AAV mediated carboxyl terminus of Hsp70 interacting protein overexpression mitigates the cognitive and pathological phenotypes of APP/PS1 mice

The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control system.In this study,we aimed to investigate the neuroprotective effect of overexpressed CHIP on Alzheimer’s disease.We used an adeno-associated virus vector that can cross the blood-brain barrier to mediate CHIP overexpression in APP/PS1 mouse brain.CHIP overexpression significantly ameliorated the performance of APP/PS1 mice in the Morris water maze and nest building tests,reduced amyloid-βplaques,and decreased the expression of both amyloid-βand phosphorylated tau.CHIP also alleviated the concentration of microglia and astrocytes around plaques.In APP/PS1 mice of a younger age,CHIP overexpression promoted an increase in ADAM10 expression and inhibitedβ-site APP cleaving enzyme 1,insulin degrading enzyme,and neprilysin expression.Levels of HSP70 and HSP40,which have functional relevance to CHIP,were also increased.Single nuclei transcriptome sequencing in the hippocampus of CHIP overexpressed mice showed that the lysosomal pathway and oligodendrocyte-related biological processes were up-regulated,which may also reflect a potential mechanism for the neuroprotective effect of CHIP.Our research shows that CHIP effectively reduces the behavior and pathological manifestations of APP/PS1 mice.Indeed,overexpression of CHIP could be a beneficial approach for the treatment of Alzheimer’s disease.

Characteristics of vascular lesions in patients with posterior circulation infarction according to age and region of infarct

Patients with posterior circulation infarction underwent CT angiography and magnetic resonance angiography. Intracranial and extracranial vasculopathy was evaluated according to age group and location of stroke. Patients aged 〉 60 years and 〈 60 years had similar rates of vertebral artery dominance and vertebrobasilar artery developmental or origin anomalies. Vertebrobasilar artery stenosis or occlusion and tortuosity occurred more frequently in patients aged 〉 60 years than 〈 60 years. The rates of vertebrobasilar artery anomalies and tortuosity were high in patients with posterior circulation infarction. Vertebrobasilar artery tortuosity occurred more frequently in patients aged 〉 60 years, whereas vertebrobasilar artery developmental anomalies occurred with similar frequency in patients aged 〈 60 years and 〉 60 years. Patients with infarction of the brainstem or cerebellum were more ~ikely to have vertebral artery stenosis or occlusion, basi^ar artery stenosis or occlusion, vertebral artery dominance or tortuosity, and basilar artery tortuosity, and patients with infarction of the thalamus, medial temporal, or occipital lobes were more likely to have stenosis or occlusion of the vertebral or basilar arteries. Vertebrobasilar artery tortuosity, vertebral artery dominance （hypoplasia）, and congenital variations of the vertebrobasilar system may lead to posterior circulation infarction at different locations in different age groups.

Challenges in developing polymer flocculants to improve bitumen quality in non.aqueous extraction processes:an experimental study

Western Canada’s oil sands hold the third-largest hydrocarbon deposits in the world.Bitumen,a very heavy petroleum,is currently recovered by surface mining with warm water or in situ.Recovery processes that use organic solvents are being developed to reduce water usage and tailings production.While solvent-based methods can effectively extract bitumen,removal of residual fine solids from diluted bitumen product(DBP)to meet the pipeline transport requirement of<0.5 wt%solids and water in DBP remains a major challenge.We propose a novel area of application of polymer flocculants for fine solids removal from DBP.In principle,polymer flocculants can be applied to help remove these residual solids in conjunction with physical separation processes to increase process effectiveness and energy efficiency.Several polymers are selected and screened for flocculation behavior using kaolinite suspended in DBP and toluene,as a model system.Focused beam reflectance measurements and force tensiometer techniques are used to determine flocculation and sedimentation in DBP.The observed flocculation and sedimentation rate enhancements indicate that the polymers tested have only minor effects,providing opportunities for advanced polymer development.These findings exemplify the challenges in identifying polymers that may be effective as flocculants in heavy petroleum media.

