[Assessment of the efficacy and safety of alemtuzumab in patients with highly active relapsing-remitting multiple sclerosis in Russian population]. / Otsenka effektivnosti i bezopasnosti alemtuzumaba u patsientov s vysokoaktivnym techeniem rasseyannogo skleroza v rossiiskoi populyatsii.

OBJECTIVE: To evaluate the severity and frequency of infusion reactions (IR) in patients with highly active relapsing-remitting multiple sclerosis (MS) In Russian population receiving alemtuzumab therapy. MATERIAL AND METHODS: In retrospective study, we analyzed data from 50 patients with highly active relapsing-remitting multiple sclerosis (MS) from six Regional MS Centers in the Russian Federation who received two courses of alemtuzumab between 2018 and 2022. RESULTS: Among all IRs, the most frequently reported were hives-like rashes, which were registered in 27 people, mostly of mild severity (70.6%). Headaches were the second most common IR, observed in 17 patients (34%). When comparing the group of patients who underwent music therapy (MT) with those who received alemtuzumab therapy without MT, no statistically significant difference was found in the frequency and severity of IRs. CONCLUSION: All patients experienced IRs of varying degrees of severity. A decrease in the score on the EDSS disability scale was noted. MT did not affect the occurrence or severity of IRs.

LIM-kinase 1 effects on memory abilities and male courtship song in Drosophila depend on the neuronal type.

The signal pathway of actin remodeling, including LIM-kinase 1 (LIMK1) and its substrate cofilin, regulates multiple processes in neurons of vertebrates and invertebrates. Drosophila melanogaster is widely used as a model object for studying mechanisms of memory formation, storage, retrieval and forgetting. Previously, active forgetting in Drosophila was investigated in the standard Pavlovian olfactory conditioning paradigm. The role of specific dopaminergic neurons (DAN) and components of the actin remodeling pathway in different forms of forgetting was shown. In our research, we investigated the role of LIMK1 in Drosophila memory and forgetting in the conditioned courtship suppression paradigm (CCSP). In the Drosophila brain, LIMK1 and p-cofilin levels appeared to be low in specific neuropil structures, including the mushroom body (MB) lobes and the central complex. At the same time, LIMK1 was observed in cell bodies, such as DAN clusters regulating memory formation in CCSP. We applied GAL4 × UAS binary system to induce limk1 RNA interference in different types of neurons. The hybrid strain with limk1 interference in MB lobes and glia showed an increase in 3-h short-term memory (STM), without significant effects on long-term memory. limk1 interference in cholinergic neurons (CHN) impaired STM, while its interference in DAN and serotoninergic neurons (SRN) also dramatically impaired the flies' learning ability. By contrast, limk1 interference in fruitless neurons (FRN) resulted in increased 15-60 min STM, indicating a possible LIMK1 role in active forgetting. Males with limk1 interference in CHN and FRN also showed the opposite trends of courtship song parameters changes. Thus, LIMK1 effects on the Drosophila male memory and courtship song appeared to depend on the neuronal type or brain structure.

[Gut microbiota in patients with relapsing-remitting multiple sclerosis]. / Mikrobiota kishechnika u patsientov s remittiruyushchim rasseyannym sklerozom.

Microorganisms in human life play a huge role: in particular, those that coexist with the host organism, inhabiting the skin, upper respiratory tract, external genitalia and especially the digestive tract. The intestinal microbiota, including bacteriome, mycobiome and virome, not only takes part in the digestion process, but also provides the synthesis of a number of vitamins. The intestinal microbiome also serves as the basis for a system of extensive bidirectional neuroendocrine pathways that connect microbiota with various regions of the central nervous system, the hypothalamic-pituitary-adrenal system, and the peripheral parts of the autonomic nervous system. This system of connections has got the name of gut-brain axis and has attracted close attention of scientists over the past two decades, since a targeted impact on the intestinal flora is potentially capable of changing the nature of nervous system regulatory influences on the whole body. It is especially important to study patterns of functioning of the gut-brain axis in patients with the nervous system pathology, namely neurodegenerative and demyelinating diseases. Methods for their treatment continue to improve, and perhaps the correction of the gut microbiotic composition will serve as an additional therapeutic approach. The review article describes current views on the role of the intestinal microbiota, provides the latest data on the composition of bacteriome, mycobiome, and virome in patients with relapsing-remitting multiple sclerosis.

