FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Permana, PA Nair, S Lee, YH Luczy-Bachman, G de Courten, BV Tataranni, PA AF Permana, PA Nair, S Lee, YH Luczy-Bachman, G de Courten, BV Tataranni, PA TI Subcutaneous abdominal preadipocyte differentiation in vitro inversely correlates with central obesity SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE Pima Indians; gene expression; glucocorticoid receptor; adipogenesis ID ADIPOCYTE PRECURSOR CELLS; CHEMICALLY-DEFINED MEDIUM; BODY-FAT DISTRIBUTION; C/EBP-ALPHA GENE; DIABETES-MELLITUS; GLUCOCORTICOIDS; MEN; PROLIFERATION; ADIPOGENESIS; GROWTH AB Expansion of adipose tissue mass results from increased number and size of adipocyte cells. We hypothesized that subcutaneous abdominal preadipocytes in obese individuals might have an intrinsically higher propensity to differentiate into adipocytes. Thus we investigated the relationship between obesity and the level of in vitro preadipocyte differentiation in Pima Indians. Subcutaneous abdominal stromal vascular fractions containing preadipocytes were cultured from 58 nondiabetic subjects [31 M/27 F, 30 +/- 6 yr, body fat 34 +/- 8% by dual-energy X-ray absorptiometry (means +/- SD)]. The average percentage of preadipocyte differentiation (PDIFF; cell count by microscopy) was 11 +/- 11% ( range 0.2 - 51%). PDIFF correlated negatively with percent body fat (r = - 0.35, P = 0.006) and waist circumference ( r = - 0.45, P = 0.0004). Multiple regression analysis indicated that waist circumference ( P = 0.01), sex ( P = 0.01), and percent body fat ( P = 0.05) were significant determinants of PDIFF. Molecular characterization of predifferentiated cultured cells was performed by real-time PCR measurements of glucocorticoid receptor-alpha (GRalpha), insulin-like growth factor I receptor (IGF-IR), peroxisome proliferator-activated receptor-gamma (PPARgamma), enhancer-binding protein GATA-3, CCAAT/ enhancer-binding protein-alpha undifferentiated protein (CUP/AP-2alpha), and endothelial cell-specific marker 2 (ECSM2). The mRNA concentrations of GRalpha correlated with PDIFF (r = 0.29, P = 0.03), but the others did not (IGF-IR, r = 0.003, P = 1.0; PPARgamma, r = - 0.1, P = 0.5; GATA-3, r = 0.02, P = 0.9; CUP/AP-2alpha, r = - 0.2, P = 0.1; ECSM2, r = 0.04, P = 0.7). Contrary to our hypothesis, the results may indicate a blunted in vitro differentiation potential of preadipocytes in centrally obese individuals. The lower differentiation potential of preadipocytes in the obese subjects might be due, at least partly, to decreased glucocorticoid receptor expression. C1 NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epideniol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. RP Permana, PA (reprint author), Carl T Hayden Vet Affairs Med Ctr, ERS-151,650 E Indian Sch Rd, Phoenix, AZ 85012 USA. EM paska.permana@med.va.gov OI de Courten, Barbora/0000-0001-8760-2511 NR 26 TC 59 Z9 61 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD JUN PY 2004 VL 286 IS 6 BP E958 EP E962 DI 10.1152/ajpendo.00544.2003 PG 5 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 823ZU UT WOS:000221653900013 PM 14970008 ER PT J AU Yaghi, A Bend, JR Webb, CD Zeldin, DC Weicker, S Mehta, S McCormack, DG AF Yaghi, A Bend, JR Webb, CD Zeldin, DC Weicker, S Mehta, S McCormack, DG TI Excess nitric oxide decreases cytochrome P-450 2J4 content and P-450-dependent arachidonic acid metabolism in lungs of rats with acute pneumonia SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE inflammation; CYP2J4 protein content; CYP450 activity assays; epoxyeicosatrienoic acids and omega-terminal hydroxyeicosatetraenoic acids; 1400W ID ACUTE PSEUDOMONAS PNEUMONIA; DOWN-REGULATION; IN-VIVO; EPOXYEICOSATRIENOIC ACIDS; CYCLOOXYGENASE PRODUCTS; FUNCTIONAL-SIGNIFICANCE; SYNTHASE INHIBITORS; EXPRESSION; ENDOTOXIN; LIVER AB Recently, we demonstrated that pulmonary CYP2J4 content, a prominent source of EETs and HETEs formation in rat lungs, is reduced in pneumonia. Therefore, the purpose of this study was to determine the role of iNOS-derived NO in reduced pulmonary CYP2J4 protein content and decreased CYP metabolites in pneumonia. Rats were randomized to control, control plus 1400W ( iNOS inhibitor), pneumonia, and pneumonia plus 1400W groups. Pseudomonas organisms were injected into lungs of pneumonia rats. At 40 h after surgery, rats were treated with either saline or 1400W for 4 h before death. Venous plasma samples were obtained for measuring nitrites/nitrates (NOx). There was no significant effect of 1400W on blood pressure measured in control or pneumonia rats, whereas 1400W reduced the elevated plasma NOx levels in pneumonia rats by half. CYP primary metabolites of AA formed at significantly lower rates in pulmonary microsomes from pneumonia rats compared with control rats. Treatment of pneumonia rats with 1400W resulted in a significant increase in the rate of formation of pulmonary EETs and omega-terminal HETEs compared with untreated pneumonia rats. The reduction in CYP2J4 protein content in pneumonia lung microsomes was also partially prevented by 1400W. Therefore, excess NO from iNOS decreases the pulmonary production of EETs and omega-HETEs in acute pneumonia. Inhibition of iNOS restores CYP2J4 protein content and CYP activity in acute pneumonia, indicating an important NO-CYP interaction in pulmonary responses to infection. We speculate CYP2J4 and its AA metabolites are involved in the modulation of pulmonary function in health and disease. C1 London Hlth Sci Ctr, AC Burton Vasc Biol Lab, Lawson Hlth Res Inst, London, ON N6A 4G5, Canada. Univ Western Ontario, Dept Physiol & Pharmacol, London, ON N6A 5C1, Canada. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP McCormack, DG (reprint author), London Hlth Sci Ctr, AC Burton Vasc Biol Lab, Lawson Hlth Res Inst, Victoria Campus,375 South St, London, ON N6A 4G5, Canada. EM david.mccormack@lhsc.on.ca NR 47 TC 9 Z9 10 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD JUN PY 2004 VL 286 IS 6 BP L1260 EP L1267 DI 10.1152/ajplung.00273.2003 PG 8 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 819NM UT WOS:000221321700023 PM 14766666 ER PT J AU Juknevicius I Segal, Y Kren, S Lee, R Hostetter, TH AF Juknevicius, I Segal, Y Kren, S Lee, R Hostetter, TH TI Effect of aldosterone on renal transforming growth factor-beta SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE aldosterone; transforming growth factor-beta; kidney ID ANGIOTENSIN-II; MESANGIAL CELLS; DISEASE; TGF-BETA-1; EXPRESSION; HEART AB Aldosterone participates in the pathophysiology of several models of progressive chronic renal disease. Because of the causal connection between transforming growth factor-beta1 (TGF-beta) and scarring in many such models, we hypothesized that aldosterone could evoke TGF-beta in the kidney. Aldosterone infusion for 3 days in otherwise normal rats caused a more than twofold increase in TGF-beta excretion without changes in systolic pressure or evidence of kidney damage. Concurrent treatment with amiloride did not alter this effect, indicating that aldosterone's stimulation of TGF-beta was independent of its regulation of sodium or potassium transport. However, concurrent treatment with spironolactone did block the increase in TGF-beta, indicating that the effect depends on the mineralocorticoid receptor. Renal mRNA for serum glucocorticoid kinase rose, but no change in TGF-beta message occurred, suggesting posttranscriptional enhancement of renal TGF-beta. In summary, aldosterone provokes renal TGF-beta, and this action may contribute to aldosterone's fibrotic propensity. C1 NIDDKD, NIH, Natl Kidney Dis Educ Program, Bethesda, MD 20892 USA. Univ Minnesota, Dept Med, Div Renal Dis & Hypertens, Minneapolis, MN 55455 USA. RP Hostetter, TH (reprint author), NIDDKD, NIH, Natl Kidney Dis Educ Program, 6707 Democracy Blvd,Rm 645, Bethesda, MD 20892 USA. EM hostettert@extra.niddk.nih.gov FU NIDDK NIH HHS [R01-DK-31437] NR 27 TC 62 Z9 72 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 JUN PY 2004 VL 286 IS 6 BP F1059 EP F1062 DI 10.1152/ajprenal.00202.2003 PG 4 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 818KR UT WOS:000221244500007 PM 15130897 ER PT J AU Li, CL Klein, JD Wang, WD Knepper, MA Nielsen, S Sands, JM Frokiaer, J AF Li, CL Klein, JD Wang, WD Knepper, MA Nielsen, S Sands, JM Frokiaer, J TI Altered expression of urea transporters in response to ureteral obstruction SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE collecting duct; descending vasa recta; obstructive nephropathy; urine concentrating mechanism ID MEDULLARY COLLECTING DUCT; LONG-TERM REGULATION; DOWN-REGULATION; RAT-KIDNEY; CONCENTRATING DEFECT; UT-B; VASOPRESSIN; CLONING; PROTEIN; UT-A1 AB Urea plays an important role in the urinary concentrating capacity. Renal inner medullary (IM) urea transporter expression was examined in rats with bilateral (BUO) or unilateral ureteral obstruction (UUO). BUO (24 h) was associated with markedly increased plasma urea (42.4 +/- 1.0 vs. 5.2 +/- 0.2 mmol/l) and a significant decease in expression of UT-A1 (28 +/- 8% of sham levels), UT-A3 (45 +/- 11%), and UT-B (70 +/- 8%). Immunocytochemistry confirmed downregulation of UT-A1 and UT-A3 in IM collecting duct and UT-B in the descending vasa recta. Three days after release of BUO, UT-A1, UT-A3, and UT-B remained significantly downregulated (UT-A1: 37 +/- 6%; UT-A3: 25 +/- 6%; and UT-B: 10 +/- 5% of sham levels; P < 0.05) concurrent with a persistent polyuria and a marked reduction in solute-free water reabsorption (115 +/- 11 vs. 196 +/- 8 mu l.min(-1).kg(-1), P < 0.05). Moreover, 14 days after release of BUO, total UT-A1, UT-A3, and UT-B remained significantly decreased compared with sham-operated controls and urine urea remained reduced (588 +/- 43 vs. 1,150 +/- 94 mmol/l). Consistent with increased levels of plasma urea 24 h after onset of UUO (7.4 +/- 0.3 vs. 4.8 +/- 0.3 mmol/l), the protein abundance of UT-A1, UT-A3, and UT-B in IM was markedly reduced in the obstructed kidney, which was confirmed by immunocytochemistry. In the nonobstructed kidney, the expression of urea transporters did not change. In conclusion, reduced expression of UT-A1, UT-A3, and UT-B levels in both BUO and UUO rats suggests that urea transporters play important roles in the impaired urinary concentrating capacity in response to urinary tract obstruction. C1 Aarhus Univ Hosp Skejby, Inst Expt Clin Res, Water & Salt Res Ctr, DK-8200 Aarhus N, Denmark. Aarhus Univ, Water & Salt Res Ctr, DK-8000 Aarhus C, Denmark. Aarhus Univ Hosp Skejby, Dept Clin Physiol, DK-8200 Aarhus N, Denmark. Aarhus Univ, Inst Anat, Dept Cell Biol, DK-8000 Aarhus C, Denmark. Emory Univ, Dept Med, Div Renal, Atlanta, GA 30322 USA. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Frokiaer, J (reprint author), Aarhus Univ Hosp Skejby, Inst Expt Clin Res, Water & Salt Res Ctr, DK-8200 Aarhus N, Denmark. EM JF@IEKF.AU.DK OI Frokiaer, Jorgen/0000-0002-6206-8065 FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999]; NIDDK NIH HHS [DK-63657, DK-41707, R01 DK041707] NR 40 TC 27 Z9 27 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JUN PY 2004 VL 286 IS 6 BP F1154 EP F1162 DI 10.1152/ajprenal.00453.2003 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 818KR UT WOS:000221244500019 PM 14982816 ER PT J AU Shi, YM Pedersen, M Li, CL Wen, JG Thomsen, K Stodkilde-Jorgensen, H Jorgensen, TM Knepper, MA Nielsen, S Djurhuus, JC Frokiaer, J AF Shi, YM Pedersen, M Li, CL Wen, JG Thomsen, K Stodkilde-Jorgensen, H Jorgensen, TM Knepper, MA Nielsen, S Djurhuus, JC Frokiaer, J TI Early release of neonatal ureteral obstruction preserves renal function SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE rat; obstructive nephropathy; kidney function; magnetic resonance imaging; aquaporin; sodium transporter ID RENIN-ANGIOTENSIN SYSTEM; MAGNETIC-RESONANCE; DOWN-REGULATION; NATURAL-HISTORY; COLLECTING DUCT; WATER CHANNELS; NEWBORN RATS; KIDNEY; HYDRONEPHROSIS; VASOPRESSIN AB The incidence of congenital hydronephrosis is similar to1% and is often associated with renal insufficiency. It is unknown whether early release is essential to prevent deterioration of renal function. Rats were subjected to partial unilateral ureteral obstruction (PUUO) on postnatal day 2. The obstruction was left in place or released after 1 or 4 wk. Renal blood flow (RBF) and kidney size were measured sequentially over 24 wk using MRI. In rats in which the obstruction was left in place, RBF of the obstructed kidney was progressively reduced to 0.92 +/- 0.17 vs. 1.79 +/- 0.12 ml.min(-1).100 g body wt(-1) (P < 0.05) after 24 wk. Similarly, glomerular filtration rate of the obstructed kidney was severely reduced at 24 wk: 172 +/- 36 vs. 306 +/- 42 mu l.min(-1).100 g body wt(-1) (P < 0.05). These changes were preceded by development of severe hydronephrosis and obstructive nephropathy with a reduction in total protein content: 45 +/- 3 vs. 58 +/- 4 mg/kidney. Moreover, nonreleased PUUO caused a marked natriuresis (0.32 +/- 0.07 vs. 0.11 +/- 0.02 mumol.min(-1).100 g body wt(-1), P < 0.05) and impaired solute free water reabsorption (0.47 +/- 0.16 vs. 2.71 +/- 0.67 mu l.min(-1).100 g body wt(-1), P < 0.05), consistent with a significant downregulation of Na-K-ATPase to 62 +/- 7%, aquaporin-1 to 53 +/- 3%, and aquaporin-3 to 53 +/- 7% of sham levels. Release after 1 wk completely prevented development of hydronephrosis, reduction in RBF and glomerular filtration rate, and downregulation of renal transport proteins, whereas release after 4 wk had no effect. These results suggest that early release of neonatal obstruction provides dramatically better protection of renal function than release of obstruction after the maturation process is completed. C1 Univ Aarhus, Hosp Skejby, Inst Expt Clin Res, Water & Salt Res Ctr, DK-8200 Aarhus N, Denmark. Aarhus Univ Hosp, Dept Clin Physiol, DK-8200 Aarhus N, Denmark. Aarhus Univ, Inst Anat, DK-8000 Aarhus C, Denmark. Aarhus Univ Hosp, Dept Biol Psychiat, Inst Basic Psychiat Res, DK-8240 Risskov, Denmark. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Frokiaer, J (reprint author), Univ Aarhus, Hosp Skejby, Inst Expt Clin Res, Water & Salt Res Ctr, DK-8200 Aarhus N, Denmark. EM jf@iekf.au.dk RI wen, jianguo/P-3185-2014; OI wen, jianguo/0000-0003-0952-118X; Stodkilde-Jorgensen, Hans/0000-0002-8649-4173; Frokiaer, Jorgen/0000-0002-6206-8065 FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 51 TC 19 Z9 20 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JUN PY 2004 VL 286 IS 6 BP F1087 EP F1099 DI 10.1152/ajprenal.00201.2003 PG 13 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 818KR UT WOS:000221244500011 PM 14722012 ER PT J AU Yuen, PST Dunn Sr Miyaji, T Yasuda, H Sharma, K Star, RA AF Yuen, PST Dunn, SR Miyaji, T Yasuda, H Sharma, K Star, RA TI A simplified method for HPLC determination of creatinine in mouse serum SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE Jaffe assay; mouse models; renal failure ID CHROMATOGRAPHY; MICE AB Mouse models are frequently used to study renal function. However, mouse serum contains chromagens that interfere with standard picric acid-based assays for serum creatinine. Several alternative methods exist for serum creatinine measurements, including assay by high-performance liquid chromatography ( HPLC), but only one has been adapted to mouse serum. Creatinine was measured in serum by acetonitrile deproteinization, followed by isocratic, cation exchange HPLC. The HPLC method was compared with a standard alkaline picrate colorimetric assay, using serum from animals with low-to-moderate renal injury. Acidification of acetonitrile with HCl in the deproteinization step produced variable results, including an extra peak that interfered with integration of the creatinine peak or loss of the creatinine peak. Deproteinizing with acetonitrile alone resulted in a more reliable measurement of serum creatinine, which was validated by a series of known additions of creatinine standard. The HPLC assay was reproducible with coefficients of variation from 1.6 to 5.1%. The picric acid assay overestimated serum creatinine, when directly compared with the HPLC assay. The extent of overestimation, up to sixfold, was greatest at normal (0.1 to 0.2 mg/dl) to moderately elevated (0.5 mg/dl) serum creatinine levels. Mouse serum contains substances that interfere with standard picric acid assays for creatinine. Our new HPLC assay can accurately detect creatinine from 5 mul of mouse serum. These results support the widespread adoption of HPLC to accurately measure serum creatinine in mouse models of renal injury. C1 NIDDKD, NIH, Renal Diagnost & Therapeut Unit, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Dept Med, Div Nephrol, Dorrance Hamilton Res Labs, Philadelphia, PA 19107 USA. RP Yuen, PST (reprint author), NIDDKD, NIH, Renal Diagnost & Therapeut Unit, 10 Ctr Dr,Rm 3N108, Bethesda, MD 20892 USA. EM py@nih.gov RI Yuen, Peter/B-1954-2008 OI Yuen, Peter/0000-0001-9557-3909 FU NIDDK NIH HHS [DK-60995] NR 7 TC 78 Z9 79 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JUN PY 2004 VL 286 IS 6 BP F1116 EP F1119 DI 10.1152/ajprenal.00366.2003 PG 4 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 818KR UT WOS:000221244500014 PM 14970000 ER PT J AU Wendler, D Emanuel, EJ Lie, RK AF Wendler, D Emanuel, EJ Lie, RK TI The standard of care debate: Can research in developing countries be both ethical and responsive to those countries' health needs? SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MATERNAL-INFANT TRANSMISSION; TO-CHILD TRANSMISSION; CLINICAL-RESEARCH; HIV-1 TRANSMISSION; PERINATAL TRANSMISSION; RANDOMIZED-TRIAL; DEVELOPING-WORLD; PLACEBO CONTROLS; ORAL ZIDOVUDINE AB To avoid exploitaiton of host communities, many commentators argue that subjects must receive the best methods available worldwide. Others worry that this requirement may block important research intended to improve health care, especially in developing countries. To resolve this dilemma, we propose a framework for the conditions under which it is acceptable to provide subjects with less than the best methods. Specifically, institutional review boards should assume a default of requiring the "worldwide best" methods, meaning the best methods available anywhere in the world, in all cases. However, institutional review boards should be willing to grant exceptions to this default for research studies that satisfy the following 4 conditions: (1) scientific necessity, (2) relevance for the host community, (3) sufficient host community benefit, and (4) subject and host community nonmaleficence. C1 NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. Univ Bergen, Dept Publ Hlth & Primary Hlth Care, N-5020 Bergen, Norway. RP Wendler, D (reprint author), NIH, Dept Clin Bioeth, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM dwendler@nih.gov NR 43 TC 49 Z9 49 U1 1 U2 4 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 JUN PY 2004 VL 94 IS 6 BP 923 EP 928 DI 10.2105/AJPH.94.6.923 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 824WK UT WOS:000221717700012 PM 15249290 ER PT J AU Colomo, L Loong, F Rives, S Pittaluga, S Martinez, A Lopez-Guillermo, A Ojanguren, J Romagosa, V Jaffe, ES Campo, E AF Colomo, L Loong, F Rives, S Pittaluga, S Martinez, A Lopez-Guillermo, A Ojanguren, J Romagosa, V Jaffe, ES Campo, E TI Diffuse large B-cell lymphomas with plasmablastic differentiation represent a heterogeneous group of disease entities SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE large cell lymphoma; plasmablastic; HIV; HHV-8; EBV; immunohistochemistry ID EPSTEIN-BARR-VIRUS; SARCOMA-ASSOCIATED HERPESVIRUS; HUMAN MYELOMA CELLS; CYCLIN D1 GENE; MULTIPLE-MYELOMA; PLASMA-CELLS; EXTRAMEDULLARY PLASMACYTOMA; CASTLEMAN-DISEASE; LYMPHOPROLIFERATIVE DISORDERS; UNDETERMINED SIGNIFICANCE AB Plasmablastic lymphoma was initially described as a variant of diffuse large B-cell lymphoma (DLBCL) involving the oral cavity of HIV+ patients and characterized by immunoblastic morphology and a plasma cell phenotype. However, other lymphomas may exhibit similar morphologic and immunophenotypic features. To determine the significance of plasmablastic differentiation in DLBCL and examine the heterogeneity of lymphomas with these characteristics, we examined 50 DLBCLs with low/absent CD20/CD79a and an immunophenotype indicative of terminal B-cell differentiation (MUM1/CD38/CD138/EMA-positive). We were able to define several distinct subgroups. Twenty-three tumors were classified as plasmablastic lymphoma of the oral mucosa type and showed a monomorphic population of immunoblasts with no or minimal plasmacytic differentiation. Most patients were HIV+ and EBV was positive in 74%. Eleven (48%) cases presented in the oral mucosa, but the remaining presented in other extranodal (39%) or nodal (13%) sites. Sixteen cases were classified as plasmablastic lymphoma with plasmacytic differentiation. These were composed predominantly of immunoblasts and plasmablasts, but in addition exhibited more differentiation to mature plasma cells. Only 33% were HIV+, EBV was detected in 62%, and 44% had nodal presentation. Nine cases, morphologically indistinguishable from the previous group, were secondary extramedullary plasmablastic tumors Occurring in patients with prior or synchronous plasma cell neoplasms, classified as multiple myeloma in 7 of the 9. Two additional neoplasms were ail HHV-8+ extracavitary variant of primary effusion lymphoma and an ALK+ DLBCL. HHV-8 was examined in 39 additional cases, and was negative in all. In conclusion, DLBCLs with plasmablastic differentiation are a heterogeneous group of neoplasms with different clinicopathological characteristics that may correspond to different entities. C1 Univ Barcelona, Hosp Clin Barcelona, Inst Invest Biomed August Pi I Sunyer, Pathol Lab,Dept Hematol,Hematopathol Sect, E-08036 Barcelona, Spain. NCI, Hematopathol Sect, Pathol Lab, Bethesda, MD 20892 USA. Hosp Galdakao, Pathol Lab, Vizcaya, Spain. Univ Barcelona, Hosp Llobregat, Hosp Princeps Espanya, E-08007 Barcelona, Spain. RP Campo, E (reprint author), Univ Barcelona, Hosp Clin Barcelona, Inst Invest Biomed August Pi I Sunyer, Pathol Lab,Dept Hematol,Hematopathol Sect, Villarroel 170, E-08036 Barcelona, Spain. EM ECAMPO@clinic.ub.es RI Martinez, Antonio/D-8188-2012; Colomo, Luis/A-2259-2016; OI Martinez, Antonio/0000-0003-0790-9017; Colomo, Luis/0000-0001-5236-5085; Campo, elias/0000-0001-9850-9793 NR 49 TC 209 Z9 216 U1 1 U2 2 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 JUN PY 2004 VL 28 IS 6 BP 736 EP 747 DI 10.1097/01.pas.0000126781.87158.e3 PG 12 WC Pathology; Surgery SC Pathology; Surgery GA 823XM UT WOS:000221647600005 PM 15166665 ER PT J AU Rajaram, S Nash, HA AF Rajaram, S Nash, HA TI A specific alteration in the electroretinogram of Drosophila metanogaster is induced by halothane and other volatile general anesthetics SO ANESTHESIA AND ANALGESIA LA English DT Article ID SHAKER K+ CHANNELS; POTASSIUM CHANNELS; MELANOGASTER; PHOTORECEPTORS; SYSTEM; LOCUS AB In higher organisms, physiological investigations have provided a valuable complement to assays of anesthetic effects on whole-animal behavior. However, although complex motor programs of Drosophila melanogaster have been used to identify genes that influence anesthesia, electrophysiological studies of anesthetic effects in this invertebrate have been limited. Here we show that the electroretinogram (ERG), the extracellular recording of light-evoked mass potentials from the surface of the eye, reveals a distinct effect of halothane, enflurane, isoflurane, and desflurane. Behaviorally relevant concentrations of these volatile anesthetics severely reduced the transient component of the ERG at lights-off. Other prominent ERG components, such as the photoreceptor potential and the lights-on transient, were not consistently affected by these drugs. Surprisingly, for most anesthetics, a diminished off-transient was obtained only with short light pulses. An identical effect was observed in the absence of anesthetic by depressing the function of Shaker potassium channels. The possibility that halothane acts in the visual circuit by closing potassium channels was examined with a simple genetic test; the results were consistent with the hypothesis but fell short of providing definitive support. Nevertheless, our studies establish the ERG as a useful tool both for examining the influence of volatile anesthetics on a simple circuit and for identifying genes that contribute to anesthetic sensitivity. C1 NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Nash, HA (reprint author), NIMH, Mol Biol Lab, Bldg 36,Room 1B08, Bethesda, MD 20892 USA. EM howard.nash@mail.nih.gov NR 26 TC 7 Z9 7 U1 0 U2 0 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 JUN PY 2004 VL 98 IS 6 BP 1705 EP 1711 DI 10.1213/01.ANE.0000113548.27457.A3 PG 7 WC Anesthesiology SC Anesthesiology GA 823YK UT WOS:000221650100036 PM 15155332 ER PT J AU Berra, L De Marchi, L Yu, ZX Laquerriere, P Baccarelli, A Kolobow, T AF Berra, L De Marchi, L Yu, ZX Laquerriere, P Baccarelli, A Kolobow, T TI Endotracheal tubes coated with antiseptics decrease bacterial colonization of the ventilator circuits, lungs, and endotracheal tube SO ANESTHESIOLOGY LA English DT Article; Proceedings Paper CT 99th International Conference of the American-Thoracic-Society CY MAY 16-23, 2003 CL SEATTLE, WA SP Amer Thorac Soc ID INTENSIVE-CARE UNITS; PSEUDOMONAS-AERUGINOSA BIOFILMS; NOSOCOMIAL INFECTIONS; STAPHYLOCOCCUS-EPIDERMIDIS; RESPIRATORY-INFECTION; ANTIBIOTIC-RESISTANCE; PNEUMONIA; CHLORHEXIDINE; EPIDEMIOLOGY; CATHETERS AB Background Formation of a bacterial biofilm within the endotracheal tube (ETT) after tracheal incubation is rapid and represents a ready source of lung bacterial colonization. The authors investigated bacterial colonization of the ventilator circuit, the ETT, and the lungs when the ETT was coated with silver-sulfadiazine and chlorhexidine in polyurethane, using no bacterial/viral filter attached to the ETT. Methods: Sixteen sheep were randomized into two groups. Eight sheep were incubated with a standard ETT (control group), and eight were incubated with a coated ETT (study group). Animals were mechanically ventilated for 24 h. At autopsy, the authors sampled the trachea, bronchi, lobar parenchyma, and ETT for quantitative bacterial cultures. Qualitative bacterial cultures were obtained from the filter, humidifier, inspiratory and expiratory lines, and water trap. ETTs were analyzed with light microscopy, scanning electron microscopy, and laser scanning confocal microscopy. Results: In the control group, all eight ETTs were heavily colonized (10(5)-10(8) colony-forming units [cfu]/g), forming a thick biofilm. The ventilator circuit was always colonized. Pathogenic bacteria colonized the trachea and the lungs in five of eight sheep (up to 10(9) cfu/g). In the study group, seven of eight ETTs and their ventilator circuits showed no growth, with absence of a biofilm; one ETT and the respective ventilator circuit showed low bacterial growth (10(3)-10(4) cfu/g). The trachea was colonized in three sheep, although lungs and bronchi showed no bacterial growth, except for one bronchus in one sheep. Conclusions: Coated ETTs induced a nonsignificant reduction of the tracheal colonization, eliminated (seven of eight) or reduced (one of eight) bacterial colonization of the ETT and ventilator circuits, and prevented lung bacterial colonization. C1 NHLBI, US Dept HHS, NIH, Pulm & Crit Care Med Branch, Bethesda, MD 20892 USA. RP Kolobow, T (reprint author), NHLBI, US Dept HHS, NIH, Pulm & Crit Care Med Branch, 9000 Rockville Pike,Bldg 10,Room 5D-07, Bethesda, MD 20892 USA. EM kolobowt@nhlbi.nih.gov RI Laquerriere, Patrice/P-1025-2016 OI Laquerriere, Patrice/0000-0001-7637-9094 NR 48 TC 53 Z9 56 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD JUN PY 2004 VL 100 IS 6 BP 1446 EP 1456 DI 10.1097/00000542-200406000-00017 PG 11 WC Anesthesiology SC Anesthesiology GA 822PE UT WOS:000221551300016 PM 15166564 ER PT J AU Belfer, I Wu, TX Kingman, A Krishnaraju, RK Goldman, D Max, MB AF Belfer, I Wu, TX Kingman, A Krishnaraju, RK Goldman, D Max, MB TI Candidate gene studies of human pain mechanisms - Methods for optimizing choice of polymorphisms and sample size SO ANESTHESIOLOGY LA English DT Article; Proceedings Paper CT 10th World Congress on Pain CY AUG 17-22, 2002 CL SAN DIEGO, CA SP Allergan Inc, AstraZeneca, Eli Lilly & Co, Endo Pharmaceut Inc, Grunenthal GmbH, Janssen Pharmaceut, Pfizer Inc, Pharmacia Corp, Purdue-Mundipharma-Napp Associated Co ID SINGLE-NUCLEOTIDE POLYMORPHISM; NEUROPATHIC PAIN; HUMAN GENOME; ASSOCIATION; PROMOTER; DISEASE; RISK; RECEPTOR; SCHIZOPHRENIA; EXPRESSION C1 NIDCR, Pain & Neurosensory Mechanisms Branch, Div Intramural Res, NIH,US Dept HHS, Bethesda, MD 20892 USA. NIDCR, Biostat Core, Div Populat & Hlth Promot Sci, NIH,US Dept HHS, Bethesda, MD 20892 USA. NIAAA, Neurogenet Lab, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Max, MB (reprint author), NIDCR, Pain & Neurosensory Mechanisms Branch, Div Intramural Res, NIH,US Dept HHS, Bldg 10,3C-405, Bethesda, MD 20892 USA. EM Mitchell_Max@nih.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU NIAAA NIH HHS [Z01 AA00301]; NIDCR NIH HHS [ZO1 DE00366] NR 57 TC 72 Z9 72 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD JUN PY 2004 VL 100 IS 6 BP 1562 EP 1572 DI 10.1097/00000542-200406000-00032 PG 11 WC Anesthesiology SC Anesthesiology GA 822PE UT WOS:000221551300031 PM 15166579 ER PT J AU Jeffrey, M Goodsir, CM Race, RE Chesebro, B AF Jeffrey, M Goodsir, CM Race, RE Chesebro, B TI Scrapie-specific neuronal lesions are independent of neuronal PrP expression SO ANNALS OF NEUROLOGY LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; BOVINE SPONGIFORM ENCEPHALOPATHY; 87V MURINE SCRAPIE; PRION PROTEIN; IN-VIVO; HAMSTER SCRAPIE; TRANSGENIC MICE; NEUROTOXICITY; SHEEP; NEUROPATHOLOGY AB In the transmissible spongiform. encephalopathies (TSE), accumulation of the abnormal disease-specific prion protein is associated with neurodegeneration. Previous data suggested that abnormal prion protein (PrP) could induce neuronal pathology only when neurons expressed the normal form of PrP, but conflicting evidence also has been reported. Understanding whether neuronal PrP expression is required for TSE neuropathological damage in vivo is essential for determining the mechanism of TSE pathogenesis. Therefore, these experiments were designed to study scrapie pathogenesis in vivo in the absence of neuronal PrP expression. Hamster scrapie (strain 263K) was used to infect transgenic mice expressing hamster PrP in the brain only in astrocytes. These mice previously were shown to develop clinical scrapie, but it was unclear whether the brain pathology was caused by damage to astrocytes, neurons, or other cell types. In this electron microscopic study, neurons demonstrated TSE-specific pathology despite lacking PrP expression. Abnormal PrP was identified around astrocytes, primarily in the extracellular spaces of the neuropil, but astrocytes showed only reactive changes and no damage. Therefore, in this model the pathogenesis of the disease appeared to involve neuronal damage associated with extracellular astrocytic accumulation of abnormal PrP acting upon nearby PrP-negative neurons or triggering the release of non-PrP neurotoxic factors from astrocytes. C1 Vet Labs Agcy, Lasswade Lab, Penicuik EH26 0PZ, Midlothian, Scotland. NIAID, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Jeffrey, M (reprint author), Vet Labs Agcy, Lasswade Lab, Pentlands Sci Pk, Penicuik EH26 0PZ, Midlothian, Scotland. EM m.jeffrey@vla.defra.gsi.gov.uk RI Jeffrey, Martin/D-2251-2009 NR 40 TC 60 Z9 62 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD JUN PY 2004 VL 55 IS 6 BP 781 EP 792 DI 10.1002/ana.20093 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 824VW UT WOS:000221716300004 PM 15174012 ER PT J AU Velez, G Kansupada, K Csaky, KG Reed, GF Whitcup, SM Nussenblatt, RB AF Velez, G Kansupada, K Csaky, KG Reed, GF Whitcup, SM Nussenblatt, RB TI Serous retinal detachment in posterior uveitis SO ANNALS OF OPHTHALMOLOGY LA English DT Article ID KOYANAGI-HARADA-SYNDROME; DISEASE; CHOROIDITIS; RETINITIS; MACULA AB The diagnoses and clinical characteristics of 15 patients (23 eyes) with serous retinal detachment (SRD) and posterior uveitis, including therapy and outcome are described. The most common diagnoses were Vogt-Koyanagi-Harada disease, sarcoidosis, and toxoplasmosis. Despite poor visual acuity at the time of presentation, aggressive and prompt anti-inflammatory therapy resolved the SRD in most patients with functional recovery of vision. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NEI, Div Biometry & Epidemiol, NIH, Bethesda, MD 20892 USA. RP Velez, G (reprint author), 17 Hillcrest Rd, Weston, MA 02493 USA. NR 26 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CONTEMPORARY OPHTHALMOLOGY PI CHICAGO PA 820 N ORLEANS, STE 208, CHICAGO, IL 60610 USA SN 1530-4086 J9 ANN OPHTHALMOL JI Ann. Ophthalmol. PD SUM-WIN PY 2004 VL 36 IS 2 BP 103 EP 110 PG 8 WC Ophthalmology SC Ophthalmology GA 884SR UT WOS:000226107000007 ER PT J AU Walsh, TJ Karlsson, MO Driscoll, T Arguedas, AG Adamson, P Saez-Llorens, X Vora, AJ Arrieta, AC Blumer, J Lutsar, I Milligan, P Wood, N AF Walsh, TJ Karlsson, MO Driscoll, T Arguedas, AG Adamson, P Saez-Llorens, X Vora, AJ Arrieta, AC Blumer, J Lutsar, I Milligan, P Wood, N TI Pharmacokinetics and safety of intravenous voriconazole in children after single- or multiple-dose administration SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID INVASIVE FUNGAL-INFECTIONS; ANTIFUNGAL AGENTS; AMPHOTERICIN-B; ASPERGILLOSIS; CANDIDIASIS; THERAPY; MODEL AB We conducted a multicenter study of the safety, tolerability, and plasma pharmacokinetics of the parenteral formulation of voriconazole in immunocompromised pediatric patients (2 to 11 years old). Single doses of 3 or 4 mg/kg of body weight were administered to six and five children, respectively. In the multiple-dose study, 28 patients received loading doses of 6 mg/kg every 12 h on day 1, followed by 3 mg/kg every 12 h on day 2 to day 4 and 4 mg/kg every 12 h on day 4 to day 8. Standard population pharmacokinetic approaches and generalized additive modeling were used to construct the structural pharmacokinetic and covariate models used in this analysis. In contrast to that in adult healthy volunteers, elimination of voriconazole was linear in children following doses of 3 and 4 mg/kg every 12 h. Body weight was more influential than age in accounting for the observed variability in voriconazole pharmacokinetics. Elimination capacity correlated with the CYP2C19 genotype. Exposures were similar at 4 mg/kg every 12 h in children (median area under the concentration-time curve (AUC), 14,227 ng (.) h/ml) and 3 mg/kg in adults (median AUC, 13,855 ng (.) h/ml). Visual disturbances occurred in 5 (12.8%) of the 39 patients and were the only drug-related adverse events that occurred more than once. No withdrawals from the study were related to voriconazole. We conclude that pediatric patients have a higher capacity for elimination of voriconazole per kilogram of body weight than do adult healthy volunteers and that dosages of 4 mg/kg may be required in children to achieve exposures consistent with those in adults following dosages of 3 mg/kg. C1 NICHHD, NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. NICHHD, Pediat Pharmacol Unit, Bethesda, MD 20892 USA. Uppsala Univ, Uppsala, Sweden. Duke Univ, Med Ctr, Durham, NC USA. Inst Costarricense Invest Clin, San Jose, Costa Rica. Natl Childrens Hosp, San Jose, Costa Rica. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Hosp Ninos Dr Ricardo Gutierrez, Panama City, Panama. Sheffield Childrens Hosp, Sheffield, S Yorkshire, England. Pfizer Global Res & Dev, Sandwich, Kent, England. Childrens Hosp Orange Cty, Orange, CA 92668 USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. RP Walsh, TJ (reprint author), NICHHD, NCI, Pediat Oncol Branch, Bldg 10,Rm 13N240, Bethesda, MD 20892 USA. EM walsht@mail.nih.gov RI lutsar, irja/H-3177-2015 NR 20 TC 189 Z9 209 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JUN PY 2004 VL 48 IS 6 BP 2166 EP 2172 DI 10.1128/AAC.48.6.2166-2172.2004 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 826FE UT WOS:000221813900038 PM 15155217 ER PT J AU Samuni, Y Gamson, J Samuni, A Yamada, K Russo, A Krishna, MC Mitchell, JB AF Samuni, Y Gamson, J Samuni, A Yamada, K Russo, A Krishna, MC Mitchell, JB TI Factors influencing nitroxide reduction and cytotoxicity in vitro SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID ELECTRON-PARAMAGNETIC-RESONANCE; TRANSIENT FOCAL ISCHEMIA; SPIN LABELS; STABLE NITROXIDE; LIVING CELLS; REDOX STATUS; RAT-LIVER; TEMPOL; METABOLISM; SUPEROXIDE AB Nitroxides have been shown to be effective antioxidants, radiation protectors, and redox-active probes for functional electron paramagnetic resonance (EPR) imaging. More recently, the nitroxide 4-hydroxy-2,2,6, 6-tetramethylpiperidinyl-N-oxyl (Tempol) has been shown to exert differential cytotoxicity to tumor compared with normal cell counterparts. Nitroxides are readily reduced in tissues to their respective hydroxylamines, which exhibit less cytotoxicity in vitro and do not provide radiation protection or an EPR-detectable signal for imaging. In order to better understand factors that influence nitroxide reduction, the rate of reduction of Tempol in mouse and human cell lines and in primary cultures of tumor cells was measured using EPR spectroscopy. Additionally, the cytotoxicity of high concentrations of Tempol and the hydroxylamine of Tempol (Tempol-H) was evaluated in wild-type and glucose-6-phosphate dehydrogenase (G6PD)-deficient Chinese hamster ovary cells. The results show that in general Tempol was reduced at a faster rate when cells were under hypoxic compared with aerobic conditions. Neither depletion of intracellular glutathione nor treatment of cells with sodium cyanide influenced Tempol reduction rates. G6PD-deficient cells were found to reduce Tempol at a significantly slower rate than wild-type cells. Likewise, Tempol-induced cytotoxicity was markedly less for G6PD-deficient cells compared with wild-type cells. Tempol-H exhibited no cytotoxicity to either cell type. Tempol-mediated cytotoxicity was enhanced by glutathione depletion and inhibition of 6-phosphogluconate dehydrogenase in wild-type cells, but was unaltered in GOD-deficient cells. Collectively, the results indicate that while the bioreduction of Tempol can be influenced by a number of factors, the hexose monophosphate shunt appears to be involved in both nitroxide reduction as well as cytotoxicity induced by high levels of exposure to Tempol. C1 NCI, Radiat Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP NCI, Radiat Biol Branch, Ctr Canc Res, Bldg 10,Room B3-B69, Bethesda, MD 20892 USA. EM jbm@helix.nih.gov RI Yamada, Ken-ichi/E-6318-2012 NR 46 TC 32 Z9 32 U1 2 U2 11 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD JUN PY 2004 VL 6 IS 3 BP 587 EP 595 DI 10.1089/152308604773934341 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 825QQ UT WOS:000221773500012 PM 15130285 ER PT J AU Rifkind, JM Ramasamy, S Manoharan, PT Nagababu, E Mohanty, JG AF Rifkind, JM Ramasamy, S Manoharan, PT Nagababu, E Mohanty, JG TI Redox reactions of hemoglobin SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Review ID ELECTRON-PARAMAGNETIC RESONANCE; NITRIC OXIDE HEMOGLOBIN; HYDROGEN-PEROXIDE; HEME DEGRADATION; AUTOCATALYTIC OXIDATION; SUPEROXIDE-PRODUCTION; EPR SPECTROSCOPY; CROSS-LINKING; HUMAN BLOOD; MECHANISM AB Redox reactions of hemoglobin have gained importance because of the general interest of the role of oxidative stress in diseases and the possible role of red blood cells in oxidative stress. Although electron paramagnetic resonance (EPR) is extremely valuable in studying hemoglobin redox reactions it has not been adequately used. We have focused in this review on the important contributions of EPR to our understanding of hemoglobin redox reactions. We have limited our discussion to the redox reactions thought to occur under physiological conditions. This includes autoxidation as well as the reactions of hydrogen peroxide generated by superoxide dismutation. We have also discussed redox reactions associated with nitric oxide produced in the circulation. We have pinpointed the value of using EPR to detect and study the paramagnetic species and free radicals formed during these reactions. We have shown how EPR not only identifies the paramagnetic species formed but can also be used to provide insights into the mechanism involved in the redox reactions. C1 NIA, Mol Dynam Sect, Baltimore, MD 21224 USA. Indian Inst Technol, Dept Chem, Madras 600036, Tamil Nadu, India. Indian Inst Technol, Reg Sophisticated Instrumentat Ctr, Madras 600036, Tamil Nadu, India. RP NIA, Mol Dynam Sect, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM rifkindj@grc.nia.nih.gov NR 51 TC 33 Z9 34 U1 0 U2 7 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD JUN PY 2004 VL 6 IS 3 BP 657 EP 666 DI 10.1089/152308604773934422 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 825QQ UT WOS:000221773500020 PM 15130293 ER PT J AU Woo, JH Liu, YY Stavrou, S Neville, DM AF Woo, JH Liu, YY Stavrou, S Neville, DM TI Increasing secretion of a bivalent anti-T-cell immunotoxin by Pichia pastoris SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID SINGLE-CHAIN IMMUNOTOXIN; TRUNCATED DIPHTHERIA-TOXIN; SACCHAROMYCES-CEREVISIAE; PROTEIN; DOMAIN; YEAST; TRANSLOCATION; EXPRESSION; METABOLISM; MEMBRANE AB The bivalent anti-T-cell immunotoxin A-dmDT390-bisFv(G(4)S) was developed for treatment of T-cell leukemia and autoimmune diseases and for tolerance induction for transplantation. This immunotoxin was produced extracellularly in toxin-sensitive Pichia pastoris JW102 (Mut(+)) under control of the AOX1 promoter. There were two major barriers to efficient immunotoxin production, the toxicity of the immunotoxin for P. pastoris and the limited capacity of P. pastoris to secrete the immunotoxin. The immunotoxin toxicity resulted in a decrease in the methanol consumption rate, cessation of cell growth, and low immunotoxin productivity after the first 22 h of methanol induction. Continuous cell growth and continuous immunotoxin secretion after the first 22 h of methanol induction were obtained by adding glycerol to the methanol feed by using a 4:1 methanol-glycerol mixed feed as an energy source and by continuously adding a yeast extract solution during methanol induction. The secretory capacity was increased from 22.5 to 37 mg/liter by lowering the induction temperature. A low temperature reduced the methanol consumption rate and protease activity in the supernatant but not cell growth. The effects of adding glycerol and yeast extract to the methanol feed were synergistic. Adding yeast extract primarily enhanced methanol utilization and cell growth, while adding glycerol primarily enhanced immunotoxin production. The synergy was further enhanced by decreasing the induction temperature from 23 to 15degreesC, which resulted in a robust process with a yield of 37 mg/liter, which was sevenfold greater than the yield previously reported for a toxin-resistant CHO cell expression system. This methodology should be applicable to other toxin-related recombinant proteins in toxin-sensitive P. pastoris. C1 NIMH, Mol Biol Lab, Biophys Chem Sect, Bethesda, MD 20892 USA. RP Woo, JH (reprint author), NIMH, Mol Biol Lab, Biophys Chem Sect, Bldg 36,Rm 1B-08,36 Convent Dr, Bethesda, MD 20892 USA. EM wooj@mail.nih.gov NR 27 TC 31 Z9 32 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD JUN PY 2004 VL 70 IS 6 BP 3370 EP 3376 DI 10.1128/AEM.70.6.3370-3376.2004 PG 7 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 828NX UT WOS:000221981100023 PM 15184133 ER PT J AU Weickert, CS Straub, RE McClintock, BW Matsumoto, M Hashimoto, R Hyde, TM Herman, MM Weinberger, DR Kleinman, JE AF Weickert, CS Straub, RE McClintock, BW Matsumoto, M Hashimoto, R Hyde, TM Herman, MM Weinberger, DR Kleinman, JE TI Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID DUCHENNE MUSCULAR-DYSTROPHY; CORTICAL PYRAMIDAL NEURONS; DENDRITIC SPINE DENSITY; MESSENGER-RNA; GLYCOPROTEIN COMPLEX; 6P22.3 GENE; SOMAL SIZE; PROTEIN; MOUSE; SYNAPTOPHYSIN AB Context: The schizophrenia-susceptibility gene dysbindin (DTNBP1 on 6p22.3) encodes a neuronal protein that binds to beta-dystrobrevin and may be part of the dystrophin protein complex. Little is known about dysbindin expression in normal or schizophrenic brain. Objectives: To determine whether brain regions implicated in schizophrenia express dysbindin and whether abnormal levels of dysbindin messenger RNA (mRNA) may be found in this disorder and to test whether sequence variations in the dysbindin gene in the promoter region, 5' and 3' untranslated regions, or introns would affect dysbindin mRNA levels. Methods: In patients with schizophrenia and controls, we compared dysbindin, synaptophysin, spinophilin, and cyclophilin mRNA levels in the dorsolateral prefrontal cortex and dysbindin mRNA levels in the midbrain by in situ hybridization. We genotyped brain DNA at 11 single nucleotide polymorphisms to determine whether genetic variation in the dysbindin gene affects cortical dysbindin mRNA levels. Main Outcome Measures: Quantitative assessment of dysbindin mRNA levels across various brain regions and comparative studies of dysbindin mRNA levels in brains of patients with schizophrenia compared with normal controls. Results: Dysbindin mRNA was detected in the frontal cortex, temporal cortex, hippocampus, caudate, putamen, nucleus accumbens, amygdala, thalamus, and midbrain of the adult brain. Patients with schizophrenia had statistically significantly reduced dysbindin mRNA levels in multiple layers of the dorsolateral prefrontal cortex, whereas synaptophysin, spinophilin, and cyclophilin mRNA levels were unchanged. Dysbindin mRNA levels were quantitatively reduced in the midbrain of patients with schizophrenia, but not statistically significantly. Cortical dysbindin mRNA levels varied statistically significantly according to dysbindin genotype. Conclusions: Dysbindin mRNA is expressed widely in the brain, and its expression is reduced in schizophrenia. Variation in dysbindin mRNA levels may be determined in part by variation in the promoter and the 5' and 3' untranslated regions. These data add to the evidence that dysbindin is an etiologic factor in schizophrenia risk. C1 NIMH, Intramural Res Program, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. Yamanouchi Pharmaceut Co Ltd, Dept Genom Res, Ibaraki, Japan. Natl Inst Neurosci, Dept Mental Disorder Res, Natl Ctr Neurol & Psychiat, Tokyo, Japan. RP Weickert, CS (reprint author), NIMH, Intramural Res Program, Clin Brain Disorders Branch, NIH, 10 Ctr Dr,Bldg 10,Room 4N312,Mail Stop Code 1385, Bethesda, MD 20892 USA. EM shannowc@intra.nimh.nih.gov RI Shannon Weickert, Cynthia/G-3171-2011; Matsumoto, Mitsuyuki/G-3207-2012; Hashimoto, Ryota/P-8572-2014 OI Matsumoto, Mitsuyuki/0000-0002-1172-2354; Hashimoto, Ryota/0000-0002-5941-4238 NR 71 TC 233 Z9 244 U1 1 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD JUN PY 2004 VL 61 IS 6 BP 544 EP 555 DI 10.1001/archpsyc.61.6.544 PG 12 WC Psychiatry SC Psychiatry GA 826JG UT WOS:000221824800003 PM 15184234 ER PT J AU Xu, K Lichtermann, D Lipsky, RH Franke, P Liu, XH Hu, Y Cao, LP Schwab, SG Wildenauer, DB Bau, CHD Ferro, E Astor, W Finch, T Terry, J Taubman, J Maier, W Goldman, D AF Xu, K Lichtermann, D Lipsky, RH Franke, P Liu, XH Hu, Y Cao, LP Schwab, SG Wildenauer, DB Bau, CHD Ferro, E Astor, W Finch, T Terry, J Taubman, J Maier, W Goldman, D TI Association of specific haplotypes of D-2 dopamine receptor gene with vulnerability to heroin dependence in 2 distinct populations SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID LINKAGE DISEQUILIBRIUM; ALLELIC ASSOCIATION; D2 RECEPTORS; HUMAN GENOME; A1 ALLELE; ALCOHOLISM; ABUSE; STRATIFICATION; LOCUS; DRD2 AB Context: Dopamine receptor-mediated pathways play critical roles in the mechanism of addiction. However, associations of the D-2 dopamine receptor gene (DRD2) with substance abuse are controversial. Objective: To determine whether susceptibility sites re sided at DRD2. Design: Haplotype-based case-control analysis of 2 distinct populations using 10 single nucleotide polymorphisms (SNPs) with heroin dependence. Setting: Universities of Mainz and Bonn, Germany, and 3 local hospitals in southwestern China. Patients: Cases and control subjects recruited from China (486 cases, 313 controls) and Germany (471 cases, 192 controls). Interventions: Genotyping for 10 SNPs by 5'-exonuclease fluorescence assays. The D' value of linkage disequilibrium and haplotypes were generated by the expectation-maximization algorithm. Main Outcome Measures: Genotype, allele, and haplotype frequencies were compared between cases and controls by chi(2) tests constructed for each population. An additional 32 SNPs randomly distributed in the genome were genotyped for detecting population admixture in the 2 populations. Results: A haplotype block of 25.8 kilobases (kb) was defined by 8 SNPs extending from SNP3, (TaqIB) at the 5' end to SNP10 site (TaqIA) located 10 kb distal to the 3' end of the gene. Within this block, specific haplotype cluster A (carrying TaqIB1 allele) was associated with a high risk of heroin dependence in Chinese patients (P = 1.425 x 10(-22); odds ratio, 52.80; 95% confidence interval, 7.290-382.5 for 8-SNP analysis). A putative recombination "hot spot" was found near SNP6 (intron 6 ins/del G), creating 2 new daughter haplotypes that were associated with a lower risk of heroin dependence in Germans (P = 1.94 x 10(-11) for 8-SNP analysis). There was no evidence of population stratification in either population. Conclusions: These results strongly support a role of DRD2 as a susceptibility gene with heroin dependence in Chinese patients and was associated with low risk of heroin dependence in Germans. C1 NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. Univ Bonn, Dept Psychiat, D-5300 Bonn, Germany. Sichuan Univ, Sch Med, Dept Psychiat, Sichuan, Peoples R China. NCI, Lab Populat Genet, Bethesda, MD USA. Univ Fed Rio Grande Sul, Inst Biociencias, Dept Genet, BR-90049 Porto Alegre, RS, Brazil. RP Xu, K (reprint author), NIAAA, Neurogenet Lab, 12420 Parklawn Dr,Pk Bldg,Room 451, Rockville, MD 20852 USA. EM ke@mail.nih.gov RI Bau, Claiton/C-9980-2013; Goldman, David/F-9772-2010; OI Bau, Claiton/0000-0001-5644-3845; Goldman, David/0000-0002-1724-5405; Lipsky, Robert/0000-0001-7753-1473 NR 34 TC 81 Z9 87 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD JUN PY 2004 VL 61 IS 6 BP 597 EP 606 DI 10.1001/archpsyc.61.6.597 PG 10 WC Psychiatry SC Psychiatry GA 826JG UT WOS:000221824800008 PM 15184239 ER PT J AU Rakocevic, G Raju, R Dalakas, MC AF Rakocevic, G Raju, R Dalakas, MC TI Anti-glutamic acid decarboxylase antibodies in the serum and cerebrospinal fluid of patients with Stiff-Person syndrome correlation with clinical severity SO ARCHIVES OF NEUROLOGY LA English DT Article ID NEUROLOGICAL DISORDERS; AUTOANTIBODIES AB Background: Stiff-person syndrome (SPS) is an immune-mediated central nervous system disorder characterized by fluctuating muscle stiffness, disabling spasms, and heightened sensitivity to external stimuli. Up to 80% of patients with SPS have anti-glutamic acid decarboxylase (GAD) antibodies in the serum or cerebral spinal fluid (CSF). Whether these antibodies are clinically relevant and correlate with disease severity is unknown. Objective: To correlate anti-GAD antibody titers in the serum and CSF of patients with SPS with the degree of clinical severity. Design: Patients studied the last 6 years. Setting: The Clinical Center of the National Institutes of Health, Bethesda, Md. Patients: Sixteen patients with typical SPS and elevated serum anti-GAD antibody titers. Interventions: Antibody titers in serum and CSF were measured by radioimmunoassay, and the intrathecal anti-GAD-specific IgG production was calculated. Main Outcome Measures: Comparison of antibody titers with stiffness index and heightened sensitivity scores based on scales that reliably measure disease severity. Results: The mean disease duration was 11 years (range, 5-30 years). The mean anti-GAD antibody titer in the serum was 51500 U/mL (range, 24000-200000 U/mL); and in the CSF, 181 U/mL (range, 30-400 U/mL). A 10-fold increased intrathecal production of GAD-specific IgG antibodies was noted. No correlation was found between antibody titers in serum or CSF with disease severity. In 4 patients, the anti-GAD antibody titers measured serially during a 2-year period did not correlate with clinical fluctuations. Conclusions: In patients with SPS, the anti-GAD antibody titers in serum and CSF do not correlate with disease severity or duration. Anti-GAD antibodies are an excellent marker for SPS, but monitoring their titers during the course of the disease may not be of practical value. C1 NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), NINDS, Neuromuscular Dis Sect, NIH, Bldg 10,Room 4N248,10 Ctr Dr,MSC 1382, Bethesda, MD 20892 USA. EM dalakasm@ninds.nih.gov RI Raju, Raghavan/E-9219-2011 NR 10 TC 52 Z9 53 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD JUN PY 2004 VL 61 IS 6 BP 902 EP 904 DI 10.1001/archneur.61.6.902 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 827XL UT WOS:000221936900011 PM 15210528 ER PT J AU Smith-Khuri, E Iachan, R Scheidt, PC Overpeck, MD Gabhainn, SN Pickett, W Harel, Y AF Smith-Khuri, E Iachan, R Scheidt, PC Overpeck, MD Gabhainn, SN Pickett, W Harel, Y TI A cross-national study of violence-related behaviors in adolescents SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID HIGH-SCHOOL-STUDENTS; RISK; HEALTH; ASSOCIATION; RELIABILITY; VALIDITY; CHILDREN; YOUTH AB Background: Violent behavior among adolescents is a significant problem worldwide, and a cross-national comparison of adolescent violent behaviors can provide information about the development and pattern of physical violence in young adolescents. Objectives: To determine and compare frequencies of adolescent violence-related behaviors in 5 countries and to examine associations between violence-related behaviors and potential explanatory characteristics. Design, Setting, and Participants: Cross-sectional, school-based nationally representative survey at ages 11.5, 13.5, and 15.5 years in 5 countries (Ireland, Israel, Portugal, Sweden, and the United States). Main Outcome Measures: Frequency of physical fighting, bullying, weapon carrying, and fighting injuries in relation to other risk behaviors and characteristics in home and school settings. Results: Fighting frequency among US youth was similar to that of all 5 countries (nonfighters: US, 60.2%; mean frequency of 5 countries, 60.2%), as were the frequencies of weapon carrying (noncarriers: US, 89.6%; mean frequency of 5 countries, 89.6%) and fighting injury (noninjured: US, 84.5%; mean frequency of 5 countries, 84.6%). Bullying frequency varied widely cross-nationally (nonbullies: from 57.0% for Israel to 85.2% for Sweden). Fighting was most highly associated with smoking, drinking, feeling irritable or bad tempered, and having been bullied. Conclusions: Adolescents in 5 countries behaved similarly in their expression of violence-related behaviors. Occasional fighting and bullying were common, whereas frequent fighting, frequent bullying, any weapon carrying, or any fighting injury were infrequent behaviors. These findings were consistent across countries, with little cross-national variation except for bullying rates. Traditional risk-taking behaviors (smoking and drinking) and being bullied were highly associated with the expression of violence-related behavior. C1 NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. Macro Int Inc, Calverton, MD USA. Maternal & Child Hlth Bur, Rockville, MD USA. Natl Univ Ireland Univ Coll Galway, Dept Hlth Promot, Galway, Ireland. Queens Univ, Dept Community Hlth & Epidemiol, Kingston, ON K7L 3N6, Canada. Bar Ilan Univ, Dept Sociol & Anthropol, Ramat Gan, Israel. RP Scheidt, PC (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd,MSC 7510, Bethesda, MD 20892 USA. EM Scheidtp@nih.gov FU NICHD NIH HHS [N01-HD-3272] NR 28 TC 76 Z9 77 U1 1 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD JUN PY 2004 VL 158 IS 6 BP 539 EP 544 DI 10.1001/archpedi.158.6.539 PG 6 WC Pediatrics SC Pediatrics GA 826KJ UT WOS:000221827700006 PM 15184216 ER PT J AU Chi-Fishman, G Hicks, JE Cintas, HM Sonies, BC Gerber, LH AF Chi-Fishman, G Hicks, JE Cintas, HM Sonies, BC Gerber, LH TI Ultrasound imaging distinguishes between normal and weak muscle SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE muscles; myositis; rehabilitation; ultrasonography ID KNEE EXTENSOR MUSCLES; IN-VIVO MEASUREMENTS; STRENGTH MEASUREMENTS; COMPUTED-TOMOGRAPHY; ULTRASONOGRAPHY; TENSION; ARCHITECTURE; MYOPATHIES; WOMEN AB Objective: To determine whether real-tine ultrasound imaging can provide quantitative data that distinguish pathologic from healthy muscle and that correlate with strength measures. Design: Nonrandomized matched-pair, repeated-measures design. Setting: Ultrasound imaging laboratory, rehabilitation medicine department, government research hospital. Participants: Nine patients with stable active or inactive myositis, stratified into 3 groups based on their 10-point manual muscle test (MMT) scores, and 9 age- and gender-matched controls. Interventions: Maximal isometric contraction of the rectus femoris muscle in 2 knee-flexion positions (60, 90) during simultaneous ultrasound imaging and muscle force dynamometry. Main Outcomes Measures: Changes of the rectus femoris muscle in horizontal (X) and vertical (Y) diameters between relaxed and contracted states, and muscle force measurements. Results: The X diameters decreased and the Y diameters increased during isometric contraction in all participants. For each group, average changes in cross-sectional diameters were consistently higher in controls than in patients. Patients with MMT less than 8 differed significantly from controls in both X and Y dimensions. A moderately strong correlation was found between muscle force and the Y diameter during contraction at 60degrees (r=.78) and 90degrees (r=.67) knee-flexion angles. Conclusions: Ultrasonography provided a quantitative measure of change between relaxed and contracted state of muscle, which correlated with muscle force. Ultrasound identified significant differences in cross-sectional diameters between the myopathic and normal muscles sampled and may be useful for measuring muscle response to drug and exercise therapy. (C) 2004 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation. C1 NIH, Dept Rehabil Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Gerber, LH (reprint author), NIH, Dept Rehabil Med, Warren G Magnuson Clin Ctr, 6S235-10,900 Rockville Pike, Bethesda, MD 20892 USA. EM lgerber@nih.gov NR 20 TC 33 Z9 34 U1 0 U2 10 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD JUN PY 2004 VL 85 IS 6 BP 980 EP 986 DI 10.1016/j.apmr.2003.07.008 PG 7 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 826NK UT WOS:000221835600018 PM 15179654 ER PT J AU Takemoto, K Nakajima, M Fujiki, Y Katoh, M Gonzalez, FJ Yokoi, T AF Takemoto, K Nakajima, M Fujiki, Y Katoh, M Gonzalez, FJ Yokoi, T TI Role of the aryl hydrocarbon receptor and Cyp1b1 in the antiestrogenic activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin SO ARCHIVES OF TOXICOLOGY LA English DT Article DE Cyp1b1; aryl hydrocaron receptor; estrogen receptor; 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); antiestrogenic activity ID BREAST-CANCER CELLS; ESTROGEN-RECEPTOR; MOUSE UTERUS; HEPATIC CYTOCHROME-P-450; AROMATIC-HYDROCARBONS; GENE-EXPRESSION; MICE LACKING; AH RECEPTOR; MCF-7 CELLS; FEMALE RAT AB The role of aryl hydrocarbon receptor (AhR) and cytochrome P450 (Cyp) I family in the antiestrogenic activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was investigated in vivo. Immature (21 days old) AhR, Cyp1a2, or Cyp1b1 knockout (-/-) mice were treated intraperitoneally with estradiol (E2, 20 ng/mouse per day, for 14 consecutive days) and/or TCDD (200 ng/mouse per day, on days 7, 9, 11, and 13). Uterine wet weight and uterine peroxidase activity (UPA) were measured as markers of estrogen responsiveness. UPA was a better marker of estrogen responsiveness than the uterine wet weight. In AhR wild-type (+/+) mice, UPA (208.1 +/- 81.6 units/g tissue) was increased by the administration of E2 (to 297.2 +/- 178.7 units/g). The administration of TCDD significantly (p<0.01) decreased the UPA (10.5 &PLUSMN; 3.4 units/g) compared with that in the control mice. Co-administration of TCDD with E2 also significantly (p < 0.05) decreased the UPA (18.8 +/- 19.9 units/g) compared with that in E2-treated mice. In AhR(-/-) mice, UPA (162.9 +/- 146.7 units/g) was significantly (p<0.01) increased by the administration of E2 (486.8 &PLUSMN; 108.2 units/g). In contrast to the results in AhR(+/+) mice, UPA was not affected by the administration of TCDD (51.8 &PLUSMN; 70.6 units/g) compared with control, and co-administration of TCDD with E2 (545.8 &PLUSMN; 189.4 units/g) compared with that in E2-treated mice. In Cyp1a2/1b1 (+/+) mice, UPA was significantly (p < 0.05) increased by the administration of E2 (70.0 +/- 36.4 units/g). Co-administration of TCDD with E2 significantly (p < 0.05) decreased the UPA (29.6 &PLUSMN; 22.2 units/g) compared with that in E2-treated mice. In Cypla2(-/-) mice, co-administration of TCDD with E2 significantly (p<0.01) decreased the UPA (6.8 +/- 5.1 units/g) compared with that in E2-treated mice. In Cyp1b1(-/-) mice, UPA (5.5 +/- 8.1 units/g) was significantly (p < 0.05) increased by the administration of E2 (56.6 &PLUSMN; 34.1 units/g). In contrast to the results in Cyp1a2/1b1 (+/+) mice or Cyp1a2(-/-) mice, UPA was not affected by the co-administration of TCDD and E2 (52.6130.1 units/g) compared with that in E2-treated mice. This is the first demonstration that Cyp1b1 as well as AhR is involved in the antiestrogenic effects of TCDD. C1 Kanazawa Univ, Fac Pharmaceut Sci, Div Drug Metab, Kanazawa, Ishikawa 9200934, Japan. NCI, Bethesda, MD 20892 USA. RP Yokoi, T (reprint author), Kanazawa Univ, Fac Pharmaceut Sci, Div Drug Metab, Takara Machi 13-1, Kanazawa, Ishikawa 9200934, Japan. EM TYOKOI@kenroku.kanazawa-u.ac.jp RI Nakajima, Miki/C-3990-2015; yokoi, tsuyoshi/I-7115-2014 NR 38 TC 19 Z9 20 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0340-5761 J9 ARCH TOXICOL JI Arch. Toxicol. PD JUN PY 2004 VL 78 IS 6 BP 309 EP 315 DI 10.1007/s00204-004-0550-7 PG 7 WC Toxicology SC Toxicology GA 841PN UT WOS:000222943200003 PM 15004665 ER PT J AU Illei, GG Tackey, E Lapteva, L Lipsky, PE AF Illei, GG Tackey, E Lapteva, L Lipsky, PE TI Biomarkers in systemic lupus erythematosus - 1. General overview of biomarkers and their applicability SO ARTHRITIS AND RHEUMATISM LA English DT Review ID MANNOSE-BINDING LECTIN; CONVERTING-ENZYME GENE; NECROSIS-FACTOR-ALPHA; SURROGATE END-POINTS; GAMMA RECEPTOR IIA; CHINESE PATIENTS; JAPANESE PATIENTS; PROTEIN GENE; PROMOTER POLYMORPHISMS; RHEUMATOID-ARTHRITIS C1 NIAMSD, NIH, Off Clin Director, Bethesda, MD 20892 USA. NIAMSD, NIH, DHHS, Bethesda, MD 20892 USA. RP Illei, GG (reprint author), NIAMSD, NIH, Off Clin Director, 10 Ctr Dr,Room 9S205, Bethesda, MD 20892 USA. EM illeig@mail.nih.gov NR 93 TC 60 Z9 67 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD JUN PY 2004 VL 50 IS 6 BP 1709 EP 1720 DI 10.1002/art.20344 PG 12 WC Rheumatology SC Rheumatology GA 827CL UT WOS:000221876000004 PM 15188346 ER PT J AU Galligan, CL Matsuyama, W Matsukawa, A Mizuta, H Hodge, DR Howard, OMZ Yoshimura, T AF Galligan, CL Matsuyama, W Matsukawa, A Mizuta, H Hodge, DR Howard, OMZ Yoshimura, T TI Up-regulated expression and activation of the. orphan chemokine receptor, CCRL2, in rheumatoid arthritis SO ARTHRITIS AND RHEUMATISM LA English DT Article ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; LEUKOCYTE POPULATIONS; FUNCTIONAL EXPRESSION; MOLECULAR-CLONING; CC-CHEMOKINE; T-CELLS; NEUTROPHILS; ANTAGONIST; SYNOVITIS; CYTOKINES AB Objective. Rheumatoid arthritis (RA) is a chronic inflammatory condition characterized by a cellular influx and destruction of the joint architecture. Chemokines characteristically regulate leukocyte recruitment and activation. Chemokine (CC motif) receptor-like 2 (CCRL2) is an orphan receptor with homology to other CC chemokine receptors. We undertook this study to examine CCRL2 expression in RA, cytokine regulation of expression, and the source of a putative ligand in an attempt to determine the role of this receptor during inflammation. Methods. Expression of CCRL2 on joint-infiltrating leukocytes was examined by immunocytochemistry. In vitro studies evaluated CCRL2 expression in primary neutrophils using Northern and Western blotting and reverse transcriptase-polymerase chain reaction. HEK 293 cells expressing two splice variants of CCRL2 (HEK/CCRL2A or HEK/CCRL2B) were generated with a retroviral expression system, and their migration in response to fractions of synovial fluid (SF) from RA patients was examined using a 48-well chamber. Results. CCRL2 expression was observed on all infiltrating neutrophils and on some macrophages obtained from the SF of 5 RA patients. In vitro studies of primary neutrophils revealed that CCRL2 messenger RNA (mRNA) was rapidly up-regulated following stimulation with lipopolysaccharide (1 mug/ml) or tumor necrosis factor (5 ng/ml). The mRNA for both CCRL2A and CCRL2B were expressed in cytokine-stimulated neutrophils. Cells expressing either of these splice variants migrated in response to a fraction of RA SF. Conclusion. CCRL2 expression is up-regulated on synovial neutrophils of RA patients. Inflammatory products present in the SF activate this receptor, indicating that CCRL2 is a functional receptor that may be involved in the pathogenesis of RA. C1 NCI, Frederick, MD 21702 USA. Kumamoto Univ, Grad Sch Med Sci, Kumamoto, Japan. RP Yoshimura, T (reprint author), NCI, Bldg 559,Room 9, Frederick, MD 21702 USA. EM yoshimur@mail.ncifcrf.gov RI Howard, O M Zack/B-6117-2012 OI Howard, O M Zack/0000-0002-0505-7052 NR 31 TC 30 Z9 34 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD JUN PY 2004 VL 50 IS 6 BP 1806 EP 1814 DI 10.1002/art.20275 PG 9 WC Rheumatology SC Rheumatology GA 827CL UT WOS:000221876000015 PM 15188357 ER PT J AU Karlson, EW Liang, MH Eaton, H Huang, J Fitzgerald, L Rogers, MP Daltroy, LH AF Karlson, EW Liang, MH Eaton, H Huang, J Fitzgerald, L Rogers, MP Daltroy, LH TI A Randomized clinical trial of a psychoeducational intervention to improve outcomes in systemic lupus erythematosus SO ARTHRITIS AND RHEUMATISM LA English DT Article ID ARTHRITIS PATIENT EDUCATION; QUALITY-OF-LIFE; RHEUMATOID-ARTHRITIS; SOCIAL SUPPORT; SOCIOECONOMIC-STATUS; SELF-EFFICACY; FUNCTIONAL STATUS; DISEASE-ACTIVITY; HEALTH-STATUS; WOMEN AB Objective. In a cross-sectional study, we previously identified 2 potentially modifiable risk factors for adverse outcomes in systemic lupus erythematosus (SLE): self-efficacy and social support. The goal of this study was to evaluate in a randomized controlled trial a theory-based intervention to improve patient self-efficacy and partner support to manage SLE. Methods. Patients with SLE ages 18 years and older who met the American College of Rheumatology criteria and were able to identify a partner (spouse or family member) were recruited from 2 academic medical centers and randomized into an experimental group or a control group. Patients in the experimental group and their partners received an intervention designed to enhance self-efficacy, couples communication about lupus, social support, and problem solving, in the form of a I-hour session with a nurse educator followed by monthly telephone counseling for 6 months. Patients in the control group and their partners received an attention placebo, including a 45-minute video presentation about lupus, and monthly telephone calls. Measures of physical and mental health status, disease activity, and psychosocial factors were collected at baseline, 6 months, and 12 months. The effect of the intervention on physical and mental health and disease activity at 6 and at 12 months was modeled with linear regression and adjusted for baseline health status, disease activity, sociodemographic factors, treatment change, and psychosocial factors. Results. One hundred twenty-two patients (plus their partners) were enrolled and randomized as follows: 64 to the experimental intervention and 58 to the attention control group. The participants were predominantly white, approximately half were college educated, and the groups were balanced for sociodemographic factors. At 6 months, significantly higher scores for couples communication (P = 0.01) and problem-focused coping (P = 0.03) were seen in the experimental group compared with the control group. At 12 months (6 months after the intervention ended), social support was higher (4.4 versus 4.1; P = 0.03), self-efficacy was higher (7.2 versus 6.2; P = 0.02), couples communication was higher (3.5 versus 3.1; P = 0.03), and fatigue was lower (5.1 versus 6.3; P = 0.02) in the experimental group compared with the control group. Global mental health status at 12 months, as measured by the Short Form 36 survey, was 69 points in the experimental group compared with 58 points in the control group (P = 0.04). In multivariate models, adjusting for baseline covariates, scores for couple communication (P = 0.01) were significantly higher at 6 months, and scores for self-efficacy (P = 0.004) and global mental health status (P = 0.03) were significantly higher at 12 months in the experimental group compared with the control group, and the mean score for global physical function was higher by 7 points, which was a clinically meaningful change (P = 0.2). The mean score for fatigue was also significantly lower in the experimental group than in the control group (P = 0.05). SLE disease activity was unchanged by this intervention. Conclusion. This randomized, controlled trial of a theory-based educational intervention in SLE demonstrated significantly higher scores for couple communication, self-efficacy, and mental health status, and lower fatigue scores in the experimental group compared with the control group. Because couple communication and self-efficacy appear to be modifiable risk factors, they may also be potential targets in more disadvantaged populations. C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Robert B Brigham Arthrit & Musculoskeletal Dis Cl, Boston, MA USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. NIAMSD, Bethesda, MD 20892 USA. Beth Israel Deaconess Hosp, Boston, MA USA. RP Karlson, EW (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM ekarlson@partners.org FU NIAMS NIH HHS [AR-30692, AR-36308, AR-41607] NR 66 TC 64 Z9 68 U1 1 U2 14 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD JUN PY 2004 VL 50 IS 6 BP 1832 EP 1841 DI 10.1002/art.20279 PG 10 WC Rheumatology SC Rheumatology GA 827CL UT WOS:000221876000018 PM 15188360 ER PT J AU Hansen, A Gosemann, M Pruss, A Reiter, K Ruzickova, S Lipsky, PE Dorner, T AF Hansen, A Gosemann, M Pruss, A Reiter, K Ruzickova, S Lipsky, PE Dorner, T TI Abnormalities in peripheral B cell memory of patients with primary Sjogren's Syndrome SO ARTHRITIS AND RHEUMATISM LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; CYTIDINE DEAMINASE AID; SALIVARY-GLANDS; SOMATIC HYPERMUTATION; CHAIN DIVERSITY; LYMPHOID-TISSUE; GENE ANALYSIS; PLASMA-CELLS; EXPRESSION; BLOOD AB Objective. To delineate disturbances in peripheral B cell memory in primary Sjogren's syndrome (SS). Methods. Isotype-specific immunoglobulin (Ig) heavy-chain transcripts were analyzed in single-sorted CD19+,CD27- naive and CD19+,CD27+ memory B cells from patients with primary SS and normal healthy control subjects. Results. A significantly higher frequency of B cells expressing mu-, alpha-, and/or gamma-chain transcripts were found in patients with primary SS compared with controls (58.0% versus 14.3%; P < 0.0001). Notably, 30.5% of individual B cells (for primary SS, 38.7%; for controls, 12.7% [P < 0.0001]) simultaneously expressed transcripts for different Ig heavy-chain isotypes using identical V-H-D-J(H) rearrangements. However, these cells lacked surface expression of more than one of the respective Ig heavy-chain isotypes as well as messenger RNA (mRNA) transcripts for 2 germinal center markers, activation-induced cytidine deaminase, and Bcl-6. In contrast with the findings in normal healthy controls, peripheral B cell memory in patients with primary SS was characterized by 1) circulating CD27+ B cells expressing heavily mutated Ig V-H transcripts (mutational frequency 8.6% versus 4.3%; P < 0.0001), 2) significantly enhanced mutational frequencies of Cmu transcripts (9.6% versus 2.5%; P < 0.0001), 3) a high proportion (61.2%) of CD27+ B cells expressing transcripts for multiple Ig heavy-chain isotypes, and 4) a CD27- memory-type B cell subpopulation expressing mutated Cmu transcripts. Conclusion. Altogether, both B cell hyperactivity and striking abnormalities in peripheral B cell memory are indicated at the single-cell mRNA level in patients with primary SS. Detection of multiple Ig heavy-chain transcripts in peripheral CD19+,CD27+ memory B cells of patients with SS may represent the abnormal retention of pre-switch mRNA transcripts in circulating post-switch B cells. C1 Univ Hosp Charite, Dept Med, D-10098 Berlin, Germany. Univ Hosp Charite, Outpatients Dept, D-10098 Berlin, Germany. Charles Univ, Inst Rheumatol, Prague, Czech Republic. Charles Univ, Gene Express Lab, Prague, Czech Republic. NIAMSD, NIH, Bethesda, MD 20892 USA. RP Hansen, A (reprint author), Univ Hosp Charite, Dept Med, D-10098 Berlin, Germany. EM arne.hansen@charite.de NR 48 TC 52 Z9 53 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD JUN PY 2004 VL 50 IS 6 BP 1897 EP 1908 DI 10.1002/art.20276 PG 12 WC Rheumatology SC Rheumatology GA 827CL UT WOS:000221876000024 PM 15188366 ER PT J AU Chhabra, RS Ress, NB Harbell, JW Curren, RD AF Chhabra, RS Ress, NB Harbell, JW Curren, RD TI Evaluation of some in vitro tests to reduce and replace the sub-acute animal toxicity studies SO ATLA-ALTERNATIVES TO LABORATORY ANIMALS LA English DT Article; Proceedings Paper CT 4th World Congress on Alternatives and Animal Use in the Life Sciences CY AUG 11-15, 2002 CL New Orleans, LA DE in vitro testing; sub-acute animal toxicity; systemic toxicity ID NATIONAL TOXICOLOGY PROGRAM AB The toxicologic and carcinogenic potential of chemicals is usually determined through a sequence of acute, sub-acute (14-day), sub-chronic (90-day) and chronic (two-year) studies in rats and mice of both sexes. The US National Toxicology Program (NTP) 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 protocol for 14-day studies consists of five doses and control groups and five animals per group of each sex and species, resulting in the use of 120 animals per study. At present, in addition to refining the current testing protocols, the NTP is evaluating the potential for in vitro test methods to partially or completely avoid the need for 14-day toxicity studies, especially for chemicals where the dermal route of exposure is used. The in vitro assays used were the EpiDerm(TM) bioassay to estimate dermal irritation, the neutral red uptake (NRU) bioassay to estimate systemic toxicity and the primary rat hepatocyte cytotoxicity (PRHC) assay to estimate hepatotoxicity. The purpose of using these assays was to assess their potential for predicting relative in vivo toxicity and to support dose selection decisions for 90-day studies. In general, based on these limited number of studies, the EpiDerm and NRU tests were predictive of the responses observed in in vivo studies. However, a larger comparative database is needed to derive definitive conclusions regarding the value of in vitro tests in the prediction of in vivo effects. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Inst In Vitro Sci, Gaithersburg, MD USA. RP Chhabra, RS (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM Chhabrar@NIEHS.NIH.Gov NR 6 TC 0 Z9 0 U1 0 U2 4 PU FRAME PI NOTTINGHAM PA RUSSELL & BURCH HOUSE 96-98 NORTH SHERWOOD ST, NOTTINGHAM NG1 4EE, NOTTS, ENGLAND SN 0261-1929 J9 ATLA-ALTERN LAB ANIM JI ATLA-Altern. Lab. Anim. PD JUN PY 2004 VL 32 SU 1A BP 137 EP 140 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 833QB UT WOS:000222352100020 PM 23577447 ER PT J AU Schechtman, LM Stokes, WS AF Schechtman, LM Stokes, WS TI The FDA's regulatory role in the ICCVAM process SO ATLA-ALTERNATIVES TO LABORATORY ANIMALS LA English DT Article; Proceedings Paper CT 4th World Congress on Alternatives and Animal Use in the Life Sciences CY AUG 11-15, 2002 CL New Orleans, LA DE alternative methods; Food and Drug Administration (FDA); Food Drug and Cosmetic Act; ICCVAM Authorization Act; Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM); NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM); regulatory acceptance; validation ID ALTERNATIVE METHODS; ECVAM AB The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), a permanent body set forth in the ICCVAM Authorization Act of 2000 (Public Law 106-545), is charged with establishing criteria and processes for the validation and regulatory acceptance of toxicological test methods of interest to Federal agencies, including alternative methods that reduce, refine, or replace the use of animals for research and testing purposes. In response to that mandate, 15 Federal regulatory and research agencies and programmes that would consider utilising such methods or the results derived from them, now participate in cross-agency efforts directed toward the identification, standardisation, validation, acceptance, regulatory implementation and international harmonisation and adoption of such test methods. As an integral member of ICCVAM since its inception, the US Food and Drug Administration (FDA) has established processes for responding to ICCVAM issues and recommendations. The participating FDA units include all FDA research and product-based centres and oversight offices. FDA product centres respond to distinct regulatory mandates and regulate different products. Upon completion of a validation effort, ICCVAM forwards its recommendations to member Government agencies regarding the validity and technical acceptability of a method. The FDA's response consists of the conclusions reached by each of its regulatory components and addresses such factors as their concurrence with ICCVAM's conclusions, the practical applicability of the method to the products they regulate and the feasibility of implementation of an accepted method to supplement or supplant those currently used. Each centre/office independently determines which of the ICCVAM-recommended tests are appropriate for implementation to satisfy its regulatory obligations to ensure product safety and to protect human health. The adoption of a method triggers a notification process to announce the availability and utility of a method, encourage its use, and inform, educate and train end-users and regulatory review staff. C1 FDA Natl Ctr Toxicol Res, Washington Operat, Rockville, MD 20857 USA. Natl Inst Environm Hlth Sci, Environm Toxicol Program, Res Triangle Pk, NC USA. RP Schechtman, LM (reprint author), FDA Natl Ctr Toxicol Res, Washington Operat, HFT-10,5600 Fishers Lane, Rockville, MD 20857 USA. EM lschechtman@nctr.fda.gov NR 16 TC 2 Z9 2 U1 0 U2 1 PU FRAME PI NOTTINGHAM PA RUSSELL & BURCH HOUSE 96-98 NORTH SHERWOOD ST, NOTTINGHAM NG1 4EE, NOTTS, ENGLAND SN 0261-1929 J9 ATLA-ALTERN LAB ANIM JI ATLA-Altern. Lab. Anim. PD JUN PY 2004 VL 32 SU 1B BP 663 EP 668 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 833QA UT WOS:000222352000049 PM 23581155 ER PT J AU Sarkar, K Miller, FW AF Sarkar, K Miller, FW TI Autoantibodies as predictive and diagnostic markers of idiopathic inflammatory myopathies SO AUTOIMMUNITY LA English DT Article ID TRANSFER-RNA-SYNTHETASE; MUSCLE-TISSUE; CLASS-I; POLYMYOSITIS; MYOSITIS; DERMATOMYOSITIS; EXPRESSION; DISEASE; INTERLEUKIN-1-ALPHA; CLASSIFICATION C1 NIH, Bethesda, MD 20892 USA. RP Sarkar, K (reprint author), NIH, 9000 Rockville Pike,9-1W107,MSC 0958, Bethesda, MD 20892 USA. EM sarkark@mail.nih.gov OI Miller, Frederick/0000-0003-2831-9593 NR 25 TC 10 Z9 12 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0891-6934 J9 AUTOIMMUNITY JI Autoimmunity PD JUN PY 2004 VL 37 IS 4 BP 291 EP 294 DI 10.1080/08916930410001710839 PG 4 WC Immunology SC Immunology GA 847DD UT WOS:000223372000010 PM 15518044 ER PT J AU Reines, BP AF Reines, BP TI Is rheumatoid arthritis premature osteoarthritis with fetal-like healing? SO AUTOIMMUNITY REVIEWS LA English DT Article DE rheumatoid; arthritis; fibroblast; inflammation; regulatory T cell ID CARTILAGE DESTRUCTION; NEO-FIBROBLASTS; CELLS; ATHEROSCLEROSIS; CHONDROSARCOMA; PROLIFERATION; INFLAMMATION; EXPRESSION; TARGET; HLA AB Rheumatoid arthritis is now known to share many pathogenetic features with osteoarthritis including synovial activation with release of pro-inflammatory cytokines into the synovial fluid. As premature chondrocyte aging and dedifferentiation is increasingly accepted as integral to OA pathogenesis, premature aging of chondrocytes,and perhaps subchondral bone may underlie RA. This hypothesis explains many otherwise enigmatic features of RA joint pathology such as the homing of pannus to cartilage. In addition, the surprising finding of mesenchymal precursor cells in RA joints has led to speculation that some aspect of RA pathogenesis involves an attempt to recapitulate the embryonic limb development program. In its totality, RA seems to consist of an attempt to regenerate damaged cartilage and subchondral bone in an adult organism. Since this is impossible, the best the pannus can do is to crawl through empty cartilage lacunae and replace the cartilage and subchondral bone with scar tissue. As opposed to fetal healing, inflammation is necessary to sustain and control the fibroproliferation. Two recently-discovered blood cell types seem to maintain and regulate fibroplastic states in humans: (1) CD34+ and/or monocytoid stem-cell precursors replace aging mesenchymal cells, and (2) regulatory-type adherent CD4+CD28- T cells control growth of those increasingly apoptosis-resistant mesenchymal cells. Such cells occur at multiple sites in AID patients. (C) 2003 Elsevier B.V. All rights reserved. C1 NIAID, T Cell tolerance & Memory Sect, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Reines, BP (reprint author), NIAID, T Cell tolerance & Memory Sect, Cellular & Mol Immunol Lab, NIH, 4 Ctr Dr,Rm 111, Bethesda, MD 20892 USA. EM breines@niaid.nih.gov NR 39 TC 6 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-9972 J9 AUTOIMMUN REV JI Autoimmun. Rev. PD JUN PY 2004 VL 3 IS 4 BP 305 EP 311 DI 10.1016/j.autrev.2003.11.002 PG 7 WC Immunology SC Immunology GA 845IY UT WOS:000223237200009 PM 15246027 ER PT J AU Hanakawa, T Honda, M Hallett, M AF Hanakawa, T Honda, M Hallett, M TI Amodal imagery in rostral premotor areas SO BEHAVIORAL AND BRAIN SCIENCES LA English DT Editorial Material ID MENTAL CALCULATION; TASKS AB Inspired by Rick Grushs emulation theory, we reinterpreted a series of our neuroimaging experiments which were intended to examine the representations of complex movement, modality-specific imagery, and supramodal imagery. The emulation theory can explain motor and cognitive activities observed in cortical motor areas, through the speculation that caudal areas relate to motor-specific imagery and rostral areas embrace an emulator for amodal imagery. C1 Kyoto Univ, Grad Sch Med, Human Brain Res Ctr, Sakyo Ku, Kyoto 6068507, Japan. NIPS, Lab Cerebral Integrat, Okazaki, Aichi 4448585, Japan. Japan Sci & Technol Agcy, PRESTO, Kawaguchi 3320012, Japan. NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Hanakawa, T (reprint author), Kyoto Univ, Grad Sch Med, Human Brain Res Ctr, Sakyo Ku, Kyoto 6068507, Japan. EM han@kuhp.kyoto-u.ac.jp; honda@nips.ac.jp; hallettm@ninds.nih.gov NR 7 TC 6 Z9 8 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0140-525X J9 BEHAV BRAIN SCI JI Behav. Brain Sci. PD JUN PY 2004 VL 27 IS 3 BP 406 EP + PG 9 WC Psychology, Biological; Behavioral Sciences; Neurosciences SC Psychology; Behavioral Sciences; Neurosciences & Neurology GA 883NY UT WOS:000226021100048 ER PT J AU Bredeson, CN Pavletic, SZ AF Bredeson, CN Pavletic, SZ TI Considerations when designing a clinical trial of haematopoietic stem cell transplantation for autoimmune disease SO BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY LA English DT Article DE clinical trials; controlled clinical trials; phase II; haematopoietic stem cell transplantation; data safety and monitoring boards; sample size; autoimmune diseases; equipoise; outcome measures ID BONE-MARROW TRANSPLANTS; PROGRESSIVE MULTIPLE-SCLEROSIS; HIGH-DOSE CHEMOTHERAPY; SURROGATE END-POINTS; RHEUMATOID-ARTHRITIS; IMPORTANT DIFFERENCE; STATISTICAL-METHODS; SYSTEMIC-SCLEROSIS; PHASE; LEUKEMIA AB The design and conduct of clinical trials of haematopoietic stem cell transplantation (HSCT) for autoimmune diseases requires investigators to address issues unique to this therapeutic approach and patient population. The proper composition of the protocol team is central to success. It is important to recognize that transplant physicians are no longer also the disease experts when transplanting patients with autoimmune diseases, and a close collaborative relationship between these groups early in the design stage must continue through the care of patients on trial to the assessment of toxicity and response. The early involvement of statisticians expert in clinical trial design and patient representatives are also vital to developing the optimal protocol. Each step in design and implementation requires particular consideration of the unique aspects of applying HSCT to autoimmune diseases. Some areas discussed are the role of disease and transplant databases in designing and analysing clinical trials, design options for early-phase trials, maintaining clinical equipoise, eligibility criteria, blinding, outcome measures and statistical analysis, and the composition and role of the data safety and monitoring boards. Although no blueprint for designing and conducting a trial of HSCT for autoimmune diseases can be laid out, the process should take into consideration the issues highlighted herein. C1 Med Coll Wisconsin, Hlth Policy Inst, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. NCI, NIH, Expt Transplantat & Immunol Branch, Graf Versus Host & Autoimmun Unit, Bethesda, MD 20892 USA. RP Bredeson, CN (reprint author), Med Coll Wisconsin, Hlth Policy Inst, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. EM bredeson@mcw.edu; pavletis@mail.nih.gov NR 39 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1521-6926 J9 BEST PRACT RES CL HA JI Best Pract. Res. Clin. Haematol. PD JUN PY 2004 VL 17 IS 2 BP 327 EP 343 DI 10.1016/j.beha.2004.04.007 PG 17 WC Hematology SC Hematology GA 891VS UT WOS:000226609700011 PM 15302344 ER PT J AU Christopher-Stine, L Plotz, PH AF Christopher-Stine, L Plotz, PH TI Adult inflammatory myopathies SO BEST PRACTICE & RESEARCH IN CLINICAL RHEUMATOLOGY LA English DT Article DE myositis; polymyositis; dermatomyositis; inclusion body myositis; inflammatory myopathy ID INCLUSION-BODY MYOSITIS; INTERSTITIAL LUNG-DISEASE; POPULATION-BASED COHORT; POLYMYOSITIS-DERMATOMYOSITIS; FOLLOW-UP; MUSCLE; CANCER; METHOTREXATE; MALIGNANCY; CELLS AB The major inflammatory myopathies of adults-dermatomyositis, polymyositis and inclusion body myositis-are uncommon and can be difficult to distinguish from many conditions that mimic them clinically. They have a high morbidity; they are not infrequently the first sign of an associated malignancy; and they may be a part of another connective tissue disease. Their pathogenetic features suggest that they are different illnesses. Dermatomyositis and polymyositis are clearly inflammatory, both clinically and histologically, and both generally respond to therapy directed towards inflammation. Inclusion body myositis is now generally recognized as the most common myopathy presenting in patients over the age of 50 years, and it responds only modestly and sometimes not at all to immunosuppressive therapy. In this review, we have summarised the major newly recognized features of pathogenesis, the involvement of extramuscular organs, the differential diagnosis, diagnostic approaches and the main lines of therapy. C1 NIAMSD, NIH, Ctr Clin, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Med, Div Rheumatol, Baltimore, MD 21205 USA. RP Christopher-Stine, L (reprint author), NIAMSD, NIH, Ctr Clin, 9N244, Bethesda, MD 20892 USA. EM plotzp@mail.nih.gov; lchrist4@jhmi.edu NR 69 TC 23 Z9 26 U1 0 U2 1 PU BAILLIERE TINDALL PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1521-6942 J9 BEST PRACT RES CL RH JI Best Pract. Res. Clin. Rheumatol. PD JUN PY 2004 VL 18 IS 3 BP 331 EP 344 DI 10.1016/j.berh.2004.02.009 PG 14 WC Rheumatology SC Rheumatology GA 833AD UT WOS:000222307900005 PM 15158744 ER PT J AU Kobayashi, SD DeLeo, FR AF Kobayashi, SD DeLeo, FR TI An apoptosis differentiation programme in human polymorphonuclear leucocytes SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT Meeting on Apoptosis in Myeloid Cells CY NOV 19-20, 2003 CL Edinburgh, SCOTLAND SP ALEXIS Corp, New England Biolabs DE apoptosis; differentiation programme; human polymorphonuclear leucocyte; inflammation; microarray; neutrophil; transcription ID HUMAN NEUTROPHIL APOPTOSIS; CELL-DEATH; PHOSPHOINOSITIDE 3-KINASE; IN-VIVO; INFLAMMATION; EXPRESSION; PHAGOCYTOSIS; CHEMOKINES; INTERLEUKIN-8; GRANULOCYTES AB Human PMNs (polymorphonuclear leucocytes or neutrophils) are essential to the innate immune response against bacterial pathogens and are a key part of the acute inflammatory response. Although progress has been made, the molecular basis for termination of inflammation during bacterial infection in humans is largely undefined. To that end, we used genomics strategies to gain new insight into processes that facilitate resolution of neutrophil-mediated inflammation and bacterial infection. On the basis of a series of recent studies, we propose that global changes in PMN gene expression after phagocytosis comprise an apoptosis differentiation programme, which represents the final stage of transcription-regulated PMN maturation. Our studies indicate that the apoptosis differentiation programme regulates multiple post-phagocytic processes in human neutrophils, such as cell fate and proinflammatory activity, and is modulated by PMN-derived reactive oxygen species. Collectively, these studies establish a global model of host cell-pathogen interaction, which provides fundamental insight into the resolution of infection in humans. C1 NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, Natl Inst Hlth, Hamilton, MT 59840 USA. RP DeLeo, FR (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, Natl Inst Hlth, 903 S 4th St, Hamilton, MT 59840 USA. EM fdeleo@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516 NR 33 TC 23 Z9 24 U1 0 U2 1 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD JUN PY 2004 VL 32 BP 474 EP 476 DI 10.1042/BST0320474 PN 3 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 833LD UT WOS:000222337900019 PM 15157164 ER PT J AU Chizmadzhev, YA AF Chizmadzhev, YA TI The mechanisms of lipid-protein rearrangements during viral infection SO BIOELECTROCHEMISTRY LA English DT Article; Proceedings Paper CT 17th Symposium on Bioelectrochemistry and Bioenergetics CY JUN 19-24, 2003 CL Florence, ITALY DE lipid-protein; rearrangement; viral infection ID MEMBRANE-FUSION; INFLUENZA HEMAGGLUTININ; STALK MODEL; BILAYERS; CONTACT AB Membrane fusion and fission are important events in living cell functioning. In spite of the great variety of specific cases, all of these phenomena are probably governed by the same physical principles. The first insight into physics of membrane fusion has been achieved through studies on model lipid systems. These results served as a base for subsequent investigations of the mechanisms of biological fusion. The main objective of this brief review is to expose the landmarks on the pathway of these studies and to discuss problems and perspectives. Fusion is a multistage process that includes transitions between several numbers of the intermediates. It is adopted that in the case of fusion of two planar bilayers, the following stages take place: formation of close inter-membrane contact, appearance of local monolayer bridge called a stalk, expansion of stalk leading to formation of hemifusion diaphragm (HD) and, finally, creation of fusion pore. Note that the stalk is nanoscopic and still an invisible object. However, there are no doubts that some kinds of monolayer bridge exist while its shape and structure, energetic and kinetic properties are unknown. The main results on the mechanism of biological fusion were obtained on the cells expressing fusion protein of influenza virus, hemagglutinin (HA). However, this system has no M1 and M2 proteins of influenza, which are responsible for the release of the genetic material of the virus into the target cell. An experimental system developed in our laboratory allows to monitor the fusion of single virions with lipid bilayer and detect RNA release as well as the role of M1 and M2 in this process. Biological fusion is a result of complicated interplay of lipids and special proteins at nanoscopic range. It seems probable that the first function of the proteins is the preparation of a pre-fusion state also known as membrane docking. Redistribution of the energy between proteins and lipids leads to the creation of so-called dimples accumulating bending energy, which facilitates stalk formation. Probably, proteins participate in the subsequent stages of fusion in the course of a set of downhill conformational changes. Unfortunately, the data on the kinetics of these transitions are not available. Therefore, theoretical analysis is limited by a consideration of lipidic subsystem, while proteins participate as boundary conditions or some superimposed constraints. As a result, taking into account lipid tilting and fusion pore compression, low-energy pathway was proposed, leading directly from modified stalk to pore. (C) 2004 Elsevier B.V. All rights reserved. C1 Russian Acad Sci, AN Frumkin Electrochem Inst, Moscow 119071, Russia. NICHHD, Lab Cellular & Mol Biophys, Bethesda, MD 20892 USA. RP Chizmadzhev, YA (reprint author), Russian Acad Sci, AN Frumkin Electrochem Inst, 31 Leninsky Prospet,Bldg 5, Moscow 119071, Russia. EM chiz@elchem.ac.ru RI Chizmadzhev, Yuri/L-1984-2013 NR 21 TC 18 Z9 20 U1 0 U2 0 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 1567-5394 J9 BIOELECTROCHEMISTRY JI Bioelectrochemistry PD JUN PY 2004 VL 63 IS 1-2 BP 129 EP 136 DI 10.1016/j.bioelechem.2003.10.016 PG 8 WC Biochemistry & Molecular Biology; Biology; Biophysics; Electrochemistry SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Biophysics; Electrochemistry GA 825VP UT WOS:000221786900026 PM 15110263 ER PT J AU McClure, EB Monk, CS Nelson, EE Zarahn, E Leibenluft, E Bilder, RM Charney, DS Ernst, M Pine, DS AF McClure, EB Monk, CS Nelson, EE Zarahn, E Leibenluft, E Bilder, RM Charney, DS Ernst, M Pine, DS TI A developmental examination of gender differences in brain engagement during evaluation of threat SO BIOLOGICAL PSYCHIATRY LA English DT Article DE gender; development; fMRI; facial expression; emotion; threat ID EMOTIONAL FACIAL EXPRESSIONS; SEX-DIFFERENCES; RESPONSES; CHILDREN; BEHAVIOR; FMRI; PERCEPTION; ATTENTION; ADULTS; FACES AB Background: Females appear to be more sensitive and responsive to social cues, including threat signals, than are males. Recent theoretical models suggest that developmental changes in brain functioning play important roles in the emergence of such gender differences. Methods: We used functional magnetic resonance imaging to examine developmental and gender differences in activation of neural structures thought to mediate attention to emotional faces depicting varying degrees of threat. Analyses focused on the orbitofrontal cortex, amygdala, and anterior cingulate cortex during the evaluation of threat conveyed by faces. Healthy adolescents (n = 17.53% male) and adults (n = 17; 53% male) were scanned while they rated how threatening pictures of neutral and emotional (angry, fearful, or happy) faces appeared. Results: Results indicate significant interactions among aged, gender, and,face type for activation during explicit threat monitoring. In particular adult women activated orbitofrontal cortex and amygdala selectively to unambiguous threat (angry) cues, while adult men showed a less discriminating pattern of activation. No gender differences were evident for adolescents, who as a group resembled adult males. Conclusions: These findings suggest that there are gender differences in patterns of neural responses to emotional laces that are not fully apparent until adulthood. C1 Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. Columbia Univ, Dept Psychiat, New York, NY USA. NIMH, Mood & Anxiety Disorders Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIMH, Sect Dev & Affect Neurosci, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. NIMH, Mood & Anxiety Disorders Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP McClure, EB (reprint author), NIMH, NIH, MAP, 15K North Dr,MSC 2670, Bethesda, MD 20892 USA. RI Nelson, Eric/B-8980-2008; Monk, Christopher/J-1805-2014; Bilder, Robert/A-8894-2008 OI Nelson, Eric/0000-0002-3376-2453; Bilder, Robert/0000-0001-5085-7852 NR 51 TC 129 Z9 131 U1 3 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 1 PY 2004 VL 55 IS 11 BP 1047 EP 1055 DI 10.1016/j.biopsych.2004.02.013 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 823IZ UT WOS:000221605800001 PM 15158422 ER PT J AU Baas, JM Nugent, M Lissek, S Pine, DS Grillon, C AF Baas, JM Nugent, M Lissek, S Pine, DS Grillon, C TI Fear conditioning in virtual reality contexts: A new tool for the study of anxiety SO BIOLOGICAL PSYCHIATRY LA English DT Article DE virtual reality; classical conditioning; fear conditioning; context conditioning; startle; psychophysiology; anxiety ID POTENTIATED STARTLE; BED NUCLEUS; AMYGDALA; HUMANS; HIPPOCAMPUS; REFLEX AB Background; Context conditioning has been suggested to model clinical anxiety, but context, as manipulated in animal models, has not been translated to human studies. A virtual environment might prove to be the ideal tool for innovative experimental paradigms to study explicitly cued fear and contextual anxiety in humans. Methods: Subjects were guided through a virtual environment that consisted of two rooms connected by a street scene. In each of the rooms, a blue and a yellow panel on a wall served as explicit conditioned stimuli (CS). The panels; were displayed several times. One of the panels (CS+) was associated with a shock in one of the rooms (shock room). No shock was administered in the other room (safe room). Acoustic startle stimuli were administered in. the presence and in the absence of the panels to assess explicit cued conditioning to the CS and context conditioning to the rooms, respectively. Results: Startle was potentiated by the CS+ in both rooms, which suggests generalization of fear across contexts. After acquisition, startle was potentiated in the shock room, compared with the safe room, in the absence of the CS+. Conclusions: These results support the future use of virtual reality to design new conditioning experiments to study both fear and anxiety. C1 NIMH, Mood & Anxiety Disorders Program, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Grillon, C (reprint author), NIMH, Mood & Anxiety Disorders Program, NIH, US Dept Hlth & Human Serv, 15K North Dr,Bldg 15K,Room 113,MSC 2670, Bethesda, MD 20892 USA. RI Lissek, Shmuel/B-6577-2008; OI Baas, Johanna/0000-0001-6267-8712 NR 19 TC 52 Z9 52 U1 4 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 1 PY 2004 VL 55 IS 11 BP 1056 EP 1060 DI 10.1016/j.biopsych.2004.02.024 PG 5 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 823IZ UT WOS:000221605800002 PM 15158423 ER PT J AU Shepard, JD Bossert, JM Liu, SY Shaham, Y AF Shepard, JD Bossert, JM Liu, SY Shaham, Y TI The anxiogenic drug yohimbine reinstates methamphetamine seeking in a rat model of drug relapse SO BIOLOGICAL PSYCHIATRY LA English DT Article DE alpha-2 adrenoceptors; drug self-administration; extinction; incubation; reinstatement; relapse; stress ID STRESS-INDUCED REINSTATEMENT; COCAINE-INDUCED REINSTATEMENT; CORTICOTROPIN-RELEASING FACTOR; CONDITIONED PLACE PREFERENCE; TIME-DEPENDENT CHANGES; DISCRIMINATIVE-STIMULUS; STRIA TERMINALIS; HEROIN-SEEKING; BED NUCLEUS; PREFRONTAL CORTEX AB Background: Brain noradrenaline is involved in footshock stress-induced reinstatement of drug seeking in a rat relapse model. We studied whether yohimbine, an alpha-2 adrenoceptor antagonist that increases noradrenaline release and induces anxiety-like responses in human and nonhuman subjects, would reinstate methamphetamine seeking in rats. Methods: In experiment 1, the effect of yohimbine (1.25-25 mg/kg) on reinstatement was compared with that of intermittent footshock (5 min; 2-.6 mA) in rats that were trained to lever press for intravenous methamphetamine (9-11 days) and subsequently underwent 7 days of extinction training. In experiment 2, the effect of yohimbine on reinstatement of drug seeking was determined during early (1 day) and late (21 or 51 days) withdrawal periods. On the test days, rats were first given 3-hour extinction sessions and were then tested for reinstatement induced by yohimbine. Results: In experiment 1, both yohimbine and footshock stress reinstated methamphetamine seeking after extinction. In experiment 2, extinction responding was higher after 21 or 51 withdrawal days than after 1 withdrawal day. In contrast, no significant time-dependent changes in yohimbine-induced reinstatement were observed. Conclusions: Results indicate that yohimbine is a potent stimulus for reinstatement of methamphetamine seeking in a rat relapse model. C1 NIDA, Behav Neurosci Branch, IRP, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. NIDA, Cellular Neurobiol Branch, Intramural Res Program, NIH,Dept Hlth & Hlth Human Serv, Baltimore, MD 21224 USA. RP Shaham, Y (reprint author), NIDA, Behav Neurosci Branch, IRP, NIH,Dept Hlth & Human Serv, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI shaham, yavin/G-1306-2014 NR 75 TC 168 Z9 170 U1 3 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 1 PY 2004 VL 55 IS 11 BP 1082 EP 1089 DI 10.1016/j.biopsych.2004.02.032 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 823IZ UT WOS:000221605800006 PM 15158427 ER PT J AU Wolde-meskel, E Berg, T Peters, NK Frostegard, A AF Wolde-meskel, E Berg, T Peters, NK Frostegard, A TI Nodulation status of native woody legumes and phenotypic characteristics of associated rhizobia in soils of southern Ethiopia SO BIOLOGY AND FERTILITY OF SOILS LA English DT Article DE African acacia spp.; rhizobia; Ethiopia; provenance; nodulation ID DIVERSE KENYAN CONDITIONS; NITROGEN-FIXATION; ACACIA-ALBIDA; TREE LEGUMES; AGROFORESTRY; POPULATIONS; GROWTH; SINORHIZOBIUM; SPECIFICITY; DIVERGENCE AB The nodulation of provenances of Acacia seyal, Acacia tortilis and Faidherbia albida, and other indigenous multipurpose tree species were tested in 14 different soil samples collected from diverse agro-ecological zones in southern Ethiopia. Associated rhizobia were isolated from these and from excavated nodules of field standing mature trees, and phenotypically characterized. Indigenous rhizobia capable of eliciting nodules on at least one or more of the woody legume species tested were present in most of the soils. Tree species were markedly different in nodulation in the different site soils. Sesbania sesban and Acacia abyssinica showed higher nodulation ability across the different sites indicating widespread occurrence of compatible rhizobia in the soils. The nodulation patterns of the different provenances of Acacia spp. suggested the existence of intraspecific provenance variations in rhizobial affinity which can be exploited to improve N fixation through tree selection. Altogether, 241 isolates were recovered from the root nodules of trap host species and from excavated nodules. Isolates were differentiated by growth rate and colony morphology and there were very fast-, fast-, slow-, and very slow-growing rhizobia. The bulk of them (68.5%) were fast-growing acid-producing rhizobia while 25.3% were slow-growing alkali-producing types. Fast-growing alkali-producing (2.9%) and slow-growing acid-producing strains (3.3%) were isolated from trap host species and excavated nodules, respectively. All isolates fell into four colony types: watery translucent, white translucent, dull glistering and milky (curdled) type. The diversity of indigenous rhizobia in growth rate and colony morphology suggested that the collection probably includes several rhizobial genera. C1 Debub Univ, Dept Plant Prod & Dryland Farming, Awassa Coll Agr, Awasa, Ethiopia. Agr Univ Norway, Dept Chem Biotechnol & Food Sci, N-1432 As, Norway. Agr Univ Norway, Ctr Int Environm & Dev Studies, NORAGRIC, N-1432 As, Norway. NIGMS, NIH, Bethesda, MD 20892 USA. RP Wolde-meskel, E (reprint author), Debub Univ, Dept Plant Prod & Dryland Farming, Awassa Coll Agr, POB 5, Awasa, Ethiopia. EM endame@nlh.no OI Peters, Norman/0000-0003-0795-1362 NR 44 TC 11 Z9 11 U1 1 U2 6 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0178-2762 J9 BIOL FERT SOILS JI Biol. Fertil. Soils PD JUN PY 2004 VL 40 IS 1 BP 55 EP 66 DI 10.1007/s00374-004-0743-5 PG 12 WC Soil Science SC Agriculture GA 825IS UT WOS:000221750600008 ER PT J AU Evarts, JL Rasweiler, JJ Behringer, RR Hennighausen, L Robinson, GW AF Evarts, JL Rasweiler, JJ Behringer, RR Hennighausen, L Robinson, GW TI A morphological and immunohistochemical comparison of mammary tissues from the short-tailed fruit bat (Carollia perspicillata) and the mouse SO BIOLOGY OF REPRODUCTION LA English DT Article DE developmental biology; mammary glands ID MILK-COMPOSITION; DELAYED DEVELOPMENT; LACTATION; PTEROPODIDAE; PROLACTIN; DIFFERENTIATION; CHIROPTERA; MINERALS; NITROGEN; MYOTIS AB In the present study, mammary tissues from the fruit bat (Carollia perspicillata) and mouse (Mus musculus) were compared using histological and immunohistochemical methods. Because the female bat exhibits greater reproductive similarities to humans, it might provide a useful animal model for studying mammary physiology and disease with relevance to our own species. In lactating and recently lactating specimens, bat tissue had significantly fewer adipocytes and more collagenous connective tissue compared to the mouse. The proteins Stat5a, keratin 5, Npt2b, and E-cadherin were all similarly localized in mouse and bat mammary tissues taken from lactating animals. The present study demonstrates that whereas the epithelial compartment and the presence of differentiation markers are conserved between the mouse and bat, differences exist in the stromal compartment. C1 NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. Suny Downstate Med Ctr, Dept Obstet & Gynecol, Brooklyn, NY 11203 USA. Univ Texas, MD Anderson Canc Ctr, Dept Mol Genet, Houston, TX 77530 USA. RP Robinson, GW (reprint author), NIDDK, Lab Genet & Physiol, NIH, Bldg 8,Room 101, Bethesda, MD 20892 USA. EM traudl@nih.gov RI Robinson, Gertraud/I-2136-2012 NR 30 TC 5 Z9 5 U1 0 U2 1 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD JUN PY 2004 VL 70 IS 6 BP 1573 EP 1579 DI 10.1095/biolreprod.103.022988 PG 7 WC Reproductive Biology SC Reproductive Biology GA 823JC UT WOS:000221606200004 PM 14749297 ER PT J AU Couty, JP Gershengorn, MC AF Couty, JP Gershengorn, MC TI Insights into the viral G protein-coupled receptor encoded by human herpesvirus type 8 (HHV-8) SO BIOLOGY OF THE CELL LA English DT Article; Proceedings Paper CT International Symposium on G Protein-Coupled Receptors CY OCT 23-24, 2003 CL Paris, FRANCE DE Kaposi's sarcoma (KS); KS-associated herpesvirus (KSHV); HHV-8 G protein-coupled receptor (HHV-8-GPCR) ID SARCOMA-ASSOCIATED HERPESVIRUS; NF-KAPPA-B; KAPOSIS-SARCOMA; CHEMOKINE RECEPTOR; CONSTITUTIVE ACTIVITY; ENDOTHELIAL-CELLS; INVERSE AGONISTS; MAMMALIAN-CELLS; DNA-SEQUENCES; CYCLIN D AB HHV-8-GPCR is a chemokine-like receptor encoded by KSHV, the etiologic agent of KS. HHV-8-GPCR is constitutively active. Although it is homologous to mammalian CXCR2, it binds CXC and CC chemokines. Structure-function analysis showed that chemokines bind primarily to the amino terminus whereas signaling occurs in the absence of: the amino terminus, which is, therefore, not a tethered agonist. In in vitro systems, HHV-8-GPCR signals via multiple transduction pathways including, activation of phospholipase C and PKC, inhibition of adenylyl cyclase, activation of nuclear factor-kappaB; activation PI 3-kinase, p42/44 MAPK and Akt/PKB, and activation of JNK/SAPK, p38 MAPK and RAFFK. HHV-8-GPCR is important in the HHV-8 life cycle because HHV-8-GPCR-deficient viruses do not replicate in response to chemokines and exhibit, less efficient reactivation from latency. Although the role of HHV-8-GPCR in the pathogenesis of KS has not been defined, expression of HHV-8-GPCR resulted in the development of angioproliferative, KS-like tumors in transgenic mice. As endothelial cells may be targets of HHV-8 infection, HHV-8-GPCR has been studied in endothelial cells in vitro in which it affects cell adhesion and migration, increases cell survival, and stimulates secretion of proinflammatory cytokines and proangiogenic factors. Based on these findings and the observation that HHV-8-GPCR is expressed in only a few endothelial-like "spindle cells" within KS lesions, we propose that HHV-8-GPCR is involved in KS pathogenesis by stimulating secretion of proinflammatory/proangiogenic c factors that act in a paracrine fashion to cause tumorigenesis. (C) 2004 Elsevier SAS. All rights reserved. C1 Inst Cochin, Dept Cellular Biol, F-75014 Paris, France. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Gershengorn, MC (reprint author), Bldg 50,Room 4134,9000 Rockville Pike, Bethesda, MD 20892 USA. EM marving@intra.niddk.nih.gov NR 36 TC 20 Z9 23 U1 0 U2 2 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0248-4900 J9 BIOL CELL JI Biol. Cell PD JUN PY 2004 VL 96 IS 5 BP 349 EP 354 DI 10.1016/j.biolcel.2004.03.011 PG 6 WC Cell Biology SC Cell Biology GA 836SD UT WOS:000222575200005 PM 15207903 ER PT J AU Li, KCP Pandit, SD Guccione, S Bednarski, MD AF Li, KCP Pandit, SD Guccione, S Bednarski, MD TI Molecular Imaging applications in nanomedicine SO BIOMEDICAL MICRODEVICES LA English DT Article; Proceedings Paper CT United States-Japan Symposium on Nanotechnology in Advanced Therapy and Diagnosis CY OCT 09-11, 2003 CL Yokohama, JAPAN SP Natl Sci Fdn, Minist Educ, Culture, Sports, Sci & Technol Japan DE molecular imaging; nanomedicine; targeted therapy; personalized treatment ID PARAMAGNETIC POLYMERIZED LIPOSOMES; IN-VIVO; DRUG; DELIVERY; PERSPECTIVES; ANGIOGENESIS; ANTIBODIES; ONCOLOGY; AGENTS; CANCER AB The purpose of this article is to explore how molecular imaging techniques can be used as useful adjunts in the development of "nanomedicine" and in personalizing treatment of patients. The discussion focuses on in vivo applications at the whole organism level even though imaging can also play an important role in research at the cellular and subcellular level. C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Li, KCP (reprint author), NIH, Ctr Clin, Bldg 10 1C660,10 Ctr Dr MSC 1182, Bethesda, MD 20892 USA. EM Kingli@nih.gov NR 37 TC 46 Z9 49 U1 1 U2 11 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1387-2176 J9 BIOMED MICRODEVICES JI Biomed. Microdevices PD JUN PY 2004 VL 6 IS 2 BP 113 EP 116 DI 10.1023/B:BMMD.0000031747.05317.81 PG 4 WC Engineering, Biomedical; Nanoscience & Nanotechnology SC Engineering; Science & Technology - Other Topics GA 829BF UT WOS:000222017300003 PM 15320632 ER PT J AU Teng, C Gladwell, W Raphiou, I Liu, E AF Teng, C Gladwell, W Raphiou, I Liu, E TI Methylation and expression of the lactoferrin gene in human tissues and cancer cells SO BIOMETALS LA English DT Article; Proceedings Paper CT 6th International Conference on Lactoferrin, Structure, Function and Application CY MAY 05-09, 2003 CL Capri, ITALY DE bisulfite genomic sequencing; cancer cells; lactoferrin; methylation ID DNA; LEUKOCYTES; PROMOTER AB The lactoferrin gene promoter contains GC-rich regions that harbor consensus sequences for a variety of transcription factors. Previous work in our laboratory has demonstrated a link between methylation at the CpG sites of the mouse lactoferrin gene promoter and the level of its expression. The current work investigates the methylation profile in three regions of the human lactoferrin gene by bisulfite genomic sequencing. In addition, the methylation profiles of normal leukocyte DNA, and leukemia cell line and patient DNA were compared. The three regions are located at the -504/-190, which includes the estrogen response element, the -282/+271 which contains the lactoferrin promoter and the +1087/+1476, a region within the first intron that has the alternative delta lactoferrin promoter. Differential methylations were found within all the regions. Increased methylation at the CpG sites and the presence of non-CpG methylation of the lactoferrin promoters were found in the cancer samples. C1 NIEHS, Reprod & Dev Toxicol Lab, Gene Regulat Sect, NIH, Res Triangle Pk, NC 27709 USA. RP Teng, C (reprint author), NIEHS, Reprod & Dev Toxicol Lab, Gene Regulat Sect, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM Teng@niehs.nih.gov NR 12 TC 27 Z9 29 U1 0 U2 4 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0966-0844 J9 BIOMETALS JI Biometals PD JUN PY 2004 VL 17 IS 3 BP 317 EP 323 DI 10.1023/B:BIOM.0000027711.13818.8a PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 820MC UT WOS:000221392300021 PM 15222484 ER PT J AU Dunson, DB Chen, Z AF Dunson, DB Chen, Z TI Selecting factors predictive of heterogeneity in multivariate event time data SO BIOMETRICS LA English DT Article DE gamma frailties; MCMC algorithm; model averaging; multivariate survival analysis; proportional hazards; random effects; test for homogeneity; variable selection ID PROPORTIONAL HAZARDS MODEL; BAYESIAN-ANALYSIS; FRAILTY MODELS; SURVIVAL-DATA; LIFE-TABLES; LIKELIHOOD; TESTS; HOMOGENEITY; DIAGNOSTICS; INFERENCE AB In multivariate survival analysis, investigators are often interested in testing for heterogeneity among clusters, both overall and within specific classes. We represent different hypotheses about the heterogeneity structure using a sequence of gamma frailty models, ranging from a null model with no random effects to a full model having random effects for each class. Following a Bayesian approach, we define prior distributions for the frailty variances consisting of mixtures of point masses at zero and inverse-gamma densities. Since frailties with zero variance effectively drop out of the model, this prior allocates probability to each model in the sequence, including the overall null hypothesis of homogeneity. Using a counting process formulation, the conditional posterior distributions of the frailties and proportional hazards regression coefficients have simple forms. Posterior computation proceeds via a data augmentation Gibbs sampling algorithm, a single run of which can be used to obtain model-averaged estimates of the population parameters and posterior model probabilities for testing hypotheses about the heterogeneity structure. The methods are illustrated using data from a lung cancer trial. C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. RP Dunson, DB (reprint author), NIEHS, Biostat Branch, POB 12233, Res Triangle Pk, NC 27709 USA. EM dunson1@niehs.nih.gov NR 32 TC 8 Z9 8 U1 0 U2 5 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0006-341X J9 BIOMETRICS JI Biometrics PD JUN PY 2004 VL 60 IS 2 BP 352 EP 358 DI 10.1111/j.0006-341X.2004.00179.x PG 7 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 830MN UT WOS:000222126400007 PM 15180660 ER PT J AU Neelon, B Dunson, DB AF Neelon, B Dunson, DB TI Bayesian isotonic regression and trend analysis SO BIOMETRICS LA English DT Article DE additive model; autoregressive prior; constrained estimation; monotonicity; order restricted inference; smoothing; threshold model; trend test ID BIOASSAY; CURVE AB In many applications, the mean of a response variable can be assumed to be a nondecreasing function of a continuous predictor, controlling for covariates. In such cases, interest often focuses on estimating the regression function, while also assessing evidence of art association. This article proposes a new framework for Bayesian isotonic regression and order-restricted inference. Approximating the regression function with a high-dimensional piecewise linear model, the nondecreasing constraint is incorporated through a prior distribution for the slopes consisting of a product mixture of point masses (accounting for flat regions) and truncated normal densities. To borrow information across the intervals and smooth the curve., the prior is formulated as a latent autoregressive normal process. This structure facilitates efficient posterior computation, since the full conditional distributions of the parameters have simple conjugate forms. Point and interval estimates of the regression function and posterior probabilities of an association for different regions of the predictor can be estimated from a single MCMC run. Generalizations to categorical outcomes and multiple predictors are described, and the approach is applied to an epidemiology application. C1 Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Neelon, B (reprint author), Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. EM dunson1@niehs.nih.gov NR 20 TC 41 Z9 41 U1 0 U2 5 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0006-341X J9 BIOMETRICS JI Biometrics PD JUN PY 2004 VL 60 IS 2 BP 398 EP 406 DI 10.1111/j.0006-341X.2004.00184.x PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 830MN UT WOS:000222126400012 PM 15180665 ER PT J AU Albert, PS Dodd, LE AF Albert, PS Dodd, LE TI A cautionary note on the robustness of latent class models for estimating diagnostic error without a gold standard SO BIOMETRICS LA English DT Article DE diagnostic accuracy; latent class models; misclassification; prevalence; sensitivity; specificity ID CONDITIONAL DEPENDENCE; TESTS; ACCURACY AB Modeling diagnostic error without a gold standard has been an active area of biostatistical research. In a majority of the approaches, model-based estimates of sensitivity, specificity, and prevalence are derived from a latent class model in which the latent variable represents an individual's true unobserved disease status. For simplicity, initial approaches assumed that the diagnostic test results on the same subject were independent given the true disease status (i.e., the conditional independence assumption). More recently, various authors have proposed approaches for modeling the dependence structure between test results given true disease status. This note discusses a potential problem with these approaches. Namely, we show that when the conditional dependence between tests is misspecified, estimators of sensitivity, specificity, and prevalence can be biased. Importantly, we demonstrate that with small numbers of tests, likelihood comparisons and other model diagnostics may not be able to distinguish between models with different dependence structures. We present asymptotic results that show the generality of the problem. Further, data analysis and simulations demonstrate the practical implications of model misspecification. Finally, we present some guidelines about the use of these models for practitioners. C1 NCI, Div Canc Treatment & Diagnost, Biometr Res Branch, Bethesda, MD 20892 USA. RP Albert, PS (reprint author), NCI, Div Canc Treatment & Diagnost, Biometr Res Branch, Bethesda, MD 20892 USA. EM Albertp@ctep.nci.nih.gov NR 17 TC 92 Z9 93 U1 1 U2 12 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0006-341X J9 BIOMETRICS JI Biometrics PD JUN PY 2004 VL 60 IS 2 BP 427 EP 435 DI 10.1111/j.0006-341X.2004.00187.x PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 830MN UT WOS:000222126400015 PM 15180668 ER PT J AU O'Brien, SM AF O'Brien, SM TI Cutpoint selection for categorizing a continuous predictor SO BIOMETRICS LA English DT Article DE multiple changepoint fitting; optimal categorization; piecewise constant regression; regression tree; smoothing ID REGRESSION AB This article presents a new approach for choosing the number of categories and the location of category cutpoints when a continuous exposure variable needs to be categorized to obtain tabular summaries of the exposure effect. The optimum categorization is defined as the partition that minimizes a measure of distance between the true expected value of the outcome for each subject and the estimated average outcome among subjects in the same exposure category. To estimate the optimum. partition, an efficient nonparametric estimate of the unknown regression function is substituted into a formula for the asymptotically optimum categorization. This new approach is easy to implement and it outperforms existing cutpoint selection methods. C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP O'Brien, SM (reprint author), NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. EM obrien4@niehs.nih.gov RI O'Brien, Sean/H-6268-2013 NR 20 TC 18 Z9 18 U1 1 U2 6 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0006-341X J9 BIOMETRICS JI Biometrics PD JUN PY 2004 VL 60 IS 2 BP 504 EP 509 DI 10.1111/j.0006-341X.2004.00196.x PG 6 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 830MN UT WOS:000222126400024 PM 15180677 ER PT J AU Ohno, M Gao, ZG Van Rompaey, P Tchilibon, S Kim, SK Harris, BA Gross, AS Duong, HT Van Calenbergh, S Jacobson, KA AF Ohno, M Gao, ZG Van Rompaey, P Tchilibon, S Kim, SK Harris, BA Gross, AS Duong, HT Van Calenbergh, S Jacobson, KA TI Modulation of adenosine receptor affinity and intrinsic efficacy in adenine nucleosides substituted at the 2-position SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article ID A(3) RECEPTOR; SELECTIVE AGONISTS; MOLECULAR-CLONING; DERIVATIVES; LIGANDS; ACTIVATION; BINDING; POTENT; IDENTIFICATION; PHARMACOLOGY AB We studied the structural determinants of binding affinity and efficacy of adenosine receptor (AR) agonists. Substituents at the 2-position of adenosine were combined with N-6-substitutions known to enhance human A(3)AR affinity. Selectivity of binding of the analogues and their functional effects on cAMP production were studied using recombinant human A(1), A(2A), A(2B), and A(3)ARs. Mainly sterically small substituents at the 2-position modulated both the affinity and intrinsic efficacy at all subtypes. The 2-cyano group decreased hA(3)AR affinity and efficacy in the cases of N-6-(3-iodobenzyl) and N-6-(trans-2-phenyl-1-cyclopropyl), for which a full AAR agonist was converted into a selective antagonist; the 2-cyano-N-6-methyl analogue was a full A(3)AR agonist. The combination of N-6-benzyl and various 2-substitutions (chloro, trifluoromethyl, and cyano) resulted in reduced efficacy at the A(1)AR. The environment surrounding the 2-position within the putative A(3)AR binding site was explored using rhodopsin-based homology modeling and ligand docking. (C) 2004 Elsevier Ltd. All rights reserved. C1 NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH,DHHS, Bethesda, MD 20892 USA. FFW, Med Chem Lab, B-9000 Ghent, Belgium. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH,DHHS, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Van Calenbergh, Serge/A-3167-2008; Jacobson, Kenneth/A-1530-2009 OI Van Calenbergh, Serge/0000-0002-4201-1264; Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031117-20] NR 37 TC 38 Z9 40 U1 0 U2 4 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 JUN 1 PY 2004 VL 12 IS 11 BP 2995 EP 3007 DI 10.1016/j.bmc.2004.03.031 PG 13 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 824HG UT WOS:000221676700018 PM 15142558 ER PT J AU Beguin, C LeTiran, A Stables, JP Voyksner, RD Kohn, H AF Beguin, C LeTiran, A Stables, JP Voyksner, RD Kohn, H TI N-substituted amino acid N '-benzylamides: synthesis, anticonvulsant, and metabolic activities SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article ID ANTIEPILEPTIC DRUG DEVELOPMENT; BENZYLACETAMIDE DERIVATIVES; AGENTS; DEALKYLATION; OXIDATION; SERIES; ALA AB Amino acid amides (AAA) were prepared and evaluated in seizure models. The AAA displayed moderate-to-excellent activity in the maximal electroshock seizure (MES) test and were devoid of activity in the subcutaneous Metrazol-induced (scMet) seizure test. The AAA anticonvulsant activity was neither strongly influenced by the C(2) substituent nor by the degree of terminal amine substitution. An in vitro metabolism study suggested that the structure-activity relationship pattern was due, in part, to metabolic processes that occurred at the N-terminal amine unit. (C) 2004 Elsevier Ltd. All rights reserved. C1 Univ N Carolina, Div Med Chem & Nat Prod, Sch Pharm, Chapel Hill, NC 27599 USA. Univ Houston, Dept Chem, Houston, TX 77204 USA. NINDS, Epilepsy Branch, NIH, Rockville, MD 20852 USA. LCMS Ltd, Raleigh, NC 27611 USA. Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. RP Kohn, H (reprint author), Univ N Carolina, Div Med Chem & Nat Prod, Sch Pharm, CB 7360, Chapel Hill, NC 27599 USA. EM harold_kohn@unc.edu NR 42 TC 20 Z9 22 U1 2 U2 5 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 JUN 1 PY 2004 VL 12 IS 11 BP 3079 EP 3096 DI 10.1016/j.bmc.2004.02.043 PG 18 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 824HG UT WOS:000221676700027 PM 15142567 ER PT J AU Yang, LJ Beard, WA Wilson, SH Broyde, S Schlick, T AF Yang, LJ Beard, WA Wilson, SH Broyde, S Schlick, T TI Highly organized but pliant active site of DNA polymerase beta: Compensatory mechanisms in mutant enzymes revealed by dynamics simulations and energy analyses SO BIOPHYSICAL JOURNAL LA English DT Article ID STATE KINETIC-ANALYSIS; BASE EXCISION-REPAIR; I KLENOW FRAGMENT; REVERSE-TRANSCRIPTASE; CRYSTAL-STRUCTURE; ANGSTROM RESOLUTION; NUCLEOTIDE INCORPORATION; CONFORMATIONAL-CHANGES; BIOMOLECULAR DYNAMICS; REPLICATION FIDELITY AB To link conformational transitions noted for DNA polymerases with kinetic results describing catalytic efficiency and fidelity, we investigate the role of key DNA polymerase g residues on subdomain motion through simulations of five single-residue mutants: Arg-283-Ala, Tyr-271-Ala, Asp-276-Val, Arg-258-Lys, and Arg-258-Ala. Since a movement toward a closed state was only observed for R258A, we suggest that Arg(258) is crucial in modulating motion preceding chemistry. Analyses of protein/DNA interactions in the mutant active Site indicate distinctive hydrogen bonding and van der Waals patterns arising from compensatory structural adjustments. By comparing closed mutant complexes with the wild-type enzyme, we interpret experimentally derived nucleotide binding affinities in molecular terms: R283A (decreased), Y271A (increased), D276V (increased), and R258A (decreased). Thus, compensatory interactions (e.g., in Y271A with adjacent residues Phe(272), Asn(279), and Arg(283)) increase the overall binding affinity for the incoming nucleotide although direct interactions may decrease. Together with energetic analyses, we predict that R258G might increase the rate of nucleotide insertion and maintain enzyme fidelity as R258A; D276L might increase the nucleotide binding affinity more than D276V; and R283A/K280A might decrease the nucleotide binding affinity and increase misinsertion more than R283A. The combined observations regarding key roles of specific residues (e.g., Arg(258)) and compensatory interactions echo the dual nature of polymerase active site, namely versatility (to accommodate various basepairs) and specificity (for preserving fidelity) and underscore an organized but pliant active site essential to enzyme function. C1 NYU, Dept Chem, New York, NY 10003 USA. NYU, Courant Inst Math Sci, New York, NY USA. Howard Hughes Med Inst, New York, NY USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. NYU, Dept Biol, New York, NY 10003 USA. RP Schlick, T (reprint author), NYU, Dept Chem, New York, NY 10003 USA. EM schlick@nyu.edu FU NCI NIH HHS [CA28038, CA75449, R01 CA028038, R01 CA075449]; NIGMS NIH HHS [R01 GM055164, R01 GM55164] NR 73 TC 37 Z9 38 U1 0 U2 3 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUN PY 2004 VL 86 IS 6 BP 3392 EP 3408 DI 10.1529/biophysj.103.036012 PG 17 WC Biophysics SC Biophysics GA 829GK UT WOS:000222035200005 PM 15189842 ER PT J AU Zweckstetter, M Hummer, G Bax, A AF Zweckstetter, M Hummer, G Bax, A TI Prediction of charge-induced molecular alignment of biomolecules dissolved in dilute liquid-crystalline phases SO BIOPHYSICAL JOURNAL LA English DT Article ID RESIDUAL DIPOLAR COUPLINGS; STREPTOCOCCAL PROTEIN-G; IMMUNOGLOBULIN-BINDING DOMAIN; HIGH-RESOLUTION NMR; BIOLOGICAL MACROMOLECULES; NEMATIC PHASE; DNA DODECAMER; CYANOVIRIN-N; SOLUTES; MEDIA AB Alignment of macromolecules in nearly neutral aqueous lyotropic liquid-crystalline media such as bicelles, commonly used in macromolecular NMR studies, can be predicted accurately by a steric obstruction model (Zweckstetter and Bax, 2000). A simple extension of this model is described that results in improved predictions for both the alignment orientation and magnitude of protein and DNA solutes in charged nematic media, such as the widely used medium of filamentous phage Pf1. The extended model approximates the electrostatic interaction between a solute and an ordered phage particle as that between the solute's surface charges and the electric field of the phage. The model is evaluated for four different proteins and a DNA oligomer. Results indicate that alignment in charged nematic media is a function not only of the solute's shape, but also of its electric multipole moments of net charge, dipole, and quadrupole. The relative importance of these terms varies greatly from one macromolecule to another, and evaluation of the experimental data indicates that these terms scale differently with ionic strength. For several of the proteins, the calculated alignment is sensitive to the precise position of the charged groups on the protein surface. This suggests that NMR alignment measurements can potentially be used to probe protein electrostatics. Inclusion of electrostatic interactions in addition to steric effects makes the extended model applicable to all liquid crystals used in biological NMR to date. C1 Max Planck Inst Biophys Chem, D-37077 Gottingen, Germany. