Double-walled carbon nanotubes trigger IL-1β release in human monocytes through Nlrp3 inflammasome activation

Because of their outstanding physical properties, carbon nanotubes (CNTs) are promising new materials in the field of nanotechnology. It is therefore imperative to assess their adverse effects on human health. Monocytes/macrophages that recognize and eliminate the inert particles constitute the main target of CNTs. In this article, we report our finding that double-walled CNTs (DWCNTs) synergize with Tolllike receptor agonists to enhance IL-1β release in human monocytes. We show that DWCNTs–induced IL-1β secretion is exclusively linked to caspase-1 and to Nlrp3 inflammasome activation in human monocytes. We also establish that this activation requires DWCNTs phagocytosis and potassium efflux, but not reactive oxygen specied (ROS) generation. Moreover, inhibition of lysosomal acidification or cathepsin-B activation reduces DWCNT-induced IL-1β secretion, suggesting that Nlrp3 inflammasome activation occurs via lysosomal destabilization. Thus, DWCNTs present a health hazard due to their capacity to activate Nlrp3 inflammasome, recalling the inflammation caused by asbestos and hence demonstrating that they should be used with caution. From the Clinical Editor: This is a very important biosafety/toxicity study regarding double walled carbon nanotubes. The investigators demonstrate that such nanotubes do represent a health hazard due to their capacity to activate Nlrp3 inflammasome, resembling the inflammation caused by asbestos. While further study of this phenomenon is definitely needed, the above findings clearly suggest that special precautions need to be taken when applying these nanoparticles in human disease research

Modelling and Simulation of a catchment in order to evaluate water resources

International audienceOur work addresses this problem in the domain of water management at a catchment scale and consists in evaluating water balances. We have developed a software framework allowing simulation scenarios to be easily run and results about outlet flow and groundwater variation to be easily interpreted. In this paper, we study anthropogenic scenarios consisting in modifying the land cover at different scales: parcel, slopes or catchment. The simulation is supported by a methodology allowing catchment models to be built up using a hierarchical and modular approach based on components formalised by sequential machines. Few modelling parameters are necessary because our purpose is not to build up a "perfect" model to represent a catchment from a hydrological point of view but to illustrate the impact of climatic changes or anthropogenic activities on water balance. The simulation interface allows climatic data files to be selected to compare various scenarios. It allows the land-use to be easily modified to understand the impact of anthropogenic activities on water from a quantitative point of view. Modelling and results of simulation are illustrated on a catchment located in the area of Cévennes (South of France)

What can designing learning-by-concordance clinical reasoning cases teach us about instruction in the health sciences?

Introduction: Learning-by-concordance (LbC) is an online learning strategy to practice reasoning skills in clinical situations. Writing LbC clinical cases, comprising an initial hypothesis and supplementary data, differs from typical instructional design. We sought to gain a deeper understanding from experienced LbC designers to better support clinician educators’ broader uptake of LbC. Methods: A dialogic action research approach was selected because it yields triangulated data from a heterogeneous group. We conducted three 90-minute dialogue-group sessions with eight clinical educators. Discussions focused on the challenges and pitfalls of each LbC design stage described in the literature. Recordings were transcribed and analyzed thematically. Results: We identified three themes by thematic analysis about the challenges inherent in designing LbC that are unique for this type of learning strategy: 1) the distinction between pedagogical intent and learning outcome; 2) the contextual cues used to challenge students and advance their learning and 3) the integration of experiential with formalized knowledge for cognitive apprenticeship. Discussion: A clinical situation can be experienced and conceptualized in many ways, and multiple responses are appropriate. LbC designers use contextual cues from their experience and combine them with formalized knowledge and protocols to write effective LbC clinical reasoning cases. LbC focuses learners’ attention on decision-making in grey areas that characterize the nature of professional clinical work. This in-depth study on LbC design, indicating the integration of experiential knowledge, might call for new thinking about instructional design

