儿童接种乙肝疫苗后无(弱)应答影响因素的研究进展

乙型肝炎病毒(hepatitis B virus,HBV)感染严重威胁着当今世界人类的健康,在我国尤为突出.由于对乙肝疫苗(Hepatitis B Vaccine,HepB)接种的免疫应答率随着年龄的增长而呈逐渐下降趋势[1],故对新生儿及学龄前儿童进行HepB疫苗接种尤为重要.据统计,约5％～10％的健康人群在完成3针HepB接种后出现无应答(抗-HBs＜2.1MIU/ml)或弱应答者(抗-HBs＜10MIU/ml)[2].疫苗对无(弱)应答者可能不会产生保护作用,这给预防乙肝带来了新的挑战.对儿童这一特殊人群来说,机体抗体产生的多少受很多因素的影响,如遗传、机体免疫、疫苗问题、接种年龄和部位等多因素影响.本文就影响儿童HepB免疫应答因素的研究及其对策进行简要综述.     

自然人群接种乙肝疫苗免疫效果观察

为了探讨接种过乙肝疫苗后机体产生保护性抗体抗－HBs的情况，我们采用固相放射免疫（SPRIA）及酶联免疫（ELISA）两种方法分别为373例，446例全程接种过乙肝疫苗者进行抗－HBs的产生与时间关系的分析，现将结果报告如下。     

乙肝疫苗接种无应答者免疫因素的研究进展北大核心CSCD

接种乙型肝炎疫苗是预防乙型肝炎病毒感染的有效策略,但仍有5%~10%的接种者无应答,机制尚未明确。乙肝疫苗无应答受多种因素影响,主要有疫苗因素、机体自身特征及环境特征、免疫相关遗传因素及分子特征等方面,其中免疫相关遗传因素及分子特征对乙肝疫苗免疫应答起关键作用。本文主要对乙型肝炎病毒疫苗接种无应答者的免疫相关遗传因素及细胞分子特征的研究进展进行阐述,旨在为乙型肝炎病毒疫苗免疫无应答的遗传机制研究提供理论依据。     

乙肝疫苗无应答者CD4~+T细胞TCR Vβ基因克隆化特征的研究

目的:研究乙肝疫苗接种者CD4+T细胞TCR Vβ基因克隆化特征,分析乙肝疫苗有应答者和无应答者TCR Vβ基因单克隆改变的差异性。方法:采用多引物PCR技术扩增80例乙肝疫苗接种者CD4+T细胞TCR Vβ基因22个家族的CDR3区基因片段,对PCR产物分别应用琼脂糖凝胶电泳和基因扫描两种方法检测。结果:80例乙肝疫苗接种者中有58例产生抗体,有22例未产生抗体。TCR Vβ基因单克隆改变主要集中在Vβ2、Vβ8、Vβ9、Vβ11和Vβ17五个家族上,乙肝疫苗无应答组这五个Vβ基因单克隆改变频率明显低于乙肝疫苗有应答组(P<0.01或P<0.05)。结论:CD4+T细胞TCR Vβ基因克隆化改变是影响机体对乙肝疫苗免疫应答效果的重要因素之一。     

乙肝疫苗接种后抗体无弱应答与遗传有关

乙肝疫苗接种后抗体无弱应答与遗传有关中国医学科学院基础医学研究所与中国协和医科大学流行病教研室、西安医科大学流行病学教研室合作，在美国中华医学基金会资助的课题研究中，对乙肝疫苗免疫后抗体无、弱应答与遗传的关系进行了探讨，发现有少数人接种乙肝疫苗后不能...     

Aβ_(15)老年性痴呆疫苗接种小鼠的剂量优化研究

目的探讨Aβ15老年性痴呆疫苗接种Tg2576转基因小鼠及C57小鼠的最优化剂量。方法将本室前期制备的重组Aβ15疫苗分别以25.0、12.5及6.25μg三种剂量接种Tg2576转基因小鼠及C57小鼠,比较其诱导小鼠产生的抗体滴度大小;Western检测抗体与Aβ42结合的特异性;免疫组化检测小鼠产生的抗体是否能特异性结合老年斑。结果 25、12.5μg两种剂量均能诱导机体产生高滴度的抗体,6.25μg剂量未能诱导小鼠产生特性抗体;相同的接种次数下,C57小鼠产生的抗体滴度较Tg2576转基因小鼠高;接种小鼠产生的特异性抗体均能和Aβ42及老年斑结合。结论 Aβ15疫苗接种小鼠的最优化剂量为12.5μg,Tg2576转基因小鼠对Aβ疫苗有轻度免疫耐受。     

