Aim. To determine the clinical, anamnestic, and immunological predictors of adenomyosis by developing a prognostic model of uterine fibroids with concomitant adenomyosis. Materials and methods. A retrospective single-center study was conducted at Kurbatov Novokuznetsk City Clinical Hospital №1, from 2012 to 2019. The model included 284 women with histologically confirmed uterine fibroids, of which 34.9% (99/284) were fibroids with adenomyosis and 65.1% (185/284) were isolated uterine fibroids. Logistic regression was used to develop the mathematical model. Results. Predictors of adenomyosis in patients with uterine fibroids have been established: age 43 years and older, concomitant endometrial hyperplasia, chronic inflammatory diseases of the cervix, menometrorrhagia, history of childbirth, history of endometrial disorders, varicose veins of the lower extremities, history of appendectomy, blood serum lactoferrin of more than 1.8 mg/L, interleukin-6 levels more than 2.8 pg/mL. The model has an accuracy of 91%, a sensitivity of 90%, a specificity of 92%, a positive predictive value of 85%, and a negative predictive value of 94%. Conclusion. The established predictors of adenomyosis allow for predicting the risk of adenomyosis in patients with uterine fibroids, facilitating effective treatment choices.

Objective. To identify prognostic markers of intrauterine infection (IUI) of the fetus and newborn in maternal serum, amniotic fluid, and umbilical cord serum in case of preterm birth. Patients and methods. We examined 93 pregnant women who had preterm birth (PB) from 24 to 33 weeks of gestation. Thirtyfive women delivered babies without any signs of IUI, while 30 women had newborns with mild IUI (conjunctivitis, lymphadenitis, pyoderma) and 28 women had newborns with severe IUI (early neonatal sepsis, advanced herpesvirus infection, chlamydiosis, candidiasis, pneumonia, and meningitis). We measured the levels of alpha 2-macroglobulin (α2-MG) in maternal serum (MS), umbilical cord serum (UCS) using rocket immunoelectrophoresis and in amniotic fluid (AF) using enzyme-linked immunosorbent assay (ELISA). The level of lactoferrin (LF) was assessed using ELISA. MS and UCS levels of albumin (ALB) were measured using biochemical methods, while AF level ALB was evaluated using rocket immunoelectrophoresis. Statistical analysis was performed using logistic regression. Results. We found no association between the concentration of LF in all biological fluids and the condition of newborns. Levels of ALB in MS and UCS also demonstrated no correlation with the condition of newborns. AF ALB in women who delivered babies with IUI (any grade of severity) was significantly higher than that in women who delivered babies without IUI. Women who delivered babies with severe IUI demonstrated the lowest concentration of α2-MG in their serum, whereas women who delivered babies with mild IUI had the highest α2-MG concentration. The AF α2-MG level was 10 to 20 times higher in women who had babies with IUI (any grade of severity) compared to those who had babies without IUI. Conclusion. Low α2-MG level in MS (<2.2 g/L) along with elevated α2-MG level in AF (≥6.0 mg/L) in 86–89% of PB cases indicated generalized fetal IUI and required urgent delivery without prolongation of pregnancy. Key words: albumin, alpha-2-macroglobulin, intrauterine infection, lactoferrin. premature birth

