Central Nervous System Damage Research Articles

The emerging roles of ferroptosis in cells of the central nervous system.

Ferroptosis is morphologically characterized by shrunken mitochondria and biochemically characterized by iron overload, lipid peroxidation and lipid reactive oxygen species (ROS) accumulation; these phenomena are suppressed by iron chelation, genetic inhibition of cellular iron uptake, and intervention on other pathways such as lipid metabolism. The induction of ferroptosis may be related to pathological cellular conditions in the central nervous system (CNS); thus, ferroptosis may cause disability via CNS damage. Here, we review the role of ferroptosis in the main cells of the CNS, including glial cells, neurons, and pericytes; in various diseases of the CNS; and in the interaction of glia and neurons in CNS diseases. Some small molecules and traditional Chinese drugs which inhibit ferroptosis in cells of the CNS are shown as potential therapeutic strategies for neurological diseases.

Dysregulation of miR-301a-3p serves as a non-invasive biomarker and is associated with inflammatory responses in traumatic spinal cord injury.

Spinal cord injury (SCI) led by trauma is a serious damage in central nervous system. This study aimed at confirming the expression levels and clinical significance of miRNA-301a-3p (miR-301a-3p) in SCI patients, and exploring the potential mechanisms of miR-301a-3p participating in SCI progression. One hundred and thirty nine acute spinal trauma patients, included neurologically normal, incomplete and complete SCI cases, were analyzed in this study. Quantitative real-time PCR was used to measure the expression of miR-301a-3p. Receiver operating characteristic (ROC) was used to evaluate the diagnostic accuracy of serum miR-301a-3p in SCI. LPS-treated SH-SY5Y cells were used to mimic SCI inflammatory injury. The levels of IL-1β, IL-6, TNF-α were detected using enzyme-linked immunosorbent assay. Expression of serum miR-301a-3p was significantly higher in both incomplete and complete SCI patients than that in neurologically normal controls, and had a significant ability to distinguish SCI patients from controls. Additionally, complete SCI cases had markedly increased miR-301a-3p compared to incomplete cases, and the two groups of patients could be distinguished based on serum deregulated miR-301a-3p. In the SCI cell model, miR-301a-3p overexpression led to decreased cell viability. The inflammatory responses of the cell model were enhanced by miR-301a-3p, which was consistent with the findings in SCI patients that serum miR-301a-3p was positively correlated with pro-inflammatory cytokines. The expression of miR-301a-3p is increased in SCI patients, and serves as a candidate biomarker for SCI diagnosis. MiR-301a-3p may be involved in SCI progression by affecting neuronal viability and inflammation.

Bone marrow mesenchymal stem cells improve cognitive impairments induced by methamphetamine in rats and reduce relapse.

Introduction: Chronic exposure to methamphetamine (Meth) results in permanent central nervous system damage and learning and memory dysfunction. This study aimed at investigating the therapeutic effects of bone marrow mesenchymal stem cells (BMMSCs) on cognitive impairments in Meth addicted rats and comparing intravenous (IV) delivery with intranasal (IN) delivery of BMMSCs. Methods: Adult Wistar rats were randomly divided into 6 groups; Control; Meth-addicted; IV-BMMSC (Meth administered and received IV BMMSCs); IN-BMMSC (Meth administered and received IN BMMSCs); IV-PBS (Meth administered and received IV Phosphate-buffered saline (PBS); IN-PBS (Meth administered and received IN PBS). BMMSCs were isolated, expanded in vitro, immunophenotyped, labeled, and administered to BMMSCs-treated groups (2 × 106 cells). The therapeutic effect of BMMSCs was measured using Morris water maze and Shuttle Box. Moreover, relapse-reduction was evaluated by conditioning place preference after 2 weeks following BMMSCs administration. The expression of brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) in rat hippocampus was assessed using immunohistochemistry method. Results: Administration of BMMSCs caused a significant improvement in the learning and memory functions of Meth-addicted rats and reduced the relapse (P<0.01). In behavioral tests, comparison of IV and IN BMMSC-treated groups did not show any significant difference. Administration of BMMSCs improved the protein level of BDNF and GDNF in the hippocampus, as well as causing behavioral improvement (P<0.001). Conclusion: BMMSC administration might be a helpful and feasible method to treat Meth-induced brain injuries in rats and to reduce relapse. BMMSCs were significantly higher in IV-treated group compared to the IN route. Moreover, the expression of BDNF and GDNF was higher in IN-treated rats compared with IV treated group.