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Zweckstetter, M (reprint author), Max Planck Inst Biophys Chem, Fassberg 11, D-37077 Gottingen, Germany. EM mzwecks@gwdg.de RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 72 TC 84 Z9 85 U1 1 U2 14 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUN PY 2004 VL 86 IS 6 BP 3444 EP 3460 DI 10.1529/biophysj.103.035790 PG 17 WC Biophysics SC Biophysics GA 829GK UT WOS:000222035200009 PM 15189846 ER PT J AU Sprague, BL Pego, RL Stavreva, DA McNally, JG AF Sprague, BL Pego, RL Stavreva, DA McNally, JG TI Analysis of binding reactions by fluorescence recovery after photobleaching SO BIOPHYSICAL JOURNAL LA English DT Article ID CORRELATION SPECTROSCOPY; LIVING CELLS; IN-VIVO; GLUCOCORTICOID-RECEPTOR; LATERAL DIFFUSION; INTERSEGMENT TRANSFER; PROTEIN DYNAMICS; NUCLEAR-MATRIX; MOBILITY; TRANSPORT AB Fluorescence recovery after photobleaching (FRAP) is now widely used to investigate binding interactions in live cells. Although various idealized solutions have been identified for the reaction-diffusion equations that govern FRAP, there has been no comprehensive analysis or systematic approach to serve as a guide for extracting binding information from an arbitrary FRAP curve. Here we present a complete solution to the FRAP reaction-diffusion equations for either single or multiple independent binding interactions, and then relate our solution to the various idealized cases. This yields a coherent approach to extract binding information from FRAP data which we have applied to the question of transcription factor mobility in the nucleus. We show that within the nucleus, the glucocorticoid receptor is transiently bound to a single state, with each molecule binding on average 65 sites per second. This rapid sampling is likely to be important in finding a specific promoter target sequence. Further we show that this predominant binding state is not the nuclear matrix, as some studies have suggested. We illustrate how our analysis provides several self-consistency checks on a FRAP fit. We also define constraints on what can be estimated from FRAP data, show that diffusion should play a key role in many FRAP recoveries, and provide tools to test its contribution. Overall our approach establishes a more general framework to assess the role of diffusion, the number of binding states, and the binding constants underlying a FRAP recovery. C1 NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. Univ Maryland, Dept Math, College Pk, MD 20742 USA. RP McNally, JG (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. EM mcnallyj@exchange.nih.gov RI Sprague, Brian/A-8923-2009; Pego, Robert/A-7641-2017 OI Pego, Robert/0000-0001-8502-2820 NR 49 TC 330 Z9 335 U1 4 U2 59 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUN PY 2004 VL 86 IS 6 BP 3473 EP 3495 DI 10.1529/biophysj.103.026765 PG 23 WC Biophysics SC Biophysics GA 829GK UT WOS:000222035200011 PM 15189848 ER PT J AU Sachs, JN Nanda, H Petrache, HI Woolf, TB AF Sachs, JN Nanda, H Petrache, HI Woolf, TB TI Changes in phosphatidylcholine headgroup tilt and water order induced by monovalent salts: Molecular dynamics simulations SO BIOPHYSICAL JOURNAL LA English DT Article ID CHARGED PHOSPHOLIPID-BILAYERS; LIPID-BILAYERS; LECITHIN BILAYERS; HYDRATION FORCE; CHANNEL CONDUCTANCE; MEMBRANE SURFACES; CHAOTROPIC ANIONS; DIVALENT-CATIONS; SODIUM-CHLORIDE; HEAD GROUP AB The association between monovalent salts and neutral lipid bilayers is known to influence global bilayer structural properties such as headgroup conformational fluctuations and the dipole potential. The local influence of the ions, however, has been unknown due to limited structural resolution of experimental methods. Molecular dynamics simulations are used here to elucidate local structural rearrangements upon association of a series of monovalent Na+ salts to a palmitoyl-oleoyl-phosphatidylcholine bilayer. We observe association of all ion types in the interfacial region. Larger anions, which are meant to rationalize data regarding a Hofmeister series of anions, bind more deeply within the bilayer than either Cl- or Na+. Although the simulations are able to reproduce experimentally measured quantities, the analysis is focused on local properties currently invisible to experiments, which may be critical to biological systems. As such, for all ion types, including Cl-, we show local ion-induced perturbations to headgroup tilt, the extent and direction of which is sensitive to ion charge and size. Additionally, we report salt-induced ordering of the water well beyond the interfacial region, which may be significant in terms of hydration repulsion between stacked bilayers. C1 Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Program Mol Biophys, Baltimore, MD 21205 USA. NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. RP Woolf, TB (reprint author), Johns Hopkins Univ, Sch Med, Dept Physiol, 206 Biophys Bldg, Baltimore, MD 21205 USA. FU NIGMS NIH HHS [R01 GM064746] NR 72 TC 104 Z9 104 U1 1 U2 29 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUN PY 2004 VL 86 IS 6 BP 3772 EP 3782 DI 10.1529/biophysj.103.035816 PG 11 WC Biophysics SC Biophysics GA 829GK UT WOS:000222035200036 PM 15189873 ER PT J AU Costes, SV Daelemans, D Cho, EH Dobbin, Z Pavlakis, G Lockett, S AF Costes, SV Daelemans, D Cho, EH Dobbin, Z Pavlakis, G Lockett, S TI Automatic and quantitative measurement of protein-protein colocalization in live cells SO BIOPHYSICAL JOURNAL LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; IMAGE CORRELATION SPECTROSCOPY; CONFOCAL MICROSCOPY; GLUCOCORTICOID-RECEPTOR; NUCLEAR EXPORT; REV; REPLICATION; SITES; TRANSCRIPTION; MEMBRANE AB We introduce a novel statistical approach that quantifies, for the first time, the amount of colocalization of two fluorescent-labeled proteins in an image automatically, removing the bias of visual interpretation. This is done by estimating simultaneously the maximum threshold of intensity for each color below which pixels do not show any statistical correlation. The sensitivity of the method was illustrated on simulated data by statistically confirming the existence of true colocalization in images with as little as 3% colocalization. This method was then tested on a large three-dimensional set of fixed cells cotransfected with CFP/YFP pairs of proteins that either co-compartmentalized, interacted, or were just randomly localized in the nucleolus. In this test, the algorithm successfully distinguished random color overlap from colocalization due to either co-compartmentalization or interaction, and results were verified by fluorescence resonance energy transfer. The accuracy and consistency of our algorithm was further illustrated by measuring, for the first time in live cells, the dissociation rate (k(d)) of the HIV-1 Rev/CRM1 export complex induced by the cytotoxin leptomycin B. Rev/CRM1 colocalization in nucleoli dropped exponentially after addition of leptomycin B at a rate of 1.25 x 10(-3) s(-1). More generally, this algorithm can be used to answer a variety of biological questions involving protein-protein interactions or co-compartmentalization and can be generalized to colocalization of mora than two colors. C1 NCI, Sci Applicat Int Corp, Frederick, MD 21701 USA. NCI, Image Anal Lab, Frederick, MD 21701 USA. NCI, Human Retrovirus Sect, Frederick, MD 21701 USA. RP Costes, SV (reprint author), NCI, Sci Applicat Int Corp, Frederick, MD 21701 USA. EM SVCostes@lbl.gov RI Costes, Sylvain/D-2522-2013 OI Costes, Sylvain/0000-0002-8542-2389 FU PHS HHS [N01-C056000] NR 29 TC 533 Z9 534 U1 5 U2 35 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUN PY 2004 VL 86 IS 6 BP 3993 EP 4003 DI 10.1529/biophysj.103.038422 PG 11 WC Biophysics SC Biophysics GA 829GK UT WOS:000222035200058 PM 15189895 ER PT J AU Rodriguez, IR AF Rodriguez, IR TI Rapid analysis of oxysterols by HPLC and UV spectroscopy SO BIOTECHNIQUES LA English DT Article ID CHOLESTEROL C1 NEI, Retinal Cell & Mol Biol Lab, Sect Mech Retinal Dis, NIH, Bethesda, MD 20892 USA. RP Rodriguez, IR (reprint author), NEI, Retinal Cell & Mol Biol Lab, Sect Mech Retinal Dis, NIH, 7 Mem Dr,MSC 0706, Bethesda, MD 20892 USA. EM rodriguezi@nei.nih.gov NR 5 TC 5 Z9 5 U1 0 U2 1 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD JUN PY 2004 VL 36 IS 6 BP 952 EP + PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 829CL UT WOS:000222021000008 PM 15211745 ER PT J AU Korn, EL Habermann, JK Upender, MB Ried, T McShane, LM AF Korn, EL Habermann, JK Upender, MB Ried, T McShane, LM TI Objective method of comparing DNA microarray image analysis systems SO BIOTECHNIQUES LA English DT Article AB Many image analysis systems are available for processing the images produced by laser scanning of DNA microarrays. The image processing system takes pixel-level intensity data and converts it to a set of gene-level expression or copy number summaries that will be used in further analyses. Image analysis systems currently in use differ with regard to the specific algorithms they implement, ease of use, and cost. Thus, it would be desirable to have an objective means of comparing systems. Here we describe a systematic method of comparing image processing results produced by different image analysis systems using a series of replicate microarray experiments. We demonstrate the method with a comparison of cDNA microarray data generated by the UCSF Spot and the GenePix(R) image processing systems. C1 NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. RP Korn, EL (reprint author), NCI, Biometr Res Branch, NIH, EPN-8129, Bethesda, MD 20892 USA. EM korne@ctep.nci.nih.gov RI Habermann, Jens/E-2968-2010 NR 14 TC 13 Z9 14 U1 0 U2 0 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD JUN PY 2004 VL 36 IS 6 BP 960 EP + PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 829CL UT WOS:000222021000009 PM 15211746 ER PT J AU Galperin, MM Traicoff, JL Ramesh, A Freebern, WJ Haggerty, CM Hartmann, DP Emmert-Buck, MR Gardner, K Knezevic, V AF Galperin, MM Traicoff, JL Ramesh, A Freebern, WJ Haggerty, CM Hartmann, DP Emmert-Buck, MR Gardner, K Knezevic, V TI Multimembrane dot-blotting: a cost-effective tool for proteome analysis SO BIOTECHNIQUES LA English DT Article AB The molecular profiles of protein expression from? hundreds of cell lysates can be determined in a high-throughput mannerly using fluorescent bead technologies, enzyme-linked immunosorbent assays (ELISAs), and protein microarrays. Although powerful, these tools are costly and technically challenging and thus have limited accessibility for many research groups. We propose a modification of traditional dot blotting that increases throughput of this approach and provides a simple and cost-effective technique for profiling multiple samples. In contrast to traditional blotting that uses a single membrane, we introduce blotting onto a stock of novel, thin, sieve-like membranes. These membranes have a high affinity for binding proteins, but have a lower capacity of protein binding compared to traditional (nitroceullose) membrones. We compare the linear binding capacity and variability of these novel membranes with nitrocellulose membranes. Also, we describe the use of these membranes in a multilayer dot blot format for profiling mitogen-mediated signal transduction pathways in T cells. C1 20 20 Genesyst Inc, Rockville, MD 20850 USA. NCI, Bethesda, MD 20892 USA. Georgetown Univ Hosp, Washington, DC 20007 USA. RP Knezevic, V (reprint author), 20 20 Genesyst Inc, 20-20,9700 Great Seneca Highway, Rockville, MD 20850 USA. EM vknezevic@2020gene.com NR 10 TC 8 Z9 8 U1 0 U2 0 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD JUN PY 2004 VL 36 IS 6 BP 1046 EP 1051 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 829CL UT WOS:000222021000020 PM 15211757 ER PT J AU Kang, D Andriole, GL Van de Vooren, RC Crawford, D Chia, D Urban, DA Reding, D Huang, WY Hayes, RB AF Kang, D Andriole, GL Van de Vooren, RC Crawford, D Chia, D Urban, DA Reding, D Huang, WY Hayes, RB TI Risk behaviours and benign prostatic hyperplasia SO BJU INTERNATIONAL LA English DT Article DE smoking; alcohol; BPH; PLCO; risk ID CANCER SCREENING TRIAL; CIGARETTE-SMOKING; HORMONE LEVELS; ASSOCIATION; ALCOHOL; LUNG; SUPPRESSION; POPULATION; COMMUNITY; HISTORY AB OBJECTIVE To identify risk factors for benign prostatic hyperplasia (BPH). SUBJECTS AND METHODS Medical history data, including reported urological conditions and treatments, and risk factor data were collected from 34 694 participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, a randomized controlled trial designed to evaluate methods for the early detection of cancer. RESULTS Asian men had the lowest risks (odds ratio, 95% confidence interval) for nocturia (0.7, 0.5-0.9), physician-diagnosed BPH (0.3, 0.2-0.5) and transurethral prostatectomy (TURP, 0.2, 0.1-0.6), while risks for Whites and Blacks were similar for most measures of BPH. Greater alcohol intake was associated with decreased nocturia (P trend = 0.002), BPH (P trend < 0.001) and TURP (P trend < 0.001). Current tobacco use was associated with decreased nocturia (0.8, 0.7-0.9), BPH (0.7, 0.6-0.8) and TURP (0.6, 0.4-0.8) but dose-response patterns were weak. CONCLUSION Asian-Americans have the lowest risk of clinical BPH. Alcohol and possibly cigarettes are related to a lower risk for BPH. C1 NCI, Div Canc Epidemiol & Genet, DHHS, Bethesda, MD 20892 USA. Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. Washington Univ, St Louis, MO USA. Univ Utrecht, Utrecht, Netherlands. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. Univ Calif Los Angeles, Los Angeles, CA USA. Univ Alabama, Birmingham, AL USA. Marshfield Med Res & Educ Fdn, Marshfield, WI USA. RP Hayes, RB (reprint author), NCI, Div Canc Epidemiol & Genet, DHHS, 6120 Execut Blvd,EPS 8114,MSC 7240, Bethesda, MD 20892 USA. EM hayesr@mail.nih.gov RI Kang, Dae Hee/E-8631-2012; OI Hayes, Richard/0000-0002-0918-661X NR 35 TC 41 Z9 46 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 1464-4096 J9 BJU INT JI BJU Int. PD JUN PY 2004 VL 93 IS 9 BP 1241 EP 1245 DI 10.1111/j.1464-410X.2004.04839.x PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 825FX UT WOS:000221742500021 PM 15180615 ER PT J AU Klion, AD Law, MA Riemenschneider, W McMaster, ML Brown, MR Horne, M Karp, B Robinson, M Sachdev, V Tucker, E Turner, M Nutman, TB AF Klion, AD Law, MA Riemenschneider, W McMaster, ML Brown, MR Horne, M Karp, B Robinson, M Sachdev, V Tucker, E Turner, M Nutman, TB TI Familial eosinophilia: a benign disorder? SO BLOOD LA English DT Article ID IDIOPATHIC HYPEREOSINOPHILIC SYNDROME; ACTIVATION; BLOOD; CD69; INTERLEUKIN-5; IMATINIB; PROTEINS; ASTHMA AB Familial eosinophilia (FE) is an autosomal dominant disorder characterized by marked eosinophilia and progression to end organ damage in some, but not all, affected family members. To better define the pathogenesis of FE, 13 affected and 11 unaffected family members (NLs) underwent a detailed clinical evaluation at the National Institutes of Health (NIH). No clinical abnormalities were more frequent in the family members with FE compared with the NLs. There was, however, a decreased prevalence of asthma in family members with FE compared with unaffected family members. Eosinophil morphology as assessed by either light or transmission electron microscopy was normal in family members with and without FE. Although levels of eosinophil-derived neurotoxin (EDN) and major basic protein (MBP) were elevated in patients with FE compared with NL, levels of both granule proteins were lower than in nonfamilial hypereosinophilic syndrome (HES). Similarly, increased surface expression of the activation markers C1369, CD25, and HLA-DR was detected by flow cytometry on eosinophils from patients with FE compared with NL, albeit less than that seen in HES. These data suggest that, despite prolonged marked eosinophilia, FE can be distinguished from HES by a more benign clinical course that may be related to a relative lack of eosinophil activation. (C) 2004 by The American Society of Hematology C1 NINDS, NIAID, NHLBI, NCI,Natl Eye Inst, Bethesda, MD USA. NIH, Parasit Dis Lab, Warren Grant Magnusson Clin Ctr, Bethesda, MD 20892 USA. RP Klion, AD (reprint author), NIH, Parasit Dis Lab, Warren Grant Magnusson Clin Ctr, Bldg 4,Rm126, Bethesda, MD 20892 USA. EM aklion@niaid.nih.gov OI Klion, Amy/0000-0002-4986-5326 NR 26 TC 31 Z9 31 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 1 PY 2004 VL 103 IS 11 BP 4050 EP 4055 DI 10.1182/blood-2003-11-3850 PG 6 WC Hematology SC Hematology GA 824BB UT WOS:000221657600018 PM 14988154 ER PT J AU Hanawa, H Hematti, P Keyvanfar, K Metzger, ME Krouse, A Donahue, RE Kepes, S Gray, J Dunbar, CE Persons, DA Nienhuis, AW AF Hanawa, H Hematti, P Keyvanfar, K Metzger, ME Krouse, A Donahue, RE Kepes, S Gray, J Dunbar, CE Persons, DA Nienhuis, AW TI Efficient gene transfer into rhesus repopulating hematopoietic stem cells using a simian immunodeficiency virus-based lentiviral vector system SO BLOOD LA English DT Article ID IN-VIVO SELECTION; MURINE BETA-THALASSEMIA; BLOOD CD34(+) CELLS; PSEUDOTYPED RETROVIRAL VECTORS; CHRONIC GRANULOMATOUS-DISEASE; GREEN FLUORESCENT PROTEIN; LONG-TERM ENGRAFTMENT; NONHUMAN-PRIMATES; PERIPHERAL-BLOOD; BONE-MARROW AB High-titer, HIV-1-based lentiviral vector particles were found to traniduce cytokine-mobilized rhesus macaque CD34(+) cells and clonogenic progenitors very poorly (< 1%), reflecting the postentry restriction in rhesus cells to HIV infection. To overcome this barrier, we developed a simian immunodeficiency virus (SIV)-based vector system. A single exposure to a low concentration of amphotropic pseudotyped SIV vector particles encoding the green fluorescent protein (GFP) resulted in gene transfer into 68% +/- 1 % of rhesus bulk CD34(+) cells and 75% +/- 1% of clonogenic progenitors. Polymerase chain reaction (PCR) analysis of DNA from individual hematopoietic colonies confirmed these relative transduction efficiencies. To evaluate SIV vector-mediated stem cell gene transfer in vivo, 3 rhesus macaques underwent transplantation with transduced, autologous cytokine-mobilized peripheral blood CD34+ cells following myeloalblative conditioning. Hematopoietic reconstitution was rapid, and an average of 18% +/- 8% and 15% +/- 7% GFP-positive granulocytes and monocyles, respectively, were observed 4 to 6 months after transplantation, consistent with the average vector copy number of 0.19 +/- 0.05 in peripheral blood leukocytes as determined by real-time PCR. Vector insertion site analysis demonstrated polyclonal reconstitution with vector-containing cells. SIV vectors appear promising for evaluating gene therapy approaches in nonhuman primate models. (C) 2004 by The American Society of Hematology C1 St Jude Childrens Res Hosp, Expt Hematol Div, Dept Hematol Oncol, Memphis, TN 38105 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Nienhuis, AW (reprint author), St Jude Childrens Res Hosp, Expt Hematol Div, Dept Hematol Oncol, 332 N Lauderdale, Memphis, TN 38105 USA. EM arthur.nienhuis@stjude.org FU NCI NIH HHS [P30 CA 21765]; NHLBI NIH HHS [P01 HL 53749] NR 80 TC 114 Z9 121 U1 1 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 1 PY 2004 VL 103 IS 11 BP 4062 EP 4069 DI 10.1182/blood-2004-01-0045 PG 8 WC Hematology SC Hematology GA 824BB UT WOS:000221657600020 PM 14976042 ER PT J AU Kuramoto, K Follmann, DA Hematti, P Sellers, S Agricola, BA Metzger, ME Donahue, RE von Kalle, C Dunbar, CE AF Kuramoto, K Follmann, DA Hematti, P Sellers, S Agricola, BA Metzger, ME Donahue, RE von Kalle, C Dunbar, CE TI Effect of chronic cytokine therapy on clonal dynamics in nonhuman primates SO BLOOD LA English DT Article ID COLONY-STIMULATING-FACTOR; HEMATOPOIETIC STEM-CELLS; SEVERE CONGENITAL NEUTROPENIA; ACUTE MYELOID-LEUKEMIA; PROGENITOR CELLS; IN-VIVO; FOLLOW-UP; FACTOR-RECEPTOR; BONE-MARROW; G-CSF AB Hematopoietic cytokines such as filgrastim are used extensively to stimulate granulocyte production or to mobilize hematopoietic progenitors into the circulation; however, their effect on more primitive hematopoietic progenitor and stem cells in vivo is unknown, particularly in large animals or humans. In particular, there is concern that chronic therapy with cytokines could result in stem cell exhaustion or clonal dominance; however, direct assessment of the dynamics of individual stem and progenitor cell clones in vivo has not been previously reported. A number of models can be proposed regarding the mechanisms by which the marrow responds to cytokine stimulation, including recruitment of previously quiescent clones, stimulation of proliferation of already active clones, or prevention of apoptosis of more mature progenitors from all clones. Using retroviral marking and comprehensive insertion site tracking of individual stem and progenitor cell clones in 2 rhesus macaques, we analyzed the effect of chronic administration of granulocyte colony-stimulating factor (G-CSF), or a combination of G-CSF plus stem cell factor (SCIF). The overall number of contributing clones remained constant, and the relative output from each clone did not change significantly during or following cytokine treatments. These results suggest that individual transduced stem or progenitor cells can contribute to hematopoiesis for prolonged periods, with no evidence for an effect of G-CSF or G-CSF/SCF on the number, the lifespan, or the relative activity of individual stem or progenitor cell clones. These relevant large animal studies are reassuring regarding clinical applications of cytokines and provide new insights into their mechanisms of action. (C) 2004 by The American Society of Hematology C1 NHLBI, Mol Hematopoiesis Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. Childrens Hosp, Med Ctr, Childrens Res Fdn, Div Expt Hematol, Cincinnati, OH 45229 USA. RP Dunbar, CE (reprint author), NHLBI, Mol Hematopoiesis Sect, Hematol Branch, NIH, Bldg 10,Rm 7C103,9000 Rockville Pike, Bethesda, MD 20892 USA. EM dunbarc@nhlbi.nih.gov NR 45 TC 14 Z9 14 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 1 PY 2004 VL 103 IS 11 BP 4070 EP 4077 DI 10.1182/blood-2003-08-2934 PG 8 WC Hematology SC Hematology GA 824BB UT WOS:000221657600021 PM 14962906 ER PT J AU Schmidt, M Bies, J Tamura, T Ozato, K Wolff, L AF Schmidt, M Bies, J Tamura, T Ozato, K Wolff, L TI The interferon regulatory factor ICSBP/IRF-8 in combination with PU.1 up-regulates expression of tumor suppressor p15(Ink4b) in murine myeloid cells SO BLOOD LA English DT Article ID SEQUENCE BINDING-PROTEIN; KINASE INHIBITOR P15(INK4B); TRANSCRIPTION FACTOR PU.1; C-MYC; TERMINAL DIFFERENTIATION; GROWTH-INHIBITION; PROGENITOR CELLS; LEUKEMIA CELLS; DNA-BINDING; GENE AB CDKN2B (INK4B), which encodes the cyclin-dependent kinase inhibitor p15(INK4b), is up-regulated by many cytokines found in hematopoietic environments in vivo. In human acute myeloid leukemias (AMLs), it is inactivated with high frequency. To gain insight into the regulatory pathways leading to the normal activation of p15(Ink4b) expression, we examined interferon beta (IFNbeta)-induced transcription. Using reporter gene assays in murine myelold cells M1, we determined that a 328-bp fragment, located 117 to 443 bp upstream of the translation initiation site, was sufficient to activate transcription. Both the interferon consensus sequence-binding protein/interferon regulatory factor 8 (ICSBP/IRF-8) and PU.1 were able to increase transcription from this region. It was determined that both ICSBP and PUA must bind to DNA to form a stable PU.1/ ICSBP binding complex. Interestingly, introduction of the ICSBP into ICSBP-null Tot2 cells led to a significant increase in p15(Ink4b) RNA expression. This regulation of the Ink4b promoter is apparently myelold specific because both ICSBP and PUA are myeloid commitment factors. Importantly, this provides a mechanism to explain in part the tumor suppressor activity of ICSBP, since ICSBP-deficient mice develop a chronic myelogenous leukemia (CML)-like disease and a high percentage of human AML and CML lack ICSBP transcripts. D 2004 by The American Society of Hematology C1 NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. NICHHD, Lab Mol Growth Regulat, Bethesda, MD 20892 USA. RP Wolff, L (reprint author), NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. EM lwolff@helix.nih.gov NR 51 TC 46 Z9 46 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 1 PY 2004 VL 103 IS 11 BP 4142 EP 4149 DI 10.1182/blood-2003-01-0285 PG 8 WC Hematology SC Hematology GA 824BB UT WOS:000221657600030 PM 14976051 ER PT J AU Crawford, MP Yan, SX Ortega, SB Mehta, RS Hewitt, RE Price, DA Stastny, P Douek, DC Koup, RA Racke, MK Karandikar, NJ AF Crawford, MP Yan, SX Ortega, SB Mehta, RS Hewitt, RE Price, DA Stastny, P Douek, DC Koup, RA Racke, MK Karandikar, NJ TI High prevalence of autoreactive, neuroantigen-specific CD8(+) T cells in multiple sclerosis revealed by novel flow cytometric assay SO BLOOD LA English DT Article ID MYELIN BASIC-PROTEIN; CHEMOKINE RECEPTOR EXPRESSION; POLYMERASE-CHAIN-REACTION; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; AMINO-ACID SEQUENCE; PROTEOLIPID PROTEIN; PERIPHERAL-BLOOD; INTERFERON-GAMMA; CEREBROSPINAL-FLUID; FINE SPECIFICITY AB Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) with features suggestive of T-cell-mediated pathology. Most prior reports have focused on CD4(+) T cells with the underlying assumption that MS is predominantly a CD4(+) T helper 1 (Th1)-mediated disease. In this report, we used a novel flow cytometric approach to evaluate autoreactive T-cell responses against a large variety of neuroantigenic targets. We found that both CD4(+) and CD8(+) T cells targeted against several CNS autoantigens were widely prevalent in patients with MS and healthy individuals. Whereas the distribution of CD4(+) responses was similar in different groups, patients with relapsing-remitting MS showed a higher proportion of CNS-specific CD8(+) responses. Autoreactive CD4(+) T cells from patients with MS exhibited a more differentiated Th1 phenotype compared with healthy subjects. Similarly, CNS-specific CD8(+) T-cell responses from patients with MS were functionally distinct from those in healthy individuals. Collectively, these studies reveal the high prevalence of class I-restricted autoreactive CD8(+) T-cell responses in MS that has been underappreciated thus far. The results emphasize the need to evaluate both CD4(+) and CD8(+) T-cell responses in MS and to make both subsets a consideration in the development of novel therapeutic strategies. (C) 2004 by The American Society of Hematology. C1 Univ Texas, SW Med Ctr, Dept Pathol, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Dept Internal Med, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Dept Neurol, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Ctr Immunol, Dallas, TX USA. Univ Oxford, Nuffield Dept Clin Med, Oxford, England. NIAID, NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Karandikar, NJ (reprint author), Univ Texas, SW Med Ctr, Dept Pathol, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM nitin@pathology.swmed.edu RI Price, David/C-7876-2013; OI Price, David/0000-0001-9416-2737; Hewitt, Rachel/0000-0002-2367-1822 FU Multiple Sclerosis Society [589]; NIAID NIH HHS [AI47133, AI49990, AI53439]; NINDS NIH HHS [NS37513, NS044250] NR 77 TC 139 Z9 142 U1 1 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 1 PY 2004 VL 103 IS 11 BP 4222 EP 4231 DI 10.1182/blood-2003-10-4025 PG 10 WC Hematology SC Hematology GA 824BB UT WOS:000221657600042 PM 14976054 ER PT J AU Rimsza, LM Roberts, RA Miller, TP Unger, JM LeBlanc, M Braziel, RM Weisenberger, DD Chan, WC Muller-Hermelink, HK Jaffe, ES Gascoyne, RD Campo, E Fuchs, DA Spier, CM Fisher, RI Delabie, J Rosenwald, A Staudt, LM Grogan, TM AF Rimsza, LM Roberts, RA Miller, TP Unger, JM LeBlanc, M Braziel, RM Weisenberger, DD Chan, WC Muller-Hermelink, HK Jaffe, ES Gascoyne, RD Campo, E Fuchs, DA Spier, CM Fisher, RI Delabie, J Rosenwald, A Staudt, LM Grogan, TM TI Loss of MHC class II gene and protein expression in diffuse large B-cell lymphoma is related to decreased tumor immunosurveillance and poor patient survival regardless of other prognostic factors: a follow-up study from the Leukemia and Lymphoma Molecular Profiling Project SO BLOOD LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; HLA-DR; INVARIANT CHAIN; SCID MICE; IMMUNODEFICIENT MICE; RADIATION CHIMERA; MOUSE MODEL; DQ; INTERLEUKIN-2; IMMUNOTHERAPY AB The Leukemia and Lymphoma Molecular Profiling Project recently published results from DNA microarray analyses of 240 diffuse large B-cell lymphomas (DLBCLs). Four gene expression "signatures" were identified as correlated with patient outcome, including the major histocompatibility complex (MHC) class II genes (eg, HLA-DRA) which correlated with better survival. We further analyzed the effects of HLA-DRA on survival and correlated gene expression with protein status and tumor-infiltrating lymphocytes. The 5-year overall survival was 24% in the lowest 10% of HLA-DRA expression, 37% in the 10% to 25% group, 50% in the 25% to 50% group, and 55% for patients in the highest 50%. Further analysis demonstrated that the hazard ratio of death was a nonlinear function of HLA-DRA expression. Adjustment for the International Prognostic Index did not alter the impact of HLA-DRA on survival. Other MHC class II genes were found to predict survival similarly. Microarray HLA-DRA expression correlated with the presence or absence of human leukocyte antigen-DR (HLA-DR) protein in 20 of 22 cases assessed. Fewer tumor-infiltrating CD8(+) T cells were detected in MHC class II-negative cases compared with positive cases (2.8% versus 11.0%; P = .001), supporting the hypothesis that loss of tumor immunosurveillance has a devastating effect on patient outcome in DLBCL. (C) 2004 by The American Society of Hematology. C1 Univ Arizona, Coll Med, Dept Pathol, Tucson, AZ 85724 USA. Univ Arizona, Coll Med, Dept Internal Med, Tucson, AZ 85724 USA. Fred Hutchinson Canc Res Ctr, Ctr Stat, Seattle, WA 98104 USA. Oregon Hlth Sci Univ, Dept Pathol, Portland, OR USA. Univ Nebraska, Dept Pathol, Omaha, NE 68182 USA. Univ Wurzburg, Dept Pathol, D-8700 Wurzburg, Germany. NCI, Metab Branch, Bethesda, MD 20892 USA. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. Univ Barcelona, Hosp Clin Prov, Barcelona, Spain. Univ Rochester, James P Wilmot Canc Ctr, Rochester, NY USA. Norwegian Radium Hosp, Oslo, Norway. RP Rimsza, LM (reprint author), Univ Arizona, Coll Med, Dept Pathol, 1501 N Campbell Ave,POB 245043, Tucson, AZ 85724 USA. EM rimsza@ahsc.arizona.edu NR 38 TC 153 Z9 158 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 1 PY 2004 VL 103 IS 11 BP 4251 EP 4258 DI 10.1182/blood-2003-07-2365 PG 8 WC Hematology SC Hematology GA 824BB UT WOS:000221657600046 PM 14976040 ER PT J AU Blair, RJR AF Blair, RJR TI The roles of orbital frontal cortex in the modulation of antisocial behavior SO BRAIN AND COGNITION LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; BORDERLINE PERSONALITY-DISORDER; HUMAN PREFRONTAL CORTEX; ORBITOFRONTAL CORTEX; FACIAL EXPRESSIONS; PSYCHOPATHIC TENDENCIES; TRYPTOPHAN DEPLETION; RESPONSE REVERSAL; DECISION-MAKING; IMPULSIVE AGGRESSION AB This article considers potential roles of orbital frontal cortex in the modulation of antisocial behavior. Two forms of aggression are distinguished: reactive aggression elicited in response to frustration/threat and goal directed, instrumental aggression. It is suggested that orbital frontal cortex is directly involved in the modulation of reactive aggression. It is argued that orbital frontal cortex does not "inhibit" reactive aggression but rather may both increase or decrease its probability as a function of social cues present in the environment. Early dysfunction in this function of orbital frontal cortex may be linked to the development of Borderline Personality Disorder. Instrumental aggression is linked to a fundamental failure in moral socialization. However, the available data suggest that the amygdala, but not orbital frontal cortex, is required for functions such as aversive conditioning and passive avoidance learning that are necessary for moral socialization. Psychopathic individuals who present with significant instrumental aggression, are impaired in aversive conditioning and passive avoidance learning and show evidence of amygdala dysfunction. Orbital frontal cortex and the amygdala are involved in response reversal where instrumental responses must be reversed following contingency change. Impairments in response reversal are also seen in psychopathic individuals. However, it remains unclear whether impairment in response reversal per se is associated with antisocial behavior. Published by Elsevier Inc. C1 NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Blair, RJR (reprint author), NIMH, Mood & Anxiety Disorders Program, 15K North Dr,Room 206,MSC 2670, Bethesda, MD 20892 USA. EM blairj@intra.nimh.nih.gov NR 122 TC 336 Z9 342 U1 26 U2 106 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0278-2626 J9 BRAIN COGNITION JI Brain Cogn. PD JUN PY 2004 VL 55 IS 1 BP 198 EP 208 DI 10.1016/s0278-2626(03)00276-8 PG 11 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 822TK UT WOS:000221563000015 PM 15134853 ER PT J AU Rogozin, IB Makarova, KS Wolf, YI Koonin, EV AF Rogozin, IB Makarova, KS Wolf, YI Koonin, EV TI Computational approaches for the analysis of gene neighbourhood in prokaryotic genomes SO BRIEFINGS IN BIOINFORMATICS LA English DT Article DE gene order; operon; phylogenetic analysis; functional signal; local alignment; dot-plot; conserved gene pair ID COMPLETE MICROBIAL GENOMES; FUNCTIONALLY RELATED GENES; ESCHERICHIA-COLI; COG DATABASE; BACTERIAL GENOMES; SELFISH OPERONS; REPAIR SYSTEM; WEB-SERVER; EVOLUTION; PREDICTION AB Gene order in prokaryotes is conserved to a much lesser extent than protein sequences. Only some operons, primarily those that encode physically interacting proteins, are conserved in all or most of the bacterial and archaeal genomes. Nevertheless, even the limited conservation of operon Organisation that is observed provides valuable evolutionary and functional clues through multiple genome comparisons. With the rapid growth in the number and diversity of sequenced prokaryotic genomes, functional inferences for uncharacterised genes located in the same conserved gene neighborhood with well-studied genes are becoming increasingly important. In this review, we discuss various computational approaches for identification of conserved gene strings and construction of local alignments of gene orders in prokaryotic genomes. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RAS, Inst Cytol & Genet, Novosibirsk, Russia. RP Rogozin, IB (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, 8600 Rockville Pike,Bldg 38A, Bethesda, MD 20894 USA. EM rogozin@ncbi.nlm.nih.gov NR 79 TC 30 Z9 35 U1 0 U2 2 PU HENRY STEWART PUBLICATIONS PI LONDON PA RUSSELL HOUSE, 28/30 LITTLE RUSSELL ST, LONDON WC1A 2HN, ENGLAND SN 1467-5463 J9 BRIEF BIOINFORM JI Brief. Bioinform. PD JUN PY 2004 VL 5 IS 2 BP 131 EP 149 DI 10.1093/bib/5.2.131 PG 19 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 842VU UT WOS:000223033300004 PM 15260894 ER PT J AU de Sanjose, S Goedert, JJ Marshall, V Bellas, C Benavente, Y Bosch, R Domingo, A Fernandez, A de Sevilla, AF Servitje, O Whitby, D AF de Sanjose, S Goedert, JJ Marshall, V Bellas, C Benavente, Y Bosch, R Domingo, A Fernandez, A de Sevilla, AF Servitje, O Whitby, D TI Risk of malignant lymphoma associated with human herpesvirus-8: a case-control study in Spain SO BRITISH JOURNAL OF CANCER LA English DT Article DE lymphoma; herpesvirus-8; case-control study ID SARCOMA-ASSOCIATED HERPESVIRUS; KAPOSIS-SARCOMA; DNA-SEQUENCES; ANTIBODIES; KSHV/HHV-8; PREVALENCE; DISORDERS; INFECTION; DISEASE; CANCER AB No overall increased risk of lymphoma associated with antibodies to human herpesvirus-8 was found in 526 lymphomas and 599 controls (odds ratio (OR) = 1.04, 95% confidence interval (CI) = 0.62-1.75); significant increases were noted for 19 lymphoplasmacytic lymphomas (OR = 4.47, 95% CI = 1.34-14.85) and nine low-grade lymphoma/lymphoma B-cell NOS (OR = 5.82, 95% CI = 1.07-31.73). (C) 2004 Cancer Research UK. C1 Inst Catala Oncol, Serv Epidemiol & Registre Canc, Barcelona, Spain. NCI, Viral Epidemiol Branch, Bethesda, MD USA. NCI, Viral Epidemiol Sect, AVP, SAIC, Frederick, MD USA. Hosp Verge Cinta, Tortosa, Spain. Ramon & Cajal, Madrid, Spain. Bellvitge Hosp, Barcelona, Spain. Inst Catal Oncol, Barcelona, Spain. Univ Bellvitge, Barcelona, Spain. Ciutat Sanitaria, Barcelona, Spain. RP de Sanjose, S (reprint author), Hosp Llobregat, Serv Epidemiol & Registre Canc, Inst Catala Oncol, Avda Gran Via S-N Km 2-7, Barcelona 08907, Spain. EM s.sanjose@ico.scs.es RI de Sanjose Llongueras, Silvia/H-6339-2014; Benavente, Yolanda/H-9810-2014 FU NCI NIH HHS [N01CO12400] NR 18 TC 9 Z9 9 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUN 1 PY 2004 VL 90 IS 11 BP 2145 EP 2148 DI 10.1038/sj.bjc.6601858 PG 4 WC Oncology SC Oncology GA 834MR UT WOS:000222415700018 PM 15150582 ER PT J AU Li, H Loehrer, PJ Hisada, M Henley, J Whitby, D Engels, EA AF Li, H Loehrer, PJ Hisada, M Henley, J Whitby, D Engels, EA TI Absence of human T-cell lymphotropic virus type 1 and human foamy virus in thymoma SO BRITISH JOURNAL OF CANCER LA English DT Article DE thymoma; human T-cell lymphotropic virus type 1 (HTLV-1); human foamy virus; simian foamy virus; retrovirus ID MYASTHENIA-GRAVIS; INFECTION; IDENTIFICATION; PCR AB The cause of thymoma, a rare malignancy of thymic epithelial cells, is unknown. Recent studies have reported the detection of DNA from human T-cell lymphotropic virus type I (HTLV-I) and human foamy virus (HFV) in small numbers of thymoma tumours, suggesting an aetiologic role for these retroviruses. In the present study, we evaluated 21 US thymoma patients and 20 patients with other cancers for evidence of infection with these viruses. We used the polymerase chain reaction to attempt to amplify viral DNA from tumour tissues, using primers from the pol and tax (HTLV-I) and gag and bel1 (HFV) regions. In these experiments, we did not detect HTLV-I or HFV DNA sequences in any thymoma or control tissues, despite adequate sensitivity of our assays (one HTLV-I copy per 25000 cells, one HFV copy per 7500 cells). Additionally, none of 14 thymoma patients evaluated serologically for HTLV I/II infection was positive by enzyme-linked immunoassay (ELISA), while five (36%) had indeterminate Western blot reactivity. In comparison, one of 20 US blood donors was HTLV-I/II ELISA positive, and nine (45%) donors, including the ELISA-positive donor, had indeterminate Western blot reactivity. Western blot patterns varied across individuals and consisted mostly of weak reactivity. In conclusion, we did not find evidence for the presence of HTLV-I or HFV in US thymoma patients. (C) 2004 Cancer Research UK. C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Indiana Univ, Sch Med, Indianapolis, IN 46204 USA. Indiana Univ, Ctr Canc, Indianapolis, IN 46204 USA. NCI, Viral Epidemiol Sect, AIDS Vaccine Program, SAIC Frederick, Frederick, MD 21701 USA. RP Engels, EA (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 8010, Bethesda, MD 20892 USA. EM engelse@exchange.nih.gov FU NCI NIH HHS [N01 CO 12400, N01CO12400] NR 24 TC 5 Z9 5 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUN 1 PY 2004 VL 90 IS 11 BP 2181 EP 2185 DI 10.1038/sj.bjc.6601841 PG 5 WC Oncology SC Oncology GA 834MR UT WOS:000222415700025 PM 15150553 ER PT J AU Simak, J Holada, K Risitano, AM Zivny, JH Young, NS Vostal, JG AF Simak, J Holada, K Risitano, AM Zivny, JH Young, NS Vostal, JG TI Elevated circulating endothelial membrane microparticles in paroxysmal nocturnal haemoglobinuria SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE adhesion molecules; endothelial cells; flow cytometry; paroxysmal nocturnal haemoglobinuria; sickle cell disease ID THROMBOTIC THROMBOCYTOPENIC PURPURA; CELL-DERIVED MICROPARTICLES; ACUTE CORONARY SYNDROMES; PLASMINOGEN-ACTIVATOR; DISEASE; PLASMA; APOPTOSIS; RECEPTOR; BLOOD; VESICULATION AB We analysed endothelial cell membrane microparticles (ECMP) in the peripheral blood of patients with paroxysmal nocturnal haemoglobinuria (PNH) (n = 9), aplastic anaemia (AA) (n = 10), sickle cell disease (SCD) (n = 8), and healthy donors (HD) (n = 11). There was no clinically manifested thrombosis in the PNH or AA group, except one cured thrombophlebitis (PNH), while all SCD patients had a history of vaso-occlusive crises. We used three-colour flow cytometry with blood cell-specific antibodies and antibodies to endothelial antigens CD105 and CD144. Phosphatidylserine-positive microparticles were detected using the annexin V-binding (AVB) assay. The population of CD105+AVB+ ECMP was significantly (P < 0.05) higher in SCD (median: 0.568 x 10(9)/l; 25-75th percentile range: 0.351-0.976 x 10(9)/l) and PNH (0.401 x 10(9)/l ; 0.19-0.441 x 10(9)/l) patients when compared with AA (0.122 x 10(9)/l; 0.061-0.172 x 10(9)/l) or HD (0.180 x 10(9)/l; 0.137-0.217 x 10(9)/l) group. Even more pronounced differences were observed in ECMP exhibiting a marker of inflammatory stimulation CD54 (CD105+CD54+). Similarly, ECMP that exhibited endothelial specific and proteolysis-sensitive antigen CD144 were increased in SCD and PNH, but not in AA. Elevated CD54+ ECMP may reflect the inflammatory status of endothelial cells in SCD and PNH, while CD144+ ECMP could indicate continuous endothelial stimulation and/or injury. Analysis of circulating ECMP appears promising to provide useful information on the status of the vascular endothelium in PNH and SCD. C1 US FDA, Lab Cellular Hematol, Div Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. Charles Univ, Sch Med 1, Inst Microbiol & Immunol, Prague, Czech Republic. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Simak, J (reprint author), US FDA, CBER, 1401 Rockville Pike,HFM-335, Rockville, MD 20852 USA. EM jan.simak@fda.hhs.gov RI Simak, Jan/C-1153-2011 NR 37 TC 75 Z9 77 U1 0 U2 8 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD JUN PY 2004 VL 125 IS 6 BP 804 EP 813 DI 10.1111/j.1365-2141.2004.04974.x PG 10 WC Hematology SC Hematology GA 826YK UT WOS:000221865200014 PM 15180871 ER PT J AU Sprague, JE Brutcher, RE Mills, EM Caden, D Rusyniak, DE AF Sprague, JE Brutcher, RE Mills, EM Caden, D Rusyniak, DE TI Attenuation of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy)-induced rhabdomyolysis with alpha(1)- plus beta(3)-adrenoreceptor antagonists SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE 3,4-methylenedioxymethamphetamine (MDMA); rhabdomyolysis; creatine kinase; UCP-3; thermogenesis ID MDMA INDUCED HYPERTHERMIA; SKELETAL-MUSCLE; UNCOUPLING PROTEIN-2; BODY-TEMPERATURE; ADIPOSE-TISSUE; RENAL-FAILURE; ECSTASY; PHARMACOLOGY; RECEPTORS; TOXICITY AB 1 Studies were designed to examine the effects of alpha(1) (alpha(1)AR)-plus beta3-adrenoreceptor (beta(3)AR) antagonists on 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy)-induced hyperthermia and measures of rhabdomyolysis (creatine kinase (CK)) and renal function (blood urea nitrogen ( BUN) and serum creatinine (sCr)) in male Sprague-Dawley rats. 2 MDMA (40 mg kg(-1), s.c.) induced a rapid and robust increase in rectal temperature, which was significantly attenuated by pretreatment with the alpha(1)AR antagonist prazosin (100 mug kg(-1), i.p.) plus the beta(3)AR antagonist SR59230A (5 mg kg(-1), i.p.). 3 CK levels significantly increased ( peaking at 4 h) after MDMA treatment and were blocked by the combination of prazosin plus SR59230A. 4 At 4 h after MDMA treatment, BUN and sCr levels were also significantly increased and could be prevented by this combination of alpha(1)AR-plus beta(3)AR-antagonists. 5 The results from this study suggest that alpha(1)AR and beta(3)AR play a critical role in the etiology of MDMA-mediated hyperthermia and subsequent rhabdomyolysis. British Journal of Pharmacology (2004). C1 Ohio No Univ, Raabe Coll Pharm, Dept Pharmaceut & Biomed Sci, Ada, OH 45810 USA. NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Dept Anim Med & Surg, NIH, Bethesda, MD 20892 USA. Indiana Univ, Sch Med, Dept Emergency Med & Pharmacol & Toxicol, Indianapolis, IN 46202 USA. RP Sprague, JE (reprint author), Ohio No Univ, Raabe Coll Pharm, Dept Pharmaceut & Biomed Sci, Ada, OH 45810 USA. EM j-sprague@onu.edu OI Rusyniak, Daniel/0000-0002-6199-0840 NR 27 TC 31 Z9 31 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD JUN PY 2004 VL 142 IS 4 BP 667 EP 670 DI 10.1038/sj.bjp.0705823 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 836CI UT WOS:000222532400005 PM 15159279 ER PT J AU Chen, JR Chatterjee, B Meyer, R Yu, JC Borke, JL Isales, CM Kirby, ML Lo, CW Bollag, RJ AF Chen, JR Chatterjee, B Meyer, R Yu, JC Borke, JL Isales, CM Kirby, ML Lo, CW Bollag, RJ TI Tbx2 represses expression of Connexin43 in osteoblastic-like cells SO CALCIFIED TISSUE INTERNATIONAL LA English DT Article DE bone; development; gap junctions; T-box ID ULNAR-MAMMARY SYNDROME; HOLT-ORAM-SYNDROME; GAP-JUNCTION GENE; T-BOX GENE; CONSERVED PROTEIN MOTIF; TRANSCRIPTION FACTOR; HEART DEVELOPMENT; BETA-GALACTOSIDASE; MESODERM FORMATION; DNA-BINDING AB Tbx2 belongs to a family of developmental transcription regulatory factors. We evaluated whether the gap junction protein Connexin43 (Cx43), an important regulator of osteoblast function and bone development, may be a downstream target gene regulated by Tbx2. The Cx43 promoter contains direct repeats of the consensus T-box binding motif, TCACAC, and moreover, Tbx2 and Cx43 show overlapping expression domains in precursors to bone and in osteoblasts. In vitro analysis showed that the Cx43 promoter contains two Tbx2 binding sites, and this binding was dependent on the TCACAC consensus sequence. Transient transfection analysis with a Cx43 promoter-driven lacZ reporter construct revealed negative regulation mediated by these two Tbx2 binding sites in osteoblast-like cells. Thus, downregulation of Tbx2 led to de-repression of wild-type Cx43 promoter activity, whereas a promoter construct with mutated binding sites showed no de-repression. In stably transfected osteosarcoma cells in which expression of the endogenous Tbx2 gene was downregulated with a Tbx2 antisense construct, a marked de-repression of the endogenous Cx43 gene was observed. This was accompanied by a marked increase in the abundance of Cx43 gap junctions and increased functional gap junction-mediated cell-cell communication. Analysis of lacZ expression in transgenic mice containing the mutated Cx43 promoter-driven lacZ construct further suggested de-repression of the Cx43 promoter in limb buds, a region destined to give rise to long bones of the limbs. Taken together, these findings indicate that the promoter of Cx43 is repressible by Tbx2, both in cultured osteoblast-like cells in vitro and likely in the developing embryo. C1 Med Coll Georgia, Dept Cell Biol & Anat, Augusta, GA 30912 USA. Med Coll Georgia, Inst Mol Med & Genet, Dev Biol Program, Augusta, GA 30912 USA. I Shou Univ, Dept Biol Sci & Technol, Kaohsiung, Taiwan. NHLBI, Dev Biol Lab, NIH, Bethesda, MD 20892 USA. Med Coll Georgia, Dept Surg, Sect Plast Surg, Augusta, GA 30912 USA. Med Coll Georgia, Dept Oral Biol & Maxillofacial Pathol, Augusta, GA 30912 USA. Med Coll Georgia, Inst Mol Med & Genet, Program Synapses & Cell Signaling, Augusta, GA 30912 USA. Augusta VA Med Ctr, Augusta, GA 30910 USA. RP Bollag, RJ (reprint author), Med Coll Georgia, Dept Cell Biol & Anat, Augusta, GA 30912 USA. EM rbollag@mail.mcg.edu RI Isales, Carlos/J-9902-2013 OI Isales, Carlos/0000-0002-4480-3484 FU NHLBI NIH HHS [HL36059, HL51533]; NICHD NIH HHS [HD17069, HD34149]; NIDCR NIH HHS [DE12812] NR 61 TC 18 Z9 19 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0171-967X J9 CALCIFIED TISSUE INT JI Calcif. Tissue Int. PD JUN PY 2004 VL 74 IS 6 BP 561 EP 573 DI 10.1007/s00223-003-0106-5 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 827VO UT WOS:000221931700009 PM 15354864 ER PT J AU Macpherson, GR Figg, WD AF Macpherson, GR Figg, WD TI Small molecule-mediated anti-cancer therapy via hypoxia-inducible factor-1 blockade SO CANCER BIOLOGY & THERAPY LA English DT Article DE HIF-1 alpha; hypoxia; HIF-1; angiogenesis; glycolysis; VEGF; cancer; VHL; PX-478; drug development ID UBIQUITIN-PROTEASOME PATHWAY; FACTOR 1-ALPHA; ACTIVATION; CELLS; HIF-1 AB Despite reservations regarding potential toxicities, small molecule-mediated blockade of the hypoxia-inducible factor-1 transcription factor has emerged as a viable anti-cancer strategy in vivo. Recent experiments by Welsh et al.(1) revealed unprecedented anti-tumor responses of various aggressive solid tumors to the HIF-1 -inhibitory small molecule drug PX-478. Compared with other anti-cancer drugs, PX-478 had markedly improved regression, growth delay and log(10) cell kill profiles, particularly against large tumors that are normally refractory to small molecule drug therapy. Importantly, pharmacokinetic and toxicity profiles were within acceptable limits, providing rationale for the clinical development of HIF-1 inhibitors in general. Though the mechanism of action for PX-478 is not completely understood, inhibition of glycolysis rather than angiogenesis appeared to be the primary mode of anti-cancer activity. C1 Natl Canc Inst, Canc Therapeut Branch, Ctr Canc Res, Mol Pharmacol Sect, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), Natl Canc Inst, Canc Therapeut Branch, Ctr Canc Res, Mol Pharmacol Sect, Bldg 10,Room 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 NR 15 TC 17 Z9 18 U1 0 U2 2 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD JUN PY 2004 VL 3 IS 6 BP 503 EP 504 PG 2 WC Oncology SC Oncology GA 898RP UT WOS:000227094200008 PM 15197355 ER PT J AU Boyapati, SM Bostick, RM McGlynn, KA Fina, MF Roufail, WM Geisinger, KR Hebert, JR Coker, A Wargovich, M AF Boyapati, SM Bostick, RM McGlynn, KA Fina, MF Roufail, WM Geisinger, KR Hebert, JR Coker, A Wargovich, M TI Folate intake, MTHFR C677T polymorphism, alcohol consumption, and risk for sporadic colorectal adenoma (United States) SO CANCER CAUSES & CONTROL LA English DT Article DE alcohol; colorectal adenoma; folate; MTHFR polymorphism ID METHYLENETETRAHYDROFOLATE REDUCTASE POLYMORPHISM; FOOD FREQUENCY QUESTIONNAIRE; HAMSTER OVARY CELLS; COLON-CANCER; METHIONINE; REPRODUCIBILITY; DEFICIENCY; SUPPRESSION; NEOPLASIA; VALIDITY AB Objective: The purpose of this study was to investigate whether folate intake is associated with risk for incident sporadic colorectal adenoma, and whether the association differs according to methylenetetrahydrofolate reductase (MTHFR) genotypes or is modified by intakes of alcohol or other micronutrients in the folate metabolism pathway. Methods: The authors analyzed data from a colonoscopy-based case-control study (n = 177 cases, 228 controls) conducted in North Carolina between 1995 and 1997. Results: The multivariate-adjusted odds ratio (OR) comparing the highest to lowest tertile of total folate intake was 0.61 (95% confidence interval [CI] 0.35-1.05); for MTHFR C677T polymorphism CT and TT genotypes relative to the CC genotype they were, respectively, 1.09 (Cl: 0.71-1.66) and 0.68 (CI: 0.29-1.61); and for heavy drinkers (>3 drinks/week) compared to non-drinkers it was 1.67 (Cl: 1.00-2.81). The multivariate-adjusted ORs comparing the highest to lowest tertile of total folate intake according to those with the MTHFR CC, CT, and TT genotypes, were, respectively, 0.65 (CI: 0.30-1.39), 0.57 (CI: 0.23-1.44), and 0.22 (CI: 0.02-3.19). For those in the lowest tertile of folate intake who drank more than three drinks a week compared to those who were in the highest tertile of folate intake and did not drink alcohol the OR was 6.54 (CI: 1.96-21.80). There was no substantial evidence for interactions of folate with intakes of methionine, vitamins B2, B6, or B12. Conclusions: These data are consistent with hypotheses and previous findings that higher folate intake may reduce risk for colorectal neoplasms, perhaps especially among those who consume more alcohol. C1 Emory Univ, Rollins Sch Publ Hlth, Dept Hematol & Oncol, Dept Epidemiol, Atlanta, GA 30322 USA. Vanderbilt Univ, Sch Med, Ctr Hlth Serv Res,Dept Med, Div Gen Internal Med, Nashville, TN 37212 USA. Emory Univ, Sch Med, Dept Hematol & Oncol, Atlanta, GA USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Forsyth Med Specialists PA, Winston Salem, NC USA. Wake Forest Univ, Winston Salem, NC 27109 USA. Univ Texas, Sch Publ Hlth, Houston, TX USA. Univ S Carolina, Sch Med, Dept Pathol, Columbia, SC 29208 USA. RP Bostick, RM (reprint author), Emory Univ, Rollins Sch Publ Hlth, Dept Hematol & Oncol, Dept Epidemiol, 1518 Clifton Rd NE, Atlanta, GA 30322 USA. EM rmbosti@sph.emory.edu FU NCI NIH HHS [R01CA66539] NR 40 TC 32 Z9 32 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD JUN PY 2004 VL 15 IS 5 BP 493 EP 501 DI 10.1023/B:CACO.0000036447.45446.2c PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 850VE UT WOS:000223641700007 PM 15286469 ER PT J AU Adamson, PC Blaney, SM Widemann, BC Kitchen, B Murphy, RF Hannah, AL Cropp, GF Patel, M Gillespie, AF Whitcomb, PG Balis, FM AF Adamson, PC Blaney, SM Widemann, BC Kitchen, B Murphy, RF Hannah, AL Cropp, GF Patel, M Gillespie, AF Whitcomb, PG Balis, FM TI Pediatric phase I trial and pharmacokinetic study of the platelet-derived growth factor (PDGF) receptor pathway inhibitor SU101 SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article; Proceedings Paper CT 90th Annual Meeting of the American-Association-for-Cancer-Research CY APR 10-14, 1999 CL PHILADELPHIA, PA SP Amer Assoc Canc Res DE signal transduction; pharmacokinetics; pediatric; SU101; leflunomide ID ROUND-CELL TUMOR; REFRACTORY PROSTATE-CANCER; HUMAN NEUROBLASTOMA-CELLS; FACTOR-BETA-RECEPTOR; MESSENGER-RNAS; FACTOR-ALPHA; FACTOR-B; IMMUNOHISTOCHEMICAL EVIDENCE; UP-REGULATION; HUMAN GLIOMA AB Purpose. To determine the maximum tolerated dose and the toxicity profile of the PDGF receptor pathway inhibitor SU101 in pediatric patients with refractory solid tumors, and to define the plasma pharmacokinetics of SU101 and its active metabolite SU0020 in children. Experimental design. Patients between 3 and 21 years of age with CNS malignancy, neuroblastoma, or sarcoma refractory to standard therapy were eligible. The starting dose of SU101 was 230 mg/m(2) per day administered as a 96-h continuous infusion every 21 days. Blood for pharmacokinetic analysis was obtained during the first cycle. Results. Entered into the trial were 27 patients, and 24 were fully evaluable for toxicity. Dose-limiting central nervous system toxicity was observed in two patients at the 440 mg/m(2) per day dose level. Non-dose-limiting toxicities included nausea, vomiting, headache, fatigue, abdominal discomfort, diarrhea, pruritus, anorexia, constipation, and paresthesias. There were no complete or partial responses. One patient with rapidly progressive desmoplastic small round-cell tumor experienced symptomatic improvement and prolonged stable disease. Steady-state concentrations of SU101 were rapidly achieved and proportional to dose. The concentration of SU0020 was 100- to 1000-fold greater than that of SU101. The median clearance of SU0020 was 0.19 l/day per m(2) and its terminal elimination half-life was 14 days. Conclusions. SU101 administered on this schedule was generally well tolerated. The maximum tolerated dose of SU101 is 390 mg/m(2) per day for 4 days repeated every 3 weeks. The neurotoxicity observed at the 440 mg/m(2) per day dose level suggests that patients receiving repetitive cycles must be monitored closely, as SU0020 may accumulate over time. C1 NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. Baylor Coll Med, Texa Childrens Canc Ctr, Houston, TX 77030 USA. Sugen Inc, San Francisco, CA USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Adamson, PC (reprint author), NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. EM adamsonp@mail.med.upenn.edu NR 42 TC 18 Z9 19 U1 0 U2 1 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 JUN PY 2004 VL 53 IS 6 BP 482 EP 488 DI 10.1007/s00280-004-0769-2 PG 7 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 819VR UT WOS:000221344600004 PM 14999430 ER PT J AU Vernon, SW Meissner, H Klabunde, C Rimer, BK Ahnen, DJ Bastani, R Mandelson, MT Nadel, MR Sheinfeld-Gorin, S Zapka, J AF Vernon, SW Meissner, H Klabunde, C Rimer, BK Ahnen, DJ Bastani, R Mandelson, MT Nadel, MR Sheinfeld-Gorin, S Zapka, J TI Measures for ascertaining use of colorectal cancer screening in behavioral, health services, and epidemiologic research SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Editorial Material ID FECAL-OCCULT-BLOOD; INCREASE MAMMOGRAPHY USE; SOCIETY GUIDELINES; AVERAGE-RISK; INTERVENTIONS; PREVENTION; SIGMOIDOSCOPY; MORTALITY; UPDATE; QUESTIONNAIRES C1 Univ Texas, Sch Publ Hlth, Houston, TX 77030 USA. Univ Texas, Ctr Hlth Promot & Prevent Res, Houston, TX 77030 USA. Natl Canc Inst, Div Canc Control & Populat Sci, Bethesda, MD USA. Univ N Carolina, Dept Hlth Behav & Hlth Educ, Chapel Hill, NC USA. Univ Colorado, Sch Med, Denver, CO 80202 USA. Denver Vet Affairs Med Ctr, Denver, CO 80202 USA. Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA USA. Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA USA. Grp Hlth Cooperat Ctr Hlth Studies, Seattle, WA USA. Ctr Dis Control & Prevent, Div Canc Prevent & Control, Atlanta, GA USA. Columbia Univ, Joseph L Mailman Sch Publ Hlth, New York, NY USA. Univ Massachusetts, Sch Med, Worcester, MA 01605 USA. Med Univ S Carolina, Charleston, SC 29425 USA. RP Vernon, SW (reprint author), Univ Texas, Sch Publ Hlth, 7000 Fannin,Suite 2650, Houston, TX 77030 USA. EM svernon@sph.uth.tmc.edu FU NCI NIH HHS [U01 CA086322-01] NR 58 TC 76 Z9 76 U1 2 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2004 VL 13 IS 6 BP 898 EP 905 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 826ZL UT WOS:000221867900002 PM 15184243 ER PT J AU Sinicrope, FA Half, E Morris, JS Lynch, PM Morrow, JD Levin, B Hawk, ET Cohen, DS Ayers, GD Stephens, LC AF Sinicrope, FA Half, E Morris, JS Lynch, PM Morrow, JD Levin, B Hawk, ET Cohen, DS Ayers, GD Stephens, LC CA Familial Adenomatous Polyposis St TI Cell proliferation and apoptotic indices predict adenoma regression in a placebo-controlled trial of celecoxib in familial adenomatous polyposis patients SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; RECTAL EPITHELIAL APOPTOSIS; COLON ADENOCARCINOMA CELLS; COLORECTAL-CANCER; SULINDAC SULFIDE; GASTROINTESTINAL TOXICITY; PROSTATE-CANCER; CYCLOOXYGENASE-2; PATHWAY; CHEMOPREVENTION AB Background: Celecoxib was shown to regress colorectal adenomas in familial adenomatous polyposis (FAP) patients relative to placebo. To address the mechanism of polyp regression, we determined whether celecoxib can modulate cell proliferation, apoptosis, and prostaglandin E-2 (PGE(2)) levels in colorectal epithelia from FAP trial participants and whether such alterations correlate with observed reductions in polyp number. Materials and Methods: Colorectal mucosal biopsies were obtained at baseline and on last day of celecoxib (100 or 400 mg twice daily) or placebo administration (6 months). Residual paraffin-embedded adenomas and normal mucosa from the same patients (n = 17) or normal tissue alone (n = 15) were analyzed. Immunoperoxidase staining for Ki-67 was performed and apoptotic cells were identified by their morphology. Ki-67 and apoptotic labeling indices and their ratios were calculated in superficials (s) and nonsuperficial (ns) regions of adenomas and normal mucosa, and baseline to 6-month differences were calculated. PGE2 levels were analyzed by mass spectroscopy (normal, n = 64; adenoma, n = 56). Biomarkers were analyzed by treatment arm and correlated with previously determined mean percentage reductions in colorectal polyp number. Results: In adenomas, a reduction in the superficial proliferative activity i.e., Ki-67, labeling index, accompanied polyp regression (r = -0.76, P = 0.006). An increase in the apoptotic ratio [i.e., superficial apoptotic index (AI(s))/nonsuperficial apoptotic index (AI(ns))] was found to correlate with reduced polyp counts in that higher apoptotic ratios correlated with better response to celecoxib (r = 0.71, P = 0.004). Furthermore, the Al-s/Ki-67(s), ratio (r = 0.58, P = 0.026) accompanied polyp regression. In normal mucosa, a trend toward increased AI, (r = 0.33, P = 0.053) and polyp regression was found. PGE2 levels did not significantly correlate with polyp regression. Changes in biomarker levels (baseline to 6 months) were correlated in adenomas and normal mucosa (AI(s), r = 0.29, P = 0.024; AI(ns), r = 0.34, P = 0.009; PGE(2), r = 0.50, P = 0.059) within individual patients. Conclusion: Suppression of cell proliferation and an increased apoptotic ratio, as well as the ratio of apoptosis to cell proliferation, accompany polyp regression in a chemoprevention trial in FAP patients. These findings suggest potential mechanisms for the efficacy of celecoxib and warrant further study of these biomarkers as intermediate endpoints in FAP patients. C1 Univ Texas, MD Anderson Canc Ctr, Dept Gastrointestinal Med & Nutr, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Vet Med & Surg, Houston, TX 77030 USA. NCI, Bethesda, MD 20892 USA. Vanderbilt Univ, Ctr Med, Dept Med & Pharmacol, Nashville, TN 37232 USA. RP Sinicrope, FA (reprint author), Mayo Clin, Div Gastroenterol & Hepatol, 200 1st St SW, Rochester, MN 55905 USA. EM sinicrope.frank@mayo.edu NR 47 TC 45 Z9 49 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2004 VL 13 IS 6 BP 920 EP 927 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 826ZL UT WOS:000221867900006 PM 15184247 ER PT J AU de Sanjose, S Dickie, A Alvaro, T Romagosa, V Villanueva, MG Domingo-Domenech, E de Sevilla, AF El-Omar, E AF de Sanjose, S Dickie, A Alvaro, T Romagosa, V Villanueva, MG Domingo-Domenech, E de Sevilla, AF El-Omar, E TI Helicobacter pylori and malignant lymphoma in Spain SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SPLENIC MARGINAL ZONE; B-CELL LYMPHOMAS; GASTRIC MALT LYMPHOMA; ALCOHOL-CONSUMPTION; PANCREATIC-CANCER; VIRUS-INFECTION; TISSUE TYPE; ASSOCIATION; ERADICATION; SPECIFICITY AB Helicobacter pylori has been associated with gastric adenocarcinoma and gastric lymphoma. We report on the systematic evaluation of serologic detection of H. pylori in a lymphoma case-control study. Methods: Cases (N = 536) were consecutive patients newly diagnosed with a lymphoid malignancy between 1998 and 2002 in four centers in Spain. Lymphomas were diagnosed and classified using the WHO Classification. Controls (N = 603) were hospitalized patients frequency-matched to the cases by 5-year age group, sex, and study center. Severe immunocompromised patients were excluded as controls. Patients underwent a personal interview and blood sampling. H. pylori infection was evaluated by the presence of IgG antibodies using the Premier enzyme immunoassay kit (Meridian Diagnostics Inc., Cincinnati, OH). Logistic regression analysis was used to estimate the odds ratios and 95% confidence intervals (OR, 95% Cl) for lymphoma categories. Results: Anti-H. pylori antibodies were detected in 68.5% of the cases and 71.3% of the controls (P = 0.29) H. pylori was associated with a 3-fold excess risk of splenic marginal B-cell lymphoma (OR = 3.97, 95% Cl = 0.92-17.16). H. pylori was not associated with an overall increased risk of extranodal lymphomas (OR = 0.73, 95% Cl = 0.44-1.22) but when specific sites were explored, the four mucosa-associated lymphoid tissue and the six diffuse large B-cell lymphomas primary localized in the stomach were all H. pylori seropositive. Conclusion: Persistent infection with H. pylori may be implicated in the development of lymphomas of the gastric mucosa and of the spleen. These results could have clinical implications in the management of splenic marginal zone lymphomas. C1 Inst Catala Oncol, Serv Epidemiol & Registre Canc, Barcelona 08907, Spain. NCI, Viral Epidemiol Branch, Bethesda, MD 20892 USA. Univ Aberdeen, Dept Med & Therapeut, Aberdeen AB9 1FX, Scotland. Hosp Verge Cinta, Tortosa, Spain. Ciutat Sanit & Univ Bellvitge, Barcelona, Spain. Ramon y Cajal Univ Alcala, Madrid, Spain. RP de Sanjose, S (reprint author), Inst Catala Oncol, Serv Epidemiol & Registre Canc, Gran Via Km 2 7, Barcelona 08907, Spain. EM s.sanjose@ico.scs.es RI de Sanjose Llongueras, Silvia/H-6339-2014; Tomas, Alvaro/L-5531-2015 OI Tomas, Alvaro/0000-0002-7858-2384 NR 34 TC 11 Z9 12 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2004 VL 13 IS 6 BP 944 EP 948 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 826ZL UT WOS:000221867900009 PM 15184250 ER PT J AU Millen, AE Tucker, MA Hartge, P Halpern, A Elder, DE Guerry, D Holly, EA Sagebiel, RW Potischman, N AF Millen, AE Tucker, MA Hartge, P Halpern, A Elder, DE Guerry, D Holly, EA Sagebiel, RW Potischman, N TI Diet and melanoma in a case-control study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CUTANEOUS MALIGNANT-MELANOMA; ALPHA-TOCOPHEROL; BETA-CAROTENE; VITAMIN-E; 1,25-DIHYDROXYVITAMIN D-3; INDUCED ERYTHEMA; DYSPLASTIC NEVI; HUMAN-SKIN; RISK; CANCER AB Background: Malignant melanoma has been one of the most rapidly increasing cancers within the United States with few modifiable risk factors. This study investigates risk related to dietary factors, which are potentially modifiable. Methods: Newly diagnosed patients with melanoma (n = 502) were recruited from pigment lesion clinics and controls (n = 565) were recruited from outpatient clinics. To investigate the relationship between melanoma and dietary factors in this case-control study, study subjects were requested to complete a food frequency questionnaire, which assessed diet over the previous year. Using logistic regression, odds ratios (ORs) for melanoma were computed for nutrient and alcohol intake. Results: Persons in high versus low quintiles of energy-adjusted vitamin D, a-carotene, P-carotene, cryptoxanthin, lutein, and lycopene had significantly reduced risk for melanoma (ORs less than or equal to 0.67), which remained after adjustment for presence of dysplastic nevi, education, and skin response to repeated sun exposure. Addition of micronutrients from supplements did not add an additional reduction in risk. High alcohol consumption was associated with an increased risk for melanoma, which remained after adjustment for confounders [OR (95% confidence interval) in highest versus lowest quintiles, 1.65 (1.09-2.49)]. Conclusions: Diets consisting of foods rich in vitamin D and carotenoids and low in alcohol may be associated with a reduction in risk for melanoma. These analyses should be repeated in large, prospective studies. C1 NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Dermatol Serv, New York, NY 10021 USA. Univ Penn, Pigmented Les Study Grp, Philadelphia, PA 19104 USA. Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Melanoma Clin, San Francisco, CA 94143 USA. RP Millen, AE (reprint author), NCI, Appl Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM millena@mail.nih.gov RI Tucker, Margaret/B-4297-2015 NR 48 TC 91 Z9 97 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2004 VL 13 IS 6 BP 1042 EP 1051 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 826ZL UT WOS:000221867900021 PM 15184262 ER PT J AU Abnet, CC Saadatian-Elahi, M Pourshams, A Boffetta, P Feizzadeh, A Brennan, P Taylor, PR Kamangar, F Dawsey, SM Malekzadeh, R AF Abnet, CC Saadatian-Elahi, M Pourshams, A Boffetta, P Feizzadeh, A Brennan, P Taylor, PR Kamangar, F Dawsey, SM Malekzadeh, R TI Reliability and validity of opiate use self-report in a population at high risk for esophageal cancer in Golestan, Iran SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article AB Objective: To assess the reliability and validity of self-reported opium use in a rural Iranian population at high risk for esophageal cancer in preparation for a large cohort study. Method: 1,057 subjects ages 33 to 84 years were recruited from Gonbad city and three surrounding villages in Golestan province of Iran and completed a questionnaire and provided biological samples. The history and duration of using opium, smoking tobacco, chewing nass, and drinking alcohol were measured by questionnaire in the entire cohort. A subgroup of 130 people was reinterviewed after 2 months to assess reliability. Validity of the opium question was assessed by comparing the questionnaire responses with the presence of codeine and morphine in the urine of 150 selected subjects. Results: Self-reported opiate use is reliable and valid in this population. The reliability of ever opium use and duration of opium use had kappa's of 0.96 and 0.74, respectively. The validity of self-reported opium use was also high. Using urine codeine or morphine as the gold standard for use of opium, self-report had a sensitivity of 0.93 and a specificity of 0.89. Conclusions: The self-reported use of opium can provide a reliable and valid measurement in this population and will be useful for studying associations between opium use and occurrence of esophageal cancer and other diseases. C1 NCI, Canc Res Ctr, Canc Prevent Studies Branch, Bethesda, MD 20892 USA. Eduard Herriot Hosp, Int Agcy Res Canc, Lyon, France. Eduard Herriot Hosp, Dept Biochem, Lyon, France. Univ Tehran Med Sci, Digest Dis Res Ctr, Shariati Hosp, Tehran, Iran. RP Abnet, CC (reprint author), NCI, Canc Res Ctr, Canc Prevent Studies Branch, 6116 Execut Blvd,Room 705, Bethesda, MD 20892 USA. EM abnetc@mail.nih.gov RI Abnet, Christian/C-4111-2015; OI Abnet, Christian/0000-0002-3008-7843; Malekzadeh, Reza/0000-0003-1043-3814 NR 9 TC 47 Z9 47 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2004 VL 13 IS 6 BP 1068 EP 1070 PG 3 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 826ZL UT WOS:000221867900025 PM 15184266 ER PT J AU Stolzenberg-Solomon, R El Ghormli, L Schatzkin, A Rosen, C Clevidence, B Campbell, W Snyder, K Judd, J Taylor, P AF Stolzenberg-Solomon, R El Ghormli, L Schatzkin, A Rosen, C Clevidence, B Campbell, W Snyder, K Judd, J Taylor, P TI Effects of a low fat, high fiber-complex carbohydrate diet on components of the IGF axis measured in plasma: A controlled feeding study in men SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article C1 NCI, Nutrit Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NCI, Canc Prevent Studies Branch, Ctr Clin Res, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. St Joseph Hosp, MECORE Lab, Bangor, ME USA. USDA ARS, Beltsville Human Nutr Res Ctr, Beltsville, MD USA. Informat Management Serv Inc, Silver Spring, MD USA. RP Stolzenberg-Solomon, R (reprint author), NCI, Nutrit Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,Suite 320,EPS,Room 3022,MSC 7232, Bethesda, MD 20892 USA. EM rs221z@nih.gov NR 3 TC 1 Z9 1 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUN PY 2004 VL 13 IS 6 BP 1086 EP 1087 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 826ZL UT WOS:000221867900030 PM 15184271 ER PT J AU Kielosto, M Nummela, P Katainen, R Leaner, V Birrer, MJ Holtta, E AF Kielosto, M Nummela, P Katainen, R Leaner, V Birrer, MJ Holtta, E TI Reversible regulation of the transformed phenotype of ornithine decarboxylase and ras-overexpressing cells by dominant-negative mutants of c-Jun SO CANCER RESEARCH LA English DT Article ID ACTIVATED PROTEIN-KINASES; N-TERMINAL PHOSPHORYLATION; TRANSCRIPTION FACTOR AP-1; HA-RAS; SIGNAL-TRANSDUCTION; CYCLE PROGRESSION; DELETION MUTANT; GENE-EXPRESSION; MAP KINASES; NUDE-MICE AB c-Jun is an oncogenic transcription factor involved in the regulation of cell proliferation, apoptosis and transformation. We have previously reported that cell transformations induced by ornithine decarboxylase (ODC) and c-Ha-ras oncogene, commonly activated in various cancer cells, are associated with constitutively increased phosphorylation of c-Jun on Ser residues 63 and 73. In the present study, we examined the significance of c-Jun phosphorylation and activation on the phenotype of the ODC- and ras-transformants, by using specific inhibitors and dominant-negative (DN) mutants to c-Jun NH2-terminal kinase (JNK) and its upstream kinase, SEK1/MKK4 ( mitogen-activated protein kinase kinase 4), and to c-Jun. The transformed morphology of both the ODC- and ras-expressing cells was reversed partially by JNK inhibitors and DN JNK1, more effectively by DN SEK1/MKK4 and phosphorylation-deficient c-Jun mutants (c-Jun(S63,73A), c-Jun S-63,S-73A,S-T91,S-93A) and most potently by a trans-activation domain deletion mutant of c-Jun (TAM67). Moreover, tetracycline-inducible TAM67 expression in ODC- and ras-transformed cells showed that the transformed phenotype of the cells is reversibly regulatable. TAM67 also inhibited the tumorigenicity of the cells in nude mice. These inducible cell lines, together with their parental cell lines, provide good models to identify the genes and proteins relevant to cellular transformation. C1 Univ Helsinki, Haartman Inst, FIN-00014 Helsinki, Finland. Univ Helsinki, Cent Hosp, Dept Pathol, FIN-00014 Helsinki, Finland. NCI, Ctr Canc Res, Canc & Cell Biol Dept, Rockville, MD USA. RP Holtta, E (reprint author), Univ Helsinki, Haartman Inst, POB 21, FIN-00014 Helsinki, Finland. EM erkki.holtta@helsinki.fi NR 68 TC 20 Z9 20 U1 1 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 JUN 1 PY 2004 VL 64 IS 11 BP 3772 EP 3779 DI 10.1158/0008-5472.CAN-3188-2 PG 8 WC Oncology SC Oncology GA 825AB UT WOS:000221727300010 PM 15172983 ER PT J AU Pulling, LC Vuillemenot, BR Hutt, JA Devereux, TR Belinsky, SA AF Pulling, LC Vuillemenot, BR Hutt, JA Devereux, TR Belinsky, SA TI Aberrant promoter hypermethylation of the death-associated protein kinase gene is early and frequent in murine lung tumors induced by cigarette smoke and tobacco carcinogens SO CANCER RESEARCH LA English DT Article ID O-6-METHYLGUANINE-DNA METHYLTRANSFERASE GENE; CHLORIDE-INDUCED LUNG; NECK-CANCER PATIENTS; K-RAS GENE; DAP-KINASE; METHYLENE-CHLORIDE; B6C3F1 MICE; MOUSE LUNG; CPG ISLAND; INDUCED APOPTOSIS AB Loss of expression of the death-associated protein (DAP)-kinase gene by aberrant promoter methylation may play an important role in cancer development and progression. The purpose of this investigation was to determine the commonality for inactivation of the DAP-kinase gene in adenocarcinomas induced in mice by chronic exposure to mainstream cigarette smoke, the tobacco carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and vinyl carbamate, and the occupational carcinogen methylene chloride. The timing for inactivation was also determined in alveolar hyperplasias that arise in lung cancer induced in the A/J mouse by NNK. The DAP-kinase gene was not expressed in three of five NNK-induced lung tumor-derived cell lines or in a spontaneously arising lung tumor-derived cell line. Treatment with 5-aza-2'-deoxycytidine restored expression; dense methylation throughout the DAP-kinase CpG island detected by bisulfite sequencing supported methylation as the inactivating event in these cell lines. Methylation-specific PCR detected inactivation of the DAP-kinase gene in 43% of tumors associated with cigarette smoke, a frequency similar to those reported in human non-small cell lung cancer. In addition, DAP-kinase methylation was detected in 52%, 60%, and 50% of tumors associated with NNK, vinyl carbamate, and methylene chloride, respectively. Methylation was observed at similar prevalence in both NNK-induced hyperplasias and adenocarcinomas (46 % versus 52 %), suggesting that inactivation of this gene is one pathway for tumor development in the mouse lung. Bisulfite sequencing of both premalignant and malignant lesions revealed dense methylation, substantiating that this gene is functionally inactivated at the earliest histological stages of adenocarcinoma development. This study is the first to use a marine model of cigarette smoke-induced lung cancer and demonstrate commonality for inactivation by promoter hypermethylation of a gene implicated in the development of this disease in humans. C1 Lovelace Resp Res Inst, Lung Canc Program, Albuquerque, NM 87108 USA. NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Belinsky, SA (reprint author), Lovelace Resp Res Inst, Lung Canc Program, 2425 Ridgecrest Dr SE, Albuquerque, NM 87108 USA. EM sbelinsk@LRRI.org FU NIEHS NIH HHS [ES08801, P30-ES-012072] NR 50 TC 76 Z9 79 U1 1 U2 2 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 JUN 1 PY 2004 VL 64 IS 11 BP 3844 EP 3848 DI 10.1158/0008-5472.CAN-03-2119 PG 5 WC Oncology SC Oncology GA 825AB UT WOS:000221727300019 PM 15172992 ER PT J AU Cheung, C Akiyama, TE Ward, JM Nicol, CJ Feigenbaum, L Vinson, C Gonzalez, FJ AF Cheung, C Akiyama, TE Ward, JM Nicol, CJ Feigenbaum, L Vinson, C Gonzalez, FJ TI Diminished hepatocellular proliferation in mice humanized for the nuclear receptor peroxisome proliferator-activated receptor alpha SO CANCER RESEARCH LA English DT Article ID PPAR-ALPHA; MAMMALIAN-CELLS; GENE-EXPRESSION; MOUSE-LIVER; METABOLISM; AGONIST; RATS; HEPATOCARCINOGENESIS; IDENTIFICATION; WY-14,643 AB Lipid-lowering fibrate drugs function as agonists for the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha). Sustained activation of PPARalpha leads to the development of liver tumors in rats and mice. However, humans appear to be resistant to the induction of peroxisome proliferation and the development of liver cancer by fibrate drugs. The molecular basis of this species difference is not known. To examine the mechanism determining species differences in peroxisome proliferator response between mice and humans, a PPARalpha-humanized mouse line was generated in which the human PPARalpha was expressed in liver under control of the tetracycline responsive regulatory system. The PPARalpha-humanized and wild-type mice responded to treatment with the potent PPARalpha ligand Wy-14643 as revealed by induction of genes encoding peroxisomal and mitochondrial fatty acid metabolizing enzymes and resultant decrease of serum triglycerides. However, surprisingly, only the wild-type mice and not the PPARalpha-humanized mice exhibited hepatocellular proliferation as revealed by elevation of cell cycle control genes, increased incorporation of 5-bromo-2'-deoxyuridine into hepatocyte nuclei, and hepatomegaly. These studies establish that following ligand activation, the PPARalpha-mediated pathways controlling lipid metabolism are independent from those controlling the cell proliferation pathways. These findings also suggest that structural differences between human and mouse PPARalpha are responsible for the differential susceptibility to the development of hepatocarcinomas observed after treatment with fibrates. The PPARalpha-humanized mice should serve as models for use in drug development and human risk assessment and to determine the mechanism of hepatocarcinogenesis of peroxisome proliferators. C1 NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Vet & Tumor Pathol Sect, Ctr Canc Res, Frederick, MD 21701 USA. NCI, Lab Anim Sci Program, SAIC, Frederick, MD 21701 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov FU PHS HHS [N01-C0-56000] NR 33 TC 125 Z9 127 U1 1 U2 3 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 JUN 1 PY 2004 VL 64 IS 11 BP 3849 EP 3854 DI 10.1158/0008-5472.CAN-04-0322 PG 6 WC Oncology SC Oncology GA 825AB UT WOS:000221727300020 PM 15172993 ER PT J AU Chen, W Lee, JW Cho, SY Fine, HA AF Chen, W Lee, JW Cho, SY Fine, HA TI Proteasome-mediated destruction of the cyclin A/cyclin-dependent kinase 2 complex suppresses tumor cell growth in vitro and in vivo SO CANCER RESEARCH LA English DT Article ID TRANSCRIPTION FACTOR E2F-1; S-PHASE ENTRY; RETINOBLASTOMA PROTEIN; DNA-BINDING; DIFFERENTIAL REGULATION; FUNCTIONAL INACTIVATION; NEGATIVE REGULATORS; STRUCTURAL BASIS; CARCINOMA CELLS; APOPTOSIS AB Cyclin-dependent kinases (cdks) represent potentially promising molecular targets for cancer therapeutic strategies. To evaluate the antitumor activity of selective cyclin/cdk inhibition, we constructed a chimeric protein composed of a F-box protein (TrCP) fused to a peptide comprising the cyclin/cdk2 binding motif in p21-like cdk inhibitors (TrCP-LFG). We now demonstrate that endogenous cyclin A and its binding substrate, cdk2, can be tethered to beta-TrCP, ubiquitinated, and effectively degraded. Degradation of cdk2 and cyclin A together, but not cdk2 alone, results in massive tumor cell apoptosis in vitro and in vivo in a proteasome-dependent manner with no toxicity to normal tissue. These data demonstrate that cyclin A and/or the cyclin A/cdk2 complex is a promising anticancer target with a high therapeutic index. C1 NINDS, Neurooncol Branch, NIH, Bethesda, MD 20892 USA. RP Fine, HA (reprint author), NINDS, Neurooncol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 65 TC 42 Z9 45 U1 2 U2 4 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 JUN 1 PY 2004 VL 64 IS 11 BP 3949 EP 3957 DI 10.1158/0008-5472.CAN-03-3906 PG 9 WC Oncology SC Oncology GA 825AB UT WOS:000221727300034 PM 15173007 ER PT J AU Calvisi, DF Ladu, S Factor, VM Thorgeirsson, SS AF Calvisi, DF Ladu, S Factor, VM Thorgeirsson, SS TI Activation of beta-catenin provides proliferative and invasive advantages in c-myc/TGF-alpha hepatocarcinogenesis promoted by phenobarbital SO CARCINOGENESIS LA English DT Article ID GROWTH-FACTOR-ALPHA; MOUSE-LIVER TUMORS; TRANSGENIC MICE; WNT/BETA-CATENIN; E-CADHERIN; HEPATOCELLULAR CARCINOMAS; SIGNAL-TRANSDUCTION; COLON-CANCER; CELLS; EXPRESSION AB Previously, we have found that phenobarbital (PB) enhanced cell survival and facilitated tumor growth in our c-myc/transforming growth factor (TGF)-alpha transgenic mouse model of liver cancer. Given that PB selectively promoted initiated cells harboring beta-catenin mutations during chemically induced hepatocarcinogenesis and that Wnt/beta-catenin signaling is involved in both anti-apoptotic and proliferative processes, we now have extended our analysis to investigate whether promotion by PB affects the occurrence of beta-catenin mutations in c-myc/TGF-alpha-driven tumors. The frequency of beta-catenin activation as judged by somatic mutations and/or nuclear localization was significantly increased in hepatocellular carcinomas (HCCs) from c-myc/TGF-alpha mice treated with PB (15/28; 53.6%) as compared with that in control HCCs (2/28; 7.1%). Furthermore, an intact beta-catenin locus was detected in all neoplasms following PB treatment, whereas 57.1% (16/28) of malignant tumors from c-myc/TGF-alpha untreated mice displayed loss of heterozygosity at the beta-catenin locus. Strikingly, in the majority of PB-treated HCCs beta-catenin nuclear localization was limited to small cells with high nuclear/cytoplasmic ratio forming an invasion front (NAinv). beta-Catenin NAinv cells showed cytoplasmic redistribution of E-cadherin associated with intense mucin 1 and matrilysin immunostaining, suggesting their invasive phenotype. All beta-catenin-positive HCCs displayed increased proliferation and tumor size, but no difference in the apoptotic rate when compared with beta-catenin negative tumors. These findings show that PB treatment positively selects for a cell population displaying activation of beta-catenin in c-myc/TGF-alpha HCCs. beta-Catenin activation confers additional growth and invasive advantages in a model of liver cancer already accelerated by synergistic activity of the c-myc and TGF-alpha transgenes. C1 NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Thorgeirsson, SS (reprint author), NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM snorri_thorgeirsson@nih.gov NR 40 TC 40 Z9 42 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD JUN PY 2004 VL 25 IS 6 BP 901 EP 908 DI 10.1093/carcin/bgh083 PG 8 WC Oncology SC Oncology GA 825IQ UT WOS:000221750400007 PM 14742323 ER PT J AU Freudenheim, JL Bonner, M Krishnan, S Ambrosone, CB Graham, S McCann, SE Moysich, KB Bowman, E Nemoto, T Shields, PG AF Freudenheim, JL Bonner, M Krishnan, S Ambrosone, CB Graham, S McCann, SE Moysich, KB Bowman, E Nemoto, T Shields, PG TI Diet and alcohol consumption in relation to p53 mutations in breast tumors SO CARCINOGENESIS LA English DT Article ID SQUAMOUS-CELL CARCINOMA; LIFE-STYLE FACTORS; CANCER RISK; CIGARETTE-SMOKING; POSTMENOPAUSAL WOMEN; DUCTAL CARCINOMA; FOLATE INTAKE; MICROSATELLITE INSTABILITY; PROTEIN EXPRESSION; DNA METHYLATION AB There is evidence linking alcohol consumption to p53 mutations in tumors, considerable evidence linking alcohol consumption with risk of breast cancer and some evidence that alcohol and folate consumption interact to affect risk. Further, while there is some indication that oxidation may play a role in breast cancer etiology, there has been little examination of an association of oxidative stress with p53 mutations. We examined several dietary components related to one-carbon metabolism and antioxidants to determine if these factors were related to the prevalence of p53 mutations in breast tumors. We conducted a case-control study of primary, histologically confirmed breast cancer in western New York. Controls <65 were selected from drivers license lists; those greater than or equal to65 were selected from Health Care Finance Administration lists. p53 mutations in archived tumor blocks were identified in exons 2-11 and flanking intron sequences. Usual dietary intake was assessed by interview regarding intake in the previous 2 years; alcohol consumption was queried for 2, 10 and 20 years in the past. Our data were consistent with increased likelihood of tumors with p53 mutations for premenopausal breast cancer with increased alcohol intake 10 or 20 years previous; for intake of 16 or more drinks per month in the period 20 years before the interview compared with non-drinkers, the OR was 5.25, 95% CI 1.48-18.58. For postmenopausal women, there was increased likelihood of tumors with p53 mutations among women with higher folate. Antioxidant nutrients were not differentially related to p53 mutations. These results indicate that there may be heterogeneity in breast tumors, as indicated by differences in associations for those with or without p53 mutations, and that causal pathways for these nutrients may vary for pre- and postmenopausal women. For premenopausal women, alcohol consumption in the past was associated with p53 mutations. C1 SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14214 USA. Georgetown Univ, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. New York State Dept Hlth, Roswell Pk Canc Inst, Buffalo, NY 14263 USA. Natl Canc Inst, Human Carcinogenesis Lab, Bethesda, MD USA. SUNY Buffalo, Dept Surg, Buffalo, NY 14214 USA. RP Freudenheim, JL (reprint author), SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14214 USA. EM Jfreuden@buffalo.edu RI Shields, Peter/I-1644-2012 FU NCI NIH HHS [CA/ES 62995, CA11535] NR 59 TC 16 Z9 16 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 JUN PY 2004 VL 25 IS 6 BP 931 EP 939 DI 10.1093/carcin/bgh088 PG 9 WC Oncology SC Oncology GA 825IQ UT WOS:000221750400010 PM 14742318 ER PT J AU Stern, MD Cheng, HP AF Stern, MD Cheng, HP TI Putting out the fire: what terminates calcium-induced calcium release in cardiac muscle? SO CELL CALCIUM LA English DT Article DE sarcoplasmic reticulum; cardiac muscle; ryanodine receptor ID RYANODINE RECEPTOR CHANNELS; RAT VENTRICULAR MYOCYTES; PHYSIOLOGICAL IONIC CONDITIONS; RETICULUM LUMENAL CA2+; SARCOPLASMIC-RETICULUM; SKELETAL-MUSCLE; HEART-CELLS; CALMODULIN-BINDING; CA-2+ RELEASE; LOCAL-CONTROL AB The majority of contractile calcium in cardiac muscle is released from. stores in the sarcoplasmic reticulum (SR), by a process of calcium-induced calcium release (CICR) through ryanodine receptors. Because CICR is intrinsically self-reinforcing, the stability of and graded regulation of cardiac EC coupling appear paradoxical. It is now well established that this gradation results from the stochastic recruitment of varying numbers of elementary local release events, which may themselves be regenerative, and which can be directly observed as calcium sparks. Ryanodine receptors (RyRs) are clustered in dense lattices, and most calcium sparks are now believed to involve activation of multiple RyRs. This implies that local CICR is regenerative, requiring a mechanism to terminate it. It was initially assumed that this mechanism was inactivation of the RyR, but during the decade since the discovery of sparks, no sufficiently strong inactivation mechanism has been demonstrated in vitro and all empirically determined. gating schemes for the RyR give unstable EC coupling in Monte Carlo simulations. We consider here possible release termination mechanisms. Stochastic attrition is the spontaneous decay of active clusters due to random channel closure; calculations show that it is much too slow unless assisted by another process. Calcium-dependent RyR inactivation involving third-party proteins remains a viable but speculative mechanism; current candidates include calmodulin and sorcin. Local depletion of SR release terminal calcium could terminate release, however calculations and measurements leave it uncertain whether a sufficient diffusion resistance exists within the SR to sustain such depletion. Depletion could be assisted by dependence of RyR activity on SR lumenal [Ca2+]. There is substantial evidence for such lumenal activation, but it is not clear if it is a strong enough effect to account for the robust termination of sparks. The existence of direct interactions among clustered RyRs might account for the discrepancy between the inactivation properties of isolated RyRs and intact clusters. Such coupled gating remains controversial. Determining the mechanism of release termination is the outstanding unsolved problem of cardiac EC coupling, and will probably require extensive genetic manipulation of the EC coupling apparatus in its native environment to unravel the solution. Published by Elsevier Ltd. C1 NIA, Cardiovasc Sci Lab, Ctr Gerontol Res, NIH, Baltimore, MD 21224 USA. RP Stern, MD (reprint author), NIA, Cardiovasc Sci Lab, Ctr Gerontol Res, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM sternm@grc.nia.nih.gov NR 59 TC 104 Z9 110 U1 0 U2 6 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4160 J9 CELL CALCIUM JI Cell Calcium PD JUN PY 2004 VL 35 IS 6 BP 591 EP 601 DI 10.1016/j.ceca.2004.01.013 PG 11 WC Cell Biology SC Cell Biology GA 821JY UT WOS:000221457700012 PM 15110149 ER PT J AU Lakatta, EG AF Lakatta, EG TI Beyond Bowditch: the convergence of cardiac chronotropy and inotropy SO CELL CALCIUM LA English DT Article DE cardiac pacemaker cells; cardiac myocytes; Ca2+ cycling; sarcoplasmic reticulum; ryanodine receptors; beta-adrenergic receptor signalling ID BETA-ADRENERGIC STIMULATION; INTRACELLULAR CA2+ RELEASE; RABBIT SINOATRIAL NODE; NA+-CA2+ EXCHANGE CURRENT; CAT RIGHT ATRIUM; SARCOPLASMIC-RETICULUM; RYANODINE RECEPTOR; PACEMAKER ACTIVITY; CALCIUM-RELEASE; HEART-CELLS AB The ability of the heart to acutely beat faster and stronger is central to the vertebrate survival instinct. Released neurotransmitters, norepinephrine and epinephrine, bind to p-adrenergic receptors (beta-AR) on pacemaker cells comprising the sinoatrial node, and to beta-AR on ventricular myocytes to modulate cellular mechanisms that govern the frequency and amplitude, respectively, of the duty cycles of these cells. While a role for sarcoplasmic reticulum Ca2+ cycling via SERCA2 and ryanodine receptors (RyR) has long been appreciated with respect to cardiac inotropy, recent evidence also implicates Ca2+ cycling with respect to chronotropy. In spontaneously beating primary sinoatrial nodal pacemaker cells, RyR Ca2+ releases occurring during diastolic depolarization activate the Na+-Ca2+ exchanger (NCX) to produce an inward current that enhances their diastolic depolarization rate, and thus increases their beating rate. beta-AR stimulation synchronizes RyR activation and Ca2+ release to effect an increased beating rate in pacemaker cells and contraction amplitude in myocytes: in pacemaker cells, the beta-AR stimulation synchronization of RyR activation occurs during the diastolic depolarization, and augments the NCX inward current; in ventricular myocytes, beta-AR stimulation synchronizes the openings of unitary L-type Ca2+ channel activation following the action potential, and also synchronizes RyR Ca2+ releases following depolarization, and in the absence of depolarization, both leading to the generation of a global cytosolic Ca-i transient of increased amplitude and accelerated kinetics. Thus, beta-AR stimulation induced synchronization of RyR activation (recruitment of additional RyRs to fire) and of the ensuing Ca2+ release cause the heart to beat both stronger and faster, and is thus, a common mechanism that links both the maximum achievable cardiac inotropy and chronotropy. Published by Elsevier Ltd. C1 NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP Lakatta, EG (reprint author), NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. EM lakattae@grc.nia.nih.gov NR 70 TC 33 Z9 33 U1 0 U2 4 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4160 J9 CELL CALCIUM JI Cell Calcium PD JUN PY 2004 VL 35 IS 6 BP 629 EP 642 DI 10.1016/j.ceca.2004.01.017 PG 14 WC Cell Biology SC Cell Biology GA 821JY UT WOS:000221457700016 PM 15110153 ER PT J AU Price, DK Figg, WD AF Price, DK Figg, WD TI hTert-immortalized endothelial cells - An important new research tool SO CELL CYCLE LA English DT Article DE hTert; endothelial; angiogenesis; preclinical; aging C1 NCI, Mol Pharmacol Sect, Canc Therapeut Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, Canc Therapeut Branch, Ctr Canc Res, Bldg 10,Room 5AD1,MSC1910,9000 Rockville Pike, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 NR 6 TC 2 Z9 5 U1 0 U2 0 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD JUN PY 2004 VL 3 IS 6 BP 789 EP 789 PG 1 WC Cell Biology SC Cell Biology GA 846ZB UT WOS:000223357200025 PM 15153813 ER PT J AU McNeil, EL Tacelosky, D Basciano, P Biallas, B Williams, R Damiani, P Deacon, S Fox, C Stewart, B Petruzzi, N Osborn, C Klinger, K Sellers, JR Smith, CK AF McNeil, EL Tacelosky, D Basciano, P Biallas, B Williams, R Damiani, P Deacon, S Fox, C Stewart, B Petruzzi, N Osborn, C Klinger, K Sellers, JR Smith, CK TI Actin-dependent motility of melanosomes from fish retinal pigment epithelial (RPE) cells investigated using in vitro motility assays SO CELL MOTILITY AND THE CYTOSKELETON LA English DT Article; Proceedings Paper CT National Conference on Undergraduate Research CY 2003 CL Salt Lake City, UT ID MYOSIN-VIIA; PHOTORECEPTOR CELLS; GRANULE MIGRATION; MOUSE MELANOCYTES; MICROTUBULES; TRANSPORT; MOTOR; EXPRESSION; MOVEMENT; MELANOPHORES AB Melanosomes (pigment granules) within retinal pigment epithelial (RPE) cells of fish and amphibians undergo massive migrations in response to light conditions to control light flux to the retina. Previous research has shown that melanosorne motility within apical projections of dissociated fish RPE cells requires an intact actin cytoskeleton, but the mechanisms and motors involved in melanosome transport in RPE have not been identified. Two in vitro motility assays, the Nitella assay and the sliding filament assay, were used to characterize actin-dependent motor activity of RPE melanosomes. Melanosomes applied to dissected filets of the Characean alga, Nitella, moved along actin cables at a mean rate of 2 mum/min, similar to the rate of melanosome motility in dissociated, cultured RPE cells. Path lengths of motile melanosomes ranged from 9 to 37 mum. Melanosome motility in the sliding filament assay was much more variable, ranging from 0.4-33 mum/min; 70% of velocities ranged from 1-15 mum/min. Latex beads coated with skeletal muscle myosin 11 and added to Nitella filets moved in the same direction as RPE melanosomes, indicating that the motility is barbed-end directed. Immunoblotting using antibodies against myosin VIIa and rab27a revealed that both proteins are enriched on melanosome membranes, Suggesting that they could play a role in melanosome transport within apical projections of fish RPE. (C) 2004 Wiley-Liss, Inc. C1 St Josephs Univ, Dept Biol, Philadelphia, PA 19131 USA. NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. RP Smith, CK (reprint author), St Josephs Univ, Dept Biol, 5600 City Ave, Philadelphia, PA 19131 USA. EM csmith@sju.edu FU NIGMS NIH HHS [R15 GM066961, R15 GM59460] NR 36 TC 12 Z9 12 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0886-1544 J9 CELL MOTIL CYTOSKEL JI Cell Motil. Cytoskeleton PD JUN PY 2004 VL 58 IS 2 BP 71 EP 82 DI 10.1002/cm.10179 PG 12 WC Cell Biology SC Cell Biology GA 825BG UT WOS:000221730400001 PM 15083529 ER PT J AU Fang, S Weissman, AM AF Fang, S Weissman, AM TI A field guide to ubiquitylation SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE ubiquitin; ubiquitin protein ligase; ubiquitylation; RING finger; HECT; proteasome ID UBIQUITIN-PROTEIN LIGASE; KAPPA-B-ALPHA; N-TERMINAL RESIDUE; RETICULUM-ASSOCIATED DEGRADATION; ANAPHASE-PROMOTING COMPLEX/; VALOSIN-CONTAINING PROTEIN; ER-ASSOCIATED DEGRADATION; TUMOR-SUPPRESSOR PROTEIN; EPITHELIAL NA+ CHANNEL; RING FINGER DOMAIN AB The capacity for exquisite regulation of ubiquitylation provides eukaryotic cells with a means to fine-tune both protein function and levels. This complex set of processes affects myriad proteins and potentially impacts all cellular processes. Ubiquitylation is brought about through multienzyme processes, with specificity conferred primarily by interactions of substrates with specific ubiquitin protein ligases (E3s) in association with ubiquitin conjugating enzymes (E2s). Regulation of ubiquitylation occurs at multiple levels, including E2-E3 interactions, substrate recognition, chain elongation, binding of ubiquitin to conserved motifs and deubiquityation. This review presents the fundamentals of the ubiquitin conjugating system. C1 NCI, Ctr Canc Res, Lab Prot Dynam & Signaling, Frederick, MD 21702 USA. Univ Maryland, Inst Biotechnol, Ctr Med Biotechnol, Baltimore, MD 21201 USA. RP Fang, S (reprint author), NCI, Ctr Canc Res, Lab Prot Dynam & Signaling, Bldg 560,Room 22-103,1050 Boyles St, Frederick, MD 21702 USA. EM fangs@umbi.umd.edu; amw@nih.gov RI Fang, Shengyun/H-3802-2011 NR 208 TC 198 Z9 208 U1 1 U2 29 PU BIRKHAUSER VERLAG AG PI BASEL PA VIADUKSTRASSE 40-44, PO BOX 133, CH-4010 BASEL, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD JUN PY 2004 VL 61 IS 13 BP 1546 EP 1561 DI 10.1007/s00018-004-4129-5 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 833QS UT WOS:000222354000002 PM 15224180 ER PT J AU Bregonzio, C Moreno, GN Cabrera, RJ Donoso, AO AF Bregonzio, C Moreno, GN Cabrera, RJ Donoso, AO TI NMDA receptors in the medial zona incerta stimulate luteinizing hormone and prolactin release SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article DE zona incerta; NMDA; luteinizing hormone; prolactin; estrogen; glutamate ID OVARIECTOMIZED RATS; FEMALE RATS; DOPAMINE; GONADOTROPIN; ACID; N-METHYL-D,L-ASPARTATE; SECRETION; OVULATION; ESTRADIOL; SEROTONIN AB 1. The aim of the present work is to demonstrate the interaction between the glutamatergic/ NMDA and dopaminergic systems in the medial zona incerta on the control of luteinizing hormone and prolactin secretion and the influence of reproductive hormones. 2. Proestrus and ovariectomized rats were primed with estrogen and progesterone to induce high or low levels of luteinizing hormone and prolactin. 2-Amino-7-phosphonoheptanoic acid, an NMDA receptor antagonist, and dopamine were injected in the medial zona incerta. Blood samples were withdrawn every hour between 1600 and 2000 hours or 2200 hours via intracardiac catheter from conscious rats. Additional groups of animals injected with the NMDA receptor antagonist were killed 1 or 4 h after injection. Dopamine and its metabolite 3,4-dihydroxyphenylacetic acid were measured in different hypothalamic regions. 3. 2-Amino-7-phosphonoheptanoic acid blocked the ovulatory luteinizing hormone surge in proestrus rats. 2-Amino-7-phosphonoheptanoic acid also blocked the increase in luteinizing hormone induced by ovarian hormones in ovariectomized rats, an effect that was partially reversed by dopamine injection. Conversely, the increased release of luteinizing hormone and prolactin induced by dopamine was prevented by 2-amino-7-phosphonoheptanoic acid. We found that the NMDA antagonist injection decreased the dopaminergic activity - as evaluated by the 3,4-dihydroxyphenylacetic acid/dopamine ratio - in the medio basal hypothalamus and increased in the preoptic area. 4. Our results show an stimulatory role of NMDA receptors on the ovulatory luteinizing hormone release and on luteinizing hormone release induced by sexual hormones and demonstrate that the stimulatory effect of dopamine on luteinizing hormone and prolactin is mediated by the NMDA receptors. These results suggest a close interaction between the glutamatergic and dopaminergic in certohypothalamic systems on the control of luteinizing hormone and prolactin release. C1 Univ Nacl Cuyo, Lab Invest Neuroquim Comportamentales & Endocrina, Unidad Neuroquim & Farmacol Compartamiento, Fac Ciencias Med, RA-5500 Mendoza, Argentina. RP Bregonzio, C (reprint author), NIMH, Sect Pharmacol, NIH, 2D-57,Bldg 10, Bethesda, MD 20892 USA. EM bregonzc@intra.nimh.nih.gov NR 25 TC 6 Z9 7 U1 0 U2 1 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 JUN PY 2004 VL 24 IS 3 BP 331 EP 342 DI 10.1023/B:CEMN.0000022766.73469.b0 PG 12 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 809ZP UT WOS:000220674900003 PM 15209061 ER PT J AU El-Assal, O Hong, F Kim, WH Radaeva, S Gao, B AF El-Assal, Osama Hong, Feng Kim, Won-Ho Radaeva, Svetlana Gao, Bin TI IL-6-deficient Mice Are Susceptible to Ethanol-induced Hepatic Steatosis: IL-6 Protects against Ethanol-induced Oxidative Stress and Mitochondrial Permeability Transition in the Liver SO CELLULAR & MOLECULAR IMMUNOLOGY LA English DT Article DE IL-6; alcoholic liver injury; oxidative stress; mitochondria; metallothionein AB Interleukin-6 (IL-6)-deficient mice are prone to ethanol-induced apoptosis and steatosis in the liver; however, the underlying mechanism is not fully understood. Mitochondrial dysfunction caused by oxidative stress is an early event that plays an important role in the pathogenesis of alcoholic liver disease. Therefore, we hypothesize that the protective role of IL-6 in ethanol-induced liver injury is mediated via suppression of ethanol-induced oxidative stress and mitochondrial dysfunction. To test this hypothesis, we examined the effects of IL-6 on ethanol-induced oxidative stress, mitochondrial injury, and energy depletion in the livers of IL-6 (-/-) mice and hepatocytes from ethanol-fed rats. Ethanol consumption leads to stronger induction of malondialdehyde (MDA) in IL-6 (-/-) mice compared to wild-type control mice, which can be corrected by administration of IL-6. In vitro, IL-6 treatment prevents ethanol-mediated induction of reactive oxygen species (ROS), MDA, mitochondrial permeability transition (MPT), and ethanol-mediated depletion of adenosine triphosphate (ATP) in hepatocytes from ethanol-fed rats. Administration of IL-6 in vivo also reverses ethanol-induced MDA and ATP depletion in hepatocytes. Finally, IL-6 treatment induces metallothionein protein expression, but not superoxide dismutase and glutathione peroxidase in cultured hepatocytes. In conclusion, IL-6 protects against ethanol-induced oxidative stress and mitochondrial dysfunction in hepatocytes via induction of metallothionein protein expression, which may account for the protective role of IL-6 in alcoholic liver disease. C1 [El-Assal, Osama; Hong, Feng; Kim, Won-Ho; Radaeva, Svetlana; Gao, Bin] NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. RP Gao, B (reprint author), NIAAA, Sect Liver Biol, NIH, Pk Bldg Rm 120,12420 Parklawn Dr,MSC 8115, Bethesda, MD 20892 USA. EM bgao@mail.nih.gov NR 39 TC 82 Z9 84 U1 0 U2 1 PU CHIN SOCIETY IMMUNOLOGY PI BEING PA 5 DONGDAN SANTIAO, DONGCHEN DISTRICT, BEING, 100005, PEOPLES R CHINA SN 1672-7681 EI 2042-0226 J9 CELL MOL IMMUNOL JI Cell. Mol. Immunol. PD JUN PY 2004 VL 1 IS 3 BP 205 EP 211 PG 7 WC Immunology SC Immunology GA V32AF UT WOS:000208923400008 PM 16219169 ER PT J AU Adams, EW Ratner, DM Bokesch, HR McMahon, JB O'Keefe, BR Seeberger, PH AF Adams, EW Ratner, DM Bokesch, HR McMahon, JB O'Keefe, BR Seeberger, PH TI Oligosaccharide and glycoprotein Microarrays as tools in HIV glycobiology: Glycan-dependent gp120/protein interactions SO CHEMISTRY & BIOLOGY LA English DT Article ID PROTEIN-CARBOHYDRATE INTERACTIONS; CYANOVIRIN-N; DC-SIGN; ENVELOPE GLYCOPROTEIN; INACTIVATING PROTEIN; ANTIBODY 2G12; GP120; TYPE-1; RECOGNITION; RECEPTOR AB Defining HIV envelope glycoprotein interactions with host factors or binding partners advances our understanding of the infectious process and provides a basis for the design of vaccines and agents that interfere with HIV entry. Here we employ carbohydrate and glycoprotein microarrays to analyze glycan-dependent gp120-protein interactions. In concert with new linking chemistries and synthetic methods, the carbohydrate arrays combine the advantages of microarray technology with the flexibility and precision afforded by organic synthesis. With these microarrays, we individually and competitively determined the binding profiles of five gp120 binding proteins, established the carbohydrate structural requirements for these interactions, and identified a potential strategy for HIV vaccine development. C1 MIT, Dept Chem, Cambridge, MA 02139 USA. SAIC Frederick Inc, Basic Res Program, Frederick, MD USA. NCI, Canc Res Ctr, Mol Targets Dev Program, Frederick, MD 21702 USA. ETH Honggerberg, Organ Chem Lab, CH-8093 Zurich, Switzerland. RP Seeberger, PH (reprint author), MIT, Dept Chem, Cambridge, MA 02139 USA. EM seeberger@org.chem.ethz.ch FU NCI NIH HHS [N01 CO 12400] NR 32 TC 170 Z9 179 U1 2 U2 27 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD JUN PY 2004 VL 11 IS 6 BP 875 EP 881 DI 10.1016/j.chembiol.2004.04.010 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 834KI UT WOS:000222409600019 PM 15217620 ER PT J AU Green, AE Lissina, A Hutchinson, SL Hewitt, RE Temple, B James, D Boulter, JM Price, DA Sewell, AK AF Green, AE Lissina, A Hutchinson, SL Hewitt, RE Temple, B James, D Boulter, JM Price, DA Sewell, AK TI Recognition of nonpeptide antigens by human V gamma 9V delta 2 T cells requires contact with cells of human origin SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE T lymphocytes; gamma delta T cell receptors; alkylphosphate; alkylamine; aminobisphosphonate ID GAMMA-DELTA CELLS; PERIPHERAL-BLOOD; IN-VITRO; LISTERIA-MONOCYTOGENES; IMMUNE-RESPONSE; CALMETTE-GUERIN; PROTECTIVE ROLE; TUMOR-CELLS; LYMPHOCYTES; RECEPTOR AB It is becoming apparent that gammadelta T cells form an important part of the adaptive immune response. However, the ligands recognized by gammadelta T cell receptors (TCRs) and the exact biological function of the cells that express this receptor remain unclear. Numerous studies have shown that the dominant human peripheral blood subset of gammadelta T cells, which express a Vgamma9Vdelta2 TCR, can activate in response to low molecular weight nonpeptidic molecules. Some of these components have been purified from bacteria or parasites. We examined the activation of polyclonal gammadelta T cell lines, clones with Vgamma9Vdelta2 and Vgamma9Vdelta1 TCRs, and gammadelta T cells directly ex vivo in response to multiple phosphate, alkylamine and aminobisphosphonate (nBP) antigens and purified protein derivative from Mycobacterium tuberculosis (PPD). Vgamma9Vdelta2 T cells were able to respond to multiple small organic molecules of highly variable structure whereas cells expressing a similar Vgamma9 chain paired with a Vdelta1 chain failed to recognize these antigens. Thus, the TCR delta chain appears to make an important contribution to the recognition of these antigens. The kinetics of responses to alkylphosphate and alkylamine antigens differ from those of responses to the nBP pamidronate. These different classes of antigen are believed to have differed mechanisms of action. Such differences explain why nBPs can be pulsed onto antigen presenting cells (APCs) and still retain their ability to activate gammadelta T cells while alkylphosphate and alkylamine antigens cannot. We also demonstrate that a substantial proportion of the cells that produce IFNgamma directly ex vivo in response to PPD are gammadelta T cells and that gammadelta T cell activation requires contact with cells of human origin. C1 Univ Oxford, T Cell Modulat Grp, Oxford OX1 3SY, England. Univ Oxford, Nuffield Dept Med, Oxford, England. Univ Oxford, Dept Biochem, Oxford, England. Univ Oxford, Dept Zool, Oxford OX1 3PS, England. Avidex Ltd, Abingdon, Oxon, England. NIAID, NIH, Vaccine Res Ctr, Human Immunol Sect, Bethesda, MD USA. RP Sewell, AK (reprint author), Univ Oxford, T Cell Modulat Grp, Peter Medawar Bldg Pathogen Res,S Parks Rd, Oxford OX1 3SY, England. EM andy.sewell@ndm.ox.ac.uk RI Price, David/C-7876-2013; OI Price, David/0000-0001-9416-2737; Sewell, Andrew/0000-0003-3194-3135; Hewitt, Rachel/0000-0002-2367-1822; Fenton-May, Angharad/0000-0002-6267-1315 FU Multiple Sclerosis Society [589] NR 63 TC 43 Z9 44 U1 1 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0009-9104 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD JUN PY 2004 VL 136 IS 3 BP 472 EP 482 DI 10.1111/j.1365-2249.2004.02472.x PG 11 WC Immunology SC Immunology GA 820WP UT WOS:000221420700011 PM 15147349 ER PT J AU Karp, JE Gojo, I Pili, R Gocke, CD Greer, J Guo, CF Qian, D Morris, L Tidwell, M Chen, H Zwiebel, J AF Karp, JE Gojo, I Pili, R Gocke, CD Greer, J Guo, CF Qian, D Morris, L Tidwell, M Chen, H Zwiebel, J TI Targeting vascular endothelial growth factor for relapsed and refractory adult acute myelogenous leukemias: Therapy with sequential 1-beta-D-arabinofuranosylcytosine, mitoxantrone, and bevacizumab SO CLINICAL CANCER RESEARCH LA English DT Article ID ACUTE MYELOID-LEUKEMIA; HIGH-DOSE CYTARABINE; CYTOSINE-ARABINOSIDE; CELL-GROWTH; PHASE-II; MYELODYSPLASTIC SYNDROMES; INCREASED ANGIOGENESIS; RANDOMIZED-TRIAL; BONE-MARROW; FACTOR VEGF AB Purpose: Vascular endothelial growth factor (VEGF) promotes acute myelogenous leukemia (AML) cell growth and survival and may contribute to drug resistance. bevacizumab, an anti-VEGF monoclonal antibody, exhibits clinical activity against diverse malignancies when administered with cytotoxic chemotherapy. We conducted a Phase II clinical trial of bevacizumab administered after chemotherapy to adults with refractory or relapsed AML, using a timed sequential therapy (TST) approach. Experimental Design: bevacizumab 10 mg/kg was administered on day 8 after 1-beta-D-arabinofuranosylcytosine 2 g/m(2)/72 h beginning day I and mitoxantrone 40 mg/m(2) beginning day 4. In vivo laboratory. correlates included AML cell VEGF receptor-1 (FLT-1) expression, marrow microvessel density, and free serum VEGF before and during TST with bevacizumab. Results: Forty-eight adults received induction therapy. Myelosuppression occurred in all of the patients similar to other TST regimens. Toxicities were decreased ejection fraction (6%), cerebrovascular bleed (4%), and mortality of 15%. Overall response was 23 of 48 (48%), with complete response (CR) in 16 (33%). Eighteen (14 CR and 4 partial response) underwent one consolidation cycle and 5 (3 CR and 2 partial response) underwent allogeneic transplant. Median overall and disease-free survivals for CR patients were 16.2 months (64%, 1 year) and 7 months (35%, 1 year). Marrow blasts demonstrated FLT-1 staining before bevacizumab and marked decrease in microvessel density after bevacizumab. VEGF was detected in pretreatment serum in 67% of patients tested, increased by day 8 in 52%, and decreased in 93% (67% undetectable) 2 h after bevacizumab. Conclusions: In this single arm study, cytotoxic chemotherapy followed by bevacizumab yields a favorable CR rate and duration in adults with AML that is resistant to traditional treatment approaches. The clearance of marrow blasts in some patients after bevacizumab suggests that VEGF neutralization might result directly in leukemic cell death. The potential biological and clinical activity of bevacizumab in AML warrants additional clinical and laboratory study. C1 Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Div Hematol Malignancies, Baltimore, MD 21231 USA. Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. Blood & Marrow Transplant Grp Georgia, Atlanta, GA USA. NCI, Div Canc Treatment & Diagnosis, Clin Trials Evaluat Program, Investigat Drug Branch, Bethesda, MD USA. RP Karp, JE (reprint author), Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Div Hematol Malignancies, 1650 Orleans St,Room 289, Baltimore, MD 21231 USA. EM jkarp2@jhmi.edu FU NCI NIH HHS [CA70095, CA69854] NR 50 TC 116 Z9 125 U1 0 U2 0 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 JUN 1 PY 2004 VL 10 IS 11 BP 3577 EP 3585 DI 10.1158/1078-0432.CCR-03-0627 PG 9 WC Oncology SC Oncology GA 825UU UT WOS:000221784700001 PM 15173063 ER PT J AU Kelloff, GJ Bast, RC Coffey, DS D'Amico, AV Kerbel, RS Park, JW Ruddon, RW Rustin, GJS Schilsky, RL Sigman, CC Woude, GFV AF Kelloff, GJ Bast, RC Coffey, DS D'Amico, AV Kerbel, RS Park, JW Ruddon, RW Rustin, GJS Schilsky, RL Sigman, CC Woude, GFV TI Biomarkers, surrogate end points, and the acceleration of drug development for cancer prevention and treatment: An update SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTOR; UNITED-STATES; TUMOR; EXPRESSION; TRIALS; PREDICTION; APPROVAL; LEUKEMIA; ISSUES; GENE C1 NCI, Div Canc Treatment & Diag, Canc Imaging Program, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Translat Res, Houston, TX 77030 USA. Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Toronto Sunnybrook Reg Canc Ctr, Toronto, ON, Canada. Univ Calif San Francisco, San Francisco Canc Ctr, San Francisco, CA 94143 USA. Johnson & Johnson Corp, New Brunswick, NJ USA. Mt Vernon Canc Ctr, Dept Med Oncol, Northwood, Middx, England. Univ Chicago, Div Biol Sci, Chicago, IL 60637 USA. CCS Associates, Mountain View, CA USA. Van Andel Res Inst, Grand Rapids, MI USA. RP Kelloff, GJ (reprint author), NCI, Div Canc Treatment & Diag, Canc Imaging Program, Execut Plaza S,Room 6058, Bethesda, MD 20892 USA. EM kelloffg@mail.nih.gov RI Bast, Robert/E-6585-2011 OI Bast, Robert/0000-0003-4621-8462 NR 30 TC 42 Z9 42 U1 0 U2 1 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 JUN 1 PY 2004 VL 10 IS 11 BP 3881 EP 3884 DI 10.1158/1078-0432.CCR-03-0783 PG 4 WC Oncology SC Oncology GA 825UU UT WOS:000221784700035 PM 15173097 ER PT J AU Park, JW Kerbel, RS Kelloff, GJ Barrett, JC Chabner, BA Parkinson, DR Peck, J Ruddon, RW Sigman, CC Slamon, DJ AF Park, JW Kerbel, RS Kelloff, GJ Barrett, JC Chabner, BA Parkinson, DR Peck, J Ruddon, RW Sigman, CC Slamon, DJ TI Rationale for biomarkers and surrogate end points in mechanism-driven oncology drug development SO CLINICAL CANCER RESEARCH LA English DT Review ID METASTATIC BREAST-CANCER; CHRONIC MYELOID-LEUKEMIA; GROWTH-FACTOR RECEPTOR; CHRONIC MYELOGENOUS LEUKEMIA; CELL LUNG-CANCER; GASTROINTESTINAL STROMAL TUMORS; TYROSINE-KINASE INHIBITORS; GREEN FLUORESCENT PROTEIN; SOFT-TISSUE SARCOMAS; IMATINIB MESYLATE C1 Univ Calif San Francisco, San Francisco Canc Ctr, San Francisco, CA 94115 USA. Toronto Sunnybrook Reg Canc Ctr, Toronto, ON, Canada. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. Amgen Inc, Thousand Oaks, CA 91320 USA. Inst Alternat Futures, Alexandria, VA USA. Johnson & Johnson Corp, New Brunswick, NJ USA. CCS Associates, Mountain View, CA USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. RP Park, JW (reprint author), Univ Calif San Francisco, San Francisco Canc Ctr, 1600 Divisadero St,2nd Floor, San Francisco, CA 94115 USA. EM jpark@cc.ucsf.edu NR 107 TC 107 Z9 114 U1 3 U2 10 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 JUN 1 PY 2004 VL 10 IS 11 BP 3885 EP 3896 DI 10.1158/1078-0432.CCR-03-0785 PG 12 WC Oncology SC Oncology GA 825UU UT WOS:000221784700036 PM 15173098 ER PT J AU Woude, GFV Kelloff, GJ Ruddon, RW Koo, HM Sigman, CC Barrett, JC Day, RW Dicker, AP Kerbel, RS Parkinson, DR Slichenmyer, WJ AF Woude, GFV Kelloff, GJ Ruddon, RW Koo, HM Sigman, CC Barrett, JC Day, RW Dicker, AP Kerbel, RS Parkinson, DR Slichenmyer, WJ TI Reanalysis of cancer drugs: Old drugs, new tricks SO CLINICAL CANCER RESEARCH LA English DT Review ID ACUTE MYELOID-LEUKEMIA; B-CELL LYMPHOMA; N-RAS GENE; BREAST-CANCER; PROGNOSTIC-SIGNIFICANCE; ENDOTHELIAL-CELLS; BONE-MARROW; WILMS-TUMOR; CARCINOMA-CELLS; FLOW-CYTOMETRY C1 Van Andel Res Inst, Grand Rapids, MI 49503 USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. Johnson & Johnson Corp, New Brunswick, NJ USA. CCS Associates, Mountain View, CA USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. Toronto Sunnbrook Reg Canc Ctr, Toronto, ON, Canada. Amgen Inc, Thousand Oaks, CA 91320 USA. Pfizer Global Res & Dev, New London, CT USA. RP Woude, GFV (reprint author), Van Andel Res Inst, 333 Bostwick,NE, Grand Rapids, MI 49503 USA. EM george.vanderwoude@vai.org OI Dicker, Adam/0000-0003-0733-3337 NR 82 TC 13 Z9 13 U1 0 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 JUN 1 PY 2004 VL 10 IS 11 BP 3897 EP 3907 DI 10.1158/1078-0432.CCR-03-0786 PG 11 WC Oncology SC Oncology GA 825UU UT WOS:000221784700037 ER PT J AU Kelloff, GJ Schilsky, RL Alberts, DS Day, RW Guyton, KZ Pearce, HL Peck, JC Phillips, R Sigman, CC AF Kelloff, GJ Schilsky, RL Alberts, DS Day, RW Guyton, KZ Pearce, HL Peck, JC Phillips, R Sigman, CC TI Colorectal adenomas: A prototype for the use of surrogate end points in the development of cancer prevention drugs SO CLINICAL CANCER RESEARCH LA English DT Review ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; ABERRANT CRYPT FOCI; SELECTIVE CYCLOOXYGENASE-2 INHIBITOR; INDUCED COLON CARCINOGENESIS; RANDOMIZED CONTROLLED-TRIAL; ACID-INDUCED APOPTOSIS; ASPIRIN USE; URSODEOXYCHOLIC ACID; F344 RATS; NATURAL-HISTORY C1 NCI, Div Canc Treatment & Diagnost, Natl Inst Hlth, Bethesda, MD 20892 USA. Univ Chicago, Div Biol Sci, Chicago, IL 60637 USA. Univ Arizona, Ctr Canc, Tucson, AZ USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. CCS Associates, Mountain View, CA USA. Lilly Res Labs, Indianapolis, IN USA. Inst Alternat Futures, Alexandria, VA USA. Ontario Canc Res Network, Toronto, ON, Canada. RP Kelloff, GJ (reprint author), NCI, Div Canc Treatment & Diagnost, Natl Inst Hlth, EPN 6130 Execut Blvd,Suite 6058, Bethesda, MD 20892 USA. EM kelloffg@mail.nih.gov NR 132 TC 35 Z9 36 U1 0 U2 2 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 JUN 1 PY 2004 VL 10 IS 11 BP 3908 EP 3918 DI 10.1158/1078-0432.CCR-03-0789 PG 11 WC Oncology SC Oncology GA 825UU UT WOS:000221784700038 PM 15173100 ER PT J AU Rustin, GJS Bast, RC Kelloff, GJ Barrett, JC Carter, SK Nisen, PD Sigman, CC Parkinson, DR Ruddon, RW AF Rustin, GJS Bast, RC Kelloff, GJ Barrett, JC Carter, SK Nisen, PD Sigman, CC Parkinson, DR Ruddon, RW TI Use of CA-125 in clinical trial evaluation of new therapeutic drugs for ovarian cancer SO CLINICAL CANCER RESEARCH LA English DT Review ID GYNECOLOGIC-ONCOLOGY-GROUP; METASTATIC BREAST-CANCER; PLATINUM-BASED CHEMOTHERAPY; SINGLE-AGENT CARBOPLATIN; CHRONIC MYELOID-LEUKEMIA; PHASE-II TRIALS; MONOCLONAL-ANTIBODY; CA 125; SERUM CA-125; HALF-LIFE C1 Mt Vernon Canc Ctr, Dept Med Oncol, Northwood HA6 2RN, Middx, England. Univ Texas, MD Anderson Canc Ctr, Dept Translat Res, Houston, TX 77030 USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. Abbott Labs, Global Oncol Dev, Abbott Pk, IL 60064 USA. CCS Associates, Mountain View, CA USA. Amgen Inc, Thousand Oaks, CA 91320 USA. Johnson & Johnson Corp, New Brunswick, NJ USA. RP Rustin, GJS (reprint author), Mt Vernon Canc Ctr, Dept Med Oncol, Northwood HA6 2RN, Middx, England. EM rustin@mtvern.co.uk RI Bast, Robert/E-6585-2011 OI Bast, Robert/0000-0003-4621-8462 NR 82 TC 89 Z9 96 U1 0 U2 4 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 JUN 1 PY 2004 VL 10 IS 11 BP 3919 EP 3926 DI 10.1158/1078-0432.CCR-03-0787 PG 8 WC Oncology SC Oncology GA 825UU UT WOS:000221784700039 PM 15173101 ER PT J AU Kelloff, GJ Coffey, DS Chabner, BA Dicker, AP Guyton, KZ Nisen, PD Soule, HR D'Amico, AV AF Kelloff, GJ Coffey, DS Chabner, BA Dicker, AP Guyton, KZ Nisen, PD Soule, HR D'Amico, AV TI Prostate-specific antigen doubling time as a surrogate marker for evaluation of oncologic drugs to treat prostate cancer SO CLINICAL CANCER RESEARCH LA English DT Review ID METASTATIC BREAST-CANCER; CHRONIC MYELOID-LEUKEMIA; RADICAL PROSTATECTOMY; MONOCLONAL-ANTIBODY; RADIATION-THERAPY; PREOPERATIVE NOMOGRAM; REFERENCE RANGES; END-POINT; PHASE-II; PROGRESSION C1 NCI, Div Canc Treatment & Diag, Canc Imaging Program, Bethesda, MD 20892 USA. Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. CCS Associates, Mountain View, CA USA. Abbott Labs, Global Oncol Dev, Abbott Pk, IL 60064 USA. CaP CURE, Santa Monica, CA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Kelloff, GJ (reprint author), NCI, Div Canc Treatment & Diag, Canc Imaging Program, Execut Plaza S,Room 6058, Bethesda, MD 20892 USA. EM kelloffg@mail.nih.gov OI Dicker, Adam/0000-0003-0733-3337 NR 44 TC 36 Z9 38 U1 0 U2 0 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 JUN 1 PY 2004 VL 10 IS 11 BP 3927 EP 3933 DI 10.1158/1078-0432.CCR-03-0788 PG 7 WC Oncology SC Oncology GA 825UU UT WOS:000221784700040 PM 15173102 ER PT J AU Cecco, SA Rehak, NN AF Cecco, SA Rehak, NN TI Rejection rules for hemolysis, icterus and lipemia indices on Synchron LX20 Clinical System. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-for-Clinical-Chemistry CY JUL 25-29, 2004 CL Los Angeles, CA SP Amer Assoc Clin Chem C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2004 VL 50 IS 6 SU S BP A109 EP A109 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 828EC UT WOS:000221955200363 ER PT J AU Costello, R Vu, C Hortin, GL Csako, G AF Costello, R Vu, C Hortin, GL Csako, G TI On the measurement of plasma beta-hydroxybutyrate (beta-HB) and free (non-esterified) fatty acids (FFA). SO CLINICAL CHEMISTRY LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-for-Clinical-Chemistry CY JUL 25-29, 2004 CL Los Angeles, CA SP Amer Assoc Clin Chem C1 NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2004 VL 50 IS 6 SU S BP A104 EP A104 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 828EC UT WOS:000221955200345 ER PT J AU Delgado, RM Rahim, US Shoobridge, RT Sunderland, T Costello, R Csako, G AF Delgado, RM Rahim, US Shoobridge, RT Sunderland, T Costello, R Csako, G TI Evaluation of real-time PCR methods for methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms that may affect plasma homocysteine (Hcy) and cysteine (Cys) levels SO CLINICAL CHEMISTRY LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-for-Clinical-Chemistry CY JUL 25-29, 2004 CL Los Angeles, CA SP Amer Assoc Clin Chem C1 NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. NIMH, Clin Psychiat Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2004 VL 50 IS 6 SU S BP A121 EP A121 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 828EC UT WOS:000221955200399 ER PT J AU Sampson, ML Ruddel, M Rehak, NN Remaley, AT AF Sampson, ML Ruddel, M Rehak, NN Remaley, AT TI Optimization of delta check rules by a cumulative detection score plot SO CLINICAL CHEMISTRY LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-for-Clinical-Chemistry CY JUL 25-29, 2004 CL Los Angeles, CA SP Amer Assoc Clin Chem C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2004 VL 50 IS 6 SU S BP A41 EP A41 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 828EC UT WOS:000221955200135 ER PT J AU Sullivan, P Freeto, S Eisenhofer, G Costello, R Csako, G AF Sullivan, P Freeto, S Eisenhofer, G Costello, R Csako, G TI Analytical and diagnostic performance of a new commercial, HPLC method for the measurement of plasma free metanephrines SO CLINICAL CHEMISTRY LA English DT Meeting Abstract CT 56th Annual Meeting of the American-Association-for-Clinical-Chemistry CY JUL 25-29, 2004 CL Los Angeles, CA SP Amer Assoc Clin Chem C1 NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. ESA Inc, Chelmsford, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2004 VL 50 IS 6 SU S BP A104 EP A104 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 828EC UT WOS:000221955200346 ER PT J AU Rahman, F Rehermann, B AF Rahman, Fareed Rehermann, Barbara TI Ethnicity and Hepatitis C Virus Infection SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Editorial Material C1 [Rahman, Fareed] Johannes Gutenberg Univ Mainz, Dept Internal Med, D-6500 Mainz, Germany. [Rehermann, Barbara] NIDDK, Liver Dis Sect, NIH, DHHS, Bethesda, MD USA. RP Rahman, F (reprint author), Johannes Gutenberg Univ Mainz, Dept Internal Med, D-6500 Mainz, Germany. NR 17 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD JUN PY 2004 VL 2 IS 6 BP 456 EP 458 DI 10.1053/S1542-3565(04)00161-2 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA V19KR UT WOS:000208071800003 PM 15181611 ER PT J AU Bernstein, WB Cox, JH Aronson, NE Tracy, LR Schlienger, K Ratto-Kim, S Garner, R Cotte, J Zheng, ZH Winestone, L Liebig, C Galley, LM Connors, M Birx, DL Carroll, RG Levine, BL AF Bernstein, WB Cox, JH Aronson, NE Tracy, LR Schlienger, K Ratto-Kim, S Garner, R Cotte, J Zheng, ZH Winestone, L Liebig, C Galley, LM Connors, M Birx, DL Carroll, RG Levine, BL TI Immune reconstitution following autologous transfers of CD3/CD28 stimulated CD4(+) T cells to HIV-infected persons SO CLINICAL IMMUNOLOGY LA English DT Article DE HIV; adoptive transfer; immune reconstitution; immunotherapy; ELISpot; TCR V beta; CD28 ID IMMUNODEFICIENCY-VIRUS-INFECTION; ACTIVE ANTIRETROVIRAL THERAPY; CD28 COSTIMULATION; ADOPTIVE TRANSFER; TREATMENT INTERRUPTION; COMBINATION THERAPY; CD8(+); LYMPHOCYTES; REPERTOIRE; RESPONSES AB We have previously shown that adoptive transfer of in vitro CD3/CD28 activated autologous CD4(+) T cells results in increased CD4 counts and CD4/CD8 ratios in HIV+ subjects. In this report, analysis of variable beta (Vbeta) chain T cell receptor (TCR) repertoire showed that CD3/ CD28 stimulation was able to increase polyclonality within skewed spectra types in vitro. In vivo, two of eight subjects showed increase in TCR diversity and importantly, in no subject did a highly skewed in vivo repertoire emerge. Measurement of proliferative response to alloantigen showed increases following infusions. Response to pharmacological stimulus and lectin via Interferon-gamma ELISpot assay showed increases in a subset of subjects following infusions. However, interferon-gamma response to HIV antigens and peptides declined concurrent with stable or diminishing latent infectious viral load in CD4(+) T cells. These data provide further evidence that adoptive transfer of activated autologous CD4(+) T cells can augment the immune system. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Penn, Ctr Canc, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. Walter Reed Army Inst Res, Div Retrovirol, Rockville, MD 20850 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. Natl Naval Med Res Inst, Bethesda, MD 20889 USA. Henry M Jackson Fdn, Rockville, MD 20850 USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. US FDA, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. NIAID, Bethesda, MD 20892 USA. RP Levine, BL (reprint author), Univ Penn, Ctr Canc, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. EM levinebl@mail.med.upenn.edu RI Levine, Bruce/D-1688-2009; OI Winestone, Lena/0000-0001-9982-1594 NR 51 TC 17 Z9 22 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2004 VL 111 IS 3 BP 262 EP 274 DI 10.1016/j.clim.2004.03.004 PG 13 WC Immunology SC Immunology GA 830WS UT WOS:000222155500005 PM 15183147 ER PT J AU Kresina, TF Normand, J Khalsa, J Mitty, J Flanigan, T Francis, H AF Kresina, TF Normand, J Khalsa, J Mitty, J Flanigan, T Francis, H TI Addressing the need for treatment paradigms for drug-abusing patients with multiple morbidities SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID SEXUALLY-TRANSMITTED-DISEASES; HUMAN-IMMUNODEFICIENCY-VIRUS; NEW-YORK-CITY; CRACK COCAINE USE; HIV-INFECTION; HEPATITIS-B; OPIOID DEPENDENCE; YOUNG-ADULTS; USERS; INJECTION AB Persons who use and abuse drugs are at risk for multiple morbidities that involve addiction, bloodborne infectious diseases, and sexually transmitted diseases, in addition to psychiatric illness and social instability. Infectious diseases acquired as a result of drug use can diffuse into non-drug using populations through other high-risk behaviors. Drug users also have substantial comorbidities from noncommunicable diseases and complications that can affect virtually every organ system in the body. Diagnosis of comorbidities and complications associated with drug abuse usually occurs late in the disease course, particularly for persons who are disenfranchised and have limited or no access to medical care. Medical management of these comorbid conditions constitutes a significant challenge. Directly observed therapy ( DOT) can be useful but needs to conform to the needs of the targeted treatment population for full efficacy. DOT may have its greatest impact with drug users destabilized by cocaine or methamphetamine use but has yet to be fully investigated in this patient population. C1 Natl Inst Drug Abuse, Ctr AIDS & Other Med Consequences Drug Abuse, NIH, Bethesda, MD 20892 USA. Brown Med Sch, Providence, RI USA. RP Kresina, TF (reprint author), Natl Inst Drug Abuse, Ctr AIDS & Other Med Consequences Drug Abuse, NIH, 6001 Execut Blvd,MSC 9593, Bethesda, MD 20892 USA. EM Tk13v@nih.gov NR 42 TC 12 Z9 12 U1 2 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 1 PY 2004 VL 38 SU 5 BP S398 EP S401 DI 10.1086/421403 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 821QP UT WOS:000221477500005 PM 15156429 ER PT J AU Markovic-Plese, S Pinilla, C Martin, R AF Markovic-Plese, S Pinilla, C Martin, R TI The initiation of the autoimmune response in multiple sclerosis SO CLINICAL NEUROLOGY AND NEUROSURGERY LA English DT Article; Proceedings Paper CT 2nd Dubrovnik International Conference on Multiple Sclerosis CY MAY 21-24, 2003 CL Dubrovnik, CROATIA DE multiple sclerosis; autoimmune disease; autoreactive T-cell activation; T-cell receptor degeneracy; costimulatory pathways ID MYELIN BASIC-PROTEIN; ALTERED PEPTIDE LIGANDS; T-CELL RECOGNITION; PROTEOLIPID PROTEIN; LYME-DISEASE; CBL-B; ACTIVATION; COSTIMULATION; DEGENERACY; LIBRARIES AB Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Most evidence supports the autoimmune pathogenesis of the disease. According to this hypothesis, the activation of autoreactive T-cells is a central event in the development of autoimmune response in MS. We examined molecular events involved in the initiation of autoimmune response in MS. Recent studies in our laboratory have reported an unexpectedly high degree of T-cell receptor (TCR) degeneracy and molecular mimicry as a frequent phenomenon that might play a role in the initiation of autoimmune response in MS, This paper provides insights into the physiologic and pathologic role of autoreactive T-cells, and characterizes structurally and functionally the specific targets for new therapies of MS. (C) 2004 Elsevier B.V. All rights reserved. C1 Univ N Carolina, Dept Neurol, Chapel Hill, NC 27599 USA. Torrey Pines Inst Mol Studies & Mixture Sci, San Diego, CA USA. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Markovic-Plese, S (reprint author), Univ N Carolina, Dept Neurol, 6019 Neurosci Res Bldg, Chapel Hill, NC 27599 USA. EM markovics@neurology.unc.edu NR 26 TC 14 Z9 16 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0303-8467 J9 CLIN NEUROL NEUROSUR JI Clin. Neurol. Neurosurg. PD JUN PY 2004 VL 106 IS 3 SI SI BP 218 EP 222 DI 10.1016/j.clineuro.2004.02.018 PG 5 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 831MK UT WOS:000222198300009 PM 15177771 ER PT J AU Glantz, MD Compton, WM AF Glantz, MD Compton, WM TI Mental health and substance abuse innovations: Issues of diffusion and adoption SO CLINICAL PSYCHOLOGY-SCIENCE AND PRACTICE LA English DT Article ID PROJECT DARE; FOLLOW-UP C1 NIDA, NIH, Bethesda, MD 20892 USA. RP Glantz, MD (reprint author), NIDA, NIH, 6001 Execut Blvd,RM 5153 MSC 9589, Bethesda, MD 20892 USA. EM mglantz@nida.nih.gov NR 4 TC 3 Z9 3 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0969-5893 J9 CLIN PSYCHOL-SCI PR JI Clin. Psychol.-Sci. Pract. PD SUM PY 2004 VL 11 IS 2 BP 183 EP 185 DI 10.1093/clipsy/bph069 PG 3 WC Psychology, Clinical SC Psychology GA 821IG UT WOS:000221453000008 ER PT J AU Lomax, J McCray, AT AF Lomax, J McCray, AT TI Mapping the gene ontology into the unified medical language system SO COMPARATIVE AND FUNCTIONAL GENOMICS LA English DT Article DE ontologies; semantic networks; controlled vocabularies; gene ontology; unified medical language system ID CLINICAL-PRACTICE; GENOMICS; BIOLOGY AB We have recently mapped the Gene Ontology (GO), developed by the Gene Ontology Consortium, into the National Library of Medicine's Unified Medical Language System (UMLS). GO has been developed for the purpose of annotating gene products in genome databases, and the UMLS has been developed as a framework for integrating large numbers of disparate terminologies, primarily for the purpose of providing better access to biomedical information sources. The mapping of GO to UMLS highlighted issues in both terminology systems. After some initial explorations and discussions between the UMLS and GO teams, the GO was integrated with the UMLS. Overall, a total of 23% of the GO terms either matched directly (3%) or linked (20%) to existing UMLS concepts. All GO terms now have a corresponding, official UMLS concept, and the entire vocabulary is available through the web-based UMLS Knowledge Source Server. The mapping of the Gene Ontology, with its focus on structures, processes and functions at the molecular level, to the existing broad coverage UMLS should contribute to linking the language and practices of clinical medicine to the language and practices of genomics. Copyright (C) 2004 John Wiley Sons, Ltd. C1 European Bioinformat Inst, Cambridge CB10 1SD, England. Natl Lib Med, Bethesda, MD USA. RP Lomax, J (reprint author), European Bioinformat Inst, Cambridge CB10 1SD, England. EM jane@ebi.ac.uk OI Lomax, Jane/0000-0001-8865-4321 NR 19 TC 14 Z9 15 U1 0 U2 2 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1531-6912 J9 COMP FUNCT GENOM JI Compar. Funct. Genom. PD JUN PY 2004 VL 5 IS 4 BP 354 EP 361 DI 10.1002/cfg.407 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 831YA UT WOS:000222231600004 PM 18629164 ER PT J AU Ward, JM Morse, HC AF Ward, JM Morse, HC TI Classification of lymphoid neoplasms in mice SO COMPARATIVE MEDICINE LA English DT Editorial Material C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Ward, JM (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1532-0820 J9 COMPARATIVE MED JI Comparative Med. PD JUN PY 2004 VL 54 IS 3 BP 259 EP 261 PG 3 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 832WY UT WOS:000222299600004 ER PT J AU Moutsopoulos, NM Nikitakis, NG Powell, DA Reynolds, MA AF Moutsopoulos, NM Nikitakis, NG Powell, DA Reynolds, MA TI Carcinosarcoma of the maxilla in a squirrel monkey (Saimiri sciureus) SO COMPARATIVE MEDICINE LA English DT Article ID MALIGNANT MIXED TUMORS; AMELOBLASTIC ODONTOMA; NONHUMAN PRIMATE; SALIVARY-GLANDS; MAMMARY-TUMORS; OSTEOSARCOMA; CARCINOMAS; NEOPLASMS AB We present the first, to our knowledge, described case of carcinosarcoma of the maxilla in a squirrel monkey. Carcinosarcomas are rare tumors of the upper aerodigestive tract, and consist of carcinomatous and sarcomatous tissue. Histologic analysis revealed a neoplasm composed of an adenocarcinomatous component (epithelial element) and a mesenchymal component (sarcomatous element). Metastatic growth was documented in the lung tissue and the submandibular lymph node. The histolopathologic findings, the pattern of metastasis, and the clinical progression closely resembled those of carcinosarcoma involving salivary glands in humans. C1 Univ Maryland, Sch Dent, Dept Periodont, Baltimore, MD 21201 USA. Univ Maryland, Sch Dent, Dept Diagnost Sci & Pathol Surg, Baltimore, MD 21201 USA. NIH, Vet Resources Program, Off Res Serv, Poolesville, MD 20837 USA. RP Reynolds, MA (reprint author), Univ Maryland, Sch Dent, Dept Periodont, 666 W Baltimore St, Baltimore, MD 21201 USA. NR 20 TC 1 Z9 1 U1 0 U2 1 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1532-0820 J9 COMPARATIVE MED JI Comparative Med. PD JUN PY 2004 VL 54 IS 3 BP 333 EP 336 PG 4 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 832WY UT WOS:000222299600018 PM 15253282 ER PT J AU Goldfarb, LG Cervenakova, L Gajdusek, DC AF Goldfarb, LG Cervenakova, L Gajdusek, DC TI Genetic studies in relation to Kuru: An overview SO CURRENT MOLECULAR MEDICINE LA English DT Review ID CREUTZFELDT-JAKOB-DISEASE; BOVINE SPONGIFORM ENCEPHALOPATHY; FATAL FAMILIAL INSOMNIA; CENTRAL NERVOUS SYSTEM; NATURAL SHEEP SCRAPIE; MICE EXPRESSING HUMAN; HUMAN PRION PROTEIN; EXPERIMENTAL TRANSMISSION; VARIANT CJD; NEW-GUINEA AB Kuru is a subacute neurodegenerative disease presenting with limb ataxia, dysarthria, and a shivering tremor. The disease progress to complete motor and mental incapacity and death within 6 to 24 months. Neuropathologically, a typical pattern of neuronal loss, astrocytic and microglial proliferation, characteristic "kuru-type" amyloid plaques, and PrP deposits in the cerebral cortex and cerebellum are observed. Kuru is the prototype of a group of human transmissible spongiform encephalopathies (TSEs), or "prion" diseases, that include hereditary, sporadic and infectious forms. The latest member of this group, the variant Creutzfeldt-Jakob disease (vCJD), linked to transmission of bovine spongiform encephalopathy (BSE) to humans, shows features similar to kuru. Kuru has emerged at the beginning of the 1900s in a small indigenous population of New-Guinean Eastern Highlands, reached epidemic proportions in the mid-1950s and disappeared progressively in the latter half of the century to complete absence at the end of the 1990s. Early studies made infection, the first etiologic assumption, seem unlikely and led to a hypothesis that kuru might be a genetically determined or genetically mediated illness. After transmissibility of kuru had been discovered and all major epidemiologic phenomena adequately explained by the spread of an infectious agent with long incubation period through the practice of cannibalism, the pattern of occurrence still continued to suggest a role for genetic predisposition. Recent studies indicate that individuals homozygous for Methionine at a polymorphic position 129 of the prion protein were preferentially affected during the kuru epidemic. The carriers of the alternative 129Met/Val and 129Val/Nal genotypes had a longer incubation period and thus developed disease at a later age and at a later stage of the epidemic. Observations made during the kuru epidemic are helpful in the understanding of the current vCJD outbreak, and vice versa clinical and experimental data accumulated in studies of other TSE disorders contribute to better understanding of the documented kuru phenomena. C1 NINDS, NIH, Bethesda, MD 20892 USA. Amer Red Cross, Jerome H Holland Lab, Rockville, MD 20855 USA. CNRS, Inst Alfred Fessard, Gif Sur Yvette, France. RP Goldfarb, LG (reprint author), NINDS, NIH, Bldg 10,Room 4B37,10 Ctr Dr,MSC 1361, Bethesda, MD 20892 USA. EM goldfarbl@ninds.nih.gov NR 96 TC 28 Z9 28 U1 0 U2 13 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1566-5240 J9 CURR MOL MED JI Curr. Mol. Med. PD JUN PY 2004 VL 4 IS 4 BP 375 EP 384 DI 10.2174/1566524043360627 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 824BK UT WOS:000221658700004 PM 15354868 ER PT J AU Galperin, MY Baker, AJM AF Galperin, MY Baker, AJM TI Environmental biotechnology - From biofouling to bioremediation: the good, the bad and the vague - Editorial overview SO CURRENT OPINION IN BIOTECHNOLOGY LA English DT Editorial Material ID GENOME; PHYTOREMEDIATION C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Galperin, MY (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM galperin@ncbi.nlm.nih.gov; ajmb@unimelb.edu.au RI Galperin, Michael/B-5859-2013 OI Galperin, Michael/0000-0002-2265-5572 NR 7 TC 3 Z9 3 U1 1 U2 4 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 JUN PY 2004 VL 15 IS 3 BP 167 EP 169 DI 10.1016/j.copbio.2004.04.011 PG 3 WC Biochemical Research Methods; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 835ZF UT WOS:000222523800001 PM 15193321 ER PT J AU Grewal, SIS Rice, JC AF Grewal, SIS Rice, JC TI Regulation of heterochromatin by histone methylation and small RNAs SO CURRENT OPINION IN CELL BIOLOGY LA English DT Review ID TANDEM MASS-SPECTROMETRY; H3 LYSINE-9 METHYLATION; HP1 CHROMO DOMAIN; TIME-OF-FLIGHT; FISSION YEAST; DNA METHYLATION; EPIGENETIC REGULATION; CYTOSINE METHYLATION; CRYSTAL-STRUCTURE; MAMMALIAN-CELLS AB Heterochromatin mediates various nuclear processes including centromere function, gene silencing and nuclear organization. Although it was discovered nearly 75 years ago, the pathways involved in heterochromatin establishment, assembly and epigenetic maintenance have been elusive. Recent reports have demonstrated that distinct and novel chromatin-associated factors, including DNA, RNA and histone modifications, are involved in each of these events. These new findings define a novel conserved mechanism of heterochromatin formation that is likely to have an impact on all eukaryotic silencing pathways. C1 NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. RP Grewal, SIS (reprint author), NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM grewals@mail.nih.gov; juddrice@usc.edu RI Rice, Judd/B-7806-2009 NR 85 TC 131 Z9 138 U1 1 U2 12 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD JUN PY 2004 VL 16 IS 3 BP 230 EP 238 DI 10.1016/j.ceb.2004.04.002 PG 9 WC Cell Biology SC Cell Biology GA 828FM UT WOS:000221959200003 PM 15145346 ER PT J AU Mounkes, LC Stewart, CL AF Mounkes, LC Stewart, CL TI Aging and nuclear organization: lamins and progeria SO CURRENT OPINION IN CELL BIOLOGY LA English DT Review ID HUTCHINSON-GILFORD PROGERIA; ATYPICAL WERNERS-SYNDROME; A-TYPE; PARTIAL LIPODYSTROPHY; SYNDROME PROTEIN; LMNA MUTATIONS; DEFICIENT MICE; A/C GENE; ENVELOPE; CELLS AB The discoveries of at least eight human diseases arising from mutations in LMNA, which encodes the nuclear A-type lamins, have revealed the nuclear envelope as an organelle associated with a variety of fundamental cellular processes. The most recently discovered diseases associated with LMNA mutations are the premature aging disorders Hutchinson-Gilford progeria syndrome (HGPS) and atypical Werner's syndrome. The phenotypes of both HGPS patients and a mouse model of progeria suggest diverse compromised tissue functions leading to defects reminiscent of aging. Aspects of the diseases associated with disrupted nuclear envelope/lamin functions may be explained by decreased cellular proliferation, loss of tissue repair capability and a decline in the ability to maintain a differentiated state. C1 NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. RP Mounkes, LC (reprint author), NCI, Canc & Dev Biol Lab, POB b, Frederick, MD 21702 USA. EM stewartc@ncifcrf.gov NR 50 TC 58 Z9 62 U1 1 U2 5 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD JUN PY 2004 VL 16 IS 3 BP 322 EP 327 DI 10.1016/j.ceb.2004.03.009 PG 6 WC Cell Biology SC Cell Biology GA 828FM UT WOS:000221959200015 PM 15145358 ER PT J AU Cannons, JL Schwartzberg, PL AF Cannons, JL Schwartzberg, PL TI Fine-tuning lymphocyte regulation: what's new with tyrosine kinases and phosphatases? SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID T-CELL-RECEPTOR; LINKED LYMPHOPROLIFERATIVE DISEASE; ANTIGEN-RECEPTOR; IMMUNOLOGICAL SYNAPSE; SIGNAL-TRANSDUCTION; NFATC TRANSLOCATION; FAMILY KINASES; CUTTING EDGE; ACTIVATION; SAP AB Although the basic mechanisms of lymphocyte signaling have been established, recent studies have provided new insights into how fine-tuning the regulation of tyrosine kinases and phosphatases contributes to the delicate balance required for appropriate lymphocyte activation. Recent studies include new work on the roles of the immune synapse in regulating T-cell receptor signaling, the discovery of new functions for the Src-family kinase Fyn and the Tec kinase Itk, particularly in regulation of the actin cytoskeleton, and new insights into positive and negative feedback mechanisms in antigen receptor signaling. C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Cannons, JL (reprint author), NHGRI, NIH, 49-4A38,49 Covent Dr, Bethesda, MD 20892 USA. EM jcannons@mail.nih.gov; pams@mail.nih.gov NR 57 TC 22 Z9 23 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD JUN PY 2004 VL 16 IS 3 BP 296 EP 303 DI 10.1016/j.coi.2004.03.011 PG 8 WC Immunology SC Immunology GA 825UW UT WOS:000221784900008 PM 15134778 ER PT J AU Haley, M Cui, XH Minneci, PC Deans, KJ Natanson, C Eichacker, PQ AF Haley, M Cui, XH Minneci, PC Deans, KJ Natanson, C Eichacker, PQ TI Activated protein C in sepsis: emerging insights regarding its mechanism of action and clinical effectiveness SO CURRENT OPINION IN INFECTIOUS DISEASES LA English DT Review DE sepsis; activated protein C; therapy; cost-effectiveness ID DISSEMINATED INTRAVASCULAR COAGULATION; RANDOMIZED CONTROLLED-TRIAL; HUMAN BRAIN ENDOTHELIUM; SEPTIC SHOCK; POSTMARKETING SURVEILLANCE; ANTIINFLAMMATORY AGENTS; COST-EFFECTIVENESS; ORGAN DYSFUNCTION; ANTITHROMBIN-III; IN-VIVO AB Purpose of review Dysregulation of endogenous coagulant and anticoagulant systems is now believed to play an important role in the pathogenesis of sepsis and septic shock. Reductions in host activated protein C levels and resultant microvascular thrombosis provided a basis for the use of recombinant human activated protein C in sepsis. Although controversial, the findings from an initial phase III trial testing this agent resulted in its approval for use in patients with severe sepsis and high risk of death. This review highlights emerging insights into the biology of protein C and activated protein C in sepsis, summarizes additional analysis growing out of the phase III trial testing recombinant human activated protein C, and assesses the cost-effectiveness that the clinical use of the agent has had thus far. Recent findings Binding of activated protein C to the endothelial cell protein C receptor is recognized to result in a growing number of actions including increased activity of activated protein C itself and inhibition of both nuclear factor-kappaB, a central regulator in the host inflammatory response, and apoptosis. Additional analysis of the original phase III trial testing recombinant human activated protein C appears to emphasize one of the US Food and Drug Administration's original concerns regarding an association between severity of sepsis and this agent's effects. Postmarketing analysis and growing experience with other anticoagulant agents and corticosteroids in sepsis raise questions regarding the ultimate cost-effectiveness of activated protein C. Summary The protein C pathway is important both to coagulant and inflammatory pathways during sepsis. Based on emerging investigations, its actions appear to be increasingly complex ones. Despite potentially promising results in an initial phase III trial, the role of recombinant human activated protein C in the treatment of septic patients must continue to be evaluated. C1 NIH, Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Haley, M (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bldg 10,Room 7D43, Bethesda, MD 20892 USA. EM MHaley@cc.nih.gov NR 57 TC 15 Z9 16 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0951-7375 J9 CURR OPIN INFECT DIS JI Curr. Opin. Infect. Dis. PD JUN PY 2004 VL 17 IS 3 BP 205 EP 211 DI 10.1097/01.qco.000012961.76002.ee PG 7 WC Infectious Diseases SC Infectious Diseases GA 826ZO UT WOS:000221868200005 PM 15166822 ER PT J AU Wang, E Panelli, MC Monsurro, V Marincola, FM AF Wang, E Panelli, MC Monsurro, V Marincola, FM TI Gene expression profiling of anticancer immune responses SO CURRENT OPINION IN MOLECULAR THERAPEUTICS LA English DT Article DE human leukocyte antigen; IL-2; immunoresponsiveness; polymorphism; T-cell ID TUMOR-INFILTRATING LYMPHOCYTES; CUTANEOUS MALIGNANT-MELANOMA; BLOOD MONONUCLEAR-CELLS; T-CELLS; MESSENGER-RNA; HUMAN CANCERS; IMMUNOTHERAPY; ANTIGENS; INTERLEUKIN-2; VACCINES AB Anticancer immune responses can be enhanced by immune manipulation, however, the biological mechanism responsible for these immune responses remains largely unexplained. Conventional immunology researchers have extensively studied specific interactions between immune and cancer cells, and additional investigations have identified co-factors that may enhance the effectiveness of such interactions. As the molecular understanding of individual interactions increases, it is becoming apparent that no single mechanism can explain the phenomenon of tumor rejection. The contribution of several components of the innate and adaptive immune response is likely to be required for successful tumor rejection. These components may be variably recruited and activated by molecules with immune modulatory properties being produced by tumor and bystander cells within the tumor micro-environment. Such complexity can only be appreciated and solved by high-throughput tools capable of providing a global view of biological processes as they occur. This review will present selected examples of how high-throughput gene expression profiling may contribute to the understanding of anticancer immune responses. As reviews on technological aspects of the genomic analysis of cancer are already available, this review will provide a speculative discussion about their potential usefulness. C1 NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM FMarincola@cc.nih.gov NR 66 TC 12 Z9 13 U1 0 U2 0 PU CURRENT DRUGS LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1P 6LB, ENGLAND SN 1464-8431 J9 CURR OPIN MOL THER JI Curr. Opin. Mol. Ther. PD JUN PY 2004 VL 6 IS 3 BP 288 EP 295 PG 8 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 838UD UT WOS:000222737900007 PM 15264431 ER PT J AU Babu, MM Luscombe, NM Aravind, L Gerstein, M Teichmann, SA AF Babu, MM Luscombe, NM Aravind, L Gerstein, M Teichmann, SA TI Structure and evolution of transcriptional regulatory networks SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Review ID ESCHERICHIA-COLI K-12; HIDDEN MARKOV-MODELS; PROTEIN FAMILIES; SACCHAROMYCES-CEREVISIAE; EUKARYOTES; MODULES; YEAST; ORGANIZATION; DISCOVERY; PROFILES AB The regulatory interactions between transcription factors and their target genes can be conceptualised as a directed graph. At a global level, these regulatory networks display a scale-free topology, indicating the presence of regulatory hubs. At a local level, substructures such as motifs and modules can be discerned in these networks. Despite the general organisational similarity of networks across the phylogenetic spectrum, there are interesting qualitative differences among the network components, such as the transcription factors. Although the DNA-binding domains of the transcription factors encoded by a given organism are drawn from a small set of ancient conserved superfamilies, their relative abundance often shows dramatic variation among different phylogenetic groups. Large portions of these networks appear to have evolved through extensive duplication of transcription factors and targets, often with inheritance of regulatory interactions from the ancestral gene. Interactions are conserved to varying degrees among genomes. Insights from the structure and evolution of these networks can be translated into predictions and used for engineering of the regulatory networks of different organisms. C1 MRC, Mol Biol Lab, Cambridge CB2 2QH, England. Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA. Natl Lib Med, Natl Inst Hlth, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Babu, MM (reprint author), MRC, Mol Biol Lab, Hills Rd, Cambridge CB2 2QH, England. EM madanm@mrc-lmb.cam.ac.uk; sat@mrc-lmb.cam.ac.uk OI Teichmann, Sarah/0000-0002-6294-6366 NR 42 TC 376 Z9 394 U1 3 U2 36 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD JUN PY 2004 VL 14 IS 3 BP 283 EP 291 DI 10.1016/j.sbi.2004.05.004 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 836EM UT WOS:000222538400004 PM 15193307 ER PT J AU Khuu, HM Stock, F McGann, M Carter, CS Atkins, JW Murray, PR Read, EJ AF Khuu, HM Stock, F McGann, M Carter, CS Atkins, JW Murray, PR Read, EJ TI Comparison of automated culture systems with a CFR/USP-compliant method for sterility testing of cell-therapy products SO CYTOTHERAPY LA English DT Article DE cell therapy products; somatic cell therapy; sterility testing ID BACTERIAL-CONTAMINATION; PERIPHERAL-BLOOD; BONE-MARROW; BODY-FLUIDS; MICROBIOLOGIC CONTAMINATION; CLINICAL-SIGNIFICANCE; TRANSPLANTATION; RESINS AB Background Although widely used, commercially available automated culture methods are not US Food and Drug Administration-approved for sterility testing of cell-therapy products. For cell-therapy products regulated under Section 351 of the Public Health Service Act, sterility testing must be performed by the methods described in 21 CFR 610.12 and USP < 71 > (CFR/USP method), or by methods demonstrated to be equivalent. Methods Two automated methods, BacT/Alert (BTA; bioMerieux) and Bactec (Becton Dickinson), were compared with the CFR/USP method. Representative mononuclear cell (MNC) products were formulated using six different product media. MNC product aliquots containing 10-50 x 10(6) cells in a 0.5 mL volume were seeded with organisms, and cultured for 14 days in aerobic and anaerobic bottles of each system. Ten different organisms at target concentrations of 10 and 50 colony-forming units (CFU) per bottle were tested. Results Positives were detected in a mean (range) of 72% (7-100%) of cultures for CFR/USP, 82% (0-100%) for BTA, and 93% (57-100%) for Bactec. For nine of the 10 organisms tested, overall detection rates for BTA and Bactec were equivalent to or higher than CFR/USP. Of the six product media tested, detection of organisms was impaired only by the medium containing multiple antibiotics: this occurred in all three systems. Both BTA and Bactec had shorter times to detection than the CFR/USP method, with overall means ( ranges) of 87 (24-264) h for CFR/USP, 24 (12-54) h for BTA, and 33 (12-80) h for Bactec. Detection occurred consistently within 7 days for both BTA and Bactec, but not for CFR/USP. Discussion Both BTA and Bactec are superior to the CFR/USP method for overall detection and time to detection of organisms in MNC products suspended in commonly used media. These data support general use of either BTA or Bactec for sterility testing of a variety of cell-therapy products, and suggest that a 7-day culture period is sufficient to detect clinically relevant organisms. These results confirm the need for bacteriostasis and fungistasis testing of antibiotic-containing products, even when antibiotic-binding substances are used. C1 NIH, Warren Grant Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Lab Med, Bethesda, MD 20892 USA. RP Khuu, HM (reprint author), NIH, Warren Grant Magnuson Clin Ctr, Dept Transfus Med, Bldg 10,Room 1C711,MSC 1184,10 Ctr Dr, Bethesda, MD 20892 USA. NR 28 TC 13 Z9 13 U1 0 U2 1 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 1465-3249 J9 CYTOTHERAPY JI Cytotherapy PD JUN PY 2004 VL 6 IS 3 BP 183 EP 195 DI 10.1080/14653240410005997 PG 13 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA 822FH UT WOS:000221522500001 PM 15203975 ER PT J AU Tsang, M Maegawa, S Kiang, A Habas, R Weinberg, E Dawid, IB AF Tsang, M Maegawa, S Kiang, A Habas, R Weinberg, E Dawid, IB TI A role for MKP3 in axial patterning of the zebrafish embryo SO DEVELOPMENT LA English DT Article DE MAPK phosphatase; dorsoventral polarity; midblastula transition ID ACTIVATED PROTEIN-KINASE; DUAL-SPECIFICITY PHOSPHATASE; MIDBRAIN-HINDBRAIN BOUNDARY; XENOPUS MESODERM INDUCTION; ENDOTHELIAL-GROWTH-FACTOR; MATERNAL BETA-CATENIN; MAP-KINASE; TGF-BETA; CATALYTIC ACTIVATION; INDUCED ANTAGONIST AB Fibroblast growth factors (FGFs) are secreted molecules that can activate the RAS/mitogen-activated protein kinase (MAPK) pathway to serve crucial functions during embryogenesis. Through an in situ hybridization screen for genes with restricted expression patterns during early zebrafish development, we identified a group of genes that exhibit similar expression patterns to FGF genes. We report the characterization of zebrafish MAP kinase-phosphatase 3 (MKP3; DUSP6 - Zebrafish Information Network), a member of the FGF synexpression group, showing that it has a crucial role in the specification of axial polarity in the early zebrafish embryo. MKP3 dephosphorylates the activated form of MAPK, inhibiting the RAS/MAPK arm of the FGF signaling pathway. Gain- and loss-of-function studies reveal that MKP3 is required to limit the extent of FGF/RAS/MAPK signaling in the early embryo, and that disturbing this inhibitory pathway disrupts dorsoventral patterning at the onset of gastrulation. The earliest mkp3 expression is restricted to the future dorsal region of the embryo where it is initiated by a maternal P-catenin signal, but soon after its initiation, mkp3 expression comes under the control of FGF signaling. Thus, mkp3 encodes a feedback attenuator of the FGF pathway, the expression of which is initiated at an early stage so as to ensure correct FGF signaling levels at the time of axial patterning. C1 NICHHD, Mol Genet Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. RP Dawid, IB (reprint author), NICHHD, Mol Genet Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. EM idawid@nih.gov RI TSANG, Michael/E-2758-2013; Tsang, Michael/I-9305-2014 OI TSANG, Michael/0000-0001-6384-2422; Tsang, Michael/0000-0001-7123-0063 FU NICHD NIH HHS [R01 HD39272] NR 79 TC 86 Z9 88 U1 1 U2 5 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD JUN PY 2004 VL 131 IS 12 BP 2769 EP 2779 DI 10.1242/dev.01157 PG 11 WC Developmental Biology SC Developmental Biology GA 838EG UT WOS:000222695700002 PM 15142973 ER PT J AU Sinha, RK Mage, RG AF Sinha, RK Mage, RG TI Developing neonatal rabbit appendix, a primary lymphoid organ, is seeded by immature blood-borne B cells: evidence for roles for CD62L/PNAd, CCR7/CCL21, alpha 4 beta 1 and LFA-1 SO DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY LA English DT Article DE B-cell recruitment; rabbit appendix; adhesion molecules; chemokines; cell trafficking ID HIGH ENDOTHELIAL VENULES; L-SELECTIN LIGAND; H-MUTANT RABBITS; SIALYL-LEWIS-X; SOMATIC DIVERSIFICATION; GENE CONVERSION; PEYERS-PATCHES; T-LYMPHOCYTES; AVIAN BURSA; EXPRESSION AB Young rabbit appendix is a homologue of chicken bursa of Fabricius; both are crucial sites for preimmune B-cell repertoire development. We describe here some of the molecules involved in the multi-step recruitment of blood-borne B cells into neonatal rabbit developing appendix. Sialyl-Lewis-x, CD62L and integrins such as LFA-1 and alpha4beta1 were detected on B cells in peripheral blood. Peripheral lymph node addressin (PNAd), a CD62L counter-receptor was observed on appendix HEV. We also detected chemokine receptor CCR7 on peripheral blood B cells and one of the CCR7 ligands, CCL21, on appendix HEV but not in appendix follicles. Higher levels of CXCR5 expression compared to CCR7 on appendix B cells suggest that CXCR5 may be involved in recruitment of B cells into follicles. The proportions of appendix B cells expressing CD62L, sialyl-Lewis-x and alpha4beta1 declined between day 3 and 4 weeks after birth while percentages of Lewis-x(+) appendix B cells increased. These changes correlate with the stage of repertoire diversification by gene conversion in both rabbits and chickens. The cross-reactivity of antibodies to mouse or human adhesion molecules described in this study indicates that some of the structures of these important molecules are conserved across species. Published by Elsevier Ltd. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Mage, RG (reprint author), NIAID, Immunol Lab, NIH, Bldg 10,Room 11N311,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. EM rm3z@nih.gov NR 47 TC 6 Z9 7 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-305X J9 DEV COMP IMMUNOL JI Dev. Comp. Immunol. PD JUN PY 2004 VL 28 IS 7-8 BP 829 EP 841 DI 10.1016/j.dci.2004.01.003 PG 13 WC Immunology; Zoology SC Immunology; Zoology GA 811DG UT WOS:000220752000015 PM 15043950 ER PT J AU Davis, S Miura, S Hill, C Mishina, Y Klingensmith, J AF Davis, S Miura, S Hill, C Mishina, Y Klingensmith, J TI BMP receptor IA is required in the mammalian embryo for endodermal morphogenesis and ectodermal patterning SO DEVELOPMENTAL BIOLOGY LA English DT Article DE BMPRIA; BMP signaling; epiblast; mouse; forebrain; ectoderm; endoderm; anterior visceral endoderm ID ANTERIOR PRIMITIVE ENDODERM; MOUSE EMBRYO; VISCERAL ENDODERM; NEURAL PLATE; FOREBRAIN DEVELOPMENT; MESODERM FORMATION; HEAD INDUCTION; KNOCKOUT MICE; IBMP RECEPTOR; GENE-FUNCTION AB BMPRIA is a receptor for bone morphogenetic proteins with high affinity for BMP2 and BMP4. Mouse embryos lacking Bmprla fail to gastrulate, complicating studies on the requirements for BMP signaling in germ layer development. Recent work shows that BMP4 produced in extraembryonic tissues initiates gastrulation. Here we use a conditional allele of Bmprla to remove BMPRIA only in the epiblast, which gives rise to all embryonic tissues. Resulting embryos are mosaics composed primarily of cells homozygous null for Bmprla, interspersed with heterozygous cells. Although mesoderm and endoderm do not form in Bmprla null embryos, these tissues are present in the mosaics and are populated with mutant cells. Thus, BMPRIA signaling in the epiblast does not restrict cells to or from any of the germ layers. Cells lacking Bmprla also contribute to surface ectoderm; however, from the hindbrain forward, little surface ectoderm forms and the forebrain is enlarged and convoluted. Prechordal plate, early definitive endoderm, and anterior visceral endoderm appear to be expanded, likely due to defective morphogenesis. These data suggest that the enlarged forebrain is caused in part by increased exposure of the ectoderm to signaling sources that promote anterior neural fate. Our results reveal critical roles for BMP signaling in endodermal morphogenesis and ectodermal patterning. (C) 2004 Elsevier Inc. All rights reserved. C1 Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Klingensmith, J (reprint author), Duke Univ, Med Ctr, Dept Cell Biol, Box 3709, Durham, NC 27710 USA. EM kling@cellbio.duke.edu FU NICHD NIH HHS [P01HD39948]; NIDCR NIH HHS [R01DE013674] NR 77 TC 44 Z9 45 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2004 VL 270 IS 1 BP 47 EP 63 DI 10.1016/j.ydbio.2004.01.048 PG 17 WC Developmental Biology SC Developmental Biology GA 822IK UT WOS:000221532300004 PM 15136140 ER PT J AU Kanaya, AM Harris, T Goodpaster, BH Tylavsky, F Cummings, SR AF Kanaya, AM Harris, T Goodpaster, BH Tylavsky, F Cummings, SR CA Hlth Aging Body Composition Study TI Adipocytokines attenuate the association between visceral adiposity and diabetes in older adults SO DIABETES CARE LA English DT Article ID NECROSIS-FACTOR-ALPHA; PLASMINOGEN-ACTIVATOR INHIBITOR-1; BODY-FAT DISTRIBUTION; INSULIN-RESISTANCE; MEXICAN-AMERICANS; GLUCOSE-TOLERANCE; MEN; OBESITY; ACCUMULATION; MELLITUS AB OBJECTIVE - To examine whether adiponectin is independently associated with diabetes and whether adiponectin and other adipocytokines account for the relationship between fat and diabetes. RESEARCH DESIGN AND METHODS - A nested case-control study from the Health, Aging, and Body Composition (Health ABC) Study. We measured four adipocytokines: adiponectin, interleukin (IL)-6, tumor necrosis factor-a, and plasminogen activator inhibitor 1 (PAl-1). Regional fat area was determined by computed tomography scan. The 519 case subjects had diabetes defined by fasting plasma glucose level greater than or equal to126 mg/dl or by use of diabetes medications. The 519 control subjects had normal glucose tolerance and were matched by sex, race, and study site. Sex-specific logistic models were adjusted for age, race, site, total adiposity, smoking, and physical activity. RESULTS- Higher adiponectin levels were associated with lower risk of diabetes (P < 0.001). Visceral fat was the only adiposity measure associated with diabetes after adjusting for BMI (odds ratio 3.0 [2.1-4.3] in women and 1.3 [1.0-1.6] in men, P < 0.001 between-sex comparison). Adipocytokines attenuated the association between visceral fat and diabetes for both sexes but more strongly in men (women 2.3 [1.5-3.3], men 1.1 [0.9-1.4]). In men, adiponectin, IL-6, and PAI-1 remained independently associated with diabetes after adjusting for fat depots; in women, adiponectin was the only independently associated adipocytokine. Controlling for insulin, HDL, triglycerides, and blood pressure did not change these results. CONCLUSIONS - Adiponectin is associated with lower odds of diabetes in older men and women. Whereas several adipocytokines explained the relationship between visceral adiposity and diabetes in men, only adiponectin partially mediated this association among women. C1 Univ Tennessee, Memphis, TN USA. Univ Pittsburgh, Pittsburgh, PA USA. NIA, NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Kanaya, AM (reprint author), 1635 Divisadero St,Suite 600, San Francisco, CA 94115 USA. EM alkak@itsa.ucsf.edu FU NIA NIH HHS [N01 AG 62101, N01 AG 62103, N01 AG 62106, P30 AG 15272]; NIAMS NIH HHS [5K12 AR 47659] NR 23 TC 64 Z9 66 U1 1 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD JUN PY 2004 VL 27 IS 6 BP 1375 EP 1380 DI 10.2337/diacare.27.6.1375 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 824MM UT WOS:000221690700020 PM 15161791 ER PT J AU Nair, S Lee, YH Lindsay, RS Walker, BR Tataranni, PA Bogardus, C Baier, LJ Permana, PA AF Nair, S Lee, YH Lindsay, RS Walker, BR Tataranni, PA Bogardus, C Baier, LJ Permana, PA TI 11 beta-Hydroxysteroid dehydrogenase Type 1: genetic polymorphisms are associated with Type 2 diabetes in Pima Indians independently of obesity and expression in adipocyte and muscle SO DIABETOLOGIA LA English DT Article DE sdipocyte; henetic polymorphisms; insulinaemia; 11 beta-hydroxysteroid dehydrogenase Type 1; obesity; Type 2 diabetes mellitus ID HEPATIC INSULIN SENSITIVITY; BODY-MASS INDEX; CORTISOL METABOLISM; ADIPOSE-TISSUE; CELLS; MICE; DIFFERENTIATION; CARBENOXOLONE; PATHOGENESIS; DEFICIENCY AB Aims/hypothesis. The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) modulates tissue-specific glucocorticoid concentrations by generating active cortisol. We have shown that adipose tissue 11beta-HSD1 mRNA levels were associated with adiposity and insulinaemia. Here we conducted further expression and genetic association studies in Pima Indians. Methods. The 11beta-HSD1 mRNA concentrations were measured in abdominal subcutaneous adipocytes (n=61) and skeletal muscle tissues (n=64). Single nucleotide polymorphisms in the HSD11B1 gene were genotyped in a larger group of full-blooded Pima Indians. Results. Two representative SNPs (SNP1, n=706; SNP5, n=839) were associated with Type 2 diabetes mellitus (p=0.01), although neither SNP was associated with obesity. Among subjects with normal glucose tolerance, SNP1 (n=127) and SNP5 (n=159) were associated with insulin-mediated glucose uptake rates (p=0.03 and p=0.04), and SNP1 was further associated with fasting, 30-min, and 2-h plasma insulin concentrations (p=0.002, p=0.002 and p=0.03). Adipocyte 11beta-HSD1 mRNA concentrations were correlated positively with adiposity and insulinaemia, and were additionally negatively correlated with insulin-mediated glucose uptake rates; nevertheless, the adipocyte 11beta-HSD1 expression did not correlate with genotypes of the donors. The muscle 11beta-HSD1 mRNA concentrations did not correlate with any anthropometric or metabolic variables. Conclusions/interpretation. We confirmed that adipocyte 11beta-HSD1 mRNA concentrations were associated with adiposity, and showed that genetic variations in the HSD11B1 gene were associated with Type 2 diabetes mellitus, plasma insulin concentrations and insulin action, independent of obesity. The variable adipose expression might not be a primary consequence of these HSD11B1 SNPs. Therefore, it is possible that the HSD11B1 gene is under tissue-specific regulation, and has tissue-specific consequences. C1 Carl T Hayden VA Med Ctr, Phoenix, AZ 85012 USA. NIDDK, NIH, Phoenix, AZ USA. Univ Glasgow, Western Infirm, Gardiner Inst, Div Cardiovasc & Med Sci, Glasgow G11 6NT, Lanark, Scotland. Univ Edinburgh, Western Gen Hosp, Endocrinol Unit, Edinburgh, Midlothian, Scotland. RP Permana, PA (reprint author), Carl T Hayden VA Med Ctr, Phoenix, AZ 85012 USA. EM paska.permana@med.va.gov NR 39 TC 71 Z9 73 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD JUN PY 2004 VL 47 IS 6 BP 1088 EP 1095 DI 10.1007/s00125-004-1407-6 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 832AT UT WOS:000222240100017 PM 15156315 ER PT J AU Derfoul, A Carlberg, AL Tuan, RS Hall, DJ AF Derfoul, A Carlberg, AL Tuan, RS Hall, DJ TI Differential regulation of osteogenic marker gene expression by Wnt-3a in embryonic mesenchymal multipotential progenitor cells SO DIFFERENTIATION LA English DT Article DE Wnt-3a; osteogenesis; alkaline phosphatase; mesenchymal differentiation; BMP-2 ID CHICK LIMB BUD; BONE MORPHOGENETIC PROTEIN-2; RECEPTOR-RELATED PROTEIN-5; BETA-CATENIN; STEM-CELLS; CHONDROGENIC DIFFERENTIATION; C3H10T1/2 CELLS; AER FORMATION; SELF-RENEWAL; INITIATION AB The Wnt family of secreted glycoproteins plays an integral role in embryonic development and differentiation. To explore the role of Wnt's in one aspect of differentiation, namely osteogenesis, we employed a retroviral gene transfer approach to express Wnt-3a in the multipotent murine embryonic mesenchymal cell line C3H10T1/2. We found that expression of Wnt-3a in these cells had a significant, positive effect on cell growth in serum-containing medium, in that the cells grew to very high densities compared to the control cells. Additionally, apoptosis was markedly inhibited by Wnt-3a. However, when the cells were grown in serum-deficient medium, the Wnt-3a-expressing cells arrested efficiently in G1 phase, indicating that serum growth factors were needed in addition to Wnt-3a for enhanced proliferation. Wnt-3a-expressing cells exhibited high levels of alkaline phosphatase gene expression and enzymatic activity, but did not show any matrix mineralization. Unexpectedly, basal expression of bone sialoprotein, osteocalcin, and osteopontin were markedly inhibited by Wnt-3a, as were other known target genes of Wnt-3a, such as Brachyury, FGF-10, and Cdx1. When Wnt-3a-expressing cells were treated with osteogenic supplements in the presence of BMP-2, alkaline phosphatase gene expression and activity were further elevated. Additionally, BMP-2 was able to reverse the inhibitory effect of Wnt-3a on osteocalcin and osteopontin gene expression. These results indicate that while Wnt-3a represses basal expression of some osteogenic genes, this repression can be partially reversed by BMP-2. Finally, the enhanced gene expression of alkaline phosphatase induced by Wnt-3a could be effectively suppressed by the combined action of dexamethasone and 1,25-dihydroxyvitamin D-3. These data show for the first time that Wnt-3a has an unusual effect on multipotential embryonic cells, in that it enhances cellular proliferation and expression of alkaline phosphatase, while it represses most other marker genes of osteogenic differentiation. C1 NIAMSD, NIH, Dept Hlth & Human Serv, Cartilage Biol & Orthopaed Branch, Bethesda, MD 20892 USA. RP NIAMSD, NIH, Dept Hlth & Human Serv, Cartilage Biol & Orthopaed Branch, Bethesda, MD 20892 USA. EM halld@mail.nih.gov NR 48 TC 29 Z9 33 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0301-4681 EI 1432-0436 J9 DIFFERENTIATION JI Differentiation PD JUN PY 2004 VL 72 IS 5 BP 209 EP 223 DI 10.1111/j.1432-0436.2004.07205003.x PG 15 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 839YO UT WOS:000222821400003 PM 15270777 ER PT J AU de Jong, DJ Drenth, JPH AF de Jong, DJ Drenth, JPH TI Absence of an association of the IBD2 locus gene keratin 8 and inflammatory bowel disease in a large genetic association study SO DIGESTIVE AND LIVER DISEASE LA English DT Editorial Material ID VITAMIN-D-RECEPTOR; CROHNS-DISEASE; CHRONIC-PANCREATITIS; CANDIDATE GENE; LIVER-DISEASE; SUSCEPTIBILITY; MUTATION; MICE; POLYMORPHISM; COLITIS C1 Univ Nijmegen, Med ctr St Radboud, Dept Med, Div Gastroenterol & Hepatol, Nijmegen, Netherlands. NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Drenth, JPH (reprint author), Univ Nijmegen, Med ctr St Radboud, Dept Med, Div Gastroenterol & Hepatol, Nijmegen, Netherlands. EM joostphdrenth@cs.com RI Drenth, J.P.H./H-8025-2014; Jong, D.J./L-4417-2015 NR 30 TC 0 Z9 0 U1 0 U2 0 PU PACINI EDITORE PI PISA PA VIA DELLA GHERARDESCA-ZONA INDUSTRIALE OSPEDALETTO, 56121 PISA, ITALY SN 1590-8658 J9 DIGEST LIVER DIS JI Dig. Liver Dis. PD JUN PY 2004 VL 36 IS 6 BP 380 EP 383 DI 10.1016/j.dld.2004.02.002 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 829AY UT WOS:000222016400003 PM 15248376 ER PT J AU Anderton, MJ Manson, MM Verschoyle, R Gescher, A Steward, WP Williams, ML Mager, DE AF Anderton, MJ Manson, MM Verschoyle, R Gescher, A Steward, WP Williams, ML Mager, DE TI Physiological modeling of formulated and crystalline 3,3 '-diindolylmethane pharmacokinetics following oral administration in mice SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID CANCER-CELLS; INDUCE APOPTOSIS; DIETARY INDOLES; CERVICAL-CANCER; INDOLE-3-CARBINOL; METABOLISM; PRODUCTS; ACID; RAT; DIINDOLYLMETHANE AB 3,3'-Diindolylmethane (DIM) is a naturally occurring indole, which is currently under investigation as a potential chemopreventive agent. The concentrations of DIM in plasma, liver, kidney, lung, heart, and brain tissues were determined following oral administration of two different formulations to mice (250 mg/kg). Mice were sacrificed periodically from 0 to 24 h after administration of either a crystalline or an absorption-enhanced formulation (BioResponse-DIM; Indolplex) of DIM, and plasma and tissue concentrations were determined by high-performance liquid chromatography (UV detection, 280 nm). A physiologically based pharmacokinetic (PBPK) model was developed to characterize the pharmacokinetic properties of the two different formulations. The final model included parameters reflecting linear first-order absorption, systemic clearance, and distributional clearance in the remainder compartment, which were considered independent of formulation. All pharmacokinetic profiles from the two formulations were fitted simultaneously to estimate unknown model parameters. Plasma and tissue concentration-time profiles exhibited a rapid rise to peak values at 0.5 to 1 h, followed by a polyexponential decline with an extended terminal phase. These profiles were well described by the final model and unknown parameters were estimated with relatively low coefficients of variation. Relative drug exposure and absorption parameters suggest that BioResponse-DIM exhibited approximately 50% higher bioavailability than the crystalline formulation. Clearance of DIM was estimated as 7.18 ml/h. This is the first study to characterize the pharmacokinetics of DIM in mice, and the established PBPK model should prove useful in the design and analysis of future preclinical studies aimed at evaluating the in vivo pharmacological effects of DIM. C1 NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Univ Leicester, Dept Biochem, Leicester LE1 7RH, Leics, England. Univ Leicester, Dept Canc Studies, Leicester LE1 7RH, Leics, England. RP Williams, ML (reprint author), NIA, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM williamsma@grc.nia.nih.gov NR 39 TC 75 Z9 79 U1 0 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD JUN 1 PY 2004 VL 32 IS 6 BP 632 EP 638 DI 10.1124/dmd.32.6.632 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 822LJ UT WOS:000221541200009 PM 15155555 ER PT J AU Acharya, MR Venitz, E Figg, WD Sparreboom, A AF Acharya, MR Venitz, E Figg, WD Sparreboom, A TI Chemically modified tetracyclines as inhibitors of matrix metalloproteinases SO DRUG RESISTANCE UPDATES LA English DT Review DE matrix metalloproteinase; chemically modified tetracyclines; drug development; anticancer drugs ID BREAST-CARCINOMA CELLS; LAMININ-5 GAMMA-2 CHAIN; ANGIOGENESIS IN-VITRO; TISSUE INHIBITOR; PROSTATE-CANCER; NONANTIMICROBIAL TETRACYCLINE; COLLAGENASE ACTIVITY; TUMOR INVASION; NITRIC-OXIDE; 4-DEDIMETHYLAMINO SANCYCLINE AB Matrix metalloproteinases belong to a diverse group of enzymes that are not only involved in restructuring the extracellular matrix, but also play a major role in various pathophysiological conditions by virtue of their complicated expression, activation, and regulation processes. They have been widely implicated to function as major contenders in cancer progression, frequently due to their role in invasion, proliferation and metastasis. MMP inhibitors have been specifically designed to target these altered activities of MMPs, mostly by means of inhibiting their function and by diminishing their increased expression in various disease states, particularly cancer. Tetracyclines and chemically modified tetracyclines (CMTs) have been rationally designed to inhibit the activity of MMPs and thus decrease the potential risk of spread of tumor cells to distant sites by invasion and metastasis. Pre-clinical and early clinical data for one of these CMTs, COL-3 (formerly CMT-3) indicate considerable potential for this group of anticancer agents. Further testing and rational modifications of these CMT analogues might lead to new anticancer agents. (C) 2004 Elsevier Ltd. All rights reserved. C1 NCI, Clin Pharmacol Res Core, NIH, Bethesda, MD 20892 USA. Virginia Commonwealth Univ, Sch Pharm, Dept Pharmaceut, Richmond, VA USA. RP Figg, WD (reprint author), NCI, Clin Pharmacol Res Core, NIH, Bldg 10,Rm 5A01,MSC 1910,9000 Rockville Pike, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 NR 126 TC 83 Z9 87 U1 1 U2 4 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1368-7646 J9 DRUG RESIST UPDATE JI Drug Resist. Update PD JUN PY 2004 VL 7 IS 3 BP 195 EP 208 DI 10.1016/j.drup.2004.04.002 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 850OU UT WOS:000223623100004 PM 15296861 ER PT J AU Phillips, TM AF Phillips, TM TI Rapid analysis of inflammatory cytokines in cerebrospinal fluid using chip-based immunoaffinity electrophoresis SO ELECTROPHORESIS LA English DT Article DE chip-based immunoaffinity capillary electrophoresis; head trauma; inflammatory cytokines; miniaturization ID INDUCED FLUORESCENCE DETECTION; CENTRAL-NERVOUS-SYSTEM; TRAUMATIC BRAIN INJURY; CAPILLARY-ELECTROPHORESIS; LIQUID-CHROMATOGRAPHY; MASS-SPECTROMETRY; BIOLOGICAL-FLUIDS; COLUMN CLEANUP; INTERLEUKIN-6; PROTEINS AB A chip-based capillary electrophoresis system has been designed for rapidly measuring the concentrations of inflammatory cytokines in the cerebrospinal fluid of patients with head trauma. Isolation of the reactive cytokines was achieved by immunoaffinity capture using a panel of six immobilized antibodies, directly attached to the injection port of the chip. The captured cytokines were labeled in situ with a red light-emitting laser dye and electroeluted into the separation channel. Separation of the isolated cytokines was achieved by electrophoresis in under 2 min with quantification of the resolved peaks being achieved by on-line laser-induced fluorescence and integration of each peak area. Comparison of the results to commercially available high-sensitivity immunoassays demonstrates that the chip-based assay provides a fast, accurate procedure for studying the concentrations of these analytes in complex biological materials. The degree of accuracy and precision achieved by the chip-based CE is comparable to conventional immunoassays, the system being able to analyze between 10-12 samples per hour. With the ever-expanding array of antibodies that are commercially available, this chip-based system can be applied to a wide variety of different analyses. C1 NIH, ORS, DBEPS, UAIR, Bethesda, MD 20892 USA. RP Phillips, TM (reprint author), NIH, ORS, DBEPS, UAIR, 13-3E42 9000 Rockville Pike, Bethesda, MD 20892 USA. EM phillipt@mail.nih.gov NR 34 TC 69 Z9 69 U1 1 U2 5 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD JUN PY 2004 VL 25 IS 10-11 BP 1652 EP 1659 DI 10.1002/elps.200305873 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 830RK UT WOS:000222140400031 PM 15188254 ER PT J AU Steffensen, KR Holter, E Bavner, A Nilsson, M Pelto-Huikko, M Tomarev, S Treuter, E AF Steffensen, KR Holter, E Bavner, A Nilsson, M Pelto-Huikko, M Tomarev, S Treuter, E TI Functional conservation of interactions between a homeodomain cofactor and a mammalian FTZ-F1 homologue SO EMBO REPORTS LA English DT Article DE nuclear receptor; homeodomain; Prox1; FTZ-F1; LRH1 ID BILE-ACID BIOSYNTHESIS; NUCLEAR RECEPTOR SHP; PROTEIN FTZ; FACTOR-I; LIVER; PANCREAS; PROX1; ACTIVATION; METABOLISM; PROSPERO AB Nuclear receptors are master regulators of metazoan gene expression with crucial roles during development and in adult physiology. Fushi tarazu factor 1 (FTZ-F1) subfamily members are ancient orphan receptors with homologues from Drosophila to human that regulate diverse gene expression programs important for developmental processes, reproduction and cholesterol homeostasis in an apparently ligand-independent manner. Thus, developmental and tissue-specific cofactors may be particularly important in modulating the transcriptional activities of FTZ-F1 receptors. In Drosophila, the homeodomain protein Fushi tarazu acts as a cofactor for FTZ-F1 (NR5A3), leading to the hypothesis that a similar type of homeodomain cofactor-nuclear receptor relationship might exist in vertebrates. In this study, we have identified and characterized the homeodomain protein Prox1 as a co-repressor for liver receptor homologue 1 (LRH1/NR5A2), a master regulator of cholesterol homeostasis in mammals. Our study suggests that interactions between LRH1 and Prox1 may fulfil roles both during development of the enterohepatic system and in adult physiology of the liver. C1 Karolinska Inst, Novum, Dept Biosci, S-14157 Huddinge, Sweden. Tampere Univ, Dept Dev Biol, Sch Med, FIN-33101 Tampere, Finland. Tampere Univ Hosp, Dept Pathol, Tampere 33101, Finland. NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Treuter, E (reprint author), Karolinska Inst, Novum, Dept Biosci, S-14157 Huddinge, Sweden. EM eckardt.treuter@cbt.ki.se OI Steffensen, Knut/0000-0001-6093-2801 NR 23 TC 44 Z9 44 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1469-221X J9 EMBO REP JI EMBO Rep. PD JUN PY 2004 VL 5 IS 6 BP 613 EP 619 DI 10.1038/sj.embor.7400147 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 836MT UT WOS:000222560600015 PM 15143342 ER PT J AU Chen, AM Rogan, WJ AF Chen, AM Rogan, WJ TI Malaria control and public health - In reply SO EMERGING INFECTIOUS DISEASES LA English DT Letter ID MILK; DDE C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Rogan, WJ (reprint author), NIEHS, Epidemiol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. EM rogan@niehs.nih.gov RI Rogan, Walter/I-6034-2012 OI Rogan, Walter/0000-0002-9302-0160 NR 5 TC 2 Z9 2 U1 0 U2 1 PU CENTER DISEASE CONTROL PI ATLANTA PA ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD JUN PY 2004 VL 10 IS 6 BP 1171 EP 1172 PG 2 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 825IH UT WOS:000221749300040 ER PT J AU Conrads, TP Fusaro, VA Ross, S Johann, D Rajapakse, V Hitt, BA Steinberg, SM Kohn, EC Fishman, DA Whiteley, G Barrett, JC Liotta, LA Petricoin, EF Veenstra, TD AF Conrads, TP Fusaro, VA Ross, S Johann, D Rajapakse, V Hitt, BA Steinberg, SM Kohn, EC Fishman, DA Whiteley, G Barrett, JC Liotta, LA Petricoin, EF Veenstra, TD TI High-resolution serum proteomic features for ovarian cancer detection SO ENDOCRINE-RELATED CANCER LA English DT Review ID PROSTATE-CANCER; PATTERNS AB Serum proteomic pattern diagnostics is an emerging paradigm employing low-resolution mass spectrometry (MS) to generate a set of biomarker classifiers. In the present study, we utilized a well-controlled ovarian cancer serum study set to compare the sensitivity and specificity of serum proteomic diagnostic patterns acquired using a high-resolution versus a low-resolution MS platform. In blinded testing sets the high-resolution mass spectral data contained multiple diagnostic signatures that were superior to the low-resolution spectra in terms of sensitivity and specificity (P < 0.00001) throughout the range of modeling conditions. Four mass spectral feature set patterns acquired from data obtained exclusively with the high-resolution mass spectrometer were 100% specific and sensitive in their diagnosis of serum samples as being acquired from either unaffected patients or those suffering from ovarian cancer. Important to the future of proteomic pattern diagnostics is the ability to recognize inferior spectra statistically, so that those resulting from a specific process error are recognized prior to their potentially incorrect (and damaging) diagnosis. To meet this need, we have developed a series of quality-assurance and in-process control procedures to (a) globally evaluate sources of sample variability, (b) identify outlying mass spectra, and (c) develop quality-control release specifications. From these quality-assurance and control (QA/QC) specifications, we identified 32 mass spectra out of the total 248 that showed statistically significant differences from the norm. Hence, 216 of the initial 248 high-resolution mass spectra were determined to be of high quality and were remodeled by pattern-recognition analysis. Again, we obtained four mass spectral feature set patterns that also exhibited 100% sensitivity and specificity in blinded validation tests (68/68 cancer: including 18/18 stage 1, and 43/43 healthy). We conclude that (a) the use of high-resolution MS yields superior classification patterns as compared with those obtained with lower resolution instrumentation; (b) although the process error that we discovered did not have a deleterious impact on the present results obtained from proteomic pattern analysis, the major source of spectral variability emanated from mass spectral acquisition, and not bias at the clinical collection site; (c) this variability can be reduced and monitored through the use of QA/QC statistical procedures; (d) multiple and distinct proteomic patterns, comprising low molecular weight biomarkers, detected by high-resolution MS achieve accuracies surpassing individual biomarkers, warranting validation in a large clinical study. C1 Natl Canc Inst, SAIC Frederick Inc, Biomed Proteom Program, Lab Proteom & Analyt Technol, Frederick, MD 21702 USA. US FDA, Ctr Biol Evaluat & Res, NCI, Clin Proteom Program, Bethesda, MD 20892 USA. NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. Correl Syst Inc, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. Northwestern Univ, Natl Ovarian Canc Early Detect Program, Chicago, IL 60611 USA. NCI, SAIC Frederick Inc, Serum Proteomic Patterns Clin Reference Lab, Frederick, MD 21702 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Veenstra, TD (reprint author), Natl Canc Inst, SAIC Frederick Inc, Biomed Proteom Program, Lab Proteom & Analyt Technol, POB B, Frederick, MD 21702 USA. EM veenstra@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 16 TC 164 Z9 169 U1 0 U2 7 PU SOC ENDOCRINOLOGY PI BRISTOL PA 22 APEX COURT, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD JUN PY 2004 VL 11 IS 2 BP 163 EP 178 DI 10.1677/erc.0.0110163 PG 16 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 833RM UT WOS:000222356400002 PM 15163296 ER PT J AU Bossis, I Voutetakis, A Bei, T Sandrini, F Griffin, KJ Stratakis, CA AF Bossis, I Voutetakis, A Bei, T Sandrini, F Griffin, KJ Stratakis, CA TI Protein kinase A and its role in human neoplasia: the Carney complex paradigm SO ENDOCRINE-RELATED CANCER LA English DT Review ID NODULAR ADRENOCORTICAL DISEASE; SPOTTY SKIN PIGMENTATION; RI-ALPHA SUBUNIT; PSAMMOMATOUS MELANOTIC SCHWANNOMA; MAMMARY EPITHELIAL-CELLS; FAMILIAL CARDIAC MYXOMAS; I REGULATORY SUBUNIT; POLO-LIKE KINASE; ENDOCRINE OVERACTIVITY; CYCLIC-AMP AB The type 1 alpha regulatory subunit (R1alpha) of cAMP-dependent protein kinase A (PKA) (PRKAR1A) is an important regulator of the serine-threonine kinase activity catalyzed by the PKA holoenzyme. Carney complex (CNC) describes the association 'of spotty skin pigmentation, myxomas, and endocrine overactivity'; CNC is in essence the latest form of multiple endocrine neoplasia to be described and affects the pituitary, thyroid, adrenal and gonadal glands. Primary pigmented nodular adrenocortical disease (PPNAD), a micronodular form of bilateral adrenal hyperplasia that causes a unique, inherited form of Cushing syndrome, is also the most common endocrine manifestation of CNC. CNC and PPNAD are genetically heterogeneous but one of the responsible genes is PRKAR1A, at least for those families that map to 17q22-24 (the chromosomal region that harbors PRKAR1A). CNC and/or PPNAD are the first human diseases to be caused by mutations in one of the subunits of the PKA holoenzyme. Despite the extensive literature on R1alpha and PKA, little is known about their potential involvement in cell cycle regulation, growth and/or proliferation. The presence of inactivating germline mutations and the loss of its wild-type allele in CNC lesions indicated that PRKAR1A could function as a tumor-suppressor gene in these tissues. However, there are conflicting data in the literature about PRKAR1A's role in human neoplasms, cancer cell lines and animal models. In this report, we review briefly the genetics of CNC and focus on the involvement of PRKAR1A in human tumorigenesis in an effort to reconcile the often diametrically opposite reports on R1alpha. C1 NICHHD, Sect Endocrinol & Genet, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NICHHD, Sect Endocrinol & Genet, Dev Endocrinol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov NR 157 TC 55 Z9 59 U1 0 U2 2 PU SOC ENDOCRINOLOGY PI BRISTOL PA 22 APEX COURT, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD JUN PY 2004 VL 11 IS 2 BP 265 EP 280 DI 10.1677/erc.0.0110265 PG 16 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 833RM UT WOS:000222356400008 PM 15163302 ER PT J AU Zhang, GQ Veldhuis, JD AF Zhang, GQ Veldhuis, JD TI Requirement for proximal putative Sp1 and AP-2 cis-deoxyribonucleic acid elements in mediating basal and luteinizing hormone- and insulin-dependent in vitro transcriptional activation of the CYP17 gene in porcine theca cells SO ENDOCRINOLOGY LA English DT Article ID POLYCYSTIC-OVARY-SYNDROME; GROWTH-FACTOR-I; GRANULOSA-CELLS; EXPRESSION; LH; BIOSYNTHESIS; RECRUITMENT; STIMULATION; MECHANISMS; SEQUENCE AB The cytochrome P450 17alpha-hydroxylase/C17-20 lyase (CYP17) enzyme catalyzes the first committed step in androgen biosynthesis. In primary cultures of immature swine theca cells, LH and insulin induce CYP17 mRNA and incompletely processed heteronuclear RNA supraadditively over 2-6 h. To monitor in vitro transcriptional control by these two physiological signals, we cloned a -976 to +31-bp 5'-upstream region of the homologous CYP17 gene and fused it to a cytoplasmically targeted firefly luciferase minigene (CYP17/luc). LH and insulin individually stimulated transcriptional activity of transiently transfected CYP17/luc in theca cells by 2.7 +/- 0.31- and 2.5 +/- 0.24-fold over basal, respectively, at an optimal concentration (both 100 ng/ml) and time (6 h; both P < 0.01). Combined peptidyl agonists stimulated CYP17/luc by 6.6 +/- 1.2-fold (P < 0.001). To identify possible LH- and insulin-sensitive cis-acting DNA regulatory regions, we prepared four deletional constructs, -839, -473, -174, and -75/+35 bp 5' upstream of the transcriptional start site. Deletion from -976 to -839 bp decreased basal transcriptional activity by 89% and that stimulated by LH, insulin, and both effectors by 82%, 91%, and 78%, respectively (each P < 0.01). Further deletion to -473 bp conferred partial responsiveness to combined hormone stimulation, suggesting an intervening inhibitory sequence. Truncation to -174 bp and more proximally reduced basal CYP17/luc activity and hormonal action by more than 95% (P < 0.001). The marked loss of combined LH and insulin stimulation caused by deleting the region between -473 and - 175 bp suggested the possible relevance of partially overlapping specificity protein-1 (Sp1) and activating protein-2 (AP-2)-like binding sites located between -193 and -180 bp. Point mutation of the proximal Sp1-like element in full-length -976/+31 CYP17/luc impaired basal transcription minimally (by 21%; P = NS) and stimulation by LH (76%), insulin (67%), and combined peptides (54%) significantly (each P < 0.05 vs. wild type). Mutation of the AP-2 site alone decreased basal CYP17/luc activity nonsignificantly (by 25%), but repressed stimulated transcriptional responses prominently, viz. to LH (57%), insulin (77%), and both effectors (82%; each P < 0.025 vs. wild type). Mutation of both sites inhibited basal and hormonally stimulated CYP17/luc activity by more than 95% (P < 0.001). At the level of second messenger signaling, insulin did not potentiate LH-enhanced cAMP accumulation, whereas a stable cAMP analog mimicked LH action and augmented insulin's stimulation of full-length and deletional fragments of CYP17/luc. In summary, LH and insulin stimulate transcriptional activity of a -976/+31 bp 5'-upstream cis-acting region of the (porcine) CYP17 gene individually and jointly in primary cultures of theca cells. Maximal transcriptional responsiveness to these peptide hormones requires proximal Sp1 and AP-2-like sequences -193 to -180 bp 5' upstream of the transcriptional start site. Exogenous cAMP mimics transcriptional upregulation by LH and interacts analogously with insulin. These data are consistent with convergent drive of CYP17 gene expression by cAMP-protein kinase A and insulin-signaling pathways in untransformed theca cells. C1 Mayo Clin & Mayo Grad Sch Med, Gen Clin Res Ctr, Dept Internal Med,Endocrine Res Unit, Div Endocrinol & Metab, Rochester, MN 55905 USA. Univ Virginia, Sch Med, NIH,Specialized Cooperat Ctr Reprod Res, Dept Internal Med,Div Endocrinol, Charlottesville, VA 22908 USA. RP Veldhuis, JD (reprint author), Mayo Clin & Mayo Grad Sch Med, Gen Clin Res Ctr, Dept Internal Med,Endocrine Res Unit, Div Endocrinol & Metab, Rochester, MN 55905 USA. EM veldhuis.johannes@mayo.edu FU NICHD NIH HHS [R01-HD-16393, U54-HD-28934] NR 26 TC 9 Z9 9 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD JUN PY 2004 VL 145 IS 6 BP 2760 EP 2766 DI 10.1210/en.2003.1545 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 823UR UT WOS:000221639300028 PM 15001547 ER PT J AU Nyska, A Jokinen, MP Brix, AE Sells, DM Wyde, ME Orzech, D Haseman, JK Flake, G Walker, NJ AF Nyska, A Jokinen, MP Brix, AE Sells, DM Wyde, ME Orzech, D Haseman, JK Flake, G Walker, NJ TI Exocrine pancreatic pathology in female harlan Sprague-Dawley rats after chronic treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin and dioxin-like compounds SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE carcinogenesis; dioxin; furans; inflammation; pancreas; polychlorinated biphenyls ID ACINAR CELL-CARCINOMA; CCK-A RECEPTOR; PROLIFERATIVE LESIONS; METABOLIZING-ENZYMES; TCDD ALTERS; CANCER; CARCINOGENESIS; CHOLECYSTOKININ; EXPRESSION; MORTALITY AB We evaluated the effect of chronic exposure to dioxin and dioxin-like compounds on the pancreas in female Harlan Sprague-Dawley rats. This investigation represents part of an ongoing National Toxicology, Program initiative to determine the relative potency of chronic toxicity and carcinogenicity of polychlorinated dioxins, furans, and biphenyls. Animals were treated by gavage for up to 2 years with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3',4,4',5-pentachlorobiphenyl (PCB-126), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), or a toxic-equivalency-factor (TEF) mixture of these agents; control animals received corn oil-acetone vehicle alone. A complete necropsy was performed on all animals, and a full complement of tissues was collected and examined microscopically. Administration of each of the four compounds was associated with increased incidences of several nonneoplastic changes in the exocrine pancreas, including cytoplasmic vacuolation, chronic active inflammation, atrophy, and arteritis. Low incidences, but higher than those in the historical database, of pancreatic acinar adenoma and carcinoma were seen in the TCDD, PeCDF, and TEF-mixture groups. These results indicate that the pancreatic acini are target tissues for dioxin and certain dioxin-like compounds. C1 NIEHS, Lab Expt Pathol, Natl Inst Hlth, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. A Charles River Co, Pathol Assoc, Durham, NC USA. Expt Pathol Labs, Res Triangle Pk, NC USA. Battelle Columbus Labs, Columbus, OH USA. Natl Inst Environm Hlth Sci, Toxicol Operat Branch, Res Triangle Pk, NC USA. Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC USA. Natl Inst Environm Hlth Sci, Lab Computat Biol & Risk Anal, Natl Inst Hlth, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. RP Nyska, A (reprint author), NIEHS, Lab Expt Pathol, Natl Inst Hlth, Dept Hlth & Human Serv, MD B3-06,POB 12233, Res Triangle Pk, NC 27709 USA. EM nyska@niehs.nih.gov RI Walker, Nigel/D-6583-2012 OI Walker, Nigel/0000-0002-9111-6855 NR 56 TC 15 Z9 15 U1 0 U2 2 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 2004 VL 112 IS 8 BP 903 EP 909 DI 10.1289/ehp.6869 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 829BO UT WOS:000222018200041 PM 15175180 ER PT J AU Burkhart, J AF Burkhart, J TI Reviews of environmental health, 2004 SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Burkhart, J (reprint author), NIEHS, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 2004 VL 112 IS 9 BP 943 EP 943 DI 10.1289/ehp.04112943 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 833DE UT WOS:000222315800001 ER PT J AU Kamel, F Hoppin, JA AF Kamel, F Hoppin, JA TI Association of pesticide exposure with neurologic dysfunction and disease SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review DE fumigant; fungicide; insecticide; neurobehavioral performance; neurodegenerative disease; neurologic symptoms; organophosphate; Parkinson disease; pesticide ID ENVIRONMENTAL RISK-FACTORS; MOTOR-NEURON-DISEASE; LONG-TERM EXPOSURE; AMYOTROPHIC-LATERAL-SCLEROSIS; KENYAN AGRICULTURAL-WORKERS; PERIPHERAL-NERVE FUNCTION; LOW-LEVEL EXPOSURE; PARKINSONS-DISEASE; ORGANOPHOSPHATE PESTICIDES; FARM-WORKERS AB Poisoning by acute high-level exposure to certain pesticides has well-known neurotoxic effects, but whether chronic exposure to moderate levels of pesticides is also neurotoxic is more controversial. Most studies of moderate pesticide exposure have found increased prevalence of neurologic symptoms and changes in neurobehavioral performance, reflecting cognitive and psychomotor dysfunction. There is less evidence that moderate exposure is related to deficits in sensory or motor function or peripheral nerve conduction, but fewer studies have considered these outcomes. It is possible that the most sensitive manifestation of pesticide neurotoxicity is a general malaise lacking in specificity and related to mild cognitive dysfunction, similar to that described for Gulf War syndrome. Most studies have focused on organophosphate insecticides, but some found neurotoxic effects from other pesticides, including fungicides, fumigants, and organochlorine and carbamate insecticides. Pesticide exposure may also be associated with increased risk of Parkinson disease; several classes of pesticides, including insecticides, herbicides, and fungicides, have been implicated. Studies of other neurodegenerative diseases are limited and inconclusive. Future studies will need to improve assessment of pesticide exposure in individuals and consider the role of genetic susceptibility. More studies of pesticides other than organophosphates are needed. Major unresolved issues include the relative importance of acute and chronic exposure, the effect of moderate exposure in the absence of poisoning, and the relationship of pesticide-related neurotoxicity to neurodegenerative disease. C1 NIEHS, Epidemiol Branch, Natl Inst Hlth, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Kamel, F (reprint author), NIEHS, Epidemiol Branch, Natl Inst Hlth, Dept Hlth & Human Serv, MD A3-05,Box 12233, Res Triangle Pk, NC 27709 USA. EM kamel@niehs.nih.gov OI Kamel, Freya/0000-0001-5052-6615 NR 129 TC 249 Z9 264 U1 4 U2 50 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 2004 VL 112 IS 9 BP 950 EP 958 DI 10.1289/ehp.7135 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 833DE UT WOS:000222315800003 PM 15198914 ER PT J AU Nuckols, JR Ward, MH Jarup, L AF Nuckols, JR Ward, MH Jarup, L TI Using geographic information systems for exposure assessment in environmental epidemiology studies SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE enviromental epidemiology; exposure assessment; geographic information systems ID AGRICULTURAL PESTICIDE USE; CANCER INCIDENCE RATES; WASTE LANDFILL SITES; CHILDHOOD-CANCER; AIR-POLLUTION; CONGENITAL-ANOMALIES; RELATIVE RISK; BIRTH-WEIGHT; HEALTH; CALIFORNIA AB Geographic information systems (GIS) are being used with increasing frequency in environmental epidemiology studies. Reported applications include locating the study population by geocoding addresses (assigning mapping coordinates), using proximity analysis of contaminant source as a surrogate for exposure, and integrating environmental monitoring data into the analysis of the health outcomes. Although most of these studies have been ecologic in design, some have used GIS in estimating environmental levels of a contaminant at the individual level and to design exposure metrics for use in epidemiologic studies. In this article we discuss fundamentals of three scientific disciplines instrumental to using GIS in exposure assessment for epidemiologic studies: geospatial science, environmental science, and epidemiology. We also explore how a GIS can be used to accomplish several steps in the exposure assessment process. These steps include defining the study population, identifying source and potential routes of exposure, estimating environmental levels of target contaminants, and estimating personal exposures. We present and discuss examples for the first three steps. We discuss potential use of GIS and global positioning systems (GPS) in the last step. On the basis of our findings, we conclude that the use of GIS in exposure assessment for environmental epidemiology studies is not only feasible but can enhance the understanding of the association between contaminants in our environment and disease. C1 Colorado State Univ, Dept Environm & Radiol Hlth Sci, Ft Collins, CO 80523 USA. Natl Canc Inst, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Natl Inst Hlth,Dett Hlth & Human Serv, Bethesda, MD USA. Univ London Imperial Coll Sci Technol & Med, Small Area Hlth Stat Unit, Dept Epidemiol & Publ Hlth, London, England. RP Nuckols, JR (reprint author), Colorado State Univ, Dept Environm & Radiol Hlth Sci, Ft Collins, CO 80523 USA. EM jnuckols@colostate.edu RI Mavoa, Suzanne/B-5372-2010 NR 63 TC 143 Z9 149 U1 9 U2 62 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 2004 VL 112 IS 9 BP 1007 EP 1015 DI 10.1289/ehp.6738 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 833DE UT WOS:000222315800010 PM 15198921 ER PT J AU Melnick, RL Huff, J AF Melnick, RL Huff, J TI Testing toxic pesticides in humans: Health risks with no health benefits SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Letter ID INDUSTRY C1 Natl Inst Environm Hlth Sci, Natl Inst Hlth, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. RP Melnick, RL (reprint author), Natl Inst Environm Hlth Sci, Natl Inst Hlth, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. EM melnickr@nichs.nih.gov NR 10 TC 7 Z9 7 U1 0 U2 3 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 2004 VL 112 IS 8 BP A459 EP A461 PG 3 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 829BO UT WOS:000222018200005 PM 15175190 ER PT J AU Tyson, FL Rice, DL Dearry, A AF Tyson, FL Rice, DL Dearry, A TI Connecting the oceans and human health SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 NIEHS, Natl Inst Hlth, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. Natl Sci Fdn, Chem Oceanog Program, Div Ocean Sci, Arlington, VA 22230 USA. RP Tyson, FL (reprint author), NIEHS, Natl Inst Hlth, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM tyson2@niehs.nih.gov NR 8 TC 7 Z9 7 U1 2 U2 2 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUN PY 2004 VL 112 IS 8 BP A455 EP A456 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 829BO UT WOS:000222018200002 PM 15175187 ER PT J AU Galperin, MY AF Galperin, MY TI Metagenomics: from acid mine to shining sea SO ENVIRONMENTAL MICROBIOLOGY LA English DT Editorial Material ID GENOME SEQUENCE; REVEALS C1 Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Galperin, MY (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM galperin@ncbi.nlm.nih.gov RI Galperin, Michael/B-5859-2013 OI Galperin, Michael/0000-0002-2265-5572 NR 14 TC 17 Z9 20 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 1462-2912 J9 ENVIRON MICROBIOL JI Environ. Microbiol. PD JUN PY 2004 VL 6 IS 6 BP 543 EP 545 DI 10.1111/j.1462-2920.2004.00652.x PG 3 WC Microbiology SC Microbiology GA 819FE UT WOS:000221299200001 PM 15142241 ER PT J AU Galperin, MY AF Galperin, MY TI Bacterial signal transduction network in a genomic perspective SO ENVIRONMENTAL MICROBIOLOGY LA English DT Review ID PERIPHERAL BENZODIAZEPINE-RECEPTOR; SENSOR KINASE KDPD; SP STRAIN PCC-7120; ESCHERICHIA-COLI; BINDING DOMAIN; ACETOBACTER-XYLINUM; PROTEIN-KINASES; TRANSMEMBRANE RECEPTORS; GENETIC ORGANIZATION; TRANSCRIPTION FACTOR AB Bacterial signalling network includes an array of numerous interacting components that monitor environmental and intracellular parameters and effect cellular response to changes in these parameters. The complexity of bacterial signalling systems makes comparative genome analysis a particularly valuable tool for their studies. Comparative studies revealed certain general trends in the organization of diverse signalling systems. These include (i) modular structure of signalling proteins; (ii) common organization of signalling components with the flow of information from N-terminal sensory domains to the C-terminal transmitter or signal output domains (N-to-C flow); (iii) use of common conserved sensory domains by different membrane receptors; (iv) ability of some organisms to respond to one environmental signal by activating several regulatory circuits; (v) abundance of intracellular signalling proteins, typically consisting of a PAS or GAF sensor domains and various output domains; (vi) importance of secondary messengers, cAMP and cyclic diguanylate; and (vii) crosstalk between components of different signalling pathways. Experimental characterization of the novel domains and domain combinations would be needed for achieving a better understanding of the mechanisms of signalling response and the intracellular hierarchy of different signalling pathways. C1 Natl Lib Med, Natl Ctr Biotechnol Informay, NIH, Bethesda, MD 20894 USA. RP Galperin, MY (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informay, NIH, Bethesda, MD 20894 USA. EM galperin@ncbi.nlm.nih.gov RI Galperin, Michael/B-5859-2013 OI Galperin, Michael/0000-0002-2265-5572 FU NLM NIH HHS [Z01 LM000073-10] NR 99 TC 214 Z9 225 U1 1 U2 23 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 1462-2912 J9 ENVIRON MICROBIOL JI Environ. Microbiol. PD JUN PY 2004 VL 6 IS 6 BP 552 EP 567 DI 10.1111/j.1462-2920.2004.00633.x PG 16 WC Microbiology SC Microbiology GA 819FE UT WOS:000221299200003 PM 15142243 ER PT J AU Jarosinska, D Peddada, S Rogan, WJ AF Jarosinska, D Peddada, S Rogan, WJ TI Assessment of lead exposure and associated risk factors in urban children in Silesia, Poland SO ENVIRONMENTAL RESEARCH LA English DT Article DE blood lead level; urban children; risk factors; season; airborne lead ID BLOOD LEAD; ENVIRONMENTAL LEAD; EASTERN GERMANY; US POPULATION; AMBIENT AIR; PETROL LEAD; HOUSE-DUST; SOIL; HEALTH; INTELLIGENCE AB A program of childhood lead poisoning prevention was conducted in six cities of Silesia, the most industrialized region of Poland. We analyzed records of 11,877 children aged 24-84 months, tested between 1993 and 1998, to assess children's exposure to lead and associations of blood lead levels (BLL) with season of sampling, questionnaire data, and environmental levels of lead. Air lead concentrations and lead fallout, as measured in the ambient air monitoring system, were below current Polish air quality standards and gradually decreased. The geometric mean (GM) BLL was 6.3 mug/dL (range from 0.6 to 48 mug/dL), and > 13% of children had BLL greater than or equal to 1 0 mug/dL. Mean BLL declined from 6.8 mug/dL in 1993-1994 to almost 5.5 mug/dL in 1998: GM BLL in spring and summer ('nonheating' season) months were 10% higher than BLL in children tested in fall and winter ('heating' season), although air lead concentrations were lower in nonheating and higher in the heating season. For both the heating and nonheating seasons, there was a significant increase in the mean BLL with increasing air lead concentrations. Poor housing (odds ratio (OR): 1.82; 95% CI: 1.4, 2.3), two or more siblings in the family (OR: 3.12; 95% CI: 2.6, 3.7), lack of recreational trips outside the region (OR: 1.66; 95% CI: 1.47, 1.89), and the time child spent outdoors were associated with elevated BLL. Variables found to affect BLL in the Silesian children should be used to propose criteria to improve identification of children at risk and to focus prevention activities more effectively. (C) 2003 Elsevier Inc. All rights reserved. C1 Inst Occupat Med & Environm Hlth, PL-41200 Sosnowiec, Poland. NIEHS, Res Triangle Pk, NC 27709 USA. RP Jarosinska, D (reprint author), Inst Occupat Med & Environm Hlth, 13 Koscielna, PL-41200 Sosnowiec, Poland. EM d-jarosinska@imp.sosnowiec.pl RI Peddada, Shyamal/D-1278-2012; Rogan, Walter/I-6034-2012 OI Rogan, Walter/0000-0002-9302-0160 NR 61 TC 33 Z9 37 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 J9 ENVIRON RES JI Environ. Res. PD JUN PY 2004 VL 95 IS 2 BP 133 EP 142 DI 10.1016/S0013-9351(03)00139-7 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 825SY UT WOS:000221779800003 PM 15147918 ER PT J AU Pendrak, ML Yan, SS Roberts, DD AF Pendrak, ML Yan, SS Roberts, DD TI Hemoglobin regulates expression of an activator of mating-type locus alpha genes in Candida albicans SO EUKARYOTIC CELL LA English DT Article ID MULTIPLE SEQUENCE ALIGNMENT; WHITE-OPAQUE TRANSITION; SACCHAROMYCES-CEREVISIAE; MOLECULAR-GENETICS; SWITCHING-SYSTEM; HEME OXYGENASE; CELL-WALL; YEAST; FIBRONECTIN; PROTEIN AB Phenotypic switching from the white to the opaque phase is a necessary step for mating in the pathogenic fungus Candida albicans. Suppressing switching during vascular dissemination of the organism may be advantageous, because opaque cells are more susceptible to host defenses. A repressor of white-opaque switching, HBR1 (hemoglobin response gene 1), was identified based on its specific induction following growth in the presence of exogenous hemoglobin. Deletion of a single HBR1 allele allowed opaque phase switching and mating competence, accompanied by a lack of detectable MTL alpha1 and alpha2 gene expression and enhanced MTLa1 gene expression. Conversely, overexpression of Hbr1p or exposure to hemoglobin increased MTLalpha gene expression. The a1/alpha2 repressed target gene CAG1 was derepressed in the same mutant in a hemoglobin-sensitive manner. Regulation of CAG1 by hemoglobin required an intact MTLa1 gene. Several additional Mt1p targets were perturbed in HBR1 mutants in a manner consistent with commitment to an a mating phenotype, including YEL007w, MFalpha, HST6, and RAM2. Therefore, Hbr1 is part of a host factor-regulated signaling pathway that controls white-opaque switching and mating in the absence of allelic deletion at the MTL locus. C1 NCI, Pathol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP NCI, Pathol Lab, Canc Res Ctr, NIH, 10 Ctr Dr,MSC 1500,Bldg 10,Room 2A33, Bethesda, MD 20892 USA. EM droberts@helix.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 NR 65 TC 26 Z9 41 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1535-9778 EI 1535-9786 J9 EUKARYOT CELL JI Eukaryot. Cell PD JUN PY 2004 VL 3 IS 3 BP 764 EP 775 DI 10.1128/EC.3.3.764-775.2004 PG 12 WC Microbiology; Mycology SC Microbiology; Mycology GA 829UP UT WOS:000222076000019 PM 15189997 ER PT J AU Christov, KT Moon, RC Lantvit, DD Boone, CW Kelloff, GJ Steele, VE Lubet, RA Pezzuto, JM AF Christov, KT Moon, RC Lantvit, DD Boone, CW Kelloff, GJ Steele, VE Lubet, RA Pezzuto, JM TI Prostate intraepithelial neoplasia in Noble rats, a potential intermediate endpoint for chemoprevention studies SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE prostate carcinogenesis; PIN; noble rats; chemoprevention ID METHYL-N-NITROSOUREA; LOBUND-WISTAR RATS; TESTOSTERONE PROPIONATE; SEQUENTIAL TREATMENT; CYPROTERONE-ACETATE; MAMMARY-GLAND; BREAST-CANCER; DEHYDROEPIANDROSTERONE; CARCINOGENESIS; INHIBITION AB In most prostate chemoprevention studies conducted with animal models, the incidence and multiplicity of tumours have been used as endpoints for efficacy. However, the latency of tumours is usually over 1 year, making these studies costly and time consuming. The main purpose of this study was to assess the utility of prostate intraepithelial neoplasia (PIN), induced in Noble rats by continuous testosterone + oestradiol (T + E) administration, as a potential intermediate endpoint biomarker of efficacy in chemoprevention studies. Noble rats at the age of 12 weeks were treated for 36 weeks with T + E given subcutaneously via Silastic capsules. The incidence and multiplicity of PIN were assessed in various prostate glands by serial sections generated at three separate tissue levels. The efficacy of dehydroepiandrosterone (DHEA) and DHEA 8354 (1000 and 2000 mg/kg diet), difluoromethylornithine (DFMO) (1000 and 2000 mg/kg diet) and oltipraz (125 and 250 mg/kg diet) to inhibit PIN was assessed in two independent sets of experiments. T + E induced multiple PIN in the dorsolateral prostate (DLP) of 80-100%, of the animals. DHEA and DHEA 8354 did not affect the incidence but decreased the multiplicity of PIN in the DLP, from 3.2 +/- 1.0 in control group to 1.5 +/- 1.0 in the low-dose and to 1.6 +/- 0.6 in the high-dose group for DHEA (P < 0.05 and P < 0.02, respectively), and to 1.9 +/- 0.8 in the high-dose (P < 0.05) DHEA 8354. Both agents did not affect PIN in anterior prostate, seminal vesicles or ventral prostate. In a second experiment, DFMO and oltipraz were found not effective in inhibiting PIN. In this study, we provide new evidence that PIN in Noble rats, induced by continuous T + E treatment, is a useful intermediate endpoint for determining the efficacy of DHEA and other potential chemopreventive agents. The hormonal pathogenesis, high multiplicity, short latency, preferential location in the DLP, similarity in morphology and biology to PIN of human prostate, and the sensitivity to agents that suppress prostate carcinogenesis, makes PIN in Noble rats a promising intermediate endpoint for chemoprevention studies. (C) 2004 Elsevier Ltd. All rights reserved. C1 Univ Illinois, Dept Surg Oncol Labs, Chicago, IL 60612 USA. Univ Illinois, Coll Pharm, Chicago, IL USA. NCI, Bethesda, MD 20892 USA. Purdue Univ, Coll Pharm, Lafayette, IN USA. RP Christov, KT (reprint author), Univ Illinois, Dept Surg Oncol Labs, 840 S Wood Str,MC 820, Chicago, IL 60612 USA. EM christov@uic.edu FU NCI NIH HHS [CA-25492] NR 33 TC 8 Z9 8 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUN PY 2004 VL 40 IS 9 BP 1404 EP 1411 DI 10.1016/j.ejca.2003.11.037 PG 8 WC Oncology SC Oncology GA 834GF UT WOS:000222398900024 PM 15177500 ER PT J AU Mathew, A Sinha, R Burt, R Caan, B Paskett, E Iber, F Kikendall, W Lance, P Shike, M Weissfeld, J Schatzkin, A Lanza, E AF Mathew, A Sinha, R Burt, R Caan, B Paskett, E Iber, F Kikendall, W Lance, P Shike, M Weissfeld, J Schatzkin, A Lanza, E CA Polyp Prevention Study Grp TI Meat intake and the recurrence of colorectal adenomas SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Article DE recurrent colorectal adenomas; red meat; white meat ID COLON-CANCER; PROSPECTIVE COHORT; UNITED-STATES; RISK; CONSUMPTION; WOMEN; FIBER; FAT; DIET; MEN AB A large multicenter randomized controlled trial was reassessed to check whether meat intake and a reduction in its consumption are associated with recurrence of adenomatous polyps of the large bowel, which are precursors of most colorectal malignancies. All subjects (n = 1905; 958 interventions and 947 controls) had one or more histologically confirmed colorectal adenomas removed during a colonoscopy within 6 months before randomization. The subjects were followed-up for approximately 4 years after randomization and a colonoscopy for detecting adenomas was conducted at the 1st and 4th year after randomization. Dietary variables were assessed at baseline (TO) and in conjunction with annual visits at the end of the 1st (T1), 2nd (T2), 3rd (T3) and 4th (T4) years. Odds ratios using logistic regression models for meat variables were estimated based on the average intake at TO, T1, T2, T3 and T4 (prior to the T4 colonoscopy) as well as change (T0-T4) in intake. In the intervention group, the total reduction in median intake of red meat from TO to T4 was observed by the end of 1st year itself (30 and 31% for men and women, respectively). The analysis provide no evidence to suggest that lower intake or reduction in total and in red meat consumption during a period of 4 years reduces the risk of adenoma recurrence (including multiple or advanced adenoma), whereas the data suggest that high intake of fish is associated with lower risk of adenoma recurrence. (C) 2004 Lippincott Williams Wilkins. C1 Reg Canc Ctr, Div Epidemiol & Clin Res, Nutrit Epidemiol Branch, Trivandrum 695011, Kerala, India. Univ Utah, Salt Lake City, UT 84112 USA. Kaiser Fdn Res Inst, Oakland, CA USA. Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Vet Affairs Med Ctr, Hines, IL 60141 USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. SUNY Buffalo, Sch Med & Biomed Sci, Buffalo, NY 14260 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. NCI, Canc Prevent Studies Branch, Bethesda, MD 20892 USA. RP Mathew, A (reprint author), Reg Canc Ctr, Div Epidemiol & Clin Res, Nutrit Epidemiol Branch, Trivandrum 695011, Kerala, India. EM amathew@rcctvm.org RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 NR 22 TC 15 Z9 16 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-8278 J9 EUR J CANCER PREV JI Eur. J. Cancer Prev. PD JUN PY 2004 VL 13 IS 3 BP 159 EP 164 DI 10.1097/cej.0000130022.23806.7b PG 6 WC Oncology SC Oncology GA 830EA UT WOS:000222103200002 PM 15167213 ER PT J AU Haider, AW Roubenoff, R Wilson, PWF Levy, D D'Agostino, R Silbershatz, H O'Donnell, CI AF Haider, AW Roubenoff, R Wilson, PWF Levy, D D'Agostino, R Silbershatz, H O'Donnell, CI TI Monocyte cytokine production, systemic inflammation and cardiovascular disease in very elderly men and women: The Framingham Heart Study SO EUROPEAN JOURNAL OF CARDIOVASCULAR PREVENTION & REHABILITATION LA English DT Article DE monocyte cytokine; systemic inflammation; cardiovascular disease ID RISK; MECHANISMS AB In very elderly participants of the Framingham Heart Study (mean age 79 years, 276 men and 462 women), interleukin-6 correlated with C-reactive protein (CRP) levels. Interleukin-6, tumour necrosis factor alpha and interieukin-1 production, and CRP were not associated with prevalent cardiovascular disease, and nonsteroidal anti-inflammatory drug use did not influence cytokine or CRP levels. Further studies are warranted to examine the prognostic implications of CRP and related cytokines for CVD in the elderly. (C) 2004 The European Society of Cardiology. C1 NHLBI, Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. Boston Univ, Sch Med, Prevent Med & Epidemiol Sect, Boston, MA 02215 USA. Drexel Univ, Coll Med, Div Cardiol, Dept Med, Philadelphia, PA 19104 USA. Tufts Univ, Jean Mayer USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Cardiol Div, Boston, MA 02115 USA. RP O'Donnell, CI (reprint author), NHLBI, Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM Chris@fram.nhlbi.nih.gov NR 7 TC 4 Z9 4 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1741-8267 J9 EUR J CARDIOV PREV R JI Eur. J. Cardiovasc. Prev. Rehabil. PD JUN PY 2004 VL 11 IS 3 BP 214 EP 215 DI 10.1097/01.hjr.0000124212.21584.3c PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 834DP UT WOS:000222392100006 PM 15179102 ER PT J AU Zhu, GS Bartsch, O Skrypnyk, C Rotondo, A Akhtar, LA Harris, C Virkkunen, M Cassano, G Goldman, D AF Zhu, GS Bartsch, O Skrypnyk, C Rotondo, A Akhtar, LA Harris, C Virkkunen, M Cassano, G Goldman, D TI Failure to detect DUP25 in lymphoblastoid cells derived from patients with panic disorder and control individuals representing European and American populations SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE chromosomal duplication; panic disorder; fluorescence in situ hybridization; real-time PCR ID FISH; PCR AB Investigation of the co-occurrence of panic and phobic disorders with joint laxity led to the identification of interstitial duplications involving human chromosome 15q24 - 26 ( named 'DUP25') in a Spanish population. DUP25 was observed in 97% of patients and in 7% of control individuals. In the present study, we used two different methods to detect DUP25: high-throughput molecular gene dosage analysis and fluorescence in situ hybridization ( FISH). We evaluated 56 lymphoblastoid cell lines derived from 26 unrelated patients with panic disorder obtained from several European and American populations and 30 normal controls. We could not find any cell line showing a result consistent with DUP25. These data do not support any association of DUP25 with panic disorder. C1 NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Changhai Hosp, Shanghai 200433, Peoples R China. Dresden Univ Technol, Inst Clin Genet, D-01307 Dresden, Germany. Univ Oradea, Dept Genet, Oradea 3700, Romania. Univ Pisa, Dept Psychiat, I-56100 Pisa, Italy. Univ Helsinki, Dept Psychiat, SF-00180 Helsinki, Finland. RP Goldman, D (reprint author), NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM dgneuro@box-d.nih.gov RI Goldman, David/F-9772-2010; OI Goldman, David/0000-0002-1724-5405; SKRYPNYK, CRISTINA/0000-0003-3469-1973 NR 6 TC 13 Z9 13 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD JUN PY 2004 VL 12 IS 6 BP 505 EP 508 DI 10.1038/sj.ejhg.5201181 PG 4 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 823VE UT WOS:000221640700013 PM 15054397 ER PT J AU Oleksyk, TK Goldfarb, LG Sivtseva, T Danilova, AP Osakovsky, VL Shrestha, S O'Brien, SJ Smith, MW AF Oleksyk, TK Goldfarb, LG Sivtseva, T Danilova, AP Osakovsky, VL Shrestha, S O'Brien, SJ Smith, MW TI Evaluating association and transmission of eight inflammatory genes with Viliuisk encephalomyelitis susceptibility SO EUROPEAN JOURNAL OF IMMUNOGENETICS LA English DT Article ID COMBINED TRANSMISSION/DISEQUILIBRIUM TEST; AIDS PROGRESSION; DISEASE; RECONSTRUCTION; CHEMOKINES; INTERLEUKIN-10; POLYMORPHISMS; PATHWAYS; RECEPTOR; SIBERIA AB Since the discovery of Viliuisk encephalomyelitis (VE) in 1887, scientists have tried to understand the natural history and aetiology of this endemic neurological disorder among the native Sakha population of Central Siberia. Familial aggregation and segregation analysis suggested a genetic influence on VE incidence. However, recent studies have implicated an unknown virus, possibly from the alpha herpesvirus family, as a possible cause for this disease. As VE is a neurological disease characterized by the inflammatory reactions systematically observed in the spinocerebellar fluid and in the brain tissue of deceased patients, we examined 17 single nucleotide polymorphisms (SNPs) across seven inflammation-related candidate gene regions, including chemokine receptors type 2 and 5 (CCR2/CCR5), interferon-gamma (IFN-gamma), interleukin-4 (IL-4), IL-6, IL-10, stromal cell-derived factor (SDF) and chemokine regulated upon activation, normal T-cell expressed and presumably secreted (RANTES). Our main objective was to analyse the degree of genetic association between VE and candidate genes that have been previously implicated in other inflammatory diseases. Samples were collected from 83 affected families comprising 88 verified VE cases, 156 family members, and an additional 69 unrelated, unaffected inhabitants of the same geographical area. This collection included substantially all of the cases that are currently on the VE Registry. The experimental design included both case-control and transmission/disequilibrium test (TDT)-based familial association analyses. None of 17 SNPs analysed was significantly associated with VE occurrence. Exclusion of these eight genes based on the lack of association has important implications for identifying the disease agent, as well as prescribing therapy and understanding Viliuisk encephalomyelitis. C1 NCI, Lab Genom Divers, NIH, Ft Detrick, MD 21702 USA. NINDS, Clin Neurogenet Unit, NIH, Bethesda, MD 20892 USA. Natl Acad Sci, Inst Hlth, Yakutsk, Russia. SAIC Frederick Inc, Basic Res Program, NCI, NIH, Frederick, MD USA. RP Smith, MW (reprint author), NCI, Lab Genom Divers, NIH, Bldg 560,Rm 21-74, Ft Detrick, MD 21702 USA. EM smithm@ncifcrf.gov RI Smith, Michael/B-5341-2012; Taras, Oleksyk/J-8805-2013 OI Taras, Oleksyk/0000-0002-8148-3918 FU NCI NIH HHS [N01-CO-12400] NR 45 TC 3 Z9 3 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0960-7420 J9 EUR J IMMUNOGENET JI Eur. J. Immunogenet. PD JUN PY 2004 VL 31 IS 3 BP 121 EP 128 DI 10.1111/j.1365-2370.2004.00459.x PG 8 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 833AN UT WOS:000222308900003 PM 15182325 ER PT J AU Depboylu, C Reinhart, TA Takikawa, O Imai, Y Maeda, H Mitsuya, H Rausch, D Eiden, LE Weihe, E AF Depboylu, C Reinhart, TA Takikawa, O Imai, Y Maeda, H Mitsuya, H Rausch, D Eiden, LE Weihe, E TI Brain virus burden and indoleamine-2,3-dioxygenase expression during lentiviral infection of rhesus monkey are concomitantly lowered by 6-chloro-2 ',3 '-dideoxyguanosine SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article; Proceedings Paper CT 4th International Symposium of Neurovirology/10th Conference on Neuroscience of HIV Infection CY JUN 18-22, 2002 CL DUSSELDORF, GERMANY DE antiretroviral; kynurenine pathway; microglia/ macrophage; neuroinflammation; quinolinic acid ID SIMIAN IMMUNODEFICIENCY VIRUS; INDOLEAMINE 2,3-DIOXYGENASE EXPRESSION; ACTIVE ANTIRETROVIRAL THERAPY; NEUROTOXIN QUINOLINIC ACID; IMMUNE-DEFICIENCY-SYNDROME; NITRIC-OXIDE SYNTHASE; INTERFERON-GAMMA; CEREBROSPINAL-FLUID; HIV-1-ASSOCIATED DEMENTIA; NERVOUS-SYSTEM AB Increased kynurenine pathway metabolism has been implicated in the aetiology of lentiviral encephalopathy. Indoleamine-2,3-dioxygenase (IDO) initiates the increased production of kynurenine pathway metabolites like quinolinic acid (QUIN). QUIN itself is elevated in AIDS-diseased monkey and human brain parenchyma and cerebrospinal fluid at levels excitotoxic for neurons in vitro. This study investigates the cellular origin of IDO biosynthesis in the brain of rhesus monkeys infected with simian immunodeficiency virus (SIV) and explores the effects of CNS-permeant antiretroviral treatment. IDO transcript and protein were absent from the brain of non-infected and SIV-infected asymptomatic monkeys. IDO biosynthesis was induced in the brain of monkeys exhibiting AIDS. Nodule and multinucleated giant cell-forming macrophages were the main sources of IDO synthesis. Treatment with the lipophilic 6-chloro-2',3'-dideoxyguanosine suppressed IDO expression in the brain of AIDS-diseased monkeys. The effectiveness of this treatment was confirmed by the reduction of virus burden and SIV-induced perivascular infiltrates, mononuclear nodules and multinucleated giant cells. Our data demonstrate that brain IDO biosynthesis is induced in a subset of monocyte-derived cells, depends on viral burden and is susceptible to antiretroviral treatment. Thus, IDO induction is associated with reversible overt inflammatory events localized to areas of active viral replication in the SIV-infected brain. C1 Univ Marburg, Inst Anat & Cell Biol, Dept Mol Neurosci, Marburg, Germany. Univ Marburg, Dept Neurol, Marburg, Germany. Univ Pittsburgh, Dept Infect Dis & Microbiol, Pittsburgh, PA USA. Hokkaido Univ, Sch Med, Cent Res Inst, Dept Mol Biochem, Sapporo, Hokkaido 060, Japan. Natl Inst Neurosci, Dept Neurochem, Tokyo, Japan. NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, Ctr Clin Res,NIH, Bethesda, MD 20892 USA. NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. RP Weihe, E (reprint author), Univ Marburg, Inst Anat & Cell Biol, Dept Mol Neurosci, Marburg, Germany. EM weihe@staff.uni-marburg.de OI Eiden, Lee/0000-0001-7524-944X NR 52 TC 21 Z9 21 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD JUN PY 2004 VL 19 IS 11 BP 2997 EP 3005 DI 10.1111/j.1460-9568.2004.03404.x PG 9 WC Neurosciences SC Neurosciences & Neurology GA 825WP UT WOS:000221789800010 PM 15182307 ER PT J AU Erdely, HA Lahti, RA Lopez, MB Myers, CS Roberts, RC Tamminga, CA Vogel, MW AF Erdely, HA Lahti, RA Lopez, MB Myers, CS Roberts, RC Tamminga, CA Vogel, MW TI Regional expression of RGS4 mRNA in human brain SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE G-protein; in situ hybridization; regional distribution; regulator of G-protein signalling ID RAT-BRAIN; REGULATORS; PROTEINS; AMPHETAMINE; RECEPTORS; STRIATUM; DISEASE AB Regulators of G-protein signalling (RGS) proteins are a recently discovered class of proteins that modulate G-protein activity. More than 20 RGS proteins have been identified and are expressed throughout the body and brain. In particular, RGS4 appears to regulate dopamine receptor function and has been implicated in several dopamine related diseases, including schizophrenia. This study presents an extensive examination of the regional distribution of RGS4 mRNA in postmortem human brain. Using in situ hybridization, the expression levels of RGS4 mRNA were determined in human hemicoronal (Talairach sections +8 and -20) brain sections. In the rostral slice (Talairach +8) highest levels were found in the inferior frontal cortex, the superior frontal, and the cingulate cortex. Slightly lower levels were found in the insular cortex and inferior temporal cortex. The caudate, putamen and nucleus accumbens had lower levels. In the caudal slice (-20), the cortical layers showed the highest levels, with moderate levels observed in the parahippocampal gyrus, low levels in the CA-pyramidal region, and almost undetectable levels in the thalamus. In the frontal cortex a dense band was apparent near one of the inner layers of the cortex. In conclusion, RGS4 mRNA distribution in human postmortem tissue from normal persons was very dense in most cortical layers examined, with lower density in the basal ganglia and thalamus. C1 Univ Maryland, Sch Med, Dept Pharmacol & Expt Therapeut, Baltimore, MD 21201 USA. Univ Maryland, Maryland Psychiat Res Ctr, Catonsville, MD 21228 USA. NIDA, Clin Pharmacol & Therapeut Branch, Baltimore, MD 21224 USA. Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX 75390 USA. RP Erdely, HA (reprint author), Univ Maryland, Sch Med, Dept Pharmacol & Expt Therapeut, Baltimore, MD 21201 USA. EM herdely@mprc.umaryland.edu OI Vogel, Michael/0000-0002-8402-1495 FU NIMH NIH HHS [MH 60744, MH 067998, MH 62236-01] NR 18 TC 46 Z9 47 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD JUN PY 2004 VL 19 IS 11 BP 3125 EP 3128 DI 10.1111/j.1460-9568.2004.03364.x PG 4 WC Neurosciences SC Neurosciences & Neurology GA 825WP UT WOS:000221789800025 PM 15182322 ER PT J AU Solinas, M Zangen, A Thiriet, N Goldberg, SR AF Solinas, M Zangen, A Thiriet, N Goldberg, SR TI beta-Endorphin elevations in the ventral tegmental area regulate the discriminative effects of Delta-9-tetrahydrocannabinol SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE abuse; cannabis; drug discrimination; microdialysis; opioid; rat THC ID RECEPTOR KNOCKOUT MICE; NUCLEUS-ACCUMBENS; CANNABINOID RECEPTORS; DRUG DISCRIMINATION; OPIOID RECEPTORS; RAT-BRAIN; SQUIRREL-MONKEYS; DOPAMINE; DELTA(9)-TETRAHYDROCANNABINOL; DEPENDENCE AB beta-Endorphin is an endogenous opioid that produces behavioral effects similar to heroin and morphine and is released in the nucleus accumbens by cocaine, amphetamine and ethanol, suggesting a general involvement in the reinforcing effects of abused drugs. Here we show that, in rats, Delta-9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, produces large increases in extracellular levels of beta-endorphin in the ventral tegmental area and lesser increases in the shell of the nucleus accumbens. We then used a two-lever choice THC-discrimination procedure to investigate whether THC-induced changes in endogenous levels of beta-endorphin regulate the discriminative effects of THC. In rats that had learned to discriminate injections of THC from injections of vehicle, the opioid agonist morphine did not produce THC-like discriminative effects but markedly potentiated discrimination of THC. Conversely, the opioid antagonist naloxone reduced the discriminative effects of THC. Bilateral microinjections of beta-endorphin directly into the ventral tegmental area, but not into the shell of the nucleus accumbens, markedly potentiated the discriminative effects of ineffective threshold doses of THC but had no effect when given alone. This potentiation was blocked by naloxone. Together these results indicate that certain psychotropic effects of THC related to drug abuse liability are regulated by THC-induced elevations in extracellular beta-endorphin levels in brain areas involved in opiate reward and reinforcement processes. C1 NIDA, Preclin Pharmacol Sect, Dept Hlth & Human Serv, NIH,IRP, Baltimore, MD 21224 USA. NIDA, Behav Neurosci Sect, Dept Hlth & Human Serv, NIH,IRP, Baltimore, MD 21224 USA. NIDA, Mol Neuropsychiat Sect, Dept Hlth & Human Serv, NIH,IRP, Baltimore, MD 21224 USA. Weizmann Inst Sci, Dept Neurobiol, Rehavot, Israel. Univ Poitiers, CNRS 6558, Poitiers, France. RP Goldberg, SR (reprint author), NIDA, Preclin Pharmacol Sect, Dept Hlth & Human Serv, NIH,IRP, Baltimore, MD 21224 USA. EM sgoldber@intra.nida.nih.gov RI Solinas, Marcello/M-3500-2016 OI Solinas, Marcello/0000-0002-0664-5964 NR 49 TC 50 Z9 52 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD JUN PY 2004 VL 19 IS 12 BP 3183 EP 3192 DI 10.1111/j.1460-9568.2004.03420.x PG 10 WC Neurosciences SC Neurosciences & Neurology GA 832TE UT WOS:000222289300006 PM 15217374 ER PT J AU He, YJ Panyutin, IG Karavanov, A Demidov, VV Neumann, RD AF He, YJ Panyutin, IG Karavanov, A Demidov, VV Neumann, RD TI Sequence-specific DNA strand cleavage by In-111-labeled peptide nucleic acids SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article DE DTPA; In-111; peptide nucleic acids; DNA damage; gene targeting ID TRIPLEX-FORMING OLIGONUCLEOTIDES; AUGER-ELECTRON EMITTERS; DUPLEX DNA; GENE RADIOTHERAPY; MAMMALIAN-CELLS; IN-VIVO; PNA; ANTISENSE; INVASION; BREAKS AB Peptide nucleic acids (PNAs) bind tightly and sequence-specifically to single- and double-stranded nucleic acids, and are hence of interest in the design of gene-targeted radiotherapeutics that could deliver the radiodamage to designated DNA and/or RNA sites. As a first step towards this goal, we developed a procedure for incorporation of Auger electron-emitting radionuclide (indium-111) into PNA oligomers and studied the efficiency of PNA-directed cleavage of single-stranded DNA targets. Accordingly, diethylene triamine penta-acetic acid (DTPA) was conjugated to the lysine-appended mixed-base PNAs and sequence-homologous DNA oligomer with a proper linker for comparative studies. By chelation of PNA-DTPA and DNA-DTPA conjugates with In-111(3+) in acidic aqueous solutions, In-111-labeled PNA and DNA oligomers were obtained. Targeting of single-stranded DNA with PNA-DTPA-[In-111] conjugates yielded highly localized DNA strand cleavage; the distribution of breaks along the target DNA strand has two maxima corresponding to both termini of PNA oligomer. After 10-14 days, the overall yield of breaks thus generated within the PNA-targeted DNA by In-111 decay was 5-7% versus less than or equal to2% in the case of control oligonucleotide DNA-DTPA-[In-111]. The estimated yield of DNA strand breaks per nuclear decay is similar to0.1 for the PNA-directed delivery of In-111, which is three times more than for the DNA-directed delivery of this radionuclide. This in vitro study shows that In-111-labeled PNAs are much more effective than radiolabeled DNA oligonucleotides for site-specific damaging of DNA targets. Accordingly, we believe that PNA oligomers are promising radionuclide delivery tools for future antisense/antigene radiotherapy trials. C1 NIH, Warren G Magnuson Clin Ctr, Dept Nucl Med, Bethesda, MD 20892 USA. Ciphergen BioSyst Inc, Fremont, CA USA. Boston Univ, Ctr Adv Biotechnol, Boston, MA 02215 USA. RP Panyutin, IG (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Nucl Med, Bethesda, MD 20892 USA. EM igorp@helix.nih.gov NR 53 TC 17 Z9 19 U1 2 U2 7 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 1619-7070 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD JUN PY 2004 VL 31 IS 6 BP 837 EP 845 DI 10.1007/s00259-003-1446-0 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 824FP UT WOS:000221671800007 PM 14762696 ER PT J AU Csaky, KG Baffi, JZ Byrnes, GA Wolfe, JD Hilmer, SC Flippin, J Cousins, SW AF Csaky, KG Baffi, JZ Byrnes, GA Wolfe, JD Hilmer, SC Flippin, J Cousins, SW TI Recruitment of marrow-derived endothelial cells to experimental choroidal neovascularization by local expression of vascular endothelial growth factor SO EXPERIMENTAL EYE RESEARCH LA English DT Article; Proceedings Paper CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY MAY 04-09, 2003 CL FT LAUDERDALE, FL SP Assoc Res Vis & Ophthalmol DE choroidal neovascularization; bone marrow; vascular endothelial growth factor; Tie-2 LacZ; transplantation ID HEMATOPOIETIC STEM-CELLS; BONE-MARROW; MACULAR DEGENERATION; PROGENITOR CELLS; POSTNATAL NEOVASCULARIZATION; MEDIATED EXPRESSION; PRECURSOR CELLS; NUDE-MICE; IN-VIVO; ANGIOGENESIS AB Purpose. The question of whether adult animals maintain a reservoir of endothelial progenitor cells (EPCs) in the bone marrow that is involved in neovascularization is under investigation. The following study was undertaken to examine the potential contribution of EPCs to the development of choroidal neovascularization (CNV) in adult mice and to examine the role of local expression of vascular endothelial growth factor (VEGF) in this process. Methods. Lethally irradiated, adult female nude mice were engrafted with whole bone marrow isolated from male transgenic mice expressing LacZ driven by the endothelial specific Tie-2 promoter. Two months, following bone mar-row reconstitution, confirmed by quantitative Taqman PCR, an E1-deleted adenoviral vector expressing vascular endothelial growth factor (165) (Ad.VEGF165) was injected subretinally to induce CNV, confirmed by collagen IV immunohistochemistry. Bone marrow-derived endothelial cells were detected using either X-gal staining or Y chromosome in situ hybridization. Y chromosome positive cells within the CNV were confirmed to be endothelial cells by lectin staining. Results. Subretinal Ad.VEGF(165) was capable of inducing CNV. Four-week old lesions were found to contain LacZ expressing cells within the CNV in bone marrow transplanted animals but not in negative control animals. Eighteen percent of all Y chromosome positive cells within the CNV were found to be lectin positive while 27% of all endothelial cells within the CNV were Y chromosome positive. Conclusion. Engrafted bone marrow-derived EPCs were shown to differentiate into endothelial cells at the site of subretinal VEGF-induced CNV in mice. These results suggest that EPCs contribute to the formation of neovascularization and that subretinal expression of VEGF might play an important role in recruitment of these cells to the site of CNV. (C) 2004 Elsevier Ltd. All rights reserved. C1 NEI, NIH, Bethesda, MD 20892 USA. Univ Miami, Dept Ophthalmol, Miami, FL 33152 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. Natl Naval Med Res Inst, Dept Ophthalmol, Bethesda, MD USA. RP Csaky, KG (reprint author), NEI, NIH, Bldg 10-10B11,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kcsaky@helix.nih.gov NR 59 TC 55 Z9 59 U1 0 U2 3 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 J9 EXP EYE RES JI Exp. Eye Res. PD JUN PY 2004 VL 78 IS 6 BP 1107 EP 1116 DI 10.1016/j.exer.2004.01.010 PG 10 WC Ophthalmology SC Ophthalmology GA 821AM UT WOS:000221431600007 PM 15109917 ER PT J AU Lane, MA de Cabo, R Mattison, J Anson, RM Roth, GS Ingram, DK AF Lane, MA de Cabo, R Mattison, J Anson, RM Roth, GS Ingram, DK TI The Roy Walford legacy: diet restriction from molecules to mice to monkeys to man and onto mimetics SO EXPERIMENTAL GERONTOLOGY LA English DT Article ID PROTECTS HIPPOCAMPAL-NEURONS; MALE RHESUS-MONKEYS; CALORIC RESTRICTION; OXIDATIVE INJURY; MACACA-MULATTA; 2-YEAR PERIOD; HUMANS; BIOSPHERE-2; INVOLVEMENT; PRIMATES C1 NIA, Lab Expt Geronotol, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Ingram, DK (reprint author), NIA, Lab Expt Geronotol, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM ingramd@grc.nia.nih.gov RI de Cabo, Rafael/E-7996-2010; de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 NR 25 TC 8 Z9 10 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD JUN PY 2004 VL 39 IS 6 BP 897 EP 902 DI 10.1016/j.exger.2004.03.007 PG 6 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 825TU UT WOS:000221782000012 PM 15217686 ER PT J AU Leker, RR Aharonowiz, M Greig, NH Ovadia, H AF Leker, RR Aharonowiz, M Greig, NH Ovadia, H TI The role of p53-induced apoptosis in cerebral ischemia: effects of the p53 inhibitor pifithrin alpha SO EXPERIMENTAL NEUROLOGY LA English DT Article DE cerebral ischemia; neuroprotection; animals; p53; apoptosis ID NEURONAL CELL-DEATH; P53-MEDIATED APOPTOSIS; PROTEIN EXPRESSION; ARTERY OCCLUSION; TRANSGENIC MICE; GROWTH ARREST; CYCLIN G1; BRAIN; P21(WAF1/CIP1); RAT AB No neuroprotective compounds are clinically available for the treatment of ischemic stroke. The potential salutary effect of pifithrin a, a novel-specific inhibitor of the transcription factor p53, administered 1-6 h following focal reversible cerebral ischemia, was investigated. Studies measuring histological, motor, and behavioral outcomes showed significant improvements in pifithrin a-treated animals. Pifithrin a reduced the number of apoptotic cells in the ischemic brain by inhibiting the binding of p53 to its DNA sites as it reduced the expression of the p53-related gene p21(WAF) without changing the amount of p53 protein itself. (C) 2004 Elsevier Inc. All rights reserved. C1 Hebrew Univ Jerusalem, Hadassah Med Sch, Hadassah Univ Hosp, Agnes Ginges Ctr Human Neurogenet,Dept Neurol, IL-91120 Jerusalem, Israel. NIA, Neurosci Lab, Gerontol Res Ctr 4F01, Baltimore, MD 21224 USA. RP Leker, RR (reprint author), NINDS, Mol Biol Lab, NIH, Bldg 36,Room 3E12,36 Convent Dr,MSC 4092, Bethesda, MD 20892 USA. EM Ickerr@nih.ninds.gov NR 37 TC 84 Z9 96 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUN PY 2004 VL 187 IS 2 BP 478 EP 486 DI 10.1016/j.expneurol.2004.01.030 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 823HU UT WOS:000221602200027 PM 15144874 ER PT J AU Rao, MS AF Rao, MS TI Toward cell replacement therapy - Response SO EXPERIMENTAL NEUROLOGY LA English DT Letter C1 NIA, Gerontol Res Ctr, Stem Cell Biol Unit, Neurosci Lab, Baltimore, MD 21224 USA. RP Rao, MS (reprint author), NIA, Gerontol Res Ctr, Stem Cell Biol Unit, Neurosci Lab, 5600 Nathan Stock Dr, Baltimore, MD 21224 USA. EM raomah@grc.nia.