Rationale : Recently, the incidence of inflammatory bowel disease (IBD) and non-alcoholic steatohepatosis has increased in developed countries. Also, there are fundamental prerequisites to mutually negative influence of these diseases. Therefore, evaluation of the characteristics of non-alcoholic steatohepatosis in patients with IBD is of practical interest. Aim : To identify particulars of non-alcoholic steatohepatosis / steatohepatitis in IBD patients. Materials and methods : This cross-sectional study included 245 patients aged from 18 to 77 years from the IBD Registry the Novosibirsk State Medical University and the State Scientific-Research Institute of Physiology and Basic Medicine (Novosibirsk, Russian Federation). Within one year before the study entry, the patients were assessed by abdominal ultrasound and diagnosed with steatohepatosis. All patients were examined clinically with measurement of their antropometric parameters and underwent laboratory assessments, including hematology tests, alanine and aspartate transaminases, creatinine, triglycerides and total cholesterol measurements. Patients with viral and autoimmune hepatitis, alcoholic liver disease, primary sclerosing cholangitis, iron and copper metabolism disorders were excluded. In the colon biopsy samples of 45 patients, Epstein-Barr virus, cytomegalovirus, herpes simplex virus were identified by polymerase chain reaction. One hundred and fifty two (152) patients were also assessed for small intestine bacterial overgrowth (SIBO) syndrome. Results : The prevalence of steatosis in patients with Crohn's disease (CD) was 34.2%, and in those with ulcerative colitis (UC), 30.4%. IBD patients with steatohepatosis were more likely to have received steroids (63.6% vs. 53%, p = 0.0006), had greater IBD du-ration (median 5.9 years, Q 1 /Q 3 , 2.7/12.9 years vs. 4.5, 2.9/8.5 years; p = 0.0324) and a higher body mass index (median 24.1, Q 1 /Q 3 , 21.4/29.9 vs. 21, 18.6/23.5; p = 0.0336). UC patients with non-alcoholic steatosis / steatohepatitis were older (odds ratio [OR] for the age above 40 years, 1.46; 95% confidence interval [CI] 1.01-2.1). CD patients with steatohepatosis had higher platelet counts (median 287 x 10 9 /L, Q 1 /Q 3 , 192 x 10 9 /L / 420 x 10 9 /L vs. 250 x 10 9 /L, 180 x 10 9 /L / 379 x 10 9 /L; p = 0.0183). SIBO was a risk factor for the development of steatohepatosis in IBD patients (OR 2.34, 95% CI 1.4-4.8, p = 0.021). Conclusion : The study has identified the differences in the steatohepatosis-associated factors in UC and CD patients. There is a link between the presence of SIBO and the risk of steatohepatosis development in IBD patients.

Psoriasis, psoriatic arthritis (PsA) and inflammatory bowel disease (IBD) are multifactorial chronic immunoinflammatory disorders with characteristic common genetic markers that determine their common pathophysiology and similar immune abnormalities. In particular, IL12/23 signaling pathway of the immune pathogenesis of the above mentioned diseases is related to the IL23R gene polymorphism. Common pathophysiological features, in their turn, produce a high risk and prevalence of comorbidity. Clinicians' unawareness of these particulars of the immunoinflammatory disorders might lead to the absence of interdisciplinary collaboration, late diagnosis of one of these disorders and polypharmacy, because each specialist (i.e., a dermatologist, a rheumatologist, a gastroenterologist) would administer his/hers treatments independently. In this context, the issues of the multidisciplinary approach to this problem are becoming highly relevant for earlier diagnosis and adequate treatment choice that is optimal for all disorders which contribute to the pathological process, taking into account common mechanism of their development. Therefore, there is the necessity to establish an interdisciplinary working group consisting of the leading specialists of the Russian Federation in rheumatology, dermatology, and gastroenterology, with a purpose to elaborate a consensus on the immunoinflammatory comorbidities. At the discretion of the Russian Association of Rheumatologists (RAR), Russian Society of Dermatovenerologists and Cosmetologists (RSDVC), Russian IBD Study Society (RIBDS), such a group has been formed of 11 experts corresponding to their scientific expertise in the area. The main aim of the Working Group was to develop a universal interdisciplinary questionnaire for detection of the signs and symptoms of the immunoinflammatory disorders (psoriasis, PsA, IBD), as well as development of a draft project of the interdisciplinary guidelines on the early diagnosis, methods of activity assessment and indications to the use of genetically