Pathways Related to NLRP3 Inflammasome Activation Induced by Gold Nanorods

Gold; Inflammation; NanorodOro; Inflamación; NanorodOr; Inflamació; NanorodThe widespread and increasing use of engineered nanomaterials (ENM) increases the risk of human exposure, generating concern that ENM may provoke adverse health effects. In this respect, their physicochemical characteristics are critical. The immune system may respond to ENM through inflammatory reactions. The NLRP3 inflammasome responds to a wide range of ENM, and its activation is associated with various inflammatory diseases. Recently, anisotropic ENM have become of increasing interest, but knowledge of their effects on the immune system is still limited. The objective of the study was to compare the effects of gold ENM of different shapes on NLRP3 inflammasome activation and related signalling pathways. Differentiated THP-1 cells (wildtype, ASC- or NLRP3-deficient), were exposed to PEGylated gold nanorods, nanostars, and nanospheres, and, thus, also different surface chemistries, to assess NLRP3 inflammasome activation. Next, the exposed cells were subjected to gene expression analysis. Nanorods, but not nanostars or nanospheres, showed NLRP3 inflammasome activation. ASC- or NLRP3-deficient cells did not show this effect. Gene Set Enrichment Analysis revealed that gold nanorod-induced NLRP3 inflammasome activation was accompanied by downregulated sterol/cholesterol biosynthesis, oxidative phosphorylation, and purinergic receptor signalling. At the level of individual genes, downregulation of Paraoxonase-2, a protein that controls oxidative stress, was most notable. In conclusion, the shape and surface chemistry of gold nanoparticles determine NLRP3 inflammasome activation. Future studies should include particle uptake and intracellular localization.This research was funded by the EU FP7 project FutureNanoNeeds (GA N° 604602), RIVM, and VITO

An Air-liquid Interface Bronchial Epithelial Model for Realistic, Repeated Inhalation Exposure to Airborne Particles for Toxicity Testing.

For toxicity testing of airborne particles, air-liquid interface (ALI) exposure systems have been developed for in vitro tests in order to mimic realistic exposure conditions. This puts specific demands on the cell culture models. Many cell types are negatively affected by exposure to air (e.g., drying out) and only remain viable for a few days. This limits the exposure conditions that can be used in these models: usually relatively high concentrations are applied as a cloud (i.e., droplets containing particles, which settle down rapidly) within a short period of time. Such experimental conditions do not reflect realistic long-term exposure to low concentrations of particles. To overcome these limitations the use of a human bronchial epithelial cell line, Calu-3 was investigated. These cells can be cultured at ALI conditions for several weeks while retaining a healthy morphology and a stable monolayer with tight junctions. In addition, this bronchial model is suitable for testing the effects of repeated exposures to low, realistic concentrations of airborne particles using an ALI exposure system. This system uses a continuous airflow in contrast to other ALI exposure systems that use a single nebulization producing a cloud. Therefore, the continuous flow system is suitable for repeated and prolonged exposure to airborne particles while continuously monitoring the particle characteristics, exposure concentration, and delivered dose. Taken together, this bronchial model, in combination with the continuous flow exposure system, is able to mimic realistic, repeated inhalation exposure conditions that can be used for toxicity testing

Long-term exposure to ultrafine particles and incidence of cardiovascular and cerebrovascular disease in the EPIC-NL cohort

Background: There is a small but growing evidence base that exposure to ultrafine particles (UFP – particles smaller than 100nm) may play an important role in the etiology of several illnesses, including cardiovascular disease (CVD). However, this has been under-explored in population-level studies. Methods: Using Cox proportional hazard models we studied the association between long-term exposure to UFP (predicted via recently developed land use regression models) and incident cardiovascular disease in the Dutch arm of the European Prospective Investigation into Cancer cohort (EPIC-NL), which contains 33,831 Dutch residents. Hazard ratios (HR) for UFP were compared to HRs for more routinely monitored air pollutants, including PM$_{10}$, PM$_{coarse}$, PM$_{2.5}$, PM$_{2.5}$ absorbance, NO$_{x}$, and NO$_{2}$. Joint-pollutant effects were also evaluated in two-pollutant models. Results: Long-term exposure to UFP was associated with increased HRs for all incident cardiovascular disease (HR = 1.18 per 10,000 particles/cm$_{3}$, 95% CI: 1.03, 1.34), myocardial infarction (HR = 1.34, 95% CI: 1.00, 1.79), and heart failure (HR = 1.76, 95% CI: 1.17, 2.66). Positive associations were also observed for NO2 (HR for heart failure = 1.22, 95% CI: 1.01, 1.48 per 20 μg/m$^{3}$) and coarse PM (HR for all CVD = 1.21, 95% CI: 1.01, 1.45 per 10 μg/m$^{3}$). CVD was not positively associated with PM$_{2.5}$ (HR for all CVD = 0.95, 95% CI: 0.75, 1.28 per 5 μg/m$^{3}$). HRs for UFP and cerebrovascular diseases were positive, but not significant. In two-pollutant models (UFP + NO$_{2}$ and UFP + PM$_{coarse}$), positive associations tended to remain for UFP, while HRs for PM$_{coarse}$ and NO$_{2}$ generally attenuated towards the null. Conclusions: These findings strengthen the overall evidence that UFP exposure plays an important role in cardiovascular health and that risks of ambient air pollution, based on conventional air pollution metrics, may underestimate the true population risk.ment data and biological responses as viability (AlamarBlue assay), cytotoxicity (LDH release), and release of cytokines during long-term exposure are reported

