Tirofiban combined with Aspirin in the Treatment of Acute Penetrating Artery Territory Infarction (STRATEGY): protocol for a multicentre, randomised controlled trial

Background Perforating artery territorial infarction(PAI)caused by branch atheromatous disease(BAD)is prone to recurrence and early progression without an effective and well-documented antiplatelet treatment regimen.Tirofiban,an adjunctive antiplatelet agent,has shown great potential to treat acute ischaemic stroke.However,whether the combination of tirofiban and aspirin can improve the prognosis of PAI remains unclear.Aim To explore an effective and safe antiplatelet regimen for reducing the risk of recurrence and early neurological deterioration(END)in PAI caused by BAD by comparing the tirofiban and aspirin combination with placebo and aspirin combination.Methods Tirofiban combined with Aspirin in the Treatment of Acute Penetrating Artery Territory Infarction(STRATEGY)trial is an ongoing multicentre,randomised,placebo-controlled trial in China.Eligible patients shall be randomly assigned to receive standard aspirin with tirofiban or placebo on the first day and standard aspirin from days 2 to 90.The primary endpoint is a new stroke or END within 90 days.The primary safety endpoint is severe or moderate bleeding within 90 days.Discussion The STRATEGY trial will assess whether tirofiban combined with aspirin is effective and safe in preventing recurrence and END in patients with PAI.Trial registration number NCT05310968.

Safety and efficacy of a novel responsive neurostimulation system in China for drug-refractory focal epilepsy:The first-in-man study

To the Editor:Recent studies have characterized drugresistant epilepsy(DRE)as essentially a neural network disease.[1]Detection and disconnection of this pathological epileptic connectome or network can greatly improve seizure outcomes.Our team also proposes the development of the newly emerging branch of epileptic networks neurosurgery(ENN).Responsive neurostimulation(RNS)is an ENN-oriented emerging treatment option without the resection of the seizure-onset zone or epileptic focus and aims to control the seizure or other epileptic manifestations by modulating or disrupting the network’s key nodes(epileptic hubs)in a self-responsive way.

Moderate alcohol preconditioning activates BKCa channels to protect brain damage-induced by cerebral ischemia and reperfusion

OBJCETIVE Epidemiologic studies have demonstrated that consumption of moderate amounts of red wine is associated with significant reductions in incidences of cardiovascular and cerebrovascular diseases,which may be related to alcohol in red wine.Our previous study demonstrated that ethanol ingestion 24 h prior to induction of cerebral ischemic/reperfusion(I/R)reduced delayed neuronal death(DND).Our most recent results supported a role for big Ca2+-sensitive K+channel(BKCa channel)activation in the neuroprotective effects of ethanol preconditioning(Et OH-PC)in global cerebral I/R.Therefore,we hypothesis that moderate Et OH-PC activates BKCa channel to protect brain damage induced by focal cerebral I/R.This project will utilize focal cerebral I/R animal model to explore the function of BKCa channel in Et OH-PC protection in vivo levels by means of pharmacological intervention such as BKCa channel opene(rNS11021,NS)and blocke(rpaxilline,PX).The results will provide theoretical evidence for neuroprotective effect of moderate alcohol preconditioning against ischemic stroke,and the conclusion will also bring to a concept that extrinsic moderate ethanol preconditioning may activate intrinsic protective mechanism in the brain.METHODS The SD rat were randomly divided into the following six groups(n=10):sham,I/R,Et OH-PC+I/R,NS11021-PC+I/R,paxilline+Et OH-PC+I/R,Paxilline+NS11021-PC+I/R.Both Et OH-PC and NS11021-PC(0.1mg·kg-1;ip)were induced 24 h before I/R.The volume of 95%ethanol to be instilled(inμL)was calculated as follows:〔body weight(g)×0.6〕+0.3.This volume of ethanol was mixed in 0.3 m L of sterile distilled water just before administration to the animals by gavage.The Paxilline(2.5 mg·kg-1;ip)was administered 10min beforeEt OH-PC and NS11021-PC.The right middle cerebral artery occlusion(MCAO)was produced by inversion of a 4-0-nylon filament.The filament was withdrawn 2 h after onset of MCAO and then reperfused.Neurological deficits and infarct volume were measured 24 h after I/R.Another 36 rats were randomly divided into 6 groups as above,6 in each group.DWI were performed 2h after ischemic and T2WI MRI were performed 24 h after I/R to observe the infarct volume of brain and the penumbra volume of brain in each group.Then rats were killed and detected the apoptotic cell death and degeneration of neurons.RESULTS Compared to I/R group,the neurological score(P<0.01),the infarct volume of brain(P<0.01),the infarct volume of ischemic penumbra(P<0.01),the percentage of apoptotic cell death(P<0.01)and the percentage of degenerative neurons(P<0.01)were significantly decreased after ethanol preconditioning,while these changes were reversed by paxilline(P<0.05);compared to I/R group,the neurological score(P<0.01),the infarct volume of brain(P<0.01),the infarct volume of ischemic penumbra(P<0.01),the percentage of apoptotic cell death(P<0.01)and the percentage of degenerative neurons(P<0.01)were significantly decreased after NS11021 preconditioning,while these changes were reversed by paxilline(P<0.05).CONCLUSION Our results show that moderate alcohol preconditioning activates BKCa channels to protect brain damage induced by focal cerebral I/R.

