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Vol 75, No 5 (2020)

Clinical and Immunomorphological Features of Liver Damage in Severe Preeclampsia
Sidorova I.S., Nikitina N.A., Ageev M.B., Kokin A.A.

Background. Liver diseases associated with pregnancy are recorded in 0.7–3% of pregnant women, often accompanied by the development of hepatic dysfunction/insufficiency, and are the cause of increased morbidity and mortality in both mother and child. A pathomorphological study helps to understand the pathophysiology of severe liver damage in preeclampsia, and to optimize the management of such patients. Aims — to study the clinical, morphological and immunohistochemical features of liver tissue lesions in the most severe forms of preeclampsia and eclampsia, which ended in death. Methods. Autopsy material analysis of 10 patients who died from preeclampsia, eclampsia and their complications (main group) and 3 patients who died from other causes (comparison group). Pathomorphological and immunohistochemical studies of organs and tissues (in particular, liver tissue) were performed using a marker of neurons and neuroendocrine cells γ-NSE and a marker of endotheliocytes CD-34. Results. An immunohistochemical study with a CD-34 endotheliocyte marker in the main group revealed a vascularization deficiency in the 2nd and 3rd zone of hepatic acini, there were also foci of necrosis. Such changes indicate deep and prolonged hypoperfusion. The use of the NSE marker in the group of patients who died from preeclampsia/eclampsia revealed a sharp increase in Kupffer cells in the first and second zones of acini with pronounced immunoexpression of NSE in the nuclei and cytoplasm of these cells, which indicates severe hepatic dysfunction (in particular, impaired detoxification and elimination functions of the liver). At the same time, only 3 out of 10 women in the main group are clinically registered with HELLP syndrome, while the rest had signs of multiple organ (including acute liver) failure. Conclusions. The clinical symptoms of liver damage, including those with severe preeclampsia, arise, as a rule, already against the background of severe morphological changes in its tissue and, as a rule, indicate functional decompensation. Liver immunology remains little studied, which requires further research on this problem.

Annals of the Russian academy of medical sciences. 2020;75(5):481–489
A Randomized Controlled Study of the Effectiveness of Electrophysiological Monitoring of Dexmedetomidine in Patients with Brain Damage of Various Origins
Kiryachkov Y.Y., Petrova M.V., Muslimov B.G., Bosenko S.A., Gorlachev M.M.

Background. At the same time, the main effect of the use of this drug is the elimination of the autonomic nervous system dysfunction and sympatholysis. It seems important to search for a method of indications and selection of a dose of dexmedetomidine in intensive care. Aims — to improve the clinical effectiveness of the electrophysiological navigation of the prolonged use of dexmedetomidine in patients with brain pathology of various origins. Methods. The study included 83 patients 20–50 days after the traumatic brain injury, anoxic damage; consequences of acute disorders of cerebral. 37 patients comprised the 1st intervention group with a clinical course of dexmedetomidine (male — 28; female — 9; average age 49.6 ± 2.3 years) and 46 patients comprised the 2nd control group without pharmacological correction with dexmedetomidine (male — 23; female — 23, average age 51 ± 2.5 years). Criteria for the inclusion of prolonged infusion of the drug dexmedetomidine (Orion Pharma, Finland) are based on heart rate variability (HRV) indicators characteristic of sympathetic hyperactivity, the target task of titration of doses of dexmedetomidine served as the parameters for achieving normal HRV indicators, the appearance of parasympathetic hyperactivity served as the basis for reducing the dosage of the drug or stopping it of application. HRV parameters were recorded before dexmetomedine infusion-initially, on 1–3; 4–5; 9–10; 15–20 days of drug administration. Results. The starting dose of dexmedetomidine with sympathetic hyperactivity in patients was 0.12 to 0.24 μ––1 (average dose 0.16 ± 0.01; total 200 mg/day). According to digital data from HRV, the effective dose of dexmedetomidine ED50 was 0.26 ± 0.03 μ––1 (total daily 353.8 ± 35.1 μg) and was achieved on day 9–10 using dexmedetomidine. Conclusions. The protective role of dexmedetomidine with correction of sympathetic hyperactivity based on electrophysiological navigation according to the HRV is reliable in the following indicators: The improvement of consciousness; a significant decrease in the incidence of distress lung syndrome; septic shock; mortality.