An electron microscopic study of neocortex of Syrian hamsters (&lt;i&gt;Mesocricetus auratus&lt;/i&gt;) infected with SARS-CoV-2 (Coronaviridae: &lt;i&gt;Coronavirinae: Betacoronavirus: Sarbecovirus&lt;/i&gt;)

Convalescent COVID-19 patients have various signs of central nervous system damage, including those directly associated with SARS-CoV-2. Hence, studies of SARS-COV-2 related morphological changes in neocortex are particularly relevant for understanding the mechanisms of their formation and development of approaches to preclinical evaluation of the effectiveness of antiviral drugs. The purpose of the research is a longitudinal study of the ultrastructural alterations in Syrian hamsters neocortex after experimental SARS-CoV-2 infection. Male Syrian hamsters weighing 80100 g, aged 4 to 6 weeks, were infected with 26 l SARS-CoV-2 intranasally with 4104 TCD50/ml of viral particles. The animals were euthanized on days 3, 7 or 28 post-infection, the brain was extracted with the cortex excision. The material analysis was performed using transmission electron microscopy. On day 3 post-infection, the number of moderately hyperchromic neurons in neocortex increased, while by the day 7 the number of apoptotic cells significantly increased. Simultaneously, an increased signs of neuronophagy and representation of atypical glia were observed. Increased number of altered oligodendrocytes was observed on day 28 post-infection. Viral invasion was accompanied by changes in neocortical cells since day 3 post-infection, such as transformation of their nucleus, the rough endoplasmic reticulum and the Golgi vesicles as well as microvascular spasm with perivascular edema. As a result of electron microscopic study, the ultrastructural alterations in neocortex were described in an experimental model of SARS-CoV-2 infection. The findings can be used to identify the mechanisms of infection pathogenesis and to search for the new directions in development of medicines.

Skeletal Muscle Dysfunction in People With Multiple Sclerosis: A Physiological Target for Improving Physical Function and Mobility

Impaired mobility is amongst the most debilitating symptoms reported by people with multiple sclerosis (MS). Historically, it has been viewed that walking impairments in people with MS are directly caused by the physical damage to the neurons in the central nervous system (CNS) which results from the immunopathology of MS. However, research from over the past 4 decades has revealed that physical function in people with MS is also affected by skeletal muscle dysfunction characterized by a reduced capacity to produce, regulate, and sustain the force-generating muscle contractions that propel human movement. While the immediate CNS damage caused by MS can alter the neural activation of muscle by disrupting neuromotor transmission, chronic reductions in mobility and extreme fatigue can lead to physically inactive lifestyles that negatively affect skeletal muscle through mechanisms of deconditioning. Consequently, people with MS can experience alterations in activation patterns, muscle mass and tissue composition, contractility, metabolism, and perfusion that contribute to reductions in muscle function that ultimately impair key physical functions such as walking. This article provides an overview of the cellular mechanisms that contribute to skeletal muscle dysfunction in people with MS and a discussion of the current evidence suggesting that skeletal muscle may be a key physiological target for interventions aiming to improve mobility in this population. We specifically highlight recent evidence demonstrating the potential for rehabilitation and exercise interventions to induce muscle plasticity in people with MS who have moderate to severe levels of disability. In conclusion, we discuss future directions in basic science and clinical research that may advance our understanding of muscle dysfunction in MS and lead to the development of more precise and effective treatment strategies.

Artesunate regulates the proliferation and differentiation of neural stem cells by activating the JAK‑2/STAT‑3 signaling pathway in ischemic stroke.

