Central Nervous System In Patients Research Articles

GM-CSF and CXCR4 define a T helper cell signature in multiple sclerosis.

Cytokine dysregulation is a central driver of chronic inflammatory diseases such as multiple sclerosis (MS). Here we sought to determine the characteristic cellular and cytokine polarization profile in patients with relapsing-remitting multiple sclerosis (RRMS) by high-dimensional single-cell mass cytometry (CyTOF). Using a combination of neural network-based representation learning algorithms, we identified an expanded T helper cell subset in MS patients, characterized by the expression of GM-CSF and the C-X-C chemokine receptor type 4. This cellular signature, which includes expression of very late antigen 4 (VLA4) in peripheral blood, was also enriched in the central nervous system of RRMS patients. In independent validation cohorts, we confirmed that this cell population is increased in MS patients compared to other inflammatory and non-inflammatory conditions. Lastly, we also found the population to be reduced under effective disease-modifying therapy, suggesting that the identified T cell profile represents a specific therapeutic target in MS.

A High-dose Pharmacokinetic Study of a New IgG4 Monoclonal Antibody Temelimab/GNbAC1 Antagonist of an Endogenous Retroviral Protein pHERV-W Env

PurposeTemelimab/GNbAC1 is a humanized immunoglobulin G4 monoclonal antibody antagonist of the human endogenous retrovirus W envelope protein, which is associated with multiple sclerosis (MS) pathophysiology and possibly with other autoimmune disorders. Human endogenous retrovirus W envelope protein is expressed in the central nervous system of patients with MS, and sufficient amount of temelimab must reach the target. The safety of very high dosages of temelimab should be tested to support further clinical trials in MS. MethodsThis randomized, placebo-controlled, dose-escalation study evaluated the safety and pharmacokinetic profile of temelimab in 24 healthy volunteers after a single intravenous infusion at doses of 36, 60, 85, and 110 mg/kg administered sequentially. FindingsTemelimab was well tolerated, with no particular adverse drug reactions at any dose. The maximal dose of 110 mg/kg could be administered, and no antidrug antibodies were induced. After administration of 36–110 mg/kg, mean temelimab Cmax increased from 859 to 2450 μg/mL, and AUC values increased from 319,900 to 1,030,000 μg·h/mL. There was an approximate dose-proportional increase in exposure, similar to observations at lower doses. ImplicationsThe favorable data in terms of safety and pharmacokinetic variables support temelimab use at high doses in future MS trials to optimally neutralize the temelimab target in the central nervous system. ClinicalTrials.gov identifier: NCT03574428.

Evaluation and extension of the two-site, two-step model for binding and activation of the chemokine receptor CCR1

Interactions between secreted immune proteins called chemokines and their cognate G protein-coupled receptors regulate the trafficking of leukocytes in inflammatory responses. The two-site, two-step model describes these interactions. It involves initial binding of the chemokine N-loop/β3 region to the receptor's N-terminal region and subsequent insertion of the chemokine N-terminal region into the transmembrane helical bundle of the receptor concurrent with receptor activation. Here, we test aspects of this model with C-C motif chemokine receptor 1 (CCR1) and several chemokine ligands. First, we compared the chemokine-binding affinities of CCR1 with those of peptides corresponding to the CCR1 N-terminal region. Relatively low affinities of the peptides and poor correlations between CCR1 and peptide affinities indicated that other regions of the receptor may contribute to binding affinity. Second, we evaluated the contributions of the two CCR1-interacting regions of the cognate chemokine ligand CCL7 (formerly monocyte chemoattractant protein-3 (MCP-3)) using chimeras between CCL7 and the non-cognate ligand CCL2 (formerly MCP-1). The results revealed that the chemokine N-terminal region contributes significantly to binding affinity but that differences in binding affinity do not completely account for differences in receptor activation. On the basis of these observations, we propose an elaboration of the two-site, two-step model-the "three-step" model-in which initial interactions of the first site result in low-affinity, nonspecific binding; rate-limiting engagement of the second site enables high-affinity, specific binding; and subsequent conformational rearrangement gives rise to receptor activation.

Functional MRI reveals effects of high intraocular pressure on central nervous system in high-tension glaucoma patients.

