Characteristics of cerebral ischemic stroke based on moyamoya disease and atherosclerosis-associated intracranial arterial stenosis.

PURPOSE: To analyze the characteristics of acute ischemic stroke (AIS) resulting from moyamoya disease (MMD) and intracranial large artery atherosclerotic stenosis (LAS). METHOD: This real-world case control study enrolled imaging-confirmed AIS patients owing to MMD or LAS hospitalized from January 2015 through September 2020 consecutively. The features of risk factors, peripheral blood, and imaging presentations were compared between the two cohorts. RESULTS: A total of 191 eligible patients entered into final analysis, including 70 cases with MMD stroke and 121 with LAS stroke. LAS stroke vs. MMD stroke, the ratios of hyperlipidemia, hypertension, diabetes, and hyperhomocysteinemia were higher in the former (65.3 vs.12.9%, 65.3% vs. 4.3%, 39.7% vs. 2.9%, and 43.8% vs.12.9%; all p < 0.01) as well as baseline plasma arachidonic acid (AA) and adenosine diphosphate (ADP)-stimulated maximum platelet aggregation rates (75.3% vs. 60.8% and 73.1% vs.64.9%, respectively, all p < 0.01), which were positively correlated with triglycerides and cholesterol levels, blood glucose, age, and platelet counts (all p < 0.01). Classical watershed infarction (WSI) accounted for 87.14% in MMD stroke and 40.49% in LAS stroke, respectively (p < 0.01). Almost all of the patients with LAS showed plaques in arterial walls on CTA maps and non-homogeneous thickening with irregular luminal narrowing on HRMRI, while plaques were seldom found in MMD besides homogeneous thickening with regular luminal narrowing. CONCLUSIONS: Differing from LAS stroke, MMD stroke mainly presents with WSI and does not feature with platelet hyper-aggregation and fragmentation of ulcer plaque. Whereby, focusing on perfusion improvement rather than antiplatelets and statins may be the predominant step in MMD-stroke correction.

CDK4/6 inhibition suppresses tumour growth and enhances the effect of temozolomide in glioma cells.

In adults, glioma is the most commonly occurring and invasive brain tumour. For malignant gliomas, the current advanced chemotherapy includes TMZ (temozolomide). However, a sizeable number of gliomas are unyielding to TMZ, hence, giving rise to an urgent need for more efficient treatment choices. Here, we report that cyclin-dependent kinases 4 (CDK4) is expressed at significantly high levels in glioma cell lines and tissues. CDK4 overexpression enhances colony formation and proliferation of glioma cells and extends resistance to inhibition of TMZ-mediated cell proliferation and induction of apoptosis. However, CDK4 knockdown impedes colony formation and cell proliferation, and enhances sensitivity of glioma cells to TMZ. The selective inhibition of CDK4/6 impedes glioma cell proliferation and induces apoptotic induction. The selective inhibitors of CDK4/6 may enhance glioma cell sensitivity to TMZ. We further showed the possible role of RB phosphorylation mediated by CDK4 for its oncogenic function in glioma. The growth of glioma xenografts was inhibited in vivo, through combination treatment, and corresponded to enhanced p-RB levels, reduced staining of Ki-67 and enhanced activation of caspase 3. Therefore, CDK4 inhibition may be a favourable strategy for glioma treatment and overcomes TMZ resistance.

Lestaurtinib potentiates TRAIL-induced apoptosis in glioma via CHOP-dependent DR5 induction.

Lestaurtinib, also called CEP-701, is an inhibitor of tyrosine kinase, causes haematological remission in patients with AML possessing FLT3-ITD (FLT3 gene) internal tandem duplication and strongly inhibits tyrosine kinase FLT3. Treatment with lestaurtinib modulates various signalling pathways and leads to cell growth arrest and programmed cell death in several tumour types. However, the effect of lestaurtinib on glioma remains unclear. In this study, we examined lestaurtinib and TRAIL interactions in glioma cells and observed their synergistic activity on glioma cell apoptosis. While U87 and U251 cells showed resistance to TRAIL single treatment, they were sensitized to apoptosis induced by TRAIL in the presence of lestaurtinib because of increased death receptor 5 (DR5) levels through CHOP-dependent manner. We also demonstrated using a xenograft model of mouse that the tumour growth was absolutely suppressed because of the combined treatment compared to TRAIL or lestaurtinib treatment carried out singly. Our findings reveal a potential new strategy to improve antitumour activity induced by TRAIL in glioma cells using lestaurtinib through a mechanism dependent on CHOP.

Progress in moyamoya disease.

