Xenon Antiaggregant Effects.

In in vitro model of short-term therapeutic inhalation of Xe/O2 mixture, xenon in millimolar concentrations led to a pronounced decrease in induced platelet aggregation in the platelet-enriched blood plasma. The maximum and statistically significant decrease occurred in response to induction by collagen (by ≈30%, p≤0.01) and ADP (by ≈25%, p≤0.01). A slightly weaker but statistically significant reduction in aggregation appeared in response to ristocetin (by ≈12%, p≤0.01) and epinephrine (by ≈9%, p≤0.01). It should be noted that the spontaneous aggregation exceeded the reference values in the control group. Nevertheless, even at minimal absolute values, spontaneous platelet aggregation decreased by 2 times in response to xenon (p≤0.01). The reasons for the decrease of spontaneous and induced aggregation are xenon accumulation in the lipid bilayer of the membrane with subsequent nonspecific (mechanical) disassociation of membrane platelet structures and specific block of its distinct from neuronal NMDA receptor.

Effect of Xe/O2 Inhalation on Hemostasis in Experimental Thromboplastin Pneumonitis.

We studied the effectiveness of Xe/O2 mixture inhalation (30% Xe and 70% O2, 20 min for 5 days) in a model of experimental thromboplastin pneumonitis. Inhalation of the studied mixture decreased the intensity of the inflammatory process in the lung tissue assessed by the temperature response of animals, changed lung weight and lung weight coefficient. At acute stage of pneumonitis, an increase in xenon consumption was recorded due to its retention in the gas exchange zone and a natural decrease in oxygen consumption due to partial alveolar/capillary block. The formation of pneumonitis was accompanied by a pronounced procoagulant shift in the regulation system of the aggregate state of blood. The Xe/O2 inhalations ensured physiologically optimal levels of prothrombin and activated partial thromboplastin time against the background of a moderate decrease in fibrinogen level throughout the experiment. At the same time, the activity of the natural anticoagulant antithrombin III increased from day 5 to day 14.

[Expression of immune checkpoints PD-L1, CTLA4, LAG3 in the microenvironment of colon adenocarcinoma depending on MMR status]. / Ekspressiya immunnykh kontrol'nykh tochek PD-L1, CTLA4, LAG3 v mikrookruzhenii adenokartsinomy tolstoi kishki v zavisimosti ot MMR-statusa.

OBJECTIVE: Study of the features of expression of immune checkpoint proteins PD-L1, CTLA4 and LAG3 in the microenvironment of colon adenocarcinoma depending on MMR status. MATERIAL AND METHODS: The study group consisted of 32 patients with a morphologically confirmed diagnosis of colon cancer; all of them underwent surgical treatment in the form of hemicolonectomy or resection. The work assessed samples of tumor tissue obtained as a result of surgery, the study was carried out in 3 stages: morphological examination of histological slides of colon tumors at the light-optical level, immunohistochemistry examination of tumor samples to determine the dMMR/pMMR status of carcinoma using a panel of antibodies to proteins of the unpaired nucleotide repair system MLH1, MSH2, MSH6 and PMS2, multiplex analysis of PD-L1, CTLA4, LAG3, CD3+, CD8+, CD163+ markers using the Vectra 3.0.3 tissue scanning system (Perkin Elmer, USA). RESULTS: Significant differences in the expression of PD-L1, CTLA4, LAG3 in the area of the invasive tumor margin were revealed between the dMMR and pMMR groups of colon adenocarcinomas in patients comparable in clinical and morphological characteristics and treatment. In the group of tumors with dMMR status, an increase in the expression of all studied markers was noted. The number of CD3+ TILs was also significantly higher in the invasive margin of tumors with dMMR status. Similarly, in this group of colon carcinomas, a large number of CD163+ macrophages were noted both in the center and in the invasive margin zone. No statistically significant differences were found in the expression of immune checkpoints and the composition of TILs in the central zone of tumors with different MMR status. CONCLUSION: A study using multiplex immunohistochemical analysis showed that MMR-deficient colon adenocarcinomas are characterized by more pronounced immune infiltration and increased expression of immune checkpoints in microenvironmental cells, mainly in the area of invasive tumor growth. The data obtained may be important for understanding the mechanisms of immune-mediated control of tumor growth and the choice of immunotherapy tactics depending on MMR status.

