选择性缄默症女孩的沙盘游戏治疗个案报告

一、背景（一）受理小E，某小学一年级学生，由老师推荐而来，入学以来在班级中从不讲话，与同伴、教师交往方面有严重困难。（二）成长经历及现状自然情况：小E，7岁，独生女，核心家庭，健康状况良好。成长经历：小E出生后与父母一起生活，与妈妈关系亲密；从小内向、怕生，与外界接触不多，出门会害怕、哭泣；坐、走路、说话等发育比同龄孩子较晚；父母均有喝斥制止小E的行为。父母的关注点：父母关心孩子的学习，认为孩子脑子笨，学习成绩不好；表示其在家表现正常，能讲话。初步印象：肤色较黑，面容黯淡，异常拘谨，神情呆滞，恐惧不安。

维甲酸受体激动剂AM80抗阿尔治海默症最新研究进展

目的综述AM80他米巴罗汀(tamibarotene,AM80)抗阿尔治海默症(Alzheimer's Disease,AD)药理作用及其作用机制、不良反应以及临床用药安全等最新研究进展。方法通过阅读近几年国内外的相关文献,对AM80抗阿尔治海默症最新研究报道进行详细的归纳总结。结果 AM80是一个合成的维甲酸受体激动剂,具有很好的抗阿尔治海默症作用。AM80作为一个多靶点药物,它通过转录调控多种与AD发病相关的基因;能够减少β淀粉样肽在脑部的沉积;还能够改善AD小鼠的学习记忆功能;有效弥补脑内乙酰胆碱的减少;并且能够增加小胶质细胞对Aβ(beta amyloid)的降解功能并伴随脑部炎症的减少。结论 AM80有望成为一个安全和有效的预防和治疗AD的药物,具有广泛的临床应用前景。

基于老年人失智症预防的游戏APP设计研究

失智症(Dementia)是一种因脑部伤害或疾病所导致的渐进性认知功能退化病症,是疾病现象而非正常老化现象。随着全球人口老龄化趋向日益明显,老年人失智症的病患率逐年飙升,对失智症进行预防及治疗成为全社会面临的共同难题,而我国在这方面的需求更加紧迫与广泛。笔者致力于设计面向罹患失智症高风险族群的移动设备端游戏APP,试图通过提前训练脑力、活化脑细胞达到预防失智症发生的目的。

不同程度血尿酸水平对老年人群认知功能损害的影响

目的探讨不同水平血尿酸与老年人群的认知功能损害的关系。方法本研究入组年龄>60岁人群共1 304例,其中男性816例,女性488例,收集年龄、受教育年限、吸烟史、疾病信息、BMI等一般资料,行简易智能精神状态量表检查(MMSE)、抑郁量表、Hachinski缺血量表,并测定血尿酸和低密度脂蛋白指标。按照男女性别分类以及血尿酸水平(360μmol/L)分层进行一般线性模型和Logistic回归分析,并调整了年龄,受教育年限及心血管疾病危险因素。结果 (1)在男性人群中,血尿酸水平与MMSE值呈显著正相关(beta=2.58,P<0.05),但在女性人群中不显著。按照尿酸水平分层,在低水平尿酸组(<360μmol/L),两组人群的血尿酸水平与MMSE值成显著正相关(P均<0.05),但在较高血尿酸组(≥360μmol/L),两组人群均无此相关性。(2)在低血尿酸水平组中,较高的血尿酸能显著降低认知功能损害的风险,该相关性在男女人群中都存在(男性OR=0.69,95%CI:0.53~0.90,P<0.001,女性OR=0.77,95%CI:0.52~0.90,P=0.001)。而在较高水平血尿酸组中,血尿酸与认知功能损害风险无统计学意义(P均>0.05)。结论血尿酸对认知功能具有保护作用,但该相关性可能仅在一定水平内发挥作用。

