Severe Neurological Disease Research Articles

Clinical epidemiology, determinants, and outcomes of viral encephalitis in Ghana; a cross-sectional study.

Viral encephalitis is a rare, yet severe neurological disorder. It poses a significant public health threat due to its high morbidity and mortality. Despite the disproportionate burden of the disease in impoverished African countries, the true extent of the problem remains elusive due to the scarcity of accurate diagnostic methods. The absence of timely and effective diagnostic tools, particularly Real-time Polymerase Chain Reaction, has led to misguided treatment, and an underestimation of the disease burden in Ghana. We conducted a prospective cross-sectional study to determine the viral aetiologies of encephalitis among patients presenting to a major referral hospital in Ghana from May 2019 and August 2022. The study aimed at providing a comprehensive information on the clinical epidemiology, and outcomes of viral encephalitis in Ghana. Clinical samples were collected from patients presenting with signs and symptoms of encephalitis and tested for viral agents using real-time polymerase chain reaction. We assessed the clinical epidemiology, risk factors and outcome of individuals using descriptive and logistic regression analysis. Seventy-seven (77) patients were enrolled unto the study. The participants frequently presented with fever (85.7%), seizures (80.5%), lethargy (64.9%) and headache (50.6%). Viruses were detected in 40.3% of the study participants in either cerebrospinal fluid, rectal or oral swab samples. The most frequently detected viruses were cytomegalovirus (48.4%), enteroviruses (38.7%) and HSV (29.0%). Twenty-one (27.3%) of the patients died while on hospital admission. Gender (OR = 5.70 (1.536-1.172), p = 0.01), and negative polymerase chain reaction test results were identified as significant factors associated with death. Antiviral treatment increased the chance of survival of viral encephalitis patients by 21.8%. Our results validate the crucial role of molecular tools as essential for the rapid diagnosis of viral encephalitis, enabling effective treatment and improved patient outcomes. This study contributes valuable epidemiological and clinical insight into viral encephalitis in Ghana.

Identification of the pyridoxal 5'-phosphate allosteric site in human pyridox(am)ine 5'-phosphate oxidase.

Adequate levels of pyridoxal 5'-phosphate (PLP), the catalytically active form of vitamin B6 , and its proper distribution in the body are essential for human health. The PLP recycling pathway plays a crucial role in these processes and its defects cause severe neurological diseases. The enzyme pyridox(am)ine 5'-phosphate oxidase (PNPO), whose catalytic action yields PLP, is one of the key players in this pathway. Mutations in the gene encoding PNPO are responsible for a severe form of neonatal epilepsy. Recently, PNPO has also been described as a potential target for chemotherapeutic agents. Our laboratory has highlighted the crucial role of PNPO in the regulation of PLP levels in the cell, which occurs via a feedback inhibition mechanism of the enzyme, exerted by binding of PLP at an allosteric site. Through docking analyses and site-directed mutagenesis experiments, here we identified the allosteric PLP binding site of human PNPO. This site is located in the same protein region as the allosteric site we previously identified in the Escherichia coli enzyme homologue. However, the identity and arrangement of the amino acid residues involved in PLP binding are completely different and resemble those of the active site of PLP-dependent enzymes. The identification of the PLP allosteric site of human PNPO paves the way for the rational design of enzyme inhibitors as potential anti-cancer compounds.

Covert consciousness.

Covert consciousness is a state of residual awareness following severe brain injury or neurological disorder that evades routine bedside behavioral detection. Patients with covert consciousness have preserved awareness but are incapable of self-expression through ordinary means of behavior or communication. Growing recognition of the limitations of bedside neurobehavioral examination in reliably detecting consciousness, along with advances in neurotechnologies capable of detecting brain states or subtle signs indicative of consciousness not discernible by routine examination, carry promise to transform approaches to classifying, diagnosing, prognosticating and treating disorders of consciousness. Here we describe and critically evaluate the evolving clinical category of covert consciousness, including approaches to its diagnosis through neuroimaging, electrophysiology, and novel behavioral tools, its prognostic relevance, and open questions pertaining to optimal clinical management of patients with covert consciousness recovering from severe brain injury.

