Unveiling novel cell clusters and biomarkers in glioblastoma and its peritumoral microenvironment at the single-cell perspective.

BACKGROUND: Glioblastoma (GBM) is a highly heterogeneous, recurrent and aggressively invasive primary malignant brain tumor. The heterogeneity of GBM results in poor targeted therapy. Therefore, the aim of this study is to depict the cellular landscape of GBM and its peritumor from a single-cell perspective. Discovering new cell subtypes and biomarkers, and providing a theoretical basis for precision therapy. METHODS: We collected 8 tissue samples from 4 GBM patients to perform 10 × single-cell transcriptome sequencing. Quality control and filtering of data by Seurat package for clustering. Inferring copy number variations to identify malignant cells via the infercnv package. Functional enrichment analysis was performed by GSVA and clusterProfiler packages. STRING database and Cytoscape software were used to construct protein interaction networks. Inferring transcription factors by pySCENIC. Building cell differentiation trajectories via the monocle package. To infer intercellular communication networks by CellPhoneDB software. RESULTS: We observed that the tumor microenvironment (TME) varies among different locations and different GBM patients. We identified a proliferative cluster of oligodendrocytes with high expression of mitochondrial genes. We also identified two clusters of myeloid cells, one primarily located in the peritumor exhibiting an M1 phenotype with elevated TNFAIP8L3 expression, and another in the tumor and peritumor showing a proliferative tendency towards an M2 phenotype with increased DTL expression. We identified XIST, KCNH7, SYT1 and DIAPH3 as potential factors associated with the proliferation of malignant cells in GBM. CONCLUSIONS: These biomarkers and cell clusters we discovered may serve as targets for treatment. Targeted drugs developed against these biomarkers and cell clusters may enhance treatment efficacy, optimize immune therapy strategies, and improve the response rates of GBM patients to immunotherapy. Our findings provide a theoretical basis for the development of individualized treatment and precision medicine for GBM, which may be used to improve the survival of GBM patients.

Activation of G-protein coupled estrogen receptor 1 improves early-onset cognitive impairment via PI3K/Akt pathway in rats with traumatic brain injury.

Previous studies experimentally reveal that G-protein coupled estrogen receptor 1(GPER) has neuroprotection against ischemic injury. However, its effect on traumatic brain injury (TBI) is less well-established. Cognitive impairment following human TBI is a common clinical observation, and TBI is considered as a risk factor for Alzheimer's disease (AD). This study aimed to observe the possible protective effect of GPER on early-onset cognitive impairment after a single TBI and investigate the cellular mechanism underlying its actions. We found that selective GPER agonist G-1 significantly reduced hippocampal CA1 neuronal loss and improved cognitive impairment in TBI rats. Although previous studies have shown that AD-like tau pathology occurs many years after both repetitive and single TBI, accumulation of hyperphosphorylated tau was not observed within days (detected at 24 h and 7d) after TBI. Furthermore, tau phosphorylation was not altered by G-1 treatment. It was found that G-1 administration caused an increase in p-Akt level. However, the neuroprotective effects of G-1 on spatial cognition and neuronal death were attenuated by PI3K/Akt inhibitor LY294002. These findings indicate that GPER agonist G-1 had protection on cognitive function via activation of PI3K/Akt signaling. Early-onset cognitive impairment following a single TBI was closely associated with acute hippocampal neuronal loss rather than tau pathology. This study suggests that early activation of GPER might be a promising therapeutic strategy for improvement of TBI-induced cognitive outcomes.

The efficacy of simultaneous bilateral axillary brachial plexus block under the guidance of neurostimulator or ultrasound: a prospective study.

