Publications

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that promotes cardiomyocyte survival and contributes to ischemic preconditioning. S1P lyase (SPL) is a stress-activated enzyme responsible for irreversible S1P catabolism. We hypothesized that SPL contributes to oxidative stress by depleting S1P pools available for cardioprotective signaling. Accordingly, we evaluated SPL inhibition as a strategy for reducing cardiac ischemia-reperfusion (I/R) injury. We measured SPL expression and enzyme activity in murine hearts. Basal SPL activity was low in wild-type cardiac tissue but was activated in response to 50 min of ischemia (n = 5, P < 0.01). Hearts of heterozygous SPL knockout mice exhibited reduced SPL activity, elevated S1P levels, smaller infarct size, and increased functional recovery after I/R compared with littermate controls (n = 5, P < 0.01). The small molecule tetrahydroxybutylimidazole (THI) is a Federal Drug Administration-approved food additive that inhibits SPL. When given overnight at 25 mg/l in drinking water, THI raised S1P levels and reduced SPL activity (n = 5, P < 0.01). THI reduced infarct size and enhanced hemodynamic recovery in response to 50 min of ischemia and to 40 min of reperfusion in ex vivo hearts (n = 7, P < .01). These data correlated with an increase in MAP kinase-interacting serine/threonine kinase 1, eukaryotic translation initiation factor 4E, and ribosomal protein S6 phosphorylation levels after I/R, suggesting that SPL inhibition enhances protein translation. Pretreatment with an S1P₁ and S1P₃ receptor antagonist partially reversed the effects of THI. These results reveal, for the first time, that SPL is an ischemia-induced enzyme that can be targeted as a novel strategy for preventing cardiac I/R injury.

Lipodystrophy is commonly reported in Africa after antiretroviral therapy (ART) is initiated, but few studies have objectively measured changes in body composition. Body composition was determined in 76 HIV-infected participants from Mbarara, Uganda after starting a thymidine-analog regimen, and annual change was determined using repeated measures analysis. We measured skinfolds (tricep, thigh, subscapular, and abdomen), circumferences (arm, hip, thigh, waist), and total lean and fat mass (using bioelectric impedance analysis). A cross-sectional sample of 49 HIV-uninfected participants was studied for comparison. At baseline, most body composition measures were lower in HIV-infected than uninfected participants, but waist circumference was similar. After 12 months on ART, there was little difference in body composition measures between HIV-infected and uninfected participants; median waist circumference appeared higher in HIV-infected participants (79 vs. 75 cm; p = 0.090). Among HIV-infected participants, increases were observed in total lean and fat mass, circumference, and skinfold measures; only the increase in tricep skinfold did not reach statistical significance (+1.05 mm; 95% confidence interval: -0.24, 2.34; p = 0.11). Regional anthropometry in peripheral and central body sites increased over 12 months after ART initiation in HIV-infected persons from southwestern Uganda, suggesting a restoration to health. Gains in the tricep skinfold, a reliable marker of subcutaneous fat, appeared blunted, which could indicate an inhibitory effect of zidovudine on peripheral subcutaneous fat recovery.

BACKGROUND

Skeletal muscle (SM) mass decreases with advanced age and with disease in HIV infection. It is unknown whether age-related muscle loss is accelerated in the current era of antiretroviral therapy and which factors might contribute to muscle loss among HIV-infected adults. We hypothesized that muscle mass would be lower and decline faster in HIV-infected adults than in similar-aged controls.

METHODS

Whole-body (1)H-magnetic resonance imaging was used to quantify regional and total SM in 399 HIV-infected and 204 control men and women at baseline and 5 years later. Multivariable regression identified associated factors.

RESULTS

At baseline and Year 5, total SM was lower in HIV-infected than control men. HIV-infected women were similar to control women at both time points. After adjusting for demographics, lifestyle factors, and total adipose tissue, HIV infection was associated with lower Year 5 SM in men and higher SM in women compared with controls. Average overall 5-year change in total SM was small and age related, but rate of change was similar in HIV-infected and control men and women. CD4 count and efavirenz use in HIV-infected participants were associated with increasing SM, whereas age and stavudine use were associated with decreasing SM.

CONCLUSIONS

Muscle mass was lower in HIV-infected men compared with controls, whereas HIV-infected women had slightly higher SM than control women after multivariable adjustment. We found evidence against substantially faster SM decline in HIV infected versus similar-aged controls. SM gain was associated with increasing CD4 count, whereas stavudine use may contribute to SM loss.

CONTEXT

In 2005, the Healthcare Effectiveness Data and Information Set (HEDIS) introduced a quality measure to assess the receipt of disease-modifying antirheumatic drugs (DMARDs) among patients with rheumatoid arthritis (RA).

OBJECTIVE

To identify sociodemographic, community, and health plan factors associated with DMARD receipt among Medicare managed care enrollees.

DESIGN, SETTING, AND PARTICIPANTS

We analyzed individual-level HEDIS data for 93,143 patients who were at least 65 years old with at least 2 diagnoses of RA within a measurement year (during 2005-2008). Logistic regression models with generalized estimating equations were used to determine factors associated with DMARD receipt and logistic regression was used to adjust health plan performance for case mix.

MAIN OUTCOME MEASURES

Receipt or nonreceipt of DMARD.

RESULTS

The mean age of patients was 74 years; 75% were women and 82% were white. Overall performance on the HEDIS measure for RA was 59% in 2005, increasing to 67% in 2008 (P for trend <.001). The largest difference in performance was based on age: patients aged 85 years and older had a 30 percentage point lower rate of DMARD receipt (95% confidence interval [CI], -29 to -32 points; P < .001), compared with patients 65 to 69 years of age, even after adjusting for other factors. Lower percentage point rates were also found for patients who were men (-3 points; 95% CI, -5 to -2 points; P < .001), of black race (-4 points; 95% CI, -6 to -2 points; P < .001), with low personal income (-6 points; 95% CI, -8 to -5 points; P < .001), with the lowest zip code-based socioeconomic status (-4 points; 95% CI, -6 to 2 points; P < .001), or enrolled in for-profit health plans (-4 points; 95% CI, -7 to 0 points; P < .001); and in the Middle Atlantic region (-7 points; 95% CI, -13 to -2 points; P < .001) and South Atlantic regions (-11 points; 95% CI, -20 to -3 points; P < .001) as compared with the Pacific region. Performance varied widely by health plan, ranging from 16% to 87%.

CONCLUSIONS

Among Medicare managed care enrollees carrying a diagnosis of RA between 2005 and 2008, 63% received a DMARD. Receipt of DMARDs varied based on demographic factors, socioeconomic status, geographic location, and health plan.