Comparative Analysis of the Pharmacological Activity of Bis(3,5-di-Tert-Butyl-4-Hydroxyphenylthiolate)Dimethylol in Different Modes of Administration on a Mouse Model of Melanoma B16 Tumor Growth.

We performed a comparative analysis of the pharmacological activity of the hybrid organotin compound bis(3,5-di-tert-butyl-4-hydroxyphenylthiolate)dimethylol (Me-3) administered in different modes to mice with transplanted melanoma B16 to identify the most effective dosage regimen. Three modes of administration were used: preventive (before transplantation of tumor cells), classical according to Z. P. Sof'ina (48 h after transplantation of tumor cells), and delayed (7 days after transplantation of tumor cells, after formation of nodules of the primary tumor node). Compound Me-3 was administered at a total dose of 375 mg/kg intraperitoneally once a day for 5 days. The classical mode of administration was identified as the most effective, which indicates the preventive antimetastatic activity of Me-3 on the model of the transplanted mouse tumor melanoma B16.

[Multiple myeloma: response to treatment and survival of patients according to the interim analysis of the Russian observational, retrospective-prospective, multicenter cohort study (MULTISPECT)].

AIM: The primary objective of the interim analysis of the MULTISPECT study was to evaluate the short-term efficacy of the treatment and long-term outcomes in cohorts of primary and pretreated patients with multiple myeloma (MM) receiving treatment in actual clinical practice in various regions of the Russian Federation. Secondary objectives were a description of the main characteristics of patients; analysis of the most commonly used therapy regimens of the 1st and later lines and the sequence of their changes; evaluation of the response to therapy. Additional objectives included evaluation of the effect of the new COVID-19 coronavirus infection on the course of MM in patients. MATERIALS AND METHODS: The study is an observational retrospective-prospective multicenter cohort study. For its implementation, a structured database of patients with MM was used, provided by hematologists of the centers affiliated for the study. RESULTS: The study included 1,294 patients (cohort 1 806, cohort 2 488). In both cohorts, patients aged 6069 years were in the majority. 3 lines of therapy (L1, L2, L3) were used for cohort 1; in cohort 2, the 4th line of therapy was also used in 2 patients. The therapy regimens were analyzed for 290 (22.41%) of all patients in the study. Responses to therapy were analyzed for 214 patients of cohort 1 and 109 patients of cohort 2. Autologous and allogeneic hematopoietic stem cell transplantations were carried out for a limited proportion of patients in both cohorts. At the end of the study and upon presentation of its results, the status of patients was the following: 96% of patients in cohort 1 and 89% in cohort 2 were alive. The therapy regimens in both cohorts were characterized by variability. The most commonly used regimens in each of the lines of therapy have been identified. The most used therapy regimen in patients with MM of both cohorts was the VCD-regime. Rd-regime in cohort 1 and RD-regime in cohort 2 were the second most frequent used regimens. In patients of both cohorts, the therapy regimens including Bortezomib were most often used. CONCLUSION: The variety of therapy regimens used to treat MM in actual clinical practice may be due to the factors of availability of new medicines and updated recommendations for the treatment of the disease. Further, in the context of this study, a more detailed analysis of the efficacy of certain therapy regimens in the 1st and later lines on progression free survival and overall survival of MM patients should be carried out.

Statistical theory for the reaction N + OH → NO + H: thermal low-temperature rate constants.

The reaction N + OH → NO + H involves the intermediate formation of NOH adducts which in part rearrange to HNO conformers. A statistical treatment of the process is developed in which an initial adiabatic channel capture of the reactants is accompanied by partial primary redissociation of the N⋯OH collision pairs. A criterion for the extent of this primary redissociation in competition to the formation of randomized, long-lived, complex of NOH is proposed. The NOH adducts then may decompose to NO + H, rearrange in a unimolecular process to HNO, or undergo secondary redissociation back to the reactants N + OH, while HNO may also decompose to NO + H. As the reactants N(4S) + OH(2Π) have open electronic shells, non-Born-Oppenheimer effects have to be considered. Their influence on thermal rate constants of the reaction at low temperatures is illustrated and compared with such effects in other reactions such as C(3P) + OH(2Π).

[Social jetlag: possibilities of micronutrient support].