Genetic predisposition to inflammation:a new risk factor of Alzheimer's disease

Inflammation has been shown to play an important role in the progression of Alzheimer＇s disease （AD）. Recent epidemical study indicates that the incidence of AD in some populations is substantially influenced by the gene polymorphisms of the inflammation mediators. Meanwhile, an ensured risk factor, the ApoE ε4 allele is also reported to directly promote inflammation. Accordingly, it appears that an individual genetic background has partly determined his predisposition for AD by the extent of the inflammation response to the chronic stimulus by β-amyloid peptide （Aβ） deposits and other antigen stressor in the elderly. Hence we present a hypothesis that the inflammation genotypes may contribute to AD susceptibility. This may provide a new orientation both for future identification of individuals at risk and for personalized medication.

New lead discovery for novel M_1 agonists:pharmacophore model based on DISCO computation and virtual screening

To discover new lead compounds for M1 agonists. Ten typical M1 agonists were superimposed to build a M1 agonists 3D-pharmacophore model using distance-comparisons （DISCO） method without the previous knowledge of the three-dimensional structure of M1 receptor. Virtual screening strategy was used to analyze the Available Chemicals Directory-Screening Compounds （ACD-SC） to identify possible new hits. Twenty-two compounds which fit the pharmacophore model well and are not similar with known M1 agonists were purchased in order to evaluate their M1 receptor agonist activity. One of them shows M1 receptor agonist activity with EC50 of 4.90 μmol/L and maximum response. Multiple of 10.0 which shows it worthy of further study as a new lead compound for M1 agonists.

Alzheimer’s disease classification based on sparse functional connectivity and non-negative matrix factorization

A novel framework is proposed to obtain physiologically meaningful features for Alzheimer's disease(AD)classification based on sparse functional connectivity and non-negative matrix factorization.Specifically,the non-negative adaptive sparse representation(NASR)method is applied to compute the sparse functional connectivity among brain regions based on functional magnetic resonance imaging(fMRI)data for feature extraction.Afterwards,the sparse non-negative matrix factorization(sNMF)method is adopted for dimensionality reduction to obtain low-dimensional features with straightforward physical meaning.The experimental results show that the proposed framework outperforms the competing frameworks in terms of classification accuracy,sensitivity and specificity.Furthermore,three sub-networks,including the default mode network,the basal ganglia-thalamus-limbic network and the temporal-insular network,are found to have notable differences between the AD patients and the healthy subjects.The proposed framework can effectively identify AD patients and has potentials for extending the understanding of the pathological changes of AD.

The pathogenesis of Alzheimer and pharmaceutical research on prevention

Senile Dementia is the illness with a symptom of ongoing cognitive obstacle and loss of memory function. With our population aging, dementia and depression in old age is increasing rapidly. It is estimated that by 2020, depressive disorder will become the second largest human disease leading to crippling. By 2040, globally the number of people with dementia will reach 81.1 million while the number of dementia patients in China will be the sum of that in all developed countries. Its incidence increases exponentially with age and the incidence of the elderly over 85 reach up to 8% -10%. Among all dementia patients, people with Alzheimer＇ s disease （Alzheimer＇ s disease, AD） accounted for 50 % -70%, the rest is vascular dementia （vascular dementia, VD） and mixed dementia. In the United States, Alzheimer＇ s disease has become the fourth leading cause of death followed after cardiovascular disease, cancer and stroke. Through comprehensive control strategy, we can improve the mental health level of old people, so as to protect the physical and mental health, improving the life quality of old people.

Pathway and mechanism of oxidative stress in Alzheimer's disease

Current hypotheses of pathogenesis of neuronal degeneration in Alzheimer's disease (AD) have been proposed, including formation of free radicals, oxidative stress, mitochondrial dysfunction, inflammatory processes, genetic factors, environmental impact factors, apoptosis, and so on. Especially, oxidative stress plays an essential role in AD pathogenesis by the function of linking agent. Oxidative stress in AD mainly includes lipid peroxidation, protein oxidation and DNA oxidation. Lipid peroxidation plays a key role in the development and progression of AD. Protein oxidation is an important mechanism in AD. Oxidative damage to DNA may plays an important role in aging and AD.

