Vol 74, No 2 (2019)


Epigenetics of Friedreich’s Disease: Methylation of the (GAA)n-Repeats Region in FXN Gene

Abramycheva N.Y., Fedotova E.Y., Nuzhnyi E.P., Nikolaeva N.S., Klyushnikov S.A., Ershova M.V., Tanas A.S., Illarioshkin S.N.


Background: Friedreich’s disease (FD) is the most common hereditary ataxia. It is associated, most frequently, with homozygous GAA repeats expansion in intron 1 of the FXN gene. Methylation of the FXN gene can play an important role in the pathogenesis of FD. Aims: to study methylation pattern in CpG sites flanking GAA-expansion in intron 1 of the FXN gene in patients with FD and their heterozygous relatives as well as its relationship with clinical features. Materials and methods: We studied DNA samples from patients with FD (n=18), their relatives carrying heterozygous GAA expansion (n=12), and control group (n=15). Pattern of methylation was studied by direct sequencing of DNA regions after bisulphide processing. Results: We analyzed 18 CpG sites in the UP-GAA region of the gene (before GAA-repeats) and 12 CpG sites in the DOWN-GAA region (after GAA-repeats). In the UP-region, the mean methylation level of CpG sites in FD patients was higher compared to controls (n=15) (р<0.05), while in the DOWN-region there was a decrease of mean methylation level in FD compared to controls (р<0.05). Analysis of methylation level in different CpG sites in the UP-GAA region revealed hypermethylation for 15 of 18 CpG-sites as compared to controls (р<0.05). The most significant differences in methylation level in the UP-GAA region were seen for CpG sites 50−54, 57 and 58. In contrast, in the DOWN-GAA region almost all CpG sites were fully methylated in the control group, while in FD patients methylation was significantly lower (р<0.05). We revealed positive correlation of mean methylation level and more expanded allele length for the UP-GAA region in FD (r=0.63; p=0.03), and no correlations for the DOWN-GAA region. In heterozygous carriers we observed an analogous positive correlations in the UP-GAA region for CpG site 50 (r=0.77; p=0.04), while in the DOWN-GAA region there was inverse correlation of methylation with GAA repeat number in the expanded allele (r=-0.83, p=0.02). Negative correlation was found between the hypermethylation of some CpG-sites in the UP-GAA region and age of the disease onset (p<0.05). Conclusion: We revealed hypermethylation in the UP-GAA region and hypomethylation in the DOWN-GAA region in patients with FD compared to controls and correlations of methylation level with the GAA expansion length and age of disease onset.

Annals of the Russian academy of medical sciences. 2019;74(2):80-87
pages 80-87 views


The Impact of Migration on HIV Infection Situation (Analytical Review)

Pokrovskaya A.V., Yumaguzin V.V., Kireev D.E., Vinnik M.V., Pokrovskiy V.V.


Today, the unstable political and economic situation in the world has led to an intensified migration and changes in their directions. The legal norms regarding the status of migrants, including people living with HIV, are also changing. Over the past 10 years laws restricting the entry and residence of HIV-infected foreign citizens have been repealed in many countries, but in Russia the deportation and prohibition of long-term stay of HIV positive international migrants are still in effect. This review presents the main aspects of the impact of migration on the spread of HIV in the world and Russia, as well as the possible positive and negative effects of decriminalization of migrants living with HIV in terms of epidemic situation, socio-demographic and economic processes. The argument for retaining the deportation is due to the potential risk of the spread of the disease by foreigners and the unresolved organization of medical care and treatment of HIV infection for foreign migrants, which are provided for Russian citizens from the state budget. On the other hand, the deportation law touches upon ethical aspects, violating freedom of movement, the right to privacy and freedom from discrimination. Despite the presence or absence of restrictive measures against HIV-positive migrants, HIV has spread throughout all countries and led to a global epidemic. Prevention of HIV infection among general population of the country, regardless of their migration status, is a priority on the way to stop the spread of infection.


