Increased retinal venule diameter as a prognostic indicator for recurrent cerebrovascular events:a prospective observational study

Microvasculature of the retina is considered an alternative marker of cerebral vascular risk in healthy populations.However,the ability of retinal vasculature changes,specifically focusing on retinal vessel diameter,to predict the recurrence of cerebrovascular events in patients with ischemic stroke has not been determined comprehensively.While previous studies have shown a link between retinal vessel diameter and recurrent cerebrovascular events,they have not incorporated this information into a predictive model.Therefore,this study aimed to investigate the relationship between retinal vessel diameter and subsequent cerebrovascular events in patients with acute ischemic stroke.Additionally,we sought to establish a predictive model by combining retinal veessel diameter with traditional risk factors.We performed a prospective observational study of 141 patients with acute ischemic stroke who were admitted to the First Affiliated Hospital of Jinan University.All of these patients underwent digital retinal imaging within 72 hours of admission and were followed up for 3 years.We found that,after adjusting for related risk factors,patients with acute ischemic stroke with mean arteriolar diameter within 0.5-1.0 disc diameters of the disc margin(MAD_(0.5-1.0DD))of≥74.14μm and mean venular diameter within 0.5-1.0 disc diameters of the disc margin(MVD_(0.5-1.0DD))of≥83.91μm tended to experience recurrent cerebrovascular events.We established three multivariate Cox proportional hazard regression models:model 1 included traditional risk factors,model 2 added MAD_(0.5-1.0DD)to model 1,and model 3 added MVD0.5-1.0DD to model 1.Model 3 had the greatest potential to predict subsequent cerebrovascular events,followed by model 2,and finally model 1.These findings indicate that combining retinal venular or arteriolar diameter with traditional risk factors could improve the prediction of recurrent cerebrovascular events in patients with acute ischemic stroke,and that retinal imaging could be a useful and non-invasive method for identifying high-risk patients who require closer monitoring and more aggressive management.

Multiple factors to assist human-derived induced pluripotent stem cells to efficiently differentiate into midbrain dopaminergic neurons

Midbrain dopaminergic neurons play an important role in the etiology of neurodevelopmental and neurodegenerative diseases.They also represent a potential source of transplanted cells for therapeutic applications.In vitro differentiation of functional midbrain dopaminergic neurons provides an accessible platform to study midbrain neuronal dysfunction and can be used to examine obstacles to dopaminergic neuronal development.Emerging evidence and impressive advances in human induced pluripotent stem cells,with tuned neural induction and differentiation protocols,makes the production of induced pluripotent stem cell-derived dopaminergic neurons feasible.Using SB431542 and dorsomorphin dual inhibitor in an induced pluripotent stem cell-derived neural induction protocol,we obtained multiple subtypes of neurons,including 20%tyrosine hydroxylase-positive dopaminergic neurons.To obtain more dopaminergic neurons,we next added sonic hedgehog(SHH)and fibroblast growth factor 8(FGF8)on day 8 of induction.This increased the proportion of dopaminergic neurons,up to 75%tyrosine hydroxylase-positive neurons,with 15%tyrosine hydroxylase and forkhead box protein A2(FOXA2)co-expressing neurons.We further optimized the induction protocol by applying the small molecule inhibitor,CHIR99021(CHIR).This helped facilitate the generation of midbrain dopaminergic neurons,and we obtained 31-74%midbrain dopaminergic neurons based on tyrosine hydroxylase and FOXA2 staining.Thus,we have established three induction protocols for dopaminergic neurons.Based on tyrosine hydroxylase and FOXA2 immunostaining analysis,the CHIR,SHH,and FGF8 combined protocol produces a much higher proportion of midbrain dopaminergic neurons,which could be an ideal resource for tackling midbrain-related diseases.

