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We report herein a Pt(IV) prodrug with metronidazole in axial positions

We report herein the design, synthesis, and biological investigation of a series of novel Pt(IV) prodrugs with non-steroidal anti-inflammatory drugs naproxen, diclofenac, and flurbiprofen, as well as these with stearic acid in the axial position. Six Pt(IV) prodrugs

According to studies, the prevalence of constipation in the population can reach 27% due to the low intake of dietary fiber. Increasing dietary fiber intake can improve bowel movements.

The aim of the research was to establish the features of age-related and individual anatomical variability of the brachioradialis, its blood supply, and innervation options. Materials and methods: The study of the variant anatomy of the brachioradialis and its vascular and nervous structures was carried out on 25 preparations of human fetuses of 4-7 months, 81.0-270.0 mm parietal-coccygeal length (PCL) using macromicroscopic preparation, injection vessels, and morphometry. Results: Spindle-like (56%) and round (24%) shapes of the brachioradialis were found in most of the studied fetuses; its elongated flat (12%) and triangular (8%) forms occur less often. In a fetus of 185.0 mm TKD, the right brachioradialis consisted of two separate parts: upper and lower, which were connected at the level of the middle of the forearm into a common short muscle belly. In another human fetus of 220.0 mm TKD, the right brachioradialis also consisted of two separate parts – upper and lower, triangular in shape, but separated by a pronounced horizontal gap. Conclusions: The features of the fetal anatomy of the brachioradialis are established: its variability and bilateral asymmetry of shape and size, variability of the places of origin and attachment, etc. In individual human fetuses, the brachioradialis consists of two separate parts that have special topographical relationships. The area of the greatest concentration of both extra- and intramuscular nerves and arteries is the upper and middle third of the brachioradialis. In the area of the forearm, the course of radial vascular-nerve formations is determined by the brachioradialis.

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347, BACKGROUND: The COVID-19 pandemic presented major challenges for critical care facilities worldwide. Infections which develop alongside or subsequent to viral pneumonitis are a challenge under sporadic and pandemic conditions; however, data have suggested that patterns of these differ between COVID-19 and other viral pneumonitides. This secondary analysis aimed to explore patterns of co-infection and intensive care unit-acquired infections (ICU-AI) and the relationship to use of corticosteroids in a large, international cohort of critically ill COVID-19 patients. METHODS: This is a multicenter, international, observational study, including adult patients with PCR-confirmed COVID-19 diagnosis admitted to ICUs at the peak of wave one of COVID-19 (February 15th to May 15th, 2020). Data collected included investigator-assessed co-infection at ICU admission, infection acquired in ICU, infection with multi-drug resistant organisms (MDRO) and antibiotic use. Frequencies were compared by Pearson's Chi-squared and continuous variables by Mann-Whitney U test. Propensity score matching for variables associated with ICU-acquired infection was undertaken using R library MatchIT using the "full" matching method. RESULTS: Data were available from 4994 patients. Bacterial co-infection at admission was detected in 716 patients (14%), whilst 85% of patients received antibiotics at that stage. ICU-AI developed in 2715 (54%). The most common ICU-AI was bacterial pneumonia (44% of infections), whilst 9% of patients developed fungal pneumonia; 25% of infections involved MDRO. Patients developing infections in ICU had greater antimicrobial exposure than those without such infections. Incident density (ICU-AI per 1000 ICU days) was in considerable excess of reports from pre-pandemic surveillance. Corticosteroid use was heterogenous between ICUs. In univariate analysis, 58% of patients receiving corticosteroids and 43% of those not receiving steroids developed ICU-AI. Adjusting for potential confounders in the propensity-matched cohort, 71% of patients receiving corticosteroids developed ICU-AI vs 52% of those not receiving corticosteroids. Duration of corticosteroid therapy was also associated with development of ICU-AI and infection with an MDRO. CONCLUSIONS: In patients with severe COVID-19 in the first wave, co-infection at admission to ICU was relatively rare but antibiotic use was in substantial excess to that indication. ICU-AI were common and were significantly associated with use of corticosteroids. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021)., European Society of Intensive Care Medicine ACM is supported by a Clinician Scientist Fellowship from the Medical Research Council (MR/V006118/1)

A great deal of research was being done in studying of the age-related characteristics of carbohydrate metabolism and the provision of vitamins B1, B2 among the population of the Subarctic (SR) and Arctic (AR) regions, differing in the extreme natural and climatic-geographic living conditions. The surveyed population was divided into five age groups: 16-21, 22-35, 36-45, 46-60 and 61-74 years old. The parameters of carbohydrate metabolism (glucose, lactate, pyruvate) were determined in the blood serum, the content of thiamine (thiamin diphosphate effect) and riboflavin - in hemolysates, and the values of the lactate/pyruvate ratio (Lac/Pyr) were calculated. Statistical data processing was performed by nonparametric methods. An increase in glucose levels was found in persons of older age groups. Age-related fluctuations of metabolites of carbohydrate metabolism were manifested by a lower content of lactate and the value of the Lac/Pyr ratio in persons aged 16-21 years. Regardless of the age and region of the survey, there were revealed high lactate concentrations, Lac/Pyr values and reduced pyruvate levels, as well as low glucose levels in group aged 16-21 year in AR. For vitamins B1, B2, no pronounced age-related changes were observed, while the content of riboflavin was higher in persons of SR. Moderate hypovitaminosis of thiamin was detected in 13-20,1% and 6,1-22,7% of cases in SR and AR, pronounced - 8,3-11,6% and 4,6-23,5%, respectively, vitamin B2 deficiency was noted in 19,4-23,9% of persons in the AR and in 33,8-42,9% of persons in the AR. Vitamins in both regions at different age periods contributed to the formation of levels of indicators of carbohydrate metabolism: glucose and pyruvate in SR, lactate in AR.

Human rotavirus (HRV) is a major cause of childhood diarrhea in developing countries where widespread malnutrition contributes to the decreased oral vaccine efficacy and increased prevalence of other enteric infections, which are major concerns for global health. Neonatal gnotobiotic (Gn) piglets closely resemble human infants in their anatomy, physiology, and outbred status, providing a unique model to investigate malnutrition, supplementations, and HRV infection. To understand the molecular signatures associated with immune enhancement and reduced diarrheal severity by Escherichia coli Nissle 1917 (EcN) and tryptophan (TRP), immunological responses and global nontargeted metabolomics and lipidomics approaches were investigated on the plasma and fecal contents of malnourished pigs transplanted with human infant fecal microbiota and infected with virulent (Vir) HRV. Overall, EcN + TRP combined (rather than individual supplement action) promoted greater and balanced immunoregulatory/immunostimulatory responses associated with greater protection against HRV infection and disease in malnourished humanized piglets. Moreover, EcN + TRP treatment upregulated the production of several metabolites with immunoregulatory/immunostimulatory properties: amino acids (

Guanine-rich DNA sequences tending to adopt noncanonical G-quadruplex (G4) structures are over-represented in promoter regions of oncogenes. Ligands recognizing G4 were shown to stabilize these DNA structures and drive their formation regulating expression of corresponding genes. We studied the interaction of several plant secondary metabolites (PSMs) with G4s and their effects on gene expression in a cellular context. The binding of PSMs with G4s formed by the sequences of well-studied oncogene promoters and telomeric repeats was evaluated using a fluorescent indicator displacement assay.

Accumulation of liposomal drugs into human tumors has substantial variability influencing the probability of positive response to the therapy. Therefore, it becomes very important to identify the eligibility of patients for various treatment options. The existing strategies of tumor stratification using companion diagnostics are based on the assumption that the initial and subsequent doses of nanoparticles (NP) behave in a sufficiently similar manner to enable a valuable prognosis. Here, we use a combination of in vivo imaging techniques to validate the applicability of magnetic liposomes (ML) as a reliable tool to predict whether or not the tumor would respond to nanomedicine therapy. The results demonstrated that liposome biodistribution, interactions with immune cells, and extravasation behavior in tumors were not affected by the pretreatment with liposomes 24 h prior to the repeat dosing. Co-administration of liposomal doxorubicin (DXR) and liposomes loaded with maghemite NP resulted in a high colocalization rate between two nanomedicines in tumors suggesting that neither contrast agent, nor chemotherapeutics altered biodistribution of liposomes. Based on magnetic resonance imaging of 4T1 tumors performed before and 6 h after ML treatment, animals were classified into high and low accumulation subgroups. Higher ML deposition in tumors was associated with a reduction in lesion size and enhanced survival in animals treated with liposomal DXR, but not with DXR alone. Given that liposomes are the most numerous class of clinically approved nanomedicines the development of safe and cost-effective liposomal companion diagnostic suitable for non-invasive imaging is of paramount importance for improving the efficacy of cancer therapy.

