Репозиторий Университета

To the editor, In the excellent study recently published in the Annals of the Rheumatic Disease, Damoiseaux et al showed a high diagnostic performance of antigen-specific immunoassay for the detection of myeloperoxidase (MPO) and proteinase 3 (PR3) antineutrophil cytoplasmic antibodies (ANCAs). These data challenge the role of indirect immunofluorescence in the ANCA testing algorithm. In our centre, we have discarded ANCA indirect immunofluorescence more than a decade ago. Therefore, new data showing the feasibility of screening by antigen-specific immunoassay have a particular value for us. In the recent series of 284 patients with ANCA-associated vasculitides, we have detected ANCAs by this approach in 96.9% of patients with microscopic polyangiitis (MPA) but only in 72.7% of patients with granulomatosis with polyangiitis (GPA) (table 1). The latter result can be explained by a relatively high occurrence of localised GPA in our series, since a rate of ANCA positivity reached 92.2% in patients with renal GPA. ANCA testing should be performed only in the clinical context since PR3-ANCA and MPO-ANCA can be found in the other conditions than vasculitis, for example, infective endocarditis, tuberculosis, primary sclerosing cholangitis and interstitial lung diseases. The results of several studies suggest that in such patients, ANCAs have not been merely a chance finding and may be clinically relevant, for example, a high prevalence of ANCAs was identified in unselected patients with infective endocarditis (24%). Seropositive patients presented more commonly with a subacute form of infective endocarditis leading to multiple valve involvement and a more frequent renal impairment.

Over the last decades, numerous randomised clinical trials and long-term observational studies were conducted in dozens or hundreds patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) and provided a basis for an evidence-based treatment. With immunosuppressive therapy, up to 85%–90% of patients will achieve remission, though the disease can follow a relapsing course in a significant proportion of patients, and prolonged exposure to glucocorticoids and immunosuppressive agents may have devastating consequences. However, the attempts to shorten maintenance therapy can lead to recurrent exacerbations of AAV and an accumulation of irreversible organ damage.

In the recent randomised, prospective REMAIN (prolonged REmission-MAINtenance therapy in systemic vasculitis) study, conducted in 117 patients with AAV in stable remission after cyclophosphamide/prednisolone-based induction, Karras et al showed that prolonged maintenance therapy with azathioprine/prednisolone (up to 48 months from diagnosis) was relatively safe and more effective than withdrawal of azathioprine/prednisolone by 24 months1. Extension of immunosuppression was associated with a significantly lower risk both of any and major relapses (22% vs 63%, p<0.0001, and 14% vs 35%, p<0.007, respectively) and resulted in a better renal survival. Notably, almost all patients completed the prolonged follow-up. The results of the REMAIN study were satisfying to us since prolonged immunosuppression with low dose cyclophosphamide and currently azathioprine or metothrexate in combination with corticosteroids for many years remains a preferred treatment option for patients with AAV in our clinic.

However, there is the other side of the coin. A paradigm for treating patients with AAV has changed significantly over recent years. Currently, it is apparent that …

Tick-borne encephalitis virus (TBEV) is the causative agent of tick-borne encephalitis (TBE), a vector-borne zoonotic neuroinfection. For successful circulation in natural foci the virus has to survive in the vector for a long period of time. Information about the effect of long-term infection of ticks on properties of the viral population is of great importance. In recent years, changes in the eco-epidemiology of TBEV due to changes in distribution of ixodid ticks have been observed. These changes in TBEV-endemic areas could result in a shift of the main tick vector species, which in turn may lead to changes in properties of the virus. In the present study we evaluated the selective pressure on the TBEV population during persistent infection of various species of ticks and tick cell lines. TBEV effectively replicated and formed persistent infection in ticks and tick cell lines of the vector species (Ixodes spp.), potential vectors (Dermacentor spp.) and non-vector ticks (Hyalomma spp.). During TBEV persistence in Ixodes and Dermacentor ticks, properties of the viral population remained virtually unchanged. In contrast, persistent TBEV infection of tick cell lines from both vector and non-vector ticks favoured selection of viral variants with low neuroinvasiveness for laboratory mice and substitutions in the E protein that increased local positive charge of the virion. Thus, selective pressure on viral population may differ in ticks and tick cell lines during persistent infection. Nevertheless, virus variants with properties of the original strain adapted to mouse CNS were not eliminated from the viral population during long-term persistence of TBEV in ticks and tick cell lines.

