Disease Of Nervous System Research Articles

UPLC-MS/MS Combined with Microdialysis for Determination of Two Active Components of Chuanxiong Rhizoma Extracts in Rat Brain: Application in Pharmacokinetic Study.

Chuanxiong Rhizoma (Chuanxiong), a traditional Chinese medicine, has been widely used to treat various nervous and cardiovascular system-related conditions. Its active components, senkyunolide A (SA) and 3-n-butylphthalide (NBP), have been proven effective in treating nervous system diseases. A new method was established based on microdialysis coupled with ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to estimate the concentrations of these components in brain extracellular fluid. Chromatographic separation was achieved using an Acquity UPLC BEH C8 column (2.1 × 100mm, 1.7μm) with acetonitrile and 0.1% formic acid as mobile phase. The calibration curves of SA and NBP were linear in the concentration ranges of 0.25-100.00 and 0.12-48.00ng/mL, respectively, with a correlation coefficient above 0.9992. All validation parameters, including intra- and inter-day precision, accuracy, matrix effect and stability, were within the acceptance limits of bioanalytical guidelines. The validated method was successfully applied to study the pharmacokinetics of SA and NBP in rat brain microdialysis after oral administration of Chuanxiong extracts. The results showed that both components penetrated the brain and reached maximum concentrations in the microdialysates of 72.31 and 9.93ng/mL at 1.50 and 1.58h, respectively.

Data mining in FAERS: association of newer-generation H1-antihistamines with nervous system disorders

BackgroundH1-antihistamines are widely used to treat symptoms depending on histamine release in a variety of conditions. However, neurological adverse events have been reported in post-marketing surveillance studies and there are limited literatures comparing the neurological disorders associated with newer-generation H1-antihistamines from real-world datasets.AimsWe performed a comparative analysis of nervous system disorders and several newer-generation H1-antihistamines including: cetirizine, loratadine, levocetirizine, desloratadine and fexofenadine.MethodsDisproportionality analysis was used to identify the suspected drug neurological adverse events associated with H1-antihistamines of interest via the Food and Drug Administration Adverse Event Reporting System. The proportional reporting ratio (PRR), χ2 (chi-square) and the reporting odds ratio (ROR) with 95% confidence interval (CI) were used to estimate the association.ResultsAE reports of 43,815 cases from 2017 to 2021 were extracted from FAERS. The H1-antihistamines included in our study were associated with various neurological adverse events that could be classified into 12 aspects, containing 42 preferred terms. The majority of adverse event reports were concentrated at somnolence: cetirizine [N = 1342, ROR (95%CI) = 11.8 (11.2–12.5), PRR = 10.8, χ2 = 11755.4], levocetirizine [N = 1276, ROR(95%CI) = 28.5 (26.7–30.3), PRR = 22.7, χ2 = 26218.4], loratadine[N = 516, ROR(95%CI) = 4.6 (4.2-5.0), PRR = 4.4, χ2 = 1378.1], desloratadine [N = 33, ROR(95%CI) = 6.1 (4.3–8.6), PRR = 5.8, χ2 = 131.9], fexofenadine [N = 498, ROR(95%CI) = 5.0 (4.6–5.5), PRR = 4.8, χ2 = 1519.0].ConclusionNeurological AEs associated with individual newer generation H1-antihistamines of interest varies a lot, whereas somnolence was the most common AE reports. Fexofenadine was highly associated with headaches. Sedative effects associated with levocetirizine and cetirizine should arouse more concern. Seizures significantly associated with levocetirizine and desloratadine were infrequently reported, further research is needed to avoid possible serious outcomes. Patients taking cetirizine probably have higher risk of dystonia and anticholinergic syndrome.

