胰岛素抑制糖尿病大鼠皮质tau蛋白磷酸化作用的研究

目的探讨胰岛素抑制糖尿病大鼠皮质tau蛋白磷酸化、改善记忆障碍的可能机制。方法用链脲佐菌素(STZ)建立糖尿病大鼠模型,用32P放射性标记法检测对照组、DM(Diabetes mellitus)组及Insulin组糖原合酶激酶-3(glycogen synthase kinase-3,GSK-3)的活性,用蛋白印迹法检测tau蛋白磷酸化水平,用电跳台试验检测大鼠的保留记忆。结果与对照组相比,DM组的GSK-3活性明显增加(P<0.01),tau蛋白在Ser198/Ser199/Ser202位点出磷酸化程度明显升高(P<0.01,),且伴有记忆障碍。与DM组相比较,Insulin组GSK-3活性降低(P<0.01),tau蛋白在Ser198/Ser199/Ser202位点磷酸化降低,(P<0.05),记忆障碍改善,与对照组比较无统计学差异(P>0.05)。结论糖尿病大鼠脑皮质GSK-3活性升高,tau蛋白过度磷酸化增加,胰岛素通过抑制GSK-3活性,降低tau蛋白过度磷酸化,改善糖尿病大鼠的记忆障碍。     

单相与双相抑郁障碍患者外周血GSK-3β差异表达的研究

目的 探讨单相和双相抑郁患者外周血单核细胞内糖原合成酶激酶-3β(glycogen synthase kinase-3 GSK-3β)蛋白表达差异。方法 从门诊及病房患者中选取单相及双相抑郁障碍患者各30例。正常对照30例。入组当天收集受试者一般资料,并评定单相及双相抑郁组汉密顿抑郁量表（hamilton depression scale HAMD）评分,取受试者静脉血并提取其外周血单核细胞。利用免疫印迹法检测其细胞中总糖原合成酶激酶-3β(total glycogen synthase kinase-3beta总GSK-3β)及磷酸化GSK-3β(phosphorylated-glycogen synthase kinase-3beta p-GSK-3β)蛋白含量。结果 (1).单相与双相抑郁障碍组患者p-GSK-3β/总GSK-3β比值均较正常组增加,差异有统计学意义（P=0.000）;双相较单相抑郁障碍组p-GSK-3β/总GSK-3β比值增加,差异有统计学意义（P=0.000）。(2).双相抑郁障碍患者p-GSK-3β/总GSK-3β比值与其HAMD分数呈正相关（R=0.424...     

轻度认知障碍及阿尔茨海默病患者外周血淋巴细胞中蛋白磷酸酯酶-2A的改变

目的 探讨轻度认知功能障碍(MCI)及阿尔茨海默病(AD)患者外周血淋巴细胞蛋白磷酸酯酶-2A(PP-2A)的变化.方法 用放射性配体结合试验检测11名健康对照者、11例MCI患者及11例AD患者外周血淋巴细胞PP-2A的活性,并用Western bolt检测PP-2A蛋白的表达.结果 MCI组外周血淋巴细胞PP-2A活性(0.71±0.12)及蛋白表达(0.80±0.05)与健康对照组[分别为(1.01±0.09)和(0.96±0.07)]相比明显降低(均P＜0.01);AD组PP-2A活性(0.64±0.11)及蛋白表达(0.76±0.06)亦明显降低,与对照组相比差异有统计学意义(均P＜0.01);AD组PP-2A活性及蛋白表达比MCI组有降低的趋势,但差异无统计学意义.结论 MCI及AD患者外周血淋巴细胞PP-2A的活性及表达降低,在MCI的诊断中可能有参考价值,同时亦可能对AD的诊断有一定的潜在的意义.     

