Clinical-morphological parallels of the PNPLA3 gene polymorphism in patients with nonalcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and its detection in the general population has reached a global scale. Despite the fact that in the early stages the disease is characterized by a relatively mild period, the development during its natural course of nonalcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma causes deterioration of long-term forecast. Growing evidence indicates that NAFLD is a complex, multifaceted etiology, involving many factors, including genetic. In the present review, we focused on the genetic component of NAFLD, namely, the role of the PNPLA3 gene polymorphism in the development and course of the disease, and States its progression, such as non-alcoholic steatohepatitis, liver cirrhosis and hepatocellular carcinoma

Биохимические критерии токсичности терапии высокими дозами метотрексата у детей с остеосаркомой

Methotrexate (Mtx) is a cytotoxic drug from the group of antimetabolites, folic acid antagonists. High-dose (HD) Mtx in pediatric oncology are used for the treatment of osteosarcoma (OS), and other types of tumors. This therapy has allowed to achieve a five-year relapse-free survival rates up to 80 % in patients with OS. However, the high toxicity of Mtx is a serious constraint in achieving the maximum therapeutic effect, which in most cases poses the occurrence of side effects in patients on various organs and systems. Treatment should be under strict laboratory monitoring, primarily therapeutic drug monitoring the concentration of Mtx in serum.246 children (boys – 125, girls – 121) aged 5 to 16 years with osteosarcoma (mean age 12.2 years) who were treated in N.N. Blokhin Russian Cancer Research Center from 2006 to 2013. Patients were conducted from 1 to 8 courses HD Mtx at a dose of 8 or 12 g/m2 , administered within 4 h of infusion on the background of alkaline prehydrate. Leucovorin was administered intravenously, every 6 hours, starting 24 h from the start of the Mtx infusion. 1137 courses of HD Mtx were conducted with FPIA method (analyzer TDx/Flx, Abbott, USA). The technique of monitoring of homocysteine (Hcy) in the blood serum by analyzer Vitros 5/1FS (Johnson & Johnson, USA) during the entire course of high-dose Mtx was tested. In groups calculated pharmacokinetic parameters Mtx were tested: area under the pharmacokinetic curve (MtxAUC), clearance of methotrexate (ClMtx), the elimination half-life (T1/2 ) and the total time of excretion (Ttotal). Normal excretion of Mtx was revealed at 1050 courses Mtx, corresponding to the following values: 4 h – 1109 ± 283 μmol/l; 24 h – 4,67 ± 0,95 μmol/l; 42 h – 0,38 ± 0.16 µmol/l; 48 h – less than 0,23 ± 0.04 µmol/l; 72 h of 0.07 ± 0,03 µmol/l; 96 h of 0.03 ± 0.01 µmol/l. At 87 courses identified delayed Mtx excretion, accounting for 7.6 % of all courses. In all measured parameters: hourly concentration of Mtx, Ttotal, MtxAUC, Clmtx, T1/2 , is obtained statistically significant differences between normal and delayed Mtx excretion. Patients in group of delayed excretion of methotrexate were characterized by the development of hepatotoxicity, there were also observed 4 cases of the occurrence of acute renal failure.Monitoring of biochemical parameters (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase) also revealed differences between the two groups – hepatotoxicity directly depended on MtxAUC, ClMtx and Ttotal, and the amplitude changes in activities of enzymes from course to course by increasing the number of course decreased.Our developed methodology of monitoring of Hcy in serum during the course of HD Mtx revealed that Hcy metabolic interconnected with Mtx – the higher the concentration of Mtx, the greater the amount of Hcy released into the blood. Hcy has a close metabolic relationship with Mtx – it can serve as a marker of the efficiency of suppression of the transformation of folates. During slow excretion of Mtx Hcy significantly increased in the blood, which also suggests that it can serve as a marker of pharmacodynamic effects of HD Mtx.