Classification of Glioblastoma Associated with Immune Checkpoints and Tumor Microenvironment based on Immunogenomic Profiling.

BACKGROUND: Immune microenvironment is involved in tumor initiation and progression, and its effect on glioblastoma (GBM) is still unknown. OBJECT: We sought to investigate the association between immune status and GBM. METHODS: Transcriptome data and the relevant clinical data were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus (GEO) databases, and we identified two immune subtypes based on 29 immune-associated gene sets. RESULTS: Through single-sample gene set enrichment analysis (ssGSEA), we found that the high-immunity subtype had the most tumor-infiltrating immune cells and immune checkpoint molecules in GBM patients. Furthermore, we could more effectively identify immune signature pathways in GBM. CONCLUSION: After validation with the GEO dataset, we conclude that the identified GBM high-immune subtypes may be amenable to the application of novel immune therapy for GBM.

Novel Immune-Related LncRNA Pairs are Associated with Immunol Infiltration and Survival Status in Glioblastoma.

Background: Immune-related lncRNA is involved in tumor initiation and progression, while its effect in glioblastoma (GBM) is still unknown. Objective: We sought to investigate the association between immune-related lncRNA (ir-lncRNA) and GBM. Methods: Transcriptomic and clinical data were obtained from the TCGA dataset, and we found 2008 ir-lncRNA differentially expressed between GBM and adjacent brain tissues. Results: Appling the univariate Cox and Lasso regression model, we found 30 prognosis-related ir-lncRNA pairs to construct a Cox regression risk model to associate the outcome of GBM patients. Furthermore, with this risk model, we can identify the tumor immune infiltration status, the expression of immunosuppressive biomarkers, and chemical sensitivity in GBM patients. Conclusions: We constructed an immunologic risk model with lncRNA to associate the survival outcome of GBM patients, which can provide useful biomarkers.

Blood-Brain Barrier Dysfunction and the Potential Mechanisms in Chronic Cerebral Hypoperfusion Induced Cognitive Impairment.

Chronic cerebral hypoperfusion (CCH) is a major cause of vascular cognitive impairment and dementia (VCID). Although the underlying mechanisms have not been fully elucidated, the emerging data suggest that blood-brain barrier (BBB) dysfunction is one of the pivotal pathological changes in CCH. BBB dysfunction appears early in CCH, contributing to the deterioration of white matter and the development of cognitive impairment. In this review, we summarize the latest experimental and clinical evidence implicating BBB disruption as a major cause of VCID. We discuss the mechanisms of BBB dysfunction in CCH, focusing on the cell interactions within the BBB, as well as the potential role of APOE genotype. In summary, we provide novel insights into the pathophysiological mechanisms underlying BBB dysfunction and the potential clinical benefits of therapeutic interventions targeting BBB in CCH.

Associations of Abdominal Visceral Fat Content and Plasma Adiponectin Level With Intracranial Atherosclerotic Stenosis: A Cross-Sectional Study.

Background: Abdominal obesity and adipocytokines are closely related to atherosclerosis, and adiponectin level is considered one of the important clinical indicators. This study aimed to analyze the associations of abdominal visceral fat content and adiponectin level with intracranial atherosclerotic stenosis (ICAS). Methods: A total of 186 patients were enrolled in this study. Patients were distributed into ICAS and non-ICAS by the degree of artery stenosis. Plasma adiponectin levels and the ratio of visceral adipose tissue (VAT) to subcutaneous adipose tissue (SAT) were measured. The related factors of intracranial atherosclerotic stenosis were determined using multivariable logistic regression analysis. Results: The VAT/SAT ratio (OR, 26.08; 95% CI, 5.92-114.83; p < 0.001) and adiponectin (OR, 0.61; 95% CI, 0.44-0.84; p = 0.002) were found to be the independent predictors of ICAS in a multivariable logistic regression analysis. The prevalence of ICAS increased (T1: 27.4%; T2: 50.0%; T3: 75.8%) as the VAT/SAT ratio tertile increased (p < 0.001). The prevalence of ICAS decreased (T1: 72.6%; T2: 54.8%; T3: 25.8%) as the adiponectin tertile increased (p < 0.001). In ROC curves analysis, VAT/SAT ratio had a sensible accuracy for the prediction of ICAS. The optimal cut-off value of VAT/SAT ratio to predict ICAS in this study was 1.04 (AUC: 0.747; p < 0.001; sensitivity: 67.4%; specificity: 74.7%). The optimal adiponectin cutoff was 3.03 ug/ml (AUC: 0.716; p < 0.001; sensitivity:75.8%; specificity: 61.5%). Conclusion: Higher VAT/SAT ratio and lower plasma adiponectin levels were closely related to the increased risk of intracranial atherosclerotic stenosis.