Ischemic stroke is one of the most common causes of disability and death globally; therefore, the repair and reconstruction of the central nervous system (CNS) after stroke is very important. Neural stem/progenitor cells (NSPCs) may be the key to cell replacement therapy to treat CNS damage. It has previously been reported that artesunate (ART) is involved in the regulation of the biological functions of NSPCs; however, the mechanism of action of ART remains unclear. In the present study, different concentrations of ART were used to treat NSPCs following oxygen-glucose deprivation (OGD). Cell viability and apoptosis were analyzed using Cell Counting Kit-8 assay and flow cytometry, respectively, whereas immunofluorescence analysis was used to measure the expression levels of the differentiation-related molecule doublecortin (DCX) and proliferating cell nuclear antigen (PCNA). Western blotting was performed to analyze the expression levels of molecules related to the JAK-2/STAT-3 signaling pathway. The present results indicated that treatment with ART following OGD significantly promoted the viability of NSPCs, inhibited the apoptosis of NSPCs, and promoted the expression of PCNA and DCX. Moreover, ART significantly downregulated the protein expression levels of phosphorylated (p)-JAK-2 and p-STAT-3. Furthermore, activation of the JAK-2/STAT-3 signaling pathway and treatment with ART reversed the effects of ART on the proliferation, apoptosis and differentiation of NSPCs. In conclusion, the present data suggested that ART may promote the proliferation and differentiation of NSPCs, and reduce the apoptosis of NSPCs, by inhibiting the JAK-2/STAT-3 signaling pathway. ART may potentially be used for the treatment of ischemic stroke.

Evaluating the validity of a functional electrical stimulation clinical decision making tool: A qualitative study

Following central nervous system damage, the recovery of motor function is a priority. For some neurological populations, functional electrical stimulation (FES) is recommended in best practice guidelines for neurorehabilitation. However, limited resources exist to guide FES application, despite clinicians reporting that a lack of FES knowledge prevents use in clinical practice. The FES Clinical Decision Making Tool was developed to assist clinicians with FES application and translation into clinical practice. The purpose of this study was to evaluate the content validity of the Tool from the perspectives of Canadian physical and occupational therapists using FES in neurorehabilitation. Thirteen participants (twelve women, one man), aged 40.5 ± 10.3 years, participated in individual semi-structured interviews to explore their clinical decision making experiences when applying FES and to evaluate the content validity (i.e., appropriateness, comprehensibility, and comprehensiveness) of the Tool. Interviews were analyzed using a qualitative conventional content analysis following the DEPICT model. Three themes were identified. 1) Clinician context influences FES usage. Participants' experiences with FES use varied and application was influenced by treatment goals. 2) Parameter selection in clinical practice. Participants identified decision-making strategies and the challenges of parameter selection. 3) With modifications, the Tool is a valid resource to inform FES applications. Participants discussed its strengths, limitations, and suggested changes. While the Tool is useful, a more extensive resource (e.g., appendix) for the Tool is warranted. A revised Tool was created to improve its comprehensiveness and comprehensibility. Thus, the Tool is a valid resource for applying FES in neurorehabilitation.

Bridging the gap of axonal regeneration in the central nervous system: A state of the art review on central axonal regeneration.

Neuronal regeneration in the central nervous system (CNS) is an important field of research with relevance to all types of neuronal injuries, including neurodegenerative diseases. The glial scar is a result of the astrocyte response to CNS injury. It is made up of many components creating a complex environment in which astrocytes play various key roles. The glial scar is heterogeneous, diverse and its composition depends upon the injury type and location. The heterogeneity of the glial scar observed in different situations of CNS damage and the consequent implications for axon regeneration have not been reviewed in depth. The gap in this knowledge will be addressed in this review which will also focus on our current understanding of central axonal regeneration and the molecular mechanisms involved. The multifactorial context of CNS regeneration is discussed, and we review newly identified roles for components previously thought to solely play an inhibitory role in central regeneration: astrocytes and p75NTR and discuss their potential and relevance for deciding therapeutic interventions. The article ends with a comprehensive review of promising new therapeutic targets identified for axonal regeneration in CNS and a discussion of novel ways of looking at therapeutic interventions for several brain diseases and injuries.

Postnatal maternal behaviour expression depends on lambing difficulty in Merino ewes

Dystocia, a prolonged or non-progressive birth event, is the main contributor to lamb mortality in Australia and across the world. Dystocia can cause neonatal hypoxia, central nervous system (CNS) damage leading to increased risk of starvation, exposure and mismothering, and death. These prolonged birth events can also cause fatigue, injury and death in the ewe. Dystocia may interrupt the expression of maternal behaviour and the strength of the ewe-lamb bond, and consequently lamb survival. This study focused on the effect of dystocia on ewe behaviour in the 2 h post-lambing. A total of 18 ewes were chosen for continuous behaviour annotation and analysis (dystocic (n = 9) and eutocic (n = 9)) based on the quality of video recordings, length of stage 2 parturition and classification by a single experienced observer. Dystocic ewes showed significantly lower expression of maternal behaviours and a significantly greater expression of avoidance behaviours compared to eutocic ewes. Additionally, dystocic ewes performed fewer behaviours in total compared to eutocic ewes.Dystocia can significantly affect the quality and quantity of ewe maternal behaviour expression, leading to increased avoidance of the lamb, increased risk of maternal disinterest, and increased risk of death for the lamb. If dystocic events can be identified quickly and accurately, measures can be taken to ensure the ewe and lamb recover successfully.

