Impact of the local inflammatory environment on mucosal vitamin D metabolism and signaling in chronic inflammatory lung diseases

Vitamin D plays an active role in the modulation of innate and adaptive immune responses as well as in the protection against respiratory pathogens. Evidence for this immunomodulatory and protective role is derived from observational studies showing an association between vitamin D deficiency, chronic airway diseases and respiratory infections, and is supported by a range of experimental studies using cell culture and animal models. Furthermore, recent intervention studies have now shown that vitamin D supplementation reduces exacerbation rates in vitamin D-deficient patients with chronic obstructive pulmonary disease (COPD) or asthma and decreases the incidence of acute respiratory tract infections. The active vitamin D metabolite, 1,25-dihydroxy-vitamin D (1,25(OH)(2)D), is known to contribute to the integrity of the mucosal barrier, promote killing of pathogens (via the induction of antimicrobial peptides), and to modulate inflammation and immune responses. These mechanisms may partly explain its protective role against infections and exacerbations in COPD and asthma patients. The respiratory mucosa is an important site of local 1,25(OH)(2)D synthesis, degradation and signaling, a process that can be affected by exposure to inflammatory mediators. As a consequence, mucosal inflammation and other disease-associated factors, as observed in e.g., COPD and asthma, may modulate the protective actions of 1,25(OH)(2)D. Here, we discuss the potential consequences of various disease-associated processes such as inflammation and exposure to pathogens and inhaled toxicants on vitamin D metabolism and local responses to 1,25(OH)(2)D in both immune- and epithelial cells. We furthermore discuss potential consequences of disturbed local levels of 25(OH)D and 1,25(OH)(2)D for chronic lung diseases. Additional insight into the relationship between disease-associated mechanisms and local effects of 1,25(OH)(2)D is expected to contribute to the design of future strategies aimed at improving local levels of 1,25(OH)(2)D and signaling in chronic inflammatory lung diseases.Pathogenesis and treatment of chronic pulmonary disease

Impact of ischemic and valvular heart disease on atrial excitation

Background--The influence of underlying heart disease or presence of atrial fibrillation (AF) on atrial excitation during sinus rhythm (SR) is unknown. We investigated atrial activation patterns and total activation times of the entire atrial epicardial surface during SR in patients with ischemic and/or valvular heart disease with or without AF. Methods and Results--Intraoperative epicardial mapping (N=128/192 electrodes, interelectrode distances: 2 mm) of the right atrium, Bachmann's bundle (BB), left atrioventricular groove, and pulmonary vein area was performed during SR in 253 patients (186 male [74%], age 66±11 years) with ischemic heart disease (N=132, 52%) or ischemic valvular heart disease (N=121, 48%). As expected, SR origin was located at the superior intercaval region of the right atrium in 232 patients (92%). BB activation occurred via 1 wavefront from right-to-left (N=163, 64%), from the central part (N=18, 7%), or via multiple wavefronts (N=72, 28%). Left atrioventricular groove activation occurred via (1) BB: N=108, 43%; (2) pulmonary vein area: N=9, 3%; or (3) BB and pulmonary vein area: N=136, 54%; depending on which route had the shortest interatrial conduction time (P < 0.001). Ischemic valvular heart disease patients more often had central BB activation and left atrioventricular groove activation via pulmonary vein area compared with ischemic heart disease patients (N=16 [13%] versus N=2 [2%]; P=0.009 and N=86 [71%] versus N=59 [45%]; P < 0.001, respectively). Total activation times were longer in patients with AF (AF: 136±20 [92-186] ms; no AF: 114±17 [74-156] ms; P < 0.001), because of prolongation of right atrium (P=0.018) and BB conduction times (P < 0.001). Conclusions--Atrial excitation during SR is affected by underlying heart disease and AF, resulting in alternative routes for BB and left atrioventricular groove activation and prolongation of total activation times. Knowledge of atrial excitation patterns during SR and its electropathological variations, as demonstrated in this study, is essential to further unravel the pathogenesis of AF

QUest for the Arrhythmogenic Substrate of Atrial fibRillation in Patients Undergoing Cardiac Surgery (QUASAR Study): Rationale and Design

The heterogeneous presentation and progression of atrial fibrillation (AF) implicate the existence of different pathophysiological processes. Individualized diagnosis and therapy of the arrhythmogenic substrate underlying AF may be required to improve treatment outcomes. Therefore, this single-center study aims to identify t