Endovascular transvenous treatment for superficial intracranial arteriovenous malformations

Objective:The objective of this study was to evaluate the feasibility and outcomes of transvenous endovascular embolization(TVE) for superficial intracranial arteriovenous malformations(AVMs).Methods:After collecting clinical and imaging data,a prospective series of 11 patients presenting with superficial AVMs were treated by endovascular embolization using a transvenous approach between November 2016 and October 2018.Results:Ten patients(90.9%) had ruptured AVMs before TVE.The mean nidus size was 3.27 ± 1.47 cm,and the median Spetzler-Martin grade was II.The rate of immediate angiographic occlusion of the AVMs was 90.9%(10/11).One patient was treated with transarterial embolization since TVE was not achieved due to an unsuccessful positioning of the microcatheter.Two patients(cases 8 and 11) suffered a intracranial hemorrhage and a cerebral infarction with encephaledema,respectively,but no procedure-related mortalities were observed.Eight patients(72.7%) were independent with a modified Rankin Score(mRS) 2 at discharge and the m RSs of all patients,which were collected 30 days postintervention,were not more than 2.The mean follow-up period was 17 months.There were no nidus recurrences during the follow-up period.Conclusions:The curative transvenous embolization of superficial AVMs seems feasible and effective while carefully monitoring for embolization-related complications.

Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders:executive summary and 2019 update of the management of high-risk population

Aim Cerebrovascular disease is the leading cause of death and disability in China,causing a huge burden among patients and their families.Hence,stroke prevention is critical,especially in the high-risk population.Here,we present the evidence-based guideline suitable for the Chinese population.Methods Literature search of PubMed and Cochrane library(from January 1964 to June 2019)was done.After thorough discussion among the writing group members,recommendations were listed and summarised.This guideline was reviewed and discussed by the fellow writing committees of the Chinese Stroke Association’s Stroke.Results This evidence-based guideline was written in three parts:controlling the risk factors of stroke,utilisation of antiplatelet agents and assessing the risks of first-ever stroke.All recommendations were listed along with the recommending classes and levels of evidence.Conclusions This guideline provides recommendations for primary prevention of cerebrovascular disease among high-risk population in China.Controlling related risk factors,appropriately using antiplatelet agents,assessing the risk of developing first-ever stroke should help reduce the rate of cerebrovascular disease in China.

Changing the strategy and culture of stroke awareness education in China: implementing Stroke 1-2-0

This project implemented the Stroke1-2-0 stroke awareness programme across China and investigated its impact over a 2-year period.We initiated the Stroke1-2-0 educational campaign and Stroke1-2-0 special task forces(STF)across the nation.Massive media coverage,community-based educational sessions with videos and other related materials and induction of Stroke1-2-0 STF were the major means of promotion.We delivered a survey at the end of 2016 and 2018 to evaluate the impact of our effort.A total of 3066 participants responded to the first survey in 2016,and 15207 participants responded in 2018 across China.The acceptance rate for Stroke1-2-0 versus FAST(an English-language stroke awareness tool)was 50.2%versus 19.1%in 2016,and changed significantly to 82.2%versus 8.0%in 2018(p<0.001).Stroke1-2-0 was well accepted by all ages and by people with different academic qualifications.Only 6.5%of survey respondents were aware that there was a therapeutic window for thrombolytic therapy in 2016,but this awareness increased significantly to 32.8%in 2018.Only 12.6%of people in 2016 indicated that they would send patients with stroke to the nearest hospital capable of performing thrombolytic therapy,but there was a nearly threefold increase(52.5%)in this number by 2018.More than 1000 major hospitals joined the Stroke1-2-0 STF,and more than 20000‘stroke warriors’have joined our stroke awareness improvement effort so far.Stroke1-2-0 stroke awareness programme is well-implemented and accepted,and is generating profound improvement in stroke awareness in China.

Risk stratification in symptomatic intracranial atherosclerotic disease with conventional vascular risk factors and cerebral haemodynamics

Background and purpose Symptomatic intracranial atherosclerotic stenosis(sICAS)is associated with a considerable risk of recurrent stroke despite contemporarily optimal medical treatment.Severity of luminal stenosis in sICAS and its haemodynamic significance quantified with computational fluid dynamics(CFD)models were associated with the risk of stroke recurrence.We aimed to develop and compare stroke risk prediction nomograms in sICAS,based on vascular risk factors and these metrics.Methods Patients with 50%-99%sICAS confirmed in CT angiography(CTA)were enrolled.Conventional vascular risk factors were collected.Severity of luminal stenosis in sICAS was dichotomised as moderate(50%-69%)and severe(70%-99%).Translesional pressure ratio(PR)and wall shear stress ratio(WSSR)were quantified via CTA-based CFD modelling;the haemodynamic status of sICAS was classified as normal(normal PR&WSSR),intermediate(otherwise)and abnormal(abnormal PR&WSSR).All patients received guideline-recommended medical treatment.We developed and compared performance of nomograms composed of these variables and independent predictors identified in multivariate logistic regression,in predicting the primary outcome,recurrent ischaemic stroke in the same territory(SIT)within 1 year.Results Among 245 sICAS patients,20(8.2%)had SIT.The D2H2A nomogram,incorporating diabetes,dyslipidaemia,haemodynamic status of sICAS,hypertension and age≥50 years,showed good calibration(P for Hosmer-Lemeshow test=0.560)and discrimination(C-statistic 0.73,95%CI 0.60 to 0.85).It also had better performance in risk reclassification and provided larger net benefits in decision curve analysis,compared with nomograms composed of conventional vascular risk factors only,and plus the severity of luminal stenosis in sICAS.Sensitivity analysis in patients with anterior-circulation sICAS showed similar results.Conclusions The D2H2A nomogram,incorporating conventional vascular risk factors and the haemodynamic significance of sICAS as assessed in CFD models,could be a useful tool to stratify sICAS patients for the risk of recurrent stroke under contemporarily optimal medical treatment.

