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Background Elizabethkingia anophelis, an emerging opportunistic pathogen, is commonly seen in immunocompromised patients, preterm infants, patients with long-term intravenous catheters, patients with underlying diseases (malignancies, diabetes, etc.), and patients in intensive care units undergoing invasive treatment. The complexity of species identification methods, multiple drug resistance, complications and high mortality rate pose great challenges for treatment, and there is no standard treatment.Case presentation We report a case of leukopenia following meningitis and septicaemia in an adult male patient infected with E. anophelis. Despite effective anti-infective therapy, the patient eventually died due to pulmonary infection. Besides, we performed a literature review.Conclusions It is recommended to accurately identify the rare pathogen, such as E. anophelis, and use appropriate antibiotic therapy. In addition, the control of complications is worthy of attention.

BackgroundIt is unknown whether balloon angioplasty can be a first-choice treatment for intracranial atherosclerosis-related emergent large vessel occlusion (ICAS-ELVO) with small clot burden. The microcatheter “first-pass effect” is a valid predictor of ICAS-ELVO with small clot.ObjectiveTo determine balloon angioplasty’s efficacy as first-choice treatment for ICAS-ELVO involving the microcatheter “first-pass effect” during endovascular treatment (EVT).MethodsThis continuous retrospective analysis assessed ICAS-ELVO patients presenting with the microcatheter “first-pass effect” during EVT. Patients were divided into two first-choice treatment-based groups: preferred balloon angioplasty (PBA) and preferred mechanical thrombectomy (PMT). Efficacy and safety outcomes were compared between groups.ResultsSeventy-six patients with ICAS-ELVO involving the microcatheter “first-pass effect” during EVT were enrolled. Compared with patients in PMT group, patients in PBA group were associated with (i) a higher rate of first-pass recanalization (54.0% vs. 28.9%, p=.010) and complete reperfusion (expanded thrombolysis in cerebral ischemia≥2c; 76.0% vs. 53.8%, p=.049), (ii) a shorter puncture-to-recanalization time (49.5 min vs. 56.0 min, p.999) and mortality (10.0% vs. 7.7%, p>.999) were noted. Logistic regression analysis revealed that first-choice treatment was an independent predictor of 90-day excellent functional outcomes (adjusted odds ratio [aOR] =0.10, 95% CI: 0.02–0.66, p=.017).ConclusionBalloon angioplasty, as the first-choice treatment, potentially improves 90-day functional outcomes for ICAS-ELVO patients with microcatheter “first-pass effect” during EVT.What is already known on this topicCompared with large vessel occlusion caused by embolization, mechanical thrombectomy has lower recanalization rate, longer procedure time, and poorer prognosis for patients with intracranial atherosclerosis-related emergent large vessel occlusion(ICAS-ELVO).What this study addsThis study revealed that balloon angioplasty, as the first-choice treatment, potentially improves 90-day outcomes, shortens procedure time, and reduces operation costs for patients with ICAS-ELVO involving the microcatheter “first-pass effect” during endovascular treatment.How this study might affect research, practice or policyWe believe that our study makes a significant contribution to the literature because its findings suggest that rapid and accurate methods of diagnosing the etiology and clot burden of ELVO as well as the development of an individualized EVT strategy based on etiology and clot burden need to be established.

Background: The possible correlation between oral microbiota dysbiosisand acute ischemic stroke, regarding different pathogenesis and stroke severity, remains unclear. Therefore, this study aimed to identify the specific microbiota for different subtypes of stroke to discover the underlying risk factors for ischemic stroke, which is of important clinical research value. Methods:Oral microbiota communities from 162 stroke patients and 62 stroke-free controls were prospectively assessed by sequencing the V3–V4 region of the 16S DNA gene. Demographic and clinical data were obtained for both groups. Triglycerides, total cholesterol, low-density lipoprotein, homocysteine, high-sensitivity C-reactive protein, SLCO1B1, APOE, CYP2C19, IL6, IL8, IL1β, TNF-α, and sCD40L were measured, and their relationship with oral microbiota was analyzed. Cranial magnetic resonance and carotid artery ultrasound were performed for both groups within seven days of admission. Results: IL6, IL8, IL1β, TNF-α, and sCD40L were significantly higher in stroke patients than in controls. Although the oral microbiota of the stroke and control groups were similar in diversity and structure, that of the severe stroke (National Institutes of Health Stroke Scale score > 5) and cardioembolic stroke subgroups differed from those of the control group. Linear discriminant analysis effect size analysis showed that Megasphaera, Prevotella_1, Clostridia, Selenomonas_3, Prevotella_6, and Dialister were mainly enriched in the severe stroke subgroup. Prevotella_6, Staphylococcus, Staphylococcaceae, and Peptostreptococcus were significantly enriched in the cardioembolic stroke subgroup. Spearman correlation analysis revealed that IL6, IL8, IL1β, TNF-α, and sCD40L were significantly correlated with Peptostreptococcus, Staphylococcus, Selenomonas, Megasphaera, and other bacteria (p < 0.01; p < 0.05). Conclusions: The oral microbiota in stroke patients were not significantly different from that in the stroke-free controls. However, certain stroke subgroups, such as the severe or cardioembolic stroke subgroups, exhibited significant oral microbiota dysbiosis, which was associated with elevated inflammatory cytokines.

