Resilience to structural and molecular changes in excitatory synapses in the hippocampus contributes to cognitive function recovery in Tg2576 mice

Plaques of amyloid-β(Aβ)and neurofibrillary tangles are the main pathological characteristics of Alzheimer’s disease(AD).However,some older adult people with AD pathological hallmarks can retain cognitive function.Unraveling the factors that lead to this cognitive resilience to AD offers promising prospects for identifying new therapeutic targets.Our hypothesis focuses on the contribution of resilience to changes in excitatory synapses at the structural and molecular levels,which may underlie healthy cognitive performance in aged AD animals.Utilizing the Morris Water Maze test,we selected resilient(asymptomatic)and cognitively impaired aged Tg2576 mice.While the enzyme-linked immunosorbent assay showed similar levels of Aβ42 in both experimental groups,western blot analysis revealed differences in tau pathology in the pre-synaptic supernatant fraction.To further investigate the density of synapses in the hippocampus of 16-18 month-old Tg2576 mice,we employed stereological and electron microscopic methods.Our findings indicated a decrease in the density of excitatory synapses in the stratum radiatum of the hippocampal CA1 in cognitively impaired Tg2576 mice compared with age-matched resilient Tg2576 and non-transgenic controls.Intriguingly,through quantitative immunoelectron microscopy in the hippocampus of impaired and resilient Tg2576 transgenic AD mice,we uncovered differences in the subcellular localization of glutamate receptors.Specifically,the density of GluA1,GluA2/3,and mGlu5 in spines and dendritic shafts of CA1 pyramidal cells in impaired Tg2576 mice was significantly reduced compared with age-matched resilient Tg2576 and non-transgenic controls.Notably,the density of GluA2/3 in resilient Tg2576 mice was significantly increased in spines but not in dendritic shafts compared with impaired Tg2576 and non-transgenic mice.These subcellular findings strongly support the hypothesis that dendritic spine plasticity and synaptic machinery in the hippocampus play crucial roles in the mechanisms of cognitive resilience in Tg2576 mice.

TSC1-mTOR-PLK轴以阶段特异性方式调节从施旺细胞增殖到髓鞘形成的内稳态开关

恰如其分的外周髓鞘形成取决于雪旺细胞增殖与分化进程间的平衡。丝氨酸/苏氨酸激酶(mTOR)整合多种环境因素,是细胞生长、代谢、发挥作用的中枢调节者。本文报道了一种mTOR的负性调节剂——结节性硬化复合体(TSC1),通过控制细胞增殖和髓鞘稳态,建立了雪旺细胞谱系进展和髓鞘形成的阶段依赖性程序。小鼠雪旺细胞祖细胞中TSC1的解离导致mTOR信号通路激活,继而导致雪旺细胞过量增殖,分化受阻,髓鞘形成减少。转录组分析显示,TSC1突变体中的mTOR活化使得polo样激酶(PLK)依赖性通路和细胞周期调节剂上调。弱化mTOR或者对PLK进行药理抑制部分挽救了因TSC1缺失导致的外周神经发育过程中的髓鞘形成减少。相较之下,成年小鼠成熟雪旺细胞中TSC1缺失可导致髓鞘的过度增殖和过度生长。本文的发现提示了TSC1-mTOR-PLK信号轴在控制雪旺细胞的发育过程中,从增殖到分化和髓鞘内稳态中起到的阶段特异性功能。

Clinical Assessment of the Use of Propinox Hydrochloride and Scopolamine Hydrochloride in the Treatment of Abdominal Colic: A Retrospective, Comparative Study

Objectives: The purpose of this study was to evaluate and compare the use of propinox hydrochloride and scopolamine hydrochloride in patients presenting abdominal colic (abdominal pain), in terms of treatment efficacy and tolerability. Material & Methods: This was an analytical, retrospective, comparative study based on hospital records of outpatients treated at Serviço de Clínica Médica do Hospital das Clínicas Costantino Otaviano (HCTCO) and at Santa Casa de Misericórdia do Rio de Janeiro, from 1988-1998. Subjects were divided into two groups: patients from Group 1 were treated with propinox hydrochloride, while patients from Group 2 were treated with scopolamine hydrochloride. Statistical analysis was performed using GraphPad Prism version 5.0. For comparison of categorical variables, we used the chi-squared or Fisher’s test, while continuous variables were analyzed using ANOVA or the Student’s T test. Results: A total of 1042 subjects were included, of which 525 were allocated to Group 1 and 517 to Group 2. Mean treatment duration was 9.166 days (±4.208) in Group 1 and 8.795 days (±5.052) in Group 2, with no statistically significant difference in treatment duration between the two groups (p = 0.198). All subjects in Group 1 were treated with propinox 10 mg (2 coated tablets, three times per day) while all subjects in Group 2 were treated with scopolamine hydrochloride 10 mg (2 coated tablets, three times per day). There were no statistically significant between-group differences in weight, BMI, heart rate, and respiratory rate at pre- and post-treatment;with the exception of higher post-treatment systolic blood pressure in Group 1, blood pressure measures also remained homogenous. Adverse events were reported among both treatment groups with no significant between-group difference in incidence (p = 0566). At pretreatment, pain intensity was more severe in Group 1 (p = 0.0257), while at post-treatment, there was no statistically significant difference between the two treatment groups (p = 0.895). There was a statistically significant improvement in pain intensity within both treatment groups (χ2 = 631.4;df = 3;p < 0.0001 for Group 1 and χ2 = 554.3;df = 3;p < 0.0001 for Group 2). Conclusion: The results obtained in this study indicate a therapeutic equivalence between propinox hydrochloride and scopolamine hydrochloride. Both treatments demonstrated good efficacy and tolerability in the treatment of abdominal colic pain, in the population evaluated.

