Effect of Oxidized Dextran on Cytokine Production and Activation of IRF3 Transcription Factor in Macrophages from Mice of Opposite Strains with Different Sensitivity to Tuberculosis Infection.

We studied differences in the production of pro- and anti-inflammatory cytokines and IRF3 transcription factor by peritoneal macrophages from mice of opposite strains CBA/J and C57Bl/6 and the effect of 60-kDa oxidized dextran on these parameters. Macrophages from C57Bl/6 mice were mainly characterized by the production of proinflammatory cytokines TNFα, IL-12, and MCP-1 (markers of M1 polarization). By contrast, CBA/J mice exhibited a relatively high level of anti-inflammatory cytokine IL-10 and lower expression of proinflammatory cytokines (M2 phenotype). IRF3 content in peritoneal macrophages of CBA/J mice was higher than in C57Bl/6 mice. Oxidized dextran decreased the expression of IRF3 upon stimulation of cells from CBA/J mice with LPS, but increased this process in C57Bl/6 mice. Despite a diversity of oxidized dextran-induced changes in cytokine production, the data confirm our hypothesis that this agent can stimulate the alternative activation of macrophages.

Oxidized Dextran Enhances Alternative Activation of Macrophages in Mice of Opposite Lines.

Differences in peritoneal macrophage polarization in mice of opposite lines CBA and C57Bl/6 and the effects of 60 kDa oxidized dextran were studied. Macrophages of C57Bl/6 mice demonstrated a phenotype close to M1, with increasing expression of CD86 costimulatory molecule and unchanged CD206 expression in response to activation. Macrophages of CBA mice demonstrated higher plasticity in response to activating agents; expression of the markers increased irrespectively on stimulated receptor (TLR-4 or mannose receptor) and both CD86 (classical activation) and CD206 (alternative activation) increased. Macrophage response to addition of oxidized dextran (60 kDa) to the culture medium could be characterized as potentiation of their alternative activation: expression of CD86 in CBA mice in response to LPS and LPS+IL-4 and in C57Bl/6 mice in response to IFN-γ and LPS+IFN-γ decreased, while expression of CD206 by intact macrophages of CBA mice and by macrophages stimulated by IFN-γ and IL-4 increased under the effect of 60 kDa oxidized dextran.

Effects of Liposomal Compositions with Oxidized Dextrans on Functional Activity of U937 Macrophage-Like Cells In Vitro.

We studied the effects of liposomal pharmaceutical compositions with oxidized dextrans on functional activity of U937 monocyte/macrophage-like cells. Liposomes in the emulsion contained oxidized dextran with a molecular weights of 40 kDa or 70 kDa or isonicotinic acid hydrazide (INAH) conjugated with oxidized dextran (40 kDa). Cell viability was evaluated by MTT test; mitochondrial transmembrane potential and production of superoxide anion and H2O2 were studied by fluorescent methods. The studied compositions exhibited no cytotoxic effect and even improved cell viability and mitochondrial respiration. Liposomes with oxidized 40 kDa dextran, including those with INAH-conjugated dextran, inhibited production of superoxide anion, but increased H2O2 generation.

Effect of highly mineralized natural water on redox processes in HaCaT keratinocytes.

We studied ROS production by HaCaT keratinocytes, the state of transmembrane mitochondrial potential, and activation of transcription factor Nrf2 in response to brine exposure. It was demonstrated that this exposure induces rapid but moderate decrease in mitochondrial potential, stimulates ROS production, and leads to activation of transcription factor Nrf2.

[Medico-genetic prediction of cerebral stroke risk].

A population family study including 1410 residents of Rostov region (280 families) was conducted. The study included questioning and analysis of medical records for the presence or absence of chronic diseases, including cardiovascular pathology, arterial hypertension, coronary heart disease, diabetes mellitus, and their complications, cerebral stroke (CS) and myocardial infarction, as well as the time of their occurrence. Statistic analysis included conventional descriptive statistics and regressive analysis, as well as a special part, population genetic analysis. The results showed that MI mortality was 21.4 times higher in the group of a high genotypic risk vs. the low risk group, 8.1 and 0.38%, respectively. The authors developed tools of MI risk prediction depending on hereditary burden, the use of which present a significant addition to the conventional system of phenotypic risk assessment. In order to adapt calculations to practical healthcare, the authors developed risk charts which allow MI risk assessment according to the magnitude of risk factors.

