Central Nervous System Dysfunction Research Articles

Development of Measures to Reduce Air Pollutants As Much As Possible

The papers include contemporary ecological challenges, steps taken to reduce artificial pollution, and environmental issues relating to the atmosphere's circulation through natural and artificial processes. A major threat to world health, air pollution can have a range of negative consequences on the environment, such as haze, eutrophication, acid rain, and harm to animals. The combustion of fossil fuels for energy production and transportation is the main cause of air pollution. The effects of air pollution on human health are significant, with millions of people affected by respiratory and cardiovascular diseases, reproductive and central nervous system dysfunctions, and cancer. The articles emphasize the importance of reducing air pollution through various measures, such as improving energy efficiency, promoting renewable energy sources, reducing emissions from transportation, and implementing policies and regulations to control air pollution. The articles also highlight the need for public awareness and a multidisciplinary approach to tackle the problem of air pollution and its impact on climate change and public health.

Joubert syndrome presenting bilateral peroneal neuropathies: A case report.

Joubert syndrome (JS) is a rare genetic disorder that presents with various neurological symptoms, primarily involving central nervous system dysfunction. Considering the etiology of JS, peripheral nervous system abnormalities cannot be excluded; however, cases of JS accompanied by peripheral nervous system abnormalities have not yet been reported. Distinct radiological findings on brain magnetic resonance imaging were considered essential for the diagnosis of JS. However, recently, cases of JS with normal or nearly normal brain morphology have been reported. To date, there is no consensus on the most appropriate diagnostic method for JS when imaging-based diagnostic approach is challenging. This report describes the case of an adult patient who exhibited bilateral peroneal neuropathies and was finally diagnosed with JS through genetic testing. A 27-year-old man visited our outpatient clinic due to a gait disturbance that started at a very young age. The patient exhibited difficulty maintaining balance, especially when walking slowly. Oculomotor apraxia was observed on ophthalmic evaluation. During diagnostic workups, including brain imaging and direct DNA sequencing, no conclusive findings were detected. Only nerve conduction studies revealed profound bilateral peroneal neuropathies. We performed whole genome sequencing to obtain a proper diagnosis and identify the gene mutation responsible for JS. This case represents the first instance of peripheral nerve dysfunction in JS. Further research is needed to explore the association between JS and peripheral nervous system abnormalities. Detailed genetic testing may serve as a valuable tool for diagnosing JS when no prominent abnormalities are detected in brain imaging studies.

Exertional Heatstroke Survivors' Knowledge and Beliefs about Exertional Heatstroke Diagnosis, Treatment, and Return to Play.

Little information exists regarding what exertional heatstroke (EHS) survivors know and believe about EHS best practices. Understanding this would help clinicians focus educational efforts to ensure survival and safe return-to-play following EHS. We sought to better understand what EHS survivors knew about EHS seriousness (e.g., lethality, short- and long-term effects), diagnosis and treatment procedures, and recovery. Design: Multi-year, cross-sectional, descriptive design. An 11.3-km road race located in the Northeastern United States in August 2022 and 2023. Forty-two of 62 runners with EHS (15 women, 27 men; age: 33±15 y; pre-treatment rectal temperature [TREC]: 41.5±0.9°C). Medical professionals evaluated runners requiring medical attention at the finish line. If they observed TREC ≥40°C with concomitant central nervous system dysfunction (CNS) EHS was diagnosed and patients were immersed in a 189.3-L tub filled with ice-water. Before medical discharge, we asked EHS survivors 15 questions about their experience and knowledge of select EHS best practices. Survey items were piloted and validated by experts and laypersons a priori (content validity index ≥0.88 for items and scale). Survey responses. Sixty-seven percent (28/42) of patients identified EHS as potentially fatal and 76% (32/42) indicated it negatively affected health. Seventy-nine percent (33/42) correctly identified TREC as the best temperature site to diagnose EHS. Most patients (74%, 31/42) anticipated returning to normal exercise within 1 week post-EHS; 69% (29/42) stated EHS would not impact future race participation. Patients (69%, 29/42) indicated it was important to tell their primary care physician about their EHS. Our patients were knowledgeable on the potential seriousness and adverse health effects of EHS and the necessity of TREC for diagnosis. However, educational efforts should be directed towards helping patients understand safe recovery and return-to-play timelines following EHS.

