SIRT1 Allele Frequencies in Depressed Patients of European Descent in Russia

Depressive disorder (DD) is a widespread mental disorder. Although DD is to some extent inherited, the genes contributing to the risk of this disorder and its genetic mechanisms remain poorly understood. A recent large-scale genome-wide association Chinese study revealed a strong association between the SIRT1 gene variants and DD. The aim of this study was to analyze the occurrence of heterozygote carriers and search for rare SNP variants of the SIRT1 gene in a cohort of DD patients as compared with a cohort of randomly selected members of the Russian population. The complete coding sequences of the SIRT1 gene from 1024 DNA samples from the general Russian population and from 244 samples from patients with DD were analyzed using targeted sequencing. Four new genetic variants of the SIRT1 were discovered. While no significant differences in the allele frequencies were found between the DD patients and the general population, differences between the frequencies of homozygote carriers of specific alleles and occurrences of heterozygous were found to be significant for rs2236318 (P < 0.0001), and putatively, rs7896005 (P < 0.05), and rs36107781 (P < 0.05). The study found for the first time that two new SNPs (i.e., 10:69665829 and 10:69665971) along with recently reported ones (rs773025707 and rs34701705), are putatively associated with DD. The revealed DD-associated SIRT1 SNPs might confer susceptibility to this disorder in Russian population of European descent

Association of COMT gene polymorphisms with Parkinson's disease

Parkinson’s disease (PD) is one of the most serious and widespread neurodegenerative disorders. Genetic susceptibility plays a significant role in the development of PD.The aim of our study was to investigate associations between single nucleotide polymorphisms (SNPs) of the COMT gene coding dopamine catabolism enzyme and Parkinson’s disease.Materials and methods. In this study seven SNPs (rs4680, rs6269, rs4633, rs4818, rs769224, rs165774, rs174696) of COMT were genotyped. 232 patients with PD and 127 healthy individuals in the Siberian region of Russia were examined. Venous blood samples were drawn as a marker of PD. Statistical differences in the prevalence of alleles and genotypes between groups of patients were assessed using IBM SPSS Statistics 23.1 software.Results. A significant association between the rs165774 polymorphism and PD was observed. Our study demonstrates that polymorphisms in the COMT gene may play an important role in the pathophysiology of Parkinson’s disease

Association study indicates a protective role of phosphatidylinositol-4-phosphate-5-kinase against tardive dyskinesia

Background: Tardive dyskinesia is a disorder characterized by involuntary muscle movements that occur as a complication of long-term treatment with antipsychotic drugs. It has been suggested to be related to a malfunctioning of the indirect pathway of the motor part of the cortical-striatal-thalamic-cortical circuit, which may be caused by oxidative stress-induced neurotoxicity. Methods: The purpose of our study was to investigate the possible association between phosphatidylinositol-4-phosphate-5-kinase type IIa (PIP5K2A) function and tardive dyskinesia in 491 Caucasian patients with schizophrenia from 3 different psychiatric institutes in West Siberia. The Abnormal Involuntary Movement Scale was used to assess tardive dyskinesia. Individuals were genotyped for 3 single nucleotide polymorphisms in PIP5K2A gene: rs10828317, rs746203, and rs8341. Results: A significant association was established between the functional mutation N251S-polymorphism of the PIP5K2A gene (rs10828317) and tardive dyskinesia, while the other 2 examined nonfunctional single nucleotide polymorphisms were not related. Conclusions: We conclude from this association that PIP5K2A is possibly involved in a mechanism protecting against tardive dyskinesia-inducing neurotoxicity. This corresponds to our hypothesis that tardive dyskinesia is related to neurotoxicity at striatal indirect pathway medium-sized spiny neurons

Отдаленные последствия цитостатических воздействий на зародышевые клетки тестикулярной ткани (экспериментальное исследование)

