Molecular effects of cardiac contractility modulation in patients with heart failure of ischemic aetiology uncovered by transcriptome analysis.

Cardiac contractility modulation (CCM) is based on electrical stimulation of the heart without alteration of action potential and mechanical activation, the data on its fundamental molecular mechanisms are limited. Here we demonstrate clinical and physiological effect of 12 months CCM in 29 patients along with transcriptomic molecular data. Based on the CCM effect the patients were divided into two groups: responders (n = 13) and non-responders (n = 16). RNA-seq data were collected for 6 patients before and after CCM including 3 responders and 3 non-responders. The overall effect of CCM on gene expression was mainly provided by samples from the responder group and included the upregulation of the genes involved in the maintenance of proteostasis and mitochondrial structure and function. Using pathway enrichment analysis, we found that baseline myocardial tissue samples from responder group were characterized by upregulation of mitochondrial matrix-related genes, Z disc-protein encoding genes and muscle contraction-related genes. In summary, twelve months of ССM led to changes in signaling pathways associated with cellular respiration, apoptosis, and autophagy. The pattern of myocardial remodeling after CCM is associated with initial expression level of myocardial contractile proteins, adaptation reserves associated with mitochondria and low expression level of inflammatory molecules.

[The role of antidiabetic drugs in the treatment of Alzheimer's disease: systematic review].

Recent studies show that Alzheimer's disease (AD) has many common links with conditions associated with insulin resistance, including neuroinflammation, impaired insulin signaling, oxidative stress, mitochondrial dysfunction and metabolic syndrome. The authors conducted an electronic search for publications in the PubMed/MEDLINE and Google Scholar databases using the keywords "amyloid beta", "Alzheimer type-3-diabetes", "intranasal insulin", "metformin", "type 2 diabetes mellitus", "incretins" and "PPARy agonists¼. A systematic literature search was conducted among studies published between 2005 and 2022. The authors used the following inclusion criteria: 1) Subjects who received therapy for AD and/or DM2, if the expected result concerned the risk of cognitive decline or the development of dementia; 2) The age of the study participants is > 50 years; 3) The type of studies included in this review were randomized clinical trials, population-based observational studies or case-control studies, prospective cohort studies, as well as reviews and meta-analyses; 4) The included articles were written in English. In recent years, there has been considerable interest in identifying the mechanisms of action of antidiabetic drugs and their potential use in AD. Human studies involving patients with mild cognitive impairment and Alzheimer's disease have shown that the administration of certain antidiabetic drugs, such as intranasal insulin, metformin, incretins and thiazolidinediones, can improve cognitive function and memory. The purpose of this study is to evaluate the effectiveness of antidiabetic drugs in the treatment of AD. According to the results of the study, metformin, intranasal insulin, thiazolidinediones and incretins showed a positive effect both in humans and in animal models. Recent studies show that thiazolidinediones can activate pathways in the brain that are regulated by IGF-1; however, rosiglitazone may pose a significant risk of side effects. The results of clinical studies on the use of metformin in AD are limited and contradictory.

[Encephalopathy GNAO1]. / Entsefalopatiya GNAO1.

OBJECTIVE: To study the clinical picture of all patients with GNAO1 encephalopathy detected in the Russian Federation. This publication is a multicenter study combining data from epileptological centers in Moscow, Novosibirsk, St. Petersburg, Nizhny Novgorod, Tyumen. MATERIAL AND METHODS: Nine patients were included, aged 2 to 19 years, with 4 mutations. Male to female sex ratio = 5:4. RESULTS: 8 patients (5 with mutation c.607G>A (p.Gly203Arg), 1 - c.155A>G (Gln52Arg), 1 - c.485G>A (p.Arg162Gln)) had a variant of epileptic encephalopathy, developmental encephalopathy, 1 patient had torsion dystonia without epilepsy (mutation c.713A>G (p.Asp238Gly)). Epileptic seizures in 8 children with epileptic encephalopathy GNAO1 in 100% debuted at 1 month of life, becoming the earliest symptom of the disease. Motor development delayed in 100% of cases. Mental development was not affected only in the case of the dystonic variant. Hyperkinesis (dystonia, choreoathetosis, ballism) followed later, from 2 to 8 months. They were more severe than epilepsy. 4 patients with the c.607G>A (p.Gly203Arg) mutation developed repeated dystonic storms that were resistant to most drugs. CONCLUSION: Epilepsy in GNAO1 is difficult to treat, but temporary or complete remission is possible. Effective drug strategies for the treatment of hyperkinesis have not yet been developed. Expansion of indications for surgical therapy (DBS) of hyperkinesis in this syndrome is desirable.

