[Clinical and morphological features of lung injury long-term after SARS-CoV-2 recovery].

AIM: To study the clinical and histological profile of lung tissue in patients with persistent pulmonary disease, respiratory symptoms and CT findings after SARS-CoV-2 infection. MATERIALS AND METHODS: The study included 15 patients (7 females and 8 males) with a mean age of 57.7 years. All patients underwent laboratory tests, chest computed tomography, echocardiography, and pulmonary function tests. Pulmonary tissue and bronchoalveolar lavage samples were obtained by fibrobronchoscopy, transbronchial forceps (2 patients), and lung cryobiopsy (11 patients); open biopsy was performed in 2 patients. Cellular composition, herpesvirus DNA, SARS-CoV-2, Mycobacterium tuberculosis complex, galactomannan optical density index, and bacterial and fungal microflora growth were determined in bronchoalveolar lavage. SARS-CoV-2 was also identified in samples from the nasal mucosa, throat and feces using a polymerase chain reaction. RESULTS: The results showed no true pulmonary fibrosis in patients recovered from SARS-CoV-2 infection with persistent respiratory symptoms, functional impairment, and CT findings after SARS-CoV-2 infection. The observed changes comply with the current and/or resolving infection and inflammatory process. CONCLUSION: Thus, no true pulmonary fibrosis was found in patients after SARS-CoV-2 infection with persistent respiratory symptoms, functional impairment, and CT findings. The observed changes comply with the current and/or resolving infection and inflammatory process.

[Nimodipine in treatment of bipolar disorder]. / Primenenie nimodipina v terapii bipolyarnogo affektivnogo rasstroistva.

The purpose of this review is to correlate current data on the molecular mechanisms of action of the drug Nimodipine with its clinical effects and applicability in mental disorders belonging to the spectrum of affective pathology. The article discusses the prospects for using the calcium channel blocker nimodipine as a method of both mono and combination therapy for bipolar disorders with various types of course. Nimodipine is a selective blocker of voltage-dependent calcium channels, a dihydropyridine derivative. By blocking L type calcium channels, it prevents the entry of calcium ions into the cell. Due to its pronounced ability to penetrate the blood-brain barrier, it has a selective effect on brain neurons and has a vasodilating, antihypertensive and normotimic effect. Nimodipine blocks LTCC channels in brain neurons, thereby influencing synaptic plasticity, transmitter release and excitation-transcription coupling, which makes it possible to influence various clinical conditions with pathology in the area of affect, including bipolar disorders with ultra-rapid cycling, and also, in cases with high resistance and intolerance to other mood stabilizers.

[Treatment of mental disorders caused or triggered by somatic and neurological diseases with the use of the multimodal antidepressant trazodone]. / Terapiya psikhicheskikh rasstroistv, obuslovlennykh libo provotsirovannykh somaticheskoi i nevrologicheskoi patologiei, s primeneniem mul'timodal'nogo antidepressanta trazodon.

The purpose of this narrative review is to relate current data on the molecular mechanisms of action of trazodone with its clinical effects and applicability in mental disorders caused or triggered by somatic and neurological disease, according to available publications. In the article, the prospects for the use of the multimodal antidepressant trazodone are discussed in accordance with therapeutic targets. The latter are discussed in accordance with the typology of the mentioned above psychosomatic disorders. Trazodone is an antidepressant acting primarily due to the blockade of postsynaptic serotonin 5H2A- and 5H2C-receptors, as well as the blockade of serotonin reuptake, but also has affinity for a number of additional receptors. The drug has a favorable safety profile and a wide range of beneficial effects: antidepressive, somnolent, anxiolytic, anti-dysphoric and somatotropic. This makes it possible to influence a wide range of therapeutic targets in the structure of mental disorders caused or triggered by somatic and neurological diseases, carrying out safe and effective psychopharmacotherapy.

[Comparative pathomorphological characteristics of idiopathic pulmonary fibrosis and fibrotic hypersensitivity pneumonitis]. / Sravnitel'naya patomorfologicheskaya kharakteristika idiopaticheskogo legochnogo fibroza i fibroznogo giperchuvstvitel'nogo pnevmonita.

The paper presents an X-ray morphological differential diagnosis of idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (FHP). It describes the etiology, pathogenesis, radiological signs, and pathoanatomy of IPF and FHP. For differential diagnosis, radiological and morphological signs were studied in 105 patients with IPF and in 111 patients with FHP. The mean ages of patients with IPF or FHP were 65.0±8.9 and 48.9±12.3 years, respectively. The history of IPF to the moment of its diagnosis ranged from 1 to 18 months, while that of FHP was 35 to 79 days. The authors describe the additional morphological signs of FHP: delicate collagen fibrosis; smooth muscle metaplasia in the interalveolar septa and fibrotic areas; fibroblastic foci mainly in the walls of bronchioles; plasma cell infiltration of interalveolar septa with a touch of neutrophils and eosinophils. A table has been compiled for differential diagnosis according to the morphological signs of IPF and FHP.

