text: DSpace Collection: http://hdl.handle.net/2381/9 2017-07-21T04:54:48Z 2017-07-21T04:54:48Z Vitamin D3 supplementation of a high fat high sugar diet ameliorates prediabetic phenotype in female LDLR(-/-) and LDLR(+/+) mice Kheder, Ramiar Hobkirk, James Saeed, Zeayd Janus, Justyna Carroll, Sean Browning, Michael J. Stover, Cordula http://hdl.handle.net/2381/40075 2017-07-13T02:22:22Z 2017-07-12T14:22:52Z Title: Vitamin D3 supplementation of a high fat high sugar diet ameliorates prediabetic phenotype in female LDLR(-/-) and LDLR(+/+) mice Authors: Kheder, Ramiar; Hobkirk, James; Saeed, Zeayd; Janus, Justyna; Carroll, Sean; Browning, Michael J.; Stover, Cordula Abstract: INTRODUCTION: Fatty liver disease is prevalent in populations with high caloric intake. Nutritherapeutic approaches are being considered, such as supplementary Vitamin D3 , to improve aspects of metabolic syndrome, namely fatty liver disease, hyperlipidemia, and insulin resistance associated with obesity. METHODS: We analyzed female LDLR(-/-) and LDLR(+/+) mice on a 10-week diabetogenic diet for markers of fatty liver disease, metabolic strain, and inflammation. RESULTS: The groups on a high fat high sugar diet with supplementary Vitamin D3 , in comparison with the groups on a high fat high sugar diet alone, showed improved transaminase levels, significantly less hypertriglyceridemia and hyperinsulinemia, and histologically, there was less pericentral hepatic steatosis. Levels of non-esterified fatty acids and lipid peroxidation products were significantly lower in the group supplemented with additional Vitamin D3 , as were systemic markers of inflammation (serum endotoxin and IL-6). M2 macrophage phenotype predominated in the group supplemented with additional Vitamin D3 . Beneficial changes were observed as early as five weeks' supplementation with Vitamin D3 and extended to restoration of high fat high sugar diet induced decrease of bone mineral density. CONCLUSION: In summary, Vitamin D3 was a significantly beneficial dietary additive to blunt a prediabetic phenotype in diet-induced obesity of female LDLR(-/-) and LDLR(+/+) mice. 2017-07-12T14:22:52Z Responsiveness to oral prednisolone in severe asthma is related to the degree of eosinophilic airway inflammation Sousa, A. R. Marshall, R. P. Warnock, L. C. Bolton, S. Hastie, A. Symon, F. Hargadon, B. Marshall, H. Richardson, M. Brightling, C. E. Haldar, P. Milone, R. Chalk, P. Williamson, R. Panettieri, R. Knowles, R. Bleecker, E. R. Wardlaw, Andrew John http://hdl.handle.net/2381/40056 2017-07-12T02:26:15Z 2017-07-11T10:49:13Z Title: Responsiveness to oral prednisolone in severe asthma is related to the degree of eosinophilic airway inflammation Authors: Sousa, A. R.; Marshall, R. P.; Warnock, L. C.; Bolton, S.; Hastie, A.; Symon, F.; Hargadon, B.; Marshall, H.; Richardson, M.; Brightling, C. E.; Haldar, P.; Milone, R.; Chalk, P.; Williamson, R.; Panettieri, R.; Knowles, R.; Bleecker, E. R.; Wardlaw, Andrew John Abstract: BACKGROUND: Patients with severe asthma appear relatively corticosteroid resistant. Corticosteroid responsiveness is closely related to the degree of eosinophilic airway inflammation. The extent to which eosinophilic airway inflammation in severe asthma responds to treatment with systemic corticosteroids is not clear. OBJECTIVE: To relate the physiological and inflammatory response to systemic corticosteroids in asthma to disease severity and the baseline extent of eosinophilic inflammation. METHODS: Patients with mild/moderate and severe asthma were investigated before and after 2 weeks of oral prednisolone (Clintrials.gov NCT00331058 and NCT00327197). We pooled the results from two studies with common protocols. The US study contained two independent centres and the UK one independent centre. The effect of oral corticosteroids on FEV1 , Pc20, airway inflammation and serum cytokines was investigated. Baseline measurements were compared with healthy subjects. RESULTS: Thirty-two mild/moderate asthmatics, 50 severe asthmatics and 35 healthy subjects took part. At baseline, both groups of asthmatics had a lower FEV1 and Pc20 and increased eosinophilic inflammation compared to healthy subjects. The severe group had a lower FEV1 and more eosinophilic inflammation compared to mild/moderate asthmatics. Oral prednisolone caused a similar degree of suppression of eosinophilic inflammation in all compartments in both groups of asthmatics. There were small improvements in FEV1 and Pc20 for both mild/ moderate and severe asthmatics with a correlation between the baseline eosinophilic inflammation and the change in FEV1 . There was a ~50% reduction in the serum concentration of CXCL10 (IP-10), CCL22 (MDC), CCL17 (TARC), CCL-2 (MCP-1) and CCL-13 (MCP-4) in both asthma groups after oral corticosteroids. CONCLUSIONS AND CLINICAL RELEVANCE: Disease severity does not influence the response to systemic corticosteroids. The study does not therefore support the concept that severe asthma is associated with corticosteroid resistance. Only baseline eosinophilic inflammation was associated with the physiological response to corticosteroids, confirming the importance of measuring eosinophilic inflammation to guide corticosteroid use. Description: The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above. 2017-07-11T10:49:13Z Promiscuous signaling by a regulatory system unique to the pandemic PMEN1 pneumococcal lineage Kadam, Anagha Eutsey, Rory A. Rosch, Jason Miao, Xinyu Longwell, Mark Xu, Wenjie Woolford, Carol A. Hillman, Todd Motib, Anfal Shakir Yesilkaya, Hasan Mitchel, Aaron P. l Hiller, N. Luisa http://hdl.handle.net/2381/40017 2017-07-08T02:22:38Z 2017-07-07T10:34:26Z Title: Promiscuous signaling by a regulatory system unique to the pandemic PMEN1 pneumococcal lineage Authors: Kadam, Anagha; Eutsey, Rory A.; Rosch, Jason; Miao, Xinyu; Longwell, Mark; Xu, Wenjie; Woolford, Carol A.; Hillman, Todd; Motib, Anfal Shakir; Yesilkaya, Hasan; Mitchel, Aaron P. l; Hiller, N. Luisa Abstract: Streptococcus pneumoniae (pneumococcus) is a leading cause of death and disease in children and elderly. Genetic variability among isolates from this species is high. These differences, often the product of gene loss or gene acquisition via horizontal gene transfer, can endow strains with new molecular pathways, diverse phenotypes, and ecological advantages. PMEN1 is a widespread and multidrug-resistant pneumococcal lineage. Using comparative genomics we have determined that a regulator-peptide signal transduction system, TprA2/PhrA2, was acquired by a PMEN1 ancestor and is encoded by the vast majority of strains in this lineage. We show that TprA2 is a negative regulator of a PMEN1-specific gene encoding a lanthionine-containing peptide (lcpA). The activity of TprA2 is modulated by its cognate peptide, PhrA2. Expression of phrA2 is density-dependent and its C-terminus relieves TprA2-mediated inhibition leading to expression of lcpA. In the pneumococcal mouse model with intranasal inoculation, TprA2 had no effect on nasopharyngeal colonization but was associated with decreased lung disease via its control of lcpA levels. Furthermore, the TprA2/PhrA2 system has integrated into the pneumococcal regulatory circuitry, as PhrA2 activates TprA/PhrA, a second regulator-peptide signal transduction system widespread among pneumococci. Extracellular PhrA2 can release TprA-mediated inhibition, activating expression of TprA-repressed genes in both PMEN1 cells as well as another pneumococcal lineage. Acquisition of TprA2/PhrA2 has provided PMEN1 isolates with a mechanism to promote commensalism over dissemination and control inter-strain gene regulation. 2017-07-07T10:34:26Z Patient profiles and clinical utility of mepolizumab in severe eosinophilic asthma Haldar, Pranabashis http://hdl.handle.net/2381/39971 2017-07-01T02:22:54Z 2017-06-30T14:35:02Z Title: Patient profiles and clinical utility of mepolizumab in severe eosinophilic asthma Authors: Haldar, Pranabashis Abstract: Mepolizumab (Nucala®) is an effective and specific anti-eosinophil molecular therapy that has recently been approved as add-on therapy for the management of severe eosinophilic asthma by the US Food and Drug Administration (FDA), European Medicines Agency (EMA; European Union) and more recently National Institute for Health and Care Excellence (NICE; UK). It is one of several molecular therapies in development for this indication and is illustrative of the strategic trajectory for pharmaceutical drug development taken over the past decade in several disease areas. Molecular therapies offer the prospect of improved specificity and effectiveness of biological effect. However, this necessitates a clear understanding of the underlying mechanistic pathways underpinning pathological processes, to inform drug development that yields novel more efficacious treatment options with a better clinical profile than existing agents. For the first time, utilization of molecular therapies in clinical trials is providing a novel in vivo model to characterize the association between specific pathways and clinical disease expression. It is increasingly recognized that asthma exhibits both clinical and pathological heterogeneity. It follows that a one-size-fits-all approach will not be appropriate and cost-effectiveness may only be achieved by identifying responder subgroups. This so-called personalized approach to therapy is being supported by the parallel development of companion biomarkers for clinical application. In this review, the author summarizes the clinical studies, their interpretation and the lessons learnt with mepolizumab that have informed our understanding of the approach to personalized molecular therapy in asthma. 2017-06-30T14:35:02Z Breastfeeding and Respiratory Tract Infections during the First 2 Years of Life. Wang, Jingying Ramette, Alban Jurca, Maja Goutaki, Myrofora Beardsmore, Caroline S. Kuehni, Claudia E. http://hdl.handle.net/2381/39858 2017-06-06T02:20:26Z 2017-06-05T15:33:22Z Title: Breastfeeding and Respiratory Tract Infections during the First 2 Years of Life. Authors: Wang, Jingying; Ramette, Alban; Jurca, Maja; Goutaki, Myrofora; Beardsmore, Caroline S.; Kuehni, Claudia E. Abstract: Breastfeeding protects against respiratory tract infections (RTIs) in infants [1–3], but whether its effects persist beyond that age is not well understood. Some studies have reported that protection diminishes soon after weaning [2], while others have found that it extends until the age of 2 years [4] or more [5, 6]. It is noteworthy that many previous studies grouped RTIs broadly into upper or lower tract infections, rather than studying specific diseases [3, 7], and few adjusted adequately for confounding factors [5] or investigated a possible effect modification by sex, which had been suggested by several studies showing a stronger protection in girls [8, 9]. This study aimed to quantify the protective effect of breastfeeding against RTIs during the first 2 years of life, while adjusting for potential confounding factors and testing whether the effect varied by sex. We analysed data from the Leicester Respiratory Cohorts, a population-based random sample of children from Leicestershire, UK, which has been described in detail elsewhere [10]. For this analysis we included only children born between 1996 and 1997 who were aged 1–1.99 years at the date of the first survey in 1998. Parents completed a standardised questionnaire that requested detailed information on breastfeeding and respiratory symptoms. We assessed the duration of breastfeeding (no breastfeeding, ⩽6 months or >6 months), the prevalence of frequent colds (>6 episodes), ear infections and croup within the last 12 months, and any episodes of bronchiolitis or pneumonia. We extracted perinatal data and demographic information from maternity records. The Leicestershire Health Authority Research Ethics Committee approved the study. The survey requested information on a number of RTIs for each child, so we first performed an omnibus logistic regression to determine whether breastfeeding was associated with the occurrence of any RTI. By reforming the data into long format, this omnibus logistic regression also adjusted for the clustering of observations within each child [11]. Following a significant omnibus test, we performed unadjusted and adjusted logistic regressions to determine which RTIs were affected by breastfeeding practice. Adjusted models controlled for sex, ethnicity, socioeconomic status (Townsend deprivation score [12]), perinatal factors (gestational age, birthweight, birth season), environmental factors ( pre- and post-natal maternal smoking, number of older siblings, day care attendance) and parental history of asthma, hay fever and bronchitis. We tested for effect modification by sex by adding interaction terms into adjusted models. Finally, we performed a sensitivity analysis including a subgroup of children with information on exact breastfeeding duration, by using breastfeeding as a continuous exposure, rather than categorical. All analyses were performed in Stata (version 14.2, Stata Corporation, Austin, TX, USA). The survey in 1998 was sent to 5400 families with children aged between 1 and 1.99 years. Questionnaires were returned by 4100 parents (response rate of 76%). After excluding 47 children who had no breastfeeding information and 13 children born extremely prematurely (gestational age