2017 Update of ESC/EAS Task Force on practical clinical guidance for proprotein convertase subtilisin/kexin type 9 inhibition in patients with atherosclerotic cardiovascular disease or in familial hypercholesterolaemia

A correction has been published: European Heart Journal, Volume 39, Issue 22, 7 June 2018, Pages 2105Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017.info:eu-repo/semantics/publishedVersio

Role of Suppressor of cytokine signalling 1 and 3 in Rhinovirus infection in vitro and in vivo

Rhinovirus (RV) infection is responsible for most asthma exacerbations. Defective RV induced interferon (IFN)-β and IFN-λs has been observed in asthmatic bronchial epithelial cells (BECs). Suppressors of cytokine signalling (SOCS) are negative regulators of cytokine signalling including IFNs. This study investigated the role of SOCS in the regulation of RV infection in vitro and in vivo using human BECs (HBECs) and mouse models of RV infection to determine whether SOCS were responsible for impaired IFN ex vivo. This was accomplished by measuring SOCS and IFN-β/λ mRNA and protein expression and IFN promoter activation. RV induced SOCS1 and SOCS3 mRNA and protein in HBECs and in lung from C57/Bl6 mice and SOCS1 mRNA in mouse BAL macrophages ex vivo. SOCS1 and SOCS3 acted as negative regulators of RV induced IFN-β and IFN-λ1 promoter activation in HBECs. SOCS1 protein was increased in bronchial biopsies from mild asthmatics compared to non-asthmatics. SOCS1 mRNA expression was increased in HBECs from severe asthmatic children compared to non-asthmatics. Increased SOCS1 mRNA levels negatively correlated with RV1B induced IFN-λ mRNA and positively correlated with RV16 release. RV1B induced IFN-β mRNA was increased in BAL macrophages from SOCS1-/- IFN-γ-/- mice compared to IFN-γ-/- mice. Upon induction of SOCS1 by IL-13 in IFN-γ-/- mice and subsequent RV1B infection, reduced IFN-α and IFN-λ protein in BAL was observed compared to SOCS1-/- IFN-γ-/- mice. This is the first report investigating SOCS1 and SOCS3 in relation to RV induced IFN responses. RV induced SOCS1 and SOCS3 in vitro, ex vivo and in vivo. SOCS3 negatively regulated RV induced IFN responses in vitro. SOCS1 negatively regulated RV induced IFN responses in vitro, ex vivo and in vivo. This is the first report finding an association between increased expression of a gene, SOCS1, with impaired IFN production and increased RV release in asthma

Splashing Drops

The outcome of a drop impact event depends on many parameters. In this thesis, we focused on how three different substrate properties influence the splashing behavior of impacting drops. These properties can be used to control splashing in the extreme ultraviolet (EUV) source chamber of lithography machines produced by ASML. We measured and modeled how the substrate orientation changes the outcome of a drop impact event onto a deep liquid pool. Both the splashing threshold and the direction at which the splashed droplets are ejected can be controlled by tuning the substrate orientation, the drop size and velocity. The temperature of a solid substrate is also found to influence drop impact behavior. On cold substrates, drop solidification limits its spreading diameter. For the drop splashing a two-fold behavior is observed: On the one hand the last observed deposition event is found at higher impact velocities as compared to isothermal impact due to energy loss by solidification. On the other hand the impact velocity at which the first splashing event is found decreases, as the solidified liquid forms irregularities on the substrate. Finally, we investigated how substrate elasticity can be used to suppress drop splashing, by studying the impact of drops onto an elastic membrane. The splashing threshold was found to increase with decreasing membrane tension. The velocity at which the membrane deforms and the maximal membrane deformation were measured from simultaneous profilometry measurements. These properties are then used in a model for drop splashing to explain the experimentally determined splashing threshold. In the EUV source chamber one can exploit these substrate properties to suppress drop splashing. Thereby, contamination formed by splashed drops can be minimized such that the source will operate at higher efficiency

DCE-MRI in Glioma, Infiltration Zone and Healthy Brain to Assess Angiogenesis: A Biopsy Study

Purpose: To explore the focal predictability of vascular growth factor expression and neovascularization using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in glioma. Methods: 120 brain biopsies were taken in vital tumor, infiltration zone and normal brain tissue of 30 glioma patients: 17 IDH(isocitrate dehydrogenase)-wildtype glioblastoma (GBM), 1 IDH-wildtype astrocytoma °III (together prognostic group 1), 3 IDH-mutated GBM (group 2), 3 anaplastic astrocytomas IDH-mutated (group 3), 4 anaplastic oligodendrogliomas and 2 low-grade oligodendrogliomas (together prognostic group 4). A mixed linear model evaluated the predictabilities of microvessel density (MVD), vascular area ratio (VAR), mean vessel size (MVS), vascular endothelial growth factor and receptors (VEGF-A, VEGFR‑2) and vascular endothelial-protein tyrosine phosphatase (VE-PTP) expression from Tofts model kinetic and model-free curve parameters. Results: All kinetic parameters were associated with VEGF‑A (all p < 0.001) expression. K trans, k ep and v e were associated with VAR (p = 0.006, 0.004 and 0.01, respectively) and MVS (p = 0.0001, 0.02 and 0.003, respectively) but not MVD (p = 0.84, 0.74 and 0.73, respectively). Prognostic groups differed in K trans (p = 0.007) and v e (p = 0.004) values measured in the infiltration zone. Despite significant differences of VAR, MVS, VEGF‑A, VEGFR‑2, and VE-PTP in vital tumor tissue and the infiltration zone (p = 0.0001 for all), there was no significant difference between kinetic parameters measured in these zones. Conclusion: The DCE-MRI kinetic parameters show correlations with microvascular parameters in vital tissue and also reveal blood-brain barrier abnormalities in the infiltration zones adequate to differentiate glioma prognostic groups

Experimental Rhinovirus Infection as a Human Model of Chronic Obstructive Pulmonary Disease Exacerbation

Rationale: Respiratory virus infections are associated with chronic obstructive pulmonary disease (COPD) exacerbations, but a causative relationship has not been proven. Studies of naturally occurring exacerbations are difficult and the mechanisms linking virus infection to exacerbations are poorly understood. We hypothesized that experimental rhinovirus infection in subjects with COPD would reproduce the features of naturally occurring COPD exacerbations and is a valid model of COPD exacerbations

TLR7 stimulation induced type I and III IFN in HBECs.

<p>Graphs depict IFN-β protein [A], IFN-β mRNA [B], IFN-λ protein [C], IFN-λ1 mRNA [D] and IFN-λ2/3 mRNA [E] at 24 h following stimulation with R848. Squares represent asthmatics, circles represent non-asthmatics. * = p<0.05, ** = p<0.01, *** = p<0.001.</p

TLR7 stimulation induced type I but not type III IFN in PBMCs.

<p>Graphs depict IFN-α protein production 8 h [A], 24 h [B] and 48 h [C] and IFN-β protein at 8 h [D], 24 h [E] and 48 h [F] post R848 stimulation. Squares represent asthmatics, circles represent non-asthmatics. * = p<0.05, ** = p<0.01, *** = p<0.001.</p

IL-6 induction following TLR stimulation in PBMCs.

<p>Graphs depict IL-6 production at 8 h following stimulation with PIC [A], R848 [D], LPS [G] and LPS [K], 24 h following PIC [B], R848 [E], LPS [H] and LPS [L] and 48 h following PIC [C], R848 [F], LPS [J] and LPS [M]. Squares represent asthmatics, circles represent non-asthmatics. * = p<0.05, ** = p<0.01, *** = p<0.001.</p