Anaesthetic Impairment of Immune Function Is Mediated via GABAA Receptors

GABA(A) receptors are members of the Cys-loop family of neurotransmitter receptors, proteins which are responsible for fast synaptic transmission, and are the site of action of wide range of drugs. Recent work has shown that Cys-loop receptors are present on immune cells, but their physiological roles and the effects of drugs that modify their function in the innate immune system are currently unclear. We are interested in how and why anaesthetics increase infections in intensive care patients; a serious problem as more than 50% of patients with severe sepsis will die. As many anaesthetics act via GABA(A) receptors, the aim of this study was to determine if these receptors are present on immune cells, and could play a role in immunocompromising patients.We demonstrate, using RT-PCR, that monocytes express GABA(A) receptors constructed of α1, α4, β2, γ1 and/or δ subunits. Whole cell patch clamp electrophysiological studies show that GABA can activate these receptors, resulting in the opening of a chloride-selective channel; activation is inhibited by the GABA(A) receptor antagonists bicuculline and picrotoxin, but not enhanced by the positive modulator diazepam. The anaesthetic drugs propofol and thiopental, which can act via GABA(A) receptors, impaired monocyte function in classic immunological chemotaxis and phagocytosis assays, an effect reversed by bicuculline and picrotoxin.Our results show that functional GABA(A) receptors are present on monocytes with properties similar to CNS GABA(A) receptors. The functional data provide a possible explanation as to why chronic propofol and thiopental administration can increase the risk of infection in critically ill patients: their action on GABA(A) receptors inhibits normal monocyte behaviour. The data also suggest a potential solution: monocyte GABA(A) receptors are insensitive to diazepam, thus the use of benzodiazepines as an alternative anesthetising agent may be advantageous where infection is a life threatening problem

Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects.

BACKGROUND: The long-term effects of sibutramine treatment on the rates of cardiovascular events and cardiovascular death among subjects at high cardiovascular risk have not been established. METHODS: We enrolled in our study 10,744 overweight or obese subjects, 55 years of age or older, with preexisting cardiovascular disease, type 2 diabetes mellitus, or both to assess the cardiovascular consequences of weight management with and without sibutramine in subjects at high risk for cardiovascular events. All the subjects received sibutramine in addition to participating in a weight-management program during a 6-week, single-blind, lead-in period, after which 9804 subjects underwent random assignment in a double-blind fashion to sibutramine (4906 subjects) or placebo (4898 subjects). The primary end point was the time from randomization to the first occurrence of a primary outcome event (nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death). RESULTS: The mean duration of treatment was 3.4 years. The mean weight loss during the lead-in period was 2.6 kg; after randomization, the subjects in the sibutramine group achieved and maintained further weight reduction (mean, 1.7 kg). The mean blood pressure decreased in both groups, with greater reductions in the placebo group than in the sibutramine group (mean difference, 1.2/1.4 mm Hg). The risk of a primary outcome event was 11.4% in the sibutramine group as compared with 10.0% in the placebo group (hazard ratio, 1.16; 95% confidence interval [CI], 1.03 to 1.31; P=0.02). The rates of nonfatal myocardial infarction and nonfatal stroke were 4.1% and 2.6% in the sibutramine group and 3.2% and 1.9% in the placebo group, respectively (hazard ratio for nonfatal myocardial infarction, 1.28; 95% CI, 1.04 to 1.57; P=0.02; hazard ratio for nonfatal stroke, 1.36; 95% CI, 1.04 to 1.77; P=0.03). The rates of cardiovascular death and death from any cause were not increased. CONCLUSIONS: Subjects with preexisting cardiovascular conditions who were receiving long-term sibutramine treatment had an increased risk of nonfatal myocardial infarction and nonfatal stroke but not of cardiovascular death or death from any cause. (Funded by Abbott; ClinicalTrials.gov number, NCT00234832.

Economic evaluation of ezetimibe combined with simvastatin for the treatment of primary hypercholesterolaemia

Vascular Biology and Interventio

Criando Caim e Abel: pensando a prevenção da infração juvenil Raising Caim and Abel: thinking on juvenile delinquency prevention

Este artigo é parte de uma pesquisa que envolveu adolescentes infratores e seus irmãos não infratores, realizada nas cidades do Rio de Janeiro e Recife. O principal objetivo foi o de conhecer os motivos que levam jovens a trilhar caminhos distintos, visando à prevenção da delinqüência juvenil. Foram incluídos casos de homicídio, assalto à mão armada, lesão corporal, estupro e atentado violento ao pudor e tráfico de drogas. A técnica de história de vida foi usada em entrevistas semi-estruturadas que foram aplicadas a 61 infratores e 31 não infratores. Nelas, buscou-se conhecer a sua realidade familiar, comunitária e social. A técnica de análise de conteúdo foi utilizada nas entrevistas. Foi feita ainda uma abordagem quantitativa dos dados (estudo de concordância e de associação de variáveis) com o objetivo de identificar os fatores predisponentes à infração. No presente trabalho apresenta-se um modelo teórico explicativo da gênese da delinqüência juvenil e suas formas de prevenção; uma síntese dos achados qualitativos e quantitativos da pesquisa; e um ensaio de proposta para identificação dos fatores envolvidos na rede causal da infração cometida por adolescentes.<br>This article is part of a research with juvenile delinquents and its siblings non delinquents. It was realized in the cities of Rio de Janeiro and Recife. It has the objective of studying the reasons that take young people to choose different roads, seeking the prevention of the juvenile delinquency. Cases of homicide, armed robbery, assault, rape and indecent act using force and drug traffic were included. The technique of life history was used in semi-structured interviews that were applied to 61 offenders and 31 non offenders. It stressed themes like family, community and social reality. The technique of content analysis was used in the interviews. It was still made a quantitative analysis of the data (agreement study and of association of variables) with the objective of identifying the factors leading to the infraction. This article still presents an explanatory theoretical model of the genesis of juvenile delinquency and its prevention; a synthesis of the qualitative and quantitative results; and an attempt to identify which factors are involved in juvenile delinquency