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Biomedical subjects

J Wright

Publications and source records attributed to J Wright.

At least 181 records · Page 10Linked to original sources
PubMed1999

Patient Outcomes Research Teams: contribution to outcomes and effectiveness research.

This paper describes the key methodological and substantive findings of Patient Outcomes Research Teams, the first outcomes and effectiveness research centers funded by the Agency for Health Care Policy and Research. Patient Outcomes Research Teams contributed to our increased understanding of how to perform meta analysis on nontrial data, use administrative data to characterize patterns of care, develop general and disease-specific outcome measures, and disseminate important outcome information to patients and physicians to reduce practice variation. Patient Outcomes Research Teams also influenced the development of outcomes measurement in the private sector.

Health Services Research↗
PubMed1999

Role of neutrophils and alpha1-antitrypsin in coal- and silica-induced connective tissue breakdown.

Mineral dusts produce emphysema, and administration of dust to rats results in the rapid appearance of desmosine and hydroxyproline in lavage fluid, confirming that dusts directly induce connective tissue breakdown. To examine the role of neutrophils and alpha1-antitrypsin (alpha1-AT) in this process, we instilled silica or coal into normal rats or rats that had been pretreated with antiserum against neutrophils. One day after dust exposure, lavage fluid neutrophils and desmosine and hydroxyproline levels were all elevated; treatment with antiserum against neutrophils reduced neutrophils by 75%, desmosine by 40-50%, and hydroxyproline by 25%. By 7 days, lavage fluid neutrophils and desmosine level had decreased, whereas macrophages and hydroxyproline level had increased. By ELISA analysis, lavage fluid alpha1-AT levels were increased four- to eightfold at both times. On Western blot, some of the alpha1-AT appeared as degraded fragments, and by HPLC analysis, 5-10% of the methionine residues were oxidized. At both times, lavage fluid exhibited considerably elevated serine elastase inhibitory capacity and also showed elevations in metalloelastase activity. We conclude that, in this model, connective tissue breakdown is initially driven largely by neutrophil-derived proteases and that markedly elevated levels of functional alpha1-AT do not prevent breakdown, thus providing in vivo support for the concept of quantum proteolysis proposed by Liou and Campbell (T. G. Liou and E. J. Campbell. Biochemistry 34: 16171-16177, 1995). Macrophage-derived proteases may be of increasing importance over time, especially in coal-treated animals.

Animals↗
PubMed1999

Diurnal variations in peripheral insulin resistance and plasma non-esterified fatty acid concentrations: a possible link?

Glucose tolerance becomes impaired towards the evening. Increased peripheral insulin resistance may be responsible, at least in part, for this effect. The mechanism for the diurnal variation in insulin sensitivity is undefined. It is, however, possible that variations in non-esterified fatty acids (NEFA) could contribute to this variation because NEFA have been implicated in the pathogenesis of insulin resistance. Therefore, we have investigated insulin sensitivity and plasma NEFA responses to insulin at 0830 h and 2030 h in nine healthy men by measuring arterialized plasma glucose and venous plasma NEFA concentrations during a short insulin tolerance test. The studies were standardized for a period of fasting, pre-test meal and exercise. Insulin sensitivity measured KITT was greater (P < 0.05) in the morning [(20 +/- 7) x 10(-3) mmol/L/min] than in the evening [(11.6 +/- 2) x 10(-3) mmol/L/min]. Fasting NEFA levels were lower (P < 0.01) in the morning (373 +/- 84 mumol/L) than in the evening (913 +/- 122 mumol/L). Following insulin, NEFA fell more slowly (P < 0.01) in the morning (149 +/- 26 mumol/L/15 min) than in the evening (491 +/- 91 mumol/L/15 min). These results confirm diurnal variations in insulin sensitivity and plasma NEFA concentrations irrespective of feeding and exercise. We speculate that the relatively elevated plasma NEFA levels in the evening are the cause rather than the consequence of increased insulin resistance at this time.

Adult↗
PubMed1999

Evidence-based guidelines for early stroke management.

Stroke disease is the commonest neurological emergency encountered by the junior medical team. We have reviewed the literature to produce a series of substantiated guidelines to assist the admitting doctor in managing early stroke care optimally.

Aged↗
PubMed1999

Carboplatin and paclitaxel, alone and in combination: dose escalation, measurement of renal function, and role of the p53 tumor suppressor gene.

In this pharmacokinetic and dose-escalation study of the carboplatin/paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) combination, patients were randomly assigned to receive paclitaxel either as a 1-hour or a 3-hour infusion. The 1-hour infusion was feasible, with maximum tolerated doses similar to those previously reported for a 3-hour infusion. Using patients' age, height, plasma creatinine, and plasma creatine kinase provided an improved estimate of the glomerular filtration rate compared with the more traditional creatinine-based formulas according to population analysis of data derived from glomerular filtration rate estimates performed by an isotope method. Studies of the p53 gene sequence of ovarian tumors at diagnosis suggest that p53 mutations are a potent predictor of response to subsequent treatment with carboplatin.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Lack of influence of test meal fatty acid composition on the contribution of intestinally-derived lipoproteins to postprandial lipaemia.

