外泌体在阿尔茨海默病发病机制中的研究进展

外泌体(exosomes)是一种可被多种细胞分泌的纳米级膜性微囊泡,其易透过血脑屏障并参与细胞间物质交换及信号传导,可影响多种生理和病理过程。近年来,外泌体逐渐被重视,然而外泌体在阿尔茨海默病(AD)中的研究还相对不足。因此,本文综述了其在AD发病机制中的研究,着重总结了外泌体在β-淀粉样蛋白(Aβ)聚集和斑块形成、高磷酸化tau形成神经原纤维缠结等病理过程中的研究进展,为其作为疾病诊断标志物和治疗载体提供新思路。     

抗抑郁药联合治疗之前应考虑各种单药优化治疗方案(英文)

许多慢性抑郁症患者或反复发作的抑郁症患者对现有的各种抗抑郁药物治疗反应不理想。医生在治疗这些患者时,可能在原来抗抑郁药物的基础上增加其他药物,包括用第二种或第三种抗抑郁药物辅助治疗。虽然在高收入国家这是精神科医生和初级保健医生广泛使用的方法,但是证明这种抗抑郁药联合治疗方法有效的证据不多。只有当不同种类的抗抑郁药物的单药优化治疗方案无效后,才可谨慎使用联合治疗的方法。     

阿米洛利对复杂型热性惊厥的影响

目的观察阿米洛利对复杂型热性惊厥的作用及其可能机制。方法建立Sprague-Dawley(SD)幼鼠复杂型热性惊厥模型,将40只SD幼鼠分为正常对照组、热性惊厥组、阿米洛利两种剂量预处理组(1.3阿米洛利组和10阿米洛利组),每组10只。在热性惊厥发作过程中观察阿米洛利预处理对体温升高、发作潜伏期的影响,以及对热性惊厥后海马区星形胶质细胞数及白细胞介素1β(IL-1β)mRNA含量的影响。结果热性惊厥组于4.3~6.8 min体温达到39.5℃,1.3阿米洛利组和10阿米洛利组分别于8.3~10 min和9.3~11.6 min达到39.5℃,后两者体温达39.5℃的时间明显晚于热性惊厥组(P0.01),且1.3阿米-洛利组和10阿米洛利组间有显著性差异(P0.05)。1.3阿米洛利组发作潜伏期为10.67~14.50 min,体温阈值为41.3~42.1℃,10阿米洛利组潜伏期为12.33~16.60 min,体温阈值为41.4~42.1℃,而热性惊厥组潜伏期为7.67~9.50分钟,体温阈值为41.0~41.7℃,1.3和10阿米洛利两组潜伏期较热性惊厥组明显延长,并且全身强直发作的体温阈值明显高于热性惊厥组(P0.01),阿米洛利高低剂量组间有明显差异(P0.05)。阿米洛利预处理组星形胶质细胞较正常对照组增多,而较热性惊厥组明显减少(均P0.01)。阿米洛利预处理组IL-1βmRNA含量明显少于热性惊厥组(P0.01)。结论阿米洛利可抑制复杂型热性惊厥发作,具有一定的抗热性惊厥作用,这可能与抑制星形胶质细胞增殖、抑制炎性因子生成有关。     

MPTP小鼠脑沉默信息调节因子1和缺氧诱导因子-1α的表达及行为学检测

目的本研究旨在研究MPTP模型小鼠中沉默信息调节因子1(SIRT1)和缺氧诱导因子1α(HIF-1α)的表达情况以及行为学的变化。方法选用MPTP处理C57BL/6小鼠构建PD动物模型,采用行为学实验、高效液相色谱(HPLC)、免疫组化等方法检验模型的建立是否成功,并在小鼠模型中检测SIRT1和HIF-1α的表达情况。结果 MPTP处理的小鼠表现出显著的行为学异常,主要体现在自主活动减少(P0.001)、步距缩短(P0.001),且有显著运动迟缓(P0.001)。HPLC结果发现,模型组小鼠纹状体区域多巴胺(DA)及其代谢产物减少(P0.001)。免疫组化结果提示黑质区域多巴胺能神经元标志物酪氨酸羟化酶(TH)和多巴胺转运体(DAT)的表达明显下调(P0.01)。分子生物学方面,PD模型小鼠的SIRT1表达降低(P0.05),HIF-1α表达增加(P0.05)。结论 PD模型小鼠表现出明显的行为学异常,多巴胺能神经元标志物检测提示成功复制PD动物模型,同时发现模型小鼠的SIRT1/HIF-1α的表达异常,提示该信号通路可能参与了PD的疾病过程。     