MRI-guided thrombolysis for lenticulostriate artery stroke within 12 h of symptom onset.

Stroke thrombolysis treatment is generally administered within 4.5 h, but a greater time window may be permitted depending upon the ischemic penumbra on neuroimaging. This observational cohort study investigated the outcomes of thrombolysis given within 12 h after symptom onset of lenticulostriate artery stroke. The population comprised 160 patients. Thrombolysis was administered via tissue plasminogen activator, alteplase (TPA). Thrombolysis was indicated by a mismatch between diffusion-weighted imaging (DWI) and T2-weighted imaging (T2WI), that is, an acute ischemic lesion on DWI without a corresponding lesion on T2WI. Demographics and medical history were compared with the modified Rankin scale (mRS) score, to reflect outcome. Patients with a favorable clinical outcome (mRS 0-1) had significantly lower hypertension, baseline NIH Stroke Scale (NIHSS) score, and admission systolic/diastolic blood pressure compared with patients with mRS 2-6. Lower admission systolic blood pressure and NIHSS score were significantly associated with favorable outcome. In patients either with IV-TPA within 4.5 h, or between 4.5 and 12 h, lower admission systolic blood pressure and/or NIHSS score similarly independently predict favorable outcome. However, in all groups, the onset-to-treatment time did not significantly influence the outcomes. We conclude that in our cohort higher admission systolic blood pressure and higher baseline NIHSS and not time were associated with poor outcome in patients with magnetic resonance-guided thrombolysis within 12 h of isolated lenticulostriate artery stroke, therefore loosening the traditionally perceived dependency of outcome on time.

Effectiveness and Predictors of Poor Prognosis Following Intravenous Thrombolysis in Patients with Wake-Up Ischemic Stroke Guided by Rapid MRI.

PURPOSE: Our aim was to investigate the effectiveness and predictors of poor prognosis in WUIS patients who received alteplase thrombolysis under the guidance of diffusion-weighted imaging (DWI)-T2-weighted imaging (T2WI) mismatch. PATIENTS AND METHODS: We recruited patients within 4.5 h of acute ischemic stroke (AIS) and WUIS patients with uncertain onset times from two stroke centers. To evaluate effectiveness, we compared National Institutes of Health Stroke Scale (NIHSS) scores between the two groups at admission and at 24 h, 3 days, and 1 week thereafter. We also compared the two groups with respect to the modified Rankin Scale (mRS) score at 90 days after thrombolysis. The WUIS patients were divided into a favorable prognosis group (mRS score: 0-1 points) and a poor prognosis group (mRS score ≥2 points). Data were compared between the two subgroups to identify factors that influence poor prognoses. The receiver operating characteristic (ROC) curve was used to evaluate the predictive value of factors related to poor prognosis. RESULTS: A total of 114 patients with WUIS and 316 patients with AIS were enrolled in the study. There were no significant differences between the two groups in terms of NIHSS or 90-day mRS scores (p > 0.05). Baseline NIHSS score (odds ratio [OR] = 1.490, 95% confidence interval [CI] 1.248-1.779, p < 0.001) and atrial fibrillation (OR = 3.825, 95% CI 1.218-12.016, p = 0.022) were identified as independent predictors of poor prognosis following thrombolysis in WUIS patients. The combined ROC diagnosis of these two variables had an area under the curve of 0.850. CONCLUSION: The DWI-T2WI sequence is an effective method to guide intravenous thrombolytic therapy for WUIS. Baseline NIHSS score and atrial fibrillation were identified as independent predictors of poor prognosis following thrombolysis in WUIS patients.