Spontaneous recovery after CNS injury is often very limited and incomplete, leaving most stroke patients with permanent disability. Maf1 is known as a key growth suppressor in proliferating cells. However, its role in neuronal cells after stroke remains unclear.We aimed to investigate the mechanistic role of Maf1 in spontaneous neural repair and evaluated the therapeutic effect of targeting Maf1 on stroke recovery.We used mouse primary neurons to determine the signaling mechanism of Maf1, and the cleavage-under-targets-and-tagmentation-sequencing to map the whole-genome promoter binding sites of Maf1 in isolated mature cortical neurons. Photothrombotic stroke model was used to determine the therapeutic effect on neural repair and functional recovery by AAV-mediated Maf1 knockdown.We found that Maf1 mediates mTOR signaling to regulate RNA polymerase III (Pol III)-dependent rRNA and tRNA transcription in mouse cortical neurons. mTOR regulates neuronal Maf1 phosphorylation and subcellular localization. Maf1 knockdown significantly increases Pol III transcription, neurite outgrowth and dendritic spine formation in neurons. Conversely, Maf1 overexpression suppresses such activities. In response to photothrombotic stroke in mice, Maf1 expression is increased and accumulates in the nucleus of neurons in the peripheral region of infarcted cortex, which is the key region for neural remodeling and repair during spontaneous recovery. Intriguingly, Maf1 knockdown in the peri-infarct cortex significantly enhances neural plasticity and functional recovery. Mechanistically, Maf1 not only interacts with the promoters and represses Pol III-transcribed genes, but also those of CREB-associated genes that are critical for promoting plasticity during neurodevelopment and neural repair.These findings indicate Maf1 as an intrinsic neural repair suppressor against regenerative capability of mature CNS neurons, and suggest that Maf1 is a potential therapeutic target for enhancing functional recovery after ischemic stroke and other CNS injuries.

To investigate thrombus age and its association with clinical and procedural parameters in patients with acute ischemic stroke (AIS) due to anterior circulation occlusions.The thrombi of 107 consecutive AIS patients with occlusions in anterior circulation large-arteries were collected during mechanical recanalization. By hematoxylin-eosin staining analysis, thrombi were classified as fresh ( 3 days) or old (≥ 3 days) according to the hemosiderin positivity. Old thrombi were further classified as thrombi with focal hemosiderin or diffuse hemosiderin according to their predominant distribution. Neuro-interventional data and clinical outcomes were compared based on thrombus age.We identified fresh thrombi in 29 patients and old thrombi in 78 patients. Compared with patients with fresh thrombi, patients with old thrombi were associated with (i) a longer mechanical recanalization time (p = 0.027), (ii) a higher percentage of fibrin/platelets and leukocytes (all p = 0.02) and a lower percentage of erythrocytes (p = 0.001), and (iii) less favorable clinical outcomes at discharge (p = 0.019) and 90 days later (OR = 2.76, 95% CI = 1.09-6.99, p = 0.032). Furthermore, 18 (16.8%) of all patients had focal hemosiderin in old thrombi, which was independently linked to a poor clinical outcome 90 days later (adjusted OR = 5.37, 95% CI = 1.14-25.28, p = 0.034).The presence of old thrombi, particularly those with focal hemosiderin, may aid in identifying patients with acute ischemic anterior circulation stroke who are at a higher risk of poor clinical outcome at 3-month follow-up.

Purpose Endovascular treatment in severe middle cerebral artery (MCA) stenosis is controversial owing to high rates of periprocedural complications, especially occlusion of the lenticulostriate arteries (LSA). The characteristics of LSAs and the spatial relationships between MCA plaques and LSAs using the fusion of three-dimensional (3D) digital subtraction angiography (DSA) and magnetic resonance imaging (3D DSA-MRI fusion) were investigated. Methods We retrospectively analyzed data from 32 ischemic stroke or transient ischemic attack patients with severe MCA stenosis, who underwent MRI and DSA within 2 weeks after symptom onset. The patients were divided into culprit and non-culprit MCA stenosis groups. The 3D DSA-MRI fusion was performed on dedicated workstations, which allowed automated overlays of the target vessels. The characteristics of LSAs, plaque distribution and lesion patterns, and their relationships were evaluated. Results The 3D DSA-MRI fusion image was able to illustrate the spatial relationships between MCA plaques and LSA orifices. Of 42 LSA stems in 32 patients, 10 had MCA plaque over the LSA orifice and were all found in the culprit MCA stenosis group. Over half (51.9%) of the LSA stems in patients with culprit MCA stenosis originated from the stenotic MCA segment. The MCA plaque-LSA orifice spatial relationships were classified into four types, which were significantly different between the two groups (p = 0.016). Conclusion The 3D DSA-MRI fusion technique enables visualization of the LSA orifice and MCA plaque and their spatial relationships. This classification of the type of spatial relationships can provide insights into the pathogenesis of MCA stroke and useful guides for treatment strategies.