To evaluate the effects of high intraocular pressure (IOP) on central nervous system in patients with high-tension glaucoma (HTG) by using resting-state functional magnetic resonance imaging (rs-fMRI). Thirty-six patients with HTG and twenty age- and gender-matched healthy controls (HCs) were recruited and underwent IOP measurement and rs-fMRI scan. The whole brain regional homogeneity (ReHo) value was calculated among the enrolled subjects. Two-sample t tests with permutation test and threshold-free cluster enhancement was performed between HTG group and HCs. Correlation analyses between IOP and ReHo values were conducted. Compared with HCs, HTG group showed increased ReHo values in the left lobule 8 of cerebellar hemisphere, left lobule 4 and 5 of cerebellar hemisphere and left fusiform gyrus (FG) (p<0.05). HTG group showed decreased ReHo value in the left middle frontal gyrus (MFG) (p<0.05). Intraocular pressure of the left eye in HTG group experienced a significant positive correlation with ReHo value of the left FG (r=0.370, p=0.026), IOP of the right eye in HTG group showed a significant negative correlation with ReHo value in the left MFG (r=-0.421, p=0.011). Resting-state fMRI ReHo analyses associated elevated IOP with abnormal regional activity in several brain regions related to higher visual function and visual memory consolidation. High-tension glaucoma patients also showed diminished integration of visual information and cerebellar function. These results may provide imaging support for pathophysiological research of HTG and may reveal new targets for the accurate treatment of HTG.

Peripheral adaptive immunity of the triple transgenic mouse model of Alzheimer\u2019s disease

BackgroundImmunologic abnormalities have been described in peripheral blood and central nervous system of patients suffering from Alzheimer’s disease (AD), yet their role in the pathogenesis still remains poorly defined.Aim and methodsWe used the triple transgenic mouse model (3xTg-AD) to reproduce Aβ (amyloid plaques) and tau (neurofibrillary tangles) neuropathologies. We analyzed important features of the adaptive immune system in serum, primary (bone marrow) as well as secondary (spleen) lymphoid organs of 12-month-old 3xTg-AD mice using flow cytometry and ELISPOT. We further investigated serum cytokines of 9- and 13-month-old 3xTg-AD mice using multiplex ELISA. Results were compared to age-matched non-transgenic controls (NTg).ResultsIn the bone marrow of 12-month-old 3xTg-AD mice, we detected decreased proportions of short-term reconstituting hematopoietic stem cells (0.58-fold, P = 0.0116), while lymphocyte, granulocyte, and monocyte populations remained unchanged. Our results also point to increased activation of both B and T lymphocytes. Indeed, we report elevated levels of plasma cells in bone marrow (1.3-fold, P = 0.0405) along with a 5.4-fold rise in serum IgG concentration (P < 0.0001) in 3xTg-AD animals. Furthermore, higher levels of interleukin (IL)-2 were detected in serum of 9- and 13-month-old 3xTg-AD mice (P = 0.0018). Along with increased concentrations of IL-17 (P = 0.0115) and granulocyte-macrophage colony-stimulating factor (P = 0.0085), these data support helper T lymphocyte activation with Th17 polarization.ConclusionCollectively, these results suggest that the 3xTg-AD model mimics modifications of the adaptive immunity changes previously observed in human AD patients and underscore the activation of both valuable and harmful pathways of immunity in AD.

Immune Cell Activation in the Cerebrospinal Fluid of Patients With Parkinson's Disease.

Background: Parkinson's disease (PD) is a common neurodegenerative disorder. The contribution of the immune system to its pathogenesis remains incompletely understood.Methods: In this study, we performed comprehensive immune cell profiling in the cerebrospinal fluid (CSF) and peripheral blood (PB) of PD patients. Ten PD patients were diagnosed according to brain bank criteria and underwent detailed clinical examination, magnetic resonance imaging, PB and CSF immune cell profiling by multiparameter flow cytometry, and cytokine and chemokine measurements by bead-based arrays. Thirteen healthy elderly volunteers served as control population.Results: The proportions of activated T-lymphocytes and non-classical monocytes in the CSF were increased in patients with PD compared to the control group. In accordance, we found increased levels of the pro-inflammatory cytokines IL-2, IL-6 and TNFα and of the monocyte chemoattractant protein 1 (MCP-1) in the CSF of the included PD patients.Conclusions: Our data provide novel evidence for a response of the innate and adaptive immune system in the central nervous system of patients with PD.