IgG4-related disease is an immune-mediated disorder with tumor-like multiorgan involvement, elevated serum IgG4 level and specific histopathological appearance (lymphoplasmacytic infiltrate rich in IgG4+ plasma cells and storiform fibrosis). The article presents rare clinical and morphological observations of IgG4-related mastopathy in women with suspected tumor process. A strategy for the treatment of IgG4-related disease should be based on the results of pre-surgery histopathological examination, which may help to avoid unreasonable surgical intervention and choose glucocorticoids or rituximab as the first-line treatment.IgG4-связанное заболевание (IgG4-СЗ) — иммуноопосредованное заболевание с опухолеподобным поражением различных органов, сопровождающееся повышением уровня IgG4 в сыворотке крови и характеризующееся особой патоморфологической картиной (наличием лимфоплазмоцитарного инфильтрата с преобладанием IgG4-позитивных плазмоцитов и формированием «муарового» фиброза). В статье представлены редкие клинико-морфологические наблюдения IgG4-СЗ молочной железы у женщин с подозрением на опухолевый процесс. Патоморфологическому исследованию на дооперационном этапе отводится ключевая роль в диагностике IgG4-СЗ, что позволяет избежать необоснованных хирургических вмешательств и назначить лекарственную терапию (глюкокортикоиды, ритуксимаб).

Rotaviruses (RVs) are a significant cause of severe diarrheal illness in infants and young animals, including pigs. Group C rotavirus (RVC) is an emerging pathogen increasingly reported in pigs and humans worldwide, and is currently recognized as the major cause of gastroenteritis in neonatal piglets that results in substantial economic losses to the pork industry. However, little is known about RVC pathogenesis due to the lack of a robust cell culture system, with the exception of the RVC Cowden strain. Here, we evaluated the permissiveness of porcine crypt-derived 3D and 2D intestinal enteroid (PIE) culture systems for RVC infection. Differentiated 3D and 2D PIEs were infected with porcine RVC (PRVC) Cowden G1P[1], PRVC104 G3P[18], and PRVC143 G6P[5] virulent strains, and the virus replication was measured by qRT-PCR. Our results demonstrated that all RVC strains replicated in 2D-PIEs poorly, while 3D-PIEs supported a higher level of replication, suggesting that RVC selectively infects terminally differentiated enterocytes, which were less abundant in the 2D vs. 3D PIE cultures. While cellular receptors for RVC are unknown, target cell surface carbohydrates, including histo-blood-group antigens (HBGAs) and sialic acids (SAs), are believed to play a role in cell attachment/entry. The evaluation of the selective binding of RVCs to different HBGAs revealed that PRVC Cowden G1P[1] replicated to the highest titers in the HBGA-A PIEs, while PRVC104 or PRVC143 achieved the highest titers in the HBGA-H PIEs. Further, contrasting outcomes were observed following sialidase treatment (resulting in terminal SA removal), which significantly enhanced Cowden and RVC143 replication, but inhibited the growth of PRVC104. These observations suggest that different RVC strains may recognize terminal (PRVC104) as well as internal (Cowden and RVC143) SAs on gangliosides. Finally, several cell culture additives, such as diethylaminoethyl (DEAE)-dextran, cholesterol, and bile extract, were tested to establish if they could enhance RVC replication. We observed that only DEAE-dextran significantly enhanced RVC attachment, but it had no effect on RVC replication. Additionally, the depletion of cellular cholesterol by MβCD inhibited Cowden replication, while the restoration of the cellular cholesterol partially reversed the MβCD effects. These results suggest that cellular cholesterol plays an important role in the replication of the PRVC strain tested. Overall, our study has established a novel robust and physiologically relevant system to investigate RVC pathogenesis. We also generated novel, experimentally derived evidence regarding the role of host glycans, DEAE, and cholesterol in RVC replication, which is critical for the development of control strategies.

Purpose To accommodate the unprecedented number of critically ill patients with pneumonia caused by coronavirus disease 2019 (COVID-19) expansion of the capacity of intensive care unit (ICU) to clinical areas not previously used for critical care was necessary. We describe the global burden of COVID-19 admissions and the clinical and organizational characteristics associated with outcomes in critically ill COVID-19 patients. Methods Multicenter, international, point prevalence study, including adult patients with SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR) and a diagnosis of COVID-19 admitted to ICU between February 15th and May 15th, 2020. Results 4994 patients from 280 ICUs in 46 countries were included. Included ICUs increased their total capacity from 4931 to 7630 beds, deploying personnel from other areas. Overall, 1986 (39.8%) patients were admitted to surge capacity beds. Invasive ventilation at admission was present in 2325 (46.5%) patients and was required during ICU stay in 85.8% of patients. 60-day mortality was 33.9% (IQR across units: 20%-50%) and ICU mortality 32.7%. Older age, invasive mechanical ventilation, and acute kidney injury (AKI) were associated with increased mortality. These associations were also confirmed specifically in mechanically ventilated patients. Admission to surge capacity beds was not associated with mortality, even after controlling for other factors. Conclusions ICUs responded to the increase in COVID-19 patients by increasing bed availability and staff, admitting up to 40% of patients in surge capacity beds. Although mortality in this population was high, admission to a surge capacity bed was not associated with increased mortality. Older age, invasive mechanical ventilation, and AKI were identified as the strongest predictors of mortality. Correction in: Intensive Care Medicine, vol. 48, issue 8, pages 1130-1131.DOI: 10.1007/s00134-022-06801-2

During space missions cosmonauts are exposed to a myriad of distinct stressors such as radiation, overloads, weightlessness, radiation, isolation in artificial environmental conditions, which causes changes in immune system. During space flights it is very difficult to determine the particular factor associated with the observed immunological responses. This makes ground-based experiments examining the effect of each space flight associated factor along of particular value. Determining mechanisms causing alterations in cosmonauts’ immunity can lead to potential targets for different countermeasures. In the current article we present the study of the early period of adaptation of human innate immunity of 6 healthy test-subjects, 4 males and 2 females aged 25 through 40, to isolation factors (hypodynamia, psychological stress, artificial environment). We measured multiple parameters characterizing innate immunity status in blood samples at chosen time points before, during and after the mission. In the experiment, highly enhanced cytokine responses were observed upon ex vivo antigen stimulations in comparison to baseline values. For cellular parameters we found multidirectional dynamics with a persistent prevalence of increasing TLRs+ monocytes as well as TLRs expression. Our study provides evidence that even a short-term confinement leads to immune changes in healthy humans that may trigger aberrant immune response.

Introduction. The causative agent of African swine fever (Asfarviridae: Asfivirus: African swine fever virus) (ASF) is a double-stranded DNA virus of 175–215 nm. To date, 24 of its genotypes are known. Clustering of ASF genotype II isolates is carried out by examining a limited number of selected genome markers. Despite the relatively high rate of mutations in the genome of this infectious agent compared to other DNA viruses, the number of known genome molecular markers for genotype II isolates is still insufficient for detailed subclustering. The aims of this work were the comparative analysis of ASFV/Zabaykali/WB-5314/2020 virus isolate and determination of additional molecular markers which can be used for clustering of viral genotype II sequences. Material and methods. ASF virus isolate ASFV/Zabaykali/WB-5314/2020 was used to extract genomic DNA (gDNA). Sequencing libraries were constructed using the Nextera XT DNA library prepare kit (Illumina, USA) using the methodology of the next generation sequencing (NGS). Results. The genome length was 189,380 bp, and the number of open reading frames (ORFs) was 189. In comparison with the genome of reference isolate Georgia 2007/1, 33 single nucleotide polymorphisms (SNPs) were identified, of which 13 were localized in the intergenic region, 10 resulted to the changes in the amino acid sequences of the encoded proteins, and 10 affected the ORF of ASF virus genes. Discussion. When analyzing intergenic regions, the ASFV/Zabaykali/WB-5314/2020 isolate is grouped separately from a number of isolates from Poland and three isolates from People’s Republic of China (PRC), since it does not harbor additional tandem repeat sequence (TRS). At the same time, the construction of a phylogenetic tree based on DP60R gene sequencing relates ASFV/Zabaykali/WB-5314/2020 to isolates from PRC and Poland. Moreover, phylogenetic analysis of full-genome sequences confirmed previous studies on the grouping of viruses of genotype II, and as for the studied isolate, it was grouped with the variants from China. Conclusion. A new variable region was identified, the DP60R gene, clustering for which gave a result similar to the analysis of full-length genomes. Probably, further study of the distribution of ASF virus isolates by groups based on the analysis of this gene sequences will reveal its significance for studying the evolution of the virus and its spread.

