Non-alcoholic fatty liver disease and stroke: A Mendelian randomization study.

BACKGROUND: The association between non-alcoholic fatty liver disease (NAFLD) and the risk of stroke is heterogeneous. Therefore, we aimed to examine any potential causal relationship between these two traits through Mendelian randomization. METHODS: The genetic instruments associated with NAFLD were selected from a large genome-wide association study in individuals of European ancestry (1483 cases and 17,781 controls, replicated in 559 cases and 945 controls). The genetic associations for stroke (40,585 cases and 406,111 controls) and ischemic stroke (34,217 cases and 406,111 controls) were selected from the MEGASTROKE consortium of European ancestry participants. The causal effects on ischemic stroke subtypes, including large artery atherosclerosis (LAA) (4373 cases and 146,392 controls), small vessel occlusion (SVO) (5386 cases and 192,662 controls), and cardioembolic stroke (7193 cases and 204,570 controls), were also analyzed. The inverse variant weighted method was performed to obtain the casual estimates. Heterogeneity and pleiotropy of individual single nucleotide polymorphisms were also tested for the robustness of the results. RESULTS: NAFLD was not associated with stroke (odds ratio [OR] 1.015; 95% confidence interval [CI] 0.996-1.034; p = 0.121) and ischemic stroke (OR 1.017; 95% CI 0.997-1.037; p = 0.092). Regarding ischemic stroke subtypes, there were positive causal inferences on LAA (OR 1.065; 95% CI 1.004-1.129; p = 0.037) and SVO (OR 1.058; 95% CI 1.003-1.116; p = 0.037), while it was not significant for cardioembolic stroke (OR 1.026; 95% CI 0.983-1.071; p = 0.243). CONCLUSION: This study suggests that the potential causal effect of NAFLD on ischemic stroke may be confined to the LAA and SVO subtypes.

Risk Factors and Outcomes of Stroke-Associated Pneumonia in Patients with Stroke and Acute Large Artery Occlusion Treated with Endovascular Thrombectomy.

BACKGROUND AND PURPOSE: Stroke-associated pneumonia (SAP) often increases high hospital mortality, prolongs length of hospital stay, and has considerable economic impact on healthcare costs. We aimed to explore independent predictors of SAP in acute anterior large artery occlusion patients who treated with endovascular treatment (EVT). METHODS: Consecutive patients with acute anterior large artery occlusion stroke who underwent EVT from the Nanjing Stroke Registry from January 2019 to January 2020 were identified retrospectively. Patients were divided into SAP group and Non-SAP group. In the univariate analysis, variables including demographics, clinical factors, labs, and EVT features were compared between the two groups. Then a multivariable logistic regression analysis was conducted to determine independent predictors of SAP. RESULTS: One hundred and twelve patients were enrolled. Patients with SAP, compared to those without SAP, had lower modified treatment in cerebral infarction (mTICI) score 2b-3 rate (54.8% vs 85.2%; P = 0.001), higher asymptomatic intracerebral hemorrhage rate (48.4% vs 28.4%; P = 0.046), lower modified Rankin Scale (mRS) score 0-2 rate at 90days rate (9.7% vs 60.5%; P < 0.001), and higher mortality at 90days (38.7% vs 11.1%; P = 0.001). The independent predictors of SAP were dysphagia (Unadjusted Odds ratio[OR] 6.49, 95% Confidence interval[CI] 2.49-16.92; P = 0.02; Adjusted OR 3.59, 95% CI 1.19-10.83; P = 0.02), neutrophil-lymphocyte ratio (Unadjusted OR 1.19, 95% CI 1.1-1.3; P = 0.001; Adjusted OR 1.15, 95% CI 1.06-1.25; P = 0.001), and mTICI 2b-3 (Unadjusted OR 0.21, 95% CI 0.08-0.54; P = 0.001; Adjusted OR 0.3, 95% CI 0.1-0.92; P = 0.04). CONCLUSION: Dysphagia, higher neutrophil-lymphocyte ratio, and failed recanalization were associated with SAP in acute ischemic stroke patients underwent endovascular therapy. Identification and prevention of SAP was necessary and important.

Lipocalin-2 may produce damaging effect after cerebral ischemia by inducing astrocytes classical activation.