of <28 weeks [13]), 4040 children remained in the analysis. Of these, 52% were boys, 81% were white and 19% were of South Asian ethnic origin, 1659 (41%) had never been breastfed, 1639 (41%) had been breastfed for ⩽6 months and 742 (18%) for >6 months. Of the 4040 included children, 769 (19%) were reported by their parents to have had frequent colds, 1685 (42%) ear infections and 293 (7%) croup within the last 12 months. Any episodes of bronchiolitis were reported for 453 children (11%) and pneumonia for 53 (1%) 2017-06-05T15:33:22Z PknG senses amino acid availability to control metabolism and virulence of Mycobacterium tuberculosis Rieck, Barbara Degiacomi, Giulia Zimmermann, Michael Cascioferro, Alessandro Boldrin, Francesca Lazar-Adler, Natalie R. Bottrill, Andrew R. le Chevalier, Fabien Frigui, Wafa Bellinzoni, Marco Lisa, María-Natalia Alzari, Pedro M. Nguyen, Liem Brosch, Roland Sauer, Uwe Manganelli, Riccardo O'Hare, Helen M. http://hdl.handle.net/2381/39841 2017-05-25T02:22:31Z 2017-05-24T15:02:16Z Title: PknG senses amino acid availability to control metabolism and virulence of Mycobacterium tuberculosis Authors: Rieck, Barbara; Degiacomi, Giulia; Zimmermann, Michael; Cascioferro, Alessandro; Boldrin, Francesca; Lazar-Adler, Natalie R.; Bottrill, Andrew R.; le Chevalier, Fabien; Frigui, Wafa; Bellinzoni, Marco; Lisa, María-Natalia; Alzari, Pedro M.; Nguyen, Liem; Brosch, Roland; Sauer, Uwe; Manganelli, Riccardo; O'Hare, Helen M. Abstract: Sensing and response to changes in nutrient availability are essential for the lifestyle of environmental and pathogenic bacteria. Serine/threonine protein kinase G (PknG) is required for virulence of the human pathogen Mycobacterium tuberculosis, and its putative substrate GarA regulates the tricarboxylic acid cycle in M. tuberculosis and other Actinobacteria by protein-protein binding. We sought to understand the stimuli that lead to phosphorylation of GarA, and the roles of this regulatory system in pathogenic and non-pathogenic bacteria. We discovered that M. tuberculosis lacking garA was severely attenuated in mice and macrophages and furthermore that GarA lacking phosphorylation sites failed to restore the growth of garA deficient M. tuberculosis in macrophages. Additionally we examined the impact of genetic disruption of pknG or garA upon protein phosphorylation, nutrient utilization and the intracellular metabolome. We found that phosphorylation of GarA requires PknG and depends on nutrient availability, with glutamate and aspartate being the main stimuli. Disruption of pknG or garA caused opposing effects on metabolism: a defect in glutamate catabolism or depletion of intracellular glutamate, respectively. Strikingly, disruption of the phosphorylation sites of GarA was sufficient to recapitulate defects caused by pknG deletion. The results suggest that GarA is a cellular target of PknG and the metabolomics data demonstrate that the function of this signaling system is in metabolic regulation. This function in amino acid homeostasis is conserved amongst the Actinobacteria and provides an example of the close relationship between metabolism and virulence. Description: The current version of this paper is marked as an uncorrected proof. The final published version will be added to this record when available. 2017-05-24T15:02:16Z Two Novel Myoviruses from the North of Iraq Reveal Insights into Clostridium difficile Phage Diversity and Biology Rashid, Srwa J. Barylski, Jakub Hargreaves, Katherine R. Millard, Andrew A. Vinner, Gurinder K. Clokie, Martha R. J. http://hdl.handle.net/2381/39809 2017-05-18T02:21:55Z 2017-05-17T14:52:36Z Title: Two Novel Myoviruses from the North of Iraq Reveal Insights into Clostridium difficile Phage Diversity and Biology Authors: Rashid, Srwa J.; Barylski, Jakub; Hargreaves, Katherine R.; Millard, Andrew A.; Vinner, Gurinder K.; Clokie, Martha R. J. Abstract: Bacteriophages (phages) are increasingly being explored as therapeutic agents to combat bacterial diseases, including Clostridium difficile infections. Therapeutic phages need to be able to efficiently target and kill a wide range of clinically relevant strains. While many phage groups have yet to be investigated in detail, those with new and useful properties can potentially be identified when phages from newly studied geographies are characterised. Here, we report the isolation of C. difficile phages from soil samples from the north of Iraq. Two myoviruses, CDKM15 and CDKM9, were selected for detailed sequence analysis on the basis of their broad and potentially useful host range. CDKM9 infects 25/80 strains from 12/20 C. difficile ribotypes, and CDKM15 infects 20/80 strains from 9/20 ribotypes. Both phages can infect the clinically relevant ribotypes R027 and R001. Phylogenetic analysis based on whole genome sequencing revealed that the phages are genetically distinct from each other but closely related to other long-tailed myoviruses. A comparative genomic analysis revealed key differences in the genes predicted to encode for proteins involved in bacterial infection. Notably, CDKM15 carries a clustered regularly interspaced short palindromic repeat (CRISPR) array with spacers that are homologous to sequences in the CDKM9 genome and of phages from diverse localities. The findings presented suggest a possible shared evolutionary past for these phages and provides evidence of their widespread dispersal. 2017-05-17T14:52:36Z Human Group 2 innate lymphoid cells do not express the IL-5 receptor Wright, Adam K. A. Weston, Cathryn Rana, Batika M. J. Brightling, Christopher E. Cousins, David J. http://hdl.handle.net/2381/39796 2017-07-11T02:21:12Z 2017-05-16T08:58:58Z Title: Human Group 2 innate lymphoid cells do not express the IL-5 receptor Authors: Wright, Adam K. A.; Weston, Cathryn; Rana, Batika M. J.; Brightling, Christopher E.; Cousins, David J. Abstract: Group 2 innate lymphoid cells (ILC2s) are upstream regulators of IL-5-dependent eosinophil function in asthma. We've shown that ILC2s do not express the IL-5R and thus IL-5R- dependent therapeutic interventions (e.g. Benralizumab) are unlikely to be mediated directly on ILC2s. 2017-05-16T08:58:58Z Pneumococcal galactose catabolism is controlled by multiple regulators acting on pyruvate formate lyase Al-Bayati, Firas A. Y. Kahya, Hasan F. H. Damianou, Andreas Shafeeq, Sulman Kuipers, Oscar P. Andrew, Peter W. Yesilkaya, Hasan http://hdl.handle.net/2381/39694 2017-04-26T02:22:29Z 2017-04-25T10:51:44Z Title: Pneumococcal galactose catabolism is controlled by multiple regulators acting on pyruvate formate lyase Authors: Al-Bayati, Firas A. Y.; Kahya, Hasan F. H.; Damianou, Andreas; Shafeeq, Sulman; Kuipers, Oscar P.; Andrew, Peter W.; Yesilkaya, Hasan Abstract: Catabolism of galactose by Streptococcus pneumoniae alters the microbe's metabolism from homolactic to mixed acid fermentation, and this shift is linked to the microbe's virulence. However, the genetic basis of this switch is unknown. Pyruvate formate lyase (PFL) is a crucial enzyme for mixed acid fermentation. Functional PFL requires the activities of two enzymes: pyruvate formate lyase activating enzyme (coded by pflA) and pyruvate formate lyase (coded by pflB). To understand the genetic basis of mixed acid fermentation, transcriptional regulation of pflA and pflB was studied. By microarray analysis of ΔpflB, differential regulation of several transcriptional regulators were identified, and CcpA, and GlnR's role in active PFL synthesis was studied in detail as these regulators directly interact with the putative promoters of both pflA and pflB, their mutation attenuated pneumococcal growth, and their expression was induced on host-derived sugars, indicating that these regulators have a role in sugar metabolism, and multiple regulators are involved in active PFL synthesis. We also found that the influence of each regulator on pflA and pflB expression was distinct in terms of activation and repression, and environmental condition. These results show that active PFL synthesis is finely tuned, and feed-back inhibition and activation are involved. 2017-04-25T10:51:44Z Sputum Inflammatory Mediators Are Increased in Aspergillus fumigatus Culture-Positive Asthmatics Ghebre, Michael A. Desai, Dhananjay Singapuri, Amisha Woods, Joanne Rapley, Laura Cohen, Suzanne Herath, Athula Wardlaw, Andrew J. Pashley, Catherine H. May, Richard Brightling, Chris E. http://hdl.handle.net/2381/39631 2017-04-11T02:23:10Z 2017-04-10T10:48:38Z Title: Sputum Inflammatory Mediators Are Increased in Aspergillus fumigatus Culture-Positive Asthmatics Authors: Ghebre, Michael A.; Desai, Dhananjay; Singapuri, Amisha; Woods, Joanne; Rapley, Laura; Cohen, Suzanne; Herath, Athula; Wardlaw, Andrew J.; Pashley, Catherine H.; May, Richard; Brightling, Chris E. Abstract: Aspergillus fumigatus sensitization and culture in asthma are associated with disease severity and lung function impairment, but their relationship with airway inflammation is poorly understood. We investigated the profile of 24 sputum inflammatory mediators in A. fumigatus culture-positive or-negative moderate-to-severe asthmatics. Fifty-two subjects were recruited from a single center. A. fumigatus was cultured from 19 asthmatics. Asthma control, symptom score, lung function, and sputum cell count were not significantly different between the asthmatics with and without a positive A. fumigatus culture. All of the sputum mediators were numerically increased in subjects with a positive versus negative sputum A. fumigatus culture. Sputum TNF-R2 was significantly elevated (P=0.03) and the mediator that best distinguished A. fumigatus culture-positive from culture-negative subjects (receiver-operator characteristic area under the curve 0.66 [95% CI: 0.51 to 0.82, P=0.045]). A. fumigates-positive culture in moderate-to-severe asthma is associated with increased inflammatory sputum mediators. 2017-04-10T10:48:38Z Native T1 mapping: inter-study, inter-observer and inter-center reproducibility in hemodialysis patients Graham-Brown, Matthew P. Rutherford, Elaine Levelt, E. March, Daniel S. Churchward, Darren R. Stensel, David J. McComb, Christie Mangion, Kenneth Cockburn, Samantha Berry, Colin Moon, James C. Mark, Patrick B. Burton, James O. McCann, Gerry P. http://hdl.handle.net/2381/39630 2017-04-11T02:23:10Z 2017-04-10T10:40:02Z Title: Native T1 mapping: inter-study, inter-observer and inter-center reproducibility in hemodialysis patients Authors: Graham-Brown, Matthew P.; Rutherford, Elaine; Levelt, E.; March, Daniel S.; Churchward, Darren R.; Stensel, David J.; McComb, Christie; Mangion, Kenneth; Cockburn, Samantha; Berry, Colin; Moon, James C.; Mark, Patrick B.; Burton, James O.; McCann, Gerry P. Abstract: BACKGROUND: Native T1 mapping is a cardiovascular magnetic resonance (CMR) technique that associates with markers of fibrosis and strain in hemodialysis patients. The reproducibility of T1 mapping in hemodialysis patients, prone to changes in fluid status, is unknown. Accurate quantification of myocardial fibrosis in this population has prognostic potential. METHODS: Using 3 Tesla CMR, we report the results of 1) the inter-study, inter-observer and intra-observer reproducibility of native T1 mapping in 10 hemodialysis patients; 2) inter-study reproducibility of left ventricular (LV) structure and function in 10 hemodialysis patients; 3) the agreement of native T1 map and native T1 phantom analyses between two centres in 20 hemodialysis patients; 4) the effect of changes in markers of fluid status on native T1 values in 10 hemodialysis patients. RESULTS: Inter-study, inter-observer and intra-observer variability of native T1 mapping were excellent with co-efficients of variation (CoV) of 0.7, 0.3 and 0.4% respectively. Inter-study CoV for LV structure and function were: LV mass = 1%; ejection fraction = 1.1%; LV end-diastolic volume = 5.2%; LV end-systolic volume = 5.6%. Inter-centre variability of analysis techniques were excellent with CoV for basal and mid-native T1 slices between 0.8-1.2%. Phantom analyses showed comparable native T1 times between centres, despite different scanners and acquisition sequences (centre 1: 1192.7 ± 7.5 ms, centre 2: 1205.5 ± 5 ms). For the 10 patients who underwent inter-study testing, change in body weight (Δweight) between scans correlated with change in LV end-diastolic volume (ΔLVEDV) (r = 0.682;P = 0.03) representing altered fluid status between scans. There were no correlations between change in native T1 between scans (ΔT1) and ΔLVEDV or Δweight (P > 0.6). Linear regression confirmed ΔT1 was unaffected by ΔLVEDV or Δweight (P > 0.59). CONCLUSIONS: Myocardial native T1 is reproducible in HD patients and unaffected by changes in fluid status at the levels we observed. Native T1 mapping is a potential imaging biomarker for myocardial fibrosis in patients with end-stage renal disease. 