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Biomedical subjects

J M Fisher

Publications and source records attributed to J M Fisher.

At least 19 recordsLinked to original sources
PubMed2005

DFT and in situ EXAFS investigation of gold/ceria-zirconia low-temperature water gas shift catalysts: identification of the nature of the active form of gold.

A combined experimental and theoretical investigation of the nature of the active form of gold in oxide-supported gold catalysts for the water gas shift reaction has been performed. In situ extended X-ray absorption fine structure (EXAFS) and X-ray absorption near-edge structure (XANES) experiments have shown that in the fresh catalysts the gold is in the form of highly dispersed gold ions. However, under water gas shift reaction conditions, even at temperatures as low as 100 degrees C, the evidence from EXAFS and XANES is only consistent with rapid, and essentially complete, reduction of the gold to form metallic clusters containing about 50 atoms. The presence of Au-Ce distances in the EXAFS spectra, and the fact that about 15% of the gold atoms can be reoxidized after exposure to air at 150 degrees C, is indicative of a close interaction between a fraction (ca. 15%) of the gold atoms and the oxide support. Density functional theory (DFT) calculations are entirely consistent with this model and suggest that an important aspect of the active and stable form of gold under water gas shift reaction conditions is the location of a partially oxidized gold (Audelta+) species at a cerium cation vacancy in the surface of the oxide support. It is found that even with a low loading gold catalysts (0.2%) the fraction of ionic gold under water gas shift conditions is below the limit of detection by XANES (<5%). It is concluded that under water gas shift reaction conditions the active form of gold comprises small metallic gold clusters in intimate contact with the oxide support.

Journal Article↗
PubMed2005

Attributable risk of alcohol and other drugs for crashes in the transit industry.

OBJECTIVE: To estimate the impact of employee alcohol and drug use on crashes in the transit industry from 1995-2000. DESIGN: Secondary analysis of federally mandated post crash and random alcohol and drug testing results. SETTING: The US transit industry. SUBJECTS: Transit industry employees. MAIN OUTCOME MEASURES: Relative risk (RR), population attributable risk (PAR), and population attributable risk percentage (PAR%). RESULTS: For alcohol testing, the estimated PAR% ranged from 0.02% (1999) to 0.03% (1995). For drug testing, the estimated PAR% ranged from 0.38% (1998) to 0.67% (1997). Based on these calculations, the estimated number of crashes per 1000 crashes attributable to alcohol was less than one during 1995-2000, and the number attributable to drugs ranged from about four to about six. The number of crashes attributable to either alcohol or drugs did not vary greatly from 1995-2000. Estimated rates of crashes attributable to alcohol or drugs were substantially lower in 1995, the first year of testing, than had been projected based on previous estimates, and did not show substantial change from 1995-2000. CONCLUSIONS: Approaches to transit safety based on reducing employee use of alcohol and other drugs have modest potential for reducing number of fatalities, injuries, and crashes.

Accidents, Traffic↗
PubMed2001

Induction of CYP3A4 by 1 alpha,25-dihydroxyvitamin D3 is human cell line-specific and is unlikely to involve pregnane X receptor.

