Acute intestinal inflammation involves early accumulation of neutrophils (PMNs) followed by either resolution or progression to chronic inflammation. Based on recent evidence that mucosal metabolism ...influences disease outcomes, we hypothesized that transmigrating PMNs influence the transcriptional profile of the surrounding mucosa. Microarray studies revealed a cohort of hypoxia-responsive genes regulated by PMN-epithelial crosstalk. Transmigrating PMNs rapidly depleted microenvironmental O2 sufficiently to stabilize intestinal epithelial cell hypoxia-inducible factor (HIF). By utilizing HIF reporter mice in an acute colitis model, we investigated the relative contribution of PMNs and the respiratory burst to “inflammatory hypoxia” in vivo. CGD mice, lacking a respiratory burst, developed accentuated colitis compared to control, with exaggerated PMN infiltration and diminished inflammatory hypoxia. Finally, pharmacological HIF stabilization within the mucosa protected CGD mice from severe colitis. In conclusion, transcriptional imprinting by infiltrating neutrophils modulates the host response to inflammation, via localized O2 depletion, resulting in microenvironmental hypoxia and effective inflammatory resolution.
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•Infiltrating PMNs consume sufficient O2 to render adjacent colonic epithelia hypoxic•Hypoxia reporter mice demonstrate PMN-dependent hypoxia in inflamed colitic lesions•CGD mice do not incite mucosal hypoxia and develop severe nonresolving colitis•Mucosal HIF stabilization ameliorates colitis severity in wild-type and CGD mice
Obstructive sleep apnoea (OSA) is associated with significantly increased risk of cardiovascular disease. Carotid ultrasonography and retrospective, uncontrolled, coronary imaging studies have ...suggested an association of OSA with subclinical atherosclerosis, but there is a lack of prospective, controlled studies directly evaluating the relationship of OSA with occult coronary artery disease. We performed coronary computed tomographic angiography and inpatient-attended sleep studies on a cohort of otherwise healthy males attending our sleep laboratory, and compared coronary artery plaque volume between subjects with low and high apnoea/hypopnoea index (AHI) scores. 29 subjects participated. The median AHI was 15.5 events · h(-1), with subjects who scored above this classified as high AHI. No significant differences were observed in demographic, anthropometric and clinical variables between the high- and low-AHI groups. Coronary plaque volume was significantly greater in the high-AHI group (mean plaque volume 2.6 ± 0.7 mm(2) versus 0.8 ± 0.2 mm(2); p=0.017) and, furthermore, correlated significantly with AHI (Spearman's r=0.433; p=0.019). Following adjustment for dyslipidaemia and fasting plasma glucose levels, AHI remained a significant predictor of plaque volume (standardised β=0.424; p=0.027). In this prospective case-control study, we found that severity of OSA may predict occult coronary atherosclerosis in otherwise healthy overweight or obese male subjects.
Nitric oxide (NO{bullet}) competitively inhibits oxygen consumption by mitochondria at cytochrome c oxidase and S-nitrosates thiol proteins. We developed mitochondria-targeted S-nitrosothiols ...(MitoSNOs) that selectively modulate and protect mitochondrial function. The exemplar MitoSNO1, produced by covalently linking an S-nitrosothiol to the lipophilic triphenylphosphonium cation, was rapidly and extensively accumulated within mitochondria, driven by the membrane potential, where it generated NO{bullet} and S-nitrosated thiol proteins. MitoSNO1-induced NO{bullet} production reversibly inhibited respiration at cytochrome c oxidase and increased extracellular oxygen concentration under hypoxic conditions. MitoSNO1 also caused vasorelaxation due to its NO{bullet} generation. Infusion of MitoSNO1 during reperfusion was protective against heart ischemia-reperfusion injury, consistent with a functional modification of mitochondrial proteins, such as complex I, following S-nitrosation. These results support the idea that selectively targeting NO{bullet} donors to mitochondria is an effective strategy to reversibly modulate respiration and to protect mitochondria against ischemia-reperfusion injury.