2017-04-10T10:40:02Z Erratum to: Scaling up strategies of the chronic respiratory disease programme of the European Innovation Partnership on Active and Healthy Ageing (Action Plan B3: Area 5). Bousquet, J. Farrell, J. Crooks, G. Hellings, P. Bel, E. H. Bewick, M. Chavannes, N. H. de Sousa, J. C. Cruz, A. A. Haahtela, T. Joos, G. Khaltaev, N. Malva, J. Muraro, A. Nogues, M. Palkonen, S. Pedersen, S. Robalo-Cordeiro, C. Samolinski, B. Strandberg, T. Valiulis, A. Yorgancioglu, A. Zuberbier, T. Bedbrook, A. Aberer, W. Adachi, M. Agusti, A. Akdis, C. A. Akdis, M. Ankri, J. Alonso, A. Annesi-Maesano, I. Ansotegui, I. J. Anto, J. M. Arnavielhe, S. Arshad, H. Bai, C. Baiardini, I. Bachert, C. Baigenzhin, A. K. Barbara, C. Bateman, E. D. Beghé, B. Kheder, A. B. Bennoor, K. S. Benson, M. Bergmann, K. C. Bieber, T. Bindslev-Jensen, C. Bjermer, L. Blain, H. Blasi, F. Boner, A. L. Bonini, M. Bonini, S. Bosnic-Anticevitch, S. Boulet, L. P. Bourret, R. Bousquet, P. J. Braido, F. Briggs, A. H. Brightling, Christopher E. Brozek, J. Buhl, R. Burney, P. G. Bush, A. Caballero-Fonseca, F. Caimmi, D. Calderon, M. A. Calverley, P. M. Camargos, P. A. Canonica, G. W. Camuzat, T. Carlsen, K. H. Carr, W. Carriazo, A. Casale, T. Cepeda Sarabia, A. M. Chatzi, L. Chen, Y. Z. Chiron, R. Chkhartishvili, E. Chuchalin, A. G. Chung, K. F. Ciprandi, G. Cirule, I. Cox, L. Costa, D. J. Custovic, A. Dahl, R. Dahlen, S. E. Darsow, U. De Carlo, G. De Blay, F. Dedeu, T. Deleanu, D. De Manuel Keenoy, E. Demoly, P. Denburg, J. A. Devillier, P. Didier, A. Dinh-Xuan, A. T. Djukanovic, R. Dokic, D. Douagui, H. Dray, G. Dubakiene, R. Durham, S. R. Dykewicz, M. S. El-Gamal, Y. Emuzyte, R. Fabbri, L. M. Fletcher, M. Fiocchi, A. Fink Wagner, A. Fonseca, J. Fokkens, W. J. Forastiere, F. Frith, P. Gaga, M. Gamkrelidze, A. Garces, J. Garcia-Aymerich, J. Gemicioğlu, B. Gereda, J. E. González Diaz, S. Gotua, M. Grisle, I. Grouse, L. Gutter, Z. Guzmán, M. A. Heaney, L. G. Hellquist-Dahl, B. Henderson, D. Hendry, A. Heinrich, J. Heve, D. Horak, F. Hourihane, J. O. Howarth, P. Humbert, M. Hyland, M. E. Illario, M. Ivancevich, J. C. Jardim, J. R. Jares, E. J. Jeandel, C. Jenkins, C. Johnston, S. L. Jonquet, O. Julge, K. Jung, K. S. Just, J. Kaidashev, I. Khaitov, M. R. Kalayci, O. Kalyoncu, A. F. Keil, T. Keith, P. K. Klimek, L. Koffi N'Goran, B. Kolek, V. Koppelman, G. H. Kowalski, M. L. Kull, I. Kuna, P. Kvedariene, V. Lambrecht, B. Lau, S. Larenas-Linnemann, D. Laune, D. Le, L. T. Lieberman, P. Lipworth, B. Li, J. Lodrup Carlsen, K. Louis, R. MacNee, W. Magard, Y. Magnan, A. Mahboub, B. Mair, A. Majer, I. Makela, M. J. Manning, P. Mara, S. Marshall, G. D. Masjedi, M. R. Matignon, P. Maurer, M. Mavale-Manuel, S. Melén, E. Melo-Gomes, E. Meltzer, E. O. Menzies-Gow, A. Merk, H. Michel, J. P. Miculinic, N. Mihaltan, F. Milenkovic, B. Mohammad, G. M. Molimard, M. Momas, I. Montilla-Santana, A. Morais-Almeida, M. Morgan, M. Mösges, R. Mullol, J. Nafti, S. Namazova-Baranova, L. Naclerio, R. Neou, A. Neffen, H. Nekam, K. Niggemann, B. Ninot, G. Nyembue, T. D. O'Hehir, R. E. Ohta, K. Okamoto, Y. Okubo, K. Ouedraogo, S. Paggiaro, P. Pali-Schöll, I. Panzner, P. Papadopoulos, N. Papi, A. Park, H. S. Passalacqua, G. Pavord, I. Pawankar, R. Pengelly, R. Pfaar, O. Picard, R. Pigearias, B. Pin, I. Plavec, D. Poethig, D. Pohl, W. Popov, T. A. Portejoie, F. Potter, P. Postma, D. Price, D. Rabe, K. F. Raciborski, F. Radier Pontal, F. Repka-Ramirez, S. Reitamo, S. Rennard, S. Rodenas, F. Roberts, J. Roca, J. Rodriguez Mañas, L. Rolland, C. Roman Rodriguez, M. Romano, A. Rosado-Pinto, J. Rosario, N. Rosenwasser, L. Rottem, M. Ryan, D. Sanchez-Borges, M. Scadding, G. K. Schunemann, H. J. Serrano, E. Schmid-Grendelmeier, P. Schulz, H. Sheikh, A. Shields, M. Siafakas, N. Sibille, Y. Similowski, T. Simons, F. E. Sisul, J. C. Skrindo, I. Smit, H. A. Solé, D. Sooronbaev, T. Spranger, O. Stelmach, R. Sterk, P. J. Sunyer, J. Thijs, C. To, T. Todo-Bom, A. Triggiani, M. Valenta, R. Valero, A. L. Valia, E. Valovirta, E. Van Ganse, E. van Hage, M. Vandenplas, O. Vasankari, T. Vellas, B. Vestbo, J. Vezzani, G. Vichyanond, P. Viegi, G. Vogelmeier, C. Vontetsianos, T. Wagenmann, M. Wallaert, B. Walker, S. Wang, D. Y. Wahn, U. Wickman, M. Williams, D. M. Williams, S. Wright, J. Yawn, B. P. Yiallouros, P. K. Yusuf, O. M. Zaidi, A. Zar, H. J. Zernotti, M. E. Zhang, L. Zhong, N. Zidarn, M. Mercier, J. http://hdl.handle.net/2381/39629 2017-04-11T02:23:09Z 2017-04-10T09:55:28Z Title: Erratum to: Scaling up strategies of the chronic respiratory disease programme of the European Innovation Partnership on Active and Healthy Ageing (Action Plan B3: Area 5). Authors: Bousquet, J.; Farrell, J.; Crooks, G.; Hellings, P.; Bel, E. H.; Bewick, M.; Chavannes, N. H.; de Sousa, J. C.; Cruz, A. A.; Haahtela, T.; Joos, G.; Khaltaev, N.; Malva, J.; Muraro, A.; Nogues, M.; Palkonen, S.; Pedersen, S.; Robalo-Cordeiro, C.; Samolinski, B.; Strandberg, T.; Valiulis, A.; Yorgancioglu, A.; Zuberbier, T.; Bedbrook, A.; Aberer, W.; Adachi, M.; Agusti, A.; Akdis, C. A.; Akdis, M.; Ankri, J.; Alonso, A.; Annesi-Maesano, I.; Ansotegui, I. J.; Anto, J. M.; Arnavielhe, S.; Arshad, H.; Bai, C.; Baiardini, I.; Bachert, C.; Baigenzhin, A. K.; Barbara, C.; Bateman, E. D.; Beghé, B.; Kheder, A. B.; Bennoor, K. S.; Benson, M.; Bergmann, K. C.; Bieber, T.; Bindslev-Jensen, C.; Bjermer, L.; Blain, H.; Blasi, F.; Boner, A. L.; Bonini, M.; Bonini, S.; Bosnic-Anticevitch, S.; Boulet, L. P.; Bourret, R.; Bousquet, P. J.; Braido, F.; Briggs, A. H.; Brightling, Christopher E.; Brozek, J.; Buhl, R.; Burney, P. G.; Bush, A.; Caballero-Fonseca, F.; Caimmi, D.; Calderon, M. A.; Calverley, P. M.; Camargos, P. A.; Canonica, G. W.; Camuzat, T.; Carlsen, K. H.; Carr, W.; Carriazo, A.; Casale, T.; Cepeda Sarabia, A. M.; Chatzi, L.; Chen, Y. Z.; Chiron, R.; Chkhartishvili, E.; Chuchalin, A. G.; Chung, K. F.; Ciprandi, G.; Cirule, I.; Cox, L.; Costa, D. J.; Custovic, A.; Dahl, R.; Dahlen, S. E.; Darsow, U.; De Carlo, G.; De Blay, F.; Dedeu, T.; Deleanu, D.; De Manuel Keenoy, E.; Demoly, P.; Denburg, J. A.; Devillier, P.; Didier, A.; Dinh-Xuan, A. T.; Djukanovic, R.; Dokic, D.; Douagui, H.; Dray, G.; Dubakiene, R.; Durham, S. R.; Dykewicz, M. S.; El-Gamal, Y.; Emuzyte, R.; Fabbri, L. M.; Fletcher, M.; Fiocchi, A.; Fink Wagner, A.; Fonseca, J.; Fokkens, W. J.; Forastiere, F.; Frith, P.; Gaga, M.; Gamkrelidze, A.; Garces, J.; Garcia-Aymerich, J.; Gemicioğlu, B.; Gereda, J. E.; González Diaz, S.; Gotua, M.; Grisle, I.; Grouse, L.; Gutter, Z.; Guzmán, M. A.; Heaney, L. G.; Hellquist-Dahl, B.; Henderson, D.; Hendry, A.; Heinrich, J.; Heve, D.; Horak, F.; Hourihane, J. O.; Howarth, P.; Humbert, M.; Hyland, M. E.; Illario, M.; Ivancevich, J. C.; Jardim, J. R.; Jares, E. J.; Jeandel, C.; Jenkins, C.; Johnston, S. L.; Jonquet, O.; Julge, K.; Jung, K. S.; Just, J.; Kaidashev, I.; Khaitov, M. R.; Kalayci, O.; Kalyoncu, A. F.; Keil, T.; Keith, P. K.; Klimek, L.; Koffi N'Goran, B.; Kolek, V.; Koppelman, G. H.; Kowalski, M. L.; Kull, I.; Kuna, P.; Kvedariene, V.; Lambrecht, B.; Lau, S.; Larenas-Linnemann, D.; Laune, D.; Le, L. T.; Lieberman, P.; Lipworth, B.; Li, J.; Lodrup Carlsen, K.; Louis, R.; MacNee, W.; Magard, Y.; Magnan, A.; Mahboub, B.; Mair, A.; Majer, I.; Makela, M. J.; Manning, P.; Mara, S.; Marshall, G. D.; Masjedi, M. R.; Matignon, P.; Maurer, M.; Mavale-Manuel, S.; Melén, E.; Melo-Gomes, E.; Meltzer, E. O.; Menzies-Gow, A.; Merk, H.; Michel, J. P.; Miculinic, N.; Mihaltan, F.; Milenkovic, B.; Mohammad, G. M.; Molimard, M.; Momas, I.; Montilla-Santana, A.; Morais-Almeida, M.; Morgan, M.; Mösges, R.; Mullol, J.; Nafti, S.; Namazova-Baranova, L.; Naclerio, R.; Neou, A.; Neffen, H.; Nekam, K.; Niggemann, B.; Ninot, G.; Nyembue, T. D.; O'Hehir, R. E.; Ohta, K.; Okamoto, Y.; Okubo, K.; Ouedraogo, S.; Paggiaro, P.; Pali-Schöll, I.; Panzner, P.; Papadopoulos, N.; Papi, A.; Park, H. S.; Passalacqua, G.; Pavord, I.; Pawankar, R.; Pengelly, R.; Pfaar, O.; Picard, R.; Pigearias, B.; Pin, I.; Plavec, D.; Poethig, D.; Pohl, W.; Popov, T. A.; Portejoie, F.; Potter, P.; Postma, D.; Price, D.; Rabe, K. F.; Raciborski, F.; Radier Pontal, F.; Repka-Ramirez, S.; Reitamo, S.; Rennard, S.; Rodenas, F.; Roberts, J.; Roca, J.; Rodriguez Mañas, L.; Rolland, C.; Roman Rodriguez, M.; Romano, A.; Rosado-Pinto, J.; Rosario, N.; Rosenwasser, L.; Rottem, M.; Ryan, D.; Sanchez-Borges, M.; Scadding, G. K.; Schunemann, H. J.; Serrano, E.; Schmid-Grendelmeier, P.; Schulz, H.; Sheikh, A.; Shields, M.; Siafakas, N.; Sibille, Y.; Similowski, T.; Simons, F. E.; Sisul, J. C.; Skrindo, I.; Smit, H. A.; Solé, D.; Sooronbaev, T.; Spranger, O.; Stelmach, R.; Sterk, P. J.; Sunyer, J.; Thijs, C.; To, T.; Todo-Bom, A.; Triggiani, M.; Valenta, R.; Valero, A. L.; Valia, E.; Valovirta, E.; Van Ganse, E.; van Hage, M.; Vandenplas, O.; Vasankari, T.; Vellas, B.; Vestbo, J.; Vezzani, G.; Vichyanond, P.; Viegi, G.; Vogelmeier, C.; Vontetsianos, T.; Wagenmann, M.; Wallaert, B.; Walker, S.; Wang, D. Y.; Wahn, U.; Wickman, M.; Williams, D. M.; Williams, S.; Wright, J.; Yawn, B. P.; Yiallouros, P. K.; Yusuf, O. M.; Zaidi, A.; Zar, H. J.; Zernotti, M. E.; Zhang, L.; Zhong, N.; Zidarn, M.; Mercier, J. Abstract: Erratum to: Clinical and Translational Allergy (2016) 6:29 DOI 10.1186/s13601-016-0116-9 In this version of this article that was originally published [1], the name M. R. Khaitov was misspelled as M. R. Kaitov. 2017-04-10T09:55:28Z Characteristics and longitudinal progression of chronic obstructive pulmonary disease in GOLD B patients. Lawrence, Philip J. Kolsum, Umme Gupta, Vandana Donaldson, Gavin Singh, Richa Barker, Bethan George, Leena Webb, Adam Brookes, Anthony J. Brightling, Christopher Wedzicha, Jawiga Singh, Dave http://hdl.handle.net/2381/39627 2017-04-11T02:22:46Z 2017-04-10T08:55:39Z Title: Characteristics and longitudinal progression of chronic obstructive pulmonary disease in GOLD B patients. Authors: Lawrence, Philip J.; Kolsum, Umme; Gupta, Vandana; Donaldson, Gavin; Singh, Richa; Barker, Bethan; George, Leena; Webb, Adam; Brookes, Anthony J.; Brightling, Christopher; Wedzicha, Jawiga; Singh, Dave Abstract: BACKGROUND: The characteristics and natural history of GOLD B COPD patients are not well described. The clinical characteristics and natural history of GOLD B patients over 1 year in a multicentre cohort of COPD patients in the COPDMAP study were assessed. We aimed to identify the subgroup of patients who progressed to GOLD D (unstable GOLD B patients) and identify characteristics associated with progression. METHODS: Three hundred seventy COPD patients were assessed at baseline and 12 months thereafter. Demographics, lung function, health status, 6 min walk tests and levels of systemic inflammation were assessed. Students t tests and Mann Whitney-U tests were used. RESULTS: One hundred seven (28.9%) of patients were categorised as GOLD B at baseline. These GOLD B patients had similar FEV1 to GOLD A patients (66% predicted). More GOLD B patients were current smokers (p = 0.031), had chronic bronchitis (p = 0.0003) and cardiovascular comorbidities (p = 0.019) compared to GOLD A. At 12 months, 25.3% of GOLD B patients progressed to GOLD D. These patients who progressed (unstable patients) had worse health status and symptoms (SGRQ-C Total, 50.0 v 41.1, p = 0.019 and CAT, 21.0 v 14.0, p = 0.006) and lower FEV1 (60% v 69% p = 0.014) at baseline compared to stable patients who remained in GOLD B. CONCLUSIONS: Unstable GOLD B patients who progressed to GOLD D had a higher level of symptoms at baseline. A high symptom burden may predict an increased likelihood of disease progression in GOLD B patients. 2017-04-10T08:55:39Z Making an IMPAKT; Improving care of Chronic Kidney Disease patients in the community through collaborative working and utilizing Information Technology. Xu, Gang Major, Rupert Shepherd, David Brunskill, Nigel http://hdl.handle.net/2381/39615 2017-04-04T02:21:01Z 2017-04-03T10:35:04Z Title: Making an IMPAKT; Improving care of Chronic Kidney Disease patients in the community through collaborative working and utilizing Information Technology. Authors: Xu, Gang; Major, Rupert; Shepherd, David; Brunskill, Nigel Abstract: Chronic kidney disease (CKD) is a serious long-term condition, which if left untreated causes significant cardiovascular sequele. It is well recognized management of modifiable risk factors, such as blood pressure (BP), can lead to improved long-term outcomes. A novel information technology (IT) solution presents a possible solution to help clinicians in the community identify and manage at risk patients more efficiently. The IMproving Patient care and Awareness of Kidney disease progression Together (IMPAKT) IT tool was used to identify patients with CKD and uncontrolled hypertension in the community. A CKD nurse utilized the tool at primary care practices to identify patients who warranted potential intervention and disseminated this information to clinical staff. Blood pressure management targets and incidence of coded CKD were used to evaluate the project. Altogether 48 practices participated in an 18 month project from April 2014, and data from 20 practices, with a total adult population of 121,362, was available for analysis. Two full consecutive QI (Quality Improvement) audit cycles were completed. There was an increase in the mean recorded prevalence of coded CKD patients over the course of the project. Similarly, there was an increase in the percentage of patients with BP been recorded and importantly there was an accompanying significant increase in CKD patients achieving BP targets. At the end of the project an additional 345 individuals with CKD achieved better blood pressure control. This could potentially prevent 9 cardiovascular events in the CKD group, translating to a cost saving of £320,000 for the 20 practices involved. The most significant change in clinical markers occurred during cycle 1 of the audit, the improvement was maintained throughout cycle 2 of the audit. Our results show the real-life clinical impact of a relatively simple and easy to implement QI project, to help improve outcomes in patients with CKD. This was achieved through more efficient working by targeting of high-risk groups, and improved communication between primary/secondary care. The project could be adapted for other chronic disease conditions. Despite the recorded improvements in blood pressure management, a large proportion of high-risk patients remained above ideal blood pressure, additional interventions in this area need to be explored. Through collaborative and multi-professional working and utilizing IT resources, we have shown it is possible to deliver measurable and sustainable improvements in blood pressure control for patients with CKD in a real life clinical setting. 