[The clinic of autistic disorders at an early age]. / Klinika autisticheskikh rasstroistv v rannem vozraste.

OBJECTIVE: To study disorders of mental development and psychopathological symptoms in young children with autistic disorders of various origins. MATERIAL AND METHODS: Two hundred and sixty-five children, aged 9 months to 4 years, (201 boys, 64 girls) with symptoms of autistic disorder were examined. The patients were divided into two age groups - the 1st group consisted of 36 children, aged 9 months to 2 years, the 2nd group consisted of 229 children from 2 years to 4 years. Psychopathological, neurological and clinical-dynamic methods were used, taking into account the results of consultations with a speech therapist, defectologist, psychologist. RESULTS: The number of visits to a psychiatrist by parents of children older than two years becomes significantly higher - 13.6% (n=36) and 86.4% (n=112), respectively (p≤0.05), as well as the diagnosis of autistic disorder - 8.3% (n=3) and 16.2% (n=37) respectively, p≤0.05). In both age groups, the diagnosis of «Other general developmental disorders¼ (F84.8) was most often established, with a significant predominance in the younger group - 80.5% and 72%, respectively (p≤0.05). Characteristic symptoms-markers of autism for both age groups are highlighted. It is shown that the diagnoses of childhood autism, Kanner syndrome, exposed at the first treatment, were preserved in all patients after three years. By the age of four, it was possible to clarify the diagnosis in 32% of cases. At the same time, 68% of patients, aged 4 years, retained a clinically undifferentiated diagnosis of F84.8. CONCLUSION: The study showed an increase in the diagnosis of autistic disorder during the first years of life. The necessity of increasing the knowledge of early-age psychiatry among specialists and the organization of a system of early detection, timely treatment and rehabilitation of autistic disorders in children of the first years of life in children's polyclinics is noted.

[Bilateral uveitis associated with protein kinase inhibitor-based treatment of skin melanoma (case study)]. / Dvustoronnii uveit, obuslovlennyi priemom ingibitora proteinkinazy pri lechenii melanomy kozhi (klinicheskoe nablyudenie).

The article presents a clinical case of bilateral uveitis with macular edema that developed during long-term administration of vemurafenib. Methods of conservative treatment of malignant tumors are presently available and reasonably effective. However, at the same time drugs can have toxic effect on normal cells in various tissues of the body. According to our data, the use of corticosteroids can ameliorate the clinical signs of macular edema associated with uveitis, but with a tendency to recur. Only complete cancellation of vemurafenib provided remission of sufficient duration, which is fully consistent with clinical observations made by colleagues. Therefore, when prescribing long-term therapy with vemurafenib, in addition to periodic observation by an oncologist, it is also mandatory to continue follow-up observation by an ophthalmologist. Partnership between health care specialists could help avoid severe ocular complications.

[Genome-Wide Analysis of DNA Methylation in Cd4+ T Lymphocytes of Patients with Primary Progressive Multiple Sclerosis Indicates Involvement of This Epigenetic Process in the Disease Immunopathogenesis].

The pathogenesis of multiple sclerosis (MS), a chronic disease of the CNS, includes autoimmune and neurodegenerative components. In most cases, patients develop relapsing-remitting MS (RRMS), while 10-15% of patients develop primary progressive MS (PPMS), which differs from RRMS in the mechanisms of the pathological process, some demographic, and some clinical characteristics. These differences may be explained by the epigenetic regulation of gene expression in PPMS including DNA methylation as one of the key epigenetic processes. The features of DNA methylation in various cell populations in PPMS patients remain understudied. The goal of this study is to identify differentially methylated CpG sites (DMSs) of the genome of CD4+ T lymphocytes, which characterize PPMS. The study included eight treatment-naive PPMS patients and eight healthy controls. Genome-wide analysis of DNA methylation of CD4+ T lymphocytes was performed using high-density DNA microarrays. We have identified 108 DMSs, which distinguish PPMS patients from healthy controls. In PPMS patients 81% of the DMSs are hypermethylated. More than a half of the identified DMSs are located in known genes in CpG islands and adjacent regions, which indicates a high functional significance of these DMSs in PPMS development. Analysis of the overrepresentation of DMS-containing genes in the main biological processes demonstrates their involvement in the regulation of cell adhesion to the extracellular matrix and the development of the immune response, i.e., antigen processing and presentation, and development of the immune system. Genome-wide analysis of DNA methylation in CD4+ T lymphocytes of PPMS patients indicates the involvement of this epigenetic process in the immunopathogenesis of the disease. These results may help better understand the pathogenesis of this severe form of MS.