[New opportunities in the treatment of patients with multiple sclerosis (Resolution of the Council of Experts on April 23, 2022, Moscow, JSC «BIOCAD¼)]. / Novye vozmozhnosti v terapii patsientov s rasseyannym sklerozom¼ (Rezolyutsiya soveta ekspertov 23 aprelya 2022 goda, Moskva, AO «BIOKAD¼).

One of the target areas for the development of the Russian pharmaceutical industry at present is the development of next-in-class drugs medicines. These are original, patent-protected drugs that act on known biological targets, improved or modified in structure and mechanism of action compared to existing, successfully proven medicine. The article presents the results of an expert council on the management of patients with multiple sclerosis and the place of new original medicines of the JSC BIOCAD company (SamPEG-IFN-ß1a and divozilimab) in multiple sclerosis therapy algorithm.

[Genome-Wide Analysis of DNA Methylation in Cd4+ T Lymphocytes of Patients with Primary Progressive Multiple Sclerosis Indicates Involvement of This Epigenetic Process in the Disease Immunopathogenesis].

The pathogenesis of multiple sclerosis (MS), a chronic disease of the CNS, includes autoimmune and neurodegenerative components. In most cases, patients develop relapsing-remitting MS (RRMS), while 10-15% of patients develop primary progressive MS (PPMS), which differs from RRMS in the mechanisms of the pathological process, some demographic, and some clinical characteristics. These differences may be explained by the epigenetic regulation of gene expression in PPMS including DNA methylation as one of the key epigenetic processes. The features of DNA methylation in various cell populations in PPMS patients remain understudied. The goal of this study is to identify differentially methylated CpG sites (DMSs) of the genome of CD4+ T lymphocytes, which characterize PPMS. The study included eight treatment-naive PPMS patients and eight healthy controls. Genome-wide analysis of DNA methylation of CD4+ T lymphocytes was performed using high-density DNA microarrays. We have identified 108 DMSs, which distinguish PPMS patients from healthy controls. In PPMS patients 81% of the DMSs are hypermethylated. More than a half of the identified DMSs are located in known genes in CpG islands and adjacent regions, which indicates a high functional significance of these DMSs in PPMS development. Analysis of the overrepresentation of DMS-containing genes in the main biological processes demonstrates their involvement in the regulation of cell adhesion to the extracellular matrix and the development of the immune response, i.e., antigen processing and presentation, and development of the immune system. Genome-wide analysis of DNA methylation in CD4+ T lymphocytes of PPMS patients indicates the involvement of this epigenetic process in the immunopathogenesis of the disease. These results may help better understand the pathogenesis of this severe form of MS.

A New In Vitro Blood Hyperviscosity Model.

We developed a model of blood hyperviscosity avoiding extreme impact on the blood. The model shows reproducibility in rat blood under common storage conditions (4±1°C; stabilization with citrate-phosphate-glucose additive solution). Storage of rat blood under these condition leads to impairment of its rheological properties, which manifested in an increase in blood viscosity in a wide range of shear rates (3-300 sec-1). An increase in blood viscosity appeared the first day of storage and reached a maximum on the third day. During further 11-day storage, the blood viscosity did not change significantly. A hybrid macromolecular compound O-(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propanoyl)-(1→6)-α-D-glucan improved the hemorheological properties during storage. The most pronounced effect was observed on the third day of storage and manifested in a decrease in blood viscosity in the range of shear rates of 50-300 sec-1. Thus, storage of rat blood with citrate-phosphate-glucose additive solution for 3 days at 4±1°C reproduces the phenomenon of blood hyperviscosity; this model can be used to screen agents with hemorheological activity.

Parent-of-origin effects on nuclear chromatin organization and behavior in a Drosophila model for Williams-Beuren Syndrome.

