Preparation of protected peptidyl thioester intermediates for native chemical ligation by Nα‐9‐fluorenylmethoxycarbonyl (Fmoc) chemistry: considerations of side‐chain and backbone anchoring strategies,and compatible protection for N‐terminal cysteine*,†

Abstract: Native chemical ligation has proven to be a powerful method for the synthesis of small proteins and the semisynthesis of larger ones. The essential synthetic intermediates, which are C‐terminal peptide thioesters, cannot survive the repetitive piperidine deprotection steps of N^α‐9‐fluorenylmethoxycarbonyl (Fmoc) chemistry. Therefore, peptide scientists who prefer to not use N^α‐t‐butyloxycarbonyl (Boc) chemistry need to adopt more esoteric strategies and tactics in order to integrate ligation approaches with Fmoc chemistry. In the present work, side‐chain and backbone anchoring strategies have been used to prepare the required suitably (partially) protected and/or activated peptide intermediates spanning the length of bovine pancreatic trypsin inhibitor (BPTI). Three separate strategies for managing the critical N‐terminal cysteine residue have been developed: (i) incorporation of N^α‐9‐fluorenylmethoxycarbonyl‐S‐(N‐methyl‐N‐phenylcarbamoyl)sulfenylcysteine [Fmoc‐Cys(Snm)‐OH], allowing creation of an otherwise fully protected resin‐bound intermediate with N‐terminal free Cys; (ii) incorporation of N^α‐9‐fluorenylmethoxycarbonyl‐S‐triphenylmethylcysteine [Fmoc‐Cys(Trt)‐OH], generating a stable Fmoc‐Cys(H)‐peptide upon acidolytic cleavage; and (iii) incorporation of N^α‐t‐butyloxycarbonyl‐S‐fluorenylmethylcysteine [Boc‐Cys(Fm)‐OH], generating a stable H‐Cys(Fm)‐peptide upon cleavage. In separate stages of these strategies, thioesters are established at the C‐termini by selective deprotection and coupling steps carried out while peptides remain bound to the supports. Pilot native chemical ligations were pursued directly on‐resin, as well as in solution after cleavage/purification.     

留置超滑乳胶气囊导尿管并发症的原因分析及对策

目的探讨留置超滑乳胶气囊导尿管并发症的原因及对策。方法对586例留置超滑乳胶气囊导尿管患者进行观察,回顾分析。结果留置超滑导尿管并发症与导尿方法、规范操作、留置导尿管的时间及相关知识宣教有关。结论严格无菌操作,选择合适的导尿管、缩短留置尿管的时间是降低并发症的重要措施。     

上消化道出血相关因素分析及防护对策探讨

目的：分析上消化道出血相关因素，制定预防和护理对策。方法：对120例上消化道出血病人相关因素进行总结分析，提出对策。结果：本病相关因素最多的分别是发病原因系十二指肠溃疡和胃溃疡；有发病诱因，主要是饮食不当、饮酒、药物和劳累；中青年、农村和农民发生率各占72．5％、69．17％和57．50％；中度出血35．00％；出血发生24小时后就诊68．33％。结论：本病应从个人、家庭、社会和早期诊治四方面预防，并通过系统护理，促进疾病康复。     

A simple method for screening assessment of acute toxicity of chemicals

We proposed a simple method for screening assessment of acute oral and dermal toxicity using only three rats and mice of each sex at each dose level. Animals were first treated with chemicals at a dose of 2000 mg/kg and were carefully observed for compound-related morbidity and mortality. If none of the animals died, the following toxicity tests were suspended. If some of the animals died, toxicity tests at doses of 200 and 20 mg/kg were performed. The approximate LD₅₀ values calculated by this method showed little difference between two separate laboratories and were in good agreement with LD₅₀ values reported in the literature. Our toxicological data also showed that LD₅₀ values were about 2–2.5 times the MNLD (maximum non lethal dose) in acute oral and dermal toxicity. This meant that a chemical could be regarded as having an LD₅₀ of about 4000 mg/kg or higher when there was no mortality at the dose of 2000 mg/kg. A chemical with such low toxicity would not require further testing for lethal effects. Therefore, this simple method combining the fixed-dose procedure with the limit test is suitable for determination of approximate LD₅₀ values of chemicals and for screening for necessity for classical full LD₅₀ test using many animals.This work was supported by a grant from Ministry of Health and Welfare in Japan (No. 467 and 511)     

医学生"网络成瘾症"产生的原因和对策

文章针对目前医学生“网络成瘾症”的现状进行了分析,并指出了产生的原因和解决问题的办法,以求达到标本兼治。最后提出三点预防医学生“网络成瘾症”的对策：一是高校及其附属医院要为医学生营造宽松愉快的学习、生活环境;二是呼吁家长关注医学生身心发展的特殊规律,建立良好的家庭环境;三是建立和完善与网络社会相应的法律法规,规范医学生的网上行为。     