Cerebral perfusion in corresponding blood supply areas of transient ischemic attack patients with intracranial stenosis Seven cases of diamox-perfusion verified by magnetic resonance-perfusion-weighted imaging

BACKGROUND： Due to collateral circulation and cerebrovascular reserve, arterial stenosis and reduced cerebral blood flow may not necessarily indicate impaired cerebral peffusion. Therefore, according to degree of stenosis and clinical symptoms, interventional surgery to relieve arterial stenosis in transient ischemic attack （TIA） patients with major intracranial stenosis is imprudent. Rather, cerebral perfusion and reserve capacity are direct indicators for the assessment of degree and presence of cerebral ischemia. OBJECTIVE： To evaluate cerebral perfusion and reserve in TIA patients with major intracranial stenosis or occlusion using magnetic resonance-perfusion-weighted imaging （MR-PWl） data prior to and following diamox administration. DESIGN, TIME AND SETTING： A self-comparative, neuroimaging observation was performed at the Neurological Department and Radiological Center of the First Affiliated Hospital of Jinan University between December 2007 and April 2009. PARTICIPANTS： Seven acute TIA patients, who were admitted to the Neurological Department of the First Affiliated Hospital of Jinan University between December 2007 and April 2009, were enrolled in the present study. Magnetic resonance imaging confirmed that no acute cerebral infarction happened, nor did bleeding exist. Magnetic resonance angiography, transcranial Doppler ultrasound, and/or digital subtraction angiography confirmed the presence of major intracranial arterial stenosis. Clinical symptoms corresponded to blood supplying regions of the arterial stenosis. METHODS： Baseline MR-PWI was performed on seven patients with intracranial stenosis or occlusion. Two grams of acetazolamide （diamox） were orally administered after 2 days. A second PWl was performed after 2 hours to compare cerebral perfusion parameters prior to and following diamox administration. MAIN OUTCOME MEASURES： PWI results of cerebral perfusion prior to and following diamox administration. RESULTS： The baseline PWl from five patients indicated decreased cerebral perfusion areas. Following oral administration of diamox, cerebral perfusion significantly decreased in those areas. Moreover, new areas of decreased cerebral perfusion were observed in two out of the five patients. In one patient, no significant decrease in cerebral perfusion was found. In another patient, baseline PWl indicated decreased cerebral perfusion in the left hemisphere. However, normal perfusion was observed in both cerebral lobes following diamox administration. CONCLUSION： TIA patients with intracranial stenosis, who are diagnosed by PWI and exhibited decreased cerebral perfusion and reserve, might require further treatment such as intervention by angioptasty.

Effects of Different Flue-curing Technologies on Submicroscopic Structure of Flue-cured Tobacco Leaves

[ Objective] This study aimed to compare the effects of low-temperature low-humidity tobacco flue-curing technology, moderate-temperature moderate- humidity tobacco flue-curing technology and moderate-temperature high-humidity tobacco flue-curing technology on submicroscopic structure of flue-cured tobacco leaves to provide theoretical basis for tobacco flue-curing. [ Method] Middle leaves of tobacco cuhivar K326 were collected in Pengshui County of Chongqing City for flue-curing experiment using three flue-curing technologies. Leaf samples were collected regularly in the flue-curing process, to investigate the submicroscopic structure of flue-cured tobacco leaves. [ Result] Morphology changes and structural rupture of chloroplasts occurred at different time during three flue-curing proces- ses. In low-temperature low-humidity flue-curing process, morphology changes and structural rupture of chloroplasts occurred late but rapidly; in moderate-tempera- ture moderate-humidity flue-curing process and moderate-temperature high-humidity flue-curing process, morphology changes and structural rupture of chloroplasts occurred early but slowly. Among these three flue-curing processes, the speed of changes in mitochondria morphology, cristae number and membrane rupture pres- ented an upward order of low-temperature low-humidity flue-curing process 〈 moderate-temperature high-humidity flue-curlng process 〈 moderate-temperature moderate-humidity flue-curing process. In low-temperature low-humldity flue-curing process, starch granules in chloroplasts ruptured after flue-curing for 36 -48 h ; in moderate-temperature moderate-humidity flue-curing process, starch granules in chloroplasts ruptured after flue-curing for 24 - 36 h; in moderate-temperature high-humidity flue-curing process, starch granules in chloroplasts ruptured after flue-curing for 12 - 24 h. [ Conclusion ] Using low-temperature low-humidity flue- curing technology could prolong the maintenance duration of the submicroscopic structure integrity of flue-cured tobacco leaves, which was conducive to fully decom- posing and transforming substances in tobacco leaves and obtaining high-quality flue-cured tobacco leaves.