Метотрексат (Mtx) – цитостатический препарат из группы антиметаболитов, антагонистов фолиевой кислоты. Высокие дозы (ВД) Mtx в детской онкологии применяются для лечения остеосаркомы (ОС) и других типов опухолей и позволяют достичь 5-летней безрецидивной выживаемости до 80 %. Однако высокая токсичность Mtx является серьезным ограничением в достижении максимального лечебного действия и в большинстве случаев обусловливает возникновение у больных серьезных побочных эффектов со стороны различных органов и систем. Лечение должно проводиться под строгим контролем лабораторных исследований, в первую очередь терапевтического лекарственного мониторинга (ТЛМ), концентрации Mtx в сыворотке крови и других биохимических показателей.Обследовано 246 детей (125 мальчиков и 121 девочка) в возрасте от 5 до 16 лет с ОС (средний возраст 12,2 года), которые находились на лечении в НИИ ДОГ ФГБНУ «РОНЦ им. Н.Н. Блохина» с 2006 по 2013 г. Больным было проведено от 1 до 8 курсов ВД Mtx – 8 или 12 г/м2 за 4 ч инфузии на фоне щелочной прегидратации. Лейковорин назначался внутривенно через каждые 6 ч, начиная с 24 ч от начала инфузии Mtx. Проведено 1137 курсов ТЛМ Mtx методом флуоресцентно-поляризационного иммуноанализа на анализаторе TDx/Flx (Abbott, США). Отработана методика мониторинга гомоцистеина (Hcy) в сыворотке крови на анализаторе Vitros 5/1FS (Johnson & Johnson, США) в течение всего курса ВД Mtx. В группах рассчитаны фармакокинетические показатели Mtx: площадь под фармакокинетической кривой (MtxAUC), клиренс Mtx (ClMtx), период полувыведения (T1/2 ) и общее время выведения (Ttotal ).При 1050 курсах ВД Mtx выведение Mtx было нормальным и соответствовало следующим значениям: через 4 ч – 1109 ± 283 мкмоль/л; через 24 ч – 4,67 ± 0,95 мкмоль/л; через 42 ч – 0,38 ± 0,16 мкмоль/л; через 48 ч – менее 0,23 ± 0,04 мкмоль/л; через 72 ч – 0,07 ± 0,03 мкмоль/л; через 96 ч – 0,03 ± 0,01 мкмоль/л. Замедленное выведение Mtx выявлено при 87 курсах, что составляет 7,6 % от всех курсов. По всем измеряемым параметрам: концентрации выведения Mtx по часам, Ttotal, MtxAUC, ClMtx, T1/2 – получены статистически достоверные различия между нормальным и замедленным выведением Mtx. Для пациентов группы замедленного выведения было характерно развитие гепатотоксичности, также наблюдались 4 случая возникновения острой почечной недостаточности. Проведение мониторинга биохимических показателей (аланинаминотрансферазы, аспартатаминотрансферазы, лактатдегидрогеназы) также позволило выявить различия между двумя группами – гепатотоксичность непосредственно зависела от MtxAUC, ClMtx и Ttotal, причем амплитуда изменения активностей ферментов от курса к курсу уменьшалась.Отработанная нами методика мониторинга Hcy в сыворотке крови в течение курса ВД Mtx позволила выявить, что Hcy метаболически взаимосвязан с Mtx – чем выше концентрация Mtx, тем большее количество Hcy выбрасывается в кровь. Hcy может служить маркером эффективности подавления трансформации фолатов. При замедленном выведении Mtx уровень Hcy значительно повышается в крови. Это также свидетельствует о том, что он может служить маркером фармакодинамического воздействия ВД Mtx

