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Exudative enteropathy is a clinical syndrome characterized by excessive loss of proteins through the gastrointestinal tract and is a rare complication of various gastrointestinal diseases. One of the rarest causes of protein malabsorption is Langerhans cell histiocytosis, which occurs as a result of inflammatory neoplasia of myeloid precursor cells caused by mutations in the mitogenactivated protein kinase pathway. Abnormal proliferation and accumulation of Langerhans cells in the intestinal wall leads to a violation of the outflow of lymph, and causes clinical manifestations characteristic of enteropathy. Given that the lesion of the gastrointestinal tract with histiocytosis from Langerhans cells occurs in 2–3% of cases, and the clinical signs are not highly specific, timely diagnosis is difficult. Delayed verification of the diagnosis and late initiation of adequate treatment are risk factors for multisystem lesions and lead to an unfavorable outcome. The literature describes a few observations of the onset or manifestation of the disease with symptoms of protein malabsorption. We present a rare clinical case of diagnosing histiocytosis from Langerhans cells in a young child with severe manifestations of exudative enteropathy at the onset. The patient's parents gave their consent to the use of their child's data, including photographs, for research purposes and in publications.Refractory gastrointestinal symptoms require mandatory endoscopic and histological examination to identify rare causes of malabsorption. Timely initiation of targeted therapy with vemurafenib in combination with subsequent chemotherapy provided the child with a favorable prognosis and stable remission of the disease.

Abstract A norbornene-substituted cationic iridium(III) complex containing 1-phenylisoquinoline cyclometalating ligands and an additional phenylimidazophenanthroline ligand was synthesized. On the base of this complex, water-soluble polymers were obtained by ring-opening metathesis polymerization (ROMP). The resulting polymers showed oxygen-dependent phosphorescence in the orange spectral region and high cytotoxicity against HCT116 cancer cells.

The pathology in WilsonConovalov disease (WCD) results from impaired excretion of copper, thus leading to its excessive accumulation in tissues. Hypercupreniluria is characteristic to the WCD. Toxic effects of copper on liver tissue can manifest as fatty degeneration of hepatocytes, hepatitis, fibrosis and cirrhosis. Purpose of the present work was as follows: estimation of immune status in children with WD depending on the stage of liver fibrosis. Fifty-three patients with WCD aged 6 to 18 years, were examined. The stage of liver fibrosis was assessed by transient liver elastography using FibroScan F502 (EchoSence, France). The immune status of peripheral blood lymphocytes was examined using CYTOMICS FC500 flow cytofluorimeter (Beckman Coulter, USA). The relative numbers of B lymphocytes (B1 and B2 populations), NK cells, T helper cells, cytotoxic T lymphocytes, Th17 lymphocytes, regulatory T cells, activated T helper cells were assessed in the lymphoid area. All indices of the patients immune status were recalculated for percentage of deviation from the age-dependent reference values. Mass concentration of copper in daily urine was determined by atomic absorption method using AAnalyst 800 spectrometer. Statistical processing was performed by Statistica10.0 program. The WCD patients are characterized by an increase of Т helpers, regulatory Т cells, Th17 lymphocytes and activated Т helpers, along with decrease of cytotoxic Т lymphocytes and NK cells against normal levels. The number of B cells did not depend on the stage of liver fibrosis and was at the lower limit of normal range, or decreased. Upon increase of the liver fibrosis stage, the number of B1 lymphocytes increases and B2 lymphocytes become decreased. The urinary copper content in the examined patients varied from 19 to 835 g/day, being higher than the reference values in 88% of children, with median value of 175 g/day (71-330). A correlation between urinary copper concentration and degree of immune status deviation was revealed (R = 0.63): urinary copper concentration was increased when the number of Th17 lymphocytes, B1 lymphocytes and regulatory T cells became higher, and when the number of B2 lymphocytes decreased. A significant decrease in the population of cytotoxic T lymphocytes (p = 0.034) was observed in children with WCD in the presence of KaiserFleischer ring. Indexes of cellular immunity in children with WCD are an informative tool to assess the severity of liver damage.