Effects of Different Flue-curing Technologies on Microscopic Structure of Flue-cured Tobacco Leaves

[Objective] This study aimed to compare the effects of Chinese quality-improving fragrunce-increasing tobacco flue-curing technology, Chinese three- stage tobaeeo flue-curing technology and Zimbabwean tobaceo flue-euring technology on microscopie structure of flue-cured tobacco leaves to provide theoretical basis for tobacco flue-curing. [ Method ] Middle leaves of tobacco cultivar K326 were collected in Pengshui County of Chongqing City for flue-curing experiment using three flue-curing technologies. Leaf samples were collected regularly in the flue-curing process, to investigate the microscopic structure of flue-cured tobaceo leaves. [ Result] During three flue-curing processes, leaves, palisade tissues and sponge tissues shrank gradually. Three flue-euring processes exhibited significant differ- ences in the peak of tissue shrinkage ： microscopic structure of flue-cured tobacco leaves in Chinese three-stage tobacco flue-curing process shrank earliest, follower by Chinese quality-improving fragrance-increasing tobacco flue-curing process; flue-eured tobacco leaves in Zimbabwean tobacco flue-curing process presented the latest shrinkage. At 84 h post-curing, leaf thickness in three flue-curing processes showed a descend order of Chinese three-stage tobacco flue-curing process 〉 Chinese quality-improving fragrance-increasing tobacco flue-curing process 〉 Zimbabwean tobacco flue-curing process. Upper and lower epidermal cells in Zimb- abwean tobacco flue-curing process ruptured earlier than other two flue-curing processes; eventually, the majority of cells ruptured and mixed with palisade tissues and sponge tissues. In Chinese quality-improving fragranee-increasing tobacco flue-curing process, only a small number of epidermal cells in dried leaves ruptured. Among three flue-curing technologies, Zimbabwean tobacco flue-curing technology exhibited the greatest damage to epidermal cells, followed by Chinese three-stage tobaceo flue-curing technology; Chinese quality-improving fragrance-increasing tobacco flue-curing technology had the minimum damage to epidermal cells. Mese- phyll cross-section exhibited significant morphological changes in stomata. To be specific, at 0 - 12 h post-curing, stomata of tobacco leaves closed with slightly prominent stamatal apparatuses on upper and lower epidermis; at 24 -72 h post-curing, stomata of tobaceo leaves changed gradually from opening to closure with significantly prominent stomatal apparatuses on upper and lower epidermis; at 84 h post-curing, stomata of tobacco leaves closed, and the majority of stomatal appa- ratuses were significantly prominent. In Chinese quality-improving fragrance-increasing tobacco flue-curing process, only a small number of epidermal ceils ruptured at 84 h pest-flue-curing; palisade tissues and sponge tissues shrank almost simultaneously. Significant gaps were observed between palisade tissues and between pal- isade tissues and sponge tissues. Chinese quality-improving fragrance-increasing tobacco flue-curing technology exhibited lower disorder level compared with other two flue-curing technologies. [ Conclusion] Chinese quality-improving fragrance-increasing tobacco flue-curlng technology was conducive to maintaining the micro- scopic structure integrity of flue-cured tobacco leaves and obtaining high-quality flue-cured tobacco leaves.

Associations of HDL-C/LDL-C with myocardial infarction,all-cause mortality,haemorrhagic stroke and ischaemic stroke:a longitudinal study based on 384093 participants from the UK Biobank