PURPOSE: This study was designed to investigate the risk of local anesthetic toxicity and efficacy of simultaneous bilateral axillary brachial plexus block performed under the guidance of ultrasound or a neurostimulator. METHODS: One hundred and twenty patients who were anesthetized with bilateral axillary plexus block simultaneously between February 2012 and March 2014 were enrolled in the study. The patients were anesthetized under the guidance of a neurostimulator (group N, n = 60) or ultrasound (group U, n = 60). The block performance time, procedure-related pain, adverse events, total and free plasma concentrations of ropivacaine, and other data were recorded. The comparison was analyzed statistically. RESULTS: The block performance time, and onset of the sensory and motor block, of group N was longer than that of group U (p < 0.001). The procedure-related pain of group N was more serious than that of group U (p < 0.05). The patient satisfaction rate of group U was higher than that of group N (p < 0.05). The total plasma concentrations of ropivacaine in group N were comparable to those of group U, except for the value at 50 min after injection (p < 0.05). The free plasma concentrations of ropivacaine of group N at 5 min were significantly higher than that of group U (p < 0.001). No apparent serious adverse events were observed perioperatively in both groups. CONCLUSIONS: Simultaneous bilateral axillary brachial plexus block guided by neurostimulator or ultrasound in bilateral distal upper extremity surgery seems to have a low risk of local anesthetic toxicity and to be effective. The ultrasound-guided block is superior in terms of providing the same degree of anesthesia with shorter duration, less pain, and faster onset of sensory and motor blockades, which is important in clinical practice.

Overactivation of NR2B-containing NMDA receptors through entorhinal-hippocampal connection initiates accumulation of hyperphosphorylated tau in rat hippocampus after transient middle cerebral artery occlusion.

Middle cerebral artery occlusion (MCAO) induces secondary damages in the hippocampus that is remote from primary ischemic regions. Tau hyperphosphorylation is an important risk for neurodegenerative diseases. Increased tau phosphorylation has been identified in ischemic cortex, but little is known regarding the changes in the hippocampus. We showed that unilateral transient MCAO induced accumulation of hyperphosphorylated tau and concurrent dephosphorylation of glycogen synthase kinase-3ß at Ser 9 in the ipsilateral hippocampus. These MCAO-induced changes were not reproduced when glutamatergic inputs from the entorhinal cortex to the hippocampus were transected; however, the changes were mimicked by intrahippocampal N-methyl-d-aspartate (NMDA) administration. Inhibition of NMDA receptor (NMDAR) subunit NR2B, but not NR2A activity in the hippocampus attenuated the accumulation of hyperphosphorylated tau and spatial cognitive impairment in MCAO rats. Together, our data suggest that overactivation of NR2B-containing NMDARs through entorhinal-hippocampal connection plays an important role in the accumulation of hyperphosphorylated tau in the hippocampus following MCAO. Glycogen synthase kinase-3ß is an important protein kinase involved in NMDARs-mediated tau hyperphosphorylation. This study indicates that early inhibition of NR2B-containing NMDARs may represent a potential strategy to prevent or delay the occurrence of post-stroke dementia. Middle cerebral artery occlusion induces secondary damage in the hippocampus that is remote from primary ischemic regions. We propose that excessive activation of NR2B-containing NMDA receptors through entorhinal-hippocampal connection initiated the accumulation of hyperphosphorylated tau in the hippocampus, which subsequently induced cognitive deficit. This study provides new insights into the prospects of NR2B inhibition in stoke therapy.

Involvement of ROS-alpha v beta 3 integrin-FAK/Pyk2 in the inhibitory effect of melatonin on U251 glioma cell migration and invasion under hypoxia.