AimStroke is the leading cause of disability and death in China. Ischaemic stroke accounts for about 60%–80% of all strokes. It is of considerable significance to carry out multidimensional management of ischaemic cerebrovascular diseases. This evidence-based guideline aims to provide the latest detailed and comprehensive recommendations on the diagnosis, treatment and secondary prevention of ischaemic cerebrovascular diseases.MethodsWe had performed comprehensive searches of MEDLINE (via PubMed) (before 30 June 2019), and integrated the relevant information into charts and distributed to the writing group. Writing group members discussed and determined the recommendations through teleconference. We used the level of evidence grading algorithm of Chinese Stroke Association to grade each recommendation. The draft was reviewed by the Guideline Writing Committee of Chinese Stroke Association Stroke and finalised. This guideline is fully updated every 3 years.ResultsThis evidence-based guideline is based on the treatment, care and prevention of ischaemic cerebrovascular diseases, which emphasises on pathogenesis evaluation, intravenous thrombolysis, endovascular therapy, antiplatelet therapy, prevention and treatment of complications, and risk factor management.ConclusionsThis updated guideline presents a framework for the management of ischaemic cerebrovascular diseases. Timely first-aid measures, professional care in the acute stage, and proactive secondary prevention will be helpful to patients.

BackgroundCerebral venous disorder may have a harmful effect on ischaemic stroke; however, the underlying mechanism remains to be elucidated. Although Dl-3-n-butylphthalide is a multitarget agent for antiischaemic stroke, its neuroprotective role in brain ischaemia accompanied by brain venous disturbance remains unclear. In this study, we induced cerebral venous disturbance by the occlusion of bilateral external jugular veins (EJVs) to explore the potential mechanism of the adverse effects of cerebrovenous disorders in cerebral infarction and explore the protective effect of Dl-3-n-butylphthalide on cerebral infarction accompanied through cerebral venous disturbance.MethodsCerebral venous disturbance was induced in Sprague-Dawley rats through the permanent occlusion of bilateral EJVs, and cerebral ischaemic stroke was induced through the permanent occlusion of the right cortical branches of the middle cerebral artery. 2,3,5-triphenyltetrazolium chloride staining, MRI, Evans blue extravasation and behavioural test were performed to evaluate infarction volume, cerebral blood flow (CBF), blood–brain barrier (BBB) integrity and neurological function. Immunofluorescence staining and western blot analysis were performed to detect loss of neuron, endothelial cells, pericytes and tight junctions.ResultsBilateral EJVs occlusion did not cause cerebral infarction; however, it increased the infarction volume compared with the simple middle cerebral artery occlusion (MCAO) group, accompanied by severe neuron loss, worse neurological function, lower CBF, increased EJVs pressure, exacerbated Evans blue extravasation and brain oedema, as well as attenuated angiogenesis. Dl-3-n-butylphthalide displayed a neuroprotective effect in rats with MCAO accompanied by EJVs occlusion by reducing neuron loss, accelerating CBF restoration, promoting angiogenesis and relieving BBB damage.ConclusionBilateral EJVs occlusion did not significantly affect normal rats but aggravated brain damage in the case of ischaemic stroke. Dl-3-n-butylphthalide treatment plays a neuroprotective role in rats with MCAO accompanied by EJVs occlusion, mainly due to the promotion of CBF restoration and BBB protection.

As a carrier of “history” and “culture”, historical and cultural documentary not only shows rich cultural phenomena, but also contains profound cultural and spiritual connotations” “Cultural identity” shows the identity of a specific group to a certain culture. In this paper, the micro motion feature representation method of high resolution range change information is used to classify and recognize different human actions. Experimental results show that the average recognition accuracy of the proposed feature representation and recognition method for two types of 15 actions is more than 90%.

Purpose The recommendation strength of the guidelines for mechanical thrombectomy among patients with large pre-treatment core infarct is weak. We evaluated the safety and outcome of endovascular treatment for acute ischemic stroke with diffusion-weighted imaging-Alberta Stroke Program Early Computed Tomography Score (DWI-ASPECTS) ≤ 5. Methods Data on acute ischemic stroke patients with DWI-ASPECTS ≤ 5 who underwent endovascular treatment within 6 h, or presented an arterial spin labeling-DWI (ASL-DWI) mismatch within 12 h, at our center were retrospectively collected. We report the clinical characteristics and outcome of every patient, and review the relevant literature. Results Among the 19 patients who were enrolled, all experienced successful reperfusion, and 10 achieved a favorable outcome (modified Rankin scale (mRS) ≤ 2). Two patients presented with symptomatic intracranial hemorrhage (sICH); both of them had a poor outcome (mRS > 2). Conclusion Acute ischemic stroke patients with large DWI lesions caused by large vessel occlusion can achieve a favorable clinical outcome with endovascular treatment if recanalization is performed within 6 h, or after 6 h in case of an ASL-DWI mismatch. Electronic supplementary material The online version of this article (10.1007/s00234-019-02177-1) contains supplementary material, which is available to authorized users.