A novel intra-operative, high-resolution atrial mapping approach

Purpose: A new technique is demonstrated for extensive high-resolution intra-operative atrial mapping that will facilitate the localization of atrial fibrillation (AF) sources and identification of the substrate perpetuating AF. Methods: Prior to the start of extra-corporal circulation, a 8 × 24-electrode array (2-mm inter-electrode distance) is placed subsequently on all the right and left epicardial atrial sites, including Bachmann’s bundle, for recording of unipolar electrograms during sinus rhythm and (induced) AF. AF is induced by high-frequency pacing at the right atrial free wall. A pacemaker wire stitched to the right atrium serves as a reference signal. The indifferent pole is connected to a steal wire fixed to subcutaneous tissue. Electrograms are recorded by a computerized mapping system and, after amplification (gain 1000), filtering (bandwidth 0.5–400 Hz), sampling (1 kHz) and analogue to digital conversion (16 bits), automatically stored on hard disk. During the mapping procedure, real-time visualization secures electrogram quality. Analysis will be performed offline. Results: This technique was performed in 168 patients of 18 years and older, with coronary and/or structural heart disease, with or without AF, electively scheduled for cardiac surgery and a ventricular ejection fraction above 40 %. The mean duration of the entire mapping procedure including preparation time was 9 ± 2 min. Complications related to the mapping procedure during or after cardiac surgery were not observed. Conclusions: We introduce the first epicardial atrial mapping approach with a high resolution of ≥1728 recording sites which can be performed in a procedure time of only 9±2 mins. This mapping technique can potentially identify areas responsible for initiation and persistence of AF and hopefully can individualize both diagnosis and therapy of AF

TGF-beta 1 Impairs Vitamin D-Induced and Constitutive Airway Epithelial Host Defense Mechanisms

Airway epithelium is an important site for local vitamin D (VD) metabolism; this can be negatively affected by inflammatory mediators. VD is an important regulator of respiratory host defense, for example, by increasing the expression of hCAP18/LL-37. TGF-beta 1 is increased in chronic obstructive pulmonary disease (COPD), and known to decrease the expression of constitutive host defense mediators such as secretory leukocyte protease inhibitor (SLPI) and polymeric immunoglobulin receptor (pIgR). VD has been shown to affect TGF-beta 1-signaling by inhibiting TGF-beta 1-induced epithelial-to-mesenchymal transition. However, interactions between VD and TGF-beta 1, relevant for the understanding host defense in COPD, are incompletely understood. Therefore, the aim of the present study was to investigate the combined effects of VD and TGF-beta 1 on airway epithelial cell host defense mechanisms. Exposure to TGF-beta 1 reduced both baseline and VD-induced expression of hCAP18/LL-37, partly by increasing the expression of the VD-degrading enzyme CYP24A1. TGF-beta 1 alone decreased the number of secretory club and goblet cells and reduced the expression of constitutive host defense mediators SLPI, s/lPLUNC and pIgR, effects that were not modulated by VD. These results suggest that TGF-beta 1 may decrease the respiratory host defense both directly by reducing the expression of host defense mediators, and indirectly by affecting VD-mediated effects such as expression of hCAP18/LL-37.Pathogenesis and treatment of chronic pulmonary disease

Networking by small-molecule hormones in plant immunity

Plants live in complex environments in which they intimately interact with a broad range of microbial pathogens and insect herbivores with different lifestyles and infection or feeding strategies. The evolutionary arms race between plants and their attackers provided plants with a sophisticated defense system that, like the animal innate immune system, recognizes the attacker and responds by activating specific defenses that are specifically directed against the invader. Recent advances in plant immunity research provided exciting new insights into the underlying defense signaling network. Diverse small-molecule hormones play pivotal roles in the regulation of this network. Their signaling pathways cross-communicate in an antagonistic or synergistic manner, providing the plant with a powerful capacity to finely tailor its immune response to the attacker encountered. Pathogens and insects, on the other hand, can manipulate the plant’s defense signaling network for their own benefit by affecting phytohormone homeostasis to antagonize the host immune response

PTSD Symptom dynamics after the great east japan earthquake: mapping the temporal structure using Dynamic Time Warping

Background: After the Great East Japan Earthquake [GEJE], approximately 70,000 Japan Ground Self Defense Force [JGSDF] personnel were deployed, risking Post-Traumatic Stress Disorder [PTSD]. The network approach to psychopathology suggests that symptoms may cause and exacerbate each other, resulting in the emergence and maintenance of disorders, including PTSD. It is therefore important to further explore the temporal interplay between symptoms. Most studies assessing the factor structure of the Impact of Event Scale-Revised [IES-R] have used cross-sectional designs. In this study, the structure of the IES-R was re-evaluated while incorporating the temporal interplay between symptoms. Methods: Using Dynamic Time Warping [DTW] the distances between PTSD symptoms on the IES-R were modelled in 1120 JGSDF personnel. Highly correlated symptoms were clustered at the group level using Distatis three-way principal component analyses of the distance matrices. The resulting clusters were compared to the original three subscales of the IES-R using a Confirmatory Factor Analysis (CFA). Results: The DTW analysis yielded four symptom clusters: Intrusion (five items), Hyperarousal (six items), Avoidance (six items), and Dissociation (five items). CFA yielded better fit estimates for this four-factor solution (RMSEA = 0.084, CFI = 0.918, TLI = 0.906), compared to the original three subscales of the IES-R (RMSEA = 0.103, CFI = 0.873, TLI = 0.858). Conclusions: DTW offers a new method of modelling the temporal relationships between symptoms. It yielded four IES-R symptom clusters, which may facilitate understanding of PTSD as a complex dynamic system