Therapeutic tactics in the hypothalamic syndrome of puberty in girls.

Hypothalamic syndrome of puberty (HSP) is a pathological symptom complex that occurs as a result of dysfunction of hypothalamus, pituitary gland and other endocrine glands during puberty. Purpose – to improve the therapeutic tactics in patients with HSP based on the results of study of the clinical course of the disease, the state of the nervous and endocrine systems. The study included 125 patients aged 11-17 years with HSP, divided into two clinical groups: 50 patients aged 11-14 years and 75 girls aged 15-17 years. The examination included the collection of anamnesis, anthropometric, general clinical and gynecological examination, the study of hormonal profile, lipid and carbohydrate metabolism, instrumental studies, consultations of a neurologist, endocrinologist. It was found that the formation and course of HSP in girls during puberty occurs against a background of perinatal hypoxic involvement of the central nervous system, early obesity, viral loads, disorders of menstrual function, increased secretion of prolactin, androgens, cortisol and reduced level of estradiol. Neurofunctional research methods confirmed the functional nature of changes in the central nervous system in patients with hypothalamic syndrome of puberty. HSP therapy should be comprehensive and systematic, including normalization of body weight, correction of nutrition, mental and physical activity, sleep, thyroid function, hyperandrogenism, insulin resistance, menstrual cycle. In the follow-up dynamics after 2-3 courses of therapy (on average 6-15 months), restoration of the menstrual cycle was observed in all 25 (100%) patients with secondary amenorrhea and regression of cystic ovarian formations in all 11 (100%) patients. Weight loss was noted in most patients with overweight and obesity in 70 (92.1%) cases.

Performing neurological observations.

Trauma to the brain from injury or illness can cause sustained, raised intracranial pressure. In such patients, neurological observations are a fundamental aspect of nursing care and the ability to make and record such observations accurately is an essential nursing skill. Neurological observations are a collection of information on the function and integrity of a patient's central nervous system-the brain and and spinal cord. This article will discuss the tools used in their observation, including the Glasgow Coma Scale tool, pupillary response, and limb power observations, and provide a 'how-to' guide on neurological observations.

Cerebrospinal Fluid Inflammatory Cytokine Aberrations in Alzheimer's Disease, Parkinson's Disease and Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.

It has been suggested that cytokine-mediated inflammation plays a key role for the onset and/or development of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). However, clinical studies have yielded inconsistent results for the aberrant cytokine levels in circulation of patients with AD, PD, and ALS. Previous studies have used meta-analysis to address the inconsistent data for blood cytokine levels in the patients with AD, PD, and ALS. Here, we performed a systemic review of cerebrospinal fluid inflammatory cytokine data in patients with AD, PD and ALS, and sought to quantitatively summarize the CSF inflammatory cytokine data with a meta-analytical technique. The systematic search from Pubmed and Web of Science identified 71 articles with 2629 patients and 2049 controls for the meta-analysis. Random-effects meta-analysis demonstrated that CSF TGF-β, MCP-1, and YKL-40 levels were significantly elevated in AD patients when compared with controls. In addition, patients with PD had heightened levels of TGF-β1, IL-6, and IL-1β in CSF. Furthermore, G-CSF, IL-2, IL-15, IL-17, MCP-1, MIP-1α, TNF-α, and VEGF levels were significantly increased in patients with ALS as compared with controls. Taken together, these results not only strengthen the clinical evidence that neurodegenerative diseases are accompanied by the increased inflammatory response, but also reveal the unique inflammatory response profile in the central nervous system of patients with AD, PD and ALS. Given the robust associations between some cytokines and neurodegenerative diseases found in this meta-analysis, CSF inflammatory cytokines may be used as biomarkers for these diseases in the future.

Berberine alleviates amyloid β25-35-induced inflammatory response in human neuroblastoma cells by inhibiting proinflammatory factors.

