Mechanism of inflammatory response and therapeutic effects of stem cells in ischemic stroke:current evidence and future perspectives

Ischemic stroke is a leading cause of death and disability worldwide,with an increasing trend and tendency for onset at a younger age.China,in particular,bears a high burden of stroke cases.In recent years,the inflammatory response after stroke has become a research hotspot:understanding the role of inflammatory response in tissue damage and repair following ischemic stroke is an important direction for its treatment.This review summarizes several major cells involved in the inflammatory response following ischemic stroke,including microglia,neutrophils,monocytes,lymphocytes,and astrocytes.Additionally,we have also highlighted the recent progress in various treatments for ischemic stroke,particularly in the field of stem cell therapy.Overall,understanding the complex interactions between inflammation and ischemic stroke can provide valuable insights for developing treatment strategies and improving patient outcomes.Stem cell therapy may potentially become an important component of ischemic stroke treatment.

Epigenetic regulation of the inflammatory response in stroke

Stroke is classified as ischemic or hemorrhagic,and there are few effective treatments for either type.Immunologic mechanisms play a critical role in secondary brain injury following a stroke,which manifests as cytokine release,blood–brain barrier disruption,neuronal cell death,and ultimately behavioral impairment.Suppressing the inflammatory response has been shown to mitigate this cascade of events in experimental stroke models.However,in clinical trials of anti-inflammatory agents,longterm immunosuppression has not demonstrated significant clinical benefits for patients.This may be attributable to the dichotomous roles of inflammation in both tissue injury and repair,as well as the complex pathophysiologic inflammatory processes in stroke.Inhibiting acute harmful inflammatory responses or inducing a phenotypic shift from a pro-inflammatory to an anti-inflammatory state at specific time points after a stroke are alternative and promising therapeutic strategies.Identifying agents that can modulate inflammation requires a detailed understanding of the inflammatory processes of stroke.Furthermore,epigenetic reprogramming plays a crucial role in modulating post-stroke inflammation and can potentially be exploited for stroke management.In this review,we summarize current findings on the epigenetic regulation of the inflammatory response in stroke,focusing on key signaling pathways including nuclear factor-kappa B,Janus kinase/signal transducer and activator of transcription,and mitogen-activated protein kinase as well as inflammasome activation.We also discuss promising molecular targets for stroke treatment.The evidence to date indicates that therapeutic targeting of the epigenetic regulation of inflammation can shift the balance from inflammation-induced tissue injury to repair following stroke,leading to improved post-stroke outcomes.

Analysis of Preoperative Factors Influencing Hypoglossal-facial ‘Side’-to-side Neurorrhaphy for Facial Paralysis after Excision of Acoustic Neuroma

Objective Hypoglossal nerve-facial nerve‘side’-to-side neurorrhaphy is a new method for the treatment of potential incomplete facial paralysis after acoustic neuroma.However,there are differences in postoperative outcomes among patients.This study analysed preoperative factors that may influence the treatment outcomes of neurorrhaphy.Methods We performed a retrospective study of 53 patients who were treated by neurorrhaphy for facial paralysis after acoustic neuroma resection.After a one-year follow-up period,the patients were divided into two groups according to facial functional outcome:better recovery or ordinary recovery.We analysed the following factors:gender,age,tumour size,and characteristics,tumour adhesion to the facial nerve,the duration of facial paralysis(DFP)and F wave appearance prior to neurorrhaphy(F wave).Results Univariate analysis showed significant differences between the two groups in DFP(P=0.0002),tumour adhesion to the facial nerve(P=0.0079)and F waves(P=0.0048).Logistic regression analysis of these factors also showed statistical significance with P values of 0.042 for the DFP,0.043 for F waves,and 0.031 for tumour adhesion to the facial nerve.Conclusions Tumour adhesion to the facial nerve,F waves appearance and DFP prior to neurorrhaphy are the predominant factors that influence treatment outcomes.