Myelin-based inhibitors of oligodendrocyte myelination: clues from axonal growth and regeneration

The differentiation of and myelination by oligodendrocytes （OLs） are exquisitely regulated by a series of intrinsic and extrinsic mechanisms. As each OL can make differing numbers of myelin segments with variable lengths along similar axon tracts, myelination can be viewed as a graded process shaped by inhibitory/ inductive cues during development. Myelination by OLs is a prime example of an adaptive process determined by the microenvironment and architecture of the central nervous system （CNS）. In this review, we discuss how myelin formation by OLs may be controlled by the heterogeneous microenvironment of the CNS. Then we address recent findings demonstrating that neighboring OLs may compete for available axon space, and highlight our current understanding of myelin-based inhibitors of axonal regeneration that are potentially responsible for the reciprocal dialogue between OLs and determine the numbers and lengths of myelin internodes. Understanding the mechanisms that control the spatiotemporal regulation of myelinogenic potential during development may provide valuable insight into therapeutic strategies for promoting remyelination in an inhibitory microenvironment.

Temporal trends in diagnosis,treatment,and outcome for non-ST-segment elevation acute coronary syndrome in three regions of China,2008–2015

To the Editor:As acute coronary syndromes(ACS)is common causes of morbidity and mortality in China,they serve as an important case example to assess the impact of these health reforms on the quality,safety,and efficiency of healthcare.[1]ACS comprises a wide spectrum of disease subgroups,including ST-segment elevation myocardial infarction(STEMI),unstable angina(UA),and non-ST-segment elevation myocardial infarction(NSTEMI).Previous studies have shown increases in the intensity of testing and treatment while stable in-hospital mortality for STEMI in China between 2001 and 2011.[2]As non-ST-segment elevation acute coronary syndrome(NSTE-ACS)patients,who account for about two-thirds of ACS patients,have a wide spectrum of disease severity,risk-stratified management is recommended to ensure appropriate allocation of resources,especially in limited-resource settings of China.As limited data exist on the use of medical services and clinical outcomes in relation to health reforms,we aimed to determine temporal trends in diagnosis,treatment,and outcome for hospitalized NSTE-ACS patients in three regions of China between 2008 and 2015.

Safety of endovascular therapy for symptomatic intracranial artery stenosis:a national prospective registry

Introduction The safety outcomes of endovascular therapy for intracranial artery stenosis in a real-world stetting are largely unknown.The Clinical Registration Trial of Intracranial Stenting for Patients with Symptomatic Intracranial Artery Stenosis(CRTICAS)was a prospective,multicentre,real-world registry designed to assess these outcomes and the impact of centre experience.Methods 1140 severe,symptomatic intracranial arterial stenosis(ICAS)patients treated with endovascular therapy were included from 26 centres,further divided into three groups according to the annual centre volume of intracranial angioplasty and stent placement procedures over 2 years:(1)high volume for≥25 cases/year;(2)moderate volume for 10–25 cases/year and(3)low volume for<10 cases/year.Results The rate of 30-day stroke,transient ischaemic attack or death was 9.7%(111),with 5.4%,21.1%and 9.7%in high-volume,moderate-volume and low-volume centres,respectively(p<0.05).Multivariable logistic regression confirmed high-volume centres had a significantly lower primary endpoint compared with moderate-volume centres(OR=0.187,95%CI:0.056 to 0.627;p≤0.0001),while moderate-volume and low-volume centres showed no significant difference(p=0.8456).Conclusion Compared with the preceding randomised controlled trials,this real-world,prospective,multicentre registry shows a lower complication rate of endovascular treatment for symptomatic ICAS.Non-uniform utilisation in endovascular technology,institutional experience and patient selection in different volumes of centres may have an impact on overall safety of this treatment.

Expert Consensus on Clinical Diagnostic Criteria for Fatal Familial Insomnia

INTRODUCTION Fatal familial insomnia （FFI） is a serious and rare prion disease, which was first reported by Lugaresi et al. in 1986.Early diagnosis of FFI might be important for early and sufficient counseling of patients and their relatives, also concerning the risk of inheritance, and potentially also for treatment studies. However, the diagnosis of FFI might be difficult because of the heterogeneity of clinical features, low sensitivity of diagnostic tests, and absence of family history. The aim of the present study was to develop a clinical scheme and diagnostic criteria for FFI based on our research and expert consensus.