Multiple sclerosis and self-alienation: a study based on self and others representations

BackgroundMultiple sclerosis (MS) is an autoimmune disease of the central nervous system. MS causes many changes in the lives of its patients, forcing them to renegotiate their lives. Part of these changes are related to patients’ self- and others- mental representations. Despite the importance of mental representations in changes caused by or adaptation to MS, limited research has been conducted to examine the mental representations of people with MS.MethodsThis study examines the mental representations that Healthy Controls (HC) and people with MS (PWMS) have of themselves and others, including childhood and current self-images, as well as those of their mothers, love partners, and close friends. In both groups (HC (n = 82) and PWMS (n = 82)), participants completed demographic variables as well as a modified version of the comfortable interpersonal distance (CID) task in both passive (when protagonists approached them) and active modes (when participants approach protagonists). Participants estimated the point at which they felt discomforted.ResultsThe PWMS group preferred a significantly larger interpersonal distance than the HC group for both current self-image and love partner. There is no difference between the two groups in preferring interpersonal distance from their childhood self-image, mother, and friends.ConclusionsBased on the research results, it seems that PWMS experience a kind of alienation at the level of self-mental representations. This research can be helpful in modifying MS interventions and increasing the engagement of support systems.

Utility of Oligoclonal Band Testing in Differentiating Immune-Mediated From Infectious Central Nervous System Disorders.

This study aimed to evaluate the clinical utility of oligoclonal bands (OCB) in differentiating between immune and infectious diseases of the central nervous system (CNS). The study enrolled patients hospitalized with suspected autoimmune or infectious CNS disorders between 2021 and 2023. Patients were categorized into diagnostic groups: multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), autoimmune encephalitis (AE), and viral encephalitis (VE). Relevant clinical and laboratory data were collected and subjected to comparative analysis. Comparative analysis among the 4 groups revealed that the immunoglobulin G (IgG) index of patients in the MS group was significantly higher than that of patients in the NMOSD and VE groups (P < 0.05). The 24-hour intrathecal synthesis rate of IgG also differed significantly between the MS and NMOSD groups, the NMOSD and AE groups, as well as the AE and VE groups (P < 0.05). The positive rate of OCB was significantly higher in the MS group than in the other 3 groups (P < 0.05). Functional abilities, measured by scores of the Modified Rankin Scale (mRS) and the Expanded Disability Status Scale (EDSS), were higher in the immune group than in the infection group at 1-week, 1-month, 6-month, and 1-year post-treatment. Among patients with immune diseases, those who were OCB-positive showed significantly smaller ΔmRS and ΔEDSS at 1-month, 6-month, and 1-year post-treatment compared with patients who were OCB-negative (P < 0.05). The IgG index and 24-hour intrathecal synthesis rate of IgG served as valuable early indicators for distinguishing between CNS immune and infectious diseases. Positive OCB findings were more common in patients with MS and often associated with poor prognosis and increased risk of disease recurrence.

CHI3L1 in Multiple Sclerosis—From Bench to Clinic

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) with a complex and not fully understood etiopathological background involving inflammatory and neurodegenerative processes. CHI3L1 has been implicated in pathological conditions such as inflammation, injury, and neurodegeneration, and is likely to play a role in the physiological development of the CNS. CHI3L1 is primarily produced by CNS macrophages, microglia, and activated astrocytes. The CHI3L1 expression pattern in MS lesions might support the important role of astrocytes in modulating inflammatory processes in this disease. The potential applications of CHI3L1 as a biomarker in MS are multifactorial. The measurement of CHI3L1 in body fluids might find its role in the early diagnosis of MS. In further stages, the monitoring of CHI3L1 levels might provide information on disease severity and progression, enabling a better adjustment of therapeutic strategies. Importantly, CHI3L1 might potentially serve as a marker of ongoing glial activation, reflecting the dynamic response of the CNS cells to the inflammatory processes in MS. Although preliminary findings have been promising, further research is needed to validate the utility of CHI3L1 measurements in the diagnosis and prediction of the progression of MS. Additionally, comparisons with other biomarkers might be useful in clinical practice.