Monocrotaline induces acutely cerebrovascular lesions, astrogliosis and neuronal degeneration associated with behavior changes in rats: A model of vascular damage in perspective

Pyrrolizidine alkaloids (PAs) are secondary plant metabolites playing an important role as phytotoxins in the plant defense mechanisms and can be present as contaminant in the food of humans and animals. The PA monocrotaline (MCT), one of the major plant derived toxin that affect humans and animals, is present in a high concentration in Crotalaria spp. (Leguminosae) seeds and can induce toxicity after consumption, characterized mainly by hepatotoxicity and pneumotoxicity. However, the effects of the ingestion of MCT in the central nervous system (CNS) are still poorly elucidated. Here we investigated the effects of MCT oral acute administration on the behavior and CNS toxicity in rats. Male adult Wistar were treated with MCT (109 mg/Kg, oral gavage) and three days later the Elevated Pluz Maze test demonstrated that MCT induced an anxiolytic-like effect, without changes in novelty habituation and in operational and spatial memory profiles. Histopathology revealed that the brain of MCT-intoxicated animals presented hyperemic vascular structures in the hippocampus, parahippocampal cortex and neocortex, mild perivascular edema in the neocortex, hemorrhagic focal area in the brain stem, hemorrhage and edema in the thalamus. MCT also induced neurotoxicity in the cortex and hippocampus, as revealed by Fluoro Jade-B and Cresyl Violet staining, as well astrocyte reactivity, revealed by immunocytochemistry for glial fibrillary acidic protein. Additionally, it was demonstrated by RT-qPCR that MCT induced up-regulation on mRNA expression of neuroinflammatory mediator, especially IL1β and CCL2 in the hippocampus and cortex, and down-regulation on mRNA expression of neurotrophins HGDF and BDNF in the cortex. Together, these results demonstrate that the ingestion of MCT induces cerebrovascular lesions and toxicity to neurons that are associated to astroglial cell response and neuroinflammation in the cortex and hippocampus of rats, highlighting CNS damages after acute intoxication, also putting in perspective it uses as a model for cerebrovascular damage.

САХАРНЫЙ ДИАБЕТ I ТИПА В ПЕДИАТРИЧЕСКОЙ ПРАКТИКЕ И ПОРАЖЕНИЯ ЦЕНТРАЛЬНОЙ НЕРВНОЙ СИСТЕМЫ

Diabetes mellitus (DM) is one of severe and progressive endocrine system diseases that occur in childhood. Type 1 DM, the form most commonly seen in children and adolescents, develops as an autoimmune process that gradually inflicts damage and causes death of pancreatic β cells. During its course MD gives rise to a number of severe complications, the most significant of which is the dysfunction and damage of the central nervous system (CNS). The leading causes of CNS damage in DM can be subdivided into vascular, metabolic, neurodegenerative and inflammatory. The main clinical presentation of DM in pediatric practice is cognitive impairment, characterized by a decline in memory and intellectual function. Despite the success that have been achieved in the MD treatment field, prevention and detection of CNS function impairment occurring in this disease remains an important direction for research in the endocrine practice, especially when treating children and adolescents.

Inflammation and endothelial toxicity: pathogenetic aspects of central nervous system damage due to novel coronavirus disease