Neurotoxicity and Biomarkers of Lead Exposure: a Review

Appropriate selection and measurement of lead biomarkers of exposure are critically important for health care management purposes,public health decision making,and primary prevention synthesis.Lead is one of the neurotoxicants that seems to be involved in the etiology of psychologies.Biomarkers are generally classified into three groups:biomarkers of exposure,effect,and susceptibility.The main body compartments that store lead are the blood,soft tissues,and bone;the half-life of lead in these tissues is measured in weeks for blood,months for soft tissues,and years for bone.Within the brain,lead-induced damage in the prefrontal cerebral cortex,hippocampus,and cerebellum can lead to a variety of neurological disorders,such as brain damage,mental retardation,behavioral problems,nerve damage,and possibly Alzheimer’s disease,Parkinson’s disease,and schizophrenia.This paper presents an overview of biomarkers of lead exposure and discusses the neurotoxic effects of lead with regard to children and adults.

Spatial learning deficits in amyloid precursor protein 770 transgenic mice

Objective To determine whether learning deficits could be seen in transgenic mice expressing human amyloid precursor protein 770 (APP 770 ) Methods Female heterozygous transgenic and nontransgenic mice aged 3, 6 and 9 months at the start of testing were used, with eight mice in each age group All mice were subjected to various behavioral tasks including the Y maze task and the Morris water maze After behavioral testing, the mice were sacrificed, and their brain tissues were used for measuring the choline acetyltransferase (ChAT) activity Results Nine month old transgenic mice exhibited spatial learning deficits in the Morris water maze and in spontaneous alternation in the Y maze, compared with those of the age matched non transgenic mice The behavioral changes accompanied a reduction of ChAT activity in the cortical and hippocampal regions of transgenic mice On the other hand, these behavioral deficits were not observed in transgenic mice either at 3 or at 6 months of age, in which ChAT activity remained unchanged Conclusions The present results show that the learning impairment observed in 9 month old APP 770 transgenic mice are accompanied by a decrease in cortical and hippocampal ChAT activities This suggests that cholinergic deficits may be involved in the learning impairment observed in these APP 770 mice This model will be a useful tool in advancing our understanding of the relationship between the cholinergic system and the cognitive deficits observed in Alzheimer's disease (AD)

Vanadyl complexes work with cinnamaldehyde in promoting cell viability under the β-amyloid burden in SH-SY5Y neural cells

The Alzheimer＇s disease （AD） is one of the common cognitive disorders in the elderly. AD shares some similar pathological characters with diabetes mellitus （DM）, suggesting potential application of anti-diabetic agents, such as vanadyl complexes, in therapeutic treatment of AD. In the present work, we studied the effects of vanadyl acetylacetonate （VO（acac）2） and cinnamaldehyde （CA） on an AD model based on SH-SY5Y neural cells. The experimental results showed that VO（acac）2 at sub-micromolar concentrations could improve the viability of neural cells with or without increased β-amyloid （Aβ） burden; and the combination of VO（acac）2 and CA showed an additive cell protection effects. Further investigation revealed that for SH-SY5Y neural cells, VO（acac）2 could activate PPART-AMPK signal transduction and inhibit GSK 3β, one of the major kinases for Tau hyperphosphorylation. Meanwhile, CA could correct the abnormal mitochondrial morphology due to Aβ-induced excessive mitochondrial fission, thus restoring/enhancing the mitochondrial function. In addition, both VO（acac）2 and CA decreased intracellular reactive oxygen species （ROS） level and inhibited formation of toxic Aβ oligomers. Overall, VO（acac）2 might work with CA in improving the neural cell viability under the Aβ burden, suggesting application of vanadium metallodrugs in AD treatment.

