皮质下多灶状巨大灰质异位的病理学观察北大核心CSCD

目的观察皮质下多灶状巨大灰质异位的临床病理学特点,并结合文献探讨其可能的发生机制。方法对首都医科大学宣武医院功能神经外科2014年1月至2017年10月期间手术切除的难治性癫痫病例共计3000例中5例经病理确诊为皮质下多灶状巨大灰质异位的病例进行回顾性总结,分析其临床、影像学特征及病理学特点,并结合相关文献复习。结果5例患者中3例男性．2例女性。年龄20-39岁,平均年龄28．6岁。5例患者均以发作性意识丧失为主要临床表现,病程7-21年,平均病程15．4年。影像学提示颞叶单独受累者2例,顶叶单独受累者1例．颞叶及枕叶同时受累者1例,颞叶及顶叶同时受累者1例。病理检查均可见病变区域脑回结构异常,大脑皮质及白质构筑紊乱,皮质下及深部白质可见多量大小不一、形态不规则的团块状灰质结构,其间可见胶质细胞增生;免疫组织化学提示,在异位的灰质团块中,可见不同成熟阶段的神经元。1例患者同时伴有软脑膜下、脑室旁灰质异位及多小脑回形成,另有3例患者分别伴有多小脑回形成（2例）或海马硬化（1例）的病理表现。5例患者经手术治疗后均未见癫痫发作。结论灰质异位是一组神经元迁移障碍导致的皮质发育畸形,这一组疾病中神经元可以沉积在脑室至软脑膜之间的任何区域。广泛异常神经元迁移所导致的多灶状巨大灰质异位,特别是同时伴有多小脑回形成等其他皮质发育畸形者十分罕见。尽管如此,其临床表现仍相对单一,经由手术完整切除后,预后良好。     

一例貌似强直性肌营养不良的脊肌萎缩症的临床、病理及基因诊断

目的 明确1例表型复杂的神经肌病患者的诊断.方法 对该患者进行电生理、病理和致病基因突变分析,并结合国内外文献进行总结.结果 该患者临床病理表现貌似强直性肌营养不良( myotonic dystrophy,DM).基因诊断未发现假肥大型肌营养不良(Duchenne/Becker muscular dystrophy,DMD/BMD)致病基因Dystrophin 21个外显子的缺失突变以及DM1型致病基因DMPK的(CTG)n和DM2型致病基因ZNF9的(CCTG)n的重复扩增突变,但发现脊肌萎缩症(spinal muscular atrophy,SMA)致病基因SMN第7和8外显子的纯合缺失突变.结论 报告1例极为罕见的临床病理表现特殊而经基因诊断确诊的SMA.SMA有明显的临床异质性,临床电生理和病理诊断有其局限性,确诊必须结合基因诊断.     

一个先天性头皮单纯少毛症家系的临床表型及CDSN基因突变分析

目的 通过对1个先天性头皮单纯少毛症(hypotrichosis simplex of the scalp,HSS)家系的临床特征调查及CDSN基因突变分析,以确定该家系的疾病类型和致病基因并建立产前诊断的方法.方法 经家系调查及临床检查确定疾病类型;抽取3例患者及7名正常家系成员和100名正常对照的外周血提取基因组DNA,PCR扩增CDSN基因的第1、2外显子,用直接双向测序、BLAST比对进行突变分析.结果 家系中3例患者均表现为先天性头皮单纯少毛症,呈常染色体显性遗传;在3例患者的CDSN基因第2外显子cDNA序列发现717C＞G无义杂合突变(Y239X),正常家系成员和对照中均未发现该突变.结论 CDSN基因Y239X无义突变是该家系先天性头皮单纯少毛症的致病突变,此突变是首次在中国HSS疾病人群中报道.     

一个遗传性多发性骨软骨瘤家系的基因突变检测

目的 确定一个遗传性多发性骨软骨瘤(hereditary multiple exostoses,HME)家系的致病基因.方法 应用与EXT1、EXT2紧密连锁的短串联重复序列(short tandem repeat,STR)对该家系进行连锁分析,确定候选基因,然后对候选基因的编码区及外显子与内含子交界处进行PCR-测序法突变分析.结果 该家系致病基因被定位在EXT2基因区,测序发现EXT2基因536G>A无义突变,该突变位于EXT2基因第3外显子,导致编码第180位氨基酸的密码子成为终止密码,突变与疾病共分离,其余外显子未发现突变.另发现1例外显不全.结论 EXT2基因536G>A突变是导致这个家系发生骨软骨瘤的原因.     