BACKGROUND Immunoregulatory proteins (alpha-2-macroglobulin, lactoferrin) actively participate in inflammatory and autoimmune processes, affect synthesis and transport of hormones and cytokines, and control cell proliferation and apoptosis. However, the role of these proteins in the pathogenesis of Graves' disease (GD) is poorly understood. Objective - the study objective was to determine blood levels of alpha-2-macroglobulin (α2-MG), lactoferrin (LF), and cytokines (TNF-α, IL-6, IL-8, and IFN-γ) in GD. MATERIAL AND METHODS We determined blood levels of TSH, free T4, TSH receptor antibodies, TNF-α, IL-6, IL-8, IFN-γ, and LF by ELISA as well as α2-MG by quantitative rocket immunoelectrophoresis in 50 patients with decompensated and compensated (4-6 months and 1.5-2 years after treatment onset) GD and 25 healthy females (control group). RESULTS GD clinically manifested by body weight l in 84% of patients, sinus tachycardia in almost all patients, paroxysmal atrial fibrillation in 18% of cases, endocrine ophthalmopathy in 12% of patients, and neurological changes. In decompensated GD, there was a statistically significant increase in levels of IFN-γ, IL-6, and α2-MG and an especially significant increase in levels of IL-8 and LF. At 4-6 months after treatment onset, clinical manifestations were stopped in all patients, levels of IL-6 and α2-MG decreased, but the concentrations of TSH receptor antibodies (TSHR-Abs), IL-8, IFN-γ, and LF remained elevated. At 1.5-2 years, levels of the studied proteins and cytokines did not differ from those in the control group. CONCLUSION An increase in blood levels of IL-8, LF, IL-6, and α2-MG in incident or recurrent GD and a decrease in the levels during treatment confirm involvement of immunoregulatory proteins in pathogenesis of the disease.

Pathogenetic mechanisms of uterine leiomyoma, adenomyosis and their combination are complicated and poorly understood, a differential diagnosis of leiomyosarcoma of the uterus is difficult. Our study aimed for a comparative analysis of the serum contents of α2-MG, PAG, some cytokines, sex steroids and the expression of steroid receptor genes in the patients with different variants of uterine proliferative diseases, in order to determine their pathological role, diagnostic and prognostic value. Expression of estrogen receptor genes adenomyosis nodes was 1.5 to 2-fold higher than in leiomyoma, the combined pathology showed intermediate values, and expression of ER and PGR genes in leiomyosarcoma was minimal. In cellular leiomyoma, expression of ER receptor genes in the surrounding myometrium was 2 to 3-fold higher than in cases of simple leiomyomas. At the same time, concentration of estrogen and progesterone in the blood is comparable between the groups and control groups. All the patients have a deficiency of immunomodulatory α2-MG (12-13% for leiomyomas, 20% for adenomyosis, and 23% for malignant pathology). The concentration of immunosuppressive PAG is increased in combined conditions and leiomyosarcoma. In addition, the contents of IL-6 and TNFα increase, the VEGF levels exceed normal values 4 to 4.5-fold, in leiomyoma, 5.5-fold, in combined pathology, 6.5, in adenomyosis, and 10-fold, in leiomyosarcoma.The obtained results confirm that immunomodulatory proteins, cytokines and cell-targeting sex hormones exert an interdependent influence upon each other in the studied diseases, and their significant changes may be used in diagnostics and prognosis.

Treatment efficiency of chronic infertility does not exceed 40% when using in vitro fertilization (IVF) programs. Therefore, sufficient attention should be given to studies of pathogenetic mechanisms, identification and correction of the factors that adversely affect onset and outcomes of pregnancy. It is known that hypersecretion of cytokines interferes with implantation, but their relationship with immunoregulatory proteins is poorly understood for various types of infertility. The aim of present study was to investigate changes in cytokine contents (IL-8, IL-6, TNFα, IFNγ), lactoferrin and α2-macroglobulin concentration in follicular fluid and venous blood of women with infertility of various genesis, and to evaluate their effects upon results of the IVF programs.The studied proteins were determined in the samples obtained on the day of transvaginal puncture of follicles in 28 infertile women with external genital endometriosis, 38 cases of chronic endometritis, 31 women with polycystic ovary syndrome, 25 patients with adenomyosis, and in 37 women with pure tubal infertility factor (comparison group). According to IVF outcomes, the patients were retrospectively divided into those who became gravid, and women with pregnancy failure. In cases of external genital endometriosis, we have found reduced contents of chemoattractant IL-8 in follicular fluid and blood, as well decreased levels of lactoferrin, which modulates its synthesis and shows antiproliferative activity. In blood of non-pregnant women with tubal infertility associated with chronic endometritis, increased concentrations of pro-inflammatory TNFα and lactoferrin were revealed, thus suggesting presence of latent inflammation. Among women with polycystic ovary syndrome, the TNFα concentration in follicular fluid and blood was reduced, along with increased content of IFNγ. In cases of adenomyosis, the IFNγ levels in follicular fluid were increased, accompanied by reduced content of regulatory-transport α2-macroglobulin in blood samples.The revealed changes in cytokine concentrations and proteins which regulate their synthesis, in biological samples from infertile women may explain the ineffectiveness of IVF programs in a number of cases. Such an imbalance has a negative impact upon development of oocytes, growth of embryos, and their ability for implantation. It is important to continue further investigations of such pathogenetic factors in order to improve approaches providing better efficiency of IVF in chronic infertility treatment.