Currently, cytostatic drugs are widely used not only in cancer treatment, but also in the treatment of autoimmune infammatory diseases. A favorable prognosis of the disease, ability to reproduce, young age and the absence of children serve as an incentive to decide on the need for childbearing. There is concern, that the mutagenic effects of chemotherapy in germ cells, the ability to induce epigenetic changes in them, may have phenotypic manifestations in offspring. Conception in the early stages after treatment (impact on mature and differentiating germ cells) has been proven to increase the risk of defective offspring. Data on the health of the offspring of patients conceived in the long term after treatment (impact on stem spermatogenic cells) are contradictory. The aim of the study was to assess long-term toxic effects of cytostatic drugs in the male rat offspring copulated in terms corresponding to the effect on stem spermatogonial cells (SSCs). Material and Methods. The experiments were carried out on autobred male Wistar rats (n=140), aged 2.5 months, 70 of which made up the group of intact animals. The effect of cytostatic drugs (etoposide, irinotecan, cisplatin, carboplatin, methotrexate, farmorubicin, and paclitaxel) injected 3 and 6 months before mating was assessed on the offspring of intact female and male rats. Results. The male rat offspring treated with cytostatic drugs was found to be viable. Gross external developmental anomalies were detected in 2 cases. In several offspring, a slowdown in physical development, decrease in the rate of formation of sensory-motor refexes and learning ability were observed. The most toxic drugs were etoposide and paclitaxel. Conclusion. The offspring of rats treated with cytostatic drugs in terms corresponding to the effect on the SSCs is at risk. The degree of severity of long-term effects varies signifcantly and depends on the type of the drugs used. A decrease in the ability to learn is the most frequently detected abnormalities in offspring. Judging by the timing of conception after cytostatic exposure, a signifcant increase in the period of time after the administration of the drug before mating is not always justifed.Цитостатические препараты широко используются сегодня не только в онкологической клинике, но и при терапии аутоиммунных воспалительных заболеваний. Благоприятный прогноз заболевания, наличие способности к воспроизводящей функции, молодой возраст и отсутствие детей служат побудительным моментом для принятия решения о необходимости деторождения. Опасение вызывает тот факт, что мутагенные эффекты химиотерапии в зародышевых клетках, способность вызывать в них эпигенетические изменения могут иметь фенотипические проявления у потомства. Доказано, что при зачатии в ранние сроки после лечения (воздействие на зрелые и дифференцирующиеся половые клетки) риск появления неполноценного потомства высок. Данные о состоянии потомства пациентов при зачатии в отдаленные сроки после лечения (воздействия на стволовые сперматогенные клетки) противоречивы. Целью исследования явилась оценка состояния потомства крыс-самцов, получавших цитостатические препараты разных групп, при скрещивании в сроки, соответствующие проявлению воздействия на стволовые сперматогониальные клетки (ССК). Материал и методы. Эксперименты проведены на аутобредных крысах-самцах Вистар (n=140), в возрасте 2,5 мес, 70 из которых составили группу интактных животных. Оценивалось состояние потомства (в постнатальном периоде развития) интактных крыс-самок и самцов, получавших этопозид, иринотекан, цисплатин, карбоплатин, метотрексат, фарморубицин, паклитаксел за 3 и 6 мес до скрещивания. Результаты. Установлено, что потомство крыс-самцов, получавших цитостатические препараты, оказалось жизнеспособным. В 2 (0,24 %) случаях выявлены грубые внешние аномалии развития. У части потомства наблюдалось замедление физического развития, снижение скорости формирования сенсорно-двигательных рефлексов, способности к обучению. Наиболее токсичными оказались этопозид и паклитаксел. Выводы. Потомство животных, получавших цитостатические препараты в сроки, соответствующие воздействию на ССК, относится к группе риска. Степень выраженности отдаленных последствий существенно варьирует и зависит от вида цитостатического воздействия. К числу наиболее часто выявляемых отклонений у потомства относится снижение способности к обучению. Судя по срокам зачатия после цитостатического воздействия, существенное увеличение периода времени после введения препарата до скрещивания не всегда является оправданным.

