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.

ClinicalTrials.gov, NCT01056406.

Despite its overall excellent outcomes, weight loss after Roux-en-Y gastric bypass (RYGB) is highly variable. We conducted this study to identify clinical predictors of weight loss after RYGB. We reviewed charts from 300 consecutive patients who underwent RYGB from August 1999 to November 2002. Data collected included patient demographics, medical comorbidities, and diet history. Of the 20 variables selected for univariate analysis, 9 with univariate P values ≤ 0.15 were entered into a multivariable regression analysis. Using backward selection, covariates with P < 0.05 were retained. Potential confounders were added back into the model and assessed for effect on all model variables. Complete records were available for 246 of the 300 patients (82%). The patient characteristics were 75% female, 93% white, mean age of 45 years, and mean initial BMI of 52.3 kg/m2. One year after surgery, patients lost an average of 64.8% of their excess weight (s.d. = 20.5%). The multivariable regression analysis revealed that limited physical activity, higher initial BMI, lower educational level, diabetes, and decreased attendance at postoperative appointments had an adverse effect on weight loss after RYGB. A model including these five factors accounts for 41% of the observed variability in weight loss (adjusted r2 = 0.41). In this cohort, higher initial BMI and limited physical activity were the strongest predictors of decreased excess weight loss following RYGB. Limited physical activity may be particularly important because it represents an opportunity for potentially meaningful pre- and postsurgical intervention to maximize weight loss following RYGB.

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

ObjectiveAlthough Roux-en-Y gastric bypass (RYGB) is a generally effective treatment for severe obesity, weight loss (WL) after this operation is highly variable. Accurate predictors of outcome would thus be useful in identifying those patients who would most benefit from this invasive therapy. WL has been characterized using several different metrics, including the number of BMI units lost (ΔBMI), percent baseline WL (%WL), and percent excess body WL (%EBWL). To identify clinically relevant predictors most sensitively it is necessary to avoid confounding by other factors, including preoperative BMI (pBMI), the strongest known predictor of RYGB-induced WL.Design and MethodsTo determine the WL measure least associated with pBMI, we analyzed outcomes of 846 patients undergoing RYGB.ResultsPatients in this cohort had an average pBMI of 50.0 kg/m2. At weight nadir, they lost an average 19.4 kg/m2, 38.7% WL, and 81.2% EBWL. pBMI was strongly and positively associated with ΔBMI at both one year (r=0.56, p=4.7×10−51) and nadir (r=0.58, p=2.8×10−77) and strongly but negatively associated with %EBWL at one year (r=−0.52, p=3.8×10−44) and nadir (r=−0.45, p=7.2×10−43). In contrast, pBMI was not significantly associated with %WL at one year (r=0.04, p=0.33), and only weakly associated at nadir (r=0.13, p=0.0002).ConclusionsOf the metrics examined, %WL is the parameter describing WL after RYGB least influenced by pBMI. It thus improves comparison of WL outcomes across studies of patients undergoing surgery and facilitates the most sensitive identification of novel predictors of surgery-induced WL. We therefore recommend that %WL be adopted more broadly in reporting weight loss after RYGB.

OBJECTIVELipoprotein-associated phospholipase A2 (Lp-PLA2) has been shown to be associated with increased risk of coronary heart disease (CHD) in general adult populations. Because men and women with type 2 diabetes are at particularly high risk for CHD, the aim of this study was to assess the association of Lp-PLA2 with future coronary events among diabetic men and women.RESEARCH DESIGN AND METHODSWe measured Lp-PLA2 activity among 740 men and 777 women with confirmed diabetes enrolled in the Health Professionals Follow-Up Study (HPFS) and Nurses' Health Study (NHS). Participants were free of all cardiovascular disease and cancer at baseline.RESULTSDuring 10 years of follow-up among men and 14 years among women, we documented 178 and 146 cases of CHD, respectively. We defined CHD as coronary artery bypass graft, angioplasty, nonfatal myocardial infarction, and fatal CHD. After adjustment for age, smoking, medical history, and biomarkers including C-reactive protein, HDL, and LDL, the relative risk of total CHD comparing extreme tertiles of Lp-PLA2 was 1.39 (95% CI 1.01–1.90; P trend = 0.03). When we restricted analyses to only nonfatal myocardial infarction and fatal CHD, the relative risk was 1.75 (95% CI 1.05–2.92; P for trend = 0.001). LDL, HDL, C-reactive protein, hormone replacement therapy use, and diabetes duration did not modify these relationships.CONCLUSIONSLevels of Lp-PLA2 activity were significantly associated with incident CHD among men and women with type 2 diabetes, independent of traditional and inflammatory risk factors. This positive association was strongest for more severe clinical end points.