Search

MicroRNA-491-5p (miR-491-5p) plays an important role in regulating cell proliferation and migration; however, the effect of miR-491-5p on neovascularization after traumatic brain injury remains poorly understood. In this study, a controlled cortical injury model in C57BL/6 mice and an oxygen-glucose deprivation model in microvascular endothelial cells derived from mouse brain were established to simulate traumatic brain injury in vivo and in vitro, respectively. In the in vivo model, quantitative real-time-polymerase chain reaction results showed that the expression of miR-491-5p increased or decreased following the intracerebroventricular injection of an miR-491-5p agomir or antagomir, respectively, and the expression of miR-491-5p decreased slightly after traumatic brain injury. To detect the neuroprotective effects of miR-491-p, neurological severity scores, Morris water maze test, laser speckle techniques, and immunofluorescence staining were assessed, and the results revealed that miR-491-5p downregulation alleviated neurological dysfunction, promoted the recovery of regional cerebral blood flow, increased the number of lectin-stained microvessels, and increased the survival of neurons after traumatic brain injury. During the in vitro experiments, the potential mechanism of miR-491-5p on neovascularization was explored through quantitative real-time-polymerase chain reaction, which showed that miR-491-5p expression increased or decreased in brain microvascular endothelial cells after transfection with an miR-491-5p mimic or inhibitor, respectively. Dual-luciferase reporter and western blot assays verified that metallothionein-2 was a target gene for miR-491-5p. Cell counting kit 8 (CCK-8) assay, flow cytometry, and 2?,7?-dichlorofluorescein diacetate (DCFH-DA) assay results confirmed that the downregulation of miR-491-5p increased brain microvascular endothelial cell viability, reduced cell apoptosis, and alleviated oxidative stress under oxygen-glucose deprivation conditions. Cell scratch assay, Transwell assay, tube formation assay, and western blot assay results demonstrated that miR-491-5p downregulation promoted the migration, proliferation, and tube formation of brain microvascular endothelial cells through a metallothionein-2-dependent hypoxia-inducible factor-1α/vascular endothelial growth factor pathway. These findings confirmed that miR-491-5p downregulation promotes neovascularization, restores cerebral blood flow, and improves the recovery of neurological function after traumatic brain injury. The mechanism may be mediated through a metallothionein-2-dependent hypoxia-inducible factor-1α/vascular endothelial growth factor signaling pathway and the alleviation of oxidative stress. All procedures were approved by Ethics Committee of the First Affiliated Hospital of Chongqing Medical University, China (approval No. 2020-304) on June 22, 2020.

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating cerebrovascular disease with high mortality and morbidity. In recent years, a large number of studies have focused on the mechanism of early brain injury (EBI) and delayed cerebral ischemia (DCI), including vasospasm, neurotoxicity of hematoma and neuroinflammatory storm, after aSAH. Despite considerable efforts, no novel drugs have significantly improved the prognosis of patients in phase III clinical trials, indicating the need to further re-examine the multifactorial pathophysiological process that occurs after aSAH. The complex pathogenesis is reflected by the destruction of the dynamic balance of the energy metabolism in the nervous system after aSAH, which prevents the maintenance of normal neural function. This review focuses on the fluid metabolic pathways of the central nervous system (CNS), starting with ruptured aneurysms, and discusses the dysfunction of blood circulation, cerebrospinal fluid (CSF) circulation and the glymphatic system during disease progression. It also proposes a hypothesis on the metabolic disorder mechanism and potential therapeutic targets for aSAH patients. Cover Image for this issue: https://doi.org/10.1111/jnc.15384.

Aim To establish an artery and venous sinus occlusion image score (AVOIS) which is compatible in both cerebral arteries and venous system diseases. Methods A total of 188 consecutive patients with the final diagnosis of anterior circulation infarct (ACI) and 56 consecutive patients with cerebral venous and sinus thrombosis (CVST) were retrospectively studied. The AVOIS was developed based on the severity of occlusive changes of main intracranial arteries and venous sinuses (present = 0, partial occlusion = 1, absent = 2), and divided into four groups (CVST group: 0, 1‐5, 6‐10, >10. ACI group: 0, 1‐5, 6‐10, >10) arbitrarily. A receiver operating characteristic (ROC) curve was applied to discover the sensitivity and specificity of AVOIS. The National Institutes of Health Stroke Scale (NIHSS), Clot Burden Score (CBS) were set as the reference. Logistic regression models were developed to adjust for baseline clinical variables and AVOIS. Length of hospital stay (LOS) was also evaluated using the Kaplan‐Meier estimator. Results For the CVST group, a positive correlation between AVOIS and NIHSS was discovered (Spearman's ρ = 0.54, p, A novel score system called the Artery and Venous Sinus Occlusion Image Score (AVOIS) was developed based on quantification analysis of the intracranial thrombus in both artery and venous sinus (Table 1). According to the CTA or MRA, anterior circulation and venous sinuses were allotted different scores (present = 0, partial occlusion = 1, absent = 2) by researchers. The total score on AVOIS in anterior circulation or venous sinus was accumulated to 14 points.

Studies have shown that downregulation of nuclear-enriched autosomal transcript 1 (Neat1) may adversely affect the recovery of nerve function and the increased loss of hippocampal neurons in mice. Whether Neat1 has protective or inhibitory effects on neuronal cell apoptosis after secondary brain injury remains unclear. Therefore, the effects of Neat1 on neuronal apoptosis were observed. C57BL/6 primary neurons were obtained from the cortices of newborn mice and cultured in vitro, and an oxygen and glucose deprivation cell model was established to simulate the secondary brain injury that occurs after traumatic brain injury in vitro. The level of Neat1 expression in neuronal cells was regulated by constructing a recombinant adenovirus to infect neurons, and the effects of Neat1 expression on neuronal apoptosis after oxygen and glucose deprivation were observed. The experiment was divided into four groups: the control group, without any treatment, received normal culture; the oxygen and glucose deprivation group were subjected to the oxygen and glucose deprivation model protocol; the Neat1 overexpression and Neat1 downregulation groups were treated with Neat1 expression intervention techniques and were subjected to the in oxygen and glucose deprivation protocol. The protein expression levels of neurons p53-induced death domain protein 1 (PIDD1, a pro-apoptotic protein), caspase-2 (an apoptotic priming protein), cytochrome C (a pro-apoptotic protein), and cleaved caspase-3 (an apoptotic executive protein) were measured in each group using the western blot assay. To observe changes in the intracellular distribution of cytochrome C, the expression levels of cytochrome C in the cytoplasm and mitochondria of neurons from each group were detected by western blot assay. Differences in the cell viability and apoptosis rate between groups were detected by cell-counting kit 8 assay and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, respectively. The results showed that the apoptosis rate, PIDD1, caspase-2, and cleaved caspase-3 expression levels significantly decreased, and cell viability significantly improved in the Neat1 overexpression group compared with the oxygen and glucose deprivation group; however, Neat1 downregulation reversed these changes. Compared with the Neat1 downregulation group, the cytosolic cytochrome C level in the Neat1 overexpression group significantly decreased, and the mitochondrial cytochrome C level significantly increased. These data indicate that Neat1 upregulation can reduce the release of cytochrome C from the mitochondria to the cytoplasm by inhibiting the PIDD1-caspase-2 pathway, reducing the activation of caspase-3, and preventing neuronal apoptosis after oxygen and glucose deprivation, which might reduce secondary brain injury after traumatic brain injury. All experiments were approved by the Animal Ethics Committee of the First Affiliated Hospital of Chongqing Medical University, China, on December 19, 2020 (approval No. 2020-895).

Early brain injury (EBI) is a major contributor to the high mortality and morbidity after subarachnoid hemorrhage (SAH). Inflammatory responses and neuronal apoptosis are important causes of EBI. Because 5- lipoxygenase (5-LOX) is known to be involved various central nervous system diseases, we investigated the effects of 5-LOX inhibition during EBI after SAH. Zileuton and LY294002 were used to inhibit expression of 5-LOX and Akt, respectively. We found that 5-LOX expression was significantly increased in the cytoplasm of cortical neurons after SAH and was accompanied by upregulated expression of the inflammatory factors LTB4, TNF-α, IL-1β and IL-6; upregulation of the pro-apoptotic factor Bax; downregulation of the anti-apoptotic factor Bcl-2; and an increased apoptosis rate. Gastric Zileuton administration significantly suppressed all of those effects and improved neurological function. Zileuton also upregulated activated (phosphorylated) AKT levels, and these beneficial effects of Zileuton were abolished by intracerebroventricular infusion of the PI3K inhibitor LY294002. Taken together, these findings indicate that 5-LOX mediates pro-inflammatory and pro-apoptotic effects that contribute to EBI after SAH and that those effects are suppressed by activation of PI3K/Akt signaling. This suggests targeting 5-LOX may be an effective approach to treating EBI after SAH.

