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Journal articleMohamed NA, Davies RP, Lickiss PD, et al., 2017,
Chemical and biological assessment of metal organic frameworks (MOFs) in pulmonary cells and in an acute in vivo model: relevance to pulmonary arterial hypertension therapy
, Pulmonary Circulation, Vol: 7, Pages: 1-11, ISSN: 2045-8940Pulmonary arterial hypertension (PAH) is a progressive and debilitating condition. Despite promoting vasodilation, current drugs have a therapeutic window within which they are limited by systemic side effects. Nanomedicine uses nanoparticles to improve drug delivery and/or reduce side effects. We hypothesize that this approach could be used to deliver PAH drugs avoiding the systemic circulation. Here we report the use of iron metal organic framework (MOF) MIL-89 and PEGylated MIL-89 (MIL-89 PEG) as suitable carriers for PAH drugs. We assessed their effects on viability and inflammatory responses in a wide range of lung cells including endothelial cells grown from blood of donors with/without PAH. Both MOFs conformed to the predicted structures with MIL-89 PEG being more stable at room temperature. At concentrations up to 10 or 30 µg/mL, toxicity was only seen in pulmonary artery smooth muscle cells where both MOFs reduced cell viability and CXCL8 release. In endothelial cells from both control donors and PAH patients, both preparations inhibited the release of CXCL8 and endothelin-1 and in macrophages inhibited inducible nitric oxide synthase activity. Finally, MIL-89 was well-tolerated and accumulated in the rat lungs when given in vivo. Thus, the prototypes MIL-89 and MIL-89 PEG with core capacity suitable to accommodate PAH drugs are relatively non-toxic and may have the added advantage of being anti-inflammatory and reducing the release of endothelin-1. These data are consistent with the idea that these materials may not only be useful as drug carriers in PAH but also offer some therapeutic benefit in their own right.
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Journal articleBelvisi MG, Birrell MA, Wortley MA, et al., 2017,
XEN-D0501, a novel TRPV1 antagonist, does not reduce cough in refractory cough patients
, American Journal of Respiratory and Critical Care Medicine, Vol: 196, Pages: 1255-1263, ISSN: 1073-449XRATIONALE: Heightened cough responses to inhaled capsaicin, a TRPV1 agonist, are characteristic of patients with chronic cough. However, previously a TRPV1 antagonist (SB-705498) failed to improve spontaneous cough frequency in these patients despite small reductions in capsaicin-evoked cough. OBJECTIVES: XEN-D0501 (potent TRPV1 antagonist) was compared with SB-705498 in pre-clinical studies to establish whether an improved efficacy profile would support a further clinical trial of XEN-D0501 in refractory chronic cough. METHODS: XEN-D0501 and SB-705498 were profiled against capsaicin in a sensory nerve activation assay and in vivo potency established against capsaicin-induced cough in the guinea pig. Twenty patients with refractory chronic cough participated in a double-blind, randomised, placebo-controlled, crossover study evaluating the effect of 14 days XEN-D0501 (oral, 4mg bd) versus placebo on awake cough frequency (primary outcome), capsaicin-evoked cough and patient reported outcomes. MEASUREMENTS AND MAIN RESULTS: XEN-D0501 was more efficacious and 1000-fold more potent than SB-705498 at inhibiting capsaicin-induced depolarization of guinea pig and human isolated vagus. In vivo, XEN-D0501 completely inhibited capsaicin-induced cough whereas 100-times more SB-705498 was required to achieve the same effect. In patients, XEN-D0501 substantially reduced maximal cough responses to capsaicin (mean change from baseline XEN-D0501 -19.3(±16.4) coughs vs. placebo -1.8(±5.8), p<0.0001), but not spontaneous awake cough frequency (mean change from baseline XEN-D0501 6.7c/h(±16.9) vs. placebo 0.4c/h(±13.7), p =0.41). CONCLUSIONS: XEN-D0501 demonstrated superior efficacy and potency in pre-clinical and clinical capsaicin challenge studies; despite this improved pharmacodynamic profile, spontaneous cough frequency did not improve, ruling out TRPV1 as an effective therapeutic target for refractory cough. Clinical trial registration available ww
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Journal articleNakamura T, Goverdovsky V, Morrell M, et al., 2017,
Automatic sleep monitoring using ear-EEG
, IEEE Journal of Translational Engineering in Health and Medicine, Vol: 5, ISSN: 2168-2372The monitoring of sleep patterns without patient’s inconvenience or involvement of a medical specialist is a clinical question of significant importance. To this end, we propose an automatic sleep stage monitoring system based on an affordable, unobtrusive, discreet, and long-term wearable in-ear sensor for recording the Electroencephalogram (ear-EEG). The selected features for sleep pattern classification from a single ear-EEG channel include the spectral edge frequency (SEF) and multiscale fuzzy entropy (MSFE), a structural complexity feature. In this preliminary study, the manually scored hypnograms from simultaneous scalp-EEG and ear-EEG recordings of four subjects are used as labels for two analysis scenarios: 1) classification of ear-EEG hypnogram labels from ear-EEG recordings and 2) prediction of scalp-EEG hypnogram labels from ear-EEG recordings. We consider both 2-class and 4-class sleep scoring, with the achieved accuracies ranging from 78.5% to 95.2% for ear-EEG labels predicted from ear-EEG, and 76.8% to 91.8% for scalp-EEG labels predicted from ear-EEG. The corresponding Kappa coefficients range from 0.64 to 0.83 for Scenario 1, and indicate Substantial to Almost Perfect Agreement, while for Scenario 2 the range of 0.65 to 0.80 indicates Substantial Agreement, thus further supporting the feasibility of in-ear sensing for sleep monitoring in the community.
