Severe Neurological Disease Research Articles

Retrospective Genotyping of Enteroviruses Using a Diagnostic Nanopore Sequencing Workflow.

Enteroviruses are among the most common viruses pathogenic to humans. They are associated with various forms of disease, ranging from mild respiratory illness to severe neurological diseases. In recent years, an increasing number of isolated cases of children developing meningitis or encephalitis as a result of enterovirus infection have been reported, as well as discrete enterovirus D68 outbreaks in North America in 2014 and 2016. We developed an assay to rapidly genotype enteroviruses by sequencing a region within the VP1 gene using nanopore Flongles. We retrospectively analyzed enterovirus-/rhinovirus-positive clinical samples from the Zurich, Switzerland area mainly collected during two seasons in 2019/2020 and 2021/2022. Respiratory, cerebrospinal fluid, and stool samples were analyzed. Whole-genome sequencing was performed on samples with ambiguous genotyping results and enterovirus D68-positive samples. Out of 255 isolates, a total of 95 different genotypes were found. A difference in the prevalence of enterovirus and rhinovirus infections was observed for both sample type and age group. In particular, children aged 0-4 years showed a higher frequency of enterovirus infections. Comparing the respiratory seasons, a higher prevalence was found, especially for enterovirus A and rhinovirus A after the SARS-CoV-2 pandemic. The enterovirus genotyping workflow provides a rapid diagnostic tool for individual analysis and continuous enterovirus surveillance.

Lysosomal storage diseases. Sphingolipidoses – leukodystrophy

Lysosomal storage diseases. Sphingolipidoses – leukodystrophy

Exploring Structural Insights of Aβ42 and α-Synuclein Monomers and Heterodimer: A Comparative Study Using Implicit and Explicit Solvent Simulations.

Protein misfolding, aggregation, and fibril formation play a central role in the development of severe neurological disorders, including Alzheimer's and Parkinson's diseases. The structural stability of mature fibrils in these diseases is of great importance, as organisms struggle to effectively eliminate amyloid plaques. To address this issue, it is crucial to investigate the early stages of fibril formation when monomers aggregate into small, toxic, and soluble oligomers. However, these structures are inherently disordered, making them challenging to study through experimental approaches. Recently, it has been shown experimentally that amyloid-β 42 (Aβ42) and α-synuclein (α-Syn) can coassemble. This has motivated us to investigate the interaction between their monomers as a first step toward exploring the possibility of forming heterodimeric complexes. In particular, our study involves the utilization of various Amber and CHARMM force-fields, employing both implicit and explicit solvent models in replica exchange and conventional simulation modes. This comprehensive approach allowed us to assess the strengths and weaknesses of these solvent models and force fields in comparison to experimental and theoretical findings, ensuring the highest level of robustness. Our investigations revealed that Aβ42 and α-Syn monomers can indeed form stable heterodimers, and the resulting heterodimeric model exhibits stronger interactions compared to the Aβ42 dimer. The binding of α-Syn to Aβ42 reduces the propensity of Aβ42 to adopt fibril-prone conformations and induces significant changes in its conformational properties. Notably, in AMBER-FB15 and CHARMM36m force fields with the use of explicit solvent, the presence of Aβ42 significantly increases the β-content of α-Syn, consistent with the experiments showing that Aβ42 triggers α-Syn aggregation. Our analysis clearly shows that although the use of implicit solvent resulted in too large compactness of monomeric α-Syn, structural properties of monomeric Aβ42 and the heterodimer were preserved in explicit-solvent simulations. We anticipate that our study sheds light on the interaction between α-Syn and Aβ42 proteins, thus providing the atom-level model required to assess the initial stage of aggregation mechanisms related to Alzheimer's and Parkinson's diseases.

Vaccination and Control Methods of West Nile Virus Infection in Equids and Humans.