Although erythropoietin (EPO) has been proven to significantly promote the proliferation of cancer cells, the mechanism for promoting glioma proliferation is poorly understood. Here, we examined the functional role of the AKT/GSK-3β/β-catenin signaling pathway in the EPO-mediated proliferation of glioma. The distribution of EPO and Ki-67 among clinical samples with different WHO grades was plotted by Immunological Histological Chemistry analysis. U87 and U251 glioma cell lines were treated with short hairpin RNA targeting (shEPO), recombinant human erythropoietin (rhEPO) and/or AKT-specific inhibitor (MK-2206). The changes in phosphorylated AKT, nuclear β-catenin, cyclin D1 and p27kip1 expression were detected. Cell cycle distributions and glioma proliferation in vitro and in vivo were analyzed. The expression level of EPO was significantly elevated with the increase of WHO grade and Ki67 in clinical glioma specimens. In vitro, knockdown of endogenous EPO in U87 and U251 cells effectively block the phosphorylation of AKT and GSK-3β and the expression of nuclear β-catenin. shEPO treatment also significantly decreased the expression of cyclin D1 and increased the expression of p27kip1. The cell cycle transition then slowed down and the proliferation of glioma cells or mouse xenograft tumors both decreased. Treatment of cells or tumors with extra rhEPO reversed the above biological effects mediated by shEPO. rhEPO-induced activation of the AKT/GSK-3β/β-catenin pathway and proliferation were abolished by MK-2206. Our study identified the AKT/GSK-3β/β-catenin axis as a critical mediator of EPO-induced glioma proliferation and further provided a clinically significant dimension to the biology of EPO.

Purpose This study aimed to elucidate the biological function and upstream regulatory mechanism of CELSR1 in glioma. Materials and Methods We evaluated the expression of CELSR1 in glioma by TCGA_GEPIA tool, RT-qPCR, and Western blot assays. CCK-8, wound healing, and transwell invasion assays were, respectively, performed to detect the effect of CELSR1 on cell proliferation, migration, and invasion. The upstream regulatory miRNAs of CELSR1 were predicted by TargetScan and validated by luciferase activity reporter assay. Results CELSR1 is overexpressed in glioma (P

Emerging evidence indicates that pentraxin 3 is an acute-phase protein that is linked with the immune response to inflammation. It is also a newly discovered marker of anti-inflammatory A2 reactive astrocytes, and potentially has multiple protective effects in stroke; however, its role in the adult brain after traumatic brain injury is unknown. In the present study, a moderate model of traumatic brain injury in mice was established using controlled cortical impact. The models were intraventricularly injected with recombinant pentraxin 3 (the recombinant pentraxin 3 group) or an equal volume of vehicle (the control group). The sham-operated mice underwent craniotomy, but did not undergo the controlled cortical impact. The potential neuroprotective and neuroregenerative roles of pentraxin 3 were investigated on days 14 and 21 after traumatic brain injury. Western blot assay showed that the expression of endogenous pentraxin 3 was increased after traumatic brain injury in mice. Furthermore, the neurological severity test and wire grip test revealed that recombinant pentraxin 3 treatment reduced the neurological severity score and increased the wire grip score, suggesting an improved recovery of sensory-motor functions. The Morris water maze results demonstrated that recombinant pentraxin 3 treatment reduced the latency to the platform, increased the time spent in the correct quadrant, and increased the number of times traveled across the platform, thus suggesting an improved recovery of cognitive function. In addition, to investigate the effects of pentraxin 3 on astrocytes, specific markers of A2 astrocytes were detected in primary astrocyte cultures in vitro using western blot assay. The results demonstrated that pentraxin 3 administration activates A2 astrocytes. To explore the protective mechanisms of pentraxin 3, immunofluorescence staining was used. Intraventricular injection of recombinant pentraxin 3 increased neuronal maintenance in the peri-injured cortex and ipsilateral hippocampus, increased the number of doublecortin-positive neural progenitor cells in the subventricular and subgranular zones, and increased the number of bromodeoxyuridine (proliferation) and neuronal nuclear antigen (mature neuron) double-labeled cells in the hippocampus and peri-injured cortex. Pentraxin 3 administration also increased the number of neurospheres and the number of bromodeoxyuridine and doublecortin double-labeled cells in neurospheres, and enhanced the proliferation of neural progenitor cells in primary neural progenitor cell cultures in vitro. In conclusion, recombinant pentraxin 3 administration activated A2 astrocytes, and consequently improved the recovery of neural function by increasing neuronal survival and enhancing neurogenesis. All experiments were approved by the Animal Ethics Committee of the First Affiliated Hospital of Chongqing Medical University, China on March 1, 2016.

The objective of this study is to propose a definition of intraventricular hemorrhage (IVH) growth and to investigate whether IVH growth is associated with ICH expansion and functional outcome. We performed a prospective observational study of ICH patients between July 2011 and March 2017 in a tertiary hospital. Patients were included if they had a baseline CT scan within 6 h after onset of symptoms and a follow-up CT within 36 h. IVH growth was defined as either any newly occurring intraventricular bleeding on follow-up CT scan in patients without baseline IVH or an increase in IVH volume ≥ 1 mL on follow-up CT scan in patients with initial IVH. Poor outcome was defined as modified Rankin Scale score of 3–6 at 90 days. The association between IVH growth and functional outcome was assessed by using multivariable logistic regression analysis. IVH growth was observed in 59 (19.5%) of 303 patients. Patients with IVH growth had larger baseline hematoma volume, higher NIHSS score and lower GCS score than those without. Of 44 patients who had concurrent IVH growth and hematoma growth, 41 (93.2%) had poor functional outcome at 3-month follow-up. IVH growth (adjusted OR 4.15, 95% CI 1.31–13.20; P = 0.016) was an independent predictor of poor functional outcome (mRS 3–6) at 3 months in multivariable analysis. IVH growth is not uncommon and independently predicts poor outcome in ICH patients. It may serve as a promising therapeutic target for intervention.

Introduction Axonal injury results in long‐term neurological deficits in traumatic brain injury (TBI) patients. Apolipoprotein E (ApoE) has been reported to activate intracellular adaptor protein Disabled‐1 (Dab1) phosphorylation via its interaction with ApoE receptors. The Dab1 pathway acts as a regulator of axonal outgrowth and growth cone formation in the brain. Aims We hypothesized that ApoE may alleviate axonal injury and regulate axonal regeneration via the Dab1 pathway after TBI. Results In this study, we established a model of controlled cortical impact (CCI) to mimic TBI in vivo. Using diffusion tensor imaging to detect white matter integrity, we demonstrated that APOE‐deficient mice exhibited lower fractional anisotropy (FA) values than APOE+/+ mice at 28 days after injury. The expression levels of axonal regeneration and synapse plasticity biomarkers, including growth‐associated protein 43 (GAP43), postsynaptic density protein 95 (PSD‐95), and synaptophysin, were also lower in APOE‐deficient mice. In contrast, APOE deficiency exerted no effects on the levels of myelin basic protein (MBP) expression, oligodendrocyte number, or oligodendrocyte precursor cell number. Neurological severity score (NSS) and behavioral measurements in the rotarod, Morris water maze, and Y maze tests revealed that APOE deficiency caused worse neurological deficits in CCI mice. Furthermore, Dab1 activation downregulation by the ApoE receptor inhibitor receptor‐associated protein (RAP) or Dab1 shRNA lentivirus attenuated the beneficial effects of ApoE on FA values, GAP43, PSD‐95, and synaptophysin expression, and neurological function tests. Additionally, the effects of ApoE on axonal regeneration were further validated in vitro. In a mechanical scratch injury model of primary cultured neurons, recombinant ApoE protein treatment enhanced axonal outgrowth and growth cone formation in injured neurons; however, these effects were attenuated by Dab1 shRNA, consistent with the in vivo results. Conclusion Collectively, these data suggest that ApoE promotes axonal regeneration partially through the Dab1 pathway, thereby contributing to functional recovery following TBI.

Cerebellopontine angle (CPA) medulloblastoma is rare and short of system description. We attempted to clarify its epidemiology, clinical manifestations, imaging features, pathological and molecular types, and surgical outcomes. 8 patients from 7 to 52 years old were enrolled in this retrospective study, with mean age 21.6 ± 16.4 years. The most frequent symptoms were raised intracranial pressure (100%), followed by cerebellar signs (50%), decreased hearing (50%), facial paralysis (50%), abducent paralysis (50%), and facial paresthesia (37.5%). MRI demonstrated a solid CPA lesion with heterogeneously weak or significant enhancement after gadolinium administration, accompanied with peritumoral oedema (75%), cystic change (62.5%) and dural tail sign (50%), while CT showed petrous bone and internal auditory canal intact. All cases received tumor excision, with 6 (75%) cases undergoing gross total resection, and the remaining (25%) getting partial excision. Pathological examination confirmed 5 (62.5%) classic, 2 (25%) desmoplastic, and 1 (12.5%) anaplastic. Further molecular analysis identified 5 (62.5%) WNT and 3 (37.5%) SHH. Immediately after the primary surgery, 7 (87.5%) cases gained improvement of the symptoms and signs and 1 (12.5%) kept the preoperative status stable. Follow up was available ranged from 5 to 34 months, during that period 5 cases kept symptom free and 3 cases recurred/progressed. In conclusion, CPA medulloblastoma is rare and lacking of special clinical manifestations and radiological features, and should be considered in the differential diagnosis of CPA lesions. In this series the most frequent pathological and molecular type is classic and WNT. Microsurgery excision is effective to prevent progressive decline of neurological status.