Background: Extensive analysis has focused on the brain-gut axis interaction between stroke and the gut, but the most direct cause of stroke involves thrombi that block blood flow. The role of bacteria in thrombi on stroke onset has rarely been studied. Thus, it is of interest to fully characterize the microbial features of the thrombus and explore the underlying mechanism.Materials and methods: Clot samples were collected from 104 acute ischemic stroke (AIS) patients who underwent clot retrieval with mechanical thrombectomy. After inclusion, oral, fecal, and isolated plasma samples of the same patients were synchronously gathered within 12 hours of admission. The microbial composition of all samples was compared using 16S rRNA gene amplicon next-generation sequencing. Fluorescent in situ hybridization (FISH) was selected to detect the bacteria in the thrombus with the bacterial probe EUB338. The markers of inflammatory cytokines and intestinal barrier integrity were measured using ELISAs. We performed a comprehensive analysis of the characteristics of the thrombus bacterial community in stroke patients and calculated the correlation between specific bacterial genera and clinical outcomes.Results: Of the 104 AIS patients, the presence of bacterial DNA in the thrombus was confirmed by qPCR analysis of the 16S rRNA gene and FISH experiments. Operational taxonomic units (OTUs) from 14 different phyla were identified, with the majority of the OTUs belonging to Proteobacteria (73.3%); these were mainly predicted by BugBase to be potential opportunistic pathogens. Bray-Curtis distance analysis revealed that the microbiota in the thrombus were significantly different from the oral, fecal and plasma microbiota (all PAcinetobacter and Enterobacteriaceae were associated with a risk of adverse events within 48 hours of admission, and a higher abundance of Acinetobacter was also associated with a risk of death by the 3rd month. Univariate and multivariate Cox regression analysis showed that, in addition to important clinical indicators (preoperative National Institutes of Health Stroke Scale (NIHSS) score, atrial fibrillation and history of stroke), the relative abundance of Acinetobacter in the thrombus was an important risk factor for 90-day mortality (HR 1.957, 95% CI 1.198-3.196, P=0.007; adjusted HR 2.664, 95% CI 1.384-5.129, P=0.003). Higher concentrations of IL 1β and IL 6 were associated with a higher risk of adverse events and death.Conclusion: The study showed evidence for significant diversity of bacteria in the thrombus in ischemic stroke patients and visually confirmed their adherence in FISH. It is among the first to fully characterize the clot microbial feature as overexpansion of the phylum Proteobacteria and observe a close correlation between conditional pathogens and risk of death in patients receiving mechanical thrombectomy. It warrants further investigations on the role of bacteria in the thrombus in the pathogenesis and prognosis of stroke.

BackgroundThe risk of recurrent stroke following a minor stroke or transient ischemic attack (TIA) is high, when inflammation might play an important role. We aimed to evaluate the value of neutrophil to lymphocyte ratio (NLR) in predicting composite cardiovascular events in patients with minor stroke and TIA.MethodsConsecutive patients with acute minor stroke or TIA admitted within 24 h of symptoms onset during a 5-year period in a prospective stroke registry were analyzed. We calculated the NLR dividing absolute neutrophil count by absolute lymphocyte count tested within 24 h of admission. NLR ≥4th quartile was defined as high NLR. A composite outcome was defined as stroke, acute coronary syndrome or vascular death within 1 year. We investigated associations between NLR and the composite outcome in univariate and multivariate analyses, among all patients and in those aged over 60 years (i.e., older patients).ResultsOverall, 841 patients (median age 68 years; 60.4% males) were recruited. No significant independent association was found between NLR and the composite outcome in multivariate analysis in the overall cohort. Among the 612 older patients (median age 73 years; 59.2% males), the median NLR was 2.76 (interquartile range 1.96−4.00) and 148 (24.2%) patients had high NLR. The composite outcome occurred in 77 (12.6%) older patients, who were more likely to have a high NLR (39.0% versus 22.1%; p = 0.001) than those without a composite outcome. In multivariate logistic regression, high NLR (adjusted odds ratio 2.00; 95% confidence interval 1.07−3.75; p = 0.031) was independently associated with the composite outcome in older patients.ConclusionIn older (aged ≥60 years) patients with acute minor stroke or TIA, a higher NLR, a marker of systemic inflammation that can be easily obtained in routine blood tests, is an independent predictor of subsequent cardiovascular events.

