Early autoimmunity and outcome in virus encephalitis: a retrospective study based on tissue-based assay.

To explore the autoimmune response and outcome in the central nervous system (CNS) at the onset of viral infection and correlation between autoantibodies and viruses. METHODS: A retrospective observational study was conducted in 121 patients (2016-2021) with a CNS viral infection confirmed via cerebrospinal fluid (CSF) next-generation sequencing (cohort A). Their clinical information was analysed and CSF samples were screened for autoantibodies against monkey cerebellum by tissue-based assay. In situ hybridisation was used to detect Epstein-Barr virus (EBV) in brain tissue of 8 patients with glial fibrillar acidic protein (GFAP)-IgG and nasopharyngeal carcinoma tissue of 2 patients with GFAP-IgG as control (cohort B). RESULTS: Among cohort A (male:female=79:42; median age: 42 (14-78) years old), 61 (50.4%) participants had detectable autoantibodies in CSF. Compared with other viruses, EBV increased the odds of having GFAP-IgG (OR 18.22, 95% CI 6.54 to 50.77, p<0.001). In cohort B, EBV was found in the brain tissue from two of eight (25.0%) patients with GFAP-IgG. Autoantibody-positive patients had a higher CSF protein level (median: 1126.00 (281.00-5352.00) vs 700.00 (76.70-2899.00), p<0.001), lower CSF chloride level (mean: 119.80±6.24 vs 122.84±5.26, p=0.005), lower ratios of CSF-glucose/serum-glucose (median: 0.50[0.13-0.94] vs 0.60[0.26-1.23], p=0.003), more meningitis (26/61 (42.6%) vs 12/60 (20.0%), p=0.007) and higher follow-up modified Rankin Scale scores (1 (0-6) vs 0 (0-3), p=0.037) compared with antibody-negative patients. A Kaplan-Meier analysis revealed that autoantibody-positive patients experienced significantly worse outcomes (p=0.031). CONCLUSIONS: Autoimmune responses are found at the onset of viral encephalitis. EBV in the CNS increases the risk for autoimmunity to GFAP.

Pericytes Regulate Cerebral Perfusion through VEGFR1 in Ischemic Stroke.

Neurons in the penumbra (the area surrounding ischemic tissue that consists of still viable tissue but with reduced blood flow and oxygen transport) may be rescued following stroke if adequate perfusion is restored in time. It has been speculated that post-stroke angiogenesis in the penumbra can reduce damage caused by ischemia. However, the mechanism for neovasculature formation in the brain remains unclear and vascular-targeted therapies for brain ischemia remain suboptimal. Here, we show that VEGFR1 was highly upregulated in pericytes after stroke. Knockdown of VEGFR1 in pericytes led to increased infarct area and compromised post-ischemia vessel formation. Furthermore, in vitro studies confirmed a critical role for pericyte-derived VEGFR1 in both endothelial tube formation and pericyte migration. Interestingly, our results show that pericyte-derived VEGFR1 has opposite effects on Akt activity in endothelial cells and pericytes. Collectively, these results indicate that pericyte-specific expression of VEGFR1 modulates ischemia-induced vessel formation and vascular integrity in the brain.

Risk factors for the progression of unruptured intracranial aneurysms in patients followed by CT/MR angiography.

