Dendritic cells transfected with DNA constructs encoding CCR9, IL-10, and type II collagen demonstrate induction of immunological tolerance in an arthritis model

IntroductionRestoring immune tolerance is a promising area of therapy for autoimmune diseases. One method that helps restore immunological tolerance is the approach using tolerogenic dendritic cells (tolDCs). In our study, we analyzed the effectiveness of using dendritic cells transfected with DNA constructs encoding IL-10, type II collagen, and CCR9 to induce immune tolerance in an experimental model of arthritis.MethodsDendritic cell cultures were obtained from bone marrow cells of Balb/c mice. Dendritic cells (DCs) cultures were transfected with pmaxCCR9, pmaxIL-10, and pmaxCollagen type II by electroporation. The phenotype and functions of DCs were studied using enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Migration of electroporated DCs was assessed in vitro. Induction of antigen-collagen induced arthritis (ACIA) was carried out according to the protocol in Balb/c mice. DCs were then administered to ACIA mice. The development of arthritis was monitored by measuring paw swelling with a caliper at different time points. The immunological changes were assessed by analyzing the content of antibodies to type II collagen using enzyme immunoassay. Additionally, a histological examination of the joint tissue was conducted, followed by data analysis.The results are as followsDCs were obtained, characterized by reduced expression of CD80, CD86, and H-2Db (MHC class I), increased expression of CCR9, as well as producing IL-10 and having migratory activity to thymus cells. Transfected DCs induced T-regulatory cells (T-reg) and increased the intracellular content of IL-10 and TGF-β in CD4+T cells in their co-culture, and also suppressed their proliferative activity in response to antigen. The administration of tolDCs transfected with DNA constructs encoding type II collagen, IL-10, and CCR9 to mice with ACIA demonstrated a reduction in paw swelling, a reduction in the level of antibodies to type II collagen, and a regression of histological changes.ConclusionThe study presents an approach by which DCs transfected with DNA constructs encoding epitopes of type II collagen, IL-10 and CCR9 promote the development of antigen-specific tolerance, control inflammation and reduce the severity of experimental arthritis through the studied mechanisms: induction of T-reg, IL-10, TGF-β

Эпидемиологические и фармакоэкономические аспекты ВИЧ-инфекции у военнослужащих

The goals of the research are to determine the latent morbidity and financial losses of the Russian Ministry of Defense due to the dismissal of service members with HIV infection at symptomatic stages; to establish the supposed clinical and pharmacoeconomic effectiveness of the early detection and treatment of service members.The materials compile 379 case histories of patients of the only specialized department for HIV-positive military personnel in the Armed Forces for 2017–2019, as well as various reporting forms. The study uses the following methods for the analysis: Markov chains are employed to calculate QALYs (Quality Adjusted Life Years), “cost-effectiveness”, and “willingness to pay”. The research compares two competitive models: “Current Situation” - without the introduction of algorithms for early detection and treatment of HIV infection, and “Prognosis” - with the introduction of these algorithms.The following results are obtained: implementing a mandatory triennial screening for HIV-antibodies among military personnel allows to raise the detection of HIV-positive military personnel in the early stages of the disease by 55%. At the same time, early administered antiretroviral therapy prevents the progression of HIV infection, while the number of military personnel who have reached symptomatic stages of HIV infection and the number of deaths decreases by 35,6% and 80,2% (six-fold), respectively. The economic effectiveness of these measures includes a reduced cost of treatment and an increased length of military service. The sensitivity analysis of the method shows that the proposed measures remain pharmacoeconomically highly effective with a wide variability of the initial data.Conclusion. The results of the study demonstrate that a significant improvement of the epidemiological situation in the field of HIV infection in the Armed Forces is achievable at very low economic costs. With the full implementation of the proposed measures, the cohort of military personnel of the Armed Forces is able to achieve the World Health Organization’s “90-90-90”criteria of in 3–5 years.Цель: определение скрытой заболеваемости и финансовых потерь Минобороны России вследствие увольнения военнослужащих с ВИЧ-инфекцией в стадии вторичных заболеваний, а также установление предполагаемой клинической и фармакоэкономической эффективности мероприятий по раннему выявлению и лечению военнослужащих.Материалы составили 379 историй болезни пациентов единственного в Вооруженных силах специализированного отделения для ВИЧ-позитивных военнослужащих за 2017–2019 гг., а также различные формы отчетности. Для анализа использованы следующие методы: Марковское моделирование процесса позволило определить QALY (Quality Adjusted Life Years – годы жизни с поправкой на качество) и провести фармакоэкономический анализ «Затраты – эффективность» и «Порог готовности платить». Сравнивались две конкурентные модели, названные «Актуальная ситуация» – без введения алгоритмов раннего выявления и лечения ВИЧ-инфекции и «Прогноз» – при введении указанных алгоритмов.Результаты: введение обязательного периодического лабораторного обследования 1 раз в 3 года для военнослужащих по контракту позволит увеличить на 55% выявление ВИЧ-позитивных военнослужащих на ранних стадиях заболевания. При этом раннее назначение антиретровирусной терапии позволит предупредить прогрессирование ВИЧ-инфекции, число военнослужащих, достигших стадии 4 ВИЧ-инфекции, снизится на 35,6%, а число летальных исходов – на 80,2% (в 6 раз), что обеспечит существенную экономическую эффективность за счет снижения стоимости лечения и увеличения длительности военной службы. Анализ чувствительности метода показал, что предложенные мероприятия остаются фармакоэкономически высокоэффективными при широкой вариативности исходных данных.Заключение. По результатам проведенного исследования показано, что существенное улучшение эпидемиологической обстановки в области ВИЧ-инфекции в Вооруженных силах достижимо при очень малых экономических затратах. При полноценной реализации предложенных мероприятий когорта военнослужащих Вооруженных сил Российской Федерации способна достичь критериев Всемирной организации здравоохранения «90-90-90» уже через 3–5 лет