Annals of the Russian academy of medical sciences. 2020;75(5):490-499
DERMATOLOGY and VENEROLOGY: current issues
Cytokine Levels of Skin Lesions in Moderate and Severe Psoriasis as Predictors for the Type 4 Fosphodiesterase Inhibitor (Apremilast) Therapy Effectivness
Kubanov A.A., Artamonova O.G., Karamova A.E., Vasileva E.L., Deryabin D.G.

Background. Psoriasis is a widespread skin disorder characterized by cytokines as the main modulators of skin inflammation. A promising psoriasis therapy approach is targeted on cytokine networks by inhibiting the phosphodiesterase 4 (PDE-4). The efficacy and safety of the PDE-4 inhibitor apremilast in psoriasis confirmed in multicenter controlled studies, which, however, are accompanied by reports of unsuccessful therapy cases. Aims — to determine early immunological predictors for PDE-4 inhibitor (apremilast) therapy efficacy based on skin lesions cytokines analyzes in patients with moderate to severe psoriasis. Methods. An open, uncontrolled prospective clinical study was performed. Efficacy of apremilast was analyzed by PASI, BSA, sPGA and DLQI. The outcomes at 26 therapy week were compared with the cytokine levels in skin biopsies selected before starting therapy and analyzed using xMAP technology. The multiparameter prognostic model for apremilast therapy effectiveness was developed based on a heterogeneous sequential recognition procedure. Results. The 34 patients with moderate to severe psoriasis were included in the study. According to the clinical outcomes, two comparison groups were formed: high (75% reduction in PASI score or more; n = 14) and insufficient (50% reduction in PASI score or less; n = 20) apremilast efficiency. Cytokines analyses showed an inverse relationship between the initial anti-inflammatory IL-10 level and the PASI reduction (r = –0.37; p < 0.025). On the other hand, the relationships between pro-inflammatory cytokines IL-1β and IL-6 levels and PASI score at the 26th week of therapy were characterized by positive correlation: r = 0.31 (p < 0.05) and r = 0.37 (p < 0.025), respectively. Based on the data obtained, a predictive model for the apremilast therapy efficiency was developed. The expected predictive values of this model were 86% for a high therapy effectiveness and 60% for an insufficient effectiveness, respectively. Conclusions. The study results for the first time describe the cytokine profiles in the skin lesions in patients, who responded differently to PDE-4 inhibitor therapy. These dada allows to predict the treatment efficacy and give a chance to personalize apremilast usage for the moderate and severe psoriasis treatment.

Annals of the Russian academy of medical sciences. 2020;75(5):500-507
Features of Takotsubo Syndrome in Male Patients
Karaoglanova T.E., Manzyuk A.V.

Takotsubo syndrome has particular significance among heart diseases, as with the increase in the number of publications, there is more and more evidence that this syndrome can cause serious complications and even death of patients. Similarity with acute coronary syndrome is even more important reason for interest in Takotsubo syndrome, coupled with the lack of a clear diagnostic criterion to distinguish these pathologies. The lack of understanding of the pathogenesis of Takotsubo syndrome is one of the obstacles to the formation of such a diagnostic criterion. Despite a large number of publications on the causes and pathogenesis of Takotsubo syndrome, course of the disease has not been studied in men, since this pathology is much more often observed in women. Identifying the gender characteristics of this disease and their causes can be an important step towards explaining the pathogenesis of Takotsubo syndrome. In this review, a sample of 45 clinical cases of Takotsubo syndrome in men was compared with a mixed group from a clinical study. Takotsubo syndrome in men has a number of distinctive features: the greater importance of physical stress in the structure of the causes, in contrast to the predominance of emotional stress in the mixed group, a higher proportion of the basal form of the disease, as well as a significant decrease in the ejection fraction of the left ventricle and the frequent occurrence of cardiogenic shock manifestations of a more severe course of this disease.

Annals of the Russian academy of medical sciences. 2020;75(5):508-513
The Results of the Use of Angiotensin Receptor Inhibitors and Neprilisin in Secondary Functional Mitral Regurgitation in Outpatient Practice
Ryazanov A.S., Kapitonov K.I., Makarovskaya M.V., Kudryavtsev A.A.

