Репозиторий Университета

© 2019, SPb RAACI. Inhibitory receptors CTLA-4 and PD-1 (immune checkpoints) play a key role in regulation of immune reactions. They suppress excessive immune response against pathogenic microbes and prevent autoimmune reactions. The immune checkpoints are targets of the modern effective therapy based on human and humanized monoclonal antibodies (ipilimumab and nivolumab, tremelimumab, pembrolizumab, etc). However, despite its high efficiency compared to standard chemotherapy, the therapy based on blocking immune check points is facing several problems, i.e., high therapy cost and severe negative autoimmune-related side effects. Unfortunately, this therapy helps to minority of the patients. Hence, further studies are required to improve its efficiency and safety, as well as to search for selection criteria of the patients who would benefit from the therapy. An appealing approach to reduce negative side effects from immune checkpoint inhibition is application of the blocking antibodies, aiming for ex vivo generation of patients’ activated immune cells for cancer therapy, thus avoiding systemic drug administration. Our aim was to elucidate influence of immune checkpoint blocking antibodies on the expression of CTLA-4 and PD-1 in such an in vitro model. First of all, we have determined quantities of lymphocyte receptors in peripheral blood of healthy volunteers, or cancer patients with disseminated melanoma. Moreover, we defined effect from the addition of antibodies against immune checkpoints on proportions of cells expressing CTLA-4 and PD-1 in the population of phytohemagglutinin-activated lymphocytes. Our study demonstrated that, in presence of antibodies to either of the two checkpoints during in vitro cell activation, the blockade of specific target receptor is accompanied by reduced number of cells positive for another checkpoint. Hence, the antibodies directed against PD-1 or CTLA-4 seem to suppress both negative signal cascades at once, if tested under such experimental conditions. Noteworthy, the response to blocking antibodies for different immune checkpoints varied for different donors. Our data may be used for development of effective combinations of lymphocyte activators and immune check-point inhibitors, for in vitro generation of activated lymphocytes applied for adoptive cancer therapy, as well as for prediction of possible responses to antibodies against CTLA-4 or PD-1, aiming to select the best personalized cancer immunotherapy.

© 2018 National Research University Higher School of Economics. All rights reserved. The aim of this study was to identify predictors of poor outcomes in patients hospitalized for severe acute exacerbation of COPD (AECOPD). Methods. This retrospective, observational cohort study was conducted in Pulmonology Department of a city hospital in 2015 - 2016 and involved patients hospitalized for severe AECOPD. Patients were divided according to outcomes. Poor outcomes included at least one of the followings: the need in invasive (IMV) or non-invasive (NIV) ventilation, admission to ICU, in-hospital death and COPD-related readmission during 2 months. Demographic, clinical, laboratory parameters, pulmonary function tests and blood gas analysis were analyzed; different multidimensional prognostic scores were also evaluated and compared. Results. Of 121 patients included, a poor outcome had occurred in 45 patients (37%). Among them, NIV was required in 21 (17%), IMV in 8 (6%), and admission to ICU in 16 patients (13%); death was registered in 6 patients (5%) and readmission in 27 (22%) of the patients. Patients with poor outcomes were admitted more frequently by ambulance (62% vs 40%; p = 0.003), more often were admitted to a hospital for AECOPD in the previous year (69% vs 45%; p = 0.0006), and had lower pH (p = 0.001), lower PaO2 (p = 0.001), higher PaCO2 (p = 0.001), and a worse score on several prognostic scales such as APACHE II (13.9 ± 5.4 vs 7.8 ± 3.6; p = 0.001), DECAF (2.4 ± 0.6 vs 1.5 ± 0.6; p = 0.001), BODEx (5.6 ± 1.8 vs 3.9 ± 1.1; p = 0.001), DOSE (2.9 ± 1.5 vs 2.2 ± 1.2; p = 0.029), and ADO (4.9 ± 1.5 vs 4.3 ± 1.3; p = 0.015) at admission. They more frequently received O2 therapy (87% vs 46%; p = 0.001) and had longer hospital stay (19.2 ± 6.2 days vs 12.5 ± 1.8 days; p = 0.001). Conclusions. Hypercapnia, hypoxemia and worse prognostic scores on admission predicted poor outcome in patients hospitalized for AECOPD during the previous year.