Annals of the Russian academy of medical sciences. 2019;74(2):88-97
pages 88-97 views


Anticoagulant Therapy for Atrial Fibrillation in Real Practice: Problems and Prospects

Skirdenko Y.P., Nikolaev N.A., Livzan M.А., Ershov A.V.


In the review of the current literature urgent issues of treatment of patients with atrial fibrillation are analyzed, namely prevention of thrombosis and the use of anticoagulants therapy. The article describes the current possibilities of prevention thromboembolic complications in patients with atrial fibrillation at high risk. The fact of insufficient use of preventive antithrombotic therapy in patients with atrial fibrillation with high thrombotic risk is demonstrated, which is associated both with incomplete adherence of doctors to the implementation of clinical recommendations, and with low adherence of patients to receiving prescribed anticoagulants. The review of the literature discusses the difficulties of the use of oral anticoagulants, in particular direct action and their high financial burden, and anticoagulants indirect action and instability of their pharmacological effect. The article demonstrates the difficulties of warfarin therapy, such as insufficient adherence to treatment, genetic characteristics of the patient, alimentary and drug interactions. When discussing the issue of insufficient adherence, it is shown that the data on adherence to drug therapy are not homogeneous and do not fully take into account the influence of patient-dependent characteristics. The prospects of developing an individualized algorithm for choosing an anticoagulant for long-term administration for patients with atrial fibrillation from the position of a patient-oriented approach are separately discussed.

Annals of the Russian academy of medical sciences. 2019;74(2):98-107
pages 98-107 views


Oncolytic Viruses As Immunotherapeutic Agents for the Treatment of Malignant Tumors

Glukhov A.I., Sivokhin D.A., Seryak D.A., Rodionova T.S., Kamynina M.I.


Oncolytic viruses (OVs) are novel and rapidly developing class of therapeutic agents for combating cancer, which can effectively infect and destroy tumor cells, leaving healthy tissues intact. Many viruses have a natural antitumor activity which causes cytolysis of cancer cells due to direct pathogenic action. Along with non-immunogenic cell death, oncolytic viruses have been shown to be capable of inducing immunogenic cancer cell death (necrosis, pyroptosis, etc.) accompanied by the release of OV-lysed tumor-associated antigens (TAAs). Releasing DAMPs and TAAs, in its turn, leads to the activation of adaptive antitumor immunity. In order to further enhance the antitumor immunity, OVs have been armed with immunostimulatory transgenes such as granulocyte-macrophage colony-stimulating factor (GM-CSF), type I interferons, interleukins (IL-2, 12, 15), costimulatory ligands (CD40, CD80), tumor antigens («prime-boost» vaccination), which further enhances the safety and effectiveness of oncolytic virotherapy. Preliminary results of randomized clinical trials of different approaches of oncolytic virotherapies in combination with immunotherapy confirm their high efficacy. However, there are some drawbacks, which necessitates their further study.

Annals of the Russian academy of medical sciences. 2019;74(2):108-117
pages 108-117 views

Principles of Diagnosis and Personalized Treatment of Hereditary Colorectal Cancer

Tsukanov A.S., Shelygin Y.A., Achkasov S.I., Frolov S.A., Kashnikov V.N., Kuzminov A.M., Pikunov D.Y., Shubin V.P.


The most frequent forms of hereditary colorectal cancer syndromes are Lynch syndrome and familial adenomatous polyposis (FAP). All the patients with suspicion to these syndromes need precise clinical and genetic diagnostics. Affected patients need personalized program of treatment because standard algorithm cannot be considered sufficiently effective. Identification of a pathogenic mutation in a patient indicates the need for DNA diagnostics in his close relatives and only in this case all the carriers of pathogenic germline mutations can be included in the high-risk group. Algorithms of clinical monitoring and operative treatment for mutation carriers were developed in different countries. However, different populations have their own genetic and clinical features. The aim of this work was to highlight the principles of diagnosis and personalized treatment of patients with hereditary colorectal cancer, taking into account international and Russian recommendations.