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Journal articleFritzsche M, Fernandes RA, Chang VT, et al., 2017,
Cytoskeletal actin dynamics shape a ramifying actin network underpinning immunological synapse formation
, Science Advances, Vol: 3, Pages: 1-18, ISSN: 2375-2548T cell activation and especially trafficking of T cell receptor microclusters during immunological synapse formation are widely thought to rely on cytoskeletal remodeling. However, important details on the involvement of actin in the latter transport processes are missing. Using a suite of advanced optical microscopes to analyze resting and activated T cells, we show that, following contact formation with activating surfaces, these cells sequentially rearrange their cortical actin across the entire cell, creating a previously unreported ramifying actin network above the immunological synapse. This network shows all the characteristics of an inward-growing transportation network and its dynamics correlating with T cell receptor rearrangements. This actin reorganization is accompanied by an increase in the nanoscale actin meshwork size and the dynamic adjustment of the turnover times and filament lengths of two differently sized filamentous actin populations, wherein formin-mediated long actin filaments support a very flat and stiff contact at the immunological synapse interface. The initiation of immunological synapse formation, as highlighted by calcium release, requires markedly little contact with activating surfaces and no cytoskeletal rearrangements. Our work suggests that incipient signaling in T cells initiates global cytoskeletal rearrangements across the whole cell, including a stiffening process for possibly mechanically supporting contact formation at the immunological synapse interface as well as a central ramified transportation network apparently directed at the consolidation of the contact and the delivery of effector functions.
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Journal articleSonnappa S, Martin R, Israel E, et al., 2017,
Risk of pneumonia in obstructive lung disease: A real-life study comparing extra-fine and fine-particle inhaled corticosteroids
, PLOS ONE, Vol: 12, ISSN: 1932-6203Background:Regular use of inhaled corticosteroids (ICS) in patients with obstructive lung diseases has been associated with a higher risk of pneumonia, particularly in COPD. The risk of pneumonia has not been previously evaluated in relation to ICS particle size and dose used.Methods:Historical cohort, UK database study of 23,013 patients with obstructive lung disease aged 12–80 years prescribed extra-fine or fine-particle ICS. The endpoints assessed during the outcome year were diagnosis of pneumonia, acute exacerbations and acute respiratory events in relation to ICS dose. To determine the association between ICS particle size, dose and risk of pneumonia in unmatched and matched treatment groups, logistic and conditional logistic regression models were used.Results:14788 patients were stepped-up to fine-particle ICS and 8225 to extra-fine ICS. On unmatched analysis, patients stepping-up to extra-fine ICS were significantly less likely to be coded for pneumonia (adjusted odds ratio [aOR] 0.60; 95% CI 0.37, 0.97]); experience acute exacerbations (adjusted risk ratio [aRR] 0.91; 95%CI 0.85, 0.97); and acute respiratory events (aRR 0.90; 95%CI 0.86, 0.94) compared with patients stepping-up to fine-particle ICS. Patients prescribed daily ICS doses in excess of 700 mcg (fluticasone propionate equivalent) had a significantly higher risk of pneumonia (OR [95%CI] 2.38 [1.17, 4.83]) compared with patients prescribed lower doses, irrespective of particle size.Conclusions:These findings suggest that patients with obstructive lung disease on extra-fine particle ICS have a lower risk of pneumonia than those on fine-particle ICS, with those receiving higher ICS doses being at a greater risk.
