Topical Simvastatin as Host-Directed Therapy against Severity of Cutaneous Leishmaniasis in Mice.

We recently demonstrated that statins mediate protection against intracellular pathogens, Mycobacterium tuberculosis and Listeria monocytogenes in mice. Here, we investigated the immunomodulatory potential of simvastatin as a topical or systemic host-directed drug therapy in controlling inflammatory responses in an experimental mouse model of cutaneous leishmaniasis caused by Leishmania major (LV39). In an ear infection model, topical application of simvastatin directly on established lesions significantly reduced severity of the disease reflected by ear lesion size and ulceration. The host protective effect was further accompanied by decreased parasite burden in the ear and draining lymph nodes in both BALB/c and C57BL/6 mice. Pre-treatment of these mice on a low-fat cholesterol diet and systemic simvastatin also reduced footpad swelling, as well as parasite burdens and ulceration/necrosis in the more robust footpad infection model, demonstrating the prophylactic potential of simvastatin for cutaneous leishmaniasis. Mechanistically, following L. major infection, simvastatin-treated primary macrophages responded with significantly reduced cholesterol levels and increased production of hydrogen peroxide. Furthermore, simvastatin-treated macrophages displayed enhanced phagosome maturation, as revealed by increased LAMP-3 expression in fluorescent microscopy and Western blot analysis. These findings demonstrate that simvastatin treatment enhances host protection against L. major by increasing macrophage phagosome maturation and killing effector functions

Temperature Coefficient of the Modulus of Rigidity of Aircraft Instrument Diaphragm and Spring Materials

Experimental data are presented on the variation of the modulus of rigidity in the temperature range -20 to +50 degrees C. of a number of metals which are of possible use for elastic elements for aircraft and other instruments. The methods of the torsional pendulum was used to determine the modulus of rigidity and its temperature coefficient for aluminum, duralumin, monel metal, brass, phosphor bronze, coin silver, nickel silver, three high carbon steels, and three alloy steels. It was observed that tensile stress affected the values of the modulus by amounts of 1 per cent or less

eredeti vigjáték 3 felvonásban - irta Tóth Kálmán

Debreceni Nemzeti Színház. Szerdán Április 11-kén 1866. Szathmáry Károly, a pesti nemzeti szinház volt tagja, mint vendég. Szakál Rózsa, szerződött tag első fellépteDebreceni Egyetem Egyetemi és Nemzeti Könyvtá

IL-4Rα Signaling in Keratinocytes and Early IL-4 Production Are Dispensable for Generating a Curative T Helper 1 Response in Leishmania major-Infected C57BL/6 Mice.

Experimental infection with the protozoan parasite Leishmania major has been extensively used to understand the mechanisms involved in T helper cell differentiation. Following infection, C57BL/6 mice develop a small self-healing cutaneous lesion and they are able to control parasite burden, a process linked to the development of T helper (Th) 1 cells. The local presence of IL-12 has been reported to be critical in driving Th1 cell differentiation. In addition, the early secretion of IL-4 was reported to potentially contribute to Th1 cell differentiation. Following infection with L. major, early keratinocyte-derived IL-4 was suggested to contribute to Th1 cell differentiation. To investigate a putative autocrine role of IL-4 signaling on keratinocytes at the site of infection, we generated C57BL/6 mice deficient for IL-4Rα expression selectively in keratinocytes. Upon infection with L. major, these mice could control their inflammatory lesion and parasite load correlating with the development of Th1 effector cells. These data demonstrate that IL-4 signaling on keratinocytes does not contribute to Th1 cell differentiation. To further investigate the source of IL-4 in the skin during the first days after L. major infection, we used C57BL/6 IL-4 reporter mice allowing the visualization of IL-4 mRNA expression and protein production. These mice were infected with L. major. During the first 3 days after infection, skin IL-4 mRNA expression was observed selectively in mast cells. However, no IL-4 protein production was detectable locally. In addition, early IL-4 blockade locally had no impact on subsequent Th1 cell differentiation and control of the disease. Taken together, the present data rule out a major role for skin IL-4 and keratinocyte IL-4Rα signaling in the development of a Th1 protective immune response following experimental infection with L. major

IL-4Rα on CD4\u3csup\u3e+\u3c/sup\u3e T cells plays a pathogenic role in respiratory syncytial virus reinfection in mice infected initially as neonates