Identification of Senescence-Related Biomarkers and Regulatory Networks in Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) is a severe neurological disorder with substantial societal implications. Cellular senescence plays a critical role in ICH pathogenesis. This study aims to identify senescence-related biomarkers in ICH for diagnostic and therapeutic purposes. Raw data from GSE24265 in Gene Expression Omnibus was downloaded. Senescence-related genes were acquired from CellAge. Differential gene analysis was done between patients with ICH and controls. The intersection of ICH differentially expressed genes and senescence-related genes for senescence-related ICH genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed. Protein-protein interaction network was constructed through the Search Tool for the Retrieval of Interacting Genes. Single sample gene set enrichment analysis was done for immune cell infiltration and function evaluation in control and ICH groups. miRWalk2.0 database was used for microRNA predictions targeting ICH biomarkers. Transcriptional regulatory relationships unraveled by sentence-based text mining database was employed to predict transcription factors regulating identified biomarkers. Thirteen senescence-related ICH genes were identified. They were primarily enriched in the positive regulation of angiogenesis and the Advanced Glycation End Product -Receptor for AGE signaling pathway in diabetic complications. Validation in the GSE149317 data set and receiver operating characteristic analysis highlighted Caveolin 1, C-X-C Motif Chemokine Ligand 1, ETS proto-oncogene 1, transcription factor, and Serpin Family E Member 1 as potential ICH biomarkers. Single sample gene set enrichment analysis revealed increased Type 2 T helper cell 2_cells, Treg cells, and immune functions like Antigen-presenting cells_co_stimulation in patients with ICH. Fourteen microRNA, including has-miR-6728-3p, were predicted to regulate these biomarkers. transcription factors such as PPARG, RARA, HMGA1, and NFKB1 were identified as potential regulators of the ICH biomarkers. Caveolin 1, C-X-C Motif Chemokine Ligand 1, ETS proto-oncogene 1, transcription factor, and Serpin Family E Member 1 may serve as valuable biomarkers in ICH. Targeting these genes could contribute to ICH prevention and treatment.

Evaluation of Microbiological quality and antibacterial activity of Cannabis artisanal oil used in Brazil

The medicinal use of Cannabis sativa has been highlighted as an alternative in the treatment of neurological diseases, due to the cannabidiol (CBD), with anticonvulsant properties. This study evaluated the microbiological quality and antibacterial activity of Cannabis extracts used by patients with refractory epilepsy in order to bring more safety in their use and prescription. Around of 70 samples of Cannabis extracts were evaluated, 10 of them used for antibacterial activity tests. Microbiological quality was measured by observing the growth of bacteria, after the inoculation of the Cannabis extract into BHI Agar, BEM Agar, MacConkey Agar and Mueller-Hinton Agar culture media. For antimicrobial activity, a modified Kirby-Bauer method was performed with 11 bacterial isolates considered potentially pathogenic. Of the analyzed samples, 70 showed no bacterial contamination during its preparation, distribution and storage process, making them safe from a microbiological perspective for human consumption. Regarding antimicrobial activity, the 10 samples tested showed no inhibitory activity against the listed bacteria. The product may not interfere with the microbiota of users being treated, as some of the isolates are part of the human microbiota. Analysis of the microbiological quality and antibacterial activity of cannabis used in patients with severe neurological disorder is of fundamental importance to ensure better safety in its use. Therefore, all Cannabis extracts tested are free of microbial contamination that may compromise product quality, and none of the extracts used in this study inhibited the in vitro growth of the tested bacteria.