Pathological Features in 100 Deceased Patients With COVID-19 in Correlation With Clinical and Laboratory Data.

Background: Autopsies on COVID-19 deceased patients have many limitations due to necessary epidemiologic and preventative measures. The ongoing pandemic has caused a significant strain on healthcare systems and is being extensively studied around the world. Clinical data does not always corelate with post-mortem findings. The goal of our study was to find pathognomonic factors associated with COVID-19 mortality in 100 post-mortem full body autopsies. Materials and Methods: Following necessary safety protocol, we performed 100 autopsies on patients who were diagnosed with COVID-19 related death. The macroscopic and microscopic pathologies were evaluated along with clinical and laboratory findings. Results: Extensive coagulopathic changes are seen throughout the bodies of diseased patients. Diffuse alveolar damage is pathognomonic of COVID-19 viral pneumonia, and is the leading cause of lethal outcome in younger patients. Extrapulmonary pathology is predominantly seen in the liver and spleen. Intravascular thrombosis is often widespread and signs of septic shock are often present. Conclusion: The described pathological manifestations of COVID-19 in deceased patients are an insight into the main mechanisms of SARS-CoV-2 associated lethal outcome. The disease bears no obvious bias in severity, but seems to be more severe in some patients, hinting at genetic or epigenetic factors at play.

Telocytes in the Myocardium of Children with Congenital Heart Disease Tetralogy of Fallot.

Telocytes, a new type of interstitial stem cells with long thin processes that form a three-dimensional network around cardiomyocytes, vessels, and nerve fibers were described in the myocardium of children with tetralogy of Fallot. Two types of morphologically different telocytes, spindle-shaped and rounded, were identified. Contacts of telocytes with stem cells and interstitial macrophages were found. Telocytes were more common in the immature myocardium, where the assembly of myofibrils in cardiomyocytes was not completed and small Ki-67+ cardiomyocyte progenitor cells were present. Telocytes expressed immunohistochemical markers CD117, vimentin, CD34, and CD44. Localization and ultrastructural characteristics of telocytes suggested their participation in stem cell differentiation, coordination of neoangiogenesis, and paracrine regulation of all components of the interstitium.

[Histological differential diagnosis of granulomatous lung diseases (Part II)]. / Gistologicheskaia differentsial'naia diagnostika granulematoznykh boleznei legkikh (chast' II).

Granulomatous diseases are a heterogeneous group of the diseases of different etiology, which are manifested by a variety of clinical syndromes and variants of tissue changes, by non-uniform sensitivity to therapy and by the predominance of the common dominant histologic sign - the presence of granulomas that determine the clinical and morphological essence of each disease. Granuloma is a chronic inflammatory response, which involves macrophages and other inflammatory cells. After antigen exposure, the activation of T lymphocytes, macrophages, epithelioid cells, and multinucleated giant cells results in granuloma formation. Granuloma also contains the extracellular matrix produced by fibroblasts, which can demarcate and isolate the antigen. Granulomatous diseases are classified by their etiology as infectious and non-infectious. However, recent investigations demonstrate that pathogenic microorganisms can cause granulomas in the diseases previously considered non-infectious. In some cases, it is very difficult to classify a granulomatous process as infectious and non-infectious. The aim of this paper is to draw the attention of readers to the diversity of granulomatous diseases, to describe the key points of pathological and anatomical manifestations of various infectious diseases, and to determine an approach to the differential diagnosis of granulomatoses.

[Histological differential diagnosis of granulomatous lung diseases (part I)]. / Gistologicheskaia differentsial'naia diagnostika granulematoznykh boleznei legkikh (chast' I).

Granulomatous diseases are a heterogeneous group of the diseases of different etiology, which are manifested by a variety of clinical syndromes and variants of tissue changes, by non-uniform sensitivity to therapy, and by the predominance of the common dominant histologic sign - the presence of granulomas that determine the clinical and morphological essence of each disease. Granuloma is a chronic inflammatory response, which involves macrophages and other inflammatory cells. After exposure to an antigen, T-lymphocytes, macrophages, epithelioid cells, and multinucleated giant cells are activated, resulting in the formation of granulomas. Granuloma also includes the extracellular matrix produced by fibroblasts, which can demarcate and isolate the antigen. According to etiology, granulomatous diseases are classified as infectious and non-infectious. However, recent investigations demonstrate that pathogenic microorganisms can cause granulomas in diseases previously considered non-infectious. In some cases, it is very difficult to classify a granulomatous process as infectious and non-infectious. The aim of this paper is to draw the attention of readers to the diversity of granulomatous diseases, to describe the key points of pathological and anatomical manifestations of various non-infectious diseases, as well as to determine an approach to the differential diagnosis of granulomatoses.

