The Emerging Role of Extracellular Vesicle Derived From Neurons/Neurogliocytes in Central Nervous System Diseases: Novel Insights Into Ischemic Stroke.

Neurons and neurogliocytes (oligodendrocytes, astrocytes, and microglia) are essential for maintaining homeostasis of the microenvironment in the central nervous system (CNS). These cells have been shown to support cell-cell communication via multiple mechanisms, most recently by the release of extracellular vesicles (EVs). Since EVs carry a variety of cargoes of nucleic acids, lipids, and proteins and mediate intercellular communication, they have been the hotspot of diagnosis and treatment. The mechanisms underlying CNS disorders include angiogenesis, autophagy, apoptosis, cell death, and inflammation, and cell-EVs have been revealed to be involved in these pathological processes. Ischemic stroke is one of the most common causes of death and disability worldwide. It results in serious neurological and physical dysfunction and even leads to heavy economic and social burdens. Although a large number of researchers have reported that EVs derived from these cells play a vital role in regulating multiple pathological mechanisms in ischemic stroke, the specific interactional relationships and mechanisms between specific cell-EVs and stroke treatment have not been clearly described. This review aims to summarize the therapeutic effects and mechanisms of action of specific cell-EVs on ischemia. Additionally, this study emphasizes that these EVs are involved in stroke treatment by inhibiting and activating various signaling pathways such as ncRNAs, TGF-ß1, and NF-κB.

Clipping versus coiling for the treatment of oculomotor nerve palsy induced by posterior communicating artery aneurysms: A comparison of effectiveness.

BACKGROUND: A long debate has been going on in the clinical effectiveness to determine whether surgical clipping or coiling more favorable for oculomotor nerve palsy (ONP) caused by PcomAA. We aimed to perform a study, focusing on the effectiveness of ONP induced by PcomAA after treatment of surgical clipping and endovascular coiling. METHOD: Potential studies were searched on PubMed, EMBASE, Web of Science, and Cochrane Library from database inception to February 2021, and STATA version 12.0 was exerted to process the pooled data. RESULTS: A total of 16 articles are included in the study, hailing from the United States, South Korea, the United Kingdom, France, Germany, Korea, China, Japan, Britain, and Singapore. The results showed that the clipping group was related to a higher incidence of complete ONP recovery at follow-up (OR = 5.808, 95% CI 2.87 to 11.76, p < 0.001), the lower rates of partial ONP recovery (OR = 0.264, 95% CI 0.173 to 0.402, p < .001) and no improvement of ONP at follow-up (RD = -0.149, 95% CI -0.247 to -0.051, p = .003). In the subgroup of complete ONP recovery based on the condition of patients, clipping was associated with a higher incidence of complete ONP recovery in patients with the incomplete initial ONP (OR = 3.579, p = .020) and ruptured aneurysm (OR = 5.38, p = .020). Regarding the subgroup of complete ONP recovery based on the quality of studies, similar results also appeared. CONCLUSION: Surgical clipping was more favorable to the recovery from ONP caused by PcomAA endovascular coiling due to a higher rate of recovery and recovery degree of ONP. Besides that, more evidence-based performance is necessary to supplement this opinion.

A Meta-Analysis of Endoscopic vs. Microscopic Transsphenoidal Surgery for Non-functioning and Functioning Pituitary Adenomas: Comparisons of Efficacy and Safety.

Background: Although microscopic (MTSS) and endoscopic transsphenoidal surgery (ETSS) are both effective approaches for treating non-functioning pituitary adenomas (NFPA) and functioning pituitary adenomas (FPA), the consensus remains unidentified on whether there are differences in the risk of postoperative complications between the two surgical approaches. Method: A meta-analysis of the study of MTSS vs. ETSS for NFPA and FPA was conducted by searching the electronic databases of PubMed, Cochrane Library, and EMBASE, from the date of establishment of electronic databases to September 2020 based on the PRISMA guidelines. Results: In this study, a total of 16 studies were selected, hailing from Belgium, the USA, India, Finland, France, Korea, Spain, China, and Canada. We enrolled 1003 patients in the ETSS and 992 patients in the MTSS group. In patients with NFPA, the ETSS group was related to a higher incidence of post-operative gross-total resection (GTR). (OR = 1.655, 95% CI 1.131-2.421, P = 0.010). In participants with FPA, the results illustrated that the ETSS group had higher rates of visual improvement (OR = 2.461, 95% CI 1.109-5.459) and gross-total resection (OR = 2.033, 95% CI 1.335-3.096), as well as lower meningitis rates (OR = 0.195, 95% CI 0.041-1.923). In participants with acromegaly, no significant difference was shown in the postoperative complications. Conclusion: Based on current evidence, participants with NFPA treated by endoscopy were related to higher rates of GTR; patients with FPA treated by ETSS were related to higher rates of visual improvement and GTR, as well as a lower rates of meningitis.