Abdominal Obesity and Its Attribution to All-cause Mortality in the General Population with 14 Years Follow-up:Findings from Shanxi Cohort in China

Objective This study aimed to assess the association of waist circumference(WC)with all-cause mortality among Chinese adults.Methods The baseline data were from Shanxi Province of 2002 China Nutrition and Health Survey.The death investigation and follow-up visit were conducted from December 2015 to March 2016.The visits covered up to 5,360 of 7,007 participants,representing a response rate of 76.5%.The Cox regression model and floating absolute risk were used to estimate hazard ratio and 95%floating CI of death by gender and age groups(≥60 and<60 years old).Sensitivity analysis was performed by excluding current smokers;participants with stroke,hypertension,and diabetes;participants who accidentally died;and participants who died during the first 2 years of follow-up.Results This study followed 67,129 person-years for 12.5 years on average,including 615 deaths.The mortality density was 916 per 100,000 person-years.Low WC was associated with all-cause mortality among men.Multifactor-adjusted hazard ratios(HR)were 1.60(1.35–1.90)for WC<75.0 cm and 1.40(1.11–1.76)for WC ranging from 75.0 cm to 79.9 cm.Low WC(<70.0 cm and 70.0–74.9 cm)and high WC(≥95.0 cm)groups had a high risk of mortality among women.The adjusted HRs of death were 1.43(1.11–1.83),1.39(1.05–1.84),and 1.91(1.13–3.22).Conclusion WC was an important predictor of death independent of body mass index(BMI).WC should be used as a simple rapid screening and predictive indicator of the risk of death.

Prognostic values of optic nerve sheath diameter for comatose patients with acute stroke:An observational study

BACKGROUND Optic nerve sheath diameter(ONSD)measurement is one of the non-invasive methods recommended for increased intracranial pressure(ICP)monitoring.AIM This study aimed to evaluate the roles of optic nerve sheath diameter(ONSD)and ONSD/eyeball transverse diameter(ETD)ratio in predicting prognosis of death in comatose patients with acute stroke during their hospitalization.METHODS A total of 67 comatose patients with acute stroke were retrospectively recruited.The ONSD and ETD were measured by cranial computed tomography(CT)scan.All patients underwent cranial CT scan within 24 h after coma onset.Patients were divided into death group and survival group according to their survival status at discharge.The differences of the ONSD and ONSD/ETD ratio between the two groups and their prognostic values were compared.RESULTS The ONSD and ONSD/ETD ratio were 6.07±0.72 mm and 0.27±0.03 in the comatose patients,respectively.The ONSD was significantly greater in the death group than that in the survival group(6.32±0.67 mm vs 5.65±0.62 mm,t=4.078,P<0.0001).The ONSD/ETD ratio was significantly higher in the death group than that in the survival group(0.28±0.03 vs 0.25±0.02,t=4.625,P<0.0001).The area under the receiver operating characteristic curve was 0.760(95%CI:0.637-0.882,P<0.0001)for the ONSD and 0.808(95%CI:0.696-0.920,P<0.0001)for the ONSD/ETD ratio.CONCLUSION The mortality increased in comatose patients with acute stroke when the ONSD was>5.7 mm or the ONSD/ETD ratio was>0.25.Both indexes could be used as prognostic tools for comatose patients with acute stroke.The ONSD/ETD ratio was more stable than the ONSD alone,which would be preferred in clinical practice.

Effect of Age and Sex on Stroke Mortality of Young and Middle-aged Adults in China,2002–2019,and Predictions to 2030

Objective This study aimed to examine the trends in stroke mortality among young and middle-aged adults in China.Methods Data were obtained from the China national vital registration system.Significant changes in mortality were assessed by Joinpoint regression.Age-period-cohort analysis was used to explain the reasons for the changes.Future mortality and counts were predicted by the Bayesian age-period-cohort model.Results Between 2002 and 2019,a total of 6,253,951 stroke mortality in young and middle-aged adults were recorded.The age-adjusted mortality rates(AAMRs)of women showed a downward trend.The annual percent changes(APC)were-3.5%(-5.2%,-1.7%)for urban women and-2.8%(-3.7%,-1.9%)for rural women.By contrast,the AAMRs per 100,000 for rural men aged 25–44 years continued to rise from 9.40 to 15.46.The AAMRS for urban men aged 25–44 years and urban and rural men aged 45–64years did not change significantly.Between 2020 and 2030,the projected stroke deaths are 1,423,584 in men and 401,712 in women.Conclusion Significant sex and age disparities in the trends of stroke mortality among young and middle-aged adults were identified in China.Targeted health policy measures are needed to address the burden of stroke in the young generation,especially for rural men,with a focus on the prevention and management of high risk factors.

