Potential of valsartan+sacubitril therapy in hypertensive heart disease

The course of hypertension is often complicated by left ventricular hypertrophy (or hypertensive heart disease, HHD). The main “corridor” of natural HHD is development of heart failure with preserved ejection fraction (HFpEF). With HFpEF, the bioavailability of natriuretic peptides (NP) is significantly reduced, as a result of which the activity of cGMP-PKG signaling pathway, which plays a key role in maintaining normal diastolic function, weakens. It is possible to increase the activity of this pathway using the neprilysin inhibitor sacubitril. In case of HFpEF, the greatest efficacy from valsartan+sacubitril therapy should be expected in patients with severe concentric LVH, who have the most pronounced natriuretic peptide deficiency. Valsartan+sacubitril therapy has a clear hypotensive effect, causes a reversal of left ventricular hypertrophy and fibrosis. Since no effective treatment has yet been found for HFpEF, the main way for HHD treatment should be to prevent the diastolic dysfunction progression, which justifies valsartan+sacubitril therapy starting from the early/ asymptomatic stages

Кишечная микробиота у недоношенных детей — современное состояние проблемы (обзор литературы)

The problem of intestinal microbiota influencing the health of early aged children has become especially relevant over the past few years. On one hand, this is due to the significant worsening of the human environment ecology, on the other — due to the high prevalence of digestive disorders in children, especially premature ones. The introduction of modern high-informative molecular-genetic research methods (PCR-amplification with gene sequenation) made it possible to reveal the primary stage of human colonization by bacteria even at the stage of fetal ontogenesis and to thoroughly decode the microbiota structure in newborns and first-year babies. It is established, that the mothers microbiota has a direct effect on the quantity and quality of the child’s microbiota. The mother’s microbiota depends not only on her possessing inflammatory, but also metabolic diseases (obesity). There is also a direct correlation between the children’s microbiota and the wway they were born (microbiota is better in cases of natural birth), and these differences are prevalent after a number of months after birth. One of the main factors affecting microbiota after birth from the very first day is nutrition. Most studies earnestly confirm the role of breastfeeding in contributing to an optimal microbiocenosis in the child. Antibacterial therapy, being received by either the mother or the child has a negative effect on the colonization of the intestines by symbiont microbes. The negative impacts on the micro flora are especially significant for premature children especially those born with a very low and extremely low body mass. The ontogenesis of these children is most severed by malicious factors (infections followed by the necessity of a massive antibacterial therapy, hypoxia, surgical birth, forced artificial feeding) in connection with a general immaturity, including not yet fully-fledged body defense systems. Directive microbiota correction in premature children is an important condition for prevention and treatment of such severe diseases as sepsis necrotizing enterocolitis. For this reason, the usage of probiotics is considered as one of the promising practices of practical neonatology. The article contains an example of studying the effectiveness of probiotic therapy in premature babies with a combined perinatal pathology.Проблема влияния микробиоты кишечника на состояние здоровья детей раннего возраста приобрела особую актуальность в последние годы. Это связано, с одной стороны, со значительным ухудшением экологии среды обитания человека, с другой — с высокой частотой расстройств пищеварения у детей, особенно родившихся преждевременно. Внедрение современных высокоинформативных молекулярно-генетических методов исследования (ПЦР-амплификация с секвенированием генов) позволило выявить начальный этап микробной колонизации человека еще в периоде внутриутробного онтогенеза и подробно расшифровать структуру микробиоты у новорожденных и младенцев 1-го года жизни. Установлено, что на количественную выраженность и качественный состав кишечной микробиоты влияет состав микробиоты матери, который зависит от наличия/отсутствия у нее не только воспалительных, но и метаболических болезней (ожирения). Обнаружено, что имеется достоверная связь состава микробиоты у младенцев со способом родоразрешения их матерей (более благоприятный состав после естественных родов), причем указанные различия сохраняются на протяжении нескольких месяцев после рождения. Один из основных факторов, влияющих на микробиоту с первых дней, — питание; большинство исследований убедительно подтверждают роль грудного вскармливания в становлении оптимального микробиоценоза у младенца. Антибактериальная терапия, получаемая матерью и/или ребенком, оказывает негативное воздействие на колонизацию кишечника микробами-симбионтами. Негативные внешние влияния на микробиоту особенно значимы у недоношенных детей, прежде всего у родившихся с очень низкой и экстремально низкой массой тела. Онтогенез этих младенцев наиболее отягощен вредными факторами (инфекцией и необходимостью массивной антибактериальной терапии, гипоксией, оперативным родоразрешением, вынужденным искусственным вскармливанием) на фоне общей незрелости, в том числе несформированности защитных механизмов организма. Направленная коррекция микробиоты у недоношенных детей является важным условием профилактики и лечения таких грозных заболеваний, как сепсис и некротизирующий энтероколит. Именно поэтому использование препаратов-пробиотиков представляется одним из перспективных направлений практической неонатологии. В статье приводится пример исследования эффективности пробиотикотерапии у недоношенных детей с сочетанной перинатальной патологией