Introduction. There are inconsistent data on the incidence of stroke in patients with COVID-19, including acute cerebrovascular accidents in younger people without obligate risk factors, as well as the risk of SARS-CoV-2 infection in patients with acute stroke.&#x0D; The aim of the study was to evaluate the features of concomitant stroke and COVID-19, and the role of inflammation and endothelial toxicity in cerebral damage.&#x0D; Materials and methods. The study included 1,524 patients admitted to vascular clinics across St. Petersburg in 20202021, including 1,068 people with confirmed COVID-19 infection and 551 death cases. The patients were divided into four groups depending on disease severity, for clinical and laboratory data analysis.&#x0D; Results. There were marked changes in the laboratory markers of inflammation, haemostasis, fibrinolysis, cytolysis, iron metabolism, cerebral ischaemia, proteolysis, immunodeficiency (lymphocytopenia, monocytopenia, elevated white blood cell count, elevated levels of C-reactive protein, fibrinogen, D-dimer, creatine kinase, ferritin and neutrophil elastase), with statistically significant differences when compared with patients without COVID-19. Changes in inflammatory markers in the first 2472 hours provided the most information. A multifold increase (escalation) in the marker values was always correlated with an imminent adverse outcome and was usually accompanied by subsequent laboratory confirmation of COVID-19 infection or specific signs of viral pneumonia.&#x0D; Conclusion. COVID-19 should be considered an independent risk factor for acute stroke, while the virus-induced thrombosis, manifesting in an escalation in inflammatory factors and products of endothelial damage, should be considered a pathogenetic link leading to cerebral tissue damage.

Mutation profile of diffuse large B-cell lymphoma with relapses in the central nervous system

Introduction . The recurrence of diffuse large B-cell cell lymphoma in the central nervous system in the vast majority of cases is a fatal manifestation of the disease. The study of the lymphoma mutational profile can improve the accuracy of the prognosis of relapse in the central nervous system and justify the selection of patients for preventive treatment. Aim. To evaluate the mutational profile of cases of diffuse large B-cell cell lymphoma with central nervous system damage in relapse based on the results of our own experiment on high-performance sequencing. Materials and methods . On the Illumina platform, full-exome sequencing of diagnostic samples of diffuse large B-cell cell lymphoma with relapses in the central nervous system was performed. A panel including more than 70 genes was analyzed. Results . Four main groups of genetic events can be distinguished in the group of studied samples, namely: combined mutations in the NF-kB ( MYD88, NOTCH1, CD79B, CARD11 ) and JAK-STAT ( PIM1, STAT6 ) signaling pathways, as well as aberrations in the main oncosuppressor TP53 and chromatin remodeling system genes ( ARID1A, KMT2D, EP300, SMARCA4 ). A recurrent mutation c. 794T&gt;C, p.L265P MYD88 was detected in the study group. Among other findings, mutations in the CIITA and CD58 genes should be noted, which are important in avoiding tumor cells from immune surveillance. Conclusion . Despite the apparent heterogeneity of the mutational profile of diffuse large B-cell cell lymphoma with relapses in the central nervous system, in most cases, tumor cells were characterized by genetic disorders leading to the production of a large number of pro-inflammatory cytokines by malignant lymphocytes, as well as aberrations that reduce immunogenicity and contribute to the avoidance of immune surveillance by the tumor.

Development of a drug risk analysis and assessment system and its application in signal excavation and analysis of 263 cases of fluoroquinolone-induced adverse reactions.

Background: Adverse drug reaction (ADR) signal mining is essential for assessing drug safety. However, the currently available methods for this are rather cumbersome. Objective: We aimed to develop a drug risk analysis and assessment system using Java language and conduct pharmacovigilance data mining for fluoroquinolones at our hospital. Methods: We used ADR data reported by Shandong Provincial Third Hospital between July 2007 and August 2021. The signal detection methods included proportional reporting ratio (PRR), reporting odds ratio (ROR), Bayesian Confidence Propagation Neural Network (BCPNN), Medicines and Healthcare products Regulatory Agency (MHRA). The BCPNN method was used as the reference standard for comparing the remaining three signal detection methods based on sensitivity, specificity, positive predictive value, negative predictive value, and Jorden index. Results: The hospital database contained a total of 2,621 ADR reports, among which 263 were attributed to fluoroquinolones. There were 391 fluoroquinolone-ADR pairs. Using the PRR, ROR, MHRA, and BCPNN method, we detected 13 signals, 13 signals, 10 signals, and 11 weak signals, respectively. After signal detection, levofloxacin and moxifloxacin were shown to induce high risk signals for mental and sleep disorders, with the signal intensity of moxifloxacin being the most significant. Compared with BCPNN, the PRR and ROR methods showed better sensitivity, whereas the MHRA method showed better specificity. Conclusion: We developed a drug risk analysis and assessment system that can help hospitals and other medical institutions to detect and analyse ADR signals in the self-reporting system database, and thus improve drug safety. Further, it indicates that the central nervous system damage caused by fluoroquinolones should be monitored closely, and thus provides a reference for the clinical application of these drugs.