Under certain culture conditions, exposure of the human colon adenocarcinoma cell line Caco-2 to 1,25-(OH)(2)-D(3) induces expression of CYP3A4 to levels comparable to that in human small intestinal epithelium. To determine whether 1,25-(OH)(2)-D(3) could be used to restore CYP3A expression in other culture models, we examined several cell lines derived from malignancies of human tissues known to express CYP3A enzymes: Hep G2 (liver), LS180 (colon), HPAC (pancreas), Hs746T (stomach). Primary cultures of human hepatocytes from two donors were also examined. 1,25-(OH)(2)-D(3) increased CYP3A catalytic activity in LS180 (15-fold), HPAC (6-fold), and hepatocytes (2- to 3-fold); this was accompanied by induction of CYP3A4 mRNA and CYP3A immunoreactive protein. However, 1,25-(OH)(2)-D(3) had no effect on CYP3A expression in Hs746T or Hep G2. Known ligands for pregnane X receptor (PXR) (rifampin, dexamethasone, and dexamethasone t-butyl acetate) markedly induced CYP3A4 expression in human hepatocytes. In contrast, these ligands had little or no effect on CYP3A4 expression in Caco-2 cells, even at concentrations 1 to 2 orders of magnitude greater than effective concentrations of 1,25-(OH)(2)-D(3) or two other vitamin D receptor (VDR) ligands (25-OH-D(3) and 1-OH-D(3)). The retinoic acid receptor ligand all-trans-retinoic acid augmented the 1,25-(OH)(2)-D(3)-mediated induction of CYP3A4 catalytic activity up to 2-fold in Caco-2 cells, while having no demonstrable effect on levels of CYP3A4 mRNA or protein. The retinoid X receptor ligand 9-cis-retinoic acid appeared to slightly reduce CYP3A4 catalytic activity. We conclude that 1,25-(OH)(2)-D(3) can be used to increase CYP3A4 expression in some, but not all, human cell lines derived from tissues known to express CYP3A enzymes. The mechanisms involved in this induction are unlikely to involve PXR and may involve VDR.

Caco-2 Cells↗
PubMed2001

Identification of Candida dubliniensis in a HIV-positive South African population.

Candida dubliniensis was identified as a distinctly separate species of the genus Candida in 1995. Since then the yeast has attracted considerable interest due to its prevalence in HIV/AIDS patients and its ability to develop fluconazole resistance in HIV-seropositive individuals. Although C. dubliniensis has been identified in many centres around the world it has not yet been isolated in Africa. The purpose of this study was to identify C. dubliniensis in an HIV-positive population in the Western Cape, South Africa. A cohort of 50 tuberculosis patients co-infected with HIV was selected on admission to the Brooklyn Chest Hospital, Western Cape. The inclusion criteria for patients accepted for the study were: confirmed HIV seroconversion with a diagnosis of tuberculosis obtained from chest X-rays and sputum microscopy. C. dubliniensis was identified in 6 of the 50 patients accepted onto the study. The prevalence of C. dubliniensis in our study population was lower than that reported in similar North American and European studies. These results confirm the presence of C. dubliniensis in the South African HIV/AIDS population and indicate the urgent need for further investigations into the prevalence and pathogenesis of this clinically important species in both adult and paediatric HIV-positive patients.

AIDS-Related Opportunistic Infections↗
PubMed2000

Occupational stress factors and alcohol-related behavior in urban transit operators.

BACKGROUND: If alcohol consumption mitigates psychological and physiological aspects of the response to stressors, then alcohol consumption might be elevated for individuals exposed to high occupational stressors. Frequency of work stressors and reaction to those stressors were studied in relation to several alcohol-related outcomes. METHODS: During the period 1993-1995, 1979 transit operators underwent medical examinations for commercial driver's license renewal. Questionnaire and interview data concerning occupational stress factors and alcohol-related outcomes were available for 1386 (70.2%) of the operators. RESULTS: A positive association was found between the two job stressor-related measures and each of six alcohol-related outcomes. Of these 12 associations, ten were statistically significant. Individuals experiencing high self-reported frequency of job stressors and a higher perceived severity of those job stressors were more likely to drink and more likely to be heavy drinkers. They reported more consequences of alcohol consumption, reported increased consumption since beginning work as transit drivers, and were more likely to report drinking to deal with work stress. They also drank more, but this effect was not significant for either job stress measure. There was virtually no association between either stressor-related measure and alcohol dependency (CAGE). CONCLUSIONS: Together with other published findings, these results suggest increased alcohol-related outcomes in the presence of work stressors. This conclusion has potential implications for worksite health promotion and job design. Because our findings are cross-sectional, further research is needed to clarify the causal nature of the work stressor-alcohol association. Further research also is needed to clarify the role of individual differences and context.

Adult↗
PubMed1999

Quantitative measurement of mast cell degranulation using a novel flow cytometric annexin-V binding assay.

