Explore the vast range of titles available.

Cigarette smoking is the leading cause of preventable death worldwide. It causes chronic lung disease and predisposes individuals to acute lung injury and pulmonary infection. Alveolar macrophages are sentinel cells strategically positioned in the interface between the airway lumen and the alveolar spaces. These are the most abundant immune cells and are the first line of defence against inhaled particulates and pathogens. Recently, there has been a better understanding about the ontogeny, phenotype and function of alveolar macrophages and their role, not only in phagocytosis, but also in initiating and resolving immune response. Many of the functions of the alveolar macrophage have been shown to be dysregulated following exposure to cigarette smoke. While the mechanisms for these changes remain poorly understood, they are important in the understanding of cigarette smoking-induced lung disease. We review the mechanisms by which smoking influences alveolar macrophage: (1) recruitment, (2) phenotype, (3) immune function (bacterial killing, phagocytosis, proteinase/anti-proteinase release and reactive oxygen species production) and (4) homeostasis (surfactant/lipid processing, iron homeostasis and efferocytosis). Further understanding of the mechanisms of cigarette smoking on alveolar macrophages and other lung monocyte/macrophage populations may allow novel ways of restoring cellular function in those patients who have stopped smoking in order to reduce the risk of subsequent infection or further lung injury.

Soluble salts and clays are major intrinsic causes of degradation of porous cultural heritage materials. Identifying their presence and concentrations can allow environmental control to prevent decay before it is observed. Such control is often energy- and carbon-intensive and better targeted towards those objects that require it rather than a general approach. The use of poultices has been investigated to determine salt species and concentrations in stone to replace drilling samples. A non-invasive method using two types of moisture meter has been developed to map the conductivity of salt solutions in stone. Fourier transform and near-infrared spectroscopies have been investigated to non-invasively quantify the amount of muscovite clay in limestones without the need to take drilled samples. Salts can react with extrinsic acetic acid from display and storage environments, causing extensive damaging surface efflorescences. A rapid analytical procedure based on external reflectance Fourier transform infra-red (FTIR) microscopy has been developed. This allows analysis of multiple salts on a cuneiform tablet surface. Analyses of soluble salts inside the tablets has indicated the sulphate-to-chloride ratio is a good predictor of whether mixed acetate efflorescences will occur on exposure.

This work explores the potential of using damage functions to assess cultural heritage environments. Changes caused by dimensional variation due to fluctuations in relative humidity are assessed using two accessible functions, and a third is discussed. The risk of mould growth is assessed from a time series of temperature and RH data. The results of previous studies comparing predictions from four functions to observed mould formation are reviewed, and the practical aspects of using the functions are described. Two situations related to metal and stone risk are described, comparing environments for display and assessing new or refitted buildings for storage. The use of functions to improve sustainability and their combination with performance models to predict carbon footprints are discussed.

The altered nature of archaeological metals means they deteriorate at much lower relative humidity (RH) conditions than historical metals. The study of deterioration for such materials is hampered by their complexity, variability and difficulties in measuring deterioration. Placing an object in a sealed container, controlling the RH and pollutant gases and measuring any decrease in oxygen concentration is an accessible method to measure the deterioration rate. It has been used for research into suitable environmental conditions to manage the deterioration rates of such artefacts, including the differences in the response of artefacts from different excavation sites. Some objects need the careful control of RH to low values; this is expensive to maintain and poses risks to other artefacts displayed together. Many objects are actually stable up to quite high RH values, and oxygen depletion testing has been used to identify those that can be safely displayed with minimal environmental control. The accelerated corrosion ‘Oddy’ test is frequently used to sift out unsuitable display materials. T the visual assessment is widely recognized to be subjective. the test container has been modified and oxygen depletion appears to give good quantitative measurements of corrosion that correspond with both visual comparison and corrosion loss measurement with linear stripping voltametry or chemical stripping for copper, lead and steel but not for silver.