The suppressive effect of the specific KCC2 modulator CLP290 on seizure in mice

Epilepsy is a chronic neurological disorder characterized by episodic dysfunction of central nervous system. The most basic mechanism of epilepsy falls to the imbalance between excitation and inhibition. In adults, GABAA receptor (GABAAR) is the main inhibitory receptor to prevent neurons from developing hyperexcitability, while its inhibition relies on the low intracellular chloride anion concentration ([Cl-]i). Neuronal-specific electroneutral K+-Cl− cotransporter (KCC2) can mediate chloride efflux to lower [Cl-]i for GABAAR mediated inhibition. Our previous study has revealed that the coordinated downregulation of KCC2 and GABAAR participates in epilepsy. According to a high-throughout screen for compounds that reduce [Cl−]i, CLP290 turns out to be a specific KCC2 functional modulator. In current study, we first confirmed that CLP290 could dose-dependently suppress convulsant-induced seizures in mice in vivo as well as the epileptiform burst activities in cultured hippocampal neurons in vitro. Then, we discovered that CLP290 functioned through preventing the downregulation of the KCC2 phosphorylation at Ser940 and hence the KCC2 membrane expression during convulsant stimulation, and consequently restored the GABA inhibition. In addition, while CLP290 was given in early epileptogenesis period, it also effectively decreased the spontaneous recurrent seizures. Generally, our current results demonstrated that CLP290, as a specific KCC2 modulator by enhancing KCC2 function, not only inhibits the occurrence of the ictal seizures, but also suppresses the epileptogenic process. Therefore, we believe KCC2 may be a suitable target for future anti-epileptic drug development.

Circular RNA expression profiles and functional predication after restraint stress in the amygdala of rats.

Prolonged or repeated exposure to stress elevates the risk of various psychological diseases, many of which are characterized by central nervous system dysfunction. Recent studies have demonstrated that circular RNAs (circRNAs) are highly abundant in the mammalian brain. Although their precise expression and function remain unknown, they have been hypothesized to regulate transcriptional and post-transcriptional gene expression. In this investigation, we comprehensively analyzed whether restraint stress for 2 days altered the circRNA expression profile in the amygdala of male rats. The impact of restraint stress on behavior was evaluated using an elevated plus maze and open field test. Serum corticosterone levels were measured using an enzyme-linked immunosorbent assay. A total of 10,670 circRNAs were identified using RNA sequencing. Ten circRNAs were validated by reverse transcription and quantitative polymerase chain reaction analysis. Gene ontology and Kyoto encyclopedia of genes and genomes pathway analyzes supported the notion that genes associated with differentially expressed circRNAs are primarily implicated in neuronal activity and neurotransmitter transport. Moreover, the three differentially expressed circRNAs showed high specificity in the amygdala. Overall, these findings indicate that differentially expressed circRNAs are highly enriched in the amygdala and offer a potential direction for further research on restraint stress.

Retraction Note: Pericyte degeneration causes white matter dysfunction in the mouse central nervous system.

Retraction Note: Pericyte degeneration causes white matter dysfunction in the mouse central nervous system.

Inflammation and Connexin 43 profiles in the prefrontal cortex are relevant to stress susceptibility and resilience in mice

Depression is a major chronic mental illness worldwide, characterized by anhedonia and pessimism. Exposed to the same stressful stimuli, some people behave normally, while others exhibit negative behaviors and psychology. The exact molecular mechanisms linking stress-induced depressive susceptibility and resilience remain unclear. Connexin 43 (Cx43) forms gap junction channels between the astrocytes, acting as a crucial role in the pathogenesis of depression. Cx43 dysfunction could lead to depressive behaviors, and depression down-regulates the expression of Cx43 in the prefrontal cortex (PFC). Besides, accumulating evidence indicates that inflammation is one of the most common pathological features of the central nervous system dysfunction. However, the roles of Cx43 and peripheral inflammation in stress-susceptible and stress-resilient individuals have rarely been investigated. Thus, animals were classified into the chronic unpredictable stress (CUS)-susceptible group and the CUS-resilient group based on the performance of behavioral tests following the CUS protocol in this study. The protein expression of Cx43 in the PFC, the Cx43 functional changes in the PFC, and the expression levels including interleukin (IL)-1β, tumor necrosis factor-α, IL-6, IL-2, IL-10, and IL-18 in the peripheral serum were detected. Here, we found that stress exposure triggered a significant reduction in Cx43 protein expression in the CUS-susceptible mice but not in the CUS-resilient mice accompanied by various Cx43 phosphorylation expression and the changes of inflammatory signals. Stress resilience is associated with Cx43 in the PFC and fluctuation in inflammatory signaling, showing that therapeutic targeting of these pathways might promote stress resilience.