Use of non-specific immunoglobulins in Catalonia in three third-level hospitals: a descriptive analysis of a hospital-prescribed medication registry

BackgroundThe increasing use of non-specific immunoglobulins (NSIGs) and their current shortage show a need for NSIGs’ use prioritization. Data from a clinical perspective are necessary, mainly for pediatric patients.ObjectivesThe aim of the study was to assess the level of clinical evidence (LoE) of the indications that NSIGs are used for, the reasons for discontinuation, and the costs invested.MethodsA retrospective multicentric study was conducted on NSIG incident users between September 2019 and December 2021 retrieved from the Registry of Patients and Treatments (RPT) from Catalonia (Spain). LoE was categorized as A) authorized indications, B) unauthorized with scientific support, C) unauthorized without support, and D) unknown (UNK), following local and the United Kingdom’s guidelines as a sensitivity analysis. We also estimated overall spending and costs per patient visit.ResultsA total of 400 patients were included (17.3% pediatric), with a mean follow-up of 122.1/person-years for adults. The most frequent indications were nervous system and blood diseases. Almost all pediatric patients (56; 81.2%) were treated under A-level indications, as for 217 (65.6%) adults. In the sensitivity analysis, the A-level usage rate decreased to one-third and the B-level usage rate increased by 2–3 times. Furthermore, 37.8% (151) of individuals discontinued. This was predominantly due to remission or no response. The total costs were 868,462.6€/year, with median spending per visit amounting to 1,500€ for adults and 700€ for pediatric patients.ConclusionNSIGs are used in clinical practice mainly for approved indications; however, non-approved indications are still an important issue. This could represent a significant economic burden on the healthcare system, focusing on the pediatric population and those at risk for discontinuation with alternative therapeutic options.

MRI Findings in Demyelinating Diseases of the Central Nervous System

Demyelinating diseases of the brain represent a complex group of neurological disorders characterised by the destruction of the myelin sheath surrounding nerve fibres, which disrupts neural transmission and leads to a wide range of neurological deficits1 . This article reviews the pathophysiology, radiologic features, and diagnostic criteria of key demyelinating disorders, including Multiple sclerosis (MS), Neuromyelitis optica, Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), Tumefactive demyelinating lesions, Acute necrotizing encephalopathy, and Krabbe disease. Advanced imaging techniques, particularly Magnetic resonance imaging (MRI), play a crucial role in the identification and differentiation of these diseases. Key MRI findings, such as T2-weighted hyperintense lesions in specific brain regions, contrast enhancement patterns, and lesion evolution, aid in diagnosis and disease monitoring. Radiologists play a vital role in early diagnosis, monitoring treatment response, and detecting complications, thereby guiding clinical management and improving patient outcomes in demyelinating brain diseases.

Microglia programmed cell death in neurodegenerative diseases and CNS injury.

Programmed cell death (PCD) has emerged as a critical regulatory mechanism in the initiation and progression of various pathological conditions. PCD in microglia, including necroptosis, pyroptosis, apoptosis, ferroptosis, and autophagy, occurs in a variety of central nervous system (CNS) diseases. Dysregulation of microglia can lead to excessive tissue damage or neuronal death in CNS injury. Various injury stimuli trigger aberrant activation of the PCD pathway of microglia, which then further leads to inflammatory cascades that exacerbates CNS pathology in a vicious cycle. Therefore, targeting PCD in microglia is considered an important avenue for the treatment of various neurodegenerative diseases and CNS injury. In this review, we summarize the major and recent findings focusing on the mechanisms of PCD in microglia modulating functions in neurodegenerative diseases and CNS injury and provide a systematic overview of the current inhibitors targeting various PCD pathways, which may provide important therapeutic targets that merit further investigation.

Clickable, Thermally Responsive Hydrogels Enabled by Recombinant Spider Silk Protein and Spy Chemistry for Sustained Neurotrophin Delivery.