Prospects for the use of indicators of sialic acid metabolism in medicine (review of literature).

Sialic acids (SA) determine the degree of molecular hydrophilia, relieve binding together and their transportation, they increase mucin viscosity, stabilize the protein and membrane structure. Apart from that, SA are structural components of gangliosides participating in the formation of the outer layer of the plasma membrane. The degree of silyliation of glycoproteins and glycolipids is an important factor of molecular recognition in the cell, between the cells, between a cell and territorial matrix, as well as between a cell and some outer pathogenic factors. They can either mask the sites of recognition or be determinants of recognition. The most well-studied enzymes taking part in the SA metabolism and sialo-containing compounds are N-acetylneuraminate, cythydiltransferase, sialyltransferase, sialydase, aldolase SA and sialyl-O-acetylesterase. Numerous investigations have shown that aberrant sialylation is a specific feature of various changes and disorders of metabolism. Besides that, sialic acids are the first point of contact for different pathogenic microorganisms and the host's body due to their presence on the external surface of the cells and tissue of the mucous membrane. That is why the study of the above-mentioned various sialic acids fractions as well as of the activity of the enzymes participating in their metabolism in the blood plasma and tissues, and of the influence on the activity of these enzymes with the help of medicine can make an essential contribution to the diagnosis and treatment of many diseases.

Influence of exogenous and endogenous factors on the quality of the preanalytical stage of laboratory tests (review of literature).

A literature review in the article presents an analysis of the influence of endogenous and exogenous factors on quality of preanalytical phase of laboratory testing. The review shows significance of external and internal factors influencing blood samples at preanalytical phase of laboratory testing. Among the exogenous factors considered: phlebotomy, test tubes for samples, transportation and storage. A number of factors exist at this phase that significantly affect test results. We examined these aspects of phlebotomy process: staff training, disinfectant contamination, needle diameter, needle material contamination. The review considers possible contamination with tube components and the importance of choosing the right anticoagulants and excipients. Transportation and storage of biological samples can be a source of errors at the preanalytical phase of laboratory testing. We analyzed the problem of determining the stability of analytes during storage and aspects of transportation samples by modern means. Among the endogenous factors considered: hemolysis, lipemia, icterricity, cell metabolism.. Hemolysis is one of the most frequent consequences of errors at the preanalytical phase. We analyzed importance of choosing a method for identifying hemolized tubes and the heterogeneity of bias results on different analytical systems. The review shows contribution of various classes of lipoproteins to turbidity of sample, possible preanalytical errors and impact on analytical tests. We examined possible effects of high bilirubin concentrations on analyte measurements. In the review, we also examined metabolism of some cells and its effect on samples.

[The marketing of anti-aging services in aesthetic medicine].

The article defines the main trends of the market of medical anti-aging services and prospects of aesthetic medicine. The paper presents the data of research on the impact of contextual advertising in social networks on the decision of patients of middle and retirement age on the use of anti-aging cosmetology and treatment for the provision of cosmetic services of an aesthetic nature. The article presents the analysis of the main options of Internet advertising of a medical nature for anti-aging subjects, in addition, describes the methodology that is developed for commercial medical organizations, and analysis of anti-aging medical procedures in the aspect of aesthetic medicine and the search for the necessary information on anti-aging medicine in social networks. The article draws an important conclusion that an important factor affecting the medical market of aesthetic medicine services is the decrease in consumer activity and solvency of the population, which requires a revision of the price and assortment policy of clinics. The article demonstrates the results of obtaining valuable data on popular requests and effective advertising sources, conversion into circulation from different advertising channels and from different devices, the activity of consumers of medical aesthetic services during the week and day. Special attention was paid to the advertising of anti-aging aesthetic medicine in social networks.

