Репозиторий Университета

© Russian Association of Endocrinologists, 2018. BACKGROUND. Intensive glycaemic control in patients with type 1 diabetes may lead to hypoglycaemia and thus increase the risk of cardiovascular and cerebrovascular events. Platelet activation and/or decreased activity of physiological anticoagulants during hypoglycaemia may play a role in the development of cardiovascular or cerebrovascular complications. AIMS. To investigate induced platelet activity, the activity of physiological anticoagulants, and the von Wil-lebrand factor in patients with type 1 diabetes with the hyperinsulinaemic-hypoglycaemic clamp. MATERIALS AND METHODS. We examined 11 patients with type 1 diabetes without macro- and micro-vascular complications (6 males, 5 females, mean age 23.7 ± 5.6 years, A1C 9.7 ± 2.3%). Induced platelet aggregation, physiological anticoagulants (Protein S, Protein C, AT III) and the von Willebrand factor were studied at hyperglycaemic, euglycaemic, and hypoglycaemic stages during use of a hyperinsulinaemic (1 mU/kg/min) hypoglycaemic clamp. RESULTS. Platelet aggregation to all agonists increased significantly during the hypoglycaemic stage, compared with the euglycaemic or hyperglycaemic stages. There was no difference in platelet aggregation between the euglycaemic and hyperglycaemic stages. Platelet aggregation to all agonists increased during the hypoglycaemic stage compared with the hyperglycaemic period: thrombin-23.9%, ADP-30.6%, arachidonic acid-30.9%, collagen-69.4% and ristocetin-70.8%. During hypoglycaemia aggregation to ADP, arachidonic acid and collagen remained within normal limits (upper quartile); aggregation to thrombin was significantly above normal limits and aggregation to ristocetin remained significantly below lower limits. Protein S activity was significantly increased during hypoglycaemia compared with euglycaemia (p = 0.046) and hyperglycaemia (p = 0.046). Antithrombin-III activity decreased significantly at the euglycaemic and hypoglycaemic stages, compared with the hyperglycaemic period, but still remained significantly elevated above the upper threshold. Protein C and vWf activity did not change significantly. CONCLUSIONS. In patients with type 1 diabetes platelet aggregation and protein S activity increases significantly at the hypoglycaemic stage of the hyperinsulinaemic-hypoglycaemic clamp. Platelet activation is directly caused by hypoglycaemia and not by decreasing glucose levels. Increased protein S activity is a compensatory response to platelet activation.

© 2018 Ima-Press Publishing House. All rights reserved. Cognitive impairment (CI) is a basis for the clinical presentation of chronic cerebral ischemia (CCI). However, the role of the mechanisms of inflammation and angiogenesis in the origin of CI is unclear, as is its relationship to the number and localization of foci during a neuroimaging examination. Objective: to investigate the relationship between the presence of CI, focal brain tissue changes, and the plasma and serum levels of vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1) in patients with CCI. Patients and methods. Examinations were made in 59 patients with CCI and in 20 apparently healthy individuals. The investigators evaluated the cognitive status using the Mini-Mental State Examination (MMSE) and the clock drawing test), performed brain magnetic resonance imaging (MRI), duplex scanning of cerebral vessels, and determined laboratory indicators: the serum levels of MCP-1 and C-reactive protein, and the serum and plasma concentrations of VEGF. Results. The patients with CI were found to have higher values of inflammatory markers, lower serum and plasma concentrations of angiogenic factors, and a greater number of focal changes on MRI than those without CI (5.06±0.23 and 2.36±0.3 scores, respectively; p(0.05). Imbalance of angiogenic and antiangiogenic factors can cause disease progression and moderate vascular CI in patients with CCI.

The paper deals with the mechanisms of a T-cell immune response, which depends on the balance between costimula-tory and coinhibitory signals that have been called as immune checkpoints (ICP). The imbalance of T-cell activation within ICTs (CTLA4/CD28 and PD1/PD1L) is considered to be a fundamental mechanism not only of autoimmune disease, but also impaired antitumor immunity underlying the development of malignant tumors. The use of monoclonal antibodies against negative regulatory ICTs (CTLA4, PD1, and PD1L) is a major achievement in the treatment of malignant neoplasms in the early 21st century. However, since CTLA4 and PD1 control the activation of auto-reactive T cells, the inhibition of these ICTs is associated with the development of autoimmune disease that is defined as immune-mediated adverse even. The paper considers the clinical manifestations of IMAR, primarily rheumatic ones and discusses the prospects of pharmacotherapy from the standpoint of achievements of modern rheumatology.