This article presents the results of a comprehensive survey of the burden of tick-borne infectious diseases (TBIDs) in the Altai region of Russia. Official data for TBID incidence were analyzed and 201 samples from patients with suspected TBID were studied. Furthermore, questing ticks and ticks recovered from humans were examined to estimate prevalence of TBID-causative agents. The Altai region was determined to have a heightened risk for TBIDs in Russia. The most epidemiologically significant… CONTINUE READING

Transfusion of packed red blood cells (PRBC) to patients in critical states is often accompanied by post-transfusion complications. This may be related with disturbance of properties of PRBC and their membranes during long-term storage in the hemopreservative solution. The purpose of our work is the study of transformation of morphology, membranes stiffness and nanostructure for assessment of PRBC quality, in vitro. By atomic force microscopy we studied the transformation of cell morphology, the appearance of topological nanodefects of membranes and by atomic force spectroscopy studied the change of membrane stiffness during 40 days of storage of PRBC. It was shown that there is a transition period (20–26 days), in which we observed an increase in the Young’s modulus of the membranes 1.6–2 times and transition of cells into irreversible forms. This process was preceded by the appearance of topological nanodefects of membranes. These parameters can be used for quality assessment of PRBC and for improvement of transfusion rules.

Patients with coronary artery aneurysms (CAA) resulting from Kawasaki Disease (KD) are at risk for thrombosis and myocardial infarction. Current guidelines recommend CAA diameter ≥8mm as the criterion for initiating systemic anticoagulation. Transluminal Attenuation Gradient (TAG) analysis has been proposed as a non-invasive method for evaluating functional significance of coronary stenoses using Computerized Tomography Angiography (CTA), but has not previously been used in CAA. We hypothesized that abnormal hemodynamics in CAA caused by KD could be quantified using TAG analysis. We studied 23 patients with a history of KD who had undergone clinically indicated CTA. We quantified TAG in the major coronary arteries and aneurysm geometry was characterized using maximum diameter, aneurysm shape index (ASI) and sphericity index. A total of 55 coronary arteries were analyzed, 25 of which had at least one aneurysmal region. TAG in aneurysmal arteries was significantly lower than in normal arteries (-23.5±10.7 vs. -10.5±9.0, p=0.00002). Aneurysm diameter, ASI, and sphericity index were weakly correlated with TAG (r²=0.01, p=0.6: r²=0.15, p=0.06; r²=0.16, p=0.04). This is the first application of TAG analysis to CAA caused by KD, and demonstrates significantly different TAG values in aneurysmal versus normal arteries. Lack of correlation between TAG and CAA geometry suggests that TAG may provide hemodynamic information not available from anatomy alone. TAG represents a possible extension to standard CTA for KD patients that may improve thrombotic risk-stratification and aid in clinical decision-making.

Chitosan-g-oligolactide copolymers with relatively long oligolactide grafted chains of various stereochemical compositions have been synthetized via a solvent-free mechanochemical technique and tailored to fabricate three-dimensional hydrogels using two-photon induced microstereolithography. An effect of the characteristics of chitosan and oligolactide used for the synthesis on the grafting yield and copolymer's behavior were evaluated using fractional analysis, FTIR-spectroscopy, dynamic light scattering, and UV-spectrophotometry. The lowest copolymer yield was found for the system based on chitosan with higher molecular weight, while the samples consisting of low-molecular weight chitosan showed higher grafting degrees, which were comparable in both the cases of L,L- or L,D-oligolactide grafting. The copolymer processability in the course of two-photon stereolithography was evaluated as a function of the copolymer's characteristics and stereolithography conditions. The structure and mechanical properties of the model film samples and fabricated 3D hydrogels were studied using optical and scanning electron microscopy, as well as by using tensile and nanoindenter devices. The application of copolymer with oligo(L,D-lactide) side chains led to higher processability during two-photon stereolithography in terms of the response to the laser beam, reproduction of the digital model, and the mechanical properties of the fabricated hydrogels.

This work is aimed at exhaustive and detailed study of chemical, physical and physico-chemical characteristics of NO-containing gas flow (NO-CGF) generated by a plasma-chemical generator of Plason device, which has been used in medical practice for more than 15 years for effectively healing wound and inflammatory conditions with exogenous nitric oxide (NO-therapy). Data was obtained on spatial structure of the gas flow, and values of its local parameters in axial and radial directions, such as nitric oxide content, velocity, temperature and mass flow density of nitric oxide, providing altogether the effectiveness of treatment by the exogenous NO-therapy method, were determined experimentally and by computations. It was demonstrated that plasma-chemical synthesis of NO from atmospheric air in a low direct current (DC) arc provides a high mass flow of nitric oxide at the level of 1.6-1.8 mg/s, while in the area of impact of NO-CGF on the biological tissue, on its axis, NO content is 400-600 ppm, flow velocity about 5 m/s, nitric oxide mass flow density 0.25-0.40 mg/(s·cm(2)), temperature 40-60 °C. Tendencies were determined for designing new devices for further experimental biological and medical research in the field of NO-therapy: lowering the temperature of NO-CGF to ambient temperature will enable variation, in experiments, of the affecting flow parameters in a wide range up to their maximum values: NO content up to 2000 ppm, velocity up to 20 m/s, nitric oxide mass flow density up to 2.5 mg/(s·cm(2)).

