Universal platform for accurately damage-free mapping of sEVs cargo information.

SEVs (small extracellular vesicles) contents signatures appear to mirror pathological changes of diseases, and mapping sEVs contents profile is a promising approach for non-invasive diagnosis of the disease. Herein, we propose a universal system for accurately and damage-freely mapping of sEVs content profile using dual-recognition triggered CHA (catalytic hairpin assembly) and DNAzyme based signal amplification strategy. After immunoassay based capture of CD63 positive sEVs by anti-CD63 lgG coated on the surface of polystyrene plates, probes are incubated with fixed sEVs to penetrate sEVs membrane and act to sense sEVs contents. In detection step, integrated CHA and DNAzyme based strategy is initiated by released initiator from capture probe after recognizing targets, forming a dual circle signal recycling process, realizing signal amplification for high sensitivity. Given the attractive analytical features that i) a universal platform for indistinctive sEVs nucleic acids and protein molecules detection; ii) high sensitivity derived from dual circle signal recycling process; iii) enzyme-free characteristic of integrated CHA and DNAzyme minimizes the interference to sEVs biological activity; iv) mapping of sEVs contents profiles indicates a brand-new strategy for non-invasive diagnosis of the disease, the present approach shows great promise for analyzing additional different analytes in clinical and experimental researches.

Efficacy and safety of 3-n-butylphthalide combined with endovascular treatment in acute ischemic stroke due to large vessel occlusion.

BACKGROUND: The drug 3-n-butylphthalide (NBP) was developed and approved in China, where it has been used to treat ischemic cerebrovascular diseases. It is also considered to have a neuroprotective effect. This study aimed to evaluate whether NBP combined with endovascular treatment (EVT) can improve the clinical outcome and safety in patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO). METHODS: Data from three studies of patients treated with EVT for AIS due to LVO were combined in this study. Patients of LVO undergoing EVT were dichotomized into NBP and non-NBP subgroups. The primary efficacy outcome was the shift of the modified Rankin Scale (mRS) score at 90 days. The secondary efficacy outcome included favorable functional outcomes, functional independence, and excellent outcome (defined as an mRS score of 3 or less) at 90 days. Safety outcomes included mortality within 90 days and symptomatic intracranial hemorrhage (sICH) within 48 h. RESULTS: A total of 1820 patients undergoing EVT were included in this study; 628 (37.5%) patients received NBP treatment, whereas 1138 (62.5%) did not. After adjusting for multiple factors, NBP was associated with the improvement of functional outcomes at 90 days (adjusted common odds ratio [OR]: 1.503; 95% confidence interval (CI): 1.254-1.801; p < 0.001). NBP was associated with a higher rate of 90-day favorable outcomes (adjusted OR: 1.589; 95% CI: 1.251-2.020; p < 0.001) and a lower rate of 90-day mortality (adjusted OR: 0.486 [95% CI: 0.372-0.635]; p < 0.001). sICH occurred in 74 of 682 (10.9%) patients in the NBP group and 155 of 1126 (13.8%) patients in the non-NBP group; no statistical difference was detected (adjusted OR: 0.787 [95% CI: 0.567-1.092]; p = 0.152). CONCLUSION: Among patients with AIS due to LVO, NBP combined with EVT is associated with better functional outcomes and reduced mortality risk without increasing the risk of sICH.

A Comparison of Safety and Effectiveness Between Wingspan and Neuroform Stents in Patients With Middle Cerebral Artery Stenosis.

Background: Percutaneous transluminal angioplasty and stenting with the Wingspan stent has proven safe and effective in patients with middle cerebral artery stenosis (MCAS), but the off-label use of the Neuroform stent might be an alternative treatment. This study aimed to compare the safety and effectiveness of the above two intracranial stents in patients with MCAS. Methods: We retrospectively analyzed consecutive patients with symptomatic MCAS who had been treated with the Neuroform EZ or the Wingspan stent. A propensity score was generated to control for differences in baseline characteristics. The endpoints were the rate of peri-procedural complications within 30 days after stenting, the in-stent restenosis rate, and any target-vessel-related stroke or deaths during follow-up. Results: After matching for propensity score, the peri-procedural complication rate in the Wingspan group was 7.4% compared with 5.6% in the Neuroform group (p = 1.00), while the follow-up in-stent restenosis rates were 23.3 vs. 14.3%, respectively (p = 0.41). In the restenosis group, the patients tended to be younger (p < 0.01) and the degree of artery stenosis before stenting was higher (p < 0.01). Conclusion: This study indicated that in patients with symptomatic MCAS, Neuroform EZ stents are an alternative to Wingspan. Moreover, younger age and higher degree of artery stenosis before stenting might be a risk factor of in-stent restenosis.