RENAL REPLACEMENT THERAPY IN A POLYTRAUMATIZED PATIENT WITH HEMOPHILIA

Zatajenje bubrežne funkcije je rijetka pojava u bolesnika s nasljednim koagulacijskim poremećajima. Međutim, kada nastupi veoma brzo napreduje do završnog stadija bubrežne bolesti i potrebe za nadomještanjem bubrežne funkcije. Javljaju se problemi vezani uz odabir metode dijalize, periproceduralne nadoknade nedostatnog faktora koagulacije te heparinizacije dijaliznog sustava. Kod hemoiličara uvijek treba biti oprezan tijekom samog postupka dijalize zbog mogućeg razvoja komplikacija koje ih mogu vitalno ugroziti. Ovo je prikaz slučaja teško politraumatiziranog bolesnika koji boluje od hemofilije A. Tijekom intenzivnog liječenja razvio je akutno bubrežno zatajenje te tešku sepsu. S obzirom na okolnosti najbolja metoda izbora za njega je bila kontinuirana veno-venska hemodijaliza. Unato uspješno provedenoj dijalizi bez komplikacija bolesnik umire od protrahirane sepseRenal failure is a rare complication of hereditary coagulopathies. However, when it occurs, it rapidly progresses to a stage that requires replacement of renal function. Major problems include the choice of dialysis method, prevention of complications and supplementation of deicient factor. In hemodialysis, it is challenging to prevent system clotting and avoid bleeding. We present a case of polytraumatized male patient with hemophilia A, who developed compartment syndrome with acute renal failure. Continuous venovenous hemodialysis (CVVHD) improved his condition and he recovered his kidney function. However, over the next few days he developed severe sepsis with deterioration of renal function. CVVHDF (hemodiailtration) was restarted. Several large hematomas were found in the abdominal cavity and in the inguinal region, one of them inducing compartment syndrome with leg necrosis. The patient died from cardiorespiratory arrest

The development of a multidisciplinary fall risk evaluation tool for demented nursing home patients in the Netherlands

BACKGROUND: Demented nursing home patients are at high risk for falls. Falls and associated injuries can have a considerable influence on the autonomy and quality of life of patients. The prevention of falls among demented patients is therefore an important issue. In order to intervene in an efficient way in this group of patients, it is important to systematically evaluate the fall risk profile of each individual patient so that for each patient tailor-made preventive measures can be taken. Therefore, the objective of the present study is to develop a feasible and evidence based multidisciplinary fall risk evaluation tool to be used for tailoring preventive interventions to the needs of individual demented patients. METHODS: To develop this multidisciplinary fall risk evaluation tool we have chosen to combine scientific evidence on the one hand and experts' opinions on the other hand. Firstly, relevant risk factors for falling in elderly persons were gathered from the literature. Secondly, a group of Dutch experts in the field of falls and fall prevention in the elderly were consulted to judge the suitability of these risk factors for use in a multidisciplinary fall risk evaluation tool for demented nursing home patients. Thirdly, in order to generate a compact list of the most relevant risk factors for falling in demented elderly, all risk factors had to fulfill a set of criteria indicating their relevance for this specific target population. Lastly the final list of risk factors resulting from the above mentioned procedure was presented to the expert group. The members were also asked to give their opinion about the practical use of the tool. RESULTS: The multidisciplinary fall risk evaluation tool we developed includes the following items: previous falls, use of medication, locomotor functions, and (correct) choice and use of assistive and protective devices. The tool is developed for the multidisciplinary teams of the nursing homes. CONCLUSION: This evidence and practice based multidisciplinary fall risk evaluation tool targets the preventive interventions aimed to prevent falls and their negative consequences in demented nursing home patients

