Detection of Functional Significance of Coronary Stenoses Using Dynamic 13N-Ammonia Stress-PET/CT with Absolute Values of Myocardial Blood Flow and Coronary Flow Reserve

Objectives. The aim of the study was to compare the values of myocardial blood flow (MBF) at stress, MBF at rest and coronary flow reserve (CFR) obtained by 13Nammonia stress-PET/CT in patients with various degrees of coronary stenosis and in healthy patients. And thus to estimate the possible contribution of the stress-PET/CT quantitative data to the detection of functionally significant coronary stenoses in patients with coronary artery disease (CAD). Materials and methods. 63 patients (mean age 64±9 years) with known CAD underwent dynamic 13N-ammonia stress-PET/CT followed by calculation of MBF both at stress and at rest in absolute units and CFR. We compared quantitative values in two groups of patients with coronary artery stenosis: 1) ≥75% (n = 36) and 2) <75% (n = 27) confirmed by invasive coronary angiography and in group of healthy patients (n = 11). Results. MBF at stress was significantly lower in group with ≥75% diameter stenoses (median 1,44 [1,21; 1,85] mL/min per g) compared with group with <75% diameter stenoses (2,42 [1,75; 2,89] mL/min/g) and the normal group (2,54 [2,31; 2,86] mL/min/g), (p <0,001). There was no reliable difference in MBF at rest between the three groups (p = NS). CFR was significantly lower in the group of patients with severe ≥75% stenoses (1,85 [1,54; 2,31]) in comparison with patients group with stenoses of intermediate <75% severity (2,73 [2,19; 3,21]), and also in comparison with the normal group (3,12 [2,75; 3,23]), (p <0,001). Conclusion. The values of MBF at stress and CFR are significantly lower in patients with severe coronary arteries stenoses comparing with the group of patients with mild and moderate stenoses. The value of MBF at rest used independently has no diagnostic utility for detection of functional significance of coronary artery stenoses. Keywords: myocardial blood flow, coronary flow reserve, PET/CT, 13N-ammonia, coronary stenosis

Мультиспиральная компьютерная томография в ранней диагностике пневмонии, вызванной SARS-CoV-2

The high informative value of chest computed tomography in the diagnosis of pneumonia caused by SARS-CoV-2 is generally recognized, but there is no enough data on the diagnostic capabilities of this method within 5 first days of the clinical manifestations of the disease. The paper presents the results of chest multispiral (multislice) computed tomography (MSCT) of 56 patients with COVID-19 pneumonia in the early days of the disease. The aim of the study was to analyze the semiotics of pathological changes in the lungs in the first days of the onset of clinical symptoms of COVID-19 and to clarify the methodology for conducting MSCT. Methods. The data of chest MSCT of 56 patients with clinical symptoms of a new coronavirus infection SARS-CoV-2 were analyzed. MSCT was carried out in the first 4 – 5 days of the disease. Results. Five variants for the development of the disease were revealed, including atypical, characterized by the prevalence and CT semiotics of lung damage and apparently due to the different response of the patients to SARS-CoV-2 infection. The leading signs of COVID-19 pneumonia in the early stages of the disease were foci of ground glass opacification (GGO), multifocal lesions of the lungs, edema of the interalveolar pulmonary interstitium, which distinguishes it from pneumonia of another etiology. Conclusion. Comparison of MSCT data and the clinical picture of the disease during the first 5 days suggests with high confidence the pneumonia associated with COVID-19. A prerequisite for conducting MSCT in case of suspicion of this type of pneumonia is the implementation of thin 0.5 – 1.5 mm sections, MSCT performance at suspended full inspiration, post-processing of unenhanced tomogram data in MinIP mode.Высокая информативность компьютерной томографии (КТ) органов грудной клетки (ОГК) в диагностике COVID-19-ассоциированной пневмонии общепризнанна, однако данные о диагностических возможностях и особенностях выполнения этого метода в первые 5 суток клинических проявлений заболевания отсутствуют. В работе представлены результаты мультиспиральной КТ (МСКТ) ОГК пациентов (n = 56) с COVID-19-ассоциированой пневмонией в первые 4–5 суток развития симптомов болезни. Целью исследования явилось изучение семиотики патологических изменений в легких в первые дни появления клинических симптомов COVID-19 и описание особенностей методики проведения МСКТ. Материалы и методы. Проанализированы данные МСКТ ОГК пациентов с клинической симптоматикой новой коронавирусной инфекции SARS-CoV-2. МСКТ выполнялась в первые 4–5 суток заболевания. Результаты. Выявлено 5 вариантов развития заболевания, включая атипичный, различавшихся распространенностью и КТ-семиотикой поражения легких и обусловленных, по-видимому, различной реакцией организма пациентов на инфекцию SARS-CoV-2. Ведущими признаками COVID-19-ассоциированной пневмонии в ранние сроки заболевания являлись очаги «матового стекла», мультифокальность поражения легких, отек межальвеолярного легочного интерстиция, в чем и состояли отличия COVID-19-ассоциированной пневмонии от таковой другой этиологии. Заключение. Сопоставление данных МСКТ и клинической картины заболевания в течение первых 5 суток заболевания позволяет с высокой достоверностью предположить наличие пневмонии, ассоциированной с COVID-19. Необходимым условием проведения МСКТ при подозрении на пневмонию данного типа является выполнение тонких (0,5–1,5 мм) срезов, контроль за полнотой вдоха пациента, постпроцессинговая обработка данных нативной томограммы в MinIP-режиме