CRYOBALLOON ABLATION FOR ATRIAL FIBRILLATION IN DIFFERENT ANATOMY OF PULMONARY VEINS

Aim. To evaluate the results of cryo-ablation in a variety of pulmonary veins (PV) anatomy.Material and methods. Into prospective randomized study, 94 patients were included, with tolerant to drug treatment atrial fibrillation (AF), age 55,9±9,8 y.o., of those 48 males and 46 females. The median of an arrhythmic anamnesis lasted for 4 (1,5; 5) years. Seven patients had undergone radiofrequency ablation (RFA) of cavotricuspid isthmus (CTI), 5 had recurrent AF after former RFA. Seven — at the moment of admittance, had persistent AF. Under the framework of preoperational investigation, all patients underwent contrast multispiral computed tomography of the heart. The architectonics of the PV was assessed: number, diameter, specifics of opening, thrombi. Depending on the anatomy of the PV, patients were selected to 2 groups — typical and variant anatomy. The prevalence of a variety of PV anatomy was 13,8%. By the key clinical characteristics, the groups were comparable. All patients underwent cryoballoon isolation of the PV with the ArcticFront28 mm and ArcticFront Advance28 mm catheters. All patients with variants of PV anatomy underwent the procedure with the 2nd generation catheter. For verification of the PV isolation, Achieve catheter was used. In all cases of PV isolation it was verified as the enter and exit block, with no adenosine test.Results. In the group of variation PV anatomy, in 11 cases, there was collector of the left PV or their opening into the left atrium (LA) by common ostium. There were no significant differences in a direct specifics of procedures: duration of ablation (75 (46,2; 105) vs 60 (52; 70) min, p=0,40) and duration of fluoroscopy (17 (16; 23,7) vs 20 (16,3; 23,8) min, p=0,64). The analysis of non-related groups showed significantly higher prevalence of complications development in the variation anatomy group, and the prevalence of nervus phrenicus palsy (NPP) (6,9 vs 3,7%) as vascular approach complications (3,19 vs 2,5%), were comparable (p>0,05). Also, in patients with the common ostium of PV there was pericarditis development more frequently during post-operation period, that led to anti-inflammatory treatment prescription. Long-term analysis shows the significant decrease of the method efficacy in variation PV anatomy, especially in presence of collector/vestibule of PV, even with the 2nd generation balloon usage.Conclusion. Existence of a collector/vestibule of the left PV is associated with significant worsening of the long-term results of cryoballoon ablation, even in 2nd generation devices utilization

COMPARISON OF THE DISORDERED MECHANICAL FUNCTION OF THE LEFT ATRIUM AFTER ANTRAL ISOLATION OF PULMONARY VEINS BY RADIOFREQUENCY OR CRYOBALLOON ABLATION

Aim. To assess and compare mechanical functioning of the left atrium before and just after cryoballoon or radiofrequency ablation.Material and methods. Totally, 43 patients included, with sympthomatic atrial fibrillation resistant to drug treatment. Of those 21 — for cryoballoon ablation (mean age 57,8±8,7 y. o., 11 males and 10 females) and 22 candidates for radiofrequency ablation, at the age 54,4±11 y. o., 16 males and 6 females. Before procedure, just after and on the 5th day, transthoracal echocardiography was performed, with measurement of Doppler parameters of intracardiac hemodynamics, as mechanical function of the left atrium assessment, including 3D imaging.Results. By the data from transthoracal echocardiography and direct intraoperation manometry, the significant disorders of the left atrium (LA) mechanical function were found in both treatment groups, with some differences. Pulmonary veins (PV) isolation by any method does not influence diastolic and systolic function of the left ventricle, that confirmed by invasive measurements of the end-diastolic pressure in LV, as the changes of volumes and ejection fraction by echocardiography. Therefore transmitral blood flow dynamics, as PV and pulmonary artery flow, related to PV isolation procedure, is a result of the LA functioning disorder due to its passive dilatability and active contractility decrease, dysfunction of the PV sleeves, increase of pulmonary vascular resistance. The significant decrease found in LA pumping function, more prominent in radiofrequency group just after the procedure, with further improvement to the 5th day after procedure. Also, mean pulmonary artery pressure increase, and till the 5th day in radiofrequency group it was significantly higher than in cryoablation group.Conclusion. Both cryo and radio ablation procedures of PV isolation significantly impact on the mechanical functioning of the LA, however cryo ablation leads to less severe disorder at short follow-up