[Reverse remodelling of the heart after atrial fibrillation ablation in patients with heart failure with reduced ejection fraction].

AIM: To evaluate the effect of atrial fibrillation (AF) catheter ablation (CA) on long-term freedom from AF and left heart reverse remodeling in patients with heart failure with reduced ejection fraction (HFrEF). METHODS: There were 47 patients (mean age 53.3 ± 10 years, 39 males) enrolled into single-center observational study, with left ventricular ejection fraction (LVEF) <40 %. Patients underwent CA for AF refractory to antiarrhythmic drugs. Baseline clinical data and diagnostic tests results were obtained during personal visits and / or via secure telemedical services. Personal contact with evaluation of recurrence of AF and echocardiographic values was performed with 30 (64 %) patients. RESULTS: Paroxysmal AF was present in 12 (40 %) patients, persistent - in 18 (60 %). During mean follow-up of 3 years (0.5-6 years) redo ablation was performed in 9 patients (30 %) with average number of 1.3 procedures per patient. At 6 months 24 (80 %) patients were free from AF, at last follow-up - 16 (53 %). The mean time to first recurrence following CA was 15.6±13.3 months. Follow-up echocardiography revealed significant LVEF improvement (р<0,0001), reduction of left atrium size (р<0,0001), left ventricle end-diastolic volume (р<0,002) and left ventricle endsystolic volume (p<0,0001) and mitral regurgitation (р=0,001). CONCLUSION: AF CA in patients with HFrEF is associated with improvement in systolic function and left heart reverse remodeling. Durable long-term antiarrhythmic effect often requires repeated procedures.

A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer.

BACKGROUND: The effect of histology-based treatment regimen on diffuse gastric adenocarcinoma has not been evaluated in clinical trials. This international phase III trial evaluated the efficacy and safety of S-1 (a contemporary oral fluoropyrimidine)/cisplatin versus 5-fluorouracil (5-FU)/cisplatin in chemotherapy-naïve patients with diffuse-type adenocarcinoma involving the gastroesophageal junction or stomach. PATIENTS AND METHODS: Eligibility criteria included untreated, measurable, advanced diffuse adenocarcinoma confirmed by central pathology and performance status of 0-1. Patients were randomized (2 : 1) to receive S-1/cisplatin or 5-FU/cisplatin. Primary end point was overall survival (OS), and secondary end points were progression-free survival, time to treatment failure, overall response rate, and safety. A multivariable analysis was also carried out. RESULTS: Overall, 361 patients were randomized (S-1/cisplatin, n = 239; 5-FU/cisplatin, n = 122); half (51%) were men, and median age was 56.0 years. In each group, median number of treatment cycles per patient was 4 (range, S-1/cisplatin: 1-20; 5-FU/cisplatin: 1-30), and dose intensity was >95%. OS was not different in the two groups {median OS with S-1/cisplatin, 7.5 [95% confidence interval (CI): 6.7, 9.3]; 5-FU/cisplatin, 6.6 [95% CI: 5.7, 8.1] months; hazard ratio, 0.99 [95% CI: 0.76, 1.28]; P = 0.9312}. Overall response rate was significantly higher in the S-1/cisplatin than 5-FU/cisplatin group (34.7% versus 19.8%; P = 0.01), but progression-free survival and time to treatment failure were not different. Safety was similar between the 2 groups; however, fewer patients treated with S-1/cisplatin than 5-FU/cisplatin had ≥1 grade 3/4 treatment-emergent adverse event or ≥1 adverse event resulting in treatment discontinuation. One treatment-related death occurred in each group. Slow accrual led to early termination. CONCLUSIONS: These data suggest that S-1/cisplatin and 5-FU/cisplatin are similar in efficacy and safety in untreated patients with advanced diffuse adenocarcinoma of the gastroesophageal junction or stomach. The primary end point was not met. CLINICALTRIAL.GOV REGISTRATION NUMBER: NCT01285557.