Although widely accepted as a water sterilisation technique, chlorination results in the production of potentially harmful by-products, mainly Trihalomethanes. Furthermore, the chlorination process ...requires specialised infrastructure, management and high costs. In this research paper a potential alternative sterilisation technique was investigated. This rapid three-step process utilized Goethite Nanoparticles and the photosensitising capabilities of a xanthene dye. Rose Bengal (RB) a compound primarily used as a stain to diagnose damaged tissue in the eye was utilized under visible light excitation to sterilise water containing gram-positive Staphylococcus aureus and Bacillus cereus. Bacterial reductions (cfu/ml) of up to 6log10 are reported at RB concentrations of 0.5 mg/L and 10 mg/L for S. aureus and B. cereus, respectively. Goethite Nanoparticles (GNP's), an iron oxyhydroxide, were synthesised by co-precipitation of iron salts and used to adsorb RB post-sterilisation. Poly-vinyl Alcohol (PVA) functionalised GNP's were synthesised to highlight the adsorbent capabilities of the GNP surface. The adsorption capacity for uncoated GNPs was 476.19 mg/g, this reduced to 170.4 mg/g for PVA-GNP's, highlighting the highly porous nature of the synthesised GNP surface. Adsorption was optimal in slightly acidic conditions (pH5-6). The adsorption parameters best followed Lagergens Pseudo-second order kinetics with correlation coefficients close to unity. At the highest envisaged RB concentration (10 mg/L) approximately 20 mg/L GNP's was required to remove the dye from solution post-treatment. Flame Atomic Absorption analysis of the water post-removal revealed Iron concentrations of 0.058 mg/L. This correlates to removal efficacy of 99.71% with residual iron levels below the EU recommended limit of 0.2 mg/L.
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•Magnetic nanoparticle/Photosensitiser combination for sterilized water.•Photocatalytic Bacterial reductions of 6 log utilizing two Gram-positive strains.•Porous goethite nanoparticles with a maximum adsorption capacity of 467.62 mg/g.•Minimal Photosentizer or nanoparticle residues post treatment.•Nano Particle Removal efficiency of 99.71%.
Mitochondrial biogenesis occurs in response to increased cellular ATP demand. The mitochondrial electron transport chain requires molecular oxygen to produce ATP. Thus, increased ATP generation after ...mitochondrial biogenesis results in increased oxygen demand that must be matched by a corresponding increase in oxygen supply. We found that overexpression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), which increases mitochondrial biogenesis in primary skeletal muscle cells, leads to increased expression of a cohort of genes known to be regulated by the dimeric hypoxia-inducible factor (HIF), a master regulator of the adaptive response to hypoxia. PGC-1α-dependent induction of HIF target genes under physiologic oxygen concentrations is not through transcriptional coactivation of HIF or up-regulation of HIF-1α mRNA but through HIF-1α protein stabilization. It occurs because of intracellular hypoxia as a result of increased oxygen consumption after mitochondrial biogenesis. Thus, we propose that at physiologic oxygen concentrations, PGC-1α is coupled to HIF signaling through the regulation of intracellular oxygen availability, allowing cells and tissues to match increased oxygen demand after mitochondrial biogenesis with increased oxygen supply.
Hypoxia is a feature of the microenvironment in a number of chronic inflammatory conditions due to increased metabolic activity and disrupted perfusion at the inflamed site. Hypoxia contributes to ...inflammation through the regulation of gene expression via key oxygen-sensitive transcriptional regulators including the hypoxia-inducible factor (HIF) and NF-κB. Recent studies have revealed a high degree of interdependence between HIF and NF-κB signaling; however, the relative contribution of each to hypoxia-induced inflammatory gene expression remains unclear. In this study, we use transgenic mice expressing luciferase under the control of NF-κB to demonstrate that hypoxia activates NF-κB in the heart and lungs of mice in vivo. Using small interfering RNA targeted to the p65 subunit of NF-κB, we confirm a unidirectional dependence of hypoxic HIF-1α accumulation upon an intact canonical NF-κB pathway in cultured cells. Cyclooxygenase-2 and other key proinflammatory genes are transcriptionally induced by hypoxia in a manner that is both HIF-1 and NF-κB dependent, and in mouse embryonic fibroblasts lacking an intact canonical NF-κB pathway, there is a loss of hypoxia-induced inflammatory gene expression. Finally, under conditions of hypoxia, HIF-1α and the p65 subunit of NF-κB directly bind to the cyclooxygenase-2 promoter. These results implicate an essential role for NF-κB signaling in inflammatory gene expression in response to hypoxia both through the regulation of HIF-1 and through direct effects upon target gene expression.