Background Early diagnosis of tuberculosis (TB) is important to reduce transmission, morbidity and mortality in people living with HIV (PLWH). Methods PLWH with a diagnosis of TB were enrolled from HIV and TB clinics in Eastern Europe and followed until 24 months. Delayed diagnosis was defined as duration of TB symptoms (cough, weight-loss or fever) for ≥ 1 month before TB diagnosis. Risk factors for delayed TB diagnosis were assessed using multivariable logistic regression. The effect of delayed diagnosis on mortality was assessed using Kaplan–Meier estimates and Cox models. Findings 480/740 patients (64.9%; 95% CI 61.3–68.3%) experienced a delayed diagnosis. Age ≥ 50 years (vs. Conclusion Nearly two thirds of PLWH with TB in Eastern Europe had a delayed TB diagnosis, in particular those of older age, people who inject drugs, ART naïve, with disseminated disease, and presenting with weight loss. Patients with delayed TB diagnosis were subsequently at higher risk of death in unadjusted analysis. There is a need for optimisation of the current TB diagnostic cascade and HIV care in PLWH in Eastern Europe.

Coronaviruses (CoVs) comprise a large group of positive stranded RNA viruses that infect a diverse host range including birds and mammals. Infection with CoVs typically presents as mild to severe respiratory or enteric disease, but CoVs have the potential to cause significant morbidity or mortality in highly susceptible age groups. CoVs have exhibited a penchant for jumping species barriers throughout history with devastating effects. The emergence of highly pathogenic or infectious CoVs in humans over the past 20 years, including severe acute respiratory syndrome CoV (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV), and most recently severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), underscores the significant threat that CoV spillovers pose to humans. Similar to the emergence of SARS-CoV-2, CoVs have been devastating to commercial animal production over the past century, including infectious bronchitis virus in poultry and bovine CoV, as well as the emergence and reemergence of multiple CoVs in swine including transmissible gastroenteritis virus, porcine epidemic diarrhea virus, and porcine deltacoronavirus. These naturally occurring animal CoV infections provide important examples for understanding CoV disease as many animal CoVs have complex pathogenesis similar to SARS-CoV-2 and can shed light on the ongoing SARS-CoV-2 outbreak. We provide an overview and update regarding selected existing animal CoVs and their primary host species, diseases caused by CoVs, how CoVs jump species, whether these CoVs pose an outbreak risk or risk to humans, and how we can mitigate these risks.

The low efficacy of human rotavirus (HRV) vaccines in low- and middle-income countries (LMIC) remains a major challenge for global health. Protein-calorie malnutrition (kwashiorkor) affects the gut microbiota and compromises immune development, leading to environmental enteropathy, vaccine failures, and increased susceptibility to enteric diseases in young children. Relationship between diet and reduced vaccine efficacy in developing countries is not well established; therefore, we investigated the interconnections between the host-microbiota-nutrition-HRV vaccine using HRV-vaccinated, human infant faecal microbiota (HIFM)-transplanted neonatal gnotobiotic pigs fed with a protein deficient or sufficient diet. The microbiota from faecal, intestinal (duodenum, ileum, jejunum, and colon), and systemic tissue (liver, spleen, and mesenteric lymph node [MLN]) samples was analysed before and after HRV challenge using MiSeq 16S rRNA sequencing. Overall, microbiota from deficient fed HIFM pigs displayed, compared to the sufficient group, significantly higher Shannon index, especially in the faeces and lower intestines; higher level of Proteus and Enterococcus, and lower level of Bifidobacterium, Clostridium, and Streptococcus in the three types of samples collected (P2≤0.5 or ≥-0.5; P+ CD4+ and CD8+ T cells, IFN-γ and interleukin (IL)-12], and inflammatory [tumour necrosis factor-α, IL-17 and IL-22]) and with opposite trends between diet groups. Differences described above were increased after HRV challenge. We demonstrated that a protein deficient diet affects the composition of the gut microbiota and those changes may further correlate with immune responses induced by HRV and perturbed by the deficient diet. Thus, our findings suggest that the reduced efficacy of HRV vaccine observed in Gn pig model is in part attributed to the altered microbiota composition.

Modular nanotransporters (MNTs) are multifunctional chimeric polypeptides for the multistep transport of locally acting cytotoxic agents into the nuclei of cancer target cells. MNTs consist of several polypeptide domains (functional modules) for the recognition of a cell-surface internalizable receptor, pH-dependent endosomal escape and subsequent transport into the nucleus through the nuclear pores. MNTs are a promising means for cancer treatment. As has been shown previously, all of the modules of MNTs retain their functionalities. Despite their importance, there is no structural information available about these chimeric polypeptides, which hampers the creation of new MNT variants. Here, a low-resolution 3D structure of an MNT is presented which was obtained by atomic force microscopy, transmission electron microscopy and small-angle X-ray scattering coupled to size-exclusion chromatography. The data suggest that the MNT can adopt two main conformations, but in both conformations the protein N- and C-termini are distanced and do not influence each other. The change in the MNT conformation during acidification of the medium was also studied. It was shown that the fraction of the elongated conformation increases upon acidification. The results of this work will be useful for the development of MNTs that are suitable for clinical trials and possible therapeutic applications.

A series of 73 ligands and 73 of their Cu+2 and Cu+1 copper complexes with different geometries, oxidation states of the metal, and redox activities were synthesized and characterized. The aim of the study was to establish the structure-activity relationship within a series of analogues with different substituents at the N(3) position, which govern the redox potentials of the Cu+2/Cu+1 redox couples, ROS generation ability, and intracellular accumulation. Possible cytotoxicity mechanisms, such as DNA damage, DNA intercalation, telomerase inhibition, and apoptosis induction, have been investigated. ROS formation in MCF-7 cells and three-dimensional (3D) spheroids was proven using the Pt-nanoelectrode. Drug accumulation and ROS formation at 40-60 μm spheroid depths were found to be the key factors for the drug efficacy in the 3D tumor model, governed by the Cu+2/Cu+1 redox potential. A nontoxic in vivo single-dose evaluation for two binuclear mixed-valence Cu+1/Cu+2 redox-active coordination compounds, 72k and 61k, was conducted.

To evaluate nutritional patterns in patient with arterial hypertension (AH) compared to the control group without elevated blood pressure.Retrospective search for unique records of the patients aged 1875 y.o. with complete data on usual nutrition with food frequency methods who had no mentions of diabetes mellitus, food intolerance or allergies, and history of major abdominal surgery, as well as signs of secondary reasons of AH. Nutritional patterns were assessed with the use of healthy eating pyramid principles. Ststistical analysis was performed with the use of SPSS 13.0 for Windows software (SPSS Inc., USA).The data of 711 patients were available for the final analysis (595 of them in AH group). Both groups consumed lower compared to the recommended amounts of fruits, dairy and higher amounts of meat. Those with AH consumed larger amounts of vegetables (1.130.74 compared to the values of healthy eating pyramid vs 0.940.63 in the control group; p=0.004), fruits (0.800.66 vs 0.520.57; p=0.001), meat (1.851.05 vs 1.620.91; p=0.002) and fats (0.770.60 vs 0.490.55; p=0.001). On the other hand, there were lower rates of consumption of sugars, and confectionaries in the structure of nutritional patterns in patients with AH compared to the control group: (0.350.44 of the healthy eating pyramid in AH vs 1.930.98, in the control group; p=0.0001).Nutritional patterns of patients with arterial hypertension significantly differ compared to the control group. The obtained data may be used for diet modification in patients with arterial hypertension.Цель. Изучить структуру (паттерн) питания больных артериальной гипертензией (АГ) в сравнении с контрольной группой без повышения артериального давления (контрольная группа). Материалы и методы. Проведен ретроспективный анализ базы данных системы ПО Нутрилоджик (ООО Нутрилоджик, Россия), в ходе которого идентифицированы данные пациентов в возрасте от 18 до 75 лет с полностью заполненными и адекватными данными анализа фактического питания методом частотного анализа, без признаков вторичной АГ и сопутствующих заболеваний, которые могли бы привести к искажению пищевых привычек вследствие необходимости специальных ограничений в питании (сахарный диабет, пищевая непереносимость, операции на желудочно-кишечном тракте). Оценка структуры питания проводилась по частоте и количеству потребления основных групп продуктов в сравнении с принципом пирамиды здорового питания. Дополнительный анализ проведен в отношении состава подгрупп продуктов. Для математической обработки результатов использовался непараметрический модуль ПО SPSS 13.0 for Windows (SPSS Inc., USA). Результаты. Конечному анализу доступны данные 711 обследуемых (595 в группе АГ). Как для группы АГ, так и контрольной, характерны недостаточное потребление фруктов и молочных продуктов, а также избыточное потребление мяса. При сравнении групп между собой выявлено, что больные АГ потребляли больше овощей (1,130,74 относительно величины пирамиды здорового питания против 0,940,63 в группе контроля соответственно; р=0,004), фруктов (0,800,66 против 0,520,57; р=0,001), мяса (1,851,05 против 1,620,91; р=0,002) и жиров (0,770,60 против 0,490,55; р=0,001). В то же время структура рациона больных АГ характеризовалась меньшим относительным количеством сахара и кондитерских изделий, чем в группе контроля (0,350,44 относительно показателей пирамиды здорового питания в группе АГ против 1,930,98 в группе контроля; р=0,0001). Заключение. Структура рациона больных АГ существенно отличается от таковой без признаков заболевания. Полученные данные могут быть использованы для научно обоснованной модификации рационов у больных АГ.