BACKGROUND: The progression of an unruptured intracranial aneurysm (UIA) is associated with a higher rupture risk. The aim of this study was to identify the risk factors for the progression of UIAs among Chinese adults and compare them with the ELAPSS (Earlier subarachnoid hemorrhage, IA Location, Age, Population, IA Size and Shape) score. METHODS: Four hundred thirty-eight consecutive patients with 491 UIAs were followed and reviewed retrospectively from August 2011 to November 2019. Follow-up images of the UIAs were used to determine changes in IA size and shape. Patients and IAs were divided into non-progression and progression groups. In addition to the clinical characteristics of the patients, the features of the IAs (e.g., size and shape) were evaluated by computed tomography angiography (CTA) or magnetic resonance angiography (MRA). Independent risk factors for UIA progression were studied using multiple Cox proportional hazards regression analysis. In addition, the diagnostic value of the ELAPSS score for the prediction of UIA progression was calculated. RESULTS: Seventy-two IAs in 68 patients progressed during a mean follow-up time of 24.2±19.68 months. IAs located at the bifurcation [odds ratio (OR) 2.600], with an irregular shape (OR 2.981) or having a high aspect ratio (AR, OR 2.430) were correlated with progression. Based on these three factors, the threshold value of our predictive score was 0.5, and the area under the curve (AUC), sensitivity and specificity were 0.756, 93.1% and 40.6%, respectively, while the AUC, sensitivity and specificity of the ELAPSS score were 0.711, 55.6%, and 75.2%, respectively. CONCLUSIONS: IAs located at the bifurcation, with an irregular shape and with an elevated AR are risk factors for UIA progression in the Chinese population. Our predictive score is of great value in predicting the risk of UIA progression.

Current Situation of Methamphetamine Abuse and Related Research Progress.

Drug problem is a major social and public security problem in the world. Drug abuse poses a great threat to economic development, social stability and public health. In recent years, synthetic drugs represented by methamphetamine have surpassed traditional drugs such as morphine, heroin, ketamine and become one of the most abused drugs in the world. In order to solve the problem of drug abuse, it is of great theoretical value and practical significance to carry out all-round and multi-level scientific research on drug-related issues. Based on the current situation of drug abuse, this article reviews research progresses on the epidemiology of methamphetamine abuse, the monitoring technology, the basic researches on toxicity damage, the withdrawal drug screening, the related clinical comorbidity and the testing technologies, comprehensively presenting the development trend of methamphetamine abuse related issues.

SRT2104 attenuates chronic unpredictable mild stress-induced depressive-like behaviors and imbalance between microglial M1 and M2 phenotypes in the mice.

Although activated microglia-induced neuroinflammation link to the physiopathology of major depressive disorder, the homeostasis of switchable M1/M2 microglia in treating depression are unclear. Recent accumulating evidences suggest that Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, plays a key role in mood regulation, yet its role in the polarization of microglia acting on depressive behaviors remains unknown. Here, we intended to investigate whether activation of SIRT1 in hippocampus has antidepressant potential in relation to microglial phenotypic switch. Chronic unpredictable mild stress (CUMS) treatment was performed on C57BL/6 mice, followed by injecting with SRT2104, a selective SIRT1 agonists. We found that activation of SIRT1 in hippocampus ameliorate CUMS-induced depressive-like behaviors, as indicated by sucrose preference test, tail suspension test and forced swim test. Moreover, activation of SIRT1 abrogated the increased expression of M1 markers (IL-6, IL-1ß and iNOS,) and decreased expression of M2 markers (IL-10, TGF-ß and Arignase1) induced by CUMS. Notably, activation of SIRT1 shifted microglia polarization toward the M2 phenotype in CUMS-induced depressive-like behaviors of mice. In addition, SRT2104 treatment ameliorated CUMS-induced SIRT1 decreased expression in the hippocampus coincides with the up-regulation phosphorylation levels of GSK3ß and PTEN. Taken together, these findings indicated that activation of SIRT1 ameliorate CUMS-induced depressive-like behaviors via shifting microglial polarization toward the M2 phenotype, thereby providing a novel and beneficial therapeutic approach for depression that may be translatable to depression patients in the future.

Cardiovascular outcomes of liraglutide in patients with type 2 diabetes: A systematic review and meta-analysis.