© 2018, Media Sphera Publishing Group. All rights reserved. Non-motor disturbances represented by sensory, affective, obsessive-compulsive disorders, cognitive dysfunction, sleep disturbances are often found in patients with dystonia and have a negative impact on their quality of life. The prevalence of sensory and affective disorders and sleep disturbances is above 50% in patients with cervical dystonia and is 25% in patients with blepharospasm, writing spasm; cognitive dysfunction is found in more than 25% of patients with focal dystonia. The relationship of nonmotor, in particular psychiatric disorders, with the impairment of social and everyday life and worsening of quality of life in whole was shown. Common pathophysiological mechanisms of non-motor disorders as well as approaches to treatment of these disorders are discussed. The authors present the results on the positive effect of botulinum toxin therapy that reduces cognitive dysfunction, sensory disorders and depressive syndrome. Non-medication treatment of non-motor disorders in patients with dystonia is considered.

© 2018 Media Sphera Publishing Group.All Rights Reserved. Aim. To evaluate the presence and the severity of the complaints (headache, dizziness, memory loss, concentration of attention, sleep disturbances, decreased mood, increased anxiety), the state of cognitive functions, emotional status and quality of night sleep in treatmentnaïve middle-aged patients with mild to moderate EAH compared to healthy volunteers of the same age. Materials and methods. 103 treatment-naïve patients with EAH aged 40-59 years at the enrollment, who met the inclusion/exclusion criteria and provided written informed consent (46 men, mean age 53.6±0.8 years) and 50 healthy volunteers (17 men, mean age 51.5±1.0 years) with normal blood pressure (BP) level - control group - were enrolled to the study. Mean EAH duration was 2.9±5.7 years. Cognitive assessment included Montreal cognitive assessment, 10-words learning task, verbal fluency test, TMT, Stroop color and word test. Anxiety and depression were evaluated via Hamilton rating scales (HARS and HDRS). 24-hours ambulatory BP monitoring (ABPM) was performed according to European guidelines. Results. 70% of patients with EAH complained of memory disturbance, 68% - lack of attention, 22% - sleep disturbances, 12% - dizziness, 9% - headache. It took statistically significant more time for patients with EAH to perform on TMT B (p<0.05), they had significantly higher TMT B - TMT A difference score (p<0.01) and lower mean MoCA score (p<0.05). Patients with EAH had significantly higher mean score in Hamilton anxiety (2.1±3.7) and depression (1.1±2.4) rating scales compared to controls (0.3±0.9 points, p<0.01 and 0.1±0.5 points, p<0.001, respectively). Patients with EAH who complained of sleep disturbances had low sleep quality (8.7±2.8 points). Among patients with EAH who complained about headaches 66.6% had episodic migraine and chronic tension type headache (33.4%). Those patients had a substantial impact of headache on life and daily living according to HIT-6 (mean score - 57.5±6.1). Only 2 patients out of 12 with complains about dizziness had benign paroxysmal positional vertigo and Ménière's disease. Conclusion. Complaints about memory dysfunction, lack of attention, sleep disturbances, less common - dizziness and headaches, are most typical in patients with EAH on the early stages of the disease. They differ from healthy volunteers of the same age by having cognitive impairment and higher anxiety and depression scores. Patients with EAH who complained about sleep disturbances had low sleep quality. Headache in patients with EAH was due to episodic migraine and tension type headache which had a negative impact on life and daily living.