BACKGROUND: Functions of astrocytes in the rehabilitation after ischemic stroke, especially their impacts on inflammatory processes, remain controversial. This study uncovered two phenotypes of astrocytes, of which one was helpful, and the other harmful to anoxic neurons after brain ischemia. METHODS: We tested the levels of inflammatory factors including TNF-a, IL-6, IL-10, iNOS, IL-1beta, and CXCL10 in primary astrocytes at 0 h, 6 h, 12 h, 24 h, and 48 h after OGD, grouped the hypoxia astrocytes into iNOS-positive (iNOS(+)) and iNOS-negative (iNOS(-)) by magnetic bead sorting, and then co-cultured the two groups of cells with OGD-treated neurons for 24 h. We further verified the polarization of astrocytes in vivo by detecting the co-localization of iNOS, GFAP, and Iba-1 on MCAO brain sections. Lentivirus overexpressing LCN2 and LCN2 knockout mice (#024630. JAX, USA) were used to explore the role of LCN2 in the functional polarization of astrocytes. 7.0-T MRI scanning and the modified Neurological Severity Score (mNSS) were used to evaluate the neurological outcomes of the mice. RESULTS: After oxygen-glucose deprivation (OGD), iNOS mRNA expression increased to the peak at 6 h in primary astrocytes, but keep baseline expression in LCN2-knockout astrocytes. In mice with transient middle cerebral artery occlusion (tMCAO), LCN2 was proved necessary for astrocyte classical activation. In LCN2 knockout mice with MCAO, no classically activated astrocytes were detected, and smaller infarct volumes and better neurological functions were observed. CONCLUSIONS: The results indicated a novel pattern of astrocyte activation after ischemic stroke and lipocalin-2 (LCN2) plays a key role in polarizing and activating astrocytes.

Periprocedural intravenous heparin in patients with acute ischemic stroke treated with endovascular thrombectomy after intravenous thrombolysis.

OBJECTIVE: The benefit-to-risk ratio of periprocedural heparin in patients treated with endovascular thrombectomy (EVT) after intravenous thrombolysis (IVT) remains unclear. This study aimed to evaluate the potential effects of periprocedural heparin on clinical outcomes of EVT after IVT. METHODS: The authors retrospectively analyzed patients from multicenter studies treated with EVT after IVT in the anterior circulation. The endpoints were unfavorable outcome (defined as modified Rankin Scale score ≥ 3 at 90 days), 90-day mortality, symptomatic intracranial hemorrhage (SICH), successful recanalization, and early neurological deterioration. Patients were divided into two groups based on whether they were treated with heparin (heparin-treated group) or not (untreated group), and the efficacy and safety outcomes were compared using multivariable logistic regression models and propensity score-matching methods. RESULTS: Among the 322 included patients (mean age 67.4 years, 54.3% male), 32% of patients received periprocedural heparin. In multivariable analyses, the administration of periprocedural heparin was a significant predictor for unfavorable outcome (OR 2.821, 95% CI 1.15-7.326; p = 0.027), SICH (OR 24.925, 95% CI 2.363-780.262; p = 0.025), and early neurological deterioration (OR 5.344, 95% CI 1.299-28.040; p = 0.029). Regarding successful recanalization and death, no significant differences between the groups were found after propensity score matching. CONCLUSIONS: The results showed that periprocedural heparin is associated with an increased risk of unfavorable outcomes and SICH in patients treated with EVT after IVT. Further studies are warranted to evaluate the utility and safety of periprocedural heparin.

Trajectories of stroke severity and functional outcomes after endovascular treatment in ischemic stroke: A post hoc analysis of a randomized controlled trial.

BACKGROUND: The trajectory of early neurological changes in patients with acute ischemic stroke has been understudied. This study aimed to investigate the association between longitudinal trajectories of stroke severity and 90-day functional outcomes in patients with acute ischemic stroke receiving endovascular treatment. METHODS: We enrolled patients from a prospective, multicenter, randomized controlled trial. The stroke severity was assessed with the National Institute of Health Stroke Scale at the pre-procedure, 24 hours, and seven days after the procedure. Group-based trajectory modeling (GBTM) was used to identify trajectories of stroke severity. Multivariable logistic regression was performed to explore the association between stroke severity markers and 90-day functional outcomes. RESULTS: Of 218 enrolled patients, 127 (58.3%) had poor functional outcomes at 90 days. We identified three trajectories of stroke severity in the GBTM: stable symptom (38.1%), symptom deterioration (17.0%), and symptom improvement (44.9%). In multivariable analyses, trajectories of stroke severity were associated with an increased risk of poor functional outcomes (symptom improvement versus symptom deterioration: odds ratio, 0.007; 95% confidence interval, 0.001-0.040; P <0.001). Reclassification indexes revealed that trajectories of stroke severity would increase the predictive ability for poor functional outcomes at 90 days. CONCLUSION: After endovascular treatment, patients would follow one of three distinct trajectories of stroke severity. Symptom deterioration trajectory was associated with an increased risk of poor functional outcomes at 90 days. TRIAL REGISTRATION NUMBER: NCT04973332.

Periodontitis and stroke: A Mendelian randomization study.