BACKGROUND: Liraglutide is a novel, long-acting glucagon-like peptide-1 (GLP-1) analogue used to treat type 2 diabetes mellitus. However, the cardiovascular safety and benefits of liraglutide treatment on type 2 diabetes patients remain in debate. In this study, we aimed to examine the overall cardiovascular outcomes of liraglutide in patients with type 2 diabetes. METHODS: In this systematic review and meta-analysis, we searched the PubMed, Embase, and Web of Knowledge databases up to September 1st, 2017 for randomized trials in which type 2 diabetes patients were assigned to liraglutide and placebo or other comparators groups. RESULTS: Eight studies fulfilled the eligibility criteria for inclusion and 14,608 patients were analyzed in this systematic review and meta-analysis. We found patients in the liraglutide group had a lower risk of major cardiovascular events (MACE) (RR = 0.89, 95% CI: 0.82-0.96, P = .002), acute myocardial infarction (AMI) (RR = 0.85, 95% CI: 0.74-0.99, P = .036), all-cause death (RR = 0.84, 95% CI: 0.74-0.96, P = .009), and cardiovascular death (RR = 0.77, 95% CI: 0.65-0.91, P = .002) than all comparator groups. However, liraglutide treatment did not decrease incidence of stroke (RR = 0.86, 95% CI: 0.70-1.04, P = .124). But among the MACE subgroups analysis, a significant reduction of MACE with liraglutide was only observed in placebo-controlled trials (RR = 0.89, 95% CI: 0.83-0.96, P = .004) but not in studies concerning other comparators (RR = 0.58, 95% CI: 0.29-1.16, P = .122). CONCLUSIONS: In conclusion, our results suggest that liraglutide treatment decreases the risk of MACE, AMI, all-cause death and cardiovascular death among patients with type 2 diabetes.

Computed Tomography Angiography Evaluation of Risk Factors for Unstable Intracranial Aneurysms.

OBJECTIVE: To evaluate risk factors for instability in intracranial aneurysms (IAs) using computed tomography angiography (CTA). METHODS: A total of 614 consecutive patients diagnosed with 661 IAs between August 2011 and February 2016 were reviewed. Patients and IAs were divided into stable and unstable groups. Along with clinical characteristics, IA characteristics were evaluated by CTA. Multiple logistic regression analysis was used to identify the independent risk factors associated with unstable IAs. Receiver operating characteristic (ROC) curve analysis was performed on the final model, and optimal thresholds were obtained. RESULTS: Patient age (odds ratio [OR], 0.946), cerebral atherosclerosis (CA; OR, 0.525), and IAs located at the middle cerebral artery (OR, 0.473) or internal carotid artery (OR, 0.512) were negatively correlated with instability, whereas IAs with irregular shape (OR, 2.157), deep depth (OR, 1.557), or large flow angle (FA; OR, 1.015) were more likely to be unstable. ROC analysis revealed threshold values of age, depth, and FA of 59.5 years, 4.25 mm, and 87.8°, respectively. CONCLUSIONS: The stability of IAs is significantly affected by several factors, including patient age and the presence of CA. IA shape and location also have an impact on the stability of IAs. Growth into an irregular shape, with a deep depth, and a large FA are risk factors for a change in IAs from stable to unstable.

Risk Factors for the Rupture of Intracranial Aneurysms Using Computed Tomography Angiography.

OBJECTIVE: To study the clinical and morphologic characteristics associated with risk factors for the rupture of intracranial aneurysms (IAs). METHODS: A total of 1115 consecutive patients with 1282 IAs were reviewed from August 2011 to February 2016. The patients and IAs were divided into ruptured and unruptured groups. Based on the clinical and morphologic findings, the risk factors for IA rupture were assessed using statistical methods. RESULTS: Age, hypertension, diabetes mellitus, and cerebral atherosclerosis were associated with ruptured IAs. IAs located in the anterior cerebral artery, the anterior communicating artery, the posterior communicating artery, and the internal carotid artery were associated with ruptured IAs. Ruptures were also associated with arterial bifurcations, irregular aneurysm shapes, and all continuous data, except neck width. Binary logistic regression showed that IAs located at bifurcations (odds ratio [OR], 1.804), with irregular shapes (OR, 4.677), with high aspect ratios (ARs) (OR, 5.037) or with small mean diameters (MDs) (OR, 0.495) are more prone to rupture. Receiver operating characteristic analysis showed that the threshold values of the AR and MD were 1 and 3.70 mm, respectively. CONCLUSIONS: Morphologic characteristics, such as being located at bifurcations, being irregularly shaped, having a high AR (>1), and having a small MD (<3.70 mm), were better predictors of rupture.

