Alzheimer's disease(AD),a progressive dementia,is one of the most common neurodegenerative diseases.Clinical trial results of amyloid-β(Aβ)and tau regulators based on the pretext of straightforward amyloid and t...Alzheimer's disease(AD),a progressive dementia,is one of the most common neurodegenerative diseases.Clinical trial results of amyloid-β(Aβ)and tau regulators based on the pretext of straightforward amyloid and tau immunotherapy were disappointing.There are currently no effective strategies for slowing the progression of AD.Herein,we spotlight the dysregulation of lipid metabolism,particularly the elevation of ceramides(Cers),as a critical yet underexplored facet of AD pathogenesis.Our study delineates the role of Cers in promoting microglial pyroptosis,a form of programmed cell death distinct from apoptosis and necroptosis,characterized by cellular swelling,and membrane rupture mediated by the NLRP3 inflammasome pathway.Utilizing both in vivo experiments with amyloid precursor protein(APP)/presenilin 1(PS1)transgenic mice and in vitro assays with BV-2 microglial cells,we investigate the activation of microglial pyroptosis by Cers and its inhibition by icariin(ICA),a flavonoid with known antioxidant and anti-inflammatory properties.Our findings reveal a significant increase in Cers levels and pyroptosis markers(NOD-like receptor family,pyrin domain containing 3(NLRP3),apoptosis-associated speck-like protein containing a caspase recruitment domain,caspase-1,gasdermin D(GSDMD),and interleukin-18(IL-18))in the brains of AD model mice,indicating a direct involvement of Cers in AD pathology through the induction of microglial pyroptosis.Conversely,ICA treatment effectively reduces these pyroptotic markers and Cer levels,thereby attenuating microglial pyroptosis and suggesting a novel therapeutic mechanism of action against AD.This study not only advances our understanding of the pathogenic role of Cers in AD but also introduces ICA as a promising candidate for AD therapy,capable of mitigating neuroinflammation and pyroptosis through the cyclooxygenase-2(COX-2)-NLRP3 inflammasome-gasdermin D(GSDMD)axis.Our results pave the way for further exploration of Cer metabolism disorders in neurodegenerative diseases and highlight the therapeutic potential of targeting microglial pyroptosis in AD.展开更多
In recent years,a large number of differentially expressed genes have been identified in human umbilical cord mesenchymal stem cell(hUMSC)transplants for the treatment of ischemic cerebral infarction.These genes are i...In recent years,a large number of differentially expressed genes have been identified in human umbilical cord mesenchymal stem cell(hUMSC)transplants for the treatment of ischemic cerebral infarction.These genes are involved in various biochemical processes,but the role of microRNAs(miRNAs)in this process is still unclear.From the Gene Expression Omnibus(GEO)database,we downloaded two microarray datasets for GSE78731(messenger RNA(mRNA)profile)and GSE97532(miRNA profile).The differentially expressed genes screened were compared between the hUMSC group and the middle cerebral artery occlusion group.Gene ontology enrichment and pathway enrichment analyses were subsequently conducted using the online Database for Annotation,Visualization,and Integrated Discovery.Identified genes were applied to perform weighted gene co-suppression analyses,to establish a weighted co-expression network model.Furthermore,the protein-protein interaction network for differentially expressed genes from turquoise modules was built using Cytoscape(version 3.40)and the most highly correlated subnetwork was extracted from the protein-protein interaction network using the MCODE plugin.The predicted target genes for differentially expressed miRNAs were also identified using the online database starBase v3.0.A total of 3698 differentially expressed genes were identified.Gene ontology analysis demonstrated that differentially expressed genes that are related to hUMSC treatment of ischemic cerebral infarction are involved in endocytosis and inflammatory responses.We identified 12 differentially expressed miRNAs in middle cerebral artery occlusion rats after hUMSC treatment,and these differentially expressed miRNAs were mainly involved in signaling in inflammatory pathways,such as in the regulation of neutrophil migration.In conclusion,we have identified a number of differentially expressed genes and differentially expressed mRNAs,miRNA-mRNAs,and signaling pathways involved in the hUMSC treatment of ischemic cerebral infarction.Bioinformatics and interaction analyses can provide novel clues for further research into hUMSC treatment of ischemic cerebral infarction.展开更多
Background In June 2015,the Chinese Stroke Association(CSA)initiated the Chinese Stroke Center Alliance(CSCA)to establish the national hospital-based stroke care quality assessment and improvement platform.This articl...Background In June 2015,the Chinese Stroke Association(CSA)initiated the Chinese Stroke Center Alliance(CSCA)to establish the national hospital-based stroke care quality assessment and improvement platform.This article outlines its objectives,operational structure,patient population,quality improvement(QI)intervention tools,data elements,data collection methodology and current patient and hospital data.Methods The CSCA is a national,hospital-based,multicentre,voluntary,multifaceted intervention and continuous QI initiative.This multifaceted intervention includes stroke centre development,written care protocols,workshops and a monitoring/feedback system of evidencebased performance measures.The data coordinating centre of the CSCA resides at the China National Clinical Research Center for Neurological Diseases,Beijing Tiantan Hospital.results As of July 2017,1576 hospitals in China have contributed detailed clinical information to serve as a benchmark for the stroke care quality of 433264 patients with acute stroke/transient ischaemic attacks(TIA),including 352572(81.38%)acute ischaemic stroke,30362(7.01%)TIA,42080(9.71%)spontaneous intracranial haemorrhage,5505(1.27%)subarachnoid haemorrhage and 2745(0.63%)not specified stroke.Conclusion The CSCA programme is designed to establish a continuous national stroke registry and help healthcare providers develop stroke centres and treat patients in a consistent manner in accordance with accepted national guidelines and,ultimately,improve patient outcomes.It supports the CSA mission to reduce stroke burden in China.展开更多
