CLINICAL AND IMMUNOLOGICAL CHARACTERISTICS OF DIABETES-ASSOCIATED OSTEOARTHRITIS

Osteoarthritis (OA) has been shown to be a heterogeneous disease. Diabetes mellitus (DM)associated represents a special OA subtype. Its clinical and immunological characteristics are poorly understood. To assess immune phenotype of the diabetes-associated OA and appropriate relationship between its clinical manifestations and cytokine concentrations in peripheral blood, we examined 78 patients with generalized OA including 52 patients in experimental group (82.6% females) who exhibited clinical manifestations of OA preceded by DM type II for, at least, 1 year, and 26 OA diabetes-free patients (84.6% females). We found that clinical manifestations of DM-associated OA were associated with increased body weight, more pronounced level of joint pains, longer duration of morning stiffness, decreased functionality of hands and large joints, impaired quality of life and more severe clinical pattern of the illness. Pronounced clinical manifestations in OA patients were more typical to the patients who required insulin therapy. The patients with DM type II-associated OA had elevated levels of proinflammatory (IL-6, IL-18) and reduced serum concentrations of anti-infammatory cytokines (IL-10, adiponectin), thus suggesting more pronounced systemic inflammation in patients of the first group. Concentrations of circulating IL-6 correlated with several functional indexes of OA severity. In conclusion, the DM-associated OA represents a special subtype of osteoarthritis, and deserves further studies of its immune pathogenesis and development of new treatment strategies

CLINICAL EFFICACY AND SAFETY OF ADEMETIONINE IN PATIENTS WITH DIABETES-ASSOCIATED OSTEOARTHRITIS: A CROSS-OVER PILOT STUDY

Osteoarthritis (OA) is one of most common rheumatic diseases, and currently there is no effective pharmacological treatment of OA. It has been suggested that lack of effective treatment is, in part, due to the disease heterogeneity which may lead to development of several OA subtypes (phenotypes). Diabetes-associated OA is among the proposed OA phenotypes. The key mechanism involved into inflammatory and degenerative changes in OA is a decrease in DNA methylation suggested for several cell types, that was also demonstrated in type 2 diabetes mellitus. Therefore, pharmacological increase of DNA methylation may be an effective treatment strategy which may exert pleiotropic effects in diabetes-associated OA. In a randomized crossover study, we have evaluated efficacy and safety of ademetionine, a methyl group donor, in comparison with chondroitine sulfate in patients with OA associated with type 2 diabetes mellitus. The patients were randomly assigned to sequential treatment of chondroitine sulfate/ademetionine or ademetionine/chondroitine sulfate during one month, with a washout period of 2 weeks. The primary endpoint was pain measured according to visual analogue scale (VAS). Painful symptoms, as well as function and disease signs in knee, hip and hand joints were also assessed with KOOS, WOMAC, and FIHOA scales. General performance was assessed with SF–36 scale. To evaluate systemic inflammation, we measured serum IL-6, IL-18, adiponectin, and CRP using ELISA technique. Concentrations of serum cartilage destruction biomarkers (aggrecan and antibodies to collagen type II) were assessed by ELISA. Serum lipid levels were measured with standard method; glycated hemoglobin was assessed with liquid chromatography. Ten patients (all women, age 61.7-74.2 year with BMI of 1.1-38.4 kg/m2) were included in the study. It has been demonstrated that ademetionine showed a statistically significant analgetic effect (decrease in VAS pain), improved knee function and reduced symptoms in knee joints (as measured by KOOS subscales), and did not influence the levels of systemic inflammation or cartilage destruction biomarkers. There was also no change in lipid levels and glycated hemoglobin concentrations. Ademetionine was well tolerated, no serious adverse events occurred during the treatment. In conclusion, ademetionine does not have pleiotropic pharmacological effects in diabetes-associated OA. Its potential application in cases of different comorbidities requires further studies

Combination treatment of patients with metabolic phenotype of osteoarthritis: an exploratory study