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Journal articleAyas NT, Drager LF, Morrell MJ, et al., 2017,
Update in Sleep-disordered Breathing 2016
, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 195, Pages: 1561-1566, ISSN: 1073-449X -
Journal articleToussaint M, Jackson DJ, Swieboda D, et al., 2017,
Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation
, Nature Medicine, Vol: 23, Pages: 681-691, ISSN: 1078-8956Respiratory viral infections represent the most common cause of allergic asthma exacerbations. Amplification of the type-2 immune response is strongly implicated in asthma exacerbation, but how virus infection boosts type-2 responses is poorly understood. We report a significant correlation between the release of host double-stranded DNA (dsDNA) following rhinovirus infection and the exacerbation of type-2 allergic inflammation in humans. In a mouse model of allergic airway hypersensitivity, we show that rhinovirus infection triggers dsDNA release associated with the formation of neutrophil extracellular traps (NETs), known as NETosis. We further demonstrate that inhibiting NETosis by blocking neutrophil elastase or by degrading NETs with DNase protects mice from type-2 immunopathology. Furthermore, the injection of mouse genomic DNA alone is sufficient to recapitulate many features of rhinovirus-induced type-2 immune responses and asthma pathology. Thus, NETosis and its associated extracellular dsDNA contribute to the pathogenesis and may represent potential therapeutic targets of rhinovirus-induced asthma exacerbations.
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Journal articleRosenzweig I, Morrell MJ, 2017,
Hypotrophy versus Hypertrophy: It's Not Black or White with Gray Matter
, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 195, Pages: 1416-1418, ISSN: 1073-449X -
Journal articleKhazaie H, Veronese M, Noori K, et al., 2017,
Functional reorganization in obstructive sleep apnoea and insomnia: A systematic review of the resting-state fMRI
, NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS, Vol: 77, Pages: 219-231, ISSN: 0149-7634- Author Web Link
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Journal articleSmyth E, Solomon A, Birrell MA, et al., 2017,
Influence of inflammation and nitric oxide upon platelet aggregation following deposition of diesel exhaust particles in the airways.
, British Journal of Pharmacology, Vol: 174, Pages: 2130-2139, ISSN: 0007-1188Background and Purpose: Exposure to nanoparticulate pollution has been implicated in platelet-driven thrombotic events such as myocardial infarction. Inflammation and impairment of NO bioavailability have been proposed as potential causative mechanisms. It is unclear, however, whether airways exposure to combustion-derived nanoparticles such as diesel exhaust particles (DEP) or carbon black (CB) can augment platelet aggregation in vivo and the underlying mechanisms remain undefined. We aimed to investigate the effects of acute lung exposure to DEP and CB on platelet activation and the associated role of inflammation and endothelial-derived NO.Experimental Approach: DEP and CB were intratracheally instilled into wild-type (WT) and eNOS−/− mice and platelet aggregation was assessed in vivo using an established model of radio-labelled platelet thromboembolism. The underlying mechanisms were investigated by measuring inflammatory markers, NO metabolites and light transmission aggregometry.Key Results: Platelet aggregation in vivo was significantly enhanced in WT and eNOS−/− mice following acute airways exposure to DEP but not CB. CB exposure, but not DEP, was associated with significant increases in pulmonary neutrophils and IL-6 levels in the bronchoalveolar lavage fluid and plasma of WT mice. Neither DEP nor CB affected plasma nitrate/nitrite concentration and DEP-induced human platelet aggregation was inhibited by an NO donor.Conclusions and Implications: Pulmonary exposure to DEP and subsequent platelet activation may contribute to the reports of increased cardiovascular risk, associated with exposure to airborne pollution, independent of its effects on inflammation or NO bioavailability.
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Journal articleHopkinson NS, 2017,
Conservatism and the cancer drugs fund: Are some patients and some people-more deserving than others?