Obstructive sleep apnoea (OSA) is a growing and serious worldwide health problem with significant health and socioeconomic consequences. Current diagnostic testing strategies are limited by cost, ...access to resources and over reliance on one measure, namely the apnoea-hypopnoea frequency per hour (AHI). Recent evidence supports moving away from the AHI as the principle measure of OSA severity towards a more personalised approach to OSA diagnosis and treatment that includes phenotypic and biological traits. Novel advances in technology include the use of signals such as heart rate variability (HRV), oximetry and peripheral arterial tonometry (PAT) as alternative or additional measures. Ubiquitous use of smartphones and developments in wearable technology have also led to increased availability of applications and devices to facilitate home screening of at-risk populations, although current evidence indicates relatively poor accuracy in comparison with the traditional gold standard polysomnography (PSG). In this review, we evaluate the current strategies for diagnosing OSA in the context of their limitations, potential physiological targets as alternatives to AHI and the role of novel technology in OSA. We also evaluate the current evidence for using newer technologies in OSA diagnosis, the physiological targets such as smartphone applications and wearable technology. Future developments in OSA diagnosis and assessment will likely focus increasingly on systemic effects of sleep disordered breathing (SDB) such as changes in nocturnal oxygen and blood pressure (BP); and may also include other factors such as circulating biomarkers. These developments will likely require a re-evaluation of the diagnostic and grading criteria for clinically significant OSA.
Life cycle assessment (LCA) provides holistic information on systems including the trade-offs between environmental impacts and the drivers of such impacts. Coupling life cycle assessment with a ...decision analysis (DA) method can help ensure that a life cycle assessment is focused on pertinent decision performance measures. In this paper, a framework integrating life cycle assessment with a decision analysis method to enhance the application of life cycle assessment is presented with a real-world case study of developing a material inclusion criterion for sustainable electronics standards. The proposed DA-LCA framework is a five-step process that tracks the flow of information between the steps of decision analysis and life cycle assessment. The case study considered the level of post-consumer-recycled or biobased content in laptop enclosures. Elicitation with a mock stakeholder panel was used to structure a means-ends network and create a utility-based influence diagram to link changes in material inclusion to environmental objectives using life cycle impact scores. Unlike typical life cycle assessment, the decision analysis approach allows for explicit incorporation of non-environmental factors and better constrains product options. Using this approach, the optimum decision for a possible range of 0–30% material content is 5% or 10%, depending on weighting. The DA-LCA framework can provide a blueprint for placing life cycle assessment results in context for decision-makers.
•A framework implementing life cycle assessment within decision analysis is proposed and demonstrated.•Interpretation and visualization of life cycle assessment results is improved using an influence diagram.•Contextual aspects that matter to decision-makers are included to enhance life cycle assessment for product standards.•Case study results show criteria adoption rates are key for environmental product standards.
Summary
Side‐effects directly due to the nasal mask are common in patients with obstructive sleep apnoea syndrome (OSAS) commencing continuous positive airway pressure (CPAP). Recently, nasal pillows ...have been designed to overcome these issues. Limited evidence exists of the benefits and effectiveness of these devices. Twenty‐one patients (19 male, 49 ± 10 years) with the established diagnosis of OSAS apnoea/hypopnoea index (AHI): 52 ± 22 and who had a successful CPAP titration were commenced on CPAP therapy (10 ± 2 cmH2O), and randomized to 4 weeks of a nasal pillow (P) and a standard nasal mask (M) in a crossover design. Outcome measures were objective compliance, AHI, quality of life, Epworth Sleepiness Score (ESS) and CPAP side‐effects. There was no difference in compliance (M versus P: 5.1 ± 1.9 h versus 5.0 ± 1.7 h; P = 0.701) and AHI (2.6 ± 2.7 versus 3.0 ± 2.9; P = 0.509). Quality of life and ESS improved with CPAP, but there was no difference in the extent of improvement between both devices. Usage of nasal pillows resulted in less reported pressure on the face and more subjects found the nasal pillow the more comfortable device. However, there was no clear overall preference for either device at the end of the study (mask = 57%, pillow = 43%; P = 0.513). The applied CPAP pressure did not correlate with compliance, AHI and ESS. Furthermore, no differences in outcome parameters were noted comparing groups with CPAP pressure <10 and ≥10 cm H2O. Nasal pillows are equally effective in CPAP therapy, but do not generally lead to improved compliance.
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