Neonatal microglia and proteinase inhibitors-treated adult microglia improve traumatic brain injury in rats by resolving the neuroinflammation.

Microglia participate in the regulation of neuroinflammation caused by traumatic brain injury (TBI). This research aimed to explore the repair effects of intracranial injection of neonatal microglia or protease-treated adult microglia on TBI in rat model. Lateral fluid percussion injury was used to establish rat brain injury model. E64 and serpinA3N were employed for the treatment of adult microglia. Cleaved caspase-3 level was analyzed through immunoblotting assay. Enzyme-linked immunosorbent assay was employed to analyze cytokine and chemokine levels. Astrocytosis and microgliosis were shown by immunofluorescence. The cognitive function of rats was analyzed by water maze. The injection of neonatal microglia inhibited cell apoptosis, reduced astrocytosis and microgliosis, decreased the level of chemokines and cytokines in cortex and ipsilateral hippocampus, and improved cognitive function of TBI rat model. The transplantation of peptidase inhibitors-treated adult microglia also inhibited cell apoptosis, reduced astrocytosis and microgliosis, and improved cognitive function of rats with TBI. The transplantation of either neonatal microglia or peptidase inhibitors-treated adult microglia significantly inhibited the pathogenesis of TBI in rat model, while untreated adult microglia showed no significant effect.

Integrated single-cell multiomics reveals novel immune candidate markers for post-traumatic coagulopathy.

Introduction: Post-traumatic coagulopathy (PTC) is a critical pathology in traumatic brain injury (TBI), however, its potential mechanism is not clear. To explore this in peripheral samples, we integrated single cell RNA-sequencing and T cell repertoire (TCR)-sequencing across a cohort of patients with TBI. Methods: Clinical samples from patients with more brain severity demonstrated overexpression of T cell receptor-encoding genes and less TCR diversity. Results: By mapping TCR clonality, we found patients with PTC have less TCR clones, and the TCR clones are mainly distributed in cytotoxic effector CD8+T cell. In addition, the counts of CD8+ T cell and natural killer (NK) cells are associated with the coagulation parameter by WGCNA, and the granzyme and lectin-like receptor profiles are also decreased in the peripheral blood from TBI patients, suggesting that reduced peripheral CD8+ clonality and cytotoxic profiles may be involved in PTC after TBI. Conclusion: Our work systematically revealed the critical immune status in PTC patients at the single-cell level.

Isolation and neuronal apoptosis inhibitory property of bacoside-A3 via downregulation of ß-amyloid induced inflammatory response.

Alzheimer's disease is one of the neurodegenerative disorders caused by neuronal degeneration and apoptosis in brain. Bacoside A and B isolated from the Bacopa monniera plant are responsible for cognitive effects. These compounds repair damaged neurons by promoting activity of kinases, synaptic activity restoration, and improvement of nerve transmission. The present study explored the effect of bacoside-A3 on ß-amyloid-induced reduction of U87MG cell viability, generation of oxidative radicals, and activation of nuclear factor-κB. The U87MG cells were stimulated with ß-amyloid (10 µM) after 24 h of bacoside-A3 pretreatment or without pretreatment to induce characteristics of Alzheimer disease in vitro. Sulforhodamine B (SRB) assay was used to count viable cells and ELISA kit for analysis of PGE2 secretion. The pretreatment with bacoside-A3 prevented ß-amyloid-mediated suppression of U87MG cell proliferation. Pretreatment of U87MG cells with bacoside-A3 prior to ß-amyloid stimulation suppressed generation of ROS in a concentration-based manner. The ß-amyloid-mediated formation of iNOS in U87MG cells was suppressed by bacoside-A3 in a dose-based manner. The ß-amyloid-mediated PGE2 secretion was suppressed by bacoside-A3 pretreatment in U87MG cells in the dose-based manner. The overexpression of COX-2 by ß-amyloid stimulation was suppressed in bacoside-A pretreated cells in the dose-based manner. The bacoside-A3 pretreatment prevented nuclear translocation of NF-κB in U87MG cells in the dose-based manner. In summary, bacoside-A3 prevented ß-amyloid-mediated suppression of U87MG cell viability, inhibited generation of oxidative radicals, PGE2, and synthesis of iNOS. Therefore, bacoside-A3 has therapeutic potential for Alzheimer disease and further in vivo studies need to be performed.