Background and purpose:5 recent trials have shown the benefit of endovascular treatment for acute ischaemic stroke(AIS)due to large vessel occlusion of the anterior circulation.This study aims to evaluate the safety a...Background and purpose:5 recent trials have shown the benefit of endovascular treatment for acute ischaemic stroke(AIS)due to large vessel occlusion of the anterior circulation.This study aims to evaluate the safety and efficacy of Solitaire thrombectomy in patients with moderate-to-severe stroke in the Chinese population,which has a high prevalence of intracranial atherosclerosis.Methods and analysis:This multicentre prospective control study will involve 17 stroke centres in China,and plans to recruit 150 patients in the intervention group,and 150 patients in the medical group,in which patients meet enrolment criteria but refuse intervention.Patients with AIS due to large vessel occlusion indicated for treatment with Solitaire stent retriever within 12 hours of symptom onset,and who meet the inclusion and exclusion criteria,will be enrolled in this study.The primary efficacy endpoint is functional independence as defined by a modified Rankin Scale(mRS)score≤2 at 90 days or by functional improvement as defined by mRS,using shift analysis.The procedural efficacy endpoint is arterial recanalisation of the occluded target vessel measured by a modified Thrombolysis in Cerebral Infarction(mTICI)score equal or superior to 2b right following the use of the study device.The primary safety endpoint is symptomatic intracranial haemorrhage(sICH)within 24±3 hours postprocedure.Ethics and dissemination:The protocol was approved by the Ethics Committee at the coordinating centre and by the local Institutional Review Board of each participating centre.Trial registration number:NCT02350283.展开更多
Backgrounds Embolic stroke is one of the main mechanisms of ischaemic stroke.Even if treated with recommended antithrombotic agents,stroke recurrence remains high.The Shuxuetong injection,a purified extract of traditi...Backgrounds Embolic stroke is one of the main mechanisms of ischaemic stroke.Even if treated with recommended antithrombotic agents,stroke recurrence remains high.The Shuxuetong injection,a purified extract of traditional Chinese medicine widely used for thrombus diseases in clinical practice in China,could be a promising agent to prevent stroke recurrence.Aims To describe the design of the Shuxuetong injection for prevention of recurrence in acute ischaemic stroke with embolism mechanisms.Design The Shuxuetong for Prevention of recurrence in Acute Cerebrovascular events with Embolism(SPACE)trial is a multicentre,randomised,double-blind,placebo-controlled,parallel-group,superiority trial to evaluate the efficacy and safety of Shuxuetong injection in reducing recurrence or silent new ischaemic lesions on patients with acute embolic stroke within 10 days.An estimated 2416 patients with embolic stroke within 72 hours of symptom onset from 80 hospitals will be randomly assigned to one of two groups receiving Shuxuetong injection or placebo injection for 10 days.The primary endpoint is symptomatic or asymptomatic new cerebral infarction within 10 days after randomisation.Conclusion The SPACE Trial will provide valuable evidence for the efficacy and safety of Shuxuetong injection for the prevention of stroke recurrence in patients with imaging-defined embolic stroke.展开更多
Objective To investigate the effects of DL-3-N butylphthalide(NBP)via intranasal delivery after ischaemic stroke in mice.Methods C57BL/6 mice were divided into three groups:sham,stroke with vehicle and stroke with NBP...Objective To investigate the effects of DL-3-N butylphthalide(NBP)via intranasal delivery after ischaemic stroke in mice.Methods C57BL/6 mice were divided into three groups:sham,stroke with vehicle and stroke with NBP treatment.Ischaemic stroke was induced by permanent ligation of right middle cerebral artery with 7 min common carotid artery occlusion.NBP(100 mg/kg)or vehicle was intranasally administered at 1 hour after stroke and repeated once a day until sacrifice.Bromodeoxyuridine(BrdU)(50 mg/kg/day)was given from the third day until sacrifice.Sensorimotor function was tested during 1-21 days after stroke.Local cerebral blood flow in the ischaemic and peri-infarct regions was measured using laser Doppler flowmetry before,during and 3 days after ischaemia.Expressions of vascular endothelial growth factor(VEGF)and endothelial nitric oxide synthase as well as regenerative marker BrdU in the peri-infarct region were analysed by western blotting and immunohistochemical methods.Results Compared with the vehicle group,NBP treatment significantly increased the VEGF expression in the poststroke brain.Stroke mice that received NBP showed significantly less vascular damage after stroke and more new neurons and blood vessels in the peri-infarct region at 21 days after stroke.In the adhesive removal test,the sensorimotor function of stroke mice treated with NBP performed significantly better at 1,3 and 7 days after stroke compared with vehicle controls.Conclusion Daily intranasal NBP treatment provides protective and neurogenic/angiogenic effects in the poststroke brain,accompanied with functional improvements after a focal ischaemic stroke in mice.展开更多
Aim:The aim of this study was to explore the difference between haemorrhagic events among those patients on either aspirin or aspirin plus clopidogrel who were enrolled in the Clopidogrel in High-Risk Patients with Ac...Aim:The aim of this study was to explore the difference between haemorrhagic events among those patients on either aspirin or aspirin plus clopidogrel who were enrolled in the Clopidogrel in High-Risk Patients with Acute Non-disabling Ischemic Cerebrovascular Events(CHANCE)trial.Methods:This was an ad hoc analysis of the CHANCE trial;data on all patients with any haemorrhagic event were reviewed and analysed.Cox proportional hazards regression was used to determine factors association with any bleeding.Results:In the CHANCE trial,there were a total of 101(2%)haemorrhagic events reported from 50 different hospitals.The clopidogrel–aspirin group had 60(2.3%)cases and the aspirin group had 41(1.6%,p=0.09).Moderate or severe haemorrhagic events occurred in 7 patients(0.3%)in the clopidogrel–aspirin group and in 8(0.3%)in the aspirin group(p=0.73).Of 36(0.7%)cases of intracranial haemorrhages,20(0.4%)were in the clopidogrel–aspirin group and 16(0.3%)in the aspirin group.Each group had 8(0.3%)cases of symptomatic haemorrhagic strokes.Other common haemorrhagic events included 24(0.5%)cases of skin bruises,13(0.3%)gastrointestinal haemorrhages,9(0.2%)gum haemorrhages and 8(0.2%)intraocular haemorrhages.Conclusions:There was no overall significant difference in haemorrhagic events(p=0.29),especially in the rate of intracranial haemorrhages between the 2 treatment groups.However,patients enrolled with minor strokes had an increased risk of haemorrhagic events regardless of treatment group,not seen in patients with high-risk transient ischaemic attacks.Being elderly,of male gender and with a history of aspirin or proton pump inhibitor usage were associated with increased risk of haemorrhage.Patients with higher body mass index had lower risk of haemorrhagic events.展开更多