Рентгенография и компьютерная томография в диагностике различных видов идиопатических интерстициальных пневмоний

Results of radiography and computed tomography (KT) of 38 patients with various morphological types of idiopathic interstitial pneumonia were analyzed. Differentiated diagnosis of various types of the idiopathic interstitial pneumonia at the initial stage of the disease was found to be difficult but test therapy and CT monitoring make possible to reject or confirm the idiopathic interstitial fibrosis which is one of the most frequent and hardly treated types of the pneumonia. At the advanced stage, when significant destructive lesions of the lung parenchyma take place, the CT was quite specific and sensitive to specify the disease's nature that allowed to avoid the lung tissue biopsy.Проанализированы данные рентгенографии и компьютерной томографии (КТ) 38 больных с идиопатическими интерстициальными пневмониями различной морфологической формы. Установлено, что в начальной фазе развития болезни проведение дифференциальной диагностики различных видов идиопатических интерстициальных пневмоний затруднительно, однако пробное лечение и динамический КТ-мониторинг дают возможность исключить или подтвердить идиопатический интерстициальный фиброз — один из наиболее частых и трудных для лечения видов пневмонии. В стадии разгара, значительных деструктивных изменений легочной паренхимы КТ обладает высокой чувствительностью и специфичностью в уточнении природы болезни, что позволяет избежать биопсии легкого

The Spectrum and Frequency of Inner Ear Anomalies in Patients with Congenital Hearing Impairment in Yakutia

Objective. To analyze the spectrum and frequency of inner ear anomalies in patients with congenital hearing impairment in Yakutia.Material and methods. A total of 165 patients with congenital hearing impairment were surveyed. All the patients were examined by an audiologist, an educational audiologist, and a neuropsychiatrist. All the patients underwent X-ray computed tomography (X-ray CT) of temporal bone structures (which was supplemented by magnetic resonance imaging (MRI) in some cases).Results. Based on modern ideas about inner ear anomalies and their classification, the authors first analyzed the spectrum and frequency of inner ear anomalies in patients with congenital hearing impairment in Yakutia. Inner ear malformations were identified in 16 (9.7%) of the 165 patients with hearing impairment, which corresponds to that in the previously studied samples of deaf people in different countries (from 3% to 35%). Of the inner ear structures, the cochlea and vestibule were more commonly affected. Abnormalities of the internal auditory meatus, semicircular canals, and vestibular aqueduct were less common. In general, the spectrum of anomalies was represented by 7 different malformations. Incomplete partition type II (IP-II) (34.3%) came first in incidence among all the abnormalities. Incomplete partition type III (IP-III) (18.7%) ranked second in incidence. The expansion of the internal auditory meatus (12.5%) and vestibular aqueduct (12.5%) occupied the third place. Inner ear anomalies occurred as concurrences that are difficult to interpret and classify in half (50%) of all the cases.Conclusion. Analysis of the spectrum and frequency of temporal bone abnormalities in Yakutia suggests that every 10 patients with congenital hearing impairment have one or another inner ear structural malformation (9.7%) and require accurate and timely diagnosis using up-to-date X-ray CT and MRI techniques