Prognostic value of systemic immune- inflammation index in acute/subacute patients with cerebral venous sinus thrombosis

Objective To evaluate the prognosis values of systemic immune-inflammation index(SII)in non-chronic cerebral venous sinus thrombosis(CVST).Methods patients with CVST,admitted to the First Affiliated Hospital of Zhengzhou University,were retrospectively identified from January 2013 to December 2018.We selected patients in acute/subacute phase from database.Functional outcomes of patients were evaluated with the modified Rankin Scale(mRS)-mRS 3-6 as poor outcomes and mRS 6 as death.The overall survival time was defined as the date of onset to the date of death or last follow-up date.Survival analysis was described by the Kaplan-Meier curve and Cox regression analysis.Multivariate logistic regression analysis assessed the relationship between SII and poor functional outcome.The area under the Receiver Operating Curve curve(AUC)was estimated to evaluate the ability of SII in prediction.Results A total of 270 patients were included and their duration of follow-up was 22 months(6-66 months),of whom 31 patients had poor outcomes and 24 patients dead.Cox regression analysis showed that SII(HR=1.304,95%CI:1.101 to 1.703,p=0.001)was a predictor of death in non-chronic CVST.Patients with higher SII presented lower survival rates(p=0.003).The AUC of SII was 0.792(95%CI:0.695 to 0.888,p=0.040)with a sensitivity of 69.6%and specificity of 80.1%.Subgroups analysis demonstrated that SII was an important predictor of poor outcomes in male(OR=1.303,95%CI:1.102 to 1.501,p=0.011)and pregnancy/puerperium female(OR=1.407,95%CI:1.204 to 1.703,p=0.034).Conclusions SII was a potential predictor in the poor prognosis of patients with acute/subacute CVST,especially in male and pregnancy/puerperium female.

Effectiveness of intravenous r- tPA versus UK for acute ischaemic stroke: a nationwide prospective Chinese registry study

Background Intravenous recombinant tissue plasminogen activator(r-tPA)and urokinase(UK)are both recommended for the treatment of acute ischaemic stroke(AIS)in China,but with few comparative outcome data being available.We aimed to compare the outcomes of these two thrombolytic agents for the treatment of patients within 4.5 hours of onset of AIS in routine clinical practice in China.Methods A pre-planned,prospective,nationwide,multicentre,real-world registry of consecutive patients with AIS(age≥18 years)who received r-tPA or UK within 4.5 hours of symptom onset according to local decision-making and guideline recommendations during 2017-2019.The primary effectiveness outcome was the proportion of patients with an excellent functional outcome(defined by modified Rankin scale scores 0 to 1)at 90 days.The key safety endpoint was symptomatic intracranial haemorrhage according to standard definitions.Multivariable logistic regression was used for comparative analysis,with adjustment according to propensity scores to ensure balance in baseline characteristics.Results Overall,4130 patients with AIS were registered but 320 had incomplete or missing data,leaving 3810 with available data for analysis of whom 2666 received r-tPA(median dose 0.88(IQR 0.78-0.90)mg/kg)and 1144 received UK(1.71(1.43-2.00)×104 international unit per kilogram).There were several significant intergroup differences in patient characteristics:r-tPA patients were more educated,had less history of stroke,lower systolic blood pressure,greater neurological impairment and shorter treatment times from symptom onset than UK patients.However,in adjusted analysis,the frequency of excellent outcome(OR 1.18,95%CI 1.00 to 1.40,p=0.052)and symptomatic intracranial haemorrhage(OR 0.70,95%CI 0.33 to 1.47,p=0.344)were similar between groups.Conclusions UK may be as effective and carry a similar safety profile as r-tPA in treating mild to moderate AIS within guidelines in China.Registration http://www.clinicaltrials.gov.unique identifier:NCT02854592.

