Възможности и перспективи за прилагането на Инфлуцид в класическата профилактика на ОРВИ

Профилактичното назначаване на инфлуцид допринася за намаляване в срок от три месеца на честотата, продължителността и тежестта на ОРВИ, което е придружено от спад в цитотоксичната активност на NK-клетките, отговорни за антивирусната защита.Оценката на ефективността на препарата инфлуцид спрямо причинителите на ОРВИ е проведена в открито плацебо контролирано клинично проучване за деца на 5-6-годишна възраст, посещаващи предучилищни детски заведения в епидемичния сезон януари-април 2009 г. (фиг. 1 и фиг. 2) Особено внимание се отделя за изследване влиянието на инфлуцид върху морфологичните показатели на NK-клетките, които са показател за тяхната цитотоксична активност. В състояние на вирусна инфекция NK-клетките атакуват заразените клетки и активността им е повишена. Според изследването (фиг. 3) при профилактично прилагане на инфлуцид се отбелязва явен спад в цитотоксичността на NK-клетките, поради изразеното защитно действие на инфлуцид спрямо развитието на ОРВИ.Анализът на поносимостта на инфлуцид в профилактичен режим на дозиране не показва никакви неблагоприятни и нежелани ефекти

Proposals for the Organization of International Logistics Activities of Agricultural and Agro-Processing Enterprises During the War Period

The agricultural sector is the driver and “point of growth” of the national economy of Ukraine. Agriculture accounts for an average of 16% of gross value added in some regions and play a key role in ensuring food security. However, the current conditions of martial law in Ukraine have led to problems in the organization of logistics activities of enterprises of the agro-industrial complex as a result of non-fulfilment of the terms of contracts; emergence of risks of disruption of the sowing campaign; decrease in final harvest indicators and the level of food security; decrease in the volume of export deliveries of agricultural products; disruption of food supply chains; lack of adequate financing and logistics infrastructure facilities; insufficiently effective use of marketing management tools and a network approach in the process of distributing agricultural products to the final consumer; increase in transaction costs, etc. The article provides a statistical analysis of the main indicators of the development of foreign economic activity of enterprises of the agro-industrial complex of Ukraine in the pre-war period. Barriers that inhibit the effective organization of international logistics activities of agrarian enterprises in wartime have been identified. Priority directions for eliminating existing barriers that prevent the organization of foreign economic logistics activities are proposed, the essence of which is to activate network interaction and partnership relations based on the creation of agro-cluster structures; unification of small farms for the proper execution of contracts, as well as joint activity in the agrarian sphere of two or more companies and different groups of stakeholders to achieve a common goal and a synergistic effect.Аграрний сектор є драйвером і «точкою зростання» національної економіки України. Сільське господарство формує у деяких регіонах у середньому 16% валової доданої вартості та відіграє ключову роль у забезпеченні продовольчої безпеки. Однак сучасні умови воєнного стану в Україні призвели до проблем організації логістичної діяльності підприємств агропромислового комплексу унаслідок невиконання умов контрактів; появі ризиків зриву посівної кампанії; зменшення фінальних показників врожаю та рівня продовольчої безпеки; зниження обсягів експортних поставок сільськогосподарської продукції; порушення ланцюгів постачання продовольства; відсутності належного фінансування та об’єктів логістичної інфраструктури; недостатньо ефективного використання інструментарію маркетингового менеджменту і мережевого підходу в процесі розподілу аграрної продукції до кінцевого споживача; збільшення трансакційних витрат тощо. У статті виконано статистичний аналіз основних показників розвитку зовнішньоекономічної діяльності підприємств агропромислового комплексу України у довоєнний період. Виявлено бар’єри, які гальмують ефективну організацію міжнародної логістичної діяльності аграрних підприємств у воєнний час. Запропоновано пріоритетні напрями усунення існуючих бар’єрів, що перешкоджають організації зовнішньоекономічної логістичної діяльності, суть яких полягає в активізації мережевої взаємодії та партнерських взаємовідносин на основі створення агрокластерних структур; об’єднання дрібним фермерських господарств для належного виконання контрактів, а також спільної діяльності в аграрній сфері двох або більше компаній і різних груп стейкхолдерів для досягнення загальної мети і синергетичного ефекту

Problems of professional training of doctors of general practice – family medicine in the system of postgraduate education.

