药物的聚乙二醇修饰研究进展

目的 介绍了药物聚乙二醇技术及其在药物研究中的应用最新进展。方法 以国外大量有代表性的献为基础，简要论述了聚乙二醇的生理化学特性、药物的聚乙二醇修饰的优势、修饰技术及其在药物研究中的应用和存在的问题，并评述其应用前景。结果 药物的聚乙二醇修饰技术改变了药物的分子结构，从而改进了药物动力学和药效学的性质，增加了注射药物的临床应用范围和疗效。结论 聚乙二醇修饰技术成功应用于蛋白质药物、有机小分子的前体药物和脂质体药物的研究，显示了药物的聚乙二醇修饰技术良好的应用前景。     

人甲状旁腺素1-34及其聚乙二醇修饰物对鸡血钙含量的影响

目的：通过观察人甲状旁腺素(hPTH1-34)及其聚乙二醇修饰物对鸡血钙含量的影响判断它们的体内活性。方法：12日龄的小鸡分别翼静脉注射赋形剂，hPTH1-34，Cys(mPEG5000-MAL)-hPTH1-34和hPTH1-34-Cys(mPEG5000-MAL)-NH2。60min和120min后翼静脉采血，分离血清并测定钙含量。结果：给药后60min，hPTHI1-34，Cys(mPEG5000-MAL)hPTH1-34和hPTH1-34-Cys(mPEG5000-MAL)-NH2组静脉血清钙含量均明显升高；120min后，Cys(mPEG5000-MAL)-hPTH1-34组血清钙含量仍维持升高水平，而hPTH1-34和hPTH1-34-Cys(mPEG5000-MAL)-NH2组血清钙含量则明显回落。结论：合成人甲状旁腺素(hPTH1-34)及其聚乙二醇修饰物可以明显升高小鸡的血清钙水平；N端聚乙二醇修饰的hPTH1-34维持血钙升高的时间较长。     

聚乙二醇修饰的多肽-阿霉素偶联物的合成及其性能

目的 合成聚乙二醇(PEG)修饰的多肽-阿霉素(DOX)偶联物,并评价其性能.方法 以异官能团双取代的PEG衍生物为交联剂,将转铁蛋白受体(TfR)特异性结合多肽类似物与DOX偶联,合成一种PEG修饰的多肽-阿霉素偶联物,MALDI-TOFMS予以表征.通过考察该偶联物的体外血清稳定性、体外HepG2肝癌细胞增殖抑制活...     

甲氧基聚乙二醇修饰几种红细胞稀有血型抗原的初步研究

目的：研究用甲氧基聚乙二醇(mmthoxy polyethylene glycol，mPEG)修饰红细胞稀有血型抗原，为制备通用型血寻找可能的途径。方法：用3种具有不同瑞基的mPEG修饰红细胞，观察其对红细胞表面4种稀有血型抗原的修饰效果及对红细胞结构、功能和存活期的影响。结果：实验表明，在1．0mmol／L时mPEG-BTC(苯并三唑碳酸酯端基PEG)就可以使红细胞表面Jk^a，Jk^b，k和P1抗原性消失，而对红细胞形态、渗透脆性、自身溶血、乙酰胆碱酯酶、胆固醇、ATP、2，3-DPG含量、变形性以及存活期无影响，其他2种mPEG对红细胞修饰效果不好。结论：mPEG-BTC(可有效遮蔽红细胞表面的稀有血型抗原，对其结构、功能及存活期无影响，本实验为mPEG包裹法制备通用型血提供了有力的实验证据。     

聚乙二醇化蛋白类药物的药代动力学

聚乙二醇化蛋白质药物的研究开发是改善蛋白药物药代动力学、药效学、毒性和安全性的重要研究领域。本文通过文献资料分析聚乙二醇和聚乙二醇-蛋白质类药物与药代动力学(包括分布、代谢、消除)的关系,认识聚乙二醇化药物的药代动力学对聚乙二醇化蛋白质药物的有效性、毒性、安全性的影响。本文利用聚乙二醇化集落刺激因子长效制剂在比格犬的药代动力学与药效学和聚乙二醇化重组集成干扰素变异体在猕猴的药代动力学研究结果。     