虹膜畸形青光眼家系中PITX2基因新生无义突变的遗传学分析

目的对一个虹膜畸形青光眼核心家系的致病突变进行鉴定及遗传学分析。方法对1例无虹膜青光眼患者进行眼专科检查,采用全外显子组测序技术筛选先证者中致病基因突变,采用SangerDNA测序技术检测核心家系成员中致病突变位点的基因型,并对致病突变位点进行生物信息学分析。结果患者PITX2基因(NM_000325)第二外显子存在5bp碱基缺失引起的杂合无义突变:c.296_300delAATCC(p.F99X),其父母表型未见异常,均未发现此突变,该突变为新生突变(denovomutation)。该突变在第99位密码子处产生终止密码,可形成截短蛋白。全外显子测序未在患者中发现其他已报道的相关基因突变。结论我们的结果提示先证者的临床诊断应为由PITX2基因p.F99X新发无义突变所致的罕见常染色体显性遗传病Axenfeld-Rieger综合征(ARS)。本研究结果进一步扩展了PITX2突变谱和ARS的遗传异质性,为虹膜畸形的分子病因诊断和遗传咨询提供更多实验证据。     

遗传性出血性毛细血管扩张症基因突变分析

目的 分析遗传性出血性毛细血管扩张症(hereditary hemorrhagic telangiectasia,HHT)家系ENG、ACVEL1和SMAD4基因突变.方法 收集4个HHT家系临床资料并分析其临床特点,应用直接测序和多重连接探针扩增技术对11例临床确诊及可疑患者的ENG、ACVRL1和SMAD4基因进行突变分析,将结果与HHT基因突变数据库进行对比.结果 家系2先证者及2个妹妹的ENG基因发生了第2外显子c.207G＞A(p.L69L)同义突变、第8外显子c.1004A＞T(p.Q335L)错义突变、ACVRL1基因第7外显子c.817C＞T(L273L)同义突变;家系3先证者及其母亲和弟的ENG基因发生了第8外显子c.1004A＞T(p.Q335L)突变;也检测到家系4先证者及其兄的ENG基因第8外显子c.1004A＞T(p.Q335L)突变.家系1先证者及其他HHT患者,未检测到基因突变.其中ENG基因第8外显子c.1004A＞ T(p.335Q＞L)为新突变,在200名正常对照中也未检测到该突变.结论 HHT具有遗传异质性,ENG基因第8外显子c.1004A＞T(p.Q335L)为HHT新的致病突变.     

一例遗传性多发性骨软骨瘤患者的基因突变分析

目的对1例遗传性多发性骨软骨瘤患者进行相关基因的突变检测,以寻找致病位点。方法采集患者及其家系成员的外周血标本,提取其全基因组DNA,用PCR对EXT1和EXT2基因的所有外显子进行扩增并测序,测序结果在Gen Bank上比对分析。结果患者:EXT1基因中发现一种内含子突变(c.1721+203TTC),EXT2基因中发现三种内含子突变(c.1526-195CT、c.1807-51TC、c.1936-41TC)。父亲:EXT1(c.1721+203TTC)、EXT2(c.1526-195CT、c.1807-51TC、c.1936-41TC),母亲:EXT2(c.1807-51TCT),妹妹:EXT2(c.1807-51TC)。结论通过对患者进行EXT1、EXT2基因的所有外显子扩增并测序分析,未发现明确的致病位点,该患者的发病是否由除EXT1、EXT2基因以外的其他相关基因突变引起,还需进一步的连锁定位分析。     

一个婴儿神经轴索营养不良家系的基因变异分析

目的对1个临床拟诊婴儿神经轴索营养不良(infantile neuroaxonal dystrophy,INAD)家系的患儿及父母进行基因变异分析,明确其致病原因为遗传咨询及产前诊断提供依据。方法应用高通量测序方法对患儿相关致病基因进行初步筛查,再通过直接测序对患儿及父母可疑致病基因进行验证,寻找可能的致病突变位点,采用SIFT及PolyPhen-2生物信息学软件对变异位点进行致病性预测。结果高通量测序筛查显示患儿PLA2G6基因第5和第16外显子存在可疑致病突变;Sanger测序结果显示患儿PLA2G6基因第5外显子c.668C>A(p.Pro223Gln)和第16外显子c.2266C>T(p.Gln756Ter)复合杂合变异,父亲携带c.668C>A杂合变异,母亲携带c.2266C>T杂合变异。c.668C>A变异导致PLA2G6基因编码的第223位脯氨酸被谷氨酰胺替代,为已报道的致病变异;c.2266C>T变异导致编译第756位谷氨酰胺的密码子变为终止密码,使肽链合成提前终止,该变异尚未见文献报道,蛋白功能预测为有害变异;患儿的复合杂合变异分别来自父母。结论PLA2G6基因第5外显子c.668C>A(p.Pro223Gln)和第16外显子c.2266C>T(p.Gln756Ter)变异可能是患儿的致病原因,新变异的发现丰富了PLA2G6基因变异谱。     