Here we review the existing evidence of animal alphacoronaviruses (

To determine the effectiveness of a new treatment regimen for patients with widespread peritonitis with an accent on enteroprotection based on the use of a drug of the metabolic type of action of remaxol and physiotherapy.Clinical and laboratory studies of 82 patients with widespread peritonitis, mainly with grade 2 severity according to the Mannheim peritonitis Index, severe form - according to the ARASNE II scale. In the 1st group (28) patients underwent intraoperative intestinal intubation in the traditional way; in the 2nd (22) - intestinal intubation according to the original method; in the 3rd (32) - intestinal intubation according to the original method and combined use of remaxol (parenterally, enterally and intraperitoneally). An intestinal tube of an original design was used, which allows electrical stimulation of the duodenum in the postoperative period. The study evaluates clinical data, the results of instrumental and laboratory studies: ultrasound examination of the abdominal cavity, assessment of the functional state of the small intestine, a number of indicators of homeostasis.It was shown that in patients with acute widespread peritonitis who underwent intestinal intubation according to the original method (group 2), as well as in combination with remaxol (group 3), the postoperative period was relatively more favorable. One of the factors optimizing the course of the disease was the relatively rapid restoration of the structural and functional state of the small intestine due to its electrical stimulation. The clinical and laboratory positive effect was especially significant in the 3rd group of patients, in which the use of remaxol, which has a membrane-stabilizing effect, played a special role in the enteroprotective effect. Timely correction of enteral distress syndrome resulted in a significant decrease in the severity of the syndrome of endogenous intoxication and oxidative stress, which was important in significantly improving the results of treatment of patients.The use of technical innovations in the form of an original nasointestinal tube, which allows to quickly restore intestinal motility due to electrical stimulation, as well as the use of remaxol (parenterally, enterally and intraperitoneally) significantly optimize the course of the early postoperative period of patients with acute widespread peritonitis.Определить эффективность новой схемы лечения пациентов с распространенным перитонитом с акцентом на энтеропротекцию на основе использования препарата метаболического типа действия ремаксола и физиотерапии.Проведены клинико-лабораторные исследования у 82 пациентов с распространенным перитонитом, преимущественно со 2-й степенью тяжести по Мангеймскому индексу перитонита, тяжелой формой по шкале APACHE II. Пациентам 1-й группы (28 больных) интраоперационно выполнена интубация кишечника традиционным способом; 2-й группы (22) — интубация кишечника по оригинальной методике; в 3-й группе (32) пациентам проведена интубация кишечника по оригинальной методике и назначено комбинированное применение ремаксола (парентерально, энтерально и внутрибрюшинно). Использован кишечный зонд оригинальной конструкции, который позволяет в послеоперационном периоде осуществлять электростимуляцию двенадцатиперстной кишки. В работе оценивали клинические данные, результаты инструментальных и лабораторных исследований: ультразвукового исследования брюшной полости, функционального состояния тонкой кишки, ряда показателей гомеостаза.Показано, что у пациентов с острым распространенным перитонитом, которым проводили интубацию кишечника по оригинальной методике (2-я группа), а также в комбинации с ремаксолом (3-я группа) послеоперационный период протекал благоприятнее в сравнении с группой традиционной методики. Одним из факторов, оптимизирующих течение болезни, явилось более быстрое восстановление структурно-функционального состояния тонкой кишки за счет ее электростимуляции. Особенно значимым было клинико-лабораторное положительное действие в 3-й группе пациентов, в которой в энтеропротективном эффекте особую роль сыграло применение ремаксола, обладающего мембраностабилизирующим действием. Своевременная коррекция энтерального дистресс-синдрома выразилась в существенном уменьшении выраженности синдрома эндогенной интоксикации и оксидативного стресса, что явилось немаловажным в существенном улучшении результатов лечения пациентов.Использование технических новаций в виде оригинального назоинтестинального зонда, позволяющего за счет электростимуляции быстро восстанавливать моторику кишечника, а также применения ремаксола (парентерально, энтерально и внутрибрюшинно) существенно оптимизируют течение раннего послеоперационного периода больных с острым распространенным перитонитом.

Organic cation transporter 1 (OCT1) is a membrane transporter that affects hepatic uptake of cationic and weakly basic drugs. OCT1 transports structurally highly diverse substrates. The mechanisms conferring this polyspecificity are unknown. Here, we analyzed differences in transport kinetics between human and mouse OCT1 orthologs to identify amino acids that contribute to the polyspecificity of OCT1. Following stable transfection of HEK293 cells, we observed more than twofold differences in the transport kinetics of 22 out of 28 tested substrates. We found that the β2-adrenergic drug fenoterol was transported with eightfold higher affinity but at ninefold lower capacity by human OCT1. In contrast, the anticholinergic drug trospium was transported with 11-fold higher affinity but at ninefold lower capacity by mouse Oct1. Using human-mouse chimeric constructs and site-directed mutagenesis, we identified nonconserved amino acids Cys36 and Phe32 as responsible for the species-specific differences in fenoterol and trospium uptake. Substitution of Cys36 (human) to Tyr36 (mouse) caused a reversal of the affinity and capacity of fenoterol but not trospium uptake. Substitution of Phe32 to Leu32 caused reversal of trospium but not fenoterol uptake kinetics. Comparison of the uptake of structurally similar β2-adrenergics and molecular docking analyses indicated the second phenol ring, 3.3 to 4.8 Å from the protonated amino group, as essential for the affinity for fenoterol conferred by Cys36. This is the first study to report single amino acids as determinants of OCT1 polyspecificity. Our findings suggest that structure-function data of OCT1 is not directly transferrable between substrates or species.

Rotavirus (RV) is the foremost enteric pathogen associated with severe diarrheal illness in young children (

Malnutrition refers to inadequate energy and/or nutrient intake. Malnutrition exhibits a bidirectional relationship with infections whereby malnutrition increases risk of infections that further aggravates malnutrition. Severe malnutrition (SM) is the main cause of secondary immune deficiency and mortality among children in developing countries. SM can manifest as marasmus (non-edematous), observed most often (68.6% of all malnutrition cases), kwashiorkor (edematous), detected in 23.8% of cases, and marasmic kwashiorkor, identified in ~7.6% of SM cases. Marasmus and kwashiorkor occur due to calorie-energy and protein-calorie deficiency (PCD), respectively. Kwashiorkor and marasmic kwashiorkor present with reduced protein levels, protein catabolism rates, and altered levels of micronutrients leading to uncontrolled oxidative stress, exhaustion of anaerobic commensals, and proliferation of pathobionts. Due to these alterations, kwashiorkor children present with profoundly impaired immune function, compromised intestinal barrier, and secondary micronutrient deficiencies. Kwashiorkor-induced alterations contribute to growth stunting and reduced efficacy of oral vaccines. SM is treated with antibiotics and ready-to-use therapeutic foods with variable efficacy. Kwashiorkor has been extensively investigated in gnotobiotic (Gn) mice and piglet models to understand its multiple immediate and long-term effects on children health. Due to numerous physiological and immunological similarities between pigs and humans, pig represents a highly relevant model to study kwashiorkor pathophysiology and immunology. Here we summarize the impact of kwashiorkor on children’s health, immunity, and gut functions and review the relevant findings from human and animal studies. We also discuss the reciprocal interactions between PCD and rotavirus—a highly prevalent enteric childhood pathogen due to which pathogenesis and immunity are affected by childhood SM.

