Associations between SNPs in candidate immune-relevant genes and rubella antibody levels: a multigenic assessment

<p>Abstract</p> <p>Background</p> <p>The mechanisms of immune response are structured within a highly complex regulatory system. Genetic associations with variation in the immune response to rubella vaccine have typically been assessed one locus at a time. We simultaneously assessed the associations between 726 SNPs tagging 84 candidate immune response genes and rubella-specific antibody levels. Blood samples were obtained from 714 school-aged children who had received two doses of MMR vaccine. Associations between rubella-specific antibody levels and 726 candidate tagSNPs were assessed both one SNP at a time and in a variety of multigenic analyses.</p> <p>Results</p> <p>Single-SNP assessments identified 4 SNPs that appeared to be univariately associated with rubella antibody levels: rs2844482 (p = 0.0002) and rs2857708 (p = 0.001) in the 5'UTR of the LTA gene, rs7801617 in the 5'UTR of the IL6 gene (p = 0.0005), and rs4787947 in the 5'UTR of the IL4R gene (p = 0.002). While there was not significant evidence in favor of epistatic genetic associations among the candidate SNPs, multigenic analyses identified 29 SNPs significantly associated with rubella antibody levels when selected as a group (p = 0.017). This collection of SNPs included not only those that were significant univariately, but others that would not have been identified if only considered in isolation from the other SNPs.</p> <p>Conclusions</p> <p>For the first time, multigenic assessment of associations between candidate SNPs and rubella antibody levels identified a broad number of genetic associations that would not have been deemed important univariately. It is important to consider approaches like those applied here in order to better understand the full genetic complexity of response to vaccination.</p

Extended LTA, TNF, LST1 and HLA Gene Haplotypes and Their Association with Rubella Vaccine-Induced Immunity

Recent studies have suggested the importance of HLA genes in determining immune responses following rubella vaccine. The telomeric class III region of the HLA complex harbors several genes, including lymphotoxin alpha (LTA), tumor necrosis factor (TNF) and leukocyte specific transcript -1 (LST1) genes, located between the class I B and class II DRB1 loci. Apart from HLA, little is known about the effect of this extended genetic region on HLA haplotypic backgrounds as applied to immune responses.We examined the association between immune responses and extended class I-class II-class III haplotypes among 714 healthy children after two doses of rubella vaccination. These extended haplotypes were then compared to the HLA-only haplotypes. The most significant association was observed between haplotypes extending across the HLA class I region, ten-SNP haplotypes, and the HLA class II region (i.e. A-C-B-LTA-TNF-LST1-DRB1-DQA1-DQB1-DPA1-DPB1) and rubella-specific antibodies (global p-value of 0.03). Associations were found between both extended A*02-C*03-B*15-AAAACGGGGC-DRB1*04-DQA1*03-DQB1*03-DPA1*01-DPB1*04 (p = 0.002) and HLA-only A*02-C*03-B*15-DRB1*04-DQA1*03-DQB1*03-DPA1*01-DPB1*04 haplotypes (p = 0.009) and higher levels of rubella antibodies. The class II HLA-only haplotype DRB1*13-DQA1*01-DQB1*06-DPA1*01-DPB1*04 (p = 0.04) lacking LTA-TNF-LST1 SNPs was associated with lower rubella antibody responses. Similarly, the class I-class II HLA-only A*01-C*07-B*08-DRB1*03-DQA1*05-DQB1*02-DPA1*01-DPB1*04 haplotype was associated with increased TNF-alpha secretion levels (p = 0.009). In contrast, the extended AAAACGGGGC-DRB1*01-DQA1*01-DQB1*05-DPA1*01-DPB1*04 (p = 0.01) haplotype was found to trend with decreased rubella-specific IL-6 secretion levels.These data suggest the importance of examining both HLA genes and genes in the class III region as part of the extended haplotypes useful in understanding genomic drivers regulating immune responses to rubella vaccine

FEATURES OF STEROID REGULATION OF CONGENITAL PROTECTIVE FACTORS AND OSTEOTROPIC MEDIATORS OF ORAL FLUID IN PREGNANT WOMEN WITH INFLAMMATORY PERIODONTAL DISEASES