2017-04-03T10:35:04Z Deacetylation of sialic acid by esterases potentiates pneumococcal neuraminidase activity for mucin utilization, colonization and virulence. Kahya, Hasan F. Andrew, Peter W. Yesilkaya, Hasan http://hdl.handle.net/2381/39610 2017-03-31T02:24:08Z 2017-03-30T15:17:05Z Title: Deacetylation of sialic acid by esterases potentiates pneumococcal neuraminidase activity for mucin utilization, colonization and virulence. Authors: Kahya, Hasan F.; Andrew, Peter W.; Yesilkaya, Hasan Abstract: Pneumococcal neuraminidase is a key enzyme for sequential deglycosylation of host glycans, and plays an important role in host survival, colonization, and pathogenesis of infections caused by Streptococcus pneumoniae. One of the factors that can affect the activity of neuraminidase is the amount and position of acetylation present in its substrate sialic acid. We hypothesised that pneumococcal esterases potentiate neuraminidase activity by removing acetylation from sialic acid, and that will have a major effect on pneumococcal survival on mucin, colonization, and virulence. These hypotheses were tested using isogenic mutants and recombinant esterases in microbiological, biochemical and in vivo assays. We found that pneumococcal esterase activity is encoded by at least four genes, SPD_0534 (EstA) was found to be responsible for the main esterase activity, and the pneumococcal esterases are specific for short acyl chains. Assay of esterase activity by using natural substrates showed that both the Axe and EstA esterases could use acetylated xylan and Bovine Sub-maxillary Mucin (BSM), a highly acetylated substrate, but only EstA was active against tributyrin (triglyceride). Incubation of BSM with either Axe or EstA led to the acetate release in a time and concentration dependent manner, and pre-treatment of BSM with either enzyme increased sialic acid release on subsequent exposure to neuraminidase A. qRT-PCR results showed that the expression level of estA and axe increased when exposed to BSM and in respiratory tissues. Mutation of estA alone or in combination with nanA (codes for neuraminidase A), or the replacement of its putative serine active site to alanine, reduced the pneumococcal ability to utilise BSM as a sole carbon source, sialic acid release, colonization, and virulence in a mouse model of pneumococcal pneumonia. 2017-03-30T15:17:05Z Intestinal Barrier Disturbances in Haemodialysis Patients: Mechanisms, Consequences, and Therapeutic Options March, D. S. Graham-Brown, M. P. Stover, C. M. Bishop, N. C. Burton, James O. http://hdl.handle.net/2381/39603 2017-03-31T02:24:00Z 2017-03-30T10:18:35Z Title: Intestinal Barrier Disturbances in Haemodialysis Patients: Mechanisms, Consequences, and Therapeutic Options Authors: March, D. S.; Graham-Brown, M. P.; Stover, C. M.; Bishop, N. C.; Burton, James O. Abstract: There is accumulating evidence that the intestinal barrier and the microbiota may play a role in the systemic inflammation present in HD patients. HD patients are subject to a number of unique factors, some related to the HD process and others simply to the uraemic milieu but with common characteristic that they can both alter the intestinal barrier and the microbiota. This review is intended to provide an overview of the current methods for measuring such changes in HD patients, the mechanisms behind these changes, and potential strategies that may mitigate these modifications. Lastly, intradialytic exercise is an increasingly employed intervention in HD patients; however the potential implications that this may have for the intestinal barrier are not known; therefore future research directions are also covered. 2017-03-30T10:18:35Z The relationship between biomarkers of fungal allergy and lung damage in asthma. Woolnough, K. F. Richardson, M. Newby, C. Craner, M. Bourne, M. Monteiro, W. Siddiqui, S. Bradding, P. Pashley, C. H. Wardlaw, A. J. http://hdl.handle.net/2381/39564 2017-03-24T03:21:58Z 2017-03-23T15:54:30Z Title: The relationship between biomarkers of fungal allergy and lung damage in asthma. Authors: Woolnough, K. F.; Richardson, M.; Newby, C.; Craner, M.; Bourne, M.; Monteiro, W.; Siddiqui, S.; Bradding, P.; Pashley, C. H.; Wardlaw, A. J. Abstract: BACKGROUND: Immunological biomarkers are the key to the diagnosis of allergic bronchopulmonary aspergillosis (ABPA) and fungal sensitisation, but how these relate to clinically relevant outcomes is unclear. OBJECTIVES: To assess how fungal immunological biomarkers are related to fixed airflow obstruction and radiological abnormalities in moderate to severe asthma. METHODS: Cross-sectional study of 431 asthmatics. Inflammatory biomarkers, lung function and an IgE fungal panel to colonising filamentous fungi, yeasts and fungal aeroallergens were measured. CT scans were scored for the presence of radiological abnormalities. Factor analysis informed the variables used in a k-means cluster analysis. Fixed airflow obstruction and radiological abnormalities were then mapped to these immunological variables in the cluster analysis. RESULTS: 329 (76.3%) subjects were sensitised to ≥ 1 fungi. Sensitisation to Aspergillus fumigatus and/or Penicillium chrysogenum was associated with a lower post-bronchodilator FEV1 compared with those not sensitised to fungi ((73.0 (95% CI 70.2-76) vs. 82.8 (95% CI 78.5-87.2)% predicted, P < 0.001), independent of atopic status (P = 0.005)), and an increased frequency of bronchiectasis (54.5%, P < 0.001), tree-in-bud (18.7%, P < 0.001) and collapse/consolidation (37.5%, P = 0.002). Cluster analysis identified three clusters: (i) hypereosinophilic (n = 71, 16.5%), (ii) high immunological biomarker load and high frequency of radiological abnormalities (n = 34, 7.9%) and (iii) low levels of fungal immunological biomarkers (n = 326, 75.6%). CONCLUSIONS AND CLINICAL RELEVANCE: IgE sensitisation to thermotolerant filamentous fungi, in particular A. fumigatus but not total IgE, is associated with fixed airflow obstruction and a number of radiological abnormalities in moderate to severe asthma. All patients with IgE sensitisation to A. fumigatus are at risk of lung damage irrespective of whether they meet the criteria for ABPA. Description: The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above. 2017-03-23T15:54:30Z Spatial and temporal variations in airborne Ambrosia pollen in Europe Sikoparija, B. Skjøth, C. A. Celenk, S. Testoni, C. Abramidze, T. Alm Kübler, K. Belmonte, J. Berger, U. Bonini, M. Charalampopoulos, A. Damialis, A. Clot, B. Dahl, Å. de Weger, L. A. Gehrig, R. Hendrickx, M. Hoebeke, L. Ianovici, N. Kofol Seliger, A. Magyar, D. Mányoki, G. Milkovska, S. Myszkowska, D. Páldy, A. Pashley, C. H. Rasmussen, K. Ritenberga, O. Rodinkova, V. Rybníček, O. Shalaboda, V. Šaulienė, I. Ščevková, J. Stjepanović, B. Thibaudon, M. Verstraeten, C. Vokou, D. Yankova, R. Smith, M. http://hdl.handle.net/2381/39558 2017-03-24T03:21:58Z 2017-03-23T15:03:02Z Title: Spatial and temporal variations in airborne Ambrosia pollen in Europe Authors: Sikoparija, B.; Skjøth, C. A.; Celenk, S.; Testoni, C.; Abramidze, T.; Alm Kübler, K.; Belmonte, J.; Berger, U.; Bonini, M.; Charalampopoulos, A.; Damialis, A.; Clot, B.; Dahl, Å.; de Weger, L. A.; Gehrig, R.; Hendrickx, M.; Hoebeke, L.; Ianovici, N.; Kofol Seliger, A.; Magyar, D.; Mányoki, G.; Milkovska, S.; Myszkowska, D.; Páldy, A.; Pashley, C. H.; Rasmussen, K.; Ritenberga, O.; Rodinkova, V.; Rybníček, O.; Shalaboda, V.; Šaulienė, I.; Ščevková, J.; Stjepanović, B.; Thibaudon, M.; Verstraeten, C.; Vokou, D.; Yankova, R.; Smith, M. Abstract: The European Commission Cooperation in Science and Technology (COST) Action FA1203 "SMARTER" aims to make recommendations for the sustainable management of Ambrosia across Europe and for monitoring its efficiency and cost-effectiveness. The goal of the present study is to provide a baseline for spatial and temporal variations in airborne Ambrosia pollen in Europe that can be used for the management and evaluation of this noxious plant. The study covers the full range of Ambrosia artemisiifolia L. distribution over Europe (39°N–60°N; 2°W–45°E). Airborne Ambrosia pollen data for the principal flowering period of Ambrosia (August–September) recorded during a 10-year period (2004–2013) were obtained from 242 monitoring sites. The mean sum of daily average airborne Ambrosia pollen and the number of days that Ambrosia pollen was recorded in the air were analysed. The mean and standard deviation (SD) were calculated regardless of the number of years included in the study period, while trends are based on those time series with 8 or more years of data. Trends were considered significant at p < 0.05. There were few significant trends in the magnitude and frequency of atmospheric Ambrosia pollen (only 8% for the mean sum of daily average Ambrosia pollen concentrations and 14% for the mean number of days Ambrosia pollen were recorded in the air). The direction of any trends varied locally and reflected changes in sources of the pollen, either in size or in distance from the monitoring station. Pollen monitoring is important for providing an early warning of the expansion of this invasive and noxious plant. Description: The online version of this article (doi:10.1007/s10453-016-9463-1) contains supplementary material, which is available to authorized users 2017-03-23T15:03:02Z Regular exercise during haemodialysis promotes an anti-inflammatory leukocyte profile Dungey, Maurice Young, Hannah M. L. Churchward, Darren R. Burton, James O. Smith, Alice C. Bishop, Nicolette C. http://hdl.handle.net/2381/39504 2017-04-20T02:20:43Z 2017-03-20T10:14:07Z Title: Regular exercise during haemodialysis promotes an anti-inflammatory leukocyte profile Authors: Dungey, Maurice; Young, Hannah M. L.; Churchward, Darren R.; Burton, James O.; Smith, Alice C.; Bishop, Nicolette C. Abstract: Background Cardiovascular disease (CVD) is the most common cause of mortality in haemodialysis (HD) patients and is highly predicted by markers of chronic inflammation. Regular exercise may have beneficial anti-inflammatory effects, but this is unclear in HD patients. This study assessed the effect of regular intradialytic exercise on soluble inflammatory factors and inflammatory leukocyte phenotypes. Methods Twenty-two HD patients from a centre where intradialytic cycling was offered thrice-weekly and 16 HD patients receiving usual care volunteered. Exercising patients aimed to cycle for 30 min at RPE of "somewhat hard". Baseline characteristic were compared with 16 healthy age-matched individuals. Physical function, soluble inflammatory markers and leukocyte phenotypes were assessed again after 6 months of regular exercise. Results Patients were less active than their healthy counterparts and had significant elevations in measures of inflammation (IL-6, CRP, TNF-α, intermediate and non-classical monocytes; all P<0.001). Six months of regular intradialytic exercise improved physical function (sit-to- stand 60). After 6 months the proportion of intermediate monocytes in the exercising patients reduced compared to non-exercisers (7.58±1.68 to 6.38±1.81% vs. 6.86±1.45 to 7.88±1.66%; P<0.01). Numbers (but not proportion) of regulatory T cells decreased in the non-exercising patients only (P<0.05). Training had no significant effect on circulating IL-6, CRP or TNF-α concentrations. Conclusions These findings suggest regular intradialytic exercise is associated with an anti-inflammatory effect at a circulating cellular level but not in circulating cytokines. This may be protective against the increased risk of CVD and mortality that is associated with chronic inflammation and elevated numbers of intermediate monocytes. 