The ability to deliver protein therapeutics in a minimally invasive, safe, and sustained manner, without resorting to viral delivery systems, will be crucial for treating a wide range of chronic injuries and diseases. Among these challenges, achieving axon regeneration and functional recovery post-injury or disease in the central nervous system remains elusive to most clinical interventions, constantly calling for innovative solutions. Here, a thermally responsive hydrogel system utilizing recombinant spider silk protein (spidroin) is developed. The protein solution undergoes rapid sol-gel transition at an elevated temperature (37°C) following brief sonication. This thermally triggered gelation confers injectability to the system. Leveraging SpyTag/SpyCatcher chemistry, the hydrogel, composed of SpyTag-fusion spidroin, can be functionalized with diverse SpyCatcher-fusion bioactive motifs, such as neurotrophic factors (e.g., ciliary neurotrophic factor) and cell-binding ligands (e.g., laminin), rendering it well-suited for neuronal culturing. More importantly, the intravitreous injection of the protein materials decorated with SpyCatcher-fusion CNTF into the vitreous body after optic nerve injury leads to prolonged JAK/STAT3 signaling, increased neuronal survival, and enhanced axon regeneration. This study illustrates a generalizable material system for injectable and sustained delivery of protein therapeutics for neuroprotection and regeneration, with the potential for extension to other chronic diseases and injuries.

Oligodendroglial heterogeneity in health, disease, and recovery: deeper insights into myelin dynamics.

Decades of research asserted that the oligodendroglial lineage comprises two cell types: oligodendrocyte precursor cells and oligodendrocytes. However, recent studies employing single-cell RNA sequencing techniques have uncovered novel cell states, prompting a revision of the existing terminology. Going forward, the oligodendroglial lineage should be delineated into five distinct cell states: oligodendrocyte precursor cells, committed oligodendrocyte precursor cells, newly formed oligodendrocytes, myelin-forming oligodendrocytes, and mature oligodendrocytes. This new classification system enables a deeper understanding of the oligodendroglia in both physiological and pathological contexts. Adopting this uniform terminology will facilitate comparison and integration of data across studies. This, including the consolidation of findings from various demyelinating models, is essential to better understand the pathogenesis of demyelinating diseases. Additionally, comparing injury models across species with varying regenerative capacities can provide insights that may lead to new therapeutic strategies to overcome remyelination failure. Thus, by standardizing terminology and synthesizing data from diverse studies across different animal models, we can enhance our understanding of myelin pathology in central nervous system disorders such as multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis, all of which involve oligodendroglial and myelin dysfunction.

Comparative efficacy and tolerability of ublituximab vs. other monoclonal antibodies in the treatment of relapsing multiple sclerosis: a systematic review and network meta-analysis of randomized trials

BackgroundRelapsing multiple sclerosis (RMS) is a chronic, inflammatory disease of the central nervous system. Ublituximab, an anti-CD20 monoclonal antibody (mAb), is indicated for the treatment of RMS. We performed a systematic literature review (SLR) to identify randomized trials reporting the clinical efficacy and tolerability of ublituximab or comparator disease-modifying therapies (DMTs) for treatment of RMS, and assessed their comparative effects using network meta-analysis (NMA).MethodsThe SLR involved a comprehensive search across various medical databases to identify relevant studies. Included studies were randomized controlled trials (RCTs) of an adult RMS population, focusing on treatment with at least one of ublituximab, alemtuzumab, natalizumab, ocrelizumab, or ofatumumab. For outcomes included in the NMA (annualized relapse rate (ARR), confirmed disability progression (CDP), and treatment discontinuation rate), rate ratios (RR) or hazard ratios (HR), along with their 95% confidence intervals (CIs), were calculated. We performed NMA using a contrast-based random-effects model within a frequentist framework for all outcomes. Ranking probabilities among comparators, and intervention rankings for the NMA, were estimated using surface under the cumulative ranking curve (SUCRA).ResultsWe included 15 RCTs in the review. For the ARR outcome, there was no statistically significant difference between ublituximab and the other included mAbs [ofatumumab (RR 1.02 (95% CI 0.64–1.62)), natalizumab (RR 0.99 (0.59–1.65)), alemtuzumab (RR 0.86 (0.51–1.46)), and ocrelizumab (RR 0.75 (0.44–1.28))]. For CDP at 6 months, our results showed no statistically significant difference between ublituximab and the comparator mAbs [ofatumumab (HR 0.97 (0.49–1.92)), natalizumab (HR 1.13 (0.53–2.40)), alemtuzumab (HR 1.25 (0.56–2.81)), and ocrelizumab (HR 1.29 (0.57–2.90))]. For CDP at 3 and 6 months, there was no statistically significant difference between ublituximab and placebo. The all-cause treatment discontinuation rate analysis showed no significant difference between ublituximab and other mAbs, except for alemtuzumab.ConclusionsResults of this SLR-informed NMA showed that there is no statistically significant difference between ublituximab and the other mAbs in terms of clinical efficacy. Additionally, the findings show that there is no statistically significant difference in discontinuation rates with the exception of the comparison with alemtuzumab, which may be attributed to its unique dosing schedule.