Objective: With the aging of the world population, the number of elderly patients suffering from aneurysmal subarachnoid hemorrhage (aSAH) is gradually growing. We aim to investigate the potential association between plasma ALT level and clinical complications of elderly aSAH patients, and explore its predictive value for clinical outcomes of elderly aSAH patients. Methods: Between January 2013 and March 2018, 152 elderly aSAH patients were analyzed in this study. Clinical information, imaging findings and laboratory data were reviewed. According to the Glasgow Outcome Scale (GOS), clinical outcomes at 3 months were classified into favorable outcomes (GOS 4-5) and poor outcomes (GOS 1-3). Logistic regression analysis was used to assess the indicators associated with poor outcomes, and receiver curves (ROC) and corresponding area under the curve (AUC) were used to detect the accuracy of the indicator. Results: A total of 48 (31.6 %) elderly patients with aSAH had poor outcome at 3 months. In addition to ICH, IVH, Hunt-Hess 4 or 5 Grade and Modified Fisher 3 or 4 Grade, plasma ALT level was also strongly associated with poor outcome of elderly aSAH patients. After adjusting for other covariates, plasma ALT level remained independently associated with pulmonary infection (OR 1.05; 95% CI 1.00–1.09; P = 0.018), cardiac complications (OR 1.05; 95% CI 1.01–1.08; P = 0.014) and urinary infection (OR 1.04; 95% CI 1.00–1.08; P = 0.032). Besides, plasma ALT level had a predictive ability in the occurrence of systemic complications (AUC 0.676; 95% CI: 0.586– 0.766; P Conclusion: Plasma ALT level of elderly patients with aSAH was significantly associated with systemic complications, and had additional clinical value in predicting outcomes. Given that plasma ALT levels on admission could help to identify high-risk elderly patients with aSAH, these findings are of clinical relevance.

The purpose of this study was to investigate the imaging characteristics of fenestrated anterior communicating artery (AcomA) aneurysm and clinical outcome of patients with fenestrated AcomA aneurysm.We performed a retrospective study of consecutive patients with AcomA aneurysms between January 2013 and December 2017. According to the vascular variations of the AcomA, the patients were divided into 2 groups: fenestrated AcomA aneurysms and non-fenestrated AcomA aneurysms. Baseline characteristics, clinical complications, and outcomes of patients were analyzed.A total of 217 patients with AcomA aneurysms were included in this study. Compared to non-fenestrated AcomA aneurysms, the size of fenestrated AcomA aneurysms was significantly smaller (P0.001). Moreover, the patients with fenestrated AcomA aneurysms had a higher rate of rebleeding (P = 0.036), hydrocephalus (P = 0.017), delayed cerebral ischemia (P = 0.021), and pulmonary infection (P = 0.017) than those with non-fenestrated AcomA aneurysms. According to the Glasgow Outcome Scale (GOS) at follow-up, the patients with fenestrated AcomA aneurysms had a higher rate of disability (P = 0.035) (GOS 2-3) and mortality (P = 0.013) (GOS 1).Fenestrated AcomA aneurysms are associated with higher clinical complications, and identification of AcomA fenestration contributes to successful clipping of AcomA aneurysms.

microRNAs (miRNAs) can function as a tumor suppressor or oncogenic genes in human cancers. Alternation expression of miR-199a-5p has been revealed in several human cancers. However, its expression pattern and biological roles in glioma remain unclear. Expression levels of miR-199a-5p in glioma were evaluated at first. The effects of miR-199a-5p expression on cell proliferation, migration, and invasion were investigated using the MTT assay, wound-healing assay, and transwell invasion assay. The expression of miR-199a-5p was found to be reduced in glioma cell lines. Overexpression of miR-199a-5p inhibits glioma cell proliferation, migration, and invasion in vitro. Furthermore, the target of miR-199a-5p was predicted by TargetScan and validated by luciferase activity reporter assay. We found magnesium transporter 1 (MAGT1) was a direct target of miR-199a-5p. Overexpression of MAGT1 reversed the effects of miR-199a-5p on glioma cell behaviors. Taken together, our study revealed that miR-199a-5p and MAGT1 have the potential to be used as a biomarker for glioma.

Yue Wu,1 Qiuguang He,2 Yuling Wei,3 Ji Zhu,1 Zhaohui He,1 Xiaodong Zhang,1 Zongduo Guo,1 Rui Xu,1 Chongjie Cheng,1 Zhijian Huang,1 Xiaochuan Sun11Department of Neurosurgery, First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Neurosurgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Pharmacy, Chongqing Traditional Chinese Medicine Hospital, Chongqing, People’s Republic of ChinaBackground and purpose: Emerging evidence suggests that systemic inflammation is associated with the pathophysiological process of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). This study aimed to investigate the association of white blood cell (WBC) count and neutrophil-to-lymphocyte ratio (NLR) with the occurrence of DCI in SAH patients.Methods: A total of 122 patients diagnosed with aSAH within 72 h of onset were retrospectively enrolled. The count of WBC, neutrophil count (NC), and lymphocyte (LC) was collected on admission. Computed tomography perfusion was performed within 7 days after SAH. The occurrence of DCI was recorded during the hospitalization.Results: Among enrolled patients, 43 (35.2%) developed DCI during hospitalization. Patients who developed DCI had a higher count of WBC, NC, and NLR as well as a lower count of LC. NC and NLR were independently associated with the occurrence of DCI, while NLR was the best predictive parameter according to the receiver operating characteristic curve. Moreover, there was a strong correlation between NLR and mean cerebral blood flow, mean transit time and mean time to peak.Conclusion: Leukocytosis is an early pathology of SAH, and NLR may be a practical predictor for the occurrence of DCI in SAH patients.Keywords: aneurismal subarachnoid hemorrhage, neutrophil-to-lymphocyte ratio, cerebral blood flow, delayed cerebral ischemia

Objective The aim of this study is to detail the background, training, and career of Dr. Georgette Kidess, the first and still the only female neurosurgeon in Palestine. In addition, we mention the obstacles that women face during their neurosurgical career and how to overcome them. Also, we discuss different methods to attract female medical students to neurosurgery. Methods Information was gathered only from direct face-to-face interviews with Dr. Kidess. Results Georgette Kidess was born on May 2, 1952, in Nablus, Palestine. She received the degree of Doctor of Medicine (M.D.) at Eberhard Karls Universitat, Tubingen, Germany in 1979. She worked as a neurosurgeon at the Hadassah EinKarem Hospital in Jerusalem and subsequently established the first neurosurgical department at the Ramallah Governmental Hospital in Ramallah in 1986. Thereafter, she has continued a career in private practice, currently at Saint Luke's Hospital, Nablus. Dr. Kidess played a major part in establishing neurosurgery in Palestine. She was among the founders of the Palestinian Neurosurgical Society in 2014. Conclusions In this article, we recount Dr. Kidess's contributions and achievements to neurosurgery in Palestine. Her commitment, persistence, and diligence enabled her to overcome great odds and become the first female neurosurgeon in Palestine. We hope that her story will inspire and open the doors for subsequent women to enter and enhance neurosurgery, especially in the Middle East.

As a highly evolutionary conserved lncRNA, MALAT1 was first demonstrated to associate with metastasis of lung tumor by promoting angiogenesis. Activated vasculature was recently indicated to assist neurogenesis by secreting neurotrophic factor Ang1 (Angiopoietin-1). The purpose of this study is to investigate the potential role of MALAT1 in angiogenesis following traumatic brain injury (TBI). Adult male mice were subjected to controlled cortical impact (CCI) and brain microvacular endothelial cells were exposed to oxygen-glucose deprivation (OGD). MALAT1 RNA levels were quantitified by qRT-PCR in different cells of CNS and located by RNA-FISH. Angiogenesis were measured by cell viability, migration assay, tube formation assay in vitro, and immunohistochemistry in vivo. Expression of Angiopoietin-1 was assessed by Western blot. Neurological functions were performed by NSS, Wire grip and MWM tests. Our results indicated that 1) MALAT1 RNA was localized in cerebral endothelium, enhanced by OGD stimuli. 2) Inhibition of MALAT1 by siRNA suppressed angiogenesis, as indicated by endothelial viability, tube formation, migration, and functional vessel density. 3) MALAT1 inhibition further decreased Ang1 expression in the endothelium. 4) Mice with MALAT1 inhibition exhibited worse behavioral performances (NSS, wire grip, Morris water maze), as compared to control. MALAT1 could promote angiogenesis, subsequently contributing to the Ang1 synthesis from active vasculature. It may eventually benefit to functional recovery following TBI.

