Approach to a cerebral hernia caused by an intratumoral hemorrhage of a cystic oligodendroglioma: a case report.

The incidence of cerebral herniation caused by intratumoral hemorrhage (ITH) in cystic oligodendroglioma (COD) is exceedingly rare. This study presents a case of cerebral herniation subsequent to cystic oligodendroglioma (COD) and sudden intratumoral hemorrhage. Following initial emergency treatment and evaluation, we successfully circumvented the solid component of the tumor and proceeded with cystic puncture and external drainage to prevent the incidence of brain herniation and mitigate the severity of associated symptoms. Based on preoperative examination results, the cystic glioma was successfully resected, and the patient experienced an uneventful recovery. According to the pathological findings, the oligodendroglioma was classified as World Health Organization (WHO) grade III. The treatment efficacy was comparable to cases of the same pathological grade, in which neither intratumoral hemorrhage nor cerebral hernia was observed.

Intraparenchymal atypical meningioma in the posterior fossa: a case report and literature review.

Intraparenchymal meningiomas without dural attachments are extremely rare. A 32-year-old female adult was admitted to our hospital, complaining of occasional dizziness. The patient had no neurological deficits. MRI demonstrated a lesion with mild edema located in the left cerebellar parenchyma. CT revealed calcification within the mass. Gross total resection was achieved. The histopathological examination indicated that the lesion was an atypical meningioma (WHO-II). We herein report an extremely rare case of an intraparenchymal meningioma located in the left cerebellar hemisphere. The significance of the differential diagnosis of lesions in the cerebellum should be emphasized.

Case report: An illusive cortical venous infarction mimicking glioma hemorrhage.

Cortical vein thrombosis (CVT) is a rare subtype of cerebral venous thrombosis. Because CVT is rare and its clinical and imaging findings are atypical, the misdiagnosis of CVT may be extremely high. We report a case of cortical venous infarction (CVI) secondary to CVT. Due to the atypical symptoms, we were perplexed about confirming the diagnosis between CVI and glioma hemorrhage. Eventually, CVT was confirmed by pathology combined with imaging.

Astrocytic NDRG2-PPM1A interaction exacerbates blood-brain barrier disruption after subarachnoid hemorrhage.

Blood-brain barrier (BBB) injury critically exacerbates the poor prognosis of patients with subarachnoid hemorrhage (SAH). The massively increased matrix metalloproteinases 9 (MMP-9) plays a deleterious role in BBB. However, the main source and mechanism of MMP-9 production after SAH remain unclear. We reported that the increased MMP-9 was mainly derived from reactive astrocytes after SAH. Ndrg2 knockout in astrocytes inhibited MMP-9 expression after SAH and attenuated BBB damage. Astrocytic Ndrg2 knockout decreased the phosphorylation of Smad2/3 and the transcription of MMP-9. Notably, cytoplasmic NDRG2 bound to the protein phosphatase PPM1A and restricted the dephosphorylation of Smad2/3. Accordingly, TAT-QFNP12, a novel engineered peptide that could block the NDRG2-PPM1A binding and reduce Smad2/3 dephosphorylation, decreased astrocytic MMP-9 production and BBB disruption after SAH. In conclusion, this study identified NDRG2-PPM1A signaling in reactive astrocytes as a key switch for MMP-9 production and provided a novel therapeutic avenue for BBB protection after SAH.

Risk factors influencing cerebral venous infarction after meningioma resection.

BACKGROUND: Cerebral venous infarction (CVI) is a serious complication after meningioma resection. The risk factors of postoperative cerebral venous infarction after surgical resection of meningioma can be determined through large samples and this study can add evidence to the literature. METHODS: The clinical and imaging data of 1127 patients with intracranial meningiomas who underwent resection in our hospital were retrospectively collected and analyzed. CVI was evaluated by postoperative imaging and clinical manifestations. Univariate and multivariate analyses were performed to identify risk factors associated with CVI. RESULTS: Overall, 4.7% (53/1127) of patients experienced CVI after meningioma resection. Multivariate analysis revealed superficial meningioma, moderate to severe peritumoral edema, peritumoral critical vein and WHO grade II-III as independent predictors of a postoperative CVI. After timely intervention, the symptoms were clearly alleviated in one month, and the prognosis was good, but injury to key veins could cause irreversible neurological disorders. CONCLUSIONS: Intraoperative protection of veins is the primary way to prevent CVI. The present study identified several significant and independent risk factors for postoperative venous infarction, thereby enabling the identification of high-risk patients who require special attention during clinical and surgical management.