, BMJ, Vol: 357, Pages: j2451-j2451, ISSN: 0959-8138 -
Journal articleAllinson JP, Hardy R, Donaldson GC, et al., 2017,
Combined impact of smoking and early life exposures on adult lung function trajectories
, American Journal of Respiratory and Critical Care Medicine, Vol: 195, Pages: 1021-1030, ISSN: 1073-449XBACKGROUND: Both adverse early life exposures and adult smoking can negatively influence adult lung function trajectory but few studies consider how the impact of early life exposures may be modified by subsequent smoking. METHODS: The Medical Research Council National Survey of Health and Development is a nationally representative cohort, initially of 5362 individuals, followed since enrolment at birth in March 1946. Using data collected prospectively across life and multilevel modelling we investigated how the relationships between early life exposures (infant lower respiratory infection, manual social class, home overcrowding and pollution exposure) and FEV1 and FVC trajectories between ages 43 and 60-64 were influenced by smoking behaviour. RESULTS: Among 2172 individuals, there were synergistic interactions of smoking with infant respiratory infection (P=0.04) and early life home overcrowding (P=0.009), for FEV1 at 43 years. Within smoker-stratified models, there were FEV1 deficits among ever-smokers associated with infant lower respiratory infection (-108.2ml; P=0.001) and home overcrowding (-89.2ml; P=0.002) which were not evident among never-smokers (-15.9ml; P=0.69 and -13.7ml; P=0.70 respectively). FVC modelling, including 1960 individuals, yielded similar results. FEV1 decline was greater in smokers (P<0.001) but there was no effect of any early life exposure on FEV1 decline. Neither smoking nor early life exposures were associated with FVC decline. CONCLUSIONS: Besides accelerating adult FEV1 decline, cigarette smoking also modifies how early life exposures impact upon both mid-life FEV1 and FVC. These findings are consistent with smoking impairing pulmonary development during adolescence or early adulthood thereby preventing catch-up from earlier acquired deficits.
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Journal articleTo M, Swallow EB, Akashi K, et al., 2017,
Reduced HDAC2 in skeletal muscle of COPD patients
, Respiratory Research, Vol: 18, ISSN: 1465-993XBACKGROUND: Skeletal muscle weakness in chronic obstructive pulmonary disease (COPD) is an important predictor of poor prognosis, but the molecular mechanisms of muscle weakness in COPD have not been fully elucidated. The aim of this study was to investigate the role of histone deacetylases(HDAC) in skeletal muscle weakness in COPD. METHODS AND RESULTS: Twelve COPD patients, 8 smokers without COPD (SM) and 4 healthy non-smokers (NS) were recruited to the study. HDAC2 protein expression in quadriceps muscle biopsies of COPD patients (HDAC2/β-actin: 0.59 ± 0.34) was significantly lower than that in SM (1.9 ± 1.1, p = 0.0007) and NS (1.2 ± 0.7, p = 0.029). HDAC2 protein in skeletal muscle was significantly correlated with forced expiratory volume in 1 s % predicted (FEV1 % pred) (rs = 0.53, p = 0.008) and quadriceps maximum voluntary contraction force (MVC) (rs = 0.42, p = 0.029). HDAC5 protein in muscle biopsies of COPD patients (HDAC5/β-actin: 0.44 ± 0.26) was also significantly lower than that in SM (1.29 ± 0.39, p = 0.0001) and NS (0.98 ± 0.43, p = 0.020). HDAC5 protein in muscle was significantly correlated with FEV1 % pred (rs = 0.64, p = 0.0007) but not with MVC (rs = 0.30, p = 0.180). Nuclear factor-kappa B (NF-κB) DNA binding activity in muscle biopsies of COPD patients (10.1 ± 7.4) was significantly higher than that in SM (3.9 ± 7.3, p = 0.020) and NS (1.0 ± 1.2, p = 0.004and significantly correlated with HDAC2 decrease (rs = -0.59, p = 0.003) and HDAC5 (rs = 0.050, p = 0.012). HDAC2 knockdown by RNA interfe
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Conference paperMoghal MEU, Goburdhun AR, Morrell M, et al., 2017,
A Novel Smartphone Based Auto-Titrating Oxygen System Reduces Intermittent Hypoxia During Activities Of Daily Living In Patients On Long-Term Oxygen Therapy
, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X -
Journal articleRobinson RK, Birrell MA, Adcock JJ, et al., 2017,
Mechanistic link between diesel exhaust particles and respiratory reflexes
, Journal of Allergy and Clinical Immunology, Vol: 141, Pages: 1074-1084.e9, ISSN: 1097-6825BackgroundDiesel exhaust particles (DEPs) are a major component of particulate matter in Europe's largest cities, and epidemiologic 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.ObjectiveWe sought to identify the mechanisms involved in activation of airway sensory afferents by DEPs.MethodsIn this study we use in vitro and in vivo electrophysiologic techniques, including a unique model that assesses depolarization (a marker of sensory nerve activation) of human vagus.ResultsWe demonstrate a direct interaction between DEP and airway C-fiber afferents. In anesthetized guinea pigs intratracheal administration of DEPs 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 transient receptor potential ankyrin-1 antagonist and the antioxidant N-acetyl cysteine. Polycyclic aromatic hydrocarbons, major constituents of DEPs, were implicated in this process through activation of the aryl hydrocarbon receptor and subsequent mitochondrial reactive oxygen species production, which is known to activate transient receptor potential ankyrin-1 on nociceptive C-fibers.ConclusionsThis 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 subjects who are most at risk.