[Kaposi's sarcoma in the grafted lung]. / Sarkoma Kaposhi v transplantirovannykh legkikh.

The paper provides a clinical note. A 45-year-old patient suffered from severe primary emphysema and underwent bilateral lung transplantation. A year after surgery, exercise dyspnea again appeared in the patient. Lung computed tomography revealed multiple rounded soft tissue masses; thoracoscopic biopsy and further histological examination proved the development of Kaposi's sarcoma in the patient. The tumor disappeared completely following corrected immunosuppressive therapy. After 22 months of transplantation, the patient died from gastrointestinal bleeding. This case is of interest due to that Kaposi's sarcoma develops extremely rarely in the allogeneic lung after its transplantation.

[Morphogenetic Networks which Determine the Spatial Expression of Zygotic Genes in Early Drosophila Embryo].

This review deals with the recent studies expanding the idea of positional information in the early embryogenesis of Drosophila melanogaster. Previous studies showed that, in the course of segment determination in Drosophila, information created by gradients of products of maternal coordinate genes is not "read" statically, being interpreted by their zygotic target genes via regulatory interactions. This leads to spatial shifts in the expression of target genes relative to the original positions as well as to dynamic reduction in the zygotic expression variability. However, according to recent data, interpretation of positional information includes the interaction between not only zygotic target genes but also the maternal coordinate genes themselves. Different systems of maternal coordinate genes (maternal systems)­the posterior-anterior, terminal, and dorsoventral­ can interact with each other. This is usually expressed in the regulation of zygotic target genes of one maternal system by other maternal systems. The concept of a "morphogenetic network" was introduced to define the interaction of maternal systems during determination of spatial gene expression in the early Drosophila embryo.

[Numerical Analysis of Particle Trajectories in Living Cells under Uncertainty Conditions].

We have developed a numerical method for the analysis of particle trajectories in living cells, where a type of movement is determined by Akaike's information criterion, while model parameters are identified by a weighted least squares method. The method is realized in computer software, written in the Java programming language, that enables us to automatically conduct the analysis of trajectories. The method is tested on synthetic trajectories with known parameters, and applied to the analysis of replication complexes in cells, infected with hepatitis C virus. Results of the analysis are in agreement with available data on the movement of biological objects along microtubules.

[The dynamics of feed-forward loop depends on regulator type in indirect pathway].

Gene networks contain a recurring motif, called the feed-forward loop, in which a transcription factor regulates target expression directly and indirectly via the second regulator. Here we present the results of mathematical modeling of feed-forward loops with either the transcription factor or miRNA as a repressor in the indirect pathway. We showed that the substitution of the transcription factor with miRNA changes the dynamic behavior of the feed-forward loop and lends new properties critical for biological system functioning.

[Modelling of Drosophila gap gene network under Bcd morphogen variation].

Expression patterns of segmentation genes are formed under the influence of maternal transcription factor gradients, which initiate spatially localized expression in the cascade of segmentation genes. Bcd is one of these activators. We have studied one model of regulation in the gap gene network by varying the concentration of this protein. We have shown that the known gap gene network topology is not sufficient to explain experimental data on the shifts exhibited by the hb anterior expression domain by change in Bcd concentration in the embryo. As the result of modeling with these experimental data taken into account, a new topology is obtained that determines the correct shifts of the hb expression domain. These results suggest that interactions among the three hb, Kr and gt genes are key regulatory factors for the valid behaviour of the hb expression pattern with Bcd concentration changes. This study made it possible to specify the limits of validity for phenomenological models of gene networks.

[Method of Entirely Parallel Differential Evolution for Model Adaptation in Systems Biology].

We developed a method of entirely parallel differential evolution for identification of unknown parameters of mathematical models by minimization of the objective function that describes the discrepancy of the model solution and the experimental data. The method is implemented in the free and open source software available on the Internet. The method demonstrated a good performance comparable to the top three methods from CEC-2014 and was successfully applied to several biological problems.

[Pathomorphological features of pulmonary Langerhans cell histiocytosis].

The paper provides the clinical and X-ray characteristics of pulmonary Langerhans cell histiocytosis (PLCH). It describes pulmonary pathohistological changes in this disease, characterizes the cellular composition of granuloma, and gives methods that can verify the diagnosis of PLCH. A case of PLCH with severe respiratory failure, for which bilateral lung transplantation and histological examination of removed lungs have been made, is described.