Since the approval of intravenous(IV)tissue plasminogen activator(tPA)to treat patients with acute ischaemic stroke(AIS)within 3 hours of onset in 1996,it took 12 years to expand the treatment time window to 4.5 hours...Since the approval of intravenous(IV)tissue plasminogen activator(tPA)to treat patients with acute ischaemic stroke(AIS)within 3 hours of onset in 1996,it took 12 years to expand the treatment time window to 4.5 hours by the European Cooperative Acute Stroke Trial II(ECASS III).1 It took another 10 years to expand the treatment time window to 6 hours with the bridging of IV tPA and intra-arterial(IA)thrombectomy.2 In 2018,22 years later after the approval of IV tPA and less than 3 years from the approval of IA thrombectomy,we have learnt that IA thrombectomy was effective in treating patients with AIS from large vessel occlusion(LVO)type of stroke up to 24 hours.3 This continued expansion of the treatment time window has brought hope to many patients with stroke who will present to the emergency room at a later time.展开更多
Background The COVID-19 pandemic and physical distancing guidelines have compelled stroke practices worldwide to reshape their delivery of care significantly.We aimed to illustrate how the stroke services were interru...Background The COVID-19 pandemic and physical distancing guidelines have compelled stroke practices worldwide to reshape their delivery of care significantly.We aimed to illustrate how the stroke services were interrupted during the pandemic in China.Methods A 61-item questionnaire designed on Wenjuanxing Form was completed by doctors or nurses who were involved in treating patients with stroke from 1 February to 31 March 2020.Results A total of 415 respondents completed the online survey after informed consent was obtained.Of the respondents,37.8%,35.2%and 27.0%were from mild,moderate and severe epidemic areas,respectively.Overall,the proportion of severe impact(reduction>50%)on the admission of transient ischaemic stroke,acute ischaemic stroke(AIS)and intracerebral haemorrhage(ICH)was 45.0%,32.0%and 27.5%,respectively.Those numbers were 36.9%,27.9%and 22.3%;36.5%,22.1%and 22.6%;and 66.4%,47.5%and 41.1%in mild,moderate and severe epidemic areas,respectively(all p<0.0001).For AIS,thrombolysis was moderate(20%-50%reduction)or severely impacted(>50%),as reported by 54.4%of the respondents,while thrombectomy was 39.3%.These were 44.4%,26.3%;44.2%,39.4%;and 78.2%,56.5%,in mild,moderate and severe epidemic areas,respectively(all p<0.0001).For patients with acute ICH,39.8%reported the impact was severe or moderate for those eligible for surgery who had surgery.Those numbers were 27.4%,39.0%and 58.1%in mild,moderate and severe epidemic areas,respectively.For staff resources,about 20%(overall)to 55%(severe epidemic)of the respondents reported moderate or severe impact on the on-duty doctors and nurses.Conclusion We found a significant reduction of admission for all types of patients with stroke during the pandemic.Patients were less likely to receive appropriate care,for example,thrombolysis/thrombectomy,after being admitted to the hospital.Stroke service in severe COVID-19 epidemic areas,for example,Wuhan,was much more severely impacted compared with other regions in China.展开更多
Background and purpose Retinal pathologies are an independent risk factor for ischaemic stroke,but research on the predictive value of retinal abnormalities for recurrent vascular events in patients with prior stroke ...Background and purpose Retinal pathologies are an independent risk factor for ischaemic stroke,but research on the predictive value of retinal abnormalities for recurrent vascular events in patients with prior stroke is inconclusive.We investigated the association of retinal pathologies with subsequent vascular events.Methods In a substudy of the Intensified secondary prevention intending a reduction of recurrent events in TIA and minor stroke patients(INSPiRE-TMS)trial,we enrolled patients with recent transient ischaemic attack(TIA)or minor stroke with at least one modifiable risk factor.Primary outcome was the composite of subsequent vascular events.Retinal photographs were taken at baseline and categorised into three different fundus groups by a telemedically linked ophthalmologist.Results 722 patients participated in the current study and 109 major vascular events occurred.After multivariable adjustments,we did not find a significant association between fundus categories and risk for subsequent vascular events(HRs for moderate vascular retinopathy and vascular retinopathy with vessel rarefaction in comparison to no vascular retinopathy 1.03(95%CI 0.64 to 1.67),p=0.905 and 1.17(95%CI 0.62 to 2.20),p=0.626).In a selective post hoc analysis in patients with diabetes mellitus and hypertension,patients with vascular retinopathy with vessel rarefaction had a higher risk for recurrent stroke(HR 24.14(95%CI 2.74 to 212.50),p=0.004).Conclusions Retinal changes did not predict major subsequent vascular events in patients with recent TIA or minor stroke.Further studies are needed to examine the utility of fundus photography in assessing the risk of stroke recurrence in patients with diabetes mellitus and hypertension.展开更多
Background Stroke aetiology remains cryptogenic in a relevant proportion of patients with acute ischaemic stroke(AIS).We assessed whether enhanced diagnostic workup after AIS yields a higher rate of prespecified patho...Background Stroke aetiology remains cryptogenic in a relevant proportion of patients with acute ischaemic stroke(AIS).We assessed whether enhanced diagnostic workup after AIS yields a higher rate of prespecified pathological findings compared with routine diagnostic care in-hospital.Methods Hospitalised patients with AIS were prospectively enrolled in the investigator-initiated observational HEart and BRain Interfaces in Acute Ischaemic Stroke(HEBRAS)study at the Charité,Berlin,Germany.Patients with AIS without known atrial fibrillation(AF)underwent cardiovascular MR imaging(CMR),MR-angiography of the aortic arch and prolonged Holter-ECG monitoring on top of routine diagnostic care.Results Among 356 patients with AIS(mean age 66 years,37.6%female),enhanced workup yielded a higher rate of prespecified pathological findings compared with routine care(17.7%vs 5.3%;p<0.001).Consequently,fewer patients were classified as cryptogenic after enhanced diagnostic workup(38.5%vs 45.5%,p<0.001).Routine care included echocardiography in 228(64.0%)patients.CMR was successfully performed in 292(82.0%)patients and revealed more often a prespecified pathological finding compared with routine echocardiography(16.1%vs 5.3%).Furthermore,study-related ECG monitoring(median duration 162 hours(IQR 98–210))detected AF in 16(4.5%)patients,while routine monitoring(median duration 51 hours(IQR 34–74))detected AF in seven(2.0%)patients.Conclusions Enhanced diagnostic workup revealed a higher rate of prespecified pathological findings in patients with AIS compared with routine diagnostic care and significantly reduced the proportion of patients with cryptogenic stroke.Trial registration number NCT02142413.展开更多