Effect of Ginkgolide in Ischemic Stroke patients with large Artery Atherosclerosis: Results from a randomized trial.

BACKGROUND: Dual antiplatelet therapy is considered beneficial in acute ischemic stroke (AIS) patients with intracranial artery stenosis (ICAS), with more bleeding events. Ginkgolide is shown to reduce platelet activation after infarction, which might be of benefit in AIS. We aimed to explore the effect of Ginkgolide in AIS patients with ICAS. METHODS: This was a randomized, double-blinded, placebo-controlled trial conducted at 61 centers in China. Within 72 h after onset, consecutive patients diagnosed as AIS with ICAS were randomized to either Ginkgolide or placebo treatment. The primary outcome was the composite of mortality and recurrent stroke (ischemic or hemorrhagic) during first 4 weeks in an intention-to-treat analysis. Secondary functional outcome was assessed by modified Rankin Scale and improvement of stroke severity was assessed by National Institution of Health Stroke Scale at day 28. Safety outcome was measured by the rate of severe adverse event (SAE). RESULTS: There were 936 patients randomized to either Ginkgolide or placebo treatment. Their average age was 64.2 ± 10.4 years old and 36.0% of the patients were female. The composite index event occurred in six patients in placebo group, and none occurred in Ginkgolide group (risk ratio 1.01; 95% CI 1.00-1.02). There were more patients who achieved favorable outcome in Ginkgolide group, compared with that of the placebo group (OR 2.16, 95%CI 1.37-3.41). SAE occurred in five (1.1%) patients in the Ginkgolide group and three (0.6%) in the placebo group (OR0.60, 95CI% 0.14-2.53). Intracranial hemorrhage occurred in 1/473 (0.2%) in the placebo group. CONCLUSIONS: Ginkgolide, working as PAF antagonist, may reduce recurrent stroke in AIS with ICAS patients within 72 hours after onset. It might be an optional treatment in moderate-to-severe AIS patients with ICAS. (http://www.chictr.org.cn Number as ChiCTR-IPR-17012310).

miR-433 Inhibits Neuronal Growth and Promotes Autophagy in Mouse Hippocampal HT-22 Cell Line.

Background: MicroRNAs (miRNAs) have an increasing functional role in some neurodegenerative diseases. Autophagy, the degradation of bulk protein in the cytoplasm, is the quality control function of protein and has a protective role in the survival of neural cells. miR-433 may play a regulatory role in neurodegenerative diseases. Many aspects underlying the mechanism of miR-433 in neural development and neurodegeneration are not clear. Methods: In this study, we established stable cell lines expressing miR-433 by infecting mouse hippocampal neural cell line (HT-22) cells with rLV-miR-433 and the control rLV-miR. Pre-miR-433 expression was analyzed using polymerase chain reaction (PCR). Mature miR-433 expression was measured using quantitative PCR (qPCR). The effect of miR-433 overexpression on cell proliferation was determined using a CCK-8 assay and flow cytometry. RNA interference was used to analyze the function of Cdk12 in mediating the effect of miR-433 on cell proliferation. The effect of miR-433 overexpression on cell apoptosis was determined by flow cytometry. Autophagy-related genes Atg4a, LC3B, and Beclin-1 were determined using qPCR, Western blot, or immunofluorescence. In addition, RNA interference was used to analyze the effect of Atg4a on the induction of autophagy. TargetScan 7.2 was used to predict the target genes of miR-433, and Smad9 was determined using qPCR. Results: Our results indicated that miR-433 increased the expression of Atg4a and induced autophagy by increasing the expression of LC3B-Ⅱ and Beclin-1 in an Atg4a-dependent manner. In addition, miR-433 upregulated the expression of Cdk12 and inhibited cell proliferation in a Cdk12-dependent manner and promoted apoptosis in HT-22 cells under the treatment of 10-hydroxycamptothecin. Conclusion: The results of our study suggest that miR-433 may regulate neuronal growth by promoting autophagy and attenuating cell proliferation. This might be a potential therapeutic intervention in neurodegenerative diseases.

