TLR4 activation induces IL-1ss release via an IPAF dependent but caspase 1/11/8 independent pathway in the lung

Background: The IL-1 family of cytokines is known to play an important role in inflammation therefore understanding the mechanism by which they are produced is paramount. Despite the recent plethora of publications dedicated to the study of these cytokines, the mechanism by which they are produced in the airway following endotoxin, Lipopolysaccharide (LPS), exposure is currently unclear. The aim was to determine the mechanism by which the IL-1 cytokines are produced after LPS inhaled challenge. Methods:Mice were challenged with aerosolised LPS, and lung tissue and bronchiolar lavage fluid (BALF) collected. Targets were measured at the mRNA and protein level; caspase activity was determined using specific assays. Results: BALF IL-1b/IL-18, but not IL-1a, was dependent on Ice Protease-Activating Factor (IPAF), and to a lesser extent Apoptosis-associated Speck-like protein containing a CARD (ASC). Interestingly, although we measured an increase in mRNA expression for caspase 1 and 11, we could not detect an increase in lung enzyme activity or a role for them in IL-1a/b production. Further investigations showed that whilst we could detect an increase in caspase 8 activity at later points in the time course (during resolution of inflammation), it appeared to play no role in the production of IL-1 cytokines in this model system. Conclusions: TLR4 activation increases levels of BALF IL-1b/IL-18 via an IPAF dependent and caspase 1/11/8 independent pathway. Furthermore, it would appear that the presence of IL-1a in the BALF is independent of these pathways. This novel data sheds light on innate signalling pathways in the lung that control the production of these key inflammatory cytokines

The Formation of the Bicoid Morphogen Gradient Requires Protein Movement from Anteriorly Localized mRNA

New quantitative data show that the Bicoid morphogen gradient is generated from a dynamic localized source and that protein gradient formation requires protein movement along the anterior-posterior axis

Graphical User Interfaces: Mess them up!

Today's graphical user interfaces simulate a perfect world. Windows have always the same look and buttons have identical shapes and colors and are aligned to regular grids. The only distinction between graphical elements is their label. The current visual design of user interfaces ignores the capabilities of modern displays for an effective visual coding and the resulting uniformness makes it very difficult for the user to recognize graphical elements at first sight. This paper presents some ideas and propositions for the visual design and the 'look & feel'-concept of next generation user interfaces. New concepts for the layout and the visual coding of graphical elements are proposed. The suggested new layout and coding rules should help the user to recognize and remember graphical elements easily and to distinguish them from other elements of the same type. Keywords Graphical interaction, graphical user interfaces, human-computer interaction, visual design, visual coding, look & fee..

Mechanistic link between diesel exhaust particles and respiratory reflexes

Background: Diesel exhaust particles (DEP) are a major component of particulate matter in Europe’s largest cities and epidemiological evidence links exposure with respiratory symptoms and asthma exacerbations. Respiratory reflexes are responsible for symptoms and are regulated by vagal afferent nerves which innervate the airway. It is not known how DEP exposure activates airway afferents to elicit symptoms such as cough and bronchospasm. Objective: To identify the mechanisms involved in the activation of airway sensory afferents by DEPs. Methods: In this study we utilize in vitro and in vivo electrophysiological techniques including a unique model which assess depolarization (a marker of sensory nerve activation) of human vagus. Results: We demonstrate a direct interaction between DEP and airway C-fiber afferents. In anaesthetized guinea pigs, intratracheal administration of DEP activated airway C-fibers. The organic extract (DEP-OE), and not the cleaned particles, evoked depolarization of guinea-pig and human vagus and this was inhibited by a TRPA1 antagonist and the antioxidant N-acetyl cysteine (NAC). Polycyclic aromatic hydrocarbons (PAHs), major constituents of DEP, were implicated in this process via activation of the aryl hydrocarbon receptor (AhR) and subsequent mitochondrial ROS production, which is known to activate TRPA1 on nociceptive C-fibers. Conclusions: This study provides the first mechanistic insights into how exposure to urban air pollution leads to activation of guinea-pig and human sensory nerves which are responsible for respiratory symptoms. Mechanistic information will enable the development of appropriate therapeutic interventions and mitigation strategies for those susceptible individuals who are most at risk

Contemporary Outcomes After Partial Resection of Infected Aortic Grafts

Introduction: Aortic graft infection remains a considerable clinical challenge, and it is unclear which variables are associated with adverse outcomes among patients undergoing partial resection. Methods: A retrospective, multi-institutional study of patients who underwent partial resection of infected aortic grafts from 2002 to 2014 was performed using a standard database. Baseline demographics, comorbidities, operative, and postoperative variables were recorded. The primary outcome was mortality. Descriptive statistics, Kaplan-Meier (KM) survival analysis, and Cox regression analysis were performed. Results: One hundred fourteen patients at 22 medical centers in 6 countries underwent partial resection of an infected aortic graft. Seventy percent were men with median age 70 years. Ninety-seven percent had a history of open aortic bypass graft: 88 (77%) patients had infected aortobifemoral bypass, 18 (16%) had infected aortobiiliac bypass, and 1 (0.8%) had an infected thoracic graft. Infection was diagnosed at a median 4.3 years post-implant. All patients underwent partial resection followed by either extra-anatomic (47%) or in situ (53%) vascular reconstruction. Median follow-up period was 17 months (IQR 1, 50 months). Thirty-day mortality was 17.5%. The KM-estimated median survival from time of partial resection was 3.6 years. There was no significant survival difference between those undergoing in situ reconstruction or extra-anatomic bypass (P = 0.6). During follow up, 72% of repairs remained patent and 11% of patients underwent major amputation. On univariate Cox regression analysis, Candida infection was associated with increased risk of mortality (HR 2.4; P = 0.01) as well as aortoenteric fistula (HR 1.9, P = 0.03). Resection of a single graft limb only to resection of abdominal (graft main body) infection was associated with decreased risk of mortality (HR 0.57, P = 0.04), as well as those with American Society of Anesthesiologists classification less than 3 (HR 0.35, P = 0.04). Multivariate analysis did not reveal any factors significantly associated with mortality. Persistent early infection was noted in 26% of patients within 30 days postoperatively, and 39% of patients were found to have any post-repair infection during the follow-up period. Two patients (1.8%) were found to have a late reinfection without early persistent postoperative infection. Patients with any post-repair infection were older (67 vs . 60 years, P = 0.01) and less likely to have patent repairs during follow up (59% vs. 32%, P = 0.01). Patients with aortoenteric fistula had a higher rate of any post-repair infection (63% vs . 29%, P < 0.01) Conclusion: This large multi-center study suggests that patients who have undergone partial resection of infected aortic grafts may be at high risk of death or post-repair infection, especially older patients with abdominal infection not isolated to a single graft limb, or with Candida infection or aortoenteric fistula. Late reinfection correlated strongly with early persistent postoperative infection, raising concern for occult retained infected graft material