© 2018 Medical Education. All rights reserved. The aim of the study was to investigate an efficacy of short-term treatment with acetazolamide (ACET) in patients with acute exacerbation of COPD (AECOPD) and noninvasive ventilation (NIV). Methods. This was a prospective case-control study. The study involved 20 patients. Inclusion criteria were as follows: AECOPD; pH > 7.33; PaCO2 > 48 mmHg; HCO3 - > 26 mmol/L; and treatment with NIV. Clinical characteristics, Charlson comorbidity index, APACHE II score, arterial blood gases, and serum electrolytes were recorded before inclusion. Patients were defined as cases when they had received ACET (500 mg per day) for 3 days; they were compared to a matched control group who did not receive ACET. Clinical parameters, arterial blood gases, serum electrolytes, potential adverse effects, and length of hospital stay were monitored daily. Results. No significant differences in baseline characteristics, comorbidities, or concomitant drugs used were found between the groups. Mean duration of hospital stay was significantly shorter in the ACET group (16.2 ± 8.4 days vs 19.1 ± 2.8 days; p = 0.023). An iIntra-group analysis showed a significant improvement in clinical and arterial blood gas parameters in both groups already in the first day of the treatment. In the ACET group, systolic blood pressure (SBP), respiratory rate (RR), and SpO2 significantly improved at day 4 (112.5 ± 4.9 mmHg vs 125 ± 7.1 mmHg (p = 0.001); 15.2 ± 1.1 min-1 vs 17.1 ± 0.9 min-1 (p = 0.001) and 94.7 ± 1.1% vs 92.3 ± 0.8% (p = 0.0001), respectively). There was a significant decrease in PaCO2, pH and HCO3- at day 3 (48 ± 3.8 mmHg vs 52.4 ± 5.3 mmHg (p = 0.0288); 7.374 ± 0.4 vs 7.502 ± 0.17 (p = 0.0015) and 26.4 ± 2.8 mmol/L vs 36.9 ± 4.1 mmol/L (p = 0.00001), respectively) and day 4 (44 ± 2.4 mmHg vs 48.4 ± 4.6 mmHg (p = 0.0115); 7.387 ± 0.02 vs 7.480 ± 0.02 (p = 0.00001) and 24.2 ± 2.1 mmol/L vs 35.6 ± 3.0 mmol/L (p = 0.00001), respectively) in the ACET group. No adverse events were recorded in both groups. Conclusions. ACET adjuvant to NIV appears to be effective and could prevent post-NIV alkalosis occurrence and could reduce the length of hospital stay in patients with AECOPD and mixed metabolic disorders (respiratory acidosis and metabolic alkalosis).

© 2018, Nizhny Novgorod State Medical Academy. All rights reserved. Persistent bronchial inflammation in chronic obstructive pulmonary disease (COPD) is considered the cause of ventilation disorders and related contamination with conditionally pathogenic microorganisms; the latter can proceed and transform into a full infection, which can aggravate and exacerbate COPD. The aim of the study was to evaluate the relations between the oropharyngeal microbiota in patients with COPD and the clinical, functional, and prognostic parameters of the disease. Materials and Methods. 64 patients with COPD were included in the study; the participants were scheduled to visit our clinic on two occasions. In the first visit, their medical history was studied in detail and the major examination procedures were conducted. Those included an assessment of the respiratory function, the 6-minute walk test, the degree of dyspnea by the Medical Research Council scale, body plethysmography, the diffusion capacity of the lungs, and a chest CT scan. The second visit took place 12 months after the first one to assess the changes in the course of the disease. The result was considered negative if, in the second examination, the patient‘s condition was found more severe. Oropharyngeal samples of all patients were sequenced to identify the V3–V4 variable sites of the 16S rRNA gene. Results. It is found that the microbiological oropharyngeal patterns in COPD patients depend on the source of micro-aspiration. In addition, the changes in the oropharyngeal microbiota correlate with the severity and prognosis of the disease, as well as the patient phenotype. Based on the data obtained by sequencing parts of the 16S rRNA gene, the role of oropharyngeal microbiota in determining the course and prognosis of COPD has been elucidated. Conclusion. The presented clinical and functional characteristics associated with oropharyngeal microbiota indicate that microaspirations from other body compartments not only affect the composition of oropharyngeal microbiota in patients with COPD but also have an important prognostic significance.