To the Editor:Fabry disease(FD)is a recessive X-linked hereditary disease.The onset age of the disease is in children and adolescents mostly.The average time from the onset of symptoms to the definite diagnosis needs ...To the Editor:Fabry disease(FD)is a recessive X-linked hereditary disease.The onset age of the disease is in children and adolescents mostly.The average time from the onset of symptoms to the definite diagnosis needs 13.7 years in male patients and 16.3 years in female patients.FD happens rarely and it is easy to cause diagnosis and treatment delay.Here,we report a case of FD in a 27-year-old man who developed clinical symptoms with acute cerebral infarction onset to improve doctors'understanding of FD.展开更多
Artificial intelligence(AI)aims to mimic human cognitive functions.It is bringing a paradigm shift to healthcare,powered by increasing availability of healthcare data and rapid progress of analytics techniques.We surv...Artificial intelligence(AI)aims to mimic human cognitive functions.It is bringing a paradigm shift to healthcare,powered by increasing availability of healthcare data and rapid progress of analytics techniques.We survey the current status of AI applications in healthcare and discuss its future.AI can be applied to various types of healthcare data(structured and unstructured).Popular AI techniques include machine learning methods for structured data,such as the classical support vector machine and neural network,and the modern deep learning,as well as natural language processing for unstructured data.Major disease areas that use AI tools include cancer,neurology and cardiology.We then review in more details the AI applications in stroke,in the three major areas of early detection and diagnosis,treatment,as well as outcome prediction and prognosis evaluation.We conclude with discussion about pioneer AI systems,such as IBM Watson,and hurdles for real-life deployment of AI.展开更多
Very small superparamagnetic iron oxide nanoparticles （VSOPs） rapidly accumulate in atherosclerotic lesions, thereby enabling plaque visualization by magnetic resonance imaging （MRI）. This study was performed to i...Very small superparamagnetic iron oxide nanoparticles （VSOPs） rapidly accumulate in atherosclerotic lesions, thereby enabling plaque visualization by magnetic resonance imaging （MRI）. This study was performed to identify the uptake mechanisms of VSOPs into atherosclerotic plaques. Low-density lipoprotein receptor-deficient （LDLR^-/-） mice with advanced atherosclerosis were analyzed using MRI and transmission electron microscopy （TEM） at various time points after intravenous administration of VSOPs. Post-mortem MRI detected VSOP labeling of atherosclerotic plaques 10 min after injection, and the signal increased over the first 3 h. TEM revealed that the intensive plaque labeling was mediated by accelerated transcytosis of VSOPs through endothelial cells overlaying atherosclerotic lesions. Experiments with endocytosis inhibitors and small interfering RNA （siRNA） revealed a dynamin-dependent mechanism involving both clathrin- and caveolin-mediated processes. In cell culture experiments, endothelial VSOP uptake was enhanced under proatherogenic flow and TNFα stimulation, conditions that are both present in plaque areas. Our study demonstrates that VSOPs enable non-invasive MRI assessment of accelerated endothelial transcytosis, an important pathomechanism in atherosclerotic plaque formation.展开更多
Background and purpose Triage tools to identify candidates for thrombectomy are of utmost importance in acute stroke.No prognostic tool has yet gained any widespread use.We compared the predictive value of various mod...Background and purpose Triage tools to identify candidates for thrombectomy are of utmost importance in acute stroke.No prognostic tool has yet gained any widespread use.We compared the predictive value of various models based on National Institutes of Health Stroke Scale(NIHSS)subitems,ranging from simple to more complex models,for predicting large artery occlusion(LAO)in anterior circulation stroke.Methods Patients registered in the SITS international Stroke Register with available NIHSS and radiological arterial occlusion data were analysed.We compared 2042 patients harbouring an LAO with 2881 patients having no/distal occlusions.Using binary logistic regression,we developed models ranging from simple 1 NIHSS-subitem to full NIHSS-subitems models.Sensitivities and specificities of the models for predicting LAO were examined.results The model with highest predictive value included all NIHSS subitems for predicting LAO(area under the curve(AUC)0.77),yielding a sensitivity and specificity of 69%and 76%,respectively.The second most predictive model(AUC 0.76)included 4-NIHSS-subitems(level of consciousness commands,gaze,facial and arm motor function)yielding a sensitivity and specificity of 67%and 75%,respectively.The simplest model included only deficits in arm motor-function(AUC 0.72)for predicting LAO,yielding a sensitivity and specificity of 67%and 72%,respectively.Conclusions Although increasingly more complex models yield a higher discriminative performance for predicting LAO,differences between models are not large.Assessing grade of arm dysfunction along with an established stroke-diagnosis model may serve as a surrogate measure of arterial occlusion-status,thereby assisting in triage decisions.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.:82374552)Hunan Provincial Natural Science Foundation of China for Distinguished Young Scholars(Grant No.:2024JJ2086)+1 种基金the Science and Technology Innovation Program of Hunan Province,China(Grant No.:2022RC1220)Support Plan for High-level Health and Medical Talents in Hunan Province,China.