含HBV PreS2/S的抗体化乙肝基因疫苗可增强乙肝病毒特异性CTL应答

目的：构建乙肝病毒抗原PreS2/S和抗体Fc段的融合分子,观察该抗体化的乙肝疫苗诱导特异性细胞免疫应答的能力及状况。方法：用PCR的方法扩增乙肝病毒抗原PreS2/S和鼠IgG1Fc段基因,依次克隆到载体上;体外转染小鼠肌细胞,观察表面抗原转录水平和蛋白水平的表达情况;基因免疫小鼠,观察其诱导的特异性CTL免疫应答状况。结果：基因克隆融合分子经酶切和测序鉴定构建成功;体外转染实验表明融合分子可以在肌肉细胞中表达;免疫小鼠脾脏细胞用特异性抗原刺激后能产生很强的细胞免疫应答,其中特异性CTL反应明显增强。结论：基于抗体Fc段的抗体化乙肝疫苗能增强机体对HBV的特异性CTL反应,有利于打破HBV感染导致的免疫耐受。     

细胞免疫和遗传因素对乙型肝炎疫苗阻断母婴传播效果的影响

目的比较接种重组乙肝疫苗后不同体液免疫应答高危儿童的细胞免疫反应特点,进一步探讨母婴阻断失败、无应答的机理。方法124名母亲HBsAg和HBeAg双阳性的新生儿按常规乙肝的免疫程序接种重组CHO和酵母乙肝疫苗,于第1针免后3、7、12月检测HBsAg和抗-HBs,判定免疫成功或失败的新生儿,首针后60～120月(平均80月)再次检测HBsAg和抗-HBs指标,选取8名免疫重组乙肝疫苗母婴阻断失败儿童、4名免后无应答抗体反应的儿童和11名母婴阻断成功的儿童采集静脉血样,分离淋巴细胞,应用ELISPOT方法检测产生IL-2斑点形成细胞的数量,并对斑点数和表面抗体滴度的相关性进行比较,同时分析HLA-A、-B、DRB1和DQB1等位基因的多态性。结果(1)124名研究对象中有77．4％的儿童可产生保护性表面抗体,成功阻断母婴传播;13．7％的人免疫失败,感染乙肝;8．9％的儿童则对乙肝疫苗呈无应答状态。(2)免疫成功组产生IL-2细胞数(55．2±42．22)显著高于免疫失败组(3,75±3．24)和抗体无应答组(6．75±3．59),P<0．01。(3)儿童免疫乙肝疫苗后的表面抗体滴度与经乙肝疫苗诱导产生的特异性分泌IL-2的T细胞数量呈显著性正相关(r =0．601,P<0．01)。(4)HLA-B*48在对酵母乙肝疫苗无应答的儿童中占有25％的频率,显著高于免疫成功(2．2％)和失败的儿童(0％),P<0．05。对CHO疫苗无应答儿童的HLA-DRB1*15的频率显著高于免疫成功和失败的儿童(P<0．05)。结论乙肝疫苗母婴阻断失败和免后抗体无应答儿童的细胞免疫应答显著低于阻断成功的儿童,并且可能与遗传因素有关。     

rhGM-CSF作为成人乙肝疫苗无(弱)应答者免疫佐剂初探

目的 探讨重组人粒细胞.巨噬细胞集落刺激因子(rhGM-CSF)对提高成人乙肝疫苗无(弱)应答免疫的作用.方法 将两年内完成1～2个标准乙肝疫苗接种程序、复查HBV标志物均阴性的健康人群随机分为A、B两组.A组:33人,按标准免疫程序予10μg乙肝疫苗;B组:34人,先予rhGM-CSF 300μg皮下注射,次日始按A组方案予乙肝疫苗.接种首针后第1、2、8个月(T1、T2、T8)采血检测抗-HBs.结果 A、B组T8抗-HBs阳性率分别为39.39%和64.71%(P=0.038);A组三次抗体滴度检测结果 无显著性变化;B组升高明显,分别为(113.85±198.56)mIU/ml,(312.40±349.44)mIU/ml,(427.74±411.58)mIU/ml(P=0.001).A组和B组T8抗体水平差异有统计学意义(P=0.010).结论 rhGM-CSF联合乙肝疫苗复种对无(弱)应答者免疫效果优于单纯复种,GM-CSF具有提高机体对乙肝疫苗免疫应答的能力.     