RSV is the major cause of severe bronchiolitis in infants, and severe bronchiolitis as a result of RSV is associated with subsequent asthma development. A biased Th2 immune response is thought to be responsible for neonatal RSV pathogenesis; however, molecular mechanisms remain elusive. Our data demonstrate, for the first time, that IL-4Rα is up-regulated in vitro on human CD4+ T cells from cord blood following RSV stimulation and in vivo on mouse pulmonary CD4+ T cells upon reinfection of mice, initially infected as neonates. Th cell-specific deletion of Il4ra attenuated Th2 responses and abolished the immunopathophysiology upon reinfection, including airway hyper-reactivity, eosinophilia, and mucus hyperproduction in mice infected initially as neonates. These findings support a pathogenic role for IL-4Rα on Th cells following RSV reinfection of mice initially infected as neonates; more importantly, our data from human cells suggest that the same mechanism occurs in humans

Hepatitis E in pig-derived food products in Cape Town, South Africa, 2014

Background. Hepatitis E virus (HEV) genotypes 3 and 4 are zoonoses, with domestic pigs being the most important reservoir. A high anti- HEV IgG seroprevalence of 26 - 28% has been found in humans in Cape Town, South Africa (SA). Studies in industrialised countries have indicated a high prevalence of HEV in pigs and their associated food products.Objectives. To determine whether HEV could be found in pig-derived food products in Cape Town.Methods. Pork-containing food products were purchased from supermarkets and butcheries around the Cape Town metropolitan area. HEV detection by polymerase chain reaction (PCR) was performed, and an amplified viral genome fragment was sequenced from positive samples. Phylogenetic analysis was done on the sequenced fragment.Results. HEV was detected by PCR in 2/144 food samples – both were liver spread samples. One genome fragment sequence was obtained, which was closely related to HEV sequences obtained from humans in Cape Town.Conclusions. HEV can be found in pork-containing meat products available for sale in Cape Town, suggesting that these products could be a potential source of HEV transmission in our geographical area. Meat of pig origin should be thoroughly cooked before being consumed

On-site data cast doubts on the hypothesis of shifting cultivation in the Late Neolithic (c. 4300-2400 cal. BC): Landscape management as an alternative paradigm

This article brings together in a comprehensive way, and for the first time, on- and off-site palaeoenvironmental data from the area of the Central European lake dwellings (a UNESCO World Cultural Heritage Site since 2011). The types of data considered are as follows: high-resolution off-site pollen cores, including micro-charcoal counts, and on-site data, including botanical macro- and micro-remains, hand-collected animal bones, remains of microfauna, and data on woodland management (dendrotypology). The period considered is the late Neolithic (c. 4300–2400 cal. BC). For this period, especially for its earlier phases, discussions of land-use patterns are contradictory. Based on off-site data, slash-and-burn – as known from tropical regions – is thought to be the only possible way to cultivate the land. On-site data however show a completely different picture: all indications point to the permanent cultivation of cereals (Triticum spp., Hordeum vulgare), pea (Pisum sativum), flax (Linum usitatissimum) and opium-poppy (Papaver somniferum). Cycles of landscape use are traceable, including coppicing and moving around the landscape with animal herds. Archaeobiological studies further indicate also that hunting and gathering were an important component and that the landscape was manipulated accordingly. Late Neolithic land-use systems also included the use of fire as a tool for opening up the landscape. Here we argue that bringing together all the types of palaeoenvironmental proxies in an integrative way allows us to draw a more comprehensive and reliable picture of the land-use systems in the late Neolithic than had been reconstructed previously largely on the basis of off-site data

Signaling via interleukin-4, receptor alpha chain is required for successful vaccination against schistosomiasis in BALB/c mice

Radiation-attenuated (RA) schistosome larvae are potent stimulators of innate immune responses at the skin site of exposure (pinna) that are likely to be important factors in the development of Th1-mediated protective immunity. In addition to causing an influx of neutrophils, macrophages, and dendritic cells (DCs) into the dermis, RA larvae induced a cascade of chemokine and cytokine secretion following in vitro culture of pinna biopsy samples. While macrophage inflammatory protein 1 and interleukin-1 (IL-1) were produced transiently within the first few days, the Th1-promoting cytokines IL-12 and IL-18 were secreted at high levels until at least day 14. Assay of C3H/HeJ mice confirmed that IL-12 secretion was not due to lipopolysaccharide contaminants binding Toll-like receptor 4. Significantly, IL-12 p40 secretion was sustained in pinnae from vaccinated mice but not in those from nonprotected infected mice. In contrast, IL-10 was produced from both vaccinated and infected mice. This cytokine regulates IL-12-associated dermal inflammation, since in vaccinated IL-10/ mice, pinna thickness was greatly increased concurrent with elevated levels of IL-12 p40. A significant number of IL-12 p40 cells were detected as emigrants from in vitro-cultured pinnae, and most were within a population of rare large granular cells that were Ia, consistent with their being antigen-presenting cells. Labeling of IL-12 cells for CD11c, CD205, CD8, CD11b, and F4/80 indicated that the majority were myeloid DCs, although a proportion were CD11c F4/80, suggesting that macrophages were an additional source of IL-12 in the skin