In this work, we obtained three new phosphorescent iridium complexes (Ir1–Ir3) of general stoichiometry [Ir(N^C)2(N^N)]Cl decorated with oligo(ethylene glycol) fragments to make them water-soluble and biocompatible, as well as to protect them from aggregation with biomolecules such as albumin. The major photophysical characteristics of these phosphorescent complexes are determined by the nature of two cyclometallating ligands (N^C) based on 2-pyridine-benzothiophene, since quantum chemical calculations revealed that the electronic transitions responsible for the excitation and emission are localized mainly at these fragments. However, the use of various diimine ligands (N^N) proved to affect the quantum yield of phosphorescence and allowed for changing the complexes’ sensitivity to oxygen, due to the variations in the steric accessibility of the chromophore center for O2 molecules. It was also found that the N^N ligands made it possible to tune the biocompatibility of the resulting compounds. The wavelengths of the Ir1–Ir3 emission maxima fell in the range of 630–650 nm, the quantum yields reached 17% (Ir1) in a deaerated solution, and sensitivity to molecular oxygen, estimated as the ratio of emission lifetime in deaerated and aerated water solutions, displayed the highest value, 8.2, for Ir1. The obtained complexes featured low toxicity, good water solubility and the absence of a significant effect of biological environment components on the parameters of their emission. Of the studied compounds, Ir1 and Ir2 were chosen for in vitro and in vivo biological experiments to estimate oxygen concentration in cell lines and tumors. These sensors have demonstrated their effectiveness for mapping the distribution of oxygen and for monitoring hypoxia in the biological objects studied.

In this work, we obtained three new phosphorescent iridium complexes (Ir1-Ir3) of general stoichiometry [Ir(N^C)2(N^N)]Cl decorated with oligo(ethylene glycol) fragments to make them water soluble and biocompatible, as well as to protect them from aggregation with biomolecules such as albumin. The major photophysical characteristics of these phosphorescent complexes are determined by the nature of two cyclometallating ligands (N^C) based on 2-pyridine-benzothiophene, since quantum chemical calculations revealed that the electronic transitions responsible for the excitation and emission are localized mainly at these fragments. However, the use of various diimine ligands (N^N) proved to affect the quantum yield of phosphorescence and allows for changing the complexes sensitivity to oxygen, due to the variations in the steric accessibility of the chromophore center for O2 molecules. It was also found that the N^N ligands made possible to tune the biocompatibility of the resulting compounds. The wavelengths of the Ir1-Ir3 emission maxima fall in the range of 630-650 nm, the quantum yields reach 17% (Ir1) in deaerated solution and sensitivity to molecular oxygen, estimated as ratio of emission lifetime in deaerated and aerated water solution, displays the highest value 8.2 for Ir1. The obtained complexes feature low toxicity, good water solubility and the absence of a significant effect of biological environment components on the parameters of their emission. Of the studied compounds Ir1 and Ir2 have been chosen for in vitro and in vivo biological experiments aimed at estimation of oxygen concentration in cell lines and tumors. These sensors have demonstrated their effectiveness for mapping the distribution of oxygen and for monitoring hypoxia in biological objects studied.

The design, synthesis, and investigation of new molecular oxygen probes for bioimaging, based on phosphorescent transition metal complexes are among the topical problems of modern chemistry and advanced bioimaging. Three new iridium [Ir(N^C)2(N^N)]+ complexes with cyclometallating 4-(pyridin-2-yl)-benzoic acid derivatives and different di-imine chelate ligands have been synthesized and characterized by mass spectrometry and NMR spectroscopy. The periphery of these complexes is decorated with three relatively small “double-tail” oligo(ethylene glycol) fragments. All these complexes exhibit phosphorescence; their photophysical properties have been thoroughly studied, and quantum chemical calculations of their photophysical properties were also performed. It turned out that the changes in the nature of the di-imine ligand greatly affected the character of the electronic transitions responsible for their emission. Two complexes in this series show the desired photophysical characteristics; they demonstrate appreciable quantum yield (14–15% in degassed aqueous solutions) and a strong response to the changes in oxygen concentration, ca. three-fold increase in emission intensity, and an excited state lifetime upon deaeration of the aqueous solution. The study of their photophysical properties in model biological systems (buffer solutions containing fetal bovine serum—FBS) and cytotoxicity assays (MTT) showed that these complexes satisfy the requirements for application in bioimaging experiments. It was found that these molecular probes are internalized into cultured cancer cells and localized mainly in mitochondria and lysosomes. Phosphorescent lifetime imaging (PLIM) experiments showed that under hypoxic conditions in cells, a 1.5-fold increase in the excitation state lifetime was observed compared to aerated cells, suggesting the applicability of these complexes for the analysis of hypoxia in biological objects.