幼儿园儿童接种乙肝疫苗的免疫效果观察

为了解我园幼儿接种乙肝疫苗的效果,进一步搞好乙肝防治工作,2000年3月对接种乙肝疫苗的376例儿童检测了抗-HBs水平,报道如下. 1 对象选择广钢幼儿园小班、中班、大班出生时已严格按0、1、6程序全程接种乙肝疫苗的儿童376名.所有受试者取静脉血 3ml,用酶联免疫吸附法检测血中的乙型肝炎表面抗体.试剂由上海实业科华生物有限公司出品.操作过程及结果判定严格按试剂说明书进行. 2 结果 376中抗-HBs阳性者 295人(78.5%).小班阳性最高为104例(83.9)%.中班阳性100例(82.6%).大班阳性91例(69.5%). 3 讨论乙型肝炎疫苗广泛用于我国婴幼儿等易感人群.众所周知,乙型肝炎难以治愈,而且可能发展为肝硬化,甚至肝癌.从上结果看,接种乙肝疫苗后抗-HBs阳性率随着全程免疫接种后的时间推移逐渐降低.在初免后60个月,抗-HBs低滴度构成较高,是加强免疫的最好时间［1］.所以在初免后4～5年应再加强免疫.建议入托新生常规检查乙肝表面抗原和表面抗体.对HbsAg阴性,而抗-HBs阳性的婴幼儿不接种乙肝疫苗.对HbsAg阳性者不准入托.而HbsAg和抗-HBs阴性者作为乙肝疫苗的接种对象.这样做既防止了乙肝在幼儿园内的交叉感染,又使婴幼儿体内形成足够的抗体,防止乙型肝炎的发生.     

Schizophrenia in a North Swedish geographical isolate, 1900–1977. Epidemiology, genetics and biochemistry

Over 200 schizophrenic patients belonging to three major and interrelated pedigree complexes have been investigated over the past 30 years in a North Swedish geographically isolated population, presently numbering about 6,000. An intensive investigation of a number of biochemical correlates and genetic markers in a few selected families belonging to one of the major pedigrees has indicated new strategies for the current research program.
Schizophrenia, as defined operationally, is significantly associated with decreased activities of two enzymes (1) blood platelet monoamine oxidase, (2) plasma dopamine-β-hydroxylase, and (3) with the genetic marker Gc² (group specific antigen). Both enzymes are subject to genetic variation. A positive score for linkage between schizophrenia and low plasma DBH activity has been calculated, but, so far, available data are insufficient for discrimination between linkage and partial contribution of genetically controlled low plasma DBH to the pathogenesis of the disease. Alternatively, both mechanisms could be involved.
As a model for continued research, schizophrenia is explained as based on a double dominant-recessive genotype (Aabb), representing a vulnerability which in about 50 % of cases develops into clinical schizophrenia. It is suggested that the dominant mutation (A) operates on or affects MAO activity, and that the recessive genotype (bb) is instrumental in low variates of DBH activity and very likely such variates within the normal range of physiological variation. Moreover, it is suggested that the combined effects of MAO- and DBH-reduced efficiency on the metabolism of e.g. dopamine could be an essential pathogenic mechanism for the schizophrenic illness which is segregating in this population.     

Renal dysplasia and asplenia in two sibs

A family is reported in which two sibs, one male and the other female, both died within 24 hours of birth with enlarged polycystic kidneys. Postmortem histology in the second child showed gross renal dysplasia. In both children the pancreas was enlarged, nodular and cystic but the liver appeared macroscopically normal. In the second child, histological examination confirmed pancreatic fibrosis with cystic dilation of ducts, but showed portal fibrosis with bile duct proliferation in the liver.
This combination of findings is very reminiscent of those in a girl and her brother reported by Ivemark et al. (1959). The children reported here also showed absence or hypoplasia of the spleen, cardiac anomalies and other features of the Ivemark syndrome (Ivemark 1955), a quite different, usually sporadic, congenital disorder. It is suggested that the children described here have a distinct lethal congenital disorder, probably inherited in an autosomal recessive manner.     