engineered biological agents in patients with comorbid immunoinflammatory comorbidities (psoriasis, PsA, IBD). Procedure of the interdisciplinary guidelines elaboration . The Working Group elaborated a draft project of the up-to-date evidence-based guidelines and proposed a multidisciplinary questionnaire. An interdisciplinary expert council of specialists in dermatology, rheumatology and gastroenterology discussed each position of the proposed guidelines and was adopted by a simple majority of votes through an open voting at the Second Russian Debates “Dermatology, Rheumatology, Gastroenterology: focus on the interdisciplinary interaction” (Moscow, December 12–13, 2017). Results : 1 . A universal interdisciplinary questionnaire to detect clinical signs of immunoinflammatory disorders (psoriasis, PsA, IBD) has been created. It contains the main questions the answers to which are needed for a specialist physician (a dermatologist, a rheumatologist or a gastroenterologist) to suspect comorbidity and to refer the patient to a corresponding specialist. The questionnaire has three parts, each of them with questions to the patient aimed at the detection of the symptoms of psoriasis, PsA, and IBD. 2 . An algorithm for interaction between dermatologists, rheumatologists and gastroenterologists has been developed aimed at optimal management of patients with comorbid immunoinflammatory disorders. 3 . Goals of treatment of immunoinflammatory disorders (psoriasis, PsA, Crohn's disease) have been formulated according to the “treat-to-target” (Т2Т) concept. 4 . Criteria for assessment of activity and severity of the immunoinflammatory disorders (psoriasis, PsA, and Crohn's disease) have been formulated. 5 . The draft describes the indications for the administration of genetically engineered biological agents (GEBA), factors influencing the choice of treatment, criteria for GEBA efficacy assessment, indications to a change of a GEBA in primary or secondary treatment failure. Conclusion : In accordance with the results of discussion with specialists from various regions of the Russian Federation and with the decision of the Expert Council, it is planned to validate the questionnaire, with subsequent inclusion of the position of the draft project into the clinical guidelines on the management of patients with psoriasis, PsA, and Crohn's disease.

Rationale: In the recent years, an increased interest to autoimmune pancreatitis (AIP) has been seen, related to growing diagnostic potential. In its turn, this leads to an increase in numbers of diagnosed AIP cases. At present, two types of AIP have been described with diverse clinical manifestation and morphology of the pancreas. However, the reproducibility of the differential diagnosis between AIP type 1 and 2 is low even among pancreatic pathologists.Aim: To identify criteria for the morphologic diagnosis of AIP type 1 and 2.Materials and methods: A morphological study of biopsy and surgical specimens from 26 patients with AIP was performed. There were 22 cases of AIP type 1 and 4 cases of AIP type 2. In addition to hematoxylin eosin staining of the specimens, immunohistochemistry was used with counting of CD138+ absolute numbers, determination of IgG+ and IgG4+ cells in the inflammatory infiltrates, as well as the ratios of IgG4+/IgG+ and IgG4+/CD138+ cells.Results: AIP type 1 was characterized by storiform fibrosis of the pancreatic tissue (81.8% cases), involving the parapancreatic fat tissue, by moderateto-severe lymphoplasmocytic infiltration and signs of obliterative/non-obliterative phlebitis. Type 2 AIP was characterized by severe fibrosis with predominantly periductal (centrilobular) fibrosis and mild chronic inflammatory infiltration of the pancreas, while there was no extension of fibrosis and inflammatory infiltration to the parapancreatic tissues in any case. The mean number of CD138+ cell in AIP type 1 was 101.2 ± 27.9 per 1 high-power field (HPF), and in AIP type 2, it was 42.8 ± 20.9 per 1 HPF. The mean absolute number of IgG+ cells in AIP type 1 was 99.6 ± 25.7 per 1 HPF, whereas in AIP type 2, 42.1 ± 20.8 per 1 HPF. In AIP type 1, the mean number of IgG4+ plasmatic cells in the infiltrates was 74.5 ± 27.2 per 1 HPF, whereas in AIP type 2, it was 3.4 ± 2.7 per 1 HPF. The IgG4+/IgG+ ratio was 75 ± 12.6% vs. 8.4 ± 6.2%, and the IgG4+/CD138+ ratio was 72.4 ± 12.3% vs. 8.3 ± 5.9% in AIP type 1 and type 2, respectively.Conclusion: For the differential diagnosis of type 1 and 2 AIP, it is necessary to take into consideration not only typical histological abnormalities, but also the numbers of CD138+, IgG+ and IgG4+ cells within the inflammatory infiltrate, as well as the IgG4+/IgG+ and IgG4+/CD138+ ratios.