Aim. To study changes in antimicrobial and osteotropic oral fluid mediators during pregnancy in women with chronic generalized periodontitis (CGР) of mild and moderate severity, taking into account the factor of steroid regulation by cortisol.Materials and methods. Among the 62 pregnant women (age 18 to 35 years), depending on the presence or absence of inflammatory periodontal diseases, the main group (n=31) with moderate and moderate CGР and control group (n=31) with no disease were formed. In addition, 32 healthy non-pregnant women (age 18 to 30 years) examined the oral fluid in the same diagnostic volume. In the oral liquid, the amount of catelicidin LL-37, osteoprotegerin and cortisol was determined using a solid-phase immunoassay method. Laboratory studies were conducted in I (8-12 weeks), II (13-27 weeks) and III (28-40 weeks) trimester of pregnancy.Results. In pregnant women with a physiologically pregnant pregnancy and in the absence of dental diseases in the oral fluid with a consequent increase in the concentration of cortisol, there was a decrease in the content of catelicidin LL-37 1 trimester followed by an increase in the 2nd and 3rd trimesters of the antimicrobial potential of the oral biological environment, an increase in the concentration of osteoprotegerin that inhibits the activity of osteoresorption in the alveolar bone. In pregnant women with CGR of mild and moderate severity, a marked increase in the concentration of cortisol in the oral fluid was accompanied in the first two terms by an increased content of cathelicidin LL-37 and activation of antimicrobial congenital mechanisms of resistance to pathogenic bacteria, followed by a decrease in the antimicrobial factor to the third trimester of the gestation period, a consistent decrease in the content of osteoprotegerin in mixed saliva.Conclusion. The presence of CGР of mild and moderate severity in pregnant women leads to a dissociation of the connection between cortisol mixed saliva and immune defense factors, osteotropic mediators in contrast to women who do not suffer from dental pathology during the gestational period

Psychophysiological adaptation of students to information training in high school

The health status of young people depends on the adaptation reserves. Assessment of students’ adaptation to the teaching load is one of the most important tasks of age physiology. The results showed that students adapt to the educational process for the academic year passed with a functional voltage cardio-vascular system and a small decrease in health.Состояние здоровья молодых людей зависит от резервов адаптации. Оценка адаптации учащихся к учебным нагрузкам является одной из важнейших задач возрастной физиологии. Результаты исследования показали, что у студентов адаптация к учебному процессу за год обучения прошла с функциональным напряжением сердечно-сосудистой системы и небольшим снижением здоровья

Оптимизация формы сигналов с квадратурной амплитудной модуляцией с использованием критерия заданной скорости спада уровня внеполосных излучений

