Dynamics of serum levels of TNF-α in a longitudinal follow-up study in 98 patients with juvenile idiopathic arthritis treated with anti-TNF-α biological drugs.

OBJECTIVE: To determine the dynamics of serum levels of TNF-α in patients with juvenile idiopathic arthritis (JIA) treated with anti-TNF-α biological drugs and investigate their association with the disease activity. METHODS: We conducted a single-centre, observational cohort study in 98 patients with JIA (30 boys, 68 girls, mean age 11.3 years) treated with anti-TNF-α biological drugs. Clinical examinations and laboratory assessments of serum levels of TNF-α were performed before starting therapy with biological drug and at 6-month intervals afterwards up to 2.5 years. RESULTS: The analysis of serum levels of TNF-α in relation to the disease activity states showed the highest mean serum levels of TNF-α in patients on etanercept who had low disease activity states and in patients on adalimumab who had inactive disease. The correlation analysis in patients with JIA treated with etanercept or adalimumab showed a weak negative correlation between the serum levels of TNF-α and JADAS10 scores (p = 0.007), (r = - 0.177). CONCLUSION: The assessment of serum levels of TNF-α in children with JIA during treatment with etanercept or adalimumab is not a reliable biomarker of disease activity or immunological remission. Longitudinal measurement of TNF-α has no added clinical value in patients with JIA treated with anti-TNF-α biological drugs. Key Points • There is limited evidence regarding the effect of anti-TNF therapy on serum concentrations of TNF-α in patients with juvenile idiopathic arthritis • Our study showed an increase in the serum level of TNF-α after the initiation of therapy with either etanercept or adalimumab, which was more significant in patients with inactive or low disease activity • Serum TNF-α is most likely not biologically active during therapy with TNF-α inhibitors and therefore not a reliable biomarker of disease activity or immunological remission in patients with juvenile idiopathic arthritis.

[V. N. Vinogradov Faculty Therapy Clinic of Sechenov University: the flagship of the therapeutic service of the Russian Federation. A review].

The history of the Faculty Therapy Clinic of Sechenov University is presented. The stages of the formation of its therapeutic school are discussed. Diagnostic and therapeutic methods first developed and implemented in the clinic are described in detail.

The Synthesis and Transfection Activity of Disulfide Polycationic Amphiphiles.

Some new polycationic amphiphiles containing a disulfide group were synthesized. Cationic liposomes formed from the compounds synthesized and a helper lipid 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine were not toxic for HEK293 and HeLa cells and were highly effective when delivering a fluorescently labeled oligodeoxyribonucleotide. The efficacy of plasmid DNA delivery depended on the cell line and the amphiphile structure, liposomes based on tetracationic amphiphiles being the most effective transfectants. These liposomes can be used for in vitro transfection of eukaryotic cells as well as for further in vivo biological studies.

Preclinical Study of Therapeutic Efficacy of a New Russian Radiopharmaceutical 177Lu-DOTA-PSMA.

The therapeutic efficacy of a Russian radiopharmaceutical 177Lu-DOTA-PSMA was studied in vivo using male BALB/c nu/nu (nude) mice with prostate carcinoma 22Rv1 xenografts by tumor growth inhibition criterion. The mean tumor volumes in mice treated with 177Lu-DOTA-PSMA were significantly lower than in animals of the control group. There were no significant differences in the values of tumor growth inhibition between the groups of animals receiving 3.7 or 7.4 MBq of 177Lu-DOTA-PSMA.

[Editing of Phage Genomes - Recombineering-Assisted SpCas9 Modification of Model Coliphages T7, T5, and T3].

Bacteriophages-viruses that infect bacterial cells - are the most abundant biological entities on Earth. The use of phages in fundamental research and industry requires tools for precise manipulation of their genomes. Yet, compared to bacterial genome engineering, modification of phage genomes is challenging because of the lack of selective markers and thus requires laborious screenings of recombinant/mutated phage variants. The development of the CRISPR-Cas technologies allowed to solve this issue by the implementation of negative selection that eliminates the parental phage genomes. In this manuscript, we summarize current methods of phage genome engineering and their coupling with CRISPR-Cas technologies. We also provide examples of our successful application of these methods for introduction of specific insertions, deletions, and point mutations in the genomes of model Escherichia coli lytic phages T7, T5, and T3.

Model of Morphogenesis with Repelling Signaling.

