[Correction of gait stereotype and reduction of the risk of falling in patients with equinovarus foot placement and central hemiparesis]. / Korrektsiya stereotipa khod'by i snizhenie riska padeniya u bol'nykh s ekvinovarusnoi ustanovkoi stopy pri tsentral'nom gemipareze.

OBJECTIVE: To test a new approach to gait stereotype correction for patients with central hemiparesis with talipes equinovarus. MATERIAL AND METHODS: The study was performed in a group of patients with formed talipes equinovarus and post-stroke hemiparesis. Footwear with orthopaedic elements was offered to the patients. Evaluation of spatial and temporal gait parameters was performed and the risk of falls was assessed. RESULTS: In the process of work, data were obtained confirming the effectiveness of using specialized shoes for equinovarus foot placement. The risk of falling significantly decreased when walking; walking became more symmetrical due to an increase in the anterior extension of the paretic limb. CONCLUSION: Application of this method does not decrease the tone in the paretic limb but optimises the gait stereotype, facilitates the increases of its velocity and decreases the risk of falling.

[Cardiovascular effects of omega-3 polyunsaturated fatty acids: position of omega-3 polyunsaturated fatty acids in Russian and international guidelines. Council of Experts].

This Expert Council focuses on the meta-analysis of studies on the risk of atrial fibrillation (AF) in patients taking omega-3 polyunsaturated fatty acids (PUFA) and of data on the omega-3 PUFA treatment in patients with cardiovascular and kidney diseases.The major statements of the Expert Council: the meta-analysis of AF risk in patients taking omega-3 PUFA showed an increased risk of this arrhythmia. However, it should be taken into account that the risk of complications was low, and there was no significant increase in the risk of AF when omega-3 PUFA was used at a dose of ≤1 g and a standard dose of the only omega-3 PUFA drug registered in the Russian Federation, considering all AF episodes in the ASCEND study.At the present time, according to Russian and international clinical guidelines, the use of omega-3 PUFA can be considered in the following cases: • for patients with chronic heart failure (CHF) with reduced left ventricular ejection fraction as a supplement to the basic therapy (2B class of recommendations according to the 2020 Russian Society of Cardiology guidelines (RSC) and the 2022 AHA / ACC / HFSA guidelines); • for patients with hypertriglyceridemia (>1.5 mmol/l) as a part of combination therapy (IIb class of recommendations and B level of evidence according to the 2021 European guidelines on cardiovascular disease prevention, etc.); • for adult patients with stage 3-4 chronic kidney disease (CKD), long-chain omega-3 PUFA 2 g/day is recommended for reducing the level of triglycerides (2C class of recommendations). Data on the use of omega-3 PUFA for other indications are heterogenous, which can be partially explained by using different form and doses of the drugs.

[Diagnosis of hypomimia in Parkinson's disease]. / Diagnostika gipomimii pri bolezni Parkinsona.

OBJECTIVE: A clinical approbation of a proprietary method for evaluation of the diagnostic value of computer video analysis of hypomimia in patients with Parkinson's disease (PD). MATERIAL AND METHODS: The study included 31 patients diagnosed with PD and 31 healthy people. The method consists in contactless recognition of 68 reference points on the face that are used to determine the movement of eyebrows, eyelids and the mouth during diagnostic tests: smiling, drawing of the letter "O", winking, eyebrow raising, frowning, and text reading. RESULTS: Comparison of the results obtained with characteristics of healthy subjects has revealed statistically significant difference in the amplitude and speed of eyebrow, eyelid and mouth movement in PD patients. CONCLUSION: The method offers prospects for screening of patients with suspected PD and evaluation of therapy efficacy.

[Inclisiran - a new era in lipid-lowering therapy].

Inclisiran is a novel hypolipidemic drug that inhibits synthesis of the PCSK9 protein through the process called RNA interference. Inclisiran is a double-stranded, modified RNA bound to the N-acetylgalactosamine (GalNAc) carbohydrate molecule, a ligand of the acialoglycoprotein receptor, that is expressed by hepatocytes. After entering hepatocytes, inclisiran cleaves matrix RNA and, thereby, reduces the PCSK9 protein synthesis. This, in turn, enhances the uptake of circulating low-density lipoproteins (LDL) by specific receptors on hepatocytes, thereby lowering LDL levels in circulation. Efficacy and safety of inclisiran for lowering LDL cholesterol (C) in blood and its effect on the risk of clinical complications of atherosclerosis have been studied in the ORION program that includes multiple clinical trials. According to results of this program, inclisiran effectively reduces both LDL-C levels and the incidence of cardiovascular complications in the absence of clinically significant adverse reactions. An important advantage of inclisiran compared with other lipid-lowering drugs is the administration schedule (twice a year), which allows a considerable improvement of patients' compliance with the treatment and also of the effectiveness of the hypolipidemic treatment.