Mfsd2a (Major Facilitator Superfamily Domain Containing 2a) Attenuates Intracerebral Hemorrhage-Induced Blood-Brain Barrier Disruption by Inhibiting Vesicular Transcytosis.

BACKGROUND: Blood-brain barrier (BBB) disruption aggravates brain injury induced by intracerebral hemorrhage (ICH); however, the mechanisms of BBB damage caused by ICH remain elusive. Mfsd2a (major facilitator superfamily domain containing 2a) has been known to play an essential role in BBB formation and function. In this study, we investigated the role and underlying mechanisms of Mfsd2a in BBB permeability regulation after ICH. METHODS AND RESULTS: Using ICH models, we found that Mfsd2a protein expression in perihematomal brain tissues was significantly decreased after ICH. Knockdown and knockout of Mfsd2a in mice markedly increased BBB permeability, neurological deficit score, and brain water contents after ICH, and these were rescued by overexpressing Mfsd2a in perihematomas. Moreover, we found that Mfsd2a regulation of BBB permeability after ICH correlated with changes in vesicle number. Expression profiling of tight junction proteins showed no differences in Mfsd2a knockdown, Mfsd2a knockout, and Mfsd2a overexpression mice. However, using electron microscopy following ICH, we observed a significant increase in pinocytotic vesicle number in Mfsd2a knockout mice and decreased the number of pinocytotic vesicles in mouse brains with Mfsd2a overexpression. Finally, using multiple reaction monitoring, we screened out 3 vesicle trafficking-related proteins (Srgap2, Stx7, and Sec22b) from 31 vesicle trafficking-related proteins that were markedly upregulated in Mfsd2a knockout mice compared with controls after ICH. CONCLUSIONS: In summary, our results suggest that Mfsd2a may protect against BBB injury by inhibiting vesicular transcytosis following ICH.

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.

Regulatory T cells ameliorate intracerebral hemorrhage-induced inflammatory injury by modulating microglia/macrophage polarization through the IL-10/GSK3ß/PTEN axis.

Inflammation mediated by the peripheral infiltration of inflammatory cells plays an important role in intracerebral hemorrhage (ICH) induced secondary injury. Previous studies have indicated that regulatory T lymphocytes (Tregs) might reduce ICH-induced inflammation, but the precise mechanisms that contribute to ICH-induced inflammatory injury remain unclear. Our results show that the number of Tregs in the brain increases after ICH. Inducing Tregs deletion using a CD25 antibody or Foxp3DTR-mice increased neurological deficient scores (NDS), the level of inflammatory factors, hematoma volumes, and neuronal degeneration. Meanwhile, boosting Tregs using a CD28 super-agonist antibody reduced the inflammatory injury. Furthermore, Tregs depletion shifted microglia/macrophage polarization toward the M1 phenotype while boosting Tregs shifted this transition toward the M2 phenotype. In vitro, a transwell co-culture model of microglia and Tregs indicated that Tregs changed the polarization of microglia, decreased the expression of MHC-II, IL-6, and TNF-α and increased CD206 expression. IL-10 originating from Tregs mediated the microglia polarization by increasing the expression of Glycogen Synthase Kinase 3 beta (GSK3ß), which phosphorylates and inactivates Phosphatase and Tensin homologue (PTEN) in microglia, TGF-ß did not participate in this conversion. Thus, Tregs ameliorated ICH-induced inflammatory injury by modulating microglia/macrophage polarization toward the M2 phenotype through the IL-10/GSK3ß/PTEN axis.