Prognosis of neuropsychiatric disorders in progeny requires consideration of individual (1) parent-of-origin effects (POEs) relying on (2) the nerve cell nuclear 3D chromatin architecture and (3) impact of parent-specific miRNAs. Additionally, the shaping of cognitive phenotypes in parents depends on both learning acquisition and forgetting, or memory erasure. These processes are independent and controlled by different signal cascades: the first is cAMPdependent, the second relies on actin remodeling by small GTPase Rac1 - LIMK1 (LIM-kinase 1). Simple experimental model systems such as Drosophila help probe the causes and consequences leading to human neurocognitive pathologies. Recently, we have developed a Drosophila model for Williams-Beuren Syndrome (WBS): a mutant agnts3 of the agnostic locus (X:11AB) harboring the dlimk1 gene. The agnts3 mutation drastically increases the frequency of ectopic contacts (FEC) in specific regions of intercalary heterochromatin, suppresses learning/memory and affects locomotion. As is shown in this study, the polytene X chromosome bands in reciprocal hybrids between agnts3 and the wild type strain Berlin are heterogeneous in modes of FEC regulation depending either on maternal or paternal gene origin. Bioinformatic analysis reveals that FEC between X:11AB and the other X chromosome bands correlates with the occurrence of short (~30 bp) identical DNA fragments partly homologous to Drosophila 372-bp satellite DNA repeat. Although learning acquisition in a conditioned courtship suppression paradigm is similar in hybrids, the middle-term memory formation shows patroclinic inheritance. Seemingly, this depends on changes in miR-974 expression. Several parameters of locomotion demonstrate heterosis. Our data indicate that the agnts3 locus is capable of trans-regulating gene activity via POEs on the chromatin nuclear organization, thereby affecting behavior.

Genome Analysis of the Probiotic Strain Enterococcus faecium Ef79OSAU.

We report here the draft genome sequence of Enterococcus faecium strain Ef79OSAU, which was isolated from swine feces. The characteristics of strain Ef79OSAU reveal the absence of pathogenicity factors, a wide range of antimicrobial activity in vitro, and antilisteriosis activity in vivo. Analysis of the E. faecium Ef79OSAU genome revealed a cluster of genes encoding enterocin A without genetic determinants of pathogenicity.

[New tools for early detection of multiple sclerosis progression: MSProDiscuss questionnaire]. / Novye instrumenty dlya rannego vyyavleniya progressirovaniya rasseyannogo skleroza. Oprosnik MSProDiscuss.

Diagnosis of secondary progressive multiple sclerosis (SPMS) is based on a history of gradual worsening of neurological symptoms within 6-12 months without exacerbations following an initial relapsing-remitting (RRMS) disease course. In the absence of reliable MRI, immunological and clinical markers, it is hardly possible to achieve objectivity in determining the transition of MS to a progressive stage. This often leads to a long period of diagnostic uncertainty, which prevents timely therapeutic decisions. Physicians expressed an unmet need for a tool that could be used in routine clinical practice to assess the risks of progression to SPMS quickly and reliably, in an easy-to-interpret output for a joint discussion with the patient. From a wide range of disease symptoms and lifestyle factors reflecting the progression to SPMS and obtained by analysis of large clinical data (3294 cases) and a survey of patients and specialists, significant were identified and ranked by categories according to combined expert opinion. A mathematical model was developed and validated, and an electronic version of the MSProDiscuss questionnaire created. Test sensitivity for SPMS diagnosis is 0.82, specificity 0.84, interrater reliability 0.95. Median time for completion of the questionnaire was 2.16 minutes per patient. Physicians of the Russian Federation who used the questionnaire confirmed its high feasibility. Thus, the methodology of the questionnaire development based on the combined opinion of patients and physicians, along with the large clinical data, made it possible to obtain high sensitivity, specificity and reproducibility of the test and takes little time with a clear output. MSProDiscuss may be useful not only in the differential diagnosis of RRMS and SPMS, but also to determine the risks of progression to SPMS, which is of great clinical importance.

[Diagnosis and prediction of the course of primary open-angle glaucoma by the level of local cytokines]. / Diagnostika i prognozirovanie pervichnoi otkrytougol'noi glaukomy po urovnyu mestnykh tsitokinov.

Glaucoma is the leading cause of irreversible blindness in all countries and is expected to increase in patients with this pathology in the coming years. Currently, the development of the disease is associated with a change in the interleukin profile of the lacrimal fluid, but the diagnostic significance of interleukins has not been sufficiently studied. PURPOSE: To determine the diagnostic significance of interleukins at the local level to improve the diagnosis and prognosis of glaucoma. MATERIAL AND METHODS: The study examined the content of interleukins in the lacrimal fluid of 109 patients with stage II glaucoma and 52 healthy individuals by sandwich-variant of enzyme-linked immunosorbent assay (ELISA) with calculation of the information content of immune parameters. RESULTS: The study has established high diagnostic significance for the verification of glaucoma IL-2, IL-17, IL-8, which is proposed to be used in laboratory diagnosis and prognosis of the disease. CONCLUSION: The created regression model provides high-accuracy prediction of the course of glaucoma progression with increasing IL-2, IL-17, IL-8.