BACKGROUND AND PURPOSE: Periodontitis has been implicated in the incidence of ischemic stroke. However, the generalizability of results to individuals with different subtypes of periodontitis is unknown. We aimed to investigate the causal relationship of chronic periodontitis (CP) and aggressive periodontitis (AgP) with ischemic stroke and its subtypes in the Mendelian randomization framework. METHODS: The genetic proxies of CP were derived from large-scale summary statistics from the UK Biobank datasets (950 cases and 455,398 controls). The genetic associations of AgP were selected from another large genome-wide association study of European ancestry (851 cases and 6836 controls). The instruments of ischemic stroke (34,217 cases and 406,111 controls) and its subtypes were selected from the MEGASTROKE consortium of European ancestry. The inverse variant weighted method was performed to determine the causal inference and a comprehensive set of sensitivity analyses to test the robustness of the results. RESULTS: In population-wide genetic analysis, there was no association of genetically predicted AgP (odds ratio [OR], 0.982; 95% confidence interval [CI], 0.956-1.009; p = .197) with ischemic stroke or its subtypes. For patients with CP, there was also no significant causal inference on ischemic stroke (OR, 1.017; 95% CI, 0.992-1.043; p = .184). However, regarding the stroke subtypes, the genetic analysis provided evidence of a causal relationship of CP with cardioembolic stroke (OR, 1.052; 95% CI, 1.002-1.104; p = .042), but not with large artery atherosclerosis (OR, 1.005; 95% CI, 0.944-1.069; p = .875) or small vessel occlusion (OR, 1.039; 95% CI, 0.981-1.101; p = .193). CONCLUSION: This study suggested that there was a potential causal effect of CP on cardioembolic stroke.

Increased Renal Dysfunction, Apoptosis, and Fibrogenesis Through Sympathetic Hyperactivity After Focal Cerebral Infarction.

Sympathetic nervous system plays an important role in secondary injury of diseases. Accumulating evidence has observed association between ischemic stroke and renal dysfunction, but the mechanisms are incompletely clear. In this study, we investigated whether sympathetic hyperactivity can cause the development of renal dysfunction, apoptosis, and fibrogenesis after focal cerebral infarction. To determine the renal consequences of focal cerebral ischemia, we subjected a mice model of transient middle cerebral artery occlusion (tMCAO) and examined systolic blood pressure, heart rate, renal structure and function, serum catecholamine, and cortisol levels, and the expression of active caspase-3 bcl-2, bax, and phosphorylated p38 MAPK after 8 weeks. We also analyzed the relationship between insular cortex infarction and acute kidney injury (AKI) in 172 acute anterior circulation ischemic stroke (ACIS) patients. Transient right middle cerebral artery occlusion induced sympathetic hyperactivity, renal dysfunction, upregulation of apoptosis, and fibrogenesis in kidneys of mice. Metoprolol treatment relieves the development of renal injury. Study in stroke patients demonstrated that insular cortex infarction, especially the right insular cortex infarction, is an independent risk factor of AKI. Focal cerebral ischemia in mice leads to the development of renal injury driven by sympathetic hyperactivity. Right insular cortex infarction is an independent risk factor of AKI in older patients. Understanding the brain-kidney interaction after stroke would have clinical implications for the treatment and overall patient outcome.

Off-hour effect on time metrics and clinical outcomes in endovascular treatment for large vessel occlusion: A systematic review and meta-analysis.

BACKGROUND: There is an ongoing debate on the off-hour effect on endovascular treatment (EVT) for acute large vessel occlusion (LVO). AIM: This meta-analysis aimed to compare time metrics and clinical outcomes of acute LVO patients who presented/were treated during off-hour with those during working hours. SUMMARY OF REVIEW: Structured searches on the PubMed, Embase, Web of Science, and Cochrane Library databases were conducted through 23 February 2021. The primary outcomes were onset to door (OTD), door to imaging, door to puncture (DTP), puncture to recanalization, procedural time, successful recanalization, symptomatic intracranial hemorrhage (SICH), mortality in hospital, good prognosis (90-day modified Rankin Scale (mRS) score 0-2), and 90-day mortality. The secondary outcomes were imaging to puncture (ITP), onset to puncture (OTP), onset to recanalization (OTR), door to recanalization (DTR) time, mRS 0-2 at discharge, and consecutive 90-day mRS score. The odds ratio (OR) and weighted mean difference (WMD) with 95% confidence interval (CI) of the outcomes were calculated using random-effect models. Heterogenicity and publication bias were analyzed. Subgroup and sensitivity analyses were conducted as appropriate. Nineteen studies published between 2014 and 2021 with a total of 14,185 patients were eligible for quantitative synthesis. Patients in the off-hour group were significantly younger than those in the on-hour group and with comparable stroke severity and intravenous thrombolysis rate. The off-hour group had longer OTD (WMD [95% CI], 12.83 [1.84-23.82] min), DTP (WMD [95% CI], 11.45 [5.93-16.97] min), ITP (WMD [95% CI], 10.39 [4.61-16.17] min), OTP (WMD [95% CI], 25.30 [13.11-37.50] min), OTR (WMD [95% CI], 25.16 [10.28-40.04] min), and DTR (WMD [95% CI], 18.02 [10.01-26.03] min) time. Significantly lower successful recanalization rate (OR [95% CI], 0.85 [0.76-0.95]; p = 0.004; I2 = 0%) was detected in the off-hour group. No significant difference was noted regarding SICH and prognosis. But a trend toward lower OR of good prognosis was witnessed in the off-hour group (OR [95% CI], 0.92 [0.84-1.01]; p = 0.084; I2 = 0%). CONCLUSIONS: Patients who presented/were treated during off-hour were associated with excessive delays before the initiation of EVT, lower successful reperfusion rate, and a trend toward worse prognosis when compared with working hours. Optimizing the workflows of EVT during off-hour is needed.