West Nile virus (WNV) is capable of causing severe neurologic disease in both humans and equines, making it a disease of importance in both human medicine and veterinary medicine. No targeted treatments exist for WNV infection in either humans or equines. Infection is treated symptomatically through management of symptoms like fever and seizures. As treatment for WNV is purely supportive, the response to WNV has focused primarily on methods of disease prevention. To this end, research efforts have yielded several effective vaccines for equine use as well as numerous conventional mosquito control techniques. Even with the implementation of these techniques, disease caused by WNV remains a concern since no human vaccine exists. Due to the lack of a human vaccine, novel preventative strategies are under active research and development. Of these strategies, some of the most conceptually promising are techniques using genetically modified mosquitoes, addressing the disease at the vector level with minimal ecological side effects. Taken together, the use of combined, synergistic methods, such as physical barriers, transgenic mosquitoes, and immunological targets, will be the best way to prevent WNV disease.

Antiviral drug discovery: Pyrimidine entry inhibitors for Zika and dengue viruses

Vector-borne diseases, constituting over 17 % of infectious diseases, are caused by parasites, viruses, and bacteria, and their prevalence is shaped by environmental and social factors. Dengue virus (DENV) and Zika virus (ZIKV), some of the most prevalent infectious agents of this type of diseases, are transmitted by mosquitoes belonging to the genus Aedes. The highest prevalence is observed in tropical regions, inhabited by around 3 billion people. DENV infects millions of people annually and constitutes an additional sanitary challenge due to the circulation of four serotypes, which has complicated vaccine development. ZIKV causes large outbreaks globally and its infection is known to lead to severe neurological diseases, including microcephaly in newborns. Besides, not only mosquito control programs have proved to be not totally effective, but also, no antiviral drugs have been developed so far. The envelope protein (E) is a major component of DENV and ZIKV virion surface. This protein plays a key role during the virus cell entry, constituting an attractive target for the development of antiviral drugs. Our previous studies have identified two pyrimidine analogs (3e and 3h) as inhibitors; however, their activity was found to be hindered by their low water solubility. In this study, we performed a low-throughput antiviral screening, revealing compound 16a as a potent DENV-2 and ZIKV inhibitor (EC50 = 1.4 μM and 2.4 μM, respectively). This work was aimed at designing molecules with improved selectivity and pharmacokinetic properties, thus advancing the antiviral efficacy of compounds for potential therapeutic use.

Assessing Knowledge and First-aid Practice Scores of Caregivers of Epilepsy Patients Before and After an Educational Programme in the Kingdom of Saudi Arabia

Background Although epilepsy is one of the most prevalent and severe neurologic disorders, our knowledge of its intricate pathophysiology and skills to manage are still limited. Recognising its early signs and symptoms are crucial skills for caregivers of epileptic patients to acquire. This study was aimed at assessing the effectiveness of an education programme on improvement in the caregivers’ knowledge of epilepsy and first-aid practices. The findings will assist caregivers of children with seizures who frequently experience fear and anxiety relative to their perceived confidence to manage seizures. Education to caregivers could improve their perceived level of self-efficacy. Methods A community-based, pre- and post-intervention survey was conducted at neurologic care clinics across Saudi Arabia. Data were collected using a pretested, semi-structured, interviewer-administered questionnaire. The educational intervention was aimed at disseminating information via a short talk and video demonstration of epilepsy-related first-aid good practices. Data were analysed using SPSS version 21. Results Pre-intervention survey of 586 caregivers revealed that nearly 60% had inadequate knowledge of epilepsy; this was reduced to 23.2% after education. Similarly, 84% of caregivers had inadequate knowledge of first-aid practices before the educational intervention, but this was reduced to 32.4% after that. Having resided in the Western regions was a negative predictor of good first-aid practice knowledge scores, both before and after education. A university degree or higher education was positive predictor of higher knowledge scores both before (T=-4.564; p<0.001) and after education (T=-2.775; p=0.025). The oldest caregivers (>50 years) exhibited a significantly lower mean first-aid practice knowledge score (F=7.771; p=0.001). Conclusion Caregivers’ general and first-aid practice knowledge were generally poor prior to but were both markedly improved after educational interventions. Targeted educational health promotion could bring awareness to those with lower levels of education and older caregivers living in particularly the Western regions of Saudi Arabia. (255 words)

First person – Eli Matsell

ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping researchers promote themselves alongside their papers. Eli Matsell is first author on ‘ Functional and in silico analysis of ATP8A2 and other P4-ATPase variants associated with human genetic diseases’, published in DMM. Eli is a PhD student in the lab of Dr Robert Molday at the University of British Columbia, Vancouver, Canada, investigating the role that the P4-ATPase ATP8A2 plays in severe neurological disease.