ЗНАЧЕНИЕ ГРУДНОГО ВСКАРМЛИВАНИЯ В ПРОФИЛАКТИКЕ ОТДАЛЕННЫХ НАРУШЕНИЙ МЕТАБОЛИЗМА: ОБЗОР ЛИТЕРАТУРЫ

The literature review is dedicated to the preventive role of breastfeeding in preserving long-term health of individuals and the population in whole. The issue is urgent due to high prevalence of multifactor metabolic diseases (obesity, pancreatic diabetes, hypertonic disease etc.) in adolescents and adults; these socially significant have started to set on in younger persons in the recent years. The article presents results of the studies dedicated to the association between the nature of the infant's feeding and risk of metabolic pathology conducted in the recent decades in various countries. Most works put premature infants in the high risk group, as the diets involving special formulas contributing to "catching-up" growth of neonates with low birth weight are statistically significantly associated with high risk of long-term cardiovascular diseases. According to numerous studies, artificial feeding significantly increases the risk of excess weight and obesity, hypertonic disease and atherogenic dyslipidemia. Possible mechanisms of realization of hereditary susceptibility to metabolic disorders in the setting of artificial feeding are enhanced insulin burst paired with further development of insulin resistance; preventive role of breast milk is associated with the hormones therein, which program the individual's metabolism. Along with that, breastfeeding provides metabolic and immunological programming by means of forming optimal intestinal microbiota in a child. All the studies indicate importance of prolonged breastfeeding during infancy, which is why medical administrative support provided by medical personnel of medical and preventive facilities is important for preventing hypolactasia. District pediatricians and nurses not only control, but also organize the process of breastfeeding; when necessary, they recommend special devices intended to optimize lactation (breast pumps, nipple shields); if breast latching is not feasible – feeding with extracted breast milk using bottles and pacifiers reproducing natural breast sucking mechanism. Обзор литературы посвящен оценке профилактической роли грудного вскармливания в обеспечении отдаленного здоровья индивидуума и популяции в целом. Актуальность проблемы обусловлена высокой распространенностью мультифакториальных метаболических заболеваний (ожирения, сахарного диабета, гипертонической болезни и др.) у подростков и взрослых; в последние годы отмечена тенденция к омоложению возраста дебюта этих социально-значимых заболеваний. Приводятся результаты исследований, выполненных в последние десятилетия в различных странах и посвященных связи характера вскармливания ребенка на первом году жизни со степенью риска реализации метаболической патологии. В большинстве работ указывается, что в группе особого риска находятся недоношенные дети, поскольку диеты с использованием специальных смесей, способствующих «догоняющему» росту маловесных новорожденных, статистически достоверно были связаны с высоким риском отдаленных сердечно-сосудистых заболеваний. Искусственное вскармливание, как установлено многочисленными исследованиями, значимо повышает риск формирования избыточного веса и ожирения, а также гипертонической болезни, атерогенной дислипидемии. К возможным механизмам реализации наследственной предрасположенности метаболических расстройств на фоне искусственного вскармливания относят усиленный выброс инсулина с последующим формированием инсулинорезистентности; профилактическая роль грудного молока связывается с наличием в нем гормонов, обладающих программирующим воздействием на метаболизм индивидуума. Наряду с этим метаболическое и иммунологическое программирование при грудном вскармливании осуществляется через формирование оптимальной микробиоты кишечника ребенка. Все исследования свидетельствуют о важности пролонгирования грудного вскармливания на протяжении первого года жизни, поэтому в профилактике гиполактазии важную роль играет медико-организационная поддержка, которую оказывают медицинские работники лечебно-профилактических учреждений. Участковый педиатр и медицинская сестра не только контролирует, но и организуют процесс грудного вскармливания; при необходимости рекомендуют специальные приспособления, оптимизирующие лактацию (молокоотсосы, накладки для соска), в случае невозможности прикладывания к груди — вскармливание сцеженным грудным молоком с использованием бутылочек и сосок, воспроизводящих механизм естественного сосания из груди

