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Сергей Гольцов
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Phenotypic dermatology

 

The article is concerned with the study of the dynamics of states of subpopulations of human skin cells based on the results of few patented inventions in biology and cell medicine. The variety of potential states of subpopulations is substantiated with the methods of conceptual analysis. The article presents the results of this analysis demonstrating the need for profound changes in diagnostic and therapeutic approaches in dermatology as a scientific discipline and practice. The possibility of obtaining the skin cytoimmunogram enables us to study the phenomenology of the cell subpopulations states dynamics by conceptual methods. Extending of these conceptual differences gives us the access to a wide range of research objectives in dermatology, based on the distinctions of the phenotypes of skin cells subpopulations called phenotypic dermatology. Conceptualization of the phenomenology of states of subpopulations of skin cells and its dynamics reveals classes of potential situations that are still not distinguishable in dermatology. Further extension of the conceptual distinctions between the states of the subpopulations of skin cells and its dynamics, the unfolding of the generic structures of this dynamics will make it possible to deduce hidden circumstances of skin pathologies to an explicit level up to now. These opportunities give an expansive character to the generation of objectives of theoretical research that can not be put in any other way. Thus, the deduced problems become the basis for setting new, increasingly «subtle» experiments and the generator of the requirements for the development of the experimental base of dermatology.

GENERAL DESCRIPTION OF WORK

Held in 2017, the Council under the President of the Russian Federation on strategic development and priority projects outlined the main criteria for the effectiveness of the health sector – accurate and rapid diagnosis, effective treatment, friendly, human attitude to the patient, availability, quality and effectiveness of medicines.

According to its prevalence, skin diseases are among the top five among all diseases. The incidence of skin diseases remains at a high level – among the adult population it is every 25th person in the Russian Federation and every 15th child. In absolute numbers, in 2016, 8 604 183 cases of skin and subcutaneous tissue diseases were registered, while 6 240 955 cases of diseases were registered for the first time (Kubanova A. A. et al. 2017).

Along with this information, which determines the unconditional social and economic importance of skin diseases in the life of the population, the development of modern dermatology is not possible in isolation from new technologies, thanks to which this science, studying human skin, is integrated into the most complex forms of human activity.

At the same time, the ongoing modernization of Russian health care is focused on the development of high-tech and highly effective methods of diagnosis and treatment, as well as the rapid introduction of scientific developments in practical health care (Skvortsova VI, 2011; Starodubov VI, 2012.). Dermatology, in this case is no exception. By 2018, the need to develop methods that fully meet the recommendations of the great Russian Clinician Mudrov M. Ya., who two centuries ago argued the need to "treat the patient, not the disease", had already matured.

Representatives of domestic and foreign schools of dermatology have already done a lot to provide an objective understanding of the morphological and functional features of human skin (Mordovtsev V. N. with et al., 1992; Yamshchikov N. In. et al., 2005; Myadelets O. D. et al., 2006; wolf K. et al., 2007; Razikin A. V. et al. In 2009; Starsider Y. Y. et al., 2011; Afanasyev, Y. I. et al., 2012; Barinov E. F. et al., 2012; S. S. Kryazheva et al., 2015; Antonova O. V. et al., 2016).

As the most important barrier tissue, it is an independent organ of the immune system. With a variety of cooperation of immune cells, it functions as a set of immunological reactions, which are manifested in the morphological changes of the skin, visible to the naked eye (Borovik T. E. et al. In 2009; Afanas'ev, Y. I. et al., 2012).

Taking this into account, as well as the fact that visually distinct patterns of skin pathology are only a consequence of a complex complex of intercellular interactions, the study of the phenotype of its cells forming it is an urgent task of dermatology (Antonova O. V., et al., 2016). Due to the unique structure of skin cell bonds that prevent the separation and study of cells separately in vitro in a viable state, this task is extremely difficult.

For a long time, the only way to obtain objective information about the morphological state of the skin was an incisional biopsy, the invasiveness of which, according to I. L. Shlivko (2014), significantly limited its use and practically excluded multi-focal and dynamic observations. However, the same author notes that modern dermatology is in urgent need of in vivo methods of morphological and functional skin examination, the search for which is still ongoing, and the main method of assessing the condition of the skin is still a visual examination.

Paradoxical seems the fact that known methods of skin research, whether non-invasive – corneometry, salumeria, cutometry, profilometry, ultrasonography, confocal scanning laser microscopy, optical coherence tomography, ultrasonic microscopy, magnetic resonance imaging or invasive histological methods (D. Zimnyakov et al., 2002; Zolotenkov G. V. et al, 2015; Kuzmina T. S. et al. In 2009; Razikin A.V. et al, 2009; Agafonov S. G. et al., 2010; Kamensky V. A., 2011; Lukasheva N. N. et al. 2012), for all its credibility and reliability in solving individual problems of dermatology, are not ready for the evaluation of cell-expressed molecules, and therefore to assess the dynamics of changes in the state of subpopulations of skin cells.

In turn, the observed indistinguishability of skin conditions at the cellular level, the assessment of cells fixed by histological methods, does not allow dermatologists of our time to fully assess the dynamics of skin disease, the degree of skin response to environmental influences, the functional activity of cellular subpopulations of the skin under normal and pathological conditions, objectify the criteria of age-related skin changes and the effectiveness of external medicines and cosmetics.

In fact, the extensive development of dermatology has formed adherents of two extremes in the study of skin.

Some authors update invasive methods that allow to study the skin at the cellular level, at the same time not being able to assess the function of cells, because they work with fixed (dead) cells. Others – supporters of non-invasive methods, though based on the ability to conduct research on the skin and its functions, but on the tissue rather than cellular level – where there is a huge amount of inflammatory reactions that determine the condition of the skin as an organ of the immune system.

The observed state of dermatology, aggravated by the increase in the variety of skin diseases, comorbidity and the lagging rate of development of diagnostic methods, is a reflection of the weakness of dermatology as a theory. Within the framework of the existing paradigm of dermatology, based on visual diagnostics, restrained and limited using advanced methods of cellular diagnosis, there are no new conceptual problems that would act as motives for its development, not only improvement.

Dermatology is moving in line with the search for the same type of therapeutic agents universally satisfying practice. Obviously, this brings an improvement in the indicators, but at the same time indicates that the paradigm has exhausted itself.

At the same time, global technologization and development of areas of medicine related to dermatology (immunology, Cytology) stimulate technological renewal of dermatology (Belova O. V. et al., 2014).

So, based on the technology of distinguishing subpopulations of skin cells while maintaining their viability have the opportunity to get citymanager skin that reflects the state and dynamics of its cells (S. V. Goltsov et al., 2016, 2018).