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUN PY 2004 VL 187 IS 2 BP 538 EP 538 DI 10.1016/j.expneurol.2004.02.017 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 823HU UT WOS:000221602200035 ER PT J AU Coscia, M Kwak, LW AF Coscia, M Kwak, LW TI Therapeutic idiotype vaccines in B lymphoproliferative diseases SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE antitumour vaccination; B cell lymphoma; idiotype vaccines; multiple myeloma ID MULTIPLE-MYELOMA PATIENTS; COLONY-STIMULATING FACTOR; HIGH-DOSE CHEMOTHERAPY; DENDRITIC CELLS; MONOCLONAL GAMMOPATHIES; IMMUNE-RESPONSES; T-CELLS; TRANSPLANTATION RESISTANCE; ANTITUMOR IMMUNITY; TUMOR-IMMUNITY AB The recognition of the surface immunoglobulin protein of the tumour B cells as a specific tumour antigen has prompted the development of vaccination strategies aimed at the induction of humoral and cellular antitumour responses. Results obtained in preclinical models of B lymphoproliferative diseases, as well as in initial clinical trials, have shown the immunogenic potential of the idiotype (Id) when administered in association with proper adjuvants. The definitive evidence for clinical efficacy of this therapeutic approach awaits ongoing randomised Phase III studies. Research efforts at present include identification of new vaccination settings to improve the clinical benefit of vaccine treatment, the establishment of more convenient methods to produce individual Id vaccines and the development of new strategies of vaccination, including genetic vaccination. C1 NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Coscia, M (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bldg 657,Room 207, Frederick, MD 21702 USA. EM mcoscia@ncifcrf.gov RI coscia, marta/K-4832-2016 OI coscia, marta/0000-0003-2123-7675 NR 42 TC 9 Z9 10 U1 0 U2 0 PU ASHLEY PUBLICATIONS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1471-2598 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD JUN PY 2004 VL 4 IS 6 BP 959 EP 963 DI 10.1517/14712598.4.6.959 PG 5 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 831OO UT WOS:000222204300019 PM 15174977 ER PT J AU Chen, XD Fisher, LW Robey, PG Young, MF AF Chen, XD Fisher, LW Robey, PG Young, MF TI The small leucine-rich proteoglycan biglycan modulates BMP-4-induced osteoblast differentiation SO FASEB JOURNAL LA English DT Article DE microenvironment; osteoblastic progenitors ID BONE MORPHOGENETIC PROTEIN-4; GROWTH-FACTOR-BETA; EXTRACELLULAR-MATRIX; TARGETED DISRUPTION; STROMAL CELLS; DECORIN; EXPRESSION; CBFA1; GENE; ABNORMALITIES AB Biglycan (bgn) is a small leucine-rich proteoglycan enriched in extracellular matrices of skeletal tissues. Bgn-deficient mice develop age-related osteopenia with a phenotype that resembles osteoporosis and premature arthritis. In the present study, we have examined the differentiation of bgn-deficient osteoblasts from neonatal murine calvariae and found that the absence of bgn caused less BMP-4 binding, which reduced the sensitivity of osteoblasts to BMP-4 stimulation. The loss of sensitivity resulted in a reduction of Cbfa1 expression, which ultimately led to a defect in the differentiation of osteoblasts. However, the response of bgn-deficient osteoblasts to BMP-4 was completely rescued by reintroduction of biglycan by viral transfection. We propose that biglycan modulates BMP-4-induced signaling to control osteoblast differentiation. C1 Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. RP Chen, XD (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bldg 30,Room 225,9000 Rockville Pike,MSC 4320, Bethesda, MD 20892 USA. EM xchen@dir.nidr.nih.gov RI CAI, RONG/I-7095-2013; Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 39 TC 113 Z9 122 U1 0 U2 5 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUN PY 2004 VL 18 IS 9 BP 948 EP 958 DI 10.1096/fj.03-0899com PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 833HJ UT WOS:000222327500012 PM 15173106 ER PT J AU Cho, HY Reddy, SPM Yamamoto, M Kleeberger, SR AF Cho, HY Reddy, SPM Yamamoto, M Kleeberger, SR TI The transcription factor NRF2 protects against pulmonary fibrosis SO FASEB JOURNAL LA English DT Article DE bleomycin; reactive oxygen species; oxidative stress; lung; knockout mice; antioxidant ID GAMMA-GLUTAMYLCYSTEINE SYNTHETASE; INDUCED LUNG INJURY; GENE-EXPRESSION; ALVEOLAR BRONCHIOLIZATION; INTRATRACHEAL BLEOMYCIN; SUPEROXIDE-DISMUTASE; AIRWAY EPITHELIUM; OXIDATIVE STRESS; KNOCKOUT MICE; INDUCTION AB The molecular mechanisms of pulmonary fibrosis are poorly understood, although reactive oxygen species are thought to have an important role. NRF2 is a transcription factor that protects cells and tissues from oxidative stress by activating protective antioxidant and detoxifying enzymes. We hypothesized that NRF2 protects lungs from injury and fibrosis induced by bleomycin, an anti-neoplastic agent that causes pulmonary fibrosis in susceptible patients. To test this hypothesis, mice with targeted deletion of Nrf2 (Nrf2(-/-)) and wild-type (Nrf2(+/+)) mice were treated with bleomycin or vehicle, and pulmonary injury and fibrotic responses were compared. Bleomycin-induced increases in lung weight, epithelial cell death, and inflammation were significantly greater in Nrf2(-/-) mice than in Nrf2(+/+) mice. Indices of lung fibrosis (hydroxyproline content, collagen accumulation, fibrotic score, cell proliferation) were significantly greater in bleomycin-treated Nrf2(-/-) mice, compared with Nrf2(+/+) mice. NRF2 expression and activity were elevated in Nrf2(+/+) mice by bleomycin. Bleomycin caused greater up-regulation of several NRF2-inducible antioxidant enzyme genes and protein products in Nrf2(+/+) mice compared with Nrf2(-/-) mice. Further, bleomycin-induced transcripts and protein levels of lung injury and fibrosis markers were significantly attenuated in Nrf2(+/+) mice compared with Nrf2(-/-) mice. Results demonstrated that NRF2 has a critical role in protection against pulmonary fibrosis, presumably through enhancement of cellular antioxidant capacity. This study has important implications for the development of intervention strategies against fibrosis. C1 NIEHS, Resp Biol Lab, Res Triangle Pk, NC 27709 USA. Johns Hopkins Univ, Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. Univ Tsukuba, Inst Basic Med Sci, Tsukuba, Ibaraki 305, Japan. Univ Tsukuba, Ctr Tsukuba Adv Res Alliance, Tsukuba, Ibaraki, Japan. RP Cho, HY (reprint author), NIEHS, Resp Biol Lab, 111 TW Alexander Dr,Bd 101,MD D-201, Res Triangle Pk, NC 27709 USA. EM cho2@niehs.nih.gov RI Yamamoto, Masayuki/A-4873-2010 FU NHLBI NIH HHS [HL-66109]; NIEHS NIH HHS [ES-03819] NR 45 TC 194 Z9 199 U1 0 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUN PY 2004 VL 18 IS 9 BP 1258 EP + PG 29 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 833HJ UT WOS:000222327500020 PM 15208274 ER PT J AU Maloney, B Ge, YW Greig, N Lahiri, DK AF Maloney, B Ge, YW Greig, N Lahiri, DK TI Presence of a "CAGA box" in the APP gene unique to amyloid plaque-forming species and absent in all APLP-1/2 genes: implications in Alzheimer's disease SO FASEB JOURNAL LA English DT Article DE phylogenetic analysis; aging; dementia; rational drug design ID PRECURSOR PROTEIN GENE; MESSENGER-RNA; 5'-UNTRANSLATED REGION; TGF-BETA; TRANSGENIC MICE; CELL-LINES; TRANSFORMING GROWTH-FACTOR-BETA-1; TRANSCRIPTIONAL ACTIVATION; REGULATES EXPRESSION; SIGNALING CROSSTALK AB Potentially toxic amyloid beta-peptide (Abeta) in Alzheimer's disease ( AD) is generated from a family of Abeta-containing precursor proteins (APP), which is regulated via the 5'-untranslated region (5'-UTR) of its mRNA. We analyzed 5'-UTRs of the APP superfamily, including amyloid plaque-forming and non-amyloid plaque-forming species, and of prions (27 different DNA sequences). A "CAGA" sequence proximal to the "ATG" start codon was present in a location unique to APP genes of amyloid plaque-forming species and absent in all other genes surveyed. This CAGA box is immediately upstream of an interleukin-1-responsive element (acute box). In addition, the proximal CAGA box is predicted to appear on a stem-loop structure in both human and guinea pig APP mRNA. This stem-loop is part of a predicted bulge-loop that encompasses a known iron regulatory element (IRE). Electrophoretic mobility shift with segments of the APP 5'-UTR showed that a region with the proximal CAGA sequence binds nuclear proteins, and this UTR fragment is active in a reporter gene functional assay. Thus, the 5'-UTR in the human APP but not those of APP-like proteins contains a specific region that may participate in APP regulation and may determine a more general model for amyloid generation as seen in AD. The 5'-UTR of human APP contains several interesting control elements, such as an acute box element, a CAGA box, an IRE, and a transforming growth factor-beta-responsive element, that could control APP expression and provide suitable and specific drug targets for AD. C1 Indiana Univ, Sch Med, Inst Psychiat Res, Dept Psychiat, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Inst Psychiat Res, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. RP Lahiri, DK (reprint author), Indiana Univ, Sch Med, Inst Psychiat Res, Dept Psychiat, 791 Union Dr, Indianapolis, IN 46202 USA. EM dlahiri@iupui.edu RI Maloney, Bryan/C-4924-2011 OI Maloney, Bryan/0000-0003-2364-9649 FU NIA NIH HHS [AG 18379, AG 18884] NR 66 TC 38 Z9 39 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUN PY 2004 VL 18 IS 9 BP 1288 EP + DI 10.1096/fj.03-1703fje PG 33 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 833HJ UT WOS:000222327500002 PM 15208260 ER PT J AU Tou, JS Smith, BC Bojanowski, CM Meleth, AD Gery, I Csaky, KG Chew, EY Chan, CC AF Tou, JS Smith, BC Bojanowski, CM Meleth, AD Gery, I Csaky, KG Chew, EY Chan, CC TI The involvement of sequence variation and expression of CX3CR1 in the pathogenesis of age-related macular degeneration SO FASEB JOURNAL LA English DT Article DE chemoattractant; single nucleotide polymorphism; archived paraffin-embedded slide; gene expression; risk factor ID FAMILIAL AGGREGATION; APOLIPOPROTEIN-E; RECEPTOR CX3CR1; GENETIC RISK; FRACTALKINE; CX(3)CR1; DISEASE; EYE; INFLAMMATION; MACULOPATHY AB This study examined the association between the sequence variation/expression of CX3CR1, a chemokine receptor, and age-related macular degeneration (AMD). Peripheral blood from 85 AMD patients and 105 subjects without AMD (controls), as well as ocular tissue from 40 pathological sections with AMD and two normal eye sections, were screened for V249I and T280M, two single nucleotide polymorphisms (SNPs) in CX3CR1. An increased prevalence, with the highest odds ratio of 3.57, of the I249 and M280 carriers was found among the AMD cases as compared with the controls. When comparing CX3CR1 expression in the archived eye sections, CX3CR1 transcripts were not detectable in the maculae of AMD eyes bearing T/M280; however, transcripts were detected in the maculae of normal eyes bearing T/T280 or T/M280 as well as in the AMD maculae bearing T/T280. Furthermore, lower CX3CR1 protein expression was observed in the maculae of AMD eyes bearing T/M280 compared with the controls bearing T/T280. The I249 and M280 alleles result in a lowered number of receptor binding sites and a decreased ligand affinity. Our data suggest that a decrease, caused by sequence variation and/or lower CX3CR1 expression, in CX3CR1-induced cellular activities could contribute to AMD development. C1 NEI, Immunol Lab, Bethesda, MD 20892 USA. NEI, Div Epidemiol & Clin Res, Bethesda, MD 20892 USA. NEI, HHMI, Bethesda, MD 20892 USA. NEI, Sect Gene Therapy, Bethesda, MD 20892 USA. RP Chan, CC (reprint author), NEI, Immunol Lab, Bldg 10,10 Ctr Dr,Rm 10N103, Bethesda, MD 20892 USA. EM chanc@nei.nih.gov NR 40 TC 1 Z9 1 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUN PY 2004 VL 18 IS 9 BP 1297 EP + PG 24 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 833HJ UT WOS:000222327500016 ER PT J AU El-Agnaf, OMA Paleologou, KE Greer, B Abogrein, AM King, JE Salem, SA Fullwood, NJ Benson, FE Hewitt, R Ford, KJ Martin, FL Harriot, P Cookson, MR Allsop, D AF El-Agnaf, OMA Paleologou, KE Greer, B Abogrein, AM King, JE Salem, SA Fullwood, NJ Benson, FE Hewitt, R Ford, KJ Martin, FL Harriot, P Cookson, MR Allsop, D TI A strategy for designing inhibitors of alpha-synuclein aggregation and toxicity as a novel treatment for Parkinson's disease and related disorders SO FASEB JOURNAL LA English DT Article DE amyloid fibrils; drug discovery; neurodegeneration; peptide delivery ID MULTIPLE-SYSTEM ATROPHY; SHEET BREAKER PEPTIDES; APOPTOTIC CELL-DEATH; BETA-SHEET; NEURODEGENERATIVE DISEASES; LEWY BODIES; WILD-TYPE; NEUROBLASTOMA-CELLS; ALZHEIMERS-DISEASE; HYDROGEN-PEROXIDE AB Convergent biochemical and genetic evidence suggests that the formation of alpha-synuclein (alpha-syn) protein deposits is an important and, probably, seminal step in the development of Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). It has been reported that transgenic animals overexpressing human alpha-syn develop lesions similar to those found in the brain in PD, together with a progressive loss of dopaminergic cells and associated abnormalities of motor function. Inhibiting and/or reversing alpha-syn self-aggregation could, therefore, provide a novel approach to treating the underlying cause of these diseases. We synthesized a library of overlapping 7-mer peptides spanning the entire alpha-syn sequence, and identified amino acid residues 64-100 of alpha-syn as the binding region responsible for its self-association. Modified short peptides containing alpha-syn amino acid sequences from part of this binding region (residues 69-72), named alpha-syn inhibitors (ASI), were found to interact with full-length alpha-syn and block its assembly into both early oligomers and mature amyloid-like fibrils. We also developed a cell-permeable inhibitor of alpha-syn aggregation (ASID), using the polyarginine peptide delivery system. This ASID peptide was able to inhibit the DNA damage induced by Fe(II) in neuronal cells transfected with alpha-syn(A53T), a familial PD-associated mutation. ASI peptides without this delivery system did not reverse levels of Fe(II)-induced DNA damage. Furthermore, the ASID peptide increased (P<0.0005) the number of cells stained positive for Bcl-2, while significantly (P<0.05) decreasing the percentage of cells stained positive for BAX. These short peptides could serve as lead compounds for the design of peptidomimetic drugs to treat PD and related disorders. C1 Univ Lancaster, Div Biol Sci, Lancaster LA1 4YQ, England. Queens Univ Belfast, Sch Biol & Biochem, Belfast BT9 7BL, Antrim, North Ireland. NIA, Neurogenet Lab, Bethesda, MD 20892 USA. RP El-Agnaf, OMA (reprint author), Univ Lancaster, Div Biol Sci, Lancaster LA1 4YQ, England. EM o.el-agnaf@lancaster.ac.uk RI Allsop, David/B-9725-2008; OI Allsop, David/0000-0002-0513-5575; L Martin, Francis/0000-0001-8562-4944 NR 57 TC 95 Z9 100 U1 1 U2 8 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUN PY 2004 VL 18 IS 9 BP 1315 EP + DI 10.1096/fj.03-1346fje PG 34 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 833HJ UT WOS:000222327500026 PM 15180968 ER PT J AU Hu, WG Berry, J Chen, J Gu, XX AF Hu, WG Berry, J Chen, J Gu, XX TI Exploration of Moraxella catarrhalis outer membrane proteins, CD and UspA, as new carriers for lipooligosaccharide-based conjugates SO FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY LA English DT Article DE carrier; CD; UspA; conjugate; LOS; Moraxella catarrhalis ID NONTYPABLE HAEMOPHILUS-INFLUENZAE; EPITOPE-SPECIFIC REGULATION; BRANHAMELLA-CATARRHALIS; CAPSULAR POLYSACCHARIDE; NEISSERIA-MENINGITIDIS; ANTIBODY-RESPONSES; DETOXIFIED LIPOOLIGOSACCHARIDE; RESPIRATORY-INFECTIONS; OTITIS-MEDIA; VACCINE AB Moraxella catarrhalis outer membrane proteins, CD and ubiquitous surface protein A (UspA), were used as carriers for M catarrhalis detoxified lipooligosaccharide (dLOS)-based conjugates. Our study was designed to investigate the feasibility of CD and UspA as protein carriers for dLOS-based conjugates and their possible synergic effects on protection from both anti-LOS and anti-CD or anti-UspA antibody responses. Female Balb/c mice were immunized subcutaneously three times with dLOS-CD or dLOS-UspA conjugate in Ribi adjuvant. Antisera elicited by the conjugates showed high titers of specific anti-LOS antibodies with complement-dependent bactericidal activity towards M catarrhalis strain 25238. In a mouse aerosol challenge model, mice immunized with both conjugates showed a significant enhancement of the clearance of strain 25238 from lungs as compared with the control mice. Although both conjugates elicited reduced (relative to unconjugated CD or UspA) but significant levels of anti-CD or UspA antibodies, they did not show synergetic effects with anti-LOS antibodies on the bactericidal activity or the pulmonary bacterial clearance. Nevertheless, CD and UspA are safe and effective new carriers for dLOS-based or other potential carbohydrate-based conjugate vaccines to help thymus-independent carbohydrate antigens for production of anti-carbohydrate antibodies against target pathogens. (C) 2004 Federation of European Microbiological Societies. Published by Elsevier B.V. All rights reserved. C1 Natl Inst Deafness & Other Commun Disorders, Vaccine Res Sect, Rockville, MD 20850 USA. RP Gu, XX (reprint author), Natl Inst Deafness & Other Commun Disorders, Vaccine Res Sect, Rockville, MD 20850 USA. EM guxx@nidcd.nih.gov NR 43 TC 11 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0928-8244 J9 FEMS IMMUNOL MED MIC JI FEMS Immunol. Med. Microbiol. PD JUN 1 PY 2004 VL 41 IS 2 BP 109 EP 115 DI 10.1016/j.femsim.2004.02.001 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 828BS UT WOS:000221948300003 PM 15145454 ER PT J AU Fu, Y Lee, H Collins, M Tsai, HF Spellberg, B Edwards, JE Kwon-Chung, KJ Ibrahim, AS AF Fu, Y Lee, H Collins, M Tsai, HF Spellberg, B Edwards, JE Kwon-Chung, KJ Ibrahim, AS TI Cloning and functional characterization of the Rhizopus oryzae high affinity iron permease (rFTR1) gene SO FEMS MICROBIOLOGY LETTERS LA English DT Article; Proceedings Paper CT 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy CY SEP 26-30, 2002 CL SAN DIEGO, CA DE mucormycosis; zygomycosis; complementation; virulence; iron permease; Rhizopus oryzae ID SACCHAROMYCES-CEREVISIAE; CANDIDA-ALBICANS; TRANSPORT; ENCODES; FE(II); DEFEROXAMINE; EXPRESSION; YEAST AB Rhizopus oryzae is the most common etiologic agent of mucormycosis. Clinical and animal model data clearly demonstrate that the presence of elevated available serum iron predisposes the host to develop mucormycosis. Therefore, the high affinity iron permease (rFTR1) which encodes a protein required to scavenge iron from the environment, is highly likely to be a critical determinant of virulence for R. oryzae. We have cloned rFTR1 by using a PCR approach relying on degenerate primers designed from the conserved regions of Saccharomyces cerevisiae high affinity iron permease. Sequence analysis of a 2.0 kb EcoRI genomic clone revealed a single open reading frame of 1107 bp that lacked introns. The putative rFtr1p had significant homology to known fungal high affinity iron permeases from Candida albicans (46% identity) and S. cerevisiae (44% identity). In R. oryzae, rFTR1 was expressed in iron-depleted and not in iron-rich media. Finally, rFTR1 restored the ability of an ftr1 null mutant of S. cerevisiae to grow on iron-limited medium and to take up radiolabeled iron, whereas S. cerevisiae transformed with the empty vector did not. These data demonstrate that we have cloned the gene encoding a R. oryzae high affinity iron permease and the putative rFtr1p is involved in assimilation of iron from iron-depleted environments. (C) 2004 Federation of European Microbiological Societies. Published by Elsevier B.V. All rights reserved. C1 Harbor UCLA, Res & Educ Inst, Torrance, CA 90502 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90024 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Ibrahim, AS (reprint author), Harbor UCLA, Res & Educ Inst, Torrance, CA 90502 USA. EM Ibrahim@humc.edu RI a, a/M-9467-2013 FU NIAID NIH HHS [R01 AI 19990, R03 AI 054531, P01 AI 37194] NR 28 TC 23 Z9 24 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1097 J9 FEMS MICROBIOL LETT JI FEMS Microbiol. Lett. PD JUN 1 PY 2004 VL 235 IS 1 BP 169 EP 176 DI 10.1016/j.femsle.2004.04.031 PG 8 WC Microbiology SC Microbiology GA 827TL UT WOS:000221923800024 PM 15158278 ER PT J AU Potlog-Nahari, C Stratton, P Winkel, C Widra, E Sinaii, N Connors, S Nieman, LK AF Potlog-Nahari, C Stratton, P Winkel, C Widra, E Sinaii, N Connors, S Nieman, LK TI Urine vascular endothelial growth factor-A is not a useful marker for endometriosis SO FERTILITY AND STERILITY LA English DT Article DE endometriosis; VEGF; diagnosis ID TUMOR-NECROSIS-FACTOR; FLUID CA-125 LEVELS; PERITONEAL-FLUID; MENSTRUAL-CYCLE; SERUM; WOMEN; VEGF; LAPAROSCOPY; INTERLEUKIN-6; ANGIOGENESIS AB Objective: To determine whether urine VEGF is elevated in women with endometriosis. Design: Prospective observational study. Setting: Tertiary care government and private hospitals. Patient(s): During laparoscopy for pelvic pain or infertility, urine was collected and possible endometriosis lesions were excised. Of 62 women, 40 had histology-proven endometriosis and 22 had no histological proof of the disease. Intervention: None. Main Outcome Measure(s): Urine VEGF-A(121, 165) was measured and compared in women with and without biopsy-proven endometriosis. Result(s): Urine VEGF levels corrected for creatinine excretion were similar in women with (83.6 +/- 11.3 pg/mg Cr) and without (88.5 +/- 10.4 pg/mg Cr) endometriosis (P = .77). The frequency distribution of urine VEGF measurements for women with and without endometriosis was similar. No significant difference was noted in urine VEGF levels when comparing endometriosis stages or in those with endometriomas compared to controls. Urine VEGF did not vary significantly over the menstrual cycle or between groups by cycle phase. No cutoff point discriminated individuals with and without the condition. Conclusion(s): It is unlikely that urine VEGF-A(121, 165), as measured in this study, will be a useful non-invasive marker for endometriosis. C1 NICHD, PREB, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Washington, DC 20007 USA. Childrens Hosp, Dept Surg, Boston, MA 02115 USA. RP Potlog-Nahari, C (reprint author), NICHD, PREB, Bldg 10,Room 9D42, Bethesda, MD 20892 USA. EM naharic@mail.nih.gov NR 30 TC 12 Z9 13 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD JUN PY 2004 VL 81 IS 6 BP 1507 EP 1512 DI 10.1016/j.fertnstert.2003.10.040 PG 6 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 830GB UT WOS:000222108800010 PM 15193469 ER PT J AU Farci, P Roskams, T Chessa, L Peddis, G Mazzoleni, AP Scioscia, R Serra, G Lai, ME Loy, M Caruso, L Desmet, V Purcell, RH Balestrieri, A AF Farci, P Roskams, T Chessa, L Peddis, G Mazzoleni, AP Scioscia, R Serra, G Lai, ME Loy, M Caruso, L Desmet, V Purcell, RH Balestrieri, A TI Long-term benefit of interferon a therapy of chronic hepatitis D: Regression of advanced hepatic fibrosis SO GASTROENTEROLOGY LA English DT Article ID CHRONIC ACTIVE HEPATITIS; CHRONIC DELTA-HEPATITIS; LIVER FIBROSIS; AUTOIMMUNE HEPATITIS; CIRRHOSIS; VIRUS; REVERSIBILITY; RESOLUTION; ALPHA; TRANSPLANTATION AB Background & Aims: Little is known about the long-term effects of interferon alpha on clinical outcome and survival of patients with chronic hepatitis D. Methods: Thirty-six patients with chronic hepatitis D who participated in a randomized controlled trial of a 48-week course of high (9 million units) or low (3 million units) doses of interferon alpha or no treatment were followed for an additional 2 to 14 years. Results: Long-term survival was significantly longer in the high-dose group than in untreated controls (P = 0.003) or in the low-dose group (P = 0.019) but did not differ between patients treated with 3 million units and controls. Among surviving patients at 12 years of follow-up, a biochemical response was present in 7 of 12 treated with 9 million units, in 2 of 4 who received 3 million units, and in none of 3 controls. Long-term alanine aminotransferase (ALT) normalization correlated with improved hepatic function and loss of IgM antibody to hepatitis delta antigen (anti-HD). Patients in the high-dose group had a sustained decrease in HDV replication (P = 0.008), leading to clearance of HDV RNA and, eventually, hepatitis B virus (HBV) in some patients, as well as a dramatic improvement in liver histology with respect to activity grade (P = 0.0004) and fibrosis stage (P = 0.007). Strikingly, we documented an absence of fibrosis in the final biopsy of 4 patients with a long-term biochemical response and an initial diagnosis of active cirrhosis. Conclusions: High doses of interferon alpha-2a significantly improved the long-term clinical outcome and survival of patients with chronic hepatitis D, even though the majority had active cirrhosis before the onset of therapy. C1 Univ Cagliari, Dipartimento Sci Med, I-09042 Cagliari, Italy. Katholieke Univ Leuven, Dept Pathol, Louvain, Belgium. Catania Univ, Dipartimento Med Interna & Patol Sistemiche, Catania, Italy. NIAID, Infect Dis Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Farci, P (reprint author), Univ Cagliari, Dipartimento Sci Med, SS 554 Bivio Sestu, I-09042 Cagliari, Italy. EM farcip@pacs.unica.it RI Chessa, Luchino/H-7561-2012 OI Chessa, Luchino/0000-0002-9474-0995 NR 30 TC 134 Z9 140 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUN PY 2004 VL 126 IS 7 BP 1740 EP 1749 DI 10.1053/j.gastro.2004.03.017 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 827GS UT WOS:000221888300018 PM 15188169 ER PT J AU Drenth, JPH Martina, JA Morsche, RHMT Jansen, JBMJ Bonifacino, JS AF Drenth, JPH Martina, JA Morsche, RHMT Jansen, JBMJ Bonifacino, JS TI Molecular characterization of hepatocystin, the protein that is defective in autosomal dominant polycystic liver disease SO GASTROENTEROLOGY LA English DT Article ID KIDNEY-DISEASE; QUALITY-CONTROL; GLUCOSIDASE II; MUTATIONS; PRKCSH; CELLS; MEMBRANE; CHANNEL; 80K-H AB Background & Aims: Autosomal dominant polycystic liver disease is characterized by the presence of numerous cysts spread throughout the liver parenchyma. Recently, we discovered that polycystic liver disease is caused by mutations in the protein kinase C substrate 80K-H gene, which encodes a protein named hepatocystin. Previous studies have identified hepatocystin as a protein kinase C substrate, a component of a cytosolic signal transduction complex, a receptor for advanced glycation end products, a vacuolar protein, and the P subunit of endoplasmic reticulum glucosidase H. Thus, the exact localization and cellular function of hepatocystin remain unclear. Methods: The localization and biochemical properties of normal and polycystic liver disease mutant forms of hepatocystin were examined by using a combination of immunofluorescence microscopy, immunoblotting, metabolic labeling, immuno-precipitation, and carbohydrate analyses. Results: Normal hepatocystin localizes to the endoplasmic reticulum, where it assembles with the glulcosidase II alpha subunit. The 1338-2A-->G truncating mutation in hepatocystin observed in some polycystic liver disease patients produces a protein that is not retained in the endoplasmic reticulum but is secreted into the medium. This mutant protein fails to assemble with the glucosidase II alpha subunit. As a consequence, mutant hepatocystin is undetectable in liver cysts. In addition, levels of normal hepatocystin and of the glucosidase II alpha subunit are substantially reduced in liver and Epstein-Barr virus-immortalized B lymphoblasts from patients with polycystic liver disease. Conclusions: These findings are consistent with a role of hepatocystin in carbohydrate processing and quality control of newly synthesized glycoproteins in the endoplasmic reticulum. Therefore, altered endoplasmic reticulum processing of some key regulator of cell proliferation may underlie polycystic liver disease. C1 NICHHD, Cell Biol & Metab Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. Univ Nijmegen, Med Ctr St Radboud, Dept Med, Div Gastroenterol & Hepatol, Nijmegen, Netherlands. RP Drenth, JPH (reprint author), NICHHD, Cell Biol & Metab Branch, Natl Inst Hlth, Bldg 18T,Room 101, Bethesda, MD 20892 USA. EM joostphdrenth@cs.com RI Drenth, J.P.H./H-8025-2014; te Morsche, Rene/P-9143-2015; OI Bonifacino, Juan S./0000-0002-5673-6370 NR 29 TC 35 Z9 35 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUN PY 2004 VL 126 IS 7 BP 1819 EP 1827 DI 10.1053/j.gastro.2004.02.023 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 827GS UT WOS:000221888300026 PM 15188177 ER PT J AU Karacki, PS Gao, X Thio, CL Thomas, DL Goedert, JJ Vlahov, D Kaslow, R Strathdee, S Hilgartner, MW O'Brien, SJ Carrington, M AF Karacki, PS Gao, X Thio, CL Thomas, DL Goedert, JJ Vlahov, D Kaslow, R Strathdee, S Hilgartner, MW O'Brien, SJ Carrington, M TI MICA and recovery from hepatitis C virus and hepatitis B virus infections SO GENES AND IMMUNITY LA English DT Article DE HCV; HBV; MICA; genetics; viral persistence; pathogenesis ID CYTOMEGALOVIRUS UL16 GLYCOPROTEIN; MULTICENTER AIDS COHORT; CLASS-I; VIRAL-HEPATITIS; T-CELLS; HEPATOCELLULAR-CARCINOMA; INTRACELLULAR RETENTION; CLINICAL-OUTCOMES; ENVELOPE PROTEIN; NATURAL-HISTORY AB The polymorphic MHC class I chain-related A (MICA) gene encodes a ligand that has different binding affinities for the NKG2D activating receptor of CD8+ T cells and natural killer (NK) cells. We hypothesized that MICA heterogeneity would affect recovery from hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. To test the hypothesis, we initially typed known MICA polymorphisms for 228 persons who cleared HCV infection and 442 persons with persistent hepatitis C matched on other factors affecting viral persistence. Although MICA*015 was detected more than two-fold more often in persons with viral clearance (odds ratio 0.36, 95% confidence interval = 0.19, 0.80), it occurred in fewer than 5% of the study population. In a similar analysis of 442 persons with chronic hepatitis B and 768 matched controls who recovered, MICA*015 was detected in 2.0% of persons with chronic hepatitis B and only 0.9% of controls. No significant associations were detected with other MICA polymorphisms. While further investigation may reveal a structural basis of the MICA*015 associations, these data provide little support for the hypothesis that differential distribution of MICA alleles substantially affects recovery from HCV and HBV infections. C1 Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Dept Epidemiol, Baltimore, MD 21205 USA. SAIC Frederick, Basic Res Program, Intramural Res Support Program, Frederick, MD USA. NCI, Viral Epidemiol Branch, Rockville, MD USA. New York Acad Med, New York, NY USA. Univ Alabama, Dept Epidemiol, Birmingham, AL USA. New York Presbyterian Hosp, Cornell Med Ctr, Dept Pediat, New York, NY USA. NCI, Lab Genom Divers, Frederick, MD 21701 USA. RP Thomas, DL (reprint author), Johns Hopkins Univ, Sch Med, Viral Hepatitis Lab, 1503 E Jefferson St, Baltimore, MD 21231 USA. RI Strathdee, Steffanie/B-9042-2009 FU NCI NIH HHS [N01-CP-33002]; NCRR NIH HHS [5 M01-RR-00722]; NIAID NIH HHS [U01-AI-35039, U01-AI-35040, U01-AI-35041, U01-AI-35042, U01-AI-35043, U01-AI-37613, U01-AI-37984]; NIDA NIH HHS [DA00441, DA04334, DA13324]; PHS HHS [N01-C0-56000] NR 42 TC 18 Z9 25 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD JUN PY 2004 VL 5 IS 4 BP 261 EP 266 DI 10.1038/sj.gene.6364065 PG 6 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 827BL UT WOS:000221873100004 PM 15029237 ER PT J AU Thio, CL Goedert, JJ Mosbruger, T Vlahov, D Strathdee, SA O'Brien, S Astemborski, J Thomas, DL AF Thio, CL Goedert, JJ Mosbruger, T Vlahov, D Strathdee, SA O'Brien, S Astemborski, J Thomas, DL TI An analysis of tumor necrosis factor alpha gene polymorphisms and haplotypes with natural clearance of hepatitis C virus infection SO GENES AND IMMUNITY LA English DT Article DE TNF; viral hepatitis; genetics; infectious diseases; genetic epidemiology ID FACTOR (TNF)-ALPHA GENE; INJECTION-DRUG USERS; TNF-ALPHA; 5'-FLANKING REGION; PROMOTER POLYMORPHISM; TRANSCRIPTION FACTOR; ANTIVIRAL THERAPY; KAPPA-B; INTERFERON; INTERLEUKIN-10 AB The cytokine tumor necrosis factor alpha (TNF-alpha) is important in generating an immune response against a hepatitis C virus (HCV) infection. The functions of TNF-alpha may be altered by single-nucleotide polymorphisms (SNPs) in its gene, TNF. We hypothesized that SNPs in TNF may be important in determining the outcome of an HCV infection. To test this hypothesis, we typed nine TNF SNPs in a cohort of individuals with well-defined HCV outcomes. Three of these SNPs were typed in a second cohort. Data were analyzed using logistic regression stratifying by ethnicity, since rates of HCV clearance differ in black subjects versus white subjects. The SNP -863A was associated with viral clearance in black subjects (odds ratios (OR) 0.52, 95% confidence interval (CI) 0.29-0.93). Furthermore, the common wild-type haplotype -863C/-308G was associated with viral persistence in black subjects (OR 1,91, 95% Cl 1.24-2.95). These findings were independent of linkage with human leukocyte antigen (HLA) alleles. Further study of this polymorphism and haplotype is needed to understand these associations and the role of TNF-alpha in determining outcomes of HCV infection. C1 Johns Hopkins Univ, Dept Med, Baltimore, MD 21231 USA. NCI, Viral Epidemiol Branch, Rockville, MD USA. New York Acad Med, New York, NY USA. Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD 21231 USA. Lab Genom Divers, Frederick, MD USA. RP Thio, CL (reprint author), Johns Hopkins Univ, Dept Med, 1503 E Jefferson St, Baltimore, MD 21231 USA. EM cthio@jhmi.edu RI Strathdee, Steffanie/B-9042-2009 FU NCI NIH HHS [N01-CP-33002]; NIDA NIH HHS [DA04334, DA00441, DA12568, DA13324]; NIDDK NIH HHS [DK56415]; PHS HHS [N01-C0-12400] NR 42 TC 31 Z9 36 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD JUN PY 2004 VL 5 IS 4 BP 294 EP 300 DI 10.1038/sj.gene.6364072 PG 7 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 827BL UT WOS:000221873100009 PM 15071492 ER PT J AU Kadaba, S Krueger, A Trice, T Krecic, AM Hinnebusch, AG Anderson, J AF Kadaba, S Krueger, A Trice, T Krecic, AM Hinnebusch, AG Anderson, J TI Nuclear surveillance and degradation of hypomodified initiator tRNA(Met) in S-cerevisiae SO GENES & DEVELOPMENT LA English DT Article DE transfer RNA; exosome; RNA processing; RNA turnover; tRNA modification ID MESSENGER-RNA DECAY; SISTER-CHROMATID COHESION; METHIONYL-TRANSFER-RNA; DNA TOPOISOMERASE-I; HUMAN PM-SCL; ESCHERICHIA-COLI; QUALITY-CONTROL; POLY(A) POLYMERASE; YEAST EXOSOME; RIBOSOMAL-RNA AB The tRNA m(1)A58 methyltransferase is composed of two subunits encoded by the essential genes TRM6 and TRM61 (formerly GCD10 and GCD14). The trm6-504 mutation results in a defective m(1)A methyltransferase (Mtase) and a temperature-sensitive growth phenotype that is attributable to the absence of m(1)A58 and consequential tRNA(i)(Met) instability. We used a genetic approach to identify the genes responsible for tRNA(i)(Met) degradation in trm6 cells. Three recessive extragenic mutations that suppress trm6-504 mutant phenotypes and restore hypomodified tRNA(i)(Met) to near normal levels were identified. The wild-type allele of one suppressor, DIS3/RRP44, encodes a 3'-5' exoribonuclease and a member of the multisubunit exosome complex. We provide evidence that a functional nuclear exosome is required for the degradation of tRNA(i)(Met) lacking m(1)A58. A second suppressor gene encodes Trf4p, a DNA polymerase (pol sigma) with poly(A) polymerase activity. Whereas deletion of TRF4 leads to stabilization of tRNA(i)(Met), overexpression of Trf4p destabilizes the hypomodified tRNA(i)(Met) in trm6 cells. The hypomodified, but not wild-type, pre-tRNA(i)(Met) accumulates as a polyadenylated species, whose abundance and length distribution both increase upon Trf4p overexpression. These data indicate that a tRNA surveillance pathway exists in yeast that requires Trf4p and the exosome for polyadenylation and degradation of hypomodified pre-tRNA(i)(Met). C1 Marquette Univ, Dept Biol Sci, Milwaukee, WI 53201 USA. NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Anderson, J (reprint author), Marquette Univ, Dept Biol Sci, Milwaukee, WI 53201 USA. EM james.anderson@marquette.edu NR 67 TC 289 Z9 296 U1 0 U2 14 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUN 1 PY 2004 VL 18 IS 11 BP 1227 EP 1240 DI 10.1101/gad.1183804 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 826SP UT WOS:000221849200002 PM 15145828 ER PT J AU Couedel, C Mills, KD Barchi, M Shen, L Olshen, A Johnson, RD Nussenzweig, A Essers, J Kanaar, R Li, GC Alt, FW Jasin, M AF Couedel, C Mills, KD Barchi, M Shen, L Olshen, A Johnson, RD Nussenzweig, A Essers, J Kanaar, R Li, GC Alt, FW Jasin, M TI Collaboration of homologous recombination and nonhomologous end-joining factors for the survival and integrity of mice and cells SO GENES & DEVELOPMENT LA English DT Article DE DNA double-strand break; homologous recombination; nonhomologous end-joining; Ku80, Rad54 ID DOUBLE-STRAND BREAKS; MAMMALIAN-CELLS; DNA-DAMAGE; IONIZING-RADIATION; EMBRYONIC NEUROGENESIS; GENOMIC INSTABILITY; REPAIR PATHWAY; HISTONE H2AX; KINASE; GENE AB Homologous recombination (HR) and nonhomologous end-joining (NHEJ) are mechanistically distinct DNA repair pathways that contribute substantially to double-strand break (DSB) repair in mammalian cells. We have combined mutations in factors from both repair pathways, the HR protein Rad54 and the DNA-end-binding factor Ku80, which has a role in NHEJ. Rad54(-/-)Ku80(-/-) mice were severely compromised in their survival, such that fewer double mutants were born than expected, and only a small proportion of those born reached adulthood. However, double-mutant mice died at lower frequency from tumors than Ku80 single mutant mice, likely as a result of rapid demise at a young age from other causes. When challenged with an exogenous DNA damaging agent, ionizing radiation, double-mutant mice were exquisitely sensitive to low doses. Tissues and cells from double-mutant mice also showed indications of spontaneous DNA damage. Testes from some Rad54(-/-)Ku80(-/-) mice displayed enhanced apoptosis and reduced sperm production, and embryonic fibroblasts from Rad54(-/-)Ku80(-/-) animals accumulated foci of gamma-H2AX, a marker for DSB s. The substantially increased DNA damage response in the double mutants implies a cooperation of the two DSB repair pathways for survival and genomic integrity in the animal. C1 Mem Sloan Kettering Canc Ctr, Program Mol Biol, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Med Phys, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. CBR Inst Biomed Res, Boston, MA 02115 USA. Univ Massachusetts, Sch Med, Ctr Canc, Worcester, MA 01605 USA. Univ Massachusetts, Sch Med, Dept Cell Biol, Worcester, MA 01605 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Erasmus MC, Dept Cell Biol & Genet, NL-3000 DR Rotterdam, Netherlands. Erasmus MC, Dept Radiat Oncol, NL-3000 DR Rotterdam, Netherlands. Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. RP Jasin, M (reprint author), Mem Sloan Kettering Canc Ctr, Program Mol Biol, 1275 York Ave, New York, NY 10021 USA. EM m-jasin@ski.mskcc.org OI Barchi, Marco/0000-0003-1104-6234 FU NCI NIH HHS [R01 CA056909, CA56909, CA78497]; NICHD NIH HHS [HD40916, R01 HD040916]; NIGMS NIH HHS [GM54668, R01 GM054668] NR 41 TC 103 Z9 106 U1 3 U2 6 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUN 1 PY 2004 VL 18 IS 11 BP 1293 EP 1304 DI 10.1101/gad.1209204 PG 12 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 826SP UT WOS:000221849200008 PM 15175261 ER PT J AU Cheng, J Dutra, A Takesono, A Garrett-Beal, L Schwartzberg, PL AF Cheng, J Dutra, A Takesono, A Garrett-Beal, L Schwartzberg, PL TI Improved generation of C57BL/6J mouse embryonic stem cells in a defined serum-free media SO GENESIS LA English DT Article DE embryonic stem cells; gene targeting; defined media; KSR-KDMEM; C57BL/6J ID ESTABLISHMENT; DISRUPTION; MICE; GENE; LINES AB C57BL/6 is a well-characterized mouse strain that is used extensively for immunological and neurological research. The establishment of C57BL/6 ES cell lines has facilitated the study of gene-altered mice in a pure genetic background - however, relatively few such lines exist. Using a defined media supplement, knockout serum replacement (KSR) with knockout DMEM (KSR-KD- MEM), we find that we can readily establish ES cell lines from blastocysts of C57BL/6J mice. Six lines were established, all of which were karyotypically normal and could be maintained in the undifferentiated state on mouse embryonic fibroblast (MEF) feeders. One line was further tested and found to be karyotypically stable and germline competent, both prior to manipulation and after gene targeting. For this cell line, efficiencies of cell cloning and chimera generation were greater when maintained in KSR-KDMEM. Our work suggests that the use of defined serum-free media may facilitate the generation of ES cells from inbred mouse strains. genesis Published 2004 Wiley-Liss, Inc.(dagger) C1 NIH, NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. RP Garrett-Beal, L (reprint author), NIH, NHGRI, Genet Dis Res Branch, 49 Convent Dr, Bethesda, MD 20892 USA. EM lgarrett@mail.nih.gov NR 16 TC 86 Z9 97 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1526-954X J9 GENESIS JI Genesis PD JUN PY 2004 VL 39 IS 2 BP 100 EP 104 DI 10.1002/gene.20031 PG 5 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 835NM UT WOS:000222490500005 PM 15170695 ER PT J AU Pompeia, C Hurle, B Belyantseva, IA Noben-Trauth, K Beisel, K Gao, J Buchoff, P Wistow, G Kachar, B AF Pompeia, C Hurle, B Belyantseva, IA Noben-Trauth, K Beisel, K Gao, J Buchoff, P Wistow, G Kachar, B TI Gene expression profile of the mouse organ of corti at the onset of hearing SO GENOMICS LA English DT Article DE deafness; expressed sequence tag database; hair cells; genetics; internal ear; cDNA library; apoptosis cell division ID INNER-EAR; CDNA LIBRARY; AUTOSOMAL-DOMINANT; HAIR-CELLS; NONSYNDROMIC DEAFNESS; MESSENGER-RNA; PROTEIN; GROWTH; FAMILY; DIFFERENTIATION AB We describe the generation of an expressed sequence tag (EST) database of the mouse organ of Corti (OC). Over 20,000 independent clones were isolated, analyzed, and grouped into 8690 unique gene clusters. A large pool of novel genes unique to the OC was identified. Sequence alignments frequently revealed alternatively spliced forms of known genes potentially relevant in the OC function. We have also electronically mapped a subset of OC mouse ESTs to several syntenic regions associated with human autosomal and recessive deafness, which may prove useful for the identification of new positional candidates for these human diseases. The EST dataset is available as an interactive Web-based public database at http://neibank.nei.nih.gov. This resource provides both a view of the profile of gene expression in the OC at the onset of hearing and a tool to identify novel genes of importance in hearing. Published by Elsevier Inc. C1 NIDCD, Sect Struct Cell Biol, Natl Inst Hlth, Bethesda, MD 20892 USA. NHGRI, Genome Technol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. NIDCD, Neurogenet Sect, Natl Inst Hlth, Rockville, MD 20850 USA. Creighton Univ, Dept Biomed Sci, Omaha, NE 68178 USA. NEI, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Kachar, B (reprint author), NIDCD, Sect Struct Cell Biol, Natl Inst Hlth, Bldg 50 Room 4249,50 S Dr, Bethesda, MD 20892 USA. NR 42 TC 12 Z9 17 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD JUN PY 2004 VL 83 IS 6 BP 1000 EP 1011 DI 10.1016/j.yengo.2004.01.005 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 824CY UT WOS:000221662900006 PM 15177554 ER PT J AU Beisel, KW Shiraki, T Morris, KA Pompeia, C Kachar, B Arakawa, T Bono, H Kawai, J Hayashizaki, Y Carninci, P AF Beisel, KW Shiraki, T Morris, KA Pompeia, C Kachar, B Arakawa, T Bono, H Kawai, J Hayashizaki, Y Carninci, P TI Identification of unique transcripts from a mouse full-length, subtracted inner ear cDNA library SO GENOMICS LA English DT Article ID RECESSIVE DEAFNESS DFNB29; OUTER HAIR-CELLS; USHER-SYNDROME; SENSORY EPITHELIA; GENE DISCOVERY; HEARING-LOSS; ACETYLCHOLINE-RECEPTOR; FUNCTIONAL ANNOTATION; MAMMALIAN COCHLEA; ALPORT-SYNDROME AB A small-scale full-length library construction approach was developed to facilitate production of a mouse full-length cDNA encyclopedia representing similar to 250 enriched, normalized, and/or Subtracted cDNA libraries. One library produced using this approach was a subtracted adult mouse inner car cDNA library (sIEa). The average size of the inserts was similar to 2.5 kb, with the majority ranging from 0.5 to 7.0 kb. From this library 22,574 sequence reads were obtained from 15,958 independent clones. Sequencing and chromosomal localization established 5240 clusters, with 1302 clusters being unique and 359 representing new ESTs. Our sIEa library contributed 56.1% of the 7773 nonredundant Unigene clusters associated with the four mouse inner ear libraries in the NCBI dbEST. Based on homologous chromosomal regions between human and mouse, we identified 1018 UniGene clusters associated with the deafness locus critical regions. Of these, 59 clusters were found only in our sIEa library and represented similar to 50% of the identified critical regions. (C) 2004 Elsevier Inc. All rights reserved. C1 Creighton Univ, Dept Biomed Sci, Omaha, NE 68178 USA. RIKEN, Genom Sci Ctr, Lab Genome Explorat, Res Grp, Tsukuba, Ibaraki, Japan. NIDCD, Sect Struct Cell Biol, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Beisel, KW (reprint author), Creighton Univ, Dept Biomed Sci, 2500 Calif, Omaha, NE 68178 USA. EM beisel@creighton.edu RI Carninci, Piero/K-1568-2014; Kawai, Jun/A-6451-2016; OI Carninci, Piero/0000-0001-7202-7243; Bono, Hidemasa/0000-0003-4413-0651 FU NIDCD NIH HHS [DC05009, DC04279, R01 DC004279, R01 DC005009] NR 87 TC 15 Z9 19 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 0888-7543 J9 GENOMICS JI Genomics PD JUN PY 2004 VL 83 IS 6 BP 1012 EP 1023 DI 10.1016/j,ygeno.2004.01.006 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 824CY UT WOS:000221662900007 PM 15177555 ER PT J AU Reuben, DB Seeman, TE Keeler, E Hayes, RP Bowman, L Sewall, A Hirsch, SH Wallace, RB Guralnik, JM AF Reuben, DB Seeman, TE Keeler, E Hayes, RP Bowman, L Sewall, A Hirsch, SH Wallace, RB Guralnik, JM TI The effect of self-reported and performance-based functional impairment on future hospital costs of community-dwelling older persons SO GERONTOLOGIST LA English DT Article DE health care costs; disability; medicare ID HEALTH-CARE EXPENDITURES; LOWER-EXTREMITY FUNCTION; SUBSEQUENT DISABILITY; ADMISSION; PREDICTORS; MORTALITY; BATTERY; RISK AB Purpose: We determined the prognostic value of selfreported and performance-based measurement of function, including functional transitions and combining different measurement approaches, on utilization. Design and Methods: Our cohort study used the 6th, 7th, and 10th waves of three sites of the Established Populations for Epidemiologic Studies of the Elderly, linked to 1- and 4-year Medicare Part A hospital costs. We examined mean hospital expenditures based on (a) 1- and 4-year transitions in selfreported functional status; (b) 4-year transitions in performance-based functional status; (c) combined baseline self-reported and perform a nce-based functional status; and (d) poorest self-reported and performance-based functional status during a 4-year period. Results: Even modest declines in selfreported or performance-based functional status were associated with increased expenditures. When baseline self-reported and perform a nce-based assessments were combined, mean 1-and 4-year adjusted costs were higher with progressively worse performance-based scores, even among those who were independent in self-reported function. When the poorest 4-year self-reported and performance-based functions were examined, self-reported functioning was the most important determinant of hospital costs, but within each self-reported functional level, poorer performance-based function was associated with progressively higher costs. Implications: The costs associated with even modest functional decline are high. Combining self-reported and performance-based measurements can provide more precise estimates of future hospital costs. C1 Univ Calif Los Angeles, Multicampus Program Geriatr Med & Gerontol, David Geffen Sch Med, Los Angeles, CA 90095 USA. RAND Corp, Santa Monica, CA USA. Eli Lilly & Co, Indianapolis, IN 46285 USA. Sewall Inc, Bethesda, MD USA. Univ Iowa, Dept Epidemiol, Ames, IA USA. NIA, Bethesda, MD 20892 USA. RP Reuben, DB (reprint author), Univ Calif Los Angeles, Multicampus Program Geriatr Med & Gerontol, David Geffen Sch Med, 10945 Le Conte Ave,Suite 2339, Los Angeles, CA 90095 USA. EM dreuben@mednet.ucla.edu FU NIA NIH HHS [AG16677, 5 P60 AG10415-08] NR 25 TC 12 Z9 12 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD JUN PY 2004 VL 44 IS 3 BP 401 EP 407 PG 7 WC Gerontology SC Geriatrics & Gerontology GA 829AK UT WOS:000222015000011 PM 15197294 ER PT J AU Ashktorab, H Frank, S Khaled, AR Durum, SK Kifle, B Smoot, DT AF Ashktorab, H Frank, S Khaled, AR Durum, SK Kifle, B Smoot, DT TI Bax translocation and mitochondrial fragmentation induced by Helicobacter pylori SO GUT LA English DT Article ID GASTRIC EPITHELIAL-CELLS; NECROSIS-FACTOR-ALPHA; CYTOCHROME-C RELEASE; BCL-X-L; INDUCED APOPTOSIS; IN-VIVO; PERMEABILITY TRANSITION; VACUOLATING CYTOTOXIN; CYCLE PROGRESSION; TUMOR-SUPPRESSOR AB Background and aims: Previous in vitro and in vivo studies have revealed an association between Helicobacter pylori infection and apoptosis in gastric epithelial cells. Although involvement of the Bcl-2 family of proteins as well as cytochrome c release has been demonstrated in H pylori induced cell death, the exact role of the mitochondria during this type of programmed cell death has not been fully elucidated. Therefore, we sought to determine whether or not Bax translocation and mitochondrial fragmentation occur on exposure of gastric epithelial cells to H pylori, resulting in cell death. Methods: Experiments were performed with human gastric adenocarcinoma (AGS) cells, AGS cells transfected with the HPV-E6 gene (which inactivates p53 function), AGS-neo cells (transfected with the backbone construct), mouse embryonic fibroblasts (MEFs), and p19(ARF) null (ARF(-/-)) MEFs. Cells were incubated with a cag positive H pylori strain for up to 24 hours, lysed, and cytoplasmic and mitochondrial membrane fractions were analysed by western blot for Bax translocation. Results: Bax translocation was detected in AGS, AGS-neo, and normal MEF cells after exposure to H pylori for three hours, but not in ARF(-/-) MEFs cells. Translocation of Bax after H pylori incubation was also detected in AGS-E6 cells (inactive p53 gene) but to a lesser degree than in AGS-neo cells. In parallel studies, the mitochondrial morphology of living cells infected with H pylori was assessed by confocal microscopy. Mitochondrial fragmentation was detectable after 10 hours of H pylori incubation with AGS cells and after seven hours with MEF cells. In wild-type MEFs, mitochondrial fragmentation was significantly increased in comparison with ARF null MEFs (43% v 10.4%, respectively). Furthermore, mitochondrial depolarisation and caspase-3 activity were initiated within four hours in cells incubated with H pylori, and these events were inhibited by forced expression of Bcl-2. Conclusions: These data suggest that during H pylori induced apoptosis, Bax translocates to the mitochondria which subsequently undergo depolarisation and profound fragmentation. Functional ARF and p53 proteins may play an important role in H pylori induced mitochondrial modification. C1 Howard Univ, Ctr Canc, Washington, DC 20059 USA. Howard Univ, GI Div, Dept Med, Washington, DC 20059 USA. NIH, Bethesda, MD 20892 USA. NCI, Frederick, MD 21701 USA. RP Ashktorab, H (reprint author), Howard Univ Hosp, Ctr Canc, 2041 Georgia Ave NW, Washington, DC 20060 USA. EM hashktorab@howard.edu FU NIDDK NIH HHS [R01 DK053713, DK53713, DK56664] NR 69 TC 41 Z9 44 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 J9 GUT JI Gut PD JUN PY 2004 VL 53 IS 6 BP 805 EP 813 DI 10.1136/gut.2003.024372 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 819YC UT WOS:000221351200008 PM 15138206 ER PT J AU Sorensen, G Fagan, P Hunt, MK Stoddard, AM Girod, K Eisenberg, M Frazier, L AF Sorensen, G Fagan, P Hunt, MK Stoddard, AM Girod, K Eisenberg, M Frazier, L TI Changing channels for tobacco control with youth: developing an intervention for working teens SO HEALTH EDUCATION RESEARCH LA English DT Article ID CONSEQUENCES; HEALTH AB Worksites represent an untapped resource for reaching teens with tobacco control messages, given that 80% of teens have held at least one job by the time they graduate from high school. This paper presents formative research findings from a methods development study aimed at designing and testing a tobacco control intervention targeting working teens. Formative research included qualitative methods as well as quantitative data from a cross-sectional survey of teens employed in 10 participating grocery stores. Contrary to our a priori hypothesis, smoking rates among employed youth in this study were not higher than statewide averages and most of the teen workers were still in school, indicating that worksite interventions, at least in this setting, represent an alternative or adjunct to school-based programs, but do not necessarily capture a unique population. Employed teen tobacco use patterns and work characteristics that emerged from our formative research are presented in this paper, and may be useful in planning future worksite interventions for employed teens. C1 Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Hlth & Social Behav, Boston, MA 02115 USA. NCI, Tobacco Control Res Branch, Rockville, MD 20852 USA. Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Amherst, MA 01003 USA. Harvard Univ, Brigham & Womens Hosp, Med Sch & Pediat Oncol, Channing Lab, Boston, MA 02115 USA. RP Sorensen, G (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, 44 Binney St, Boston, MA 02115 USA. EM Glorian_Sorensen@dfci.harvard.edu FU NINR NIH HHS [R01 NR04748] NR 16 TC 6 Z9 6 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1153 J9 HEALTH EDUC RES JI Health Educ. Res. PD JUN PY 2004 VL 19 IS 3 BP 250 EP 260 DI 10.1093/her/cyg019 PG 11 WC Education & Educational Research; Public, Environmental & Occupational Health SC Education & Educational Research; Public, Environmental & Occupational Health GA 822QJ UT WOS:000221554400004 PM 15140845 ER PT J AU Gavrilin, Y Khrouch, V Shinkarev, S Drozdovitch, V Minenko, V Shemiakina, E Ulanovsky, A Bouville, A Anspaugh, L Voilleque, P Luckyanov, N AF Gavrilin, Y Khrouch, V Shinkarev, S Drozdovitch, V Minenko, V Shemiakina, E Ulanovsky, A Bouville, A Anspaugh, L Voilleque, P Luckyanov, N TI Individual thyroid dose estimation for a case-control study of Chernobyl-related thyroid cancer among children of Belarus - Part I: I-131, short-lived radioiodines (I-132, I-133, I-135), and short-lived radiotelluriums (Te-131M and Te-132) SO HEALTH PHYSICS LA English DT Article DE Chernobyl; thyroid; cancer; children ID ACCIDENT; RECONSTRUCTION AB Large amounts of radioiodines were released into the atmosphere during the accident at the Chernobyl nuclear power plant on 26 April 1986. In order to investigate whether the thyroid cancers observed among children in Belarus could have been caused by radiation exposures from the Chernobyl accident, a team of Belarusian, Russian, and American scientists conducted a case-control study to compare cases and controls according to estimated thyroid dose. The primary purpose of this paper is to present detailed information on the estimated thyroid doses, due to intakes of I-131, that were used in the case-control study. The range of the I-131 thyroid doses among the 107 cases and the 214 controls was found to extend from 0.00002 to 4.3 Gy, with medians of approximately 0.2 Gy for the cases and 0.07 Gy for the controls. In addition, the thyroid doses resulting from the intakes of short-lived radioiodines (I-132, I-133, and I-135) and radiotelluriums (Te-131m and Te-132) were estimated and compared to the doses from I-131. The ratios of the estimated thyroid doses from the short-lived radionuclides and from I-131 for the cases and the controls range from 0.003 to 0.1, with median values of approximately 0.02 for both cases and controls. C1 State Res Ctr, Inst Biophys, Moscow, Russia. Int Agcy Res Canc, F-69372 Lyon, France. Republ Sci & Pract Ctr Radiat Med & Human Ecol, Minsk, Byelarus. GSF, Natl Res Ctr Environm & Hlth, Inst Radiat Protect, D-85764 Neuherberg, Germany. NCI, Div Canc Epidemiol & Genet, DHHS, NIH, Bethesda, MD USA. Univ Utah, Dept Radiol, Div Radiobiol, Salt Lake City, UT 84132 USA. MJP Risk Assessment Inc, Denver, CO USA. RP Bouville, A (reprint author), NCI, Radiat Epidemiol Branch, 6120 Execut Blvd,EPS 7094, Bethesda, MD 20822 USA. EM bouvilla@epndce.nci.nih.gov RI Shinkarev, Sergey /B-3254-2017 NR 39 TC 34 Z9 41 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD JUN PY 2004 VL 86 IS 6 BP 565 EP 585 DI 10.1097/00004032-200406000-00002 PG 21 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 822DM UT WOS:000221515700002 PM 15167120 ER PT J AU Bukh, J AF Bukh, J TI A critical role for the chimpanzee model in the study of hepatitis C SO HEPATOLOGY LA English DT Review ID VIRUS-INOCULATED CHIMPANZEES; 1 SEQUENCE STABILITY; T-CELL RESPONSES; CDNA-CLONE; IN-VIVO; RECOVERED CHIMPANZEES; PROTECTIVE IMMUNITY; B-HEPATITIS; INFECTION; REPLICATION AB Chimpanzees remain the only recognized animal model for the study of hepatitis C virus (HCV). Studies performed in chimpanzees played a critical role in the discovery of HCV and are continuing to play an essential role in defining the natural history of this important human pathogen. In the absence of a reproducible cell culture system, the infectivity titer of HCV challenge pools can be determined only in chimpanzees. Recent studies in chimpanzees have provided new insight into the nature of host immune responses-particularly the intrahepatic responses-following primary and secondary experimental HCV infections. The immunogenicity and efficacy of vaccine candidates against HCV can be tested only in chimpanzees. Finally, it would not have been possible to demonstrate the infectivity of infectious clones of HCV without chimpanzees. Chimpanzees became infected when RNA transcripts from molecular clones were inoculated directly into the liver. The infection generated by such transfection did not differ significantly from that observed in animals infected intravenously with wild-type HCV. The RNA inoculated into chimpanzees originated from a single sequence, and the animals therefore had a monoclonal HCV infection. Monoclonal infection simplifies studies of HCV, because virus interaction with the host is not confounded by the quasispecies invariably present in a natural infection. It furthermore permits true homologous challenge in studies of protective immunity and in testing the efficacy of vaccine candidates. Finally, this in vivo transfection system has made it possible to test for the first time the importance of genetic elements for HCV infectivity. C1 NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Bukh, J (reprint author), NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bldg 50,Room 6529,50 South Dr,MSC 8009, Bethesda, MD 20892 USA. EM jbukh@niaid.nih.gov NR 49 TC 118 Z9 128 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUN PY 2004 VL 39 IS 6 BP 1469 EP 1475 DI 10.1002/hep.20268 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 826SN UT WOS:000221849000001 PM 15185284 ER PT J AU Ilias, I Alesci, S Pacak, K AF Ilias, I Alesci, S Pacak, K TI Current views on imaging of adrenal tumors SO HORMONE AND METABOLIC RESEARCH LA English DT Article; Proceedings Paper CT 6th German Adrenal Conference CY NOV 21-23, 2003 CL Kloster Drubeck, GERMANY DE adrenal gland neoplasms; radionuclide imaging; magnetic resonance imaging; emission-computed tomography; X-ray computed tomography ID POSITRON-EMISSION-TOMOGRAPHY; OF-THE-ART; ADRENOCORTICAL CARCINOMA; FDG-PET; PHEOCHROMOCYTOMA; MASSES; CT; INCIDENTALOMA; DIAGNOSIS; METAIODOBENZYLGUANIDINE AB Anatomical imaging modalities (such as computed tomography [CT] or magnetic resonance imaging [MRI]) and functional imaging modalities (that is, nuclear medicine) are used in the evaluation of adrenal glands. The use of CT (unenhanced, followed by contrast-enhanced) evaluation is the cornerstone of imaging of adrenal tumors. Attenuation values of less than 10 Hounsfield units at unenhanced CT are practically diagnostic for adenomas, while attenuation values of greater than 10 HU are not diagnostic of metastatic disease since non-metastatic disease is also a possibility. When lesions cannot be characterized adequately with CT, MRI evaluation (with T1 and T2-weighted sequences and chemical shift and fat-suppression refinements) is sought. Functional nuclear medicine imaging can be of utility in the evaluation of adrenal masses, more particularly for lesions not adequately characterized with CT and MRI. Nuclear medicine techniques are based on physiological and pathophysiological processes (cellular metabolism, tissue perfusion and local synthesis, uptake, storage of hormones and their receptors). Functional imaging aids initial preoperative staging, diagnostic evaluation of suspicious lesions, identification of metastatic or recurrent tumors, refining prognosis, and deciding on and predicting responses to therapy. [I-131]-6-iodomethyl norcholesterol scintigraphy can differentiate adenomas from carcinomas. Pheochromocytomas appear as areas of abnormal/increased [I-131]- and [I-123]-meta-iodobenzylguanidine uptake. Our experience has shown that [F-18]-fluorodopamine is an excellent agent for localizing adrenal and extra-adrenal pheochromocytomas. C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Univ Patras, Sch Hlth Sci, Fac Med, Dept Pharmacol, Rion Patras, Greece. NIMH, Clin Neuroendocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), NICHD, Unit Clin Neuroendocrinol, PREB, NIH, Bldg 10 Room 9D42,MSC-1583,10 Ctr Dr, Bethesda, MD 20892 USA. EM karel@mail.nih.gov NR 31 TC 6 Z9 6 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 J9 HORM METAB RES JI Horm. Metab. Res. PD JUN PY 2004 VL 36 IS 6 BP 430 EP 435 DI 10.1055/s-2004-814582 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 838VD UT WOS:000222740500016 PM 15241736 ER PT J AU Parks, CG Pandey, JP Dooley, MA Treadwell, EL St Clair, EW Gilkeson, GS Feghali-Botswick, CL Cooper, GS AF Parks, CG Pandey, JP Dooley, MA Treadwell, EL St Clair, EW Gilkeson, GS Feghali-Botswick, CL Cooper, GS TI Genetic Polymorphisms in tumor necrosis factor (TNF)-alpha and TNF-beta in a population-based study of systemic lupus erythematosus: Associations and interaction with the interleukin-1 alpha-889 C/T polymorphism SO HUMAN IMMUNOLOGY LA English DT Article DE TNF; polymorphism; systemic lupus erythematosus; population-based; genetics ID TUMOR-NECROSIS-FACTOR; MAJOR HISTOCOMPATIBILITY COMPLEX; SOUTHEASTERN UNITED-STATES; ALPHA MONOCLONAL-ANTIBODY; CLASS-II; RHEUMATOID-ARTHRITIS; TNFB-ASTERISK-2 HOMOZYGOTE; PROMOTER POLYMORPHISMS; FUNCTIONAL-ANALYSIS; ITALIAN POPULATION AB Tumor necrosis factor (TNF) is involved in the pathogenesis of systemic lupus erythematosus (SLE), but the role of TNF polymorphisms in SLE susceptibility remains unclear. Previous studies in different populations report an inconsistent association of the TNF-alpha -308A allele with SLE, sometimes depending on the presence of HLA-DR3. We examined the association of polymorphisms in TNF-alpha (-308G/A, -238G/A) and TNFbeta (+252A/G) in a population-based study of SLE in the southeastern United States and considered TNF-SLE associations with respect to HLA-DR3 and DR2 and the interleukin (IL)-1alpha -889C/T polymorphism, previously linked to SLE in this population. Genotypes were analyzed for 230 recently diagnosed SLE patients who met American College of Rheumatology classification criteria and 276 age- and sex-matched controls, randomly selected from driver's license registries. Carriage of the TNF-alpha -308A allele was significantly associated with SLE in Caucasians (OR = 2.3; 95% Cl 1.4, 3-9), but not African Americans. Analyses stratified by IL-1alpha -889 genotypes (C/C vs C/T or T/T) revealed independent associations of SLE with TNF-alpha -308A or HLA-DR2 and DR3. This reflected a significant interaction of TNF and IL-1 genotypes in Caucasians, and yielded a strong association (OR = 8.0, p < 0.00001) for the combined "HLA-DR3, TNF-alpha -308A, IL-1alpha -889C/C" genotype. These findings provide evidence of cytokine gene epistasis in SLE susceptibility. (C) American Society for Histocompatibility and Immunogenetics, 2004. Published by Elsevier Inc. C1 NIEHS, Epidemiol Branch, Durham, NC 27709 USA. Med Univ S Carolina, Charleston, SC 29425 USA. Univ N Carolina, Sch Med, Chapel Hill, NC USA. E Carolina Univ, Sch Med, Greenville, NC USA. Duke Univ, Med Ctr, Durham, NC USA. Univ Pittsburgh, Pittsburgh, PA USA. RP Parks, CG (reprint author), NIEHS, Epidemiol Branch, POB 12233, Durham, NC 27709 USA. EM parks@niehs.nih.gov OI Parks, Christine/0000-0002-5734-3456 NR 66 TC 43 Z9 49 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0198-8859 J9 HUM IMMUNOL JI Hum. Immunol. PD JUN PY 2004 VL 65 IS 6 BP 622 EP 631 DI 10.1016/j.humimm.2004.03.001 PG 10 WC Immunology SC Immunology GA 838UQ UT WOS:000222739200007 PM 15219382 ER PT J AU Uda, M Ottolenghi, C Deiana, M Kimber, W Forabosco, A Cao, A Schlessinger, D Pilia, G AF Uda, M Ottolenghi, C Deiana, M Kimber, W Forabosco, A Cao, A Schlessinger, D Pilia, G TI Foxl2 disruption causes mouse ovarian failure by pervasive blockage of follicle development SO HUMAN MOLECULAR GENETICS LA English DT Article ID TRANSCRIPTION FACTOR FOXL2; INVERSUS SYNDROME; DIFFERENTIATION; EXPRESSION; RECEPTORS; GONAD; TIME; GENE; SEX AB FOXL2 mutations cause gonadal dysgenesis or premature ovarian failure (POF) in women, as well as eyelid/forehead dysmorphology in both sexes (the 'blepharophimosis-ptosis-epicanthus inversus syndrome', BPES). Here we report that mice lacking Foxl2 recapitulate relevant features of human BPES: males and females are small and show distinctive craniofacial morphology with upper eyelids absent. Furthermore, in mice as in humans, sterility is confined to females. Features of Foxl2 null animals point toward a new mechanism of POF, with all major somatic cell lineages failing to develop around growing oocytes from the time of primordial follicle formation. Foxl2 disruption thus provides a model for histogenesis and reproductive competence of the ovary. C1 Osped Microcitem, CNR, Ist Neurogenet & Neurofarmacol, I-09100 Cagliari, Italy. NIA, Genet Lab, Baltimore, MD 21224 USA. Univ Modena & Reggio Emilia, Policlin, Dept Mother & Child, I-41100 Modena, Italy. RP Pilia, G (reprint author), Osped Microcitem, CNR, Ist Neurogenet & Neurofarmacol, Via Jenner S-N, I-09100 Cagliari, Italy. EM pilia@unica.it FU Telethon [GP0049Y01] NR 33 TC 255 Z9 264 U1 2 U2 22 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUN 1 PY 2004 VL 13 IS 11 BP 1171 EP 1181 DI 10.1093/hmg/ddh124 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 820RC UT WOS:000221406000008 PM 15056605 ER PT J AU Goldstein, AM AF Goldstein, Alisa M. TI Familial Melanoma, Pancreatic Cancer and Germline CDKN2A Mutations SO HUMAN MUTATION LA English DT Article DE melanoma; familial; pancreatic cancer; CDKN2A AB Germline CDKN2A mutations have been observed in approximately 20 percent of familial melanoma kindreds from North America, Europe and Australasia. There is also an increased risk of pancreatic cancer in a subset of families with mutations, however, the precise relationship between the CDKN2A gene and pancreatic cancer remains unknown. The relationships between familial melanoma, pancreatic cancer and germline CDKN2A mutations were examined using published data. There were 67 different CDKN2A mutations in 189 melanoma-prone families. Forty-two families (18 mutations) had pancreatic cancer reported. For families without reported pancreatic cancer, the most common types of mutations were missense (56%), frameshift (12%), and deletions (12%). For families with pancreatic cancer, missense (56%), splicing (17%), and frameshift (11%) mutations were most common. Seventy percent of the mutations were observed only once, while the remainder recurred in different families. Comparison of 147 melanoma-prone families without pancreatic cancer to the 42 families that had pancreatic cancer reported showed no significant differences in the types or locations of mutations. However, there was a significant difference (p=0.002) in the distribution of families across the four ankyrin repeats. This finding primarily resulted from the six most frequent mutations where the distribution of pancreatic cancer varied significantly (p=0.02) from at least 30% in c. 301G>T (p.G101W), c.225_ 243del19 (p.P75fs), c.337_ 338insGTC (p. R112_ L113insR), and c. 377T>A (p.V126D) families to less than 10% in c.71G>C (p.R24P) and c.159G>C (p.M53I) families. Further research utilizing individual-specific data will be required to determine whether these patterns represent etiologic differences or incomplete reporting of cancer and mutation data. Published 2004 Wiley-Liss, Inc.dagger C1 [Goldstein, Alisa M.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. RP Goldstein, AM (reprint author), NCI, Genet Epidemiol Branch, NIH, DHHS, Execut Plaza South,Room 7004,6120 Execut Blvd MSC, Bethesda, MD 20892 USA. NR 78 TC 68 Z9 72 U1 3 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 EI 1098-1004 J9 HUM MUTAT JI Hum. Mutat. PD JUN PY 2004 VL 23 IS 6 BP 630 EP + DI 10.1002/humu.9247 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA V30GI UT WOS:000208804100004 PM 15146471 ER PT J AU Eldadah, BA Pacak, K Eisenhofer, G Holmes, C Kopin, IJ Goldstein, DS AF Eldadah, BA Pacak, K Eisenhofer, G Holmes, C Kopin, IJ Goldstein, DS TI Cardiac uptake-1 inhibition by high circulating norepinephrine levels in patients with pheochromocytoma SO HYPERTENSION LA English DT Article DE heart; norepinephrine; pheochromocytoma; radiography ID SYMPATHETIC-NERVE FUNCTION; TYROSINE-HYDROXYLASE; IN-VIVO; TRANSPORTER; HEART; REMOVAL; MIBG; INNERVATION; KINETICS; INVIVO AB Neuronal reuptake (uptake-1) constitutes the main route of inactivation of the sympathetic neurotransmitter norepinephrine in the heart and therefore contributes importantly to cardiac sympathetic neuroeffector function. In laboratory animals and in vitro preparations, half saturation of the transporter occurs at norepinephrine concentrations of 0.1 to 1 mumol/L. This study addressed whether endogenous norepinephrine can attain high enough plasma concentrations in humans to inhibit cardiac uptake-1. Patients with increased plasma norepinephrine levels due to pheochromocytoma were assessed by 6-[F-18]fluorodopamine positron emission tomography. Above an antecubital venous plasma concentration of 3 nmol/L (approximate to500 pg/mL), left ventricular myocardial 6-[F-18]fluorodopamine-derived radioactivity varied inversely with the logarithm of the plasma norepinephrine concentration (r= -0.77, P < 0.0001). Reduction of plasma norepinephrine levels by treatment of the pheochromocytoma increased myocardial 6-[F-18] fluorodopamine-derived radioactivity. At sufficiently high plasma concentrations, endogenous norepinephrine can compete with sympathetic imaging agents for uptake-1. The results call for caution in drawing quantitative conclusions about uptake-1 in the setting of high circulating concentrations of endogenous norepinephrine. C1 NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. NICHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Eldadah, BA (reprint author), NINDS, Clin Neurocardiol Sect, NIH, Bldg 10,Room 6N252,10 Ctr Dr,MSC-1620, Bethesda, MD 20892 USA. EM eldadahb@ninds.nih.gov NR 28 TC 14 Z9 14 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD JUN PY 2004 VL 43 IS 6 BP 1227 EP 1232 DI 10.1161/01.HYP.0000127305.87552.d6 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 824HC UT WOS:000221676300018 PM 15078865 ER PT J AU Mitchell, GF Parise, H Benjamin, EJ Larson, MG Keyes, MJ Vita, JA Vasan, RS Levy, D AF Mitchell, GF Parise, H Benjamin, EJ Larson, MG Keyes, MJ Vita, JA Vasan, RS Levy, D TI Changes in arterial stiffness and wave reflection with advancing age in healthy men and women - The Framingham Heart Study SO HYPERTENSION LA English DT Article DE aging; aorta; arteries; arteriosclerosis; elasticity; elderly; vasculature ID AORTIC INPUT IMPEDANCE; PULSE PRESSURE; NONINVASIVE DETERMINATION; CARDIOVASCULAR MORTALITY; SYSTOLIC HYPERTENSION; INDEPENDENT PREDICTOR; BLOOD-PRESSURE; DISEASE; GENDER; RISK AB With advancing age, arterial stiffness and wave reflections increase and elevate systolic and pulse pressures. An elevated central pulse pressure is generally ascribed to increased wave reflection and portends an unfavorable prognosis. Using arterial tonometry, we evaluated central (carotid-femoral) and peripheral (carotid-brachial) pulse wave velocity, amplitudes of forward and reflected pressure waves, and augmentation index in 188 men and 333 women in the Framingham Heart Study offspring cohort who were free of clinical cardiovascular disease, hypertension, diabetes, smoking within the past 12 months, dyslipidemia, and obesity. In multivariable linear regression models, advancing age was the predominant correlate of higher carotid-femoral pulse wave velocity; other correlates were higher mean arterial pressure, heart rate, and triglycerides and walk test before tonometry (model R-2 = 0.512, P < 0.001). A similar model was obtained for carotid-brachial pulse wave velocity (model R-2 = 0.227, P < 0.001), although the increase with advancing age was smaller. Owing to different relations of age to central and peripheral stiffness measures, carotid-femoral pulse wave velocity was lower than carotid-brachial pulse wave velocity before age 50 years but exceeded it thereafter, leading to reversal of the normal central-to-peripheral arterial stiffness gradient. In this healthy cohort with a minimal burden of cardiovascular disease risk factors, an age-related increase in aortic stiffness, as compared with peripheral arterial stiffness, was associated with increasing forward wave amplitude and pulse pressure and reversal of the arterial stiffness gradient. This phenomenon may facilitate forward transmission of potentially deleterious pressure pulsations into the periphery. C1 Cardiovasc Engn Inc, Holliston, MA 01746 USA. Boston Univ, Sch Med, Dept Math & Stat, Boston, MA 02118 USA. Boston Univ, Sch Med, Evans Dept Med, Boston, MA 02118 USA. Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02118 USA. NHLBI, Framingham Study, Framingham, MA USA. RP Mitchell, GF (reprint author), Cardiovasc Engn Inc, 327 Fiske St, Holliston, MA 01746 USA. EM GaryFMitchell@mindspring.com OI Vita, Joseph/0000-0001-5607-1797; Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [1R01-HL60040, 1R01-HL70100, 2K24-HL04334, N01-HC38038] NR 43 TC 652 Z9 694 U1 2 U2 32 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD JUN PY 2004 VL 43 IS 6 BP 1239 EP 1245 DI 10.1161/01.HYP.0000128420.01881.aa PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 824HC UT WOS:000221676300020 PM 15123572 ER PT J AU Saad, MF Rewers, M Selby, J Howard, G Jinagouda, S Fahmi, S Zaccaro, D Bergman, RN Savage, PJ Haffner, SM AF Saad, MF Rewers, M Selby, J Howard, G Jinagouda, S Fahmi, S Zaccaro, D Bergman, RN Savage, PJ Haffner, SM TI Insulin resistance and hypertension - The Insulin Resistance Atherosclerosis Study SO HYPERTENSION LA English DT Article DE insulin resistance; insulin; hypertension; blood pressure; diabetes ID CARDIOVASCULAR RISK-FACTORS; GLUCOSE-TOLERANCE TEST; MINIMAL MODEL ANALYSIS; HIGH BLOOD-PRESSURE; DIABETIC SUBJECTS; RACIAL-DIFFERENCES; OBESE MAN; HYPERINSULINEMIA; SENSITIVITY; METABOLISM AB The association between insulin resistance and insulinemia and hypertension is controversial. We examined the relation between insulin resistance and hypertension in 564 non-Hispanic whites (NHW), 505 Hispanics (H), and 413 African Americans (AA) who participated in the Insulin Resistance Atherosclerosis Study (IRAS). Insulin sensitivity was measured with a frequently sampled intravenous glucose tolerance test with minimal model analysis. The prevalence of hypertension was 32.5%, 49.4%, and 32.3% in NHW, AA, and H, respectively (P < 0.001). When subjects without diabetes in all ethnic groups were combined, age, male sex, race (AA), body mass index (BMI), and insulin resistance, but not fasting insulin, were significantly associated with hypertension. When each ethnic group was analyzed separately, insulin resistance was significantly associated with hypertension in NHW and H, but not AA. After excluding subjects taking antihypertensive medications, male sex, BMI, fasting glucose, and insulin resistance, but not fasting insulin, were significant determinants of blood pressure. When the 3 ethnic groups were analyzed separately, insulin resistance was significantly associated with blood pressure in H, but not NHW, or AA. Neither insulin resistance nor fasting insulin was significantly associated with hypertension or blood pressure in subjects with diabetes of the 3 ethnic groups after adjusting for age, sex, BMI, and waist. In conclusion, insulin resistance, but not insulinemia, was related to hypertension and blood pressure in subjects without diabetes, but ethnic differences in these relations appear to exist. Neither insulin resistance nor insulinemia was related to hypertension or blood pressure in patients with type 2 diabetes in the 3 ethnic groups. C1 Univ Calif Los Angeles, Sch Med, Dept Med, Div Clin Epidemiol, Los Angeles, CA 90024 USA. Univ Colorado, Dept Prevent Med & Biometr, Denver, CO 80202 USA. Kaiser Permanente, Div Res, Oakland, CA USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, Winston Salem, NC USA. Univ So Calif, Dept Physiol & Biophys, Los Angeles, CA 90089 USA. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. Univ Texas, Dept Med, San Antonio, TX 78285 USA. RP Saad, MF (reprint author), Univ Calif Los Angeles, Sch Med, Dept Med, Div Clin Epidemiol, 924 Westwood Blvd,Suite 335,Mail Box 15, Los Angeles, CA 90024 USA. EM msaad@mednet.ucla.edu FU NHLBI NIH HHS [U01-HL47889, U01-HL47887, U01-HL47892, U01-HL47902]; NIDDK NIH HHS [R01 DK029867] NR 40 TC 63 Z9 71 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD JUN PY 2004 VL 43 IS 6 BP 1324 EP 1331 DI 10.1161/01.HYP.0000128019.19363.f9 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 824HC UT WOS:000221676300033 PM 15123571 ER PT J AU Batkai, S Pacher, P Osei-hyiaman, D Radaeva, S Offertaler, L Bukoski, R Kunos, G AF Batkai, S Pacher, P Osei-hyiaman, D Radaeva, S Offertaler, L Bukoski, R Kunos, G TI Endocannabinoids are involved in regulating cardiovascular function in spontaneously hypertensive rats SO HYPERTENSION LA English DT Meeting Abstract CT 57th Annual Fall Conference of the Council-for-High-Blood-Pressure-Research CY SEP 23-26, 2003 CL WASHINGTON, DC SP Council High Blood Pressure Res, Amer Heart Assoc, Council Nutrit, Phys Activ & Metabolism C1 NIAAA, NIH, Bethesda, MD USA. N Carolina Cent Univ, Durham, NC USA. RI Batkai, Sandor/G-3889-2010; Batkai, Sandor/H-7983-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD JUN PY 2004 VL 43 IS 6 BP 1354 EP 1354 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 824HC UT WOS:000221676300076 ER PT J AU Lafont, BAP Buckler-White, A Plishka, R Buckler, C Martin, MA AF Lafont, BAP Buckler-White, A Plishka, R Buckler, C Martin, MA TI Pig-tailed macaques (Macaca nemestrina) possess six MHC-E families that are conserved among macaque species: implication for their binding to natural killer receptor variants SO IMMUNOGENETICS LA English DT Article DE MHC; non-human primate; polymorphism; NK cells ID CLASS-I GENES; MAJOR HISTOCOMPATIBILITY COMPLEX; MOLECULE HLA-E; CELL-RECEPTORS; RHESUS-MONKEY; E LOCUS; ANTIGEN PRESENTATION; T-LYMPHOCYTES; PRIMATES; ALLELES AB MHC loci encode highly polymorphic molecules involved in the presentation of self and non-self peptides to cells of the adaptive and innate immune systems. Although variable, MHC-E genes are well conserved among primates and provide signals to natural killer cells. In this study, we sequenced and analyzed MHC-E alleles of pig-tailed macaque (Macaca nemestrina), a nonhuman primate used for HIV pathogenesis and vaccine studies. Among a group of seven macaques, the characterization of eight Mane-E alleles revealed an increased number of polymorphic sites compared with human HLA-E alleles. Phylogenetic analyses of MHC-E alleles from pig-tailed macaque, rhesus monkey (Macaca mulatta) and cynomolgus macaque (Macaca fascicularis) demonstrated that the three macaque species shared six families of macaque MHC-E alleles and indicated that these families existed in the common ancestor 5.5 million years ago. Polymorphic Mane-E sites were not concentrated within the peptide-binding pockets, but were distributed throughout the entire ORF. The peptide-binding domain of Mane-E is similar to its human analogue, and peptide substrates theoretically capable of binding to Mane-E molecules were found in the leader sequence of classical Mane-A and -B molecules. Additionally, the polymorphic amino acids located in the alpha(1) and alpha(2) domains of Mane-E molecules have side chains expected to be oriented toward solvent and away from the peptide-binding groove, suggesting that some of them (positions 19, 73, 79 and 145) might be available for interaction with polymorphic receptors of natural killer cells. C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Martin, MA (reprint author), NIAID, Mol Microbiol Lab, NIH, 4 Ctr Dr, Bethesda, MD 20892 USA. EM malm@niaid.nih.gov RI Lafont, Bernard/B-7236-2014 NR 53 TC 13 Z9 13 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0093-7711 J9 IMMUNOGENETICS JI Immunogenetics PD JUN PY 2004 VL 56 IS 3 BP 142 EP 154 DI 10.1007/s00251-004-0663-4 PG 13 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 829OO UT WOS:000222059000002 PM 15148641 ER PT J AU Chenoweth, MR Greene, CE Krause, DC Gherardini, FC AF Chenoweth, MR Greene, CE Krause, DC Gherardini, FC TI Predominant outer membrane antigens of Bartonella henselae SO INFECTION AND IMMUNITY LA English DT Article ID ENDOTHELIAL-CELLS; DOMESTIC CATS; HEMIN-BINDING; POLYACRYLAMIDE GELS; IN-VITRO; BACILLIFORMIS; INFECTION; PROTEINS; QUINTANA; ERYTHROCYTES AB A hallmark of Bartonella henselae is persistent bacteremia in cats despite the presence of a vigorous host immune response. To understand better the long-term survival of B. henselae in cats, we examined the feline humoral immune response to B. henselae outer membrane (OM) proteins in naturally and experimentally infected cats. Initially, a panel of sera (n = 42) collected throughout North America from naturally infected cats was used to probe B. henselae total membranes to detect commonly recognized antigens. Twelve antigens reacted with sera from at least 85% of cats, and five were recognized by sera from all cats. To localize these antigens further, Oms were purified on discontinuous sucrose density step gradients. Each membrane fraction (OM, hybrid or inner membrane [IM]) contained less than 1% of the total malate dehydrogenase activity (soluble marker), indicating very little contamination by cytoplasmic proteins. FtsI, an integral IM cell division protein, was used to identify the low-density fraction (rho = 1.13 g/cm(3)) as putative IM (<5% of the total FtsI localized to the high-density fraction) while lipopolysaccharide (LPS) and Pap31, a homolog of the Bartonella quintana heme-binding protein A (HbpA), defined the high-density fraction (p = 1.20 g/cm(3)) as putative OM. Additionally, little evidence of cross-contamination between the IM and OM was evident by two-dimensional gel electrophoresis. When purified OMs were probed with feline sera, antigenic proteins profiles were very similar to those observed with total membranes, indicating that many, but not all, of the immunoreactive proteins detected in the initial immunoblots were OM components. Interestingly, two-dimensional immunoblots indicated that B. henselae LPS and members of the Hbp family of proteins did not appear to stimulate an humoral response in any infected cats. Seven proteins were recognized by at least 70% of sera tested, but only three were recognized by all sera. Nanospray-tandem mass spectrometry was used to identify OM components, including the immunodominant M proteins. Recognition of the nonimmunogenic nature of the major OM components, such as LPS, and identification of the predominant immunogens should elucidate the mechanisms by which B. henselae establishes persistent bacteremic infections within cats. Additionally, the common antigens may serve as potential feline vaccine candidates to eliminate the pathogen from its animal reservoir. C1 NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, Hamilton, MT 59840 USA. Univ Georgia, Coll Vet Med, Dept Microbiol, Athens, GA 30602 USA. Univ Georgia, Coll Vet Med, Dept Small Anim Med, Athens, GA 30602 USA. RP NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM FGHERARDINI@NIAID.NIH.GOV NR 43 TC 22 Z9 22 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD JUN PY 2004 VL 72 IS 6 BP 3097 EP 3105 DI 10.1128/IAI.72.6.3097-3105.2004 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 824CT UT WOS:000221662400002 PM 15155610 ER PT J AU Viau, M Longo, NS Lipsky, PE Bjorck, L Zouali, M AF Viau, M Longo, NS Lipsky, PE Bjorck, L Zouali, M TI Specific in vivo deletion of B-cell subpopulations expressing human immunoglobulins by the B-cell superantigen protein L SO INFECTION AND IMMUNITY LA English DT Article ID EPSILON-RI+ CELLS; MARGINAL ZONE; BINDING-SITE; HIV-1 GP120; STRUCTURAL BASIS; B-1 CELLS; STAPHYLOCOCCAL-ENTEROTOXIN; MOLECULAR-MECHANISMS; GENE REPERTOIRE; IMMUNE-SYSTEM AB Some pathogens have evolved to produce proteins, called B-cell superantigens, that can interact with human immunoglobulin variable regions, independently of the combining site, and activate B lymphocytes that express the target immunoglobulins. However, the in vivo consequences of these interactions on human B-cell numbers and function are largely unknown. Using transgenic mice expressing fully human immunoglobulins, we studied the consequences of in vivo exposure of protein L of Peptostreptococcus magnus with human immunoglobulins. In the mature pool of B cells, protein L exposure resulted in a specific reduction of splenic marginal-zone B cells and peritoneal B-1 cells. Splenic B cells exhibited a skewed light-chain repertoire consistent with the capacity of protein L to bind specific kappa gene products. Remarkably, these two B-cell subsets are implicated in innate B-cell immunity, allowing rapid clearance of pathogens. Thus, the present study reveals a novel mechanism that may be used by some infectious agents to subvert a first line of the host's immune defense. C1 INSERM, Immunopathol Humaine, Inst Natl Sante & Rech Med, U 430, F-75006 Paris, France. NIAMSD, Bethesda, MD 20892 USA. Lund Univ, Dept Cell & Mol Biol, SE-22184 Lund, Sweden. RP Zouali, M (reprint author), INSERM, Immunopathol Humaine, Inst Natl Sante & Rech Med, U 430, 15 Rue Ecole Med, F-75006 Paris, France. EM moncef.zouali@wanadoo.fr NR 69 TC 20 Z9 21 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD JUN PY 2004 VL 72 IS 6 BP 3515 EP 3523 DI 10.1128/IAI.72.6.3515-3523.2004 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 824CT UT WOS:000221662400051 PM 15155659 ER PT J AU Oberdorster, G Sharp, Z Atudorei, V Elder, A Gelein, R Kreyling, W Cox, C AF Oberdorster, G Sharp, Z Atudorei, V Elder, A Gelein, R Kreyling, W Cox, C TI Translocation of inhaled ultrafine particles to the brain SO INHALATION TOXICOLOGY LA English DT Article; Proceedings Paper CT 4th Colloquium on PM and Human Health CY MAR 31-APR 04, 2003 CL Pittsburgh, PA ID AIR-POLLUTION; RAT-BRAIN; OLFACTORY TRANSPORT; SIZE DISTRIBUTIONS; NASAL EPITHELIUM; BLOOD; DEPOSITION; NEURONS; IDENTIFICATION; MANGANESE AB Ultrafine particles (UFP, particles <100 nm) are ubiquitous in ambient urban and indoor air from multiple sources and may contribute to adverse respiratory and cardiovascular effects of particulate matter (PM). Depending on their particle size, inhaled UFP are efficiently deposited in nasal, tracheobronchial, and alveolar regions due to diffusion. Our previous rat studies have shown that UFP can translocate to interstitial sites in the respiratory tract as well as to extrapulmonary organs such as liver within 4 to 24 h postexposure. There were also indications that the olfactory bulb of the brain was targeted. Our objective in this follow-up study, therefore, was to determine whether translocation of inhaled ultrafine solid particles to regions of the brain takes place, hypothesizing that UFP depositing on the olfactory mucosa of the nasal region will translocate along the olfactory nerve into the olfactory bulb. This should result in significant increases in that region on the days following the exposure as opposed to other areas of the central nervous system (CNS). We generated ultrafine elemental C-13 particles (CMD=36 nm; GSD=1.66) from [C-13] graphite rods by electric spark discharge in an argon atmosphere at a concentration of 160 μg/m(3). Rats were exposed for 6 h, and lungs, cerebrum, cerebellum and olfactory bulbs were removed 1, 3, 5, and 7 days after exposure. C-13 concentrations were determined by isotope ratio mass spectroscopy and compared to background C-13 levels of sham-exposed controls (day 0). The background corrected pulmonary C-13 added as ultrafine C-13 particles on day 1 postexposure was 1.34 μg/lung. Lung C-13 concentration decreased from 1.39 μg/g ( day 1) to 0.59 μg/g by 7 days postexposure. There was a significant and persistent increase in added C-13 in the olfactory bulb of 0.35 μg/g on day 1, which increased to 0.43 μg/g by day 7. Day 1 C-13 concentrations of cerebrum and cerebellum were also significantly increased but the increase was inconsistent, significant only on one additional day of the postexposure period, possibly reflecting translocation across the blood-brain barrier in certain brain regions. The increases in olfactory bulbs are consistent with earlier studies in nonhuman primates and rodents that demonstrated that intranasally instilled solid UFP translocate along axons of the olfactory nerve into the CNS. We conclude from our study that the CNS can be targeted by airborne solid ultrafine particles and that the most likely mechanism is from deposits on the olfactory mucosa of the nasopharyngeal region of the respiratory tract and subsequent translocation via the olfactory nerve. Depending on particle size, >50% of inhaled UFP can be depositing in the nasopharyngeal region during nasal breathing. Preliminary estimates from the present results show that similar to20% of the UFP deposited on the olfactory mucosa of the rat can be translocated to the olfactory bulb. Such neuronal translocation constitutes an additional not generally recognized clearance pathway for inhaled solid UFP, whose significance for humans, however, still needs to be established. It could provide a portal of entry into the CNS for solid UFP, circumventing the tight blood-brain barrier. Whether this translocation of inhaled UFP can cause CNS effects needs to be determined in future studies. C1 Univ Rochester, Dept Environm Med, Rochester, NY 14642 USA. Univ New Mexico, Albuquerque, NM 87131 USA. Natl Res Ctr Environm & Hlth, Neuherberg, Germany. NIH, Bethesda, MD 20892 USA. RP Oberdorster, G (reprint author), Univ Rochester, Dept Environm Med, 575 Elmwood Ave,Med Ctr Box 850, Rochester, NY 14642 USA. EM gunter_oberdorster@urmc.rochester.edu OI Kreyling, Wolfgang/0000-0002-0702-6567 FU NIEHS NIH HHS [ESO1247] NR 52 TC 978 Z9 1049 U1 18 U2 155 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0895-8378 J9 INHAL TOXICOL JI Inhal. Toxicol. PD JUN PY 2004 VL 16 IS 6-7 BP 437 EP 445 DI 10.1080/08958370490439597 PG 9 WC Toxicology SC Toxicology GA 816LJ UT WOS:000221111100012 PM 15204759 ER PT J AU Ribeiro, JMC Charlab, R Pham, VM Garfield, M Valenzuela, JG AF Ribeiro, JMC Charlab, R Pham, VM Garfield, M Valenzuela, JG TI An insight into the salivary transcriptome and proteome of the adult female mosquito Culex pipiens quinquefasciatus SO INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE mosquito; salivary gland; hematophagy; transcriptome; sialome ID VECTOR ANOPHELES-GAMBIAE; FLY LUTZOMYIA-LONGIPALPIS; WEST-NILE-VIRUS; C-TYPE LECTINS; AEDES-AEGYPTI; SAND FLY; ADENOSINE-DEAMINASE; RHODNIUS-PROLIXUS; BINDING PROTEIN; HIGH-AFFINITY AB To obtain an insight into the salivary transcriptome and proteome (sialome) of the adult female mosquito Culex quinquefasciatus, a cDNA library was randomly sequenced, and aminoterminal information for selected proteins and peptides was obtained. cDNA sequence clusters coding for secreted proteins were further analyzed. The transcriptome revealed messages coding for several proteins of known families previously reported in the salivary glands of other blood-feeding insects as well as immune-related products such as C-type lectin, gambicin, and members of the prophenol oxidase cascade. Additionally, several transcripts coding for low-complexity proteins were found, some clearly coding for mucins. Many novel transcripts were found, including a novel endonuclease previously described in crabs and shrimps but not in insects; a hyaluronidase, not described before in mosquito salivary glands but found in venom glands and in salivary glands of sand flies and black flies; several cysteine-rich peptides with possible anticlotting function, including one similar to a previously described nematode family of anti-proteases; and a completely novel family of cysteine- and tryptophane-rich proteins (CWRC family) for which 12 full-length sequences are described. Also described are 14 additional novel proteins and peptides whose function and/or family affiliation are unknown. In total, 54 transcripts coding for full-length proteins are described. That several of these are translated into proteins was confirmed by finding the corresponding aminoterminal sequences in the SDS-PAGE/Edman degradation experiments. Electronic versions of all tables and sequences can be found at http://www.nebi.nlm.nih.gov/projects/Mosquito/C_quinquefasciatus_sialome. Published by Elsevier Ltd. C1 NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. Celera Genom, Rockville, MD 20850 USA. NIAID, Biol Resources Branch, NIH, Bethesda, MD 20892 USA. RP Ribeiro, JMC (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy,Room 2E32, Rockville, MD 20852 USA. EM jribeiro@nih.gov OI Ribeiro, Jose/0000-0002-9107-0818 NR 62 TC 98 Z9 105 U1 2 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0965-1748 J9 INSECT BIOCHEM MOLEC JI Insect Biochem. Mol. Biol. PD JUN PY 2004 VL 34 IS 6 BP 543 EP 563 DI 10.1016/j.ibmb.2004.02.008 PG 21 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 828BV UT WOS:000221948600005 PM 15147756 ER PT J AU Brostedt, EM de Faire, U Westerholm, P Knutsson, A Alfredsson, L AF Brostedt, EM de Faire, U Westerholm, P Knutsson, A Alfredsson, L TI Job strain and plasminogen activator inhibitor-1: results from the Swedish WOLF study SO INTERNATIONAL ARCHIVES OF OCCUPATIONAL AND ENVIRONMENTAL HEALTH LA English DT Article DE plasminogen activator inhibitor-1; work; psychological stress; cardiovascular disease; risk factors ID CARDIOVASCULAR RISK-FACTORS; CORONARY-HEART-DISEASE; DECISION LATITUDE; MYOCARDIAL-INFARCTION; WORKING MEN; STOCKHOLM; DEMANDS; PLASMA; WOMEN AB Objectives. To investigate the association between job strain and elevated levels of plasminogen activator inhibitor-1. Methods. A cross-sectional study was carried out, comprising 1,954 actively working men and women between the ages of 19-64 years. Data were collected by questionnaire, clinical examination and blood samples. Results. Elevated plasminogen activator inhibitor-1 levels were more commonly noted in women exposed to job strain than in unexposed women (odds ratio 1.33; 95% confidence interval 1.06-1.65). This association remained after we had adjusted for factors related to behaviour and general health, but became close to 1 after we had adjusted for factors related to the metabolic syndrome. For men, no association between job strain and elevated levels of plasminogen activator inhibitor-1 was observed (odds ratio 0.94; 95% confidence interval 0.71-1.26). Conclusions. Women exposed to job strain were more inclined to respond with increased plasminogen activator inhibitor-1 than men. In this first study on the association between job strain and plasminogen activator inhibitor-1 in both men and women, we observed such a relationship among women but not among men. The data support the notion that job strain might affect the risk of coronary heart disease by influencing an important cardiovascular system: the metabolic syndrome. C1 NIMH, Sect Dev Genet Epidemiol, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. Karolinska Inst, Div Cardiovasc Med, Inst Environm Med, Stockholm, Sweden. Karolinska Inst, Dept Med Epidemiol, Stockholm, Sweden. Karolinska Hosp, Dept Cardiovasc Med, S-10401 Stockholm, Sweden. Natl Inst Working Life, Stockholm, Sweden. Umea Univ Hosp, Dept Publ Hlth & Clin Med, S-90185 Umea, Sweden. RP Brostedt, EM (reprint author), NIMH, Sect Dev Genet Epidemiol, Mood & Anxiety Disorders Program, NIH, 15 K N Dr,MSC 2670, Bethesda, MD 20892 USA. EM ericabrostedt@mail.nih.gov OI Alfredsson, Lars/0000-0003-1688-6697 NR 15 TC 2 Z9 4 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0340-0131 J9 INT ARCH OCC ENV HEA JI Int. Arch. Occup. Environ. Health PD JUN PY 2004 VL 77 IS 5 BP 341 EP 344 DI 10.1007/s00420-004-0514-5 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 835VZ UT WOS:000222514900007 PM 15103467 ER PT J AU Kuznetsova, SA Roberts, DD AF Kuznetsova, SA Roberts, DD TI Functional regulation of T lymphocytes by modulatory extracellular matrix proteins SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY LA English DT Article DE thrombospondins; thymus; cell migration; adhesion; T cell activation ID TISSUE GROWTH-FACTOR; INTEGRIN-MEDIATED ADHESION; CELL-ACTIVATION; TUMOR-GROWTH; MULTIPLE-SCLEROSIS; IN-VITRO; THROMBOSPONDIN-1; OSTEOPONTIN; TENASCIN; EXPRESSION AB In addition to the major structural molecules, which are constitutively present in extracellular matrices, several proteins appear in the extracellular matrix only at specific stages in development or in association with specific pathological conditions. These proteins include thrombospondin-1 and -2, tenascin C, osteopontin, members of the cysteine-rich 61/connective tissue growth factor/nephroblastoma overexpressed family, and secreted protein acidic and rich in cysteine (osteonectin). These proteins play important roles in regulating cell fate during development and in the pathogenesis of several diseases in adult animals. We will review the interactions of T cells with this class of molecules and their resulting effects on T cell behavior. Receptors and signal transduction pathways that mediate the actions of matricellular proteins on T cells are beginning to be defined. Transgenic mice are providing new insights into the functions of these proteins in vivo and are yielding insights into the significance of their reported dysregulation in several human diseases. Published by Elsevier Ltd. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Roberts, DD (reprint author), NCI, Pathol Lab, NIH, Room 2A33,Bldg 10,10 Ctr Dr,MSC1500, Bethesda, MD 20892 USA. EM droberts@helix.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 NR 69 TC 23 Z9 25 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1357-2725 J9 INT J BIOCHEM CELL B JI Int. J. Biochem. Cell Biol. PD JUN PY 2004 VL 36 IS 6 BP 1126 EP 1134 DI 10.1016/j.biocel.2003.12.006 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 818YZ UT WOS:000221281700021 PM 15094127 ER PT J AU Orlic, D AF Orlic, D TI The strength of plasticity: stem cells for cardiac repair SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article; Proceedings Paper CT Conference on Cardiac Tissue Repair CY JUN 04-05, 2004 CL Sirmione, ITALY ID MYOCARDIAL INFARCT REPAIR; BONE-MARROW; ISCHEMIC-MYOCARDIUM; PRIMATE MODEL; IN-VIVO; TRANSPLANTATION; CARDIOMYOCYTES; FUSION; REGENERATION; HEPATOCYTES C1 NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Orlic, D (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, Bldg 49,Room 3A04, Bethesda, MD 20892 USA. EM dorlic@nhgri.nih.gov NR 29 TC 14 Z9 15 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0167-5273 J9 INT J CARDIOL JI Int. J. Cardiol. PD JUN PY 2004 VL 95 SU 1 BP S16 EP S19 DI 10.1016/j.ijcard.2004.04.000 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 831ZF UT WOS:000222234900006 PM 15336838 ER PT J AU Cologne, JB Sharp, GB Neriishi, K Verkasalo, PK Land, CE Nakachi, K AF Cologne, JB Sharp, GB Neriishi, K Verkasalo, PK Land, CE Nakachi, K TI Improving the efficiency of nested case-control studies of interaction by selecting controls using counter matching on exposure SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE nested case-control studies; probability sample; matching; counter matching; breast cancer; radiation effects ID BREAST-CANCER; BOMB SURVIVORS; RISK; 2-STAGE; DESIGN; COHORT; WOMEN AB Background Studies of the effect of exposure to a risk factor measured in an entire cohort may be augmented by nested case-control subsets to investigate confounding or effect modification by additional factors not practically assessed on all cohort members. We compared three control-selection strategies-matching on exposure, counter matching on exposure, and random sampling-to determine which was most efficient in a situation where exposure is a known, continuous variable and high doses are rare. Methods We estimated the power to detect interaction using four control-to-case ratios (1:1, 2:1, 4:1, and 8:1) in a planned case-control study of the joint effect of atomic bomb radiation exposure and serum oestradiol levels on breast cancer. Radiation dose is measured in the entire cohort, but because neither serum oestradiol level nor the true degree of interaction was known, we simulated values of oestradiol and hypothetical levels of oestradiol-radiation interaction. Results Compared with random sampling, power to detect interaction was similarly higher with either matching or counter matching with two or more controls. Conclusions Because counter matching is generally at least as efficient as random sampling, whereas matching on exposure can result in loss of efficiency and precludes estimation of exposure risk, we recommend counter matching for selecting controls in nested case-control studies of the joint effects of multiple risk factors when one is previously measured in the full cohort. C1 Radiat Effects Res Fdn, Dept Stat, Minami Ku, Hiroshima 7320815, Japan. Radiat Effects Res Fdn, Dept Epidemiol, Minami Ku, Hiroshima 7320815, Japan. Radiat Effects Res Fdn, Dept Clin Studies, Minami Ku, Hiroshima 7320815, Japan. Radiat Effects Res Fdn, Dept Radiobiol Mol Epidemiol, Minami Ku, Hiroshima 7320815, Japan. Natl Publ Hlth Inst, Environm Epidemiol Unit, Helsinki, Finland. NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. RP Cologne, JB (reprint author), Radiat Effects Res Fdn, Dept Stat, Minami Ku, 5-2 Hijiyama Pk, Hiroshima 7320815, Japan. EM cologne@rerf.or.jp NR 31 TC 24 Z9 26 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD JUN PY 2004 VL 33 IS 3 BP 485 EP 492 DI 10.1093/ije/dyh097 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 832MR UT WOS:000222272100012 PM 15105408 ER PT J AU Kjaer, SK Mellemkjaer, L Brinton, LA Johansen, C Gridley, G Olsen, JH AF Kjaer, SK Mellemkjaer, L Brinton, LA Johansen, C Gridley, G Olsen, JH TI Tubal sterilization and risk of ovarian, endometrial and cervical cancer. A Danish population-based follow-up study of more than 65 000 sterilized women SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE tubal sterilization; cohort study; risk; gynaecological cancer ID ORAL-CONTRACEPTIVES; LIGATION; HYSTERECTOMY; DETERMINANTS; ASSOCIATION AB Background On the basis of a population-based cohort, we assessed the cancer risk, focusing on gynaecological cancers and pre-malignant lesions, among women with a previous tubal sterilization. Methods Using the Danish Hospital Discharge Register we identified 65 232 women who had a tubal sterilization (1977-1993). The cohort was followed for cancer occurrence, and compared with the expected number based on the national cancer incidence rates. Results The overall risk of ovarian cancer was decreased (standardized incidence ratio [SIR] = 0.82; 95% CI: 0.6, 1.0), and it was still decreased greater than or equal to10 years after the sterilization (SIR = 0.65; 95% CI: 0.4, 1.0). The rate of endometrial cancer was also decreased (SIR = 0.66; 95% CI: 0.5, 1.0), the risk continued being moderately reduced during follow-up, although it was not statistically significant. Conclusions In this nationwide, population-based study we find that women with tubal sterilization have a decreased risk of subsequent development of ovarian cancer. As the protective effect is not decreasing with years of follow-up, our data do not support that 'screening' bias can explain the protective effect, but indicate that the sterilization itself may convey a reduction in risk. The same pattern is found for endometrial cancer, the association being less strong. C1 Danish Canc Soc, Inst Canc Epidemiol, DK-2100 Copenhagen O, Denmark. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Kjaer, SK (reprint author), Danish Canc Soc, Inst Canc Epidemiol, Strandblvd 49, DK-2100 Copenhagen O, Denmark. EM susanne@cancer.dk RI Brinton, Louise/G-7486-2015; OI Brinton, Louise/0000-0003-3853-8562; Olsen, Jorgen Helge/0000-0001-9633-5662; Kjaer, Susanne/0000-0002-8347-1398 FU NCI NIH HHS [N01-CP-61111] NR 43 TC 36 Z9 38 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD JUN PY 2004 VL 33 IS 3 BP 596 EP 602 DI 10.1093/ije/dyh046 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 832MR UT WOS:000222272100031 PM 15163640 ER PT J AU Xing, GQ Russell, S Webster, MJ Post, RM AF Xing, GQ Russell, S Webster, MJ Post, RM TI Decreased expression of mineralocorticoid receptor mRNA in the prefrontal cortex in schizophrenia and bipolar disorder SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE bipolar disorder; MR mRNA; post-mortem brain; prefrontal cortex; schizophrenia ID DEXAMETHASONE-SUPPRESSION TEST; CORTICOTROPIN-RELEASING HORMONE; GLUCOCORTICOID-RECEPTOR; MAJOR DEPRESSION; CORTICOSTEROID RECEPTORS; HIPPOCAMPAL-FORMATION; RAT-BRAIN; STRESS; INCREASES; ILLNESS AB Abnormal prefrontal cortical activity, activation of the hypothalamic-pituitary-adrenal (HPA) axis, and deficits in slow-wave sleep (SWS) have been extensively reported in patients with affective disorders and schizophrenia, yet the underlying pathophysiological mechanisms have not been completely elucidated. Mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) are two nuclear hormone receptors of primary importance in the control of stress-related and circadian HPA activity. A recent study showed that blocking brain MR activity not only enhances CRF-induced ACTH and cortisol release, but also significantly reduces SWS in humans. We hypothesized that the expression of MR would be deficient in the prefrontal cortex of patients with schizophrenia and affective disorders. The MR mRNA expression in the post-mortem prefrontal cortex of patients with major depression (MD), bipolar (BP), and schizophrenic (SZ) disorders and non-psychiatric controls (n=15 for each patient group, and n=14 for controls) was determined by in-situ hybridization. In the dorsolateral prefrontal cortex Brodmann's area 9 (BA 9), MR mRNA was significantly lower (p < 0.05) in all laminae (I-VI) in BP, and in laminae I, III, IV and VI in SZ than in the controls. MR mRNA in BA 9 was negatively correlated with the duration of psychiatric illnesses. In BA 46, MR mRNA was not significantly different among groups, but was positively correlated with brain pH. These results provide the first evidence of deficient prefrontal MR mRNA expression in BP and SZ. Whether these findings may be linked to the abnormal prefrontal function, HPA axis activation, or the deficits in SWS found in these major psychiatric illnesses remains to be further explored. C1 Uniformed Serv Univ Hlth Sci, Dept Psychiat, Bethesda, MD 20814 USA. NIMH, Dept Hlth & Human Serv, NIH, Biol Psychiat Branch, Bethesda, MD 20892 USA. RP Xing, GQ (reprint author), Uniformed Serv Univ Hlth Sci, Dept Psychiat, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM gxing@usuhs.mil OI Xing, Guoqiang/0000-0002-4706-3063 NR 47 TC 49 Z9 51 U1 0 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 IS 2 BP 143 EP 153 DI 10.1017/S1461145703004000 PG 11 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 828OM UT WOS:000221982600006 PM 14741058 ER PT J AU Agnati, LF Leo, G Vergoni, V Genedani, S Franco, R Lluis, C Woods, A Ferre, S Fuxe, K AF Agnati, LF Leo, G Vergoni, V Genedani, S Franco, R Lluis, C Woods, A Ferre, S Fuxe, K TI Multimeric receptor complexes of the basal ganglia as a basis for learning and memory of motor programs and for the expression of L-DOPA induced dyskinesias SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 Univ Modena & Reggio Emilia, Dept Biomed Sci, Modena, Italy. Univ Barcelona, Dept Biochem & Mol Biol, E-08007 Barcelona, Spain. Natl Inst Drug Abuse, DHHS, NIH, Intramural Res Program, Baltimore, MD USA. Karolinska Inst, Dept Neurosci, Div Cellular & Mol Neurochem, Stockholm, Sweden. RI Franco, Rafael/C-3694-2015; Vergoni, Anna Valeria/I-4214-2014; Genedani, Susanna/K-4370-2016 OI Franco, Rafael/0000-0003-2549-4919; Vergoni, Anna Valeria/0000-0003-2580-4163; Genedani, Susanna/0000-0003-1526-153X NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S47 EP S47 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663000176 ER PT J AU Bayle, FJ Amado, I Krebs, MO Dougherty, DM Caci, HM Grillon, C Orain-Pelissolo, S Jouvent, R Olie, JP Barratt, ES AF Bayle, FJ Amado, I Krebs, MO Dougherty, DM Caci, HM Grillon, C Orain-Pelissolo, S Jouvent, R Olie, JP Barratt, ES TI Attention, orienting and timing: Interaction of basic process variations underlying impulsive behavior SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 Univ Paris 05, INSERM, E117, St Anne Hosp, Paris, France. Univ Texas, Sch Med, Houston, TX USA. CHU Nice, Hop Archet 2, Nice, France. NIMH, Bethesda, MD 20892 USA. CNRS, UMR 7593, Paris, France. Univ Texas, Med Branch, Galveston, TX 77550 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S57 EP S58 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663000215 ER PT J AU Benninghoff, J Schmitt, A Moessner, R Gritti, A Rizzi, M Schloesser, RJ Vescovi, AL Lesch, KP AF Benninghoff, J Schmitt, A Moessner, R Gritti, A Rizzi, M Schloesser, RJ Vescovi, AL Lesch, KP TI Studying adult neurogenesis in serotonin transporter deficient (5-HTTKO) mice SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 Hosp San Raffaele, I-20132 Milan, Italy. Univ Wurzburg, D-97070 Wurzburg, Germany. NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S203 EP S204 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663001175 ER PT J AU Berlin, I Gorelick, DA AF Berlin, I Gorelick, DA TI Comparison of the French and US systems for human subject protection SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 Grp Hosp Univ Pitie Salpetriere, Dept Pharmacol, Paris, France. Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S10 EP S10 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663000033 ER PT J AU Berman, KF Meyer-Lindenberg, A Egan, MF Dreher, JC Kolachana, B Weinberger, DR AF Berman, KF Meyer-Lindenberg, A Egan, MF Dreher, JC Kolachana, B Weinberger, DR TI The role of dopamine in the pathophysiology of schizophrenia SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 NIMH, Clin Brain Disorders Branch, NIH, IRP,DHHS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S65 EP S66 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663000248 ER PT J AU Borlongan, CV Wang, Y Su, TP AF Borlongan, CV Wang, Y Su, TP TI Delta opioid peptide, a hibernation inducing trigger, protects against acute and chronic central nervous system diseases SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 Med Coll Georgia, Neurol Inst Mol Med Genet, Augusta, GA 30912 USA. Augusta VA Med Ctr, Augusta, GA USA. NIDA, Intramural Res Program, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S122 EP S122 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663000458 ER PT J AU Chen, G AF Chen, G TI Involvement of extracellular signal regulated kinase pathway in the pathogenesis of stress-related disorders and the therapeutic actions of mood stabilizers SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 NIMH, LMP, MAP, NIH, Bethesda, MD USA. RI Chen, Guang/A-2570-2017 NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S78 EP S79 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663000298 ER PT J AU Dreher, J Kohn, P Kolachana, B Egan, M Weinberger, D Berman, K AF Dreher, J Kohn, P Kolachana, B Egan, M Weinberger, D Berman, K TI Effect of COMT val108/158 Met genotype on brain activation during anticipation of uncertain rewards SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 NIMH, NIH, CBDB, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S304 EP S304 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663001548 ER PT J AU Du, J Gray, N Falke, C Chen, W Manji, H AF Du, J Gray, N Falke, C Chen, W Manji, H TI The role of AMPA receptor trafficking in the pathophysiology and treatment of Bipolar Disorder SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 NIMH, NIH, Mol Pathophysiol Lab, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S185 EP S185 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663001101 ER PT J AU Engel, S Manji, H Chen, G AF Engel, S Manji, H Chen, G TI Behavioral effects of prenatal fluvoxamine in rats SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 NIMH, Bethesda, MD 20892 USA. RI Chen, Guang/A-2570-2017 NR 0 TC 0 Z9 0 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S186 EP S187 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663001107 ER PT J AU Ernst, M AF Ernst, M TI Neural substrates of decision-making and expectation in health, development and attention-deficit hyperactivity disorder SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 NIMH, Mood & Anxiety Disorders Program, NIH, DHHS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S74 EP S74 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663000281 ER PT J AU Ferre, S Ciruela, P Karcz-Kubicha, M Quarta, D Solinas, M Hope, BT Morales, M Goldberg, SR Woods, AS Agnati, LF Fuxe, K Lluis, C Franco, R AF Ferre, S Ciruela, P Karcz-Kubicha, M Quarta, D Solinas, M Hope, BT Morales, M Goldberg, SR Woods, AS Agnati, LF Fuxe, K Lluis, C Franco, R TI Adenosine, a key modulator of striatal function SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 NIDA, Behav Neurosci Branch, IRP, NIH,DHHS, Bethesda, MD USA. RI Hope, Bruce/A-9223-2010; Franco, Rafael/C-3694-2015 OI Hope, Bruce/0000-0001-5804-7061; Franco, Rafael/0000-0003-2549-4919 NR 0 TC 0 Z9 0 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S45 EP S46 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663000173 ER PT J AU Gallinat, J Bajbouj, M Xu, K Goldman, D Winterer, G AF Gallinat, J Bajbouj, M Xu, K Goldman, D Winterer, G TI Association of the G1947A COMT (Val108/158Met) gene polymorphism with prefrontal P300 during information processing SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. RI Bajbouj, Malek/B-3579-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S63 EP S63 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663000240 ER PT J AU Goldberg, TE AF Goldberg, TE TI Thought disorder and semantic function in schizophrenia SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 NIMH, Clin Brain Disorders Branch, IRP, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S26 EP S27 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663000097 ER PT J AU Goldman, D Xu, K Enoch, MA Heitzeg, MM Smith, YR Bueller, JA Xu, Y Koeppe, RA Stohler, CS Virkkunen, M Roy, A Meier, W Zubieta, J AF Goldman, D Xu, K Enoch, MA Heitzeg, MM Smith, YR Bueller, JA Xu, Y Koeppe, RA Stohler, CS Virkkunen, M Roy, A Meier, W Zubieta, J TI Imaging genetics in the addictions: Identification of counterbalancing roles of COMT Val158Met in the behavioral domains of cognition and anxiety/stress response SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S56 EP S56 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663000211 ER PT J AU Gorelick, DA AF Gorelick, DA TI Ethical issues in clinical substance abuse research SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S10 EP S10 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663000036 ER PT J AU Gould, T Einat, H Eberhart, C Manji, H AF Gould, T Einat, H Eberhart, C Manji, H TI Beta-catenin transgenic mice show endogenous mood stabilizer-like behaviors SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD 21218 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S185 EP S186 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663001103 ER PT J AU Grant, SJ AF Grant, SJ TI Review of the evidence for cognitive dysfunction and dependence in MDMA users SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 NIDA, Neurobiol Branch, Div Treatment Res & Dev, NIH,Dept Hlth & Human Serv, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S84 EP S84 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663000320 ER PT J AU Hazlett, EA Buchsbaum, MS Buchsbaum, BR New, A Siever, L AF Hazlett, EA Buchsbaum, MS Buchsbaum, BR New, A Siever, L TI fMRI and modulation of prepulse inhibition in the schizophrenia spectrum SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 Mt Sinai Sch Med, Bronx, NY USA. NIMH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S223 EP S223 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663001253 ER PT J AU Heinz, A Bertolino, A Saunders, RC Kolachana, BS Jones, DW Knable, M Weinberger, DR AF Heinz, A Bertolino, A Saunders, RC Kolachana, BS Jones, DW Knable, M Weinberger, DR TI Brain imaging studies on striatal dopaminergic dysfunction in a primate model and in schizophrenia SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 Univ Med Berlin, Charite, Dept Psychiat, Berlin, Germany. NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S9 EP S10 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663000032 ER PT J AU Hiramatsu, M Tarukado, H Sora, I Uhl, G AF Hiramatsu, M Tarukado, H Sora, I Uhl, G TI Low dose endomorphin-1 improvement of scopolamine-induced memory impairment: MU-independent mechanisms SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 Tohoku Univ, Sendai, Miyagi 980, Japan. NIDA, NIH, DHSS, Bethesda, MD USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S298 EP S298 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663001526 ER PT J AU Lipska, BK AF Lipska, BK TI Prefrontal-hippocampal disconnection and dopamine dysregulation in schizophrenia: from basic to clinical research SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 NIMH, CBDB, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S8 EP S9 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663000028 ER PT J AU Maurice, T Vignes, M Mechti, N Ozato, K Gongora, C AF Maurice, T Vignes, M Mechti, N Ozato, K Gongora, C TI Impaired spatial working memory and enhanced long-term potentiation in histone acetylase PCAF knock-out mice SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 CNRS, FRE 2693, F-75700 Paris, France. CNRS, UMR 5094, F-75700 Paris, France. NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S215 EP S216 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663001222 ER PT J AU Merikangas, KR Low, NCP Herrell, R Angst, J AF Merikangas, KR Low, NCP Herrell, R Angst, J TI Familial and longitudinal patterns of comorbidity of migraine and mental disorders SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 NIMH, Bethesda, MD 20892 USA. Univ Zurich, Zurich, Switzerland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S33 EP S33 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663000123 ER PT J AU Nemes, Z Devreese, B Steinert, PM Vanbeeumen, J Fesus, L AF Nemes, Z Devreese, B Steinert, PM Vanbeeumen, J Fesus, L TI Isopeptide cross-links in neuronal inclusions SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 Univ Debrecen, Debrecen, Hungary. State Univ Ghent, Ghent, Belgium. NIH, Bethesda, MD USA. RI Devreese, Bart/B-2011-2009 OI Devreese, Bart/0000-0002-9764-2581 NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S296 EP S296 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663001520 ER PT J AU Rapoport, JL Gogtay, N Sporn, A AF Rapoport, JL Gogtay, N Sporn, A TI Treatment of childhood schizophrenia SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 NIMH, Bethesda, MD 20892 USA. RI Gogtay, Nitin/A-3035-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S42 EP S42 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663000160 ER PT J AU Rapoport, JL AF Rapoport, JL TI Childhood onset schizophrenia: A progressive neurodevelopmental disorder SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 NIMH, Bethesda, MD 20892 USA. NR 3 TC 3 Z9 3 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S22 EP S22 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663000081 ER PT J AU Siever, LJ Goodman, M Buchsbaum, M Frankle, WG Laruelle, M Gelernter, J Goldman, D AF Siever, LJ Goodman, M Buchsbaum, M Frankle, WG Laruelle, M Gelernter, J Goldman, D TI Genes of susceptibility and intermediate phenotypes in the impulsive personality disorders SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 Mt Sinai Sch Med, Dept Psychiat 1, New York, NY USA. Bronx Vet Adm Med Ctr, Bronx, NY USA. Columbia Univ, New York State Psychiat Inst, New York, NY 10027 USA. Yale Univ, Sch Med, New Haven, CT 06520 USA. NIAAA, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S57 EP S57 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663000213 ER PT J AU Stein, D AF Stein, D TI The social anxiety disorder spectrum SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 NIDA, NIH, Bethesda, MD 20892 USA. Univ Stellenbosch, ZA-7600 Stellenbosch, South Africa. NR 0 TC 0 Z9 0 U1 1 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S112 EP S112 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663000422 ER PT J AU Sunderland, T AF Sunderland, T TI Relationship between APO E4 allele frequency and cerebrospinal fluid (CSF) in subjects "at risk" SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 NIMH, Geriatr Psychiat Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S134 EP S134 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663000500 ER PT J AU Volkow, ND Fowler, JS Wang, GJ AF Volkow, ND Fowler, JS Wang, GJ TI Imaging the addicted brain SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 NIDA, NIH, Bethesda, MD 20892 USA. Brookhaven Natl Lab, Upton, NY 11973 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S65 EP S65 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663000245 ER PT J AU Wang, G Engel, S Yuan, P Zhou, R Einat, H Manj, HK Chen, G AF Wang, G Engel, S Yuan, P Zhou, R Einat, H Manj, HK Chen, G TI Induction of depression-related behaviors in rodents and detection of gene expression patterns associated with depression-related behavior SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 NIMH, NIH, Bethesda, MD 20892 USA. RI Chen, Guang/A-2570-2017 NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S356 EP S356 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663002132 ER PT J AU Weinberger, DR AF Weinberger, DR TI Schizophrenia susceptibility genes, response to treatment, and the new therapeutic horizon SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 NIMH, Clin Brain Disorders Branch, IRP, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S105 EP S105 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663000394 ER PT J AU Zhang, L Schloesser, R Barker, J Manjii, HK AF Zhang, L Schloesser, R Barker, J Manjii, HK TI The role of glial cells in the pathophysiology and treatment of severe, recurrent mood disorders SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th CINP Congress CY JUN 20-24, 2004 CL Paris, FRANCE SP CINP C1 NIMH, Lab Mol Pathophysiol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2004 VL 7 SU 1 BP S11 EP S11 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864WF UT WOS:000224663000039 ER PT J AU Duan, JM Chen, Z Liu, PH Zhang, ZY Tong, TJ AF Duan, JM Chen, Z Liu, PH Zhang, ZY Tong, TJ TI Wild-type p16(INK4a) suppresses cell growth, telomerase activity and DNA repair in human breast cancer MCF-7 cells SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE p16(INK4a); cell growth; cell cycle; telomerase and telomere; DNA repair; breast cancer cells ID HUMAN FIBROBLASTS; REPLICATIVE SENESCENCE; P53; DAMAGE; PROGRESSION; EXPRESSION; IMMORTALIZATION; DEREGULATION; INHIBITION; APOPTOSIS AB p16(INK4a), a cell cycle inhibitor that inhibits cyclin-dependent kinase 4 (cdk4) and cdk6, has been found as the tumor suppressor gene and is frequently deleted, methylated or mutated in many malignancies. Since p16(INK4a) is also a key element controlling cellular senescence and other functions, we hypothesized that p16(INK4a) induced tumor suppression may not be limited to the inhibition of cdks. To investigate the role of p16(INK4a) in tumor suppression and the potential interaction between p16(INK4a) and other cellular controlling elements, such as telomerase activity and DNA repair ability, the full-length of p16(INK4a) cDNA was cloned into a retroviral vector and introduced into human breast cancer MCF-7 cells that were previously demonstrated to harbor homozygous deletions of the p16(INK4a) gene. Stable expression of p16(INK4a) suppressed the malignant phenotype in MCF-7 cells, including cell proliferation, anchorage-independent growth, G1/G0 cell cycle arrest, and the blockage of pRB phosphorylation. In addition, expression of p16(INK4a) suppressed telomerase activity and restored the telomere shortening process, and decreased cell DNA repair ability and sensitized cells to the DNA damage reagent. Our data suggest that the wild-type p16(INK4a) plays an important role in suppression of tumor malignancy, not only by inhibiting cell proliferation through cell cycle arrest, but also by inhibiting other cellular controlling mechanisms, such as telomerase activity and DNA repair capacity. C1 Peking Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Beijing 100083, Peoples R China. Natl Inst Deafness & Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD 20892 USA. RP Tong, TJ (reprint author), Peking Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Beijing 100083, Peoples R China. EM ttj@bjmu.edu.cn NR 43 TC 14 Z9 14 U1 0 U2 2 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD JUN PY 2004 VL 24 IS 6 BP 1597 EP 1605 PG 9 WC Oncology SC Oncology GA 821DX UT WOS:000221441300031 PM 15138605 ER PT J AU Vernacchio, L Lesko, SM Vezina, RM Corwin, MJ Hunt, CE Hoffman, HJ Mitchell, AA AF Vernacchio, L Lesko, SM Vezina, RM Corwin, MJ Hunt, CE Hoffman, HJ Mitchell, AA TI Racial/ethnic disparities in the diagnosis of otitis media in infancy SO INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY LA English DT Article DE otitis media; race; ethnicity ID ARTIFICIALLY FED INFANTS; RISK-FACTORS; EAR INFECTIONS; YOUNG-CHILDREN; 1ST YEAR; DAY-CARE; LIFE; EPIDEMIOLOGY; MORBIDITY; AGE AB Objective: Otitis media (OM) is an extremely common pediatric diagnosis. Several risk factors have been associated with OM, but the relationship between OM and race/ethnicity remains controversial. We sought to define the relationship between OM diagnosis and race/ethnicity in infants. Methods: By multivariable logistic regression, we evaluated the association between OM diagnosis and race/ethnicity in 11,349 non-low-birthweight infants who were participants in a prospective cohort study of infant care practices. Results: As in previous studies, breastfeeding was associated with a decreased risk of OM diagnosis while other factors were independently associated with a substantially increased risk of OM diagnosis: out-of-home daycare, multiple children living in the home, and mother's multiparity. Daycare was associated with a "dose effect" in that the risk of OM diagnosis increased with an increasing number of children in the daycare. White the crude analysis suggested little relation of OM diagnosis and race/ethnicity, the association was confounded by several covariates including maternal marital status, number of children living in the home, breastfeeding status, and maternal age. After adjustment for relevant confounders, Black (OR 0.74; 95% CI 0.61-0.89) and Asian infants (OR 0.77; 95% CI 0.57-1.0]) were less likely to be diagnosed with OM than White infants. Conclusions: This large prospective study confirms previous risk factors for OM and demonstrates a strong "dose effect" of the size of daycare centers on OM. The study also demonstrates that the association between race/ethnicity and OM diagnosis is confounded by social factors. After adjusting for such factors, Black and Asian infants are less likely to be diagnosed with OM than White infants. The reason for this racial disparity remains unknown. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 Boston Univ, Sloane Epidemiol Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. Med Coll Ohio, Dept Pediat, Toledo, OH 43699 USA. NIDOCD, Epidemiol & Biostat Program, NIH, Bethesda, MD USA. RP Vernacchio, L (reprint author), Boston Univ, Sloane Epidemiol Ctr, 1010 Commonwealth Ave, Boston, MA 02215 USA. EM lvernacchio@slone.bu.edu OI Corwin, Michael/0000-0002-6591-209X; Vernacchio, Louis/0000-0002-2012-5404; Mitchell, Allen/0000-0003-0950-6799 FU NICHD NIH HHS [1 HD-4-3221] NR 32 TC 28 Z9 28 U1 1 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0165-5876 J9 INT J PEDIATR OTORHI JI Int. J. Pediatr. Otorhinolaryngol. PD JUN PY 2004 VL 68 IS 6 BP 795 EP 804 DI 10.1016/j.ijporl.2004.01.012 PG 10 WC Otorhinolaryngology; Pediatrics SC Otorhinolaryngology; Pediatrics GA 823CX UT WOS:000221588400008 PM 15126021 ER PT J AU Bigoni, F Houck, ML Ryder, OA Wienberg, J Stanyon, R AF Bigoni, F Houck, ML Ryder, OA Wienberg, J Stanyon, R TI Chromosome painting shows that Pygathrix nemaeus has the most basal karyotype among Asian Colobinae SO INTERNATIONAL JOURNAL OF PRIMATOLOGY LA English DT Article DE primates; in situ hybridization; comparative mapping; phylogeny; evolution ID IN-SITU HYBRIDIZATION; OLD-WORLD MONKEYS; NASALIS-LARVATUS; EVOLUTION; PRIMATE; HUMANS; CERCOPITHECIDAE; REARRANGEMENT; HOMOLOGIES; SPECIATION AB We mapped the chromosomal homology of Pygathrix namaeus (douc) with human and other primates by in situ hybridization of human chromosome paints. The synteny of 3 human chromosomes ( 1, 2, 19) is fragmented in the douc karyotype and the 23 human probes (autosomes plus X) provided 26 signals. There are associations between human chromosomes 14/15, 21/22, and 1/19. Human chromosomes 1 and 19 are divided in two segments and associated on douc chromosomes 8 and 10. The fragmentation and association of human chromosomes 1 and 19 is best explained as the result of a reciprocal translocation, which occurs in all documented Asian colobines studied, but not in the African species Colobus guereza. However, the homologs to douc chromosome 10 in all other Asian documented colobines show an additional pericentric inversion. Our results indicate that Pygathrix nemeus is karyologically the most conservative colobine species yet studied and that this species probably diverged early after the separation of Asian and African Colobinae. The data reinforce the monophyly of the Colobinae and their division into an African and an Asian clade. C1 NCI, Comparat Cytogenet Core, Frederick, MD 21702 USA. Zool Soc San Diego, Ctr Reprod Endangered Species, San Diego, CA 92112 USA. Tech Univ Munich, Inst Human Genet, D-85764 Munich, Germany. GSF, Forschungszentrum, Munich, Germany. RP Stanyon, R (reprint author), NCI, Comparat Cytogenet Core, Bldg 560,Rm 11-74A, Frederick, MD 21702 USA. EM stanyonr@ncifcrf.gov OI Stanyon, Roscoe/0000-0002-7229-1092 NR 38 TC 13 Z9 14 U1 0 U2 3 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0164-0291 J9 INT J PRIMATOL JI Int. J. Primatol. PD JUN PY 2004 VL 25 IS 3 BP 679 EP 688 DI 10.1023/B:IJOP.0000023580.46185.9c PG 10 WC Zoology SC Zoology GA 812CN UT WOS:000220817700008 ER PT J AU Pras, E Raz, J Yahalom, V Frydman, M Garzozi, HJ Pras, E Hejtmancik, JF AF Pras, E Raz, J Yahalom, V Frydman, M Garzozi, HJ Pras, E Hejtmancik, JF TI A nonsense mutation in the glucosaminyl (N-acetyl) transferase 2 gene (GCNT2): Association with autosomal recessive congenital cataracts SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID BLOOD-GROUP; MOLECULAR-GENETICS; I-ANTIGEN; LOCUS; PHENOTYPE; BLINDNESS; LINKAGE; ETIOLOGY; FAMILY; MAPS AB PURPOSE. To identify the genetic defect associated with autosomal recessive congenital cataract in four Arab families from Israel. METHODS. Genotyping was performed using microsatellite markers spaced at approximately 10 cM intervals. Two-point lod scores were calculated using MLINK of the LINKAGE program package. Mutation analysis of the glucosaminyl (N-acetyl) transferase 2 gene (GCNT2) gene was performed by direct sequencing of PCR-amplified exons. RESULTS. The cataract locus was mapped to a 13.0-cM interval between D6S470 and D6S289 on Chr. 6p24. A maximum two-point lod score of 8.75 at theta = 0.019 was obtained with marker D6S470. Sequencing exons of the GCNT2 gene, mutations of which have been associated with cataracts and the i blood group phenotype, revealed in these families a homozygous G-->A substitution in base 58 of exon-2, resulting in the formation of premature stop codons W328X, W326X, and W328X, of the GCAT2A, -B, and -C isoforms, respectively. Subsequent blood typing of affected family members confirmed the possession of the rare adult i blood group phenotype. CONCLUSIONS. A nonsense mutation in the GCNT2 gene isoforms is associated with autosomal recessive congenital cataract in four distantly related Arab families from Israel. These findings provide further insight into the dual role of the I-branching GCNT2 gene in the lens and in reticulocytes. C1 NEI, OGVFB, NIH, Bethesda, MD 20892 USA. Meir Hosp, Sapir Med Ctr, Dept Ophthalmol, Kefar Sava, Israel. Magen David Adom Natl Blood Serv Ctr, Natl Blood Grp Reference Lab, Tel Hashomer, Israel. Chaim Sheba Med Ctr, Danek Gartener Inst Human Genet, IL-52621 Tel Hashomer, Israel. Bnai Zion Med Ctr, Dept Ophthalmol, Haifa, Israel. RP Hejtmancik, JF (reprint author), NEI, OGVFB, NIH, Bldg 10,Room 10B10,10 Ctr Dr,MSC 1860, Bethesda, MD 20892 USA. EM f3h@helix.nih.gov NR 32 TC 48 Z9 49 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUN PY 2004 VL 45 IS 6 BP 1940 EP 1945 DI 10.1167/iovs.03-1117 PG 6 WC Ophthalmology SC Ophthalmology GA 824EO UT WOS:000221668900041 PM 15161861 ER PT J AU Winchester, R Pitt, J Charurat, M Magder, LS Goring, HHH Landay, A Read, JS Shearer, W Handelsman, E Luzuriaga, K Hillyer, GV Blattner, W AF Winchester, R Pitt, J Charurat, M Magder, LS Goring, HHH Landay, A Read, JS Shearer, W Handelsman, E Luzuriaga, K Hillyer, GV Blattner, W TI Mother-to-child transmission of HIV-1: Strong association with certain maternal HLA-B alleles independent of viral load implicates innate immune mechanisms SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV-1 vertical transmission; HLA-B alleles; viral load; NK receptor; KIR3DL1 receptor ID KILLER-CELL RECEPTORS; PEPTIDE MOTIFS; NK CELLS; INFECTION; PROGRESSION; AIDS; RECOGNITION; RESPONSES; ESCAPE; INTRAPARTUM AB The transmission of HIV-1 from mother to child during pregnancy is unlike other types of HIV-1 transmission because the child shares major histocompatibility complex (MHC) genes with the mother during a time while the mother is induced to tolerate the paternally derived fetal MHC molecules, in part through natural killer (NK) recognition of MHC polymorphisms. The relevance of these immune mechanisms to HIV-1 transmission was assessed by determining the HLA-B alleles of mother and infant. Almost half (48%) of mothers who transmitted with low viral loads had HLA-B*1302, B*3501, B*3503, B*4402, or B*5001 alleles, compared with 8% of nontransmitting mothers (P = 0.001). Conversely, 25% of mothers who did not transmit despite high viral loads had B*4901 and B*5301, vs. 5% of transmitting mothers (P = 0.003), a pattern of allelic involvement distinct from that influencing HIV-1 infection outcome. The infant's HLA-B alleles did not appear associated with transmission risk. The HLA-B*4901 and B*5301 alleles that were protective in the mother both differed respectively from the otherwise identical susceptibility alleles, B*5001 and B*3501, by 5 amino acids encoding the ligand for the KIR3DL1 NK receptor. These results suggest that the probable molecular basis of the observed association involves definition of the matemal NK recognition repertoire by engagement of NK receptors with polymorphic ligands encoded by matemal HLA-B alleles, and that the placenta is the likely site of the effect that appears to protect against transmission of maternal HIV-1 through interrelating adaptive and innate immune recognition. C1 Columbia Univ, Dept Pediat, New York, NY 10032 USA. Columbia Univ, Dept Pathol & Med, New York, NY 10032 USA. Univ Maryland, Dept Epidemiol & Prevent Med, Inst Human Virol, Baltimore, MD 21201 USA. SW Fdn Biomed Res, Dept Genet, San Antonio, TX USA. Rush Med Coll, Dept Immunol & Microbiol, Chicago, IL 60612 USA. NICHHD, Adolescent & Maternal AIDS Branch, Bethesda, MD 20892 USA. Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. SUNY Downstate, Brooklyn, NY USA. Univ Massachusetts, Sch Med, Dept Pediat, Worcester, MA 01605 USA. Univ Massachusetts, Sch Med, Dept Mol Med, Worcester, MA 01605 USA. Univ Puerto Rico, Sch Med, Dept Pathol & Lab Med, San Juan, PR 00936 USA. RP Winchester, R (reprint author), Columbia Univ, Dept Pediat, 30 W 168th St, New York, NY 10032 USA. EM rjw8@columbia.edu FU NCRR NIH HHS [RR00188, RR00645]; NIAID NIH HHS [N01 AI 85339, U01 AI 34858, R01 AI39369, U01 AI 34841, 1 U01 AI 50274-01]; NICHD NIH HHS [U01 HD 36117, U01 HD 41983]; NIDA NIH HHS [U01 DA 15053, 9U01 DA 15054] NR 39 TC 31 Z9 34 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUN 1 PY 2004 VL 36 IS 2 BP 659 EP 670 DI 10.1097/00126334-200406010-00002 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 825PC UT WOS:000221769400002 PM 15167284 ER PT J AU Cohn, RD Arbes, SJ Yin, M Jaramillo, R Zeldin, DC AF Cohn, RD Arbes, SJ Yin, M Jaramillo, R Zeldin, DC TI National prevalence and exposure risk for mouse allergen in US households SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE asthma; allergens; mouse allergen; mus m 1 ID LABORATORY-ANIMAL ALLERGY; RESPONSE RELATIONSHIPS; SENSITIZATION; WORKERS; RATS; CHALLENGE; ENDOTOXIN; CHILDREN; ASTHMA; LEAD AB Background: Exposure to mouse allergen is a known cause of asthma in occupational settings and exhibits high prevalence and association with allergic sensitization in inner-city home environments. It has never been characterized on a nationally representative scale. Objective: This study was designed to characterize mouse allergen prevalence in a representative sample of US homes and to assess risk factors for increased concentrations. Methods: Allergen, questionnaire, and observational data were analyzed from the first National Survey of Lead and Allergens in Housing, a cross-sectional survey of 831 US housing units. Allergen levels were characterized and related to demographic factors and household characteristics. Results: Detectable levels of mouse allergen (Mus m 1) exist in 82% of US homes. Kitchen floor concentrations exceed 1.6 mug/ g, a level associated with increased sensitization rates, in 22% of homes. Increased concentrations (>1.6 mug/g) were observed in high-rise apartments and mobile homes, older homes, and low-income homes. Odds of having increased concentrations were increased when rodent (odds ratio [OR], 3.38) or cockroach (OR, 1.81) problems were reported and when floor mopping (OR, 2.17) was performed instead of vacuuming. Conclusions: Household mouse allergen is widespread in many settings at levels that might contribute to asthma morbidity. The likelihood of exposure can be assessed by consideration of demographic and household determinants. C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. Constella Grp Inc, Durham, NC USA. RP Zeldin, DC (reprint author), NIEHS, NIH, 111 Alexander Dr,Mail Drop D2-02, Res Triangle Pk, NC 27709 USA. NR 24 TC 57 Z9 58 U1 0 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUN PY 2004 VL 113 IS 6 BP 1167 EP 1171 DI 10.1016/j.jaci.2003.12.592 PG 5 WC Allergy; Immunology SC Allergy; Immunology GA 829ZI UT WOS:000222091000024 PM 15208600 ER PT J AU Cohen, SG AF Cohen, SG TI Lowell and Franklin on double-blind hyposensitization therapy for ragweed hay fever: The people SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article ID ASTHMA; DISEASE C1 NIAID, NIH, Bethesda, MD 20892 USA. Natl Lib Med, NIH, Bethesda, MD USA. RP Cohen, SG (reprint author), NIAID, NIH, Bethesda, MD 20892 USA. NR 20 TC 1 Z9 1 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUN PY 2004 VL 113 IS 6 BP 1227 EP 1231 DI 10.1016/j.jaci.2003.12.003 PG 5 WC Allergy; Immunology SC Allergy; Immunology GA 829ZI UT WOS:000222091000042 PM 15208609 ER PT J AU Chen, X Krakauer, T Oppenheim, JJ Howard, OMZ AF Chen, X Krakauer, T Oppenheim, JJ Howard, OMZ TI Yin Zi Huang, an injectable multicomponent Chinese herbal medicine, is a potent inhibitor of T-cell activation SO JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE LA English DT Article ID HEPATITIS-C; ZHI-HUANG; METABOLIZING-ENZYMES; BILIRUBIN; COMPONENT; INDUCTION; ACID; EXPRESSION; BAICALEIN; SHIKONIN AB Objectives: The clinical efficacy of many multiherbal Traditional Chinese Medicines (TCM) is partially attributable to their immunoregulatory properties. In this study we evaluated the effect of eight commonly used, commercially available multiherbal Chinese medicines on T-cell activation. We focused on Yin Zhi Huang (YZH, an injectable herbal medicine commonly used for the treatment of liver diseases in China), because it was the most potent inhibitor of T-cell activation in our experimental system. The effects of 10 ingredient components of YZH were also evaluated. Methods: [H-3] thymidine incorporation assay was used to assess mouse T-cell proliferation after stimulation with latex beads coated with anti-CD3/CD28 antibodies. CD25, CD69, PD-1, and I-COS expression by purified mouse CD4(+) T cells treated with plate-bound anti-CD3 antibody and soluble anti-CD28 antibody was analyzed by fluorescent-activated cell sorter (FACS). Cytokine/chemokine production by human peripheral blood mononuclear cells (PBMC) stimulated with staphylococcal enterotoxin B (SEB) was determined by enzyme-linked immunosorbent assay (ELISA). Results: Among tested herbal medicines, YZH was the most potent inhibitor of T-cell activation. In splenocyte proliferation assays, the inhibitory effect of YZH was dose-dependent, with a 50% inhibition concentration (IC50) of 1:3200-1:1600. Ten (10) purified compounds found in YZH were evaluated for their activity. Among them, ursolic acid (1-10 mumol), luteolin (1-10 mumol), baicalein (1-10 mumol), scopran (5-50 mumol), and crocin (5-50 mumol), exhibited dose-dependent inhibition. YZH also inhibited CD25, CD69, PD-1, and ICOS expression by stimulated mouse CD4(+) T cells. In human PBMCs, YZH inhibited SEB-stimulated cytokine (interleukin [IL]-1, IL-2, IL-6, tumor necrosis factor[TNF]-alpha, interferon [IFN]-gamma) and chemokine (IP-10, MCP-1, MIP-1alpha and MIP-1beta) production in a dose-dependent manner. Conclusion: Our data show for the first time that YZH is a potent inhibitor of T-cell activation, and this property may be the major mechanism underlying the clinical efficacy of YZH. Our experimental results pave the way for identification of active component(s) and/or analysis of synergistic/additive effect of a YZH ingredient in future studies. C1 NCI, Ctr Canc Res, Mol Immunoregulat Lab, NIH, Ft Detrick, MD 21702 USA. SAIC Frederick Inc, Basic Res Program, NCI, Frederick, MD USA. USA, Med Res Inst Infect Dis, Frederick, MD USA. NCI, Ctr Canc Res, Mol Immunoregulat Lab, NIH, Frederick, MD USA. RP Howard, OMZ (reprint author), NCI, Ctr Canc Res, Mol Immunoregulat Lab, NIH, POB B,Bldg 560,Room 31-19, Ft Detrick, MD 21702 USA. EM howardz@mail.ncifcrf.gov RI Howard, O M Zack/B-6117-2012; Chen, Xin/I-6601-2015 OI Howard, O M Zack/0000-0002-0505-7052; Chen, Xin/0000-0002-2628-4027 FU NCI NIH HHS [N01-CO-12400] NR 29 TC 12 Z9 15 U1 0 U2 8 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1075-5535 J9 J ALTERN COMPLEM MED JI J. Altern. Complement Med. PD JUN PY 2004 VL 10 IS 3 BP 519 EP 526 DI 10.1089/1075553041323687 PG 8 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA 835ID UT WOS:000222475200016 PM 15253857 ER PT J AU Byram, R Stewart, PE Rosa, P AF Byram, R Stewart, PE Rosa, P TI The essential nature of the ubiquitous 26-kilobase circular replicon of Borrelia burgdorferi SO JOURNAL OF BACTERIOLOGY LA English DT Article ID LYME-DISEASE SPIROCHETE; LINEAR PLASMID TELOMERES; COVALENTLY CLOSED ENDS; OUTER-SURFACE PROTEIN; BACTERIAL GENOME; PROPHAGE N-15; OSPC GENE; TICKS; INFECTIVITY; SEQUENCE AB The genome of the type strain (B31) of Borrelia burgdorferi, the causative agent of Lyme disease, is composed of 12 linear and 9 circular plasmids and a linear chromosome. Plasmid content can vary among strains, but one 26-kb circular plasmid (cp26) is always present. The ubiquitous nature of cp26 suggests that it provides functions required for bacterial viability. We tested this hypothesis by attempting to selectively displace cp26 with an incompatible but replication-proficient vector, pBSV26. While pBSV26 transformants contained this incompatible vector, the vector coexisted with cp26, which is consistent with the hypothesis that cp26 carries essential genes. Several cp26 genes with ascribed or predicted functions may be essential. These include the BBB29 gene, which has sequence homology to a gene encoding a glucose-specific phosphotransferase system component, and the resT gene, which encodes a telomere resolvase involved in resolution of the replicated telomeres of the linear chromosome and plasmids. The BBB29 gene was successfully inactivated by allelic exchange, but attempted inactivation of resT resulted in merodiploid transformants, suggesting that resT is required for B. burgdorferi growth. To determine if resT is the only cp26 gene essential for growth, we introduced resT into B. burgdorferi on pBSV26. This did not result in displacement of cp26, suggesting that additional cp26 genes encode vital functions. We concluded that B. burgdorferi plasmid cp26 encodes functions critical for survival and thus shares some features with the chromosome. C1 NIAID, Rocky Mt Lab, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. Univ Wyoming, Dept Biol Mol, Laramie, WY 82071 USA. RP Rosa, P (reprint author), 903 S 4th St, Hamilton, MT 59840 USA. EM prosa@niaid.nih.gov NR 53 TC 62 Z9 66 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD JUN PY 2004 VL 186 IS 11 BP 3561 EP 3569 DI 10.1128/JB.186.11.3561-3569.2004 PG 9 WC Microbiology SC Microbiology GA 822TE UT WOS:000221562300033 PM 15150244 ER PT J AU Bae, NS Swanson, MJ Vassilev, A Howard, BH AF Bae, NS Swanson, MJ Vassilev, A Howard, BH TI Human histone deacetylase SIRT2 interacts with the homeobox transcription factor HOXA10 SO JOURNAL OF BIOCHEMISTRY LA English DT Article DE HOXA10; SIRT2 ID NAD-DEPENDENT DEACETYLASE; SACCHAROMYCES-CEREVISIAE; SIR2-LIKE PROTEINS; GENE-EXPRESSION; DNA-BINDING; YEAST; REPRESSION; COMPLEXES; HOMOLOGY AB Histone deacetylases are required for transcriptional repression in eukaryotes. Saccharomyces cerevisiae has several histone deacetylases, of which ySir2p is the most conserved throughout evolution. Currently, there is no report on the interacting protein partner of a human Sir2 homolog, SIRT2. Here we show for the first time that SIRT2 interacts with the homeobox transcription factor, HOXA10, which was identified in a two-hybrid screen. Interactions were confirmed by co-immunoprecipitation from in vitro translations as well as in human cell-free extracts. Taken together with mouse knockout studies, our results raise the intriguing possibility that SIRT2 plays a role in mammalian development. C1 NICHHD, Lab Mol & Growth Regulat, NIH, Bethesda, MD 20892 USA. NICHHD, Lab Eukaryot Gene Regulat, NIH, Bethesda, MD 20892 USA. RP Bae, NS (reprint author), Stowers Inst Med Res, Kansas City, MO 64110 USA. EM NSB@stowers-institute.org; howard@helix.nih.gov NR 30 TC 48 Z9 53 U1 1 U2 4 PU JAPANESE BIOCHEMICAL SOC PI TOKYO PA ISHIKAWA BLDG-3F, 25-16 HONGO-5-CHOME, BUNKYO-KU, TOKYO, 113, JAPAN SN 0021-924X J9 J BIOCHEM JI J. Biochem. PD JUN PY 2004 VL 135 IS 6 BP 695 EP 700 DI 10.1093/jb/mvh084 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 833KO UT WOS:000222336400006 PM 15213244 ER PT J AU Ishima, R Baber, J Louis, JM Torchia, DA AF Ishima, R Baber, J Louis, JM Torchia, DA TI Carbonyl carbon transverse relaxation dispersion measurements and ms-mu s timescale motion in a protein hydrogen bond network SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE chemical exchange; conformational change; CPMG; NMR; R-2 ID TIME-SCALE DYNAMICS; HIV-1 PROTEASE; CAVITY MUTANT; T4 LYSOZYME; INTERNAL DYNAMICS; CHEMICAL-EXCHANGE; NMR-SPECTROSCOPY; SIDE-CHAINS; RESIDUES; SPECTRA AB A constant-time, Carr-Purcell-Meiboom-Gill (CPMG) transverse relaxation, R-2, dispersion experiment for carbonyl carbons was designed and executed to detect mus-ms time-scale dynamics of protein backbone carbonyl sites. Because of the large (ca. 55 Hz) C-alpha- C' J-coupling, the carbonyl signal intensity is strongly modulated as the spacing between CPMG pulses is varied, in uniformly C-13 enriched proteins, unless care is taken to minimize the perturbation of the C-alpha magnetization by the CPMG pulses. CPMG pulse trains consisting of either a band-selective pulse, such as RE-BURP, or rectangular ( with an excitation null in the C-alpha region of the spectrum) pulses were employed in order to minimize C' signal modulation by C-alpha-C' J-coupling. The performance of these types of CPMG refocusing pulses was assessed by computer simulation, and by comparing dispersion profiles measured for (1) uniformly [C-13, N-15, H-2] (H-2 at non-labile hydrogen sites) labeled, and (2) uniformly N-15/selectively-C-13 labeled samples of HIV-1 protease bound to a potent inhibitor, DMP323. In addition, because the uniformly C-13/N-15/H-2 labeled sample was well suited to measure N-15 and H-1 R-2 dispersion as well as C-13' dispersion, conformational exchange in the inter subunit beta-sheet hydrogen-bond network of the inhibitor-bound protease was elucidated using relaxation dispersion data of all three types of nuclei. C1 Natl Inst Dent & Craniofacial Res, Struct Mol Biol Unit, NIH, Bethesda, MD 20892 USA. NIDDKD, Labs Chem Phys, NIH, Bethesda, MD 20892 USA. RP Ishima, R (reprint author), Natl Inst Dent & Craniofacial Res, Struct Mol Biol Unit, NIH, Bethesda, MD 20892 USA. EM rishima@dir.nidcr.nih.gov NR 28 TC 58 Z9 58 U1 1 U2 5 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD JUN PY 2004 VL 29 IS 2 BP 187 EP 198 DI 10.1023/B:JNMR.0000019249.50306.5d PG 12 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 801ZP UT WOS:000220134100006 PM 15014232 ER PT J AU Aprelikova, O Chandramouli, GVR Wood, M Vasselli, JR Riss, J Maranchie, JK Linehan, WM Barrett, JC AF Aprelikova, O Chandramouli, GVR Wood, M Vasselli, JR Riss, J Maranchie, JK Linehan, WM Barrett, JC TI Regulation of HIF prolyl hydroxylases by hypoxia-inducible factors SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE hypoxia; prolyl hydroxylases; HIF; siRNA; microarray ID TRANSCRIPTION FACTOR; FACTOR 1-ALPHA; BINDING; HIF-1-ALPHA; OXYGEN; VHL; EXPRESSION; PATHWAY; PROTEIN; CELLS AB Hypoxia and induction of hypoxia-inducible factors (HIF-1alpha and HIF-2alpha) is a hallmark of many tumors. Under normal oxygen tension HIF-alpha subunits are rapidly degraded through prolyl hydroxylase dependent interaction with the von Hippel-Lindau (VHL) tumor suppressor protein, a component of E3 ubuiquitin ligase complex. Using microarray analysis of VHL mutated and re-introduced cells, we found that one of the prolyl hydroxylases (PHD3) is coordinately expressed with known HIFtarget genes,while theother twofamily members (PHD1 and 2)did not respond to VHL.We further tested the regulation of these genes by HIF-1 and HIF-2and found that siRNA targeted degradation of HIF-1 alpha and HIF-2alpha results in decreased hypoxia-induced PHD3 expression. Ectopic overexpression of HIF-2alpha in two different cell lines provided a much better induction of PHD3 gene than HIF-1alpha. In contrast, we demonstrate that PHD2 is not affected by overexpression or downregulation of HIF-2alpha. However, induction of PHD2 by hypoxia has HIF-1-independent and -dependent components. Short-term hypoxia (4 h) results in induction of PHD2 independent of HIF-1, while PHD2 accumulation by prolonged hypoxia (16 h) was decreased by siRNA-mediated degradation of HIF-1alpha subunit. These data further advance our understanding of the differential role of HIF factors and putative feedback loop in HIF regulation. (C) Published 2004 Wiley-Liss, Inc.dagger. C1 NCI, Canc Res Ctr, Lab Biosyst & Canc, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, Urol Branch, Bethesda, MD 20892 USA. RP Barrett, JC (reprint author), NCI, Canc Res Ctr, Lab Biosyst & Canc, 31 Ctr Dr,Rm 3A11, Bethesda, MD 20892 USA. EM barrett@mail.nih.gov OI Maranchie, Jodi/0000-0002-8534-9468 NR 42 TC 128 Z9 133 U1 1 U2 13 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD JUN 1 PY 2004 VL 92 IS 3 BP 491 EP 501 DI 10.1002/jcb.20067 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 826NM UT WOS:000221835800007 PM 15156561 ER PT J AU Takahashi, K Ginis, I Nishioka, R Klimanis, D Barone, FC White, RF Chen, Y Hallenbeck, JM AF Takahashi, K Ginis, I Nishioka, R Klimanis, D Barone, FC White, RF Chen, Y Hallenbeck, JM TI Glucosylceramide synthase activity and ceramide levels are modulated during cerebral ischemia after ischemic preconditioning SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE ceramide; glucosylceramide synthase; ischemic tolerance; middle cerebral artery occlusion; spontaneously hypertensive rats ID SPONTANEOUSLY HYPERTENSIVE-RATS; NECROSIS-FACTOR-ALPHA; TNF-ALPHA; HIPPOCAMPAL-NEURONS; INDUCED APOPTOSIS; CORTICAL-NEURONS; GENE-EXPRESSION; UP-REGULATION; CELL-DEATH; TOLERANCE AB After 24-hour middle cerebral artery occlusion (MCAO) in spontaneously hypertensive rats, brain ceramide level increased from baseline reached 595% (ischemic core) and 460% (perifocal/penumbral areas); brain glucosylceramide synthase (GCS) activities in these areas simultaneously decreased by 70%, and 50%. respectively. Ten-minute MCAO preconditioning significantly attenuated 24-hour MCAPO-induced ceramide accumulation by 40% to 60% in ischemic core and perifocal areas. and GCS activities improved by 60% to 70% in both areas. Thus, potentially toxic levels of brain ceramide induced by MCAO were attenuated to intermediate levels in preconditioned animals; brain GCS activity was relatively preserved. In ischemic tolerance, GCS appears to modulate otherwise high levels of brain ceramide. C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. GlaxoSmithKline Pharmaceut, Discovery Res Biol, King Of Prussia, PA USA. RP Hallenbeck, JM (reprint author), NINDS, Stroke Branch, NIH, 36 Convent Dr,Room 4A03, Bethesda, MD 20892 USA. EM HallenbJ@ninds.nih.gov NR 48 TC 19 Z9 19 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUN PY 2004 VL 24 IS 6 BP 623 EP 627 PG 5 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 826IY UT WOS:000221824000004 PM 15181369 ER PT J AU Cooley, MR Boyce, CA AF Cooley, MR Boyce, CA TI An introduction to assessing anxiety in child and adolescent multiethnic populations: Challenges and opportunities for enhancing knowledge and practice SO JOURNAL OF CLINICAL CHILD AND ADOLESCENT PSYCHOLOGY LA English DT Editorial Material ID DSM-III DISORDERS; SOCIAL PHOBIA; COMMUNITY SAMPLE; AFRICAN-AMERICAN; PSYCHOPATHOLOGY; PSYCHOLOGY; PREVALENCE; BEHAVIOR; ISSUES; RACE AB Recognizing that researchers and clinicians are increasingly faced with assessing, treating, and studying ethnically, racially, and culturally diverse populations, one question is whether the appropriate tools exist. This special section aspires to advance the available assessment strategies that are appropriate for the treatment, prevention, and research of diverse children and adolescents with anxiety symptoms and disorders. This introduction presents an overview of anxiety and its disorders among multiethnic youth and identifies emerging challenges and opportunities in the assessment and treatment of anxiety symptoms and disorders among Asian American and Pacific Islander Hispanic/Latino, African American, and European American children and adolescents within a sociocultural context. C1 Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD 21205 USA. NIMH, Dept Hlth & Human Serv, Bethesda, MD 20814 USA. RP Cooley, MR (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, 624 N Broadway,HH 8th Floor, Baltimore, MD 21205 USA. EM mcooley@jhsph.edu FU NIMH NIH HHS [R21 MH63143, K01 MH01661] NR 69 TC 19 Z9 19 U1 1 U2 1 PU LAWRENCE ERLBAUM ASSOC INC PI MAHWAH PA 10 INDUSTRIAL AVE, MAHWAH, NJ 07430-2262 USA SN 1537-4416 J9 J CLIN CHILD ADOLESC JI J. Clin. Child Adolesc. Psychol. PD JUN PY 2004 VL 33 IS 2 BP 210 EP 215 DI 10.1207/s15374424jccp3302_1 PG 6 WC Psychology, Clinical; Psychology, Developmental SC Psychology GA 816KN UT WOS:000221108900001 PM 15136184 ER PT J AU Grant, KE Compas, BE Thurm, AE McMahon, SD Gipson, PY AF Grant, KE Compas, BE Thurm, AE McMahon, SD Gipson, PY TI Stressors and child and adolescent psychopathology: Measurement issues and prospective effects SO JOURNAL OF CLINICAL CHILD AND ADOLESCENT PSYCHOLOGY LA English DT Review ID INNER-CITY ADOLESCENTS; LIFETIME EXIT EVENTS; SCHOOL-AGE-CHILDREN; DEPRESSIVE SYMPTOMS; SOCIAL SUPPORT; PSYCHOLOGICAL SYMPTOMS; POSTTRAUMATIC STRESS; YOUNG ADOLESCENTS; HURRICANE-ANDREW; ATTRIBUTIONAL STYLE AB This article reviews existing research on the association between stressors and symptoms of psychopathology in children and adolescents with a focus on measurement issues and prospective effects. The first half of the article focuses on the measurement of stressors, emphasizing checklists and interviews. Available measures of stressful experiences are reviewed and critiqued. Results of this review reveal both substantial progress (i.e., development of valid stressor assessment tools) and remaining problems (i.e., inconsistent measurement across studies). The second half of this article reviews studies that have tested for prospective associations between stressors and symptoms of psychopathology in children and adolescents. Studies that have examined the prospective effects of recent or prior stressors on current psychological symptoms, while controlling for prior psychological symptoms, are reviewed. Results overall suggest that stressors predict changes in rates of symptoms of psychopathology in children and adolescents over time. Results also suggest that symptoms of psychopathology predict changes in rates of stressors over time. Implications of these findings are that conclusive evidence now exists for the importance of stressors in the development of child and adolescent psychopathology. C1 De Paul Univ, Dept Psychol, Chicago, IL 60614 USA. Vanderbilt Univ, Dept Psychiat & Human Dev, Nashville, TN 37240 USA. NIMH, Bethesda, MD 20892 USA. RP Grant, KE (reprint author), De Paul Univ, Dept Psychol, 2219 N Kenmore Ave, Chicago, IL 60614 USA. EM kgrant@depaul.edu; bruce.compas@vanderbilt.edu NR 130 TC 200 Z9 201 U1 8 U2 32 PU LAWRENCE ERLBAUM ASSOC INC PI MAHWAH PA 10 INDUSTRIAL AVE, MAHWAH, NJ 07430-2262 USA SN 1537-4416 J9 J CLIN CHILD ADOLESC JI J. Clin. Child Adolesc. Psychol. PD JUN PY 2004 VL 33 IS 2 BP 412 EP 425 DI 10.1207/s15374424jccp3302_23 PG 14 WC Psychology, Clinical; Psychology, Developmental SC Psychology GA 816KN UT WOS:000221108900023 PM 15136206 ER PT J AU Kronmal, RA Barzilay, JI Tracy, RP Savage, PJ Orchard, TJ Burke, GL AF Kronmal, RA Barzilay, JI Tracy, RP Savage, PJ Orchard, TJ Burke, GL TI The relationship of fasting serum radioimmune insulin levels to incident coronary heart disease in an insulin-treated diabetic cohort SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CARDIOVASCULAR-DISEASE; RISK FACTOR; MACROVASCULAR DISEASE; HYPERINSULINEMIA; MELLITUS; ABSORPTION; PREVALENCE; FIBRINOGEN; GLUCOSE; EVENTS AB It is not known whether insulin levels, in the setting of insulin treatment, are an independent risk factor for coronary heart disease (CHD). We studied a cohort of 116 insulin-treated individuals, 65 yr or older, who were followed for 5.6 - 9 yr. All were free of CHD at baseline. There were 47 incident CHD events. In Cox proportional hazards modeling, with fasting immune-reactive insulin levels as a continuous variable, the hazard ratio for CHD was statistically significant ( P < 0.0001). When insulin levels were divided into intervals, those in the third interval [ 43 - 150 mu U/ml ( 258 - 900 pmol/liter)] had an adjusted 30% increased relative risk (95% confidence interval, 0.57, 2.98) compared with those in the first interval [< 20 muU/ml (< 120 pmol/liter)]. Those in the fourth interval [151 - 400 mu U/ml (906 - 2400 pmol/ liter)] had an adjusted 5.6-fold increased risk (2.3 - 13.1; P < 0.0001). Approximately 15% of the cohort had such elevated insulin levels. Immune-reactive insulin levels were strongly correlated with specific insulin, proinsulin, and insulin antibody levels. Markedly elevated fasting immune-reactive insulin levels were an independent risk factor for CHD in this study of insulin-treated older adults. These observational findings should be confirmed through larger prospective studies, given their implications for insulin therapy. C1 Univ Washington, Dept Biostat, Cardiovasc Hlth Study Coordinating Ctr, Seattle, WA 98115 USA. Emory Univ, Kaiser Permanente Georgia, Atlanta, GA 30082 USA. Emory Univ, Div Endocrinol, Atlanta, GA 30082 USA. Univ Vermont, Coll Med, Dept Pathol & Biochem, Colchester, VT 05446 USA. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15251 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27157 USA. RP Kronmal, RA (reprint author), Univ Washington, Dept Biostat, Cardiovasc Hlth Study Coordinating Ctr, Bldg 29,Suite 310,6200 NE 74th St, Seattle, WA 98115 USA. EM kronmal@u.washington.edu OI orchard, trevor/0000-0001-9552-3215 FU NHLBI NIH HHS [N01-HC-15103, N01-HC-35129, N01-HC-85079] NR 27 TC 19 Z9 20 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2004 VL 89 IS 6 BP 2852 EP 2858 DI 10.1210/jc.2003-031822 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 826PB UT WOS:000221839900051 PM 15181068 ER PT J AU Salbe, AD Tschop, MH DelParigi, A Venti, CA Tataranni, PA AF Salbe, AD Tschop, MH DelParigi, A Venti, CA Tataranni, PA TI Negative relationship between fasting plasma ghrelin concentrations and ad libitum food intake SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PRADER-WILLI-SYNDROME; CIRCULATING GHRELIN; ENERGY-EXPENDITURE; ACYLATED PEPTIDE; HUMAN OBESITY; HUMANS; SECRETION; STOMACH; RATS; QUESTIONNAIRE AB Ghrelin is a novel GH secretagogue with orexigenic effects. We hypothesized that high fasting plasma ghrelin concentrations (FxGhr) might predict high ad libitum food intake. FxGhr were measured in 30 normoglycemic subjects: 15 Pima Indians ( 8 male/7 female; age, 32 +/- 7 yr; body weight, 87 +/- 21 kg; mean +/- SD) and 15 Caucasians (12 male/3 female, 36 +/- 8 yr, 94 +/- 26 kg) in energy balance for 3 d before testing. Subjects then self-selected their food ad libitum for the following 3 d. Mean daily energy intake ( DEI) was calculated from the weight of foods consumed and expressed as a percent of weight maintenance energy needs. FxGhr were twice as high in Caucasians as in Pima Indians (103 +/- 53 vs. 52 +/- 18 fmol/ml, P < 0.001) and remained higher after adjustment for age, gender, and body weight ( P < 0.0001). Neither DEI, nor percent of weight maintenance energy needs, nor percent of calories from fat differed between the races. In both groups, FxGhr were negatively correlated with DEI (r = - 0.61, P = 0.01; r= - 0.54, P = 0.04, respectively). These negative relationships were not explained by interindividual differences in age, gender, or body weight. This unexpected finding that low FxGhr predict ad libitum food intake suggests that the role of endogenous ghrelin in the regulation of energy homeostasis remains uncertain. C1 NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. Univ Cincinnati, Genome Res Inst, Obes Res Ctr, Dept Psychiat, Cincinnati, OH 45237 USA. RP Salbe, AD (reprint author), NIDDKD, Clin Diabet & Nutr Sect, NIH, 4212 N 16th St,Room 541, Phoenix, AZ 85016 USA. EM arline_salbe@nih.gov RI Tschoep, Matthias/I-5443-2014; OI Tschoep, Matthias/0000-0002-4744-371X NR 35 TC 35 Z9 37 U1 1 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2004 VL 89 IS 6 BP 2951 EP 2956 DI 10.1210/jc.2003-032145 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 826PB UT WOS:000221839900066 PM 15181083 ER PT J AU Berzofsky, JA Terabe, M Oh, SK Belyakov, IM Ahlers, JD Janik, JE Morris, JC AF Berzofsky, JA Terabe, M Oh, SK Belyakov, IM Ahlers, JD Janik, JE Morris, JC TI Progress on new vaccine strategies for the immunotherapy and prevention of cancer SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Review ID COLONY-STIMULATING FACTOR; CYTOTOXIC T-LYMPHOCYTES; PULSED DENDRITIC CELLS; PEPTIDE-BASED VACCINES; HUMAN TUMOR-ANTIGENS; LASTING ANTITUMOR IMMUNITY; AUTOLOGOUS MELANOMA-CELLS; PHASE-I TRIAL; METASTATIC MELANOMA; CARCINOEMBRYONIC ANTIGEN AB In recent years, great strides in understanding and regulating the immune system have led to new hope for harnessing its exquisite specificity to destroy cancer cells without affecting normal tissues. This review examines the fundamental immunologic advances and the novel vaccine strategies arising from these advances, as wen as the early clinical trials studying new approaches to treat or prevent cancer. C1 NCI, Vaccine Branch, Ctr Canc Res, Mol Immunogenet & Vaccin Res Sect,NIH, Bethesda, MD 20892 USA. NIAID, Div Aids, Bethesda, MD 20892 USA. NCI, Clin Trials Team, Metab Branch, CCR,NIH, Bethesda, MD 20892 USA. RP Berzofsky, JA (reprint author), NCI, Vaccine Branch, Ctr Canc Res, Mol Immunogenet & Vaccin Res Sect,NIH, Bldg 10,Room 6B-12,10 Ctr Dr MSC 1578, Bethesda, MD 20892 USA. EM berzofsk@helix.nih.gov NR 126 TC 162 Z9 184 U1 2 U2 13 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN PY 2004 VL 113 IS 11 BP 1515 EP 1525 DI 10.1172/JCI200-421926 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 826BZ UT WOS:000221805200001 PM 15173875 ER PT J AU Murphy, E AF Murphy, E TI Inhibit GSK-3 beta or there's heartbreak dead ahead SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID PROTEIN-KINASE-C; PERMEABILITY TRANSITION PORE; INDUCED CARDIOPROTECTION; CARDIAC MITOCHONDRIA; REPERFUSION INJURY; EPSILON AB Numerous signaling pathways have been shown to mediate cardioprotection, but the end effectors that mediate protection are only beginning to be elucidated. Numerous cardioprotective drugs are shown to converge on glycogen synthase kinase-3beta (GSK-3beta) (see the related article beginning on page 1535). The phosphorylation and inhibition of GSK-3beta lead to inhibition or delayed activation of the mitochondrial permeability transition, a key regulator of apoptosis. C1 NIEHS, Lab Signal Transduct, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. RP Murphy, E (reprint author), NIEHS, Lab Signal Transduct, Dept Hlth & Human Serv, NIH, 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM murphy1@niehs.nih.gov NR 16 TC 32 Z9 35 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN PY 2004 VL 113 IS 11 BP 1526 EP 1528 DI 10.1172/JCI200421986 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 826BZ UT WOS:000221805200002 PM 15173876 ER PT J AU Juhaszova, M Zorov, DB Kim, SH Pepe, S Fu, Q Fishbein, KW Ziman, BD Wang, S Ytrehus, K Antos, CL Olson, EN Sollott, SJ AF Juhaszova, M Zorov, DB Kim, SH Pepe, S Fu, Q Fishbein, KW Ziman, BD Wang, S Ytrehus, K Antos, CL Olson, EN Sollott, SJ TI Glycogen synthase kinase-3 beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID FATTY-ACID OXIDATION; PROTEIN-KINASE-C; SENSITIVE K+ CHANNEL; CARDIAC MYOCYTES; CELL-DEATH; ISCHEMIA/REPERFUSION INJURY; SULFONYLUREA DRUGS; ATP CHANNELS; RAT-HEART; BCL-2 AB Environmental stresses converge on the mitochondria that can trigger or inhibit cell death. Excitable, postmitotic cells, in response to sublethal noxious stress, engage mechanisms that afford protection from subsequent insults. We show that reoxygenation after prolonged hypoxia reduces the reactive oxygen species (ROS) threshold for the mitochondrial permeability transition (MPT) in cardiomyocytes and that cell survival is steeply negatively correlated with the fraction of depolarized mitochondria. Cell protection that exhibits a memory (preconditioning) results from triggered mitochondrial swelling that causes enhanced substrate oxidation and ROS production, leading to redox activation of PKC, which inhibits glycogen synthase kinase-3beta (GSK-3beta). Alternatively, receptor tyrosine kinase or certain G protein-coupled receptor activation elicits cell protection (without mitochondrial swelling or durable memory) by inhibiting GSK-3beta, via protein kinase B/Akt and mTOR/p70(s6k) pathways, PKC pathways, or protein kinase A pathways. The convergence of these pathways via inhibition of GSK-3beta on the end effector, the permeability transition pore complex, to limit MPT induction is the general mechanism of cardiomyocyte protection. C1 NIA, Cardiovasc Sci Lab, Ctr Gerontol Res, Intramural Res Program,NIH, Baltimore, MD 21224 USA. AN Belozersky Inst Physico Chem Biol, Dept Bioenerget, Moscow, Russia. Chonbuk Natl Univ, Sch Med, Dept Physiol, Jeonju, South Korea. Monash Univ, Fac Med, Alfred Hosp & Baker Med Res Inst, Cardiac Surg Res Unit, Melbourne, Vic 3004, Australia. NIA, Clin Invest Lab, Ctr Gerontol Res, Intramural Res Program,NIH, Baltimore, MD USA. Univ Tromso, Inst Med Biol, Dept Med Physiol, Tromso, Norway. Univ Texas, Dept Biol Mol, SW Med Sch, Dallas, TX 75230 USA. RP Sollott, SJ (reprint author), NIA, Cardiovasc Sci Lab, Ctr Gerontol Res, Intramural Res Program,NIH, Box 13,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM sollotts@grc.nia.nih.gov RI Antos, Christopher/E-8171-2010 NR 62 TC 660 Z9 720 U1 4 U2 37 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN PY 2004 VL 113 IS 11 BP 1535 EP 1549 DI 10.1172/JCI200419906 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 826BZ UT WOS:000221805200006 PM 15173880 ER PT J AU Endres, M Biniszkiewicz, D Sobol, RW Harms, C Ahmadi, M Lipski, A Katchanov, J Mergenthaler, P Dirnagl, U Wilson, SH Meisel, A Jaenisch, R AF Endres, M Biniszkiewicz, D Sobol, RW Harms, C Ahmadi, M Lipski, A Katchanov, J Mergenthaler, P Dirnagl, U Wilson, SH Meisel, A Jaenisch, R TI Increased postischemic brain injury in mice deficient in uracil-DNA glycosylase SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID BASE-EXCISION-REPAIR; FOCAL CEREBRAL-ISCHEMIA; RAT-BRAIN; MUTATOR PHENOTYPE; OXIDATIVE LESIONS; NITRIC-OXIDE; MITOCHONDRIA; CELLS; MUTATIONS; REPLICATION AB Uracil-DNA glycosylase (UNG) is involved in base excision repair of aberrant uracil residues in nuclear and mitochondrial DNA. Ung knockout mice generated by gene targeting are viable, fertile, and phenotypically normal and have regular mutation rates. However, when exposed to a nitric oxide donor, Ung(-/-) fibroblasts show an increase in the uracil/cytosine ratio in the genome and augmented cell death. After combined oxygen-glucose deprivation, Ung(-/-) primary cortical neurons have increased vulnerability to cell death, which is associated with early mitochondrial dysfunction. In vivo, LING expression and activity are low in brains of naive WT mice but increase significantly after reversible middle cerebral artery occlusion and reperfusion. Moreover, major increases in infarct size are observed in Ung(-/-) mice compared with littermate control mice. In conclusion, our results provide compelling evidence that LING is of major importance for tissue repair after brain ischemia. C1 Humboldt Univ, Charite, Dept Neurol, Berlin, Germany. MIT, Whitehead Inst Biomed Res, Cambridge, MA 02139 USA. Natl Inst Environm Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC USA. Univ Pittsburgh, Inst Canc, Hillman Canc Ctr, Pittsburgh, PA USA. RP Endres, M (reprint author), Charite Univ Med Berlin, Neurol Klin & Poliklin, Campus Mitte,Schumannstr 20-21, D-10117 Berlin, Germany. EM matthias.endres@charite.de RI Sobol, Robert/E-4125-2013; OI Sobol, Robert/0000-0001-7385-3563; Meisel, Andreas/0000-0001-7233-5342; Harms, Christoph/0000-0002-2063-2860; Dirnagl, Ulrich/0000-0003-0755-6119 NR 37 TC 75 Z9 77 U1 0 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN PY 2004 VL 113 IS 12 BP 1711 EP 1721 DI 10.1172/JCI200420926 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 829JV UT WOS:000222045300009 PM 15199406 ER PT J AU Cheung, WC Kim, JS Linden, M Peng, LP Van Ness, B Polakiewicz, RD Janz, S AF Cheung, WC Kim, JS Linden, M Peng, LP Van Ness, B Polakiewicz, RD Janz, S TI Novel targeted deregulation of c-Myc cooperates with Bcl-X-L to cause plasma cell neoplasms in mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID HUMAN MULTIPLE-MYELOMA; TRANSGENIC MICE; CHROMOSOMAL TRANSLOCATIONS; B-LYMPHOCYTES; BALB/C MICE; SWITCH RECOMBINATION; MOUSE PLASMACYTOMAS; NEGATIVE SELECTION; TUMOR PROGRESSION; INDUCED APOPTOSIS AB Deregulated expression of both Myc and Bcl-X-L are consistent features of human plasma cell neoplasms (PCNs). To investigate whether targeted expression of Myc and BCl-X-L in mouse plasma cells might lead to an improved model of human PCN, we generated Myc transgenics by inserting a single-copy histidine-tagged mouse Myc gene, Myc(His), into the mouse Ig heavy-chain Calpha locus. We also generated Bcl-X-L transgenic mice that contain a multicopy Flag-tagged mouse Bcl-x(Flag) transgene driven by the mouse Ig K fight-chain 3' enhancer. Single-transgenic Bcl-X-L mice remained tumor free by 380 days of age, whereas single-transgenic Myc mice developed B cell tumors infrequently (4 of 43, 9.3%). In contrast, double-transgenic Myc/Bcl-X-L mice developed plasma cell tumors with short onset (135 days on average) and full penetrance (100% tumor incidence). These tumors produced monoclonal Ig, infiltrated the bone marrow, and contained elevated amounts of Myc(His) and Bcl-X-L(Flag) proteins compared with the plasma cells that accumulated in large numbers in young tumor-free Myc/Bcl-X-L mice. Our findings demonstrate that the enforced expression of Myc and Bcl-X-L by Ig enhancers with peak activity in plasma cells generates a mouse model of human PCN that recapitulates some features of human multiple myeloma. C1 NCI, Genet Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Cell Signaling Technol Inc, Beverly, MA USA. Univ Minnesota, Minneapolis, MN USA. RP Janz, S (reprint author), NCI, Genet Lab, Ctr Canc Res, NIH, Bldg 37,Room 3140A, Bethesda, MD 20892 USA. EM sj4s@nih.gov FU NCI NIH HHS [T32 CA09138-27, T32 CA009138] NR 87 TC 70 Z9 72 U1 0 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN PY 2004 VL 113 IS 12 BP 1763 EP 1773 DI 10.1172/JCI200420369 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 829JV UT WOS:000222045300014 PM 15199411 ER PT J AU Kaufman, HL Wang, W Manola, J DiPaola, RS Ko, YJ Sweeney, C Whiteside, TL Schlom, J Wilding, G Weiner, LM AF Kaufman, HL Wang, W Manola, J DiPaola, RS Ko, YJ Sweeney, C Whiteside, TL Schlom, J Wilding, G Weiner, LM TI Phase II randomized study of vaccine treatment of advanced prostate cancer (E7897): A trial of the Eastern Cooperative Oncology group SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RADICAL RETROPUBIC PROSTATECTOMY; RADIATION-THERAPY; DIVERSIFIED PRIME; ANTIGEN PSA; POX VIRUS; T-CELLS; GENERATION; PROGRESSION; SURVIVAL; PEPTIDE AB Purpose. A phase II clinical trial was conducted to evaluate the feasibility and tolerability of a prime/boost vaccine strategy using vaccinia virus and fowlpox virus expressing human prostate-specific antigen (PSA) in patients with biochemical progression after local therapy for prostate cancer. The induction of PSA-specific immunity was also evaluated. Patients and Methods. A randomized clinical trial was conducted by the Eastern Cooperative Oncology group and 64 eligible patients were randomly assigned to receive four vaccinations with fowlpox-PSA (rF-PSA), three rF-PSA vaccines followed by one vaccinia-PSA (rV-PSA) vaccine, or one rV-PSA vaccine followed by three rF-PSA vaccines. The major end point was PSA response at 6 months, and immune monitoring included measurements of anti-PSA and anti-vaccinia antibody titers and PSA-specific T-cell responses. Results. The prime/boost schedule was well tolerated with few adverse events. Of the eligible patients, 45.3% of men remained free of PSA progression at 19.1 months and 78.1 % demonstrated clinical progression-free survival. There was a trend favoring the treatment group that received a priming dose of rV-PSA. Although no significant increases in anti-PSA antibody titers were detected, 46% of patients demonstrated an increase in PSA-reactive T-cells. Conclusion. Therapy with poxviruses expressing PSA and delivered in a prime/boost regimen was feasible and associated with minimal toxicity in the cooperative group setting. A significant proportion of men remained free of PSA and clinical progression after 19 months follow-up, and nearly half demonstrated an increase in PSA-specific T-cell responses. Phase III studies are needed to define the role of vaccination in men with prostate cancer or those who are at risk for the disease. C1 Columbia Univ, Med Ctr, New York, NY 10032 USA. Dana Farber Canc Inst, Beth Israel Deaconess Med Ctr, Boston, MA USA. Canc Inst New Jersey, New Brunswick, NJ USA. Indiana Univ, Med Ctr, Indianapolis, IN USA. Univ Pittsburgh, Pittsburgh, PA USA. NCI, Bethesda, MD 20892 USA. Univ Wisconsin, Madison, WI USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. RP Kaufman, HL (reprint author), Columbia Univ, Med Ctr, 177 Ft Washington Ave, New York, NY 10032 USA. EM hlk2003@columbia.edu FU NCI NIH HHS [CA23318, CA14958, CA39229, CA66636, CA80775, CA21115, CA21076, CA49883, CA49957] NR 34 TC 174 Z9 180 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 1 PY 2004 VL 22 IS 11 BP 2122 EP 2132 DI 10.1200/JCO.2004.08.083 PG 11 WC Oncology SC Oncology GA 826DG UT WOS:000221808800013 PM 15169798 ER PT J AU Okunieff, P Augustine, E Hicks, JE Cornelison, TL Altemus, RM Naydich, BG Ding, I Huser, AK Abrahim, EH Smith, JJ Coleman, N Gerber, LH AF Okunieff, P Augustine, E Hicks, JE Cornelison, TL Altemus, RM Naydich, BG Ding, I Huser, AK Abrahim, EH Smith, JJ Coleman, N Gerber, LH TI Pentoxifylline in the treatment of radiation-induced fibrosis SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID REGIMEN-RELATED TOXICITIES; TGF-BETA; MARROW-TRANSPLANTATION; PULMONARY FIBROSIS; CONTROLLED-TRIAL; TISSUE-INJURY; LUNG INJURY; TNF-ALPHA; PROLIFERATION; NECROSIS AB Purpose. Fibrotic sequelae remain the most important dose-limiting toxicity of radiation therapy to soft tissue. Functionally, this is reflected in loss of range of motion and muscle strength and the development of limb edema and pain. Tumor necrosis factor alpha and fibroblast growth factor 2 (FGF2), which are abnormally elevated in irradiated tissues, may mediate radiation fibrovascular injury. Patients and Methods. In an open label drug trial, we studied the effects of pentoxifylline (400 mg orally tid for 8 weeks) on 30 patients who displayed late, radiation-induced fibrosis at 1 to 29 years posttreatment (40 to 84 Gy). The primary outcome measurement was change in physical impairments thought to be secondary to radiation, including active and passive range of motion (AROM and PROM), muscle strength, limb edema, and pain. Plasma levels of cytokines (tumor necrosis factor alpha and FGF2) also were measured. Twenty-seven patients completed baseline and 8-week assessments, and 24 patients completed baseline, 8-week, and 16-week assessments. Results. After 8 weeks of pentoxifylline intervention, 20 of 23 patients with impaired AROM and 19 of 22 with impaired PROM improved; 11 of 19 patients with muscle weakness showed improved motor strength; five of seven patients with edema had decreased limb girth; and nine of 20 patients had decreased pain. Pretreatment FGF2 levels dropped from an average of 44.9 pg/mL to 24.0 l after 8 weeks of treatment. Conclusion. Patients receiving pentoxifylline demonstrated improved AROM, PROM, and muscle strength and decreased limb edema and pain. Reversal of these delayed radiation effects was associated with a decrease in circulating FGF2. C1 Univ Rochester, Ctr Med, James P Wilmot Canc Ctr, Dept Radiat Oncol, Rochester, NY USA. NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. Maryland Reg Canc Care, Waldorf, MD USA. RP Okunieff, P (reprint author), Univ Rochester, Sch Med, 601 Elmwood Ave,Box 647, Rochester, NY 14642 USA. EM Paul_Okunieff@urmc.rochester.edu NR 37 TC 68 Z9 69 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 1 PY 2004 VL 22 IS 11 BP 2207 EP 2213 DI 10.1200/JCO.2004.09.101 PG 7 WC Oncology SC Oncology GA 826DG UT WOS:000221808800025 PM 15169810 ER PT J AU Hoza, B Gerdes, AC Hinshaw, SP Arnold, LE Pelham, WE Molina, BSG Abikoff, HB Epstein, JN Greenhill, LL Hechtman, L Odbert, C Swanson, JM Wigal, T AF Hoza, B Gerdes, AC Hinshaw, SP Arnold, LE Pelham, WE Molina, BSG Abikoff, HB Epstein, JN Greenhill, LL Hechtman, L Odbert, C Swanson, JM Wigal, T TI Self-perceptions of competence in children with ADHD and comparison children SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; TREATMENT STRATEGIES; MENTAL-HEALTH; MULTIMODAL TREATMENT; DARK SIDE; BOYS; MTA; HYPERACTIVITY; AGGRESSION; PERFORMANCE AB The self-perceptions of children with attention-deficit/hyperactivity disorder (ADHD; n = 487) were compared with those of children in a local normative comparison group (n = 287), relative to teacher- and parent-rated perceptions of their competence. Children were participants in the ongoing follow-up portion of the Multimodal Treatment Study of Children with ADHD. Children with ADHD were much more likely than comparison children to overestimate their competence relative to adult report, regardless of who was used as the criterion rater (teacher, mother, or father). Examination by comorbidity subgroups revealed that children with ADHD inflated their self-perceptions the most in domains of greatest deficit. Gender effects also are reported. C1 Purdue Univ, Dept Psychol Sci, W Lafayette, IN 47907 USA. Univ Calif Berkeley, Dept Psychol, Berkeley, CA 94720 USA. Ohio State Univ, Dept Psychiat, Columbus, OH 43210 USA. SUNY Buffalo, Dept Psychol, Buffalo, NY 14260 USA. Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15260 USA. NYU, Sch Med, Dept Psychiat, New York, NY USA. Duke Univ, Dept Psychiat & Behav Sci, Durham, NC 27706 USA. Columbia Univ, Dept Psychiat, New York, NY 10027 USA. McGill Univ, Dept Psychiat, Montreal, PQ H3A 2T5, Canada. NIMH, Div Serv & Intervent Res, Biostat & Data Management Unit, Bethesda, MD 20892 USA. Univ Calif Irvine, Dept Pediat & Cognit Sci, Irvine, CA 92717 USA. RP Hoza, B (reprint author), Purdue Univ, Dept Psychol Sci, 703 3rd St, W Lafayette, IN 47907 USA. EM blaze@psych.purdue.edu FU NIMH NIH HHS [UO1 MH50440, UO1 MH50447, UO1 MH50453, UO1 MH50454, UO1 MH50461, UO1 MH50467] NR 31 TC 110 Z9 112 U1 2 U2 17 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD JUN PY 2004 VL 72 IS 3 BP 382 EP 391 DI 10.1037/0022-006X.72.3.382 PG 10 WC Psychology, Clinical SC Psychology GA 823PH UT WOS:000221624800002 PM 15279522 ER PT J AU Clarke, EB Luce, JM Curtis, JR Danis, M Levy, M Nelson, J Solomon, MZ AF Clarke, EB Luce, JM Curtis, JR Danis, M Levy, M Nelson, J Solomon, MZ CA R W Johnson Fdn Critical Care End TI A content analysis of forms, guidelines, and other materials documenting end-of-life care in intensive care units SO JOURNAL OF CRITICAL CARE LA English DT Article ID CLINICAL-PRACTICE GUIDELINES; CRITICALLY-ILL PATIENTS; PALLIATIVE CARE; ADVANCE DIRECTIVES; CANCER-PATIENTS; SEDATION; SCALE; DELIRIUM; COMMUNICATION; EXPERIENCE AB Objective:The purpose of this study was to determine the extent to which data entry forms, guidelines, and other materials used for documentation in intensive care units (ICUs) attend to 6 key end-of-life care (EOLC) domains: 1) patient and family-centered decision making, 2) communication, 3) continuity of care, 4) emotional and practical support, 5) symptom management and comfort care, and 6) spiritual support. A second purpose was to determine how these materials might be modified to include more EOLC content and used to trigger clinical behaviors that might improve the quality of EOLC. Participants: Fifteen adult ICUs-8 medical, 2 surgical, and 4 mixed ICUs from the United States, and 1 mixed ICU in Canada, all affiliated with the Critical Care End-of-Life Peer Workgroup Methods: Physician-nurse teams in each ICU received detailed checklists to facilitate and standardize collection of requested documentation materials. Content analysis was performed on the collected documents, aimed at characterizing the types of materials in use and the extent to which EOLC content was incorporated. Measurements and Main Results: The domain of symptom management and comfort care was integrated most consistently on forms and other materials across the 15 ICUs, particularly pain assessment and management. The 5 other EOLC domains of patient and family centered decision-making, communication, emotional and practical support, continuity of care, and spiritual support were not well-represented on documentation. None of the 15 ICUs supplied a comprehensive EOLC policy or EOLC critical pathway that outlined an overall, interdisciplinary, sequenced approach for the care of dying patients and their families. Nursing materials included more cues for attending to EOLC domains and were more consistently preprinted and computerized than materials used by physicians. Computerized forms concerning EOLC were uncommon. Across the 15 ICUs, there were opportunities to make EOLC-related materials more capable of triggering and documenting specific EOLC clinical behaviors. Conclusions: Inclusion of EOLC items on ICU formatted data entry forms and other materials capable of triggering and documenting clinician behaviors is limited, particularly for physicians. Standardized scales, protocols, and guidelines exist for many of the EOLC domains and should be evaluated for possible use in ICUs. Whether such materials can improve EOLC has yet to be determined. (C) 2004 Elsevier Inc. All rights reserved. C1 Brown Univ, Rhode Isl Hosp, Dept Crit Care Med, Providence, RI 02903 USA. Univ Calif San Francisco, Div Pulm & Crit Care Med, San Francisco, CA 94143 USA. Univ Washington, Div Pulm & Crit Care Med, Seattle, WA 98195 USA. San Francisco Gen Hosp, San Francisco, CA 94110 USA. NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. Mt Sinai Sch Med, Div Pulm & Crit Care Med, Brooklyn, NY USA. Educ Dev Ctr Inc, Newton, MA USA. RP Clarke, EB (reprint author), 188 Union St, Hingham, MA 02043 USA. EM pinzetta@comcast.net NR 72 TC 19 Z9 19 U1 1 U2 10 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0883-9441 J9 J CRIT CARE JI J. Crit. Care PD JUN PY 2004 VL 19 IS 2 BP 108 EP 117 DI 10.1016/j.jcrc.2004.05.001 PG 10 WC Critical Care Medicine SC General & Internal Medicine GA 840KH UT WOS:000222857000007 PM 15236144 ER PT J AU Kim, UK Breslin, PAS Reed, D Drayna, D AF Kim, UK Breslin, PAS Reed, D Drayna, D TI Genetics of human taste perception SO JOURNAL OF DENTAL RESEARCH LA English DT Review DE taste; genetics; variation; gene identification ID BITTER-TASTE; UMAMI TASTE; SENSORY THRESHOLDS; CHANNEL SUBUNITS; RECEPTOR GENES; PHENYLTHIOCARBAMIDE; AMILORIDE; SWEET; RAT; SENSITIVITY AB Genetic approaches are rapidly yielding new information about our sense of taste. This information comes from both molecular studies of genes encoding taste receptors and other taste-signaling components, and from studies of inherited variation in taste abilities. Our understanding of bitter taste has advanced by combined information from discovery and study of the TAS2R family of taste receptor genes, hand in hand with genetic linkage and positional cloning studies, notably on the ability to taste phenylthiocarbamide ( PTC). Sweet and umami tastes, mediated by TAS1R receptors, are becoming well-characterized at the molecular genetic level, and these taste classes are now targets for linkage, positional cloning, and genetic association strategies. Salty and sour tastes are still poorly characterized in genetic terms, and represent opportunities for the future. C1 Natl Inst Deafness & Other Commun Disorders, NIH, Rockville, MD 20850 USA. Monell Chem Senses Ctr, Philadelphia, PA 19104 USA. RP Drayna, D (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, 5 res Court,Room 2B46, Rockville, MD 20850 USA. EM drayna@nidcd.nih.gov OI Reed, Danielle/0000-0002-4374-6107 FU NIDCD NIH HHS [DC004698, DC02995]; PHS HHS [Z01-000046-04] NR 63 TC 64 Z9 65 U1 13 U2 86 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUN PY 2004 VL 83 IS 6 BP 448 EP 453 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 891RJ UT WOS:000226597900003 PM 15153450 ER PT J AU Ruhl, S Sandberg, AL Cisar, JO AF Ruhl, S Sandberg, AL Cisar, JO TI Salivary receptors for the proline-rich protein-binding and lectin-like adhesins of oral actinomyces and streptococci SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE Actinomyces naeslundii; adhesins; salivary receptors; Streptococcus gordonii; Streptococcus sanguis ID VIRIDANS GROUP STREPTOCOCCI; CELL-WALL POLYSACCHARIDES; APATITIC SURFACES; PROMOTES ADHESION; AMYLASE-BINDING; VISCOSUS T14V; GORDONII; SANGUIS; NAESLUNDII; FIMBRIAE AB Colonization of the tooth surface by actinomyces and viridans group streptococci involves the attachment of these bacteria to adsorbed salivary components of the acquired enamel pellicle. The hypothesis that this attachment depends on specific adhesins has now been assessed from the binding of bacteria with well-defined adhesive properties to blots of SDS-PAGE-separated parotid and submandibular-sublingual ( SM-SL) saliva. Streptococcus sanguis and type 2 fimbriated Actinomyces naeslundii, which bound terminal sialic acid and Galbeta1-3GalNAc, respectively, recognized only a few SM-SL salivary components, primarily MG2. In contrast, type 1 fimbriated A. naeslundii and S. gordonii, which bound purified proline-rich proteins ( PRPs), recognized several other components from both SM-SL and parotid saliva. Significantly, bacteria that lacked PRP-binding and the lectin-like activities detected by binding to MG2 failed to bind any immobilized salivary component. These findings suggest the involvement of specific adhesins in bacterial recognition of many adsorbed salivary proteins and glycoproteins. C1 Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, Bethesda, MD 20892 USA. RP Cisar, JO (reprint author), Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, Bldg 30,Room 532, Bethesda, MD 20892 USA. EM john.cisar@nih.gov NR 32 TC 56 Z9 60 U1 0 U2 4 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD JUN PY 2004 VL 83 IS 6 BP 505 EP 510 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 891RJ UT WOS:000226597900014 PM 15153461 ER PT J AU McCoy, RC Hunt, CE Lesko, SM Vezina, R Corwin, MJ Willinger, M Hoffman, HJ Mitchell, AA AF McCoy, RC Hunt, CE Lesko, SM Vezina, R Corwin, MJ Willinger, M Hoffman, HJ Mitchell, AA TI Frequency of bed sharing and its relationship to breastfeeding SO JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS LA English DT Article; Proceedings Paper CT Annual Meeting of the Pediatric-Academic-Societies CY MAY 15, 2000 CL Boston, MA SP Pediatr Acad Soc DE bed sharing; breastfeeding; sudden infant death syndrome ID INFANT-DEATH-SYNDROME; SLEEP POSITION; UNITED-STATES; NEW-ZEALAND; RISK; ENVIRONMENT; POPULATION; PROXIMITY; SIDS AB Bed sharing has been promoted as facilitating breastfeeding but also may increase risks for sudden, unexpected infant deaths. This prospective cohort study was performed to determine the prevalence of adult and infant bed sharing and its association with maternal and infant characteristics. Demographic data were collected from 10,355 infant-mother pairs at birth hospitals in Eastern Massachusetts and Northwest Ohio, and follow-up data were collected at 1, 3, and 6 months by questionnaire. Associations with bed sharing were estimated using odds ratios and 95% confidence intervals from multiple logistic regression models while adjusting for confounding variables. At 1, 3, and 6 months, 22%, 14%, and 13% of infant-mother pairs shared a bed, respectively. On multivariate analysis, race/ethnicity and breastfeeding seemed to have the strongest association with bed sharing. These factors need to be considered in any comprehensive risk to benefit analysis of bed sharing. C1 Med Coll Ohio, Childrens Mercy Hosp, Richard Ruppert Hlth Ctr, Dept Pediat, Toledo, OH 43614 USA. NHLBI, Natl Ctr Sleep Disorders Res, NIH, Bethesda, MD 20892 USA. Boston Univ, Sch Publ Hlth, Slone Epidemiol Ctr, Boston, MA USA. Boston Univ, Sch Med, Dept Pediat, Boston, MA 02118 USA. NICHHD, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, Dept Hlth & Human Serv, NIH, Bethesda, MD USA. Boston Univ, Sch Publ Hlth, Slone Epidemiol Ctr, Boston, MA USA. RP McCoy, RC (reprint author), Med Coll Ohio, Childrens Mercy Hosp, Richard Ruppert Hlth Ctr, Dept Pediat, Suite 1602,3120 Glendale Ave, Toledo, OH 43614 USA. EM rmccoy@mco.edu FU NICHD NIH HHS [N01-HD-4-3221] NR 38 TC 46 Z9 48 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-206X J9 J DEV BEHAV PEDIATR JI J. Dev. Behav. Pediatr. PD JUN PY 2004 VL 25 IS 3 BP 141 EP 149 DI 10.1097/00004703-200406000-00001 PG 9 WC Behavioral Sciences; Psychology, Developmental; Pediatrics SC Behavioral Sciences; Psychology; Pediatrics GA 830LJ UT WOS:000222123300002 PM 15194897 ER PT J AU Baumann, BL Pelham, WE Lang, AR Jacob, RG Blumenthal, JD AF Baumann, BL Pelham, WE Lang, AR Jacob, RG Blumenthal, JD TI The impact of maternal depressive symptomatology on ratings of children with ADHD and child confederates SO JOURNAL OF EMOTIONAL AND BEHAVIORAL DISORDERS LA English DT Article ID DSM-III-R; PARENTAL ALCOHOL-CONSUMPTION; CLINIC-REFERRED CHILDREN; BEHAVIOR PROBLEMS; DISRUPTIVE BEHAVIOR; PRESCHOOL-CHILDREN; CONDUCT PROBLEMS; LIFE STRESS; MOTHERS; PERCEPTIONS AB Some researchers who have studied children with behavior problems have suggested that depressed mothers distort reports of deviance in their children, perhaps contributing to misdiagnoses; however, investigations studying mothers with current or past depression have not clearly indicated such a bias. Because some of this equivocation may be due to the confounding effects of the mother-child history, the present study examined maternal ratings of the standardized behavior of child confederates, thereby providing an objective standard from which bias could be determined. Maternal lifetime diagnoses of depression and contemporary reports of depressive symptomatology were also evaluated. Mothers of 4- to 12-year-old sons with attention-deficit/hyperactivity disorder (ADHD) interacted with and rated boys in the same age range whose behavior was carefully scripted to represent either ADHD or the absence of any disorder. Forty-four of these mothers had a history of clinical depression, and the entire sample represented a range of depressive symptomatology. Analyses revealed no significant differences in ratings of the child confederates' behaviors as a function of maternal history of depression or current depressive symptomatology. These findings thus call into question at least some of the prior assertions of maternal bias in the reporting of behavior problems in children. C1 NIMH, Child Psychiat Branch, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Pittsburgh, Med Ctr, Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. SUNY Buffalo, Ctr Children & Families, Buffalo, NY USA. Florida State Univ, Dept Psychol, Tallahassee, FL 32306 USA. RP Baumann, BL (reprint author), Univ Pittsburgh, Med Ctr, Western Psychiat Inst & Clin, 3811 OHara St, Pittsburgh, PA 15213 USA. EM baumannBL@upmc.edu NR 44 TC 14 Z9 14 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1063-4266 J9 J EMOT BEHAV DISORD JI J. Emot. Behav. Disord. PD SUM PY 2004 VL 12 IS 2 BP 90 EP 98 DI 10.1177/10634266040120020301 PG 9 WC Education, Special; Psychology, Educational; Psychology, Multidisciplinary SC Education & Educational Research; Psychology GA 822ON UT WOS:000221549600003 ER PT J AU Pennington, J Stumbo, P AF Pennington, J Stumbo, P TI Message from guest editors SO JOURNAL OF FOOD COMPOSITION AND ANALYSIS LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. Univ Iowa, Iowa City, IA USA. RP Pennington, J (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 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 0889-1575 J9 J FOOD COMPOS ANAL JI J. Food Compos. Anal. PD JUN-AUG PY 2004 VL 17 IS 3-4 BP 247 EP 248 DI 10.1016/j.jfca.2004.04.004 PG 2 WC Chemistry, Applied; Food Science & Technology SC Chemistry; Food Science & Technology GA 829TE UT WOS:000222071900001 ER PT J AU Dwyer, JT Picciano, MF Betz, JM Coates, PM AF Dwyer, JT Picciano, MF Betz, JM Coates, PM TI Mission and activities of the NIH Office of Dietary Supplements SO JOURNAL OF FOOD COMPOSITION AND ANALYSIS LA English DT Article; Proceedings Paper CT 5th International Food Data Conference/27th National Nutrient Databank Conference CY JUN 30-JUL 03, 2003 CL Washington, DC DE dietary supplements; analytical substantiation; dietary supplement composition; certified reference materials; standard reference materials ID AMERICA-NHANES; EAT AB Major initiatives of the US National Institutes of Health Office of Dietary Supplements (ODS) include development of analytical methods and reference materials to make the development of analytically substantiated dietary supplement databases possible in the future. ODS has an active evidence-based review program focused on efficacy and safety of dietary supplements. It also sponsors basic and clinical research, and information and educational resources, including continuing education conferences and training efforts. (C) 2004 Published by Elsevier Ltd. C1 Tufts Univ, Sch Nutr, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. Tufts New England Med Ctr, Friedman Sch Nutr Sci & Policy, Sch Med, Boston, MA 02111 USA. NIH, US Dept HHS, Off Dietary Supplements, Bethesda, MD 20892 USA. NIH, Dietary Supplement Methods & Reference Mat Progra, Off Dietary Supplements, Us Dept HHS, Bethesda, MD 20892 USA. RP Dwyer, JT (reprint author), Tufts Univ, Sch Nutr, Jean Mayer USDA Human Nutr Res Ctr Aging, 750 Washington St, Boston, MA 02111 USA. EM Jdwyer1@tufts-nemc.org OI Dwyer, Johanna/0000-0002-0783-1769 NR 17 TC 2 Z9 2 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 0889-1575 J9 J FOOD COMPOS ANAL JI J. Food Compos. Anal. PD JUN-AUG PY 2004 VL 17 IS 3-4 BP 493 EP 500 DI 10.1016/j.jfca.2004.03.021 PG 8 WC Chemistry, Applied; Food Science & Technology SC Chemistry; Food Science & Technology GA 829TE UT WOS:000222071900026 ER PT J AU Wolkersdorfer, GW Morris, JC Ehninger, G Ramsey, WJ AF Wolkersdorfer, GW Morris, JC Ehninger, G Ramsey, WJ TI Trans-complementing adenoviral vectors for oncolytic therapy of malignant melanoma SO JOURNAL OF GENE MEDICINE LA English DT Article DE adenoviral vectors; oncolytic therapy; malignant melanoma ID VIRUS THYMIDINE-KINASE; P53 GENE-TRANSFER; E4ORF4 PROTEIN; CANCER-CELLS; ANTITUMORAL EFFICACY; RECEPTOR EXPRESSION; CYTOSINE DEAMINASE; TRANSFORMED-CELLS; BLADDER-CANCER; CLINICAL-TRIAL AB Background Despite attempts to develop efficient viral-based gene transfer therapies for the treatment of malignant tumors, only limited progress has been made to improve the efficacy of this approach. As an alternative, the use of replicating oncolytic adenoviruses with and without the expression of therapeutic transgenes is an area of active investigation. Methods We used a human melanoma xenograft tumor nude mouse model to test the efficacy of a bivalent vector approach consisting of two transcomplementing replication-incompetent adenoviral vectors that resulted in tumor-restricted oncolysis. We combined an El-deleted non-replicating adenoviral vector expressing the herpes simplex virus thymidine kinase gene (AV.C2.TK) and Ac15.dl1O14, an E4-deleted/E4orf4-only expressing adenovirus, to allow full replication competence when tumor cells were co-infected with both vectors. Results A375 tumors showed apoptosis at the ultrastructural level after transduction with the trans-complementing vector system that was not seen with injection of either vector alone. Apoptotic DNA fragments could be co-localized to sites of infection with the adenoviral vectors. A significant survival benefit was achieved for the trans-complementing vector treated animals compared to animals treated with either vector alone. Interestingly, the administration of GCV did not further increase animal survival over treatment with the trans-complementing system of viruses alone, and long-term survival was only seen in the trans-complementing vector treatment group. Intraperitoneal administration of a pseudo-wild-type vector Ad.d1327 resulted in significant hepatotoxicity, while intraperitoneal administration of the trans-complementing vectors resulted in only mild liver abnormalities. Conclusions The trans-complementing vector approach using a combination of E1- and E4-deleted adenoviral vectors showed similar antitumor efficacy as reported for monovalent replicating vector systems, but may offer additional safety by reducing the risk of dissemination of the replication-competent vectors by requiring the presence of both vectors in a cell to achieve replication competence. Copyright (C) 2004 John Wiley Sons, Ltd. C1 Tech Univ Dresden, Fac Med Carl Gustav Carus, Dept Med 1, D-01307 Dresden, Germany. NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NewLink Genet, Ames, IA USA. RP Wolkersdorfer, GW (reprint author), Tech Univ Dresden, Fac Med Carl Gustav Carus, Dept Med 1, Fetscherstasse 74, D-01307 Dresden, Germany. EM wolkersdoerfer@mk1.med.tu-dresden.de NR 71 TC 19 Z9 20 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1099-498X J9 J GENE MED JI J. Gene. Med. PD JUN PY 2004 VL 6 IS 6 BP 652 EP 662 DI 10.1002/jgm.551 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 832OK UT WOS:000222276600007 PM 15170736 ER PT J AU Jiao, XM Wang, RYH Qiu, Q Alter, HJ Shih, JWK AF Jiao, XM Wang, RYH Qiu, Q Alter, HJ Shih, JWK TI Enhanced hepatitis C virus NS3 specific Th1 immune responses induced by co-delivery of protein antigen and CpG with cationic liposomes SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID NONSTRUCTURAL PROTEIN-3; BACTERIAL-DNA; CELLULAR-IMMUNITY; IMMUNIZATION; OLIGODEOXYNUCLEOTIDES; INFECTION; CELLS; INTERFERON; ADJUVANTS; RIBAVIRIN AB Mice were immunized intramuscularly with free recombinant hepatitis C virus (HCV) NS3 (non-structural protein 3) protein, liposomes encapsulating rNS3 or rNS3 and CpG mixture, liposomes co-encapsulating rNS3 and CpG or liposomes co-encapsulating rNS3 and GpC. Liposomes co-encapsulating rNS3 and CpG induced a much higher titre of anti-HCV NS3 IgG and the dominant IgG subtype was IgG2a.. Liposomes co-encapsulating rNS3 and GpC also induced high levels of anti-HCV NS3 IgG antibody, but the dominant IgG subtype was still IgG1, the same as in free HCV/NS3 immunized mice. Liposomes encapsulating rHCV NS3 and the mixture of rHCV NS3 and CpG did not increase the antibody response but switched the IgG subtype. A cytokine profile analysis revealed that the levels of Th1 cytokines in the mice immunized with liposomes co-encapsulating rHCV NS3 and CpG were significantly higher than in other mice while the levels of Th2 cytokine were significantly lower than in the mice immunized with naked rNS3. IL-12 in the mice immunized with liposome-NS3-CpG was significantly higher than in other mice. In conclusion, liposomes co-encapsulating HCV NS3 and CpG are a good candidate vaccine to induce strong Th1 immune responses against hepatitis C viruses. C1 NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. RP Shih, JWK (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bldg 10, Bethesda, MD 20892 USA. EM jshih@mail.cc.nih.gov NR 49 TC 40 Z9 42 U1 0 U2 2 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD JUN PY 2004 VL 85 BP 1545 EP 1553 DI 10.1099/vir.0.79896-0 PN 6 PG 9 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 830IW UT WOS:000222116600023 PM 15166438 ER PT J AU Huang, FF Sun, ZF Emerson, SU Purcell, RH Shivaprasad, HL Pierson, FW Toth, TE Meng, XJ AF Huang, FF Sun, ZF Emerson, SU Purcell, RH Shivaprasad, HL Pierson, FW Toth, TE Meng, XJ TI Determination and analysis of the complete genomic sequence of avian hepatitis E virus (avian HEV) and attempts to infect rhesus monkeys with avian HEV SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID CROSS-SPECIES INFECTION; SPLEEN DISEASE VIRUS; UNITED-STATES; GENETIC-CHARACTERIZATION; PHYLOGENETIC ANALYSIS; MOLECULAR-CLONING; CAPSID PROTEIN; ORF3 PROTEIN; BIG LIVER; SWINE AB Avian hepatitis E virus (avian HEV), recently identified from a chicken with hepatitis-splenomegaly syndrome in the United States, is genetically and antigenically related to human and swine HEVs. In this study, sequencing of the genome was completed and an attempt was made to infect rhesus monkeys with avian HEV. The full-length genome of avian HEV, excluding the poly(A) tail, is 6654 bp in length, which is about 600 bp shorter than that of human and swine HEVs. Similar to human and swine HEV genomes, the avian HEV genome consists of a short 5' non-coding region (NCR) followed by three partially overlapping open reading frames (ORFs) and a 3'NCR. Avian HEV shares about 50% nucleotide sequence identity over the complete genome, 48-51% identity in ORF1, 46-48% identity in ORF2 and only 29-34% identity in ORF3 with human and swine HEV strains. Significant genetic variations such as deletions and insertions, particularly in ORF1 of avian HEV, were observed. However, motifs in the putative functional domains of ORF1, such as the helicase and methyltransferase, were relatively conserved between avian HEV and mammalian HEVs, supporting the conclusion that avian HEV is a member of the genus Hepevirus. Phylogenetic analysis revealed that avian HEV represents a branch distinct from human and swine HEVs. Swine HEV infects non-human primates and possibly humans and thus may be zoonotic. An attempt was made to determine whether avian HEV also infects across species by experimentally inoculating two rhesus monkeys with avian HEV. Evidence of virus infection was not observed in the inoculated monkeys as there was no seroconversion, viraemia, faecal virus shedding or serum liver enzyme elevation. The results from this study confirmed that avian HEV is related to, but distinct from, human and swine HEVs; however, unlike swine HEV, avian HEV is probably not transmissible to non-human primates. C1 Virginia Polytech Inst & State Univ, Coll Vet Med, Ctr Mol Med & Infect Dis, Blacksburg, VA 24060 USA. NIAID, Hepatitis Viruses & Mol Hepatitis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Univ Calif Davis, Calif Anim Hlth & Food Safety Lab Syst, Fresno, CA 93725 USA. RP Meng, XJ (reprint author), Virginia Polytech Inst & State Univ, Coll Vet Med, Ctr Mol Med & Infect Dis, 1410 Prices Fork Rd, Blacksburg, VA 24060 USA. EM xjmeng@vt.edu RI Meng, X.J./B-8769-2009 OI Meng, X.J./0000-0002-2739-1334 FU NIAID NIH HHS [AI46505, AI01653, AI50611] NR 42 TC 138 Z9 158 U1 2 U2 5 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD JUN PY 2004 VL 85 BP 1609 EP 1618 DI 10.1099/vir.0.79841-0 PN 6 PG 10 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 830IW UT WOS:000222116600030 PM 15166445 ER PT J AU Siefert, K Heflin, CM Corcoran, ME Williams, DR AF Siefert, K Heflin, CM Corcoran, ME Williams, DR TI Food insufficiency and physical and mental health in a longitudinal survey of welfare recipients SO JOURNAL OF HEALTH AND SOCIAL BEHAVIOR LA English DT Article ID NUTRITION EXAMINATION SURVEY; UNITED-STATES; NATIONAL-HEALTH; INSECURITY; PREVALENCE; HUNGER; SELF; DEPRESSION; FAMILIES; VIOLENCE AB Food insufficiency is a significant problem in the United States, and poor African American women with children are at especially high risk. An inadequate householdfood supply can potentially affect the well-being of household members, but it is difficult to distinguish the effects of food insufficiency from risk factors for poor health that are also common among the food insufficient, such as poverty. We examined food insufficiency and physical and mental health among African American and white women (n = 676) who were welfare recipients in 1997. Controlling for common risk factors, women who reported food insufficiency in both 1997 and 1998 were more likely to report fair or poor health at the later date. Food insufficiency in 1998 was significantly associated with meeting the diagnostic screening criteria for recent major depression. Food insufficiency at both times and in 1998 only was related to women sense of mastery. These findings add to growing evidence that householdfood insufficiency is associated with poor physical and mental health. C1 Univ Michigan, NIMH, Res Ctr Poverty Risk & Mental Hlth, Ann Arbor, MI 48109 USA. Univ Kentucky, Lexington, KY 40506 USA. RP Siefert, K (reprint author), Univ Michigan, NIMH, Res Ctr Poverty Risk & Mental Hlth, 1080 S Univ, Ann Arbor, MI 48109 USA. EM ksiefert@umich.edu FU NIMH NIH HHS [R24-MH51361] NR 55 TC 89 Z9 89 U1 1 U2 17 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-1465 EI 2150-6000 J9 J HEALTH SOC BEHAV JI J. Health Soc. Behav. PD JUN PY 2004 VL 45 IS 2 BP 171 EP 186 PG 16 WC Public, Environmental & Occupational Health; Psychology, Social SC Public, Environmental & Occupational Health; Psychology GA 909EB UT WOS:000227841900004 PM 15305758 ER PT J AU Anlauf, M Schafer, MKH Depboylu, C Hartschuh, W Eiden, LE Kloppel, G Weihe, E AF Anlauf, M Schafer, MKH Depboylu, C Hartschuh, W Eiden, LE Kloppel, G Weihe, E TI The vesicular monoamine transporter 2 (VMAT2) is expressed by normal and tumor cutaneous mast cells and langerhans cells of the skin but is absent from langerhans cell histiocytosis SO JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY LA English DT Article DE Birbeck granules; CD1a; dendritic cell; histamine; mast cell; mastocytosis; serotonin; tryptase; vesicular monoamine transporter ID L-DOPA HISTOFLUORESCENCE; AMINE TRANSPORTER; BIRBECK GRANULES; ENDOCRINE TUMORS; NEUROTRANSMITTER TRANSPORTERS; GENERALIZED MASTOCYTOSIS; SYSTEMIC MASTOCYTOSIS; ATOPIC-DERMATITIS; DENDRITIC CELLS; NERVOUS-SYSTEM AB Monoamine storage in secretory granules is mediated by the vesicular monoamine transporters 1 and 2 (VMAT1 and VMAT2). The aim of our study was to identify monoamine-handling normal and neoplastic inflammatory cells in the skin by their expression of VMAT1 and VMAT2. Normal skin from various parts of the body, as well as 21 cases of cutaneous mastocytosis and 10 cases of cutaneous Langerhans cell histiocytosis were analyzed by immunohistochemistry, radioactive in situ hybridization, and double-fluorescence confocal microscopy. VMAT2-positive cells in the subepidermal layer were identified as mast cells by their expression of tryptase. Neoplastic mast cells in all cases of cutaneous mastocytosis retained their VMAT2 positivity. The intraepidermal VMAT2-expressing cells were identified as Langerhans cells by their CD1 a positivity. VMAT2 was absent from Langerhans cell histiocytosis. VMAT2 is an excellent marker for normal and neoplastic mast cells. The expression of VMAT2 demonstrates the capacity of mast cells for monoamine storage and handling. The presence of VMAT2 in epidermal Langerhans cells revealed a previously unrecognized monoamine-handling phenotype of these cells and indicates possible involvement of amine storage and release associated with antigen presentation. Absence of VMAT2 in neoplastic Langerhans cells indicates a loss of monoamine handling capacity of these cells during tumorigenesis. C1 Univ Marburg, Inst Anat & Cell Biol, Dept Mol Neurosci, D-35037 Marburg, Germany. Univ Kiel, Dept Pathol, D-2300 Kiel, Germany. Univ Bonn, Dept Neurol, Bonn, Germany. Univ Heidelberg, Dept Dermatol, D-6900 Heidelberg, Germany. NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. RP Weihe, E (reprint author), Univ Marburg, Inst Anat & Cell Biol, Dept Mol Neurosci, Robert Koch Str 8, D-35037 Marburg, Germany. EM weihe@staff.uni-marburg.de OI Eiden, Lee/0000-0001-7524-944X NR 58 TC 9 Z9 9 U1 0 U2 1 PU HISTOCHEMICAL SOC INC PI SEATTLE PA UNIV WASHINGTON, DEPT BIOSTRUCTURE, BOX 357420, SEATTLE, WA 98195 USA SN 0022-1554 J9 J HISTOCHEM CYTOCHEM JI J. Histochem. Cytochem. PD JUN PY 2004 VL 52 IS 6 BP 779 EP 788 DI 10.1369/jhc.4A6264.2004 PG 10 WC Cell Biology SC Cell Biology GA 826PP UT WOS:000221841300007 PM 15150286 ER PT J AU Cutler, J Piller, L Pressel, S Graumlich, J Hamilton, B Parish, D Qureshi, N Randall, O Davis, B AF Cutler, J Piller, L Pressel, S Graumlich, J Hamilton, B Parish, D Qureshi, N Randall, O Davis, B CA ALLHAT Collaboration Res Grp TI Results of monotherapy in ALLHAT: On-treatment analyses SO JOURNAL OF HYPERTENSION LA English DT Meeting Abstract CT 14th European Meeting on Hypertension CY JUN 13-17, 2004 CL Paris, FRANCE C1 NHLBI, Bethesda, MD 20892 USA. Univ Texas, Sch Publ Hlth, Houston, TX USA. Univ Illinois, Coll Med, Peoria, IL 61656 USA. Vet Affairs Med Ctr, Baltimore, MD USA. Mercer Univ, Macon, GA 31207 USA. Athens Internal Med, Athens, AL USA. Howard Univ Hosp, 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 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 2004 VL 22 SU 2 BP S248 EP S248 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 843QN UT WOS:000223099400867 ER PT J AU Fedorova, O Agalakova, N Zhuravin, I Talan, M Lakatta, E Bagrov, A AF Fedorova, O Agalakova, N Zhuravin, I Talan, M Lakatta, E Bagrov, A TI Angiotensin II (ATII) mediated cross-talk between central and peripheral sodium pump inhibitors in salt loaded Dahl-S rats SO JOURNAL OF HYPERTENSION LA English DT Meeting Abstract CT 14th European Meeting on Hypertension CY JUN 13-17, 2004 CL Paris, FRANCE C1 NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. IM Sechenov Evolutionary Physiol & Biochem Inst, St Petersburg 194223, Russia. NR 0 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 2004 VL 22 SU 2 BP S64 EP S64 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 843QN UT WOS:000223099400216 ER PT J AU Fedorova, O St Louis, J Agalakova, N Lopatin, D Tapilskaya, N Ailamazian, E Kolodkin, N Lakatta, E Bagrov, A AF Fedorova, O St Louis, J Agalakova, N Lopatin, D Tapilskaya, N Ailamazian, E Kolodkin, N Lakatta, E Bagrov, A TI The endogenous Na pump ligand, marinobufagenin, is a target for therapy in preeclampsia SO JOURNAL OF HYPERTENSION LA English DT Meeting Abstract CT 14th European Meeting on Hypertension CY JUN 13-17, 2004 CL Paris, FRANCE C1 NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. Univ Montreal, Hop St Justine, Res Ctr, Montreal, PQ H3T 1C5, Canada. Do Ott Inst Obstet & Gynecol, St Petersburg, Russia. Sch Pediat Med, Dept Obstet & Gynecol, St Petersburg, Russia. State Inst Highly Pure Biopreparat, St Petersburg, Russia. IM Sechenov Evolutionary Physiol & Biochem Inst, St Petersburg 194223, Russia. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 2004 VL 22 SU 2 BP S14 EP S15 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 843QN UT WOS:000223099400042 ER PT J AU Sancho, J Gonzalez, O Bagrov, A Fedorova, O Garcia-Robles, R AF Sancho, J Gonzalez, O Bagrov, A Fedorova, O Garcia-Robles, R TI Purification of marinobufogenin and HHIF from bovine CNS and adrenal tissues SO JOURNAL OF HYPERTENSION LA English DT Meeting Abstract CT 14th European Meeting on Hypertension CY JUN 13-17, 2004 CL Paris, FRANCE C1 Hosp Ramon y Cajal, Dept Endocrinol, E-28034 Madrid, Spain. NIA, NIH, Cardiovasc Sci Lab, Baltimore, MD 21224 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 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 2004 VL 22 SU 2 BP S187 EP S187 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 843QN UT WOS:000223099400645 ER PT J AU Thornton, AM Donovan, EE Piccirillo, CA Shevach, EM AF Thornton, AM Donovan, EE Piccirillo, CA Shevach, EM TI Cutting edge: IL-2 is critically required for the in vitro activation of CD4(+)CD25(+) T cell suppressor function SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SELF-TOLERANCE; HOMEOSTASIS; CD4(+); MICE; RECEPTOR; AUTOIMMUNITY; LIGAND; CD28 AB CD4(+) CD25(+) T cells are potent immunoregulatory cells that suppress TCR-induced proliferation of CD4 and CD8 T cells in vitro by a cell contact-dependent mechanism. Addition of IL-2 or anti-CD28 abrogates CD4(+) CD25(+) -mediated suppression of proliferation and has been assumed to "break suppression." We examined IL-2 mRNA by quantitative PCR in cocultures of mouse CD4(+) CD25(+) and CD4(+) CD25(-) T cells. Although IL-2 gene transcription was inhibited in the presence or absence of exogenous IL-2, the addition of anti-CD28 stimulated endogenous IL-2 production. Surprisingly, transcrition of IL-2 mRNA was also restored in the cocultures in the presence of anti-IL-2. These results are most compatible with a model in which CD4(+) CD25(+) T cells do not suppress the initial activation of CD4(+) CD25(-) T cells, but mediate their suppressive effects following production of IL-2 by the responder cells resulting in both the expansion of the CD4(+) CD25(+) T cells and the induction of their suppressor function. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Thornton, AM (reprint author), NIAID, Immunol Lab, NIH, Bldg 10,Room 11N315,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. EM athornton@niaid.nih.gov NR 22 TC 380 Z9 398 U1 0 U2 10 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2004 VL 172 IS 11 BP 6519 EP 6523 PG 5 WC Immunology SC Immunology GA 822ZN UT WOS:000221579600002 PM 15153463 ER PT J AU Souto-Carneiro, MM Longo, NS Russ, DE Sun, HW Lipsky, PE AF Souto-Carneiro, MM Longo, NS Russ, DE Sun, HW Lipsky, PE TI Characterization of the human Ig heavy chain antigen binding complementarity determining region 3 using a newly developed software algorithm, JOINSOLVER SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN PERIPHERAL-BLOOD; V(D)J RECOMBINATION; B-CELLS; GENE SEGMENTS; MRL MICE; HYPERVARIABLE REGIONS; TRANSGENIC MINILOCUS; DIVERSITY; REARRANGEMENTS; REPERTOIRE AB We analyzed 77 nonproductive and 574 productive human V(H)DJ(H) rearrangements with a newly developed program, JOINSOLVER. In the productive repertoire, the H chain complementarity determining region 3 (CDR3(H)) was significantly shorter (46.7 +/- 0.5 nucleotides) than in the nonproductive repertoire (53.8 +/- 1.9 nucleotides) because of the tendency to select rearrangements with less TdT activity and shorter D segments. Using criteria established by Monte Carlo simulations, D segments could be identified in 71.4% of nonproductive and 64.4% of productive rearrangements, with a mean of 17.6 +/- 0.7 and 14.6 +/- 0.2 retained germline nucleotides, respectively. Eight of 27 D segments were used more frequently than expected in the nonproductive repertoire, whereas 3 D segments were positively selected and 3 were negatively selected, indicating that both molecular mechanisms and selection biased the D segment usage. There was no bias for D segment reading frame (RF) use in the nonproductive repertoire, whereas negative selection of the RFs encoding stop codons and positive selection of RF2 that frequently encodes hydrophilic amino acids were noted in the productive repertoire. Except for serine, there was no consistent selection or expression of hydrophilic amino acids. A bias toward the pairing of 5' D segments with 3' J(H) segments was observed in the nonproductive but not the productive repertoire, whereas V-H usage was random. Rearrangements using inverted D segments, DIR family segments, chromosome 15 D segments and multiple D segments were found infrequently. Analysis of the human CDR3(H) with JOINSOLVER has provided comprehensive information on the influences that shape this important Ag binding region of V-H chains. C1 NIAMSD, Intramural Res Program, Repertoire Anal Grp, Autoimmun Branch, Bethesda, MD 20892 USA. NIAMSD, Div Computat Biosci, Ctr Informat Technol, NIH, Bethesda, MD 20892 USA. NIAMSD, Biodata Mining & Discovery Sect, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. RP Lipsky, PE (reprint author), NIAMSD, Intramural Res Program, Repertoire Anal Grp, Autoimmun Branch, 9000 Rockville Pike,Bldg 10,Room 9N228, Bethesda, MD 20892 USA. EM LipskyP@mail.nih.gov RI Souto-Carneiro, Margarida/C-4386-2016; OI Souto-Carneiro, Margarida/0000-0001-6923-0590; Russ, Daniel/0000-0003-4040-4416 NR 55 TC 98 Z9 98 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 JUN 1 PY 2004 VL 172 IS 11 BP 6790 EP 6802 PG 13 WC Immunology SC Immunology GA 822ZN UT WOS:000221579600036 PM 15153497 ER PT J AU Tsujimura, H Tamura, T Kong, HJ Nishiyama, A Ishii, KJ Klinman, DM Ozato, K AF Tsujimura, H Tamura, T Kong, HJ Nishiyama, A Ishii, KJ Klinman, DM Ozato, K TI Toll-like receptor 9 signaling activates NF-kappa B through IFN regulatory Factor-8/IFN consensus sequence binding protein in dendritic cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CPG-DNA; GENE-EXPRESSION; BACTERIAL-DNA; KINASE COMPLEX; IKK-ALPHA; PHOSPHORYLATION; MOTIFS; MICE; INTERLEUKIN-12; ICSBP/IRF-8 AB Unmethylated CpG DNA binds to the Toll-like receptor 9 (TLR9) and activates NF-kappaB to induce cytokine genes in dendritic cells (DCs). IFN regulatory factor (IRF)-8/IFN consensus sequence binding protein is a transcription factor important for development and activation of DCs. We found that DCs from IRF-8(-/-) mice were unresponsive to CpG and failed to induce TNF-alpha and IL-6, targets of NF-kappaB. Revealing a signaling defect selective for CpG, these cytokines were robustly induced in IRF-8(-/-) DCs in response to LPS that signals through TLR4. IRF-8(-/-) DCs expressed TLR9, adaptor myeloid differentiation factor 88, and other signaling molecules, but CpG failed to activate NF-kappaB in -/- cells. This was due to the selective inability of -/- DCs to activate I-kappaB kinase alphabeta the kinases required for NF-kappaB in response to CpG. IRF-8 reintroduction fully restored CpG activation of NF-kappaB and cytokine induction in -/- DCs. Together, TLR signals that activate NF-kappaB are diverse among different TLRs, and TLR9 signaling uniquely depends on IRF-8 in DCs. C1 NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Ozato, K (reprint author), NICHHD, Lab Mol Growth Regulat, NIH, Bldg 6 Room 2A01,6 Ctr Dr, Bethesda, MD 20892 USA. EM ozatok@nih.gov RI Ishii, Ken/B-1685-2012 OI Ishii, Ken/0000-0002-6728-3872 NR 47 TC 92 Z9 96 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2004 VL 172 IS 11 BP 6820 EP 6827 PG 8 WC Immunology SC Immunology GA 822ZN UT WOS:000221579600039 PM 15153500 ER PT J AU Del Rio, L Butcher, BA Bennouna, S Hieny, S Sher, A Denkers, EY AF Del Rio, L Butcher, BA Bennouna, S Hieny, S Sher, A Denkers, EY TI Toxoplasma gondii triggers myeloid differentiation factor 88-dependent IL-12 and chemokine ligand 2 (monocyte chemoattractant protein 1) responses using distinct parasite molecules and host receptors SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CELL-MEDIATED-IMMUNITY; HUMAN POLYMORPHONUCLEAR LEUKOCYTES; TOLL-LIKE RECEPTORS; GLYCOSYLPHOSPHATIDYLINOSITOL TOXIN; DENDRITIC CELLS; TNF-ALPHA; MICROBIAL INFECTION; SIGNAL-TRANSDUCTION; NEUTROPHILS PLAY; EXPRESSION AB Toll-like receptors (TLR) that signal through the common adaptor molecule myeloid differentiation factor 88 (MyD88) are essential in proinflammatory cytokine responses to many microbial pathogens. In this study we report that Toxoplasma gondii triggers neutrophil IL-12 and chemokine ligand 2 (CCL2; monocyte chemoattractant protein 1) production in strict dependence upon functional MyD88. Nevertheless, the responses are distinct. Although we identify TLR2 as the receptor triggering CCL2 production, parasite-induced IL-12 release did not involve this TLR. The production of both IL-12 and CCL2 was increased after neutrophil activation with IFN-gamma. However, the synergistic effect of IFN-gamma on IL-12, but not CCL2, was dependent upon Stat1 signal transduction. Although IL-10 was a potent down-regulator of Toxoplasma-triggered neutrophil IL-12 release, the cytokine had no effect on parasite-induced CCL2 production. Soluble tachyzoite Ag fractionation demonstrated that CCL2- and IL-12 inducing activities are biochemically distinct. Importantly, Toxoplasma cyclophilin-18, a molecule previously shown to induce dendritic cell IL-12, was not involved in neutrophil IL-12 production. Our results show for the first time that T. gondii possesses multiple molecules triggering distinct MyD88-dependent signaling cascades, that these pathways are independently regulated, and that they lead to distinct profiles of cytokine production. C1 Cornell Univ, Dept Microbiol & Immunol, Coll Vet Med, Ithaca, NY 14850 USA. NIAID, Immunobiol Sect, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA. RP Denkers, EY (reprint author), Cornell Univ, Dept Microbiol & Immunol, Coll Vet Med, Ithaca, NY 14853 USA. EM eyd1@cornell.edu OI Del Rio, Laura/0000-0003-4719-8926 FU NIAID NIH HHS [AI47888] NR 45 TC 65 Z9 69 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2004 VL 172 IS 11 BP 6954 EP 6960 PG 7 WC Immunology SC Immunology GA 822ZN UT WOS:000221579600054 PM 15153515 ER PT J AU Ying, GG Iribarren, P Zhou, Y Gong, WH Zhang, N Yu, ZX Le, Y Cui, Y Wang, JM AF Ying, GG Iribarren, P Zhou, Y Gong, WH Zhang, N Yu, ZX Le, Y Cui, Y Wang, JM TI Humanin, a newly identified neuroprotective factor, uses the g protein-coupled formylpeptide receptor-like-1 as a functional receptor SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FORMYL-PEPTIDE RECEPTORS; MURINE MICROGLIAL CELLS; ALZHEIMERS-DISEASE; NERVOUS-SYSTEM; CHEMOATTRACTANT RECEPTOR; NEUROTROPHIN RECEPTOR; CHEMOTACTIC AGONIST; A-BETA; FPRL1; 7-TRANSMEMBRANE AB Alzheimer's disease (AD) is characterized by overproduction of 6 amyloid peptides in the brain with progressive loss of neuronal cells. The 42-aa form of the beta amyloid peptide (Abeta(42)) is implied as a major causative factor, because it is toxic to neurons and,elicits inflammatory responses in the brain by activating microglial cells. Despite the overproduction of Abeta(42), AD brain tissue also generates protective factor(s) that may antagonize the neurodestructive effect of Abeta(42). Humanin is a gene cloned from an apparently normal region of an AD brain and encodes a 24-aa peptide. Both secreted and synthetic Humanin peptides protect neuronal cells from damage by Abeta(42), and the effect of Humanin may involve putative cellular receptor(s). To elucidate the molecular identity of such. receptor(s), we examined the activity of synthetic Humanin on various cells and found that Humanin induced chemotaxis of mononuclear phagocytes by using a human G protein-coupled formylpeptide receptor-like-1 (FPRL1) and its murine counterpart FPR2. Coincidentally, FPRL1 and FPR2 are also functional receptors used by Abeta(42) to chemoattract and activate phagocytic cells. Humanin reduced the aggregation and fibrillary formation by suppressing the effect of Abeta(42) on mononuclear phagocytes. In neuroblast cells, Humanin and Abeta(42) both activated FPRL1; however, only Abeta(42) caused apoptotic death of the cells, and its cytopathic effect was blocked by Humanin. We conclude that Humanin shares human FPRL1 and mouse FPR2 with Abeta(42) and suggest that Humanin may exert its neuroprotective effects by competitively inhibiting the access of FPRL1 to Abeta(42). C1 NCI, Lab Mol Immunoregulat, Canc Res Ctr, Ft Detrick, MD 21702 USA. NCI, Basic Res Program, Canc Res Ctr, SAIC Frederick, Ft Detrick, MD 21702 USA. NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. RP Wang, JM (reprint author), NCI, Lab Mol Immunoregulat, Canc Res Ctr, Bldg 560,Room 31-40, Ft Detrick, MD 21702 USA. EM wangji@mail.ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 39 TC 106 Z9 113 U1 1 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2004 VL 172 IS 11 BP 7078 EP 7085 PG 8 WC Immunology SC Immunology GA 822ZN UT WOS:000221579600069 PM 15153530 ER PT J AU Su, KH Wu, JM Edberg, JC Li, XL Ferguson, P Cooper, GS Langefeld, CD Kimberly, RP AF Su, KH Wu, JM Edberg, JC Li, XL Ferguson, P Cooper, GS Langefeld, CD Kimberly, RP TI A promoter haplotype of the immunoreceptor tyrosine-based inhibitory motif-bearing Fc gamma RIIb alters receptor expression and associates with autoimmunity. I. Regulatory FCGR2B polymorphisms and their association with systemic lupus erythematosus SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FOLLICULAR DENDRITIC CELLS; DEFICIENT MICE; B-CELLS; SIGNAL-TRANSDUCTION; RISK-FACTORS; HUMAN GENOME; DISEASE; SUSCEPTIBILITY; GENE; IGG AB FcgammaRIIb, the immunoreceptor tyrosine-based inhibitory motif-containing receptor for IgG (Mendelian Inheritance in Man no. 604590), plays an important role in maintaining the homeostasis of immune responses. We have identified 10 novel single-nucleotide polymorphisms in the promoter region of human FCGR2B gene and characterized two functionally distinct haplotypes in its proximal promoter. In luciferase reporter assays, the less frequent promoter haplotype leads to increased expression of the reporter gene in both B lymphoid and myeloid cell lines under constitutive and stimulated conditions. Four independent genomewide scans support linkage of the human FcgammaR region to the systemic lupus erythematosus (SLE; Online Mendelian Inheritance in Man no. 152700) phenotype. Our case-control study in 600 Caucasians indicates a significant association of the less frequent FCGR2B promoter haplotype with the SLE phenotype (odds ratio = 1.65; p = 0.0054). The FCGR2B haplotype has no linkage disequilibrium with previously identified FCGR2A and FCGR3A polymorphisms, and after adjustment for FCGR2A and FCGR3A, FCGR2B showed a persistent association with SLE (odds ratio = 1.72; p = 0.0083). These results suggest that an expression variant of FCGR2B is a risk factor for human lupus and implicate FCGR2B in disease pathogenesis. C1 Univ Alabama, Div Clin Immunol & Rheumatol, Dept Med, Birmingham, AL 35294 USA. Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Wake Forest Univ, Dept Publ Hlth Sci, Winston Salem, NC 27157 USA. RP Kimberly, RP (reprint author), Univ Alabama, Div Clin Immunol & Rheumatol, Dept Med, Tinsley Harrison Tower 429,1900 Univ Blvd, Birmingham, AL 35294 USA. EM rpk@uab.edu FU NCRR NIH HHS [M01 RR00032]; NIAMS NIH HHS [P01 AR49084, P30 AR048311, P30 AR48311, P50 AR45231, R01 AR2476]; PHS HHS [R01 33062] NR 56 TC 100 Z9 103 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2004 VL 172 IS 11 BP 7186 EP 7191 PG 6 WC Immunology SC Immunology GA 822ZN UT WOS:000221579600082 PM 15153543 ER PT J AU Dybul, M Nies-Kraske, E Dewar, R Maldarelli, F Hallahan, CW Daucher, M Piscitelli, SC Ehler, L Weigand, A Palmer, S Metcalf, JA Davey, RT Kress, DMR Powers, A Beck, I Frenkel, L Baseler, M Coffin, J Fauci, AS AF Dybul, M Nies-Kraske, E Dewar, R Maldarelli, F Hallahan, CW Daucher, M Piscitelli, SC Ehler, L Weigand, A Palmer, S Metcalf, JA Davey, RT Kress, DMR Powers, A Beck, I Frenkel, L Baseler, M Coffin, J Fauci, AS TI A proof-of-concept study of short-cycle intermittent antiretroviral therapy with a once-daily regimen of didanosine, lamivudine, and efavirenz for the treatment of chronic HIV infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; STRUCTURED TREATMENT INTERRUPTIONS; REVERSE-TRANSCRIPTASE; PROTEASE INHIBITORS; RISK-FACTORS; HIV/AIDS TREATMENT; BODY-COMPOSITION; TYPE-1 RNA; LIPODYSTROPHY; NEVIRAPINE AB Background. We previously demonstrated that short-cycle structured intermittent therapy ( SIT; 7 days without therapy followed by 7 days with antiretroviral therapy [ART]) with a ritonavir-boosted, indinavir-based, twice-daily regimen maintained suppression of plasma HIV viremia while reducing serum levels of lipids. Adherence to such a regimen may be problematic for certain patients. Methods. Eight patients with a history of receiving combination ART that maintained suppression of plasma HIV RNA to <50 copies/mL received a once-daily SIT regimen of didanosine, lamivudine, and efavirenz. Results. For 7 patients, suppression of plasma HIV RNA to <50 copies/mL was maintained for 60-84 weeks. Four patients with adequate samples had no evidence for an increase in plasma viremia for up to 72 weeks, by use of an assay with a limit of detection of <1 copy/mL. The lack of rebound viremia may be the result of the persistence of efavirenz in plasma on day 7 of the no-therapy period, as was detected in 7 of 7 patients. There was no significant change in CD4(+) T cell counts or serum hepatic transaminase or lipid levels. Conclusion. A once-daily short-cycle SIT regimen maintained suppression of plasma HIV RNA while preserving CD4(+) T cell counts. Such a regimen may have importance in resource-limited settings where the monetary cost of continuous ART is prohibitive. C1 NIAID, Lab Immunoregulat, NIH, US Dept HHS, Bethesda, MD 20892 USA. NCI, NIH, US Dept HHS, Bethesda, MD 20892 USA. Sci Applicat Int Corp, Rockville, MD USA. Univ Washington, Seattle, WA 98195 USA. Childrens Hosp, Seattle, WA USA. Tibotec Virco, Mechelen, Belgium. RP Dybul, M (reprint author), NIAID, Lab Immunoregulat, NIH, US Dept HHS, Bldg 31,Rm 7A-03, Bethesda, MD 20892 USA. EM mdybul@nih.gov NR 43 TC 44 Z9 45 U1 1 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 1 PY 2004 VL 189 IS 11 BP 1974 EP 1982 DI 10.1086/386344 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 823ZQ UT WOS:000221653500002 PM 15143462 ER PT J AU Guttman-Yassky, E Cohen, A Kra-Oz, Z Friedman-Birnbaum, R Sprecher, E Zaltzman, N Friedman, E Silbermann, M Rubin, D Linn, S Whitby, D Gideoni, O Pollack, S Bergman, R Sarid, R AF Guttman-Yassky, E Cohen, A Kra-Oz, Z Friedman-Birnbaum, R Sprecher, E Zaltzman, N Friedman, E Silbermann, M Rubin, D Linn, S Whitby, D Gideoni, O Pollack, S Bergman, R Sarid, R TI Familial clustering of classic Kaposi sarcoma SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 5th International Workshop on Kaposi Sarcoma-Assocaited Herpesvirus and Related Agents CY AUG, 2002 CL Kloster Isree, GERMANY SP Israel Canc Assoc, Middle E Canc Consortium ID JEWISH POPULATION; REVEALS EVIDENCE; HERPESVIRUS; HUMAN-HERPESVIRUS-8; EPIDEMIOLOGY; POLYMORPHISM; INFECTION; DISEASES; VIRUS; RISK AB It is widely accepted that there is a causal association between Kaposi sarcoma-associated herpesvirus ( KSHV) and Kaposi sarcoma (KS). However, the majority of individuals infected with KSHV never develop KS. Here, we present a unique familial case of classic KS, in which the disease occurs in 4 siblings who have no recognized underlying immunodeficiency. We examine risk factors that could play a role in this condition, including KSHV infection, KSHV DNA load, genetic variants of KSHV, infection with additional viruses, interleukin-6-promoter polymorphism, and HLA genotype. We hypothesize that a genetic susceptibility to KS, in combination with KSHV infection, may play an important role in the presented familial case. C1 Rambam Med Ctr, Dept Dermatol, Haifa, Israel. Rambam Med Ctr, Dept Virol, Haifa, Israel. Rambam Med Ctr, Dept Immunol, Haifa, Israel. Rambam Med Ctr, Epidemiol Unit, Haifa, Israel. Technion Israel Inst Technol, Bruce Rappaport Fac Med, Dept Cell Biol & Anat, IL-31096 Haifa, Israel. Bar Ilan Univ, Fac Life Sci, Ramat Gan, Israel. Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel. NCI, Viral Epidemiol Sect, AIDS Vaccine Program, Frederick, MD 21701 USA. RP Sarid, R (reprint author), Bar Ilan Univ, Fac Life Sci, IL-52900 Ramat Gan, Israel. EM saridr@mail.biu.ac.il RI Linn, Shai/C-8212-2013 OI Linn, Shai/0000-0001-5471-5034 NR 15 TC 26 Z9 26 U1 0 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 1 PY 2004 VL 189 IS 11 BP 2023 EP 2026 DI 10.1086/386308 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 823ZQ UT WOS:000221653500009 PM 15143469 ER PT J AU Paessler, S Aguilar, P Anishchenko, M Wang, HQ Aronson, J Campbell, G Cararra, AS Weaver, SC AF Paessler, S Aguilar, P Anishchenko, M Wang, HQ Aronson, J Campbell, G Cararra, AS Weaver, SC TI The hamster as an animal model for eastern equine encephalitis - and its use in studies of virus entrance into the brain SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID ENCEPHALOMYELITIS VIRUS; INFECTION; MICE AB Eastern equine encephalitis virus ( EEEV) produces the most severe human arboviral diseases in the United States, with mortality rates of 30%-70%. Vasculitis associated with microhemorrhages in the brain dominates the pathological picture in fatal human eastern equine encephalitis, and neuronal cell death is detectable during the late stage of the disease. We describe use of the golden hamster to study EEEV-induced acute vasculitis and encephalitis. In hamsters, EEEV replicates in visceral organs, produces viremia, and penetrates the brain. The pathological manifestations and antigen distribution in the brain of a hamster are similar to those described in human cases of EEEV. C1 Univ Texas, Dept Pathol, Ctr Trop Dis, Med Branch, Galveston, TX 77555 USA. Univ Texas, Ctr Biodef & Emerging Infect Dis, Med Branch, Galveston, TX 77555 USA. Univ Texas, Dept Pathol, Med Branch, Galveston, TX 77555 USA. Univ Texas, Dept Microbiol & Immunol, Med Branch, Galveston, TX 77555 USA. Univ Texas, Res Histol Core, NIEHS,Serv Ctr, Med Branch, Galveston, TX 77555 USA. RP Weaver, SC (reprint author), Univ Texas, Dept Pathol, Ctr Trop Dis, Med Branch, 301 Univ Blvd, Galveston, TX 77555 USA. EM sweaver@utmb.edu RI Weaver, Scott/D-6490-2011 FU NIAID NIH HHS [AI48807, T32 AI07536] NR 20 TC 34 Z9 35 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUN 1 PY 2004 VL 189 IS 11 BP 2072 EP 2076 DI 10.1086/383246 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 823ZQ UT WOS:000221653500015 PM 15143475 ER PT J AU Spiegel, AM AF Spiegel, AM TI Endocrine neoplasia syndromes: from phenotype to genotype and back SO JOURNAL OF INTERNAL MEDICINE LA English DT Meeting Abstract CT 9th Workshop on Multiple Endocrine Neoplasia CY JUN 20-22, 2004 CL Bethesda, MD SP NIH C1 NIDDKD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 2004 VL 255 IS 6 MA O1 BP 697 EP 697 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 821CH UT WOS:000221436800015 ER PT J AU Agarwal, SK Novotny, EA Cerrato, A Hickman, AB Crabtree, JS Scacheri, PC Weitzman, JB Kennedy, PA Rice, T Moore, JB Sukhodolets, KE Rao, S Ji, YM Yaniv, M Burns, AL Oliver, B Chandrasekharappa, SC Collins, FS Spiegel, AM Marx, SJ AF Agarwal, SK Novotny, EA Cerrato, A Hickman, AB Crabtree, JS Scacheri, PC Weitzman, JB Kennedy, PA Rice, T Moore, JB Sukhodolets, KE Rao, S Ji, YM Yaniv, M Burns, AL Oliver, B Chandrasekharappa, SC Collins, FS Spiegel, AM Marx, SJ TI Partnering and functioning of the MEN1 tumour suppressor gene SO JOURNAL OF INTERNAL MEDICINE LA English DT Meeting Abstract CT 9th Workshop on Multiple Endocrine Neoplasia CY JUN 20-22, 2004 CL Bethesda, MD SP NIH C1 NIDDK, Metab Dis Branch, NIH, Bethesda, MD USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD USA. NICHD, Mol Pathophysiol Sect, NIH, Bethesda, MD USA. Inst Pasteur, Dept Dev Biol, Unit Gene Express & Dis, Paris, France. NR 0 TC 0 Z9 0 U1 0 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 2004 VL 255 IS 6 MA O15 BP 701 EP 701 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 821CH UT WOS:000221436800029 ER PT J AU Ried, T Difilippantonio, MJ Montagna, C Padilla-Nash, H Habermann, J Upender, M AF Ried, T Difilippantonio, MJ Montagna, C Padilla-Nash, H Habermann, J Upender, M TI Patterns and consequences of chromosomal aneuploidy in cancer cells SO JOURNAL OF INTERNAL MEDICINE LA English DT Meeting Abstract CT 9th Workshop on Multiple Endocrine Neoplasia CY JUN 20-22, 2004 CL Bethesda, MD SP NIH C1 NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 2004 VL 255 IS 6 MA O16 BP 701 EP 702 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 821CH UT WOS:000221436800030 ER PT J AU Linehan, WM Vasselli, J Srinivasan, R Walther, MM Merino, M Choyke, P Vocke, C Schmidt, L Burke, T Bottaro, D Zbar, B Neckers, L AF Linehan, WM Vasselli, J Srinivasan, R Walther, MM Merino, M Choyke, P Vocke, C Schmidt, L Burke, T Bottaro, D Zbar, B Neckers, L TI Molecular targeting of kidney cancer gene pathways SO JOURNAL OF INTERNAL MEDICINE LA English DT Meeting Abstract CT 9th Workshop on Multiple Endocrine Neoplasia CY JUN 20-22, 2004 CL Bethesda, MD SP NIH C1 NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RI Bottaro, Donald/F-8550-2010 OI Bottaro, Donald/0000-0002-5057-5334 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 2004 VL 255 IS 6 MA O17 BP 702 EP 702 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 821CH UT WOS:000221436800031 ER PT J AU Pacak, K Ilias, I Adams, KT Eisenhofer, G AF Pacak, K Ilias, I Adams, KT Eisenhofer, G TI Current approaches to the biochemical diagnosis, localization and treatment of pheochromocytoma in patients with MEN-2 SO JOURNAL OF INTERNAL MEDICINE LA English DT Meeting Abstract CT 9th Workshop on Multiple Endocrine Neoplasia CY JUN 20-22, 2004 CL Bethesda, MD SP NIH C1 NICHHD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 2004 VL 255 IS 6 MA O20 BP 703 EP 703 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 821CH UT WOS:000221436800034 ER PT J AU Matyakhina, L Sarlis, NJ Bauer, AJ Stratakis, CA AF Matyakhina, L Sarlis, NJ Bauer, AJ Stratakis, CA TI Topology of chromosomes 10 and 17 in interphase nuclei of thyroid tumour cells SO JOURNAL OF INTERNAL MEDICINE LA English DT Meeting Abstract CT 9th Workshop on Multiple Endocrine Neoplasia CY JUN 20-22, 2004 CL Bethesda, MD SP NIH C1 NICHHD, Sect Endocrinol & Genet, DEB, NIH, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 2004 VL 255 IS 6 MA P2008 BP 713 EP 713 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 821CH UT WOS:000221436800059 ER PT J AU Skarulis, M Hao, W Simonds, W Weinstein, L Agarwal, S Mateo, C James-Newton, L Hobbs, G Gibril, F Jensen, R Marx, S AF Skarulis, M Hao, W Simonds, W Weinstein, L Agarwal, S Mateo, C James-Newton, L Hobbs, G Gibril, F Jensen, R Marx, S TI MEN1 variant with frequent prolactinoma and rare gastrinoma SO JOURNAL OF INTERNAL MEDICINE LA English DT Meeting Abstract CT 9th Workshop on Multiple Endocrine Neoplasia CY JUN 20-22, 2004 CL Bethesda, MD SP NIH C1 NIDDKD, MDB, NIH, Bethesda, MD 20892 USA. W Virginia Univ, Sch Med, Dept Community Med & Stat, Morgantown, WV 26506 USA. NIDDKD, DDB, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 2004 VL 255 IS 6 MA 6002 BP 718 EP 718 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 821CH UT WOS:000221436800074 ER PT J AU Schacheri, PC Crabtree, JS Kennedy, AL Swain, GP Ward, JM Marx, SJ Spiegel, AM Collins, FS AF Schacheri, PC Crabtree, JS Kennedy, AL Swain, GP Ward, JM Marx, SJ Spiegel, AM Collins, FS TI Tissue specificity of a tumor suppressor: homozygous loss of menin is well tolerated in hepatocytes SO JOURNAL OF INTERNAL MEDICINE LA English DT Meeting Abstract CT 9th Workshop on Multiple Endocrine Neoplasia CY JUN 20-22, 2004 CL Bethesda, MD SP NIH C1 NHGRI, NIH, Bethesda, MD 20892 USA. Univ Penn, Dept Med, Philadelphia, PA 19104 USA. NCI, NIH, Frederick, MD 21701 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. NIDCD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 2004 VL 255 IS 6 MA 7001 BP 721 EP 721 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 821CH UT WOS:000221436800082 ER PT J AU Collins, MT Kelly, MH Brillante, BA Cherman, N Kuznetsov, SA Bianco, P Robey, PG AF Collins, MT Kelly, MH Brillante, BA Cherman, N Kuznetsov, SA Bianco, P Robey, PG TI The McCune-Albright syndrome: a multiple endocrine neoplasia syndrome caused by somatic mutations of GNAS SO JOURNAL OF INTERNAL MEDICINE LA English DT Meeting Abstract CT 9th Workshop on Multiple Endocrine Neoplasia CY JUN 20-22, 2004 CL Bethesda, MD SP NIH C1 Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. Univ Roma La Sapienza, Dipartimento Med Sperimentale & Patol, Rome, Italy. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 2004 VL 255 IS 6 MA 9001 BP 724 EP 725 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 821CH UT WOS:000221436800094 ER PT J AU Batista, DL Stergiopoulos, SG Griffin, KJ Weinberg, F Stratakis, CA AF Batista, DL Stergiopoulos, SG Griffin, KJ Weinberg, F Stratakis, CA TI Protein kinase A activity in the pituitary gland of mice expressing the PRKAR1A antisense construct SO JOURNAL OF INTERNAL MEDICINE LA English DT Meeting Abstract CT 9th Workshop on Multiple Endocrine Neoplasia CY JUN 20-22, 2004 CL Bethesda, MD SP NIH C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 2004 VL 255 IS 6 MA 9003 BP 725 EP 725 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 821CH UT WOS:000221436800096 ER PT J AU Batista, D Weinberg, F Meoli, E Griffin, KJ Hill, J Stratakis, CA AF Batista, D Weinberg, F Meoli, E Griffin, KJ Hill, J Stratakis, CA TI Behavioural assessment of mice expressing an antisense construct for the PRKAR1A gene SO JOURNAL OF INTERNAL MEDICINE LA English DT Meeting Abstract CT 9th Workshop on Multiple Endocrine Neoplasia CY JUN 20-22, 2004 CL Bethesda, MD SP NIH C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 2004 VL 255 IS 6 MA 9006 BP 726 EP 726 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 821CH UT WOS:000221436800099 ER PT J AU Griffin, KJ Kirschner, LS Weinberg, FD Claflin, ES Stergiopoulos, SG Carney, JA Stratakis, CA AF Griffin, KJ Kirschner, LS Weinberg, FD Claflin, ES Stergiopoulos, SG Carney, JA Stratakis, CA TI A transsgenic mouse model for carney complex has elevated serum corticosterone levels and thyroid follicular hyperplasia SO JOURNAL OF INTERNAL MEDICINE LA English DT Meeting Abstract CT 9th Workshop on Multiple Endocrine Neoplasia CY JUN 20-22, 2004 CL Bethesda, MD SP NIH C1 NICHHD, Sect Genet & Endocrinol, DEB, NIH, Bethesda, MD 20892 USA. Ohio State Univ, Columbus, OH 43210 USA. Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 2004 VL 255 IS 6 MA 9005 BP 726 EP 726 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 821CH UT WOS:000221436800098 ER PT J AU Stergiopoulos, SG Weinberg, F Bauer, A Batista, D Meoli, E Smith, A Stratakis, CA AF Stergiopoulos, SG Weinberg, F Bauer, A Batista, D Meoli, E Smith, A Stratakis, CA TI The function of protein kinase A (PKA) in visceral adipose tissue from patients with Cushing's syndrome SO JOURNAL OF INTERNAL MEDICINE LA English DT Meeting Abstract CT 9th Workshop on Multiple Endocrine Neoplasia CY JUN 20-22, 2004 CL Bethesda, MD SP NIH C1 NICHHD, Sect Endocrinol & Genet, DEB, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 2004 VL 255 IS 6 MA 9004 BP 726 EP 726 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 821CH UT WOS:000221436800097 ER PT J AU Robinson-White, AJ Meoli, E Stergiopoulos, S Stratakis, CA AF Robinson-White, AJ Meoli, E Stergiopoulos, S Stratakis, CA TI Interaction of the PKA and MAPK pathways in PPNAD tumorigenicity SO JOURNAL OF INTERNAL MEDICINE LA English DT Meeting Abstract CT 9th Workshop on Multiple Endocrine Neoplasia CY JUN 20-22, 2004 CL Bethesda, MD SP NIH C1 NICHHD, SEGEN, DEB, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 2004 VL 255 IS 6 MA 9008 BP 727 EP 727 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 821CH UT WOS:000221436800101 ER PT J AU Robinson-White, AJ Leitner, W Stratakis, CA AF Robinson-White, AJ Leitner, W Stratakis, CA TI Investigation of apoptosis in normal and PRKAR1A mutant B-lymphocytes SO JOURNAL OF INTERNAL MEDICINE LA English DT Meeting Abstract CT 9th Workshop on Multiple Endocrine Neoplasia CY JUN 20-22, 2004 CL Bethesda, MD SP NIH C1 NICHHD, SEGEN, DEB, NIH, Bethesda, MD 20892 USA. NCI, DB, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 2004 VL 255 IS 6 MA 9007 BP 727 EP 727 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 821CH UT WOS:000221436800100 ER PT J AU Weinberg, FD Griffin, KJ Bauer, AJ Stratakis, CA AF Weinberg, FD Griffin, KJ Bauer, AJ Stratakis, CA TI SiRNA-induced down-regulation of PRKAR1A in PRKAR1A (+/-) mouse embryonic fibroblast cell lines: a model for Carney complex SO JOURNAL OF INTERNAL MEDICINE LA English DT Meeting Abstract CT 9th Workshop on Multiple Endocrine Neoplasia CY JUN 20-22, 2004 CL Bethesda, MD SP NIH C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 2004 VL 255 IS 6 MA 9009 BP 727 EP 728 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 821CH UT WOS:000221436800102 ER PT J AU Eisenhofer, G Huynh, TT Pacak, K Brouwers, FM Walther, MM Linehan, WM Munson, PJ Mannelli, M Goldstein, DS Elkahloun, AG AF Eisenhofer, G Huynh, TT Pacak, K Brouwers, FM Walther, MM Linehan, WM Munson, PJ Mannelli, M Goldstein, DS Elkahloun, AG TI Distinct gene expression profiles in noradrenaline and epinephrine producing hereditary and sporadic pheochromocytomas SO JOURNAL OF INTERNAL MEDICINE LA English DT Meeting Abstract CT 9th Workshop on Multiple Endocrine Neoplasia CY JUN 20-22, 2004 CL Bethesda, MD SP NIH C1 NIH, Bethesda, MD 20892 USA. Univ Florence, Dept Clin Pathophysiol, Florence, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 2004 VL 255 IS 6 MA 10002 BP 728 EP 729 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 821CH UT WOS:000221436800105 ER PT J AU Huynh, TT Pacak, K Brouwers, F Walther, MM Mannelli, M Elkahloun, AG Goldstein, DS Eisenhofer, G AF Huynh, TT Pacak, K Brouwers, F Walther, MM Mannelli, M Elkahloun, AG Goldstein, DS Eisenhofer, G TI Differences in storage and release of catecholamines in pheochromocytomas in multiple endocrine neoplasia type 2 and von Hippel-Lindau syndrome SO JOURNAL OF INTERNAL MEDICINE LA English DT Meeting Abstract CT 9th Workshop on Multiple Endocrine Neoplasia CY JUN 20-22, 2004 CL Bethesda, MD SP NIH C1 NIH, Bethesda, MD 20892 USA. Univ Florence, Dept Clin Pathophysiol, Florence, Italy. NR 1 TC 1 Z9 1 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 2004 VL 255 IS 6 MA 10001 BP 728 EP 728 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 821CH UT WOS:000221436800104 ER PT J AU Robinson-White, AJ AF Robinson-White, AJ TI Alteration of cell proliferation in mouse embryonic fibroblasts by antisense PRKAR1A SO JOURNAL OF INTERNAL MEDICINE LA English DT Meeting Abstract CT 9th Workshop on Multiple Endocrine Neoplasia CY JUN 20-22, 2004 CL Bethesda, MD SP NIH C1 NICHHD, SEGEN, DEB, NIH, Bethesda, MD 20892 USA. Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUN PY 2004 VL 255 IS 6 MA 9010 BP 728 EP 728 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 821CH UT WOS:000221436800103 ER PT J AU Granados, S Hwang, ST AF Granados, S Hwang, ST TI Roles for CD30 in the biology and treatment of CD30(+) lymphoproliferative diseases SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Review ID GROWTH-FACTOR-BETA; LARGE-CELL LYMPHOMA; PROGRESSION; PAPULOSIS; LIGAND; INHIBITION; GUIDELINES; DISORDERS; RECEPTOR; TRAF2 C1 NCI, Dermatol Branch, CCR, Bethesda, MD 20892 USA. RP Hwang, ST (reprint author), Bldg 10,Rm 12N246,10 Ctr Dr, Bethesda, MD 20892 USA. EM hwangs@mail.nih.gov NR 19 TC 7 Z9 7 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUN PY 2004 VL 122 IS 6 BP 1345 EP 1347 DI 10.1111/j.0022-202X.2004.22616.x PG 3 WC Dermatology SC Dermatology GA 824NO UT WOS:000221693500004 PM 15175022 ER PT J AU Yamaguchi, N Sarno, RJ Johnson, WE O'Brien, SJ MacDonald, DW AF Yamaguchi, N Sarno, RJ Johnson, WE O'Brien, SJ MacDonald, DW TI Multiple paternity and reproductive tactics of free-ranging American minks, Mustela vison SO JOURNAL OF MAMMALOGY LA English DT Article DE American mink; delayed implantation; intrasexual territoriality; lowland England; Mustela vison; spatial organization; superfetation; superfecundation ID DELAYED IMPLANTATION; SPACING PATTERNS; MALE STOATS; EVOLUTION; ERMINEA; MOVEMENTS AB Demography and spatial patterns of free-ranging American mink were documented by continuous year-round trapping and radiotracking along 24 km of the River Thames in England, United Kingdom. An estimated average of 7.19 +/- 0.58 SE minks per month were present between May 1995 and August 1997. Kit and juvenile paternity was assessed using 7 microsatellite markers and we observed evidence that multiple paternity occurred in this population. Although males maintained territories during most of the year, they sired litters in areas beyond their territory boundaries. We suggest that a male's inability to monopolize paternity, along with a female's ability to continue ovulation after successful matings (i.e., superfetation) explains why males abandon territoriality during the breeding season. We suggest that the main function of a brief delayed implantation of this species may be to enable female mink to retain superfetation, which facilitates the fertilization of ova from different ovulations by different males. This mink model, consisting of disarticulating residency from fatherhood and the possibility of superfetation, may occur more widely among related species and requires a re-evaluation of mustelid sociobiology. C1 Dept Zool, Wildlife Conservat Res Unit, Oxford OX1 3PS, England. NCI, Lab Genom Divers, Frederick, MD 21702 USA. RP MacDonald, DW (reprint author), Dept Zool, Wildlife Conservat Res Unit, S Parks Rd, Oxford OX1 3PS, England. EM david.macdonald@zoo.ox.ac.uk RI Johnson, Warren/D-4149-2016 OI Johnson, Warren/0000-0002-5954-186X NR 50 TC 31 Z9 32 U1 2 U2 14 PU ALLIANCE COMMUNICATIONS GROUP DIVISION ALLEN PRESS PI LAWRENCE PA 810 EAST 10TH STREET, LAWRENCE, KS 66044 USA SN 0022-2372 J9 J MAMMAL JI J. Mammal. PD JUN PY 2004 VL 85 IS 3 BP 432 EP 439 DI 10.1644/1545-1542(2004)085<0432:MPARTO>2.0.CO;2 PG 8 WC Zoology SC Zoology GA 827JV UT WOS:000221896600009 ER PT J AU Marcin, JP Pretzlaff, RK Pollack, MM Patel, KM Ruttimann, UE AF Marcin, J. P. Pretzlaff, R. K. Pollack, M. M. Patel, K. M. Ruttimann, U. E. TI Certainty and mortality prediction in critically ill children SO JOURNAL OF MEDICAL ETHICS LA English DT Article; Proceedings Paper CT 30th International Educational and Scientific Symposium of the Society-for-Critical-Care-Medicine CY FEB 11-14, 2001 CL SAN FRANCISCO, CA SP Soc Crit Care Med ID INTENSIVE-CARE-UNIT; RISK; PROGNOSTICATION; JUDGMENTS; PROGNOSES AB Objectives: The objective of this study is to investigate the relationship between a physician's subjective mortality prediction and the level of confidence with which that mortality prediction is made. Design and participants: The study is a prospective cohort of patients less than 18 years of age admitted to a tertiary Paediatric Intensive Care Unit (ICU) at a University Children's Hospital with a minimum length of ICU stay of 10 h. Paediatric ICU attending physicians and fellows provided mortality risk predictions and the level of confidence associated with these predictions on consecutive patients at the time of multidisciplinary rounds within 24 hours of admission to the paediatric ICU. Median confidence levels were compared across different ranges of mortality risk predictions. Results: Data were collected on 642 of 713 eligible patients ( 36 deaths, 5.6%). Mortality predictions greater than 5% and less than 95% were made with significantly less confidence than those predictions <5% and >95%. Experience was associated with greater confidence in prognostication. Conclusions: We conclude that a physician's subjective mortality prediction may be dependent on the level of confidence in the prognosis; that is, a physician less confident in his or her prognosis is more likely to state an intermediate survival prediction. Measuring the level of confidence associated with mortality risk predictions ( or any prognostic assessment) may therefore be important because different levels of confidence may translate into differences in a physician's therapeutic plans and their assessment of the patient's future. C1 Univ Calif Davis, Childrens Hosp, Dept Pediat, Sect Crit Care Med, Sacramento, CA 95817 USA. George Washington Univ, Sch Med, Washington, DC 20052 USA. Childrens Natl Med Ctr, Childrens Res Inst, Ctr Hlth Serv & Clin Res, Washington, DC 20010 USA. NIAAA, NIH, Bethesda, MD USA. RP Marcin, JP (reprint author), Univ Calif Davis, Childrens Hosp, Dept Pediat, Sect Crit Care Med, 2516 Stockton Blvd, Sacramento, CA 95817 USA. EM jpmarcin@ucdavis.edu NR 19 TC 12 Z9 12 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 J9 J MED ETHICS JI J. Med. Ethics PD JUN 1 PY 2004 VL 30 IS 3 BP 304 EP 307 DI 10.1136/jme.2003.001537 PG 4 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 825TJ UT WOS:000221780900016 PM 15173368 ER PT J AU Goldstein, AM Struewing, JP Fraser, MC Smith, MW Tucker, MA AF Goldstein, AM Struewing, JP Fraser, MC Smith, MW Tucker, MA TI Prospective risk of cancer in CDKN2A germline mutation carriers SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID PANCREATIC-CANCER; MELANOMA FAMILIES AB Background: The CDKN2A gene is the major known high-risk melanoma susceptibility gene. Susceptibility to other cancers has also been suggested. However, most studies examining the risks of other cancers classified individuals according to the family's CDKN2A mutation rather than determining individual mutation status. For non-population-based studies, risks could also be biased because of cancer occurrence prior to family ascertainment. Methods: We examined the risk of non-melanoma cancer in 117 mutation-positive and 136 mutation-negative members from 15 families that had at least two first degree relatives with melanoma and CDKN2A mutations restricting the analysis to the period after the families were ascertained ( that is, the prospective period) and using individual mutation data. The families have been followed prospectively for 4 - 26 years starting in the 1970s. Results: Overall, there was no significant association for mutation-negative subjects (Obs/Exp = 0.3, 95% confidence interval (CI) 0.0 to 1.2) although this group had only two observed cancers. In contrast, mutation-positive subjects had a significantly increased risk for all cancers combined (Obs/ Exp = 12/ 5.5 = 2.2, 95% CI 1.1 to 3.8) primarily because of digestive system tumours, particularly pancreatic cancer. No other organ systems or individual tumour sites showed significantly increased risks. Conclusions: Differences in CDKN2A - non-melanoma cancer associations across studies may result from variation in genetic backgrounds, insufficient follow up, misclassification of mutation carriers, or the presence of other genetic and/or environmental risk factors in both CDKN2A mutation carriers and non-carriers. Larger sample sizes, prospective follow up, and individual mutation data will be required to understand these differences. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. NCI, Lab Populat Genet, Ctr Canc Res, NIH,DHHS, Bethesda, MD 20892 USA. NCI, Lab Genom Divers, Ctr Canc Res, NIH,DHHS, Frederick, MD 21702 USA. NCI, Basic Res Program, SAIC Frederick, NIH,DHHS, Frederick, MD 21702 USA. RP Goldstein, AM (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Execut Plaza S,Room 7004,6120 Execut Blvd,MSC 723, Bethesda, MD 20892 USA. EM goldstea@exchange.nih.gov RI Struewing, Jeffery/C-3221-2008; Smith, Michael/B-5341-2012; Tucker, Margaret/B-4297-2015; Struewing, Jeffery/I-7502-2013 OI Struewing, Jeffery/0000-0002-4848-3334 FU NCI NIH HHS [N01-CO-12400] NR 10 TC 35 Z9 36 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD JUN PY 2004 VL 41 IS 6 BP 421 EP 424 DI 10.1136/jmg.2004.019349 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 825TG UT WOS:000221780600004 PM 15173226 ER PT J AU Garrison, NA Yi, Z Cohen-Barak, O Huizing, M Hartnell, LM Gahl, WA Brilliant, MH AF Garrison, NA Yi, Z Cohen-Barak, O Huizing, M Hartnell, LM Gahl, WA Brilliant, MH TI P gene mutations in patients with oculocutaneous albinism and findings suggestive of Hermansky-Pudlak syndrome SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID CHEDIAK-HIGASHI-SYNDROME; VESICLE FORMATION; DEFICIENCY; DISORDERS; OCA2; FORM C1 Univ Arizona, Coll Med, Dept Pediat, Tucson, AZ 85724 USA. Univ Arizona, Grad Interdisciplinary Program Genet, Tucson, AZ 85724 USA. NICHHD, Sect Human Biochem Genet, Heritable Disrorders Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. NICHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Brilliant, MH (reprint author), Univ Arizona, Coll Med, Dept Pediat, POB 245073, Tucson, AZ 85724 USA. EM mhb@peds.arizona.edu FU NIAMS NIH HHS [AR4596]; NIGMS NIH HHS [T34 GM08718] NR 23 TC 9 Z9 9 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD JUN PY 2004 VL 41 IS 6 AR e86 DI 10.1136/jmg.2003.014902 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 825TG UT WOS:000221780600030 PM 15173252 ER PT J AU Bennett, AJ DePetrillo, PB AF Bennett, AJ DePetrillo, PB TI Sex differences in total body water in adolescent rhesus macaques estimated by ethanol dilution SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Article DE blood ethanol concentration; ethanol elimination rate; nonhuman primate; sex differences; volume of distribution ID GENDER-DIFFERENCES; ALCOHOL-CONSUMPTION; PHARMACOKINETICS; BLOOD; METABOLISM; MONKEYS; HUMANS; LIVER; MASS AB Non-human primates are widely used in research, yet relatively few studies have addressed potential pharmacokinetic differences between males and females. The present study examined the relationship between total body water, sex, age, and weight in the rhesus macaque (Macaca mulatta). Ethanol-naive, adolescent rhesus macaques (n=119) were administered ethanol (males, 2.1 g/kg; females, 2.0 g/kg) intravenously, and blood samples for blood ethanol concentration obtained at 5, 10, and 60 minutes following the end of the infusion. Non-linear regression was used to compare and contrast a series of pharmacokinetic models examining the relationship between weight, sex, age, V-d and zero-order elimination rate. V-d (mean+/-SEM) for male rhesus was 0.771+/-0.008 l/kg and for females was 0.730+/-0.008 l/kg, different at P<0.00001. There were no sex differences in the rate of zero-order ethanol elimination, estimated to be 0.0032+/-0.0004 g/kg/minute. The data reported here may be useful in designing and interpreting pharmacokinetic studies using rhesus monkeys. C1 Wake Forest Univ, Bowman Gray Sch Med, Dept Physiol Pharmacol, Winston Salem, NC 27157 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Pediat, Winston Salem, NC 27157 USA. NIAAA, Div Intramural Clin & Biochem Res, Unit Clin & Biochem Pharmacol, Clin Studies Lab, Bethesda, MD USA. RP Bennett, AJ (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Physiol Pharmacol, Winston Salem, NC 27157 USA. EM abennett@wfubmc.edu FU NIAAA NIH HHS [R01AA13995] NR 22 TC 4 Z9 4 U1 0 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD JUN PY 2004 VL 33 IS 3 BP 163 EP 166 DI 10.1111/j.1600-0684.2004.00065.x PG 4 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 814GL UT WOS:000220963100006 PM 15102073 ER PT J AU Kopelman, LM Resnick, D Weed, DL AF Kopelman, LM Resnick, D Weed, DL TI What is the role of the precautionary principle in the philosophy of medicine and bioethics? SO JOURNAL OF MEDICINE AND PHILOSOPHY LA English DT Editorial Material C1 E Carolina Univ, Brody Sch Med, Dept Med Humanities, Greenville, NC 27858 USA. NCI, Rockville, MD USA. RP Kopelman, LM (reprint author), E Carolina Univ, Brody Sch Med, Dept Med Humanities, Greenville, NC 27858 USA. EM kopelmanlo@mail.ecu.edu NR 0 TC 12 Z9 12 U1 0 U2 1 PU SWETS ZEITLINGER PUBLISHERS PI LISSE PA P O BOX 825, 2160 SZ LISSE, NETHERLANDS SN 0360-5310 J9 J MED PHILOS JI J. Med. Philos. PD JUN PY 2004 VL 29 IS 3 BP 255 EP 258 DI 10.1080/03605310490500482 PG 4 WC Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Biomedical Social Sciences GA 869KP UT WOS:000224982200001 PM 15512971 ER PT J AU Weed, DL AF Weed, DL TI Precaution, prevention, and public health ethics SO JOURNAL OF MEDICINE AND PHILOSOPHY LA English DT Article DE causation; decision-making; epidemiology; ethics; precautionary principle; prevention; public health; scientific methods ID CAUSAL INFERENCE; BETA-CAROTENE; LUNG-CANCER; EPIDEMIOLOGY; UNDERDETERMINATION; DISEASE AB The precautionary principle brings a special challenge to the practice of evidence-based public health decision-making, suggesting changes in the interpretative methods of public health used to identify causes of disease. In this paper, precautionary changes to these methods are examined: including discounting contrary evidence, reducing the number of causal criteria, weakening the rules of evidence assigned to the criteria, and altering thresholds for statistical significance. All such changes reflect the precautionary goal of earlier primary preventive intervention, i.e. acting on insufficient evidence, the least amount, or minimum level, of evidence for causation. Evaluating the impact of these changes will be difficult without a careful study of how well the current methods of causal inference work, their theoretical foundations, and the ethical implications of their applications. That research program will be most productive if it is jointly developed by public health professionals trained in the ethics and philosophy and by bioethicists and philosophers trained in the theories, methods, and practice of public health. C1 NCI, Off Prevent Oncol, Div Canc Prevent, EPN 3112, Bethesda, MD 20892 USA. RP Weed, DL (reprint author), NCI, Off Prevent Oncol, Div Canc Prevent, EPN 3112, 6130 Execut Blvd, Bethesda, MD 20892 USA. EM dw102i@nih.gov NR 34 TC 28 Z9 29 U1 1 U2 7 PU SWETS ZEITLINGER PUBLISHERS PI LISSE PA P O BOX 825, 2160 SZ LISSE, NETHERLANDS SN 0360-5310 J9 J MED PHILOS JI J. Med. Philos. PD JUN PY 2004 VL 29 IS 3 BP 313 EP 332 DI 10.1080/03605310490500527 PG 20 WC Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Biomedical Social Sciences GA 869KP UT WOS:000224982200005 PM 15512975 ER PT J AU Hayashi, K Chang, FR Nakanishi, Y Bastow, KF Cragg, G McPhail, AT Nozaki, H Lee, KH AF Hayashi, K Chang, FR Nakanishi, Y Bastow, KF Cragg, G McPhail, AT Nozaki, H Lee, KH TI Antitumor agents. 233. Lantalueratins A-F, new cytotoxic naphthoquinones from Lantana involucrata SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID STREPTOCARPUS-DUNNII; BETA-LAPACHONE AB In a continuing study to isolate novel antitumor agents from rainforest plants, three new isopropenyl-furano-beta-naphthoquinones, designated lantalucratins A (1), B (2), and C (3), and three new isoprenyl-alpha-naphthoquinones, designated lantalucratins D (4), E (5), and F (6), were isolated from Lantana involucrata. Their structures were determined on the basis of NMR and X-ray crystallographic analyses. Compounds 1 and 2 showed cytotoxic activities against various human tumor cell lines, including drug-resistant variants, with IC50 values of 1.0-4.9 muM. C1 Univ N Carolina, Sch Pharm, Nat Prod Lab, Chapel Hill, NC 27599 USA. NCI, Nat Prod Branch, Div Canc Treatment & Diag, Fairview Ctr, Frederick, MD 21702 USA. Duke Univ, Paul M Gross Chem Lab, Dept Chem, Durham, NC 27708 USA. Okayama Univ Sci, Fac Sci, Dept Biochem, Okayama 7000005, Japan. RP Lee, KH (reprint author), Univ N Carolina, Sch Pharm, Nat Prod Lab, Chapel Hill, NC 27599 USA. EM khlee@unc.edu OI Hayashi, Ken-ichiro/0000-0002-9812-2801 FU NCI NIH HHS [CA-17625] NR 10 TC 14 Z9 14 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD JUN PY 2004 VL 67 IS 6 BP 990 EP 993 DI 10.1021/np030450f PG 4 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 832OP UT WOS:000222277100013 PM 15217280 ER PT J AU Ren, M Leng, Y Jeong, M Leeds, PR Chuang, DM AF Ren, M Leng, Y Jeong, M Leeds, PR Chuang, DM TI Valproic acid reduces brain damage induced by transient focal cerebral ischemia in rats: potential roles of histone deacetylase inhibition and heat shock protein induction SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE acetylated histone 3; cerebral ischemia; heat shock protein 70; neuroprotection; rat; valproic acid ID GLYCOGEN-SYNTHASE KINASE-3-BETA; SODIUM VALPROATE; ANTIEPILEPTIC DRUGS; CORTICAL-NEURONS; MOOD STABILIZER; CHRONIC LITHIUM; STROKE; CELLS; PROTECTION; HSP72 AB Growing evidence from in vitro studies supports that valproic acid (VPA), an anti-convulsant and mood-stabilizing drug, has neuroprotective effects. The present study investigated whether VPA reduces brain damage and improves functional outcome in a transient focal cerebral ischemia model of rats. Subcutaneous injection of VPA (300 mg/kg) immediately after ischemia followed by repeated injections every 12 h, was found to markedly decrease infarct size and reduce ischemia-induced neurological deficit scores measured at 24 and 48 h after ischemic onset. VPA treatment also suppressed ischemia-induced neuronal caspase-3 activation in the cerebral cortex. VPA treatments resulted in a time-dependent increase in acetylated histone H3 levels in the cortex and striatum of both ipsilateral and contralateral brain hemispheres of middle cerebral artery occlusion (MCAO) rats, as well as in these brain areas of normal, non-surgical rats, supporting the in vitro finding that VPA is a histone deacetylase (HDAC) inhibitor. Similarly, heat shock protein 70 (HSP70) levels were time-dependently up-regulated by VPA in the cortex and striatum of both ipsilateral and contralateral sides of MCAO rats and in these brain areas of normal rats. Altogether, our results demonstrate that VPA is neuroprotective in the cerebral ischemia model and suggest that the protection mechanisms may involve HDAC inhibition and HSP induction. C1 NIMH, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Chuang, DM (reprint author), NIMH, Mol Neurobiol Sect, NIH, 10 Ctr Dr,MSC 1363, Bethesda, MD 20892 USA. EM chuang@mail.nih.gov NR 45 TC 225 Z9 246 U1 0 U2 6 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUN PY 2004 VL 89 IS 6 BP 1358 EP 1367 DI 10.1111/j.1471-4159.2004.02406.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 825XM UT WOS:000221792100006 PM 15189338 ER PT J AU Wen, ZM Kim, HY AF Wen, ZM Kim, HY TI Alterations in hippocampal phospholipid profile by prenatal exposure to ethanol SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE electrospray ionization mass spectrometry; ethanol; fatty acids; hippocampus; phosphatidylserine; phospholipids ID MOLECULAR-SPECIES COMPOSITION; FATTY-ACID DEFICIENCY; DOCOSAHEXAENOIC ACID; RAT-BRAIN; MASS-SPECTROMETRY; LIPID-COMPOSITION; ALCOHOL EXPOSURE; GLIOMA-CELLS; SHORT-TERM; PHOSPHATIDYLSERINE AB It has been suggested that hippocampus-related cognitive processes are especially sensitive to ethanol. To provide an insight into the biochemical mechanisms underlying the hippocampus-related functional deficits associated with prenatal ethanol exposure, we investigated the effects of chronic ethanol exposure on the phospholipid profile in developing rat hippocampi. High-performance liquid chromatography/electrospray ionization-mass spectrometry analysis revealed that ethanol lowered the levels of total phosphatidylserine (PS) by 15-20% at all ages examined, primarily owing to the reduction in 1-stearoyl-2-docosahexaenoyl-PS (18:0,22:6n-3-PS) species. Ethanol exposure also led to a decrease in phosphatidylcholine (PC) and an increase in phosphatidylethanolamine (PE), but the total phospholipid content was not significantly changed. At the fatty acid level, ethanol exposure significantly decreased the 22:6n-3 content at postnatal days 0 and 21, with a slight increase in 22:5n-6, without changing the total fatty acid content significantly. In conclusion, ethanol depleted PS, especially 22:6-containing species, and PC from hippocampal membranes with concomitant increase in PE. Alteration of the phospholipid profile in the hippocampus resulting from exposure to ethanol during prenatal and developmental stages may have significant implications with respect to the cognitive dysfunction observed in fetal alcohol syndrome. C1 NIAAA, Sect Mass Spectrometry, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20892 USA. RP Kim, HY (reprint author), NIAAA, Sect Mass Spectrometry, Lab Membrane Biochem & Biophys, NIH, 12 420 Parklwan Dr, Rockville, MD 20892 USA. EM hykim@nih.gov NR 57 TC 50 Z9 51 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUN PY 2004 VL 89 IS 6 BP 1368 EP 1377 DI 10.1111/j.1471-4159.2004.02433.