Publications
Department of Medicine faculty members published more than 3,000 peer-reviewed articles in 2022.
Steatosis in chronic hepatitis C: relative contributions of obesity, diabetes mellitus, and alcohol.
2002
Steatosis has emerged as a histologic finding of importance to the progression of hepatitis C virus (HCV)-associated liver disease. However, most studies of HCV-associated steatosis have excluded alcohol drinkers and individuals with diabetes and thus have not addressed the relative contribution of known causes of steatosis to liver injury in HCV-associated disease. To address this issue, we studied 297 consecutive patients with HCV who met inclusion criteria. Alcohol consumption, demographics, and serologic tests were correlated with degrees of steatosis and fibrosis on liver biopsy. Liver biopsy specimens were also examined for evidence of significant alcohol or nonalcoholic steatohepatitis (NASH) injury. In univariate analysis, steatosis correlated with type 2 diabetes mellitus (P =.005) and body mass index (BMI) (P =.0001) but not with the intensity of alcohol intake (in grams per day). In multivariate analysis, BMI (P =.0002) and genotype 3a infection (P =.02) were independent predictors of steatosis. When patients with risk factors for NASH were excluded, genotype 3a infection was the only independent predictor of steatosis. Steatosis (P =.04) and inflammation (P <.0001) scores on liver biopsy were the only independent predictors of fibrosis. Significant alcohol or NASH injury was found in only 6% of biopsy specimens. In conclusion, steatosis in HCV infection is associated with risk factors for NASH, particularly obesity, rather than alcohol consumption.
View on PubMed2002
2002
The immunoregulatory cytokine transforming growth factor (TGF)-beta(1) is secreted as a biologically inactive complex with latency-associated peptide, which must be modified by local factors to expose the functionally active cytokine. The epithelial integrin alpha(v)beta(6) mediates local activation of TGF-beta(1) in the lung and beta(6)(-/-) mice exhibit exaggerated pulmonary inflammation, but their response to inflammatory stimuli in the gut has not been investigated. We found that both beta(6) and TGF-beta(1) are constitutively expressed in the jejunal epithelial compartment in uninfected mice and during infection with the intestinal nematode Nippostrongylus brasiliensis. We also present data showing that beta(6)(-/-) mice are seriously compromised in their ability to mount a mucosal mast cell response after infection, and there is a significant reduction in the expression and systemic release of the granule chymase, mouse mast cell protease-1. Because in vitro expression of this chymase is regulated by TGF-beta(1), these data indicate that in the absence of alpha(v)beta(6) epithelially expressed TGF-beta(1) may not be activated, with a consequent absence of expression of mouse mast cell protease-1 and down-regulation of the mucosal mast cell response.
View on PubMed2002
Mast cell chymases and tryptases exhibit an intriguing but potentially confusing variety of forms and functions. Thanks to recent genetic and biochemical advances, a clearer picture of phylogenetic and functional relationships in this large group of mammalian enzymes is emerging. Furthermore, there is increasing appreciation of the diversity of these enzymes among human populations. In humans, there appears to be just one mast cell chymase but multiple expressed tryptases, some of which are allelic variants and others of which are products of separate gene loci. New biological tools, including the dipeptidyl peptidase I (DPPI)-null mouse in which the entire class of mast cell chymases appears to be functionally knocked out, are helping to clarify the importance and specific roles of these most abundant of secreted mast cell proteins.
View on PubMed2002
OBJECTIVES
This study examined the impact of asthma and chronic obstructive pulmonary disease (COPD) on health status and work disability.
METHODS
We used data from a population-based sample of 3805 California adults.
RESULTS
Compared with adults with no chronic health conditions, adults with COPD or asthma had a greater risk of self-reported diminished general health (odds ratio [OR] = 10.95; 95% confidence interval [CI] = 6.31, 19.0 and OR = 3.92; 95% CI = 2.31, 6.65, respectively). Respondents with COPD or asthma also had worse mental health status, as indicated by a greater risk of depressive symptoms (OR = 10.05; 95% CI = 5.29, 19.08 and OR = 2.59; 95% CI = 1.33, 5.04). COPD was associated with reduced current employment (OR = 0.41; 95% CI = 0.24, 0.71).