Motor Network Reorganization After Repetitive Transcranial Magnetic Stimulation in Early Stroke Patients: A Resting State fMRI Study.

OBJECTIVE: To compare the effects of high-frequency (10 Hz) versus low-frequency (1 Hz) repetitive Transcranial Magnetic Stimulation (rTMS) on motor recovery and functional reorganization of the cortical motor network during the early phase of stroke. METHODS: Forty-six hospitalized, first-ever ischemic stroke patients in early stage (within two weeks) with upper limb motor deficits were recruited. They were randomly allocated to three groups with 10 Hz ipsilesional rTMS, 1 Hz contralesional rTMS, and sham rTMS of five daily session. All patients underwent motor function (Upper Extremity Fugl-Meyer), neurophysiological and resting-state  functional Magnetic Resonance Imaging (fMRI) (rs-fMRI) assessments before and after rTMS intervention. Motor recovery (△Fugl-Meyer Assessment) was defined as motor function changes before and after rTMS intervention. Motor function assessment was reevaluated at time point of three month follow-up. RESULTS: The two real rTMS groups manifested greater motor improvements than the sham group. The effect sustained for at least 3 months after the end of the treatment sessions. Compared with the sham group, 10 Hz ipsilesional rTMS group presented increased resting-state functional connectivity (FC) between ipsilesional primary motor cortex (M1) and contralesional M1 (P = .007), whereas 1 Hz contralesional rTMS group presented increased FC between contralesional M1 and ipsilesional supplementary motor area (P = .010), which were positively correlated with motor recovery (P < .05). CONCLUSION: Beneficial effect of rTMS on motor recovery might be underlaid by increased FC between stimulating site and the remote motor areas, highlighting the motor network reorganization mechanism of rTMS in early post-stroke phase.

Off-hour effect is not significant in endovascular treatment for anterior circulation large vessel occlusion in a multicentre registry.

BACKGROUND AND PURPOSE: Whether the off-hour effect has an impact on workflow and outcomes of endovascular treatment (EVT) for anterior circulation large vessel occlusion (AC-LVO) remains uncertain. This study aimed to compare the characteristics and outcomes of patients who presented or were treated during off-hour versus on-hour in a multi-center registry. METHODS: AC-LVO patients from 21 centres were categorised into the off-hour group and the on-hour group. Off-hour (weekends, holidays, and 18:00-7:59 on weekdays) and on-hour (8:00-17:59 on weekdays except for holidays) were defined according to arrival and groin-puncture time points, respectively. Subgroup comparisons between patients both arrived and treated during off-hour (true off-hour) and on-hour (true on-hour) were performed. The primary outcome was the 90-day modified Rankin Scale (mRS) score. Secondary outcomes included favourable outcome (mRS 0-2 at 90 days), EVT-related time metrics, and other clinical outcomes. Ordinary and binary logistic regression and linear regression were taken to adjust for confounding factors. RESULTS: Of all 698 patients enrolled, 435 (62.3%) and 456 (65.3%) patients were categorised into the off-hour arrival and off-hour puncture group, respectively. Shorter onset to door time (adjusted ß coefficient: -21.56; 95% CI -39.96 to -3.16; p=0.022) was noted in the off-hour arrival group. Ordinal and dichotomous mRS scores at 90 days were comparable between the off-hour group and the on-hour group regardless of off-hour definitions. Other time metrics and outcomes were comparable between the two groups. Of 595 patients both presented and were treated during off-hour or on-hour, 394 patients were categorised into the true off-hour group and 201 into the true on-hour group. Time metrics and clinical outcomes were similar between the true off-hour and the true on-hour group. CONCLUSIONS: The off-hour effect was not significant regarding clinical outcomes and in-hospital workflow in AC-LVO patients receiving EVT in this Chinese multicentre registry.