Values of Baseline Posterior Circulation Acute Stroke Prognosis Early Computed Tomography Score for Treatment Decision of Acute Basilar Artery Occlusion.

BACKGROUND AND PURPOSE: This study aimed to analyze the impact of baseline posterior circulation Acute Stroke Prognosis Early Computed Tomography Score (pc-ASPECTS) on the efficacy and safety of endovascular therapy (EVT) for patients with acute basilar artery occlusion. METHODS: The BASILAR was a nationwide prospective registry of consecutive patients with a symptomatic and radiologically confirmed acute basilar artery occlusion within 24 hours of symptom onset. We estimated the effect of standard medical therapy alone (SMT group) versus SMT plus EVT (EVT group) for patients with documented pc-ASPECTS on noncontrast CT, both as a categorical (0-4 versus 5-7 versus 8-10) and as a continuous variable. The primary outcomes included favorable functional outcomes (modified Rankin Scale ≤3) at 90 days and mortality within 90 days. RESULTS: In total, 823 cases were included: 468 with pc-ASPECTS 8 to 10 (SMT: 71; EVT: 397), 317 with pc-ASPECTS 5 to 7 (SMT: 85; EVT: 232), and 38 with pc-ASPECTS 0 to 4 (SMT: 13; EVT: 25). EVT was associated with higher rate of favorable outcomes (adjusted relative risk with 95% CI, 4.35 [1.30-14.48] and 3.20 [1.68-6.09]; respectively) and lower mortality (60.8% versus 77.6%, P=0.005 and 35.0% versus 66.2%, P<0.001; respectively) than SMT in the pc-ASPECTS 5 to 7 and 8 to 10 subgroups. Continuous benefit curves also showed the superior efficacy and safety of EVT over SMT in patients with pc-ASPECTS ≥5. Furthermore, the prognostic effect of onset to puncture time on favorable outcome with EVT was not significant after adjustment for pc-ASPECTS (adjusted odds ratio, 0.98 [95% CI, 0.94-1.02]). CONCLUSIONS: Patients of basilar artery occlusion with pc-ASPECTS ≥5 could benefit from EVT. The baseline pc-ASPECTS appears more important for decision making and predicting prognosis than time to EVT. Registration: URL: http://www.chictr.org.cn. Unique identifier: ChiCTR1800014759.

Effect of Endovascular Treatment Alone vs Intravenous Alteplase Plus Endovascular Treatment on Functional Independence in Patients With Acute Ischemic Stroke: The DEVT Randomized Clinical Trial.

Importance: For patients with large vessel occlusion strokes, it is unknown whether endovascular treatment alone compared with intravenous thrombolysis plus endovascular treatment (standard treatment) can achieve similar functional outcomes. Objective: To investigate whether endovascular thrombectomy alone is noninferior to intravenous alteplase followed by endovascular thrombectomy for achieving functional independence at 90 days among patients with large vessel occlusion stroke. Design, Setting, and Participants: Multicenter, randomized, noninferiority trial conducted at 33 stroke centers in China. Patients (n = 234) were 18 years or older with proximal anterior circulation intracranial occlusion strokes within 4.5 hours from symptoms onset and eligible for intravenous thrombolysis. Enrollment took place from May 20, 2018, to May 2, 2020. Patients were enrolled and followed up for 90 days (final follow-up was July 22, 2020). Interventions: A total of 116 patients were randomized to the endovascular thrombectomy alone group and 118 patients to combined intravenous thrombolysis and endovascular thrombectomy group. Main Outcomes and Measures: The primary end point was the proportion of patients achieving functional independence at 90 days (defined as score 0-2 on the modified Rankin Scale; range, 0 [no symptoms] to 6 [death]). The noninferiority margin was -10%. Safety outcomes included the incidence of symptomatic intracerebral hemorrhage within 48 hours and 90-day mortality. Results: The trial was stopped early because of efficacy when 234 of a planned 970 patients had undergone randomization. All 234 patients who were randomized (mean age, 68 years; 102 women [43.6%]) completed the trial. At the 90-day follow-up, 63 patients (54.3%) in the endovascular thrombectomy alone group vs 55 (46.6%) in the combined treatment group achieved functional independence at the 90-day follow-up (difference, 7.7%, 1-sided 97.5% CI, -5.1% to ∞)P for noninferiority = .003). No significant between-group differences were detected in symptomatic intracerebral hemorrhage (6.1% vs 6.8%; difference, -0.8%; 95% CI, -7.1% to 5.6%) and 90-day mortality (17.2% vs 17.8%; difference, -0.5%; 95% CI, -10.3% to 9.2%). Conclusions and Relevance: Among patients with ischemic stroke due to proximal anterior circulation occlusion within 4.5 hours from onset, endovascular treatment alone, compared with intravenous alteplase plus endovascular treatment, met the prespecified statistical threshold for noninferiority for the outcome of 90-day functional independence. These findings should be interpreted in the context of the clinical acceptability of the selected noninferiority threshold. Trial Registration: Chinese Clinical Trial Registry: ChiCTR-IOR-17013568.