MicroRNA­138 modulates glioma cell growth, apoptosis and invasion through the suppression of the AKT/mTOR signalling pathway by targeting CREB1.

Alterations in the expression of microRNA (miR)­138 have been demonstrated to result in the development of several malignant tumours. However, the possible function of miR­138 in human glioma cells remains unclear. The present study demonstrated that miR­138 was significantly downregulated in 48 human glioma specimens by quantitative PCR analysis. The upregulation of miR­138 exerted significant antiproliferative and anti­invasive effects on glioma cells and promoted their apoptosis. In addition, cAMP response element­binding protein 1 (CREB1) was confirmed as a direct target gene of miR­138 by luciferase gene reporter assay, and the antitumour effect of miR­138 on glioma cells was significantly reversed by CREB1 overexpression. Moreover, the molecular mechanisms underlying the tumour­suppressive role of miR­138 in malignant glioma may be associated with the dephosphorylation of AKT/mTOR caused by the miR­138 upregulation­induced decrease in CREB1 expression in glioma cells. The results of the present study indicated that miR­138 may affect CREB1/AKT/mTOR signalling to regulate the proliferation, apoptosis and invasion of glioma cells and the malignant progression of glioma, thereby suggesting that miR­138 may be a potential target for the treatment of gliomas.

Quercetin improves endothelial insulin sensitivity in obese mice by inhibiting Drp1 phosphorylation at serine 616 and mitochondrial fragmentation.

Studies have shown that endothelial insulin resistance induced by oxidative stress contributes to vascular dysfunction in metabolic disorders. Quercetin, a natural antioxidant, has been recently shown to exert protective effects on endothelial function. However, the effects of quercetin on endothelial insulin resistance and its underlying mechanism are unclear. Here, we found that chronic oral treatment of obese mice with quercetin increased vascular endothelial insulin sensitivity, accompanied by alleviated mitochondrial fragmentation as revealed by confocal imaging. In addition, western blot analysis showed that quercetin treatment suppressed the levels of dynamin-related protein 1 (Drp1) and phosphorylation at serine 616 in endothelial cells of obese mice. Mechanistically, quercetin specifically suppressed Drp1 phosphorylation at serine 616, whereas it showed little effects on the Drp1 level and its phosphorylation at serine 637 in cultured endothelial cells under oxidative stress. Furthermore, our results also showed that quercetin suppressed Drp1 phosphorylation at serine 616 by inhibiting PKCδ as revealed by western blot analysis. Knockdown of PKCδ with siRNA alleviated the protective effects of quercetin on endothelial-mitochondrial dynamics and insulin sensitivity. These results suggest that chronic oral treatment with quercetin exerts endothelial protective effects through inhibition of PKCδ and the resultant mitochondrial fragmentation.

Recombinant Tissue-Type Plasminogen Activator Study of Wake-Up Ischemic Strokes Guided by Rapid MRI.