Roles of the prostaglandin E2 receptors EP subtypes in Alzheimer’s disease

Neuroinflammation has always been of concern in the pathogenesis of Alzheimer’s disease （AD）. As a major inflammatory mediator, prostaglandin E2 （PGE2） plays an important role in the inflammatory process of AD. Up to now, there is still controversy on the neuroprotective or neurotoxic role of PGE2. However, the role of PGE2 in neurodegeneration may be far more complex, due to the 4 EP receptor subtypes. This article aims to summarize the relationship between PGE2 receptor EP subtypes and AD. It is believed that a better understanding of the PGE2 receptor EP subtypes may help to clarify the relation between inflammation and AD, and to develop novel therapeutic strategies targeting specific EP receptor for AD treatment.

Design and synthesis of benzimidamides as potential BACE1 inhibitors

Computer aided fragment-based lead discovery has been successfully applied to the design of inhibitors of aspartyl protease enzyme β-secretase（BACE1）.A benzimidamide fragment,which binds to the two catalytic aspartic acid residues in the active site of the enzyme,was selected as the starting compound.A novel series of 3-phenethylbenzimidamide inhibitors were designed and synthesized.Although biological evaluation results showed that the compounds displayed poor inhibitory activity towards BACE1,3-phenethylbenzimidamide analogs might be modified as potential BACE1 inhibitors.

Cinnamaldehyde promotes mitochondrial function and reduces Aβ toxicity in neural cells

Cinnamon and its major active component, cinnamaldehyde, have been shown to be neuroprotective in models of Alzheimer＇s disease （AD）. To further investigate the mechanism of cinnamaldehyde, we investigated the effects of cinnamaldehyde focusing on mitochondrial function in SH-SYSY neural cells. The results demonstrated that cinnamaldehyde could enhance neural cell viability with or without increased Aβ levels. Cinnamaldehyde facilitated the maintenance of normal mitochondrial morphology, preserved the mitochondrial membrane potential （ATm）, and reduced production of reactive oxygen species （ROS）. Cinnamaldehyde also decreased the expression of dynamin-related protein 1 （Drpl）, a protein critically involved in mitochondrial dynamics. In addition, cinnamaldehyde inhibited Aβ oligomerization, but it had no effects on Tau phosphorylation. In overall, cinnamaldehyde promoted mitochondrial function and inhibited Aβ toxicity, and these two properties may both contribute to the neuroprotective effect. These results suggest that cinnamaldehyde could be a potential nutriceutical in the prevention and even therapeutic treatment of AD as well as other aging-related metabolic syndromes.

Airborne fine particulate matter induces cognitive and emotional disorders in offspring mice exposed during pregnancy

Gestational exposure to PM_(2.5) is associated with adverse postnatal outcomes.PM_(2.5) can enter alveoli by using intratracheal instillation,even penetrate through lung cells into the blood circulation.Subsequently,they are transferred across the placenta and fetal blood brain barrier,causing the adverse birth outcomes of offspring.This study demonstrated that the gestational exposure resulted in cognitive and emotional disorders in female offspring although the offspring were not exposed to PM_(2.5).Placental metabolic pathways modulated fetal brain development and played a pivotal role for maternal-placentalfetal interactions in the fetal programming of adult behavioral and mental disorders.Samples of fetus,offspring hippocampus and placenta from the mice exposed to PM_(2.5) were investigated using a comprehensive approach including mass spectrometry-based lipidomics and three-dimensional imaging.The exposure induced the neuro-degeneration in hippocampus,impairment of placental cytoarchitecture,and reprogramming of lipidome,which might affect the modulation of maternal-fetal cross-talk and result in the behavior disorders of offspring.The variation of spatial distribution of lipids was profoundly affected in dorsal pallium and hippocampal formation regions of fetal brain,offspring hippocampus,as well as labyrinth and junctional zones of placenta.The abundance alteration of lipid markers associated with neurodegenerative diseases was validated in transgenic mouse model with Alzheimer’s disease and human cerebrospinal fluid from patients with Parkinson’s disease.The finding could help with the selection of more suitable heterogeneous-related substructures targeting PM_(2.5) exposure and the exploration of PM_(2.5)-induced toxicological effects on neurodegenerative diseases.

