or the movement of cholesterol from peripheral cells, including lipid laden macrophages, to the liver for excretion. This pathway involves multiple steps including: 1 ) the effl ux of cholesterol to lipid poor apolipoproteins and HDL; 2 ) the maturation of HDL through cholesterol esterifi cation via lethicin cholesterol acyl transferase; 3 ) the uptake of HDL cholesterol by the liver; and 4 ) hepatic cholesterol excretion into the biliary system and feces in the form of bile acids and free cholesterol ( 2, 3 ). Thus, understanding the mechanism of RCT and the pathophysiological factors affecting RCT has been a topic of immense research focus with potential clinical signifi cance.Infl ammation may be a potent source of HDL and RCT dysfunction. HDL undergoes multiple structural changes with infl ammation rendering it into "acute phase HDL", which is relatively enriched in free fatty acids, triglycerides, serum amyloid A (SAA), and apolipoprotein (apo)A-IV, whereas cholesterol esters and anti-infl ammatory enzymes including paraoxanase 1 are decreased ( 4-6 ). In addition, infl ammation induces secretion of myeloperoxidase (MPO), which has been shown to modify apoAI and impair its ability to accept cholesterol ( 7-10 ). Finally infl ammation affects gene expression in the liver, which has consequences for cholesterol uptake and excretion ( 4,11,12 ). Understanding the mechanisms behind the infl ammatory impairment of RCT is clinically relevant as chronic infl ammatory conditions such as diabetes, metabolic syndrome, and rheumatoid arthritis are prevalent in our society and associated with an increased atherosclerotic burden ( 13,14 ).Although a majority of the studies on infl ammatory impairment of RCT have been in vitro, two recent studies Abstract Infl ammation has been proposed to impair HDL function and reverse cholesterol transport (RCT). We investigated the effects of infl ammation mediated by zymosan, a yeast glucan, on multiple steps along the RCT pathway in vivo and ex vivo. Acute infl ammation with 70 mg/kg zymosan impaired RCT to plasma, liver, and feces similarly by 17-22% ( P < 0.05), with no additional block at the liver. Hepatic gene expression further demonstrated no change in ABCG5, ABCB4, and ABCB11 expression but a decline in ABCG8 mRNA (32% P < 0.05). Plasma from zymosan-treated mice had a 21% decrease in cholesterol acceptor ability ( P < 0.01) and a 35% decrease in ABCA1-specfi c effl ux capacity ( P < 0.01) in vitro. Zymosan treatment also decreased HDL levels and led to HDL remodeling with increased incorporation of serum amyloid A. In addition, cholesterol effl ux from cultured macrophages declined with zymosan treatment in a dose dependant manner. Taken together, our results suggest that zymosan impairs in vivo RCT primarily by decreasing macrophage-derived cholesterol entering the plasma, with minimal additional blocks downstream. Our study supports the notion that RCT impairment is one of the mechanisms for the increased atherosclerotic burden observed in infl ammatory conditions. -Malik...

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The majority of patients with acute myeloid leukemia (AML) are elderly and have a poor prognosis despite induction therapy. Decitabine, a DNA-hypomethylating agent that induces differentiation and apoptosis of leukemic cells, is a well-tolerated alternative to aggressive chemotherapy. It is currently FDA-approved for myelodysplastic syndrome, including patients with 20%–30% bone marrow blasts. Recent clinical attention has focused on evaluating decitabine as frontline therapy for untreated high-risk elderly AML patients. A large randomized international phase III study comparing decitabine to supportive care and cytarabine in elderly AML patients demonstrated significantly improved complete remission rates, but the survival difference did not reach significance. Due to this, decitabine did not achieve FDA approval for AML, but continues to be used off-label. Current research is focused on further defining subgroups of elderly AML patients who may derive greater benefit from decitabine therapy and combining it with other low-intensity active agents for AML.