[Optimization of lipid-lowering therapy in patients after ischemic stroke. Resolution of the Council of Experts]. / Optimizatsiya gipolipidemicheskoi terapii u patsientov, perenesshikh ishemicheskii insul't. Rezolyutsiya Soveta ekspertov.

Hyperlipidemia is the main risk factor for diseases caused by atherosclerosis including ischemic stroke. This publication provides practical recommendations and an algorithm for prescribing lipid-lowering therapy to post-ischemic stroke patients. The algorithm presents the steps for sequential administration of statins, ezetimibe, and PCSK9 inhibitors to achieve target levels of low-density lipoprotein cholesterol.

Deep microbial analysis of multiple placentas shows no evidence for a placental microbiome.

OBJECTIVES: To resolve the controversy regarding the presence of a microbiota in the placenta. DESIGN: Classical and molecular microbiological study. SETTING: All samples were collected during caesarean section. POPULATION: A total of 28 human placentas and six murine placentas. METHODS: All 28 human placentas were checked for 16S rRNA gene amplification products. Three locations from four selected human placentas and three 'environmental controls' for each placenta were placed in seven culture media. The four selected human placentas were further analysed using Gram stain, immunohistochemistry for bacteria, electron microscopy, and TaqMan RT-qPCR. Six placentas from three SPF mice were cut into four pieces each, and further analysed for 16S rRNA gene amplification. MAIN OUTCOME MEASURES: Microbiological and molecular evidence of bacteria. RESULTS: None of the placental cultures used for the full analysis, or their environmental cultures, was positive for bacterial growth. None of the other methods showed any evidence of bacteria. Immunohistochemistry showed negligible bacterial counts. None of the murine placentas showed evidence of 16S rRNA gene amplification. CONCLUSIONS: Our results support that the fetal environment in the womb is sterile. Based on the immunohistochemistry and the limit of detection of the other methods used, if a placental microbiome exists, it is of extreme low biomass, and thus its effect on clinical phenotypes is probably minor, if it exists at all. TWEETABLE ABSTRACT: Using several microbiological and molecular methods in parallel, we found no compelling evidence of bacteria in human and mouse placentas.

[Possibilities of clinical use of ezetimibe Otrio (JSC "AKRIKHIN", Russia) in patients with high and very high cardiovascular risk who have not reached the target values of lipid metabolism. Conclusion of the Board of experts].

This Conclusion of the Board of experts is devoted to the analysis of the evidence base, the position in modern clinical guidelines, the efficacy and safety analysis as well as the options of combined therapy with statins and ezetimibe (Otrio, JSC "AKRIKHIN") in various categories of patients in routine clinical practice in theRussian Federation. Cardiovascular diseases (CVD) continue to lead in the structure of morbidity and mortality inRussia. Hypercholesterolemia is one of the main modifiable risk factors for CVD. Administration of HMGCo-A-reductase inhibitors (statins) remains the basis for the prevention and treatment of the main complications of atherosclerosis, but the achievement of target levels of LDL-C on of statin monotherapy in Russian practice among different categories of risk does not exceed 50%. Proportion of patients (up to 12%) does not tolerate statin therapy, which requires the search for alternative therapies. To optimize the control of the level of LDL-C, combination therapy with statins and ezetimibe is used. Ezetimibe is an effective lipid-lowering drug, an inhibitor of intestinal absorption of cholesterol, which was investigated in many international and Russian studies, the results of which have demonstrated good tolerability, safety and efficacy (reduction of LDL-C levels by 18% in monotherapy). It was noted that the combined therapy with low/medium doses of statins and ezetimibe effectively reduces the level of LDL-C by 44-53%, which is comparable to the effect of high doses of statins and reduces CV risk in patients with CKD and ACS. Otrio (INN Ezetimib) tablets 10 mg ( JSC "AKRIKHIN",Russia) has demonstrated bioequivalence to the original drug Ezetrol tablets 10 mg (Schering-plough Labo N. V,Belgium). Broad use of a new generic product Otrio in combination with different statins will significantly increase the frequency of achievement of target lipid levels in patients with high and very high CV risk, including patients with chronic renal failure, type 2 diabetes and in patients with high hypercholesterolemia (LDL-C > 5 mmol/l) and, ultimately, reduce the burden of CV disease and mortality in Russia.