The extent and duration of postprandial lipaemia have been linked to risk of CHD but the influence of dietary variables on, and the relative contributions of, exogenous (chylomicron) and endogenous (VLDL) triacylglycerols to the total lipaemic response have not been comprehensively evaluated. In the present study the triacylglycerol, apolipoprotein (apo) B-48 and retinyl ester (RE) responses to three test meals of varying monounsaturated (MUFA) and saturated fatty acid (SFA) content were measured in the triacylglycerol-rich lipoprotein (TRL) fraction of plasma (rho = 1.006 g/ml) for 9 h after meal consumption. Fifteen healthy normolipidaemic young men consumed, on separate occasions, three test meals which were identical apart from their MUFA and SFA contents. Expressed as a percentage of total energy the MUFA/SFA contents of the meals were: (1) 12%/17%; (2) 17%/12% and (3) 24%/5%. The contribution of the intestinally-derived lipoproteins (chylomicrons) to the lipaemic response was investigated by determining the time to reach peak concentration and the total and incremental areas under the time response curves (AUC and incremental AUC) for RE, apoB-48 and triacylglycerol in the TRL fraction. No significant differences in these measurements were observed for the three meals. However, visual comparison of the postprandial responses to the three meals suggested that as meal MUFA content increased there was a tendency for the triacylglycerol, apoB-48 and RE responses to become biphasic as opposed to the typical monophasic response seen with the 12% MUFA/17% SFA meal. Comparison of the apoB-48 and RE responses for the three test meals confirmed other workers' findings of delayed entry of RE relative to apoB-48 in TRL. The value of the two markers in investigating dietary fat absorption and metabolism is discussed.

Adult↗
PubMed1999

Stereoselective metabolism of ifosfamide by human P-450s 3A4 and 2B6. Favorable metabolic properties of R-enantiomer.

The anticancer prodrug ifosfamide (IFA) contains a chiral phosphorous atom and is administered clinically as a racemic mixture of R and S enantiomers. Animal model studies and clinical data indicate enantioselective differences in cytochrome P-450 (CYP) metabolism, pharmacokinetics, and therapeutic efficacy between the two enantiomers; however, the metabolism of individual IFA enantiomers has not been fully characterized. The role of CYP enzymes in the stereoselective metabolism of R-IFA and S-IFA was investigated by monitoring the formation of both 4-hydroxy (activated) and N-dechloroethyl (DCl) (inactive, neurotoxic) metabolites. In the 4-hydroxylation reaction, cDNA-expressed CYPs 3A4 and 3A5 preferentially metabolized R-IFA, whereas CYP2B6 was more active toward S-IFA. Enantioselective IFA 4-hydroxylation (R > S) was observed with six of eight human liver samples. In the N-dechloroethylation reaction, CYPs 3A4 and 2B6 both catalyzed a significantly higher intrinsic metabolic clearance (V(max)/K(m)) of S-IFA compared with R-IFA. Striking P-450 form specificity in the formation of individual DCl metabolites was evident. CYPs 3A4 and 3A5 preferentially produced (R)N2-DCl-IFA and (R)N3-DCl-IFA (derived from R-IFA and S-IFA, respectively), whereas CYP2B6 correspondingly formed (S)N3-DCl-IFA and (S)N2-DCl-IFA. In human liver microsomes, the CYP3A-specific inhibitor troleandomycin suppressed (R)N2- and (R)N3-DCl-IFA formation by >/=80%, whereas (S)N2- and (S)N3-DCl-IFA formation were selectively inhibited (>/=85%) by a CYP2B6-specific monoclonal antibody. The overall extent of IFA N-dechloroethylation varied with the CYP3A4 and CYP2B6 content of each liver, but was significantly lower for R-IFA (32 +/- 13%) than for S-IFA (62 +/- 17%, n = 8; p <.001) in all livers examined. R-IFA thus has more favorable liver metabolic properties than S-IFA with respect to less extensive N-dechloroethylation and more rapid 4-hydroxylation, indicating that R-IFA may have a distinct clinical advantage over racemic IFA.

Antineoplastic Agents, Alkylating↗
PubMed1999

Cholesterol reduction using manufactured foods high in monounsaturated fatty acids: a randomized crossover study.