DEVT: A randomized, controlled, multicenter trial of direct endovascular treatment versus standard bridging therapy for acute stroke patients with large vessel occlusion in the anterior circulation - Protocol.

BACKGROUND: Eight randomized controlled trials have consistently shown that endovascular treatment plus best medical treatment improves outcome after acute anterior proximal intracranial large vessel occlusion strokes. Whether intravenous thrombolysis prior to endovascular treatment in patients with anterior circulation, large vessel occlusion is of any additional benefits remains unclear. OBJECTIVE: This study compares the safety and efficacy of direct endovascular treatment versus intravenous recombinant tissue-type plasminogen activator bridging with endovascular treatment (bridging therapy) in acute stroke patients with intracranial internal carotid artery or middle cerebral artery-M1 occlusion within 4.5 h of symptom onset. METHODS AND DESIGN: The DEVT study is a randomized, controlled, multicenter trial with blinded outcome assessment. This trial uses a five-look group-sequential non-inferiority design. Up to 194 patients in each interim analysis will be consecutively randomized to direct endovascular treatment or bridging therapy group in 1:1 ratio over three years from about 30 hospitals in China. OUTCOMES: The primary end-point is the proportion of independent neurological function defined as modified Rankin scale score of 0 to 2 at 90 days. The primary safety measure is symptomatic intracerebral hemorrhage at 48 h and mortality at 90 days. TRIAL REGISTRY NUMBER: ChiCTR-IOR-17013568 (www.chictr.org.cn).

Cold-inducible RNA-binding protein contributes to intracerebral hemorrhage-induced brain injury via TLR4 signaling.

INTRODUCTION: Excessive neuroinflammation aggravates the brain injury caused by intracerebral hemorrhage (ICH), while the upstream mechanisms that initiate neuroinflammation remain unclear. Toll-like receptor 4 (TLR4) signaling is important to trigger inflammatory responses in ICH, and cold-inducible RNA-binding protein (CIRP) has been shown as a novel ligand of TLR4 by recent studies. However, whether the CIRP could trigger the neuroinflammation via activating TLR4 signaling in ICH still needs to be investigated. METHODS: Human serum CIRP levels were measured using the ELISA kits. Western blot, FJB staining, brain water content, and neurological deficit scores were used to investigate the roles of CIRP in brain injury caused by ICH. RESULT: First, we found increased CIRP levels in the blood of patients with ICH when compared to the control individuals, and the ICH patients with mRS > 2 have higher serum CIRP levels in contrast to those with mRS ≤ 2. In the ICH mice, we also found that brain CIRP protein and mRNA levels were also increased after ICH. Furthermore, using the CIRP-/- mice, we found that CIRP-/- mice had less brain damages showing in less FJB+ cells, reduced brain water content (BWC) and lower neurological deficit scores (NDS) compared to that in WT mice after ICH. Cytokines including IL-6, TNF-α, and IL-1ß from CIRP-/- mice were attenuated after ICH. CIRP-/- mice also exhibited reduced TLR4 expression which was accompanied by the decreased activity of NF-κB. This suggests that TLR4 signaling might be involved in CIRP-mediated inflammatory injury possibly via NF-κB activation after ICH. CONCLUSION: Our findings suggest that CIRP may activate TLR4 signaling, and further inducing NF-κB activation to increase the expression levels of cytokines and aggravate inflammatory injury in ICH. Targeting CIRP may be a promising strategy for ICH treatment.