Identification of predictive patient characteristics for assessing the probability of COVID-19 in-hospital mortality.

As the world emerges from the COVID-19 pandemic, there is an urgent need to understand patient factors that may be used to predict the occurrence of severe cases and patient mortality. Approximately 20% of SARS-CoV-2 infections lead to acute respiratory distress syndrome caused by the harmful actions of inflammatory mediators. Patients with severe COVID-19 are often afflicted with neurologic symptoms, and individuals with pre-existing neurodegenerative disease have an increased risk of severe COVID-19. Although collectively, these observations point to a bidirectional relationship between severe COVID-19 and neurologic disorders, little is known about the underlying mechanisms. Here, we analyzed the electronic health records of 471 patients with severe COVID-19 to identify clinical characteristics most predictive of mortality. Feature discovery was conducted by training a regularized logistic regression classifier that serves as a machine-learning model with an embedded feature selection capability. SHAP analysis using the trained classifier revealed that a small ensemble of readily observable clinical features, including characteristics associated with cognitive impairment, could predict in-hospital mortality with an accuracy greater than 0.85 (expressed as the area under the ROC curve of the classifier). These findings have important implications for the prioritization of clinical measures used to identify patients with COVID-19 (and, potentially, other forms of acute respiratory distress syndrome) having an elevated risk of death.

PROTAC EZH2 degrader-1 overcomes the resistance of podophyllotoxin derivatives in refractory small cell lung cancer with leptomeningeal metastasis

BackgroundLeptomeningeal metastasis (LM) of small cell lung cancer (SCLC) is a highly detrimental occurrence associated with severe neurological disorders, lacking effective treatment currently. Proteolysis-targeting chimeric molecules (PROTACs) may provide new therapeutic avenues for treatment of podophyllotoxin derivatives-resistant SCLC with LM, warranting further exploration.MethodsThe SCLC cell line H128 expressing luciferase were mutated by MNNG to generate H128-Mut cell line. After subcutaneous inoculation of H128-Mut into nude mice, H128-LM and H128-BPM (brain parenchymal metastasis) cell lines were primarily cultured from LM and BPM tissues individually, and employed to in vitro drug testing. The SCLC-LM mouse model was established by inoculating H128-LM into nude mice via carotid artery and subjected to in vivo drug testing. RNA-seq and immunoblotting were conducted to uncover the molecular targets for LM.ResultsThe SCLC-LM mouse model was successfully established, confirmed by in vivo live imaging and histological examination. The upregulated genes included EZH2, SLC44A4, VEGFA, etc. in both BPM and LM cells, while SLC44A4 was particularly upregulated in LM cells. When combined with PROTAC EZH2 degrader-1, the drug sensitivity of cisplatin, etoposide (VP16), and teniposide (VM26) for H128-LM was significantly increased in vitro. The in vivo drug trials with SCLC-LM mouse model demonstrated that PROTAC EZH2 degrader-1 plus VM26 or cisplatin/ VP16 inhibited H128-LM tumour significantly compared to VM26 or cisplatin/ VP16 alone (P < 0.01).ConclusionThe SCLC-LM model effectively simulates the pathophysiological process of SCLC metastasis to the leptomeninges. PROTAC EZH2 degrader-1 overcomes chemoresistance in SCLC, suggesting its potential therapeutic value for SCLC LM.

Japanese encephalitis virus NS1 and NS1' protein disrupts the blood-brain barrier through macrophage migration inhibitory factor-mediated autophagy.

