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Vol 74, No 5 (2019)

DERMATOLOGY and VENEROLOGY: current issues
Possibility of combined therapy with an oral phosphodiesterase-4 inhibitor (apremilast) and dihydrofolatereductase inhibitor (methotrexate) in patients with psoriatic arthritis plaque psoriasis
Kubanov A.A., Artamonova O.G., Karamova A.E.
Abstract

Background: Data on the possible combinations of apremilast with other types of psoriasis therapy is limited.

Description of clinical cases: We present the data on the efficacy and safety of combination therapy of the selective phosphodiesterase 4 inhibitor and dihydrofolatereductase inhibitor (methotrexate) for the treatment of psoriasis and psoriatic arthritis in patients with moderate-to-severe plaque psoriasis and active psoriatic arthritis with lack of efficacy of methotrexate in the anamnesis. The selective phosphodiesterase 4 inhibitor (apremilast) was administered according to the prescription. The severity psoriatic arthritis of was estimated by PASI. The effectiveness of therapy was evaluated at week 14. Due to the lack of effect, methotrexate was added subcutaneously at week 14. The effectiveness of combination therapy was assessed at week 26. In both cases, the significant clinical improvement was reached (patients reached PASI 75 and PASI 90), a decrease of the psoriatic arthritis’ activity according to the DAS28 and DAPSA.

Conclusion: These clinical cases demonstrate the efficacy and safety of combined therapy with methotrexate and apremilast inpatients with active psoriatic arthritis and moderate to severe plaque psoriasis.

Annals of the Russian academy of medical sciences. 2019;74(5):292-298
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CARDIOLOGY AND CARDIOVASCULAR SURGERY: CURRENT ISSUES
Clinical pharmacology technologies for personalization of cardiovascular diseases drug treatment: focus on direct oral anticoagulants
Sychev D.A., Sychev I.N., Mirzaev K.B., Rytkin E.I., Ivashchenko D.V., Bure I.V., Otdelenov V.A.
Abstract

One of the main causes for adverse reactions development is not taking into account the pharmacokinetics of drugs and the dose. Pharmacokinetics of drugs is mostly defined by the cytochrome P-450 isoenzymes activity, carboxylesterases and many other isoenzymes of drug metabolism, as well as ADME transporters (P-gp etc.) which take part in the process of drug metabolism. The activity of these isoenzymes is defined by the genetic aspects of patients and non-genetic aspects such as comorbidity and drug-drug interactions. The development of complex algorithms for personalization of therapy based on the results of pharmacogenetic studies and in the form of a decision support system will play an important role in reduction of adverse drug reactions. A lot can be achieved for personalization of Direct Oral Anticoagulants for treatment of cardiovascular diseases. New approaches are being developed based on the results of pharmacogenetic and pharmacokinetic testing that will help diminish adverse effects of drugs.

Annals of the Russian academy of medical sciences. 2019;74(5):299-306
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Heart involvement in AL-amyloidosis. Current state of the issue
Trukhin I.V., Schekochikhin D.Y., Novikova N.A., Akselrod A.S., Syrkin A.L., Syrkina H.A., Grachev A.E., Gribanova H.O., Okhota V.K., Ryzhko V.V., Pershina E.S.
Abstract

AL cardiac amyloidosis is a relatively rare disorder that belongs to the group of infiltrative cardiomyopathies. Diagnosis of primary amyloidosis is challenging due to many unspecific symptoms and sings, which often leads to late diagnosis when treatment options are limited. Primary amyloidosis particularly needs to be excluded in patients with heart failure with preserved ejection fraction. Therapy in cardiac amyloidosis has to main vectors: 1) chemotherapy to eliminate amyloidogenic plasmatic cells 2) heart failure treatment. The main challenge for cardiologists is to support hemodynamics until response to chemotherapy occurs. In the article the issue of diagnostics, risk stratification and treatment of primary cardiac amyloidosis is addressed.

Annals of the Russian academy of medical sciences. 2019;74(5):307-316
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ONCOLOGY: CURRENT ISSUES
Role of galectins 1 and 3 in the recruitment of eosinophilic granulocytes into tumor tissue in gastric and colon cancers
Kolobovnikova Y.V., Urazova O.I., Vasilieva O.A., Romanova E.V., Komar A.A., Litvinova L.S., Poletika V.S., Chumakova S.P., Novitsky V.V.
Abstract

Background: Gastric and colon tumors are often associated with eosinophilic infiltration of tumor tissue, the significance of which is still not entirely clear. The recruitment of eosinophils into the tissues can be in part regulated by galectins ― galactose-binding proteins which are expressed by a variety of tissues and are capable of exerting a broad range of effects.