文摘Alzheimer's disease(AD),a progressive dementia,is one of the most common neurodegenerative diseases.Clinical trial results of amyloid-β(Aβ)and tau regulators based on the pretext of straightforward amyloid and tau immunotherapy were disappointing.There are currently no effective strategies for slowing the progression of AD.Herein,we spotlight the dysregulation of lipid metabolism,particularly the elevation of ceramides(Cers),as a critical yet underexplored facet of AD pathogenesis.Our study delineates the role of Cers in promoting microglial pyroptosis,a form of programmed cell death distinct from apoptosis and necroptosis,characterized by cellular swelling,and membrane rupture mediated by the NLRP3 inflammasome pathway.Utilizing both in vivo experiments with amyloid precursor protein(APP)/presenilin 1(PS1)transgenic mice and in vitro assays with BV-2 microglial cells,we investigate the activation of microglial pyroptosis by Cers and its inhibition by icariin(ICA),a flavonoid with known antioxidant and anti-inflammatory properties.Our findings reveal a significant increase in Cers levels and pyroptosis markers(NOD-like receptor family,pyrin domain containing 3(NLRP3),apoptosis-associated speck-like protein containing a caspase recruitment domain,caspase-1,gasdermin D(GSDMD),and interleukin-18(IL-18))in the brains of AD model mice,indicating a direct involvement of Cers in AD pathology through the induction of microglial pyroptosis.Conversely,ICA treatment effectively reduces these pyroptotic markers and Cer levels,thereby attenuating microglial pyroptosis and suggesting a novel therapeutic mechanism of action against AD.This study not only advances our understanding of the pathogenic role of Cers in AD but also introduces ICA as a promising candidate for AD therapy,capable of mitigating neuroinflammation and pyroptosis through the cyclooxygenase-2(COX-2)-NLRP3 inflammasome-gasdermin D(GSDMD)axis.Our results pave the way for further exploration of Cer metabolism disorders in neurodegenerative diseases and highlight the therapeutic potential of targeting microglial pyroptosis in AD.
基金supported by the National Key Research&Development Program of China,No.2016YFC1301600Program for Jilin University Science and Technology Innovation Team,No.2017TD-12(both to YY)
文摘In recent years,a large number of differentially expressed genes have been identified in human umbilical cord mesenchymal stem cell(hUMSC)transplants for the treatment of ischemic cerebral infarction.These genes are involved in various biochemical processes,but the role of microRNAs(miRNAs)in this process is still unclear.From the Gene Expression Omnibus(GEO)database,we downloaded two microarray datasets for GSE78731(messenger RNA(mRNA)profile)and GSE97532(miRNA profile).The differentially expressed genes screened were compared between the hUMSC group and the middle cerebral artery occlusion group.Gene ontology enrichment and pathway enrichment analyses were subsequently conducted using the online Database for Annotation,Visualization,and Integrated Discovery.Identified genes were applied to perform weighted gene co-suppression analyses,to establish a weighted co-expression network model.Furthermore,the protein-protein interaction network for differentially expressed genes from turquoise modules was built using Cytoscape(version 3.40)and the most highly correlated subnetwork was extracted from the protein-protein interaction network using the MCODE plugin.The predicted target genes for differentially expressed miRNAs were also identified using the online database starBase v3.0.A total of 3698 differentially expressed genes were identified.Gene ontology analysis demonstrated that differentially expressed genes that are related to hUMSC treatment of ischemic cerebral infarction are involved in endocytosis and inflammatory responses.We identified 12 differentially expressed miRNAs in middle cerebral artery occlusion rats after hUMSC treatment,and these differentially expressed miRNAs were mainly involved in signaling in inflammatory pathways,such as in the regulation of neutrophil migration.In conclusion,we have identified a number of differentially expressed genes and differentially expressed mRNAs,miRNA-mRNAs,and signaling pathways involved in the hUMSC treatment of ischemic cerebral infarction.Bioinformatics and interaction analyses can provide novel clues for further research into hUMSC treatment of ischemic cerebral infarction.
基金This work was supported by grants from the Ministry of Science and Technology and the Ministry of Health of the People’s Republic of China(National S&T Major Project of China:2011BAI08B02,2012ZX09303,2013BAI09B14,2013BAI09B03,2015BAI12B02,2015BAI12B04,2017YFC1310900,2017YFC1310901 and 2017YFC1310903)the National Key Technology Research and Development Program of the Ministry of Science and Technology of China(2013BAI09B03)+1 种基金Beijing Municipal Committee of Science and Technology(D15110700200000,D151100002015001,D151100002015002,Z161100000516223 and Z141107002514125)Beijing Institute for Brain Disorders(BIBD-PXM2013_014226_07_000084).
文摘Background In June 2015,the Chinese Stroke Association(CSA)initiated the Chinese Stroke Center Alliance(CSCA)to establish the national hospital-based stroke care quality assessment and improvement platform.This article outlines its objectives,operational structure,patient population,quality improvement(QI)intervention tools,data elements,data collection methodology and current patient and hospital data.Methods The CSCA is a national,hospital-based,multicentre,voluntary,multifaceted intervention and continuous QI initiative.This multifaceted intervention includes stroke centre development,written care protocols,workshops and a monitoring/feedback system of evidencebased performance measures.The data coordinating centre of the CSCA resides at the China National Clinical Research Center for Neurological Diseases,Beijing Tiantan Hospital.results As of July 2017,1576 hospitals in China have contributed detailed clinical information to serve as a benchmark for the stroke care quality of 433264 patients with acute stroke/transient ischaemic attacks(TIA),including 352572(81.38%)acute ischaemic stroke,30362(7.01%)TIA,42080(9.71%)spontaneous intracranial haemorrhage,5505(1.27%)subarachnoid haemorrhage and 2745(0.63%)not specified stroke.Conclusion The CSCA programme is designed to establish a continuous national stroke registry and help healthcare providers develop stroke centres and treat patients in a consistent manner in accordance with accepted national guidelines and,ultimately,improve patient outcomes.It supports the CSA mission to reduce stroke burden in China.
基金This study is sponsored and conducted by the Cerebrovascular Disease Center of Tiantan Hospital,which is also responsible for data analysis.This study is funded by the National Science and Technology Major Project of China(2011BAI08B02,2015BAI12B04 and 2015BAI12B02).