Xenon-Induced Effects in Relieving Experimental Acute Respiratory Distress Syndrome.

The effects of inhalations of an oxygen-xenon (70%/30%) mixture were studied in two models of acute respiratory distress syndrome caused by intratracheal administration of 0.5 mg/kg LPS or 0.04 ml acidin-pepsin (pH 1.2). Inhalation of the oxygen-xenon mixture inhibited the development and reduced the intensity of the inflammatory process in the lung tissue, which was assessed by the dynamics of lung weight and body weight of animals: the therapeutic exposure decreased both parameters. It was found that the thrombogenic stimulus, pathognomonic for the development of acute respiratory distress syndrome, decreased under the effect of oxygen-xenon inhalations, while the level of natural anticoagulant antithrombin III increased.

Xenon-Induced Recovery of Functional Activity of Pulmonary Surfactant (In Silico Study).

To understand the nature of xenon-induced recovery of the functional activity of pulmonary surfactant during inhalation of a gas mixture of Xe/O2, the mechanisms of the ongoing processes were studied in silico. Impaired ability of pulmonary surfactant to maintain low surface tension preventing alveolar atelectasis occurs due to formation of aggregates of its phospholipids and a decrease in their lateral mobility. Aggregated lipid systems, whose structure can explain the loss of lateral mobility of surfactant phospholipids, were modeled in silico at the molecular level. Changes in the Gibbs energy and enthalpy in the reactions of the formation and decomposition of xenon intermediates with model systems of various compositions/structures were calculated. The simulation was carried out for atomic xenon and for xenon polarized by molecular oxygen in the gas phase and taking into account solvation with water. The loss of lateral mobility of phospholipids can be explained by specific features of electronic structure of hydrophobic hydrocarbon molecules (acyl chains), which, under certain conditions, are capable of forming structured common regions of the electrostatic potential, to which xenon has an affinity. In this case, inclusion coordination compounds of the "guest-host" type are formed, which subsequently decompose due to the nature of the polarization of the Xe atoms. The formation and decomposition of xenon intermediates in these systems lead to recovery of the lateral mobility (fluidity) of phospholipids, which restores functional activity of surfactant films.

Mechanisms of the Effects of Short-Term Inhalations of Xe and O2 Gas Mixture in the Rehabilitation of Post-COVID Ventilation Failure.

The article presents a theoretical rationale and a clinical case of relief of post-COVID ventilation failure by inhalation of Xe and O2 gas mixture. Pneumonitis of coronavirus etiology transforms saturated phospholipids of surfactant into a solid-ordered phase, which disrupts surface tension, alveolar pneumatization, and alveolar-capillary gas exchange. Using molecular modeling (B3LYP/lanl2dz; GAUSSIAN09), we demonstrated that Xe atom due to the van der Waals dispersion interaction increases the distance between the phospholipid acyl chains providing a phase transition from the solid-ordered to liquid phase and restored the surface-active monolayer surfactant film. A clinical case confirmed that short-term inhalations of the Xe and O2 gas mixture relieved manifestations of ventilation insufficiency and increased SpO2 and pneumatization of the terminal parts of the lungs.

[Surgical treatment of patients with abdominal aortic aneurysm and ischaemic heart disease]. / Khirurgicheskoe lechenie bol'nykh s anevrizmami infrarenal'nogo otdela aorty i ishemicheskoi bolezn'iu serdtsa.

Presented herein are the results of treatment of 137 patients with infrarenal aneurysms of the abdominal portion of the aorta in a combination with ischaemic heart disease. Severity of lesions to the coronary bed and the risk of cardiac complications were assessed according to the SYNTAX score. Depending on severity of angina pectoris and the clinical course of infrarenal aortic aneurysms, we used different tactical approaches to operative treatment of patients. In a low risk of coronary complications, we performed isolated prosthetic repair or endoprosthetic reconstruction of the abdominal aorta. In patients with haemodynamically significant lesions of the coronary bed and positive non-invasive tests, the first stage consisted in coronary artery bypass grafting or stenting of coronary arteries taking into account the risk of cardiac complications according to the SYNTAX Score. The second stage consisted in prosthetic repair or endoprosthetic reconstruction of the abdominal aorta. The terms of the second stage differed and were determined by the course of abdominal aortic aneurysms. In symptomatic large aneurysms (more than 8 cm), prosthetic repair of the abdominal aorta was carried out within 2 weeks after previous stenting of coronary arteries. Simultaneous myocardial revascularization and abdominal aortic reconstruction were performed only in patients with severe angina pectoris, lesions of the trunk of the left coronary artery, three-vessel lesions of the coronary bed, high risk of cardiac complications according to the SYNTAX Score and a complicated or symptomatic course of an infrarenal aortic aneurysm. During implantation of stent grafts into the abdominal aorta there were neither lethal outcomes nor cardiac complications. In open operations, the 30-day mortality rate amounted to 2.2%, with the 5-year survival rate of 92%.