Lower lymphocyte to monocyte ratio is a potential predictor of poor outcome in patients with cerebral venous sinus thrombosis

Background Lymphocyte to monocyte ratio(LMR)is associated with functional outcome in patients with stroke.But the relationship between the LMR value and the prognosis of cerebral venous sinus thrombosis(CVST)has not been investigated.Methods CVST patients,admitted to the First Affiliated Hospital of Zhengzhou University,were retrospectively identified from November 2010 to January 2017.Functional outcomes of patients were evaluated with the modified Rankin Scale(mRS).Patients were divided into good(mRS 0-2)and poor(mRS 3-6)outcomes groups.Univariate and multivariate Cox regression analyses were used to assess the relationship between LMR and the poor survival outcome.Results A total of 228 patients were included of which 41 had poor outcomes(18.0%).The duration of follow-up was 22 months(6-66 months).LMR(2.3±1.2 vs 3.2±1.8,p<0.01)was significantly lower in the poor outcome group.Multivariate Cox regression analysis showed that LMR(HR 0.726,95%CI 0.546 to 0.964,p=0.027)was a independent predictor of poor prognosis.Conclusions LMR may be a predictor of poor prognosis in CVST patients.

Homocysteine impedes neurite outgrowth recovery after intracerebral haemorrhage by downregulating pCAMK2A

Hyperhomocysteinemia(HHcy)is independently associated with poorer long-term prognosis in patients with intracerebral haemorrhage(ICH);however,the effect and mechanisms of HHcy on ICH are still unclear.Here,we evaluated neurite outgrowth and neurological functional recovery using simulated models of ICH with HHcy in vitro and in vivo.We found that the neurite outgrowth velocity and motor functional recovery in the ICH plus HHcy group were significantly slower than that in the control group,indicating that homocysteine(Hcy)significantly impedes the neurite outgrowth recovery after ICH.Furthermore,phosphoproteomic data and signalome analysis of perihematomal brain tissues suggested that calmodulin-dependent protein kinases 2(CAMK2A)kinase substrate pairs were significantly downregulated in ICH with HHcy compared with autologous blood injection only,both western blot and immunofluorescence staining confirmed this finding.Additionally,upregulation of pCAMK2A significantly increased neurite outgrowth recovery in ICH with HHcy.Collectively,we clarify the mechanism of HHcy-hindered neurite outgrowth recovery,and pCAMK2A may serve as a therapeutic strategy for promoting neurological recovery after ICH.

Autologous Transplantation for Parkinson's Disease Patients:Feasibility and Challenge

Parkinson’s Disease(PD),second only to Alzheimer’s disease,is a neurodegenerative disease,most commonly occurring in people over the age of 65 years and is mostly caused by loss of dopamine neurons[1].Clinically,motor symptoms such as resting tremor,motor retardation,muscular rigidity,and disturbance of postural balance are the main symptoms,followed by non-motor symptoms such as cognitive impairment,autonomic nervous system dysfunction,depression,and sleep disorder[2].In 2016,>6.1 million people were affected with PD globally,2.4 times the number in 1990.The large number of affected people,coupled with the high mortality and disability rates,has placed a great burden on society[3].Traditional treatment methods mainly include drugs and surgery and are supplemented by physical therapy.

Seed amplification assay of nasal swab extracts for accurate and non-invasive molecular diagnosis of neurodegenerative diseases

Nasal swabs are non-invasive testing methods for detecting diseases by collecting samples from the nasal cavity or nasopharynx.Dysosmia is regarded as an early sign of coronavirus disease 2019(COVID-19),and nasal swabs are the gold standard for the detection.By nasal swabs,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)nucleic acids can be cyclically amplified and detected using real-time reverse transcriptase-polymerase chain reaction after sampling.Similarly,olfactory dysfunction precedes the onset of typical clinical manifestations by several years in prion diseases and other neurodegenerative diseases,such as Alzheimer’s disease,Parkinson’s disease,dementia with Lewy bodies,and multiple system atrophy.In neurodegenerative diseases,nasal swab tests are currently being explored using seed amplification assay(SAA)of pathogenic misfolded proteins,such as prion,α-synuclein,and tau.These misfolded proteins can serve as templates for the conformational change of other copies from the native form into the same misfolded form in a prion-like manner.SAA for misfolded prion-like proteins from nasal swab extracts has been developed,conceptually analogous to PCR,showing high sensitivity and specificity for molecular diagnosis of degenerative diseases even in the prodromal stage.Cyclic amplification assay of nasal swab extracts is an attractive and feasible method for accurate and non-invasive detection of trace amount of pathogenic substances for screening and diagnosis of neurodegenerative disease.