Background and Purpose: Traumatic brain injury (TBI) destroys white matter, and this destruction is aggravated by secondary neuroinflammatory reactions. Although white matter injury (WMI) is strongly correlated with poor neurological function, understanding of white matter integrity maintenance is limited, and no available therapies can effectively protect white matter. One candidate approach that may fulfill this goal is cannabinoid receptor 2 (CB2) agonist treatment. Here, we confirmed that a selective CB2 agonist, JWH133, protected white matter after TBI. Methods: The controlled cortical impact (CCI) was used to establish a moderate TBI model in adult male Sprague-Dawley rats ( 8–10 weeks, 250–300g). The motor evoked potentials (MEPs), open field test, and Morris water maze test were used to assess neurobehavioral outcomes. Brain tissue loss, WM damage, Endoplasmic reticulum stress (ER stress), and microglia responses were evaluated after TBI. The functional integrity of WM was measured by diffusion tensor imaging (DTI) and transmission electron microscopy (TEM). Primary microglia and oligodendrocyte cocultures were used for additional mechanistic studies.Results: JWH133 increased myelin basic protein (MBP) and neurofilament heavy chain (NF200) levels and anatomic preservation of myelinated axons revealed by DTI and TEM. JWH133 also increased the numbers of oligodendrocyte precursor cells and mature oligodendrocytes. Furthermore, JWH133 drove microglial polarization toward the protective M2 phenotype and modulated the redistribution of microglia in the striatum. Further investigation of the underlying mechanism revealed that JWH133 downregulated phosphorylation of the protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK) signaling pathway and its downstream signals eukaryotic translation initiation factor 2 α (eIF2α), activating transcription factor 4 (ATF4) and Growth arrest and DNA damage-inducible protein (GADD34); this downregulation was followed by p-Protein kinase B(p-Akt) upregulation. In primary cocultures of microglia and oligodendrocytes, JWH133 decreased phosphorylated PERK expression in microglia stimulated with tunicamycin and facilitated oligodendrocyte survival. These data reveal that JWH133ultimately alleviates WMI and improves neurological behavior following TBI. However, these effects were were prevented by SR144528(i.p. injection 3 min before receiving JWH133 intraperitoneally), a selective CB2 antagonist.Conclusions: This work illustrates the PERK-mediated interaction between microglia and oligodendrocytes. In addition, the results are consistent with recent findings that microglial polarization switching accelerates WMI, highlighting a previously unexplored role for CB2 agonists. Thus, CB2 agonists are potential therapeutic agents for TBI and other neurological conditions involving white matter destruction.

The present study aimed to investigate the function of the single nucleotide polymorphism (SNP) rs41291957 in the prognosis of intracerebral hemorrhage (ICH). In addition, the molecular mechanisms underlying the role of microRNA (miR)‑143, Toll‑like receptor 2 (TLR2) and interleukin‑16 (IL‑16) were studied in patients with ICH that carried different alleles in the locus of the rs41291957 SNP. Kaplan‑Meier survival curves were calculated for 182 patients with ICH, genotyped as CC, presenting a cytosine in both chromosome, CT, presenting both variants, and TT, presents a thymine in both chromosomes. In addition, the possible regulatory relationships between miR‑143 and TLR2/IL‑16 were studied using computational analysis, luciferase assays and western blot assay. In addition, the inflammatory profiles of cerebrospinal fluid (CSF) and serum samples collected from the subjects were compared. The patients genotyped as TT presented the lowest survival rate, while patients genotyped as CC presented the highest survival rate. TLR2 mRNA was identified as a potential target of miR‑143, while IL‑16 showed no direct interaction with miR‑143. The above regulatory relationships were further investigated using cells transfected with miR‑143 precursor or TLR2 small interfering RNA. In addition, the expression levels of inflammatory factors, such as tumor necrosis factor α, interferon, IL‑6, IL‑10 and NF‑L‑6, were highest in the CSF/serum samples collected from patients genotyped as TT and lowest in patients genotyped as CC. By contrast, the expression levels of miR‑143 showed an opposite trend in the expression of the above inflammatory factors. The rs41291957 SNP, located in the promoter region of miR‑143, reduced the expression of miR‑143 and upregulated the expression of the pro‑inflammatory factor TLR2, eventually leading to a poorer prognosis in patients with ICH.

Background and TargetFollowing brain trauma, blood–brain barrier (BBB) disruption and inflammatory response are critical pathological steps contributing to secondary injury, leading to high mortality and morbidity. Both pathologies are closely associated with endothelial remodeling. In the present study, we concentrated on annexin A1 (ANXA1) as a novel regulator of endothelial function after traumatic brain injury.MethodsAfter establishing controlled cortical impact (CCI) model in male mice, human recombinant ANXA1 (rANXA1) was administered intravenously, followed by assessments of BBB integrity, brain edema, inflammatory response, and neurological deficits.ResultAnimals treated with rANXA1 (1 μg/kg) at 1 h after CCI exhibited optimal BBB protection including alleviated BBB disruption and brain edema, as well as endothelial junction proteins loss. The infiltrated neutrophils and inflammatory cytokines were suppressed by rANXA1, consistent with decreased adhesive and transmigrating molecules from isolated microvessels. Moreover, rANXA1 attenuated the neurological deficits induced by CCI. We further found that the Ras homolog gene family member A (RhoA) inhibition has similar effect as rANXA1 in ameliorating brain injuries after CCI, whereas rANXA1 suppressed CCI-induced RhoA activation.ConclusionOur findings suggest that the endothelial remodeling by exogenous rANXA1 corrects BBB disruption and inflammatory response through RhoA inhibition, hence improving functional outcomes in CCI mice.

Background and Purpose: Stent-assisted coiling (SAC) of intracranial aneurysms is usually treated with antiplatelet therapy to reduce the risk of postoperative ischemic events. However, using the same antiplatelet therapy for all patients may increase the risk of bleeding in patients with aneurysmal subarachnoid hemorrhage (aSAH). Thromboelastography-platelet mapping (TEG-PM) measures platelet function, which reflects the effect of antiplatelet drugs. This study aimed to evaluate the benefits of individualized antiplatelet regimens based on TEG-PM parameters for patients with aSAH who underwent SAC.Methods: We retrospectively included patients with aSAH who treated with SAC during the period from June 2012 to December 2019. Patients were divided into two groups: patients whose antiplatelet therapy adjusted by TEG-PM parameters after surgery (adjustment group) and patients who were treated with standard dual antiplatelet therapy without TEG-PM test (control group). The occurrence of major/minor bleeding events, major/minor thromboembolic events, and favorable outcome (modified Rankin scale Results: Of 188 aSAH patients considered for this study, 145 met the criteria for inclusion and were included in the analysis (93 patients in the adjustment group and 52 patients in the control group). The risks of minor bleeding events (1.1 vs. 9.6%, p = 0.02) were significantly lower in patients in the adjustment group. However, there was no significant difference in the rate of major bleeding events at discharge between adjustment and control groups (p = 0.35). The rates of thromboembolic events and favorable outcome were similar in both groups (22.6 vs. 28.8%, p = 0.42, 95.7 vs. 96.2%, p = 1.00). Furthermore, the minor thromboembolic events rate was significantly lower in the patients treated with treatment plan C (p = 0.02 for treatment plan C vs. treatment A, p = 0.03 for treatment plan C vs. treatment plan B). However, there was no significant difference in the rate of other mentioned above complications and favorable outcomes among patients treated with different antiplatelet regimens.Conclusions: Individualized antiplatelet therapy based on TEG-PM parameters might positively impact the bleeding risk of aSAH patients, without increasing the risk for clinically relevant thromboembolic events.

