NMDA glutamate receptor antagonist MK-801 induces proteome changes in adult human brain slices which are partially counteracted by haloperidol and clozapine.

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.

Outcomes of decompressive craniectomy for malignant middle cerebral artery stroke in an academic hospital in Brazil.

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.

ANTECEDENTES: O acidente vascular cerebral (AVC) isquêmico é uma causa importante da morte em todo o mundo. O infarto maligno da artéria cerebral média (IMACM) tem mortalidade de até 80% quando tratado clinicamente. Nesse contexto, a craniectomia descompressiva é uma medida salvadora de vidas, apesar da alta morbidade entre os sobreviventes. OBJETIVO: Avaliar os desfechos dos pacientes com IMACM tratados com craniectomia descompressiva em um centro acadêmico terciário de AVC no Brasil. MéTODOS: Um banco de dados prospectivo de AVC foi avaliado retrospectivamente e todos os pacientes tratados com craniectomia descompressiva para IMACM entre janeiro de 2014 e dezembro de 2017 foram incluídos. As características clínicas e demográficas foram avaliadas. Os desfechos funcionais, medidos pela escala modificada da Rankin (mRS), foram avaliados na alta hospitalar, após 3 meses e após 1 ano de seguimento. RESULTADOS: Foram incluídos 53 pacientes na análise final. A idade média foi 54,6 ± 11,6 anos e 64,2% eram homens. A mediana do tempo dos sintomas à admissão foi 4,8 (3­9,7) horas e o tempo médio dos sintomas à cirurgia foi 36 ± 17 horas. O hemisfério esquerdo foi o afetado em 39,6%. A pontuação na escala de AVC do National Institute of Health (NIHSS) à admissão foi 20 (16­24). A mortalidade hospitalar foi 30,2%. Após uma mediana de 337 (157­393) dias, 47,1% dos pacientes tinham atingido um desfecho favorável (mRS ≤ 4) e 39,6% tinham morrido. CONCLUSãO: Craniectomia descompressiva é uma medida salvadora de vidas no contexto do IMACM e seus efeitos permanecem importantes no cenário de um país em desenvolvimento em situação de vida real.

Outcomes of decompressive craniectomy for malignant middle cerebral artery stroke in an academic hospital in Brazil / Desfechos da craniectomia descompressiva para infarto maligno da artéria cerebral média em um hospital acadêmico no Brasil

Abstract 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.

Resumo Antecedentes O acidente vascular cerebral (AVC) isquêmico é uma causa importante da morte em todo o mundo. O infarto maligno da artéria cerebral média (IMACM) tem mortalidade de até 80% quando tratado clinicamente. Nesse contexto, a craniectomia descompressiva é uma medida salvadora de vidas, apesar da alta morbidade entre os sobreviventes. Objetivo Avaliar os desfechos dos pacientes com IMACM tratados com craniectomia descompressiva em um centro acadêmico terciário de AVC no Brasil. Métodos Um banco de dados prospectivo de AVC foi avaliado retrospectivamente e todos os pacientes tratados com craniectomia descompressiva para IMACM entre janeiro de 2014 e dezembro de 2017 foram incluídos. As características clínicas e demográficas foram avaliadas. Os desfechos funcionais, medidos pela escala modificada da Rankin (mRS), foram avaliados na alta hospitalar, após 3 meses e após 1 ano de seguimento. Resultados Foram incluídos 53 pacientes na análise final. A idade média foi 54,6 ± 11,6 anos e 64,2% eram homens. A mediana do tempo dos sintomas à admissão foi 4,8 (3-9,7) horas e o tempo médio dos sintomas à cirurgia foi 36 ± 17 horas. O hemisfério esquerdo foi o afetado em 39,6%. A pontuação na escala de AVC do National Institute of Health (NIHSS) à admissão foi 20 (16-24). A mortalidade hospitalar foi 30,2%. Após uma mediana de 337 (157-393) dias, 47,1% dos pacientes tinham atingido um desfecho favorável (mRS ≤ 4) e 39,6% tinham morrido. Conclusão Craniectomia descompressiva é uma medida salvadora de vidas no contexto do IMACM e seus efeitos permanecem importantes no cenário de um país em desenvolvimento em situação de vida real.

Progressive chronic calvarial osteomyelitis in rhino-orbital mucormycosis associated with COVID-19.

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.

The role of coagulopathy on clinical outcome following traumatic brain injury in children: analysis of 66 consecutive cases in a single center institution.

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.