Background. Morbidity and mortality in patients with functional mitral regurgitation (FMR) remains high, however, no pharmacological therapy has been proven to be effective. Aims — to study the effect of sacubitrile/valsartan and valsartan on functional mitral regurgitation in chronic heart failure. Methods. This double-blind study randomly assigned sacubitrile/valsartan or valsartan in addition to standard drug therapy for heart failure among 100 patients with heart failure with chronic FMR (secondary to left ventricular (LV) dysfunction). The primary endpoint was a change in the effective area of the regurgitation hole during the 12-month follow-up. Secondary endpoints included changes in the volume of regurgitation, the final systolic volume of the left ventricle, the final diastolic volume of the left ventricle, and the area of incomplete closure of the mitral valves. Results. The decrease in the effective area of the regurgitation hole was significantly more pronounced in the sacubitrile/valsartan group than in the valsartan group (–0.07 ± 0.066 against –0.03 ± 0.058 sm2; p = 0.018) in the treatment efficacy analysis, which included 100 patients (100%). The regurgitation volume also significantly decreased in the sacubitrile/valsartan group compared to the valsartan group (mean difference: –8.4 ml; 95% CI, from –13.2 until –1.9; р = 0.21). There were no significant differences between the groups regarding changes in the area of incomplete closure of the mitral valves and LV volumes, with the exception of the index of the final LV diastolic volume (p = 0.07). Conclusion. Among patients with secondary FMR, sacubitril/valsartan reduced MR more than valsartan. Thus, angiotensin receptor inhibitors and neprilysin can be considered for optimal drug treatment of patients with heart failure and FMR.

Annals of the Russian academy of medical sciences. 2020;75(5):514-522
Mechanisms of Arrhythmogenesis and Risk Factors for Thromboembolic Events in Patients with Atrial Fibrillation without Concomitant Coronary and Valvular Heart Disease
Golukhova E.Z., Gromova O.I., Bulaeva N.I., Arakelyan M.G.

Aims  identification the correlates between parameters of tissue Doppler imaging, EF thickness by MRI and biochemical markers of fibrosis and inflammation in patients with nonvalvular AF. Retrospectively to evaluate clinical and instrumental parameters influencing the development of thromboembolic events. Methods. Data analysis was performed on 151 patients with different type of AF. A retrospective analysis included 112 patients. 15 (13%) had a history of LAA thrombosis and/or thromboembolic events (stroke, TIA). The prospective analysis included 39 patients. We identified groups with idiopathic AF (N = 21), AF with arterial hypertension (N = 18). And also a group with normal or slightly enlarged (<4.5 sm) LA s (N = 29), and with LA ≥ 4.5 sm (N = 10). Echocardiography with tissue Doppler imaginе and cardiac MRI were performed. The level of: matrix metalloproteinases (MMP-2, MMP-9), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), transforming growth factor beta-1 (TGF beta-1), soluble intercellular adhesion molecule (sICAM) was assessed. Results. The following parameters were significantly associated with LA thrombosis and thromboembolic events: age over 50 years (p = 0.001), obesity (p = 0.036), persistent AF (p = 0.003), the phenomenon of spontaneous ECHO contrast in LA (p = 0.03), the blood flow velocity in the LAA less than 30 sm / s (p = 0.005), morphological type III of LAA (p = 0.012). The greatest correlation between the thickness of the EFT and biomarkers was observed relative to: MMP-9 (τ  = 0.65; Tcr = 0.16), TIMP-1 (τ = 0.71; Tcr = 0.18) in the group of idiopathic AF; and TGF-beta1 (τ = 0.22; Tcr = 0.19) in the general group. The percentage of left atrial myocardial fibrosis was correlated with TIMP-1 levels. There was a correlation between E/e‘ and MMP-9, TIMP-1 in patients with idiopathic AF (τ = 0.65; Tcr = 0.16 and τ = 0.56; Tcr = 0.21 respectively). Conclusion. The increasing levels of MMP-9 and TIMP-1 are associated with epicardial fat thickness by MRI. In addition to CHA2DS2VASc scale, we identified novel predictors of LA thrombosis and/or thromboembolic events, which are: chronic type AF, low LAA blood flow velocity, the phenomenon of spontaneous ECHO contrast in LA and the morphological LAA type III by CT.

Annals of the Russian academy of medical sciences. 2020;75(5):523-531
Effect of Anesthesia in the Ante- and Intranatal Periods of Development on the Cognitive Status of Children Aged from 0 to 3 Years
Aleksandrovich Y.S., Gorkovaya I.A., Miklyaeva A.V.

The article presents the results of a systematic review of publications aimed at analizing the effects of anesthesia during ante- and intranatal periods of development on the cognitive status of infants and young children. The search for publications was carried out by analyzing electronic bibliographic databases Web of Science and PubMed. The analysis revealed five factors, which determine the effects of ante- and intranatal anesthesia on the cognitive development of children: the type of anesthesia, the type of anesthetic, the period of child’s development, the frequency and duration of exposure as well as the dosage and concentration of the substance. Such cognitive functions as memory, learning ability, speech, perceptual processes and motor activity as a predictor for intelligence formation in early childhood are the most vulnerable to the effects of ante- and intranatal anesthesia. The analysis led to the conclusion that regional anesthesia is the safest option of analgesia for operative delivery and non-surgical operations in pregnant women (in terms of the risks of neurocognitive development disorders in children). In the case of general anesthesia, the lowest risks of negative consequences for cognitive status of a child during early childhood are associated with the exposure of sevoflurane.

Annals of the Russian academy of medical sciences. 2020;75(5):532-540
Molecular Markers in Occupational Chronic Obstructive Pulmonary Disease Comorbid with Heart Failure
Shpagina L.A., Kamneva N.V., Shpagin I.S., Kotova O.S., Anikina E.V., Gerasimenko D.A.

Background. Comorbid heart failure (HF) is common in chronic obstructive pulmonary disease (COPD). Comorbid condition features are studied well in COPD due to tobacco smoke. There is a lack of data about mechanisms, clinical and functional specificity of occupational COPD and HF comorbidity. As occupational COPD and HF share common symptoms and sometimes lung function disorders, there is an unmet need in new markers of HF in occupational COPD. Aims — to establish molecular markers associated with occupational COPD with HF comorbidity. Methods. Subjects with occupational COPD were enrolled in a single-center prospective cohort observational study. Comparison group — COPD due to tobacco smoke. Then groups were stratified according to HF so the following subgroups were compared: occupational COPD with HF (n = 63), occupational COPD without HF (n = 52), COPD due to tobacco smoke with HF (n = 41), COPD due to tobacco smoke without HF (n = 74). Control group — healthy people (n = 115). Groups were matched by demographics, duration of COPD and HF. CODP was diagnosed according to GOLD 2011–2020 criteria, HF — according to Russian Federal clinical guidelines. Occupational etiological factors were silica dust, organic solvents, metal fumes. Clinical and functional characteristics of CODP and HF were obtained. Serum levels of pulmonary and activation-regulated chemokine (PARC/CCL-18), protein S100β, troponin, N terminal pro brain natriuretic peptide (NT-pro-BNP), von Willebrand factor, C-reactive protein were measured by enzyme linked immunosorbent assay, fibrinogen were measured by Clauss method, lactate dehydrogenase, creatine phosphokinase, alanine aminotransferase, aspartate aminotransferase were measured by standard biochemical method. Data are presented as median and interquartile range. Linear regression were used to explore relationships. Results. The molecular specificity of occupational COPD comorbid with HF were the largest increase in serum concentration of PARC-CCL18, NT-pro-BNP, protein S100β, troponin, von Willebrand factor and fibrinogen. This factors were associated with length of service. For PARC-CCL18 В = 1.1; for NT-pro-BNP В = 0.9; for protein S100β В = 1.3; for troponin В = 0.8, for von Willebrand factor В = 1.5 and for fibrinogen В = 1.1. Molecular factors also were related to phenotype characteristics of COPD and HF. In multiply regression model the best predictors of comorbidity of CODP and HF were PARC-CCL18 (В = 1.1; р = 0.002), NT-pro-BNP (В = 1.5; р = 0.001), protein S100β (В = 1.2; р = 0.002), troponin (В = 0.9; р = 0.003). The model was adjusted for gender, age, duration of CODP and HF, FEV1. Conclusions. Occupational CODP comorbid with heart failure is the distinct phenotype. The perspective molecular markers of this phenotype are serum levels of PARC-CCL18, NT-pro-BNP, protein S100β, troponin.

Annals of the Russian academy of medical sciences. 2020;75(5):541-551
Vitamin D Effects on Guided Bone Regeneration and Osseointegration of Dental Implants (Literature Review)
Ivanov S.Y., Kalinchenko S.Y., Guseynov N.A., Muraev A.A., Safi A.Т., Polyakov K.A., Smykalova A.S.