Background and Purpose: Primary brain swelling occurs in aneurysmal subarachnoid hemorrhage (aSAH) patients. The absence of a dynamic quantitative method restricts further study of primary brain swelling. This study compared differences in the change rate of brain volume (CRBV) between patients with and without primary brain swelling in the early stage of aSAH. Moreover, the relationship between CRBV and clinical outcomes was evaluated.Methods: Patients hospitalized within 24 h after aSAH were included in this retrospective study. Utilizing a qualitative standard established before the study to recognize primary brain swelling through brain CT after aSAH, clinical outcomes after 3 months of SAH were evaluated with a modified Rankin scale (mRS). The brain volume (BV) of each patient was calculated with a semiautomatic threshold algorithm of 3D-slicer, and the change in brain volume (CIBV) was obtained by subtracting the two extreme values (CIBV = BVmax – BVmin). The CRBV was obtained by CIBV/BVmin × 100%. The CRBV values that predicted unfavorable prognoses were estimated.Results: In total, 130 subjects were enrolled in the study. The mean CRBV in the non-swelling group and swelling group were 4.37% (±4.77) and 11.87% (±6.84), respectively (p < 0.05). CRBV was positively correlated with the length of hospital stay, blood in the ambient cistern, blood in the lateral ventricle, and lateral ventricular volume (Spearman ρ = 0.334; p < 0.001; Pearson ρ = 0.269, p = 0.002; Pearson ρ = 0.278, p = 0.001; Pearson ρ = 0.233, p = 0.008, respectively). Analysis of variance showed significant differences in CIBV, CRBV, blood in the ambient cistern, blood in the lateral ventricle, and lateral ventricular volume among varying modified Fisher scale (mFisher), with higher admission mFisher scale, indicating larger values of these variables. After adjusting for risk factors, the model showed that for every 1% increase in the CRBV, the probability of poor clinical prognosis increased by a factor of 1.236 (95% CI = 1.056–1.446). In the stratified analysis, the odds of worse clinical outcomes increased with increases in the CRBV. Receiver operating characteristic curve analysis showed that HH grade, mFisher scale, and score of CRBV (SCRBV) had diagnostic performance for predicting unfavorable clinical outcomes.Conclusion: Primary brain swelling increases brain volume after aSAH. The CRBV quantified by 3D-Slicer can be used as a volumetric representation of the degree of brain swelling. A larger CRBV in the early stage of aSAH is associated with poor prognosis. The CRBV can be used as a neuroimaging biomarker of early brain injury after bleeding and may be an effective predictor of patients' clinical prognoses.

This study aims to test the validity of a new quantitative scoring instrument-the Venous Occlusion Image Score (VOIS), and assess the diagnostic and prognostic value of VOIS for cerebral venous sinus thrombosis (CVST).The VOIS divided the major cerebral venous sinuses and internal jugular veins into nine parts of interest. CT venography and DSA source images and reconstruction were extracted from the database, then interpreted and scored independently according to VOIS by a panel of three reviewers. Inter-observer and intra-observer reliability were determined using the intraclass correlation coefficient (ICC) and the kappa coefficient (κ). The primary outcome was the 3-month functional outcome and evaluated by modified Rankin Scale (mRS). The sensitivity and specificity of VOIS for the primary outcomes were computed. Logistic regression was applied to evaluate the association between the score on VOIS and the primary outcomes.Fifty-six patients with CVST were included in the study. For 16 patients underwent cerebral CTV and DSA, excellent interobserver agreement was observed for DSA (ICC=0.90, 95%CI = 0.87 - 0.92, P0.001), and CTV (ICC = 0.92, 95%CI = 0.84 - 0.93, P0.001). The κ coefficient of agreement for the two radiology measures was 0.88 (95%CI = 0.79-0.92), indicating good inter-method agreement. For 56 patients followed up by CTV, baseline VOIS value correlated inversely with the severity of stroke on the National Institutes of Health Stroke Scale (r = -0·53, P0·001), and modified Rankin Scale (r = -0·59, P0·001). Baseline CTV-VOIS value predicted functional outcome (P0·05).VOIS may serve as a convenient and reliable method in the treatment guidance and outcome prediction of patients with CVST.

Objective: To investigate the effects of the apolipoprotein E gene (APOE) on the cerebral oxygen saturation of patients after traumatic brain injury (TBI).Methods: Clinical data of 114 patients with TBI and 54 normal people were collected. The APOE genotypes of all subjects were determined by quantitative fluorescent polymerase chain reaction (QF-PCR). The regional cerebral oxygen saturation (rScO2) of TBI patients and normal people were monitored by near-infrared spectroscopy (NIRS).Results: The mean rScO2 of patients was (55.06 ± 7.60)% in the early stage of TBI, which was significantly lower than that of normal people (67.21 ± 7.80)% (P < 0.05). Single-factor and multifactor logistic regression analyses showed APOEε4 was an independent risk factor that caused the early decline of rScO2 in TBI patients. Furthermore, in the TBI group, the rScO2 of APOEε4 carriers (52.23 ± 8.02)% was significantly lower than that of non-ε4 carriers (60.33 ± 7.12)% (P < 0.05). But in the normal group, no significant differences in rScO2 were found between APOEε4 carriers and non-carriers.Conclusion: The rScO2 may be significantly decreased after TBI, and APOEε4 may be a risk factor for decreased rScO2 in the early stage of TBI.

Solid/cystic hemangioblastomas are rare, and they lack a systematic description. We clarify the epidemiology, clinical features, imaging characteristics, and surgical outcomes of sporadic solid/cystic hemangioblastomas in the cerebellum.A total of 75 patients with sporadic hemangioblastomas from 2006 to 2018 were enrolled in this retrospective study and divided into solid (26/75), cystic (40/75), and solid/cystic (9/75) groups according to the imaging findings. All patients underwent microsurgical resection and had a definite 31 pathologic diagnosis.The age at diagnosis in the solid/cystic group was the highest among the 3 groups (P0.05). The solid/cystic group showed the shortest symptom duration (P0.05), which was related to obvious peritumoral brain edema (P0.05). The combination of computed tomography angiography and magnetic resonance imaging helped with the differential diagnosis. The solid/cystic group showed the lowest rate of gross total resection (P0.05) as a result of the obscure brain-tumor interface, and the guidance of intraoperative ultrasonography helped with the microsurgical procedures to a certain extent. Patients in the solid/cystic group showed greater intraoperative blood loss (P0.05), a lower ratio of symptom improvement (P0.05), and a longer mean hospital stay (P0.05) than did patients in the cystic group.Cerebellar sporadic solid/cystic hemangioblastomas are rare and usually affect elderly people. The combination of computed tomography angiography and magnetic resonance imaging may improve the preoperative diagnosis. Solid/cystic hemangioblastomas showed the lowest rate of gross total resection as a result of the obscure brain-tumor interface.

Objective: To analyze the incidence and risk factors of microbleeds lesions and to use thromboelastography (TEG) to evaluate the relationship between perioperative platelet function and microbleed events in patients with unruptured intracranial aneurysms (UIAs) undergoing Stent-Assisted Coil (SAC) embolization. Methods: We retrospectively enrolled 261 patients with UIAs undergoing SAC embolization between November 2017 and October 2019. All patients received unanimous antiplatelet protocol (aspirin 300 mg and clopidogrel 300 mg). Platelet function was evaluated by TEG, and magnetic resonance susceptibility-weighted imaging (SWI) was performed for microbleeds detection before and after surgery. Univariate and multivariate logistic regression analyses were used to identify potential risk factors for microbleeds following embolization. Results: Microbleed lesions were identified in 122 of 261 patients (46.7%). Most of the microbleeds were asymptomatic, except for 22 patients complaining slight headaches, and 3 patients who developed cerebral hemorrhage after discharge. Among the clinical characters, female, previous intracerebral hemorrhage (ICH) history and TEG parameters variation (higher reaction time (R) and lower maximum amplitude of adenosine diphosphate (MAADP)) were associated with microbleeds occurrence. Subsequent multivariate analysis indicated that gender, hemorrhage history, R, and MAADP were still independent risk factors of microbleeds. The R-value (>7.6 min) and MAADP ( Conclusion: The incidence of microbleeds may be high in UIA patients treated with SAC and dual antiplatelet therapy. Lesions occurred more frequently in female patients and patients with ICH history. Among the TEG parameters, the R-value and MAADP were predictors for microbleed events.

Background To explore the effect of estrogen on human cerebral vascular smooth muscle cells (VSMCs) and to clarify the molecular mechanism of estrogen inhibition of VSMC proliferation, which could provide an important reference basis for the clinical treatment of hypertensive intracerebral hemorrhage. Method Firstly, the effects of different concentrations of estradiol and estrogen receptor (ESR) blocker (tamoxifen) on the proliferation of human VSMCs and the expression of estrogen-related receptor gene (ESR: ESR1, ESR2, GPER), myocardin (MYOCD), serum reaction factor (SRF), and apoptosis gene caspase-3 were measured to discover the effect and mechanism of tamoxifen on the proliferation and apoptosis of VSMCs. Secondly, the effects of estradiol on human VSMCs treated with angiotensin II (Ang II) were observed by measuring the expression of vascular smooth muscle markers, α-smooth muscle actin (α-SMA), SM22α, FLN, MCP-1, and TLR4. Results Estradiol inhibited the proliferation of VSMCs by upregulating the expression of ESR1, ESR2, and GPER and downregulating the expression of caspase-3, MYOCD, and SRF, thereby inhibiting the apoptosis of vascular smooth muscle. At the same time, tamoxifen had opposite effects. Angiotensin II decreased the expression of α-SMA and SM22α and promoted the expression of FLN, MCP-1, and TLR4 protein, while estrogen had the opposite effects. Conclusions Estrogen suppresses apoptosis by inhibiting the proliferation of human VSMCs and preventing it from changing from contractile to synthetic. Estrogen can further prevents vascular damage and regulate peripheral inflammatory reaction, thereby producing a protective effect on cardiovascular and cerebrovascular.