血脑屏障与β-淀粉样蛋白相互作用在阿尔茨海默病的研究进展

既往研究普遍认为血脑屏障的破坏为血管性痴呆的始动因素,β淀粉样蛋白(Aβ)沉积为阿尔茨海默病的始动因素。然而随着对阿尔茨海默病发病机制研究的深入,越来越多的证据表明,血脑屏障与Aβ相互作用共同促进阿尔茨海默病的发生发展。     

胸腺素β4在血管再生中的研究进展

胸腺素β4（thymosin beta4,Tβ4）作为一种多功能的多肽,广泛分布于哺乳动物和其他脊椎动物中。Tβ4的促进血管再生、神经轴突再生、肿瘤生长和伤口愈合、抑制炎症等功能已经成为国内外研究的焦点,并且Tβ4可能成为治疗卒中的新靶点。本文就Tβ4在血管再生中的研究进展做一综述。     

高压氧治疗可影响受损眼眶中视神经的三维有限元分析

实验选择右侧眼眶粉碎性骨折中年男性患者1例,根据其CT扫描的图像,建立带组织的眼部三维有限元模型,通过改变受损侧颅骨的弹性模量和外界压强,模拟分析视神经在高压氧环境下的受力情况。模拟结果显示,受损和完整眼眶侧的视神经最大应力值均发生在视神经和眼球的接触部位。当外界压强保持不变,随着受损眼眶侧的颅骨弹性模量的降低,受损眼眶侧的视神经应力逐渐增大,随着颅骨弹性模量的降低,视神经的应力显著增加,而完整侧的应力值变化不大。当颅骨弹性模量不变时,随着外界压强的增加,视神经的最大应力均迅速增加。说明在高压氧环境中,患者的视神经可能受到压迫,受损眼眶侧视神经的应力远远大于完整眼眶侧的视神经应力。     

脑小血管病患者病程进展与血管内皮功能障碍因子表达水平的相关性研究

目的 探讨脑小血管病（CSVD）患者病程进展与血管内皮功能障碍（ED）因子[同型半胱氨酸（Hcy）、肿瘤坏死因子α（TNF-α）、白细胞介素6（IL-6）和C反应蛋白（CRP）]表达水平的相关性。方法 选取2016年6月至2017年9月在我科诊断为CSVD的患者60例作为研究对象,所有患者均进行了头颅MRI检查。采集外周血,利用ELISA检测与血管内皮功能障碍相关因子Hcy、TNF-α、IL-6和CRP的表达水平。对所纳入患者进行1年时间的随访,随访期内均进行头颅MRI检查。根据随访观察结果,将所纳入患者分为进展组和无进展组,比较两组患者血清Hcy、TNF-α、IL-6和CRP表达水平的差异,并分析它们与CSVD进展的相关性。结果 在60例患者中,病程进展的有38例,病程无进展的有22例。与病程无进展组相比,病程进展组患者血清Hcy（17.62±7.23 VS 11.35±5.41,P=0.007）和IL-6（17.46±6.97 VS 8.48±4.67,P=0.001）的表达水平高;TNF-α和CRP的表达水平在两组间无差异。经Spearman等级相关分析发现,CSVD患者的病程进展与血清Hcy（r=0.587,P=0.015）和IL-6（r=0.644,P=0.009）的表达水平存在相关性;而与TNF-α和CRP的表达水平不存在相关性。结论 CSVD患者血清中血管内皮功能障碍因子Hcy、IL-6的表达水平与病程进展存在相关性,检测这些因子的表达对于判断病情预后具有一定参考意义。     

α-内收蛋白基因rs4963多态性与脑出血的关系

目的研究α-内收蛋白基因rs4963多态性与脑出血的关系。方法对甘肃地区238例脑出血患者和240例健康对照者应用血液基因组DNA提取试剂盒方法检测α-内收蛋白基因rs4963多态性,分析比较脑出血病例组和对照组rs4963多态性的分布差异。结果病例组和对照组α-内收蛋白基因rs4963基因型分布、等位基因频率差异均无统计学意义(P0.05)。按性别分层后,病例组与对照组基因型分布和等位基因频率差异仍无统计学意义(P0.05)。结论甘肃地区α-内收蛋白基因rs4963多态性与脑出血无关联。     

阿尔茨海默病中β-淀粉样蛋白清除机制的研究进展

β-淀粉样蛋白(Aβ)形成的斑块沉积是阿尔茨海默病(AD)的一个特征性病理改变。在早发型和散发型AD患者脑中均可出现Aβ清除障碍。了解Aβ清除途径的具体机制对寻找有效的AD治疗策略至关重要。本文将对Aβ细胞内降解清除途径、血脑屏障转运清除途径、脑间质液泵流清除途径及脑脊液吸收清除途径的具体机制作一综述。     