Early Unplanned Reoperation After Glioma Craniotomy: Incidence, Predictor and Process Improvement.

Objective: To evaluate the rate of, reasons for, and predictors of unplanned reoperation after craniotomy for glioma in a single-institution consecutive series. Methods: Patients who underwent glioma resection at our hospital from 2015 to 2021 were included (n=1563). Multivariate logistic regression was used to examine the predictors of early unplanned cranial reoperation. The predictors that were screened included patient age, sex, tumor properties, blood loss, blood pressure and antiplatelets drugs usage. Results: A total of 3.6% (56/1563) of the patients underwent an early unplanned reoperation after craniotomy for glioma. The reasons for early unplanned reoperation were brain edema (48.2%), cerebral infarction (33.9%) and hemorrhage (17.9%). The predictors of early unplanned reoperation were WHO grade III-IV, peritumoral edema ≥1 cm, subtotal resection, arterial/venous involvement and elevation in blood pressure ≥50 mmHg. Conclusions: Glioma properties and blood pressure management are decisive predictors of early unplanned reoperation for glioma resection. The authors provide a nuanced discussion regarding early unplanned reoperations and perioperative process improvement as a quality indicator for glioma patient populations.

Preoperative antiepileptic drug prophylaxis for early postoperative seizures in supratentorial meningioma: a single-center experience.

OBJECTIVE: Perioperative antiepileptic drug (AED) prophylaxis for early postoperative seizures (EPSs) in patients with supratentorial meningiomas without preoperative seizures is controversial. This paper discusses the incidence, risk factors, control rate and AED withdrawal indications of EPS in patients undergoing supratentorial convexity and parasagittal/falx meningioma resection without preoperative seizures. METHODS: Patients treated for a histologically confirmed supratentorial convexity and parasagittal/falx meningioma at the authors' institution between 2015 and 2021 were retrospectively examined. Clinical and imaging data were assessed. Variates were analyzed using univariate and multivariate regression analyses. A PubMed review of the literature published between 2011 and 2021 was performed. RESULTS: In total, 517 patients met the selection criteria. EPS (within the first postoperative week) was observed in 30/517 cases (5.8%). Multivariate analysis revealed that surgical/medical complications (OR 16.33, 95% CI 7.07-37.7, P < 0.001) were the only independent predictors of EPS. The dose of valproic was increased and levetiracetam was added based on the frequency of seizures (≤ 2, > 2 times and status epilepticus). EPS control rates were 94.1% (16/17) and 92.3% (12/13), respectively. AEDs were discontinued at 2 weeks and 4-6 weeks, respectively. The authors identified 10 relevant studies in the literature. Based on their review of the literature, the incidence of EPS was 3.7% (47/1282) with AED use and 6.2% (95/1525) without AED use patients in supratentorial meningiomas without preoperative seizures. The incidence of EPS was 9.0% (19/209) in patients without AED use with convexity and parasagittal/falx meningiomas without preoperative seizures. CONCLUSIONS: AED prophylaxis can reduce the incidence of EPS in patients with convexity and parasagittal/falx meningiomas without preoperative seizures. Avoiding postoperative complications is an important means to prevent EPS. Combined medication has a significant effect on controlling repeated EPS. The timing of AED withdrawal was evaluated according to the clinical symptoms and imaging findings.

Polydatin alleviates traumatic brain injury: Role of inhibiting ferroptosis.