This has led to the emergence of new questions to dermatology, to which the existing scientific paradigm does not give answers:

  • What is the condition of the skin evidenced by certain cell compositions of all kinds in a particular sample of its biopsy?
  • What a complete variety of characteristics of cells of all types?
  • What combinations of signs of cells of each type create certain functions in the skin?
  • What is the full composition of the possible functions of skin cells arising in a variety of combinations of all signs of cells of all kinds?
  • What functions occur in certain types of cells when activating their specific shares in a particular skin biopsy?
  • Can a cell of each species act simultaneously in functionally different States and in what?
  • Are there any restrictions on the occurrence of subpopulations of cells forming its various cell phenotypes?
  • What are the properties of cell phenotypes, formed by combining certain shares of cells of each species with their functions?
  • What structure of cells, their features, functions, distribution of cell shares should be taken as a "unit" of skin condition measurement for its pragmatic use in research and treatment practices of dermatology of the future?

As this questioning space expands, difficulties arise objectively in the use of knowledge about the dynamics of the diversity of skin cell phenotypes in diagnostic and therapeutic practice, approaches to the measurement of this diversity and approaches to the development of treatment methods. These and similar questions expose the problem, which is formulated as follows:

how is it possible to see and understand the picture of skin conditions, opening at the level of research of its cellular phenotypes, with practical and theoretical use of knowledge about the consequences of the dynamics of its cellular diversity?

This problem is a problem of conceptual importance, in relation to which it is not yet clear how to think about it to solve.

What is significant in this area of research practice is what can be called "the lack of concepts to distinguish and explain the new reality". This fact leads to the formation of a front of new concepts regarding skin conditions and to the search for methods of generating meanings for a new type of dermatology.

The resolution of the indicated scientific problem of dermatology, which turned to the cellular level of research of skin conditions, is proposed to be based on the tools of the conceptual scientific and technical direction (Nikanorov S. P., 1970-2018) and the technologies built on its basis.

All of them are focused on instrumental analysis, construction, synthesis of concepts in those areas of practice that need conceptually strict distinctions of reality (Teslinov A. G., 2009). The use of this device allows you to theoretically develop the results of practical experiments on the study of skin conditions using flow cytometry. 

The object of the study in this work were skin conditions determined at the level of subpopulations of cells.

The subject of the study is the properties of the phenotypic variety of skin cell subpopulations that determine the possibilities of a new type of dermatology – phenotypic dermatology.

The aim of this work is to develop a conceptual basis of the theory of phenotypic diversity of human skin cells to explain the dynamics of the States of the cells of the skin at the level of subpopulations.

The scientific hypothesis is that this problem will be solved if:

  • As a "unit" of the diversity of skin conditions at the cellular level will be taken phenotype subpopulations of skin cells, which is their special, different from the other set of cells of the elementary fragment of the skin, forming a specific functional structure of cells simultaneously of all kinds;
  • The theory explaining the state of the skin at the level of its phenotypes will be based on the tools operating with concepts and suitable for deducing logically strict consequences from the results of experimental studies of the skin at the cellular level; 
  • The approach to the construction of the theory will be based on the development and synthesis of fields of concepts to determine the state of the skin in statics; transitions of skin conditions; transitions of the skin condition due to various types of artificial and natural intervention in it at the cellular level;
  • A number of conceptual designs of the emerging theory will be tested experimentally during the diagnosis of skin conditions at the level of phenotypes of subpopulations of its cells and on this basis practical results can be obtained that are important for the development of medical practice;
  • From the constructed conceptual space of the theory, new classes of problems will be derived, developing dermatology with a pace that is ahead of the speed of the front complication of skin pathology.


To confirm this scientific hypothesis and achieve the goal in the work set a number of tasks that have been solved in the course of the study: 
1.    Analysis of the present state of dermatology and justify the problems that arise with the advent of citymanager skin.
2.    Substantiate the conceptual "unit" diversity of skin conditions at the cellular level.
3.    To determine the phenotype of subpopulations of human skin cells.
4.    To develop methods of obtaining viable heterogeneous population of skin cells, determine subpopulation composition of skin cells and receive citymanager skin.
5.    To justify the approach to the construction of the field of concepts that determine the full variety of subpopulations of skin cells and develop these concepts.
6.    To prove experimentally the practical usefulness of the constructed concepts in the study of the properties of subpopulations of skin cells and the application of this knowledge for medical practice.
7.    To develop a remedy for healing wounds, the method of its obtaining and method of treatment of wounds of different etiologies received by the tool.
8.    To develop a device for activation of the reparative potential of the cells.
9.    To formulate new scientific tasks for the development of methods for the prediction, diagnosis and treatment of skin diseases.

Theoretical and methodological basis of the research and solution of the formulated problems are the achievements of modern Cytology, immunology, dermatology, systemology and conceptology.

At the decision of tasks and verification of scientific hypotheses has been used a complex of complementary research methods:

  • 3D visualization and measurement of structures of the skin,
  • salumerie,
  • corneometry,
  • cutometry,
  • profilometry,
  • punch-biopsy,
  • mechanical homogenization of tissues,
  • flow cytofluorimetry,
  • cryopreservation of tissues,
  • system analysis,
  • concept clearing complex subject areas,
  • column of ascending from experiential to the theoretically specific concrete through the abstract,
  • registrycure explication of concepts,
  • propositional calculus and others.

 

The scientific novelty of the research results is as follows:

  1. During the experiments, the obtained citymanager skin, allowing you to explore and display in numbers of the subpopulation composition of skin cells and their functional activity. A method of producing citymanager allowed to give lifetime characteristic of morphofunctional condition of human skin cells. The results have led to the formulation of new questions in dermatology, based on the study of the skin as an organic tissue and does not penetrate into the mechanics of cellular level processes.
  2. The productivity of the study of skin conditions on the structure and properties of the variety of cellular subpopulations and their dynamics is substantiated. It is shown that as a conceptual "unit", explaining the variety of skin conditions, it is necessary to take the phenotype of subpopulations. The phenotype of the subpopulation is a special subpopulation, different from the others, consisting of skin cells of the same species and having a specific functional cell structure of the elementary fragment of the skin. The transition from a symptomatic approach in the study of skin and treatment of skin diseases to phenotypic is a transition to a new type of dermatology, which should be based on the mechanisms of cytoimmunology, able to explore and use knowledge about the properties of all possible phenotypes of subpopulations of skin cells.
  3. The tools for constructing ideas about the variety of phenotypes of subpopulations of skin cells are proposed. The tools are based on the synthesis of methods of experimental dermatology and immunology, technologically advanced to the level of study and operation of skin cell complexes, with methods of conceptual analysis of the experimental results. This idea has shown its productivity in generating a large number of classes of new concepts in dermatology.
  4. An approach to the construction of concepts about the phenotypes of subpopulations of skin cells, determining their diversity and dynamics. The approach is based on the fact that with the help of conceptual methods three subject areas will be explicated, arranged in the logic of complication and at the same time deepening the differences between the features of phenotypically possible skin conditions:
    1. Phenomenology of skin conditions in statics.
    2. The phenomenology of state transitions of the skin (dynamic conditions).
    3. Due to the phenomenology of state transitions of the skin. At the same time, a research strategy for the consistent mastery of these subject areas and those that can be synthesized from them has been adopted. Built concepts has enabled to distinguish and to explore the properties of the variety of the components of which formed the real picture of the condition of the skin, and the painting. The results of the conceptual explication revealed classes of potential situations that have not yet been discernible in dermatology and have not been the subject of study and use in medical practice.
  5. Experimentally confirmed the possibility of transition from the constructed conceptual diversity of the phenotypes of the subpopulations to the practice of the study of their properties and to utilize the acquired knowledge in the processes of diagnosis and treatment of skin diseases. A device for selective activation of skin cells of a certain phenotype in the form of an amplifier of reparative potencies of skin cells was developed in the form of the embodiment of the term of the conceptually constructed theory. This result opened the possibility to create a number of solutions for the so-called "targeted delivery" of drugs. On the basis of the obtained possibility of controlled activation of reparative potencies, a means for wound healing, a method for its preparation and a method for treating wounds of various etiologies have been developed and put into practice.
  6. A number of scientific tasks of phenotypic dermatology concerning approaches to the study of skin conditions for the development of methods of forecasting, diagnosis and treatment of skin diseases are formulated.

The paper for the first time developed the conceptual foundations of the theory of phenotypic diversity of human skin cells, providing an intensive transition to the development of research and medical practice in dermatology. This became possible as a result of the synthesis of modern provisions of dermatology and immunology, meaningful through conceptual methods.

 

The practical significance of the study of the results is as follows:

  • The experimental results of the study of skin cell States that maintain their viability, open the front of research, which objectively lead to the expansion of experimental knowledge in dermatology. The proposed transition to an interdisciplinary approach to mastering the human skin conditions, based on the achievements of immunology, Cytology and dermatology is of practical importance for all these branches of scientific knowledge.
  • The developed approach to the analysis of experimental data, based on the use of methods of conceptual analysis and synthesis of complex subject areas, opens up the possibility for the intensive development of dermatology as a theory with a front of solutions to complex problems and problems, ahead of the dynamics of skin pathology.
  • The results of the conceptualization of the phenomenology of skin conditions at the cellular level can lead to a multiple increase in the accuracy of the diagnosis of skin conditions, as they can be investigated not by the morphological picture of its pathological symptoms determined by visual examination, but by the features of distinguishable subpopulations of cells of its specific area, measured instrumentally. This kind of transition from a symptomatic approach in skin research and treatment of skin diseases to a phenotypic one is a transition to another, a new type of dermatology – to phenotypic dermatology, which creates a sample (paradigm) of deep penetration into the nature of skin diseases and opportunities, bordering on digital technologies. In this research the paradigm of the condition of the skin can be calculated. This fact is important for the removal of dermatology to the level of prognosis of pathologies, significantly ahead of the front of the natural evolution of skin diseases.

Provisions for the protection of the theory:

  1. The method of obtaining a viable heterogeneous population of skin cells, allows you to divide the skin cells with the preservation of their life for further research on the selection and testing of drugs in the treatment of skin diseases in vitro, isolation and cultivation of individual cell populations and the development of new generation drugs.
  2. Way to determine subpopulation composition of skin cells and receive citymanager skin is the achievement of the technical result includes the extracted biopsy of the skin, homogenization of the tissue, filtering the homogenate, centrifuging the homogenate, the determination of the viability of the cells, incubation of the cells with the monoclonal antibody anywhereanytime with fluorochrome, the full cells of the skin to determine the number of cells of a particular phenotype.
  3. The method allows to carry out quantitative and functional assessment of the state of subpopulations of viable skin cells in different sex-age groups of patients and to establish the correlation of structural and functional parameters of the studied cells. For the first time morphofunctional features of viable human skin cells within one bioptate are shown.
  4. The invention of tools for wound healing "Cellgel", method of its obtaining and method of treatment of wounds of different etiologies received by the tool the effect of creating a controlled wound healing, ensuring the reduction of its timing and closure of the defect tissue with restoration of function, without scar formation.
  5. The device for the activation of reparative potencies of skin cells, allows you to selectively activate in vitro skin cells of a certain phenotype.
  6. As a "unit", explaining the variety of skin conditions at the cellular level, it is necessary to consider the phenotype of subpopulations. It is a subpopulation consisting of skin cells of the same species, which has a distinctive (specific) functional cell structure of the elementary fragment of the skin. This "unit" of research makes it possible to distinguish subpopulations of cells with all different functions, including those in which all types of cells simultaneously exhibit all their functions. On the basis of distinguishing the properties of specific phenotypes of subpopulations, new classes of tasks can be set for the study of health/disease situations.
  7. An effective tool for the development of theoretical knowledge about skin conditions, obtained on the basis of experimental data, should be one that is based on the synthesis of methods of experimental dermatology and immunology with methods of conceptual analysis and synthesis of complex subject areas. This synthesis allows a strictly logical form and submit for biophysical studies explicitly the notion of the full variety of skin conditions visible at the cellular level.
  8. A rational approach to the construction of concepts about the phenotypes of subpopulations of skin cells that determine their diversity and dynamics consists in a consistent explication of the results of experiments in the form of the development of generic conceptual schemes of the phenomenology of skin conditions in statics, the phenomenology of transitions of skin conditions (dynamics); phenomenology of transitions of skin conditions due to different types of intervention and the subsequent synthesis of these conceptual schemes. This approach will allow to generate a set of concepts that allows to distinguish and to explore the properties of the variety of the components of which formed the real picture of the skin conditions.
  9. The concepts of phenotype subpopulations of skin cells and other phenomena associated with its conditions, should be used as tasks for the experiments to investigate the properties of the skin, development to create diagnostic and therapeutic devices and drugs, the formulation of new classes of research problems. Deepening of conceptual distinctions of skin cell subpopulations and their dynamics in the form of scanning of generic structures of this dynamics and interpretation of terms of the formal theory will allow to bring the hidden circumstances of skin pathology to the explicit level and to create new means of treatment of skin diseases.
  10. Developing areas of dermatology, using as "units" of the study of skin conditions phenotypes of subpopulations of its cells, can be generated not in the form of insights of talented researchers, and in the form of setting tasks to identify the biophysical properties of methodically deduced species concepts of formal theory, formed by constructed rhodostructural conceptual schemes. This kind of method of working with the unknown in dermatology will create a field of advanced research, years ahead of the evolution of skin pathology.
  11. Cognitive possibilities of studying the phenotypes of subpopulations of skin cells and specific rules of their research form a new field of medicine, which should be called phenotypic dermatology. The transition to it will strengthen the intellectual power of the paradigm of diagnosis and treatment of skin diseases.

32 scientific works, including 22 articles, 11 of them are published in scientific journals from the list of HAC of the Ministry of education of the Russian Federation, 5 patents, 2 monographs, 2 manuals.

THE MAIN CONTENT OF THE WORK

The first Chapter is devoted to an analytical review of the works of modern and foreign authors.

The analysis revealed existing contradictions in dermatology. More precisely, its further development as a practice. Based on obtaining objective information about the morphological state of the skin on an incisional biopsy, the invasiveness of which significantly limits its use, modern dermatology is in urgent need of in vivo methods of morphological and functional skin research, the search for which is still ongoing, and the main method of assessing the condition of the skin is still a visual examination. The development of methods of skin research, whether non-invasive – corneometry, salumeria, cutometry, profilometry, ultrasonography, confocal scanning laser microscopy, optical coherence tomography, ultrasonic microscopy, magnetic resonance imaging or invasive – histological methods, with all their credibility and reliability in solving individual problems of dermatology, do not solve the problems of the distinguishability of skin conditions at the cellular level, and the assessment of cells fixed by histological methods (not viable cells) does not allow dermatologists of our time to fully assess the dynamics of skin disease, the degree of skin response to environmental influences, the functional activity of cellular subpopulations of the skin under normal and pathological conditions, objectify the criteria of age-related skin changes and the effectiveness of external medicines and cosmetics. In confirmation of this, the analysis of modern achievements in the field of immunology and cytology. The challenges to dermatology emanating from the results of the development of adjacent subject areas and the acceleration of the front of complication of skin pathologies are revealed. The scientific problem of research is formulated. The object of study, the subject and purpose of the study are substantiated. The research tasks are formulated and the scientific hypothesis of their solution is proposed.

In the second Chapter 

the results of experimental studies of the skin at the cellular level are reflected. Experimental structure of citymanager of the skin was performed in an invasive way, including fence biopsy of the skin to a depth of 2 mm in the gluteal region of the person using the tool for biopsy DERMO-PUNCH 2 mm (STERYLAB, Italy). Skin biopsy and 1 ml of 0.9 % aqueous sodium chloride solution were placed in the working chamber of the automatic system for mechanical homogenization of medimachine tissue (Becton Dickinson, USA).

Homogenization of the tissue was carried out for 30 seconds at a temperature of +23°C. the Homogenate was extracted with a sterile syringe. The working chamber of the homogenizer were washed three times with 0.9% aqueous sodium chloride solution and 1 ml of the Homogenate filtered through filter cells Falcon (Becton Dickinson, USA) nylon mesh structure and a pore diameter of 20 µm. Further, the homogenate was centrifuged to remove the supernatant at 400 g for 5 minutes at a temperature of + 23°C.

After that, cell viability was determined using intracellular dye 7-amino-actinomycin D RUO (7AAD) (Beckman Coulter, USA). The analysis was performed on the flow cytometry cytometry Cytomics FC500 (Beckman Coulter, USA). Cell identification was performed by registering two parameters: lateral light scattering (side scatter) and fluorescence registration by channel 3 (FL3).

The resulting skin sample was studied ex tempora, or after prolonged cryopreservation. To do this, the sterility-tested sample was placed in a Costar 2 ml cryoprobe with a freezing solution (90% Fetal Bovine Serum and 10% DMSO as a cryoprotector), then the sample was frozen in liquid nitrogen vapors of t°-140°C at a rate of 1°C per minute, by vitrification.

Skin cells were incubated for 20 minutes in a dark place with monoclonal antibodies conjugated with fluorochrome fluoresceinisothiocyanate (FITC), phycoeritrin (PE), PE – Texred (ESD), PE/CY5(PC5), PE/CY7(PC7) (Beckman Coulter, USA).

Flow cytometry was used to phenotype cell suspension on flow cytometry cytometry cytometry Cytomics FC500 (Beckman Coulter, USA) using specific markers: CD3, CD4, CD8, CD14, CD16, CD19, CD34, CD44, CD45, CD49, CD54, CD63, CD80, CD146, CD203c; CD207, CD249 with the help of which cell subpopulations were identified and their determination phenotype.

Identified a set of markers of differentiation of cells, most accurately reflects the state of the subpopulations of skin cells:

cd49f+ keratinocytes, including activated CD49f+HLA-DR+;
fibroblasts (fibrocytes) CD45-CD14-CD44+, including activated CD45-CD14-CD44+CD80+;
fat cells CD249+ of them activated CD249+CD63+;
monocytes (macrophages) CD45+CD14+, including activated CD45+CD14+HLA-DR+;
intraepidermal macrophages CD207+, including activated CD207+CD80+, CD207+HLA-DR+, CD207+CD80+HLA-DR+;
endothelial cells CD146+, including activated CD146+CD34+, CD146+HLA-DR+, CD146+CD54+, CD146+CD54+HLA-DR+;
epithelial cells CD34+CD45dim;
lymphocytic populations: T-lymphocytes CD45+CD3+, T-helpers CD45+CD3+CD4+CD8-, T-suppressors CD45+CD3+CD4-CD8+, B-lymphocytes CD45+CD3-CD19+, NK-lymphocytes CD45+CD3-CD16+CD56+.
To register the results and ease of use developed a form of medical document "skin Cytoimmunogram", which presents the composition of skin cells, indicating the phenotype of each subpopulation to fill the laboratory numerical data in relative and/or absolute units according to the results of the study.

To demonstrate the possibility of using the skin cytoimmunogram ex tempora and after cryopreservation, 64 subjects were selected, which were divided into groups by sex and age 25-45 years and 45-65 years, 16 people each. The study consisted of two stages:

Stage 1 – biopsy from the gluteal region was studied in a patented way;

Stage 2 – determination of cell phenotype from native and cryopreserved samples.

As an example of functional assessment of subpopulations of skin cells associated with the physical one, the observation of the number of keratinocytes and fibroblasts in the studied samples is demonstrated:

Stage 1 – survey of 64 participants and their division into groups.

Stage 2 – assessment of the condition of the skin methods of salumerie, corneometry, cutometry, profilometry. We used an optical system for 3D measurement of the skin structure of the company PRIMOS GFMesstechnic GmbH and the instrument Multi Probe Adapter Cutometer® MPA 580, including the sensor Corneometer® CM 825 to measure the humidity of the skin, the optical system of a Sebumeter® SM 815.

Stage 3 – were investigated by biopsy from the gluteal region patented method – citymanager skin.

Stage 4 - evaluation of the reliability of indicators in the comparison groups.

The invention of the skin cytoimmunogram opened the way to a new understanding of the processes taking place in the human skin at the level of subpopulations of cells and made it possible to quantitatively and functionally assess the indicators of the skin condition.

Third chapter 

it is devoted to the development of an approach to the analysis of experimental results and the construction of conceptual foundations of the theory explaining the state of the skin at the level of cellular subpopulations, and the development of the field of concepts of this theory.

Using the opened opportunities of research of subpopulations of skin cells, the approach to the solution of conceptual problems of dermatology is offered. The essence of the approach is as follows:

 As the main tool for the analysis of experimental data on the States and dynamics of cellular subpopulations, a technology operating with concepts (concepts) based on strict mathematical methods and allowing to derive logically consistent consequences from the statements and assumptions obtained empirically was chosen. This technology is the technology of conceptual analysis and synthesis of systems – the domestic school of thinking, developing as a conceptual scientific and technical direction since the mid 70-ies of the last century (school of S. P. Nikanorov).
The reasons for the choice of conceptual methods and technologies in relation to the detected problems of dermatology are as follows:

Concepts, as units of operating meanings, are used in these methods in the inextricable relationship of its two essential facets: the scope of concepts and content. And since the cellular level of the study of skin conditions directly leads to the study of the structures of subpopulations of cells formed from different sets, it gives a chance through the study of these sets as the volume of concepts behind them to reach the content of these concepts and conceptually distinguish all the variety of skin conditions;
The basic logic of conceptual methods is the logic of ascent from the observed concrete to the mentally abstract and through it to the generation of the diversity of the mentally concrete. This means that a variety of all theoretically possible cellular phenomena can be obtained from the limited composition of experimentally obtained structures of cell subpopulations. This will allow to reach a theoretically complete picture of skin conditions. This possibility of conceptualization of the experimental results opens the scope of scientific research, significantly ahead of the front development of dermatological pathologies;
All operations on concepts are performed in the conceptual technology instrumentally. For this purpose, developed in the school of logical and mathematical means: the calculation of statements, mathematical theory of genera structures (Bourbaki N., 1965) and the apparatus of steps of sets (Nikanorov S. P., 2013). This allows you to methodically and strictly derive all the logical consequences of the results of the synthesis of concepts. Such consequences are new concepts that were not obvious at the beginning of conceptualization and could not appear in the course of the experiments. The ability of tool to generate new concepts will allow, first, to significantly enhance the performance of experimental dermatology, the conclusion from experiments of the investigation, far beyond the boundaries of the experiments. Second, it will make the process of new theoretical results intensive.
2. The conceptualization of experimental phenomena is proposed to be carried out in three subject areas built in the logic of complication and at the same time deepening of distinctions of features of skin conditions:

Subject area 1. Phenomenology of skin conditions in statics. Within the boundaries of this subject area can be derived the concepts that define the full diversity of cell subpopulations, the diversity of subpopulations of discernment in their diversity of characteristics of cells, States, activity of cells, function of cells in the structure of the specific puncture biopsies of the skin, structures, functions, populations and other phenomena that are considered static.
Subject area 2. The phenomenology of state transitions of the skin (dynamic conditions). Within the boundaries of this subject area can be distinguished all kinds of changes of skin conditions, built a typology of the dynamics of skin conditions, set a variety of chains of possible transitions, chain structures and other possible phenomena of changes in skin conditions.
Subject area 3. Due to the phenomenology of state transitions of the skin. Within the boundaries of this subject area can be developed ideas (concepts) about the phenomena arising from various types of artificial and natural intervention in the skin, their dynamics, the typology of interventions, the typology of theoretically possible chains of transitions between skin conditions caused by interventions and other phenomena of practical impact on the skin.
3. The research strategy of consecutive mastering of these subject areas and those which can be synthesized from them is chosen. There are two reasons for this decision. First, the fact that the results of conceptualization of one, simpler subject area, will inevitably have an impact not the original ideas needed to comprehend the other, more complex. Second, in parallel to the work with subject areas to develop and pilot the branch of dermatology focused on the study citymanchester properties of the skin.

For the construction of a number of concepts in the mathematical apparatus delivery structures, which is involved in conceptual methods, the following assumptions derived from analysis of the results of the experiments with skin cells and obtained citymanager:

In the creation of certain phenomena of the skin involved a limited variety of cell types;
The cell of each species has a certain measurable (detectable) composition of features. The number of signs is limited;
Cells of each species may (may not) exhibit one or several different functions. This is determined by the composition (combination) signs of cells;
The number of potentially possible functions of each cell is determined by all combinations of all its features;
Cells are combined into subpopulations. Each subpopulation involves cells of each species with different functions. Restrictions on the variety of so-formed subpopulations are not known;
Each combination of subpopulations uniquely corresponds to a specific immunological condition of the skin, expressed in a clinical symptom.
On the basis of these assumptions, a number of concepts were constructed, which made it possible to distinguish the variety of situations that arise in the skin during the theoretical expansion of the results of its study at the cellular level.

The concept of "Diversity of species functions in skin cells»

Basis sets:

X1 is a set of cell characteristics of any kind, which are experimentally detected by special markers.

Generic relation: D1 ∈ B(X1).

Here "B" is a sign of the operation of generating a set from all subsets of the initial set (Boolean).

The type of this structure is "the Set of all subsets of cell traits".

Since any cell of each species can manifest any combination of features, this structure establishes a complete variety of all combinations of features that can only be a skin cell of any kind. Given that each combination of features of a cell indicates the activity of its specific function, this structure simultaneously expresses the full variety of functions that can activate cells, regardless of their type.

If the number of signs of each cell is equal to P, and one of them determine the type of the cell itself, the variety of combinations of signs and, consequently, the functions of cells can reach the number 2 (P-1)-1. Here it is taken into account that if the cell does not show any signs (an empty subset of signs – ∅) , then it is functionally passive. Taking into account the known number of features of each cell type (P=24), it turns out that the maximum power of the hypothetical diversity of functions of one cell of any kind (F) is more than 8 million (specifically: F=8388607). Moreover, each of these functions can be distinguished.

This result of conceptualization makes it possible to theoretically derive (determine) each function of the cell, studying its impact on health; to set tasks to find effective ways to detect functions; to look for ways to activate each function or its suppression. Currently, from the variety of functions of skin cells dermatologically takes into account a negligible part. Some potential functions may never appear or may appear in some unique situations. But, in the absence of reasonable statements in this regard, it is impossible to exclude the appearance of unfamiliar functional phenomena of skin cells.

The concept of "Species cells with functions»

Basis sets:

X1 – a set of cell characteristics of any kind, which are experimentally detected by special markers;

X2 – many types of skin cells. These are all those different cells that are involved in the creation of skin health phenomena.

The generic relation has the following form:

D2 ∈ X2 × B(X1).

Here " × " is the sign of the Cartesian product of sets.

Type of this structure: "Many types of cells and many of their functions." This structure determines all situations in which it is necessary to distinguish specific species cells with all their functions.

This concept is used for the formulation of narrow theoretical problems in dermatology. Thus, the consideration of cells with their full set of functions allows us to study the features of the action of all functions of each species cell. There may be an answer to the question of whether the effect on the skin will change the fact that the same function will appear in different species cells at the same time. Based on the fact that the number of specific cells To=12, and the number of functions of each species of the cells is equal to F=8 388 607, the variety of formulations "of the species of cells to their function" (S) is equal to S=R×F=100 663 284. Of course, the empirical study of the properties of all these situations will take many years. But, the scope for theoretical research is open.

The concept of "diversity of the species of cells with sets of their functions»

Basis sets of this concept:

X2 – many types of skin cells;

X3 is a set of cell functions.

The generic relation has the following form:

D3 ∈ B(X2 × B(X3)).

The type of this structure is "a Set of subsets of species cells together with a set of subsets of their functions". It expresses all situations when, in a particular puncture biopsy of the skin can be considered separately from each other such subpopulations, which are collected cells of all types (or only a few), together with their manifested functions.

Such a situation occurs due to the evolution of the state of skin cells, are the "phenotypes subpopulations". A variety of large:

Single cell types and their functions. These are all those phenotypes of subpopulations, which are determined by the previous kind of structure.
Phenotypes of subpopulations formed from several types of cells (not all) simultaneously with their different functions; 
Phenotypes of subpopulations formed by cells of all kinds, and each type of cell shows one or two of its functions;
Phenotypes of subpopulations formed by cells of all kinds, and each type of cell shows all its functions simultaneously.

This concept opens up the possibility to distinguish phenotypes with complete/incomplete sets of cell types with all different functions, including those in which all cell types simultaneously exhibit all their functions. On its basis, it is already possible to set new classes of tasks for the study of health/disease situations with different compositions of functions with a full set of species cells and other situations. But, in these conceptual designs have not yet taken into account the circumstances when a portion of the skin is a certain proportion of cells of each species with specific (different functions). This is another concept that expresses the full diversity of the phenotypes of the subpopulations of cells. At the same time, unusual theoretically possible situations can be expressed. For example, when a full variety of cells of all kinds among cells of the same species will be cells with different sets of functions. This will force researchers to answer a series of questions about the properties of such phenotypes of cell subpopulations and how this is associated with pathologies that are the subject of study of dermatology, as the science of skin and its diseases.

The genetically determined process of formation of a variety of specialized cell phenotypes reflecting their function is the result of coordinated expression of a certain set of genes, as a result of which the differentiation of cells, changing their functions, morphology and metabolic activity, creates the prerequisites for their high specialization and selectivity action, which ultimately is realized in a huge variety of visible dermatologists clinical phenomena of the same skin diseases.

The deepening of these conceptual distinctions allows us to reach a wide class of research tasks in dermatology, based on the distinction of phenotypes of subpopulations of skin cells – phenotypic dermatology.

The results of conceptualization indicate the possibility of transformation of modern dermatology. A sign of this transformation is that the "unit" of the study of skin conditions is not a picture of its pathological symptoms, and especially the subpopulation of cells of its particular area. Each special subpopulation, consisting of cells of all kinds at the same time, reflecting the specific functional cell structure of the elementary fragment of the skin, is its specific phenotype. The transition from a symptomatic approach to the study and treatment of the skin to phenotypic is a transition to another type of dermatology, a new type – to phenotypic dermatology. It should be based on the mechanisms of cytoimmunology, able to explore and use the properties of all possible phenotypes of subpopulations of skin cells.

In the fourth Chapter 

explores the possibility of using the conceptual distinctions of the phenotypes of the subpopulations of cells for the development of the theory and practice of dermatology.

The diversity of the constructed concepts of separate types (terms) that could represent a value for the current practice of diagnostics of skin pathologies. Thus, in one of the conceptual schemes the specific concept of one of the skin phenotypes was singled out, in relation to which the task of developing a technical device capable of activating the functions of the cells forming it was set. As a result of solving this problem, an amplifier of reparative potencies of skin cells was developed - a device for selective activation of skin cells of a certain phenotype in vitro. This invention made it possible to create a number of solutions for the so-called "targeted delivery" of drugs. This possibility is due to the fact that the dynamics of skin conditions can now be controlled at the level of its cellular composition.

Confirmation of this idea was the invention wound-healing agent "Cellgel", based on the effect of changing the cell phenotype CD34+CD45dim skin by selective exposure of the activator of xenogenic origin. This means for wound healing of various etiologies, the use of which is confirmed by the test Report № 594-12P/7-NT from 24.12.2012 testing laboratory №ROSS RU.0001.21АВ65 from 13.07.2011 and Customs Union Declaration of compliance №TC RU D-RU.AL14.B. 03012 from 25.12.2012 g. A number of such inventions made it possible to create the effect of controlled wound healing, providing a significant (several times) reduction in its terms, closing the tissue defect with the restoration of function, without scar formation

These results demonstrate that the emerging opportunities of phenotypic dermatology point to special, new ways to treat skin diseases, in which treatment can become a controlled process with specified requirements for the course and result.

In the fifth Chapter 

new classes of research tasks, important for dermatology of the future, are formed. It is shown that each step of conceptual development should and can be accompanied by the formulation of tasks and directions of experimental studies designed to test theoretically derived concepts. This allows, on the one hand, to stimulate the development of dermatological practice, commensurate with the speed of generation of new concepts and, on the other hand, creates conditions for testing the practice of theoretical postulates, adjusting the course of conceptual development.

On the basis of the typology of conceptual diversity built in the previous Chapter, new classes of problems are developed:

the task of identifying the full diversity of skin cells of each species, all possible signs and functions of skin cells of each species;
tasks of diagnostics, detection of influence of possible functions and combinations of functions of cells on skin conditions;
the task of identifying ways to activate/suppress the functions of cells of each species;
problems of revealing the properties of transitions between the States of cell populations with different functional capabilities;
identifying the concentrations of specific cells with diverse functions activated on the condition of the skin;
the tasks of identifying ways of purposeful change (control) of transitions between the States of cell populations and others.
These are tasks that could not be set before.

The sixth Chapter

summarizes the study to the strict derivation of the provisions of phenotypic dermatology as a theory.

In conclusion,

the main scientific and practical results of the study are presented.

SUMMARY

  1. Synthesis of methods of experimental dermatology, technologically advanced to the level of study and operation of skin cell complexes, with methods of conceptual analysis of the experimental results showed its productivity in generating a large number of classes of new concepts in the field of medicine, clearly exhausted the potential of its scientific paradigm.
  2. Conceptualization of the phenomenology of static States of subpopulations of skin cells reveals classes of potential situations that have not yet been discernible in dermatology and have not been the subject of study and use in medical practice.
  3. A method for obtaining a viable heterogeneous population of skin cells has been developed, which allows to separate skin cells with preservation of their vital activity for further research on the selection and testing of drugs in the treatment of skin diseases in vitro, isolation and cultivation of individual cell populations and the development of new generation drugs.
  4. A method was developed to determine subpopulation composition of skin cells and receive citymanager skin, allowing you to explore and display in numbers of the subpopulation composition of skin cells and their functional activity. The invention makes it possible to give a lifetime characteristic of the morphofunctional state of human skin cells, which opens up the prospect of its use in practical medicine and biology.
  5. Deepening of conceptual distinctions of cellular phenomena behind the phenomena of skin pathologies allows to form new research directions in medicine. Particularly promising in this regard is the conceptual explication of the phenomenology of the dynamics of skin conditions and the dynamics of these conditions.
  6. The construction and development of conceptual schemes in these subject areas of phenotypic dermatology allows, firstly, to bring it to the level of prognosis of pathologies, significantly ahead of the front of the natural complication of skin diseases. Secondly, it will allow to bring medical practice to the form of technological purposeful influence on the course of treatment of skin diseases, as conceptual distinctions penetrate into the field of methods of artificial intervention in the dynamics of the phenotypic pattern of the skin.
  7. Conceptually, technological work with a large number of experimental results obtained in Cytology, immunology and dermatology will give an expansive character to the development of these branches of knowledge and their intersectoral synthesis.
  8. Developed a remedy for healing wounds "Cellgel", method of its obtaining and method of treatment of wounds of different etiologies received by the tool. The invention makes it possible to create the effect of controlled wound healing, providing a significant (several times) reduction in its terms, closing the tissue defect with the restoration of function, without scar formation.
  9. A device has been developed to activate the reparative potencies of skin cells, allowing to selectively activate invitro skin cells of a certain phenotype.
  10. The results of the study indicate the solution of the formulated scientific problem.

MAIN PUBLICATIONS ON THE TOPIC

Articles in journals from the list WAC Russia:

Goltsov S. V. Number of keratinocytes and fibroblasts as a marker of skin aging. /Goltsov S. V., Khlyupina E. V.// Bulletin of the Ural medical academic science. 2012. № 4(41). P. 68-69.
Sukhovey Yuri G. Regenerative-reparative and anti-bacterial properties of the drug Cellgel in the experiment. /Sukhovey Yuri G., Kostolomov E. G., Crateva S. B., Argunova, G. A., Unger, I. G., Goltsov, S. V.// Russian journal of immunology 2015, 9(2), 44.
Sukhovey Yuri G. Age-related characteristics of the cellular elements of the skin, as a basis of technology-ageing. / Sukhovey Yuri G., Kostolomov E. G., Unger I. G., Goltsov, S. V., S. A. Strelin, Okuneva T. V. // Russian journal of immunology 2016, 2(19), 526-527.
Kostolomov E. G. Some immunbiologische mechanisms of regeneration of wounds in terms of healing wounds Cellgel. / Kostolomov E. G., sukhovey Yuri G., Goltsov, S. V., Unger I. G., Okuneva T. V. // Russian journal of immunology 2016, 10(19), 289-291.
Goltsov V. Citymanager skin as a way to assess her immune status. /Gol'tsova, E. N., Sukhovey Yuri G., Kostolomov E. G., Pauwels, V. Y.// Cosmetics and medicine. 2017. No. 3. P. 56-58.
Goltsov V. Citymanager skin – a new method for objective assessment of the subpopulation composition of skin cells. / N. S. V. Gol'tsova, E. N., Sukhovey Yuri G., Kostolomov E. G., Pauwels, V. Y. // Medical immunology. 2018, 20(3), 373-382
Goltsov S. V. Conceptualization of States of subpopulations of human skin cells. /N. S. V., Teslinov A. G.// Russian journal of immunology. 2018. Vol. 12(21), 11-20.
Volkov A. I. Two cases of dystrophic congenital epidermolysis bullosa / Volkov A. I., Matusevich S. L., Goltsov S. V. // Russian journal of skin and venereal diseases. 1998. No. 2. 48-50.
Goltsov, S. V. Nutritional deficiency in the light of immunological abnormalities in patients with extensive psoriasis, occurring with secondary immunodeficiency / Goltsov, S. V., Matusevich, S. L., sukhovey Yuri G., Matusevich N. N., Kovaleva, O. L. // journal of postgraduate medical education. 2001.  No. 1. C. 23-24.
Matusevich S. L. Influence of secondary immunodeficiency state on the course and clinical manifestations of common psoriasis / Matusevich S. L., Goltsov S. V., Kungurov N. In. Sukhovey Yu. G., Tuzankina I. A. // Russian journal of skin and venereal diseases. 2001.  No. 5. P.14-16.
Kungurov N. In. Comparative characteristics of immunological parameters in patients with common psoriasis in the presence of clinical signs of immunodeficiency / Kungurov N. In. Matusevich S. L., Goltsov S. V., sukhovey Yu. G. //Vesnik of dermatology and venereology. 2002.  No. 2. P. 33-36.
Mataev S. I. Immunotherapy in the treatment of patients with extensive psoriasis with amino acid complex / Mataev S. I., Sukhova G., Matusevich, S. L., Goltsov, S. V. // problems of nutrition. 2004. Volume 73, No. 2. Pp. 8-11.