In patients who had a stroke or TIA, enlarged perivascular spaces in basal ganglia may cause future haemorrhagic strokes

Introduction It remains unclear whether enlarged perivascular spaces(EPVS)predict poor clinical outcomes in patients with acute ischaemic stroke(AIS)or transient ischaemic attack(TIA).Method Data were obtained from the Third China National Stroke Registry study.We estimated EPVS in basal ganglia(BG)and centrum semiovale(CSO)using a semiquantified scale(Grade from 0 to 4).Using Cox and logistic regression analyses,the associations of EPVS with 3-month and 1-year adverse outcomes(including recurrent stroke,ischaemic stroke,haemorrhagic stroke,combined vascular event,disability and mortality)were explored.Sensitivity analyses of any association of cerebral small vessel disease at baseline and development of a small arterial occlusion(SAO)were conducted.Result Among 12603 patients with AIS/TIA,median age was 61.7±11.6 years,and 68.2%were men.After adjusting for all potential confounders,frequent-to-severe BG-EPVS was associated with a decreased risk of recurrent ischaemic stroke(HR 0.71,95%CI 0.55 to 0.92,p=0.01)but an increased risk of haemorrhagic stroke(HR 1.99,95%CI 1.11 to 3.58,p=0.02)at 1 year after AIS/TIA,compared with none-to-mild BG-EPVS.Patients with frequent-to-severe CSO-EPVS had a decreased risk of disability(OR 0.76,95%CI 0.62 to 0.92,p=0.004)and all-cause death(HR 0.55,95%CI 0.31 to 0.98,p=0.04)within 3-month but not 1-year follow-ups,compared with those with none-to-mild BG-EPVS.Sensitivity analyses showed that both BG-EPVS(HR 0.43,95%CI 0.21 to 0.87,p=0.02)and CSO-EPVS(HR 0.58,95%CI 0.35 to 0.95,p=0.03)were associated with a decreased risk of subsequent ischaemic stroke in patients with SAO during 1-year follow-up.Conclusion BG-EPVS increased the risk of haemorrhagic stroke in patients already with AIS/TIA within 1 year.Therefore,caution is recommended when selecting antithrombotic agents for secondary stroke prevention in patients with AIS/TIA and more severe BG-EPVS.

Association of TRMT2B gene variants with juvenile amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons,and it demonstrates high clinical heterogeneity and complex genetic architecture.A variation within TRMT2B(c.1356G>T;p.K452N)was identified to be associated with ALS in a family comprising two patients with juvenile ALS(JALS).Two missense variations and one splicing variation were identified in 10 patients with ALS in a cohort with 910 patients with ALS,and three more variants were identified in a public ALS database including 3317 patients with ALS.A decreased number of mitochondria,swollen mitochondria,lower expression of ND1,decreased mitochondrial complex I activities,lower mitochondrial aerobic respiration,and a high level of ROS were observed functionally in patient-originated lymphoblastoid cell lines and TRMT2B interfering HEK293 cells.Further,TRMT2B variations overexpression cells also displayed decreased ND1.In conclusion,a novel JALS-associated gene called TRMT2B was identified,thus broadening the clinical and genetic spectrum of ALS.

Critical thinking of Alzheimer's transgenic mouse model:current research and future perspective

Transgenic models are useful tools for studying the pathogenesis of and drug development for Alzheimer's Disease(AD).AD models are constructed usually using overexpression or knock-in of multiple pathogenic gene mutations from familial AD.Each transgenic model has its unique behavioral and pathological features.This review summarizes the research progress of transgenic mouse models,and their progress in the unique mechanism of amyloid-βoligomers,including the first transgenic mouse model built in China based on a single gene mutation(PSEN1 V97L)found in Chinese familial AD.We further summarized the preclinical findings of drugs using the models,and their future application in exploring the upstream mechanisms and multi-target drug development in AD.