TWEAK and TNFɑ Pro-inflammatory Soluble Cytokines and their Specific Autoantibodies Secretion in Multiple Sclerosis Patients.

Multiple sclerosis (MS) is a complex, chronic inflammatory disease of the central nervous system, where immune dysregulation plays a critical role. We sought to explore the modulation of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNFɑ) and TNF-like weak inducer of apoptosis (TWEAK), along with their respective autoantibodies, TNAb and TWAb, and to decipher potential associations between these and clinical characteristics which could assist personalized therapy in MS. We also assessed the complementarity to leading candidate biomarkers in MS patient monitoring, namely, glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL). Serum levels of these cytokines and their autoantibodies were measured in 150 MS patients and 186 healthy controls (HC) by ELISA. We found that sTWEAK levels were significantly higher, while sTNFɑ levels were lower in MS patients compared to HC. Additionally, we detected TWAb in 10% of MS patients, a prevalence significantly higher than in HC (4%) and TNAb in only one patient. TWAb-positive patients were significantly younger, had lower EDSS scores, a shorter disease duration, and predominantly presented with the relapsing-remitting form of MS. Together, these results provide new actors to be considered in the development of a biomarker profiling panel to be used in MS patient management. Further research is warranted to elucidate the clinical significance of these autoantibodies and their role in MS neuroinflammatory modulation.

Peptide-Purified Anti-N-methyl-D-aspartate Receptor (NMDAR) Autoantibodies Have Inhibitory Effect on Long-Term Synaptic Plasticity

Background/Objectives: Recent studies, typically using patient cerebrospinal fluid (CSF), have suggested that different autoantibodies (Aabs) acting on their respective receptors, may underlie neuropsychiatric disorders. The GluN1 (NR1) subunit of the N-methyl-D-aspartate receptor (NMDAR) has been identified as a target of anti-NMDAR Aabs in a number of central nervous system (CNS) diseases, including encephalitis and autoimmune epilepsy. However, the role or the nature of Aabs responsible for effects on neuronal excitability and synaptic plasticity is yet to be established fully. Methods: Peptide immunisation was used to generate Aabs against selected specific GluN1 extracellular sequences based on patient-derived anti-NMDAR Aabs that have been shown to bind to specific regions within the GluN1 subunit. ‘Protein A’ purification was used to obtain the total IgG, and further peptide purification was used to obtain a greater percentage of NMDAR-target specific IgG Aabs. The binding and specificity of these anti-NMDAR Aabs were determined using a range of methodologies including enzyme-linked immunosorbent assays, immunocytochemistry and immunoblotting. Functional effects were determined using different in vitro electrophysiology techniques: two-electrode voltage-clamps in Xenopus oocytes and measures of long-term potentiation (LTP) in ex vivo hippocampal brain slices using multi-electrode arrays (MEAs). Results: We show that anti-NMDAR Aabs generated from peptide immunisation had specificity for GluN1 immunisation peptides as well as target-specific binding to the native protein. Anti-NMDAR Aabs had no clear effect on isolated NMDARs in an oocyte expression system. However, peptide-purified anti-NMDAR Aabs prevented the induction of LTP at Schaffer collateral-CA1 synapses in ex vivo brain slices, consistent with causing synaptic NMDAR hypofunction at a network level. Conclusions: This work provides a solid basis to address outstanding questions regarding anti-NMDAR Aab mechanisms of action and, potentially, the development of therapies against CNS diseases.