© Bionika Media Ltd. Background. Ovarian cancer develops from benign tumors in 80% of cases during long-term follow-up. According to the literature, the incidence of giant ovarian cystadenoma is extremely low. There are difficulties in verifying these ovarian tumors. Description. The paper describes a rare clinical case of a 54-year-old patient with giant ovarian cystadenoma. It depicts the patient’s clinical, medical history, laboratory, and instrumental data and demonstrates the technical complexities of surgery and the features of postoperative management. Conclusion. The early diagnosis and timely treatment of ovarian tumors will be able to avoid technically difficult surgical interventions and to minimize postoperative complications, which will substantially improve the prognosis of the disease. Such operations should be performed by a surgeon having extensive surgical experience and high qualification.

© 2018, SPb RAACI Search for novel prognostic criteria predicting successful in vitro fertilization remains a nonresolved problem at the present time. The aim of our study was to analyse a predictive role of IL-1? as an additional marker of pregnancy after in vitro fertilization (IVF). The study included 120 women with tubo-peritoneal infertility subjected to the IVF procedure. Retrospectively, two groups were formed of this cohort, dependent on efficiency of in vitro fertilization. Group I included 40 women with successful pregnancy whereas group II comprised 80 women with failed pregnancy. IL-1? concentrations in serum were detected by ELISA technique. A polymorphic rs1800587 marker at 5`UTR region has been amplified by PCR followed by Sanger sequencing. We have shown IL-1? hyperproduction in the women from group I. The women with effective IVF outcome exhibited positive correlation between IL-1? and luteinizing hormone, prolactin, progesterone, 17-hydroxyprogesterone, dehydroepiandrosterone sulfate levels. The women with ineffective in vitro fertilization have detected a negative correlation between IL-1? levels and anti-Muellerian hormone, a positive correlation of IL-1? with 17-hydroxyprogesterone. The women with T allele of the polymorphic rs1800587 marker at 5`UTR region have shown a 2.5-fold higher chance to become pregnant after IVF than the women carrying C allele (95% CI = [1.45-4.35], ? = 0.0009). The women with T/T genotype exhibited a positive correlation between IL-1? and estradiol, testosterone; the subjects with heterozygous C/T genotype showed correlation with estradiol, and those harboring C/C genotype exhibited correlation with follicle-stimulating hormone. The revealed changes suggest a potential involvement of IL-1? into regulation of cyclic processes in the ovary including ovulation. Moreover, IL-1? may participate in formation of pro-inflammatory environment for successful blastocyst implantation.

© 2018 Sychev et al. Background: Non-vitamin K oral anticoagulants (NOACs) are commonly used for prophylaxis of venous thromboembolism (VTE) in orthopedic patients. Despite known safety and high potency of NOACs, potential interactions of NOACs with genetic polymorphisms are poorly understood. Dabigatran etexilate is one of the most commonly prescribed direct thrombin inhibitors for the prevention of VTE. The objectives of this study were to assess the effect of ABCB1 (rs1045642 and rs4148738) and CES1 (rs2244613) polymorphisms on dabigatran pharmacokinetics in patients after total knee arthroplasty. Patients and methods: A total of 60 patients, aged 37–81 years, who underwent surgery for knee replacement have been included in the study. VTE prophylaxis was conducted via administration of dabigatran etexilate 220 mg once daily. Genotyping for carrier state of polymorphic variants such as rs1045642 and rs4148738 of the ABCB1 gene and rs2244613 of the CES1 gene was carried out using real-time polymerase chain reaction (PCR). We also measured the peak and trough concentrations of plasma dabigatran by using high-performance liquid chromatography (HPLC). Results: Our study revealed that TT genotype of rs1045642 polymorphism of the ABCB1 gene was associated with higher dabigatran equilibrium peak concentrations and the higher risk of bleeding than the presence of CC genotype (p<0.008). There was no statistically significant genotype-dependent difference in the trough concentrations between rs1045642 and rs4148738 of the ABCB1 gene and rs2244613 of the CES1 gene. Conclusion: Our findings indicate that the polymorphisms of ABCB1 rs1045642 may have a prominent contribution to the safety of dabigatran in patients after knee surgery. Moreover, TT genotype may be associated with the higher risk of hemorrhagic complications in this population. There were no influence of polymorphism of ABCB1 rs4148738 and CES1 rs2244613 on dabigatran peak and through concentrations. Larger studies are needed to confirm our observations.

