THE CLINICAL SIGNIFICANCE OF MATRIX METALLOPROTEINASES IN RHEUMATOID ARTHRITIS PATIENTS (REVIEW OF THE LITERATURE AND OUR OWN DATA)

Matrix metalloproteinases (MMPs) are a group of over 20 proteolytic enzymes responsible for cleavage of protein components of the extracellular matrix. Three types of MMPs play an important role in the development of joint damage in patients with rheumatoid arthritis (RA): collagenases (MMP1, 8 and 13), stromelysins (MMP3), and gelatinases (MMP9). MMP3 is considered to be one of the key mediators of joint damage. Increased serum level of MMP is not specific for RA and may be registered in other rheumatic diseases (osteoarthritis, psoriatic arthritis, gout, ankylosing spondylitis, systemic lupus erythematosus); however, monitoring of the level of MMP is of particular clinical importance in patients with RA. MMP3 serum level may be a useful marker of disease activity. Several studies have shown a correlation of MMP3 concentration with clinical and laboratorial parameters of inflammatory activity (ESR and C-reactive protein – CRP) in RA patients. The elevated level of MMP3 is associated with radiological changes in joints and can also be a predictor of severe destructive lesions in RA patients. Evaluation of the MMP3 level can also be useful for monitoring the therapy effectiveness using both standard disease-modifying antirheumatic drugs (DMARDs) and genetically engineered biological drugs (GEBD). Thus, evaluation of MMP3 concentration is useful for assessing disease activity and efficacy of treatment with DMARDs and GEBD, as well as for predicting the severity of destructive changes in joints

AUTOIMMUNE RHEUMATIC DISEASES: RESULTS AND PROSPECTS FOR RESEARCHES

According to the present-day views, autoimmunity is a complex pathological process, the essence of which is intolerance and hence a pathological immune response to intrinsic tissue components (autoantigens), which underlies the pathogenesis of a broad spectrum of human autoimmune diseases. Recently, diverse immune disorders underlying autoimmune rheumatic diseases (ARD) and syndromes have been revealed; an association has been found between the development of ARD and autoinflammatory diseases and syndromes; a classification of human immunoinflammatory diseases has been elaborated. The paper considers the results of the authors’ investigations of ARD treatment with innovative biologics, the pathogenetic mechanisms and diagnosis of ARD, by conducting immunological and molecular biological studies of a wide range of molecular and cellular biomarkers (autoantibodies, acute phase proteins, cytokines, chemokines, vascular endothelial activation markers, complement system components, lymphocyte subpopulations, bone and cartilage tissue metabolic products, genetic, epigenetic, transcriptomic markers), and approaches to personalized treatment of ARD

CHANGES OF CYTOKINE LEVELS DURING THERAPY WITH METHOTREXATE AND ADALIMUMAB IN PATIENTS WITH EARLY RHEUMATOID ARTHRITIS (REMARCA STUDY)