中国人von Hippel-Lindau综合征种系突变研究

目的探讨中国人von Hippel-Lindau综合征（VHL）种系突变的特点及其临床应用价值。方法分析6个VHL家系的临床资料，采用聚合酶链反应和扩增产物直接测序的方法对其中的21位成员进行VHL基因种系突变研究。结果在6个家系中，5个Ⅰ型家系，1个ⅡA型家系。6种不同的VHL基因种系突变被确定，其中包括错义突变4个，无义突变1个，缺失突变1个。4个分布在第1外显子、1个在第2外显子和1个在第3外显子。21人接受基因检测的个体中，14人存在VHL基因种系突变，其中包括10例均符合VH临床诊断标准的患者、1例疑似VHL患者和3例致病基因携带者。结论中国汉族人VHL患者存在基因种系突变且第1外显子的后1／3可能为主要的突变区域；VHL基因种系突变检测在疾病诊断和早期发现无症状患者及致病基因携带者方面具有重要作用。     

自发KDM6A剪切位点突变致歌舞伎综合征合并性早熟和矮小一例

目的 分析一例组蛋白特异性赖氨酸脱甲基酶(KDM6A)基因自发突变导致歌舞伎综合征(KS)2型患者的临床特点及致病基因,增加对疾病致病基因和临床特点的认识.方法 收集患者的临床表现、生化检验及影像学资料进行分析,抽取患者及父母外周静脉血,提取基因组DNA,对全外显子基因进行测序.结果 1)患儿以真性性早熟、矮小为主要临...     

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.     

The universal muscular chain reaction,muscle spasm,Torsions, ruptures and extravasations. Chameleons of pathology and some manifestations of simple muscular disorders

Most bodily functions require the coordinated actions of complementary and supplementary paired muscle groups. Where this essential muscular cooperation is lacking, hollow organs may burst and others become literally screwed up, giving rise to many similar spastic diseases such as Torticollis, Twisted ovarian cyst, Torsion of the Testis, Volvulus of the intestines, Varicose Veins, Megacolon, Aortamegaly, Scoliosis, Erb's Palsy, Peyronie's Disease, Main-en-Griffe, Undescended Foot (Pes Cavus), Talipes, Strabismus. Spasm is “panenepidemic” and unclassified examples of Torsion Dystonia and Dyskinesia really are as common as debt and taxes.     

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.     