A fully human IgG1 antibody targeting connexin 32 extracellular domain blocks CMTX1 hemichannel dysfunction in an in vitro model

Connexins (Cxs) are fundamental in cell–cell communication, functioning as gap junction channels (GJCs) that facilitate solute exchange between adjacent cells and as hemichannels (HCs) that mediate solute exchange between the cytoplasm and the extracellular environment. Mutations in the GJB1 gene, which encodes Cx32, lead to X-linked Charcot-Marie-Tooth type 1 (CMTX1), a rare hereditary demyelinating disorder of the peripheral nervous system (PNS) without an effective cure or treatment. In Schwann cells, Cx32 HCs are thought to play a role in myelination by enhancing intracellular and intercellular Ca2+ signaling, which is crucial for proper PNS myelination. Single-point mutations (p.S85C, p.D178Y, p.F235C) generate pathological Cx32 HCs characterized by increased permeability (“leaky”) or excessive activity (“hyperactive”).We investigated the effects of abEC1.1-hIgG1, a fully human immunoglobulin G1 (hIgG1) monoclonal antibody, on wild-type (WT) and mutant Cx32D178Y HCs. Using HeLa DH cells conditionally co-expressing Cx and a genetically encoded Ca2+ biosensor (GCaMP6s), we demonstrated that mutant HCs facilitated 58% greater Ca2+ uptake in response to elevated extracellular Ca2+ concentrations ([Ca2+]ex) compared to WT HCs. abEC1.1-hIgG1 dose-dependently inhibited Ca2+ uptake, achieving a 50% inhibitory concentration (EC50) of ~ 10 nM for WT HCs and ~ 80 nM for mutant HCs. Additionally, the antibody suppressed DAPI uptake and ATP release. An atomistic computational model revealed that serine 56 (S56) of the antibody interacts with aspartate 178 (D178) of WT Cx32 HCs, contributing to binding affinity. Despite the p.D178Y mutation weakening this interaction, the antibody maintained binding to the mutant HC epitope at sub-micromolar concentrations.In conclusion, our study shows that abEC1.1-hIgG1 effectively inhibits both WT and mutant Cx32 HCs, highlighting its potential as a therapeutic approach for CMTX1. These findings expand the antibody’s applicability for treating diseases associated with Cx HCs and inform the rational design of next-generation antibodies with enhanced affinity and efficacy against mutant HCs.

Developmental delay, seizures, and behavioral disorder caused by new SETD1B mutation: A case report

The article presents a clinical observation of a patient with atypical absences, myoclonia, psychomotor, and speech retardation. Whole-exome sequencing of the patient’s genetic material revealed a previously undescribed mutation in the SETD1B gene. The phenotypic picture of our case is similar to the data of patients with variants in the SETD1B gene, previously described in the scientific literature. The majority of the identified mutations occur in the catalytic domains, single-electron transfer (SET) and N-single-electron transfer (N-SET). There are only 6 cases in the RNA binding domain (RNA recognition motif), accounting for 3 exons of the gene. However, regardless of the location and type of mutation, the phenotypic manifestations of the described cases have common features. We want to draw the attention of the global scientific community for further research and a better understanding of the genotype-phenotypic correlation in SETD1B-associated nervous system disorder.

Evaluating the Auditory and Vestibular Functions of Patients with Multiple Sclerosis