文摘Background and purpose:5 recent trials have shown the benefit of endovascular treatment for acute ischaemic stroke(AIS)due to large vessel occlusion of the anterior circulation.This study aims to evaluate the safety and efficacy of Solitaire thrombectomy in patients with moderate-to-severe stroke in the Chinese population,which has a high prevalence of intracranial atherosclerosis.Methods and analysis:This multicentre prospective control study will involve 17 stroke centres in China,and plans to recruit 150 patients in the intervention group,and 150 patients in the medical group,in which patients meet enrolment criteria but refuse intervention.Patients with AIS due to large vessel occlusion indicated for treatment with Solitaire stent retriever within 12 hours of symptom onset,and who meet the inclusion and exclusion criteria,will be enrolled in this study.The primary efficacy endpoint is functional independence as defined by a modified Rankin Scale(mRS)score≤2 at 90 days or by functional improvement as defined by mRS,using shift analysis.The procedural efficacy endpoint is arterial recanalisation of the occluded target vessel measured by a modified Thrombolysis in Cerebral Infarction(mTICI)score equal or superior to 2b right following the use of the study device.The primary safety endpoint is symptomatic intracranial haemorrhage(sICH)within 24±3 hours postprocedure.Ethics and dissemination:The protocol was approved by the Ethics Committee at the coordinating centre and by the local Institutional Review Board of each participating centre.Trial registration number:NCT02350283.
基金This work was supported by grants from the Ministry of Science and Technology of the People’s Republic of China[2017YFC1310901,2017YFC1307905,2018YFC1312903]grants from Beijing Municipal Administration of Hospitals’Mission Plan[SML20150502]+3 种基金grants from National Natural Science Foundation of China[81600999]grants from Beijing Municipal Science&Technology Commission[D171100003017002,D151100002015003]grants from National Science and Technology Major Project[2014ZX09201022-010,2017ZX09304018]Mudanjiang Youbo Pharmaceutical Co.,Ltd.
文摘Backgrounds Embolic stroke is one of the main mechanisms of ischaemic stroke.Even if treated with recommended antithrombotic agents,stroke recurrence remains high.The Shuxuetong injection,a purified extract of traditional Chinese medicine widely used for thrombus diseases in clinical practice in China,could be a promising agent to prevent stroke recurrence.Aims To describe the design of the Shuxuetong injection for prevention of recurrence in acute ischaemic stroke with embolism mechanisms.Design The Shuxuetong for Prevention of recurrence in Acute Cerebrovascular events with Embolism(SPACE)trial is a multicentre,randomised,double-blind,placebo-controlled,parallel-group,superiority trial to evaluate the efficacy and safety of Shuxuetong injection in reducing recurrence or silent new ischaemic lesions on patients with acute embolic stroke within 10 days.An estimated 2416 patients with embolic stroke within 72 hours of symptom onset from 80 hospitals will be randomly assigned to one of two groups receiving Shuxuetong injection or placebo injection for 10 days.The primary endpoint is symptomatic or asymptomatic new cerebral infarction within 10 days after randomisation.Conclusion The SPACE Trial will provide valuable evidence for the efficacy and safety of Shuxuetong injection for the prevention of stroke recurrence in patients with imaging-defined embolic stroke.
基金the National Natural Science Foundation of China(81371355 to YZ,81500989 to YZ,81671191 to YZ and 81820108012 to LL).
文摘Objective To investigate the effects of DL-3-N butylphthalide(NBP)via intranasal delivery after ischaemic stroke in mice.Methods C57BL/6 mice were divided into three groups:sham,stroke with vehicle and stroke with NBP treatment.Ischaemic stroke was induced by permanent ligation of right middle cerebral artery with 7 min common carotid artery occlusion.NBP(100 mg/kg)or vehicle was intranasally administered at 1 hour after stroke and repeated once a day until sacrifice.Bromodeoxyuridine(BrdU)(50 mg/kg/day)was given from the third day until sacrifice.Sensorimotor function was tested during 1-21 days after stroke.Local cerebral blood flow in the ischaemic and peri-infarct regions was measured using laser Doppler flowmetry before,during and 3 days after ischaemia.Expressions of vascular endothelial growth factor(VEGF)and endothelial nitric oxide synthase as well as regenerative marker BrdU in the peri-infarct region were analysed by western blotting and immunohistochemical methods.Results Compared with the vehicle group,NBP treatment significantly increased the VEGF expression in the poststroke brain.Stroke mice that received NBP showed significantly less vascular damage after stroke and more new neurons and blood vessels in the peri-infarct region at 21 days after stroke.In the adhesive removal test,the sensorimotor function of stroke mice treated with NBP performed significantly better at 1,3 and 7 days after stroke compared with vehicle controls.Conclusion Daily intranasal NBP treatment provides protective and neurogenic/angiogenic effects in the poststroke brain,accompanied with functional improvements after a focal ischaemic stroke in mice.
基金The authors would like to express appreciation to all participating institutes and clinicians.This study was sponsored by grants(2008ZX09312-008,200902004,2011BAI08B02,2012ZX09303 and 2013BAI09B03)from the Ministry of Science and Technology of the People’s Republic of China(PRC)In addition,the study was supported by the Excellence in Young Investigator Projects(81322019,81301015 and 81371274)of the Ministry of Science and Technology of the PRCthe Beijing Institute for Brain Disorders(BIBD-PXM2013_014226_07_000084).