Intravascular ultrasound-guided internal carotid artery stenting. / Stentirovanie vnutrennikh sonnykh arterii pod kontrolem vnutrisosudistogo ul'trazvukovogo issledovaniia.

AIM: The study was aimed at demonstrating efficacy and feasibility of intravascular ultrasound during internal carotid artery stenting for assessment of atheromatous plaque protrusion through a stent. PATIENTS AND METHODS: Over the period from October to December 2018, the specialists of our Centre performed a total of 90 internal carotid artery stenting procedures in 83 patients (of these, 7 patients underwent bilateral staged stenting of both internal carotid arteries) using intravascular ultrasound in order to assess intraoperative protrusion of an atherosclerotic plaque through the implanted stent. The patients' age varied from 42 to 87 (mean 68.6±6.9) years. Symptomatic lesions of internal carotid arteries were revealed in 14 (16.9%) operated patients and asymptomatic lesions in 69 (83.1%). The degree of stenosis varied from 60% to 90% according to the findings of preliminary duplex ultrasonography and was subsequently confirmed by the results of multislice computed tomography or selective angiography. The assessment of the patients' neurological status, as well as duplex ultrasonography of brachiocephalic arteries were performed at a scheduled follow-up visit on day 30 after discharge from hospital. RESULTS: The technical success of stenting was achieved in 100% of patients. According to the findings of intravascular ultrasound, plaque protrusion was observed in eight (8.8%) stented patients. Among them, six (6.6%) were free from angiographic signs of protrusion and only two (2.2%) had apparent angiographic signs of protrusion. During the early postoperative period, transient ischaemic attack was identified in four (4.4%) cases. One (1.1%) patient was found to develop ST-segment elevation acute myocardial infarction 24 hours after internal carotid artery stenting, followed by large hemispheric stroke on the side of stenting revealed on postoperative day 3. Nine (10%) patients according to the findings of intravascular ultrasound were diagnosed as having incomplete stent apposition after postdilatation, with the absence of such signs on angiography. CONCLUSION: Intravascular ultrasound during carotid stenting provides a more accurate assessment of such an event as atherosclerotic plaque protrusion through a stent's cells. At the same time, IVUS-guided assessment of the intraoperative outcome may prevent the risk for the development of stroke in the early postoperative period. Besides, intravascular ultrasound allows a more detailed assessment of stent apposition and the degree of stent expansion in order to optimize and improve the remote results of the operation.

Damage-free plasma etching of porous organo-silicate low-k using micro-capillary condensation above -50 °C.

The micro-capillary condensation of a new high boiling point organic reagent (HBPO), is studied in a periodic mesoporous oxide (PMO) with ∼34 % porosity and k-value ∼2.3. At a partial pressure of 3 mT, the onset of micro-capillary condensation occurs around +20 °C and the low-k matrix is filled at -20 °C. The condensed phase shows high stability from -50 < T ≤-35 °C, and persists in the pores when the low-k is exposed to a SF6-based plasma discharge. The etching properties of a SF6-based 150W-biased plasma discharge, using as additive this new HBPO gas, shows that negligible damage can be achieved at -50 °C, with acceptable etch rates. The evolution of the damage depth as a function of time was studied without bias and indicates that Si-CH3 loss occurs principally through Si-C dissociation by VUV photons.

[PSYCHOPHARMACOLOGY OF ANTIPARKINSONIAN DRUGS].

Parkinson's disease as an extrapyramidal pathology is accompanied by some non-motor symptoms (depression, cognitive disorders, and sleep disturbance), which are based on disturbances of nigrostriatal dopaminergic neurotransmission supplemented by disorganization of other neuromediator systems. Traditional antiparkinsonian drugs with different cellular mechanism of action are capable of restricting these symptoms in patients and on animal models, while exhibiting their own psychotropic activity. This circumstance should be taken into account in assessing the pharmacological activity profiles of drugs.

