Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, miR-148a, miR-130b, and miR-301b) control the expression of key proteins involved in cholesterol-lipoprotein trafficking, such as the low-density lipoprotein (LDL) receptor (LDLR) and the ATP-binding cassette A1 (ABCA1) cholesterol transporter. Consistent with human liver expression data and genetic links to abnormal blood lipid levels, overexpression and antisense targeting of miR-128-1 or miR-148a in high-fat diet–fed C57BL/6J and Apoe-null mice resulted in altered hepatic expression of proteins involved in lipid trafficking and metabolism, and in modulated levels of circulating lipoprotein-cholesterol and triglycerides. Taken together, these findings support the notion that altered expression of miRNAs may contribute to abnormal blood lipid levels, predisposing individuals to human cardiometabolic disorders.

S Y N OPSIS During a five year period at the Harlem Hospital Center nine heroin addicts were seen with strokes. Four occurred after loss of consciousness following intravenous heroin. Two occurred in patients using heroin at the time, but were not related to overdose or to a particular recent injection. The youth of these patients and lack of other predisposing factors suggests that heroin played a role in their strokes. In the other three patients, the relationships of stroke to heroin is less persuasive. There are several possible mechanisms by which heroin abuse could lead to stroke.A variety of medical (Louria et al., 1967) and neurological (Richter et al., 1973;Richter and Pearson, 1975) In 1970, a 25 year old heroin addict injected himself intravenously and within an hour noticed weakness which remained for a few days. He was unable to recall if the heroin he gave himself at that time was more than his usual amount, or if it had been his first injection after a period of abstinence.At the age of 26 years, he began sniffing cocaine and during this period of about two weeks did not take heroin. Then, feeling uncomfortably 'high' on cocaine, he gave himself his usual dose of heroin intravenously and became abruptly unresponsive. Brought to Harlem Hospital, he was comatose with a respiratory rate of 3/min and pinpoint pupils. There was prompt response to nallorphine 10 mg intravenously: respiration increased to 1 6/min, pupils became mid-position, and he awoke. He was lethargic and had mild difficulty in naming, moderate agraphia (writing with his left hand), alexia, right homonymous hemianopia, right facial weakness, flaccid paralysis of the right arm, and moderate weakness of the right leg. Position sense was decreased in the right fingers, and there were decreased deep tendon reflexes of the right limbs.White blood cell count was 13 250/ml (700O polymorphonuclears, 27% lymphocytes, 2% monocytes,

MC4R is the first gene identified that is required for the sustained effects of bariatric surgery. The need for MC4R signaling for the weight loss effects of RYGB in mice underscores the physiological mechanisms of action of this procedure and demonstrates that RYGB both influences and is dependent on the normal pathways that regulate energy balance.