Objective: Multiple sclerosis, a demyelinating disease of the central nervous system, is characterized by weakness of the arms and legs, sensory symptoms, ataxia, fatigue, diplopia, memory, concentration, attention disorder, and motor speech disorder. Common symptoms include epileptic seizures, cognitive impairment, hearing loss, and cortical symptoms. Materials and Methods: This study evaluated patients' mental functions with multiple sclerosis (MS) by considering their auditory and vestibular functions. A total of 30 patients, 15 healthy and 15 diseased, were recruited. In contrast, the experimental group consisted of individuals diagnosed with MS who had not had an attack for the last two months, over the age of 18, under the age of 60, and with similar characteristics in terms of gender. The audiological and vestibular tests on the experimental and patient groups were applied and the data obtained from these two groups were compared. Impedance audiometry test was performed on patients simultaneously. Result: The data obtained from our study, significant results were obtained for the right and left ears of MS patients to whom we applied the pure tone audiometry test. In the ABR test, unilateral hearing loss was observed in seven patients. In the VHIT test, while the VOR gains of 9 MS patients were outside the normal limits, the VOR gains of one patient in the left lateral canal were low. In the VEMP test, the wave latencies of 12 patients in the patient group were delayed, and the two patients' left-side P1 and N1 waveforms were not observed.

Agmatine Attenuates Behavioral and Biochemical Alterations in Rats Exposed to Ethanol during Adolescence

Background: Ethanol is a psychoactive substance and its use throughout adolescence may have a role in the development of alcoholism in adulthood which causes behavioral changes and structural alterations in particular brain regions that may be the source of these cognitive and motor impairments. As an endogenous amine, agmatine has drawn a lot of interest in relation to drug addiction and its aftereffects. It is an endogenous neuromodulator that has been shown to be a potential agent to manage diverse central nervous system (CNS) disorders. The current investigation aims to elucidate the role of agmatine in mediating behavioral alterations resulting from prolonged exposure to ethanol in rats during their early adolescent years. Methods: Rats received saline (1 ml/kg, p.o.) or ethanol (5 g/kg/day, 35% v/v) once a day from PND 28 to PND 49. Chronic ethanol intoxication during the CNS developing may induce sustainable neurobehavioral alterations in rats. After PND 70, the rats were subjected to behavioural and biochemical tests. Results: Chronic ethanol exposure significantly reduced locomotor activity, increased anxiety-like and depressive behaviors, and impaired cognitive function in adolescent rats. These behavioral alterations were accompanied by elevated oxidative stress, decreased hippocampal BDNF levels, increased levels of proinflammatory cytokines, and disrupted neurotransmitter balance. Agmatine administration at both 40 mg/kg and 80 mg/kg doses notably improved locomotor activity, reduced anxiety and depressive behaviors, and enhanced cognitive performance. Additionally, agmatine treatment reduced oxidative stress, restored BDNF levels, normalized TNF-α and IL6 levels, and corrected the neurotransmitter imbalance in ethanol-exposed rats. Conclusion: Prolonged exposure to ethanol during adolescence elicits persistent behavioural changes, characterized by diminished spontaneous locomotion and impaired balance. Administration of Agmatine effectively restores locomotor activity, alleviates anxiety and depression, and enhances both spatial learning and recognition memory in rats exposed to ethanol. Additionally, agmatine treatment attenuates oxidative stress indicators, including nitrite and lipid peroxidation levels, specifically in the cerebral cortex. These findings suggest that Agmatine holds potential as a viable therapeutic intervention for mitigating both the behavioural and biochemical repercussions induced by ethanol exposure in the rat model.

Заболеваемость болезнями нервной системы детей и подростков мегаполиса.