Background:Well-differentiated pancreatic neuroendocrine tumors (pNETs) represent a group of rare epithelial neoplasms with a highly variable clinical course. AKT1 is one of the most frequently activated protein kinases in pNETs, which promotes the tumor growth and is of interest as a prognostic factor and a target for new treatment approaches.Aim:To study the expression of the phosphorylated variant of AKT1-kinase (p-AKT1) in primary pNETs and their liver metastases and to correlate the results with various clinical and pathological parameters and the disease prognosis.Materials and methods:P-AKT1 expression was studied by the immunohistochemical analysis of the primary lesions and liver metastases in 52 pNETs patients.Results:A high level of cytoplasmic and/or nuclear immunoreactivity was detected in 24/52 of the primary pNETs (46.2%) and in 16/27 of their liver metastases (59.3%). p-AKT1 expression was observed in 3 (21.4%) of NET grade (G) 1, in 14 (46.7%) of NET G2, and in 7 (87.5%) of NET G3. p-AKT1 expression was more frequently identified in pNET G3 category and increased during the tumor progression in metachronous liver metastases, as compared to the corresponding primary tumor. In addition, p-AKT1 positivity was significantly associated with an increase of grade from G1 to G3 (p = 0.004), the Ki-67 index (p = 0.029), the pTNM stage (p = 0.0008), perineural invasion (p = 0.031) and a decrease in disease-free survival (p = 0.05).Conclusion:The results suggest that p-АКТ1 plays an important role in the pathogenesis of pNETs and may be an additional criterion for assessment of the prognosis and treatment effectiveness in this type of tumors.

Leukoplakia is a chronic precancerous skin and mucosal lesion with a multifactorial etiology.Aim: To retrospective analyze clinical and morphological characteristics of leukoplakia in the Perm region.Materials and methods: The study was based on the data extracted from outand in-patient medical files and biopsy samples of 332 patients referred to the Perm Regional Oncological Dispensary (Perm, Russian Federation) in 2005 to 2016. The analysis of clinical and morphological characteristics was carried out with consideration of anatomical localization, gender and histopathological findings.Results: Among the patients with leukoplakia, there were mostly women (77.7%) of the older age (61.6 ± 3.5 years), with frequent lesions of the vulvar mucosa (71.7%). Men had similar prevalence of genital (47.3%) and oral (52.7%) leukoplakia. Simple (flat) leukoplakia was found in 31.7% of the cases, verrucous in 45.0%, and erosive/ ulcerative in 23.3%. Verrucous leukoplakia was more often characterized by hyperkeratosis (95.5%) and vacuolar degeneration (94.8%). The erosive/ulcerative type was characterized by parakeratosis (95.7%), acanthosis (84.3%), dyskeratosis (90.0%), and dermal vascularization (95.7%). Dysplasia was observed in 52.3% of the cases, with 90% in erosive/ulcerative leukoplakia, 31.5% in simple leukoplakia and 47.4% in verrucous type. The frequency of dysplasia signs increased with an increase of the dysplasia grade (SIN).Conclusion: In the Perm region, leukoplakia was more prevalent in female patients and had predominantly genital localization (96.9%). The risk of verrucous and erosive/ulcerative genital leukoplakia in women was 2,27and 1,75-fold higher than in men, respectively. In all clinical types, there was a slight predominance of SIN1, whereas the ratio of dysplasia grades was similar. Only combined assessment of clinical and morphological data could improve prediction of transformation to cancer.