Annals of the Russian academy of medical sciences. 2019;74(2):118-124
pages 118-124 views


Comparison of Results and Cost-Effectiveness of Minimally Invasive and Open Transforaminal Lumbar Interbody Fusion: A Meta-Analysis of Prospective Cohort Studies

Byvaltsev V.A., Kalinin A.A., Shepelev V.V.


Backgraund: Minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) is becoming the most popular treatment method in modern vertebrology. But at the same time, limited working space, significant intraoperative radiation exposure and high risks of developing perioperative complications associated with a long learning curve are constraints for the widespread use of this technology by most spinal surgeons. Aims: to conduct a meta-analysis based on the results of prospective cohort clinical studies that compare the results of the application of minimally invasive and open transforaminal interbody spinal fusion techniques in treating patients with degenerative lumbar diseases. Materials and methods: A search for randomized clinical trials was conducted in the Pubmed, EMBASE, eLibrary and Cochrane Library databases published from January 2008 to December 2018, which compared the results of minimally invasive (MIS-TLIF) and open (Open-TLIF) techniques transforaminal interbody fusion in treating patients with degenerative diseases of the lumbar spine. For dichotomous variables, the relative risk and 95% confidence interval were calculated; in turn, standardized difference of mean values and their 95% confidence intervals were used for continuous variables, using the random effects model. Results: The meta-analysis included 21 prospective cohort studies, three of which were randomized controlled clinical trials. The results of the surgical treatment of 1762 patients with degenerative diseases of the lumbar spine were evaluated in total. In the MIS-TLIF group, reliably smaller parameters of the duration of surgical intervention (p<0.00001), the volume of intraoperative blood loss (p<0.00001), the timing of postoperative inpatient treatment (p<0.00001), the economic costs of treatment (p<0.00001) and the number of perioperative adverse effects (p=0.006). At the same time, the duration of intraoperative fluoroscopy is registered significantly less in the Open-TLIF group (p<0.00001). Conclusions: The MIS-TLIF method in comparison with the Open-TLIF method has significantly lower objective indicators characterizing the invasiveness of the surgical intervention, as well as the development of undesirable consequences, the associated shorter duration of hospitalization and financial costs for treating patients with degenerative diseases of the lumbar spine. At the same time, significantly more time of intraoperative irradiation was confirmed, due to the technical features of performing transcutaneous closed manipulations in the absence of direct visualization of the operated segment in the MIS-TLIF group.

Annals of the Russian academy of medical sciences. 2019;74(2):125-135
pages 125-135 views


The Parathyroid Hormone and Peptides Like It. Literature Review

Mokrysheva N.G., Krupinova J.A., Kovaleva E.V.


Wide prevalence of the parathyroid glands pathology and the need for new methods of diagnosis and treatment are forcing researchers all over the world to go more deeply into the pathophysiological mechanisms. A parathyroid hormone (PTH) is main cause of mineral disorders. In addition, humans have a family with similar in structure molecules that contribute to the maintenance of calcium and phosphate homeostasis. The family includes PTH, parathyroid hormone-related protein (PTHrP) and tuberoinfundibular peptide 39 (TIP39, also known as PTH2). The genes encoding these peptides have highly homologous amino acid regions in the N-(amino) terminal receptor-binding sites of each family member, as well as the preserved structure of their organization, which seems to be due to the presence of one parent gene. The variety of classical and “non-classical” effects allows to expand the understanding of these substances and consider them as hormones that go beyond the regulation of phosphorus-calcium metabolism. The review provides information on the structure and biosynthesis of these peptides, as well as a wide range of their effects on the human body.

Annals of the Russian academy of medical sciences. 2019;74(2):136-144
pages 136-144 views

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