β-BLOCKERS and BLOOD SUGARS

Catecholamines mediate sympathetic activity throughout the body and, since carbohydrate metabolism is under sympathetic control they influence the availability of glucose for utilization as energy. They achieve this by modifying the response to a raised blood sugar by either suppressing insulin release, an a-receptor stimulant effect, or by promoting insulin release, probably a β₂ stimulant effect. When the blood sugar falls, catecholamines initiate metabolic processes which increase blood glucose and restore it to normal. This is also thought to be a β₂-receptor stimulant effect. It would therefore be expected that drugs which blocked β-adrenoreceptors would interfere with both the insulin release which occurs during hyperglycaemia and the glycogenosis and gluconeogenesis which occur in response to a fall in blood sugar. Both of these actions have been demonstrated in acute studies usually in volunteers. The clinical relevance of these effects remains to be determined though some guidelines can be suggested on the basis of data currently available, and are given at the end of the paper.     

Association of Long-Term Air Pollution with Prevalence and Incidence of Distal Sensorimotor Polyneuropathy: KORA F4/FF4 Study

Background: Air pollution contributes to type 2 diabetes and cardiovascular diseases, but its relevance for other complications of diabetes, in particular distal sensorimotor polyneuropathy (DSPN), is unclear. Recent studies have indicated that DSPN is also increasingly prevalent in obesity.Objectives: We aimed to assess associations of air pollutants with prevalent and incident DSPN in a population-based study of older individuals with high rates of type 2 diabetes and obesity.Methods: Cross-sectional analyses on prevalent DSPN were based on 1,075 individuals 62–81 years of age from the German Cooperative Health Research in the Region of Augsburg (KORA) F4 survey (2006–2008). Analyses on incident DSPN included 424 individuals without DSPN at baseline (KORA F4), of whom 188 had developed DSPN by the KORA FF4 survey (2013–2014). Associations of annual average air pollutant concentrations at participants’ residences with prevalent and incident DSPN were estimated using Poisson regression models with a robust error variance adjusting for multiple confounders.Results: Higher particle number concentrations (PNCs) were associated with higher prevalence [risk ratio (RR) per interquartile range (IQR) increase=1.10 (95% CI: 1.01, 1.20)] and incidence [1.11 (95% CI: 0.99, 1.24)] of DSPN. In subgroup analyses, particulate (PNC, PM10, PMcoarse, PM2.5, and PM2.5abs) and gaseous (NOx, NO2) pollutants were positively associated with prevalent DSPN in obese participants, whereas corresponding estimates for nonobese participants were close to the null [e.g., for an IQR increase in PNC, RR=1.17 (95% CI: 1.05, 1.31) vs. 1.06 (95% CI: 0.95, 1.19); pinteraction=0.22]. With the exception of PM2.5abs, corresponding associations with incident DSPN were positive in obese participants but null or inverse for nonobese participants, with pinteraction≤0.13 [e.g., for PNC, RR=1.28 (95% CI: 1.08, 1.51) vs. 1.03 (95% CI: 0.90, 1.18); pinteraction=0.03].Discussion: Both particulate and gaseous air pollutants were positively associated with prevalent and incident DSPN in obese individuals. Obesity and air pollution may have synergistic effects on the development of DSPN. https://doi.org/10.1289/EHP7311     

Cholelithiasis: a serious complication after total gastrectomy

To establish the incidence of cholelithiasis after total gastrectomy, patients operated on between 1979 and 1985 were reviewed. The study group consisted of 30 patients, all free of gallstones at the time of their gastrectomy. The median age of the patients was 56 years, the average follow-up 40 months. Cholelithiasis developed in 47 per cent of patients (14/30) and always within 2 years of total gastrectomy. The incidence of cholelithiasis was not related significantly to the sex or age of the patients. Morbidity from cholelithiasis was not negligible. Three of the fourteen patients presenting with gallstones required medical treatment in hospital and later came to cholecystectomy because of specific biliary symptoms. Cholelithiasis appears to be a significant complication after total gastrectomy. It may be related to the vagotomy which is performed at the time of gastrectomy.     