Assessment of fatigue and its impact in chronic liver disease

Patient reported outcomes (PROs) such as health related quality of life (HRQL) are important outcome measures for patients with chronic liver diseases (CLDs). Presence of cirrhosis and advanced liver disease have been associated with worsened HRQL and fatigue. On the other hand, some patients with earlier stages of CLD such as primary biliary cholangitis (PBC), chronic hepatitis C viral infection (HCV) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), also experience fatigue causing PRO impairment. Treatment for some CLDs may improve HRQL and, sometimes, levels of fatigue. We aimed to provide an in-depth expert review of concepts related to fatigue and HRQL in patients with PBC, HCV and MASLD. As such, a panel of experts in fatigue and CLD reviewed and discussed the literature and collaborated to provide this expert review of fatigue in CLD. Herein, we review and report on the complexity of fatigue highlighting that fatigue is comprised of peripheral (neuromuscular failure, often in conjunction with sub-maximal cardiorespiratory function) and central (central nervous system dysfunction) causes. Fatigue and HRQL are measured using validated self-report instruments. Additionally, fatigue can be measured through objective tests (e.g. grip strength). Fatigue has deleterious effects on HRQL and one’s ability to be physically active and socially engaged but does not always correlate with CLD severity. Treatments for HCV and MASLD can improve levels of fatigue and HRQL, but current treatments for PBC do not seem to affect levels of fatigue. We conclude that obtaining PRO data to include HRQL and fatigue are essential for determining the comprehensive burden of CLD and its potential treatments. Impact and ImplicationsFatigue is a complex phenomenon associated with both a peripheral cause (neuromuscular failure and sub-maximal cardiorespiratory function) and a central cause (central nervous system dysfunction). Although fatigue is common among patients with CLD, it does not always correlate with the severity of the liver disease, but fatigue is related with significant decreases in patients’ health related quality of life (HRQL). Appreciating the impact of fatigue using validated self-report measurements is important to better understand the burden of CLD and the effectiveness of treatment.

Hydroxocobalamin is not associated with methemoglobinemia in patients with inhalation injury and suspected cyanide toxicity and a proposed algorithm for hydroxocobalamin administration

BackgroundCyanide poisoning poses a significant threat to burn patients exposed to smoke in residential or workplace fires, leading to central nervous system dysfunction, hemodynamic instability, cardiovascular collapse, and death. Prompt administration of an effective antidote is critical. Hydroxocobalamin, a form of vitamin B12, is the gold standard treatment for cyanide toxicity, by binding to cyanide molecules and converting them into non-toxic cyanocobalamin that is eliminated by the kidneys. This mechanism is distinct from previous cyanide antidotes, which induce the formation of methemoglobin to bind to cyanide. Recent case studies have reported elevated methemoglobin levels after hydroxocobalamin administration, raising concerns regarding its safety. The current study investigates smoke inhalation patients treated with hydroxocobalamin at a single institution Burn Unit in hopes of enhancing our understanding of the complexities surrounding cyanide antidote therapy. MethodsAfter Institutional Board Approval, a retrospective cohort study was conducted. Our sample comprised burn patients with inhalation injury admitted to a single institution from 2013 to 2023 and treated with hydroxocobalamin for suspected cyanide toxicity. We also analyzed a matched control cohort of similar patients with inhalation injury not treated with hydroxocobalamin. We analyzed changes and peaks in methemoglobin levels, lactate levels, blood urea nitrogen (BUN) and creatinine, ventilator days, % total body surface area (TBSA), various types of medications and dressings, and mortality. Statistical analyses included t-tests, chi-square, linear and logistic regressions, and correlation analysis. ResultsIn the study, 36 patients with suspected inhalation injury were treated with hydroxocobalamin at the Los Angeles General (LAG) Burn Unit from 2013 to 2023, who were matched to 32 control patients with inhalation injury who were not treated with hydroxocobalamin. Demographic and baseline characteristics showed no statistically significant differences between the groups, including age, gender, BMI, and %TBSA. No significant differences were found in initial, final, peak, or change in methemoglobin levels. The study also revealed no significant disparities in initial lactate levels, mortality, kidney function tests, ventilator days, surgeries, or use of medications/treatments (e.g., Silvadene dressings, Vitamin C) between the two groups. When controlling for covariates, multiple linear regression analysis (age, gender, and %TBSA) indicated that hydroxocobalamin administration was not significantly associated with changes in methemoglobin or mortality. Increased %TBSA, however, was linked to elevated lactate levels. ConclusionsOur investigation sought to assess the potential risks associated with hydroxocobalamin administration in burn patients with concomitant inhalation injury. Contrary to our initial hypothesis, we found no statistically significant differences in methemoglobinemia, lactate levels, mortality, or kidney function. The influence of other factors, such as methemoglobinemia-inducing drugs or hydroxocobalamin's interference with co-oximetry, adds complexity. Although elevated methemoglobin levels were observed in some cases, their clinical significance was limited. However, this study's limitations, particularly the rarity of inhalation injury cases with concern for cyanide toxicity, warrant consideration. Further research is required to comprehensively elucidate the impact of hydroxocobalamin administration on burn patients' outcomes.