OBJECTIVE The risk of hemorrhagic events in small ruptured aneurysms remains unclear. Due to less arterial wall, small ruptured aneurysms may be correlated with massive bleeding and rebleeding. Therefore, it may contribute to treatment to evaluate the amount of bleeding and the risk of rebleeding in small ruptured aneurysms. METHODS A retrospective cohort study of all consecutive patients with intracranial aneurysms admitted to our hospital from February 2013 to December 2017 was carried out. Ruptured aneurysms were divided into small ruptured aneurysm (0-5 mm) group and large ruptured aneurysm (5 mm) group for analysis. The difference of bleeding volume, rebleeding and clinical outcome were analyzed between the two groups. RESULTS A total of 738 patients with aneurysmal subarachnoid hemorrhage (SAH) were included in this study and small ruptured aneurysms accounted for 49.2% of all ruptured aneurysms. Univariate analysis showed that the amount of bleeding (14.5 ± 7.1 vs. 14.4 ± 7.3; P = 0.867), rebleeding (8.3% vs. 10.9%; P = 0.261) and poor outcome (29.6% vs. 23.1%; P = 0.055) were similar between the two groups. Multivariable analysis showed that hypertension was obviously associated with the amount of bleeding (adjusted odds ratio (aOR), 3.25 [1.81-4.69]; P

Traumatic brain injury (TBI) has been regarded as one of the leading cause of injury-related death and disability. White matter injury after TBI is characterized by axon damage and demyelination, resulting in neural network impairment and neurological deficit. Brain-derived neurotrophic factor (BDNF) can promote white matter repair. The activation of peroxisome proliferator-activated receptor gamma (PPARγ) has been reported to promote microglia/macrophages towards anti-inflammatory state and therefore to promote axon regeneration. Bexarotene, an agonist of retinoid X receptor (RXR), can activate RXR/PPARγ heterodimers. The aim of the present study was to identify the effect of bexarotene on BDNF in microglia/macrophages and axon sprouting after TBI in mice. Bexarotene was administered intraperitoneally in C57BL/6 mice undergoing controlled cortical impact (CCI). PPARγ dependency was determined by intraperitoneal administration of a PPARγ antagonist T0070907. We found that bexarotene promoted axon regeneration indicated by increased growth associated protein 43 (GAP43) expression, myelin basic protein (MBP) expression, and biotinylated dextran amine (BDA)+ axon sprouting. Bexarotene also increased microglia/macrophages-specific brain derived neurotrophic factor (BDNF) expression after TBI. In addition, bexarotene reduced the number of pro-inflammatory microglia/macrophages while increased the number of anti-inflammatory microglia/macrophages after TBI. Moreover, bexaortene inhibited pro-inflammatory cytokine secretion. In addition, bexarotene treatment improved neurological scores and cognitive function of CCI-injured mice. These effects of bexarotene were partially abolished by T0070907. In conclusion, bexarotene promotes axon sprouting, increases microglia/macrophages-specific BDNF expression, and induces microglia/macrophages from a pro-inflammatory state towards an anti-inflammatory one after TBI at least partially in a PPARγ-dependent manner.

Background: Small ruptured cerebral aneurysms (≤5 mm) account for the majority of aneurysmal subarachnoid hemorrhages, and its clinical management remains a challenge. The aim of this study was to identify the effect of age-related complications on the outcome of patients with small ruptured aneurysm.Methods: A retrospective review was performed in patients with small ruptured aneurysms who underwent microsurgical clipping or endovascular coiling from September 2012 to December 2018. According to their ages, the patients were divided into the elderly group and the non-elderly group. Baseline characteristics, clinical complications, and outcome of patients were analyzed between the two groups. A multivariate logistic regression analysis was used to determine the risk factors associated with the poor outcome of the elderly patients.Results: In the elderly group, 83 patients were treated with clipping and 50 were treated with coiling. In the non-elderly group, 188 patients were treated with clipping and 117 were treated with coiling. The incidence of neurological complications with neurologic deficit in the elderly group was significantly higher compared with that in the non-elderly group (P = 0.006). The elderly patients had a longer hospital stay (P = 0.032) and a poorer outcome (P = 0.001) compared with the non-elderly patients. A multivariate analysis showed that irregular aneurysms (P = 0.045) and ischemic events (P < 0.001) were independent risk factors associated with poor outcome in the elderly.Conclusions: Neurological complications with neurologic deficit, especially ischemic complications, were clearly more common in the elderly patients. Irregular small aneurysms or postoperative ischemic events should be paid attention as the higher risk of poor outcome in the elderly.

The level of microRNA‐9‐5p (miRNA‐9‐5p) in brain tissues is significantly changed after traumatic brain injury (TBI). However, the effect of miRNA‐9‐5p for brain function in TBI has not been elucidated. In this study, a controlled cortical impact model was used to induce TBI in Sprague–Dawley rats, and an oxygen glucose deprivation model was used to mimic the pathological state in vitro. Brain microvascular endothelial cells (BMECs) and astrocytes were extracted from immature Sprague–Dawley rats and cocultured to reconstruct blood–brain barrier (BBB) in vitro. The results show that the level of miRNA‐9‐5p was significantly increased in brain tissues after TBI, and up‐regulation of miRNA9‐5p contributed to the recovery of neurological function. Up‐regulation of miRNA‐9‐5p with miRNA agomir may significantly alleviate apoptosis, neuroinflammation, and BBB damage in rats after TBI. Moreover, a dual luciferase reporter assay confirmed that miRNA‐9‐5p is a post‐transcriptional modulator of Ptch‐1. In in vitro experiments, the results confirmed that up‐regulation of miRNA‐9‐5p with miRNA mimic alleviates cellular apoptosis, inflammatory response, and BBB damage mainly by inhibiting Ptch‐1. In addition, we found that the activation of Hedgehog pathway was accompanied by inhibition of NF‐κB/MMP‐9 pathway in the BMECs treated with miRNA‐9‐5p mimic. Taken together, these results indicate that up‐regulation of miRNA‐9‐5p alleviates BBB damage and neuroinflammatory responses by activating the Hedgehog pathway and inhibiting NF‐κB/MMP‐9 pathway, which promotes the recovery of neurological function after TBI., Hedgehog pathway and NF‐κB proteins play important roles in cellular apoptosis and inflammatory responses. Using bioinformatics techniques, we find that Ptch‐1, which is an inhibitor of Hedgehog pathway, and NF‐κB are potential targets for microRNA‐9‐5p. We propose the following cascade for microRNA‐9‐5p that alleviates the damage of blood–brain barrier and neuroinflammation after traumatic brain injury: over‐expression of microRNA‐9‐5p activates Hedgehog pathway and blocks NF‐κB/MMP‐9 pathway by inhibiting Ptch‐1 and NF‐κB, which inhibit cellular apoptosis and inflammatory responses of brain microvascular endothelial cells. We think these findings may provide a new target for the treatment of traumatic brain injury.

Background T-SPOT.TB may yield indeterminate results, including high nil responses and insufficient mitogen responses. We explored the incidence and risk factors of high nil responses. Methods A 1:1 matched case-control study of patients who underwent T-SPOT.TB tests in Peking Union Medical College Hospital from Jan 1, 2015 to Apr 30, 2017 was conducted. High nil responses were defined as >10 spots in negative control wells. Cases and controls were matched based on when the tests were performed. Demographic, clinical and laboratory data were obtained from the Medical Record System. Results A total of 644 out of 36,316 (1.76%, 95% CI: 1.63%–1.90%) patients presented with high nil responses (280 cases and 280 controls were enrolled). Multivariate analysis revealed that male (OR = 1.882, 95% CI: 1.222–2.899), Behcet's disease (OR = 7.764, 95% CI: 1.714–35.167), heavy use of corticosteroids within a month (OR = 0.357, 95% CI: 0.138–0.921, for >1000 mg group) and hypoalbuminemia (OR = 0.385, 95% CI: 0.241–0.615) are significantly associated with high nil responses. Conclusions High nil responses in T-SPOT.TB assays are quite rare. Male gender and Behcet's disease are suggested as independent risk factors, while recent excessive use of corticosteroids and hypoalbuminemia seem to be independent protective factors.

Hypertension is common in patients with aneurysmal subarachnoid hemorrhage (SAH). However, it is still unclear whether premorbid antihypertensive therapy can help to reduce the risk of severe aneurysmal bleeding. Therefore, this study aims to assess the effect of premorbid hypertension control on outcome of patients with aneurysmal SAH. We retrospectively reviewed the clinical data of patients with intracranial aneurysms admitted to our institution from February 2012 to December 2017. Based on premorbid hypertension history and use of antihypertensive agents, all patients with aneurysmal SAH were divided into antihypertensive group and uncontrolled group. Patient characteristics, imaging features, clinical complication, and outcome were analyzed between the two groups. A total of 348 patients with ruptured aneurysms were included in this study. Compared to those with premorbid controlled hypertension, patients with premorbid uncontrolled hypertension presented worse clinical grade, with more severe aneurysmal SAH and more frequent intracerebral hematoma. Patients receiving a treatment for ACEI type or ARB type of drugs in the antihypertensive group suffered from less amount of aneurysmal bleeding, while patients with grade 3 hypertension in the uncontrolled group suffered from more amount of aneurysmal bleeding. Patients with premorbid controlled hypertension had a lower incidence of rebleeding, hydrocephalus, and cerebral vasospasm, and had a lower rate of disability and mortality. Premorbid hypertension control is associated with favorable clinical outcome of patients with aneurysmal SAH. Besides, the ACEI type or ARB type of antihypertensive agents is associated with the less amount of bleeding after aneurysm rupture.