ObjectiveVaping may increase the cytotoxic effects of e-cigarette liquid (ECL). We compared the effect of unvaped ECL to e-cigarette vapour condensate (ECVC) on alveolar macrophage (AM) function.MethodsAMs were treated with ECVC and nicotine-free ECVC (nfECVC). AM viability, apoptosis, necrosis, cytokine, chemokine and protease release, reactive oxygen species (ROS) release and bacterial phagocytosis were assessed.ResultsMacrophage culture with ECL or ECVC resulted in a dose-dependent reduction in cell viability. ECVC was cytotoxic at lower concentrations than ECL and resulted in increased apoptosis and necrosis. nfECVC resulted in less cytotoxicity and apoptosis. Exposure of AMs to a sub-lethal 0.5% ECVC/nfECVC increased ROS production approximately 50-fold and significantly inhibited phagocytosis. Pan and class one isoform phosphoinositide 3 kinase inhibitors partially inhibited the effects of ECVC/nfECVC on macrophage viability and apoptosis. Secretion of interleukin 6, tumour necrosis factor α, CXCL-8, monocyte chemoattractant protein 1 and matrix metalloproteinase 9 was significantly increased following ECVC challenge. Treatment with the anti-oxidant N-acetyl-cysteine (NAC) ameliorated the cytotoxic effects of ECVC/nfECVC to levels not significantly different from baseline and restored phagocytic function.ConclusionsECVC is significantly more toxic to AMs than non-vaped ECL. Excessive production of ROS, inflammatory cytokines and chemokines induced by e-cigarette vapour may induce an inflammatory state in AMs within the lung that is partly dependent on nicotine. Inhibition of phagocytosis also suggests users may suffer from impaired bacterial clearance. While further research is needed to fully understand the effects of e-cigarette exposure in humans in vivo, we caution against the widely held opinion that e-cigarettes are safe.

IntroductionPostoperative pulmonary complications (PPC) such as atelectasis and pneumonia are common following lung resection. PPCs have a significant clinical impact on postoperative morbidity and mortality. We studied the long-term effects of PPCs and sought to identify independent risk factors.MethodsA prospective observational study involved all patients following lung resection in a regional thoracic centre over 4 years. PPCs were assessed daily in hospital using the Melbourne group scale based on chest X-ray, white cell count, fever, purulent sputum, microbiology, oxygen saturations, physician diagnosis and intensive therapy unit (ITU)/high-dependency unit readmission. Follow-up included hospital length of stay (LOS), 30-day readmissions, and mortality.Results86 of 670 patients (13%) who had undergone a lung resection developed a PPC. Those patients had a significantly longer hospital LOS in days (13, 95% CI 10.5–14.9 vs 6.3, 95% CI 5.9 to 6.7; p<0.001) and higher rates of ITU admissions (28% vs 1.9%; p<0.001) and 30-day hospital readmissions (20.7% vs 11.9%; p<0.05). Significant independent risk factors for development of PPCs were COPD and smoking (p<0.05), not age. Excluding early postoperative deaths, developing a PPC resulted in a significantly reduced overall survival in months (40, 95% CI 34 to 44 vs 46, 95% CI 44 to 47; p=0.006). Those who developed a PPC had a higher rate of non-cancer-related deaths (11% vs 5%; p=0.020). PPC is a significant independent risk factor for late deaths in non-small cell lung cancer patients (HR 2.0, 95% CI 1.9 to 3.2; p=0.006).ConclusionsDeveloping a PPC after thoracic surgery is common and is associated with a poorer long-term outcome.

\"Science means constantly walking a tight rope\" Heinrich Rohrer, physicist, 1933. Community-acquired pneumonia (CAP) is the leading cause of death from infectious disease worldwide and disproportionately affects older adults and children. In high-income countries, pneumonia is one of the most common reasons for hospitalisation and (when recurrent) is associated with a risk of developing chronic pulmonary conditions in adulthood. Pneumococcal pneumonia is particularly prevalent in older adults, and here, pneumonia is still associated with significant mortality despite the widespread use of pneumococcal vaccination in middleand high-income countries and a low prevalence of resistant organisms. In older adults, 11% of pneumonia survivors are readmitted within months of discharge, often with a further pneumonia episode and with worse outcomes. In children, recurrent pneumonia occurs in approximately 10% of survivors and therefore is a significant cause of healthcare use. Current antibiotic trials focus on short-term outcomes and increasingly shorter courses of antibiotic therapy. However, the high requirement for further treatment for recurrent pneumonia questions the effectiveness of current strategies, and there is increasing global concern about our reliance on antibiotics to treat infections. Novel therapeutic targets and approaches are needed to improve outcomes. Neutrophils are the most abundant immune cell and among the first responders to infection. Appropriate neutrophil responses are crucial to host defence, as evidenced by the poor outcomes seen in neutropenia. Neutrophils from older adults appear to be dysfunctional, displaying a reduced ability to target infected or inflamed tissue, poor phagocytic responses and a reduced capacity to release neutrophil extracellular traps (NETs); this occurs in health, but responses are further diminished during infection and particularly during sepsis, where a reduced response to granulocyte colony-stimulating factor (G-CSF) inhibits the release of immature neutrophils from the bone marrow. Of note, neutrophil responses are similar in preterm infants. Here, the storage pool is decreased, neutrophils are less able to degranulate, have a reduced migratory capacity and are less able to release NETs. Less is known about neutrophil function from older children, but theoretically, impaired functions might increase susceptibility to infections. Targeting these blunted responses may offer a new paradigm for treating CAP, but modifying neutrophil behaviour is challenging; reducing their numbers or inhibiting their function is associated with poor clinical outcomes from infection. Uncontrolled activation and degranulation can cause significant host tissue damage. Any neutrophil-based intervention must walk the tightrope described by Heinrich Rohrer, facilitating necessary phagocytic functions while preventing bystander host damage, and this is a significant challenge which this review will explore.

