Remodeling of an in vitro microvessel exposed to cyclic mechanical stretch.

In the lung, vascular endothelial cells experience cyclic mechanical strain resulting from rhythmic breathing motions and intraluminal blood pressure. Mechanical stress creates evident physiological, morphological, biochemical, and gene expression changes in vascular endothelial cells. However, the exact mechanisms of the mechanical signal transduction into biological response remain to be clarified. Besides, the level of mechanical stress is difficult to determine due to the complexity of the local distension patterns in the lung and thus assumed to be the same as the one acting on the alveolar epithelium. Existing in vitro models used to investigate the effect of mechanical stretch on endothelial cells are usually limited to two-dimensional (2D) cell culture platforms, which poorly mimic the typical three-dimensional structure of the vessels. Therefore, the development of an advanced in vitro vasculature model that closely mimics the dynamic of the human lung vasculatures is highly needed. Here, we present the first study that investigates the interplay of the three-dimensional (3D) mechanical cyclic stretch and its magnitude with vascular endothelial growth factor (VEGF) stimulation on a 3D perfusable vasculature in vitro. We studied the effects of the cyclic strain on a perfusable 3D vasculature, either made of human lung microvascular endothelial cells or human umbilical vein endothelial cells embedded in a gel layer. The in vitro 3D vessels underwent both in-vivo-like longitudinal and circumferential deformations, simultaneously. Our results showed that the responses of the human lung microvascular endothelial cells and human umbilical vein endothelial cells to cyclic stretch were in good agreement. Although our 3D model was in agreement with 2D model in predicting a cytoskeletal remodeling in response to different magnitudes of cyclic stretch, however we observed several phenomena in 3D model that 2D model was unable to predict to. Angiogenic sprouting induced by VEGF decreased significantly in presence of cyclic stretch. Similarly, while treatment with VEGF increased vascular permeability, the cyclic stretch restored vascular barrier tightness and significantly decreased vascular permeability. One of the major findings of this study was that a 3D microvasculature can be exposed to a much higher mechanical cyclic stress level than reported in the literature without any dysfunction of its barrier. For higher magnitudes of the cyclic stretch, the applied longitudinal strain level was 14% and the associated circumferential strain reached the equivalent of 63%. In sharp contrast with our findings, such strain typically leads to the disruption of the endothelial barrier in a 2D stretching assay and is considered pathological. This highlights the importance of 3D modeling to investigate mechanobiology effects rather than using a simple endothelial monolayer which truly recapitulates the in vivo situation

Azithromycin for the Treatment of Chronic Cough in Idiopathic Pulmonary Fibrosis: A Randomized Controlled Cross-over Trial.

RATIONALE Patients with idiopathic pulmonary fibrosis (IPF) frequently suffer from difficult to treat chronic cough, which substantially affects their quality of life. Azithromycin has been demonstrated to relieve chronic cough in some populations, however this has not been investigated in IPF. OBJECTIVES To determine the safety and efficacy of azithromycin for the treatment of chronic cough in patients with IPF. METHODS In a double-blind randomized controlled cross-over trial, patients with IPF underwent two 12-week intervention periods (azithromycin 500mg or placebo 3 times per week). The primary outcome was change in cough-related quality of life measured by the Leicester cough questionnaire (LCQ). Secondary outcomes included cough severity measured using Visual Analog Scale (VAS), health-related quality of life assessed by the St. George's Respiratory Questionnaire (SGRQ), and objective cough frequency using audiovisual readings from 24h respiratory polygraphy. RESULTS 25 patients were randomized (23 men, 2 women), 20 patients completed the study. Mean (standard deviation, SD) age was 67 (8) years, mean (SD) forced vital capacity (FVC) was 65 (16) %-predicted, and diffusion capacity (DLCO) 43 (16) %-predicted. Mean (SD) baseline LCQ was 11.7 (3.7) and 11.3 (3.3) for the azithromycin and the placebo period, respectively, and the corresponding mean (SD) cough VAS 5.6 (2.3) and 5.8 (2.1). There was no significant change in LCQ and VAS with azithromycin or placebo. Similarly, there was no significant difference in change in polygraphy measured cough frequency between the azithromycin and placebo periods. Gastrointestinal adverse effects were more frequent with azithromycin than with placebo (diarrhea 43% vs 5%, p=0.03). CONCLUSIONS This randomized controlled trial does not support the use of low dose azithromycin for chronic cough in patients with IPF. Clinical trial registered with ClinicalTrials.gov (NCT02173145)

Serum calprotectin as new biomarker for disease severity in idiopathic pulmonary fibrosis: a cross-sectional study in two independent cohorts

Background: Non-invasive biomarkers for the assessment of disease severity in idiopathic pulmonary fibrosis (IPF) are urgently needed. Calprotectin belongs to the S-100 proteins produced by neutrophils, which likely contribute to IPF pathogenesis. Calprotectin is a well-established biomarker in inflammatory bowel diseases. In this cross-sectional study, we aimed to establish the potential role of calprotectin as a biomarker in IPF. Specifically, we hypothesised that patients with IPF have higher serum calprotectin levels compared with healthy controls, and that calprotectin levels are associated with disease severity. Methods: Blood samples were obtained from healthy volunteers (n=26) and from two independent IPF cohorts (derivation cohort n=26, validation cohort n=66). Serum calprotectin levels were measured with a commercial kit adapted for that purpose and compared between healthy controls and patients with IPF. Clinical parameters, including forced vital capacity, diffusing capacity for carbon monoxide (DLCO) and the Composite Physiologic Index (CPI), were correlated with calprotectin serum levels. Results: The IPF derivation cohort showed increased serum calprotectin levels compared with healthy controls (2.47 +/- 1.67 vs 0.97 +/- 0.53 mu g/mL, p<0.001). In addition, serum calprotectin levels correlated with DLCO% predicted (r=-0.53, p=0.007) and with CPI (r=0.66, p=0.007). These findings were confirmed in an independent IPF validation cohort. Conclusion: Serum calprotectin levels are significantly increased in patients with IPF compared with healthy controls and correlate with DLCO and CPI. Calprotectin might be a potential new biomarker for disease severity in IPF

Frailty assessment for COVID-19 follow-up: a prospective cohort study.