The present study investigated the effect of berberine (BBR) on amyloid β 25-35 (Aβ25-35)-induced inflammatory response in human neuroblastoma cells. To model the inflammatory response observed in the central nervous system of patients with Alzheimer's disease, SH-SY5Y and SK-N-SH neuroblastoma cells were induced by Aβ25-35 (5 µM) for 24 h. Subsequently, cells were treated with BBR or indomethacin for 2 h. The cell survival rate was determined by the MTT assay. The activity of lactate dehydrogenase (LDH) in the cell culture medium was examined by spectrophotometry. The expression levels of inflammatory factors prostaglandin E2 (PGE2) and tumor necrosis factor-α (TNF-α) were determined by ELISA assays. The mRNA and protein expression levels of interleukin (IL)-1β, cyclooxygenase 2 (COX-2) and tumor necrosis factor receptor 1 (TNFR1) were measured by reverse-transcription-quantitative polymerase chain reaction and Western blotting, respectively. The results indicated that, treatment with Aβ25-35 increased the expression levels of PGE2 and TNF-α, increased the activity of LDH, and up-regulated the mRNA and protein expression of COX-2, IL-1β, and TNFR1. Treatment with BBR down-regulated the expression levels of PGE2 and TNF-α, decreased the activity of LDH, and downregulated the mRNA and protein expression of COX-2, IL-1β, and TNFR1. Taken together, the present results suggested that BBR suppressed the inflammatory response induced by Aβ25-35 in neuroblastoma cells. The mechanism of action may be associated with the inhibition of proinflammatory factors.

Exophiala dermatitidis isolates from various sources: using alternative invertebrate host organisms (Caenorhabditis elegans and Galleria mellonella) to determine virulence

Exophiala dermatitidis causes chromoblastomycosis, phaeohyphomycosis and fatal infections of the central nervous system of patients with Asian background. It is also found in respiratory secretions from cystic fibrosis (CF) patients. In this study a variety of E. dermatitidis strains (isolates from Asia, environmental and CF) were characterized in their pathogenicity by survival analyzes using two different invertebrate host organisms, Caenorhabditis elegans and Galleria mellonella. Furthermore, the morphological development of hyphal formation was analyzed. E. dermatitidis exhibited pathogenicity in C. elegans. The virulence varied in a strain-dependent manner, but the nematodes were a limited model to study hyphal formation. Analysis of a melanin-deficient mutant (Mel-3) indicates that melanin plays a role during virulence processes in C. elegans. The strains isolated from Asian patients exhibited significantly higher virulence in G. mellonella compared to strains from other sources. Histological analyzes also revealed a higher potential of invasive hyphal growth in strains isolated from Asian patients. Interestingly, no significant difference was found in virulence between the Mel-3 mutant and their wild type counterpart during infection in G. mellonella. In conclusion, invasive hyphal formation of E. dermatitidis was associated with increased virulence. This work is the basis for future studies concerning E. dermatitidis virulence.

Neuroactive Steroids and Sex-Dimorphic Nervous Damage Induced by Diabetes Mellitus.

Diabetes mellitus is a metabolic disease where improper glycaemic control may induce severe complications in different organs. In this review, we will discuss alterations occurring in peripheral and central nervous system of patients with type 1 (i.e., insulin dependent diabetes mellitus,) or type 2 diabetes (i.e., non-insulin dependent diabetes mellitus), as well as related experimental models. A particular focus will be on the role exerted by neuroactive steroids (i.e., important regulators of nervous functions) in the nervous damage induced by diabetes. Indeed, the nervous levels of these molecules are affected by the pathology and, in agreement, their neuroprotective effects have been reported. Interestingly, the sex is another important variable. As discussed, nervous diabetic complications show sex dimorphic features in term of incidence, functional outcomes and neuroactive steroid levels. Therefore, these features represent an interesting background for possible sex-oriented therapies with neuroactive steroids aimed to counteract nervous damage observed in diabetic pathology.

