Publications

HIV-infected patients have metabolic abnormalities that put them at increased risk of cardiovascular disease (CVD), including abnormalities associated with HIV infection itself, antiretroviral treatment, restoration to health, and body composition changes. The 2 major components of dyslipidemia in HIV-infected patients are hypertriglyceridemia and reduction in high-density lipoprotein (HDL) cholesterol (with likely altered function of HDL cholesterol); these abnormalities contribute to increased atherosclerotic risk. Adverse effects of antiretroviral drugs on lipids are not class specific but rather are associated with particular drugs. Thus, practitioners need to be cognizant of the risks of metabolic abnormalities posed by individual drugs. HIV infection increases CVD risk independent of the effects of traditional risk factors. The relative risk of CVD in HIV-infected patients has decreased in recent years with increasing use of lipid-lowering therapy. However, use of lipid-lowering therapy is complicated by numerous potential drug interactions with antiretroviral drugs that practitioners need to consider when prescribing lipid-lowering therapy. This article summarizes a presentation made by Carl Grunfeld, MD, PhD, at the International AIDS Society-USA continuing medical education program in Los Angeles in March 2010. The original presentation is available as a Webcast at www.iasusa.org.

ABCG1, a member of the ATP binding cassette superfamily, facilitates the efflux of cholesterol from cells to HDL. In this study, we demonstrate that ABCG1 is expressed in cultured human keratinocytes and murine epidermis, and induced during keratinocyte differentiation, with increased levels in the outer epidermis. ABCG1 is regulated by liver X receptor (LXR) and peroxisome proliferator-activated receptor-δ (PPAR-δ) activators, cellular sterol levels, and acute barrier disruption. Both LXR and PPAR-δ activators markedly stimulate ABCG1 expression in a dose- and time-dependent fashion. PPAR-γ activators also increase ABCG1 expression, but to a lesser degree. In contrast, activators of PPAR-α, retinoic acid receptor, retinoid X receptor, and vitamin D receptor do not alter ABCG1 expression. In response to increased intracellular sterol levels, ABCG1 expression increases, whereas inhibition of cholesterol biosynthesis decreases ABCG1 expression. In vivo, ABCG1 is stimulated 3-6 h after acute barrier disruption by either tape stripping or acetone treatment, an increase that can be inhibited by occlusion, suggesting a potential role of ABCG1 in permeability barrier homeostasis. Although Abcg1-null mice display normal epidermal permeability barrier function and gross morphology, abnormal lamellar body (LB) contents and secretion leading to impaired lamellar bilayer formation could be demonstrated by electron microscopy, indicating a potential role of ABCG1 in normal LB formation and secretion.

The regulation of epidermal ontogenesis is a complex process. Previous studies have shown that cytokines (IL-1, TNFalpha and IL-6) regulate permeability barrier homeostasis in adult mice. Recently, we reported that IL-1 and TNFalpha accelerate stratum corneum (SC) formation and permeability barrier development in foetal rodents. Here, we determined whether IL-6 also regulates SC formation and permeability barrier development during late gestation. Using a rat skin explant model, we demonstrated that IL-6 accelerates permeability barrier formation in a time- and dose-dependent fashion. This acceleration of barrier formation is attributable to (a) accelerated lamellar membrane maturation, (b) formation of a multi-layer SC and (c) enhanced expression of epidermal differentiation markers. When comparing epidermis of IL-6-deficient (knockout mice) and wild-type foetal mice at days 16-18, we could not detect any abnormalities in either SC formation or the expression of differentiation markers in knockout (KO) mice. In parallel, the basal expression levels of IL-6 mRNA in epidermis and IL-6 protein in amniotic fluid were very low, with only a minimal change in IL-6 receptor mRNA levels in epidermis of days 16-22 foetal mice. These low IL-6 levels may account, at least in part, for the absence of epidermal abnormalities in IL-6 KO mice. In conclusion, exogenous IL-6 accelerates epidermal ontogenesis, but it is not essential for normal epidermal maturation.

INTRODUCTION

Fipronil is a broad-spectrum phenylpyrazole insecticide widely used to control residential pests and is also commonly used for flea and tick treatment on pets. It is a relatively new insecticide and few human toxicity data exist on fipronil.

OBJECTIVE

This paper describes the magnitude and characteristics of acute illnesses associated with fipronil exposure.

METHODS

Illness cases associated with exposure to fipronil-containing products from 2001 to 2007 were identified from the Sentinel Event Notification System for Occupational Risks (SENSOR)-Pesticides Program and the California Department of Pesticide Regulation.

RESULTS

A total of 103 cases were identified in 11 states. Annual case counts increased from 5 in 2001 to 30 in 2007. Of the cases, 55% were female, the median age was 37 years, and 11% were <15 years old. The majority (76%) had exposure in a private residence, 37% involved the use of pet-care products, and 26% had work-related exposures. Most cases (89%) had mild, temporary health effects. Neurological symptoms (50%) such as headache, dizziness, and paresthesia were the most common, followed by ocular (44%), gastrointestinal (28%), respiratory (27%), and dermal (21%) symptoms/signs. Exposures usually occurred from inadvertent spray/splash/spill of products or inadequate ventilation of the treated area before re-entry.