The concept of social jetlag refers to asynchronous communication of a person's biological clock with tempo of modern living, which occurs mainly as a result of intensive work. At the core of social jetlag is sleep deprivation or chronic sleep restriction caused by social factors: pervasive use of electronic solutions and networks, intensive round the clock operation, chronic diseases. The aim of the work was to determine vitamins, minerals, and other micronutrients, the availability of which is important for supporting the organism in case of circadian rhythm sleep disorders and sleep restrictions, the so-called social jetlag. Material and methods. The analysis of 78 sources from PubMed and Google Scholar bibliographic bases was carried out with a detailed analysis of data from the published studies. Results. Circadian rhythm sleep disorders and sleep restrictions affects cognitive functions, increasing risk of anxiety and depressive disorders, enhances processes of chronic inflammation, oxidative stress, cardiometabolic disorders. Scientific evidence has been collected that lack of such elements as magnesium, folates, omega-3 polyunsaturated fatty acids and probiotics in diet can worsening effects of social jetlag and increase the risk of chronic diseases. Preventive course intake of this micronutrients is reasonable in people predisposed to social jetlag. Conclusion. In risk groups of people predisposed to social jetlag, along with diverse diet and adequate nutrition, sleep hygiene, it is necessary to provide targeted supplementation with magnesium, folates, omega-3 polyunsaturated fatty acids and probiotic products.

Effect of Hybrid Organotin Compound on Activity of LPO and Antioxidant Protection of the Liver Tissues in Animals with Melanoma B16.

The central element of the "metastatic organotropism" is a shift of the pro/antioxidant balance in cells and activation of oxidative stress and protective antioxidant systems. We studied the effects of bis(3,5-di-tert-butyl-4-hydroxyphenylthiolate)dimethylol (Me-3) in the maximum effective and toxic total doses on the level of markers of oxidative stress and antioxidant protection in the liver of mice with melanoma B16 before the appearance of macroscopic metastases. In 48 h after tumor inoculation, Me-3 was administered intraperitoneally once a day for 5 days in total doses of 375 and 500 mg/kg according to the classical method. Administration of the hybrid organotin compound Me-3 produced different effects on the pro/antioxidant state of the microenvironment of liver tissue as the target of melanoma B16 metastasis. The results suggest that inversion of the anti/prooxidant profile of Me-3 is determined by its dose.

Potassium channels as prominent targets and tools for the treatment of epilepsy.

INTRODUCTION: K+ channels are of great interest to epilepsy research as mutations in their genes are found in humans with inherited epilepsy. At the level of cellular physiology, K+ channels control neuronal intrinsic excitability and are the main contributors to membrane repolarization of active neurons. Recently, a genetically modified voltage-dependent K+ channel has been patented as a remedy for epileptic seizures. AREAS COVERED: We review the role of potassium channels in excitability, clinical and experimental evidence for the association of potassium channelopathies with epilepsy, the targeting of K+ channels by drugs, and perspectives of gene therapy in epilepsy with the expression of extra K+ channels in the brain. EXPERT OPINION: Control over K+ conductance is of great potential benefit for the treatment of epilepsy. Nowadays, gene therapy affecting K+ channels is one of the most promising approaches to treat pharmacoresistant focal epilepsy.

[Monoclonal gammopathy of renal significance: consensus of hematologists and nephrologists of Russia on the establishment of nosology, diagnostic approach and rationale for clone specific treatment].

Monoclonal gammopathy of renal significance (MGRS) is a new nosology in modern nephrology and oncohematology. MGRS is defined as kidney injury due to nephrotoxic monoclonal immunoglobulin produced by the B-cell line clone which does not reach the hematological criteria for specific treatment initiation. Monoclonal proteins pathological effects on kidney parenchyma result in irreversible decline of kidney function till the end stage renal disease that in line with the position of International Consensus of hematologists and nephrologists determinates critical necessity for clone specific treatment in patients with MGRS despite the absence of hematological indications for treatment initiation. Main challenge of MGRS in Russian Federation is an inaccessibility of an in-time diagnostic and appropriate treatment for the great majority of patients due to the following reasons: 1) limited knowledge about the MGRS among hematologists and nephrologists; 2) lack of necessary diagnostic resources in most health-care facilities; 3) lack of approved clinical recommendations and medical economic standards for treatment of this pathological entity. Consensus document comprises the opinion of experts leading nephrologists and hematologists of Russian Federation on the problem of MGRS including the incoherence in nosology classification, diagnostics approach and rationale for clone specific treatment. Consensus document is based on conclusions and agreements reached during the conference of leading nephrologists and hematologists of Russia which was held in the framework of symposia Plasma cell dyscrasias and lymphoproliferative diseases: modern approaches to therapy, 1516 of March 2019, Pavlov First Saint Petersburg State Medical University. The present Consensus is intended to define the principal practical steps to resolve the problem of MGRS in Russian Federation that are summarized as final clauses.

