let-7 microRNAs regulate microglial function and suppress glioma growth through Toll-like receptor 7

Microglia express Toll-like receptors (TLRs) that sense pathogen- and host-derived factors, including single-stranded RNA. In the brain, let-7 microRNA (miRNA) family members are abundantly expressed, and some have recently been shown to serve as TLR7 ligands. We investigated whether let-7 miRNA family members differentially control microglia biology in health and disease. We found that a subset of let-7 miRNA family members function as signaling molecules to induce microglial release of inflammatory cytokines, modulate antigen presentation, and attenuate cell migration in a TLR7-dependent manner. The capability of the let-7 miRNAs to control microglial function is sequence specific, mapping to a let-7 UUGU motif. In human and murine glioblastoma/glioma, let-7 miRNAs are differentially expressed and reduce murine GL261 glioma growth in the same sequence-specific fashion through microglial TLR7. Taken together, these data establish let-7 miRNAs as key TLR7 signaling activators that serve to regulate the diverse functions of microglia in health and glioma

Activation of Toll-like receptor 5 in microglia modulates their function and triggers neuronal injury

Microglia are the primary immune-competent cells of the central nervous system (CNS) and sense both pathogen- and host-derived factors through several receptor systems including the Toll-like receptor (TLR) family. Although TLR5 has previously been implicated in different CNS disorders including neurodegenerative diseases, its mode of action in the brain remained largely unexplored. We sought to determine the expression and functional consequences of TLR5 activation in the CNS. Quantitative real-time PCR and immunocytochemical analysis revealed that microglia is the major CNS cell type that constitutively expresses TLR5. Using Tlr5(-/-) mice and inhibitory TLR5 antibody we found that activation of TLR5 in microglial cells by its agonist flagellin, a principal protein component of bacterial flagella, triggers their release of distinct inflammatory molecules, regulates chemotaxis, and increases their phagocytic activity. Furthermore, while TLR5 activation does not affect tumor growth in an ex vivo GL261 glioma mouse model, it triggers microglial accumulation and neuronal apoptosis in the cerebral cortex in vivo. TLR5-mediated microglial function involves the PI3K/Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway, as specific inhibitors of this signaling pathway abolish microglial activation. Taken together, our findings establish TLR5 as a modulator of microglial function and indicate its contribution to inflammatory and injurious processes in the CNS

Neurofibromatosis 1 (NF1) mutation results in impaired function of human induced pluripotent stem cell-derived microglia

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by germline mutations in the NF1 gene. Children with NF1 are prone to the development of multiple nervous system abnormalities, including autism and brain tumors, which could reflect the effect of NF1 mutation on microglia function. Using heterozygous Nf1-mutant mice, we previously demonstrated that impaired purinergic signaling underlies deficits in microglia process extension and phagocytosis in situ. To determine whether these abnormalities are also observed in human microglia in the setting of NF1, we leveraged an engineered isogenic series of human induced pluripotent stem cells to generate human microglia-like (hiMGL) cells heterozygous for three different NF1 patient-derived NF1 gene mutations. While all NF1-mutant and isogenic control hiMGL cells expressed classical microglia markers and exhibited similar transcriptomes and cytokine/chemokine release profiles, only NF1-mutant hiMGL cells had defects in P2X receptor activation, phagocytosis and motility. Taken together, heterozygous NF1 mutation impairs a subset of human microglia functional properties, which could contribute to the neurological abnormalities seen in children with NF1

Gender differences in perceptions and attitudes of medical students towards neurosurgery: a german nationwide survey

BACKGROUND: Despite advances in gender equity, the paucity of women neurosurgeons remains. In Germany, women accounted for only 24% of the specialists who completed their neurosurgical training in 2019. We sought to explore the perceptions of medical students in Germany towards a neurosurgical career, focusing on gender-specific differences. METHODS: A digital 26-item questionnaire with a Likert 4-point scale and open-ended questions was distributed to the German Medical School student bodies. Data was analyzed to determine statistically significant intra-group variability between women and men. RESULTS: 210 medical students participated in the survey. Women and men were equally interested in brain pathologies (38% vs. 47%, strongly agreed), whereas interest in neurosurgery was significantly greater in men (12% vs. 26%, strongly agreed). Men were less likely to believe that women neurosurgery residents would face inequality at work. They were also less likely to support a gender quota in neurosurgery. Yet, both women and men were convinced that a rise in the number of women would positively impact the field. No gender-dependency was seen in students' strive for success and prestige. Men felt discouraged from pursuing neurosurgery because they feared an unpleasant work environment whereas women were concerned about neurosurgery not being family-friendly. Regardless of gender, the greatest factor deterring students from neurosurgery was poor work-life balance. CONCLUSION: Awareness must be raised concerning gender inequity and discrimination in our specialty. A multifaceted approach is imperative to develop neurosurgery into a profession where gender no longer hinders access to training and success in the field

Basal cisternostomy for traumatic brain injury: A case report of unexpected good recovery

In subarachnoid hemorrhage following traumatic brain injury (TBI), the high intracisternal pressure drives the cerebrospinal fluid into the brain parenchyma, causing cerebral edema. Basal cisternostomy involves opening of the basal cisterns to atmospheric pressure and draining cerebrospinal fluid in an attempt to reverse the edema. We describe a case of basal cisternostomy combined with decompressive craniectomy. A 35-year-old man with severe TBI following a road vehicle accident presented with acute subdural hematoma, Glasgow coma scale score of 6, fixed pupils and no corneal response. Opening of the basal cisterns and placement of a temporary cisternal drain led to immediate relaxation of the brain. The patient had a Glasgow coma scale score of 15 on postoperative day 6 and was discharged on day 10. We think basal cisternostomy is a feasible and effective procedure that should be considered in the management of TBI. © 2021 Chinese Medical Associatio

