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Deciphering the molecular pathways associated with N-methyl-D-aspartate receptor (NMDAr) hypofunction and its interaction with antipsychotics is necessary to advance our understanding of the basis of schizophrenia, as well as our capacity to treat this disease. In this regard, the development of human brain-derived models that are amenable to studying the neurobiology of schizophrenia may contribute to filling the gaps left by the widely employed animal models. Here, we assessed the proteomic changes induced by the NMDA glutamate receptor antagonist MK-801 on human brain slice cultures obtained from adult donors submitted to respective neurosurgery. Initially, we demonstrated that MK-801 diminishes NMDA glutamate receptor signaling in human brain slices in culture. Next, using mass-spectrometry-based proteomics and systems biology in silico analyses, we found that MK-801 led to alterations in proteins related to several pathways previously associated with schizophrenia pathophysiology, including ephrin, opioid, melatonin, sirtuin signaling, interleukin 8, endocannabinoid, and synaptic vesicle cycle. We also evaluated the impact of both typical and atypical antipsychotics on MK-801-induced proteome changes. Interestingly, the atypical antipsychotic clozapine showed a more significant capacity to counteract the protein alterations induced by NMDAr hypofunction than haloperidol. Finally, using our dataset, we identified potential modulators of the MK-801-induced proteome changes, which may be considered promising targets to treat NMDAr hypofunction in schizophrenia. This dataset is publicly available and may be helpful in further studies aimed at evaluating the effects of MK-801 and antipsychotics in the human brain., (© 2024 International Society for Neurochemistry.)

We describe two cases of extensive indolent calvarial osteomyelitis after rhino-orbital-mucormycosis in diabetic patients previously diagnosed with COVID-19. Both patients presented with acute rhino-orbital symptoms about one month after being diagnosed with COVID-19. Treatment with intravenous liposomal Amphotericin B and prompt radical surgical debridement was instituted, but calvarial osteomyelitis ensued and persisted chronically despite maintenance of antifungal therapy and partial debridement of necrotic calvarial bone. The patients were discharged to continue antifungal therapy on a day-hospital regime. After more than 8 months of treatment, they remain with radiological signs of osteomyelitis but with no symptoms or intracranial extension of the infection. Calvarial indolent osteomyelitis secondary to mucormycosis is extremely rare, and little is known regarding its treatment. We believe it can be controlled with medical treatment and partial bony debridement although more studies are necessary to better define therapy.

Recurrence of meningiomas is unpredictable by current invasive methods based on surgically removed specimens. Identification of patients likely to recur using noninvasive approaches could inform treatment strategy, whether intervention or monitoring. In this study, we analyze the DNA methylation levels in blood (serum and plasma) and tissue samples from 155 meningioma patients, compared to other central nervous system tumor and non-tumor entities. We discover DNA methylation markers unique to meningiomas and use artificial intelligence to create accurate and universal models for identifying and predicting meningioma recurrence, using either blood or tissue samples. Here we show that liquid biopsy is a potential noninvasive and reliable tool for diagnosing and predicting outcomes in meningioma patients. This approach can improve personalized management strategies for these patients., (© 2023. Springer Nature Limited.)

Background: Ischemic stroke is an important cause of death in the world. The malignant middle cerebral artery infarction (MMCAI) has mortality as high as 80% when clinically treated. In this setting, decompressive craniectomy is a life-saving measure, in spite of high morbidity among survivors., Objective: To evaluate the outcomes of patients with MMCAI treated with decompressive craniectomy in a Brazilian academic tertiary stroke center., Methods: A prospective stroke database was retrospectively evaluated, and all patients treated with decompressive craniectomy for MMCAI between January 2014 and December 2017 were included. The demographics and clinical characteristics were evaluated. The functional outcome, measured by the modified Rankin Scale (mRS), was assessed at hospital discharge, after 3-months and 1-year of follow-up., Results: We included 53 patients on the final analysis. The mean age was 54.6 ± 11.6 years and 64.2% were males. The median time from symptoms to admission was 4.8 (3-9.7) hours and the mean time from symptoms to surgery was 36 ± 17 hours. The left hemisphere was the affected in 39.6%. The median NIHSS at admission was 20 (16-24). The in-hospital mortality was 30.2%. After a median of 337 [157-393] days, 47.1% of patients had achieved favorable outcome (mRS ≤ 4) and 39.6% had died., Conclusion: Decompressive craniectomy is a life-saving measure in the setting of MMCAI, and its effects remains important in the scenario of a middle-income country in real-world situations., Competing Interests: The authors have no conflict of interest to declare., (Academia Brasileira de Neurologia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/).)

Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of "long COVID-19" syndrome) has been frequently observed after mild infection. We show the spectrum of cerebral impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal transethmoidal access) from individuals who died of COVID-19. In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell-derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike-NRP1 interaction. SARS-CoV-2-infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability. Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.