© 2018, Pediatria Ltd.. All rights reserved.  Objective of the research – to reveal the correlation between neurochemical criteria in the neonatal period and the consequences of severe hypoxic hemorrhagic CNS lesions in children according to catamnesis data. Materials and methods: researchers analyzed 54 cases of newborns of different gestational age (GA) that were in the ICU after birth due to severe condition; all newborns had combined hypoxic hemorrhagic brain lesion detected by neurosonography – periventricular leukomalacia (PVL) and intraventricular hemorrhage (IVH) of various severity. Catamnesis follow-up was performed up to 2–2,5 years of age. The control group consisted of 20 newborns, comparable in GA, body weight at birth, with an Apgar score of at least 6 points in the 1st minute of life and without changes in neurosonography. In the neonatal period, serum concentrations of S100, BDNF, VEGF, ALCAM, DR5 were studied in dynamics using the quantitative ELISA (Enzyme Linked Immuno Sorbent Assay) according to a standard protocol. Results: the concentration of factors contributing to destructive changes in tissues (S100, DR5, ALCAM) in the serum, was in inverse correlation with the level of VEGF and BDNF. The latter had a direct correlation relationship. VEGF directly correlated with CNTF by the end of the 2 nd week of life. Results of catamnesis follow-up: 43 children diagnosed with cerebral palsy, 25 with spastic diplegia, 18 with spastic tetraparesis, and 11 without evident motor disorders. In 28 children I–III level of motor disorders was determined according to GMFS, in 26 children – IV–V level. At the age of 2 years, all children underwent MRI of the brain and gliio-atrophic changes were detected. Significant differences in the implementation of neurological consequences were found between the number of children with grade I and II IVH and PVL and III–IV degree IVH and PVL. Conclusion: children with PVL and IVH III–IV degree have a high risk of severe neurological outcomes – spastic tetraparesis, impaired motor activity by GMFS IV–V level, mental retardation and symptomatic epilepsy.

© The Author(s) 2018. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. Vitamin B12 (B-12) deficiency is still relatively common in low-, medium-, and high-income countries, mainly because of dietary inadequacy and, to a lesser extent, malabsorption. This narrative review is based on a systematic search of evidence on methods to assess B-12 bioavailability and technologies to enhance its absorption. A total of 2523 scientific articles identified in PubMed and 1572 patents identified in Orbit Intelligence were prescreened. Among the reviewed methods, Schilling's test and/or its food-based version (using cobalamin-labeled egg yolk) were used for decades but have been discontinued, largely because they required radioactive cobalt. The qualitative CobaSorb test, based on changes in circulating holo-transcobalamin before and after B-12 administration, and the14C-labeled B-12 test for quantitative measurement of absorption of a low-dose radioactive tracer are currently the best available methods. Various forms of B-12 co-formulated with chemical enhancers (ie, salcaprozate sodium, 8-amino caprylate) or supplied via biotechnological methods (ie, microbiological techniques, plant cells expressing cobalamin binding proteins), encapsulation techniques (ie, emulsions, use of chitosan particles), and alternative routes of administration (ie, intranasal, transdermal administration) were identified as potential technologies to enhance B-12 absorption in humans. However, in most cases the evidence of absorption enhancement is limited.