Background: The use of molecular genetic technologies has made it possible to show that the genetic factor plays a significant role in the development of obesity. In addition, in obese people the supply with vitamins, in particular with folic acid, is largely controlled genetically.Aim: To study an association of the rs1801133 polymorphism of the MTHFR gene with folic acid deficiency in the residents of the Moscow region depending on their body mass index.Materials and methods: rs1801133 polymorphisms were identified in 326 subjects (74 male and 252 female) aged from 20 to 65 years, living in the Moscow region. The DNA was isolated from blood by the sorption on silica gel-coated magnetic particles. DNA was isolated with the use of the epMotion 5075 automatic station (Eppendorf, Germany). To identify the polymorphism, a polymerase chain reaction was used, followed by cleavage of the Hinf1 restriction endonuclease products, with analysis of these products by gel electrophoresis. The equipment CFX96 Real Time System (BIO-RAD, USA) was used. Folic acid was measured by ID-Vit® Folic Acid test system (R-Biopharm, Germany).Results: According to the results of folic acid measurements in blood, a deficiency of this vitamin was found in 24.2% of the studied residents of the Moscow region. Analysis of the genotyping results did not show any association of the rs1801133 MTHFR gene polymorphism with the serum levels of folic acid. However, in the subjects with overweight and obesity, there was a statistically significant association between the T allele of the rs1801133 of the MTHFR gene polymorphism and a low level of folic acid (odds ratio 2.5, 95% confidence interval 1.09–5.74, p = 0.03).Conclusion: The rs1801133 polymorphism of the MTHFR gene significantly contributes to the development of folic acid deficiency in overweight and obese individuals.

The article presents a draft of clinical guidelines for intensive care of children, who require interhospital transport; it was elaborated with consideration of territorial characteristics of the Russian Federation. Legal aspects of organization of interhospital transport service and possible side effects of transportation are considered in detail. General description and the main advantages and disadvantages of the air transport and ground ambulance transport are presented. A system for transport risk assessment is proposed, based on ranks that correspond to the duration of safe transport time. Original scales to assess the transportation risk based on the necessity of emergency rehydration, inotropic, vasopressor and respiratory support are presented. Special attention is focused on the preparation of critically ill children to interhospital transport, with detailed protocol for intensive care, monitoring and caring activities while transporting. The goal parameters for patient stabilization in the next six hours after transport are described. The use of proposed key principles of safe transport would significantly improve the quality of medical care for children, who require transportation to specialized units.

Aim: To estimate the prevalence of the rheumatic diseases in an epidemiological study.Materials and methods: During a questionnaire survey among 76 162 adult individuals in 12 regions of the Russian Federation, those with complaints of joint pain and swelling were selected and a group (n = 4894) was formed at random for subsequent clinical assessment by rheumatologists to identify main rheumatic diseases. In all regions, the study was conducted according to the unified protocol, with the unified strategy of the population selection and the use of unified questionnaires. Diagnoses were made based on widely adopted classification criteria for rheumatic diseases.Results: For the first time in Russia it was found that among adult Russian population, the life-time prevalence of joint pain (mostly knee and hip) was 39.5%, whereas that of joint swelling amounted to 26%. From those, arthralgias eventually disappear in 8% and arthritis, in 7%. Among all rheumatic clinical entities, knee and/or hip osteoarthritis ranks the first, with its prevalence calculated to all adult population of Russia above 18 years of age being 13%. The prevalence of rheumatoid arthritis was 0.61%, of ankylosing spondylitis, 0.1%, psoriatic arthritis, 0.37%, reactive arthritis, 0.42%, gout, 0.3%, and of systemic connective tissue disorders (systemic lupus erythematosus, systemic sclerosis, dermatomyositis/polymyositis, Sjogren's syndrome, systemic vasculitis, etc), 0.11%.Conclusion: The true prevalence of the rheumatic diseases found in the epidemiological study was higher than the data of the official statistics as follows: 2.5-fold for rheumatoid arthritis, 5-fold for osteoarthritis, 3.5-fold for spondyloarthritis and 3-fold for systemic connective tissue disorders. The results obtained showed an underestimation of the rheumatic diseases and incomplete data in the country statistics. This might be related to low referral levels for medical care due to significant distances of the vast regional areas from the specialized centers, as well as with insufficient qualification of primary care physicians in the field of rheumatology. All together, this leads to inevitable and serious misdiagnoses and low registration of the rheumatic diseases.