Regeneration of articular cartilage has been a long-standing challenge in the field of regenerative medicine. In the past 2 years, several studies have genetically identified the presence of stem cells in the surface of articular cartilage, but questions remain as to the healing properties of these cells.

Clinical utility of conventional oral therapies is limited by their inability to deliver therapeutic molecules at the local or targeted site, causing a variety of side effects. Transdermal delivery has made a significant contribution in the management of skin diseases with enhanced therapeutic activities over the past two decades. In the modern era, various biomimetic and biocompatible polymer−lipid hybrid systems have been used to augment the transdermal delivery of therapeutics such as dermal patches, topical gels, iontophoresis, electroporation, sonophoresis, thermal ablation, microneedles, cavitational ultrasound, and nano or microlipid vesicular systems. Nevertheless, the stratum corneum still represents the main barrier to the delivery of vesicles into the skin. Lipid based formulations applied to the skin are at the center of attention and are anticipated to be increasingly functional as the skin offers many advantages for the direction of such systems. Accordingly, this review provides an overview of the development of conventional to advanced biomimetic lipid vesicles for skin delivery of a variety of therapeutics, with special emphasis on recent developments in this field including the development of transferosomes, niosomes, aquasomes, cubosomes, and other new generation lipoidal carriers.

The primary aim of this investigation was to determine the biocompatibility and cell culture potential of a newly designed class of thermoresponsive polymers. The attractiveness of these polymers lies in the fact that they swell rather than dissolve when the temperature is reduced below their respective lower critical solution temperature, due to the incorporation of octadecyl methacrylate (ODMA). The ODMA monomer acts as a physical crosslinker, preventing polymer dissolution upon temperature reduction. Two polymers were studied in this investigation poly(N isorpoylacrylamide (NIPAm)(99.25%)-co-ODMA(0.75%)) and poly(NIPAm(65%)-co-N-tert-butylacrylamide (NtBAm)(34.25%)-co-ODMA(0.75%)). Thin thermoresponsive films of the polymers were prepared via spin coating. 3T3 cells were then seeded on the prepared films and cell viability was assessed quantitatively through cell viability and activity assays and qualitatively by light microscopy. Cells were successfully seeded and grown on the poly(NIPAm-co-ODMA) and poly(NIPAm-co-NtBAm-co-ODMA) copolymer films after film modification with cell adhesion promoters (CAPs). Cell sheets successfully detached from the CAP coated poly(NIPAm-co-ODMA) platforms upon temperature reduction.

    Both negative and positive social experiences during sensitive life phases profoundly shape brain and behaviour. Current research is therefore increasingly focusing on mechanisms mediating the interaction between varying life experiences and the epigenome. Here, male mice grew up under either adverse or beneficial conditions until adulthood, when they were subdivided into groups exposed to situations that either matched or mismatched previous conditions. It was investigated whether the resulting four life histories were associated with changes in anxiety-like behaviour, gene expression of selected genes involved in anxiety and stress circuits, and arginine vasopressin receptor 1a (Avpr1a) gene methylation. Varying experiences during life significantly modulated (1) anxiety-like behaviour; (2) hippocampal gene expression of Avpr1a, serotonin receptor 1a (Htr1a), monoamine oxidase A (Maoa), myelin basic protein (Mbp), glucocorticoid receptor (Nr3c1), growth hormone (Gh); and (3) hippocampal DNA methylation within the Avpr1a gene. Notably, mice experiencing early beneficial and later adverse conditions showed a most pronounced downregulation of Avpr1a expression, accompanied by low anxiety-like behaviour. This decrease in Avpr1a expression may have been, in part, a consequence of increased methylation in the Avpr1a gene. In summary, this study highlights the impact of interactive social experiences throughout life on the hippocampal epigenotype and associated behaviour.

