Cellules dendritiques et activité immunomodulatrice des opioïdes endogènes

Le système opioïde endogène est constitué d'une vingtaine de neuropeptides répartis en trois familles : les endorphines, les enképhalines et les dynorphines qui se lient respectivement à trois classes de récepteurs opioïdes : mu, delta, kappa. Les opioïdes, connus principalement pour leur activité analgésique, ont aussi de nombreux effets sur le système immunitaire. Les cellules dendritiques (DC) qui permettent le lien entre l'immunité innée et adaptative, jouent un rôle prépondérant dans l'initiation de la réponse immunitaire spécifique de l'antigène. Les cellules dendritiques capturent les antigènes puis, après maturation, migrent vers les ganglions drainant le site inflammatoire et stimulent les lymphocytes T. La migration des DC vers les organes lymphoïdes secondaires représente donc une étape clé dans l'initiation de la réponse immunitaire. Mon projet avait pour but d'apprécier l'effet des opioïdes endogènes produits au cours de l'inflammation sur la migration des DC. Nous avons montré que le récepteur opioïde d (DOR), faiblement exprimé dans les cellules dendritiques immatures, est surexprimé après leur maturation. L'expression du DOR par les cellules dendritiques matures est responsable de l'activité chimiotactique des opioïdes in vitro et in vivo. La surexpression du DOR étant concomitante à celle de CCR7, récepteur indispensable à la migration des DC matures dans les organes lymphoïdes, nous avons étudié l'interaction fonctionnelle entre ces deux récepteurs. Nos résultats suggèrent que les opioïdes endogènes auraient un effet restreint au site inflammatoire pauvre en ligands de CCR7. Le récepteur MOR, quant à lui, principal médiateur de l'effet immunosuppresseur de la morphine in vivo, n'est pas exprimé par les cellules immunitaires dans les conditions normales. La démonstration que l'expression du récepteur MOR peut être induite par des cytokines, nous a conduit à émettre l'hypothèse que son expression pourrait avoir des conséquences physiopathologiques péjoratives, notamment dans le lymphome. Nos résultats ont montré que le MOR, et l'un de ses ligands, sont retrouvés quasi exclusivement dans le lymphome T cutanée de type Sézary. L'expression du MOR dans les ganglions des patients est associée à la production d'IL-13. L'IL-13 n'induit pas le MOR dans toutes les cellules immunitaires présentes dans le ganglion mais uniquement dans les cellules de Langerhans activées, particulièrement représentées dans les ganglions drainant la peau des patients atteints du syndrome de Sézary. Compte tenu de l'implication du MOR dans les effets immunosuppresseurs des opioïdes, nos résultats suggèrent qu'en agissant sur les cellules de Langerhans matures, ils pourraient participer à l'échappement des cellules de Sézary à la réaction anti-tumorale.Endogenous opioid peptides belong to three families: endorphins, enkephalins, and dynorphins which bind respectively to three types of opioid receptors: mu (MOR), delta (DOR) and kappa (KOR). Opioids, mainly knew for their analgesic function, affect also immune system. Dendritic cells (DC) play a major role in initiation of antigen specific immune response. DCs capture antigen then, after maturation, migrate to draining lymph node and stimulate antigen specific T cell. DCs migration to secondary lymphoid organ is thus a key step in adaptative immune response initiation. My project was to identify endogenous opioids effect produced during inflammation on DCs migration. We showed that the d opioid receptor (DOR), weakly expressed in immature DCs, was overexpressed after DCs maturation. DOR expression by matures DCs was responsible for opioid chemotactic activity in vitro and in vivo. DOR surexpression being associated in the same time with up-regulation of CCR7, receptor indispensable for mature DCs migration to lymphoid organs, we further examined the functional cross-talk between these two receptors. Our results suggest that endogenous opioids would have a limited effect on inflammatory site low in CCR7 ligands. The MOR receptor, meanwhile, main mediator of immunosuppressive effect of morphine in vivo, is not expressed by immune cells in normal conditions. Demonstration that MOR receptor expression may be induced by cytokines suggests that MOR expression could have negative consequences in some pathological situations such as lymphomas. Our results showed that MOR, and one of his ligands, are almost exclusively found in patients with Sezary syndrome, a cutaneous T-cell lymphoma. MOR expression in lymph nodes from patients is associated with IL-13 production. Among the lymph node immune cells, IL-13 induce MOR only in activated Langerhans cells, which are very present in lymph nodes draining skin from patients with Sezary syndrome. Considering that MOR is the main mediator of the deleterious effects of opioids on immunity, our results suggest that endogenous opioids, acting on matures Langerhans cells, might participate in the escape of Sezary cells from the immune response

THE MEMS FLUX CONCENTRATOR: POTENTIAL LOW-COST, HIGHSENSITIVITY MAGNETOMETER

Progress on the development of a device, the MEMS flux concentrator, for mitigating the problem of 1/f noise in magnetic sensors will be presented. The MEMS flux concentrator essentially eliminates the effect of 1/f noise by increasing the operating frequency of the sensor to a frequency region where 1/f noise is small. This is accomplished by putting flux concentrators on MEMS structures whose motion modulates the magnetic field at the position of the magnetic sensor. Depending on the sensor, mitigating the effect of 1/f noise will increase the sensitivity of magnetic sensors by one to three orders of magnitude. Combining the MEMS flux concentrator with magnetic tunnel junctions with MgO barriers should lead to low cost magnetic sensors that are able to detect 1 pT signals at 1 Hz