BACKGROUND: Mast cells are primary mediators of allergic inflammation. Antigen-mediated crosslinking of their cell surface immunoglobulin E (IgE) receptors results in degranulation and the release of proinflammatory mediators including histamine, tumor necrosis factor-alpha, and leukotrienes. METHODS: Mast cells were stimulated to degranulate by using either IgE crosslinking or ionophore treatment. Exogenously added annexin-V was used to stain exocytosing granules, and the extent of binding was measured flow cytometrically. Release of the enzyme beta-hexosaminidase was used for population-based measurements of degranulation. Two known inhibitors of degranulation, the phosphatidylinositol 3 kinase inhibitor wortmannin and overexpression of a mutant rab3d protein, were used as controls to validate the annexin-V binding assay. RESULTS: Annexin-V specifically bound to mast cell granules exposed after stimulation in proportion to the extent of degranulation. Annexin-V binding was calcium dependent and was blocked by phosphatidylserine containing liposomes, consistent with specific binding to this membrane lipid. Visualization of annexin-V staining showed granular cell surface patches that colocalized with the exocytic granule marker VAMP-green fluorescent protein (GFP). Wortmannin inhibited both annexin-V binding and beta-hexosaminidase release in RBL-2H3 cells, as did the expression of a dominant negative rab3d mutant protein. CONCLUSIONS: The annexin-V binding assay represents a powerful new flow cytometric method to monitor mast cell degranulation for functional analysis.

Androstadienes↗
PubMed1999

First-pass midazolam metabolism catalyzed by 1alpha,25-dihydroxy vitamin D3-modified Caco-2 cell monolayers.

Cytochrome P-450 (CYP) 3A4 accounts for approximately 50% of all P-450s found in the small intestine (Paine et al., 1997) and contributes to the extensive and variable first-pass extraction of drugs such as cyclosporine and saquinavir. We recently demonstrated that CYP3A4 expression in a differentiated Caco-2 subclone is increased when cell monolayers are treated with 1alpha,25-dihydroxy-vitamin-D3 (Schmiedlin-Ren et al., 1997). This improved metabolic capacity permits the in vitro modeling of first-pass intestinal metabolic kinetics. Midazolam (MDZ) 1'-hydroxylation was used as a specific probe for CYP3A-mediated metabolism in modified Caco-2 monolayers. Caco-2 cells were grown to confluence on laminin-coated culture inserts, and then for two additional weeks in the presence of 1alpha,25-dihydroxy vitamin-D3. Cell monolayers were subsequently exposed to MDZ for varying lengths of time and concentrations. The amount of MDZ in the monolayer increased rapidly after apical drug administration, reaching a pseudo steady state within 6 min. The cellular uptake rate was considerably slower after a basolateral dose. By either route of administration, the rate of 1'-hydroxymidazolam formation was stable and linear for 2 h. Under basolateral sink conditions and low apical MDZ dosing concentration (1-8 microM), the first-pass extraction ratio was found to be approximately 15%. Higher dosing concentrations led to saturation of the hydroxylation reaction and reduction in the extraction ratio. The modified Caco-2 cell monolayer is an excellent model for studying drug absorption and first-pass intestinal metabolic kinetic processes. In this system, the selective CYP3A probe MDZ was rapidly absorbed, yet extensively metabolized, as is observed in vivo.

Biotransformation↗
PubMed1999

Midazolam metabolism by modified Caco-2 monolayers: effects of extracellular protein binding.