Oropouche virus (OROV) is an emerging arbovirus in South and Central Americas with high spreading potential. OROV infection has been associated with neurological complications and OROV genomic RNA has been detected in cerebrospinal fluid from patients, suggesting its neuroinvasive potential. Motivated by these findings, neurotropism and neuropathogenesis of OROV have been investigated in vivo in murine models, which do not fully recapitulate the complexity of the human brain. Here we have used slice cultures from adult human brains to investigate whether OROV is capable of infecting mature human neural cells in a context of preserved neural connections and brain cytoarchitecture. Our results demonstrate that human neural cells can be infected ex vivo by OROV and support the production of infectious viral particles. Moreover, OROV infection led to the release of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) and diminished cell viability 48 h post-infection, indicating that OROV triggers an inflammatory response and tissue damage. Although OROV-positive neurons were observed, microglia were the most abundant central nervous system (CNS) cell type infected by OROV, suggesting that they play an important role in the response to CNS infection by OROV in the adult human brain. Importantly, we found no OROV-infected astrocytes. To the best of our knowledge, this is the first direct demonstration of OROV infection in human brain cells. Combined with previous data from murine models and case reports of OROV genome detection in cerebrospinal fluid from patients, our data shed light on OROV neuropathogenesis and help raising awareness about acute and possibly chronic consequences of OROV infection in the human brain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Almeida, Souza, Mendes, Pontelli, Pinheiro, Nogueira, Cardoso, Paiva, Ferrari, Veras, Cunha, Horta-Junior, Alberici, Cunha, Podolsky-Gondim, Neder, Arruda and Sebollela.)

Objective With the aging of the global population, an increase in the proportion of elderly patients presenting with traumatic brain injury (TBI) is expected. This population presents several distinctive characteristics that impact management and outcome of TBI, such as comorbidities, frailty, and preinjury use of medications - specially antiplatelets and anticoagulants. The purpose of this study was to assess the general characteristics and prognostic factors of elderly patients with TBI that were surgically managed at a single institution. Methods The authors performed a retrospective review of all elderly patients (age ≥ 65 years) with a history of TBI that underwent cranial neurosurgical procedures at their institution, between 2015 and 2019. Clinical characteristics, laboratory tests, and radiological scans, as well as surgeries, performed, outcome, and prognostic factors were analyzed, comprising 133 consecutive cases overall. Results The mean age of patients was 76.6 ± 7.3 years, ranging from 65 years to 97 years. There was a predominance of males (71.4%) and the most frequent mechanism of injury was fall (80.4%). Mild TBI comprised 57.1% of the cases, followed by severe TBI in 25.6%. Frequent signs and symptoms were impaired consciousness (69.9%), focal motor deficits (32.3%), and gait disturbances (12.8%). The majority had reported comorbidities upon admission (79.7%), with cardiac disease (79.2%) and diabetes (24.5%) as the most frequent. Preinjury anticoagulation was reported in 18.8% and use of antiplatelet drugs in 17.3%. The most common finding in the head CT was chronic subdural hematoma (48.1%), followed by acute subdural hematoma (37.6%). Coagulation was found to be altered in 12.8% of the patients. The most common neurosurgical procedure performed was trephination for hematoma evacuation (56.3%), followed by craniotomy (21.2%). Blood product transfusion was needed in 61.7% of the patients. Overall mortality was 42.1%, with the majority in the first month after admission (83.9%). Unfavorable outcome (Glasgow Outcome Scale <5) at discharge was identified in 73% of the patients. Identified prognostic factors were TBI severity, absent pupillary reactivity, acute intracranial bleeding on head CT, basal cisterns obliteration, altered coagulation status, and need for blood transfusion. Conclusions TBI severity, pupillary reactivity, coagulation status, need for blood products transfusion and acute bleeding, as well as basal cisterns obliteration found in head CT, are factors that influenced the outcome in this series of elderly patients with TBI that need surgical management. It is paramount to observe the particularities of this population in this context, to optimize outcomes, avoid complications and ultimately generate awareness focused on prevention., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Podolsky-Gondim et al.)

Introduction: Head injury is a significant economic, social, and medical problem in developing countries and remains one of the leading causes of pediatric morbidity and mortality. The association of traumatic brain injury and coagulopathy in children is linked with an increase in mortality and poor functional outcomes. However, its impact on long-term outcome has not been discussed in the literature so far., Objectives: The aim of this paper was to investigate the effect of coagulopathy diagnosed by routine laboratory tests on neurological outcome following traumatic brain injury in children., Methods: A retrospective review was carried out using medical records of children with a traumatic brain injury admitted at a level I trauma center, between January 2013 and December 2016, submitted to any neurosurgical procedures. Statistical analysis was performed accordingly to identify factors predicting unfavorable or favorable outcomes at 1- and 6-month follow-ups. Data regarding age, gender, trauma mechanism, Glasgow Coma Scale at admission and at discharge, highest and lowest stable intracranial pressure, serum glucose and coagulation assessment, radiological findings, and length of stay were analyzed., Results: We identified 66 children with surgical head trauma. Mean age was 10.9 years (ranges from 3 months to 17 years), with male predominance (77.3%). Common mechanisms were road traffic accidents (66.7%), falls (19.7%), and blunt trauma (10.6%). Brain edema was detected in 68.2% of the patients, surgical fractures or intracranial bleeding in 75.8%. ICP monitoring was performed in 24.2% of the patients, and of these, 18.7% underwent consecutive decompressive craniectomy. Mean length of in-patient treatment was 16.3 ± 28.2 days. At 1- and 6-month follow-ups, favorable outcome was detected in 71.2 and 78.7% of the patients, respectively. The mortality rate was 12.1%. Routine coagulation assessments such as prothrombin time, fibrinogen levels, and thrombocyte count upon admission were potential prognostic variables identified., Conclusions: The present study concluded that a trauma-related coagulopathy is an important predictor of unfavorable neurological outcome following TBI in pediatric patients. Initial GCS score, age, and neuroradiological findings, such as severe brain edema and different types of intracranial bleeding, correlated with GOS in the first 6 months following TBI. Sustained intracranial hypertension also predicted unfavorable outcome and death in this series.