Ribosomal s6 kinase 2 is a growth factor activated serine/threonine kinase and member of the ERK signaling pathway. Mutations in the Rsk2 gene cause Coffin-Lowry syndrome, a rare syndromic form of intellectual disability. The Rsk2 KO mouse model was shown to have learning and memory defects. We focused on the investigation of the emotional behavioral phenotype of Rsk2 KO mice mainly in the IntelliCage. They exhibited an anti-depressive, sucrose reward seeking phenotype and showed reduced anxiety. Spontaneous activity was increased in some conventional tests. However, KO mice did not show defects in place learning, working memory and motor impulsivity. In addition, we found changes of the monoaminergic system in HPLC and qRT-PCR experiments. Taken together, RSK2 not only plays a role in cognitive processes but also in emotional and reward-related behaviors.

Dysfunction of the serotonergic (5-HTergic) system has been implicated in the cognitive and behavioural symptoms of Alzheimer’s disease (AD). Accumulation of toxic amyloid-β (Aβ) species is a hallmark of AD and an instigator of pathology. Serotonin (5-HT) augmentation therapy by treatment with selective serotonin reuptake inhibitors (SSRIs) in patients with AD has had mixed success in improving cognitive function, whereas SSRI administration to mice with AD-like disease has been shown to reduce Aβ pathology. The objective of this study was to investigate whether an increase in extracellular levels of 5-HT induced by chronic SSRI treatment reduces Aβ pathology and whether 5-HTergic deafferentation of the cerebral cortex could worsen Aβ pathology in the APPswe/PS1ΔE9 (APP/PS1) mouse model of AD.

Recently, a novel phenomenon of horizontal gene transfer of helicase-encoding sequence from positive-stranded RNA viruses to LINE transposons in insect genomes was described. TRAS family transposons encoding an ORF2 protein, which comprised all typical functional domains and an additional helicase domain, were found to be preserved in many families during the evolution of the order Lepidoptera. In the present paper, in species of orders Hemiptera and Orthoptera, we found helicase domain-encoding sequences integrated into ORF1 of retrotransposons of the Jockey family. RNA helicases encoded by transposons of TRAS and Jockey families represented separate brunches in a phylogenetic tree of helicase domains and thus could be considered as independently originated in the evolution of insect transposons. Transcriptome database analyses revealed that both TRAS and Jockey transposons encoding the helicase domain represented transcribed genome sequences. Moreover, the transposon-encoded helicases were found to contain the full set of conserved motifs essential for their enzymatic activities. Taking into account the previously reported ability of RNA helicase encoded by TRAS ORF2 to suppress post-transcriptional RNA silencing, we propose possible scenarios of evolutionary fixation of actively expressed functional helicases of viral origin in insect retrotransposons as genetic elements advantageous for both transposons and their insect hosts.

Ювенильный идиопатический артрит (ЮИА) — это тяжелое прогрессирующее заболевание у детей до 16 лет, характеризующееся деструктивно-воспалительным процессом преимущественно суставов, также вовлечением других органов и систем. У детей с ЮИА нередко наблюдаются нарушения роста. Цель исследования: изучение динамики роста и костного возраста (KB) у детей с ЮИА с нормальным ростом и низкорослостью на фоне генно-инженерной биологической терапии (ГИБТ). Материалы и методы исследования: была проведена оценка KB и SDS роста у 45 детей с разными формами ЮИА (32 пациента с нормальным ростом и 13 детей с низкорослостью, средний возраст 14,1 лет, длительность заболевания до начала ГИБТ 8,5 лет) до начала ГИБТ (исходно) и по истечении 24 месяцев лечения, у детей с низкорослостью был произведен расчет прогнозируемого конечного роста (ИКР). Результаты: в ходе исследования выявлено, что степень низкорослости у детей с ЮИА коррелирует с длительностью, формой и активностью заболевания, объемом терапии глюкокортикостероидами (ГКС). Наиболее тяжелая задержка роста отмечена у пациентов с системной формой ЮИА, длительностью заболевания не менее 5 лет, высокой лабораторной активностью. У 32 детей с исходно нормальным ростом (SDS роста 0,12±1,07) отставания KB не выявлено, через 24 месяца лечения SDS роста составила 0,22±0,99, KB соответствовал паспортному. У 13 детей с исходной задержкой роста (SDS роста — 3,19±0,36) было выявлено отставание KB в среднем на 2,9±0,5 лет, ПКР составлял у девочек 147,2±3,2 см, у мальчиков — 163,7±5,9 см. Через 24 месяца терапии отмечено достоверное улучшение показателей роста у всех 13 детей (SDS роста — 2,73±0,34, р<0,05), при этом KB и ПКР изменились незначительно (отставание KB 2,3±0,4 лет, ПКР у девочек 147,5±4,2 см, у мальчиков — 165,9±3,1 см, р>0,05). Обсуждение: по результатам исследования, у детей с ЮИА задержка роста чаще возникает при системной форме, сопровождающейся высокой клинико-лабораторной активностью заболевания, а также зависит от длительности заболевания, продолжительности и кумулятивной дозы ГКС. Задержка роста также часто сопровождается отставанием KB от паспортного. Заключение: у детей с ЮИА и низкорослостью, получающих ГИБТ, происходит увеличение темпов роста, при этом отставание KB от паспортного остается, что свидетельствует о сохранении потенциала роста и возможности достижения более высокого конечного роста.