ObjectivesWe aimed to determine predictors of mortality within 90 days and develop a simple score for patients with mechanical thrombectomy (MT).DesignAnalysis of a multicentre prospective registry.SettingIn six participating centres, patients who had an acute ischaemic stroke (AIS) treated by MT between March 2017 and May 2018 were documented prospectively.Participants224 patients with AIS were treated by MT.ResultsOf 224 patients, 49 (21.9%) patients died, and 87 (38.8%) were independent. Variables associated with 90-day mortality were age, previous stroke, admission National Institutes of Health Stroke Scale (NIHSS), fasting blood glucose and occlusion site. Logistic regression identified four variables independently associated with 90-day mortality: age ≥80 years (OR 3.26, 95% CI 1.45 to 7.33), previous stroke (OR 2.33, 95% CI 1.04 to 5.21), admission NIHSS ≥18 (OR 2.37, 95% CI 1.13 to 4.99) and internal carotid artery or basilar artery occlusion (OR 2.92, 95% CI 1.34 to 6.40). Using these data, we developed predicting 90-day mortality of AIS with MT (PRACTICE) score ranging from 0 to 6 points. The receiver operator curve analysis found that PRACTICE score (area under the curve (AUC)=0.744, 95% CI 0.669 to 0.820) was numerically better than iScore (AUC=0.661, 95% CI 0.577 to 0.745) and Predicting Early Mortality of Ischemic Stroke score (AUC=0.638, 95% CI 0.551 to 0.725) for predicting 90-day mortality.ConclusionsWe developed a simple score to estimate the 90-day mortality of patients who had an AIS treated with MT. But the score needs to be prospectively validated.Trial registration numberChinese Clinical Trial Registry (ChiCTR-OOC-17013052).

Endovascular treatment (EVT) has been accepted as the standard of care for patients with acute ischemic stroke. The aim of the present study was to compare clinical outcomes of patients who received EVT within and beyond 6 h from symptom onset to groin puncture without perfusion software in Guangdong district, China. Between March 2017 and May 2018, acute ischemic stroke patients who received EVT from 6 comprehensive stroke centers, were enrolled into the registry study. In this subgroup study, we included all patients who had acute proximal large vessel occlusion in the anterior circulation. The demographic, clinical and neuroimaging data were collected from each center. A total of 192 patients were included in this subgroup study. They were divided into two groups: group A (n = 125), within 6 h; group B (n = 67), 6–24 h from symptom onset to groin puncture. There were no substantial differences between these two groups in terms of 90 days favorable outcome (modified Rankin scale [mRS] ≤ 2, P = 0.051) and mortality (P = 0.083), and the risk of symptomatic intracranial hemorrhage at 24 h (P = 0.425). The NIHSS (median 16, IQR12-20, group A; median 12, IQR8-18, group B; P = 0.009) and ASPECTS (median 10, IQR8-10, group A; median 9, IQR8-10, group B; P = 0.034) at baseline were higher in group A. The anesthesia method (general anesthesia, 21.3%, group A vs. 1.5% group B, P = 0.001) were also statistically different between the two groups. The NIHSS and ASPECTS were higher, and general anesthesia was also more widely used in group A. Clinical outcomes were not significantly different within 6 h versus 6–24 h from symptom onset to groin puncture in this real world study.

Background: The risk of recurrent stroke following a minor stroke or transient ischemic attack (TIA) is high, when inflammation might play an important role. We aimed to evaluate the value of neutrophil-to-lymphocyte ratio (NLR) in predicting composite cardiovascular events in patients with minor stroke and TIA. Methods: Consecutive patients with acute minor stroke or TIA admitted within 24 hours of symptoms onset during a 5-year period in a prospective stroke registry were analyzed. We calculated the NLR dividing absolute neutrophil count by absolute lymphocyte count tested within 24 hours of admission. NLR ≥ 4th quartile was defined as high NLR. A composite outcome was defined as ischemic stroke, acute coronary syndrome or vascular death within 1 year. We investigated associations between NLR and the composite outcome in univariate and multivariate analyses, among all patients and in those aged over 60 years (i.e., older patients). Results: Overall, 841 patients (median age 68 years; 60.4% males) were recruited. No significant independent association was found between NLR and the composite outcome in multivariate analysis in the overall cohort. Among the 612 older patients (median age 73 years; 59.2% males), the median NLR was 2.76 (interquartile range 1.96-4.00) and 148 (24.2%) patients had high NLR. The composite outcome occurred in 77 (12.6%) older patients, who were more likely to have a high NLR (39.0% versus 22.1%; p=0.001) than those without a composite outcome. In multivariate logistic regression, high NLR (adjusted odds ratio 2.00; 95% confidence interval 1.07-3.75; p=0.031) was independently associated with the composite outcome in older patients. Conclusions: In older patients with acute minor stroke or TIA, a higher NLR is an independent predictor of subsequent cardiovascular events, indicating inflammation as an important factor and potential therapeutic target for secondary prevention of such patients.

Human immune system functions over an entire lifetime, yet how and why the immune system becomes less effective with age are not well understood. Here, we characterize peripheral blood mononuclear cells transcriptome from 172 healthy adults with 21~90 years of age using RNA-seq and the weighted gene correlation network analyses (WGCNA). These data reveal a set of insightful gene expression modules and representative gene biomarkers for human immune system aging from Asian and Caucasian ancestry, respectively. Among them, the aging-specific modules show an age-related gene expression variation spike around early-seventies. In addition, it is not known whether Asian and Caucasian immune systems go through similar gene expression changes throughout their lifespan, and to what extent these aging-associated changes are shared among ethnicities. We find the top hub genes including NUDT7, CLPB, OXNAD1 and MLLT3 are shared between Asian and Caucasian aging related modules and further validated in human PBMCs from different age groups. Overall, the impact of age and race on transcriptional variation elucidated from this study provide insights into the transcriptional driver of immune aging.