Association between Baseline SBP/DBP and All-Cause Mortality in Residents of Shanxi,China:A Population-based Cohort Study from 2002 to 2015

Objective To investigate the association between blood pressure and all-cause mortality in Shanxi,China.Methods The‘2002 China Nutrition and Health Survey’baseline data in Shanxi province was used.A retrospective investigation was performed in 2015.The effects of SBP and DBP on the all-cause mortality were analyzed using the Cox regression model.The hazard ratio(HR)and 95%confidence interval(CI)were estimated by the sex and age groups.Results The follow-up rate was 76.52%over 13 years,while the cumulative mortality rate for all participants was 917.12/100,000 person-years.The mortality rose with an increasing SBP(χ_(trend)^(2)=270.537,P<0.001)or DBP level(χ_(trend)^(2)=57.240,P<0.001).After adjustment for the confounding factors,a significant association between mortality and high SBP(≥160 mm Hg)and high DBP(≥100 mm Hg),with adjusted HR ranging from 1.405-to 2.179-fold for SBP and 1.550-to 2.854-fold for DBP,was noted.Significant HRs for most DBP subgroups were found in>60-year-old participants.Males with DBP≥100 mm Hg had a significantly higher mortality,with an HR(95%CI)of 2.715(1.377–5.351).Conclusion Adults with SBP>160 mm Hg and DBP>100 mm Hg had a higher mortality risk.Sex and age difference was noted in both DBP and mortality risk.

Melatonin improves synapse development by PI3K/Akt signaling in a mouse model of autism spectrum disorder

Autism spectrum disorders are a group of neurodevelopmental disorders involving more than 1100 genes,including Ctnnd2 as a candidate gene.Ctnnd2knockout mice,serving as an animal model of autis m,have been demonstrated to exhibit decreased density of dendritic spines.The role of melatonin,as a neuro hormone capable of effectively alleviating social interaction deficits and regulating the development of dendritic spines,in Ctnnd2 deletion-induced nerve injury remains unclea r.In the present study,we discove red that the deletion of exon 2 of the Ctnnd2 gene was linked to social interaction deficits,spine loss,impaired inhibitory neurons,and suppressed phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt) signal pathway in the prefrontal cortex.Our findings demonstrated that the long-term oral administration of melatonin for 28 days effectively alleviated the aforementioned abnormalities in Ctnnd2 gene-knockout mice.Furthermore,the administration of melatonin in the prefro ntal cortex was found to improve synaptic function and activate the PI3K/Akt signal pathway in this region.The pharmacological blockade of the PI3K/Akt signal pathway with a PI3K/Akt inhibitor,wo rtmannin,and melatonin receptor antagonists,luzindole and 4-phenyl-2-propionamidotetralin,prevented the melatonin-induced enhancement of GABAergic synaptic function.These findings suggest that melatonin treatment can ameliorate GABAe rgic synaptic function by activating the PI3K/Akt signal pathway,which may contribute to the improvement of dendritic spine abnormalities in autism spectrum disorders.

Association of DNA methylation/demethylation with the functional outcome of stroke in a hyperinflammatory state