Introduction. The growth in the volume of information transmitted through communication channels leads to their significant congestion. Almost all methods conventionally used to increase the data transfer rate in given frequency bands have been exhausted. In this regard, it is of interest to use new approaches aimed at improving the spectral efficiency of radio engineering and telecommunication systems by applying optimal signals that make it possible to use the bandwidth reserves of transmission channels given by Shannon's theory.Aim. Improvement of the spectral efficiency of digital messaging systems by using signals with a compact spectrum and increased volume of the channel alphabet at the same time as minimizing energy losses.Materials and methods. When searching for optimal signals, the mathematical apparatus of communication theory and functional analysis, as well as the methods of calculus of variations, were used. The evaluation of bit error rate performance of the obtained optimal signals transmitted in a channel with additive white Gaussian noise was performed in the MatLab environment. Results. It was established that, in a channel with additive white Gaussian noise, optimal signals with a signal constellation size of 64 in the case of quadrature amplitude-phase modulation provide an energy gain of more than 1 dB relative to signals obtained by narrowband filtering under the conditions of uncontrolled intersymbol interference. Optimal signals were shown to provide for an energy gain of 4.9 dB with respect to signals based on narrow-band filtering at a fixed spectral efficiency of 7 (bit/s)/Hz.Conclusion. The paper proposes a method for improving the spectral efficiency of quadrature signals with amplitudephase modulation, based on the use of optimal pulse shapes obtained as a result of solving an optimization problem. The optimization problem was solved according to the criterion of minimizing out-of-band emissions with the constraint on bit error rate performance in case of amplitude-phase modulation. The energy and spectral efficiency of signals with optimal pulse shapes and signals based on narrow-band filtering were compared.Введение. Рост объемов передаваемой информации по каналам связи приводит к их существенной перегруженности. Практически все используемые традиционные методы повышения скорости передачи данных в заданных полосах частот исчерпаны. В этой связи представляет интерес использование новых подходов, направленных на повышение спектральной эффективности радиотехнических и телекоммуникационных систем путем применения оптимальных сигналов, позволяющих задействовать резервы пропускной способности каналов передачи, которые дает теория Шеннона.Цель работы. Повышение спектральной эффективности систем передачи цифровых сообщений путем применения сигналов с компактным спектром и увеличения объема канального алфавита при минимизации энергетических потерь.Материалы и методы. При поиске оптимальных сигналов используется математический аппарат теории связи и функционального анализа, а также методы вариационного исчисления. Оценка помехоустойчивости приема полученных оптимальных сигналов при передаче в канале с аддитивным белым гауссовским шумом выполнена в среде MatLab.Результаты. Установлено, что в канале с аддитивным белым гауссовским шумом оптимальные сигналы при размере сигнального созвездия 64 в случае квадратурной амплитудно-фазовой модуляции обеспечивают энергетический выигрыш более 1 дБ относительно сигналов, которые получаются путем узкополосной фильтрации в условиях неконтролируемой межсимвольной интерференции. Показано, что оптимальные сигналы позволяют получить энергетический выигрыш 4.9 дБ по отношению к сигналам, построенным на основе узкополосной фильтрации, при фиксированной спектральной эффективности 7 (бит/с)/Гц.Заключение. Предложен метод повышения спектральной эффективности квадратурных сигналов с амплитудно-фазовой модуляцией, основанный на применении оптимальных форм импульсов, полученных в ходе решения оптимизационной задачи. Приведена процедура решения оптимизационной задачи по критерию минимизации внеполосных излучений при наличии ограничения на помехоустойчивость приема в случае амплитудно-фазовой модуляции. Выполнено сравнение энергетической и спектральной эффективности, обеспечиваемой сигналами с оптимальными формами импульсов и сигналами, построенными на основе узкополосной фильтрации

Index Evaluation of Clinical Efficacy of Immunomodulatory and Osteotropic Therapy for Chronic Generalized Periodontitis of Varying Severity: A Prospective Cohort Study

Background. The significant prevalence of chronic generalized periodontitis, the severity of its course, the increase in the number of complicated forms and short-term remissions cause a constant search for new methods and means of its treatment. When choosing the most effective methods of therapy, specialists mostly prefer a complex effect on the main pathogenetic links of the disease, while often losing sight of the body's own defenses, especially in terms of pharmacotherapeutic support and immunity strengthening. This study presents the results of a study of the clinical efficacy of the treatment of chronic generalized periodontitis by means of the developed therapy complex, including the use of immunomodulatory and osteotropic drugs.Objective — to study clinical efficacy of the developed complex immunomodulatory and osteotropic treatment for chronic generalized periodontitis.Methods. A prospective cohort study was conducted in 154 patients aged 20 to 75 with periodontitis of varying severity. Conventional examination of patients was carried out in specialized dental clinics DentoProma (Krasnodar) and Dentalife (Stavropol) based at the Dentistry Department, Stavropol State Medical University (Russia). The study period was 24 months. The patients were divided into a main group of 118 participants and a control group of 36 participants. The comprehensive treatment plan, prescribed to all patients, included proper oral hygiene education, individual and professional dental hygiene, topical anti-inflammatory agents, Vector therapy, open flap debridement, flap surgery, relevant splinting prosthetics (if necessary). The authors developed a comprehensive therapy, which included administration of the immunomodulatory agent Hepon (Immapharma Company, Russia), glucosamine hydrochloride and chondroitin sulfate sodium. All patients of the main and control groups were additionally ranked into subgroups depending on the severity of diagnosed periodontitis: slight (subgroup 1), moderate (subgroup 2) and severe (subgroup 3). The major focus of the study was to establish efficacy of the developed therapy which was defined by the degree of resolution of the inflammatory process and increase in the period of remission. Reflecting the presence and degree of inflammation, dental plaque index and oral hygiene status were considered to be the target indicators. Analysis and statistical processing of the obtained data were carried out using Microsoft Excel (Microsoft, USA).Results. The analysis of the data revealed that the immediate clinical results of the developed complex therapy both in the main group and in the control group were approximately identical. According to the follow-up data obtained one month after the treatment, additional prescription of complex osteotropic treatment to the patients with chronic generalized periodontitis contributed to rapid resolution of infection in the gingival tissues and provided stable treatment results.Conclusion. Introduction of the complex clinical and hygienic treatment promoted resolution of the inflammatory process in the gingival tissues of all patients who received immunomodulatory and osteotropic therapy