CONCLUSIONS
Asthma and COPD are associated with poor health status and greater work disability.
View on PubMed2002
BACKGROUND
Perceived control of certain chronic conditions influences health status outcomes.
OBJECTIVE
To explore the impact of perceived control of asthma on asthma-specific and generic health status outcomes among adults with asthma. Perceived control was defined as individuals' perceptions of their ability to deal with asthma and its exacerbations.
METHODS
Data were drawn from the baseline and first two followups of a longitudinal study of adults with asthma surveyed by telephone at 18-month intervals. An 11-item questionnaire (Perceived Control of Asthma Questionnaire [PCAQ]) was developed and validated.
RESULTS
The PCAQ demonstrated high internal consistency (Cronbach's alpha = 0.79). Greater perceived control was associated with less severe asthma, greater asthma self-efficacy, lower perceived asthma severity, lower perceived danger from asthma, and greater perceived usefulness of asthma medicines. Greater perceived control was significantly associated with better asthma-specific quality of life concurrently and 18 and 36 months later, after controlling for demographics, smoking, and severity of asthma. Greater perceived control as also significantly associated with generic mental health outcomes concurrently and 18 and 36 months later, after controlling for covariates. Perceived control was associated with physical function concurrently and 18 months later, but not 36 months later.
CONCLUSIONS
The PCAQ is a reliable and valid measure of perceived control of asthma. Perceived control of asthma was associated with both asthma-specific and generic health status outcomes, concurrently and predictively. If perceived control could be modified, better outcomes, particularly better psychologic outcomes, might be achieved for individuals with asthma.
View on PubMed2002
OBJECTIVES
In California, state law now prohibits smoking in most public places. We examined the prevalence and short-term health impact of environmental tobacco smoke (ETS) exposure during travel among adults with asthma.
DESIGN, SETTING, AND PARTICIPANTS
A cohort of 374 nonsmoking adults with asthma recruited from a random sample of allergy, pulmonary, and family practice physicians in northern California underwent structured telephone interviews.
MEASUREMENTS AND RESULTS
The prevalence of self-reported ETS exposure during travel in the past 12 months was substantial (30%; 95% confidence interval, 25 to 35%). Of the exposed subjects, approximately one third (34%) indicated no other regular source of ETS exposure. ETS-related cough, wheezing, or chest tightness during travel was the most common complaint (66%), followed by eye irritation (46%) and nose irritation (43%). After ETS exposure, many subjects indicated extra inhaled asthma medication use (55%). Subjects with no other regular ETS exposure reported a greater likelihood of eye irritation (58% vs 40%; p = 0.068) and nose irritation (58% vs 36%; p = 0.025) than persons with regular exposure. In contrast, there were no differences in respiratory symptoms, asthma medication use, or asthma exacerbation by regular ETS exposure status.
CONCLUSIONS
In adults with asthma, ETS exposure is common during travel. For many subjects, travel is their principal source of exposure.
View on PubMed2002
OBJECTIVE
To understand the mechanism underlying the nasal congestive response to irritant challenge.
METHODS
We exposed 22 subjects--8 with seasonal allergic rhinitis (SAR), 6 with perennial allergic rhinitis (PAR), and 8 normals--to chlorine (Cl2) gas (1.0 ppm x 15 min.) by nasal CPAP mask. Control exposures (filtered air) were carried out on separate days, with counter-balancing of exposure order. Nasal airway resistance (NAR) was measured in triplicate before and after the provocation sequence using active posterior rhinomanometry. For each subject, this experiment was repeated twice, after [double-blinded] pre-treatment with: 1) ipratropium bromide (IB) 0.6% nasal spray, and 2) vehicle.