Patient selection considerations for AADC deficiency gene therapy

AbstractBackgroundAromatic ʟ‐amino acid decarboxylase (AADC) deficiency is a rare, severe neurological disorder caused by pathogenic variants in the dopa decarboxylase (DDC) gene, resulting in a combined deficiency of monoamine neurotransmitters. Clinically, patients present with a range of dysfunctions that impact motor, autonomic, and cognitive development. The constellation of symptoms of AADC deficiency varies among patients, and clinical presentation falls across a wide spectrum. However, most patients with AADC deficiency experience significant impairments when compared with children with normal development, irrespective of genotype, phenotype, or disease severity. Further, AADC deficiency is associated with increased mortality.MethodsIn response to the recent approval of a disease‐modifying gene therapy for AADC deficiency, this review presents considerations for the selection of patients for treatment.ConclusionSuggested clinical criteria to determine whether a patient is a candidate for gene therapy are: (1) genetically and biochemically confirmed AADC deficiency; (2) lack of achievement of gross motor milestones and/or persistence of clinically significant movement disorders; (3) persistent neurocognitive or systemic symptoms secondary to AADC deficiency despite standard medical therapy; and (4) informed parental/guardian decision and consent to treatment.

Automatic detection of epileptic seizure using machine learning-based IANFIS-LightGBM system

A sudden increase in electrical activity in the brain is a defining feature of one of the severe neurological diseases known as epilepsy. This abnormality appears as a seizure, and identifying seizures is an important field of research. An essential technique for examining the features of neurological issues brain activities, and epileptic seizures is electroencephalography (EEG). In EEG data, analyzing epileptic irregularities visually requires a lot of time from neurologists. For accurate detection of epileptic seizures, numerous scientific techniques have been used with EEG data, and most of these techniques have produced promising results. For EEG signal classification with a high classification accuracy rate, the present research proposes an enhanced machine learning-based epileptic seizure detection model. The present research provides a hybrid Improved Adaptive Neuro-Fuzzy Inference System (IANFIS)-Light Gradient Boosting Machine (LightGBM) technique for automatically detecting and diagnosing epilepsy from EEG data. The experimental findings were supported by EEG records made available by the German University of Bonn and scalp EEG data acquired at Children’s Hospital Boston. The suggested IANFIS-LightGBM, according to the results, offers the most significant classification accuracy ratings in both situations.

The BONSAI (Brain and Optic Nerve Study with Artificial Intelligence) deep learning system can accurately identify pediatric papilledema on standard ocular fundus photographs

BackgroundPediatric papilledema often reflects an underlying severe neurologic disorder and may be difficult to appreciate, especially in young children. Ocular fundus photographs are easy to obtain even in young children and in nonophthalmology settings. The aim of our study was to ascertain whether an improved deep-learning system (DLS), previously validated in adults, can accurately identify papilledema and other optic disk abnormalities in children. MethodsThe DLS was tested on mydriatic fundus photographs obtained in a multiethnic pediatric population (<17 years) from three centers (Atlanta-USA; Bucharest-Romania; Singapore). The DLS’s multiclass classification accuracy (ie, normal optic disk, papilledema, disks with other abnormality) was calculated, and the DLS’s performance to specifically detect papilledema and normal disks was evaluated in a one-vs-rest strategy using the AUC, sensitivity and specificity, with reference to expert neuro-ophthalmologists. ResultsExternal testing was performed on 898 fundus photographs:447 patients; mean age, 10.33 (231 patients ≤10 years of age; 216, 11-16 years); 558 normal disks, 254 papilledema, 86 other disk abnormalities. Overall multiclass accuracy of the DLS was 89.6% (range, 87.8%-91.6%). The DLS successfully distinguished “normal” from “abnormal” optic disks (AUC 0.99 [0.98-0.99]; sensitivity, 87.3% [84.9%-89.8%]; specificity, 98.5% [97.6%-99.6%]), and “papilledema” from “normal and other” (AUC 0.99 [0.98-1.0]; sensitivity, 98.0% [96.8%-99.4%]; specificity, 94.1% (92.4%-95.9%)]. ConclusionsOur DLS reliably distinguished papilledema from normal optic disks and other disk abnormalities in children, suggesting it could be utilized as a diagnostic aid for the assessment of optic nerve head appearance in the pediatric age group.