Analysis of radial artery occlusion causes and methods of its prevention after interventions using radial access. Results of the APRIORI study

Aim. To study predictors of radial artery occlusion (RAO) and ways to prevent it after interventions using radial access.Material and methods. The study consisted of prospective and retrospective parts. The total number of included patients was 2284. Patients undergoing interventions by radial access in various medical organizations were retrospectively considered. The prospective study included 1284 patients who were subject to interventional treatment. Patients were randomized into two groups as follows: in group 1, hemostasis was performed within 4 hours, in group 2 — >6 hours. All patients underwent a bedside Barbeau test with a pulse oximeter and an ultrasound of access arteries to determine the radial artery patency/occlusion.Results. The RAO rate in the retrospective part was 21,8%, while in the prospective one — 10,1% with long-term hemostasis and 1,4% with short-term hemostasis (p<0,001). Predictors of RAO were type 2 diabetes (odds ratio (OR), 1,9, 95% confidence interval (CI), 1,1-3,4, p=0,03) and an increase in hemostasis duration by 1 hour (OR, 1,2, 95% CI, 1,1-1,3, p<0,001). When analyzing the retrospective part, the predictors of RAO were body mass index (OR, 1,06, 95% CI, 1,02-1,09, p=0,002), female sex (OR, 0,6, 95% CI, 0,4-0,9, p=0,02), smoking (OR, 1,38, 95% CI, 1-1,91, p=0,047). The administration of statins in different dosages, as well as antihypertensive and anti-ischemic agents, did not have a significant effect on the RAO rate.Conclusion. The main predictors of RAO were type 2 diabetes, an increase in hemostasis duration, female sex, smoking, and the artery-to-introducer diameter ratio. Taking statins, anti-ischemic and antihypertensive agents does not have a protective effect on RAO rate

Population genomics of post-glacial western Eurasia.

Western Eurasia witnessed several large-scale human migrations during the Holocene <sup>1-5</sup> . Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes-mainly from the Mesolithic and Neolithic periods-from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a 'great divide' genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 BP, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 BP, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a 'Neolithic steppe' cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations

Intestinal Microbiota in Premature Children — the Modern State of the Problem (Literature Analysis)

The problem of intestinal microbiota influencing the health of early aged children has become especially relevant over the past few years. On one hand, this is due to the significant worsening of the human environment ecology, on the other — due to the high prevalence of digestive disorders in children, especially premature ones. The introduction of modern high-informative molecular-genetic research methods (PCR-amplification with gene sequenation) made it possible to reveal the primary stage of human colonization by bacteria even at the stage of fetal ontogenesis and to thoroughly decode the microbiota structure in newborns and first-year babies. It is established, that the mothers microbiota has a direct effect on the quantity and quality of the child’s microbiota. The mother’s microbiota depends not only on her possessing inflammatory, but also metabolic diseases (obesity). There is also a direct correlation between the children’s microbiota and the wway they were born (microbiota is better in cases of natural birth), and these differences are prevalent after a number of months after birth. One of the main factors affecting microbiota after birth from the very first day is nutrition. Most studies earnestly confirm the role of breastfeeding in contributing to an optimal microbiocenosis in the child. Antibacterial therapy, being received by either the mother or the child has a negative effect on the colonization of the intestines by symbiont microbes. The negative impacts on the micro flora are especially significant for premature children especially those born with a very low and extremely low body mass. The ontogenesis of these children is most severed by malicious factors (infections followed by the necessity of a massive antibacterial therapy, hypoxia, surgical birth, forced artificial feeding) in connection with a general immaturity, including not yet fully-fledged body defense systems. Directive microbiota correction in premature children is an important condition for prevention and treatment of such severe diseases as sepsis necrotizing enterocolitis. For this reason, the usage of probiotics is considered as one of the promising practices of practical neonatology. The article contains an example of studying the effectiveness of probiotic therapy in premature babies with a combined perinatal pathology