Flaviviruses in the Japanese encephalitis virus (JEV) serogroup, such as JEV, West Nile virus, and St. Louis encephalitis virus, can cause severe neurological diseases. The nonstructural protein 1 (NS1) is a multifunctional protein of flavivirus that can be secreted by infected cells and circulate in the host bloodstream. NS1' is an additional form of NS1 protein with 52 amino acids extension at its carboxy-terminal and is produced exclusively by flaviviruses in the JEV serogroup. In this study, we demonstrated that the secreted form of both NS1 and NS1' can disrupt the blood-brain barrier (BBB) of mice, with NS1' exhibiting a stronger effect. Using the in vitro BBB model, we found that treatment of soluble recombinant JEV NS1 or NS1' protein increases the permeability of human brain microvascular endothelial cells (hBMECs) and leads to the degradation of tight junction proteins through the autophagy-lysosomal pathway. Consistently, NS1' protein exhibited a more pronounced effect compared to NS1 in these cellular processes. Further research revealed that the increased expression of macrophage migration inhibitory factor (MIF) is responsible for triggering autophagy after NS1 or NS1' treatment in hBMECs. In addition, TLR4 and NF-κB signaling was found to be involved in the activation of MIF transcription. Moreover, administering the MIF inhibitor has been shown to decrease viral loads and mitigate inflammation in the brains of mice infected with JEV. This research offers a novel perspective on the pathogenesis of JEV. In addition, the stronger effect of NS1' on disrupting the BBB compared to NS1 enhances our understanding of the mechanism by which flaviviruses in the JEV serogroup exhibit neurotropism.IMPORTANCEJapanese encephalitis (JE) is a significant viral encephalitis worldwide, caused by the JE virus (JEV). In some patients, the virus cannot be cleared in time, leading to the breach of the blood-brain barrier (BBB) and invasion of the central nervous system. This invasion may result in cognitive impairment, behavioral disturbances, and even death in both humans and animals. However, the mechanism by which JEV crosses the BBB remains unclear. Previous studies have shown that the flavivirus NS1 protein plays an important role in causing endothelial dysfunction. The NS1' protein is an elongated form of NS1 protein that is particularly produced by flaviviruses in the JEV serogroup. This study revealed that both the secreted NS1 and NS1' of JEV can disrupt the BBB by breaking down tight junction proteins through the autophagy-lysosomal pathway, and NS1' is found to have a stronger effect compared to NS1 in this process. In addition, JEV NS1 and NS1' can stimulate the expression of MIF, which triggers autophagy via the ERK signaling pathway, leading to damage to BBB. Our findings reveal a new function of JEV NS1 and NS1' in the disruption of BBB, thereby providing the potential therapeutic target for JE.

Pathogenesis, diagnosis, and treatment of epilepsy: electromagnetic stimulation-mediated neuromodulation therapy and new technologies.

Epilepsy is a severe, relapsing, and multifactorial neurological disorder. Studies regarding the accurate diagnosis, prognosis, and in-depth pathogenesis are crucial for the precise and effective treatment of epilepsy. The pathogenesis of epilepsy is complex and involves alterations in variables such as gene expression, protein expression, ion channel activity, energy metabolites, and gut microbiota composition. Satisfactory results are lacking for conventional treatments for epilepsy. Surgical resection of lesions, drug therapy, and non-drug interventions are mainly used in clinical practice to treat pain associated with epilepsy. Non-pharmacological treatments, such as a ketogenic diet, gene therapy for nerve regeneration, and neural regulation, are currently areas of research focus. This review provides a comprehensive overview of the pathogenesis, diagnostic methods, and treatments of epilepsy. It also elaborates on the theoretical basis, treatment modes, and effects of invasive nerve stimulation in neurotherapy, including percutaneous vagus nerve stimulation, deep brain electrical stimulation, repetitive nerve electrical stimulation, in addition to non-invasive transcranial magnetic stimulation and transcranial direct current stimulation. Numerous studies have shown that electromagnetic stimulation-mediated neuromodulation therapy can markedly improve neurological function and reduce the frequency of epileptic seizures. Additionally, many new technologies for the diagnosis and treatment of epilepsy are being explored. However, current research is mainly focused on analyzing patients' clinical manifestations and exploring relevant diagnostic and treatment methods to study the pathogenesis at a molecular level, which has led to a lack of consensus regarding the mechanisms related to the disease.