BACKGROUND: Melatonin, a well-known antioxidant, has been shown to possess anti-invasive properties for glioma. However, little is known about the effect of melatonin on glioma cell migration and invasion under hypoxia, which is a crucial microenvironment for tumor progress. In addition, focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) are closely associated with cell migration and invasion. Therefore, we investigated the possible role of these kinases and its related signaling in the regulation of human U251 glioma cells behavior by melatonin under hypoxia. METHODS: The abilities of migration and invasion of U251 glioma cells were determined by wound healing and transwell assay in vitro. The intracellular production of reactive oxygen species (ROS) was measured by using the fluorescent probe 6-carboxy-2', 7'-dichorodihydrofluorescein diacetate (DCFH-DA). Immunofluorescence experiments and western blotting analysis were used to detect the expression level of protein. Small interfering RNAs (siRNA) was used to silence specific gene expression. RESULTS: The pharmacologic concentration (1 mM) of melatonin significantly inhibited the migration and invasion of human U251 glioma cells under hypoxia. The inhibitory effect of melatonin was accompanied with the reduced phosphorylation of FAK and Pyk2, and decreased expression of alpha v beta 3 (αvß3) integrin. Additionally, inhibition of αvß3 integrin by siRNA reduced the phosphorylation of FAK/Pyk2 and demonstrated the similar anti-tumor effects as melatonin, suggesting the involvement of αvß3 integrin- FAK/Pyk2 pathway in the anti-migratory and anti-invasive effect of melatonin. It was also found that melatonin treatment decreased the ROS levels in U251 glioma cells cultured under hypoxia. ROS inhibitor apocynin not only inhibited αvß3 integrin expression and the phosphorylation levels of FAK and Pyk2, but also suppressed the migratory and invasive capacity of U251 glioma cells under hypoxia. CONCLUSIONS: These results suggest that melatonin exerts anti-migratory and anti-invasive effects on glioma cells in response to hypoxia via ROS-αvß3 integrin-FAK/Pyk2 signaling pathways. This provides evidence that melatonin may be a potential therapeutic molecule targeting the hypoxic microenvironment of glioma.

Induction of proline-rich tyrosine kinase 2 activation-mediated C6 glioma cell invasion after anti-vascular endothelial growth factor therapy.

BACKGROUND: Anti-angiogenic therapy inhibits tumor growth and is considered as a potential clinical therapy for malignant glioma. However, inevitable recurrences and unexpected tumor resistance, particularly increased invasion ability of glioma cell, were observed after anti-angiogenic treatment. The underlying mechanism remains undetermined. Focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) are closely associated with cell migration; therefore, we investigated the possible role of these kinases in rat C6 glioma cell invasion induced by bevacizumab, a recombinant monoclonal antibody against vascular endothelial growth factor (VEGF). METHODS: The effects of bevacizumab on migration and invasion of C6 glioma cells were investigated in vitro and in vivo. The cells proliferation, migration, and invasion were determined by MTT assay, wound healing, and transwell assay, respectively. Invasive potential of glioma cells in vivo was assessed by counting vimentin-positive cells crossing the solid tumor rim by immunohistochemical staining. The total and phosphorylated protein levels of FAK and Pyk2 were detected by Western blotting. RESULTS: Bevacizumab exposure increased migration and invasion of cultured C6 cells in a concentration-dependent manner. In addition, the continuous bevacizumab treatment also promoted tumor invasion in rat C6 intracranial glioma models. Bevacizumab treatment enhanced Pyk2 phosphorylation at Tyr402, but no effect on FAK phosphorylation at Tyr397 both in vitro and in vivo. Knockdown of Pyk2 by siRNA or inhibition of Pyk2 phosphorylation by Src kinase specific inhibitor PP1 partially inhibited bevacizumab-induced cell invasion in cultured C6 glioma cells. Furthermore, the combined administration of bevacizumab and PP1 significantly suppressed glioma cell invasion into surrounding brain tissues compared to bevacizumab treatment alone in experimental rats. CONCLUSIONS: These results suggest that anti-VEGF treatment promotes glioma cell invasion via activation of Pyk2. Inhibition of Pyk2 phosphorylation might be a potential target to ameliorate the therapeutic efficiency of anti-VEGF treatment.

TNC upregulation promotes glioma tumourigenesis through TDG-mediated active DNA demethylation.

Gliomas represent the most predominant primary malignant tumor in central nervous system. Thymine DNA glycosylase (TDG) is a central component in active DNA demethylation. However, the specific mechanisms of TDG-mediated active DNA demethylation in gliomas remain unclear. This research indicates TDG expression is overexpressed in gliomas and correlated with poor prognosis. TDG knockdown suppressed the malignant phenotype of gliomas both in vitro and vivo. Notably, RNA-seq analysis revealed a strong association between TDG and tenascin-C (TNC). ChIP-qPCR and MeDIP-qPCR assays were undertaken to confirm that TDG participates in TNC active DNA demethylation process, revealing decreased DNA methylation levels and elevated TNC expression as a result. Silencing TNC expression also suppressed the tumor malignant phenotype in both in vitro and in vivo experiments. Additionally, simultaneous silencing of TNC reduced or even reversed the glioma promotion caused by TDG overexpression. Based on our findings, we conclude that TDG exerts an indispensable role in TNC active DNA demethylation in gliomas. The DNA demethylation process leads to alternations in TNC methylation levels and promotes its expression, thereby contributing to the development of gliomas. These results suggest a novel epigenetic therapeutic strategy targeting active DNA demethylation in gliomas.