Assessing structural integrity of the pyramidal tracts with difusion spectrum imaging to predict postoperative motor function in pediatric epilepsy patients with hemispherectomy

Background:Hemispherectomy is an efective treatment option for patients with drug-resistant epilepsy caused by hemispheric lesions.However,patients often have deterioration of their motor functions postoperatively.Difusion spectrum imaging(DSI)was reliable in presenting the natural shape of the white matter fbers.At the same time,the natural sprawl pyramid tract(PT)might be more intuitive for predicting postoperative motor functions.Therefore,we assessed the motor functions by the natural shape revealed by DSI tractography.Methods:Ten children with drug-resistant epilepsy who were candidates for hemispherectomy performed DSI PTs tractography and transcranial magnetic stimulation(TMS)for motor mapping.The motor function was evaluated with muscle strength and hand grasping capability.Pyramidal tract(PT)structural integrity and TMS mapping results were compared between patients who remained stable and those with deteriorated motor functions.Receiver operating characteristic(ROC)curves with PTs asymmetric ratio were analyzed to evaluate DSI tractography diagnostic value.Results:All patients underwent DSI acquisition,while four patients successfully performed TMS.One patient had no response to TMS until the maximal machine output was reached.Four patients failed to perform TMS due to lacking cooperation.One patient was contraindicated to TMS.DSI successfully reconstructed the sharp angle fan-shaped PTs within the hemisphere.The accurate fber distribution with fber termination and thickness within the lesioned hemisphere was replicated with DSI tractography.No signifcance was found in patients’age,sex,seizure frequency,or medication between patients with stable or deteriorated postoperative motor functions.DSI efectively predicted postoperative motor function as stable with damaged PTs,mild deterioration with atrophied PTs,and intact PTs with contralateral innervation confrmed by intracranial stimulation.The area under the curve(AUC)of DSI tractography was 0.84.According to ROC,the cut-of value of PTs asymmetric ratio was 11.5%with 100%sensitivity and 75%specifcity.The sensitivity and specifcity of TMS were 2/3 and 1/2,respectively.Conclusions:The anatomic integrity of PTs with DSI tractography could efectively predict postoperative motor function after hemispherectomy.This enables neurosurgeons to inform patients and relatives about postoperative motor functions with direct morphological evidence of PTs to help them with their surgical decisions.

Rationale and design of a randomised double-blind 2×2 factorial trial comparing the effect of a 3-month intensive statin and antiplatelet therapy for patients with acute mild ischaemic stroke or high-risk TIA with intracranial or extracranial atherosclerosis(INSPIRES)

Background It remains unclear if intensive antiplatelet and statin treatments begun within 24-72 hours of cerebral ischaemic events from intracranial or extracranial atherosclerosis is effective or safe.Methods The Intensive Statin and Antiplatelet Therapy for High-risk Intracranial or Extracranial Atherosclerosis(INSPIRES)trial is a randomised,double-blind,placebo-controlled,multicentre and 2×2 factorial trial.6100 individuals between the ages of 35 and 80 who have experienced a mild ischaemic stroke or high-risk transient ischaemic attack(TIA)within the previous 72 hours that is attributed to≥50%atherosclerotic stenosis of a major intracranial or extracranial artery or multiple infarctions of atherosclerotic origin will be enrolled in the trial.Eligible subjects will be randomised 1:1:1:1 to one of four groups:(1)intensive antiplatelet therapy(combined clopidogrel and aspirin for days 1-21,then aspirin placebo and clopidogrel for days 22-90)plus immediate intensive statin therapy(atorvastatin at a dose of 80 mg daily for the first 21 days,then 40 mg daily for days 22-90);(2)intensive antiplatelet therapy plus delayed intensive statin therapy(atorvastatin placebo for days 1-3,followed by 40 mg per day of atorvastatin for days 4-90);(3)standard antiplatelet therapy(combination of clopidogrel placebo with aspirin for 90 days)plus immediate intensive statin therapy and(4)standard antiplatelet therapy plus delayed intensive statin therapy.The primary efficacy endpoint is any new stroke(ischaemic or haemorrhagic)within 90 days after randomisation.The primary safety endpoint is moderate to severe bleeding at 90 days.Conclusion The INSPIRES trial will assess the efficacy and safety of intensive antiplatelet therapy and immediate intensive statin therapy begun within 72 hours of onset in decreasing the recurrent stroke at 90 days in patients with acute mild ischaemic stroke or high-risk TIA of intracranial or extracranial atherosclerosis origin.