The 5-chlorouracil:7-deazaadenine base pair as an alternative to the dT:dA base pair.

5-Chloro-2'-deoxyuridine as a possible component of a chemically modified genome has been discussed in terms of its influence on duplex stability and DNA polymerase incorporation properties. The search for its counterpart among different deoxyadenosine analogs (7-deaza-, 8-aza- and 8-aza-7-deaza-2'-deoxyadenosines) showed that the stable duplex formation as well as the synthesis of long constructs, more than 2 kb, were successful with the 5-chloro-2'-deoxyuridine and 7-deaza-2'-deoxyadenosine combination and with Taq DNA polymerase.

Achiral, acyclic nucleic acids: synthesis and biophysical studies of a possible prebiotic polymer.

The search for prebiotic, nucleic acid precursors is, at its best, a speculative undertaking. Given the complex structure of RNA, it is not very likely that RNA was the first information system in the universe and thus finding possible precursor/s i.e. pre-RNA remains an open challenge. We, in this paper, have tried to construct nucleic acid polymers with a simple acyclic, achiral backbone. Such a linear, achiral backbone may have been formed from simple monomers that may have existed in the "prebiotic soup". We have shown that such polymers are capable of identifying the complementary "other self" and thus forming a potential system for information storage and transmission. This study thus involves investigation of nucleic acid analogues with a modified backbone that are likely to have formed in the prebiotic setting.

NMR study on the interaction of the conserved CREX 'stem-loop' in the Hepatitis E virus genome with a naphthyridine-based ligand.

A 2-amino-1,8-naphthyridine derivative that is described to bind single guanine bulges in RNA-DNA and RNA-RNA duplexes was synthesized and its interaction with the single G bulge in the conserved CREX of the Hepatitis E Virus (HEV) genome was explored by NMR and molecular modeling. Results indicate that the ligand intercalates in the internal loop, though none of the expected hydrogen bonds with the single G in the bulge could be demonstrated.

Sulfonate derived phosphoramidates as active intermediates in the enzymatic primer-extension of DNA.

Novel unnatural 5'-phosphoramidate nucleosides, capable of being processed as substrates by DNA polymerases for multiple nucleotide incorporations, have been designed. The mimics feature metabolites such as taurine and a broad range of aliphatic sulfonates coupled through a P-N bond to the 5'-phosphate position of deoxynucleotides, to allow binding interactions in the enzyme active site. The utility of all of the analogues as pyrophosphate mimics was demonstrated for the chain elongation of DNA, using both thermophilic and mesophilic microbial polymerases.

[Effectiveness of DNA repair and expression of MLH1, MSH2 and FASR in lymphocytes of patients with chemotherapy-responsive, disseminated cutaneous melanoma].