Cerebellar Purkinje cell firing promotes conscious recovery from anesthesia state through coordinating neuronal communications with motor cortex.

Background: The neurobiological basis of gaining consciousness from unconscious state induced by anesthetics remains unknown. This study was designed to investigate the involvement of the cerebello-thalamus-motor cortical loop mediating consciousness transitions from the loss of consciousness (LOC) induced by an inhalational anesthetic sevoflurane in mice. Methods: The neural tracing and fMRI together with opto-chemogenetic manipulation were used to investigate the potential link among cerebello-thalamus-motor cortical brain regions. The fiber photometry of calcium and neurotransmitters, including glutamate (Glu), γ-aminobutyric acid (GABA) and norepinephrine (NE), were monitored from the motor cortex (M1) and the 5th lobule of the cerebellar vermis (5Cb) during unconsciousness induced by sevoflurane and gaining consciousness after sevoflurane exposure. Cerebellar Purkinje cells were optogenetically manipulated to investigate their influence on consciousness transitions during and after sevoflurane exposure. Results: Activation of 5Cb Purkinje cells increased the Ca2+ flux in the M1 CaMKIIα+ neurons, but this increment was significantly reduced by inactivation of posterior and parafascicular thalamic nucleus. The 5Cb and M1 exhibited concerted calcium flux, and glutamate and GABA release during transitions from wakefulness, loss of consciousness, burst suppression to conscious recovery. Ca2+ flux and Glu release in the M1, but not in the 5Cb, showed a strong synchronization with the EEG burst suppression, particularly, in the gamma-band range. In contrast, the Glu, GABA and NE release and Ca2+ oscillations were coherent with the EEG gamma band activity only in the 5Cb during the pre-recovery of consciousness period. The optogenetic activation of Purkinje cells during burst suppression significantly facilitated emergence from anesthesia while the optogenetic inhibition prolonged the time to gaining consciousness. Conclusions: Our data indicate that cerebellar neuronal communication integrated with motor cortex through thalamus promotes consciousness recovery from anesthesia which may likely serve as arousal regulation.

Anti-tumor effects of telmisartan in glioma-astrocyte non-contact co-cultures: A critical role of astrocytic IL-6-mediated paracrine growth promotion.

Telmisartan, an angiotensin II type 1 receptor (AT1R) blocker, exhibits broad anti-tumor activity. However, in vitro, anti-proliferative effects are shown at doses far beyond the therapeutic plasma concentration. Considering the role of tumor microenvironment in glioma progression, glioma-astrocyte co-cultures were employed to test the anti-tumor potential of low-dose telmisartan. When a high dose was required for a direct anti-proliferative effect on glioma cell lines, a low dose significantly inhibited glioma cell proliferation and migration in the co-culture system. Under co-culture conditions, upregulated IL-6 expression in astrocytes played a critical role in glioma progression. Silencing IL-6 in astrocytes or IL-6R in glioma cells reduced proliferation and migration. Telmisartan (5 µM) inhibited astrocytic IL-6 expression, and its anti-tumor effects were reversed by silencing IL-6 or IL-6R and inhibiting signal transducer and activator of transcription 3 (STAT3) activity in glioma cells. Moreover, the telmisartan-driven IL-6 downregulation was not imitated by losartan, an AT1R blocker with little capacity of peroxisome proliferator-activated receptor-gamma (PPARγ) activation, but was eliminated by a PPARγ antagonist, indicating that the anti-glioma effects of telmisartan rely on its PPARγ agonistic activity rather than AT1R blockade. This study highlights the importance of astrocytic IL-6-mediated paracrine signaling in glioma growth and the potential of telmisartan as an adjuvant therapy for patients with glioma, especially those with hypertension.