Gamma-glutamyl transpeptidase is a promising biological marker of heart failure

Introduction. Currently, the search and study of new biological markers that can help early diagnosis of heart failure, serve as a laboratory tool for assessing the effectiveness of therapy, be a predictive marker of possible adverse clinical outcomes and a significant criterion for risk stratification is very relevant. While cardiospecific markers, including natriuretic peptides, their precursors, and highly sensitive troponins, are widely used in clinical practice, the need to use other markers does not have sufficient evidence. aspect of a biological marker of heart failure.Gamma-glutamyl transpeptidase is an enzyme localized on the outer side of cell membranes and involved in the metabolism of glutathione and cysteine. This enzyme is a dimeric glycoprotein (68 kDa), consisting of 2 subunits – a large and a small (46 and 22 kDa). Gamma-glutamyl transpeptidase is encoded by a multigene family consisting of at least 7 different genes located on chromosome 22; however, only 1 of these genes is involved in the formation of a functional enzyme. Gamma-glutamyl transpeptidase was found in all cells except erythrocytes. There is a significant variability in enzyme activity, which is especially high in tissues with a secretory and absorptive function, such as the kidneys, biliary tract, intestines, and epididymis.Purpose of the review is to present an overview of current publications devoted to the study of γ-glutamyl transpeptidase in the aspect of a biological marker of heart failure.Materials and methods. The analysis of literature sources (foreign and domestic articles) was carried out in the databases: PubMed, RSCI, MedLine, Google Scholar, Science Direct. The search was performed according to the following keywords: biological markers, heart failure, γ-glutamyl transpeptidase, biological markers, heart failure, γ-glutamyl transpeptidase.Results. In addition to its clinical use as a test for liver disease, biliary tract disease, and alcohol abuse, γ-glutamyl transpeptidase is of great interest because of its association with cardiovascular disease, diabetes, metabolic syndrome, and cancer. In the literature available to us, we found a small number of works devoted to the study of γ-glutamyl transpeptidase in patients with heart failure. In the review, we have presented data from experimental and clinical studies indicating a clear link between γ-glutamyl transpeptidase and heart failure. The pathogenetic mechanism of the possible relationship between γ-glutamyl transpeptidase and heart failure is not completely clear. The localization of this enzyme in tissues with a transport function has led to the assumption that it is involved in the transport of amino acids through the γ-glutamyl cycle.Conclusion. Further deeper understanding of the structure and function of the enzyme is needed, as well as future clinical studies to determine the diagnostic, prognostic and possibly therapeutic significance of this biological marker

Терапевтический лекарственный мониторинг метотрексата при применении его в высоких дозах для лечения остеосаркомы у детей

In children oncology high doses of methotrexate (HD Mtx) use for treatment of osteosarcoma, acute lymphoblastic leukemia and many others tumors. Due to high intra- and interindividual Mtx pharmacokinetic variability it is essential perform monitoring its concentration in the saliva. The most dangerous phenomena in the case of HD Mtx are so-termed "delayed Mtx excretion", "prolonged Mtx excretion". Their development is multifactorial and unpredictable. Having big actual material we set task: analyze pharmacokinetics HD Mtx in case of osteosarcoma in children, determine its peculiarities, elucidate whether similar or not proceed disorders of Mtx excretion, perform their quantification.В детской онкологии высокие дозы метотрексата (ВД Mtx) используются для лечения остеосаркомы (ОС), острого лимфобластного лейкоза и ряда других опухолей. В связи с высокой интра- и экстраиндивидуальной изменчивостью фармакокинетики Mtx необходимо проводить мониторинг его концентрации в сыворотке крови. Самым опасным явлением при терапии ВД Mtx является т.н. «отсроченная экскреция Mtx», «замедленное выведение Mtx». Их развитие многофакторное и непредсказуемое. В данной работе, имея большой фактический материал, была поставлена задача проанализировать фармакокинетику ВД Mtx при остеосаркоме у детей, выявить ее особенности, установить, однотипно ли протекают нарушения выведения Mtх, провести их количественный анализ

