. Government work and is in the public domain in the United States. C1 NCI, DCCPS, Bethesda, MD 20892 USA. Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. Natl Acad Sci, Washington, DC 20418 USA. RP Pickle, LW (reprint author), NCI, DCCPS, 6130 Execut Blvd,MSC 7644,EPN Rm 313, Bethesda, MD 20892 USA. NR 39 TC 28 Z9 29 U1 1 U2 3 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD DEC 15 PY 1999 VL 18 IS 23 BP 3211 EP + DI 10.1002/(SICI)1097-0258(19991215)18:23<3211::AID-SIM311>3.0.CO;2-Q PG 13 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 262QF UT WOS:000084077400006 PM 10602146 ER PT J AU Heyliger, SO Jackson, C Rice, KC Rothman, RB AF Heyliger, SO Jackson, C Rice, KC Rothman, RB TI Opioid peptide receptor studies. 10. Nor-BNI differentially inhibits kappa receptor agonist-induced G-protein activation in the guinea pig caudate: Further evidence of kappa receptor heterogeneity SO SYNAPSE LA English DT Article DE U69,593; (+)-tifluadom; CTAP; kappa-receptor subtypes; [S-35]-GTP-delta-S; Nor-BNI ID GAMMA-S BINDING; MEDIATING PRESYNAPTIC INHIBITION; RAT-BRAIN; SPINAL-CORD; PHARMACOLOGICAL CHARACTERIZATION; ACETYLCHOLINE-RELEASE; OPIATE RECEPTORS; SUBTYPES; SITES; ANTAGONIST AB There is strong evidence supporting the existence of multiple kappa receptors. Previous studies proposed that U69,593 and (+)-tifluadom act on different kappa receptor subtypes, kappa(1) (kappa(1)) and kappa(2) (kappa(2)), respectively. In this study, we investigated the effects of the kappa selective antagonist nor-binaltorphimine (Nor-BNI) on U69,593- and (+)-tifluadom-induced receptor-mediated stimulation of [S-35]-GTP-gamma-S binding in the guinea pig caudate. The IC50 value of Nor-BNI in the presence of a stimulating concentration of U69,593 (1 mu M) was 0.19 +/- 0.02; while the IC50 for Nor-BNI in the presence of (+)-tifluadom (1 mu M) was 13.9 +/- 1.62 nM. The mu-opioid receptor antagonist CTAP (10,000 nM) significantly reduced (+)-tifluadom-stimulated [S-35]-GTP-gamma-S binding in rat brain sections and guinea pig brain membranes, indicating that (+)-tifluadom has mu agonist activity. Under conditions in which the mu agonist activity of(+)-tifluadom was blocked by 1000 nM CTAP the Ki value for Nor-BNI for inhibition of U69,593-stimulated [S-35]-GTP-gamma-S binding was 0.036 +/- .004 nM, whereas, its Ki value for the (+)-tifluadom-stimulated [S-35]-GTP-gamma-S binding was 0.27 +/- .015 nM. These results suggest that (+)-tifluadom and U69,593 activate pharmacologically different receptors. This study provides functional evidence in support of kappa receptor heterogeneity. Published 1999 Wiley-Liss, Inc. C1 NIDA, CPS, DIR, NIH, Baltimore, MD 21224 USA. Florida A&M Univ, Coll Arts & Sci, Tallahassee, FL 32307 USA. NIDDK, Med Chem Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Rothman, RB (reprint author), NIDA, CPS, DIR, NIH, POB 5180,5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 71 TC 8 Z9 8 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD DEC 15 PY 1999 VL 34 IS 4 BP 256 EP 265 DI 10.1002/(SICI)1098-2396(19991215)34:4<256::AID-SYN2>3.0.CO;2-6 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 252XM UT WOS:000083527600002 PM 10529720 ER PT J AU Spurney, CF Baca, SM Murray, AM Jaskiw, GE Kleinman, JE Hyde, TM AF Spurney, CF Baca, SM Murray, AM Jaskiw, GE Kleinman, JE Hyde, TM TI Differential effects of haloperidol and clozapine on ionotropic glutamate receptors in rats SO SYNAPSE LA English DT Article DE glutamate receptors; brain; haloperidol; clozapine; rat ID METHYL-D-ASPARTATE; MESSENGER-RNA LEVELS; ATYPICAL ANTIPSYCHOTIC-DRUGS; SCHIZOPHRENIC-PATIENTS; AMINO-ACID; CEREBROSPINAL-FLUID; DOPAMINE RELEASE; BINDING-SITES; AUTORADIOGRAPHIC CHARACTERIZATION; PARKINSONS-DISEASE AB Despite multiple lines of investigation the effect of neuroleptics on glutamate-mediated neurotransmission remains controversial. To study the effects of typical and atypical neuroleptics on selected parameters of glutamate-mediated neurotransmission, male Sprague-Dawley rats were randomly assigned to a 21-day oral treatment course with vehicle, haloperidol (HDL), or clozapine (CLZ). Coronal slices of rat brain were then incubated with tritiated ligands to measure NMDA, AMPA, and kainate receptor, and glutamate reuptake site density. Regions of interest included the frontal cortex, anterior cingulate cortex, dorsal striatum, ventral striatum, and the nucleus accumbens. CLZ increased the density of AMPA receptors significantly in the frontal and anterior cingulate cortices compared with normal controls. In the dorsal and ventral striatum, and nucleus accumbens as a whole, CLZ-treated rats had a higher AMPA receptor density compared with both the HDL- and vehicle-treated controls. Additionally, within the nucleus accumbens, CLZ-treated rats had a higher density of AMPA receptors compared with the HDL group in the core, and at trend level in the shell. There was a group by region interaction for NMDA receptor density, primarily reflecting the tendency of HDL treated rats to have high receptor densities in the frontal and anterior cingulate cortices. Kainate receptors and glutamate reuptake site densities did not differ significantly across groups. These results suggest a critical role for glutamate in the mediation of atypical antipsychotic drug action in anatomically-specific regions, and further encourage the investigation of glutamate neurotransmitter systems in schizophrenia. Published 1999 Wiley-Liss, Inc. C1 NIMH, Clin Brain Disorders Branch, IRP, NIH, Bethesda, MD 20892 USA. Cleveland VAMC, Psychiat Serv 116AB, Brecksville, OH 44141 USA. RP Hyde, TM (reprint author), Suite 233,4701 Willard Ave, Chevy Chase, MD 20815 USA. NR 71 TC 38 Z9 38 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD DEC 15 PY 1999 VL 34 IS 4 BP 266 EP 276 DI 10.1002/(SICI)1098-2396(19991215)34:4<266::AID-SYN3>3.0.CO;2-2 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 252XM UT WOS:000083527600003 PM 10529721 ER PT J AU Thomas, JM Contreras, JL Jiang, XL Eckhoff, DE Wang, PX Hubbard, WJ Lobashevsky, AL Wang, WL Asiedu, C Stavrou, S Cook, WJ Robbin, ML Thomas, FT Neville, DM AF Thomas, JM Contreras, JL Jiang, XL Eckhoff, DE Wang, PX Hubbard, WJ Lobashevsky, AL Wang, WL Asiedu, C Stavrou, S Cook, WJ Robbin, ML Thomas, FT Neville, DM TI Peritransplant tolerance induction in macaques: Early events reflecting the unique synergy between immunotoxin and deoxyspergualin (Retracted article. See vol 86, pg. 482, 2008) SO TRANSPLANTATION LA English DT Article; Proceedings Paper; Retracted Publication CT 17th Annual Meeting of the American-Society-of-Transplant-Physicians CY MAY 09-13, 1998 CL CHICAGO, IL SP Amer Soc Transplant Physicians ID TOTAL LYMPHOID IRRADIATION; RENAL-ALLOGRAFT REJECTION; KAPPA-B ACTIVATION; DONOR BONE-MARROW; T-CELL DEPLETION; DENDRITIC CELLS; ORGAN-TRANSPLANTATION; KIDNEY ALLOGRAFTS; RHESUS-MONKEYS; IN-VIVO AB Background. Day of transplant T cell depletion with anti-CDS immunotoxin or F(Ab)(2) immunotoxin induces stable tolerance to renal allografts in rhesus monkeys given 15-deoxyspergualin (DSG), a NF-kappa B inhibitor that suppresses proinflammatory cytokine (PC) production. Because PC and NF-kappa B are involved in dendritic cell (DC) maturation, we asked if impaired DC maturation and Th2-type cytokine deviation might be related to the synergistic effect of DSG in this novel model. Methods. Immunosuppression was initialed 4 hr before transplanting a major histocompatibility complex mismatched renal allograft, Some groups received a supplemental 5-day course of cyclosporine A or DSG or a 15-day course of DSG. Peripheral lymph nodes were sequentially examined for presence of mature DC. In vitro effects of DSG on PC-induced maturation of DC were also examined. Results. Allografts survived without rejection in 87% of recipients given immunotoxin or F(Ab)(2) immunotoxin with DSG x 15 days, in 50% with DSG x 5 days, and 0% with cyclosporine A. The longest DSG survivors are >1000 days with normal graft function and tolerance validated, including acceptance of challenge second donor kidneys without treatment. DSG-treated recipients were unique in developing polarized Th2-type plasma cytokines, In DSG recipients, mature DC were significantly reduced in day +5 lymph node biopsies, with complete repopulation by 30 days. In vitro studies verified an inhibitory effect of DSG on DC maturation, Conclusions, The study suggests DSG arrests DC maturation. The unusual synergy of immunotoxin and DSG: apparently involves coincidental reduction in lymph node T cell mass and mature DC, a transient circumstance favoring development of stable tolerance. C1 Univ Alabama, Dept Surg, Div Transplantat Immunobiol, Birmingham, AL 35294 USA. Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. Univ Alabama, Dept Radiol, Birmingham, AL 35294 USA. NIMH, NIH, Mol Biol Lab, Bethesda, MD 20800 USA. RP Thomas, JM (reprint author), Div Transplantat Immunol, 531 Boshell Diabet Bldg,1808 7th Ave S, Birmingham, AL 35294 USA. FU NIAID NIH HHS [AI RO1-AI122293] NR 72 TC 106 Z9 109 U1 6 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD DEC 15 PY 1999 VL 68 IS 11 BP 1660 EP 1673 DI 10.1097/00007890-199912150-00009 PG 14 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 266NJ UT WOS:000084305800009 PM 10609942 ER PT J AU Mage, RG Sehgal, D Schiaffella, E Anderson, AO AF Mage, RG Sehgal, D Schiaffella, E Anderson, AO TI Gene-conversion in rabbit B-cell ontogeny and during immune responses in splenic germinal centers SO VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY LA English DT Article; Proceedings Paper CT 5th International Veterinary Immunology Symposium CY NOV 08-13, 1998 CL PUNJAB AGR UNIV, LUDHIANA, INDIA SP Punjab Agr Univ HO PUNJAB AGR UNIV ID IMMUNOGLOBULIN HEAVY-CHAIN; SOMATIC DIVERSIFICATION; ANTIBODY DIVERSITY; ADULT-RABBITS; VH-GENE; CHICKEN; SEQUENCES; HYPERCONVERSION; ORGANIZATION; REPERTOIRE AB Combinatorial diversity is limited in rabbits because only a few V-H genes rearrange. Most diversification of the primary repertoire is generated by somatic hypermutation and gene conversion-like changes of rearranged V-H in B cells that migrate to appendix and other gut associated lymphoid tissues (GALT) of young rabbits. The changes are referred to as gene conversion-like because the non-reciprocal nature of the alterations introduced has not yet been demonstrated. There are many similarities between rabbits and chickens in how their B cells develop and diversify their repertoires. However, although the majority of rabbit B cells may have rearranged and diversified their V genes early in life, some B cells in adult rabbits have rearranged V-H sequences that are identical or nearly identical to germline sequences. We found these cells in splenic germinal centers (GC) on days 7 and 10 after immunization of normal adult rabbits with DNP-BGG. By day 15, all rearranged V-H sequences were diversified. We find an overall pattern of splenic precursor cells whose germline or near germline sequences change both by gene conversion and point mutations during early divisions and mainly by point mutations during later divisions. These events, in parallel with diversification of light chain sequences, may produce the diverse combining sites that serve as substrates for further affinity maturation by selection either within GC or later among emigrant cells in sites such as bone marrow. Some of the sequences altered by gene conversion in splenic germinal centers may also produce new members of the B-cell repertoire in adult rabbits comparable to those produced in GALT of neonatal rabbits. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIAID, NIH, Immunol Lab, Bethesda, MD 20892 USA. USA, Med Res Inst Infect Dis, Frederick, MD 21702 USA. RP Mage, RG (reprint author), NIAID, NIH, Immunol Lab, Bldg 10,Rm 11N311,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. NR 37 TC 7 Z9 7 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2427 J9 VET IMMUNOL IMMUNOP JI Vet. Immunol. Immunopathol. PD DEC 15 PY 1999 VL 72 IS 1-2 BP 7 EP 15 DI 10.1016/S0165-2427(99)00110-5 PG 9 WC Immunology; Veterinary Sciences SC Immunology; Veterinary Sciences GA 265QZ UT WOS:000084256000003 PM 10614487 ER PT J AU McKee, ML FitzGerald, DJ AF McKee, ML FitzGerald, DJ TI Reduction of furin-nicked Pseudomonas exotoxin A: An unfolding story SO BIOCHEMISTRY LA English DT Article ID PROTEIN-DISULFIDE-ISOMERASE; RECEPTOR-RELATED PROTEIN; SEGREGATION GENE CSE1; RATE-LIMITING STEP; DIPHTHERIA-TOXIN; AERUGINOSA EXOTOXIN; LOW PH; INTERCHAIN DISULFIDE; CELLULAR PROTEASE; CHOLERA-TOXIN AB Upon entering mammalian cells, Pseudomonas exotoxin A (PE) is proteolytically processed by furin to produce an N-terminal fragment of 28 kDa and a C-terminal fragment of 37 kDa. Cleavage is followed by the reduction of a key disulfide bond (cysteines 265-287). This combination of proteolysis and reduction releases the 37 kDa C-terminal fragment, which then translocates to the cytosol where it ADP-ribosylates elongation factor 2 and inhibits protein synthesis. To investigate toxin reduction, furin-nicked PE or a hypercleavable mutant, PEW281A, was subjected to various treatments and then analyzed for fragment production. Reduction was evident only when unfolding conditions and a reducing agent were applied. Thermal unfolding of PE, as evidenced by changes in or-helical content and increased sensitivity to trypsin, rendered nicked toxin susceptible to protein disulfide isomerase- (PDI-) mediated reduction. When subcellular fractions from toxin-sensitive cells were incubated with nicked PE, toxin unfolding and reducing activities were present in the membrane fraction but not the soluble fraction. These data indicate that PE reduction is a two-step process: unfolding that allows access to the Cys265-287 disulfide bond, followed by reduction of the sulfur-sulfur bond by PDI or a PDI-like enzyme. With regard to cellular processing, we propose that the toxin's three-dimensional structure retains a "closed" conformation that restricts solvent access to the Cys265-287 disulfide bond until after a cell-mediated unfolding event. C1 NCI, Biotherapy Sect, Lab Mol Biol, Div Basic Sci,NIH, Bethesda, MD 20892 USA. RP FitzGerald, DJ (reprint author), 37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. NR 47 TC 50 Z9 53 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD DEC 14 PY 1999 VL 38 IS 50 BP 16507 EP 16513 DI 10.1021/bi991308+ PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 266FE UT WOS:000084289300012 PM 10600112 ER PT J AU Francischetti, IMB Valenzuela, JG Ribeiro, JMC AF Francischetti, IMB Valenzuela, JG Ribeiro, JMC TI Anophelin: Kinetics and mechanism of thrombin inhibition SO BIOCHEMISTRY LA English DT Article ID HUMAN ALPHA-THROMBIN; HUMAN THROMBOMODULIN; CRYSTAL-STRUCTURE; ANTITHROMBIN-III; GLYCOPROTEIN-IB; FACTOR-XA; HIRUDIN; BINDING; ANTICOAGULANT; SPECIFICITY AB Anophelin is a 6.5-kDa peptide isolated from the salivary gland of Anopheles albimanus that behaves as an alpha-thrombin inhibitor. In this paper, kinetic analyses and the study of mechanism of alpha-thrombin inhibition by anophelin were performed. Anophelin was determined to be a reversible, slow, tight-binding inhibitor of alpha-thrombin, displaying a competitive type of inhibition. The binding of anophelin to or-thrombin is stoichiometric with a dissociation constant (K-i) of 5.87 +/- 1.46 pM, a calculated association rate constant (k(1)) of 2.11 +/- 0.06 x 10(8) M-1 s(-1), and a dissociation rate constant (k(-1)) of 4.05 +/- 0.97 x 10(-4) s(-1). In the presence of 0.15 and 0.4 M NaCl, a 17.6- and 207-fold increase in the K-i of anophelin-alpha-thrombin complex was observed, respectively, indicating that ionic interactions are important in anophelin-alpha-thrombin complex formation. Incubation of alpha-thrombin with C-terminal hirudin fragment 54-65 that binds to alpha-thrombin anion binding exosite 1 (TABE1) attenuates alpha-thrombin inhibition by anophelin; anophelin also blocks TABE1-dependent trypsin;mediated proteolysis of alpha-thrombin. Using gamma-thrombin, an alpha-thrombin derivative where the anion binding exosite has been disrupted, anophelin behaves as a fast and classical competitive inhibitor of gamma-thrombin hydrolysis of small chromogenic substrate (K-i = 0.694 +/- 0.063 nM). In addition, anophelin-gamma-thrombin complex formation is prevented by treatment of the enzyme with D-Phe-Pro-Arg-chloromethyl ketone (PPACK), a reagent that irreversibly blocks the catalytic sire of thrombin. It; is concluded that anophelin is a potent dual inhibitor of cr-thrombin because it binds both to TABE1 and to the catalytic site, optimal binding being dependent on the availability of both domains. Finally, anophelin inhibits clot-bound cr-thrombin with an IC50 of 45 nM and increases the lag phase that precedes explosive in vitro alpha-thrombin generation after activation of intrinsic pathway of blood coagulation. Because of its unique primary sequence, anophelin may be used as a novel reagent to study the structure and function of alpha-thrombin. C1 NIAID, Med Entomol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Ribeiro, JMC (reprint author), NIAID, Med Entomol Sect, Parasit Dis Lab, NIH, Bldg 4,Rm 126,4 Ctr Dr, Bethesda, MD 20892 USA. OI Ribeiro, Jose/0000-0002-9107-0818 NR 40 TC 74 Z9 76 U1 1 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD DEC 14 PY 1999 VL 38 IS 50 BP 16678 EP 16685 DI 10.1021/bi991231p PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 266FE UT WOS:000084289300031 PM 10600131 ER PT J AU Neale, EA Bowers, LM Jia, M Bateman, KE Williamson, LC AF Neale, EA Bowers, LM Jia, M Bateman, KE Williamson, LC TI Botulinum neurotoxin a blocks synaptic vesicle exocytosis but not endocytosis at the nerve terminal SO JOURNAL OF CELL BIOLOGY LA English DT Article DE botulinum toxin type A; presynaptic terminals; synaptic vesicles; endocytosis; exocytosis ID FROG NEUROMUSCULAR-JUNCTION; SPINAL-CORD NEURONS; CULTURED HIPPOCAMPAL-NEURONS; ADRENAL CHROMAFFIN CELLS; TETANUS-TOXIN; NEUROTRANSMITTER RELEASE; TRANSMITTER RELEASE; RAPID ENDOCYTOSIS; PLASMA-MEMBRANE; V-SNARE AB The supply of synaptic vesicles in the nerve terminal is maintained by a temporally linked balance of exo- and endocytosis, Tetanus and botulinum neurotoxins block :neurotransmitter release by the enzymatic cleavage of proteins identified as critical for synaptic vesicle exocytosis. We show here that botulinum neurotoxin A is unique in that the toxin-induced block in exocytosis does not arrest vesicle membrane endocytosis. In the murine spinal cord, cell cultures exposed to botulinum neurotoxin A, neither K+-evoked neurotransmitter release nor synaptic currents can be detected, twice the ordinary number of synaptic vesicles are docked at the synaptic active zone, and its protein substrate is cleaved, which is similar to observations with tetanus and other botulinal neurotoxins, In marked contrast, K+ depolarization, in the presence of Ca2+, triggers the endocytosis of the vesicle membrane in botulinum neurotoxin A-blocked cultures as evidenced by FM1-43 staining of synaptic terminals and uptake of HRP into synaptic vesicles. These experiments are the first demonstration that botulinum neurotoxin A uncouples vesicle exo- from endocytosis, and provide evidence that Ca2+ is required for synaptic vesicle membrane retrieval. C1 NICHD, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Neale, EA (reprint author), NICHD, Dev Neurobiol Lab, NIH, Bldg 49,Room 5A38, Bethesda, MD 20892 USA. NR 68 TC 55 Z9 57 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 DEC 13 PY 1999 VL 147 IS 6 BP 1249 EP 1260 DI 10.1083/jcb.147.6.1249 PG 12 WC Cell Biology SC Cell Biology GA 266VM UT WOS:000084321000012 PM 10601338 ER PT J AU Kuppenbender, KD Albers, DS Iadarola, MJ Landwehrmeyer, GB Standaert, DG AF Kuppenbender, KD Albers, DS Iadarola, MJ Landwehrmeyer, GB Standaert, DG TI Localization of alternatively spliced NMDAR1 glutamate receptor isoforms in rat striatal neurons SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Review DE glutamate receptors; projection neurons; interneurons; striatum; cholinergic; calbindin ID D-ASPARTATE RECEPTOR; NITRIC-OXIDE SYNTHASE; PROTEIN-KINASE-C; SUBUNIT MESSENGER-RNA; PARVALBUMIN-IMMUNOREACTIVE NEURONS; CALCIUM-BINDING PROTEIN; EXCITATORY AMINO-ACIDS; HUNTINGTONS-DISEASE; BASAL GANGLIA; PROJECTION NEURONS AB Alternative splicing of the mRNA encoding the N-methyl-D-aspartate (NMDA) receptor subunit NR1 changes the structural, physiologic, and pharmacologic properties of the resultant NMDA receptors. We used dual label immunocytochemistry and confocal microscopy to localize the four alternatively spliced segments of the NR1 subunit (N1, C1, C2, and C2') in rat striatal neurons. Striatofugal projection neurons and four populations of interneurons were studied. Projection neurons, which were identified by immunolabeling for calbindin and by retrograde tracing from the globus pallidus and the substantia nigra, were the only striatal neurons containing C1 segment immunoreactivity. Projection neurons were also C2 segment immunopositive, as were all other neuronal populations studied. Projection neurons were C2' segment immunonegative. In contrast, each of the interneuron types were labeled by the antibody to the C2' segment: nitric oxide synthase interneurons were labeled intensely, calretinin and parvalbumin neurons were labeled moderately strongly, and cholinergic neurons were also labeled but less strongly than the other types of interneurons. Parvalbumin interneurons showed distinct N1 segment immunolabeling, which was not found in other types of striatal neurons. Our results suggest that all striatal neurons studied synthesize NR1 subunit proteins, but the isoforms of the protein present in projection neurons and the several types of interneurons are distinct. This differential expression of NR1 isoforms may affect both neuronal function and selective vulnerability of neurons to injury. (C) 1999 Wiley-Liss, Inc. C1 Massachusetts Gen Hosp, Neurol Serv, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Univ Freiburg, Dept Neurol, D-79106 Freiburg, Germany. NIDR, Pain & Neurosensory Mechanisms Branch, Bethesda, MD 20892 USA. RP Standaert, DG (reprint author), Massachusetts Gen Hosp, Neurol Serv, Dept Neurol, Warren 408,Fruit St, Boston, MA 02114 USA. OI Standaert, David/0000-0003-2921-8348 FU NINDS NIH HHS [NS31579, NS34361] NR 122 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 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD DEC 13 PY 1999 VL 415 IS 2 BP 204 EP 217 PG 14 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 252TP UT WOS:000083518600005 PM 10545160 ER PT J AU Ashcroft, M Vousden, KH AF Ashcroft, M Vousden, KH TI Regulation of p53 stability SO ONCOGENE LA English DT Review DE p53; Mdm2; protein stability ID TUMOR-SUPPRESSOR P53; DNA-DAMAGE; ONCOPROTEIN MDM2; EMBRYONIC LETHALITY; MDM2-DEFICIENT MICE; IONIZING-RADIATION; PROTEIN STABILITY; ACTIVATES P53; FEEDBACK LOOP; HUMAN CANCER AB Leading the way in imposing a policy of zero tolerance of cellular abnormalities that might lead to tumor development is the p53 protein. The efficiency of p53 in preventing cell growth is a strong deterrent to malignant progression, but this activity must be kept tightly restrained to allow normal cell growth and development. Essential components of this regulation are the mechanisms by which the p53 protein is degraded, and efficient turnover of p53 in normal cells prevents the accumulation of the protein. Modulation of these degradation pathways in response to stress leads to the rapid stabilization and accumulation of p53, and activation of the p53 response. It is now becoming clear that the Mdm2 protein is central to the regulation of p53 stability and multiple pathways exist through which the activity of Mdm2 can be inhibited. Defects in the ability to stabilize p53 are likely to contribute to malignant development, and restoration of this activity represents an extremely attractive possibility for tumor therapy. C1 NCI FCRDC, ABL Basic Res Program, Frederick, MD 21702 USA. RP Vousden, KH (reprint author), NCI FCRDC, ABL Basic Res Program, Bldg 560,Room 22-96,W 7th St, Frederick, MD 21702 USA. NR 92 TC 305 Z9 313 U1 6 U2 16 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD DEC 13 PY 1999 VL 18 IS 53 BP 7637 EP 7643 DI 10.1038/sj.onc.1203012 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 272DD UT WOS:000084634500002 PM 10618703 ER PT J AU Luo, YQ Kokkonen, GC Hattori, A Chrest, FJ Roth, GS AF Luo, YQ Kokkonen, GC Hattori, A Chrest, FJ Roth, GS TI Dopamine stimulates redox-tyrosine kinase signaling and p38 MAPK in activation of astrocytic C6-D2L cells SO BRAIN RESEARCH LA English DT Article DE D2 receptor; glial fibrillary acidic protein; p38 MAPK; signal transduction; mitogenesis; astrocyte; C6 glioma cell; reactive oxygen species ID FIBRILLARY ACIDIC PROTEIN; RECEPTOR MESSENGER-RNA; RAT STRIATUM; INTRASTRIATAL INJECTION; CULTURED ASTROCYTES; FOREBRAIN ISCHEMIA; SUBSTANTIA-NIGRA; DNA-SYNTHESIS; BRAIN INJURY; GLIOMA-CELLS AB An increase in dopamine (DA) availability in rat brain has been suggested to participate in certain neurodegenerative processes. However, the regulatory effects of DA on glial cells have not been extensively studied. Using a rat C6 glioma cell line stably expressing recombinant D2L receptors, we have found that micromolar levels of DA stimulate mitogenesis and glial fibrillary acidic protein (GFAP) expression, both serving as parameters of reactive gliosis. This mitogenesis occurs about 29 h after exposure to DA and requires D2-receptor-mediated intracellular redox-tyrosine kinase activation. Either DA or quinpirole, a D2 receptor agonist, stimulates protein tyrosine phosphorylation. Application of either DPI, a potent inhibitor of NADPH-dependent oxidase, or NAG, an anti-oxidant, effectively prevented DA-induced tyrosine phosphorylation and DNA synthesis. Preincubation of (+)-butaclamol, a D2 receptor antagonist, inhibits both DA-stimulated tyrosine phosphorylation and mitogenesis. DA at micromolar levels also stimulates GFAP expression. This DA-regulated GFAP expression can be completely inhibited by SB203580, a selective p38 MAPK inhibitor, but not influenced by (+)-butaclamol and genistein, a protein tyrosine kinase inhibitor. Thus, our data suggest that regulation of DNA synthesis and GFAP expression induced by DA is mediated by independent signaling pathways. The mitogenesis requires a D2-receptor-mediated protein tyrosine kinase cascade, while GFAP expression needs a D2-receptor-independent p38 MAPK activation. This observation may help to understand the processes of reactive gliosis in some dopaminergic-related neurodegenerative diseases. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIA, Gerontol Res Ctr, Mol Physiol & Genet Sect, Baltimore, MD 21224 USA. NIA, Gerontol Res Ctr, Flow Cytometry Lab, Baltimore, MD 21224 USA. RP Luo, YQ (reprint author), NIA, Gerontol Res Ctr, Mol Physiol & Genet Sect, 4C01,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 51 TC 12 Z9 13 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD DEC 11 PY 1999 VL 850 IS 1-2 BP 21 EP 38 DI 10.1016/S0006-8993(99)02021-1 PG 18 WC Neurosciences SC Neurosciences & Neurology GA 265CD UT WOS:000084222800003 PM 10629745 ER PT J AU Makino, S Shibasaki, T Yamauchi, N Nishioka, T Mimoto, T Wakabayashi, I Gold, PW Hashimoto, K AF Makino, S Shibasaki, T Yamauchi, N Nishioka, T Mimoto, T Wakabayashi, I Gold, PW Hashimoto, K TI Psychological stress increased corticotropin-releasing hormone mRNA and content in the central nucleus of the amygdala but not in the hypothalamic paraventricular nucleus in the rat SO BRAIN RESEARCH LA English DT Article DE corticotropin-releasing hormone; amygdala; bed nucleus of the stria terminalis; paraventricular nucleus; psychological stress ID FACTOR-LIKE IMMUNOREACTIVITY; MESSENGER-RIBONUCLEIC-ACID; BIOCHEMICAL MANIFESTATIONS; DIFFERENTIAL REGULATION; BEHAVIORAL-RESPONSES; RESTRAINT STRESS; FACTOR RECEPTORS; LOCUS-COERULEUS; RNA LEVELS; BRAIN AB The central administration of corticotropin-releasing hormone (CRH) to experimental animals sets into motion a coordinated series of physiological and behavioral events that promote survival during threatening situation. A large body of evidence suggest that CRH in the central nucleus of the amygdala (CEA) induces fear-related behaviors and is essential to fear conditioning; however, evidence of CRH-mediated activation of the amygdala under physiological situation is Still limited. We report here a study of the impact of a psychological stressor on hypothalamic and amygdala CRH systems in the rat. Non-footshocked rats placed in a floored compartment surrounded by footshocked rats were defined as the psychological stress group. Rats were exposed to psychological stress for 15 min, and then sacrificed 1.5 and 3 h after cessation of stress. We found, that our psychological stressor induced an increase in both CRH mRNA levels, as assessed by in situ hybridization histochemistry, and CRH content, as assessed by micropunch RIA, in the CEA. Exposure to the psychological stressor also caused a significant increase in CRH mRNA levels with a trend for an increase in CRH content in the dorsolateral subdivision of the bed nucleus of the shia terminalis (BNST) which is anatomically associated with the CEA. In contrast, psychological stress induced a small, but significant increase in type-1 CRH receptor (CRHR-1) mRNA in the hypothalamic paraventricular nucleus (PVN), while it failed to elevate either PVN CRH mRNA levels or content, CRH content in the median eminence (ME), or levels of plasma ACTH or corticosterone (CORT), Thus, in the context of a psychological stressor, the activation of the amygdala CRH system can occur without robust activation of the hypothalamic CRH system. In the light of previous data that the psychological stress-induced loss of sleep was reversed by the central administration of a CRH antagonist, these data suggest that CRH in the CEA may contribute to the psychological stress-evoked fear-related behavior such as hyperarousal. These data also indicate that in response to a psychological stressor, the amygdala CRH system is much more sensitive than is the CRH system emanating from the PVN. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Kochi Med Sch, Dept Internal Med 2, Nankoku, Kochi 783, Japan. Nippon Med Sch, Dept Physiol, Bunkyo Ku, Tokyo 113, Japan. Nippon Med Sch, Dept Med, Bunkyo Ku, Tokyo 113, Japan. NIMH, Clin Neuroendocrinol Branch, Bethesda, MD 20892 USA. RP Makino, S (reprint author), Kochi Med Sch, Dept Internal Med 2, Okoh Cho, Nankoku, Kochi 783, Japan. NR 46 TC 118 Z9 121 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD DEC 11 PY 1999 VL 850 IS 1-2 BP 136 EP 143 DI 10.1016/S0006-8993(99)02114-9 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 265CD UT WOS:000084222800015 PM 10629757 ER PT J AU Fauci, AS AF Fauci, AS TI Host factors in the pathogenesis of HIV disease SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract C1 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 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD DEC 10 PY 1999 VL 15 IS 18 BP 1598 EP 1599 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 263VV UT WOS:000084146700002 ER PT J AU Margolis, L AF Margolis, L TI Cytopathicity of R5 and X4 HIV-1 isolates in human lymphoid tissue (ex vivo) SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract C1 NICHD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD DEC 10 PY 1999 VL 15 IS 18 BP 1614 EP 1614 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 263VV UT WOS:000084146700029 ER PT J AU Powderly, WG Gallant, JE Ghannoum, MA Mayer, KH Navarro, EE Perfect, JR AF Powderly, WG Gallant, JE Ghannoum, MA Mayer, KH Navarro, EE Perfect, JR TI Oropharyngeal candidiasis in patients with HIV: Suggested guidelines for therapy SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID RESISTANT CANDIDIASIS; INFECTED PATIENTS; ORAL CANDIDIASIS; FLUCONAZOLE; EMERGENCE AB The high frequency of oropharyngeal candidiasis in immunocompromised patients has led many institutions to develop protocols to guide the use of antifungal agents in the treatment of this opportunistic infection. However, few specific recommendations have been made for directing the management of oropharyngeal candidiasis in patients infected with HIV, To meet this need, a panel of experts representing a variety of disciplines met to formulate a consensus and devise a treatment strategy for clinical application. Among other recommendations, the algorithm calls for use of a topical agent for the treatment of initial and recurring oropharyngeal candidiasis in HIV-infected patients, provided there is no esophageal involvement, patients' CD4(+) lymphocyte cell count is >50 cells/mm(3), and they are currently receiving or expected to receive effective antiretroviral treatment. For episodes of oropharyngeal candidiasis with concurrent esophageal involvement or where patients have a CD4(+) cell count of <50 cells/mm(3), are not receiving or anticipating highly active antiretroviral therapy (HAART), and have a high viral load, the algorithm suggests a systemic oral azole as the more appropriate treatment choice. Acute treatment of all oropharyngeal candidiasis episodes is preferred. Chronic suppressive antifungal treatment is to be avoided in recognition of the potential for the development of drug-resistant infection. C1 Washington Univ, Sch Med, Div Infect Dis, St Louis, MO 63110 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. Case Western Reserve Univ, Univ Hosp Cleveland, Cleveland, OH 44106 USA. Mem Hosp Rhode Isl, Providence, RI 02912 USA. NCI, NIH, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Durham, NC 27710 USA. RP Powderly, WG (reprint author), Washington Univ, Sch Med, Div Infect Dis, Campus Box 8051,660 S Euclid, St Louis, MO 63110 USA. NR 17 TC 28 Z9 29 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD DEC 10 PY 1999 VL 15 IS 18 BP 1619 EP 1623 DI 10.1089/088922299309658 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 263VV UT WOS:000084146700034 PM 10606084 ER PT J AU Zaal, KJM Smith, CL Polishchuk, RS Altan, N Cole, NB Ellenberg, J Hirschberg, K Presley, JF Roberts, TH Siggia, E Phair, RD Lippincott-Schwartz, J AF Zaal, KJM Smith, CL Polishchuk, RS Altan, N Cole, NB Ellenberg, J Hirschberg, K Presley, JF Roberts, TH Siggia, E Phair, RD Lippincott-Schwartz, J TI Golgi membranes are absorbed into and reemerge from the ER during mitosis SO CELL LA English DT Article ID ENDOPLASMIC-RETICULUM; RETROGRADE TRANSPORT; LIVING CELLS; BREFELDIN-A; HELA-CELLS; MATRIX PROTEIN; APPARATUS; FRAGMENTATION; DYNAMICS; COMPLEX AB Quantitative imaging and photobleaching were used to measure ER/Golgi recycling of GFP-tagged Golgi proteins in interphase cells and to monitor the dissolution and reformation of the Golgi during mitosis. In interphase, recycling occurred every 1.5 hr, and blocking ER egress trapped cycling Golgi enzymes in the ER with loss of Golgi structure. In mitosis, when ER export stops, Golgi proteins redistributed into the ER as shown by quantitative imaging in vivo and immuno-EM. Comparison of the mobilities of Golgi proteins and lipids ruled out the persistence of a separate mitotic Golgi vesicle population and supported the idea that all Golgi components are absorbed into the ER. Moreover, reassembly of the Golgi complex after mitosis failed to occur when ER export was blocked. These results demonstrate that in mitosis the Golgi disperses and reforms through the intermediary of the ER, exploiting constitutive recycling pathways. They thus define a novel paradigm for Golgi genesis and inheritance. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. Rockefeller Univ, Ctr Studies Phys & Biol, New York, NY 10021 USA. BioInformat Serv, Rockville, MD 20854 USA. NINCDS, Light Imaging Facil, NIH, Bethesda, MD 20892 USA. Ist Ric Farmacol Mario Negri, Consorzio Mario Negri Sud, Mol Neurobiol Lab, I-66030 Santa Maria Imbaro, Italy. RP Lippincott-Schwartz, J (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RI Ward, Theresa/E-9650-2013; Ellenberg, Jan/I-4688-2014 OI Ward, Theresa/0000-0002-9881-8649; Ellenberg, Jan/0000-0001-5909-701X FU NIGMS NIH HHS [R01 GM59018-01] NR 48 TC 239 Z9 247 U1 0 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 DEC 10 PY 1999 VL 99 IS 6 BP 589 EP 601 DI 10.1016/S0092-8674(00)81548-2 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 266AP UT WOS:000084278700006 PM 10612395 ER PT J AU Gow, A Southwood, CM Li, JS Pariali, M Riordan, GP Brodie, SE Danias, J Bronstein, JM Kachar, B Lazzarini, RA AF Gow, A Southwood, CM Li, JS Pariali, M Riordan, GP Brodie, SE Danias, J Bronstein, JM Kachar, B Lazzarini, RA TI CNS myelin and Sertoli cell tight junction strands are absent in Osp/Claudin-11 null mice SO CELL LA English DT Article ID OLIGODENDROCYTE-SPECIFIC PROTEIN; ZONULA OCCLUDENS; NERVOUS-SYSTEM; EXPRESSION; GENE; BARRIER; TESTIS; PERMEABILITY; ARCHITECTURE; MUTATION AB Oligodendrocyte-specific protein (OSP)/claudin-11 is a recently identified transmembrane protein found in CNS myelin and testis with unknown function. Herein we demonstrate that Osp null mice exhibit both neurological and reproductive deficits: CNS nerve conduction is slowed, hindlimb weakness is conspicuous, and males are sterile. Freeze fracture reveals that tight junction intramembranous strands are absent in CNS myelin and between Sertoli cells of mutant mice. Our results demonstrate that OSP is the mediator of parallel-array tight junction strands and distinguishes this protein from other intrinsic membrane proteins in tight junctions. These novel results provide direct evidence of the pivotal role of the claudin family in generating the paracellular physical barrier of tight junctions necessary for spermatogenesis and normal CNS function. C1 CUNY, Mt Sinai Med Ctr, Brookdale Ctr Dev & Mol Biol, New York, NY 10029 USA. CUNY, Mt Sinai Med Ctr, Dept Ophthalmol, New York, NY 10029 USA. NICHHD, Sect Struct Cell Biol, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. RP Lazzarini, RA (reprint author), CUNY, Mt Sinai Med Ctr, Brookdale Ctr Dev & Mol Biol, 1 Gustave L Levy Pl, New York, NY 10029 USA. FU NEI NIH HHS [1K08 EY 00390-01A1]; NINDS NIH HHS [NS01596, NS33165] NR 47 TC 441 Z9 449 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 DEC 10 PY 1999 VL 99 IS 6 BP 649 EP 659 DI 10.1016/S0092-8674(00)81553-6 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 266AP UT WOS:000084278700011 PM 10612400 ER PT J AU Kudryashov, DS Chibalina, MV Birukov, KG Lukas, TJ Sellers, JR Van Eldik, LJ Watterson, DM Shirinsky, VP AF Kudryashov, DS Chibalina, MV Birukov, KG Lukas, TJ Sellers, JR Van Eldik, LJ Watterson, DM Shirinsky, VP TI Unique sequence of a high molecular weight myosin light chain kinase is involved in interaction with actin cytoskeleton SO FEBS LETTERS LA English DT Article DE myosin light chain kinase; calmodulin; cytoskeleton; microfilament ID SMOOTH-MUSCLE MYOSIN; BINDING; PROTEIN; PURIFICATION; FILAMENTS; COMPLEX; ATP AB Myosin light chain kinase (MLCK) is the key regulator of cell motility and smooth muscle contraction in higher vertebrates, We searched for the features of the high molecular weight MLCK (MLCK-210) associated with its unique N-terminal sequence not found in a more ubiquitous lower molecular weight MLCK (MLCK-108). MLCK-210 demonstrates stronger association with the Triton-insoluble cytoskeletons than MLCK-108, suggesting the role for this sequence in subcellular targeting. Indeed, the expressed unique domain of MLCK-210 binds and bundles F-actin in vitro and colocalises with the microfilaments in transfected cells reproducing endogenous MLCK-210 distribution. Thus, MLCK-210 features an extensive actin binding interface and, perhaps, acts as an actin cytoskeleton stabiliser. (C) 1999 Federation of European Biochemical Societies. C1 Russian Cardiol Res Ctr, Inst Expt Cardiol, Lab Cell Motil, Moscow 121552, Russia. Northwestern Univ, Dept Mol Pharmacol & Biol Chem, Chicago, IL 60611 USA. Northwestern Univ, Dept Cell & Mol Biol, Chicago, IL 60611 USA. Northwestern Univ, NW Drug Discovery Program, Chicago, IL 60611 USA. NHLBI, Mol Cardiol Lab, Bethesda, MD 20892 USA. RP Shirinsky, VP (reprint author), Russian Cardiol Res Ctr, Inst Expt Cardiol, Lab Cell Motil, 3rd Cherepkovskaya St 15A, Moscow 121552, Russia. RI Kudryashov, Dmitri/P-9004-2014; OI Watterson, Daniel/0000-0001-7605-5866 FU NCRR NIH HHS [RR13810]; NIGMS NIH HHS [GM30861] NR 22 TC 33 Z9 34 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD DEC 10 PY 1999 VL 463 IS 1-2 BP 67 EP 71 DI 10.1016/S0014-5793(99)01591-4 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 265HR UT WOS:000084237000016 PM 10601640 ER PT J AU Wang, F Van Brocklyn, JR Hobson, JP Movafagh, S Zukowska-Grojec, Z Milstien, S Spiegel, S AF Wang, F Van Brocklyn, JR Hobson, JP Movafagh, S Zukowska-Grojec, Z Milstien, S Spiegel, S TI Sphingosine 1-phosphate stimulates cell migration through a G(i)-coupled cell surface receptor - Potential involvement in angiogenesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTOR; MOUSE MELANOMA-CELLS; LYSOPHOSPHATIDIC-ACID; SIGNALING PATHWAYS; ENDOTHELIAL-CELLS; MOLECULAR-CLONING; GROWTH-FACTOR; TYROSINE PHOSPHORYLATION; KINASE PATHWAY; SPHINGOSINE-1-PHOSPHATE AB Sphingosine l-phosphate (SPP) has been shown to inhibit chemotaxis of a variety of cells, in some cases through intracellular actions, while in others through receptor-mediated effects. Surprisingly, we found that low concentrations of SPP (10-100 nm) increased chemotaxis of HEK293 cells overexpressing the G protein-coupled SPP receptor EDG-1. In agreement with previous findings in human breast cancer cells (Wang, F., Nohara, K., Olivera, O., Thompson, E. W., and Spiegel, S. (1999) Exp. Cell Res. 247, 17-28), SPP, at micromolar concentrations, inhibited chemotaxis of both vector- and EDG-1-overexpressing HEK293 cells. Nanomolar concentrations of SPP also induced a marked increase in chemotaxis of human umbilical vein endothelial cells (HUVEC) and bovine aortic endothelial cells (BAEC), which express the SPP receptors EDG-1 and EDG-3, while higher concentrations of SPP were less effective. Treatment with pertussis toxin, which ADP-ribosylates and inactivates G(i)-coupled receptors, blocked SPP-induced chemotaxis. Checkerboard analysis indicated that SPP stimulates both chemotaxis and chemokinesis. Taken together, these data suggest that SPP stimulates cell migration by binding to EDG-1. Similar to SPP, sph-inganine 1-phosphate (dihydro-SPP), which also binds to this family of SPP receptors, enhanced chemotaxis; whereas, another structurally related lysophospholipid, lysophosphatidic acid, did not compete with SPP for binding nor did it have significant effects on chemotaxis of endothelial cells. Furthermore, SPP increased proliferation of HUVEC and BAEC in a pertussis toxin-sensitive manner. SPP and dihydro-SPP also stimulated tube formation of BAEC grown on collagen gels (in vitro angiogenesis), and potentiated tube formation induced by basic fibroblast growth factor. Pertussis toxin treatment blocked SPP-, but not bFGF-stimulated in vitro angiogenesis. Our results suggest that SPP may play a role in angiogenesis through binding to endothelial cell Gi-coupled SPP receptors. C1 Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Dept Physiol & Biophys, Washington, DC 20007 USA. NIMH, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, 353 Basic Sci Bldg,3900 Reservoir Rd NW, Washington, DC 20007 USA. RI Van Brocklyn, Jim/A-9733-2010 FU NCI NIH HHS [1P30-CA-51008, CA61774]; NIGMS NIH HHS [F32GM19209] NR 80 TC 300 Z9 305 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 10 PY 1999 VL 274 IS 50 BP 35343 EP 35350 DI 10.1074/jbc.274.50.35343 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 264NG UT WOS:000084187900013 PM 10585401 ER PT J AU Yang, XN Safrany, ST Shears, SB AF Yang, XN Safrany, ST Shears, SB TI Site-directed mutagenesis of diphosphoinositol polyphosphate phosphohydrolase, a dual specificity NUDT enzyme that attacks diadenosine polyphosphates and diphosphoinositol polyphosphates SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MYO-INOSITOL PHOSPHATES; AMINO-ACID-SEQUENCE; COLI MUTT ENZYME; ATP-BINDING; IN-VITRO; P-LOOP; TETRAKISPHOSPHATE; PROTEIN; DICTYOSTELIUM; KINASE AB Diphosphoinositol polyphosphate phosphohydrolase (DIPP) hydrolyzes diadenosine 5',5"-P-1,P-6-hexaphosphate (Ap(6)A), a Nudix (nucleoside diphosphate attached-moiety "x") substrate, and two non-Nudix compounds: diphosphoinositol pentakisphosphate (PP-InsP(5),) and bis-diphosphoinositol tetrakisphosphate (PP)(2)-InsP(4)), Guided by multiple sequence alignments, we used site-directed mutagenesis to obtain new information concerning catalytically essential amino acid residues in DIPP, Mutagenesis of either of two conserved glutamate residues (Glu(66) and Glu(70)) within the Nudt (Nudix-type) catalytic motif impaired hydrolysis of Ap(6)A, PP-InsP(5), and (PP)(2)-InsP(4) >95%; thus, all three substrates are hydrolyzed at the same active site, Two Gly-rich domains (glycine-rich regions 1 and 2 (GR1 and GR2) flank the Nudt motif with potential sites for cation coordination and substrate binding. GR1 comprises a GGG tripeptide, while GR2 is identified as a new functional motif (GX(2)GX(6)G) that is conserved in yeast homologues of DIPP. Mutagenesis of any of these Gly residues in GR1 and GR2 reduced catalytic activity toward all three substrates by up to 95%. More distal to the Nudt motif, H91L and F84Y mutations substantially decreased the rate of Ap(6)A and (PP)(2)-InsP(4) metabolism (by 71 and 96%), yet PP-InsP(5) hydrolysis was only mildly reduced (by 30%); these results indicate substrate-specific roles for His(91) and phe(84), This new information helps define DIPP's structural, functional, and evolutionary relationships to Nudix hydrolases. C1 NIEHS, Inositide Signaling Grp, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Yang, XN (reprint author), NIEHS, Inositide Signaling Grp, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 44 TC 31 Z9 33 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 10 PY 1999 VL 274 IS 50 BP 35434 EP 35440 DI 10.1074/jbc.274.50.35434 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 264NG UT WOS:000084187900025 PM 10585413 ER PT J AU Tomic, M Koshimizu, TA Yuan, D Andric, SA Zivadinovic, D Stojilkovic, SS AF Tomic, M Koshimizu, TA Yuan, D Andric, SA Zivadinovic, D Stojilkovic, SS TI Characterization of a plasma membrane calcium oscillator in rat pituitary somatotrophs SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INTRACELLULAR CA2+ CONCENTRATION; NUCLEOTIDE-ACTIVATED CHANNEL; HORMONE-RELEASING HORMONE; ANTERIOR-PITUITARY; ACTION-POTENTIALS; CONCENTRATION I; SYMPATHETIC NEURONS; PROLACTIN SECRETION; RYANODINE RECEPTORS; PACEMAKER ACTIVITY AB In excitable cells, oscillations in intracellular free calcium concentrations ([Ca2+](i)) can arise from action-potential-driven Ca2+ influx, and such signals can have either a localized or global form, depending on the coupling of voltage-gated Ca2+ influx to intracellular Ca2+ release pathway. Here we show that rat pituitary somatotrophs generate spontaneous [Ca2+](i) oscillations, which rise from fluctuations in the influx of external Ca2+ and propagate within the cytoplasm and nucleus. The addition of caffeine and ryanodine, modulators of ryanodine-receptor channels, and the depletion of intracellular Ca2+ stores by thapsigargin and ionomycin did not affect the global nature of spontaneous [Ca2+](i) signals. Bay K 8644, an L-type Ca2+ channel agonist, initiated [Ca2+](i) signaling in quiescent cells, increased the amplitude of [Ca2+](i) spikes in spontaneously active cells, and stimulated growth hormone secretion in perifused pituitary cells. Nifedipine, a blocker of L-type Ca2+ channels, decreased the amplitude of spikes and basal growth hormone secretion, whereas Ni2+, a blocker of T-type Ca2+ channels, abolished spontaneous [Ca2+](i) oscillations, Spiking was also abolished by the removal of extracellular Na+ and by the addition of 10 mM Ca2+, Mg2+, or Sr2+, the blockers of cyclic nucleotide-gated channels. Reverse transcriptase-polymerase chain reaction and Southern blot analyses indicated the expression of mRNAs for these channels in mixed pituitary cells and purified somatotrophs, Growth hormone-releasing hormone, an agonist that stimulated cAMP and cGMP productions in a dose-dependent manner, initiated spiking in quiescent cells and increased the frequency of spiking in spontaneously active cells, These results indicate that in somatotrophs a cyclic nucleotide-controlled plasma membrane Ca2+ oscillator is capable of generating global Ca2+ signals spontaneously and in response to agonist stimulation. The Ca2+-signaling activity of this oscillator is dependent on voltage-gated Ca2+ influx but not on Ca2+ release from intracellular stores. C1 NICHD, Endocrinol & Reprod Res Branch, Sect Cellular Signaling, Bethesda, MD 20892 USA. RP Stojilkovic, SS (reprint author), NICHD, Endocrinol & Reprod Res Branch, Sect Cellular Signaling, Bldg 49,Room 6A-36,49 Convent Dr, Bethesda, MD 20892 USA. RI Tomic, Melanija/C-3371-2016; OI Koshimizu, Taka-aki/0000-0001-5292-7535 NR 51 TC 37 Z9 37 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 DEC 10 PY 1999 VL 274 IS 50 BP 35693 EP 35702 DI 10.1074/jbc.274.50.35693 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 264NG UT WOS:000084187900061 PM 10585449 ER PT J AU Chung, HO Yang, Q Catt, KJ Arora, KK AF Chung, HO Yang, Q Catt, KJ Arora, KK TI Expression and function of the gonadotropin-releasing hormone receptor are dependent on a conserved apolar amino acid in the third intracellular loop SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; SIGNAL-TRANSDUCTION PATHWAYS; AT(1) ANGIOTENSIN RECEPTOR; 3RD CYTOPLASMIC LOOP; LIGAND-BINDING; MOLECULAR-BASIS; ACTIVATION; INTERNALIZATION; MUTAGENESIS; DOMAINS AB The coupling of agonist-activated heptahelical receptors to; their cognate G proteins is often dependent on the amino-terminal region of the third intracellular loop. Like many G protein coupled receptors, the gonadotropin-releasing hormone (GnRH) receptor contains an apolar amino acid in this region at a constant distance fi om conserved Pro and Tyr/Asn residues in the fifth transmembrane domain (TM V). An analysis of the role of this conserved residue (Leu(237)) in GnRH receptor function revealed that the binding affinities of the L237I and L237V mutant receptors were unchanged, but their abilities to mediate GnRH-induced inositol phosphate signaling, G; protein coupling, and agonist-induced internalization were significantly impaired. Receptor expression at the cell surface was reduced by replacement of LeU(237) With Val, and abolished by replacement with Ala, Arg, or Asp residues, These results are consistent with molecular modeling of the TM V and VI regions of the GnRH receptor, which predicts that LeU(237) is caged by several apolar amino acids (Ile(233), Ile(234), and Val(240) in TM V, and LeU(262), LeU(265), and Val(269) in TM VI) to form a tight hydrophobic cluster. These findings indicate that the conserved apolar residue (LeU(237)) in the third intracellular loop is an important determinant of GnRH receptor expression and activation, and possibly that of other G protein-coupled receptors. C1 NICHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Arora, KK (reprint author), NICHD, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Rm 6A36, Bethesda, MD 20892 USA. NR 50 TC 15 Z9 16 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 DEC 10 PY 1999 VL 274 IS 50 BP 35756 EP 35762 DI 10.1074/jbc.274.50.35756 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 264NG UT WOS:000084187900069 PM 10585457 ER PT J AU Tomasevic, N Peculis, B AF Tomasevic, N Peculis, B TI Identification of a U8 snoRNA-specific binding protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SMALL NUCLEOLAR RNAS; RIBOSOMAL-RNA; PSEUDOURIDINE SYNTHASE; YEAST; FIBRILLARIN; ELEMENTS; SEQUENCE; CBF5P; COMPLEX; U3 AB Eukaryotic nucleoli contain a large and diverse population of small nucleolar ribonucleoprotein particles (snoRNPs) that play diverse and essential roles in ribosome biogenesis. We previously demonstrated that U8 snoRNP is essential for processing of both 5.8 and 28 S rRNA. The RNA component of the U8 RNP particle is necessary but not sufficient for processing. Using an electrophoretic mobility sift assay, we enriched for U8-specific binding proteins from Xenopus ovary extracts. UV cross-linking reactions with partially purified fractions implicated a 29-kDa protein directly binding to U8 RNA. This protein interacted specifically and with high affinity with U8 snoRNA; it did not bind other snoRNAs and is probably not a common component of all snoRNPs. This is the first report of a protein component specific to an snoRNP essential for processing of the large ribosomal subunit in vertebrates. C1 NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Peculis, B (reprint author), NIDDK, Genet & Biochem Branch, NIH, 10 Ctr Dr 10-8N322, Bethesda, MD 20892 USA. NR 34 TC 22 Z9 23 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 10 PY 1999 VL 274 IS 50 BP 35914 EP 35920 DI 10.1074/jbc.274.50.35914 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 264NG UT WOS:000084187900089 PM 10585477 ER PT J AU Akamatsu, M Aota, S Suwa, A Ueda, K Amachi, T Yamada, KM Akiyama, SK Kioka, N AF Akamatsu, M Aota, S Suwa, A Ueda, K Amachi, T Yamada, KM Akiyama, SK Kioka, N TI Vinexin forms a signaling complex with Sos and modulates epidermal growth factor-induced c-Jun N-terminal kinase/stress-activated protein kinase activities SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RECEPTOR TYROSINE KINASES; GUANINE-NUCLEOTIDE EXCHANGE; PDGF-BETA-RECEPTORS; INSULIN-RECEPTOR; SH3 DOMAIN; CELL-ADHESION; STRESS FIBERS; EGF RECEPTOR; FACTOR HSOS1; RAS AB Vinexin, a novel protein that plays a hey role in cell spreading and cytoskeletal organization, contains three SH3 domains and binds to vinculin through its first and second SH3 domains. We show here that the third SH3 domain binds to Sos, a guanine nucleotide exchange factor for Pas and Pac, both in vitro and in vivo. Point mutations in the third SH3 domain abolished the vinexin-Sos interaction. Stimulation of NIH/3T3 cells with serum, epidermal growth factor (EGF), or platelet derived growth factor (PDGF) decreased the electro phoretic mobility of Sos and concomitantly inhibited formation of the vinexin-Sos complex. Phosphatase treatment of lysates restored the binding of Sos to vinexin, suggesting that signaling from serum, EGF, or PDGF regulates the vinexin-Sos complex through the Sos phosphorylation. To evaluate the function of vinexin downstream of growth factors, we examined the effects of wild-type and mutant vinexin expression on extracellular signal-regulated kinase (Erk) and c-Jun N-terminal kinase/stress activated protein kinase (JNK/SAPK) activation in response to EGF. Exogenous expression of vinexin beta in NIH/3T3 cells enhanced JNK/SAPK activation but did not affect Erk activation. Moreover mutations in the third SH3 domain abolished EGF activation of JNK/SAPK in a dominant-negative fashion, whereas they slightly stimulated Erk. Together these results suggest that vinexin can selectively modulate EGF-induced signal transduction pathways leading to JNK/SAPK kinase activation. C1 Kyoto Univ, Grad Sch Agr, Div Appl Life Sci, Sakyo Ku, Kyoto 6068502, Japan. Biomol Engn Res Inst, Suita, Osaka 565, Japan. NIDCR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Kioka, N (reprint author), Kyoto Univ, Grad Sch Agr, Div Appl Life Sci, Sakyo Ku, Kyoto 6068502, Japan. OI Yamada, Kenneth/0000-0003-1512-6805 NR 48 TC 37 Z9 38 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 10 PY 1999 VL 274 IS 50 BP 35933 EP 35937 DI 10.1074/jbc.274.50.35933 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 264NG UT WOS:000084187900092 PM 10585480 ER PT J AU Chowdhury, PS Pastan, I AF Chowdhury, PS Pastan, I TI Analysis of cloned Fvs from a phage display library indicates that DNA immunization can mimic antibody response generated by cell immunizations SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE antibodies; antigens/peptides/epitopes; cell surface molecules; molecular biology ID SURFACE-EPITOPE MASKING; MONOCLONAL-ANTIBODIES; OVARIAN CANCERS; SOLID TUMORS; MESOTHELIN; FRAGMENTS; IMMUNOTOXIN; CLONING; THERAPY AB Background: Generation and cloning of antibodies against cell surface antigens can be simplified by combining DNA immunization which enables generation of antibodies against a protein in its natural configuration without the need for any protein purification step and antibody phage display which due to its immense screening power and physical coupling between the phenotype and genotype of antibodies simplifies the cloning of antibody genes. Objectives: Since DNA immunization is expected to elicit antibodies against a protein in its natural configuration, we wanted to see if it can mimic the antibody response generated by cell immunization. Study Design: A phage display library made from splenic mRNA of a mouse immunized with mesothelin cDNA was panned on mesothelin-positive cells. The single-chain Fvs (scFvs) selected were then analyzed. Results: We obtained several anti-mesothelin scFvs. One of these Fvs is almost identical to the Fv of a monoclonal antibody that was previously obtained from a hybridoma in which the mice were immunized with a mesothelin-positive ovarian cancer cell line. Another Fv was found to be specific for mesothelin present on human cells. Conclusion: Our results indicate that an antibody phage display library made from spleens of DNA-immunized mice is a rapid and efficient alternative to cell immunization for obtaining antibodies against different epitopes of a membrane antigen that is very difficult to purify in a native form. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NCI, NIH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, NIH, Mol Biol Lab, Bldg 37,Room 4B20,37 Convent Rd,MSC-4255, Bethesda, MD 20892 USA. NR 26 TC 10 Z9 11 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 DEC 10 PY 1999 VL 231 IS 1-2 BP 83 EP 91 DI 10.1016/S0022-1759(99)00142-8 PG 9 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 290JU UT WOS:000085673800008 PM 10648929 ER PT J AU Newton, DL Pollock, D DiTullio, P Echelard, Y Harvey, M Wilburn, B Williams, J Hoogenboom, HR Raus, JCM Meade, HM Rybak, SM AF Newton, DL Pollock, D DiTullio, P Echelard, Y Harvey, M Wilburn, B Williams, J Hoogenboom, HR Raus, JCM Meade, HM Rybak, SM TI Antitransferrin receptor antibody-RNase fusion protein expressed in the mammary gland of transgenic mice SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE transgenic mice; ribonuclease; immunotoxin; antitransferrin receptor antibody ID HUMAN ANGIOGENIN; NEUTRALIZING ANTIBODIES; TRANSFERRIN RECEPTOR; PRODRUG ACTIVATION; BETA-LACTAMASE; BREAST-CANCER; CELL-LINES; MILK; RIBONUCLEASE; IMMUNOTOXINS AB Antibodies fused to human enzymes offer an alternative to specifically targeting tumors with antibodies linked to plant or bacterial toxins. Since large amounts of these reagents can be administered without eliciting non-specific toxicities, efficient methods of production are needed. The goal of this work was to express a complex immunoenzyme fusion protein (immunotoxin) in the mammary gland of transgenic mice. A chimeric mouse/human antibody directed against the human transferrin receptor (E6) was fused at its CH2 domain to the gene for a human angiogenic ribonuclease, angiogenin (Ang). It was expressed in the mammary gland of mice and secreted into mouse milk. Expression levels in milk were approximately 0.8 g/l. The chimeric protein retained antibody binding activity and protein synthesis inhibitory activity equivalent to that of free Ang. It was specifically cytotoxic to human tumor cells in vitro. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NCI, Pharmacol Expt Therapeut Sect, Lab Drug Discovery Res & Dev,Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Canc Res & De, Frederick, MD 21702 USA. NCI, Intramural Res Support Program, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Genzyme Transgen, Framingham, MA 01701 USA. Maastricht Univ, Dept Pathol, CESAME, NL-6202 AZ Maastricht, Netherlands. DL Willems Inst, B-3590 Diepenbeek, Belgium. RP Rybak, SM (reprint author), NCI, Pharmacol Expt Therapeut Sect, Lab Drug Discovery Res & Dev,Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Canc Res & De, Bldg 567,Room 152, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 42 TC 22 Z9 25 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 DEC 10 PY 1999 VL 231 IS 1-2 BP 159 EP 167 DI 10.1016/S0022-1759(99)00154-4 PG 9 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 290JU UT WOS:000085673800014 PM 10648935 ER PT J AU Takeuchi, S Imafuku, I Waragai, M Roth, C Kanazawa, I Buettner, R Mouradian, MM Okazawa, H AF Takeuchi, S Imafuku, I Waragai, M Roth, C Kanazawa, I Buettner, R Mouradian, MM Okazawa, H TI AP-2 beta represses D-1A dopamine receptor gene transcription in Neuro2a cells SO MOLECULAR BRAIN RESEARCH LA English DT Article DE AP-2 beta; D-1A dopamine receptor; gene regulation; silencer; repressor; differentiation ID RETINOIC ACID; ENHANCER; IDENTIFICATION; EXPRESSION; CLONING; AP-2; DIFFERENTIATION; AP-2-ALPHA; PROTEIN; FAMILY AB Expression of the D-1A dopamine receptor in brain is restricted to specific neuronal populations. To investigate the mechanism of this selective expression, we localized a silencer upstream of the human D-1A gene and identified its binding transcription factor in the D-1A-negative neural cell line Neuro2a. Using deletion CAT analysis, we narrowed this silencer to the region between nucleotides -561 and -532 relative to the CAP site. This 30-bp region, designated D1AS1, contains a sequence homologous to the AP-2 binding site and binds to a factor that also interacts with the AP-2 consensus sequence. In gel supershift assays, this factor is recognized by anti-AP-2 beta antibody. Co-transfection of Neuro2a cells with an AP-2 beta expression vector repressed the basal CAT activity of D-1A promoter-reporter plasmids in a D1AS1-dependent manner. RT-PCR analysis indicated that, among AP-2 family members, Neuro2a cells express only AP-2 beta. Furthermore, co-transfection of these cells with decoy oligonucleotides corresponding to the D1AS1 sequence de-repressed the D-1A gene promoter. Unlike in Neuro2a cells, AP-2 beta could not repress the D-1A promoter in the D-1A-positive neural cell line, NS20Y. in addition, the expression of AP-2 beta in different brain regions does not inversely correlate with that of D-1A dopamine receptor. These observations taken together indicate that AP-2 beta is a repressive transcription factor that acts on the D1AS1 silencer of the D-1A dopamine receptor gene via some cell-specific mechanism(s) in Neuro2a. (C) 1999 Elsevier Science B.V. All rights reserved. C1 Univ Tokyo, Grad Sch Med, Dept Neurol, Bunkyo Ku, Tokyo 113, Japan. Univ Regensburg, Sch Med, Inst Pathol, D-93042 Regensburg, Germany. NINDS, Genet Pharmacol Unit, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Okazawa, H (reprint author), Univ Tokyo, Grad Sch Med, Dept Neurol, Bunkyo Ku, 7-3-1 Hongo, Tokyo 113, Japan. OI Mouradian, M. Maral/0000-0002-9937-412X NR 24 TC 5 Z9 5 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 DEC 10 PY 1999 VL 74 IS 1-2 BP 208 EP 216 DI 10.1016/S0169-328X(99)00298-3 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 269WA UT WOS:000084499500022 ER PT J AU Dickson, DW Brown, P AF Dickson, DW Brown, P TI Multiple prion types in the same brain - Is a molecular diagnosis of CJD possible? SO NEUROLOGY LA English DT Editorial Material ID PHENOTYPIC VARIABILITY; DISEASE; PROTEIN; SCRAPIE C1 Mayo Clin Jacksonville, Dept Pathol, Jacksonville, FL 32224 USA. NINCDS, NIH, Cent Nervous Syst Studies Lab, Bethesda, MD USA. RP Dickson, DW (reprint author), Mayo Clin Jacksonville, Dept Pathol, 4500 San Pablo Rd,Birdsall 317, Jacksonville, FL 32224 USA. OI Dickson, Dennis W/0000-0001-7189-7917 NR 12 TC 11 Z9 11 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 DEC 10 PY 1999 VL 53 IS 9 BP 1903 EP 1904 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 265QR UT WOS:000084255300001 PM 10599755 ER PT J AU Smith, MJ Keel, JC Greenberg, BD Adams, LF Schmidt, PJ Rubinow, DA Wassermann, EM AF Smith, MJ Keel, JC Greenberg, BD Adams, LF Schmidt, PJ Rubinow, DA Wassermann, EM TI Menstrual cycle effects on cortical excitability SO NEUROLOGY LA English DT Article DE motor cortex; menstrual cycle; magnetic stimulation; paired stimulation; neurosteroids; gamma-aminobutyric acid receptors; progesterone ID TRANSCRANIAL MAGNETIC STIMULATION; HUMAN MOTOR CORTEX; INTRACORTICAL FACILITATION; GABA(A) RECEPTOR; PROGESTERONE; INHIBITION; EPILEPSY; ESTROGEN; WOMEN AB Objective: To determine whether there are menstrual cycle-related effects on cortical excitability in normal women. Background: Ovarian steroid hormones affect neurotransmission in the brain. Data from animal experiments have shown that progesterone metabolites enhance the action of gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the cortex, producing benzodiazepine-like (e.g., diazepam and lorazepam) physiologic and behavioral effects. Estradiol has excitatory effects on measures of neuronal excitability, possibly acting through the glutamate system. These effects have been difficult to detect in women using conventional techniques. However, recently, paired transcranial magnetic stimulation (TMS) has been used to detect the effects of GABAergic and glutamatergic drugs in humans. We used this method to measure the effects of the menstrual cycle in normal women. Methods: We tested 13 healthy women during the follicular (low-progesterone) and luteal (high-progesterone) phases of the menstrual cycle using paired TMS. The effect of a subthreshold conditioning pulse on the cortex was tested by measuring the response to a second suprathreshold test pulse and comparing it with the response elicited by the test pulse administered alone. Results: Conditioning TMS produced more inhibition in the luteal phase than in the follicular phase (p = 0.01), of similar magnitude to the reported effect of benzodiazepine drugs. Conclusions: This study provides the first direct evidence of changes in the excitability of a cortical network with the menstrual cycle. The results also show a potential confound for studies using transcranial magnetic stimulation in populations that include menstruating women. C1 NINDS, NIH, Bethesda, MD 20892 USA. NIMH, NIH, Bethesda, MD 20892 USA. RP Wassermann, EM (reprint author), NINDS, NIH, 10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. NR 24 TC 168 Z9 170 U1 3 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD DEC 10 PY 1999 VL 53 IS 9 BP 2069 EP 2072 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 265QR UT WOS:000084255300029 PM 10599783 ER PT J AU Lovblad, KO Thomas, R Jakob, PM Scammell, T Bassetti, C Griswold, M Ives, J Matheson, J Edelman, RR Warach, S AF Lovblad, KO Thomas, R Jakob, PM Scammell, T Bassetti, C Griswold, M Ives, J Matheson, J Edelman, RR Warach, S TI Silent functional magnetic resonance imaging demonstrates focal activation in rapid eye movement sleep SO NEUROLOGY LA English DT Article DE functional imaging; MRI; sleep; REM sleep ID POSITRON EMISSION TOMOGRAPHY; CEREBRAL GLUCOSE-UTILIZATION; BLOOD-FLOW; NEUROANATOMY; STAGE-2 AB Functional imaging of human sleep has been performed with nuclear medicine methods, but MRI has been difficult to implement, in part because of the noise associated with echo-planar imaging as well as the difficulty in reading physiologic signals in the MRI environment. We describe a silent MR sequence that can record brain activation over many hours with simultaneous acquisition of an EEG. This shows activation of occipital cortex and deactivation of frontal cortex during REM sleep, in agreement with previous studies using other techniques. C1 Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA USA. Univ Bern, Dept Neuroradiol, Bern, Switzerland. Univ Bern, Dept Neurol, Bern, Switzerland. NINDS, Sect Stroke Diagnost & Therapeut, Bethesda, MD 20892 USA. RP Lovblad, KO (reprint author), Univ Bern, Inselspital, Inst Diagnost Radiol, Dept Neuroradiol C212, Freiburgstr, CH-3010 Bern, Switzerland. EM loevk@insel.ch NR 10 TC 59 Z9 62 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD DEC 10 PY 1999 VL 53 IS 9 BP 2193 EP 2195 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 265QR UT WOS:000084255300053 PM 10599807 ER PT J AU Okada, Y Fukumizu, A Takahashi, M Yamazaki, J Yokoi, T Tsuda, Y Bryant, SD Lazarus, LH AF Okada, Y Fukumizu, A Takahashi, M Yamazaki, J Yokoi, T Tsuda, Y Bryant, SD Lazarus, LH TI Amino acids and peptides. LVI. Synthesis of pyrazinone ring-containing opioid mimetics and examination of their opioid receptor binding activity SO TETRAHEDRON LA English DT Article DE dipeptidyl chloromethyl ketone; cyclization; pyrazinone ring-containing amino acids; opioid mimetics ID CHLOROMETHYL KETONES; ANALOGS; DELTORPHIN; AGONIST; POTENT; DETERMINANTS; SELECTIVITY; DERIVATIVES; INHIBITION AB Cyclization of dipeptidyl chloromethyl ketones gave 6-(4-aminobutyl)-3-carboxyethyl-5-methyl-2(1H)-pyrazinone (3), 3-(4-aminobutyl)-6-carboxyethyl-5-methyl-2(1H)-pyrazinone (6), and 3,6-bis(4-aminobutyl)-5-methyl-2(1H)-pyrazinone (15), Using above pyrazinone derivatives, three opioid mimetics were prepared (III-V). Derivatives containing 3 and 6 demonstrated weak mu and delta-opioid receptor affinities ranging from 1.6 mM to 4.1 mM while the opioid mimetic containing derivative 15 displayed higher mu-opioid receptor binding affinity (K-i mu = 61 nM) and selectivity (K-i mu/K-i delta = 31). (C) 1999 Elsevier Science Ltd. All rights reserved. C1 Kobe Gakuin Univ, Fac Pharmaceut Sci, Nishi Ku, Kobe, Hyogo 6512180, Japan. NIEHS, LCBRA, Res Triangle Pk, NC 27709 USA. RP Okada, Y (reprint author), Kobe Gakuin Univ, Fac Pharmaceut Sci, Nishi Ku, Kobe, Hyogo 6512180, Japan. NR 22 TC 15 Z9 16 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4020 J9 TETRAHEDRON JI Tetrahedron PD DEC 10 PY 1999 VL 55 IS 50 BP 14391 EP 14406 DI 10.1016/S0040-4020(99)00908-4 PG 16 WC Chemistry, Organic SC Chemistry GA 261CR UT WOS:000083990700014 ER PT J AU Leitner, WW Ying, H Restifo, NP AF Leitner, WW Ying, H Restifo, NP TI DNA and RNA-based vaccines: principles, progress and prospects SO VACCINE LA English DT Review DE genetic vaccines; dendritic cells; replicase ID DIRECT GENE-TRANSFER; CYTOTOXIC T-LYMPHOCYTES; IMMUNODEFICIENCY-VIRUS TYPE-1; HEPATITIS-B SURFACE; COLONY-STIMULATING FACTOR; ANTIGEN-PRESENTING CELLS; RECOMBINANT ANTICANCER VACCINES; EPIDERMAL LANGERHANS CELLS; NUCLEIC-ACID VACCINES; IN-VIVO TRANSFECTION AB DNA vaccines were introduced less than a decade ago but have already been applied to a wide range of infectious and malignant diseases, Here we review the current understanding of the mechanisms underlying the activities of these new vaccines. We focus on recent strategies designed to enhance their function including the use of immunostimulatory (CpG) sequences, dendritic cells (DC), co-stimulatory molecules and cytokine- and chemokine-adjuvants. Although genetic vaccines have been significantly improved, they may not be sufficiently immunogenic for the therapeutic vaccination of patients with infectious diseases or cancer in clinical trials. One promising approach aimed at dramatically increasing the immunogenicity of genetic vaccines involves making them 'self-replicating'. This can be accomplished by using a gene encoding RNA replicase, a polyprotein derived from alphaviruses, such as Sindbis virus. Replicase-containing RNA vectors are significantly more immunogenic than conventional plasmids, immunizing mice at doses as low as 0.1 mu g of nucleic acid injected once intramuscularly. Cells transfected with 'self-replicating' vectors briefly produce large amounts of antigen before undergoing apoptotic death. This death is a likely result of requisite double-stranded (ds) RNA intermediates, which also have been shown to super-activate DC. Thus, the enhanced immunogenicity of 'self-replicating' genetic vaccines may be a result of the production of pro-inflammatory dsRNA, which mimics an RNA-virus infection of host cells. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 NCI, NIH, Bethesda, MD 20892 USA. RP Restifo, NP (reprint author), NCI, NIH, Bldg 10, Bethesda, MD 20892 USA. RI Restifo, Nicholas/A-5713-2008; Leitner, Wolfgang/F-5741-2011; OI Leitner, Wolfgang/0000-0003-3125-5922; Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 BC010763-01, Z99 CA999999] NR 142 TC 183 Z9 203 U1 1 U2 17 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 DEC 10 PY 1999 VL 18 IS 9-10 BP 765 EP 777 DI 10.1016/S0264-410X(99)00271-6 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 262RA UT WOS:000084079200001 PM 10580187 ER PT J AU Hu, WG Chen, J Collins, FM Gu, XX AF Hu, WG Chen, J Collins, FM Gu, XX TI An aerosol challenge mouse model for Moraxella catarrhalis SO VACCINE LA English DT Article DE aerosol challenge; animal model; M-catarrhalis ID OUTER-MEMBRANE PROTEIN; BRANHAMELLA-CATARRHALIS; PULMONARY CLEARANCE; OTITIS-MEDIA; IMMUNE-RESPONSE; ANIMAL-MODEL; IMMUNIZATION; PATHOGEN; VACCINE; CHINCHILLA AB A simple, reproducible, and non-invasive mouse pulmonary clearance model for Moraxella catarrhalis via aerosol challenge was established. All of eight tested strains could be inoculated into mice at more than 10(5) colony-forming units (CFU)/lung with a challenge concentration of 1 x 10(9)-6 x 10(9) CFU/ml in a nebulizer. The number of bacteria retained at 6 h postchallenge was more than 10(4) CFU/lung while at 24 h postchallenge, approximate 10(3) CFU/ml or less remained in the lungs. A maximum of 100 mice could be challenged per aerosol exposure. The number of bacteria inoculated in the lungs could be adjusted by the bacterial challenge concentration, the exposure time, and the negative pressure. Lung tissue sections revealed that bacteria were evenly distributed in the lungs. Passive immunization significantly enhanced pulmonary clearance of the homologous strain in this model. These data indicate that this model will be useful for evaluating M. catarrhalis vaccine candidates and studying roles of immunity against M, catarrhalis. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 Natl Inst Deafness & Commun Disorders, Immunol Lab, NIH, Rockville, MD 20850 USA. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Gu, XX (reprint author), Natl Inst Deafness & Commun Disorders, Immunol Lab, NIH, 5 Res Court, Rockville, MD 20850 USA. NR 23 TC 12 Z9 12 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 DEC 10 PY 1999 VL 18 IS 9-10 BP 799 EP 804 DI 10.1016/S0264-410X(99)00335-7 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 262RA UT WOS:000084079200007 PM 10580192 ER PT J AU Treanor, JJ Kotloff, K Betts, RF Belshe, R Newman, F Iacuzio, D Wittes, J Bryant, M AF Treanor, JJ Kotloff, K Betts, RF Belshe, R Newman, F Iacuzio, D Wittes, J Bryant, M TI Evaluation of trivalent, live, cold-adapted (CAIV-T) and inactivated (TIV) influenza vaccines in prevention of virus infection and illness following challenge of adults with wild-type influenza A (H1N1), A (H3N2), and B viruses SO VACCINE LA English DT Article DE influenza; vaccines; clinical studies ID A-VIRUS; YOUNG-CHILDREN; RECOMBINANT; EFFICACY; VOLUNTEERS; HUMANS; IMMUNOGENICITY; MONOVALENT; RESISTANCE; ANTIBODY AB Trivalent, live, cold-adapted influenza vaccine (CAIV-T) is highly effective in the prevention of influenza in children, and a variety of monovalent and bivalent cold-adapted influenza vaccines have been efficacious in adults. In order to determine the efficacy of CAIV-T in healthy adults, we administered CAIV-T, trivalent inactivated influenza vaccine (TIV) or placebo to 103 adults in randomized double-blind fashion, and then challenged those subjects who had pre-screening serum hemagglutination-inhibition antibody titers of 1:8 or less with wild-type influenza viruses corresponding to the strains contained in the vaccine, CAIV-T was well tolerated. Upon challenge with wild-type influenza virus, laboratory documented influenza illness (respiratory symptoms with either isolation of wild-type influenza virus from nasal secretions or 4-fold and/or greater HAI antibody response to challenge) occurred in 14/31 (45%) placebo recipients, 4/32 (13%) TIV recipients, and 2/29 (7%) CATV-T recipients. The estimated protective efficacy of CAIV-T was therefore 85% and of TIV was 71%. These results are consistent with those of previous studies using monovalent preparations of cold-adapted influenza vaccine in this model, and indicate that CAIV-T will be an effective means to prevent influenza illness in adults. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 Univ Rochester, Sch Med, Dept Med, Infect Dis Unit, Rochester, NY 14642 USA. Univ Maryland, Dept Med, Baltimore, MD 21201 USA. St Louis Univ, Dept Med, St Louis, MO 63103 USA. NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. Stat Collaborat, Washington, DC USA. Aviron, Mt View, CA USA. RP Treanor, JJ (reprint author), Univ Rochester, Sch Med, Dept Med, Infect Dis Unit, Box 689,601 Elmwood Ave, Rochester, NY 14642 USA. RI kotloff, karen/E-7768-2012 OI kotloff, karen/0000-0003-1808-6431 FU NIAID NIH HHS [N01 AI 45248, N01 AI 45250, N01 AI 45251] NR 25 TC 154 Z9 165 U1 0 U2 4 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 DEC 10 PY 1999 VL 18 IS 9-10 BP 899 EP 906 DI 10.1016/S0264-410X(99)00334-5 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 262RA UT WOS:000084079200019 PM 10580204 ER PT J AU Cohen, HT Zhou, M Welsh, AM Zarghamee, S Scholz, H Mukhopadhyay, D Kishida, T Zbar, B Knebelmann, B Sukhatme, VP AF Cohen, HT Zhou, M Welsh, AM Zarghamee, S Scholz, H Mukhopadhyay, D Kishida, T Zbar, B Knebelmann, B Sukhatme, VP TI An important von Hippel-Lindau tumor suppressor domain mediates Sp1-binding and self-association SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; RENAL-CELL CARCINOMA; RNA-POLYMERASE-II; GENE-PRODUCT; NEGATIVE REGULATION; GERMLINE MUTATIONS; DISEASE; PROTEIN; BINDING; SP1 AB VHL is the causative gene for both von Hippel-Lindau (VHL) disease and sporadic clear-cell renal cancer. We showed earlier that VHL downregulates vascular endo thelial growth factor transcription by directly binding and inhibiting the transcriptional activator Spl. We have now mapped the VHL Spl-binding domain to amino acids 96-122. The 96-122 domain is disproportionately affected by substitution mutations, which interfere with the VHL-Sp1 interaction. Deletion of the 96-122 domain prevents VHL effects on Spl DNA binding and on VHL target gene expression, indicating the domain contributes importantly to VHL tumor suppressor activity, Nevertheless, prevention of the VHL-Sp1 interaction only partially abrogates VHL's transcriptional repressor activity, supporting the existence of VHL transcriptional effecters in addition to Spl. VHL also directly interacts with the Spl zinc fingers and self-associates via the 96-122 domain, which furthermore suggest the domain may bind other metalloproteins and contribute to VHL dominant-negative effects. (C) 1999 Academic Press. C1 Boston Univ, Med Ctr, Renal Sect, Boston, MA 02118 USA. Boston Univ, Med Ctr, Hematol Oncol Sect, Boston, MA 02118 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Div Renal, Boston, MA 02215 USA. NCI, Frederick Canc Res Ctr, Immunobiol Lab, Frederick, MD 21702 USA. RP Cohen, HT (reprint author), Boston Univ, Med Ctr, Renal Sect, E-428,88 E Newton St, Boston, MA 02118 USA. FU NCI NIH HHS [F32 CA79133]; NIDDK NIH HHS [DK02280] NR 32 TC 39 Z9 42 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 DEC 9 PY 1999 VL 266 IS 1 BP 43 EP 50 DI 10.1006/bbrc.1999.1767 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 263TF UT WOS:000084140800008 PM 10581162 ER PT J AU Venugopal, M Agarwal, R Callaway, A Schut, HAJ Snyderwine, EG AF Venugopal, M Agarwal, R Callaway, A Schut, HAJ Snyderwine, EG TI Inhibition of cell death in human mammary epithelial cells by the cooked meat-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID SPRAGUE-DAWLEY RATS; HETEROCYCLIC AMINES; TYROSINE PHOSPHORYLATION; SIGNALING PATHWAYS; TUMOR PROMOTION; BREAST-CANCER; HIGH-FAT; APOPTOSIS; GLAND; PHIP AB 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a mammary bland carcinogen present in the human diet in cooked meat. To examine if PhIP and its reactive metabolite N-hydroxy-PhIP inhibit apoptosis in human mammary epithelial MCF-10A cells, confluent cultures deprived of serum and growth factors were incubated for 24 h with either compound. The percentages of dead cells (mean +/- SEM n = 3) as measured by trypan blue exclusion were 5.7 +/- 0.6, 3.4 +/- 0.3, 2.7 +/- 0.3, and 0.2 +/- 0.003%, in control, 1 mu M N-hydroxy-PhIP-, 5 mu M N-hydroxy-PhIP-, and 100 mu M PhIP-treated dishes, respectively. The expression of Bcl-2 and Bcl-x(L) as quantitated by Western blotting was 1.2- to 1.9-fold higher in the treated groups. PhIP-DNA adducts induced by N-hydroxy-PhIP in MCF-10A cells measured by the P-32-postlabeling assay were low (<1 x 10(7), relative adduct labeling). No adducts were detected after incubation with PhIP. Western blot analysis indicated that PhIP increased ERK2 phosphorylation concomitant with Bcl-2. The results suggest that the inhibition of cell death in mammary epithelial cells by PhIP occurs independently of PhIP-DNA adducts and may involve enhanced signaling through the MAP kinase pathways. (C) 1999 Academic Press. C1 NCI, Div Basic Sci, Expt Carcinogenesis Lab, Chem Carcinogenesis Sect, Bethesda, MD 20892 USA. Med Coll Ohio, Dept Pathol, Toledo, OH 43614 USA. RP Snyderwine, EG (reprint author), NCI, Div Basic Sci, Expt Carcinogenesis Lab, Chem Carcinogenesis Sect, Bldg 37,Room 3C28,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. NR 44 TC 10 Z9 10 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 DEC 9 PY 1999 VL 266 IS 1 BP 203 EP 207 DI 10.1006/bbrc.1999.1801 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 263TF UT WOS:000084140800036 PM 10581190 ER PT J AU Tormo, J Natarajan, K Margulies, DH Marluzza, RA AF Tormo, J Natarajan, K Margulies, DH Marluzza, RA TI Crystal structure of a lectin-like natural killer cell receptor bound to its MHC class I ligand SO NATURE LA English DT Article ID MANNOSE-BINDING PROTEIN; CARBOHYDRATE-RECOGNITION DOMAIN; INHIBITORY RECEPTOR; 3-DIMENSIONAL STRUCTURE; LY-49A RECOGNIZES; H-2D(D); PEPTIDE; COMPLEX; SPECIFICITY; MOLECULES AB Natural killer (NK) cell function is regulated by NK receptors that interact with MHC class I (MHC-I) molecules on target cells. The murine NK receptor Ly49A inhibits NK cell activity by interacting with H-2D(d) through its G-type-lectin-like NK receptor domain. Here we report the crystal structure of the complex between the Ly49A NK receptor domain and unglycosylated H-2D(d), The Ly49A dimer interacts extensively with two H-2D(d) molecules at distinct sites, At one interface, a single Ly49A subunit contacts one side of the MHC-I peptide-binding platform, presenting an open cavity towards the conserved glycosylation site on the H-2D(d) alpha 2 domain, At a second, larger interface, the Ly49A dimer binds in a region overlapping the CD8-binding site. The smaller interface probably represents the interaction between Ly49A on the NK cell and MHC-I on the target cell, whereas the larger one suggests an interaction between Ly49A and MHC-I on the NK cell itself. Both Ly49A binding sites on MHC-I are spatially distinct from that of the T-cell receptor. C1 Univ Maryland, Inst Biotechnol, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. CSIC, Inst Biol Mol Barcelona, ES-08034 Barcelona, Spain. NIAID, Mol Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Marluzza, RA (reprint author), Univ Maryland, Inst Biotechnol, Ctr Adv Res Biotechnol, 9,600 Gudelsky Dr, Rockville, MD 20850 USA. RI Margulies, David/H-7089-2013 NR 49 TC 213 Z9 215 U1 0 U2 1 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD DEC 9 PY 1999 VL 402 IS 6762 BP 623 EP 631 DI 10.1038/45170 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 264PC UT WOS:000084189800055 PM 10604468 ER PT J AU DeCristofaro, MF Betz, BL Wang, WD Weissman, BE AF DeCristofaro, MF Betz, BL Wang, WD Weissman, BE TI Alteration of hSNF5/INI1/BAF47 detected in rhabdoid cell lines and primary rhabdomyosarcomas but not Wilms' tumors SO ONCOGENE LA English DT Article DE BAF47; SWI/SNF; rhabdomyosarcomas; rhabdoid; tumor suppressor genes ID TRANSCRIPTIONAL ACTIVATION; RETINOBLASTOMA PROTEIN; SWI/SNF COMPLEX; HUMAN HOMOLOG; YEAST; BINDING; SNF5; STIMULATION; SWI2/SNF2; COOPERATE AB The organization of genomic DNA into chromatin aids in the regulation of gene expression by limiting the access of transcriptional binding domains. The SWI/SNF family of chromatin-remodeling complexes, which are conserved from yeast to humans, open the chromatin to facilitate the transcriptional machinery to access their targets. The gene encoding the BAF47/hSNF5 subunit of the complex has been found mutated in both rhabdoid cell lines and in primary rhabdoid tumors. Since the pediatric tumors rhabdomyosarcoma (RMS) and Wilms' tumor (WT) share a similar genetic link with rhabdoid tumors, it was hypothesized that they may also show alterations of the BAF47 gene. Using primary tumors, the BAF47 protein was detected in all WT but less than 75% of the RMS tested, In cell lines, the BAF47 protein was missing in all rhabdoid cell lines and one RMS cell Line. Analysis of sample DNA displayed either a mutation or deletion of the BAF47 gene in all samples negative for the protein. Several other subunits of the human SWI/SNF complex, including BRG1 which is the subunit directly interacting with the Rb tumor suppressor gene, were detected in all tumor samples. Alteration of BAF47 may be a genetic marker associated with the poor prognosis seen in all rhabdoid tumors but only some RMS. C1 Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. NIA, Gerontol Res Ctr, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Weissman, BE (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, CB 7295,Rm 32-062, Chapel Hill, NC 27599 USA. FU NCI NIH HHS [CA63176]; NIGMS NIH HHS [5-T32-GM08581]; PHS HHS [5-T32-WS07017] NR 29 TC 70 Z9 71 U1 0 U2 1 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD DEC 9 PY 1999 VL 18 IS 52 BP 7559 EP 7565 DI 10.1038/sj.onc.1203168 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 263HQ UT WOS:000084119600017 PM 10602515 ER PT J AU Levine, M Daruwala, R Park, J Rumsey, SC AF Levine, M Daruwala, R Park, J Rumsey, SC TI Recommendations for vitamin C intake - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID RISK C1 NIH, Bethesda, MD 20892 USA. USDA, Beltsville, MD 20705 USA. Mead Johnson Nutr, Evansville, IN USA. RP Levine, M (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 6 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 DEC 8 PY 1999 VL 282 IS 22 BP 2119 EP 2119 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 260UG UT WOS:000083971400017 ER PT J AU Chow, WH Devesa, SS Fraumeni, JF AF Chow, WH Devesa, SS Fraumeni, JF TI Increasing incidence of renal cell cancer - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID UNITED-STATES C1 NCI, Bethesda, MD 20892 USA. RP Chow, WH (reprint author), NCI, Bethesda, MD 20892 USA. NR 3 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 DEC 8 PY 1999 VL 282 IS 22 BP 2121 EP 2121 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 260UG UT WOS:000083971400020 ER PT J AU Visser, M Bouter, LM McQuillan, GM Wener, MH Harris, TB AF Visser, M Bouter, LM McQuillan, GM Wener, MH Harris, TB TI Elevated C-reactive protein levels in overweight and obese adults SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CORONARY HEART-DISEASE; CARDIOVASCULAR-DISEASE; FAT DISTRIBUTION; NATIONAL-HEALTH; ADIPOSE-TISSUE; US ADULTS; RISK; INTERLEUKIN-6; MEN; ASSOCIATION AB Context Human adipose tissue expresses and releases the proinflammatory cytokine interleukin 6, potentially inducing low-grade systemic inflammation in persons with excess body fat. Objective To test whether overweight and obesity are associated with low-grade systemic inflammation as measured by serum C-reactive protein (CRP) level. Design and Setting The Third National Health and Nutrition Examination Survey, representative of the US population from 1988 to 1994, Participants A total of 16 616 men and nonpregnant women aged 17 years or older Main Outcome Measures Elevated CRP level of 0.22 mg/dL or more and a more stringent clinically raised CRP level of more than 1.00 mg/dL. Results Elevated CRP levels and clinically raised CRP levels were present in 27.6% and 6.7% of the population, respectively. Both overweight (body mass index [BMI], 25-29.9 kg/m(2)) and obese (BMI, greater than or equal to 30 kg/m(2)) persons were more likely to have elevated CRP levels than their normal-weight counterparts (BMI, <25 kg/m(2)). After adjustment for potential confounders, including smoking and health status, the odds ratio (OR) for elevated CRP was 2.13 (95% confidence interval [CI], 1.56-2.91) for obese men and 6.21 (95% CI, 4.94-7.81) for obese women. In addition, BMI was associated with clinically raised CRP levels in women, with an OR of 4.76 (95% CI, 3.42-6.61) for obese women. Waist-to-hip ratio was positively associated with both elevated and clinically raised CRP levels, independent of BMI. Restricting the analyses to young adults (aged 17-39 years) and excluding smokers, persons with inflammatory disease, cardiovascular disease, or diabetes mellitus and estrogen users did not change the main findings. Conclusion Higher BMI is associated with higher CRP concentrations, even among young adults aged 17 to 39 years. These findings suggest a state of low-grade systemic inflammation in overweight and obese persons. C1 Vrije Univ Amsterdam, Fac Med, Inst Res Extramural Med, NL-1081 BT Amsterdam, Netherlands. NIA, Epidemiol Demog & Biometry Program, NIH, Bethesda, MD USA. Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD USA. Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. RP Visser, M (reprint author), Vrije Univ Amsterdam, Fac Med, Inst Res Extramural Med, Boechorststr 7, NL-1081 BT Amsterdam, Netherlands. OI Bouter, Lex/0000-0002-2659-5482 NR 45 TC 1263 Z9 1308 U1 7 U2 54 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 DEC 8 PY 1999 VL 282 IS 22 BP 2131 EP 2135 DI 10.1001/jama.282.22.2131 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 260UG UT WOS:000083971400031 PM 10591334 ER PT J AU Horne, MK Chang, R AF Horne, MK Chang, R TI Thrombolytic therapy for deep venous thrombosis? SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ORAL ANTICOAGULANT-THERAPY; VEIN THROMBOSIS; STREPTOKINASE; HEPARIN; THROMBOEMBOLISM; EPISODE; LYSIS AB We present the case of a man bedridden by deep venous thrombosis who was given intraclot instillations of recombinant tissue plasminogen activator with remarkable improvement. Although such aggressive treatment may be justified in severe cases, the role for thrombolytic agents for less symptomatic deep venous thrombosis is undefined. We discuss the question of when thrombolytic therapy should be considered. However, proper clinical trials are needed before firm recommendations can be made. C1 NIH, Hematol Serv, Dept Clin Pathol, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NIH, Special Procedures Unit, Dept Radiol, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Horne, MK (reprint author), NIH, Hematol Serv, Dept Clin Pathol, Warren G Magnuson Clin Ctr, Bldg 10,Room 2C306,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 26 TC 4 Z9 5 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 8 PY 1999 VL 282 IS 22 BP 2164 EP 2166 DI 10.1001/jama.282.22.2164 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 260UG UT WOS:000083971400036 PM 10591339 ER PT J AU Berezhkovskii, AM Szabo, A Weiss, GH Zhou, HX AF Berezhkovskii, AM Szabo, A Weiss, GH Zhou, HX TI Reaction dynamics on a thermally fluctuating potential SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID ACTIVATED RATE-PROCESSES; SLOW CONFORMATIONAL-CHANGES; RESONANT ACTIVATION; KRAMERS PROBLEM; ANISOTROPIC FRICTION; REACTION COORDINATE; BARRIER PROBLEM; HARMONIC MODE; ESCAPE; SYSTEM AB This paper analyzes the kinetics of escape of a particle over a barrier fluctuating between two states, the fluctuations being produced by thermal noise. By this we mean that the jump rates for transitions between the two states are position-dependent, satisfying detailed balance at any point along the reaction coordinate. The fast-fluctuation limit can be analyzed in terms of the potential of mean force, and for high barriers the survival probability is found to be a single exponential. In the slow-fluctuation regime the survival probability is a linear combination of two exponentials. In the case of a linear potential the slow-fluctuation solution describes the kinetics, as obtained from simulations, quite well over the entire range of the jump rates between the two states. Our analysis suggests that this is true for more general forms of the potential. Further, for a thermally fluctuating potential the mean lifetime is shown to decrease monotonically as the jump rate increases. This is in contrast to the turnover behavior, or resonant activation, which can occur when fluctuations are produced by nonthermal noise. An extension of our approach to systems with thermal fluctuations between more than two states is discussed. (C) 1999 American Institute of Physics. [S0021-9606(99)52345-3]. C1 NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. LY Karpov Phys Chem Res Inst, Moscow 103064, Russia. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. Drexel Univ, Dept Phys & Atmospher Sci, Philadelphia, PA 19104 USA. RP Berezhkovskii, AM (reprint author), NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. RI Szabo, Attila/H-3867-2012 NR 35 TC 15 Z9 15 U1 1 U2 8 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 DEC 8 PY 1999 VL 111 IS 22 BP 9952 EP 9957 DI 10.1063/1.480348 PG 6 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 258RK UT WOS:000083852700007 ER PT J AU Al Suwaidi, J Velianou, JL Gertz, MA Cannon, RO Higano, ST Holmes, DR Lerman, A AF Al Suwaidi, J Velianou, JL Gertz, MA Cannon, RO Higano, ST Holmes, DR Lerman, A TI Systemic amyloidosis presenting with angina pectoris SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID ISCHEMIC-HEART-DISEASE; CARDIAC AMYLOIDOSIS; CHEST PAIN; CORONARY; ARTERIES AB Background: Manifestations of cardiac amyloidosis may include congestive heart failure and sudden cardiac death. Although vascular involvement in patients with amyloidosis is common, systemic amyloidosis presenting with angina is rare. Objectives: To report on patients with systemic amyloidosis presenting with angina pectoris. Design: Case series. Setting: Academic medical center. Patients: Five patients who presented with angina pectoris and normal coronary angiogram as the initial manifestation of systemic amyloidosis. Measurements: Endothelial-dependent and endothelialin-dependent coronary flow reserve. Results: All patients had coronary flow reserve abnormalities and subsequently developed congestive heart failure and systemic manifestations of amyloidosis. Histologic evaluation revealed amyloid deposition in the intramyocardial coronary vessels. Conclusions: Cardiac amyloidosis can present as angina pectoris associated with coronary flow reserve abnormalities despite normal coronary angiograms. This finding may have major therapeutic and prognostic implications in this patient population. C1 Mayo Clin & Mayo Fdn, Div Cardiovasc Dis, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Div Hematol, Rochester, MN 55905 USA. NHLBI, NIH, Cardiol Branch, Bethesda, MD 20892 USA. RP Lerman, A (reprint author), Mayo Clin & Mayo Fdn, Div Cardiovasc Dis, 200 1st St SW, Rochester, MN 55905 USA. OI al suwaidi, MB, ChB, FACC, FESC, FSCAI, jassim/0000-0002-5299-9106 NR 18 TC 30 Z9 33 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 DEC 7 PY 1999 VL 131 IS 11 BP 838 EP 841 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 262ET UT WOS:000084053200006 PM 10610629 ER PT J AU Masur, H Kaplan, JE Holmes, KK Alston, BL Ampel, N Anderson, JR Baker, AC Barr, D Bartlett, JG Bennett, JE Benson, CA Bozzette, SA Chaisson, RE Crumpacker, CS Currier, JS Deyton, L Drew, WL Duncan, WR Eisinger, RW El-Sadr, W Feinberg, J Freedberg, KA Furrer, H Gnann, JW Goldberger, MJ Goldie, S Goosby, EP Gross, PA Hafner, R Havlir, D Hooton, TM Jabs, DA Jacobson, MA Janoff, E Kitahata, M Kovacs, JV Leport, C Levin, MJ Lopez, JC Marco, M Mayers, DL Melnick, DA Mofenson, LM Montaner, JSG Moore, R Neaton, J Nelson, C O'Neill, JF Palefsky, J Pau, A Phair, JP Piscitelli, S Polis, MA Quinn, TC Reiss, P Rimland, D Sears, CL Seeff, L Sepkowitz, KA Slama, TG Sloand, EM Spector, SA Thomas, DL Van Dyke, RB Watts, DH Wheat, LJ Whitcup, SM Williams, P Wright, TC Castro, KG DeCock, KM Dowell, SF Dworkin, MS Dykewicz, C Ellerbrock, T Hajjeh, R Holmberg, S Holtgrave, DR Jaffe, HW Jones, JL Juranek, DD Mast, E Navin, T Pellett, PE Reeves, WC Stewart, JA Villarino, ME Kaplan, JE AF Masur, H Kaplan, JE Holmes, KK Alston, BL Ampel, N Anderson, JR Baker, AC Barr, D Bartlett, JG Bennett, JE Benson, CA Bozzette, SA Chaisson, RE Crumpacker, CS Currier, JS Deyton, L Drew, WL Duncan, WR Eisinger, RW El-Sadr, W Feinberg, J Freedberg, KA Furrer, H Gnann, JW Goldberger, MJ Goldie, S Goosby, EP Gross, PA Hafner, R Havlir, D Hooton, TM Jabs, DA Jacobson, MA Janoff, E Kitahata, M Kovacs, JV Leport, C Levin, MJ Lopez, JC Marco, M Mayers, DL Melnick, DA Mofenson, LM Montaner, JSG Moore, R Neaton, J Nelson, C O'Neill, JF Palefsky, J Pau, A Phair, JP Piscitelli, S Polis, MA Quinn, TC Reiss, P Rimland, D Sears, CL Seeff, L Sepkowitz, KA Slama, TG Sloand, EM Spector, SA Thomas, DL Van Dyke, RB Watts, DH Wheat, LJ Whitcup, SM Williams, P Wright, TC Castro, KG DeCock, KM Dowell, SF Dworkin, MS Dykewicz, C Ellerbrock, T Hajjeh, R Holmberg, S Holtgrave, DR Jaffe, HW Jones, JL Juranek, DD Mast, E Navin, T Pellett, PE Reeves, WC Stewart, JA Villarino, ME Kaplan, JE CA USPHS IDSA Prevention Oportunisti TI 1999 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID PNEUMOCYSTIS-CARINII PNEUMONIA; MYCOBACTERIUM-AVIUM COMPLEX; PLACEBO-CONTROLLED TRIAL; ACTIVE ANTIRETROVIRAL THERAPY; TRIMETHOPRIM-SULFAMETHOXAZOLE; CYTOMEGALOVIRUS RETINITIS; RANDOMIZED TRIAL; TOXOPLASMIC ENCEPHALITIS; AEROSOLIZED PENTAMIDINE; MAINTENANCE THERAPY C1 NIH, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. Univ Washington, Seattle, WA 98195 USA. Univ Arizona, Tucson, AZ USA. Johns Hopkins Univ, Baltimore, MD USA. Natl Assoc People AIDS, Washington, DC USA. Forum Collaborat HIV Res, Washington, DC USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. Univ Calif San Diego, La Jolla, CA 92093 USA. Harvard Univ, Med Ctr, Boston, MA 02115 USA. Univ Calif Los Angeles, Med Ctr, Los Angeles, CA 90024 USA. US Dept Vet Affairs, Washington, DC USA. Univ Calif San Francisco, Mt Zion Med Ctr, San Francisco, CA 94120 USA. Harlem Hosp, New York, NY USA. Holmes Hosp, Cincinnati, OH USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Univ Hosp Bern, CH-3010 Bern, Switzerland. Univ Alabama, Birmingham, AL USA. US FDA, Rockville, MD 20857 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. US Dept Hlth & Human Serv, Washington, DC USA. Hackensack Med Ctr, Hackensack, NJ 07604 USA. Univ Washington, Harborview Med Ctr, Seattle, WA 98104 USA. Vet Adm Med Ctr, Minneapolis, MN 55417 USA. Univ Washington, Seattle, WA 98195 USA. Hop Bichat Claude Bernard, F-75877 Paris 18, France. Hosp Univ Gregorio Maranon, Madrid, Spain. Treatment Act Grp, New York, NY USA. Henry Ford Hosp, Detroit, MI 48202 USA. Kaiser Permanente, Springfield, VA USA. St Pauls Hosp, Vancouver, BC V6Z 1Y6, Canada. Univ Minnesota, Minneapolis, MN USA. US Hlth Resources & Serv Adm, Rockville, MD 20857 USA. Northwestern Univ, Chicago, IL 60611 USA. Johns Hopkins Hosp, Baltimore, MD 21287 USA. Univ Amsterdam, Amsterdam, Netherlands. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Natl Fdn Infect Dis, Indianapolis, IN USA. Tulane Univ, Sch Med, New Orleans, LA 70112 USA. Indiana Univ, Sch Med, Indianapolis, IN USA. Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. RP Masur, H (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. RI Furrer, Hansjakob/G-6768-2013 OI Furrer, Hansjakob/0000-0002-1375-3146 NR 90 TC 19 Z9 19 U1 0 U2 3 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 DEC 7 PY 1999 VL 131 IS 11 BP 873 EP 908 PG 36 WC Medicine, General & Internal SC General & Internal Medicine GA 262ET UT WOS:000084053200019 ER PT J AU Sagnella, DE Straub, JE Jackson, TA Lim, M Anfinrud, PA AF Sagnella, DE Straub, JE Jackson, TA Lim, M Anfinrud, PA TI Vibrational population relaxation of carbon monoxide in the heme pocket of photolyzed carbonmonoxy myoglobin: Comparison of time-resolved mid-IR absorbance experiments and molecular dynamics simulations SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NORMAL-MODE ANALYSIS; ENERGY RELAXATION; MONATOMIC SOLVENTS; PROTEIN DYNAMICS; DIPOLAR MOLECULE; DOCKING SITE; LIQUIDS; CO; WATER; PHOTODISSOCIATION AB The vibrational energy relaxation of carbon monoxide in the heme pocket of sperm whale myoglobin was studied by using molecular dynamics simulation and normal mode analysis methods. Molecular dynamics trajectories of solvated myoglobin were run at 300 K for both the delta- and epsilon-tautomers of the distal His-64, Vibrational population relaxation times of 335 +/- 115 ps for the delta-tautomer and 640 +/- 185 ps for the epsilon-tautomer were estimated by using the Landau-Teller model. Normal mode analysis was used to identify those protein residues that act as the primary "doorway" modes in the vibrational relaxation of the oscillator. Although the CO relaxation rates in both the epsilon- and delta-tautomers are similar in magnitude, the simulations predict that the vibrational relaxation of the CO is faster in the delta-tautomer with the distal His playing an important role in the energy relaxation mechanism. Time-resolved mid-IR absorbance measurements were performed on photolyzed carbonmonoxy hemoglobin (Hb(13)CO). From these measurements, a T-1 time of 600 +/- 150 ps was determined. The simulation and experimental estimates are compared and discussed. C1 Boston Univ, Dept Chem, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Pusan Natl Univ, Dept Chem, Pusan 609735, South Korea. Natl Inst Diabet & Digest & Kidney Dis, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Straub, JE (reprint author), Boston Univ, Dept Chem, 590 Commonwealth Ave, Boston, MA 02215 USA. NR 61 TC 80 Z9 80 U1 0 U2 14 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 DEC 7 PY 1999 VL 96 IS 25 BP 14324 EP 14329 DI 10.1073/pnas.96.25.14324 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 263XC UT WOS:000084149700035 PM 10588704 ER PT J AU Marassi, FM Ma, C Gratkowski, H Straus, SK Strebel, K Oblatt-Montal, M Montal, M Opella, SJ AF Marassi, FM Ma, C Gratkowski, H Straus, SK Strebel, K Oblatt-Montal, M Montal, M Opella, SJ TI Correlation of the structural and functional domains in the membrane protein Vpu from HIV-1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; SOLID-STATE NMR; CYTOPLASMIC DOMAIN; CHEMICAL-SHIFT; GRAMICIDIN-A; U VPU; POLYPEPTIDE BACKBONE; TRANSMEMBRANE DOMAIN; LIPID BILAYER; ION CHANNELS AB Vpu is an 81-residue membrane protein encoded by the HIV-1 genome. NMR experiments show that the protein folds into two distinct domains, a transmembrane hydrophobic helix and a cytoplasmic domain with two in-plane amphipathic alpha-helices separated by a linker region. Resonances in one-dimensional solid-state NMR spectra of uniformly N-15 labeled Vpu are clearly segregated into two bands at chemical shift frequencies associated with NH bonds in a transmembrane alpha-helix, perpendicular to the membrane surface, and with NH bonds in the cytoplasmic helices parallel to the membrane surface. Solid-state NMR spectra of truncated Vpu(2-51) (residues 2-51), which contains the transmembrane alpha-helix and the first amphipathic helix of the cytoplasmic domain, and of a construct Vpu(28-81) (residues 28-81), which contains only the cytoplasmic domain, support this structural model of Vpu in the membrane. Full-length Vpu (residues 2-81) forms discrete ion-conducting channels of heterogeneous conductance in lipid bilayers. The most frequent conductances were 22 +/- 3 pS and 12 +/- 3 pS in 0.5 M KCl and 29 +/- 3 pS and 12 +/- 3 pS in 0.5 M NaCl. In agreement with the structural model, truncated Vpu(2-51), which has the transmembrane helix, forms discrete channels in lipid bilayers, whereas the cytoplasmic domain Vpu(28-81), which lacks the transmembrane helix, does not. This finding shows that the channel activity is associated with the transmembrane helical domain. The pattern of channel activity is characteristic of the self-assembly of conductive oligomers in the membrane and is compatible with the structural and functional findings. C1 Univ Penn, Dept Chem, Philadelphia, PA 19104 USA. Wistar Inst, Philadelphia, PA 19104 USA. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. Univ Calif San Diego, Dept Biol, La Jolla, CA 92093 USA. RP Opella, SJ (reprint author), Univ Penn, Dept Chem, Philadelphia, PA 19104 USA. FU NCRR NIH HHS [P41RR09793]; NIGMS NIH HHS [P01 GM56538] NR 51 TC 138 Z9 139 U1 2 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 7 PY 1999 VL 96 IS 25 BP 14336 EP 14341 DI 10.1073/pnas.96.25.14336 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 263XC UT WOS:000084149700037 PM 10588706 ER PT J AU Recillas-Targa, F Bell, AC Felsenfeld, G AF Recillas-Targa, F Bell, AC Felsenfeld, G TI Positional enhancer-blocking activity of the chicken beta-globin insulator in transiently transfected cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DROSOPHILA-MELANOGASTER; PROMOTER INTERACTIONS; CHROMOSOMAL DOMAINS; GENE-EXPRESSION; DNA; BOUNDARIES; CHROMATIN; ELEMENTS; PROTEIN; IDENTIFICATION AB It is thought that insulators demarcate transcriptionally and structurally independent chromatin domains. Insulators are detected by their ability to block enhancer-promoter interactions in a directional manner, and protect a transgene from position effects. Most studies are performed in stably transformed cells or organisms. Here we analyze the enhancer-blocking activity of the chicken P-globin insulator in transient transfection experiments in both erythroid and nonerythroid cell lines. We show that four tandem copies of a 90-bp fragment of this insulator were able to block an enhancer in these experiments. In circular plasmids, placement on either side of the enhancer reduced activity, but: when the plasmid was linearized, the enhancer-blocking activity was observed only when the insulator was placed between the promoter and the enhancer. These observations are consistent with the position-dependent enhancer-blocking activity of the insulator observed in stable transformation experiments. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Felsenfeld, G (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 35 TC 80 Z9 87 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 DEC 7 PY 1999 VL 96 IS 25 BP 14354 EP 14359 DI 10.1073/pnas.96.25.14354 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 263XC UT WOS:000084149700040 PM 10588709 ER PT J AU Lee, KS Song, S Erikson, RL AF Lee, KS Song, S Erikson, RL TI The polo-box-dependent induction of ectopic septal structures by a mammalian polo kinase, Plk, in Saccharomyces cerevisiae SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE septin; mitosis; cytokinesis ID XENOPUS EGG EXTRACTS; CELL-CYCLE CONTROL; PROTEIN-KINASE; SERINE/THREONINE KINASE; DROSOPHILA POLO; FISSION YEAST; GENE; CYTOKINESIS; ENCODES; CDC5 AB Members of the polo subfamily of protein kinases play pivotal roles in cell-cycle control and proliferation. In addition to a high degree of sequence similarity in the kinase domain, polo kinases contain a strikingly conserved motif termed "polo-box" in the noncatalytic C-terminal domain. We have previously shown that the mammalian polo-like kinase Plk is a functional homolog of Saccharomyces cerevisiae Cdc5. Here, we show that, in a polo-box- and kinase activity-dependent manner, ectopic expression of Plk in budding yeast can induce a class of cells with abnormally elongated buds. In addition to localization at spindle poles and cytokinetic neck filaments, Plk induces and localizes to ectopic septin ring structures within the elongated buds. In contrast, mutations in the polo-box abolish both localization to, and induction of, septal structures. Consistent with the polo-box-dependent subcellular localization, the C-terminal domain of Plk, but not its polo-box mutant is sufficient for subcellular localization. Our data suggest that Plk may contribute a signal to initiate or promote cytokinetic event(s) and that an intact polo-box is required for regulation of these cellular processes. C1 NCI, Met Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. RP Lee, KS (reprint author), NCI, Met Lab, Div Basic Sci, NIH, 9000 Rockville Pike,Bldg 37,Room 3D25, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA42580] NR 41 TC 37 Z9 37 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 DEC 7 PY 1999 VL 96 IS 25 BP 14360 EP 14365 DI 10.1073/pnas.96.25.14360 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 263XC UT WOS:000084149700041 PM 10588710 ER PT J AU Morales, J Homey, B Vicari, AP Hudak, S Oldham, E Hedrick, J Orozco, R Copeland, NG Jenkins, NA McEvoy, LM Zlotnik, A AF Morales, J Homey, B Vicari, AP Hudak, S Oldham, E Hedrick, J Orozco, R Copeland, NG Jenkins, NA McEvoy, LM Zlotnik, A TI CTACK, a skin-associated chemokine that preferentially attracts skin-homing memory T cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LEUKOCYTE ADHESION MOLECULE-1; POLYMERASE CHAIN-REACTION; CYTOKINE MESSENGER-RNA; TUMOR NECROSIS FACTOR; ENDOTHELIAL-CELLS; CC-CHEMOKINE; LYMPHOCYTES; EXPRESSION; HECA-452; ANTIGEN AB In contrast to naive lymphocytes, memory/effector lymphocytes can access nonlymphoid effector sires and display restricted, often tissue-selective, migration behavior. The cutaneous lymphocyte-associated antigen (CLA) defines a subset of circulating memory T cells that selectively localize in cutaneous sites mediated in part: by the interaction of CLA with its vascular ligand E-selectin. Here, we report the identification and characterization of a CC chemokine, cutaneous T cell-attracting chemokine (CTACK), Both human and mouse CTACK are detected only in skin by Southern and Northern blot analyses. Specifically, CTACK message is found in the mouse epidermis and in human keratinocytes, and anti-CTACK mAbs predominantly stain the epithelium. Finally, CTACK selectively attracts CLA(+) memory T cells. Taken together, these results suggest an important role for CTACK in recruitment of CLA(+) T cells to cutaneous sites. CTACK is predominantly expressed in the skin and selectively attracts a tissue-specific subpopulation of memory lymphocytes. C1 DNAX Res Inst Mol & Cellular Biol Inc, Dept Immunobiol, Palo Alto, CA 94304 USA. Schering Plough, Lab Immunol Res, Dardilly, France. Schering Plough Corp, Res Inst, Human Genome Res, Kenilworth, NJ 07033 USA. Inst Nacl Nutr, Mexico City, DF, Mexico. NCI, Mammalian Genet Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Zlotnik, A (reprint author), DNAX Res Inst Mol & Cellular Biol Inc, Dept Immunobiol, 901 Calif Ave, Palo Alto, CA 94304 USA. RI Zlotnik, Albert/C-3791-2011 NR 28 TC 332 Z9 344 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 7 PY 1999 VL 96 IS 25 BP 14470 EP 14475 DI 10.1073/pnas.96.25.14470 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 263XC UT WOS:000084149700060 PM 10588729 ER PT J AU Khaled, AR Kim, K Hofmeister, R Muegge, K Durum, SK AF Khaled, AR Kim, K Hofmeister, R Muegge, K Durum, SK TI Withdrawal of IL-7 induces Bax translocation from cytosol to mitochondria through a rise in intracellular pH SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RECEPTOR-DEFICIENT MICE; TRITON X-114; CELL-DEATH; T-CELLS; APOPTOSIS; BCL-2; DIMERIZATION; INHIBITION; THYMOCYTES; PROTEINS AB IL-7 functions as a trophic factor during T lymphocyte development by a mechanism that is partly based on the induction of Bcl-2, which protects cells from apoptosis. Here we report a mechanism by which cytokine withdrawal activates the prodeath protein Bax. On loss of IL-7 in a dependent cell line, Bax protein translocated from the cytosol to the mitochondria, where it integrated into the mitochondrial membrane. This translocation was attributable to a conformational change in the Bax protein itself. We show that a rise in intracellular pH preceded mitochondrial translocation and triggered the change in Bax conformation. Intracellular pH in the IL-7-dependent cells rose steadily to peak over pH 7.8 by 6 hr after cytokine withdrawal, paralleling the time point of Bax translocation (a similar alkalinization and Bax translocation was also observed after IL-3 withdrawal from a dependent cell line). The conformation of Bax was directly altered by pH of 7.8 or higher and was demonstrated by increased protease sensitivity, exposure of N terminus epitopes, and exposure of a hydrophobic domain in the C terminus. Eliminating charged amino acids at the C or N termini of Bax induced a conformational change similar to that induced by raising pH, implicating these residues in the pH effect. Therefore, we have shown that by either cytokine withdrawal, experimental manipulation of pH, or sire-directed mutagenesis. Bax protein changes conformation, exposing membrane-seeking domains, thereby inducing mitochondrial translocation and initiating the cascade of events leading to apoptotic death. C1 NCI, Sect Cytokines & Immun, Mol Immunoregulat Lab, Frederick, MD 21702 USA. NCI, Sci Applicat Int Corp, Div Basic Sci, Frederick, MD 21702 USA. RP Durum, SK (reprint author), NCI, Sect Cytokines & Immun, Mol Immunoregulat Lab, Bldg 560,Rm 31-71, Frederick, MD 21702 USA. NR 35 TC 203 Z9 204 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 DEC 7 PY 1999 VL 96 IS 25 BP 14476 EP 14481 DI 10.1073/pnas.96.25.14476 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 263XC UT WOS:000084149700061 PM 10588730 ER PT J AU Ma, XL Cao, F Liu, GL Lopez, BL Christopher, TA Fukuto, JM Wink, DA Feelisch, M AF Ma, XL Cao, F Liu, GL Lopez, BL Christopher, TA Fukuto, JM Wink, DA Feelisch, M TI Opposite effects of nitric oxide and nitroxyl on postischemic myocardial injury SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE free radicals; reperfusion; neutrophils ID ISCHEMIA-REPERFUSION INJURY; PATHOPHYSIOLOGICAL ROLE; INFARCT SIZE; L-ARGININE; PEROXYNITRITE; GENERATION; SYNTHASE; NO; ATTENUATION; INHIBITION AB Recent experimental evidence suggests that reactive nitrogen oxide species can contribute significantly to postischemic myocardial injury. The aim of the present study was to evaluate the role of two reactive nitrogen oxide species, nitroxyl (NO(-)) and nitric oxide (NO(-)), in myocardial ischemia and reperfusion injury. Rabbits were subjected to 45 min of regional myocardial ischemia followed by 180 min of reperfusion. Vehicle (0.9% NaCl), 1 mu mol/kg 5-nitrosoglutathione (GSNO) tan NO(.) donor), or 3 mu mol/kg Angeli's salt (AS) (a source of NO(-)) were given i.v. 5 min before reperfusion. Treatment with GSNO markedly attenuated reperfusion injury, as evidenced by improved cardiac function, decreased plasma creatine kinase activity, reduced necrotic size, and decreased myocardial myeloperoxidase activity. In contrast, the administration of AS at a hemodynamically equieffective dose not only failed to attenuate but, rather, aggravated reperfusion injury, indicated by an increased left ventricular end diastolic pressure, myocardial creatine kinase release and necrotic size. Decomposed AS was without effect. Go-administration of AS with ferricyanide, a one-electron oxidant that converts NO(-) to NO(.), completely blocked the injurious effects of AS and exerted significant cardioprotective effects similar to those of GSNO. These results demonstrate that, although NO(.) is protective, NO(-) increases the tissue damage that occurs during ischemia/reperfusion and suggest that formation of nitroxyl may contribute to postischemic myocardial injury. C1 Thomas Jefferson Univ, Jefferson Med Coll, Dept Surg, Philadelphia, PA 19107 USA. Univ Calif Los Angeles, Sch Med, Dept Pharmacol, Los Angeles, CA 90024 USA. NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. UCL, Wolfson Inst Biomed Res, London, England. RP Ma, XL (reprint author), Thomas Jefferson Univ, Jefferson Med Coll, Dept Surg, 1020 Sansom St, Philadelphia, PA 19107 USA. EM xin.ma@mail.tju.edu RI Feelisch, Martin/C-3042-2008 OI Feelisch, Martin/0000-0003-2320-1158 NR 32 TC 125 Z9 129 U1 0 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 7 PY 1999 VL 96 IS 25 BP 14617 EP 14622 DI 10.1073/pnas.96.25.14617 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 263XC UT WOS:000084149700085 PM 10588754 ER PT J AU Gavrilova, O Leon, LR Marcus-Samuels, B Mason, MM Castle, AL Refetoff, S Vinson, C Reitman, ML AF Gavrilova, O Leon, LR Marcus-Samuels, B Mason, MM Castle, AL Refetoff, S Vinson, C Reitman, ML TI Torpor in mice is induced by both leptin-dependent and -independent mechanisms SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE fasting; lipoatrophic diabetes; body temperature; hypothermia; A-ZIP/F-1 mice ID BROWN ADIPOSE-TISSUE; INSULIN-RESISTANCE; BODY-WEIGHT; OB/OB MICE; OBESE GENE; HYPOTHERMIA; RECEPTORS; MOUSE; FAT AB We tested the effect of chronic leptin treatment on fasting-induced torpor in leptin-deficient A-ZIP/F-1 and ob/ob mice. A-ZIP/F-1 mice have virtually no white adipose tissue and low leptin levels. whereas ob/ob mice have an abundance of fat but no leptin. These two models allowed us to examine the roles of adipose tissue and leptin in the regulation of entry into torpor. Torpor is a short-term hibernation-like state that allows conservation of metabolic fuels. We first characterized the A-ZIP/F-1 animals, which have a 10-fold reduction in total body triglyceride stores. Upon fasting, A-ZIP/F-1 mice develop a lower metabolic rate and decreased plasma glucose, insulin, and triglyceride levels, with no increase in free fatty acids or beta-hydroxybutyrate. Unlike control mice, by 24 hr of fasting, they have nearly exhausted their triglycerides and are catabolizing protein. To conserve energy supplies during fasting. A-ZIP/F-1 (but not control) mice entered deep torpor, with a minimum core body temperature of 24 degrees C, 2 degrees C above ambient. In ob/ob mice, fasting-induced torpor was completely reversed by leptin treatment. In contrast, neither leptin nor thyroid hormone prevented torpor in A-ZIP/F-1 mice. These data suggest that there are at least two signals for entry into torpor in mice, a low leptin level and another signal that is independent of leptin and thyroid hormone levels. Studying rodent torpor provides insight into human torpor-like states such as near drowning in cold water and induced hypothermia for surgery. C1 NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. Univ Chicago, Dept Med & Pediat, Chicago, IL 60637 USA. RP Reitman, ML (reprint author), NIDDKD, Diabet Branch, NIH, Bldg 10,Room 8N-250, Bethesda, MD 20892 USA. RI Reitman, Marc/B-4448-2013 OI Reitman, Marc/0000-0002-0426-9475 FU NIDDK NIH HHS [R37 DK015070, R01 DK015070, DK 15070] NR 42 TC 133 Z9 135 U1 1 U2 11 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 DEC 7 PY 1999 VL 96 IS 25 BP 14623 EP 14628 DI 10.1073/pnas.96.25.14623 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 263XC UT WOS:000084149700086 PM 10588755 ER PT J AU Lomenzo, SA Izenwasser, S Gerdes, RM Katz, JL Kopajtic, T Trudell, ML AF Lomenzo, SA Izenwasser, S Gerdes, RM Katz, JL Kopajtic, T Trudell, ML TI Synthesis, dopamine and serotonin transporter binding affinities of novel analogues of meperidine SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID CAUDATE-PUTAMEN; COCAINE; INHIBITORS; PHARMACOLOGY; SITES AB A series of meperidine analogues was synthesized and the binding affinities for the dopamine and serotonin transporters were determined. The substituents on the phenyl ring greatly influenced the potency and selectivity of these compounds for the transporter binding sites. In general, meperidine (3) and its analogues were more selective for serotonin transporter binding sites and the eaters 9 were more potent than the corresponding nitriles 8. The 3,4-dichloro derivative 9e was the most potent ligand of the series for dopamine transporter binding sites while the 2-naphthyl derivative 9g exhibited the most potent binding affinity and was highly selective for serotonin transporter binding sites. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 Univ New Orleans, Dept Chem, New Orleans, LA 70148 USA. Univ Miami, Sch Med, Dept Neurol, Miami, FL 33136 USA. NIDA, Div Intramural Res, Baltimore, MD 21224 USA. RP Trudell, ML (reprint author), Univ New Orleans, Dept Chem, New Orleans, LA 70148 USA. RI Izenwasser, Sari/G-9193-2012; OI Katz, Jonathan/0000-0002-1068-1159 NR 18 TC 9 Z9 10 U1 0 U2 0 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 DEC 6 PY 1999 VL 9 IS 23 BP 3273 EP 3276 DI 10.1016/S0960-894X(99)00606-X PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 263YT UT WOS:000084153400003 PM 10612583 ER PT J AU Thomas, JB Atkinson, RN Herault, XM Rothman, RB Mascarella, SW Dersch, CM Xu, H Horel, RB Carroll, FI AF Thomas, JB Atkinson, RN Herault, XM Rothman, RB Mascarella, SW Dersch, CM Xu, H Horel, RB Carroll, FI TI Optically pure (-)-4-[(N-allyl-3-methyl-4-piperidinyl)phenyl-amino]-N,N-diethylbenzamid e displays selective binding and full agonist activity for the delta opioid receptor SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID POTENT AB The optical isomers of 4-[(N-allyl-3-methyl-4-piperidiny)phenylamino]-N,N-diethylbenzamine (3) have been prepared and tested in both binding and functional assays. The data show that (-)-3 is responsible for the delta opioid activity demonstrated by the racemic material. This compound displays a binding affinity of 5.5 nM for the delta opioid receptor as well as a 470-fold delta versus mu selectivity. Importantly, (-)-3 is a full agonist at the delta receptor in comparison with SNC-80 (2). Taken together, the data suggest that (-)-3 behaves more like the prototypical delta agonists, BW373U86 of SNC-80, and less like the peptidomimetic compound SL-3111 (5). (C) 1999 Elsevier Science Ltd. All rights reserved. C1 Res Triangle Inst, Res Triangle Pk, NC 27709 USA. NIDA, Clin Psychopharmacol Sect, Addict Res Sect, Baltimore, MD 21224 USA. RP Carroll, FI (reprint author), Res Triangle Inst, POB 12194, Res Triangle Pk, NC 27709 USA. FU NIDA NIH HHS [DA09045] NR 9 TC 10 Z9 10 U1 0 U2 0 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 DEC 6 PY 1999 VL 9 IS 23 BP 3347 EP 3350 DI 10.1016/S0960-894X(99)00613-7 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 263YT UT WOS:000084153400017 PM 10612597 ER PT J AU Rajagopal, K Sommers, CL Decker, DC Mitchell, EO Korthauer, U Sperling, AI Kozak, CA Love, PE Bluestone, JA AF Rajagopal, K Sommers, CL Decker, DC Mitchell, EO Korthauer, U Sperling, AI Kozak, CA Love, PE Bluestone, JA TI RIBP, a novel R1k/Txk- and Itk-binding adaptor protein that regulates T cell activation SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE T cell activation; signal transduction; adaptor protein; Tec tyrosine kinases; T helper type 1/T helper type 2 cells ID TYROSINE KINASE; TEC FAMILY; SIGNAL-TRANSDUCTION; ANTIGEN RECEPTORS; ZETA-CHAIN; GENE; DOMAIN; ZAP-70; INTERLEUKIN-2; CD28 AB A novel T cell-specific adaptor protein, RIBP, was identified based on its ability to bind Rlk/Txk in a yeast two-hybrid screen of a mouse T cell lymphoma library. RIBP was also found to interact with a related member of the Tec family of tyrosine kinases, Itk. Expression of RIBP is restricted to T and natural killer cells and is upregulated substantially after T cell activation. RIBP-disrupted knockout mice displayed apparently normal T cell development. However, proliferation of RIBP-deficient T cells in response to T cell receptor (TCR)-mediated activation was significantly impaired. Furthermore, these activated T cells were defective in the production of interleukin (IL)-2 and interferon gamma, but not IL-4. These data suggest that RIBP plays an important role in TCR-mediated signal transduction pathways and that its binding to Itk and Rlk/Txk may regulate T cell differentiation. C1 Univ Chicago, Ben May Inst Canc Res, Chicago, IL 60637 USA. Univ Chicago, Dept Med, Pulm & Crit Care Med Sect, Chicago, IL 60637 USA. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. Univ Chicago, Comm Immunol, Chicago, IL 60637 USA. NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Bluestone, JA (reprint author), Univ Chicago, Ben May Inst Canc Res, MC 1089,5482 S Maryland Ave, Chicago, IL 60637 USA. FU NIAID NIH HHS [P01 AI35294-6] NR 50 TC 62 Z9 65 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD DEC 6 PY 1999 VL 190 IS 11 BP 1657 EP 1668 DI 10.1084/jem.190.11.1657 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 263QY UT WOS:000084137800011 PM 10587356 ER PT J AU Chen, DY Luongo, CL Nibert, ML Patton, JT AF Chen, DY Luongo, CL Nibert, ML Patton, JT TI Rotavirus open cores catalyze 5 '-capping and methylation of exogenous RNA: Evidence that VP3 is a methyltransferase SO VIROLOGY LA English DT Article ID MINUS-STRAND SYNTHESIS; MESSENGER-RNA; CAPPING ENZYME; GUANYLYLTRANSFERASE ACTIVITY; 5'-TRIPHOSPHATASE ACTIVITY; BLUETONGUE VIRUS; PROTEIN; POLYMERASE; REPLICATION; GENOME AB Rotavirus open cores prepared from purified virions consist of three proteins: the RNA-dependent RNA polymerase, VP1; the core shell protein, VP2; and the guanylyltransferase, VP3. In addition to RNA polymerase activity, open cores have been shown to contain a nonspecific guanylyltransferase activity that caps viral and nonviral RNAs in vitro. In this study, we examined the structure of RNA caps made by open cores and have analyzed open cores for other capping-related enzymatic activities. Utilizing RNase digestion and thin-layer chromatography, we found that the majority (similar to 70%) of caps made by open cores contain the tetraphosphate linkage, GppppG, rather than the triphosphate linkage, GpppG, found on mRNAs made by rotavirus double-layered particles. Enzymatic analysis indicated that the GppppG caps resulted from the lack of a functional RNA 5'-triphosphatase in open cores, to remove the gamma-phosphate from the RNA prior to capping. RNA 5'-triphosphatases commonly exhibit an associated nucleoside triphosphatase activity, and this too was not detected in open cores. Caps of some RNAs contained an extra GMP moiety (underlined) and had the structure 3'-GpGp(p)ppGpGpC-RNA-3'. The origin of the extra GMP is not known but may reflect the cap serving as a primer for RNA synthesis. Methylated caps were produced in the presence of the substrate, S-adenosyl-L-methionine (SAM), indicating that open cores contain methyltransferase activity. UV cross-linking showed that VP3 specifically binds SAM. Combined with the results of earlier studies, our results suggest that the viral guanylyltransferase and methyltransferase are both components of VP3 and, therefore, that VP3 is a multifunctional capping enzyme. (C) 1999 Academic Press. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Univ Wisconsin, Inst Mol Virol, Dept Biochem, Madison, WI 53706 USA. RP Patton, JT (reprint author), NIAID, Infect Dis Lab, NIH, 7 Ctr Dr,MSC 0720,Room 117, Bethesda, MD 20892 USA. RI Patton, John/P-1390-2014 FU NIAID NIH HHS [R29 AI39533]; PHS HHS [F32 18409A] NR 43 TC 59 Z9 63 U1 1 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD DEC 5 PY 1999 VL 265 IS 1 BP 120 EP 130 DI 10.1006/viro.1999.0029 PG 11 WC Virology SC Virology GA 264GP UT WOS:000084172500012 PM 10603323 ER PT J AU Grafman, J Litvan, I AF Grafman, J Litvan, I TI Importance of deficits in executive functions SO LANCET LA English DT Editorial Material ID DEMENTIA; MANAGEMENT C1 NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. Henry M Jackson Fdn, Def & Vet Head Injury Program, Cognit Neuropharmacol Unit, Bethesda, MD USA. RP Grafman, J (reprint author), NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. OI Grafman, Jordan H./0000-0001-8645-4457; Litvan, Irene/0000-0002-3485-3445 NR 11 TC 57 Z9 60 U1 2 U2 7 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD DEC 4 PY 1999 VL 354 IS 9194 BP 1921 EP 1923 DI 10.1016/S0140-6736(99)90438-5 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 261XA UT WOS:000084034700005 PM 10622291 ER PT J AU Nijhuis, M Schuurman, R de Jong, D Erickson, J Gustchina, E Albert, J Schipper, P Gulnik, S Boucher, CAB AF Nijhuis, M Schuurman, R de Jong, D Erickson, J Gustchina, E Albert, J Schipper, P Gulnik, S Boucher, CAB TI Increased fitness of drug resistant HIV-1 protease as a result of acquisition of compensatory mutations during suboptimal therapy SO AIDS LA English DT Article DE evolution; fitness; HIV; resistance ID HUMAN-IMMUNODEFICIENCY-VIRUS; DYNAMICS IN-VIVO; REVERSE-TRANSCRIPTASE; TYPE-1 PROTEASE; POPULATION-DYNAMICS; VIRAL FITNESS; INFECTION; RNA; INHIBITORS; RITONAVIR AB Objective: It is thought as a consequence of continuous replication, HIV-1 has acquired an optimal fitness state and that suboptimal antiretroviral therapy selects for drug resistant variants which show impaired Fitness in the absence of the drug. In this paper we studied the evolution and fitness of viral populations appearing in a patient who received protease monotherapy. Methods: Two factors contributing to fitness, drug resistance and protease catalytic activity, were studied at the enzymatic and virological level. Results: The first drug resistant viral variants that were selected in vivo harboured one to three protease substitutions. These mutants showed reduced protease activity and consequently a reduction in viral replication capacity. During continued in vivo replication of these viruses in the presence si the drug, novel variants harbouring additional substitutions in the viral protease appeared. These variants did not display any further increase in drug resistance but demonstrated clearly increased protease activity. Consequently the replication capacity of these viruses was raised to a level at which they replicated better than the original wild-type virus. Conclusion: This study indicates that the viral population in the patient does not have to represent the fittest possible variants, and thus antiretroviral therapy may drive the viral population first through a lower fitness level and then to a higher fitness level. (C) 1999 Lippincott Williams & Wilkins. C1 Univ Utrecht Hosp, Eijkman Winkler Inst, Dept Virol, NL-3584 CX Utrecht, Netherlands. NCI, Frederick Canc Res & Dev Ctr, SAIC, Frederick, MD USA. Swedish Inst Infect Dis Control, Dept Clin Virol, S-10521 Stockholm, Sweden. RP Boucher, CAB (reprint author), Univ Utrecht Hosp, Eijkman Winkler Inst, Dept Virol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands. NR 56 TC 267 Z9 270 U1 0 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD DEC 3 PY 1999 VL 13 IS 17 BP 2349 EP 2359 DI 10.1097/00002030-199912030-00006 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 261JZ UT WOS:000084007200006 PM 10597776 ER PT J AU Ekhterae, D Lin, ZW Lundberg, MS Crow, MT Brosius, FC Nunez, G AF Ekhterae, D Lin, ZW Lundberg, MS Crow, MT Brosius, FC Nunez, G TI ARC inhibits cytochrome c release from mitochondria and protects against hypoxia-induced apoptosis in heart-derived H9c2 cells SO CIRCULATION RESEARCH LA English DT Article DE apoptosis; ARC; hypoxia; cardiomyocyte; cytochrome c ID ACUTE MYOCARDIAL-INFARCTION; MYOCYTE APOPTOSIS; CARDIAC MYOCYTES; RAT; DEATH; P53; REPERFUSION; CASPASE-3; BCL-X(L); INJURY AB Ischemia induces apoptosis as well as necrosis of cardiac myocytes. We recently reported the cloning of a cDNA chat encodes an apoptotic inhibitor, ARC, that is expressed predominantly in cardiac and skeletal muscle, in the present study, we examined the ability of ARC to protect rat embryonic heart-derived H9c2 cells from apoptosis induced by hypoxia, a component of ischemia, We found that H9c2 cells express ARC and that exposure to hypoxia substantially reduces ARC expression while inducing apoptosis. Transfected H9c2 cells in which cytosolic ARC protein levels remain elevated during hypoxia were significantly more resistant to hypoxia-induced apoptosis than parental H9c2 cells or H9c2, cells transfected with a control vector. Loss of endogenous ARC in the cytosol of H9c2 cells was associated with translocation of ARC from the cytosol to intracellular membranes, release of cytochrome c from the mitochondria, activation of caspase-3, poly(ADP-ribose)polymerase (PARP) cleavage, and DNA fragmentation. All of these events were inhibited in H9c2 cells overexpressing ARC when compared with control cells, In contrast, caspase inhibitors prevented PARP cleavage but not cytochrome c release, suggesting that exogenously expressed ARC acts upstream of caspase activation in this model of apoptosis, These results demonstrate that ARC can protect heart myogenic H9c2 cells from hypoxia-induced apoptosis, and that ARC prevents cytochrome c release by acting upstream of caspase activation, perhaps at the mitochondrial level. The full text, of this article is available at http://.www.circresaha.org. C1 Univ Michigan, Sch Med, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Michigan, Sch Med, Dept Physiol, Ann Arbor, MI 48109 USA. Univ Michigan, Ctr Canc, Dept Pathol, Sch Med, Ann Arbor, MI 48109 USA. Vet Affairs Hosp, Ann Arbor, MI USA. NIA, Lab Cardiovasc Sci, NIH, Baltimore, MD 21224 USA. RP Nunez, G (reprint author), Univ Michigan, Ctr Canc, Dept Pathol, Sch Med, 1500 E Med Ctr Dr,4215 CCGC, Ann Arbor, MI 48109 USA. FU NCI NIH HHS [CA-64421, CA-64556]; NHLBI NIH HHS [HL-060156] NR 42 TC 97 Z9 102 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD DEC 3 PY 1999 VL 85 IS 12 BP E70 EP E77 PG 8 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 265BQ UT WOS:000084219500017 PM 10590251 ER PT J AU Fenyofalvi, G Bagossi, P Copeland, TD Oroszlan, S Boross, P Tozser, J AF Fenyofalvi, G Bagossi, P Copeland, TD Oroszlan, S Boross, P Tozser, J TI Expression and characterization of human foamy virus proteinase SO FEBS LETTERS LA English DT Article DE human foamy virus; proteinase; enzyme kinetics; substrate specificity ID MOLECULAR CHARACTERIZATION; RETROVIRAL PROTEINASES; SUBSTRATE-SPECIFICITY; POL POLYPROTEIN; LEUKEMIA-VIRUS; PROTEASE; HIV-1; GAG; INFECTIVITY; SITE AB The human foamy virus proteinase was expressed in fusion with maltose binding protein in Escherichia coli and purified. The specific activity of the fusion protein was similar to that of the processed enzyme. The kinetic constants on foamy virus cleavage site substrates were very low but comparable to those obtained with the gag-encoded avian proteinase on its own substrates. The proteinase showed preference for high ionic strength and a pH optimum of 6.6. None of the tested retroviral cleavage site peptides were substrates, however, some peptides representing cleavage sites in retrotransposons were properly processed by the enzyme. (C) 1999 Federation of European Biochemical Societies. C1 Debrecen Univ Med, Sch Med, Dept Biochem & Mol Biol, H-4012 Debrecen, Hungary. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Special Program Prot Chem, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Mol Virol & Carcinogenesis Lab, Frederick, MD 21702 USA. RP Tozser, J (reprint author), Debrecen Univ Med, Sch Med, Dept Biochem & Mol Biol, POB 6, H-4012 Debrecen, Hungary. EM tozser@indi.biochem.dote.hu RI Tozser, Jozsef/A-7840-2008; OI Tozser, Jozsef/0000-0003-0274-0056; Tozser, Jozsef/0000-0001-5076-8729 NR 28 TC 12 Z9 12 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 EI 1873-3468 J9 FEBS LETT JI FEBS Lett. PD DEC 3 PY 1999 VL 462 IS 3 BP 397 EP 401 DI 10.1016/S0014-5793(99)01563-X PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 263XU UT WOS:000084151200033 PM 10622733 ER PT J AU Barrett, WC DeGnore, JP Keng, YF Zhang, ZY Yim, MB Chock, PB AF Barrett, WC DeGnore, JP Keng, YF Zhang, ZY Yim, MB Chock, PB TI Roles of superoxide radical anion in signal transduction mediated by reversible regulation of protein-tyrosine phosphatase 1B SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EPIDERMAL GROWTH-FACTOR; HYDROGEN-PEROXIDE; SULFENIC ACID; PHOSPHORYLATION; MECHANISM; H2O2; INACTIVATION; INTERMEDIATE; GENERATION; CELLS AB Growth factors induce intracellular production of reactive oxygen species in non-phagocytic cells and elevation of their phosphorylated protein tyrosine level. The latter can be achieved by activating protein-tyrosine kinases and/or inactivating protein-tyrosine phosphatases (PTPs). A highly abundant PTP, PTP-1B, is known to be inactivated by oxidation of its catalytic site Cys-215. We show that O-2 is kinetically more efficient and chemically more specific oxidant than H2O2 for inactivating PTP-1B. The second-order rate constant for the O-2- and H2O2-mediated inactivation is 334 +/- 45 M-1 s(-1) and 42.8 +/- 3.8 M-1 s(-1), respectively. PTP-1B oxidized by H2O2 exhibits significantly more oxidized methionine residues and shows a lower degree of reversibility. The initial oxidative product, the Cys-215 sulfenic derivative, can easily be oxidized further to its irreversible sulfinic and sulfonic derivatives. This step is prevented by glutathionylation of the sulfenic derivative to form a S-glutathionylated PTP-1B, which can be reactivated by dithiothreitol or thioltransferase. Thus, a signal transduction mechanism mediated by the O-2(radical anion) and the participation of glutathione is proposed for the regulation of PTP-1B. This mechanism is supported by the in vivo demonstration that glutathionylated PTP-1B at Cys-215 is formed in A431 cells when they were treated with epidermal growth factor. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA. RP Chock, PB (reprint author), NHLBI, Biochem Lab, NIH, Bldg 3,Rm 204,3 Ctr Dr,MSC-0342, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA69202] NR 25 TC 260 Z9 270 U1 1 U2 7 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 DEC 3 PY 1999 VL 274 IS 49 BP 34543 EP 34546 DI 10.1074/jbc.274.49.34543 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 260XW UT WOS:000083979600010 PM 10574916 ER PT J AU Zhao, WQ Chen, H Xu, H Moore, E Meiri, N Quon, MJ Alkon, DL AF Zhao, WQ Chen, H Xu, H Moore, E Meiri, N Quon, MJ Alkon, DL TI Brain insulin receptors and spatial memory - Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; DIABETES-MELLITUS; ALZHEIMERS-DISEASE; CELLS; TRANSDUCTION; DEMENTIA; SHC; ASSOCIATION; METABOLISM; POPULATION AB Evidence accumulated from clinical and basic research has indirectly implicated the insulin receptor (IR) in brain cognitive functions, including learning and memory (Wickelgren, I. (1998) Science 280, 517-519), The present study investigates correlative changes in IR expression, phosphorylation, and associated signaling molecules in the rat hippocampus following water maze training. Although the distribution of IR protein matched that of IR mRNA in most forebrain regions, a dissociation of the IR mRNA and protein expression patterns was found in the cerebellar cortex. After training, IR mRNA in the CA1 and dentate gyrus of the hippocampus was up-regulated, and there was increased accumulation of LR protein in the hippocampal crude synaptic membrane fraction. In the CA1 pyramidal neurons, changes in the distribution pattern of LR in particular cellular compartments, such as the nucleus and dendritic regions, was observed only in trained animals. Although IR showed a low level of in vivo tyrosine phosphorylation, an insulin-stimulated increase of in vitro Tyr phosphorylation of IR was detected in trained animals, suggesting that learning may induce IR functional changes, such as enhanced receptor sensitivity. Furthermore, a training-induced co-immunoprecipitation of IR with Shc-66 was detected, along with changes in in vivo Tyr phosphorylation of Shc and mitogen-activated protein kinase, as well as accumulation of Shc-66, Shc-52, and Grb-2 in hippocampal synaptic membrane fractions following training. These findings suggest that IR may participate in memory processing through activation of its receptor Tyr kinase activity, and they suggest possible engagement of Shc/Grb-2/Ras/mitogen-activated protein kinase cascades. C1 NINDS, Lab Adapt Syst, NIH, Bethesda, MD 20892 USA. NHLBI, Hypertens Endocrine Branch, NIH, Bethesda, MD 20892 USA. Agr Res Org, Volcani Ctr, Inst Anim Sci, IL-50250 Bet Dagan, Israel. RP Zhao, WQ (reprint author), NINDS, Lab Adapt Syst, NIH, Bethesda, MD 20892 USA. EM wqzhao@helix.nih.gov RI Quon, Michael/B-1970-2008; OI Quon, Michael/0000-0002-9601-9915; Quon , Michael /0000-0002-5289-3707 NR 48 TC 299 Z9 320 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 3 PY 1999 VL 274 IS 49 BP 34893 EP 34902 DI 10.1074/jbc.274.49.34893 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 260XW UT WOS:000083979600057 PM 10574963 ER PT J AU Tarasova, NI Rice, WG Michejda, CJ AF Tarasova, NI Rice, WG Michejda, CJ TI Inhibition of G-protein-coupled receptor function by disruption of transmembrane domain interactions SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHOLECYSTOKININ RECEPTOR; MEMBRANE-PROTEIN; BACTERIORHODOPSIN; FRAGMENTS; PEPTIDES; IDENTIFICATION; RECONSTITUTION; COEXPRESSION; TRAFFICKING; ACTIVATION AB G-protein-coupled receptors (GPCR) represent a superfamily of proteins that mediate the function of neurotransmitters and peptide hormones and are involved in viral entry and perception of light, smell, and taste. GPCRs are characterized by the presence of seven transmembrane domains (TMs). We demonstrate here that structural analogs of individual TMs of GPCRs can serve as potent and specific receptor antagonists. Peptides derived from the transmembrane regions of CXCR4 and CCR5 chemokine receptors specifically inhibited receptor signaling and the in vitro replication of human immunodeficiency virus-1 (HIV-1) at concentrations as low as 0.2 mu M. Similarly, peptides mimicking the TMs of cholecystokinin receptor A, were found to abolish ligand binding and signaling through the receptor. Negative charges positioned at the extracellular termini of peptide antagonists appeared to be important for correct spontaneous insertion of the compounds into the cell membrane and for their activity. Targeting of the specific interactions between transmembrane domains of GPCRs is suggested as a general sequence-based method to disrupt receptor function for application in drug design and for structure-function studies of the receptors. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Mol Aspects Drug Design Sect, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Lab Antiviral Drug Mechanisms, Frederick, MD 21702 USA. RP Tarasova, NI (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Mol Aspects Drug Design Sect, POB B, Frederick, MD 21702 USA. NR 29 TC 67 Z9 67 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 DEC 3 PY 1999 VL 274 IS 49 BP 34911 EP 34915 DI 10.1074/jbc.274.49.34911 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 260XW UT WOS:000083979600059 PM 10574965 ER PT J AU Pacini, A Quattrone, A Denegri, M Fiorillo, C Nediani, C Cajal, SRY Nassi, P AF Pacini, A Quattrone, A Denegri, M Fiorillo, C Nediani, C Cajal, SRY Nassi, P TI Transcriptional down-regulation of poly(ADP-ribose) polymerase gene expression by E1A binding to pRb proteins protects murine keratinocytes from radiation-induced apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA-DAMAGING AGENTS; FUNCTIONAL INTERACTIONS; CELLULAR PROTEINS; SP1 BINDING; RB PROTEIN; CELLS; INDUCTION; REGION; P53; TRANSFORMATION AB Adenovirus E1A confers enhanced cell sensitivity to radiation and drug-induced DNA damage by a mechanism involving the binding to cellular proteins. Mutant analysis in E1A-transfected murine keratinocytes demonstrates that increased sensitivity to DNA damage requires at least E1A binding to the p300/CREB-binding protein (CBP) transcriptional coactivators and to pRb family members, indicating that this biological activity of E1A is the result of the concomitant perturbation of different cell pathways. Here we show that in the same cells E1A binding to members of the retinoblastoma protein family induces transcriptional down-regulation of the poly(ADP-ribose) polymerase (PARP) gene, coding for a NAD-dependent enzyme stimulated by DNA breaks, Inhibition of PARP expression is accompanied by a decrement of gamma-irradiation-induced apoptosis, which is overridden by reconstitution of wild type levels of PARP. Hence, E1A effects on PARP transcription are central determinant of the apoptotic sensitivity of E1A-expressing keratinocytes, Conversely, E1A binding to only p300/CBP results in an increase in PARP enzyme activity and consequently in cell death susceptibility to irradiation, which is effectively counteracted by the PARP chemical inhibitor 3-aminobenzamide. Therefore, our results identify in the E1A-mediated effects on PARP expression and activity a key molecular event involved in E1A-induced cell sensitization to genotoxic stress. C1 Univ Florence, Dept Biochem Sci, I-50121 Florence, Italy. CNR, Inst Genet & Evolutionary Biochem, I-27100 Pavia, Italy. NINDS, Lab Adapt Syst, NIH, Bethesda, MD 20892 USA. Clin Puerta Hierro, Dept Pathol, Madrid 28035, Spain. RP Pacini, A (reprint author), Univ Florence, Dept Biochem Sci, I-50121 Florence, Italy. RI Espinosas, Maribel /H-8083-2012; Ramon y Cajal, Santiago/H-4955-2016; OI Ramon y Cajal, Santiago/0000-0002-3867-1390; Fiorillo, Claudia/0000-0003-1165-1581; Quattrone, Alessandro/0000-0003-3333-7630 NR 43 TC 17 Z9 17 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 DEC 3 PY 1999 VL 274 IS 49 BP 35107 EP 35112 DI 10.1074/jbc.274.49.35107 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 260XW UT WOS:000083979600086 PM 10574992 ER PT J AU Ciolino, HP Yeh, GC AF Ciolino, HP Yeh, GC TI The steroid hormone dehydroepiandrosterone inhibits CYP1A1 expression in vitro by a post-transcriptional mechanism SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ARYL-HYDROCARBON RECEPTOR; 7,12-DIMETHYLBENZ(A) ANTHRACENE DMBA; BREAST-CANCER CELLS; MAMMARY-CARCINOMA; MICE; GLUCOSE-6-PHOSPHATE-DEHYDROGENASE; SULFATE; DHEA; RAT; TUMORIGENESIS AB The adrenal steroid hormone dehydroepiandrosterone (DHEA) is a potent inhibitor of mammary carcinogenesis induced by polycyclic aromatic hydrocarbons (PAH), though its mechanism is unclear. We examined the effect of DHEA on the expression of the carcinogen-activating enzyme cytochrome P450 1A1 (CYP1A1) in MCF-7 human breast epithelial carcinoma cells. DHEA inhibited the increase in CYP1A1 enzyme activity that occurs when MCF-7 cells are exposed to the PAM dimethylbenzanthracene (DMBA) or 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD). However, DHEA did not directly inhibit enzyme activity as it had no effect when added to the cells after induction by DMBA or TCDD. We observed that the increase of CYP1A1 mRNA in MCF-7 cells caused by DMBA or TCDD was inhibited by DHEA in a concentration-dependent manner. However, DHEA did not inhibit CYP1A1 promoter-driven transcription, indicating that it did not affect the aryl hydrocarbon receptor, which regulates transcription of the CYP1A1 gene. Actinomycin D chase experiments showed that DHEA caused a time- and concentration-dependent decrease in CYP1A1 mRNA levels, indicating that DHEA inhibits CYP1A1 expression by decreasing CYP1A1 mRNA stability. These data demonstrate that DHEA inhibits PAM-induced CYP1A1 mRNA expression and enzyme activity in vitro by a post-transcriptional mechanism. This regulation of the expression of carcinogen-activating enzymes may be responsible for the chemopreventive activity of DHEA and may be one of its physiologic functions in vivo. C1 NCI, Frederick Canc Res & Dev Ctr, Cellular Def & Carcinogenesis Sect, Basic Res Lab,Div Basic Sci,NIH, Ft Detrick, MD 21702 USA. RP Ciolino, HP (reprint author), NCI, Frederick Canc Res & Dev Ctr, Cellular Def & Carcinogenesis Sect, Basic Res Lab,Div Basic Sci,NIH, Bldg 560,Rm 12-05,POB B, Ft Detrick, MD 21702 USA. NR 40 TC 24 Z9 25 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 DEC 3 PY 1999 VL 274 IS 49 BP 35186 EP 35190 DI 10.1074/jbc.274.49.35186 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 260XW UT WOS:000083979600096 PM 10575002 ER PT J AU Wickner, S Maurizi, MR Gottesman, S AF Wickner, S Maurizi, MR Gottesman, S TI Posttranslational quality control: Folding, refolding, and degrading proteins SO SCIENCE LA English DT Review ID ENERGY-DEPENDENT PROTEASES; COLI CLPAP PROTEASE; ESCHERICHIA-COLI; TAGGING SYSTEM; DEGRADATION; CHAPERONE; PROTEOLYSIS; SPECIFICITY; TARGETS; HSP70 AB Polypeptides emerging from the ribosome must fold into stable three-dimensional structures and maintain that structure throughout their functional Lifetimes. Maintaining quality control over protein structure and function depends on molecular chaperones and proteases, both of which can recognize hydrophobic regions exposed on unfolded polypeptides. Molecular chaperones promote proper protein folding and prevent aggregation, and energy-dependent proteases eliminate irreversibly damaged proteins. The kinetics of partitioning between chaperones and proteases determines whether a protein will be destroyed before it folds properly. When both quality control options fail, damaged proteins accumulate as aggregates, a process associated with amyloid diseases. C1 NCI, Mol Biol Lab, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, Bethesda, MD 20892 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, Bethesda, MD 20892 USA. NR 62 TC 762 Z9 777 U1 4 U2 50 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 DEC 3 PY 1999 VL 286 IS 5446 BP 1888 EP 1893 DI 10.1126/science.286.5446.1888 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 261HH UT WOS:000084003400037 PM 10583944 ER PT J AU Ma, JY Katz, E Ziffer, H AF Ma, JY Katz, E Ziffer, H TI A new synthetic route to 10 beta-alkyldeoxoartemisinins SO TETRAHEDRON LETTERS LA English DT Article DE artemisinin; lactol acetate; trimethyloxy group; titanium tetrachloride ID QINGHAOSU ARTEMISININ; DERIVATIVES; ACID AB Artemisinin was reduced with DIBAL and acetylated to yield 10 alpha-acetoxyartemisinin. The latter compound was treated with titanium tetrachloride and a series of trimethylsiloxyl enol ethers to produce a series of 10 beta-alkyldeoxoartemisinins. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 NIDDK, Chem Phys Lab, Bethesda, MD 20892 USA. NIDDK, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Ziffer, H (reprint author), NIDDK, Chem Phys Lab, Bethesda, MD 20892 USA. NR 8 TC 17 Z9 17 U1 0 U2 0 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 DEC 3 PY 1999 VL 40 IS 49 BP 8543 EP 8545 DI 10.1016/S0040-4039(99)01824-9 PG 3 WC Chemistry, Organic SC Chemistry GA 255JK UT WOS:000083665600011 ER PT J AU Lee, RE Smith, MD Pickering, L Fleet, GWJ AF Lee, RE Smith, MD Pickering, L Fleet, GWJ TI An approach to combinatorial library generation of galactofuranose mimics as potential inhibitors of mycobacterial cell wall biosynthesis: Synthesis of a peptidomimetic of uridine 5 '-diphosphogalactofuranose (UDP-Galf) SO TETRAHEDRON LETTERS LA English DT Article DE amide; combinatorial chemistry; tuberculosis; galactofuranose; transferase; inhibition ID TUBERCULOSIS; ANALOGS; GLYCOSYLTRANSFERASES; ARABINOSE; ENVELOPE; MUTASE; ASSAY; DONOR AB An approach to the synthesis of amide libraries based upon an alpha-iminogalactofuranose template as potential inhibitors of mycobacterial cell wall biosynthesis is described. The synthesis of peptide analogues of uridine 5'-phosphogalactofuranose (UDP-Galf) is also described. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 Univ Oxford, Dyson Perrins Lab, Oxford Ctr Mol Sci, Oxford OX1 3QY, England. NAID, Host Def Lab, DIR, NIH, Rockville, MD 20852 USA. RP Fleet, GWJ (reprint author), Univ Oxford, Dyson Perrins Lab, Oxford Ctr Mol Sci, S Parks Rd, Oxford OX1 3QY, England. RI Lee, Richard/J-4997-2013 OI Lee, Richard/0000-0002-2397-0443 NR 19 TC 49 Z9 49 U1 0 U2 5 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 DEC 3 PY 1999 VL 40 IS 49 BP 8689 EP 8692 DI 10.1016/S0040-4039(99)01844-4 PG 4 WC Chemistry, Organic SC Chemistry GA 255JK UT WOS:000083665600044 ER PT J AU Kovanen, PE Leonard, WJ AF Kovanen, PE Leonard, WJ TI Cytokine signaling: Inhibitors keep cytokines in check SO CURRENT BIOLOGY LA English DT Article ID SOCS-BOX MOTIF; INTERFERON-GAMMA; TRANSGENIC MICE; INDUCIBLE GENE; PROTEIN; LIVER; ERYTHROPOIETIN; INTERLEUKIN-2; DEFICIENCIES; SUPPRESSION AB Some members of the CIS/SOCS/IAB/SSI family have been demonstrated to be cytokine-inducible inhibitors of cytokine signaling. Steps have now been made towards clarifying the biological function of two of these proteins, revealing that these inhibitors are essential for the correct maintenance of cytokine signaling. C1 NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Kovanen, PE (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 29 TC 29 Z9 29 U1 0 U2 1 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD DEC 2 PY 1999 VL 9 IS 23 BP R899 EP R902 DI 10.1016/S0960-9822(00)80079-2 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 348GN UT WOS:000088977300012 PM 10607559 ER PT J AU Salvadori, S Guerrini, R Balboni, G Bianchi, C Bryant, SD Cooper, PS Lazarus, LH AF Salvadori, S Guerrini, R Balboni, G Bianchi, C Bryant, SD Cooper, PS Lazarus, LH TI Further studies on the Dmt-Tic pharmacophore: Hydrophobic substituents at the C-terminus endow delta antagonists to manifest mu agonism or mu antagonism SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID OPIOID RECEPTOR ANTAGONIST; RENAL-ALLOGRAFT SURVIVAL; TETRAHYDROISOQUINOLINE-3-CARBOXYLIC ACID; DIKETOPIPERAZINE FORMATION; INDUCED ANALGESIA; LIGAND-BINDING; HIGHLY POTENT; DELTORPHIN-I; PEPTIDES; SELECTIVITY AB Twenty N- and/or C-modified Dmt-Tic analogues yielded similar K-i values with either [H-3]DPDPE (delta(1) agonist) or [H-3]N,N(Me)(2)-Dmt-Tic-OH (delta antagonist). N-Methylation enhanced delta antagonism while N-piperidine-1-yl, N-pyrrolidine-1-yl, and N-pyrrole-1-yl were detrimental. Dmt-Tic-X (X = -NHNH2, -NHCH3, -NH-1-adamantyl, -NH-tBu, -NH-5-tetrazolyl) had high delta affinities (K-i = 0.16 to 1 nM) with variable mu affinities to yield nonselective or weakly mu-selective analogues, N,N-(Me)(2)Dmt-Tic-NH-1-adamantane exhibited dual delta and mu receptor affinities (K(i)delta = 0.16 nM and K(i)mu =1.12 nM) and potent delta antagonism (pA(2) = 9.06) with mu agonism (IC50 = 16 nM). H-Dmt-beta HTic-OH (methylene bridge between C-alpha of Tic and carboxylate function) yielded a biostable peptide with high delta affinity (K-i = 0.85 nM) and delta antagonism (pA(2) = 8.85) without mu bioactivity, Dmt-Tic-Ala-X (X = -NHCH3, -OCH3, -NH-1-adamantyl, -NHtBu) exhibited high delta affinities (K-i = 0.06 to 0.2 nM) and elevated mu affinities (K-i = 2.5 to 11 nM), but only -Dmt-Tic-Ala-NH-1-adamantane and H-Dmt-Tic-Ala-NHtBu yielded delta receptor antagonism (pA(2) = 9.29 and 9.16, respectively). Thus, Dmt-Tic with hydrophobic C-terminal substituents enhanced mu affinity to provide delta antagonists with dual receptor affinities and bifunctional activity. C1 NIEHS, LCBRA, Res Triangle Pk, NC 27709 USA. Univ Ferrara, Dept Pharmaceut Sci, I-441000 Ferrara, Italy. Univ Ferrara, Ctr Biotechnol, I-441000 Ferrara, Italy. Univ Ferrara, Inst Pharmacol, I-44100 Ferrara, Italy. Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP NIEHS, LCBRA, MD C3-04,POB 12233, Res Triangle Pk, NC 27709 USA. EM lazarus@niehs.nih.gov OI Guerrini, Remo/0000-0002-7619-0918; SALVADORI, Severo/0000-0002-8224-2358 NR 69 TC 55 Z9 57 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD DEC 2 PY 1999 VL 42 IS 24 BP 5010 EP 5019 DI 10.1021/jm990165m PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 262HX UT WOS:000084062200010 PM 10585210 ER PT J AU Lewis, DB Matecka, D Zhang, Y Hsin, LW Dersch, CM Stafford, D Glowa, JR Rothman, RB Rice, KC AF Lewis, DB Matecka, D Zhang, Y Hsin, LW Dersch, CM Stafford, D Glowa, JR Rothman, RB Rice, KC TI Oxygenated analogues of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909) as potential extended-action cocaine-abuse therapeutic agents SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID DOPAMINE REUPTAKE INHIBITORS; TRANSPORTER KNOCKOUT MICE; UPTAKE COMPLEX; NOREPINEPHRINE TRANSPORTER; EXTRACELLULAR DOPAMINE; O-DEMETHYLATION; RHESUS-MONKEYS; BINDING; GBR-12909; SEROTONIN AB An investigation into the preparation of potential extended-release cocaine-abuse therapeutic agents afforded a series of compounds related to 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl) piperazine(1a) and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (1b) (GBR 12935 and GBR 12909, respectively), which were designed, synthesized, and evaluated for their ability to bind to the dopamine transporter (DAT) and to inhibit the uptake of [(3)H]-labeled dopamine (DA). The addition of hydroxy and methoxy substituents to the benzene ring on the phenylpropyl moiety of 1a-1d resulted in a series of potent and selective ligands for the DAT (analogues 5-28). The hydroxyl groups were included to incorporate a medium-chain carboxylic acid ester into the molecules, to form oil-soluble prodrugs, amenable to "depot" injection techniques. The introduction of an oxygen-containing functionality to the propyl side chain provided ketones 29 and 30, which demonstrated greatly reduced affinity for the DAT and decreased potency in inhibiting the uptake of [(3)H]DA, and benzylic alcohols 31-36, which were highly potent and selective at binding to the DAT and inhibiting [(3)H]DA uptake. The enantiomers of 32 (34 and 36) were practically identical in biological testing. Compounds Ib, 32, 34, and 36 all demonstrated the ability to decrease cocaine-maintained responding in monkeys without affecting behaviors maintained by food, with 34 and 36 equipotent to each other and both more potent in behavioral tests than the parent compound Ib. Intramuscular injections of compound 41 (the decanoate ester of racemate 32) eliminated cocaine-maintained behavior for about a month following one single injection, without affecting food-maintained behavior. The identification of analogues 32, 34, and 36, thus, provides three potential candidates for esterification and formulation as extended-release cocaine-abuse therapeutic agents. C1 NIDDK, Med Chem Lab, NIH, Bethesda, MD 20892 USA. NIDA, Clin Psychopharmacol Sect, IRP, NIH, Baltimore, MD 21224 USA. Louisiana State Univ, Med Ctr, Dept Pharmacol & Therapeut, Shreveport, LA 71130 USA. RP Rice, KC (reprint author), NIDDK, Med Chem Lab, NIH, 8 Ctr Dr,MSC 0815,Bldg 8,Room B1-23,9000 Rockvill, Bethesda, MD 20892 USA. EM KR21F@NIH.gov OI HSIN, LING-WEI/0000-0001-5018-4491 NR 68 TC 51 Z9 52 U1 2 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD DEC 2 PY 1999 VL 42 IS 24 BP 5029 EP 5042 DI 10.1021/jm990291q PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 262HX UT WOS:000084062200012 PM 10585212 ER PT J AU Cassman, M Patrinos, A AF Cassman, M Patrinos, A TI Who's doing what in US protein initiative SO NATURE LA English DT Letter C1 Natl Inst Gen Med Sci, NIH, Bethesda, MD 20892 USA. Dept Energy, Germantown, MD 20874 USA. RP Cassman, M (reprint author), Natl Inst Gen Med Sci, NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD DEC 2 PY 1999 VL 402 IS 6761 BP 457 EP 458 DI 10.1038/44935 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 261MP UT WOS:000084013200021 PM 10591199 ER PT J AU Tyler, JK Adams, CR Chen, SR Kobayashi, R Kamakaka, RT Kadonaga, JT AF Tyler, JK Adams, CR Chen, SR Kobayashi, R Kamakaka, RT Kadonaga, JT TI The RCAF complex mediates chromatin assembly during DNA replication and repair SO NATURE LA English DT Article ID SACCHAROMYCES-CEREVISIAE; II TRANSCRIPTION; YEAST; PROTEIN; GENES; IDENTIFICATION; ACETYLATION; REPRESSION; TELOMERES; INVITRO AB Chromatin assembly is a fundamental biological process that is essential for the replication and maintenance of the eukaryotic genome(1-4). In dividing cells, newly synthesized DNA is rapidly assembled into chromatin by the deposition of a tetramer of the histone proteins H3 and H4, followed by the deposition of two dimers of histones H2A and H2B to complete the nucleosome-the fundamental repeating unit of chromatin(5). Here we describe the identification, purification, cloning, and characterization of replication-coupling assembly factor (RCAF), a novel protein complex that facilitates the assembly of nucleosomes onto newly replicated DNA in vitro. RCAF comprises the Drosophila homologue of anti-silencing function 1 protein ASF1(6) and histones H3 and H4. The specific acetylation pattern of H3 and H4 in RCAF is identical to that of newly synthesized histones. Genetic analyses in Saccharomyces cerevisiae demonstrate that ASF1 is essential for normal fell cycle progression, and suggest that RCAF mediates chromatin assembly after DNA replication and the repair of double-strand DNA damage in vivo. C1 Univ Calif San Diego, Dept Biol, La Jolla, CA 92093 USA. Univ Calif San Diego, Ctr Mol Genet, La Jolla, CA 92093 USA. NICHD, NIH, Bethesda, MD 20892 USA. Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. RP Tyler, JK (reprint author), Univ Calif San Diego, Dept Biol, La Jolla, CA 92093 USA. NR 28 TC 371 Z9 376 U1 1 U2 8 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD DEC 2 PY 1999 VL 402 IS 6761 BP 555 EP 560 DI 10.1038/990147 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 261MP UT WOS:000084013200063 PM 10591219 ER PT J AU Wolfe, RA Ashby, VB Milford, EL Ojo, AO Ettenger, RE Agodoa, LYC Held, PJ Port, FK AF Wolfe, RA Ashby, VB Milford, EL Ojo, AO Ettenger, RE Agodoa, LYC Held, PJ Port, FK TI Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID STAGE RENAL-DISEASE; QUALITY-OF-LIFE; FOLLOW-UP; SURVIVAL; IMPACT; ACCESS; RATES AB Background: The extent to which renal allotransplantation -- as compared with long-term dialysis -- improves survival among patients with end-stage renal disease is controversial, because those selected for transplantation may have a lower base-line risk of death. Methods: In an attempt to distinguish the effects of patient selection from those of transplantation itself, we conducted a longitudinal study of mortality in 228,552 patients who were receiving long-term dialysis for end-stage renal disease. Of these patients, 46,164 were placed on a waiting list for transplantation, 23,275 of whom received a first cadaveric transplant between 1991 and 1997. The relative risk of death and survival were assessed with time-dependent nonproportional-hazards analysis, with adjustment for age, race, sex, cause of end-stage renal disease, geographic region, time from first treatment for end-stage renal disease to placement on the waiting list, and year of initial placement on the list. Results: Among the various subgroups, the standardized mortality ratio for the patients on dialysis who were awaiting transplantation (annual death rate, 6.3 per 100 patient-years) was 38 to 58 percent lower than that for all patients on dialysis (annual death rate, 16.1 per 100 patient-years). The relative risk of death during the first 2 weeks after transplantation was 2.8 times as high as that for patients on dialysis who had equal lengths of follow-up since placement on the waiting list, but at 18 months the risk was much lower (relative risk, 0.32; 95 percent confidence interval, 0.30 to 0.35; P<0.001). The likelihood of survival became equal in the two groups within 5 to 673 days after transplantation in all the subgroups of patients we examined. The long-term mortality rate was 48 to 82 percent lower among transplant recipients (annual death rate, 3.8 per 100 patient-years) than patients on the waiting list, with relatively larger benefits among patients who were 20 to 39 years old, white patients, and younger patients with diabetes. Conclusions: Among patients with end-stage renal disease, healthier patients are placed on the waiting list for transplantation, and long-term survival is better among those on the waiting list who eventually undergo transplantation. (N Engl J Med 1999;341:1725-30.) (C)1999, Massachusetts Medical Society. C1 Univ Michigan, US Renatl Data Syst Coordinating Ctr, Ann Arbor, MI 48103 USA. Univ Michigan, Dept Biostat, Ann Arbor, MI 48103 USA. Univ Michigan, Dept Internal Med, Ann Arbor, MI 48103 USA. Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48103 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Univ Calif Los Angeles, Dept Pediat Nephrol, Los Angeles, CA 90024 USA. NIDDKD, Bethesda, MD 20892 USA. Univ Renal Res Educ Assoc, Ann Arbor, MI USA. RP Wolfe, RA (reprint author), Univ Michigan, US Renatl Data Syst Coordinating Ctr, 315 W Huron,Suite 240, Ann Arbor, MI 48103 USA. FU NIDDK NIH HHS [N01-DK-3-2202] NR 20 TC 2172 Z9 2234 U1 10 U2 44 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 DEC 2 PY 1999 VL 341 IS 23 BP 1725 EP 1730 DI 10.1056/NEJM199912023412303 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 260NB UT WOS:000083955800003 PM 10580071 ER PT J AU Kang, SH Bang, YJ Im, YH Yang, HK Lee, DA Lee, HY Lee, HS Kim, NK Kim, SJ AF Kang, SH Bang, YJ Im, YH Yang, HK Lee, DA Lee, HY Lee, HS Kim, NK Kim, SJ TI Transcriptional repression of the transforming growth factor-beta type I receptor gene by DNA methylation results in the development of TGF-beta resistance in human gastric cancer SO ONCOGENE LA English DT Article DE transforming growth factor-beta; CpG methylation; cancer; receptor ID TUMOR-SUPPRESSOR GENE; COLON-CARCINOMA CELLS; MICROSATELLITE INSTABILITY; CPG ISLAND; COLORECTAL-CANCER; MISMATCH REPAIR; EXPRESSION; ACTIVATION; MALIGNANCY; PROMOTER AB The transforming growth factor-beta (TGF-beta) signaling pathway subserves an essential tumor suppressor function in various cell types. A heteromeric complex composed of TGF-beta type I (RI) and type II (RII) receptors is required for TGF-beta signaling. We have identified a subset of human gastric cancer cell lines which are insensitive to TGF-beta and which express a low level of TGF-beta type I receptor mRNA relative to a gastric cancer cell line which is highly responsive to TGF-beta. Using these cells, we show that hypermethylation of a CpG island in the 5' region of the TGF-beta RI gene provides another potentially important mechanism of escape from negative growth control by TGF-beta, This hypermethylation was found in four of five human gastric cancer cell lines and five out of 40 (12.5%) primary tumors examined, In human gastric cancer cell lines, treatment with the demethylating agent, 5-aza-2'-deoxycytidine, resulted in increased expression of the TGF-beta RI gene, but not the RII gene, Transient transfection of an RI expression vector into the TGF-beta resistant SNU-601 cell line restores TGF-beta responsiveness. These findings suggest that one of the mechanisms of escape from autocrine or paracrine growth control by TGF-beta during carcinogenesis could involve aberrant methylation of CpG islands in the 5' region of the TGF-beta RI gene. C1 Seoul Natl Univ, Coll Med, Canc Res Ctr, Seoul, South Korea. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Kim, SJ (reprint author), Seoul Natl Univ, Coll Med, Canc Res Ctr, Seoul, South Korea. RI Yang, Han-Kwang/J-2767-2012; Bang, Yung Jue/J-2759-2012 NR 41 TC 92 Z9 101 U1 1 U2 4 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD DEC 2 PY 1999 VL 18 IS 51 BP 7280 EP 7286 DI 10.1038/sj.onc.1203146 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 263HN UT WOS:000084119400012 PM 10602482 ER PT J AU Kriebel, P Patel, BKR Nelson, SA Grusby, MJ LaRochelle, WJ AF Kriebel, P Patel, BKR Nelson, SA Grusby, MJ LaRochelle, WJ TI Consequences of Stat6 deletion on Sis/PDGF- and IL-4-induced proliferation and transcriptional activation in murine fibroblasts SO ONCOGENE LA English DT Article DE PDGF; IL-4; Stat-6; transcriptional activation ID SIMIAN SARCOMA-VIRUS; HUMAN RECOMBINANT INTERLEUKIN-4; GROWTH-FACTOR RECEPTORS; JAK-3 JANUS KINASE; NF-KAPPA-B; TYROSINE PHOSPHORYLATION; FACTOR-I; HEMATOPOIETIC-CELLS; MYELOID CELLS; GENE AB Aberrant communication among growth factors and cytokines that regulate tissue homeostasis often results in malignancy. Among the many cell types that participate in this process, stromal fibroblasts communicate in a paracrine and juxtracrine manner with cells of epithelial, endothelial, and hematopoietic origin. For fibroblasts, platelet-derived growth factor (PDGF) is a major proliferative and differentiation agent, Interleukin-4 (IL-4), however, possesses only modulating functions in this cell type. Here, we investigated the consequences of deleting Stat6 on PDGF and IL-4 signaling, proliferation, and transcriptional activation by establishing and characterizing early passage fibroblasts from wild-type and Stat6 null mice. Both wild-type and Stat6(-/-) fibroblasts showed nearly identical PDGFR and IL-4R activation, gross substrate tyrosine phosphorylation, PI 3-kinase activation, as well as Stat1, 3 and 5 DNA binding activities. Unexpectedly, IL-4's enhancement of PDGF-induced [H-3]thymidine incorporation was greatly diminished in Stat6(-/-), but not wild-type fibroblasts, PDGF-induced [H-3]thymidine uptake was largely unaffected. Strikingly, IL-3, but not PDGF induction of the proinflammatory gene products, IL-6 and MCP-1 was markedly reduced in Stat6(-/-) fibroblasts. Thus, Stat6 is an important and specific mediator of IL-1-enhanced PDGF-induced proliferation as well as IL-4's transcriptional activation of IL-6 and MCP-1. C1 NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Sch Publ Hlth, Dept Canc Biol, Boston, MA 02115 USA. RP LaRochelle, WJ (reprint author), NCI, Cellular & Mol Biol Lab, Bldg 37,Room 1E24, Bethesda, MD 20892 USA. FU NIAID NIH HHS [AI40171] NR 65 TC 9 Z9 9 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD DEC 2 PY 1999 VL 18 IS 51 BP 7294 EP 7302 DI 10.1038/sj.onc.1203148 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 263HN UT WOS:000084119400014 PM 10602484 ER PT J AU Palayoor, ST Youmell, MY Calderwood, SK Coleman, CN Price, BD AF Palayoor, ST Youmell, MY Calderwood, SK Coleman, CN Price, BD TI Constitutive activation of I kappa B kinase alpha and NF-kappa B in prostate cancer cells is inhibited by ibuprofen SO ONCOGENE LA English DT Article DE NF-kappa B; ibuprofen; prostate; tumor; IKK alpha; androgen ID ANDROGEN RECEPTOR GENE; IKK-ALPHA; PHOSPHORYLATION; PROTEIN; BETA; SALICYLATE; EXPRESSION; APOPTOSIS; ASPIRIN; STIMULI AB Apoptotic pathways controlled by the Rel/NF-kappa B family of transcription factors may regulate the response of cells to DNA damage. Here, we have examined the NF-kappa B status Of several prostate tumor cell lines. In the androgen-independent prostate tumor cells PC-3 and DU-145, the DNA-binding activity of NF-kappa B was constitutively activated and I kappa B-alpha levels were decreased, In contrast, the androgen-sensitive prostate tumor cell line LNCaP had low levels of NF-kappa B which were upregulated following exposure to cytokines or DNA damage, The activity of the I kappa B-alpha kinase, IKK alpha, which mediates NF-kappa B activation, was also measured. In PC-3 cells, IKK alpha activity was constitutively active, whereas LNCaP cells had minimal IKK alpha activity that was activated by cytokines. The anti-inflammatory agent ibuprofen inhibited the constitutive activation of NF-kappa B and IKK alpha in PC-3 and DU-145 cells, and blocked stimulated activation of NF-kappa B in LNCaP cells. However, ibuprofen did not directly inhibit I kappa B-alpha kinase, The results demonstrate that NF-kappa B is constitutively activated in the hormone-insensitive prostate tumor cell lines PC-3 and DU-145, but not in the hormone responsive LNCaP cell line. The constitutive activation of NF-kappa B in prostate tumor cells may increase expression of anti-apoptotic proteins, thereby decreasing the effectiveness of anti-tumor therapy and contributing to the development of the malignant phenotype. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Joint Ctr Radiat Therapy,Dept Adult Oncol, Boston, MA 02115 USA. NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. RP Price, BD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Joint Ctr Radiat Therapy,Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA64585] NR 31 TC 243 Z9 247 U1 0 U2 7 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD DEC 2 PY 1999 VL 18 IS 51 BP 7389 EP 7394 DI 10.1038/sj.onc.1203160 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 263HN UT WOS:000084119400026 PM 10602496 ER PT J AU Gu, J Yu, LC AF Gu, J Yu, LC TI X-ray diffraction of helices with arbitrary periodic ligand binding SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID RABBIT PSOAS MUSCLE; FILAMENTS; RIGOR AB The classical formalism for studying diffraction from helical structures extended to include ligand binding is presented. The diffraction from such a binding pattern is the convolution of the Fourier transforms of the helix and the one-dimensional binding distribution. It is shown in the present analysis that it is not necessary to assume that the binding distribution is strictly periodic, as long as its Fourier transform can be determined. Analysis of the convolution gives a general expression for the diffracted intensities and the selection rule for the layer-lines. It shows two groups of layer-lines: one group is the familiar layer-line set from the original helix, while the other group shows reciprocal spacings shifted by 1/a from the original helix layer-lines, where a is the average repeat of the binding distribution. This group of layer-lines is contributed by the ligand only. By way of examples, calculated diffraction patterns from muscle actin filaments with bound myosin heads in three different binding patterns are presented. This approach provides a method for determining the ligand-binding distribution along helices by an analysis of their X-ray diffraction patterns. C1 NIAMSD, NIH, Bethesda, MD 20892 USA. RP Yu, LC (reprint author), NIAMSD, NIH, Bethesda, MD 20892 USA. NR 17 TC 3 Z9 3 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD DEC PY 1999 VL 55 BP 2022 EP 2027 DI 10.1107/S0907444999013335 PN 12 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 268WD UT WOS:000084440000008 PM 10666578 ER PT J AU Kordek, R Hainfellner, JA Liberski, PP Budka, H AF Kordek, R Hainfellner, JA Liberski, PP Budka, H TI Deposition of the prion protein (PrP) during the evolution of experimental Creutzfeldt-Jakob disease SO ACTA NEUROPATHOLOGICA LA English DT Article DE transmissible spongiform encephalopathy; prion protein; apolipoprotein E; Creutzfeldt-Jakob disease; neuropathology ID CENTRAL-NERVOUS-SYSTEM; APOLIPOPROTEIN-E; ALZHEIMERS-DISEASE; SPONGIFORM ENCEPHALOPATHY; SEQUENTIAL DEVELOPMENT; TRANSGENIC MICE; SCRAPIE; TRANSMISSION; ACCUMULATION; NEURODEGENERATION AB We studied the immunocytochemical distribution of the prion or proteinase-resistant protein (PrP) during the evolution of experimental Creutzfeldt-Jakob disease (CJD) in mice. Fifty-one brains were collected up to 22 weeks following intracerebral inoculation with the Fujisaki strain of the CJD agent. Slides were also immunostained for apolipoprotein E (apoE) and glial fibrillary acidic protein. Vacuolar changes with focal astrocytosis first occurred around the needle track at week 2 and later spread along white matter tracks. Until week 12, changes were asymmetrical, affecting more the side of inoculation. Spongiform change and astrogliosis spread subsequently to the gray matter. Time course and intensity of spongiform change and immunocytochemistry for PrP were discrepant: in most brain regions, severe vacuolation preceded immunocytochemically detectable PrP accumulation. PrP deposits in form of small dots were first detectable at week 6 in the area surrounding the needle track. After week 7, plaque-like amorphous PrP deposits were observed in white matter pathways. Finally, PrP was detectable also in basal ganglia and in the dorsal hippocampus (week 13) and in the neocortex (week 17), as the synaptic type of PrP immunopositivity. In the hippocampus, diffuse PrP deposits paralleled spongiform change, while in the cortex severe vacuolation was accompanied only by weak synaptic PrP deposits. Immunocytochemically detectable apoE was restricted to compact plaque-type PrP deposits after week 15. We conclude that disease-specific neuropathology spreads from the needle track along white matter pathways towards the gray matter; in this model, there is some discrepancy between development of tissue pathology and immunocytochemically detectable deposition of PrP. Immunocytochemically detectable apoE deposition follows PrP accumulation. C1 Univ Vienna, Neurol Inst, A-1097 Vienna, Austria. NINDS, Cent Nervous Syst Studies Lab, NIH, Bethesda, MD 20892 USA. Med Acad Lodz, Dept Mol Biol, Chair Oncol, Lodz, Poland. RP Budka, H (reprint author), Univ Vienna, Neurol Inst, AKH 04J, A-1097 Vienna, Austria. RI Kordek, Radzislaw/S-9616-2016; OI Budka, Herbert/0000-0002-1933-1577 NR 37 TC 22 Z9 22 U1 0 U2 1 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0001-6322 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD DEC PY 1999 VL 98 IS 6 BP 597 EP 602 PG 6 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 261KF UT WOS:000084007800006 PM 10603035 ER PT J AU Rhodes, F Deren, S Wood, MM Shedlin, MG Carlson, RG Lambert, EY Kochems, LM Stark, MJ Falck, RS Wright-DeAguero, L Weir, B Cottler, L Rourke, KM Trotter, RT AF Rhodes, F Deren, S Wood, MM Shedlin, MG Carlson, RG Lambert, EY Kochems, LM Stark, MJ Falck, RS Wright-DeAguero, L Weir, B Cottler, L Rourke, KM Trotter, RT TI Understanding HIV risks of chronic drug-using men who have sex with men SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article ID USERS; BEHAVIOR; ORIENTATION; AMPHETAMINE; STOCKHOLM; GAY AB Focus groups and individual structured interviews were conducted in six cities with 98 predominantly street-recruited men who had a recent history of smoking crack or injecting drugs and who reported having had sex with other men (MSM) in the past year. Twenty-six focus groups explored the cultural and social context of participants' drug use and sexual activity and addressed outreach and HIV prevention issues pertinent to this population. Narrative summaries developed from verbatim focus group transcripts identified seven themes: (a) sexual orientation and gender identity; (b) interactions within and between MSM networks; (c) drug use, sexual activity and personal relationships; (d) HIV transmission bridges; (e) preferred HIV information sources; (f) HIV knowledge, prevention practices and risk behaviours; and (g) availability of HIV and drug-related services. Of the 98 MSM drug users, 42% identified publicly as gay or homosexual; 35% identified publicly, but only 21% privately, as heterosexual. A total of 51% had one or more female sex partners in the past year. There was a high frequency of unprotected sex in conjunction with drug use and a distinct preference for having sex when high. For most participants, drug use rather than sexual orientation formed the core of personal identity. Participants reported associating primarily with other drug users, usually MSM, and had limited contact with people who did not use drugs and the,mainstream gay community. Participants' sexual and drug-injecting activities were judged to be a bridge for transmission of HIV to both people who used drugs and those who did not. C1 Calif State Univ Long Beach, Ctr Behav Res & Serv, Long Beach, CA 90813 USA. Natl Dev & Res Inst Inc, New York, NY 10013 USA. Wright State Univ, Dayton, OH 45435 USA. NIDA, Rockville, MD 20857 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. Washington Univ, St Louis, MO USA. No Arizona Univ, Flagstaff, AZ 86011 USA. RP Rhodes, F (reprint author), Calif State Univ Long Beach, Ctr Behav Res & Serv, 1090 Atlantic Ave, Long Beach, CA 90813 USA. OI Shedlin, Michele/0000-0003-2112-7601 FU NIDA NIH HHS [1-U01-DA-07474, 1-U01-DA-07286, 1-U01-DA-07305] NR 27 TC 19 Z9 19 U1 1 U2 1 PU CARFAX PUBLISHING PI BASINGSTOKE PA RANKINE RD, BASINGSTOKE RG24 8PR, HANTS, ENGLAND SN 0954-0121 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids/Hiv PD DEC PY 1999 VL 11 IS 6 BP 629 EP 648 DI 10.1080/09540129947550 PG 20 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Respiratory System; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychology; Respiratory System; Biomedical Social Sciences GA 271LY UT WOS:000084596500001 PM 10716005 ER PT J AU Albertorio, JR Holden-Pitt, L Rawlings, B AF Albertorio, JR Holden-Pitt, L Rawlings, B TI Preliminary results of the Annual Survey of Deaf and Hard of Hearing Children and Youth in Puerto Rico: The first wave SO AMERICAN ANNALS OF THE DEAF LA English DT Article ID LANGUAGE AB Preliminary findings are provided from the data collected in Puerto Rico through the Annual Survey of Deaf and Hard of Hearing Children and Youth during the 1997-1998 school year. The study was conducted as a part of an initiative to increase participation in the Annual Survey among the deaf and hard of hearing school-age population in Puerto Rico. Demographic, instructional, etiological, audiological, and communication data on 336 deaf and hard of hearing school age children were collected and summarized. The findings suggest the existence of a heterogeneous deaf community rather than the traditionally conceived homogenous community. The discussion emphasizes the description of those attributes that suggest heterogeneity and the urgent need to continue to collect the kind of data gathered in the survey. The authors urge that Puerto Rican educators and researchers be stimulated to address the educational and health-related needs of Puerto Rico's deaf and hard of hearing school-age population. C1 Natl Inst Deafness & Other Commun Disorders, Off Res Minor Hlth, Partnership Program, NIH, Bethesda, MD 20892 USA. Gallaudet Res Inst, Washington, DC USA. RP Albertorio, JR (reprint author), Natl Inst Deafness & Other Commun Disorders, Off Res Minor Hlth, Partnership Program, NIH, Bethesda, MD 20892 USA. NR 19 TC 5 Z9 5 U1 0 U2 1 PU AMERICAN ANNALS OF THE DEAF PI WASHINGTON PA FOWLER HALL 409, 800 FLORIDA AVE NE, WASHINGTON, DC 20002 USA SN 0002-726X J9 AM ANN DEAF JI Am. Ann. Deaf PD DEC PY 1999 VL 144 IS 5 BP 386 EP 394 PG 9 WC Education, Special; Rehabilitation SC Education & Educational Research; Rehabilitation GA 295BE UT WOS:000085945400008 PM 10734694 ER PT J AU Goff, DC Feldman, HA McGovern, PG Goldberg, RJ Simons-Morton, DG Cornell, CE Osganian, SK Cooper, LS Hedges, JR AF Goff, DC Feldman, HA McGovern, PG Goldberg, RJ Simons-Morton, DG Cornell, CE Osganian, SK Cooper, LS Hedges, JR CA REACT Study Grp TI Prehospital delay in patients hospitalized with heart attack symptoms in the United States: The REACT trial SO AMERICAN HEART JOURNAL LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; CORONARY-CARE UNIT; RAPID-EARLY-ACTION; CHEST PAIN; THROMBOLYTIC THERAPY; ARRIVAL; SEEKING; DISEASE; REASONS; PHASE AB Background The use of thrombolytic therapy for patients with myocardial infarction has been limited by patient delay in seeking care. We sought to characterize prehospital delay in patients hospitalized For evaluation of heart attack symptoms. Methods and Results The Rapid Early Action for Coronary Treatment (REACT) is a multicenter, randomized community trial designed to reduce patient delay. At baseline, data were abstracted from the medical records of 3783 patients hospitalized for evaluation of heart attack symptoms in 20 communities. The median prehospital delay was 2.0 hours; 25% of patients delayed longer than 5.2 hours. In a multivariable analysis, delay time was longer among non-Hispanic blacks than among non-Hispanic whites, longer at older ages, longer among Medicaid-only recipients and shorter among Medicare recipients than among privately insured patients, and shorter among patients who used an ambulance. Conclusions The observed pattern of differences is consistent with the contention that demographic, cultural, and/or socioeconomic barriers exist that impede rapid care seeking. C1 Wake Forest Univ, Sch Med, Winston Salem, NC 27157 USA. New England Res Inst, Watertown, MA 02172 USA. Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. Univ Massachusetts, Sch Med, Worcester, MA USA. NHLBI, Bethesda, MD 20892 USA. Univ Alabama, Sch Med, Birmingham, AL USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. RP Goff, DC (reprint author), Wake Forest Univ, Sch Med, Med Ctr Blvd, Winston Salem, NC 27157 USA. FU NHLBI NIH HHS [HL-53142, HL-53149, HL-53155] NR 47 TC 115 Z9 118 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 DEC PY 1999 VL 138 IS 6 BP 1046 EP 1057 DI 10.1016/S0002-8703(99)70069-4 PN 1 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 262EU UT WOS:000084053300013 PM 10577434 ER PT J AU Pepine, CJ Mark, DB Bourassa, MG Chaitman, BR Davies, RF Knatterud, GL Forman, S Pratt, CM Sopko, G Conti, CR AF Pepine, CJ Mark, DB Bourassa, MG Chaitman, BR Davies, RF Knatterud, GL Forman, S Pratt, CM Sopko, G Conti, CR CA ACIP Study Grp TI Cost estimates for treatment of cardiac ischemia (from the Asymptomatic Cardiac Ischemia Pilot [ACIP] study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID TRANSIENT MYOCARDIAL-ISCHEMIA; CORONARY-ARTERY DISEASE; STABLE ANGINA-PECTORIS; UNSTABLE ANGINA; SILENT ISCHEMIA; PROGNOSTIC-SIGNIFICANCE; MEDICAL THERAPY; DAILY-LIFE; FOLLOW-UP; BASE-LINE AB Costs for management of myocardial ischemia are enormous, yet comparison cost and outcome data for various ischemia treatment strategies from randomized trials are lacking and will require cost and resource utilization data fram a large prospective trial. The Asymptomatic Cardiac Ischemia Pilot provided feasibility data for planning such a trial and on opportunity to estimate the long-term costs of different treatment strategies. Economic implications for ischemia management were compared in 558 patients with stable coronary artery disease and myocardial ischemia during both stress testing and daily life. Participants were randomized to 3 different initial treatment strategies and followed for 2 years. Based on cost trends over follow-up, costs for subsequent care were estimated. As expected, due to initial procedural costs, at 3 months, estimated costs for revascularization were approximately 10 times greater than costs for a medical care strategy. Extrapolated costs for anticipated resource consumption for care beyond 2 years, however, were approximately 2 times greater for an initial medical care strategy than for initial revascularization. This was due to increased need for drugs and hospitalizations for bath late revascularizations and other ischemia-related events. Estimated costs for anticipated care in the medical strategies reached the anticipated cost of the revascularization strategy within 10 years. Because this cost-equal time period is well within the median life expectancy for such a patient population, these findings could have important public health implications and require testing in a full-scale prognosis trial. We anticipate that over the patients' life expectancy, early revascularization is likely to become either cost-neutral or cost-effective. (C) 1999 by Excerpta Medica, Inc. C1 Univ Florida, Coll Med, Div Cardiovasc Med, Gainesville, FL USA. Duke Univ, Sch Med, Durham, NC USA. Montreal Heart Inst, Res Ctr, Montreal, PQ H1T 1C8, Canada. St Louis Univ, Med Ctr, St Louis, MO USA. Univ Ottawa, Inst Heart, Res Ctr, Ottawa, ON, Canada. Maryland Med Res Inst, Baltimore, MD USA. Baylor Coll Med, Houston, TX 77030 USA. NHLBI, Bethesda, MD 20892 USA. RP Knatterud, GL (reprint author), ACIP Clin Coordinating Ctr, Maryland Med Res Inst, 600 Wyndhurst Ave, Baltimore, MD 21210 USA. OI Mark, Daniel/0000-0001-6340-8087; Bourassa, Martial G./0000-0002-4439-8650 FU NHLBI NIH HHS [HV-90-07, HV-90-08, HV-91-05] NR 29 TC 3 Z9 3 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 DEC 1 PY 1999 VL 84 IS 11 BP 1311 EP 1316 DI 10.1016/S0002-9149(99)00563-9 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 260MA UT WOS:000083953400006 PM 10614796 ER PT J AU Zhang, YQ Kreger, BE Dorgan, JF Cupples, LA Myers, RH Splansky, GL Schatzkin, A Ellison, RC AF Zhang, YQ Kreger, BE Dorgan, JF Cupples, LA Myers, RH Splansky, GL Schatzkin, A Ellison, RC TI Parental age at child's birth and son's risk of prostate cancer - The Framingham Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cohort studies; maternal age; paternal age; prostatic neoplasms ID PATERNAL AGE AB The authors examined the relation of parental age at birth to the risk of prostate cancer among sons with the use of data from the Framingham Study. During 42 years of follow-up (1949-1993), 141 prostate cancer cases occurred in 2,164 men. All but six cases were confirmed by histologic report. The incidence rate of prostate cancer increased from 1.70 per 1,000 person-years among sons in the lowest quartile of paternal age (<27 years), to 2.00, 2.32, and 2.74 among those of each increased paternal age category (27-<32, 32-<38, and greater than or equal to 38 years), respectively. After adjustment for age and other covariates, men in the second, third, and oldest quartiles of paternal age had 1.2, 1.3, and 1.7 times increased risk of prostate cancer compared with men in the youngest quartile (p for trend = 0.049). Further adjustment for maternal age did not change the relation materially. The association of older paternal age with risk of early-onset prostate cancer (<65 years) appeared stronger than that with late-onset disease (greater than or equal to 65 years). No increased risk of prostate cancer was observed among subjects in the older maternal age category. The effect of increased paternal age on prostate cancer risk may operate through increased germ cell mutation rate or by mechanisms not yet defined. C1 Boston Univ, Sch Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Gen Internal Med Sect, Evans Dept Med, Boston, MA 02118 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA USA. NHLBI, Framingham Heart Study, Framingham, MA USA. RP Zhang, YQ (reprint author), Boston Univ, Sch Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. FU NHLBI NIH HHS [N01-HC-38038] NR 15 TC 45 Z9 45 U1 3 U2 6 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 DEC 1 PY 1999 VL 150 IS 11 BP 1208 EP 1212 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 261GW UT WOS:000084002300010 PM 10588081 ER PT J AU Appukuttan, B Gillanders, E Juo, SH Freas-Lutz, D Ott, S Sood, R Van Auken, A Bailey-Wilson, J Wang, XG Patel, RJ Robbins, CM Chung, M Annett, G Weinberg, K Borchert, MS Trent, JM Brownstein, MJ Stout, JT AF Appukuttan, B Gillanders, E Juo, SH Freas-Lutz, D Ott, S Sood, R Van Auken, A Bailey-Wilson, J Wang, XG Patel, RJ Robbins, CM Chung, M Annett, G Weinberg, K Borchert, MS Trent, JM Brownstein, MJ Stout, JT TI Localization of a gene for Duane retraction syndrome to chromosome 2q31 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID ANTERIOR-POSTERIOR AXIS; ACID RESPONSE ELEMENT; RETINOIC ACID; EMBRYONIC EXPRESSION; FUNCTIONAL-ANALYSIS; LINKAGE ANALYSIS; HOMEOBOX GENES; HOXD4 GENE; MURINE; HINDBRAIN AB Duane retraction syndrome (DRS) is a congenital eye-movement disorder characterized by a failure of cranial nerve VI (the abducens nerve) to develop normally, resulting in restriction or absence of abduction, restricted adduction, and narrowing of the palpebral fissure and retraction of the globe on attempted adduction. DRS has a prevalence of similar to 0.1% in the general population and accounts for 5% of all strabismus cases. Undiagnosed DRS in children can lead to amblyopia, a permanent uncorrectable loss of vision. A large family with autosomal dominant DRS was examined and tested for genetic linkage. After exclusion of candidate regions previously associated with DRS, a genomewide search with highly polymorphic microsatellite markers was performed, and significant evidence for linkage was obtained at chromosome 2q31 (D2S2314 maximum LOD score 11.73 at maximum recombination fraction .0). Haplotype analysis places the affected gene in a 17.8-cM region between the markers D2S2330 and D2S364. No recombinants were seen with markers between these two loci. The linked region contains the homeobox D gene cluster. Three of the genes within this cluster, known to participate in hindbrain development, were sequenced in affected and control individuals. Coding sequences for these genes were normal or had genetic alterations unlikely to be responsible for the DRS phenotype. Identifying the gene responsible for DRS may lead to an improved understanding of early cranial-nerve development. C1 Childrens Hosp Los Angeles, Div Ophthalmol, Los Angeles, CA 90027 USA. Childrens Hosp Los Angeles, Div Res Immunol Bone Marrow Transplant, Los Angeles, CA 90027 USA. NIH, NGHRI, Canc Genet Branch, Bethesda, MD USA. NIMH, Genet Lab, NHGRI, NIH, Bethesda, MD 20892 USA. NIH, Sect Stat Genet, Ctr Inherited Dis Res, NHGRI, Baltimore, MD USA. Rockefeller Univ, Lab Stat Genet, New York, NY USA. RP Stout, JT (reprint author), Childrens Hosp Los Angeles, Div Ophthalmol, 4650 Sunset Blvd, Los Angeles, CA 90027 USA. RI Brownstein, Michael/B-8609-2009; Juo, Suh-Hang/A-1765-2010; Juo, Suh-Hang/C-9545-2009; OI Bailey-Wilson, Joan/0000-0002-9153-2920 NR 39 TC 54 Z9 55 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD DEC PY 1999 VL 65 IS 6 BP 1639 EP 1646 DI 10.1086/302656 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 266CF UT WOS:000084282500018 PM 10577917 ER PT J AU Wacholder, S Hartge, P AF Wacholder, S Hartge, P TI Modeling the probability that Ashkenazi Jewish women carry a founder mutation in BRCA1 or BRCA2 - Response SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Letter C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Wacholder, S (reprint author), NCI, Div Canc Epidemiol & Genet, EPS 8046, Bethesda, MD 20892 USA. NR 4 TC 1 Z9 1 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD DEC PY 1999 VL 65 IS 6 BP 1775 EP 1776 DI 10.1086/302688 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 266CF UT WOS:000084282500033 ER PT J AU Struewing, JP Coriaty, ZM Ron, E Livoff, A Konichezky, M Cohen, P Resnick, MB Lifzchiz-Mercerl, B Lew, S Iscovich, J AF Struewing, JP Coriaty, ZM Ron, E Livoff, A Konichezky, M Cohen, P Resnick, MB Lifzchiz-Mercerl, B Lew, S Iscovich, J TI Founder BRCA1/2 mutations among male patients with breast cancer in Israel SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Letter ID FAMILIES; JEWS C1 NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. NCI, Radiat Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Hadassah Med Org, Dept Pathol, Jerusalem, Israel. Carmel Med Ctr, Dept Pathol, Haifa, Israel. Rabin Med Ctr, Dept Pathol, Tel Aviv, Israel. Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. Ichilov Med Ctr, Dept Pathol & Canc Res, Tel Aviv, Israel. Meir Hosp, Dept Pathol, Tel Aviv, Israel. Natl Inst Fertil, Raanana, Israel. RP Struewing, JP (reprint author), NCI, Lab Populat Genet, NIH, 41 Lib Dr,Room D702, Bethesda, MD 20892 USA. RI Struewing, Jeffery/C-3221-2008; Struewing, Jeffery/I-7502-2013 OI Struewing, Jeffery/0000-0002-4848-3334 NR 12 TC 32 Z9 32 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD DEC PY 1999 VL 65 IS 6 BP 1800 EP 1802 DI 10.1086/302678 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 266CF UT WOS:000084282500041 PM 10577940 ER PT J AU Zhang, J Klebanoff, MA Levine, RJ Puri, M Moyer, P AF Zhang, J Klebanoff, MA Levine, RJ Puri, M Moyer, P TI The puzzling association between smoking and hypertension during pregnancy SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE hypertension; preeclampsia; pregnancy; smoking ID HEALTHY NULLIPAROUS WOMEN; CIGARETTE-SMOKING; RISK-FACTORS; GESTATIONAL HYPERTENSION; PREECLAMPSIA AB OBJECTIVE: The object of this study was to examine the association between maternal smoking and hypertension during pregnancy. STUDY DESIGN: We used data from the Collaborative Perinatal Project, a large prospective cohort study that collected detailed information on blood pressure, proteinuria, smoking, and placental morphologic and histologic characteristics. A total of 9651 healthy primigravid women without chronic hypertension who had been enrolled in the study at the first or second trimester (average 18 weeks' gestation) and had had greater than or equal to 3 prenatal visits were included. Gestational hypertension was defined as diastolic blood pressure greater than or equal to 90 mm Hg on 2 occasions from 24 weeks' gestation to 2 weeks post partum. Preeclampsia was defined as gestational hypertension plus greater than or equal to 2 urine samples containing greater than or equal to 1+ protein according to dipstick measurement during the same gestational period. RESULTS: After we controlled for prepregnancy body mass, age, socioeconomic status, and race, both past smoking and smoking during pregnancy were associated ina dose-response pattern with reduced risks of gestational hypertension and preeclampsia. For women who smoked greater than or equal to 10 cigarettes/d the relative risks with respect to women who had never smoked were 0.6 (95% confidence interval, 0.4-0.9) for gestational hypertension and 0.5 (95% confidence interval, 0.4-0.7) for preeclampsia. This protective effect was observed both for mild and severe gestational hypertension and for preeclampsia. The more and the longer a woman had smoked previously the lower was her risk of development of hypertension during pregnancy. This association could not be explained by confounding factors, by changes in placental morphologic or histopathologic characteristics, by maternal net weight gain, or by elevated liver enzyme bioactivity. CONCLUSION: Smoking is associated with a reduced risk of hypertension during pregnancy. The protective effect appears to continue even after cessation of smoking. Further basic research-on this issue is warranted. C1 NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. RP Zhang, J (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Bldg 6100,Room 7B03, Bethesda, MD 20892 USA. NR 25 TC 72 Z9 73 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 DEC PY 1999 VL 181 IS 6 BP 1407 EP 1413 DI 10.1016/S0002-9378(99)70384-4 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 265VE UT WOS:000084265900032 PM 10601921 ER PT J AU Zhang, K Garibaldi, DC Kniazeva, M Albini, T Chiang, MF Kerrigan, M Sunness, JS Han, M Allikmets, R AF Zhang, K Garibaldi, DC Kniazeva, M Albini, T Chiang, MF Kerrigan, M Sunness, JS Han, M Allikmets, R TI A novel mutation in the ABCR gene in four patients with autosomal recessive Stargardt disease SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID FUNDUS-FLAVIMACULATUS; MACULAR DYSTROPHY; RETINITIS-PIGMENTOSA; DOMINANT; LOCUS; MAPS AB PURPOSE: To identify additional mutations in the ABCR gene and describe the clinical features of four affected siblings with autosomal recessive Stargardt disease. METHODS: A cohort of eight siblings was identified for study. Four of these individuals were diagnosed with Stargardt disease based on clinical evaluation and fluorescein angiography, Blood samples were obtained from seven of eight siblings, including all those affected. All 50 exons of the ABCR gene were analyzed by single stranded confirmation polymorphism analysis, followed by direct sequencing of observed variants, to identify mutations in the ABCR gene. RESULTS: We identified a previously unreported kindred of eight siblings, four of whom had mutations in both of their ABCR alleles, A previously described G-to-C transversion of nucleotide 2588, predicting a Gly863Ala amino acid substitution, and a novel G-to A transition of nucleotide 161, resulting in a Cys54Tyr substitution, were identified, These mutations co-segregated with the affected members of this family. Three of the siblings demonstrated clinical features characteristic of classic Stargardt disease, with bilateral regions of macular atrophy associated with yellow white "flavimaculatus" flecks in the posterior pole at the level of the retinal pigment epithelium. The fourth affected sibling showed features of early Stargardt disease, with a beaten-bronze appearance to both maculas, as well as perimacular flecks. In all four affected patients, fluorescein angiography showed a characteristic peripheral dark choroid, CONCLUSIONS: We have identified both a previously described and a novel mutation in the ABCR gene in four patients with autosomal recessive Stargardt disease. In depth knowledge of the ABCR mutation spectrum in patients with Stargardt disease will provide for more efficient screening and may provide potential therapies for Stargardt disease and other retinal diseases. (C) 1999 by Elsevier Science Inc, All rights reserved. C1 Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21287 USA. Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA. NCI, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. RP Zhang, K (reprint author), Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, 809 Maumenee Bldg, Baltimore, MD 21287 USA. RI Kniazeva, Marina/D-4085-2012; OI Albini, Thomas/0000-0003-2199-9047 FU NCI NIH HHS [N01-CO-56000] NR 16 TC 9 Z9 11 U1 0 U2 4 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 DEC PY 1999 VL 128 IS 6 BP 720 EP 724 DI 10.1016/S0002-9394(99)00236-6 PG 5 WC Ophthalmology SC Ophthalmology GA 262XB UT WOS:000084092600008 PM 10612508 ER PT J AU Davis, RL Holohan, PD Shrimpton, AE Tatum, AH Daucher, J Collins, GH Todd, R Bradshaw, C Kent, P Feiglin, D Rosenbaum, A Yerby, MS Shaw, CM Lacbawan, F Lawrence, DA AF Davis, RL Holohan, PD Shrimpton, AE Tatum, AH Daucher, J Collins, GH Todd, R Bradshaw, C Kent, P Feiglin, D Rosenbaum, A Yerby, MS Shaw, CM Lacbawan, F Lawrence, DA TI Familiar encephalopathy with neuroserpin inclusion bodies SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID LEWY BODY DISEASE; NEURODEGENERATIVE DISORDERS; CONFORMATIONAL DISEASE; PLASMINOGEN-ACTIVATOR; NERVOUS-SYSTEM; UBIQUITIN; BRAIN; ALPHA(1)-ANTITRYPSIN; IMMUNOHISTOCHEMISTRY; DEFICIENCY AB We report on a new familial neurodegenerative disease with associated dementia that has presented clinically in the fifth decade, in both genders, and in each of several generations of a large family from New York State-a pattern of inheritance consistent with an autosomal dominant mode of transmission. A key pathological finding is the presence of neuronal inclusion bodies distributed throughout the gray matter of the cerebral cortex and in certain subcortical nuclei; These inclusions are distinct from any described previously and henceforth are identified as Collins bodies. The Collins bodies can be isolated by simple biochemical procedures and have a surprisingly simple composition; neuroserpin (a serine protease inhibitor) is their predominant component. An affinity-purified antibody against neuroserpin specifically labels the Collins bodies, confirming their chemical composition. Therefore, we propose a new disease entity-familial encephalopathy with neuroserpin inclusion bodies (FENIB). The conclusion that FENIB is a previously unrecognized neurodegenerative disease is supported by finding Collins bodies in a small kindred from Oregon with familial dementia who are unrelated to the New York family. The autosomal dominant inheritance strongly suggests that FENIB is caused by mutations in the neuroserpin gene, resulting in: intracellular accumulation of the mutant protein. C1 SUNY Hlth Sci Ctr, Dept Pharmacol, Syracuse, NY 13210 USA. SUNY Hlth Sci Ctr, Dept Pathol, Syracuse, NY 13210 USA. SUNY Hlth Sci Ctr, Dept Neurol, Syracuse, NY 13210 USA. SUNY Hlth Sci Ctr, Dept Nucl Med, Syracuse, NY 13210 USA. SUNY Hlth Sci Ctr, Dept Radiol, Syracuse, NY 13210 USA. Oregon Hlth Sci Univ, Dept Neurol, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Dept Publ Hlth, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98195 USA. Natl Human Genome Res Inst, NIH, Bethesda, MD USA. Amer Red Cross, Holland Labs, Rockville, MD USA. RP Holohan, PD (reprint author), SUNY Hlth Sci Ctr, Dept Pharmacol, 750 E Adams St, Syracuse, NY 13210 USA. FU NIA NIH HHS [AG16954] NR 52 TC 76 Z9 79 U1 0 U2 2 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD DEC PY 1999 VL 155 IS 6 BP 1901 EP 1913 DI 10.1016/S0002-9440(10)65510-1 PG 13 WC Pathology SC Pathology GA 262XD UT WOS:000084092800017 PM 10595921 ER PT J AU Carroll, S Nicotera, P Pette, D AF Carroll, S Nicotera, P Pette, D TI Calcium transients in single fibers of low-frequency stimulated fast-twitch muscle of rat SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE calcium buffering; free calcium; mitochondria; parvalbumin; sarcoplasmic reticulum calcium-adenosinetriphosphatase ID SARCOPLASMIC-RETICULUM CA-2+-ATPASE; SKELETAL-MUSCLE; MYOSIN EXPRESSION; RABBIT MUSCLE; TRANSFORMATION; INACTIVATION; CALCINEURIN; TRANSITIONS; INHIBITION; ISOFORMS AB Ca2+ transients were investigated in single fibers isolated from rat extensor digitorum longus muscles exposed to chronic low-frequency stimulation far different time periods up to 10 days. Approximately 2.5-fold increases in resting Ca2+ concentration ([Ca2+]) were observed 2 h after stimulation onset and persisted throughout the stimulation period. The elevated [Ca2+] levels were in the range characteristic of slow-twitch fibers from soleus muscle. In addition, we noticed a transitory elevation of the integral [Ca2+] per pulse with a maximum (similar to 5-fold) after 1 day Steep decreases in rate constant of [Ca2+] decay could be explained by an immediate impairment of Ca2+ uptake and, with longer stimulation periods, by an additional loss of cytosolic Ca2+ binding capacity resulting from a decay in parvalbumin content. A partial recovery of the rate constant of [Ca2+] decay in 10-day stimulated muscle could be explained by an increasing mitochondrial contribution to Ca2+ sequestration. C1 Univ Konstanz, Fak Biol, D-78457 Constance, Germany. RP Carroll, S (reprint author), NIH, Bldg 6,Room 408,6 Ctr Dr MSC 2755, Bethesda, MD 20892 USA. NR 34 TC 43 Z9 43 U1 0 U2 3 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 DEC PY 1999 VL 277 IS 6 BP C1122 EP C1129 PG 8 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 265LE UT WOS:000084245100013 PM 10600763 ER PT J AU Kurihara, K Moore-Hoon, ML Saitoh, M Turner, RJ AF Kurihara, K Moore-Hoon, ML Saitoh, M Turner, RJ TI Characterization of a phosphorylation event resulting in upregulation of the salivary Na+-K+-2Cl(-) cotransporter SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article ID K-CL COTRANSPORT; PAROTID ACINAR-CELLS; SHARK RECTAL GLAND; BUMETANIDE-BINDING; EPITHELIAL-CELLS; NA+/K+/CL COTRANSPORT; FUNCTIONAL EXPRESSION; MOLECULAR-CLONING; UP-REGULATION; PROTEIN AB Previous studies from our laboratory have shown a close correlation between increased Na+-K+-2Cl(-) cotransporter activity and increased cotransporter phosphorylation after beta-adrenergic stimulation of rat parotid acinar cells. Ne demonstrate here that these effects are paralleled by an increase in the number of high-affinity binding sites for the cotransporter inhibitor bumetanide in membranes prepared from stimulated acini. Ne also shaw that the sensitivity of cotransporter fluxes to inhibition by bumetanide is the same in both resting and isoproterenol-stimulated cells, consistent with the hypothesis that beta-adrenergic stimulation and the accompanying phosphorylation result in the activation of previously quiescent transporters rather than in a change in the properties of already active proteins. In addition, we demonstrate that the increased phosphorylation on the cotransporter resulting from beta-adrenergic stimulation is localized to a 30-kDa phosphopeptide obtained by cyanogen bromide digestion. Immunoprecipitation and Western blotting experiments demonstrate that this peptide is derived from the NH2-terninal cytosolic tail of the cotransporter, which surprisingly does not contain the sole protein kinase A consensus site on the molecule. C1 Natl Inst Dent & Craniofacial Res, Membrane Biol Sect, NIH, Bethesda, MD 20892 USA. Meikai Univ, Sch Dent, Dept Oral Physiol, Sakado, Saitama 35002, Japan. RP Turner, RJ (reprint author), Natl Inst Dent & Craniofacial Res, Membrane Biol Sect, NIH, Bldg 10,Rm 1A06,10 Ctr Dr,MSC 1190, Bethesda, MD 20892 USA. NR 30 TC 44 Z9 44 U1 0 U2 0 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 DEC PY 1999 VL 277 IS 6 BP C1184 EP C1193 PG 10 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 265LE UT WOS:000084245100020 PM 10600770 ER PT J AU Kono, H Bradford, BU Yin, M Sulik, KK Koop, DR Peters, JM Gonzalez, FJ McDonald, T Dikalova, A Kadiiska, MB Mason, RP Thurman, RG AF Kono, H Bradford, BU Yin, M Sulik, KK Koop, DR Peters, JM Gonzalez, FJ McDonald, T Dikalova, A Kadiiska, MB Mason, RP Thurman, RG TI CYP2E1 is not involved in early alcohol-induced liver injury SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE CYP2E1 knockout mouse; intragastric feeding ID INTRAGASTRIC ETHANOL INFUSION; KUPFFER CELLS; RATS; CYTOCHROME-P450; INDUCTION; PATHOGENESIS; DISEASE; INHIBITION; PATHOLOGY; EXPOSURE AB The continuous intragastric enteral feeding protocol in the rat was a major development in alcohol-induced liver injury (ALI) research. Much of what has been learned to date involves inhibitors or nutritional manipulations that may not be specific. Knockout technology avoids these potential problems. Therefore, we used long-term intragastric cannulation in mice to study early ALI. Reactive oxygen species are involved in mechanisms of early ALI; however, their key source remains unclear. Cytochrome P-450 (CYP)2E1 is induced predominantly in hepatocytes by ethanol and could be one source of reactive oxygen species leading to liver injury. We aimed to determine if CYP2E1 was involved in ALI by adapting the enteral alcohol (EA) feeding model to CYP2E1 knockout (-/-) mice. Female CYP2E1 wild-type (+/+) or -/- mice were given a high-fat liquid diet with either ethanol or isocaloric maltose-dextrin as control continuously for 4 wk. All mice gained weight steadily over 4 wk, and there were no significant differences between groups. There were also no differences in ethanol elimination rates between CYP2E1 +/+ and -/- mice after acute ethanol administration to naive mice or mice receiving EA for 4 wk. However, EA stimulated rates 1.4-fold in both groups. EA elevated serum aspartate aminotransferase levels threefold to similar levels over control in both CYP2E1 +/+ and -/- mice. Liver histology was normal in control groups. In contrast, mice given ethanol developed mild steatosis, slight inflammation, and necrosis; however, there were no differences between the CYP2E1 +/+ and -/- groups. Chronic EA induced other CYP families (CYP3A, CYP2A12, CYP1A, and CYP2B) to the same extent in CYP2E1 +/+ and -/- mice. Furthermore, POBN radical adducts were also similar in both groups. Data presented here are consistent with the hypothesis that oxidants from CYP2E1 play only a small role in mechanisms of early ALI in mice. Moreover, this new mouse model illustrates the utility of knockout technology in ALI research. C1 Univ N Carolina, Dept Pharmacol, Hepatobiol & Toxicol Lab, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Cell Biol, Hepatobiol & Toxicol Lab, Chapel Hill, NC 27599 USA. NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. Oregon Hlth Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97201 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Thurman, RG (reprint author), Univ N Carolina, Dept Pharmacol, Hepatobiol & Toxicol Lab, CB 7365,Mary Ellen Jones Bldg, Chapel Hill, NC 27599 USA. RI Peters, Jeffrey/D-8847-2011 NR 35 TC 91 Z9 94 U1 0 U2 7 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 DEC PY 1999 VL 277 IS 6 BP G1259 EP G1267 PG 9 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 265GT UT WOS:000084234600018 PM 10600824 ER PT J AU Aeschbach, D Matthews, JR Postolache, TT Jackson, MA Giesen, HA Wehr, TA AF Aeschbach, D Matthews, JR Postolache, TT Jackson, MA Giesen, HA Wehr, TA TI Two circadian rhythms in the human electroencephalogram during wakefulness SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE homeostatic process; alertness; melatonin; body temperature; evening wake maintenance ID HUMAN SLEEP EEG; WAKING EEG; BRAIN; POWER; PERFORMANCE; DYNAMICS; CAFFEINE; NIGHT; TIME; METABOLISM AB The influence of the circadian pacemaker and of the duration of time awake on the electroencephalogram (EEG) was investigated in 19 humans during similar to 40 h of sustained wakefulness. Two circadian rhythms in spectral power density were educed. The first rhythm was centered in the theta band (4.25-8.0 Hz) and exhibited a minimum similar to 1 h after the onset of melatonin secretion. The second rhythm was centered in the high-frequency alpha band (10.25-13.0 Hz) and exhibited a minimum close to the body temperature minimum. The latter rhythm showed a close temporal association with the rhythms in subjective alertness, plasma melatonin, and body temperature. In addition, increasing time awake was associated with an increase of power density in the 0.25- to 9.0-Hz and 13.25- to 20.0-Hz ranges. It is concluded that the waking EEG undergoes changes that can be attributed to circadian and homeostatic (i.e., sleep-cake dependent) processes. The distinct circadian variations of EEG activity in the theta band and in the high-frequency alpha band may represent electrophysiological correlates of different aspects of the circadian rhythm in arousal. C1 NIMH, Sect Biol Rhythms, Intramural Res Program, Bethesda, MD 20892 USA. RP NIMH, Sect Biol Rhythms, Intramural Res Program, Bldg 10,Rm 3S-231,10 Ctr Dr MSC 1390, Bethesda, MD 20892 USA. EM aschbach@box-a.nih.gov NR 44 TC 81 Z9 81 U1 7 U2 11 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 EI 1522-1490 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD DEC PY 1999 VL 277 IS 6 BP R1771 EP R1779 PG 9 WC Physiology SC Physiology GA 265DB UT WOS:000084225100029 PM 10600925 ER PT J AU Sweet, DH Pritchard, JB AF Sweet, DH Pritchard, JB TI rOCT2 is a basolateral potential-driven carrier, not an organic cation/proton exchanger SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE rat; kidney; Xenopus laevis; expression cloning; Madin-Darby canine kidney; transfection ID BORDER MEMBRANE-VESICLES; RENAL BRUSH-BORDER; CATION TRANSPORTER; FUNCTIONAL EXPRESSION; RAT-KIDNEY; CLONING; PH; TETRAETHYLAMMONIUM; SECRETION; PROTEIN AB The driving forces mediating tetraethylammonium (TEA) transport were systematically assessed in Xenopus oocytes and MDCK cells expressing organic cation transporter (OCT) 2 cloned from rat kidney (rOCT2). In rOCT2 cRNA-injected oocytes, uptake of [(14)C]TEA was saturable, with an estimated Michaelis constant (K(m)) of 393 mu M, and was specifically inhibited by organic cations. Furthermore, TEA uptake demonstrated two distinct components, one that was potential sensitive and one that was pH sensitive. When membrane potential was intact, TEA uptake was largely unaffected by changes in medium pH; when the oocyte membrane was depolarized (K(+) in = out = 102.5 mM, plus valinomycin), decreasing external medium pH significantly reduced TEA uptake. Consistent with the potential sensitivity of uptake, electrophysiological analysis of rOCT2-injected oocytes demonstrated movement of positive charge into the oocyte upon TEA addition. To further evaluate the nature of the pH effect and assess the properties of rOCT2 in a renal epithelium, rOCT2 was introduced into MDCK cells. A stably transfected single cell clone (MDCK-rOCT2) showed mediated, potential-sensitive, pH-sensitive TEA uptake (K(m) = 48 mu M). TEA efflux from preloaded MDCK-rOCT2 cells was stimulated by externally applied (trans) tetramethylammonium but was trans-inhibited by H(+) (external pH 5.4). The effect of external H(+) was to modulate rOCT2-mediated transport. Thus rOCT2 is a potential-driven transporter, not an organic cation/H(+) exchanger, consistent with a physiological role in the basolateral entry step in renal organic cation secretion. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Pritchard, JB (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, Mail Drop F1-03,POB 12233, Res Triangle Pk, NC 27709 USA. EM pritchard@niehs.nih.gov RI Sweet, Douglas/H-7914-2013 OI Sweet, Douglas/0000-0002-8911-9184 NR 35 TC 48 Z9 48 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD DEC PY 1999 VL 277 IS 6 BP F890 EP F898 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 264XR UT WOS:000084209100010 PM 10600936 ER PT J AU Yang, TX Michele, DE Park, J Smart, AM Lin, ZW Brosius, FC Schnermann, JB Briggs, JP AF Yang, TX Michele, DE Park, J Smart, AM Lin, ZW Brosius, FC Schnermann, JB Briggs, JP TI Expression of peroxisomal proliferator-activated receptors and retinoid X receptors in the kidney SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE 15-deoxy-Delta(12,14)-prostaglandin J(2); reverse transcription-polymerase chain reaction; acyl-coenzyme A synthase; microdissected nephron segments ID ACYL-COA SYNTHETASE; PPAR-GAMMA; DIFFERENTIAL EXPRESSION; TISSUE DISTRIBUTION; GROWTH-INHIBITION; RAT; PROSTAGLANDINS; BINDING; HORMONE; BETA AB The discovery that 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) is a ligand for the gamma-isoform of peroxisome proliferator-activated receptor (PPAR) suggests nuclear signaling by prostaglandins. Studies were undertaken to determine the nephron localization of PPAR isoforms and their heterodimer partners, retinoid X receptors (RXR), and to evaluate the function of this system in the kidney. PPAR alpha mRNA, determined by RT-PCR, was found predominately in cortex and further localized to proximal convoluted tubule (PCT); PPAR gamma was abundant in renal inner medulla, localized to inner medullary collecting duct (IMCD) and renal medullary interstitial cells (RMIC); PPAR beta, the ubiquitous form of PPAR, was abundant in all nephron segments examined. RXR alpha was localized to PCT and IMCD, whereas RXR beta was expressed in almost all nephron segments examined. mRNA expression of acyl-CoA synthase (ACS), a known PPAR target gene, was stimulated in renal cortex of rats fed with fenofibrate, but the expression was not significantly altered in either cortex or inner medulla of rats fed with troglitazone. In cultured RMIC cells, both troglitazone and 15d-PGJ(2) significantly inhibited cell proliferation and dramatically altered cell shape by induction of cell process formation. We conclude that PPAR and RXR isoforms are expressed in a nephron segment-specific manner, suggesting distinct functions, with PPAR alpha being involved in energy metabolism through regulating ACS in PCT and with PPAR gamma being involved in modulating RMIC growth and differentiation. C1 Univ Michigan, Dept Physiol, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. NIDDKD, Bethesda, MD 20892 USA. RP Briggs, JP (reprint author), NIDDK, NIH, Bldg 31,Rm 9A17,31 Ctr Dr,MSC 2560, Bethesda, MD 20892 USA. EM BriggsJ@hq.niddk.nih.gov RI Briggs, Josephine/B-9394-2009 OI Briggs, Josephine/0000-0003-0798-1190 FU NIDDK NIH HHS [DK-37448, DK-39255, DK-40042] NR 35 TC 96 Z9 97 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD DEC PY 1999 VL 277 IS 6 BP F966 EP F973 PG 8 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 264XR UT WOS:000084209100018 PM 10600944 ER PT J AU Westergaard, GC Izard, MK Drake, JH Suomi, SJ Higley, JD AF Westergaard, GC Izard, MK Drake, JH Suomi, SJ Higley, JD TI Rhesus macaque (Macaca mulatta) group formation and housing: Wounding and reproduction in a specific pathogen free (SPF) colony SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Article DE group formation; husbandry; Macaca mulatta; rhesus macaque ID MONKEYS AB In the present report, we examined the effects of group formation strategy and corral design on wounding and reproduction rates in rhesus macaques. Specifically, we examined group formation using a staged strategy, in which small groups of animals were introduced incrementally over a period of weeks, and a rapid formation strategy, in which all animals were introduced in 1 day. We also examined group formation using a divided corral design that facilitated visual and social separation of individuals, and an undivided corral design that did not facilitate visual or social separation. Dependent measures were wounding and reproductive rates over each of the 2 years that followed group formation. Results indicate that incrementally releasing subgroups of animals, and using a corral design that provides for visual and social separation of individuals, are effective strategies far reducing rates of traumatic wounding when forming multimale-multifemale rhesus macaque breeding groups. However,it must be noted that differences in formation strategy and corral design did not lead to higher reproductive rates. We conclude that incrementally releasing animals in hierarchical subgroups, and using a divided vs. undivided housing design, reduced intra-group wounding and associated demands on veterinary and animal management resources following formation of rhesus macaque breeding groups. Am. J. Primatol. 