Endovascular coiling versus surgical clipping for the treatment of unruptured cerebral aneurysms: Direct comparison of procedure-related complications.

BACKGROUND: Endovascular coiling and surgical clipping are routinely used to treat unruptured cerebral aneurysms (UCAs). However, the evidence to support the efficacy of these approaches is limited. We aimed to analyze the efficacy of endovascular coiling compared with surgical clipping in patients with UCAs. METHOD: A systematic search of 4 databases was conducted to identify comparative articles involving endovascular coiling and surgical clipping in patients with UCAs. We conducted a meta-analysis using the random-effects model when I> 50%. Otherwise, a meta-analysis using the fixed-effects model was performed. RESULTS: Our results showed that endovascular coiling was associated with a shorter length of stay (WMD: -4.14, 95% CI: (-5.75, -2.531), P < .001) and a lower incidence of short-term complications compared with surgical clipping (OR: 0.518; 95% CI (0.433, 0.621); P < .001), which seems to be a result of ischemia complications (OR: 0.423; 95% CI (0.317, 0.564); P < .001). However, surgical clipping showed a higher rate of complete occlusion after surgery, in both short-term (OR: 0.179, 95% CI (0.064, 0.499), P = .001) and 1-year follow-ups (OR: 0.307, 95% CI (0.146, 0.646), P = .002), and a lower rate of short-term retreatment (OR: 0.307, 95% CI (0.146, 0.646), P = .002). Meanwhile, there was no significant difference in postoperative death, bleeding, and modified Rankin Scale (mRS) > 2 between the 2 groups. CONCLUSIONS: The latest evidence illustrates that surgical clipping resulted in lower retreatment rates and was associated with a higher incidence of complete occlusion, while endovascular coiling was associated with shorter LOS and a lower rate of complications, especially ischemia.

Dual versus Single Antiplatelet Therapy in Carotid Artery Endarterectomy: Direct Comparison of Complications Related to Antiplatelet Therapy.

BACKGROUND: Dual and single antiplatelet therapies are routinely used in carotid artery endarterectomy (CEA). However, the efficacy and safety of these therapies are controversial. The present study aimed to comprehensively compare the clinical outcomes between dual and single antiplatelet therapies in CEA. METHODS: This study retrieved available academic studies evaluating the complications related to antiplatelet therapy between dual and single antiplatelet therapies in CEA from the databases of ScienceDirect, the Cochrane Library, EMBASE, and PubMed. References to previous reviews and related clinical trials were manually checked to retrieve potential literature that was not included in our electronic search results. RESULTS: A total of 10 articles (1 randomized controlled trial, 9 non-randomized controlled trials) were included in the study. The overall number of patients in the dual antiplatelet group was 14,280, and the number of patients in the single antiplatelet group was 125,850. The results revealed that the single antiplatelet group had a lower incidence of 30-day death (rate difference [RD] 0.002; 95% confidence interval [CI] 0.000-0.003; P = 0.014), neck hematoma (odds ratio [OR] 2.120; 95% CI 1.431-3.142; P < 0.001), myocardial infarction (RD 0.004; 95% CI 0.001-0.007; P = 0.003), and major bleeding (RD 0.005; 95% CI 0.002-0.008; P < 0.001). Meanwhile, the single antiplatelet group was associated with a shorter operation time (weighted mean difference 4.000; 95% CI= 2.564-5.436; P < 0.001). However, there was no significant difference in the rate of postoperative transient ischemic attack (P = 0.215), stroke (P = 0.130), or length of stay (P = 0.563). CONCLUSIONS: Based on current evidence, using single antiplatelet therapy in CEA may reduce operation time and the incidences of 30-day death, neck hematoma, major bleeding, and myocardial infarction without increasing the risks of transient ischemic attack, stroke, or a longer operation time.

Efficacy of Biomedical Glue Sling Technique Versus Traditional Technique for Microvascular Decompression for Hemifacial Spasm with Refractory Hypertension.

BACKGROUND: Microvascular decompression (MVD) is useful treatment for hemifacial spasm (HFS) with refractory hypertension (RHTN). The biomedical glue sling technique is a new method for MVD. In this study, we retrospectively compared the outcome of the biomedical glue sling technique with traditional technique in MVD for HFS with RHTN. METHODS: A retrospective study of HFS with RHTN treated by MVD was conducted between January 2010 and June 2016. Among 155 patients who underwent their first MVD at our institution, traditional technique was performed in 73 cases of patients and the biomedical glue sling technique was performed on 82 patients. RESULTS: At 3 days, 7 days, 1 month, 3 months, and 1 year after MVD surgery, in the traditional technique group the effective rates of MVD for HFS were 86.30%, 84.93%, 87.14%, 84.06%, and 83.33%. The effective rates for RHTN were 68.49%, 67.12%, 65.71%, 57.97%, and 57.58%. The incidence rates of complication were 5.48%, 5.48%, 4.29%, 2.90%, and 3.03%. In the biomedical glue sling technique group, the effective rates of MVD for HFS were 97.56%, 97.56%, 98.75%, 96.15%, and 94.59% (P < 0.05). The effective rates for RHTN were 85.37%, 82.93%, 81.25%, 79.49%, and 75.68% (P < 0.05). The incidence rates of complication were 6.10%, 6.10%, 5.00%, 3.85%, and 2.70% (P > 0.05). CONCLUSION: When HFS is associated with RHTN, the efficacy of the biomedical glue sling technique for MVD is higher than that of the traditional technique for both HFS and RHTN.