现代中医药发展战略思考

建国几十年来，由于党和政府的大力提倡和扶持，中医药得到了很大发展，但相对于西医的发展势头仍显不足。尤其是近10多年来，由于现代科技及现代管理学的有力推动，西医获得了突飞猛进的发展，然而，中医却由于种种原因发展相对缓慢。在这各行各业竞相发展的现代社会，中医要生存，就蓝须发展，中医要发展，就妊须总揽全局，从战略高度克服中医药发展的各种不利因素，充分发挥各方面的有利条件。     

浙江省某乡村慢性肾脏病的流行病学研究

目的 研究我国南方某农村人群中慢性肾脏病（CKD）的患病率及相关因素。方法 对浙江省东阳市某乡村18岁以上的常住居民慢性肾脏病情况及相关因素进行调查和检测。结果 获得完整资料的居民占该村18岁以上自然人口的76．2％。将该村自然人口按年龄性别构成校正后，白蛋白尿发生率为10．4％；肾小球滤过率〈60ml·min^-1·（1．73m^2）^-1的发生率为3．0％；血尿发生率为1．4％。本研究中40岁以上调查对象与北京市某社区及NHANESⅢ中40岁以上调查对象相比，高血压及糖尿病的患病率较低，白蛋白尿和肾功能下降的发生率介于2者之间。多因素Logistic回归提示，年龄增加10岁、糖代谢异常及收缩压水平与白蛋白尿的发生独立相关；女性、年龄增加10岁、高尿酸血症与肾功能下降独立相关；年龄增加10岁及吸烟与血尿独立相关。结论 在该经济快速发展的南方乡村，CKD的疾病谱和相关因素已经与我国大城市和发达国家类似。此外，该人群可能另有导致CKD高发的特殊原因，需进一步研究。     

单亲大学生心理健康状况及心理问题的教育对策研究

目的针对单亲大学生心理健康问题提供有效的教育对策．方法针对大学新生开展16PF调查并发现单亲大学生的心理问题。结果本次测查共测量被试8302人，删除部分无效量表．实际有效数据为7742人，问卷有效率为93．27％．以一般情况问卷中“是否是单亲家庭子女”回答“是”的．作为单亲大学生的认定标准，检出单亲家庭子女555人，占总人数的7．17%，其中男生占40．0％．女生60．0％．17．5％的单亲出现各种心理问题．调查表明．单亲家庭子女与非单亲家庭子女相比，在乐群性和怀疑性两个因子有显着区别。事实上也表现为与正常大学生心理健康状况的显着差异。结论单亲大学生心理问题表现为：自卑心理、怀旧心理、逆反心理、猜疑心理等等。教育对策：加强社会教育系统、学校教育系统、家庭教育对单亲大学生心理的干预与影响，同时．单亲大学生遗要加强心理健康的自我教育．以多元系统帮助他们形成健全人格。     

江门市区实施乙型肝炎免疫策略16年的效果评价

目的：对江门市区1986年1月1日起全面实施的乙型肝炎(乙肝)免疫策略进行效果评价。方法：运用血清流行病学调查和疫情资料对比分析，比较实施“免疫策略”前后江门市区0～15岁人群乙肝发病率和感染率变化情况和乙肝表面抗体(抗-HBs)增长情况。结果：实施“免疫策略”后16年，0～15人群的乙肝发病率由1985年的367．39／10万，降至2001年的21．10／10万，下降94．26％；HBsAg阳性率由1985年的9．17％降至2002年的0．6％，下降93．46％；乙肝病毒总感染率由1985年的35．82％降至2002年的1．20％，下降96．65％；抗-HBs阳性率由1985年的24．64％上升到2002年的93．00％，上升2．77倍。结论：江门市区现行乙肝免疫策略效果显，能有效预防和控制地区性大面积的乙肝流行与传播。经过一代人的努力，能彻底改变人口乙肝高发病率和HBV高感染率及高携带率的状况。     

Diagnostic Validity of Fecal Occult Blood Tests for Detecting Gastroenterological Cancers

In order to estimate the diagnostic validity of chemical fecal occult blood tests, i.e. orthotolidine (Shionogi A) and guajac (Shionogi B) slides for detecting cancers of the esophagus, stomach and colorectum, the authors followed up all the examinees (n=3,449) of comprehensive medical check-ups at the Center for Adult Diseases, Osaka, by means of record linkage to the Osaka Cancer Registry's files. Then, diagnostic validity was calculated based on the results of two years' follow-up. Sensitivity for the respective cancers was 20.0%, 11.8% and 62.5% for Shionogi A, and 20.0%, 5.9% and 43.8% for Shionogi B slides. Likelihood ratio for the respective cancers was 1.4, 0.8 and 4.5 for Shionogi A, and 3.3, 1.0 and 7.5 for Shionogi B. Specificity was analogous among the three cancer sites, being 86% for Shionogi A and 94% for Shionogi B. These results suggest that the diagnostic validity of chemical occult blood tests for detecting cancers of the esophagus and the stomach is very poor, and therefore imply that close examinations of these sites for screening positives is unnecessary in mass screenings for colorectal cancer.