Treatment of osteoarthritis (OA) patients with comorbidities can be challenging due to adverse events and non-sufficient efficacy of modern drugs. A safe and effective alternative could be the methods of traditional medicine and their combinations. The aim of this study was to evaluate efficacy and safety of combination of curcuma-based parapharmaceutical preparation and acupuncture in metabolic phenotype of OA (MPOA). The trial design was pilot open-label “before – after” study with the duration of 12 weeks. The patients with MPOA received parapharmaceutical preparation Epigenorm Antivir in a daily dose of 1000 mg and underwent 15-20 sessions of classical acupuncture. We enrolled twenty three women with metabolic syndrome (MS), clinical and radiographic signs of gonarthrosis, mean age 66.5 years, mean body mass index 34.5. At the end of treatment there was a decrease in pain levels according to visual analogue scale (VAS) (before 65 (12.7), after 24.6 (21.0), р=0.001), WOMAC pain scale (before 210.6 (102.2), after 103 (80.8), p = 0.014), KOOS (before 47.8 (12.1), after 66.7 (16.2), р = 0.001). The treatment resulted in statistically significant improvement of daily and social activities, role functioning, and quality of life. The results were clinically significant as evidenced by the moderate (Cohen d > 0.5) and large (Cohen d > 0.8) effect sizes of most outcome changes in accordance with the Cohen classification. The clinical improvement was accompanied by the decrease in MS components – LDL cholesterol (before 3.26 (0.26) mmol/l, after 2.43 (0.2) mmol/l, р = 0.001), triglycerides (before 2.02 (0.16) mmol/l, after 1.31 (0.1) mmol/l, р = 0.005). The treatment resulted in the reduction of systemic inflammation as evidenced by the decrease in the concentrations of TNFα (before 15.9 (1.2) pg/ml, after 12.4 (0.8), р = 0.002), histamine (before 1.6 (0.2) ng/ml, after 0.7 (0.2) pg/ml, р = 0.034), IL-18 (before 208.8 (32.6 ) pg/ml, after 160.0 (26.0) pg/ml, р = 0.002) and CRP (before 6.05 (1.3) mg/l, after 3.2 (0.7) mg/l, р = 0.022). At the same time there was an increase of concentration of IL-10 (before 1.5 (0.7) pg/ml, after 3.8 (1.2), р = 0,006) and adiponectin (before 34.0 (5.6) pg/ml, after 40.0 (6.9), р = 0.034). The treatment was well tolerated, no serious adverse events were registered. The pleiotropic actions of combination treatment occured probably due to synergistic effects of herbal therapies and acupunctures. The results provide a rationale for larger scale, randomized controlled double-blind clinical trials

Clinical and immunological features of metabolic phenotype of osteoarthritis

Forty women with gonarthrosis were included in this study. The main group consisted of 19 patients having osteoarthritis (OA) with metabolic syndrome (MS), the control group consisted of 21 patients with OA but without MS. It was found that metabolic phenotype of gonarthrosis, i.e. OA with concomitant MS, was different from OA without MS in terms of pain measured with visual analogue scale (VAS) (65 mm in the main group vs 47 mm in control group, р = 0.001) and other OA symptoms in accordance with Knee Osteoarthritis Outcome Scale (KOOS) (43.2 points in the main group vs 76.1 points in the control group, р = 0.001). These main distinguishing features were associated with low quality of life measured with non-specific questionnaire Short Form -36 (SF-36) (30 points in the main group and 40 points in the control) and clinically significant signs of depression, detected with Patient Health Questionnaire-9 (PHQ-9) (12 points in the main group and 7 points in the control group). The metabolic phenotype of gonarthrosis was characterized with laboratory features of low-grade systemic inflammation as evidenced by increased CRP (11.4 mg/ml in the main group vs 3.2 mg/ml in the control group, р = 0.03), IL-6 (2.6 pg/ml in the main group vs 0.7 pg/ml in the control group, р = 0.001), IL-18 (196.6 pg/ml in the main group vs 61.4 pg/ml in the control group, р = 0.001) in the peripheral blood serum, as well as increase in antibodies against Col2 (27.1 ng/ml in the main vs 5.5 ng/ml in the control group, р = 0.01) , and dyslipidaemia — increase in LDL-cholesterol (5.5 mmol/l in the main group vs 5.9 mmol/l in the control group, р = 0.032) and triglycerides (2.026 mmol/l in the main group and 1.36 mmol/l in the control gropu, р = 0.02). In conclusion, MS-associated OA phenotype occurs due to pathogenetic similarities between OA and MS (syntropy) based on systemic low grade inflammation. This OA phenotype is not well studied and needs further research to develop new treatments targeting these two comorbid disorders as a single disease

Management of the mother and child care system in the Moscow city

Survey of the current situation of the mother and child care program in Moscow city, including modern organization and medical technologies, upgrade of the public health system. As result, a very good medico-demography level in the last years.Обобщены результаты работы системы охраны здоровья матери и ребенка в городе Москве. Показано роль современных организационных и медицинских технологий, повышение качества общественного здравоохранения. В результате, в последние годы в городе значительно улучшились медико-демографические показатели

Two-Fermion Production in Electron-Positron Collisions

This report summarizes the results of the two-fermion working group of the LEP2-MC workshop, held at CERN from 1999 to 2000. Recent developments in the theoretical calculations of the two fermion production process in the electron-positron collision at LEP2 center of the mass energies are reported. The Bhabha process and the production of muon, tau, neutrino and quark pairs is covered. On the basis of comparison of various calculations, theoretical uncertainties are estimated and compared with those needed for the final LEP2 data analysis. The subjects for the further studies are identified.Comment: 2-fermion working group report of the LEP2 Monte Carlo Workshop 1999/2000, 113 pages, 24 figures, 35 table