Efficacy and safety of rescue stenting following failed mechanical thrombectomy for anterior circulation large vessel occlusion: propensity score analysis.

PURPOSE: To evaluate the effectiveness and safety of rescue stenting (RS) after failed mechanical thrombectomy (MT) for patients with large artery occlusion in the anterior circulation. METHODS: Consecutive patients who experienced failed reperfusion and subsequently did or did not undergo RS at 16 comprehensive stroke centers were enrolled from January 2015 to June 2018. Propensity score matching was used to achieve baseline balance between the patient groups. Symptomatic intracranial hemorrhage (sICH) at 48 hours and the modified Rankin Scale scores and mortality at 3 months in the two groups were compared. RESULTS: A total of 90 patients with RS and 117 patients without RS after failed MT were enrolled. Propensity score matching analysis selected 132 matched patients. The good outcome rate was significantly higher in matched patients with RS than in those without RS (36.4% vs 19.7%, p=0.033), whereas the sICH (13.6% vs 21.2%, p=0.251) and mortality (31.9% vs 43.9%, p=0.151) were not significantly different between the groups. CONCLUSIONS: RS seems to be an effective safe choice for patients with large vessel occlusion of the anterior circulation who underwent failed MT.

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.

Angioplasty and stenting for severe symptomatic atherosclerotic stenosis of intracranial vertebrobasilar artery.

This retrospective study is to investigate the safety and efficacy of the stent implanting for treating severe symptomatic atherosclerotic stenosis of the intracranial vertebrobasilar artery (ICVBA). 213 patients who had undergone intervention for severe symptomatic ICVBA stenosis between September 2012 to May 2018 were enrolled into this study. Among the 213 enrolled patients, 210 patients (98.6%) obtained successfully revascularization and 206 patients (96.7%) had good revascularization after stenting. The extent of stenosis before and after intervention was 86.3 ±â€¯6.8% and 9.1 ±â€¯3.7%, respectively. Within 90 days after stenting, 10 patients (4.7%) experienced primary endpoint events, including 4 cases (4.2%) in the intracranial vertebral artery (V4) group and 6 (5.1%) in basilar artery (BA) group. Among them, 2 (2.1%) and 3 cases (2.5%) of ischemic stroke in V4 and BA group, respectively; and 2 (2.1%) and 2 (1.7%) cases of TIA in V4 and BA group, respectively. One (0.8%) case in the BA group dead because of the acute stent occlusion resulted in the top of the basilar syndrome. Six patients (2.8%) experienced adverse events, including 2 (2.1%) and 4 (3.4%) cases of groin hematoma in the V4 and BA group, respectively. No cases of hemorrhagic stroke, stent dislocation and vessel dissection in both groups. Our study showed that a low complication rate and a high and good revascularization rate would be achieved by the treatment of severe symptomatic atherosclerotic stenosis of the ICVBA using the stents.

Wall enhancement ratio determined by vessel wall MRI associated with symptomatic intracranial aneurysms.

PURPOSE: To study the association of the enhancement ratio (ER) of aneurysmal wall enhancement (AWE) with symptomatic intracranial aneurysms (IAs), we hypothesized that the ER of AWE would be stronger in symptomatic IAs than in asymptomatic IAs, as assessed by high-resolution magnetic resonance imaging (HRMRI). MATERIALS AND METHODS: Between February 2016 and February 2018, 80 consecutive patients with 89 unruptured IAs were reviewed. Patients and IAs were divided into symptomatic and asymptomatic groups. In addition to the clinical characteristics, the IA features (e.g., size, shape) were evaluated via computed tomography angiography, while the ER and enhanced patterns were evaluated by HRMRI. Multiple logistic regression analysis was performed to determine the independent risk factors for symptomatic IAs. Receiver operating characteristic curve analysis was used for the final model to obtain the optimal thresholds. RESULTS: Multiple logistic regression analysis indicated that only the ER was associated with symptomatic IAs. The threshold value of the ER was 60.5%. CONCLUSIONS: A higher ER was more frequently identified in symptomatic IAs. More attention should be paid to this factor in the management of IAs.

