鼻腔滴入胰岛素改善2型糖尿病大鼠海马阿尔茨海默病样改变

 目的：2型糖尿病（type 2 diabetes, T2D）时大脑出现胰岛素水平下降及胰岛素信号通路下调,使大脑海马tau蛋白出现过度磷酸化的阿尔茨海默病(Alzheimer disease,AD)样改变。本研究选取2型糖尿病大鼠,皮下注射及鼻腔滴入胰岛素,观察大脑AD样病变的改变,并探讨其机制。方法：高糖、高脂、高蛋白喂饲3个月后链脲佐菌素腹腔注射制备T2D大鼠模型。运用2种方法干预：鼻腔滴入胰岛素（T2D+I-I）及皮下注射胰岛素（T2D+S-I）。检测血浆葡萄糖、血浆胰岛素和脑脊液胰岛素水平,免疫印记方法检测大脑海马总tau蛋白和tau蛋白部分位点磷酸化状态、胰岛素信号转导途径中关键酶磷脂酰肌醇3-激酶(phosphatidylinositol 3-kinase, PI3K)/Akt及糖原合成激酶3β(glycogen synthase kinase 3β, GSK-3β)活性。结果：T2D组大鼠血浆葡萄糖及胰岛素水平显著升高,脑脊液胰岛素水平显著降低,大脑海马组织中tau蛋白呈过度磷酸化状态,PI3K/Akt活性下降, GSK-3β磷酸化水平升高; T2D+I-I组大鼠血浆胰岛素及葡萄糖水平无显著改变,但大脑海马tau蛋白过度磷酸化状态显著好转,PI3K/Akt活性显著升高,GSK-3β活性显著下降; T2D+S-I组大鼠血糖显著下降,但血浆及脑脊液胰岛素水平无显著改变,大脑海马tau蛋白磷酸化水平有轻度改善,但变化不显著。结论：运用鼻腔滴入胰岛素可减轻T2D时大脑海马组织的AD样病变;外周皮下胰岛素注射对T2D时AD样病变无明显作用。     

糖尿病与阿尔茨海默病相关性的研究进展

近年来,阿尔茨海默病(Alzheimer's disease,AD)和糖尿病已成为影响人们健康的两大主要疾病,许多研究证实二者有许多共同的发病基础,因此对两大疾病的相关性研究已成为国内外学者探讨的热点.AD的病因学和发病机制复杂,也没有客观的特异的早期诊断AD的生物学标志及有效的治疗措施,本文从胰岛素及胰岛素生物作用障碍等角度探讨糖尿病与AD的相互关系.     

2型糖尿病的发病机制

2型糖尿病（T2D）是目前全世界增长最快的疾病之一,2型糖尿病是一种多因子疾病,由环境因素和遗传因素双方决定,2型糖尿病（DM2）病理机制仍然有很多未知因素,对2型糖尿病的预防和管理在很大程度上依赖于对这种机理的了解,DM2代表了一组异质性的疾病,在外围组织中胰岛素抵抗性存在差异,胰腺β细胞胰岛素分泌的破坏也存在差异,这两种异常存在交互作用。     

神经血管损伤介导2型糖尿病轻度认知障碍的研究进展

2型糖尿病(T2DM)是轻度认知功能障碍(MCI)的危险因素,认知功能障碍严重影响T2DM患者的生活质量。T2DM伴MCI主要表现为多维度认知功能损伤但机制不明,微血管和神经元损伤是导致大脑认知改变的主要原因。本篇综述深入探讨了2型糖尿病引发神经元和微血管损伤的潜在机制,由此揭示出T2DM可能通过多种途径引起T2DM患者神经血管失偶联,最终导致MCI。     

阻止2型糖尿病发生的基因突变

<正>据Nat Genet[2014,46(6):357-363.]报道,哈佛医学院遗传学Altshuler D教授研究团队最近发现一个有助防止2型糖尿病的基因突变(即该基因突变有助防止糖尿病),这为治疗糖尿病带来了新的希望。同时研究也揭示了如何使用遗传学工具,来猎取那些能起到防止疾病作用的"被破坏基因"(被关闭基因)。研究人员筛选一类人的基因组(此类人理论应该患糖尿病,但实际上没有患此疾病),通过将该基因组结果与其他人群比较,     

胰岛素受体与胰岛素样生长因子受体1在阿尔茨海默病中的作用机制

近年来,越来越多的研究岁示阿尔茨海默病（Alzheimer’s disease,AD）与2型糖尿病（Type 2 diabetes mellitus,T2DM）相关,进一步研究表明,胰岛素受体（insulinreceptor,IR）和胰岛素样生长因子受体1（Insulin-like growth factor I receptor,IGF-1R）在AD的发生发展中占有很重要的地位。本文通过对眼和IGF-1R在阿尔茨海默病中的作用机制进行综述,为阿尔茨海默病的研究和治疗提供新的方向。     