The effects of chemotherapy on the tumor microenvironment remain poorly investigated, although these are crucial for the drug delivery and anti-tumor activity and can modify physiological behavior of cancer cells. Optical coherence angiography and phosphorescence lifetime spectroscopy are promising optical methods to characterize both tumor vasculature and its oxygenation, respectively. In this study, we used these methods to explore the influence of irinotecan, a widely used chemotherapeutic agent, on tumor angiogenesis and oxygen content in a mouse model of colorectal cancer in vivo . For the first time, it was shown that irinotecan at conventional dosing reduces tumor oxygenation and blood perfusion via antiangiogenic mechanism of action. Immunohistochemistry for hypoxia and for the endothelial cell marker CD31 verified the in vivo findings. These data show the prospects of the optical techniques to monitor tumor microenvironment in the course of chemotherapy, which can help to optimize and individualize the treatment.

In this article, we offer a novel classification of progressive changes in the connective tissue of dermis in vulvar lichen sclerosus (VLS) relying on quantitative assessment of the second harmonic generation (SHG) signal received from formalin fixed and deparaffinized tissue sections. We formulate criteria for distinguishing four degrees of VLS development: Initial-Mild-Moderate-Severe. Five quantitative characteristics (length and thickness type I Collagen fibers, Mean SHG signal intensity, Skewness and Coherence SHG signal) are used to describe the sequential degradation of connective tissue (changes in the structure, orientation, shape and density of collagen fibers) up to the formation of specific homogeneous masses. Each of the degrees has a characteristic set of quantitatively expressed features. We focus on the identification and description of early, initial changes of the dermis as the least specific. The results obtained by us and the proposed classification of the degrees of the disease can be used to objectify the dynamics of tissue changes during treatment.

Pannexins are a family of three proteins which play an important role in intercellular communications. This study shows that mice with knockout of the Panx1 gene(Panx1–/–) have elevated levels of movement activity and increased proportions of waking, due to decreases in slow-wave sleep, as compared with control animals, as a result of decreases in the adenosine content of the brain. We suggest that these mice may also show impairments to thermoregulation and the daily temperature curve rhythm. To test this suggestion, eight adult male C57BL/6J mice and eight adult male Panx1–/– mice, derived from them, underwent i.p. implantation of autonomous temperature and movement activity sensors. Recordings were made over several months at an environmental temperature of 23 ± 1°C. The results confirmed our previous data indicating higher movement activity in Panx1–/– mice compared with controls. The daily body temperature rhythm in Panx1–/– mice persisted and was no different from that in control animals. The first series of experiments showed an increased tendency to fall into torpor in Panx1–/– mice as compared with controls. However, no onset of torpor occurred in the next series, using a further four pairs of animals. Thus, the role of the Panx1 gene in the diurnal activity-rest rhythm was confirmed, while its role in the temperature rhythm and thermoregulatory reactions remains unclear and requires further study.

Objectives. To confirm the authors’ previous suggestion that mutations in the Panx1 gene (pannexin-1) may play an important role in the development of impairments to the sleep-waking cycle. Materials and methods. Studies were carried out using mice with knockout of the Panx1 gene. Experiments used continuous 24-h EEG recording of the EEG and motor activity. Results and conclusions. A statistically significant increase in the proportion of waking was found, due to a decrease in the slow-wave sleep phase (as compared with controls), particularly marked in the dark period of the day, along with an increase in motor activity. The results were compared with data obtained during investigation of a recently published case of a patient with a homozygous mutation in this gene. The possible physiological role of pannexin-1 protein in health and pathology is discussed.