Genomics in cardiac metabolism

Cell biology is in transition from reductionism to a more integrated science. Large-scale analysis of genome structure, gene expression, and metabolites are new technologies available for studying cardiac metabolism in diseases known to modify cardiac function. These technologies have several limitations and this review aims both to assess and take a critical look at some important results obtained in genomics restricted to molecular genetics, transcriptomics and metabolomics of cardiac metabolism in pathophysiological processes known to alter myocardial function. Therefore, our goal was to delineate new signalling pathways and new areas of research from the vast amount of data already published on genomics as applied to cardiac metabolism in diseases such as coronary heart disease, heart failure, and ischaemic reperfusio

PPARγ ligands switched high fat diet-induced macrophage M2b polarization toward M2a thereby improving intestinal Candida elimination.

International audienceObesity is associated with a chronic low-grade inflammation that predisposes to insulin resistance and the development of type 2 diabetes. In this metabolic context, gastrointestinal (GI) candidiasis is common. We recently demonstrated that the PPARγ ligand rosiglitazone promotes the clearance of Candida albicans through the activation of alternative M2 macrophage polarization. Here, we evaluated the impact of high fat diet (HFD)-induced obesity and the effect of rosiglitazone (PPARγ ligand) or WY14643 (PPARα ligand) both on the phenotypic M1/M2 polarization of peritoneal and cecal tissue macrophages and on the outcome of GI candidiasis. We demonstrated that the peritoneal macrophages and the cell types present in the cecal tissue from HF fed mice present a M2b polarization (TNF-α(high), IL-10(high), MR, Dectin-1). Interestingly, rosiglitazone induces a phenotypic M2b-to-M2a (TNF-α(low), IL-10(low), MR(high), Dectin-1(high)) switch of peritoneal macrophages and of the cells present in the cecal tissue. The incapacity of WY14643 to switch this polarization toward M2a state, strongly suggests the specific involvement of PPARγ in this mechanism. We showed that in insulin resistant mice, M2b polarization of macrophages present on the site of infection is associated with an increased susceptibility to GI candidiasis, whereas M2a polarization after rosiglitazone treatment favours the GI fungal elimination independently of reduced blood glucose. In conclusion, our data demonstrate a dual benefit of PPARγ ligands because they promote mucosal defence mechanisms against GI candidiasis through M2a macrophage polarization while regulating blood glucose level

Neurally adjusted ventilatory assist (NAVA) improves patient-ventilator interaction during non-invasive ventilation delivered by face mask

Purpose: To determine if, compared to pressure support (PS), neurally adjusted ventilatory assist (NAVA) reduces patient-ventilator asynchrony in intensive care patients undergoing noninvasive ventilation with an oronasal face mask. Methods: In this prospective interventional study we compared patient-ventilator synchrony between PS (with ventilator settings determined by the clinician) and NAVA (with the level set so as to obtain the same maximal airway pressure as in PS). Two 20-min recordings of airway pressure, flow and electrical activity of the diaphragm during PS and NAVA were acquired in a randomized order. Trigger delay (T d), the patient's neural inspiratory time (T in), ventilator pressurization duration (T iv), inspiratory time in excess (T iex), number of asynchrony events per minute and asynchrony index (AI) were determined. Results: The study included 13 patients, six with COPD, and two with mixed pulmonary disease. T d was reduced with NAVA: median 35ms (IQR 31-53ms) versus 181ms (122-208ms); p=0.0002. NAVA reduced both premature and delayed cyclings in the majority of patients, but not the median T iex value. The total number of asynchrony events tended to be reduced with NAVA: 1.0events/min (0.5-3.1events/min) versus 4.4events/min (0.9-12.1events/min); p=0.08. AI was lower with NAVA: 4.9 % (2.5-10.5 %) versus 15.8 % (5.5-49.6 %); p=0.03. During NAVA, there were no ineffective efforts, or late or premature cyclings. PaO2 and PaCO2 were not different between ventilatory modes. Conclusion: Compared to PS, NAVA improved patient ventilator synchrony during noninvasive ventilation by reducing T d and AI. Moreover, with NAVA, ineffective efforts, and late and premature cyclings were absen