聚乙二醇修饰对尿激酶原性质的影响

为了延长尿激酶原的半衰期，采用聚乙二醇５０００（ＰＥＧ５０００）对该酶进行了修饰，结果表明，尿激酶原经ＰＥＧ修饰后，在兔体内的半衰期延长了９￣１３倍，同时酶活性也有损失，溶酰胺活性保持６２％，溶纤活性保持３．８％￣１０％。     

EBOV三聚体糖蛋白在新型糖基工程酵母中的表达与纯化

目的 用新型糖基工程酵母表达并纯化得到具有类似哺乳动物细胞糖基化修饰的埃博拉病毒三聚体糖蛋白(EBOV-GP),为其亚单位疫苗研究提供基础.方法 人工合成EBOV-GP基因,将编码全长EBOV-GP基因和编码缺失黏蛋白样域(MLD)与穿膜区的EBOV-GPΔMLDΔTM基因分别克隆到pPICZ-αA载体上,电转化糖基工程酵母,与在HEK-293T细胞中表达的EBOV-GP进行比较,利用PNGaseF和EndoH酶切分析其糖基化修饰,利用亲和层析与离子交换层析纯化目的蛋白,蛋白质N端测序分析其在蛋白翻译修饰过程中是否正确切除了信号肽,同时利用凝胶柱分析是否能形成三聚体结构.结果 PNGaseF酶切结果显示,用糖基工程酵母和HEK-293T细胞表达的EBOV-GP糖蛋白相对分子质量大小与N-糖基化程度均一致,EndoH酶切显示EBOV-GPΔMLDΔTM的N-糖基化修饰是非高甘露糖形式的复杂型糖基化修饰;经三步纯化得到的目的蛋白,N端测序显示为GP蛋白成熟肽序列,其自身信号肽被正确切除;凝胶柱分析显示纯化得到的目的蛋白以三聚体形式存在.结论 用糖基工程酵母表达制备了具有复杂型糖基化修饰的EBOV-GP.     

新型HIV-1 gp41融合抑制剂CP32M的构效关系研究

目的研究新型融合多肽CP32M中VEWNEMT序列的长短、残基的极性及其他部位残基的极性对其抑制gp41融合活性的影响。方法在多肽CP32M的基础上,通过对前7个氨基酸序列进行截取、部分替换、全部替换及改变其他位置氨基酸残基的极性设计合成系列多肽,测定多肽抑制HIV-1融合活性。应用圆二色谱、分子排阻色谱测定多肽与N36的结合功能。结果截取、替换氨基酸后的肽抑制gp41融合的活性都不同程度降低,与N36结合形成六束螺旋的能力减弱。在CP32M中部及C端i与i+4位置引入Lys增加Glu-Lys离子对作用后,肽活性降低。用C34的C端氨基酸序列NEKDLLE及可与gp120结合的序列RINNIPWSEAM置换QIWNNMT后,多肽仍有很高活性。结论片段VEWNEMT是关键片段,其中VE及MT是关键功能氨基酸。其他片段替代该片段后仍有较强活性,也与N36形成螺旋结构,提示该片段含有共性结合区。     