New water-soluble polynorbornenes P1–P4 containing oligoether, amino acid groups and luminophoric complexes of iridium(III) were synthesized by ring-opening metathesis polymerization. The polymeric products in organic solvents and in water demonstrate intense photoluminescence in the red spectral region. The polymers P1 and P3 with 1-phenylisoquinoline cyclometalating ligands in iridium fragments reveal 4–6 fold higher emission quantum yields in solutions than those of P2 and P4 that contain iridium complexes with 1-(thien-2-yl)isoquinoline cyclometalating ligands. The emission parameters of P1–P4 in degassed solutions essentially differ from those in the aerated solutions showing oxygen-dependent quenching of phosphorescence. Biological testing of P1 and P3 demonstrates that the polymers do not penetrate into live cultured cancer cells and normal skin fibroblasts and do not possess cytotoxicity within the concentrations and time ranges reasonable for biological studies. In vivo, the polymers display longer phosphorescence lifetimes in mouse tumors than in muscle, as measured using phosphorescence lifetime imaging (PLIM), which correlates with tumor hypoxia. Therefore, preliminary evaluation of the synthesized polymers shows their suitability for noninvasive in vivo assessments of oxygen levels in biological tissues.

Synthesis of biocompatible near infrared phosphorescent complexes and their application in bioimaging as triplet oxygen sensors in live systems are still challenging areas of organometallic chemistry. We have designed and synthetized four novel iridium [Ir(N^C)2(N^N)]+ complexes (N^C–benzothienyl-phenanthridine based cyclometalated ligand, N^N–pyridin-phenanthroimidazol diimine chelate), decorated with oligo(ethylene glycol) groups to impart these emitters’ solubility in aqueous media, biocompatibility, and to shield them from interaction with bio-environment. These substances were fully characterized using NMR spectroscopy and ESI mass-spectrometry. The complexes exhibited excitation close to the biological “window of transparency”, NIR emission at 730 nm, and quantum yields up to 12% in water. The compounds with higher degree of the chromophore shielding possess low toxicity, bleaching stability, absence of sensitivity to variations of pH, serum, and complex concentrations. The properties of these probes as oxygen sensors for biological systems have been studied by using phosphorescence lifetime imaging experiments in different cell cultures. The results showed essential lifetime response onto variations in oxygen concentration (2.0–2.3 μs under normoxia and 2.8–3.0 μs under hypoxia conditions) in complete agreement with the calibration curves obtained “in cuvette”. The data obtained indicate that these emitters can be used as semi-quantitative oxygen sensors in biological systems.

Background Therapeutic effects of PDT depend on many factors, including the amount of singlet oxygen, localization of photosensitizer and irradiation protocol. The present study was aimed to compare the cytotoxic mechanisms of PDT under continuous-wave (CW) and pulsed irradiation using a tumor spheroid model and a genetically encoded photosensitizer miniSOG. Methods 1O2 detection in miniSOG and flavin mononucleotide (FMN) solutions was performed. Photobleaching of miniSOG in solution and in HeLa tumor spheroids was analyzed. Tumor spheroid morphology and growth and the cell death mechanisms after PDT in CW and pulsed modes were assessed. Results We found a more rapid 1O2 generation and a higher photobleaching rate in miniSOG solution upon irradiation in pulsed mode compared to CW mode. Photobleaching of miniSOG in tumor spheroids was also higher after irradiation in the pulsed mode. PDT of spheroids in CW mode resulted in a moderate expansion of the necrotic core of tumor spheroids and a slight inhibition of spheroid growth. The pulsed mode was more effective in induction of cell death, including apoptosis, and suppression of spheroid growth. Conclusions Comparison of CW and pulsed irradiation modes in PDT with miniSOG showed more pronounced cytotoxic effects of the pulsed mode. Our results suggest that the pulsed irradiation regimen enables enhanced 1O2 production by photosensitizer and stimulates apoptosis. General significance Our results provide more insights into the cellular mechanisms of anti-cancer PDT and open the way to improvement of light irradiation protocols.