2017-03-20T10:14:07Z The relationship between the Leicester cough questionnaire, eosinophilic airway inflammation and asthma patient related outcomes in severe adult asthma Natarajan, Sushiladevi Free, Robert C. Bradding, Peter McGarvey, Lorcan Siddiqui, Salman http://hdl.handle.net/2381/39490 2017-03-17T03:20:30Z 2017-03-16T15:27:50Z Title: The relationship between the Leicester cough questionnaire, eosinophilic airway inflammation and asthma patient related outcomes in severe adult asthma Authors: Natarajan, Sushiladevi; Free, Robert C.; Bradding, Peter; McGarvey, Lorcan; Siddiqui, Salman Abstract: Severe asthma is characterised by a variety of symptoms, which include chronic cough, however the mechanisms responsible for cough reflex hypersensitivity in asthma remain poorly elucidated. Current asthma patient-related outcome instruments such as the six-point Juniper Asthma Control Score (ACQ-6) and Asthma Quality of Life Questionnaire (AQLQ) were not primarily designed to capture cough and its related morbidity in asthma. The Leicester Cough Questionnaire (LCQ) is a patient-related outcome instrument designed to capture the health-related quality of life associated with cough. To date the LCQ has not been evaluated in a severe asthma population. Methods: We evaluated 262 extensively characterised adult patients with severe asthma attending the Leicester Severe Asthma Service. All patients had a clinician diagnosis of asthma and objective physiological evidence and met the ATS/ERS criterion for servere asthma. In all patients we evaluated a) the LCQ distribution and b) the relationships between the LCQ and ACQ-6, AQLQ, airway inflammation in sputum. Results: The LCQ demonstrated the following properties; mean: 15.0, standard deviation: 4.54, median: 15.48, and range: 11.6-19.2. We found a moderate correlation between LCQ and ACQ-6 (r = - 0.605, p < 0.0001) and a LCQ and AQLQ (r = 0.710, p < 0.0001). There was no relationship between LCQ and log10 sputum percentage eosinophils (%). Conclusion: A proportion of patients with severe asthma have a significant degree of cough-related morbidity that appears independent of eosinophilic airway inflammation and is not captured fully by existing asthma patient-reported outcome instruments. Our preliminary findings suggest that further research is now required to validate the LCQ and its responsiveness in severe asthma populations to capture cough-related morbidity and response to specific interventions. Description: The datasets during and/or analysed during the current study available from the corresponding author on reasonable request. 2017-03-16T15:27:50Z HMGB1 is upregulated in the airways in asthma and potentiates airway smooth muscle contraction via TLR4 Di Candia, Leonarda Gomez, Edith Venereau, Emilie Chachi, Latifa Kaur, Davinder Bianchi, Marco E. Challiss, R. A. John Brightling, Christopher E. Saunders, Ruth M. http://hdl.handle.net/2381/39429 2017-03-11T04:12:19Z 2017-03-10T09:46:36Z Title: HMGB1 is upregulated in the airways in asthma and potentiates airway smooth muscle contraction via TLR4 Authors: Di Candia, Leonarda; Gomez, Edith; Venereau, Emilie; Chachi, Latifa; Kaur, Davinder; Bianchi, Marco E.; Challiss, R. A. John; Brightling, Christopher E.; Saunders, Ruth M. Abstract: [First paragraph] Asthma is characterized by variable airflow obstruction, airway hyperresponsiveness, and inflammation. Airway smooth muscle (ASM) contributes to asthma pathophysiology via hypercontractility, increased mass, and inflammatory mediator release.1 Clinical studies and animal models demonstrate a role for high-mobility group box 1 (HMGB1) and its receptors in airway inflammation and asthma.2 ; 3 HMGB1's activity and receptor interactions is determined by its redox state, with oxidation rendering HMGB1 inactive.4 We have investigated the redox state of airway HMGB1 and the role of HMGB1 in ASM function. Description: In Press, Corrected Proof 2017-03-10T09:46:36Z Allergic Fungal Airway Disease. Rick, E. M. Woolnough, K. Pashley, C. H. Wardlaw, A. J. http://hdl.handle.net/2381/39418 2017-03-15T02:45:07Z 2017-03-08T14:31:47Z Title: Allergic Fungal Airway Disease. Authors: Rick, E. M.; Woolnough, K.; Pashley, C. H.; Wardlaw, A. J. Abstract: Fungi are ubiquitous and form their own kingdom. Up to 80 genera of fungi have been linked to type I allergic disease, and yet, commercial reagents to test for sensitization are available for relatively few species. In terms of asthma, it is important to distinguish between species unable to grow at body temperature and those that can (thermotolerant) and thereby have the potential to colonize the respiratory tract. The former, which include the commonly studied Alternaria and Cladosporium genera, can act as aeroallergens whose clinical effects are predictably related to exposure levels. In contrast, thermotolerant species, which include fungi from the Candida, Aspergillus, and Penicillium genera, can cause a persistent allergenic stimulus independent of their airborne concentrations. Moreover, their ability to germinate in the airways provides a more diverse allergenic stimulus, and may result in noninvasive infection, which enhances inflammation. The close association between IgE sensitization to thermotolerant filamentous fungi and fixed airflow obstruction, bronchiectasis, and lung fibrosis suggests a much more tissue-damaging process than that seen with aeroallergens. This review provides an overview of fungal allergens and the patterns of clinical disease associated with exposure. It clarifies the various terminologies associated with fungal allergy in asthma and makes the case for a new term (allergic fungal airway disease) to include all people with asthma at risk of developing lung damage as a result of their fungal allergy. Lastly, it discusses the management of fungirelated asthma.; Los hongos son obicuos y forman su propio reino. Hasta 80 géneros de hongos han sido asociados con la enfermedad alérgica tipo I; sin embargo, los reactivos comerciales para testar las sensibilizaciones a los mismos, se encuentran disponibles para un número relativamente pequeño de especies. En cuanto al asma, es importante distinguir entre especies incapaces de crecer en temperatura ambiente y aquellas que son termotolerantes y que, por lo tanto, tienen una capacidad potencial para colonizar el tracto respiratorio. Los primeros, que incluyen los géneros comúnmente estudiados Alternaria y Cladosporium, pueden actuar como aeroalérgenos y sus efectos clínicos están relacionados con los niveles de exposición. En contraste, las especies termotolerantes, que incluyen hongos del género Candida, Aspergillus y Penicillium, pueden causar un estímulo alergénico persistente independiente de su concentración en el aire. Además, su capacidad para germinar en las vías aéreas da lugar a estímulos alergénicos más diversos y puede dar como resultado infecciones no invasivas que facilitan la inflamación. La estrecha asociación entre sensibilización dependiente de IgE a hongos filamentosos termotolerantes y la obstrucción del flujo aéreo, bronquiectasias y fibrosis pulmonar sugiere que esto lleva a un proceso de daño tisular mucho mayor que el producido por aeroalérgenos. Esta revisión ofrece una visión general de los alérgenos de los hongos y los patrones de las enfermedades clínicas asociadas a su exposición. Trata de aclarar la terminología variada asociada con la alergia a hongos en asma, ofreciendo un nuevo término (enfermedad alérgica de las vías aéreas por hongos) para englobar a todos los pacientes asmáticos con riesgo de desarrollar daños pulmonares como resultados de su alergia a hongos. Por último, se discute el manejo del asma relacionada con hongos. 2017-03-08T14:31:47Z Tumour cell conditioned medium reveals greater M2 skewing of macrophages in the absence of properdin. Al-Rayahi, Izzat A.M. Browning, Michael J. Stover, Cordula http://hdl.handle.net/2381/39407 2017-03-08T03:21:50Z 2017-03-07T15:33:24Z Title: Tumour cell conditioned medium reveals greater M2 skewing of macrophages in the absence of properdin. Authors: Al-Rayahi, Izzat A.M.; Browning, Michael J.; Stover, Cordula Abstract: INTRODUCTION: The tumour microenvironment is shaped by the interaction of immune, non immune, and tumour cells present in close proximity. Tumour cells direct the development of a locally immune suppressed state, affecting the activity of anti tumour T cells and preparing the escape phase of tumour development. Macrophages in the tumour typically develop into so-called tumour associated macrophages with a distinct profile of activities which lead to a reduction in inflammation and antigen presentation. The direct impact of tumour cell conditioned medium on the activity profile of macrophages in dependence of their complement component expression has not yet been investigated. METHODS: In our in vitro study, macrophages differentiated from bone marrows of properdin deficient and wildtype mice were stimulated with conditioned medium of a syngeneic tumour cell line, B16F10, a mouse melanoma subline. RESULTS: In comparison with macrophages from wildtype mice, those from congenic properdin deficient mice showed skewing towards M2 profile, encompassing mRNA expression for genes involved in arginine metabolism, production of type 2 cytokines, and relatively lower surface expression of molecules needed for antigen presentation. CONCLUSIONS: These data suggest that properdin insufficiency promotes a tumour environment that helps the tumour evade the immune response. 2017-03-07T15:33:24Z Individualised risk in patients undergoing lung volume reduction surgery (LVRS): The Glenfield BFG Score Greening, Neil J. Vaughn, Paul Oey, Inger Steiner, Michael C. Morgan, Mike D. Rathinam, Sridhar Waller, David A. http://hdl.handle.net/2381/39364 2017-06-15T13:20:47Z 2017-02-22T14:55:37Z Title: Individualised risk in patients undergoing lung volume reduction surgery (LVRS): The Glenfield BFG Score Authors: Greening, Neil J.; Vaughn, Paul; Oey, Inger; Steiner, Michael C.; Morgan, Mike D.; Rathinam, Sridhar; Waller, David A. Abstract: Introduction: LVRS has been shown to be beneficial in patients with COPD but there is low uptake, partly due to perceived concerns of high operative mortality. We aimed to develop an individualised risk score after LVRS. Methods: This was a cohort study of patients undergoing LVRS. Factors independently predicting 90 day mortality and a risk prediction score were identified. Reliability of the score was tested using area under receiver operator characteristic curve (AUROC). Results: 237 LVRS procedures were performed. The multivariate analysis factors associated independently with death were; BMI <18.5 kg/m2(OR 2.83, p=0.059), FEV1<0.71L (OR 5.47, p=0.011) and TLCO<20% (OR 5.56, p=0.031). A risk score was calculated and a total score assigned. AUROC for the risk score was 0.80 and a better predictor than individual components (p<0.01). The score was stratified into three risk groups. 46% of patients were classified as low risk. Similar improvements in lung function and health status were seen in all groups. The score was introduced and tested in a further 71 patients. AUROC for 90 day mortality in this cohort was 0.84. Conclusion: It is possible to provide an individualised predictive risk score for LVRS, which may aid decision making for both clinicians and patients. Description: The file associated with this record is under embargo until 18 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above. 2017-02-22T14:55:37Z Improving acute care for older people at scale - the Acute Frailty Network Rumley-Buss, A. Thompson, D. Gladman, J. Guest, J. Hawkins, J. Smith, L. Tite, M. Burge, P. Conroy, Simon Griffiths, S. http://hdl.handle.net/2381/39339 2017-02-08T03:22:04Z 2017-02-07T10:54:35Z Title: Improving acute care for older people at scale - the Acute Frailty Network Authors: Rumley-Buss, A.; Thompson, D.; Gladman, J.; Guest, J.; Hawkins, J.; Smith, L.; Tite, M.; Burge, P.; Conroy, Simon; Griffiths, S. Abstract: Older people form a growing proportion and volume of those accessing urgent care. Non-specific presentations, multiple comorbidities and functional decline make assessment and management of this cohort challenging. Comprehensive Geriatric Assessment offers an evidence based framework to assess and mange older people, especially those with frailty. In this article we describe the CGA approach, underpinned by specific examples illustrating some of the key competencies required, and describe the role of the Acute Frailty Network (AFN). The AFN is a national improvement collaborative designed to support hospitals in delivering evidence based care for older people with frailty and urgent care needs. We describe the principles underlying the approach of the AFN, derived from working with over 20 hospitals, and some of the early successes. Description: The file associated with this record is embargoed while permission to archive is sought from the publisher. The final published version may be available through the links above. 2017-02-07T10:54:35Z Flexibility in Mannan-Binding Lectin-Associated Serine Proteases-1 and -2 Provides Insight on Lectin Pathway Activation. Nan, R. Furze, Christopher M. Wright, D. W. Gor, J. Wallis, Russell Perkins, S. J. http://hdl.handle.net/2381/39338 2017-02-08T03:22:04Z 2017-02-07T09:47:18Z Title: Flexibility in Mannan-Binding Lectin-Associated Serine Proteases-1 and -2 Provides Insight on Lectin Pathway Activation. Authors: Nan, R.; Furze, Christopher M.; Wright, D. W.; Gor, J.; Wallis, Russell; Perkins, S. J. Abstract: The lectin pathway of complement is activated by complexes comprising a recognition component (mannose-binding lectin, serum ficolins, collectin-LK or collectin-K1) and a serine protease (MASP-1 or MASP-2). MASP-1 activates MASP-2, and MASP-2 cleaves C4 and C4b-bound C2. To clarify activation, new crystal structures of Ca(2+)-bound MASP dimers were determined, together with their solution structures from X-ray scattering, analytical ultracentrifugation, and atomistic modeling. Solution structures of the CUB1-EGF-CUB2 dimer of each MASP indicate that the two CUB2 domains were tilted by as much as 90° compared with the crystal structures, indicating considerable flexibility at the EGF-CUB2 junction. Solution structures of the full-length MASP dimers in their zymogen and activated forms revealed similar structures that were much more bent than anticipated from crystal structures. We conclude that MASP-1 and MASP-2 are flexible at multiple sites and that this flexibility may permit both intra- and inter-complex activation. Description: Supplemental Information includes Supplemental Experimental Procedures, two figures, one table, and six pdb files and can be found with this article online at http://dx.doi.org/10.1016/j.str.2016.12.014. 