Wall enhancement ratio and partial wall enhancement on MRI associated with the rupture of intracranial aneurysms.

OBJECTIVES: To evaluate the risk factors for rupture of intracranial aneurysms (IAs) using high resolution MRI (HRMRI). METHODS: 91 consecutive patients with 106 IAs were reviewed from February 2016 to April 2017. Patients and IAs were divided into ruptured and unruptured groups. In addition to the clinical characteristics of the patients, the features of IAs (eg, shape) were evaluated by CT angiography, whereas wall thickness, enhanced patterns, and enhancement ratio (ER) were evaluated by MRI. Multiple logistic regression analysis was used to identify independent risk factors associated with the rupture of IAs. Receiver operating characteristic curve analysis was performed on the final model, and the optimal thresholds were obtained. RESULTS: ER (OR 6.638) and partial wall enhancement (PWE) (OR 6.710) were not markers of aneurysms more prone to rupture, but simply were more commonly found in the ruptured aneurysm cohort. The threshold value for ER was 61.5%. CONCLUSIONS: ER (≥61.5%) and IAs with PWE are better predictors of rupture. Increased attentions should be paid to these factors during assessment of IA rupture.

Clinical significances and features of prompt brain CT scan after intracranial artery stenting: analysis of 501 cases.

Cerebral hemorrhage is a serious complication of intracranial artery stenting that could be fatal without timely identification and treatment. Prompt brain CT scan would help to evaluate whether cerebral hemorrhage occurs, however, the diverse features of the CT scan immediately after stenting could influence the judgement sometimes. Therefore, we analyzed and summarized these features to help to determine the clinical significance of these CT features. The prompt CT features after stenting were classified into three types. Type I indicates that no high-density shadows. Type II indicates that high-density shadows scattered in the infarct areas and/or subarachnoid spaces without mass effect. Type III indicates high-density shadows scattered in and/or out of the infarct areas and/or subarachnoid space with obvious mass effects. Based on this classification, the patients in both Type I and II would continue the double anti-platelet treatment (DAPT) and anti-coagulation treatment, while the later need closer monitoring. However, patients in Type III must immediately withdraw the DAPT and anti-coagulation treatment with close monitoring and surgical intervention was needed when necessary. Nineteen (3.79%) patients were classified into Type III, and 5 (1.00%) of the 19 were accepted surgical intervention. Two of these patients died (0.40%). The prompt CT scan timely distinguishing the cerebral hemorrhage was necessary after intracranial artery stent angioplasty. Additionally, based on the different prompt CT features to take different therapeutic strategies after stenting would achieve better outcomes for ischemic stroke or transient ischemic stroke (TIA) patients underwent intracranial artery endovascular therapy.

Safety and Efficacy of Wingspan Stenting for Severe Symptomatic Atherosclerotic Stenosis of the Middle Cerebral Artery: Analysis of 278 Continuous Cases.

OBJECTIVE: Our objective is to investigate the safety and long-term efficacy of the Wingspan stent (Boston Scientific, Natick, MA, USA) for treating severe atherosclerotic stenosis of the middle cerebral artery (MCA). METHODS: A total of 278 consecutive patients from our stroke database with clinical symptoms within the prior 90 days and intracranial atherosclerotic stenosis of 70% or above of the MCA were enrolled in this study between September 2012 and November 2014, and these patients were followed until the end of June 2015. The endpoint events included any stroke or death within 30 days after stenting and any subsequent ipsilateral ischemic stroke. RESULTS: Among the 278 enrolled patients, 277 patients (99.6%) successfully underwent stenting. The mean rate of stenosis decreased from 82.5 ± 7.9% to 9.0 ± 3.2% following treatment. Within 30 days after stenting, 12 patients (4.3%) experienced endpoint events, including 8 cases (2.9%) of hemorrhagic stroke and 4 cases (1.4%) of ischemic stroke; 2 perioperative deaths occurred. During 8-33 months of follow-up, 19 patients developed endpoint events. The 1- and 2-year endpoint event rates were 5.8% (95% confidence interval [CI], 5.0%-15.7%) and 7.2% (95% CI, 4.3%-10.1%), respectively. CONCLUSIONS: From this study, we can conclude that the treatment of severe symptomatic atherosclerotic stenosis of the MCA using the Wingspan stent was safe and effective and that the long-term stroke recurrence rate after stenting was low.