Ca2+-activated KCa3.1 potassium channels contribute to the slow afterhyperpolarization in L5 neocortical pyramidal neurons.

Layer 5 neocortical pyramidal neurons are known to display slow Ca2+-dependent afterhyperpolarization (sAHP) after bursts of spikes, which is similar to the sAHP in CA1 hippocampal cells. However, the mechanisms of sAHP in the neocortex remain poorly understood. Here, we identified the Ca2+-gated potassium KCa3.1 channels as contributors to sAHP in ER81-positive neocortical pyramidal neurons. Moreover, our experiments strongly suggest that the relationship between sAHP and KCa3.1 channels in a feedback mechanism underlies the adaptation of the spiking frequency of layer 5 pyramidal neurons. We demonstrated the relationship between KCa3.1 channels and sAHP using several parallel methods: electrophysiology, pharmacology, immunohistochemistry, and photoactivatable probes. Our experiments demonstrated that ER81 immunofluorescence in layer 5 co-localized with KCa3.1 immunofluorescence in the soma. Targeted Ca2+ uncaging confirmed two major features of KCa3.1 channels: preferential somatodendritic localization and Ca2+-driven gating. In addition, both the sAHP and the slow Ca2+-induced hyperpolarizing current were sensitive to TRAM-34, a selective blocker of KCa3.1 channels.

Sleep spindles in bipolar disorder - a comparison to healthy control subjects.

OBJECTIVE: Bipolar disorder is a severe mental disorder for which currently no reliable biomarkers exist. It has been shown that patients with schizophrenia but not with unipolar depression have a reduced density of fast sleep spindles during N2 sleep. The aim of this study was to assess fast sleep spindle density in euthymic patients with bipolar disorder. METHODS: Patients with bipolar disorder (n = 24) and healthy control subjects (n = 25) were assessed using all-night polysomnography. Sleep spindles within stage N2 sleep were identified by visual inspection and subdivided into fast (>13 Hz) and slow (≤13 Hz) spindles. All spindles were subsequently characterised by density, frequency, amplitude, duration and coherence. RESULTS: Euthymic patients with bipolar disorder were found to have a reduced density and a lower mean frequency of fast spindles. Slow spindle density and frequency did not differ between groups. There were no differences regarding amplitude, duration or coherence. CONCLUSIONS: A reduction in fast spindle density during N2 sleep points towards thalamic dysfunction as a potential neurobiological mechanism of relevance in bipolar disorder. In addition, a reduced sleep spindle density could be interpreted as a common endophenotype shared with schizophrenia but not unipolar depression and may - if replicated - be of utility in early recognition and risk stratification.

Electronically nonadiabatic mechanism of the vibrational relaxation of NO in Ar: Rate coefficients from ab initio potentials and asymptotic coupling.

In this paper, the electronically nonadiabatic Landau-Zener (LZ) mechanism for the vibrational relaxation v = 1 → v = 0 of NO(X2Π) in collisions with Ar(S01) is discussed. It corresponds to nonadiabatic transitions between two crossing vibronic potential energy surfaces (PESs) originating from vibrational states of the collision complex and supported by two coupled electronic PESs. The LZ rate coefficients k10LZ are calculated within the uniform Airy approach in the reaction coordinate approximation with parameters derived from ab initio PESs and an asymptotic estimation of the Franck-Condon factor in the nonadiabatic coupling region. The rate coefficients are close to the experimental rate coefficients available over the range of 900-2500 K, where the electronically adiabatic Landau-Teller (LT) mechanism with the rate coefficients k10LT does not make a noticeable contribution to the total relaxation rate. The ratio k10LZ/k10LT increases with temperature and the LZ and LT mechanisms have comparable rates at about 4000 K.

Relocking of intrinsic angular momenta in collisions of diatoms with ions: Capture of H2(j = 0,1) by H2.

Rate coefficients for capture of H2(j = 0,1) by H2+ are calculated in perturbed rotor approximation, i.e., at collision energies considerably lower than Bhc (where B denotes the rotational constant of H2). The results are compared with the results from an axially nonadiabatic channel (ANC) approach, the latter providing a very good approximation from the low-temperature Bethe-Wigner to the high temperature Langevin limit. The classical ANC approximation performs satisfactorily at temperatures above 0.1 K. At 0.1 K, the rate coefficient for j=1 is about 25% higher than that for j = 0 while the latter is close to the Langevin rate coefficient. The Bethe-Wigner limit of the rate coefficient for j = 1 is about twice that for j = 0. The analysis of the relocking of the intrinsic angular momentum of H2 during the course of the collision illustrates the significance of relocking in capture dynamics in general.