Impact of anxiety and depression disorders on adherence to anticoagulant therapy among patients with atrial fibrillation

Aim. To determine the possible impact of anxiety and depression disorders on the adherence of patients with atrial fibrillation (AF) to anticoagulant the rapy.Material and methods. The study included outpatients with AF of any type. After signing the informed consent, patients filled out questionnaires and scales that determined the level of anxiety and personal predisposition (MMAS-8, MMAS-4, SF-36, SHAI, STAI, HADS, NEO-FFI).Results. A total of 117 outpatients treated for AF were included. The mean age of patients was 74±5 years (men, 38%). Based on MMAS-4 and MMAS-8 results, adherent and non-adherent cohorts of patients were formed. Low adherence group had significantly higher situational anxiety according to STAI (45,9±9,9 vs 41,1±10,7, p=0,045) and depression according to HADS (7,9±3,6 vs 5,9±3,5, p=0,018). SF 36 showed that non-adherent patients had a lower general health (41,6±12,9 vs 52,2±20,0, p=0,01). Five-factor model revealed an association between low compliance and low extraversion (21,3±6,6 vs 26,4±7,2, p=0,002). Pharmacokinetic data on blood concentrations of anticoagulants or its metabolites at the second visit were available in 76 (67%) patients. Assessment of pharmacokinetic and compliance data revealed a moderate direct correlation (Matthews correlation coefficient (MCC), 0,345) and a weak direct correlation with the MMAS-8 (MCC, 0,177). The difference in MMAS-4 and MMAS-8 scores between high and low pharmacokinetic adherence groups was significant on both scales (p=0,011 and 0,015, respectively).Conclusion. The rationale for widespread introduction of standardized questionnaires and scales (MMAS 4, MMAS 8, STAI, HADS, SF 36, Big 5) was shown in order to early identify patients with low adherence to treatment. The results highlight the need for further study of the contribution of psychiatric disorders to low compliance to anticoagulant therapy