Association of CYP2C19 Polymorphisms with the Clinical Efficacy of Clopidogrel Therapy in Patients Undergoing Carotid Artery Stenting in Asia.

The CYP2C19 gene plays a detrimental role in the metabolism of clopidogrel. This study aimed to investigate the association between CYP2C19 polymorphisms and the clinical efficacy of clopidogrel therapy in patients who have undergone carotid artery stenting (CAS). CYP2C19 genotype screening was performed on 959 ischemic stroke patients. Of these patients, 241 who had undergone CAS were enrolled in the study. They were all followed up for 1 year after stent surgery, and the primary clinical end-points were ischemic events. The frequencies of the CYP2C19*2 and *3 alleles among the 959 patients were 31.80% and 5.06%, respectively. Regarding the 241 participants who had undergone CAS, multivariate Cox regression analysis showed that the CYP2C19 loss-of-function (LOF) alleles (*2 and *3) were risk factors for post-CAS prognosis. Within 1 year of follow-up, the patients carrying the CYP2C19 LOF alleles were more likely to experience ischemic events than those carrying none. The occurrence of ischemic events did not significantly differ between the *2 and *3 allele carriers. Our results suggest that CYP2C19 LOF alleles (*2 and *3) significantly impact the prognosis of patients on clopidogrel therapy after CAS and that the CYP2C19*2 and CYP2C19*3 alleles have the same effects on prognosis.

Critical contribution of adenosine A2A receptors in bone marrow-derived cells to white matter lesions induced by chronic cerebral hypoperfusion.

Adenosine A2A receptors (A2ARs) in distinct cellular types may exert different and even opposite effects on many neurologic disorders; A2ARs in bone marrow-derived cells (BMDCs) have been shown to play important roles in various brain injuries. We previously showed that global A2AR inactivation aggravates chronic cerebral hypoperfusion-induced white matter lesions (WMLs); however, the specific cell populations responsible for A2AR-mediated signaling remain unknown. In the present study, we developed chimeric mice in which A2ARs were either selectively inactivated or reconstituted in BMDCs by transplanting bone marrow from global A2AR gene knockout or wild-type mice into wild-type or gene knockout mice, respectively. Chimeric mice were subsequently subjected to chronic cerebral hypoperfusion by bilateral common carotid artery stenosis, and the effects of BMDC A2ARs on WMLs were evaluated. The selective inactivation of A2AR in BMDCs aggravated chronic cerebral hypoperfusion-induced WMLs, promoted microglial activation, and increased proinflammatory cytokine expression, whereas the selective reconstitution or activation of A2AR in BMDCs using the agonist CGS21680 produced the opposite effects. These results demonstrate that A2ARs in BMDCs are important modulators of WMLs induced by chronic cerebral hypoperfusion; this modulation might be associated with the regulation of inflammatory cytokine production.

Fractalkine promotes chemotaxis of bone marrow-derived mesenchymal stem cells towards ischemic brain lesions through Jak2 signaling and cytoskeletal reorganization.

The fractalkine (FKN)-CX3CR1 (FKN receptor) axis reportedly plays an important role in the progression of many neural pathologies. However, its role in the recruitment of bone marrow-derived progenitor cells for neurogenesis remains elusive. The chemokine-based mechanism underlying the migration of bone marrow-derived mesenchymal stem cells (BMSCs) was investigated in a double-chamber transmigration model with recombinant FKN and endogenous FKN extract, and the results confirmed the involvement of FKN in migration. This chemotactic response was CX3CR1-dependent and FKN-sensitive. Western blotting, immunoprecipitation and transmigration assays revealed that the Janus kinase (Jak)2-signal transducer and activator of transcription (Stat)5α-extracellular signal-related kinase (ERK)1/2 pathway was activated by FKN. Confocal laser scanning microscopy was used to demonstrate cytoskeletal reorganization caused by remodeling of the surface receptor integrin α5ß1, intracellular phosphorylation of Fak and Pax, and upregulation of intercellular adhesion molecule-1 during BMSC migration. Moreover, significant inhibition of signaling and migration was detected after treatment of cells with Jak2-interfering RNA or the antagonist AG490. In addition, the results of a fluorescence immunohistochemical analysis of an in vivo chemotactic model, developed via transplantation of BMSCs into transient middle cerebral artery-occluded rats, were consistent with the in vitro results. These findings suggest that FKN activates Jak2-Stat5α-ERK1/2 signaling through CX3CR1, thereby triggering integrin-dependent machinery reorganization to allow chemotactic migration of BMSCs towards an ischemic cerebral lesion.