Mechanistic insight into glioma through spatially multidimensional proteomics.

Characterizing the tumor microenvironment at the molecular level is essential for understanding the mechanisms of tumorigenesis and evolution. However, the specificity of the blood proteome in localized region of the tumor and its linkages with other systems is difficult to investigate. Here, we propose a spatially multidimensional comparative proteomics strategy using glioma as an example. The blood proteome signature of tumor microenvironment was specifically identified by in situ collection of arterial and venous blood from the glioma region of the brain for comparison with peripheral blood. Also, by integrating with different dimensions of tissue and peripheral blood proteomics, the information on the genesis, migration, and exchange of glioma-associated proteins was revealed, which provided a powerful method for tumor mechanism research and biomarker discovery. The study recruited multidimensional clinical cohorts, allowing the proteomic results to corroborate each other, reliably revealing biological processes specific to gliomas, and identifying highly accurate biomarkers.

Hippocampal glutamate level and glutamate aspartate transporter (GLAST) are up-regulated in senior rat associated with isoflurane-induced spatial learning/memory impairment.

Postoperative cognitive decline is a clinical concern especially for senior patients. It is generally recognized that glutamatergic system plays a crucial role in the physiopathologic process of neurocognitive deterioration. However, alterations of glutamatergic system in prolonged isoflurane-induced learning/memory decline are still unclear. This study investigates the question whether glutamate concentration and corresponding transporters or receptors display any alternations in aged rat suffering from isoflurane-induced learning/memory impairment. 111 male Sprague-Dawley rats (>18 months) were randomly divided into two main groups: hippocampal microdialysis group (n = 38) and western blotting group (n = 73). Each group was subdivided into three subgroups including (1) control subgroup (n = 6 and 10, receiving no behavioral trial, anesthesia or air exposure); (2) air-exposed subgroup (n = 7 and 15, receiving behavioral trial and air exposure but not anesthesia); (3) isoflurane anesthesia subgroup (n = 25 and 48, receiving both behavioral trial and anesthesia). The isoflurane-exposed rats were further divided into a learning/memory-impaired subgroup and a non-learning/memory-impaired subgroup according to their behavioral performance, which was measured using Morris water maze. Hippocampal glutamate concentrations in microdialysates were determined by high-performance liquid chromatography. Expression levels of GLAST, GLT-1, NMDAR1, NMDAR2A/B, AMPAR and tau in hippocampus were assessed via quantitative Western blotting. The incidences of learning/memory impairment of isoflurane-exposed rats in hippocampal microdialysis group and western blotting group were 12.0 (3/25) and 10.4 % (5/48) respectively. The intra-anesthesia hippocampal glutamate levels were significantly lower than those of non-anesthesized rats. The learning/memory-impaired rats showed a long-lasting increased glutamate level from 24 h after isoflurane exposure to the end of the study, but the other 22 isoflurane-exposed rats did not. The learning/memory-impaired subgroup displayed a significantly higher GLAST level than the other three subgroups (p = 0.026, 0.02 and 0.032 respectively). The expression levels of GLT-1, NMDAR1, NMDAR2A/B and AMPAR of every subgroup were comparable. We found a continuous raised hippocampal glutamate and an up-regulation of GLAST rather than GLT-1, NMDAR1, NMDAR2A/B, AMPAR or tau in hippocampus of aged rats associated with isoflurane-induced learning/memory impairment.

VEGF promotes proliferation of human glioblastoma multiforme stem-like cells through VEGF receptor 2.