Retrospective analysis of 620 cases of brain abscess in Chinese patients in a single center over a 62-year period.

BACKGROUND: Despite advances in laboratory diagnostics, antibiotic regimens, and neurosurgical techniques, brain abscess (BA) remains a potentially fatal infectious disease. This study analyzed clinical and epidemiological aspects of BA in Chinese patients treated at a single center during a 62-year period. METHOD: We retrospectively analyzed 620 BA patients treated at Tianjin Medical University General Hospital, Tianjin, PR China from 1952 to 2014. Because of the initiation of imaging technology use in 1992, and other specific changes, we analyzed data over three study periods: 1952-1972, 1980-1991, and 2002-2014. Information including incidence, sex, age, community distribution, BA size and location, therapeutic method, prognosis and outcome of BA patients was collected and evaluated. RESULTS: Our study included 620 BA patients. The percentage mortality significantly decreased from 22.8 % in 1952 to 6.3 % in 2014 (p < 0.001). Although the incidence of BA was higher in males than females, there was no significant change in the male/female incidence ratio over time: 2.5 in 1952-1972, 2.6 in 1980-1991, and 2.2 in 2002-2014. The cryptogenic infection incidence significantly increased over time (p < 0.001). The number of positive bacterial cultures significantly decreased over the three study periods (p < 0.01). CONCLUSIONS: The prognosis of patients with BA has gradually improved over the past 62 years in Tianjin, China. This may be because improvements in neurosurgical techniques, cranial imaging, and antimicrobial regimens have facilitated less invasive and more precise neurosurgical procedures.

CTA Characteristics of the Circle of Willis and Intracranial Aneurysm in a Chinese Crowd with Family History of Stroke.

BACKGROUND AND PURPOSE: The vascular morphology in crowd with family history of stroke remains unclear. The present study clarified the characteristics of the intracranial vascular CoW and prevalence of intracranial aneurysms in subjects with family history of stroke. METHODS: A stratified cluster, random sampling method was used for subjects with family history of stroke among rural residents in Jixian, Tianjin, China. All the subjects underwent a physical examination, head computed tomography (CT) scan, and cephalic and cervical computed tomography angiography (CTA) scan. Anatomic variations in the Circle of Willis and cerebrovascular disease in this population were analyzed. RESULTS: In the crowd with similar living environment, stable genetic background, and family history of stroke and without obvious nerve function impairment (1) hypoplasia or absence of A1 segment was significantly different in gender (male versus female: 9.8% versus 18.8%, p = 0.031), especially the right-side A1 (male versus female: 5.9% versus 16.4%, p = 0.004). (2) Hypoplasia or absence of bilateral posterior communicating arteries was more common in men than women (58.2% versus 45.3%, p = 0.032). Unilateral fetal posterior cerebral artery was observed more often in women than men (17.2% versus 8.5%, p = 0.028). (3) The percentage of subjects with incomplete CoW did not increase significantly with age. Compared to healthy Chinese people, the crowd had a higher percentage of incomplete CoW (p < 0.001). (4) No obvious correlation between risk factors and CoW was found. (5) The prevalence of aneurysm was 10.3% in the special crowd. CONCLUSIONS: The certain variations of CoW showed significant relation to gender, but not to age in people with family history of stroke. The incomplete circle may be a dangerous factor that is independent of common risk factors for stroke and tend to lead to cerebral ischemia in the crowd with family history of stroke. The prevalence of intracranial aneurysm is comparatively high in the present subjects compared to other people.

Exploring the potential relationship between Notch pathway genes expression and their promoter methylation in mice hippocampal neurogenesis.