文摘Aim:The aim of this study was to explore the difference between haemorrhagic events among those patients on either aspirin or aspirin plus clopidogrel who were enrolled in the Clopidogrel in High-Risk Patients with Acute Non-disabling Ischemic Cerebrovascular Events(CHANCE)trial.Methods:This was an ad hoc analysis of the CHANCE trial;data on all patients with any haemorrhagic event were reviewed and analysed.Cox proportional hazards regression was used to determine factors association with any bleeding.Results:In the CHANCE trial,there were a total of 101(2%)haemorrhagic events reported from 50 different hospitals.The clopidogrel–aspirin group had 60(2.3%)cases and the aspirin group had 41(1.6%,p=0.09).Moderate or severe haemorrhagic events occurred in 7 patients(0.3%)in the clopidogrel–aspirin group and in 8(0.3%)in the aspirin group(p=0.73).Of 36(0.7%)cases of intracranial haemorrhages,20(0.4%)were in the clopidogrel–aspirin group and 16(0.3%)in the aspirin group.Each group had 8(0.3%)cases of symptomatic haemorrhagic strokes.Other common haemorrhagic events included 24(0.5%)cases of skin bruises,13(0.3%)gastrointestinal haemorrhages,9(0.2%)gum haemorrhages and 8(0.2%)intraocular haemorrhages.Conclusions:There was no overall significant difference in haemorrhagic events(p=0.29),especially in the rate of intracranial haemorrhages between the 2 treatment groups.However,patients enrolled with minor strokes had an increased risk of haemorrhagic events regardless of treatment group,not seen in patients with high-risk transient ischaemic attacks.Being elderly,of male gender and with a history of aspirin or proton pump inhibitor usage were associated with increased risk of haemorrhage.Patients with higher body mass index had lower risk of haemorrhagic events.
文摘Since the approval of intravenous(IV)tissue plasminogen activator(tPA)to treat patients with acute ischaemic stroke(AIS)within 3 hours of onset in 1996,it took 12 years to expand the treatment time window to 4.5 hours by the European Cooperative Acute Stroke Trial II(ECASS III).1 It took another 10 years to expand the treatment time window to 6 hours with the bridging of IV tPA and intra-arterial(IA)thrombectomy.2 In 2018,22 years later after the approval of IV tPA and less than 3 years from the approval of IA thrombectomy,we have learnt that IA thrombectomy was effective in treating patients with AIS from large vessel occlusion(LVO)type of stroke up to 24 hours.3 This continued expansion of the treatment time window has brought hope to many patients with stroke who will present to the emergency room at a later time.
文摘Background The COVID-19 pandemic and physical distancing guidelines have compelled stroke practices worldwide to reshape their delivery of care significantly.We aimed to illustrate how the stroke services were interrupted during the pandemic in China.Methods A 61-item questionnaire designed on Wenjuanxing Form was completed by doctors or nurses who were involved in treating patients with stroke from 1 February to 31 March 2020.Results A total of 415 respondents completed the online survey after informed consent was obtained.Of the respondents,37.8%,35.2%and 27.0%were from mild,moderate and severe epidemic areas,respectively.Overall,the proportion of severe impact(reduction>50%)on the admission of transient ischaemic stroke,acute ischaemic stroke(AIS)and intracerebral haemorrhage(ICH)was 45.0%,32.0%and 27.5%,respectively.Those numbers were 36.9%,27.9%and 22.3%;36.5%,22.1%and 22.6%;and 66.4%,47.5%and 41.1%in mild,moderate and severe epidemic areas,respectively(all p<0.0001).For AIS,thrombolysis was moderate(20%-50%reduction)or severely impacted(>50%),as reported by 54.4%of the respondents,while thrombectomy was 39.3%.These were 44.4%,26.3%;44.2%,39.4%;and 78.2%,56.5%,in mild,moderate and severe epidemic areas,respectively(all p<0.0001).For patients with acute ICH,39.8%reported the impact was severe or moderate for those eligible for surgery who had surgery.Those numbers were 27.4%,39.0%and 58.1%in mild,moderate and severe epidemic areas,respectively.For staff resources,about 20%(overall)to 55%(severe epidemic)of the respondents reported moderate or severe impact on the on-duty doctors and nurses.Conclusion We found a significant reduction of admission for all types of patients with stroke during the pandemic.Patients were less likely to receive appropriate care,for example,thrombolysis/thrombectomy,after being admitted to the hospital.Stroke service in severe COVID-19 epidemic areas,for example,Wuhan,was much more severely impacted compared with other regions in China.
基金The INSPIRE-TMS trial was funded by the German Federal Ministry of Education and Research,Pfizer and German Stroke Foundation.
文摘Background and purpose Retinal pathologies are an independent risk factor for ischaemic stroke,but research on the predictive value of retinal abnormalities for recurrent vascular events in patients with prior stroke is inconclusive.We investigated the association of retinal pathologies with subsequent vascular events.Methods In a substudy of the Intensified secondary prevention intending a reduction of recurrent events in TIA and minor stroke patients(INSPiRE-TMS)trial,we enrolled patients with recent transient ischaemic attack(TIA)or minor stroke with at least one modifiable risk factor.Primary outcome was the composite of subsequent vascular events.Retinal photographs were taken at baseline and categorised into three different fundus groups by a telemedically linked ophthalmologist.Results 722 patients participated in the current study and 109 major vascular events occurred.After multivariable adjustments,we did not find a significant association between fundus categories and risk for subsequent vascular events(HRs for moderate vascular retinopathy and vascular retinopathy with vessel rarefaction in comparison to no vascular retinopathy 1.03(95%CI 0.64 to 1.67),p=0.905 and 1.17(95%CI 0.62 to 2.20),p=0.626).In a selective post hoc analysis in patients with diabetes mellitus and hypertension,patients with vascular retinopathy with vessel rarefaction had a higher risk for recurrent stroke(HR 24.14(95%CI 2.74 to 212.50),p=0.004).Conclusions Retinal changes did not predict major subsequent vascular events in patients with recent TIA or minor stroke.Further studies are needed to examine the utility of fundus photography in assessing the risk of stroke recurrence in patients with diabetes mellitus and hypertension.
基金supported by the German Ministry of Education and Research(grant G.2.17,Center for Stroke Research Berlin)by the DZHK(German Center for Cardiovascular Research)(grant B14-035_SE)and by the GETEMED AG,Teltow,Germany by supplying ECG recorders.