轻度认知障碍患者认知水平与血清"淀粉样蛋白42磷酸化Tau同型半胱氨酸水平相关性分析

目的探讨轻度认知障碍患者认知水平与血清"淀粉样蛋白42、磷酸化Tau、同型半胱氨酸水平的相关性。方法选择2008-2011年济宁各社区近1 100例50~80岁的中老年人,筛选出MCI患者36例,并选取年龄、学历相匹配的健康对照组36例。检测MCI组与对照组的认知功能水平与血清Aβ-42、p-tan、Hcy水平,使用相关性分析MMSE水平与血清指标的关系。结果 2组患者性别比例、平均年龄、受教育年限方面比较差异无统计学意义(P0.05),对照组平均MMSE明显高于MCI组,差异有统计学意义(P≤0.05),MCI组平均Aβ-42、p-tan、Hcy水平明显高于对照组,差异有统计学意义(P≤0.05),MCI组及对照组的Aβ-42、p-tan、Hcy均与患者的MMSE得分呈相关性(P≤0.05),其中MMSE得分与Aβ-42、p-tan、Hcy为负相关。结论血清Aβ-42、p-tan、Hcy可指示认知功能水平。     

促红细胞生成素对Aβ25-35诱导的细胞tau蛋白磷酸化的抑制作用

目的 探讨促红细胞生成素(Epo)对凝聚态β淀粉样蛋白25-35片断(Aβ25-35)诱导的SH-SY5Y细胞tau蛋白磷酸化的影响.方法 MTT法观察不同浓度的Epo(0、5、10、20、50 U)单独作用24 h对SH-SY5Y细胞存活率的影响;20 μmol/L的凝聚态Aβ25-35作用于SH-SY5Y细胞不同时间点(0 min、30 min、1 h、3 h、6 h、12 h、24 h)后,Western blot法检测tau蛋白磷酸化(Ser199、Ser396及taul)水平的变化;观察不同浓度的Epo(5、10、20 U)预处理细胞3 h后对Aβ25-35作用的影响以及P13K/Akt抑制剂LY294002(50μmol/L)预处理细胞1 h后Epo抑制作用受到的影响.结果 不同浓度的Epo作用24 h后,MTT示细胞存活率无明显变化.20 μmol/L的Aβ25-35作用不同时间点后,tau蛋白Ser396、Ser199位点的磷酸化水平3 h时开始增加,6 h达到最高峰,12 h后又逐渐下降,24h时仍维持较高水平,与0min、30min时比较,差异均有统计学意义(P<0.05);而总的tau蛋白没有任何变化.5、10、20U Epo预处理均可有效地抑制Aβ25-35引起的Ser396、Ser199位点的磷酸化,与正常对照组比较,差异均有统计学意义(P<0.05).LY294002预处理细胞后,Epo的作用受到抑制.结论 Epo可通过P13K/Akt途径对Aβ25-35诱导的tau蛋白磷酸化发挥抑制作用,本研究为研究AD的发病机制及探索新的有效治疗药物提供了重要的理论基础.     