Hypo- und Hypermagnesämie aus kardiologischer Sicht

Zusammenfassung Eine Reihe pathologischer Zustände bedingen Magnesiummangel. Zustände mit Hypermagnesämie sind ebenfalls bekannt, doch wesentlich seltener. Für den Kardiologen beachtenswert ist, daß unter Therapie mit bestimmten Diuretica bei Herzinsuffizienz, bei Herzinfarkt, Kardiomyopathie, Digitalisintoxikation und bestimmten Herzrhythmusstörungen Hypomagnesämie beobachtet wurde. Leider kann in der klinischen Routine nur ein extracelluläres Magnesiumdefizit durch Serumbestimmungen gemessen werden; über Magnesiummangel einzelner Organe kann nichts ausgesagt werden. Hinweise für Magnesiummangel geben aber neben der Messung des Serumspiegels Anamnese, klinischer Befund, bestimmte EKG-Veränderungen wie auch evtl. Hypokalämie, ein Zustand, bei dem sich oft — besonders bei Aldosteronismus — parallele Veränderungen zeigten.Tierexperimente deuten darauf hin, daß infarktähnliche Läsionen unter Magnesiummangel entstehen, doch ob Herzinfarkt beim Menschen durch Magnesiummangel ausgelöst werden kann, ist noch ungeklärt. In Leichenherzen zeigte sich im Infarktgebiet neben Calciumakkumulation signifikanter Magnesiumverlust, wobei unklar blieb, ob sich Ursache oder Folge des Infarktes widerspiegelten. Falls ein ursächlicher Zusammenhang besteht, ist er im Myokardstoffwechsel selbst zu suchen, wie bei der Alkoholkardiomyopathie, wo myokardialer Magnesiummangel zumindest als pathogenetischer Teilfaktor anerkannt wird. Andererseits versucht man aber auch Beziehungen zwischen Atherosklerose, Blutgerinnung und Hypomagnesämie herzustellen, in der Meinung, daß Magnesiummangel auch über den coronaren Pathomechanismus des Herzinfarktes wirken könnte. Sicher scheint, daß gewisse EKG-Veränderungen und Herzrhythmusstörungen durch einen irritierten Magnesiumhaushalt bedingt sein können, da sie bei Gabe bzw. Entzug von Magnesium verschwinden. Daß Magnesiummangel die Glykosidtoleranz verringert, wird tierexperimentell bestätigt. Unter Hypomagnesämie bewirkt Acetylstrophanthidin eher und länger Rhythmusstörungen als ohne, außerdem lassen diese sich durch Magnesiumgaben eliminieren. Da in gewissen Fällen spontane und digitalisinduzierte Herzrythmusstörungen durch Magnesiuminjektionen beseitigt wurden, scheint Magnesium als Therapeuticum angebracht. Einsatz verschiedener Magnesiumsalze bei Angina pectoris, degenerativen Herzerkrankungen und Herzinsuffizienz ohne geprüften und offensichtlich gestörten Magnesiumhaushalt ist fragwürdig, weil keine eindeutigen klinischen Erfolgsbeweise vorliegen. Immerhin mag es aber larvierte, durch Serumbestimmungen nicht erfaßbare Mangelzustände geben. Allgemein erscheint es aus kardiologischer Sicht ratsam, den Magnesiumhaushalt zu überwachen und in entsprechenden Fällen auszugleichen, um möglichen Myokardläsionen oder fatalen Herzrhythmusstörungen entgegenzuwirken.     

Environmental risk factors and their role in the management of atopic dermatitis

Introduction: The etiology of atopic dermatitis (AD) is multifactorial with interaction between genetics, immune and environmental factors.

Areas covered: We review the role of prenatal exposures, irritants and pruritogens, pathogens, climate factors, including temperature, humidity, ultraviolet radiation, outdoor and indoor air pollutants, tobacco smoke exposure, water hardness, urban vs. rural living, diet, breastfeeding, probiotics and prebiotics on AD.

Expert commentary: The increased global prevalence of AD cannot be attributed to genetics alone, suggesting that evolving environmental exposures may trigger and/or flare disease in predisposed individuals. There is a complex interplay between different environmental factors, including individual use of personal care products and exposure to climate, pollution, food and other exogenous factors. Understanding these complex risk factors is crucial to developing targeted interventions to prevent the disease in millions. Moreover, patients require counseling on optimal regimens for minimization of exposure to irritants and pruritogens and other harmful exposures.     

'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 genes in Amerindians from Mexico San Vicente Tancuayalab Teenek/Huastecos

Huastecos or Teenek Amerindians are presently living at North East Mexico (San Luis Potosi State). They have probably one of the most ancient culture of Mexico and Central America together with Mayas and Olmec groups with which also show close relationships. Proximity to Atlantic Ocean/Mexican Gulf originated that Spaniards had very early contact with them at about 1519 CE or before. In the present paper we have aimed to study HLA gene profile which may be useful for HLA and disease epidemiology and transplant programs in Teeneks. HLA-DRB1*04:07, -DRB1*14:06 and -DRB1*04:11 have been found in high frequency like in other Amerindian groups. High frequency typical Amerindians HLA extended haplotypes have been found, such as A*02-B*35-DRB1*04:07-DQB1*03:02; A*68-B*39-DRB1*04:07-DQB1*03:02 and A*02-B*39-DRB1*04:07-DQB1*03:02; also new haplotypes have been described, like A*02-B*52-DRB1*04:11-DQB1*03:02, A*68-B*35-DRB1*14:02-DQB1*03:01 and A*68-B*40-DRB1*16:02-DQB1*03:01. Genetic proximity is observed not only to linguistically close Mayans, but also to Mazatecans, Mixtecans and Zapotecans, who speak an altogether different languages; it shows once more that genes and languages do not correlate. This population was greatly diminished after European contact between 1500 and 1600 years CE; in fact, North and South America First Inhabitants population was brought from 80 down to 8 million people because of diseases (i.e.: measles, smallpox or influenza), slavery and war.     

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.