Novel indolocarbazole derivatives named LCS were synthesized by our research group. Two of them were selected as the most active anticancer agents in vivo. We studied the mechanisms of anticancer activity in accordance with the previously described effects of indolocarbazoles. Cytotoxicity was estimated by MTT assay. We analyzed LCS-DNA interactions by circular dichroism in cholesteric liquid crystals and fluorescent indicator displacement assay. The effect on the activity of topoisomerases I and II was studied by DNA relaxation assay. Expression of interferon signaling target genes was estimated by RT-PCR. Chromatin remodeling was analyzed–the effect on histone H1 localization and reactivation of epigenetically silenced genes. LCS-induced change in the expression of a wide gene set was counted by means of PCR array. Our study revealed the cytotoxic activity of the compounds against 11 cancer cell lines and it was higher than in immortalized cells. Both compounds bind DNA; binding constants were estimated—LCS-1208 demonstrated higher affinity than LCS-1269; it was shown that LCS-1208 intercalates into DNA that is typical for rebeccamycin derivatives. LCS-1208 also inhibits topoisomerases I and IIα. Being a strong intercalator and topoisomerase inhibitor, LCS-1208 upregulates the expression of interferon-induced genes. In view of LCSs binding to DNA we analyzed their influence on chromatin stability and revealed that LCS-1269 displaces histone H1. Our analysis of chromatin remodeling also included a wide set of epigenetic experiments in which LCS-1269 demonstrated complex epigenetic activity. Finally, we revealed that the antitumor effect of the compounds is based not only on binding to DNA and chromatin remodeling but also on alternative mechanisms. Both compounds induce expression changes in genes involved in neoplastic transformation and target genes of the signaling pathways in cancer cells. Despite of being structurally similar, each compound has unique biological activities. The effects of LCS-1208 are associated with intercalation. The mechanisms of LCS-1269 include influence on higher levels such as chromatin remodeling and epigenetic effects.

International audience; The molecular complexity of human breast cancer (BC) renders the clinical management of the disease challenging. Long non-coding RNAs (lncRNAs) are promising biomarkers for BC patient stratification, early detection, and disease monitoring. Here, we identified the involvement of the long intergenic non-coding RNA 01087 (LINC01087) in breast oncogenesis. LINC01087 appeared significantly downregulated in triple-negative BCs (TNBCs) and upregulated in the luminal BC subtypes in comparison to mammary samples from cancer-free women and matched normal cancer pairs. Interestingly, deregulation of LINC01087 allowed to accurately distinguish between luminal and TNBC specimens, independently of the clinicopathological parameters, and of the histological and TP53 or BRCA1/2 mutational status. Moreover, increased expression of LINC01087 predicted a better prognosis in luminal BCs, while TNBC tumors that harbored lower levels of LINC01087 were associated with reduced relapse-free survival. Furthermore, bioinformatics analyses were performed on TNBC and luminal BC samples and suggested that the putative tumor suppressor activity of LINC01087 may rely on interferences with pathways involved in cell survival, proliferation, adhesion, invasion, inflammation and drug sensitivity. Altogether, these data suggest that the assessment of LINC01087 deregulation could represent a novel, specific and promising biomarker not only for the diagnosis and prognosis of luminal BC subtypes and TNBCs, but also as a predictive biomarker of pharmacological interventions.

The C-terminal domain (CTD) of the largest subunit of RNA polymerase II (Pol II) is a regulatory hub for transcription and RNA processing. Here, we identify PHD-finger protein 3 (PHF3) as a regulator of transcription and mRNA stability that docks onto Pol II CTD through its SPOC domain. We characterize SPOC as a CTD reader domain that preferentially binds two phosphorylated Serine-2 marks in adjacent CTD repeats. PHF3 drives liquid-liquid phase separation of phosphorylated Pol II, colocalizes with Pol II clusters and tracks with Pol II across the length of genes. PHF3 knock-out or SPOC deletion in human cells results in increased Pol II stalling, reduced elongation rate and an increase in mRNA stability, with marked derepression of neuronal genes. Key neuronal genes are aberrantly expressed in Phf3 knock-out mouse embryonic stem cells, resulting in impaired neuronal differentiation. Our data suggest that PHF3 acts as a prominent effector of neuronal gene regulation by bridging transcription with mRNA decay., Here the authors identify PHF3 SPOC domain as a reader of the phosphorylated RNA polymerase II (Pol II) C-terminal domain. They show that PHF3 clusters with Pol II complexes in cells, drives phase separation of Pol II in vitro, and regulates neuronal gene expression and neuronal differentiation.

To study the significance of clinical and laboratory non-invasive indexes along with the insulin resistance index when carrying out diagnostic assessment of non-alcoholic fatty liver disease (NAFLD) during screening examinations.The study involved 348 employees working at oil-production enterprises. An ultrasound scanning of the liver was carried out to assess the criteria of NAFLD. The following indexes were calculated: fatty liver index (FLI), hepatic steatosis index (HSI), lipid accumulation products (LAP), and homeostasis model assessment of insulin resistance (HOMA1-IR). The prognostic significance of these indexes in relation to the probability of NAFLD diagnosis based on ultrasound data was studied using single-factor and multi-factor logistic regression models followed by ROC-analysis.The FLI, HSI, and HOMA1-IR indexes in single-factor logistic regression models showed a high statistical significance when carrying out diagnostic assessment the NAFLD with good model calibration capability. The percentage of correct binary classification regards the presence/absence of NAFLD amounted to 82.4% for FLI, 79.7% for HSI, and 72.7% for HOMA1-IR (p0.001). According to the ROC-analysis, the area under the curve (AUC) by the NAFLD diagnostic assessment was 0.917 (95% CI 0.8890.945); 0.880 (95% CI 0.8460.915) and 0.849 (95% CI 0.7640.934), respectively. The multi-factor logistic regression model with the inclusion of FLI and HOMA1-IR 72.7% enabled us to achieve the correct binary classification in terms of NAFLD in 84.2% of cases. When it comes to the ROC-analysis, considering the probabilities predicted in the multi-factor logistic model as the test variable and NAFLD in ultrasound examination as the state variable, it was possible to set the value of AUC 0.933 (95% CI 0.8820.985).The studied clinical and laboratory indexes (FLI, HSI, HOMA1-IR) have a high diagnostic significance regarding NAFLD diagnosed using ultrasonographic criteria. The application of the proposed two-factor logistics model makes it possible to predict the presence of NAFLD when examining a large number of patients, without involving additional ultrasound diagnostics specialists in order to use medical resources rationally.Цель. Изучить значимость клинико-лабораторных неинвазивных индексов в сочетании с индексом инсулинорезистентности в диагностике неалкогольной жировой болезни печени (НАЖБП) при скрининговых обследованиях. Материалы и методы. В исследование включены 348 работников нефтедобывающего предприятия. Выполнялось ультразвуковое сканирование (УЗИ) печени с оценкой критериев НАЖБП. Вычислялись индексы: fatty liver index (FLI), hepatic steatosis index (HSI), lipid accumulation products (LAP), индекс инсулинорезистентности (HOMA1-IR). Прогностическая значимость данных индексов в отношении вероятности диагностики НАЖБП по данным УЗИ изучалась в моделях однофакторной и многофакторной логистической регрессии с выполнением ROC-анализа. Результаты. Индексы FLI, HSI и HOMA1-IR в моделях однофакторной логистической регрессии показали высокую статистическую значимость в диагностике НАЖБП с хорошей калибрационной способностью моделей. Доля правильной бинарной классификации в отношении наличия/отсутствия НАЖБП составила для FLI 82,4%, для HSI 79,7%, а для HOMA1-IR 72,7% (р0,001). По данным ROC-анализа, площадь под кривой (AUC) при диагностике НАЖБП составила для этих индексов 0,917 (95% доверительный интервал ДИ 0,8890,945), 0,880 (95% ДИ 0,8460,915) и 0,849 (95% ДИ 0,7640,934) соответственно. Многофакторная логистическая регрессионная модель с включением FLI и HOMA1-IR позволила достичь правильной бинарной классификации в отношении НАЖБП в 84,2% случаев, а в ROC-анализе на основании предсказанных в многофакторной логистической модели вероятностей в качестве тестируемой переменной и НАЖБП при УЗИ в качестве переменной состояния установили значение AUC=0,933 (95% ДИ 0,8820,985). Заключение. Изученные клинико-лабораторные индексы (FLI, HSI, HOMA1-IR) обладают высокой диагностической значимостью в отношении НАЖБП, установленной по ультрасонографическим критериям. Применение предложенной двухфакторной логистической модели позволяет в условиях массового обследования достаточно точно прогнозировать наличие НАЖБП без дополнительного широкого привлечения специалистов ультразвуковой диагностики в целях рационального использования медицинских ресурсов.