The paper is devoted to a conceptual model of cell patterning, based on a generalized notion of the epigenetic code of a cell determining its state. We introduce the concept of signaling depending both upon the spatial distance between cells and the distance between their cell states (s-distance); signaling can repel cells in the space of cell states (s-space) or attract them. The influence of different types of repelling signaling on the evolution of cells is considered. Stabilizing signaling, namely a signaling monotonically decreasing with s-distance, causes the restoring of cell states after perturbations; destabilizing signaling, i.e., the one in which the signaling monotonically increases with s-distance, causes the appearance of pairs of cells with alternating cell states (one close to the state conventionally called "head", and another close to the "tail" state). Non-monotonic (in s-space) signaling splits the cells into groups. The model shows that different types of signaling may provide different types of cellular patterns. General principles for applying this model to complex cellular structures are discussed.

[Characterization of genetic polymorphisms associated with neurophysiological processes and analysis of their allele frequency distribution in the Russian population]. / Kharakteristika geneticheskikh polimorfizmov, svyazannykh s neirofiziologicheskimi protsessami, i analiz raspredeleniya chastoty ikh vstrechaemosti v rossiiskoi populyatsii.

OBJECTIVE: This paper presents an analysis of polymorphic gene loci, the products of which are directly involved in the molecular mechanisms of regulation of neurophysiological processes. MATERIAL AND METHODS: The sample of subjects consisted of 128 unrelated males and females living in the European part of Russia. The study assessed the frequency of occurrence of 11 single-nucleotide substitutions located in genes encoding serotonin receptors, ciliary neurotrophic factor, uncoupling protein 2, methylenetetrahydrofolate reductase, methionine synthase, methionine synthase reductase, dipeptidyl carboxypeptidase 1, gamma-coactivator of the receptor activated by the proliferator peroxisome and neurotrophic factor of the brain. Genotyping of the samples was carried out by PCR with fluorescence detection and analysis of the polymorphism of the lengths of restriction fragments. RESULTS: The distribution of polymorphism genotypes corresponded to the Hardy-Weinberg equilibrium with the exception of rs1801133 MTHFR (χ2=5.3088, p=0.0212) in which a decrease in heterozygosity was observed. These studies of minor allele distribution have no statistically significant deviations from the European population, but there are deviations from the Asian, African, and Latin American populations. CONCLUSION: Statistically significant correlations of allele frequencies in the study group with populations from other regions and the studies conducted in them are the basis for the inclusion of selected single-nucleotide polymorphisms in the list of a limited set of molecular genetic markers, which makes it possible to supplement the system of mental health monitoring and improve the professional training of people in extreme professions.

The study protocol: COVID-19 awareness and perception among dentists in the Russian Federation.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) has spread rapidly worldwide since it has been first identified in November 2018. It is transmissible via air droplets from infected individuals. Close contact between dentists and patients has aggravated the pandemic situation in Russia. It is necessary to reduce the risk of spreading COVID-19 during dental appointments by adhering to the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) recommendations. SUBJECTS AND METHODS: Questionnaires were developed to assess levels of COVID-19 infection and preventive measures in private and state-funded dental practices in Moscow and other cities in Russia. Two questionnaires were developed to assess the COVID-19 situation among dental professionals and their patients. The first, for dentists, included four domains: demographic data, signs, and symptoms of COVID-19 experienced by dentists, personal protective measures taken by dentists, and presence or absence of dental practice during the pandemic. For dentists' patients, the second included domains regarding their health status after their dental appointment. 1,500 questionnaires were sent to different cities and regions of Russia; 1,011 questionnaires (67.4%) were returned. We used statistical observation (monitoring) and clustering to analyze the data. The x2 was used to check the significance level. RESULTS: We found a direct relationship between those patients who contracted COVID-19 after dental treatment by those dentists who did not follow recommended measures in the dental clinic. However, patients were less likely to become infected after dental treatment by those dentists who followed the measures, such as the disinfection of surfaces and dental equipment several times a day, the wearing of medical masks by all patients, and the airing of the dental office after each patient for 10 minutes. CONCLUSIONS: Dentists wearing an FFP2 or FFP3 respirator, as well as a sterile disposable microfiber medical gown, prevented their patients from becoming infected with COVID-19 at dental appointments and, as a result, the spread of the virus. A key aspect of this study is its knowledge regarding preventive measures against COVID-19. The findings of this study can potentially help in formulating strategies to reduce the prevalence of COVID-19.

Morphological changes in salivary glands of neonatal rats after intra-abdominal hypertension.