BACKGROUND: rt-PA intravenous thrombolytic therapy and its efficacy have been widely recognized and proved for strokes. However, for patients with wake-up ischemic stroke (WUIS), they lose the opportunity to receive rt-PA intravenous thrombolytic therapy because of the difficulty of determining the onset time window. AIM: This study is aimed at investigating the intravenous thrombolytic therapy of WUIS guided by rapid MRI. METHODS: Data were collected from patients with acute ischemic stroke within 4.5 h and from WUIS patients with uncertain onset time window, who received the treatment of rt-PA intravenous thrombolytic therapy in our hospital from November 2006 to April 2018. The improved Rankin scale was used to evaluate neurological function recovery. According to the Rankin scale score, patients were divided into two groups: those with good prognosis (modified Rankin scale [mRS] score 0-1) and those with poor prognosis (mRS score 2-6). RESULTS: A total of 253 patients received rt-PA intravenous thrombolysis after head MRI evaluation; this included 177 cases of acute ischemic stroke and 76 cases of WUIS (which contains 2 death cases, 0.8% mortality; 3 cases of symptomatic bleeding, 1.2% bleeding rate; and 5 cases of aggravation, 2.0% aggravation rate). There was no statistical difference between the baseline data from the acute ischemic stroke patients with 4.5 h onset time window and the baseline data from the WUIS patients with undetermined onset time window, when the treatment was guided by rapid MRI. There were also no significant statistical differences in National Institutes of Health Stroke Scale score, Rankin scale score, symptomatic bleeding, death and aggravation of the disease between the 2 groups at 24 h, 3 days, and 7 days after admission (p < 0.05). CONCLUSION: According to the characteristic of undetermined onset time window of WUIS, more WUIS patients would be benefited from the rt-PA intravenous thrombolytic treatment when it is conducted under the guidance of rapid MRI.

Epigenome-Wide Association Study Indicates Hypomethylation of MTRNR2L8 in Large-Artery Atherosclerosis Stroke.

Background and Purpose- Ischemic stroke, a complex and heterogeneous disease, is the second leading cause of death worldwide. Genetic factors and epigenetic modification contribute to the pathogenesis of this disease. However, the effects of epigenetic factors on this disease have not been systematically investigated. Our study was designed to identify methylation alterations in large-artery atherosclerotic stroke. Methods- We conducted an epigenome-wide association analysis of large-artery atherosclerotic stroke using an Infinium HumanMethylation450 array (cases:controls=12:12), and the differentially methylated loci were validated in 2 cohorts (cases:controls, 110:122 and 191:191, respectively) using a Sequenom EpiTYPER assay. Results- In the screening stage, 1012 differentially methylated CpG sites annotated in 672 genes were found to be significantly associated with large-artery atherosclerotic stroke (mean methylation difference >5%, P<0.01). Disease, Gene Ontology, and pathway analysis highlighted the enrichment of these differentially methylated genes in cardiovascular, metabolic, neurological and immune-related functional gene clusters ( P<0.05). We identified a differentially methylated region in the promoter of a humanin gene ( MTRNR2L8, mean methylation difference=-13.01%, P=8.86×10-14). We constructed a diagnostic prediction model that was based on the mean number of significantly changed CpG loci in MTRNR2L8 and showed high diagnostic specificity and sensitivity ( P<0.0001, area under the curve=0.774). Conclusions- Together, these findings demonstrate that DNA methylation plays an important role in large-artery atherosclerotic stroke and that methylation of MTRNR2L8 is a potential therapeutic target and diagnostic biomarker for stroke.

Treating ischaemic stroke with intravenous tPA beyond 4.5 hours under the guidance of a MRI DWI/T2WI mismatch was safe and effective.

