Complete deletion of Cd39 is atheroprotective in apolipoprotein E-deficient mice.

Cd39 scavenges extracellular ATP and ADP, ultimately generating adenosine, a nucleoside, which has anti-inflammatory effects in the vasculature. We have evaluated the role of Cd39 in the development of atherosclerosis in hyperlipidemic mice. ApoE KO (Cd39+/+/ApoE-/-) and Cd39/ApoE double KO (DKO) (Cd39-/-/ApoE-/-) mice were maintained on chow or Western diet for up to 20 weeks before evaluation of atherosclerotic lesions. We found that DKO mice exhibited significantly fewer atherosclerotic lesions than ApoE KO mice, irrespective of diet. Analyses of plaque composition revealed diminished foam cells in the fatty streaks and smaller necrotic cores in advanced lesions of DKO mice, when compared with those in ApoE KO mice. This atheroprotective phenotype was associated with impaired platelet reactivity to ADP in vitro and prolonged platelet survival, suggesting decreased platelet activation in vivo. Further studies with either genetic deletion or pharmacological inhibition of Cd39 in macrophages revealed increased cholesterol efflux mediated via ABCA1 to ApoA1. This phenomenon was associated with elevated plasma HDL levels in DKO mice. Our findings indicate that complete deletion of Cd39 paradoxically attenuates development of atherosclerosis in hyperlipidemic mice. We propose that this phenotype occurs, at least in part, from diminished platelet activation, increased plasma HDL levels, and enhanced cholesterol efflux and indicates the complexity of purinergic signaling in atherosclerosis.

Associations of anthropometry and lifestyle factors with HDL subspecies according to apolipoprotein C-III.

The presence of apoC-III on HDL impairs HDL's inverse association with coronary heart disease (CHD). Little is known about modifiable factors explaining variation in HDL subspecies defined according to apoC-III. The aim was to investigate cross-sectional associations of anthropometry and lifestyle with HDL subspecies in 3,631 participants from the Diet, Cancer, and Health study originally selected for a case-cohort study (36% women; age 50-65 years) who were all free of CHD. Greater adiposity and less activity were associated with higher HDL containing apoC-III and lower HDL lacking apoC-III. Per each 15 cm higher waist circumference, the level of HDL containing apoC-III was 2.8% higher (95% CI: 0.4, 5.3; P = 0.024) and the level of HDL not containing apoC-III was 4.7% lower (95% CI: -6.0, -3.4; P = <0.0001). Associations for physical activity were most robust to multivariable modeling. Each 20 metabolic equivalent task hours per week reported higher physical activity was associated with 0.9% (95% CI: -1.7, -0.1; P = 0.031) lower HDL containing apoC-III and 0.5% higher (95% CI: 0.1, 1.0; P = 0.029) HDL lacking apoC-III. Lower alcohol consumption was associated with lower HDL lacking apoC-III (percent difference per 15 g/day: 1.58 (95% CI: 0.84, 2.32; P = <0.0001). Adiposity and sedentary lifestyle were associated with a less favorable HDL subspecies profile.

A randomized study of ceftriaxone for the prevention of infections in hospitalized patients with advanced cirrhosis.

BACKGROUND: Infections frequently complicate hospital admission among patients with cirrhosis and are associated with adverse outcomes. In specific settings, administration of prophylactic antibiotics has been shown to improve outcomes. In this pilot study, we aimed to assess the feasibility of a randomized study of whether prophylactic ceftriaxone (CTX), administered to hospitalized patients with advanced cirrhosis (Model for End-Stage Liver Disease-Sodium ≥ 18) without known infection, could reduce the incidence of infection. We also sought to determine whether we could identify patients most likely to benefit through the use of clinical and laboratory parameters. METHODS: Hospitalized patients with cirrhosis, with Model for End-Stage Liver Disease-Sodium ≥ 18 and no known infection after evaluation, were randomly assigned in a double-blinded fashion to receive either CTX 1 gr/day or placebo for up to 7 days. Subjects were monitored for incident infection and other outcomes of interest, including adverse reactions such as the development of C. difficile infection. Biomarkers of interest, including C-reactive protein and procalcitonin, were measured before initiation of treatment. RESULTS: Thirty subjects were enrolled and received CTX or placebo (15 subjects each) per protocol. There were no observed statistically significant differences between groups in incidence of infection, mortality, length of stay, or key laboratory parameters, including C-reactive protein and procalcitonin. Adverse events related to treatment were rare and clinically of minor significance. CONCLUSIONS: Overall, enrollment of subjects proved feasible, and results from this pilot study, while inadequate for confirmation of the potential efficacy of CTX, provide evidence of study feasibility for future, more definitive clinical trials.