Inflammation is closely related to stroke prognosis, and high inflammation status leads to poor functional outcome in stroke. DNA methylation is involved in the pathogenesis and prognosis of stroke. However, the effect of DNA methylation on stroke at high levels of inflammation is unclear. In this study, we constructed a hyperinflammatory cerebral ischemia mouse model and investigated the effect of hypomethylation and hypermethylation on the functional outcome. We constructed a mouse model of transient middle cerebral artery occlusion and treated the mice with lipopolysaccharide to induce a hyperinflammatory state. To investigate the effect of DNA methylation on stroke, we used small molecule inhibitors to restrain the function of key DNA methylation and demethylation enzymes. 2,3,5-Triphenyltetrazolium chloride staining, neurological function scores, neurobehavioral tests, enzyme-linked immunosorbent assay, quantitative reverse transcription PCR and western blot assay were used to evaluate the effects after stroke in mice. We assessed changes in the global methylation status by measuring DNA 5-mc and DNA 5-hmc levels in peripheral blood after the use of the inhibitor. In the group treated with the DNA methylation inhibitor, brain tissue 2,3,5-triphenyltetrazolium chloride staining showed an increase in infarct volume, which was accompanied by a decrease in neurological scores and worsening of neurobehavioral performance. The levels of inflammatory factors interleukin 6 and interleukin-1 beta in ischemic brain tissue and plasma were elevated, indicating increased inflammation. Related inflammatory pathway exploration showed significant overactivation of nuclear factor kappa B. These results suggested that inhibiting DNA methylation led to poor functional outcome in mice with high inflammation following stroke. Further, the effects were reversed by inhibition of DNA demethylation. Our findings suggest that DNA methylation regulates the inflammatory response in stroke and has an important role in the functional outcome of hyperinflammatory stroke.

The Third China National Stroke Registry (CNSR-Ⅲ) for patients with acute ischaemic stroke or transient ischaemic attack: design, rationale and baseline patient characteristics

Background and purpose Stroke is the leading cause of mortality and disability in China.Precise aetiological classification,imaging and biological markers may predict the prognosis of stroke.The Third China National Stroke Registry(CNSR-Ⅲ),a nationwide registry of ischaemic stroke or transient ischaemic attack(TIA)in China based on aetiology,imaging and biology markers,will be considered to clarify the pathogenesis and prognostic factors of ischaemic stroke.Methods Between August 2015 and March 2018,the CNSR-Ⅲrecruited consecutive patients with ischaemic stroke or TIA from 201 hospitals that cover 22 provinces and four municipalities in China.Clinical data were collected prospectively using an electronic data capture system by face-to-face interviews.Patients were followed for clinical outcomes at 3 months,6 months and 1-5 year annually.Brain imaging,including brain MRI and CT,were completed at baseline.Blood samples were collected and biomarkers were tested at baseline.Results A total of 15166 stroke patients were enrolled,among which 31.7%patients were women with the average age of 62.2±11.3 years.Ischaemic stroke was predominant(93.3%,n=14146)and 1020(6.7%)TIAs were enrolled.Conclusions CNSR-Ⅲis a large scale nationwide registry in China.Data from this prospective registry may provide opportunity to evaluate imaging and biomarker prognostic determinants of stroke.

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.

Rationale and design of Patient-centered Retrospective Observation of Guideline-Recommended Execution for Stroke Sufferers in China: China PROGRESS

Background In 2009,China launched ambitious healthcare reform plans to provide affordable and equitable basic healthcare for all patients,including the substantial number of patients who had a stroke.However,little is known about the pattern of evidence-based stroke care and outcomes across hospitals,regions and time during the last decade.Aims The Patient-centered Retrospective Observation of Guideline-Recommended Execution for Stroke Sufferers in China(China PROGRESS)Study aims to use findings from a representative sample of Chinese hospitals over the last decade to improve future stroke care for patients hospitalised with ischaemic stroke(IS)or transient ischaemic attack(TIA).Design The China PROGRESS Study will use a two-stage cluster sampling method to identify over 32000 patient records from 208 hospitals across the Eastern,Central and Western geographical regions in China.To assess the temporal trends in patient characteristics,treatment and outcomes,study investigators will select records from 2005,2010 and 2015.A double data reading/entry system will be developed to conduct this assessment.A central coordinating centre will monitor case ascertainment,data abstraction and data management.Analyses will examine patient characteristics,testing patterns,in-hospital treatment and outcomes,and variations across regions and across time.Conclusions The China PROGRESS Study is the first nationally representative study that aims to better understand care quality and outcomes for patients with IS or TIA before and after the national healthcare reform in China.This initiative will translate findings into clinical practices that improve care quality for patients who had a stroke and policy recommendations that allow these changes to be implemented widely.Ethics approval This study has also been approved by the central institutional review board(IRB)at Beijing Tiantan Hospital.