To establish the universality and regularity of hepatic disorders, their role in pathogenesis of homeostasis impairment and determine scientific base for a new syndrome - hepatic distress syndrome in surgery.Chronic experiments on outbred dogs were carried out. Acute peritonitis was simulated in the first group (Experimental and clinical studies have shown significant liver damage in all diseases with various pathogenesis. Regardless of urgent disease, one of the leading component is membrane-destabilizing process. The last one is determined by excessive activity of membrane lipid peroxidation and phospholipases in liver tissue. Severe abnormalities are followed by impairment of liver detoxification ability and liver may be a source of toxins per se. Remaxol infusion in the treatment of experimental and clinical acute peritonitis increased liver tolerance to trigger pathogenetic agents. This process resulted improvement of laboratory and clinical parameters. In general, we obtained high significance of liver damage in pathogenesis of acute urgent abdominal pathology.Experimental and clinical data for determining hepatic distress syndrome as important aspect in acute abdominal surgical diseases have been obtained. Hepatic distress syndrome in surgery is a combination of abnormal processes with progression of endogenous intoxication, oxidative stress and phospholipase activity following membrane-destabilizing phenomena and secondary liver dysfunction.На основе объективных данных по модификациям структурно-функционального состояния печени при различных ургентных заболеваниях (перитонит, панкреонекроз, кишечная непроходимость) установить универсальность и закономерность развития гепатических нарушений, участие их в патогенезе расстройств гомеостаза на организменном уровне и на основании фактического материала подвести научную базу под разработку нового синдромокомплекса «гепатический дистресс-синдром» в хирургии.Хронические опыты на беспородных собаках (4 группы по 15 особей). В 1-й группе моделировали острый перитонит, во 2-й — острый деструктивный панкреатит, в 3-й — острую обтурационную кишечную непроходимость, в 4-й — острый перитонит, в схему лечения включили инфузии ремаксола (20 мл/кг). В динамике оценено функциональное состояние печени по показателям эндогенной интоксикации, липидного обмена в крови, притекающей к печени и оттекающей от нее, в тканях органа — состав липидов. Клинико-лабораторные исследования выполнены у 44 больных перитонитом (в 1-й подгруппе (Экспериментально-клиническими исследованиями показано, что при изученных заболеваниях с различным патогенезом происходит значительное поражение печени. Установлено, что вне зависимости от характера основного заболевания одним из ведущих компонентов его патогенеза закономерно является процесс разрушения мембран клеток различных органов, который развивается из-за избыточной активности перекисного окисления мембранных липидов и фосфолипаз в тканевых структурах того или иного органа. Выявлено, что при запредельной их выраженности печень утрачивает детоксикационную способность и сама может явиться источником токсинов. При включении в лечение ремаксола при остром перитоните в эксперименте и клинике повышало толерантность печени к триггерным патогенетическим агентам, что проявлялось в улучшении лабораторных и клинических показателей и в целом явилось дополнительным доказательством высокой значимости поражений печени в патогенезе острых хирургических заболеваний органов живота.Получены экспериментально-клинические основания для определения патологического состояния (синдромокомплекса) при острых хирургических болезнях живота под названием гепатический дистресс-синдром.

In cases of any acute surgical abdominal disease the progression of purulent inflammation can lead to local or diffuse peritonitis. The indicators of the degree and specificity of the inflammatory response in blood such as cytokine concentration, neutrophil activity, plasma antioxidant capacity (thiols concentration) could be considered as potential predictors of complications. The luminol-dependent chemiluminescence (CL) response of blood activated by the phorbol ester (PMA), and the concentration of cytokines IL-6, IL-8, IL-10, myeloperoxidase (MPO) and thiols in plasma were measured in patients with uncomplicated condition (group 1, n=8), local peritonitis (group 2, n=9) or diffuse peritonitis (group 3, n=9) at admission to surgery (before surgical operation, b/o), immediately after surgical operation (a/o) and a day after surgery (1 day) as well as in healthy volunteers (norm, n=12). In all time-points the cytokines and MPO concentrations measured by ELISA, in group 3 were higher than in healthy volunteers and in patients in groups 1 and 2. Blood CL demonstrated a more than 5-fold increase above the normal values in all patients, and was also higher in group 2 as compared to group 1 (b/o and a/o). Patients in group 3 had shown both maximum and minimum of CL values, which could be a consequence of neutrophil priming or exhaustion ("immune paralysis"), respectively. The same patients' plasma exhibited low thiol concentration (≤30% vs normal values). In patients with fatal outcomes (group 3, n=2) within a day after surgery, either a decrease of the CL to zero values concurrently with elevated IL-8 and IL-6 concentrations and low thiol levels was observed, or CL exceeded normal values more than 20 times with concurrent complete exhaustion of the plasma thiol pool. No clear dependency between the plasma parameters and neutrophil activity was found. Hence a parameter set for prognosis and/or early diagnosis of infectious complications in acute abdominal pathology should include different biomarkers of the inflammatory response: cytokine profile (IL-6, IL-8, IL-10), MPO and neutrophil activity, antioxidant plasma capacity (e.g., total thiols concentration).Progressirovanie gnoĭno-vospalitel'nogo protsessa pri liuboĭ ostroĭ khirurgicheskoĭ abdominal'noĭ patologii privodit k razvitiiu mestnogo ili rasprostranennogo peritonita. Potentsial'nymi prediktorami oslozhneniĭ mogut byt' pokazateli, kharakterizuiushchie stepen' i osobennosti vospalitel'noĭ reaktsii v krovi — soderzhanie tsitokinov, aktivnost' neĭtrofilov, sostoiatel'nost' antioksidantogo zvena. U patsientov s neoslozhnennoĭ patologieĭ (gruppa 1, n=8), mestnym peritonitom (gruppa 2, n=9) i rasprostranennym peritonitom (gruppa 3, n=9) pri postuplenii v khirurgicheskoe otdelenie (do operatsii), nemedlenno posle operatsii i cherez sutki, a takzhe u zdorovykh dobrovol'tsev (norma, n=12) izmeriali liuminol-zavisimuiu khemiliuminestsentsiiu(KhL) krovi, aktivirovannuiu forbol-12-miristat-13-atsetatom, i kontsentratsiiu IL-6, IL-8, IL-10, mieloperoksidazy (MPO) i tiolov v plazme krovi. Po dannym immunofermentnogo analiza, vo vsekh vremennykh tochkakh kontsentratsiia tsitokinov IL-6, IL-8 i IL-10, a takzhe MPO v gruppe 3 byla vyshe, chem u zdorovykh dobrovol'tsev i patsientov grupp 1 i 2. Velichina KhL krovi u vsekh patsientov bolee chem v 5 raz uvelichivalas' po sravneniiu s normoĭ, a u patsientov gruppy 2 — po sravneniiu s gruppoĭ 1. V gruppe 3 vyiavlialis' patsienty kak s maksimal'nymi, tak i s minimal'nymi iz vsekh zaregistrirovannykh znacheniĭ KhL, chto mozhet byt' sledstviem praĭminga i istoshcheniia neĭtrofilov sootvetstvenno. U étikh zhe patsientov soderzhanie tiolov snizhalos' v 3 i bolee raz po sravneniiu s normoĭ. U patsientov s letal'nym iskhodom v techenie pervykh sutok posle operatsii (gruppa 3, n=2) otmecheno libo snizhenie KhL do nulevykh znacheniĭ na fone vysokogo soderzhaniia IL-8 i IL-6 i nizkogo (v 3 i bolee raz nizhe normy) urovnia tiolov, libo KhL otvet, 20-kratno prevyshaiushchiĭ normu, pri polnom istoshchenii pula tiolov v plazme. Odnoznachnoĭ zavisimosti mezhdu pokazateliami v plazme i aktivnost'iu neĭtrofilov ne bylo. Éto oznachaet, chto panel' pokazateleĭ dlia prognoza i/ili ranneĭ diagnostiki infektsionnykh oslozhneniĭ pri ostroĭ khirurgicheskoĭ patologii dolzhna vkliuchat' v sebia razlichnye biomarkery vospalitel'nogo otveta: tsitokinovyĭ profil' (IL-6, IL-8, IL-10), MPO i aktivnost' neĭtrofilov, antioksidantnuiu emkost' plazmy (kontsentratsiiu tiolov).