Nano(bio)materials Do Not Affect Macrophage Phenotype – A Study Conducted by the REFINE Project

Macrophages are well known for the involvement in the biocompatibility, as well as biodistribution, of nano(bio)materials. Although there are a number of rodent cell lines, they may not fully recapitulate primary cell responses; particularly for those of human cells. Isolation of tissue resident macrophages, from humans, is difficult and may result in insufficient cells with which to determine the possible interaction with nano(bio)materials. Isolation of primary human monocytes, and differentiation to monocyte-derived macrophages, may provide a useful tool with which to study, further, these interactions. To that end, we developed a standard operating procedure for this differentiation, as part of the REFINE project, and used it to measure the secretion of bioactive molecules from M1 and M2 differentiated monocytes in response to model nano(bio)materials, following an initial assessment of pyrogenic contamination which may confound, potential, observations. The SOP was deployed in two partner institutions with, broadly, similar results. The work presented here shows the utility of this assay but, highlights the relevance of donor variability in responses to nano(bio)materials. Whilst donor variability can provide some, logistical, challenges to application of such assays, this variability is much closer to the heterogeneous cells that are present in vivo, compared to homogeneous, non-human, cell lines.</jats:p

Nursing competencies for family-centred care in the hospital setting: a multinational Q-methodology study

Aim: to identify: (1) nursing competencies for FCC in a hospital setting; and (2) to explore perspectives on these competencies among Dutch and Australian professionals including lecturers, researchers, Registered Nurses and policy makers. Design: A multinational cross-sectional study using Q-methodology. Methods: First, an integrative review was carried out to identify known competencies regarding FCC and to develop the Q-set (search up to July 2018). Second, purposive sampling was used to ensure stakeholder involvement. Third, participants sorted the Q-set using a web-based system between May and August 2019. Lastly, the data were analysed using a by-person factor analysis. The commentaries on the five highest and lowest ranked competencies were thematically analysed. Results: The integrative review identified 43 articles from which 72 competencies were identified. In total 69 participants completed the Q-sorting. We extracted two factors with an explained variance of 24%. The low explained variance hampered labelling. Based on a post-hoc qualitative analysis, four themes emerged from the competencies that were considered most important, namely: (a) believed preconditions for FCC; (b) promote a partnership between nurses, patients and families; (c) be a basic element of nursing; and (d) represent a necessary positive attitude and strong beliefs of the added value of FCC. Three themes appeared from the competencies that were considered least important because they: (a) were not considered a specific nursing competency; (b) demand a multidisciplinary approach; or (c) require that patients and families take own responsibility. Conclusions: Among healthcare professionals, there is substantial disagreement on which nursing competencies are deemed most important for FCC. Impact: Our set of competencies can be used to guide education and evaluate practicing nurses in hospitals. These findings are valuable to consider different views on FCC before implementation of new FCC interventions into nursing practice

A quantitative approach to assess the potency of skin sensitizers in the elicitation phase

The concept that thresholds exist for the induction of allergic contact dermatitis by chemicals with skin sensitizing properties has been used for a quantitative risk assessment approach. In this approach the potency of skin sensitizers as determined in the Local Lymph Node Assay is used to calculate the threshold for induction of sensitization. These are then used to estimate safe exposure levels for consumers. Whether these exposure levels will protect subjects that are already sensitized is unknown. The elicitation of allergic contact dermatitis supposedly occurs above a certain threshold as well and this threshold is most likely lower than that for the induction. It is unclear if induction thresholds can be extrapolated to elicitation thresholds. The aim of this study was to assess the potency of sensitizers with different sensitizing potencies in the elicitation phase in a mouse model for elicitation. Mice were sensitized by topical application on days 0 and 7 using equipotent concentrations of oxazolone, 2,4-dinitrochlorobenzene (DNCB) and eugenol to ensure that the sensitization strength would not influence the elicitation potency. Mice were challenged on day 21 by topical application on the ears in a dose-dependent manner and dose-response data were used to calculate the elicitation potency. Unexpectedly, sensitizers with different sensitizing potencies induced not the same dose-response curves in sensitized mice. The most potent sensitizer in the elicitation phase was oxazolone, followed by DNCB and eugenol. Similar to the induction phase, under equipotent sensitization conditions strong sensitizers such as oxazolone and DNCB elicit allergic reactions at lower concentrations than weak sensitizers such as eugenol. Our results indicate that elicitation thresholds cannot be readily deduced from sensitization thresholds