Background IBD are immunomediated diseases that usually manifest at an early age, require lifelong pathogenetic therapy and significantly reduce the quality of life of a patient. Methods Since February 2017, the ‘North-West register of IBD patients’ has installed data of 1130 patients with an introduced diagnosis of UC or CD: 41.3% of them are patients with a diagnosis of CD and 58.7%—with a diagnosis of UC. Results Among patients with IBD the majority had mild (33.4%) and moderate activity (34%), a quarter was in remission and 7.65%—expressed activity. A population researches study using the University of Manitoba’s IBD epidemiology database (UMIBDED) reported that 6.2% of IBD patients had at least one extraintestinal manifestation, and 0.3% had several. The extraintestinal manifestations were observed in 43.4% of patients; meanwhile, 25% of them revealed mostly than one extraintestinal manifestation. System manifestations were more often registered in CD than in UC. The most frequent extraintestinal manifestations were signs of involvement of skeletal and muscular system. On the first place, it is peripheral arthropathy (73.6%), sacroiliitis (8.8%), ankylosing spondyloarthritis (8.8%), entezitis (10.3%) rheumatoid arthritis (1.5%), dactylitis (1.5%) were less frequent. Generally, articulate manifestations were noted by 17.5% of all included patients. In CD and UC, extra-intestinal manifestations were more often common in patients with a moderate attack (in 75.6 % and 51.6% of cases). In CD, extra-intestinal manifestations were more often frequent in patients with moderate attack −50.8%, in patients in remission there numbered to 32.8%, in severe attack-14.8%, in mild-1.6%. In UC, extra-intestinal manifestations were observed in severe attack in 2.6%, in moderate attack 35.9%, in mild attack 41%, in patients in remission 20.5%. Conclusion Among patients with IBD, extraintestinal manifestations, among which joint lesions prevail, are detected in 43.4% of the examined persons. The trend is noted to reduce the number of patients with severe attacks of the disease and extraintestinal manifestations, that can be related with improving the quality of diagnosis, reduction of terms of diagnosing and developing new methods of treatment for IBD. Peripheral arthropathy predominate among the extra-intestinal manifestations. We found no correlation between the severity of IBD and the presence of extra-intestinal manifestations. The spectrum of extra-intestinal manifestations includes more than 20 manifestations (diseases), which requires skills and experience in their diagnosis, as well as joint management of such patients by specialists of various profiles.

Background Untimely diagnosis increases the number of severe forms of IBD, which enlarges the possibility of life-threatening complications, extraintestinal presentations, and the patient’s need for surgical treatment. Methods We analysed the data of 1130 patients with an established diagnosis of UC or CD. The dynamics of the timing of diagnosis of IBD, the nature of the disease, the frequency of occurrence of intestinal complications, extraintestinal presentations were evaluated. Results The maximum frequency of start of both UC and CD falls on the young age of patients - from 19 to 38 years. The duration of symptoms before diagnosis is established is 2.3 years (27.4 months) for CD, 1.1 years (12.1 months) for UC. 81.8% of patients with UC are diagnosed no more than 4 years, but in 10.9% of patients this interval was 4–9 years; in 3.6%, 9–13 years; in 1.9%, 13–18 years, and in another 1.8%, more than 20 years. In CD 59.5% of patients fall into the diagnosis interval up to 4 years, in 27.4% this period takes from 4 to 9 years, in 7%—10–15 years, and in 6% more than 6 years. At the age of 18–25 years severe course of IBD is observed in 12% of patients, at the age of 26–30 years—in 18%, 31–40 years—in 9%. Older people are more likely to experience mild IBD, and the percentage of severe and moderate forms is 4% and 29%, respectively, after 60, and less than 0.5% and 19.5%, respectively, after 70 years. Extraintestinal presentations were observed in 43.4% of patients, with 25% of them having more than one of them. In patients with CD, the development of complications in the first 4 years of the disease was noted in 62%, in UC—in 58.9%. In patients with intestinal complications, the diagnosis period was 2.9 years, without them—2.4 years. However, in patients with a history of surgical treatment of IBD, the diagnosis period was less than 1 year. 69, 3% of revealed patients with a history of needing one or more hospitalisations associated with IBD, and 15.8% underwent surgery for IBD. Conclusion Based on the data obtained, it can be concluded that the main part of complications occurs in the first few years after the onset of the disease. With late diagnosis, the probability of developing not only intestinal complications, but also extra-intestinal presentations significantly increase, which reflects a more severe form of the disease. The shorter time of diagnosis of IBD in patients who need surgical treatment is explained by more pronounced symptoms that require urgent medical care. However, the proportion of IBD with severe and moderate form is greater in young age groups, and as the ‘growing up’ groups - the number of patients with mild IBD begins to prevail.