Development of a Novel Low-Cost Exoscope to Expand Access to Microneurosurgical Care in Low- and Middle-Income Countries

Background: Less than a quarter of the world population has access to microneurosurgical care within a range of 2 hours. We introduce a simplified exoscope system to achieve magnification, illumination, and video recording in low-resource settings. Methods: We combined an industrial microscope tube, a heavy-duty support arm, a wide-field c-mount digital microscope camera, and a light-emitting diode ring light. All parts were sterilized with ethylene oxide. We performed 13 spinal and 3 cranial surgeries with the help of the low-budget exoscope. Results: The average preoperative setup time was 12.8 minutes. The exoscope provided similar magnification and illumination like a conventional binocular microscope. It allowed operating in a comfortable posture. The field of vision ranged from 30 mm–60 mm. The surgical field was captured by a 16-megapixel two-dimensional camera and projected to a 55-inch high-definition television screen in real time. Image quality was similar to that of a conventional microscope although our exoscope lacked stereoscopic view. Adjusting camera position and angle was time-consuming. Thus, the benefit of the exoscope was most notable in spine surgeries where the camera remained static for most of the time. The total cost of the exoscope was approximately U.S. $ 750. Conclusions: Our low-budget exoscope offers similar image quality, magnification, and illumination like a conventional binocular microscope. It may thus help expand access to neurosurgical care worldwide. Users may face difficulty adapting to the lack of depth perception in the beginning. Prospective studies are needed to assess its usability and effectiveness compared to the microscope. © 2022 Elsevier Inc

Tumor associated microglia/macrophages utilize GPNMB to promote tumor growth and alter immune cell infiltration in glioma

Tumor-associated microglia and blood-derived macrophages (TAMs) play a central role in modulating the immune suppressive microenvironment in glioma. Here, we show that GPNMB is predominantly expressed by TAMs in human glioblastoma multiforme and the murine RCAS-PDGFb high grade glioma model. Loss of GPNMB in the in vivo tumor microenvironment results in significantly smaller tumor volumes and generates a pro-inflammatory innate and adaptive immune cell microenvironment. The impact of host-derived GPNMB on tumor growth was confirmed in two distinct murine glioma cell lines in organotypic brain slices from GPNMB-KO and control mice. Using published data bases of human glioma, the elevated levels in TAMs could be confirmed and the GPNMB expression correlated with a poorer survival

Synergistic toll-like receptor 3/9 signaling affects properties and impairs glioma-promoting activity of microglia

In murine experimental glioma models, TLR3 or TLR9 activation of microglial/macrophages has been shown to impair glioma growth, which could, however, not been verified in recent clinical trials. We therefore tested whether combined TLR3 and TLR9 activation of microglia/macrophages would have a synergistic effect. Indeed, combined TLR3/9 activation augmented the suppression of glioma growth in organotypic brain slices from male mice in a microglia-dependent fashion, and this synergistic suppression depended on interferon β release and phagocytic tumor clearance. Combined TLR3/9 stimulation also augmented several functional features of microglia such as the release of pro-inflammatory factors, motility and phagocytosis activity. TLR3/9 stimulation combined with CD47 blockade further augmented glioma clearance. Finally, we confirmed that the co-activation of TLR3/9 also augments the impairment of glioma growth in vivo. Our results show that combined activation of TLR3/9 in microglia/macrophages results in a more efficient glioma suppression, which may provide a potential strategy for glioma treatment. SIGNIFICANCE STATEMENT: GAMs (Glioma associated microglia/macrophages) are the predominant immune cells in glioma growth and are recently considered as anti-tumor targets. TLRs are involved in glioma growth, but the TLR3 or TLR9 ligands were not successful in clinical trials in treating glioma. We therefore combined TLR3 and TLR9 activation of GAMs resulting in a strong synergistic effect of tumor clearance in vitro, ex vivo and in vivo. Mechanisms of this GAM-glioma interaction involve IFNß signaling and increased tumor clearance by GAMs. Interfering with CD47 signaling had an additional impact on tumor clearance. We propose that these signaling pathways could be exploited as anti-glioma targets

Surgical management of a penetrating drill bit injury to the skull base

Background: Low-energy penetrating brain injuries are rarely encountered in neurosurgical practice. Immediate surgical management remains the primary treatment strategy to control potential bleeding and prevents infectious complications. Case Description: A 28-year-old man presented with an orbital injury with left-sided chemosis, amaurosis, and ophthalmoplegia following an assault. Cranial CT revealed an industrial drill bit causing a penetrating injury to the skull base. The tip of the object reached the petrous apex. CT angiography showed no signs of cerebrovascular damage. The drill bit was visualized through a frontotemporal craniotomy. It was then carefully removed under direct microscopic vision. Postoperative ceftriaxone was administered. The patient was discharged in good condition on postoperative day 6. His vision impairment remained.Conclusion: Timely access to neuroimaging diagnostics and microneurosurgical facilities allows for good outcomes in the surgical treatment of low-velocity penetrating brain injuries. © 2022 Scientific Scholar. All rights reserved