РАДИАЦИОННАЯ ОБСТАНОВКА НА ТЕРРИТОРИИ КАЛУЖСКОЙ ОБЛАСТИ 30 ЛЕТ СПУСТЯ ПОСЛЕ АВАРИИ НА ЧЕРНОБЫЛЬСКОЙ АЭС

The article describes radiation conditions in the Kaluga region 30 years after the Chernobyl NPP accident. The Chernobyl NPP accident caused radioactive contamination of nine Kaluga region territories: Duminichsky, Zhizdrinsky, Kuibyshevsky, Kirovsky, Kozelsky, Ludinovsky, Meshchovsky, Ulyanovsky and Hvastovichsky districts. Radioactive fallout was the strongest in three southern districts: Zhizdrinsky, Ulyanovsky and Hvastovichsky, over there cesium-137 contamination density is from 1 to 15Ci/km. According to the Russian Federation Government Order in 2015 there are 300 settlements (S) in the radioactive contamination zone, including 14 settlements with caesium-137 soil contamination density from 5 to 15 Ci/ km2 and 286 settlements with the contamination density ranging from 1 to 5 Ci/km2. In the first years after the Chernobyl NPP accident in Kaluga region territories, contaminated with caesium-137, there were introduced restrictive land usage, were carried out agrochemical activities (ploughing, mineral fertilizer dressing), there was toughened laboratory radiation control over the main doze-forming foodstuff. All these measures facilitated considerable decrease of caesium-137 content in local agricultural produce. Proceeding from the achieved result, in 2002 there took place the transition to more tough requirements SanPiN 2.3.2.1078-01. Analysis of investigated samples from Zhizdrinsky, Ulyanovsky and Hvastovichsky districts demonstrated that since 2005 meat samples didn’t exceed the standard values, same for milk samples since 2007. Till the present time, the use of wild-growing mushrooms, berries and wild animals meat involves radiation issues. It was demonstrated that average specific activity of caesium-137 in milk samples keeps decreasing year after year. Long after the Chernobyl NPP accident, the main products forming internal irradiation doses in population are the wild-growing mushrooms and berries. Population average annual effective doses, caused90by Chernobyl fallouts, do not exceed 1 mSv/year. In 2014 AAEDmaximum calculated value for adultpopulation of 0,91 mSv was established in the following settlements:, Martynki village(Ulyanovsky district) and Lovatyanka village (Hvastovichsky district). The doses, accumulated in the period after the accident, are generally not high. According to calculations numerical value of forecasted accumulated doses varies from 0,23 to 21 mSv. Maximum calculated values of 21 mSv are established in Hvastovichsky district (Lovatyanka village) and Ulyanovsky district (Martynki village). Between 1986 and 2005, the effective irradiation doses did not exceed 29 mSv. Hence, in 70 years after the Chernobyl NPP accident standard value of 70 mSv will not be exceeded in the Kaluga region settlements. After 30 years, the main cause of population internal exposure is consumption of products from private subsidiary farms and especially of wild-growing products. There was conducted radiation monitoring of local agricultural foodstuff produce and of products from the forest. It demonstrated that caesium-137 average specific activity in samples of milk from private subsidiary farms in settlements of Zhizdrinsky, Ulyanovsky and Hvastovichsky districts decreased several-fold. It is between 20,0 Bq/l in 2007 and 1,7 Bq/l in 2015. In 2015, maximum levels of caesium-137 contamination in milk was 3,1% of the standard value, in potatoes - 4,7%, in meat - 4,4%.Average specific activity of caesium-137 in forest mushrooms samples from Zhizdrinsky, Ulyanovsky and Hvastovichsky districts doesn’t decline. Peaks of average caesium-137 activity were observed in 2012, 2013 and 2014; they depend on mushrooms abundance, species, dry summer weather and locations of sampling in the forest. In 2015 in three southern districts, the maximum content of caesium-137 in mushrooms exceeded the permissible level (500 Bq/kg) 4,5-fold; about 2% of the samples do not correspond to it. The maximum contamination of berries with caesium-137 also exceeds the permissible level (160 Bq/kg) nearly 5-fold, and about 43% of samples don’t correspond to it. Obtained results have demonstrated that long after the Chernobyl NPP accident (30 years) the main part of population internal exposure is caused by consumption of wild- growing mushrooms and berries. In the recent years, milk consumption does not play a considerable role in forming of internal dose any more. Conclusion: in 30 years since Chernobyl NPP accident in the Kaluga region radiation and environment conditions have considerably improved on the territories with radionuclides contamination. However, problems remain. The major task for mitigation of the Chernobyl NPP accident consequences is comprehensive radiation, social and economic rehabilitation of the contaminated territories.