轻度认知功能障碍患者情绪记忆损害特征

目的探讨轻度认知功能障碍(MCI)患者情绪记忆的改变。方法采用情绪记忆神经认知心理学检查评价22例MCI患者(MCI组)及22名健康成年人(正常对照组)的情绪记忆,并采用事件诱发电位(ERPs)检测P300的潜伏期和波幅。结果与正常对照组比较,MCI组MMSE、词汇流畅性试验、数字广度试验评分均显著降低(均P 0. 01)。MCI组与正常对照组正性、中性和负性情绪图片效价度差异无统计学意义(均P 0. 05)。与正常对照组比较,MCI组正性和负性图片再认正确率均显著降低(P 0. 05～0. 01),中性图片再认正确率差异无统计学意义(P 0. 05)。MCI组及正常对照组正性、负性与中性图片再认正确率差异有统计学意义(F=6. 27,F=39. 13;均P 0. 05)。与正常对照组比较,MCI组正性和负性图片再认反应时间差异有统计学意义(P 0. 05～0. 01),中性图片差异无统计学意义(P 0. 05)。MCI组及正常对照组正性、负性与中性图片再认反应时间差异有统计学意义(F=3. 74,F=16. 48;均P 0. 05)。MCI组与正常对照组学习阶段ERPs-P300的潜伏期、波幅差异无统计学意义(均P 0. 05)。与正常对照组比较,MCI组再认阶段正性和负性图片ERPs-P300潜伏期显著增加,波幅显著降低(P 0. 05～0. 01);中性图片潜伏期及波幅差异无统计学意义(均P 0. 05)。MCI组学习阶段(F=55. 20,P 0. 05; F=43. 12,P 0. 05)及再认阶段(F=29. 36,P 0. 05; F=19. 39,P 0. 05)正性、负性与中性情绪图片ERPs-P300潜伏期及波幅差异均有统计学意义;正性与负性ERPs-P300潜伏期及波幅比较差异无统计学意义(均P 0. 05)。正常对照组的学习阶段(F=55. 66,P 0. 05; F=39. 33,P 0. 05)及再认阶段(F=114. 48,P 0. 05; F=51. 77,P 0. 05)正性、负性与中性情绪图片ERPs-P300潜伏期及波幅差异均有统计学意义。结论 MCI患者存在情绪记忆的受损及反应时间延长,且情绪效价"正向"选择性偏向受损。     

轻度认知功能障碍和阿尔茨海默病患者血小板α和β分泌酶活性的变化

目的 研究轻度认知功能障碍(MCI)和阿尔茨海默病(AD)患者血小板α和β分泌酶活性及α分泌酶的产物sAPPα含量的变化.方法 对48例其他疾病老年对照者、42例MCI患者及40例AD患者分别进行神经功能评定,用荧光法测定各组患者血小板α和β分泌酶的活性,并用Western印迹检测血小板sAPPα含量.结果 对照组、MCI组和AD组患者α分泌酶活性分别为100.0％±10.6％、78.2％±9.4％和61.8％±7.2％,MCI和AD组与对照组相比均降低,差异有统计学意义(F=22.935,P=0.001)；AD组与MCI组相比亦明显降低,差异有统计学意义.对照组、MCI组和AD组β分泌酶的活性分别为100.0％士11.2％、145.8％士12.7％和189.8％士14.2％；MCI组和AD组均较对照组升高,差异有统计学意义(F=16.368,P=0.001),AD组较MCI组高,差异有统计学意义.sAPPα的含量MCI组和AD组与对照组相比均明显降低；AD组与MCI组相比亦显著降低,差异有统计学意义.结论 MCI组和AD组患者的α分泌酶活性及其产物sAPPα均较对照组降低,β分泌酶活性升高；α和β分泌酶活性改变可能在MCI和AD的发病过程中起着一定的作用,在MCI和AD的诊断中有一定的潜在价值.     

MCI患者血清中Tau蛋白 Aβ1-42P-tau的检测价值分析

目的 探讨血清磷酸化Tau（P-tau）、β淀粉样蛋白1-42（Aβ1-42）以及Tau蛋白在轻度认知障碍（MCI）患者中的临床应用价值.方法 采用酶联免疫法测定主诉健忘组（SMC）30例,MCI患者30例,阿尔茨海默病组（AD）68例（轻度AD 24例,中度AD 22例,重度AD 22例）以及健康对照组35例血清中P-tau、Aβ1-42、Tau蛋白水平,并分析三种标记物与疾病的相关性.结果 与对照组及MCI组相比,MCI组、AD组MMSE评分显著上升,差异有统计学意义（P〈0.05）,重度AD组MMSE评分显著高于轻度、中度AD组,两两比较差异有统计学意义（P〈0.05）.与对照组相比,MCI组、AD组P-tau、Tau蛋白水平显著上升,且AD组高于MCI组,而Aβ1-42水平显著下降,且AD组下降幅度大于MCI组,差异有统计学意义（P〈0.05）.其中重度AD组P-tau、Tau蛋白水平高于轻度、中度AD组,而Aβ1-42水平低于轻、中度组,差异有统计学意义（P〈0.05）.SMC 组与对照组相比,各标记物水平差异无统计学意义（P〉0.05）.与单纯Tau蛋白、Aβ1-42、P-tau诊断相比,Tau蛋白、Aβ1-42、P-tau联合诊断的灵敏性、特异性、准确性显著增加,差异有统计学意义（P〈0.05）.结论 MCI病情发生及发展过程可能与血清P-tau、Aβ1-42、Tau蛋白水平异常有关,通过测定这三种标记物可有效预测MCI患者病情进展情况.     