Objective: The endovascular filament-perforation model turned out to become the most popular one for the reproduction of prominent pathophysiological features observed after human subarachnoid haem...

Following central nervous system injury in mammals, failed axonal regeneration is closely related to dysneuria. Previous studies have shown that the obvious effects of apolipoprotein E (ApoE) on traumatic brain injury (TBI) were associated with an axonal mechanism. However, little information on the actions of ApoE and its isoforms on axonal regeneration following TBI was provided. In our study, the cerebral cortices of ApoE-deficient (ApoE-/-) and wild-type (ApoE+/+) mice were cultured in vitro, and an axonal transection model was established. Interventions included the conditioned medium of astrocytes, human recombinant ApoE2/3/4 isoforms and inhibitors of the JNK/ERK/p38 pathway. Axonal growth and regeneration were evaluated by measuring the maximum distance and area of the axons. The expression levels of β-tubulin III, MAP2, ApoE, p-JNK, p-ERK and p-p38 were detected by immunofluorescence and western blotting. The results showed that ApoE mRNA and protein were expressed in intact axons and regenerated axons. Axonal growth and regeneration were attenuated in ApoE-/-mice but recovered by exogenous ApoE. Human recombinant ApoE3 positively influenced axonal growth and regeneration; these effects were mediated by the JNK/ERK/p38 pathway. These results suggest ApoE and its isoforms may have influenced axonal growth and regeneration via the MAPK signaling pathway in vitro.

Objective To detect cerebral autoregulation (CA) in patients with aneurysmal subarachnoid hemorrhage (aSAH) by near-infrared spectroscopy and to assess its association with delayed cerebral ischemia (DCI). Methods From January to August 2017, 81 patients (average age 53.25 ± 10.27 years) were studied. Near-infrared spectroscopy was used to monitor CA, and associated factors were evaluated. Monitoring of CA was carried out at 5 time points (preoperative day 1 and postoperative days 1, 2, 3, and 7). Patients were sorted into 2 groups according to whether DCI occurred (DCI group and non-DCI group). The relationship between CA and DCI in patients with aSAH was analyzed. Results Among 81 patients, CA trended toward being impaired in patients with aSAH with a poorer grade. DCI occurred in 39 of 51 (48.15%) patients with impaired CA. DCI occurred in 6 of 30 (7.4%) patients with intact CA. Conclusions Impaired CA monitored by near-infrared spectroscopy was shown in patients with aSAH before and after surgical intervention. Older age, smoking, hypertension, and especially impaired CA are independent risk factors for patients with DCI.

Subarachnoid hemorrhage (SAH) is a neurologically destructive stroke in which early brain injury (EBI) plays a pivotal role in poor patient outcomes. Expanding upon our previous work, multiple techniques and methods were used in this preclinical study to further elucidate the mechanisms underlying the beneficial effects of apolipoprotein E (ApoE) against EBI after SAH in murine apolipoprotein E gene-knockout mice (Apoe−/−, KO) and wild-type mice (WT) on a C57BL/6J background. We reported that Apoe deficiency resulted in a more extensive EBI at 48 h after SAH in mice demonstrated by MRI scanning and immunohistochemical staining and exhibited more extensive white matter injury and neuronal apoptosis than WT mice. These changes were associated with an increase in NADPH oxidase 2 (NOX2) expression, an important regulator of both oxidative stress and inflammatory cytokines. Furthermore, immunohistochemical analysis revealed that NOX2 was abundantly expressed in activated M1 microglia. The JAK2/STAT3 signaling pathway, an upstream regulator of NOX2, was increased in WT mice and activated to an even greater extent in Apoe−/− mice; whereas, the JAK2-specific inhibitor, AG490, reduced NOX2 expression, oxidative stress, and inflammation in Apoe-deficient mice. Also, apoE-mimetic peptide COG1410 suppressed the JAK2/STAT3 signaling pathway and significantly reduced M1 microglia activation with subsequent attenuation of oxidative stress and inflammation after SAH. Taken together, apoE and apoE-mimetic peptide have whole-brain protective effects that may reduce EBI after SAH via M1 microglial quiescence through the attenuation of the JAK2/STAT3/NOX2 signaling pathway axis.

Traumatic brain injury (TBI) causes a high rate of mortality and disability worldwide, and there exists almost none effective drugs to protect against TBI. Neurotoxicity occurring after TBI can be derived from microglia and astrocytes, and causes neuronal death and synapse loss. Bexarotene has been demonstrated to protect neurons in CNS diseases. In the present study, we aimed to investigate the potential role of bexarotene in protecting against neurotoxicity after TBI, as well as the underlying mechanism. The controlled cortical impact (CCI) model was established on adult C57BL/6 mice, followed by intraperitoneal administration of bexarotene for 14 consecutive days. We found that bexarotene improved sensorimotor function and cognitive recovery in CCI mice. In addition, bexarotene decreased neuronal death and synapse loss, as well as inhibited apoptotic cascade. Moreover, bexarotene treatment reduced M1 microglia polarization, microglia-derived pro-inflammatory cytokines, and the number of A1 astrocytes after CCI. These effects of bexarotene were partially abolished by T0070907, an antagonist of peroxisome proliferator-activated receptor gamma (PPARγ). Additionally, bexarotene enhanced nuclear translocation and transcriptional activity of PPARγ. These findings show that bexarotene inhibits neurotoxicity in mice after TBI, at least in part through a PPARγ-dependent mechanism.

Backgrounds Whole-body bone scintigraphy (WBBS) and MRI are widely used in assessment of patients with synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. However, the value of F-18 fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG PET/CT) in SAPHO syndrome was unclear. The aim of this study was to characterize the manifestation of SAPHO syndrome on 18F-FDG PET/CT and explore its relationship with clinical symptoms and WBBS. Methods Twenty-six patients who suffered from SAPHO syndrome and had undergone whole-body 18F-FDG PET/CT were recruited in Peking Union Medical College Hospital from 2004 to 2016. Clinical manifestations and laboratory findings were recorded for all patients. Imaging data on 18F-FDG PET/CT and WBBS were collected and analyzed retrospectively. Results All the 26 patients (20 females and 6 males) exhibited skeletal abnormalities on 18F-FDG PET/CT. Multiple skeletal lesions affecting the anterior chest wall or spine with low to moderate 18F-FDG uptake and coexistence of osteolysis and osteosclerosis presented as the typical features of SAPHO syndrome. Sixteen (61.5%) patients had abnormal 18F-FDG uptake outside the osteoarticular system. PET scan had moderate to substantial agreement with CT and WBBS in revealing lesions in the anterior chest wall and axial skeleton. Nonetheless, the correlation between increased 18F-FDG uptake and clinical symptoms was weak. Conclusions SAPHO syndrome exhibits characteristic features on 18F-FDG PET/CT. It showed comparable capacity in revealing skeletal lesions with bone scintigraphy. Electronic supplementary material The online version of this article (10.1186/s13018-018-0795-0) contains supplementary material, which is available to authorized users.

The level of microRNA-9-5p (miRNA-9-5p) in brain tissues is significantly changed in the chronic phase after traumatic brain injury (TBI). However, the effect of miRNA-9-5p on brain function after TBI has not been elucidated. In this study, we used a controlled cortical impact (CCI) model to induce TBI in Sprague-Dawley rats. Brain microvascular endothelial cells (BMECs), astrocytes, and neurons were extracted from immature Sprague-Dawley rats and cocultured to reconstruct the neurovascular unit (NVU) in vitro. The results showed that downregulation of miRNA-9-5p in the chronic phase contributed to neurological function recovery by promoting astrocyte proliferation and increasing the release of astrocyte-derived neurotrophic factors around injured brain tissues after TBI. A dual-luciferase reporter assay validated that miRNA-9-5p was a post-transcriptional modulator of thrombospondin 2 (Thbs-2), and downregulation of miRNA-9-5p promoted Thbs-2 expression in astrocytes. Furthermore, we verified that Thbs-2 can promote Notch pathway activation by directly binding to Jagged and Notch. Through in vitro experiments, we found that the expression of synaptic proteins and the number of synaptic bodies were increased in neurons in the NVU, which was constructed using astrocytes pretreated with miRNA-9-5p inhibitor. Moreover, we also found that downregulation of miRNA-9-5p promoted Thbs-2 expression in astrocytes, which activated the Notch/cylindromatosis/transforming growth factor-β-activated kinase 1 pathway in neurons and promoted the expression of synaptic proteins, including post-synaptic density protein 95 and synaptotagmin. Based on these results, miRNA-9-5p may be a new promising prognostic marker and treatment target for TBI.