Novel Approaches in Evaluating and Predicting the Potential Benefit of Middle Cerebral Artery Angioplasty & Stenting.

OBJECTIVE: Our aim was to investigate a novel approach to perform preoperative evaluation patients who underwent middle cerebral artery (MCA) percutaneous transluminal angioplasty and stenting (PTAS). METHOD: Sixty-five patients with symptomatic MCA stenosis of at least >70% who underwent MCA PTAS were enrolled. The multimodal stroke assessment using CT (MOSAIC) score was used to evaluate the preoperative condition. The Alberta Stroke Program Early Computed Tomography Scoring (ASPECTS) was used to assess the time-to-peak (TTP) parameter of Computer tomography perfusion (CTP). The factors potentially improving TTP following stenting were investigated. The prognostic value of the MOSAIC scores to predict TTP improvement was analyzed and compared. RESULTS: The MOSAIC score was a reliable prognostic tool for the degree of improvement of TTP (odds ratio 1.89 [1.08-2.07], P < .01) in patients with PTAS. The MOSAIC score had a higher prognostic accuracy than the degree of CBF deficit, the degree of stenosis, and the amount of tissue infarction. During 1-year follow-up, the stroke and death rate of was 8.1%, the in-stent restenosis rate was 6.5%, and good final outcome (modified Rankin Scale ≤ 2) was observed in 76.9%. CONCLUSIONS: The MOSAIC score can be reliably used in selecting patients with MCA stenosis for PTAS.

Effects of ultrasound-combined microbubbles on hippocampal AchE fibers in rats.

OBJECTIVE: To investigate the protective effect of ultrasound-combined microbubbles on hippocampal acetylcholinesterase (AchE) fibers in rats. METHODS: According to random digits table, 60 SD rats were divided into two groups, marrow stromal cells (MSCs) intracranial transplantation group and MSCs intracranial transplantation + ultrasonic microbubbles group. Marrow stromal cells were cultivated and isolated in vitro; 12 weeks after transplantation, spatial learning and memorizing abilities of rats were assessed by Morris water maze; AchE staining method was used to observe changes in density and appearance of AchE staining positive fibers in hippocampal CA1 region. RESULTS: There was a significant increase in spatial learning and memorizing abilities of rats in MSCs intracranial transplantation + ultrasonic microbubbles group. Hippocampal AchE staining suggested an increase in the density of AchE staining positive fibers in MSCs intracranial transplantation group; the fibers were regular, intact and dense. Density of hippocampal AchE positive fibers was negatively correlated with the escape latent period and was positively correlated with percentage of the time needed to cross each platform quadrant. CONCLUSIONS: Better promotion of spatial learning and memorizing abilities of rats in MSCs intracranial transplantation + ultrasonic microbubbles group may be related with the protective effect of ultrasound-combined microbubbles on hippocampal acetylcholine fibers.

Ultrasound-microbubble transplantation of bone marrow stromal cells improves neurological function after forebrain ischemia in adult mice.

In this study, bone marrow stromal cells (MSCs) were transplanted into the brain of adult rats after forebrain ischemia induced by 4VO. SD rats (n = 60) were randomly divided into three groups: (I) rats (n = 20) were subjected to 4VO and transplanted with MSCs into the ischemic region using ultrasound-microbubble method, (2) rats (n = 20) were subjected to 4VO and transplanted with MSCs into the ischemic region (n = 20), and (3) 4VO alone (n = 20). Rats were sacrificed 28 days after treatment. Neurological functions of rats were evaluated by Morris Water Maze. The current findings suggest that the ultrasound microbubble transplanted MSCs survived in the ischemic brain and significantly improved functional recovery of adult rats compared to regular transplantation.