The dominant diseases of modernized societies as omega-3 essential fatty acid deficiency syndrome: Substrate beriberi

About 1900, modern food selection and processing caused widespread $\text{epidemics}$ of the B vitamin deficiency diseases of beriberi and pellagra which, for genetic reasons, often expressed as different diseases ranging from bowel and heart disease to dermatoses and psychoses. But the B vitamins merely help convert essential fatty acids (EFA) into the prostaglandin (PG) tissue regulators and it now turns out that, through hydrogenation, milling and selection of w3-poor southern foods, we have also been systematically depleting, by as much as 90%, a newly discovered trace Nordic EFA (w3) of special importance to primates and sole precursor of the PG3(4) series, even as a concurrent fiber deficiency increases body demand for EFA. Since substrate EFA is processed by many B vitamin catalysts, an EFA deficiency will mimic a $\text{panh}$ypovitaminosis B, i.e., a mixture of $\text{substrate}$ beriberi and $\text{substrate}$ pellagra resembling vitamin beriberi and pellagra but exhibiting as even more diverse $\text{endemic}$ disease. This would consitute a second stage of the Modern Malnutrition and explain why some workers now hold the dominant diseases of modermized societies to be new, nutritionally based, pellagraform yet lipid-related and to range, once again, from heart disease to psychosis. It is an assumption that our dominant diseases are unrelated to each other or are merely revealed by our diagnostic acumen and therapeutic success; and that hydrogenating millions of tons of food oils annually, to destroy the rancidity producing w3-EFA, is safe for $\text{primates}$. Extensive beriberiform disease is reported here in 32 typical cases taken from medical practice which responds strikingly to linseed oil supplements (60% w3-EFA) in confirmation of identical results in Capuchins.     

'Very sore nights and days': the child's experience of illness in early modern England, c.1580-1720

Sick children were ubiquitous in early modern England, and yet they have received very little attention from historians. Taking the elusive perspective of the child, this article explores the physical, emotional, and spiritual experience of illness in England between approximately 1580 and 1720. What was it like being ill and suffering pain? How did the young respond emotionally to the anticipation of death? It is argued that children’s experiences were characterised by profound ambivalence: illness could be terrifying and distressing, but also a source of emotional and spiritual fulfilment and joy. This interpretation challenges the common assumption amongst medical historians that the experiences of early modern patients were utterly miserable. It also sheds light on children’s emotional feelings for their parents, a subject often overlooked in the historiography of childhood. The primary sources used in this article include diaries, autobiographies, letters, the biographies of pious children, printed possession cases, doctors’ casebooks, and theological treatises concerning the afterlife.     

Guidelines for the Validation and Use of Immunoassays for Determination of Introduced Proteins in Biotechnology Enhanced Crops and Derived Food Ingredients

Recent advancements in agricultural biotechnology have created a need for analytical techniques to determine introduced proteins in crops enhanced through modern biotechnology techniques. These proteins are expressed in plant tissues and may be present in food ingredients. Immunoassays are ideally suited for protein detection and may be used as both quantitative and threshold methods. Microplate ELISA and lateral flow devices are two of the most commonly used immunoassay formats for agricultural biotechnology applications. This paper provides general background information and a discussion of criteria for the validation and application of immunochemical methods to the analysis of proteins introduced into plants and food ingredients using biotechnology methods. It is the result of a collaborative effort of members of the Analytical Environmental Immunochemical Consortium. This collaborative effort represents the combined expertise of several organizations to reach consensus on establishing guidelines for the validation and use of immunoassays. Further, the paper offers developers and users a consistent approach to adopting the technology as well as aid in producing accurate and meaningful results.     