新型HIV-1 gp41融合抑制剂CP32M的构效关系研究

目的研究新型融合多肽CP32M中VEWNEMT序列的长短、残基的极性及其他部位残基的极性对其抑制gp41融合活性的影响。方法在多肽CP32M的基础上,通过对前7个氨基酸序列进行截取、部分替换、全部替换及改变其他位置氨基酸残基的极性设计合成系列多肽,测定多肽抑制HIV-1融合活性。应用圆二色谱、分子排阻色谱测定多肽与N36的结合功能。结果截取、替换氨基酸后的肽抑制gp41融合的活性都不同程度降低,与N36结合形成六束螺旋的能力减弱。在CP32M中部及C端i与i＋4位置引入Lys增加Glu-Lys离子对作用后,肽活性降低。用C34的C端氨基酸序列NEKDLLE及可与gp120结合的序列RINNIPWSEAM置换QIWNNMT后,多肽仍有很高活性。结论片段VEWNEMT是关键片段,其中VE及MT是关键功能氨基酸。其他片段替代该片段后仍有较强活性,也与N36形成螺旋结构,提示该片段含有共性结合区。     

单甲氧基聚乙二醇-醛修饰超氧化物歧化酶的研究

目的考察使用单甲氧基聚乙二醇．醛修饰超氧化物歧化酶的可行性。方法单甲氧基聚乙二醇一醛在弱酸性环境下（pH5-3）修饰超氧化物歧化酶生成schiff碱,再于同样环境下使用氰基硼氢化钠还原schiff碱生成稳定的仲胺结构,利用SDS—PAGE电泳对反应产物进行分子量鉴定。结果单甲氧基聚乙二醇．醛可以成功修饰超氧化物歧化酶,耦联条件温和。结论含醛基的化合物可以有效修饰蛋白质的氨基,建立了单甲氧基聚乙二醇．醛修饰超氧化物歧化酶的工艺。     

大鼠深静脉血栓形成模型建立及观察

目的建立大鼠深静脉血栓形成（DVT）模型,观察实验大鼠术前及术后不同时间凝血酶原时间、纤维蛋白原含量、D-二聚体含量及血栓长度的变化情况。 方法将30只SD大鼠用结扎阻断下腔静脉及其分支,并用微血管夹钳夹损伤静脉壁的方法诱导深静脉血栓形成。于术前第1天及术后第1、4、7、10、14、21天采静脉血检测纤维蛋白原含量、D-二聚体含量及凝血酶原时间,并行血管造影观察血栓及血管再通情况。 结果共23只大鼠深静脉血栓模型制作成功,功率76.67%（23/30）。纤维蛋白原含量、凝血酶原时间及D-二聚体含量在术前与术后之间的差异有统计学意义,但术后不同时间之间差异无统计学意义;术后血栓长度在不同时间的差异均有统计学意义。 结论凝血酶原时间、纤维蛋白原及D-二聚体可作为是否有血栓形成的重要参考指标,但在评价病情进展及严重程度方面价值有限;血栓长度随时间先增长,后又溶解,直至消失。     

Population crises and population cycles

To prevent a population irretrievably depleting its resources, mammals have evolved a behavioural and physiological response to population crisis. When a mammalian population becomes dangerously dense, there is a reversal of behaviour. Co‐operation and parental behaviour are replaced by competition, dominance and aggressive violence, leading to high mortality, especially of females and young, and a reduced population. The stress of overpopulation and the resulting violence impairs both the immune and the reproductive systems. Hence epidemics complete the crash of the population, and reproduction is slowed for three or four generations, giving the resources ample time to recover. In some mammal species, crisis and crisis response recur regularly, leading to cycles of population growth and relapse, oscillating about a fixed mean.

Population crisis response and population cycles have been equally prominent in the history of human societies. But in man successive advances in food production have made possible growing populations, though with every such advance population soon outgrew resources again. Hence human cycles have been superimposed on a rising curve, producing a saw‐tooth graph. Because advances in food production amounted to sudden disturbances in the relations between human populations and their environments, the crisis response in man has failed to avert famine and resource damage. In the large human societies evolved since the coming of settled agriculture and cities, the basic effects of violence, epidemics, famine and resource damage have been mediated by such specifically human disasters as inflation, unemployment, and political tyranny.