49:339-347, 1999. (C) 1999 Wiley-Liss, Inc. C1 LABS Virginia Inc, Div Res, Yemassee, SC 29945 USA. NICHHD, Comparat Ethol Lab, Bethesda, MD 20892 USA. LABS Virginia Inc, Div Primate Breeding & Behav, Yemassee, SC USA. NIAAA, Clin Studies Lab, Bethesda, MD 20892 USA. RP Westergaard, GC (reprint author), LABS Virginia Inc, Div Res, 95 Castle Hall Rd,POB 557, Yemassee, SC 29945 USA. FU NCRR NIH HHS [5U42RR05083, R24 RR09983] NR 10 TC 15 Z9 15 U1 0 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD DEC PY 1999 VL 49 IS 4 BP 339 EP 347 DI 10.1002/(SICI)1098-2345(199912)49:4<339::AID-AJP4>3.0.CO;2-E PG 9 WC Zoology SC Zoology GA 250GM UT WOS:000083380700004 PM 10553961 ER PT J AU Huang, W Alexander, GE Daly, EM Shetty, HU Krasuski, JS Rapoport, SI Schapiro, MB AF Huang, W Alexander, GE Daly, EM Shetty, HU Krasuski, JS Rapoport, SI Schapiro, MB TI High brain myo-inositol levels in the predementia phase of Alzheimer's disease in adults with Down's syndrome: A H-1 MRS study SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT 5th Annual Meeting of the International-Society-of-Magnetic-Resonance-in-Medicine CY APR 12-18, 1997 CL VANCOUVER, CANADA SP Int Soc Magnet Resonance Med ID MAGNETIC-RESONANCE SPECTROSCOPY; CEREBROSPINAL-FLUID; IN-VIVO; COGNITIVE FUNCTION; SENILE DEMENTIA; MYOINOSITOL; AGE; CHOLINE; METABOLITES; MORPHOMETRY AB Objective: An extra portion of chromosome 21 in Down's syndrome leads to a dementia in later life that is phenotypically similar to Alzheimer's disease. Down's syndrome therefore represents a model for studying preclinical stages of Alzheimer's disease. Markers that have been investigated in symptomatic Alzheimer's disease are myo-inositol and N-acetyl-aspartate, The authors investigated whether abnormal brain levels of myo-inositol and other metabolites occur in the preclinical stages of Alzheimer's disease associated with Down's syndrome. Method: The authors used H-1 magnetic resonance spectroscopy (MRS) with external standards to measure absolute brain metabolite concentrations in 19 nondemented adults with Down's syndrome and 17 age- and sex-matched healthy comparison subjects. Results: Concentrations of myo-inositol and choline-containing compounds were significantly higher in the occipital and parietal regions of the adults with Down's syndrome than in the comparison subjects. Within the Down's syndrome group, older subjects (42-62 years, N = 11) had higher myo-inositol levels than younger subjects (28-39 years, N = 8). Older subjects in both groups had lower N-acetylaspartate levels than the respective younger subjects, although this old-young difference was not greater in the Down's syndrome group, Conclusions: The approximately 50% higher level of myo-inositol in Down's Syndrome suggests a gene dose effect of the extra chromosome 21, where the human osmoregulatory sodium/myo-inositol cotransporter gene is located. The even higher myoinositol level in older adults with Down's syndrome extends to the predementia phase earlier findings of high myo-inositol levels in symptomatic Alzheimer's disease. C1 NIA, Neurosci Lab, Ctr Clin, NIH, Bethesda, MD 20892 USA. RP Huang, W (reprint author), SUNY Stony Brook, Dept Radiol, Stony Brook, NY 11794 USA. EM whuang@clio.rad.sunysb.edu RI daly, eileen/B-6716-2011; OI Daly, Eileen/0000-0003-3625-3467 NR 50 TC 72 Z9 74 U1 0 U2 2 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD DEC PY 1999 VL 156 IS 12 BP 1879 EP 1886 PG 8 WC Psychiatry SC Psychiatry GA 260DT UT WOS:000083934800007 PM 10588400 ER PT J AU Frye, MA Denicoff, KD Bryan, AL Smith-Jackson, EE Ali, SO Luckenbaugh, D Leverich, GS Post, RM AF Frye, MA Denicoff, KD Bryan, AL Smith-Jackson, EE Ali, SO Luckenbaugh, D Leverich, GS Post, RM TI Association between lower serum free T-4 and greater mood instability and depression in lithium-maintained bipolar patients SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT 2nd International Conference on Bipolar Disorder CY JUN 19-21, 1997 CL PITTSBURGH, PENNSYLVANIA ID PITUITARY-THYROID AXIS; HORMONE LEVELS; PROPHYLACTIC EFFICACY; MAJOR DEPRESSION; CARBAMAZEPINE; THYROTROPIN; THYROXINE; DISORDER; ILLNESS; THERAPY AB Objective: This investigation evaluated the relationship between changes in thyroid indices and mood stability during lithium and carbamazepine prophylaxis for bipolar disorder. Method: In the first 2 years, 30 patients with bipolar mood disorder were randomly assigned to 1 year of lithium and then 1 year of carbamazepine, or vice versa; in the third year, they received lithium plus carbamazepine. By stepwise regression analysis, the degree and timing of lithium- and carbamazepine-induced thyroid changes and their subsequent relationship to long-term mood stability were evaluated. Results: During the lithium phase, there was a significant inverse relationship between morbidity and mean serum level of free T-4, i.e., a lower mean serum level of free T-4 was associated with more affective episodes and greater severity of depression as shown by the Beck Depression Inventory. During the carbamazepine phase, there was an inverse relationship between mean level of total T-4 and global severity rating. During the combination phase, no relationships between thyroid indices and clinical outcome were significant. Conclusions: In the lithium phase, a low level of free T-4 was associated with more affective episodes and greater severity of depression. Whether this mood instability is causally related to low free T-4 levels and whether it can be attenuated with T-4 replacement remain to be studied in a controlled setting. C1 NIMH, Biol Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP Post, RM (reprint author), NIMH, Biol Psychiat Branch, NIH, Room 3N 212,Bldg 10, Bethesda, MD 20892 USA. OI Ali, Syed/0000-0003-3131-3299 NR 46 TC 53 Z9 54 U1 1 U2 1 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD DEC PY 1999 VL 156 IS 12 BP 1909 EP 1914 PG 6 WC Psychiatry SC Psychiatry GA 260DT UT WOS:000083934800011 PM 10588404 ER PT J AU Leibenluft, E Suppes, T AF Leibenluft, E Suppes, T TI Treating bipolar illness: Focus on treatment algorithms and management of the sleep-wake cycle SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID ANTIDEPRESSANT-INDUCED MANIA; LITHIUM PROPHYLAXIS; DEPRESSIVE ILLNESS; MOOD STABILIZER; PHASE ADVANCE; LIFE EVENTS; DISORDER; EFFICACY; ANTIPSYCHOTICS; DEPRIVATION C1 NIMH, Pediat & Dev Neuropsychiat Branch, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dept Psychiat, Bipolar Disorder Program, Dallas, TX USA. RP Leibenluft, E (reprint author), NIMH, Pediat & Dev Neuropsychiat Branch, 10-4N-208,10 Ctr Dr,MSC 1255, Bethesda, MD 20892 USA. NR 73 TC 26 Z9 26 U1 2 U2 4 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD DEC PY 1999 VL 156 IS 12 BP 1976 EP 1981 PG 6 WC Psychiatry SC Psychiatry GA 260DT UT WOS:000083934800020 PM 10588413 ER PT J AU Bedwell, JS Keller, B Smith, AK Hamburger, S Kumra, S Rapoport, JL AF Bedwell, JS Keller, B Smith, AK Hamburger, S Kumra, S Rapoport, JL TI Why does postpsychotic IQ decline in childhood-onset schizophrenia? SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID HUMAN BRAIN AB Objective: The authors' goal was to examine whether the postpsychotic decline in full-scale IQ during adolescence for patients with childhood-onset schizophrenia is due to a dementing process or simply failure to acquire new information and skills. Method: Linear regression was used to determine the rate of change for scaled and raw scores on subtests of 31 patients with childhood-onset schizophrenia. The resulting slopes were examined and related to changes in the patients' brains determined by magnetic resonance imaging. Results: Th ree postpsychotic subtest scaled scores declined significantly: picture arrangement, information, and block design. In contrast, there was no decline in the non-age-corrected (raw) scores for any subtest. A significant correlation was found between decrease in hippocampal volume and a smaller increase in raw score on the information subtest. Conclusions: The decline during adolescence in the full-scale IQ of patients with childhood-onset schizophrenia does not reflect dementia but, rather, an inability to acquire new information and abilities. C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Rapoport, JL (reprint author), NIMH, Child Psychiat Branch, 9000 Rockville Pike,10-3N202, Bethesda, MD 20892 USA. NR 7 TC 38 Z9 38 U1 4 U2 4 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD DEC PY 1999 VL 156 IS 12 BP 1996 EP 1997 PG 2 WC Psychiatry SC Psychiatry GA 260DT UT WOS:000083934800027 PM 10588420 ER PT J AU Little, RE Monaghan, SC Gladen, BC Shkyryak-Nyzhnyk, ZA Wilcox, AJ AF Little, RE Monaghan, SC Gladen, BC Shkyryak-Nyzhnyk, ZA Wilcox, AJ TI Outcomes of 17137 pregnancies in 2 urban areas of Ukraine SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article AB Objectives. Frequent terminations of pregnancy and high rates of fetal loss have been reported but not confirmed, in the former eastern bloc. A census of pregnancies in Ukraine, a former eastern bloc country, was conducted to determine the rates of these events. Methods. All pregnancies registered in 2 urban areas were enumerated. During a 19-month period between 1992 and 1994, 17137 pregnancies and their outcomes were recorded. Results. Sixty percent of the pregnancies were voluntarily terminated, generally before the 13th week. In pregnancies delivered at 20+ weeks, fetal mortality was 29 per 1000, nearly 5 times the rate among Whites in the United States. There was a greater proportion of very early deliveries (20-27 weeks) in Ukraine, as well as higher death rates at all gestational ages. Perinatal mortality was estimated to be 35 per 1000, about 3 times the US rate. Conclusion. This is believed to be the first study in the former eastern bloc to ascertain all of the clinically recognized pregnancies in a specified period and to determine their outcomes. The data document elevated reproductive risks in a former Soviet state. C1 Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Univ Illinois, Sch Publ Hlth, Chicago, IL USA. Inst Pediat Obstet & Gynecol, Kyiv, Ukraine. RP Little, RE (reprint author), Natl Inst Environm Hlth Sci, Epidemiol Branch, A3-05,POB 12233, Res Triangle Pk, NC 27709 USA. OI Wilcox, Allen/0000-0002-3376-1311 NR 13 TC 11 Z9 11 U1 1 U2 1 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 DEC PY 1999 VL 89 IS 12 BP 1832 EP 1836 DI 10.2105/AJPH.89.12.1832 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 259YU UT WOS:000083922200008 PM 10589311 ER PT J AU Fernandes, AM Hamburger, AW Gerwin, BI AF Fernandes, AM Hamburger, AW Gerwin, BI TI Dominance of ErbB-1 heterodimers in lung epithelial cells overexpressing ErbB-2 - Both ErbB-1 and ErbB-2 contribute significantly to tumorigenicity SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article ID EPIDERMAL GROWTH-FACTOR; FACTOR-RELATED PEPTIDES; SINGLE-CHAIN ANTIBODY; HUMAN EGF RECEPTOR; FACTOR-ALPHA; INTRACELLULAR EXPRESSION; SYNERGISTIC INTERACTION; NEU; DIFFERENTIATION; TRANSFORMATION AB This article examines differential expression and heterodimer formation of ErbB family members in tumorigenic and nontumorigenic human bronchial epithelial cells (HBECs). This cell system was developed previously as a model for lung adenocarcinoma by overexpression of c-erbB-2 in nontumorigenic, T antigen-immortalized HBECs. Earlier studies demonstrated that a tumorigenic clone from T antigen-immortalized nontumoringenic cells overexpressing ErbB-2 endogenously produced high levels of transforming growth factor (TGF)-alpha, and that reducing TGF-alpha by 93% eliminated tumorigcnicity. In the present report, comparison of ErbB species between the tumorigenic cells (E6T) and their nontumorigenic derivatives (EGTA) demonstrated all four receptors in both cell types, However, in EGTA cells, ErbB-3 and -4 were present primarily in ErbB-1 heterodimers, suggesting that ErbB-1 is a preferred heterodimer partner within this cell system, expressing endogenous ErbB receptors and ligands and overexpressing ErbB-2. The ErbB-1/-2 species was present at high levels in E6T and absent in E6TA cells, Mitogen-activated protein kinase activity was elevated in E6T relative to E6TA, Elevated activity was eliminated by blocking surface expression of either ErbB-1 or ErbB-2, Endoplasmic reticulum trapping of ErbB-1 eliminated tumorige nicity, whereas ErbB-2 internalization was selected against during tumor formation. These data demonstrate the importance of TGF-alpha-mediated signaling through the ErbB-1/-2 heterodimer in development of the tumorigenic phenotype, This work further suggests that ErbB-3 and -4 species may also contribute to tumorigenic conversion and that their expression levels may be increased by signaling initiated by TGF-alpha. Fernandes, A. M., A. W. Hamburger, and B. I. Gerwin. 1999. Dominance of ErbB-1 heterodimers in lung epithelial cells overexpressing ErbB-2: both ErtiB-1 and ErbB-2 contribute significantly to tumorigenicity. C1 NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. Univ Maryland, Ctr Canc, Sch Med, Baltimore, MD 21201 USA. Univ Maryland, Dept Pathol, Sch Med, Baltimore, MD 21201 USA. RP Gerwin, BI (reprint author), NCI, Human Carcinogenesis Lab, Bldg 37,Room 2C08,37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. FU NCI NIH HHS [F32CA63763] NR 33 TC 11 Z9 11 U1 0 U2 0 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 DEC PY 1999 VL 21 IS 6 BP 701 EP 709 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 265UT UT WOS:000084264700008 PM 10572067 ER PT J AU Lubensky, IA Schiffmann, R Goldin, E Tsokos, M AF Lubensky, IA Schiffmann, R Goldin, E Tsokos, M TI Lysosomal inclusions in gastric parietal cells in mucolipidosis type IV - A novel cause of achlorhydria and hypergastrinemia SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE gastric biopsy; lysosomal storage disease; mucolipidosis type IV; gastritis; atrophy; ECL cell hyperplasia ID CULTURED SKIN FIBROBLASTS; STORAGE DISEASES; NATURAL-HISTORY; DIAGNOSIS; CHILDREN; BIOPSY; MUCOSA; BASAL; PAIN AB Mucolipidosis type IV (ML-IV) is an autosomal recessive lysosomal storage disease that causes severe neurologic abnormalities. The brain disease is characterized by pigmented cytoplasmic granules in neurons and accumulation of lamellated membrane structures in lysosomes. The gastrointestinal disease in ML-IV was not previously recognized. Clinical examination of 20 patients with ML-IV (age range, 2-23 years) at the National Institutes of Health showed hypergastrinemia and constitutive achlorhydria. Endoscopic biopsy specimens, from the gastric fundus, body, and antrum and from the duodenum of four such patients (ages 4, 6, 7, and 22 years) were evaluated histologically and by electron microscopy. Histologically, all gastric fundus and body biopsy specimens showed parietal cells in normal numbers. However, a striking cytoplasmic vacuolization of parietal cells was seen on hematoxylin and eosin stain. Electron microscopy showed the parietal cells to be markedly distended by large lysosomes containing lamellar, concentric, and cystic membranous inclusions. Additionally, chronic atrophic gastritis and enterochromaffin-like (ECL) cell hyperplasia were observed. Foveolar and chief cells in stomach and duodenum biopsy specimens were normal. We conclude that the cytoplasmic lysosomal inclusions in gastric parietal cells is a unique histologic feature of gastric biopsy in ML-IV. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Lubensky, IA (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Room 2A33,10 Ctr Dr, Bethesda, MD 20892 USA. NR 25 TC 19 Z9 19 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 DEC PY 1999 VL 23 IS 12 BP 1527 EP 1531 DI 10.1097/00000478-199912000-00010 PG 5 WC Pathology; Surgery SC Pathology; Surgery GA 259CN UT WOS:000083876500010 PM 10584706 ER PT J AU Jones, D Basile, J Cushman, W Egan, B Ferrario, C Hill, M Lackland, D Mensah, G Moore, M Ofili, E Roccella, EJ Smith, R Taylor, H AF Jones, D Basile, J Cushman, W Egan, B Ferrario, C Hill, M Lackland, D Mensah, G Moore, M Ofili, E Roccella, EJ Smith, R Taylor, H TI Managing hypertension in the southeastern United States: Applying the guidelines from the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) SO AMERICAN JOURNAL OF THE MEDICAL SCIENCES LA English DT Article DE hypertension; blood pressure; guidelines; southeast; stroke belt ID CONGESTIVE-HEART-FAILURE; DISEASE MORTALITY; DIETARY POTASSIUM; RANDOMIZED TRIAL; STROKE; METAANALYSIS; PROGRESSION; REDUCTION; MORBIDITY; OBESITY AB The southeastern United States has the highest occurrence of heart disease and stroke and among the highest rates of congestive heart failure and renal failure in the country. The Consortium for Southeastern Hypertension Control (COSEHC) is cooperating with other organizations in implementing initiatives to reduce morbidity and mortality from hypertension-related conditions in the southeastern United States. This article outlines for clinicians special consideration for implementation of the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure ONC VI in the southeastern United States. Clinicians are encouraged to adapt the recommendations of JNC VI to their own patient groups, paying attention to these specific areas: (1) Ensure screening for hypertension in your practice and community. (2) Evaluate all patients for accompanying risk factors and target organ damage. (3) Promote lifestyle management for individual patients and populations for prevention and treatment of hypertension. (4) Set a goal blood pressure for each patient, and monitor progress toward that goal. (5) Recognize that many patients will be candidates for blood pressure goals of <130/85 mm Hg. (6) Pay attention to compelling and special indications such as diabetes, congestive heart failure, and renal dysfunction. (7) Consider combination therapy. (8) Maximize staff contributions to enhance patient adherence. (9) Encourage patient, family, and community activities to promote healthy lifestyles and blood pressure control. C1 Univ Mississippi, Med Ctr, Div Hypertens, Jackson, MS 39216 USA. Med Univ S Carolina, Charleston, SC 29425 USA. Vet Adm Med Ctr, Charleston, SC 29403 USA. Univ Tennessee, Sch Med, Memphis, TN 38163 USA. Wake Forest Univ, Med Ctr, Winston Salem, NC USA. Johns Hopkins Univ, Sch Nursing, Baltimore, MD USA. Med Coll Georgia, Augusta, GA 30912 USA. Danville Urol Clin, Danville, VA USA. Emory Univ, Med Ctr, Atlanta, GA 30322 USA. NHLBI, Bethesda, MD 20892 USA. RP Jones, D (reprint author), Univ Mississippi, Med Ctr, Div Hypertens, 2500 N State St, Jackson, MS 39216 USA. OI Mensah, George/0000-0002-0387-5326 NR 41 TC 20 Z9 21 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-9629 J9 AM J MED SCI JI Am. J. Med. Sci. PD DEC PY 1999 VL 318 IS 6 BP 357 EP 364 DI 10.1097/00000441-199912000-00001 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 267HC UT WOS:000084351400001 PM 10616159 ER PT J AU Henkin, RI Martin, BM Agarwal, RP AF Henkin, RI Martin, BM Agarwal, RP TI Decreased parotid saliva gustin/carbonic anhydrase VI secretion: An enzyme disorder manifested by gustatory and olfactory dysfunction SO AMERICAN JOURNAL OF THE MEDICAL SCIENCES LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Society-for-Clinical-Investigation CY MAY 05, 1996 CL WASHINGTON, D.C. SP Amer Soc Clin Investigat DE carbonate dehydratase; taste; smell; zinc; saliva ID EPIDERMAL GROWTH-FACTOR; ATOMIC-ABSORPTION SPECTROPHOTOMETRY; PROGRAMMED CELL-DEATH; CARBONIC-ANHYDRASE; ZINC-METABOLISM; DOUBLE-BLIND; IDIOPATHIC HYPOGEUSIA; SUBMANDIBULAR GLANDS; SMELL DYSFUNCTION; TASTE DISTURBANCE AB Background: Taste and smell dysfunction has been reported to occur in patients with a variety of clinical problems. We wanted to investigate a specific group of patients in whom taste and smell dysfunction occurred putatively related to a specific biochemical abnormality in a salivary growth factor [gustin/carbonic anhydrase (CA) VI] considered responsible for maintenance of taste bud function. Methods: Eighteen patients developed loss and/or distortion of taste and smell after an acute influenza-type illness. They were evaluated clinically, by psychophysical tests of taste and smell function, by measurement of parotid salivary gustin/CAVI by a radioimmunoassay and by measurement of serum, urine? and salivary zinc. Biopsies of circumvallate papillae were obtained in 6 patients and examined by transmission electron microscopy. Similar studies were performed in 55 asymptomatic volunteers with biopsies of circumvallate papillae performed in 4. Re suits: Taste and smell acuity were impaired in patients compared with healthy volunteers and parotid gustin/CAVI, salivary, and serum zinc concentrations were lower in patients than in healthy volunteers. Taste buds in circumvallate papillae of patients exhibited severe vacuolization, cellular degeneration, and absence of dense extracellular material. Conclusions: These results describe a clinical disorder formulated as a syndrome of hyposmia (decreased smell acuity), hypogeusia (decreased taste acuity), dysosmia (distorted smell function), dysgeusia (distorted taste function), and decreased secretion of parotid saliva gustin/CAVI with associated pathological changes in taste bud anatomy. Because gustin/CAVI is found in humans only in parotid saliva and has been associated with taste bud growth and development these results suggest that inhibition of synthesis of gustin/CAVI is associated with development of taste bud abnormalities and thereby loss of taste function. C1 Taste & Smell Clin, Washington, DC 20016 USA. NIMH, Clin Neurosci Branch, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Dept Pathol, Washington, DC 20007 USA. RP Henkin, RI (reprint author), Taste & Smell Clin, 5125 MacArthur Blvd NW, Washington, DC 20016 USA. NR 160 TC 67 Z9 69 U1 2 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-9629 J9 AM J MED SCI JI Am. J. Med. Sci. PD DEC PY 1999 VL 318 IS 6 BP 380 EP 391 DI 10.1097/00000441-199912000-00005 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 267HC UT WOS:000084351400005 PM 10616163 ER PT J AU Henkin, RI Martin, BM Agarwal, RP AF Henkin, RI Martin, BM Agarwal, RP TI Efficacy of exogenous oral zinc in treatment of patients with carbonic anhydrase VI deficiency SO AMERICAN JOURNAL OF THE MEDICAL SCIENCES LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Society-for-Clinical-Investigation CY MAY 05, 1996 CL WASHINGTON, D.C. SP Amer Soc Clin Investigat DE carbonate dehydratase; carbonic anhydrase VI deficiency; zinc; taste; smell; saliva; gustin; growth factors; stem cells ID NERVE GROWTH-FACTOR; HUMAN PAROTID-SALIVA; STEM-CELL FACTOR; CHRONIC-RENAL-FAILURE; INFLUENZA-VIRUS; DOUBLE-BLIND; 1,25-DIHYDROXYVITAMIN D-3; TRANSCRIPTION FACTORS; SMELL DYSFUNCTION; GENE-EXPRESSION AB Background: We previously described a disorder in 18 patients with decreased parotid saliva gustin/carbonic anhydrase (CA) VI secretion associated with loss of taste (hypogeusia) and smell (hyposmia) and distorted taste (dysgeusia) and smell (dysosmia). Because gustin/CAVI is a zinc-dependent enzyme we instituted a study of treatment with exogenous zinc to attempt to stimulate synthesis/secretion of gustin/CAVI and thereby attempt to correct the symptoms of this disorder. Methods: Fourteen of the 18 patients with this disorder completed the study. They were treated with 100 mg of exogenous zinc daily for 4 to 6 months, in an open clinical trial. Both before and after treatment, measurements were obtained of parotid saliva gustin/CAVI, parotid saliva, serum and urine zinc, taste and smell function, and, in some patients, examination of circumvallate taste buds by electron microscopy. Results: Treatment success was predicated upon significant increases in parotid saliva gustin/CAVI. This occurred in 10 of the 14 patients who were labeled responders; they also exhibited improvement in taste and smell acuity, a diminution in dysgeusia and dysosmia and increased zinc concentrations in parotid saliva, serum, and urine. Taste bud morphology returned to normal in each responder in whom it was measured. No increase in gustin/CAVI occurred in 4 patients who were labeled nonresponders; they exhibited no improvement in taste or smell acuity and no increases in parotid saliva zinc. However, serum and urine zinc increased to levels similar to those measured in the 10 responders. Two of 4 nonresponders reported diminution in dysgeusia and dysosmia. Taste bud morphology did not change from the abnormal state in the 1 nonresponder in whom it was measured. Conclusions: Zinc treatment is effective in patients in whom this trace metal increases synthesis/secretion of gustin/CAVI and ineffective in those in whom it does not. Increased gustin/CAVI in this disorder is probably associated with zinc stimulation of the gene responsible for the synthesis/secretion of gustin/CAVI. Among nonresponders, zinc was ineffective for several possible reasons, including resistance to zinc and possible sialylation of gustin/CAVI, which may render it functionally ineffective. Results suggest the hypothesis that gustin/CAVI is a trophic factor that promotes growth and development of taste buds through its action on taste bud stem cells. C1 Taste & Smell Clin, Washington, DC 20016 USA. NIMH, Clin Neurosci Branch, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Dept Pathol, Washington, DC 20007 USA. RP Henkin, RI (reprint author), Taste & Smell Clin, 5125 MacArthur Blvd NW, Washington, DC 20016 USA. NR 171 TC 60 Z9 61 U1 3 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-9629 J9 AM J MED SCI JI Am. J. Med. Sci. PD DEC PY 1999 VL 318 IS 6 BP 392 EP 405 DI 10.1097/00000441-199912000-00006 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 267HC UT WOS:000084351400006 PM 10616164 ER PT J AU Somerfield, MR Costa, PT AF Somerfield, MR Costa, PT TI Toward more evidence-based guidelines for psychology SO AMERICAN PSYCHOLOGIST LA English DT Editorial Material C1 Amer Soc Clin Oncol, Alexandria, VA 22314 USA. NIA, Bethesda, MD 20892 USA. RP Somerfield, MR (reprint author), Amer Soc Clin Oncol, 225 Reinekers Lane,Suite 650, Alexandria, VA 22314 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0003-066X J9 AM PSYCHOL JI Am. Psychol. PD DEC PY 1999 VL 54 IS 12 BP 1131 EP 1132 PG 2 WC Psychology, Multidisciplinary SC Psychology GA 271KW UT WOS:000084593600009 PM 15332532 ER PT J AU Strassels, SA Carr, DB Meldrum, M Cousins, MJ AF Strassels, SA Carr, DB Meldrum, M Cousins, MJ TI Toward a canoe of the pain and analgesia literature: A citation analysis SO ANESTHESIA AND ANALGESIA LA English DT Article ID COCHRANE-COLLABORATION; PHYSICAL THERAPY; PERSPECTIVE; JOURNALS; CLASSICS; AUTHORS; INDEX AB The purpose of this study was to use citation analysis to identify major themes and contributors to the pain and analgesia Literature over the past two decades. A citation analysis was performed on a database of more than 110,000 articles in the biomedical literature from January 1981 through June 1997, and in the interval from January 1988 through June 1997. Articles and authors related to pain and analgesia research and practice were identified by searching approximately 7,700 journals. The 20 articles and 20 authors with the most citations were then checked by hand to ensure relevance to pain or analgesia. Most of the high-impact articles identified pertained to research on basic pain pathways. Nearly all the articles concerned opioids, nonsteroidal antiinflammatory drugs, and consequences of analgesic use. None of the highest-impact articles address assessment of clinical pain. Few women were first authors of any most frequently cited paper. Citation analysis is a useful tool in identifying important contributions to the biomedical literature. Recent and continuing research trends include the use of nonsteroidal antiinflammatory drugs, opioid mechanisms, and persistent pain disorders. Current trends expected to become stronger include description of pain from the patient's perspective and mechanisms of the transit-ion from acute to chronic pain. Implications: We performed a citation analysis to identify important contributions and contributors to the biomedical literature. Recent pain and analgesia research has been focused on mechanisms of pain, but evidence suggests the importance of understanding the pain experience from the patient's perspective and the transition from acute to chronic pain. C1 Tufts Univ New England Med Ctr, Dept Anesthesia, Boston, MA 02111 USA. Tufts Univ New England Med Ctr, Dept Pharm, Boston, MA 02111 USA. NIH, Hist Off, Bethesda, MD USA. Royal N Shore Hosp, Dept Anaesthesia & Pain Management, St Leonards, NSW 2065, Australia. RP Strassels, SA (reprint author), Tufts Univ New England Med Ctr, Dept Anesthesia, 750 Washington St,NEMC Box 345, Boston, MA 02111 USA. NR 34 TC 16 Z9 16 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD DEC PY 1999 VL 89 IS 6 BP 1528 EP 1533 DI 10.1097/00000539-199912000-00040 PG 6 WC Anesthesiology SC Anesthesiology GA 260ZB UT WOS:000083982400040 PM 10589642 ER PT J AU Eitel, P Friend, R AF Eitel, P Friend, R TI Reducing denial and sexual risk behaviors in college students: A comparison of a cognitive and a motivational approach SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article ID SOCIAL DESIRABILITY SCALE; UNREALISTIC OPTIMISM; USE CONDOMS; AIDS; SUSCEPTIBILITY; PERCEPTIONS; ADOLESCENTS; ATTITUDES; EGOCENTRISM; HYPOCRISY AB This study compared two interventions designed to decrease denial of sexually transmitted disease (STD)/human immunodeficiency virus (HN) risk, to increase purchase of and intent to use condoms, and to decrease sexual risk behaviors. One hundred and fifty sexually active male and female undergraduates were assessed at baseline for denial of STD/HIV risk, knowledge of sexual risk behaviors, and self-reports of sexual behavior and were randomly assigned to either a motivational or cognitive intervention or a control condition. After the intervention, subjects were offered the opportunity to purchase condoms and were assessed for denial and intent To use condoms. Two months later sexual risk behaviors and denial were measured The motivational approach was most effective in reducing denial and in increasing intent to use condom immediately following the intervention and in reducing sexual risk behaviors 2 months later. C1 NICHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. SUNY Stony Brook, Stony Brook, NY 11794 USA. RP Eitel, P (reprint author), NICHD, Div Epidemiol Stat & Prevent Res, NIH, Bldg 6100,Room 7B05,9000 Rockville Pike MSC 7510, Bethesda, MD 20892 USA. NR 43 TC 15 Z9 15 U1 1 U2 10 PU SOC BEHAVIORAL MEDICINE PI MIDDLETON PA 7611 ELMWOOD AVE, STE 201, MIDDLETON, WI 53562-3161 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD WIN PY 1999 VL 21 IS 1 BP 12 EP 19 DI 10.1007/BF02895028 PG 8 WC Psychology, Multidisciplinary SC Psychology GA 288AC UT WOS:000085538800003 PM 18425649 ER PT J AU Wildner, O AF Wildner, O TI In situ use of suicide genes for therapy of brain tumours SO ANNALS OF MEDICINE LA English DT Article DE brain tumours; bystander; ganciclovir; gene therapy; herpes simplex virus; thymidine kinase; vector-producing cells; viral vectors ID VIRUS THYMIDINE KINASE; IN-VIVO; CYTOSINE DEAMINASE; GAP-JUNCTIONS; CYTOMEGALOVIRUS-INFECTION; INTRAVENOUS GANCICLOVIR; EXPERIMENTAL GLIOMAS; ADENOVIRUS VECTORS; BARRIER DISRUPTION; NUCLEOSIDE ANALOGS AB Suicide gene therapy represents a new therapeutic approach to the treatment of patients with otherwise incurable malignant brain tumours. This strategy involves the introduction of a gene that renders the tumour cell susceptible to an otherwise nontoxic prodrug. The most often used genetic prodrug activation system is the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) paradigm. An important aspect of this system is the 'bystander effect', the extension of cytotoxic effects to untransduced cells. For gene delivery, retroviral, adenoviral vectors and HSV-1 mutants have been used. Clinical studies have revealed that the HSV-tk/GCV approach is safe, but also that responses are observed only in very small brain tumours, indicating insufficient vector distribution and very low transduction efficiency with replication-deficient vector systems. To improve treatment efficacy, the use of replication-competent oncolytic vectors in combination with new or improved prodrug-suicide gene systems as a part of a multimodal approach is warranted. In the context of replication-competent vectors, suicide genes might also be used as fail-safe genes in the case of runaway infection. C1 Natl Human Genome Res Inst, Clin Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. RP Wildner, O (reprint author), Natl Human Genome Res Inst, Clin Gene Therapy Branch, NIH, 10 Ctr Dr,Bldg 10,Room 10C103, Bethesda, MD 20892 USA. NR 75 TC 24 Z9 25 U1 0 U2 0 PU ROYAL SOC MEDICINE PRESS LTD PI LONDON PA 1 WIMPOLE STREET, LONDON W1M 8AE, ENGLAND SN 0785-3890 J9 ANN MED JI Ann. Med. PD DEC PY 1999 VL 31 IS 6 BP 421 EP 429 DI 10.3109/07853899908998799 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 276NY UT WOS:000084885400008 PM 10680856 ER PT J AU Harris, NL Jaffe, ES Diebold, J Flandrin, G Muller-Hermelink, HK Vardiman, J Lister, TA Bloomfield, CD AF Harris, NL Jaffe, ES Diebold, J Flandrin, G Muller-Hermelink, HK Vardiman, J Lister, TA Bloomfield, CD TI The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues SO ANNALS OF ONCOLOGY LA English DT Editorial Material DE classification; histiocytic; lymphoma; leukemia; myeloid; mast cell AB Introduction: Since 1995, the European Association of Pathologists (EAHP) and the Society for Hematopathology (SH) have been developing a new World Health Organization (WHO) Classification of hematologic malignancies. The classification includes lymphoid, myeloid, histiocytic, and mast cell neoplasms. Design: The WHO project involves 10 committees of pathologists, who have developed lists and definitions of disease entities. A Clinical Advisory Committee (CAC) ) of international hematologists and oncologists was formed to ensure that the classification will be useful to clinicians. A meeting was held in November, 1997, to discuss clinical issues related to the classification. Results: The WHO has adopted the 'Revised European-American Classification of Lymphoid Neoplasms' (R.E.A.L.), published in 1994 by the International Lymphoma Study Group (ILSG), as the classification of lymphoid neoplasms. This approach to classification is based on the principle that a classification is a list of 'real' disease entities, which are defined by a combination of morphology, immunophenotype, genetic features, and clinical features. The relative importance of each of these features varies among diseases, and there is no one 'gold standard'. The WHO Classification has applied the principles of the R.E.A.L. Classification to myeloid and histiocytic neoplasms. The classification of myeloid neoplasms recognizes distinct entities defined by a combination of morphology and cytogenetic abnormalities. The CAC meeting, which was organized around a series of clinical questions, was able to reach a consensus on most of the questions posed. The questions and the consensus are discussed in detail below. Among other things, the CAC concluded that clinical groupings of lymphoid neoplasms were neither necessary nor desirable. Patient treatment is determined by the specific type of lymphoma, with the addition of grade within the tumor type, if applicable, and clinical prognostic factors such as the international prognostic index (IPI). Conclusion: The experience of developing the WHO Classification has produced a new and exciting degree of cooperation and communication between oncologists and pathologists from around the world, which should facilitate progress in the understanding and treatment of hematologic malignancies. C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA USA. NCI, Bethesda, MD 20892 USA. Hotel Dieu, Paris, France. Hop Necker, Paris, France. Univ Wurzburg, Wurzburg, Germany. Univ Chicago, Pritzker Sch Med, Chicago, IL 60637 USA. St Bartholomews Hosp, Dept Med Oncol, London, England. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. RP Harris, NL (reprint author), Massachusetts Gen Hosp, Dept Pathol, Warren 2,Fruit St, Boston, MA 02114 USA. NR 4 TC 345 Z9 368 U1 1 U2 7 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 DEC PY 1999 VL 10 IS 12 BP 1419 EP 1432 DI 10.1023/A:1008375931236 PG 14 WC Oncology SC Oncology GA 278TL UT WOS:000085005000014 PM 10643532 ER PT J AU Callender, DP Jayaprakash, N Bell, A Petraitis, V Petraitiene, R Candelario, M Schaufele, R Dunn, JM Sei, S Walsh, TJ Balis, FM AF Callender, DP Jayaprakash, N Bell, A Petraitis, V Petraitiene, R Candelario, M Schaufele, R Dunn, JM Sei, S Walsh, TJ Balis, FM TI Pharmacokinetics of oral zidovudine entrapped in biodegradable nanospheres in rabbits (vol 43, pg 972, 1999) SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Correction C1 NCI, Pediat Oncol Branch, Div Clin Sci, Bethesda, MD 20892 USA. NCI, HIV & AIDS Malignancy Branch, Div Clin Sci, Bethesda, MD 20892 USA. Verex Labs Inc, Englewood, CO 80112 USA. RP Callender, DP (reprint author), NCI, Pediat Oncol Branch, Div Clin Sci, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 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 DEC PY 1999 VL 43 IS 12 BP 3046 EP 3046 PG 1 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 261YE UT WOS:000084037900046 ER PT J AU Roberts, KP Lamb, ME Sternberg, KJ AF Roberts, KP Lamb, ME Sternberg, KJ TI Effects of the timing of postevent information on preschoolers' memories of an event SO APPLIED COGNITIVE PSYCHOLOGY LA English DT Article; Proceedings Paper CT 1997 Biennial Meeting of the Society-of-Research-in-Child-Development CY MAR-APR -, 1997 CL WASHINGTON, D.C. SP Soc Res Child Dev ID CHILDRENS MEMORY; EYEWITNESS TESTIMONY; FALSE MEMORIES; SEXUAL ABUSE; SUGGESTIBILITY; REMINISCENCE; SUGGESTIONS; RETENTION; REMEMBER; ADULTS AB Few researchers have investigated whether the timing of postevent information affects the accuracy of children's reports of events they have experienced. In this study, four-year-olds dressed up in costumes and had their photographs taken. An unfamiliar adult spoke to the children about the event either a day (immediate condition) or a month (delayed condition) later, providing both accurate and misleading information about the staged event. When questioned five weeks after the event, children in a control group who had not received the review were more inaccurate answering focused questions than children who had been reminded of the event. A review a while after the event but shortly before the interview increased the amount of details recalled and this was not at the expense of accuracy. Misinformation was seldom reported spontaneously, although children in all groups acquiesced to leading questions in line with the misleading suggestions. Copyright (C) 1999 John Wiley & Sons, Ltd. C1 NICHHD, Sect Social & Emot Dev, Bethesda, MD 20814 USA. RP Roberts, KP (reprint author), NICHHD, Sect Social & Emot Dev, 9190 Rockville Pike, Bethesda, MD 20814 USA. NR 55 TC 26 Z9 26 U1 0 U2 2 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0888-4080 J9 APPL COGNITIVE PSYCH JI Appl. Cogn. Psychol. PD DEC PY 1999 VL 13 IS 6 BP 541 EP 559 DI 10.1002/(SICI)1099-0720(199912)13:6<541::AID-ACP618>3.3.CO;2-X PG 19 WC Psychology, Experimental SC Psychology GA 269UQ UT WOS:000084496300004 ER PT J AU Cooper, DR Watson, JE Patel, N Illingworth, P Acevedo-Duncan, M Goodnight, J Chalfant, CE Mischak, H AF Cooper, DR Watson, JE Patel, N Illingworth, P Acevedo-Duncan, M Goodnight, J Chalfant, CE Mischak, H TI Ectopic expression of protein kinase C beta II, -delta, and -epsilon, but not -beta I or -zeta, provide for insulin stimulation of glucose uptake in NIH-3T3 cells SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE protein kinase C; insulin action; hexose transport; NIH-3T3 cells ID ISOLATED RAT ADIPOCYTES; BC3H-1 MYOCYTES; PHORBOL ESTER; MUSCLE-CELLS; PKC-EPSILON; PHOSPHATIDYLINOSITOL 3-KINASE; 2-DEOXYGLUCOSE UPTAKE; 3T3-L1 ADIPOCYTES; HEXOSE-TRANSPORT; SKELETAL-MUSCLES AB Insulin regulates a diverse array of signaling pathways involved in the control of growth, differentiation, proliferation, and metabolism. Insulin increases in glucose uptake via a protein kinase C-dependent pathway in target tissues such as fat and muscle are well documented. Insulin-regulated events, however, occur in all cells, The utilization of glucose as a preferred energy source is a ubiquitous event in eukaryotic cells. In NIH-3T3 fibroblasts, insulin treatment increased levels of the cPKC and nPKC activator, diacylglycerol. Insulin-responsive 2-[H-3]deoxyglucose uptake was stimulated in a dose-dependent manner. The overexpression of protein kinase C (PKC)beta I, -beta II, -delta, -epsilon, and -zeta was used to investigate the specificity of PKC isozymes for insulin-sensitive glucose uptake. The stable overexpression of PKC beta II, -delta, and -epsilon resulted in increases in insulin-stimulated 2-[H-3]deoxyglucose uptake compared to vector control cells, while basal 2-deoxyglucose uptake levels were not elevated. Overexpression of PKC beta I and PKC zeta isozymes had no further effect on basal or insulin-stimulated 2-deoxyglucose uptake. The PKC-specific inhibitor, CGP41251, blocked insulin effects on 2-deoxyglucose uptake but not its effects on tyrosine phosphorylation of cellular substrates. Insulin-stimulated 3-O-methylglucose uptake was also greater in cells overexpressing PKC beta II,-delta, and -epsilon, compared to control cells. The increased responsiveness was not accompanied by conversion of 3T3 cells to the adipocyte phenotype or the increased expression of insulin receptors or glucose transporters (GLUT1-type). Insulin-stimulated recruitment of GLUT1 to plasma membranes of cells overexpressing PKC beta II, -delta, and -epsilon, was greater than that in control cells. The data suggest that more than one PKC isozyme is involved in insulin signaling pathways in fibroblasts, resulting in increased GLUT1 transporter recruitment to cell membranes. (C) 1999 Academic Press. C1 Univ S Florida, Coll Med, James A Haley Vet Hosp, Res Serv, Tampa, FL 33612 USA. Univ S Florida, Coll Med, Dept Biochem & Mol Biol, Tampa, FL 33612 USA. Univ S Florida, Coll Med, Dept Internal Med, Tampa, FL 33612 USA. Univ S Florida, Coll Med, Dept Chem, Tampa, FL 33612 USA. NCI, NIH, Bethesda, MD 20892 USA. GSF, Inst Klin Mol Biol & Tumorgenet, Munich, Germany. RP Cooper, DR (reprint author), Univ S Florida, Coll Med, James A Haley Vet Hosp, Res Serv, 151,13000 Bruce B Downs Blvd, Tampa, FL 33612 USA. RI Mischak, Harald/E-8685-2011; Patel, Niketa/A-1392-2012 NR 62 TC 22 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 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD DEC 1 PY 1999 VL 372 IS 1 BP 69 EP 79 DI 10.1006/abbi.1999.1472 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 261TN UT WOS:000084025400009 PM 10562418 ER PT J AU Landi, MT Calista, D Landi, G Bernucci, I Bertazzi, PA Clark, WH Goldstein, AM Tucker, MA AF Landi, MT Calista, D Landi, G Bernucci, I Bertazzi, PA Clark, WH Goldstein, AM Tucker, MA TI Clinical characteristics of 20 Italian melanoma-prone families SO ARCHIVES OF DERMATOLOGY LA English DT Letter ID NEVI C1 NCI, Genet Epidemiol Branch, NIH, Bethesda, MD 20892 USA. RP Landi, MT (reprint author), NCI, Genet Epidemiol Branch, NIH, EPS 7114,6120 Execut Blvd, Bethesda, MD 20892 USA. RI Tucker, Margaret/B-4297-2015; bertazzi, pietro alberto/D-5039-2017 OI bertazzi, pietro alberto/0000-0003-3475-2449 NR 5 TC 6 Z9 6 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD DEC PY 1999 VL 135 IS 12 BP 1554 EP 1555 DI 10.1001/archderm.135.12.1554 PG 2 WC Dermatology SC Dermatology GA 263QP UT WOS:000084137000036 PM 10606077 ER PT J AU Jensen, PS Arnold, LE Richters, JE Severe, JB Vereen, D Vitiello, B Schiller, E Hinshaw, SP Elliott, GR Conners, CK Wells, KC March, J Swanson, J Wigal, T Cantwell, DP Abikoff, HB Hechtman, L Greenhill, LL Newcorn, JH Pelham, WE Hoza, B Kraemer, HC AF Jensen, PS Arnold, LE Richters, JE Severe, JB Vereen, D Vitiello, B Schiller, E Hinshaw, SP Elliott, GR Conners, CK Wells, KC March, J Swanson, J Wigal, T Cantwell, DP Abikoff, HB Hechtman, L Greenhill, LL Newcorn, JH Pelham, WE Hoza, B Kraemer, HC CA MTA Cooperative Grp TI A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID DEFICIT HYPERACTIVITY DISORDER; STIMULANT MEDICATION; MULTIMODAL TREATMENT; REGRESSION-ANALYSIS; COMPUTER-PROGRAM; FOLLOW-UP; CHILDREN; METHYLPHENIDATE; BEHAVIOR; ADHD AB Background: Previous studies have demonstrated the short-term efficacy of pharmacotherapy and behavior therapy for attention-deficit/hyperactivity disorder (ADHD), but no longer-term tie, >4 months) investigations have compared these 2 treatments or their combination. Methods: A group of 579 children with ADHD Combined Type, aged 7 to 9.9 years, were assigned to 13 months of medication management (titration followed by monthly visits); intensive behavioral treatment (parent, school, and child components, with therapist involvement gradually reduced over time); the two combined; or standard community care (treatments by community providers). Outcomes were assessed in multiple domains before and during treatment and at treatment end point (with the combined treatment and medication management groups continuing medication at all assessment points). Data were analyzed through intent to-treat random-effects regression procedures. Results: All 4 groups showed sizable reductions in symptoms over time, with significant differences among them in degrees of change. For most ADHD symptoms, children in the combined treatment and medication management groups showed significantly greater improvement than those given intensive behavioral treatment and community care. Combined and medication management treatments did not differ significantly on any direct comparisons, but in several instances (oppositional/aggressive symptoms, internalizing symptoms, teacher-rated social skills, parent-child relations, and reading achievement) combined treatment proved superior to intensive behavioral treatment and/or community care while medication management did not. Study medication strategies were superior to community care treatments, despite the fact that two thirds of community-treated subjects received medication during the study period. Conclusions: For ADHD symptoms, our carefully crafted medication management was superior to behavioral treatment and to routine community care that included medication. Our combined treatment did not yield significantly greater benefits than medication management for core ADHD symptoms, but may have provided modest advantages for non-ADHD symptom and positive functioning outcomes. C1 NIMH, Off Director, Rockville, MD 20857 USA. Ohio State Univ, Dept Psychiat, Columbus, OH 43210 USA. Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. Univ Calif Berkeley, Dept Psychiat, Berkeley, CA 94720 USA. Duke Univ, Dept Psychiat & Behav Sci, Durham, NC USA. Univ Calif Irvine, Dept Pediat & Cognit Sci, Irvine, CA 92717 USA. Univ Calif Los Angeles, Dept Psychiat, Inst Neuropsychiat, Los Angeles, CA 90024 USA. Montreal Childrens Hosp, Montreal, PQ H3H 1P3, Canada. Long Isl Jewish Med Ctr, New York, NY USA. NYU, Sch Med, Dept Psychiat, New York, NY 10012 USA. McGill Univ, Dept Psychiat, Montreal, PQ, Canada. Columbia Univ, New York State Psychiat Inst, Ctr Advancement Childrens Mental Hlth, Dept Child Psychiat,Unit 78, New York, NY 10032 USA. CUNY Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. Univ Pittsburgh, Pittsburgh, PA USA. SUNY Buffalo, Dept Psychol, Buffalo, NY 14260 USA. Purdue Univ, Dept Psychol Sci, W Lafayette, IN 47907 USA. Stanford Univ, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA. NIMH, Dev Psychopathol & Prevent Res Branch, Rockville, MD 20857 USA. NIMH, Res Projects & Publicat Branch, Rockville, MD 20857 USA. NIMH, Off Drug Control Policy, Rockville, MD 20857 USA. NIMH, Child & Adolescent Treatment & Prevent Intervent, Rockville, MD 20857 USA. US Dept Educ, Off Special Educ Programs, Washington, DC USA. RP Jensen, PS (reprint author), Columbia Univ, New York State Psychiat Inst, Ctr Advancement Childrens Mental Hlth, Dept Child Psychiat,Unit 78, 1051 Riverside Dr, New York, NY 10032 USA. OI Jensen, Peter/0000-0003-2387-0650 NR 55 TC 1566 Z9 1594 U1 32 U2 253 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD DEC PY 1999 VL 56 IS 12 BP 1073 EP 1086 PG 14 WC Psychiatry SC Psychiatry GA 262ER UT WOS:000084053100001 ER PT J AU Jensen, PS Arnold, LE Richters, JE Severe, JB Vereen, D Vitiello, B Schiller, E Hinshaw, SP Elliott, GR Conners, CK Wells, KC March, J Swanson, J Wigal, T Cantwell, DP Abikoff, HB Hechtman, L Greenhill, LL Newcorn, JH Pelham, WE Hoza, B Kraemer, HC AF Jensen, PS Arnold, LE Richters, JE Severe, JB Vereen, D Vitiello, B Schiller, E Hinshaw, SP Elliott, GR Conners, CK Wells, KC March, J Swanson, J Wigal, T Cantwell, DP Abikoff, HB Hechtman, L Greenhill, LL Newcorn, JH Pelham, WE Hoza, B Kraemer, HC CA MTA Cooperative Grp TI Moderators and mediators of treatment response for children with attention-deficit/hyperactivity disorder - The multimodal treatment study of children with attention-deficit/hyperactivity disorder SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID RANDOMIZED CLINICAL-TRIAL; ANXIETY DISORDERS; ADHD; METHYLPHENIDATE; PREDICTORS; VALIDITY AB Background: Intent-to-treat analyses of the study revealed that medication management, alone or combined with intensive behavioral treatment, was superior to behavioral treatment and community care in reducing attention-deficit/hyperactivity disorder (ADHD) symptoms; but only combined treatment showed consistently greater benefit than community care across other outcome domains (disruptive and internalizing symptoms, achievement, parent-child relations and social skills). We examine response patterns in subgroups defined by baseline variables (moderators) or variables related to treatment implementation (mediators). Methods: We reconducted random-effects regression (RR) analyses, adding factors defined by moderators (ses, prior medication use, comorbid disruptive or anxiety disorder, and public assistance) and a mediator (treatment acceptance/attendance). Results: Study outcomes (N = 579) were upheld in most moderator subgroups (boys and girls, children with and without prior medication, children with and without co-morbid disruptive disorders). Comorbid anxiety disorder did moderate outcome. in participants without anxiety, results paralleled intent-to-treat findings. For those with anxiety disorders, however, behavioral treatment yielded significantly better outcomes than community care (and was no longer statistically different from medication management and combined treatment) regarding ADHD-related and internalizing symptoms. In families receiving public assistance, medication management yielded decreased closeness in parent-child interactions, and combined treatment yielded relatively greater benefits for teacher-reported social skills. In families with high treatment acceptance/attendance, intent-to-treat results were upheld. Acceptance/attendance was particularly important for medication treatments. Finally, two thirds of children given community care received stimulants. Behavioral treatment did not significantly differ from, but medication management was superior to, this subgroup. Conclusions: Exploratory analyses revealed that our study (the Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder [MTA]) re suits were confirmed across most baseline variables and treatment acceptance/attendance. Tn children with ADHD plus anxiety, behavioral treatment surpassed community. care and approached medication-based treatments regarding parent-reported ADHD symptoms. C1 Univ Calif Berkeley, Dept Psychol, Berkeley, CA 94720 USA. Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. NIMH, Off Director, Rockville, MD 20857 USA. NIMH, Dev Psychopathol & Prevent Res Branch, Rockville, MD 20857 USA. NIMH, Res Projects & Publicat Branch, Rockville, MD 20857 USA. NIMH, Off Drug Control Policy, Rockville, MD 20857 USA. NIMH, Child & Adolescent Treatment & Prevent Intervent, Rockville, MD 20857 USA. Ohio State Univ, Dept Psychiat, Columbus, OH 43210 USA. US Dept Educ, Off Special Educ Programs, Washington, DC USA. Duke Univ, Dept Psychiat & Behav Sci, Durham, NC USA. Univ Calif Irvine, Dept Pediat & Cognit Sci, Irvine, CA USA. Univ Calif Los Angeles, Inst Neuropsychiat, Dept Psychiat, Los Angeles, CA 90024 USA. Long Isl Jewish Med Ctr, New York, NY USA. Montreal Childrens Hosp, Montreal, PQ H3H 1P3, Canada. NYU, Sch Med, Dept Psychiat, New York, NY 10012 USA. McGill Univ, Dept Psychiat, Montreal, PQ, Canada. Columbia Univ, New York State Psychiat Inst, Dept Psychiat, Mt Sinai Med Ctr, New York, NY USA. CUNY Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. SUNY Buffalo, Dept Psychol, Buffalo, NY 14260 USA. Purdue Univ, Dept Psychol Sci, W Lafayette, IN 47907 USA. Stanford Univ, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA. RP Hinshaw, SP (reprint author), Univ Calif Berkeley, Dept Psychol, Tolman Hall 1650, Berkeley, CA 94720 USA. EM hinshaw@socrates.berkeley.edu NR 27 TC 425 Z9 429 U1 6 U2 41 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0003-990X EI 1538-3636 J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD DEC PY 1999 VL 56 IS 12 BP 1088 EP 1096 PG 9 WC Psychiatry SC Psychiatry GA 262ER UT WOS:000084053100002 ER PT J AU Chew, EY Benson, WE Remaley, NA Lindley, AA Burton, TC Csaky, K Williams, GA Ferris, FL AF Chew, EY Benson, WE Remaley, NA Lindley, AA Burton, TC Csaky, K Williams, GA Ferris, FL CA Early Treatment Diabetic Retinopat TI Results after lens extraction in patients with diabetic retinopathy - Early treatment diabetic retinopathy study report number 25 SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID EXTRACAPSULAR CATARACT-EXTRACTION; SURGERY AB Objective: To assess the visual results after surgical lens removal in patients with diabetic retinopathy. Design: A multicenter randomized clinical trial designed to assess the effect of photocoagulation and aspirin ill patients with mild to severe nonproliferative or early proliferative diabetic retinopathy and/or macular edema. Participants: Of the 3711 patients enrolled in the Early Treatment Diabetic Retinopathy Study, lens surgery was performed on 205 patients (270 eyes) during follow-up that ranged from 4 to 9 years. Outcome Measurements: Visual acuity, macular edema status, and degree of diabetic retinopathy. In addition, risk factors associated with lens extraction and with poor postoperative visual acuity (worse than 20/100) were assessed. Results: The risk of lens extraction increased with increasing age, female sex, and baseline proteinuria. Ocular variables associated with increased risk of lens surgery included poor baseline visual acuity and vitrectomy performed during the course of the study. At 1 year after lens surgery, visual acuity improvement of 2 or more lines from preoperative levels occurred in 64.3% of the operated-on eyes assigned to early photocoagulation and 59.3% of eyes assigned to deferral of photocoagulation. In eyes assigned to early photocoagulation, 46% of eyes achieved visual acuity better than 20/40; 73%, better than 20/100; and 8%, 5/200 or worse at 1 year after surgery. Visual acuity results for eyes assigned to deferral of laser photocoagulation at I year were not as favorable; 36% achieved visual acuity better than 20/40; 55%, better than 20/100; and 17%, 5/200 or worse at 1 year after surgery. Evaluation of 1-year postoperative visual acuities for all eyes with mild to moderate nonproliferative diabetic retinopathy at the annual visit before lens surgery showed that 53% were better than 20/40; 90%, better than 20/100; and 1%, 5/200 or worse. However, for eyes with severe nonproliferative or worse retinopathy at the annual visit before lens surgery, only 25% were better than 20/40; 42%, better than 20/100; and 22%, 5/200 or worse at 1 year after lens surgery. There was little change in visual acuity between 1 and 2 years postoperatively. Increased severity of retinopathy and poor visual acuity before surgery were associated with visual acuity of worse than 20/100 at 1 year after surgery. Lens surgery was associated with a borderline statistically significant increased risk of progression of diabetic retinopathy in the adjusted analyses (P = .03). No statistically significant long-term increased risk of macular edema was documented after lens surgery. Conclusions: Visual acuity results after lens surgery in patients in the Early Treatment Diabetic Retinopathy Study were better than published results for similar patients. This map be because of more intensive photocoagulation for lesions of diabetic retinopathy in the Early Treatment Diabetic Retinopathy Study than in previously reported studies. Although patients with severe nonproliferative retinopathy or worse before lens surgery had poorer visual results, visual improvement was seen in 55% of these patients at 1-year follow-up. The main causes of poor visual results in eyes after lens surgery were complications of proliferative retinopathy and/or macular edema. C1 NEI, Div Biometry & Epidemiol, NIH, Bethesda, MD 20892 USA. NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA. William Beaumont Hosp, Royal Oak, MI 48072 USA. RP Chew, EY (reprint author), NEI, Div Biometry & Epidemiol, NIH, Bldg 31,Room 6a52,31 Ctr Dr,Mail Stop MSC-2510, Bethesda, MD 20892 USA. EM echew@nei.nih.gov FU Intramural NIH HHS [Z99 EY999999] NR 23 TC 62 Z9 64 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0003-9950 EI 1538-3601 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD DEC PY 1999 VL 117 IS 12 BP 1600 EP 1606 PG 7 WC Ophthalmology SC Ophthalmology GA 263QN UT WOS:000084136900002 PM 10604663 ER PT J AU Langford, CA Talar-Williams, C Barron, KS Sneller, MC AF Langford, CA Talar-Williams, C Barron, KS Sneller, MC TI A staged approach to the treatment of Wegener's granulomatosis - Induction of remission with glucocorticoids and daily cyclophosphamide switching to methotrexate for remission maintenance SO ARTHRITIS AND RHEUMATISM LA English DT Article ID RHEUMATOID-ARTHRITIS; THERAPY AB Objective. To determine the efficacy of a daily cyclophosphamide (CYC) and glucocorticoid induction and methotrexate (MTX) remission-maintenance regimen for the treatment of Wegener's granulomatosis (WG), Methods. An open-label, prospective, standardized trial for the treatment of WG was performed using CYC and glucocorticoids for remission induction and MTX for remission maintenance, Thirty-one patients were enrolled in this study. Outcome was assessed using predetermined definitions based on clinical characteristics and pathologic, laboratory, and radiographic findings. Results, The use of CYC and glucocorticoids for remission induction and MTX for remission maintenance resulted in disease remission for all 31 patients. The median time to remission was 3 months and the median time to discontinuation of glucocorticoids was 8 months. No patients have died, and 5 patients (16%) have had disease relapses at a median of 13 months after achieving remission. Only 2 patients (6%) have had to withdraw from the trial as a result of medication toxicity. Conclusion. The use of CYC and glucocorticoids for remission induction and MTX for remission maintenance was shown by this study to be an acceptable alternative therapy for patients with active WG, including those with severe disease at onset. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Langford, CA (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 18 TC 137 Z9 141 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 DEC PY 1999 VL 42 IS 12 BP 2666 EP 2673 DI 10.1002/1529-0131(199912)42:12<2666::AID-ANR24>3.0.CO;2-E PG 8 WC Rheumatology SC Rheumatology GA 267TZ UT WOS:000084376500023 PM 10616016 ER PT J AU Houston, AL Chen, HC Hubbard, SM Schatz, BR Ng, TD Sewell, RR Tolle, KM AF Houston, AL Chen, HC Hubbard, SM Schatz, BR Ng, TD Sewell, RR Tolle, KM TI Medical data mining on the Internet: Research on a cancer information system SO ARTIFICIAL INTELLIGENCE REVIEW LA English DT Article DE CancerLit; concept spaces; data mining; Hopfield net; information retrieval; Kohonen net; medical knowledge; neural networks ID HOPFIELD NET; DATABASES; NETWORKS AB This paper discusses several data mining algorithms and techniques that we have developed at the University of Arizona Artificial Intelligence Lab. We have implemented these algorithms and techniques into several prototypes, one of which focuses on medical information developed in cooperation with the National Cancer Institute (NCI) and the University of Illinois at Urbana-Champaign. We propose an architecture for medical knowledge information systems that will permit data mining across several medical information sources and discuss a suite of data mining tools that we are developing to assist NCI in improving public access to and use of their existing vast cancer information collections. C1 NCI, Med Branch, Bethesda, MD 20852 USA. Univ Illinois, Community Architecture Network Informat Syst Lab, Digital Lib Initiat Project, Urbana, IL 61801 USA. Univ Arizona, Sch Lib Sci, Tucson, AZ 85721 USA. Univ Arizona, Management & Informat Syst Dept, Tucson, AZ 85721 USA. Univ Arizona, MIS Artificial Intelligence Lab, Tucson, AZ 85721 USA. Univ Illinois, Community Architecture Network Informat Syst Lab, DARPA Informat Management Program, Urbana, IL 61801 USA. RP Houston, AL (reprint author), Louisiana State Univ, ISBS Dept, Baton Rouge, LA 70803 USA. NR 35 TC 11 Z9 11 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0269-2821 J9 ARTIF INTELL REV JI Artif. Intell. Rev. PD DEC PY 1999 VL 13 IS 5-6 BP 437 EP 466 DI 10.1023/A:1006548623067 PG 30 WC Computer Science, Artificial Intelligence SC Computer Science GA 317YH UT WOS:000087254300006 ER PT J AU Siahpush, M Singh, GK AF Siahpush, M Singh, GK TI Social integration and mortality in Australia SO AUSTRALIAN AND NEW ZEALAND JOURNAL OF PUBLIC HEALTH LA English DT Article ID INCOME INEQUALITY; HEALTH; POPULATION AB Objective: To investigate the relationship between social integration and mortality at the aggregate level of analysis. Method: The data were compiled from several Australian Bureau of Statistics documents. The unit of analysis was State (Territory)-year. The multivariate regression analysis included data from all States and the Australian Capital Territory for 1990-96. Five indicators of social integration percentage of people living alone; divorce rate; unemployment rate; proportion of people who are discouraged job seekers; and unionisation rate - were used as predictors of nine measures of mortality. Results: Higher levels of social integration, as measured by all indicators except unionisation, were associated with lower mortality rates. In the case of unionisation, higher levels were associated with increased mortality rates. Conclusion: Studies concerning the relationship between social integration and health should investigate the 'type' and 'level' of social integration that is conducive to better health. Implications: To help reduce disparities in health and mortality across communities, public health researchers and policy makers need to closely monitor geographic and temporal trends in social integration measures. Social policies that emphasise investment in social integration or social capital through job creation and training, provision of gainful employment and social services for discouraged and marginalised workers, improved work conditions and social support may lower mortality directly or through their beneficial effects on health-promoting behaviours such as reduced levels of smelting, drinking and physical inactivity. C1 La Trobe Univ, Fac Humanities & Social Sci, Wodonga, Vic 3689, Australia. NCI, NIH, Bethesda, MD 20892 USA. RP Siahpush, M (reprint author), La Trobe Univ, Fac Humanities & Social Sci, POB 821,Parkers Rd, Wodonga, Vic 3689, Australia. NR 28 TC 17 Z9 19 U1 0 U2 2 PU PUBLIC HEALTH ASSOC AUSTRALIA INC PI CURTIN PA PO BOX 319, CURTIN, ACT 2600, AUSTRALIA SN 1326-0200 J9 AUST NZ J PUBL HEAL JI Aust. N. Z. Publ. Health PD DEC PY 1999 VL 23 IS 6 BP 571 EP 577 DI 10.1111/j.1467-842X.1999.tb01539.x PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 267AY UT WOS:000084333500002 PM 10641345 ER PT J AU Elenkov, IJ Chrousos, GP AF Elenkov, IJ Chrousos, GP TI Stress, cytokine patterns and susceptibility to disease SO BEST PRACTICE & RESEARCH CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article DE stress; cytokines; Th1/Th2 cells; interleukin-12; interleukin-10; inflammation; autoimmunity; rheumatoid arthritis ID CORTICOTROPIN-RELEASING HORMONE; MAST-CELL DEGRANULATION; NECROSIS-FACTOR-ALPHA; IL-12 PRODUCTION; HUMAN INTERLEUKIN-12; CD4(+) LYMPHOCYTES; IGE PRODUCTION; TH2 CLONES; IFN-GAMMA; T-CELLS AB Recent evidence indicates that glucocorticoids and catecholamines, the end-products of the stress system, and histamine, a product of activated mast cells, might selectively suppress cellular immunity, and favour humoral immune responses. This is mediated by a differential effect of stress hormones and histamine, on T helper I (Th1)/Th2 patterns and type I/type 2-cytokine production. Thus, systemically, stress might induce a Th2 shift, while, locally, under certain conditions, it might induce pro-inflammatory activities through neural activation of the peripheral corticotropin-releasing factor-mast cell-histamine axis. Through the above mechanisms, stress may influence the onset and/or course of infectious, autoimmune/ inflammatory, allergic and neoplastic diseases. C1 NICHD, Pediat Endocrinol Sect, PRDEB, NIH, Bethesda, MD 20892 USA. NIAMSD, Inflammatory Joint Dis Sect, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. RP Elenkov, IJ (reprint author), NICHD, Pediat Endocrinol Sect, PRDEB, NIH, Bldg 10,Room 10N262, Bethesda, MD 20892 USA. NR 54 TC 73 Z9 74 U1 2 U2 5 PU BAILLIERE TINDALL PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1521-690X J9 BEST PRACT RES CL EN JI Best Pract. Res. Clin. Endoc. Metab. PD DEC PY 1999 VL 13 IS 4 BP 583 EP 595 DI 10.1053/beem.1999.0045 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 317KB UT WOS:000087223600008 PM 10903816 ER PT J AU Baruch, DI AF Baruch, DI TI Adhesive receptors on malaria-parasitized red cells SO BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY LA English DT Article DE malaria; Plasmodium falciparum; cytoadhesion; antigenic variation; PfEMPI; var genes; erythrocyte ID FALCIPARUM-INFECTED ERYTHROCYTES; CHONDROITIN SULFATE-A; MEMBRANE PROTEIN-1 PFEMP1; AMELANOTIC MELANOMA-CELLS; HUMAN-ENDOTHELIAL-CELLS; HISTIDINE-RICH PROTEIN; PLASMODIUM-FALCIPARUM; ANTIGENIC VARIATION; FLOW CONDITIONS; BLOOD-CELLS AB Antigenic variation, resetting and cytoadhesion are key determinants in the survival and virulence of the malaria parasite Plasmodium falciparum. These properties reside in a multigene protein family called P. falciparum erythrocyte membrane protein 1 (PfEMP1), encoded by the large and diverse var gene family. PfEMP1 plays a central role in the biology of P. falciparum and its interaction with the human host. The molecular mechanism and the domains involved in cytoadherence, resetting and antigenic variation are beginning to unfold. Domains mediating resetting and adhesion to several key host receptors have already been identified. Understanding the role of PfEMP1 in the pathogenesis and survival of malaria parasites is the key for the development of anti-adhesion vaccines and therapeutics to reduce the mortality and morbidity of P. falciparum infections. RP Baruch, DI (reprint author), NIAID, Parasit Dis Lab, NIH, Bldg 4,Room BI-37,4 Ctr Dr,MSC 0425, Bethesda, MD 20892 USA. NR 89 TC 36 Z9 38 U1 0 U2 6 PU BAILLIERE TINDALL PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1521-6926 J9 BEST PRACT RES CL HA JI Best Pract. Res. Clin. Haematol. PD DEC PY 1999 VL 12 IS 4 BP 747 EP 761 DI 10.1053/beha.1999.0051 PG 15 WC Hematology SC Hematology GA 326VV UT WOS:000087758500009 PM 10895262 ER PT J AU Zhang, HJ Akbar, M Kim, HY AF Zhang, HJ Akbar, M Kim, HY TI Melatonin: an endogenous negative modulator of 12-lipoxygenation in the rat pineal gland SO BIOCHEMICAL JOURNAL LA English DT Article DE arachidonic acid; 12-hydroxyeicosatetraenoic acid (12-HETE); 12-lipoxygenase ID IONIZATION MASS-SPECTROMETRY; ARACHIDONATE 12-LIPOXYGENASE; BINDING-SITES; ACID; RECEPTORS; CELL; LIPOXYGENATION; LOCALIZATION; ENDOTHELIUM; METABOLITES AB Major biochemical activities of the pineal gland include melatonin biosynthesis and 12-lipoxygenation. In this paper, we provide evidence in vivo that melatonin regulates 12-lipoxygenation via l-lipoxygenase (LOX) expression. The relationship between these two biochemical activities was established by monitoring levels of endogenous melatonin and a 12-LOX metabolite, 12-hydroxyeicosatetraenoic acid (12-HETE), in the rat pineal gland both during the light-dark cycle and after isoproterenol injection using GC/MS with negative ion chemical ionization. As pineal melatonin production reflected a typical diurnal variation, 12-HETE levels showed an off-phase diurnal pattern in relation to melatonin levels. Intravenous administration of isoproterenol, which has been shown to elevate melatonin production, decreased the 12-HETE level significantly. The reduction of 12-HETE levels during the dark phase and after isoproterenol injection was accompanied by decreases in 12-LOX mRNA and protein levels. Direct administration of melatonin to rats by intravenous injection decreased pineal 12-LOX protein levels significantly, indicating that melatonin plays a role in down-regulating 12-LOX expression. When pineal glands were incubated with exogenous melatonin in culture, time-dependent reduction of 12-LOX protein levels was observed. The melatonin-induced reduction in 12-LOX protein was abolished in the presence of the melatonin receptor antagonist luzindole, establishing further the role of melatonin in this process. Incubation of pineal homogenates with exogenous melatonin partially inhibited 12-LOX activity. Taken together, an inverse relationship exists in the endogenous production of 12-HETE, 12-LOX mRNA and protein with respect to melatonin production in the rat pineal gland. Melatonin decreased both 12-LOX mRNA and protein levels in addition to 12-LOX enzyme activity, indicating that melatonin is an endogenous modulator of pineal 12-lipoxygenation. C1 NIAAA, Sect Mass Spectrometry, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. RP Kim, HY (reprint author), NIAAA, Sect Mass Spectrometry, Lab Membrane Biochem & Biophys, NIH, 12501 Washington Ave, Rockville, MD 20852 USA. NR 42 TC 23 Z9 23 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 DEC 1 PY 1999 VL 344 BP 487 EP 493 DI 10.1042/0264-6021:3440487 PN 2 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 265VT UT WOS:000084267200026 PM 10567232 ER PT J AU Chiang, PK Chamberlin, ME Nicholson, D Soubes, S Su, XZ Subramanian, G Lanar, DE Prigge, ST Scovill, JP Miller, LH Chou, JY AF Chiang, PK Chamberlin, ME Nicholson, D Soubes, S Su, XZ Subramanian, G Lanar, DE Prigge, ST Scovill, JP Miller, LH Chou, JY TI Molecular characterization of Plasmodium falciparum S-adenosylmethionine synthetase SO BIOCHEMICAL JOURNAL LA English DT Article DE phylogeny; cycloleucine; modelling; chromosome ID METHIONINE ADENOSYLTRANSFERASE; ESCHERICHIA-COLI; NUCLEOTIDE-SEQUENCE; GENE; METHYLATION; PHYLOGENIES; EXPRESSION; DEFICIENCY; HYDROLASE; MALARIA AB S-Adenosylmethionine (AdoMet) synthetase (SAMS : EC 2.5.1.6) catalyses the formation of AdoMet from methionine and ATP. We have cloned a gene for Plasmodium falciparum AdoMet synthetase (PfSAMS) (GenBank accession no. AF097923), consisting of 1209 base pairs with no introns, The gene encodes a polypeptide (PRAMS) of 402 amino acids with a molecular mass of 44844 Da, and has an overall base composition of 67% A + T. PfSAMS is probably a single copy gene, and was mapped to chromosome 9, The PfSAMS protein is highly homologous to all other SAMS, including a conserved motif for the phosphate-binding P-loop, HGGGAFSGKD, and the signature hexapeptide, GAGDQG. All the active-site amino acids for the binding of ADP, P-i and metal ions are similarly preserved, matching entirely those of human hepatic SAMS and Escherichia coli SAMS. Molecular modelling of PfSAMS guided by the Xray crystal structure of E. coli SAMS indicates that PRAMS binds ATP/Mg2+ in a manner similar to that seen in the E, coli SAMS structure. However, the PfSAMS model shows that it can not form tetramers as does E. coli SAMS, and is probably a dimer instead. There was a differential sensitivity towards the inhibition by cycloleucine between the expressed PfSAMS and the human hepatic SAMS with K-i values of 17 and 10 mM, respectively. Based on phylogenetic analysis using protein parsimony and neighbour-joining algorithms, the malarial PfSAMS is closely related to SAMS of other protozoans and plants. C1 Walter Reed Army Inst Res, Div Expt Therapeut, Washington, DC 20307 USA. NICHHD, NIH, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. NIAAA, NIH, Bethesda, MD 20892 USA. RP Chiang, PK (reprint author), Walter Reed Army Inst Res, Div Expt Therapeut, Washington, DC 20307 USA. RI Lanar, David/B-3560-2011; OI Su, Xinzhuan/0000-0003-3246-3248 NR 42 TC 17 Z9 17 U1 1 U2 5 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD DEC 1 PY 1999 VL 344 BP 571 EP 576 DI 10.1042/0264-6021:3440571 PN 2 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 265VT UT WOS:000084267200036 PM 10567242 ER PT J AU Morin, PJ AF Morin, PJ TI beta-catenin signaling and cancer SO BIOESSAYS LA English DT Review ID TUMOR-SUPPRESSOR PROTEIN; ADENOMATOUS POLYPOSIS-COLI; UBIQUITIN-PROTEASOME PATHWAY; TRANSCRIPTION FACTOR LEF-1; CELL-ADHESION MOLECULE; XENOPUS EMBRYOS; GENE-PRODUCT; HEPATOCELLULAR CARCINOMAS; FUNCTIONAL INTERACTION; NUCLEAR-LOCALIZATION AB Since its discovery as a protein associated with the cytoplasmic region of E-cadherin, beta-catenin has been shown to perform two apparently unrelated functions: it has a crucial role in cell-cell adhesion in addition to a signaling role as a component of the Wnt/wg pathway. Wnt/wg signaling results in beta-catenin accumulation and transcriptional activation of specific target genes during development. It is now apparent that deregulation of beta-catenin signaling is an important event in the genesis of a number of malignancies, such as colon cancer, melanoma, hepatocellular carcinoma, ovarian cancer, endometrial cancer, medulloblastoma pilomatricomas, and prostate cancer. beta-catenin mutations appear to be a crucial step in the progression of a subset of these cancers, suggesting an important role in the control of cellular proliferation or cell death. The APC/beta-catenin pathway is highly regulated and includes players such as GSK3-beta, CBP, Groucho, Axin, Conductin, and TCF, c-MYC and cyclin D1 were recently identified as a key transcriptional targets of this pathway and additional targets are likely to emerge. BioEssays 21:1021-1030, 1999. Published 1999 John Wiley & Sons, Inc.dagger C1 NIA, Biol Chem Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21287 USA. RP Morin, PJ (reprint author), NIA, Biol Chem Lab, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 85 TC 654 Z9 683 U1 2 U2 34 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0265-9247 J9 BIOESSAYS JI Bioessays PD DEC PY 1999 VL 21 IS 12 BP 1021 EP 1030 DI 10.1002/(SICI)1521-1878(199912)22:1<1021::AID-BIES6>3.0.CO;2-P PG 10 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 260WJ UT WOS:000083976200006 PM 10580987 ER PT J AU Schaffer, AA Wolf, YI Ponting, CP Koonin, EV Aravind, L Altschul, SF AF Schaffer, AA Wolf, YI Ponting, CP Koonin, EV Aravind, L Altschul, SF TI IMPALA: matching a protein sequence against a collection of PSI-BLAST-constructed position-specific score matrices SO BIOINFORMATICS LA English DT Article ID HIDDEN MARKOV-MODELS; MYCOPLASMA-GENITALIUM PROTEINS; DISTANTLY RELATED PROTEINS; BINDING-SITES; STATISTICAL SIGNIFICANCE; PROFILE ANALYSIS; ACID-SEQUENCES; ALIGNMENT; DATABASE; SEARCHES AB Motivation: Many studies have shown that database searches using position-specific score matrices (PSSMs) or profiles as queries are more effective at identifying distant protein relationships than are searches that use simple sequences as queries. One popular program for constructing a PSSM and comparing it with a database of sequences is Position-Specific Iterated BLAST (PSI-BLAST). Results: This paper describes a new software package, IMPALA, designed for the complementary procedure of comparing a single query sequence with a database of PSI-BLAST-generated PSSMs. We illustrate the use of IMPALA to search a database of PSSMs for protein folds, and one for protein domains involved in signal transduction. IMPALA's sensitivity to distant biological relationships is very similar to that of PSI-BLAST. However, IMPALA employs a more refined analysis of statistical significance and, unlike PSI-BLAST, guarantees the output of the optimal local alignment by using the rigorous Smith-Waterman algorithm. Also, it is considerably faster when run with a large database of PSSMs than is BLAST or PSI-BLAST when run against the complete non-redundant protein database. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Texas A&M Univ, Dept Biol, College Stn, TX 77843 USA. RP Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM schaffer@helix.nih.gov RI Schaffer, Alejandro/F-2902-2012 NR 68 TC 222 Z9 229 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD DEC PY 1999 VL 15 IS 12 BP 1000 EP 1011 PG 12 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 293DJ UT WOS:000085836000008 PM 10745990 ER PT J AU Foote, SL AF Foote, SL TI Development and vulnerability: New perspectives for anxiety disorders SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID STRESS; FEAR C1 NIMH, Bethesda, MD 20892 USA. RP Foote, SL (reprint author), NIMH, 6001 Execut Blvd,Room 7204,MSC 9645, Bethesda, MD 20892 USA. NR 21 TC 3 Z9 3 U1 0 U2 0 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 DEC 1 PY 1999 VL 46 IS 11 BP 1457 EP 1460 DI 10.1016/S0006-3223(99)00278-4 PG 4 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 283DY UT WOS:000085261900001 PM 10599475 ER PT J AU Baler, R Covington, S Klein, DC AF Baler, R Covington, S Klein, DC TI Rat arylalkylamine N-acetyltransferase gene: Upstream and intronic components of a bipartite promoter SO BIOLOGY OF THE CELL LA English DT Article DE AA-NAT gene promoter; cAMP ID CAMP-RESPONSIVE ELEMENT; FIBRONECTIN GENE; TRANSCRIPTIONAL ACTIVITY; PINEAL-GLAND; CYCLIC-AMP; CCAAT BOX; EXPRESSION; ATF-2; FRA-2 AB The daily rhythm in the activity of arylalkylamine N-acetyltransferase (AA-NAT) controls the rhythm in melatonin synthesis in the pineal gland. In the rat, transcriptional regulatory mechanisms play a major role in determining the observed pattern of AA-NAT gene expression. Remarkably, high levels of AA-NAT transcripts can only be detected in the night pineal; significant levels can also be found in the retina. To characterize the regulatory events that impinge upon the activity of the AA-NAT gene we embarked on the systematic analysis of the AA-NAT promoter. To this end we transfected several AA-NAT promoter derivative constructs to monitor reporter gene activity in both pineal and non-pineal primary cell cultures. Our studies revealed a cooperative arrangement between upstream promoter and downstream intronic regions which appear to contain most of the key elements necessary to ensure the proper spatio-temporal pattern of AA-NAT gene expression. (C) 1999 Editions scientifiques et medicales Elsevier SAS. C1 NICHHD, Sect Neuroendocrinol, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. NIMH, Unit Temporal Gene Regulat, NIH, Bethesda, MD 20892 USA. RP Klein, DC (reprint author), NICHHD, Sect Neuroendocrinol, Dev Neurobiol Lab, NIH, Bethesda 49-6A82,49 Convent Dr, Bethesda, MD 20892 USA. NR 23 TC 30 Z9 30 U1 0 U2 1 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS CEDEX 15 PA 23 RUE LINOIS, 75724 PARIS CEDEX 15, FRANCE SN 0248-4900 J9 BIOL CELL JI Biol. Cell PD DEC PY 1999 VL 91 IS 9 BP 699 EP 705 DI 10.1016/S0248-4900(00)88533-0 PG 7 WC Cell Biology SC Cell Biology GA 273PD UT WOS:000084715300006 PM 10668100 ER PT J AU Gail, MH Kessler, L Midthune, D Scoppa, S AF Gail, MH Kessler, L Midthune, D Scoppa, S TI Two approaches for estimating disease prevalence from population-based registries of incidence and total mortality SO BIOMETRICS LA English DT Article DE bias of prevalence estimate; cancer registry; chronic disease prevalence; Lexis diagram; precision of prevalence estimate; prevalence estimation ID CANCER AB Two approaches are described for estimating the prevalence of a disease that may have developed in a previous restricted age interval among persons of a given age at a particular calendar time. The prevalence for all those who ever developed disease is treated as a special case. The counting method (CM) obtains estimates of prevalence by dividing the estimated number of diseased persons by the total population size, taking loss to follow-up into account. The transition rate method (TRM) uses estimates of transition rates and competing risk calculations to estimate prevalence. Variance calculations are described for CM and TRM as well as for a variant of CM, called counting method times 10 (CM10), that is designed to yield more precise estimates than Chi. We compare these three estimators in terms of precision and in terms of the underlying assumptions required to justify the methods. CM makes fewer assumptions but is typically less precise than TRM or CM10. For common diseases such as breast cancer, CM may be preferred because its precision is excellent even though not as high as for TRM or CM10. For less common diseases, such as brain cancer, however, TRM or CM10 and other methods that make stabilizing assumptions may be preferred to CM. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. US FDA, Rockville, MD 20855 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. Informat Management Serv, Silver Spring, MD 20904 USA. RP Gail, MH (reprint author), NCI, Div Canc Epidemiol & Genet, Execut Plaza S,Room 8032,6120 Execut Blvd,MSC 724, Bethesda, MD 20892 USA. NR 13 TC 28 Z9 28 U1 0 U2 3 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD DEC PY 1999 VL 55 IS 4 BP 1137 EP 1144 DI 10.1111/j.0006-341X.1999.01137.x PG 8 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 265BB UT WOS:000084218000020 PM 11315059 ER PT J AU Follmann, DA Proschan, MA AF Follmann, DA Proschan, MA TI A multivariate test of interaction for use in clinical trials SO BIOMETRICS LA English DT Article DE Bonferroni correction; likelihood ratio statistic; quadratic form; subgroups AB An important issue in clinical trials is whether the effect of treatment is essentially homogeneous as a function of baseline covariates. Covariates that have the potential for an interaction with treatment may be suspected on the basis of treatment mechanism or may be known risk factors, as it is often thought that the sickest patients may benefit most from treatment. If disease severity is more accurately determined by a collection of baseline covariates rather than a single risk factor, methods that examine each covariate in turn for interaction may be inadequate. We propose a procedure whereby treatment interaction is examined along a single severity index that is a linear combination of baseline covariates. Formally, we derive a likelihood ratio test based on the null beta(0) = beta(1) versus the alternative a beta(0) = beta(1), where X'beta(k), (k = 0,1) corresponds to the severity index in arm k and X is a vector of baseline covariates. While our explicit test requires a Gaussian response, it can be readily implemented whenever the estimates of beta(0), beta(1) are approximately multivariate normal. For example, it is appropriate for large clinical trials where <(beta)over cap>(k) is based on a logisitic or Cox regression of response on X. C1 NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. RP Follmann, DA (reprint author), NHLBI, Off Biostat Res, 2 Rockledge Ctr, Bethesda, MD 20892 USA. NR 11 TC 11 Z9 11 U1 0 U2 1 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD DEC PY 1999 VL 55 IS 4 BP 1151 EP 1155 DI 10.1111/j.0006-341X.1999.01151.x PG 5 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 265BB UT WOS:000084218000022 PM 11315061 ER PT J AU Shih, JH Fay, MP AF Shih, JH Fay, MP TI A class of permutation tests for stratified survival data SO BIOMETRICS LA English DT Article DE censored data; permutation test; rank test; shrinkage estimator; strata ID CENSORED-DATA; RANK AB We propose a class of permutation tests for stratified survival data. The tests are derived using the framework of Fay and Shih (1998, Journal of the American Statistical Association. 93, 387-396), which creates tests by permuting scores based on a functional of estimated distribution functions. Here the estimated distribution function for each possibly right-, left-, or interval-censored observation is based on a shrinkage estimator similar to the nonparametric empirical estimator of Ghosh, Lahiri, and Tiwari (1989, Communications in. Statistics-Theory and Methods 18, 121-146), and permutation is carried out within strata. The proposed test with a weighted Mann-Whitney functional is similar to the permutation form of the stratified log-rank test when there is a large strata effect or the sample size in each stratum is large and is similar to the permutation form of the ordinary log-rank test when there is little strata effect. Thus, the proposed test unifies the advantages of both the stratified and ordinary log-rank tests. By changing the functional, we may obtain a stratified Prentice-Wilcoxon test or a difference in means test with similar unifying properties. We show through simulations the advantage of the proposed test over existing tests for uncensored and right-censored data. C1 NHLBI, Off Biostat Res, Rockledge Ctr 2, Bethesda, MD 20892 USA. NCI, Surveillance Modeling & Methods Sect, Bethesda, MD 20892 USA. RP Shih, JH (reprint author), NHLBI, Off Biostat Res, Rockledge Ctr 2, Room 8218,6701 Rockledge Dr,MSC 7938, Bethesda, MD 20892 USA. RI Fay, Michael/A-2974-2008; OI Fay, Michael P./0000-0002-8643-9625 NR 10 TC 1 Z9 2 U1 0 U2 0 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD DEC PY 1999 VL 55 IS 4 BP 1156 EP 1161 DI 10.1111/j.0006-341X.1999.01156.x PG 6 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 265BB UT WOS:000084218000023 PM 11315062 ER PT J AU Tang, DI Geller, NL AF Tang, DI Geller, NL TI Closed testing procedures for group sequential clinical trials with multiple endpoints SO BIOMETRICS LA English DT Article DE early stopping; several treatments versus a control; step-down procedures; strong type I error control ID LIKELIHOOD RATIO TEST; END-POINTS; PAIRWISE COMPARISONS; OUTCOMES; DESIGN AB A simple approach is given for conducting closed testing in clinical trials with multiple endpoints in which group sequential monitoring is planned. The approach allows a flexible stopping time; the earliest and latest stopping times are described. The paradigm is applicable both to clinical trials with multiple endpoints and to the one-sided multiple comparison problem of several treatments versus a control. The approach leads to enhancements of previous methods and suggestions for new methods. An example of a respiratory disease trial with four endpoints is given. C1 Nathan S Kline Inst Psychiat Res, Div Stat Sci & Epidemiol, Orangeburg, NY 10962 USA. NHLBI, Off Biostat Res, Bethesda, MD USA. RP Tang, DI (reprint author), Nathan S Kline Inst Psychiat Res, Div Stat Sci & Epidemiol, Orangeburg, NY 10962 USA. NR 24 TC 36 Z9 36 U1 1 U2 4 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD DEC PY 1999 VL 55 IS 4 BP 1188 EP 1192 DI 10.1111/j.0006-341X.1999.01188.x PG 5 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 265BB UT WOS:000084218000027 PM 11315066 ER PT J AU Shih, JH Albert, PS AF Shih, JH Albert, PS TI Latent model for correlated binary data with diagnostic error SO BIOMETRICS LA English DT Article DE correlation; diagnostic error; latent model; misclassification; random effects ID TESTS; ACCURACY AB We propose a methodology for modeling correlated binary data measured with diagnostic error. A shared random effect is used to induce correlations in repeated true latent binary outcomes and in observed responses and to link the probability of a true positive outcome with the probability of having a diagnosis error. We evaluate the performance of our proposed approach through simulations and compare it with an ad hoc approach. The methodology is illustrated with data from a study that assessed the probability of corneal arcus in patients with familial hypercholesterolemia. C1 NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. NCI, Biometr Res Inst, Bethesda, MD 20892 USA. RP Shih, JH (reprint author), NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. NR 8 TC 3 Z9 3 U1 0 U2 1 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD DEC PY 1999 VL 55 IS 4 BP 1232 EP 1235 DI 10.1111/j.0006-341X.1999.01232.x PG 4 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 265BB UT WOS:000084218000035 PM 11315074 ER PT J AU Albert, PS AF Albert, PS TI A mover-stayer model for longitudinal marker data SO BIOMETRICS LA English DT Article DE hidden Markov models; incidence; measurement error; prevalence; threshold models ID MAXIMUM-LIKELIHOOD; MEASUREMENT ERROR; CHAINS AB Studies of chronic disease often focus on estimating prevalence and incidence in which the presence of active disease is based on dichotomizing a continuous marker variable measured with error. Examples include hypertension, asthma, and depression, where active disease is defined by setting a threshold on a continuous measure of blood pressure, respiratory function, and mood, respectively. This paper proposes a model for inference about prevalence and incidence when active disease is determined by dichotomizing a continuous marker variable in a population-based study. In this formulation, it is postulated that there are three groups of people, those that are not susceptible to the disease, those who are always in the disease state, and those who have the potential to transition between the disease and the disease-free states over time. The model is used to estimate the prevalence and incidence of the disease in the population while accounting for measurement error in the marker. An EM algorithm is used for parameter estimation and the methodology is illustrated on Framingham heart study hypertension data. A simulation study is conducted in order to demonstrate the importance of accounting for measurement error in estimating prevalence and incidence for this example. C1 NCI, Biometr Res Branch, Bethesda, MD 20892 USA. RP Albert, PS (reprint author), NCI, Biometr Res Branch, Execut Plaza N,Room 739,MSC 7434, Bethesda, MD 20892 USA. NR 17 TC 3 Z9 3 U1 0 U2 2 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD DEC PY 1999 VL 55 IS 4 BP 1252 EP 1257 DI 10.1111/j.0006-341X.1999.01252.x PG 6 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 265BB UT WOS:000084218000039 PM 11315078 ER PT J AU Prasad, JVNV Boyer, FE Domagala, JM Ellsworth, EL Gajda, C Hamilton, HW Hagen, SE Markoski, LJ Steinbaugh, BA Tait, BD Humblet, C Lunney, EA Pavlovsky, A Rubin, JR Ferguson, D Graham, N Holler, T Hupe, D Nouhan, C Tummino, PJ Urumov, A Zeikus, E Zeikus, G Gracheck, SJ Saunders, JM VanderRoest, S Brodfuehrer, J Iyer, K Sinz, M Gulnik, SV Erickson, JW AF Prasad, JVNV Boyer, FE Domagala, JM Ellsworth, EL Gajda, C Hamilton, HW Hagen, SE Markoski, LJ Steinbaugh, BA Tait, BD Humblet, C Lunney, EA Pavlovsky, A Rubin, JR Ferguson, D Graham, N Holler, T Hupe, D Nouhan, C Tummino, PJ Urumov, A Zeikus, E Zeikus, G Gracheck, SJ Saunders, JM VanderRoest, S Brodfuehrer, J Iyer, K Sinz, M Gulnik, SV Erickson, JW TI Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390: A lead HIV protease inhibitor SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE HIV protease inhibitors; nonpeptidic HIV protease inhibitors; aspartic protease inhibitors; antivirals; anti-HIV agents ID HUMAN-IMMUNODEFICIENCY-VIRUS; STRUCTURE-BASED DESIGN; POTENT; DISCOVERY; OPTIMIZATION; METABOLISM; PNU-140690; BINDING; MODE AB With the insight generated by the availability of X-ray crystal structures of various 5,6-dihydropyran-2-ones bound to HIV PR, inhibitors possessing various alkyl groups at the 6-position of 5,6-dihydropyran-2-one ring were synthesized. The inhibitors possessing a 6-alkyl group exhibited superior antiviral activities when compared to 6-phenyl analogues. Antiviral efficacies were further improved upon introduction of a polar group (hydroxyl or amino) on the 4-position of the phenethyl moiety as well as the polar group (hydroxymethyl) on the 3-(tert-butyl-5-methyl-phenylthio) moiety. The polar substitution is also advantageous for decreasing toxicity, providing inhibitors with higher therapeutic indices, The best inhibitor among this series, (S)-6-[2-(4-aminophenyl)-ethyl]-(3-(2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one (34S), exhibited an EC50 of 200 nM with a therapeutic index of >1000. More importantly, these non-peptidic inhibitors, 16S and 34S, appear to offer little cross-resistance to the currently marketed peptidomimetic PR inhibitors. The selected inhibitors tested in vitro against mutant HIV PR showed a very small increase in binding affinities relative to wild-type HIV PR. C-max and absolute bioavailability of 34S were higher and half-life and time above EC95 were longer compared to 16S. Thus 34S, also known as PD 178390, which displays good antiviral efficacy, promising pharmacokinetic characteristics and favorable activity against mutant enzymes and CYP3A4, has been chosen for further preclinical evaluation. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 Warner Lambert Parke Davis, Parke Davis Pharmaceut Res, Dept Chem, Ann Arbor, MI 48105 USA. Warner Lambert Parke Davis, Parke Davis Pharmaceut Res, Dept Biochem, Ann Arbor, MI 48105 USA. Warner Lambert Parke Davis, Parke Davis Pharmaceut Res, Dept Infect Dis, Ann Arbor, MI 48105 USA. Warner Lambert Parke Davis, Parke Davis Pharmaceut Res, Dept PDM, Ann Arbor, MI 48105 USA. NCI, Struct Biochem Program, Frederick Canc Res & Dev Ctr, PRI Dyncorp, Frederick, MD 21702 USA. RP Prasad, JVNV (reprint author), Warner Lambert Parke Davis, Parke Davis Pharmaceut Res, Dept Chem, 2800 Plymouth Rd, Ann Arbor, MI 48105 USA. RI ID, IMCACAT/D-5867-2014 NR 40 TC 21 Z9 22 U1 0 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD DEC PY 1999 VL 7 IS 12 BP 2775 EP 2800 PG 26 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 270GP UT WOS:000084527300014 PM 10658583 ER PT J AU Merzlyak, PG Yuldasheva, LN Rodrigues, CG Carneiro, CMM Krasilnikov, OV Bezrukov, SM AF Merzlyak, PG Yuldasheva, LN Rodrigues, CG Carneiro, CMM Krasilnikov, OV Bezrukov, SM TI Polymeric nonelectrolytes to probe pore geometry: Application to the alpha-toxin transmembrane channel SO BIOPHYSICAL JOURNAL LA English DT Article ID SIZE-EXCLUSION CHROMATOGRAPHY; LIPID BILAYER-MEMBRANES; SINGLE-ION CHANNEL; CONDUCTANCE; PROTEINS; CONDUCTIVITY; HEMOLYSIN; DIMENSIONS; SIMULATION; DIFFUSION AB Asymmetrical (one-sided) application of penetrating water-soluble polymers, polyethylene glycols (PEGs), to a well-defined channel formed by Staphylococcus aureus oc-toxin is shown to probe channel pore geometry in more detail than their symmetrical (two-sided) application. Polymers added to the cis side of the planar lipid membrane (the side of protein addition) affect channel conductance differently than polymers added to the trans side. Because a satisfactory theory quantitatively describing PEG partitioning into a channel pore does not exist, we apply the simple empirical rules proposed previously (Krasilnikov et al., 1998, J. Membr. Biol. 161:83-92) to gauge the size of pore openings as well as the size and position of constrictions along the pore axis. We estimate the radii of the two openings of the channel to be practically identical and equal to 1.2-1.3 nm. Two apparent constrictions with radii of similar to 0.9 nm and similar to 0.6-0.7 nm are inferred to be present in the channel lumen, the larger one being closer to the cis side. These structural findings agree well with crystallographic data on the channel structure (Song et al., 1996, Science. 274:1859-1866) and verify the practicality of polymer probing. The general features of PEG partitioning are examined using available theoretical considerations, assuming there is no attraction between PEG and the channel lumen. It is shown that the sharp dependence of the partition coefficient on polymer molecular weight found under both symmetrical and asymmetrical polymer application can be rationalized within a "hard sphere nonideal solution model." This finding is rather surprising because PEG forms highly flexible coils in water with a Kuhn length of only several Angstroms. C1 NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. Univ Fed Pernambuco, Lab Membrane Biophys, Dept Biophys & Radiobiol, BR-50670901 Recife, PE, Brazil. Inst Physiol & Biophys, Lab Mol Physiol, Tashkent 700095, Uzbekistan. St Petersburg Nucl Phys Inst, Gatchina 188350, Russia. RP Bezrukov, SM (reprint author), NICHHD, Lab Phys & Struct Biol, NIH, Bldg 9,Room 1E-122, Bethesda, MD 20892 USA. NR 55 TC 96 Z9 99 U1 0 U2 9 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD DEC PY 1999 VL 77 IS 6 BP 3023 EP 3033 PG 11 WC Biophysics SC Biophysics GA 264VG UT WOS:000084203200012 PM 10585924 ER PT J AU Jiang, L Yang, YH Chatterjee, S Seidel, B Wolf, G Yang, SL AF Jiang, L Yang, YH Chatterjee, S Seidel, B Wolf, G Yang, SL TI The expression of proUK in Escherichia coli: The vgb promoter replaces IPTG and coexpression of argU compensates for rare codons in a hypoxic induction model SO BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY LA English DT Article DE pro-urokinase expression; vgb promoter; argU coexpression; anaerobic induction ID GENE-EXPRESSION; TRANSFER-RNA; GLOBIN GENE; VITREOSCILLA; FRAMESHIFT; ARGININE; CLONING; VECTORS; FUSION; AGA AB The expression of the proUK gene was improved by the coexpression of the argU gene cloned in a moderate copy number vector. As the proUK gene contains 2% AGG/AGA condons, which is much higher than the normal frequency in E. coli, about 0.14%-0.21%, the argU gene cloned in a multicopy plasmid was coexpressed with the proUK expression vector in our experiments. In E. coli strain BL21(DE3), IPTG is known to induce the expression of T7 RNA polymerase gene and this enzyme can transcribe the proUK gene under the control of the T7 promoter leading to expression of proUK. To replace IPTG by a cheaper alternative on a large scale, we constructed a plasmid in which the vgb promoter--which is known to be activated by the onset of hypoxic conditions-controls the T7RNA polymerase gene expression. Low oxygen conditions were then used to activate the vgb promoter causing T7RNA polymerase gene expression and finally leading to the expression of pro UK as inactive inclusion bodies. our experiments on a large scale in a bioreactor show that the expression of proUK accounts for about 30% of total protein after about 6 h of anaerobic cultivation, so the presented model represents an economical alternative to IPTG induction. C1 Chinese Acad Sci, Shanghai Res Ctr Biotechnol, Shanghai 200233, Peoples R China. Otto Von Guericke Univ, Inst Med Neurobiol, D-39120 Magdeburg, Germany. RP Jiang, L (reprint author), NIEHS, Neuropharmacol Sect, NIH, Mail Drop F1-01,POB 12233, Res Triangle Pk, NC 27709 USA. EM lanjiang@hotmail.com NR 18 TC 4 Z9 5 U1 0 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0916-8451 EI 1347-6947 J9 BIOSCI BIOTECH BIOCH JI Biosci. Biotechnol. Biochem. PD DEC PY 1999 VL 63 IS 12 BP 2097 EP 2101 DI 10.1271/bbb.63.2097 PG 5 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry, Applied; Food Science & Technology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry; Food Science & Technology GA 273PE UT WOS:000084715400009 PM 10664843 ER PT J AU Gubin, AN Koduru, S Njoroge, JM Bhatnagar, R Miller, JL AF Gubin, AN Koduru, S Njoroge, JM Bhatnagar, R Miller, JL TI Stable expression of green fluorescent protein after liposomal transfection of K562 cells without selective growth conditions SO BIOTECHNIQUES LA English DT Article ID MAMMALIAN-CELLS; TRANSGENE; GENE AB Little is known about the durability of plasmid DNA transgene expression in mammalian cells in the absence of growth selection. For this purpose, we have begun the study of liposomal transfer and expression of plasmid DNA encoding green fluorescent protein (GFP) in human erythroleukemia K562 cells. Detection and selection of GFP expression were accomplished visually and by flow cytometry. GFP expression was noticeable in cells within 4 h of transfection. In nine separate transfections, approximately 20% of the transfected cells expressed GFP with a mean fluorescence 40-50x that of control cells (15 fluorescent units [FU] vs. 0.3 FU) during the first five days after transfection. The percentage of GFP positive cells dropped rapidly to 0.1% by day 14 post-transfection, but fluorescence activated cell sorting on this day resulted in the identification of stable transfectants expressing GFP for an additional 6-12 months in culture. GFP expression is adequate for the identification, isolation and monitoring of stable transfection events after lipid-mediated transfection of eukaryotic cells. C1 NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. RP Miller, JL (reprint author), NIDDKD, Biol Chem Lab, NIH, Bldg 10,Room 9N308, Bethesda, MD 20892 USA. NR 11 TC 15 Z9 16 U1 0 U2 2 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD DEC PY 1999 VL 27 IS 6 BP 1162 EP + PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 263YN UT WOS:000084153000014 PM 10631495 ER PT J AU Tanabe, L Scherf, U Smith, LH Lee, JK Hunter, L Weinstein, JN AF Tanabe, L Scherf, U Smith, LH Lee, JK Hunter, L Weinstein, JN TI MedMiner: An Internet text-mining tool for biomedical information, with application to gene expression profiling SO BIOTECHNIQUES LA English DT Article AB The trend toward high-throughput techniques in molecular biology and the explosion of online scientific data threaten to overwhelm the ability of researchers to take full advantage of available information. This problem is particularly severe in the rapidly expanding al ea of gene expression experiments, Sol example, those carried our with cDNA microarrays or oligonucleotide chips. We present an Internet-based hypertext program, MedMiner; which filters and organizes large amounts of textual and structured information returned from public search engines like GeneCards and PubMed We demonstrate the value of the approach for the analysts of gene expression data, but MedMiner can also be extended to other areas involving molecular genetic or pharmacological information. More generally still, MedMiner can be used to organize the information returned from any arbitrary PubMed search. C1 Natl Inst Hlth, Bethesda, MD USA. George Mason Univ, Fairfax, VA 22030 USA. RP Tanabe, L (reprint author), 37 Convent Dr,Bldg 37,Rm 5B12, Bethesda, MD 20892 USA. OI Hunter, Lawrence/0000-0003-1455-3370 NR 14 TC 121 Z9 129 U1 0 U2 4 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD DEC PY 1999 VL 27 IS 6 BP 1210 EP + PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 263YN UT WOS:000084153000019 PM 10631500 ER PT J AU Pongor, S Landsman, D AF Pongor, S Landsman, D TI Bioinformatics and the developing world SO BIOTECHNOLOGY AND DEVELOPMENT MONITOR LA English DT Article AB Bioinformatics is the science of managing and analyzing biological information. While all branches of modern biology make some use of computers, molecular biology and especially genetic engineering could not even exist without them. Given a certain research and computer infrastructure, developing countries may have relatively easy access to the products of bioinformatics. However, their future use of this technology hinges on the availability of bioinformatics knowledge in the public domain. C1 Int Ctr Genet Engn & Biotechnol, Trieste Component, I-34012 Trieste, Italy. NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, Bethesda, MD 20894 USA. RI Landsman, David/C-5923-2009; OI Landsman, David/0000-0002-9819-6675 NR 3 TC 2 Z9 2 U1 0 U2 0 PU BIOTECHNOLOGY DEV MONITOR PI AMSTERDAM PA UNIV AMSTERDAM DEPT INT RELAT PUBLIC INT LAW OUDEZIJDS ACHTERBURGWAL 237, 1012 DL AMSTERDAM, NETHERLANDS SN 0924-9877 J9 BIOTECHNOL DEV MONIT JI Biotechnol. Dev. Monit. PD DEC PY 1999 IS 40 BP 10 EP 13 PG 4 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 278YE UT WOS:000085015900004 ER PT J AU Sconocchia, G Titus, JA Mazzoni, A Visintin, A Pericle, F Hicks, SW Malavasi, F Segal, DM AF Sconocchia, G Titus, JA Mazzoni, A Visintin, A Pericle, F Hicks, SW Malavasi, F Segal, DM TI CD38 triggers cytotoxic responses in activated human natural killer cells SO BLOOD LA English DT Article ID PERIPHERAL-BLOOD LYMPHOCYTES; SIGNAL-TRANSDUCTION; T-CELLS; MONOCLONAL-ANTIBODIES; TYROSINE PHOSPHORYLATION; CYTOLYTIC ACTIVITY; SURFACE-ANTIGENS; NK CELLS; RECEPTOR; CD44 AB Receptors used by natural killer (NK) cells to mediate natural cytotoxicity are poorly defined, although it is now clear that a number of adhesion molecules can serve this function. CD38 transduces signals on T- and B-cell lines, and we asked whether it could trigger lytic and secretory responses in human NK cells. By using an anti-CD38 monoclonal antibody in reverse antibody-dependent cellular cytotoxicity experiments, it is shown that CD38 engagement triggers cytotoxic responses by activated NK cells, but not by cytotoxic T lymphocytes or fresh NK cells. Cross-linking with anti-CD38 F(ab')(2) caused activated NK cells to release granzymes and cytokines, but did not trigger an increase in intracellular Ca2+. Fresh NK cells acquired CD38-dependent lytic function during activation with interleukin-2 (IL-2), and inhibitor studies suggested that IL-2 stimulated the de novo expression of proteins that act between CD38 and the lytic machinery in NK cells. The induction of proteins that link commonly expressed adhesion molecules to effector mechanisms could provide a paradigm for pathogen recognition by the innate immune system. This is a US government work. There are no restrictions on its use. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Univ Ancona, Sch Med, Inst Biol & Genet, Ancona, Italy. RP Segal, DM (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Room 4B36, Bethesda, MD 20892 USA. OI MALAVASI, Fabio/0000-0002-1844-174X FU Telethon [E.0662] NR 49 TC 32 Z9 33 U1 0 U2 1 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 DEC 1 PY 1999 VL 94 IS 11 BP 3864 EP 3871 PG 8 WC Hematology SC Hematology GA 260MB UT WOS:000083953500030 PM 10572102 ER PT J AU Yao, W Jee, WSS Zhou, H Lu, J Cui, L Setterberg, R Liang, T Ma, Y AF Yao, W Jee, WSS Zhou, H Lu, J Cui, L Setterberg, R Liang, T Ma, Y TI Anabolic effect of prostaglandin E-2 on cortical bone of aged male rats comes mainly from modeling-dependent bone gain SO BONE LA English DT Article DE prostaglandin estradiol (PGE(2)); cortical bone; male rats; bone formation; modeling ID OSTEOPENIC OVARIECTOMIZED RATS; METAPHYSEAL HARD TISSUE; CANCELLOUS BONE; TRABECULAR BONE; GROWING-RATS; ADDS BONE; IGF-I; GROWTH; MASS; E(2) AB In this study, prostaglandin E-2 (3 mg/kg per day) was administered to 20-month-old male Wistar rats for 10 and 30 days. Histomorphometric analyses were performed on double-fluorescent-labeled undecalcified tibial shaft sections. Thirty days of prostaglandin E-2 (PGE(2)) administration increased bone formation rate/total bone surface from undetectable levels to 0.6 mu m/day at the periosteal surface and from 0.5 to 2.1 mu m/day at the endocortical surface. Endocortical osteoid surface area increased from 2% to 67% at day 10 and decreased to 6% at day 30; woven and lamellar bone formation started at day 0, but was most obvious at day 30, resulting in a 12% increase of total bone mass. The red to yellow marrow ratio was 0.2 in pretreatment controls, and increased to 1.6 by day 10 and 2.4 by day 30 with PGE(2) administration. Intracortical cavity number and area increased after 10 days of PGE(2) treatment, but with forming osteon number and area far exceeding those of resorption cavities at day 30, Endocortical modeling surface/endocortical surface was only 1.5%, and remodeling was 11.1% in pretreatment controls. PGE(2) treatment increased modeling to 24.5% in the 10 day group and 93.7% in the 30 day group, whereas remodeling remained unchanged at 10 days, and decreased to 6.2% at 30 days. Osteoprogenitor cells and osteoblasts could not be detected in pretreatment controls, but increased by day 10, and returned almost to control levels by 30 days. Our data indicate that PGE(2) induced periosteal and endocortical bone formation mainly by modeling-dependent bone gain, accompanied by increases in intracortical remodeling and red bone marrow, and a transient increase in the osteoprogenitor cells adjacent to the endocortical surface, These findings suggest that 20-month-old male Wistar rats were very responsive to the anabolic action of PGE(2) in the tibial shaft, a site consisting mainly of cortical bone and yellow marrow. (C) 1999 by Elsevier Science Inc. All rights reserved. C1 Univ Utah, Div Radiobiol, Salt Lake City, UT 84108 USA. NIH, NIA, Gerontol Res Ctr, Baltimore, MD USA. RP Yao, W (reprint author), Univ Utah, Div Radiobiol, 729 Arapeen Dr,Suite 234, Salt Lake City, UT 84108 USA. NR 48 TC 29 Z9 30 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 8756-3282 J9 BONE JI Bone PD DEC PY 1999 VL 25 IS 6 BP 697 EP 702 DI 10.1016/S8756-3282(99)00220-3 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 260AF UT WOS:000083925600010 PM 10593415 ER PT J AU Bluthe, RM Jafarian-Tehrani, M Michaud, B Haour, F Dantzer, R Homo-Delarche, F AF Bluthe, RM Jafarian-Tehrani, M Michaud, B Haour, F Dantzer, R Homo-Delarche, F TI Increased sensitivity of prediabetic nonobese diabetic mouse to the behavioral effects of IL-1 SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Article DE NOD mouse; stress; infection; interleukin-1 (IL-1); brain IL-1 receptors; behavior ID INTERLEUKIN-1 RECEPTOR ANTAGONIST; PITUITARY-ADRENAL AXIS; BETA-CELL DESTRUCTION; NECROSIS-FACTOR-ALPHA; NOD MOUSE; MICE; MELLITUS; STRESS; BRAIN; IDDM AB The nonobese diabetic (NOD) mouse is a model of spontaneous insulin-dependent diabetes mellitus (IDDM) or type I diabetes. In humans, and in animal models of IDDM, the progression of the disease is modulated by various environmental factors, particularly infectious agents. Interleukin-1 (IL-1) plays a pivotal role in the development of IDDM, and modulation of its synthesis may be a mechanism by which environmental modulation of disease progression occurs. Since various alterations at the level of the gene, number, and sensitivity of IL-1 receptors have been described in different animal models of autoimmune disease, we investigated, in the prediabetic NOD mouse, the presence of IL-1 receptors and their functional behavioral characteristics. Here we present evidence that prediabetic NOD mice exhibit a normal distribution and density of functional brain IL-1 receptors, but are more sensitive to the behavioral effects of IL-1 than the control ICR strain. (C) 1999 Academic Press. C1 INRA, INSERM U394, Inst Francois Magendie, F-33077 Bordeaux, France. NIMH, Clin Neuroendocrinol Branch, Bethesda, MD 20892 USA. Hop St Antoine, INSERM U339, F-75571 Paris, France. Univ Paris 05, Hop Necker, CNRS URA 1461, F-75015 Paris, France. RP Bluthe, RM (reprint author), INRA, INSERM U394, Inst Francois Magendie, Rue Camille St Saens, F-33077 Bordeaux, France. OI Dantzer, Robert/0000-0001-9399-6107 NR 63 TC 15 Z9 15 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 EI 1090-2139 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD DEC PY 1999 VL 13 IS 4 BP 303 EP 314 DI 10.1006/brbi.1998.0542 PG 12 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 260XR UT WOS:000083979200005 ER PT J AU Koch, CA AF Koch, CA TI How should patients with porencephaly and generalized seizures such as West syndrome be treated? SO BRAIN & DEVELOPMENT LA English DT Letter C1 NICHHD, Bethesda, MD 20892 USA. RP Koch, CA (reprint author), NICHHD, Bethesda, MD 20892 USA. RI Koch, Christian/A-4699-2008 OI Koch, Christian/0000-0003-3127-5739 NR 4 TC 0 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0387-7604 J9 BRAIN DEV-JPN JI Brain Dev. PD DEC PY 1999 VL 21 IS 8 BP 566 EP 566 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 259CM UT WOS:000083876400011 PM 10598061 ER PT J AU Ikemoto, S Panksepp, J AF Ikemoto, S Panksepp, J TI The role of nucleus accumbens dopamine in motivated behavior: a unifying interpretation with special reference to reward-seeking SO BRAIN RESEARCH REVIEWS LA English DT Review DE learning; operant; Pavlovian; arousal; aversion; novelty; self-stimulation; feeding; sexual behavior; conditioned reinforcement; locomotion; avoidance; latent inhibition; incentive motivation ID VENTRAL TEGMENTAL AREA; INTRACRANIAL SELF-STIMULATION; INCREASED EXTRACELLULAR DOPAMINE; FREELY MOVING RATS; CONDITIONED AVOIDANCE-BEHAVIOR; INDUCED LOCOMOTOR-ACTIVITY; NON-PSYCHOSTIMULANT DRUGS; MEDIAL PREFRONTAL CORTEX; 3 STRIATAL SUBREGIONS; FREE FOOD-CONSUMPTION AB Studies addressing behavioral functions of dopamine (DA) in the nucleus accumbens septi (NAS) are reviewed. A role of NAS DA in reward has long been suggested. However, some investigators have questioned the role of NAS DA in rewarding effects because of its role in aversive contexts. As findings supporting the role of NAS DA in mediating aversively motivated behaviors accumulate, it is necessary to accommodate such data for understanding the role of NAS DA in behavior. The aim of the present paper is to provide a unifying interpretation that can account for the functions of NAS DA in a variety of behavioral contexts: (1) its role in appetitive behavioral arousal, (2) its role as a facilitator as well as an inducer of reward processes, and (3) its presently undefined role in aversive contexts. The present analysis suggests that NAS DA plays an important role in sensorimotor integrations that facilitate flexible approach responses. Flexible approach responses an contrasted with fixed instrumental approach responses (habits), which may involve the nigro-striatal DA system more than the meso-accumbens DA system. Functional properties of NAS DA transmission are considered in two stages: unconditioned behavioral invigoration effects and incentive learning effects. (1) When organisms are presented with salient stimuli (e.g., novel stimuli and incentive stimuli), NAS DA is released and invigorates flexible approach responses (invigoration effects). (2) When proximal exteroceptive receptors are stimulated by unconditioned stimuli, NAS DA is released and enables stimulus representations to acquire incentive properties within specific environmental context. It is important to make a distinction that NAS DA is a critical component for the conditional formation of incentive representations but not the retrieval of incentive stimuli or behavioral expressions based on over-learned incentive responses (i.e., habits). Nor is NAS DA essential for the cognitive perception of environmental stimuli. Therefore, even without normal NAS DA transmission, the habit response system still allows animals to perform instrumental responses given that the tasks take place in fixed environment. Such a role of NAS DA as an incentive-property constructor is not limited to appetitive contexts but also aversive contexts. This dual action of NAS DA in invigoration and incentive learning may explain the rewarding effects of NAS DA as well as other effects of NAS DA in a variety of contexts including avoidance and unconditioned/conditioned increases in open-field locomotor activity. Particularly, the present hypothesis offers the following interpretation for the finding that both conditioned and unconditioned aversive stimuli stimulate DA release in the NAS: NAS DA invigorates approach responses toward 'safety'. Moreover. NAS DA modulates incentive properties of the environment so that organisms emit approach responses toward 'safety' (i.e., avoidance responses) when animals later encounter similar environmental contexts. There may be no obligatory relationship between NAS DA release and positive subjective effects, even though these systems probably interact with other brain systems which can mediate such effects. The present conceptual framework may be valuable in understanding the dynamic interplay of NAS DA neurochemistry and behavior, both normal and pathophysiological. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIDA, Intramural Res Program, Behav Neurosci Branch, Baltimore, MD 21224 USA. Bowling Green State Univ, Dept Psychol, Bowling Green, OH 43402 USA. RP Ikemoto, S (reprint author), NIDA, Intramural Res Program, Behav Neurosci Branch, 550 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Ikemoto, Satoshi/0000-0002-0732-7386 NR 311 TC 769 Z9 781 U1 9 U2 89 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0173 J9 BRAIN RES REV JI Brain Res. Rev. PD DEC PY 1999 VL 31 IS 1 BP 6 EP 41 DI 10.1016/S0165-0173(99)00023-5 PG 36 WC Neurosciences SC Neurosciences & Neurology GA 269UY UT WOS:000084497000002 PM 10611493 ER PT J AU Rao, GN Ney, E Herbert, RA AF Rao, GN Ney, E Herbert, RA TI Changes associated with delay of mammary cancer by retinoid analogues in transgenic mice bearing c-neu oncogene SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE N-(4-hydroxyphenyl) retinamide; arotinoid Ro 40-8757; breast cancer; erbB2 expression; IGF-1 levels; toxicity ID GROWTH-FACTOR-I; BREAST-CANCER; BINDING-PROTEIN; DIET NTP-2000; RATS; CARCINOGENESIS; HEPATOCYTES; TOXICOLOGY; MOFAROTENE; INDUCTION AB Breast cancer is one of the common cancers and is a leading cause of cancer mortality in women. The TG. NK transgenic mouse line on FVB strain background expresses the c-neu oncogene under the control of a MMTV promoter in mammary tissue and appears to be a useful animal model for evaluation of strategies to delay or prevent mammary cancer. Fiber-rich nonpurified diet (NTP-2000) and some retinoid analogues have delayed mammary cancer in the TG. NK model. Four week old hemizygous TG. NK female mice with MMTV/c-neu (erbB2) activated oncogene were fed NTP-2000 diet containing the retinoid analogue 4-hydroxyphenylretinamide (4-HPR) at 7 mmol/kg or the arotinoid Ro 40-8757 at 1.5 and 2.5 mmol/kg for 26 weeks. The 4-HPR at 7 mmol/kg diet delayed the development of palpable tumors up to 24 weeks, but by 26 weeks, the incidence markedly increased and was closer to the NTP-2000 diet control group. However, the 4-HPR diet markedly decreased the average weight of the tumors at 26 weeks with no decrease in multiplicity. The 4-HPR also caused significant increase in liver weights without an effect on body weight. Arotinoid Ro 40-8757 caused marked decrease in the number and branching of mammary ducts, and inhibited mammary tumor development with significant decrease in the incidence, multiplicity, and tumor weights compared to the NTP-2000 diet control. Arotinoid also caused a significant dose-related increase in liver weights without a significant effect on body weights. At the doses tested, the arotinoid but not 4-HPR decreased the circulating levels of IGF-1. However, there was no association between the IGF-1 levels and the size, incidence, or absence of tumors when evaluated for any treatment group or for all mice in the study irrespective of treatment. The oncogene erbB2 (c-neu) and the growth factor EGF expression were more prominent in the small tumors of the mice treated with arotinoid than in the larger tumors of the control group. PCNA staining was observed in areas where there was high erbB2 and EGF staining. The delay in onset of mammary tumors by the above retinoid analogues may be related to the delay in development of mammary glands. C1 NIEHS, Environm Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. RP Rao, GN (reprint author), NIEHS, Environm Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. NR 38 TC 11 Z9 11 U1 0 U2 0 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 DEC PY 1999 VL 58 IS 3 BP 241 EP 254 PG 14 WC Oncology SC Oncology GA 278VM UT WOS:000085009700006 PM 10718486 ER PT J AU Forozan, F Veldman, R Ammerman, CA Parsa, NZ Kallioniemi, A Kallioniemi, OP Ethier, SP AF Forozan, F Veldman, R Ammerman, CA Parsa, NZ Kallioniemi, A Kallioniemi, OP Ethier, SP TI Molecular cytogenetic analysis of 11 new breast cancer cell lines SO BRITISH JOURNAL OF CANCER LA English DT Article DE molecular cytogenetics; FISH; CGH; chromosomal aberrations; oncogene amplification ID COMPARATIVE GENOMIC HYBRIDIZATION; EPIDERMAL GROWTH-FACTOR; MAMMARY EPITHELIAL-CELLS; GENE AMPLIFICATION; CARCINOMA CELLS; ACTIVATION; RECEPTOR; KINASE; SITES; CGH AB We describe a survey of genetic changes by comparative genomic hybridization (CGH) in 11 human breast cancer cell lines recently established in our laboratory. The most common gains took place at 8q (73%), 1q (64%), 7q (64%), 39 (45%) and 79 (45%), whereas losses were most frequent at Xp (54%), 8p (45%), 189 (45%) and Xq (45%). Many of the cell lines displayed prominent, localized DNA amplifications by CGH. One-third of these loci affected breast cancer oncogenes, whose amplifications were validated with specific probes: 17q12 (two cell lines with ERBB2 amplifications), 11q13 (two with cyclin-D1), 8p11-p12 (two with FGFR1) and 10q25 (one with FGFR2). Gains and amplifications affecting 8q were the most common genetic alterations in these cell lines with the minimal, common region of involvement at 8q22-q23. No high-level MYC (at 8q24) amplifications were found in any of the cell lines. Two-thirds of the amplification sites took place at loci not associated with established oncogenes, such as 1q41-q43, 7q21-q22, 7q31, 8q23, 9p21-p23, 11p12-p14, 15q12-q14, 16q13-q21, 17q23, 20p11-p12 and 20q13. Several of these locations have not been previously reported and may harbour important genes whose amplification is selected for during cancer development. In summary, this set of breast cancer cell lines displaying prominent DNA amplifications should facilitate discovery and functional analysis of genes and signal transduction pathways contributing to breast cancer development. (C) 1999 Cancer Research Campaign. C1 Univ Michigan, Sch Med, Dept Radiat Oncol, Div Radiat & Canc Biol,Canc Ctr 7312, Ann Arbor, MI 48109 USA. Natl Human Genome Res Inst, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Ethier, SP (reprint author), Univ Michigan, Sch Med, Dept Radiat Oncol, Div Radiat & Canc Biol,Canc Ctr 7312, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. RI Kallioniemi, Olli/H-5111-2011; Kallioniemi, Olli/H-4738-2012; OI Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Anne/0000-0003-3552-8158 NR 30 TC 118 Z9 119 U1 1 U2 3 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 DEC PY 1999 VL 81 IS 8 BP 1328 EP 1334 DI 10.1038/sj.bjc.6695007 PG 7 WC Oncology SC Oncology GA 261XQ UT WOS:000084036300009 PM 10604729 ER PT J AU Cassedy, JH AF Cassedy, JH TI An alternative path: The making and remaking of Hahnemann Medical Collage and Hospital of Philadelphia. SO BULLETIN OF THE HISTORY OF MEDICINE LA English DT Book Review C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Cassedy, JH (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4319 USA SN 0007-5140 J9 B HIST MED JI Bull. Hist. Med. PD WIN PY 1999 VL 73 IS 4 BP 725 EP 726 DI 10.1353/bhm.1999.0153 PG 2 WC Health Care Sciences & Services; History & Philosophy Of Science SC Health Care Sciences & Services; History & Philosophy of Science GA 263YM UT WOS:000084152900027 ER PT J AU Hill, RN Stokes, WS AF Hill, RN Stokes, WS TI Validation and regulatory acceptance of alternatives SO CAMBRIDGE QUARTERLY OF HEALTHCARE ETHICS LA English DT Article ID EYE IRRITATION TEST; ANIMAL USE; IN-VITRO; RECOMMENDATIONS; REFINEMENT; WORKSHOP C1 US EPA, Off Prevent Pesticides & Tox Subst, Washington, DC 20460 USA. NIEHS, Anim & Alternat Resources Environm Toxicol Progra, Res Triangle Pk, NC 27709 USA. RP Hill, RN (reprint author), US EPA, Off Prevent Pesticides & Tox Subst, Washington, DC 20460 USA. NR 16 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0963-1801 J9 CAMB Q HEALTHC ETHIC JI Camb. Q. Healthc. Ethics PD WIN PY 1999 VL 8 IS 1 BP 73 EP 79 DI 10.1017/S096318019980111X PG 7 WC Health Care Sciences & Services; Health Policy & Services; Social Sciences, Biomedical SC Health Care Sciences & Services; Biomedical Social Sciences GA 157UF UT WOS:000078079500010 PM 9924621 ER PT J AU Jensen, PS AF Jensen, PS TI Fact versus fancy concerning the multimodal treatment study for attention-deficit hyperactivity disorder SO CANADIAN JOURNAL OF PSYCHIATRY-REVUE CANADIENNE DE PSYCHIATRIE LA English DT Review DE attention-deficit hyperactivity disorder; multimodal treatment; efficacy; effectiveness; outcome; clinical trial ID CHILDREN; METHYLPHENIDATE; CLASSROOM; TRIAL; ADHD AB Findings from the Multimodal Treatment Study of Children With Attention-Deficit Hyperactivity Disorder (ADHD), the MTA, have been much discussed but frequently misinterpreted or mischaracterized. Misinterpretations regarding the specific nature of and rationale for the study design, the effectiveness of the behavioural treatment arm, the possible advantages of combined treatments over single-component (medication management or behavioural therapy) interventions, and the feasibility and applicability of MTA treatments for "real-world" practitioners are addressed. Careful interpretation of the MTA findings suggests that for ADHD symptoms, carefully crafted medication-management approaches are superior to behavioural treatment and to routine community care that includes medication. For non-ADHD areas of functioning (for example, social skills, academic performance), combined treatments may offer modest advantages over single-component approaches. Longer-term outcomes past 14 months of intensive MTA treatments las well as their relative effectiveness with respect to each other) remain unknown, pending further MTA analyses. The MTA treatments by and large consisted of evidence-based "best practices." Thus, rather than characterizing these treatments as infeasible, the substantially superior outcomes of these treatments (versus routine clinical care) across diverse settings should help set the standard for future treatment practices in real-would settings. Despite important study limitations, the MTA study, by virtue of its size, scope, and length; parallel-groups design,. explicit use of manualized, evidence-based treatments; and comprehensive range of outcome assessments sets an important benchmark for future trials testing new treatments for childhood ADHD and defines a new standard for optimal outcomes that can be achieved with the best of clinical care. C1 Columbia Univ, New York State Psychiat Inst, Dept Child Psychiat, New York, NY 10032 USA. NIMH, Rockville, MD 20857 USA. RP Jensen, PS (reprint author), Columbia Univ, New York State Psychiat Inst, Dept Child Psychiat, 1051 Riverside Dr,Unit 78, New York, NY 10032 USA. OI Jensen, Peter/0000-0003-2387-0650 FU NIMH NIH HHS [U01-MH50461, MH50467, U01-MH50453] NR 20 TC 26 Z9 26 U1 2 U2 5 PU CANADIAN PSYCHIATRIC ASSOC PI OTTAWA PA 260-441 MACLAREN ST, OTTAWA, ONTARIO K2H 2P3, CANADA SN 0706-7437 J9 CAN J PSYCHIAT JI Can. J. Psychiat.-Rev. Can. Psychiat. PD DEC PY 1999 VL 44 IS 10 BP 975 EP 980 PG 6 WC Psychiatry SC Psychiatry GA 268ZE UT WOS:000084450000003 PM 10637676 ER PT J AU Greene, MH AF Greene, MH TI The genetics of hereditary melanoma and nevi - 1998 update SO CANCER LA English DT Article; Proceedings Paper CT American-Cancer-Society 2nd National Conference on Cancer Genetics CY JUN 26-28, 1998 CL SAN FRANCISCO, CALIFORNIA SP Amer Canc Soc DE hereditary melanoma; dysplastic nevi; CDKN2A; CDK4; melanoma/astracytoma syndrome ID CUTANEOUS MALIGNANT-MELANOMA; ATYPICAL-MOLE SYNDROME; SPORADIC DYSPLASTIC NEVUS; SUSCEPTIBILITY LOCUS MLM; MULTICENTER CASE-CONTROL; TUMOR-SUPPRESSOR GENE; PROSPECTIVE FOLLOW-UP; FAMILIAL MELANOMA; RISK-FACTORS; MELANOCYTIC NEVI AB Although the first English-language report of melanoma in 1820 contained a description of a melanoma-prone family, it was 1983 before formal genetic analysis suggested an autosomal dominant mode of inheritance for both melanoma and the then newly described melanoma precursor, dysplastic nevi (DN). Subsequent genetic studies have assumed this model to be correct, although when viewed in aggregate, the data are inconsistent. The first proposed melanoma gene (CMM1) was mapped to chromosome 1p36. This gene assignment has not been confirmed. A second melanoma gene, designated CMM2, has been mapped to chromosome 9p21. This gene assignment has been confirmed, and the cell cycle regulator CDKN2A has been proposed as the candidate gene. Germline mutations in this gene have been identified in about 20% of melanoma-prone families that have been studied to dale. Pancreatic cancer occurs excessively in melanoma families with germline mutations in CDKN2A. Germline mutations in the cyclin-dependent kinase gene CDK4 (chromosome 12q14) have been described in three melanoma families. This finding represents a third melanoma gene but one that accounts for only a tiny fraction of all hereditary melanoma. Recently, a familial melanoma-astrocytoma syndrome has been reported. Large germline deletions of 9p21 occur in these families, with the p19 gene implicated in its pathogenesis. At present, clinical predictive genetic testing for mutations in the CDKN2A gene is available commercially, but its use has been limited by uncertainty as to how test results would affect the management of melanoma-prone family members. Currently, management recommendations include monthly skin self-examination, clinical skin examination once or twice yearly, a low threshold for simple excision of changing pigmented lesions, moderation of sun exposure, and appropriate use of sunscreens. A heritable determinant for total nevus number has been suggested by twin studies. Other data suggest the presence of a major gene responsible for "total nevus density" in melanoma-prone families. Approximately 55% of the mole phenotype in multiplex melanoma families was explained by this proposed gene. An autosomal dominant mode of inheritance has been proposed for DN, and data exist to suggest that DN may be a pleiotropic manifestation of the 1p36 familial melanoma gene. However, there clearly are melanoma-prone families that do not express the dysplastic nevus trait, and some of the families linked to CDKN2A also present with dysplastic nevi. Several studies have shown a surprisingly high prevalence of DN on the skin of family members of probands with DN. In light of the extensive evidence documenting that persons with DN (both sporadic and familial) have an increased prospective risk of melanoma, these family studies suggest that relatives of persons with DN Should be examined for both DN and melanoma. Genetic determinants play a major role in the pathogenesis of normal nevi, DN, and melanoma. Identifying the molecular basis of these genetic events promises to enhance melanoma risk-reduction strategies and, ultimately, reduce melanoma-associated mortality. Cancer 1999;86:2464-77. (C) 1999 American Cancer Society. C1 Mayo Clin Scottsdale, Div Hematol Oncol, Scottsdale, AZ USA. RP Greene, MH (reprint author), NCI, Clin Genet Branch, 6120 Execut Blvd,EPS 7022, Rockville, MD 20852 USA. NR 123 TC 87 Z9 89 U1 0 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER JI Cancer PD DEC 1 PY 1999 VL 86 IS 11 SU S BP 2464 EP 2477 DI 10.1002/(SICI)1097-0142(19991201)86:11+<2464::AID-CNCR3>3.0.CO;2-F PG 14 WC Oncology SC Oncology GA 265BU UT WOS:000084219800003 PM 10630172 ER PT J AU Hawk, E Lubet, R Limburg, P AF Hawk, E Lubet, R Limburg, P TI Chemoprevention in hereditary colorectal cancer syndromes SO CANCER LA English DT Article; Proceedings Paper CT American-Cancer-Society 2nd National Conference on Cancer Genetics CY JUN 26-28, 1998 CL SAN FRANCISCO, CALIFORNIA SP Amer Canc Soc DE chemoprevention; colorectal cancer; familial adenomatous polyposis; genetic; hereditary nonpolyposis colorectal cancer; nonsteroidal antiinflammatory drugs ID FAMILIAL ADENOMATOUS POLYPOSIS; APC(DELTA-716) KNOCKOUT MICE; SPONTANEOUS INTESTINAL ADENOMAS; EPITHELIAL-CELL PROLIFERATION; MIN MOUSE MODEL; SULINDAC THERAPY; RECTAL POLYPS; COLON CARCINOGENESIS; PROSTAGLANDIN LEVELS; GARDNERS-SYNDROME AB Understanding of the neoplastic events involved in heritable colorectal cancer syndromes is increasing at the molecular and clinical levels. This knowledge is foundational to cancer chemoprevention, which attempts to inhibit or reverse the tumorigenic process through pharmacologic interventions applied before cancer occurrence. We reviewed all relevant published reports identified from Medline databases (1966-1998) regarding cancer chemoprevention in familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, and heritable colorectal cancer cohorts, including rodent models of these diseases. Additional references were obtained from citations listed in the reviewed reports. A large amount of experience exists with cancer chemopreventive agents in both genetically-based rodent models and patient populations with familial adenomatous polyposis. These studies have provided important data on the natural history of neoplasia in this syndrome and have identified several classes of compounds with chemopreventive activity. Cyclooxygenase inhibitors, for example, yield substantial cancer prevention in animals and adenoma regression in humans, although reductions or delays in cancer incidence have not been proven to date. The data from chemoprevention studies in hereditary nonpolyposis colorectal cancer or other familial nonpolyposis colorectal cancer syndromes are less mature. Persons in heritable colorectal cancer cohorts are at substantial risk for early-onset malignancy in multiple target organs and therefore represent ideal subjects for cancer chemoprevention trials. The goals of chemoprevention are to reduce cancer risk and improve quality of life. Eventual success in family cancer cohorts may be measured through declines in the frequency of invasive surveillance procedures, surgical resections, neoplasia incidence, and cancer-related deaths. Disease-modifying agents that have shown promise in preliminary efficacy trials with intermediate endpoints require further testing to establish definitive clinical effectiveness. The lessons learned in these high-risk cohorts may have application to the prevention of colorectal cancers arising in the sporadic setting as well. Cancer 1999;86: 2551-63, (C) 1999 American Cancer Society. C1 NCI, Div Canc Prevent, Gastrointestinal & Other Canc Res Grp, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, Off Prevent Oncol, Bethesda, MD 20892 USA. RP Hawk, E (reprint author), NCI, DCP,CPRP, Chemoprevent Branch, EPN, Suite 201,6130 Execut Blvd,MSC-7322, Bethesda, MD 20892 USA. NR 111 TC 54 Z9 55 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER JI Cancer PD DEC 1 PY 1999 VL 86 IS 11 SU S BP 2551 EP 2563 DI 10.1002/(SICI)1097-0142(19991201)86:11+<2551::AID-CNCR12>3.0.CO;2-1 PG 13 WC Oncology SC Oncology GA 265BU UT WOS:000084219800012 PM 10630181 ER PT J AU Widemann, BC Balis, FM Godwin, KS McCully, C Adamson, PC AF Widemann, BC Balis, FM Godwin, KS McCully, C Adamson, PC TI The plasma pharmacokinetics and cerebrospinal fluid penetration of the thymidylate synthase inhibitor raltitrexed (Tomudex (TM)) in a nonhuman primate model SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE antifols; thymidylate synthase inhibitor; pharmacokinetic model; enzyme inhibition assay ID ZD1694 TOMUDEX; RHESUS-MONKEY; SOLID TUMORS AB Purpose:Raltitrexed (Tomudex(TM)), (ZD1694) is a novel quinazoline folate analog that selectively inhibits thymidylate synthase. Intracellularly, raltitrexed is polyglutamated to its active form which can be retained in cells for prolonged periods. The pharmacokinetics of raltitrexed in plasma and cerebrospinal fluid (CSF) were studied in a nonhuman primate model. Methods: Animals received 3 mg/m(2) (n = I), 6 mg/m(2) (n = 3), or 10 mg/m(2) (n = 3) i.v. over 15 min, and frequent plasma samples were obtained over 48 h. CSF samples were drawn from an indwelling 4th ventricular Ommaya reservoir over 48 h. Plasma and CSF raltitrexed concentrations were measured with a novel, sensitive enzyme inhibition assay with a lower limit of quantification of 0.005 mu M. A three-compartment pharmacokinetic model was fitted to the raltitrexed plasma concentration-time data. Results: The plasma concentration-time profile of raltitrexed was triexponential with a rapid initial decline and a prolonged terminal elimination phase (t(1/2) > 24 h), which was related to retention of raltitrexed in a deep tissue compartment. At the peak approximately 30% of the administered dose was in the deep tissue compartment, and 24 h after the dosing > 20% of the administered dose remained in the body with >99% in the deep tissue compartment. The mean peak (end of infusion) plasma concentrations after the 3, 6, and 10 mg/m(2) doses were 1.5, 2.4 and 4.8 mu M respectively. The clearance of raltitrexed ranged from 110 to 165 ml/min per m(2), and the steady-state volume of distribution exceeded 200 l/m(2). The CSF penetration of raltitrexed was limited (0.6 to 2.0%) and drug could only be detected in the CSF following a 10 mg/m(2) dose. Conclusions: The elimination of raltitrexed is triexponential with a prolonged terminal elimination phase. The pharmacokinetic profile is consistent with extensive polyglutamation and intracellular retention of ralitrexed. The three-compartment model presented here may be useful for the analysis of the pharmacokinetics of raltitrexed in humans. C1 NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Widemann, BC (reprint author), NCI, Pediat Oncol Branch, NIH, Bldg 10,Room 13N240,10 Ctr Dr, Bethesda, MD 20892 USA. EM widemanb@pbmac.nci.nih.gov NR 19 TC 12 Z9 12 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD DEC PY 1999 VL 44 IS 6 BP 439 EP 443 DI 10.1007/s002800051116 PG 5 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 250UC UT WOS:000083405700001 PM 10550563 ER PT J AU Brown, AP Morrissey, RL Crowell, JA Levine, BS AF Brown, AP Morrissey, RL Crowell, JA Levine, BS TI Difluoromethylornithine in combination with tamoxifen in female rats: 13-week oral toxicity study SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE tamoxifen; difluoromethylornithine; rats; reproductive system toxicity; GI toxicity; dermal toxicity; ornithine decarboxylase; estrogen ID CERVICAL INTRAEPITHELIAL NEOPLASIA; ORNITHINE DECARBOXYLASE INHIBITOR; BREAST-CANCER PREVENTION; PHASE-I TRIAL; ALPHA-DIFLUOROMETHYLORNITHINE; CHEMOPREVENTION; DRUG; CARCINOGENESIS; POLYAMINES AB Purpose: Cancer chemoprevention is the use of pharmacologic or natural agents to inhibit the development of cancer. Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase, the rate-limiting enzyme in the biosynthesis of polyamines. DFMO has demonstrated chemopreventive efficacy in animal models of tumorigenesis. Tamoxifen (TAM) is currently used for treatment of estrogen receptor-positive breast carcinoma and has demonstrated efficacy in chemoprevention of breast cancer in women at high risk for the disease. The administration of tamoxifen with DFMO is being considered for development by the National Cancer Institute as a potential drug regimen for the chemoprevention of breast carcinoma. Methods: The toxicity of DFMO in combination with TAM was evaluated in female rats following 13 weeks of daily administration by gavage. Dose groups were vehicle control, DFMO (1000 mg/kg per day), low TAM (0.25 mg/kg per day), high TAM (2.5 mg/kg per day), low combination (1000 + 0.25) and high combination (1000 + 2.5). Results: No mortalities occurred in the study. Clinical signs of toxicity were limited to dermal lesions consisting of scab formation and abrasions produced by DFMO. Administration of either DFMO or TAM resulted in decreased body weight gains, with coadministration having an additive effect. Serum albumin, total protein, cholesterol and triglyceride levels were decreased in all drug-treated dose groups, although histologic evidence of liver lesions were not seen. TAM resulted in increased numbers of red blood cells, whereas DFMO produced a slightly anemic response. DFMO produced lesions in the small intestine consisting of necrosis of crypt epithelium and crypt microabscess, which were enhanced by TAM coadministration. Administration of TAM resulted in histologic changes in the ovaries, fallopian tube, vagina, cervix and uterus, indicating that inhibition of ovulation and reproductive cycle arrest in the proestrus stage had occurred. Coadministration with DFMO did not affect the changes to the reproductive system induced by TAM. Conclusions: Coadministration of DFMO with tamoxifen did not result in toxicity unique to the combination drug regimen, but rather toxicity resulted from administration of each drug. Under the conditions of the study, the overall toxicity produced by dual administration of DFMO with tamoxifen was additive with respect to the toxicity associated with each agent alone. C1 Univ Illinois, Dept Pharmacol, Toxicol Res Lab, Chicago, IL 60612 USA. Pathol Associates Int, Chicago, IL USA. NCI, Div Canc Prevent & Control, NIH, Rockville, MD USA. RP Brown, AP (reprint author), Univ Illinois, Dept Pharmacol, Toxicol Res Lab, 1940 W Taylor St, Chicago, IL 60612 USA. FU NCI NIH HHS [N01-CN-55144-MAO] NR 33 TC 9 Z9 9 U1 0 U2 0 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 DEC PY 1999 VL 44 IS 6 BP 475 EP 483 DI 10.1007/s002800051121 PG 9 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 250UC UT WOS:000083405700006 PM 10550568 ER PT J AU Garcia-Closas, M Rothman, N Lubin, J AF Garcia-Closas, M Rothman, N Lubin, J TI Misclassification in case-control studies of gene-environment interactions: Assessment of bias and sample size SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BREAST-CANCER; RELATIVE RISK; DISEASE; POWER AB In studies of gene-environment interactions, exposure misclassification can lead to bias in the estimation of an interaction effect and increased sample size. The magnitude of the bias and the consequent increase in sample size for fixed misclassification probabilities are highly dependent on the prevalence of the misclassified factor and on the interaction model. This paper describes a relatively simple approach to assess the impact of misclassification on bias in the estimation of multiplicative or additive interactions and on sample size requirements. Applications of this method illustrate that even small errors in the assessment of environmental or genetic factors can result in biased interaction parameters and substantially increased sample size requirements that can compromise the feasibility of the study. Also, an example is provided where nondifferential misclassification biases an additive interaction parameter away from the null value, even under conditions where a multiplicative interaction parameter will always be biased toward the null value. Efforts to improve the accuracy in measuring both genetic and environmental factors are critical for the valid assessment of gene-environment interactions in case-control studies. C1 NCI, Div Canc Epidemiol & Genet, EPS, Bethesda, MD 20892 USA. RP Garcia-Closas, M (reprint author), NCI, Div Canc Epidemiol & Genet, EPS, Room 7076,6120 Execut Blvd, Bethesda, MD 20892 USA. RI Garcia-Closas, Montserrat /F-3871-2015 OI Garcia-Closas, Montserrat /0000-0003-1033-2650 NR 31 TC 77 Z9 78 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 DEC PY 1999 VL 8 IS 12 BP 1043 EP 1050 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 266VC UT WOS:000084320100001 PM 10613335 ER PT J AU Lacey, JV Brinton, LA Abbas, FM Barnes, WA Gravitt, PE Greenberg, MD Greene, SM Hadjimichael, OC McGowan, L Mortel, R Schwartz, PE Silverberg, SG Hildesheim, A AF Lacey, JV Brinton, LA Abbas, FM Barnes, WA Gravitt, PE Greenberg, MD Greene, SM Hadjimichael, OC McGowan, L Mortel, R Schwartz, PE Silverberg, SG Hildesheim, A TI Oral contraceptives as risk factors for cervical adenocarcinomas and squamous cell carcinomas SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID UTERINE CERVIX; YOUNG-WOMEN; IN-SITU; CANCER; EPIDEMIOLOGY; NEOPLASIA; INSITU; ASSOCIATION; COLOMBIA; TRENDS AB To assess the hypothesis that oral contraceptives (OCs) increase the risk of cervical adenocarcinomas, we conducted a six-center case-control study of 124 patients with adenocarcinomas, 139 with squamous cell carcinomas, and 307 population controls. Women between the ages of 18 and 69 who were newly diagnosed with cervical adenocarcinomas between 1992 and 1996 were eligible. Healthy female controls and a second case group of incident cervical squamous cell carcinomas were matched to the adenocarcinoma cases, All participants were interviewed regarding OCs, other risk factors for cervical carcinoma, and utilization of cytological screening, and a PCR-based test determined HPV genotype of cervical samples for both case groups and controls. Use of OCs was positively and significantly associated with adenocarcinomas and positively but weakly associated with squamous cell carcinomas. Associations between OCs and invasive adenocarcinomas (n = 91), squamous cell carcinoma in situ (n = 48), and invasive squamous cell carcinomas (n = 91) disappeared after accounting for HPV infection, sexual history, and cytological screening, but a positive association remained between current use of OCs and cervical adenocarcinoma in situ (n = 33), This association persisted after stratification by screening and sexual history and after restriction according to HPV status, but small numbers made it difficult to exclude detection bias, selection bias, or residual confounding by HPV as potential explanations. Current OC use was associated with cervical adenocarcinomas in situ, but we saw no other evidence that OCs independently increase the risk of cervical carcinomas. C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Sinai Hosp, Baltimore, MD 21215 USA. Georgetown Univ, Lombardi Canc Ctr, Washington, DC 20007 USA. Roche Mol Syst Inc, Alameda, CA 94501 USA. Grad Hosp Philadelphia, Philadelphia, PA 19146 USA. Westat Inc, Rockville, MD 20850 USA. Yale Univ, Sch Med, New Haven, CT 06504 USA. George Washington Univ, Washington, DC 20052 USA. Penn State Univ, Milton S Hershey Med Ctr, Hershey, PA 17033 USA. Univ Maryland, Baltimore, MD 21201 USA. RP Lacey, JV (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,MSC 7234, Rockville, MD 20852 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 50 TC 79 Z9 82 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 DEC PY 1999 VL 8 IS 12 BP 1079 EP 1085 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 266VC UT WOS:000084320100006 PM 10613340 ER PT J AU Bacus, JW Boone, CW Bacus, JV Follen, M Kelloff, GJ Kagan, V Lippman, SM AF Bacus, JW Boone, CW Bacus, JV Follen, M Kelloff, GJ Kagan, V Lippman, SM TI Image morphometric nuclear grading of intraepithelial neoplastic lesions with applications to cancer chemoprevention trials SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BREAST-CANCER; FLOW-CYTOMETRY; DNA-ANALYSIS; CELL-NUCLEI; DISCRIMINATION; PROGRESSION; EXPRESSION; ANEUPLOIDY; CARCINOMA; DISEASE AB A new image morphometric method of nuclear grading is described and assessed in the context of the evaluation of histological samples from ductal carcinoma irt situ of the breast and cervical intraepithelial neoplasia, The method results in a continuous scaled variable, or nuclear grading scale, expressed in SD units from measured normal nuclei from breast or cervix. For a given histological preinvasive neoplastic lesion, the mean nuclear grade of measured nuclei was shown to be analogous to the histopathological nuclear grade of the same lesion assigned subjectively by the pathologist. In a chemoprevention trial of the effect of difluoromethylornithine given for 1 month to subjects with cervical intraepithelial neoplasia grade 3, pathologists could see no difference in 14 histological sections taken before and after difluoromethylornithine treatment. However, the image morphometric method detected a systematic effect of lowered mean nuclear grade and a decrease in the variability of nuclear grade expression. Twelve of 14 samples showed a lower posttreatment mean nuclear grade (P < 0.05), and 13 of the 14 samples showed a decrease in the SD of their nuclear grade distributions (P < 0.01), This study demonstrates the use of image morphometric nuclear grading in a chemoprevention setting. It may be very useful in supplementing the pathologist's histopathological grading by providing objective, quantitative assessments. C1 Bacus Labs Inc, Lombard, IL 60148 USA. NCI, Div Canc Prevent, Chemoprevent Program, NIH, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Bacus, JW (reprint author), Bacus Labs Inc, 410 Eisenhower Lane N, Lombard, IL 60148 USA. FU NCI NIH HHS [N01-CN-65004] NR 48 TC 39 Z9 39 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD DEC PY 1999 VL 8 IS 12 BP 1087 EP 1094 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 266VC UT WOS:000084320100007 PM 10613341 ER PT J AU Sun, EC Curtis, R Melbye, M Goedert, JJ AF Sun, EC Curtis, R Melbye, M Goedert, JJ TI Salivary gland cancer in the United States SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HUMAN PAPILLOMAVIRUS DNA; EPSTEIN-BARR-VIRUS; CERVICAL-CANCER; CARCINOMA; TUMORS; EPIDEMIOLOGY; ASSOCIATION; PREVALENCE; RADIATION; RISK AB The risk of salivary gland cancer (SGC) is increased in atomic bomb survivors and after radiotherapy, but other risk factors are not well established. Some studies have suggested an association of SGC with breast cancer and with exposure to various viruses or UVB radiation. Corroborating evidence of these associations was sought by using population-based registries to examine the demographic distribution of SGC, patterns of secondary primary cancers after SGC, and risk of SGC with AIDS. SGC incidence per 100,000 persons did not change between 1973 and 1992, averaging 1.2 in males and 0.8 in females, with a steep age gradient. To examine the relationship between UVB exposure and SGC, population-based, age-adjusted incidence rates of SGC were plotted against the UVB insolation of each registry site. Regression analysis suggested no correlation between SGC incidence and increasing UVB insolation (beta = 0.10, R-2 = 0.08). SGC also did not appear to be associated with second cancers that have been linked to herpes or papilloma viruses or with AIDS [observed/expected (O/E) ratio, <2.8], but all of these conditions are so uncommon that only very large relative risks would have been statistically significant. Women with SGC before age 35 had a statistically nonsignificant elevation in breast cancer risk [O/E, 3.30; 95% confidence interval (CI), 0.66-9.65], and older women had no increased risk of breast cancer. SGC patients were at increased risk for nonsalivary, second-primary oropharyngeal cancers (O/E, 3.27; 95% CI, 2.00-5.05), thyroid cancer (O/E, 3.31; 95% CI, 1.07-7.73), and lung cancer (O/E, 1.86; 95% CI, 1.45-2.35), particularly in patients whose SGC was treated with radiotherapy (O/E, 2.83; 95% CI, 2.06-3.80). In summary, SGC remains rare and does not appear to be associated with AIDS, vitally related malignancies, or UVB. Patients who have had SGC, however, should be monitored for subsequent oropharyngeal, thyroid, and lung cancers. C1 NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. Statens Serum Inst, Danish Epidemiol Sci Ctr, DK-2300 Copenhagen S, Denmark. RP Goedert, JJ (reprint author), NCI, Viral Epidemiol Branch, 6120 Execut Blvd,Room 8012,MSC 7248, Rockville, MD 20852 USA. NR 45 TC 43 Z9 45 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD DEC PY 1999 VL 8 IS 12 BP 1095 EP 1100 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 266VC UT WOS:000084320100008 PM 10613342 ER PT J AU Freedman, DM Tangrea, JA Virtamo, J Albanes, D AF Freedman, DM Tangrea, JA Virtamo, J Albanes, D TI The effect of beta-carotene supplementation on serum vitamin D metabolite concentrations SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CANCER PREVENTION; ALPHA-TOCOPHEROL; LUNG-CANCER; RETINOL; RISK AB In the alpha-Tocopherol, beta-Carotene Cancer Prevention (ATBC) study, a large randomized placebo-controlled trial designed to test the cancer prevention effects of alpha-tocopherol (50 mg/day) and beta-carotene (20 mg/day), participants receiving supplemental beta-carotene had significantly higher rates of lung cancer than those not receiving beta-carotene, It has been hypothesized that the supplemental beta-carotene may have interfered with the synthesis of vitamin D and that the resulting lower concentrations of vitamin D contributed to the elevated cancer incidence. We evaluated whether supplementation with p-carotene altered the serum concentrations of either 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D in the ATBC Study, by comparing on-study changes between baseline and follow-up serum samples among 20 randomly selected matched pairs of subjects from the beta-carotene and placebo groups. In a matched-pair analysis, the difference between the changes in both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in the beta-carotene supplement and placebo groups were small and statistically nonsignificant. These results provide no evidence that beta-carotene supplementation interferes with the endogenous production of 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D and suggest that it is unlikely that an interaction between supplemental beta-carotene and vitamin D metabolites contributed to the modest increase in lung cancer incidence observed in the ATBC Study. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Div Clin Sci, Bethesda, MD 20892 USA. Natl Publ Hlth Inst, Helsinki, Finland. RP Freedman, DM (reprint author), NCI, Div Canc Epidemiol & Genet, EPS Room 7087,6220 Execut Blvd, Bethesda, MD 20892 USA. RI Albanes, Demetrius/B-9749-2015 FU NCI NIH HHS [N01-CN-45165] NR 9 TC 8 Z9 8 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD DEC PY 1999 VL 8 IS 12 BP 1115 EP 1116 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 266VC UT WOS:000084320100012 PM 10613346 ER PT J AU Hankey, BF Ries, LA Edwards, BK AF Hankey, BF Ries, LA Edwards, BK TI The surveillance, epidemiology, and end results program: A national resource SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Review ID PROSTATE-CANCER; OVARIAN-CANCER; BREAST-CANCER; NEW-MEXICO; MORTALITY; TRENDS; RISK; MISCLASSIFICATION; COMORBIDITY; PREDICTORS C1 NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Hankey, BF (reprint author), NCI, Hlth Serv, EPH, Room 343J,6130 Execut Blvd, Bethesda, MD 20892 USA. NR 43 TC 312 Z9 317 U1 5 U2 9 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD DEC PY 1999 VL 8 IS 12 BP 1117 EP 1121 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 266VC UT WOS:000084320100013 PM 10613347 ER PT J AU Zhao, W He, CY Rotter, V Merrick, BA Selkirk, JK AF Zhao, W He, CY Rotter, V Merrick, BA Selkirk, JK TI An intragenic deletion of nuclear localization signal-1 of p53 tumor suppressor gene results in loss of apoptosis in murine fibroblasts SO CANCER LETTERS LA English DT Article DE apoptosis; DNA damage; p53; p21; tumor suppressor gene ID CELL-CYCLE ARREST; WILD-TYPE P53; PROTEIN; BINDING; P21; EXPRESSION; COMPLEXES; GROWTH AB We established mouse lines containing either full-length wild-type p53 or nuclear localization signal-I (NLS-I) deleted p53 to study the role of NLS-I in p53 translocation and function. Induction of apoptosis in response to DNA damage, a primary function of p53, was tested in these cell lines. After exposure to gamma-ionizing radiation or hydrogen peroxide, DNA ladders and labeling of nucelosomal fragments were detected in cells with wild-type p53 gene, but not in p53 null cells or NLS-I deleted cells, suggesting that the NLS-I of p53 protein is necessary for apoptosis. Analysis of p53 protein from subcellular fractions indicated that NLS-I deprived p53 remained in the cytoplasmic fraction, which may explain why NLS-I deleted p53 failed to induce apoptosis. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. Weizmann Inst Sci, Dept Cell Biol, IL-76100 Rehovot, Israel. RP Selkirk, JK (reprint author), NIEHS, Mol Carcinogenesis Lab, POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 19 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD DEC 1 PY 1999 VL 147 IS 1-2 BP 101 EP 108 DI 10.1016/S0304-3835(99)00283-9 PG 8 WC Oncology SC Oncology GA 265FZ UT WOS:000084232800015 PM 10660095 ER PT J AU Li, H Kramer, PM Lubet, RA Steele, VE Kelloff, GJ Pereira, MA AF Li, H Kramer, PM Lubet, RA Steele, VE Kelloff, GJ Pereira, MA TI Termination of piroxicam treatment and the occurrence of azoxymethane-induced colon cancer in rats SO CANCER LETTERS LA English DT Article DE aberrant crypt foci; apoptosis; cell proliferation; chemoprevention; colon cancer; piroxicam ID FAMILIAL ADENOMATOUS POLYPOSIS; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; ABERRANT CRYPT FOCI; CHEMOPREVENTIVE AGENTS; COLORECTAL-CANCER; INDUCED REGRESSION; RECTAL POLYPOSIS; ASPIRIN USE; LARGE-BOWEL; SULINDAC AB Piroxicam has been shown to prevent azoxymethane (AOM)-induced colon cancer when administered during the promotion/progression phase. The requirement for continued treatment with piroxicam in order to maintain prevention of colon cancer was investigated. Male F344 rats were administered 15 mg/kg AOM at 7 and 8 weeks of age and started to receive piroxicam (200 mg/kg) in their diet at 11 weeks after the second dose of AOM. Piroxicam was removed from the diet of some of the rats at weeks 19 and 28 and the animals were held until week 47. Other rats continued to receive piroxicam until sacrificed at week 47. Treatment with piroxicam from week 11-47 reduced the yield of colon tumors. When treatment was terminated at week 19 or 28 the yield of tumors at week 47 was not reduced. Within 1 week of the start of piroxicam treatment, the number of aberrant crypt foci (ACF)/animal was decreased. Termination of treatment resulted in the recurrence of ACF. Apoptosis in adenomas was increased when piroxicam treatment was continued to week 47 but not when treatment was terminated earlier at week 19 or 28. The proliferating cell nuclear antigen-labeling index in adenomas was not affected by piroxicam even when treatment was from week 11 to 47. In summary, termination of treatment resulted in the occurrence of ACF and colon cancer indicating that prevention by piroxicam was reversible. Furthermore, enhancement of apoptosis and not decreased cell proliferation correlated with prevention of colon cancer. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. C1 Med Coll Ohio, Dept Pathol, Toledo, OH 43614 USA. NCI, Chemoprevent Branch, Div Canc Prevent & Control, Bethesda, MD 20892 USA. RP Pereira, MA (reprint author), Med Coll Ohio, Dept Pathol, Hlth Educ Bldg,Room 200F,3055 Arlington Ave, Toledo, OH 43614 USA. EM mpereira@mco.edu FU NCI NIH HHS [N01-CN-55151] NR 41 TC 21 Z9 21 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD DEC 1 PY 1999 VL 147 IS 1-2 BP 187 EP 193 DI 10.1016/S0304-3835(99)00296-7 PG 7 WC Oncology SC Oncology GA 265FZ UT WOS:000084232800025 PM 10660105 ER PT J AU Ito, H Rovira, II Bloom, ML Takeda, K Ferrans, VJ Quyyumi, AA Finkel, T AF Ito, H Rovira, II Bloom, ML Takeda, K Ferrans, VJ Quyyumi, AA Finkel, T TI Endothelial progenitor cells as putative targets for angiostatin SO CANCER RESEARCH LA English DT Article ID GROWTH IN-VIVO; TUMOR-GROWTH; ANGIOGENESIS; METASTASES; APOPTOSIS AB Angiostatin, a product of the proteolytic cleavage of plasminogen, possesses potent antitumor and antiangiogenic properties in vivo. Studies with cultured endothelial cells suggest that under certain conditions, angiostatin inhibits the migration and proliferation of these cells or, alternatively, increases their rate of apoptosis. In general, the effects of angiostatin have been considerably less potent in vitro than in vivo. One potential explanation for this disparity is that the in vivo target of angiostatin is not the mature endothelial cell. Recently, evidence has accumulated to show that circulating endothelial progenitor cells (EPCs) contribute to neovascularization. In this study, we have isolated EPCs from human subjects and demonstrated that, in contrast to that of mature endothelial cells, the growth of EPCs is exquisitely sensitive to angiostatin. These results suggest that angiostatin and related compounds may exert their biological effects by inhibiting the contribution of EPCs to angiogenesis and not by altering the growth of mature endothelial cells. C1 NHLBI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. RP Finkel, T (reprint author), NHLBI, Mol Biol Lab, NIH, Bldg 10-7B-15,10 Ctr Dr, Bethesda, MD 20892 USA. NR 15 TC 124 Z9 136 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 DEC 1 PY 1999 VL 59 IS 23 BP 5875 EP 5877 PG 3 WC Oncology SC Oncology GA 266JL UT WOS:000084296800004 PM 10606226 ER PT J AU Brangi, M Litman, T Ciotti, M Nishiyama, K Kohlhagen, G Takimoto, C Robey, R Pommier, Y Fojo, T Bates, SE AF Brangi, M Litman, T Ciotti, M Nishiyama, K Kohlhagen, G Takimoto, C Robey, R Pommier, Y Fojo, T Bates, SE TI Camptothecin resistance: Role of the ATP-binding cassette (ABC), mitoxantrone-resistance half-transporter (MXR), and potential for glucuronidation in MXR-expressing cells SO CANCER RESEARCH LA English DT Article ID MULTIDRUG-RESISTANCE; TOPOISOMERASE-I; UDP-GLUCURONOSYLTRANSFERASES; CARCINOMA CELLS; PROTEIN MRP; HUMAN COLON; GENE; CYTOTOXICITY; GLUTATHIONE; ASSAY AB The mitoxantrone resistance (MXR) gene encodes a recently characterized ATP-binding cassette half-transporter that confers multidrug resistance. We studied resistance to the camptothecins in two sublines expressing high levels of MXR: S1-M1-80 cells derived from parental S1 colon cancer cells and MCF-7 AdVp3000 isolated from parental MCF-7 breast cancer cells. Both cell lines were 400- to 1000-fold more resistant to topotecan, 9-amino-20(S)-camptothecin, and the active metabolite of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), than their parental cell lines, The cell lines demonstrated much less resistance to camptothecin and to several camptothecin analogues, Reduced accumulation and energy-dependent efflux of topotecan was demonstrated by confocal microscopy. A significant reduction in cleavable complexes in the resistant cells could be observed after SN-38 treatment but not after camptothecin treatment. In addition to topotecan and SN-38, MXR-overexpressing cells are highly resistant to mitoxantrone and epirubicin. Because these compounds are susceptible to glucuronidation, we examined UDP-glucuronosyltransferase (UGT) activity in parental and resistant cells by TLC, Glucuronides were found at equal levels in both parental and resistant colon cancer cell lines for epirubicin and to a lesser extent for SN-38 and mitoxantrone. Low levels of glucuronidation could also be detected in the resistant breast cancer cells. These results were confirmed by analysis of the UGT1A family mRNAs, We thus conclude that colon and breast cancer cells have a capacity for glucuronidation that could contribute to intrinsic drug resistance in colon cancer cells and may be acquired in breast cancer cells. The lack of selection for higher level of UGT capacity in the colon cells suggests that high levels of expression of MXR alone are sufficient to confer resistance to the camptothecins. C1 NCI, Div Canc Treatment, Med Branch, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Treatment, Mol Pharmacol Lab, Dev Therapeut Program,NIH, Bethesda, MD 20892 USA. NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Div Canc Treatment, Med Branch, NIH, Bethesda, MD 20892 USA. NR 44 TC 205 Z9 209 U1 2 U2 6 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 1 PY 1999 VL 59 IS 23 BP 5938 EP 5946 PG 9 WC Oncology SC Oncology GA 266JL UT WOS:000084296800017 PM 10606239 ER PT J AU Lewis, KC Hochadel, JF AF Lewis, KC Hochadel, JF TI Retinoid metabolism in the prostate: Effects of administration of the synthetic retinoid N-(4-hydroxyphenyl)retinamide SO CANCER RESEARCH LA English DT Article ID ACID-BINDING-PROTEIN; VITAMIN-A STATUS; BREAST-CANCER; CARCINOMA CELLS; RAT-LIVER; FENRETINIDE; RETINAMIDE; ASSAY; N-<4-HYDROXYPHENYL>RETINAMIDE; ACYLTRANSFERASE AB We have carried out a series of complementary in vivo and in vitro studies to better understand the metabolism of vitamin A by the prostate gland. Male Sprague-Dawley rats were fed either a control diet sufficient in vitamin A [CON group; 0.8 mu g retinol equivalents (RE)/g diet] or a CON diet supplemented with the synthetic retinoid N-(4-hydroxyphenyl) retinamide (4-HPR; CON+4HPR group; 1173 mu g of 4-HPR/g diet). After an i.v. injection of a physiological radiolabeled dose of retinol, the vitamin A content and radioactivity of plasma and a number of tissues, including the prostate glands, were monitored for time periods ranging between 30 min and 41 days. On the basis of the results of these vitamin A turnover studies, we developed tissue subsystem models to describe vitamin A dynamics in the prostates of both the CON and CON+4HPR groups. There was a gradual decrease in the vitamin A content of the prostates of the 4-HPR-treated group as compared with the control, such that by the end of the study period, the CON+4HPR group averaged 0.166 +/- 0.0827 (mean +/- SD) REs, whereas the CON group was 0.732 +/- 0.190 REs. The fraction of vitamin A exiting the prostate each day was not significantly different in the CON as compared with the CON+4HPR group [0.149 +/- 0.103 versus 0.155 +/- 0.191 h(-1) (mean +/- FSD), respectively]; however, the average amount of vitamin A turning over from the CON+4HPR group prostates (0.0885 mu g/day) was nearly three times less than that of the CON group (0.243 mu g/day). To obtain more detailed information on the mechanisms that might be involved in the changes in vitamin A kinetics observed in our in vivo studies, we used both a normal human prostate cell line (PrEC) and a human prostate adenocarcinoma cell line (LNCaP) to monitor in vitro retinol and 4-HPR dynamics. Cells were treated with 4-HPR for different time periods up to 48 h (PrEC) or 96 h (LNCaP). Retinol in the media was taken up readily by both PrEC and LNCaP cells, and there was conversion of retinol to the major storage esters of vitamin A, retinyl palmitate and retinyl stearate, as well as several minor retinyl esters, in a pattern indicative of normal retinoid esterification activity, Although 4-HPR was taken up readily and over time accumulated in both cell lines, conversion of 4-HPR to its major metabolite, N-[4-methoxyphenyl]retinamide, as well as several other metabolites of 4-HPR was apparent only in the LNCaP cells. Our findings would suggest that a study design that includes appropriately designed complementary in vivo and in vitro experimental systems represents a useful approach to better understanding possible mechanisms involved in basic retinoid functioning and interactions in the prostate as well as in other organs and related tissue culture systems. C1 NCI, Frederick Canc Res & Dev Ctr, Basic Res Lab, Div Basic Sci, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, Sci Applicat Int Corp, Frederick, MD 21702 USA. RP Lewis, KC (reprint author), NCI, Frederick Canc Res & Dev Ctr, Basic Res Lab, Div Basic Sci, Bldg 560,Room 12-27, Frederick, MD 21702 USA. NR 47 TC 9 Z9 9 U1 2 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 DEC 1 PY 1999 VL 59 IS 23 BP 5947 EP 5955 PG 9 WC Oncology SC Oncology GA 266JL UT WOS:000084296800018 PM 10606240 ER PT J AU Schiltz, M Cui, XX Lu, YP Yagi, H Jerina, DM Zdzienicka, MZ Chang, RL Conney, AH Wei, SJC AF Schiltz, M Cui, XX Lu, YP Yagi, H Jerina, DM Zdzienicka, MZ Chang, RL Conney, AH Wei, SJC TI Characterization of the mutational profile of (+)-7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene at the hypoxanthine (guanine) phosphoribosyltransferase gene in repair-deficient Chinese hamster V-H1 cells SO CARCINOGENESIS LA English DT Article ID DOSE-DEPENDENT DIFFERENCES; MAMMALIAN-CELLS; V-79 CELLS; 7,8-DIOL 9,10-EPOXIDES; OPTICAL ENANTIOMERS; DNA ADDUCTS; BENZOPYRENE; REGION; CARCINOGEN; LINES AB Earlier studies have shown that the profile of mutations induced by (+)-7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(+)-BPDE] at the hypoxanthine (guanine) phosphoribosyltransferase (hprt) gene of Chinese hamster V79 cells was dependent on the concentration of(+)-BPDE, In the present study, we examined the effect of the concentration of(+)-BPDE on its mutational profile at the hprt gene in repair-deficient V-H1 cells (a derivative of V79 cells) to explore the role of DNA repair in the dose-dependent mutational profile of (+)-BPDE, Independent hprt mutant clones were isolated after exposing V-H1 cells to dimethylsulfoxide (DMSO) or to low (4-6 nM; 95% cell survival) or high (40-48 nM; 31% cell survival) concentrations of (+)-BPDE in DMSO. The mutation frequencies for the DMSO control and for the low and high concentration groups were 0.1, 2.1 and 32.9 mutant colonies/10(5) survivors, respectively. The profile of mutations at the hprt gene was characterized for 148 (+)-BPDE-induced mutant clones and the results from the present study were compared with those obtained earlier with V79 cells. The data indicated that: (i) V-H1 cells were similar to 9-fold more sensitive to the cytotoxic effects of(+)-BPDE than V79 cells; (ii) the mutation frequency in V-H1 cells was similar to that observed in V79 cells following exposure to similar concentrations of (+)-BPDE; (iii) (+)-BPDE-induced mutations at guanine on the transcribed strand of the hprt gene were common in V-H1 cells but were extraordinarily rare in V79 cells; (iv) (+)-BPDE-induced mutations at adenine on the transcribed strand of the hprt gene were common in both V-H1 and V79 cells; (v) although exposure of V79 cells to different doses of (+)-BPDE resulted in a dose-dependent mutational profile at the hprt gene, this was not observed in V-H1 cells. Our observations indicate a defect in the transcription-coupled repair of (+)-BPDE-DNA adducts in V-H1 cells and that the repair activity deficient in V-H1 cells is essential for the dose-dependent mutational profile observed with (+)-BPDE in V79 cells. C1 Rutgers State Univ, Coll Pharm, Dept Biol Chem, Canc Res Lab, Piscataway, NJ 08854 USA. NIDDKD, Sect Oxidat Mechanisms, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Leiden Univ, LUMC, Dept Radiat Genet & Chem Mutagenesis, Leiden, Netherlands. JA Cohen Inst, Interuniv Res Inst Radiopathol & Radiat Protect, Leiden, Netherlands. RP Wei, SJC (reprint author), Rutgers State Univ, Coll Pharm, Dept Biol Chem, Canc Res Lab, Piscataway, NJ 08854 USA. FU NCI NIH HHS [CA 49756] NR 29 TC 33 Z9 33 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 DEC PY 1999 VL 20 IS 12 BP 2279 EP 2285 DI 10.1093/carcin/20.12.2279 PG 7 WC Oncology SC Oncology GA 270GB UT WOS:000084526100011 PM 10590220 ER PT J AU Wali, RK Skarosi, S Hart, J Zhang, YC Dolan, ME Moschel, RC Nguyen, L Mustafi, R Brasitus, TA Bissonnette, M AF Wali, RK Skarosi, S Hart, J Zhang, YC Dolan, ME Moschel, RC Nguyen, L Mustafi, R Brasitus, TA Bissonnette, M TI Inhibition of O-6-methylguanine-DNA methyltransferase increases azoxymethane-induced colonic tumors in rats SO CARCINOGENESIS LA English DT Article ID ABERRANT CRYPT FOCI; K-RAS MUTATIONS; DNA-REPAIR METHYLTRANSFERASE; SUPPLEMENTAL DIETARY CALCIUM; O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; INDUCED TUMORIGENESIS; ALKYLATING AGENT; TRANSGENIC MICE; H-RAS AB Azoxymethane (AOM) causes O-6-methylguanine adduct formation which leads to G-->A transitions. Their repair is carried out by O-6-methylguanine-DNA methyltransferase (MGMT), To evaluate the importance of this repair event in AOM-induced carcinogenesis, we examined the effect of O-6-benzylguanine (BG), a potent inhibitor of MGMT, on colonic tumor development. Rats were treated weekly for 2 weeks at 0 and 24 h with BG (60 mg/kg body wt i.p.) or vehicle (40% polyethylene glycol, PEG-400), followed 2 h after the first dose of BG with AOM (15 mg/kg body wt) or vehicle (saline) i.p. Rats were killed 35 weeks later and tumors harvested and DNA extracted, In the AOM-treated groups, BG caused a significant increase in tumor incidence with tumors in 65.9%, versus 30.8% in the AOM/PEG-treated group (P < 0.05), In the BG/AOM group there was also a significant increase in tumor multiplicity, with 2.3 tumors/tumor-bearing rat, versus 1.6 tumors/tumor-bearing rat in the AOM/PEG group (P < 0.05), Since O-6-methylguanine adducts can cause activating mutations in the K-ras and beta-catenin genes, we examined the effects of BG on these mutations. In the BG group there were seven mutations in codon 12 or 13 of exon 1 of the K-ras gene in 51 tumors examined, compared with no K-ras mutations in 17 tumors analyzed in the AOM/PEG group (P = 0.12), In the BG/AOM group there were 10 mutations in exon 3 of the beta-catenin gene among 48 tumors evaluated, compared with six mutations in 16 tumors analyzed in the PEG/AOM group (P 0,16), In summary, MGMT inhibition increases AOM-induced colonic tumor incidence and multiplicity in rats. C1 Univ Chicago, Dept Med, Chicago, IL 60637 USA. Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. NCI, ABL Basic Res Program, FCRDC, Frederick, MD 21701 USA. RP Bissonnette, M (reprint author), Univ Chicago Hosp & Clin, Dept Med, MC 4076,5841 S Maryland Ave, Chicago, IL 60637 USA. FU NCI NIH HHS [CA69532, CA36745]; NIDDK NIH HHS [DK42086] NR 37 TC 19 Z9 21 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD DEC PY 1999 VL 20 IS 12 BP 2355 EP 2360 DI 10.1093/carcin/20.12.2355 PG 6 WC Oncology SC Oncology GA 270GB UT WOS:000084526100024 PM 10590233 ER PT J AU Lohrum, MAE Vousden, KH AF Lohrum, MAE Vousden, KH TI Regulation and activation of p53 and its family members SO CELL DEATH AND DIFFERENTIATION LA English DT Review DE p53; p73; p63; MDM2; E2F-1; protein stability ID HUMAN PAPILLOMAVIRUS TYPE-16; TUMOR-SUPPRESSOR PROTEIN; ABL TYROSINE KINASE; FEEDBACK LOOP; DNA-DAMAGE; IN-VIVO; C-ABL; P53-DEPENDENT APOPTOSIS; EMBRYONIC LETHALITY; MDM2-DEFICIENT MICE AB Regulation of the p53 tumor suppressor protein occurs to a large extent through control of protein stability, and the MDM2 protein has been shown to play a key role in targeting p53 for degradation. Stress signals that activate the p53 response lead to stabilization of p53 through inhibition of MDM2 mediated degradation, and it is becoming evident that a number of mechanisms exist to abrogate this activity of MDM2. Other members of the p53 protein family may also be regulated through protein stability, although MDM2 is not responsible for the degradation of p73. Nevertheless, interactions of p63 and p73 with MDM2 or p53 have been described, suggesting that each of the p53-related proteins can play some role in regulating the activity of the others. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. RP Vousden, KH (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Bldg 560,Room 22-96,W 7th St, Frederick, MD 21702 USA. NR 115 TC 74 Z9 75 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD DEC PY 1999 VL 6 IS 12 BP 1162 EP 1168 DI 10.1038/sj.cdd.4400625 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 274QH UT WOS:000084776200005 PM 10637431 ER PT J AU Shi, D Daly, JW AF Shi, D Daly, JW TI Chronic effects of xanthines on levels of central receptors in mice SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article DE caffeine; adenosine receptors; adrenergic receptors; serotonergic receptors; cholinergic receptors ID TERM CAFFEINE TREATMENT; BRAIN ADENOSINE RECEPTORS; RAT CEREBRAL-CORTEX; LOCOMOTOR-ACTIVITY; MOUSE-BRAIN; THEOPHYLLINE; BINDING; NUMBER; METHYLXANTHINES; UPREGULATION AB 1. Chronic ingestion of caffeine causes a significant increase in levels of A(1)-adenosine, nicotinic and muscarinic receptors, serotonergic receptors, GABA(A) receptors and L-type calcium channels in cerebral cortical membranes from mice NIH Swiss strain mice. 2. Chronic theophylline and paraxanthine had effects similar to those of caffeine except that levels of L-type channels were unchanged. Chronic theobromine, a weak adenosine antagonist, and 1-isobutyl-3-methylxanthine (IBMX), a potent adenosine antagonist and phosphodiesterase inhibitor, caused only an increase in levels of A(1)-adenosine receptors. A combination of chronic caffeine and IBMX had the same effects on receptors as caffeine alone. Chronic 3,7-dimethyl-1-propargylxanthine (DMPX), a somewhat selective A(2A)-antagonist, caused only an increase in levels of A(1)-adenosine receptors. Pentoxyfylline, an adenosine-uptake inhibitor inactive at adenosine receptors, had no effect on receptor levels or calcium channels. 3. A comparison of plasma and brain levels of xanthines indicated that caffeine penetrated more readily and attained somewhat higher brain levels than theophylline or theobromine. Penetration and levels were even lower for IBMX, paraxanthine, DMPX, and pentoxyfylline. 4. The results suggest that effective blockade of both A(1) and A(2A)-adenosine receptors is necessary for the full spectrum of biochemical changes elicited by chronic ingestion of xanthines, such as caffeine, theophylline, and paraxanthine. C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Daly, JW (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bldg 8,Room 1A17, Bethesda, MD 20892 USA. NR 40 TC 37 Z9 37 U1 0 U2 5 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD DEC PY 1999 VL 19 IS 6 BP 719 EP 732 DI 10.1023/A:1006901005925 PG 14 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 224FY UT WOS:000081888100004 PM 10456233 ER PT J AU Mulshine, JL AF Mulshine, JL TI Reducing lung cancer risk - Early detection SO CHEST LA English DT Article; Proceedings Paper CT Symposium on Multimodality Therapy of Chest Malignancies - Update 1998 CY MAR 12-14, 1998 CL CAMBRIDGE, MA SP Harvard Med Sch, Dept Oncol, Dana Farber Canc Inst, Div Thorac Surg & Harvard Joint Ctr Radiat Therapy, Brigham & Womens Hosp ID NUCLEAR RIBONUCLEOPROTEIN A2/B1; ISOTRETINOIN; EXPRESSION; CARCINOMA; CHEMOPREVENTION; CARCINOGENESIS; EPITHELIUM; ANTIGEN; CELLS AB Strategies for the early detection of lung cancer are being: investigated in an attempt to improve the poor prognosis associated with the disease. Such approaches, which include the identification of biomarkers for preclinical disease, must be integrated into multimodal cancer prevention strategies. Recent investigations have identified potential markers of early disease, including heterogeneous nuclear ribonucleoprotein, although the use of multiple markers may be required to provide the sensitivity and specificity necessary for mass screening. Early detection necessitates the development of effective chemoprevention strategies for the airway-confined phase of lung cancer. Current research efforts explore the utility of direct drug delivery, such as with the use of aerosolized delivery of retinoids, to maximize delivery of the active agent to the site of early lung cancer while avoiding systemic adverse effects. C1 NCI, Intervent Sect, Dept Cell & Canc Biol, Med Branch,Div Clin Sci,NIH,Clin Ctr, Bethesda, MD 20892 USA. RP Mulshine, JL (reprint author), NCI, Intervent Sect, Dept Cell & Canc Biol, Med Branch,Div Clin Sci,NIH,Clin Ctr, Bldg 10,Rm 12N226, Bethesda, MD 20892 USA. EM mulshinej@bprb.nci.nih.gov NR 28 TC 5 Z9 5 U1 0 U2 1 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD DEC PY 1999 VL 116 IS 6 SU S BP 493S EP 496S DI 10.1378/chest.116.suppl_3.493S PG 4 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 268AE UT WOS:000084390800015 PM 10619517 ER PT J AU Espada, R Rodarte, J Miller, C Barnard, C Carter, J DuBose, K Flanigan, T Fox, P Haddad, J Hale, K Hood, E Jahn, A King, K Nguyen, C Norman, S Officer, T Reardon, M Ricketts, J Sax, S Tucker, M Williams, K Reilly, J Sugarbaker, D Fanning, C Birkenmaier, K Body, S Catanzano, C Duffy, S Formanek, V Fuhlbrigge, A Hartigan, P Hunsaker, A Jacobson, F Mark, L Russell, R Saunders, D Simons, G Swanson, S McKenna, R Mohsenifar, Z Geaga, C Aberle, D Brown, J Clark, S Cooper, C Ferrill, R Frantz, R Gelb, A Goldin, J Gordon, J Head, D Joyner, M Julien, P Levine, M Lewis, M Pendio, M Silverman, J Walker, P Williams, B Yegyan, V Yoou, C Maurer, J De Camp, M Meli, Y Aviv, L Hearn, C Kraenzler, E Marlow, S McCarthy, K Mehta, A Meziane, M O'Donovan, P Schilz, R Sullivan, E Ginsburg, M Scharf, S Jellen, P Asegu, A Austin, J Bartels, M Berkman, Y Berkoski, P Brogan, F Delphin, E Demercado, G DiMango, A DePrisco, L Gonzales, J Gotthelf, J Herman, P Khan, A Mantinaos, M McKeon, K Mets, B Pearson, G Pfeffer, J Rossoff, L Sunshine, A Simonelli, P Stavrolakes, K Thomashow, B Vilotijevic, D Yip, C MacIntyre, N Davis, RD Howe, J Crouch, R Grichnik, K Harpole, D Krichman, A Lawlor, B McAdams, H Norten, J Rinaldo-Gallo, S Steele, M Tapson, V Hubmayr, R Deschamps, C Bartling, S Aughenbaugh, G Bradt, K Edgar, M Elliott, B Edell, E Garrett, J Hanson, K Hanson, L Harms, G Hartman, T Kalra, S Karsell, P Midthun, D Miller, D Mottram, C Odenbrett, K Swensen, S Sykes, AM Torres, N Utz, J Cherniack, R Make, B Gilmartin, M Buquor, B Canterbury, J Carlos, M Chetham, P Fernandez, E Geyman, L Lynch, D Newell, J Pomerantz, M Raymond, C Safilian, B Tolliver, R Whalen-Price, J Winner, K Zamora, M Diaz, P Ross, P Kelsey, M Dinant, S King, M Harter, R Mikelinich, E Rittenger, D Shaffer, S Naunheim, K Keller, C Osterloh, J Alvarez, F Borosh, S Bowen, C Frese, S Glockner, J Heidberg, E Hibbett, A Kleinhenz, ME McCain, D Ruppel, G Turnage, S Criner, G Furukawa, S Kuzman, AM Barnette, R Boiselle, P Brester, N D'Alonzo, G Gilmartin, M Keresztury, M Kish, L Lautensack, K Leonard, E Leyenson, V Lorenzon, M O'Brien, G O'Grady, T Rising, P Schartel, S Travaline, J Ries, A Kaplan, R Ramirez, C Brewer, N Colt, H Crawford, S Frankville, D Friedman, P Johnson, J Kapelanski, D Larsen, C Limberg, T Magliocca, M Olson, L Papatheofanis, J Prewitt, L Resnikoff, P Sassi-Dambron, D Krasna, M Orens, J Moskowitz, I Altemus, M Bochicchio, D Britt, J Cook, L Fessler, H Gaetani, D Gheorghiu, I Gilbert, T Hasnain, J Kearney, A Kim, S King, K Markus, S Miller, N Schneider, R Shade, D Silver, K Smith, K Turner, BS Weir, C Wheeler, J White, C Martinez, F Iannettoni, M Meldrum, C Alexander, J Bria, W Campbell, K Christensen, P Foss, C Gill, P Kazanjian, P Kazerooni, E Knieper, V Lowenbergh, N Meldrum, M Miller, R Ojo, T Pergentili, D Poole, L Qunt, L Rysso, P Spear, M True, M Woodcock, B Kaiser, L Hansen-Flaschen, J Wurster, A Alavi, A Alcorn, T Aronchick, J Arcasoy, S Aukberg, S Benedict, B Craemer, S Edelman, J Gefter, W Kotler-Klein, L Kotloff, R Manaker, S Mendez, J Miller, W Miller, W Palevsky, H Russell, W Simcox, R Snedeker, S Tino, G Keenan, R Sciurba, F George, E Ayres, G Bauldoff, G Brown, M Costello, P Donahoe, M Fuhrman, C Hoffman, R Holbert, M Johnson, P Kopp, T Lacomis, J Sexton, J Silfies, L Slivka, W Stroll, D Sullivan, E Tullock, W Benditt, J Wood, D Snyder, M Anable, K Battaglia, N Boitanao, L Bowdle, A Chan, L Chwalik, C Culver, B Godwin, D Golden, S Ibrahim, A Lockhart, D Marglin, S McDowell, P Nellum, K Van Norman, G Bosco, L Chiang, YP Clancy, C Handelsman, H Piantadosi, S Tonascia, J Belt, P Collins, K Collison, B Dawson, C Dawson, D Donithan, M Edmonds, V Harle, J Jackson, R Lee, S Levine, C Meinert, J Nowakowski, D Reshef, D Smith, M Simon, B Sternberg, A Van Natta, M Wise, R Kaplan, RM Chaing, YP Fahs, MC Fendrick, AM Moskowitz, AJ Pathak, D Ramsey, SD Richter, E Schwartz, JS Sheingold, S Shroyer, AL Wagner, J Yusen, R Waldhausen, J Bernard, G DeMets, D Hoover, E Levine, R Mahler, D McSweeney, AJ Wiener-Kronish, J Williams, OD Younes, M Sheingold, S McVearry, K Mone, C Proctor-Young, J Fishman, AP Weinmann, G Deshler, J Albert, P Hurd, S Kiley, J Wu, M AF Espada, R Rodarte, J Miller, C Barnard, C Carter, J DuBose, K Flanigan, T Fox, P Haddad, J Hale, K Hood, E Jahn, A King, K Nguyen, C Norman, S Officer, T Reardon, M Ricketts, J Sax, S Tucker, M Williams, K Reilly, J Sugarbaker, D Fanning, C Birkenmaier, K Body, S Catanzano, C Duffy, S Formanek, V Fuhlbrigge, A Hartigan, P Hunsaker, A Jacobson, F Mark, L Russell, R Saunders, D Simons, G Swanson, S McKenna, R Mohsenifar, Z Geaga, C Aberle, D Brown, J Clark, S Cooper, C Ferrill, R Frantz, R Gelb, A Goldin, J Gordon, J Head, D Joyner, M Julien, P Levine, M Lewis, M Pendio, M Silverman, J Walker, P Williams, B Yegyan, V Yoou, C Maurer, J De Camp, M Meli, Y Aviv, L Hearn, C Kraenzler, E Marlow, S McCarthy, K Mehta, A Meziane, M O'Donovan, P Schilz, R Sullivan, E Ginsburg, M Scharf, S Jellen, P Asegu, A Austin, J Bartels, M Berkman, Y Berkoski, P Brogan, F Delphin, E Demercado, G DiMango, A DePrisco, L Gonzales, J Gotthelf, J Herman, P Khan, A Mantinaos, M McKeon, K Mets, B Pearson, G Pfeffer, J Rossoff, L Sunshine, A Simonelli, P Stavrolakes, K Thomashow, B Vilotijevic, D Yip, C MacIntyre, N Davis, RD Howe, J Crouch, R Grichnik, K Harpole, D Krichman, A Lawlor, B McAdams, H Norten, J Rinaldo-Gallo, S Steele, M Tapson, V Hubmayr, R Deschamps, C Bartling, S Aughenbaugh, G Bradt, K Edgar, M Elliott, B Edell, E Garrett, J Hanson, K Hanson, L Harms, G Hartman, T Kalra, S Karsell, P Midthun, D Miller, D Mottram, C Odenbrett, K Swensen, S Sykes, AM Torres, N Utz, J Cherniack, R Make, B Gilmartin, M Buquor, B Canterbury, J Carlos, M Chetham, P Fernandez, E Geyman, L Lynch, D Newell, J Pomerantz, M Raymond, C Safilian, B Tolliver, R Whalen-Price, J Winner, K Zamora, M Diaz, P Ross, P Kelsey, M Dinant, S King, M Harter, R Mikelinich, E Rittenger, D Shaffer, S Naunheim, K Keller, C Osterloh, J Alvarez, F Borosh, S Bowen, C Frese, S Glockner, J Heidberg, E Hibbett, A Kleinhenz, ME McCain, D Ruppel, G Turnage, S Criner, G Furukawa, S Kuzman, AM Barnette, R Boiselle, P Brester, N D'Alonzo, G Gilmartin, M Keresztury, M Kish, L Lautensack, K Leonard, E Leyenson, V Lorenzon, M O'Brien, G O'Grady, T Rising, P Schartel, S Travaline, J Ries, A Kaplan, R Ramirez, C Brewer, N Colt, H Crawford, S Frankville, D Friedman, P Johnson, J Kapelanski, D Larsen, C Limberg, T Magliocca, M Olson, L Papatheofanis, J Prewitt, L Resnikoff, P Sassi-Dambron, D Krasna, M Orens, J Moskowitz, I Altemus, M Bochicchio, D Britt, J Cook, L Fessler, H Gaetani, D Gheorghiu, I Gilbert, T Hasnain, J Kearney, A Kim, S King, K Markus, S Miller, N Schneider, R Shade, D Silver, K Smith, K Turner, BS Weir, C Wheeler, J White, C Martinez, F Iannettoni, M Meldrum, C Alexander, J Bria, W Campbell, K Christensen, P Foss, C Gill, P Kazanjian, P Kazerooni, E Knieper, V Lowenbergh, N Meldrum, M Miller, R Ojo, T Pergentili, D Poole, L Qunt, L Rysso, P Spear, M True, M Woodcock, B Kaiser, L Hansen-Flaschen, J Wurster, A Alavi, A Alcorn, T Aronchick, J Arcasoy, S Aukberg, S Benedict, B Craemer, S Edelman, J Gefter, W Kotler-Klein, L Kotloff, R Manaker, S Mendez, J Miller, W Miller, W Palevsky, H Russell, W Simcox, R Snedeker, S Tino, G Keenan, R Sciurba, F George, E Ayres, G Bauldoff, G Brown, M Costello, P Donahoe, M Fuhrman, C Hoffman, R Holbert, M Johnson, P Kopp, T Lacomis, J Sexton, J Silfies, L Slivka, W Stroll, D Sullivan, E Tullock, W Benditt, J Wood, D Snyder, M Anable, K Battaglia, N Boitanao, L Bowdle, A Chan, L Chwalik, C Culver, B Godwin, D Golden, S Ibrahim, A Lockhart, D Marglin, S McDowell, P Nellum, K Van Norman, G Bosco, L Chiang, YP Clancy, C Handelsman, H Piantadosi, S Tonascia, J Belt, P Collins, K Collison, B Dawson, C Dawson, D Donithan, M Edmonds, V Harle, J Jackson, R Lee, S Levine, C Meinert, J Nowakowski, D Reshef, D Smith, M Simon, B Sternberg, A Van Natta, M Wise, R Kaplan, RM Chaing, YP Fahs, MC Fendrick, AM Moskowitz, AJ Pathak, D Ramsey, SD Richter, E Schwartz, JS Sheingold, S Shroyer, AL Wagner, J Yusen, R Waldhausen, J Bernard, G DeMets, D Hoover, E Levine, R Mahler, D McSweeney, AJ Wiener-Kronish, J Williams, OD Younes, M Sheingold, S McVearry, K Mone, C Proctor-Young, J Fishman, AP Weinmann, G Deshler, J Albert, P Hurd, S Kiley, J Wu, M CA Natl Emphysema Treatment Trial Res TI Rationale and design of the National Emphysema Treatment Trial - A prospective randomized trial of lung volume reduction surgery SO CHEST LA English DT Article DE emphysema; lung function; lung volume reduction surgery; maximum exercise capacity; median sternotomy; medical vs surgical treatment; pulmonary rehabilitation; randomized clinical trial; video-assisted thoracoscopic surgery ID OBSTRUCTIVE PULMONARY-DISEASE; QUESTIONNAIRE; METAANALYSIS; HEALTH; COPD AB The National Emphysema Treatment Trial is a multicenter, randomized clinical trial of medical therapy vs medical therapy plus lung volume reduction surgery (LVRS) for the treatment of patients with severe bilateral emphysema. LVRS will he accomplished by bilateral nl stapled excision via median sternotomy or video-assisted thoracoscopic surgery. Every patient will complete 6 to 10 weeks of pulmonary rehabilitation prior to randomization anti will participate in a maintenance program of pulmonary rehabilitation after randomization, The primary outcome to be assessed by the trial is survival. Additional outcomes to be assessed are maximum exercise capacity, pulmonary function, oxygen requirement, distance walked in 6 min, quality of life, respiratory symptoms, and health-care utilization and costs, In addition, selected clinics will evaluate lung mechanics and respiratory muscle function, partial and maximal flow-volume curves, gas exchange during maximal exercise, and right heart function, The trial is targeted to enroll patients with severe emphysema who have no significant comorbid conditions; each patient will be randomized to one of the two treatment groups. The study duration is 4.5 years with a close-out period of 6 months. C1 Baylor Coll Med, Ctr Clin, Houston, TX 77030 USA. Brigham & Womens Hosp, Ctr Clin, Boston, MA 02115 USA. Cedars Sinai Med Ctr, Ctr Clin, Los Angeles, CA 90048 USA. Cleveland Clin Fdn, Ctr Clin, Cleveland, OH 44195 USA. Columbia Univ, Ctr Clin, New York, NY USA. Duke Univ, Med Ctr, Ctr Clin, Durham, NC 27706 USA. Mayo Clin & Mayo Fdn, Ctr Clin, Rochester, MN 55905 USA. Natl Jewish Med & Res Ctr, Ctr Clin, Denver, CO USA. Ohio State Univ, Ctr Clin, Columbus, OH 43210 USA. St Louis Univ, Ctr Clin, St Louis, MO 63103 USA. Temple Univ, Ctr Clin, Philadelphia, PA 19122 USA. Univ Calif San Diego, Ctr Clin, San Diego, CA 92103 USA. Univ Maryland, Ctr Clin, Baltimore, MD 21201 USA. Univ Michigan, Ctr Clin, Ann Arbor, MI 48109 USA. Univ Penn, Ctr Clin, Philadelphia, PA 19104 USA. Univ Pittsburgh, Ctr Clin, Pittsburgh, PA 15260 USA. Univ Washington, Ctr Clin, Seattle, WA 98195 USA. US Dept HHS, Agcy Hlth Care Policy & Res, Rockville, MD 20852 USA. Johns Hopkins Univ, Coordinating Ctr, Baltimore, MD 21218 USA. US Hlth Care Financing Adm, Baltimore, MD 21207 USA. Univ Penn, Off Chair Steering Comm, Philadelphia, PA 19104 USA. NHLBI, Project Off, Bethesda, MD 20892 USA. RP Espada, R (reprint author), Johns Hopkins Sch Hyg & Publ Hlth, Johns Hopkins Ctr Clin Trials, Natl Emphysema Treatement Trial Coordinat Ctr, Room 5010,615 N Wolfe St, Baltimore, MD 21205 USA. NR 40 TC 113 Z9 113 U1 1 U2 14 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD DEC PY 1999 VL 116 IS 6 BP 1750 EP 1761 PG 12 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 266HC UT WOS:000084293700039 ER PT J AU Slonim, AD Ognibene, FP AF Slonim, AD Ognibene, FP TI Amnestic agents in pediatric bronchoscopy SO CHEST LA English DT Article DE anesthesia; BAL; bronchoscopy; complications; fentanyl; ketamine; midazolam; pediatrics; procedures; pulmonary disease; sedation ID FLEXIBLE FIBEROPTIC BRONCHOSCOPY; INTENSIVE-CARE UNIT; BRONCHOALVEOLAR LAVAGE; INTRAVENOUS MIDAZOLAM; KETAMINE SEDATION; CHILDREN; ENDOSCOPY; INFANTS; MANAGEMENT; DIAGNOSIS AB Study objective: To assess the risk for complications with the use of sedation and analgesia techniques in pediatric fiberoptic bronchoscopy. Design: A retrospective case series, Setting: The ICU of a 325-bed tertiary care research hospital. Patients: Patients from 1 to 18 years of age who underwent fiberoptic bronchoscopy with BAL or transbronchial biopsy between June 1991 and December 1995 and received IV sedation and analgesia. Interventions: None. Methods: A retrospective chart review was performed. Extracted data included anesthetics and sedatives used and their pel kilogram dosages, procedure durations, and complications including oxygen desaturations < 90%, vital sign alterations that required intervention, and emergence reactions to ketamine, Results: A total of 103 bronchoscopies were performed on 64 patients, Ketamine was used as die primary anesthetic in GO procedures (58%). A combination of fentanyl and midazolam nas used in 38 of the 43 remaining procedures, A variety of combinations were used in the five remaining procedures, Complications occurred in 13 procedures and included oxygen desaturations, stridor, cough, apnea, and nasal bleeding, Twelve of the 13 complications occurred in patients with a diagnosis of HIV infection, Eight of the 13 complications involved children less than or equal to 3 years of age. Conclusions: Pediatric bronchoscopy is a safe and valuable procedure. However, in this study, anesthetic selection was shown to adversely affect the complication rate in the subsets of children less than or equal to 3 cars of age and with an underlying diagnosis of HIV infection. C1 NIH, Dept Crit Care Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Ognibene, FP (reprint author), NIH, Dept Crit Care Med, Warren G Magnuson Clin Ctr, Bldg 10,Room 7D43,10 Ctr Dr MSC 1662, Bethesda, MD 20892 USA. RI Andrade, Hugo/M-6631-2013 OI Andrade, Hugo/0000-0001-6781-6125 NR 50 TC 26 Z9 29 U1 0 U2 1 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD DEC PY 1999 VL 116 IS 6 BP 1802 EP 1808 DI 10.1378/chest.116.6.1802 PG 13 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 266HC UT WOS:000084293700046 PM 10593809 ER PT J AU Kopelovich, L Henson, DE Gazdar, AF Dunn, B Srivastava, S Kelloff, GJ Greenwald, P AF Kopelovich, L Henson, DE Gazdar, AF Dunn, B Srivastava, S Kelloff, GJ Greenwald, P TI Surrogate anatomic/functional sites for evaluating cancer risk: An extension of the field effect SO CLINICAL CANCER RESEARCH LA English DT Editorial Material ID CARCINOMA IN-SITU; MICROSATELLITE ALTERATIONS; BREAST-CANCER; INTRAEPITHELIAL NEOPLASIA; PREMALIGNANT LESIONS; OVARIAN-CARCINOMA; SEROUS CARCINOMA; PAGETS-DISEASE; CLONAL ORIGIN; CHROMOSOME 3P C1 NCI, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dept Pathol, Dallas, TX 75235 USA. Univ Texas, SW Med Ctr, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75235 USA. RP Kopelovich, L (reprint author), NCI, Div Canc Prevent, NIH, EPN Room 201,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kopelovich@nih.gov NR 65 TC 27 Z9 27 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC PY 1999 VL 5 IS 12 BP 3899 EP 3905 PG 7 WC Oncology SC Oncology GA 267TR UT WOS:000084375800001 PM 10632318 ER PT J AU Lange, EM Chen, H Brierley, K Perrone, EE Bock, CH Gillanders, E Ray, ME Cooney, KA AF Lange, EM Chen, H Brierley, K Perrone, EE Bock, CH Gillanders, E Ray, ME Cooney, KA TI Linkage analysis of 153 prostate cancer families over a 30-cM region containing the putative susceptibility locus HPCX SO CLINICAL CANCER RESEARCH LA English DT Article ID DOMINANT INHERITANCE; CHROMOSOME; SWEDEN AB Several genetic epidemiological studies have provided data to support the hypothesis that there are genes on the X chromosome that may contribute to prostate cancer susceptibility. A recent linkage study of 360 prostate cancer families described evidence for a prostate cancer predisposition gene, termed HPCX, which maps to Xq27-28, To confirm the potential contribution of this locus to prostate cancer susceptibility in an independent dataset, we studied 153 unrelated families who are participants in the University of Michigan Prostate Cancer Genetics Project. Families selected for this analysis have at least two living family members with prostate cancer that are related in a way that they could potentially share a common ancestral copy of an X chromosome. DNA samples were genotyped using a panel of seven polymorphic markers spanning 30 cM and containing the HPCX candidate region. The resulting data were analyzed using both nonparametric and parametric linkage methods. Analysis of all 153 families using multipoint nonparametric linkage (NPL) methods resulted in positive NPL Z-scores across the entire candidate interval (NPL Z-scores of 0.23-1.06, with corresponding one-sided Ps of 0.41 and 0.15, respectively). The 11 African-American families had negative NPL Z-scores across the same 30-cM interval. Analysis of the 140 Caucasian families produced a maximal NPL Z-score of 1.20, with a corresponding one-sided P of 0.12 at marker DXS1113, The subset of families with no evidence of male-to-male disease transmission and with early-onset prostate cancer (average age at diagnosis within a family less than or equal to 65 years) contributed disproportionately to the evidence for linkage for the entire dataset in the HPCX candidate region (near marker DXS1113), In conclusion, this study of 153 families, each with two or more living members with prostate cancer, provides some additional support for the existence of a prostate cancer susceptibility gene at Xq27-28. C1 Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Michigan, Sch Med, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. Univ Michigan, Sch Med, Dept Surg, Ann Arbor, MI 48109 USA. Dept Vet Affairs Med Ctr, Ann Arbor, MI 48109 USA. Natl Human Genome Res Inst, Canc Genet Branch, Bethesda, MD 20892 USA. RP Cooney, KA (reprint author), 7310 CCGC,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. FU NCI NIH HHS [P50 CA69568] NR 24 TC 76 Z9 76 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC PY 1999 VL 5 IS 12 BP 4013 EP 4020 PG 8 WC Oncology SC Oncology GA 267TR UT WOS:000084375800016 PM 10632333 ER PT J AU Kubo, A Nakagawa, K Varma, RK Conrad, NK Cheng, JQ Lee, WC Testa, JR Johnson, BE Kaye, FJ Kelley, MJ AF Kubo, A Nakagawa, K Varma, RK Conrad, NK Cheng, JQ Lee, WC Testa, JR Johnson, BE Kaye, FJ Kelley, MJ TI The p16 status of tumor cell lines identifies small molecule inhibitors specific for cyclin-dependent kinase 4 SO CLINICAL CANCER RESEARCH LA English DT Article ID ANTICANCER DRUG SCREEN; RETINOBLASTOMA-PROTEIN; LUNG-CANCER; CDC2 KINASE; P16(INK4); CDK6; GROWTH; RB; BRYOSTATIN-1; INACTIVATION AB Loss of p16 functional activity leading to disruption of the p16/cyclin-dependent kinase (CDK) 4:cyclin D/retinoblastoma pathway is the most common event in human tumorigenesis, suggesting that compounds with CDK4 kinase inhibitory activity may be useful to regulate cancer cell growth. To identify such inhibitors, the 60 cancer cell lines of the National Cancer Institute drug screen panel were examined for p16 alterations (biallelic deletion, intragenic mutations, or absent p16 protein), and the growth-inhibitory activity of more than 50,000 compounds against these 60 cell lines was compared with their p16 status. One compound, 3-amino thioacridone (3-ATA; NSC 680434), whose growth-inhibitory activity correlated with the p16 status of the cell lines had an IC50 of 3.1 mu M in a CDK4 kinase assay. In addition, four compounds structurally related to 3-ATA inhibited CDK4 kinase with IC(50)s ranging from 0.2-2.0 mu M. All five of these compounds were less potent inhibitors of cell division cycle 2 and CDK2 kinases, with IC(50)s 30- to 500-fold higher than that for CDK4. ATP competition experiments demonstrated a noncompetitive mode of inhibition for 3-ATA (K-i = 5.5 mu M) and a linear mixed mode for benzothiadiazine (NSC 645787; K-i = 0.73 mu M). We have successfully demonstrated a novel approach to identify specific CDK4 kinase inhibitors that may selectively induce growth inhibition of p16-altered tumors. C1 Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Fox Chase Canc Ctr, Dept Med Oncol, Philadelphia, PA 19111 USA. NCI, Med Branch, Bethesda, MD 20889 USA. NCI, Dev Therapeut Program, Bethesda, MD 20889 USA. RP Kelley, MJ (reprint author), Duke Univ VA Hosp, 508 Fulton St, Durham, NC 27705 USA. RI kaye, frederic/E-2437-2011; OI Kelley, Michael/0000-0001-9523-6080 FU PHS HHS [6S-1602] NR 37 TC 51 Z9 53 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC PY 1999 VL 5 IS 12 BP 4279 EP 4286 PG 8 WC Oncology SC Oncology GA 267TR UT WOS:000084375800054 PM 10632371 ER PT J AU Csako, G AF Csako, G TI Mesna and other free-sulfhydryl compounds produce false-positive results in a urine test strip method for ascorbic acid SO CLINICAL CHEMISTRY LA English DT Letter ID KETONE C1 NIH, Warren G Magnuson Clin Ctr, Dept Clin Pathol, Clin Chem Serv, Bethesda, MD 20892 USA. RP Csako, G (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Clin Pathol, Clin Chem Serv, Bldg 10,Rm 2C-407, Bethesda, MD 20892 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD DEC PY 1999 VL 45 IS 12 BP 2295 EP 2296 PG 2 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 262MQ UT WOS:000084071400044 PM 10585377 ER PT J AU Janik, JE Miller, LL Kopp, WC Taub, DD Dawson, H Stevens, D Kostboth, P Curti, BD Conlon, KC Dunn, BK Donegan, SE Ullrich, R Alvord, WG Gause, BL Longo, DL AF Janik, JE Miller, LL Kopp, WC Taub, DD Dawson, H Stevens, D Kostboth, P Curti, BD Conlon, KC Dunn, BK Donegan, SE Ullrich, R Alvord, WG Gause, BL Longo, DL TI Treatment with tumor necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor increases epidermal Langerhans' cell numbers in cancer patients SO CLINICAL IMMUNOLOGY LA English DT Article ID IMMUNOSTIMULATORY DENDRITIC CELLS; HEMATOPOIETIC PROGENITOR CELLS; C-KIT-LIGAND; ANTITUMOR IMMUNE-RESPONSES; CYTOTOXIC T-LYMPHOCYTES; BONE-MARROW PRECURSORS; GENERATED IN-VITRO; HUMAN BLOOD; TNF-ALPHA; NONLYMPHOID TISSUES AB Dendritic cells (DCs) initiate primary and stimulate secondary T-cell responses. We conducted a phase I trial of tumor necrosis factor (TNF-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with cancer to increase DCs in peripheral blood or skin based on in vitro data that showed that CD34(+) hematopoietic precursors require these cytokines to mature into functional antigen-presenting DCs. Eleven patients mere treated for 7 days with GM-CSF, 125 mu g/m(2) twice daily as subcutaneous injections, and TNF-alpha as a continuous infusion at dose levels of 25, 50, or 100 mu g/m(2)/day. The maximum tolerated dose of TNF-alpha was 50 mu g/m(2)/day with this dose of GM-CSF; dose-limiting toxicities occurred in both patients treated with 100 mu g/m(2)/day. One became thrombocytopenic and the other had transient confusion. Epidermal Langerhans' cells were quantitated by S100 staining of skin biopsies and DC precursors in peripheral blood by colony-forming unit dendritic (CFU-dendritic) assays. S100-positive cells in the epidermis doubled after treatment (2.55 S100(+) cells/high-powerheld before treatment to 6.05 after treatment, p = 0.029). CFU-dendritic in peripheral blood increased after treatment in 3 colorectal cancer patients but not in 3 patients with melanoma. CD11c(+) or CD123(+), HLA-DRbright, lineage-negative dendritic cell precursors were not increased in peripheral blood mononuclear cells. This trial demonstrates that treatment with TNF-alpha and GM-CSF can increase the number of DCs in the skin and the number of dendritic cell precursors in the blood of some patients with cancer. This approach may increase the efficacy of vaccination to tumor antigens in cancer patients. C1 NCI, Frederick Canc Res & Dev Ctr, Biol Response Modifiers Programme, Frederick, MD 21701 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Clin Serv Program, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Data Management Serv Inc, Frederick, MD 21702 USA. Reeders Mem Home, Boonsboro, MD USA. Frederick Mem Hosp, Frederick, MD 21701 USA. USA, Med Res Inst Infect Dis, Dept Immunol & Mol Biol, Ft Detrick, MD 21702 USA. RP Janik, JE (reprint author), NCI, Frederick Canc Res & Dev Ctr, Biol Response Modifiers Programme, 501 W 7th St,Suite 3, Frederick, MD 21701 USA. RI Dawson, Harry/H-8242-2013 NR 54 TC 21 Z9 22 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 DEC PY 1999 VL 93 IS 3 BP 209 EP 221 DI 10.1006/clim.1999.4778 PG 13 WC Immunology SC Immunology GA 263VC UT WOS:000084145100004 PM 10600331 ER PT J AU Shalev, M Ko, A Gelderman, MP Fortin, E Reed, G Slavin, S Gery, I AF Shalev, M Ko, A Gelderman, MP Fortin, E Reed, G Slavin, S Gery, I TI Multiformic modulation of endotoxin effects by linomide SO CLINICAL IMMUNOLOGY LA English DT Article DE linomide, effects of; endotoxin, effects of; cytokines, production of; inflammation, ocular; immunomodulation, by drugs ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; INDUCED UVEITIS; MULTIPLE-SCLEROSIS; IMMUNOMODULATOR LINOMIDE; DOWN-REGULATION; ANTIINFLAMMATORY CYTOKINES; MYASTHENIA-GRAVIS; GENE-EXPRESSION; RAT; INHIBITION AB Linomide is a potent immunomodulator that either enhances or suppresses certain immunological processes. Of particular interest is this compound's capacity to inhibit a variety of organ-specific autoimmune diseases. Here, we report on the effects of linomide on several immunological reactions elicited by endotoxin (LPS), both in vivo and in vitro. In rats and mice linomide inhibited the elicitation of endotoxin-induced uveitis (EIU), an acute inflammatory eye disease that develops within 24 h following footpad injection of LPS. Linomide also inhibited the production of TNF-alpha and IL-6 by LPS-stimulated rat and mouse macrophage monolayers. On the other hand, treatment with linomide significantly increased the levels of IL-1 beta (mice and less in rats), IL-6 (rats), and TNF-LU (mice) in serum samples collected 2 h following injection with LPS. The increased production of proinflammatory cytokines in linomide-treated mice was also indicated by the enhanced lethal effect of LPS in these mice. The finding of elevated levels of these cytokines in animals with suppressed EIU is also in line with previous observations of an inverse relationship between EIU severity and levels of TNF-alpha. Data recorded here underscore the unique capacity of linomide to both enhance and suppress the immune system. (C) 1999 Academic Press. C1 NEI, NIH, Bethesda, MD 20892 USA. Hadassah Univ Hosp, IL-91120 Jerusalem, Israel. RP Gery, I (reprint author), NEI, NIH, Bldg 10,Room 10N112, Bethesda, MD 20892 USA. NR 34 TC 3 Z9 4 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 DEC PY 1999 VL 93 IS 3 BP 250 EP 255 DI 10.1006/clim.1999.4800 PG 6 WC Immunology SC Immunology GA 263VC UT WOS:000084145100009 PM 10600336 ER PT J AU Rex, JH Walsh, TJ AF Rex, JH Walsh, TJ TI Editorial response: Estimating the true cost of amphotericin B SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID ACUTE-RENAL-FAILURE; CRYPTOCOCCOSIS; AMBISOME; EFFICACY C1 Univ Texas, Sch Med, Ctr Study Emerging & Reemerging Pathogens, Dept Internal Med,Div Infect Dis, Houston, TX USA. NCI, Pediat Oncol Branch, Immunocompromised Host Sect, Bethesda, MD 20892 USA. RP Rex, JH (reprint author), 6431 Fannin,1728 JFB, Houston, TX 77030 USA. NR 18 TC 25 Z9 25 U1 0 U2 0 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 DEC PY 1999 VL 29 IS 6 BP 1408 EP 1410 DI 10.1086/313555 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 273DW UT WOS:000084693400016 PM 10585787 ER PT J AU Kimko, HC Cross, JT Abernethy, DR AF Kimko, HC Cross, JT Abernethy, DR TI Pharmacokinetics and clinical effectiveness of methylphenidate SO CLINICAL PHARMACOKINETICS LA English DT Review ID DEFICIT-HYPERACTIVITY DISORDER; DL-THREO-METHYLPHENIDATE; SUSTAINED-RELEASE METHYLPHENIDATE; STIMULANT DRUG-ACTION; SOCIAL-BEHAVIOR; ENANTIOSELECTIVE PHARMACOKINETICS; ACADEMIC-PERFORMANCE; RITALINIC ACID; CHILDREN; ENANTIOMERS AB Methylphenidate is prescribed for over 90% of children in the US diagnosed as having attention-deficit hyperactivity disorder (ADHD). Although ADHD has been widely studied, the use of methylphenidate in ADHD still poses a number of unresolved questions, including its pharmacodynamic characteristics (drug concentration-effect relationship) and the effect of long term treatment on the patient's psychopathology later in life. The objective of this review is to provide an analysis of the pharmacokinetic-pharmacodynamic properties and therapeutic effectiveness of methylphenidate that may help to answer some of these questions. Methylphenidate has 2 chiral centres, but the drug used in therapy comprises only the three pair of enantiomers. d-threo-Methylphenidate is more potent than the l-enantiomer. Methylphenidate is administered as a racemic mixture that undergoes stereoselective clearance. Methylphenidate is a short-acting stimulant with a duration of action of 1 to 4 hours and a pharmacokinetic half-life of 2 to 3 hours. Maximum drug concentration after oral administration occurs at about 2 hours. Methylphenidate is absorbed well from the gastrointestinal tract and easily passes to the brain. Methylphenidate is efficacious for short term treatment for children with ADHD. Its mechanism of action is not understood, but may be associated with its influence on multiple neurotransmitters, especially the release and reuptake of dopamine in the striatum. There is marked individual variability in the dose-response relationship for methylphenidate. and therefore dosage must be titrated for optimal effect and avoidance of toxicity in each child. It is unclear whether this variability is predominantly pharmacokinetic or pharmacodynamic. If variable stereoselective metabolism occurs clinically, therapeutic drug monitoring of methylphenidate will require the application of chiral assay methods fur the analysis of the active component, d-threo-methylphenidate. It is difficult to predict which children will have a favourable response to methylphenidate, Nonetheless, several studies have been published linking the severity of ADHD in children with improved clinical response to methylphenidate. Thr use of individual single-blind medication trials may be practical solution to this problem. Additionally, the targeted condition warrants careful consideration, since different conditions (e.g.f misbehaviour or poor academic performance) may require different regimens. Further studies of the relationship between the pharmacokinetic and pharmacodynamic properties of methylphenidate are required to allow the development of optimal dosage regimens. C1 Georgetown Univ, Med Ctr, Ctr Drug Dev Sci, Dept Pharmacol, Washington, DC 20007 USA. NIA, Gerontol Res Ctr, Lab Clin Investigat, Baltimore, MD 21224 USA. RP Kimko, HC (reprint author), Georgetown Univ, Med Ctr, Ctr Drug Dev Sci, Dept Pharmacol, Room NE405,Med Dent Bldg,3900 Reservoir Rd NW, Washington, DC 20007 USA. NR 75 TC 156 Z9 158 U1 4 U2 28 PU ADIS INTERNATIONAL LTD PI AUCKLAND PA 41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 10, NEW ZEALAND SN 0312-5963 J9 CLIN PHARMACOKINET JI Clin. Pharmacokinet. PD DEC PY 1999 VL 37 IS 6 BP 457 EP 470 DI 10.2165/00003088-199937060-00002 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 269PL UT WOS:000084486700002 PM 10628897 ER PT J AU Donahue, S Flockhart, DA Abernethy, DR AF Donahue, S Flockhart, DA Abernethy, DR TI Ticlopidine inhibits phenytoin clearance SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID CLINICAL PHARMACOKINETICS; METABOLISM; P4502C19 AB Because cases of phenytoin toxicity during concomitant ticlopidine therapy have been reported, we investigated the effects of multiple doses of ticlopidine on phenytoin pharmacokinetics in six patients receiving phenytoin monotherapy, Two steady-state dosing rate and serum phenytoin minimum concentration (C-min) pairs were obtained for each patient administered oral phenytoin alone, then phenytoin plus 250 mg ticlopidine twice daily. All patients had serum C-min ticlopidine values of 0.06 to 0.25 mu g/mL when receiving ticlopidine, Individual pharmacokinetic parameters for phenytoin were calculated. The Michaelis-Menten constant (K-m) was determined as the slope and maximum velocity (V-max; equivalent to the maximal rate of elimination or the maximum daily dose that can be metabolized) as the y-intercept of the Linear Michaelis-Menten plot. Mean phenytoin K-m significantly increased from 5.8 to 12.3 during ticlopidine coadministration compared with administration of phenytoin alone (P = .02), Mean phenytoin V-max was not significantly changed by the coadministration of ticlopidine. These data indicate that ticlopidine inhibits the clearance and alters the clinical pharmacokinetics of phenytoin so that dosage adjustment of phenytoin should be considered when ticlopidine is coadministered, The results are consistent with previous human liver microsome findings that ticlopidine is a potent inhibitor of CYP2C19, a P450 isozyme that is significantly responsible for phenytoin metabolism. C1 Georgetown Univ, Sch Med, Div Clin Pharmacol, Washington, DC USA. RP Abernethy, DR (reprint author), NIA, Clin Invest Lab, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. FU NIA NIH HHS [AG-08226-07]; NIGMS NIH HHS [GM-08386-08] NR 18 TC 14 Z9 16 U1 0 U2 0 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD DEC PY 1999 VL 66 IS 6 BP 563 EP 568 DI 10.1053/cp.1999.v66.103277001 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 267TQ UT WOS:000084375700003 PM 10613611 ER PT J AU Kassoff, A Kieval, S Mehu, M Buehler, J Eglow, M Kaufman, F Margherio, RR Cox, MS Garretson, B Hassan, T Ruby, A Trese, MT Werner, JC Williams, GA Regan, V Manatrey, P Cumming, K Zajechowski, M Falk, R Streasick, P Szydlowski, L Dreyer, RF Ma, C Beardsley, C Crider, H Capone, A Aaberg, TM Martin, D Saperstein, D Sternberg, P Curtis, L Stribling, B Gilman, J Myles, B Swords, R Orth, DH Flood, TP Civantos, J deBustros, S Packo, KH MacLeod, C Morrison, C Bryant, DA Doherty, D Sandoval, S Seddon, JM Pinnolis, MK Jones-Devonish, DA Crouse, VD Snow, KK Evans, C Davis, N Callahan, C Walsh, D Dubois, J Burton, I Ferris, FL Chew, EY Csaky, K McCarthy, SA Dabas, KH Goodman, L Kim, YJ Lopez, P Mercer, R Ayres, LM LaRean, T Randall, A Chicca, M Ciatto, PF Kuehl, E Kivitz, I Koutsandreas, D Friberg, TR Eller, A Gorin, MB Alexander, J Mack, B Bressler, SB Bressler, NM Cassel, G Goldberg, M Haller, JA Ratner, L Schachat, AP Sherman, SH Sunness, JS Schenning, S Sackett, C Cain, D Emmert, D George, T Wheeler, S Elman, MJ Ballinger, R Betancourt, A Glasser, D Lammlein, J Seff, R Shuman, M Starr, J Carrigan, A Ringrose, C Mathews, T Sotirakos, P Cain, T Chandra, SR Myers, FL Nork, TM Stevens, T Blodi, B Gottlieb, J Perkins, T Blatz, M Walker, W Harrison, B Knutson, G Krolnik, D Somers, G Davis, MD Klein, BEK Klein, R Hubbard, L Magli, YL Brickbauer, J Ansay, S Armstrong, J Neider, M Wabers, H Baliker, J Kastorff, L Laher, K Badal, D Geithman, PL Miner, KD King, WN Osterly, KR Dohm, KL Onofrey, JA Esser, B Hurtenback, C Fisher, MR Robinson, NL Reimers, J Miller, D Bowman, B Gunter, E Sowell, A Lindblad, AS Ederer, F Milton, RC Gensler, G Anand, R Entler, G Stine, E Berlin, SH Scholl, PR Mengers, SA Ferris, FL Chew, EY Sperduto, R Kurinij, N AF Kassoff, A Kieval, S Mehu, M Buehler, J Eglow, M Kaufman, F Margherio, RR Cox, MS Garretson, B Hassan, T Ruby, A Trese, MT Werner, JC Williams, GA Regan, V Manatrey, P Cumming, K Zajechowski, M Falk, R Streasick, P Szydlowski, L Dreyer, RF Ma, C Beardsley, C Crider, H Capone, A Aaberg, TM Martin, D Saperstein, D Sternberg, P Curtis, L Stribling, B Gilman, J Myles, B Swords, R Orth, DH Flood, TP Civantos, J deBustros, S Packo, KH MacLeod, C Morrison, C Bryant, DA Doherty, D Sandoval, S Seddon, JM Pinnolis, MK Jones-Devonish, DA Crouse, VD Snow, KK Evans, C Davis, N Callahan, C Walsh, D Dubois, J Burton, I Ferris, FL Chew, EY Csaky, K McCarthy, SA Dabas, KH Goodman, L Kim, YJ Lopez, P Mercer, R Ayres, LM LaRean, T Randall, A Chicca, M Ciatto, PF Kuehl, E Kivitz, I Koutsandreas, D Friberg, TR Eller, A Gorin, MB Alexander, J Mack, B Bressler, SB Bressler, NM Cassel, G Goldberg, M Haller, JA Ratner, L Schachat, AP Sherman, SH Sunness, JS Schenning, S Sackett, C Cain, D Emmert, D George, T Wheeler, S Elman, MJ Ballinger, R Betancourt, A Glasser, D Lammlein, J Seff, R Shuman, M Starr, J Carrigan, A Ringrose, C Mathews, T Sotirakos, P Cain, T Chandra, SR Myers, FL Nork, TM Stevens, T Blodi, B Gottlieb, J Perkins, T Blatz, M Walker, W Harrison, B Knutson, G Krolnik, D Somers, G Davis, MD Klein, BEK Klein, R Hubbard, L Magli, YL Brickbauer, J Ansay, S Armstrong, J Neider, M Wabers, H Baliker, J Kastorff, L Laher, K Badal, D Geithman, PL Miner, KD King, WN Osterly, KR Dohm, KL Onofrey, JA Esser, B Hurtenback, C Fisher, MR Robinson, NL Reimers, J Miller, D Bowman, B Gunter, E Sowell, A Lindblad, AS Ederer, F Milton, RC Gensler, G Anand, R Entler, G Stine, E Berlin, SH Scholl, PR Mengers, SA Ferris, FL Chew, EY Sperduto, R Kurinij, N CA Age-Related Eye Dis Study Res Grp TI The Age-Related Eye Disease Study (AREDS): Design implications AREDS report no. 1 SO CONTROLLED CLINICAL TRIALS LA English DT Article DE age-related macular degeneration; cataract; clinical trial; clinical course; antioxidants; zinc; vitamin C; vitamin E; beta-carotene ID DENSITY LIPOPROTEIN-CHOLESTEROL; SENILE MACULAR DEGENERATION; FAILURE TIME DATA; CARDIOVASCULAR-DISEASE; CLINICAL-TRIALS; BETA-CAROTENE; RISK-FACTORS; ZINC; SUPPLEMENTATION; MACULOPATHY AB The Age-Related Eye Disease Study (AREDS) was initially conceived as a long-term multicenter, prospective study of the clinical course of age-related macular degeneration (AMD) and age-related cataract. Data on progression rates and risk factors from the study will increase understanding of the clinical course of both conditions, generate hypotheses about etiology, and aid in the design of clinical trials of potential interventions. In addition to collecting natural history data, AREDS includes a clinical trial of high-dose vitamin and mineral supplements for AMD and a clinical trial of high-dose vitamin supplements for cataract. The clinical trials were initiated largely because of the widespread public use in the United States of commercially available pharmacologic doses of vitamins and minerals to treat these two eye conditions and the absence of definitive studies on the safety and efficacy of their use. Important design issues for the clinical trials include: defining cataract and AMD, estimating event rates, determining the type and dosage of vitamins and minerals to be tested for each condition, and identifying the parameters necessary for monitoring safety and efficacy. This paper describes the AREDS design, including the study rationale and operational structure, and the approach adopted to combine, for two diseases, clinical trials with a natural history study. (C) Elsevier Science Inc. 1999. C1 Devers Eye Inst, Portland, OR USA. Emory Univ, Atlanta, GA 30322 USA. Ingalls Mem Hosp, Harvey, IL USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. NEI, Ctr Clin, Bethesda, MD 20892 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. Univ Wisconsin, Reading Ctr, Madison, WI USA. Ctr Dis Control & Prevent, Cent Lab, Atlanta, GA USA. NEI, Project Off, Bethesda, MD 20892 USA. Natl Inst Hlth, Div Contracts & Grants, Bethesda, MD 20892 USA. Bausch & Lomb Pharmaceut, Rochester, NY 14601 USA. RP Lindblad, AS (reprint author), EMMES Corp, AREDS Coordinating Ctr, 11325 7 Locks Rd,Suite 214, Potomac, MD 20854 USA. NR 54 TC 178 Z9 180 U1 2 U2 17 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 EI 1879-050X J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD DEC PY 1999 VL 20 IS 6 BP 573 EP 600 PG 28 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 258LV UT WOS:000083841400009 ER PT J AU Pollack, MM Koch, MA Bartel, DA AF Pollack, MM Koch, MA Bartel, DA TI Good ICU management makes a difference: Managerial practices and organizational processes are related to severe morbidity SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 Acad Natl Med Ctr, Washington, DC USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. NIH, Nih de Neonatal Initiat Network, 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 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 1999 VL 27 IS 12 SU S MA 81 BP A43 EP A43 DI 10.1097/00003246-199912001-00081 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 276RX UT WOS:000084892100081 ER PT J AU Galperin, MY Koonin, EV AF Galperin, MY Koonin, EV TI Searching for drug targets in microbial genomes SO CURRENT OPINION IN BIOTECHNOLOGY LA English DT Review ID ESCHERICHIA-COLI O157-H7; LYME-DISEASE SPIROCHETE; COMPLETE DNA-SEQUENCE; YERSINIA-PESTIS KIM5; HELICOBACTER-PYLORI; BACTERIAL GENES; BORRELIA-BURGDORFERI; PATHOGENICITY; EVOLUTION; PLASMID AB Comparative analysis of the complete genome sequences of 10 bacterial pathogens available in the public databases offers the first insights into the drug discovery approaches of the near future. Genes that are conserved in different genomes often turn out to be essential, which makes them attractive targets for new broad-spectrum antibiotics. Subtractive genome analysis reveals the genes that are conserved in all or most of the pathogenic bacteria but not in eukaryotes; these are the most obvious candidates for drug targets. Species-specific genes, on the other hand, may offer the possibility to design drugs against a particular, narrow group of pathogens. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Galperin, MY (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RI Galperin, Michael/B-5859-2013 OI Galperin, Michael/0000-0002-2265-5572 NR 60 TC 84 Z9 94 U1 1 U2 1 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0958-1669 J9 CURR OPIN BIOTECH JI Curr. Opin. Biotechnol. PD DEC PY 1999 VL 10 IS 6 BP 571 EP 578 DI 10.1016/S0958-1669(99)00035-X PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 262VB UT WOS:000084087100009 PM 10600691 ER PT J AU Green, P Koonin, E AF Green, P Koonin, E TI Genomes and evolution - Glimpses of an emerging synthesis - Editorial overview SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Editorial Material C1 Univ Washington, Dept Mol Biotechnol, Seattle, WA 98195 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Green, P (reprint author), Univ Washington, Dept Mol Biotechnol, Campus Box 357730, Seattle, WA 98195 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD DEC PY 1999 VL 9 IS 6 BP 621 EP 623 DI 10.1016/S0959-437X(99)00035-0 PG 3 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 266AF UT WOS:000084277900001 ER PT J AU Kondrashov, AS AF Kondrashov, AS TI Comparative genomics and evolutionary biology SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Article ID POSITIVE DARWINIAN SELECTION; MOLECULAR EVOLUTION; GENE; DROSOPHILA; DEHYDROGENASE; SPECIATION; PSEUDOGENE; PRIMATES; PROTEIN; SEX AB Data of large-scale DNA sequencing are relevant to some of the most fundamental issues in evolutionary biology: suboptimality, homology, hierarchy, ancestry, novelties, the role of natural selection, and the relative importance of directional versus stabilizing selection. Already, these data provided the best available evidence for some evolutionary phenomena, and in several cases led to refinement of old concepts. Still, the Darwinian evolutionary paradigm will successfully accommodate comparative genomics. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Kondrashov, AS (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bldg 38A, Bethesda, MD 20894 USA. NR 73 TC 10 Z9 10 U1 1 U2 2 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD DEC PY 1999 VL 9 IS 6 BP 624 EP 629 DI 10.1016/S0959-437X(99)00027-1 PG 6 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 266AF UT WOS:000084277900002 PM 10607612 ER EF