[Herpesviral infection as an etiological factor of acute idiopathic optic neuritis]. / Gerpes-virusnaia infektsiia kak étiologicheskii faktor ostrogo idiopaticheskogo opticheskogo nevrita.

PURPOSE: To assess the etiological significance of herpesviral infection (HVI) in patients with acute idiopathic optic neuritis (ON) using clinical and laboratory monitoring. MATERIAL AND METHODS: Clinical and laboratory examinations were conducted for 10 years and were based on the results of etiological monitoring of 79 patients (85 eyes) with acute idiopathic ON in the period of 2005-2015. RESULTS: During a complex examination of 79 patients with acute idiopathic ON, various infectious pathogens were diagnosed in 75 people (94.9±2.1%). HVI was clearly dominant (69 patients - 87.3±2.4%). These patients were divided into 3 etiological groups. The first group - 34 people with herpesviral monoinfection; the second group - 15 people with mixed viral-viral infections; the third group - 20 people with mixed viral-bacterial infections. In the general population of patients with acute idiopathic ON associated with HVI, herpes simplex virus-1 is the most frequent (by more than 2.5 times), the infections of Epstein-Barr virus and cytomegalovirus were detected less often (p<0.05). Active current HVI in the general group of patients was diagnosed in 58 patients (84%). At the same time, reactivation of chronic infection (79.7%) was noted to be prevalent, while primary acute HVI was diagnosed rarely (4.3%). The remaining 11 patients (16%) had chronic persistent HVI. CONCLUSION: Clinical and laboratory monitoring of HVI in patients with acute idiopathic ON has shown the etiological role of herpesviruses in its development. Based on a complex of serological markers in enzyme-linked immunoassay reactions of blood serum, it was found that in patients with acute idiopathic ON the frequency of herpesviral infection is 87.3±2.4%. The proportion of active (etiologically significant) herpesviral infection is 84% of the total group. The results of the clinical and laboratory studies are of great practical importance for verification of the etiologic diagnosis and selection of adequate etiopathogenetic therapy in patients with acute idiopathic ON associated with HVI.

Major pathologic response on biopsy (MPRbx) in patients with advanced melanoma treated with anti-PD-1: evidence for an early, on-therapy biomarker of response.

BACKGROUND: With increasing anti-PD-1 therapy use in patients with melanoma and other tumor types, there is interest in developing early on-treatment biomarkers that correlate with long-term patient outcome. An understanding of the pathologic features of immune-mediated tumor regression is key in this endeavor. MATERIALS AND METHODS: Histologic features of immune-related pathologic response (irPR) following anti-PD-1 therapy were identified on hematoxylin and eosin (H&E)-stained slides in a discovery cohort of pre- and on-treatment specimens from n = 16 patients with advanced melanoma. These features were used to generate an irPR score [from 0 = no irPR features to 3 = major pathologic response on biopsy (MPRbx, ≤10% residual viable tumor)]. This scoring system was then tested for an association with objective response by RECIST1.1 and overall survival in a prospectively collected validation cohort of pre- and on-treatment biopsies (n = 51 on-treatment at 4-week timepoint) from melanoma patients enrolled on the nivolumab monotherapy arm of CA209-038 (NCT01621490). RESULTS: Specimens from responders in the discovery cohort had features of immune-activation (moderate-high TIL densities, plasma cells) and wound-healing/tissue repair (neovascularization, proliferative fibrosis) compared to nonresponders, (P ≤ 0.021, for each feature). In the validation cohort, increasing irPR score associated with objective response (P = 0.009) and MPRbx associated with increased overall survival (n = 51; HR 0.13; 95%CI, 0.054-0.31, P = 0.015). Neither tumoral necrosis nor pretreatment histologic features were associated with response. Eight of 16 (50%) of patients with stable disease showed irPR features, two of which were MPRbx, indicating a disconnect between pathologic and radiographic features at the 4-week on-therapy timepoint for some patients. CONCLUSIONS: Features of immune-mediated tumor regression on routine H&E-stained biopsy slides from patients with advanced melanoma correlate with objective response to anti-PD-1 and overall survival. An on-therapy biopsy may be particularly clinically useful for informing treatment decisions in patients with radiographic stable disease. This approach is inexpensive, straightforward, and widely available.

Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC).

Background: Neoadjuvant anti-PD-1 may improve outcomes for patients with resectable NSCLC and provides a critical window for examining pathologic features associated with response. Resections showing major pathologic response to neoadjuvant therapy, defined as ≤10% residual viable tumor (RVT), may predict improved long-term patient outcome. However, %RVT calculations were developed in the context of chemotherapy (%cRVT). An immune-related %RVT (%irRVT) has yet to be developed. Patients and methods: The first trial of neoadjuvant anti-PD-1 (nivolumab, NCT02259621) was just reported. We analyzed hematoxylin and eosin-stained slides from the post-treatment resection specimens of the 20 patients with non-small-cell lung carcinoma who underwent definitive surgery. Pretreatment tumor biopsies and preresection radiographic 'tumor' measurements were also assessed. Results: We found that the regression bed (the area of immune-mediated tumor clearance) accounts for the previously noted discrepancy between CT imaging and pathologic assessment of residual tumor. The regression bed is characterized by (i) immune activation-dense tumor infiltrating lymphocytes with macrophages and tertiary lymphoid structures; (ii) massive tumor cell death-cholesterol clefts; and (iii) tissue repair-neovascularization and proliferative fibrosis (each feature enriched in major pathologic responders versus nonresponders, P < 0.05). This distinct constellation of histologic findings was not identified in any pretreatment specimens. Histopathologic features of the regression bed were used to develop 'Immune-Related Pathologic Response Criteria' (irPRC), and these criteria were shown to be reproducible amongst pathologists. Specifically, %irRVT had improved interobserver consistency compared with %cRVT [median per-case %RVT variability 5% (0%-29%) versus 10% (0%-58%), P = 0.007] and a twofold decrease in median standard deviation across pathologists within a sample (4.6 versus 2.2, P = 0.002). Conclusions: irPRC may be used to standardize pathologic assessment of immunotherapeutic efficacy. Long-term follow-up is needed to determine irPRC reliability as a surrogate for recurrence-free and overall survival.

[A phenomenological analysis of non-suicidal self-injuries in adolescents]. / Fenomenologicheskii analiz nesuitsidal'nykh samopovrezhdenii u podrostkov.

AIM: To perform a phenomenological/clinical/psychopathological analysis of non-suicidal self-injury behavior (NSSI) in adolescents. MATERIAL AND METHODS: The authors studied 155 adolescents, 140 girls and 15 boys, aged 12-17 years, including 111 with self-cutting, 5 with self-burning, 4 with self-beating. Other cases included combined, multiple and other variants of NSSI. RESULTS AND CONCLUSION: NSSI develop more often in female teenagers. NSSI may be a component of suicidal behavior or represent a relatively independent behavioral model existing out of a suicidal context. NSSI behavior can be considered as psychological defense as well as a coping strategy in response to nonspecific stress.

Activity, sleep and ambient light have a different impact on circadian blood pressure, heart rate and body temperature rhythms.