Aims: To evaluate the expression of galectin-1 and galectin-3 in tumor tissue, and gal-3 gene mRNA expression in blood eosinophils in patients with gastric and colon cancer with or without tissue eosinophilia.

Materials and methods: The study included a total of 107 patients (84 males and 23 females, average age 60,9 ± 6,8) with verified gastric cancer (52 persons) and colon cancer (55 persons), who underwent treatment or were registered at the dispensary at the regional medical institution “Tomsk Regional Oncology Center” (Tomsk, Russia). The control group consisted of 15 men and 11 women of comparable age. The materials of the research included samples of gastric and colon tumors obtained during surgery, and eosinophilic granulocytes isolated from whole blood by immunomagnetic separation. Galectin-1 and galectin-3 expression in tumor tissue was evaluated by immunohistochemistry. The expression of gal-3 gene mRNA in eosinophils was determined by real-time reverse transcription polymerase chain reaction. Statistical analysis of the results was carried out using the non-parametric Mann-Whitney U test for independent samples with Benjamini-Hochberg procedure for multiple comparisons, and the Chi-square Pearson criterion with Yates correction.

 Results: In patients with gastric cancer and colon cancer, regardless of the presence of tissue eosinophilia, low expression of galectin-3 in the tumor tissue and high expression of gal-3 gene mRNA in peripheral blood eosinophils were found. Gastric and colon cancer patients with eosinophilic infiltration of tumor tissue were characterized by low expression of galectin-1 within tumor cells (in 64.0% cases, χ2 = 4.890, р = 0.029; and in 73.9% cases, χ2 = 5.981, p = 0.031 respectively). There was a statistically significant connection between the level of galectin-1 expression by tumor cells and the presence of tissue eosinophilia both in gastric (φ = 0.307) and colon cancer (φ = 0.330).

Conclusion: Low expression of galectin 1 and 3 by tumor cells in gastric and colon cancer with tissue eosinophilia indicates the lack of a significant effect of these proteins on the process of recruiting eosinophilic granulocytes into tumor tissue. Increased expression of galectin-3 in blood eosinophils in gastric and colon cancer is not associated with the presence of eosinophilic infiltration of tumor tissue.

Annals of the Russian academy of medical sciences. 2019;74(5):317-322
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Thrombotic microangiopathy in cancer patients
Makatsariya A.D., Elalamy I., Vorobev A.V., Bakhtina A.S., Meng M., Bitsadze V.O., Khizroeva J.K.
Abstract

Thrombotic microangiopathy (TMA) is a rare phenomenon, which is severe pathology based on systemic microvascular thrombosis. TMA is characterized by thrombocytopenia and signs of microangiopathic hemolytic anemia. The review presents a modern data on the pathogenesis of tumor-associated thrombotic microangiopathy, considers the interaction of various effectors related to both tumor growth and metastasis process ― immune system activation, endotheliopathy formation, use of chemotherapeutic agents and targeted therapy in the pathogenesis of various forms of TMA. The interaction between the tumor tissue, hemostasis and immune systems are of the type of cascade of mutual activation, thus leading to the formation of a vicious circle, resulting in damage to endothelium and thrombosis in the microcirculatory channel, that is, the development of TMA. The formation of thromboembolism, which includes tumor tissue in the microvessels of the lungs, contributes to the development of pulmonary tumor thrombotic microangiopathy (PTTM). Сancer patients have higher vWF levels and lower ADAMTS13 levels or/and activity than the general population, often also depending on the stage of cancer: vWF and ADAMTS13 have been shown to be associated with thrombotic complications in cancer patients, and ADAMTS13 shows prognostic potential. Increased expression of complement proteins and/or activation of complement during chemotherapy, infectious and inflammatory complications may also cause TMA development. Pathogenesis of thrombotic microangiopathy also is associated with numerous chemotherapeutic agents, such as mitomycin C, gemcitabine, cisplatin, carboplatin and Bevacizumab, an inhibitor of VEGF. This may be the result of both the direct toxic effect of the drug on endothelium and damage of it by immune complexes caused by expression of the VEGF-antibodies. Usage of number of chemotherapeutic agents, especially anti-VEGF and tyrosine kinase inhibitors, which have a direct toxic effect on endothelium, are associated with the development of TMA. Mechanisms causing the development of TMA are considered as components of the hemostasis system, leading to the development of chronic, long-lasting disorders of the hemostasis system (chronic DIC syndrome) and are associated with high incidence of thrombotic complications.