自身免疫糖尿病的分子遗传学

自身免疫糖尿病是一种T细胞介导的疾病,以β细胞免疫损伤及胰岛素缺乏为特征,与多种基因相关,除了位于人类白细胞抗原(human leukocyte antigen,HLA)基因区的IDDM1和位于人胰岛素的基因区IDDM2被公认为是1A型糖尿病的主效基因外,不断有新的潜在致病基因被发现,如PTPN22、CTLA4、IL2RA、IFIH1等.现针对这些相关性研究结果及其中可能涉及的免疫学机制作一综述.     

2 型糖尿病性骨质疏松对骨折风险影响的研究进展

2型糖尿病性骨质疏松(type 2 diabetic osteoporosis, T2DOP)是由2型糖尿病(type 2 diabetes, T2D)导致的以骨量减少、骨微结构受损、骨强度降低和骨折风险增加为特征的肌骨系统并发症,早期无症状且发病机制复杂,诊断方法有限,患者的致残率和死亡率高。当前对T2DOP的治疗主要采用抗糖尿病药物和抗骨质疏松药物。本文结合最新相关文献,总结T2DOP的特征、发病机制、诊断方法和治疗方法,探讨T2DOP治疗的未来方向,从而降低骨折风险。     

阿尔茨海默病与载脂蛋白E基因-427C/T多态性的关联研究

目的 探讨上海地区汉族人群载脂蛋白E(apolipoprotein E，apoE)基因启动子区—427C／T多态性与Alzheimer病(Alzheimer's disease，AD)发病风险的关系。方法 采用聚合酶链反应和限制性片段长度多态性方法，在104例AD患者和110名正常人中检测了apoE基因—427C／T各基因型及基因频率的分布。按比值比(odds ratio，0R)作疾病关联分析。结果 (1)AD患者与正常对照人群之间不存在—427C／T各等位基因和基因型频率分布的差异(P＞0．05)；(2)按apoE ε4基因分层后，无论是ε4型人群还是非ε4人群都不存在AD患者与正常老人间多态分布的差异(P＞0．05)；(3)在—427C／T 3种基因型中，仅T／T型AD与apoE ε4等位基因呈正关联(OR＝3．94，95％CI：2．206—7．038，x^2＝21．48，P＜0．05)。结论 上海地区汉族人群中，apo E基因—427C／T多态不是AD的疾病易感因子。     

2型糖尿病性骨质疏松与血清胰岛素样生长因子-1、骨碱性磷酸酶、1,25羟维生素D3水平的关系

目的 研究2型糖尿病性骨质疏松与血清胰岛素样生长因子-1 (IGF-I)、骨碱性磷酸酶(BAP)、1,25羟维生素D3[1,25(OH)D3]水平的关系.方法 选择2013年1月至2017年12月于我院就诊的60例2型糖尿病伴骨质疏松患者(T2DM+OP组),另选取我院同期就诊的60例2型糖尿病不伴有骨质疏松症患者(T2DM组),再选取同期我院体检的60例健康者(对照组).分析2型糖尿病性骨质疏松与IGF-1、BAP、1,25(OH) D3水平的关系.结果 与对照组比较,T2DM+ OP组和T2DM组IGF-1、l,25(OH) D3和骨密度(BMD)水平均明显降低,且T2DM+ OP组降低程度比T2DM组大,差异有统计学意义(P＜0.05);与对照组比较,T2DM+ OP组和T2DM组BAP水平均明显升高,且T2DM+ OP组升高程度比T2DM组大,差异有统计学意义(P＜0.05);T2DM+ OP组患者BMD水平与IGF-1(γ=0.823,P=0.022)、1,25(OH)D3(γ =0.751,P=0.033)呈正相关,与BAP(γ=-0.721,P=0.023)呈负相关;多元逐步回归分析结果显示,IGF-1(P =0.035,OR =20.599)和1,25 (OH) D3(P=0.016,OR=30.188)是2型糖尿病骨质疏松的保护因素.而BAP(P=0.034,OR=18.362)为危险因素.结论 IGF-1、BAP、1,25(OH) D3水平变化与糖尿病性骨质疏松的发生密切相关,低水平IGF-1和1,25 (OH) D3,高水平BAP是2型糖屎病患者并发骨质疏松的危险因素.     

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.     

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.     

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.     

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.