Two additive mechanisms impair the differentiation of 'substrate-selective' p38 inhibitors from classical p38 inhibitors in vitro

<p>Abstract</p> <p>Background</p> <p>The success of anti-TNF biologics for the treatment of rheumatoid arthritis has highlighted the importance of understanding the intracellular pathways that regulate TNF production in the quest for an orally-available small molecule inhibitor. p38 is known to strongly regulate TNF production via MK2. The failure of several p38 inhibitors in the clinic suggests the importance of other downstream pathways in normal cell function. Recent work has described a 'substrate-selective' p38 inhibitor that is able to preferentially block the activity of p38 against one substrate (MK2) versus another (ATF2). Using a combined experimental and computational approach, we have examined this mechanism in greater detail for two p38 substrates, MK2 and ATF2.</p> <p>Results</p> <p>We found that in a dual (MK2 and ATF2) substrate assay, MK2-p38 interaction reduced the activity of p38 against ATF2. We further constructed a detailed kinetic mechanistic model of p38 phosphorylation in the presence of multiple substrates and successfully predicted the performance of classical and so-called 'substrate-selective' p38 inhibitors in the dual substrate assay. Importantly, it was found that excess MK2 results in a stoichiometric effect in which the formation of p38-MK2-inhibitor complex prevents the phosphorylation of ATF2, despite the preference of the compound for the p38-MK2 complex over the p38-ATF2 complex. MK2 and p38 protein expression levels were quantified in U937, Thp-1 and PBMCs and found that [MK2] > [p38].</p> <p>Conclusion</p> <p>Our integrated mechanistic modeling and experimental validation provides an example of how systems biology approaches can be applied to drug discovery and provide a basis for decision-making with limited chemical matter. We find that, given our current understanding, it is unlikely that 'substrate-selective' inhibitors of p38 will work as originally intended when placed in the context of more complex cellular environments, largely due to a stoichiometric excess of MK2 relative to p38.</p

A Novel Compound C12 Inhibits Inflammatory Cytokine Production and Protects from Inflammatory Injury In Vivo

Inflammation is a hallmark of many diseases. Although steroids and cyclooxygenase inhibitors are main anti-inflammatory therapeutical agents, they may cause serious side effects. Therefore, developing non-steroid anti-inflammatory agents is urgently needed. A novel hydrosoluble compound, C12 (2,6-bis(4-(3-(dimethylamino)-propoxy)benzylidene)cyclohexanone), has been designed and synthesized as an anti-inflammatory agent in our previous study. In the present study, we investigated whether C12 can affect inflammatory processes in vitro and in vivo. In mouse primary peritoneal macrophages, C12 potently inhibited the production of the proinflammatory gene expression including TNF-α, IL-1β, IL-6, iNOS, COX-2 and PGE synthase. The activity of C12 was partly dependent on inhibition of ERK/JNK (but p38) phosphorylation and NF-κB activation. In vivo, C12 suppressed proinflammatory cytokine production in plasma and liver, attenuated lung histopathology, and significantly reduced mortality in endotoxemic mice. In addition, the pre-treatment with C12 reduced the inflammatory pain in the acetic acid and formalin models and reduced the carrageenan-induced paw oedema and acetic acid-increased vascular permeability. Taken together, C12 has multiple anti-inflammatory effects. These findings, coupled with the low toxicity and hydrosolubility of C12, suggests that this agent may be useful in the treatment of inflammatory diseases

Comparative study of cytotoxicity of ferromagnetic nanoparticles and magnetitecontaining polyelectrolyte microcapsules

The work was supported by Ministry of Education and Science of the Russian Federation as part of the State task for National Research Mordovia State University, project No. 2952 and the Government of the Russian Federation (grant №14.Z50.31.0004 to support scientific research projects implemented under the supervision of leading scientists