Peptides@mica: from affinity to adhesion mechanism.

Investigating the adsorption of peptides on inorganic surfaces, on the molecular level, is fundamental for medicinal and analytical applications. Peptides can be potent as linkers between surfaces and living cells in biochips or in implantation medicine. Here, we studied the adsorption process of the positively charged pentapeptide RTHRK, a recently identified binding sequence for surface oxidized silicon, and novel analogues thereof to negatively charged mica surfaces. Homogeneous formation of monolayers in the nano- and low micromolar peptide concentration range was observed. We propose an alternative and efficient method to both quantify binding affinity and follow adhesion behavior. This method makes use of the thermodynamic relationship between surface coverage, measured by atomic force microscopy (AFM), and the concomitant free energy of adhesion. A knowledge-based fit to the autocorrelation of the AFM images was used to correct for a biased surface coverage introduced by the finite lateral resolution of the AFM. Binding affinities and mechanisms were further explored by large scale molecular dynamics (MD) simulations. The combination of well validated MD simulations with topological data from AFM revealed a better understanding of peptide adsorption processes on the atomistic scale. We demonstrate that binding affinity is strongly determined by a peptide's ability to form salt bridges and hydrogen bonds with the surface lattice. Consequently, differences in hydrogen bond formation lead to substantial differences in binding affinity despite conservation of the peptide's overall charge. Further, MD simulations give access to relative changes in binding energy of peptide variations in comparison to a lead compound.

[PROTECTIVE ROLE OF MELATONIN IN ETIOLOGY AND COURSE OF PARKINSON'S DISEASE: EXPERIMENTAL EVIDENCE.]

Literature data about participation of melatonin - the main hormone of pineal gland - in the origin and course of Parkinson's disease are reviewed. On the cellular level, melatonin demonstrates neuroprotective activity based on the limitation of oxidative stress, inflammation, and degradation of dopamine in nervous tissue, the attenuation of mitochondrial dysfunction, and the accumulation of alpha-synuclein, which are observed in parkinsonian animals and human patients. Moreover, melatonin is capable of inducing some systemic changes that limit disorganization of circadian rhythm and insomnia. It is suggested that, after extensive placebo controlled and randomized examinations in clinical practice, melatonin may be recommended for complex therapy of Parkinson's disease with obligatory taking into consideration some variable factors.

[Influence of melatonin and diclofenac on circadian rhythm of locomotor activity in rats with local inflammatory arthritis].

Inflammatory arthritis is accompanied by disorganization of the circadian rhythm of locomotion in rats. Control saline injections increased the rhythm disturbances. Chronic administration of melatonin (5 mg/kg) attenuated these chronopathological shifts. Diclofenac demonstrated much lower positive chronopharmacological activity than did melatonin.

[Twelve months results of percutaneous coronary interventions in patients with ischemic heart disease combined with diabetes mellitus using sirolimus and everolimus covered stents].

We included into this study 112 patients with ischemic heart disease (IHD) and concomitant type 2 diabetes mellitus (DM) subjected to percutaneous coronary interventions with stenting. Everolimus and sirolimus eluting stents (EES and SES) were implanted in 54 (group 1) and 58 (group 2) patients, respectively. After 12 months in groups 1 and 2 rates of repeat target lesion revascularizations (TLR) were 5.5 and 8.6% (odds ratio - OR - 0.62, 95% confidence interval - CI - 0.14- 2.74, p = 0.72); acute myocardial infarctions (MI) - 3.7 and 5.2% (OR 0.71, 95% CI 0.11- 4.4, p = 0.94); deaths - 1.85 and 1.7% (OR 1.1, 95% CI 0.1- 17.6, p = 1.0), respectively. There was no significant difference between groups by rate of unfavorable cardiac events (composite of cardiac death, nonfatal MI, and clinically indicated TLR) - 11.1 and 15.5% in groups 1 and 2, respectively (OR 0.68, 95% CI 0.225- 2.059, p = 0.69). Rates of stent thrombosis also did not differ (1.85 and 3.4% in groups 1 and 2, respectively; OR 0.53, 95% CI 0.05- 6.0; p = 0.94). Thus the use of EES and SES in patients with IHD and type-2 DM was equally effective.