Patients with advanced malignant melanoma have poor prognosis as conventional chemotherapy induces complete response in a very small fraction (not more than 20%). One of research strategies aimed at raising its efficiency is the search for markers predicting individual response to chemotherapy. Our study was concerned with evaluation of the potential of DNA damage, repair (BER, MMR), expression of proteins MLH1, MSH2 and FasR as prognosticators of chemotherapy. These parameters were assessed in lymphocytes sampled from the blood of patients with metastatic cutaneous melanoma before and after one cycle of chemotherapy with lomustine, dacarbazine, cisplatin and interferon-gamma (LDCI). Clinical response was evaluated after a full course of therapy. We established that the major DNA damage induced by chemotherapy occurred on the levels of AP sites and single strand (SS) breaks. Despite the individual variations in BER efficacy, complete repair of SS breaks was reported in lymphocytes of all patients 30 days after the first cycle of chemotherapy. As a consequence, this type of damage and relevant BER efficacy did not correlate with clinical response. Conversely, the number of DNA double strand breaks detected in lymphocytes after the first cycle of chemotherapy was in good correlation with positive clinical response (p < 0.001). This parameter does not fully represent MMR function and, if coupled with cytotoxic effect of chemotherapy on lymphocytes, may be used as a predictive marker for clinical response to LDCI chemotherapy regimens for melanoma.

[Cellular markers based on DNA damage and repair (BER, MMR), expression of MLHI, MSH2, FasR, and cell death of lymphocytes as predictive parameters for clinical response to chemotherapy of melanoma].

Melanoma is a highly aggressive neoplastic disease attributed to transformed melanocytes. The efficacy of regimens of cytotoxic chemotherapy for advanced stage patients does not exceed 20%. Search for lymphocyte markers of patients' sensitivity to chemotherapy provides a rational basis for development of cytotoxic chemotherapy. Using blood lymphocytes we evaluated efficacy of BER and MMR, expression of MLH1, MSH2 and FasR, and cell death in melanoma patients relative to clinical response to chemotherapy. We found that LDCI-chemotherapy (lomustine, dacarbazine, cisplatin and interferon gamma), induced AP sites and DNA ss-breaks which repaired trough BER pathway. However, neither initial DNA damage nor the rate of their repair correlated with clinical response. This result prompts us to think that this type of damage is not crucial in cytotoxic effect of LDCI-regimen of chemotherapy. DNA ds-breakes appeared downstream ss-breakes were attributed to repair of 06-methylguanine by MMR mechanism in PHA-stimulated lymphocytes. The number of ds-breakes appeared by 48 correlated with positive clinical response of patients to chemotherapy. The same link was observed between clinical response and the number of dead lymphocytes. However, there was no correlation between clinical response and expression of MLHI + MSH2 and FasR. These results imply possible contribution of crosslink repair through NER pathway to formation of DNA ds-breaks as well as to cytotoxicity of LDCl-therapy. The observed link between high level of secondary ds-breaks and positive response to chemotherapy indicates the potential of these instruments to serve as prognostic end point in clinical trials.

[Minimally-invasive combined radiosurgical interventions in diagnosis and treatment of pulmonary artery thromboembolism]. / Maloinvazivnye kombinirovannye rentgenokhirgicheskie vmeshatel'stva pri diagnostike i lechenii tromboémbolii legochno-arterial'nogo basseina.

Basing on the analysis of results obtained during the investigation and treatment of 38 patients suspected of pulmonary artery thromboembolism (PAT) the algorithm of measures applied in our hospital was developed. Its purpose was to put the PAT diagnosis and treatment in order. In our investigations the leading treatment method was the regional infusion therapy conducted through the transformation of diagnostic catheterization of pulmonary artery trunk into the treatment intervention. With the purpose of embolus hydrodynamic destruction the regional thrombolysis was conducted under conditions of fast high-pressure perfusion. It was preceded by the mechanical recanalization of thrombosis zone by the distal part of probe in order to create more favorable perfusion conditions. To prevent the repeated PAT when the source of thromboembolism was revealed the cava-filter implantation in the infra-renal part of inferior cava was performed.

[Treatment of inflammatory conditions of the iris and ciliary body, accompanying fibrin exudation]. / Lechenie vospalitel'nykh sostoianii raduzhki i tsiliarnogo tela, soprovozhdaiushchikhsia fibrinoidnoi ékssudatsiei.

The paper presents a description of a new method for treatment of iris and ciliary body inflammation accompanied with fibrin exudation. We used low-level blue laser destroying a fibrin clot in its initial stage of formation. We also used herapin and ascorbic acid. In the absence of the greatest impact urokinase was additionally administered.