The p38/MK2/Hsp25 Pathway Is Required for BMP-2-Induced Cell Migration

Background: Bone morphogenetic proteins (BMPs) have been shown to participate in the patterning and specification of several tissues and organs during development and to regulate cell growth, differentiation and migration in different cell types. BMP-mediated cell migration requires activation of the small GTPase Cdc42 and LIMK1 activities. In our earlier report we showed that activation of LIMK1 also requires the activation of PAKs through Cdc42 and PI3K. However, the requirement of additional signaling is not clearly known. Methodology/Principal Findings: Activation of p38 MAPK has been shown to be relevant for a number of BMP-2¿s physiological effects. We report here that BMP-2 regulation of cell migration and actin cytoskeleton remodelling are dependent on p38 activity. BMP-2 treatment of mesenchymal cells results in activation of the p38/MK2/Hsp25 signaling pathway downstream from the BMP receptors. Moreover, chemical inhibition of p38 signaling or genetic ablation of either p38¿ or MK2 blocks the ability to activate the downstream effectors of the pathway and abolishes BMP-2-induction of cell migration. These signaling effects on p38/MK2/Hsp25 do not require the activity of either Cdc42 or PAK, whereas p38/MK2 activities do not significantly modify the BMP-2-dependent activation of LIMK1, measured by either kinase activity or with an antibody raised against phospho-threonine 508 at its activation loop. Finally, phosphorylated Hsp25 colocalizes with the BMP receptor complexes in lamellipodia and overexpression of a phosphorylation mutant form of Hsp25 is able to abolish the migration of cells in response to BMP-2. Conclusions: These results indicate that Cdc42/PAK/LIMK1 and p38/MK2/Hsp25 pathways, acting in parallel and modulating specific actin regulatory proteins, play a critical role in integrating responses during BMP-induced actin reorganization and cell migration