Cancer stem-like cells, which have been described as tumor-initiating cells or tumor-propagating cells, play a crucial role in our fundamental understanding of glioblastoma multiforme (GBM) and its recurrence. GBM is a lethal cancer, characterized by florid vascularization and aberrantly elevated vascular endothelial growth factor (VEGF). VEGF promotes tumorigenesis and angiogenesis of human GBM stem-like cells (GBSCs). However, whether and how VEGF contributes to GBSCs proliferation remain largely uncertain. In this study, human GBSCs were isolated from surgical specimens of glioblastoma and cultured in medium favored for stem cell growth. Neural Colony-Forming Cell Assay and ATP assay were performed to measure GBSC proliferation under normoxia (20% O2) and hypoxia (1% O2). Our observations demonstrate that exogenous VEGF stimulates GBSC proliferation in a dose-dependent manner via VEGF Receptor 2 (VEGFR2); while VEGF Receptor 1 (VEGFR1) has a negative feedback effect on VEGFR2 when cells were exposed to higher concentration of VEGF. These results suggest that suppressing VEGFR2-dependent GBSC proliferation is a potentially therapeutic strategy in GBM.

Meningioangiomatosis Combined with Calcifying Pseudoneoplasms of Neuraxis.

Meningioangiomatosis (MA) is a rare hamartomatous or meningovascular lesion involving the central nervous system, and is sometimes associated with intracranial meningiomas. Calcifying pseudoneoplasms of the neuraxis (CAPNON) are rare, slow-growing benign tumor-like lesions that can occur anywhere along the neuraxis. Here, we report a rare case of MA combined with CAPNON. A 31-year-old woman was admitted to our hospital because of a high-density mass in the left frontal lobe, detected by computed tomography (CT) during a physical examination. She had a 3-year history of obsessive-compulsive disorder. We describe the imaging, histopathological, and molecular characteristics of the patient. To our knowledge, this is the first report describing MA combined with CAPNON. We reviewed the literature on MA and CAPNON over the last decade and summarized the points for differential diagnosis and treatment. It is difficult to preoperatively distinguish between MA and CAPNON. However, this coexisting condition should be considered when intra-axial calcification lesions are observed on radiological imaging. Accurate diagnosis and appropriate treatment are likely to benefit this patient group.

The Third Hand of Neurosurgeons - a novel intraoperative malleable adjustable continuous suction tube.

Objective: We designed a novel intraoperative malleable adjustable continuous suction tube to obtain clear surgical fields, reduce intracranial pressure, and lower the temperature of the surgical area. Methods: This device consists of six parts: continuous suction tube head and cotton patty, suction tube, fixed wire position, fixed clip, spiral plastic pressure regulating valve, and tail. It can continuously extract blood, cerebrospinal fluid, and rinsing solution from surgical fields, with minimal contact and trauma to tissues, nerves, and blood vessels, while also having a negligible impact on the surgeon's focus and procedure. Result: The excellent and safe performance (simple, malleable, adjustable, space-saving, inexpensive, safe, and effective) of this device in clearing the operating field has been proven in more than 2000 neurosurgical operative procedures. We encountered no complications associated with this device, such as cerebral hematoma, postoperative low intracranial pressure, or vascular and nerve injuries. Conclusion: The newly innovated intraoperative malleable adjustable continuous suction tube is effective and safe for microneurosurgery.

Development and Validation of a Deep Learning Predictive Model Combining Clinical and Radiomic Features for Short-Term Postoperative Facial Nerve Function in Acoustic Neuroma Patients.

OBJECTIVE: This study aims to construct and validate a predictable deep learning model associated with clinical data and multi-sequence magnetic resonance imaging (MRI) for short-term postoperative facial nerve function in patients with acoustic neuroma. METHODS: A total of 110 patients with acoustic neuroma who underwent surgery through the retrosigmoid sinus approach were included. Clinical data and raw features from four MRI sequences (T1-weighted, T2-weighted, T1-weighted contrast enhancement, and T2-weighted-Flair images) were analyzed. Spearman correlation analysis along with least absolute shrinkage and selection operator regression were used to screen combined clinical and radiomic features. Nomogram, machine learning, and convolutional neural network (CNN) models were constructed to predict the prognosis of facial nerve function on the seventh day after surgery. Receiver operating characteristic (ROC) curve and decision curve analysis (DCA) were used to evaluate model performance. A total of 1050 radiomic parameters were extracted, from which 13 radiomic and 3 clinical features were selected. RESULTS: The CNN model performed best among all prediction models in the test set with an area under the curve (AUC) of 0.89 (95% CI, 0.84-0.91). CONCLUSION: CNN modeling that combines clinical and multi-sequence MRI radiomic features provides excellent performance for predicting short-term facial nerve function after surgery in patients with acoustic neuroma. As such, CNN modeling may serve as a potential decision-making tool for neurosurgery.