Основной проблемой, с которой в настоящее время сталкиваются детские ревматологи при выборе терапии суставного варианта ювенильного идиопатического артрита (ЮИА), является отсутствие прямых (head-to-head) сравнительных контролируемых исследований эффективности и безопасности различных генно-инженерных биологических препаратов (ГИБП). Сравнение эффективности и безопасности ГИБП, таких как инфликсимаб, этанерцепт, абатацепт, является актуальным вопросом детской ревматологии. Цель: определение места инфликсимаба, этанерцепта, абатацепта в алгоритме назначения ГИБП при суставном варианте ЮИА. Материалы и методы исследования: проведен анализ ретроспективных данных и проспективное открытое нерандомизированное клиническое исследование, в которое вошли 64 ребенка с суставным вариантом ЮИА в возрасте от 3 до 18 лет, получающих ГИБП (10 детей - инфликсимаб, 32 - этанерцепт, 22 - абатацепт). Для оценки эффективности проводимой терапии использовали критерии ACR pedi и индекс LUNDEX и коэффициент приверженности к терапии. Результаты: уже к 6 месяцам от начала исследования более чем у 70% детей из всех групп было получено как минимум 50% улучшение по критериям ACR pedi. К 24 месяцам, с учетом приверженности к терапии (по I. Lundex), в группах инфликсимаба, этанерцепта и абатацепта ответ ACR pedi был получен у 80, 94 и 60% пациентов соответственно, в группах этанерцепта и абатацепта клинико-лабораторная ремиссия была достигнута у 40% детей. Заключение: проведенное исследование доказывает высокую эффективность и хорошую переносимость инфликсимаба, этанерцепта, абатацепта у детей с суставным вариантом ЮИА. Статистически достоверной разницы при сравнении эффективности препаратов получено не было.

Основной проблемой, с которой в настоящее время сталкиваются детские ревматологи при выборе терапии суставного варианта ювенильного идиопатического артрита (ЮИА), является отсутствие прямых (head-to-head) сравнительных контролируемых исследований эффективности и безопасности различных генно-инженерных биологических препаратов (ГИБП). Сравнение эффективности и безопасности ГИБП, таких как инфликсимаб, этанерцепт, абатацепт, является актуальным вопросом детской ревматологии. Цель: определение места инфликсимаба, этанерцепта, абатацепта в алгоритме назначения ГИБП при суставном варианте ЮИА. Материалы и методы исследования: проведен анализ ретроспективных данных и проспективное открытое нерандомизированное клиническое исследование, в которое вошли 64 ребенка с суставным вариантом ЮИА в возрасте от 3 до 18 лет, получающих ГИБП (10 детей - инфликсимаб, 32 - этанерцепт, 22 - абатацепт). Для оценки эффективности проводимой терапии использовали критерии ACR pedi и индекс LUNDEX и коэффициент приверженности к терапии. Результаты: уже к 6 месяцам от начала исследования более чем у 70% детей из всех групп было получено как минимум 50% улучшение по критериям ACR pedi. К 24 месяцам, с учетом приверженности к терапии (по I. Lundex), в группах инфликсимаба, этанерцепта и абатацепта ответ ACR pedi был получен у 80, 94 и 60% пациентов соответственно, в группах этанерцепта и абатацепта клинико-лабораторная ремиссия была достигнута у 40% детей. Заключение: проведенное исследование доказывает высокую эффективность и хорошую переносимость инфликсимаба, этанерцепта, абатацепта у детей с суставным вариантом ЮИА. Статистически достоверной разницы при сравнении эффективности препаратов получено не было.

В статье приведены описания двух поздно диагностированных клинических случаев ливедоид- ной васкулопатии у девочек-подростков, а также представлены данные современной литерату- ры, освещающие патогенез, клинику и лечение этого заболевания. Ливедоидная васкулопатия – это редкое хроническое заболевание неизвестной этиологии, характеризующееся пораже- нием кожи дистальных отделов нижних конечностей в виде ливедо и рецидивирующих язв, в основе которого лежит гиалинизирующий процесс в сосудах кожи с развитием микротромбоза. У большинства больных выявляются признаки генетической или приобретенной тромбофи- лии, что определяет необходимость антитромботической терапии.