Diet-induced dyslipidemia induces metabolic and migratory adaptations in regulatory T cells

A hallmark of advanced atherosclerosis is inadequate immunosuppression by regulatory T(Treg) cells inside atherosclerotic lesions. Dyslipidemia has been suggested to alter Treg cellmigration by affecting the expression of specific membrane proteins, thereby decreasing Treg cellmigration towards atherosclerotic lesions. Besides membrane proteins, cellular metabolism has beenshown to be a crucial factor in Treg cell migration. We aimed to determine whether dyslipidemiacontributes to altered migration of Treg cells, in part, by affecting cellular metabolism.Dyslipidemia was induced by feeding Ldlr-/- mice a Western-type diet for 16-20weeks and intrinsic changes in Treg cells affecting their migration and metabolism were examined.Dyslipidemia was associated with altered mTORC2 signaling in Treg cells, decreased expression ofmembrane proteins involved in migration, including CD62L, CCR7 and S1Pr1, and decreased Tregcell migration towards lymph nodes. Furthermore, we discovered that diet-induced dyslipidemiainhibited mTORC1 signaling, induced PPARδ activation and increased fatty acid (FA) oxidation inTreg cells. Moreover, mass-spectrometry analysis of serum from Ldlr-/- mice with normolipidemia ordyslipidemia showed increases in multiple PPARδ ligands during dyslipidemia. Treatment with asynthetic PPARδ agonist increased the migratory capacity of Treg cells in vitro and in vivo in an FAoxidation dependent manner. Furthermore, diet-induced dyslipidemia actually enhanced Treg cellmigration into the inflamed peritoneum and into atherosclerotic lesions in vitro.Altogether, our findings implicate that dyslipidemia does not contribute toatherosclerosis by impairing Treg cell migration as dyslipidemia associated with an effector-likemigratory phenotype in Treg cells.Analytical BioScience

Expression of Toll-like receptor 2 is up-regulated in monocytes from patients with chronic obstructive pulmonary disease

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterised by pulmonary and systemic inflammation which flare-up during episodes of acute exacerbation (AECOPD). Given the role of Toll-like receptors (TLRs) in the induction of inflammatory responses we investigated the involvement of TLRs in COPD pathogenesis. METHODS: The expression of TLR-2, TLR-4 and CD14 in monocytes was analyzed by flow cytometry. To study the functional responses of these receptors, monocytes were stimulated with peptidoglycan or lipopolysaccharide and the amounts of TNFα and IL-6 secreted were determined by ELISA. RESULTS: We found that the expression of TLR-2 was up-regulated in peripheral blood monocytes from COPD patients, either clinically stable or during AECOPD, as compared to never smokers or smokers with normal lung function. Upon stimulation with TLR-2 ligand monocytes from COPD patients secreted increased amounts of cytokines than similarly stimulated monocytes from never smokers and smokers. In contrast, the expressions of TLR-4 and CD14 were not significantly different between groups, and the response to lipopolysaccharide (a TLR-4 ligand) stimulation was not significantly different either. At discharge from hospital TLR-2 expression was down-regulated in peripheral blood monocytes from AECOPD patients. This could be due to the treatment with systemic steroids because, in vitro, steroids down-regulated TLR-2 expression in a dose-dependent manner. Finally, we demonstrated that IL-6, whose plasma levels are elevated in patients, up-regulated in vitro TLR-2 expression in monocytes from never smokers. CONCLUSION: Our results reveal abnormalities in TLRs expression in COPD patients and highlight its potential relationship with systemic inflammation in these patients

Managing the link and strengthening transition from child to adult mental health Care in Europe (MILESTONE): Background, rationale and methodology