It has been suggested that the binding of a drug to plasma proteins will influence the intestinal extraction efficiency when drug is delivered to the mucosal epithelium via either the gut lumen or vasculature. We evaluated this hypothesis using cytochrome P-450 (CYP)3A4-expressing Caco-2 monolayers as a model for the intestinal epithelial barrier and midazolam as a CYP3A-specific enzyme probe. The rate of 1'-hydroxylation was measured following apical or basolateral midazolam administration to monolayers incubated in the presence or absence of 4 g/dl of human serum albumin (HSA) in the basolateral compartment medium. The midazolam-free fraction in culture medium containing HSA was 3.3%. Inclusion of HSA in the basolateral medium decreased peak intracellular midazolam accumulation after an apical midazolam dose (3 microM) by 35% and reduced the 1'-hydroxymidazolam formation rate by approximately 20%. Because of the accelerated diffusion of midazolam through the cell monolayer and into the basolateral compartment, there was a 61% reduction in the first-pass metabolic extraction ratio: 13.3 +/- 0. 12% for control versus 5.2 +/- 1% with HSA. Compared with control, addition of HSA resulted in a 91% decrease in the peak intracellular midazolam level and a 86% decrease in the rate of 1'-hydroxylation after the administration of midazolam into basolateral medium. These findings suggest that, in vivo, binding of a drug to plasma proteins will impact both first-pass and systemic intestinal midazolam extraction efficiency. Furthermore, the effect will be more pronounced for a drug that is delivered to mucosal enterocytes by way of arterial blood, compared with oral drug delivery.

Algorithms↗
PubMed1999

Workplace discrimination and alcohol consumption: findings from the San Francisco Muni Health and Safety Study.

OBJECTIVE: There is evidence of an association between occupational stress and alcohol consumption. This study investigates the association between workplace racial discrimination and alcohol consumption in a sample of urban transit operators. METHODS: During 1993-1995, after undergoing a medical exam, 1,542 transit operators completed an interview. Depending on the outcome, we used logistic or linear regression models to examine the cross-sectional relationship between discrimination experience and alcohol consumption. RESULTS: Operators who reported discrimination in at least one situation, out of a possible four, were more likely to have had negative life consequences as a result of drinking (adjusted OR = 1.97; 95% CI, 1.20-3.83) and were more likely to be classified as having an alcohol disorder (OR = 1.56 [0.96-2.54]), compared to those who reported no instances of workplace discrimination. Results adjusted simultaneously for age, sex, race/ethnicity, education, income, marital status, and seniority. There was no association between workplace discrimination and heavy drinking or drinks per month. CONCLUSIONS: Cross-sectional data from a sample of urban transit operators indicates an association between workplace racial discrimination and some measures of alcohol consumption.

Adult↗
PubMed1998

Psychosocial job factors, physical workload, and incidence of work-related spinal injury: a 5-year prospective study of urban transit operators.

STUDY DESIGN: Five-year prospective cohort study of 1449 transit operators. OBJECTIVES: To investigate psychosocial job factors as predictors of work-related spinal injuries, controlling for current and past physical workload. SUMMARY OF BACKGROUND DATA: The association between psychosocial job factors and spinal disorders may be confounded by physical workload. A 1991 prospective study of Boeing workers found psychosocial but not physical factors to be associated with spinal injuries. However, data on physical workload were limited. Recent cross-sectional studies of transit drivers showed both physical and psychosocial factors to be independently associated with back and neck pain. This study was designed to test these findings prospectively. METHODS: Spinal injuries were ascertained from workers' compensation records, employment history from company records, and psychosocial factors from questionnaires. Logistic regression models adjusted for age, gender, height, weight, vehicle type, and current and past physical workload. RESULTS: During follow-up, 320 drivers reported a first spinal injury. Spinal injury was predicted by psychological job demands (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.33-1.95); job dissatisfaction (OR, 1.56; 95% CI, 1.09-2.23); and the frequency of job problems (OR, 1.52; 95% CI, 1.02-2.26). Marginally significant associations were found for low supervisor support (OR, 1.30; 95% CI, 0.99-1.72) and female gender (OR, 1.49; 95% CI, 0.95-2.32). Compared with full-time work, part-time work was associated with a 2.7-fold reduced risk for spinal injury (OR, 0.37; 95% CI, 0.15-0.93). Cable car crews performing the heaviest physical labor had a threefold increased risk of spinal injury compared with bus drivers (OR, 3.04; 95% CI, 1.85-5.00). CONCLUSIONS: Physical workload and psychosocial job factors both independently predict spinal injury in transit vehicle operators.