[Radiation risk in aircraft altitude flights]. / Radiatsionnyi risk pri vysotnykh aviatsionnykh poletakh.

The radiation risk in aircraft altitude flights was evaluated from calculated dose fields at the altitude of 10-30 km 0-90 degrees North modulated by the galactic cosmic radiation (GCR) in quiescent heliophysical periods. Results of dose measurements in flight are discussed in the light of present-day radiation limits. The authors suggest that pilots should be subsumed under the category of professionals who work with sources of ionizing radiation.

[Characteristics of aphakic eye in patients with diabetes]. / Nekotorye osobennosti afakicheskogo glaza u bol'nykh diabetom.

Ninety patients with aphakia and diabetes were examined. Intraocular pressure was normal in 30 patients, in 30 aphakia was concomitant with primary glaucoma, and 30 presented with aphakic glaucoma. Fundus oculi was examined with a slit lamp and +60 D lens, gonioscopy and cycloscopy were carried out using a contact prism proposed by the authors. Aphakic glaucoma developed as a result of changes in the anterior chamber corner: coarse postoperative cicatrices and vitreo-corneal adhesions. Diabetic retinopathy was equally incident in all three groups of patients. Changes in the ciliary vessels can anticipate diabetic retinopathy. New vessels on ciliary body processes is an unfavorable prognostic sign as regards visual functions in patients with aphakia and increased intraocular pressure.

[The role of the vasoconstrictor effect in realizing the radioprotective properties of indralin in experiments on dogs]. / Rol' vazokonstriktornogo éffekta v realizatsii protivoluchevykh svoistv indralina v opytakh na sobakakh.

In the experiments on dogs, the role of a pharmacological circulatory hypoxia in the mechanism of radioprotective effect of indraline and mexamine was studied. Angiography revealed 20-40% vasoconstriction of major arteries of legs of animals, of pelvis and abdomen caused by mexamine (10 mg/kg) and the absence of a significant effect of indraline. Disruption of a regional blood circulation in the marrow and spleen (40-50% and 70-80%, respectively) was caused by indraline to the same extent as by mexamine. For indraline, a decrease in pO2 in the marrow was about 50%. With these hemodynamic disturbances, indraline showed 80 to 100% radioprotective effect, while mexamine was inefficient. Acute hypoxic hypoxia (5-7% O2) increased a post-radiation survival rate for dogs by 40%. The radioprotective effect of indraline was blocked by tropaphen and reduced in cases of breathing with pure oxygen. Splenectomy has no effect on radioprotective properties of indraline. Thus, a hypothesis of the mechanism of a radioprotective effect of alpha-adrenomimetics was proposed.

[Mechanism of the radiation-protective effect of indralin]. / K mekhanizmu protivoluchevogo deistviia indralina.

Pharmacological test demonstrated that radioprotective activity of indralin occurs by interaction with alpha-adrenoreceptor. Radioprotective effect of indralin decreased by alpha-adrenoblocker, aminazine and theophylline. Normobaric hyperoxia during irradiation reduced radioprotective effect of indralin in doses about ED50. In experiment with mice and rats it was shown that indralin induced acute hypoxia, impaired oxygen consumption and heat production by 30-46%, spleen bloodflow to 26.3% of control level, rectal temperature by 1.5-2 degrees C (mouse). After 30-min indralin raised resistance of mice to hypoxic hypoxia that is believed due to rapid development of biochemical adaptive process in hypoxic cells.

[The early reaction of the neuroendocrine system to irradiation at high doses]. / Ranniaia reaktsiia neiroéndokrinnoi sistemy pri obluchenii v vysokikh dozakh.

It has been found that in 2 hours after the total gamma irradiation of rats at doses of 20 and 100 Gy the ACTH and glucagon levels in plasma increased by 5-6 and 10-12 times correspondingly. No significant changes in levels of plasma insulin and glucose have been revealed.