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The article presents result of analysis of indicator of polymorbidity in sampling of 9871 patients of therapeutic clinic of the research institute of experimental and clinical medicine (Novosibirsk)during 2003-2011. The study was carried out using archive method with statistical analysis of all nosologic forms, groups and classes of ICD-10 irrespective of particular diagnosis being main or concomitant. The gender differences of indicator trans-systemic polymorbidity during 2003-2011consisted in that in males its increasing was more dynamic than in females. The trans-systemic polymorbidity is correlated with social economic indicators considering as stressors having significant importance for its occurrence and development. These regularities are more specific for males due to direct correlation between trans-systemic polymorbidity and level of payroll salary in contrast with females. Hence, necessity to take into account impact of social economic factors on development of polymorbid pathology for improving system of secondary and tertiary prevention, diagnostic, treatment and rehabilitation of concomitant nosologies in patients. The development of new medical economic standards of treatment of patients with polymorbid pathology to implement principles of personified medicine is required.

The study in mouse model of BCG-induced granulomatous inflammation showed that early pulmonary fibrosis (day 3-30 postinfection) in tuberculous inflammation was primarily determined by increased number of fibroblasts in the lung interstitium and granulomas and enhanced fibroplastic activity. Fibroplastic processes are initiated via an increase in secretory activity of activated granuloma macrophages caused by the persistence of the pathogen in the cells of the mononuclear phagocytic system. The dynamics of hydroxyproline concentration under these conditions is determined by changes in the number and differentiation degree of fibroblasts in granulomas and lung interstitium at various stages of tuberculous inflammation.

Helicobacter pyloriis one of the most common causes of chronic gastritis. With the development of the disease cellular inflammatory infiltrates composed of lymphocytes, plasma cells, and macrophages are formed in epithelium and lamina propria of the stomach. These cells are capable of secreting a number of active substances, including inducible nitric oxide synthase (iNOS). We examined the relationship betweenH. pyloriand secretion of iNOS by cells of inflammatory infiltrates in chronic gastritis by light microscopy and immunohistochemistry. The data obtained indicate that stimulation ofH. pyloriimmune system cells of the host organism during development of chronic gastritis causes increase in number of macrophages and lymphocytes in the inflammatory infiltrate of the gastric mucosa. This is accompanied with increased expression of inducible NO-synthase with excess free radicals in the tissues, which leads to secondary alterations and exacerbates the inflammation with impaired regeneration processes.

In generalized BCG granulomatosis, fibrosis starts early (on day 3) and not only around the granulomas, but also in the organs. The severity of organ fibrosis is apparently determined by the concentration of granulomas, in particular their macrophages inducing proliferation of fibroblasts in organs and granulomas as well as activation of fibrogenesis. On day 30 after infection, the degree of fibrosis in the lungs was by 6 times higher than in the liver. The increase in hydroxyproline concentration in organs in early period of infection was determined by acute stress, while on day 30 it resulted from its enhanced synthesis by granuloma fibroblasts and resident fibroblasts in organs.

Ninety patients with new-onset pulmonary tuberculosis were examined prior to therapy The patients were randomized into 2 groups: 1) 20 patients receiving the standard antibiotic therapy regimen; 2) 70 patients taking the standard antibiotic therapy and the polyenzyme drug Wobenzym. The use of the latter in the complex therapy of patients with pulmonary tuberculosis was shown to cause an increase in the activity of the destructive inflammatory process and to regulate the function of the immune system as compared with those during the standard therapy.

Aims Linear dextrans are often proposed as drug delivery systems with milder adverse effects and lower effective drug concentrations. Linear dextrans are polysaccharides that can potentially be used to load macrophages with drugs to transport them to a site of inflammation. Recently, it was reported that dextrans may exert a protective effect vis-a-vis drug cytotoxicity and during wound healing. The aim of the current work was to evaluate molecular mechanisms of action of dextrans that may be relevant to the cytoprotective effects. Main methods We determined the effect of treatment with 40- or 70-kDa dextran on production of reactive oxygen species, lipid peroxidation, and lysosomal pH in the J774 macrophage cell line. In addition, induction of Keap1/Nrf2/ARE and autophagic activity were evaluated. Key findings Dextrans of both molecular weights protected the cells from oxidative stress induced by cumene hydroperoxide and from lysosomal stress induced by ammonium chloride. The effect was associated with induction of the Keap1/Nrf2/ARE signaling pathway. Furthermore, dextran stimulated autophagy in a dose-dependent manner but inhibited the autophagosome-lysosome fusion in a time-dependent manner. Significance This study shows possible cytoprotective effects of dextran under oxidative stress, and these findings may be used for the development of novel (dextran-based) drug delivery approaches.

A method for determining the number of aldehydes in dextran polyaldehyde (DPA) was proposed. The method was based on the production of the DPAconjugate with 2,4-dinitrophenylhydrazine, reaction of which with base formed a colored product. The developed method for quantitative determination of aldehydes was distinguished from others by its simplicity and high sensitivity. Results of physicochemical studies of DPA and their derivatives were presented in order to identify their structures and formation mechanism in the presence of KMnO4.

We studied the intensity of free radical oxidation in the liver and activity of oxidative metabolism in mouse peritoneal exudate phagocytes at the early stages of chronic generalized BCG-induced granulomatosis (days 3 and 30 after a single intraperitoneal or intravenous administration of 0.5 mg of BCG vaccine). It was found that both methods of injection did not change the intensity of free radical lipid peroxidation in the liver in comparison with the control, but activity of free radical oxidation mediated by production of hydrogen peroxide was increased in the liver and peritoneal exudate at the stages of mature granuloma formation (day 30). At the same time, intraperitoneal injection contributed to more pronounced activation of lipid peroxidation and synthesis of hydrogen peroxide in the liver.

We observed morphological manifestation of encephalitis 3, 7, 10 and 28 days after intravenous infection of adult male CBA mice with Candida albicans. Compounds were administered intraperitoneally every other day starting from the next day postinfection. Untreated animals (100%) died over the period between days 18 and 20 postinfection; 60% animals receiving oxidized dextran alone survived by day 28 of observation. All animals treated with amphotericin B and composition of amphotericin B and oxidized dextran survived. On day 3 postinfection, the count of macrophage infiltrates and granulomas in the cerebral interstitium of mice treated with amphotericin B was equal to that in untreated mice, but was sufficiently lower in animals treated with the composition or oxidized dextran alone. On day 10, this index was similar in all groups and was approximately 5 times lower than in untreated animals on day 3. On day 28, macrophage infiltrates and granulomas were absent in the brain of all treated mice. These data suggest that oxidized dextran produced a therapeutic effect, which manifested earlier than the effect of amphotericin B and potentiated its effect, probably due to its competition with Candida albicans for mannose receptors on the brain-blood barrier endothelium.

Elimination of "excessive" myocytes and their structures during involution of the myometrium after the first and third pregnancies was realized by clasmocytosis (eliminating the greatest volume of myocyte cytoplasm fragments), apoptosis, and necrosis (equal percentage by volume). In contrast to the first pregnancy, involution after the third one was not over by day 10 because of inhibited elimination of functionally lost myocytes by necrosis and apoptosis mechanisms. Presumably, this was caused by slower hydrolysis of apoptotic bodies by macrophages. The concentration of macrophages in the myometrium on day 10 of the involution period in females after the third delivery was 4-fold higher than in intact mice and in females after the first delivery during the same period.

Alloxan-induced diabetes mellitus in rats was characterized by persistent increase in blood levels of corticosterone, while chronic granulomatous inflammation induced by silicon dioxide and its combination with alloxan-induced diabetes mellitus were associated with transient increase in blood corticosterone level followed by gradual development of hypoadrenocorticism. The content of corticosterone in the adrenal glands of rats with alloxan-induced diabetes mellitus remained unchanged in the dynamics of the disease, but the level of progesterone decreased at the early terms of diabetes and then returned to the initial values. After administration of silicon dioxide to intact rats and to rats with diabetes mellitus, changes in hormone content in the adrenal glands were observed only at the initial stages of inflammation and consisted in elevation of corticosterone concentration against the background of reduced progesterone content.

Background. To study pathogenetic features of the normal type balneological response on intake of natural high mineralized water during medical rehabilitation in atopic dermatitis (AD) patients in comparison with relapse of the disease. Materials and methods. There were studied some clinical, morphological and immunological parameters and nature of correlative interlinks between their values in AD patients with different immunopathogenetic forms of the disease (IgE-dependent and IgE-independent AD) during both the relapse of the disease and development of the normal type balneological response at the treatment with natural high mineralized water. Results. The highest interlinks were between the clinical indices of disease severity during exacerbation of IgE-dependent AD and IgE, IL4, TNFб, IL 1в levels, dense infiltrate in derma; at exacerbation period of IgE-independent AD - TNFб and IL 1в dense inflammatory infiltrates in derma and number of degranulating mastocytes in their composition; at developing of the balneological response - only the number of degranulating mastocytes in composition of inflammatory infiltrates and a slightly increased TNFб level. Conclusion. The treatment of AD patients with natural high mineralized water is followed with the normal type balneological response characterized with slightly increased THFб level and is not associated with immunopathological processes, typical for the relapse of the disease, and therefore, it's medical correction is not required.

Myocytes with large homogeneous vacuoles and numerous protrusions of the cytoplasm into extracellular space (manifestations of clasmatosis) were detected in rat myometrium during normal gestation and early postpartum period. The percentage of vacuolated smooth-muscle cells and numerical density of inflammatory cells in the myometrium were evaluated. The data indicate the absence of typical inflammatory reaction in the myometrium during elimination of smooth-muscle cells in the course of postpartum involution. Clasmatosis and apoptosis are hypothesized to be the main mechanisms providing reduction of the uterine weight after delivery.

The pathogenesis of a disease caused by Qinghai-like H5N1 influenza virus in BALB/c mice was studied. Clinical, morphological, and immunological characteristics of the experimental infection caused by highly pathogenic A/duck/Tuva/01/06/ (H5N1) virus are described.

Administration of desmopressin for 4 days to homozygous Brattleboro rats lacking endogenous vasopressin induced an increase in osmotic concentration and was accompanied by typical changes in the morphofunctional state of interstitial cells of the renal papilla. These changes increase the permeability of extracellular matrix, which attested to the involvement of interstitial cells into hydrosmotic reaction to vasopressin.

In CBA mice infected with C. albicans, phasic pattern of granulomatosis development was observed. In all groups, the number of granulomas in the liver was minimum on day 56 after infection. Treatment with free amphotericin B and its composition with dialdehyde dextran (CA) reduced the number of infiltrations and granulomas in the liver, the changes were more pronounced in animals receiving CA. A different pattern of cyclic fluctuations of cortisol content in the blood and adrenal glands and progesterone content in the adrenal gland was observed. By the end of observation (day 84), cortisol content in the blood and adrenals of mice treated with CA was considerably lower than in untreated mice and animals receiving amphotericin B.

Partial hepatectomy leads to qualitative and quantitative changes in the pulmonary compartment of the mononuclear phagocyte system during different periods after surgery. These changes have compensatory and adaptive nature because of loss and subsequent partial recovery of the hepatic compartment of the mononuclear phagocyte system.

Intravenous infection of chicken with H5N1 avian influenza virus (strain A/Gs/Krasnoozerskoye/627/05) causes rapid lethal outcome. Pathomorphological study of bird viscera showed manifestations of disseminated intravascular coagulation syndrome, generalized inflammatory reaction, and wide-scale necrobiotic changes in tissues.

Activity of LPO in the liver of CBA mice during the development of granulomatous inflammation after combined infection with C. albicans and M. tuberculosis was evaluated by the levels of conjugated dienes, ketodienes, conjugated trienes, and products of interactions between intermediate LPO products and 2-TBA. The content of primary and secondary LPO products peaked on days 3 and 10 after infection by C. albicans, respectively. After M. tuberculosis infection, the maximum accumulation of TBA-active LPO products in the liver was noted on day 3, while the level of primary lipid peroxides virtually did not increase. The dynamics of primary and secondary LPO products in the liver during granulomatous inflammation development was similar to that during infection of mice with C. albicans alone. Hence, the development of granulomatous inflammation induced by C. albicans or M. tuberculosis or both these agents, was associated with increased LPO activity in the liver. The dynamics of primary and secondary LPO products depended on the infectious agent or combination of agents.

Effect of antifungal preparation amphotericin B and its lysosomotropic composition with dialdehyde-dextran on functional state of phagocytizing cells in the dynamics of granulomatous inflammation induced by C. albicans was studied on CBA mice. A stimulating effect of amphotericin B on the production of reactive oxygen species by peritoneal and bone marrow phagocytes was observed, while lysosomotropic form of the antibiotic did not stimulate generation of oxygen radicals.

We compared the effects of dextrans with a molecular weight of 35 kDa oxidized by chemical (OD(ch)) and radiochemical (OD(r)) methods on oxidative and metabolic functions of peritoneal macrophages from BALB/c mice in vitro and in vivo. It was found that none type of dextrans exhibits chemiluminescent properties. In vitro study showed that OD(ch) had a priming effect on mouse peritoneal macrophages, while OD(r) did not potentiate the oxidative and metabolic response of cells to zymosan. Being injected intraperitoneally, OD(r) more markedly enhanced chemiluminescent response of mouse peritoneal macrophages and reduced their viability than OD(ch). Thus, both dextrans are biocompatible, but in OD(ch) this parameter is higher.

Male BALB/c mice were intraperitoneally infected with BCG vaccine. Cytomorphological changes in BCG granulomas of the liver and lungs were compared during spontaneous tuberculous inflammation and after intraperitoneal injection of dialdehyde dextran for 5 months. Administration of dialdehyde dextran to mice infected with mycobacteria of BCG vaccine was followed by a decrease in the number and size of BCG granulomas in organs, contributed to the increase in the count of fibroblasts in hepatic and pulmonary granulomas, decreased the severity of destructive changes in the liver parenchyma, promoted reparative processes in hepatocytes, and reduced the degree of fibrosis in the liver and lungs due to a decrease in fibroplastic activity of fibroblasts in BCG granulomas.

Differential diagnosis of thyroid follicular adenomas, follicular cancer, and papillary cancer with follicular structure was carried out. Proliferation coefficients, probability of atypia, and tumor growth activity were evaluated on the basis of quantitative proportions of proliferation and apoptosis genes expression, derived from indexes of labeled nuclei expressing Ki-67, bcl2, p53 and cytoplasm with expression of bcl2, p53 in cells of these tumors. Significant differences between all the studied tumors of the thyroid grand with follicular structure were detected. The proposed criteria supplement the postoperative morphological differential diagnosis of thyroid tumors.

We studied the dependence of in vitro dextran biocompatibility on the method of oxidation of 35-kDa dextran. The biocompatibility of dextran oxidized with potassium permanganate was higher compared to that obtained by radiochemical oxidation. It was related to the formation of peroxide compounds during radiochemical oxidation.

Background. Little is known about the role of free-radical and oxidative stress signaling in granuloma maturation and resolution. We aimed to study the activity of free-radical oxidation processes in the dynamics of BCG-induced generalized granulomatosis in mice.Methods. Chronic granulomatous inflammation was induced in male BALB/c mice by intravenously injecting the BCG vaccine, and the production of oxidative stress (activity of free-radical oxidation processes) and histological changes in the lungs, liver, and peritoneal exudate were measured 3, 30, 60, and 90 days after infection.Results. The tuberculous granuloma numerical density and diameter continuously increased from day 30 to day 90, and the macrophage content within the granulomas progressively diminished with a concomitant elevation in the number of epithelioid cells. The activity of the free-radical oxidation processes in the liver (i.e., the intensity of the homogenate chemiluminescence) reached a maximum at postinfection day 60 and subsequently began to decrease. The peak generation of reactive oxygen species by phagocytes in the peritoneal exudate (measured using flow cytometry) was also shifted in time and fell on day 30.Conclusions. The rise in the steady-state concentration of H2O2in the liver of mice with BCG-induced granulomatosis is not related to local H2O2production by phagocytes, and a decrease in the severity of generalized inflammation precedes the resolution of local inflammation.

In adult Wistar rats, a 3B degree skin burn was modeled and treated by daily application of 5% aqueous solution of oxidized dextran (molecular weight of 60 kDa) on the wound surface. In animals treated with oxidized dextran, neutrophil count in the connective tissue adjacent to the wound increased by day 5 and then decreased by day 21 after burn infl iction; proliferation of fi broblasts was observed later than in untreated animals, in whom infl ammation run a subacute course. Oxidized dextran increased the content of macrophages in the wound and surrounding connective tissue from days 14 to 21 after burn infl iction and promoted effective and complete healing of the skin defect. Regeneration was realized mainly due to proliferation of keratinocytes at the wound edges and was completed by 7 days earlier than in untreated animals, in whom the area of injury by day 21 decreased by only 2 times (vs. 10 times in treated rats).

We studied peculiarities of morphofunctional organization of the immune system in C57Bl/6g and CBA mice differing by their susceptibility to various types of infectious agents. The revealed differences in the structure of lymphoid organs, T lymphocyte subpopulation ratio and their differentiation into Th1/Th2 cells after mitogen stimulation drove us to a conclusion on genetically determined regularities in the development of the immune response in these animal strains.

Oxidized dextran (60 kDa) exerted a pronounced preventive effect in laboratory mice infected with avian influenza subtype H5N1 A/Goose/Krasnoozerskoye/627/05 virus, which manifested in a significant increase in mouse lifetime (by 24.4%) and a decrease in mortality rate (3.3-fold). This was probably related to significant alleviation of pathological changes in the lungs and severity of hemodynamic and inflammatory complications and early fibrosis [corrected].

We performed an immunomorphological study of mast cells from undamaged skin in women with phenotypical evidence of undifferentiated connective tissue dysplasia syndrome, patients of cosmetological clinics. It was found that the numerical density of mast cells containing chymase granules in this condition 1.7-fold surpassed the corresponding parameter in patients without signs of connective tissue dysplasia syndrome, which probably was a result of compensatory and adaptive reaction aimed at activation of the synthesis of the connective tissue extracellular matrix components. It was hypothesized that increased content of chymase-positive mast cells in the skin of patients with connective tissue dysplasia syndrome contributed to the formation of associated arterial hypertension.

Male BALB/c mice were intraperitoneally infected with BCG vaccine. The therapy with isoniazid or composition of isoniazid with dialdehyde dextran (intraperitoneally, twice a week for 5 months) was started 1 month after infection. The retention time of the isoniazid-dialdehyde dextran composition in hepatocytes was much longer compared to that of isoniazid. The mice receiving the composition of isoniazid and dialdehyde dextran were characterized by a more significant decrease in the number and size of BCG granulomas, lower severity of destructive changes in the liver parenchyma, and more pronounced reparative regeneration (compared to animals of the isoniazid group).

Morphological changes in the liver of pregnant C57Bl/6 mice infected with BCG vaccine before pregnancy and on day 13 of gestation were studied by means of light microscopy and morphometry. The formation of BCG granulomas in mice of both groups was followed by a decrease in the numerical density and diameter of granulomas, increase in the volume density of hepatocyte degeneration and necrosis, and rise in the numerical density of binucleate hepatocytes (compared to nonpregnant mice infected with BCG vaccine).

Immunomorphological study of Langerhans cells in affected skin of patients with moderate exacerbation and remission of atopic dermatitis revealed an increase in numerical density (compared to healthy volunteers) and change in morphological characteristics and topography of these cells.

We studied the formation and cytophysiological characteristics of polynuclear macrophages in primary cultures of peritoneal cells from C57Bl/6 mice. Production of reactive oxygen species and phagocytic activity in polynuclear macrophages were higher than in mononuclear macrophages. The formation of polynuclear macrophages in cultures of peritoneal cells is realized via amitosis.

The therapeutic efficacy of a composition of amphotericin B and dialdehyde dextran was much higher than that of amphotericin B in the therapy for systemic candidiasis. This conclusion was derived from the earlier and progressive decrease in the number and size of candidal granulomas in the kidneys. The composition of amphotericin B and dialdehyde dextran was more potent than amphotericin B in decreasing the nephrotoxic effect of C. albicans. The opposite strains of CBA and C57Bl/6 mice differed in morphological signs of granulomatosis in the kidneys, but not in the nephrotoxic effect of C. albicans metabolites.

Light and electron microscopy and morphometry of rat myometrium revealed 5 morphological types of myometrial smooth muscle cells. Quantitative evaluation of all cytotypes was performed in nonpregnant animals, during normal pregnancy, and during the early postpartum period. Transformation of some cells with nonvacuolated cytoplasm and clear nuclei (type 1) into type 3 cells (with small vacuoles in the cytoplasm), type 4 cells (in a state of balloon degeneration), and type 5 cells (apoptotic bodies) was observed during gestation and early postpartum period.

Male BALB/c mice were intraperitoneally injected with BCG vaccine. After 1 month therapy was started: isoniazid or composition of isoniazid with dialdehyde dextran (CID) obtained by chemical and radiochemical methods. The therapeutic efficiency evaluated by the number granulomas in the liver and lungs and granuloma size was higher in mice treated with CID obtained by the radiochemical method in comparison with mice treated with isoniazid and with CID obtained by the chemical method. Hepatotoxicity evaluated by volume density of degenerative hepatocytes and necrotic zones was higher in mice treated with CID obtained by the radiochemical method than in animals treated with isoniazid, because CID contained free isoniazid and isoniazid bound to dialdehyde dextran.

Tuberculous granulomas were found in all parenchymal organs of mice infected with mycobacteria of BCG vaccine. The number and size of hepatic granulomas decreased, while the count of degenerated and necrobiotic hepatocytes in infected animals increased 3 months after the start of therapy with a composition of isoniazid and dialdehyde dextran. The composition of isoniazid and dialdehyde dextran obtained by radiochemical oxidation of dextran had greater therapeutic efficacy and lower hepatotoxicity.

Hypotrophy was found in fetuses of female C57Bl/6 mice infected with BCG vaccine. Light microscopy of liver samples revealed destructive processes, impaired reparative regeneration, and fibrosis.

A composition of amphotericin B and dialdehyde dextran was used for the therapy of male C57Bl/6 mice with systemic candidiasis. The composition was more effective than free amphotericin B. A decrease in the number and size of candidal granulomas in the lungs was more significant after therapy with the study composition (compared to free amphotericin B).

We studied the in vitro effect of hybrid molecular-nanosomal biocompatible compositions on cultured peritoneal cells. The compositions consisted of oxidized dextrans with a mean molecular weight of 35 and 60 kDa, which were obtained by chemical and radiochemical oxidation of dextran. Hybrid nanoliposomal compositions of chemically oxidized dextran (permanganate method) had greater biocompatibility and tropic activity to macrophages compared to nanoliposomes of radiochemically oxidized dextran.

Individual or combined administration of BCG vaccine and silicon dioxide to male mice induced a nonspecific stress response of the adrenal glands and gonads judging from changes in the concentration of blood cortisol and testosterone. The dynamics of cortisol concentration in the adrenal glands was similar, while changes in progesterone concentration were in antiphase to those in the blood. After combined administration of both inductors of granulomatous inflammation, changes in the concentrations of the studied hormones to a greater extent corresponded to their dynamics after injection of BCG.