Identification of Symptomatic Carotid Artery Plaque: A Three-Item Scale Combined Angiography With Optical Coherence Tomography.

Introduction: Symptomatic carotid disease conveys a high risk of recurrent stroke. Plaque morphology and specific plaque characteristics are associated with the risk of stroke. This study aimed to evaluate the detailed plaque features by optical coherence tomography (OCT) and develop a simple scale combining clinical indicators, digital subtraction angiography (DSA), and OCT imaging markers to identify symptomatic carotid plaque. Methods: Carotid plaques from consecutive patients who underwent carotid OCT imaging between June 2017 and June 2021 were evaluated. Clinical characteristics, DSA, and OCT data were compared between the symptomatic and asymptomatic groups. Logistic regression was performed to identify the factors associated with symptomatic carotid plaque and to develop a scale. The area under the receiver operating characteristic curve (AUC) was used to evaluate the performance of the scale. Results: A total of 90 carotid plaques from 90 patients were included (symptomatic 35.6%, asymptomatic 64.4%). Three main factors were found to be associated with symptomatic carotid plaque: high-density lipoprotein cholesterol (HDL-C) <0.925 mmol/L (OR, 4.708; 95% CI, 1.640 to 13.517; P = 0.004), irregular plaque (OR, 4.017; 95% CI, 1.250 to 12.910; P = 0.020), and white thrombus (OR, 4.594; 95% CI, 1.141 to 18.487; P = 0.032). The corresponding score of three items produced a scale with good discrimination (AUC, 0.768; 95% CI, 0.665 to 0.871). The optimal cutoff value of the scale was 1.5 points with 59.4% sensitivity and 84.5% specificity. Conclusion: The three-item scale comprising HDL-C <0.925 mmol/L, angiographical irregular plaque, and white thrombus detected by OCT may provide information to identify symptomatic carotid plaque. Further large-scale studies are required to validate whether the symptomatic carotid plaque scale is clinically valuable in recognizing carotid atherosclerosis in the early stages.

A Pre-Interventional Scale to Predict in situ Atherosclerotic Thrombosis in Acute Vertebrobasilar Artery Occlusion Patients.

Background and Purpose: Determining the occlusion mechanism before endovascular treatment (EVT) is of great significance for acute large vessel occlusion patients. We aimed to develop and validate a simple pre-EVT scale with readily available variables for predicting in situ atherosclerotic thrombosis (ISAT) in acute vertebrobasilar artery occlusion (VBAO) patients. Materials and Methods: Consecutive patients were retrieved from Nanjing Stroke Registry Program between January 2014 and December 2019 as a derivation cohort. Anonymous data of consecutive patients between January 2014 and December 2019 were collected from another comprehensive stroke center as an external validation cohort. Demographics, medical histories, and clinical characteristics were collected. ISAT was defined according to the following criteria: (a) detection of moderate to severe (≥50%) stenosis or stenosis with significant distal flow impairment at the occluded segment when successful reperfusion was achieved; (b) transient visualization of eccentric plaque contour or a recurrent re-occlusion tendency when reperfusion was unsuccessful. Logistic regression was taken to develop a predictive scale. The performance of the scale was assessed by area under the receiver operating characteristic curve (AUC) and Hosmer-Lemeshow test. Results: ISAT was observed in 41 of 95 (43.2%) patients included in the derivation cohort. The ISAT predictive scale consisted of three pre-interventional predictors, including the history of hypertension, atrial fibrillation rhythm, and baseline serum glucose level ≥7.55 mmol/L. The model depicted acceptable calibration (Hosmer-Lemeshow test, P = 0.554) and good discrimination (AUC, 0.853; 95% confidence interval, 0.775-0.930). The optimal cutoff value of the ISAT scale was 1 point with 95.1% sensitivity, 64.8% specificity, and 77.9% accuracy. In the validation cohort, the discrimination ability was still promising with an AUC value of 0.800 (0.682-0.918). Conclusion: The three-item scale comprised of the history of hypertension, atrial fibrillation rhythm, and dichotomous serum glucose level had a promising predictive value for ISAT before EVT in acute VBAO patients.

Calcification in Atherosclerotic Plaque Vulnerability: Friend or Foe?