Trends in the Utilization of Surgical Modalities for the Treatment of Drug-Resistant Epilepsy: A Comprehensive 10-Year Analysis Using the National Inpatient Sample.

Epilepsy is considered one of the most prevalent and severe chronic neurological disorders worldwide. Our study aims to analyze the national trends in different treatment modalities for individuals with drug-resistant epilepsy and investigate the outcomes associated with these procedural trends in the United States. Using the National Inpatient Sample database from 2010 to 2020, patients with drug-resistant focal epilepsy who underwent laser interstitial thermal therapy (LITT), open surgical resection, vagus nerve stimulation (VNS), or responsive neurostimulation (RNS) were identified. Trend analysis was performed using piecewise joinpoint regression. Propensity score matching was used to compare outcomes between 10 years prepandemic before 2020 and the first peak of the COVID-19 pandemic. This study analyzed a total of 33 969 patients with a diagnosis of drug-resistant epilepsy, with 3343 patients receiving surgical resection (78%), VNS (8.21%), RNS (8%), and LITT (6%). Between 2010 and 2020, there was an increase in the use of invasive electroencephalography monitoring for seizure zone localization (P = .003). There was an increase in the use of LITT and RNS (P < .001), while the use of surgical resection and VNS decreased over time (P < .001). Most of these patients (89%) were treated during the pre-COVID pandemic era (2010-2019), while a minority (11%) underwent treatment during the COVID pandemic (2020). After propensity score matching, the rate of pulmonary complications, postprocedural hematoma formation, and mortality were slightly higher during the pandemic compared with the prepandemic period (P = .045, P = .033, and P = .026, respectively). This study indicates a relative decrease in the use of surgical resections, as a treatment for drug-resistant focal epilepsy. By contrast, newer, minimally invasive surgical approaches including LITT and RNS showed gradual increases in usage.

VP1 codon deoptimization and high-fidelity substitutions in 3D polymerase as potential vaccine strategies for eliciting immune responses against enterovirus A71.

Enterovirus A71 (EV-A71) can induce severe neurological complications and even fatal encephalitis in children, and it has caused several large outbreaks in Taiwan since 1998. We previously generated VP1 codon-deoptimized (VP1-CD) reverse genetics (rg) EV-A71 viruses (rgEV-A71s) that harbor a high-fidelity (HF) 3D polymerase. These VP1-CD-HF rgEV-A71s showed lower replication kinetics in vitro and decreased virulence in an Institute of Cancer Research (ICR) mouse model of EV-A71 infection, while still retaining their antigenicity in comparison to the wild-type virus. In this study, we aimed to further investigate the humoral and cellular immune responses elicited by VP1-CD-HF rgEV-A71s to assess the potential efficacy of these EV-A71 vaccine candidates. Following intraperitoneal (i.p.) injection of VP1-CD-HF rgEV-A71s in mice, we observed a robust induction of EV-A71-specific neutralizing IgG antibodies in the antisera after 21 days. Splenocytes isolated from VP1-CD-HF rgEV-A71s-immunized mice exhibited enhanced proliferative activities and cytokine production (IL-2, IFN-γ, IL-4, IL-6, and TNF-α) upon re-stimulation with VP1-CD-HF rgEV-A71, as compared to control mice treated with adjuvant only. Importantly, administration of antisera from VP1-CD-HF rgEV-A71s-immunized mice protected against lethal EV-A71 challenge in neonatal mice. These findings highlight that our generated VP1-CD-HF rgEV-A71 viruses are capable of inducing both cellular and humoral immune responses, supporting their potential as next-generation EV-A71 vaccines for combating EV-A71 infection.IMPORTANCEEV-A71 can cause severe neurological diseases and cause death in young children. Here, we report the development of synthetic rgEV-A71s with the combination of codon deoptimization and high-fidelity (HF) substitutions that generate genetically stable reverse genetics (rg) viruses as potential attenuated vaccine candidates. Our work provides insight into the development of low-virulence candidate vaccines through a series of viral genetic editing for maintaining antigenicity and genome stability and suggests a strategy for the development of an innovative next-generation vaccine against EV-A71.

