Publications

Although endothelin-1-stimulated contractile force generation by stellate cells is believed to play an important role in hepatic pathophysiology, the molecular signals that mediate this process are incompletely understood. The aim of this study was to test the hypothesis that myosin mediates the contractile force generated by stellate cells in response to endothelin-1. Contractile force generation by primary and immortalized stellate cells was directly and quantitatively measured. Myosin phosphorylation and reorganization, and actin stress fiber formation were investigated in immortalized stellate cells. Endothelin-1 stimulated a rapid and robust generation of contractile force by primary and immortalized stellate cells with a similar dose dependence. Myosin phosphorylation, actin stress fiber assembly, and reorganization of myosin to stress fibers were induced by concentrations of endothelin-1 that also stimulated stellate cell contraction. BQ-123, a selective endothelin receptor antagonist, inhibited myosin phosphorylation and contractile force generation. Y-27632, which selectively inhibits rho-associated kinase, also blocked endothelin-1-stimulated myosin phosphorylation and contractile force generation with a similar dose dependence. These results suggest that endothelin-1-stimulated contractile force generation by stellate cells is mediated by myosin.

Cannabinoids, including smoked marijuana and delta9-tetrahydrocannabinol (THC) (dronabinol, Marinol), have been used to treat human immunodeficiency virus-1 (HIV)-associated anorexia and weight loss. Concerns have been raised, however, that these compounds might have adverse effects on the immune system of subjects with HIV infection. To determine whether such effects occur, the authors designed a randomized, prospective, controlled trial comparing the use of marijuana cigarettes (3.95% THC), dronabinol (2.5 mg), and oral placebo in HIV-infected adults taking protease inhibitor-containing highly active antiretroviral therapy (HAART). Assays of immune phenotype (including flow cytometric quantitation of T cell subpopulations, B cells, and natural killer [NK] cells) and immunefunction (including assays for induced cytokine production, NK cell function, and lymphoproliferation) were performed at baseline and weekly thereafter. On the basis of these measurements and during this short 21-day study period, few statistically significant effects were noted on immune system phenotypes orfunctions in this patient population.

BACKGROUND

Screening mammogram and Pap smear rates are lower for women in underserved racial and ethnic groups, yet may be overestimated due to reliance on patients' self-reports. The purpose of this study was to determine accuracy of self-reports of mammograms and Pap smears in a multiethnic, multilingual population of African American, Latina, Chinese, Filipina, and White women residing in low-income census tracts of Alameda County, California.

METHODS

Following a baseline telephone survey of 1,464 women regarding receipt of mammograms and Pap smears, we examined computerized and written medical records to validate the dates and locations of tests reported by women.

RESULTS

Of 1,464 subjects, 94.9% reported having had a Pap smear, and 87% reported having had a mammogram. For Pap smears, in a subsample of 448 cases, we validated only 69.4% of the women's self-reports, and for mammography, in a subsample of 846 women, we validated only 75.4% of the self-reports. Validation rates differed significantly by ethnicity and site of care for both Pap smears and mammograms.

CONCLUSIONS

Population estimates of breast and cervical cancer screening rates based upon patient self-reports need to be adjusted downward, by as much as one-quarter to one-third, for low-income, ethnic women.

Involucrin is a major protein of the cornified envelope of keratinocytes that provides much of the structural integrity of skin. Its expression is stimulated by a number of agents including calcium and 1,25-dihydroxy-vitamin D3 that promote the differentiation process in keratinocytes. Within the distal regulatory region of the involucrin promoter lies an AP-1 site and an element homologous to other vitamin D response elements. In previous studies mutation of the AP-1 site was found to reduce basal activity and block calcium stimulation of the involucrin promoter, whereas the vitamin D response element was not critical for calcium regulation. In this study both elements proved to be important for 1,25-dihydroxyvitamin D3 stimulation of the involucrin promoter. Mutation of the AP-1 site reduced basal activity and blocked 1,25-dihydroxyvitamin D3 stimulation of the involucrin promoter. In contrast, mutation of the vitamin D response element did not reduce basal expression of the involucrin promoter or prevent calcium stimulation of involucrin gene expression, but blocked 1,25-dihydroxyvitamin D3 stimulation. The vitamin D response element from the involucrin gene bound the vitamin D receptor and the retinoid X receptor, but not the retinoic acid receptor, in a specific manner. We conclude that the AP-1 site and the vitamin D response element in the involucrin promoter play important roles in mediating the action of 1,25-dihydroxyvitamin D3 on involucrin expression, but the vitamin D response element provides specificity for the 1,25-dihydroxyvitamin D3 response lacking at the AP-1 site.

BACKGROUND

Because they have chronic airway inflammation, adults with asthma may be particularly susceptible to indoor air pollution. Despite widespread exposure to environmental tobacco smoke (ETS), gas stoves, and woodsmoke, the impact of these exposures on adult asthma has not been well characterised.

METHODS

Data were used from a prospective cohort study of 349 adults with asthma who underwent structured telephone interviews at baseline and 18 month follow up. The prospective impact of ETS, gas stove, and woodsmoke exposure on health outcomes was examined.

RESULTS

ETS exposure at baseline interview was associated with impaired health status at longitudinal follow up. Compared with respondents with no baseline self-reported exposure to ETS, higher level exposure (>/=7 hours/week) was associated with worse severity of asthma scores at follow up, controlling for baseline asthma severity, age, sex, race, income, and educational attainment (mean score increment 1.5 points; 95% CI 0.4 to 2.6). Higher level baseline exposure to ETS was also related to poorer physical health status (mean decrement -4.9 points; 95% CI -8.4 to -1.3) and asthma specific quality of life (mean increase 4.4 points; 95% CI -0.2 to 9.0) at longitudinal follow up. Higher level baseline ETS exposure was associated with a greater risk of emergency department visits (OR 3.4; 95% CI 1.1 to 10.3) and hospital admissions for asthma at prospective follow up (OR 12.2; 95% CI 1.5 to 102). There was no clear relationship between gas stove use or woodstove exposure and asthma health outcomes.

CONCLUSION

Although gas stove and woodstove exposure do not appear negatively to affect adults with asthma, ETS is associated with a clear impairment in health status.

The aim of this study was to determine whether or not the skin acts as a reservoir for cocaine. Cocaine-d5 (1 mg/kg) was administered to five nondependent, cocaine-experienced volunteers. Skin tissue, interstitial fluid, sebum, stratum corneum, and plasma were collected for 72 h after drug administration. Cocaine and benzoylecgonine (BE) levels were determined using GC-MS. Cocaine concentrations peaked in plasma at 1 h after administration, with pharmacokinetic parameters (t(1/2), CL, Vd) also in the expected ranges. In skin, cocaine levels peaked around 1.5 h after administration and became undetectable by 6 h. A correlation was found between the plasma and skin AUC for cocaine (R = 0.99, p = 0.006, N = 4). BE was not detected in skin. In interstitial fluid (N = 4), cocaine concentrations peaked around 5 h after drug administration and were undetectable by 24 h. BE peaks varied between 2 and 24 h and were not detectable at 48 h. In sebum, cocaine levels peaked between 3 and 24 h. BE was found in three samples between 12 and 24 h. In stratum corneum, cocaine was measurable in only one sample from one subject. These findings suggest that skin does not act as a reservoir for cocaine. Rather, cocaine appears to be distributed rapidly to the skin and eliminated, following a time course similar to that of plasma.