基底节区血管周围间隙扩大与非血管性认知障碍的关系

目的探讨基底节区血管周围间隙扩大(EPVS)与非血管性认知障碍的关系。方法对63例Alzheimer's病(AD)患者(AD组)、59例非血管性轻度认知障碍(MCI)患者(MCI组)及60名健康对照者(正常对照组)行头颅MRI检查。比较各组及不同年龄段基底节区EPVS。结果 AD组及MCI组EPVS评分显著高于正常对照组(均P0.01)。AD组EPVS评分显著高于MCI组(P0.01)。与正常对照组比较,AD组及MCI组分级构成差异有统计学意义(均P0.01)。AD组与MCI组分级构成的差别无统计学意义。60岁时,AD组EPVS评分显著高于MCI组及正常对照组(均P0.01),AD组与正常对照组分级构成差异有统计学意义(P0.05)。60~80岁时,三组间EPVS评分两两比较差异有统计学意义(均P0.01),对照组的分级构成与AD组和MCI组的差异有统计学意义(均P0.01);80岁时,三组间EPVS评分及分级构成差异无统计学意义。结论在≤80岁的人群中,基底节区EPVS与非血管性认知障碍有关。     

糖原合酶激酶-3β与轻度认知障碍的相关性研究进展

最近大量研究表明~([1,2]),糖原合酶激酶-3β(GSK-3β)在MCI及AD疾病过程中不仅参与β淀粉样蛋白(Aβ)的产生,而且与tau蛋白的过度磷酸化密切相关.Aβ、tau蛋白又直接参与老年斑(SP)及神经元纤维缠结(NFT)的形成,因此研究GSK-3B与MCI的相关性有重要的基础和临床价值.     

Neuroimaging in epilepsy in tropics

Epilepsy is a major public health problem in many tropical countries. Also, some of the tropical diseases are major contributors to the higher prevalence of epilepsy in these countries. The etiologic factors responsible for epilepsy in these countries are quite different from those in the developed world. This article discusses the etiologic factors and neuroimaging of epilepsy in light of the conditions in these tropical countries.     

癫痫与抑郁关系的研究进展

抑郁是癫痫患者中常见的精神障碍,严重地影响了患者的生活质量。传统的观点认为癫痫患者因为存在着诸多社会学问题易出现抑郁倾向,癫痫和抑郁是单向的联系,但大量的研究已经证明癫痫和抑郁之间存在双向的联系,一种异常状态的存在可能易转化为另一种异常状态的发展。癫痫和抑郁存在着共同的发病机制。本文主要就癫痫和抑郁的双向联系以及抗抑郁药物在癫痫患者中的应用进行阐述。     

Sudanophilic lipid accumulation in astrocytes in periventricular leukomalacia in monkeys

Summary Sudanophilic lipid accumulation is a characteristic feature of periventricular leukomalacia (PVL) of infants. At least two types of lipid-containing cells have been identified, one being the macrophage, the other the pre-myelin glial cell. A third type of lipid-containing cell has been seen in two monkeys with spontaneous PVL. Electron microscopically this cell appears to be an astrocyte. This probably represents a reaction of the astrocyte to hypoxia and may be the equivalent of the hypertrophic astrocytes found in human infants.Supported in part by NIH grant HDO 8633 and the Regional Primate Research Center Grant RR-00166     