OBJECTIVE: Given the overall prevalence of elevated Intra-abdominal pressure (IAP), along with earlier detection and appropriate therapy of Intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS), a significant reduction in patient morbidity and mortality is currently achieved by modern medicine. This article assesses the long-term degree of salivary gland damage in rats depending on the severity of experimental IAH during the neonatal period. MATERIALS AND METHODS: To simulate IAH, newborn rats, under the control of intravesical manometry, were injected into the abdominal cavity with bulking collagen filler in the amount necessary to create a given level of IAP. RESULTS: As shown by the results obtained, rats exposed to intra-abdominal hypertension for ten days had pathological changes in their salivary glands within 120 days. The severity of sialadenitis revealed a correlation with the severity of IAH. Some rats had individual reactions expressed in relative resistance to their organs' abnormalities under hypoxia. CONCLUSIONS: It was concluded that children with severe IAH history might need the disease prevention of the CNS, kidneys, digestive, and respiratory systems and oral diseases, particularly diseases involving the salivary glands. Future research is supposed to investigate further the IAH effect on various organs and tissues, including the dentofacial system.

[Antibiotic resistance of strains of gram-positive cocci isolated from prostate secretion in men with chronic bacterial prostatitis].

OBJECTIVE: to characterize the antibiotic resistance of gram-positive cocci strains isolated from the prostate secretion in men with chronic bacterial prostatitis at the level of phenotype and genotype. MATERIALS AND METHODS: Bacteria were isolated from the prostate secretion of men of reproductive age (20-45 years) with chronic bacterial prostatitis by conventional bacteriological method. The type of microorganisms was determined by MALDI-TOF mass spectrometry. Resistance to 16 antibiotics of 31 strains of E. faecalis and 91 cultures of coagulase-negative staphylococci (CoNS) was determined by the disk diffusion method. Antibiotic resistance genes (mecA; blaZ; aac(6)- aph (2); ant (4)-Ia; aph (3)-IIIa; gyrA, grlA) were detected using polymerase chain reaction (PCR ) using selected primers. RESULTS: A high resistance of enterococci to antibacterial drugs was revealed: fluoroquinolones, carbapenens, cephalosporins (with the exception of cefoperazone), gentamicin and oxacillin. It has been established that CoNS are characterized by variable antibiotic resistance, while: isolates of S. epidermidis and S. haemolyticus are resistant to all studied fluoroquinolones and carbapenems; S. warneri to carbapenems and the vast majority of studied cephalosporins; S. saprophyticus - to aminoglycosides. Amoxiclav and cefoperazone are characterized by the highest activity against clinical isolates. Using PCR, the presence of genetic determinants of resistance to aminoglycosides and -lactams was established in the isolates, with a predominance of the studied genes in CoNS. CONCLUSION: For effective antibiotic therapy in chronic bacterial prostatitis, it is necessary to conduct regional monitoring of the resistance of microorganisms to antibacterial drugs.

Yersinia pestis Surface Antigens in Reception of Specific Bacteriophages.

The significance of Yersinia pestis surface antigens in adhesiveness to specific bacteriophages has been studied with the use of two methodological approaches. It was shown that Ail protein immobilized on the surface of polystyrene microspheres (but not in the solution), can bind both the Pokrovskaya phage and pseudotuberculous diagnostic phage. YapF autotransporter interacted with both phages in a water-soluble form, but YapF bound to polystyrene microspheres interacted only with the Pokrovskaya phage. An assumption was made that Ail and YapF proteins can be the primary receptors providing non-specific reversible binding to the phages used in this work.

[Characteristics of the pathogenic potential of Escherichia coli isolated from patients with calculous pyelonephritis].

OBJECTIVE: Comparative phenotypic and genetic assessment of the pathogenic potential of E. coli strains isolated from patients with calculous pyelonephritis. MATERIALS AND METHODS: 78 strains of E. coli isolated from urine of patients with calculous pyelonephritis in the acute phase (n=58) and in the remission phase (n=20). Escherichia were investigated for the presence of virulence genes papA, pap EF, papGII; afa, bma E, iutA, fyuA, feoB, kspMTII, usp multiplex PCR using selected primers. Phenotypically determined the ability to biofilm formation, antilysozyme, antihemoglobin, anticytokine, adhesive and sIgA-protease activity E. coli. RESULTS: The virulent potential of Escherichia coli at the pheno- and genotype levels was characterized. In strains of E. coli isolated from the urine of patients in the remission phase, the ability to form biofilms was more often and with high values of the trait; and in strains isolated in relapse - adhesive activity, the ability to inactivate pro- and anti-inflammatory cytokines, antihemoglobin activity, and genes encoding aphimbrial adhesin (afa), responsible for the synthesis of siderophore aerobactin (iutA), transporting bivalent iron (feoB). CONCLUSION: The revealed differences in the pheno- and genotypic profiles between the cultures of Escherichia coli isolated from patients with calculous pyelonephritis in the phases of exacerbation and remission make it possible to differentiate the isolated strain and predict the course of the infectious-inflammatory process.