[Physiological Aspects of the Application of Hodgkin-Huxley Model of Action Potential Initiation for Invertebrate and Vertebrate Neurons].

Recent studies have revealed.that in contrast to invertebrate systems, the initiation of action potentials in vertebrate neurons significantly differ from the relatively slow exponential dynamics predicted by Hodgkin-Huxley equations, but rather is characterized by a sharp onset with a kink. These data provided new insights into the link between action potential initiation and abilities of neurons and neuronal networks to encode. high frequency signals. Here, we review recent models describing sharp onset dynamics of action potential initiation, including an alternative model of cooperative activation of sodium channels, as well as the influence of the dynamics of action potential initiation on computational abili- ties of neuronal networks. The importance this topic is due to the fact that, despite the rapid development of neuronal modeling during last decades, the well established models are unable to capture experimentally observed details of the onset dynamics of action potentials in mammalian neurons and the abilities of neurons to reliably encode code high frequency signals Recent advances of experimental and theoretical analysis of generation of action potentials and neuronal encoding, presented in this review, are ofgreat importance for better understanding of neuronal processing and development of a more precise and realistic neuronal model.

Further insight into the tunneling contribution to the vibrational relaxation of NO in Ar.

Tunneling corrections to Landau-Zener rate coefficients for the vibrational relaxation NO(X(2)Π, v = 1) + Ar → NO(X(2)Π, v = 0) + Ar between 300 and 2000 K are determined employing ab initio potential energy surfaces calculated by the code provided by Alexander [J. Chem. Phys. 111, 7426 (1999)]. The calculations use a reaction coordinate approach and lead to vibronically nonadiabatic transition probabilities within the generalized Airy approximation as extended to the WKB underbarrier Landau-Lifshitz limit. The calculations confirm experimental evidence for an onset of major tunneling contributions to the relaxation rate at temperatures below about 900 K and rationalize large tunneling contributions at 300 K. These effects increase the rate coefficients by several orders of magnitude over the uncorrected Landau-Zener values and remove the large gap between the latter and experimental results.

[The treatment of patients with circulatory system pathology in health resorts "Tarkhovskii" and "Priozerskii"].

The authors showed the history of foundation and development of health resorts "Tarkhovsky" and "Priozersky", as well as an analysis of the treatment of patients with circulatory system diseases in these health resorts. It was found that the structure of patients fitted the profile of health resorts and in recent years has remained stable. Patients with circulatory system diseases accounted for 47.8%. The existing system of medical rehabilitation and restorative treatment of patients with diseases of the circulatory system in the health resorts "Tarkhovsky" and "Priozersky" ensures the implementation in full rehabilitation and recovery programs for all categories of contingent attached.

[DISORDERS OF LUNG FUNCTION IN THE EARLY POSTOPERATIVE PERIOD IN PATIENTS OPERATED ON THE ASCENDING AORTA WITH THE EXPANSION OF INTERVENTION ON THE AORTIC ARCH].

Precapillary artery--arterial (bronchial artery--pulmonay artery) anastomoses, come into play in cases where the locking artery open and alveoli washed arterialized blood. Normally, these anastomoses are closed. Intrapulmonary shunts carry blood supply acinar hinder extraordinary circumstances (chronic pulmonary embolism, surgery, occurring in cardiopulmonary bypass, when the flaw of blood through the Iungs is suspended for the duration of cardiopulmonary bypass). Patients operated on the ascending aorta with the expansion of intervention on the nortic arch during the correction of pathology carry blood supply only the central nervous system. All other organs and systems at this time were protected by mild hypothermia. However, during circulatory arrest, required for correction of pathology acinar damage as a result of hypoxia, probably because there is no blood flow in the pulmonary artery and there is no blood flow in the bronchial arteries. Last, in the ordinary course of artificial circulation, capable due to arterio-arterial pulmonary anastomoses prevent hypoxic damage to acinar, not lead to persistent hypoxemia in the immediate postoperative period in these patients, as a result of violations of lung diffusion capacity.

The vibrational relaxation of NO in Ar: tunneling in a curve-crossing mechanism.