A new physiological medium uncovers biochemical and cellular alterations in Lesch-Nyhan disease fibroblasts

BackgroundLesch-Nyhan disease (LND) is a severe neurological disorder caused by the genetic deficiency of hypoxanthine–guanine phosphoribosyltransferase (HGprt), an enzyme involved in the salvage synthesis of purines. To compensate this deficiency, there is an acceleration of the de novo purine biosynthetic pathway. Most studies have failed to find any consistent abnormalities of purine nucleotides in cultured cells obtained from the patients. Recently, it has been shown that 5-aminoimidazole-4-carboxamide riboside 5ʹ-monophosphate (ZMP), an intermediate of the de novo pathway, accumulates in LND fibroblasts maintained with RPMI containing physiological levels (25 nM) of folic acid (FA), which strongly differs from FA levels of regular cell culture media (2200 nM). However, RPMI and other standard media contain non-physiological levels of many nutrients, having a great impact in cell metabolism that does not precisely recapitulate the in vivo behavior of cells.MethodsWe prepared a new culture medium containing physiological levels of all nutrients, including vitamins (Plasmax-PV), to study the potential alterations of LND fibroblasts that may have been masked by the usage of non-physiological media. We quantified ZMP accumulation under different culture conditions and evaluated the activity of two known ZMP-target proteins (AMPK and ADSL), the mRNA expression of the folate carrier SLC19A1, possible mitochondrial alterations and functional consequences in LND fibroblasts.ResultsLND fibroblasts maintained with Plasmax-PV show metabolic adaptations such a higher glycolytic capacity, increased expression of the folate carrier SCL19A1, and functional alterations such a decreased mitochondrial potential and reduced cell migration compared to controls. These alterations can be reverted with high levels of folic acid, suggesting that folic acid supplements might be a potential treatment for LND.ConclusionsA complete physiological cell culture medium reveals new alterations in Lesch-Nyhan disease. This work emphasizes the importance of using physiological cell culture conditions when studying a metabolic disorder.

Development of a luminescence-based method for measuring West Nile Virus MTase activity and its application to screen for antivirals

West Nile virus (WNV) is a flavivirus responsible for causing febrile illness and severe neurological diseases, with an increasing impact on human health around the world. However, there is still no adequate therapeutic treatment available to struggle WNV infections. Therefore, there is an urgent need to develop new techniques to accelerate the discovery of drugs against this pathogen. The main protein implicated in the replication of WNV is the non-structural protein 5 (NS5). This multifunctional protein contains methyltransferase (MTase) activity involved in the capping formation at the 5′-end of RNA and the methylation of internal viral RNA residues, both functions being essential for viral processes, such as RNA translation and escape from the innate immune response.We have developed a straightforward luminescence-based assay to monitor the MTase activity of the WNV NS5 protein with potential for high-throughput screening. We have validated this method as a sensitive and suitable assay for the identification of WNV MTase inhibitors assessing the inhibitory effect of the broad MTase inhibitor sinefungin, a natural nucleoside analog of the universal methyl donor S-adenosyl methionine (SAM). The screening of a small series of purine derivatives identified an adenosine derivative as a dose-dependent inhibitor of the MTase activity. The antiviral efficacy of this compound was further confirmed in WNV infections, displaying a measurable antiviral effect. This result supports the utility of this novel method for the screening of inhibitors against WNV MTase activity, which can be of special relevance to the discovery and development of therapeutics against WNV.

Discovery and structure-activity relationship study of novel isoxazole-based small molecules targeting Zika virus infections.

The Zika virus (ZIKV), a significant public health threat, is transmitted by Aedes aegypti mosquitoes and is associated with severe neurological disorders, particularly in newborns. Currently, there are no approved vaccines or specific therapeutics for ZIKV. Our study focuses on the identification and optimization of isoxazole-based small molecules, specifically through the structural modification of KR-26827, to combat ZIKV infections. Among the synthesized derivatives, 7l emerged as the most promising candidate, showing potent antiviral activity against ZIKV strains and an improved safety profile in vitro. This research underlines the potential of 7l for further development as a ZIKV therapeutic agent.