2017-02-07T09:47:18Z Combustion of dried animal dung as biofuel results in the generation of highly redox active fine particulates Mudway, I. S. Duggan, S. T. Venkataraman, C. Habib, G. Kelly, F. J. Grigg, Jonathan http://hdl.handle.net/2381/39310 2017-01-28T03:55:48Z 2017-01-27T18:00:18Z Title: Combustion of dried animal dung as biofuel results in the generation of highly redox active fine particulates Authors: Mudway, I. S.; Duggan, S. T.; Venkataraman, C.; Habib, G.; Kelly, F. J.; Grigg, Jonathan Abstract: Background The burning of biomass in the developing world for heating and cooking results in high indoor particle concentrations. Long-term exposure to airborne particulate matter (PM) has been associated with increased rates of acute respiratory infections, chronic obstructive lung disease and cancer. In this study we determined the oxidative activity of combustion particles derived from the biomass fuel dung cake by examining their capacity to deplete antioxidants from a model human respiratory tract lining fluid (RTLF). For comparison, the observed oxidative activity was compared with that of particles derived from industrial and vehicular sources. Results Incubation of the dung cake particle suspensions in the RTLF for 4 h resulted in a mean loss of ascorbate of 72.1 ± 0.7 and 89.7 ± 2.5% at 50 and 100 μg/ml, respectively. Reduced glutathione was depleted by 49.6 ± 4.3 and 63.5 ± 22.4% under the same conditions. The capacity of these samples to deplete ascorbate was in excess of that observed with diesel or gasoline particles, but comparable to that seen with residual oil fly ash and considerably in excess of all three control particles in terms of glutathione depletion. Co-incubation with the metal chelator diethylenetriaminepentaacetate inhibited these losses, whilst minimal inhibition was seen with superoxide dismutase and catalase treatment. The majority of the activity observed appeared to be contained within aqueous particle extracts. Conclusion These data demonstrate that biomass derived particles have considerable oxidative activity, largely attributable to their transition metal content. 2017-01-27T18:00:18Z BMI-1 extends proliferative potential of human bronchial epithelial cells whilst retaining their mucociliary differentiation capacity. Munye, M. M. Shoemark, A. Hirst, Robert A. Delhove, J. M. Sharp, T. V. McKay, T. R. O'Callaghan, C. Baines, D. L. Howe, S. J. Hart, S. L. http://hdl.handle.net/2381/39309 2017-01-28T04:11:46Z 2017-01-27T17:54:36Z Title: BMI-1 extends proliferative potential of human bronchial epithelial cells whilst retaining their mucociliary differentiation capacity. Authors: Munye, M. M.; Shoemark, A.; Hirst, Robert A.; Delhove, J. M.; Sharp, T. V.; McKay, T. R.; O'Callaghan, C.; Baines, D. L.; Howe, S. J.; Hart, S. L. Abstract: Air-liquid interface (ALI) culture of primary airway epithelial cells enables mucociliary differentiation providing an in vitro model of the human airway but their proliferative potential is limited. To extend proliferation, these cells were previously transduced with viral oncogenes or mouse Bmi-1 + hTERT but the resultant cell lines did not undergo mucociliary differentiation. We hypothesised that use of human BMI-1 alone would increase the proliferative potential of bronchial epithelial cells while retaining their mucociliary differentiation potential. CF and non-CF bronchial epithelial cells were transduced by lentivirus with BMI-1 then their morphology, replication kinetics and karyotype were assessed. When differentiated at ALI, mucin production, ciliary function and transepithelial electrophysiology were measured. Finally, shRNA knockdown of DNAH5 in BMI-1 cells was used to model primary ciliary dyskinesia (PCD). BMI-1 transduced basal cells showed normal cell morphology, karyotype and doubling times despite extensive passaging. The cell lines underwent mucociliary differentiation when cultured at ALI with abundant ciliation and production of the gel-forming mucins MUC5AC and MUC5B evident. Cilia displayed a normal beat frequency and 9+2 ultrastructure. Electrophysiological characteristics of BMI-1 transduced cells were similar to un-transduced cells. shRNA knockdown of DNAH5 in BMI-1 cells produced immotile cilia and absence of DNAH5 in the ciliary axoneme as seen in cells from patients with PCD. BMI-1 delayed senescence in bronchial epithelial cells, increasing their proliferative potential but maintaining mucociliary differentiation at ALI. We have shown these cells are amenable to genetic manipulation and can be used to produce novel disease models for research and dissemination. Description: One year embargo 2017-01-27T17:54:36Z Innate immune humoral factors, C1q and factor H, with differential pattern recognition properties, alter macrophage response to carbon nanotubes. Pondman, K. M. Pednekar, L. Paudyal, B. Tsolaki, A. G. Kouser, L. Khan, H. A. Shamji, M. H. Ten Haken, B. Stenbeck, G. Sim, Robert B. Kishore, U. http://hdl.handle.net/2381/39237 2017-01-21T03:44:56Z 2017-01-20T12:37:22Z Title: Innate immune humoral factors, C1q and factor H, with differential pattern recognition properties, alter macrophage response to carbon nanotubes. Authors: Pondman, K. M.; Pednekar, L.; Paudyal, B.; Tsolaki, A. G.; Kouser, L.; Khan, H. A.; Shamji, M. H.; Ten Haken, B.; Stenbeck, G.; Sim, Robert B.; Kishore, U. Abstract: Interaction between the complement system and carbon nanotubes (CNTs) can modify their intended biomedical applications. Pristine and derivatised CNTs can activate complement primarily via the classical pathway which enhances uptake of CNTs and suppresses pro-inflammatory response by immune cells. Here, we report that the interaction of C1q, the classical pathway recognition molecule, with CNTs involves charge pattern and classical pathway activation that is partly inhibited by factor H, a complement regulator. C1q and its globular modules, but not factor H, enhanced uptake of CNTs by macrophages and modulated the pro-inflammatory immune response. Thus, soluble complement factors can interact differentially with CNTs and alter the immune response even without complement activation. Coating CNTs with recombinant C1q globular heads offers a novel way of controlling classical pathway activation in nanotherapeutics. Surprisingly, the globular heads also enhance clearance by phagocytes and down-regulate inflammation, suggesting unexpected complexity in receptor interaction. From the Clinical Editor Carbon nanotubes (CNTs) maybe useful in the clinical setting as targeting drug carriers. However, it is also well known that they can interact and activate the complement system, which may have a negative impact on the applicability of CNTs. In this study, the authors functionalized multi-walled CNT (MWNT), and investigated the interaction with the complement pathway. These studies are important so as to gain further understanding of the underlying mechanism in preparation for future use of CNTs in the clinical setting. Description: Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.nano.2015.06.009. 2017-01-20T12:37:22Z Effects of endothelin receptor antagonism in an experimental model of renal transplantation Shah, K. K. Hosgood, S. Patel, M. Nicholson, M. http://hdl.handle.net/2381/39235 2017-01-21T03:57:13Z 2017-01-20T12:11:14Z Title: Effects of endothelin receptor antagonism in an experimental model of renal transplantation Authors: Shah, K. K.; Hosgood, S.; Patel, M.; Nicholson, M. Abstract: Aim: Uncontrolled Donation after Circulatory Death (uDCD) donors provide a large potential source of kidneys but there is reluctance to use them due to prolonged warm ischaemic times. Endothelin-1, a potent vasoconstrictor, is a major contributor to ischaemic injury. This study aimed to investigate the benefit of endothelin receptor blockade in an experimental model of uDCD transplantation. Methods: Porcine kidneys underwent 60 minutes warm ischaemia and 2 hours cold ischaemia followed by 3 hours of reperfusion with autologous blood without (control, n = 6) and with (n = 6) 500μg BQ-123, a selective ETA endothelin receptor antagonist. Markers of renal function and injury were analysed. Results: Renal blood flow was significantly higher in the experimental group at 15–30 minutes of reperfusion (29.6–37.7 vs. 13.1–18.2 ml/min/100 g, p = 0.02), after which, although higher throughout, statistical significance was lost. Urine output, creatinine clearance and oxygen consumption were also higher in the experimental group throughout but statistical significance was only seen in the 1st hour urine output (83 vs. 32 ml/hr, p = 0.01). Urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL) levels were not different between the groups. Conclusion: Kidneys can recover from warm ischaemic injury. BQ-123 appeared to improve perfusion and function initially but did not have a sustained effect or significant overall benefit. 2017-01-20T12:11:14Z Temperature dependent bacteriophages of a tropical bacterial pathogen. Shan, Jinyu Korbsrisate, S. Withatanung, P. Adler, Natalie Lazar Clokie, Martha R. J. Galyov, Edouard E. http://hdl.handle.net/2381/39220 2017-01-19T03:16:47Z 2017-01-18T17:03:35Z Title: Temperature dependent bacteriophages of a tropical bacterial pathogen. Authors: Shan, Jinyu; Korbsrisate, S.; Withatanung, P.; Adler, Natalie Lazar; Clokie, Martha R. J.; Galyov, Edouard E. Abstract: There is an increasing awareness of the multiple ways that bacteriophages (phages) influence bacterial evolution, population dynamics, physiology, and pathogenicity. By studying a novel group of phages infecting a soil borne pathogen, we revealed a paradigm shifting observation that the phages switch their lifestyle according to temperature. We sampled soil from an endemic area of the serious tropical pathogen Burkholderia pseudomallei, and established that podoviruses infecting the pathogen are frequently present in soil, and many of them are naturally occurring variants of a common virus type. Experiments on one phage in the related model B. thailandensis demonstrated that temperature defines the outcome of phage-bacteria interactions. At higher temperatures (37°C), the phage predominantly goes through a lytic cycle, but at lower temperatures (25°C), the phage remains temperate. This is the first report of a naturally occurring phage that follows a lytic or temperate lifestyle according to temperature. These observations fundamentally alter the accepted views on the abundance, population biology and virulence of B. pseudomallei. Furthermore, when taken together with previous studies, our findings suggest that the phenomenon of temperature dependency in phages is widespread. Such phages are likely to have a profound effect on bacterial biology, and on our ability to culture and correctly enumerate viable bacteria. 2017-01-18T17:03:35Z Current evidence and future research needs for FeNO measurement in respiratory diseases Bjermer, L. Alving, K. Diamant, Z. Magnussen, H. Pavord, Ian Piacentini, G. Price, D. Roche, N. Sastre, J. Thomas, M. Usmani, O. http://hdl.handle.net/2381/39209 2017-01-19T03:21:07Z 2017-01-18T14:58:27Z Title: Current evidence and future research needs for FeNO measurement in respiratory diseases Authors: Bjermer, L.; Alving, K.; Diamant, Z.; Magnussen, H.; Pavord, Ian; Piacentini, G.; Price, D.; Roche, N.; Sastre, J.; Thomas, M.; Usmani, O. Abstract: Although not yet widely implemented, fraction of exhaled nitric oxide (FeNO) has emerged in recent years as a potentially useful biomarker for the assessment of airway inflammation both in undiagnosed patients with non-specific respiratory symptoms and in those with established airway disease. Research to date essentially suggests that FeNO measurement facilitates the identification of patients exhibiting T-helper cell type 2 (Th2)-mediated airway inflammation, and effectively those in whom anti-inflammatory therapy, particularly inhaled corticosteroids (ICS), is beneficial. In some studies, FeNO-guided management of patients with established airway disease is associated with lower exacerbation rates, improvements in adherence to anti-inflammatory therapy, and the ability to predict risk of future exacerbations or decline in lung function. Despite these data, concerns regarding the applicability and utility of FeNO in clinical practice still remain. This article reviews the current evidence, both supportive and critical of FeNO measurement, in the diagnosis and management of asthma and other inflammatory airway diseases. It additionally provides suggestions regarding the practical application of FeNO measurement: how it could be integrated into routine clinical practice, how its utility could be assessed and its true value to both clinicians and patients could be established. Although some unanswered questions remain, current evidence suggests that FeNO is potentially a valuable tool for improving the personalised management of inflammatory airway diseases. 