RESULTS
As a group, allergic rhinitics (SAR + PAR) showed greater [Cl2] exposure-related increases in NAR than did normals on placebo (vehicle) pretreatment days (p < 0.05). IB pre-treatment, however, did not have a systematic effect on Cl2-induced congestion.
CONCLUSION
Cholinergic mechanisms do not appear to be responsible for the nasal congestive response to irritant provocation.
View on PubMed2002
The principal enzyme involved in the oxidation of mifepristone is cytochrome P450 3A4 (CYP3A4), which undergoes mechanism-based inactivation by the drug. However, no information is available on the interaction with CYP3A5, the second most abundant CYP3A enzyme in adult human liver. Oxidation of mifepristone by recombinant CYP3A4 produced mono- and didemethylated products and one C-hydroxylated metabolite, as reported previously. However, CYP3A5 produced only the demethylated metabolites. The apparent V(max) and K(M) values for formation of the monodemethylated product by CYP3A4 and CYP3A5 were 46 and 30 nmol/min/nmol P450, and 36 and 16 microM, respectively. Unlike CYP3A4, CYP3A5 was not inactivated by mifepristone. The basis of this differential susceptibility was explored using site-directed mutants in which a CYP3A4 residue was converted to its 3A5 counterpart. Surprisingly, none of these replacements caused a significant decrease in CYP3A4 inactivation by mifepristone. Examination of selected CYP3A4 mutants at 20 other positions indicated that the relative formation rate of the C-hydroxylated product could not account for the differential susceptibility of CYP3A4 and 3A5. Together these results indicate that mifepristone fails to orient itself in the CYP3A5 active site in such a way that its propylenic group is accessible for oxidation, thus rendering CYP3A5 unable to produce the C-hydroxylated product or putative ketene that leads to enzyme inactivation. Identification of mifepristone as a selective mechanism-based inactivation of CYP3A4 may be very useful in distinguishing between the two major CYP3A enzymes collectively responsible for the oxidative metabolism of over half of the drugs currently in use.
View on PubMed2002
Cyclosporine protects the heart against ischemia/reperfusion injury, but its effect on cardiac metabolism is largely unknown. We assessed cyclosporine-induced metabolic changes in the rat heart prior to occlusion using magnetic resonance spectroscopy (MRS) and correlated effects with infarct size in a coronary occlusion/reperfusion model. The two study groups were cyclosporine and cyclosporine + coronary occlusion (n = 20/group). Rats were pretreated with cyclosporine (5, 10, 15, and 25 mg/kg/day) or the vehicle by oral gavage for 3 days (n = 4/dose). On day 4, hearts of rats in the cyclosporine group were excised, and extracted cell metabolites were measured using (1)H and (31)P MRS. The second group was subjected to 30 min of coronary artery occlusion followed by 24 h of reperfusion. Infarct size and area at risk were measured using a double staining method. In the cyclosporine group, cyclosporine reduced cardiac energy metabolism (ATP: r = -0.89, P < 0.001) via depression of oxidative phosphorylation and the Krebs' cycle in a dose-dependent manner. The decrease of ATP levels was positively correlated with changes of NAD(+) (r = 0.89), glutamate (r = 0.95), glutamine (r = 0.84), and glucose concentrations (r = 0.92, all P < 0.002). It was inversely correlated with lactate (r = -0.93, P < 0.001). In the coronary occlusion group, cyclosporine dose dependently reduced the ratio [area of infarct/area of the left ventricle] (r = -0.86, P < 0.01), with 15 mg/kg/day being the most effective cyclosporine dose. The reduction in infarct size correlated with the reduction in oxidative phosphorylation (ATP: r = 0.97; NAD(+): r = 0.82, P < 0.01). The reduction in cardiac energy metabolism before occlusion may be the cause of myocardial preservation during ischemia/reperfusion.
View on PubMed