КОМПЬЮТЕРНАЯ ТОМОГРАФИЯ В ДИАГНОСТИКЕ ЗАБОЛЕВАНИЙ И НОВООБРАЗОВАНИЙ ПРЕДСТАТЕЛЬНОЙ ЖЕЛЕЗЫ

Prostate cancer prevalence is in fourth place in the overall structure of tumors and in second place among malignant diseases in older men. The cancer detection rate of preventive inspections using traditional research methods remains very low, and the timeliness of early diagnosis of tumors of the prostate gland determine the modern methods of X-ray imaging. The aim of this study was to estimate the role of computed tomography as a method of Xray imaging, in identifying the various prostate neoplasia with specification of semiotics, diagnostic criteria of various tumors. Research conducted at multispiral 128-slice CT scanner OPTIMA 660 produced by General Electric (United States). The study involved 66 patients aged 38-79 years with various diseases of the prostate. The fact of referral to the computed tomography was preceded by a primary appointment at urology specialist followed by rectal finger study positive or dubious reaction to prostate specific antigen, by transrectal ultrasound. The study showed that CT is not a universal method of diagnosis, excluding other imaging techniques, especially multiparametric magnetic resonance imaging. But that method has a number of incontestable advantages that allow to remain indispensable in the algorithm integrated diagnostic approach. First of all, it is an extensive long area of scanning combined with small thickness of the layer to be allocated. And, in the case of some phase strengthening of the gland tissues the technique, in some cases, allows to trace a malignant neoplastic process. But in general, its differential diagnosis with benign regeneration nodes in the gland tissue is usually difficult and requires further modification. Рак предстательной железы по распространенности находится на четвертом месте в общей структуре онкопатологии и на втором месте среди злокачественных заболеваний у мужчин старшей возрастной группы. Выявляемость рака при профилактических осмотрах с помощью традиционных методов исследований остается очень низкой, а своевременность ранней диагностики новообразованийпредстательной железы определяют современными методами лучевой визуализации. Целью настоящего исследования явилась оценка роли компьютерной томографии как метода лучевой визуализации в выявлении различных неоплазий предстательной железы с уточнением семиотики, диагностических критериев различных новообразований. Исследования проводили на мультиспиральном 128-срезовом компьютерном томографе OPTIMA 660 фирмы GeneralElectric (США). В исследовании приняли участие 66 пациентов в возрасте 38-79 лет с различными заболеваниями предстательной железы. Факту направления на компьютерную томографию предшествовал первичный прием у врача-уролога с последующим ректальным пальцевым исследованием, положительной или сомнительной реакцией на простатоспецифический антиген, трансректальным ультразвуковым исследованием. Установлено, что компьютерная томография не является универсальным методом диагностики, исключающим другие методы визуализации, прежде всего такие, как мультипараметрическая магнитно-резонансная томография. Но вместе с тем метод обладает рядом неоспоримых преимуществ, позволяющих остаться незаменимым в алгоритме комплексного диагностического подхода. Прежде всего это обширная по протяженности зона сканирования в сочетании с небольшой толщиной выделяемого слоя. А применительно к контрастному фазовому усилению тканей железы методика в ряде случаев позволяет заподозрить наличие злокачественного неопластического процесса. Но в целом дифференциальная диагностика этого процесса с узлами доброкачественной регенерации в тканях железы, как правило, затруднительна и требует дальнейшей модификации

Генетическая характеристика больных муковисцидозом в Российской Федерации по данным Национального регистра (2014)