Longitudinal changes in HIV-specific IFN-γ secretion in subjects who received Remune™ vaccination prior to treatment interruption

BACKGROUND: Despite the benefits of highly active antitretroviral therapy (HAART) for suppressing viral replication in HIV infection, virus persists and rebounds during treatment interruption (TI). This study explored whether HAART intensification with Remune™ vaccination before TI can boost HIV-1-specific immunity, leading to improved control of viremia off HAART. METHODS: Ten chronically HIV-infected adults were enrolled in this proof of concept study. After a 6-month HAART intensification phase with didanosine, hydroxyurea, granulocyte-macrophage colony-stimulating factor, (GM-CSF), and a first dose of Remune™ (HIV-1 Immunogen), HAART was discontinued. Patients continued to receive Remune™ every 3 months until the end of study. HAART was restarted if viral load did not fall below 50,000 copies/ml of plasma within 3 months or if CD4+ counts decreased to <200 cells/mm(3). HIV-specific immunity was monitored with the interferon-γ (IFN-γ) ELISPOT assay. RESULTS: All subjects experienced viral rebound during TIs. Although the magnitude and breadth of HIV-specific responses to HLA-restricted optimal peptide panels and Gag p55 peptide pools increased and viral load decreased by 0.44 log(10 )units from TI#1 to TI#2, no significant correlations between these parameters were observed. The patients spent 50.4% of their 36 months follow up off HAART. CONCLUSION: Stopping HAART in this vaccinated population induced immune responses that persisted after therapy was restarted. Induction of HIV-specific immunity beyond IFN-γ secretion may be contributing to better control of viremia during subsequent TIs allowing for long periods off HAART

Tracing the Sveconorwegian orogen into the Caledonides of West Norway: Geochronological and isotopic studies on magmatism and migmatization

The Sveconorwegian orogen represents a branch of Grenville-age (~1250–950 Ma) orogenic belts that formed during the construction of the supercontinent Rodinia. This study traces the Sveconorwegian records from its type-area in the Baltic Shield of South Norway into basement windows underneath Caledonian nappes, by combining zircon U–Pb geochronology and Hf–O isotopes. Samples along a N-S trending transect reveal multiple magmatic episodes during Gothian (ca. 1650 Ma), Telemarkian (ca. 1500 Ma) and Sveconorwegian (1050–1020 Ma vs. 980–930 Ma) orogenesis as well as Sveconorwegian migmatization (1050–950 Ma). Newly documented 1050–1020 Ma magmatism and migmatization extend the Sirdal Magmatic Belt to a 300 km-long, NNW-SSE trending crustal domain, with the northern boundary corresponding to the gradual transition from Telemarkian to Gothian crust. These Precambrian crustal heterogeneities largely controlled the development of Caledonian shear zones. The ca. 1050–1040 Ma granitic and mafic magmas show similar isotopic signatures with slightly negative or positive εHf(t) and moderate δ18O values (6–7‰), which indicates that crustal reworking was more dominant than juvenile inputs during their genesis. The generation of leucosomes and leucogranites at ca. 1030–1020 Ma, which have a more evolved Hf isotopic composition, probably reflects an even higher degree of remelting of older crust. The Hf–O isotopic patterns show that Sveconorwegian magmas differ from typical arc magmas by lower involvement of sedimentary components and juvenile material. This makes the 1050–930 Ma magmatism incompatible with a long-term subduction setting. The ca. 1650–1500 Ma samples, in contrast, generally have juvenile Hf isotopic compositions associated with varying δ18O values of 4.5–9‰, consistent with subduction-accretion processes involving significant sedimentary recycling. This accretionary margin was most likely transformed into the Sveconorwegian orogen through collisional interactions of Baltica, Laurentia and Amazonia in the context of Rodinia amalgamation.publishedVersio