Secondary injury is the main cause of high mortality and poor prognosis of TBI, which has recently been suggested to be related to ferroptosis. Polydatin, a monocrystalline compound extracted from the rhizome of Polygonum, has been shown to exert potential neuroprotective effects. However, its role and mechanism in the secondary injury of TBI has not been elucidated. In this study, the inhibition of Polydatin on ferroptosis was observed both in the hemoglobin treated Neuro2A cells in vitro and in TBI mouse model in vivo, characterized by reversion of accumulation or deposition of free Fe2+, increased content of MDA, decreased activity of key REDOX enzyme GPx4, cell death and tissues loss. Although Polydatin corrected the increased mRNA levels of ferroptosis signaling molecules GPX4, SLC7A11, PTGS2, and ATP5G3 after TBI, TBI and Polydatin treatment had no significant effect on their protein expression. Notably, Polydatin could completely reverse the decrease of GPx4 activity after TBI in vivo and in vitro, and the effect was stronger than that of the classical ferroptosis inhibitor FER-1 in vitro. Further, Polydatin has been shown to reduce the severity of acute neurological impairment and significantly improve subacute motor dysfunction in TBI mice. Our findings provided translational insight into neuroprotection with Polydatin in TBI by inhibiting ferroptosis mainly depending on the maintenance of GPx4 activity.

Classification of Peritumoral Veins in Convexity and Parasagittal Meningiomas and Its Significance in Preventing Cerebral Venous Infarction.

OBJECTIVE: The medium (2-4 cm) convexity located closer to the sinus and parasagittal meningiomas (Sindou type I-Ⅲ) without obvious invasion of the superior sagittal sinus are considered simple to operate on. However, the tumors are often accompanied by the cortical bridging vein. Because of lack of collateral vein circulation in cortical areas, the damage of peritumoral veins will subsequently lead to venous infarction. To avoid the serious complications caused by intraoperative injury of peritumoral veins, it is necessary to define the classification of the progression of peritumoral veins and tumors to guide surgical safety. METHODS: The clinical information of 57 patients with convexity and parasagittal meningiomas was collected and retrospectively analyzed. All patients underwent preoperative magnetic resonance imaging and magnetic resonance venography scanning to observe the imaging characteristics of peritumoral veins and preoperative evaluation. The actual relationship between the tumor and peritumoral vein was observed intraoperatively. Postoperative computed tomography and magnetic resonance imaging were used to determine tumor resection and the presence of venous infarction. RESULTS: According to preoperative magnetic resonance venography and intraoperative findings, we divided the peritumoral veins into 3 types: type A (n = 33, 57.9%), the vein surrounds the tumor; type B (n = 15, 26.3%), the vein is located on the ventral side of the tumor; and type C (n = 9, 15.8%), the vein is located on the dorsal side of the tumor. Peritumoral vein injury occurred in 6 cases followed by serious complications. Treatments were as follows: 4 cases underwent decompression and 2 cases were treated conservatively. The prognosis Glasgow Outcome Scale (GOS) scores were as follows: 3 cases were score 5 for injury of posterior frontal vein or middle frontal vein, 2 cases were score 3 for injury of the central vein, 1 case was score 1 for death due to injury of the central vein. All cases were followed up for 6 months. CONCLUSIONS: Attention should be paid to the peritumoral vein of special meningiomas. Injured vein in the medial third of superior sagittal sinus carries a high rate of postoperative morbidity. Understanding the type of peritumoral veins preoperatively can be used as a guide in determining the corresponding protective strategy during surgery, which can significantly decrease postoperative disability and improve quality of life.

Integrated Genetics and Micronutrient Data to Inform the Causal Association Between Serum Calcium Levels and Ischemic Stroke.

There has been an increased interest for observational studies or randomized controlled trials exploring the impact of calcium intake on cardiovascular diseases (CVD) including coronary artery disease (CAD) and ischemic stroke (IS). However, a direct relationship between total calcium intake and CVD has not been well established and remains controversial. Mendelian randomization (MR) studies have been performed to evaluate the causal association between serum calcium levels and CAD risk and found that increased serum calcium levels could increase the risk of CAD. However, MR analysis found no significant association between genetically higher serum calcium levels and IS as well as its subtypes. Hence, three MR studies reported inconsistent effects of serum calcium levels on CAD and IS. Here, we performed an updated MR study to investigate the association of serum calcium levels with the risk of IS using large-scale genome-wide association study (GWAS) datasets. We selected 14 independent genetic variants as the potential instrumental variables from a large-scale serum calcium GWAS dataset and extracted summary statistics corresponding to the 14 serum calcium genetic variants from the MEGASTROKE Consortium IS GWAS dataset. Interestingly, we found a significant association between serum calcium levels and IS risk using the robust inverse-variance weighted (IVW) and penalized robust IVW methods, with ß = 0.243 and P = 0.002. Importantly, the MR results from the robust MR-Egger and penalized robust MR-Egger methods further supported the causal association between serum calcium levels and IS risk, with ß = 0.256 and P = 0.005. Meanwhile, the estimates from other MR methods are also consistent with the above findings.