A Combined Approach for Predicting Binding Affinity of Zika Virus NS2B-NS3 Protease Inhibitors Using Semi-Empirical Methods and Molecular Docking Algorithms

Zika virus (ZIKV) is a mosquito-borne virus that has emerged as a major public health concern due to its association with severe neurological disorders. In recent years, there has been increasing interest in exploring natural products as potential therapeutics for ZIKV infection. This study aimed to predict the binding affinity of natural compounds to the ZIKV NS2B-NS3 protease (NS2B-NS3pro) using multiple molecular docking algorithms and semiempirical quantum mechanical methods. Our results demonstrate that semiempirical methods can improve the accuracy of molecular docking studies for natural compounds. In this particular case, the PM7 (Parametric Method Number 7) method showed a significant improvement in the coefficient of determination (R2 = 0.85). We expect this combined approach to aid in the development of natural product-based therapies for ZIKV infection and to highlight the importance of continued research in this field.

Traversing Antepartum Wernicke’s Encephalopathy: In-Depth Insights and Strategies

Antepartum Wernicke’s encephalopathy (WE) is a severe neurological disorder caused by a deficiency of thiamine (Vitamin B1), essential for glucose metabolism, and neuronal function. This review aims to provide an in-depth analysis of WE during pregnancy, highlighting its pathophysiology, risk factors, clinical presentation, diagnostic challenges, and management strategies. Thiamine is critical in the Krebs cycle and neurotransmitter production, and its deficiency leads to substantial biochemical disruptions and neuronal damage. Pregnant women are particularly susceptible due to their increased nutritional demands to support fetal growth and maternal metabolic changes, making them prone to thiamine deficiency and its severe neurological consequences. The clinical manifestations of WE include ophthalmoplegia, ataxia, confusion or altered mental state, peripheral neuropathy, and cardiovascular issues. Diagnosing WE during pregnancy is challenging due to its atypical presentation, requiring a high degree of clinical suspicion and awareness of risk factors. Diagnostic limitations include variable clinical symptoms and challenges in interpreting serum thiamine levels and neuroimaging findings. While neuroimaging can show characteristic brain lesions, its utility is limited by variability. Managing WE during pregnancy requires prompt recognition, immediate thiamine supplementation, continued supportive measures, and careful monitoring. Severe or refractory cases may require advanced management strategies. Pharmacological treatments include standardized thiamine administration protocols, guided by clinical guidelines and recommendations. Early detection and management of WE in pregnant women are vital to prevent irreversible neurological damage and improve maternal and fetal outcomes. Adherence to clinical guidelines is crucial to mitigate the impact of this condition.

Chapter 19 - The EBMT-ADWP and the CIBMTR

Hematopoietic stem cell transplantation (HSCT) has evolved over the last 25 years as a specific treatment of patients with severe neurologic autoimmune diseases (ADs), through eradication of the pathologic, immunologic memory, and profound immune "resetting." HSCT for ADs is recently facing a unique developmental phase across transplant centers. Data from patients undergoing HSCT and cellular therapies have been captured through the established major transplant registries, such as the European Society for Blood and Marrow Transplantation (EBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR). The EBMT Autoimmune Diseases Working Party (ADWP) is central to bringing together HSCT and disease-specialist communities. The AD section of the EBMT registry is the largest database of its kind worldwide, reporting more than 3700 transplants. Multiple sclerosis (MS) covers approximately 50% of transplants in AD, HSCT being an integral and standard-of-care part of the treatment algorithm. In the Americas, at least a subset of HSCT is reported to the CIBMTR, as reporting is voluntary. A total of 1400 recipients of autologous HSCT were reported and 1030 were performed for the treatment of neurologic conditions. MS accounts for 96% of all diagnoses among neurologic indications for HSCT. Although the activity of HSCT for MS is low in the United States in relation to its prevalence, the number of transplants has increased in recent years. In contrast, Mexico has reported a sharp increase in the number of these transplants. This chapter provides an overview of the EBMT and CIBMTR registries, then offers the current status and publication outputs in relation to neurologic AD.