In two separate studies, the cholesterol-lowering efficacy of a diet high in monounsaturated fatty acids (MUFA) was evaluated by means of a randomized crossover trial. In both studies subjects were randomized to receive either a high-MUFA diet or the control diet first, which they followed for a period of 8 weeks; following a washout period of 4-6 weeks they were transferred onto the opposing diet for a further period of 8 weeks. In one study subjects were healthy middle-aged men (n 30), and in the other they were young men (n 23) with a family history of CHD recruited from two centres (Guildford and Dublin). The two studies were conducted over the same time period using identical foods and study designs. Subjects consumed 38% energy as fat, with 18% energy as MUFA and 10% as saturated fatty acids (MUFA diet), or 13% energy as MUFA and 16% as saturated fatty acids (control diet). The polyunsaturated fatty acid content of each diet was 7%. The diets were achieved by providing subjects with manufactured foods such as spreads, 'ready meals', biscuits, puddings and breads, which, apart from their fatty acid compositions, were identical for both diets. Subjects were blind to which of the diets they were following on both arms of the study. Weight changes on the diets were less than 1 kg. In the groups combined (n 53) mean total and LDL-cholesterol levels were significantly lower at the end of the MUFA diet than the control diet by 0.29 (SD 0.61) mmol/l (P < 0.001) and 0.38 (SD 0.64) mmol/l (P < 0.0001) respectively. In middle-aged men these differences were due to a mean reduction in LDL-cholesterol of -11 (SD 12)% on the MUFA diet with no change on the control diet (-1.1 (SD 10)%). In young men the differences were due to an increase in LDL-cholesterol concentration on the control diet of +6.2 (SD 13)% and a decrease on the MUFA diet of -7.8 (SD 20)%. Differences in the responses of middle-aged and young men to the two diets did not appear to be due to differences in their habitual baseline diets which were generally similar, but appeared to reflect the lower baseline cholesterol concentrations in the younger men. There was a moderately strong and statistically significant inverse correlation between the change in LDL-cholesterol concentration on each diet and the baseline fasting LDL-cholesterol concentration (r -0.49; P < 0.0005). In conclusion, diets in which saturated fat is partially replaced by MUFA can achieve significant reductions in total and LDL-cholesterol concentrations, even when total fat and energy intakes are maintained. The dietary approach used to alter fatty acid intakes would be appropriate for achieving reductions in saturated fat intakes in whole populations.

Adult↗
PubMed1998

Perils of opera

Explore the source record for details and available documents.

Journal Article↗
PubMed1998

Washing and trypsin treatment of in vitro derived bovine embryos exposed to bovine viral diarrhea virus.

Gametes, somatic cells and materials of animal origin in media are potential sources for introducing bovine viral diarrhea virus (BVDV) into systems for production of IVF bovine embryos. Further, the efficacy of washing and trypsin treatment for removal of BVDV from IVF embryos is questionable. Washing and trypsin treatments recommended by the International Embryo Transfer Society for in vivo-derived embryos were applied to in vitro-derived, virus-exposed, bovine embryos in this side-by-side comparison of treatments. Embryos for the study were produced in a virus-free system in which follicular oocytes were matured and fertilized in vitro and presumptive zygotes were co-cultured with bovine uterine tubal cells for 7 d. A total of 18 trials was performed, 9 using a noncytopathic BVDV and 9 using a cytopathic BVDV. In each trial, 4 equal groups of 10 or less, zona pellucida-intact embryos/ova were assembled, including 2 groups of morulae and blastocysts (M/B) and 2 groups of nonfertile or degenerated ova (NFD). Each group was prewashed and exposed to 10(4) to 10(6) TCID50/mL of either noncytopathic (SD-1) or cytopathic (NADL) BVDV for 2 h. Following in vitro viral exposure, one group of M/B and one group of NFD were washed. The other groups of M/B and NFD were trypsin-treated. Both treatments were consistent with IETS guidelines. After in vitro exposure to noncytopathic BVDV and washing, viral assays of 100% (9/9) and 78% (7/9) of the groups of M/B and NFD ova, respectively, were positive. After in vitro exposure to cytopathic BVDV and washing, viral assay of 33% (3/9) of the groups of both M/B and NFD ova were positive. After in vitro exposure to noncytopathic BVDV and trypsin treatment, viral assay of 44% (4/9) of groups of M/B and 67% (6/9) of groups of NFD ova were positive. Finally, after in vitro exposure to cytopathic BVDV and trypsin treatment, viral assay of 22% (2/9) of the groups of M/B and 44% (4/9) of the groups of NFD ova were positive. Contingency table analysis, in which data was stratified by embryo type and virus biotype, was used to compare results. While a difference existed between results of the 2 treatments of groups of M/B within the noncytopathic biotype (P = 0.01, Mantel Haenszel Chi-square), no difference was observed between comparison of treatment between all groups in both biotypes (P > 0.05).

Animals↗
PubMed1998

Clinical applications of the camptothecins.

The camptothecin topoisomerase I-targeting agents are new class of antitumor drugs with demonstrated clinical activity in human malignancies, such as colorectal cancer and ovarian cancer. Currently, irinotecan and topotecan are the most widely used camptothecin analogs in clinical use and clinical trials are ongoing to better characterize their spectra of clinical activity, to determine their optimal schedules of administration and to define their use in combination with other chemotherapeutic agents. Newer camptothecin analogs in clinical development, such as 9-aminocamptothecin, 9-nitrocamptothecin, GI147211 and DX-8951f, are also being studied to determine if they have improved toxicity and efficacy profiles compared with existing analogs. Other potential clinical applications include the use of camptothecin derivatives as radiation sensitizers or as antiviral agents. The successful development of the camptothecins as antitumor agents highlights the importance of topoisomerase I as a target for cancer chemotherapy.

Antineoplastic Agents↗