THE INFLUENCE OF ATORVASTATIN AND ROSUVASTATIN IN ATHEROSCLEROSIS ON THE PARAMETERS OF CELLULAR IMMUNITY AND IN VITRO LEUCOCYTE ACTIVATION

Aim. To compare the influence of “lipophilic” atorvastatin and “hydrophilic” rosuvastatin on the parameters of cellular immunity in atherosclerosis patients.Material and methods. Totally, 35 participants included, mean age 62 [57;68] y.o., 18 males and 17 females, directed for follow-up to Myasnikov Cardiovascular Center with preliminary diagnosis coronary heart disease, atherosclerosis of coronary and carotid arteries, and with indications for intensified statin therapy. In 17 patients the dosage of atorvastatin was increased from 20 to 80 mg, in 18 — dosage of rosuvastatin from 10 to 40 mg. All patients at baseline and in 1 month, by the methods of direct immune fluorescence and cytofluometry underwent the measurement of content of monocytes and lymphocyte populations in peripheral blood, incl. regulatory and effectory subpopulations of the latter. Under the circumstances of cellular culture the influence studied, of atorvastatin and rosuvastatin on CD4+ T-lymphocytes populations, as the lipopolysaccharideinduced synthesis of cytokines by monocytes of donors blood.Results. At the background of atorvastatin, there was marked increase of relative content of circulating regulatory T-lymphocytes (Treg), increase of the relation of Treg/Thelper 17 (Th17) and changes of cellular immunity parameters. Statins did not influence subpopulations of blood monocytes. There was dose-dependent inhibition by statins of CD4+ T-lymphocytes proliferation: atorvastatin action was noted in 10 nM/L, rosuvastatin — in 10 times higher concentration. Introduction ofstatins, 10-100 nM/L, to the culture of monocytes did not influence neither spontaneous, nor endotoxin induced secretion of cytokines.Conclusion. In therapeutic dosages atorvastatin shows immune modulating activity presenting with an increase of relative content of regulatory T-lymphocytes subpopulations that might be determined by suppression of effectory cells proliferation

ROLE OF BREASTFEEDING IN PREVENTING LONG-TERM METABOLIC DISORDERS: REVIEW

The literature review is dedicated to the preventive role of breastfeeding in preserving long-term health of individuals and the population in whole. The issue is urgent due to high prevalence of multifactor metabolic diseases (obesity, pancreatic diabetes, hypertonic disease etc.) in adolescents and adults; these socially significant have started to set on in younger persons in the recent years. The article presents results of the studies dedicated to the association between the nature of the infant's feeding and risk of metabolic pathology conducted in the recent decades in various countries. Most works put premature infants in the high risk group, as the diets involving special formulas contributing to "catching-up" growth of neonates with low birth weight are statistically significantly associated with high risk of long-term cardiovascular diseases. According to numerous studies, artificial feeding significantly increases the risk of excess weight and obesity, hypertonic disease and atherogenic dyslipidemia. Possible mechanisms of realization of hereditary susceptibility to metabolic disorders in the setting of artificial feeding are enhanced insulin burst paired with further development of insulin resistance; preventive role of breast milk is associated with the hormones therein, which program the individual's metabolism. Along with that, breastfeeding provides metabolic and immunological programming by means of forming optimal intestinal microbiota in a child. All the studies indicate importance of prolonged breastfeeding during infancy, which is why medical administrative support provided by medical personnel of medical and preventive facilities is important for preventing hypolactasia. District pediatricians and nurses not only control, but also organize the process of breastfeeding; when necessary, they recommend special devices intended to optimize lactation (breast pumps, nipple shields); if breast latching is not feasible – feeding with extracted breast milk using bottles and pacifiers reproducing natural breast sucking mechanism