RationaleVitamin D deficiency has been implicated as a pathogenic factor in sepsis and intensive therapy unit mortality but has not been assessed as a risk factor for acute respiratory distress syndrome (ARDS). Causality of these associations has never been demonstrated.ObjectivesTo determine if ARDS is associated with vitamin D deficiency in a clinical setting and to determine if vitamin D deficiency in experimental models of ARDS influences its severity.MethodsHuman, murine and in vitro primary alveolar epithelial cell work were included in this study.FindingsVitamin D deficiency (plasma 25(OH)D levels <50 nmol/L) was ubiquitous in patients with ARDS and present in the vast majority of patients at risk of developing ARDS following oesophagectomy. In a murine model of intratracheal lipopolysaccharide challenge, dietary-induced vitamin D deficiency resulted in exaggerated alveolar inflammation, epithelial damage and hypoxia. In vitro, vitamin D has trophic effects on primary human alveolar epithelial cells affecting >600 genes. In a clinical setting, pharmacological repletion of vitamin D prior to oesophagectomy reduced the observed changes of in vivo measurements of alveolar capillary damage seen in deficient patients.ConclusionsVitamin D deficiency is common in people who develop ARDS. This deficiency of vitamin D appears to contribute to the development of the condition, and approaches to correct vitamin D deficiency in patients at risk of ARDS should be developed.Trial registrationUKCRN ID 11994.

Background Type 2 alveolar epithelial cells (AT2s) behave as stem cells and show clonal proliferation upon alveolar injury followed by trans-differentiation (TD) into Type 1 alveolar epithelial cells (AT1s). In the present study we identified signaling pathways involved in the physiological AT2-to-AT1 TD process. Methods AT2 cells can be isolated from human lungs and cultured in vitro where they undergo TD into AT1s. In the present study we identified signaling pathways involved in the physiological AT2-to-AT1 TD process using Affymetrix microarray, qRT-PCR, fluorescence microscopy, and an in vitro lung aggregate culture. Results Affymetrix microarray revealed Wnt signaling to play a crucial role in the TD process. Wnt7a was identified as a ligand regulating the AT1 marker, Aquaporin 5 (AQP5). Artificial Neural Network (ANN) analysis of the Affymetrix data exposed ITGAV: Integrin alpha V (ITGAV), thrombospondin 1 (THBS1) and epithelial membrane protein 2 (EMP2) as Wnt signaling targets. Conclusions Wnt signaling targets that can serve as potential alveolar epithelial repair targets in future therapies of the gas exchange surface after injury. As ITGAV is significantly increases during TD and is regulated by Wnt signaling, ITGAV might be a potential target to speed up the alveolar healing process.

Neutrophil responses are critical during inflammatory and infective events, and neutrophil dysregulation has been associated with poor patient outcomes. Immunometabolism is a rapidly growing field that has provided insights into cellular functions in health and disease. Neutrophils are highly glycolytic when activated, with inhibition of glycolysis associated with functional deficits. There is currently very limited data available assessing metabolism in neutrophils. Extracellular flux (XF) analysis assesses real time oxygen consumption and the rate of proton efflux in cells. This technology allows for the automated addition of inhibitors and stimulants to visualise the effect on metabolism. We describe optimised protocols for an XFe96 XF Analyser to (i) probe glycolysis in neutrophils under basal and stimulated conditions, (ii) probe phorbol 12-myristate 13-acetate induced oxidative burst, and (iii) highlight challenges of using XF technology to examine mitochondrial function in neutrophils. We provide an overview of how to analyze XF data and identify pitfalls of probing neutrophil metabolism with XF analysis. In summary we describe robust methods for assessing glycolysis and oxidative burst in human neutrophils and discuss the challenges around using this technique to assess mitochondrial respiration. XF technology is a powerful platform with a user-friendly interface and data analysis templates, however we suggest caution when assessing neutrophil mitochondrial respiration.