© 2018, Media Sphera Publishing Group. All rights reserved. Hereditary thrombophilias (HT) and undifferentiated connective tissue dysplasia (uCTD) are important causes of female infertility. Moreover, there are signs of their common pathogenesis: a number of proteins, such as PAI-1, play an important role in the pathogenesis of both conditions, as well as in the development of infertility in patients with HT and uCTD Objective — to determine the morphological substrate and molecular mechanisms of impaired pregnancy outcomes in women with uCTD and HT. Subject and methods. A study group included 130 reproductive-aged female patients with primary infertility and a control group consisted of 11 patients (surrogate mothers). An endometrial pipelle biopsy sample was taken from each patient on days 6—8 after ovulation according to the ultrasound findings. The study group patients were divided into subgroups: 1A) infertility and HT (n=91); 1B) infertility, NT, and uCTD (n=19); 1C) infertility and uCTD (n=20). The investigators examined obstetric/gynecological history data, determined the levels of PAI-1 and homocysteine in the blood samples of patients in the subgroups with HT (1A and 1B); assessed the results of the methionine test, and identified the polymorphism or mutations of the following genes: FII, FV (Leiden), FVII, FXII, FXIII, GpIa, GpIb (-5), GpIb (T145M), GpIIIa, PAI-1, FBGb, MTHFR, MTRR, MTR, SLC19A1, angiotensin gene (M235T and T145M), angiotensin-converting enzyme, and their homo-or heterozygosity. Endometrial morphological and immunohistochemical examinations were carried out using primary antibodies to sex hormone receptors, LIF, PAI-1, and osteopontin. Results. The number of pregnancies in the study group was comparable to the number of patients in each subgroup. Childbirth was considered to be a favorable pregnancy outcome; missed miscarriage was an unfavorable one. There were the most favorable outcomes in Subgroup 1C with uCTD and the least one in Subgroup 1B. Comparison of hemostatic system indicators revealed statistically significant differences only in the incidence of disaggregated thrombopathy (88% in Group 1B and 55% in Group 1A). In the endometrium of the study group, there was delayed maturation; sclerotic foci and dyscirculatory disorders were more frequent in the stroma. Conclusion. In HT, uCTD, and, to a greater extent, its concurrence, a genetically determined predisposition to impaired implantation develops due to genetically determined endometrial remodeling that leads to infertility and impaired pregnancy outcomes.

© 2018 Bentham Science Publishers. The burden of cardiovascular and metabolic diseases is increasing with every year. Although the management of these conditions has improved greatly over the years, it is still far from perfect. With all of this in mind, there is a need for new methods of prophylaxis and treatment. Coenzyme Q10 (CoQ10) is an essential compound of the human body. There is growing evidence that CoQ10 is tightly linked to cardiometabolic disorders. Its supplementation can be useful in a variety of chronic and acute disorders. This review analyses the role of CoQ10 in hypertension, ischemic heart disease, myocardial infarction, heart failure, viral myocarditis, cardiomyopathies, cardiac toxicity, dyslipidemia, obesity, type 2 diabetes mellitus, metabolic syndrome, cardiac procedures and resuscitation.

© 2018, Media Sphera Publishing Group. All Rights Reserved. Mutant forms of the gene IDH1 progress significantly slower, have a lower risk of neoplastic transformation, and generally, mutations of this gene have a pronounced anti-oncogenic effect. At the same time, almost all mutations are quite stereotyped (98,9%) and occur in the same region of the gene — R132H mutations. IDH1 gene mutations is a complex multi-layered process, which is a completely new, not previously described anti-oncogene activation mechanism of intracellular protection. The reason that there is a mutation in the tumor cells is associated with de novo blocking differentiation processes and development of brain cells in the development process, as evidenced by severe cerebral hypoplasia in patients with congenital forms of this mutation. A completely new mechanism of antitumor protection has been described — stereotypical IDH1 gene mutation is a gene, in fact, is a key event, causing a cascade of further anti-oncogenic mechanisms in brain gliomas.

© 2018 Ima-Press Publishing House. All rights reserved. Anxiety disorders are an important biomedical problem due to the high prevalence and significant negative impact on the quality of life and the course of concomitant somatic and neurological diseases. Cognitive impairment (CI) is one of the most intensively studied aspects of pathological anxiety. Impairments in attention, executive functions, memory, cognitive deficit, as well as abnormal cognitions and metacognitions are identified in anxiety disorders. Moreover, the treatment of the latter with the most frequently used drugs (antidepressants, atypical antipsychotics, anticonvulsants, tranquilizers) does not lead to a significant improvement in cognitive functions, and often contributes to their worsening. In this connection, in addition to psychotherapy, cognitive function-improving agents play a large role in treating anxiety diseases associated with cognitive dysfunction. Ginkgo Biloba extract (EGb 761, Tanakan®) that positively affects cognitive functions, especially in the domains of memory, concentration and attention deserves special attention.