Denervation study of synapses of organ of corti of old world monkeys

Fine structural characteristics of synapses in the spiral organ of Corti were examined, with reference to differences between inner and outer haircell systems, and to location of neurons of origin of efferent axons. Surgical interruption of crossed olivocochlear bundle, of vestibular nerve, of facial nerve, and excision of superior cervical ganglia were used to determine the pathways of efferent axons. Interruption of the vestibular nerve near the brainstem results in degeneration of all efferent terminals on outer hair cells. Mid-line lesions at, and caudal to, the facial colliculus result in degeneration of about half of these efferent terminals. Efferent synaptic bulbs to the inner hair-cell system are small, of the order of one micron, and form type 2 junctions with afferent dendrites. They tend to have more large dense-core vesicles (about 80 nm) than the large efferent terminals of the outer hair-cell system, and appear to be the terminals of axons in the habenula perforata, which exhibit varicosities laden with large dense core vesicles. The varicosities are unaffected by excision of the superior cervical ganglia. So far as our material can reveal, it appears that the varicosities in the habenula perforata do not survive vestibular root interruption, nor do the efferent processes in the internal spiral bundle or at the base of inner hair cells. Most interestingly, the afferent processes of the inner hair-cell system, as identified for example by their relation to pre-synaptic bodies in the inner hair cells, are subject to a trans-synaptic reaction after severance of the vestibular root. They undergo a dramatic cytological transformation, characterized by increase of volume, engorgement with microtubules, microfilaments, microvesicles of various sizes, and clusters of lysosomes. Thus, both the efferent and afferent terminals of the inner hair-cell system show marked cytological differences from the corresponding terminals of the outer hair cell system.     

Mechanism of action of tubocurarine on nicotinic cholinoreceptors of neurons of the sympathetic ganglia of rats

Tubocurarine (Tc) effect on membrane currents elicited by acetylcholine (ACh) was studied in isolated superior cervical ganglion neurons of rat using patch-clamp method in the whole-cell recording mode. The "use-dependent" block of ACh current by Tc was revealed in the experiments with ACh applications, indicating that Tc blocked the channels opened by ACh. Mean lifetime of Tc-open channel complex, tau, was found to be 9.8 +/- 0.5 s (n = 7) at -50 mV and 20-24 degrees C. tau exponentially increased with membrane hyperpolarization (e-fold change in tau corresponded to the membrane potential shift by 61 mV). Inhibition of the ACh-induced current by Tc (3-30 microM/1) was completely abolished by membrane depolarization to the level of 80-100 mV. Inhibition of ACh-induced current was augmented at increased ACh doses. It is concluded that the open channel block produced by Tc is likely to be the only mechanism for Tc action on nicotinic acetylcholine receptors in superior cervical ganglion neurons of rat.     

The effect of age of onset of PD on risk of dementia

Background Dementia occurs in the majority of patients with Parkinson’s disease (PD). Late onset of PD has been reported to be associated with a higher risk for dementia. However, age at onset (AAO) and age at baseline assessment are often correlated. The aim of this study was to explore whether AAO of PD symptoms is a risk factor for dementia independent of the general effect of age. Methods Two community-based studies of PD in New York (n = 281) and Rogaland county, Norway (n = 227) and two population-based groups of healthy elderly from New York (n = 180) and Odense, Denmark (n = 2414) were followed prospectively for 3–4 years and assessed for dementia according to DSM-IIIR. All PD and control cases underwent neurological examination and were followed with neurological and neuropsychological assessments. We used Cox proportional hazards regression based on three different time scales to explore the effect of AAO of PD on risk of dementia, adjusting for age at baseline and other demographic and clinical variables. Findings In both PD groups and in the pooled analyses, there was a significant effect of age at baseline assessment on the time to develop dementia, but there was no effect of AAO independent of age itself. Consistent with these results, there was no increased relative effect of age on the time to develop dementia in PD cases compared with controls. Interpretation This study shows that it is the general effect of age, rather than AAO that is associated with incident dementia in subjects with PD. Received in revised form: 22 December 2005     

Limits of deinstitutionalization--perspectives of relatives of psychiatric patients

After a hopeful beginning, the social process of the reintegration of those with severe mental illness has come to a standstill. I am led to wonder whether "the community" really wants to live together with people suffering from severe mental illness, and if so, how closely? As long as the medical treatment of mental illness provided by the general practitioners is fundamentally deficient, as they are not able to prescribe the necessary interventions--such as out-patient psychiatric nursing, and service providers in the out-patient sector are content with offering increasingly intensive forms of care for the less seriously ill at the cost of the Social Welfare System--the reintegration of those with serious mental illness remains an illusion--which is mainly to the benefit of providers of residential care in homes and hostels.