488 National Trends in the Treatment of Refractory Epilepsy: A Nationwide Inpatient SampleBased Propensity Score Matching Analysis

INTRODUCTION: Epilepsy is considered one of the most prevalent and severe chronic neurological disorders worldwide. METHODS: Using the NIS database from 2010-2020, patients with focal intractable epilepsy who underwent Laser Interstitial Thermal Therapy (LITT), open surgical resection, Vagal Nerve Stimulation (VNS), or Responsive Neuro-Stimulation (RNS) were identified. Outcomes such as discharge disposition, length of stay, complications, and mortality were analyzed. Propensity score matching was used to compare outcomes between pre-pandemic and pandemic (first peak of COVID-19) periods. RESULTS: A total of 33,969 focal intractable epilepsy cases were found with 3,343 patients receiving different treatment modalities including surgical resection (77.83%), VNS (8.21%), RNS (7.83%), and LITT (6.13%). Most of these patients (89.32%) were treated during the pre-COVID pandemic era (2010-2019), while a minority (10.67%) underwent treatment during the COVID pandemic (2020). Among all treated patients, 2.7% had postoperative neurologic complications and 0.3% died. After propensity-score matching, 658 patients (329 in each group) were included. During the pandemic period, 7% presented with preoperative paralysis/aphasia, and 0.6% had subarachnoid hemorrhages, which was significantly higher than the pre-pandemic rate (1.8%; p &lt; 0.001). There were no statistical differences in neurologic complications, discharge disposition, or LOS between the pre-pandemic and pandemic periods. On the other hand, the mortality rate was slightly higher during the pandemic compared to the pre-pandemic period (N = 4; 1.2% vs. N = 1; 0.2%; p = 0.026). CONCLUSIONS: Our study shows an increase in the diagnosis of focal intractable epilepsy and a decrease in resections, while LITT and RNS usage is rising. Improving access to surgery and encouraging newer treatment modalities for DRE is crucial. Further research is needed to optimize patient outcomes and identify factors that influence treatment choices.

Pathogenicity of de novo CACNA1D Ca2+ channel variants predicted from sequence co-variation

Voltage-gated L-type Cav1.3 Ca2+ channels support numerous physiological functions including neuronal excitability, sinoatrial node pacemaking, hearing, and hormone secretion. De novo missense mutations in the gene of their pore-forming α1-subunit (CACNA1D) induce severe gating defects which lead to autism spectrum disorder and a more severe neurological disorder with and without endocrine symptoms. The number of CACNA1D variants reported is constantly rising, but their pathogenic potential often remains unclear, which complicates clinical decision-making. Since functional tests are time-consuming and not always available, bioinformatic tools further improving pathogenicity potential prediction of novel variants are needed. Here we employed evolutionary analysis considering sequences of the Cav1.3 α1-subunit throughout the animal kingdom to predict the pathogenicity of human disease-associated CACNA1D missense variants. Co-variation analyses of evolutionary information revealed residue–residue couplings and allowed to generate a score, which correctly predicted previously identified pathogenic variants, supported pathogenicity in variants previously classified as likely pathogenic and even led to the re-classification or re-examination of 18 out of 80 variants previously assessed with clinical and electrophysiological data. Based on the prediction score, we electrophysiologically tested one variant (V584I) and found significant gating changes associated with pathogenic risks. Thus, our co-variation model represents a valuable addition to complement the assessment of the pathogenicity of CACNA1D variants completely independent of clinical diagnoses, electrophysiology, structural or biophysical considerations, and solely based on evolutionary analyses.

Investigating the important proteins in causing West Nile virus infection in retinal pigment cells

Introduction: West Nile virus is an infection transmitted through blood-sucking arthropods. Ocular manifestations are one of the characteristics of West Nile virus infection. They occur mostly in connection with severe neurological disease. In this study، using bioinformatics analysis، we investigated and identified the genes in the pathways related to West Nile virus infection in the retina.&#x0D; Methods: In this study, using bioinformatics methods and referring to the GEO dataset, the appropriate dataset was selected for analysis. This dataset included gene expression profiles in West Nile virus infection with retinal pigment cells. Gene clusters with high and low expression were categorized. For more accurate data evaluation, databases such as Enrichr، STRING and Network analyst were used. The candidate genes were isolated and their protein relationship was also measured using cytoescape software version 3.7.1. The obtained values with P-Value˂0.05 were selected as significant data.&#x0D; Results: The number of 830 genes with high expression and 500 genes with low expression was involved in the development pathways of West Nile virus infection in the eye. Apoptosis، necroptosis، AMPK and MAPK autophagy pathways were clearly observed. After evaluating the relationship between protein networks، RIPK1، STAT1/3 and JAK2 increased expression and GSK3B، MAPK8 and TSC2 genes had decreased expression.&#x0D; Conclusion: The present study showed that important proteins and genes played a major role in strengthening West Nile virus inflammation in the retina, among which RIPK1,TSC2, STAT1 and JAK2 showed a more prominent role in this pathway.