Влияние модуляторов метилирования ДНК на продукцию остеопротегерина ревматоидными фибробластоподобными синовиоцитами in vitro, их миграцию и инвазию

Objective. The purpose of the research was to study the effect of DNA methylation modulators on the production of proinflammatory cytokines by fibroblast-like synovial cells (FLC).Materials and methods. We used the cells derived from the synovial tissue of 6 patients with active rheumatoid arthritis (RA) after 3–7 in vitro culturing passages.Results. There was an IL-1β-induced up-regulation of osteoprotegerin (OPG) synthesis in the RA FLC cultures. The addition of methylating compounds S-Adenosyl methionine (SAMe) and genistein into the cultures resulted in a statistically significant decrease in the production of OPG, while the addition of the demethylating agent hydralazine did not change the synthesis of the cytokine. All three DNA methylation modulators used at different concentrations significantly reduced the percentage of spontaneous migration and invasion of FLC in the Boyden chamber.Conclusion. Enzymes and molecular complexes involved in DNA methylation could be potential therapeutic targets, and in vitro FLC cultures of RA patients can be used as a model for preclinical screening of new drug compounds. Цель. Изучить влияние модуляторов метилирования ДНК на продукцию провоспалительных цитокинов фибробластоподобными синовиальными клетками (ФСК).Материалы и методы. Использовались клетки, полученные из синовиальной ткани шести больных активным ревматоидным артритом (РА) после 3–7 пассажей культивирования in vitro.Результаты. Установлено, что культуры ФСК больных РА при стимуляции IL-1β увеличивают продукцию остеопротегерина (ОПГ). Внесение в культуры метилирующих соединений – S-аденозилметионина (SAMе) и генистеина – приводило к статистически значимому снижению продукции ОПГ, а добавление деметилирующего агента гидралазина не меняло синтез цитокина. Все три используемых модулятора метилирования ДНК в разных концентрациях статистически значимо снижали количество спонтанно мигрировавших и инвазивных ФСК в камере Бойдена.Заключение. Ферменты и молекулярные комплексы, участвующие в процессах метилирования ДНК, являются потенциальными терапевтическими мишенями, а культура ФСК больных РА in vitro может быть моделью для доклинического скрининга новых лекарственных соединений.

Single hadron response measurement and calorimeter jet energy scale uncertainty with the ATLAS detector at the LHC

The uncertainty on the calorimeter energy response to jets of particles is derived for the ATLAS experiment at the Large Hadron Collider (LHC). First, the calorimeter response to single isolated charged hadrons is measured and compared to the Monte Carlo simulation using proton-proton collisions at centre-of-mass energies of sqrt(s) = 900 GeV and 7 TeV collected during 2009 and 2010. Then, using the decay of K_s and Lambda particles, the calorimeter response to specific types of particles (positively and negatively charged pions, protons, and anti-protons) is measured and compared to the Monte Carlo predictions. Finally, the jet energy scale uncertainty is determined by propagating the response uncertainty for single charged and neutral particles to jets. The response uncertainty is 2-5% for central isolated hadrons and 1-3% for the final calorimeter jet energy scale.Comment: 24 pages plus author list (36 pages total), 23 figures, 1 table, submitted to European Physical Journal

Expected Performance of the ATLAS Experiment - Detector, Trigger and Physics

A detailed study is presented of the expected performance of the ATLAS detector. The reconstruction of tracks, leptons, photons, missing energy and jets is investigated, together with the performance of b-tagging and the trigger. The physics potential for a variety of interesting physics processes, within the Standard Model and beyond, is examined. The study comprises a series of notes based on simulations of the detector and physics processes, with particular emphasis given to the data expected from the first years of operation of the LHC at CERN

Measurement of the production cross section for W-bosons in association with jets in pp collisions at s=7 TeV with the ATLAS detector

This Letter reports on a first measurement of the inclusive W + jets cross section in proton-proton collisions at a centre-of-mass energy of 7 TeV at the LHC, with the ATLAS detector. Cross sections, in both the electron and muon decay modes of the W-boson, are presented as a function of jet multiplicity and of the transverse momentum of the leading and next-to-leading jets in the event. Measurements are also presented of the ratio of cross sections sigma (W + >= n)/sigma(W + >= n - 1) for inclusive jet multiplicities n = 1-4. The results, based on an integrated luminosity of 1.3 pb(-1), have been corrected for all known detector effects and are quoted in a limited and well-defined range of jet and lepton kinematics. The measured cross sections are compared to particle-level predictions based on perturbative QCD. Next-to-leading order calculations, studied here for n <= 2, are found in good agreement with the data. Leading-order multiparton event generators, normalized to the NNLO total cross section, describe the data well for all measured jet multiplicitie