[Updated recommendations of the Council of Experts on the use and safety of alemtuzumab (Lemtrada)]. / Obnovlennye rekomendatsii soveta ekspertov po primeneniyu i obespecheniyu bezopasnosti terapii preparatom alemtuzumab (Lemtrada).

Alemtuzumab (Lemtrada) is a recombinant humanized IgG1 kappa monoclonal antibody to the surface cell glycoprotein, a CD52 differentiation cluster. The drug is approved for use in more than 65 countries, including the Russian Federation. The drug is one of the most effective methods of treating patients with aggressive multiple sclerosis, but the risk management plan should be followed. The safety profile of the drug includes infusion-associated reactions, thyroid dysfunction, immune cytopenia, acute cardiovascular events, infections, and other autoimmune diseases. This publication provides updated practical recommendations for the use of the drug and ensuring the safety of patients treated with alemtuzumab.

[The use of alemtuzumab after non-selective immunosuppression in a patient with highly active rapidly progressive remitting multiple sclerosis]. / Primenenie preparata alemtuzumab posle neselektivnoi immunosupressii u bol'nogo vysokoaktivnym bystroprogressiruiushchim remittiruiushchim rasseiannym sklerozom.

This article presents a clinical case of a patient with aggressive multiple sclerosis treated with alemtuzumab after non-selective immunosuppression.

[Variability of the MIR196A2 Gene as a Risk Factor in Primary-Progressive Multiple Sclerosis Development].

Multiple sclerosis is a chronic disease of the central nervous system, combining in its pathogenesis both autoimmune and neurodegenerative components, and is characterized by a highly heterogeneous clinical phenotype. Genetic susceptibility to the development of the most common relapsing-remitting course of the disease is extensively studied, while the genetic architecture of the aggressive primary progressive course of multiple sclerosis remains poorly understood. We analyzed the association of polymorphic variants in miRNA genes MIR146A, MIR196A2, and MIR499A with the risk of primary progressive multiple sclerosis one by one and in biallelic combinations with variants of immune-related genes; the analysis was performed in comparison with healthy individuals and with relapsing-remitting multiple sclerosis patients. The allele MIR196A2*C was useful in discriminating between two main courses of multiple sclerosis, one by one and in combination with alleles of the IFNAR2, IL7RA, IL6, PVT1, CD86, CCL5, and PSMB9 genes. The data presented in the current work may be used for the construction of a biomarker panel, to differentiate primary progressive and relapsing-remitting courses of multiple sclerosis on the initial stages of the disease.

[Comorbid pathology of the cardiovascular system in young patients with relapsing-remitting multiple sclerosis]. / Komorbidnaia patologiia serdechno-sosudistoi sistemy u molodykh patsientov s remittiruiushchim techeniem rasseiannogo skleroza.

AIM: To study the state of the cardiovascular system and peripheral microcirculation in young patients with relapsing-remitting multiple sclerosis (MS). MATERIAL AND METHODS: The study included 45 MS patients (17 men and 28 women, age 28 [24; 32] years, disease duration 5.5 [2; 7] years). The control group included healthy controls (age 30 [25; 33] years). Neurological and cardiologic examinations included 24-hour Holter ECG monitoring and 24-hour blood pressure monitoring with determination of the daily arterial vascular stiffness, echocardiography, laser doppler flowmetry followed by an occlusive test to assess the state of microvasculation, levels of serum vascular cellular adhesion molecule-1 (VCAM-1). RESULTS: In MS group, the results of 24-hour blood pressure monitoring showed that the variability of systolic blood pressure and diastolic blood pressure during daytime hours was reduced compared to the control group (p<0.026 and p<0.002, respectively). The indicators of daily arterial stiffness in MS group were significantly increased (p<0.001). According to the results of Holter ECG monitoring, no heart rhythm disorder was detected in both groups, except an increase in the number of supraventricular extrasystoles in MS patients compared to the control group (p<0.005). There were no between group differences in echocardiography indicators. The level of VCAM-1 was significantly increased in MS group compared to controls (p<0.001). CONCLUSION: Young MS patients are at risk of cardiovascular diseases associated with the variability of blood pressure and indexes of daily arterial vascular stiffness.

