Yohimbine Depresses Excitatory Transmission in BNST and Impairs Extinction of Cocaine Place Preference Through Orexin-Dependent,Norepinephrine-Independent Processes

The alpha2 adrenergic receptor (α₂-AR) antagonist yohimbine is a widely used tool for the study of anxiogenesis and stress-induced drug-seeking behavior. We previously demonstrated that yohimbine paradoxically depresses excitatory transmission in the bed nucleus of the stria terminalis (BNST), a region critical to the integration of stress and reward pathways, and produces an impairment of extinction of cocaine-conditioned place preference (cocaine-CPP) independent of α₂-AR signaling. Recent studies show yohimbine-induced drug-seeking behavior is attenuated by orexin receptor 1 (OX₁R) antagonists. Moreover, yohimbine-induced cocaine-seeking behavior is BNST-dependent. Here, we investigated yohimbine-orexin interactions. Our results demonstrate yohimbine-induced depression of excitatory transmission in the BNST is unaffected by alpha1-AR and corticotropin-releasing factor receptor-1 (CRFR₁) antagonists, but is (1) blocked by OxR antagonists and (2) absent in brain slices from orexin knockout mice. Although the actions of yohimbine were not mimicked by the norepinephrine transporter blocker reboxetine, they were by exogenously applied orexin A. We find that, as with yohimbine, orexin A depression of excitatory transmission in BNST is OX₁R–dependent. Finally, we find these ex vivo effects are paralleled in vivo, as yohimbine-induced impairment of cocaine-CPP extinction is blocked by a systemically administered OX₁R antagonist. These data highlight a new mechanism for orexin on excitatory anxiety circuits and demonstrate that some of the actions of yohimbine may be directly dependent upon orexin signaling and independent of norepinephrine and CRF in the BNST.     

Changes of gastric mucosal architecture during long-term omeprazole therapy: results of a randomized clinical trial

Background The impact of long‐term acid suppression on the gastric mucosa remains controversial. Aim To report further observations on an established cohort of patients with gastro‐oesophageal reflux disease, after 7 years of follow‐up. Methods Of the original cohort randomized to either antireflux surgery or omeprazole, 117 and 98 patients remained in the medical and surgical arms, respectively. Gastric biopsies were taken at baseline and throughout the study. Results Fifty‐three antireflux surgery and 39 omeprazole‐treated patients had Helicobacter pylori infection at randomization. Eighty‐three omeprazole‐treated and 60 antireflux surgery patients remained H. pylori negative over the 7 years, and no change was observed in mucosal morphology except for a change in endocrine cell population (linear and diffuse hyperplasia, P = 0.03). During the 7‐year study many patients, who were initially H. pylori infected, had the infection eradicated leaving only 13 omeprazole and 12 antireflux surgery patients still infected. In these patients, omeprazole induced a deterioration of the mucosal inflammation scores (P = 0.01) with a numerical increase of glandular atrophy. Conclusions Long‐term omeprazole therapy does not alter the exocrine oxyntic mucosal morphology in H. pylori‐negative patients, but mucosal endocrine cells appear to be under proliferative stimulation; in H. pylori‐positive patients there are changes in mucosal inflammation and atrophy.     

Clinical trial design in adult reflux disease: a methodological workshop

Background  The development of well-tolerated acid suppressant drugs has stimulated substantial growth in the number of trials assessing therapy options for gastro-oesophageal reflux disease (GERD).
Aim  To develop consensus statements to inform clinical trial design in adult patients with GERD.
Methods  Draft statements were developed employing a systematic literature review. A modified Delphi process including three rounds of voting was used to reach consensus. Between voting, statements were revised based on feedback from the Working Group and additional literature reviews. The final vote was at a face-to-face meeting that included discussion time. Voting was conducted using a six-point scale.
Results  At the last vote, 93% of the final 102 statements achieved consensus (defined a priori as being supported by ≥75% of the votes). The Working Group strongly supported the development of validated patient-reported outcome instruments. Symptom assessments carried out by the investigator were considered unacceptable. There was agreement that exclusion from clinical trials should be minimized to improve generalizability, that prospective evaluation ideally requires electronic timed/dated methods and that endoscopists should be blinded to patient symptom status.
Conclusions  Implementation of the consensus statements will improve the quality and comparability of trials, and make them compatible with regulatory requirements.     

N－甲基－N－（α－取代萘甲基）取代苄胺类化合物的合成及抗真菌活性

报道２５个Ｎ－甲基－Ｎ－（α－取代萘甲基）取代苄胺类化合物的合成及抗真菌活性。抑菌测试结果表明，目标化合物对于８种试验菌种均有不同程度的抑菌活性，化合物６，７，８，１０，１１和２１等活性为ｎａｆｔｉｆｉｎｅ的４～２０倍，化合物８，１０，１１和２１等活性为ｂｕｔｅｎａｆｉｎｅ的２～１０倍，化合物８，９，１０，１１和２１等对Ｓｐｏｒｏｔｒｉｃｈｕｍｓｃｈｅｎｃｋｉｉ及Ａｓｐｅｒｇｉｌｌｕｓｆｕｍｉｇａｔｕｓ的活性为ｃｌｏｔｒｉｍａｚｏｌｅ的８～１５倍，化合物７，８，９和２１等对Ｃｒｙｐｔｏｃｃｏｃｕｓｎｅｏｆｏｒｍａｎｓ亦表现出较高活性，ＭＩＣ为０．３１～１．２５μｇ·ｍｌ－１。     

用气相色谱研究抗氧化剂对膜脂肪酸的保护作用

本文应用气相色谱技术直接测定三种生物膜(人红细胞膜,人血小板膜和鼠肝线粒体膜)多不饱和脂肪酸的含量变化,检测脂质过氧化程度。实验证实几种多羟酚类化合物(儿茶精,阿魏酸钠和没食子酸及其衍生物)不同程度地抑制(OH)诱导的脂质过氧化反应,并呈量效和构效关系。这类抗氧化剂对保护生物膜的结构与功能是有益的。     

关于全科医生若干问题的答复

本对医学院校学生就全科医生有关问题给于相应的答复，其中还包括自１９９７年以来由美国全科医学会举办的学生代表大会上所提出的一些问题，例如：什么是全科医生？全科医生的行业范围是什么？全科医生的工作，生活及收入情况如何等等问题。（Ａｍ．Ｆａｍ．Ｐｈｙｓｉｃｉａｎ１９９０．６０：１６７－１７４）。