Background: As a major antioxidant in serum, uric acid (UA) was once considered only as the leading cause of gout; however, recent studies have validated its neuroprotective role in ischemic stroke. Because the potential protective effects of UA in traumatic brain injury (TBI) remain largely unknown, this study investigated the role of UA in TBI in both clinical patients and experimental animals. Methods: In TBI patients, serum UA concentrations were measured within 3 days after injury. Clinical outcomes at discharge were classified according to the Glasgow Outcome Scale: good outcome (4-5) and poor outcome (1-3). Risk factors for good outcome were identified via backward logistic regression analysis. For the animal study, a controlled cortical impact (CCI) injury model was established in mice. These mice were given UA at different doses intraperitoneally, and subsequent UA concentrations in mouse serum and brain tissue were determined. Neurological function, oxidative stress, inflammatory response, neuronal maintenance, cerebral blood flow, and lesion size were also assessed. Results: The serum UA level was significantly lower in TBI patients who had a good outcome (P0.05). Conclusions: UA acted to attenuate neuronal loss, cerebral perfusion impairment and neurological deficits in TBI mice through suppression of neuronal and vascular oxidative stress. Following TBI, active antioxidant defense in the brain may result in consumption of UA in the serum, and thus, a decreased serum UA level could be predictive of good clinical recovery.

Human glioblastoma is one of the most malignant types of brain tumor in the world. In the present study, the functional mechanisms of microRNA-141 (miR-141) were assessed, and the potential role of miR-141 as a prognostic biomarker in glioblastoma was examined. The gene expression of miR-141 in glioblastoma cell lines and glioblastoma tumors was assessed by reverse transcription-quantitative polymerase chain reaction. Glioblastoma LN229 and U89 cell lines were transfected with synthetic miR-141 mimics to upregulate endogenous miR-141. The subsequent effect on glioblastoma proliferation was assessed by MTT assay. In human glioblastoma, miR-141 expression was compared between patients with tumors of different pathological grades. Statistical analyses were performed to assess the correlation between miR-141 and the clinicopathological properties and overall survival rates (OS) of the patients. In addition, a Cox regression model was used to examine whether miR-141 was a potential biomarker of glioblastoma. miR-141 was aberrantly downregulated in glioblastoma cell lines and human glioblastoma tumors. Forced miR-141 upregulation in glioblastoma LN229 and U89 cell lines suppressed cancer proliferation. In patients with glioblastoma, miR-141 downregulation was closely associated with an advanced disease stage, poor clinicopathological properties and a shorter OS time. The multivariate Cox regression model demonstrated that low miR-141 expression was an effective prognostic biomarker for patients with glioblastoma. Overall, the present study showed that miR-141 may be a functional cancer regulator and a prognostic biomarker for glioblastoma.

Background Palestinian neurosurgery started with Dr. Antone Tarazi as the first Palestinian neurosurgeon. Before that, there was no organized neurosurgery specialty, and general surgeons performed neurosurgical procedures. Here we review the history of neurosurgery and neurosurgical applications in Palestine, evaluate some limitations of the current system, and discuss major challenges to improving this system. Methods We collected information from various sources in either English or Arabic. Results The development of neurosurgery and neurosurgical training in Palestine began in 1960 with the first center established in Jerusalem, which provided much-needed neurosurgical services and training in the fields of neurosurgery and neurology. Palestine has produced a number of its own neurosurgeons and has promoted further progress by establishing the Palestinian Neurosurgical Society in 2014. Today, there are 34 neurosurgeons (including 1 female neurosurgeon) and 17 residents providing expert care in 17 centers across Palestine, along with 1 neurosurgical residency program. Conclusions Neurosurgery in Palestine has faced many challenges, some of which have been overcome. However, there remain many challenges, which will require much time and effort to surmount. Political stabilization is a significant factor in the progress of neurosurgery in Palestine.

Many degenerative diseases of the central nervous system are associated with demyelination. Oligodendrocyte progenitor cells (OPCs) are potential stem cells that can differentiate into various cell types, including oligodendrocytes (OLs). Promoting the proliferation and differentiation of OPCs into mature OLs that can myelinate axons is the key to stimulate remyelination. Here, we report that astrocytes (ASTs) increase the number of sphingosine-1-phosphate receptors 3 (S1pR3) on OPCs and promote OPCs proliferation through a direct contact via connexin 47 (Cx47). Our results demonstrate that ASTs can regulate the proliferation of OPCs through Cx47-mediated induction of S1pR3 expression on OPCs. Cx47/S1pR3 remarkably increases the number of OPCs and promotes cell transition from the G1 to the S phase. Furthermore, inhibiting either Cx47 or S1pR3 decreases OPC proliferation. In summary, ASTs regulate the expression of S1pR3 in OPCs via Cx47, which could be a valuable approach for promoting OPC proliferation. This strategy may therefore represent a potential treatment for neurological diseases caused by OLs death and demyelination.

Objective: Dual leucine zipper kinase (DLK/MA3K12) has been reported involved in apoptosis and neuronal degeneration during neural development and traumatic brain injury. This study was designed to investigate the role of DLK with its adaptor protein JNK interacting protein-3 (JIP3), and its downstream MA2K7/JNK signaling pathway in early brain injury (EBI) after subarachnoid hemorrhage (SAH) in a rat model. Design: Controlled in vivo laboratory study. Setting: Animal research laboratory. Subjects: Two hundred and twenty-three adult male Sprague-Dawley rats weighing 280–320 g. Interventions: SAH was induced by endovascular perforation in rats. The SAH grade, neurological score, and brain water content were measured at 24 and 72 h after SAH. Immunofluorescence staining was used to detect the cells that expressed DLK. The terminal deoxynucleotid transferase-deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) was used to detect the neuronal apoptosis. In mechanism research, the expression of DLK, JIP3, phosphorylated-JNK (p-JNK)/JNK, and cleaved caspase-3 (CC-3) were analyzed by western blot at 24 h after SAH. The DLK small interfering RNA (siRNA), JIP3 siRNA, MA2K7 siRNA and recombinant DLK protein which injected intracerebroventricularly were given as the interventions. Measurements and main results: The DLK expression was increased in the left cortex neurons and peaked at 24 h after SAH. DLK siRNA attenuated brain edema, reduced neuronal apoptosis, and improved the neurobehavioral functions after SAH, but the recombinant DLK protein deteriorated neurobehavioral functions and brain edema. DLK siRNA decreased and recombinant DLK protein increased the expression of MA2K7/p-JNK/CC-3 at 24 h after SAH. The JIP3 siRNA reduced the level of JIP3/MA2K7/p-JNK/CC-3, combined DLK siRNA and JIP3 siRNA further decreased the expression of DLK/MA2K7/p-JNK/CC-3, and MA2K7 siRNA lowered the amount of MA2K7/p-JNK/CC-3 at 24 h after SAH. Conclusions: As a negative role, DLK was involved in EBI after SAH, possibly mediated by its adaptor protein JIP3 and MA2K7/JNK signaling pathways. To reduce the level of DLK may be a new target as intervention for SAH.

Previous studies showed recombinant annexin A2 (rA2) in combination with low-dose tissue-type plasminogen activator (tPA) improved thrombolytic efficacy and long-term neurological outcomes after embolic focal ischemia in rats. The objective of this study was to investigate the effects and mechanisms of the combination in early BBB integrity and cerebrovascular patency in the rat focal embolic stroke model. Ischemic brain infarct volume and hemorrhagic transformation were quantified at 24 h after stroke. At an earlier time point, 16 h after stroke, BBB integrity was evaluated by IgG extravasation, and the involved mechanisms were assessed for tight junction ZO-1 and adhesion junction ve-cadherin protein expression, matrix metalloproteinase activation, extracellular matrix collagen IV and endothelial barrier antigen expression, and activation of microglia/macrophages and astrocytes. While at the same time point, cerebrovascular patency was assessed by intravascular fibrin and platelet depositions. At 24 h after stroke, the combination showed significant reduction in brain infarction and intracerebral hemorrhage. At 16 h after stroke onset, the combination therapy significantly reduced BBB disruption, and improved preservation of the junction proteins ZO-1 and ve-cadherin, decreased activation of matrix metalloproteinase, inhibited degradation of extracellular matrix collagen IV and endothelial barrier antigen, and reduced microglia/macrophage and astrocytes activations. Meanwhile, the combination also significantly improved cerebrovascular patency by reducing intravascular fibrin and platelet depositions in the peri-infarct brain tissues. These results suggest the beneficial effects of the rA2 plus low-dose tPA combination may be mediated in part by the amelioration of BBB disruption and improvement of cerebrovascular patency.