Aim. A comparative study of the effect ofbovine and human lactoferrin (LF) on Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Candida albicans strains. Materials and methods. The daily agar cultures of museum and clinical strains of microorganisms were standardized, diluted with physiological solution up (from 5000 microbial cells/ ml to 0.1 ml) was added to the stepwise dilution of LF (from 1000 pg /ml) and incubated 18 - 24 hours at 37°C. The amount of LF in the sample with the total apparent growth retardation of the microbes was the minimum inhibitory concentration (MIC) for the strain. Results. The MIC of human LF was 4 - 8 times less than MIC of bovine LF. The smallest dose was required for the suppression of C. albicans (11.3±1.5 and 43.8±9.5 pg/ml respectively), the largest when using human LF was needed to suppress S. aureus (38,2±4,6), and in a case of bovine LF - E. faecalis (206,3±51,1). Conclusion. Human LF is much more effective in suppressing bacterial infection, but in the course of evolution, there is an increase in the resistance of S. aureus to LF. The higher availability of bovine LF and the lack of a tendency to increase resistance, it is advisable to use high-doses of bovine LF in the treatment of resistant forms of bacteria and C. albicans.

Goal. To determine the blood serum level of α2-macroglobulin (α2-MG), α1-antitrypsin (α1-AT), lactoferrin (LF) and albumin in patients with IgE-mediated and IgE-independent atopic dermatitis (AD). Materials and methods. The authors tested blood serum of 60 adult patients suffering from atopic dermatitis at the exacerbation stage (30 patients with IgE-mediated and 30 patients with IgE-independent atopic dermatitis) and 20 healthy donors in order to determine the level of these proteins by rocket immunoelectrophoresis, enzyme-linked immunosorbent assay and immunoturbidimetry methods. Major results. The albumin level is reliably reduced in case of IgE-mediated AD while the LF and α1-AT levels are increased, and concentrations of LF α1-AT and a2-MG are increased as compared to healthy people. There are differences between the level of LF, α2-MG and α1-AT. There was a statistically significant correlation between the LF levels and SCORAD score in both forms, and α2-MG and α1-AT only in case of IgE-independent AD. Conclusion. These results confirm the difference in the roles of these polyfunctional proteins in the pathogenesis of IgE-mediated and IgE-independent AD.

В представленном обзоре проведены обобщение и анализ данных литературы, касающихся патогенеза хронического эндометрита. Особенности патогенеза хронического эндометрита до конца не раскрыты вследствие их мультифакторности, сложностей диагностики и стертости симптоматики. В поддержании вялотекущего хронического воспаления, на фоне персистенции условно-патогенной микрофлоры значительную роль играют локальные и системные иммунные нарушения, приводящие к бесплодию, неудачным попыткам экстракорпорального оплодотворения, привычной потере беременности, а также к акушерским осложнениям — более 80% женщин репродуктивного возраста с хроническим эндометритом бесплодны и не способны выносить беременность. Важную роль в патогенезе хронического эндометрита играют дисбаланс между процессами пролиферации и апоптоза, расстройства субэндометриального кровотока и склеротические изменения в эндометрии. Описана роль цитокинов (факторы роста TGF-1β, VEGF, лейкемия-ингибирующий фактор, провоспалительные TNF-α и IL-1β, иммунорегуляторный IL-6, а также хемокины, в том числе IL-8) в поддержании воспалительных проявлений, снижающих рецептивность эндометрия, в нарушениях микроциркуляции и регуляции ангиогенеза, усилении экссудации, формировании спаек и отложении фибрина в строме эндометрия. При хроническом эндометрите повышена экспрессия Toll-подобных рецепторов 2-го и 4-го типов, определение маркеров плазматических клеток CD138 рекомендуется как дополнительный метод при диагностике хронического эндометрита. Существует теория аутоиммунного самоподдерживающегося процесса, индуцированного инфекцией. Высказан ряд предположений о роли белков-иммуномодуляторов (лактоферрин, альфа-2-макроглобулин) в патогенезе хронического эндометрита, а также гормонов гипоталамо-гипофизарной надпочечниковой системы. Представленные данные свидетельствуют об отсутствии единой точки зрения на этиологию хронического эндометрита и его патогенетические аспекты, обосновывая актуальность дальнейших исследований.