Management of incidental anterior skull base large and giant meningiomas in elderly patients.

INTRODUCTION: The incidence of meningiomas among the elderly is considered to be high, and are at increased risk of severe morbidity and mortality following surgery due to their aging physiology and unexpected comorbidities. This study aimed to evaluate the optimal management strategies of meningiomas in elderly patients. METHODS: We retrospectively analyzed 150 patients with incidental large (≥ 3 cm) and giant (≥ 6 cm) anterior skull base meningiomas from 2009 to 2018. These patients were divided into elderly group (≥ 65 years, n = 70) and younger group (< 65 years, n = 80). Information of patients with regard to their medical records, operative details, relevant imaging, and follow-up data were obtained from their respective electronic medical records. RESULTS: The elderly patients had significantly longer length of hospital stay (15.9 ± 3.5) compared to younger patients (13.6 ± 3.6, P < 0.001). Karnofsky Performance Scale (KPS) at discharge was significantly lower in elderly group when compared to younger group (P = 0.04). However, the KPS at 1-year after surgery was similar between the two groups. In addition, there was no significant difference in the incidence of surgical complications between the two groups. Multivariate regression analysis of postoperative complications revealed blood loss ≥ 800 mL (P = 0.007) and BMI (< 18.5 or ≥ 24, P < 0.001) as risk factors, rather than age. CONCLUSIONS: Surgical resection in elderly patients with incidental anterior skull base large and giant meningiomas is considered to be a safe and effective therapeutic option owing to acceptable mortality, postoperative complications and postoperative clinical outcomes.

The characteristics of brain injury following cerebral venous infarction induced by surgical interruption of the cortical bridging vein in mice.

Cerebral venous infarction (CVI) caused by the injury of cortical bridging veins (CBVs), is one of the most serious complications following neurosurgical craniotomy. Different from cerebral artery infarction, this CVI pathological process is more complicated, accompanied by acute venous hypertension, brain edema, cerebral ischemia and hemorrhage in the veins bridged brain area. Therefore, a reliable and stable small animal model is particularly important for the pathological study of CVI induced by surgical CBV interruption (CBVi). A mouse model established by cutting off the right CBVs from bregma to lambda with microsurgical technique is used for the assessment of the pathological process. Adult male mice underwent craniotomy after transection of the parietal skin under anesthesia. The right CBVs were exposed by removing the right skull along the right lateral edge of the sagittal sinus (forming a 4 mm × 3 mm bone window from bregma to lambda) with a drill under the operating microscope. Following the final inspection of the cerebral veins, the CBVs (30% one, 60% two, 10% none) were sacrificed using bipolar coagulation technique. Intracranial pressure (ICP) monitoring, motor function examination, brain edema assessment and brain histopathological observation after perfusion were performed at different time points (6 h, 12 h, 24 h, and 48 h) in the postoperative mice. Cerebral hemisphere swelling, midline shift and subcortical petechial hemorrhage were found on histological sections 6 h after CBVs dissection. The change of ICP was consistent with cerebral edema and peaked at 12 h after surgery, as well as the disruption of the blood-brain barrier assessed by Evans Blue staining. Tissue necrosis, nerve cell loss and monocytes infiltration were also dynamically increased in the postoperative hemispheric cortex. Behavioral tests showed obvious somato- and forelimb-motor dysfunction, and severe somatosensory disorder on the operative mice at 12 h, which were substantially recovered at 48 h. Our study provided a novel mouse model of CVI caused by surgical CBVi that was close to clinical practice, and preliminarily confirmed its pathological process. This model might become an important tool to study the clinical pathology and the molecular mechanism of nerve injury following CVI.