Increase in cathepsin D activity in rat brain in aging

Cathepsin D-like activity in homogenates of five brain areas of 3-month-old and 24-month-old Fischer 344 rats was measured. With hemoglobin as substrate at pH 3.2, more than 90% of the activity was inhibited by pepstatin. In each area studied, activity was more than twice as high in the old rat brain: 140-160% higher in the cortex, cerebellum, pons-medulla, and striatum and 90-100% higher in the hippocampus and spinal cord. The greatly increased metabolic capacity in the absence of an increase in protein turnover may have a role in age-related pathological degeneration in the brain.     

Characteristics of nociceptors in the periodontium--an in vitro study in rats

Recent studies have indicated that nociceptors can be classified into various types according to their physiological properties. These studies have clarified that the frequency distribution of various nociceptor types is different among body sites and animal species. In the present study, we investigated the physiological properties of rat's periodontal nociceptors in an in vitro jaw-nerve preparation. Responses were recorded from functional single filaments in the inferior alveolar nerve. To determine the nociceptor type, calibrated von Frey filaments, heat, and bradykinin (BK) stimuli were used. We found five subtypes of nociceptors in the periodontal ligaments of the lower incisor: Adelta-high threshold mechanonociceptors (Adelta-HTM, n=28), Adelta-mechanoheat nociceptors (Adelta-MH, n=6), Adelta-polymodal nociceptors (Adelta-POLY, n=26), C-high threshold mechanonociceptors (C-HTM, n=3) and C-polymodal nociceptors (C-POLY, n=4). Most nociceptors were Adelta-innervated, while only a small number of C-innervated nociceptors were found. The present results suggest that periodontal nociceptors transmit mainly fast pain, and may thus play a role in rapid detection of injure-related stimuli during mastication.     

Gender in Voice Perception in Autism

Deficits in the perception of social stimuli may contribute to the characteristic impairments in social interaction in high functioning autism (HFA). Although the cortical processing of voice is abnormal in HFA, it is unclear whether this gives rise to impairments in the perception of voice gender. About 20 children with HFA and 20 matched controls were presented with voice fragments that were parametrically morphed in gender. No differences were found in the perception of gender between the two groups of participants, but response times differed significantly. The results suggest that the perception of voice gender is not impaired in HFA, which is consistent with behavioral findings of an unimpaired voice-based identification of age and identity by individuals with autism. The differences in response times suggest that individuals with HFA use different perceptual approaches from those used by typically developing individuals.     

Defects in Bioenergetic Coupling in Schizophrenia

Synaptic neurotransmission relies on maintenance of the synapse and meeting the energy demands of neurons. Defects in excitatory and inhibitory synapses have been implicated in schizophrenia, likely contributing to positive and negative symptoms as well as impaired cognition. Recently, accumulating evidence has suggested that bioenergetic systems, important in both synaptic function and cognition, are abnormal in psychiatric illnesses such as schizophrenia. Animal models of synaptic dysfunction demonstrated endophenotypes of schizophrenia as well as bioenergetic abnormalities. We report findings on the bioenergetic interplay of astrocytes and neurons and discuss how dysregulation of these pathways may contribute to the pathogenesis of schizophrenia, highlighting metabolic systems as important therapeutic targets.     