Calcification is a clinical marker of atherosclerosis. This review focuses on recent findings on the association between calcification and plaque vulnerability. Calcified plaques have traditionally been regarded as stable atheromas, those causing stenosis may be more stable than non-calcified plaques. With the advances in intravascular imaging technology, the detection of the calcification and its surrounding plaque components have evolved. Microcalcifications and spotty calcifications represent an active stage of vascular calcification correlated with inflammation, whereas the degree of plaque calcification is strongly inversely related to macrophage infiltration. Asymptomatic patients have a higher content of plaque calcification than that in symptomatic patients. The effect of calcification might be biphasic. Plaque rupture has been shown to correlate positively with the number of spotty calcifications, and inversely with the number of large calcifications. There may be certain stages of calcium deposition that may be more atherogenic. Moreover, superficial calcifications are independently associated with plaque rupture and intraplaque hemorrhage, which may be due to the concentrated and asymmetrical distribution of biological stress in plaques. Conclusively, calcification of differential amounts, sizes, shapes, and positions may play differential roles in plaque homeostasis. The surrounding environments around the calcification within plaques also have impacts on plaque homeostasis. The interactive effects of these important factors of calcifications and plaques still await further study.

Insulin enhances neointimal hyperplasia following arterial injury through the PI3K/Akt pathway in type 1 diabetic rats.

Although insulin is known to affect neointimal hyperplasia via distinct signaling pathways, how neointimal hyperplasia is affected in insulin­deficient type 1 diabetes remains unknown. The aim of the current study was to investigate two major signaling branches of insulin action regulating neointimal hyperplasia following arterial injury in type 1 diabetes with or without exogenous insulin administration. Rats were treated with vehicle (control group), streptozotocin (STZ) alone (STZ group; uncontrolled type 1 diabetes) or STZ followed by insulin (STZ + I group; controlled type 1 diabetes). Subsequently, a type 1 diabetic rat model of carotid artery balloon injury was established. Following this, the intima­to­media area ratios were examined for evidence of neointimal hyperplasia in the carotid arteries of the rats by performing hematoxylin­eosin staining. Furthermore, the protein expression of extracellular signal­regulated kinase (ERK), phosphorylated (p­) ERK, protein kinase B (Akt) and p­Akt in the carotid arteries of the rats was determined via immunoblotting. Moreover, an in vitro model of type 1 diabetes was induced by incubation of primary vascular smooth muscle cells (VSMCs) with glucose and/or insulin. Cellular proliferation and signaling protein expression levels in VSMCs were determined by measuring the incorporation of tritiated thymidine and performing immunoblotting, respectively. The results demonstrated that compared with that in control rats, neointimal hyperplasia and expression of p­Akt in uncontrolled type 1 diabetic rats were significantly decreased. This decrease was recovered in controlled type 1 diabetes with insulin therapy. Furthermore, the difference in the expression of p­ERK between groups was not significant. Additionally, the results of the cell experiments were consistent with those from the animal studies. In conclusion, the preferential signaling along the phosphatidylinositol 3­kinase/Akt pathway of insulin action in response to insulin restoration may contribute to neointimal hyperplasia. The present study provides a novel approach for the further treatment of neointimal hyperplasia in type 1 diabetes.

Renal impairment on clinical outcomes following endovascular recanalization.

OBJECTIVE: To determine the influence of renal impairment (RI) on clinical outcomes at 3 months and the risk of recurrent stroke in patients presenting with emergent large vessel occlusion (ELVO) treated with emergent endovascular treatment (EVT). METHODS: Consecutive patients with anterior circulation stroke due to ELVO treated with EVT in 21 endovascular centers were included. Multivariate regressions were used to evaluate the association of RI with mortality, functional independence (modified Rankin Scale [mRS] score 0-2), and functional improvement (shift in mRS score) at 3 months. The association between RI and the risk of recurrent stroke was evaluated with multivariate competing-risk regression analyses. RESULTS: A total of 628 patients with ELVO (mean age 64.7 ± 12.5 years, median NIH Stroke Scale score 17 points, 99 [15.8%] with RI) who underwent EVT were enrolled. After adjustment for other relevant variables, multivariate regression analysis indicated that RI was independently associated with functional independence (adjusted odds ratio 0.53, 95% confidence interval [CI] 0.29-0.96, p = 0.035) at 3 months but not with mortality or functional improvement. Multivariate competing-risk regression analysis showed that patients with RI who received EVT had a significantly higher risk of recurrent stroke (adjusted hazard ratio 2.56, 95% CI 1.27-5.18, p = 0.009) compared to those with normal renal function. CONCLUSION: Our results suggest that RI is an independent predictor of functional independence at 3 months and long-term risk of recurrent stroke in patients with ELVO treated with EVT.

Endovascular treatment versus standard medical treatment for vertebrobasilar artery occlusion (BEST): an open-label, randomised controlled trial.