Purpose: Clinical trials have provided evidence that treating patients with acute ischaemic stroke (AIS) beyond 4.5 hours was feasible. Among them using MRI diffusion-weighted imaging/fluid attenuation inversion response (DWI/FLAIR) mismatch to guide intravenous tissue plasminogen activator (tPA) was successful. Our study explored the outcome and safety of using DWI/T2-weighted imaging (T2WI) mismatch to guide intravenous tPA therapy for patients with AIS between 4.5 hours and 12 hours of onset. Method: This was a retrospective study. Records of 1462 AIS patients with the time of onset of <12 hours were reviewed. Those had MRI rapid sequence study and had hyperintense signal on DWI but normal T2WI and received intravenous tPA up to 12 hours of onset were included in the analysis. Their demographics, risk factors, post-tPA complications, National Institutes of Health Stroke Scale (NIHSS) scores and outcome were recorded and analyse. χ2 was used to compare the intergroup variables. SAS was used to perform statistical calculation. A p<0.05 was considered statistically significant. Results: Of 1462 identified, 601 (41%) patients were entered into the final analysis. Among them, 327 (54%) had intravenous tPA within 4.5 hours of onset and 274 (46%) were treated between 4.5-12 hours. After intravenous tPA, 426 cases (71%) had >4 pints of improvement on NIHSS score within 24 hours. Postintravenous tPA, 32 (5.32%) cases had haemorrhagic transformation. 26 (4.33%) were asymptomatic ICH and 4 (0.67%) died. At 90 days, 523 (87%) achieved a modified Rankin scale of 0-2. Conclusion: Using MRI DWI/T2WI mismatch to identify patients with AIS for intravenous tPA between 4.5 hours and 12 hours was safe and effective. The outcome was similar to those used DWI/PWI or DWI/FLAIR mismatch as the screening tool. However, obtaining DWI/T2WI was faster and avoided the need of contrast material.

Evaluating the Efficacy of Atorvastatin on Patients with Carotid Plaque by an Innovative Ultrasonography.

BACKGROUND: The present study aimed to explore the efficacy of atorvastatin on patients with carotid plaque, applying superb microvascular imaging (SMI), and contrast-enhanced ultrasound (CEUS) for evaluating carotid intraplaque neovascularization. METHODS: A total of 82 patients (82 carotid plaques) who were randomized into treatment group and control group underwent conventional ultrasound, CEUS, and SMI examinations. Patients in treatment group received a dose of 20 mg atorvastatin per day for 6 months while those in control group received placebo instead. Lipid parameters were assessed and intraplaque neovascularization were evaluated by CEUS and SMI before and 6 months after atorvastatin treatment. RESULTS: No significant differences were found between the 2 groups at the study entry. Patients with atorvastatin treatment received marked improvement in total cholesterol, triglyceride, and LDL-cholesterol compared with those in control group (P < .001). In treatment group, SMI-detected intraplaque neovascularization reduced from 69.23% to 48.72% while CEUS-detected ones reduced from 76.92% to 69.23%. By contrast, the percentage of intraplaque neovascularization in control group did not change too much either by SMI (65.12%, 67.44%) or CEUS (74.41%, 74.41%). The consistency between CEUS and SMI was above .75 at all assessments (P < .001). CONCLUSIONS: Atorvastatin treatment works for patients with carotid plaque by reducing LDL-cholesterol and improving plaque regression. Second, the consistency between SMI and CEUS in visualizing intraplaque neovascularization is good. That indicates a high possibility to identify carotid plaque instability by a safer and cheaper ultrasonography without contrast agent.

Pretreatment with simvastatin upregulates expression of BK-2R and CD11b in the ischemic penumbra of rats.

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductases, collectively known as statins, have been shown to minimize cerebral ischemic events in patients. We assessed the mechanisms of simvastatin pretreatment in preventing cerebral ischemia/reperfusion injury in rats using a model of middle cerebral artery occlusion (MCAO). Rats were pretreated with simvastatin 14 days prior to MCAO induction. At 3, 24, and 48 hours after reperfusion, bradykinin levels in the ischemic penumbra were assayed by ELISA, mRNA levels of bradykinin B2 receptors (BK-2Rs) and CD11b were measured by fluorescent quantitative real-time PCR (RT-PCR), and co-expression of microglia and BK-2Rs was determined by immunofluorescence. Simvastatin had no effect on bradykinin expression in the ischemic penumbra at any time point. However, the levels of BK-2R and CD11b mRNA in the ischemic penumbra, which were significantly decreased 3 hours after ischemia-reperfusion, were increased in simvastatin-pretreated rats. Moreover, the co-expression of BK-2Rs and microglia was confirmed by immunofluorescence analysis. These results suggest that the beneficial effects of simvastatin pretreatment before cerebral ischemia/reperfusion injury in rats may be partially due to increased expression of BK-2R and CD11b in the ischemic penumbra.

