Like mutations with loss of function in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, inhibitors of PCSK9 (PCSK9i) may potentially favor the manifestation of diabetes. RESEARCH DESIGN AND METHODS A meta-analysis of phase 2/3 randomized clinical trials (RCTs) assessed PCSK9i versus placebo in the primary hypercholesterolemia setting. Statins and ezetimibe were used in 98.4% of these studies and balanced between PCSK9i and placebo. We calculated relative risks (RRs) and 95% CIs using random-and fixed-effect models. RESULTS We included 68,123 participants (20 RCTs) with median follow-up of 78 weeks. PCSK9i increased fasting blood glucose (weighted mean difference 1.88 mg/dL [95% CI 0.91-2.68]; I 2 = 0%; P < 0.001) and HbA 1c (0.032% [0.011-0.050]; I 2 = 15.5%; P < 0.001) when compared with placebo. This effect was not sufficient to increase incidence of diabetes (RR 1.04 [0.96-1.13]; I 2 = 0%; P = 0.427). Exploratory meta-regression analyses indicated an association between the increased risk of diabetes and the potency (P = 0.029) and duration (P = 0.026) of PCSK9i treatment. CONCLUSIONS In the short term, PCSK9i therapy favors a small but significant increase in plasma glycemia and HbA 1c .

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RUNNING TITLECholesterol efflux capacity and atherosclerosis in elderly. ABBREVIATIONSANCOVA, analysis of covariance; CAC, coronary artery calcium; CEC, cholesterol efflux capacity; CRP, Creactive protein; HDL-C, HDL cholesterol; FMD, flow mediated dilation; IMT, intima-media thickness; LDL-C, LDL cholesterol; TC, total cholesterol; TL, telomere length; WHO, world health organization. AbstractSeveral studies revealed that traditional risk factors are less effective in predicting CVD risk in the elderly, suggesting the need to identify new biomarkers. Here we evaluated the association between serum cholesterol efflux capacity (CEC), an atheroprotective property of HDL recently identified as a novel marker of CVD risk, and atherosclerotic burden in a cohort of very old, healthy individuals. Serum CEC values were not significantly correlated neither with calcium score nor with markers of vulnerable plaque, such as positive remodeling, hypodensity, spotty calcification or napking-ring sign. In addition, no association was detected between CEC and telomere length, a marker of biological aging that has been linked to atherosclerosis extent. Interestingly, elderly subjects presented a remarkably higher CEC (+30.2%; p<0.0001) compared to values obtained from a cohort of sex-matched, free of cardiovascular events, middle-aged individuals. In conclusion, serum CEC is not related to traditional risk factors in very old, free of cardiovascular events subjects, but has significantly higher values compared to a healthy, younger population. Whether this improved HDL functionality may represent a protective factor in CVD onset has to be established in future studies.

RESUMOOs hormônios tireoideanos (HTs) são necessários para a diferenciação, crescimento e metabolismo de diversos tecidos de vertebrados. Seus efeitos são mediados pelos receptores do hormônio tireoideano (TRs), membros da superfamília dos receptores nucleares. Estes receptores são fatores de transcrição modulares que se ligam em seqüências específi-cas do DNA denominadas elementos responsivos ao TR, que são encontrados nos promotores dos genes regulados pelo HT. Os TRs são codificados por dois genes distintos, α e β, localizados nos cromossomos 17 e 3, respectivamente. Estas isoformas apresentam diferentes funções e sua expressão é específica para cada tecido. O TR se liga ao DNA como monômero, homodímero ou heterodímero com o receptor de retinóide X (RXR). Além disso, o TR modula a atividade transcricional (repressão ou ativação) através da interação com correpressores e co-ativadores, na ausência e na presença do T 3 , respectivamente. A compreensão do mecanismo molecular da ação do receptor do hormônio tireoideano e a definição de sua estrutura cristalográfica contribuirão para a aquisição de novos conceitos envolvidos na transcrição e nos distúrbios hormonais presentes nas doenças endócrinas, assim como facilitará o desenho de novas drogas, agonistas ou antagonistas, com grande valor terapêutico. Thyroid hormones (TH) are involved in normal differentiation, growth, and metabolism in several tissues of all vertebrates. Their actions are mediated by the TH receptors (TRs), members of the nuclear hormone receptor superfamily. These receptors are transcription factors that bind to DNA on specific sequences, the TR response element (TREs), in promoters of target genes. Two genes encode TRs, α e β, located in chromosomes 17 and 3, respectively. These isoforms show different functions and exhibit a tissue specific expression. TRs function as monomers, homodimers or heterodimers with retinoid X receptor (RXR) and modulate transcription activity (repression or activation) by interacting with co-repressor and coactivators, which associate with TR in the absence or presence of T 3 , respectively. Understanding the molecular mechanism of TR action and the definition of its crystallographic structure will provide new insights into transcription mechanisms and will facilitate the design of new drugs with greater therapeutic value.