© 2018, Bionika Media Ltd. All rights reserved. Objective. To investigate the signs of neoplastic transformation of the epithelium in the foci of ovarian endometriosis (OE). Material and methods. Histological and immunohistochemical examinations were used to study 78 and 35 OE cases, respectively, and 8 adenocarcinomas. Anti-Ki-67, anti-Bcl-2, anti-p53, and anti-hepatocyte nuclear factor-1β (HNF-1s) antibodies were employed. Results. The epithelium of endometrioid cyst walls showed papillary syncytial changes (39.7%), metaplasia with clear cytoplasm сells (15.4%), and epithelial atypia with a low-to-relatively low Ki-67 and Bcl-2 expression and with a low p53 expression (41.0%). The expression of HNF-1β in the foci with and without atypia was revealed in 94.7 and 56.3% of cases, respectively; it was detected only in clear cell adenocarcinomas. Conclusion. HNF-1s hyperexpression suggests the adaptive nature and histogenetic relationship of OE to clear cell tumors of the ovary.

© ISUCT Publishing. Macrolide antibiotics represent a valuable class of broad-spectrum, high active natural compounds with polyketide structure. A well-known FOF1 ATP-synthase inhibitor,[1] namely oligomycin A (1), is a 26-membered α,β-unsaturatedpolyketide lactone with conjugated diene, fused to spiroketal moiety. Oligomycin A possesses strong antifungal, antiactinomycotic and cytotoxic activity, but lacks antibacterial activity. According to recent investigations, the development of anti-cancer drugs based on oligomycin A is quite perspective due to its high cytotoxic activity toward tumor cells, ability to inhibit a multidrug resistance protein p-gp and to prevent an activation of oncogenic K-Ras by inhibition of its localization at the plasma membrane.[2-4] However, high toxicity for mammalian cells and low water solubility are significant limitations of oligomycin A, making it unacceptable for clinical application. Chemical modification is a promising way to improve pharmacological properties of natural compounds. Recently we have found that site-selective modifications of oligomycin A afforded semi-synthetic derivatives with high antiproliferative activity against tumor cell lines[5-7] or selective antifungal activity against Candida spp.[8] and, at the same time, with lower toxicity toward mammalian cells. Also, semi-synthetic oligomycin A derivatives are useful tools for molecular genetic studies of additional targets for this family of antibiotics.[9,10] Previously Ramirez F. et al. have described the reaction of oligomycins with sodium borohydride resulting in mixture of diastereomeric 7-dihydro-and 7,11-tetrahydro derivatives without further separation and characterization of individual products.[11] Also, there is no data on biological activity of these reduced oligomycins against fungal/actinomycetes strains and tumor cell lines in article mentioned above. Thus, in this paper we report regio-and stereoselective methods for borohydride reduction of oligomycin A, structure determination of obtained derivatives and investigation of theirs antiproliferative, antifungal and antiactinomycotic properties. The feasibility of regio-and stereoselective reduction of C7-carbonyl group in a core structure of oligomycin A was proposed due to the presence of haptophilic hydroxyl groups[12] at C5 and C9 positions and sterical hindrance of C-11 carbonyl group. Actually, treatment of oligomycin A with bulky sodium triacetoxyborohydride in acetic acid according to the method[13] led to (7S)-dihydrooligomycin A (2) in a good yield. The second carbonyl group (C-11) reduced in more harsh conditions: only the extended treatment of (7S)-dihydrooligomycin A with sodium borohydride in ethanol give (7S,11R)-7,11-tetrahydrooligomycin A (3) as major product. Reaction proceeds with acceptable stere-oselectivity and gives tetrahydro derivative 3, but in low yield (35 %), which associated with low stability of oligomycins in basic conditions.[14] Structure of compounds 2 and 3 was confirmed by high resolution mass spectrometry (HRMS ESI) and NMR spectroscopy. Absolute configurations at C7 and C11 positions of obtained derivatives were unambiguously confirmed by observed interactions between neighboring protons in corresponding1H-1H ROESY spectra. Testing of antimicrobial properties of oligomycins 2 and 3 against Candida spp., filamentous fungi and S. fradiae (strain, extremely sensitive to oligomycins) that of the parent antibiotic in comparison with starting oligomycin A revealed that reduction of carbonyl groups led to decreasing of activity (except strain M. canis). Also, reduced derivatives 2, 3 were less potent against human colon carcinoma cell line HCT116 and its doxorubicin-resistant subline HCT116(-/-), while activity against leukemia cell line K562 and doxorubicin-resistant subline K562/4 retained at the same level as for 1. It might be pointed that biological properties of (7S)-dihydrooligomycin A and (7S,11R)-7,11-tetrahydrooligomycin A are quite similar, consequently C7-carbonyl group has a greater influence on biological activity of oligomycin A than C-11 carbonyl group.