The aim of this study was to investigate genetic features of patients with cystic fibrosis (CF) according to the National Register findings in Russia. Methods. The study involved 2,131 CF patients living in 74 regions of Russia who were included in the National Register of CF patients in 2014. Results. Genetic testing was performed in 89% of patients. The total mutant allele frequency was 81.2%. One hundred and twenty two mutations were found which comprised 173 genotypes; «mild» mutations took 23%. The most common mutant allele frequencies in the descending order were as follows: F508del, 51.53%; СFTRdele2,3, 5.93%; E92K, 2.62%; 3849+10kbC>T, 2.14%; 2184insA, 1.80%; W1282X, 1.80%; 2143delT, 1.69 %; N1303K, 1.43%; G542X, 1.16%; 1677delTA, 0.98%; L138ins, 0.95%; R334W, 0.85%; 394delTT, 0.85%; 3821delT, 0.42%; 2789+5G>A, 0.37%; S466X, 0.37%; S1196X, 0.37%; 3272-16T>A, 0.34%; W1282R, 0.29%; 3944delGT, 0.21%. Typical features of CFTR mutation distribution in Russian CF patients were lower frequency of mutations which are predominant worldwide, such as F508del, G542X, N1303K, and scarce G551D, 1717-1G>A, 2183AA>G mutations. On contrary, СFTRdele2,3, E92K, 2184insA, 2143delT, 1677delTA, L138ins mutations which are quite rare in Western Europe were encountered more often in Russia. «Mild» mutations were more common in Russian population of CF patients compared to European countries and have being increasing last years. Conclusion. Genetic features of Russian CF patients could be provided by Slavic, Turkic and Finno-Ugric genetic influence on Russian population.Генетическому разнообразию больных муковисцидозом (МВ) в России посвящены единичные работы на ограниченной выборке больных. Цель. Выявление особенностей генетического профиля больных МВ в России по данным Национального регистра (2014). Материалы и методы. Данные пациентов с МВ (n = 2 131) из 74 регионов России, включенные в Национальный регистр больных МВ (2014). Результаты. Генетическое обследование проведено у 89,0 % больных, суммарная аллельная частота выявленных мутаций составила 81,2 %. Выявлено 122 мутации, которые сформировали 173 различных генотипа, среди которых доля «мягких» генотипов составила 23,0 %. Аллельная частота самых распространенных мутаций представлена в порядке убывания: F508del – 51,53 %, СFTRdele2,3 – 5,93 %, E92K – 2,62 %, 3849+10kbC>T – 2,14 %, 2184insA – 1,80 %, W1282X – 1,80 %, 2143delT – 1,69 %, N1303K – 1,43 %, G542X – 1,16 %, 1677delTA – 0,98 %, L138ins – 0,95 %, R334W – 0,85 %, 394delTT – 0,85 %, 3821delT – 0,42 %, 2789+5G>A – 0,37 %, S466X – 0,37 %, S1196X – 0,37 %, 3272-16T>A – 0,34 %, W1282R – 0,29 %, 3944delGT – 0,21 %. Выявлено, что особенностями распределения мутаций. CFTRсреди российских больных МВ являются меньшая частота доминирующих в мире мутаций, таких как F508del, G542X, N1303K, единичная встречаемость мутаций G551D, 1717-1G>A, 2183AA>G и наоборот – более высокая частота мутаций, являющихся относительно редкими в западноевропейских странах: СFTRdele2,3, E92K, 2184insA, 2143delT, 1677delTA, L138ins. Другой особенностью является более высокая встречаемость «мягких» мутаций в России по сравнению со странами Европы. Выявлено, что доля «мягких» мутаций в популяции больных МВ на протяжении последних лет увеличивается. Заключение. При формировании населения России особенности генетического профиля российских больных МВ определяются славянскими, тюркскими и финно-угорскими влияниями

