The diverse roles of mononuclear phagocytes in prion disease pathogenesis

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are neurological diseases that can be transmitted through a number of different routes. A wide range of mammalian species are affected by the disease. After peripheral exposure, some TSE agents accumulate in lymphoid tissues at an early stage of disease prior to spreading to the nerves and the brain. Much research has focused on identifying the cells and molecules involved in the transmission of TSE agents from the site of exposure to the brain and several crucial cell types have been associated with this process. The identification of the key cells that influence the different stages of disease transmission might identify targets for therapeutic intervention. This review highlights the involvement of mononuclear phagocytes in TSE disease. Current data suggest these cells may exhibit a diverse range of roles in TSE disease from the transport or destruction of TSE agents in lymphoid tissues, to mediators or protectors of neuropathology in the brain

Patterns of neighborhood environment attributes related to physical activity across 11 countries: A latent class analysis

published_or_final_versio

Exosome-Producing Follicle Associated Epithelium Is Not Involved in Uptake of PrPd from the Gut of Sheep (Ovis aries): An Ultrastructural Study

In natural or experimental oral scrapie infection of sheep, disease associated prion protein (PrPd) often first accumulates in Peyer's patch (PP) follicles. The route by which infectivity reaches the follicles is unknown, however, intestinal epithelial cells may participate in intestinal antigenic presentation by delivering exosomes as vehicles of luminal antigens. In a previous study using an intestinal loop model, following inoculation of scrapie brain homogenate, inoculum associated PrPd was detected by light microscopy shortly (15 minutes to 3.5 hours) after inoculation in the villous lacteals and sub-mucosal lymphatics. No PrPd was located within the follicle-associated epithelium (FAE), sub-FAE domes or the PP follicles. To evaluate this gut loop model and the transportation routes in more detail, we used electron microscopy (EM) to study intestinal tissues exposed to scrapie or control homogenates for 15 minutes to 10 days. In addition, immuno-EM was used to investigate whether exosomes produced in the FAE may possess small amounts of PrPd that were not detectable by light microscopy. This study showed that the integrity of the intestinal epithelium was sustained in the intestinal loop model. Despite prominent transcytotic activity and exosome release from the FAE of the ileal PP in sheep, these structures were not associated with transportation of PrPd across the mucosa. The study did not determine how infectivity reaches the follicles of PPs. The possibility that the infectious agent is transported across the FAE remains a possibility if it occurs in a form that is undetectable by the methods used in this study. Infectivity may also be transported via lymph to the blood and further to all other lymphoid tissues including the PP follicles, but the early presence of PrPd in the PP follicles during scrapie infection argues against such a mechanism

Expression of selected genes isolated from whole blood, liver and obex in lambs with experimental classical scrapie and healthy controls, showing a systemic innate immune response at the clinical end-stage

Abstract Background Incubation period, disease progression, pathology and clinical presentation of classical scrapie in sheep are highly dependent on PRNP genotype, time and route of inoculation and prion strain. Our experimental model with pre-colostrum inoculation of homozygous VRQ lambs has shown to be an effective model with extensive PrPSc dissemination in lymphatic tissue and a short incubation period with severe clinical disease. Serum protein analysis has shown an elevation of acute phase proteins in the clinical stages of this experimental model, and here, we investigate changes in gene expression in whole blood, liver and brain. Results The animals in the scrapie group showed severe signs of illness 22 weeks post inoculation necessitating euthanasia at 23 weeks post inoculation. This severe clinical presentation was accompanied by changes in expression of several genes. The following genes were differentially expressed in whole blood: TLR2, TLR4, C3, IL1B, LF and SAA, in liver tissue, the following genes differentially expressed: TNF-α, SAA, HP, CP, AAT, TTR and TF, and in the brain tissue, the following genes were differentially expressed: HP, CP, ALB and TTR. Conclusions We report a strong and evident transcriptional innate immune response in the terminal stage of classical scrapie in these animals. The PRNP genotype and time of inoculation are believed to contribute to the clinical presentation, including the extensive dissemination of PrPSc throughout the lymphatic tissue

C6, a new monoclonal antibody, reacts with the follicle-associated epithelium of calf ileal Peyer's patches