Our data confirm the current validity of the reference values obtained in 1981, which continue to be significantly different from those of the UniCAP method for Swedish donors. The population of allergic subjects can be divided into two subgroups: subjects with total IgE levels similar to those of the donors, which we refer to as LRs, and which represent 44% of all allergic subjects, and a second subgroup with total IgE values above those of the donors (HRs), who would therefore be the only subjects that would be identified by individual serum IgE study.

BackgroundDespite the high incidence and mortality of ST-segment elevation myocardial infarction (STEMI) among the very elderly, risk markers for this condition remain poorly defined. This study was designed to identify independent markers of STEMI among individuals carefully selected for being healthy or manifesting STEMI in < 24 h.MethodsWe enrolled participants aged 80 years or older of whom 50 were STEMI patients and 207 had never manifested cardiovascular diseases. Blood tests, medical and psychological evaluations were obtained at study admission. Odds Ratio (OR) and attributed risk (AR) were obtained by multivariate regression models using STEMI as dependent variable.ResultsLow glomerular filtration rate (GFR) [OR:4.41 (1.78–10.95); p = 0.001], reduced levels of HDL-C [OR:10.70 (3.88–29.46); p = 0.001], male gender [OR:12.08 (5.82–25.08); p = 0.001], moderate to severe depressive symptoms [OR:10.00 (2.82–35.50); p = 0.001], prior smoking [OR:2.00 (1.05–3.80); p = 0.034] and current smoking [OR:6.58 (1.99–21.70); p = 0.002] were significantly associated with STEMI. No association was found between STEMI and age, diabetes, hypertension, mild depressive symptoms, triglyceride or LDL-C.ConclusionsThis is the first case–control study carried out with very elderlies to assess STEMI risk. Our findings indicate that reduced HDL-C, GFR, male gender, smoking habits and moderate to severe depressive symptoms are markers of STEMI in this age group.General SignificanceIn Individuals aged 80 or more years, a greater attention must be paid to low HDL-C and GFR at the expense of conventional STEMI risk factors for younger adults such as diabetes mellitus, hypertension and high LDL-C or triglyceride.

Objective. To evaluate the effectiveness of a distance-learning course in the training of pharmacists in drug dispensing. Methods. This interventional study was carried out with community pharmacists throughout Brazil. A 12-week distance-learning course was conducted. Pharmacists' knowledge and performance during drug dispensing were evaluated before and after completion of the course. Results. Community pharmacists' knowledge of drug dispensing was greater after completing the distance-learning course than before (mean55.7, SD52.8 points vs mean53.8, SD51.9 points, respectively). However, no improvement was observed in pharmacists' drug-dispensing practice. Almost all participants (96.5%) considered that they were more qualified to perform the drug dispensing after the course. There were 1492 pharmacists enrolled in the course, of which 1061 were included in the study, and 472 completed the surveys. Only pharmacists from Ribeirão Preto, Brazil, were invited to take the mytery shopper evaluation (n526). However, 10 pharmacists completed the mystery shopper encounter. Conclusion. A distance-learning course was effective in improving community pharmacists' knowledge. However, the course did not seem to improve overall drug-dispensing performance. Additional educational strategies should be adopted in future studies to address this gap.

This study investigated the potential effects of flunitrazepam (known as "date rape drug") on the developmental cycle of Chrysomya megacephala, an important forensic species, and their possible implications for the calculation of the PMI. A 1050 C. megacephala eggs were divided into five groups with seven replications each. The eggs were placed on artificial diet prepared with four drug concentrations of flunitrazepam (4, 8, 16, and 32 ng/g), besides the control group (prepared with water). Were evaluated the potential effects on development time, weight gain, and mortality during the cycles. The drug had no significant effect on development time or mortality although it did affect the weight of the pupae and adults (Kruskal-Wallis, p < 0.05). The result can be deduced that the determination of the postmortem interval is not affected.