To assess food patterns in patients with different types of SIBO and their impact onto the course and treatment outcomes.The data of 988 patients who signed informed consent surved as a source data. On the basis of lactulose breath test (LBT; GastroCH4eck, Bedfont, UK), the patients were selected into one of the studied groups: SIBO-H2, SIBO-CH4, SIBO-CH4-H2 and control. Twenty - four hours food recall test was used to analyze nutritional habits. In patients with SIBO-H2, standard treatment with Tilichinol 100 mg/Tilbrochinol 200 mg (Intetrix, Beaufour-Ipsen International, France) 2 caps BID for 10 days) was provided. Efficacy of treatment was assessed on the bass of the result of LBT 2 month after treatment completion. Mann-Whitney T test (Statistica 10, StatSoft, USA) was used to compare nutritional patterns in patients with or without SIBO, in different types of SIBO and in accordance to the results of treatment.Nine hundred eighty eight patients were enrolled. On the basis of hydrogene breath test they were divided into 4 main groups: SIBO of hydrogen - producing flora (SIBO-H2, n=526), methane - producing flora (SIBO-CH4, n=129), SIBO with hyperproduction of methane and hydrogene (SIBO-CH4-H2, n=225). The control group consisted of 108 patients with no no excessive gas production on LBT. In contrast to controls, nutritional patterns of patients with SIBO were characterized by low dietary fiber and amount of red meat dishes in the rations. Those with SIBO-CH4 consumed more fruits (p=0.03), vegetables (p=0.003), and fish (p=0.026), compared to those with other variants of SIBO and the control group. Nutritional patterns of SIBO-H2 group were characterized by larger amount of poultry meat consumption (p=0.026) compared to other SIBO groups and controls. In SIBO-H2 "cured" group greater amounts of buckwheat (p.Цель. Оценить особенности паттернов питания пациентов с различными вариантами синдрома избыточного бактериального роста в тонкой кишке (СИБР) и их влияние на эффективность терапии у больных СИБР водород - продуцирующей флоры (СИБР-Н2). Материалы и методы. Материалом исследования явились данные обследования пациентов, подписавших информированное согласие на участие в нем. Всем пациентам выполнен водородно - метановый дыхательный тест с лактулозой (GastroCh4eck, Bedfont, Великобритания) для диагностики избыточного бактериального роста в тонкой кишке. На основании результатов теста пациенты разделены на группы СИБР-H2, СИБР-CH4, СИБР-CH4-H2 и контрольную группу, без СИБР. Анализ данных фактического питания выполнен при помощи метода суточного воспроизведения. В группе СИБР-H2 проведена стандартная терапия препаратом, содержащим тилихинол 100 мг / тилброхинол 200 мг (Интетрикс; Beaufour Ipsen International, Франция) по 2 капсулы 2 раза в сутки в течение 10 дней. Оценка эффективности терапии проводилась через 2 мес после окончания курса лечения при помощи водородно - метанового дыхательного теста с лактулозой. Проведен анализ паттернов питания пациентов в зависимости от наличия или отсутствия СИБР, в зависимости от выявленного варианта СИБР, а также в группах с наличием и отсутствием эффекта от лечения. Результаты и обсуждение. Анализу доступны данные 988 пациентов: СИБР-Н2 (n=526); СИБР-СН4 (n=129), СИБР-СН4-Н2 (n=225), контрольная группа (без СИБР; n=108). При наличии СИБР (любой вариант) структура питания отличалась низким содержанием пищевых волокон (p=0,07) и блюд из красного мяса (p=0,01) в сравнении с контрольной группой. В группе СИБР-СН4 отмечено большее потребление фруктов (р=0,03), овощей (р=0,003), рыбной продукции (p=0,026) в сравнении с другими вариантами СИБР и контролем. Пищевые паттерны в группе СИБР-Н2 характеризовались большим потреблением мяса птицы (p=0,026) в сравнении с другими группами. Пищевые паттерны пациентов СИБР-Н2 с отсутствием эффекта от лечения характеризовались большим потреблением гречихи (р.

To assess the role of Methanobrevibacter smithii in patients with irritable bowel syndrome associated with small intestinal bowel overgrowth.Sixty - seven patients with IBS according to Rome IV were enrolled into the study in whom hydrogen breath test was performed. Thirty - two healthy subjects with negative breath test was used as a control. All IBS symptoms assessed daily with 5 grade Lykert scale for 7 days, stool was assessed by Brystol stool scale. M. smithii was confirmed in stool samples by PCR.In 67 IBS patients CH4 overproduction was found in 32 (47.7%), H2 overproduction in 31 (46.2%) and normal values in 4 (5.9%) by hydrogen breath test. M. smithii was confirmed by stool PCR in all patients with CH4 overproduction. Severity and prevalence of main clinical features of IBS were similar in both SIBO groups but were significantly higher than in control (p.Цель исследования. Оценить роль Methanobrevibacter smithii в формировании симптомов заболевания у пациентов с синдромом раздраженного кишечника (СРК) и наличием синдрома избыточного бактериального роста (СИБР). Материалы и методы. У 67 пациентов с СРК согласно Римским критериям 4-го пересмотра выполнен водородно - метановый дыхательный тест с лактулозой. Для контроля использована группа пациентов (n=32) без нарушения стула и наличия абдоминальной боли/дискомфорта. Пациентами осуществлялась ежедневная регистрация согласно 5-балльной шкале Лайкерта динамики симптомов заболевания (наличие и выраженность абдоминальной боли, метеоризма, изжоги, тошноты, чувства тяжести после еды, неполного опорожнения кишечника), для оценки динамики показателей стула использовалась Бристольская шкала стула. В исследовании сопоставлялись данные интенсивности основных жалоб пациентов с СИБР СН4 и СИБР Н2, оценивались корреляционные связи интенсивности жалоб с уровнем выдыхаемого СН4. Наличие M. smithii в кале пациентов подтверждалось методом полимеразной цепной реакции (ПЦР). Результаты и обсуждение. Из 67 пациентов с СРК у 32 (47,7%) выявлен СИБР СН4, наличие M. smithii у них подтверждено ПЦР в кале, а у 31 (46,2%) пациента выявлен СИБР Н2, у 4 (5,9%) пациентов избыточного бактериального роста в кишечнике по данным дыхательного водородно - метанового теста не выявлено. Интенсивность основных жалоб в группах СИБР СН4 и СИБР Н2 имела сопоставимую интенсивность, в группе контроля выраженность абдоминальной боли, вздутия живота и чувства неполного опорожнения были достоверно ниже (р.

Neutrophil myeloperoxidase (MPO) plays an important role in protecting the body against infections. MPO products - hypohalous acids and phenoxyl radicals - are strong oxidants that can damage not only foreign intruders but also host tissues, including blood plasma proteins. Here, we compared the MPO-induced oxidation of two plasma proteins with antioxidant properties - human serum albumin (HSA) and ceruloplasmin (CP). Incubation of both proteins with hypochlorite (NaOCl) or catalytically active MPO (MPO + H2O2), which synthesizes hypochlorous acid (HOCl) in the presence of chloride ions, resulted in the quenching of protein tryptophan fluorescence. Oxidation-induced changes in the structures of HSA and CP were different. HSA efficiently neutralized MPO-generated oxidants without protein aggregation, while CP oxidation resulted in the formation of large aggregates stabilized by strong covalent bonds between the aromatic amino acid residues. Tyrosine is present in the plasma as free amino acid and also as a component of the polypeptide chains of the proteins. The number of tyrosine residues in a protein does not determine its propensity for aggregate formation. In the case of CP, protein aggregation was primarily due to the high content of tryptophan residues in its polypeptide chain. MPO-dependent oxidation of free tyrosine results in the formation of tyrosyl radicals, that do not oxidize aromatic amino acid residues in proteins because of the high rate of recombination with dityrosine formation. At the same time, free tyrosine can influence MPO-induced protein oxidation due to its ability to modulate HOCl synthesis in the MPO active site.

Intravital microscopy is widely used for in vivo studies of the mechanisms of carcinogenesis and response to antitumor therapy. For visualization of tumor cells in vivo, cell lines expressing fluorescent proteins are needed. Expression of exogenous proteins can affect cell growth rate and their tumorigenic potential. Therefore, comprehensive analysis of the morphofunctional properties of transduced cells is required for creating appropriate models of tumor microenvironment. In the present study, six lines of mouse tumor cells expressing green and red fluorescent proteins were derived. Analysis of cells morphology, growth kinetics, and response to chemotherapy in vitro revealed no significant differences between wild-type and transduced cell lines. Introduction of fluorescent proteins into the genome of 4T1 (murine breast cancer) and B16-F10 (murine melanoma) cells did not affect tumor growth rate after subcutaneous implantation to mice, while both CT26-GFP and CT26-RFP cells (murine colon cancer) were rejected starting from day 8 after implantation. Elucidation of the mechanisms underlying CT26-GFP/RFP rejection is required to modify transduction technique for creating the models of tumor microenvironment accessible for in vivo visualization. Transduced 4T1 and B16-F10 cell lines can be used for intravital microscopic imaging of tumor cells, neoplastic vasculature, and leukocyte subpopulations.

Skin disorders of different etiology, such as dermatitis, atopic dermatitis, eczema, psoriasis, wounds, burns, and others, are widely spread in the population. In severe cases, they require the topical application of drugs, such as antibiotics, steroids, and calcineurin inhibitors. With milder symptoms, which do not require acute pharmacological interventions, medications, dietary supplements, and cosmetic products of plant material origin are gaining greater popularity among professionals and patients. They are applied in various pharmaceutical forms, such as raw infusions, tinctures, creams, and ointments. Although plant-based formulations have been used by humankind since ancient times, it is often unclear what the mechanisms of the observed beneficial effects are. Recent advances in the contribution of the skin microbiota in maintaining skin homeostasis can shed new light on understanding the activity of topically applied plant-based products. Although the influence of various plants on skin-related ailments are well documented in vivo and in vitro, little is known about the interaction with the network of the skin microbial ecosystem. The review aims to summarize the hitherto scientific data on plant-based topical preparations used in Poland and Ukraine and indicate future directions of the studies respecting recent developments in understanding the etiology of skin diseases. The current knowledge on investigations of interactions of plant materials/extracts with skin microbiome was reviewed for the first time.