The follicle-associated epithelium (FAE) of Peyer's patches (PPs) contains M cells that are important for reducing mucosal immune responses by transporting antigens into the underlying lymphoid tissue. We generated a monoclonal antibody (C6) that reacted with the FAE of calf ileal PPs, and analyzed the characteristics of C6 using immunohistochemistry and Western blotting. FAE of the ileal PP was stained with C6 during both late fetal developmental and postnatal stages. Neither the villous epithelial cell nor intestinal crypt basal cells were stained at any developmental stage. During the prenatal stages, FAE of the jejunal PP was C6-negative. However, a few C6-positive cells were distributed diffusely in some FAE of the jejunal PPs during the postnatal stages. The protein molecular weight of the antigen recognized by C6 was approximately 45 kDa. These data show that C6 is useful for identifying the FAE in ileal PPs and further suggest that differentiation of the FAE in these areas is independent of external antigens

Neighborhood environments and physical activity among adults in 11 countries

Background: Understanding environmental correlates of physical activity can inform policy changes. Surveys were conducted in 11 countries using the same self-report environmental variables and the International Physical Activity Questionnaire, allowing analyses with pooled data. Methods: The participating countries were Belgium, Brazil, Canada, Colombia, China (Hong Kong), Japan, Lithuania, New Zealand, Norway, Sweden, and the U.S., with a combined sample of 11,541 adults living in cities. Samples were reasonably representative, and seasons of data collection were comparable. Participants indicated whether seven environmental attributes were present in their neighborhood. Outcomes were measures of whether health-related guidelines for physical activity were met. Data were collected in 2002–2003 and analyzed in 2007. Logistic regression analyses evaluated associations of physical activity with environmental attributes, adjusted for age, gender, and clustering within country. Results: Five of seven environmental variables were significantly related to meeting physical activity guidelines, ranging from access to low-cost recreation facilities (OR=1.16) to sidewalks on most streets (OR=1.47). A graded association was observed, with the most activity–supportive neighborhoods having 100% higher rates of sufficient physical activity compared to those with no supportive attributes. Conclusions: Results suggest neighborhoods built to support physical activity have a strong potential to contribute to increased physical activity. Designing neighborhoods to support physical activity can now be defined as an international public health issue

Transmission of prions within the gut and toward the central nervous system

The prion protein is a glycoprotein characterized by a folded α-helical structure that, under pathological conditions, misfolds and aggregates into its infectious isoform as β-sheet rich amyloidic deposits. The accumulation of the abnormal protein is responsible for a group of progressive and fatal disorders characterized by vacuolation, gliosis and spongiform degeneration. Prion disorders are characterized by a triple aetiology: familial, sporadic or acquired, although most cases are sporadic. The mechanisms underlying prion neurotoxicity remain controversial, while novel findings lead to hypothesize intriguing pathways responsible for prion spreading

Increase in Unemployment over the 2000’s: Comparison between People Living with HIV and the French General Population

The ANRS-Vespa2 Study GroupInternational audienceBackground: Despite improved health, unemployment has increased among people living with HIV (PlwHIV) over the last decade. However, since the economic recession of 2008, unemployment also increased in the French general population. This paper aimed to determine if the increase in the unemployment rate in the HIV population was higher than that in the French general population.Methods: We used data from the ANRS-Vespa study, a repeated cross-sectional survey among two national representative samples of PlwHIV followed at hospitals in France in 2003 and 2011. We compared employment and unemployment rates between HIV-infected people (overall and according to period of HIV diagnosis) and the French general population in 2003 and 2011, using multivariate Poisson regressions adjusted for individual sociodemographic characteristics.Results: The employment rate among PlwHIV was consistently lower than that in the general population in 2003 and 2011. In contrast, there was a trend of an increasing unemployment rate difference between PlwHIV and the general population: PlwHIV’s unemployment rate was 1.48 (95% confidence interval [CI]: 1.16–1.90) times higher than that of the general population in 2003, versus 1.62 (95% CI: 1.34–1.96) times higher in 2011. This unemployment rate difference was the highest for PlwHIV diagnosed in or after 2008 (adjusted prevalence rate ratio: 2.06; 95% CI: 1.59–2.67).Conclusions: These results suggest that in time of economic recession, an increasing proportion of PlwHIV may be excluded from the labor market although they are willing to re-enter it. This constitutes a major issue relative to social consequences of chronic diseas