CONCLUSIONS

Our findings indicate that exposure to fipronil can pose a risk for mild, temporary health effects in various body systems. Precautionary actions should be reinforced to prevent fipronil exposure to product users.

OBJECTIVE

To examine childhood-onset disease as a predictor of mortality in a cohort of adult patients with systemic lupus erythematosus (SLE).

METHODS

Data were derived from the University of California Lupus Outcomes Study, a longitudinal cohort of 957 adult subjects with SLE that includes 98 subjects with childhood-onset SLE. Baseline and followup data were obtained via telephone interviews conducted in 2002-2007. The number of deaths during 5 years of followup was determined and standardized mortality ratios (SMRs) for the cohort, and across age groups, were calculated. Kaplan-Meier life table analysis was used to compare mortality rates between childhood- (defined as SLE diagnosis at <18 years of age) and adult-onset SLE. Multivariate Cox proportional hazard models were used to determine predictors of mortality.

RESULTS

During the median followup period of 48 months, 72 deaths (7.5% of subjects) occurred, including 9 deaths (12.5%) in subjects with childhood-onset SLE. The overall SMR was 2.5 (95% confidence interval [95% CI] 2.0-3.2). In Kaplan-Meier survival analysis, after adjusting for age, childhood-onset subjects were at increased risk for mortality throughout the followup period (P< 0.0001). In a multivariate model adjusting for age, disease duration, and other covariates, childhood-onset SLE was independently associated with an increased mortality risk (hazard ratio [HR] 3.1, 95% CI 1.3-7.3), as was low socioeconomic status measured by education (HR 1.9, 95% CI 1.1-3.2), and end stage renal disease (HR 2.1, 95% CI 1.1-4.0).

CONCLUSION

Childhood-onset SLE was a strong predictor of mortality in this cohort. Interventions are needed to prevent early mortality in this population.

BACKGROUND

The Veterans Affairs (VA) has made significant investments in care for veterans. However, it is not known whether these investments have produced improvements in end-of-life care in the VA compared to other settings. Therefore, the goal of this study was to compare families' perceptions of end-of-life care among patients who died in VA and non-VA facilities.

DESIGN

Retrospective 32-item telephone surveys were conducted with family members of patients who died in VA and non-VA facilities.

SETTING

Five Veterans Affairs medical centers and their affiliated nursing homes and outpatient clinics.

PARTICIPANTS

Patients were eligible if they received any care from a participating VA facility in the last month of life and if they died in an inpatient setting. One family member per patient completed the survey.

RESULTS

In bivariate analysis, patients who died in VA facilities (n = 520) had higher mean satisfaction scores compared to those who died in non-VA facilities (n = 89; 59 versus 51; rank sum test p = 0.002). After adjusting for medical center, the overall score was still significantly higher for those dying in the VA (beta = 0.07; confidence interval [CI] = 0.02-0.11; p = 0.004), as was the domain measuring care around the time of death (beta = 0.11; CI = 0.04-0.17; p = 0.001).

CONCLUSION

Families of patients who died in VA facilities rated care as being better than did families of those who died in non-VA facilities. These results provide preliminary evidence that the VA's investment in end-of-life care has contributed to improvements in care in VA facilities compared to non-VA facilities.

BACKGROUND

Measures for pay-for-performance and public reporting programs may be based on clinical practice guidelines. The impact of guideline changes over time-and whether evolving clinical evidence can render measures based on prior guidelines misleading-is not known.

OBJECTIVE

To assess the impact of using different percutaneous coronary intervention (PCI) guidelines when evaluating whether PCI was indicated.

RESEARCH DESIGN

PCIs from the National Cardiovascular Data Registry's CathPCI registry performed in 2003-2004 were categorized into indication classes (Class I, IIa, IIb, III), using 2001 American College of Cardiology/American Heart Association guidelines for PCI, the guidelines available at the time of the procedures. The same procedures were recategorized using 2005 guidelines, which reflect the best evidence available to clinicians at the time of PCI. Procedures unable to be categorized were labeled as "Not Certain."

SUBJECTS

Patients undergoing PCI for stable or unstable angina in 394 hospitals.

MEASURES

Number of procedures changing classification categories using 2001 versus 2005 guidelines.

RESULTS

A total of 345,779 PCIs were evaluated. Applying 2001 guidelines, 47.9% had Class I indications; 33.3% Class IIa; 5.9% Class IIb; 3.7% Class III; and 9.2% Not Certain. Applying 2005 guidelines to the same procedures, 25.1% had Class I indications; 57.5% Class IIa; 5.5% Class IIb; 3.7% Class III; and 8.3% Not Certain; 41.1% of procedures changed the classification overall.

CONCLUSIONS

The changes in guidelines resulted in a marked shift in whether PCIs done in 2003-2004 were considered indicated. Guideline-based performance measures should be carefully evaluated before implementation to avoid incorrect assessments of quality of care.