В статье рассматриваются радиационная обстановка на территории Калужской области спустя 30 лет после аварии на Чернобыльской АЭС. В результате аварии на Чернобыльской АЭС радиоактивному загрязнению подверглись 9 районов Калужской области - Думиничский, Жиздринский, Куйбышевский, Кировский, Козельский, Людиновский, Мещовский, Ульяновский, Хвастовичский. От радиоактивных выпадений наиболее пострадали три южных района - Жиздринский, Ульяновский, Хвастовичский с плотностью загрязнения цезием-137 от 1 до 15 Ки/км2. Постановлением правительства Российской Федерации 2015 г. в зону радиоактивного загрязнения входят 300 населенных пунктов (НП), из которых 14 населенных пунктов с плотностью загрязнения почвы цезием-137 от 5 до 15 Ки/км2 и 286 населенных пунктов от 1 до 5 Ки/км2. В первые годы после аварии на Чернобыльской АЭС на всех загрязненных цезием-137 территориях Калужской области были введены ограничительные меры по землепользованию, проводились агрохимические мероприятия (вспашка, внесение минеральных удобрений), ужесточен лабораторный радиационный контроль за основными дозообразующими продуктами питания, что привело к значительному снижению содержания цезия-137 в сельскохозяйственной продукции местного производства. Исходя из достигнутого результата, в 2002 г. осуществлен переход к более жестким требованиям СанПиН 2.3.2.1078-01. Анализ исследованных проб в Жиздринском, Ульяновском, Хвастовичском районах показал, что, начиная с 2005 г., пробы мяса, а с 2007 г. - пробы молока местного производства выше нормативных значений уже не регистрировались. До настоящего времени неблагоприятная радиационная обстановка складывается с использованием дикорастущих грибов, ягод и мяса диких животных. Показано, что средняя удельная активность содержания цезия-137 в пробах молока каждый год снижается. В отдаленный период после аварии на Чернобыльской АЭС основными продуктами, влияющими на формирование доз внутреннего облучения населения, являются дикорастущие грибы и ягоды. Средние годовые эффективные дозы населения, обусловленные чернобыльскими выпадениями, ни в одном населенном пункте не превышают 1 мЗв/год. В 2014 г. максимальное расчетное значение 90СГЭД для взрослого населения, равное 0,91 мЗв, установлено в населенных пунктах Ульяновского района, д. Мартынки и Хвастовичского района, д. Ловатянка. В целом, невелики и дозы, накопленные за весь послеаварийный период. Согласно расчетам, численное значение прогнозируемых накопленных доз варьирует от 0,23 до 21 мЗв. Максимальные расчетные значения, равные 21 мЗв, установлены в Хвастовичском районе (д. Ловатянка) и Ульяновском районе (д. Мартынки). За период 1986-2005 гг. эффективные дозы облучения не превышали 29 мЗв. Следовательно, за 70 лет после аварии на Чернобыльской АЭС нормативное значение, равное 70 мЗв, не будет превышено ни в одном населенном пункте Калужской области. Спустя 30 лет, потребление продукции из личных подсобных хозяйств и особенно дикорастущих продуктов дает основной вклад в дозу внутреннего облучения населения. Радиационный мониторинг сельскохозяйственных продуктов питания местного производства и даров леса показал, что средняя удельная активность цезия-137 в пробах молока из личных подсобных хозяйств в населенных пунктах Жиздринского, Ульяновского и Хвастовичского районов снизилась в несколько раз и составила от 20,0 в 2007 г. до 1,7 Бк/л в 2015 г. Максимальные уровни загрязнения молока цезием-137 в 2015 г. составляют 3,1%, картофеля - 4,7%, мяса - 4,4% от нормативного значения.Средняя удельная активность цезия-137 в пробах лесных грибов в населенных пунктах Жиздринского, Ульяновского, Хвастовичского районов остается без положительной динамики. Отмечаются скачки средних активностей содержания цезия-137 в 2012, 2013, 2014 гг., которые зависят от урожайности грибов, вида грибов, наличия сухого лета и территорий лесных массивов, где отбирались пробы. По данным 2015 г., в трех южных районах максимальное содержание цезия-137 в грибах в 4,5 раза превышает установленный норматив (500 Бк/кг) и около 2% проб ему не соответствуют. Максимальное загрязнение ягод цезием-137 также превышает норматив (160 Бк/кг) почти в 5 раз, не отвечают ему около 43% проб. Полученные результаты показали, что в отдаленный период после аварии на Чернобыльской АЭС (30 лет) основная доля внутреннего облучения населения обусловлена потреблением дикорастущих грибов и ягод. Употребление молока в последние годы уже не играет такой значительной роли в формировании дозы внутреннего облучения.За 30 лет с момента аварии на Чернобыльской АЭС радиационная обстановка и состояние природной среды на загрязненных радионуклидами территориях Калужской области значительно улучшилась. Однако проблемы остаются. Важнейшей задачей преодоления последствий аварии на Чернобыльской АЭС является комплексная радиационная и социально-экономическая реабилитация загрязненных территорий