Chronic cerebral hypoperfusion (CCH) contributes to cognitive impairments, and hippocampal neuronal death is one of the key factors involved in this process. Dl-3-n-butylphthalide (D3NB) is a synthetic compound originally isolated from the seeds of Apium graveolens, which exhibits neuroprotective effects against some neurological diseases. However, the protective mechanisms of D3NB in a CCH model mimicking vascular cognitive impairment remains to be explored. We induced CCH in rats by a bilateral common carotid artery occlusion (BCCAO) operation. Animals were randomly divided into a sham-operated group, CCH 4-week group, CCH 8-week group, and the corresponding D3NB-treatment groups. Cultured primary hippocampal neurons were exposed to oxygen-glucose deprivation/reperfusion (OGD/R) to mimic CCH in vitro. We aimed to explore the effects of D3NB treatment on hippocampal neuronal death after CCH as well as its underlying molecular mechanism. We observed memory impairment and increased hippocampal neuronal apoptosis in the CCH groups, combined with inhibition of CNTF/CNTFRα/JAK2/STAT3 signaling, as compared with that of sham control rats. D3NB significantly attenuated cognitive impairment in CCH rats and decreased hippocampal neuronal apoptosis after BCCAO in vivo or OGD/R in vitro. More importantly, D3NB reversed the inhibition of CNTF/CNTFRα expression and activated the JAK2/STAT3 pathway. Additionally, JAK2/STAT3 pathway inhibitor AG490 counteracted the protective effects of D3NB in vitro. Our results suggest that D3NB could improve cognitive function after CCH and that this neuroprotective effect may be associated with reduced hippocampal neuronal apoptosis via modulation of CNTF/CNTFRα/JAK2/STAT3 signaling pathways. D3NB may be a promising therapeutic strategy for vascular cognitive impairment induced by CCH.

Background Chronic cerebral hypoperfusion (CCH) is common in multiple central nervous system diseases that are associated with neuronal death and cognitive impairment. Microglial activation-mediated polarization changes may be involved in CCH-induced neuronal damage. Adiponectin (APN) is a fat-derived plasma protein that affects neuroprotection. This study investigated whether a recombinant APN peptide (APN-P) improved the cognitive function of CCH rats by regulating microglial polarization in the cortex. Methods A CCH rat model was established through bilateral common carotid artery occlusion (BCCAO) surgery. An antibody microarray was used to analyze differentially expressed proteins in the cerebral cortex of CCH rats compared to the sham rats. APN-P and a solvent control were used to intervene at different time points. Western blotting and immunofluorescence staining were conducted to examine the status of microglial polarization in different treatment groups. qRT-PCR was used to detect the expression levels of inflammatory and anti-inflammatory genes. Neuronal morphology was assessed via Nissl staining, and cognitive function was assessed with the Morris water maze test. In vitro , by inhibiting the expression of NF-κB in BV2 microglia and using Transwell co-culture systems of BV2 microglia and neurons, the effects of APN-P on neuroprotection and the underlying mechanism were investigated. Results In the cortical microglia of 12-week-old CCH rats, the expression of APN protein was significantly downregulated compared to the sham rats. CCH damages neurons and activates cortical microglial polarization to an M1-type by upregulating inflammatory factors. APN-P supplementation upregulated APN expression in cortical microglia, with neuronal survival as well as microglial polarization from an M1 toward an M2 phenotype in CCH cortex. In vivo and in vitro experiments revealed that APN-P promoted the expression of anti-inflammatory factors and neuronal survival by inhibiting NF-κB signaling, thus improving the cognitive function in CCH rats. Conclusions Our study revealed a novel mechanism by which APN-P suppresses the NF-κB pathway and promotes microglial polarization from M1 toward the M2-type to reduce neuron damage in the cortex after CCH.

To investigate the safety and efficacy of intensive statin in the acute phase of ischemic stroke after intravenous thrombolysis therapy. A total of 310 stroke patients treated with rt-PA were randomly scheduled into the intensive statin group (rosuvastatin 20 mg daily × 14 days) and the control group (rosuvastatin 5 mg daily × 14 days). The primary clinical endpoint was excellent functional outcome (mRS ≤ 1) at 3 months, and the primary safety endpoint was symptomatic intracranial hemorrhage (sICH) in 90 days. The intensive statin users did not achieve a favorable outcome in excellent functional outcome (mRS ≤ 1) at 3 months compared with controls (70.3% vs. 66.5%, p = 0.464). Intensive statin also not significantly improved the overall distribution of scores on the modified Rankin scale, as compared with controls (p = 0.82 by the Cochran–Mantel–Haenszel test). The incidence of primary safety endpoint events (sICH) in 90 days did not significantly differ between the intensive statin group and control group (0.6% vs. 1.3%, p > 0.999). The INSPIRE study indicated that intensive statin therapy may not improve clinical outcomes compared with the low dose of statin therapy in AIS patients undergoing intravenous thrombolysis, and the two groups had similar safety profile. URL: http://www.chictr.org . Unique identifier: ChiCTR-IPR-16008642