Assessment of the efficacy of different procedures that remove and disassemble alpha-synuclein, tau and A-beta fibrils from laboratory material and surfaces

α-synuclein fibrillar polymorphs, Tau and Aß 1–42 fibrillar assemblies have been shown to propagate, amplify and trigger the formation of protein deposits reminiscent of those present within the central nervous system of patients developing synucleinopathies, tauopathies and amyloid plaques after injection intracerebrally, intramuscularly, intraperitoneally or within the blood stream of model animals. They are thus hazardous and there is need for decontamination and inactivation procedures for laboratory surfaces and non-disposable material. We assessed the effectiveness of different reagents to clean and disassemble potentially pathogenic assemblies adsorbed on non-disposable materials in laboratories. We show that commercial detergents and SDS are way more suited to detach α-synuclein fibrillar polymorphs, Tau and Aß 1–42 fibrillar assemblies from contaminated surfaces and disassemble the fibrils than methods designed to decrease PrP prion infectivity. Our observations reveal that the choice of the most adapted cleaning procedure for one given protein assembly or fibrillar polymorph should integrate detergent’s cleaning efficiency, material compatibility and capacity to dismantle assemblies. We provide an integrated representation where desorption and neutralization efficacy and surface compatibility are combined to facilitate the choice of the most adapted decontamination procedure. This representation, together with good laboratory practices, contributes to reducing potential health hazards associated to manipulating protein assemblies with prion-like properties.

Spontaneous brain activity and connectivity in female patients with temporomandibular joint synovitis pain: a pilot functional magnetic resonance imaging study

It has been proposed that mechanisms in the central nervous system contribute to the development and maintenance of pain in temporomandibular disorders. In this study, we tested whether spontaneous brain activity and functional connectivity (FC) were altered in patients with temporomandibular joint synovitis pain. A prospective, cross-sectional design was adopted. Each of 8 patients and 10 healthy controls (HCs) underwent 2 sessions of functional magnetic resonance imaging: mouth closed and mouth open (painful for patients). Regional homogeneity (ReHo) was used to measure spontaneous brain activity in each participant. Brain areas with altered ReHo in patients compared with HCs were identified, and their FCs with the rest of the brain was examined and compared. Compared with HCs, patients showed decreased pain-related ReHo in the right anterior insula (rAI). The rAI showed a weaker positive FC with the left middle cingulate cortex (MCC) and a weaker negative FC with the right precuneus in patients compared with HCs. Furthermore, the rAI-MCC FC showed a negative correlation with pain intensity in patients. These results provide evidence supporting altered pain-related spontaneous brain activity and functional connectivity in the central nervous system in patients with temporomandibular joint synovitis pain.

Informed Consent Decision-Making in Deep Brain Stimulation.

Deep brain stimulation (DBS) has proved useful for several movement disorders (Parkinson’s disease, essential tremor, dystonia), in which first and/or second line pharmacological treatments were inefficacious. Initial evidence of DBS efficacy exists for refractory obsessive-compulsive disorder, treatment-resistant major depressive disorder, and impulse control disorders. Ethical concerns have been raised about the use of an invasive surgical approach involving the central nervous system in patients with possible impairment in cognitive functioning and decision-making capacity. Most of the disorders in which DBS has been used might present with alterations in memory, attention, and executive functioning, which may have an impact on the mental capacity to give informed consent to neurosurgery. Depression, anxiety, and compulsivity are also common in DBS candidate disorders, and could also be associated with an impaired capacity to consent to treatment or clinical research. Despite these issues, there is limited empirical knowledge on the decision-making levels of these patients. The possible informed consent issues of DBS will be discussed by focusing on the specific treatable diseases.

Intrathecal activation of the lectin pathway in patients with eosinophilic meningitis by Angiostrongylus cantonensis