[Comparative study of the influence of melatonin and diclofenac on some hematologic indices of experimental rheumatoid arthritis in rats].

Pineal hormone melatonin (1 and 5 mg/kg) and diclofenac (8 mg/kg) significantly limited hematologic indices of inflammation and immunologic reactivity in rats with experimental adjuvant arthritis. The effect of melatonin was more pronounced than that of diclofenac.

[Anti-inflammatory potential of melatonin].

The summary of anti-inflammatory properties, cellular and systemic mechanisms of action of epiphyseal melatonin is presented. Dual effect of interaction between melatonin and non-steroidal anti-inflammatory agents is discussed with reference to enhancement of their specific activity and prevention of side effects.

[Coronary stenting in patients with ischemic heart disease with multivessel involvement of coronary vascular bed and low Syntax score].

MATERIAL AND METHODS: We followed 619 patients with ischemic heart disease (IHD) and multivessel involvement of coronary arteries: 317 patients subjected to coronary artery bypass grafting (CABG, group 1) and 302 patients subjected to multivessel percutaneous coronary intervention (PCI, group 2) with implantation of drug eluting stents. Both groups had comparable clinical characteristics. During hospitalization we registered deaths and unfavorable cardiological and cerebrovascular events. In remote period after revascularization we assessed survival, angina recurrences and related repeat revascularizations, and rate of severe cardiovascular complications (composite of deaths, acute myocardial infarctions [AMI], stroke, and repeat myocardial revascularizations). RESULTS: During hospitalization there were no significant differences between groups by parameters studied: death rate was 1.7 and 0.9%, that of AMI 2.6 and 1.9%, of stroke 0.9% and 0, of composite of death, AMI, and stroke 5.1 and 1.9% (p = 0.37) in groups 1 and 2, respectively. Survival in remote period was 90.2 (group 1) and 92.7% (group 2). Comparison of Kaplan-Meier survival curves also revealed no significant differences between groups. Angina recurrence/repeat revascularization took place in 54 (17.0%) and in 64 (21.2%) patients in groups 1 and 2, respectively (p = 0.128). Repeat revascularization was carried out in 32 of 54 patients (59.3%) in group 1 and in 58 Of 64 patients (90.6%) in group 2. Rate of severe unfavorable events during whole period of follow up was 33.1% in group 1 and 30.5% in group 2 (p > 0.05). CONCLUSION: In IHD patients with multivessel coronary artery involvement and low Syntax Score immediate and long term (5 year) results of stenting with drug eluting stents are not inferior to results of CABG.

[Complex estimation of the psychotropic activity spectrum of pineal hormone melatonin in young healthy humans].

Effects of the pineal hormone melatonin (melaxen, 1.5 mg, 2 weeks) on a complex of psychophysiological indices have been studied on a group of healthy human volunteers in comparison to placebo. The drug improved the concentration of attention, improved its stability in the presence of visual hindrances, and increased the critical frequency of merging light flashes. The administration of melatonin also significantly increased the transient memory volume and reduced the levels of depression and anxiety. Shifts in the psychoemotional state were more pronounced than changes in the cognitive functions.

Diffusion in hierarchical mesoporous materials: applicability and generalization of the fast-exchange diffusion model.

Transport properties of cyclohexane confined to a silica material with an ordered, bimodal pore structure have been studied by means of pulsed field gradient nuclear magnetic resonance. A particular organization of the well-defined pore structure, composed of a collection of spatially ordered, spherical mesopores interconnected via narrow worm-like pores, allowed for a quantitative analysis of the diffusion process in a medium with spatially ordered distribution of the fluid density for a broad range of the gas-liquid equilibria. The measured diffusion data were interpreted in terms of effective diffusivities, which were determined within a microscopic model considering long-range molecular trajectories constructed by assembling the alternating pieces of displacement in the two constituting pore spaces. It has further been found that for the system under study, in particular, and for mesoporous materials with multiple porosities, in general, this generalized model simplifies to the conventional fast-exchange model used in the literature. Thus, not only was justification of the applicability of the fast-exchange model to a diversity of mesoporous materials provided, but the diffusion parameters entering the fast-exchange model were also exactly defined. The equation resulting in this way was found to nicely reproduce the experimentally determined diffusivities, establishing a methodology for targeted fine-tuning of transport properties of fluids in hierarchical materials with multiple porosities.