BACKGROUND: Previous randomised trials have shown an overwhelming benefit of mechanical thrombectomy for treating patients with stroke caused by large vessel occlusion of the anterior circulation. Whether endovascular treatment is beneficial for vertebrobasilar artery occlusion remains unknown. In this study, we aimed to investigate the safety and efficacy of endovascular treatment of acute strokes due to vertebrobasilar artery occlusion. METHODS: We did a multicentre, randomised, open-label trial, with blinded outcome assessment of thrombectomy in patients presenting within 8 h of vertebrobasilar occlusion at 28 centres in China. Patients were randomly assigned (1:1) to endovascular therapy plus standard medical therapy (intervention group) or standard medical therapy alone (control group). The randomisation sequence was computer-generated and stratified by participating centres. Allocation concealment was implemented by use of sealed envelopes. The primary outcome was a modified Rankin scale (mRS) score of 3 or lower (indicating ability to walk unassisted) at 90 days, assessed on an intention-to-treat basis. The primary safety outcome was mortality at 90 days. Secondary safety endpoints included the rates of symptomatic intracranial haemorrhage, device-related complications, and other severe adverse events. The BEST trial is registered with ClinicalTrials.gov, NCT02441556. FINDINGS: Between April 27, 2015, and Sept 27, 2017, we assessed 288 patients for eligibility. The trial was terminated early after 131 patients had been randomly assigned (66 patients to the intervention group and 65 to the control group) because of high crossover rate and poor recruitment. In the intention-to-treat analysis, there was no evidence of a difference in the proportion of participants with mRS 0-3 at 90 days according to treatment (28 [42%] of 66 patients in the intervention group vs 21 [32%] of 65 in the control group; adjusted odds ratio [OR] 1·74, 95% CI 0·81-3·74). Secondary prespecified analyses of the primary outcome, done to assess the effect of crossovers, showed higher rates of mRS 0-3 at 90 days in patients who actually received the intervention compared with those who received standard medical therapy alone in both per-protocol (28 [44%] of 63 patients with intervention vs 13 [25%] of 51 with standard therapy; adjusted OR 2·90, 95% CI 1·20-7·03) and as-treated (36 [47%] of 77 patients with intervention vs 13 [24%] of 54 with standard therapy; 3·02, 1·31-7·00) populations. The 90-day mortality was similar between groups (22 [33%] of 66 patients in the intervention vs 25 [38%] of 65 in the control group; p=0·54) despite a numerically higher prevalence of symptomatic intracranial haemorrhage in the intervention group. INTERPRETATION: There was no evidence of a difference in favourable outcomes of patients receiving endovascular therapy compared with those receiving standard medical therapy alone. Results might have been confounded by loss of equipoise over the course of the trial, resulting in poor adherence to the assigned study treatment and a reduced sample size due to the early termination of the study. FUNDING: Jiangsu Provincial Special Program of Medical Science.

GRP78 Promotes Neural Stem Cell Antiapoptosis and Survival in Response to Oxygen-Glucose Deprivation (OGD)/Reoxygenation through PI3K/Akt, ERK1/2, and NF-κB/p65 Pathways.

When brain injury happens, endogenous neural stem cells (NSCs) located in the adult subventricular zone (SVZ) and subgranular zone (SGZ) are attacked by ischemia/reperfusion to undergo cellular apoptosis and death before being induced to migrate to the lesion point and differentiate into mature neural cells for damaged cell replacement. Although promoting antiapoptosis and NSC survival are critical to neuroregeneration, the mechanism has yet been elucidated clearly. Here in this study, we established an in vitro oxygen-glucose deprivation (OGD)/reoxygenation model on NSCs and detected glucose-regulated protein 78 (GRP78) involved in apoptosis, while in the absence of GRP78 by siRNA transfection, OGD/reoxygenation triggered PI3K/Akt, ERK1/2, and NF-κB/p65 activation, and induced NSC apoptosis was attenuated. Further investigation, respectively, with the inhibitor of PI3K/Akt or ERK1/2 demonstrated a blockage on GRP78 upregulation, while the inhibition of NF-κB rarely affected GRP78 induction by OGD/reoxygenation. The results indicated the bidirectional regulations of GRP78-PI3K/Akt and GRP78-ERK1/2 and the one-way signalling transduction through GRP78 to NF-κB/p65 on NSC survival from OGD/reoxygenation. In conclusion, we found that GRP78 mediated the signalling cross talk through PI3K/Akt, ERK1/2, and NF-κB/p65, which leads to antiapoptosis and NSC survival from ischemic stroke. Our finding gives a new evidence of GRP78 in NSCs as well as a new piece of signalling mechanism elucidation to NSC survival from ischemic stroke.

Distinctive expression signatures of serum microRNAs in ischaemic stroke and transient ischaemic attack patients.