Eosinophilic meningitis produced by Angiostrongylus cantonensis is an emerging disease in Western hemisphere. MBL and H‐ and M‐ficolins are starters of the lectin pathway.ObjectiveTo determine if MBL and H‐ and M‐ficolins can be synthesizedin central nervous system in patients suffering from eosinophilic meningitis due to Angiostrongylus cantonensis.Methods19 serum and CSF paired samples were obtained from pediatric patients with the diagnosis of eosinophilic meningitis by Angiostrongylus cantonensis. Cerebrospinal fluid was obtained by lumbar puncture and serum from blood was taken by venopuncture. Serum and CSF was stored frozen in aliquots at −80°C until analysis.The local ethics committee approved this study and all patients' tutors gave informed consent.CSF and serum albumin were quantified by immunochemical nephelometry with kinetic analysis. MBL and H‐ and M‐ficolins were measured by commercial enzyme‐linked immunosorbent assay (ELISA) kit.The MBL reibergram was employed in order to determine if MBL can be synthesized inthecentral nervous system or not. The H‐ and M‐ficolins regressions were employed in order to determine if H‐ and M‐ficolins can be synthesized in the central nervous system or not.Results8 patients do not have dysfunction of blood/CSF barrier and 4 patients have intratecal synthesis of MBL.One patient do not have intrathecal synthesis of H‐ficolin (Figure 2A) and all patients have intrathecal synthesis of M‐ficolin (Figure 2B).ConclusionsIntrathecal activation of the lectin pathway by at least one of the quantified starters in this group of patients with eosinophilic meningitis due to Angiostrongylus cantonensis.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Statе of bioelectric activity of the brain in persons who received acoustic trauma in area of combat actions with a different stage of disorders in the auditory system

Topicality: Providing medical care to patients with combat acoustic trauma remains a topical issue of military medicine. There are works in the literature that show changes in the central nervous system under the influence of intense noise and at acoustic trauma, however, only in individual studies this objective assessment of the functional state of the central nervous system in patients with sensorineural hearing loss is shown as well as the promising use of them. Aim: is to determine the most significant indicators of bioelectric activity of the brain according to the EEG in terms of prediction of the course and ways of co-rejection of sensorineural hearing disorders in persons who have received an acute trauma in the area of fighting. Materials and methods: A group of servicemen with acoustic trauma was examined with the most characteristic, typical forms of audiometric curves – with a downward, precipitous type of the curve, which were divided into three groups depending on the degree of severity of sensorineural deafness. Group 1 – patients with initial non-expressed violations of the function of sound perception in the basal part of the cochlea, group 2 – with a more significant SDP accompanied by violations of speech and supra-vocal audiometry, the 3 groups included patients with severe violations of auditory function, lesions of the mediobasal part of the cochlea, often – with a "break" of perception of tones in the conventional range. A total of 205 patients with acoustic trauma were examined. As a control group, 15 healthy normal people were examined. The EEG study was carried out using the computer electroencephalometry of the firm "DX-System" (Ukraine) according to the generally accepted methodology according to the scheme of electrodes "10-20" Results: In qualitative analysis of electroencephalograms, servicemen with combat acoustic trauma revealed deviations from the norm in the functional state of the central nervous system, expressed in varying degrees, with the most characteristic decreasing of the bioelectric activity of the brain, irritative changes, disorganization and desynchronization of rhythms, more often in the temporal and frontal leads. The most significant changes were in patients with more severe hearing impairment (group 3). These changes indicate signs of severe cortex irritation and deep brain structures in servicemen with acoustic trauma from the combat zone. The analysis of EEG quantitative indicators showed that changes in the bioelectric activity of the cerebral brain in patients with acoustic trauma were manifested by deformation of the basic rhythm with modulation and weakened response to functional loads, especially in the anterior leads. Patients had the significantly (P&lt;0,05) decreased percentage of alfa rhythm in the normal picture of the EEG and the increased representation of beta and delta rhythm, both in the background recording and in the functional loading of photostimulations and hyperventilation . The most significant (P&lt;0,05) changes in bioelectric activity, in comparison with the control group, were observed in individuals 2 and, personally, in 3 groups, with more significant violations of auditory function. We also conducted a comparative analysis of EEG quantitative indicators among the study groups. The results of the research indicate a reliable (P&lt;0,05) difference in the indices in the groups, from the first to the third group there was an increase in the representation of delta, theta and beta rhythm, most in the forward projections, and the decrease in the proportion of alpha rhythm. Moreover, these tendencies were maintained both during the background recording and at the functional loads. Conclusions: Thus, the servicemen with an acoustic trauma revealed objective signs of functional disorders in the cortical and deep structures of the brain. As the auditory function decreases in patients with acoustic trauma and redistribution of the main EEG rhythms in the direction of the growth of manifestations of slow-wave activity on a disorganized background occurs, especially in the frontal and temporal infections. In the subjects we surveyed with severe violations of auditory function, there are significantly more significant changes in the central nervous system than in patients with an initial SDE, which should be taken into account when carrying out treatment and preventive measures aimed at rehabilitation of the victims of combat operations with acoustic trauma.