Accidents, Occupational↗
PubMed1998

Objective stress factors, accidents, and absenteeism in transit operators: a theoretical framework and empirical evidence.

The authors used observational job analysis as a conceptually based technique to measure stress factors unbiased by worker appraisal with 81 transit driving tasks on 27 transit lines. Stressor dimensions included work barriers that interfere with task performance due to poor technical-organizational design, time pressure, time binding (autonomy over time management), and monotonous conditions. Line-specific average stressor values were assigned to 308 transit operators who mainly worked the particular line. Logistic regression analyses showed associations for high work barriers and sickness absences (odds ratio [OR] = 3.8, p = .05). There were elevated risks for work accidents for high time pressure operators (OR = 4.0, p = .04) and for the medium time-binding group (OR = 3.3, p = .04) and significant (alpha = .20) unadjusted interaction terms for barriers and time pressure in predicting accidents and absences, and barriers and time binding in predicting absences. Findings suggest guaranteed rest breaks and flexible timing for accident prevention and removal of work barriers for reducing absenteeism.

Absenteeism↗
PubMed1998

Studies of health outcomes in transit operators: policy implications of the current scientific database.

Urban transit operators' medical symptoms and conditions exceed other occupational groups, resulting partly from working conditions. Medical outcomes among operators have an impact on the transit system, including on performance, work attendance, and medical costs. This is exacerbated by external economic and political pressures in which expected service often exceeds the system's capacity in a congested, chaotic urban environment. A vicious cycle of poor working environment, reduced health and well-being among operators, and lowered efficiency and increased costs often results. Operator-health policies focusing solely on individuals are not sufficient to address these problems. A broader approach is needed, acknowledging the relationship between health of the system and health of employees, including redesigning the interface between transit systems and the urban environment and organizational change within companies. This comprehensive approach recognizes the dynamic reciprocity among the transit operators, the transit system, and the larger community.

Adult↗
PubMed1997

Physical workload and ergonomic factors associated with prevalence of back and neck pain in urban transit operators.

STUDY DESIGN: Back and neck pain was studied cross-sectionally in 1,449 urban transit drivers by linking medical data, self-reported ergonomic factors, and company records on job history. OBJECTIVES: The goal was to examine the relation between physical workload, ergonomic factors, and the prevalence of back and neck pain. SUMMARY OF BACKGROUND DATA: Researchers, to date, have not found an independent effect of ergonomic factors on back and neck pain while accounting for the effects of past and current physical workload. METHODS: Self-reported ergonomic factors, vehicle type, physical workload (measured as duration of driving), height, weight, age, and gender were analyzed in relation to back and neck pain, using multivariable logistic regression models. RESULTS: Physical workload showed a positive dose-response relation with back and neck pain after controlling for vehicle type, height, weight, age, and gender. The odds ratio for 10 years of driving was 3.43. Additional adjustment for ergonomic factors decreased this odds ratio to 2.55. Six out of seven ergonomic factors were significantly related to the prevalence of back and neck pain after adjustment for age, gender, height, weight, and physical workload. Problems with adjusting the seat had the largest effect (odds ratio = 3.52). Women had back and neck pain twice as frequently as men. CONCLUSION: The results support the hypothesis of a causal role of physical workload for the development of back and neck pain. Ergonomic factors partially mediated the risk of back and neck pain associated with driving, suggesting a potential for prevention of back and neck pain by ergonomic redesign of transit vehicles. Elevated risks for back and neck pain for female drivers were not explained by anthropometric and ergonomic factors.

Adult↗
PubMed1997

Objective measurement of occupational stress factors--an example with San Francisco urban transit operators.

Eighty-one observational work analyses were conducted to measure stressors independently of worker appraisal in the San Francisco transit system. On the basis of action regulation theory, stress factors were defined as hindrances for task performance due to poor work organization or technological design. Stressors included (a) work barriers, defined as obstacles that cause extra work or unsafe behavior; (b) time pressure; (c) monotonous conditions; and (d) time binding, defined as control over timing. Reliability, measured as interrater agreement, ranged between 80 and 97%, with kappas of .46-.70. Validity analyses were done with 71 transit operators who participated in the observations and 177 operators who were assigned mean line-specific observational stressor measures. High odds ratios (ORs) were found for barriers and psychosomatic complaints (OR = 3.8, p = .00), time pressure and relaxation time needed after work (OR = 3.1, p = .05), and barriers and smoking to cope (OR = 3.8, p = .02). Using observational data in conjunction with self-report data can reduce confounding and improve interpretability of stress and health studies.