Annals of the Russian academy of medical sciences. 2019;74(5):323-332
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HEALTH CARE MANAGEMENT: CURRENT ISSUES
The quality of post-graduate training of residents
Ivanov D.O., Aleksandrovich Y.S., Kulbakh O.S., Zinkevich E.R., Ditkovskaya L.V., Pshenisnov K.V.
Abstract

Background: The introduction of Federal state standards of higher education has caused the need to study the quality and condition of specialists postgraduate training in the field of health. In 2017−2019 at St. Petersburg state pediatric medical university a study aimed at examining the satisfaction of residents with educational training at the faculty of postgraduate and additional professional education was hold, the results of which allowed to identify the problem areas of training in order to further adjust the content and organizational aspects of the quality of training of highly qualified specialists in the field of health protection of citizens of Russia.

Aims: The estimation of the quality of postgraduate training of specialists in the field of health care based on the pedagogical reflection of their satisfaction with the process of training during the residency.

Methods: The study was conducted by means of a questionnaire consisting of a number of questions stated in the form of appeals aimed at obtaining information illustrating the content, organizational, operational and personal resources of postgraduate education of residents. The respondents were asked to rank their responses according to their satisfaction with the quality of education on the scale that ranged from excellent to very poor. The object of the study was 125 graduates completed their professional training at the stage of postgraduate education in residency at various clinical departments. The duration of the study, including the preparation of analytical materials, the organization, and conduct of the survey, the subsequent analysis of the data, totally amounted to two years. The analysis of the survey results allowed to identify the targets of possible correction of informative, organizational, operational and personal aspects of postgraduate training of doctors.

Results: The participants of the study were 125 respondents-resident physicians who completed the educational trajectory in various areas of professional training on the basis of clinical departments of pediatric medical university. It should be noted that the distribution of participants in the questionnaire by graduate clinical departments was characterized as uneven, due to the peculiarities of the plan of admission to the residency, social order from the health care institutions of Russia, and finally, individual educational needs and needs of students. The average age of residents is 26 years. As a result of the study, it was possible to identify informative, organizational and personal problem areas of training of residents. In particular, there were problems in the content of professional education, in the level of pedagogical skills of the teaching staff of clinical departments, in the development of professional competencies of residents, in the content of test tasks in certain specialties. Due to the factor analysis of the results, a semantic space was built that reflects the analysis of the satisfaction of graduates of Spbsmu with the quality of training at the stage of residency.

Conclusions: Based on the results of the study, it was possible to identify the targets of correctional work, involving the improvement of organizational, informative, technological and personal resources of the educational program of postgraduate training of residents.

Annals of the Russian academy of medical sciences. 2019;74(5):333-341
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PHYSIOLOGY: CURRENT ISSUES
Placebo-controlled study of xenon effect on the emotions and frequency of the EEG alpha-oscillations
Aftanas L.I., Bazanova O.M., Khabarov A.N., Pustovoit S.M., Braсk I.V.
Abstract

Background: A partial blocker of N-methyl-D-aspartate (NMDA) receptors, the noble gas Xe in sub-anesthetic (25−50%) doses performs its neuroprotective effects on the brain structures functions through binding to glycine site. According to the single studies, Xe reveals the thymoleptic properties, which are reflected in the strengthening of positive emotional activation and a decreasing ― negative. The purpose of this placebo-controlled pilot study in healthy volunteers was to evaluate the translational potential of Xe as a possible antidepressant.

Methods: In placebo-controlled, double-blind study 14 right-handed healthy volunteers (males, right handed) were randomly assigned to 15 min inhalation session either of an admixture of up to a maximum of 25% Xe (25% Хе/30% О2/45% N2) or placebo (70% N2/30% О2) for 15 min. The inspiratory Xe concentration was titrated during the first 5 min until 25% was achieved and maintained for 5 min. Across the study, we had recorded, ECG, SGR, and 64-channel EEG. As a neurophysiological index of the experienced emotion intensity changes individual alpha peak frequency (iAPF) shift was studied. Changes in intensity of experiencing ten discrete emotions (surprise, joy, happiness, bliss, awe, fear, sadness, anxiety, anger, disgust) as indexed by visual analog scales (VAS) were recorded in pre- and post Xe and placebo inhalation conditions. The research received approval of the institutional ethics committee.