Objective To explore the correlations of high-density lipoprotein cholesterol(HDL-C)/low-density lipoprotein cholesterol(LDL-C)with myocardial infarction(MI),all-cause mortality,haemorrhagic stroke and ischaemic stroke,as well as the joint association of genetic susceptibility and HDL-C/LDL-C with the MI risk.Methods and results This study selected 384093 participants from the UK Biobank(UKB)database.First,restricted cubic splines indicated non-linear associations of HDL-C/LDL-C with MI,ischaemic stroke and all-cause mortality.Second,a Cox proportional-hazards model indicated that compared with HDL-C/LDL-C=0.4-0.6,HDL-C/LDL-C<0.4 and>0.6 were correlated with all-cause mortality(HR=0.97 for HDL-C/LDL-C<0.4,95%CI=0.939 to 0.999,p<0.05;HR=1.21 for HDL-C/LDL-C>0.6,95%CI=1.16 to 1.26,p<0.001)after full multivariable adjustment.HDL-C/LDL-C<0.4 was correlated with a higher MI risk(HR=1.36,95%CI=1.28 to 1.44,p<0.05)and ischaemic stroke(HR=1.12,95%CI=1.02 to 1.22,p<0.05)after full multivariable adjustment.HDL-C/LDL-C>0.6 was associated with higher risk haemorrhagic stroke risk after full multivariable adjustment(HR=1.25,95%CI=1.03 to 1.52,p<0.05).Third,after calculating the coronary heart disease Genetic Risk Score(CHD-GRS)of each participant,the Cox proportional-hazards model indicated that compared with low CHD-GRS and HDL-C/LDL-C=0.4-0.6,participants with a combination of high CHD-GRS and HDL-C/LDL-C<0.4 were associated with the highest MI risk(HR=2.45,95%CI=2.15 to 2.8,p<0.001).Participants with HDL-C/LDL-C<0.4 were correlated with a higher MI risk regardless of whether they had a high,intermediate or low CHD-GRS.Conclusion In UKB participants,HDL-C/LDL-C ratio of 0.4-0.6 was correlated with lower MI risk,all-cause mortality,haemorrhagic stroke and ischaemic stroke.Participants with HDL-C/LDL-C<0.4 were correlated with a higher MI risk regardless of whether they had a high,intermediate or low CHD-GRS.The clinical significance and impact of HDL-C/LDL-C need to be further verified in future studies.

FUS-mediated HypEVs: Neuroprotective effects against ischemic stroke

Few studies have investigated the properties and protein composition of small extracellular vesicles (sEVs) derived from neurons under hypoxic conditions. Presently, the extent of the involvement of these plentiful sEVs in the onset and progression of ischemic stroke remains an unresolved question. Our study systematically identified the characteristics of sEVs derived from neurons under hypoxic conditions (HypEVs) by physical characterization, sEV absorption, proteomics and transcriptomics analysis. The effects of HypEVs on neurites, cell survival, and neuron structure were assessed in vitro and in vivo by neural complexity tests, magnetic resonance imaging (MRI), Golgi staining, and Western blotting of synaptic plasticity-related proteins and apoptotic proteins. Knockdown of Fused in Sarcoma (FUS) small interfering RNA (siRNA) was used to validate FUS-mediated HypEV neuroprotection and mitochondrial mRNA release. Hypoxia promoted the secretion of sEVs, and HypEVs were more easily taken up and utilized by recipient cells. The MRI results illustrated that the cerebral infarction volume was reduced by 45% with the application of HypEVs, in comparison to the non- HypEV treatment group. Mechanistically, the FUS protein is necessary for the uptake and neuroprotection of HypEVs against ischemic stroke as well as carrying a large amount of mitochondrial mRNA in HypEVs. However, FUS knockdown attenuated the neuroprotective rescue capabilities of HypEVs. Our comprehensive dataset clearly illustrates that FUS-mediated HypEVs deliver exceptional neuroprotective effects against ischemic stroke, primarily through the maintenance of neurite integrity and the reduction of mitochondria-associated apoptosis.

The Chinese Stroke Association scientific statement:intravenous thrombolysis in acute ischaemic stroke

The most effective medical treatment for acute ischaemic stroke(AIS)is to offer intravenous thrombolysis during the ultra-early period of time after the onset.Even based on the Consensus of Chinese Experts on Intravenous Thrombolysis for AIS in 2012 and 2014 Chinese Guidelines on the Diagnosis and Treatment of AIS,the rate of thrombolysis for AIS in China remained around 2.4%,and the rate of intravenous tissue plasminogen activator usage was only about 1.6%in real world.The indication of thrombolysis for AIS has been expanded,and contraindications have been reduced with recently published studies.In order to facilitate the standardisation of treating AIS,improve the rate of thrombolysis and benefit patients who had a stroke,Chinese Stroke Association has organised and developed this scientific statement.