Bilateral horizontal gaze palsy as the only manifestation of demyelination in the central nervous system

Isolated oculomotor disorders caused by central nervous system damage are quite rare. As a rule, they are combined with other signs of cerebral trunk damage. A clinical case with the focus of amyelination in the cerebral trunk area, which manifests itself in the form of bilateral horizontal gaze palsy in the absence of other focal neurological symptoms is presented. A complete regression of oculomotor disorders was observed against the background of glucocorticosteroid therapy. A differential research was carried out among amyelinating, ophthalmic, endocrinologic diseases, ANCA-associated vasculitis (AAV).

Arbovirus fevers in children and adults in the Astrakhan region: clinical cases

Natural focal infections with transmissible transmission caused by viruses of West Nile Fever, Batai, Inco, Sindbis, Tyagin are registered in various territories of Russia, in the form of sporadic cases, characterized by polymorphism of clinical symptoms, from inapparent forms to severe, occurring with Central nervous system damage (meningitis, meningoencephalitis), which complicates the timely diagnosis and treatment of this pathology.Purpose: to describe our own clinical observations of five cases of arbovirus fevers.Results. Arbovirus fevers (West Nile Fever, Batai, Inko, Tyaginya) in the five clinical cases we have presented occurred in two clinical forms: catarrhal with hypertension syndrome, febrile fever and intense headache, vomiting in the absence of signs of inflammation in the CSF; and with damage to the central nervous system (meningitis). Catarrhal forms of arboviral fevers must be differentiated from ARVI, influenza, mononucleosis. Arbovirus fevers occurring with Central nervous system lesions (meningitis) had a significant similarity with enteroviral meningitis, both in terms of seasonality and clinical symptoms.Conclusion. In the territories of Russia endemic for mosquito fevers, in the summer period of the year, febrile patients with cerebral symptoms and / or meningeal symptoms should be examined for a group of arbovirus fevers.

P.73 Structural damage in dystrophinopathies: a multimodal neuroimaging study

Dystrophinoapthies are characterized by central nervous system damage, but pattern and extent of such damage are not yet clear. For this reason, we designed a cross-sectional multimodal MRI-based study to address this point. We enrolled 50 patients (40 Duchenne and 10 Becker) and 40 age-sex matched controls. All subjects underwent 3T MRI to assess gray (GM) and white matter (WM). To evaluate the cerebral and cerebellar cortices, we used FreeSurfer. DTI-multiatlas was used to investigate microstructural-abnormalities in cerebral WM. All analyses were corrected for multiple comparisons. Mean age of patients and disease duration were 12 and 8, respectively. Group analyses showed WM microestructural abnormalities at bilateral fornix, seen as increased axial, mean and radial diffusivities, with large effect sizes (>0.8). We also found a negative correlation between fornix axial diffusivity and Motor Functional Measure scores (r=-0.338, p=0.022). Regarding volumetric analyses, there was volumetric reduction of both left thalamus and cerebellar cortex in the patient group. Dystrophinopathies are characterized by fornix, thalamus, and cerebellar cortex damage. Such structural signature helps us to understand some phenotypic traits in this disease.

Health Effects of Particulate Uranium Exposure.

Uranium contamination has become a nonnegligible global health problem. Inhalation of particulate uranium is one of the predominant routes of occupational and environmental exposure. Uranium particle is a complex two-phase flow of matter that is both particulate and flowable. This particular physicochemical property may alter its biological activity. Epidemiological studies from occupationally exposed populations in the uranium industry have concluded that there is a possible association between lung cancer risk and uranium exposure, while the evidence for the risk of other tumors is not sufficient. The toxicological effects of particulate uranium exposure to animals have been shown in laboratory tests to focus on respiratory and central nervous system damage. Fibrosis and tumors can occur in the lung tissue of the respiratory tract. Uranium particles can also induce a concentration-dependent increase in cytotoxicity, targeting mitochondria. The understanding of the health risks and potential toxicological mechanisms of particulate uranium contamination is still at a preliminary stage. The diversity of particle parameters has limited the in-depth exploration. This review summarizes the current evidence on the toxicology of particulate uranium and highlights the knowledge gaps and research prospects.