© 2018 Media Sphera Publishing Group. All rights reserved. Objective. To clarify the association between HLA-DRB1 and TNFα (-308G>A) genes polymorphism and joint destruction/further progression during 12 months of the follow-up period (FUP) in patients with early (<6 months), active, predominantly antibodies to cyclic citrullinated peptide (ACCP) and rheumatoid factor (RF)-positive rheumatoid arthritis (RA) treated according to "Treat to target" strategy. Materials and Methods. The study included 85 patients with early RA and duration of symptoms <6 months. All patients were initially assigned to subcutaneous methotrexate (MTX) with rapid dose escalation to 20-25 mg/week. Combination MTX + biological therapy, mainly adalimumab, was used when MTX was ineffective. Joint destruction was assessed by Sharp-Van der Heijde modification scoring method at baseline and after 12 months FUP. Real time polymerase chain reaction (PCR-RT) was used for TNFα gene polymorphism (-308G>A) genotyping. Low resolution PCR-RT with subsequent sequence-based typing of ∗04 were performed to study HLA-DRB1 gene polymorphism. The HLA-DRB1∗01, ∗04:01, ∗04:04, ∗04:05, ∗04:08, ∗10 alleles were categorized as SE+ (Shared Epitope) alleles. Results. As for TNFα gene polymorphism, it was demonstrated that the number of narrowings and total Sharp score values were almost twice as high at baseline in GG genotype carriers as compared to GA genotype carriers (ρ<0,005, and ρ<0,004 respectively). Similar association was found after 12mo FUP. The progression of joint destruction, assessed as the change (Δ) in the number of erosions, joint space narrowings and the total score, was statistically significantly associated with HLA-DRB1∗(SE) genotypes: The carriers of SE (SE+/SE+) double-dose had more advanced progression as compared to (SE+/SE-)/(SE-/SE-) carriers (ρ<0,028, ρ<0,019, ρ<0,035 respectively). Conclusion. Our data suggest that HLA-DRB1 (SE+) gene and TNFα (-308G>A) polymorphisms are associated with the progression of radiographic joint destruction in early, active RA patients managed according to "Treat to target" stratagy.

[This corrects the article DOI: 10.3389/fimmu.2018.02515.].

Copyright © 2017 by the Research Society on Alcoholism Background: Animal studies showed that alcoholic myopathy is characterized by the reduction in myofiber cross-sectional area (CSA) and by impaired anabolic signaling. The goal of this study was to compare changes in CSA and fiber type composition with modifications in anabolic and catabolic signaling pathways at the early stages of alcohol misuse in humans. Methods: Skeletal muscle samples from 7 male patients with chronic alcohol abuse (AL; 47.7 ± 2.0 years old; alcohol misuse duration 7.7 ± 0.6 years) were compared with muscle from a control group of 7 healthy men (C; 39.7 ± 5.0 years old). Biopsies from vastus lateralis muscles were taken and analyzed for the changes in fiber type composition, fiber CSA, and for the alterations in anabolic and catabolic signaling pathways. Results: AL patients did not have detectable clinical myopathy symptoms or muscle fiber atrophy, but the relative proportion of fast fibers was increased. There was a significant decrease in IGF-1 in plasma and IRS-1 protein content in muscle of AL group. Levels of total and phosphorylated p70S6K1, GSK3β, and p90RSK1 were not different between AL and C groups. Muscle of AL patients had increased mRNA expression of HSP70 and HSP90. A marker of anabolic pathway p-4E-BP1 was decreased, while catabolic markers (MuRF-1, MAFbx, ubiquitinated proteins) were increased in AL patients when compared with C group. Conclusions: At the early stages of alcohol misuse in humans, changes in the regulation of anabolic and catabolic signaling pathways precede the development of skeletal muscle atrophy and manifestation of clinical symptoms of alcoholic myopathy.