[A method for solution of the multi-objective inverse problems under uncertainty].

We describe a method to solve multi-objective inverse problems under uncertainty. The method was tested on non-linear models of dynamic series and population dynamics, as well as on the spatiotemporal model of gene expression in terms of non-linear differential equations. We consider how to identify model parameters when experimental data contain additive noise and measurements are performed in discrete time points. We formulate the multi-objective problem of optimization under uncertainty. In addition to a criterion of least squares difference we applied a criterion which is based on the integral of trajectories of the system spatiotemporal dynamics, as well as a heuristic criterion CHAOS based on the decision tree method. The optimization problem is formulated using a fuzzy statement and is constrained by penalty functions based on the normalized membership functions of a fuzzy set of model solutions. This allows us to reconstruct the expression pattern of hairy gene in Drosophila even-skipped mutants that is in good agreement with experimental data. The reproducibility of obtained results is confirmed by solution of inverse problems using different global optimization methods with heuristic strategies.

[Replication of the subgenomic hepatitis C virus replicon in the presence of the NS3 protease inhibitors: a stochastic model].

The hepatitis C virus (HCV) belongs to Flaviviridae family and causes hazardous liver diseases leading frequently to cirrhosis and hepatocellular carcinoma. HCV is able to rapidly acquire drug resistance and for this reason there is currently no effective anti-HCV therapy in spite of appearance of new potential drugs. Mathematical models are relevant to predict the efficacy of potential drugs against virus or host targets. One of the promising targets for development of new drugs is the viral NS3 protease. Here we developed a stochastic model of the subgenomic HCV replicon replication in Huh-7 cells and in the presence of the NS3 protease inhibitors. Along with consideration of the stochastic nature of the subgenomic HCV replicon replication the model takes into account the existence and generation of main NS3 protease drug resistant mutants, namely BILN-2061 (A156T, D168V, R155Q), VX-950 (A156S, A156T, T54A) and SCH-503034 (A156T, A156S, T54A). The model reproduces well the viral RNA kinetics in the cell from the moment of the subgenomic HCV replicon transfection to steady state, as well as the viral RNA suppression kinetics in the presence of NS3 protease inhibitors BILN-2061, VX-950 and SCH-503034. We showed that the resistant mutants should be taken into account for the correct description of biphasic kinetics of the viral RNA suppression. The mutants selected in the presence of different inhibitor concentrations have maximal replication capacity in the given inhibitor concentration range. Our model can be used to interpret the results of the new anti-HCV drug testing in replicon systems, as well as to predict the efficacy of new potential drugs and optimize the regimen of their use.

[Pneumocystic pneumonia].

The article is devoted to short description of epidemiology, clinical and radiologic demonstration of pneumocystic pneumonia. The features of pathologicoanatomic changes at pneumocystic pneumonia are described. Own observation about combination of classic and scarce histological changes at this disease is in the article.

Resident stem cells in the myocardium of patients with obstructive hypertrophic cardiomyopathy.

Interventricular septum myocardium was studied in 40 patients with obstructive hypertrophic cardiomyopathy. Immunohistochemical assay revealed c-kit-positive resident cardiac stem cells in 82.5% patients. The content of the connective tissue and myofibrillar disarray zones and the degree of cardiomyocyte hypertrophy and myolysis were determined. In 30% cases, cardiomyocytes containing atrial natriuretic peptide were detected in the interventricular septum myocardium. The data were compared with clinical and functional parameters of patients. It was found that cardiac stem cells are present in patients, whose myocardium was characterized by increased density of the connective tissue, hypertrophy of mature cardiomyocytes, medium degree of myolysis in them, and accumulation of natriuretic peptide, a cardiac failure marker, in cardiomyocytes.

[Are we controlling the sedation in ICU? A multicenter study results].

The aim of this study is to evaluate the issues of sedation and analgesia in all-purpose ICUs in Russia. To obtain that, a single-day observational survey was performed in 55 ICUs of Ural and Siberia regions. This work enabled to describe the targets, instruments of control and patterns of sedative and analgetics and sedatives prescription, as well as to make conclusions about issues in this area and possibilities of creation and necessity of analgesia and sedation standards. The study has shown a decent percentage of use of standardized scales evaluating pain in ICU and predominance of effectivae drugs and analgesia patterns, which leads to "formalization" of analgesia and decrease of it's effectiveness. Sedation indications do not satisfy the modern concept, sedation level evaluation scores are used only in 13%, schemes and drugs are traditional. The results of this study may serve as a reason for discussion of necessity of introducing of sedative and analgetic therapy in ICU standarts.