B cells in multiple sclerosis therapy-A comprehensive review.

For decades, B cells were ignored in multiple sclerosis (MS) pathogenesis, and the disease was always regarded as a T cell-mediated disorder. Recent evidence shows that there is an antigen-driven B-cell response in the central nervous system of patients with MS, and memory B cells/plasma cells are detectable in MS lesions. The striking efficacy of B cell-depleting therapies in reducing the inflammatory activity of the disease highlights that B cells may play more pathogenetic roles than expected. B cells express several unique characteristic markers on their surface, for example, CD19, CD20 molecules, that provide selective targets for monoclonal antibodies. In this respect, several B cell-targeted therapies emerged, including anti-CD20 antibodies (rituximab, ocrelizumab, and ofatumumab), anti-CD19 antibody (inebilizumab), and agents targeting the BAFF/APRIL signaling pathway (atacicept, belimumab, and LY2127399). In this review, we discuss, in detail, the immunobiology of B cells and their protective and destructive roles in MS pathogenesis. In the second part, we list the completed and ongoing clinical trials investigating the safety and efficacy of B cell-related monoclonal antibodies in MS.

Macroscopic and microscopic diversity of missplicing in the central nervous system of patients with myotonic dystrophy type 1.

Myotonic dystrophy type I (DM1) is a multiorgan disease caused by CTG-repeat expansion in the DMPK gene. Sequestration of the splicing factor MBNL1 results in aberrant splicing in many genes in DM1 skeletal muscle, whereas MBNL2 plays a leading role in missplicing in the central nervous system (CNS) of patients with DM1. Splicing misregulation of most MBNL2-regulated genes occurs in the temporal cortex but not in the cerebellum of autopsied patients with DM1. To understand the diversity at macroscopic and microscopic levels in CNS of patients with DM1. Using autopsied brain tissues, we examined alternative splicing ratios of MBNL2-regulated genes and expression levels of potential splicing factors. We found differences in splicing abnormalities among tested regions of the CNS from patients with DM1. In the frontal and temporal cortices and the hippocampus, many genes were aberrantly spliced, but severity differed among the brain regions. By contrast, there were no significant differences in the ratio of splicing variants for most of the genes in the cerebellar cortex and spinal cord between DM1 and control samples. We failed to find any change in the amount of potential factors (MBNL and CUGBP proteins and DMPK mRNA) which explain the modest missplicing in the cerebellum. LASER capture microdissection demonstrated splicing misregulation in the molecular layer of the cerebellum but not in the granular layer. This is the first study to reveal missplicing in a functional cell layer of DM1 and to compare splicing misregulation in a wide region of the CNS using statistical analysis.

ХАРАКТЕРИСТИКА ЦЕРЕБРАЛЬНОГО ТОКСОПЛАЗМОЗУ У ПАЦІЄНТІВ З ВІЛ: РЕТРОСПЕКТИВНИЙ АНАЛІЗ 135 ВИПАДКІВ У ДНІПРОПЕТРОВСЬКОМУ РЕГІОНІ