[The efficacy and safety of siponimod in the Russian population of patients with secondary progressive multiple sclerosis]. / Éffektivnost' i bezopasnost' siponimoda u patsientov s vtorichno-progressiruiushchim rasseiannym sklerozom v rossiiskoi populiatsii.

AIM: To study the efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis (SPMS) in the Russian population of the EXPAND study. MATERIAL AND METHODS: Ninety-four patients with SPMS from Russia were included in the analysis. Sixty-three patients received siponimod and 31 patients received placebo. The primary endpoint of the study was time to 3-month confirmed disability progression (3m-CDP) events, other clinical and radiological endpoints were also evaluated. RESULTS: The siponimod group showed a 54% reduction in the risk of 3m-CDP compared with the placebo group (p=0.0334). Secondary endpoints also showed the advantage of the drug over placebo. In the siponimod group, mild adverse events associated with impaired liver function, as well as arterial hypertension, were more common. No patient left the study due to an adverse event. CONCLUSION: The use of siponimod in patients with SPMS in the Russian population reduced the risk of disability progression. Siponimod showed a favorable safety profile.

[Radiologically isolated syndrome as a possible preclinical stage of primary-progressive multiple sclerosis]. / Radiologicheski izolirovannyi sindrom - vozmozhnaia doklinicheskaia stadiia pervichno-progressiruiushchego rasseiannogo skleroza.

The article presents a clinical case-report of transformation of radiologically isolated syndrome (RIS) to primary-progressive multiple sclerosis (PPMS). It also provides a review of international and Russian data on the comparison of clinical and MRI characteristics of PPMS with relapsing-remitting multiple sclerosis and secondary-progressive multiple sclerosis and the review of the current data on the risks of transition of RIS to PPMS.

[The improvement of quality of life of patients with multiple sclerosis over 15-year period]. / Uluchshenie pokazatelei kachestva zhizni bol'nykh rasseiannym sklerozom za 15-letnii period.

In this article, the authors compared the results of the studies on quality of life (SF-36 questionnaire) of large groups of patients with multiple sclerosis conducted in 2000-2003 and 2012-2016 years.

[Primary-progressive multiple sclerosis in Russia: a medical-sociological study involving patients and neurologists]. / Pervichno-progressiruiushchii rasseiannyi skleroz v Rossii: mediko-sotsiologicheskoe issledovanie s uchastiem patsientov i nevrologov.

The main results of a medical-sociological study aimed at the evaluation of the level of satisfaction with treatment in patients with primary progressive multiple sclerosis (PPMS) are presented. The survey was conducted in 19 regions of the Russian Federation and involved 437 patients with confirmed diagnosis of PPMS and 80 neurologists specialized in multiple sclerosis. The research was carried out by the All-Russian Public Organization of Disabled People with Multiple Sclerosis with the participation of the Russian Committee for Treatment and Research in Multiple Sclerosis. This is the first medical-sociological study in the Russian Federation involving patients with PPMS and neurologists. The study revealed typical medical and social problems patients with PPMS faced. A significant decrease in quality-of-life of PPMS patients was shown.

[Polymorphic variants of the immune response genes as risk factors for primary progressive multiple sclerosis]. / Polimorfnye varianty genov immunnogo otveta kak faktory riska razvitiia pervichno-progressiruiushchego rasseiannogo skleroza.

AIM: To analyze the involvement of immune response genes in the pathogenesis of primary progressive multiple sclerosis (PPMS). MATERIAL AND METHODS: This multicenter study included 111 patients with PPMS from the Russian ethnic group. The association of PPMS with genes of immune system was analyzed by the study of polymorphic variants of genes of cytokines and genes of antigen-presenting cells. RESULTS AND CONCLUSION: The genotypes of IL-4 (rs2243250)*C/C and CLEC16A (rs6498169)*G/G were associated with PPMS in Russians. The association between the HLA-DRB1*15 and PPMS found out in other populations was confirmed in Russians.

[Atypical multiple sclerosis - Balo's concentric sclerosis: two case-reports and a review]. / Atipichnyi rasseiannyi skleroz - kontsentricheskii skleroz Balo: dva klinicheskikh nabliudeniia i obzor.

This article presents two clinical cases of patients diagnosed with Balo's concentric sclerosis. Distinctive features of the pathogenesis in the aspect of differential diagnosis from other forms of multiple sclerosis and possible treatment are discussed.