BLOOD AND CEREBROSPINAL FLUID HIV LOAD INPATIENTS WITH HIV-ASSOCIATED NEUROLOGICAL DISORDERS

Relevance. The issues of replication and concentration of the human immunodeficiency virus (HIV) in various tissues and body fluids remain insufficiently studied. Solving this problem is hindered by the lack of simple, cheap and accessible methods for quantitative determination of HIV in various tissue samples.&#x0D; Objective is to establish a relationship between the presence of HIV-associated damage of the central nervous system (CNS), the number of CD4+ lymphocytes in the blood, and the level of HIV load in blood plasma and cerebrospinal fluid. The difference between the level of HIV viral load in different tissues and biological fluids may reflect the formation of several independent reservoirs of HIV replication in the human body.&#x0D; Materials and methods. 87 patients with HIV infection with clinical signs of central nervous system damage who had no experience of taking antiretroviral drugs (ARVP) were examined. Paired samples of blood and cerebrospinal fluid were analyzed to determine the level of viral load in both biological fluids, as well as the number of CD4+ lymphocytes in the blood.&#x0D; Results. It was established that the patient's presence of clinical signs of CNS damage was reliably correlated with the level of HIV load in the cerebrospinal fluid (logistic regression, P&lt;0.001) and was not associated with the content of CD4+ lymphocytes or the level of HIV load in the blood (logistic regression, P &gt;0.05).&#x0D; The level of HIV load in the cerebrospinal fluid (CSF) was on average 1.5 lg RNA copies/ml higher (P&lt;0.001) in patients with neurological disorders despite the fact that the mean CD4+-lymphocyte count and HIV load in blood in both groups of patients did not differ. The difference between the HIV load in blood and cerebrospinal fluid of patients with neurological disorders was only 0.8 lg RNA copies/ml.&#x0D; Despite the similar indicators of the content of CD4+ lymphocytes and the amount of HIV in the blood, in HIV-infected patients with clinical signs of CNS damage, the level of HIV load in CSF is 1.5 lg RNA copies/ml higher, compared with patients without symptoms of CNS dysfunction (P &lt;0.001). The difference between HIV load in blood and cerebrospinal fluid in the presence of neurocognitive disorders was reduced to 0.7 lg RNA copies/ml compared to 1.8 lg RNA copies/ml in the group of individuals without signs of CNS damage. The presence of HIV-associated damage to the central nervous system is not statistically related to the content of CD4+ lymphocytes or the level of HIV load in the blood.&#x0D; Statistical analysis showed that a CSF HIV load equal to or greater than 4.00 lg RNA copies/mL (10,000 RNA copies/mL) indicated a significant likelihood of HIV-associated CNS involvement in patients (P&lt;0.001) .&#x0D; Conclusion. The method of determining the level of HIV load in cerebrospinal fluid samples can be used to optimize the diagnostic algorithm of HIV-associated lesions of the central nervous system, differential diagnosis with neurocognitive disorders of non-infectious etiology. The threshold for making a clinical decision is the level of HIV load in the CSF sample, which is equal to or exceeds 4.00 lg RNA copies/ml, which indicates a significant probability of the presence of an HIV-associated lesion of the CNS in the patient.

Aberrant autophagy in lysosomal storage disorders marked by a lysosomal SNARE protein shortage due to suppression of endocytosis.

Lysosomal storage disorders (LSDs) are inherited metabolic diseases caused by genetic defects in lysosomal enzymes or related factors. LSDs are associated with excessive accumulation of natural substrates in lysosomes leading to central nervous system and peripheral tissue damage. Abnormal autophagy is also involved in pathogenesis, although the underlying mechanisms remain unclear. We demonstrated that impairment of lysosome-autophagosome fusion is due to suppressed endocytosis in LSDs. The fusion was reduced in several LSD cells and the brains of LSD model mice, suggesting that the completion of autophagy is suppressed by the accumulation of substrates. In this brain, the expression of the soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) proteins, VAMP8 and Syntaxin7, was decreased on the lysosomal surface but not intracellular. This aberrant autophagy preceded the development of pathological phenotypes in LSD-model mice. Furthermore, the enzyme deficiency leading to the substrate accumulation could suppress endocytosis, and the inhibited endocytosis decreased SNARE proteins localized on lysosomes. These findings suggest that the shortage of SNARE proteins on lysosomes is one of the reasons for the impairment of lysosome-autophagosome fusion in LSD cells. Defects in lysosomal enzyme activity suppress endocytosis and decrease the supply of intracellular SNARE proteins recruited to lysosomes. This shortage of lysosomal SNARE proteins impairs lysosome-autophagosome fusion in lysosomal storage disorders.