The aim of the present study was to investigate the impact of endogenous and exogenous factors for the expression of the daily rhythms of body temperature (BT), blood pressure (BP) and heart rate (HR). One hundred and seventy-three young adults (YA), 17-24 years old (y.o.), of both genders were studied under a modified constant-routine (CR) protocol for 26 h. Participants were assigned randomly to groups with different lighting regimens: CR-LD, n = 77, lights (>400 l×) on from 09:00 to 17:00 h and off (<10 l×) from 17:00 to 09:00 next morning; CR-LL, n = 81, lights on (>400 l×) during the whole experimental session; CR-DD, n = 15, constant dim light (<10 l×) during the whole experiment. Systolic (SBP) and diastolic (DBP) BP, HR and BT were measured every 2 h. For comparison, the results of the former studies performed under conditions of regular life with an activity period from 07:00 to 23:00 h and sleep from 23:00 till 07:00 h (Control) were reanalyzed. Seven-day Ambulatory Blood Pressure Monitoring (ABPM) records from 27 YA (16-38 y.o.) and BT self-measurement data from 70 YA (17-30 y.o.) taken on ≥ 3 successive days at 08:00, 11:00, 14:00, 17:00, 20:00, 23:00 and 03:00 were available. The obtained daily patterns were different between Control and CR-DD groups, due to effects of activity, sleep and light. The comparison of Control and CR-LD groups allowed the effects of sleep and activity to be estimated since the lighting conditions were similar. The activity level substantially elevated SBP, but not DBP. Sleep, on the other hand, lowered the nighttime DBP, but has no effect on SBP. HR was affected both by activity and sleep. In accordance with previous studies, these results confirm that the steep BP increase in the morning is not driven by the circadian clock, but rather by sympathoadrenal factors related to awakening and corresponding anticipatory mechanisms. The effect on BT was not significant. To investigate the impact of light during the former dark time and darkness during the former light time, the CR-LL and CR-DD groups were each compared with the CR-LD group. Light delayed the evening decrease of BT, most likely via a suppression of the melatonin rise. Besides, it had a prominent arousal effect on SBP both in the former light and dark phases, a moderate effect on DBP and no effect on HR. Darkness induced decline in BT. BP values were decreased during the former light time. No effects on HR were found. Altogether, the results of the present paper show that BT, BP and HR are affected by exogenous factors differently. Moreover, the effect was gender-specific. Especially, the response of BT and BP to ambient light was evident only in females. We suppose that the distinct, gender-specific responses of SBP, DBP and HR to activity, sleep and ambient light do reflect fundamental differences in the circadian control of various cardiovascular functions. Furthermore, the presented data are important for the elaboration of updated reference standards, the interpretation of rhythm disorders and for personalized chronotherapeutic approaches to prevent adverse cardiovascular events more effectively.

Whole-Genome DNA Methylation Analysis of Peripheral Blood Mononuclear Cells in Multiple Sclerosis Patients with Different Disease Courses.

Multiple sclerosis (MS) is a severe neurodegenerative disease of polygenic etiology affecting the central nervous system. In addition to genetic factors, epigenetic mechanisms, primarily DNA methylation, which regulate gene expression, play an important role in MS development and progression. In this study, we have performed the first whole-genome DNA methylation profiling of peripheral blood mononuclear cells in relapsing-remitting MS (RRMS) and primary-progressive MS (PPMS) patients and compared them to those of healthy individuals in order to identify the differentially methylated CpG-sites (DMSs) associated with these common clinical disease courses. In addition, we have performed a pairwise comparison of DNA methylation profiles in RRMS and PPMS patients. All three pairwise comparisons showed significant differences in methylation profiles. Hierarchical clustering of the identified DMS methylation levels and principal component analysis for data visualization demonstrated a clearly defined aggregation of DNA samples of the compared groups into separate clusters. Compared with the control, more DMSs were identified in PPMS patients than in RRMS patients (67 and 30, respectively). More than half of DMSs are located in genes, exceeding the expected number for random distribution of DMSs between probes. RRMS patients mostly have hypomethylated DMSs, while in PPMS patients DMSs are mostly hypermethylated. CpG-islands and CpG-shores contain 60% of DMSs, identified by pairwise comparison of RRMS and control groups, and 79% of those identified by pairwise comparison of PPMS and control groups. Pairwise comparison of patients with two clinical MS courses revealed 51 DMSs, 82% of which are hypermethylated in PPMS. Overall, it was demonstrated that there are more changes in the DNA methylation profiles in PPMS than in RRMS. The data confirm the role of DNA methylation in MS development. We have shown, for the first time, that DNA methylation as an epigenetic mechanism is involved in the formation of two distinct clinical courses of MS: namely, RRMS and PPMS.

Experience of thyroid gland status screening in postchernobyl period.

The main results of thirty-year period of repeated screening programs and observational studies in contaminated and non-contaminated regions of Belarus are analyzed. The possible reasons of discrepant and contradictory data about the consequences of Chernobyl catastrophe delivered by different study groups during early period after the accident are discussed. High incidence of thyroid nodular disease and cancer in children and adolescence after the catastrophe are described. The research shows high effectiveness of screening in early diagnosis thyroid disorders and radiation-induced thyroid cancer in different regions of Belarus and in various time points.