[Improvement of outcomes in patients with recent acute coronary syndrome: the place of PCSK9 inhibitors. The Resolution of National Advisory Board].

On April 9, 2018, the national advisory board "Improvement of outcomes in patients with recent ACS: the place of PCSK9 inhibitors" was held in Moscow. Leading Russian experts in the field of atherosclerosis and lipid-lowering treatment attended the board. The purpose of the Board was to determine the place of PCSK9 inhibitors in the improvement of outcomes in patients with recent (less than 1 year) acute coronary syndrome (ACS). During the Board, three major aspects of lipid-lowering treatment were discussed: 1) issues in reaching the target levels of LDL cholesterol in real clinical practice among patients with recent ACS; 2) the results of ODYSSEY OUTCOMES study and their role in the improvement of outcomes in patients with recent ACS; 3) treatment with PCSK9 inhibitors in the management of patients with recent (less than 1 year) ACS in everyday clinical practice, the role of lipid centers.

Improvement of ELISA procedures through simultaneous addition of antigen and detection antibody and elimination of washing steps.

The enzyme-linked immunosorbent assay (ELISA) is extensively used for measurement of proteins utilized for various research and diagnostic purposes in the biological disciplines. However, it is a labor-intensive and lengthy procedure due to a number of incubation and washing steps required for performing the assay. The ELISA procedure in the current study has been simplified through the simultaneous addition of antigen and detection antibody and elimination of washing steps. This resulted in a decreased time required to perform the procedure and without affecting assay capability. This approach offers the possibility of increasing ELISA productivity in low throughput laboratories without the need for alternative analytical platforms which would require significant assay redevelopment and capital expense.

Beyond traditional pharmacology: new tools and approaches.

Traditional pharmacology is defined as the science that deals with drugs and their actions. While small molecule drugs have clear advantages, there are many cases where they have proved to be ineffective, prone to unacceptable side effects, or where due to a particular disease aetiology they cannot possibly be effective. A dominant feature of the small molecule drugs is their single mindedness: they provide either continuous inhibition or continuous activation of the target. Because of that, these drugs tend to engage compensatory mechanisms leading to drug tolerance, drug resistance or, in some cases, sensitization and consequent loss of therapeutic efficacy over time and/or unwanted side effects. Here we discuss new and emerging therapeutic tools and approaches that have potential for treating the majority of disorders for which small molecules are either failing or cannot be developed. These new tools include biologics, such as recombinant hormones and antibodies, as well as approaches involving gene transfer (gene therapy and genome editing) and the introduction of specially designed self-replicating cells. It is clear that no single method is going to be a 'silver bullet', but collectively, these novel approaches hold promise for curing practically every disorder.

Caspase-cleaved arrestin-2 and BID cooperatively facilitate cytochrome C release and cell death.

Apoptosis is programmed cell death triggered by activation of death receptors or cellular stress. Activation of caspases is the hallmark of apoptosis. Arrestins are best known for their role in homologous desensitization of G protein-coupled receptors (GPCRs). Arrestins quench G protein activation by binding to activated phosphorylated GPCRs. Recently, arrestins have been shown to regulate multiple signalling pathways in G protein-independent manner via scaffolding signalling proteins. Here we demonstrate that arrestin-2 isoform is cleaved by caspases during apoptosis induced via death receptor activation or by DNA damage at evolutionarily conserved sites in the C-terminus. Caspase-generated arrestin-2-(1-380) fragment translocates to mitochondria increasing cytochrome C release, which is the key checkpoint in cell death. Cells lacking arrestin-2 are significantly more resistant to apoptosis. The expression of wild-type arrestin-2 or its cleavage product arrestin-2-(1-380), but not of its caspase-resistant mutant, restores cell sensitivity to apoptotic stimuli. Arrestin-2-(1-380) action depends on tBID: at physiological concentrations, arrestin-2-(1-380) directly binds tBID and doubles tBID-induced cytochrome C release from isolated mitochondria. Arrestin-2-(1-380) does not facilitate apoptosis in BID knockout cells, whereas its ability to increase caspase-3 activity and facilitate cytochrome C release is rescued when BID expression is restored. Thus, arrestin-2-(1-380) cooperates with another product of caspase activity, tBID, and their concerted action significantly contributes to cell death.

On the temperature dependence of ballistic Coulomb drag in nanowires.