Relationship of Retinal Nerve Fiber Layer Thickness and Retinal Vessel Calibers with Cognitive Impairment in the Asymptomatic Polyvascular Abnormalities Population

Objective Cognitive impairment(CI)in older individuals has a high morbidity rate worldwide,with poor diagnostic methods and susceptible population identification.This study aimed to investigate the relationship between different retinal metrics and CI in a particular population,emphasizing polyvascular status.Methods We collected information from the Asymptomatic Polyvascular Abnormalities Community Study on retinal vessel calibers,retinal nerve fiber layer(RNFL)thickness,and cognitive function of 3,785participants,aged 40 years or older.Logistic regression was used to analyze the relationship between retinal metrics and cognitive function.Subgroups stratified by different vascular statuses were also analyzed.Results RNFL thickness was significantly thinner in the CI group(odds ratio:0.973,95%confidence interval:0.953–0.994).In the subgroup analysis,the difference still existed in the non-intracranial arterial stenosis,non-extracranial carotid arterial stenosis,and peripheral arterial disease subgroups(P<0.05).Conclusion A thin RNFL is associated with CI,especially in people with non-large vessel stenosis.The underlying small vessel change in RNFL and CI should be investigated in the future.

Childhood strokes in China describing clinical characteristics, risk factors and performance indicators: a case-series study

Aim To investigate clinical characteristics,risk factors(RFs),neurologic deficits and medical care provided in children who had a stroke in China.Methods We conducted a retrospective case-series study using the medical records of children aged 1 month to 18 years with arterial ischaemic stroke(AIS)or haemorrhagic stroke(HS)(with the entry codes I60,I61,I62,I63(ICD-10)),who were admitted to different hospitals in Beijing,between January 2018 and December 2018.We obtained the following information from the charts:demographic characteristics,clinical presentations,RFs for paediatric stroke,laboratory examination,neuroimaging records and neurologic sequelae.Results We identified 312 first admissions for stroke(172 AIS and 140 HS).The mean age at onset was 8.6±3.9 years for patients who had an AIS and 8(5–13)years for patients who had an HS.There were more males than females in both groups(AIS:59.88%vs 40.12%;HS:52.14%vs 47.86%).A known aetiology was identified in 92.44%and 86.43%of patients who had an AIS and HS,respectively.The leading cause of AIS was cerebrovascular diseases including moyamoya(68.6%),while that for HS was arteriovenous malformation(51.43%).The most common initial clinical presentation was hemiplegia(86.05%)in patients who had an AIS and headache(67.86%)in patients who had an HS.The use of healthcare,including acute treatment(antithrombotic in 17.44%,anticoagulant in 5.23%)and secondary prevention(antithrombotic in 6.39%,anticoagulant in 1.16%),varied and was significantly lower among patients who had an AIS.The most common complications were epilepsy(22.09%)and pneumonia(4.65%)in patients who had an AIS and epilepsy(17.14%)and hydrocephalus(12.14%)in patients who had an HS.Neurological deficits occurred in 62.8%of patients who had an AIS and 72.86%of patients who had an HS.Conclusion Cerebral arteriopathy was a major RF for both AIS and HS in children living in China.Large epidemiological studies are required to identify RFs to prevent stroke as well as appropriate interventions.

Chinese Stroke Association guidelines for clinical management of ischaemic cerebrovascular diseases:executive summary and 2023 update

Background China is one of the countries with the highest burden of stroke.Implementing multidimensional management guidelines will help clinicians practise evidence-based care,improve patient outcomes and alleviate societal burdens.This update of the 2019 edition will provide the latest comprehensive recommendations for the diagnosis and treatment of ischaemic cerebrovascular diseases.Methods We conducted a comprehensive search on MEDLINE(via PubMed)up to 31 August 2023.The writing team established the recommendations through multiple rounds of online and offline discussions.Each recommendation was graded using the evidence grading algorithm developed by the Chinese Stroke Association(CSA).The draft was reviewed and finalised by the CSA Stroke Guidelines Writing Committee.Results This update included revisions of 15 existing recommendations and 136 new recommendations in the following areas of stroke care:emergency assessment and diagnosis of ischaemic cerebrovascular disease,acute-phase reperfusion therapy,evaluation of underlying mechanisms,antithrombotic therapy,prevention and treatment of complications,and risk factor management.Conclusions This guideline updated the recommendations for the clinical management of ischaemic cerebrovascular disease from 2019.