An account of past crises, periods of relative relief from population pressure, and resulting cycles, is given for a number of regions: China, North Africa and Western Asia, the northern Mediterranean, and north‐western Europe. The paper ends with an account of the present world‐wide population crisis, and the solution made possible by Malthus's discovery that, unlike animals, we can choose to check population growth by reducing the birth‐rate, instead of raising the death‐rate, as in other mammals, by the population crisis response.     

一起暴发麻疹的临床特征和流行病学特征分析及防控处理

 目的 分析某学院15例聚集麻疹患者发病的流行病学和临床特征及防控处理,有利于防止麻疹暴发。方法 对15例麻疹患者聚集发病的流行病学资料和临床资料进行调查分析、采样,对聚集发病原因、流行病学特点、临床特点及采取的防控措施进行分析。结果 15例麻疹患者春季聚集发病,临床特征为发热、皮疹、咽痛、咳嗽、流涕、鼻塞,口腔黏膜斑、发热、皮疹,合并肺部感染及结膜炎1例,心肌炎1例,麻疹病毒核酸13例阳性。流行病学特征:首发病例发生于2015-04-01,疫情高峰在4月13日至4月17日,4月17日结束,二代感染病例集中于该病的最长潜伏期内。有明确的流行病学接触史11例,占73%,主要集中在同一层楼的3个宿舍,呈现聚集性分布。均为男性学员,年龄19～25岁。结论 麻疹暴发与季节、疫苗接种、发病年龄、防控措施是否及时实施有关。建议各大专院校及居住比较密集单位的临床医师注意春季麻疹散发病例,立即隔离麻疹患者,密切接触者及时进行预防接种,防止麻疹暴发。     

Working together for health and human rights*

The right to a standard of living adequate for health and well‐being is being denied to vast numbers of people all over the world through increasing disparities in income and in wealth. In the name of economic development, a number of international and national policies have increased the grossly uneven distribution of income, with ever‐growing numbers of people living in poverty as well as in increasing depths of poverty. Globalization, crippling levels of external debt, and the ‘structural adjustment’ policies of international agencies have expanded the numbers and the suffering of people living in poverty and have resulted in the neglect of government‐funded social programs, of regulations protecting the environment, and of human development. Access to medical care, an essential element in the protection of health, is difficult for many, including the 44 million people in the United States who lack insurance coverage for the cost of medical care services. Working together for health and human rights also requires promotion of the right to peace. The right to life and health is threatened not only by the existence and active deployment of weapons of mass destruction, including nuclear, chemical and biological weapons and anti‐personnel landmines, but also other weapons. The twentieth century has been the bloodiest in human history, with an estimated 250 wars, more than 110 million people killed, countless people wounded and at the least 50 million refugees. Health workers must work together with people in our communities for the promotion of health and human rights, which, in Sandwell and elsewhere, are inextricably intertwined.     

尾悬吊大鼠牙体、牙髓、牙周组织的变化

目的 探讨模拟失重务件下钙、磷的代谢变化及转化生长因子β1(TGF-β1)、c-fos及Ⅰ、Ⅳ型胶原蛋白在牙髓、牙周组织中的功能效应。方法 采用扫描电镜及能谱分析系统对模拟失重组、失重对抗组、正常对照组大鼠牙体、牙髓、牙周组织的Ca、P相对百分含量进行检测，同时用免疫组织化学方法对3组大鼠牙髓、牙周组织中的TGF-β1、c-fos及Ⅰ、Ⅳ型胶原蛋白的表达特征进行观察。结果 模拟失重大鼠的牙体组织Ca的相对百分含量明显下降，P稍升高；牙槽骨Ca、P的含量无显著差异。牙髓组织中TGF-β1、c-fos和胶原Ⅰ的表达均减少，胶原Ⅳ在毛细血管内的表达量增多；牙周组织中它们的含量变化不大。采用人工对抗措施后可部分恢复它们的表达量。结论 失重可能引起牙本质矿化不良，1．5G对抗措施可改善其对牙体组织矿物质代谢带来的不利影响。TGF-β1、c-fos、胶原Ⅰ分泌减少是导致矿化不良的一个重要原因。     