Abstract 6380: Exploring immune checkpoint inhibitor-related adverse events in pediatric cancer patients: A pharmacovigilance analysis of VigiBase and the FDA adverse event reporting system (FAERS) database

Abstract Background: With the widespread use of immune checkpoint inhibitors (ICIs) in the treatment of childhood cancers, their associated ICIs-related adverse events (irAEs) have become an important challenge. Our study was conducted to explore the pediatric high-risk ICIs-related AEs (pediatric irAEs) and explore the underlying mechanisms of pediatric irAEs. Methods: We analyzed ICIs-related adverse reaction reports in VigiBase from 1967 to 2023 and the FDA Adverse Event Reporting System (FAERS) database from 2013 to 2022. Using three methods, the reporting odds ratio (ROR), the proportional reporting ratio (PRR), and the information component (IC), we conducted a disproportionality analysis between pediatric and adult cancer patients using ICIs to discover pediatric irAEs. Furthermore, we explored the impact of clinical factors on the occurrence of pediatric irAEs and their subsequent prognosis through univariate and multivariate logistic regression analyses. Finally, combining these data with pan-cancer transcriptome data from the Gene Expression Omnibus (GEO) database, we explored the potential biological mechanisms related to pediatric irAEs. Results: We identified 4 categories of pediatric irAEs in the VigiBase and FAERS databases, including cytokine release syndrome (RORVigiBase = 17.05; RORFAERS = 14.17), acute respiratory distress syndrome (RORVigiBase = 10.26; RORFAERS = 12.39), seizure (RORVigiBase = 7.18; RORFAERS = 10.63) and febrile neutropenia (FN) (RORVigiBase = 3.01; RORFAERS = 4.84). The occurrence of pediatric irAEs may be related to mechanisms such as activation of immune cells, imbalance of inflammatory factors, activation of pathogen recognition, downregulation of inhibitory synapses, excitation/inhibition imbalance and central nervous system dysfunction. Conclusion: This study systematically analyzed the high-risk irAEs that may occur after using ICIs in pediatric cancer patients. Next, we explored the possible biological mechanisms of these pediatric irAEs to provide certain theoretical guidance for the prevention and treatment of adverse reactions in pediatric cancer patients after treatment with ICIs. Citation Format: Junyi Shen, Anqi Lin, Quan Cheng, Jian Zhang, Peng Luo. Exploring immune checkpoint inhibitor-related adverse events in pediatric cancer patients: A pharmacovigilance analysis of VigiBase and the FDA adverse event reporting system (FAERS) database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6380.

Autoimmune and neuropsychiatric phenotypes in a Mecp2 transgenic mouse model on C57BL/6 background.