文摘Background Stroke aetiology remains cryptogenic in a relevant proportion of patients with acute ischaemic stroke(AIS).We assessed whether enhanced diagnostic workup after AIS yields a higher rate of prespecified pathological findings compared with routine diagnostic care in-hospital.Methods Hospitalised patients with AIS were prospectively enrolled in the investigator-initiated observational HEart and BRain Interfaces in Acute Ischaemic Stroke(HEBRAS)study at the Charité,Berlin,Germany.Patients with AIS without known atrial fibrillation(AF)underwent cardiovascular MR imaging(CMR),MR-angiography of the aortic arch and prolonged Holter-ECG monitoring on top of routine diagnostic care.Results Among 356 patients with AIS(mean age 66 years,37.6%female),enhanced workup yielded a higher rate of prespecified pathological findings compared with routine care(17.7%vs 5.3%;p<0.001).Consequently,fewer patients were classified as cryptogenic after enhanced diagnostic workup(38.5%vs 45.5%,p<0.001).Routine care included echocardiography in 228(64.0%)patients.CMR was successfully performed in 292(82.0%)patients and revealed more often a prespecified pathological finding compared with routine echocardiography(16.1%vs 5.3%).Furthermore,study-related ECG monitoring(median duration 162 hours(IQR 98–210))detected AF in 16(4.5%)patients,while routine monitoring(median duration 51 hours(IQR 34–74))detected AF in seven(2.0%)patients.Conclusions Enhanced diagnostic workup revealed a higher rate of prespecified pathological findings in patients with AIS compared with routine diagnostic care and significantly reduced the proportion of patients with cryptogenic stroke.Trial registration number NCT02142413.
文摘To the Editor:Fabry disease(FD)is a recessive X-linked hereditary disease.The onset age of the disease is in children and adolescents mostly.The average time from the onset of symptoms to the definite diagnosis needs 13.7 years in male patients and 16.3 years in female patients.FD happens rarely and it is easy to cause diagnosis and treatment delay.Here,we report a case of FD in a 27-year-old man who developed clinical symptoms with acute cerebral infarction onset to improve doctors'understanding of FD.
文摘Artificial intelligence(AI)aims to mimic human cognitive functions.It is bringing a paradigm shift to healthcare,powered by increasing availability of healthcare data and rapid progress of analytics techniques.We survey the current status of AI applications in healthcare and discuss its future.AI can be applied to various types of healthcare data(structured and unstructured).Popular AI techniques include machine learning methods for structured data,such as the classical support vector machine and neural network,and the modern deep learning,as well as natural language processing for unstructured data.Major disease areas that use AI tools include cancer,neurology and cardiology.We then review in more details the AI applications in stroke,in the three major areas of early detection and diagnosis,treatment,as well as outcome prediction and prognosis evaluation.We conclude with discussion about pioneer AI systems,such as IBM Watson,and hurdles for real-life deployment of AI.
文摘Very small superparamagnetic iron oxide nanoparticles （VSOPs） rapidly accumulate in atherosclerotic lesions, thereby enabling plaque visualization by magnetic resonance imaging （MRI）. This study was performed to identify the uptake mechanisms of VSOPs into atherosclerotic plaques. Low-density lipoprotein receptor-deficient （LDLR^-/-） mice with advanced atherosclerosis were analyzed using MRI and transmission electron microscopy （TEM） at various time points after intravenous administration of VSOPs. Post-mortem MRI detected VSOP labeling of atherosclerotic plaques 10 min after injection, and the signal increased over the first 3 h. TEM revealed that the intensive plaque labeling was mediated by accelerated transcytosis of VSOPs through endothelial cells overlaying atherosclerotic lesions. Experiments with endocytosis inhibitors and small interfering RNA （siRNA） revealed a dynamin-dependent mechanism involving both clathrin- and caveolin-mediated processes. In cell culture experiments, endothelial VSOP uptake was enhanced under proatherogenic flow and TNFα stimulation, conditions that are both present in plaque areas. Our study demonstrates that VSOPs enable non-invasive MRI assessment of accelerated endothelial transcytosis, an important pathomechanism in atherosclerotic plaque formation.
基金SITS is financed directly and indirectly by grants from Karolinska Institutet,Stockholm County Council,the Swedish Heart-Lung Foundation,the Swedish Order of St.John,Friends of Karolinska Institutet and private donors as well as from an unrestricted sponsorship from Boehringer-Ingelheim.SITS has previously received grants from the European Union Framework 7,the European Union Public Health Authority and Ferrer Internacional+3 种基金SITS is currently conducting studies supported by Boehringer-Ingelheim and EVER Pharma as well as in collaboration with Karolinska Institutet,supported by Stryker,Covidien and Phenox.RM has been supported by the project no.LQ1605 from the National Program of Sustainability II(MEYS CR)the project FNUSA-ICRC no.CZ.1.05/1.1.00/02.0123(OP VaVpI).JFS is participant in the CharitéClinical Scientist Program funded by the CharitéUniversitätsmedizin Berlin and the Berlin Institute of Health.
文摘Background and purpose Triage tools to identify candidates for thrombectomy are of utmost importance in acute stroke.No prognostic tool has yet gained any widespread use.We compared the predictive value of various models based on National Institutes of Health Stroke Scale(NIHSS)subitems,ranging from simple to more complex models,for predicting large artery occlusion(LAO)in anterior circulation stroke.Methods Patients registered in the SITS international Stroke Register with available NIHSS and radiological arterial occlusion data were analysed.We compared 2042 patients harbouring an LAO with 2881 patients having no/distal occlusions.Using binary logistic regression,we developed models ranging from simple 1 NIHSS-subitem to full NIHSS-subitems models.Sensitivities and specificities of the models for predicting LAO were examined.results The model with highest predictive value included all NIHSS subitems for predicting LAO(area under the curve(AUC)0.77),yielding a sensitivity and specificity of 69%and 76%,respectively.The second most predictive model(AUC 0.76)included 4-NIHSS-subitems(level of consciousness commands,gaze,facial and arm motor function)yielding a sensitivity and specificity of 67%and 75%,respectively.The simplest model included only deficits in arm motor-function(AUC 0.72)for predicting LAO,yielding a sensitivity and specificity of 67%and 72%,respectively.Conclusions Although increasingly more complex models yield a higher discriminative performance for predicting LAO,differences between models are not large.Assessing grade of arm dysfunction along with an established stroke-diagnosis model may serve as a surrogate measure of arterial occlusion-status,thereby assisting in triage decisions.