Objective: to estimate changes in cytokine profile versus disease activity in patients with early rheumatoid arthritis (RA) who use methotrexate (MTX) and adalimumab (ADA) in accordance with the treat-to-target concept. Subjects and methods. Forty-five patients (35 women; median age 53.5 [46; 59.5] years) with early RA (median dura- tion 7.0 [4.0; 11.5] months; DAS28 5.8 [4.9; 6.4]; rheumatoid factor positivity (RF+) 91%; anti-cyclic citrullinated peptide antibody positivity (ACCP) + 96%) were examined. In all the patients, MTX as the first agent was subcuta- neously used in a dose of 10 mg/week with its rapid escalation up to 20-25 mg/week. Serum cytokine concentrations were determined using the xMAP multiplexing technology before and 12 and 24 weeks after therapy. Results. Following 12 weeks of therapy, DAS28 mean value decreased to 4.33 [3.5; 5.2] (p < 0.05 vs baseline). Twenty- nine (64.4%) patients responded to treatment. It was decided to continue MTX monotherapy in 23 patients (a monotherapy group) and in 22 patients ADA was added to therapy due to its inadequate effect in accordance with the standard regimen (a combined therapy group). At 24 weeks, mean DAS28 was 2.9 [2.1; 3.6] and 19 (82.6%) patients responded to treatment in the monotherapy group. In the combined therapy group, DAS28 was 3.4 [3.2; 4.4]; nearly 30% of the patients achieved remission/low disease activity and the number of patients with the high activity of a pathological process also declined significantly (from 59.1 to 13.6%). At 12 weeks, the monotherapy group showed reduction of the level of proinflammatory (interleukin-6 (IL-6), IL-17, tumor necrosis factor-α (TNF-α)), anti-inflammatory (IL-4, IL-5, IL-9, IL-13) cytokines, chemokines (interferon induced protein-10 (IP-10)), and vascular endothelial growth factors (VEGF) (p<0.05); at 24 weeks, there were reductions in IL-6, IL-9, and IL-10, and transforming GF-bb and an increase in IL-10 concentration (p<0.05). At 12 weeks of MTX therapy, the combined therapy group displayed a reduction in IL-6, IL-1Pa, IP-10 (p<0.05); at 24 weeks of treatment (12-week ADA administration) there were decreases in proinflammatory (IL-12), anti-inflammatory (IL-9) cytokines, chemokines (IP-10, monocyte chemoattractant protein, and macrophageal inflammatory protein-1β), VEGF and an elevation of IL-10. Conclusion. Thus, the results of the investigation suggest the high clinical efficiency of therapy with subcutaneous MTX, which is associated with the lower levels of a number of proinflammatory cytokines, chemokines, and growth factors. ADA treatment is also accompanied by decreased disease activity and positive changes in the cytokine profile, by exerting a higher impact on the level of chemokines and growth factors

Adult weight gain and colorectal adenomas – a systematic review and meta-analysis

Background: Colorectal adenomas are known as precursors for the majority of colorectal carcinomas. While weight gain during adulthood has been identified as a risk factor for colorectal cancer, the association is less clear for colorectal adenomas. We conducted a systematic review and meta-analysis to quantify the evidence on this association. Methods: We searched MEDLINE up to September 2016 to identify observational (prospective, cross-sectional and retrospective) studies on weight gain during adulthood and colorectal adenoma occurrence and recurrence. We conducted meta-analysis on high weight gain versus stable weight, linear and non-linear dose-response meta-analyses to analyze the association. Summary odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using a random effects model. Results: For colorectal adenoma occurrence, the summary OR was 1.39 (95% CI: 1.17-1.65; I2 :43%, N =9 studies, cases=5,507) comparing high (midpoint: 17.4 kg) versus stable weight gain during adulthood and with each 5 kg weight gain the odds increased by 7% (2%-11%; I2 :65%, N=7 studies). Although there was indication of non-linearity (Pnon-linearity <0.001) there was an increased odds of colorectal adenoma throughout the whole range of weight gain. Three studies were identified investigating the association between weight gain and colorectal adenoma recurrence and data were limited to draw firm conclusions. Conclusions: Even a small amount of adult weight gain was related to a higher odds of colorectal adenoma occurrence. Our findings add to the benefits of weight control in adulthood regarding colorectal adenomas occurrence, which might be relevant for early prevention of colorectal cancer

Role of hepcidin in the development of anemia in patients with rheumatoid arthritis