Image quality, lesion detection, and diagnostic efficacy in digital mammography: full-field digital mammography versus computed radiography-based mammography using digital storage phosphor plates

OBJECTIVE: To compare image quality, the lesion detection, and the diagnostic efficacy of full-field digital mammography (FFDM) and computed radiography-based mammography using digital storage phosphor plates (DSPM) in the evaluation of breast lesions. MATERIALS AND METHODS: In this prospective study, 150 patients with suspicious breast lesions underwent FFDM and DSPM. Nine aspects of image quality (brightness, contrast, sharpness, noise, artifacts, and the detection of anatomic structures, i.e., skin, retromamillary space, glandular tissue, and calcifications) were evaluated by five radiologists. In addition, the detection of breast lesions and the diagnostic efficacy, based on the BI-RADS classification, were evaluated with histologic and follow-up correlation. RESULTS: For contrast, sharpness, and the detection of all anatomic structures, FFDM was rated significantly better (p<0.05). Mass lesions were equally detected, whereas FFDM detected more lesions consisting of calcifications (85 versus 75). DSPM yielded two false-negative results. Both lesions were rated BI-RADS 4 with FFDM, but BI-RADS 2 with DSPM. Both were invasive carcinoma at histology. The sensitivity, specificity, PPV, NPV, and accuracy of FFDM were 1.0, 0.397, 0.636, 1.0, and 0.707, compared to 0.974, 0.397, 0.630, 0.935, and 0.693 of DSPM. CONCLUSION: Based on image quality parameters, FFDM is, in part, significantly better than DSPM. Furthermore, the detection of breast lesions with calcifications is favorable with FFDM. However, the diagnostic efficacy of FFDM and DSPM was equal. The interpretation of the false-negative results suggests that the perception and characterization of breast lesions is not defined solely by the digital mammography system but is strongly influenced by the radiologist, who is one of the determinants in the interpretation of breast imaging.     

大鼠肝肿瘤细胞灶性凋亡MRI表现

目的:建立大鼠肝肿瘤细胞凋亡模型并研究其磁共振成像表现.方法:选取45只肝肿瘤大鼠,随机分成放疗组,酒精注射组及对照组,每组15只,分1d、3d、7d共3个时间点观察;每组大鼠每个时间点均采集磁共振MRI、DWI、~1H-MRS图像,分析磁共振图像,并测量ADC值及~1H-MRS各代谢物波峰下面积,进行统计学处理;磁共振检查后取标本送病理学(HE,TUNEL,PCNA)及电镜检查;将病理学检查结果与磁共振图像对照分析.结果:①病理学检查结果证实放疗组肝肿瘤细胞发生凋亡;酒精注射组肝肿瘤细胞以发生坏死为主;②放疗组同未治疗组比较肿瘤体积减小,T_1 WI信号等低,T_2 WI信号稍减低,DWI信号下降,呈等高信号,内见条片状等低信号区,ADC值增加,Lip、Cho、Lae、Glx峰下降,Cr峰变化不大;③酒精治疗组体积缩小,病灶中央信号强度明显减低,旱条片状,T_1 WI等低信号,T_2 WI低信号;DWI信号不均匀片状减低,ADC值介于正常组织与残留肿瘤组织之间;Lip、Cho、Lac、Glx、Cr各峰明显下降.结论:大鼠肝肿瘤放疗可诱导细胞凋亡,凋亡后磁共振检查有特异性表现.特别是T_2WI、DWI、~1H-MRS,活体检测肿瘤细胞凋亡成为可能.     