Results: Repeated measures ANOVAs of the emotional reactivity [(GAZ 2: Xe, placebo) × CONDITION (2: pre, post) × EMOTION (10)] and of the iAPF [(GAZ 2: Xe, placebo) × CONDITION: 2 (pre, post) established high significant specific effects of the Xe compared with placebo. The impact of Xe in a sample of examined subjects revealed two types of responses: in one part, an increase in the experiencing positive emotions intensity, accompanied by the rise in iAPF, in the other, insignificant changes in the initial emotional profile with a tendency to decrease in combination with a decrease in iAPF. Thus, in agreement with ad hoc hypothesis, Xe in sub-anesthetic doses induced the enhancement of the positive emotion intensity experience only in those participants who demonstrated the increasing of the iAPF. Correlation and regression analyses revealed a positive correlation of iAPF changes with an intensity of positive emotional activation (increased power of experiencing emotions of joy, happiness, and bliss), as well as the iAPF shift ability to predict the thymoleptic effect of Xe with 74% probability. Additionally, we were able to deduce that individual nature of changes in iAPF and the nature of emotional-reactivity in response to Xe depend on the absolute value of the baseline iAPF.

Conclusions: We had first established that Xe as a blocker of NMDA receptors in sub-anesthetic doses enhances positive emotional activation (increased intensity of experiencing discrete emotions of joy, happiness, and bliss) in healthy volunteers. The presence or absence of the thymoleptic response to Xe varies due to the individual characteristics of the neurophysiological endophenotype of the EEG alpha activity ― iAPF. The obtained data allow us to consider iAPF as a potential neurophysiological endophenotypic predictor of an individual thymoleptic response to Xe in sub-anesthetic doses in the clinic of the affective disorders. To assess the real Xe translational potential, as a clinical thymoleptic and antidepressant agent, it is necessary to perform large-scale placebo-controlled clinical studies in patients with various clinical forms of negative affect pathology.

Annals of the Russian academy of medical sciences. 2019;74(5):342-350
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EPIDEMIOLOGY: CURRENT ISSUES
Multivariate analysis of the megacity population immunity to measles
Semenenko T.A., Nozdracheva A.V., Asatryan M.N., Akimkin V.G., Tutelyan A.V., Shmyr I.S., Ershov I.F.
Abstract

Background: The significant reduction of measles and rubella morbidity and child mortality, which allowed WHO to set a target for their elimination by 2010, is one of the finest examples of the vaccine prevention effectiveness in the fight against infectious diseases. However, in the period from 2010 to 2019 there was a controversial situation with respect to measles, characterized by the presence of high vaccination coverage of the population on the one hand, and an increase in the incidence on the other. Obviously, the key point in resolving these contradictions is to analyze the susceptibility of the population.

Aim: Of the study was to assess the susceptibility of Moscow population to measles in the context of factors affecting its formationю.

Methods: Epidemiological, serological, statistical methods and GIS technologies were used in the work. The serological study (using the solid-phase ELISA method) included 2410 blood serum samples collected between 2013 and 2017 from healthy residents of Moscow aged from birth to 60 years. On the basis of documents on sanitary and epidemic investigation of measles cases in Moscow (2013−2015) a relational database under the management of MySQL Database Management System was formed, based on the analysis of which the coverage of the population with preventive vaccinations was estimated.

Results: Оn average, the proportion of seronegative persons to measles in 2016−2017, compared with 2013−2014 (20.5%) increased and amounted to 29.0% mainly due to the group over 36 years. The most vulnerable were children aged 1−2 years and 3−6 years, where the share of the immune persons amounted to 51,5% and 37.9%, respectively, at low coverage in a planned manner (55,9% [95% CI, 52.2 per cent; of 59.5%] and 75,3% [95% CI, 73.3 per cent; for 77.2%]). The proportion of vaccinated persons who lost post-vaccination immunity under the influence of factors preventing its formation (from 3.6% to 21.6% in the group of 7−14 years; from 11.8% to 26.4% in the group of 15−17 years) was calculated. The possibility of visualizing the spread of measles on electronic maps for the territorial and temporal analysis of the epidemic situation is shown.

Conclusions: It is reasonable to assume that over the time, the proportion of people who have suffered measles will decrease, and the proportion of people not covered by vaccination or lost post-vaccination immunity - increase, that can lead to a decrease in herd immunity and requires correction of vaccination work. The proposed information and analytical system for monitoring the epidemiological situation allows to work quickly with heterogeneous resources and choose on electronic maps the area of interest from the global level (country) to the local (house), which is necessary for the adoption of scientifically based preventive and epidemiological measures.

Annals of the Russian academy of medical sciences. 2019;74(5):351-360
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