Guidelines for evaluation and management of cerebral collateral circulation in ischaemic stroke 2017

Collateral circulation plays a vital role in sustaining blood flow to the ischaemic areas in acute,subacute or chronic phases after an ischaemic stroke or transient ischaemic attack.Good collateral circulation has shown protective effects towards a favourable functional outcome and a lower risk of recurrence in stroke attributed to different aetiologies or undergoing medical or endovascular treatment.Over the past decade,the importance of collateral circulation has attracted more attention and is becoming a hot spot for research.However,the diversity in imaging methods and criteria to evaluate collateral circulation has hindered comparisons of findings from different cohorts and further studies in exploring the clinical relevance of collateral circulation and possible methods to enhance collateral flow.The statement is aimed to update currently available evidence and provide evidence-based recommendations regarding grading methods for collateral circulation,its significance in patients with stroke and methods under investigation to improve collateral flow.

Chinese Stroke Center Alliance:a national effort to improve healthcare quality for acute stroke and transient ischaemic attack:rationale,design and preliminary findings

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.

Clopidogrel with aspirin in High- risk patients with Acute Non- disabling Cerebrovascular Events II (CHANCE-2): rationale and design of a multicentre randomised trial

Background In patients with a minor ischaemic stroke or transient ischaemic attack(TIA),separate trials have shown that dual antiplatelet therapy with clopidogrel plus aspirin(clopidogrel-aspirin)or ticagrelor plus aspirin(ticagrelor-aspirin)are more effective than aspirin alone in stroke secondary prevention.However,these two sets of combination have not been directly compared.Since clopidogrel was less effective in stroke patients who were CYP2C19 loss-of function(LOF)allele carriers,whether ticagrelor-aspirin is clinically superior to clopidogrel-aspirin in this subgroup of patients with stroke is unclear.Aim To describe the rationale and design considerations of the Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events(CHANCE-2)trial.Design CHANCE-2 is a randomised,double-blind,double-dummy,placebo-controlled,multicentre trial that compares two dual antiplatelet strategies for minor stroke or TIA patients who are CYP2C19 LOF allele carriers:ticagrelor(180 mg loading dose on day 1 followed by 90 mg twice daily on days 2-90)or clopidogrel(300 mg loading dose on day 1 followed by 75 mg daily on days 2-90),plus open-label aspirin with a dose of 75-300 mg on day 1 followed by 75 mg daily on day 2-21.All will be followed for 1 year.Study outcomes The primary efficacy outcome is any stroke(ischaemic or haemorrhagic)within 3 months and the primary safety outcome is any severe or moderate bleeding event within 3 months.Discussion The CHANCE-2 trial will evaluate whether ticagrelor-aspirin is superior to clopidogrel-aspirin for minor stroke or TIA patients who are CYP2C19 LOF allele carriers.

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.

Endovascular therapy for Acute ischemic Stroke Trial (EAST): study protocol for a prospective, multicentre control trial in China

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.

Thrombolysis with alteplase 3-4.5 hours after acute ischaemic stroke:the first multicentre,phase III trial in China

background and purpose Data on the efficacy and safety of alteplase for acute ischaemic stroke(AIS)administered 3-4.5 hours after the onset of stroke symptoms in Chinese patients is limited.We sought to determine whether AIS patients would benefit from thrombolysis with alteplase between 3 and 4.5 hours after the onset of stroke symptoms in a prospective,multicentre,single-arm trial in China.Materials and methods Eligible AIS patients were given 0.9 mg/kg alteplase intravenously.The primary efficacy endpoint was a favourable outcome at 3 months,defined as a score of 0 or 1 on the modified Rankin Scale.Thresholds for the primary efficacy endpoint were determined to be 40%based on the literature review.The primary safety endpoint was symptomatic intracranial haemorrhage(sICH)according to the European Cooperative Acute Stroke Study III(ECASS III)trial definition.Post hoc analysis between this study and the ECASS III trial were compared using the propensity score matching(PSM)method.results A total of 120 eligible AIS patients from 11 sites in China received thrombolysis therapy in this study.The median time from onset of symptoms to needle was 3 hours 54 min.The percentage of patients with a favourable outcome was 63.3%(95%CI 54.4 to 71.4),significantly higher than the predefined threshold(p<0.0001).Three patients(2.5%,95%CI 0.5 to 7.1)had sICH,including two fatal sICH.Six patients died within 3 months after treatment.The post hoc PSM analysis showed a numerically higher rate of the primary efficacy endpoint in this study(63.3%)than the matched placebo arm(56.7%)in the ECASS III trial.Conclusions Intravenous alteplase with a standard dose administered between 3 and 4.5 hours after onset of symptoms is effective and safe for Chinese AIS patients.