We have investigated within Fermi liquid theory the dependence of Coulomb drag current in a passive quantum wire on the applied voltage V across an active wire and on the temperature T for any values of eV/k(B)T. We assume that the bottoms of the 1D minibands in both wires almost coincide with the Fermi level. We conclude that: (1) within a certain temperature interval the drag current can be a descending function of the temperature T; (2) the experimentally observed temperature dependence T(-0.77) of the drag current can be interpreted within the framework of Fermi liquid theory; (3) at relatively high applied voltages the drag current saturates as a function of the applied voltage; and (4) the screening of the electron potential by metallic gate electrodes can be of importance.

[The extent of coronary stenosis and the level of antibodies to atherogenic lipoproteins in patients with coronary heart disease].

AIM: To study association between the level of antibodies to oxidized low-density lipoproteins (anti-OLDL) and the extent of coronary stenosis (CS) in patients with coronary heart disease (CHD). MATERIAL AND METHODS: Sixty CHD patients were examined for titer of anti-OLDL, levels of total cholesterol (TC), LDLP cholesterol, HDLP cholesterol, triglycerides. Selective coronarography (SC) was made on demand. RESULTS: Elevated titer of anti-OLDL was found only in 12 examinees. It was significantly lower in CHD women than in men. No significant differences by anti-OLDL were found in CHD patients with and without significant risk factors. SC registered in all CHD examinees local stenosis of different severity. Stenosis in 3 coronary arteries was detected in 31 cases, in 2 coronary arteries--in 14, in 1 coronary artery--in 15 patients, most frequently the affection was located in the diagonal branch of the left coronary artery. Stenosis of the left coronary artery trunk was diagnosed in one case. The correlation analysis revealed a strongly significant positive correlation between content of anti-OLDL and the degree of CS. CONCLUSION: The level of anti-OLDL in CHD patients directly correlates with the degree of CS and is a marker of coronary atherosclerosis severity.

Dynamical response of nanostructures and Joule heat release.

We consider Joule heat release in a quantum wire joining two classical reservoirs under the action of a nonstationary periodic electric field. The rate of heat generation and its spatial distribution is discussed. The heat is spread over the lengths of electron mean free paths in the reservoirs. We find that the total rates of heat generation in both reservoirs that are joined by the nanostructure are the same.

Reduced expression of G protein-coupled receptor kinases in schizophrenia but not in schizoaffective disorder.

Alterations of multiple G protein-mediated signaling pathways are detected in schizophrenia. G protein-coupled receptor kinases (GRKs) and arrestins terminate signaling by G protein-coupled receptors exerting a powerful influence on receptor functions. Modifications of arrestin and/or GRKs expression may contribute to schizophrenia pathology. Cortical expression of arrestins and GRKs was measured postmortem in control and subjects with schizophrenia or schizoaffective disorder. Additionally, arrestin/GRK expression was determined in elderly patients with schizophrenia and age-matched control. Patients with schizophrenia, but not schizoaffective disorder, displayed a reduced concentration of arrestin and GRK mRNAs and GRK3 protein. Arrestins and GRK significantly decreased with age. In elderly patients, GRK6 was reduced, with other GRKs and arrestins unchanged. A reduced cortical concentration of GRKs in schizophrenia (resembling that in aging) may result in altered G protein-dependent signaling, thus contributing to prefrontal deficits in schizophrenia. The data suggest distinct molecular mechanisms underlying schizophrenia and schizoaffective disorder.

Residual resistance of 2D and 3D structures and Joule heat release.

We consider a residual resistance and Joule heat release in 2D nanostructures as well as in ordinary 3D conductors. We assume that elastic scattering of conduction electrons by lattice defects is predominant. Within a rather intricate situation in such systems we discuss in detail two cases. (1) The elastic scattering alone (i.e. without regard of inelastic mechanisms of scattering) leads to a transition of the mechanical energy (stored by the electrons under the action of an electric field) into heat in a traditional way. This process can be described by the Boltzmann equation where it is possible to do the configuration averaging over defect positions in the electron-impurity collision term. The corresponding conditions are usually met in metals. (2) The elastic scattering can be considered with the help of the standard electron-impurity collision integral only in combination with some additional averaging procedure (possibly including inelastic scattering or some mechanisms of electron wavefunction phase destruction). This situation is typical for degenerate semiconductors with a high concentration of dopants and conduction electrons. Quite often, heat release can be observed via transfer of heat to the lattice, i.e. via inelastic processes of electron-phonon collisions and can take place at distances much larger than the size of the device. However, a direct heating of the electron system can be registered too by, for instance, local measurements of the current noise or direct measurement of an electron distribution function.

Arrestin-1 expression level in rods: balancing functional performance and photoreceptor health.