2017-01-18T14:58:27Z Latent tuberculosis infection screening and treatment in HIV: Insights from evaluation of UK practice White, Helena A. Miller, R. F. Pozniak, A. L. Lipman, M. C. I. Stephenson, Iain Wiselka, Martin J. Pareek, Manish http://hdl.handle.net/2381/39198 2017-02-15T09:30:28Z 2017-01-18T10:01:50Z Title: Latent tuberculosis infection screening and treatment in HIV: Insights from evaluation of UK practice Authors: White, Helena A.; Miller, R. F.; Pozniak, A. L.; Lipman, M. C. I.; Stephenson, Iain; Wiselka, Martin J.; Pareek, Manish Abstract: Latent TB infection (LTBI) screening and treatment in HIV-positive individuals in the UK is advocated by the British HIV Association (BHIVA) and National Institute for Health and Care Excellence (NICE), although each recommends differing strategies. We undertook an evaluation of UK practice, relating the responses to the local HIV/TB disease burden. 162 of 188 (86%) UK geographical areas responded; only 93/162 (57.4%) offer LTBI testing with considerable heterogeneity in practice, and no difference in HIV/TB burden between areas offering testing and those who do not. Only 33/93 (35.5%) and 6/93 (6.5%) reported full compliance with BHIVA and NICE guidance respectively. A uniform national guideline is required. 2017-01-18T10:01:50Z Use of single molecule sequencing for comparative genomics of an environmental and a clinical isolate of Clostridium difficile ribotype 078. Hargreaves, Katherine R. Thanki, Anisha M. Jose, Bethany R. Oggioni, Marco R. Clokie, Martha R. J. http://hdl.handle.net/2381/39183 2017-01-18T03:28:19Z 2017-01-17T12:59:51Z Title: Use of single molecule sequencing for comparative genomics of an environmental and a clinical isolate of Clostridium difficile ribotype 078. Authors: Hargreaves, Katherine R.; Thanki, Anisha M.; Jose, Bethany R.; Oggioni, Marco R.; Clokie, Martha R. J. Abstract: BACKGROUND: How the pathogen Clostridium difficile might survive, evolve and be transferred between reservoirs within the natural environment is poorly understood. Some ribotypes are found both in clinical and environmental settings. Whether these strains are distinct from each another and evolve in the specific environments is not established. The possession of a highly mobile genome has contributed to the genetic diversity and ongoing evolution of C. difficile. Interpretations of genetic diversity have been limited by fragmented assemblies resulting from short-read length sequencing approaches and by a limited understanding of epigenetic regulation of diversity. To address this, single molecule real time (SMRT) sequencing was used in this study as it produces high quality genome sequences, with resolution of repeat regions (including those found in mobile elements) and can generate data to determine methylation modifications across the sequence (the methylome). RESULTS: Chromosomal rearrangements and ribosomal operon duplications were observed in both genomes. The rearrangements occurred at insertion sites within two mobile genetic elements (MGEs), Tn6164 and Tn6293, present only in the M120 and CD105HS27 genomes, respectively. The gene content of these two transposons differ considerably which could impact upon horizontal gene transfer; differences include CDSs encoding methylases and a conjugative prophage only in Tn6164. To investigate mechanisms which could affect MGE transfer, the methylome, restriction modification (RM) and the CRISPR/Cas systems were characterised for each strain. Notably, the environmental isolate, CD105HS27, does not share a consensus motif for (m4)C methylation, but has one additional spacer when compared to the clinical isolate M120. CONCLUSIONS: These findings show key differences between the two strains in terms of their genetic capacity for MGE transfer. The carriage of horizontally transferred genes appear to have genome wide effects based on two different methylation patterns. The CRISPR/Cas system appears active although perhaps slow to evolve. Data suggests that both mechanisms are functional and impact upon horizontal gene transfer and genome evolution within C. difficile. Description: The two SMRT generated genomes of M120 and CD105HS27 have been deposited in the ENA in study PRJEB13565 and have accession numbers ERS1242840 and ERS1242839, respectively. The methylation data has been deposited for each isolate in REBASE as organisms #19242 and #19243, respectively. 2017-01-17T12:59:51Z ARIA 2016: Care pathways implementing emerging technologies for predictive medicine in rhinitis and asthma across the life cycle. Bousquet, J. Hellings, P. W. Agache, I. Bedbrook, A. Bachert, C. Bergmann, K. C. Bewick, M. Bindslev-Jensen, C. Bosnic-Anticevitch, S. Bucca, C. Caimmi, D. P. Camargos, P. A. Canonica, G. W. Casale, T. Chavannes, N. H. Cruz, A. A. De Carlo, G. Dahl, R. Demoly, P. Devillier, P. Fonseca, J. Fokkens, W. J. Guldemond, N. A. Haahtela, T. Illario, M. Just, J. Keil, T. Klimek, L. Kuna, P. Larenas-Linnemann, D. Morais-Almeida, M. Mullol, J. Murray, R. Naclerio, R. O'Hehir, R. E. Papadopoulos, N. G. Pawankar, R. Potter, P. Ryan, D. Samolinski, B. Schunemann, H. J. Sheikh, A. Simons, F. E. Stellato, C. Todo-Bom, A. Tomazic, P. V. Valiulis, A. Valovirta, E. Ventura, M. T. Wickman, M. Young, I. Yorgancioglu, A. Zuberbier, T. Aberer, W. Akdis, C. A. Akdis, M. Annesi-Maesano, I. Ankri, J. Ansotegui, I. J. Anto, J. M. Arnavielhe, S. Asarnoj, A. Arshad, H. Avolio, F. Baiardini, I. Barbara, C. Barbagallo, M. Bateman, E. D. Beghé, B. Bel, E. H. Bennoor, K. S. Benson, M. Białoszewski, A. Z. Bieber, T. Bjermer, L. Blain, H. Blasi, F. Boner, A. L. Bonini, M. Bonini, S. Bosse, I. Bouchard, J. Boulet, L. P. Bourret, R. Bousquet, P. J. Braido, F. Briggs, A. H. Brightling, C. E. Brozek, J. Buhl, R. Bunu, C. Burte, E. Bush, A. Caballero-Fonseca, F. Calderon, M. A. Camuzat, T. Cardona, V. Carreiro-Martins, P. Carriazo, A. M. Carlsen, K. H. Carr, W. Cepeda Sarabia, A. M. Cesari, M. Chatzi, L. Chiron, R. Chivato, T. Chkhartishvili, E. Chuchalin, A. G. Chung, K. F. Ciprandi, G. de Sousa, J. C. Cox, L. Crooks, G. Custovic, A. Dahlen, S. E. Darsow, U. Dedeu, T. Deleanu, D. Denburg, J. A. De Vries, G. Didier, A. Dinh-Xuan, A. T. Dokic, D. Douagui, H. Dray, G. Dubakiene, R. Durham, S. R. Du Toit, G. Dykewicz, M. S. Eklund, P. El-Gamal, Y. Ellers, E. Emuzyte, R. Farrell, J. Fink Wagner, A. Fiocchi, A. Fletcher, M. Forastiere, F. Gaga, M. Gamkrelidze, A. Gemicioğlu, B. Gereda, J. E. van Wick, R. G. González Diaz, S. Grisle, I. Grouse, L. Gutter, Z. Guzmán, M. A. Hellquist-Dahl, B. Heinrich, J. Horak, F. Hourihane, J. O. Humbert, M. Hyland, M. Iaccarino, G. Jares, E. J. Jeandel, C. Johnston, S. L. Joos, G. Jonquet, O. Jung, K. S. Jutel, M. Kaidashev, I. Khaitov, M. Kalayci, O. Kalyoncu, A. F. Kardas, P. Keith, P. K. Kerkhof, M. Kerstjens, H. A. Khaltaev, N. Kogevinas, M. Kolek, V. Koppelman, G. H. Kowalski, M. L. Kuitunen, M. Kull, I. Kvedariene, V. Lambrecht, B. Lau, S. Laune, D. Le, L. T. Lieberman, P. Lipworth, B. Li, J. Lodrup Carlsen, K. C. Louis, R. Lupinek, C. MacNee, W. Magar, Y. Magnan, A. Mahboub, B. Maier, D. Majer, I. Malva, J. Manning, P. De Manuel Keenoy, E. Marshall, G. D. Masjedi, M. R. Mathieu-Dupas, E. Maurer, M. Mavale-Manuel, S. Melén, E. Melo-Gomes, E. Meltzer, E. O. Mercier, J. Merk, H. Miculinic, N. Mihaltan, F. Milenkovic, B. Millot-Keurinck, J. Mohammad, Y. Momas, I. Mösges, R. Muraro, A. Namazova-Baranova, L. Nadif, R. Neffen, H. Nekam, K. Nieto, A. Niggemann, B. Nogueira-Silva, L. Nogues, M. Nyembue, T. D. Ohta, K. Okamoto, Y. Okubo, K. Olive-Elias, M. Ouedraogo, S. Paggiaro, P. Pali-Schöll, I. Palkonen, S. Panzner, P. Papi, A. Park, H. S. Passalacqua, G. Pedersen, S. Pereira, A. M. Pfaar, O. Picard, R. Pigearias, B. Pin, I. Plavec, D. Pohl, W. Popov, T. A. Portejoie, F. Postma, D. Poulsen, L. K. Price, D. Rabe, K. F. Raciborski, F. Roberts, G. Robalo-Cordeiro, C. Rodenas, F. Rodriguez-Mañas, L. Rolland, C. Roman Rodriguez, M. Romano, A. Rosado-Pinto, J. Rosario, N. Rottem, M. Sanchez-Borges, M. Sastre-Dominguez, J. Scadding, G. K. Scichilone, N. Schmid-Grendelmeier, P. Serrano, E. Shields, M. Siroux, V. Sisul, J. C. Skrindo, I. Smit, H. A. Solé, D. Sooronbaev, T. Spranger, O. Stelmach, R. Sterk, P. J. Strandberg, T. Sunyer, J. Thijs, C. Triggiani, M. Valenta, R. Valero, A. van Eerd, M. van Ganse, E. van Hague, M. Vandenplas, O. Varona, L. L. Vellas, B. Vezzani, G. Vazankari, T. Viegi, G. Vontetsianos, T. Wagenmann, M. Walker, S. Wang, D. Y. Wahn, U. Werfel, T. Whalley, B. Williams, D. M. Williams, S. Wilson, N. Wright, J. Yawn, B. P. Yiallouros, P. K. Yusuf, O. M. Zaidi, A. Zar, H. J. Zernotti, M. E. Zhang, L. Zhong, N. Zidarn, M. http://hdl.handle.net/2381/39182 2017-01-18T03:25:55Z 2017-01-17T12:54:40Z Title: ARIA 2016: Care pathways implementing emerging technologies for predictive medicine in rhinitis and asthma across the life cycle. Authors: Bousquet, J.; Hellings, P. W.; Agache, I.; Bedbrook, A.; Bachert, C.; Bergmann, K. C.; Bewick, M.; Bindslev-Jensen, C.; Bosnic-Anticevitch, S.; Bucca, C.; Caimmi, D. P.; Camargos, P. A.; Canonica, G. W.; Casale, T.; Chavannes, N. H.; Cruz, A. A.; De Carlo, G.; Dahl, R.; Demoly, P.; Devillier, P.; Fonseca, J.; Fokkens, W. J.; Guldemond, N. A.; Haahtela, T.; Illario, M.; Just, J.; Keil, T.; Klimek, L.; Kuna, P.; Larenas-Linnemann, D.; Morais-Almeida, M.; Mullol, J.; Murray, R.; Naclerio, R.; O'Hehir, R. E.; Papadopoulos, N. G.; Pawankar, R.; Potter, P.; Ryan, D.; Samolinski, B.; Schunemann, H. J.; Sheikh, A.; Simons, F. E.; Stellato, C.; Todo-Bom, A.; Tomazic, P. V.; Valiulis, A.; Valovirta, E.; Ventura, M. T.; Wickman, M.; Young, I.; Yorgancioglu, A.; Zuberbier, T.; Aberer, W.; Akdis, C. A.; Akdis, M.; Annesi-Maesano, I.; Ankri, J.; Ansotegui, I. J.; Anto, J. M.; Arnavielhe, S.; Asarnoj, A.; Arshad, H.; Avolio, F.; Baiardini, I.; Barbara, C.; Barbagallo, M.; Bateman, E. D.; Beghé, B.; Bel, E. H.; Bennoor, K. S.; Benson, M.; Białoszewski, A. Z.; Bieber, T.; Bjermer, L.; Blain, H.; Blasi, F.; Boner, A. L.; Bonini, M.; Bonini, S.; Bosse, I.; Bouchard, J.; Boulet, L. P.; Bourret, R.; Bousquet, P. J.; Braido, F.; Briggs, A. H.; Brightling, C. E.; Brozek, J.; Buhl, R.; Bunu, C.; Burte, E.; Bush, A.; Caballero-Fonseca, F.; Calderon, M. A.; Camuzat, T.; Cardona, V.; Carreiro-Martins, P.; Carriazo, A. M.; Carlsen, K. H.; Carr, W.; Cepeda Sarabia, A. M.; Cesari, M.; Chatzi, L.; Chiron, R.; Chivato, T.; Chkhartishvili, E.; Chuchalin, A. G.; Chung, K. F.; Ciprandi, G.; de Sousa, J. C.; Cox, L.; Crooks, G.; Custovic, A.; Dahlen, S. E.; Darsow, U.; Dedeu, T.; Deleanu, D.; Denburg, J. A.; De Vries, G.; Didier, A.; Dinh-Xuan, A. T.; Dokic, D.; Douagui, H.; Dray, G.; Dubakiene, R.; Durham, S. R.; Du Toit, G.; Dykewicz, M. S.; Eklund, P.; El-Gamal, Y.; Ellers, E.; Emuzyte, R.; Farrell, J.; Fink Wagner, A.; Fiocchi, A.; Fletcher, M.; Forastiere, F.; Gaga, M.; Gamkrelidze, A.; Gemicioğlu, B.; Gereda, J. E.; van Wick, R. G.; González Diaz, S.; Grisle, I.; Grouse, L.; Gutter, Z.; Guzmán, M. A.; Hellquist-Dahl, B.; Heinrich, J.; Horak, F.; Hourihane, J. O.; Humbert, M.; Hyland, M.; Iaccarino, G.; Jares, E. J.; Jeandel, C.; Johnston, S. L.; Joos, G.; Jonquet, O.; Jung, K. S.; Jutel, M.; Kaidashev, I.; Khaitov, M.; Kalayci, O.; Kalyoncu, A. F.; Kardas, P.; Keith, P. K.; Kerkhof, M.; Kerstjens, H. A.; Khaltaev, N.; Kogevinas, M.; Kolek, V.; Koppelman, G. H.; Kowalski, M. L.; Kuitunen, M.; Kull, I.; Kvedariene, V.; Lambrecht, B.; Lau, S.; Laune, D.; Le, L. T.; Lieberman, P.; Lipworth, B.; Li, J.; Lodrup Carlsen, K. C.; Louis, R.; Lupinek, C.; MacNee, W.; Magar, Y.; Magnan, A.; Mahboub, B.; Maier, D.; Majer, I.; Malva, J.; Manning, P.; De Manuel Keenoy, E.; Marshall, G. D.; Masjedi, M. R.; Mathieu-Dupas, E.; Maurer, M.; Mavale-Manuel, S.; Melén, E.; Melo-Gomes, E.; Meltzer, E. O.; Mercier, J.; Merk, H.; Miculinic, N.; Mihaltan, F.; Milenkovic, B.; Millot-Keurinck, J.; Mohammad, Y.; Momas, I.; Mösges, R.; Muraro, A.; Namazova-Baranova, L.; Nadif, R.; Neffen, H.; Nekam, K.; Nieto, A.; Niggemann, B.; Nogueira-Silva, L.; Nogues, M.; Nyembue, T. D.; Ohta, K.; Okamoto, Y.; Okubo, K.; Olive-Elias, M.; Ouedraogo, S.; Paggiaro, P.; Pali-Schöll, I.; Palkonen, S.; Panzner, P.; Papi, A.; Park, H. S.; Passalacqua, G.; Pedersen, S.; Pereira, A. M.; Pfaar, O.; Picard, R.; Pigearias, B.; Pin, I.; Plavec, D.; Pohl, W.; Popov, T. A.; Portejoie, F.; Postma, D.; Poulsen, L. K.; Price, D.; Rabe, K. F.; Raciborski, F.; Roberts, G.; Robalo-Cordeiro, C.; Rodenas, F.; Rodriguez-Mañas, L.; Rolland, C.; Roman Rodriguez, M.; Romano, A.; Rosado-Pinto, J.; Rosario, N.; Rottem, M.; Sanchez-Borges, M.; Sastre-Dominguez, J.; Scadding, G. K.; Scichilone, N.; Schmid-Grendelmeier, P.; Serrano, E.; Shields, M.; Siroux, V.; Sisul, J. C.; Skrindo, I.; Smit, H. A.; Solé, D.; Sooronbaev, T.; Spranger, O.; Stelmach, R.; Sterk, P. J.; Strandberg, T.; Sunyer, J.; Thijs, C.; Triggiani, M.; Valenta, R.; Valero, A.; van Eerd, M.; van Ganse, E.; van Hague, M.; Vandenplas, O.; Varona, L. L.; Vellas, B.; Vezzani, G.; Vazankari, T.; Viegi, G.; Vontetsianos, T.; Wagenmann, M.; Walker, S.; Wang, D. Y.; Wahn, U.; Werfel, T.; Whalley, B.; Williams, D. M.; Williams, S.; Wilson, N.; Wright, J.; Yawn, B. P.; Yiallouros, P. K.; Yusuf, O. M.; Zaidi, A.; Zar, H. J.; Zernotti, M. E.; Zhang, L.; Zhong, N.; Zidarn, M. Abstract: The Allergic Rhinitis and its Impact on Asthma (ARIA) initiative commenced during a World Health Organization workshop in 1999. The initial goals were (1) to propose a new allergic rhinitis classification, (2) to promote the concept of multi-morbidity in asthma and rhinitis and (3) to develop guidelines with all stakeholders that could be used globally for all countries and populations. ARIA-disseminated and implemented in over 70 countries globally-is now focusing on the implementation of emerging technologies for individualized and predictive medicine. MASK [MACVIA (Contre les Maladies Chroniques pour un Vieillissement Actif)-ARIA Sentinel NetworK] uses mobile technology to develop care pathways for the management of rhinitis and asthma by a multi-disciplinary group and by patients themselves. An app (Android and iOS) is available in 20 countries and 15 languages. It uses a visual analogue scale to assess symptom control and work productivity as well as a clinical decision support system. It is associated with an inter-operable tablet for physicians and other health care professionals. The scaling up strategy uses the recommendations of the European Innovation Partnership on Active and Healthy Ageing. The aim of the novel ARIA approach is to provide an active and healthy life to rhinitis sufferers, whatever their age, sex or socio-economic status, in order to reduce health and social inequalities incurred by the disease. 