[Disorders in the immune regulation and hemostasis as factors triggering the proliferative retinopathy in diabetes mellitus]. / Narusheniia immunoi reguliatsii i gemostaza kak faktory razvitiia proliferativnoi retinopatii i otsloiki setchatki pri sakharnom diabete.

A comprehensive clinical- immunological- and-hemostasiological study of the lachrymal fluid and blood of 105 patients with diabetic retinopathy (DR) showed that an "extreme" activity of the local antibody-dependent response to collagens, DNA, cytokine, TNF-alpha, increased levels of the circulating immune complexes (CIC) and of antibodies to DNA in the blood serum as well as local immune insufficiency and deficiency of free antibodies to collagens and TNF-alpha in the lachrymal fluid and serum during the onset of proliferative forms and traction retinal detachment are the key manifestations of the immune pathology in a progressing DR. Signs of hypercoagulation, free heparin deficiency, a reduced activity of fibrinolysis and insufficiency of the anti-thrombin system were detected with the development of the chronic syndrome of disseminated intravascular blood coagulation. Trends of the immunohemostatic correction of the activity of the local and systemic autoimmune responses and of hemostasis were substantiated during the generally accepted therapy of diabetes mellitus and of systemic micro- and-macroangiopathy.

[Antibodies to types II and IV collagens, tumor necrosis factor-alpha and circulating immune complexes in lacrimal fluid and serum of patients with diabetic retinopathy and different stages]. / Antitela k kollagenu II i IV tipov, faktor nekroza opukholi al'fa i tsirkuliruiushchie immunnye kompleksy v sleze i syvorotke krovi u bol'nykh s razlichnymi stadiiami diabeticheskoi angioretinopatii.

Clinical and immunological examinations are carried out in patients with preclinical, nonproliferative, preproliferative, and proliferative diabetic retinopathy (DR). On the whole, DR is characterized by a notable increase in antibody-dependent immune response, associated with appearance of antibodies to collagen of the II and IV types in the lacrimal fluid and serum, with the "local" reactions predominating. The level of reactions of cellular autoimmune response (tumor necrosis factor-alpha) and cell-to-cell reactions in the lacrimal fluid and serum is low. Increased level of circulating immune complexes in the serum and almost complete absence of free antibodies to collagen in the blood may be indicative of formation of pathogenic immune complexes precipitating on vascular walls and in other tissues. Various forms of immune response were revealed, conducive to a favorable or unfavorable course of DR.

[Heparin inhalations combined with intravenous laser exposure of blood in patients with diabetic retinopathy]. / Ispol'zovanie ingaliatsii geparina v sochetanii s vnutrivennym lazernym oblucheniiem krovi u bol'nykh s diabeticheskoi retinopatiei.

Heparin inhalations combined with intravenous laser exposure of the blood are effective in patients with nonproliferative, preproliferative, and proliferative diabetic retinopathy. Clinical effect consisted in decrease of edema in the macular area, partial resolution of hemorrhages, a tendency to decrease in the caliber of veins, improvement of visual acuity, and extension of visual field. Immunological studies revealed immunomodulating effect of heparin inhalations and intravenous laser exposure of the blood, manifesting by decreased levels of pathological circulating immune complexes and increased concentrations of immunoglobulins, mainly IgG and IgM. Diabetic hemophthalmia is to be treated by subtenon implantation of a collagen system with injection of a prourokinase thrombolytic in combination with preoperative preparation including heparin inhalations, intravenous laser exposure of the blood, and parabulbar administration of 0.5 ml 1% emoxipin for 5 days in order to normalize immune hemostatic and redox processes and create conditions for effective action of the thrombolytic.

[Heparin inhalations and laser exposure of blood in treatment of patients with open-angle glaucoma]. / Ispol'zovanie ingaliatsii geparina i lazernogo oblucheniia krovi pri lechenii bol'nykh s otkrytougol'noi glaukomoi.

Comparative assessment of methods aimed at amelioration of the immunohemostatic processes in patients with open-angle glaucoma suffering from chronic vascular diseases showed that the most remarkable improvement of the visual functions and decrease of the level of circulating immune complexes in the blood were attained in the patients treated by heparin inhalations combined with intravenous laser exposure of the blood as against patients treated by one of these methods alone or traditionally.

The role of HBV-infection in development of cataracts in children and adults.

Possible role of intrauterine HBV infection in the formation of congenital non-hereditary cataracts is testified by discoveries of HBV markers in lens masses, aqueous humor of the anterior chamber and blood serum of the operated children and in blood of mother. We consider the patients with chronic diffuse liver diseases of HBV etiology to be a risk group of post capsular cataracts' formation. The development of these cataracts is associated with the progress of the basic liver disease. Among practically healthy persons, the initial lens changes are more often observed in carriers of australian antigen. Early signs of lens diseases in children and young or middle-aged adults determine the social meaning of this problem and reasons for the regular ophthalmologic check-up of patients with virus liver diseases and somatically healthy virus carriers.

[Manifestations of immunopathology and validation of immunotherapy of diabetic retinopathy]. / Proiavleniia immunopatologii i obosnovanie immunoterapii diabeticheskoi retinopatii.

Three-year clinical and immunological studies of 378 patients with diabetic retinopathy revealed involvement of the T- and B-immunity systems and the specific features of the local autoimmune response to the retinal S-antigen, which manifest during the early preclinical stage of diabetic retinopathy. The progress of retinopathy is associated with augmenting insufficiency of T-suppressors, inhibition of lymphocyte blastogenesis with phytohemagglutinin, and an increase in the levels of B-lymphocytes, IgM, and circulating immune complexes in the blood. Two abnormalities of autoimmune response of the eye to S-antigen were observed in patients with the proliferative forms: hypersensitivity and insufficiency of the immune response. A moderate level of S-antigen in tears is a protective factor, stabilizing retinopathy. The authors validate the significance of immunological test for predicting the course of retinopathy and emphasize the differentiated approach to local and total-system's correction of immune disorders in diabetics.

[Modeling of vitreoretinal proliferation]. / Modelirovanie vitreoretinal'noi proliferatsii.

Complexes of endogenous immunopeptides produced by autologous peripheral blood lymphocytes were injected to the vitreous body of 17 chinchilla rabbits (34 eyes). The agents injected were autosupernatant. L fraction containing molecular substances with mol. weight of 40,000 to 60,000 D, and M fraction containing substances with mol. weight of 15,000 to 30,000 D. Clinical and morphologic studies demonstrated that injection of endogenous immunopeptides led to active lymphoid inflammatory infiltration associated with proliferation and formation of new vessels. In contrast to the M fraction, the exudative processes triggered by the L fraction were more definitely localized and associated with the appearance of fibroplastic cords (the proliferative component). The models created may be used for the development of methods for prevention and treatment of vitreoretinal proliferation.

[Clinico-immunological studies in dystrophic retinal detachment complicated by proliferative vitreoretinopathy]. / Kliniko-immunologicheskie issledovaniia pri distroficheskoi otsloike setchatki, oslozhnennoi proliferativnoi vitreoretinopatiei.

Clinical and immunologic study of patients with detachment of the retina complicated by proliferative vitreoretinopathy (PVRP) revealed medium and high titers of S antibodies in the lacrimal and subretinal fluid of patients with stages A and B PVRP in 92 and 70%, respectively, and did not detect these antibodies in patients with stages C and D PVRP in 68 and 78.9%, respectively. A statistically reliable increase of IgG and IgA levels in the subretinal fluid was observed, as well as of IgA and SIgA in the lacrimal fluid of patients with dystrophic detachment of the retina. The levels of circulating immune complexes (CIC) in the blood serum were decreased, with CIC detected in the subretinal fluid of all the patients. The production of antibodies to S antigen ceased 3 months after the retina adhered to the eyeball. The results indicate the impact of immunological factors in the pathogenesis of dystrophic detachment of the retina.

[The clinico-immunological validation of a differentiated approach to the use of corticosteroids in treating S-dependent uveoretinitis]. / Kliniko-immunologicheskoe obosnovanie differentsirovannogo podkhoda k primeneniiu kortikosteroidov pri lechenii S-zavisimykh uveoretinitov.

A total of 630 patients with uveitis of different etiology aged 5 to 70 were examined. Signs of autoimmunization with retinal S-antigens (mol. weight 48 kD) associated with retinal involvement were detected in more than half of them. A moderate level of S-antigen in the tears was found to promote a favorable outcome of uveoretinitis. Deficit or a drastic increase of S-antigen titers in the tears, accumulation of S-antibodies and circulating S-antigen-antibody complexes in the serum, and blood leukocyte migration inhibition in response to S-antigen were observed in chronic and complicated cases. As many as 75% focal chorioretinitis and panuveitis cases, 50% of posterior and 37% of peripheral uveitis were referred to S-related forms. The authors validate a differentiated approach to the treatment of S-uveoretinitis. If S-antibodies are accumulated only in the tears, local corticosteroids are effective; if both local and total-systems reactions are boosted, the maximal effect may be achieved by local and systemic corticosteroids and cytostatics. In case of a deficiency of S-antibodies in the tears immunodepressive therapy was of no avail, and good results could be attained only by immunomodulating therapy: corticosteroids+hemoperfusion in adults and corticosteroids+thymus preparations and/or interferonogens in children.

[Viral hepatitis B as a factor in the etiology of cataracts in adults and children]. / Virusnyi gepatit B kak faktor formirovaniia katarakt u vzroslykh i detei.

Vacuoles, aqueous fissures, crumb-like opacities, color iridescence, and thickening under the posterior capsule in the lens were found in 86% of 45 patients with chronic active hepatitis B, mean age 33 +/- 2.5 years. Seven percent of patients developed posterior capsule cataracts. examinations of 42 patients with cirrhosis of the liver caused by hepatitis B virus (mean age 39 +/- 2 years) revealed changes in the lens in 100% and mature cataracts in 36% of the eyes. In 2 of the 4 healthy HBsAg carriers aged 31 to 35 initial changes in the lens and accumulation of antilenticular antibodies in the lacrimal fluid and serum. A reliable difference by all the tested parameters between the examinees and controls (HBsAg-negative age-matched blood donors, n = 20) confirms a relationship between hepatitis B infection and lenticular abnormalities in subjects of a productive age. Markers of hepatitis B virus (HBsAg, HBeAg, anti-HBs, anti-HBe, anti-HBc) were found in the lenticular mass and blood sera of 11 out of 14 children aged 1.5 to 4 operated on for congenital nonhereditary cataracts; in 4 of them viral replication still continued. HBV markers of chronic viral carriership or markers of potential contagiousness were found in the sera of their mothers (in 6 and 5 sera, respectively), this indicating a possible intrauterine infection of children. The findings evidence a possible etiological role of hepatitis B virus infection in the formation of congenital and early acquired cataracts.

[Role of immunological factors in peripheral vitreo-chorioretinal dystrophies and macular ruptures of the retina]. / Izuchenie roli immunologicheskikh faktorov pri perifericheskikh vitreokhorioretinal'nykh distrofiiakh i makuliarnykh razryvakh setchatki.

The authors analyze the results of clinical and immunological examinations of patients with peripheral vitreo-chorioretinal dystrophies (PVCRD) and macular ruptures of the retina. No antibodies to S-AG were detected in the lacrimal fluid in 87.5% of patients with PVCRD without retinal defects. In patients with PVCRD with retinal defects antibodies to S-AG were detected in 70% of cases. These antibodies were absent in the patients with macular ruptures of the retina. In none of the patients were these antibodies detected in the blood serum. The levels of circulating immune complexes were normal in the patients PVCRD and increased in those with macular ruptures of the retina. These data permit a hypothesis on the development of local autoimmune reactions in PVCRD patients in response to the appearance of AG of the injured tissues.

[Clinical and immunological signs of retinal lesions and possibilities of their correction by drugs in patients with chronic diffuse liver diseases of viral etiology and carriers of Australia antigen]. / Kliniko-immunologicheskie priznaki porazheniia setchatki i vozmozhnosti ikh farmakokorrektsii u bol'nykh s khronicheskimi diffuznymi zabolevaniiami pecheni virusnoi étiologii i nositelei avstraliiskogo antigena.

A total of 133 subjects aged 15 to 55 were followed up, the main group (n = 87), patients with chronic diffuse diseases of the liver caused by hepatitis B virus, and two reference groups, 26 patients with uveitis and 20 normal subjects, 13 and 4 subjects of each group, respectively, were Australian antigen (HBsAg) carriers. Functional disorders of the retina were detected in 93.2% of group 1 patients, as well as intensified local (tears) and total system (blood) autoimmune reactions to tissue-specific retinal S-antigen (mol.mass 48 kD). An increased detection rate of antibodies to S-antigen and its higher titers were found in healthy virus carriers as compared to HBsAg-seronegative donors. These data may be regarded as evidence of an increased risk of uveoretinal pathology in subjects infected with hepatitis B virus, this being confirmed by a higher incidence (50%) of latent virus carriership in the group of patients with uveoretinitis. Stabilizing effect of cavinton in functional changes of the retina was revealed, this recommending this drug for combined therapy of patients with chronic diffuse diseases of the liver and for prevention of ocular diseases. The majority of the examinees in whom retinal abnormalities were found being young, the authors draw attention to the social aspect of the problem.