Prospective monitoring of adverse events following vaccination with Modified vaccinia Ankara - Bavarian Nordic (MVA-BN) administered to a Canadian population at risk of Mpox: A Canadian Immunization Research Network study

MVA-BN is an orthopoxvirus vaccine that provides protection against both smallpox and mpox. In June 2022, Canada launched a publicly-funded vaccination campaign to offer MVA-BN to at-risk populations including men who have sex with men (MSM) and sex workers. The safety of MVA-BN has not been assessed in this context. To address this, the Canadian National Vaccine Safety Network (CANVAS) conducted prospective safety surveillance during public health vaccination campaigns in Toronto, Ontario and in Vancouver, British Columbia. Vaccinated participants received a survey 7 and 30 days after each MVA-BN dose to elicit adverse health events. Unvaccinated individuals from a concurrent vaccine safety project evaluating COVID-19 vaccine safety were used as controls. Vaccinated and unvaccinated participants that reported a medically attended visit on their 7-day survey were interviewed. Vaccinated participants and unvaccinated controls were matched 1:1 based on age group, gender, sex and provincial study site. Overall, 1,173 vaccinated participants completed a 7-day survey, of whom 75 % (n = 878) also completed a 30-day survey. Mild to moderate injection site pain was reported by 60 % of vaccinated participants. Among vaccinated participants 8.4 % were HIV positive and when compared to HIV negative vaccinated individuals, local injection sites were less frequent in those with HIV (48 % vs 61 %, p = 0.021), but health events preventing work/school or requiring medical assessment were more frequent (7.1 % vs 3.1 %, p = 0.040). Health events interfering with work/school, or requiring medical assessment were less common in the vaccinated group than controls (3.3 % vs. 7.1 %, p < 0.010). No participants were hospitalized within 7 or 30 days of vaccination. No cases of severe neurological disease, skin disease, or myocarditis were identified. Our results demonstrate that the MVA-BN vaccine appears safe when used for mpox prevention, with a low frequency of severe adverse events and no hospitalizations observed.

Retinoic acid alleviates the reduction of Akt and Bad phosphorylation and regulates Bcl-2 family protein interactions in animal models of ischemic stroke.

Ischemic stroke causes a lack of oxygen and glucose supply to brain, eventually leads to severe neurological disorders. Retinoic acid is a major metabolic product of vitamin A and has various biological effects. The PI3K-Akt signaling pathway is an important survival pathway in brain. Phosphorylated Akt is important in regulating survival and apoptosis. We examined whether retinoic acid has neuroprotective effects in stroke model by regulating Akt and its downstream protein, Bad. Moreover, we investigated the relationship between retinoic acid and Bcl-2 family protein interactions. Animals were intraperitoneally administered vehicle or retinoic acid (5 mg/kg) for four days before surgery and ischemic stroke was induced by middle cerebral artery occlusion (MCAO) surgery. Neurobehavioral tests were performed 24 h after MCAO and cerebral cortical tissues were collected. Cresyl violet staining and TUNEL histochemistry were performed, Western blot and immunoprecipitation analysis were performed to elucidate the expression of various proteins. Retinoic acid reduced neurological deficits and histopathological changes, decreased the number of TUNEL-positive cells, and alleviated reduction of phospho-PDK1, phospho-Akt, and phospho-Bad expression caused by MCAO damage. Immunoprecipitation analysis showed that MCAO damage reduced the interaction between phospho-Bad and 14-3-3, which was attenuated by retinoic acid. Furthermore, retinoic acid mitigated the increase in Bcl-2/Bad and Bcl-xL/Bad binding levels and the reduction in Bcl-2/Bax and Bcl-xL/Bax binding levels caused by MCAO damage. Retinoic acid alleviated MCAO-induced increase of caspase-3 and cleaved caspase-3 expression. We demonstrate that retinoic acid prevented apoptosis against cerebral ischemia through phosphorylation of Akt and Bad, maintenance of phospho-Bad and 14-3-3 binding, and regulation of Bcl-2 family protein interactions. .