2017-01-17T12:54:40Z Monitoring asthma in childhood: management-related issues. Rottier, B. L. Eber, E. Hedlin, G. Turner, S. Wooler, E. Mantzourani, E. Kulkarni, Neeta ERS Task Force Monitoring Asthma in Children http://hdl.handle.net/2381/39107 2017-01-11T03:20:37Z 2017-01-10T09:52:52Z Title: Monitoring asthma in childhood: management-related issues. Authors: Rottier, B. L.; Eber, E.; Hedlin, G.; Turner, S.; Wooler, E.; Mantzourani, E.; Kulkarni, Neeta; ERS Task Force Monitoring Asthma in Children Abstract: Management-related issues are an important aspect of monitoring asthma in children in clinical practice. This review summarises the literature on practical aspects of monitoring including adherence to treatment, inhalation technique, ongoing exposure to allergens and irritants, comorbid conditions and side-effects of treatment, as agreed by the European Respiratory Society Task Force on Monitoring Asthma in Childhood. The evidence indicates that it is important to discuss adherence to treatment in a non-confrontational way at every clinic visit, and take into account a patient's illness and medication beliefs. All task force members teach inhalation techniques at least twice when introducing a new inhalation device and then at least annually. Exposure to second-hand tobacco smoke, combustion-derived air pollutants, house dust mites, fungal spores, pollens and pet dander deserve regular attention during follow-up according to most task force members. In addition, allergic rhinitis should be considered as a cause for poor asthma control. Task force members do not screen for gastro-oesophageal reflux and food allergy. Height and weight are generally measured at least annually to identify individuals who are susceptible to adrenal suppression and to calculate body mass index, even though causality between obesity and asthma has not been established. In cases of poor asthma control, before stepping up treatment the above aspects of monitoring deserve closer attention. Description: This is a supporting document of the ERS Task Force Monitoring Asthma in Children published in the European Respiratory Journal: Pijnenburg MW, Baraldi E, Brand PLP, et al. Monitoring asthma in children. Eur Respir J 2015; 45: 906–925. 2017-01-10T09:52:52Z Molecular Characterization of N-glycan Degradation and Transport in Streptococcus pneumoniae and Its Contribution to Virulence. Robb, M. Hobbs, J. K. Woodiga, S. A. Shapiro-Ward, S. Suits, M. D. McGregor, N. Brumer, H. Yesilkaya, H. King, S. J. Boraston, A. B. http://hdl.handle.net/2381/39090 2017-02-15T09:32:07Z 2017-01-09T14:56:15Z Title: Molecular Characterization of N-glycan Degradation and Transport in Streptococcus pneumoniae and Its Contribution to Virulence. Authors: Robb, M.; Hobbs, J. K.; Woodiga, S. A.; Shapiro-Ward, S.; Suits, M. D.; McGregor, N.; Brumer, H.; Yesilkaya, H.; King, S. J.; Boraston, A. B. Abstract: The carbohydrate-rich coating of human tissues and cells provide a first point of contact for colonizing and invading bacteria. Commensurate with N-glycosylation being an abundant form of protein glycosylation that has critical functional roles in the host, some host-adapted bacteria possess the machinery to process N-linked glycans. The human pathogen Streptococcus pneumoniae depolymerizes complex N-glycans with enzymes that sequentially trim a complex N-glycan down to the Man3GlcNAc2 core prior to the release of the glycan from the protein by endo-β-N-acetylglucosaminidase (EndoD), which cleaves between the two GlcNAc residues. Here we examine the capacity of S. pneumoniae to process high-mannose N-glycans and transport the products. Through biochemical and structural analyses we demonstrate that S. pneumoniae also possesses an α-(1,2)-mannosidase (SpGH92). This enzyme has the ability to trim the terminal α-(1,2)-linked mannose residues of high-mannose N-glycans to generate Man5GlcNAc2. Through this activity SpGH92 is able to produce a substrate for EndoD, which is not active on high-mannose glycans with α-(1,2)-linked mannose residues. Binding studies and X-ray crystallography show that NgtS, the solute binding protein of an ABC transporter (ABCNG), is able to bind Man5GlcNAc, a product of EndoD activity, with high affinity. Finally, we evaluated the contribution of EndoD and ABCNG to growth of S. pneumoniae on a model N-glycosylated glycoprotein, and the contribution of these enzymes and SpGH92 to virulence in a mouse model. We found that both EndoD and ABCNG contribute to growth of S. pneumoniae, but that only SpGH92 and EndoD contribute to virulence. Therefore, N-glycan processing, but not transport of the released glycan, is required for full virulence in S. pneumoniae. To conclude, we synthesize our findings into a model of N-glycan processing by S. pneumoniae in which both complex and high-mannose N-glycans are targeted, and in which the two arms of this degradation pathway converge at ABCNG. Description: Coordinates and structure factors have been deposited with the following accession codes into the Protein Data Bank: SpGH92 in complex with mannose (5SWI); native NgtS (5SUO); NgtS in complex with Man1GlcNAc (5SWA); NgtS in complex with Man5GlcNAc (5SWB). 2017-01-09T14:56:15Z Mucosal type 2 innate lymphoid cells are a key component of the allergic response to aeroallergen Dhariwal, J. Cameron, A. Trujillo-Torralbo, M. del Rosario, A. Bakhsoliani, E. Paulsen, M. Jackson, D. J. Edwards, M. R. Rana, B. M. J. Cousins, David J. Hansel, T. T. Johnston, S. L. Walton, R. P. http://hdl.handle.net/2381/39087 2017-04-06T01:45:08Z 2017-01-09T13:09:23Z Title: Mucosal type 2 innate lymphoid cells are a key component of the allergic response to aeroallergen Authors: Dhariwal, J.; Cameron, A.; Trujillo-Torralbo, M.; del Rosario, A.; Bakhsoliani, E.; Paulsen, M.; Jackson, D. J.; Edwards, M. R.; Rana, B. M. J.; Cousins, David J.; Hansel, T. T.; Johnston, S. L.; Walton, R. P. Abstract: Rationale: Newly characterised type 2 innate lymphoid cells display potent type 2 effector functionality, however their contribution to allergic airways inflammation and asthma is poorly understood. Mucosal biopsy used to characterise the airway mucosa is invasive, poorly tolerated and does not allow for sequential sampling. Objectives: To assess the role of type 2 innate lymphoid cells during nasal allergen challenge in subjects with allergic rhinitis, using novel non-invasive methodology. Methods: We used a human experimental allergen challenge model, with flow cytometric analysis of nasal curettage samples, to assess the recruitment of type 2 innate lymphoid cells and granulocytes to the upper airways of atopic and healthy subjects following allergen provocation. Soluble mediators in the nasal lining fluid were measured using nasosorption. Measurements and Main Results: Following allergen challenge, atopic subjects displayed rapid induction of upper airway symptoms, an enrichment of type 2 innate lymphoid cells, eosinophils and neutrophils, along with increased production of interleukin-5, prostaglandin D2, and eosinophil and T-helper type 2 cell chemokines compared to healthy subjects. The most pronounced type 2 innate lymphoid cell recruitment was observed in patients with elevated serum IgE and airway eosinophilia. Conclusions: The rapid recruitment of type 2 innate lymphoid cells to the upper airways of allergic rhinitis patients, and their association with key type 2 mediators, highlights their likely important role in the early allergic response to aeroallergen in the airways. The novel methodology described herein enables the analysis of rare cell populations from non-invasive, serial tissue sampling. 2017-01-09T13:09:23Z European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia. Lucas, J. S. Barbato, A. Collins, S. A. Goutaki, M. Behan, L. Caudri, D. Dell, S. Eber, E. Escudier, E. Hirst, Robert Hogg, C. Jorissen, M. Latzin, P. Legendre, M. Leigh, M. W. Midulla, F. Nielsen, K. G. Omran, H. Papon, J. F. Pohunek, P. Redfern, B. Rigau, D. Rindlisbacher, B. Santamaria, F. Shoemark, A. Snijders, D. Tonia, T. Titieni, A. Walker, W. T. Werner, C. Bush, A. Kuehni, C. E. http://hdl.handle.net/2381/39063 2017-01-05T03:24:08Z 2017-01-04T16:58:14Z Title: European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia. Authors: Lucas, J. S.; Barbato, A.; Collins, S. A.; Goutaki, M.; Behan, L.; Caudri, D.; Dell, S.; Eber, E.; Escudier, E.; Hirst, Robert; Hogg, C.; Jorissen, M.; Latzin, P.; Legendre, M.; Leigh, M. W.; Midulla, F.; Nielsen, K. G.; Omran, H.; Papon, J. F.; Pohunek, P.; Redfern, B.; Rigau, D.; Rindlisbacher, B.; Santamaria, F.; Shoemark, A.; Snijders, D.; Tonia, T.; Titieni, A.; Walker, W. T.; Werner, C.; Bush, A.; Kuehni, C. E. Abstract: The diagnosis of primary ciliary dyskinesia is often confirmed with standard, albeit complex and expensive, tests. In many cases, however, the diagnosis remains difficult despite the array of sophisticated diagnostic tests. There is no "gold standard" reference test. Hence, a Task Force supported by the European Respiratory Society has developed this guideline to provide evidence-based recommendations on diagnostic testing, especially in light of new developments in such tests, and the need for robust diagnoses of patients who might enter randomised controlled trials of treatments. The guideline is based on pre-defined questions relevant for clinical care, a systematic review of the literature, and assessment of the evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. It focuses on clinical presentation, nasal nitric oxide, analysis of ciliary beat frequency and pattern by high-speed video-microscopy analysis, transmission electron microscopy, genotyping and immunofluorescence. It then used a modified Delphi survey to develop an algorithm for the use of diagnostic tests to definitively confirm and exclude the diagnosis of primary ciliary dyskinesia; and to provide advice when the diagnosis was not conclusive. Finally, this guideline proposes a set of quality criteria for future research on the validity of diagnostic methods for primary ciliary dyskinesia. Description: This article has supplementary material available from erj.ersjournals.com 2017-01-04T16:58:14Z Mast cell phenotype, TNFα expression and degranulation status in non-small cell lung cancer. Shikotra, A. Ohri, C. M. Green, R. H. Waller, D. A. Bradding, P. http://hdl.handle.net/2381/39045 2017-01-05T03:24:08Z 2017-01-04T14:29:31Z Title: Mast cell phenotype, TNFα expression and degranulation status in non-small cell lung cancer. Authors: Shikotra, A.; Ohri, C. M.; Green, R. H.; Waller, D. A.; Bradding, P. Abstract: Mast cell infiltration of tumour islets represents a survival advantage in non-small cell lung cancer (NSCLC). The phenotype and activation status of these mast cells is unknown. We investigated the mast cell phenotype in terms of protease content (tryptase-only [MCT], tryptase + chymase [MCTC]) and tumour necrosis factor-alpha (TNFα) expression, and extent of degranulation, in NSCLC tumour stroma and islets. Surgically resected tumours from 24 patients with extended survival (ES; mean survival 86.5 months) were compared with 25 patients with poor survival (PS; mean survival 8.0 months) by immunohistochemistry. Both MCT and MCTC in tumour islets were higher in ES (20.0 and 5.6 cells/mm(2) respectively) compared to PS patients (0.0 cells/mm(2)) (p < 0.0001). Both phenotypes expressed TNFα in the islets and stroma. In ES 44% of MCT and 37% of MCTC expressed TNFα in the tumour islets. MCT in the ES stroma were more degranulated than in those with PS (median degranulation index = 2.24 versus 1.73 respectively) (p = 0.0022), and ES islet mast cells (2.24 compared to 1.71, p < 0.0001). Since both MCT and MCTC infiltrating tumour islets in ES NSCLC patients express TNFα, the cytotoxic activity of this cytokine may confer improved survival in these patients. Manipulating mast cell microlocalisation and functional responses in NSCLC may offer a novel approach to the treatment of this disease. 2017-01-04T14:29:31Z Hypoxia upregulates neutrophil degranulation and potential for tissue injury. Hoenderdos, K. Lodge, K. M. Hirst, Robert A. Chen, C. Palazzo, S. G. Emerenciana, A. Summers, C. Angyal, A. