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Sepsis accounts for one in three hospital deaths. Higher concentrations of high‐density lipoprotein cholesterol (HDL‐C) are associated with apparent protection from sepsis, suggesting a potential therapeutic role for HDL‐C or drugs, such as cholesteryl ester transport protein (CETP) inhibitors that increase HDL‐C. However, these beneficial clinical associations might be due to confounding; genetic approaches can address this possibility. We identified 73,406 White adults admitted to Vanderbilt University Medical Center with infection; 11,612 had HDL‐C levels, and 12,377 had genotype information from which we constructed polygenic risk scores (PRS) for HDL‐C and the effect of CETP on HDL‐C. We tested the associations between predictors (measured HDL‐C, HDL‐C PRS, CETP PRS, and rs1800777) and outcomes: sepsis, septic shock, respiratory failure, and in‐hospital death. In unadjusted analyses, lower measured HDL‐C concentrations were significantly associated with increased risk of sepsis (p = 2.4 × 10−23), septic shock (p = 4.1 × 10−12), respiratory failure (p = 2.8 × 10−8), and in‐hospital death (p = 1.0 × 10−8). After adjustment (age, sex, electronic health record length, comorbidity score, LDL‐C, triglycerides, and body mass index), these associations were markedly attenuated: sepsis (p = 2.6 × 10−3), septic shock (p = 8.1 × 10−3), respiratory failure (p = 0.11), and in‐hospital death (p = 4.5 × 10−3). HDL‐C PRS, CETP PRS, and rs1800777 significantly predicted HDL‐C (p < 2 × 10−16), but none were associated with sepsis outcomes. Concordant findings were observed in 13,254 Black patients hospitalized with infections. Lower measured HDL‐C levels were significantly associated with increased risk of sepsis and related outcomes in patients with infection, but a causal relationship is unlikely because no association was found between the HDL‐C PRS or the CETP PRS and the risk of adverse sepsis outcomes. [ABSTRACT FROM AUTHOR]

Objective Patients with rheumatoid arthritis (RA) have an increased risk of coronary heart disease (CHD). Some RA therapies may modify this risk, but the underlying mechanisms are unclear. The cholesterol efflux capacity of high-density lipoprotein (HDL) is associated with a reduced CHD risk in non-RA populations; however, inflammation may impair the function of HDL. The aim of this study was to evaluate whether reduced inflammation resulting from treatment with methotrexate (MTX), adalimumab (ADA), or tocilizumab (TCZ) would increase the net cholesterol efflux capacity of HDL in patients with RA. Methods A longitudinal multicenter study repository (Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database and Repository) provided clinical information for and serum samples from 70 patients with RA before and 6 months after starting treatment with a new drug (MTX [n = 23], ADA [n = 22], or TCZ [n = 25]). Disease activity was measured using the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR). The net cholesterol efflux capacity was measured in paired serum samples using THP-1 macrophages, and total cellular cholesterol was measured by fluorometric assay. Results The DAS28-ESR decreased with all treatments ( P < 0.001). Net cholesterol efflux capacity was not significantly changed after 6 months of new RA therapy (mean ± SD 36.9 ± 17.3% units at baseline versus 38.0% ± 16.9% units at 6 months [ P = 0.58]). However, change in net cholesterol efflux capacity was associated with change in the DAS28-ESR (ρ = −0.25, P = 0.04). In a post hoc analysis of patients with impaired net cholesterol efflux capacity at baseline, treatment with TCZ resulted in significant improvement in net cholesterol efflux capacity (21.9 ± 14.7% units at baseline versus 31.3% ± 12.8% units at 6 months [ P < 0.02]), but this was not observed with MTX or ADA. Conclusion Net cholesterol efflux capacity of HDL cholesterol did not change significantly after 6 months of new RA therapy, except in patients with impaired baseline cholesterol efflux capacity who were receiving TCZ. Change in disease activity was associated with change in the net cholesterol efflux capacity. [ABSTRACT FROM AUTHOR]