Moyamoya disease is characterized by progressive stenosis or occlusion of the intracranial portion of the internal carotid artery and their proximal branches, resulting in ischemic or hemorrhagic stroke with high rate of disability and even death. So far, available treatment strategies are quite limited, and novel intervention method is being explored. This review encapsulates current advances of moyamoya disease on the aspects of epidemiology, etiology, clinical features, imaging diagnosis and treatment. In addition, we also bring forward our conjecture, which needs to be testified by future research.

Obstructive Sleep Apnea before Ischemic Stroke: Clinical Relevance to Infarction Volume and Neurological Recovery.

BACKGROUND: Obstructive sleep apnea (OSA) is a probable risk factor with speculative roles in the induction or aggravation of acute ischemic stroke (AIS). METHODS: The association between OSA and AIS severity was retrospectively analyzed using clinical data of first-onset AIS patients, admitted to our hospital between January 2013 and September 2016. Eligible patients were categorized based on the presence of OSA prior to stroke. Stroke severity and functional outcomes were evaluated using the National Institute of Health Stroke Severity Scale (NIHSS) and the modified Rankin scale (mRS), respectively. RESULTS: No significant differences were observed among OSA and non-OSA groups for infarction volume, NIHSS at admission and discharge, or mRS at discharge and at the 3-month follow-up (all P > .05). OSA prior to stroke negatively correlated with infarction volume (P = .008), NIHSS at discharge (P = .006), and the 3-month mRS (P = .015). In addition to OSA, it was also found that infarction volume significantly correlated with large artery occlusion (LAO), anterior circulation involvement, neutrophil count, and fibrinogen level; NIHSS at discharge significantly correlated with LAO, transient ischemia attack (TIA), neutrophil count, and thrombolysis; and the 3-month mRS significantly correlated with LAO, TIA, age, neutrophil count, and thrombolysis. CONCLUSIONS: OSA before AIS does not increase the severity of stroke. The negative association between OSA and infarction volume, stroke severity, and clinical outcomes suggests an endogenous neuroprotective effect.

[Keap1-tat peptide attenuates oxidative stress damage in hippocampal CA1 region and learning and memory deficits following global cerebral ischemia].

OBJECTIVE: To design Keap1-tat peptide and explore its neuroprotective role on hipocampal CA1 neuron, as well as the effect on spacial learning and memory function following global cerebral ischemia. METHODS: Adult male Sprague Dawley (SD) rats were subjected to global cerebral ischemia (GCI) by four-vessel occlusion for 15 min and randomly divided into five groups: sham, sham+Keap1-tat, ischemia/reperfusion (I/R), Keap1-tat peptide- and vehicle-administrated groups. For Keap1-tat or vehicle groups, the rats were treated with Keap1-tat (30, 50, 100 µg in 5 µL 0.9% saline) or the same volume vehicle by intracerebroventricular injection (icv) 30 min prior to ischemia. Cresyl violet staining was used to observe the surviving neurons and 4-hydroxy-2-noneal (4-HNE) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) immunostaining were used to detect the change of markers response to oxidative stress in hippocampal CA1 region. The spatial learning and memory function of the rats was evaluated using Morris water maze. RESULTS: Compared with sham group, the number of surviving neurons in ischemia-reperfusion and vehicle groups significantly decreased in the hippocampal CA1 region (P<0.05), while administration of Keap1-tat significantly decreased the damage following GCI (P<0.05), and the dose of 50 µg existed the most effective neuroprotective role. Furthermore, immunostaining intensity of 4-HNE and 8-OHdG, markers of oxidative stress damage attenuated by Keap1-tat peptide as compared with vehicle group in CA1 region. Of significant interest, the time of finding underwater platform in Keap1-tat group animals was significantly short, and after removing the platform, the probe time of Keap1-tat group animals in the original quadrant where the platform was significantly increased compared with that of vehicle and I/R group animals (P<0.05). CONCLUSION: Keap1-tat peptide can effectively attenuate neuronal damage in hippocampal CA1 region and improve learning and memory function, which might bedue to the attenuation of oxidative stress caused by GCI.

Remote ischemic conditioning for the treatment of ischemic moyamoya disease.