© 2018 Media Sphera Publishing Group. All rights reserved. Purpose: to analyze possible associations of clinical and genetic factors with development of ischemic stroke after exacerbation of ischemic heart disease (IHD). Materials and methods: The Russian multicenter study aimed at assessment of risk of unfavorable outcomes after exacerbation of IHD "Exacerbation of IHD: logical probabilistic ways to course prognostication for optimization of treatment" (meaning of Cyrillic acronym-oracle) was conducted in 16 centers of 7 cities in Russia. We included into the study 1 208 patients with unstable angina and ST-elevation or non-ST-elevation myocardial infarction (MI). Data on outcomes were known for 1 193 patients, 15 patients were lost for follow-up. Results. Mean duration of follow-up was 64414.45 (4-1 995) days. Shortest, longest, and mean time before development of stroke was 22, 1433 and 38956.6 days after inclusion. Patients with strokes were older, more often had history of IHD prior to index hospitalization, arterial blood pressure level compatible with stage 3 arterial hypertension, less often were smokers, and more often had MI recurrences or repetitive episodes of severe ischemia during the index hospitalization. Patients also more often had documented atrial fibrillation during hospitalization, and lower level of glomerular filtration rate. Of studied genetic markers carriage of A allele of polymorphic marker G (-1082) A of interleukin-10 gene was significantly associated with risk of stroke development. Using linear regression analysis, we constructed a model of estimation of the stroke development risk. Comparison of diagnostic value of different scales for stroke risk assessment showed that area under the curve was 0.656, 0.686, and 0.756 for the GRACE, CHA2DS2-VASc, and ORACLE scores, respectively.

Human B-cell receptor-associated protein BAP31 (HsBAP31) is the endoplasmic reticulum-resident protein involved in protein sorting and transport as well as pro-apoptotic signaling. Plant orthologs of HsBAP31 termed 'plant BAP-like proteins' (PBL proteins) have thus far remained unstudied. Recently, the PBL protein from Nicotiana tabacum (NtPBL) was identified as an interactor of Nt-4/1, a plant protein known to interact with plant virus movement proteins and affect the long-distance transport of potato spindle tuber viroid (PSTVd) via the phloem. Here, we have compared the sequences of PBL proteins and studied the biochemical properties of NtPBL. Analysis of a number of fully sequenced plant genomes revealed that PBL-encoding genes represent a small multigene family with up to six members per genome. Two conserved motifs were identified in the C-terminal region of PBL proteins. The NtPBL C-terminal hydrophilic region (NtPBL-C) was expressed in bacterial cells, purified, and used for analysis of its RNA binding properties in vitro. In gel shift experiments, NtPBL-C was found to bind several tested RNAs, showing the most efficient binding to microRNA precursors (pre-miRNA) and less efficient interaction with PSTVd. Mutational analysis suggested that NtPBL-C has a composite RNA-binding site, with two conserved lysine residues in the most C-terminal protein region being involved in binding of pre-miRNA but not PSTVd RNA. Virus-mediated transient expression of NtPBL-C in plants resulted in stunting and leaf malformation, developmental abnormalities similar to those described previously for blockage of miRNA biogenesis/function. We hypothesize that the NtPBL protein represents a previously undiscovered component of the miRNA pathway.

Marine sponges contain a variety of low-molecular-weight compounds including guanidine alkaloids possessing different biological activities. Monanchomycalin B and urupocidin A were isolated from the marine sponge Monanchora pulchra. We found that they act as inhibitors of the TRPV1, TRPV2, and TRPV3 channels, but are inactive against the TRPA1 receptor. Monanchomycalin B is the most active among all published marine alkaloids (EC50 6.02, 2.84, and 3.25 μM for TRPV1, TRPV2, and TRPV3, correspondingly). Moreover, monanchomycalin B and urupocidin A are the first samples of marine alkaloids affecting the TRPV2 receptor. Two semi-synthetic urupocidin A derivatives were also obtained and tested against TRP (Transient Receptor Potential) receptors that allowed us to collect some data concerning the structure-activity relationship in this series of compounds. We showed that the removal of one of three side chains or double bonds in the other side chains in urupocidin A led to a decrease of the inhibitory activities. New ligands specific to the TRPV subfamily may be useful for the design of medicines as in the study of TRP channels biology.