© Bionika Media Ltd. Different factors caused by both equipment and the course of surgery (conditions under which the operation is performed, the location of incision, the characteristics of suture material, the type of surgical suture, and the amount of blood loss), by the course of the postoperative period, and the peculiarities of repair of damaged tissues influence wound healing of the uterus during cesarean section. Objective. To establish the value of premature amniorrhea and uterine inertia as predictors of impaired myometrial repair after cesarean section, by using clinical and morphological analyses. Subjects and methods. The investigation enrolled 129 patients who had given birth via cesarean section. Of them, 44 patients had delivery before birth activity, 85 during the first stage of labor. 49 and 80 women delivered before and after amniorrhea, respectively. During cesarean section, uterine tissue was taken from the upper edge of the wound after uterine incision. The myometrial biopsy specimens obtained during cesarean section were morphologically and immunohistochemically examined. The patients were divided into 4 groups according to the level of birth activity and the preservation of amniotic fluid at the time of cesarean section. Group 1 included patients with regular labor activity and amniorrhea at the time of caesarean section; Group 2 consisted of those with labor activity in the presence of whole amniotic fluid; Group 3 comprised those without birth activity in the presence of whole amniotic fluid; Group 4 included patients with premature amniorrhea without uterine contractions. 36 cases (9 in each group) were selected by random sampling for morphological and immunohistochemical examinations. The biopsy specimens were fixed in 10% neutral formalin and embedded in paraffin. The serial paraffin-embedded sections underwent histological examination and immunohistochemical tests for the following markers: TGF-β, VEGF, MMP2, TIMP1, types I and III collagen, TNF, and PDGF. Results. The morphological and immunohistochemical analyses revealed the most pronounced signs of myometrial damage during cesarean section in Group 4 patients having premature amniorrhea without uterine contractions. There were decreased VEGF, PDGF, MMP2, and TIMP levels and simultaneously increased TNF-α expression in leiomyocytes, vascular endothelium, and myometrial stromal cells. The findings may indicate the relatively lower reparative potential of the myometrium and the increased readiness for an inflammatory response in the group of women undergoing cesarean section in the presence of premature amniorrhea without uterine contractions. Conclusion. Clinical, morphological, and immunohistochemical analyses have revealed differences in the myometrial status in relation to typical clinical factors, such as amniorrhea and birth activity. Wound healing occurs under the influence of growth factors and the ratio of expression levels for growth factors can vary in different pathological conditions. The reduced expression of VEGF, MMP2, TIMP, and PDGF and the increased expression of TNF in the group having amniorrhea without uterine contractions (P-B+) suggest that there are pronounced inflammatory processes and impaired myometrial repair with the longer latency period in the absence of labor activity, which may refer these women to a group at risk for incompetent scar formation.

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.

© 2018 Society for Industrial and Applied Mathematics. In this paper, we study a new numerical method for the solution of partial differential equations on evolving surfaces. The numerical method is built on the stabilized trace finite element method (TraceFEM) for the spatial discretization and finite differences for the time discretization. The TraceFEM uses a stationary background mesh, which can be chosen independent of time and the position of the surface. The stabilization ensures well-conditioning of the algebraic systems and defines a regular extension of the solution from the surface to its volumetric neighborhood. Having such an extension is essential for the numerical method to be well defined. The paper proves numerical stability and optimal order error estimates for the case of simplicial background meshes and finite element spaces of order m \geq 1. For the algebraic condition numbers of the resulting systems we prove estimates, which are independent of the position of the interface. The method allows that the surface and its evolution are given implicitly with the help of an indicator function. Results of numerical experiments for a set of 2D evolving surfaces are provided.

© 2018 Bentham Science Publishers. Patients with Parkinson’s disease (PD) are looking forward to new therapeutic strategies that may gradually decelerate the rate of neurodegenerative decline, associated with mobility restrictions and related morbidity. Its continuous neurodegenerative process, exacerbated by genetic mutations or environmental toxins, involves a progressive reduction in the dopamine neurotransmission levels, synaptic uptake density, oxidative glucose intake, deficient striatal lactate accumulation and chronic inflammation. Over the last decade, novel bioproducts have received considerable interest due to their unique potential of unifying nutritional, safety and therapeutic natural effects. Some nutraceuticals play a crucial role in the control of the signaling transduction pathways in neurotransmission and inflammation affected in PD, and some natural compounds can beneficially interact with each one of these biological mechanisms to slow down disease progression. Atremorine, a novel plant-derived nutraceutical, probably with a neuroprotective effect in the dopaminergic neurons of the substantia nigra (pars compacta), is a prototype of this new category of bioproducts with potential effects in PD. The major focus of this review will be on the current knowledge and biomedical investigation strategies through a plant-derived neuroprotective approach to improve life quality in PD patients, being of paramount importance for health providers, caregivers and the patients themselves.

© 2018 Russian Association of Endocrinologists. All rights reserved. The presented paper is a third revision of the clinical recommendations for the treatment of morbid obesity in adults. Morbid obesity is a condition with body mass index (BMI) ≥40 kg / m2 or a BMI ≥35 kg / m2 in the presence of serious complications associated with obesity. The recommendations provide data on the prevalence of obesity, its etiology and pathogenesis, as well as on associated complications. The necessary methods for laboratory and instrumental diagnosis of obesity are described in detail. In this revision of the recommendations, the staging of prescribing conservative and surgical methods for the treatment of obesity are determined. For the first time, a group of patients with obesity and type 2 diabetes mellitus is selected, in whom metabolic surgery allows a long-term improvement in the control of glycemia or remission of diabetes mellitus.