The article reveals the problems of professional training of family doctors arising in the implementation of measures on preserving and promoting health, preventing diseases in children and adolescents. At present, the doctors of the first level are not able to organize and realize the entire complex of medical and social assistance in the ambulatory clinic at the proper level. The improvement of postgraduate training of family doctors in the field of outpatient pediatric care has been suggested. At the same time, the development of curricula for thematic improvement should be based on studying educational needs of the healthcare system in the region and the ongoing reform processes

A Fluorescence Reporter Model Defines “Tip-DCs” as the Cellular Source of Interferon β in Murine Listeriosis

Production of type I interferons, consisting mainly of multiple IFNα subtypes and IFNβ, represents an essential part of the innate immune defense against invading pathogens. While in most situations, namely viral infections, this class of cytokines is indispensable for host survival they mediate a detrimental effect during infection with L. monocytogenes by rendering macrophages insensitive towards IFNγ signalling which leads to a lethal bacterial pathology in mice. Due to a lack of suitable analytic tools the precise identity of the cell population responsible for type I IFN production remains ill-defined and so far these cells have been described to be macrophages. As in general IFNβ is the first type I interferon to be produced, we took advantage of an IFNβ fluorescence reporter-knockin mouse model in which YFP is expressed from a bicistronic mRNA linked by an IRES to the endogenous ifnb mRNA to assess the IFNβ production on a single cell level in situ. Our results showed highest frequencies and absolute numbers of IFNβ+ cells in the spleen 24 h after infection with L. monocytogenes where they were located predominately in the white pulp within the foci of infection. Detailed FACS surface marker analyses, intracellular cytokine stainings and T cell proliferation assays revealed that the IFNβ+ cells were a phenotypically and functionally further specialized subpopulation of TNF and iNOS producing DCs (Tip-DCs) which are known to be essential for the early containment of L. monocytogenes infection. We proved that the IFNβ+ cells exhibited the hallmark characteristics of Tip-DCs as they produced iNOS and TNF and possessed T cell priming abilities. These results point to a yet unappreciated ambiguous role for a multi-effector, IFNβ producing subpopulation of Tip-DCs in controlling the balance between containment of L. monocytogenes infection and effects detrimental to the host driven by IFNβ

Monocytes regulate the mechanism of T-cell death by inducing Fas-mediated apoptosis during bacterial infection.

Monocytes and T-cells are critical to the host response to acute bacterial infection but monocytes are primarily viewed as amplifying the inflammatory signal. The mechanisms of cell death regulating T-cell numbers at sites of infection are incompletely characterized. T-cell death in cultures of peripheral blood mononuclear cells (PBMC) showed 'classic' features of apoptosis following exposure to pneumococci. Conversely, purified CD3(+) T-cells cultured with pneumococci demonstrated necrosis with membrane permeabilization. The death of purified CD3(+) T-cells was not inhibited by necrostatin, but required the bacterial toxin pneumolysin. Apoptosis of CD3(+) T-cells in PBMC cultures required 'classical' CD14(+) monocytes, which enhanced T-cell activation. CD3(+) T-cell death was enhanced in HIV-seropositive individuals. Monocyte-mediated CD3(+) T-cell apoptotic death was Fas-dependent both in vitro and in vivo. In the early stages of the T-cell dependent host response to pneumococci reduced Fas ligand mediated T-cell apoptosis was associated with decreased bacterial clearance in the lung and increased bacteremia. In summary monocytes converted pathogen-associated necrosis into Fas-dependent apoptosis and regulated levels of activated T-cells at sites of acute bacterial infection. These changes were associated with enhanced bacterial clearance in the lung and reduced levels of invasive pneumococcal disease

Lack of PPARγ in Myeloid Cells Confers Resistance to Listeria monocytogenes Infection

The peroxisomal proliferator-activated receptor γ (PPARγ) is a nuclear receptor that controls inflammation and immunity. Innate immune defense against bacterial infection appears to be compromised by PPARγ. The relevance of PPARγ in myeloid cells, that organize anti-bacterial immunity, for the outcome of immune responses against intracellular bacteria such as Listeria monocytogenes in vivo is unknown. We found that Listeria monocytogenes infection of macrophages rapidly led to increased expression of PPARγ. This prompted us to investigate whether PPARγ in myeloid cells influences innate immunity against Listeria monocytogenes infection by using transgenic mice with myeloid-cell specific ablation of PPARγ (LysMCre×PPARγflox/flox). Loss of PPARγ in myeloid cells results in enhanced innate immune defense against Listeria monocytogenes infection both, in vitro and in vivo. This increased resistance against infection was characterized by augmented levels of bactericidal factors and inflammatory cytokines: ROS, NO, IFNγ TNF IL-6 and IL-12. Moreover, myeloid cell-specific loss of PPARγ enhanced chemokine and adhesion molecule expression leading to improved recruitment of inflammatory Ly6Chi monocytes to sites of infection. Importantly, increased resistance against Listeria infection in the absence of PPARγ was not accompanied by enhanced immunopathology. Our results elucidate a yet unknown regulatory network in myeloid cells that is governed by PPARγ and restrains both listeriocidal activity and recruitment of inflammatory monocytes during Listeria infection, which may contribute to bacterial immune escape. Pharmacological interference with PPARγ activity in myeloid cells might represent a novel strategy to overcome intracellular bacterial infection

Visualizing early splenic memory CD8+ T cells reactivation against intracellular bacteria in the mouse