In rod photoreceptors, signaling persists as long as rhodopsin remains catalytically active. Phosphorylation by rhodopsin kinase followed by arrestin-1 binding completely deactivates rhodopsin. Timely termination prevents excessive signaling and ensures rapid recovery. Mouse rods express arrestin-1 and rhodopsin at ∼0.8:1 ratio, making arrestin-1 the second most abundant protein in the rod. The biological significance of wild type arrestin-1 expression level remains unclear. Here we investigated the effects of varying arrestin-1 expression on its intracellular distribution in dark-adapted photoreceptors, rod functional performance, recovery kinetics, and morphology. We found that rod outer segments isolated from dark-adapted animals expressing arrestin-1 at wild type or higher level contain much greater fraction of arrestin-1 than previously estimated, 15-25% of the total. The fraction of arrestin-1 residing in the outer segments (OS) in animals with low expression (4-12% of wild type) is much lower, 5-7% of the total. Only 4% of wild type arrestin-1 level in the outer segments was sufficient to maintain near-normal retinal morphology, whereas rapid recovery required at least ∼12%. Supra-physiological arrestin-1 expression improved light sensitivity and facilitated photoresponse recovery, but was detrimental for photoreceptor health, particularly in the peripheral retina. Thus, physiological level of arrestin-1 expression in rods reflects the balance between short-term functional performance of photoreceptors and their long-term health.

Nonlocal dynamical response of a ballistic nanobridge.

The nonlocal dynamical response of a ballistic nanobridge to an applied potential oscillating with frequency ω is considered. It is shown that, in addition to the active conductance, there is also a reactive contribution. This contribution turns out to be inductive for relatively small frequencies ω. For bigger frequencies the current response is either inductive or capacitive, depending on the ratio of ωL/v(F), where L is the length of the bridge and v(F) is the Fermi velocity.

Dynamics of mouse rod phototransduction and its sensitivity to variation of key parameters.

The deep understanding of the biochemical and biophysical basis of visual transduction, makes it ideal for systems-level analysis. A sensitivity analysis is presented for a self-consistent set of parameters involved in mouse phototransduction. The organising framework is a spatio-temporal mathematical model, which includes the geometry of the rod outer segment (ROS), the layered array of the discs, the incisures, the biochemistry of the activation/deactivation cascade and the biophysics of the diffusion of the second messengers in the cytoplasm and the closing of the cyclic guanosine monophosphate (cGMP) gated cationic channels. These modules include essentially all the relevant geometrical, biochemical and biophysical parameters. The parameters are selected from within experimental ranges, to obey basic first principles such as conservation of mass and energy fluxes. By means of the model they are compared to a large set of experimental data, providing a strikingly close match. Following isomerisation of a single rhodopsin R * (single photon response), the sensitivity analysis was carried out on the photo-response, measured both in terms of number of effector molecules produced, and photocurrent suppression, at peak time and the activation and recovery phases of the cascade. The current suppression is found to be very sensitive to variations of the catalytic activities, Hill's coefficients and hydrolysis rates and the geometry of the ROS, including size and shape of the incisures. The activated effector phosphodiesterase (PDE *) is very sensitive to variations of catalytic activity of G-protein activation and the average lifetimes of activated rhodopsin R * and PDE *; however, they are insensitive to geometry and variations of the transduction parameters. Thus the system is separated into two functional modules, activation/deactivation and transduction, each confined in different geometrical domains, communicating through the hydrolysis of cGMP by PDE *, and each sensitive to variations of parameters only in its own module.

An improved method for the determination of Fc function of immunoglobulins.

BACKGROUND AND OBJECTIVES: The Fc function assay of immunoglobulin G is performed to ensure that the biological activity of the molecule is not compromised during purification and storage. The current British Pharmacopoeia (BP) method is cumbersome, time consuming and requires a continuous source of fresh red blood cells. We have modified the technique to improve the convenience, throughput and reproducibility of the assay by using frozen red blood cells, a microtitre plate format and electronic derivative analysis for processing results. MATERIALS AND METHOD: Immunoglobulin G samples were assayed using either the BP Fc function procedure or a new procedure incorporating frozen cells, microtitre format and electronic derivative analysis. RESULTS: The Fc function results demonstrated that there was no significant difference between the BP and the new improved procedure. CONCLUSION: In this study, we demonstrated that a new Fc function assay incorporating frozen red blood cells, microtitre format and derivative analysis of haemolysis curves has been shown to be comparable to the standard BP procedure. It offers a more convenient and quicker means of performing analysis of Fc function of immunoglobulins.