Morphological evaluation of the effectiveness of bipolar radiofrequency ablation for thyroid nodules.

Recently, radiofrequency ablation has been increasingly used for the treatment of thyroid nodules. The widespread introduction of this method, however, hampered by the lack of data on efficacy and safety of different devices that are currently on the market, the selection of the optimal mode of procedure also remains to be elucidated. Experimental data obtained during the application of the original patented device is presented. The results make it possible to move from ex vivo experiments to clinical practice.

Influence of nitrate in drinking water on the prevalence of thyroid cancer and other diseases (literature review and experience in post-chernobyl period in Belarus).

In the last 60 years dramatically increased the content of nitrates in groundwater due to intensive use of nitrogen fertilizers in agriculture. Research in post-Chernobyl period has shown that a sharp increase in the incidence of thyroid cancer depends not only on the level of thyroid dose, but also on the level of nitrates in groundwater.

[Characteristics of neurological status in children with schizophrenia and schizotypal disorder]. / Osobennosti nevrologicheskogo statusa u deteĭ s shizofrenieĭ i shizotipicheskim rasstroĭstvom.

AIM: To study characteristics of neurological status in children with schizophrenia and schizotypal disorder. MATERIAL AND METHODS: A study included 80 children, aged from 5 to 10 years: 38 children were diagnosed with schizophrenia (ICD-10 F20.8хх3) and 42 with schizotypal disorder (F21). RESULTS AND CONCLUSION: Children of both groups had a wide spectrum of neurological symptoms, diffuseness of which indicated the disintegration of the multilevel system of motor analyzer. No topical between-group differences were found whereas their intensity and frequency was not correlated to either the severity or a stage (exacerbation - remission) of disease. The more marked was disease progression and severity of mental disorders, the greater was the amount and clearness of neurological disorders. There was a predominance of disorders of motor regulation and integration, various extrapyramidal disturbances. As a consequence, in absence of paresis and paralyses, there was not merely the alteration of the function per se but rather of its integrity, completeness, consistency with other mental acts that turned to be the neurologic equivalent of discordance and inconsistency of mental functions specific of schizophrenia. These neurological symptoms may be considered as topic markers of the changes in the brain and dynamics of endogenous process. Transitory and instable character of these symptoms, along with the deficits of extrapyramidal and cortical regulation outside of the process exacerbation, indicates the insufficiency of neurotransmitter mechanisms.

[The activation of the type I interferon signaling pathway in multiple sclerosis patients treated with russian analogue of Β-interferon-1b: transcriptome profiling data]. / Aktivatsiia signal'nogo puti interferonov tipa I u bol'nykh rasseiannym sklerozom pod vozdeistviem rossiiskogo analoga Β-interferona-1b (po dannym transkriptsionnogo profilirovaniia).

Implementation of the analogues of Β-interferon (Β-IFN), produced by recombinant strains of E. coli (Β-IFN-1b), for internal use in the Russian Federation for the treatment of multiple sclerosis (MS), implies a verification of their action at the transcriptome level in order to confirm the activation of the main signaling pathways involved in IFNb mechanism of action. In this work, the analysis is carried out for Infibeta (Generium, Russia). Using genome-wide transcriptional profiling with ILLUMINA HT-12 microarray, the differentially expressed genes in peripheral blood mononuclear cells of MS patients upon administration of Infibeta were studied. Comparison of gene expression levels in treatment-naive MS patients prior to first Β-IFN administration and 10 hours after it, identified 490 genes with significantly changed expression level, where 191 genes were up-regulated and 299 genes were down-regulated. Among the involved genes are those coding the components of the inflammatory system, innate and adaptive immunity, apoptosis, signal transduction, transcription, translation, degradation. Using gene set analysis, we confirmed the involvement of type I interferon signaling pathway genes and interferon-inducible genes in a patient's individual response to drug. Thus, the transcriptome profiling analysis allows concluding that the mechanism of action of Infibeta immunomodulatory drug is equal to that described for the original Β-IFN drugs.