Use of Thiamine Supplementation in Pregnant Women Diagnosed With Hyperemesis Gravidarum and Wernicke Encephalopathy

Hyperemesis gravidarum is the most common condition requiring hospital care for women during the first 20 weeks of pregnancy and may lead to malnutrition, dehydration, and vitamin deficiencies. Depletion of vitamins such as thiamine may result in the development of Wernicke encephalopathy, a severe neurological disorder that can increase the risk for mortality and morbidity for the mother and fetus. A lack of awareness regarding the relationship of hyperemesis gravidarum and Wernicke encephalopathy may result in delayed treatment and disease management. Glucose administration in the presence of thiamine deficiency may induce Wernicke encephalopathy; protocols are needed to ensure dextrose is used for women with hyperemesis gravidarum in times of prolonged vomiting and poor oral intake only after first administering thiamine. This article includes a discussion of best practices for thiamine supplementation with hyperemesis gravidarum and Wernicke encephalopathy.

Parechovirus infection in human brain organoids: host innate inflammatory response and not neuro-infectivity correlates to neurologic disease

Picornaviruses are a leading cause of central nervous system (CNS) infections. While genotypes such as parechovirus A3 (PeV-A3) and echovirus 11 (E11) can elicit severe neurological disease, the highly prevalent PeV-A1 is not associated with CNS disease. Here, we expand our current understanding of these differences in PeV-A CNS disease using human brain organoids and clinical isolates of the two PeV-A genotypes. Our data indicate that PeV-A1 and A3 specific differences in neurological disease are not due to infectivity of CNS cells as both viruses productively infect brain organoids with a similar cell tropism. Proteomic analysis shows that PeV-A infection significantly alters the host cell metabolism. The inflammatory response following PeV-A3 (and E11 infection) is significantly more potent than that upon PeV-A1 infection. Collectively, our findings align with clinical observations and suggest a role for neuroinflammation, rather than viral replication, in PeV-A3 (and E11) infection.

Energy efficient FPGA implementation of an epileptic seizure detection system using a QDA classifier

Epilepsy is a severe neurological disorder that causes seizures. It is detected by analyzing the electrical impulses of the human brain. Monitoring the brain is commonly done using an electroencephalogram (EEG). Seizure detection from the large recorded EEG dataset is a demanding task. However, numerous machine learning classifiers and the appropriate features can detect seizures. The Hjorth and statistical parameters are used in this study to provide an effective method for field programmable gate array (FPGA) realization of epileptic seizure detectors from EEG signals. Mobility, interquartile range (IQR), median absolute deviation (MAD), energy, non-linear energy, and simple square integral (SSI) are the various features analyzed in this work. The hardware architecture of the seizure detection system is captured in Verilog hardware descriptive language and realized on the Artix-7 FPGA. This paper presents three separate seizure detection models designed by pairing three different features with the Quadratic discriminant analysis (QDA) classifier. Among these three models, the energy and non-linear energy-based seizure detection system offers better performance than existing seizure detection systems because it possesses the lowest dynamic power consumption (0.116 µW), the highest design accuracy (99.4 %), and the highest sensitivity (100 %), which makes it the best seizure detection system for real-time applications.

Morphological aspects of bedsore healing against high-frequency electrical stimulation in patients with severe brain damage