Experimental data for the vibrational relaxation NO(X(2)Π, v = 1) + Ar → NO(X(2)Π, v = 0) + Ar between 300 and 2000 K are analyzed. The measured rate coefficients k10 greatly exceed Landau-Teller values (LT)k10. This observation can be attributed to a mechanism involving curve-crossing of the (A'', v = 1) and (A', v = 0) vibronic states of the collision system. At high temperatures, the rate coefficients k10 are well represented by the thermally averaged Landau-Zener rate constant (LZ)k10 with an apparent Arrhenius activation energy Ea/kB near 4500 K. At intermediate temperatures, around T = 900 K, the measured k10 values are a factor of two higher than the extrapolated (LZ)k10 values. This deviation is attributed to tunneling in nonadiabatic curve-crossing transitions, which are analyzed within the Airy approximation (linear model for crossing diabatic curves) and an effective mass approach. This suggests a substantial contribution of hindered rotation of NO to the nonadiabatic perturbation. The extrapolation of the Airy probabilities to even lower temperatures (by the Landau-Lifshitz WKB tunneling expression for simple nonlinear model potentials) indicates a further marked increase of the tunneling contribution beyond the extrapolated (LZ)k10. Near 300 K, the k10 can be two to three orders of magnitude higher than the extrapolated (LZ)k10. This agrees with the limited available experimental data for NO-Ar relaxation near room temperature.

[The use of a "buffet" style meals in the system of health-resort treatment].

The authors summarized literature sources, concerning modern ideas about the role of nutritional therapy in the system of health-resort treatment. The authors also made a research on the basis of literature, concerning health-resort nutrition divided into two systems-- buffet system and special-order system. On the basis of sanatorium establishments of the Ministry of Defense authors summarized an experience of clinical nutrition in different age groups and categories of patients. On the basis of current regulatory acts were defined forms and methods of meal catering in the Russian Federation. The results of the study are a scientific supposition for substantiation of management decision-making process, which allows to increase an efficiency of health-resort treatment via nutrition therapy.

Hyperimmunoglobulinemia E and efficacy of elimination diet in two patients with Schnitzler syndrome.

BACKGROUND: Schnitzler syndrome (SS) is a rare clinical entity characterized by chronic recurrent urticarial rash, monoclonal IgM gammopathy, intermittent fever and other symptoms. In this report, we present the cases of two patients with SS: a male and a female aged 50 and 49 years, respectively. Both patients had hyperimmunoglobulinemia E and showed good response to elimination diet. METHODS: The patients had chronic urticaria, IgM gammopathy and an elevation of the serum levels of inflammation markers. Total IgE levels were found to be high (2000 U/ml and 540 U/ml, respectively). No underlying causes for hyperimmunoglobulinemia E (allergy, parasites, etc.) were revealed. The first patient did not respond to the treatment with antihistamines, while the second one responded only to high doses. The response to prednisolone in the second patient was incomplete. RESULTS: Following a strict elimination diet resulted in marked improvement in skin lesions in both patients. In one of our patients we observed a decrease in IgE and IgM levels after a 3 week diet. The systemic symptoms persisted and improved only after adding pefloxacin, followed by a 3-day empirical course of intravenous prednisone in the first patient and a course of plasmapheresis in the second one. CONCLUSION: The high serum levels of total IgE may be associated with chronic urticaria activity, severe disease course and a poor response to treatment with antihistamines, and may be considered a possible marker of a subset of patients with SS showing a good response to the restriction diet. In general, we can assume that elimination diet can have an influence on the skin lesions and other symptoms of SS as well as on total IgE and IgM levels, but such association, the underlying mechanisms and the reasons for excessive IgE synthesis should be investigated in further studies.

Electronic nonadiabatic effects in low temperature radical-radical reactions. I. C(3P) + OH(2Π).

The formation of collision complexes, as a first step towards reaction, in collisions between two open-electronic shell radicals is treated within an adiabatic channel approach. Adiabatic channel potentials are constructed on the basis of asymptotic electrostatic, induction, dispersion, and exchange interactions, accounting for spin-orbit coupling within the multitude of electronic states arising from the separated reactants. Suitable coupling schemes (such as rotational + electronic) are designed to secure maximum adiabaticity of the channels. The reaction between C((3)P) and OH((2)Π) is treated as a representative example. The results show that the low temperature association rate coefficients in general cannot be represented by results obtained with a single (generally the lowest) potential energy surface of the adduct, asymptotically reaching the lowest fine-structure states of the reactants, and a factor accounting for the thermal population of the latter states. Instead, the influence of non-Born-Oppenheimer couplings within the multitude of electronic states arising during the encounter markedly increases the capture rates. This effect extends up to temperatures of several hundred K.