Chronic disease anemia (CDA) diagnosed in many patients with rheumatoid arthritis (RA) was described in the early 1970s. As earlier noted, iron metabolic disturbances in CDA are its diagnostic feature and the discovery of hepcidin, an iron-regulatory acute-phase protein, could largely clarify an association between the immune mechanism of impaired iron homeostasis and the development of CDA. Objective: to define the role of hepcidin in the differential diagnosis of CDA and true iron deficiency in patients with RA. Subjects and methods. The investigation enrolled 76 patients with RA (1987 ACR criteria) admitted to the Research Institute of Rheumatology, Russian Academy of Medical Sciences, to be treated. The patients were divided into two groups. A study group comprised anemic patients (n = 47). The WHO criteria for anemia were considered to be hemoglobin (Hb) levels of below 120 g/l for women and below 130 g/l for men. A control group consisted of non-anemic patients (n = 29). The anemic and non-anemic patients were matched for age (45.5±14.3 and 49.8±14.3 years, respectively) and disease duration (2 months to 20 years) (p &gt; 0.05). Iron metabolic parameters, such as serum iron, total serum iron-binding capacity (TSIBC), iron transferrin saturation (ITS), transferrin receptors, and serum ferritin (SF), were studied and the level of hepcidin prohormone was estimated by direct enzyme immunoassay (Hepcidin Prohormone Enzyme Immunoassay Kit, IBL, Germany) in all the patients to be analyzed. Cytokines, such as interleukin 6, tumor necrosis factor-а) were determined by enzyme immunoassay (Bender MedSystems, Austria). The Institute’s differential diagnostic algorithm involving SF, TSIBC, and ITS was used to diagnose iron deficiency. The diagnosis was based on two stages of estimating iron values: isolated iron-deficiency anemia (IDA) was diagnosed if SF was below the normal value (&lt; 40 μg/l). If the patient had SF of μ40 μg/l with a simultaneous rise of TSIBC above the normal level (&gt; 70 μg/l) and a drop of ITS (&gt; 20%), he/she might be suspected as having the mixed genesis of anemia, in which both iron deficiency and CDA are detectable. The other patients could be diagnosed as having isolated CDA. Results. The study has established that irrespective of the hemoglobin level, the content of serum hepcidin prohormone in the examined patients with RA averaged 89.2±65.1 pg/ml and was much higher than that in donors (64.9+21.6 pg/ml; р &lt; 0.05). An analysis of the blood biochemical parameters characterizing iron metabolism showed that, whether they were anemic or non-anemic, the patients with RA, as compared with donors, were found to have an elevated level of SF that is an acute-phase indicator and reflects the high activity of an inflammatory process. To rule out IDA, the anemic patients with RA were subdivided into 3 subgroups according to the differential diagnostic algorithm. Subgroup 1 included patients with isolated CDA (n = 13 patients (28% of those in the study group)); Subgroup 2 consisted of 17 (32%) patients with anemia of mixed genesis (CDA ± IDA), and Subgroup 3 comprised 17 patients with IDA. An analysis of the clinical and laboratory parameters in RA independent of the nature of anemia demonstrated that only the patients with isolated CDA had significantly higher mean values of hepcidin prohormone (120.3±56.1 pg/ml) as compared to the control group (90.3±37.9 pg/ml) and RA patients with iron deficiency (both isolated IDA and that of mixed genesis). The same subgroup had a higher inflammatory RA activity characterized by the highest values of DAS 28, C-reactive protein, and SF. Conclusion. Hepcidin is a negative regulator of iron metabolism and may be used for the differential diagnosis of CDA and true iron deficiency in patients with RA

A Modern View of Anomalies in the Metal Groups of the Periodic System of D.I.Mendeleev

The article is devoted to the 150th anniversary of the Periodic Table of Chemical Elements by D.I.Mendeleev. The fundamental law of nature, discovered by D.I.Mendeleev has anomalies and paradoxes associated with certain groups of metals. When studying the physical and chemical properties of complex metal compounds, many discrepancies can be found, namely, the location of elements in groups, which primarily relate to metals with different valences. By studying the approaches and methods for predicting the arrangement of chemical elements, it can be established that D.I.Mendeleev eliminated many differences for some metals during the formation of the Periodic system of chemical elements. D.I.Mendeleev developed a principle that excludes such errors when finding and discovering new elements. Analytical studies conducted by a Russian scientist helped to calculate the atomic masses and describe the properties of three elements not known at that time – «eka-boron», «eka-silicon», «eka-aluminum», the existence of which was proved and confirmed by subsequent discoveries of scandium, germanium, boron, and gallium. The paper provides a significant assessment of the forecasting of metals in various groups of the periodic system. Changes in the properties of some metals significantly influenced their location in the table of D.I.Mendeleev