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Conference paperBhavsar PK, Sehra G, Johnson M, et al., 2017,
Pharmacological characterization Of Maba, Gsk961081 on human airway smooth muscle cells
, International Conference of the American-Thoracic-Society (ATS), Publisher: American Thoracic Society, ISSN: 1073-449X -
Journal articleRossios C, Pavlidis S, Hoda U, et al., 2017,
Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma
, Journal of Allergy and Clinical Immunology, Vol: 141, Pages: 560-570, ISSN: 1097-6825BACKGROUND: Sputum analysis in asthmatic patients is used to define airway inflammatory processes and might guide therapy. OBJECTIVE: We sought to determine differential gene and protein expression in sputum samples from patients with severe asthma (SA) compared with nonsmoking patients with mild/moderate asthma. METHODS: Induced sputum was obtained from nonsmoking patients with SA, smokers/ex-smokers with severe asthma, nonsmoking patients with mild/moderate asthma (MMAs), and healthy nonsmoking control subjects. Differential cell counts, microarray analysis of cell pellets, and SOMAscan analysis of sputum analytes were performed. CRID3 was used to inhibit the inflammasome in a mouse model of SA. RESULTS: Eosinophilic and mixed neutrophilic/eosinophilic inflammation were more prevalent in patients with SA compared with MMAs. Forty-two genes probes were upregulated (>2-fold) in nonsmoking patients with severe asthma compared with MMAs, including IL-1 receptor (IL-1R) family and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NRLP3) inflammasome members (false discovery rate < 0.05). The inflammasome proteins nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 1 (NLRP1), NLRP3, and nucleotide-binding oligomerization domain (NOD)-like receptor C4 (NLRC4) were associated with neutrophilic asthma and with sputum IL-1β protein levels, whereas eosinophilic asthma was associated with an IL-13-induced TH2 signature and IL-1 receptor-like 1 (IL1RL1) mRNA expression. These differences were sputum specific because no activation of NLRP3 or enrichment of IL-1R family genes in bronchial brushings or biopsy specimens in patients with SA was observed. Expression of NLRP3 and of the IL-1R family genes was validated in the Airway Disease Endotyping for Personalized Therapeutics cohort. Inflammasome inhibition using CRID3 prevented airway hyperresponsiveness and airway inflammati
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Journal articleYanagisawa S, Baker JR, Vuppusetty C, et al., 2017,
Decreased phosphatase PTEN amplifies PI3K signaling and enhances pro-inflammatory cytokine release in COPD
, American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol: 313, Pages: L230-L239, ISSN: 1522-1504The phosphatidylinositol 3-kinase (PI3K) pathway is activated in chronic obstructive pulmonary disease (COPD), but the regulatory mechanisms for this pathway are yet to be elucidated. Our aim was to determine the expression and role of phosphatase and tensin homolog deleted from chromosome 10 (PTEN), a negative regulator of the PI3K pathway, in COPD. PTEN expression and activity were measured in the peripheral lung of COPD patients compared to smoking and non-smoking controls. The direct influence of cigarette smoke extract (CSE) on PTEN expression was assessed using primary lung epithelial cells and a cell line (BEAS-2B) in the presence or absence of L-buthionine-sulfoximine (BSO) to deplete intracellular glutathione. The impact of PTEN knock-down by RNA interference on cytokine production was also examined. In peripheral lung, PTEN protein was significantly decreased in patients with COPD compared to the subjects without COPD (p < 0.001), and positively correlated with the severity of air-flow obstruction (FEV1 % predicted; r = 0.50; p = 0.0012), although no difference was observed in PTEN activity. Conversely, phosphorylated Akt, as a marker of PI3K activation, showed a negative correlation with PTEN protein levels (r = -0.41; p = 0.0042). Both in primary bronchial epithelial cells and BEAS-2B cell line, CSE decreased PTEN protein, which was reversed by N-acetylcysteine treatment. PTEN knock-down potentiated Akt phosphorylation and enhanced production of pro-inflammatory cytokines, such as IL-6, CXCL8, CCL2 and CCL5. In conclusion, oxidative stress reduces PTEN protein levels, which may result in increased PI3K signaling and amplification of inflammation in COPD.