Copper ions influence the toxicity of β-amyloid(1-42) in a concen-tration-dependent manner in a Caenorhabditis elegans model of Alzheimer’s disease

β-amyloid (Aβ) and copper play important roles in the pathogenesis of Alzheimer’s disease (AD).However,the behavioral correlativity and molecular mechanisms of Aβ and copper toxicity have been investigated less often.In the present study,we investigated the interaction and toxicity of Aβ1-42 and copper in the Aβ1-42 transgenic Caenorhabditis elegans worm model CL2006.Our data show that the paralysis behavior of CL2006 worms significantly deteriorated after exposure to 10-3 mol L-1 copper ions.However,the paralysis behavior was dramatically attenuated with exposure to 10-4 mol L-1 copper ions.The exogenous copper treatment also partially changed the homeostatic balance of zinc,manganese,and iron.Our data suggest that the accumulation of reactive oxygen species (ROS) was responsible for the paralysis induced by Aβ and copper in CL2006.The ROS generation induced by Aβ and copper appear to be through sod-1,prdx-2,skn-1,hsp-60 and hsp-16.2 genes.

A fusion of least squares and empirical likelihood for regression models with a missing binary covariate

Multiply robust inference has attracted much attention recently in the context of missing response data. An estimation procedure is multiply robust, if it can incorporate information from multiple candidate models, and meanwhile the resulting estimator is consistent as long as one of the candidate models is correctly specified. This property is appealing, since it provides the user a flexible modeling strategy with better protection against model misspecification. We explore this attractive property for the regression models with a binary covariate that is missing at random. We start from a reformulation of the celebrated augmented inverse probability weighted estimating equation, and based on this reformulation, we propose a novel combination of the least squares and empirical likelihood to separately handle each of the two types of multiple candidate models,one for the missing variable regression and the other for the missingness mechanism. Due to the separation, all the working models are fused concisely and effectively. The asymptotic normality of our estimator is established through the theory of estimating function with plugged-in nuisance parameter estimates. The finite-sample performance of our procedure is illustrated both through the simulation studies and the analysis of a dementia data collected by the national Alzheimer's coordinating center.

The design, synthesis and α7 nicotinic acetylcholine receptors positive allosteric modulative evaluation of 3H-quinazolin-4-one derivatives

A series of new 6-substituted 3 H-quinazolin-4-ones（3 a-3 d） were designed, synthesized and evaluated as the type I positive allosteric modulators（PAMs） of human α7 n ACh R expressed in Xenopus ooctyes by two-electrode voltage clamp. However, no compound showed a better efficacious PAM than lead compound 2 in the presence of acetylcholine（100 μM）. The structure-activity relationship（SAR） analysis suggested that thiazolo[4,5-d]pyrimidin-7（6 H）-one was the key biological skeleton.

A simple and sensitive electrochemical impedimetric immunosensor for the detection of apolipoprotein E4 based on CeZnO nanoparticle

Human apolipoprotein E4(APOE4)is an important risk factor for late-onset Alzheimer’s disease(AD).However,little progress has been made for the detection of APOE4,and most of existing detection methods suffer from time-consuming process and expensive instruments.This study firstly proposed a simple and sensitive electrochemical method for detection of APOE4 based on carboxyl-rich CeZnO nanoparticles.Under the optimal conditions,the fabricated immunosensor exhibited a good linear relationship ranging from 10 to 100 ng/mL with the detection limit of 1.8 ng/mL(S/N=3).The proposed electrochemical immunosensor had excellent selectivity,reproducibility and stability.Good performance was observed for sensitive determination of APOE4 in human serum sample,which provided a strong support for the detection of APOE4 and early clinical prevention of AD.