Aim: To perform a comparative analysis with simultaneous measurement of vascular endothelial growth factor (VEGF), insulin-like growth factor 1 (IGF1) and matrix metalloproteinase 7 (MMP7) in serum samples taken from healthy women and ovarian cancer patients; to perform association of these markers with their expression in primary tumors depending on clinical, morphological and biochemical characteristics of the disease and its prognosis. Materials and methods: We assessed 54 treatment-naïve patients with ovarian cancer aged from 23 to 74 years (mean ± SD, 53.2 ± 1.9), being at various FIGO stages of the disease. The control group consisted of 120 healthy women of matched age and reproductive status, in whom serum biomarker levels were studied. Patient survival was assessed by the Kaplan-Meier method, with survival curves compared with log-rank test. All analyses were done with “STATISTICA” and SPSS software. Results: Serum VEGF levels in ovarian cancer patients were significantly (p < 0.0001) higher compared those in the control. The most informative cut-off values differentiating the groups studied were serum VEGF values of < 350 pg/ml (median value in the control) and > 505 pg/ml (upper quartile in the control). With 505 pg/ml taken as a threshold, the test had sensitivity of 79.6% and specificity of 75%. Another cut-off value of serum VEGF level between the patients with ovarian cancer and the control group (510 pg/ml) was derived from ROC curves and 75% sensitivity and 78.2% specificity. No acceptable cut-off value for serum IGF1 to differentiate between the patients with ovarian cancer and the controls could be obtained from the ROC curves. Serum MMP7 levels in the patients with ovarian cancer were significantly higher than those in the control group (Mann-Whitney test p < 0.0001). With ROC curves, the best sensitivity to specificity ratio for MMP7 value of 4.6 ng/ml was obtained to differentiate between the patients with ovarian cancer and the controls (sensitivity 83.3%, and specificity 81%). The variance analysis did not reveal any association between serum VEGF, IGF1 and MMP7 and age of patients with ovarian cancer, tumor histology, concomitant somatic and gynecological diseases, and CA-125 levels. Serum VEGF and IGF1 levels did not correlate with the stage of ovarian cancer, in contrast to MMP7, whose levels were significantly higher in stages IIIc–IV. The median VEGF level significantly increased as the degree of differentiation decreased from 510 to 622 pg/ml (p < 0.002), while median IGF1, on the contrary, decreased from 219 to 116 pg/ml (p < 0.0001). There was a direct correlation between serum and tumor VEGF levels in ovarian cancer patients (r = 0.65, p < 0.0001). On the contrary, there was an inverse correlation between serum and tumor IGF1 levels (r = -0.68, p < 0.0001). Serum and tumor MMP7 levels remained unrelated to each other. Tumor VEGF, IGF1 and MMP7 content was unrelated to the age of the patients, their reproductive status, presence of concomitant somatic and gynecological diseases, histology of ovarian cancer, and serum CA-125 levels. VEGF levels in the tumor were not associated with the stage of ovarian cancer, but in patients with initial stages Ia and Ib stages MMP7 values significantly lower (2.1 ng/mg protein) compared to those in stages IIIc and IV (6.1 and 4.7 ng/mg protein, respectively, p < 0.05). Similar pattern was noted for IGF1: tumor IGF1 values in the patients with stages Ia–Ib were significantly lower (0.5 ng/mg protein) than those with stages IIIc–IV (median, 1.3–1.4 ng/mg protein). A significant increase in both serum and tumor VEGF levels was detected in the patients with ovarian cancer with decreased degree of differentiation. On the contrary, tumor IGF1 levels, but not serum ones, were significantly increased from 0.6 to 1.4 ng/ml in the patients with poorly differentiated ovarian cancer. MMP7 tumor expression did not depend on the degree of its differentiation. Serum VEGF levels above 700 pg/ml and tumor levels of above 590 ng/mg protein should be considered as unfavorable prognostic factors in patients with ovarian cancer.