Neutrophils traversing the pulmonary microcirculation are subjected to mechanical stimulation during their deformation into narrow capillaries. To better understand the time-dependant changes caused by this mechanical stimulus, neutrophils were caused to flow into a microchannel, which allowed simultaneous visualization of cell morphology and passive rheological measurement by tracking the Brownian motion of endogenous granules. Above a threshold stimulus, mechanical deformation resulted in neutrophil activation with pseudopod projection. The activation time was inversely correlated to the rate of mechanical deformation experienced by the neutrophils. A reduction in shear moduli was observed within seconds after the onset of the mechanical stimulus, suggesting a sudden disruption of the neutrophil cytoskeleton when subjected to mechanical deformation. However, the magnitude of the reduction in moduli was independent of the degree of deformation. Recovery to nearly the initial values of viscoelastic moduli occurred within 1 min. These observations confirm that mechanical deformation of neutrophils, similar to conditions encountered in the pulmonary capillaries, is not a passive event; rather, it is capable of activating the neutrophils and enhancing their migratory tendencies.

Neutrophils are subjected to mechanical stimulation as they deform into the narrow capillary segments of the pulmonary microcirculation. The present study seeks to understand the changes in the cytoskeletal structure and the extent of biological activation as a result of this process. Neutrophils were passed through narrow polycarbonate filter pores under physiological driving pressures, fixed, and stained downstream to visualize the F-actin content and distribution. Below a threshold capillary size, the cell remodeled its cytoskeleton through initial F-actin depolymerization, followed by recovery and increase in F-actin content associated with formation of pseudopods. This rapid depolymerization and subsequent recovery of F-actin was consistent with our previous observation of an immediate reduction in moduli with eventual recovery when the cells were subjected to deformation. Results also show that neutrophils must be retained in their elongated shape for an extended period of time for pseudopod formation, suggesting that a combination of low driving pressures and small capillary diameters promotes cellular activation. These observations show that mechanical deformation of neutrophils into narrow pulmonary capillaries have the ability to influence cytoskeletal structure, the degree of cellular activation, and migrational tendencies of the cells.

No abstract

Background There is limited real-life evidence with brodalumab in patients with plaque psoriasis in Canada. Objectives To examine real-world effectiveness of brodalumab in Canadian routine care with a focus on clinician and patient-reported outcomes, as well as measuring continuation rates and persistency. Methods Retrospective analysis was conducted on data collected through the brodalumab patient support program (PSP) in Canada for patients initiating brodalumab between June 2018 (PSP launch)- June 2020 with a minimum of 16 weeks follow-up from first dose. Effectiveness was assessed by improvements in PASI, BSA and DLQI; continuation rates and persistency on therapy were reported. Results Overall, 864 patients (male, 59%; median age, 52 years) were included in the analysis. In a subset of patients with both baseline and follow-up scores, statistically significant improvements were observed: PASI improved from 13.9 to 1.8, BSA improved from 16.6% to 2.5% and DLQI improved from 16.2 to 2.9. Brodalumab demonstrated high continuation rates (89.9%), with similar rates in biologic-naïve and biologic-experienced patients (92.1% and 88.6%, respectively) and in patients who received secukinumab or ixekizumab as their most recent biologic therapy (89.0% and 86.2%, respectively). Persistence at 6, 12, and 18 months was 82.0%, 69.9%, and 63.4%, respectively. Conclusions The effectiveness of brodalumab was demonstrated in this Canadian routine care study, with significant improvements in disease severity and patient-reported outcomes. High continuation rates were achieved; including in patients previously treated with IL-17A inhibitors. Future studies will provide further evidence of brodalumab’s benefits for the management of plaque psoriasis in the real-world setting.

A prominent feature of Hutchinson‐Gilford Progeria Syndrome (HGPS) is premature, severe atherosclerosis, resulting in fatal heart attacks and strokes. Given the critical role of endothelial dysfunction in atherogenesis, we explored the effects of progerin (the mutant gene product in HGPS) on endothelial pathobiology, utilizing a model system in which cultured human endothelial cells (EC) express progerin via adenoviral infection. Progerin accumulation in EC results in a strikingly abnormal nuclear morphology, observed as aggregation of progerin and other nuclear proteins. Accumulation of progerin also induces a proinflammatory/atherogenic program of EC activation characterized by 1) sustained expression of leukocyte adhesion molecules (VCAM‐1, E‐selectin) and proinflammatory cytokines (IL‐8, MCP‐1); 2) expression of prothrombotic genes (PAI‐1); 3) decreased expression of eNOS; and 4) downregulation of KLF2, a transcription factor critical to endothelial homeostasis. Further, conditioned medium from progerin‐expressing EC induces dysfunction when transferred onto control EC. Thus, progerin accumulation in EC appears to induce a state of chronic dysfunction, via autocrine/paracrine pathways, potentially contributing to the premature and accelerated atherosclerosis of HGPS.