AIMS: This study investigated the safety and efficacy of remote ischemic conditioning (RIC) on ameliorating the sequelae of ischemic moyamoya disease (iMMD). METHODS: A total of 30 iMMD patients underwent long-term RIC and were followed up at 0.5, 1, and 2 years for clinical outcomes, including frequency of stroke recurrence, Patient Global Impression of Change (PGIC) scale, peak systolic velocities (PSV), and cerebral perfusion. RESULTS: During the whole RIC treatment process, no RIC-related adverse event occurred. Only one of 30 patients suffered a onetime infarction (3.3%), and the ratios of acceptable PGIC were 88.2%, 64.3%, and 92.3% at 0.5, 1, and 2 years follow-up. Kaplan-Meier analysis showed the frequency of stroke recurrence was significantly reduced after RIC (P = .013). The frequency of TIA per week was 1.1 (0.6, 2.8) prior to RIC and 0.1 (0.0, 0.5) post-RIC (P < .01). Compared to baseline, PSV values were significantly reduced after RIC treatment (P = .002 at 0.5, P = .331 at 1, and P = .006 at 2 years). In patients undergoing perfusion studies, 75% obtained improvement on followed-up SPECT and 95% on followed-up PET maps. CONCLUSIONS: Remote ischemic conditioning may be beneficial on controlling iMMD-induced ischemic events, relieving symptoms, and improving cerebral perfusion, without incidence of complications in this case series.

Impact of seasonal variations on the first ischemic events in patients with moyamoya disease.

OBJECTIVES: This retrospective study aimed to explore the impact of seasonal variations on the first ischemic events in patients with moyamoya disease (MMD). PATIENTS AND METHODS: Based on the first-time ischemic event occurrence, 113 patients, including 84 with cerebral infarction and 29 with transient ischemic attack, who were diagnosed with ischemic MMD were divided into four groups: spring (March-May), summer (June-August), autumn (September-November) and winter (December-February). The incidence of cerebral infarction was considered as the primary parameter. The impact of seasonal variations on the occurrence of cerebral infarction was analyzed by Poisson regression model and seasonal analysis. RESULTS: When summer was set as the reference, patients in summer were more significantly susceptible to develop cerebral infarction as compared with spring (IRR, 0.529, 95%CI, 0.299-0.937, p = 0.03), autumn (IRR, 0.441, 95%CI, 0.240-0.810, p < 0.01) and winter (0.500, 95%CI, 0.279-0.895, p = 0.02). The seasonality of the time series in summer (1.231) was substantially higher than that in the other three seasons (-0.269 in spring, -0.656 in autumn and -0.306 in winter). No discrepancy in either NIHSS or mRS scores at admission was observed among the four seasons. CONCLUSION: Patients with MMD may be more vulnerable to cerebral infarction in summer compared with the other three seasons, and seasonal onset of cerebral infarction does not seem to be associated with the severity of neurological disability at admission.

Advances in chronic cerebral circulation insufficiency.

Chronic cerebral circulation insufficiency (CCCI) may not be an independent disease; rather, it is a pervasive state of long-term cerebral blood flow insufficiency caused by a variety of etiologies, and considered to be associated with either occurrence or recurrence of ischemic stroke, vascular cognitive impairment, and development of vascular dementia, resulting in disability and mortality worldwide. This review summarizes the features and recent progress of CCCI, mainly focusing on epidemiology, experimental research, pathophysiology, etiology, clinical manifestations, imaging presentation, diagnosis, and potential therapeutic regimens. Some research directions are briefly discussed as well.

Safety and efficacy of remote ischemic conditioning in pediatric moyamoya disease patients treated with revascularization therapy.

BACKGROUND: Revascularization surgery has been the standard treatment to prevent ischemic stroke in pediatric Moyamoya disease (MMD) patients with ischemic symptoms. However, perioperative complications, such as hyperperfusion syndrome, new infarct on imaging, or ischemic stroke, are inevitable. Remote ischemic conditioning (RIC) is a noninvasive and easy-to-use neuroprotective strategy, and it has potential effects on preventing hyperperfusion syndrome and ischemic infarction. AIMS: The aim of this study is to investigate the safety and efficacy of RIC in pediatric MMD patients undergoing revascularization surgery. METHOD: A total of 60 pediatric MMD patients with one or more ischemic symptoms will be recruited and allocated in 1:1 ratio to the RIC group and sham group, respectively. Both RIC and sham RIC will be performed twice daily for 7 consecutive days before revascularization surgery with different cuff pressures during the ischemia period (50 mmHg over-systolic blood pressure and 30 mmHg). Single photon emission computed tomography will be performed within 7 days preoperatively and 3 months postoperatively, respectively, to evaluate the cerebral perfusion status. Other outcomes, including safety, plasma biomarker, functional outcome, and the incidence of infarction and its size, will also be evaluated. CONCLUSION: This study will provide insights into the preliminary proof of principle, safety, and efficacy of RIC in pediatric MMD patients undergoing revascularization surgery therapy, and this data will provide parameters for future larger scale clinical trials if efficacious.