Variation in sub-arc mantle oxygen fugacity during partial melting recorded in refractory peridotite xenoliths from the West Bismarck Arc

This work was funded bygrants (DP120104240 and DE120100513) to Richard J Arculus andOliver Nebel from the Australian Research Council

Analysis of pit latrine microbiota reveals depth-related variation in composition, and key parameters and taxa associated with latrine fill-up rate

Funding statement This research received financial support from the Bill and Melinda Gates Foundation (grant number OPP52641 to the London School of Hygiene and Tropical Medicine). AWW and JP were supported by the Wellcome Trust [grant number 098051]. AWW and the Rowett Institute, University of Aberdeen, receive core funding support from the Scottish Government Rural and Environmental Science and In review Analysis Service (RESAS). UZI is funded by NERC Independent Research Fellowship (NE/L011956/1) and further supported by EPSRC (EP/P029329/1 and EP/V030515/1). CQ is funded through an MRC fellowship (MR/M50161X/1) as part of the MRC Cloud Infrastructure for Microbial Bioinformatics consortium (MR/L015080/1). Acknowledgements In review Pit latrine microbiota associated with depth and fill-up rate. We would like to thank all the field and laboratory teams and to all the pit latrine owners who participated in this study. We also thank Paul Scott, Richard Rance and members of the Wellcome Sanger Institute's sequencing team for generating 16S rRNA gene data.Peer reviewedPublisher PD

Validation of the StimQ2: A parent-report measure of cognitive stimulation in the home.

Considerable evidence demonstrates the importance of the cognitive home environment in supporting children's language, cognition, and school readiness more broadly. This is particularly important for children from low-income backgrounds, as cognitive stimulation is a key area of resilience that mediates the impact of poverty on child development. Researchers and clinicians have therefore highlighted the need to quantify cognitive stimulation; however existing methodological approaches frequently utilize home visits and/or labor-intensive observations and coding. Here, we examined the reliability and validity of the StimQ2, a parent-report measure of the cognitive home environment that can be delivered efficiently and at low cost. StimQ2 improves upon earlier versions of the instrument by removing outdated items, assessing additional domains of cognitive stimulation and providing new scoring systems. Findings suggest that the StimQ2 is a reliable and valid measure of the cognitive home environment for children from infancy through the preschool period

Infant Sleep and Parent Health Literacy

Child sleep problems are prevalent and have been linked to poor behavior, worse school performance, and obesity. Low health literacy (HL) is associated with suboptimal parenting practices and worse health outcomes, but the relationship between parent HL and child sleep-related issues is not known. We examined the association between parent HL and child sleep-related issues

Upregulation of CD20 Positive B-Cells and B-Cell Aggregates in the Tumor Infiltration Zone is Associated with Better Survival of Patients with Pancreatic Ductal Adenocarcinoma

Patients with pancreatic ductal adenocarcinoma (PDAC) normally have a poor long-term prognosis. However, some rare cases of long-term survivors have been reported. The tumor microenvironment, consisting of cellular and stromal components, possibly plays an important role and might influence prognosis. In this context, the role of tumor-infiltrating B-cells and its impact on the survival in patients with PDAC remains controversial. We therefore aimed to assess the prognostic value of CD20-positive B-cells and CD20-positive B-cell aggregates as well as CD138, IgM, Pax5, and Ki67 on the survival of patients with PDAC using immunohistochemistry of FFPE pancreatectomy tissue sections from patients that underwent primary surgery for pT3- and R0-pancreatic adenocarcinoma between 1995 and 2016. Patients with PDAC were matched and grouped in 16 long-term-survivors (LTS, median overall survival (OS): 96 months [range: 61–177 months]) and 16 short-term-survivors (STS, median OS: 16 months [range: 7–32 months]). CD20-positive B-cells and B-cell aggregates in the tumor infiltration zone were significantly upregulated in the LTS-group compared to the STS-group (p = 0.0499 respectively p = 0.0432). Regarding the entire patient cohort (n = 32) CD20 positive B-cell aggregates in the tumor infiltration zone were an independent prognostic marker for overall survival in multivariate analysis (HR 9.2, CI 1.6–51.4, p = 0.012). These results underline the importance of tumor-associated B-cells for prognosis of patients with PDAC. The detailed role of B cells in the pathomechanism of PDAC should be further investigated for predicting outcome, identifying appropriate treatment regimens, and developing novel therapeutic option

Liquid Medication Errors and Dosing Tools: A Randomized Controlled Experiment

Poorly designed labels and packaging are key contributors to medication errors. To identify attributes of labels and dosing tools that could be improved, we examined the extent to which dosing error rates are affected by tool characteristics (ie, type, marking complexity) and discordance between units of measurement on labels and dosing tools; along with differences by health literacy and language

Assessment of Health Literacy and Numeracy Among Spanish-Speaking Parents of Young Children: Validation of the Spanish Parental Health Literacy Activities Test (PHLAT Spanish)

To assess the health literacy and numeracy skills of Spanish-speaking parents of young children and to validate a new Spanish language health literacy assessment for parents, the Spanish Parental Health Literacy Activities Test (PHLAT-10 Spanish)

Effect of Medication Label Units of Measure on Parent Choice of Dosing Tool: A Randomized Experiment

Some experts recommend eliminating “teaspoon” and “tablespoon” terms from pediatric medication dosing instructions, as they may inadvertently encourage use of nonstandard tools (i.e. kitchen spoons), which are associated with dosing errors. We examined whether use of “teaspoon” or “tsp” on prescription labels affects parents’ choice of dosing tools, and the role of health literacy and language