Immunological non-responders (INR) are HIV-infected subjects that fail to restore CD4

In conditions of societal transformations, social institutions undergo significant alterations that are manifested by institutional inconsistency and dysfunctionality. The transformation of social professional structure of health care system resulted in change of status and trends of social mobility of social professional groups. The purpose of the study is to typologize social predictors of professional activity of physicians in health care of the Russian Federation. The social economic transformation and reforms of the National health care system of recent decades initiated trends of deprofessionalization in medicine, status inflation and marginalization of professional groups. The phenomenon of professional marginalization of physicians is discussed from perspective of the "concept of status inconsistency" by G. Lensky. In aurhoring typology low income of physicians, financial deprivation, reducing of prestige and relative status inflation of medical profession, professional stress, social frustrations and professional burnout are considered as social predictors of professional activity of physicians. The destructive consequences of status inflation are considered as social threat to preservation of manpower potential of health care of the Russian Federation.

Long-term outcomes of glucocorticosteroid therapy in pulmonary sarcoidosis patients testify for high rate of relapses, which nowadays are the most acute problem in providing care to these patients. Aim - to study clinical factors, associated with pulmonary sarcoidosis relapse. 108 patients with newly diagnosed pulmonary sarcoidosis were examined (stage II - 102 patients, stage III - 6 patients). There were 48 male and 60 female, age from 24 to 64 years. The diagnosis of sarcoidosis was verified by high-resolution computed tomography (CT). All patients received GCS therapy with methylprednisolone 0,4 mg/kg for 4 weeks with subsequent dose tapering down to 0,1 mg/kg by the end of 6th month. Treatment was continued until clinical cure. Upon discontinuation of therapy the patients were followed for 2 years using CT-control in 6, 12 and 24 months. The relapse of sarcoidosis was registered in 56 patients (group 1); no relapse - in 52 patients (group 2). The rate of relapses was assessed in association with 10 clinical factors. Significance of the differences between qualitative indices was calculated as (M ± m) and Student's t value was calculated. Pearson's chi-squared test and Fisher's exact test were used to analyze the rate of relapses in association with studied factors. Clinical phenotype model of the patient with relapsing pulmonary sarcoidosis was created. It updated the known literature data and confirmed previously demonstrated role of GCS-therapy as the risk factor for sarcoidosis relapses. The following factors correlated with higher rate of relapses: 1) use of GCS therapy; 2) slow developing clinical symptoms; 3) extrapulmonary lesions; 4) bronchoconstriction; 5) concomitant diseases. Clinical phenotype model of patients with relapsing pulmonary sarcoidosis should be complemented by radiological, immunological, biochemistry factors, associated with the risk of relapse, which requires further research.

In a recent research paper Dr. Suxing Jin et al. reported two multispecific PtIV complexes DNP and NP with non-steroidal anti-inflammatory drug naproxen (NPX) as the axial ligand(s). Herein, we clarify the mechanism of action of DNP, its therapeutic target and intracellular redox-status.

The spread of depressive disorders is extra high nowadays. Depressive disorders are widespread mental disorders in the structure of mental pathology, both causes of psychiatrists' visit, and causes of medical aid. The presence of depressive syndrome in patients with cardiovascular system leads to deterioration patient's condition and adaptive abilities and aggravates somatic abnormality. Adequate therapy causes their reduction, prevention of recurrence and decompansation of comorbid somatic pathology, and eliminates severe medical and prevents social consequences. The study of clinical aspects of depressive conditions which are accompanied with pathology is one of the direction not only psychiatric, but also common pharmacotherapeutic investigations. The aim of the investigation was to determine clinical, pharmacotherapeutic and biorhythmic peculiarities of depressive disorders in patients with comorbid cardiac pathology. And also assessment of efficacy of complex therapy based on chronotherapy principle was used. 50 patients (female patients) with depressive disorders were involved in this investigation. This was performed based on "Depressive disorders of organic genesis, characterized by somatic pathology" (F 06.35), "Somatoform disorder" of heart and cardiovascular system (F 45.30), "Mild depressive episode" (F 32.00), and also comorbid arterial hypertension confirmed by physician. Clinical, laboratory, clinical and psychopathological investigations using psychodiagnostic scales (scale HAMD-21, CGI-S, CGI-І) were used. Individual biorhythmic status was established and it requires medicamentous therapy. Comparing patients of both groups, it has been detected a group of patients in whom principles of chronotherapy, especially antihypertensive and antidepressive therapy were prescribed, dynamics of patient's improvement was better than in the investigated group where the principle of chronotherapy was observed.

Chronic generalized parodontitis is one of the most prevalent disorders among diseases of oral cavity, making the search for optimal treatment modalities of this disorder one of the mostressing matters to this day. The purpose of this study was to assess outcomes of conventional therapy and secondary prevention of chronic generalized parodontitis with in combination with use of laser therapy and antioxidant drug treatment. The study is presented as a joint multi-site investigation conducted by the group of authors from St. Petersburg and Saransk medical teaching and clinical institutions. The aim of the study was to improve the treatment and secondary prevention of chronic generalized parodontitis based on a pathogenetically substantiated scheme of laser and antioxidant therapy. The total of 98 patients (31 male and 67 female) aged 30-50 years) with the 3 to 10 year history of moderate chronic generalized parodontitis were selected for the prospective study. All patients were approximately equally divided into three groups according to the received treatment regimens: conventional treatment, laser therapy, and laser therapy with antioxidant medication. Several clinical indices were utilized for parodontal tissue assessment (PMA, SBI, AP), resistance of gingival capillary bed, osteal resorption. The lipid peroxide oxidation was determined by MDA, Fe2+ MDA and phospholipase A2. Additional implementation of laser and metabolic therapies sufficiently increases efficacy of conventional therapy and improves secondary prevention of chronic parodontitis. A marked decrease in structural-functional deviations and apparent recovery of microcirculatory vascular bed of parodontal tissue has been achieved. .

Human rotavirus (HRV) infection is a major cause of gastroenteritis in children worldwide. Broad-spectrum antibiotic-induced intestinal microbial imbalance and the ensuing immune-metabolic dysregulation contribute to the persistence of HRV diarrhea. Escherichia coli Nissle 1917 (EcN), a Gram-negative probiotic, was shown to be a potent immunostimulant and alleviated HRV-induced diarrhea in monocolonized gnotobiotic (Gn) piglets. Our goal was to determine how EcN modulates immune responses in ciprofloxacin (Cipro)-treated Gn piglets colonized with a defined commensal microbiota (DM) and challenged with virulent HRV (VirHRV). Cipro given in therapeutic doses for a short term reduced serum and intestinal total and HRV-specific antibody titers, while EcN treatment alleviated this effect. Similarly, EcN treatment increased the numbers of total immunoglobulin-secreting cells, HRV-specific antibody-secreting cells, activated antibody-forming cells, resting/memory antibody-forming B cells, and naive antibody-forming B cells in systemic and/or intestinal tissues. Decreased levels of proinflammatory but increased levels of immunoregulatory cytokines and increased frequencies of Toll-like receptor-expressing cells were evident in the EcN-treated VirHRV-challenged group. Moreover, EcN treatment increased the frequencies of T helper and T cytotoxic cells in systemic and/or intestinal tissues pre-VirHRV challenge and the frequencies of T helper cells, T cytotoxic cells, effector T cells, and T regulatory cells in systemic and/or intestinal tissues postchallenge. Moreover, EcN treatment increased the frequencies of systemic and mucosal conventional and plasmacytoid dendritic cells, respectively, and the frequencies of systemic natural killer cells. Our findings demonstrated that Cipro use altered immune responses of DM-colonized neonatal Gn pigs, while EcN supplementation rescued these immune parameters partially or completely. IMPORTANCE Rotavirus (RV) is a primary cause of malabsorptive diarrhea in children and is associated with significant morbidity and mortality, especially in developing countries. The use of antibiotics exacerbates intestinal microbial imbalance and results in the persistence of RV-induced diarrhea. Probiotics are now being used to treat enteric infections and ulcerative colitis. We showed previously that probiotics partially protected gnotobiotic (Gn) piglets against human RV (HRV) infection and decreased the severity of diarrhea by modulating immune responses. However, the interactions between antibiotic and probiotic treatments and HRV infection in the context of an established gut microbiota are poorly understood. In this study, we developed a Gn pig model to study antibiotic-probiotic-HRV interactions in the context of a defined commensal microbiota (DM) that mimics aspects of the infant gut microbiota. Our results provide valuable information that will contribute to the treatment of antibiotic- and/or HRV-induced diarrhea and may be applicable to other enteric infections in children.