An Alternative Pathway of Imiquimod-Induced Psoriasis-Like Skin Inflammation in the Absence of Interleukin-17 Receptor A Signaling

Topical application of imiquimod (IMQ) on the skin of mice induces inflammation with common features found in psoriatic skin. Recently, it was postulated that IL-17 has an important role both in psoriasis and in the IMQ model. To further investigate the impact of IL-17RA signaling in psoriasis, we generated IL-17 receptor A (IL-17RA)–deficient mice (IL-17RAdel) and challenged these mice with IMQ. Interestingly, the disease was only partially reduced and delayed but not abolished when compared with controls. In the absence of IL-17RA, we found persisting signs of inflammation such as neutrophil and macrophage infiltration within the skin. Surprisingly, already in the naive state, the skin of IL-17RAdel mice contained significantly elevated numbers of Th17- and IL-17-producing γδ T cells, assuming that IL-17RA signaling regulates the population size of Th17 and γδ T cells. Upon IMQ treatment of IL-17RAdel mice, these cells secreted elevated amounts of tumor necrosis factor-α, IL-6, and IL-22, accompanied by increased levels of the chemokine CXCL2, suggesting an alternative pathway of neutrophil and macrophage skin infiltration. Hence, our findings have major implications in the potential long-term treatment of psoriasis by IL-17-targeting drugs

The impact of regional and neighbourhood deprivation on physical health in Germany: a multilevel study

Voigtländer S, Berger U, Razum O. The impact of regional and neighbourhood deprivation on physical health in Germany: a multilevel study. BMC Public Health. 2010;10(1): 403.Background There is increasing evidence that individual health is at least partly determined by neighbourhood and regional factors. Mechanisms, however, remain poorly understood, and evidence from Germany is scant. This study explores whether regional as well as neighbourhood deprivation are associated with physical health and to what extent this association can be explained by specific neighbourhood exposures. Methods Using 2004 data from the German Socio-Economic Panel Study (SOEP) merged with regional and neighbourhood characteristics, we fitted multilevel linear regression models with subjective physical health, as measured by the SF-12, as the dependent variable. The models include regional and neighbourhood proxies of deprivation (i.e. regional unemployment quota, average purchasing power of the street section) as well as specific neighbourhood exposures (i.e. perceived air pollution). Individual characteristics including socioeconomic status and health behaviour have been controlled for. Results This study finds a significant association between area deprivation and physical health which is independent of compositional factors and consistent across different spatial scales. Furthermore the association between neighbourhood deprivation and physical health can be partly explained by specific features of the neighbourhood environment. Among these perceived air pollution shows the strongest association with physical health (-2.4 points for very strong and -1.5 points for strong disturbance by air pollution, standard error (SE) = 0.8 and 0.4, respectively). Beta coefficients for perceived air pollution, perceived noise and the perceived distance to recreational resources do not diminish when including individual health behaviour in the models. Conclusions This study highlights the difference regional and in particular neighbourhood deprivation make to the physical health of individuals in Germany. The results support the argument that specific neighbourhood exposures serve as an intermediary step between deprivation and health. As people with a low socioeconomic status were more likely to be exposed to unfavourable neighbourhood characteristics these conditions plausibly contribute towards generating health inequalities

Analyzing editosome function in high-throughput.

Mitochondrial gene expression in African trypanosomes and other trypanosomatid pathogens requires a U-nucleotide specific insertion/deletion-type RNA-editing reaction. The process is catalyzed by a macromolecular protein complex known as the editosome. Editosomes are restricted to the trypanosomatid clade and since editing is essential for the parasites, the protein complex represents a near perfect target for drug intervention strategies. Here, we report the development of an improved in vitro assay to monitor editosome function. The test system utilizes fluorophore-labeled substrate RNAs to analyze the processing reaction by automated, high-throughput capillary electrophoresis (CE) in combination with a laser-induced fluorescence (LIF) readout. We optimized the assay for high-throughput screening (HTS)-experiments and devised a multiplex fluorophore-labeling regime to scrutinize the U-insertion/U-deletion reaction simultaneously. The assay is robust, it requires only nanogram amounts of materials and it meets all performance criteria for HTS-methods. As such the test system should be helpful in the search for trypanosome-specific pharmaceuticals

Core-shell DNA-cholesterol nanoparticles exert lysosomolytic activity in African trypanosomes

Trypanosoma brucei is the causal infectious agent of African trypanosomiasis in humans and Nagana in livestock. Both diseases are currently treated with a small number of chemotherapeutics, which are hampered by a variety of limitations reaching from efficacy and toxicity complications to drug-resistance problems. Here, we explore the forward design of a new class of synthetic trypanocides based on nanostructured, core-shell DNA-lipid particles. In aqueous solution, the particles self-assemble into micelle-type structures consisting of a solvent-exposed, hydrophilic DNA shell and a hydrophobic lipid core. DNA-lipid nanoparticles have membrane-adhesive qualities and can permeabilize lipid membranes. We report the synthesis of DNA-cholesterol nanoparticles, which specifically subvert the membrane integrity of the T. brucei lysosome, killing the parasite with nanomolar potencies