Telmisartan inhibits microglia-induced neurotoxic A1 astrocyte conversion via PPARγ-mediated NF-κB/p65 degradation.

Astrocytes are crucially involved in neuroinflammation. Activated astrocytes exhibit at least two phenotypes, A1 (neurotoxic) and A2 (neuroprotective). The A1 phenotype is the major reactive astrocyte phenotype involved in aging and neurodegenerative diseases. Telmisartan, which is an antihypertensive agent, is a promising neuroprotective agent. This study aimed to investigate the effects of telmisartan on the phenotype of reactive astrocytes. Astrocytes were activated by culturing with the conditioned medium derived from lipopolysaccharide-stimulated microglia. This conditioned medium induced early, transient A2 astrocyte conversion (within 24 h) and late, sustained A1 conversion (beginning at 24 h and lasting up to 7 days), with a concomitant increase in the production of pro-inflammatory cytokines (interleukin [IL]-1ß, tumor necrosis factor [TNF]α, and IL-6) and phosphorylation of nuclear factor-κB (NF-κB)/p65. Telmisartan treatment promoted and inhibited A2 and A1 conversion, respectively. Telmisartan reduced total and phosphorylated p65 protein levels. Losartan, a specific angiotensin II type-1 receptor (AT1R) blocker, did not influence the reactive state of astrocytes. Additionally, AT1R activation by angiotensin II did not induce the expression of pro-inflammatory cytokines and A1/A2 markers, indicating that the AT1R signaling pathway is not involved in the astrocyte-mediated inflammatory response. A peroxisome proliferator-activated receptor γ (PPARγ) antagonist reversed the effects of telmisartan. Moreover, telmisartan-induced p65 downregulation was reversed by the proteasome inhibitor MG132. These results indicate that telmisartan suppresses activated microglia-induced neurotoxic A1 astrocyte conversion through p65 degradation. Our findings contribute towards the elucidation of the anti-inflammatory activity of telmisartan in brain disorders.

Delta-like ligand 4 correlates with endothelial proliferation and vessel maturation in human malignant glioma.

AIM: To investigate the role of delta-like ligand 4 (DLL4) in the angiogenesis of high-grade malignant glioma. MATERIALS AND METHODS: DLL4 expression and microvessel density (MVD) were detected by immunohistochemistry in 51 human high-grade malignant glioma tissue samples. The vessel maturation index (VMI) was calculated as the percentage of a-smooth muscle actin (a-SMA)-positive vessels in relation to the amount of CD31-positive vessels. Double fluorescent immunostaining for CD31 and EphrinB2 or EphB4 was performed to identify the arterial (EphrinB2) or venous (EphB4) origins of glioma microvessels. RESULTS: Strong immunostaining of DLL4 and a positive correlation of DLL4 with the MVD were observed in high-grade malignant gliomas. The VMI of the DLL4-positive group was significantly higher than that of the DLL4-negative group. However, no significant association was found between DLL4 and EphrinB2 or EphB4 in high-grade gliomas. CONCLUSION: DLL4 may be an important regulator for vessel proliferation and maturation in human high-grade malignant gliomas.

Which is more effective in adolescent idiopathic scoliosis surgery: batroxobin, tranexamic acid or a combination?