We compared efficacy of combined treatment of males with anogenital warts given intramuscular cycloferon or cycloferon electrophoresis. Patients with manifest HPV infection (n=107) were divided into two groups. Group 1 (n=72) received intramuscular cycloferon (2 ml 12.5% solution each other day for 10 days), group 2 (n=35) received cycloferon electrophoresis on genital region (2 ml 12.5% solution daily in 1-2 days, 5 injections). Measurements were made of local cytokines in urethral secretion, IFN-alpha, IFN-gamma, lactoferrin, sexual hormones (estradiol and testosterone) in blood serum before and after treatment. Focal immunophysiotherapy with cycloferon in combined treatment of males with anogenital warts vs intramuscular cycloferon treatment reduces recurrence rate 2 times, has no negative effect on serum level of sexual hormones, a course dose and duration of immunotherapy decreased 2-fold, is well tolerated, is not painful. Cycloferon electrophoresis has a more potent effect on improvement of local immunity. Thus, local immunophysiotherapy with cycloferon can be a method of choice in the treatment of manifest HPV infection in males.

A total of 78 patients with various forms of lupus erythematosus (LE) were examined with the use of enzyme immunoassay (EIA) to test the possibility of antibody production in response to neuraminidase, an antigenic stimulant. Positive EIA results were recorded in 54.5% of patients with the integument LE forms and in 58.3% of those with systemic LE. The intensity of antibody production depended on the patients' sex (it was more active in females), age, and the disease duration. In the course of therapy negative results replace positive ones mostly in the patients with a disease of not long standing. A correlation was revealed between the content of circulating immune complexes measured by polyethylene glycol sedimentation and the levels of IgM and IgG. The detected relationship between the level of antineuraminidase antibodies and features of the disease course and therapy, agreement of this parameter with other immunologic characteristics, availability and informative value of the method recommend it for the assessment of immunity disorders in LE patients.

The paper deals with the influence of objective and subjective factors over the trends in the incidence of inter-ethnic marriages for the USSR as a whole and the individual Union republics. The author analyses the differences between the urban and the rural population in the level of mixed-marriage incidence, as well as in the frequency with which men and women belonging to the main ethnos of each republic enter into mixed marriage. The problems of what nationalities come together in mixed marriages and of the choice of nationality made by the children in mixed families are specially examined.

Enzyme immunoassay and complement consumption test may be used to detect anti-enzyme antibodies. The availability and informative value of these tests reccomend them for practical medicine to be used in follow-up of patients with systemic lupus erythematosus.

Statistical processing, carried out by the characteristic intervals method, of the results of serologic tests for syphilis in 48 patients with latent syphilis and in 191 patients with false-positive serologic tests has revealed specific and relatively specific intervals of the titers of anti-Treponema antibodies, precipitines and reagines; these intervals make possible a tentative differential diagnosis before specific tests or in cases when these tests cannot be carried out.

The incidence rates of combinations of A and B loci histocompatibility antigens in loci and haplotypes and of ceruloplasmin phenotypes have been examined in 137 patients with lupus erythematosus (LE) and scleroderma circumscriptum (SC). The studies have revealed that LE and SC are associated with certain haplotypes and HLA antigens combinations, this indicating the contribution of these phenotypes to the realization of the genetic predisposition to these diseases. In A1B8 haplotype carriers the disease is characterized by a benign course and manifests by integument forms of LE and scleroderma. IN A2B8 haplotype carriers the disease is more grave and presents as the systemic variant of LE. The third type of ceruloplasmin not detectable in normal subjects is usually associated with A9B18, A25B18, A3B27 haplotypes and with HLA A3A9 antigenic combination mostly in LE patients.