药物导致的QT间期延长

过去的十年，上市药物撤出市场或者应用受到限制的最常见原因是引起QT间期延长，并导致致命性的多形性室性心动过速或尖端扭转性室速。由于这种少见的毒性作用，有9种结构无关联的非心脏上市药物已撤出市场或应用受到严格的限制，它们是terfenadine（叔哌丁醇，抗组胺药），astemizole（阿斯咪唑，抗组胺药），grepafloxicin，terodiline（特罗地林，冠脉扩张药），droperidol（达哌啶醇，镇静药），lidoflazine（利多氟嗪，钙通道阻滞剂），sertindole（施立碟，平喘药），levomethadyl（美沙酮，镇痛剂）和cisapride（西沙比利，胃肠动力药）。通过汇总临床医生、电生理学家及遗传学家对先天性长QT综合征（以尖端扭转性室速为特征）研究的资料，我们可以了解药物导致心律失常的部分机制。相关的指南旨在预测某些新药是否具有导致尖端扭转性室速的风险，然而不论是对于个体患者还是整个患者人群，目前对于这种严重不良反应的预测是不完善的。因此，虽然临床医生、药品监管部门、药物开发者可能能够预测某种药物具有危险性，但他们并不能准确地评估和量化此种危险。本文总结了目前药物导致QT间期延长和尖端扭转性室速的分子和临床预测因子，     

Phenotypic debrisoquine 4-hydroxylase activity among extensive metabolizers is unrelated to genotype as determined by the Xba-I restriction fragment length polymorphism.

1. The major pathway for 4-hydroxylation of debrisoquine in man is polymorphic and under genetic control. More than 90% of subjects (extensive metabolizers, EMs) have active debrisoquine 4-hydroxylase (cytochrome P450IID6) while in the remainder (poor metabolizers, PMs), cytochrome P450IID6 activity is greatly impaired. 2. Within the EM group, cytochrome P450IID6-mediated metabolism of a range of substrates varies widely. Some of this intra-phenotype non-uniformity may be explained by the presence of two subsets of subjects with different genotypes (heterozygotes and homozygotes). 3. Cytochrome P450IID6 substrates have not differentiated between these two genotypes. However, a restriction fragment length polymorphism (RFLP) which identifies mutant alleles of cytochrome P450IID6 locus has been described and can definitively assign genotype in some heterozygous EM subjects. 4. In this study, we used RFLP analysis and encainide as a model substrate to determine if non-uniformity in cytochrome P450IID6 activity among EMs is related to genotype. We tested the hypothesis that heterozygotes exhibit intermediate metabolic activity and that homozygous dominants exhibit the highest activity. We proposed encainide as a useful substrate for this purpose since cytochrome P450IID6 catalyzes not only its biotransformation to O-desmethyl encainide (ODE) but also the subsequent metabolism of ODE to 3-methoxy-O-desmethyl encainide (MODE). 5. A single 50 mg oral dose of encainide was administered to 139 normal volunteers and 14 PMs were identified. Urinary ratios among encainide, ODE and MODE in the remaining 125 EM subjects revealed a wide range of cytochrome P450IID6 activity. However, Southern blotting of genomic DNA digested with XbaI identified obligate heterozygotes in both extremes of all ratio distributions.(ABSTRACT TRUNCATED AT 250 WORDS)     

An overview of contemporary approaches to antiarrhythmic therapy.

This review discusses the evolution in the approach to the therapy of cardiac arrhythmias that has occurred during the past 2 decades. The major changes have been driven by advances in understanding arrhythmia mechanisms, in bioengineering, and in clinical trials. It seems likely that progress in understanding the cellular and molecular basis of arrhythmias and their response to drug therapy may allow further identification of patient subsets in which specific therapies are indicated or contraindicated.