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Journal articleYeo SCM, Fenwick PS, Barnes PJ, et al., 2017,
Isorhapontigenin, a bioavailable dietary polyphenol, suppresses airway epithelial cell inflammation through a corticosteroid-independent mechanism
, British Journal of Pharmacology, Vol: 174, Pages: 2043-2059, ISSN: 1476-5381Background and PurposeChronic obstructive pulmonary disease (COPD) is a corticosteroid-resistant airway inflammatory condition. Resveratrol has exhibited anti-inflammatory activities in COPD but has weak potency and poor pharmacokinetics. This study aims to evaluate the potential of isorhapontigenin, another dietary polyphenol, as a novel anti-inflammatory agent for COPD by examining its effects in vitro and its pharmacokinetics in vivo.Experimental ApproachPrimary human airway epithelial cells derived from healthy and COPD subjects and A549 epithelial cells were incubated with isorhapontigenin or resveratrol and stimulated with IL-1β in the presence or absence of cigarette smoke extract. Their effects on the release of IL-6 and chemokine (C-X-C motif) ligand 8 (CXCL8) were determined and the activation of NF-κB, AP-1, MAPKs and PI3K/Akt/FoxO3A pathways compared to dexamethasone were evaluated. The pharmacokinetic profiles of isorhapontigenin were assessed in Sprague-Dawley rats after respective intravenous and oral administration.Key ResultsIsorhapontigenin exhibited concentration-dependent inhibition of IL-6 and CXCL8 release, with IC50 values at least two-fold lower than resveratrol. These were associated with suppressed NF-κB and AP-1 activation and notably, the PI3K/Akt/FoxO3A pathway that was relatively insensitive to dexamethasone. In vivo, isorhapontigenin was rapidly absorbed with abundant plasma exposure after oral dosing. Its oral bioavailability was approximately 50% higher than resveratrol.Conclusions and ImplicationsIsorhapontigenin, an orally bioavailable dietary polyphenol, displayed superior anti-inflammatory effects compared to resveratrol. Furthermore, it suppressed the PI3K/Akt pathway that is insensitive to corticosteroids. These favourable efficacy and pharmacokinetic properties support its further development as a novel anti-inflammatory agent for COPD.
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Journal articleBrill A-K, Moghal M, Morrell MJ, et al., 2017,
Randomized crossover trial of a pressure sensing visual feedback system to improve mask fitting in noninvasive ventilation.
, Respirology, Vol: 22, Pages: 1343-1349BACKGROUND AND OBJECTIVE: A good mask fit, avoiding air leaks and pressure effects on the skin are key elements for a successful noninvasive ventilation (NIV). However, delivering practical training for NIV is challenging, and it takes time to build experience and competency. This study investigated whether a pressure sensing system with real-time visual feedback improved mask fitting. METHODS: During an NIV training session, 30 healthcare professionals (14 trained in mask fitting and 16 untrained) performed two mask fittings on the same healthy volunteer in a randomized order: one using standard mask-fitting procedures and one with additional visual feedback on mask pressure on the nasal bridge. Participants were required to achieve a mask fit with low mask pressure and minimal air leak (<10 L/min). Pressure exerted on the nasal bridge, perceived comfort of mask fit and staff- confidence were measured. RESULTS: Compared with standard mask fitting, a lower pressure was exerted on the nasal bridge using the feedback system (71.1 ± 17.6 mm Hg vs 63.2 ± 14.6 mm Hg, P < 0.001). Both untrained and trained healthcare professionals were able to reduce the pressure on the nasal bridge (74.5 ± 21.2 mm Hg vs 66.1 ± 17.4 mm Hg, P = 0.023 and 67 ± 12.1 mm Hg vs 60 ± 10.6 mm Hg, P = 0.002, respectively) using the feedback system and self-rated confidence increased in the untrained group. CONCLUSION: Real-time visual feedback using pressure sensing technology supported healthcare professionals during mask-fitting training, resulted in a lower pressure on the skin and better mask fit for the volunteer, with increased staff confidence.
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