: The article considers the results of analysis of content of regulative transport proteins in blood serum and urine of pregnant women (term III) in case of uncomplicated pregnancy and pregnancy complicated by preeclampsia and eclampsia for elaborating their pathogenic role and evaluating prognostic significance. It is established that the more severe eclampsia is the higher is the level of a2-macroglobulin and the lower is the content of lactoferrin in blood. At that, excretion of a2-macroglobulin and albumin with urine increases with aggravation of severity of processes and in urine is detected a1-antitrypsin previously undetected. The excretion of lactoferrin reaches its peak values in case of preeclampsia and decreases in case of eclampsia. The alteration of levels of a2-macroglobulin and lactoferrin are uncharacteristic for classic inflammatory reaction and testify their active involvement into pathogenesis of eclampsia. The decreasing of in blood of levels of a1-antitrypsin lesser than 5 g/l and lactoferrin lesser than 0.8 mg/l at concentration of a2-macroglobulin higher than 3.5 g/l against the background of decreased levels of albumin and crude protein in blood and also increasing in urine of concentrations of a2-macroglobulin up to 0.0005 g/l and higher and occurrence of a1-antitrypsin and increasing of content of albumin up to 10 times can be recommended as criteria of high risk of development of eclampsia in regnant women with moderately expressed preeclampsia in term III.

Colorectal cancer (CRC) is the third most common cancer worldwide, being quite complicated, with respect to diagnostics and postoperative prognosis. Proinflammatory cytokines are shown to be involved into CRC pathogenesis. However, the changes in alpha-2-macroglobulin (α2-MG), a known regulator of cytokine production, still remain unclear. The aim of this work was to compare contents and production of a2-MG and several pro-inflammatory cytokines in blood serum and supernates from short-term blood cell cultures. The samples were taken from the patients with CRC at initial terms and after surgical removal of the tumor.Studies of cytokines and a2-MG concentrations in serum and supernates of 24-h blood cell cultures from the patients with verified CRC (stages T2-3N0-1M0 and T4N0-1M0) have shown some sufficient differences from healthy volunteers (control group). Pre-surgery IL-6 and TNFα contents in blood of CRC patients was significantly increased agains healthy controls (respectively, 29.9±5.4 and 3.4±1.5 pg/mL) versus control group (1.0±0.3 and 0 pg/mL, respectively). Following surgical treatment, the cytokine levels were decreased by 40- 60% after the operation, however, without significant differences from initial values.The supernates of blood cultures stimulated with polyclonal mitogens exhibited significant reduction of IFNγ levels prior to surgery (273±123 pg/ml versus 804±154 pg/mL), and elevated IL-6 levels (14412±2570 pg/mL versus 1970±457 pg/mL). The mean α2-MG concentrations before CRC surgery comprised 1.96±0.11 g/L for blood serum, 0.0304±0.0047 g/L, for non-stimulated blood cell cultures, and 0.0300±0.0052 g/L in mitogen-induced cultures. These parameters did not significantly differ from control values (2.21±0.17 g/L, 0.0328±0.0018 g/L, and 0.0314±0.0019 g/L, respectively). Similar results have been yielded with the samples obtained after surgical treatment of the CRC patients.The obtained data indicate that surgical treatment of CRC does not lead to normalization of the serum levels and secretion of pro-inflammatory IL-6 and TNFα cytokines by the patients’ blood cells. Marginal changes in a2-MG levels in colorectal cancer seem to be not of such importance, as functional state of the molecules which may abnormally respond to changing cytokine contents. The revealed post-surgical suppression of mitogen-induced IFNγ secretion makes it necessary to suggest administration of IFNγ and IL-2 after surgical treatment of CRC.