Corrigendum: Integrated Genetics and Micronutrient Data to Inform the Causal Association Between Serum Calcium Levels and Ischemic Stroke.

[This corrects the article DOI: 10.3389/fcell.2020.590903.].

Suppression of NDRG2 alleviates brain injury after intracerebral hemorrhage through mitigating astrocyte-drived glutamate neurotoxicity via NF-κB/GLT1 signaling.

N-myc downstream-regulated gene 2 (NDRG2), a newly identified astrocytic stress response gene, is involved in the regulation of astrocytic morphology and function, and has been indicated to be a potential therapeutic target for some central nervous system (CNS) diseases. However, the role of NDRG2 in intracerebral hemorrhage (ICH) remains unknown. Here, we reported that NDRG2 suppression exerted neuroprotection effect against hemorrhagic brain injury in ICH mice and in oxyhemoglobin (OxyHb)-treated cells. Ndrg2 knockout (Ndrg2-/-) mice exhibited reduced hematoma volume and neuronal apoptosis in perihematoma although Ndrg2 deficiency showed little effect on the initial hematoma volume after ICH induction by collagenase injection. Moreover, contrary to the increase in NDRG2 expression after ICH, the expression of glutamate transporter 1 (GLT1) in astrocytes was dramatically decreased in WT (Ndrg2+/+) mice, while which could be more maintained in Ndrg2 knockout mice following ICH. Furthermore, in terms of the mechanism of epigenetic regulation of GLT1 by NDRG2, the results showed that NDRG2 directly interacted with NF-κB, and inhibited the nuclear import and DNA binding activity of the NF-κB p65 subunit after OxyHb treatment in primary astrocytes, decreasing GLT1 transcription and impairing glutamate uptake. Overall, our findings indicate that NDRG2 plays a key role in the pathology of ICH by regulating astrocytic GLT1 expression; thus suppressing NDRG2 may be a potential therapeutic target for ICH.

Correction: Opposing Effects of PI3K/Akt and Smad-Dependent Signaling Pathways in NAG-1-Induced Glioblastoma Cell Apoptosis.

[This corrects the article DOI: 10.1371/journal.pone.0096283.].

MitoQ protects dopaminergic neurons in a 6-OHDA induced PD model by enhancing Mfn2-dependent mitochondrial fusion via activation of PGC-1α.

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra compacta (SNc). Although mitochondrial dysfunction is the critical factor in the pathogenesis of PD, the underlying molecular mechanisms are not well understood, and as a result, effective medical interventions are lacking. Mitochondrial fission and fusion play important roles in the maintenance of mitochondrial function and cell viability. Here, we investigated the effects of MitoQ, a mitochondria-targeted antioxidant, in 6-hydroxydopamine (6-OHDA)-induced in vitro and in vivo PD models. We observed that 6-OHDA enhanced mitochondrial fission by decreasing the expression of Mfn1, Mfn2 and OPA1 as well as by increasing the expression of Drp1 in the dopaminergic (DA) cell line SN4741. Notably, MitoQ treatment particularly upregulated the Mfn2 protein and mRNA levels and promoted mitochondrial fusion in the presence of 6-OHDA in a Mfn2-dependent manner. In addition, MitoQ also stabilized mitochondrial morphology and function in the presence of 6-OHDA, which further suppressed the formation of reactive oxygen species (ROS), as well as ameliorated mitochondrial fragmentation and cellular apoptosis. Moreover, the activation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) was attributed to the upregulation of Mfn2 induced by MitoQ. Consistent with these findings, administration of MitoQ in 6-OHDA-treated mice significantly rescued the decrease of Mfn2 expression and the loss of DA neurons in the SNc. Taken together, our findings suggest that MitoQ protects DA neurons in a 6-OHDA induced PD model by activating PGC-1α to enhance Mfn2-dependent mitochondrial fusion.

The Ras/Raf/Erk Pathway Mediates the Subarachnoid Hemorrhage-Induced Apoptosis of Hippocampal Neurons Through Phosphorylation of p53.