HLA in North Colombia Chimila Amerindians

HLA-A,-B,-C,-DRB1 and -DQB1 alleles have been studied in Chimila Amerindians from Sabana de San Angel (North Colombian Coast) by using high resolution molecular typing. A frequent extended haplotype was found:HLA-A*24:02-B*51:10-C*15:02-BRB1*04:07-DQB1*03:02 (28.7%) which has also been described in Amerinndian Mayos Mexican population (Mexico, California Gulf, Pacific Ocean). Other haplotypes had already been found in Amerindians from Mexico (Pacific and Atlantic Coast), Peru (highlands and Amazon Basin), Bolivia and North USA. A geographic pattern according to HLA allele or haplotype frequencies is lacking in Amerindians, as already known. Also, five new extended haplotypes were found in Chimila Amerindians. Their HLA-A*24:02 high frequencies characteristic is shared with aboriginal populations of Taiwan; also, HLA-C*01:02 high frequencies are found in New Zealand Maoris, New Caledonians and Kimberly Aborigines from Australia. Finally, this study may show a model of evolutionary factors acting and rising one HLA allele frequency (-A*24:02), but not in others that belong to the same or different HLA loci.     

Ultracryotomy: development and application (with examples from the yeast cytology) (author's transl)

The preparation steps usually necessary for obtaining ultrathin frozen sections of biological material (chemical prefixation, enclosing, cryoprotective treatment, freezing, sectioning, and post-staining the sections for transmission electron microscopy) are submitted to a critical analysis. The application of cryo-ultramicrotomy, in particularly for cytochemical purposes, is reviewed. Fundamental considerations of chemical prefixation and poststaining are supported by examples from yeast cytology. Furthermore, the efficiency of the cryo-ultramicrotomy (electron optical resolution of ultrastructural details) is demonstrated on yeast cells and protoplasts.     

The universal muscular chamber. A basic unit of the genitourinary, cardiovascular, gastro-intestinal, skeletal, cutaneous, respiratory and other systems, endocameral hypertension; and spasm, the key to their idiopathic diseases and arthropathies

Starting with the integument, we see many organs are contractile sacs or multiples thereof, which tubes or bags constitute the major part of the entire body. Recognition of this basic unit and its characteristics sheds new light, individually and collectively, on many disorders previously considered unrelated. Muscular tears and perforations develop in the walls of these chambers, being no way peculiar to those organs, wherein, hydrochloric acid occurs. So, it is not necessary to explain the absence of excessive acid from patients who exhibit holes in the gastric, uterine, aortic, duodenal, rectal, pulmonary, retina, and other walls. Muscle, not acid is the great common factor relating idiopathic disorders in the gastrointestinal tract to each other and to similar diseases in other systems. When the units are linked together, the lesions tend to appear as arthropathies, i.e. at the joints. Rephrasing common-place observations, frees us from conventional, conceptual cul-de-sacs. An observation is only as good as its interpretation, so all possibilities must be considered, otherwise, we will remain blinded by our misconceptions.     

Der Einfluß von Nahrungsmitteln und Rauchen auf die klinisch-chemische Diagnostik von Phäochromozytom,Neuroblastom und Karzinoid-Syndrom

Zusammenfassung Der Einfluß von verschiedenen Nahrungsmitteln auf Methoden zur Bestimmung von Adrenalin (AD), Noradrenalin (NA), Vanillinmandelsäure (VMS), Metanephrinen (MN), Homovanillinsäure (HVS) und 5-Hydroxyindolessigsäure (5-HIE) im 24 h-Harn zur Diagnose des Phäochromozytoms bzw. Karzinoid-Syndroms wurde untersucht. Die in die Untersuchung einbezogenen Nahrungsmittel waren: Tee, Kaffee, Mandeln, Ananas, Käse, Walnüsse, Vanillepudding, Bananen, Tomaten und Milchschokolade. Außerdem wurde der Einfluß des Zigarettenrauchens auf die Bestimmung von AD, NA, VMS und MN untersucht.Walnüsse führten zu einer starken Erhöhung der 5-HIE-Ausscheidung. Bananen erhöhten die Ausscheidung von AD, NA, VMS, MN und 5-HIE. Kaffee und Ananas bewirkten eine geringe Zunahme der MN-Werte. Rauchen von 20–30 Zigaretten/Tag beeinflußte keine der vier Variablen.Wenn die beschriebenen Methoden benutzt werden, sollte lediglich auf den Verzehr von Bananen und Walnüssen vor und während der Harnsammelperioden verzichtet werden, da die oberen Normgrenzen im Harn überschritten werden könnten. Ein Verzicht auf Kaffee und Ananas in normalen Mengen ist nicht erforderlich. Es besteht kein Anlaß, weiterhin die bisherigen umfangreichen Restriktionen der übrigen Nahrungsmittel beizubehalten.