Objective: To investigate the velocity and extent of cortical venous filling (CVF) and its association with clinical manifestations in patients with severe stenosis or occlusion of the middle cerebral artery (MCA) using dynamic computed tomography angiography (CTA).Methods: Fifty-eight patients (36 symptomatic and 22 asymptomatic) with severe unilateral stenosis (≥70%) or occlusion of the MCA M1 segment who underwent dynamic CTA were included. Collateral status, antegrade flow, and CVF of each patient were observed using dynamic CTA. Three types of cortical veins were selected to observe the extent of CVF, and the absence of CVF (CVF-) was recorded. Based on the appearance of CVF in the superior sagittal sinus, instances of CVF, including early (CVF1), peak (CVF2), and late (CVF3) venous phases, were recorded. The differences in CVF times between the affected and contralateral hemispheres were represented as rCVFs, and CVF velocity was defined compared to the median time of each rCVF.Results: All CVF times in the affected hemisphere were longer than those in the contralateral hemisphere (p < 0.05). Patients with symptomatic MCA stenosis had more ipsilateral CVF- (p = 0.02) and more delayed CVF at rCVF2 and rCVF21 (rCVF2-rCVF1) (p = 0.03 and 0.001, respectively) compared to those with asymptomatic MCA stenosis. For symptomatic patients, fast CVF at rCVF21 was associated with poor collateral status (odds ratio [OR] 6.42, 95% confidence interval [CI] 1.37–30.05, p = 0.02), and ipsilateral CVF- in two cortical veins was associated with poor 3-month outcomes (adjusted OR 0.025, 95% CI 0.002–0.33, p = 0.005).Conclusions: Complete and fast CVF is essential for patients with symptomatic MCA stenosis or occlusion. The clinical value of additional CVF assessment should be explored in future studies to identify patients with severe MCA stenosis or occlusion at a higher risk of stroke occurrence and poor recovery.

Chronic cerebral hypoperfusion (CCH) contributes to cognitive impairments, and hippocampal neuronal death is one of the key factors involved in this process. Dl-3-n-butylphthalide (D3NB) is a synthetic compound originally isolated from the seeds of Apium graveolens, which exhibits neuroprotective effects against some neurological diseases. However, the protective mechanisms of D3NB in a CCH model mimicking vascular cognitive impairment remains to be explored. We induced CCH in rats by a bilateral common carotid artery occlusion (BCCAO) operation. Animals were randomly divided into a sham-operated group, CCH 4-week group, CCH 8-week group, and the corresponding D3NB-treatment groups. Cultured primary hippocampal neurons were exposed to oxygen-glucose deprivation/reperfusion (OGD/R) to mimic CCH in vitro. We aimed to explore the effects of D3NB treatment on hippocampal neuronal death after CCH as well as its underlying molecular mechanism. We observed memory impairment and increased hippocampal neuronal apoptosis in the CCH groups, combined with inhibition of CNTF/CNTFRα/JAK2/STAT3 signaling, as compared with that of sham control rats. D3NB significantly attenuated cognitive impairment in CCH rats and decreased hippocampal neuronal apoptosis after BCCAO in vivo or OGD/R in vitro. More importantly, D3NB reversed the inhibition of CNTF/CNTFRα expression and activated the JAK2/STAT3 pathway. Additionally, JAK2/STAT3 pathway inhibitor AG490 counteracted the protective effects of D3NB in vitro. Our results suggest that D3NB could improve cognitive function after CCH and that this neuroprotective effect may be associated with reduced hippocampal neuronal apoptosis via modulation of CNTF/CNTFRα/JAK2/STAT3 signaling pathways. D3NB may be a promising therapeutic strategy for vascular cognitive impairment induced by CCH.

Objective: Chronic cerebral hypoperfusion (CCH) is a common consequence of various cerebral vascular disorders, hemodynamics and blood composition changes, which can lead to neurodegenerative injury and cognitive dysfunction. Therefore, it is important to take measures to prevent or reverse its development. Methods: Eighty Sprague-Dawley rats were randomly divided into five groups: Sham group, Vehicle groups (2-week group and 4-week group), Rosuvastatin-treated groups (2-week group and 4-week group). Both vehicle and treated group rats were treated with bilateral common carotid artery occlusion (BCCAO). Then rats in the treated group were intravenously injection with rosuvastatin (0.2 mg/kg/day) daily for 14 days beginning 24 hours after BCCAO. The vehicle groups were given the same amount of saline. The MRI ASL technique was used to scan cerebral blood flow (CBF) at pre-occlusion, BCCAO, 1, 2, 3, and 4 weeks after operation. Morris water maze test detected spatial memory abilities of the treated and vehicle rats after BCCAO. Immunofluorescence staining was used to detect the expression of CD34, GFAP, NeuN and Caspase-3 positive cells in hippocampus. Results: CBF decreased significantly after BCCAO in both rosuvastatin-treated and vehicle groups and then increased gradually. The CBF of the treated group was basically recovered to baseline levels at 1 or 2 weeks after BCCAO. But it took the vehicle group 4 weeks to restore to baseline. The vertebral artery (VA) diameter of the treated group was greater than that of the vehicle group (p+ and NeuN + cells in the hippocampus of the treated group was more than that in the vehicle group (p+ and Caspase-3 + cells was less than in the vehicle group (p Conclusion: Rosuvastatin can accelerate the recovery of cerebral blood flow in CCH rats, which may be related to the dilation of VAs and angiogenesis; and its effects on reducing astrocyte activation and neuroprotection may help to ameliorate cognitive dysfunction in CCH rats.