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 825XM UT WOS:000221792100007 PM 15189339 ER PT J AU Huh, J Yao, K Quigley, L Ludwin, SK McFarland, HF Muraro, PA Martin, R Ito, K AF Huh, J Yao, K Quigley, L Ludwin, SK McFarland, HF Muraro, PA Martin, R Ito, K TI Limited repertoire of HLA-DRB1*0401-restricted MBP111-129-specific T cells in HLA-DRB 1*0401 Tg mice and their pathogenic potential SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE HLA-DRB1*0401; myelin basic protein; transgenic mouse; experimental autoimmune encephalomyelitis; multiple sclerosis ID MYELIN BASIC-PROTEIN; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MULTIPLE-SCLEROSIS; TRANSGENIC MICE; RECEPTOR; HLA-DR4; EPITOPES; PEPTIDE AB Since myelin basic protein (MBP) 111-129 is an immunodominant epitope in humans carrying HLA-DRB1*0401, we investigated the encephalitogenic potential of HLA-DRB1*0401-restricted MBP111-129-specific T cells using HLA-DRB1*0401/DRA*0101 transgenic (Tg) mice. Although we could not detect the primary recall response to MBP111-129 peptide after immunization of HLA-DRB1*0401/ DRA*0101 Tg mice with human MBP, Vbeta10(+) and Vbeta2(+) HLA-DRB1*0401-restricted MBP111-129-specific T cells proliferated after restimulation of the lymph node cells with human MBP111-129 in vitro. The Vbeta2(+) T cell line recognized only human MBP111-129 in the context of HLA-DRB1*0401, while the Vbeta10(+) T cell line recognized both the human and murine MBP111-129 epitopes. Therefore, we examined the encephalitogenic potential of the Vbeta10(+) T cell line in HLA-DRB1*0401/DRA*0101 Tg mice by adoptive transfer experiments. The Vbeta10(+) T cell line induced mild EAE and inflammatory lesions were observed in the spinal cord and the brainstem. In the spinal cord, the inflammation was observed in the peripheral nerve roots as well as in the CNS. These data suggest the pathogenic potential of HLA-DRB1*0401-restricted MBP111-129-specific T cells in humans. Published by Elsevier B.V. C1 NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Queens Univ, Dept Pathol, Kingston, ON K7L 3N6, Canada. RP Ito, K (reprint author), UMDNJ, Robert Wood Johnson Med Sch, Dept Neurol, 683 Hoes Lane, Piscataway, NJ 08854 USA. EM itoko@umdnj.edu OI Muraro, Paolo/0000-0002-3822-1218 NR 17 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD JUN PY 2004 VL 151 IS 1-2 BP 94 EP 102 DI 10.1016/j.jneuroim.2004.02.015 PG 9 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 827JG UT WOS:000221895000011 PM 15145608 ER PT J AU DeRijk, RH Eskandari, F Sternberg, EM AF DeRijk, RH Eskandari, F Sternberg, EM TI Corticosteroid resistance in a subpopulation of multiple sclerosis patients as measured by ex vivo dexamethasone inhibition of LPS induced IL-6 production SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE multiple sclerosis; cortisol; corticosteroid sensitivity; IL-6 production; dexamethasone ID PITUITARY-ADRENAL AXIS; GLUCOCORTICOID-RECEPTOR FUNCTION; CORTICOTROPIN-RELEASING HORMONE; PERIPHERAL-BLOOD LYMPHOCYTES; TUMOR-NECROSIS-FACTOR; TNF-ALPHA PRODUCTION; T-CELL; AUTOIMMUNE ENCEPHALOMYELITIS; IMMUNE FUNCTION; INTERLEUKIN-1-BETA IL-1-BETA AB We assessed corticosteroid sensitivity in multiple sclerosis (MS) patients compared to control subjects, using an in vitro assay of dexamethasone (Dex) inhibition of lipopolysaccharide (LPS) stimulated-blood interleukin-6 production. Significantly higher concentrations of dexamethasone were needed to obtain 50%-inhibition (ID50) of in vitro LPS stimulated interleukin (IL)-6 production (28.4 x 10(-7) M) in relapsing-remitting MS (RRMS) patients compared to chronic progressive MS (CPMS) patients (6.2 x 10(-7) M) or compared to controls (3.0 x 10(-7) M). We also found a trend towards worsening of clinical status over time with increasing corticosteroid resistance. These data suggest that corticosteroid sensitivity may be a factor in the pathogenesis and could be used for prognosis of MS. (C) 2004 Published by Elsevier B.V. C1 NIMH, Sect Neuroendocrine Immunol & Behav, Bethesda, MD 20892 USA. RP DeRijk, RH (reprint author), Hosp Psychiat, Gezondheidscent Rijngeestgroep, Endegeesterstr 5, NL-2342 AJ Oegstgeest, Netherlands. EM rderijk@rijngeestgroep.nl NR 60 TC 40 Z9 40 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD JUN PY 2004 VL 151 IS 1-2 BP 180 EP 188 DI 10.1016/j.jneuroim.2004.02.009 PG 9 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 827JG UT WOS:000221895000019 PM 15145616 ER PT J AU Valente, EM Abou-Sleiman, PM Caputo, V Muqit, MMK Gispert, S Ali, Z Del Turco, D Wingerter, O Bentivoglio, AR Healy, DG Albanese, A Nussbaum, R Gonzalez-Maldonado, R Deller, T Mulsch, A Bratzke, H Salvi, S Cortelli, P Gilks, WP Latchman, D Harvey, R Dallapiccola, B Auburger, G Wood, NW AF Valente, EM Abou-Sleiman, PM Caputo, V Muqit, MMK Gispert, S Ali, Z Del Turco, D Wingerter, O Bentivoglio, AR Healy, DG Albanese, A Nussbaum, R Gonzalez-Maldonado, R Deller, T Mulsch, A Bratzke, H Salvi, S Cortelli, P Gilks, WP Latchman, D Harvey, R Dallapiccola, B Auburger, G Wood, NW TI PARK6 linked Parkinson's disease is caused by mutations in a mitochondrial protein kinase SO JOURNAL OF NEUROLOGY LA English DT Meeting Abstract CT 14th Meeting of the European-Neurological-Society CY JUN 26-30, 2004 CL Barcelona, SPAIN SP European Neurol Soc C1 IRCCS, CSS Mendel Inst, Rome, Italy. Inst Neurol, London WC1N 3BG, England. Univ Roma La Sapienza, I-00185 Rome, Italy. Inst Child Hlth, London, England. JW Goethe Univ Klin, Frankfurt, Germany. Catholic Univ, Rome, Italy. Natl Neurol Inst C Besta, Milan, Italy. NIH, Bethesda, MD 20892 USA. Hosp Univ San Cecilio, Granada, Spain. Univ Modena, I-41100 Modena, Italy. Univ London, London WC1E 7HU, England. Sch Pharm, Modena, Italy. NR 0 TC 0 Z9 0 U1 0 U2 1 PU DR DIETRICH STEINKOPFF VERLAG PI DARMSTADT PA PO BOX 10 04 62, D-64204 DARMSTADT, GERMANY SN 0340-5354 J9 J NEUROL JI J. Neurol. PD JUN PY 2004 VL 251 SU 3 BP 50 EP 50 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 835QK UT WOS:000222500400177 ER PT J AU Renaud, S Hays, A Brannagan, T Sander, H Edgar, M Weimer, L Olarte, M Dalakas, M Xiang, Z Danon, M Latov, N AF Renaud, S Hays, A Brannagan, T Sander, H Edgar, M Weimer, L Olarte, M Dalakas, M Xiang, Z Danon, M Latov, N TI Gene expression profiling in CIDP SO JOURNAL OF NEUROLOGY LA English DT Meeting Abstract CT 14th Meeting of the European-Neurological-Society CY JUN 26-30, 2004 CL Barcelona, SPAIN SP European Neurol Soc C1 Univ Basel Hosp, CH-4031 Basel, Switzerland. Columbia Univ, New York, NY USA. Cornell Univ, New York, NY USA. NIH, Bethesda, MD 20892 USA. Univ Minnesota, Minneapolis, MN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU DR DIETRICH STEINKOPFF VERLAG PI DARMSTADT PA PO BOX 10 04 62, D-64204 DARMSTADT, GERMANY SN 0340-5354 J9 J NEUROL JI J. Neurol. PD JUN PY 2004 VL 251 SU 3 BP 109 EP 109 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 835QK UT WOS:000222500400415 ER PT J AU Dalakas, MC AF Dalakas, MC TI The future prospects in the classification, diagnosis and therapies of inflammatory myopathies: A view to the future from the "bench-to-bedside" SO JOURNAL OF NEUROLOGY LA English DT Review ID INCLUSION-BODY MYOSITIS; CELL-RECEPTOR REPERTOIRE; INFILTRATING LYMPHOCYTES; POLYMYOSITIS; MUSCLE; DERMATOMYOSITIS; EXPRESSION; PHENOTYPE; DISEASES; FAMILIES C1 NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), NINDS, Neuromuscular Dis Sect, NIH, Bldg 10,Room 4N248,10 Ctr Dr,MSC 1382, Bethesda, MD 20892 USA. NR 33 TC 9 Z9 10 U1 0 U2 0 PU DR DIETRICH STEINKOPFF VERLAG PI DARMSTADT PA PO BOX 10 04 62, D-64204 DARMSTADT, GERMANY SN 0340-5354 J9 J NEUROL JI J. Neurol. PD JUN PY 2004 VL 251 IS 6 BP 651 EP 657 DI 10.1007/s00415-004-0353-z PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 832EW UT WOS:000222251000001 PM 15311338 ER PT J AU Popratiloff, A Wang, YX Narvid, J Petralia, RS Giaume, C Peusner, KD AF Popratiloff, A Wang, YX Narvid, J Petralia, RS Giaume, C Peusner, KD TI AMPA receptor subunit expression in chick vestibular nucleus neurons SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE glutamate; immunocytochemistry; confocal microscopy; immunogold ID IONOTROPIC GLUTAMATE RECEPTORS; DEVELOPMENTAL-CHANGES; SYNAPTIC AMPA; DIFFERENTIAL DISTRIBUTION; MOLECULAR HETEROGENEITY; HIPPOCAMPAL-NEURONS; COCHLEAR NUCLEUS; SPINAL-CORD; BRAIN-STEM; RAT-BRAIN AB sThe principal cells of the chick tangential nucleus are vestibular nucleus neurons whose responses on vestibular nerve stimulation are abolished by glutamate receptor antagonists. Using confocal microscopy, we quantified immunolabeling for AMPA receptor subunits GluR1, GluR2, GluR2/3, and GluR4 in principal cells that were identified by the neuronal marker, microtubule-associated protein 2 (MAP2). This work was focused primarily on 9 days after hatching (H9) when the principal cells have acquired some important mature electrophysiologic properties. At H9, the principal cell bodies stained strongly with GluR2/3 and GluR4, whereas GluR1 and GluR2 produced weak signals. Moreover, GluR2/3 and GluR4 receptor subunit clusters in principal cell bodies and dendrites were localized at sites contacted by biocytin-labeled vestibular nerve terminals and synaptotagmin-labeled terminals. Developmental expression of AMPA receptor immunolabeling was studied in the principal cell bodies at embryonic day 16 (E16) and hatching (H1). At E16, labeling for GluR4 was already strong, and continued to increase at H1 and H9. In contrast, GluR2/3 labeling was weak at E16, but increased significantly at H1, and more so by H9. GluR1 and GluR2 were present at low levels at E16 and H1. From E16 to H9, overall AMPA receptor subunit expression increased steadily, with H9 showing the strongest labeling. Ultrastructural observations at E16 and H3 confirmed the presence of immunogold labeling for AMPA receptor subunits at the vestibular nerve and non-vestibular nerve synapses on the principal cell bodies. In summary, these results indicate that GluR3 and GuR4 are the major AMPA receptor subunits involved in excitatory synaptic transmission in principal cells during the perinatal period. (C) 2004 Wiley-Liss, Inc. C1 George Washington Univ, Med Ctr, Dept Anat & Cell Biol, Washington, DC 20037 USA. George Washington Univ, Med Ctr, Neurosci Program, Washington, DC 20037 USA. NIDCD, NIH, Bethesda, MD USA. Coll France, INSERM, U114, F-75231 Paris, France. RP Peusner, KD (reprint author), George Washington Univ, Med Ctr, Dept Anat & Cell Biol, Washington, DC 20037 USA. EM anakdp@gwumc.edu FU NIDCD NIH HHS [DC00970] NR 61 TC 16 Z9 16 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD JUN 1 PY 2004 VL 76 IS 5 BP 662 EP 677 DI 10.1002/jnr.20115 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 825QJ UT WOS:000221772700008 PM 15139025 ER PT J AU Maruvada, P Srivastava, S AF Maruvada, P Srivastava, S TI Biomarkers for cancer diagnosis: Implications for nutritional research SO JOURNAL OF NUTRITION LA English DT Article; Proceedings Paper CT 3rd Amino Acid Assessment Workshop CY OCT 23-24, 2003 CL Nice, FRANCE DE biomarkers; cancer; amino acids ID PROSTATE-SPECIFIC ANTIGEN; DIETARY-INTAKE; PREVENTION; CAROTENOIDS; STRATEGIES; PROTEOMICS; CARCINOMA; HEALTH; MODEL; TRIAL AB The biology of disease progression is a complex process that involves multiple sequential steps leading to cellular changes and metabolic events. These molecular events, which may serve as potential biomarkers, can be analyzed by laboratory methods and used to detect a disease such as cancer or indicate the biological exposure to environmental substances including dietary intake. Identification of the genetic, molecular, and clinical events involved in the disease process enables the development of effective therapeutic and preventive measures and the prediction of prognostic outcomes. This article describes various factors that influence nutritional and cancer biomarker research, draws similarities between them, and discusses the measures that have been adapted to validate cancer biomarkers that can potentially be applied to nutritional biomarker research. Nutritional research suffers from a lack of means to quantify relationships between diet and cancer. Biomarkers of dietary intake or metabolism, therefore, could have potential application in study designs for establishing a causal relationship between diet and disease. C1 NCI, Div Canc Prevent, Canc Biomarkers Res Grp, Bethesda, MD 20892 USA. RP Srivastava, S (reprint author), NCI, Div Canc Prevent, Canc Biomarkers Res Grp, Bethesda, MD 20892 USA. EM srivasts@mail.nih.gov NR 40 TC 8 Z9 8 U1 1 U2 2 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD JUN PY 2004 VL 134 IS 6 SU S BP 1640S EP 1645S PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 829EF UT WOS:000222026400016 PM 15173444 ER PT J AU Berenbaum, SA Bryk, KK Duck, SC Resnick, IM AF Berenbaum, SA Bryk, KK Duck, SC Resnick, IM TI Psychological adjustment in children and adults with congenital adrenal hyperplasia SO JOURNAL OF PEDIATRICS LA English DT Article ID EARLY HORMONAL INFLUENCES; EARLY ANDROGENS; SEX; ADOLESCENTS; LIFE; PERSONALITY; PREFERENCES; HYPOSPADIAS; MANAGEMENT; GENITALIA AB Objective To determine psychological health in individuals with one form of intersexuality, congenital adrenal hyperplasia (CAH), and its relation to characteristics of the disease and treatment. Study design Participants (ages 3-31 years) included 72 females and 42 males with CAH, and unaffected relatives (44 females and 69 males). Psychological adjustment was assessed with parent-reports on the Child Behavior Checklist (CBCL) and subject self-reports on the Self-Image Questionnaire for Young Adolescents (SIQYA) or the Multidimensional Personality Questionnaire (MPQ). Information about disease characteristics and genital surgery was obtained from medical records. Results There were no significant differences between females with CAH and unaffected females on any measure. Psychological adjustment was not significantly associated with genital virilization or age at genital surgery. Males with CAH were not significantly different from unaffected males in childhood, but they showed more negative affect at older ages. Conclusions Psychological adjustment is not compromised in females with virilized genitalia who are treated early in life and reared as females. Adjustment does not appear to depend on the characteristics of the disease or its treatment, but sample size and restricted range limit generalizability about adjustment-disease associations. C1 Penn State Univ, Dept Psychol, University Pk, PA 16802 USA. Penn State Univ, Dept Pediat, University Pk, PA 16802 USA. Evanston NW Healthcare, Dept Pediat, Evanston, IL USA. Natl Inst Aging, Lab Personal & Cognit, Bethesda, MD USA. Northwestern Univ, Sch Med, Evanston, IL USA. RP Berenbaum, SA (reprint author), Penn State Univ, Dept Psychol, 417 Moore Bldg, University Pk, PA 16802 USA. EM sberenbaum@psu.edu FU NICHD NIH HHS [HD19644, R01 HD019644] NR 39 TC 39 Z9 39 U1 1 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD JUN PY 2004 VL 144 IS 6 BP 741 EP 746 DI 10.1016/j.jpeds.2004.03.037 PG 6 WC Pediatrics SC Pediatrics GA 829KT UT WOS:000222047900012 PM 15192620 ER PT J AU Lindsey, KP Wilcox, KM Votaw, JR Goodman, MM Plisson, C Carroll, FI Rice, KC Howell, LL AF Lindsey, KP Wilcox, KM Votaw, JR Goodman, MM Plisson, C Carroll, FI Rice, KC Howell, LL TI Effects of dopamine transporter inhibitors on cocaine self-administration in rhesus monkeys: Relationship to transporter occupancy determined by positron emission tomography neuroimaging SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID NONHUMAN-PRIMATES; SQUIRREL-MONKEY; ABUSE; DRUGS; PHARMACOTHERAPIES; PHENYLTROPANES; ACTIVATION; BEHAVIOR; RTI-113; LIGAND AB The dopamine transporter (DAT) is a critical recognition site for cocaine and contributes to its significant abuse liability. Accordingly, the development of compounds that target the DAT represents a logical approach in the pharmacological treatment of cocaine abuse. The present study characterized the effects of DAT inhibitors as pretreatments in rhesus monkeys trained to self-administer cocaine under a second-order schedule of i.v.. drug delivery. The drugs also were substituted for cocaine to characterize their effectiveness in maintaining drug self-administration. Positron emission tomography neuroimaging with [F-18]8-(2-[F-18]fluoroethyl)-2beta-carbomethoxy-3beta-(4-chlorophenyl) nortropane established the DAT occupancy associated with behaviorally relevant doses of each drug. The drugs studied included a selective DAT inhibitor, [1-(2[bis(4-fluorophenyl-) methoxy]ethyl)4-(3-phenylpropyl)piperazine] bimesylate hydrate (GBR 12909); an inhibitor with equal potency at dopamine and norepinephrine transporters, [3beta-(4-chlorophenyl)tropane-2beta-(3-phenylisoxazol-5-yl)] HCl (RTI-177); and a nonselective inhibitor of dopamine, norepinephrinem and serotonin transporters, [(-)-3beta-(3'-methyl-4-chlorophenyl)tropane-2beta-carboxylic acid methyl ester] tartrate (RTI-112). All drugs produced dose-related reductions in cocaine self-administration. Doses of GBR 12909 and RTI-177 that reduced responding by 50% (ED50) resulted in DAT occupancies of 67 +/- 5 and 73 +/- 5%, respectively. In contrast, DAT occupancy was below the limit of detection for the ED50 dose of RTI-112. Both GBR 12909 and RTI-177 reliably maintained drug self-administration, and DAT occupancies at doses that maintained peak rates of responding were 57 +/- 1 and 92 +/- 7%, respectively. In contrast, RTI-112 failed to maintain robust drug self-administration in any subject. The results indicate that selective DAT inhibitors may require high DAT occupancy to reduce cocaine self-administration and maintain drug self-administration. Moreover, the behavioral profile of DAT inhibitors may be influenced by actions at other monoamine transporters. C1 Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USA. Emory Univ, Dept Radiol, Atlanta, GA 30329 USA. Emory Univ, Dept Psychiat & Behav Sci, Atlanta, GA 30329 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. NIDDKD, Med Chem Lab, US Dept HHS, NIH, Bethesda, MD 20892 USA. RP Howell, LL (reprint author), Emory Univ, Yerkes Natl Primate Res Ctr, 954 Gatewood Rd NE, Atlanta, GA 30329 USA. EM leonard@rmy.emory.edu RI Lindsey, Kimberly/H-9073-2012 OI Lindsey, Kimberly/0000-0002-9833-1929 FU NCRR NIH HHS [RR00165]; NIDA NIH HHS [DA00517, DA05477, DA06042, DA10344, DA06051] NR 41 TC 50 Z9 50 U1 1 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUN 1 PY 2004 VL 309 IS 3 BP 959 EP 969 DI 10.1124/jpet.103.060293 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 823VG UT WOS:000221640900011 PM 14982963 ER PT J AU Segrave, AM Mager, DE Charman, SA Edwards, GA Porter, CJH AF Segrave, AM Mager, DE Charman, SA Edwards, GA Porter, CJH TI Pharmacokinetics of recombinant human leukemia inhibitory factor in sheep SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID MEDIATED DRUG DISPOSITION; SUBCUTANEOUS INJECTION; LYMPHATIC ABSORPTION; MOLECULAR-WEIGHT; GROWTH-FACTOR; SOLUBLE FORM; FACTOR LIF; RECEPTOR; CELLS; BINDING AB The pharmacokinetics of recombinant human leukemia inhibitory factor (rhLIF) were investigated following i.v. and s.c. administration of a wide range of dose levels. Parallel studies were conducted where single i.v. bolus doses of 12.5, 25, 100, 250, 500, or 750 mug/kg rhLlF (n = 2) or s.c. doses of 10, 2 0, or 50 mug/kg rhLlF (n = 4) were administered to sheep. Blood samples were collected for up to 24 h postdosing, and the plasma concentrations of rhLIF were analyzed by enzyme-linked immunosorbent assay. Non-compartmental analysis demonstrated an increase in the terminal elimination half-life (from 0.27 to 2.29 h) and a decrease in systemic clearance (from 5.18 to 1.09 ml/min/kg) with increasing i.v. doses of rhLIF, suggesting nonlinear pharmacokinetic behavior. A greater than proportional increase in the area under the plasma concentration-time curve with dose also indicated significantly nonlinear pharmacokinetics after s.c. administration. A mechanistic compartmental model was developed to characterize the pharmacokinetics of rhLIF The key feature of the model accounting for the nonlinear pharmacokinetic behavior of rhLIF was high-affinity, saturable receptor binding and subsequent cellular internalization and degradation. The apparent total density of LIF cell surface receptors and receptor turnover dynamics were included in the model, along with nonspecific binding and linear elimination from the systemic circulation. The absorption of rhLIF from the s.c. injection site into the systemic circulation was characterized by a first-order absorption process via a delay compartment. The proposed model satisfactorily captured the complex pharmacokinetic profiles of rhLIF following both i.v. and s.c. administration. C1 Monash Univ, Victorian Coll Pharm, Dept Pharmaceut, Parkville, Vic 3052, Australia. NIA, NIH, Gerontol Res Ctr, Baltimore, MD 21224 USA. Univ Melbourne, Dept Vet Sci, Werribee, Vic 3030, Australia. RP Charman, SA (reprint author), Monash Univ, Victorian Coll Pharm, Dept Pharmaceut, 381 Royal Parade, Parkville, Vic 3052, Australia. EM susan.charman@vcp.monash.edu.au RI Porter, Christopher/C-6333-2011; Charman, Susan/E-2221-2011 OI Porter, Christopher/0000-0003-3474-7551; Charman, Susan/0000-0003-1753-8213 NR 40 TC 24 Z9 25 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUN 1 PY 2004 VL 309 IS 3 BP 1085 EP 1092 DI 10.1124/jpet.103.063289 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 823VG UT WOS:000221640900026 PM 14872093 ER PT J AU Brenneman, DE Spong, CY Hauser, JM Abebe, D Pinhasov, A Golian, T Gozes, I AF Brenneman, DE Spong, CY Hauser, JM Abebe, D Pinhasov, A Golian, T Gozes, I TI Protective peptides that are orally active and mechanistically nonchiral SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID VASOACTIVE-INTESTINAL-PEPTIDE; DEPENDENT NEUROTROPHIC FACTOR; E-DEFICIENT MICE; APOLIPOPROTEIN-E; NEUROPROTECTIVE PEPTIDE; ALZHEIMERS-DISEASE; NEURONAL CULTURES; WATER MAZE; PROTEIN; NAP AB Previous reports identified two peptides that mimic the action of neuroprotective proteins derived from astrocytes. These peptides, NAPVSIPQ and SALLRSIPA, prevent neuronal cell death produced by electrical blockade, N-methyl-D-aspartate, and beta-amyloid of NAPVSIPQ and SALLRSIPA were synthesized and compared respectively to the corresponding all L-amino acid peptides. In rat cerebral cortical test cultures cotreated with 1 muM tetrodotoxin, the D-amino acid peptides produced similar potency and efficacy for neuroprotection as that observed for their respective L-amino acid peptides. Since all these peptides tested individually exhibited attenuation of efficacy at concentrations of >10 pM, combinations of these peptides were tested for possible synergies. Equimolar D-NAPVSIPQ and D-SALLRSIPA combination treatment produced potent neuroprotection (EC50, 0.03 fM) that did not attenuate with increasing concentrations. Similarly, the combination Of L-NAPVSIPQ and D-SALLRSIPA also had high potency (EC50, 0.07 fM) without attenuation of efficacy. Combined administration of peptides was tested in a model of fetal alcohol syndrome and in a model of learning impairment: apolipoprotein E knockout mice. Intraperitoneal administration Of D-NAPVSIPQ Plus D-SALLRSIPA to pregnant mice (embryonic day 8) attenuated fetal demise after treatment with an acute high dose of alcohol. Furthermore, oral administration Of D-NAPVSIPQ Plus D-SALLRSIPA significantly increased fetal survival after maternal alcohol treatment. Apolipoprotein E knockout mice injected with D-NAPVSIPQ Plus D-SALLRSIPA showed improved performance in the Morris water maze. These studies suggest therapeutic potential for the combined administration of neuroprotective peptides that can act through a mechanism independent of chiral recognition. C1 NICHHD, Sect Dev & Mol Pharmacol, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Pregnancy & Perinatol Branch, NIH, Bethesda, MD 20892 USA. Tel Aviv Univ, Sackler Sch Med, Dept Clin Biochem, IL-69978 Tel Aviv, Israel. RP Brenneman, DE (reprint author), Johnson & Johnson Pharmaceut Res & Dev LLC, Drug Discovery, Welsh & McKean Rd, Spring House, PA 19477 USA. EM dbrennem@prdus.jnj.com NR 38 TC 46 Z9 48 U1 0 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUN 1 PY 2004 VL 309 IS 3 BP 1190 EP 1197 DI 10.1124/jpet.103.063891 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 823VG UT WOS:000221640900040 PM 15007105 ER PT J AU Makrigiannakis, A Zoumakis, E Kalantaridou, S Chrousos, G AF Makrigiannakis, A Zoumakis, E Kalantaridou, S Chrousos, G TI Endometrial and placental CRH as regulators of human embryo implantation SO JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Article; Proceedings Paper CT HIPPOKRATION Congress on Reproductive Immunology CY JUN 04-06, 2003 CL Rhodes Island, GREECE DE CRH; implantation; FasL; decidualization; antalarmin ID CORTICOTROPIN-RELEASING HORMONE; STROMAL CELLS; FAS LIGAND; EXPRESSION; RECEPTOR; DECIDUALIZATION; ANTIGEN; TISSUES; UTERUS; FETAL AB Epithelial cells of the human endometrium and differentiated endometrial stromal cells express the corticotropin-releasing hormone (CRH) gene. CRH is also produced by human placental cytotrophoblast. Endometrial and placental CRH are under the endocrine control of gonadal steroids as well as under autocrine/paracrine regulation by prostanoids and interleukins. Human endometrium, myometrium and placenta express the relevant receptors. Human trophoblast and decidualized endometrial cells also express Fas ligand (FasL), a pro-apoptotic molecule. These findings suggest that intra-uterine CRH may participate in local inflammatory phenomena associated with blastocyst implantation, while FasL may assist with maternal immune tolerance to the semi-allograft embryo. A nonpeptidic CRH receptor type I (CRH-R1)-specific antagonist decreased the expression of FasL by human trophoblasts, suggesting that CRH regulates the pro-apoptotic potential of these cells in an auto-paracrine fashion. Invasive trophoblasts promoted apoptosis of activated Fas-expressing human T lymphocytes, an effect potentiated by CRH and inhibited by the CRH antagonist. Female rats treated with the CRH antagonist in the first 6 days of gestation had a dose-dependent decrease of endometrial implantation sites and live embryos as well as markedly diminished endometrial FasL expression. However, embryos of mothers lacking T cells (nude rats) and embryos of syngeneic matings were not rejected when mothers were treated with antalarmin, suggesting that the effect of antalarmin on embryonic implantation is not due to a nonspecific toxicity of this compound but a specific effect on T cells. Our data suggest important physiological roles of endometrial and placental CRH in the regulation of blastocyst implantation and early maternal tolerance. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 Univ Crete, Sch Med, Dept Obstet & Gynecol, Iraklion 71110, Greece. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Makrigiannakis, A (reprint author), Univ Crete, Sch Med, Dept Obstet & Gynecol, Iraklion 71110, Greece. EM makrigia@med.uoc.gr NR 22 TC 9 Z9 9 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0165-0378 J9 J REPROD IMMUNOL JI J. Reprod. Immunol. PD JUN PY 2004 VL 62 IS 1-2 SI SI BP 53 EP 59 DI 10.1016/j.jri.2003.11.006 PG 7 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA 838RA UT WOS:000222729500007 PM 15288181 ER PT J AU Kalantaridou, SN Makrigiannakis, A Zoumakis, E Chrousos, GP AF Kalantaridou, SN Makrigiannakis, A Zoumakis, E Chrousos, GP TI Stress and the female reproductive system SO JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Article; Proceedings Paper CT HIPPOKRATION Congress on Reproductive Immunology CY JUN 04-06, 2003 CL Rhodes Island, GREECE DE decidualization; implantation; luteolysis; maternal tolerance; ovulation; parturition; reproductive corticotropin-releasing hormone; stress ID CORTICOTROPIN-RELEASING HORMONE; ENDOMETRIAL STROMAL CELLS; PITUITARY-ADRENAL AXIS; HUMAN-PLACENTA; POTENTIAL IMPLICATIONS; BINDING PROTEIN; FETAL MEMBRANES; MENSTRUAL-CYCLE; GENE-EXPRESSION; HUMAN-PREGNANCY AB The hypothalamic-pituitary-adrenal (HPA) axis, when activated by stress, exerts an inhibitory effect on the female reproductive system. Corticotropin-releasing hormone (CRH) inhibits hypothalamic gonadotropin-releasing hormone (GnRH) secretion, and glucocorticoids inhibit pituitary luteinizing hormone and ovarian estrogen and progesterone secretion. These effects are responsible for the "hypothalamic" amenorrhea of stress, which is observed in anxiety and depression, malnutrition, eating disorders and chronic excessive exercise, and the hypogonadism of the Cushing syndrome. In addition, corticotropin-releasing hormone and its receptors have been identified in most female reproductive tissues, including the ovary, uterus, and placenta. Furthermore, corticotropin-releasing hormone is secreted in peripheral inflammatory sites where it exerts inflammatory actions. Reproductive corticotropin-releasing hormone is regulating reproductive functions with an inflammatory component, such as ovulation, luteolysis, decidualization, implantation, and early maternal tolerance. Placental CRH participates in the physiology of pregnancy and the onset of labor. Circulating placental CRH is responsible for the physiologic hypercortisolism of the latter half of pregnancy. Postpartum, this hypercortisolism is followed by a transient adrenal suppression, which may explain the blues/depression and increased autoimmune phenomena observed during this period. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Univ Ioannina, Div Reprod Endocrinol, Sch Med, Dept Obstet & Gynecol, Ioannina 45500, Greece. Univ Crete, Dept Obstet & Gynecol, Sch Med, Iraklion 7110, Greece. Univ Athens, Sch Med, Dept Pediat 1, GR-11527 Athens, Greece. RP Chrousos, GP (reprint author), NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bldg 10,Room 9D42, Bethesda, MD 20892 USA. EM chrousog@mail.nih.gov NR 46 TC 87 Z9 96 U1 0 U2 16 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0165-0378 J9 J REPROD IMMUNOL JI J. Reprod. Immunol. PD JUN PY 2004 VL 62 IS 1-2 SI SI BP 61 EP 68 DI 10.1016/j.jri.2003.09.004 PG 8 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA 838RA UT WOS:000222729500008 PM 15288182 ER PT J AU Pillemer, SR Casciola-Rosen, L Baum, BJ Rosen, A Gelber, AC AF Pillemer, SR Casciola-Rosen, L Baum, BJ Rosen, A Gelber, AC TI Centromere protein C is a target of autoantibodies in Sjorgen's syndrome and is uniformly associated with antibodies to Ro and La SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE centromere; antibodies; Sjogren's syndrome ID SJOGRENS-SYNDROME; ANTICENTROMERE ANTIBODIES; CLASSIFICATION; SCLERODERMA; FRAGMENTS; FEATURES; CRITERIA; AGE AB Objective. To determine which centromere proteins are recognized in Sjogren's syndrome (SS) and whether antibodies recognizing centromere proteins (CENP) B and CENP C identify a specific serologic subset. Methods. Sera from 47 patients with SS, 12 xerostomic controls without SS, and 12 healthy controls were studied. All 47 patients met San Diego criteria for SS. Of these, 45 patients had primary SS and 2 had secondary SS with CREST. Sera were analyzed by immunoprecipitation of [S-35] methionine-labeled Ro 52, La, and CENP B and C generated by coupled in vitro transcription/translation. Human salivary gland cells were also lysed and immunoprecipitated to determine antibody status against Ro 60. Serological and clinical profiles of patients recognizing CENP were defined. Proportions of sera recognizing CENP B, CENP C, Ro, or La across the 3 groups were compared using Fisher's exact test. Results. Twenty-eight of 45 primary SS patients (62%) recognized Ro 52, and 24 patients (53%) recognized La. Ten of these 45 (22%) sera recognized CENP B or C. Furthermore, 7 of these 10 recognized exclusively CENP C; these 7 (100%) all tested positive for antibodies to both Ro 52 and La. This was in contrast to the group of SS patients that did not recognize CENP C alone, in whom anti-Ro 52 antibodies were. found in 21 of 38 (55%; p = 0.034), and antibodies to La in 17 (45%; p = 0.01). Five of 7 CENP C positive sera were also positive for Ro 60. One of 3 patients with antibodies to CENP B also had antibodies to Ro 52, while none of these 3 had antibodies to La. Only patients with antibodies to CENP B showed a centromere pattern on immunofluorescence staining. Conclusion. Antibodies to both CENP B and CENP C occur in SS. In a,subset representing 15% of SS patients studied, these anticentromere antibodies recognize exclusively CENP C, and were uniformly associated with antibodies to Ro 52 and La. C1 NIDCR, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Med, Baltimore, MD USA. Johns Hopkins Univ, Dept Dermatol, Baltimore, MD 21218 USA. Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD 21218 USA. RP Pillemer, SR (reprint author), NIDCR, Gene Therapy & Therapeut Branch, NIH, 10 Ctr Dr,Rm 1N113,MSC 1190, Bethesda, MD 20892 USA. EM Pillemer@NIH.GOV NR 15 TC 12 Z9 14 U1 0 U2 1 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD JUN PY 2004 VL 31 IS 6 BP 1121 EP 1125 PG 5 WC Rheumatology SC Rheumatology GA 826IT UT WOS:000221823500018 PM 15170924 ER PT J AU Bryant, A Goins, RT Bell, R Herrell, R Manson, SM Buchwald, D AF Bryant, A Goins, RT Bell, R Herrell, R Manson, SM Buchwald, D TI Health differences among Lumbee Indians using public and private sources of care SO JOURNAL OF RURAL HEALTH LA English DT Article ID AMERICAN-INDIANS; PREVENTIVE CARE; MEDICAL-CARE; CANCER; PHYSICIANS; SERVICES; SETTINGS; PATTERNS; COVERAGE; QUEBEC AB Context: Of 2.4 million American Indians, approximately 60% are eligible to receive Indian Health Service (IHS) benefits, leaving many to seek care elsewhere. It is unknown if their quality of care, health behaviors, and health status vary by source of care, as demonstrated for other populations. Purpose:The purpose of this study was to determine whether preventive services, health behaviors, and number of health conditions vary as a function of having non-IHS public versus private physicians as sources of usual care. Methods: 1,177 Lumbee Indians, who are ineligible to receive IHS services, completed a telephone interview that included information on receipt of preventive measures, tobacco use, physical activity, breast self-examination, and medical conditions. Frequencies, chi-squares, t tests, odds ratios, and confidence intervals were used to compare variables by source of care. Findings: 939 respondents (80%) had a private and 210 (18%) a public health clinic physician as their usual source of care, 28 (2%) reported having neither. Logistic regression analyses, restricted to the 1,149 participants who reported either a private or public source of care, revealed no differences in receipt of preventive services or health status by usual source of care. Smokeless tobacco use was less common among persons using private than public providers. Conclusions: Lumbees whose usual source of care was a public clinic physician did not differ in receipt of preventive services or in health status compared to their counterparts who received care from a private physician. More targeted research into health similarities and differences arising from access to public and private sources of care is warranted. C1 Univ Colorado, Amer Indian & Alaska Nat Programs, Hlth Sci Ctr, Aurora, CO 80045 USA. Univ N Carolina, Sch Educ, Pembroke, NC USA. W Virginia Univ, Sch Med, Dept Community Med, Morgantown, WV 26506 USA. W Virginia Univ, Sch Med, Ctr Aging, Morgantown, WV 26506 USA. Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. NIMH, NIH, Bethesda, MD 20892 USA. Univ Washington, Harborview Med Ctr, Dept Med, Seattle, WA 98104 USA. RP Manson, SM (reprint author), Univ Colorado, Amer Indian & Alaska Nat Programs, Hlth Sci Ctr, Nighthorse Campbell Nat Hlth Bldg,Room 322,Mail S, Aurora, CO 80045 USA. EM spero.manson@uchsc.edu FU AHRQ HHS [P01 HS10854]; NIA NIH HHS [P30 AG15297]; NIDDK NIH HHS [R03 DK54863]; NIMHD NIH HHS [P60 MD000507] NR 42 TC 1 Z9 1 U1 0 U2 0 PU NATL RURAL HEALTH ASSOC PI KANSAS CITY PA ONE WEST ARMOUR BLVD, STE 301, KANSAS CITY, MO 64111 USA SN 0890-765X J9 J RURAL HEALTH JI J. Rural Health PD SUM PY 2004 VL 20 IS 3 SI SI BP 231 EP 236 DI 10.1111/j.1748-0361.2004.tb00033.x PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 966JO UT WOS:000232016200006 PM 15298097 ER PT J AU Kajava, AV Gorbea, C Ortega, J Rechsteiner, M Steven, AC AF Kajava, AV Gorbea, C Ortega, J Rechsteiner, M Steven, AC TI New HEAT-like repeat motifs in proteins regulating proteasome structure and function SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE bioinformatics; molecular modeling; proteasome activator; sequence profiles; tandem repeats ID 26S PROTEASOME; 20S PROTEASOME; PREDICTION; ALPHA; PURIFICATION; ACIDOPHILUM; RESOLUTION; SEQUENCE; SUBUNITS; PARTICLE AB We have identified repeat motifs in the large proteasome-bin ding proteins PA200 and Ecm29 by applying a sensitive sequence profile method. These repeat motifs, especially those of PA200, resemble HEAT/ARM repeats in length and other properties but differ from them in the occupancy of certain positions. The HEAT motif consists of two alpha-helices and two turns: molecular modeling suggests that in the PA200 and Ecm29 repeats, the alpha-helices may be slightly turned relative to their orientations in typical HEAT repeats. Both PA200 and Ecm29 are composed almost entirely of such repeats, and therefore are likely to have alpha-helical solenoid structures. These observations lead us to speculate on how PA200 and Ecm29 may associate with proteasomes. (C) 2004 Published by Elsevier Inc. C1 CNRS, Ctr Rech Biochim Macromol, FRE 2593, F-34293 Montpellier 5, France. Univ Utah, Dept Biochem, Salt Lake City, UT 84132 USA. NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kajava, AV (reprint author), CNRS, Ctr Rech Biochim Macromol, FRE 2593, 1919 Route de Mende, F-34293 Montpellier 5, France. EM kajava@crbm.cnrs-mop.fr RI Kajava, Andrey/E-1107-2014 OI Kajava, Andrey/0000-0002-2342-6886 FU Canadian Institutes of Health Research [64342] NR 34 TC 48 Z9 48 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD JUN PY 2004 VL 146 IS 3 BP 425 EP 430 DI 10.1016/j.jsb.2004.01.013 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 817KP UT WOS:000221176700016 PM 15099583 ER PT J AU Nebeling, L Rogers, CJ Berrigan, D Hursting, S Ballard-Barbash, R AF Nebeling, L Rogers, CJ Berrigan, D Hursting, S Ballard-Barbash, R TI Weight cycling and immunocompetence SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Editorial Material ID NATURAL-KILLER-CELLS; IOWA WOMENS HEALTH; UNITED-STATES; OBESITY; VARIABILITY; DISEASE; CANCER; RISK C1 NCI, Appl Res Program, Div Canc Control & Poplulat Sci, Bethesda, MD 20892 USA. NCI, Hlth Promot Res Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NCI, Nutr & Mol Carcinogenesis Sect, Bethesda, MD 20892 USA. RP Ballard-Barbash, R (reprint author), NCI, Appl Res Program, Div Canc Control & Poplulat Sci, 6130 Execut Blvd,MSC 7344,EPN Room 4005, Bethesda, MD 20892 USA. EM barbashr@mail.nih.gov NR 21 TC 3 Z9 3 U1 0 U2 0 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD JUN PY 2004 VL 104 IS 6 BP 892 EP 894 DI 10.1016/j.jada.2004.03.001 PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 826BV UT WOS:000221804800007 PM 15175586 ER PT J AU Cotton, PA Subar, AF Friday, JE Cook, A AF Cotton, PA Subar, AF Friday, JE Cook, A TI Dietary sources of nutrients among US adults, 1994 to 1996 SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID NHANES-II SURVEY; QUANTITATIVE DATA; AMERICAN DIET; FOOD SOURCES; MACRONUTRIENTS AB Objective To identify major food sources of 30 nutrients and dietary constituents among US adults during 1994 to 1996, and to compare them with those identified for 1989 to 1991. Design A total of 6,419 foods were assigned to 112 food groups based on similarities in nutrient content or use. These foods included 3,778 food mixtures disaggregated by the US Department of Agriculture's (USDA) FoodLink computerized research tool, so ingredients could be assigned to the appropriate groups and nutrient values ascribed accordingly. Subjects/Setting Single 24-hour dietary recalls from a nationally representative sample of 10,019 adults aged 19 years or older in USDA's 1994 to 1996 Continuing Survey of Food Intakes by Individuals were used. Statistical Analyses Performed The population proportion formula was used to determine weighted nutrient intakes by food groups. Results were tabulated in descending rank order for food groups providing at least 1% of total nutrient intake. Results Dietary food sources found for 1994 to 1996 were fairly consistent with 1989 to 1991 results for the rank order and proportion these sources made to total nutrient intakes. Remarkable changes were seen in the higher proportion of energy from alcoholic beverages, in the shifts in the proportion of total fat and fatty acids from oil (higher ranked) and margarine (lower ranked), and in the lower proportion of vitamins and minerals from ready-to-eat cereals. Conclusions Despite changes in survey methodology, the food supply, and eating patterns, food sources of nutrients among US adults in 1994 to 1996 and 1989 to 1991 were similar. The 1994 to 1996 data are the first known national population estimates for dietary sources of vitamin A (retinol equivalents), selenium, caffeine, and theobromine among US adults. C1 USDA, Community Nutr Res Grp, Beltsville, MD 20705 USA. NCI, Div Canc Control & Populat Sci, Appl Res Program, Risk Factor Monitoring & Methods Branch, Bethesda, MD 20892 USA. RP Cotton, PA (reprint author), USDA, Community Nutr Res Grp, Bldg 005,Room 117,BARC W,10300 Baltimore Ave, Beltsville, MD 20705 USA. EM pcotton@rhbnrc.usda.gov NR 20 TC 107 Z9 111 U1 1 U2 16 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD JUN PY 2004 VL 104 IS 6 BP 921 EP 930 DI 10.1016/j.jada.2004.03.019 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 826BV UT WOS:000221804800011 PM 15175590 ER PT J AU Millen, AE Dodd, KW Subar, AF AF Millen, AE Dodd, KW Subar, AF TI Use of vitamin, mineral, nonvitamin, and nonmineral supplements in the United States: The 1987, 1992, and 2000 National Health Interview Survey results SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID CORONARY-HEART-DISEASE; E CONSUMPTION; TRENDS; RISK; PREVENTION; NUTRIENTS; PATTERNS; MEDICINE; WOMEN AB Objective To describe trends in use of specific vitamin and mineral (VM) supplements. Design The nationally representative National Health In-. terview Survey queried adult respondents about their use of VM supplements in 1987, 1992, and, 2000. Statistical Analysis Trends in use of VM supplements from 1987 to 2000 were determined using linear contrasts. Results The percentage of adults using any VM supplement daily increased from 23.2% (1987) to 23.7% (1992) to 33.9% (2000). This pattern was consistent for both sexes, all race/ethnic groups, and adults aged greater than or equal to 25 years. The increase in the percentage of daily users of multivitamins, vitamin A, and vitamin E was 10.5, 1.2, and 7.3 percentage points, respectively, from 1987 to 2000. Increases in daily use of vitamin C (3.3 percentage points) and calcium (6.1 percentage points) occurred between 1992 and 2000. All trend analyses were significant at P<.001. In the 2000 National Health Interview Survey personnel queried the use of nonvitamin/nonmineral supplements for the first time. At that time, 6.0% of respondents reported using them daily. Conclusion The increasing trend in supplement use over time and the notable use of nonvitamin/nonmineral supplements in 2000 indicates the continued need to monitor the use of all types of dietary supplements for purposes of dietary surveillance and nutrition-related research. C1 NCI, Div Canc Control & Populat Sci, Appl Res Program, Risk Factor Monitoring & Methods Branch, Bethesda, MD 20892 USA. RP Subar, AF (reprint author), NCI, Div Canc Control & Populat Sci, Appl Res Program, Risk Factor Monitoring & Methods Branch, 6130 Execut Blvd,MSC 7344,EPN 4005, Bethesda, MD 20892 USA. EM subara@mail.nih.gov NR 26 TC 134 Z9 137 U1 4 U2 12 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD JUN PY 2004 VL 104 IS 6 BP 942 EP 950 DI 10.1016/j.jada.2004.03.022 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 826BV UT WOS:000221804800013 PM 15175592 ER PT J AU McConahy, KL Smiciklas-Wright, H Mitchell, DC Picciano, MF AF McConahy, KL Smiciklas-Wright, H Mitchell, DC Picciano, MF TI Portion size of common foods predicts energy intake among preschool-aged children SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID US CHILDREN; EARLY-CHILDHOOD; PREVALENCE AB This study evaluated the relationship of food intake behaviors to total energy intake among children aged 2 to 5 years old (N=5,447) who participated in the Continuing Survey of Food Intakes by Individuals, 1994-1996, 1998 (CSFII 94-96, 98). Food intake behaviors examined were portion size for 10 commonly eaten foods, number of eating occasions per day, and number of foods consumed per day. Using regression models, we examined these eating behaviors as predictors of energy intakes with adjustment for body weight. Eating behaviors and body weight were positively related to energy intake, together explaining 38% to 39% of the variability. Portion size alone accounted for 17% to 19% of the variance in energy intake, whereas body weight predicted only 4%. Feeding recommendations should highlight the importance of age-appropriate portion sizes and provide guidance on the frequency of eating and number of foods consumed. C1 Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. Penn State Univ, Dept Nutr, University Pk, PA 16802 USA. Childrens Hosp Philadelphia, Dept GI & Nutr, Philadelphia, PA 19104 USA. Penn State Univ, Dept Nutr Sci, Diet Assessment Ctr, University Pk, PA 16802 USA. NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Smiciklas-Wright, H (reprint author), Penn State Univ, Dept Nutr Sci, 5 Henderson Bldg, University Pk, PA 16802 USA. EM hsw@psu.edu NR 18 TC 50 Z9 51 U1 0 U2 2 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD JUN PY 2004 VL 104 IS 6 BP 975 EP 979 DI 10.1016/j.jada.2004.03.027 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 826BV UT WOS:000221804800020 PM 15175599 ER PT J AU Rucker-Whitaker, C Greenland, P Liu, K Chan, CL Guralnik, JM Criqui, MH Taylor, L Pearce, WH McGraeMcDermott, M AF Rucker-Whitaker, C Greenland, P Liu, K Chan, CL Guralnik, JM Criqui, MH Taylor, L Pearce, WH McGraeMcDermott, M TI Peripheral arterial disease in african americans: Clinical characteristics, leg symptoms, and lower extremity functioning SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article; Proceedings Paper CT 25th Annual Meeting of the Society-of-General-Internal-Medicine CY MAY 02-04, 2002 CL ATLANTA, GA SP Soc Gen Internal Med DE African Americans; functioning; peripheral arterial disease (PAD) ID OCCLUSIVE DISEASE; PHYSICAL-ACTIVITY; INTERMITTENT CLAUDICATION; SUBSEQUENT DISABILITY; ANKLE/BRACHIAL INDEX; WOMENS HEALTH; 6-MINUTE WALK; RACE; PREVALENCE; POPULATION AB OBJECTIVES: The describe peripheral arterial disease (PAD) in African Americans, and compare findings in African Americans and whites with PAD. DESIGN: Cross-sectional. SETTING: Three academic medical centers. PARTICIPANTS: Three hundred sixty-six whites and 76 African Americans with PAD (as defined by an ankle brachial index (ABI) <0.90) aged 55 and older identified from lower extremity arterial studies performed between 1996 and the fall of 1999. MEASUREMENTS: Comprehensive medical interview, body mass index, and neuropathy score. Functional measurements included the 6-minute walk distance, 4-m walking velocity, and the summary performance score. RESULTS: Age- and sex-adjusted results showed that African Americans had a lower mean ABI than whites (0.60 vs 0.66, P=.001), were less likely to be college graduates (13.7% vs 44.4%, P<.001), and had nearly twice the prevalence of diabetes mellitus (46.8% vs 28.0%, P=.001). After adjusting for age, sex, education level, and ABI, African Americans had a higher prevalence of no exertional leg pain (28.0% vs 18.2%, P=.044) and leg pain with exertion and rest (30.0% vs 17.3%, P=.023). African Americans had a shorter 6-minute walk distance (989 vs 1,156 ft, P<.001), a slower normal-pace 4-m walking velocity (0.79 vs 0.89 m/s, P<.001), a slower fast-pace 4-m walking velocity (1.12 vs 1.20 m/s, P=.012), and a lower summary performance score (8.8 vs 9.6, P=.018) than whites. These differences in functioning were attenuated after adjusting for age, sex, ABI, education, and leg symptoms. CONCLUSION: Poorer lower extremity functioning in African Americans was largely explained by differences in leg symptoms and, to a somewhat lesser degree, lower ABI levels and poorer education in African Americans than in whites. Further study is needed to determine whether these findings affect racial treatment disparities and poorer outcomes previously reported in African Americans than in whites with PAD. C1 Rush Univ, Med Ctr, Dept Prevent Med, Chicago, IL 60612 USA. Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Evanston, IL USA. Northwestern Univ, Feinberg Sch Med, Div Vasc Surg, Evanston, IL USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. Oregon Hlth Sci Univ, Div Vasc Surg, Portland, OR 97201 USA. RP Rucker-Whitaker, C (reprint author), Rush Univ, Med Ctr, Dept Prevent Med, 1700 W Van Buren Suite 470, Chicago, IL 60612 USA. EM cheryl_rucker-whitaker@rush.edu FU NCRR NIH HHS [RR-0048]; NHLBI NIH HHS [R01-HL58099] NR 53 TC 21 Z9 21 U1 0 U2 2 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUN PY 2004 VL 52 IS 6 BP 922 EP 930 DI 10.1111/j.1532-5415.2004.52259.x PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 822JI UT WOS:000221534900010 PM 15161456 ER PT J AU Di Bari, M van de Poll-Franse, LV Onder, G Kritchevsky, SB Newman, A Harris, TB Williamson, JD Marchionni, N Pahor, M AF Di Bari, M van de Poll-Franse, LV Onder, G Kritchevsky, SB Newman, A Harris, TB Williamson, JD Marchionni, N Pahor, M TI Antihypertensive medications and differences in muscle mass in older persons: The Health, Aging and Body Composition study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE muscle mass; ACE-inhibition; antihypertensive medications; body composition ID CONVERTING ENZYME-INHIBITORS; OBSTRUCTIVE PULMONARY-DISEASE; HEART-FAILURE; SKELETAL-MUSCLE; STRENGTH; HYPERTENSION; CLENBUTEROL; SARCOPENIA; MORBIDITY; MORTALITY AB OBJECTIVES: To evaluate whether older persons using angiotensin-converting enzyme (ACE) inhibitors have a larger lower extremity muscle mass (LEMM) than users of other antihypertensive drugs. DESIGN: Cross-sectional analysis of data from the Health, Aging and Body Composition (Health ABC) Study. SETTING: University of Tennessee, Memphis, and University of Pittsburgh clinics. PARTICIPANTS: A community-based sample of 2,431 well functioning participants of the Health ABC, aged 70 to 79, who were free of heart failure, were selected according to use of antihypertensive medications: ACE inhibitors (n=197), beta-blockers (n=169), thiazides (n=216), calcium-channel blockers (n=340), or none (n=1,509). MEASUREMENTS: LEMM, assessed using dual-energy x-ray absorptiometry, compared by index drug in analysis of variance models unadjusted and adjusted for demographics, study site, height, body fat, physical activity, blood pressure, coronary artery disease, diabetes mellitus, and chronic pulmonary disease. RESULTS: LEMM significantly differed across the study groups, being larger in users of ACE inhibitors than in users of other drugs (unadjusted and adjusted models). LEMM was comparable in users of ACE inhibitors and no drug users. A trend toward larger LEMM was also observed in sex- and ethnicity-stratified analyses and in the subgroup of noncoronary hypertensive participants. CONCLUSION: In older persons, use of ACE inhibitors is associated cross-sectionally with larger LEMM. This finding suggests a possible explanation of the benefits of ACE inhibitors in wasting syndromes. If confirmed in longitudinal studies, this pharmacological action might have important implications for the prevention of physical disability in older patients with hypertension. C1 Wake Forest Univ, Baptist Med Ctr, Sticht Ctr Aging, Dept Internal Med, Winston Salem, NC 27109 USA. Univ Florence, Dept Crit Care Med & Surg, Unit Gerontol & Geriatr Med, Florence, Italy. Azienda Osped Careggi, Florence, Italy. Comprehens Canc Ctr S, Eindhoven, Netherlands. Univ Tennessee, Dept Prevent Med, Memphis, TN USA. Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Di Bari, M (reprint author), Univ Florence, Dept Crit Med & Surg, Unit Gerontol & Geriatr, Via Oblate 4, I-50141 Florence, Italy. EM dibari@unifi.it RI DI BARI, MAURO/J-1524-2012; Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 NR 34 TC 62 Z9 65 U1 1 U2 8 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUN PY 2004 VL 52 IS 6 BP 961 EP 966 DI 10.1111/j.1532-5415.2004.52265.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 822JI UT WOS:000221534900016 PM 15161462 ER PT J AU Abbott, KC Swanson, SJ Agodoa, LYC Kimmel, PL AF Abbott, KC Swanson, SJ Agodoa, LYC Kimmel, PL TI Human immunodeficiency virus infection and kidney transplantation in the era of highly active antiretroviral therapy and modern immunosuppression SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID SOLID-ORGAN TRANSPLANTATION; CADAVERIC RENAL-TRANSPLANTATION; MYCOPHENOLATE-MOFETIL; UNITED-STATES; LIVER-TRANSPLANTATION; HIV-1 REPLICATION; DIALYSIS PATIENTS; CYCLOSPORINE-A; GRAFT-SURVIVAL; DISEASE AB Before the era of highly active antiretroviral therapy, kidney transplant recipients infected with HIV had increased risk of death compared with HIV-uninfected recipients. More recent single-center reports have indicated improved results, but this has not been assessed in a national population. Therefore, a retrospective cohort study of US adult deceased donor kidney transplant recipients from January 1, 1996, to May 31, 2001 was conducted; patients were followed until October 3 1, 2001. A total of 27,851 patients had valid recipient HIV serology. Cox regression analysis was used to model adjusted hazard ratios for mortality and graft loss, respectively, adjusted for other factors, including comorbid conditions from Centers for Medicare and Medicaid Studies Form 2728. Factors independently associated with HIV infection were also assessed by logistic regression analysis. Only 12.8% of HIV-infected recipients were black, compared with 27.6% in the entire study cohort. HIV-infected kidney transplant recipients were significantly less likely to be black in logistic regression analysis (adjusted OR, 0.29; 95% CI, 0.08 to 0.99; P = 0.049), which was the only factor independently associated with HIV infection. It was found that HIV-infected recipients had improved survival compared with HIV-uninfected recipients, although this was not statistically significant in adjusted analysis (adjusted HR, 0.36; 95% CI, 0.05 to 2.53; P = 0.31). Kidney transplantation in HIV-infected patients is plausible and ongoing, but HIV-infected candidates who underwent kidney transplantation in the United States during the course of the study were demographically unrepresentative of HIV-infected candidates generally. C1 Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. WRAMC, Organ Transplant Serv, Washington, DC USA. NIH, Bethesda, MD 20892 USA. NIDDK, NIH, Bethesda, MD USA. George Washington Univ, Med Ctr, Dept Med, Div Kidney Dis & Hypertens, Washington, DC USA. RP Abbott, KC (reprint author), Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. EM kevin.abbott@na.amedd.army.mil OI Abbott, Kevin/0000-0003-2111-7112 NR 39 TC 72 Z9 75 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUN PY 2004 VL 15 IS 6 BP 1633 EP 1639 DI 10.1097/01.ASN.0000127987.19470.3A PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 823YD UT WOS:000221649400028 PM 15153575 ER PT J AU Moolchan, ET Hudson, DL Schroeder, JR Sehnert, SS AF Moolchan, ET Hudson, DL Schroeder, JR Sehnert, SS TI Heart rate and blood pressure responses to tobacco smoking among African-American adolescents SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE adolescent; tobacco; ethnicity; heart rate; blood pressure; health disparities ID SERUM COTININE LEVELS; ETHNIC-DIFFERENCES; CIGARETTE SMOKERS; NICOTINE; CESSATION; EXPOSURE; DEPENDENCE; TOPOGRAPHY; MORTALITY; MENTHOL AB Ethnic differences in both physiological response to and health consequences of tobacco smoking-some of which have been attributed to ethnic preferences for menthol cigarettes-have been described in the literature. We compared acute physiological responses to smoking in African-American and European-American adolescent menthol cigarette smokers seeking smoking cessation treatment. One-hundred-twenty-eight adolescents (32% African-American, 71% female; mean age 15.16 +/- 1.32 years, mean Fagerstrom Test of Nicotine Dependence (FTND) score 6.73 +/- 1.53, cigarettes per day (CPD) 16.9 +/- 2.64) participated in an experimental session during which they smoked one menthol cigarette of their usual brand. Blood pressure, heart rate, and exhaled carbon monoxide (CO) concentrations were measured before and after smoking; mean puff volume (mL), puff duration (sec) and maximal puff velocity (mL/sec) during smoking were also determined. Two sample t-tests were performed to assess ethnic differences in smoking topography; analysis of covariance was used to determine whether heart rate and blood pressure after smoking one menthol cigarette varied by ethnicity, after controlling for baseline physiological measures. No significant ethnic differences were observed in either smoking topography or acute cardiovascular response to smoking. These preliminary findings warrant extension to a broader group of non-treatment-seeking adolescent smokers of both ethnicities. C1 NIDA, Teen Tobacco Addict Treatment Res Clin, Intramural Res Program, Baltimore, MD 21224 USA. RP Moolchan, ET (reprint author), NIDA, Teen Tobacco Addict Treatment Res Clin, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM emoolcha@intra.nida.nih.gov NR 36 TC 6 Z9 6 U1 0 U2 8 PU NATL MED ASSOC PI WASHINGON PA 1012 10TH ST, N W, WASHINGON, DC 20001 USA SN 0027-9684 J9 J NATL MED ASSOC JI J. Natl. Med. Assoc. PD JUN PY 2004 VL 96 IS 6 BP 767 EP 771 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 840HO UT WOS:000222848900026 PM 15233486 ER PT J AU Xu, L Tsuji, K Mostowski, H Otsu, M Candotti, F Rosenberg, AS AF Xu, L Tsuji, K Mostowski, H Otsu, M Candotti, F Rosenberg, AS TI A convenient method for positive selection of retroviral producing cells generating vectors devoid of selectable markers SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE retroviral producing cells; selectable markers; retroviral vectors; gene therapy ID TRANSGENE EXPRESSION; ADENOSINE-DEAMINASE; VIRUS; TITER; LYMPHOCYTES; LEUKEMIA; CLONES; LINE AB Early retroviral vectors containing both a therapeutic gene and a dominant selectable marker gene, offered some distinct advantages with respect to gene therapy, in that they simplified the generation, isolation, and titration of retroviral producer cell clones, as well as the evaluation and selection of successfully targeted cells. However, a number of problems were engendered by this strategy: the promoter driving the selectable marker gene could interfere with transcription of the therapeutic gene, and immune responses could be induced to cells expressing foreign proteins of selection marker origin. Simplified retroviral vectors, which lack a selection marker gene, were constructed to address these problems, but the inability to use a selection marker has made identification and cloning of virus producing transfected cells a heavy burden. To maintain the benefits of simplified retroviral vectors, while providing a facile means to select packaging cells transfected with retroviral DNA. we cloned the bacterial selection marker gene encoding neomycin phosphotransferase (neo) into the plasmid backbone of the vector, but outside of the provirus, resulting in efficient selection of transfected packaging cells and generation of packaged virus which lacks the neo gene. This novel approach generates greater numbers of high infectious titer producing clones, after selection in G418 media, than does a co-transfection approach, due to integration of higher construct copy numbers per cell. No transmission of the selection marker gene to target cells was observed following retroviral transduction. Thus, our strategy eliminates the adverse consequences of a selection-based method, while diminishing the burden of identification of packaging cells transfected with vectors devoid of selectable markers. (C) 2004 Elsevier B.V. All rights reserved. C1 US FDA, CDER, Div Therapeut Prot, Bethesda, MD 20892 USA. US FDA, CDER, Div Cellular & Gene Therapies, Bethesda, MD 20892 USA. NHGRI, GMBB, Disorders Immun Sect, NIH, Bethesda, MD 20892 USA. RP Rosenberg, AS (reprint author), US FDA, CDER, Div Therapeut Prot, Bldg 29A,Room 2B-10,29 Lincoln Dr, Bethesda, MD 20892 USA. EM rosenberg@cber.fda.gov OI Otsu, Makoto/0000-0002-9769-0217 NR 17 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 J9 J VIROL METHODS JI J. Virol. Methods PD JUN 1 PY 2004 VL 118 IS 1 BP 61 EP 67 DI 10.1016/j.jviromet.2004.01.024 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA 862ND UT WOS:000224496700008 PM 15158069 ER PT J AU Yang, ZY Huang, Y Ganesh, L Leung, K Kong, WP Schwartz, O Subbarao, K Nabel, GJ AF Yang, ZY Huang, Y Ganesh, L Leung, K Kong, WP Schwartz, O Subbarao, K Nabel, GJ TI pH-dependent entry of Severe acute respiratory syndrome coronavirus is mediated by the spike glycoprotein and enhanced by dendritic cell transfer through DC-SIGN SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; EBOLA-VIRUS; SARS-CORONAVIRUS; MEMBRANE-FUSION; HONG-KONG; T-CELLS; INFECTION; ENVELOPE; RECEPTOR; HIV AB The severe acute respiratory syndrome coronavirus (SARS-CoV) synthesizes several putative viral envelope proteins, including the spike (S), membrane (M), and small envelope (E) glycoproteins. Although these proteins likely are essential for viral replication, their specific roles in SARS-CoV entry have not been defined. In this report, we show that the SARS-CoV S glycoprotein mediates viral entry through pH-dependent endocytosis. Further, we define its cellular tropism and demonstrate that virus transmission occurs through cell-mediated transfer by dendritic cells. The S glycoprotein was used successfully to pseudotype replication-defective retroviral and lentiviral vectors that readily infected Vero cells as well as primary pulmonary and renal epithelial cells from human, nonhuman primate, and, to a lesser extent, feline species. The tropism of this reporter virus was similar to that of wild-type, replication-competent SARS-CoV, and binding of purified S to susceptible target cells was demonstrated by flow cytometry. Although myeloid dendritic cells were able to interact with S and to bind virus, these cells could not be infected by SARS-CoV. However, these cells were able to transfer the virus to susceptible target cells through a synapse-like structure. Both cell-mediated infection and direct infection were inhibited by anti-S antisera, indicating that strategies directed toward this gene product are likely to confer a therapeutic benefit for antiviral drugs or the development of a SARS vaccine. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NIAID, Biol Imaging Facil, NIH, Bethesda, MD 20892 USA. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, Bldg 40,Room 4502,MSC-3005,40 Convent Dr, Bethesda, MD 20892 USA. EM gnabel@nih.gov NR 46 TC 198 Z9 214 U1 0 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2004 VL 78 IS 11 BP 5642 EP 5650 DI 10.1128/JVI.78.11.5642-5650.2004 PG 9 WC Virology SC Virology GA 822CW UT WOS:000221513400012 PM 15140961 ER PT J AU Haigwood, NL Montefiori, DC Sutton, WF McClure, J Watson, AJ Voss, G Hirsch, VM Richardson, BA Letvin, NL Hu, SL Johnson, PR AF Haigwood, NL Montefiori, DC Sutton, WF McClure, J Watson, AJ Voss, G Hirsch, VM Richardson, BA Letvin, NL Hu, SL Johnson, PR TI Passive immunotherapy in simian immunodeficiency virus-infected macaques accelerates the development of neutralizing antibodies SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN MONOCLONAL-ANTIBODIES; HIV-1/SIV CHIMERIC VIRUS; NEWBORN RHESUS MACAQUES; HIV TYPE-1 INFECTION; ENVELOPE GLYCOPROTEIN; SIV INFECTION; VIRAL LOAD; SYNERGISTIC NEUTRALIZATION; PROTECTIVE IMMUNITY; CONFERS PROTECTION AB Passively transferred neutralizing antibodies can block lentivirus infection, but their role in postexposure prophylaxis is poorly understood. In this nonhuman-primate study, the effects of short-term antibody therapy on 5-year disease progression, virus load, and host immunity were explored. We reported previously that postinfection passive treatment with polyclonal immune globulin with high neutralizing titers against SIVsmE660 (SIVIG) significantly improved the 67-week health of SIVsmE660-infected Macaca mulatta macaques. Four of six treated macaques maintained low or undetectable levels of virus in plasma, compared with one of ten controls, while two rapid progressors controlled viremia only as long as the SIVIG was present. SIVIG treatment delayed the de novo production of envelope (Env)-specific antibodies by 8 weeks (13). We show here that differences in disease progression were also significant at 5 years postinfection, excluding rapid progressors (P = 0.05). Macaques that maintained less than or equal to10(3) virus particles per ml of plasma and less than or equal to30 infectious virus particles per 10(6) mononuclear cells from peripheral blood and lymph nodes had delayed disease onset. All macaques that survived beyond 18 months had measurable Gag-specific CD8(+) cytotoxic T cells, regardless of treatment. Humoral immunity in survivors beyond 20 weeks was strikingly different in the SIVIG and control groups. Despite a delay in Env-specific binding antibodies, de novo, production of neutralizing antibodies was significantly accelerated in SIVIG-treated macaques. Titers of de novo neutralizing antibodies at week 12 were comparable to levels achieved in controls only by week 32 or later. Acceleration of de novo simian immunodeficiency virus immunity in the presence of passively transferred neutralizing antibodies is a novel finding with implications for postexposure prophylaxis and vaccines. C1 Seattle Biomed Res Inst, Seattle, WA 98109 USA. Duke Univ, Med Ctr, Durham, NC 27710 USA. Harvard Univ, Sch Med, Beth Israel Hosp, Boston, MA 02215 USA. NIAID, Infect Dis Lab, NIH, Rockville, MD 20852 USA. Univ Washington, Dept Pathobiol, Seattle, WA 98195 USA. Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Univ Washington, Dept Pharmaceut, Seattle, WA 98195 USA. Univ Washington, Washington Natl Primate Res Ctr, Seattle, WA 98195 USA. Childrens Hosp, Res Fdn, Columbus, OH 43205 USA. RP Haigwood, NL (reprint author), Seattle Biomed Res Inst, 307 Westlake Ave N,Suite500, Seattle, WA 98109 USA. EM Nancy.Haigwood@sbri.org RI Hu, Shiu-Lok/A-3196-2008; Johnson, Philip/A-6892-2009 OI Hu, Shiu-Lok/0000-0003-4336-7964; FU NCRR NIH HHS [P51 RR000166, RR00166]; NIAID NIH HHS [R37 AI020729, AI-20729, AI-27757, P30 AI027757, R01 AI020729] NR 59 TC 68 Z9 69 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2004 VL 78 IS 11 BP 5983 EP 5995 DI 10.1128/JVI.78.11.5983-5995.2004 PG 13 WC Virology SC Virology GA 822CW UT WOS:000221513400047 PM 15140996 ER PT J AU Johnson, TR Teng, MN Collins, PL Graham, BS AF Johnson, TR Teng, MN Collins, PL Graham, BS TI Respiratory syncytial virus (RSV) G glycoprotein is not necessary for vaccine-enhanced disease induced by immunization with formalin-inactivated RSV SO JOURNAL OF VIROLOGY LA English DT Article ID ATTACHMENT G GLYCOPROTEIN; REPLICATION IN-VITRO; MESSENGER-RNA EXPRESSION; BALB/C MICE; PULMONARY EOSINOPHILIA; G-PROTEIN; SUBGROUP-B; COTTON RATS; SH PROTEIN; CYTOKINE EXPRESSION AB Following respiratory syncytial virus (RSV) challenge, mice immunized with RSV G or with formalin-inactivated RSV (FI-RSV) exhibit severe disease associated with type 2 cytokine production and pulmonary eosinophilia. This has led to the proposal that the presence of RSV G is the factor in FI-RSV that induces disease-enhancing T-cell responses. Therefore, we evaluated the role of RSV G and its immunodominant region in the induction of aberrant immune responses during FI-RSV immunization. BALB/c mice were immunized with FI preparations of wild-type (wt) RSV or recombinant RSV (rRSV) containing deletions of (i) the entire G gene, (ii) the region of the G gene encoding amino acids 187 to 197 of the immunodominant region, or (iii) the entire SH gene. After challenge, illness, RSV titers, cytokine levels, and pulmonary eosinophilia were measured. Peak RSV titers postchallenge were significantly greater in mice immunized with FI preparations of the deletion viruses than in those immunized with FI-rRSV wt, suggesting that the absence of G or SH in FI-RSV reduced its protective efficacy. Deletion of G or its epitope did not reduce illness, cytokine production, or eosinophilia relative to that in mice immunized with FI-rRSV wt. While cytokine levels and eosinophilia were similar, illness was reduced in mice immunized with SH-deleted FI-RSV. These data suggest that G-specific immune responses may be important for vaccine-induced protection and are not solely the basis for FI-RSV vaccine-enhanced illness. These data suggest that the method of RSV antigen delivery, rather than the protein composition, influences the phenotype of the induced immune responses and that RSV G should not necessarily be excluded from potential vaccine strategies. C1 NIAID, VRC, NIH, Viral Pathogenesis Lab, Bethesda, MD 20892 USA. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Johnson, TR (reprint author), NIAID, VRC, NIH, Viral Pathogenesis Lab, Bldg 40 Room 2614,40 Convent Dr,MSC 3017, Bethesda, MD 20892 USA. EM teresaj@nih.gov RI Teng, Michael/I-5006-2012 OI Teng, Michael/0000-0002-0722-3659 NR 69 TC 51 Z9 54 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2004 VL 78 IS 11 BP 6024 EP 6032 DI 10.1128/JVI.78.11.6024-6032.2004 PG 9 WC Virology SC Virology GA 822CW UT WOS:000221513400051 PM 15141000 ER PT J AU Boyer, PL Stenbak, CR Clark, PK Linial, ML Hughes, SH AF Boyer, PL Stenbak, CR Clark, PK Linial, ML Hughes, SH TI Characterization of the polymerase and RNase H activities of human foamy virus reverse transcriptase SO JOURNAL OF VIROLOGY LA English DT Article ID LEUKEMIA-VIRUS; SARCOMA-VIRUS; GAG PROTEIN; IN-VITRO; POL; TYPE-1; REPLICATION; RESISTANCE; REGION; GENOME AB Foamy virus (FV) replication, while related to that of orthoretroviruses, differs at a number of steps. Several of these differences involve the reverse transcriptase (RT). There appear to be fewer RTs present in FV than in orthoretroviruses; we previously proposed that the polymerase of FV RT was more active than orthoretroviral RTs to compensate for the numerical difference. Here we present further characterization of the RT of FV. The polymerase activity of FV RT was greater than that of human immunodeficiency virus type I RT in a variety of assays. We also examined the RNase H activity of FV RT, and we propose that FV RT has a basic loop in the RNase H domain. Although the sequence of the basic loop of FV RT is different from the basic loop of either Moloney leukemia virus RNase H or Escherichia coli RNase H, the FV RT basic loop appears to have a similar function. C1 NCI, Frederick Canc Res & Dev Ctr, HIV Drug Resistance Program, Canc Res Ctr, Frederick, MD 21702 USA. SAIC, Basic Res Program, Frederick, MD 21702 USA. Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA. Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. RP Hughes, SH (reprint author), NCI, Frederick Canc Res & Dev Ctr, HIV Drug Resistance Program, Canc Res Ctr, POB B,Bldg 539,Room 130A, Frederick, MD 21702 USA. EM hughes@ncifcrf.gov FU NCI NIH HHS [R01 CA018282, CA 18282, CA 09229, T32 CA009229] NR 42 TC 20 Z9 20 U1 1 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2004 VL 78 IS 12 BP 6112 EP 6121 DI 10.1128/JVI.78.102.6112-6121.2004 PG 10 WC Virology SC Virology GA 825QC UT WOS:000221772000004 PM 15163704 ER PT J AU Chanturiya, AN Basanez, G Schubert, U Henklein, P Yewdell, JW Zimmerberg, J AF Chanturiya, AN Basanez, G Schubert, U Henklein, P Yewdell, JW Zimmerberg, J TI PB1-F2, an influenza A virus-encoded proapoptotic mitochondrial protein, creates variably sized pores in planar lipid membranes SO JOURNAL OF VIROLOGY LA English DT Article ID PHOSPHOLIPID-BILAYER MEMBRANES; FORMS ION CHANNELS; TERMINAL REGION; MECHANISM; CURVATURE; BREAKDOWN; BCL-X(L); VESICLES; PEPTIDE; FUSION AB A frameshifted region of the influenza A virus PB1 gene encodes a novel protein, termed PB1-F2, a mitochondrial protein that can induce cell death. Many proapoptotic proteins are believed to act at the mitochondrial outer membrane to form an apoptotic pore with lipids. We studied the interaction of isolated, synthetic PB1-F2 (sPB1-F2) peptide with planar phospholipid bilayer membranes. The presence of nanomolar concentrations of peptide in the bathing solution induced a transmembrane conductance that increased in a potential-dependent manner. Positive potential on the side of protein addition resulted in a severalfold increase in the rate of change of membrane conductance. sPB1-F2-treated membranes became permeable to monovalent cations, chloride, and to a lesser extent, divalent ions. Despite various experimental conditions, we did not detect the distinctive conductance levels typical of large, stable pores, protein channels, or even pores that are partially proteinaceous. Rather, membrane conductance induced by sPB1-F2 fluctuated and visited almost all conductance values. sPB1-F2 also dramatically decreased bilayer stability in an electric field, consistent with a decrease in the line tension of a lipidic pore. Since similar membrane-destabilizing profiles are seen with proapoptotic proteins (e.g., Bax) and the cytoplasmic helix of human immunodeficiency virus gp41, we suggest that the basis for sPB1-F2-induced cell death may be the permeabilization and destabilization of mitochondrial membranes, leading to macromolecular leakage and apoptosis. C1 NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. Univ Hamburg, Heinrich Pette Inst Expt Virol & Immunol, Hamburg, Germany. Univ Erlangen Nurnberg, Inst Clin & Mol Virol, Erlangen, Germany. Humboldt Univ, Inst Biochem, Berlin, Germany. Univ Basque Country, Unidad Biofis, CSIC, Ctr Mixto, E-48080 Bilbao, Spain. RP Zimmerberg, J (reprint author), NICHHD, Lab Cellular & Mol Biophys, NIH, Bldg 10,Room 10D14, Bethesda, MD 20892 USA. EM joshz@helix.nih.gov RI yewdell, jyewdell@nih.gov/A-1702-2012; Basanez, Gorka/L-9509-2014 OI Basanez, Gorka/0000-0002-7475-7861 NR 30 TC 98 Z9 105 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2004 VL 78 IS 12 BP 6304 EP 6312 DI 10.1128/JVI.78.12.6304-6312.2004 PG 9 WC Virology SC Virology GA 825QC UT WOS:000221772000024 PM 15163724 ER PT J AU Ansarah-Sobrinho, C Moss, B AF Ansarah-Sobrinho, C Moss, B TI Role of the 17 protein in proteolytic processing of vaccinia virus membrane and core components SO JOURNAL OF VIROLOGY LA English DT Article ID SWINE-FEVER VIRUS; VIRION COMPONENT; CONSERVED MOTIF; MORPHOGENESIS; GENE; MATURATION; EXPRESSION; IDENTIFICATION; RIFAMPICIN; CLEAVAGE AB Certain core and membrane proteins of vaccinia virus undergo proteolytic cleavage at consensus AG/X sites. The processing of core proteins is coupled to morphogenesis and is inhibited by the drug rifampin, whereas processing of the A17 membrane protein occurs at an earlier stage of assembly and is unaffected by the drug. A temperature-sensitive mutant with a lesion in the 17L gene exhibits blocks in morphogenesis and in cleavage of core proteins. We found that the mutant also failed to cleave the A17 membrane protein. To further investigate the role of the putative 17 protease, we constructed a conditional lethal mutant in which the 17L gene was regulated by the Escherichia coli lac repressor. In the absence of an inducer, the synthesis of 17 was repressed, proteolytic processing of the A17 membrane protein and the L4 core protein was inhibited, and virus morphogenesis was blocked. Under these conditions, expression of the wild-type 17 protein in trans restored protein processing. In contrast, rescue did not occur when the putative protease active site residue histidine 241 or cysteine 328 of 17 was converted to alanine. The mutation of an authentic AG/A and an alternative AG/S motif of L4 prevented substrate cleavage. Similarly, when AG/X sites of A17 were mutated, 17-induced cleavages at the N and C termini failed to occur. In conclusion, we provide evidence that 17 is a viral protease that is required for AG/X-specific cleavages of viral membrane and core proteins, which occur at early and late stages of virus assembly, respectively. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. George Washington Univ, Grad Program, Dept Genet, Washington, DC 20052 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 4 Ctr Dr,MSC 0445, Bethesda, MD 20892 USA. EM bmoss@nih.gov NR 30 TC 53 Z9 56 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2004 VL 78 IS 12 BP 6335 EP 6343 DI 10.1128/JVI.78.12.6335-6343.2004 PG 9 WC Virology SC Virology GA 825QC UT WOS:000221772000027 PM 15163727 ER PT J AU Peterson, KE Errett, JS Wei, T Dimcheff, DE Ransohoff, R Kuziel, WA Evans, L Chesebro, B AF Peterson, KE Errett, JS Wei, T Dimcheff, DE Ransohoff, R Kuziel, WA Evans, L Chesebro, B TI MCP-1 and CCR2 contribute to non-lymphocyte-mediated brain disease induced by Fr98 polytropic retrovirus infection in mice: Role for Astrocytes in retroviral neuropathogenesis SO JOURNAL OF VIROLOGY LA English DT Article ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; CENTRAL-NERVOUS-SYSTEM; CHEMOKINE RECEPTOR 2; NEURAL STEM-CELLS; CELLULAR-LOCALIZATION; CEREBROSPINAL-FLUID; ALZHEIMERS-DISEASE; VIRUS-INFECTION; HIV-1 INFECTION; BORNA-DISEASE AB Virus infection of the central nervous system (CNS) often results in chemokine upregulation. Although often associated with lymphocyte recruitment, increased chemokine expression is also associated with non-lymphocyte-mediated CNS disease. In these instances, the effect of chemokine upregulation on neurological disease is unclear. In vitro, several chemokines including monocyte chemotactic protein 1 (MCP-1) protect neurons from apoptosis. Therefore, in vivo, chemokine upregulation may be a protective host response to CNS damage. Alternatively, chemokines may contribute to pathogenesis by stimulating intrinsic brain cells or recruiting macrophages to the brain. To investigate these possibilities, we studied a neurovirulent retrovirus, Fr98, that induces severe non-lymphocyte-mediated neurological disease and causes the upregulation of several chemokines that bind to chemokine receptors CCR2 and CCR5. Knockout mice deficient in CCR2 had reduced susceptibility to Fr98 pathogenesis, with significantly fewer mice developing clinical disease than did wild-type controls. In contrast, no reduction in Fr98-induced disease was observed in CCR5 knockout mice. Thus, signaling through CCR2, but not CCR5, plays an important role in Fr98-mediated pathogenesis. Three ligands for CCR2 (MCP-1, MCP-3, and MCP-5) were upregulated during Fr98 infection of the brain. Antibody-blocking experiments demonstrated that MCP-1 was important for retrovirus-induced neurological disease. In situ hybridization analysis revealed that MCP-1 was expressed by glial fibrillary acidic protein-positive astrocytes. Thus, astrocytes, previously not thought to play an effector role in the disease process were found to contribute to pathogenesis through the production of MCP-1. This study also demonstrates that chemokines can mediate pathogenesis in the CNS in the absence of lymphocytic infiltrate and gives credence to the hypothesis that chemokine upregulation is a mechanism by which retroviruses such as human immunodeficiency virus induce neurological damage. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. Cleveland Clin Fdn, Lerner Res Inst, Dept Neurosci, Cleveland, OH 44195 USA. Prot Design Labs Inc, Autoimmune & Inflammat Dis, Fremont, CA 94555 USA. RP Chesebro, B (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM bchesebro@niaid.nih.gov RI Peterson, Karin/D-1492-2016 OI Peterson, Karin/0000-0003-4177-7249 NR 41 TC 32 Z9 34 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2004 VL 78 IS 12 BP 6449 EP 6458 DI 10.1128/JVI.78.12.6449-6458.2004 PG 10 WC Virology SC Virology GA 825QC UT WOS:000221772000038 PM 15163738 ER PT J AU Schmidt, M Katano, H Bossis, L Chiorini, JA AF Schmidt, M Katano, H Bossis, L Chiorini, JA TI Cloning and characterization of a bovine adeno-associated virus SO JOURNAL OF VIROLOGY LA English DT Article ID ADENOVIRUS-ASSOCIATED VIRUSES; SALIVARY-GLANDS; GENE-THERAPY; VECTORS; TYPE-2; PROTEINS; AAV; REP; IDENTIFICATION; TRANSDUCTION AB To better understand the relationship between primate adeno-associated viruses (AAVs) and those of other mammals, we have cloned and sequenced the genome of an AAV found as a contaminant in two isolates of bovine adenovirus that was reported to be serologically distinct from primate AAVs. The bovine AAV (BAAV) genome has 4,693 bp, and its organization is similar to that of other AAV isolates. The left-hand open reading frame (ORF) and both inverted terminal repeats (ITRs) have the highest homology with the rep ORF and ITRs of AAV serotype 5 (AAV-5) (89 and 96%, respectively). However, the right-hand ORF was only 55% identical to the AAV-5 capsid ORF; it had the highest homology with the capsid ORF of AAV-4 (76%). By comparing the BAAV cap sequence with a model of an AAV-4 capsid, we mapped the regions of BAAV VP1 that are divergent from AAV-4. These regions are located on the outside of the capsid and are partially located in exposed loops. BAAV was not neutralized by antisera raised against recombinant AAV-2, AAV-4, or AAV-5, and it demonstrated a unique cell tropism profile in four human cancer cell lines, suggesting that BAAV might have transduction activity distinct from that of other isolates. A murine model of salivary gland gene transfer was used to evaluate the in vivo performance of recombinant BAAV. Recombinant BAAV-mediated gene transfer was I I times more efficient than that with AAV-2. Overall, these data suggest that vectors based on BAAV could be useful for gene transfer applications. C1 Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Chiorini, JA (reprint author), Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, 10-1N113,10 Ctr Dr,MSC1190, Bethesda, MD 20892 USA. EM jchiorini@dir.nidcr.nih.gov RI Bossis, Ioannis/J-6883-2012 NR 35 TC 47 Z9 50 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2004 VL 78 IS 12 BP 6509 EP 6516 DI 10.1128/JVI.78.12.6509-6516.204 PG 8 WC Virology SC Virology GA 825QC UT WOS:000221772000044 PM 15163744 ER PT J AU Heidecker, G Lloyd, PA Fox, K Nagashima, K Derse, D AF Heidecker, G Lloyd, PA Fox, K Nagashima, K Derse, D TI Late assembly motifs of human T-cell leukemia virus type 1 and their relative roles in particle release SO JOURNAL OF VIROLOGY LA English DT Article ID ROUS-SARCOMA-VIRUS; UBIQUITIN-PROTEIN LIGASES; LATE DOMAIN FUNCTION; GAG PROTEIN; MULTIVESICULAR-BODY; BUDDING PROCESS; VP40 PROTEIN; NEDD4 FAMILY; WW DOMAIN; HIV-1 P6 AB Three late assembly domain consensus motifs, namely PTAP, PPPY, and LYPXL, have been identified in different retroviruses. They have been shown to interact with the cellular proteins TSG101, Nedd4, and AP2 or AIP, respectively. Human T-cell leukemia virus type 1 (HTLV-1) has a PPPY and a PTAP motif, separated by two amino acids, located at the end of MA, but only the PPPY motif is conserved in the deltaretrovirus group. Like other retroviral peptides carrying the late motif, MA is mono- or di-ubiquitinated. A mutational analysis showed that 90% of PPPY mutant particles were retained in the cell compared to 15% for the wild-type virus. Mutations of the PTAP motif resulted in a 20% decrease in particle release. In single-cycle infectivity assays, the infectious titers of late motif mutants correlated with the amounts of released virus, as determined by an enzyme-linked immunosorbent assay. We observed binding of MA to the WW domains of the Nedd4 family member WWP1 but not to the amino-terminal ubiquitin E2 variant domain of TSG101 in mammalian two-hybrid analyses. The binding to WWP1 was eliminated when the PPPY motif was mutated. However, MA showed binding to TSG101 in the yeast two-hybrid system that was dependent on an intact PTAP motif. A dominant-negative (DN) mutant of WWP1 could inhibit budding of the intact HTLV-1 virus. In contrast, DN TSG101 only affected the release of virus-like particles encoded by Gag expression plasmids. Electron and fluorescent microscopy showed that Gag accumulates in large patches in the membranes of cells expressing viruses with PPPY mutations. Very few tethered immature particles could be detected in these samples, suggesting that budding is impaired at an earlier step than in other retroviruses. C1 NCI, Basic Res Lab, Mol Biol Retroviruses Sect, Frederick, MD 21702 USA. SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA. SAIC Frederick, Image Anal Lab, Frederick, MD 21702 USA. RP Heidecker, G (reprint author), NCI, Basic Res Lab, Mol Biol Retroviruses Sect, Bldg 567,Rm 155, Frederick, MD 21702 USA. EM heidecke@ncifcrf.gov FU NCI NIH HHS [N01 CO 12400, N01CO12400] NR 66 TC 56 Z9 57 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2004 VL 78 IS 12 BP 6636 EP 6648 DI 10.1128/JVI.78.12.6636-6648.2004 PG 13 WC Virology SC Virology GA 825QC UT WOS:000221772000054 PM 15163754 ER PT J AU Srikanchana, R Xuan, JH Freedman, MT Nguyen, CC Wang, Y AF Srikanchana, R Xuan, JH Freedman, MT Nguyen, CC Wang, Y TI Non-rigid image registration by neural computation SO JOURNAL OF VLSI SIGNAL PROCESSING SYSTEMS FOR SIGNAL IMAGE AND VIDEO TECHNOLOGY LA English DT Article DE non-rigid image registration; mixture of principal axes registration; change analysis; neural computation; multilayer perceptron; control points selection ID EM ALGORITHM; MODEL AB Non-rigid image registration is a prerequisite for many medical image analysis applications such as image fusion of multimodality images and quantitative change analysis of a temporal sequence in computer-aided diagnosis. By establishing the point correspondence of the extracted feature points, it is possible to recover the deformation using nonlinear interpolation methods. However, it may be very difficult to establish such correspondence at an initial stage when confronted with large and complex deformation. In this paper, a mixture of principal axes registration (mPAR) method is proposed to resolve the correspondence problem through a neural computational approach. The novel feature of mPAR is the alignment of two point sets without the need of establishing explicit point correspondence. Instead, it aligns the two point sets by minimizing the relative entropy between their probability distributions resulting in a maximum likelihood estimate of the transformation matrix. The registration process consists of two steps: (1) a finite mixture scheme to establish an improved point correspondence and (2) a multilayer perceptron neural network (MLP) to recover the nonlinear deformation. The neural computation for registration uses a committee machine to obtain a mixture of piece-wise rigid registrations, which gives a reliable point correspondence using multiple extracted objects in a finite mixture scheme. Then the MLP is used to determine the coefficients of a polynomial transform using extracted control points. We have applied our mPAR method to register synthetic data sets, surgical prostate models, and a temporal sequence of mammograms of a single patient. The experimental results show that mPAR not only improves the accuracy of the point correspondence but also results in a desirable error-resilience property for control point selection errors. C1 NCI, Canc Res Ctr, Bethesda, MD 20892 USA. Catholic Univ Amer, Dept Elect Engn & Comp Sci, Washington, DC 20064 USA. Georgetown Univ, Ctr Med, Dept Radiol, Washington, DC 20007 USA. Catholic Univ Amer, Dept Elect Engn & Comp Sci, Washington, DC 20064 USA. Virginia Polytech Inst & State Univ, Dept Elect & Comp Engn, Alexandria, VA 22314 USA. RP NCI, Canc Res Ctr, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 21 TC 3 Z9 3 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0922-5773 J9 J VLSI SIG PROC SYST JI J. VLSI Signal Process. Syst. Signal Image Video Technol. PD JUN-JUL PY 2004 VL 37 IS 2-3 BP 237 EP 246 DI 10.1023/B:VLSI.0000027488.23703.ba PG 10 WC Computer Science, Information Systems; Engineering, Electrical & Electronic SC Computer Science; Engineering GA 833BA UT WOS:000222310200007 ER PT J AU Grim, KC McCutchan, T Li, J Sullivan, M Graczyk, TK McConkey, G Cranfield, M AF Grim, KC McCutchan, T Li, J Sullivan, M Graczyk, TK McConkey, G Cranfield, M TI Preliminary results of an anticircumsporozoite DNA vaccine trial for protection against avian malaria in captive African black-footed penguins (Spheniscus demersus) SO JOURNAL OF ZOO AND WILDLIFE MEDICINE LA English DT Article DE avian malaria; Plasmodium relictum; circumsporozoite; DNA vaccine; Spheniscus demersus; African penguin ID CIRCUMSPOROZOITE PROTEIN; PLASMODIUM; IMMUNIZATION; INFECTIONS; ANTIBODIES AB Captive juvenile African black-footed penguins (Spheniscus demersus) housed in an outdoor enclosure at the Baltimore Zoo have an average 50% mortality from avian malarial (Plasmodium sp.) infection each year without intense monitoring for disease and chemotherapeutic intervention. During the 1996 malaria transmission season, the safety and efficacy of an anti-circumsporozoite (CSP) DNA vaccine encoding the Plasmodium gallinaceum CSP protein against P. relictum were studied. The goal was to reduce clinical disease and death without initiating sterile immunity after release into an area with stable, endemic avian malaria. The birds were monitored for adverse clinical signs associated with vaccination, the stimulation of an anti-CSP antibody response, and protection afforded by the vaccine. The presence of P. relictum in trapped culicine mosquitoes within the penguin enclosure was monitored to assess parasite pressure. Among the vaccinated penguins, the parasitemia rate dropped from approximately 50% to approximately 17% despite intense parasite pressure, as determined by mosquito infection rate. During the year of the vaccine trial, no mortalities due to malaria occurred and no undesirable vaccination side effects occurred. This is the first trial of an antimalarial vaccine in a captive penguin colony. C1 Johns Hopkins Univ, Sch Med, Dept Pathol, Div Comparat Med, Baltimore, MD 21205 USA. NIAID, NIH, Bethesda, MD 20892 USA. St Clares Hosp, Dept Pathol, Denville, NJ 07884 USA. Baltimore Zoo, Dept Med, Baltimore, MD 21217 USA. Univ Leeds, Sch Biol, Leeds LS2 9JT, W Yorkshire, England. RP Cranfield, M (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Div Comparat Med, Baltimore, MD 21205 USA. NR 18 TC 10 Z9 11 U1 2 U2 12 PU AMER ASSOC ZOO VETERINARIANS PI MEDIA PA 6 NORTH PENNELL ROAD, MEDIA, PA 19063 USA SN 1042-7260 J9 J ZOO WILDLIFE MED JI J. Zoo Wildl. Med. PD JUN PY 2004 VL 35 IS 2 BP 154 EP 161 DI 10.1638/03-060 PG 8 WC Veterinary Sciences SC Veterinary Sciences GA 838HI UT WOS:000222703700004 PM 15305509 ER PT J AU Butler, RN Sprott, R Warner, H Bland, J Feuers, R Forster, M Fillit, H Harman, SM Hewitt, M Hyman, M Johnson, K Kligman, E McClearn, G Nelson, J Richardson, A Sonntag, W Weindruch, R Wolf, N AF Butler, RN Sprott, R Warner, H Bland, J Feuers, R Forster, M Fillit, H Harman, SM Hewitt, M Hyman, M Johnson, K Kligman, E McClearn, G Nelson, J Richardson, A Sonntag, W Weindruch, R Wolf, N TI Biomarkers of aging: From primitive organisms to humans SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID GENE-EXPRESSION PROFILE; VITAMIN-E CONSUMPTION; LIFE-SPAN; CAENORHABDITIS-ELEGANS; CALORIC RESTRICTION; ALZHEIMERS-DISEASE; DWARF MICE; IN-VIVO; LONGEVITY; AGE AB Leading biologists and clinicians interested in aging convened to discuss biomarkers of aging. The goals were to come to a consensus, construct an agenda for future research, and make appropriate recommendations to policy makers and the public-at-large. While there was not total agreement on all issues, they addressed a number of questions, among them whether biomarkers can be identified and used to measure the physiological age of any individual within a population, given emerging information about aging and new technological advances. The hurdles to establishing informative biomarkers include the biological variation between individuals that makes generalizations difficult; the overlapping of aging and disease processes; uncertainty regarding benign versus pathogenic age-related changes; the point at which a process begins to do damage to the organism, and, if so, when does it occur; and when to distinguish critical damage from noncritical damage. Finally, and significantly, it is difficult to obtain funding for this research. C1 Int Longev Ctr USA, New York, NY 10028 USA. Ellison Med Fdn, Bethesda, MD USA. NIA, Biol Aging Program, Bethesda, MD USA. Metagen Inc, Gig Harbor, WA, Australia. Natl Ctr Toxicol Res, Jefferson, AR USA. Tex Coll Osteopath Med, Ft Worth, TX USA. Inst Study Aging, New York, NY USA. Kronos Longev Res Inst, Phoenix, AZ USA. Canyon Ranch Hlth Resort, Tucson, AZ USA. Canyon Ranch Bershires, Lenox, MA USA. Desert Life Med Plaza, Tucson, AZ USA. Penn State Univ, Coll Hlth & Human Dev, University Pk, PA 16802 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Wake Forest Univ, Sch Med, Dept Physiol Pharmacol, Winston Salem, NC USA. Univ Wisconsin, Madison, WI USA. Univ Washington, Seattle, WA 98195 USA. RP Butler, RN (reprint author), Int Longev Ctr USA, 60 E 86th St, New York, NY 10028 USA. EM robertb@ilcusa.org NR 56 TC 41 Z9 43 U1 1 U2 5 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUN PY 2004 VL 59 IS 6 BP 560 EP 567 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 834OE UT WOS:000222419600011 ER PT J AU Guralnik, JM AF Guralnik, JM TI Population aging across time and cultures: Can we move from theory to evidence? SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Editorial Material ID COMPRESSION; MORBIDITY C1 NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20815 USA. RP Guralnik, JM (reprint author), NIA, Lab Epidemiol Demog & Biometry, 7201 Wisconsin Ave,Rm 3C-309, Bethesda, MD 20815 USA. EM jg48s@nih.gov NR 11 TC 2 Z9 2 U1 1 U2 1 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUN PY 2004 VL 59 IS 6 BP 606 EP 608 PG 3 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 834OE UT WOS:000222419600023 ER PT J AU Wendler, D AF Wendler, D TI Risk standards for pediatric research: Rethinking the Grimes ruling SO KENNEDY INSTITUTE OF ETHICS JOURNAL LA English DT Article ID V KENNEDY-KRIEGER; DECLARATION; HELSINKI; CHILDREN; ETHICS AB In Grimes v. Kennedy Krieger Institute (KKI), the Maryland Court of Appeals, while noting that U.S. federal regulations include risk standards for pediatric research, endorses its own risk standards. The Grimes case has implications for the debate over whether the minimal risk standard should be interpreted based on the risks in the daily lives of most children (the objective interpretation) or the risks in the daily lives of the children who will be enrolled in a given study (the subjective interpretation). The court's use of the objective interpretation to block studies like the KKI study protects individual children who are worse off than the average child. Unfortunately, this approach also may block research intended to improve the lives of these same individuals. A similar dilemma arises in the context of multinational research, suggesting that a "modified objective standard," proposed to address this dilemma in the multinational setting, may offer a framework for addressing the dilemma in the context of pediatric research as well. C1 NIH, Unit Vulnerable Populat, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Wendler, D (reprint author), NIH, Unit Vulnerable Populat, Dept Clin Bioeth, Bethesda, MD 20892 USA. NR 12 TC 13 Z9 13 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 1054-6863 J9 KENNEDY INST ETHIC J JI Kennedy Inst. Ethics J. PD JUN PY 2004 VL 14 IS 2 BP 187 EP 198 DI 10.1353/ken.2004.0024 PG 12 WC Ethics; Philosophy; Social Issues SC Social Sciences - Other Topics; Philosophy; Social Issues GA 830DF UT WOS:000222101100004 PM 15281189 ER PT J AU Rocco, MV Dwyer, JT Larive, B Greene, T Cockram, DB Chumlea, WC Kusek, JW Leung, J Burrowes, JD McLeroy, SL Poole, D Uhlin, L AF Rocco, MV Dwyer, JT Larive, B Greene, T Cockram, DB Chumlea, WC Kusek, JW Leung, J Burrowes, JD McLeroy, SL Poole, D Uhlin, L CA HEMO Study Grp TI The effect of dialysis dose and membrane flux on nutritional parameters in hemodialysis patients: Results of the HEMO Study SO KIDNEY INTERNATIONAL LA English DT Article DE clinical trial; serum albumin; body weight; hemodialysis; protein intake; energy intake; anthropometry ID PROTEIN-INTAKE; SERUM-ALBUMIN; MAINTENANCE HEMODIALYSIS; METABOLIC-ACIDOSIS; DIETARY-INTAKE; BASE-LINE; MALNUTRITION; MORTALITY; RISK; BIOCOMPATIBILITY AB Background. The effect of standard or high dialysis dose and low or high dialysis flux on nutritional status was ascertained in 1846 maintenance hemodialysis patients enrolled in the HEMO Study. Methods. Serum albumin levels, equilibrated protein catabolic rate, and postdialysis weight were obtained monthly, while adjusted protein and energy intake, self-reported appetite assessment, upper arm circumference, and calf circumference were obtained yearly. To account for patient attrition due to death or transfer, three statistical models were used to test the effects of the study interventions on longitudinal changes in nutritional parameters. Results. During the first 3 years of follow-up, neither mean serum albumin levels, which declined by 0.21 g/dL, nor mean postdialysis weight, which declined by 2.7 kg, were significantly affected by either study intervention. Mean levels of all anthropometric measures declined during follow-up. For years 1, 2, and 3, the mean SE declines in upper arm and calf circumferences were 0.35 0.16 cm (P=0.031) and 0.31+/-0.13 (P=0.015) cm less, respectively, in the high flux compared to the low flux group. Appetite scores and mean equilibrated protein catabolic rate also declined in all randomized groups; however, the average decline in equilibrated protein catabolic rate during years 1, 2, and 3 was 0.019+/-0.007 g/kg/day less in the high dose than the standard dose group (P=0.007). There was no significant change in either mean energy or protein intake from diet records over time, and neither parameter was affected by the study interventions. Conclusion. Although the dose and flux interventions may subtly influence certain nutritional parameters, neither intervention prevented deterioration in nutritional status over time. C1 Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Nephrol Sect, Winston Salem, NC 27157 USA. Tufts Univ, Sch Med & Nutr, Dept Med, Boston, MA 02111 USA. Tufts Univ, Sch Med & Nutr, Dept Community Hlth, Boston, MA 02111 USA. Cleveland Clin Fdn, Dept Biostat & Epidemiol, Cleveland, OH 44195 USA. Abbott Labs, Med & Regulatory Affairs, Ross Prod Div, Columbus, OH USA. Wright State Univ, Sch Med, Kettering, OH USA. NIDDK, HEMO Study, NIH, Div Kidney Urol & Hematol Dis, Bethesda, MD USA. Tufts Univ New England Med Ctr, Frances Stern Nutr Ctr, Boston, MA 02111 USA. Long Isl Univ, Brookville, NY USA. Vanderbilt Univ, Med Ctr, Nashville, TN USA. Piedmont Dialysis Ctr, Winston Salem, NC USA. Tufts Univ New England Med Ctr, Boston, MA 02111 USA. RP Rocco, MV (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Nephrol Sect, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM mrocco@wfubmc.edu OI Dwyer, Johanna/0000-0002-0783-1769 FU NIDDK NIH HHS [5 U01 DK49271] NR 63 TC 78 Z9 85 U1 0 U2 2 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JUN PY 2004 VL 65 IS 6 BP 2321 EP 2334 DI 10.1111/j.1523-1755.2004.00647.x PG 14 WC Urology & Nephrology SC Urology & Nephrology GA 823NT UT WOS:000221620600034 PM 15149346 ER PT J AU Maddala, R Deng, PF Costello, JM Wawrousek, EF Zigler, JS Rao, VP AF Maddala, R Deng, PF Costello, JM Wawrousek, EF Zigler, JS Rao, VP TI Impaired cytoskeletal organization and membrane integrity in lens fibers of a Rho GTPase functional knockout transgenic mouse SO LABORATORY INVESTIGATION LA English DT Article DE actin cytoskeleton; C3-exoenzyme; cell junctions; microarray; Rho GTPases; transgenic lens ID FAMILY GTPASES; EPITHELIAL-CELLS; BINDING PROTEINS; ACTIVATION; DIFFERENTIATION; EXPRESSION; CATARACTS; ADHESION; REORGANIZATION; COTRANSPORTER AB To investigate the effects of Rho GTPase inactivation on lens fiber cell cytoskeletal and morphological integrity, a transgenic mouse model expressing C3-exoenzyme (a bacterial toxin) in a lens-specific manner was utilized. Cryosections of whole eyes from C3 transgenic mice and littermate controls were stained for F-actin with rhodamine-phalloidin or immunostained for beta-catenin, aquaporin-0 or connexin-50, and confocal images were recorded. Lens fiber cell morphology was examined at both light and electron microscopic levels. To investigate the influence of Rho GTPase inactivation on the profiles of gene expression, cDNA libraries generated from transgenic and littermate control mouse lenses were screened by cDNA microarray analysis. In contrast to the wild-type lens, fiber cells of the transgenic lens were grossly swollen and disorganized, with abnormal membrane architecture. Staining of F-actin, beta-catenin, aquaporin-0 and connexin-50 was reduced dramatically in the C3 transgenic lens as compared to controls. Western blot analysis and cDNA microarray analysis did not reveal any noticeable decreases in actin, beta-catenin and aquaporin-0 protein levels or expression in C3 transgenic lenses, indicating that altered cytoskeletal organization in response to Rho GTPase inactivation might underlie the noted changes in staining for these proteins. Additionally, cDNA microarray analysis of C3 lens revealed altered expression (at least two-fold, compared to littermate controls) of 44 genes. These include genes encoding extracellular matrix and basement membrane proteins, cell survival and apoptotic pathways, and ion and protein transport. These data indicate that disruption of Rho GTPase function in the developing mouse lens results in abnormal cytoskeletal organization, fiber cell interactions, impaired lens fiber cell morphology and altered gene expression of cellular proteins involved in diverse functions. This work reveals that the morphological and cytoskeletal abnormalities triggered upon Rho GTPase inactivation in lens could be one of the important insults associated with cataract formation in C3 transgenic mouse lens. C1 Duke Univ, Med Ctr, Dept Ophthalmol, Durham, NC 27710 USA. Univ N Carolina, Dept Cell & Dev Biol, Chapel Hill, NC USA. NEI, NIH, Bethesda, MD 20892 USA. Duke Univ, Sch Med, Dept Pharmacol & Canc Biol, Durham, NC USA. RP Rao, VP (reprint author), Duke Univ, Med Ctr, Dept Ophthalmol, Box 3802, Durham, NC 27710 USA. EM rao00011@mc.duke.edu RI Wawrousek, Eric/A-4547-2008 FU NEI NIH HHS [EY013573, R01-EY12201] NR 42 TC 33 Z9 33 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD JUN PY 2004 VL 84 IS 6 BP 679 EP 692 DI 10.1038/labinvest.3700105 PG 14 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 840CJ UT WOS:000222834300004 PM 15094715 ER PT J AU Leon, F Roy, G AF Leon, F Roy, G TI Isolation of human small bowel intraepithelial lymphocytes by Annexin V-coated magnetic beads SO LABORATORY INVESTIGATION LA English DT Article DE human IEL isolation; Annexin-V; EATL; celiac sprue ID CELIAC-DISEASE; FLOW-CYTOMETRY; GAMMA-DELTA; HUMAN GUT; BIOPSIES; SUBSETS AB Human intestinal intraepithelial lymphocytes (IEL) are important effector cells of the mucosal immune system and their study is hampered by the difficulty of their isolation. The molecular study of enriched samples of IEL is mandatory in the diagnosis of enteropathy-associated T-cell lymphoma and refractory celiac sprue. In order to isolate human small bowel IEL, we took advantage of the stress that intestinal epithelial cells (IEC) suffer during the conventional initial steps of IEL isolation, which induces their apoptosis but not that of IEL. After cell individualization by dithiothreitol and ethylenediamine tetraacetic acid, two-thirds of human IEC can be stained with Annexin-V due to their surface exposure of phosphatidyl serine, a sign of apoptosis. This percentage increases to 95% after performing a density gradient to enrich for IEL. This allows for the use of Annexin-V-coated magnetic beads, originally designed for the removal of dead cells from cell cultures, to obtain >95% pure, 99% viable and untouched IEL after two rounds of depletion. This simple procedure has proven useful for the isolation of human IEL for functional and molecular studies and can conceivably facilitate the diagnosis of intestinal lymphoid malignancies that rely upon the study of pure IEL preparations. C1 Hosp Ramon y Cajal, Dept Immunol, E-28034 Madrid, Spain. RP Leon, F (reprint author), NIAID, Lab Mol Immunol, NIH, 10 Ctr Dr,Bldg 10,Room 11N214, Bethesda, MD 20892 USA. EM fleon@niaid.nih.gov NR 16 TC 9 Z9 10 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD JUN PY 2004 VL 84 IS 6 BP 804 EP 809 DI 10.1038/labinvest.3700099 PG 6 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 840CJ UT WOS:000222834300015 PM 15154017 ER PT J AU Suscovich, TJ Paulose-Murphy, M Harlow, JD Chen, YD Thomas, SY Mellott, TJ Walker, BD Scadden, DT Zeichner, S Brander, C AF Suscovich, TJ Paulose-Murphy, M Harlow, JD Chen, YD Thomas, SY Mellott, TJ Walker, BD Scadden, DT Zeichner, S Brander, C TI Defective immune function of primary effusion lymphoma cells is associated with distinct KSHV gene expression profiles SO LEUKEMIA & LYMPHOMA LA English DT Article DE PEL; KSHV; immune phenotype; immune evasion ID SARCOMA-ASSOCIATED HERPESVIRUS; EPSTEIN-BARR-VIRUS; MULTICENTRIC CASTLEMANS-DISEASE; MICROVASCULAR ENDOTHELIAL-CELLS; 8 DNA-SEQUENCES; KAPOSIS-SARCOMA; MEDIATED CYTOTOXICITY; PERIPHERAL-BLOOD; DOWN-REGULATION; T-CELLS AB Primary effusion lymphomas (PEL) are uniformly infected with Kaposi's sarcoma-associated herpesvirus (KSHV), and thus likely present both tumor and viral antigens to the immune system. In order to grow unrestricted and cause disease, multiple immune evasion strategies may be utilized by PEL to evade immune surveillance. Using six well-established PEL cell lines and comparing these to Epstein-Barr virus-transformed B cell lines and peripheral blood B cells, significant differences were found in the surface expression of molecules involved in antigen presentation, T cell activation and cell-cell adhesion. Significantly reduced stimulation of cytotoxic T lymphocytes, lowered sensitivity to natural killer cell-mediated lysis and impaired function as antigen presenting cells in mixed leukocyte reactions were found for three PEL cell lines with particularly low CD54, CD58 and CD81 expression. Comparative microarray analysis demonstrated specific patterns of KSHV-encoded gene expression that were associated with the different immune functions of these cell lines. Thus, the present data suggest that distinct patterns of KSHV gene expression may be associated with particular phenotypic and functional characteristics of PEL cells, which may influence PEL pathogenesis. C1 Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02129 USA. NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA. Harvard Univ, Sch Med, Boston, MA 02129 USA. Boston Univ, Sch Med, Lab Med, Boston, MA 02118 USA. RP Brander, C (reprint author), Partners AIDS Res Ctr, 149 13th St,Room 5239, Charlestown, MA 02129 USA. EM brander@helix.mgh.harvard.edu OI Brander, Christian/0000-0002-0548-5778; Thomas, Seddon/0000-0003-0075-0744 FU NCI NIH HHS [CA73580, CA78378] NR 69 TC 8 Z9 9 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD JUN PY 2004 VL 45 IS 6 BP 1223 EP 1238 DI 10.1080/10428190310001643358 PG 16 WC Oncology; Hematology SC Oncology; Hematology GA 819FV UT WOS:000221301100021 PM 15360006 ER PT J AU Murdock, J Jaffe, ES Wilson, WH McManus, DT Alexander, HD Morris, TCM AF Murdock, J Jaffe, ES Wilson, WH McManus, DT Alexander, HD Morris, TCM TI Aggressive natural killer cell leukemia/lymphoma: Case report, use of Telesynergy (TM) and review of the literature SO LEUKEMIA & LYMPHOMA LA English DT Review DE ANKL; EBV; chemotherapy; immunotherapy; telemedicine ID EPSTEIN-BARR-VIRUS; GRANULAR LYMPHOCYTE LEUKEMIA; T-CELL; NK CELL; MEDIATED CYTOTOXICITY; FAS LIGAND; LYMPHOMAS; INFECTION; NASAL; LEUKAEMIA/LYMPHOMA AB Natural killer cell malignancies, although increasingly recognized, remain rare tumors within the USA and Europe. They are somewhat more common in Asia, and have been best characterized within this population. We present a case of a young Caucasian woman who presented acutely with an aggressive natural killer cell leukemia/lymphoma. Use of Telesynergy(TM) technology enabled a transatlantic telemedicine conference with colleagues in a center of expertise. Unfortunately the patient was ultimately refractory to both conventional chemotherapy and Campath-1H and her disease course was fulminant, as has been described previously in this condition. We review the possible therapeutic options for this extremely aggressive malignancy and briefly discuss our center's experience of telemedicine technology. C1 Belfast City Hosp, Dept Haematol, Belfast BT9 7AB, Antrim, North Ireland. NIH, Bethesda, MD 20892 USA. Belfast City Hosp, Dept Histopathol, Belfast BT9 7AB, Antrim, North Ireland. RP Morris, TCM (reprint author), Belfast City Hosp, Dept Haematol, Level C,Lisburn Rd, Belfast BT9 7AB, Antrim, North Ireland. EM curly.morris@bll.n-i.nhs.uk NR 28 TC 10 Z9 10 U1 0 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD JUN PY 2004 VL 45 IS 6 BP 1269 EP 1273 DI 10.1080/10428190310001646879 PG 5 WC Oncology; Hematology SC Oncology; Hematology GA 819FV UT WOS:000221301100026 PM 15360011 ER PT J AU Broun, K AF Broun, K TI New dog, old trick: Alerts for RSS feeds SO LIBRARY JOURNAL LA English DT Article C1 NCI, Elect Informat & Lib Serv, Commun Serv Branch, Bethesda, MD 20892 USA. RP Broun, K (reprint author), NCI, Elect Informat & Lib Serv, Commun Serv Branch, Bethesda, MD 20892 USA. EM kbroun@nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU BOWKER MAGAZINE GROUP CAHNERS MAGAZINE DIVISION PI NEW YORK PA 249 W 17TH ST, NEW YORK, NY 10011 USA SN 0363-0277 J9 LIBR J JI Libr. J. PD SUM PY 2004 SU S BP 18 EP + PG 2 WC Information Science & Library Science SC Information Science & Library Science GA 839YI UT WOS:000222820500005 ER PT J AU Chen, Z Dunson, DB AF Chen, Z Dunson, DB TI Bayesian estimation of survival functions under stochastic precedence SO LIFETIME DATA ANALYSIS LA English DT Article DE censoring; order restriction; categorical data; Gibbs sampler; stochastic order; survival analysis; Kaplan-Meier estimates ID NONPARAMETRIC-ESTIMATION; INFERENCE; VARIABLES AB When estimating the distributions of two random variables, X and Y; investigators often have prior information that Y tends to be bigger than X. To formalize this prior belief, one could potentially assume stochastic ordering between X and Y; which implies Pr(X less than or equal to z) greater than or equal to Pr(Y less than or equal to z) for all z in the domain of X and Y: Stochastic ordering is quite restrictive, though, and this article focuses instead on Bayesian estimation of the distribution functions of X and Y under the weaker stochastic precedence constraint, Pr(X less than or equal to Y) greater than or equal to 0.5. We consider the case where both X and Y are categorical variables with common support and develop a Gibbs sampling algorithm for posterior computation. The method is then generalized to the case where X and Y are survival times. The proposed approach is illustrated using data on survival after tumor removal for patients with malignant melanoma. C1 Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Chen, Z (reprint author), Univ Penn, Dept Biostat & Epidemiol, 625 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM zchen@cceb.upenn.edu NR 19 TC 4 Z9 4 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1380-7870 J9 LIFETIME DATA ANAL JI Lifetime Data Anal. PD JUN PY 2004 VL 10 IS 2 BP 159 EP 173 DI 10.1023/B:LIDA.0000030201.12943.13 PG 15 WC Mathematics, Interdisciplinary Applications; Statistics & Probability SC Mathematics GA 826RD UT WOS:000221845300004 PM 15293630 ER PT J AU Yang, MH Coles, BF Caporaso, NE Choi, Y Lang, NP Kadlubar, FF AF Yang, MH Coles, BF Caporaso, NE Choi, Y Lang, NP Kadlubar, FF TI Lack of association between Caucasian lung cancer risk and O-6-methylguanine-DNA methyltransferase-codon 178 genetic polymorphism SO LUNG CANCER LA English DT Article DE MGMT; codon 178; genetic polymorphism; lung cancer; RFLP ID O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; EXPRESSION; IDENTIFICATION; TUMORIGENESIS; ADDUCTS; MICE AB The formation of DNA adducts is thought to be a critical step for the induction of chemically induced cancer. O-6-Methylguanine-DNA methyltransferase (MGMT) is a ubiquitously expressed enzyme that repairs DNA adducts formed by alkylating carcinogens. Thus, genetic polymorphisms of the MGMT that could result in differences in MGMT activity are potential risk factors for cancer. In the present study, we established a convenient and reliable genotyping method for the MGMT codon 178 polymorphism, a Lys (AAG) to Arg (AGG) substitution, using restriction fragment length polymorphism (RFLP), and studied differences in the distribution of this polymorphism in 92 Caucasian lung cancer patients and 85 controls. Frequencies of the "A" and "G" alleles (MGMT codon 178, AAG and AGG, respectively) were 0.91 and 0.09, respectively. The genetic polymorphism of the MGMT codon 178 was linked with that of the MGMT codon 143 (P < 0.05). The distribution of the MGMT codon 178 genetic polymorphism was not significantly different between lung cancer patients and controls. Thus, our study suggests that the MGMT codon 178 (and possibly 143) polymorphisms do not appear to markedly affect lung cancer risk for this population. In addition, we found an apparent 10 bp-deletion in the intron before exon 5 by DNA sequencing. Because this "deletion" was observed in all sequenced samples (N = 20), the previously reported human (Caucasian) MGMT gene sequence should be revised to exclude this 10 by segment. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 Seoul Natl Univ, Coll Med, Inst Canc Res, Dept Prevent Med, Seoul 110799, South Korea. Natl Ctr Toxicol Res, Div Mol Epidemiol, Jefferson, AR 72079 USA. NCI, NIH, Bethesda, MD 20892 USA. Cent Arkansas Vet Hlth Care Syst, Little Rock, AR 72205 USA. RP Yang, MH (reprint author), Seoul Natl Univ, Coll Med, Inst Canc Res, Dept Prevent Med, 28 Yongondong, Seoul 110799, South Korea. EM myang@snu.ac.kr NR 24 TC 26 Z9 28 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0169-5002 J9 LUNG CANCER-J IASLC JI Lung Cancer PD JUN PY 2004 VL 44 IS 3 BP 281 EP 286 DI 10.1016/j.lungcan.2003.12.003 PG 6 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 824MN UT WOS:000221690800002 PM 15140540 ER PT J AU Interewicz, B AF Interewicz, B TI Profiling of normal human leg lymph proteins using the 2-D electrophoreses and SELDI-Tof mass spectrophotometry approach SO LYMPHOLOGY LA English DT Article ID PERIPHERAL LYMPH; NORMAL MEN; COMPLEMENT; TRANSPORT; FLUID AB The parenchymatous cells are supplied by nutrients transported in fluid from blood across the capillary wall. This fluid, called tissue fluid (TF), contains proteins originating from plasma as well as those synthesized and secreted by tissue cells. The protein composition of TF remains largely unknown. The TF which has entered lymphatics is called lymph (L). Harvesting L and measuring its proteins concentrations and identifying them provide an insight into biochemical processes in the TF. Here we describe our initial evaluation of the normal human prenodal L protein profile of m.w. 2.5 to 12.5kDa using the ProteinChip SELDI MS system and compare it with that of plasma (P) protein. This is the first study in the literature providing evidence for the presence of the so far non-identified proteins in L as well as proteins identified in L but absent from P and conversely present in P but not in L. Evident differences between paired L and P samples have been found, along with similarities. Thirteen proteins were detected in P and seven in L in the region of 2.5 to 12.5 kDa. Five identical proteins, although of different relative intensity, were found in L and P. The proteins specific for L but not P had 70 70 and 8619 ion values. P proteins absent from L were of 3890, 3969, 4078, 6863, 7676, 7778, 7847 and 7937 ion values. In addition to detecting some so far unknown proteins in L, these preliminary findings throw a new light on our understanding of the mechanism of transcapillary transport of low m.w. proteins. They challenge the commonly accepted notion of unlimited free diffusion of peptides across the capillary membrane. C1 Polish Acad Sci, Dept Surg Res & Transplantol, Med Res Ctr, PL-02116 Warsaw, Poland. US FDA, CBER, Clin Proteom Program Therapeut Prot, Bethesda, MD 20014 USA. NCI, Pathol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Interewicz, B (reprint author), Polish Acad Sci, Dept Surg Res & Transplantol, Med Res Ctr, Pawinski Str 5, PL-02116 Warsaw, Poland. EM wlo@cmdik.pan.pl NR 12 TC 14 Z9 15 U1 0 U2 0 PU LYMPHOLOGY PI TUCSON PA C/O C L WITTE MD 1501 N CAMPBELL AVE DEPT SURGERY, TUCSON, AZ 85724 USA SN 0024-7766 J9 LYMPHOLOGY JI Lymphology PD JUN PY 2004 VL 37 IS 2 BP 65 EP 72 PG 8 WC Immunology; Physiology SC Immunology; Physiology GA 839YE UT WOS:000222820100006 PM 15328759 ER PT J AU Basyuk, E Lavoie, B Bordonne, M Bertrand, E AF Basyuk, E Lavoie, B Bordonne, M Bertrand, E TI RNA localization in the cytoplasm SO M S-MEDECINE SCIENCES LA French DT Review ID ASH1 MESSENGER-RNA; 3' UNTRANSLATED REGION; ASYMMETRIC LOCALIZATION; BINDING PROTEIN; DROSOPHILA-MELANOGASTER; APICAL LOCALIZATION; MYOSIN MOTOR; YEAST; TRANSLATION; VIRUS AB RNA localization in subcytoplasmic areas is a process known for more than twenty years, and more than a hundred RNAs have now been shown to be spatially regulated. In most cases, RNA localization is involved in cell polarity, either by reading spatial clues and translating them into a spatial regulation of gene expression, or more directly by controlling cytoskeletal polarity. In this review, the various functions of RNA localization will be presented, and by analyzing two examples, Ash1 mRNA in yeast and retroviral genomic RNAs in mammals, the reader will be taken step by step into the detailed mechanisms of this fascinating process. C1 Univ Montpellier 2, CNRS, IGMM, UMR 5535, F-34293 Montpellier 5, France. NINDS, Mol Plast Sect, Bethesda, MD 20892 USA. RP Basyuk, E (reprint author), Univ Montpellier 2, CNRS, IGMM, UMR 5535, 1919 Route Mende, F-34293 Montpellier 5, France. EM bertrand@igm.cnrs-mop.fr NR 38 TC 1 Z9 2 U1 0 U2 1 PU MASSON EDITEUR PI MOULINEAUX CEDEX 9 PA 21 STREET CAMILLE DESMOULINS, ISSY, 92789 MOULINEAUX CEDEX 9, FRANCE SN 0767-0974 J9 M S-MED SCI JI M S-Med. Sci. PD JUN-JUL PY 2004 VL 20 IS 6-7 BP 669 EP 673 DI 10.1051/medsci/2004206-7669 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 841QD UT WOS:000222945500018 PM 15329817 ER PT J AU Choi, IY Lee, SP Merkle, H Shen, J AF Choi, IY Lee, SP Merkle, H Shen, J TI Single-shot two-echo technique for simultaneous measurement of GABA and creatine in the human brain in vivo SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE MRS; localization; GABA; Cr; human brain in vivo ID GAMMA-AMINOBUTYRIC-ACID; MAGNETIC-RESONANCE SPECTROSCOPY; HUMAN CEREBRAL GABA; QUANTUM FILTER; PULSES; LOCALIZATION; METABOLITES AB A single-shot, two-echo method for the simultaneous detection of multiple-quantum (MQ)-filtered gamma-aminobutyric acid (GABA) and creatine (Cr) was developed and demonstrated in the human brain in vivo at 3 Tesla. The simultaneously measured Cr singlet served as a navigator for the spectral phase of GABA and any frequency shift during measurements due to drift in the static magnetic field (B-0) or subject movement, as well as an internal concentration reference. In addition, the use of a double-band frequency-selective MO filter for C-3 and C-4 methylene protons of GABA provided a very robust measurement of GABA, with excellent suppression of overlapping metabolites such as Cr and glutathione (GSH) in each single scan. Contamination from overlapping macromolecules was also demonstrated to be negligible with this method. The GABA-to-Cr ratio was 0.09 +/- 0.03 (mean +/- SD, N = 17) and the estimated concentration of GABA in the frontoparietal region of the human brain in vivo was 0.66 +/- 0.19 mumol/g (mean +/- SD, N = 17) with the internal reference method, and 0.69 +/- 0.18 mumol/g (mean +/- SD, N = 17) with the external reference method. The observed pattern of GABA doublet was consistent among all subjects, with a frequency separation of similar to13 Hz. Published 2004 Wiley-Liss, Inc. C1 Nathan S Kline Inst, Orangeburg, NY 10962 USA. NINDS, NIH, Bethesda, MD 20892 USA. NIMH, NIH, Bethesda, MD 20892 USA. RP Choi, IY (reprint author), Nathan S Kline Inst, 140 Old Orangeburg Rd,Bldg 35, Orangeburg, NY 10962 USA. OI Lee, Phil/0000-0002-2087-8887 FU NIA NIH HHS [R03AG022193]; NIBIB NIH HHS [8R01EB00315] NR 26 TC 28 Z9 30 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD JUN PY 2004 VL 51 IS 6 BP 1115 EP 1121 DI 10.1002/mrm.20082 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 826NN UT WOS:000221835900005 PM 15170830 ER PT J AU Faranesh, AZ Nastley, MT de la Cruz, CP Haller, MF Laquerriere, P Leong, KW McVeigh, ER AF Faranesh, AZ Nastley, MT de la Cruz, CP Haller, MF Laquerriere, P Leong, KW McVeigh, ER TI In vitro release of vascular endothelial growth factor from gadolinium-doped biodegradable microspheres SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE gadolinium; vascular endothelial growth factor; contrast media; drug delivery ID POLY(LACTIDE-CO-GLYCOLIDE) MICROSPHERES; CONTROLLED DELIVERY; ACID) MICROSPHERES; SUSTAINED-RELEASE; POLYLACTIC-ACID; DRUG-DELIVERY; PROTEINS; MICROPARTICLES; ARTERIOGENESIS; ANGIOGENESIS AB A drug delivery vehicle was constructed that could be visualized noninvasively with MRI. The biodegradable polymer poly(DL-lactic-co-glycolic acid) (PLGA) was used to fabricate microspheres containing vascular endothelial growth factor (VEGF) and the MRI contrast agent gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA). The microspheres were characterized in terms of size, drug and contrast agent encapsulation, and degradation rate. The PLGA microspheres had a mean diameter of 48 +/- 18 mum. The gadolinium loading was 17 +/- 3 mug/mg polymer and the VEGF loading was 163 +/- 22 ng/mg polymer. Electron microscopy revealed that the Gd was dispersed throughout the microspheres and it was confirmed that the Gd loading was sufficient to visualize the microspheres under MRI. VEGF and Gd-DTPA were released from the microspheres in vitro over a period of similar to6 weeks in three phases: a burst, followed by a slow steady-state, then a rapid steady-state. Biodegradable Gd-doped microspheres can be effectively used to deliver drugs in a sustained manner, while being monitored noninvasively with MRI. Published 2004 Wiley-Liss, Inc. C1 NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. NIH, Supramol Struct & Funct Resource, Off Res Serv, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA. RP Faranesh, AZ (reprint author), NHLBI, Cardiac Energet Lab, NIH, Bldg 10,10 Ctr Dr,Bldg 10,Room B1D416, Bethesda, MD 20892 USA. EM faranesh@nih.gov RI Leong, Kam/A-7270-2009; Laquerriere, Patrice/P-1025-2016 OI Leong, Kam/0000-0002-8133-4955; Laquerriere, Patrice/0000-0001-7637-9094 FU Intramural NIH HHS [Z01 HL004608-08] NR 28 TC 28 Z9 32 U1 1 U2 7 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD JUN PY 2004 VL 51 IS 6 BP 1265 EP 1271 DI 10.1002/mrm/20092 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 826NN UT WOS:000221835900023 PM 15170848 ER PT J AU Smith, DL McKenzie, FE AF Smith, DL McKenzie, FE TI Statics and dynamics of malaria infection in Anopheles mosquitoes SO MALARIA JOURNAL LA English DT Review ID VECTORIAL CAPACITY; BREEDING SITES; MODEL; RATES; TRANSMISSION; POPULATIONS; TANZANIA; GAMBIAE AB The classic formulae in malaria epidemiology are reviewed that relate entomological parameters to malaria transmission, including mosquito survivorship and age-at-infection, the stability index ( S), the human blood index (HBI), proportion of infected mosquitoes, the sporozoite rate, the entomological inoculation rate (EIR), vectorial capacity (C) and the basic reproductive number (R-0). The synthesis emphasizes the relationships among classic formulae and reformulates a simple dynamic model for the proportion of infected humans. The classic formulae are related to formulae from cyclical feeding models, and some inconsistencies are noted. The classic formulae are used to to illustrate how malaria control reduces malaria transmission and show that increased mosquito mortality has an effect even larger than was proposed by Macdonald in the 1950's. C1 NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Smith, DL (reprint author), NIH, Fogarty Int Ctr, Bldg 16, Bethesda, MD 20892 USA. EM smitdave@helix.nih.gov; mckenzel@mail.nih.gov RI Smith, David/L-8850-2013 OI Smith, David/0000-0003-4367-3849 FU Intramural NIH HHS [Z99 TW999999] NR 32 TC 178 Z9 182 U1 1 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD JUN PY 2004 VL 3 AR 13 DI 10.1186/1475-2875-3-13 PG 14 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 840AC UT WOS:000222828400007 PM 15180900 ER PT J AU Baker, H AF Baker, H TI Insider's view of Imaging technology grant review and funding at NCI SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 46th Annual Meeting of the American-Association-of-Physicists-in-Medicine CY JUL 25-29, 2004 CL Pittsburgh, PA SP Amer Assoc Physicists Med C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2004 VL 31 IS 6 BP 1794 EP 1794 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 832HW UT WOS:000222259100391 ER PT J AU Bloch, P Bonan, R Wallner, P Lobdell, J AF Bloch, P Bonan, R Wallner, P Lobdell, J TI Dosimetry for a brachytherapy implant of a hemodialysis graft SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 46th Annual Meeting of the American-Association-of-Physicists-in-Medicine CY JUL 25-29, 2004 CL Pittsburgh, PA SP Amer Assoc Physicists Med C1 Univ Penn, Philadelphia, PA 19104 USA. NCI, Rockville, MD USA. Novoste Corp, Norcross, GA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2004 VL 31 IS 6 BP 1881 EP 1881 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 832HW UT WOS:000222259100788 ER PT J AU Miller, R Ning, H Plazas, M Falkenstien, P Huston, A Justus, B AF Miller, R Ning, H Plazas, M Falkenstien, P Huston, A Justus, B TI Eliminating Cerenkov interference from a real-time optical radiation detector SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 46th Annual Meeting of the American-Association-of-Physicists-in-Medicine CY JUL 25-29, 2004 CL Pittsburgh, PA SP Amer Assoc Physicists Med C1 NCI, Radiat Oncol Branch, CCR, Bethesda, MD 20892 USA. Univ Nacl Colombia, Santafe d Bogata, Colombia. USN, Res Lab, Washington, DC 20350 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2004 VL 31 IS 6 BP 1884 EP 1884 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 832HW UT WOS:000222259100799 ER PT J AU Miller, R Li, G Xie, H Ning, H Citrin, D Guion, P Coleman, CN Menard, C AF Miller, R Li, G Xie, H Ning, H Citrin, D Guion, P Coleman, CN Menard, C TI Image data correction for MR guided HDR prostate brachytherapy SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 46th Annual Meeting of the American-Association-of-Physicists-in-Medicine CY JUL 25-29, 2004 CL Pittsburgh, PA SP Amer Assoc Physicists Med C1 NCI, Radiat Oncol Branch, CCR, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2004 VL 31 IS 6 BP 1889 EP 1889 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 832HW UT WOS:000222259100828 ER PT J AU Skopec, M Price, J Guardala, N Loew, M Moscovitch, M AF Skopec, M Price, J Guardala, N Loew, M Moscovitch, M TI The effect of radiation exposure order on thermoluminescent dosimeter response from mixed photon and proton irradiations SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 46th Annual Meeting of the American-Association-of-Physicists-in-Medicine CY JUL 25-29, 2004 CL Pittsburgh, PA SP Amer Assoc Physicists Med C1 NIH, Bethesda, MD 20892 USA. Naval Surface Warfare Ctr, Bethesda, MD USA. George Washington Univ, Washington, DC USA. Georgetown Univ, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2004 VL 31 IS 6 BP 1920 EP 1920 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 832HW UT WOS:000222259100976 ER PT J AU Hermoso, MA Matsuguchi, T Smoak, K Cidlowski, JA AF Hermoso, MA Matsuguchi, T Smoak, K Cidlowski, JA TI Glucocorticoids and tumor necrosis factor alpha cooperatively regulate Toll-like receptor 2 gene expression SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TOLL-LIKE RECEPTOR-2; NF-KAPPA-B; SIGNAL-TRANSDUCTION; MAPK PHOSPHATASE-1; IMMUNE CELLS; DNA-BINDING; CROSS-TALK; TRANSCRIPTION; STAT5; LIPOPOLYSACCHARIDE AB Tumor necrosis factor alpha (TNF-alpha) and glucocorticoids are widely recognized as mutually antagonistic regulators of adaptive immunity and inflammation. Surprisingly, we show here that they cooperatively regulate components of innate immunity. The Toll-like receptor 2 (TLR2) gene encodes a transmembrane receptor critical for triggering innate immunity. Although TLR2 mRNA and protein are induced by inflammatory molecules such as TNF-alpha, we show that TLR2 is also induced by the anti-inflammatory glucocorticoids in cells where they also regulate MKP-1 mRNA and protein levels. TNF-alpha and glucocorticoids cooperate to regulate the TLR2 promoter, through the involvement of a 3' NF-kappaB site, a STAT-binding element, and a 3' glucocorticoid response element (GRE). Molecular studies show that the IkappaBalpha superrepressor or a STAT dominant negative element prevented TNF-alpha and dexamethasone stimulation of TLR2 promoter. Similarly, an AF-1 deletion mutant of glucocorticoid receptor or ablation of a putative GRE notably reduced the cooperative regulation of TLR2. Using chromatin immunoprecipitation assays, we demonstrate that all three transcription factors interact with both endogenous and transfected TLR2 promoters after stimulation by TNF-alpha and dexamethasone. Together, these studies define novel signaling mechanism for these three transcription factors, with a profound impact on discrimination of innate and adaptive immune responses. C1 Natl Inst Environm Hlth Sci, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. Kagoshima Univ, Grad Sch Med & Dent Sci, Div Biochem & Mol, Kagoshima 890, Japan. Kagoshima Univ, Grad Sch Med & Dent Sect, Kagoshima, Japan. RP Cidlowski, JA (reprint author), Natl Inst Environm Hlth Sci, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. EM cidlowski@niehs.nih.gov NR 38 TC 92 Z9 98 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 2004 VL 24 IS 11 BP 4743 EP 4756 DI 10.1128/MCB.24.11.4743-4756.2004 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 822JX UT WOS:000221536600013 PM 15143169 ER PT J AU Hofmann, SR Lam, AQ Frank, S Zhou, YJ Ramos, HL Kanno, Y Agnello, D Youle, RJ O'Shea, JJ AF Hofmann, SR Lam, AQ Frank, S Zhou, YJ Ramos, HL Kanno, Y Agnello, D Youle, RJ O'Shea, JJ TI Jak3-independent trafficking of the common gamma chain receptor subunit: Chaperone function of Jaks revisited SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID INTERFERON-ALPHA/BETA RECEPTOR; CELL-SURFACE EXPRESSION; TYROSINE KINASE; ERYTHROPOIETIN RECEPTOR; SIGNAL-TRANSDUCTION; PSEUDOKINASE DOMAIN; N-TERMINUS; T-CELLS; DEGRADATION; MUTATIONS AB Janus kinases (Jaks) play an essential role in cytokine signaling and have been reported to regulate plasma membrane expression of their cognate receptors. In this study, we examined whether Jak3 and the common gamma chain (gamma(c)) reciprocally regulate their plasma membrane expression. In contrast to interleukin-2Ralpha, gamma(c) localized poorly to the plasma membrane and accumulated in endosomal-lysosomal compartments. However, gamma(c) was expressed at comparable levels on the surface of cells lacking Jak3, and plasma membrane turnover of gamma(c) was independent of Jak3. Nonetheless, overexpression of Jak3 enhanced accumulation of gamma(c) at the plasma membrane. Without gamma(c), Jak3 localized in the cytosol, whereas in the presence of the receptor, it colocalized with gamma(c) in endosomes and at the plasma membrane. Although the Jak FERM domain is necessary and sufficient for receptor binding, the requirement for full-length Jak3 in gamma(c) membrane trafficking was remarkably stringent; using truncation and deletion mutants, we showed that the entire Jak3 molecule was required, although kinase activity was not. Thus, unlike other cytokine receptors, gamma(c) does not require Jak3 for receptor membrane expression. However, full-length Jak3 is required for normal trafficking of this cytokine receptor/Jak pair, a finding that has important structural and clinical implications. C1 NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Howard Hughes Med Inst, Natl Inst Hlth Res Scholars Program, Bethesda, MD 20817 USA. Univ Bonn, Med Ctr, Dept Neuropathol, D-5300 Bonn, Germany. RP Hofmann, SR (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, 10 Ctr Dr,Bldg 10,Rm 9N256, Bethesda, MD 20892 USA. EM sigrun.hofmann@uniklinikum-dresden.de RI Kanno, Yuka/B-5802-2013; OI Kanno, Yuka/0000-0001-5668-9319 NR 37 TC 37 Z9 38 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 2004 VL 24 IS 11 BP 5039 EP 5049 DI 10.1128/MCB.24.11.5039-5049.2004 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 822JX UT WOS:000221536600038 PM 15143194 ER PT J AU Myung, K Ghosh, G Fattah, FJ Li, G Kim, H Dutia, A Pak, E Smith, S Hendrickson, EA AF Myung, K Ghosh, G Fattah, FJ Li, G Kim, H Dutia, A Pak, E Smith, S Hendrickson, EA TI Regulation of telomere length and suppression of genomic instability in human somatic cells by Ku86 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID STRAND BREAK REPAIR; SEVERE COMBINED IMMUNODEFICIENCY; END-JOINING PATHWAY; V(D)J RECOMBINATION; DNA-DAMAGE; DYSKERATOSIS-CONGENITA; SACCHAROMYCES-CEREVISIAE; MAMMALIAN CHROMOSOMES; CATALYTIC SUBUNIT; BINDING PROTEIN AB Ku86 plays a key role in nonhomologous end joining in organisms as evolutionarily disparate as bacteria and humans. In eukaryotic cells, Ku86 has also been implicated in the regulation of telomere length although the effect of Ku86 mutations varies considerably between species. Indeed, telomeres either shorten significantly, shorten slightly, remain unchanged, or lengthen significantly in budding yeast, fission yeast, chicken cells, or plants, respectively, that are null for Ku86 expression. Thus, it has been unclear which model system is most relevant for humans. We demonstrate here that the functional inactivation of even a single allele of Ku86 in human somatic cells results in profound telomere loss, which is accompanied by an increase in chromosomal fusions, translocations, and genomic instability. Together, these experiments demonstrate that Ku86, separate from its role in nonhomologous end joining, performs the additional function in human somatic cells of suppressing genomic instability through the regulation of telomere length. C1 Univ Minnesota, Sch Med, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55355 USA. NHGRI, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Cytogenet & Confocal Microscopy Core, NIH, Bethesda, MD 20892 USA. RP Hendrickson, EA (reprint author), Univ Minnesota, Sch Med, Dept Biochem Mol Biol & Biophys, 6-155 Jackson Hall,321 Church St SE, Minneapolis, MN 55355 USA. EM hendr064@tc.umn.edu RI Kim, Haeyoung/C-3069-2008 NR 84 TC 67 Z9 70 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 2004 VL 24 IS 11 BP 5050 EP 5059 DI 10.1128/MCB.24.11.5050-5059.2004 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 822JX UT WOS:000221536600039 PM 15143195 ER PT J AU Pendas, AM Folgueras, AR Llano, E Caterina, J Frerard, F Rodriguez, F Astudillo, A Noel, A Birkedal-Hansen, H Lopez-Otin, C AF Pendas, AM Folgueras, AR Llano, E Caterina, J Frerard, F Rodriguez, F Astudillo, A Noel, A Birkedal-Hansen, H Lopez-Otin, C TI Diet-induced obesity and reduced skin cancer susceptibility in matrix metalloproteinase 19-deficient mice SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ADIPOSE-TISSUE DEVELOPMENT; ADIPOCYTE DIFFERENTIATION; RHEUMATOID-ARTHRITIS; ADIPOGENESIS; EXPRESSION; GENE; INVOLVEMENT; IDENTIFICATION; PROLIFERATION; FIBROBLASTS AB Matrix metalloproteinase 19 (MMP-19) is a member of the MMP family of endopeptidases that, in contrast to most MMPs, is widely expressed in human tissues under normal quiescent conditions. MMP-19 has been found to be associated with ovulation and angiogenic processes and is deregulated in diverse pathological conditions such as rheumatoid arthritis and cancer. To gain further insights into the in vivo functions of this protease, we have generated mutant mice deficient in Mmp19. These mice are viable and fertile and do not display any obvious abnormalities. However, Mmp19-null mice develop a diet-induced obesity due to adipocyte hypertrophy and exhibit decreased susceptibility to skin tumors induced by chemical carcinogens. Based on these results, we suggest that this enzyme plays an in vivo role in some of the tissue remodeling events associated with adipogenesis, as well as in pathological processes such as tumor progression. C1 Univ Oviedo, Fac Med, Dept Bioquim & Biol Mol, Inst Oncol, Oviedo 33006, Spain. Hosp Cent Asturias, Serv Anat Pathol, Oviedo, Spain. NIDCR, MMP Unit, Bethesda, MD 20892 USA. Univ Liege, Lab Tumor & Dev Biol, B-4000 Cointe Ougree, Belgium. RP Pendas, AM (reprint author), Univ Oviedo, Fac Med, Dept Bioquim & Biol Mol, Inst Oncol, Oviedo 33006, Spain. EM amp@correo.uniovi.es RI Pendas, Alberto/L-1017-2014; Lopez-Otin, Carlos/C-6657-2013; Folgueras, Alicia/B-3281-2017; Llano, Elena/K-1723-2014; OI Lopez-Otin, Carlos/0000-0001-6964-1904; Folgueras, Alicia/0000-0003-3426-9502; Llano, Elena/0000-0002-2626-5723; Noel, Agnes/0000-0002-7670-6179; Pendas, Alberto M/0000-0001-9264-3721 NR 41 TC 62 Z9 67 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 2004 VL 24 IS 12 BP 5304 EP 5313 DI 10.1128/MCB.24.12.5304-5313.2004 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 826YA UT WOS:000221864200019 PM 15169894 ER PT J AU Ma, XF Kawamoto, S Hara, Y Adelstein, RS AF Ma, XF Kawamoto, S Hara, Y Adelstein, RS TI A point mutation in the motor domain of nonmuscle myosin II-B impairs migration of distinct groups of neurons SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; HEAVY-CHAIN; P21-ACTIVATED KINASE; NETRIN-1; CELLS; RETRACTION; ABLATION; FECHTNER; BRAIN; GENE AB We generated mice harboring a single amino acid mutation in the motor domain of nonmuscle myosin heavy chain II-B (NMHC II-B). Homozygous mutant mice had an abnormal gait and difficulties in maintaining balance. Consistent with their motor defects, the mutant mice displayed an abnormal pattern of cerebellar foliation. Analysis of the brains of homozygous mutant mice showed significant defects in neuronal migration involving granule cells in the cerebellum, the facial neurons, and the anterior extramural precerebellar migratory stream, including the pontine neurons. A high level of NMHC II-B expression in these neurons suggests an important role for this particular isoform during neuronal migration in the developing brain. Increased phosphorylation of the myosin II regulatory light chain in migrating, compared with stationary pontine neurons, supports an active role for myosin II in regulating their migration. These studies demonstrate that NMHC II-B is particularly important for normal migration of distinct groups of neurons during mouse brain development. C1 NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. Neurodev Inst, Sagamihara, Kanagawa 2291106, Japan. RP Adelstein, RS (reprint author), NHLBI, Mol Cardiol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM adelster@nhlbi.nih.gov OI Adelstein, Robert/0000-0002-8683-2144 NR 33 TC 63 Z9 65 U1 0 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUN PY 2004 VL 15 IS 6 BP 2568 EP 2579 DI 10.1091/mbc.E03-11-0836 PG 12 WC Cell Biology SC Cell Biology GA 825SJ UT WOS:000221778300005 PM 15034141 ER PT J AU Wilson, BS Steinberg, SL Liederman, K Pfeiffer, JR Surviladze, Z Zhang, J Samelson, LE Yang, LH Kotula, PG Oliver, JM AF Wilson, BS Steinberg, SL Liederman, K Pfeiffer, JR Surviladze, Z Zhang, J Samelson, LE Yang, LH Kotula, PG Oliver, JM TI Markers for detergent-resistant lipid rafts occupy distinct and dynamic domains in native membranes SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID FC-EPSILON-RI; GPI-ANCHORED PROTEINS; BASOPHILIC LEUKEMIA-CELLS; PLASMA-MEMBRANE; CHOLERA-TOXIN; LIVING CELLS; SIGNALING ASSEMBLIES; THY-1 GLYCOPROTEIN; IGE RECEPTOR; RAS PROTEINS AB Lipid rafts isolated by detergent extraction and sucrose gradient fractionation from mast cells are enriched for the glycosylphosphatidylinositol-linked protein Thy-1, the ganglioside GM1, palmitoylated LAT, and cross-linked IgE receptors, FcepsilonRI. This study addresses the relationship of fractionation data to the organization of raft markers in native membranes. Immunogold labeling and electron microscopy shows there is little or no colocalization of the raft markers Thy-1, GM1, and LAT with each other or with FcepsilonRI on native membrane sheets prepared from unstimulated cells. External cross-linking of Thy-1 promotes coclustering of Thy-1 with LAT, but not with GM1. Thy-1 and LAT clusters occur on membrane regions without distinctive features. In contrast, external cross-linking of FcepsilonRI and GM1 causes their redistribution to electron-dense membrane patches independently of each other and of Thy-1. The distinctive patches that accumulate cross-linked FCepsilonRI and GM1 also accumulate osmium, a stain for unsaturated lipids, and are sites for coated vesicle budding. Electron microscopy reveals a more complex and dynamic topographical organization of membrane microdomains than is predicted by biochemical analysis of detergent-resistant membranes. C1 Univ New Mexico, Dept Pathol, Albuquerque, NM 87131 USA. Univ New Mexico, Canc Res & Treatment Ctr, Albuquerque, NM 87131 USA. Univ New Mexico, Dept Math & Stat, Albuquerque, NM 87131 USA. Univ New Mexico, Dept Comp Sci, Albuquerque, NM 87131 USA. NCI, Canc Res Ctr, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. Sandia Natl Labs, Mat Characterizat Dept, Albuquerque, NM 87185 USA. RP Wilson, BS (reprint author), Univ New Mexico, Dept Pathol, Albuquerque, NM 87131 USA. EM bwilson@salud.umm.edu RI Kotula, Paul/A-7657-2011 OI Kotula, Paul/0000-0002-7521-2759 FU NIAID NIH HHS [R01 AI051575]; NIGMS NIH HHS [R01 GM049814, P20 GM66283, R01 GM49814] NR 56 TC 144 Z9 147 U1 1 U2 11 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUN PY 2004 VL 15 IS 6 BP 2580 EP 2592 DI 10.1091/mbc.E03-08-0574 PG 13 WC Cell Biology SC Cell Biology GA 825SJ UT WOS:000221778300006 PM 15034144 ER PT J AU Larocca, MC Shanks, RA Tian, L Nelson, DL Stewart, DM Goldenring, JR AF Larocca, MC Shanks, RA Tian, L Nelson, DL Stewart, DM Goldenring, JR TI AKAP350 interaction with cdc42 interacting protein 4 at the Golgi apparatus SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID CULTURED-MAMMALIAN-CELLS; ALDRICH-SYNDROME PROTEIN; KINASE-A ACTIVITY; BREFELDIN-A; CG-NAP; SCAFFOLDING PROTEIN; ACTIN CYTOSKELETON; BINDING-PROTEIN; TARGETING MOTIF; MDCK CELLS AB The A kinase anchoring protein 350 (AKAP350) is a multiply spliced type II protein kinase A anchoring protein that localizes to the centrosomes in most cells and to the Golgi apparatus in epithelial cells. In the present study, we sought to identify AKAP350 interacting proteins that could yield insights into AKAP350 function at the Golgi apparatus. Using yeast two-hybrid and pull-down assays, we found that AKAP350 interacts with a family of structurally related proteins, including FBP17, FBP17b, and cdc42 interacting protein 4 (CIP4). CIP4 interacts with the GTP-bound form of cdc42, with the Wiscott Aldrich Syndrome group of proteins, and with microtubules, and exerts regulatory effects on cytoskeleton and membrane trafficking. CIP4 is phosphorylated by protein kinase A in vitro, and elevation of intracellular cyclic AMP with forskolin stimulates in situ phosphorylation of CIP4. Our results indicate that CIP4 interacts with AKAP350 at the Golgi apparatus and that either disruption of this interaction by expressing the CIP4 binding domain in AKAP350, or reduction of AKAP350 expression by RNA interference leads to changes in Golgi structure. The results suggest that AKAP350 and CIP4 influence the maintenance of normal Golgi apparatus structure. C1 Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Dept Surg, Nashville, TN 37232 USA. Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Dept Cell & Dev Biol, Nashville, TN 37232 USA. Nashville VA Med Ctr, Nashville, TN 37232 USA. Med Coll Georgia, Inst Mol Med & Genet, Augusta, GA 30912 USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Goldenring, JR (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Dept Surg, Nashville, TN 37232 USA. EM jim.goldenring@vanderbilt.edu FU NIDDK NIH HHS [DK-43405, DK-48370, R01 DK043405, R01 DK048370] NR 47 TC 38 Z9 43 U1 0 U2 2 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUN PY 2004 VL 15 IS 6 BP 2771 EP 2781 DI 10.1091/mbc.E03-10-0757 PG 11 WC Cell Biology SC Cell Biology GA 825SJ UT WOS:000221778300023 PM 15047863 ER PT J AU Liu, J Li, CX Qu, W Leslie, E Bonifant, CL Buzard, GS Saavedra, JE Keefer, LK Waalkes, MP AF Liu, J Li, CX Qu, W Leslie, E Bonifant, CL Buzard, GS Saavedra, JE Keefer, LK Waalkes, MP TI Nitric oxide prodrugs and metallochemotherapeutics: JS-K and CB-3-100 enhance arsenic and cisplatin cytolethality by increasing cellular accumulation SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID GLUTATHIONE-S-TRANSFERASE; DIGLUTATHIONYL-IRON COMPLEX; BILIARY-EXCRETION; GENE-EXPRESSION; RESISTANCE; CELLS; CYTOTOXICITY; SUPERFAMILY; TRANSPORT; DEPLETION AB Development of chemotherapeutic resistance is a major cause of pharmacologic failure in cancer treatment. One mechanism of resistance in tumor cells is the overexpression of glutathione S-transferases (GSTs) that serve two distinct roles in the development of drug resistance via the formation of glutathione conjugates with drugs for their cellular efflux, and the inhibition of the mitogen-activated protein kinase pathway. To target GST-based resistance to chemotherapeutics, a series of nitric oxide (NO)-releasing diazeniumdiolates was synthesized and shown to release NO on reaction with GST and/or glutathione. Two diazeniumdiolates, JS-K [O-2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1 -yl]diazen-1-ium-1,2-dialate] and CB-3-100 [O-2-(2,4-dinitrophenyl) 1-[4-(NN-diothylcarboxamido)piperazin-1 -yl]diazen-1-ium-1,2-diolate], were studied on their ability in reversing arsenic and cisplatin resistance in a rat liver cell line that is tumorigenic and shows acquired tolerance to arsenic and cisplatin, with overexpression of GSTs. The enhanced cytolethality produced by the NO donors was accompanied by increased accumulation of arsenic and platinum within cells and by enhanced activation of mitogen-activated protein kinase members c-iun-NH-kinase and extracellular signal-regulated kinase. Our data indicate that JS-K and CB-3-100 are promising lead compounds for the possible development of a novel class of adjuvant chemotherapeutic agents potentially capable of reversing arsenic and cisplatin resistance in certain tumor cells. C1 NIEHS, NCI, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. NCI, Comparat Carcinogenesis Lab, Chem Sect, Frederick, MD 21701 USA. Sci Applicat Int Corp, Basic Res Program, Frederick, MD USA. RP Waalkes, MP (reprint author), NIEHS, NCI, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, Mail Drop F0-09,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM Waalkes@niehs.nih.gov RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU NCI NIH HHS [N01-CO-12400] NR 33 TC 38 Z9 45 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUN PY 2004 VL 3 IS 6 BP 709 EP 714 PG 6 WC Oncology SC Oncology GA 831NY UT WOS:000222202400008 PM 15210857 ER PT J AU Loaiza-Perez, AI Kenney, S Boswell, J Hollingshead, M Alley, MC Hose, C Ciolino, HP Yeh, GC Trepel, JB Vistica, DT Sausville, EA AF Loaiza-Perez, AI Kenney, S Boswell, J Hollingshead, M Alley, MC Hose, C Ciolino, HP Yeh, GC Trepel, JB Vistica, DT Sausville, EA TI Aryl hydrocarbon receptor activation of an antitumor aminoflavone: Basis of selective toxicity for MCF-7 breast tumor cells SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID SIGNAL-TRANSDUCTION PATHWAYS; CYP1A1 EXPRESSION; AH RECEPTOR; DNA-BINDING; APOPTOSIS; INDUCTION; PROTEIN; MECHANISM; CANCER; AGENT AB Aminoflavone (4H-1-benzopyran-4-one, 5-amino-2-(4amino-3-fluorophenyl)-6,8-difluoro-7-methyl; NSC 686288) demonstrates differential antiproliferative activity in the National Cancer Institute's anticancer drug screen. We demonstrate here that MCF-7 human breast cancer cells are sensitive to aminoflavone both in vitro and when grown in vivo as xenografts in athymic mice. As previous work has indicated that aminoflavone requires metabolic activation by cytochrome P450 1A1 (CYP1A1), we investigated the effect of aminoflavone on CYP1A1 expression and on the aryl hydrocarbon receptor (AhR), a transcriptional regulator of CYP1A1. In aminoflavone-sensitive but not aminoflavone-resistant cells, the drug caused a 100-fold induction of CYP1A1 mRNA and a corresponding increase in ethoxyresonufin-O-deethylase activity. An AhR-deficient variant of the MCF-7 breast carcinoma, AH(R100), with diminished CYP1A1 inducibility, exhibits cellular resistance to aminoflavone and is refractory to CYP1A1 mRNA induction by the drug. The increase in CYP1A1 mRNA in the aminoflavone-sensitive MCF-7 breast tumor cell results from transcriptional activation of xenobiotic-responsive element (XRE)-controlled transcription. Aminoflavone treatment causes a translocation of the AhR from the cytoplasm to the nucleus with subsequent formation of AhR-XRE protein DNA complexes. In resistant cell lines (MDA-MB-435, PC-3, and AH(R100)) demonstrated constitutive nuclear localization of AhR. Additionally, aminoflavone failed to induce ethoxyresorufin-O-deethylase activity, CYP1A1 transcription, AhR-XRE complex formation, and apoptosis in aminoflavone-resistant cells. These results suggest that the cytotoxicity of aminoflavone in a sensitive breast tumor cell line is the result of the engagement of AhR-mediated signal transduction. C1 NCI, Dev Therapeut Program, Div Canc Treatment & Diag, NIH, Bethesda, MD USA. NCI, Med Branch, NIH, Bethesda, MD USA. NCI, Screening Technol Branch, Basic Res Lab, Div Basic Sci, Frederick, MD 21701 USA. NCI, Biol Testing Branch, Basic Res Lab, Div Basic Sci, Frederick, MD 21701 USA. NCI, Cellular Def & Carcinogenesis Sect, Basic Res Lab, Div Basic Sci, Frederick, MD 21701 USA. RP Vistica, DT (reprint author), NCI, Dev Therapeut Program, Div Canc Treatment & Diag, Bldg 322,Room 104, Frederick, MD 21702 USA. EM vistica@dtpax2.ncifcrf.gov FU NCI NIH HHS [N01-CM-07002] NR 36 TC 50 Z9 52 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUN PY 2004 VL 3 IS 6 BP 715 EP 725 PG 11 WC Oncology SC Oncology GA 831NY UT WOS:000222202400009 PM 15210858 ER PT J AU Wang, Q Blackford, JA Song, LN Huang, Y Cho, SY Simons, SS AF Wang, Q Blackford, JA Song, LN Huang, Y Cho, SY Simons, SS TI Equilibrium interactions of corepressors and coactivators with agonist and antagonist complexes of glucocorticoid receptors SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID NUCLEAR HORMONE-RECEPTORS; N-COR; ESTROGEN-RECEPTOR; ANDROGEN RECEPTOR; TRANSCRIPTIONAL ACTIVITY; INDUCTION PROPERTIES; STEROID-RECEPTORS; PROGESTERONE-RECEPTOR; MODULATORY ELEMENT; RESPONSE ELEMENT AB Corepressors and coactivators can modulate the dose-response curve and partial agonist activity of glucocorticoid receptors (GRs) complexed with agonist and antagonist steroids, respectively, in intact cells. We recently reported that GR-antagonist complexes bind to the coactivator TIF2, (transcriptional intermediary factor 2), which is consistent with the whole-cell effects of coactivators being mediated by direct interactions with GR complexes. We now ask whether the whole-cell modulatory activity of corepressors also entails binding to both GR-agonist and -antagonist complexes and whether the association of corepressors and coactivators with GR complexes involves competitive equilibrium reactions. In mammalian two-hybrid assays with two different cell lines and in cell-free pull-down and whole-cell immunoprecipitation assays, the corepressors NCoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptor) associate with agonist and antagonist complexes of GRs. Both N- and C-terminal regions of GR are needed for corepressor binding, which requires the CoRNR box motifs that mediate corepressor binding to other nuclear/steroid receptors. Importantly, whole-cell GR interactions with corepressors are competitively inhibited by excess coactivator and vice versa. However, the regions of the coactivator TIF2 that compete for GR binding to corepressor and coactivator are not the same, implying a molecular difference in GR association with coactivators and corepressors. Finally, when the whole-cell ratio of coactivators to corepressors is altered by selective cofactor binding to exogenous thyroid receptor beta+/-thyroid hormone, the GR dose-response-curve and partial agonist activity are appropriately modified. Such modifications are independent of histone acetylation. We conclude that mutually antagonistic equilibrium interactions of corepressors and coactivators modulate the dose-response curve and partial agonist activity of GR complexes in a manner that is responsive to the intracellular ratio of these two classes of cofactors. This modulation provides an attractive mechanism for differential control of gene expression during development, differentiation, homeostasis, and endocrine therapies. C1 NIDDKD, Steroid Hormones Sect, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. RP Simons, SS (reprint author), NIDDKD, Steroid Hormones Sect, Mol & Cellular Biol Lab, NIH, Bldg 8,Room B2A-07, Bethesda, MD 20892 USA. EM steroids@helix.nih.gov NR 72 TC 77 Z9 77 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD JUN 1 PY 2004 VL 18 IS 6 BP 1376 EP 1395 DI 10.1210/me.2003-0421 PG 20 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 823ZR UT WOS:000221653600006 PM 15016838 ER PT J AU Bisello, A Manen, D Pierroz, DD Usdin, TB Rizzoli, R Ferrari, SL AF Bisello, A Manen, D Pierroz, DD Usdin, TB Rizzoli, R Ferrari, SL TI Agonist-specific regulation of parathyroid hormone (PTH) receptor type 2 activity: Structural and functional analysis of PTH- and tuberoinfundibular peptide (TIP) 39-stimulated desensitization and internalization SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTOR; BETA-ARRESTINS; (PTH)/PTH-RELATED PEPTIDE; KINASE-C; 39 RESIDUES; ACTIVATION; TRANSDUCTION; BETA-ARRESTIN2; IDENTIFICATION; REQUIREMENTS AB The human PTH receptor type 2 (PTH2R) is activated by PTH and tuberoinfundibular peptide of 39 residues (TIP39), resulting in cAMP and intracellular Ca signaling. We now report that, despite these similarities, PTH and TIP39 elicit distinct responses from PTH2R. First, TIP39 induced beta-arrestin and protein kinase Cbeta mobilization and receptor internalization, whereas PTH did not. However, PTH stimulated trafficking of these molecules for a chimeric PTH2R containing the N terminus and third extracellular loop of PTH receptor type 1 (PTH1R). Second, whereas PTH-stimulated cAMP activity was brief and rapidly resensitized, the response to TIP39 was sustained and partly desensitized for a prolonged period. PTH2R desensitization was mediated by beta-arrestin interaction with the C terminus (amino acids 426-457) of PTH2R, whereas beta-arrestin mobilization had a minor influence on PTH2R internalization in response to TIP39, as shown with C terminus deletion mutants and/or dominant negative forms of beta-arrestin and dynamin. These data contrast with PTH1R, at which these dominant negative mutants markedly inhibited receptor internalization. Collectively, these results further highlight how specific interactions within the ligand-receptor bimolecular complex mediate distinct postactivation responses of class II G protein-coupled receptors and provide novel insights into the physiological regulation of PTH2R activity. C1 Univ Hosp Geneva, Dept Rehabil & Geriatr, Div Bone Dis, CH-1211 Geneva 14, Switzerland. Univ Pittsburgh, Dept Med, Div Endocrinol & Metab, Pittsburgh, PA 15261 USA. NIMH, Genet Lab, Bethesda, MD 20892 USA. RP Ferrari, SL (reprint author), Univ Hosp Geneva, Dept Rehabil & Geriatr, Div Bone Dis, 24 Rue Micheli du Crest, CH-1211 Geneva 14, Switzerland. EM serge.ferrari@medecine.unige.ch FU NIDDK NIH HHS [DK-62078] NR 38 TC 15 Z9 17 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD JUN 1 PY 2004 VL 18 IS 6 BP 1486 EP 1498 DI 10.1210/me.2003-0487 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 823ZR UT WOS:000221653600014 PM 14988434 ER PT J AU Kleta, R Morse, RP Orvisky, E Krasnewich, D Alroy, J Ucci, AA Bernardini, I Wenger, DA Gahl, WA AF Kleta, R Morse, RP Orvisky, E Krasnewich, D Alroy, J Ucci, AA Bernardini, I Wenger, DA Gahl, WA TI Clinical, biochemical, and molecular diagnosis of a free sialic acid storage disease patient of moderate severity SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE sialic acid; N-acetylneuraminic acid; lysosomal storage; infantile free sialic acid storage disease; ISSD; Salla disease ID SALLA-DISEASE; INFANTILE-FORM; DISORDER; FIBROBLASTS; SPECTRUM; METABOLISM; PHENOTYPE; LYSOSOMES; SIALURIA; EGRESS AB The allelic autosomal recessive lysosomal storage disorders Salla disease and infantile free sialic acid storage disease (ISSD) result from mutations in SLC17A5. This gene codes for sialin, a lysosomal membrane protein that transports the charged sugar, N-acetyl-neuraminic acid (sialic acid), Out Of lysosomes. ISSD has a severe phenotype with infantile onset, while the Finnish variant, Salla disease, has a milder phenotype with later onset. Both disorders cause developmental delay, and ISSD is generally fatal in early childhood. We describe a 30-month old non-Finnish, Caucasian child with global developmental delay of postnatal onset, language, and motor skills stagnant at a 3-4 month level, hypotonia, and mild but progressive coarsening of facial features. Urinary excretion of free sialic acid was elevated 4.5 times above control. EM of a skin biopsy revealed enlarged secondary lysosornes consistent with oligosaccharide storage. Free sialic acid in fibroblasts was 3.8 +/- 0.9 nmol/rng protein (concurrent normal controls, 0.5 +/- 0.1); differential centrifugation indicated a lysosomal location. Genomic analysis revealed compound heterozygosity for two new SLC17A5 mutations. This child's clinical manifestations of a lysosomal free sialic acid storage disease are consistent with her sialin mutations and biochemical findings. The differential diagnosis of postnatal developmental delay should include free sialic acid storage disorders such as ISSD and Salla disease. Published by Elsevier Inc. C1 NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. NIH, Off Rare Dis, Intramural Program, Off Director, Bethesda, MD 20892 USA. Dartmouth Hitchcock Med Ctr, Dept Pediat, Lebanon, NH 03766 USA. NIMH, NSB, NIH, Bethesda, MD 20892 USA. Tufts Univ, Sch Med, Dept Pathol, Boston, MA 02111 USA. Tufts Univ, Sch Vet Med, Dept Pathol, Boston, MA 02111 USA. Tufts Univ, New England Med Ctr, Boston, MA 02111 USA. Tufts Univ, Sch Med, Dept Pathol, Boston, MA 02111 USA. Thomas Jefferson Univ, Jefferson Med Coll, Dept Neurol, Philadelphia, PA 19107 USA. RP Kleta, R (reprint author), NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM kletar@mail.nih.gov FU NIDDK NIH HHS [DK38795] NR 22 TC 10 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JUN PY 2004 VL 82 IS 2 BP 137 EP 143 DI 10.1016/j.ymgme.2004.03.001 PG 7 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 828RB UT WOS:000221989300006 PM 15172001 ER PT J AU Kulik, L Malaspina, A Donoghue, ET Miller, N Chun, TW Fauci, AS Holers, V Moir, S AF Kulik, L Malaspina, A Donoghue, ET Miller, N Chun, TW Fauci, AS Holers, V Moir, S TI Complement receptors CR2 and CR1 are essential for HIV loading on murine lymph node SO MOLECULAR IMMUNOLOGY LA English DT Meeting Abstract CT 20th International Complement Workshop CY JUN 13-18, 2004 CL Honolulu, HI C1 UCHSC, Dept Med, Denver, CO 80262 USA. UCHSC, Dept Immunol, Denver, CO 80262 USA. NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD JUN PY 2004 VL 41 IS 2-3 MA 133 BP 262 EP 262 PG 1 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 827XK UT WOS:000221936800143 ER PT J AU Wilson, SH Olden, K AF Wilson, SH Olden, K TI The Environmental Genome Project SO MOLECULAR INTERVENTIONS LA English DT Review ID SINGLE-NUCLEOTIDE POLYMORPHISMS; ACUTE LYMPHOBLASTIC-LEUKEMIA; GENETIC POLYMORPHISMS; LINKAGE DISEQUILIBRIUM; SEQUENCE VARIATION; INCREASED RISK; DNA; PARAOXONASE; REPAIR; XRCC1 AB Human illness is caused by many interrelated factors including aging, inherited genetic predispositions, and a variety of environmental exposures. There is increasing awareness of the role of genetics as a factor that can dramatically alter susceptibility to all disease, especially L environmentally induced chronic disease, such as cancer, asthma, diabetes, cardiovascular disease, and neurodegenerative disorders. in some cases, a genetic factor influences disease susceptibility in a small fraction of the population because it occurs at a low frequency or involves a relatively low-incidence disease; however, in other cases, a genetic factor increases susceptibility in a large number of individuals and involves a disease that occurs at high incidence, creating a large public health burden. C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, NIH, 111 T-W Alexander Dr, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov NR 31 TC 18 Z9 19 U1 1 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 1534-0384 J9 MOL INTERV JI Mol. Interv. PD JUN PY 2004 VL 4 IS 3 BP 147 EP 156 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 841EE UT WOS:000222911300004 PM 15210868 ER PT J AU Rebeil, R Ernst, RK Gowen, BB Miller, SI Hinnebusch, BJ AF Rebeil, R Ernst, RK Gowen, BB Miller, SI Hinnebusch, BJ TI Variation in lipid A structure in the pathogenic yersiniae SO MOLECULAR MICROBIOLOGY LA English DT Article ID SALMONELLA-TYPHIMURIUM VIRULENCE; OUTER-MEMBRANE PERMEABILITY; COLI-MSBB GENE; ESCHERICHIA-COLI; RHODOBACTER-SPHAEROIDES; PSEUDOMONAS-AERUGINOSA; PHOP-PHOQ; LIPOPOLYSACCHARIDE; PESTIS; EXPRESSION AB Important pathogens in the genus Yersinia include the plague bacillus Yersinia pestis and two enteropathogenic species, Yersinia pseudotuberculosis and Yersinia enterocolitica. A shift in growth temperature induced changes in the number and type of acyl groups on the lipid A of all three species. After growth at 37degreesC, Y. pestis lipopolysaccharide (LPS) contained the tetra-acylated lipid IVA and smaller amounts of lipid IVA modified with C10 or C12 acyl groups, Y. pseudotuberculosis contained the same forms as part of a more heterogeneous population in which lipid IVA modified with C16:0 predominated, and Y. enterocolitica produced a unique tetra-acylated lipid A. When grown at 21degreesC, however, the three yersiniae synthesized LPS containing predominantly hexa-acylated lipid A. This more complex lipid A stimulated human monocytes to secrete tumour necrosis factor-alpha, whereas the lipid A synthesized by the three species at 37degreesC did not. The Y. pestis phoP gene was required for aminoarabinose modification of lipid A, but not for the temperature-dependent acylation changes. The results suggest that the production of a less immunostimulatory form of LPS upon entry into the mammalian host is a conserved pathogenesis mechanism in the genus Yersinia, and that species-specific lipid A forms may be important for life cycle and pathogenicity differences. C1 NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. RP Hinnebusch, BJ (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM jhinnebusch@niaid.nih.gov FU NIAID NIH HHS [R01 AI03479, U54 AI057141] NR 56 TC 174 Z9 182 U1 2 U2 12 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD JUN PY 2004 VL 52 IS 5 BP 1363 EP 1373 DI 10.1111/j.1365-2958.2004.04059.x PG 11 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 823WJ UT WOS:000221644200013 PM 15165239 ER PT J AU Legrand, M Lephart, P Forche, A Mueller, FMC Walsh, T Magee, PT Magee, BB AF Legrand, M Lephart, P Forche, A Mueller, FMC Walsh, T Magee, PT Magee, BB TI Homozygosity at the MTL locus in clinical strains of Candida albicans: karyotypic rearrangements and tetraploid formation SO MOLECULAR MICROBIOLOGY LA English DT Article ID MATING-TYPE LOCUS; GENETIC-ANALYSIS; DRUG-RESISTANCE; COMPLEMENTATION; CONSTRUCTION; YEAST; DNA; IDENTIFICATION; CEREVISIAE; CYCLE AB One hundred and twenty Candida albicans clinical isolates from the late 1980s and early 1990s were examined for homozygosity at the MTL locus. Of these, 108 were heterozygous (MTLa/MTLalpha), whereas seven were MTLa and five were MTLalpha. Five of the homozygous isolates were able to switch to the opaque cell morphology, while opaque cells were not detectable among the remaining seven. Nevertheless, all but one of the isolates homozygous at the MTL locus were shown to mate and to yield cells containing markers from both parents; the non-mater was found to have a frameshift in the MTLalpha1 gene. In contrast to Saccharomyces cerevisiae, C. albicans homozygotes with no active MTL allele failed to mate rather than mating as a cells. There was no correlation between homozygosity and fluconazole resistance, mating and fluconazole resistance or switching and fluconazole resistance, in part because most of the strains were isolated before the widespread use of this antifungal agent, and only three were in fact drug resistant. Ten of the 12 homozygotes had rearranged karyotypes involving one or more homologue of chromosomes 4, 5, 6 and 7. We suggest that karyotypic rearrangement, drug resistance and homozygosity come about as the result of induction of hyper-recombination during the infection process; hence, they tend to occur together, but each is the independent result of the same event. Furthermore, as clinical strains can mate and form tetraploids, mating and marker exchange are likely to be a significant part of the life cycle of C. albicans in vivo. C1 Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. Natl Canc Inst, Infect Dis Sect, NIH, Bethesda, MD USA. RP Magee, PT (reprint author), Univ Minnesota, Dept Genet Cell Biol & Dev, 321 Church St SE, Minneapolis, MN 55455 USA. EM ptm@biosci.cbs.umn.edu FU NCI NIH HHS [P30 CA77598]; NIAID NIH HHS [AI05406, AI16567, AI46351]; NIGMS NIH HHS [T32-GM08347] NR 32 TC 76 Z9 83 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD JUN PY 2004 VL 52 IS 5 BP 1451 EP 1462 DI 10.1111/j.1365-2958.2004.04068.x PG 12 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 823WJ UT WOS:000221644200020 PM 15165246 ER PT J AU Broccoli, S Rallu, F Sanscartier, P Cerritelli, SM Crouch, RJ Drolet, M AF Broccoli, S Rallu, F Sanscartier, P Cerritelli, SM Crouch, RJ Drolet, M TI Effects of RNA polymerase modifications on transcription-induced negative supercoiling and associated R-loop formation SO MOLECULAR MICROBIOLOGY LA English DT Article ID DNA TOPOISOMERASE-I; ESCHERICHIA-COLI; TOPA MUTANTS; ELONGATION; BACTERIAL; TEMPLATE; ANTITERMINATION; TERMINATORS; INHIBITION; MECHANISM AB Transcription in the absence of topoisomerase I, but in the presence of DNA gyrase, can result in the formation of hypernegatively supercoiled DNA and associated R-loops. In this paper, we have used several strategies to study the effects of elongation/termination properties of RNA polymerase on such transcription-induced supercoiling. Effects on R-loop formation were exacerbated when cells were exposed to translation inhibitors, a condition that stimulated the accumulation of R-loop-dependent hypernegative supercoiling. Translation inhibitors were not acting by decreasing (p)ppGpp levels as the absence of (p)ppGpp in spoT relA mutant strains had little effect on hypernegative supercoiling. However, an rpoB mutation leading to the accumulation of truncated RNAs considerably reduced R-loop-dependent hypernegative supercoiling. Transcription of an rrnB fragment preceded by a mutated and inactive boxA sequence to abolish the rrnB antitermination system also considerably reduced R-loop-dependent supercoiling. Taken together, our results indicate that RNA polymerase elongation/termination properties can have a major impact on R-loop-dependent supercoiling. We discuss different possibilities by which RNA polymerase directly or indirectly participates in R-loop formation in Escherichia coli. Finally, our results also indicate that what determines the steady-state level of hypernegatively supercoiled DNA in topA null mutants is likely to be complex and involves a multitude of factors, including the status of RNA polymerase, transcription-translation coupling, the cellular level of RNase HI, the status of DNA gyrase and the rate of relaxation of supercoiled DNA. C1 Univ Montreal, Dept Microbiol & Immunol, Montreal, PQ H3C 3J7, Canada. NIH, Mol Genet Lab, Bethesda, MD 20892 USA. RP Drolet, M (reprint author), Univ Montreal, Dept Microbiol & Immunol, CP 6128,Succursale Ctr Ville, Montreal, PQ H3C 3J7, Canada. EM drolet@umontreal.ca NR 40 TC 33 Z9 34 U1 0 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD JUN PY 2004 VL 52 IS 6 BP 1769 EP 1779 DI 10.1111/j.1365-2958.2004.04092.x PG 11 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 826YV UT WOS:000221866300019 PM 15186424 ER PT J AU Jackson, JP Ferguson, SS Moore, R Negishi, M Goldstein, JA AF Jackson, JP Ferguson, SS Moore, R Negishi, M Goldstein, JA TI The constitutive active/androstane receptor regulates phenytoin induction of Cyp2c29 SO MOLECULAR PHARMACOLOGY LA English DT Article ID PREGNANE-X-RECEPTOR; RESPONSIVE ENHANCER MODULE; NUCLEAR RECEPTORS; ANDROSTANE RECEPTOR; HUMAN HEPATOCYTES; TRANSCRIPTIONAL REGULATION; GLUCOCORTICOID-RECEPTOR; CYP3A4 EXPRESSION; MOUSE-LIVER; CAR AB Many cytochrome P450 isoforms are known to be drug-inducible. The anticonvulsant phenytoin has been reported to be an inducer of human CYP2B6, CYP3A4, and murine CYP2C29. However, the molecular mechanism mediating phenytoin induction remains unclear. Herein, we used in vivo and in vitro gene reporter assays of the Cyp2c29 promoter to delineate the phenytoin-response activity to a phenytoin-responsive module located at -1371 kb upstream of the Cyp2c29 translation start site. The phenytoin-responsive module, consisting of two motifs of two imperfect direct repeat hexamers spaced by four nucleotides and a putative CCAAT/enhancer-binding protein-binding site, mediated luciferase reporter induction by phenytoin in mouse livers in vivo and was activated by CAR in HepG2 cells. Hepatic CYP2C29 mRNA was induced by phenytoin in wild-type but not in CAR-null mice, indicating that constitutive active or androstane receptor (CAR) regulates phenytoin-induced transcription of the Cyp2c29 gene. Furthermore, the constitutive levels of CYP2C29 mRNA were reduced similar to77-fold in CAR-null mice compared with those in the wild-type mice, suggesting that CAR may also regulate the constitutive expression of the Cyp2c29 gene either directly or indirectly. C1 NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA. RP Negishi, M (reprint author), NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM negishi@niehs.nih.gov RI Goldstein, Joyce/A-6681-2012 NR 24 TC 36 Z9 39 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUN 1 PY 2004 VL 65 IS 6 BP 1397 EP 1404 DI 10.1124/mol.65.6.1397 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 822LL UT WOS:000221541400009 PM 15155833 ER PT J AU Volkow, ND Fowler, JS Wang, GJ Swanson, JM AF Volkow, ND Fowler, JS Wang, GJ Swanson, JM TI Dopamine in drug abuse and addiction: results from imaging studies and treatment implications SO MOLECULAR PSYCHIATRY LA English DT Review DE PET; orbitofrontal cortex; cingulate gyrus; striatum; dopamine transporters; dopamine D2 receptors; reward; motivation; predisposition; salience; pharmacokinetics ID PRIMATE ORBITOFRONTAL CORTEX; POSITRON-EMISSION-TOMOGRAPHY; CONDITIONED TASTE-AVERSION; NUCLEUS-ACCUMBENS DOPAMINE; GAMMA-VINYL GABA; COCAINE DEPENDENCE; PREFRONTAL CORTEX; HUMAN BRAIN; METHAMPHETAMINE ABUSERS; INTRAVENOUS COCAINE AB The involvement of dopamine in drug reinforcement is well recognized but its role in drug addiction is much less clear. Imaging studies have shown that the reinforcing effects of drugs of abuse in humans are contingent upon large and fast increases in dopamine that mimic but exceed in the intensity and duration those induced by dopamine cell firing to environmental events. In addition, imaging studies have also documented a role of dopamine in motivation, which appears to be encoded both by fast as well as smooth DA increases. Since dopamine cells fire in response to salient stimuli, the supraphysiological activation by drugs is likely to be experienced as highly salient ( driving attention, arousal conditioned learning and motivation) and may also reset the thresholds required for environmental events to activate dopamine cells. Indeed, imaging studies have shown that in drug-addicted subjects, dopamine function is markedly disrupted ( decreases in dopamine release and in dopamine D2 receptors in striatum) and this is associated with reduced activity of the orbitofrontal cortex (neuroanatomical region involved with salience attribution and motivation and implicated in compulsive behaviors) and the cingulate gyrus ( neuroanatomical region involved with inhibitory control and attention and implicated in impulsivity). However, when addicted subjects are exposed to drug-related stimuli, these hypoactive regions become hyperactive in proportion to the expressed desire for the drug. We postulate that decreased dopamine function in addicted subjects results in decreased sensitivity to nondrug-related stimuli ( including natural reinforcers) and disrupts frontal inhibition, both of which contribute to compulsive drug intake and impaired inhibitory control. These findings suggest new strategies for pharmacological and behavioral treatments, which focus on enhancing DA function and restoring brain circuits disrupted by chronic drug use to help motivate the addicted subject in activities that provide alternative sources of reinforcement, counteract conditioned responses, enhance their ability to control their drive to take drugs and interfere with their compulsive administration. C1 NIDA, Off Director, Bethesda, MD 20892 USA. NIAAA, Bethesda, MD USA. Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. Brookhaven Natl Lab, Dept Chem, Upton, NY 11973 USA. SUNY Stony Brook, Dept Psychiat, Stony Brook, NY 11794 USA. Univ Calif Irvine, Dept Pediat, Irvine, CA 92717 USA. RP Volkow, ND (reprint author), NIDA, Off Director, 6001 Execut Blvd,Room 5274,MSC 9581, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov FU NIAAA NIH HHS [AA 09481]; NIDA NIH HHS [DA 06278, DA 06891, DA 09490] NR 113 TC 449 Z9 465 U1 13 U2 74 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JUN PY 2004 VL 9 IS 6 BP 557 EP 569 DI 10.1038/sj.mp.4001507 PG 13 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 824DK UT WOS:000221664300006 PM 15098002 ER PT J AU Bosticardo, M Witte, I Fieschi, C Novelli, F Casanova, JL Candotti, F AF Bosticardo, M Witte, I Fieschi, C Novelli, F Casanova, JL Candotti, F TI Retroviral-mediated gene transfer restores IL-12 and IL-23 signaling pathways in T cells from IL-12 receptor beta 1-deficient patients SO MOLECULAR THERAPY LA English DT Article DE cytokines; cytokine receptors; T lymphocytes; gene therapy; immunodeficiency diseases ID SEVERE COMBINED IMMUNODEFICIENCY; BETA-1 DEFICIENCY; LYMPHOID DEVELOPMENT; COMPLEX INFECTION; INTERLEUKIN-12; IMMUNITY; MICE; MYCOBACTERIAL; TUBERCULOSIS; RESISTANCE AB Genetic deficiency of human IL-12 receptor beta1 chain (IL-12Rbeta1) results in increased vulnerability to weakly pathogenic strains of Mycobacteria and Salmonella. This phenotype results from the combined lack of IL-12 and IL-23 signaling as both cytokine receptors share IL-12Rbeta1 11. Such infections can be treated by administration of antibiotics and IFN-gamma; however, patients can succumb to infections despite these treatments. Reversion of patients' susceptibility by corrective gene transfer could prevent the infectious episodes, thus providing a beneficial alternative. We therefore evaluated the feasibility of retroviral-mediated gene correction of T cells obtained from patients carrying "null" mutations, of I-12Rbeta1. Transduction of the IL-12Rbeta1 cDNA restored the expression of IL-12Rbeta1 and resulted in the reconstitution of a functional IL-12 signaling pathway, as demonstrated by STAT4 phosphorylation and IFN-gamma production. IFN-gamma production in response to IL-23 was also corrected after gene transfer. These results indicate that the biological defects of T cells from patients carrying Il-12Rbeta1 deficiency can be corrected by gene transfer and form the basis for further development of gene therapy for this disease. C1 NHGRI, Disorders Immun Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. Univ Paris 05, Lab Genet Humaine Malad Infect, INSERM, U550,Fac Med Necker, F-75015 Paris, France. San Giovanni Battista Hosp, Ctr Expt Res & Clin Studies, I-10126 Turin, Italy. RP Candotti, F (reprint author), NHGRI, Disorders Immun Sect, Genet & Mol Biol Branch, NIH, 49 Convent Dr,Bldg 49,Room 3A20,MSC 4442, Bethesda, MD 20892 USA. EM fabio@mail.nih.gov NR 30 TC 5 Z9 6 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD JUN PY 2004 VL 9 IS 6 BP 895 EP 901 DI 10.1016/j.ymthe.2004.02.024 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 831NW UT WOS:000222202200018 PM 15194056 ER PT J AU Furtado, S Payami, H Lockhart, PJ Hanson, M Nutt, JG Singleton, AA Singleton, A Bower, J Utti, RJ Bird, TD de la Fuente-Femandez, R Tsuboi, Y Klimek, ML Suchowersky, O Hardy, J Calne, DB Wszolek, ZK Farrer, M Gwinn-Hardy, K Stoessl, AJ AF Furtado, S Payami, H Lockhart, PJ Hanson, M Nutt, JG Singleton, AA Singleton, A Bower, J Utti, RJ Bird, TD de la Fuente-Femandez, R Tsuboi, Y Klimek, ML Suchowersky, O Hardy, J Calne, DB Wszolek, ZK Farrer, M Gwinn-Hardy, K Stoessl, AJ TI Profile of families with parkinsonism-predominant spinocerebellar ataxia type 2 (SCA2) SO MOVEMENT DISORDERS LA English DT Review DE parkinsonism; SCA2; Parkinson's disease; genetic mutation; PET; interrupted repeats; phenotype ID ALPHA-SYNUCLEIN GENE; BINDING PROTEIN GENE; REPEAT EXPANSION; RESPONSIVE PARKINSONISM; DISEASE; MUTATION; ONSET; CLONING; PET AB Spinocerebellar ataxia type 2 (SCA2) has been recognized recently as an uncommon cause of parkinsonism, an alternate presentation to the typical cerebellar disorder. This research review summarizes the existing literature on parkinsonism-predominant presentation SCA2 and presents new clinical cases of patients with this condition. Various phenotypes are noted in this subtype of SCA2, including parkinsonism indistinguishable from idiopathic Parkinson's disease (PD), parkinsonism plus ataxia, motor neuron disease, and postural tremor. In several kindreds with multiple affected family members, the SCA2 expansion segregated with disease; in addition, several single cases of parkinsonism with and without a family history are also described. The number of repeats in symptomatic patients ranged from 33 to 43. Interruption of the CAG repeat with CAA, CGG, or CCG was found in some individuals, possibly stabilizing the repeat structure and accounting for the relative stability of the repeat size across generations in some families; allele length is not necessarily indicative of trinucleotide repeat architecture. Positron emission tomography scanning in one family showed reduced fluorodopa uptake and normal to increased raclopride binding with a rostrocaudal gradient similar to that found in idiopathic PD. This review emphasizes the importance of testing for SCA2 in patients with parkinsonism and a family history of neurodegenerative disorders. Testing for SCA2 is also important in studies of inherited parkinsonism. (C) 2004 Movement Disorder Society. C1 Univ Calgary, Dept Clin Neurosci, Calgary, AB, Canada. Oregon Hlth Sci Univ, Dept Neurol, Portland, OR 97201 USA. New York State Dept Hlth, Wadsworth Ctr, Albany, NY USA. Mayo Clin Jacksonville, Dept Neurosci, Jacksonville, FL USA. Mayo Clin Jacksonville, Dept Neurol, Jacksonville, FL USA. NIA, Neurogenet Lab, NIH, Bethesda, MD USA. NINDS, Neurogenet Div, Parkinsons Genet Unit, NIH, Bethesda, MD USA. Mayo Clin, Dept Neurol, Rochester, MN USA. Univ Washington, Dept Neurol, Seattle, WA USA. Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. Univ British Columbia, Pacific Parkinsons Res Ctr, Vancouver, BC, Canada. RP Furtado, S (reprint author), Foothills Prov Gen Hosp, Dept Clin Neurosci, 12th Floor,1403-29 St,NW, Calgary, AB T2N 2T9, Canada. EM furtado@ucalgary.ca RI Gwinn, Katrina/C-2508-2009; Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; Lockhart, Paul/E-7753-2011; OI Lockhart, Paul/0000-0003-2531-8413; Gwinn, Katrina/0000-0002-8277-651X FU NINDS NIH HHS [R01 NS36960] NR 28 TC 56 Z9 57 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUN PY 2004 VL 19 IS 6 BP 622 EP 629 DI 10.1002/mds.20074 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 831DL UT WOS:000222173200003 PM 15197699 ER PT J AU Wiley, J Lynch, T Lincoln, S Skipper, L Hulihan, M Gosal, D Bisceglio, G Kachergus, J Hardy, J Farrer, MJ AF Wiley, J Lynch, T Lincoln, S Skipper, L Hulihan, M Gosal, D Bisceglio, G Kachergus, J Hardy, J Farrer, MJ TI Parkinson's disease in Ireland: Clinical presentation and genetic heterogeneity in patients with parkin mutations SO MOVEMENT DISORDERS LA English DT Article DE parkin; Parkinson's disease; genetics ID RECESSIVE JUVENILE PARKINSONISM; EARLY-ONSET PARKINSONISM; JAPANESE FAMILIES; LEWY BODIES; DELETIONS; EUROPE AB Early-onset autosomal recessive parkinsonism is associated with parkin gene mutations. Different parkin mutations occur in many ethnic backgrounds; however, the phenotype may vary. We studied 102 young-onset (age at onset <60 years) Parkinson's disease (PD) patients. From 102 patients, 40 with early-onset PD (<45 years at symptomatic onset) were selected for clinical assessment and parkin gene molecular analysis for duplications/deletions and point mutations. We identified parkin mutations in 7 of 40 early-onset patients; including novel compound heterozygotes and potential splice site changes. The mean age at onset in the 7 parkin mutation-positive patients was 33 +/- 9 years (age range, 18-42 years), marginally lower than that of the 33 parkin-negative early-onset patients, 38 +/- 7 years (age range, 17-45 years). A family history of PD was present in 4 of 7 patients with parkin mutations, compared with 6 of 33 early-onset parkin-negative patients. Overall, parkin mutations were found in 4 of 10 patients with a positive family history and 3 of 30 patients without a family history of PD. Patients with parkin mutations had more dystonia, dyskinesia, and sleep benefit compared with parkin-negative patients. We subsequently identified a single point mutation among the 62 young-onset (age at onset 45 to <60 years). Mutations in the parkin gene may account for similar to17% of early-onset (age at onset <45 years) parkinsonism in Ireland, in agreement with previous European studies. (C) 2004 Movement Disorder Society. C1 Mater Misericordiae Hosp, Clin Investigator Conway Inst Biomol & Biomed Res, Dept Neurol, Dublin 7, Ireland. Univ Coll Dublin, Conway Neurosci Investigator, Dublin, Ireland. Mayo Clin, Dept Neurosci, Jacksonville, FL USA. NIA, Neurogenet Lab, Bethesda, MD USA. RP Lynch, T (reprint author), Mater Misericordiae Hosp, Clin Investigator Conway Inst Biomol & Biomed Res, Dept Neurol, Eccles St, Dublin 7, Ireland. EM tlynch@materprivate.ie RI Hardy, John/C-2451-2009; OI Skipper, Lisa/0000-0002-1524-9787 NR 23 TC 7 Z9 7 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUN PY 2004 VL 19 IS 6 BP 677 EP 681 DI 10.1002/mds.10703 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 831DL UT WOS:000222173200011 PM 15197707 ER PT J AU LaRochelle, JS Karp, BI AF LaRochelle, JS Karp, BI TI Restless legs syndrome due to interferon-alpha SO MOVEMENT DISORDERS LA English DT Article DE interferon-alpha; restless legs syndrome; movement disorder ID HEPATITIS-C; THERAPY; COMPLICATIONS; AKATHISIA; PET AB A patient developed restless legs symptoms paralleling the course of interferon-alpha (IFNalpha) therapy for chronic hepatitis C. Symptoms began during a course of IFNalpha, resolved with its suspension, and recurred on rechallenge. Restless legs syndrome may thus be an adverse effect of IFNalpha treatment. (C) 2004 Movement Disorder Society. C1 NINDS, OCD, NIH, Bethesda, MD 20892 USA. Wilford Hall USAF Med Ctr, MC, San Antonio, TX 78236 USA. RP Karp, BI (reprint author), NINDS, OCD, NIH, Bldg 10,Room 5S-209, Bethesda, MD 20892 USA. EM karpb@ninds.nih.gov NR 16 TC 12 Z9 12 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUN PY 2004 VL 19 IS 6 BP 730 EP 731 DI 10.1002/mds.20049 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 831DL UT WOS:000222173200026 PM 15197722 ER PT J AU Dalakas, MC AF Dalakas, MC TI From canine to man: On antibodies, macrophages, and dendritic cells in inflammatory myopathies SO MUSCLE & NERVE LA English DT Editorial Material ID DERMATOMYOSITIS; POLYMYOSITIS; MUSCLE C1 NINDS, Neuromuscular Dis Sect, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), NINDS, Neuromuscular Dis Sect, Natl Inst Hlth, Bethesda, MD 20892 USA. EM dalakasm@ninds.nih.gov NR 8 TC 8 Z9 8 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-639X J9 MUSCLE NERVE JI Muscle Nerve PD JUN PY 2004 VL 29 IS 6 BP 753 EP 755 DI 10.1002/mus.20079 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 826LW UT WOS:000221831600001 PM 15170607 ER PT J AU Charan, RD Mckee, TC Boyd, MR AF Charan, RD Mckee, TC Boyd, MR TI Cytotoxic alkaloids from the marine sponge Thorectandra sp. SO NATURAL PRODUCT RESEARCH LA English DT Article DE beta-carboline; Thorectandra sp.; fascaplysin; 1-deoxysecofascaplysin A ID SESTERTERPENES; FASCAPLYSIN; RETICULATA; PRODUCTS AB Three beta-carboline alkaloids, Compound 1, 1-deoxysecofascaplysin A ( 2), and fascaplysin ( 3), were isolated from the aqueous and organic extracts of the marine sponge Thorectandra sp. The structures of 1 and 2 were determined on the basis of spectral data. Compound 1 inhibited the growth of MCF-7 ( breast) with an IC50 of 5.9 mug/mL while Compound 2 inhibited the growth of MCF-7 as well as OVCAR-3 ( ovarian) human tumor cell lines with IC(50)s of 1.5 and 2.2 mug/mL, respectively. C1 NCI, Mol Targets Dev Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Mckee, TC (reprint author), NCI, Mol Targets Dev Program, Ctr Canc Res, Frederick, MD 21702 USA. EM manuscripts@ncifcrf.gov NR 11 TC 14 Z9 16 U1 0 U2 3 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1478-6419 J9 NAT PROD RES JI Nat. Prod. Res. PD JUN PY 2004 VL 18 IS 3 BP 225 EP 229 DI 10.1080/14786410310001622077 PG 5 WC Chemistry, Applied; Chemistry, Medicinal SC Chemistry; Pharmacology & Pharmacy GA 818JS UT WOS:000221242000006 PM 15143832 ER PT J AU Brandenberger, R Wei, H Zhang, S Lei, S Murage, J Fisk, GJ Li, Y Xu, CH Fang, R Guegler, K Rao, MS Mandalam, R Lebkowski, J Stanton, LW AF Brandenberger, R Wei, H Zhang, S Lei, S Murage, J Fisk, GJ Li, Y Xu, CH Fang, R Guegler, K Rao, MS Mandalam, R Lebkowski, J Stanton, LW TI Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation SO NATURE BIOTECHNOLOGY LA English DT Article ID EMBRYONIC STEM-CELLS; LEUKEMIA INHIBITORY FACTOR; GENE-EXPRESSION; HUMAN BLASTOCYSTS; JAK-STAT; LINES; IDENTIFICATION; GENERATION; PATTERNS; ENHANCER AB Human embryonic stem (hES) cells hold promise for generating an unlimited supply of cells for replacement therapies. To characterize hES cells at the molecular level, we obtained 148,453 expressed sequence tags (ESTs) from undifferentiated hES cells and three differentiated derivative subpopulations. Over 32,000 different transcripts expressed in hES cells were identified, of which more than 16,000 do not match closely any gene in the UniGene public database. Queries to this EST database revealed 532 significantly upregulated and 140 significantly downregulated genes in undifferentiated hES cells. These data highlight changes in the transcriptional network that occur when hES cells differentiate. Among the differentially regulated genes are several components of signaling pathways and transcriptional regulators that likely play key roles in hES cell growth and differentiation. The genomic data presented here may facilitate the derivation of clinically useful cell types from hES cells. C1 Geron Corp, Menlo Pk, CA 94025 USA. Celera Genom, Rockville, MD 20850 USA. NIA, Baltimore, MD 21224 USA. RP Brandenberger, R (reprint author), Geron Corp, 230 Constitut Dr, Menlo Pk, CA 94025 USA. EM rbrandenberger@geron.com NR 49 TC 234 Z9 272 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD JUN PY 2004 VL 22 IS 6 BP 707 EP 716 DI 10.1038/nbt971 PG 10 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 825VA UT WOS:000221785300032 PM 15146197 ER PT J AU Ghadessy, FJ Ramsay, N Boudsocq, F Loakes, D Brown, A Iwai, S Vaisman, A Woodgate, R Holliger, P AF Ghadessy, FJ Ramsay, N Boudsocq, F Loakes, D Brown, A Iwai, S Vaisman, A Woodgate, R Holliger, P TI Generic expansion of the substrate spectrum of a DNA polymerase by directed evolution SO NATURE BIOTECHNOLOGY LA English DT Article ID GENETIC ALPHABET; ERROR-PRONE; ACTIVE-SITE; REPLICATION; FIDELITY; BYPASS; ETA; PCR AB DNA polymerases recognize their substrates with exceptionally high specificity(1,2), restricting the use of unnatural nucleotides and the applications they enable. We describe a strategy to expand the substrate range of polymerases. By selecting for the extension of distorting 3' mismatches, we obtained mutants of Taq DNA polymerase that not only promiscuously extended mismatches, but had acquired a generic ability to process a diverse range of noncanonical substrates while maintaining high catalytic turnover, processivity and fidelity. Unlike the wild-type enzyme, they bypassed blocking lesions such as an abasic site, a thymidine dimer or the base analog 5-nitroindol(3) and performed PCR amplification with complete substitution of all four nucleotide triphosphates with phosphorothioates(4) or the substitution of one with the equivalent fluorescent dye-labeled nucleotide triphosphate. Such 'unfussy' polymerases have immediate utility, as we demonstrate by the generation of microarray probes with up to 20-fold brighter fluorescence. C1 MRC, Mol Biol Lab, Cambridge CB2 2QH, England. NICHHD, Sect DNA Replicat Repair & Mutagenesis, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. BioRobotics, Haslingfield CB3 7LW, England. Univ Tokyo, Dept Chem & Biotechnol, Bunkyo Ku, Tokyo 1138656, Japan. RP Holliger, P (reprint author), MRC, Mol Biol Lab, Hills Rd, Cambridge CB2 2QH, England. EM phl@mrc-lmb.cam.ac.uk RI Vaisman, Alexandra/C-3766-2013 OI Vaisman, Alexandra/0000-0002-2521-1467 NR 27 TC 97 Z9 98 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD JUN PY 2004 VL 22 IS 6 BP 755 EP 759 DI 10.1038/nbt974 PG 5 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 825VA UT WOS:000221785300038 PM 15156154 ER PT J AU Eustace, BK Sakurai, T Stewart, JK Yimlamai, D Unger, C Zehetmeier, C Lain, B Torella, C Henning, SW Beste, G Scroggins, BT Neckers, L Ilag, LL Jay, DG AF Eustace, BK Sakurai, T Stewart, JK Yimlamai, D Unger, C Zehetmeier, C Lain, B Torella, C Henning, SW Beste, G Scroggins, BT Neckers, L Ilag, LL Jay, DG TI Functional proteomic screens reveal an essential extracellular role for hsp90 alpha in cancer cell invasiveness SO NATURE CELL BIOLOGY LA English DT Article ID HEAT-SHOCK PROTEINS; HSP90; EXPRESSION; RECEPTOR; COMPLEX; IDENTIFICATION; TRAFFICKING; METASTASIS; INHIBITION; EXOSOMES AB Tumour cell invasiveness is crucial for cancer metastasis and is not yet understood. Here we describe two functional screens for proteins required for the invasion of fibrosarcoma cells that identified the molecular chaperone heat shock protein 90 (hsp90). The hsp90alpha isoform, but not hsp90beta, is expressed extracellularly where it interacts with the matrix metalloproteinase 2 (MMP2). Inhibition of extracellular hsp90alpha decreases both MMP2 activity and invasiveness. This role for extracellular hsp90alpha in MMP2 activation indicates that cell-impermeant anti-hsp90 drugs might decrease invasiveness without the concerns inherent in inhibiting intracellular hsp90. C1 Tufts Univ, Sch Med, Dept Physiol, Boston, MA 02111 USA. Xerion Pharmaceut AG, D-81377 Munich, Germany. NCI, Cell & Canc Biol Branch, Rockville, MD 20850 USA. RP Jay, DG (reprint author), Tufts Univ, Sch Med, Dept Physiol, Boston, MA 02111 USA. EM daniel.jay@tufts.edu NR 45 TC 298 Z9 314 U1 2 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD JUN PY 2004 VL 6 IS 6 BP 507 EP 514 DI 10.1038/ncb1131 PG 8 WC Cell Biology SC Cell Biology GA 825LH UT WOS:000221759400010 PM 15146192 ER PT J AU O'Brien, SJ Nelson, GW AF O'Brien, SJ Nelson, GW TI Human genes that limit AIDS SO NATURE GENETICS LA English DT Review ID IMMUNODEFICIENCY-VIRUS TYPE-1; MAJOR HISTOCOMPATIBILITY COMPLEX; CHEMOKINE RECEPTOR GENE; HIV-1 2ND RECEPTORS; CLASS-I MOLECULES; DISEASE PROGRESSION; PROMOTER VARIANT; HOST GENES; INFECTION; CCR5 AB Discernable genetic variation among people and populations has an important role in infectious disease epidemics, including that of acquired immune deficiency syndrome (AIDS). Genetic association analysis of several large AIDS cohorts implicate 14 AIDS restriction genes, polymorphic variants in loci that regulate HIV-1 cell entry, acquired and innate immunity, and cytokine defenses to HIV-1. The influence and translational impact of these genes on individual and population sensitivity to AIDS is considerable. C1 NCI, Lab Genom Divers, Frederick, MD 21701 USA. SAIC Frederick, Basic Res Program, Lab Genom Divers, NIC, Frederick, MD USA. RP O'Brien, SJ (reprint author), NCI, Lab Genom Divers, Frederick, MD 21701 USA. EM obrien@ncifcrf.gov NR 95 TC 204 Z9 216 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUN PY 2004 VL 36 IS 6 BP 565 EP 574 DI 10.1038/ng1369 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 825MX UT WOS:000221763700010 PM 15167933 ER PT J AU Khil, PP Smirnova, NA Romanienko, PJ Camerini-Otero, RD AF Khil, PP Smirnova, NA Romanienko, PJ Camerini-Otero, RD TI The mouse X chromosome is enriched for sex-biased genes not subject to selection by meiotic sex chromosome inactivation SO NATURE GENETICS LA English DT Article ID SPERMATOGENIC CELLS; C-ELEGANS; EXPRESSION; EVOLUTION; TRANSCRIPTOME; MICROARRAYS; GERMLINE; SYNAPSIS; SPO11 AB Sex chromosomes are subject to sex-specific selective evolutionary forcest(1,2). One model predicts that genes with sex-biased expression should be enriched on the X chromosome(2-5). In agreement with Rice's hypothesis(3), spermatogonial genes are over-represented on the X chromosome of mice(6) and sex- and reproduction-related genes are over-represented on the human X chromosome(7,8). Male-biased genes are under-represented on the X chromosome in worms and flies(9-11), however. Here we show that mouse spermatogenesis genes are relatively underrepresented on the X chromosome and female-biased genes are enriched on it. We used Spo11(-/-) mice blocked in spermatogenesis early in meiosis(12) to evaluate the temporal pattern of gene expression in sperm development. Genes expressed before the Spo11 block are enriched on the X chromosome, whereas those expressed later in spermatogenesis are depleted. Inactivation of the X chromosome in male meiosis may be a universal driving force for X-chromosome demasculinization. C1 NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Camerini-Otero, RD (reprint author), NIDDK, Genet & Biochem Branch, NIH, 5 Mem Dr, Bethesda, MD 20892 USA. EM camerini@ncifcrf.gov OI Khil, Pavel/0000-0002-4903-8777 NR 30 TC 205 Z9 211 U1 3 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUN PY 2004 VL 36 IS 6 BP 642 EP 646 DI 10.1038/ng1368 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 825MX UT WOS:000221763700024 PM 15156144 ER PT J AU Alpan, O Bachelder, E Isil, E Arnheiter, H Matzinger, P AF Alpan, O Bachelder, E Isil, E Arnheiter, H Matzinger, P TI 'Educated' dendritic cells act as messengers from memory to naive T helper cells SO NATURE IMMUNOLOGY LA English DT Article ID PEYERS PATCH; IMMUNE-RESPONSE; ORAL TOLERANCE; BYSTANDER SUPPRESSION; TH2 DIFFERENTIATION; B-CELLS; IL-4; RECEPTOR; MECHANISMS; INDUCTION AB Ingested antigens lead to the generation of effector T cells that secrete interleukin 4 (IL-4) rather than interferon-gamma (IFN-gamma) and are capable of influencing naive T cells in their immediate environment to do the same. Using chimeric mice generated by aggregation of two genotypically different embryos, we found that the conversion of a naive T cell occurs only if it can interact with the same antigen-presenting cell, although not necessarily the same antigen, as the effector T cell. Using a two-step culture system in vitro, we found that antigen-presenting dendritic cells can act as 'temporal bridges' to relay information from orally immunized memory CD4 T cells to naive CD4 T cells. The orally immunized T cells use IL-4 and IL-10 (but not CD40 ligand) to 'educate' dendritic cells, which in turn induce naive T cells to produce the same cytokines as those produced by the orally immunized memory T cells. C1 NIAID, Ghost Lab, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. NINDS, Lab Dev Neurogenet, NIH, Bethesda, MD 20892 USA. Univ Nebraska, Dept Chem Engn, Lincoln, NE 68588 USA. RP Alpan, O (reprint author), NIAID, Ghost Lab, Cellular & Mol Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM oalpan@niaid.nih.gov NR 40 TC 98 Z9 103 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD JUN PY 2004 VL 5 IS 6 BP 615 EP 622 DI 10.1038/ni1077 PG 8 WC Immunology SC Immunology GA 824DH UT WOS:000221664000020 PM 15156140 ER PT J AU Rafnar, T Thorlacius, S Steingrimsson, E Schierup, MH Madsen, JN Calian, V Eldon, BJ Jonsson, T Hein, J Thorgeirsson, SS AF Rafnar, T Thorlacius, S Steingrimsson, E Schierup, MH Madsen, JN Calian, V Eldon, BJ Jonsson, T Hein, J Thorgeirsson, SS TI Opinion - The Icelandic Cancer Project - a population-wide approach to studying cancer SO NATURE REVIEWS CANCER LA English DT Article ID BREAST-CANCER; MUTATION; SUSCEPTIBILITY; DISEASE; RISK C1 NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Iceland Genom Corp, IS-105 Reykjavik, Iceland. Bioinformat ApS, DK-8000 Aarhus, Denmark. Landspitali Univ Hosp, Reykjavik, Iceland. RP Thorgeirsson, SS (reprint author), NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bldg 37,Room 4146A1,37 Convent Dr MSC4262, Bethesda, MD 20892 USA. EM snorri_thorgeirsson@nih.gov RI Schierup, Mikkel/F-1675-2010 OI Schierup, Mikkel/0000-0002-5028-1790 NR 18 TC 9 Z9 10 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X J9 NAT REV CANCER JI Nat. Rev. Cancer PD JUN PY 2004 VL 4 IS 6 BP 488 EP 492 DI 10.1038/nrc1371 PG 6 WC Oncology SC Oncology GA 825LG UT WOS:000221759300018 PM 15170451 ER PT J AU Milenic, DE Brady, ED Brechbiel, MW AF Milenic, DE Brady, ED Brechbiel, MW TI Antibody-targeted radiation cancer therapy SO NATURE REVIEWS DRUG DISCOVERY LA English DT Article ID NON-HODGKINS-LYMPHOMA; STEM-CELL TRANSPLANTATION; REFRACTORY LOW-GRADE; ALPHA-PARTICLE-EMITTER; ACUTE MYELOID-LEUKEMIA; PHASE-II TRIAL; MONOCLONAL-ANTIBODY; I-131 TOSITUMOMAB; BREAST-CANCER; FRACTIONATED RADIOIMMUNOTHERAPY AB Several monoclonal antibodies are now approved for cancer therapy, such as rituximab, an anti-CD20 monoclonal antibody for the treatment of B-cell non-Hodgkin's lymphoma. Such 'naked' antibodies can recruit the body's immune effector mechanisms to kill cells expressing the target of the antibody. In recent years, the linking of radionuclides to antibodies to either augment inherent activity or to exploit the specific targeting properties of monoclonal antibodies has been a major area of development. Two radionuclide-bearing monoclonal antibody therapies have recently been approved by the US FDA, and several more are in clinical trials. Here, we discuss the development and use of radiolabelled monoclonal antibody therapies, with a focus on radiolabelled monoclonal antibodies that have been evaluated in clinical trials. C1 NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Brechbiel, MW (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, Ctr Canc Res,NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM martinwb@mail.nih.gov NR 91 TC 194 Z9 201 U1 5 U2 24 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD JUN PY 2004 VL 3 IS 6 BP 488 EP 498 DI 10.1038/nrd1413 PG 11 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 831IH UT WOS:000222187600018 PM 15173838 ER PT J AU Seong, SY Matzinger, P AF Seong, SY Matzinger, P TI Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses SO NATURE REVIEWS IMMUNOLOGY LA English DT Editorial Material ID TOLL-LIKE RECEPTOR-4; LIPOPOLYSACCHARIDE-BINDING PROTEIN; MACROPHAGE SCAVENGER RECEPTOR; RESPIRATORY SYNCYTIAL VIRUS; LIPID TRANSFER PROTEINS; HEAT-SHOCK PROTEINS; C-REACTIVE PROTEIN; DENDRITIC CELLS; APOPTOTIC CELLS; SUPRAMOLECULAR STRUCTURE AB It is currently thought that immune responses are initiated by pathogen-associated molecular patterns or by tissue-derived danger/alarm signals. Here, we propose that these two groups of molecules might not be mutually exclusive. Many of them might be part of an evolutionarily ancient alert system in which the hydrophobic portions of biological molecules act, when exposed, as universal damage-associated molecular patterns to initiate repair, remodelling and immunity. C1 NIAID, Ghost Lab, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Seong, SY (reprint author), NIAID, Ghost Lab, Cellular & Mol Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM seongsy@snu.ac.kr RI Seong, Seung Yong /J-2764-2012 NR 127 TC 565 Z9 585 U1 2 U2 35 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD JUN PY 2004 VL 4 IS 6 BP 469 EP 478 DI 10.1038/nri1372 PG 10 WC Immunology SC Immunology GA 831IO UT WOS:000222188300016 PM 15173835 ER PT J AU Wise, RA AF Wise, RA TI Dopamine, learning and motivation SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID BRAIN-STIMULATION REWARD; COCAINE-INDUCED REINSTATEMENT; NUCLEUS-ACCUMBENS DOPAMINE; VENTRAL TEGMENTAL AREA; LONG-TERM POTENTIATION; NEUROLEPTIC-INDUCED ANHEDONIA; PIMOZIDE-INDUCED EXTINCTION; TASTE REACTIVITY ANALYSIS; INDUCED PLACE PREFERENCE; DRUG-SEEKING BEHAVIOR AB The hypothesis that dopamine is important for reward has been proposed in a number of forms, each of which has been challenged. Normally, rewarding stimuli such as food, water, lateral hypothalamic brain stimulation and several drugs of abuse become ineffective as rewards in animals given performance-sparing doses of dopamine antagonists. Dopamine release in the nucleus accumbens has been linked to the efficacy of these unconditioned rewards, but dopamine release in a broader range of structures is implicated in the 'stamping-in' of memory that attaches motivational importance to otherwise neutral environmental stimuli. C1 NIDA, Behav Neurosci Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Wise, RA (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. EM rwise@intra.nida.nih.gov RI Wise, Roy/A-6465-2012 NR 198 TC 1319 Z9 1340 U1 39 U2 248 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0048 J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD JUN PY 2004 VL 5 IS 6 BP 483 EP 494 DI 10.1038/nrn1406 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 825VG UT WOS:000221785900015 PM 15152198 ER PT J AU Swartz, KJ AF Swartz, KJ TI Opening the gate in potassium channels SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Editorial Material ID K+-CHANNEL; ACTIVATION GATE; SHAKER; INACTIVATION; PORE; CONFORMATION; DROSOPHILA; MECHANISM; RESIDUES; AXONS AB Structural studies of potassium channels suggest that opening of the gate involves large changes in the intracellular pore aperture, leaving a pore diameter >12 Angstrom recent mechanistic study on eukaryotic voltage-activated potassium channels points to an alternative picture of opening, including a smaller open pore and possibly a unique hinge or swivel point. C1 NINDS, Mol Physiol & Biophys Sect, NIH, Bethesda, MD 20892 USA. RP Swartz, KJ (reprint author), NINDS, Mol Physiol & Biophys Sect, NIH, Bethesda, MD 20892 USA. EM SwartzK@ninds.nih.gov FU Intramural NIH HHS [ZIA NS002945-13] NR 24 TC 13 Z9 15 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD JUN PY 2004 VL 11 IS 6 BP 499 EP 501 DI 10.1038/nsmb0604-499 PG 3 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 824DO UT WOS:000221664700006 PM 15164005 ER PT J AU Chen, YJ Zhang, PJ Egelman, EH Hinshaw, JE AF Chen, YJ Zhang, PJ Egelman, EH Hinshaw, JE TI The stalk region of dynamin drives the constriction of dynamin tubes SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID RECONSTRUCTION; GTPASE AB The GTPase dynamin is essential for numerous vesiculation events including clathrin-mediated endocytosis. Upon GTP hydrolysis, dynamin constricts a lipid bilayer. Previously, a three-dimensional structure of mutant dynamin in the constricted state was determined by helical reconstruction methods. We solved the nonconstricted state by a single-particle approach and show that the stalk region of dynamin undergoes a large conformational change that drives tube constriction. C1 Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA USA. NIDDKD, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Egelman, EH (reprint author), Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA USA. EM egelman@virginia.edu RI Egelman, Edward/A-2488-2009; OI Egelman, Edward/0000-0003-4844-5212 NR 12 TC 88 Z9 90 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD JUN PY 2004 VL 11 IS 6 BP 574 EP 575 DI 10.1038/nsmb762 PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 824DO UT WOS:000221664700022 PM 15133500 ER PT J AU Insel, TR AF Insel, TR TI Prologue: Expression profiling within the central nervous system, part II SO NEUROCHEMICAL RESEARCH LA English DT Editorial Material C1 NIMH, Bethesda, MD 20854 USA. RP Insel, TR (reprint author), NIMH, 6001 Execut Blvd,Room 8235, Bethesda, MD 20854 USA. EM insel@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD JUN PY 2004 VL 29 IS 6 BP I EP II PG 2 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 812CB UT WOS:000220816500001 ER PT J AU Vawter, MP Weickert, CS Ferran, E Matsumoto, M Overman, K Hyde, TM Weinberger, DR Bunney, WE Kleinman, JE AF Vawter, MP Weickert, CS Ferran, E Matsumoto, M Overman, K Hyde, TM Weinberger, DR Bunney, WE Kleinman, JE TI Gene expression of metabolic enzymes and a protease inhibitor in the prefrontal cortex are decreased in schizophrenia SO NEUROCHEMICAL RESEARCH LA English DT Article DE cytosolic malate dehydrogenase; gene expression; histidine-nucleotide triad binding protein; in situ hybridization histochemistry; microarray; neuroserpin; real-time quantitative PCR ID HISTIDINE TRIAD SUPERFAMILY; NUCLEOTIDE-BINDING PROTEINS; PSYCHIATRIC-DISORDERS; SUSCEPTIBILITY LOCUS; MICROARRAY ANALYSIS; CDNA MICROARRAYS; BIPOLAR DISORDER; SEX-DIFFERENCES; HUMAN BRAIN; RNA LEVELS AB Microarray expression studies have reported decreased mRNA expression of histidine triad nucleotide-binding protein (HINT1) and cytosolic malate dehydrogenase (MDH1) in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia. Microarray results for neuroserpin (SERPINI1) mRNA in the DLPFC have reported increased and decreased expression in individuals with schizophrenia. The relative abundances of HINT1, MDH1, and SERPINI1 mRNA in the DLPFC in individuals with schizophrenia and controls were measured by real-time quantitative polymerase chain reaction (Q-PCR) and for HINT1 expression by in situ hybridization. The Q-PCR results were compared by analysis of covariance between individuals with schizophrenia and controls. Gene expression levels for HINT1, MDH1, and SERPINI1 were significantly different between the groups. The male individuals with schizophrenia compared to male controls showed reductions by 2.8- to 3.7-fold of HINT1, neuroserpin, and MDH1 by Q-PCR. The decreases in mRNA abundance for MDH1 ( P = 0.006), HINT1 ( P = 0.050), and neuroserpin ( P = 0.005) in DLPFC of male individuals with schizophrenia is consistent with prior reports. HINT1 mRNA was reduced significantly by 34% in layer VI. Though there were no significant interactions with gender, gene expression between female patients and the female control group did not differ. These results confirm earlier reports and suggest abnormalities of specific genes related to metabolic and protease activities in the DLPFC might be considered as part of a molecular pathway in male patients with schizophrenia. C1 Univ Calif Irvine, Coll Med, Dept Psychiat & Human Behav, Irvine, CA 92697 USA. NIMH, NIH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. RP Vawter, MP (reprint author), Univ Calif Irvine, Coll Med, Dept Psychiat & Human Behav, Irvine, CA 92697 USA. EM mvawter@uci.edu RI Shannon Weickert, Cynthia/G-3171-2011; Matsumoto, Mitsuyuki/G-3207-2012 OI Matsumoto, Mitsuyuki/0000-0002-1172-2354 NR 45 TC 62 Z9 64 U1 1 U2 2 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD JUN PY 2004 VL 29 IS 6 BP 1245 EP 1255 DI 10.1023/B:NERE.0000023611.99452.47 PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 812CB UT WOS:000220816500022 PM 15176481 ER PT J AU Deco, G Rolls, ET Horwitz, B AF Deco, G Rolls, ET Horwitz, B TI Integrating fMRI and single-cell data of visual working memory SO NEUROCOMPUTING LA English DT Article; Proceedings Paper CT 12th Annual Computational Neuroscience Meeting (CSN 03) CY JUL 05-09, 2003 CL Alicante, SPAIN DE biased competition; working memory; prefrontal cortex; spiking neurons ID PREFRONTAL CORTEX; MODEL AB Based on single-cell and fMRI data, two different current models of the topographical and functional organization of the prefrontal cortex has been proposed: organization-by-stimulus-domain model, and organization-by-process model. The present work utilizes a computational neuroscience-based approach in order to integrate, via a detailed large-scale microscopic neurodynamical computational model, single-cells and fMRI measurements of the prefrontal cortex (PFC) associated with working memory processing, in order to delve into the question on the topographical structure of the PFC. For this purpose, we formulate an explicit model of the spiking and synaptic dynamical mechanisms that underly working memory-related activity during the execution of delay tasks with a 'what'-then-'where' design (object and spatial delayed response within the same trial). (C) 2004 Elsevier B.V. All rights reserved. C1 Univ Pompeu Fabra, Dept Technol & Comp Sci, Barcelona 8003, Spain. Univ Pompeu Fabra, Inst Catalana Recerca & Estudis Avancats, Barcelona 8003, Spain. Univ Oxford, Dept Expt Psychol, Oxford, England. NIH, Bethesda, MD USA. RP Deco, G (reprint author), Univ Pompeu Fabra, Dept Technol & Comp Sci, Passeig Circumval Iacio 8, Barcelona 8003, Spain. EM gustavo.deco@upf.edu RI Bonatti, Luca /E-9048-2011; Brain and Cognition, Center/H-5448-2011; Deco, Gustavo/A-6341-2008 OI Deco, Gustavo/0000-0002-8995-7583 NR 11 TC 11 Z9 11 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-2312 J9 NEUROCOMPUTING JI Neurocomputing PD JUN PY 2004 VL 58 BP 729 EP 737 DI 10.1016/j.neucom.2004.01.120 PG 9 WC Computer Science, Artificial Intelligence SC Computer Science GA 832CX UT WOS:000222245900107 ER PT J AU Jerbi, K Baillet, S Mosher, JC Nolte, G Garnero, L Leahy, RM AF Jerbi, K Baillet, S Mosher, JC Nolte, G Garnero, L Leahy, RM TI Localization of realistic cortical activity in MEG using current multipoles SO NEUROIMAGE LA English DT Article DE MEG; source localization; inverse problem; regularized leastsquares; current multipoles; current dipoles; extended sources; radial sources; cortical patches ID INVERSE PROBLEM; EXTENDED SOURCES; HUMAN-BRAIN; POTENTIALS; EXPANSIONS; GENERATORS; CORTEX; FIELDS; EEG AB We present a novel approach to MEG source estimation based on a regularized first-order multipole solution. The Gaussian regularizing prior is obtained by calculation of the sample mean and covariance matrix for the equivalent moments of realistic simulated cortical activity. We compare the regularized multipole localization framework to the classical dipole and general multipole source estimation methods by evaluating the ability of all three solutions to localize the centroids of physiologically plausible patches of activity simulated on the surface of a human cerebral cortex. The results, obtained with a realistic sensor configuration, a spherical head model, and given in terms of field and localization error, depict the performance of the dipolar and multipolar models as a function of variable source surface area (50-500 mm(2)), noise conditions (20, 10, and 5 dB SNR), source orientation (0-90degrees), and source depth (3-11 cm). We show that as the sources increase in size, they become less accurately modeled as current dipoles. The regularized multipole systematically outperforms the single dipole model, increasingly so as the spatial extent of the sources increases. In addition, our simulations demonstrate that as the orientation of the sources becomes more radial, dipole localization accuracy decreases substantially, while the performance of the regularized multipole model is far less sensitive to orientation and even succeeds in localizing quasiradial source configurations. Furthermore, our results show that the multipole model is able to localize superficial sources with higher accuracy than the current dipole. These results indicate that the regularized multipole solution may be an attractive alternative to current-dipole-based source estimation methods in MEG. (C) 2004 Elsevier Inc. All rights reserved. C1 Hop La Pitie Salpetriere, CNRS, UPR 640, Cognit Neurosci & Brain Imaging Lab, Paris, France. Univ So Calif, Inst Signal & Image Proc, Los Angeles, CA 90089 USA. Los Alamos Natl Lab, Los Alamos, NM 87545 USA. NINDS, NIH, Bethesda, MD 20892 USA. RP Baillet, S (reprint author), Hop La Pitie Salpetriere, CNRS, UPR 640, Cognit Neurosci & Brain Imaging Lab, Paris, France. EM Sylvain.Baillet@chups.jussieu.fr FU NIBIB NIH HHS [R01-EB002010] NR 49 TC 44 Z9 44 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUN PY 2004 VL 22 IS 2 BP 779 EP 793 DI 10.1016/j.neuroimage.2004.02.010 PG 15 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 829ZO UT WOS:000222091600031 PM 15193607 ER PT J AU Kansaku, K Hanakawa, T Wu, T Hallett, M AF Kansaku, K Hanakawa, T Wu, T Hallett, M TI A shared neural network for simple reaction time SO NEUROIMAGE LA English DT Article DE simple reaction time; neural network; fMRI ID SUPPLEMENTARY MOTOR AREA; SUPERIOR TEMPORAL SULCUS; HUMAN BRAIN; INTRACORTICAL MICROSTIMULATION; SOMATOTOPIC ORGANIZATION; PRECENTRAL GYRUS; PARIETAL CORTEX; MACAQUE MONKEY; MOVEMENTS; FMRI AB Simple reaction time, a simple model of sensory-to-motor behavior, has been extensively investigated and its role in inferring elementary mental organization has been postulated. However, little is known about the neuronal mechanisms underlying it. To elucidate the neuronal substrates, functional magnetic resonance imaging (fMRI) signals were collected during a simple reaction task paradigm using simple cues consisting of different modalities and simple triggered movements executed by different effectors. We hypothesized that a specific neural network that characterizes simple reaction time would be activated irrespective of the input modalities and output effectors. Such a neural network was found in the right posterior superior temporal cortex, right premotor cortex, left ventral premotor cortex, cerebellar vermis, and medial frontal gyrus. The right posterior superior temporal cortex and right premotor cortex were also activated by different modality sensory cues in the absence of movements. The shared neural network may play a role in sensory triggered movements. (C) 2004 Elsevier Inc. All rights reserved. C1 NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10,Room 5N226,10 Ctr Dr MSC 1428, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov NR 57 TC 16 Z9 16 U1 2 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUN PY 2004 VL 22 IS 2 BP 904 EP 911 DI 10.1016/j.neuroimage.2004.02.006 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 829ZO UT WOS:000222091600045 PM 15193621 ER PT J AU Horwitz, B AF Horwitz, B TI Relating fMRl and PET signals to neural activity by means of large-scale neural models SO NEUROINFORMATICS LA English DT Article; Proceedings Paper CT Brain Connectivity Workshop CY MAY, 2003 CL Cambridge, ENGLAND SP Wellcome Trust, EU Themat Network Computat Neurosci Neuroinformat, Boehringer Ingelheim Stifung DE brain; neural modeling; function imaging; network; cognition ID TRANSCRANIAL MAGNETIC STIMULATION; PRINCIPAL-COMPONENT ANALYSIS; FUNCTIONAL CONNECTIVITY; WORKING-MEMORY; PREFRONTAL CORTEX; CEREBRAL-CORTEX; VISUAL PATHWAYS; NETWORK; MODULATION; TOMOGRAPHY AB This article reviews the four ways by which large-scale, neurobiologically realistic modeling can be used in conjunction with functional neuroimaging data, especially that obtained by functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), to help investigators understand the neural bases for sensorimotor and cognitive functions. The conceptually distinct purposes served are: (1) formulating and implementing specific hypotheses about how neuronal populations mediate a task, which will be illustrated using models of visual and auditory object processing; (2) determining how well an experimental design paradigm or analysis method works, which will be illustrated by examining event-related fMRI; (3) investigating the meaning in neural terms of macro-level concepts, which will be illustrated using functional connectivity; and (4) combining different types of macroscopic data with one another, which will be illustrated using transcranial magnetic stimulation (TMS) and PET. C1 NIDOCD, Sect Brain Imaging & Modeling, NIH, Bethesda, MD USA. RP Horwitz, B (reprint author), NIDOCD, Sect Brain Imaging & Modeling, NIH, Bethesda, MD USA. EM horwitz@helix.nih.gov NR 46 TC 18 Z9 19 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1539-2791 J9 NEUROINFORMATICS JI Neuroinformatics PD SUM PY 2004 VL 2 IS 2 BP 251 EP 266 DI 10.1385/NI:2:2:251 PG 16 WC Computer Science, Interdisciplinary Applications; Neurosciences SC Computer Science; Neurosciences & Neurology GA 850AD UT WOS:000223582200011 PM 15319520 ER PT J AU Kaminski, RM Banerjee, M Rogawski, MA AF Kaminski, RM Banerjee, M Rogawski, MA TI Topiramate selectively protects against seizures induced by ATPA, a GluR5 kainate receptor agonist SO NEUROPHARMACOLOGY LA English DT Article DE topiramate; carbamazepine; Glur5; AMPA; kainate; NMDA; seizure; mouse ID ANTIEPILEPTIC DRUGS; ALPHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLE PROPIONATE; MOLECULAR PHARMACOLOGY; GRANULE CELLS; CURRENTS; NEURONS; ANTICONVULSANT; ANTAGONISTS; MICE; MODULATION AB Although the mechanism of action of topiramate is not fully Understood. its anticonvulsant properties may result, at least in part, from an interaction with AMPA/kainate receptors. We have recently shown that topiramate selectively inhibits postsynaptic responses mediated by GluR5 kainate receptors. To determine if this action of topiramate is relevant to the anticonvulsant effects of the drug in vivo, we determined the protective activity of topiramate against seizures induced by intravenous infusion of various ionotropic glutamate receptor agonists in mice. Topiramate (25 100 mg/kg, i.p.) produced a dose-dependent elevation in the threshold for clonic seizures induced by infusion of ATPA, a selective agonist of GluR5 kainate receptors. Topiramate was less effective in protecting against clonic seizures induced by kainate, a mixed agonist of AMPA and kainate receptors. Topiramate did not affect clonic seizures induced by AMPA or NMDA, In contrast, the thresholds for tonic seizures induced by higher closes of these various glutamate receptor agonists were all elevated by topiramate. Unlike topiramate, carbamazepine elevated the threshold for AMPA- but not ATPA-induced clonic seizures. Our results are consistent with the possibility that the effects of topiramate on clonic seizure activity are due to functional blockade of GluR5 kainate receptors. Protection from tonic seizures may be mediated by other actions of the drug. Together with our in vitro cellular electrophysiological results, the present observations strongly support a unique mechanism of action of topiramate which involves GluR5 kainate receptors. Published by Elsevier Ltd. C1 NINDS, Epilepsy Res Stn, NIH, Bethesda, MD 20892 USA. RP Rogawski, MA (reprint author), NINDS, Epilepsy Res Stn, NIH, Bethesda, MD 20892 USA. EM michael.rogawski@nih.gov RI Rogawski, Michael/B-6353-2009 OI Rogawski, Michael/0000-0002-3296-8193 NR 45 TC 76 Z9 80 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD JUN PY 2004 VL 46 IS 8 BP 1097 EP 1104 DI 10.1016/j.neuropharm.2004.02.010 PG 8 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 820DA UT WOS:000221365800005 PM 15111016 ER PT J AU Halim, ND Weickert, CS McClintock, BW Weinberger, DR Lipska, BK AF Halim, ND Weickert, CS McClintock, BW Weinberger, DR Lipska, BK TI Effects of chronic haloperidol and clozapine treatment on neurogenesis in the adult rat hippocampus SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE BrdU; dentate gyrus; neuroleptic; antipsychotic; schizophrenia; dentate gyrus ID BDNF MESSENGER-RNA; DENTATE GYRUS; CELL-PROLIFERATION; GENERATED NEURONS; GRANULE CELLS; BRAIN; EXPRESSION; INCREASES; IMMUNOREACTIVITY; SCHIZOPHRENIA AB It has been proposed that the therapeutic benefits of treatment with antidepressants and mood stabilizers may arise partially from their ability to stimulate neurogenesis. This study was designed to examine the effects of chronic antipsychotic treatment on cell proliferation and survival in the adult rat hippocampus. Haloperidol (0.05 and 2 mg/kg), clozapine (0.5 and 20 mg/kg), or vehicle were administered i.p. for 28 days, followed by bromodeoxyuridine (BrdU, 200 mg/kg, i.p.), a marker of DNA synthesis. One group of rats was killed 24 h following BrdU administration and BrdU-positive cells were quantified to assess the effects of drug treatment on cell proliferation. The remaining animals continued on antipsychotic medication for an additional 3 weeks following BrdU administration to assess the effects of antipsychotics on cell survival. Our results show that 24 h following BrdU, a low dose of clozapine (0.5 mg/kg) increased the number of BrdU-positive cells in the dentate gyrus (DG) by two-fold. Neither 20 mg/kg of clozapine nor haloperidol had any effect on cell proliferation in DG. Moreover, neither drug at either dose had an effect on the number of newly generated neurons surviving in the DG 3 weeks following BrdU administration. These preliminary findings suggest that clozapine may influence the number of cells which divide, but antipsychotics do not promote the survival of the newly generated neurons at 3 weeks after a BrdU injection. C1 NIMH, Intramural Res Program, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Lipska, BK (reprint author), NIMH, Intramural Res Program, Clin Brain Disorders Branch, NIH, Bldg 10,Rm 4N306, Bethesda, MD 20892 USA. EM lipskab@intra.nimh.nih.gov RI Shannon Weickert, Cynthia/G-3171-2011; Lipska, Barbara/E-4569-2017 NR 47 TC 115 Z9 122 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUN PY 2004 VL 29 IS 6 BP 1063 EP 1069 DI 10.1038/sj.npp.1300422 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 825MZ UT WOS:000221763900004 PM 15010699 ER PT J AU Broadbear, JH Winger, G Rivier, JE Rice, KC Woods, JH AF Broadbear, JH Winger, G Rivier, JE Rice, KC Woods, JH TI Corticotropin-releasing hormone antagonists, astressin B and antalarmin: Differing profiles of activity in rhesus monkeys SO NEUROPSYCHOPHARMACOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the ISPNE CY 2000 CL Melbourne, AUSTRALIA SP ISPNE DE rhesus monkey (Macaca mulatta); CRH antagonist; antalarmin; astressin B; cortisol; ACTH ID FACTOR(1) RECEPTOR ANTAGONIST; COMPETITIVE ANTAGONISTS; NONPEPTIDE ANTAGONIST; COCAINE; RAT; PITUITARY; STRESS; CP-154,526; POTENT; CRF AB The present study compares the activity of two chemically distinct corticotropin-releasing hormone (CRH) antagonists at the level of the pituitary gland in rhesus monkeys, using exogenous CRH-stimulated increases in adrenocorticotropin (ACTH) and cortisol. Of chief interest was whether the CRH-R1-selective pyrrolopyrimidine, antalarmin, shown previously to have activity in the central nervous system (CNS), would differ in its antagonist profile from the CRH-R1- & 2-selective peptide, astressin B, which is unlikely to have access to the CNS following systemic administration. Nine rhesus monkeys (eight male), each with an indwelling venous catheter, were subjects in this study. Astressin B (0.001, 0.003, 0.03, 0.1, and 0.3 mg/kg) or antalarmin (1.0, 3.2, and 10 mg/kg) was administered as an intravenous (i.v,) pretreatment 15 min prior to administration of 1 or 10 mug/kg i.v. CRH. Antalarmin (10 mg/kg) was also administered alone on six occasions and its effects on behavior as well as on ACTH and cortisol levels were measured. Astressin B was assessed following i.v. and intracisternal (i.c.) administration. Astressin B dose-dependently abolished the CRH-stimulated ACTH and cortisol responses, with an antagonist effect lasting in excess of 24 h. Astressin B was approximately 300-times more potent when given i.c. than when it was administered via the i.v. route. By contrast, antalarmin antagonized the effects of CRH on ACTH but not cortisol at 1.0 and 3.2 mg/kg. At a larger dose, antalarmin stimulated ACTH and cortisol release and produced behavioral sedation. These latter effects diminished with repeated administration of antalarmin. The differences between astressin B and antalarmin may be due either to non-CRH receptor-mediated effects of antalarmin or to a complex interaction of antalarmin's effects at both central and peripheral CRH receptors. C1 Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA. Salk Inst Biol Studies, La Jolla, CA 92037 USA. NIDDK, NIH, Bethesda, MD USA. Univ Michigan, Sch Med, Dept Psychol, Ann Arbor, MI 48109 USA. RP Broadbear, JH (reprint author), Univ Michigan, Sch Med, Dept Pharmacol, 1301 MSRB 3, Ann Arbor, MI 48109 USA. EM jillian.broadbear@med.monash.edu RI Broadbear, Jillian/A-6864-2011 FU NIDA NIH HHS [DA 09161, DA 00254]; NIDDK NIH HHS [DK 26741] NR 34 TC 29 Z9 29 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUN PY 2004 VL 29 IS 6 BP 1112 EP 1121 DI 10.1038/sj.npp.1300410 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 825MZ UT WOS:000221763900009 PM 14997174 ER PT J AU Sanacora, G Berman, RM Cappiello, A Oren, DA Kugaya, A Liu, NJ Gueorguieva, R Fasula, D Charney, DS AF Sanacora, G Berman, RM Cappiello, A Oren, DA Kugaya, A Liu, NJ Gueorguieva, R Fasula, D Charney, DS TI Addition of the alpha 2-antagonist yohimbine to fluoxetine: Effects on rate of antidepressant response SO NEUROPSYCHOPHARMACOLOGY LA English DT Article; Proceedings Paper CT 41st Annual Meeting of the American-College-of-Neuropsychopharmacology (ACNP) CY DEC 08-12, 2002 CL SAN JUAN, PR SP Amer Coll Neuropsychopharmacol DE major depression; mood disorders; treatment; alpha 2-adrenergic receptor ID ENDOGENOUS NORADRENALINE; REFRACTORY DEPRESSION; MIRTAZAPINE; NEURONS; AUGMENTATION; RELEASE; ALPHA-2-ADRENOCEPTORS; DYSFUNCTION; RELIABILITY; HIPPOCAMPUS AB Electrophysiological studies suggest that alpha2-adrenoceptors profoundly affect monoaminergic neurotransmission by enhancing noradrenergic tone and serotonergic firing rates. Recent reports suggest that alpha2-antagonism may hasten and improve the response to antidepressant medications, To test this hypothesis, a randomized double-blind controlled trial was undertaken to determine if the combination of an alpha2-antagonist (yohimbine) with a selective serotonin reuptake agent (SSRI) (fluoxetine) results in more rapid onset of antidepressant action than an SSRI agent alone. In all, 50 subjects with a DSM-IV diagnosis of major depressive disorder confirmed by SCID interview were randomly assigned to receive either fluoxeline 20 mg plus placebo (F/P) or fluxetine 20 mg plus a titrated dose of yolhimbine (F/Y). The yolhimbine dose was titrated based on blood pressure changes over the treatment period, in a blind-preserving manner, Hamilton depression scale ratings (HDRS) and clinical global impression (CGI) ratings were obtained weekly over a period of 6 weeks. The rate of achieving categorical positive responses was significantly more rapid in the F/Y group compared to the F/P group using both the HDRS and the CGI scales as outcome measures in a survival analysis using a log-rank test (chi(2)(1) = 5.86, p = 0.016 and chi(2)(1) = 5.29, p = 0.021, respectively). At the last observed visit, 18 (69%) of the 26 F/Y subjects met the response criteria for CGI compared to 10 (42%) of 24 F/P subjects. Using the HDRS criteria, 17 (65%) of 26 F/Y subject vs 10 (42%) of 24 F/P subjects were responders. The addition of the alpha2-antagonist yohimbine to fluoxetine appears to hasten the antidepressant response. There is also a trend suggesting an increased percentage of responders to the combined treatment at the end of the 6-week trial. C1 Yale Univ, Sch Med, Connecticut Mental Hlth Ctr,Dept Psychiat, Abraham Ribicoff Res Facil,Clin Neurosci Res Unit, New Haven, CT 06508 USA. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. NIMH, Bethesda, MD 20892 USA. RP Sanacora, G (reprint author), Yale Univ, Sch Med, Connecticut Mental Hlth Ctr,Dept Psychiat, Abraham Ribicoff Res Facil,Clin Neurosci Res Unit, 34 Pk St, New Haven, CT 06508 USA. EM gerard.sanacora@yale.edu FU NIMH NIH HHS [K08 MH01715-01] NR 28 TC 55 Z9 57 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUN PY 2004 VL 29 IS 6 BP 1166 EP 1171 DI 10.1038/sj.npp.1300418 PG 6 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 825MZ UT WOS:000221763900014 PM 15010697 ER PT J AU Harris-Love, MO Siegel, KL Paul, SM Benson, K AF Harris-Love, MO Siegel, KL Paul, SM Benson, K TI Rehabilitation management of Friedreich ataxia: Lower extremity force-control variability and gait performance SO NEUROREHABILITATION AND NEURAL REPAIR LA English DT Article DE Friedreich ataxia; force control; rehabilitation ID TEST-RETEST RELIABILITY; MULTIPLE-SCLEROSIS; CEREBELLAR-ATAXIA; CEREBRAL-PALSY; BALANCE TESTS; PEG TEST; COORDINATION; CHILDREN; MECHANISMS; MOVEMENT AB We describe the rehabilitation management during a 12-month period of a 14 year-old. female with Friedreich ataxia. Interventions included task-oriented bimanual reaching activities,.functional strengthening, and gait training using a walker featuring tension-controlled wheels and a reverse-braking system. Herphysical status was assessed with the Nine-Hole Peg Test, single limb stance tune, manual muscle testing, self-reported falls, isometric force control testing, and 3-dimensional gait analysis in a motion-capture laboratory. Although measures of the patient's Nine-Hole Peg Test, single limb stance time, and manual muscle testing reflected minimal changes, her gait speed decreased by 69.4%. However, the force-control targeting of her dominant knee extensors showed a 43.7% increase in force variability that was concomitant with her decline in gait performance. The decrement of her initial gait speed was reduced to 42.9 on replacing the wheeled walker with the U-Step Walking Stabilizer at the end of the intervention period. Although the patient's gait remained significantly impaired, extended use of the U-Step Walking Stabilizer modestly improved her gail performance, and her rate of falls decreased from 10 to 3 per month. Our observations suggest that use of force-control testing as proxy measures of ataxia and tension-controlled gait aids show promise in the management of Friedreich ataxia and merit further investigation. C1 NIH, Warren G Magnuson Clin Ctr, Phys Therapy Sect, Dept Rehabil Med,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIH, Dept Hlth & Human Serv, Med Sect, Bethesda, MD 20892 USA. NIH, Dept Hlth & Human Serv, Phys Disabil Branch, Bethesda, MD 20892 USA. Northeastern Univ, Bouve Coll Hlth Sci, Program Phys Therapy, Boston, MA USA. RP Harris-Love, MO (reprint author), NIH, Warren G Magnuson Clin Ctr, Phys Therapy Sect, Dept Rehabil Med,Dept Hlth & Human Serv, Bldg 10,Room 6S-235, Bethesda, MD 20892 USA. EM mlove@nih.gov RI Siegel, Karen Lohmann/B-5898-2008; Van Mulders, Benjamin/P-1241-2014; Harris-Love, Michael/J-1359-2014; OI Harris-Love, Michael/0000-0002-1842-3269; Paul, Scott/0000-0003-1274-6670; Siegel, Karen Lohmann/0000-0002-0788-6612 NR 44 TC 12 Z9 13 U1 0 U2 12 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1545-9683 EI 1552-6844 J9 NEUROREHAB NEURAL RE JI Neurorehabil. Neural Repair PD JUN PY 2004 VL 18 IS 2 BP 117 EP 124 DI 10.1177/0888439004267241 PG 8 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 846WM UT WOS:000223349900008 PM 15228808 ER PT J AU Harry, GJ AF Harry, GJ TI Emerging technologies in neurotoxicology: Session III - Summary and research needs SO NEUROTOXICOLOGY LA English DT Article; Proceedings Paper CT 20th International Neurotoxicology Conference CY NOV 18-21, 2002 CL LITTLE ROCK, AR C1 NIEHS, Neurotoxicol Grp, Res Triangle Pk, NC 27709 USA. RP Harry, GJ (reprint author), NIEHS, Neurotoxicol Grp, MD C1-04,POB 12233, Res Triangle Pk, NC 27709 USA. EM harry@niehs.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X J9 NEUROTOXICOLOGY JI Neurotoxicology PD JUN PY 2004 VL 25 IS 4 BP 503 EP 506 DI 10.1016/j.neuro.2003.09.012 PG 4 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 830KW UT WOS:000222121900003 PM 15183003 ER PT J AU Wolff, MS Berkowitz, GS Wetmur, J Matte, T Landrigan, PJ AF Wolff, MS Berkowitz, GS Wetmur, J Matte, T Landrigan, PJ TI Gene environment influences on neurologic and somatic development. SO NEUROTOXICOLOGY LA English DT Meeting Abstract CT 20th International Neurotoxicology Conference CY NOV 18-21, 2002 CL LITTLE ROCK, AR C1 US EPA, NIEHS, Childrens Environm Hlth & Dis Prevent Res Ctr, Mt Sinai Sch Med,Dept Community & Prevent Med, New York, NY USA. US EPA, NIEHS, Childrens Environm Hlth & Dis Prevent Res Ctr, Mt Sinai Sch Med,Dept Pediat, New York, NY USA. US EPA, NIEHS, Childrens Environm Hlth & Dis Prevent Res Ctr, Mt Sinai Sch Med,Dept Microbiol, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X J9 NEUROTOXICOLOGY JI Neurotoxicology PD JUN PY 2004 VL 25 IS 4 BP 667 EP 667 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 830KW UT WOS:000222121900025 ER PT J AU Longnecker, MP Klebanoff, MA Daniels, JL Gray, KA Brock, JW AF Longnecker, MP Klebanoff, MA Daniels, JL Gray, KA Brock, JW TI Prenatal exposure to PCBs and heptachlor epoxide in relation to child development in the collaborative perinatal project. SO NEUROTOXICOLOGY LA English DT Meeting Abstract CT 20th International Neurotoxicology Conference CY NOV 18-21, 2002 CL LITTLE ROCK, AR C1 NIEHS, Epidemiol Branch, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X J9 NEUROTOXICOLOGY JI Neurotoxicology PD JUN PY 2004 VL 25 IS 4 BP 674 EP 674 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 830KW UT WOS:000222121900045 ER PT J AU Suk, WA AF Suk, WA TI Global environmental threats to children's health: Research needs and future directions. SO NEUROTOXICOLOGY LA English DT Meeting Abstract CT 20th International Neurotoxicology Conference CY NOV 18-21, 2002 CL LITTLE ROCK, AR C1 Natl Inst Environm Hlth Sci, Ctr Risk & Integrated Sci, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X J9 NEUROTOXICOLOGY JI Neurotoxicology PD JUN PY 2004 VL 25 IS 4 BP 687 EP 687 PG 1 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 830KW UT WOS:000222121900077 ER PT J AU Alexander, D Scheidt, P Selevan, SG AF Alexander, D Scheidt, P Selevan, SG TI The National Children's Study 2 (NCS). SO NEUROTOXICOLOGY LA English DT Meeting Abstract CT 20th International Neurotoxicology Conference CY NOV 18-21, 2002 CL LITTLE ROCK, AR C1 NICHHD, NIH, DHHS, Bethesda, MD 20892 USA. NICHHD, NIH, HHS, Program Off,Natl Childrens Study, Bethesda, MD 20892 USA. US EPA, Off Res & Dev, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X J9 NEUROTOXICOLOGY JI Neurotoxicology PD JUN PY 2004 VL 25 IS 4 BP 706 EP 707 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 830KW UT WOS:000222121900125 ER PT J AU Deppmann, CD Acharya, A Rishi, V Wobbes, B Smeekens, S Taparowsky, EJ Vinson, C AF Deppmann, CD Acharya, A Rishi, V Wobbes, B Smeekens, S Taparowsky, EJ Vinson, C TI Dimerization specificity of all 67 B-ZIP motifs in Arabidopsis thaliana: a comparison to Homo sapiens B-ZIP motifs SO NUCLEIC ACIDS RESEARCH LA English DT Article ID BZIP TRANSCRIPTION FACTORS; HELICAL COILED COILS; GCN4 LEUCINE-ZIPPER; DNA-BINDING; AMINO-ACID; OLIGOMERIZATION STATE; NUCLEAR-PROTEIN; BASIC REGION; STABILITY; POSITION AB Basic region-leucine zipper (B-ZIP) proteins are a class of dimeric sequence-specific DNA-binding proteins unique to eukaryotes. We have identified 67 B-ZIP proteins in the Arabidopsis thaliana genome. No A.thaliana B-ZIP domains are homologous with any Homo sapiens B-ZIP domains. Here, we predict the dimerization specificity properties of the 67 B-ZIP proteins in the A.thaliana genome based on three structural properties of the dimeric alpha-helical leucine zipper coiled coil structure: (i) length of the leucine zipper, (ii) placement of asparagine or a charged amino acid in the hydrophobic interface and (iii) presence of interhelical electrostatic interactions. Many A.thaliana B-ZIP leucine zippers are predicted to be eight or more heptads in length, in contrast to the four or five heptads typically found in H.sapiens, a prediction experimentally verified by circular dichroism analysis. Asparagine in the a position of the coiled coil is typically observed in the second heptad in H.sapiens. In A.thaliana, asparagine is abundant in the a position of both the second and fifth heptads. The particular placement of asparagine in the a position helps define 14 families of homodimerizing B-ZIP proteins in A.thaliana, in contrast to the six families found in H.sapiens. The repulsive interhelical electrostatic interactions that are used to specify heterodimerizing B-ZIP proteins in H.sapiens are not present in A.thaliana. Instead, we predict that plant leucine zippers rely on charged amino acids in the a position to drive heterodimerization. It appears that A.thaliana define many families of homodimerizing B-ZIP proteins by having long leucine zippers with asparagine judiciously placed in the a position of different heptads. C1 Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. Univ Utrecht, Dept Mol Plant Physiol, NL-3584 CH Utrecht, Netherlands. RP Vinson, C (reprint author), Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. EM vinsonc@dc37a.nci.nih.gov RI Smeekens, Sjef/B-6683-2011 OI Smeekens, Sjef/0000-0001-6631-9426 FU NCI NIH HHS [R01 CA078264] NR 47 TC 55 Z9 94 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUN PY 2004 VL 32 IS 11 BP 3435 EP 3445 DI 10.1093/nar/gkh653 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 834GI UT WOS:000222399200025 PM 15226410 ER PT J AU Coumoul, X Li, WM Wang, RH Deng, CX AF Coumoul, X Li, WM Wang, RH Deng, CX TI Inducible suppression of Fgfr2 and Survivin in ES cells using a combination of the RNA interference (RNAi) and the Cre-LoxP system SO NUCLEIC ACIDS RESEARCH LA English DT Article ID MAMMALIAN-CELLS; GENE-EXPRESSION; MICE; GROWTH; RECOMBINASE; INACTIVATION; TECHNOLOGY; INDUCTION; GENOME AB RNA interference (RNAi) is a simple and powerful tool widely used for studying gene function in a number of species. Recently, inducible regulation of RNAi in mammalian cells using either tetracycline- or ecdysone-responsive systems has been developed to prevent potential lethality or non-physiological responses associated with persistent suppression of genes that are essential for cell survival or cell cycle progression. Here we show that the inducible regulation of RNAi also can be achieved by using a Cre-LoxP approach. We demonstrate that the insertion of a loxP-flanked neomycin cassette into RNA polymerase III promoter, which controls a vector-based RNAi unit, impairs the promoter activity. However, the expression of RNAi construct can be completely restored upon the removal of the neo cassette using a tamoxifen inducible Cre construct. We show that this system works with high efficiency in suppression of two endogenous genes, Fgfr2 and Survivin, in mouse embryonic stem (ES) cells, as evidenced by the decrease of levels of gene expression, reduced cell proliferation and colony formation. This system provides a potentially important yet simple approach to establish mutant mouse strains for functional study at defined stages upon turning on the inducible switches controlled by the Cre-LoxP system. C1 NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Deng, CX (reprint author), NIDDKD, Genet Dev & Dis Branch, NIH, 10-9N105, Bethesda, MD 20892 USA. EM chuxiad@bdg10.niddk.nih.gov RI deng, chuxia/N-6713-2016 NR 37 TC 45 Z9 50 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUN PY 2004 VL 32 IS 10 AR e85 DI 10.1093/nar/gnh083 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 830JQ UT WOS:000222118600007 PM 15199177 ER PT J AU Jaruga, P Theruvathu, J Dizdaroglu, M Brooks, PJ AF Jaruga, P Theruvathu, J Dizdaroglu, M Brooks, PJ TI Complete release of (5 ' S)-8,5 '-cyclo-2 '-deoxyadenosine from dinucleotides, oligodeoxynucleotides and DNA, and direct comparison of its levels in cellular DNA with other oxidatively induced DNA lesions SO NUCLEIC ACIDS RESEARCH LA English DT Article ID LIQUID CHROMATOGRAPHY/MASS SPECTROMETRY; RADICAL-INDUCED FORMATION; REPAIR PATHWAY; INDUCED DAMAGE; HUMAN-CELLS; 8,5'-CYCLO-2'-DEOXYGUANOSINE; IDENTIFICATION; RESIDUES; PROTEIN; BINDING AB 8,5'-Cyclopurine-2'-deoxynucleosides in DNA are repaired by nucleotide-excision repair, and act as strong blocks to DNA polymerases, RNA polymerase II and transcription factor binding. Thus, it is important to accurately determine the level of these lesions in DNA. There is controversy in the literature regarding the ability of different enzymes to release these compounds from oligodeoxynucleotides or DNA. We used liquid chromatography/mass spectrometry (LC/MS) to investigate the ability of several enzymes to release (5'S)-8,5'-cyclo-2'-deoxyadenosine [(5'S)-cdA] from dinucleotides and oligodeoxynucleotides and from DNA. The data show that (5'S)-cdA is completely released from DNA by hydrolysis with nuclease P1, snake venom phosphodiesterase and alkaline phosphatase. The identity of the normal nucleoside 5' to the (5'S)-cdA had a significant effect on its release. Using LC/MS, we also showed that the levels of (5'S)-cdA were within an order of magnitude of those of 8-hydroxy-2'-deoxyguanosine, and three times higher than those of 8-hydroxy-2'-deoxyadenosine in pig liver DNA. Different DNA isolation methods affected the levels of the latter two lesions, but did not influence those of (5'S)-cdA. We conclude that (5'S)-cdA can be completely released from DNA by enzymic hydrolysis, and the level of (5'S)-cdA in tissue DNA is comparable to those of other oxidatively induced DNA lesions. C1 Univ Maryland Baltimore Cty, Dept Chem & Biochem Engn, Baltimore, MD USA. Natl Inst Stand & Technol, Chem Sci & Technol Lab, Gaithersburg, MD 20899 USA. NIAAA, Mol Neurobiol Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Jaruga, P (reprint author), Univ Maryland Baltimore Cty, Dept Chem & Biochem Engn, Baltimore, MD USA. EM pawel.jaruga@nist.gov RI Jaruga, Pawel/M-4378-2015 NR 26 TC 52 Z9 52 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUN PY 2004 VL 32 IS 11 AR e87 DI 10.1093/nar/gnh087 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 834GI UT WOS:000222399200002 PM 15215337 ER PT J AU Schieve, LA Rasmussen, SA Buck, GM Schendel, DE Reynolds, MA Wright, VC AF Schieve, LA Rasmussen, SA Buck, GM Schendel, DE Reynolds, MA Wright, VC TI Are children born after assisted reproductive technology at increased risk for adverse health outcomes? SO OBSTETRICS AND GYNECOLOGY LA English DT Editorial Material ID IN-VITRO FERTILIZATION; INTRACYTOPLASMIC SPERM INJECTION; LOW-BIRTH-WEIGHT; BECKWITH-WIEDEMANN-SYNDROME; CONGENITAL-MALFORMATIONS; PREIMPLANTATION EMBRYOS; INFANTS BORN; SPONTANEOUS-ABORTION; OVARIAN STIMULATION; IMPRINTING DEFECTS AB As assisted reproductive technologies (ARTs) are increasingly used to overcome infertility, there is concern about the health of the children conceived. The empirical evidence for associations with outcomes related to child health is variable and should be evaluated with consideration of methodological shortcomings. Currently, there is convincing evidence that ART treatment may increase the risk of a few outcomes. Experimental laboratory studies document that various constituents in culture media affect various embryo characteristics both positively and negatively. Multiple-gestation pregnancy and birth are increased with ART, both because of multiple embryo transfer and embryo splitting. There is evidence of an increase in chromosomal abnormalities among pregnancies conceived using intracytoplasmic sperm injection and low birth weight and preterm delivery among singletons conceived with all types of ART; however, there remains uncertainty about whether these risks stem from the treatment or the parental infertility. For some outcomes, data of an increased risk with ART are suggestive at best largely because of lack of purposeful study of sufficient size and scope. These include specific perinatal morbidities, birth defects, developmental disabilities, and retinoblastoma. The evidence for an association between ART and spontaneous abortion is inconsistent and weak. There is inconclusive evidence that ART may be associated with genetic imprinting disorders. For childhood cancer, chronic conditions, learning and behavioral disorders, and reproductive effects there is insufficient empirical research to date, but given the data for more proximal outcomes, these outcomes merit further study. Future research needs to address the unique methodological challenges underlying study in this area. (C) 2004 by The American College of Obstetricians and Gynecologists. C1 Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Reprod Hlth, Atlanta, GA USA. Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA USA. NICHHD, Div Epidemiol Stat & Prevent Res, Dept Hlth & Human Serv, Rockville, MD USA. RP Schieve, LA (reprint author), CDC, Mailstop LSchieve K-34,4770 Buford Highway,NE, Atlanta, GA 30333 USA. OI Buck Louis, Germaine/0000-0002-1774-4490 NR 62 TC 91 Z9 92 U1 0 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JUN PY 2004 VL 103 IS 6 BP 1154 EP 1163 DI 10.1097/01.AOG.0000124571.04890.67 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 875IU UT WOS:000225414500005 PM 15172847 ER PT J AU Brinton, LA Lamb, EJ Moghissi, KS Scoccia, B Althuis, MD Mabie, JE Westhoff, CL AF Brinton, LA Lamb, EJ Moghissi, KS Scoccia, B Althuis, MD Mabie, JE Westhoff, CL TI Ovarian cancer risk after the use of ovulation-stimulating drugs SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID IN-VITRO FERTILIZATION; STATES CASE-CONTROL; FERTILITY DRUGS; INFERTILE WOMEN; COLLABORATIVE ANALYSIS; GONADOTROPIN THERAPY; WHITE WOMEN; CARCINOMA; COHORT; PATIENT AB OBJECTIVE: To assess the long-term effects of ovulation-stimulating drugs on the risk of ovarian cancer. METHODS: A retrospective cohort study of 12,193 eligible study subjects (median age 30 years) who were evaluated for infertility during the period of 1965-1988 at 5 clinical sites identified 45 subsequent ovarian cancers in follow-up through 1999. Standardized incidence ratios compared the risk of cancer among the infertile patients to the general population, whereas analyses within the cohort allowed the derivation of rate ratios for drug usage compared with no usage after adjustment for other ovarian cancer predictors. RESULTS: The infertility patients had a significantly elevated ovarian cancer risk compared with the general population (standardized incidence ratio 1.98, 95% confidence intervals [CI] 1.4, 2.6). When patient characteristics were taken into account and risks assessed within the infertile women, the rate ratios associated with ever usage were 0.82 (95% CI 0.4, 1.5) for clomiphene and 1.09 (95% CI 0.4, 2.8) for gonadotropins. There were higher, albeit nonsignificant, risks with follow-up time, with the rate ratios after 15 or more years being 1.48 (95% CI 0.7, 3.2) for exposure to clomiphene (5 exposed cancer patients) and 2.46 (95% CI 0.7, 8.3) for gonadotropins (3 exposed cancer patients). Although drug effects did not vary by causes of infertility, there was a slightly higher risk associated with clomiphene use among women who remained nulligravid, based on 6 exposed patients (rate ratio 1.75; 95% CI 0.5, 5.7). CONCLUSION: ne results of this study generally were reassuring in not confirming a strong link between ovulation-stimulating drugs and ovarian cancer. Slight but nonsignificant elevations in risk associated with drug usage among certain subgroups of users, however, support the need for continued monitoring of long-term risks. (C) 2004 by The American College of Obstetricians and Gynecologists. C1 Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. Stanford Univ, Stanford, CA 94305 USA. Wayne State Univ, Detroit, MI USA. Univ Illinois, Chicago, IL 60680 USA. Informat Management Serv Inc, Rockville, MD USA. Columbia Univ, New York, NY USA. RP Brinton, LA (reprint author), 6120 Execut Blvd,Room 7068, Rockville, MD 20852 USA. EM brinton@nih.gov RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 37 TC 90 Z9 99 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JUN PY 2004 VL 103 IS 6 BP 1194 EP 1203 DI 10.1097/01.AOG.0000128139.92313.74 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 875IU UT WOS:000225414500010 PM 15172852 ER PT J AU Trimble, EL Schoenfeldt, M AF Trimble, EL Schoenfeldt, M TI Current clinical trials of HPV vaccines SO ONCOLOGY-NEW YORK LA English DT Article ID CERVICAL INTRAEPITHELIAL NEOPLASIA; HUMAN-PAPILLOMAVIRUS; CANCER; VACCINATION; WOMEN C1 NCI, Bethesda, MD 20892 USA. Emmes Corp, Rockville, MD USA. RP Trimble, EL (reprint author), NCI, Bethesda, MD 20892 USA. NR 16 TC 1 Z9 1 U1 0 U2 0 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD JUN PY 2004 VL 18 IS 7 BP 859 EP + PG 3 WC Oncology SC Oncology GA 052DL UT WOS:000238211300011 PM 15255170 ER PT J AU Kim, HS Neubert, JK Miguel, AS Xu, K Krishnaraju, RK Iadarola, MJ Goldman, D Dionne, RA AF Kim, HS Neubert, JK Miguel, AS Xu, K Krishnaraju, RK Iadarola, MJ Goldman, D Dionne, RA TI Genetic influence on variability in human acute experimental pain sensitivity associated with gender, ethnicity and psychological temperament SO PAIN LA English DT Article DE genetic variation; gender; ethnicity; temperament; experimental pain human model ID OPIOID RECEPTOR GENE; O-METHYLTRANSFERASE COMT; SEX-DIFFERENCES; CAPSAICIN RECEPTOR; REGRESSION TREES; MENSTRUAL-CYCLE; ANXIETY; NOCICEPTION; CLASSIFICATION; POLYMORPHISM AB While a variety of cultural, psychological and physiological factors contribute to variability in both clinical and experimental contexts, the role of genetic factors in human pain sensitivity is increasingly recognized as an important element. This study was performed to evaluate genetic influences on variability in human pain sensitivity associated with gender, ethnicity and temperament. Pain sensitivity in response to experimental painful thermal and cold stimuli was measured with visual analogue scale ratings and temperament dimensions of personality were evaluated. Loci in the vanilloid receptor subtype I gene (TRPV1), delta opioid receptor subtype I gene (OPRD2) and catechol O-methyltransferase gene (COMT) were genotyped using 5' nuclease assays. A total of 500 normal participants (306 females and 194 males) were evaluated. The sample composition was 62.0% European American, 17.4% African American, 9.0% Asian American, and 8.6% Hispanic, and 3.0% individuals with mixed racial parentage. Female European Americans with the TRPV1 Val(585) Val allele and males with low harm avoidance showed longer cold withdrawal times based on the classification and regression tree (CART) analysis. CART identified gender, an OPRD1 polymorphism and temperament dimensions of personality as the primary determinants of heat pain sensitivity at 49 degreesC. Our observations demonstrate that gender, ethnicity and temperament contribute to individual variation in thermal and cold pain sensitivity by interactions with TRPV1 and OPRD1 single nucleotide polymorphisms. (C) 2004 Published by Elsevier B.V. on behalf of International Association for the Study of Pain. C1 Natl Inst Dent & Craniofacial Res, Pain & Neurosensory Mech Branch, NIH, Bethesda, MD 20892 USA. NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. RP Dionne, RA (reprint author), Natl Inst Dent & Craniofacial Res, Pain & Neurosensory Mech Branch, NIH, 10 Ctr Dr Bldg 10 Rm 1N103, Bethesda, MD 20892 USA. EM rdionne@dir.nidcr.nih.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 67 TC 214 Z9 220 U1 4 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD JUN PY 2004 VL 109 IS 3 BP 488 EP 496 DI 10.1016/j.pain.2004.02.027 PG 9 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 829HW UT WOS:000222039400034 PM 15157710 ER PT J AU Byrne, J Fears, TR Mills, JL Zeltzer, LK Sklar, C Nicholson, HS Haupt, R Reaman, GH Meadows, AT Robison, LL AF Byrne, J Fears, TR Mills, JL Zeltzer, LK Sklar, C Nicholson, HS Haupt, R Reaman, GH Meadows, AT Robison, LL TI Fertility in women treated with cranial radiotherapy for childhood acute lymphoblastic leukemia SO PEDIATRIC BLOOD & CANCER LA English DT Article DE childhood cancer; fertility; leukemia; menarche; radiotherapy ID LONG-TERM SURVIVORS; CHILDRENS CANCER GROUP; OVARIAN-FUNCTION; ADULT SURVIVORS; IRRADIATION; CHEMOTHERAPY; RADIATION; TUMORS; COHORT AB Background. Fertility impairments among women treated during childhood for cancer are known to Occur after some, but not all, types of anticancer therapy. Although leukemia is the most common cancer of childhood, until now fertility in survivors has not been comprehensively assessed. Procedure. We investigated functional impairment of fertility in women who were long-term survivors of acute lymphoblastic leukemia (ALL) with a retrospective cohort study. Proven fertility (defined as ever pregnant) was evaluated by self-report among 182 females treated on protocols of the Children's Cancer Group (age at interview, 22.6 years on average) and 170 controls drawn from among the survivors' female siblings (23.4 years). The interview included psychosocial inventories designed to detect mood problems. Results. Significant fertility deficits were noted in female survivors treated with cranial radiotherapy (CRT) at any dose around the time of menarche (relative fertility (RF)) 0.27, 959% Cl=0.09, 0.82, P=0.03). Controlling for marital status, mood at interview, and many fertility-related situations did not change the association. Conclusion. This study provides evidence for fertility deficits after treatment for ALL with CRT, and, in addition, for the first time, suggests that girls treated around the time of menarche are especially at risk. Clinical confirmation of these results is needed. if gonadal damage Occurs in women receiving these treatments, their risk for further sequelae, such as osteoporosis and heart disease, may be significantly raised, requiring active management and intervention. (C) 2004 Wiley-Liss, Inc. C1 Childrens Natl Med Ctr, Div Hematol Oncol, Washington, DC 20010 USA. NIH, Bethesda, MD 20892 USA. Childrens Canc Grp, Arcadia, CA USA. Univ Calif Los Angeles, Los Angeles, CA USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. G Gaslini Childrens Hosp, Genoa, Italy. Univ Minnesota, Ctr Canc, Minneapolis, MN USA. RP Byrne, J (reprint author), Childrens Natl Med Ctr, Div Hematol Oncol, 111 Michigan Ave NW, Washington, DC 20010 USA. EM jbyrne@cnmc.org RI Haupt, Riccardo/C-2237-2012; OI Haupt, Riccardo/0000-0003-0571-8460; Zeltzer, Lonnie/0000-0001-9306-9450 NR 29 TC 25 Z9 25 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 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2004 VL 42 IS 7 BP 589 EP 597 DI 10.1002/pbc.20033 PG 9 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 818DM UT WOS:000221225800007 PM 15127413 ER PT J AU Cho, ME Kopp, JB AF Cho, ME Kopp, JB TI Fabry disease in the era of enzyme replacement therapy: a renal perspective SO PEDIATRIC NEPHROLOGY LA English DT Review DE lysosomal storage disorder; alpha-galactosidase A; renal pathology; renal failure; dialysis; renal transplantation ID ALPHA-GALACTOSIDASE; NATURAL-HISTORY; KIDNEY INVOLVEMENT; CARDIAC-FUNCTION; TRANSPLANTATION; CERAMIDETRIHEXOSIDASE; MANIFESTATIONS; IMPROVEMENT; EXPERIENCE; DEFICIENCY AB Fabry disease, the second most prevalent lysosomal storage disorder after Gaucher disease, is caused by mutations of the gene encoding the lysosomal hydrolase, alpha-galactosidase A. The enzymatic defect is inherited in an X-linked recessive fashion and leads to systemic glycosphingolipid deposition, resulting in profound dysfunction of neurological, renal, cardiac, and cerebrovascular systems. Although symptoms typically appear in childhood in hemizygous males and some heterozygous females, the diagnosis is often delayed or unrecognized, owing to variable presentations and low incidence. The initial phase begins in childhood or adolescence and is characterized by neuropathic pain, angiokeratomas, and ocular deposits. The later phase is distinguished by progressive cardiac, cerebral, and renal involvement, leading to multi-organ dysfunction and death. Recently published clinical trials have demonstrated the efficacy of enzyme replacement therapy in decreasing neuropathic pain and substrate deposition in target organs. Pediatricians have a key role to play in making the diagnosis, so that therapy can be initiated before irreversible tissue injury develops. Further research is required to determine optimal dosing protocols for treatment and to establish whether therapy can retard the progression of organ dysfunction, or even prevent these complications altogether. C1 NIH, Bethesda, MD 20892 USA. NIDDK, Kidney Dis Sect, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Kopp, JB (reprint author), NIH, 10-3N116, Bethesda, MD 20892 USA. EM jbkopp@nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X NR 53 TC 6 Z9 9 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD JUN PY 2004 VL 19 IS 6 BP 583 EP 593 DI 10.1007/s00467-004-1466-4 PG 11 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 817ZC UT WOS:000221214400002 PM 15064943 ER PT J AU Brownstein, Z Ben-Yosef, T Dagan, O Frydman, M Abeliovich, D Sagi, M Abraham, FA Taitelbaum-Swead, R Shohat, M Hildesheimer, M Friedman, TB Avraham, KB AF Brownstein, Z Ben-Yosef, T Dagan, O Frydman, M Abeliovich, D Sagi, M Abraham, FA Taitelbaum-Swead, R Shohat, M Hildesheimer, M Friedman, TB Avraham, KB TI The R245X mutation of PCDH15 in Ashkenazi Jewish children diagnosed with nonsyndromic hearing loss foreshadows retinitis pigmentosa SO PEDIATRIC RESEARCH LA English DT Article ID CONNEXIN 26 MUTATIONS; MYOSIN-VIIA GENE; SYNDROME-TYPE-I; USHER-SYNDROME; RECESSIVE DEAFNESS; ALLELIC MUTATIONS; PREVALENCE; JEWS; HARMONIN; DEFECTS AB Usher syndrome is a frequent cause of the combination of deafness and blindness due to retinitis pigmentosa (RP). Five genes are known to underlie different forms of Usher syndrome type I (USH1). In the Ashkenazi Jewish Population, the R245X mutation of the PCDH15 gene may be the most common cause of USH1 (Ben-Yosef T. Ness SL, Madeo AC, Bar-Lev A, Wolfman JH, Ahmed ZM, Desnick RK, Willner JP, Avraham KB. Ostrer H. Oddoux C. Griffith AJ, Friedman TB N Enol J Med 348: 1664-1670 2003). To estimate what percentage of Ashkenazi Jewish children born with profound hearing loss will develop RP due to R245X, we examined the prevalence of the R245X PCDH15 Mutation and its carrier rate among Ashkenazi Jews in Israel. Among probands diagnosed with nonsyndromic hearing loss not due to mutations of connexin 26 (GJB2) and/or connexin 30 (GJB6), and below the age of 10, 2 of 20 (10%) were homozygous for the R245X mutation. Among older nonsyndromic deaf individuals. no homozygotes were detected, although one individual was heterozygous for R245X. The carrier rate of the R245X mutation among the normal hearing Ashkenazi population in Israel was estimated at 1%. Ashkenazi Jewish children with profound prelingual hearing loss should be evaluated for the R245X PCDH15 mutation and undergo ophthalmologic evaluation to determine whether they will develop RP. Rehabilitation can then begin before loss of vision. Early use of cochlear implants in such cases may rescue these individuals from a dual neurosensory deficit. C1 Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. Natl Inst Deafness & Other Commun Disorders, Sect Human Genet, Genet Mol Lab, NIH, Rockville, MD 20850 USA. Chaim Sheba Med Ctr, Danek Gertner Inst Genet, IL-52621 Tel Hashomer, Israel. Hadassah Hebrew Univ Hosp & Med Sch, Dept Human Genet, IL-91120 Jerusalem, Israel. Chaim Sheba Med Ctr, Goldschleger Eye Inst, IL-52621 Tel Hashomer, Israel. Tel Aviv Univ, Sackler Sch Med, Dept Commun Disorders, IL-52621 Tel Hashomer, Israel. Rabin Med Ctr, Dept Med Genet, IL-49100 Petah Tiqwa, Israel. RP Avraham, KB (reprint author), Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. EM karena@post.tau.ac.il FU NIDCD NIH HHS [ZO1 DC000039-06] NR 32 TC 19 Z9 20 U1 0 U2 1 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD JUN PY 2004 VL 55 IS 6 BP 995 EP 1000 DI 10.1203/01.PDR.0000125258.58267.56 PG 6 WC Pediatrics SC Pediatrics GA 822NX UT WOS:000221548000016 PM 15028842 ER PT J AU Messinger, DS Bauer, CR Das, A Seifer, R Lester, BM Lagasse, LL Wright, LL Shankaran, S Bada, HS Smeriglio, VL Langer, JC Beeghly, M Poole, WK AF Messinger, DS Bauer, CR Das, A Seifer, R Lester, BM Lagasse, LL Wright, LL Shankaran, S Bada, HS Smeriglio, VL Langer, JC Beeghly, M Poole, WK TI The maternal lifestyle study: Cognitive, motor, and behavioral outcomes of cocaine-exposed and opiate-exposed infants through three years of age SO PEDIATRICS LA English DT Article DE cocaine; opiates; prenatal exposure; BSID-II; outcome ID IN-UTERO; SUBSTANCE EXPOSURE; UNITED-STATES; DRUG EXPOSURE; TERM INFANTS; BIRTH-WEIGHT; FOLLOW-UP; PREGNANCY; CHILDREN; PERFORMANCE AB Objective. To evaluate the direct effects of prenatal cocaine exposure and prenatal opiate exposure on infant mental, motor, and behavioral outcomes longitudinally between 1 and 3 years old. Methods. As part of a prospective, longitudinal, multisite study, the Bayley Scales of Infant Development II were administered to 1227 infants who were exposed to cocaine (n=474), opiates (n=50), cocaine and opiates (n=48), and neither substance (n=655) at 1, 2, and 3 years of corrected age by certified, masked examiners. Hierarchic linear modeling of the 1-, 2-, and 3-year scores was conducted using cocaine and opiate exposure as predictors with and without controlling for covariates. Results. Overall retention was 88.4% and did not differ by cocaine or opiate exposure. Overall (at 1, 2, and 3 years), cocaine-exposed infants scored 1.6 Mental Development Index points below infants who were not exposed to cocaine. Opiate-exposed infants scored 3.8 Psychomotor Development Index points below infants who were not exposed to opiates. Neither the cocaine nor the opiate effect remained significant after controlling for covariates. Neither cocaine nor opiate exposure was associated with the Behavioral Record Score during the examination. Low birth weight and indices of nonoptimal caregiving were associated with lower Mental Development Index, Psychomotor Development Index, and Behavioral Record Score scores for all groups of infants. Conclusions. In the largest at-risk sample observed longitudinally to date, infant prenatal exposure to cocaine and to opiates was not associated with mental, motor, or behavioral deficits after controlling for birth weight and environmental risks. C1 Univ Miami, Dept Psychol, Coral Gables, FL 33124 USA. Univ Miami, Dept Pediat, Coral Gables, FL 33124 USA. Univ Miami, Sch Med, Miami, FL USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. Brown Univ, Sch Med, Women & Infants Hosp, Providence, RI 02912 USA. Bradley Hosp, Providence, RI USA. NICHHD, Bethesda, MD 20892 USA. Wayne State Univ, Sch Med, Detroit, MI USA. Univ Tennessee, Sch Med, Memphis, TN USA. NIDA, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Boston, MA USA. Childrens Hosp, Boston, MA 02115 USA. RP Messinger, DS (reprint author), Psychol Annex,POB 249229, Coral Gables, FL 33124 USA. EM dmessinger@miami.edu OI Seifer, Ronald/0000-0003-4879-2839 FU NICHD NIH HHS [U10 HD 21397, N01-HD-2-3159, U10 HD 21385, U10 HD 21415, U10 HD 27904, U10 HD 36790]; NIDA NIH HHS [U10 DA024119] NR 50 TC 92 Z9 95 U1 2 U2 10 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 JUN PY 2004 VL 113 IS 6 BP 1677 EP 1685 DI 10.1542/peds.113.6.1677 PG 9 WC Pediatrics SC Pediatrics GA 825TP UT WOS:000221781500019 PM 15173491 ER PT J AU Whittle, A Shah, S Wilfond, B Gensler, G Wendler, D AF Whittle, A Shah, S Wilfond, B Gensler, G Wendler, D TI Institutional review board practices regarding assent in pediatric research SO PEDIATRICS LA English DT Article DE child; IRB ID HEALTHY-VOLUNTEERS AB Objective. To assess how Institutional Review Boards ( IRBs) implement the assent requirement for research with children. Methods. Telephone interviews were conducted with 188 chairpersons of IRBs from a range of institutions nationwide. Respondents were queried on 4 topics: 1) which children are considered capable of assent, 2) which information investigators must provide pediatric research subjects, 3) whether IRBs favor the enrollment of children who are capable of assent, and 4) how chairpersons view payment for children's research participation. Results. Half of IRBs have a method that they require investigators to follow when determining which children are capable of assent, most commonly an age cutoff. Half of IRBs do not have a method, and the majority rely on investigators' clinical judgment. IRBs largely follow the adult research regulations when determining which information should be provided to an assenting child. A total of 58% of IRBs would enroll a child who is incapable of assent in a nonbeneficial study, even if children who are capable of assent could be enrolled instead. Almost half (46%) of chairpersons believe that it sometimes or always acceptable to offer incentive payments to children, and more than one third (35%) thought it acceptable to offer payment to the parents. Conclusion. When possible, IRBs follow the federal regulations for research with adults when implementing the assent requirement. For considerations that do not have analogs in the adult regulations, IRB practices vary widely. These data suggest that IRBs need guidance on how to implement the assent requirement in a way that provides appropriate protections for pediatric research subjects. C1 NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Emmes Corp, Bethesda, MD USA. RP Wendler, D (reprint author), NIH, Dept Clin Bioeth, Bldg 10,Rm 1C118, Bethesda, MD 20892 USA. EM dwendler@cc.nih.gov NR 10 TC 42 Z9 43 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 JUN PY 2004 VL 113 IS 6 BP 1747 EP 1752 DI 10.1542/peds.113.6.1747 PG 6 WC Pediatrics SC Pediatrics GA 825TP UT WOS:000221781500029 PM 15173501 ER PT J AU Muralidhar, D Jobby, MK Jeromin, A Roder, J Thomas, F Sharma, Y AF Muralidhar, D Jobby, MK Jeromin, A Roder, J Thomas, F Sharma, Y TI Calcium and chlorpromazine binding to the EF-hand peptides of neuronal calcium sensor-1 SO PEPTIDES LA English DT Article DE neuronal calcium sensor-1; calcium-binding; chlorpromazine binding; EF-hands; frequenin; peptides ID TROPONIN-C; PROTEINS; CALMODULIN; CHROMATOGRAPHY; LOCALIZATION; PURIFICATION; FRAGMENTS; AFFINITY; REGIONS; FAMILY AB Neuronal calcium sensor-1, a protein of calcium sensor family, is known to have four structural EF-hands. We have synthesised peptides corresponding to all the four EF-hands and studied their conformation and calcium-binding. Our data confirm that the first putative site, a non-canonical one (EF1), does not bind calcium. We have investigated if this lack of binding is due to the presence of non-favoured residues (particularly at +x and -z co-ordinating positions) of the loop. We have mutated these residues and found that after modification the peptides bound calcium. However, these mutated peptides (EF1 and its functional mutants) do not show any Ca2+ induced changes in far-UV CD. EF2, EF3, and EF4 peptides bind Ca2+, EF3 being the strongest binder, followed by EF4. Our data of Ca2+-binding to individual EF peptides show that there are three active Ca2+-binding sites in NCS-1. We have also studied the binding of a neuroleptic drug, chlorpromazine, with the protein as well as with its EF-hands. CPZ binds myristoylated as well as non-myristoylated NCS-1 in Ca2+-dependent manner, with dynamic interaction to myristoylated protein. CPZ does not bind to EF1, but binds to functional EF-hand peptides and induces changes in far-UV CD. Our results suggest that NCS-1 could be a target of such antipsychotic and neuroleptic drugs. (C) 2004 Elsevier Inc. All rights reserved. C1 Ctr Cellular & Mol Biol, Hyderabad 500007, Andhra Pradesh, India. Baylor Coll Med, Houston, TX 77030 USA. Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. NHLBI, NIH, Bethesda, MD 20892 USA. RP Sharma, Y (reprint author), Ctr Cellular & Mol Biol, Uppal Rd, Hyderabad 500007, Andhra Pradesh, India. EM yogendra@ccmb.res.in RI Roder, John/G-6468-2013 NR 24 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD JUN PY 2004 VL 25 IS 6 BP 909 EP 917 DI 10.1016/j.peptides.2004.03.017 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 834FB UT WOS:000222395900002 PM 15203236 ER PT J AU Pallesen, S Johnsen, BH Hansen, A Eid, J Thayer, JF Olsen, T Hugdahl, K AF Pallesen, S Johnsen, BH Hansen, A Eid, J Thayer, JF Olsen, T Hugdahl, K TI Sleep deprivation and hemispheric asymmetry for facial recognition reaction time and accuracy SO PERCEPTUAL AND MOTOR SKILLS LA English DT Article ID PERFORMANCE; MOOD; METAANALYSIS; PERSONALITY; MEMORY; TASK AB We investigated the processing of emotional stimuli during a non-sleep-deprived state and following sleep deprivation in 36 right-handed men. Using the visual half-field technique, cartoon line drawings of emotional facial expressions were flashed on a computer screen for 250 msec. The participants were instructed to remember the content of the picture seen and to recognize it among nine alternatives shown immediately after the display of a single picture. Compared to the nondeprived condition, response latencies increased and accuracy decreased in sleep deprivation. Moreover, response latencies indicated that the performance of the right hemisphere deteriorated more following sleep deprivation than did the performance of the left hemisphere. The results also showed that hemispheric preference (for response latencies and response accuracy) tended to favour the left hemisphere when the participants were tested during sleep deprivation. C1 Univ Bergen, Dept Psychosocial Sci, N-5015 Bergen, Norway. NIA, Baltimore, MD USA. Univ Bergen, Dept Biol & Med Psychol, Bergen, Norway. RP Pallesen, S (reprint author), Univ Bergen, Dept Psychosocial Sci, Christiesgt 12, N-5015 Bergen, Norway. EM staale.pallesen@psysp.uib.no RI Eid, Jarle/G-1346-2014 NR 38 TC 25 Z9 26 U1 2 U2 12 PU PERCEPTUAL MOTOR SKILLS PI MISSOULA PA PO BOX 9229, MISSOULA, MT 59807 USA SN 0031-5125 J9 PERCEPT MOTOR SKILL JI Percept. Mot. Skills PD JUN PY 2004 VL 98 IS 3 BP 1305 EP 1314 DI 10.2466/pms.98.3c.1305-1314 PN 2 PG 10 WC Psychology, Experimental SC Psychology GA 836FL UT WOS:000222541000024 PM 15291219 ER PT J AU Bortner, CD Cidlowski, JA AF Bortner, CD Cidlowski, JA TI The role of apoptotic volume decrease and ionic homeostasis in the activation and repression of apoptosis SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Review DE activation; apoptosis; cell shrinkage; ion flux; potassium; programmed cell death; repression; sodium ID PLASMA-MEMBRANE DEPOLARIZATION; PROGRAMMED CELL-DEATH; SMOOTH-MUSCLE-CELLS; POTASSIUM CHANNELS; REGULATORY MECHANISMS; NEURONAL APOPTOSIS; T-LYMPHOCYTES; K+ CHANNELS; SHRINKAGE; NECROSIS AB The mechanism of activation and repression of apoptosis has been a central focus of many studies examining the role of programmed cell death in both normal and pathological conditions. Despite intensive research efforts, the precise cellular and molecular mechanisms that trigger and/or prevent apoptosis remain undefined. A universal characteristic of apoptosis is the loss of cell volume or cell shrinkage, recently termed apoptotic volume decrease. While cell shrinkage has traditionally been viewed as a passive event during apoptosis, recent work from several laboratories has shown that the loss of cell volume, or more specifically the flux of ions associated with the change in cell size, play a critical role in the regulation of the cell death machinery. On going studies continue to support the hypothesis that the change in intracellular ions can alter a cells decision to die by apoptosis. C1 NIEHS, Lab Signal Transduct, US Dept HHS, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, US Dept HHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM cidlowski@niehs.nih.gov NR 45 TC 111 Z9 118 U1 1 U2 4 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. PD JUN PY 2004 VL 448 IS 3 BP 313 EP 318 DI 10.1007/s00424-004-1266-5 PG 6 WC Physiology SC Physiology GA 820NW UT WOS:000221397500006 PM 15107996 ER PT J AU Dalakas, MC AF Dalakas, MC TI The use of intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: evidence-based indications and safety profile SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE intravenous immunoglobulin; autoinumme neuromuscular diseases; multifocal motor neuropathy ID GUILLAIN-BARRE-SYNDROME; MULTIFOCAL MOTOR NEUROPATHY; INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY; INCLUSION-BODY MYOSITIS; RANDOMIZED CONTROLLED TRIAL; IMMUNE GLOBULIN THERAPY; STIFF-PERSON SYNDROME; TERM FOLLOW-UP; DOUBLE-BLIND; PLASMA-EXCHANGE AB Intravenous immunoglobulin (IVIg) has multiple actions on the immunoregulatory network that operate in concert with each other. For each autoimmune neuromuscular disease, however, there is a predominant mechanism of action that relates to the underlying immunopathogenetic cause of the respective disorder. The best understood actions of IVIg include the following: (a) modulation of pathogenic autoantibodies, an effect relevant in myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and stiff-person syndrome (SPS); (b) inhibition of complement activation and interception of membranolytic attack complex (MAC) formation, an action relevant to the complement-mediated mechanisms involved in GBS, CIDP, MG, and dermatomyositis (DM); (c) modulation of the inhibitory or activation Fc receptors on macrophages invading targeted tissues in nerve and muscle, as seen in CIDP, GBS, and inflammatory myopathies; (d) down-regulation of pathogenic cytokines and adhesion molecules; (e) suppression of T-cell functions; and (f) interference with antigen recognition. Controlled clinical trials have shown that IVIg is effective as first-line therapy in patients with GBS, CIDP, and multifocal motor neuropathy (MMN), and as second-line therapy in DM, MG, LEMS, and SPS. In paraprotememic IgM anti-MAG (myelin-associated glycoprotein) demyelinating polyneuropathies and inclusion body myositis (IBM), the benefit is variable, marginal, and not statistically significant. IVIg has a remarkably good safety record for long-term administration, however, the following side effects have been observed: mild, infusion-rate-related reactions, such as headaches, myalgia, or fever; moderate but inconsequential events, such as aseptic meningitis and skin rash; and severe, but rare, complications, such as thromboembolic events and renal tubular necrosis. Future studies are needed to (a) find the appropriate dose and frequency of infusions that maintain a response; (b) address pharmacoeconornics, comparing the high cost of IVIg to the cost of the other therapies, which, although less expensive, cause significantly more long-term side effects; (c) determine why some patients respond better than others-, and (d) examine the merits of combining IVIg with other immuno suppressive drugs. (C) 2004 Elsevier Inc. All rights reserved. C1 NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), NINDS, Neuromuscular Dis Sect, NIH, MSC 1382,Room 4N248,Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM dalakasm@ninds.nih.gov NR 137 TC 108 Z9 117 U1 1 U2 5 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 JUN PY 2004 VL 102 IS 3 BP 177 EP 193 DI 10.1016/j.pharmthera.2004.04.002 PG 17 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 836KO UT WOS:000222554800002 PM 15246245 ER PT J AU Zanuy, D Haspel, N Tsai, HH Ma, BY Gunasekaran, K Wolfson, HJ Nussinov, R AF Zanuy, D Haspel, N Tsai, HH Ma, BY Gunasekaran, K Wolfson, HJ Nussinov, R TI Side chain interactions determine the amyloid organization: a single layer beta-sheet molecular structure of the calcitonin peptide segment 15-19 SO PHYSICAL BIOLOGY LA English DT Article ID YEAST PRION SUP35; SOLID-STATE NMR; DYNAMICS SIMULATIONS; FIBRIL FORMATION; FORMING PEPTIDE; PROTEIN; FIBRILLOGENESIS; AGGREGATION; CONSTRAINTS; CONVERSION AB In this paper we present a detailed atomic model for a protofilament, the most basic organization level, of the amyloid fibre formed by the peptide DFNKF. This pentapeptide is a segment derived from the human calcitonin, a natural amyloidogenic protein. Our model, which represents the outcome of extensive explicit solvent molecular dynamics (MD) simulations of different strand/sheet organizations, is a single beta-sheet filament largely without a hydrophobic core. Nevertheless, this structure is capable of reproducing the main features of the characteristic amyloid fibril organization and provides clues to the molecular basis of its experimental aggregation behaviour. Our results show that the side chains' chemical diversity induces the formation of a complex network of interactions that finally determine the microscopic arrangement of the strands at the protofilament level. This network of interactions, consisting of both side chain-side chain and backbone-side chain interactions, confers on the final single beta-sheet arrangement an unexpected stability, both by enhancing the association of related chemical groups and, at the same time, by shielding the hydrophobic segments from the polar solvent. The chemical physical characterization of this protofilament provides hints to the possible thermodynamical basis of the supra molecular organization that allows the formation of the filaments by lateral association of the preformed protofibrils. Its regular, highly polarized structure shows how other protofilaments can assemble. In terms of structural biology, our results clearly indicate that an amyloid organization implies a degree of complexity far beyond a simple nonspecific association of peptide strands via amide hydrogen bonds. C1 NCI, Lab Expt & Computat Biol, Frederick, MD 21702 USA. Tel Aviv Univ, Fac Exact Sci, Sch Comp Sci, IL-69978 Tel Aviv, Israel. NCI, Basic Res Program, SAIC Frederick Inc, Lab Expt & Computat Biol, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Fac Med, Sackler Inst Mol Med, Dept Human Genet, IL-69978 Tel Aviv, Israel. RP Zanuy, D (reprint author), NCI, Lab Expt & Computat Biol, Bldg 469,Rm 151, Frederick, MD 21702 USA. EM zanuyd@ncifcrf.gov RI Wolfson, Haim/A-1837-2011; Ma, Buyong/F-9491-2011; Zanuy, David/G-3930-2014; Haspel, Nurit/D-1961-2017 OI Ma, Buyong/0000-0002-7383-719X; Zanuy, David/0000-0001-7704-2178; FU NCI NIH HHS [N01-CO-12400] NR 41 TC 13 Z9 13 U1 1 U2 5 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 1478-3967 J9 PHYS BIOL JI Phys. Biol. PD JUN PY 2004 VL 1 IS 1-2 BP 89 EP 99 AR PII S1478-3967(04)81452-9 DI 10.1088/1478-3967/1/2/005 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 947LJ UT WOS:000230645900017 PM 16204826 ER PT J AU Cahill, K AF Cahill, K TI Alternative splicing and genomic stability SO PHYSICAL BIOLOGY LA English DT Article ID DIVERSITY; COCHLEA AB Alternative splicing allows an organism to make different proteins in different cells at different times, all from the same gene. In a cell that uses alternative splicing, the total length of all the exons is much shorter than in a cell that encodes the same set of proteins without alternative splicing. This economical use of exons makes genes more stable during reproduction and development because a genome with a shorter exon length is more resistant to harmful mutations. Genomic stability may be the reason why higher vertebrates splice alternatively. For a broad class of alternatively spliced genes, a formula is given for the increase in their stability. C1 Univ New Mexico, Dept Phys & Astron, Albuquerque, NM 87131 USA. NIH, Ctr Mol Modeling, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Cahill, K (reprint author), Univ New Mexico, Dept Phys & Astron, Albuquerque, NM 87131 USA. EM cahill@unm.edu NR 8 TC 1 Z9 1 U1 0 U2 0 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 1478-3967 J9 PHYS BIOL JI Phys. Biol. PD JUN PY 2004 VL 1 IS 1-2 BP C1 EP C4 AR PII S1478-3967(04)81783-2 DI 10.1088/1478-3967/1/2/C01 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 947LJ UT WOS:000230645900007 PM 16204811 ER PT J AU Yu, YK AF Yu, YK TI Replica model for an unusual directed polymer in 1+1 dimensions and prediction of the extremal parameter of gapped sequence alignment statistics SO PHYSICAL REVIEW E LA English DT Article ID HIDDEN MARKOV-MODELS; MOLECULAR SEQUENCES; RANDOM IMPURITIES; SEARCH; SIMILARITIES; SUBSEQUENCES; INTERFACES; SYSTEMS; SCORES AB Sequence alignment is one of the most important bioinformatics tools for modern molecular biology. The statistical characterization of gapped alignment scores has been a long-standing problem in sequence alignment research. In this paper, we provide a self-contained exposition of sequence alignment, a short review about how this problem is related to the directed polymer problem in statistical physics, and some analytical results that can be used for predicting alignment score statistics. Basically, we present two classes of solutions for the gapped alignment statistics by explicitly calculating the evolution of the few-replica partition function in 1+1 dimensions. We have obtained the conditions under which the more important extremal parameter lambda, characterizing the alignment score statistics, becomes predictable. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. Florida Atlantic Univ, Dept Phys, Boca Raton, FL 33431 USA. RP NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. NR 60 TC 3 Z9 3 U1 0 U2 0 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 2470-0045 EI 2470-0053 J9 PHYS REV E JI Phys. Rev. E PD JUN PY 2004 VL 69 IS 6 AR 061904 DI 10.1103/PhysRevE.69.061904 PN 1 PG 31 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 835RH UT WOS:000222502700084 PM 15244614 ER PT J AU Wu, YX von Tiedemann, A AF Wu, YX von Tiedemann, A TI Light-dependent oxidative stress determines physiological leaf spot formation in barley SO PHYTOPATHOLOGY LA English DT Article DE antioxidant enzymes ID PROGRAMMED CELL-DEATH; ACTIVE OXYGEN; PHOTOOXIDATIVE STRESS; PLANTS; INJURY; LEAVES; EVENTS; OZONE; CHLOROPLASTS; INDUCTION AB We reported previously that physiological leaf spot (PLS) formation in winter and spring barley is dependent on genotype-related oxidative stress under field conditions. In the present study. we searched for factors inducing PLS symptoms in the greenhouse similar to those observed in the field and investigated its relationship to reactive oxygen species (ROS) metabolism. We found that in the greenhouse, oxidative stress induced spring barley cv. Extract, which is sensitive to PLS. to express symptoms similar to those observed in the field. Leaves severely affected by PLS showed significantly lower activities of key enzymes in the Halliwell-Asada cycle such as ascorbate peroxidase, glutathione reductase, dehydroascorbate reductase. and monodehydroascorbate reductase. The sensitive cultivar also showed lower levels of total superoxide dismutase (SOD) and Cu/Zn-SOD activity but a higher level of chloroplast-specific Fe-SOD activity than that of the insensitive cultivar. Thus, an unbalanced ROS metabolism in chloroplasts may trigger PLS incidence in sensitive cultivars, which is in agreement with the fact that light is essential for the induction of PLS expression under both field and greenhouse conditions. Accordingly, under greenhouse conditions. continuous light stress (7 days), but not light shock treatments, induced PLS similar to that of field conditions in sensitive cv. Extract, but not in resistant cv. Scarlett. Light with a high proportion of energy in the blue wavelength spectrum (350 to 560 nm) was significantly more PLS inductive than light with a pronounced red (photosynthetically active radiation) spectrum (580 to 650 nm). Exposure to ozone did not produce PLS-like symptoms. Furthermore, similar to earlier observations in the field. PLS symptom expression was closely correlated with the accumulation of superoxide (O-2(-)) detected by both biochemical and histochemical assays. Taken together, these data suggest that PLS in barley is genotype-dependent but its expression appears to be induced by certain environmental stress factors, among which photosynthetically active radiation plays a major role. C1 Univ Gottingen, Inst Plant Pathol & Plant Protect, D-37077 Gottingen, Germany. NIH, NHLBI, Cell Biol Lab, Bethesda, MD 20892 USA. RP von Tiedemann, A (reprint author), Univ Gottingen, Inst Plant Pathol & Plant Protect, Grisebachstr 6, D-37077 Gottingen, Germany. EM atiedem@gwdg.de NR 36 TC 11 Z9 11 U1 0 U2 6 PU AMER PHYTOPATHOLOGICAL SOC PI ST PAUL PA 3340 PILOT KNOB ROAD, ST PAUL, MN 55121 USA SN 0031-949X J9 PHYTOPATHOLOGY JI Phytopathology PD JUN PY 2004 VL 94 IS 6 BP 584 EP 592 DI 10.1094/PHYTO.2004.94.6.584 PG 9 WC Plant Sciences SC Plant Sciences GA 823XY UT WOS:000221648900006 PM 18943483 ER PT J AU Wheeler, MH Tsai, HF AF Wheeler, M. H. Tsai, H. -F. TI Biochemistry and genetics of fungal melanin biosynthesis SO PHYTOPATHOLOGY LA English DT Meeting Abstract C1 [Wheeler, M. H.] USDA ARS SPARC, College Stn, TX USA. [Tsai, H. -F.] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER PHYTOPATHOLOGICAL SOC PI ST PAUL PA 3340 PILOT KNOB ROAD, ST PAUL, MN 55121 USA SN 0031-949X J9 PHYTOPATHOLOGY JI Phytopathology PD JUN PY 2004 VL 94 IS 6 SU S BP S132 EP S132 PG 1 WC Plant Sciences SC Plant Sciences GA V44HJ UT WOS:000202993501266 ER PT J AU Baxter, LL Hou, L Loftus, SK Pavan, WJ AF Baxter, LL Hou, L Loftus, SK Pavan, WJ TI Spotlight on spotted mice: A review of white spotting mouse mutants and associated human pigmentation disorders SO PIGMENT CELL RESEARCH LA English DT Review DE neural crest; mutant; spotting; hypopigmentation; neurocristopathy; melanocyte ID CELL GROWTH-FACTOR; CREST-DERIVED MELANOCYTES; FACTOR RECEPTOR PROTOONCOGENE; ENDOTHELIN-B RECEPTOR; WAARDENBURG-HIRSCHSPRUNG-DISEASE; C-KIT RECEPTOR; TRANSCRIPTION FACTOR MITF; NEURAL CREST; HUMAN PIEBALDISM; STEEL FACTOR AB Mutation of genes that regulate neural crest-derived melanoblast development and survival can result in reduction and/or loss of mature melanocytes. The reduction in melanocyte number in the skin and hair follicles manifests itself as areas of hypopigmentation, commonly described as white spotting in mice. To date ten genes have been identified which are associated with white-spotting phenotypes in mouse. Seven of these genes are associated with neural crest and melanocyte disorders in humans. This review summarizes the phenotypes associated with mutation of these genes in both mouse and man. We describe our current understanding of how these genes function in development, and explore their complex roles regulating the various stages of melanocyte development. C1 NHGRI, Mouse Embryol Sect, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Pavan, WJ (reprint author), NHGRI, Mouse Embryol Sect, Genet Dis Res Branch, NIH, 49 Convent Dr,Bldg 49,Room 4A82, Bethesda, MD 20892 USA. EM bpavan@nhgri.nih.gov OI Hou, Ling/0000-0003-0705-8099 NR 139 TC 55 Z9 58 U1 0 U2 4 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0893-5785 J9 PIGM CELL RES JI Pigm. Cell. Res. PD JUN PY 2004 VL 17 IS 3 BP 215 EP 224 DI 10.1111/j.1600-0749.2004.00147.x PG 10 WC Cell Biology; Dermatology SC Cell Biology; Dermatology GA 819GT UT WOS:000221303700002 PM 15140066 ER PT J AU Imanishi, T Itoh, T Suzuki, Y O'Donovan, C Fukuchi, S Koyanagi, KO Barrero, RA Tamura, T Yamaguchi-Kabata, Y Tanino, M Yura, K Miyazaki, S Ikeo, K Homma, K Kasprzyk, A Nishikawa, T Hirakawa, M Thierry-Mieg, J Thierry-Mieg, D Ashurst, J Jia, LB Nakao, M Thomas, MA Mulder, N Karavidopoulou, Y Jin, LH Kim, S Yasuda, T Lenhard, B Eveno, E Suzuki, Y Yamasaki, C Takeda, J Gough, C Hilton, P Fujii, Y Sakai, H Tanaka, S Amid, C Bellgard, M Bonaldo, MD Bono, H Bromberg, SK Brookes, AJ Bruford, E Carninci, P Chelala, C Couillault, C de Souza, SJ Debily, MA Devignes, MD Dubchak, I Endo, T Estreicher, A Eyras, E Fukami-Kobayash, K Gopinath, GR Graudens, E Hahn, Y Han, M Han, ZG Hanada, K Hanaoka, H Harada, E Hashimoto, K Hinz, U Hirai, M Hishiki, T Hopkinson, I Imbeaud, S Inoko, H Kanapin, A Kaneko, Y Kasukawa, T Kelso, J Kersey, P Kikuno, R Kimura, K Korn, B Kuryshev, V Makalowska, I Makino, T Mano, S Mariage-Samson, R Mashima, J Matsuda, H Mewes, HW Minoshima, S Nagai, K Nagasaki, H Nagata, N Nigam, R Ogasawara, O Ohara, O Ohtsubo, M Okada, N Okido, T Oota, S Ota, M Ota, T Otsuki, T Piatier-Tonneau, D Poustka, A Ren, SX Saitou, N Sakai, K Sakamoto, S Sakate, R Schupp, I Servant, F Sherry, S Shiba, R Shimizu, N Shimoyama, M Simpson, AJ Soares, B Steward, C Suwa, M Suzuki, M Takahashi, A Tamiya, G Tanaka, H Taylor, T Terwilliger, JD Unneberg, P Veeramachaneni, V Watanabe, S Wilming, L Yasuda, N Yoo, HS Stodolsky, M Makalowski, W Go, M Nakai, K Takagi, T Kanehisa, M Sakaki, Y Quackenbush, J Okazaki, Y Hayashizaki, Y Hide, W Chakraborty, R Nishikawa, K Sugawara, H Tateno, Y Chen, Z Oishi, M Tonellato, P Apweiler, R Okubo, K Wagner, L Wiemann, S Strausberg, RL Isogai, T Auffray, C Nomura, N Gojobori, T Sugano, S AF Imanishi, T Itoh, T Suzuki, Y O'Donovan, C Fukuchi, S Koyanagi, KO Barrero, RA Tamura, T Yamaguchi-Kabata, Y Tanino, M Yura, K Miyazaki, S Ikeo, K Homma, K Kasprzyk, A Nishikawa, T Hirakawa, M Thierry-Mieg, J Thierry-Mieg, D Ashurst, J Jia, LB Nakao, M Thomas, MA Mulder, N Karavidopoulou, Y Jin, LH Kim, S Yasuda, T Lenhard, B Eveno, E Suzuki, Y Yamasaki, C Takeda, J Gough, C Hilton, P Fujii, Y Sakai, H Tanaka, S Amid, C Bellgard, M Bonaldo, MD Bono, H Bromberg, SK Brookes, AJ Bruford, E Carninci, P Chelala, C Couillault, C de Souza, SJ Debily, MA Devignes, MD Dubchak, I Endo, T Estreicher, A Eyras, E Fukami-Kobayash, K Gopinath, GR Graudens, E Hahn, Y Han, M Han, ZG Hanada, K Hanaoka, H Harada, E Hashimoto, K Hinz, U Hirai, M Hishiki, T Hopkinson, I Imbeaud, S Inoko, H Kanapin, A Kaneko, Y Kasukawa, T Kelso, J Kersey, P Kikuno, R Kimura, K Korn, B Kuryshev, V Makalowska, I Makino, T Mano, S Mariage-Samson, R Mashima, J Matsuda, H Mewes, HW Minoshima, S Nagai, K Nagasaki, H Nagata, N Nigam, R Ogasawara, O Ohara, O Ohtsubo, M Okada, N Okido, T Oota, S Ota, M Ota, T Otsuki, T Piatier-Tonneau, D Poustka, A Ren, SX Saitou, N Sakai, K Sakamoto, S Sakate, R Schupp, I Servant, F Sherry, S Shiba, R Shimizu, N Shimoyama, M Simpson, AJ Soares, B Steward, C Suwa, M Suzuki, M Takahashi, A Tamiya, G Tanaka, H Taylor, T Terwilliger, JD Unneberg, P Veeramachaneni, V Watanabe, S Wilming, L Yasuda, N Yoo, HS Stodolsky, M Makalowski, W Go, M Nakai, K Takagi, T Kanehisa, M Sakaki, Y Quackenbush, J Okazaki, Y Hayashizaki, Y Hide, W Chakraborty, R Nishikawa, K Sugawara, H Tateno, Y Chen, Z Oishi, M Tonellato, P Apweiler, R Okubo, K Wagner, L Wiemann, S Strausberg, RL Isogai, T Auffray, C Nomura, N Gojobori, T Sugano, S TI Integrative annotation of 21,037 human genes validated by full-length cDNA clones SO PLOS BIOLOGY LA English DT Review ID EXPRESSED SEQUENCE TAGS; SINGLE NUCLEOTIDE POLYMORPHISMS; COMPLETE GENOME SEQUENCE; FUNCTIONAL ANNOTATION; DROSOPHILA-MELANOGASTER; UNTRANSLATED REGIONS; HUNTINGTONS-DISEASE; MESSENGER-RNAS; LARGE PROTEINS; SUBCELLULAR-LOCALIZATION AB The human genome sequence defines our inherent biological potential; the realization of the biology encoded therein requires knowledge of the function of each gene. Currently, our knowledge in this area is still limited. Several lines of investigation have been used to elucidate the structure and function of the genes in the human genome. Even so, gene prediction remains a difficult task, as the varieties of transcripts of a gene may vary to a great extent. We thus performed an exhaustive integrative characterization of 41,118 full-length cDNAs that capture the gene transcripts as complete functional cassettes, providing an unequivocal report of structural and functional diversity at the gene level. Our international collaboration has validated 21,037 human gene candidates by analysis of high-quality full-length cDNA clones through curation using unified criteria. This led to the identification of 5,155 new gene candidates. It also manifested the most reliable way to control the quality of the cDNA clones. We have developed a human gene database, called the H-Invitational Database (H-InvDB; http://www.h-invitational.jp/). It provides the following: integrative annotation of human genes, description of gene structures, details of novel alternative splicing isoforms, non-protein-coding RNAs, functional domains, subcellular localizations, metabolic pathways, predictions of protein three-dimensional structure, mapping of known single nucleotide polymorphisms (SNPs), identification of polymorphic microsatellite repeats within human genes, and comparative results with mouse full-length cDNAs. The H-InvDB analysis has shown that up to 4% of the human genome sequence (National Center for Biotechnology Information build 34 assembly) may contain misassembled or missing regions. We found that 6.5% of the human gene candidates (1,377 loci) did not have a good protein-coding open reading frame, of which 296 loci are strong candidates for nonprotein-coding RNA genes. In addition, among 72,027 uniquely mapped SNPs and insertions/deletions localized within human genes, 13,215 nonsynonymous SNPs, 315 nonsense SNPs, and 452 indels occurred in coding regions. Together with 25 polymorphic microsatellite repeats present in coding regions, they may alter protein structure, causing phenotypic effects or resulting in disease. The H-InvDB platform represents a substantial contribution to resources needed for the exploration of human biology and pathology. C1 Natl Inst Adv Ind Sci & Technol, Integrated Database Grp, Biol Informat Res Ctr, Tokyo, Japan. Natl Inst Agrobiol Sci, Genome Res Dept, Bioinformat Lab, Ibaraki, Japan. Univ Tokyo, Inst Med Sci, Ctr Human Genome, Tokyo, Japan. EMBL Outstn, European Bioinformat Inst, Cambridge, England. Ctr Informat Biol, Shizuoka, Japan. DNA Data Bank Japan, Natl Inst Genet, Shizuoka, Japan. Nara Inst Sci & Technol, Nara, Japan. Integrated Database Grp, Japan Biol Informat Res Ctr, Japan Biol Informat Consortium, Tokyo, Japan. BITS Co, Shizuoka, Japan. Japan Atom Energy Res Inst, Quantum Bioinformat Grp, Ctr Promot Computat Sci & Engn, Kyoto, Japan. Reverse Proteom Res Inst, Chiba, Japan. Cent Res Lab, Tokyo, Japan. Kyoto Univ, Inst Chem Res, Bioinformat Ctr, Kyoto, Japan. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD USA. CNRS, Lab Phys Math, Montpellier, France. Wellcome Trust Sanger Inst, Cambridge, England. NCI, NIH, Bethesda, MD USA. Idaho State Univ, Dept Biol Sci, Pocatello, ID USA. Korea Res Inst Biosci & Biotechnolc, Taejeon, South Korea. Karolinska Inst, Ctr Genom & Bioinformat, Stockholm, Sweden. CNRS, Genexpress, Villejuif, France. Sino French Lab Life Sci & Genom, Shanghai, Peoples R China. Kyowa Hakko Kogyo Co Ltd, Tokyo Res Labs, Tokyo, Japan. GSF Natl Res Ctr Environm & Hlth, MIPS Inst Bioinformat, Neuherberg, Germany. Murdoch Univ, Sch Informat Technol, Ctr Bioinformat & Biol Comp, Murdoch, WA, Australia. Univ Iowa, Med Educ & Biomed Res Facil, Iowa City, IA USA. RIKEN Yokohama Inst, RIKEN Genom Sci Ctr, Genome Explorat Res Grp, Kanagawa, Japan. Med Coll Wisconsin, Milwaukee, WI USA. UCL, HUGO Gene Nomenclature Comm, London, England. RIKEN, Genome Sci Lab, Saitama, Japan. Ludwig Inst Canc Res, Sao Paulo, Brazil. CNRS, Vandoeuvre Les Nancy, France. Lawrence Berkeley Natl Lab, Berkeley, CA USA. Tokyo Med & Dent Univ, Med Res Inst, Dept Bioinformat, Tokyo, Japan. Swiss Inst Bioinformat, Geneva, Switzerland. RIKEN Tsukuba Inst, RIKEN Bioresource Ctr, Bioresource Informat Div, Ibaraki, Osaka, Japan. Cold Spring Harbor Lab, Genome Knowledgebase, Cold Spring Harbor, NY USA. Chinese Natl Human Genome Ctr Shanghai, Shanghai, Peoples R China. Natl Inst Infect Dis, Div Genet Resources, Tokyo, Japan. Univ Tokyo, Dept Integrated Biosci, Grad Sch Frontier Sci, Chiba, Japan. Natl Inst Adv Ind Sci & Technol, Biol Informat Res Ctr, Funct Genom Grp, Tokyo, Japan. UCL, Royal Free Univ Coll Med Sch, Dept Primary Care & Populat Sci, London, England. Inst Child Hlth, Clin & Mol Genet Unit, London, England. Tokai Univ, Sch Med, Div Mol Life Sci, Dept Genet Informat, Kanagawa, Japan. Univ Western Cape, South African Natl Bioinformat Inst, Bellville, South Africa. Kazusa DNA Res Inst, Chiba, Japan. RZPD Resource Ctr Genome Res, Heidelberg, Germany. German Canc Res Ctr, Heidelberg, Germany. Penn State Univ, University Pk, PA USA. Osaka Univ, Grad Sch Informat Sci & Technol, Dept Bioinformat Engn, Osaka, Japan. Hamamatsu Univ Sch Med, Photon Med Res Ctr, Med Photobiol Dept, Shizuoka, Japan. Natl Inst Adv Ind Sci & Technol, Computat Biol Res Ctr, Tokyo, Japan. Keio Univ, Sch Med, Dept Mol Biol, Tokyo, Japan. Tokyo Inst Technol, Grad Sch Biosci & Biotechnol, Dept Biol Sci, Kanagawa, Japan. Tokyo Inst Technol, Global Sci Informat & Comp Ctr, Tokyo, Japan. Taisho Pharmaceut Co, Med Res Labs, Mol Biol Lab, Saitama, Japan. Natl Inst Genet, Dept Populat Genet, Shizuoka, Japan. RIKEN Yokohama Inst, Genom Sci Ctr, Human Genome Res Grp, Kanagawa, Japan. Columbia Univ, New York, NY USA. Columbia Genome Ctr, New York, NY USA. KTH Royal Sch Technol, Dept Biotechnol, Stockholm, Sweden. USDA, Biol Div, Washington, DC USA. USDA, Genome Task Grp, Off Biol & Environm Res, Washington, DC USA. Nagahama Inst Biosci & Technol, Fac Biosci, Nagahama, Shiga, Japan. Inst Genom Res, Rockville, MD USA. Univ Cincinnati, Dept Environm Hlth, Ctr Genome Informat, Cincinnati, OH USA. Shanghai Med Univ 2, Rui Jin Hosp, Shanghai Inst Hematol, State Key Lab Med Genom, Shanghai, Peoples R China. PointOne Syst, Wauwatosa, WI USA. Univ Tsukuba, Grad Sch Life & Environm Sci, Tsukuba, Ibaraki, Japan. Grad Univ Adv Studies, Dept Genet, Shizuoka, Japan. Univ Tokyo, Grad Sch Frontier Sci, Dept Med Genome Sci, Tokyo, Japan. RP Natl Inst Adv Ind Sci & Technol, Integrated Database Grp, Biol Informat Res Ctr, Tokyo, Japan. EM tgojobor@genes.nig.ac.jp RI Taylor, Todd/A-7121-2009; Nakai, Kenta/B-7293-2009; Jun-ichi, Takeda/I-7483-2014; Kasukawa, Takeya/N-5070-2015; Eyras, Eduardo/A-1560-2010; Hide, Winston Hide/C-7217-2009; Ohara, Osamu/A-9119-2012; Koyanagi, Kanako/D-6354-2012; Thomas, Michael/B-7489-2008; Kanapin, Alexander/E-7632-2013; Carninci, Piero/K-1568-2014; Eyras, Eduardo/L-1053-2014; Wiemann, Stefan/E-4424-2013; Ohara, Osamu/G-5448-2015; Makalowski, Wojciech/I-2843-2016; Kanapin, Alexander/Q-7590-2016; Paulini, Michael/E-8289-2017; THIERRY-MIEG, Jean/F-1975-2017; OI Bono, Hidemasa/0000-0003-4413-0651; Taylor, Todd/0000-0003-4247-6253; Nakai, Kenta/0000-0002-8721-8883; Jun-ichi, Takeda/0000-0001-5367-5608; Kasukawa, Takeya/0000-0001-5085-0802; Hide, Winston Hide/0000-0002-8621-3271; Koyanagi, Kanako/0000-0003-1615-5077; Thomas, Michael/0000-0003-2982-0291; Carninci, Piero/0000-0001-7202-7243; Eyras, Eduardo/0000-0003-0793-6218; Wiemann, Stefan/0000-0003-4683-3174; Ohara, Osamu/0000-0002-3328-9571; Kanapin, Alexander/0000-0001-9802-5297; Paulini, Michael/0000-0002-6968-2340; THIERRY-MIEG, Jean/0000-0002-0396-6789; Apweiler, Rolf/0000-0001-7078-200X; Wilming, Laurens/0000-0002-4154-7358; Amid, Clara/0000-0001-6534-7425; Bruford, Elspeth/0000-0002-8380-5247; Kersey, Paul/0000-0002-7054-800X; Lenhard, Boris/0000-0002-1114-1509; chelala, claude/0000-0002-2488-0669; Devignes, Marie-Dominique/0000-0002-0399-8713; O'Donovan, Claire/0000-0001-8051-7429 FU NHLBI NIH HHS [R01 HL064541] NR 116 TC 243 Z9 258 U1 2 U2 21 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD JUN PY 2004 VL 2 IS 6 BP 856 EP 875 AR e162 DI 10.1371/journal.pbio.0020162 PG 20 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 833ZN UT WOS:000222380400025 PM 15103394 ER PT J AU Simons-Morton, BG Hartos, JL Beck, KH AF Simons-Morton, BG Hartos, JL Beck, KH TI Increased parent limits on teen driving: Positive effects from a brief intervention administered at the motor vehicle administration SO PREVENTION SCIENCE LA English DT Article DE teen driving; parenting; driving restrictions or limits; driving contract or agreement ID YOUNG DRIVERS; RISK-TAKING; PASSENGERS; 16-YEAR-OLD; INVOLVEMENT; DRINKING; RATES AB The purpose of this study was to determine whether exposure to a brief intervention administered at the Motor Vehicle Administration (MVA) increases parental limits on teen driving. A total of 658 parents and their 16-year-old adolescents were recruited from a local MVA site as adolescents successfully tested for provisional licenses. At the MVA, participating parents completed written surveys about expected teen driving during the 1st month of provisional licensure. One month later, 579 parent-teen dyads completed follow-up telephone interviews about teen driving within the past month. On weeks assigned as intervention, parents were exposed to a video and given the video and a driving agreement to take home. In multivariate linear regression analyses, the results indicated that when controlling for selected demographic and baseline psychosocial variables, intervention parents reported more driving rules, restricted driving, limits for high-speed roads, weekend night restrictions, and overall driving limits than did parents in the control group. When compared to control teens, intervention teens reported more limits on passengers, high-speed roads, and night driving, and on overall driving limits, but there were no differences for overall driving or driving under high-risk conditions. In addition, intervention parents were about 3 times, and intervention teens were about 5 times, more likely than controls to report using a parent-teen driving agreement. These results indicate that brief exposure to intervention at an MVA office may help increase parental limits on teen driving. C1 NICHHD, Prevent Res Branch, MPH, Bethesda, MD 20892 USA. Univ Maryland, Dept Publ & Community Hlth, College Pk, MD 20742 USA. RP Simons-Morton, BG (reprint author), NICHHD, Prevent Res Branch, MPH, 6100 Execut Blvd,Room 7B05, Bethesda, MD 20892 USA. EM mortonb@mail.nih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617 NR 29 TC 29 Z9 29 U1 1 U2 2 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1389-4986 J9 PREV SCI JI Prev. Sci. PD JUN PY 2004 VL 5 IS 2 BP 101 EP 111 DI 10.1023/B:PREV.0000023080.76550.ab PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 833CG UT WOS:000222313400003 PM 15134315 ER PT J AU Ross, LE Coates, RJ Breen, N Uhler, RJ Potosky, AL Blackman, D AF Ross, LE Coates, RJ Breen, N Uhler, RJ Potosky, AL Blackman, D TI Prostate-specific antigen test use reported in the 2000 National Health Interview Survey SO PREVENTIVE MEDICINE LA English DT Article DE prostate cancer; screening; prostate-specific antigen ID PRIMARY-CARE PHYSICIANS; PATIENTS SELF-REPORTS; UNITED-STATES; SCREENING PRACTICES; COLORECTAL-CANCER; MEN; KNOWLEDGE; BELIEFS; MAMMOGRAPHY; IMPACT AB Background. In 2000, the National Health Interview Survey (NHIS) collected information about prostate-specific antigen (PSA) test use in a representative sample of U.S. men. Methods. This study examined PSA test use in subgroups defined by personal and social characteristics. Results. Among men aged 50 and older with no history of prostate cancer, 56.8% reported ever having had a PSA test, 34.1% reported having had a screening PSA test during the previous year, and 30.0% reported having had three or more tests during the previous 5 years. Screening was greater among men aged 60-79 years, those with greater access to care, and those practicing other preventive behaviors. Among men in their 40s, use tended to be higher among African-American men. Conclusions. The prevalence and patterns of PSA screening suggest that PSA is used like other cancer screening tests among about a third of U.S. men. Because of the lack of scientific consensus on whether prostate cancer screening is beneficial, more information is needed on how knowledgeable both patients and practitioners are about the potential benefits and harms of screening and how prostate cancer screening decisions are made. (C) 2004 The Institute For Cancer Prevention and Elsevier Inc. All rights reserved. C1 Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Canc Prevent & Control, Atlanta, GA 30341 USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Ross, LE (reprint author), Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Canc Prevent & Control, Atlanta, GA 30341 USA. EM lor3@cdc.gov NR 59 TC 60 Z9 60 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD JUN PY 2004 VL 38 IS 6 BP 732 EP 744 DI 10.1016/j.ypmed.2004.01.005 PG 13 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 830IO UT WOS:000222115800007 PM 15193893 ER PT J AU Cohen-Mansfield, J Marx, MS Biddison, JR Guralnik, JM AF Cohen-Mansfield, J Marx, MS Biddison, JR Guralnik, JM TI Socio-environmental exercise preferences among older adults SO PREVENTIVE MEDICINE LA English DT Article DE exercise attitudes; exercise attributes; incentives for physical activity; motivation to exercise ID GERIATRIC DEPRESSION SCALE; PHYSICAL-ACTIVITY; DISABILITY; BARRIERS; WOMEN; AGE AB Background. To examine preferences concerning social and environmental aspects of exercise in the elderly population. Methods. Participants were 324 community-dwelling persons aged 74-85 years who completed a health questionnaire that included items on exercise preferences as well as questions on demographic variables, health, and exercise habits. Selected participants then completed a physical performance battery to measure lower body functioning. Results. A physician's advice to exercise, monitoring by a health professional, an evaluation of the exercise program by a professional, and the quality of the instructor were all rated as important or very important by at least 70% of the participants. Several other factors such as easy access to exercise facilities, type of exercise performed, free or low cost of a program, and other participants being of the same age were rated as slightly important or important. Preferences were related to participants' health and demographic characteristics. For example, participants who were not married were more interested in the social aspects of exercise programs, and those with higher levels of education and more resources were less concerned with program costs. Conclusions. The findings suggest that exercise programs should be tailored to meet the needs and wishes of subgroups of this population. In order to motivate at-risk elderly persons to exercise, programs must take these varying preferences into account and explore their meaning for program design. (C) 2004 The Institute For Cancer Prevention and Elsevier Inc. All rights reserved. C1 Hebrew Home Greater Washington, Res Inst Aging, Rockville, MD 20852 USA. George Washington Univ, Med Ctr, Washington, DC 20037 USA. NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. RP Cohen-Mansfield, J (reprint author), Hebrew Home Greater Washington, Res Inst Aging, 6121 Montrose Rd, Rockville, MD 20852 USA. EM cohen-mansfield@hebrew-home.org NR 24 TC 36 Z9 39 U1 1 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD JUN PY 2004 VL 38 IS 6 BP 804 EP 811 DI 10.1016/j.ypmed.2004.01.007 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 830IO UT WOS:000222115800016 PM 15193902 ER PT J AU Abramowitz, J Grenet, D Birnbaumer, M Torres, HN Birnbaumer, L AF Abramowitz, J Grenet, D Birnbaumer, M Torres, HN Birnbaumer, L TI XL alpha s, the extra-long form of the alpha-subunit of the Gs G protein, is significantly longer than suspected, and so is its companion Alex SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GNAS LOCUS; GENE; MUTATIONS; TRANSCRIPTS; COMPLEX AB Because of the use of alternate exons 1, mammals express two distinct forms of Gsalpha-subunits: the canonical 394-aa Gsalpha present in all tissues and a 700+-aa extra-long alphas (XLalphas) expressed in a more restricted manner. Both subunits transduce receptor signals into stimulation of adenylyl cyclase. The XL exon encodes the XL domain of XLalphas and, in a parallel ORF, a protein called Alex. Alex interacts with the XL domain of XLas and inhibits its adenylyl cyclase-stimulating function. In mice, rats, and humans, the XL exon is thought to contribute 422.3, 367.3, and 551.3 codons and to encode Alex proteins of 390, 357, and 561 aa, respectively. We report here that the XL exon is longer than presumed and contributes in mice, rats, and humans, respectively, an additional 364, 430, and 139 codons to XLas. We called the N-terminally extended XLalphas extra-extra-long Gsalpha, or XXLalphas. Alex is likewise longer. Its ORF also remains open in the 5' direction for approximate to 2,000 nt, giving rise to Alex-extended, or AlexX. RT-PCR of murine total brain RNA shows that the entire XXL domain is encoded in a single exon. Furthermore, we discovered two truncated forms of XXLalphas, XXLb1 and XXLb2, in which, because of alternative splicing, the Gsa domain is replaced by different sequences. XXLb proteins are likely to be found as stable dimers with AlexX. The N-terminally longer proteins may play regulatory roles. C1 NIEHS, Transmembrane Signal Transduct Grp, Lab Signal Transduct, Div Intramural Res,NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Birnbaumer, L (reprint author), NIEHS, Transmembrane Signal Transduct Grp, Lab Signal Transduct, Div Intramural Res,NIH,Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM birnbau1@niehs.nih.gov RI Abramowitz, Joel/A-2620-2015 NR 18 TC 35 Z9 41 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 1 PY 2004 VL 101 IS 22 BP 8366 EP 8371 DI 10.1073/pnas.0308758101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 826LY UT WOS:000221831800022 PM 15148396 ER PT J AU Wu, YP Proia, RL AF Wu, YP Proia, RL TI Deletion of macrophage-inflammatory protein 1 alpha retards neurodegeneration in Sandhoff disease mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; BONE-MARROW-TRANSPLANTATION; BLOOD-BRAIN-BARRIER; MOUSE MODELS; TAY-SACHS; MICROGLIA; GANGLIOSIDOSIS; MIP-1-ALPHA; CELLS; CHEMOKINES AB Sandhoff disease is a prototypical lysosomal storage disorder in which a heritable deficiency of a lysosomal enzyme, beta-hexosaminidase, results in the storage of the enzyme's substrates in lysosomes. As with many of the other lysosomal storage diseases, neurodegeneration is a prominent feature. Although the cellular and molecular pathways that underlie the neurodegenerative process are not yet fully understood, macrophage/microglial-mediated inflammation has been suggested as one possible mechanism. We now show that the expanded macrophage/microglial population in the CNS of Sandhoff disease mice is compounded by the infiltration of cells from the periphery. Coincident with the cellular infiltration was an increased expression of macrophage-inflammatory protein 1alpha (MIP-1alpha), a leukocyte chemokine, in astrocytes. Deletion of MIP-1alpha expression resulted in a substantial decrease in infiltration and macrophage/microglial-associated pathology together with neuronal apoptosis in Sandhoff disease mice. These mice without MIP-1alpha showed improved neurologic status and a longer lifespan. The results indicate that the pathogenesis of Sandhoff disease involves an increase in MIP-1alpha that induces monocytes to infiltrate the CNS, expand the activated macrophage/microglial population, and trigger apoptosis of neurons, resulting in a rapid neurodegenerative course. C1 NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Proia, RL (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, Bldg 10,Room 9N-314,10 Ctr Dr,MSC 1821, Bethesda, MD 20892 USA. EM proia@nih.gov RI Proia, Richard/A-7908-2012 NR 30 TC 114 Z9 118 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 1 PY 2004 VL 101 IS 22 BP 8425 EP 8430 DI 10.1073/pnas.0400625101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 826LY UT WOS:000221831800032 PM 15155903 ER PT J AU Howard, EI Sanishvili, R Cachau, RE Mitschler, A Chevrier, B Barth, P Lamour, V Van Zandt, M Sibley, E Bon, C Moras, D Schneider, TR Joachimiak, A Podjarny, A AF Howard, EI Sanishvili, R Cachau, RE Mitschler, A Chevrier, B Barth, P Lamour, V Van Zandt, M Sibley, E Bon, C Moras, D Schneider, TR Joachimiak, A Podjarny, A TI Ultrahigh resolution drug design I: Details of interactions in human aldose reductase-inhibitor complex at 0.66 angstrom SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE X-ray crystallography; subatomic resolution; drug design; diabetes complications ID SITE-DIRECTED MUTAGENESIS; ATOMIC-RESOLUTION; CRYSTAL-STRUCTURE; DIABETIC COMPLICATIONS; BINDING-SITE; PROTEIN CRYSTALLOGRAPHY; ALDEHYDE REDUCTASE; ACTIVE-SITE; HOLOENZYME; MECHANISM AB The first subatomic resolution structure of a 36 kDa protein [aldose reductase (AR)] is presented. AR was cocrystallized at pH 5.0 with its cofactor NADP(+) and inhibitor IDD 594, a therapeutic candidate for the treatment of diabetic complications. X-ray diffraction data were collected up to 0.62 Angstrom resolution and treated up to 0.66 Angstrom resolution. Anisotropic refinement followed by a blocked matrix inversion produced low standard deviations (<0.005 Angstrom). The model was very well ordered overall (CA atoms' mean B factor is 5.5 Angstrom(2)). The model and the electron-density maps revealed fine features, such as H-atoms, bond densities, and significant deviations from standard stereochemistry. Other features, such as networks of hydrogen bonds (H bonds), a large number of multiple conformations, and solvent structure were also better defined. Most of the atoms in the active site region were extremely well ordered (mean B similar to3 Angstrom(2)), leading to the identification of the protonation states of the residues involved in catalysis. The electrostatic interactions of the inhibitor's charged carboxylate head with the catalytic residues and the charged coenzyme NADP(+) explained the inhibitor's noncompetitive character. Furthermore, a short contact involving the IDD 594 bromine atom explained the selectivity profile of the inhibitor, important feature to avoid toxic effects. The presented structure and the details revealed are instrumental for better understanding of the inhibition mechanism of AR by IDD 594, and hence, for the rational drug design of future inhibitors. This work demonstrates the capabilities of subatomic resolution experiments and stimulates further developments of methods allowing the use of the full potential of these experiments. (C) 2004 Wiley-Liss, Inc. C1 IGBMC, CNRS, UMR 7104, Lab Genom & Biol Struct, F-67404 Illkirch Graffenstaden, France. Argonne Natl Lab, Biosci Div, Struct Biol Ctr, Argonne, IL 60439 USA. NCI, SAIC, Adv Biomed Comp Ctr, Frederick, MD 21701 USA. ECPM, UMR 7509, Lab Geochim Biorgan, Strasbourg, France. Inst Diabet Discovery Inc, Branford, CT USA. Inst Pharmacol & Biol Struct, UMR5089, Toulouse, France. Univ Gothenburg, Dept Struct Chem, Gottingen, Germany. RP Podjarny, A (reprint author), IGBMC, CNRS, UMR 7104, Lab Genom & Biol Struct, BP 163, F-67404 Illkirch Graffenstaden, France. EM andrzejj@anl.gov; podjarny@igbme.u-strasbg.fr RI Schneider, Thomas/B-7442-2011 OI Schneider, Thomas/0000-0001-6955-7374 FU NCI NIH HHS [N01-CO-12400] NR 59 TC 182 Z9 184 U1 2 U2 21 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-3585 J9 PROTEINS JI Proteins PD JUN 1 PY 2004 VL 55 IS 4 BP 792 EP 804 DI 10.1002/prot.20015 PG 13 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 826AU UT WOS:000221802000002 PM 15146478 ER PT J AU Maynard, EL Gatto, GJ Berg, JM AF Maynard, EL Gatto, GJ Berg, JM TI Pex5p binding affinities for canonical and noncanonical PTS1 peptides SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE peroxisome; peroxin; specificity; affinity; fluorescence anisotropy; catalase; acyl-CoA oxidase; luciferase ID PEROXISOMAL TARGETING SIGNAL; CARBOXY TERMINUS; PROTEIN IMPORT; BIOGENESIS; IDENTIFICATION; RECOGNITION; REPEAT; TPR AB The majority of proteins targeted to the peroxisomal lumen contain a C-terminal peroxisomal targeting signal-1 (PTS1) that is bound by the peroxin Pex5p. The PTS1 is generally regarded as a C-terminal tripeptide that adheres to the consensus (S/A/C)(K/R/H)(L/M). Previously, we studied the binding affinity of peptides of the form YQX(-3)X(-2)X(-1) to the peptide-binding domain of human Pex5p (referred to as Pex5p-C). Optimal affinity was found for YQSKL, which bound with an affinity of 200 +/- 40 nM. To extend this work, we investigated the properties of a peptide containing the last 9 residues of acyl-CoA oxidase (RHYLK-PLQSKL) and discovered that it binds to Pex5p-C with a dissociation constant of 1.4 +/- 0.4 nM, 180 times tighter than YQSKL. Further analysis revealed that the enhanced affinity is primarily due to the presence of leucine in the (-5) position. In addition, a peptide corresponding to the luciferase C-terminus (YKGGKSKL) was found to bind Pex5p-C about 20 times tighter than YQSKL. The majority of this effect results from having lysine in position (4). Catalase contains a noncanonical PTS1 (-AREKANL). The affinity of YQANL was found to be 3600 +/- 400 nH. This relatively weak binding is consistent with previous unsuccessful attempts to direct chloramphenicol acetyltransferase to the peroxisome by fusing -ANL to its C-terminus (-GGA-ANL). The peptides YKANL, YEKANL, YREKANL, and YAREKANL all bound Pex5p-C with higher affinities than did YQANL, but the affinities are still lower than peptides that correspond to functional targeting signals in other contexts. Because both catalase and Pex5p are tetramers (as opposed to the monomeric Pex5p-C and the peptides used in our studies), multidentate effects on binding affinity between Pex5p and other oligomeric proteins should be considered. Our study provides direct thermodynamic data revealing that peptide binding to Pex5p-C binding is favored by lysine in the (4) position and leucine in the (-5) position. Our results suggest that peptides or proteins with optimized residues in the (4) and/or (-5) positions can bind to Pex5p with affinities that are at least two orders of magnitude greater than that of YQSKL, and that this stabilization can compensates for otherwise weakly binding PTSIs. (C) 2004 Wiley-Liss, Inc. C1 Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA. RP Berg, JM (reprint author), Natl Inst Gen Med Sci, 45 Ctr Dr, Bethesda, MD 20892 USA. EM jberg@mail.nih.gov OI Berg, Jeremy/0000-0003-3022-0963 FU NIDDK NIH HHS [5F32DK060371-02] NR 23 TC 36 Z9 36 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-3585 J9 PROTEINS JI Proteins PD JUN 1 PY 2004 VL 55 IS 4 BP 856 EP 861 DI 10.1002/prot.20112 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 826AU UT WOS:000221802000008 PM 15146484 ER PT J AU Iyer, LM Aravind, L AF Iyer, LM Aravind, L TI The emergence of catalytic and structural diversity within the beta-clip fold SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article ID MULTIPLE SEQUENCE ALIGNMENT; ESCHERICHIA-COLI MOEA; SIALIC-ACID SYNTHASE; CRYSTAL-STRUCTURE; ACTINOBACILLUS-ACTINOMYCETEMCOMITANS; ENZYMATIC-ACTIVITIES; ENOLASE SUPERFAMILY; ANTIFREEZE PROTEIN; CONSERVED DOMAINS; GENOMIC CONTEXT AB The beta-clip fold includes a diverse group of protein domains that are unified by the presence of two characteristic waist-like constrictions, which bound a central extended region. Members of this fold include enzymes like deoxyuridine triphosphatase and the SET methylase, carbohydrate-binding domains like the fish antifreeze proteins/Sialate synthase C-terminal domains, and functionally enigmatic accessory subunits of urease and molybdopterin biosynthesis protein MoeA. In this study, we reconstruct the evolutionary history of this fold using sensitive sequence and structure comparisons methods. Using sequence profile searches, we identified novel versions of the beta-clip fold in the bacterial flagellar chaperone FlgA and the related pilus protein CpaB, the StrU-Iike dehydrogenases, and the UxaA/GarD-like hexuronate dehydratases (SAF superfamily). We present evidence that these versions of the beta-clip domain, like the related type III anti-freeze proteins and C-terminal domains of sialic acid synthases, are involved in interactions with carbohydrates. We propose that the FlgA and CpaB-like proteins mediate the assembly of bacterial flagella and Flp pili by means of their interactions with the carbohydrate moieties of peptidoglycan. The N-terminal beta-clip domain of the hexuronate dehydratases appears to have evolved a novel metal-binding site, while their C-terminal domain is likely to adopt a metal-binding TIM barrel-like fold. Using structural comparisons, we show that the beta-clip fold can be further classified into two major groups, one that includes the SAF, SET, dUTPase superfamilies, and the other that includes the phage lambda head decoration protein, the beta subunit of urease and the C-terminal domain of the molybdenum cofactor biosynthesis protein MoeA. Structural comparisons also suggest the beta-clip fold was assembled through the duplication of a three-stranded unit. Though the three-stranded units are likely to have had a common origin, we present evidence that complete beta-clip domains were assembled through such duplications, independently on multiple occasions. There is also evidence for circular permutation of the basic three-stranded unit on different occasions in the evolution of the beta-clip unit. We also describe how assembly of this fold from a basic three-stranded unit has been utilized to accommodate a variety of activities in its different versions. (C) 2004 Wiley-Liss, Inc. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM aravind@ncbi.nlm.nih.gov NR 64 TC 18 Z9 18 U1 1 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-3585 J9 PROTEINS JI Proteins PD JUN 1 PY 2004 VL 55 IS 4 BP 977 EP 991 DI 10.1002/prot.20076 PG 15 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 826AU UT WOS:000221802000018 PM 15146494 ER PT J AU Smith, TA Steinert, PM Parry, DAD AF Smith, TA Steinert, PM Parry, DAD TI Modeling effects of mutations in coiled-coil structures: Case study using epidermolysis bullosa simplex mutations in segment 1A of K5/K14 intermediate filaments SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE cytokeratins; mutations; coiled coil; energy refinement; epidermolysis bullosa simplex ID GCN4 LEUCINE-ZIPPER; CRYSTAL-STRUCTURE; POINT MUTATIONS; ROD DOMAIN; KERATIN-5 MUTATION; PROTEIN STRUCTURES; ATOMIC-STRUCTURE; GENE-MUTATIONS; CDNA SEQUENCE; IDENTIFICATION AB The sequence of a protein chain determines both its conformation and its function in vivo. An attempt is made to gain an understanding of the classes of deformations that can arise in an important structural motif, the a-helical coiled coil, as a consequence of mutations occurring in its underlying heptad substructure. In order to do so we consider the model structure of segment 1A in intermediate filaments and then investigate the structures arising from each of the 22 mutations observed in cytokeratin K5/K14 molecules that lead to variants of epidermolysis bullosa simplex. These are refined separately using a molecular dynamics protocol. The mutations often result in a significant distortion of the backbone over a turn or so of the a helix in either the chain itself or its constituent partner, leading to the likelihood of impaired chain aggregation and hence molecular assembly. One mutant (K14-L143P; 1A-28) gave rise to structural distortion along almost the entire length of segment 1A. The remaining structures showed less deformation, and normal-looking intermediate filaments are likely in vivo. In addition, an identical mutation in the same position in each of the chains in the heterodimer did not necessarily give equivalent structural distortions. Although proline mutations frequently lead to the most severe structural deformations, a non-proline substitution (K14-R125S; 1A-10) gave rise to the largest local structural disruption that was observed. Unexpectedly, mutations in positions a and d were not always of the greatest structural significance, although three in position a were shown by AGADIR to result in a significant increase in a-helix stability. (C) 2004 Wiley-Liss, Inc. C1 Massey Univ, Inst Fundamental Sci, Palmerston North, New Zealand. NIAMA, Skin Biol Lab, NIH, Bethesda, MD USA. RP Parry, DAD (reprint author), Massey Univ, Inst Fundamental Sci, Private Bag 11-222, Palmerston North, New Zealand. EM d.parry@massey.ac.nz NR 48 TC 25 Z9 25 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-3585 J9 PROTEINS JI Proteins PD JUN 1 PY 2004 VL 55 IS 4 BP 1043 EP 1052 DI 10.1002/prot.20089 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 826AU UT WOS:000221802000025 PM 15146501 ER PT J AU Friedman, MJ Hamblen, JL Foa, EB Charney, DS AF Friedman, MJ Hamblen, JL Foa, EB Charney, DS TI Fighting the psychological war on terrorism SO PSYCHIATRY-INTERPERSONAL AND BIOLOGICAL PROCESSES LA English DT Editorial Material ID POSTTRAUMATIC-STRESS-DISORDER; CORTICOTROPIN-RELEASING-FACTOR; POSITRON-EMISSION-TOMOGRAPHY; RANDOMIZED CONTROLLED-TRIAL; COGNITIVE-BEHAVIOR THERAPY; DISASTER VICTIMS SPEAK; HIPPOCAMPAL VOLUME; SUBANESTHETIC KETAMINE; COMBAT VETERANS; NEUROPEPTIDE-Y C1 Natl Ctr PTSD, VAM & ROC, White River Jct, VT 05009 USA. Dartmouth Coll Sch Med, Dept Psychiat & Pharmacol, Hanover, NH USA. Natl Ctr PTSD, VAM & Rock, White River Jct, VT 05009 USA. Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Friedman, MJ (reprint author), Natl Ctr PTSD, VAM & ROC, 116D,215 N Main St, White River Jct, VT 05009 USA. EM Matthew.Friedman@Dartmouth.edu NR 94 TC 4 Z9 4 U1 6 U2 9 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0033-2747 J9 PSYCHIATRY JI Psychiatry-Interpers. Biol. Process. PD SUM PY 2004 VL 67 IS 2 BP 123 EP 136 DI 10.1521/psyc.67.2.123.35954 PG 14 WC Psychiatry SC Psychiatry GA 836FV UT WOS:000222542000003 PM 15262578 ER PT J AU Bennett, GG Merritt, MM Sollers, JJ Edwards, CL Whitfield, KE Brandon, DT Tucker, RD AF Bennett, GG Merritt, MM Sollers, JJ Edwards, CL Whitfield, KE Brandon, DT Tucker, RD TI Stress, coping, and health outcomes among African-Americans: A review of the John Henryism hypothesis SO PSYCHOLOGY & HEALTH LA English DT Article DE John Henryism; coping; ethnicity; stress; socioeconomic status (SES) ID BLOOD-PRESSURE DIFFERENCES; JOHN-HENRYISM; JOB STRAIN; SOCIOECONOMIC-STATUS; CARDIOVASCULAR-DISEASE; SEX-DIFFERENCES; BLACK-MEN; WOMEN; HYPERTENSION; WORK AB The John Henryism (JH) hypothesis argues that prolonged high-effort coping with chronic psychosocial stressors may be associated with elevated risk for negative health outcomes among those without sufficient socioeconomic resources. Early JH studies found a significant association between high JH, low socioeconomic status, and hypertension among African-Americans. More recently, these findings have been extended to a wide array of health status outcomes, including cardiovascular reactivity, neurohormonal secretion, and negative health behaviors. The present review provides a comprehensive overview of JHs conceptual bases and empirical support. Limitations of the construct are discussed and recommendations are made to guide future theoretical and research efforts in the area. C1 Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. NIA, Bethesda, MD 20892 USA. Duke Univ, Ctr Med, Durham, NC 27706 USA. Penn State Univ, University Pk, PA 16802 USA. Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA USA. RP Bennett, GG (reprint author), Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, 677 Huntington Ave,7th Floor, Boston, MA 02115 USA. EM gbennett@hsph.harvard.edu NR 56 TC 46 Z9 46 U1 0 U2 12 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0887-0446 J9 PSYCHOL HEALTH JI Psychol. Health PD JUN PY 2004 VL 19 IS 3 BP 369 EP 383 DI 10.1080/0887044042000193505 PG 15 WC Public, Environmental & Occupational Health; Psychology, Multidisciplinary SC Public, Environmental & Occupational Health; Psychology GA 831GI UT WOS:000222182500007 ER PT J AU Roth, BL Hanizavareh, SM Blum, AE AF Roth, BL Hanizavareh, SM Blum, AE TI Serotonin receptors represent highly favorable molecular targets for cognitive enhancement in schizophrenia and other disorders SO PSYCHOPHARMACOLOGY LA English DT Article; Proceedings Paper CT Conference on Neuropsychopharmacological Approaches to Modulating Cognition in Schizophrenia CY JUN, 2003 CL Tokyo, JAPAN DE schizophrenia; cognition; 5-HT2A; 5-HT1A; 5-HT6; 5-HT4; serotonin ID ATYPICAL ANTIPSYCHOTIC-DRUG; SITU HYBRIDIZATION HISTOCHEMISTRY; 5-HT2A RECEPTORS; CEREBRAL-CORTEX; IN-VIVO; SUBCELLULAR-DISTRIBUTION; PARTIAL AGONIST; MESSENGER-RNA; RAT-BRAIN; NEUROCOGNITIVE DEFICITS AB Rationale. Current treatments for schizophrenia adequately treat the positive symptoms of schizophrenia but only modestly improve cognitive deficits. This review provides evidence for and against the use of selective 5-HT receptor drugs as cognition enhancing agents for schizophrenia and other disorders. Methods. Pre-clinical and clinical literature concerned with the role of the serotonergic system in cognition and memory as it relates to schizophrenia is reviewed. Individual 5-HT receptor subtypes for which selective drugs are available that are likely to improve cognition are reviewed. Recommendations for clinical testing are proposed. Results and conclusions. Four 5-HT receptor systems (5-HT1A, 5-HT2A, 5-HT4, 5-HT6) are highlighted as suitable targets for enhancing cognition and memory. Because many clinically available antipsychotic drugs already target 5-HT1A, 5-HT2A and 5-HT6 receptors, design of clinical trials will need to take into account the serotonergic pharmacology of concurrently administered antipsychotic medications. 5-HT1A partial agonists and 5-HT2A antagonists have shown modest effectiveness in improving cognition in schizophrenia. 5-HT6-selective compounds for cognition enhancement are in late-stage clinical trials, while 5-HT4 compounds have not yet been tested in humans for cognition enhancement. Recommendations. For stand-alone therapy for enhancing cognition, 5-HT1A partial agonists, 5-HT2A antagonists, 5-HT4 partial agonists and 5-HT6 antagonists are all likely to induce at least modest improvement in cognition in schizophrenia. If "add-on therapy" is contemplated, antipsychotic drugs with weak affinities for serotonin receptors should be used to avoid confounds. It is likely that serotonergic drugs will soon be available as cognition enhancing medications for disorders other than schizophrenia (e.g. dementia). C1 Case Western Reserve Univ, Sch Med, Dept Biochem, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Psychiat, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Neurosci, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, NIMH, Psychoact Drug Screening Program, Cleveland, OH 44106 USA. RP Roth, BL (reprint author), Case Western Reserve Univ, Sch Med, Dept Biochem, 2109 Adelbert Rd, Cleveland, OH 44106 USA. EM bryan.roth@case.edu RI Roth, Bryan/F-3928-2010 FU NIMH NIH HHS [KO2MH01366, N01MH80005] NR 89 TC 159 Z9 169 U1 2 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUN PY 2004 VL 174 IS 1 BP 17 EP 24 DI 10.1007/s00213-003-1683-8 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 829ON UT WOS:000222058900003 PM 15205874 ER PT J AU Chudasama, Y Robbins, TW AF Chudasama, Y Robbins, TW TI Psychopharmacological approaches to modulating attention in the five-choice serial reaction time task: implications for schizophrenia SO PSYCHOPHARMACOLOGY LA English DT Article; Proceedings Paper CT Conference on Neuropsychopharmacological Approaches to Modulating Cognition in Schizophrenia CY JUN, 2003 CL Tokyo, JAPAN DE attention; rat; schizophrenia; dopamine; serotonin; acetylcholine; noradrenaline; striatum; prefrontal cortex; 5CSRTT ID MEDIAL PREFRONTAL CORTEX; CORTICAL ACETYLCHOLINE-RELEASE; ATYPICAL ANTIPSYCHOTIC-DRUGS; CONTINUOUS PERFORMANCE-TEST; VISUAL SUSTAINED ATTENTION; LOCUS-COERULEUS NEURONS; SHORT-TERM-MEMORY; BASAL FOREBRAIN; DOPAMINE-RECEPTORS; FRONTAL-CORTEX AB Rationale. In schizophrenia, attentional disturbance is a core feature which may not only accompany the disorder, but may precede the onset of psychiatric symptoms. Objectives. The five-choice serial reaction time task (5CSRTT) is a test of visuo-spatial attention that has been used extensively in rats for measuring the effects of systemic and central neurochemical manipulations on various aspects of attentional performance, including selective attention, vigilance and executive control. These findings are relevant to our understanding of the neural systems that may be compromised in patients with schizophrenia. Methods. The 5CSRTT is conducted in an operant chamber that has multiple response locations, in which brief visual stimuli can be presented randomly. Performance is maintained using food reinforcers to criterion levels of accuracy. Various aspects of performance are measured, including attentional accuracy and premature responding, especially under different attentional challenges. Results. The effects of systemic and intra-cerebral infusions of selective dopamine, serotonin and cholinergic receptor agents on the 5CSRTT are reviewed with a view to identifying attention-enhancing effects that may be relevant to the treatment of cognitive deficits in schizophrenia. In addition, some novel agents such as modafinil and histamine receptor agents are also considered. Examining the effects of selective neurochemical lesions helped define the neural locus of attentional effects. Similarly, findings from microdialysis studies helped identify the extracellular changes in neurotransmitters and their metabolites in freely moving rats during performance of the 5CSRTT. Conclusions. The monoaminergic and cholinergic systems have independent but complementary roles in attentional function, as measured by the 5CSRTT. These functions are predominantly under the control of the prefrontal cortex and striatum. These conclusions are considered in the context of their application towards therapeutic approaches for attentional disturbances that are typically observed in schizophrenic patients. C1 NIMH, Bethesda, MD 20892 USA. Univ Cambridge, Dept Expt Psychol, Cambridge CB2 3EB, England. RP Chudasama, Y (reprint author), NIMH, Bldg 49,Room 1B80,Convent Dr, Bethesda, MD 20892 USA. EM Yogita@ln.nimh.nih.gov NR 150 TC 84 Z9 84 U1 0 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUN PY 2004 VL 174 IS 1 BP 86 EP 98 DI 10.1007/s00213-004-1805-y PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 829ON UT WOS:000222058900011 PM 15071717 ER PT J AU Hoffman, JM AF Hoffman, JM TI Can optical molecular Imaging techniques with catheter-based approaches be used for disease detection? SO RADIOLOGY LA English DT Editorial Material C1 NCI, Canc Imaging Program, DCTD, CIP, Bethesda, MD 20892 USA. RP Hoffman, JM (reprint author), NCI, Canc Imaging Program, DCTD, CIP, 6130 Execut Blvd,EPN-6070, Bethesda, MD 20892 USA. EM jhoffman@mail.nih.gov NR 7 TC 2 Z9 4 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUN PY 2004 VL 231 IS 3 BP 609 EP 610 DI 10.1148/radiol.2313040215 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 823BR UT WOS:000221585200001 PM 15163800 ER PT J AU Wheaton, AJ Borthakur, A Shapiro, EM Regatte, RR Akella, SVS Kneeland, JB Reddy, R AF Wheaton, AJ Borthakur, A Shapiro, EM Regatte, RR Akella, SVS Kneeland, JB Reddy, R TI Proteoglycan loss in human knee cartilage: Quantitation with sodium MR imaging - Feasibility study SO RADIOLOGY LA English DT Article DE arthritis, degenerative; cartilage, MR; knee, MR; magnetic resonance (MR), sodium studies; patella; test objects ID FIXED CHARGE-DENSITY; ARTICULAR-CARTILAGE; RABBIT KNEE; NA-23 MRI; DEGRADATION; SENSITIVITY; WATER; FIELD AB The feasibility of using sodium magnetic resonance (MR) imaging to detect proteoglycan loss in early-stage osteoarthritis is evaluated. Fixed charge density (FCD) maps were calculated from sodium MR imaging data collected in nine healthy volunteers and three individuals with symptoms of early-stage osteoarthritis by using a 4.0-T clinical MR imaging unit. Data from the healthy individuals revealed a mean FCD of -182 mmol/L +/- 9. Data from the symptomatic subjects revealed focal regions of decreased FCD, with mean values ranging from -108 to -144 mmol/L, indicating proteoglycan loss from the cartilage matrix. The data suggest that sodium MR imaging has potential for use as a quantitative diagnostic tool to measure changes in proteoglycan content in early-stage osteoarthritis. (C) RSNA, 2004. C1 Univ Penn, Dept Radiol, Stellar Chance Labs B1, Philadelphia, PA 19104 USA. NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. Penn Hosp, Dept Radiol, Philadelphia, PA 19107 USA. RP Wheaton, AJ (reprint author), Univ Penn, Dept Radiol, Stellar Chance Labs B1, 422 Curie Blvd, Philadelphia, PA 19104 USA. EM wheaton@seas.upenn.edu RI Regatte, Ravinder/K-2364-2014; OI Regatte, Ravinder/0000-0002-4607-7682; Reddy, Ravinder/0000-0003-4580-2392 FU NCRR NIH HHS [RR 02305]; NIAMS NIH HHS [R01 AR 45242, R01 AR 45404] NR 28 TC 92 Z9 94 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUN PY 2004 VL 231 IS 3 BP 900 EP 905 DI 10.1148/radiol.2313030521 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 823BR UT WOS:000221585200043 PM 15163825 ER PT J AU McCarthy, DO Whitney, P Hitt, A Al-Majid, S AF McCarthy, DO Whitney, P Hitt, A Al-Majid, S TI Indomethacin and ibuprofen preserve gastrocnemius muscle mass in mice bearing the colon-26 adenocarcinoma SO RESEARCH IN NURSING & HEALTH LA English DT Article DE cancer cachexia; P7016k; mice; indomethacin; ibuprofen; ubiquitin-conjugated; proteins; colon-26 adenocarcinoma; muscle wasting; western blotting ID GASTROINTESTINAL CANCER-PATIENTS; PROTEASOME PROTEOLYTIC PATHWAY; POLYUNSATURATED FATTY-ACIDS; NF-KAPPA-B; SKELETAL-MUSCLE; PROTEIN-METABOLISM; WEIGHT-LOSS; PROLONG SURVIVAL; MEDICAL-CENTER; TUMOR-GROWTH AB Skeletal muscle wasting is a prominent feature of cancer cachexia and involves decreased muscle protein synthesis and increased activity of the ubiquitin-proteasome pathway of protein degradation. We report that both indomethacin and ibuprofen improved body weight and weight of the gastrocnemius muscle in tumor-bearing mice. Ibuprofen increased the soluble protein content of the muscle without affecting muscle levels of phosphorylated p70 S6 kinase, a ribosomal kinase involved in protein synthesis. Paradoxically, indomethacin increased levels of ubiquitin-conjugated proteins. Further study is needed to understand the mechanism of action by which indomethacin and ibuprofen preserve body weight and muscle mass in the tumor-bearing mice. The data suggest that ibuprofen may have beneficial effects in the treatment of cancer cachexia. (C) 2004 Wiley Periodicals, Inc. C1 NINR, NIH, Bethesda, MD 20892 USA. Univ Wisconsin, Sch Nursing, Madison, WI USA. Virginia Commonwealth Univ, Sch Nursing, Richmond, VA 23284 USA. RP McCarthy, DO (reprint author), NINR, NIH, 31 Ctr Dr,Room 5B13, Bethesda, MD 20892 USA. RI McCarthy, Donna/A-3291-2013 NR 56 TC 19 Z9 19 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0160-6891 J9 RES NURS HEALTH JI Res. Nurs. Health PD JUN PY 2004 VL 27 IS 3 BP 174 EP 184 DI 10.1002/nur.20019 PG 11 WC Nursing SC Nursing GA 825FF UT WOS:000221740700004 PM 15141370 ER PT J AU Dalakas, MC AF Dalakas, MC TI The molecular pathophysiology in inflammatory myopathies SO REVUE DE MEDECINE INTERNE LA English DT Article; Proceedings Paper CT 50th French Conference on Internal Medicine CY JUN 07-11, 2004 CL Bruges, BELGIUM ID INCLUSION-BODY MYOSITIS; T-CELL REPERTOIRE; COSTIMULATORY MOLECULE; POLYMYOSITIS; DERMATOMYOSITIS; MUSCLE C1 NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), NINDS, Neuromuscular Dis Sect, NIH, 10 Ctr Dr,MSC 1382,Bldg 10,Room 4N248, Bethesda, MD 20892 USA. EM dalakasm@ninds.nih.gov NR 18 TC 3 Z9 5 U1 0 U2 0 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0248-8663 J9 REV MED INTERNE JI Rev. Med. Interne PD JUN PY 2004 VL 25 SU 1 BP S14 EP S16 DI 10.1016/j.revmed.2004.04.007 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 833BM UT WOS:000222311400006 PM 15165685 ER PT J AU Lemmer, ER AF Lemmer, ER TI Oesphageal squamous cell carcinoma in South Africa - an urgent need for improved efforts at screening and prevention SO SAMJ SOUTH AFRICAN MEDICAL JOURNAL LA English DT Letter ID ESOPHAGEAL CANCER C1 NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Lemmer, ER (reprint author), NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU MED ASSOC S AFRICA PI JOHANNESBURG PA MED HOUSE CENTRAL SQ 7430 PINELANDS PRIV BAG X1, JOHANNESBURG, SOUTH AFRICA SN 0256-9574 J9 SAMJ S AFR MED J JI SAMJ S. Afr. Med. J. PD JUN PY 2004 VL 94 IS 6 BP 395 EP 395 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 832NZ UT WOS:000222275500002 PM 15250437 ER PT J AU Baris, D Silverman, DT Brown, LM Swanson, GM Hayes, RB Schwartz, AG Liff, JM Schoenberg, JB Pottern, LM Greenberg, RS Stewart, PA AF Baris, D Silverman, DT Brown, LM Swanson, GM Hayes, RB Schwartz, AG Liff, JM Schoenberg, JB Pottern, LM Greenberg, RS Stewart, PA TI Occupation, pesticide exposure and risk of multiple myeloma SO SCANDINAVIAN JOURNAL OF WORK ENVIRONMENT & HEALTH LA English DT Article DE case-control study; job-exposure matrix; multiple myeloma; occupation; pesticides ID CANCER-MORTALITY; ORF VIRUS; CYTOKINE PRODUCTION; MEAT INDUSTRY; WORKERS; FARMERS; MEN; SWEDEN; WOMEN; INTERLEUKIN-10 AB Objectives This population-based case-control study examined the relationship between occupation, living or working on a farm, pesticide exposure, and the risk of multiple myeloma. Methods The study included 573 persons newly diagnosed with myeloma and 2131 controls. Information was obtained on sociodemographic factors, occupational history, and history of living and working on a farm. Occupational and industrial titles were coded by standardized classification systems. A job-exposure matrix was developed for occupational pesticide exposure. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by unconditional logistic regression. Results Farmers and farm workers had odds ratios of 1.9 (95% CI 0.8-4.6) and 1.4 (95% CI 0.8-2.3), respectively. An odds ratio of 1.7 (95% CI 1.0-2.7) was observed for sheep farm residents or workers, whereas no increased risks were found for cattle, beef, pig, or chicken farm residents or workers. A modestly increased risk was observed for pesticides (OR 1.3, 95% CI 0.9-1.8). Significantly increased risks were found for pharmacists, dieticians and therapists (OR 6.1, 95% CI 1.7-22.5), service occupations (OR 1.3, 95% Cl 1.02-1.7), roofers (OR 3.3, 95% CI 1.1-9.8), precision printing occupations (OR 10.1, 95% CI 1.03-99.8), heating equipment operators (OR 4.7, 95% CI 1.4-15.8), and hand molders and casters (OR 3.0, 95% CI 1.0-8.4). Conclusions A modest increased risk of multiple myeloma is suggested for occupational pesticide exposure. The increased risk for sheep farm residents or workers indicates that certain animal viruses may be involved in myeloma risk. C1 NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Michigan State Univ, Ctr Canc, E Lansing, MI 48824 USA. Wayne State Univ, Sch Med, Detroit, MI USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. New Jersey State Dept Hlth, Trenton, NJ 08625 USA. NHLBI, Womems Hlth Initiat, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Med Univ S Carolina, Charleston, SC 29425 USA. RP Baris, D (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Execut Plaza S,Room 8122, Bethesda, MD 20892 USA. EM barisd@mail.nih.gov NR 54 TC 43 Z9 44 U1 3 U2 6 PU SCAND J WORK ENV HEALTH PI HELSINKI PA TOPELIUKSENKATU 41A, SF-00250 HELSINKI, FINLAND SN 0355-3140 J9 SCAND J WORK ENV HEA JI Scand. J. Work Environ. Health PD JUN PY 2004 VL 30 IS 3 BP 215 EP 222 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 834UO UT WOS:000222436600006 PM 15250650 ER PT J AU Jansma, JM Ramsey, NF van der Wee, NJA Kahn, RS AF Jansma, JM Ramsey, NF van der Wee, NJA Kahn, RS TI Working memory capacity in schizophrenia: a parametric fMRI study SO SCHIZOPHRENIA RESEARCH LA English DT Article DE schizophrenia; fMRI; functional imaging; working memory; prefrontal cortex; N-back task ID DORSOLATERAL PREFRONTAL CORTEX; ATTENUATED FRONTAL ACTIVATION; ANTERIOR CINGULATE CORTEX; CEREBRAL BLOOD-FLOW; FUNCTIONAL MRI; BRAIN ACTIVATION; PHYSIOLOGICAL DYSFUNCTION; VERBAL FLUENCY; BASAL GANGLIA; GRAY-MATTER AB Impaired working memory (WM) function in schizophrenia has been associated with abnormal activation of the dorsolateral prefrontal cortex (DLPFC). It is, however, not clear whether abnormal activation is a sign of DLPFC pathology, or a correlate of poor performance. We address this question by examining activity in the WM brain system at different levels of task difficulty. A parametric fMRI paradigm is used to examine how the WM system responds to increasing load. A parametric fMRI design with four levels of a spatial N-back task was used to examine the relationships between working memory load, functional output (performance) and brain activity in 10 schizophrenic patients on atypical antipsychotic medication and to compare these to 10 healthy controls. In spite of increasingly poor performance in schizophrenic patients, activity increased normally in DLPFC and inferior parietal cortex bilaterally and in anterior cingulate, with increasing load. At 3-back, activity dropped in DLPFC in comparison with controls, but not in the other regions. The results indicate that peak activation of the WM-system is reached at a lower processing load in schizophrenic patients than in healthy controls. As a decline of DLPFC activity at high processing loads in itself is not abnormal, WM dysfunction in schizophrenia appears to be the result of an impaired functional output of the whole WM system, causing elevation of the effective burden imposed by WM tasks. (C) 2003 Elsevier B.V. All rights reserved. C1 Univ Utrecht, Med Ctr, Funct Imaging Sect,Dept Psychiat, Div Neurosci, NL-3508 GA Utrecht, Netherlands. NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Ramsey, NF (reprint author), Univ Utrecht, Med Ctr, Funct Imaging Sect,Dept Psychiat, Div Neurosci, Room HP A01-126,POB 85500, NL-3508 GA Utrecht, Netherlands. EM n.ramsey@azu.nl NR 55 TC 116 Z9 121 U1 3 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD JUN 1 PY 2004 VL 68 IS 2-3 BP 159 EP 171 DI 10.1016/S0920-9964(03)00127-0 PG 13 WC Psychiatry SC Psychiatry GA 817JD UT WOS:000221172900006 PM 15099600 ER PT J AU Keefe, RSE Goldberg, TE Harvey, PD Gold, JM Poe, MP Coughenour, L AF Keefe, RSE Goldberg, TE Harvey, PD Gold, JM Poe, MP Coughenour, L TI The Brief Assessment of Cognition in Schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery SO SCHIZOPHRENIA RESEARCH LA English DT Article DE schizophrenia; BACS; neurocognitive assessment batteries ID PLACEBO-CONTROLLED TRIAL; NEUROPSYCHOLOGICAL STATUS; REPEATABLE BATTERY; WORKING-MEMORY; SCREENING-TEST; IMPAIRMENT; PERFORMANCE; DEFICITS; VALIDITY AB Studies of neurocognitive function in patients with schizophrenia use widely variable assessment techniques. Clinical trials assessing the cognitive enhancing effect of new medications have used neurocognitive assessment batteries that differed in content, length and administration procedures. The Brief Assessment of Cognition in Schizophrenia (BACS) is a newly developed instrument that assesses the aspects of cognition found to be most impaired and most strongly correlated with outcome in patients with schizophrenia. The BACS requires less than 35 min to complete in patients with schizophrenia, yields a high completion rate in these patients, and has high reliability. The BACS was found to be as sensitive to cognitive impairment in patients with schizophrenia as a standard battery of tests that required over 2 h to administer. Compared to healthy controls matched for age and parental education, patients with schizophrenia performed 1.49 standard deviations lower on a composite score calculated from the BACS and 1.61 standard deviations lower on a composite score calculated from the standard battery. The BACS composite scores were highly correlated with the standard battery composite scores in patients (r=0.76) and healthy controls (r=0.90). These psychometric proper-ties make the BACS a promising tool for assessing cognition repeatedly in patients with schizophrenia, especially in clinical trials of cognitive enhancement. (C) 2003 Elsevier B.V All rights reserved. C1 Duke Univ, Ctr Med, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. Clin Brain Disorders Branch, NIH, Bethesda, MD USA. Mt Sinai Sch Med, New York, NY 10029 USA. Maryland Psychiat Res Ctr, Catonsville, MD 21228 USA. RP Keefe, RSE (reprint author), Duke Univ, Ctr Med, Dept Psychiat & Behav Sci, POB 3270, Durham, NC 27710 USA. EM Richard.keefe@duke.edu NR 33 TC 398 Z9 406 U1 2 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD JUN 1 PY 2004 VL 68 IS 2-3 BP 283 EP 297 DI 10.1016/j.schres.2003.09.011 PG 15 WC Psychiatry SC Psychiatry GA 817JD UT WOS:000221172900016 PM 15099610 ER PT J AU Logan, RA Park, J Shin, JH AF Logan, RA Park, J Shin, JH TI Elite sources, context, and news topics - How two Korean newspapers covered a public health crisis SO SCIENCE COMMUNICATION LA English DT Article DE Korean press; content analysis; source and topic selection; health policy coverage ID LOS-ANGELES-TIMES; WASHINGTON-POST; SCIENCE AB A content analysis of the coverage of a public health crisis in Korea from September 1999 to December 2000 explored six hypotheses about news reporting and topic selection mostly derived from qualitatively based literature. The findings suggest that two Korean daily newspapers (Chosun Ilbo and Hankyoreh) emphasized governmental officials and physicians as news sources, underemphasized other news sources, and limited in-depth reporting. The study's findings appear to support prior assertions in the international literature that critique news media performance. However Chosun Ilbo and Hankyoreh used a range of sources and provided some multidimensional news coverage during the public health crisis. While both newspapers depended on governmental officials and physicians as news sources and tended to provide less in-depth coverage, the overall findings do not reveal a pattern of journalistic neglect. C1 Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, NIH, Bethesda, MD 20894 USA. Univ So Mississippi, Hattiesburg, MS 39406 USA. RP Logan, RA (reprint author), Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, NIH, 8600 Rockville Pike Bldg 38A,Room 7S722, Bethesda, MD 20894 USA. EM logan@nlm.nih.gov NR 54 TC 7 Z9 7 U1 1 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1075-5470 J9 SCI COMMUN JI Sci. Commun. PD JUN PY 2004 VL 25 IS 4 BP 364 EP 398 DI 10.1177/1075547004265580 PG 35 WC Communication SC Communication GA 820NX UT WOS:000221397600003 ER PT J AU Logan, RA Shin, JH Park, J AF Logan, RA Shin, JH Park, J TI Prevailing impressions of social actors in Korean news coverage of a public health crisis SO SCIENCE COMMUNICATION LA English DT Article DE Korean press; content anolysis; overtones with in news; health policy coverage ID COMMUNICATION THEORY; SCIENCE AB A content analysis of coverage of a Korean public health crisis from September 1999 to December 2000 explored four hypotheses regarding how major social actors were depicted within two national newspapers, Chosun Ilbo, a conservative daily, and Hankyoreh, a more liberal, youth-oriented daily. The findings failed to support (my of the four hypotheses. The coverage of major actors tended to range from unfavorable in Hankyoreh to equivocal in Chosun Ilbo. The study, suggests that (1) the depiction of social actors was different between leading Korean news organizations and (2) a one-dimensional, broad characterization of the Korean news media's alleged biases over time was difficult to validate. The stud), also implies that a tendency to uniformly characterize the depiction of social actors by all national news organizations is difficult in Korea and, perhaps, in similar cultural contexts. C1 Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, NIH, Bethesda, MD 20894 USA. Univ So Mississippi, Hattiesburg, MS 39406 USA. RP Logan, RA (reprint author), Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, NIH, 8600 Rockville Pike,Bldg 38A,Room 7S722, Bethesda, MD 20894 USA. NR 41 TC 0 Z9 0 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1075-5470 J9 SCI COMMUN JI Sci. Commun. PD JUN PY 2004 VL 25 IS 4 BP 399 EP 416 DI 10.1177/1075547004265593 PG 18 WC Communication SC Communication GA 820NX UT WOS:000221397600004 ER PT J AU Zhang, JY Wang, YJ Khan, J Clarke, R AF Zhang, JY Wang, YJ Khan, J Clarke, R TI Gene selection in class space for molecular classification of cancer SO SCIENCE IN CHINA SERIES F-INFORMATION SCIENCES LA English DT Article DE feature space (gene space); class space; feature selection (gene selection); PCA AB Gene selection (feature selection) is generally performed in gene space (feature space), where a very serious curse of dimensionality problem always exists because the number of genes is much larger than the number of samples in gene space (G-space). This results in difficulty in modeling the data set in this space and the low confidence of the result of gene selection. How to find a gene subset in this case is a challenging subject. In this paper, the above G-space is transformed into its dual space, referred to as class space (C-space) such that the number of dimensions is the very number of classes of the samples in G-space and the number of samples in C-space is the number of genes in G-space. It is obvious that the curse of dimensionality in C-space does not exist. A new gene selection method which is based on the principle of separating different classes as far as possible is presented with the help of Principal Component Analysis (PCA). The experimental results on gene selection for real data set are evaluated with Fisher criterion, weighted Fisher criterion as well as leave-one-out cross validation, showing that the method presented here is effective and efficient. C1 Xidian Univ, Natl Key Lab Radar Signal Proc, Xian 710071, Peoples R China. Xidian Univ, Sch Engn & Comp Sci, Xian 710071, Peoples R China. Virginia Polytech Inst & State Univ, Dept Elect Engn & Comp Engn, Alexandria, VA 22314 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. RP Zhang, JY (reprint author), Xidian Univ, Natl Key Lab Radar Signal Proc, Xian 710071, Peoples R China. EM jyzhang@xidian.edu.cn RI Clarke, Robert/A-6485-2008; Khan, Javed/P-9157-2014 OI Clarke, Robert/0000-0002-9278-0854; Khan, Javed/0000-0002-5858-0488 NR 11 TC 1 Z9 4 U1 0 U2 0 PU SCIENCE CHINA PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1009-2757 J9 SCI CHINA SER F JI Sci. China Ser. F-Inf. Sci. PD JUN PY 2004 VL 47 IS 3 BP 301 EP 314 DI 10.1360/02yf0420 PG 14 WC Computer Science, Information Systems SC Computer Science GA 841AX UT WOS:000222902800004 ER PT J AU Coscia, M Biragyn, A AF Coscia, M Biragyn, A TI Cancer immunotherapy with chemoattractant peptides SO SEMINARS IN CANCER BIOLOGY LA English DT Article DE cancer immunotherapy; chemoattractant peptides; chemokine/chemokine receptor network ID CELL LUNG-CANCER; MACROPHAGE-DERIVED CHEMOKINE; INFLAMMATORY PROTEIN 1-ALPHA; CHRONIC LYMPHOCYTIC-LEUKEMIA; PLATELET FACTOR-IV; DENDRITIC CELLS; ANTITUMOR IMMUNITY; IN-VIVO; ENDOTHELIAL-CELL; SELECTIVE RECRUITMENT AB The chemokine/chemokine receptor network is an essential part of an intricate system of immuno surveillance and homeostasis, it promotes or suppresses neovascularization, affects and regulates directly or indirectly growth and metastasis of malignant cells. Numerous studies have been conducted to harness this network as therapeutic agents for cancer to redress the chemokine balance and control angiogenesis and turnout growth and metastasis. Second generation of immunotherapeutics and chemoattractant-based vaccines use chemokines and chemoattractant peptides to elicit antitumor immunity by a specific targeting and modulating subsets of effector leukocytes, including professional antigen presenting cells. (C) 2003 Published by Elsevier Ltd. C1 NIA, Gerontol Res Ctr, Immunol Lab, Baltimore, MD 21224 USA. Univ Turin, Azienda Osped San Giovanni Battista, CeRMS, Div Ematol,Lab Ematol Oncol, Turin, Italy. RP Biragyn, A (reprint author), NIA, Gerontol Res Ctr, Immunol Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM biragyna@grc.nia.nih.gov RI coscia, marta/K-4832-2016 OI coscia, marta/0000-0003-2123-7675 NR 91 TC 16 Z9 17 U1 0 U2 1 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-579X J9 SEMIN CANCER BIOL JI Semin. Cancer Biol. PD JUN PY 2004 VL 14 IS 3 BP 209 EP 218 DI 10.1016/j.semcancer.2003.10.008 PG 10 WC Oncology SC Oncology GA 825BD UT WOS:000221730100010 PM 15246057 ER PT J AU Foley, DJ AF Foley, DJ TI An epidemiological perspective on one tale of a two-tailed hypothesis SO SLEEP MEDICINE REVIEWS LA English DT Editorial Material ID CORONARY-HEART-DISEASE; SLEEP DURATION; MORTALITY RISK; WOMEN; ADULTS; POPULATION; PATTERNS C1 NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Foley, DJ (reprint author), NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. EM dfoley@samhsa.gov NR 25 TC 13 Z9 13 U1 1 U2 2 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1087-0792 J9 SLEEP MED REV JI Sleep Med. Rev. PD JUN PY 2004 VL 8 IS 3 BP 155 EP 157 DI 10.1016/j.smrv.2004.02.002 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 827IP UT WOS:000221893200001 PM 15144958 ER PT J AU Volpi, S Rabadan-Diehl, C Aguilera, G AF Volpi, S Rabadan-Diehl, C Aguilera, G TI Vasopressinergic regulation of the hypothalamic pituitary adrenal axis and stress adaptation SO STRESS-THE INTERNATIONAL JOURNAL ON THE BIOLOGY OF STRESS LA English DT Review DE corticotroph; hypothalamic paraventricular nucleus; vasopressin transcription; V1b receptor; V1b receptor mRNA ID CORTICOTROPIN-RELEASING HORMONE; RECEPTOR MESSENGER-RNA; PARVOCELLULAR NEUROSECRETORY NEURONS; GENE-EXPRESSION; V1B RECEPTOR; PARAVENTRICULAR NUCLEUS; ARGININE-VASOPRESSIN; ADRENOCORTICOTROPIN SECRETION; TRANSLATIONAL REGULATION; RIBONUCLEIC-ACID AB Vasopressin (VP) stimulates pituitary ACTH secretion through interaction with receptors of the V1b subtype (V1bR, V3R), located in the plasma membrane of the pituitary corticotroph, mainly by potentiating the stimulatory effects of corticotropin releasing hormone (CRH). Chronic stress paradigms associated with corticotroph hyperresponsiveness lead to preferential expression of hypothalamic VP over CRH and upregulation of pituitary V1bR, suggesting an important role for VP during adaptation of the hypothalamic-pituitary-adrenal (HPA) axis to stress. Vasopressinergic regulation of ACTH secretion depends on the number of V1bRs as well as coupling of the receptor to phospholipase C (PLC) in the pituitary. Regulation of V1bR gene transcription may involve a number of regulatory elements in the promoter region, of which a GAGA box was shown to be essential. Although V1bR gene transcription is necessary to maintain V1bR mRNA levels, the lack of correlation between VP binding and V1bR mRNA suggests that regulation of mRNA translation is a major regulatory step of the number of V1bRs. V1bR translation appears to be under tonic inhibition by upstream minicistrons and positive regulation through protein kinase C (PKC) activation of an internal ribosome entry site (IRES) in the 5' untranslated region (5'UTR) of the mRNA. The data provide mechanisms by which regulation of hypothalamic VP and pituitary V1bR content contribute to controlling HPA axis activity during chronic stress. C1 NICHHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Aguilera, G (reprint author), NICHHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N262,10 Ctr Dr MSC 1862, Bethesda, MD 20892 USA. EM greti@helix.nih.gov NR 61 TC 73 Z9 76 U1 0 U2 5 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1025-3890 J9 STRESS JI Stress PD JUN PY 2004 VL 7 IS 2 BP 75 EP 83 DI 10.1080/102538900410001733535 PG 9 WC Behavioral Sciences; Endocrinology & Metabolism; Neurosciences SC Behavioral Sciences; Endocrinology & Metabolism; Neurosciences & Neurology GA 844PY UT WOS:000223173300002 PM 15512850 ER PT J AU Adair, JC Charlie, J Dencoff, JE Kaye, JA Quinn, JF Camicioli, RM Stetler-Stevenson, WG Rosenberg, GA AF Adair, JC Charlie, J Dencoff, JE Kaye, JA Quinn, JF Camicioli, RM Stetler-Stevenson, WG Rosenberg, GA TI Measurement of gelatinase B (MMP-9) in the cerebrospinal fluid of patients with vascular dementia and Alzheimer disease SO STROKE LA English DT Article DE matrix metalloproteinase; dementia ID MATRIX METALLOPROTEINASES; MULTIPLE-SCLEROSIS; TISSUE INHIBITORS; CRITERIA AB Background and Purpose-Vascular causes of dementia are increasing in importance because of the aging of the population. Biological markers to distinguish patients with vascular dementia (VaD) from Alzheimer disease (AD) would be very useful. Because cerebrovascular disease increases expression of brain matrix metalloproteinases (MMPs) and tissue inhibitors to metalloproteinases (TIMPs), we hypothesized that MMPs would be elevated in the cerebrospinal fluid (CSF) of patients with VaD, but not in patients with AD. Methods-Fifteen patients with VaD were identified, including dementia caused by multiple infarcts and progressive dementia caused by disease of the small cerebral blood vessels. Patients were followed-up for 4 to 10 years to confirm the diagnosis. Thirty patients with AD were also studied. Patients had CSF collected at their initial evaluation. Gelatinase A (MMP-2) and gelatinase B (MMP-9) were quantified by gelatin-substrate zymography, and TIMPs were measured by reverse zymography. Control CSF was obtained from neurologically normal subjects. Results-MMP-9 levels were significantly elevated in the CSF of VaD patients compared either to those with AD (P<0.0001) or to controls. MMP-2, TIMP-1, and TIMP-2 were similar in patient groups and controls. Conclusions-Patients with multiinfarct and small vessel VaD have elevated levels of MMP-9 in the CSF compared with AD and controls. Although CSF MMP-9 increases in other neurological conditions and is not specific for VaD, it could provide an additional biological marker for the separation of patients with VaD and AD. C1 Univ New Mexico, Hlth Sci Ctr, Dept Neurol, Sch Med, Albuquerque, NM 87131 USA. Univ New Mexico, Sch Med, Dept Cell Biol & Physiol, Albuquerque, NM 87131 USA. Univ New Mexico, Sch Med, Dept Neurosci, Albuquerque, NM 87131 USA. Vet Adm Hlth Ctr, Albuquerque, NM USA. Oregon Hlth Sci Univ, Dept Neurol, Portland, OR 97201 USA. Univ Alberta, Edmonton, AB, Canada. NCI, Extracellular Matrix Pathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Adair, JC (reprint author), Univ New Mexico, Hlth Sci Ctr, Dept Neurol, Sch Med, Albuquerque, NM 87131 USA. EM adair.john@albuquerque.va.gov RI Stetler-Stevenson, William/H-6956-2012 OI Stetler-Stevenson, William/0000-0002-5500-5808 FU NCRR NIH HHS [5M01 RR00997-18]; NIA NIH HHS [AG08017]; NINDS NIH HHS [R01 NS21169] NR 15 TC 63 Z9 65 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUN PY 2004 VL 35 IS 6 BP E159 EP E162 DI 10.1161/01.STR.0000127420.10990.76 PG 4 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 824HF UT WOS:000221676600076 PM 15105518 ER PT J AU Bardy, J AF Bardy, J TI Molecular genetic analysis of ischaemic stroke SO STROKE LA English DT Meeting Abstract CT 5th World Stroke Congress CY JUN 23-26, 2004 CL Vancouver, CANADA SP Int Stroke Soc, Canadian Stroke Consortium, Natl Stroke Assoc, Canadian Stroke Network C1 NIA, Neurogenet Lab, 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 JUN PY 2004 VL 35 IS 6 BP E174 EP E174 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 824HF UT WOS:000221676600117 ER PT J AU Furlan, AJ Warach, S AF Furlan, AJ Warach, S TI Reperfusion strategies SO STROKE LA English DT Meeting Abstract CT 5th World Stroke Congress CY JUN 23-26, 2004 CL Vancouver, CANADA SP Int Stroke Soc, Canadian Stroke Consortium, Natl Stroke Assoc, Canadian Stroke Network C1 NINDS, NIH, Bethesda, MD 20892 USA. Cleveland Clin, Dept Neurol, Cleveland, OH 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 JUN PY 2004 VL 35 IS 6 BP E191 EP E191 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 824HF UT WOS:000221676600221 ER PT J AU Kaste, M Donnan, GA Marler, JR Dishaw, A AF Kaste, M Donnan, GA Marler, JR Dishaw, A TI Go home and go BIG! National strategies for stroke SO STROKE LA English DT Meeting Abstract CT 5th World Stroke Congress CY JUN 23-26, 2004 CL Vancouver, CANADA SP Int Stroke Soc, Canadian Stroke Consortium, Natl Stroke Assoc, Canadian Stroke Network C1 Univ Melbourne, Natl Stroke Res Inst, Parkville, Vic 3052, Australia. NINDS, Bethesda, MD 20892 USA. RI DONNAN, GEOFFREY/A-9947-2008 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 JUN PY 2004 VL 35 IS 6 BP E202 EP E202 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 824HF UT WOS:000221676600285 ER PT J AU Marler, JR AF Marler, JR TI New approaches to clinical trials SO STROKE LA English DT Meeting Abstract CT 5th World Stroke Congress CY JUN 23-26, 2004 CL Vancouver, CANADA SP Int Stroke Soc, Canadian Stroke Consortium, Natl Stroke Assoc, Canadian Stroke Network C1 NINDS, Clin Trial Grp, 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 JUN PY 2004 VL 35 IS 6 BP E205 EP E205 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 824HF UT WOS:000221676600305 ER PT J AU Mitsuyama, F AF Mitsuyama, F TI The reversing atherosclerosis by the GOBS therapy SO STROKE LA English DT Meeting Abstract CT 5th World Stroke Congress CY JUN 23-26, 2004 CL Vancouver, CANADA SP Int Stroke Soc, Canadian Stroke Consortium, Natl Stroke Assoc, Canadian Stroke Network C1 NICHD, ERRB, NIH, Bethesda, 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 JUN PY 2004 VL 35 IS 6 BP E224 EP E224 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 824HF UT WOS:000221676600419 ER PT J AU Sawaki, L Wu, CWH Cohen, LG AF Sawaki, L Wu, CWH Cohen, LG TI Enhancement of use-dependent plasticity by peripheral nerve stimulation in patients with chronic stroke SO STROKE LA English DT Meeting Abstract CT 5th World Stroke Congress CY JUN 23-26, 2004 CL Vancouver, CANADA SP Int Stroke Soc, Canadian Stroke Consortium, Natl Stroke Assoc, Canadian Stroke Network C1 Wake Forest Univ, Sch Med, Program Rehabil, Winston Salem, NC 27109 USA. NINDS, NIH, Human Cort Phsyiol Sect, 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 JUN PY 2004 VL 35 IS 6 BP E319 EP E319 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 824HF UT WOS:000221676600985 ER PT J AU Schellinger, PD Chalela, JA Kang, DW Warach, S AF Schellinger, PD Chalela, JA Kang, DW Warach, S TI Diagnostic and prognostic value of early MRI vessel signs in hyperacute stroke patients imaged < 3h before receiving rt-PA SO STROKE LA English DT Meeting Abstract CT 5th World Stroke Congress CY JUN 23-26, 2004 CL Vancouver, CANADA SP Int Stroke Soc, Canadian Stroke Consortium, Natl Stroke Assoc, Canadian Stroke Network C1 Univ Clin Heidelberg, Dept Neurol, Heidelberg, Germany. NINDS, Sect Stroke Therapeut & Diagnost, 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 JUN PY 2004 VL 35 IS 6 BP E198 EP E198 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 824HF UT WOS:000221676600261 ER PT J AU Wright, VI Olan, WJ Dick, BW Latour, L Baird, AE AF Wright, VI Olan, WJ Dick, BW Latour, L Baird, AE TI Ultrafast detection of vascular disease from the aortic arch to the Circle of Willis by Contrast-Enhanced Magnetic Resonance Angiography: Prospective evaluation SO STROKE LA English DT Meeting Abstract CT 5th World Stroke Congress CY JUN 23-26, 2004 CL Vancouver, CANADA SP Int Stroke Soc, Canadian Stroke Consortium, Natl Stroke Assoc, Canadian Stroke Network C1 Suburban Hosp, Dept Neuroradiol MRI, Bethesda, MD USA. NINDS, NIH, SNU, 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 JUN PY 2004 VL 35 IS 6 BP E199 EP E199 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 824HF UT WOS:000221676600266 ER PT J AU Wu, CWH Seo, HJ Cohen, LG AF Wu, CWH Seo, HJ Cohen, LG TI Improvement of paretic hand function by somatosensory stimulation in chronic stroke SO STROKE LA English DT Meeting Abstract CT 5th World Stroke Congress CY JUN 23-26, 2004 CL Vancouver, CANADA SP Int Stroke Soc, Canadian Stroke Consortium, Natl Stroke Assoc, Canadian Stroke Network C1 NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUN PY 2004 VL 35 IS 6 BP E310 EP E310 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 824HF UT WOS:000221676600934 ER PT J AU Anderson, S Srajer, V Pahl, R Rajagopal, S Schotte, F Anfinrud, P Wulff, M Moffat, K AF Anderson, S Srajer, V Pahl, R Rajagopal, S Schotte, F Anfinrud, P Wulff, M Moffat, K TI Chromophore conformation and the evolution of tertiary structural changes in photoactive yellow protein SO STRUCTURE LA English DT Article ID HALOPHILIC PHOTOTROPHIC BACTERIUM; TIME-RESOLVED CRYSTALLOGRAPHY; ECTOTHIORHODOSPIRA-HALOPHILA; ACTIVE-SITE; PHOTOCYCLE; PHOTORECEPTOR; SPECTROSCOPY; INTERMEDIATE; EXPRESSION; ACTIVATION AB We use time-resolved crystallography to observe the structural progression of a bacterial blue light photoreceptor throughout its photocycle. Data were collected from 10 ns to 100 ms after photoactivation of the E46Q mutant of photoactive yellow protein. Refinement of transient chromophore conformations shows that the spectroscopically distinct intermediates are formed via progressive disruption of the hydrogen bond network to the chromophore. Although structural change occurs within a few nanoseconds on and around the chromophore, it takes milliseconds for a distinct pattern of tertiary structural change to fully progress through the entire molecule, thus generating the putative signaling state. Remarkably, the coupling between the chromophore conformation and the tertiary structure of this small protein is not tight: there are leads and lags between changes in the conformation of the chromophore and the protein tertiary structure. C1 Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA. Univ Chicago, Inst Biophys Dynam, Chicago, IL 60637 USA. Univ Chicago, Consortium Adv Radiat Sources, Chicago, IL 60637 USA. NIH, Bethesda, MD 20892 USA. European Synchrotron Radiat Facil, F-38043 Grenoble 9, France. RP Anderson, S (reprint author), Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA. EM smander@midway.uchicago.edu RI Rajagopal, Sudarshan/G-8975-2013 OI Rajagopal, Sudarshan/0000-0002-3443-5040 FU NCRR NIH HHS [RR07707]; NIGMS NIH HHS [GM36452] NR 34 TC 47 Z9 47 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD JUN PY 2004 VL 12 IS 6 BP 1039 EP 1045 DI 10.1016/j.str.2004.04.008 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 830WO UT WOS:000222155100015 PM 15274923 ER PT J AU Xu, H Wang, XY Wang, J Rothman, RB AF Xu, H Wang, XY Wang, J Rothman, RB TI Opioid peptide receptor studies. 17. Attenuation of chronic morphine effects after antisense oligodeoxynucleotide knock-down of RGS9 protein in cells expressing the cloned Mu opioid receptor SO SYNAPSE LA English DT Article DE morphine; tolerance; dependence; RGS protein; [S-35]GTP-gamma-S; antisense oligodeoxynucleotide ID AGONIST EFFICACY; NERVOUS-SYSTEM; TOLERANCE; BINDING; DEPENDENCE; RAT; REGULATORS; CYCLASE; DOMAIN AB RGS proteins are a recently described class of regulators that influence G-protein-mediated signaling pathways. We have shown previously that chronic morphine results in functional uncoupling of the R opioid receptor from its G protein in CHO cells expressing cloned human mu opioid receptors. In the present study, we examined the effects of morphine treatment (1 muM, 20 h) on DAMGO-stimulated high-affinity [S-35] GTP-gamma-S binding and DAMGO-mediated inhibition of forskolin-stimulated cAMP accumulation in HN9.10 cells stably expressing the cloned rat mu opioid receptor, in the absence and presence of the RGS9 protein knock-down condition (confirmed by Western blot analysis). RGS9 protein expression was reduced by blocking its mRNA with an antisense oligodeoxynucleotide (AS-114). Binding surface analysis resolved two [S-35]GTP-gamma-S binding sites (high affinity and low affinity sites). In sense-treated control cells, DAMGO-stimulated [S-35]GTP-gamma-S binding by increasing the B-max of the high-affinity site. In sense-treated morphine-treated cells, DAMGO-stimulated [S-35]GTP-gamma-S binding by decreasing the high-affinity K, without changing the Bmax. AS-114 significantly inhibited chronic morphine-induced upregulation of adenylate cyclase activity and partially reversed chronic morphine effects as measured by DAMGO-stimulated [S-35]GTP-gamma-S binding. Morphine treatment increased the EC50 (6.2-fold) for DAMGO-mediated inhibition of forskolin-stimulated cAMP activity in control cells but not in cells treated with AS-114 to knock-down RGS9. These results provide additional evidence for involvement of RGS9 protein in modulating opioid signaling, which may contribute to the development of morphine tolerance and dependence. Published 2004 Wiley-Liss, Inc.(dagger) C1 NIDA, Intramural Res Program, Clin Psychopharmacol Sect, NIH, Baltimore, MD 21224 USA. NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Rothman, RB (reprint author), NIDA, Intramural Res Program, Clin Psychopharmacol Sect, NIH, POB 5180,5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM RROTHMAN@INTRA.NIDA.NIH.GOV NR 31 TC 18 Z9 18 U1 1 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD JUN 1 PY 2004 VL 52 IS 3 BP 209 EP 217 DI 10.1002/syn.20019 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 823IL UT WOS:000221604200004 PM 15065220 ER PT J AU Penzak, SR Shen, JM Alfaro, RM Remaley, AT Natarajan, V Falloon, J AF Penzak, SR Shen, JM Alfaro, RM Remaley, AT Natarajan, V Falloon, J TI Ritonavir decreases the nonrenal clearance of digoxin in healthy volunteers with known MDR1 genotypes SO THERAPEUTIC DRUG MONITORING LA English DT Article DE MDR1; P-glycoprotein; genotype; digoxin; ritonavir; protease inhibitor; pharmacokinetics; human immunodeficiency virus; AIDS ID P-GLYCOPROTEIN EXPRESSION; HIV PROTEASE INHIBITORS; MULTIDRUG-RESISTANCE GENE; BLOOD-BRAIN-BARRIER; ENDOTHELIAL-CELLS; DRUG-INTERACTION; TRANSPORTER; VERAPAMIL; HUMANS; ABSORPTION AB Our objective was to examine the influence of ritonavir on P-glycoprotein (P-gp) activity in humans by characterizing the effect of ritonavir on the pharmacokinetics of the P-gp substrate digoxin in individuals with known MDR1 genotypes. Healthy volunteers received a single dose of digoxin 0.4 mg orally before and after 14 days of ritonavir 200 mg twice daily. After each digoxin dose blood and urine were collected over 72 hours and analyzed for digoxin. Digoxin pharmacokinetic parameter values were determined using noncompartmental methods. MDR1 genotypes at positions 3435 and 2677 in exons 26 and 21, respectively, were determined using PCR-RFLP analysis. Ritonavir increased the digoxin AUC(0-72) from 26.20 +/- 8.67 to 31.96 +/- 11.24 ng (.) h/mL (P = 0.03) and the AUC(0-8) from 6.25 +/- 1.8 to 8.04 +/- 2.22 ng (.) h/mL (P = 0.02) in 12 subjects. Digoxin oral clearance decreased from 149 +/- 101 mL/h (.) kg(-1) to 105 +/- 57 mL/h (.) kg(-1) (P = 0.04). Other digoxin pharmacokinetic parameter values, including renal clearance, were unaffected by ritonavir. Overall, 75% (9/12) of subjects had higher concentrations of digoxin after ritonavir administration. The majority of subjects were heterozygous at position 3435 (C/T) (6 subjects) and position 2677 (G/T,A) (7 subjects); although data are limited, the effect of ritonavir on digoxin pharmacokinetics appears to occur across all tested MDR1 genotypes. Concomitant low-dose ritonavir reduced the nomenal clearance of digoxin, thereby increasing its systemic availability. The most likely mechanism for this interaction is ritonavir-associated inhibition of P-gp. Thus, ritonavir can alter the pharmacokinetics of coadministered medications that are P-gp substrates. C1 NIH, Clin Pharmacokinet Res Lab, Warren G Magnuson Clin Ctr, Dept Pharm, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Lab Med, Bethesda, MD 20892 USA. Sci Applicat Int Corp, Frederick, MD USA. RP Penzak, SR (reprint author), NIH, Clin Pharmacokinet Res Lab, Warren G Magnuson Clin Ctr, Dept Pharm, Bldg 10,Room IN 257, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CO-12400] NR 47 TC 39 Z9 40 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0163-4356 J9 THER DRUG MONIT JI Ther. Drug Monit. PD JUN PY 2004 VL 26 IS 3 BP 322 EP 330 DI 10.1097/00007691-200406000-00018 PG 9 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 831LT UT WOS:000222196600017 PM 15167636 ER PT J AU Ayo-Yusuf, OA Swart, TJP Pickworth, WB AF Ayo-Yusuf, OA Swart, TJP Pickworth, WB TI Nicotine delivery capabilities of smokeless tobacco products and implications for control of tobacco dependence in South Africa SO TOBACCO CONTROL LA English DT Article ID BLOOD-PRESSURE; CIGARETTES; CANCER; SNUFF; PREGNANCY; TOOMBAK; SMOKING; WHITE AB Objectives: Smokeless tobacco (SLT) use is popular among black South African women and children. The study sought to determine the nicotine delivery capability of popular industrialised and traditional SLT brands in South Africa, and to provide information for policy action by regulatory authorities. Design: Laboratory chemical analysis of four industrialised and one traditional SLT products commercially available, using previously published analytical methods. Potential for dependence was inferred from nicotine delivery capabilities determined by the percentage free base nicotine. Measurements: Moisture, pH, total nicotine, and percentage free base nicotine. Results: Total nicotine content was between 6-16 mg/g. The pH varied between 7-10 and this correlated with percentage free base nicotine, which ranged between 10-99%. The nicotine delivery capability of the traditional product was lower than that of the industrialised products except for the recently introduced portion bag snus, which had comparable total nicotine but the lowest pH and percentage free base nicotine. The most popular SLT brands showed the highest percentage free base nicotine ever reported for any industrialised SLT or cigarette brands. Small cans contained higher nicotine than the large cans of the same brand tested. Findings from the study support a potential for limited "product graduation" by users. Conclusions: South African SLT users are mostly exposed to potentially very highly addictive levels of nicotine that may favour tobacco dependence and its consequent health risks. The increasing use of SLT by women of childbearing age support the need for intensified policy action to control its use. C1 Univ Pretoria, Dept Community Dent, ZA-0001 Pretoria, South Africa. Univ Pretoria, Dept Oral Pathol & Oral Biol, ZA-0001 Pretoria, South Africa. NIDA, Intramural Res Program, Baltimore, MD USA. RP Ayo-Yusuf, OA (reprint author), Univ Pretoria, Oral & Dent Hosp, Dept Community Dent, POB 1266, ZA-0001 Pretoria, South Africa. EM lekan.ayoyusuf@up.ac.za RI Ayo-Yusuf, Olalekan/A-1512-2008 NR 36 TC 20 Z9 20 U1 0 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0964-4563 J9 TOB CONTROL JI Tob. Control PD JUN PY 2004 VL 13 IS 2 BP 186 EP 189 DI 10.1136/tc.2003.006601 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 825YL UT WOS:000221794700023 PM 15175538 ER PT J AU Trouba, KJ Germolec, DR AF Trouba, KJ Germolec, DR TI Micromolar concentrations of sodium arsenite induce cyclooxygenase-2 expression and stimulate p42/44 mitogen-activated protein kinase phosphorylation in normal human epidermal keratinocytes SO TOXICOLOGICAL SCIENCES LA English DT Article DE cyclooxygenase; arsenic; PD98059; SB202190; MAP kinase ID MESSENGER-RNA STABILITY; ENDOTHELIAL-CELLS; COX-2 EXPRESSION; MOUSE SKIN; PATHWAY; RECEPTOR; CARCINOGENESIS; INHIBITION; CANCER; OVEREXPRESSION AB Based on evidence that arsenic modulates proinflammatory events that are involved in skin carcinogenecity, we hypothesized that in normal human epidermal keratinocytes (NHEK) arsenic increases expression of the procarcinogenic enzyme cyclooxygenase-2 (COX-2) and that this occurs via specific mitogen and stress signaling pathways. To test this hypothesis, NHEK were exposed to sodium arsenite, and COX-2 expression, prostaglandin E2 (PGE(2)) secretion, mitogen-activated protein kinase (MAPK) phosphorylation, and DNA synthesis were quantified. Inhibitors of p42/44 and p38 MAPKs were used to evaluate the contribution of mitogen and stress signaling to the modulation of COX-2. Our results demonstrate that arsenite (0.005-5 muM) elevates COX-2 expression, PGE(2) secretion (2.5-5 muM), and DNA synthesis (1-5 muM). Arsenite stimulated p42/44 but not p38 MAPK phosphorylation (2.5 muM), responses different than those produced by epidermal growth factor. Inhibition of mitogen-activated protein kinase kinase (MAPKK) and p38 MAPK using PD98059 (20 muM) and SB202190 (5 muM), respectively, attenuated the elevation of COX-2 protein induced by arsenite, whereas physiological concentrations of three COX-2 inhibitors (e.g., NS-398, piroxicam, and aspirin) reduced arsenite-stimulated DNA synthesis. These data indicate that arsenite elevates COX-2 in NHEK at the transcriptional and translational levels as well as increases PGE(2) secretion. Compounds that inhibit COX-2 expression and activity may be useful in the scientific study, prevention, and treatment of arsenic skin carcinogenesis and deserve further investigation. C1 NIEHS, Mol Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Germolec, DR (reprint author), NIEHS, Mol Toxicol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM germolec@niehs.nih.gov NR 48 TC 19 Z9 20 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JUN PY 2004 VL 79 IS 2 BP 248 EP 257 DI 10.1093/toxsci/kfh132 PG 10 WC Toxicology SC Toxicology GA 822PD UT WOS:000221551200007 PM 15056798 ER PT J AU Jiang, YC Liu, J Waalkes, M Kang, YJ AF Jiang, YC Liu, J Waalkes, M Kang, YJ TI Changes in the gene expression associated with carbon tetrachloride-induced liver fibrosis persist after cessation of dosing in mice SO TOXICOLOGICAL SCIENCES LA English DT Article DE carbon tetrachloride; fibrosis; gene expression; immunohistochemistry ID RAT-LIVER; TOXICITY; METABOLISM; MECHANISM AB Recent studies have shown that gene expression profiles change in the livers of animals treated acutely with toxic chemicals such as carbon tetrachloride (CCl4). This study was undertaken to evaluate the changes in gene expression in mouse liver immediately after a long-term treatment with CCl4 and possible effects of treatment cessation on these changes. Adult 129/Sv(pc)J mice were treated twice a week with CCl4 at 1 ml/kg in olive oil for 4 weeks. Hepatic pathological changes observed in the CCl4-treated mice included necrosis, inflammation, and fibrosis, along with increased serum alanine aminotransferase activities. Consistent with these changes, expression of genes involved in cell death, cell proliferation, metabolism, DNA damage, and fibrogenesis were upregulated as detected by microarray analysis and confirmed by real-time RT-PCR. Four weeks after CCl4 treatment cessation, the pathological changes were recovered, with the exception of fibrosis, which was not completely reversed. Most of the gene expression profiles also returned to the control level; however, the fibrogenetic genes remained at a high level of expression. These results demonstrate that changes in gene expression profile correlate with pathological alterations in the liver in response to CCl4 intoxication. Most of these changes are recoverable upon withdrawal of the toxic insult. However, liver fibrosis is a prolonged change both in gene expression and histopathological alterations. C1 Univ Louisville, Sch Med, Dept Med, Louisville, KY 40202 USA. Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Louisville, KY 40202 USA. NCI, Inorgan Carcinogenesis Sect, NIEHS, Res Triangle Pk, NC 27709 USA. RP Kang, YJ (reprint author), Univ Louisville, Sch Med, Dept Med, 511 S Floyd St,DR 530, Louisville, KY 40202 USA. EM yjkang01@louisville.edu FU NHLBI NIH HHS [HL59225, HL63760] NR 20 TC 31 Z9 37 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JUN PY 2004 VL 79 IS 2 BP 404 EP 410 DI 10.1093/toxsci/kfh120 PG 7 WC Toxicology SC Toxicology GA 822PD UT WOS:000221551200022 PM 15056808 ER PT J AU Doi, AM Roycroft, JH Herbert, RA Haseman, JK Hailey, JR Chou, BJ Dill, JA Grumbein, SL Miller, RA Renne, RA Bucher, JR AF Doi, AM Roycroft, JH Herbert, RA Haseman, JK Hailey, JR Chou, BJ Dill, JA Grumbein, SL Miller, RA Renne, RA Bucher, JR TI Inhalation toxicology and carcinogenesis studies of propylene glycol mono-t-butyl ether in rats and mice SO TOXICOLOGY LA English DT Article DE solvent; alpha(2u)-globulin; renal tubular neoplasm; hepatocellular adenoma; hepatocellular carcinoma; hepatoblastoma ID ZERO DOSE CONTROL; ALPHA(2U)-GLOBULIN NEPHROPATHY; GENE FAMILY; IN-VIVO; ALPHA-2U-GLOBULIN; CHEMICALS; TESTS; EXPRESSION; SALMONELLA; TOXICITY AB Propylene glycol mono-t-butyl ether (PGMBE) is used as a solvent in a variety of commercial applications. Male and female F344/N rats and B6C3F(1) mice were exposed to PGMBE by whole-body inhalation for 2 or 14 weeks (0, 75, 150, 300, 600, or 1200 ppm) or 2 years (0, 75 300, or 1200 ppm); male NBR rats were exposed for 2 weeks. The kidney and the liver were targets of PGMBE toxicity in rats. Renal lesions suggestive of alpha(2u)-globulin nephropathy were observed in male F344/N, in the 2 and 14-week studies, no kidney lesions were seen in NBR rats. In the 2-year study, male rats displayed exposure-related nonneoplastic lesions in the kidney, and may have shown marginal increases in tubular neoplasms. In the liver, the incidences of hepatocellular adenomas occurred with a positive trend in male rats, and may have been related to PGMBE exposure. In mice of both sexes, the major target of PGMBE toxicity was the liver. In the 2-week study, liver weights and in the 14-week study. liver weiLhts and the incidences of centrilobular hypertrophy were increased. In the 2-year study, the incidences of exposure-related hepatocellular adenoma, adenoma or carcinoma combined, and hepatoblastoma occurred with a positive trend, and were significantly increased in 1200 ppm groups. In summary, exposure to PGMBE resulted in nonneoplastic lesions of the kidney characteristic of alpha(2u)-globulin nephropathy, and may have increased renal tubular neoplasms in male rats. Exposure to PGMBE also produced increases in hepatic tumors in male and female mice. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Battelle Mem Inst, Toxicol NW, Richland, WA 99352 USA. RP Doi, AM (reprint author), NIEHS, 79 Alexander Dr,Mail Drop EC-34, Res Triangle Pk, NC 27709 USA. EM doi@niehs.nih.gov NR 50 TC 5 Z9 6 U1 0 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD JUN 1 PY 2004 VL 199 IS 1 BP 1 EP 22 DI 10.1016/j.tox.2003.12.020 PG 22 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 824CE UT WOS:000221660800001 PM 15125995 ER PT J AU Carabeo, RA Grieshaber, SS Hasenkrug, A Dooley, C Hackstadt, T AF Carabeo, RA Grieshaber, SS Hasenkrug, A Dooley, C Hackstadt, T TI Requirement for the Rac GTPage in Chlamydia trachomatis invasion of non-phagocytic cells SO TRAFFIC LA English DT Article DE actin; chlamydia; GTPase; intracellular parasite; Rac ID ENTEROPATHOGENIC ESCHERICHIA-COLI; OUTER-MEMBRANE PROTEIN; FIBROBLASTS L-CELLS; RHO-FAMILY GTPASES; HOST-CELL; ACTIN CYTOSKELETON; EPITHELIAL-CELLS; III SECRETION; N-WASP; INTRACELLULAR PARASITISM AB Chlamydiae are gram-negative obligate intracellular pathogens to which access to an intracellular environment is paramount to their survival and replication. To this end, chlamydiae have evolved extremely efficient means of invading nonphagocytic cells. To elucidate the host cell machinery utilized by Chlamydia trachomatis in invasion, we examined the roles of the Rho GTPase family members in the internalization of chlamydial elementary bodies. Upon binding of elementary bodies on the cell surface, actin is rapidly recruited to the sites of internalization. Members of the Rho GTPase family are frequently involved in localized recruitment of actin. Clostridial Toxin B, which is a known enzymatic inhibitor of Rac, Cdc42 and Rho GTPases, significantly reduced chlamydial invasion of HeLa cells. Expression of dominant negative constructs in HeLa cells revealed that chlamydial uptake was dependent on Rac, but not on Cdc42 or RhoA. Rac but not Cdc42 was found to be activated by chlamydial attachment. The effect of dominant negative Rac expression on chlamydial uptake is manifested through the inhibition of actin recruitment to the sites of chlamydial entry. Studies utilizing Green Fluorescent Protein fusion constructs of Rac, Cdc42 and RhoA, showed Rac to be the sole member of the Rho GTPase family recruited to the site of chlamydial entry. C1 NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. RP Hackstadt, T (reprint author), NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. EM THACKSTADT@niaid.nih.gov NR 47 TC 59 Z9 61 U1 0 U2 6 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1398-9219 J9 TRAFFIC JI Traffic PD JUN PY 2004 VL 5 IS 6 BP 418 EP 425 DI 10.1111/j.1600-0854.2004.00184.x PG 8 WC Cell Biology SC Cell Biology GA 822LY UT WOS:000221542700004 PM 15117316 ER PT J AU Putney, JW AF Putney, JW TI The enigmatic TRPCs: multifunctional cation channels SO TRENDS IN CELL BIOLOGY LA English DT Article ID CAPACITATIVE CALCIUM-ENTRY; TRANSIENT RECEPTOR; STORE DEPLETION; CA2+ ENTRY; DROSOPHILA TRP; B-LYMPHOCYTES; HUMAN HOMOLOG; CELLS; PROTEIN; EXPRESSION AB Canonical transient receptor potential (TRPC) channels are vertebrate homologs of the Drosophila photoreceptor channel. Considerable research has been carried out on the seven members of this family, particularly regarding their possible role in Ca2+ entry. However, the current literature presents a confusing picture, with different laboratories describing widely differing results and interpretations. In this article, I will discuss the possibility that these diverse experimental findings arise from a true multifunctional ability of TRPC channels that serves distinct physiological functions in different cell types. C1 NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), NIEHS, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM putney@niehs.nih.gov NR 40 TC 72 Z9 81 U1 0 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD JUN PY 2004 VL 14 IS 6 BP 282 EP 286 DI 10.1016/j.tcb.2004.04.002 PG 5 WC Cell Biology SC Cell Biology GA 836LI UT WOS:000222556800003 PM 15183184 ER PT J AU Tilly, K Grimm, D Bueschel, DM Krum, JG Rosa, P AF Tilly, K Grimm, D Bueschel, DM Krum, JG Rosa, P TI Infectious cycle analysis of a Borrelia burgdorferi mutant defective in transport of chitobiose, a tick cuticle component SO VECTOR-BORNE AND ZOONOTIC DISEASES LA English DT Article DE Lyme disease; Vector-Borne disease; chbC gene ID LYME-DISEASE SPIROCHETE; PERITROPHIC MEMBRANE; CHITIN DISACCHARIDE; ESCHERICHIA-COLI; GENE; N,N'-DIACETYLCHITOBIOSE; INACTIVATION; CONSERVATION; PENETRATION; CULTIVATION AB Chitobiose is the dimer subunit of chitin, a component of tick cuticle and peritrophic matrix, which is not found in mammals. The Borrelia burgdorferi chbC gene is required for the use of chitobiose as a source of the essential nutrient N-acetyl glucosamine during growth in vitro. In order to investigate the role of chitobiose transport in the infectious cycle, we constructed isogenic chbC mutant and wild-type strains in an infectious B. burgdorferi background and confirmed that the mutants were defective in chitobiose utilization. The defect in the mutants was shown to be in chitobiose transport, consistent with the predicted function of the ChbC protein as the membrane component of a phosphotransferase transporter for chitobiose. We then tested whether this locus is also required for any stage of the experimental mouse-tick infectious cycle. We found that both wild-type and mutant bacteria successfully infect both mice and ticks and are transmitted between the two hosts. These results demonstrate that B. burgdorferi growth in vivo is independent of chitobiose transport, even in an environmental niche in which the sugar is likely to be present. C1 NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, Natl Inst Hlth, Hamilton, MT USA. RP Tilly, K (reprint author), 903 S 4th St, Hamilton, MT 59840 USA. EM ktilly@nih.gov NR 34 TC 33 Z9 33 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1530-3667 J9 VECTOR-BORNE ZOONOT JI Vector-Borne Zoonotic Dis. PD SUM PY 2004 VL 4 IS 2 BP 159 EP 168 DI 10.1089/1530366041210738 PG 10 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 833NX UT WOS:000222345800009 PM 15228817 ER PT J AU Stroncek, D AF Stroncek, D TI Granulocyte antigens and antibody detection SO VOX SANGUINIS LA English DT Article ID SEQUENCE-SPECIFIC PRIMERS; POLYMERASE CHAIN-REACTION; NEONATAL NEUTROPENIA; GENE-FREQUENCIES; MOLECULAR-BASIS; 5B; SH C1 NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. RP Stroncek, D (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, 10 Ctr Dr,MSC 1184,Bldg 10,Room 1C711, Bethesda, MD 20892 USA. EM dstroncek@mail.cc.nih.gov NR 17 TC 10 Z9 11 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0042-9007 J9 VOX SANG JI Vox Sang. PD JUN PY 2004 VL 87 SU 1 BP 91 EP 94 DI 10.1111/j.1741-6892.2004.00439.x PG 4 WC Hematology SC Hematology GA 830OI UT WOS:000222131700021 PM 15200614 ER EF