Клиническая эффективность и безопасность применения ингаляционного простациклина у больных с инфекцией, вызванной SARS-CoV-2 (проспективное сравнительное исследование)

Aim. In this study we evaluated clinical effectiveness and safety of nebulized prostacyclin in patients with Novel Coronavirus Disease (SARS-CoV-2). Materials and methods: We have included 44 male patients with moderate PCR confirmed SARS-CoV-2 infection in this study. Control group consisted of 23 patients treated with nebulized prostacyclin (PGI2). besides standard therapy. We compared intensiveness and duration of infectious intoxication syndrome, duration of fever, cough as well as SpO2 level, complete blood count and chemokine status values. Results: Statistically significant difference in duration of fever, cough, intensiveness and duration of infectious intoxication syndrome were observed. Lymphocyte and platelet counts were significantly higher in control group We have also noticed significantly lower level of proinflammatory mediators and C4-complement component in control group. Only 1 adverse effect associated with inhaled prostacyclin was reported. Conclusion. Nebulized prostacyclin showed therapeutic efficacy and good safety profile in adults with moderate COVID-19.Цель: оценка клинической эффективности и безопасность ингаляционного простациклина у пациентов с новой коронавирусной инфекцией (SARS-CoV-2). Материалы и методы: в исследование были включены 44 пациента мужского пола с подтвержденной новой коронавирусной инфекцией среднетяжелого течения. Опытную группу составили 23 пациента, которым, помимо стандартной терапии, был назначен ингаляционный простациклин (PGI2). Клиническая эффективность илопроста была оценена по длительности и выраженности общеинфекционных синдромов (интоксикации, лихорадки), длительности кашля, уровню насыщения крови кислородом, значениям параметров общеклинического анализа крови, показателю иммунологического статуса пациентов. Результаты: получено статистически значимое снижение длительности лихорадки, продолжительности кашля, выраженности и длительности синдрома общей инфекционной интоксикации в опытной группе. Также отмечено, что у этих пациентов средние значения количества лимфоцитов, тромбоцитов достоверно увеличивалось, а значение СОЭ снижалось. Средние значения провоспалительных цитокинов, хемокинов, а также С4-компонента комплемента были статистически значимо ниже, чем у больных COVID-19 в группе сравнения. Нежелательные реакции, связанные с инга ляционной терапией простациклином, были отмечены в 1 наблюдении. Заключение: показана терапевтическая эффективность и хороший профиль безопасности ингаляционного простациклина у пациентов с COVID-19 средней степени тяжести