BIOMECHANICS OF CHANGING THE POSITION OF PERMANENT TEETH WITH EARLY LOSS OF THE FIRST TEMPORARY MOLARS.

Premature removal of baby teeth is one of the main causes of deformation of the dentition. The loss of the first temporal molars is most often reported (39.9±4.8%), which leads to displacement of the teeth bordering on the defect, narrowing and shortening of the dental arch, which then leads to retention of premolars, cutting out permanent canines outside the dental arch, pathology of cutting out permanent molars. The aim of the study was to evaluate the biomechanics of permanent teeth migration in patients who prematurely lost their first temporal molars. An anthropometric study of jaw models and orthopantomograms was conducted in 25 patients (age 7-12 years) who had premature loss of the first temporal molars of the upper and lower jaws (age 7-12 years). Complications were evaluated, regularity was revealed and the biomechanics of permanent teeth displacement as a result of the prolonged absence of temporary molars were determined.

[Сardiac myxoma: challenge in diagnostics. Case report].

Cardiac myxoma is the most common primary benign cardiac tumor (up to 50% of all primary cardiac neoplasms). The implementation of the modern imaging techniques into the clinical practice, particularly, 2D echocardiography, computed tomography and magnetic resonance tomography (MRI) results to the prompt diagnosis of the myxoma. However, the absence of specific clinical features, insufficient awareness of this condition among the physicians along with a rare prevalence, may lead to a misdiagnosis. This case report is notable for the relatively late diagnosis of a giant left atrial myxoma due to a number of circumstances but with successful surgical treatment.

[VACCINE-ASSOCIATED PARALYTIC POLIOMYELITIS IN RUSSIAN FEDERATION DURING THE PERIOD OF CHANGES IN VACCINATION SCHEDULE (2006-2013 yy.)].

The results of virologic testing of clinical materials and epidemiological analysis of vaccine-associated paralytic poliomyelitis (VAPP) cases obtained in 2006-2013 during AFP surveillance are presented. Among the 2976 cases of AFP 30 cases were VAPP. 15 cases were observed in OPV recipients, whereas 15 cases were observed in non-vaccinated contacts. The age of the patients varied from 4 months to 5.5 years (13.6 ± 12.4 months old). Children younger than 1 year constituted 63.3% of the group; boys were dominant (73.3%); 53.3% of children were vaccinated with OPV; the time period between receipt of OPV and onset of palsy was from 2 to 32 days (18.7 ± 8.2). Lower paraparesis was documented in 48.3% of patients; lower monoparesis in 37.9%; upper monoparesis, in 6.9%; tetraparesis with bulbar syndrome, in 6%. The majority of the patients (85.7%) had an unfavorable premorbid status. The violations of the humoral immunity were found in 73.9% cases: CVID (52.9%), hypogammaglobulinemia (41.2%); selective lgA deflciency (5.9%). In 70.6% cases damage to humoral immunity was combined with poor premorbid status. The most frequently observed (76%, p < 0.05) represented the single type of poliovirus--type 2 (44%) and type 3 (32%). All strains were of the vaccine origin, the divergence from the homotypic Sabin strains fell within the region of the gene encoding VPI protein, which did not exceed 0.5% of nucleotide substitutions except vaccine derived poliovirus type 2--multiple recombinant (type 2/type 3/ type 2/type 1) with the degree of the divergence of 1.44% isolated from 6-month old unvaccinated child (RUS08063034001). The frequency of the VAPP cases was a total of 1 case per 3.4 million doses of distributed OPV in 2006-2013; 2.2 cases per 1 million of newborns were observed. This frequency decreased after the introduction of the sequential scheme of vaccination (IPV, OPV) in 2008-2013 as compared with the period of exclusive use of OPV in 2006-2007: 1 case per 4.9 million doses, 1.4 cases per million newborns and 1 case per 1.9 million doses, 4.9 cases per 1 million newborns, respectively. The study has been financed from Russian Federation budget within the framework of the Program for eradication of poliomyelitis in the Russian Federation, WHO Polio eradication initiative, WHO's European Regional Bureau, Russian Foundation for Basic Research (project No. 15-15-00147).

RECOVERY OF DIVISION PROCESS IN BACTERIAL CELLS AFTER INDUCTION OF SulA PROTEIN WHICH IS RESPONSIBLE FOR CYTOKINESIS ARREST DURING SOS-RESPONSE.