BACKGROUND The Clinical Frailty Scale (CFS) is increasingly used for clinical decision making in acute care but little is known about frailty after COVID-19. OBJECTIVES To investigate frailty and the CFS for post-COVID-19 follow-up. METHODS This prospective multicentre cohort study included COVID-19 survivors aged ≥50 years presenting for a follow-up visit ≥3 months after the acute illness. Nine centres retrospectively collected pre-COVID-19 CFS and prospectively CFS at follow-up. Three centres completed the Frailty Index (FI), the short physical performance battery (SPPB), 30 s sit-to-stand test and handgrip strength measurements. Mixed effect logistic regression models accounting for repeated measurements and potential confounders were used to investigate factors associated with post-COVID-19 CFS. Criterion and construct validity were determined by correlating the CFS to other concurrently assessed frailty measurements and measures of respiratory impairment, respectively. RESULTS Of the 288 participants 65% were men, mean (SD) age was 65.1 (9) years. Median (IQR) CFS at follow-up was 3 (2-3), 21% were vulnerable or frail (CFS ≥4). The CFS was responsive to change, correlated with the FI (r=0.69, p<0.001), the SPPB score (r=-0.48, p<0.001) (criterion validity) and with the St George's Respiratory Questionnaire score (r=0.59, p<0.001), forced vital capacity %-predicted (r=-0.25, p<0.001), 6 min walk distance (r=-0.39, p<0.001) and modified Medical Research Council (mMRC) (r=0.59, p<0.001). Dyspnoea was significantly associated with a higher odds for vulnerability/frailty (per one mMRC adjusted OR 2.01 (95% CI 1.13 to 3.58), p=0.02). CONCLUSIONS The CFS significantly increases with COVID-19, and dyspnoea is an important risk factor for post-COVID-19 frailty and should be addressed thoroughly

Electronic Structure Calculation by First Principles for Strongly Correlated Electron Systems

Recent trends of ab initio studies and progress in methodologies for electronic structure calculations of strongly correlated electron systems are discussed. The interest for developing efficient methods is motivated by recent discoveries and characterizations of strongly correlated electron materials and by requirements for understanding mechanisms of intriguing phenomena beyond a single-particle picture. A three-stage scheme is developed as renormalized multi-scale solvers (RMS) utilizing the hierarchical electronic structure in the energy space. It provides us with an ab initio downfolding of the global band structure into low-energy effective models followed by low-energy solvers for the models. The RMS method is illustrated with examples of several materials. In particular, we overview cases such as dynamics of semiconductors, transition metals and its compounds including iron-based superconductors and perovskite oxides, as well as organic conductors of kappa-ET type.Comment: 44 pages including 38 figures, to appear in J. Phys. Soc. Jpn. as an invited review pape

Feeding into old age: long-term effects of dietary fatty acid supplementation on tissue composition and life span in mice

Smaller mammals, such as mice, possess tissues containing more polyunsaturated fatty acids (PUFAs) than larger mammals, while at the same time live shorter lives. These relationships have been combined in the ‘membrane pacemaker hypothesis of aging’. It suggests that membrane PUFA content might determine an animal’s life span. PUFAs in general and certain long-chain PUFAs in particular, are highly prone to lipid peroxidation which brings about a high rate of reactive oxygen species (ROS) production. We hypothesized that dietary supplementation of either n-3 or n-6 PUFAs might affect (1) membrane phospholipid composition of heart and liver tissues and (2) life span of the animals due to the altered membrane composition, and subsequent effects on lipid peroxidation. Therefore, we kept female laboratory mice from the C57BL/6 strain on three diets (n-3 PUFA rich, n-6 PUFA rich, control) and assessed body weights, life span, heart, and liver phospholipid composition after the animals had died. We found that while membrane phospholipid composition clearly differed between feeding groups, life span was not directly affected. However, we were able to observe a positive correlation between monounsaturated fatty acids in cardiac muscle and life span

Constraints on the χ_(c1) versus χ_(c2) polarizations in proton-proton collisions at √s = 8 TeV

The polarizations of promptly produced χ_(c1) and χ_(c2) mesons are studied using data collected by the CMS experiment at the LHC, in proton-proton collisions at √s=8  TeV. The χ_c states are reconstructed via their radiative decays χ_c → J/ψγ, with the photons being measured through conversions to e⁺e⁻, which allows the two states to be well resolved. The polarizations are measured in the helicity frame, through the analysis of the χ_(c2) to χ_(c1) yield ratio as a function of the polar or azimuthal angle of the positive muon emitted in the J/ψ → μ⁺μ⁻ decay, in three bins of J/ψ transverse momentum. While no differences are seen between the two states in terms of azimuthal decay angle distributions, they are observed to have significantly different polar anisotropies. The measurement favors a scenario where at least one of the two states is strongly polarized along the helicity quantization axis, in agreement with nonrelativistic quantum chromodynamics predictions. This is the first measurement of significantly polarized quarkonia produced at high transverse momentum