Від 40 до 70 % хворих на ВІЛ мають неврологічні захворювання. Токсоплазмоз – одна з найчастіших причин уражень головного мозку в пацієнтів із ВІЛ, що часто призводить до летальності.Мета дослідження – визначити та порівняти основні характеристики токсоплазмозу центральної нервової системи у ВІЛ-позитивних пацієнтів, які мали різний результат захворювання (вижили або померли внаслідок хвороби).Матеріали і методи. Проведено ретроспективний когортний аналіз 135 випадків церебрального токсоплазмозу у ВІЛ-позитивних пацієнтів Дніпропетровського регіону за період з 2010 до 2017 року. Наявність токсоплазмозу було підтверджено виявленням ДНК Toxoplasma gondii в спинномозковій рідині, а у померлих хворих дослідженням автопсійного матеріалу. Статистичну обробку результатів дослідження проводили з використанням програм STAT IST ICA v.6.1® і SPSS. Для порівняння показників у групах хворих, які померли та які вижили, визначали відношення шансів (odds ratio – OR) з довірчим інтервалом (95 % CI).Результати досліджень та їх обговорення. У 30 % ВІЛ-позитивних пацієнтів із захворюваннями ЦНС було діагностовано токсоплазмоз. Більшість хворих склали чоловіки – 71 (52,6 %), середній вік становив (37,79±0,64) року. Кількість летальних випадків – 29 (21,5 %). Групи пацієнтів, які вижили або померли, суттєво не відрізнялись за віком (37,47±0,72) проти (38,93±1,46) року (p&gt;0,05) та гендерним складом (чоловіків було 53,8 % проти 48,3 % жінок). Інфікування статевим шляхом мало місце в 40,0 % випадків, через споживання ін’єкційних наркотиків (СІН) – 34,8 %, шлях інфікування був невизначений у 25,2 %. У померлих невизначений шлях інфікування склав 51,7 % проти 17,9 % (р&lt;0,001) пацієнтів, які вижили. У 43 хворих (31,9 %) на церебральний токсоплазмоз ВІЛ-статус було визначено разом із розвитком токсоплазмозу. Частота пізнього виявлення ВІЛ (менше року до маніфестації токсоплазмозу ЦНС) у хворих, які померли, була в 6,49 раза вищою (95 % CI 2,64–15,95), порівняно з тими, які вижили. 76 (56,3 %) пацієнтів мали рівень CD4 менший 50 клітин/мм3, у тому числі серед померлих пацієнтів цей показник був у 1,5 раза вищим – 75,9 % проти 50,9 % (р&lt;0,05) у тих, хто вижив. Медіана CD4 в період розвитку неврологічних захворювань у хворих із токсоплазмозом ЦНС склала 44,5 (IQR 21–100) клітин/мм3, з них у пацієнтів, які померли, – 33 (IQR 15–44) клітин/мм3 проти 52 (IQR 25–106) клітин/мм3 в осіб, які вижили (р&lt;0,05). Медіана вірусного навантаження (Lg ВН) у період розвитку неврологічних симптомів склала 4,96 (IQR 1,60–5,80) копій/мл, а у пацієнтів, які померли, дорівнювала 6,20 (IQR 6,05–6,31) копій/мл і значно перевищувала аналогічний показник у тих, кого виписали з поліпшенням стану, – 4,89 (IQR 1,60–5,72) копій/мл (р&lt;0,05). Серед клінічних симптомів найрозповсюдженішими у пацієнтів із токсоплазмозом ЦНС були: головний біль – у 86 (63,7 %) пацієнтів, запаморочення та порушення координації – у 81 (60,0 %), судоми – в 43 (31,9 %), моно- та геміпарези – у 57 (42,2 %), порушення ЧМН – у 37 (27,4 %), дизартрія – у 27 (20,0 %), когнітивні порушення – у 29 (21,5 %), порушення свідомості – у 14 (10,4 %), порушення зору – в 7 (5,2 %) випадках. У 30 (22,2 %) пацієнтів мало місце поєднання токсоплазмозу з іншими захворюваннями ЦНС. Розвиток ко-інфекції токсоплазмозу з туберкульозом у пацієнтів із летальним наслідком хвороби спостерігався у 4,5 раза частіше (95 % СI 1,42–14,29), ніж у пацієнтів, які вижили (р&lt;0,05). Поширення вірусного інфікування Епштейна–Барр серед померлих було у 4,21 раза більшим (95 % СI 1,11–15,90) (р&lt;0,05).Висновки. Церебральний токсоплазмоз складає 30,0 % усієї ВІЛ-асоційованої інфекційної патології ЦНС в пацієнтів у Дніпропетровському регіоні; у 56,3 % пацієнтів токсоплазмоз діагностують на тлі глибокої імуносупресії, у 21,5 % первиннодіагностований токсоплазмоз закінчується летально. Шанси летального наслідку хвороби не залежить від статі, віку, але значно зростають при відсутності АР Т, кількості CD4 клітин/мм3 менше 50 та наявності ко-інфекцій ЦНС, найвагомішим з яких у плані ризику є туберкульоз ЦНС. Отримані результати важливі для прогнозування перебігу хвороби та виявлення можливих ризиків, для удосконалення профілактичних заходів.