Background: Transition from distinct Child and Adolescent Mental Health (CAMHS) to Adult Mental Health Services (AMHS) is beset with multitude of problems affecting continuity of care for young people with mental health needs. Transition-related discontinuity of care is a major health, socioeconomic and societal challenge globally. The overall aim of the Managing the Link and Strengthening Transition from Child to Adult Mental Health Care in Europe (MILESTONE) project (2014-19) is to improve transition from CAMHS to AMHS in diverse healthcare settings across Europe. MILESTONE focuses on current service provision in Europe, new transition-related measures, long term outcomes of young people leaving CAMHS, improving transitional care through 'managed transition', ethics of transitioning and the training of health care professionals. Methods: Data will be collected via systematic literature reviews, pan-European surveys, and focus groups with service providers, users and carers, and members of youth advocacy and mental health advocacy groups. A prospective cohort study will be conducted with a nested cluster randomised controlled trial in eight European Union (EU) countries (Belgium, Croatia, France, Germany, Ireland, Italy, Netherlands, UK) involving over 1000 CAMHS users, their carers, and clinicians. Discussion: Improving transitional care can facilitate not only recovery but also mental health promotion and mental illness prevention for young people. MILESTONE will provide evidence of the organisational structures and processes influencing transition at the service interface across differing healthcare models in Europe and longitudinal outcomes for young people leaving CAMHS, solutions for improving transitional care in a cost-effective manner, training modules for clinicians, and commissioning and policy guidelines for service providers and policy makers

Adsorption at cell surface and cellular uptake of silica nanoparticles with different surface chemical functionalizations: impact on cytotoxicity

International audienceSilica nanoparticles are particularly interesting for medical applications because of the high inertness and chemical stability of silica material. However, at the nanoscale their innocuousness must be carefully verified before clinical use. The aim of this study was to investigate the in vitro biological toxicity of silica nanoparticles depending on their surface chemical functionalization. To that purpose, three kinds of 50 nm fluorescent silica-based nanoparticles were synthesized: 1) sterically stabilized silica nanoparticles coated with neutral polyethylene glycol (PEG) molecules, 2) positively charged silica nanoparticles coated with amine groups and 3) negatively charged silica nanoparticles coated with carboxylic acid groups. RAW 264.7 murine macrophages were incubated for 20 hours with each kind of nanoparticles. Their cellular uptake and adsorption at the cell membrane were assessed by a fluorimetric assay and cellular responses were evaluated in terms of cytotoxicity, pro-inflammatory factor production and oxidative stress. Results showed that the highly positive charged nanoparticle, were the most adsorbed at cell surface and triggered more cytotoxicity than other nanoparticles types. To conclude, this study clearly demonstrated that silica nanoparticles surface functionalization represents a key parameter in their cellular uptake and biological toxicity

Regulating inflammation through the anti-inflammatory enzyme platelet-activating factor-acetylhydrolase

Platelet-activating factor (PAF) is one of the most potent lipid mediators involved in inflammatory events. The acetyl group at the sn-2 position of its glycerol backbone is essential for its biological activity. Deacetylation induces the formation of the inactive metabolite lyso-PAF. This deacetylation reaction is catalyzed by PAF-acetylhydrolase (PAF-AH), a calcium independent phospholipase A2 that also degrades a family of PAF-like oxidized phospholipids with short sn-2 residues. Biochemical and enzymological evaluations revealed that at least three types of PAF-AH exist in mammals, namely the intracellular types I and II and a plasma type. Many observations indicate that plasma PAF AH terminates signals by PAF and oxidized PAF-like lipids and thereby regulates inflammatory responses. In this review, we will focus on the potential of PAF-AH as a modulator of diseases of dysregulated inflammation

Getuigen Verhalen, Kamp Amersfoort, interview 008

Beiden worden gevangen genomen op 16 april 1944 omdat er in Beverwijk acties door het verzet waren. Als vergelding worden veel jonge mannen gevangen genomen. Eerste transport: met de trein via Amsterdam naar Kamp Amersfoort. Geen bagage mee en ze hadden geen persoonsbewijzen meer. Lopen naar het kamp vanaf het station. Oude uniformen, kaal geschoren, sieraden werden afgenomen. Geld dat ze bij zich hadden, mochten ze houden. Krijgen roggebrood en spek van het Rode Kruis. Woensdag is pap-dag met rogge. Zijn als gijzelaars een aparte groep gevangen. Moeten stro vlechten, doen mee met voetbalwedstrijden in het kamp. Er komt een grote groep vrouwen uit Beverwijk hun echtgenoten opzoeken. Op 7 juni moeten ze naar Duitsland: Spergau, Nietleben, Zöschen. Terug gevlucht naar Nederland. Aversie tegen het verzet. Er zijn in Beverwijk veel nutteloze acties gevoerd waardoor er onnodig mensen gevangen genomen en omgekomen zijn. Beiden lang niet over hun oorlogsverleden gepraat. Pas in 1991/ 2006