Systemic Lupus Erythematosus (SLE) impacts the central nervous system (CNS), leading to severe neurological and psychiatric manifestations known as neuropsychiatric lupus (NPSLE). The complexity and heterogeneity of clinical presentations of NPSLE impede direct investigation of disease etiology in patients. The limitations of existing mouse models developed for NPSLE obstruct a comprehensive understanding of this disease. Hence, the identification of a robust mouse model of NPSLE is desirable. C57BL/6 mice transgenic for human MeCP2 (B6.Mecp2Tg1) were phenotyped, including autoantibody profiling through antigen array, analysis of cellularity and activation of splenic immune cells through flow cytometry, and measurement of proteinuria. Behavioral tests were conducted to explore their neuropsychiatric functions. Immunofluorescence analyses were used to reveal altered neurogenesis and brain inflammation. Various signaling molecules implicated in lupus pathogenesis were examined using western blotting. B6.Mecp2Tg1 exhibits elevated proteinuria and an overall increase in autoantibodies, particularly in female B6.Mecp2Tg1 mice. An increase in CD3+CD4+ T cells in the transgenic mice was observed, along with activated germinal center cells and activated CD11b+F4/80+ macrophages. Moreover, the transgenic mice displayed reduced locomotor activity, heightened anxiety and depression, and impaired short-term memory. Immunofluorescence analysis revealed IgG deposition and immune cell infiltration in the kidneys and brains of transgenic mice, as well as altered neurogenesis, activated microglia, and compromised blood-brain barrier (BBB). Additionally, protein levels of various key signaling molecules were found to be differentially modulated upon MeCP2 overexpression, including GFAP, BDNF, Albumin, NCoR1, mTOR, and NLRP3. Collectively, this work demonstrates that B6.Mecp2Tg1 mice exhibit lupus-like phenotypes as well as robust CNS dysfunctions, suggesting its utility as a new animal model for NPSLE.

Development of a fluorescence and quencher-based FRET assay for detection of endogenous peptide:N-glycanase/NGLY1 activity

Cytosolic peptide:N-glycanase (PNGase/NGLY1 in mammals) catalyzes deglycosylation of N-glycans on glycoproteins. A genetic disorder caused by mutations in the NGLY1 gene leads to NGLY1 deficiency, with symptoms including motor deficits and neurological problems. Effective therapies have not been established, though a recent study used the administration of an adeno-associated viral vector expressing human NGLY1 to dramatically rescue motor functions in young Ngly1–/– rats. Thus, early therapeutic intervention may improve symptoms arising from central nervous system dysfunction, and assay methods for measuring NGLY1 activity in biological samples are critical for early diagnostics. In this study, we established an assay system for plate-based detection of endogenous NGLY1 activity using a FRET-based probe. Using this method, we revealed significant changes in NGLY1 activity in rat brains during aging. This novel assay offers reliable disease diagnostics and provides valuable insights into the regulation of PNGase/NGLY1 activity in diverse organisms under different stress conditions.

Postural Control Characteristics in Alzheimer's Disease, Dementia With Lewy Bodies, and Vascular Dementia.

Dementia often results in postural control impairment, which could signify central nervous system dysfunction. However, no studies have compared postural control characteristics among various types of dementia. This study aimed to compare static postural control in patients with Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and vascular dementia (VaD). Cross-sectional relationship between the clinical diagnoses (AD, DLB, VaD, or normal cognition [NC]) of outpatients at a memory clinic and their upright postural control characteristics were examined. In the postural control test, participants were instructed to maintain a static upright standing on a stabilometer for 60 seconds under the eyes-open and eyes-closed conditions. Forty postural control parameters, including distance, position, and velocity in the anterior-posterior and medio-lateral directions, derived from the trajectory of the center of mass sway, were calculated. The characteristics of each type of dementia were compared to those of NC, and the differences among the 3 types of dementia were evaluated using linear regression models. The study included 1789 participants (1206 with AD, 111 with DLB, 49 with VaD, and 423 with NC). Patients with AD exhibited distinct postural control characteristics, particularly in some distance and velocity parameters, only in the eyes-closed condition. Those with DLB exhibited features in the mean position in the anterior-posterior direction. In patients with VaD, significant differences were observed in most parameters, except the power spectrum. Patients with AD, DLB, and VaD display disease-specific postural control characteristics when compared to cognitively normal individuals.

Ferroptosis and Pyroptosis in Epilepsy.