Proprotein convertase subtilisin/kexin type 9 ( PCSK9) promotes atherosclerosis by increasing low-density lipoprotein ( LDL) cholesterol levels through degradation of hepatic LDL receptor ( LDLR). Studies have described the systemic effects of PCSK9 on atherosclerosis, but whether PCSK9 has local and direct effects on the plaque is unknown. To study the local effect of human PCSK9 ( hPCSK9) on atherosclerotic lesion composition, independently of changes in serum cholesterol levels, we generated chimeric mice expressing h PCSK9 exclusively from macrophages, using marrow from h PCSK9 transgenic (h PCSK9tg) mice transplanted into apoE−/− and LDLR−/− mice, which were then placed on a high-fat diet (HFD) for 8 weeks. We further characterized the effect of h PCSK9 expression on the inflammatory responses in the spleen and by mouse peritoneal macrophages (MPM) in vitro. We found that MPMs from transgenic mice express both murine (m) Pcsk9 and h PCSK9 and that the latter reduces macrophage LDLR and LRP1 surface levels. We detected hPCSK9 in the serum of mice transplanted with h PCSK9tg marrow, but did not influence lipid levels or atherosclerotic lesion size. However, marrow-derived PCSK9 progressively accumulated in lesions of apoE−/− recipient mice, while increasing the infiltration of Ly6Chi inflammatory monocytes by 32% compared with controls. Expression of h PCSK9 also increased CD11b- and Ly6Chi-positive cell numbers in spleens of apoE−/− mice. In vitro, expression of h PCSK9 in LPS-stimulated macrophages increased mRNA levels of the pro-inflammatory markers Tnf and Il1b (40% and 45%, respectively) and suppressed those of the anti-inflammatory markers Il10 and Arg1 (30% and 44%, respectively). All PCSK9 effects were LDLR-dependent, as PCSK9 protein was not detected in lesions of LDLR−/− recipient mice and did not affect macrophage or splenocyte inflammation. In conclusion, PCSK9 directly increases atherosclerotic lesion inflammation in an LDLR-dependent but cholesterol-independent mechanism, suggesting that therapeutic PCSK9 inhibition may have vascular benefits secondary to LDL reduction. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

To comprehensively study extracellular small RNAs (sRNA) by sequencing (sRNA-seq), we developed a novel pipeline to overcome current limitations in analysis entitled, "Tools for Integrative Genome analysis of Extracellular sRNAs (TIGER)". To demonstrate the power of this tool, sRNA-seq was performed on mouse lipoproteins, bile, urine and livers. A key advance for the TIGER pipeline is the ability to analyse both host and non-host sRNAs at genomic, parent RNA and individual fragment levels. TIGER was able to identify approximately 60% of sRNAs on lipoproteins and >85% of sRNAs in liver, bile and urine, a significant advance compared to existing software. Moreover, TIGER facilitated the comparison of lipoprotein sRNA signatures to disparate sample types at each level using hierarchical clustering, correlations, beta-dispersions, principal coordinate analysis and permutational multivariate analysis of variance. TIGER analysis was also used to quantify distinct features of exRNAs, including 5ʹ miRNA variants, 3ʹ miRNA non-templated additions and parent RNA positional coverage. Results suggest that the majority of sRNAs on lipoproteins are non-host sRNAs derived from bacterial sources in the microbiome and environment, specifically rRNA-derived sRNAs from Proteobacteria. Collectively, TIGER facilitated novel discoveries of lipoprotein and biofluid sRNAs and has tremendous applicability for the field of extracellular RNA. [ABSTRACT FROM AUTHOR]

Retinoids and rexinoids are prescribed for conditions ranging from acne vulgaris to hyperkeratosis to cutaneous T cell lymphoma. Dyslipidemia is a frequent consequence of the use of these drugs, with more than one-third of patients manifesting aberrations in triglyceride (TG) levels. The efficacy of retinoic acid derivatives is linked to their influence on lipid metabolism in the skin, which can impair systemic lipid trafficking and metabolism in some patients. Thus, baseline screening for preexisting dyslipidemia and regular follow-up lipid panels are mandated, especially when powerful agents such as bexarotene are used. Dietary modification, increased physical activity, and weight management are the cornerstones of initial management for mild hypertriglyceridemia, which is a contributor to cardiovascular risk. More severe impairments (fasting TG > 500 mg/dL) warrant pharmacologic interventions early on to reduce the risk of pancreatitis. Retinoic acid derivative action, lipid metabolism, and treatment of incident dyslipidemias are reviewed to empower prescribers in management of adverse lipid effects., (© 2013 Wiley Periodicals, Inc.)