The Notch pathway is a highly conserved pathway that regulates hippocampal neurogenesis during embryonic development and adulthood. It has become apparent that intracellular epigenetic modification including DNA methylation is deeply involved in fate specification of neural stem cells (NSCs). However, it is still unclear whether the Notch pathway regulates hippocampal neurogenesis by changing the Notch genes' DNA methylation status. Here, we present the evidence from DNA methylation profiling of Notch1, Hes1 and Ngn2 promoters during neurogenesis in the dentate gyrus (DG) of postnatal, adult and traumatic brains. We observed the expression of Notch1, Hes1 and Ngn2 in hippocampal DG with qPCR, Western blot and immunofluorescence staining. In addition, we investigated the methylation status of Notch pathway genes using the bisulfite sequencing PCR (BSP) method. The number of Notch1 or Hes1 (+) and BrdU (+) cells decreased in the subgranular zone (SGZ) of the DG in the hippocampus following TBI. Nevertheless, the number of Ngn2-positive cells in the DG of injured mice was markedly higher than in the DG of non-TBI mice. Accordingly, the DNA methylation level of the three gene promoters changed with their expression in the DG. These findings suggest that the strict spatio-temporal expression of Notch effector genes plays an important role during hippocampal neurogenesis and suggests the possibility that Notch1, Hes1 and Ngn2 were regulated by changing some specific CpG sites of their promoters to further orchestrate neurogenesis in vivo.

Hes1, a Notch signaling downstream target, regulates adult hippocampal neurogenesis following traumatic brain injury.

Hairy and enhancer of split 1 (Hes1), a downstream target of Notch signaling, has long been recognized as crucial in inhibiting neuronal differentiation. However, the role of Hes1 following traumatic brain injury (TBI) in adult neurogenesis in the mouse dentate gyrus (DG) remains partially understood. Here, we investigate the role of Hes1 in regulating neurogenesis in the DG of the adult hippocampus after TBI by up- or downregulating Hes1 expression. First, adenovirus-mediated gene transfection was employed to upregulate Hes1 in vivo. The mice were then subjected to TBI, and the hippocampal tissue was collected for Western blot analysis at designated times, pre- and post-injury. Moreover, the brain slices were stained for BrdU and doublecortin (DCX). We show that enhancing Hes1 inhibits the proliferation and differentiation of neural precursor cells (NPCs) in the DG of the hippocampus soon after TBI. Second, downregulation of Hes1 via RNA interference (RNAi) results in a significant increase in neuronal production and promotes the differentiation of NPCs into mature neurons in the DG, as assessed by BrdU and NeuN double staining. Furthermore, a Morris water maze (MWM) test clearly confirmed that the knockdown of Hes1 improves the spatial learning and memory capacity of adult mice following injury. Taken together, these observations suggest that Hes1 represents a negative regulator of adult neurogenesis post-TBI and that the precise space-time regulation of Hes1 expression in the DG may promote the recovery of neural function following TBI.

Survivin, a key component of the Wnt/ß-catenin signaling pathway, contributes to traumatic brain injury-induced adult neurogenesis in the mouse dentate gyrus.

The enhancement of endogenous neurogenesis has been suggested in the treatment of traumatic brain injury (TBI); however, the factors that trigger the process of adult neurogenesis following TBI remain elusive. In the adult mammalian central nervous system, there are 2 neurogenic regions: the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricles, both of which maintain relatively quiescent states in a stable microenvironment. However, once stimulated by intrinsic and extrinsic events, relevant signals are activated in these 2 regions. In this study, in order to explore the mechanisms behind endogenous neurogenesis following TBI, we investigated potential factors regulating this process. We observed that the expression of survivin, an anti-apoptotic protein, increased in a time-dependent manner in the hippocampus in a mouse model of TBI. In addition, the number of survivin (+) cells, as well as that of BrdU (+) cells increased in the SGZ of the dentate gyrus (DG) in the hippocampus following TBI, as shown by immunofluorescence double staining; the co-localization of survivin and BrdU was shown in the merged images. The expression of survivin was also significantly increased in the doublecortin (DCX) (+) immature neurons in the DG of the hippocampus soon after the induction of TBI. Taken together, these data confirm the connection between the expression of survivin and adult neurogenesis following TBI; our data also suggest the therapeutic potential of upregulating survivin expression as a novel strategy for the effective treatment of TBI.

A new finding concerning adenoviral-mediated gene transfer: a high-level, cell-specific transgene expression in the neural stem cells of adult mice.

Adenoviruses are highly efficient vectors for gene transfer into brain cells. Restricting transgene expression to specific cell types and maintaining long-term expression are major goals for adenoviral-mediated gene transfer in the central nervous system. Human adenovirus type 5 (Ad5) mediated transgene expression is described under the control of the murine cytomegalovirus (mCMV) immediate-early promoter. It was found that the neural stem cells in the dentate subgranular zone were transduced preferentially, minimal neurons were transduced in the granule cell layer of the dentate gyrus, no EGFP was detected in the pyramidal cell layers of CAl to CA3 area and EGFP activity can be detected for 2 months after infection. Therefore, the mCMV-adenoviral vectors can be used both for studying the function of various genes in the differentiation of neural stem cells and, ultimately, for gene therapy or to modulate specific gene expression.