Epilepsy is sudden, recurrent, and transient central nervous system dysfunction caused by abnormal discharge of neurons in the brain. Ferroptosis and pyroptosis are newly discovered ways of programmed cell death. One of the characteristics of ferroptosis is the oxidative stress generated by lipid peroxides. Similarly, pyroptosis has unique pro-inflammatory properties. As both oxidative stress and neuroinflammation are significant contributors to the pathogenesis of epilepsy, increasing evidence shows that ferroptosis and pyroptosis are closely related to epilepsy. This article reviews the current comprehension of ferroptosis and pyroptosis and elucidates potential mechanisms by which ferroptosis and pyroptosis may contribute to epilepsy. In addition, we also highlight the possible interactions between ferroptosis and pyroptosis because they reportedly coexist in many diseases, and increasing studies have demonstrated the convergence of pathways between the two. This is of great significance for explaining the occurrence and development of epilepsy and provides a new therapeutic perspective for the treatment of epilepsy.

Human Adenovirus Entry and Early Events during Infection of Primary Murine Neurons: Immunofluorescence Studies In Vitro.

Human adenovirus (HAdV) is a common pathogen, which can lead to various clinical symptoms and-in some cases-central nervous system (CNS) dysfunctions, such as encephalitis and meningitis. Although the initial events of virus entry have already been identified in various cell types, the mechanism of neuronal uptake of adenoviruses is relatively little understood. The aim of this study was to investigate early events during adenoviral infection, in particular to determine the connection between cellular coxsackievirus and adenovirus receptor (CAR), clathrin, caveolin, and early endosomal proteins (EEA1 and Rab5) with the entry of HAdVs into primary murine neurons in vitro. An immunofluorescence assay and confocal microscopy analysis were carried out to determine HAdV4, 5, and 7 correlation with CAR, clathrin, caveolin, and early endosomal proteins in neurons. The quantification of Pearson's coefficient between CAR and HAdVs indicated that the HAdV4 and HAdV5 types correlated with CAR and that the correlation was more substantial for HAdV5. Inhibition of clathrin-mediated endocytosis using chlorpromazine limited the infection with HAdV, whereas inhibition of caveolin-mediated endocytosis did not affect virus entry. Thus, the entry of tested HAdV types into neurons was most likely associated with clathrin but not caveolin. It was also demonstrated that HAdVs correlate with the Rab proteins (EEA1, Rab5) present in early vesicles, and the observed differences in the manner of correlation depended on the serotype of the virus. With our research, we strove to expand knowledge regarding the mechanism of HAdV entry into neurons, which may be beneficial for developing potential therapeutics in the future.

SARS-CoV-2 infection causes dopaminergic neuron senescence

COVID-19 patients commonly present with signs of central nervous system and/or peripheral nervous system dysfunction. Here, we show that midbrain dopamine (DA) neurons derived from human pluripotent stem cells (hPSCs) are selectively susceptible and permissive to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. SARS-CoV-2 infection of DA neurons triggers an inflammatory and cellular senescence response. High-throughput screening in hPSC-derived DA neurons identified several FDA-approved drugs that can rescue the cellular senescence phenotype by preventing SARS-CoV-2 infection. We also identified the inflammatory and cellular senescence signature and low levels of SARS-CoV-2 transcripts in human substantia nigra tissue of COVID-19 patients. Furthermore, we observed reduced numbers of neuromelanin+ and tyrosine-hydroxylase (TH)+ DA neurons and fibers in a cohort of severe COVID-19 patients. Our findings demonstrate that hPSC-derived DA neurons are susceptible to SARS-CoV-2, identify candidate neuroprotective drugs for COVID-19 patients, and suggest the need for careful, long-term monitoring of neurological problems in COVID-19 patients.

Clinical Diagnosis and Management of Fetal Alcohol Spectrum Disorder and Sensory Processing Disorder in Children.

Fetal alcohol spectrum disorder (FASD) is commonly misdiagnosed because of the complexity of presentation and multiple diagnostic criteria. FASD includes four categorical entities (fetal alcohol syndrome, partial fetal alcohol syndrome, alcohol related neurodevelopmental disorder, and alcohol related birth defects). The four FASD diagnostic criteria are facial dysmorphology, growth deficiency, central nervous system dysfunction, and prenatal alcohol exposure. Sensory processing disorders (SPDs) are common in FASD and are observed as inappropriate behavioral responses to environmental stimuli. These can be either a sensory-based motor disorder, sensory discrimination disorder, or sensory modulation disorder. A child with SPD may experience challenges with their fine motor coordination, gross motor coordination, organizational challenges, or behavioral regulation impairments. FASD requires a multidimensional approach to intervention. Although FASD cannot be cured, symptoms can be managed with sleep-based therapies, sensory integration, and cognitive therapies. This paper reviews SPDs in FASD and the interventions that can be used by practitioners to help improve their therapeutic management, although it is unlikely that any single intervention will be the right choice for all patients.