Clopidogrel loading dose versus maintenance dose to treat patients with acute ischaemic stroke in China(CLASS-China):results from a prospective double-blind randomised clinical trial

Aim The role of clopidogrel in treating patients with acute ischaemic stroke is unclear.We have conducted the clinical trial in order to evaluate the efficacy and safety of clopidogrel with a loading dose in treating patients with non-cardiogenic acute ischaemic stroke.Method Clopidogrel loading dose versus maintenance dose to treat patients with acute ischaemic stroke in China(CLASS-China)was a prospective,randomised,double-blind and placebo-controlled clinical trial in China.Patients with acute ischaemic stroke of non-cardiogenic origin within 48 hours of onset were enrolled and those received thrombolysis were excluded.Enrolled patients were divided into two treatment groups:loading dose and routine dose.The primary outcome was the incidence of stroke recurrence or progression within 7 days.Primary safety outcome was measured by life-threatening haemorrhage.An intent-to-treat analysis was used for the statistical analysis.results From March 2008 to March 2010,a total of 303 patients from 16 centres were recruited into this study;six were excluded because of lack of basic information.Since the enrolment was slow and the study drug expired in March 2010,this clinical trial was stopped earlier than planned.No significant baseline and demographic differences were seen between the two groups.There was no difference in primary outcome between the loading dosage group 16.1%(24/149)and control group 14.9%(22/148),respectively(p=0.782).The mortality and disability rate within 90 days in loading dose group(19.6%)was slightly lower than that in controlled group(23.4%),p=0.444.Loading dose group had two(1.3%)cases of fatal haemorrhage and control group had four(2.7%)within 90 days,p=0.674.No significant difference was detected in other adverse events between the groups.conclusion In our study stopped early due to slow enrolment,loading dose of clopidogrel does not reduce the risk of recurrent stroke.Future trials with sufficient number of patients enrolled are needed to re-examine this hypothesis.

Study on the promotion of lymphocytes in patients with COVID-19 by broad-spectrum chemokine receptor inhibitor vMIP-Ⅱ and its Mechanism of signal transmission in vitro

Dear Editor,COVID-19 cases showed a significant decrease in the number of peripheral CD4^(+) and CD8^(+)T cells accompanied by overactivation of cells.1 HHV8-derived viral macrophage inflammatory protein vMIP-Ⅱ is the only broad-spectrum chemokine receptor inhibitor that binds to three subtribes of chemokine receptors,which can significantly increase the specific cell immune response in infected organisms and have an effect of reducing plasma viral load on the viremia period.24 Here we report the effect of vMIP-Ⅱ in COVID-19.

Penumbra-targeted CircOGDH siRNA-loaded nanoparticles alleviate neuronal apoptosis in focal brain ischaemia

Background Nanoparticles(NPs)are a class of substances that can be loaded with therapeutic agents delivered to specific areas.In our earlier research,we identified a neuron-derived circular RNA(circRNA),circular oxoglutarate dehydrogenase(CircOGDH),as a promising therapeutic target for acute ischaemic stroke.This study dedicated to explore a prospective preliminary strategy of CircOGDH-based NP delivered to the ischaemic penumbra region in middle cerebral artery occlusion/reperfusion(MCAO/R)mice.Methods Immunofluorescence in primary cortex neurons and in vivo fluorescence imaging revealed endocytosis of Poly(lactide-co-glycolide)(PLGA)poly amidoamine(PAMAM)@CircOGDH small interfering RNA(siRNA)NPs.Western blotting analysis and CCK8 assay were performed to evaluate the apoptotic level in ischaemic neurons treated with PLGA–PAMAM@CircOGDH siRNA NPs.Quantitative reverse transcription PCR experiments,mice behaviour test,T2 MRI analysis,Nissl and TdT-mediated dUTP nick end labeling(TUNEL)co-staining were performed to evaluate the apoptosis level of ischaemic penumbra neurons in MCAO/R mice.Biosafety evaluation of NPs in MCAO/R mice was detected by blood routine examination,liver and kidney function examination and HE staining.Results PLGA–PAMAM@CircOGDH siRNA NPs were successfully assembled.Endocytosis of PLGA–PAMAM@CircOGDH siRNA NPs in ischaemic neurons alleviated neuronal apoptotic level in vitro and in vivo.Furthermore,mice behaviour test showed that the neurological defects of MCAO/R mice were significantly alleviated after the tail injection of PLGA–PAMAM@CircOGDH siRNA NPs,and no toxic effects were observed.Conclusion In conclusion,our results suggest that PLGA–PAMAM@CircOGDH siRNA NPs can be delivered to the ischaemic penumbra region and alleviate neuron apoptosis in MCAO/R mice and in ischaemic neurons;therefore,our study provides a desirable approach for using circRNA-based NPs for the treatment of ischaemic stroke.