Folded Three-Spin String Solutions in AdS_5 x S^5

We construct a spinning closed string solution in AdS_5 x S^5 which is folded in the radial direction and has two equal spins in AdS_5 and a spin in S^5. The energy expression of the three-spin solution specified by the folding and winding numbers for the small S^5 spin shows a logarithmic behavior and a one-third power behavior of the large total AdS_5 spin, in the long string and in the short string located near the boundary of AdS_5 respectively. It exhibits the non-regular expansion in the 't Hooft coupling constant, while it takes the regular one when the S^5 spin becomes large.Comment: 14 pages, LaTeX, no figures, a reference adde

Diagnostic methodics of personal development of university students in studying the humanities

© The author(s). The urgency of the research of diagnostic methodics of personal development of university students in studying the humanities does not lose its science - based and practice - oriented value and at the present transitional time, which has put higher education before the need to train professionals with personal qualities as required to modify the social structure of the labor market and the needs of the personality. The purpose of the article is in scientific - practical justification of the set of diagnostic methodics of personal development of students and experimental verification of their efficiency in the process of studying the humanities. The article presents: theoretical - methodic foundations of the structure, content and implementation techniques of diagnostic methodics of personal development of students in studying the humanities and identifies practical significance of the methodic for the formation of competent professionals demanded by modern job market. The leading method of this study is to monitor the personal development of university students in the process of studying the humanities. The article stuff is designed for university teachers of humanities, young scientists and students, who are interested in research activities in the humanitarian sphere. It is recommended to university methodists and students of further teacher training centers of continuing professional education

CHANGES IN HEART RATE, HEART RATE VARIABILITY AND QT INTERVAL IN WOMEN WITH RHEUMATOID ARTHRITIS DURING RITUXIMAB TREATMENT

Rheumatoid arthritis (RA) is a proven high cardiovascular risk disease. High heart rate (HR), lower heart rate variabil- ity (HRV), and increased QT interval are considered as predictors of cardiovascular events in patients with coronary heart disease, chronic heart failure, and diabetes mellitus. In RA, there is a pronounced rise in HR, a reduction in HRV, and an increase in QT interval mainly due to the factors reflecting the severity of the disease. Rituximab (RTM) is successfully used to treat patients with high RA activity. At the same time there are only a few pieces of evidence for the effect of the drug on the cardiovascular system. Objective: to study changes in HR, HRV, and QT interval values obtained during electrocardiography (ECG) Holter monitoring (ECG HM) in RTM-treated women during a 6-month follow-up. Subjects and methods: The investigation enrolled 55 women (mean age 50 years) with a definite diagnosis of RA and its high activity. The patients were examined 6 months after administration of RTM. The latter was infused intra- venously twice (500 and 1000 mg in 22% and 78% of the patients, respectively) during therapy with disease-modifying antirheumatic and non-steroidal anti-inflammatory drugs and glucocorticoids. The RA patients were divided into two groups: 1) a satisfactory/good effect of RTM according to the EULAR criteria (n = 41); 2) no effect (n = 14). Analysis of 24-hour ECG HM yielded the values of HR and mean duration of corrected QT interval (QTc). The tim- ing HRV values obtained at ECG HM were standardized from age and mean HR (SDNNn, RMSSDn, and pNN50n). Results. The baseline HRmin and HRmean values were higher and SDNNn was lower in the RA patients in Group 1 than those in Group 2 (p &lt; 0.05). In Group 1, RTM therapy was accompanied by a reduction in HRmean and HRmin by 8% and by an increase in SDNNn by 3%, RMSSDn by 26%, and pNN50n by 33% whereas no significant changes in HR and HRV were found in Group 2. The RTM therapy-induced HRmean decrease was associated with the reductions of C-reactive protein concentration and HAQ disability index (p &lt; 0.01), the increases of rMSSDn and pNN50n associated with lower HAQ index, ERS, and DAS28 (p &lt; 0.01). There were no differences in QTc in Groups 1 and 2 during 6 months after RTM therapy. Thus, effective RTM therapy is attended by reduced HR and improved HRV values