Incident type 2 diabetes attributable to suboptimal diet in 184 countries

The global burden of diet-attributable type 2 diabetes (T2D) is not well established. This risk assessment model estimated T2D incidence among adults attributable to direct and body weight-mediated effects of 11 dietary factors in 184 countries in 1990 and 2018. In 2018, suboptimal intake of these dietary factors was estimated to be attributable to 14.1 million (95% uncertainty interval (UI), 13.814.4 million) incident T2D cases, representing 70.3% (68.871.8%) of new cases globally. Largest T2D burdens were attributable to insufficient whole-grain intake (26.1% (25.027.1%)), excess refined rice and wheat intake (24.6% (22.327.2%)) and excess processed meat intake (20.3% (18.323.5%)). Across regions, highest proportional burdens were in central and eastern Europe and central Asia (85.6% (83.487.7%)) and Latin America and the Caribbean (81.8% (80.183.4%)); and lowest proportional burdens were in South Asia (55.4% (52.160.7%)). Proportions of diet-attributable T2D were generally larger in men than in women and were inversely correlated with age. Diet-attributable T2D was generally larger among urban versus rural residents and higher versus lower educated individuals, except in high-income countries, central and eastern Europe and central Asia, where burdens were larger in rural residents and in lower educated individuals. Compared with 1990, global diet-attributable T2D increased by 2.6 absolute percentage points (8.6 million more cases) in 2018, with variation in these trends by world region and dietary factor. These findings inform nutritional priorities and clinical and public health planning to improve dietary quality and reduce T2D globally. (c) 2023, The Author(s)

Children's and adolescents' rising animal-source food intakes in 1990-2018 were impacted by age, region, parental education and urbanicity

Animal-source foods (ASF) provide nutrition for children and adolescents physical and cognitive development. Here, we use data from the Global Dietary Database and Bayesian hierarchical models to quantify global, regional and national ASF intakes between 1990 and 2018 by age group across 185 countries, representing 93% of the worlds child population. Mean ASF intake was 1.9 servings per day, representing 16% of children consuming at least three daily servings. Intake was similar between boys and girls, but higher among urban children with educated parents. Consumption varied by age from 0.6 at <1 year to 2.5 servings per day at 1519 years. Between 1990 and 2018, mean ASF intake increased by 0.5 servings per week, with increases in all regions except sub-Saharan Africa. In 2018, total ASF consumption was highest in Russia, Brazil, Mexico and Turkey, and lowest in Uganda, India, Kenya and Bangladesh. These findings can inform policy to address malnutrition through targeted ASF consumption programmes. (c) 2023, The Author(s)

LIVER TREMATODE INFECTION - OPISTHORCHIASIS AND CLONORCHIASIS: ACTUAL PROBLEMS AND PRINCIPLES OF DIAGNOSIS IN MODERN CLINICAL PRACTICE (REVIEW OF LITERATURE)

The article highlights the importance of the problem of endemic liver trematode infection (opisthorchiasis and clonorchiasis) and the principles of their diagnosis from the perspective of the clinician. Closely related pathogens (Opisthorchis felineus, Opisthorchis viverrini, Clonorchis sinensis) of these diseases are group 1 carcinogens, promoting the development of cholangiocarcinoma of the liver, gallstones, pancreatitis and gastroduodenitis. Specific and early diagnosis of opisthorchiasis in humans is crucial for an appropriate and timely treatment. The basic method of diagnostics in the world clinical practice is a detection of eggs in fecal samples. Once a fecal sample is available, the modified formalin-ether sedimentation technique, the modified thick Kato smear and with Kato - Katz are used. As a single examination does not necessarily provide diagnostic certainty, repeated examinations are necessary to improve diagnostic sensitivity. Immunoassay is considered as an addition to parasitological examination. The EL1SA shows the best performance among the serological tests. Molecular-genetic method (PCR and Loop mediated isothermal amplification (LAMP) is ranked as the most promising. Due to their high specificity, such molecular diagnostic tests are likely to play an increasingly significant role in anthelminthic drug efficacy evaluations, the rigorous monitoring of reinfection patterns, and to investigate changes in the endemic range of the liver flukes

DIFFICULT DIAGNOSIS OF CROHN’S DISEASE: A CLINICAL CASE

The paper presents a case of Crohn’s disease with isolated jejunum involvement, which exemplifies the difficulty in diagnosing this condition. The clinical picture was characterized by iron-deficiency anemia and hypoproteinemia, while other typical symptoms were absent. The late diagnosis, delayed pathogenetic therapy administration led to multiple jejunum stenosis, complicated by partial small bowel obstruction