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.

// Wenxian Li 1, * , Xiaomei Xie 1, * , Di Wei 5, * , Shijun Zhang 2 , Yuanling Wu 1 , Xuejun Fu 3 , Zhen Jing 1 , Weibiao Lu 1 , Xinqiang Lai 4, # and Li’an Huang 1, # 1 Department of Neurology, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, 510632, P.R. China 2 Department of Neurology, People’s Hospital of Zengcheng District, Guangzhou, Guangdong, 510180, P.R. China 3 Department of Neurology, People’s Hospital, Second Clinical College, Jinan University, Shenzhen, 518020, P.R. China 4 Analysis and Testing Center, Jinan University, Guangzhou, Guangdong, 510632, P.R. China 5 Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shanxi, 710032, P.R. China * These authors contributed equally to this work and share first authorship # These authors contributed equally to this study and share corresponding authorship Correspondence to: Li’an Huang, email: huanglian1306@126.com Xinqiang Lai, email: xinqianglai@126.com Keywords: mean platelet volume, platelet count, clopidogrel resistance, non-cardioembolic ischemic stroke, platelet response Received: June 11, 2017 Accepted: September 21, 2017 Published: October 07, 2017 ABSTRACT Purpose: The present study investigated whether routine baseline platelet parameters(BPPs) detected before clopidogrel therapy in acute non-cardioembolic ischemic stroke(NCIS) could predict early platelet response and future clinical outcomes. Results: The CYP2C19 polymorphisms constituted independent risk factors for LCR. The number of female patients, the incidence of diabetes mellitus (DM), the level of low-density lipoprotein(LDL) cholesterol, and the neutrophil-to-lymphocyte ratio(NLR) were significantly high in the clinical clopidogrel resistance (CCR) group. However, none of the BPPs had a significant association with laboratory clopidogrel resistance (LCR) or discriminated with the cut-off values regarding LCR or CCR. The patients were divided into two groups according to the average mean platelet volume(MPV) or platelet count(PC). We found that the HbA1c level, the number of female patients, and the CCR were higher in the groups with elevated MPV (≥ 10.6fL) and PC (≥ 235 × 10 9 /L); the LCR, the NIHSS score at discharge, and elevated MPV and PC were risk predictors for CCR. Materials and Methods: This study included 196 patients with acute NCIS who underwent routine blood tests upon admission, were treated with clopidogrel, and were followed up for 6 months. Early platelet response was assessed and the CYP2C19 genetic variants were screened for. All participants were categorized into either laboratory clopidogrel resistance(LCR) or clinical clopidogrel resistance (CCR) groups. Conclusions: Elevated baseline MPV and PC before clopidogrel therapy, as well as CYP2C19 gene variants, should be included in a risk algorithm for NCIS. Furthermore, other nongenetic clinical risk factors should be assessed for optimal prediction of the risk for thrombotic events because of individual variability in platelet response to clopidogrel.

Background: The association of genetic polymorphisms and clopidogrel efficacy in patients with ischemic stroke or transient ischemic attack (TIA) remains controversial. We performed a systematic review and meta-analysis to assess the association between genetic polymorphisms, especially CYP2C19 genotype, and clopidogrel efficacy for ischemic stroke or TIA. Methods: We conducted a comprehensive search of PubMed and EMBASE from their inceptions to June 24, 2016. Studies that reported clopidogrel-treated patients with stroke or TIA and with information on genetic polymorphisms were included. The end points were stroke, composite vascular events, and any bleeding. Results: Among 15 studies of 4762 patients with stroke or TIA treated with clopidogrel, carriers of CYP2C19 loss-of-function alleles (*2, *3, and *8) were at increased risk of stroke in comparison with noncarriers (12.0% versus 5.8%; risk ratio, 1.92, 95% confidence interval, 1.57–2.35; P CYP2C19 loss-of-function alleles than in noncarriers (13.7% versus 9.4%; risk ratio, 1.51, 95% confidence interval, 1.10–2.06; P =0.01), whereas bleeding rates were similar (2.4% versus 3.1%; risk ratio, 0.89, 95% confidence interval, 0.58–1.35; P =0.59). There was no evidence of statistical heterogeneity among the included studies for stroke, but there was for composite vascular events. Genetic variants other than CYP2C19 were not associated with clinical outcomes, with the exception that significant associations of PON1 , P2Y12 , and COX-1 with outcomes were observed in 1 study. Conclusions: Carriers of CYP2C19 loss-of-function alleles are at greater risk of stroke and composite vascular events than noncarriers among patients with ischemic stroke or TIA treated with clopidogrel.