Thrombus migration in patients with acute ischaemic stroke undergoing endovascular thrombectomy

Objective The impact of thrombus migration(TM)prior to endovascular thrombectomy(EVT)on clinical outcomes and revascularisation rates remains unknown.We aimed to examine whether preinterventional TM modifies the treatment effects of direct EVT versus bridging EVT in acute large vessel occlusion patients.Methods All patients undergoing catheter angiography in the Direct Intra-arterial thrombectomy in order to Revascularise acute ischaemic stroke patients with large vessel occlusion Efficiently in Chinese Tertiary hospitals:A Multicentre randomised clinical Trial were included.TM was determined by radiologists unaware of the study by analysing discrepancies between computed tomographic angiography at baseline and first-run digital subtraction angiography before EVT.The primary outcome was the score on the modified Rankin scale(mRS)assessed at 90 days.Results Of 627 included patients,the TM rate was 11.3%(71/627).In the multivariable logistic regression model,baseline National Institutes of Health Stroke Scale score(adjusted OR 0.956,95%CI 0.916 to 0.999;p=0.043)and intravenous thrombolysis(adjusted OR 2.614,95%CI 1.514 to 4.514;p<0.001)were independently associated with TM.The patients with TM were less likely to be completely recanalised than those without TM(21.27%vs 36.23%,p=0.040).The interaction of TM and the EVT treatment effect did not significantly affect mRS shift analysis(p=0.687)or mRS scores of 0 to 1(p=0.436).Conclusion Preinterventional TM does not modify the treatment effects of direct versus bridging EVT on functional outcomes in patients with acute ischaemic stroke with anterior large vessel occlusion.TM leads to a lower complete recanalisation rate.

Atherosclerosis-related biomarker PABPC1 predicts pan-cancer events

Background Atherosclerosis(AS)and tumours are the leading causes of death worldwide and share common risk factors,detection methods and molecular markers.Therefore,searching for serum markers shared by AS and tumours is beneficial to the early diagnosis of patients.Methods The sera of 23 patients with AS-related transient ischaemic attack were screened by serological identification of antigens through recombinant cDNA expression cloning(SEREX),and cDNA clones were identified.Pathway function enrichment analysis was performed on cDNA clones to identify their biological pathways and determine whether they were related to AS or tumours.Subsequently,gene–gene and protein–protein interactions were performed and AS-associated markers would be discovered.The expression of AS biomarkers in human normal organs and pan-cancer tumour tissues were explored.Then,immune infiltration level and tumour mutation burden of various immune cells were evaluated.Survival curves analysis could show the expression of AS markers in pan-cancer.Results AS-related sera were screened by SEREX,and 83 cDNA clones with high homology were obtained.Through functional enrichment analysis,it was found that their functions were closely related to AS and tumour functions.After multiple biological information interaction screening and the external cohort validating,poly(A)binding protein cytoplasmic 1(PABPC1)was found to be a potential AS biomarker.To assess whether PABPC1 was related to pan-cancer,its expression in different tumour pathological stages and ages was screened.Since AS-associated proteins were closely related to cancer immune infiltration,we investigated and found that PABPC1 had the same role in pan-cancer.Finally,analysis of Kaplan-Meier survival curves revealed that high PABPC1 expression in pan-cancer was associated with high risk of death.Conclusions Through the findings of SEREX and bioinformatics pan-cancer analysis,we concluded that PABPC1 might serve as a potential biomarker for the prediction and diagnosis of AS and pan-cancer.