РОССИЙСКИЙ ВЕСТНИК АКУШЕРА-ГИНЕКОЛОГА 1, 2016 © Коллектив авторов, 2016 В предупреждении проникновения инфекционных возбудителей к плаценте и плоду и реализации инфекционного заболевания у плода основную роль играет организм матери. Материнские механизмы защиты плода можно условно разделить на три группы: механические, факторы неспецифической резистентности и специфические иммунные реакции. К механическим факторам защиты относятся различные барьеры (слизистая оболочка шейки матки, сомкнутый внутренний зев матки, устья маточных труб, слизистая пробка в шеечном канале, фетоплацентарный, гемотканевой барьеры и т.д.) [1]. С помощью клеток децидуальной оболочки происходит дифференцировка трофобласта, защита плода от проникновения инфекции путем локальных отграничительных реакций. Плацента является самой мощной преградой на пути проникновения ин-

We had investigated levels of TTG, T4, TNFα, IL-6, IFNγ, and α2-MG in blood serum and supernates of short-term blood cultures in the patients with verified Graves disease before treatment and after reaching of euthyroid status, as compared with healthy controls. We have revealed that initial blood concentrations of free Т4 in the patients were increased, along with decrease in TSH, higher IL-6, IFNγ levels, as well as concentrations of α2-MG which participates in cytokine transport and synthesis. Thiamazole treatment normalized the hormonal profile and reduced blood levels of IL-6, IFNγ and α2-MG, however, without complete normalization, along with increase of serum TNFα contents. It was shown, that the patients before treatment had decreased in vitro response of cells to the mitogenic stimulation as shown by decreased induction of TNFα and IFNγ production, along with, increased spontaneous IFNγ levels. When reaching euthyroid state after Thiamazole administration, we observed an increased spontaneous IFNγ synthesis, decreased IL-6 production in resting cultures. In mitogen-stimulated cell cultures from the treated patients, IFNγ contents became normal, however, TNFα secretion remained lower than in controls. The α2-MG levels in supernates were stable and significantly lower, than in serum. We may presume that thyrotoxicosis treatment with Thiamazole causes stabilization of the endocrine state, however, being not sufficient for normalized production of cytokines, as well as α2-MG, with its regulatory and transporter functions, thus promoting recurrence of disease and reactivation of autoimmune events.

Objective — to study the blood levels of some cytokines, vascular endothelial growth factor (VEGF), and their synthesis-modulating lactoferrin (LF) and α 2 -macroglobulin (α 2 -MG) in women with uterine myoma, adenomyosis, and their concurrence to assess their possible role in the pathogenesis of proliferative uterine diseases. Subject and methods. The serum levels of some cytokines (TNF-α, IL-6, and IL-8), VEGF, and their synthesis-modulating proteins (LF and α2-MG) in 14 women with myoma of the corpus uteri, in 10 with adenomyosis, and in 17 with a concurrence of myoma and adenomyosis were studied. A control group consisted of 25 apparently healthy women. Results. A solid-phase enzyme immunoassay and a quantitative rocket immunoelectrophoretic assay were used in the investigation. There were significantly increased cytokine levels and decreased α 2 -MG concentrations in monoabnormality; the levels of IL-8 and VEGF were particularly high in adenomyosis and myoma, respectively. LF levels were increased in myoma only. The patients with comorbidity (uterine myoma and adenomyosis) had the same changes in the cytokine profile and LF levels as those with uterine myoma, and those in the concentration of VEGF were seen in the patients with adenomyosis. However, the content of α2-MG and IL-6 in patients with a concurrence of myoma and andometriosis differed from that in monoabnormality. Conclusion. Thus, with the similarities in the site and clinical manifestations of the diseases, the changes in the cytokine profile and the levels of the immunomodulatory proteins differ in adenomyosis and myoma and there are a number of characteristic dissimilarities in the presence of the comorbidity, suggesting severer defects in the immune system. The authors declare no conflicts of interest.