BACKGROUND: Bedsores or decubital ulcers are significant medical and social problems in patients with serious brain damage. The majority of local treatments are ineffective and do not ensure their healing. Therefore, the search for nondrug methods as part of the complex treatment of decubital ulcers is extremely relevant.&#x0D; AIM: To assess the morphological picture of bedsores against the background of an improved method of treatment using high-frequency electrical stimulation with pulsed currents in chronically immobilised patients who survived a cerebral catastrophe.&#x0D; MATERIALS AND METHODS: Biopsies of bedsores were examined in 12 patients with severe neurological disorders that developed after a cerebral catastrophe. The initial status of all patients was a ‘chronic critical condition’ (CCS). In all patients, the bedsore defect was located in the sacral region, with a length of 7–25 cm2. The depth of the bedsore corresponded to grade III according to the classification of the Agency for Health Care Policy and Research. Two groups of patients were formed: the main group of five patients (three men + two women), with an average age of 49.0 years, who were subjected to electrical stimulation with pulsed currents of the radiofrequency range. A control group of seven patients (three men + four women), with an average age of 60.1 years, who underwent traditional treatment. The duration of the chronic wound process ranged from 2 months to 1.5 years. The immediate cause of CCS was more often a massive ischaemic stroke (8), less often a severe traumatic brain injury (3) and radical operations to remove brain tumours (1) of various prescriptions from 3 months to 1.5 years. Morphological studies were conducted in both groups to assess the complicated wound process.&#x0D; RESULTS: The complex morphological study revealed that in the presence of high-frequency electrical stimulation, an earlier appearance of foci of fibroblastic proliferation, an increase in the regenerative potential of tissues due to increased production of type I and III collagens, and myofibroblastic and endothelial growth factors were noted.&#x0D; CONCLUSION: In the case of CCS of cerebral genesis, the wound process in bedsores inevitably becomes complicated and, according to morphological research, is characterised by severe endothelial dysfunction, deep microcirculation disorders, depletion of the potential of myofibroblastic cells and deficiency of their growth factors. Local high-frequency electrical stimulation in patients with severe brain damage and decubital ulcers as a component of complex ulcer therapy significantly optimises cellular and tissue reactions in the area of bedsores.

Marked increase in severe neurological disorders after nitrous oxide abuse: a retrospective study in the Greater Paris area

BackgroundRecreational nitrous oxide (N2O) use has become more widespread worldwide, leading to an increase in myelopathies and peripheral neuropathies. The aim of this study was to describe clinical and socioeconomical characteristics of severe N2O-induced (NI) neurological disorders (NI-NDs), to determine its incidence in the Greater Paris area and to compare it with that of similar inflammatory neurological disorders.MethodsWe performed a retrospective multicentric cohort study of all adult patients with severe NI-NDs in the neurology and general internal medicine departments of the Greater Paris area from 2018 to 2021. The incidence was compared with that of non-NI-myelitis and Guillain–Barré syndrome (GBS) using a sample of 91,000 hospitalized patients sourced from health insurance data.ResultsAmong 181 patients, 25% had myelopathy, 37% had peripheral neuropathy and 38% had mixed disease. Most were aged between 20 and 25 years, lived in socially disadvantaged urban areas, and exhibited high rates of unemployment (37%). The incidence of NI-NDs increased during 2020 and reached a peak mid-2021. The 2021 incidence in 20–25-year-olds was 6.15 [4.72; 8.24] per 100,000 persons for NI-myelopathy and 7.48 [5.59; 9.37] for NI-peripheral neuropathy. This was significantly higher than for non-NI-myelitis (0.35 [0.02; 2.00]) and GBS (2.47 [0.64; 4.30]). The incidence of NI-NDs was two to three times higher in the most socially disadvantaged areas.ConclusionThe recent increase in recreational N2O use has led to a rise in the incidence of severe NI-NDs, particularly in young adults with low socioeconomic status for whom NI-NDs strongly outweigh similar neurological disorders.

Unraveling brain diseases: The promise of brain-on-a-chip models

Brain disorders, encompassing a wide spectrum of neurological and psychiatric conditions, present a formidable challenge in modern medicine. Despite decades of research, the intricate complexity of the human brain still eludes comprehensive understanding, impeding the development of effective treatments. Recent advancements in microfluidics and tissue engineering have led to the development of innovative platforms known as "Brain-on-a-Chip" (BoC) i.e., advanced in vitro systems that aim to replicate the microenvironment of the brain with the highest possible fidelity. This technology offers a promising test-bed for studying brain disorders at the cellular and network levels, providing insights into disease mechanisms, drug screening, and, in perspective, the development of personalized therapeutic strategies. In this review, we provide an overview of the BoC models developed over the years to model and understand the onset and progression of some of the most severe neurological disorders in terms of incidence and debilitation (stroke, Parkinson's, Alzheimer's, and epilepsy). We also report some of the cutting-edge therapeutic approaches whose effects were evaluated by means of these technologies. Finally, we discuss potential challenges, and future perspectives of the BoC models.