[Clinical-immunological disorders in uveitis in patients with Behçet's syndrome]. / Kliniko-immunologicheskie narusheniia pri uveitakh u bol'nykh s sindromom Bekhcheta.

The results of comprehensive clinicoimmunologic examinations of 38 uveitis patients with Behçet's disease indicate that uveitis in the presence of Behçet's disease should be referred to multifactorial diseases to whose pathogenesis immunopathologic reactions in various combinations and genetic predisposition contribute much. Generalization of the process in the eye predominated in the clinical picture with involvement of the anterior and posterior segments, retinal vessels, this being combined with general somatic symptoms (aphthae on the buccal mucosa, genitals, arthritides, urethritis/cystitis symptoms, positive 'pricking' test). Study of the immunity status revealed depressed lymphocyte proliferative response to mitogen in 58.8% of patients, hyperimmunoglobulinemia of the A and M classes in 63.3%, impaired complex formation (increased levels of circulating immune complexes in 78.3% and cryoglobulin presence in 57.1%), and various combinations of these immunologic signs. The results indicated patients' infection with herpes virus, streptococcus, toxoplasma. An associative connection of Behçet's disease with A (II) red cell phenotype in 54.8% of patients (p < 0.05) suggests a relationship between genetic factors and the conditions of a specific geographic region. A variety of immunologic changes necessitated the use of corticosteroids, hemoperfusion, cytostatics, and immunity stimulants in the treatment of uveitis in Behçet's disease patients.

[Hemostasis in patients with diseases of the retina and uveal tract]. / Sostoianie gemostaza u bol'nykh s patologiei setchatki i sosudistogo trakta glaza.

Hemostasis studies of 152 patients with inflammatory dystrophic and circulatory diseases of the retina and the uveal tract have shown that the major hemostasis disorders consisted in the presence of soluble fibrin monomer complexes in the blood of 62-90.5% of patients and in retarded lysis of the blood euglobulin fraction. Patients with the above hemostasis disorders and central serous chorioretinopathies and abiotrophies develop delayed formation of the fibrin clot and its poor retraction, that is characteristic of latent imbalance of the coagulation and fibrinolysis processes and liability to DIC. Patients with retinal vein thrombosis develop, besides delayed fibrin polymerization in the clot and reduction of platelet contractility, a drastic depression of the blood and lacrimal fibrinolytic activity. Central choroiditis and uveitis was associated with a marked increase of lacrimal fibrinolysis and reduced blood plasma fibrinolysis, along with enhanced paracoagulation and prolonged lysis of the blood euglobulin fraction, this resulting in hypoproteolytic hypercoagulation. Local and systemic fibrinolysis test may help choose the drugs for local and general pathogenetic therapy.

[Immunologic disorders in patients with idiopathic subretinal neovascular membrane]. / Immunologicheskie narusheniia u bol'nykh idiopaticheskoi subretinal'noi neovaskuliarnoi membranoi.

The authors analyze the results of comprehensive clinical and immunologic examinations of 52 patients with this condition (SNVM) in its active and inactive phases, angiographically confirmed, aged 19 to 46; 32 of these were women (61.5%), 20 (38.4%) men. A complex of immunologic methods was employed to reveal the etiology of the condition and the immune status of SNMV patients. The origin of the condition was identified in 44.2% of patients; it was toxoplasmic in 19.2, autoimmune in 15.4, tuberculous in 7.7, and mixed toxoplasmic and tuberculous in 1.9% of cases. T lymphocyte functional activity was inhibited in 37.5% of patients with the exudative hemorrhagic phase of SNMV and in 16.7% of those in the cicatrization phase. Changes in the humoral immunity presenting as gammapathies were detected in 34% of patients, those manifesting by hyperconcentrations of circulating immune complexes in 66.7%, and of cryoglobulins in 37.8% of patients. Krypton laser coagulation was employed in multiple-modality treatment of patients with SNMV. The remissions persisted for 3-5 years.