Supersymmetric QCD corrections to e+e−→tbˉH−e^+e^-\to t\bar{b}H^- and the Bernstein-Tkachov method of loop integration

The discovery of charged Higgs bosons is of particular importance, since their existence is predicted by supersymmetry and they are absent in the Standard Model (SM). If the charged Higgs bosons are too heavy to be produced in pairs at future linear colliders, single production associated with a top and a bottom quark is enhanced in parts of the parameter space. We present the next-to-leading-order calculation in supersymmetric QCD within the minimal supersymmetric SM (MSSM), completing a previous calculation of the SM-QCD corrections. In addition to the usual approach to perform the loop integration analytically, we apply a numerical approach based on the Bernstein-Tkachov theorem. In this framework, we avoid some of the generic problems connected with the analytical method.Comment: 14 pages, 6 figures, accepted for publication in Phys. Rev.

Refractory status epilepticus syndrome FIRES (febrile infection-related epilepsy syndrome) + NORSE (new-onset refractory status epilepticus): description of a rare clinical case

The paper describes a clinical case of the rare status epilepticus syndrome FIRES (febrile infection responsive encephalopathy) + NORSE (new-onset refractory status epilepticus). The difficulty of diagnosing this condition is due to the fact that it occurs extremely rarely and the laboratory and instrumental findings are nonspecific. The disease is characterized by acute onset, fever, and subsequent development of status epilepticus, cognitive impairment, and pharmacotherapy-resistant epilepsy. The paper describes a 19-year-old male patient who was observed to have a favorable course of FIRES + NORSE syndrome without pharmacotherapy-resistant epilepsy, motor deficiency, and with the preservation of self-care skills

Statistical parameters of femtosecond laser pulse post-filament propagation on a 65 m air path with localized optical turbulence

High-power femtosecond laser radiation propagates nonlinearly in air, exhibiting pulse self-focusing and strong multiphoton medium ionization, which leads to the spatial fragmentation of laser pulses into highly localized light channels commonly called filaments. Filaments are characterized by high optical intensity and reduced (even zero) angular spreading and can contain laser plasma or be plasmaless (postfilaments). The presence of optical turbulence on the propagation path dramatically changes pulse filamentation dynamics and in some cases causes pulse fragmentation enhancement and collapse arrest. For the first time, to the best of our knowledge, we experimentally and theoretically investigate the transverse profile of Ti:sapphire femtosecond laser radiation nonlinearly propagating a 65mair path to the region of postfilament evolution after passing through an artificial localized air turbulence. We show that when a turbulence layer is placed before the filamentation region, the average number of high-intensity local fluence maxima (“hot points”) in the beam profile and their sizes grow as the turbulence strength increases, and then saturates at some levels. On the contrary, the deposition of a turbulence screen within the filamentation region has almost no effect on either the number or the average diameter of postfilaments

Can health kiosks be used to identify oral health care needs?:a pilot study

Abstract Objective: The aim of this study was to investigate the reliability of digital imaging for detecting restorative treatment need among individuals in their 20s by comparing the outcome of digital imaging with clinical caries findings at the patient level. Material and methods: Five intraoral clinical daylight and digital fluorescence images were taken extraorally of 21 patients. A clinical examination was then performed by a trained and calibrated dentist. Additionally, the patients answered a multiple-choice questionnaire about their health habits. The images were analysed and caries findings were recorded. For statistical analysis, sensitivity and specificity were calculated. Results were shown as ROC curves and AUC values. All analyses were done using SPSS (version 24.0, Chicago, IL). Results: Caries lesions were most often detected in molars and least often in canines. When using the clinical status as gold standard, digital imaging gave an AUC value of 0.617, whereas the outcome by questionnaire gave an AUC value of 0.719. When using the combined outcome of digital imaging and the questionnaire, the AUC value was 0.694 with clinical validation. Conclusions: It can be concluded that health kiosks may help to reduce the number of patients waiting for dental treatment; more specifically, the questionnaire with individual feedback may provide a new instrument for providing instructions for homecare online. However, the camera system must be developed further, and dentists and dental hygienists require training to analyse the images