Patents

Goltsov V. S. the Remedy for healing wounds "Cellgel", method of its obtaining and method of treatment of wounds of different etiologies received by the tool. / Goltsov, S. V., sukhovey Yuri G., Kostolomov E. G., Unger I. G. // Patent RU 2481115 (Russia) from 13.10.2011
Goltsov S. V. a Method of obtaining a viable heterogeneous population of skin cells. / Goltsov S. V., sukhovey Yu. G., Mitrofanov P. P. // Patent RU 2502999 (Russia) of 25.07.2012.
Goltsov V. S. the Device for activation of the reparative potential of the cells. / Goltsov, S. V., sukhovey Yuri G., Kostolomov E. G., Pauwels V. Yu. / / Patent RU 159463 (Russia) from 29.07.2015
N. S. V. method of determining the subpopulation composition of skin cells and getting citymanager skin. / Goltsov, S. V., Kostolomov E. G., sukhovey Yuri G., Pauwels V. Yu. / / Patent RU 2630607 (Russia) from 02.06.2016
Kungurov N. In. A method of treating psoriasis. / Kungurov N. In. Mataev S. I., sukhovey Yu. G., Matusevich S. L., Goltsov S. V. Patent RU 2233160 (Russia) dated 27.07.2004.


Monographs

Kungurov N. In. Skin diseases. /Kungurov N. In. Kokhan M. M., Malishevsky, N. P. Toropova N. P. Zilberberg N. In. Iglikov V. A., Keniksfest Y. V., Shakurov I. G., Ufimtseva M. A., Filimonkova N. N.. Bakurov E. V., Bakhtisin V. J., Bochkarev Y. M., Vishnevskaya I. F., Voronov O. A., Gorbunov A. P., S. V. N., Grishaeva E., Kashcheeva V. Y., Kuznetsov D. I., Kuklin I. A., Laskina, N. With., Letaev V. O., Stout, A. I., Safonova G. D., Gurkovska E. P., Gusarova, E. A., Nikolayev K. I., Rimar O. G., Polishchuk A. I., Stukova E. I., Topychkanova, E. P., Shakirova, A. N., Schaefer, A. Yu.// Monograph. Atlas. Under the editorship of Professor kungurova, N. In. - Ekaterinburg: State budgetary institution of Sverdlovsk region "Ural research Institute of dermatovenerology and immunopathology". 2014. - 176 p.
Kungurov N. In. Dermatology: principles and methodology of planning of a resource provision to meet modern challenges, and licensing requirements. / Kungurov N. In. Zilberberg N. In. Rolinco N. And. Ufimtseva M. A., Shakurov I. G., Iglikov V. A., Kokhan M. M., Grishaeva E. V., Korsun A. A., Goltsov, S. V., Evstigneeva N. P. Gerasimova N. M. Tabachnikova A. I., Y. V. Keniksfest, Filimonkova N. N., Levchik N. To., Kuznetsova Yu. N., Kuklin I. A., Ponomareva M. V., Amosov M. A., Gusarova, E. A., Laskina, N. With., Tituhin A. Yu., Maslennikov M. L., Serebrennikov A. V., Voronova O. A., Shigaev A. E. // Monograph. - Ekaterinburg: State budgetary institution of Sverdlovsk region "Ural research Institute of dermatovenerology and immunopathology". 2008. - 296 p.
training AIDS

N. S. V. Dermatovenerology. Observations in photos: tutorial. –Ekaterinburg: "Media holding "Ural worker". 2013. - 368 p.
Strelnikov A. P. Chlamydial infection of the urogenital tract: a tutorial / A. P. Strel'nikov, N. S. V. Bushin, E. V., Ermakova A. V. - M.: Medical book. 2005.  152 p.


Articles in other journals and proceedings

Goltsov, S. V., Sochnev D. Yu., Mayorova O. A. Immunocytoma leather – reality or myth? Bulletin of the Ural medical academic science 2012, 4(41), 25-26.
N. S. V. Gol'tsova, E. N., Getman, A. D., Yurkov, A. S., Chesnokova M. Z., O. A. Shemonaeva Cellgel – a new word in wound healing. Dermatology in Russia 2017, 1, 28-33.
Possible direction of restoration of functional properties of the skin in atopic dermatitis in children - athletes with the combination of the use of eikovit and fish oil / Anashkina T. I., Volkov A. I., Matusevich S. L., Goltsov S. V. // Biologically active additives-nutraceuticals and their use for preventive and therapeutic purposes in the most common diseases: collection of materials of the III international Symposium. Tyumen. 1997. P. 12-13.
Hare, Y. E. Rocaltrol in the treatment of patients with psoriasis. / Rusak Yu. E., Matusevich S. L., Goltsov S. V. // Proceedings of the international Symposium "Medicine and health protection. 99." Scientific Bulletin of the Tyumen state medical Academy. 1999. № 3-4. P. 183.
N. S. V. Immunopathological tandem: common psoriasis and clinically verified secondary immunodeficiency / Goltsov, S. V., Matusevich, S. L., sukhovey Yuri G. // Tyumen medical journal. 2000. №3-4. P. 32-33.
Kungurov N. In. Psoriasis and secondary immunodeficiency: immunological characteristics of mutual influence. / Kungurov N. In. Matusevich S. L., Goltsov S. V. // Materials of the jubilee Conf. dedicated. The 75th anniversary of the Tver regional dermatovenerologic dispensary. – Tver. 2000. P. 94-95.
Goltsov S. V. Clinical and immunological features of the course of common psoriasis in the composition of mixed pathology with secondary immunodeficiency / Goltsov S. V., Matusevich S. L., sukhovey Yu. G., Matusevich N. N., Kovaleva O. L. // Siberian journal of dermatology and venereology. 2001.  No. 1. P. 26-27.
Kungurov N. In. Optimization of external therapy of patients with atopic dermatitis in children and adolescents / Kungurov N. In. Kohan M. M., Keniksfest Yu. V., Mirina Yu. G., Goltsov S. V., Vedernikova S. V. // Ural medical journal. 2004. No. 3. P.30-34.
Frolova O. I. On the relevance of studying the quality of life of patients with psoriasis. / Frolov, O. I., Kotelnikov A. B., Matusiewicz S. L., A. P. Strel'nikov, N. S. V. // Medical science and education of the Urals: materials of the III scientific-practical conference "Outpatient care to residents of the city of Tyumen". Tyumen. 2005. No. 3. P. 134 - 135.
The Role of studying the quality of life of patients with psoriasis in the adaptation of social functioning. / Medvedeva I. V., Kotelnikova A. B., Frolova O. I., Strelnikov A. P., Goltsov S. V., Matusevich S. L. // Proceedings of the IX all-Russian Congress of dermatologists. Moscow. 2005. Vol.1. P.24.
Novikov A. I. Clinical and pathophysiological substantiation of complex therapy of patients with seroresistant syphilis / Novikov A. I., Polikarpov V. Yu., Konvay V. D., Goltsov S. V. // Omsk scientific Bulletin. 2006. №6(42). P. 225-229.