Ethnic disparities in problem behaviour in adolescence contribute to ethnic disparities in social class in adulthood

BACKGROUND: It is important for prevention of social class disparities to know how ethnic disparities in social class arise among migrant children. We contribute to this understanding by examining the role of problem behaviour in adolescence. METHODS: Prospective observational study with 753 Dutch native and 217 Turkish migrant adolescents (11-18 year) followed for 10 years. Internalising and externalising problems were assessed in adolescence and employment status and occupational level were assessed in adulthood. The difference in odds ratios (OR) before and after adjustment for internalising and externalising problems was an indication of the predictive value of disparities in internalising and externalising problems for the development of social class disparities. RESULTS: A total of 135 (62%) of the Turkish and 602 (80%) of the Dutch adults were employed. Internalising and externalising problems were not associated with employment status. Of the employed, 65 (48%) Turkish and 179 (30%) Dutch adults worked in low-level occupations (p < 0.0001). Internalising and externalising problems were associated with both ethnicity and occupation. The OR for low-level occupation for Turkish adults was 1.78 (1.19-2.65), indicating ethnic disparities. Adjustment for internalising problems lowered the OR with 36% to 1.50 (0.97-2.31), and adjustment for externalising problems lowered it with 8% to 1.72 (1.15-2.57). Findings were similar for men and women and did not vary by age. CONCLUSIONS: Ethnic disparities in occupational level in adulthood could partly be attributed to disparities in mental health between Turkish migrants and Dutch natives in adolescence. Prevention of ethnic disparities in mental health at young age may therefore also contribute to the prevention of occupational differences in adulthood.     

Progress in neuroprotection in Parkinson's disease

Slowing or aborting the progress of neurodegeneration in Parkinson's disease (PD) remains the most important unmet need of this disorder. There are several recent developments in trial design and also in drugs under investigation for possible neuroprotective effect. Emphasis has been placed on clinical as opposed to imaging end-points and these include change in a clinical rating scale, e.g. United Parkinson's disease Rating Scale (UPDRS), or time to additional therapy. The introduction of the delayed-start, or wash-in, trial design adds an additional dimension to drug evaluation for neuroprotection. Compounds that have been recently tested in clinical trial include the monoamine oxidase-B inhibitor rasagiline, the anti-apoptotic agents TCH346 and CEP1347, and the promitochondrial agent creatine. The dopamine agonists have been evaluated for a neuroprotective effect using imaging end-points. Perhaps the most important and simplest concept for neuroprotection has been the theory that early dopaminergic support for the degenerating dopaminergic system per se provides significant long-term clinical benefit for PD patients.     

Changes in parasympathetic system in medulla oblongata in male pigs in the course of tachycardia-induced cardiomyopathy

Background

Autonomic imbalance constituting a fundamental feature of heart failure (HF) has been assessed mainly at the periphery. Changes in the functioning of autonomic centers in the brain remain unclear. We investigated the molecular elements of parasympathetic system, i.e. α7 nicotinic acetylcholine receptor (α7nAChR) and enzymes metabolizing acetylcholine (acetylcholinesterase, AChE, choline acetyltransferase, ChAT) in medulla oblongata (MO) of male pigs with chronic tachycardia-induced cardiomyopathy.

Methods

The mRNA levels of AChE, ChAT, α7nAChR and X-box binding protein 1 (spliced form, XBP1s) in MO were analyzed using qPCR, AChE and ChAT activities using spectrophotometry, proteasome activity using fluorometry, and the protein level of α7nAChR using Western blotting.

Results

The development of systolic HF was accompanied by an increase in circulating catecholamines, a decrease in the AChE and α7nAChR mRNA in MO, an increase in AChE activity (all p < 0.05), and no change in either the mRNA or activity of ChAT. Both circulating catecholamine levels and AChE activity were inversely related to systolic function of left myocardial ventricle (p < 0.05). The level of α7nAChR protein in MO and its cytoplasmatic fraction were higher in pigs with moderate and severe HF as compared to the other animals (p < 0.01). There was no difference in proteasome activity in MO between diseased and healthy animals, whereas the XBP1s mRNA decreased during HF progression (p < 0.05).

Conclusions

Molecular elements of parasympathetic system are changed within the medulla oblongata during the progression of systolic non-ischemic heart failure in male pigs, indicating a functional link between MO and heart in HF.