The significant proportion in the structure of childhood disability determines the relevance of assessing the incidence rates of newly diagnosed diseases of the nervous system in the child population of the metropolis. Purpose: t o analyze the primary incidence of diseases of the nervous system in children and adolescents in a metropolis. Materials and methods. The statistical data collections of the Federal State Budgetary Institution «Central Research Institute for Health Organization and Informatization» of the Ministry of Health of the Russian Federation for 2015–2024 were used as the base material. An assessment of intensive and extensive indicators of primary morbidity of children aged 0–14 and 15–17 in St. Petersburg was carried out in dynamics over ten years. A comparative analysis of the indicators was carried out using the visibility indicator with indicators for the Russian Federation and the Northwestern Federal District. The significance of differences between the indicators was assessed using Student’s t-test. Statistical data processing was carried out using MS Office‑2019 software packages. Results and discussions. The primary incidence of nervous system diseases among the child population aged 0–14 in St. Petersburg was significantly higher than the national and Northwestern Federal District averages in the entire period 2014–2023, and has grown by 19.4% over the past ten years. The incidence of 15–17-year-old adolescents was higher than the figures for 0–14-year-old children. The incidence of newly diagnosed nervous system diseases among the adolescent population of St. Petersburg also significantly exceeded the national and federal district averages, and had an upward trend (+4.0%). In the metropolis, the proportion of newly diagnosed nervous system diseases among all newly diagnosed diseases among children aged 0–14 and adolescents aged 15–17 was significantly higher than the national and Northwestern Federal District averages over the entire period studied, but has decreased over the past ten years. The rate of decline in the share of newly diagnosed nervous system diseases in adolescents was 2.7 times higher than in children (20.8% versus 7.6%), and the difference between the metropolis’ indicators and the indicators for Russia and the federal district was less significant. The COVID‑19 pandemic had a significant impact on the primary morbidity rate of children aged 0–14 and 15–17 and the share of newly diagnosed nervous system diseases in them. In 2020, compared to 2019, the incidence rate of nervous system diseases in children and adolescents in the metropolis significantly decreased, while the share of newly diagnosed nervous system diseases, on the contrary, increased. Conclusion. The high level of primary morbidity with a high proportion of newly diagnosed diseases of the nervous system among all newly diagnosed diseases in children and adolescents in the metropolis indicates an increasing role of neurological pathology in the morbidity of the child population.

Identifying opportunities to reduce imaging overuse in hospitalized children.

Radiologic imaging is routinely performed to aid in diagnosis for hospitalized children. Identifying and reducing variability in imaging practices can improve care while reducing harms and costs. To identify common inpatient pediatric conditions with high prevalence of imaging and variation in imaging practices and imaging-related costs across hospitals. We conducted a cross-sectional study of children 0-18 years old admitted to 50 children's hospitals in the Pediatric Health Information Systems database between 2017 and 2019. We excluded patients with complex chronic conditions, pregnancy, newborn, or neonatal intensive care charges, and those who died or who were discharged to hospice or rehabilitation facilities. Conditions with at least 2500 discharges and in which ≥30% of patients received imaging were included. Outcomes included imaging frequency, standardized imaging-related costs (including all modalities across all encounters), and hospital-level variation in imaging costs using the intraclass correlation coefficient (ICC). Of the 56 included conditions, imaging was most frequently conducted in patients with pectus excavatum (97.8%), scoliosis (96.2%), and intestinal obstruction (96%). Fracture ($21.4 million), trauma ($15.7 million), and appendicitis ($8.6 million) had the highest total imaging-related costs. Conditions with the highest geometric mean standardized imaging costs were nervous system disorders ($507), osteomyelitis ($494), vesicoureteral reflux/hydronephrosis ($468). Scoliosis (ICC = 0.49) and preseptal cellulitis (ICC = 0.48) had the highest variation in imaging-related costs. To reduce imaging overuse in hospitalized children, conditions with frequent imaging, high imaging-related costs, and high hospital-level variation in imaging practices should serve as priorities for future evidence generation, guideline development, and/or improvement initiatives.

The Syndrome of Inappropriate Antidiuresis

Abstract The syndrome of inappropriate antidiuresis (SIAD)–the most frequent cause of hypotonic hyponatremia–is mediated by nonosmotic release of arginine vasopressin (AVP), which promotes water retention by activating renal vasopressin type 2 (V2) receptors. There are numerous causes of SIAD, including malignancy, pulmonary and central nervous system diseases and medications. Rare activating mutations of the V2 receptor can also cause SIAD Determination of the etiology of SIAD is important because removal of the stimulus for inappropriate AVP secretion offers the most effective therapy. Treatment of SIAD is guided by symptoms and their severity as well as the level of plasma sodium. In the absence of severe symptoms which require urgent intervention, many clinicians focus on fluid restriction as a first-line treatment. Second-line therapeutic options include loop diuretics and salt tablets, urea, and V2 receptor antagonists.