Circulating microRNAs (miRNAs) have recently emerged as promising biomarkers for ischaemic stroke (IS). However, the expression patterns of specific miRNAs in transient ischaemic attack (TIA) patients have not been investigated. Their predictive values for the presence of IS and TIA and their relationships to the neurological deficit severity of IS and the subsequent stroke risk after TIA remain unclear exactly. In this study, 754 miRNAs were initially screened by the TaqMan Low Density Array (TLDA) in two pooled serum samples from 50 IS patients and 50 controls. Markedly altered miRNAs were subsequently validated by individual quantitative reverse-transcription PCR (qRT-PCR) assays first in the same cohort of TLDA and further confirmed in another larger cohort including 177 IS, 81 TIA patients and 42 controls. Consequently, TLDA screening showed that 71 miRNAs were up-regulated and 49 miRNAs were down-regulated in IS patients. QRT-PCR validation confirmed that serum levels of miR-23b-3p, miR-29b-3p, miR-181a-5p and miR-21-5p were significantly increased in IS patients. Strikingly, serum levels of miR-23b-3p, miR-29b-3p and miR-181a-5p were also significantly elevated in TIA patients. Furthermore, up-regulated miR-23b-3p, miR-29b-3p and miR-21-5p could clearly differentiate between IS and TIA patients. Logistic regression and receiver-operating characteristic curve analyses demonstrated that these altered miRNAs may function as predictive and discriminative biomarkers for IS and TIA, and their distinctive expression signatures may contribute to assessing neurological deficit severity of IS and subsequent stroke risk after TIA.

NSFC health research funding and burden of disease in China.

BACKGROUND: Allocation of health research funds among diseases has never been evaluated in China. This study aimed to examine the relationship between disease-specific funding levels of National Nature Science Foundation of China (NSFC), the main governmental resource for health research in China, and burden of disease. METHODS: Funding magnitudes for 53 diseases or conditions were obtained from the website of NSFC. Measures of disease burden, mortality, years of life lost (YLLs) and disability-adjusted life years (DALYs), were derived from the Global Burden of Disease Study 2010. The relationship between NSFC funding and disease burden was analyzed with univariate linear regression. For each measure associated with funding, regression-derived estimates were used to calculate the expected funds for each disease. The actual and expected funds were then compared. We also evaluated the impacts of changes of disease burden metrics since 1990, and differences from the world averages on NSFC funding. RESULTS: NSFC health research funding was associated with disease burden measured in mortality (R = 0.33, P = 0.02), YLLs (R = 0.39, P = 0.004), and DALYs (R  = 0.40, P = 0.003). But none of the changes of mortality (R = 0.22, P = 0.12), YLLs (R =  -0.04, P = 0.79) and DALYs (R =  -0.003, P = 0.98) since 1990 was associated with the funding magnitudes. None of the differences of mortality (R =  -0.11, P = 0.45), YLLs (R =  -0.11, P = 0.43) and DALYs (R =  -0.12, P = 0.38) from that of the concurrent world averages were associated with the funding magnitudes. Measured by DALY, stroke and COPD received the least funding compared to expected; while leukemia and diabetes received the most funding compared to expected. CONCLUSION: Although NSFC funding were roughly associated with disease burden as measured in mortality, YLLs and DALYs. Some major diseases such as stroke were underfunded; while others such as leukaemia were overfunded. Change of disease burden during the last 20 years and country-specialized disease burden were not reflected in current allocation of NSFC funds.

Intranasal nerve growth factor attenuates tau phosphorylation in brain after traumatic brain injury in rats.

Traumatic brain injury (TBI) is a considerable cause of mild cognitive impairment and dementia. Intranasal administration of nerve growth factor (NGF) has previously been found to improve cognitive function after TBI, but the mechanism remains unclear. This study aimed to investigate the effects of intranasal NGF on the tau hyperphosphorylation following TBI. A modified Feeney's weight-drop model was used to induce TBI. Rats were randomly divided into control group, TBI group, TBI+NGF group, TBI+PDTC group and TBI+IL-1ra group. Rats in TBI+NGF group were administered with NGF (5 µg/d) for 3d before surgery. Hyperphosphorylated tau protein was remarkable in the peri-contusional cortex area with TBI. Both western blotting and immunostaining results displayed intranasal pretreatment of NGF significantly reduced tau phosphorylation. To evaluate the underlying mechanism, the levels of glycogen synthase kinase 3ß (GSK-3ß), interleukin-1ß (IL-1ß), and the DNA binding activity of nuclear factor-κB (NF-κB) were assayed. NGF markedly inhibited GSK-3ß. NGF also reduced TBI-induced elevation of IL-1ß and NF-κB DNA binding activity. Furthermore, PDTC and IL-1ra were injected to prove a potential signaling pathway among NF-κB, IL-1ß and GSK-3ß. Taken together, these findings demonstrated that intranasal NGF could effectively attenuate the hyperphosphorylation of tau after TBI, which might involve an integrated signaling pathway related to NF-κB.