SOS-response is an important tool of bacteria intended to protect their genome and thereby allow them to survive under adverse conditions. Recently SOS-response is considered to enhance mutagenesis and thus help bacteria acquire antibiotic resistance. Due to high significance of this phenomena it seems to be important to investigate processes that allow bacteria to survive after SOS-response activation. In current work the recovery of division process of Escherichia coli cells after division arrest due to expression of SOS-response protein SulA was studied. Data indicate that cells are able to rapidly restore normal division; also nucleoid occlusion seems to be the main septum positioning mechanism during the process. In the course of recovery FtsZ forms helix-like structures, which then transformate into Z-rings.

[Monitoring of influenza and other respiratory diseases causative agents in children, hospitalized with community-acquired pneumonia in 2012-2013 epidemic season].

AIM: Study the circulation of respiratory viruses in children with community-acquired pneumonia (CAP) during the period from October 2012 to May 2013. MATERIALS AND METHODS: 136 children with CAP aged from 3 months to 16 years with ARI symptoms at the disease debut were studied. RNA/DNA of influenza A, B, parainfluenza (PI); adeno-, rhino-, RS-viruses, corona-, metapneumo- (MPV) and bocaviruses were detected in nasopharynx smears by PCR with hybridization-fluorescent detection in real time. Antibodies against influenza viruses A/H1N1/pdm09 California/07/09, epidemic reference strains of influenza viruses A/H1N1/Brisbane/59/07, A/ H3N2/Victoria/361/201 1, B/Wisconsin/1/10, against PI viruses type 1, 2, 3 were determined in paired sera by HAI. RESULTS: In February-March 2013 the number of children protected by antibodies against influenza decreased, and circulation of influenza viruses A/H3N2 and A/H1N1/ pdm09 was detected. Rhinoviruses and PI viruses were determined throughout the epidemic season, bocavirus and adenoviruses--during the autumn-winter period, RS-virus and MPV--during winter-spring. Coronaviruses were not detected. The peak of virus detection was established in February when the threshold of influenza and ARI morbidity was exceeded. The main pathogens of children of the first 3 years of life are rhinoviruses, RS-virus, PI viruses and bocavirus. RS-virus infection at the debut of CAP in children younger than 3 years in 55.5% of cases is associated with the development of broncho-obstructive syndrome. Bocavirus infection in 50% of cases progresses with laryngo-tracheitis and bronchiolitis. CONCLUSION: The fraction of viruses in etiologic structure ofARI in children varies depending on immune layer, season and age of children. Etiology of viral infection at the debut of CAP could only be proven using specialized laboratory studies.

A conceptual model of morphogenesis and regeneration.

This paper is devoted to computer modelling of the development and regeneration of multicellular biological structures. Some species (e.g. planaria and salamanders) are able to regenerate parts of their body after amputation damage, but the global rules governing cooperative cell behaviour during morphogenesis are not known. Here, we consider a simplified model organism, which consists of tissues formed around special cells that can be interpreted as stem cells. We assume that stem cells communicate with each other by a set of signals, and that the values of these signals depend on the distance between cells. Thus the signal distribution characterizes location of stem cells. If the signal distribution is changed, then the difference between the initial and the current signal distribution affects the behaviour of stem cells-e.g. as a result of an amputation of a part of tissue the signal distribution changes which stimulates stem cells to migrate to new locations, appropriate for regeneration of the proper pattern. Moreover, as stem cells divide and form tissues around them, they control the form and the size of regenerating tissues. This two-level organization of the model organism, with global regulation of stem cells and local regulation of tissues, allows its reproducible development and regeneration.

[Application of Retinalamin for the treatment of glaucomatous optic neuropathy].

A case of Retinalamin (peptide-based drug) use in a patient with newly diagnosed glaucoma and therapeutically normalized intraocular pressure is reported. The results of visual field test (Humphrey Field Analyzer) and optic nerve examination (Heidelberg Retina Tomograph) as well as electrophysiological indices before and 1 and 3 month after the course of Retinalamin (10 parabulbar injections) are presented.

[The effectiveness of endonasal electrophoresis of neuroprotective agents used in the rehabilitative treatment of the patients presenting with primary open angle glaucoma].

The objective of the present study was to estimate the effectiveness of the peptide drug cortexin used to treat primary open angle glaucoma. It was shown that endonasal electrophoresis of cortexin resulted in more pronounced positive changes in the dynamics of clinical, functional, perimetric, and electrophysiological characteristics compared with intramuscular administration of the same drug to the patients of the control group. This difference was apparent both immediately after the termination of the treatment and during the long-term follow-up.