International audienceMemory CD8(+) T cells represent an important effector arm of the immune response in maintaining long-lived protective immunity against viruses and some intracellular bacteria such as Listeria monocytogenes (L.m). Memory CD8(+) T cells are endowed with enhanced antimicrobial effector functions that perfectly tail them to rapidly eradicate invading pathogens. It is largely accepted that these functions are sufficient to explain how memory CD8(+) T cells can mediate rapid protection. However, it is important to point out that such improved functional features would be useless if memory cells were unable to rapidly find the pathogen loaded/infected cells within the infected organ. Growing evidences suggest that the anatomy of secondary lymphoid organs (SLOs) fosters the cellular interactions required to initiate naive adaptive immune responses. However, very little is known on how the SLOs structures regulate memory immune responses. Using Listeria monocytogenes (L.m) as a murine infection model and imaging techniques, we have investigated if and how the architecture of the spleen plays a role in the reactivation of memory CD8(+) T cells and the subsequent control of L.m growth. We observed that in the mouse, memory CD8(+) T cells start to control L.m burden 6 hours after the challenge infection. At this very early time point, L.m-specific and non-specific memory CD8(+) T cells localize in the splenic red pulp and form clusters around L.m infected cells while naïve CD8(+) T cells remain in the white pulp. Within these clusters that only last few hours, memory CD8(+) T produce inflammatory cytokines such as IFN-gamma and CCL3 nearby infected myeloid cells known to be crucial for L.m killing. Altogether, we describe how memory CD8(+) T cells trafficking properties and the splenic micro-anatomy conjugate to create a spatio-temporal window during which memory CD8(+) T cells provide a local response by secreting effector molecules around infected cells

Depletion of Dendritic Cells Enhances Innate Anti-Bacterial Host Defense through Modulation of Phagocyte Homeostasis

Dendritic cells (DCs) as professional antigen-presenting cells play an important role in the initiation and modulation of the adaptive immune response. However, their role in the innate immune response against bacterial infections is not completely defined. Here we have analyzed the role of DCs and their impact on the innate anti-bacterial host defense in an experimental infection model of Yersinia enterocolitica (Ye). We used CD11c-diphtheria toxin (DT) mice to deplete DCs prior to severe infection with Ye. DC depletion significantly increased animal survival after Ye infection. The bacterial load in the spleen of DC-depleted mice was significantly lower than that of control mice throughout the infection. DC depletion was accompanied by an increase in the serum levels of CXCL1, G-CSF, IL-1α, and CCL2 and an increase in the numbers of splenic phagocytes. Functionally, splenocytes from DC-depleted mice exhibited an increased bacterial killing capacity compared to splenocytes from control mice. Cellular studies further showed that this was due to an increased production of reactive oxygen species (ROS) by neutrophils. Adoptive transfer of neutrophils from DC-depleted mice into control mice prior to Ye infection reduced the bacterial load to the level of Ye-infected DC-depleted mice, suggesting that the increased number of phagocytes with additional ROS production account for the decreased bacterial load. Furthermore, after incubation with serum from DC-depleted mice splenocytes from control mice increased their bacterial killing capacity, most likely due to enhanced ROS production by neutrophils, indicating that serum factors from DC-depleted mice account for this effect. In summary, we could show that DC depletion triggers phagocyte accumulation in the spleen and enhances their anti-bacterial killing capacity upon bacterial infection

Interplay between CD8α+ Dendritic Cells and Monocytes in Response to Listeria monocytogenes Infection Attenuates T Cell Responses

During the course of a microbial infection, different antigen presenting cells (APCs) are exposed and contribute to the ensuing immune response. CD8α+ dendritic cells (DCs) are an important coordinator of early immune responses to the intracellular bacteria Listeria monocytogenes (Lm) and are crucial for CD8+ T cell immunity. In this study, we examine the contribution of different primary APCs to inducing immune responses against Lm. We find that CD8α+ DCs are the most susceptible to infection while plasmacytoid DCs are not infected. Moreover, CD8α+ DCs are the only DC subset capable of priming an immune response to Lm in vitro and are also the only APC studied that do so when transferred into β2 microglobulin deficient mice which lack endogenous cross-presentation. Upon infection, CD11b+ DCs primarily secrete low levels of TNFα while CD8α+ DCs secrete IL-12 p70. Infected monocytes secrete high levels of TNFα and IL-12p70, cytokines associated with activated inflammatory macrophages. Furthermore, co-culture of infected CD8α+ DCs and CD11b+ DCs with monocytes enhances production of IL-12 p70 and TNFα. However, the presence of monocytes in DC/T cell co-cultures attenuates T cell priming against Lm-derived antigens in vitro and in vivo. This suppressive activity of spleen-derived monocytes is mediated in part by both TNFα and inducible nitric oxide synthase (iNOS). Thus these monocytes enhance IL-12 production to Lm infection, but concurrently abrogate DC-mediated T cell priming