Adult↗
PubMed1997

Expression of enzymatically active CYP3A4 by Caco-2 cells grown on extracellular matrix-coated permeable supports in the presence of 1alpha,25-dihydroxyvitamin D3.

The human colon carcinoma cell line, Caco-2, is widely used as a model for oral absorption of xenobiotics. The usefulness of Caco-2 cells has been limited, however, because they do not express appreciable quantities of CYP3A4, the principle cytochrome P450 present in human small bowel epithelial cells. We report that treatment of Caco-2 cells with 1 alpha,25-dihydroxyvitamin D3, beginning at confluence, results in a dose- and duration-dependent increase in CYP3A4 mRNA and protein, with little apparent effect on the expression of CYP3A5 or CYP3A7. This treatment also results in increases in NADPH cytochrome P450 reductase and P-glycoprotein (the MDR1 gene product) but has no detectable effect on expression of CYP1A1, CYP2D6, cytochrome b5, liver or intestinal fatty acid binding proteins, or villin. Maximal expression of CYP3A4 requires an extracellular matrix on a permeable support and the presence of serum. In the treated cells, the intrinsic formation clearance of 1'-hydroxymidazolam (a reaction characteristically catalyzed by CYP3A enzymes) was estimated to be somewhat lower than that of human jejunal mucosa (1.14 and 3.67 ml/min/g of cells, respectively). The 1'-OH-midazolam/4-OH-midazolam product ratio produced by the cells (approximately 5.3) is comparable to, but somewhat lower than, that observed in human jejunal microsomes (7.4-15.4), which may reflect the presence of CYP3A7 in the Caco-2 cells. 25-Hydroxyvitamin D3 is less efficacious but reproduces the effects of the dihydroxy compound, whereas unhydroxylated vitamin D is without appreciable effect. These observations, together with the time course of response, suggest that the vitamin D receptor may be involved in CYP3A4 regulation. The culture model we describe should prove useful in defining the role of CYP3A4 in limiting the oral bioavailability of many xenobiotics.

Caco-2 Cells↗
PubMed1997

Hypertension and years of driving in transit vehicle operators.

In this study, data from transit vehicle operators of the San Francisco Municipal Railway (Muni), and a control group of individuals newly hired but not yet working as operators, were used to investigate prevalence of hypertension as a function of exposure to bus driving (years of driving), controlling for alcohol consumption and body mass index. Data were collected from transit vehicle operators in the course of their regular biennial examination during the period November 1983 to October 1985. Groups working as operators fewer than 10 years (n = 1137), from 10 to 20 years (n = 493), and more than 20 years (n = 196) were compared to each other and to a group of individuals with no prior exposure, but who were given a medical examination just before beginning their jobs as transit vehicle operators (n = 226). For hypertension (defined as systolic blood pressure > or = 140, or diastolic blood pressure > or = 90, or taking hypertension medication), the prevalence, adjusted for age, race, and gender, increased in a stepwise fashion from 28.8 percent in the group with no exposure to 38.9 percent in the group of drivers with more than 20 years on the job. A similar pattern was found for moderate to severe hypertension (systolic blood pressure > or = 160, or diastolic blood pressure > or = 95, or hypertension medication). These patterns were diminished, but not eliminated, when body mass index and alcohol consumption were considered. Higher rates of separation from employment for hypertensive operators suggested that the effect of years of employment may be underestimated by this cross-sectional comparison. Prolonged exposure to operating a transit vehicle may be associated with increased hypertension; increased alcohol consumption and body mass index with increased years of driving may account for at least some of the increased hypertension.

Adult↗