Prognostic Value of Diffusion-Weighted Imaging (DWI) Apparent Diffusion Coefficient (ADC) in Patients with Hyperacute Cerebral Infarction Receiving rt-PA Intravenous Thrombolytic Therapy.

BACKGROUND The aim of this study was to investigate the potential value of apparent diffusion coefficient (ADC) of diffusion-weighted imaging (DWI) in the prognosis of patients with hyperacute cerebral infarction (HCI) receiving intravenous thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA). MATERIAL AND METHODS From June 2012 to June 2015, 58 cases of HCI (<6 h) undergoing rt-PA intravenous thrombolytic therapy (thrombolysis group) and 70 cases of HCI (<6 h) undergoing conventional antiplatelet and anticoagulant therapy (control group) in the same period were collected. DWI was conducted on all the subjects, and ADC maps were generated with Functool software to quantify ADC value. The clinical outcomes of HCI patients were observed for 3 months, and prognostic factors were analyzed. RESULTS Before thrombolysis treatment, the lesion area presented high signal intensity on DWI map and low signal intensity on ADC map, and gradually weakened signal intensity on DWI map and gradually enhanced signal intensity on ADC map were observed after thrombolysis. The ADC values of the thrombolysis group were significantly higher than those of the control group after treatment (24 h, 7 d, 30 d, and 90 d) (all P<0.05), and the ADC and rADC values in the thrombolysis group gradually increased over time (all P<0.05). Multiple logistic regression analysis showed that baseline National Institutes of Health Stroke Scale (NIHSS) score, baseline rADC value, and stroke history were the independent factors for the prognosis of HIC patients with thrombolysis (all P<0.05). CONCLUSIONS The values of ADC and rADC may provide guidance in the prognosis of HCI patients receiving rt-PA, and the baseline rADC value is the protective factor for the prognosis of HCI patients receiving rt-PA.

Ginsenoside Represses Symptomatic Intracerebral Hemorrhage after Recombinant Tissue Plasminogen Activator Therapy by Promoting Transforming Growth Factor-ß1.

BACKGROUND: Currently, the most effective treatment for brain ischemic stroke is recombinant tissue plasminogen activator (rt-PA); however, increased incidence of symptomatic intracerebral hemorrhage severely reduced its favorable treatment outcome. METHODS: We aimed to investigate the effect of ginsenoside (Gs) on symptomatic intracerebral hemorrhage after rt-PA treatment. Stroke patients were randomly divided into 2 treatment groups, one receiving rt-PA + placebo (Pc) and the other rt-PA + Gs. Twenty-four hours after the treatment, outcomes were assessed with transcranial Doppler (TCD) ultrasonography and National Institutes of Health Stroke Scale (NIHSS), and plasma levels of transforming growth factor-ß1 (TGF-ß1), matrix metalloproteinase (MMP)-2, and MMP-9 were also measured. After initial cotreatment, the patients were continuously administered with either Pc or Gs, and the treatment outcomes at 7 days were assessed with TCD, NIHSS, modified Rankin scale (MRS), and Glasgow outcome scale (GOS). RESULTS: Cotreatment of rt-PA with Gs significantly improved outcomes in patients compared to the Pc group, as indicated by improved TCD and NIHSS scores and reduced incidence of symptomatic intracerebral hemorrhage, which could be attributed to a Gs-induced increase in TGF-ß1 and a decrease in both MMP-2 and MMP-9 serum levels. Seven days of Gs treatment also significantly improved outcomes in patients compared to the Pc group, assessed by TCD, NIHSS, MRS, and GOS. CONCLUSION: Our study supports the clinical use of Gs as a potential supplement with rt-PA treatment, which reduces symptomatic intracerebral hemorrhage, therefore improving the treatment outcome of stroke patients.