Stereotypic Behaviour in Elephants

Abstract Stereotypic behaviour is undesirable in zoos, especially when it occurs in large sentient mammals such as elephants because there is evidence that it is often linked to poor welfare conditions and suboptimal management. Elephant managers make great efforts to prevent, or at least reduce, the performance of stereotypic behaviours and this is perceived as beneficial for individual animals. Some studies of stereotypic behaviours in mammals have found links with central nervous system dysfunction while others have suggested that stereotypies reduce stress in captive environments and function as a coping mechanism. Although repetitive behaviours are common in mammals, only some of these behaviours are strictly speaking stereotypic in nature, that is to say, they have no obvious purpose. This case study examines the nature of stereotypic behaviours and other repetitive behaviours in elephants, their aetiology and changes in elephant management that might result in a reduction in stereotypic behaviours and a consequent welfare gain. Information © The Author 2024

SEW2871 reduces seizures via the sphingosine 1-phosphate receptor-1 pathway in the pentylenetetrazol and phenobarbitone kindling model of drug-refractory epilepsy.

Epilepsy is a prevalent neurological disorder characterized by neuronal hypersynchronous discharge in the brain, leading to central nervous system (CNS) dysfunction. Despite the availability of anti-epileptic drugs (AEDs), resistance to AEDs is the greatest challenge in treating epilepsy. The role of sphingosine-1-phosphate-receptor 1 (S1PR1) in drug-resistant epilepsy is unexplored. This study investigated the effects of SEW2871, a potent S1PR1 agonist, on a phenobarbitone (PHB)-resistant pentylenetetrazol (PTZ)-kindled Wistar rat model. We measured the messenger ribonucleic acid (mRNA) expression of multi-drug resistance 1 (MDR1) and multi-drug resistance protein 5 (MRP5) as indicators for drug resistance. Rats received PHB + PTZ for 62 days to develop a drug-resistant epilepsy model. From day 48, SEW2871 (0.25, 0.5, 0.75 mg/kg, intraperitoneally [i.p.]) was administered for 14 days. Seizure scoring, behaviour, oxidative markers like reduced glutathione, catalase, superoxide dismutase, inflammatory markers like interleukin 1 beta tumour necrosis factor alpha, interferon gamma and mRNA expression (MDR1 and MRP5) were assessed, and histopathological assessments were conducted. SEW2871 demonstrated dose-dependent improvements in seizure scoring and neurobehavioral parameters with a reduction in oxidative and inflammation-induced neuronal damage. The S1PR1 agonist also downregulated MDR1 and MRP5 gene expression and significantly decreased the number of dark-stained pyknotic nuclei and increased cell density with neuronal rearrangement in the rat brain hippocampus. These findings suggest that SEW2871 might ameliorate epileptic symptoms by modulating drug resistance through downregulation of MDR1 and MRP5 gene expression.

The Role of Motivation to Excel in the Etiology of Exertional Heat Stroke.

Exertional heat stroke (EHS) is a medical emergency characterized by elevated body temperature and central nervous system dysfunction, and it can include dizziness, confusion and loss of consciousness, as well as long-term organ and tissue damage. EHS is distinct from classic, or passive, heat stroke and is most commonly observed during intense physical activity in warfighters, athletes, and laborers. EHS is an ongoing non-combat threat that represents a risk to both the health and readiness of military personnel. Potential risk factors and their mitigation have been the subject of investigation for decades. One risk factor that is often mentioned in the literature, but not well quantified, is that of individual motivation to excel, wherein highly trained military personnel and athletes exert themselves beyond their physiological limits because of a desire to complete tasks and goals. The motivation to excel in tasks with high standards of achievement, such as those within elite military schools, appears to create an environment in which a disproportionately high number of exertional heat illness casualties occur. Here, we review existing biomedical literature to provide information about EHS in the context of motivation as a risk factor and then discuss five cases of EHS treated at Martin Army Community Hospital at Fort Moore, GA, from 2020 to 2022. In our discussion of the cases, we explore the influence of motivation on each occurrence. The findings from this case series provide further evidence of motivation to excel as a risk factor for EHS and highlight the need for creative strategies to mitigate this risk.