Background. Due to the prevalence of Vitamin D deficiency as well as the frequency of reconstructive surgical interventions followed by dental implantation, the issue arises concerning the effect of Vitamin D on reparative regeneration of bone and osseointegration of dental implants. The purpose — using literature data we are conducting an impact assessment of vitamin D on reparative regeneration of bone tissue, in particular, after oral reconstruction surgeries and dental implantation. Methods. Retrieval, systematization and analysis of scientific data on application of vitamin D supplementation and its effect on reparative regeneration of jaw bone tissue. The conclusions. For the most part, the positive effect exerted on reparative regeneration of jaw bone tissue and osseointegration of dental implants is due to the role of vitamin D in physiological processes evolving in bone tissue, namely maintenance of calcium and phosphate exchange through intestinal absorption and TNFα, RANKL (Receptor activator of nuclear factor kappa-B ligand) and consequently differentiation of precursors to osteoclasts into osteoclasts through VDR stimulation (Vitamin D Receptor) – receptors for further osteogenesis. Also, according to literature data, FGF23 (Fibroblast Growth Factor) protein is a marker of osteoblasts differentiation into osteocytes, it is also known that FGF23 and 1,25(ОН)2D3 are genetically related. FGF23 is the main regulator of both phosphate exchange in bones and metabolism of vitamin D and its metabolites. Besides, indirect anti-inflammatory effect has been observed thanks to inhibition of pro-inflammatory cytokine secretion. Taking into account the abovementioned data, of particular relevance is the definition of serum concentration 25(ОН)D and development of schemes of vitamin D level pre-surgery correction in patients, who have to undergo oral reconstruction surgeries and dental implantation. Mass spectrometry is a promising diagnostic method for determining the level of vitamin D in a body, as it allows to identify the actual amount of vitamin D free from admixture of other steroid hormones. The introduction of this method into clinical practice will allow to monitor the level of vitamin D in patients, receiving reconstructive and rehabilitative treatment.

Annals of the Russian academy of medical sciences. 2020;75(5):552-560
Feeder-Free Cell Culture of Labial Oral Mucosal Epithelium for Tissue-Engineering and Regenerative Medicine
Borzenok S.A., Malyugin B.E., Gerasimov M.Y., Ostrovskiy D.S., Shatskikh A.V.

Background. The cultured cheek mucosa epithelium (buccal epithelium, BE) is used for autologous transplants generation and tissue engineering. An alternative source of cells for these purposes may be the lip mucosa, covered, like BE, with non-keratinized stratified squamous epithelium, but with some histological distinctions. Aims — to characterize the human lip mucosa as a promising source of epithelial cells for autologous transplantation and tissue engineering. Methods. Scrapings of the lip, cheek, and gum mucosa from five healthy volunteers were analyzed by cytofluorimetry to determine the level of desquamation and cytokeratin (CK) 10 and 13 expression. The lip mucosa of two patients was characterized using routine histological staining and fluorescence immunohistochemistry for CK 3, 4, 10, 13, and p63 marker. 35 samples of full-thickness strips of the patient’s lip mucosa were used to set the explant (n = 18) and enzymatic (n = 17) techniques for expansion epithelium. Culture systems with 1.05 and 0.06 mM Calcium contained 5% fetal bovine serum, 5 μg/ml human insulin, 5 μg/ml hydrocortisone, 10 ng/ml human epidermal growth factor. Stable cultures were stained for p63, vimentin, zonula occludens-1 (ZO-1), and CK10. Software tools determined levels of their expression. Results. The number of cells in the lip and gum samples was significantly lower than from the cheek. The median number of CK13 positive cells was significantly different for the gum (6.4%) and cheek (64.8%, p = 0.0089). Significant differences for CK10 positive cells were not observed. The epithelium of the lip mucosa was 72.1 ± 3.6 μm thick, relatively flat, and without keratinization sites. Samples were positively stained for CK 4 and 13, in the absence of expression of CK 3 and 10. The primary culture of epithelial cells obtained by explant technique was significantly more effective (p = 0.001) in comparison with the enzymatic method. Stable cultures had a “cobble-stone” morphology in both culture systems. The levels of vimentin and p63 expression in both culture systems was not significantly differ. ZO-1 expression was 3.6-fold higher for 1.05-mM Ca++ medium (p = 0.0006). Conclusions. Epithelium cell culture from the lip mucosa can be obtained by culturing explants without a feeder layer. Quality control steps have been developed for cultured cells and biopsy site.

Annals of the Russian academy of medical sciences. 2020;75(5):561-570
Pokrovskiy Valentin Ivanovich

On October 29, 2020, the leader of Russian medicine, a great scientist and teacher, a truly great doctor, mentor of Russian infectious disease specialists and epidemiologists, the founder of a medical dynasty, advisor to the director for innovation of the Central Research Institute of Epidemiology of Rospotrebnadzor, professor, academician of the Russian Academy of Sciences Valentin Ivanovich Pokrovsky passed away.

Annals of the Russian academy of medical sciences. 2020;75(5):571-571

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