On the issue of optimizing protein and energy supply for patients with acute cerebrovascular accident

To study the severity of systemic metabolic dysfunction in various types of stroke and determine the parameters of optimal energy and protein supply for this category of patients in the presence of severe neurological deficit (National Institutes of Health Stroke Scale - NIHSS score of 15 points or more) during different periods of the disease. The retrospective study included 512 patients with acute cerebrovascular accident (ACVA) who received nutritional support (NS) for 10 days or more: 367 (71.7%) people with ischemic stroke (IS) and 145 (28.3%) - with hemorrhagic stroke (HS). The course of stroke in all patients included in the study was accompanied by severe and extremely severe neurological disorders (15 points or more on the NIHSS scale). Energy expenditure and the severity of the catabolic reaction of the body were studied by dynamic assessment of indirect calorimetry indicators and actual nitrogen losses. More than 99% of patients received tube feeding. Using the method of indirect calorimetry, the ranges of energy expenditure during stroke were determined: for IS - 1600-2100 kcal/day (24-26 kcal/kg/day), for HS - 1900-2600 kcal/day (26-30 kcal/kg/day) in depending on the period of the disease. The average nitrogen losses at all stages of the disease in patients with IS and HS were comparable. In IS, these amounts were 19 g/day (0.25 g/kg/day), which corresponds to 119 g/day of protein (1.56 g/kg/day of protein), and in HS patients lost an average of 18.9 g/day of nitrogen (0.24 g/kg/day) or 118 g/day of protein (1.5 g/kg/day of protein). The maximum nitrogen losses were observed in the period from 10 to 20 days of illness and amounted to 24.7 g/day in patients with HS (0.31 g/kg/day or 1.93 g/kg/day protein), and in patients with IS - 24.5 g/day (0.29 g/kg/day or 1.81 g/kg/day protein). An identified trend towards a decrease in mortality in patients with acute stroke with energy supply in the amount of 27-28 kcal/kg/day and protein consumption in the amount of 1.3-1.4 g/kg/day compared with patients receiving 20-21 kcal/kg /day and 1-1.2 g/kg/day of protein requires further prospective randomized studies.

Novel Brain-Derived Neurotrophic Factor Controlled-Release Formulation Promotes Neuroprotection In Vitro

Traumatic brain injury (TBI) leads to a cascade of primary and secondary neurodegenerative events, often causing lifelong disabilities. Brain-derived neurotrophic factor (BDNF) is a potential therapeutic for functional recovery of neurons. Unfortunately, BDNF is unstable and expensive, making direct infusion impractical. Therefore, we sought to develop a controlled release formulation to deliver BDNF. Our therapeutic construct encapsulates BDNF in poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs), and further encapsulates these NPs in an alginate hydrogel. Encapsulating BDNF within NPs protects and assists in drug delivery, while further encapsulating the BDNF-NPs in alginate enables localization and sustained release. The BDNF-NPs were synthesized and evaluated for size, stability and BDNF release profile. A MATLAB model was developed to determine the approximate quantity of BDNF-NPs needed to evaluate therapeutic efficacy in neurons injured with hydrogen peroxide. We then compared the therapeutic efficacy and BDNF release profile of these BDNF-NPs to our novel alginate/BDNF-NP formulation. We have successfully designed and fabricated a double encapsulation positionally controllable construct that preserves BDNF bioactivity and extends its release. We also demonstrated that very low dosages of BDNF may be equally effective in promoting neuroprotection, thereby potentially reducing therapeutic costs without compromising efficacy. Our novel formulation offers a promising avenue for treating severe TBI and other neurological disorders which would benefit from a long-lasting and positionally controllable neuroprotective treatment. This approach can easily accommodate additional biologics for localized drug delivery with minimal re-formulation.