BACKGROUND: Adolescent idiopathic scoliosis surgery is often associated with significant blood loss and blood transfusion. In this clinical trial, the authors investigated the efficacy of reducing blood loss and allogeneic blood transfusion by using batroxobin, tranexamic acid (TXA) and the combination of the two agents. METHODS: 80 adolescent patients undergoing scheduled idiopathic scoliosis surgery were randomly divided into four groups to receive 0.9% saline (group A), batroxobin (group B), TXA (group C), and both two agents in the same manner (group D). The amounts of blood loss, transfusion requirements, frozen fresh plasma (FFP) and overall drainage were assessed. The hemoglobin concentration (Hb), hematocrit and platelet counts were recorded preoperative y, postoperatively and on the first operative day. The coagulation parameters were measured meanwhile. Deep vein thrombosis (DVT) was diagnosed by ultrasound. RESULTS: Blood loss of group B and group C decreased similarly by 35.3 and 42.8% (p = 0.212) compared with group A, while group D was reduced by 64.5, 45.1 and 37.8% compared to group A, B and C, respectively. The amount of allogeneic blood transfusion of group B and group C was comparably reduced by 57.6 and 72.4% compared to group A (p = 0.069), while group D decreased by 94.7, 87.5 and 80.9% compared to group A, B and C. Overall drainage of group B, C and D decreased by 23.0, 45.1 and 67.9% compared with group A, respectively, while group C was reduced by 28.7% compared with group B (p < 0.001). The FFP of group B, C and D was reduced by 63.4, 80.2 and 95.0% as compared with group A, while group C decreased by 45.9% as compared to group B (p = 0.025). There were no urgent coagulation disorders or DVT reported. CONCLUSIONS: In our study, batroxobin and TXA can markedly reduce the blood loss and the transfusion requirements equivalently. However, TXA performs better in minimizing FFP and the overall drainage than batroxobin. The combination seems to achieve best results and was more effective than either of the two drugs alone. No apparent adverse events were detected in these groups.

Comparative efficacy analysis of ultrasound-guided quadratus lumborum block and lumbar plexus block in hip arthroscopy: a pilot prospective randomized controlled trial.

Controlled trials assessing quadratus lumborum block (QLB) for post-operative analgesia in hip surgery are scarce. This study aimed to compare ultrasound-guided QLB and lumbar plexus block (LPB) for clinical efficacy in hip arthroscopy. Patients undergoing hip arthroscopy in Beijing Jishuitan Hospital in January-June 2019 were randomized to the lumbar plexus (L) and quadratus lumborum (Q) groups (n = 25/group). After either ultrasound-guided block for 30 min, both groups were prepared for surgery after muscle strength measurement in the affected limbs. Opioid doses for patient-controlled analgesia (PCA), visual analog scale (VAS) scores in the resting and active states, upon leaving the post-anesthesia care unit (PACU), and at 2-48 h post-surgery were recorded, and post-operative complications were also recorded. Muscle strength in the affected limbs was significantly higher in the Q group compared with the L group (4.0 versus 2.0, P < 0.001). VAS scores were similar in both groups post-surgery (P > 0.05). One patient had epidural spread in the L group, with no other complications. Compared with ultrasound-guided LPB, ultrasound-guided QLB provides similar and good post-operative analgesia after hip arthroscopy, with less impact on muscle strength and fewer complications. These results should be confirmed in larger trials.

How to Precisely Open the Internal Auditory Canal for Resection of Vestibular Schwannoma via the Retrosigmoid Approach.

Objective: The aim of this study was to investigate how to precisely expose the intrameatal portion of vestibular schwannomas (VSs) without damaging the labyrinth. Methods: This was a retrospective study of patients who had undergone retrosigmoid resection of a VS in our institution from April 2018 to December 2021. The patients were divided into microsurgery (MS) and navigation endoscopic-assisted (combined surgery, CS) groups and the effects of image guidance and endoscopy evaluated. The tumors in the CS group were then divided into medial and lateral types by fusion imaging and the differences between the two types analyzed. Results: Data of 84 patients were analyzed. Residual tumor was detected by postoperative MRI at the fundus of the internal auditory canal in 5 of the 31 patients in the MS group and 1 of the 53 in the CS group. The labyrinth was damaged in four patients in the MS group but was not damaged in any of the CS group patients. The CS group included 29 lateral type and 24 medial type schwannomas. Endoscopic-assisted resection of residual tumor in the IAC was performed significantly more often on medial than on lateral tumors. Conclusion: Navigation and endoscopy are useful in assisting the exposure of the intrameatal portion of VSs. Preoperative MRI/CT fusion imaging is helpful in preoperative evaluation and surgical planning in patients undergoing VS surgery. Tumors of the medial type require endoscopic assistance for resection.