Body mass index and clinical outcomes in patients with intracerebral haemorrhage:results from the China Stroke Center Alliance

Background and aim Obesity paradox has aroused increasing concern in recent years.However,impact of obesity on outcomes in intracerebral haemorrhage(ICH)remains unclear.This study aimed to evaluate association of body mass index(BMI)with in-hospital mortality,complications and discharge disposition in ICH.Methods Data were from 85705 ICH enrolled in the China Stroke Center Alliance study.Patients were divided into four groups:underweight,normal weight,overweight and obese according to Asian-Pacific criteria.The primary outcome was in-hospital mortality.The secondary outcomes included non-routine discharge disposition and in-hospital complications.Discharge to graded II or III hospital,community hospital or rehabilitation facilities was considered non-routine disposition.Multivariable logistic regression analysed association of BMI with outcomes.Results 82789 patients with ICH were included in the final analysis.Underweight(OR=2.057,95%CI 1.193 to 3.550)patients had higher odds of in-hospital mortality than those with normal weight after adjusting for covariates,but no significant difference was observed for patients who were overweight or obese.No significant association was found between BMI and non-disposition.Underweight was associated with increased odds of several complications,including pneumonia(OR 1.343,95%CI 1.138 to 1.584),poor swallow function(OR 1.351,95%CI 1.122 to 1.628)and urinary tract infection(OR 1.532,95%CI 1.064 to 2.204).Moreover,obese patients had higher odds of haematoma expansion(OR 1.326,95%CI 1.168 to 1.504),deep vein thrombosis(OR 1.506,95%CI 1.165 to 1.947)and gastrointestinal bleeding(OR 1.257,95%CI 1.027 to 1.539).Conclusions In patients with ICH,being underweight was associated with increased in-hospital mortality.Being underweight and obese can both increased risk of in-hospital complications compared with having normal weight.

Cellular and molecular imaging for stem cell tracking in neurological diseases

Stem cells(SCs)are cells with strong proliferation ability,multilineage differentiation potential and self-renewal capacity.SC transplantation represents an important therapeutic advancement for the treatment strategy of neurological diseases,both in the preclinical experimental and clinical settings.Innovative and breakthrough SC labelling and tracking technologies are widely used to monitor the distribution and viability of transplanted cells non-invasively and longitudinally.Here we summarised the research progress of the main tracers,labelling methods and imaging technologies involved in current SC tracking technologies for various neurological diseases.Finally,the applications,challenges and unresolved problems of current SC tracing technologies were discussed.

Safety and efficacy of Edaravone Dexborneol versus edaravone for patients with acute ischaemic stroke: a phase Ⅱ, multicentre, randomised, double-blind, multiple-dose, active-controlled clinical trial

Background Edaravone Dexborneol is a novel neuroprotective agent that comprised edaravone and(+)-borneol,a food additive with an anti-inflammatory effect in animal ischaemic stroke models.This study aims to assess the safety and efficacy of Edaravone Dexborneol compared with edaravone in treating patients with acute ischaemic stroke(AIS).Methods In this multicentre,randomised,double-blind,multiple-dose,active-controlled,phaseⅡclinical trial,patients with AIS within 48 hours after stroke onset were randomly assigned(1:1:1:1)to low-dose(12.5 mg),medium-dose(37.5 mg)or high-dose(62.5 mg)Edaravone Dexborneol groups,and an active control group with edaravone(30 mg)by 30 min intravenous infusion every 12 hours,for 14 consecutive days.The primary efficacy outcome was the proportion of modified Rankin Scale(mRS)score≤1 at 90 days and National Institutes of Health Stroke Scale(NIHSS)score change from baseline to 14 days after randomisation.The safety outcome included any adverse event during 90 days after treatment.Results Of 385 patients included in the efficacy analysis,94 were randomised to low-dose group,97 to medium-dose group,98 to high-dose group and 96 to the control group.No significant difference was observed among the four groups on mRS score(mRS≤1,p=0.4054)at 90 days or NIHSS score change at 14 days(p=0.6799).However,a numerically higher percentage of patients with mRSscore≤1 at 90 days in the medium-dose(69.39%)and high-dose(65.63%)groups was observed than in the control group(60.64%).No significant difference in severe adverse events was found among the four groups(p=0.3815).Conclusions Compared with edaravone alone,Edaravone Dexborneol was safe and well tolerated at all doses,although no significant improvement in functional outcomes was observed at 90days.