Apoptosis plays a crucial role in the pathogenesis of early brain injury (EBI) following subarachnoid hemorrhage (SAH). However, the exact molecular mechanisms underlying neuronal apoptosis in EBI after SAH have not been fully elucidated. The present study showed that EBI induced significantly neuronal apoptosis activation of Ras/Raf/Erk signals in hippocampus after SAH. Intracisternal administration of PD98059, an inhibitor of Erk1/2, decreased the hippocampal neuronal apoptosis and alleviated the cognitive deficits induced by SAH. Interestingly, an increase in phosphorylation of p53 was paralleled with p-Erk, and PD98059 also blocked the level of p-p53. In primary cultures, oxyhemoglobin (OxyHb) treatment significantly increased p-Erk, p-p53, and apoptosis, which was used to mimic the pathological injury of SAH. Both p53 small interfering RNA (siRNA) and PD98059 reduced the OxyHb-induced apoptosis. Moreover, PD98059 significantly decreased the levels of p-Erk and p-p53; however, p53 siRNA had little effect on the level of p-Erk. Taken together, our study implicates that the Ras/Raf/Erk signals contribute to neuronal death through the phosphorylation of p53 in hippocampus after SAH and also suggests Erk/p53 as a potential target for clinical drug treatment of SAH.

FGF2 alleviates PTSD symptoms in rats by restoring GLAST function in astrocytes via the JAK/STAT pathway.

In our previous study, we demonstrated that fibroblast growth factor 2 (FGF2) administration alleviated posttraumatic stress disorder (PTSD) symptoms via an "astrocyte-related" mechanism. We further investigated the changes in the astrocytic glutamate transporters GLAST and GLT-1 and in JAK/STAT3 signaling (which is involved in astrocyte activation and GLAST/GLT-1 function) in single prolonged stress (SPS) model rats. High-performance liquid chromatography (HPLC), Western blot and immunohistochemistry analyses revealed a significant SPS-induced increase in the concentration of glutamate in the cerebrospinal fluid and decrease in GLAST/GLT-1 expression and JAK/STAT3 signaling. Treatment with FGF2 significantly alleviated GLAST/GLT-1 dysfunction, JAK/STAT3 signaling inhibition, and the behavioral abnormalities. The administration of the JAK/STAT pathway inhibitor AG490 blocked the effects of FGF2 on PTSD symptoms, astrocyte activation, and GLAST, but not GLT-1, expression in vivo and in vitro. Our findings suggest that astrocytic JAK/STAT signaling is associated with SPS-induced GLAST dysfunction and that FGF2 protects against PTSD symptoms by restoring astrocytic glutamate uptake via the JAK/STAT signaling pathway.

Opposing effects of PI3K/Akt and Smad-dependent signaling pathways in NAG-1-induced glioblastoma cell apoptosis.

Nonsteroidal anti-inflammatory drug (NSAID) activated gene-1 (NAG-1) is a divergent member of the transforming growth factor-beta (TGF-ß) superfamily. NAG-1 plays remarkable multifunctional roles in controlling diverse physiological and pathological processes including cancer. Like other TGF-ß family members, NAG-1 can play dual roles during cancer development and progression by negatively or positively modulating cancer cell behaviors. In glioblastoma brain tumors, NAG-1 appears to act as a tumor suppressor gene; however, the precise underlying mechanisms have not been well elucidated. In the present study, we discovered that overexpression of NAG-1 induced apoptosis in U87 MG, U118 MG, U251 MG, and T98G cell lines via the intrinsic mitochondrial pathway, but not in A172 and LN-229 cell lines. NAG-1 could induce the phosphorylation of PI3K/Akt and Smad2/3 in all six tested glioblastoma cell lines, except Smad3 phosphorylation in A172 and LN-229 cell lines. In fact, Smad3 expression and its phosphorylation were almost undetectable in A172 and LN-229 cells. The PI3K inhibitors promoted NAG-1-induced glioblastoma cell apoptosis, while siRNAs to Smad2 and Smad3 decreased the apoptosis rate. NAG-1 also stimulated the direct interaction between Akt and Smad3 in glioblastoma cells. Elevating the level of Smad3 restored the sensitivity to NAG-1-induced apoptosis in A172 and LN-229 cells. In conclusion, our results suggest that PI3K/Akt and Smad-dependent signaling pathways display opposing effects in NAG-1-induced glioblastoma cell apoptosis.