烧伤患者外周血高密度脂蛋白变化的临床意义

目的探讨烧伤患者高密度脂蛋白的变化特点及其与感染并发症的关系。方法选取120例伤后24h内入院的18～59岁热力烧伤患者,其中轻中度、重度和特重度烧伤各40例,于入院时和伤后1、2、3、5、7、14、21d空腹采集外周血,检测甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、载脂蛋白A1(apoA1)、载脂蛋白B(apoB)水平,并监测感染并发症及预后情况。以40例健康体检者作为对照组。结果120例患者中有32例发生医院感染51例次,死亡6例,其中5例与感染有关。轻中度、重度和特重度烧伤患者的感染发生率分别为7·5%、20·0%和52·5%,三者比较差异显著(P<0·001)。TC、HDL、apoA1在伤后1d已明显降低(P<0·05),伤后5d降至最低水平,此三项指标的水平随伤情加重递减,其中以HDL降幅最大。与对照组比较,轻中度、重度和特重度组HDL平均降低33%、45%和70%。TG在伤后7d升至最高水平,其浓度随伤情加重递增,与对照组比较,轻中度、重度和特重度组TG平均升高30%、67%和153%。特重度组40例中有21例发生感染37例次,在入院时和伤后1d,感染者与非感染者血脂水平无显著差别,伤后2d感染者的TC、HDL、apoA1开始低于非感染者,直至伤后21d差别仍具有显著性(P<0·05)。伤后3～21d,感染者TG明显高于非感染者。结论烧伤患者TC、HDL、apoA1、LDL水平降低,TG水平升高,血脂异常程度与伤情及感染并发症有关。     

Neurografía de alta resolución del nervio peroneo en resonancia magnética 3T

Peroneal neuropathy is the most common mononeuropathy of the lower limbs. The causes of peroneal neuropathy include trauma, tumors of the nerve and nerve sheath, entrapment, and others like perineurioma, fibromatosis, lymphoma, and intraneural and externeural ganglia. The diagnosis is based on clinical manifestations and electrophysiological studies. Nowadays, however, magnetic resonance (MR) neurography is a complementary diagnostic technique that can help determine the location and cause of peroneal neuropathy. In this article, we describe the MR anatomy of the peroneal nerve, its relations, and the muscles it innervates. We also discuss the clinical and electrophysiological manifestations of peroneal neuropathy, describe the technical parameters used at our institution, and illustrate the MR appearance of various diseases that involve the peroneal nerve.     

Microbial forensics: the next forensic challenge

Pathogens and toxins can be converted to bioweapons and used to commit bioterrorism and biocrime. Because of the potential and relative ease of an attack using a bioweapon, forensic science needs to be prepared to assist in the investigation to bring perpetrators to justice and to deter future attacks. A new subfield of forensics—microbial forensics—has been created, which is focused on characterization of evidence from a bioterrorism act, biocrime, hoax, or an inadvertent release. Forensic microbiological investigations are essentially the same as any other forensic investigation regarding processing. They involve crime scene(s) investigation, chain of custody practices, evidence collection, handling and preservation, evidence shipping, analysis of evidence, interpretation of results, and court presentation. In addition to collecting and analyzing traditional forensic evidence, the forensic investigation will attempt to determine the etiology and identity of the causal agent, often in a similar fashion as in an epidemiologic investigation. However, for attribution, higher-resolution characterization is needed. The tools for attribution include genetic- and nongenetic-based assays and informatics to attempt to determine the unique source of a sample or at least eliminate some sources. In addition, chemical and physical assays may help determine the process used to prepare, store, or disseminate the bioweapon. An effective microbial forensics program will require development and/or validation of all aspects of the forensic investigative process, from sample collection to interpretation of results. Quality assurance (QA) and QC practices, comparable to those used by the forensic DNA science community, are being implemented. Lastly, partnerships with other laboratories will be requisite, because many of the necessary capabilities for analysis will not reside in the traditional forensic laboratory.