Маркеры ранних стадий рака легкого у ликвидаторов Чернобыльской аварии

Persons exposed to inhaled radionuclides are at high risk for lung cancer, primarily, due to lung fibrosis development. This work studied lung fibrotic changes and lung cancer genetic markers in liquidators of the Chernobyl accident consequences. The study involved 33 men worked at the Chernobyl station area in 1986-1987, aged from 37 to 65 years (average 45.45±0.95; M±m), and 10 control group men comparable on the age, hazards, social and occupational status, lung pathology, but had never exposed to radiation.Lung function tests, fibreoptic bronchoscopy, histological examination of lung and bronchi tissues biopsy specimens, and lung computed tomography were performed. Oncogene c-myc, Ki-67 proliferation marker, and a deletion in the short arm of the chromosome 3 were investigated in the bronchial epithelium.The lung fibrosis was detected in 13 (42.4%) liquidators and in no-one of the control group. The liquidators also had more bronchial epithelium dysregenerative changes with significant prevalence of basement cell hyperplasia (0.58±.09 and 0.2±0.13 cases in the groups accordingly, p&lt;0.05). Meanwhile the control group had no mild dysplasia at all and demonstrated severe dysplasia rather more frequently (0.2±0.13 vs 0.06±0.04 in the liquidators, p&lt;0.05). The liquidators showed the 3p deletion in the bronchial epithelium cells more often (0.21±0.07 and 0.1±0.1 accordingly, p&lt;0.05) and tended to show other genetic lung cancer markers quite more frequent either.The correlation was found between the lung fibrosis and 3p deletion presence (r=0.45, p&lt;0.05) and also between a pneumonia number anamnestically and Ki-67 expression in the liquidators’ group (r=0.46, p&lt;0.05). The second patients’ group did not demonstrated such the correlaions.Thus, chronic respiratory pathology liquidators develop lung fibrosis earlier than other patients with the similar lung pathology. Basement cell hyperplasia and some oncogenes (3p deletion, c-myc) encounter considerably more often in liquidators that likely to be poor prognostic signs for lung cancer occurrence. Therefore, the Chernobyl accident liquidators are at higher risk for lung cancer compared to the similar lung pathology patients without radiation exposureЛица, ингалировавшие радионуклиды в результате профессиональных воздействий либо неблагоприятной экологической обстановки, имеют высокий риск заболевания раком легкого, в первую очередь, за счет развития пневмофиброза. В данной работе исследовались фиброзные изменения легочной ткани и ряд генетических маркеров рака легкого у ликвидаторов последствий Чернобыльской аварии. В исследование вошли 33 ликвидатора (все мужчины) в возрасте от 37 до 65 лет (в среднем 45,4±0,95 года; М±т) и 10 мужчин группы сравнения, сравнимые с “ликвидаторами” по возрасту, вредным привычкам, социально-бытовым и профессиональным условиям, характеру и длительности бронхолегочной патологии, но не контактировавшие с радиацией.Пациентам проводились исследования легочной функции, фибробронхоскопия с биопсией и последующим гистологическим исследованием ткани бронхов и легких, компьютерная томография легких. В биоптатах определяли онкоген c-myc и маркер пролиферации Ki-67, делецию в коротком плече 3-й хромосомы.Среди ликвидаторов пневмофиброз был выявлен у 13 (42,4%) человек, в группе сравнения не выявлен ни у кого. Также у ликвидаторов чаще, чем в группе сравнения, встречались дисрегенераторные изменения бронхиального эпителия с достоверным преобладанием базальноклеточной гиперплазии (0,58±0,09 и 0,2±0,13 случаев соответственно по группам, р&lt;0,05). Вместе с тем в группе сравнения совсем не обнаруживалась дисплазия 1 ст. и несколько чаще встречалась дисплазия 3 ст. (0,2±0,13 в группе сравнения и 0,06±0,04 у ликвидаторов, р&lt;0,05). Делеция Зр в клетках бронхиального эпителия у ликвидаторов определялась достоверно чаще, чем в группе сравнения (0,21±0,07 и 0,1±0,1 соответственно, р&lt;0,05). Имеется тенденция к более частому обнаружению в группе ликвидаторов и других генетических маркеров.Корреляционный анализ показал достоверную связь между наличием пневмофиброза и делеции в коротком плече 3-й хромосомы (r=0,45, р&lt;0,05), а также между числом перенесенных пневмоний и экспрессией Ki-67 в группе ликвидаторов (r=0,46, р&lt;0,05). В группе сравнения такой зависимости не получено.Таким образом, у ликвидаторов с ХОБЛ фиброз легочной ткани развивается значительно раньше, чем у обычных больных ХОБЛ. У ликвидаторов достоверно чаще обнаруживаются базальноклеточная гиперплазия и генетические маркеры рака легкого (делеция Зр, с-тус), что является прогностически неблагоприятным фактором в развитии этого заболевания. В результате ликвидаторы имеют больший риск заболевания раком легкого по сравнению с обычными больными ХОБЛ.

MAPK-Activated Protein Kinase 2 Is Required for Mouse Meiotic Spindle Assembly and Kinetochore-Microtubule Attachment

MAPK-activated protein kinase 2 (MK2), a direct substrate of p38 MAPK, plays key roles in multiple physiological functions in mitosis. Here, we show for the first time the unique distribution pattern of MK2 in meiosis. Phospho-MK2 was localized on bipolar spindle minus ends and along the interstitial axes of homologous chromosomes extending over centromere regions and arm regions at metaphase of first meiosis (MI stage) in mouse oocytes. At metaphase of second meiosis (MII stage), p-MK2 was localized on the bipolar spindle minus ends and at the inner centromere region of sister chromatids as dots. Knockdown or inhibition of MK2 resulted in spindle defects. Spindles were surrounded by irregular nondisjunction chromosomes, which were arranged in an amphitelic or syntelic/monotelic manner, or chromosomes detached from the spindles. Kinetochore–microtubule attachments were impaired in MK2-deficient oocytes because spindle microtubules became unstable in response to cold treatment. In addition, homologous chromosome segregation and meiosis progression were inhibited in these oocytes. Our data suggest that MK2 may be essential for functional meiotic bipolar spindle formation, chromosome segregation and proper kinetochore–microtubule attachments