Long-term Effectiveness of Antiepileptic Drug Monotherapy in Partial Epileptic Patients： A 7-year Study in an Epilepsy Center in China

Background： It is important to choose an appropriate antiepileptic drug （AED） to manage partial epilepsy. Traditional AEDs, such as carbamazepine （CBZ） and valproate （VPA）, have been proven to have good therapeutic effects. However, in recent years, a variety of new AEDs have increasingly been used as first-line treatments for partial epilepsy. As the studies regarding the effectiveness of new drugs and comparisons between new AEDs and traditional AEDs are few, it is determined that these are areas in need of further research. Accordingly, this study investigated the long-term effectiveness of six AEDs used as monotherapy in patients with partial epilepsy. Methods： This is a retrospective, long-term observational study. Patients with partial epilepsy who received monotherapy with one of six AEDs, namely, CBZ, VPA, topiramate （TPM）, oxcarbazepine （OXC）, lamotrigine （LTG）, or levetiracetam （LEV）, were identified and followed up from May 2007 to October 2014, and time to first seizure after treatment, 12-month remission rate, retention rate, reasons for treatment discontinuation, and adverse effects were evaluated. Results： A total of 789 patients were enrolled. The median time of follow-up was 56.95 months. CBZ exhibited the best time to first seizure, with a median time to first seizure of 36.06 months （95% confidential interval： 30.64~4.07）. CBZ exhibited the highest 12-month remission rate （85.55%）, which was significantly higher than those of TPM （69.38%, P = 0.006）, LTG （70.79%, P= 0.001）, LEV （72.54%, P = 0.005）, and VPA （73.33%, P = 0.002）. CBZ, OXC, and LEV had the best retention rate, followed by LTG, TPM, and VPA. Overall, adverse effects occurred in 45.87% of patients, and the most common adverse effects were memory problems （8.09%）, rashes （7.76%）, abnormal hepatic function （6.24%）, and drowsiness （6.24%）. Conclusion： This study demonstrated that CBZ, OXC, and LEV are relatively effective in managing tbcal epilepsy as measured by time to first seizure, 12-month remission rate, and retention rate.

Neutrophil-derived interleukin-17A participates in neuroinflammation induced by traumatic brain injury

After brain injury, infiltration and abnormal activation of neutrophils damages brain tissue and worsens inflammation, but the mediators that connect activated neutrophils with neuroinflammation have not yet been fully clarified. To identify regulators of neutrophil-mediated neuroinflammation after traumatic brain injury, a mouse model of traumatic brain injury was established by controlled cortical impact. At 7 days post-injury(sub-acute phase), genome-wide transcriptomic data showed that interleukin 17 A-associated signaling pathways were markedly upregulated, suggesting that interleukin 17 A may be involved in neuroinflammation. Double immunofluorescence staining showed that interleukin 17 A was largely secreted by neutrophils rather than by glial cells and neurons. Furthermore, nuclear factor-kappaB and Stat3, both of which are important effectors in interleukin 17 A-mediated proinflammatory responses, were significantly activated. Collectively, our findings suggest that neutrophil-derived interleukin 17 A participates in neutrophil-mediated neuroinflammation during the subacute phase of traumatic brain injury. Therefore, interleukin 17 A may be a promising therapeutic target for traumatic brain injury.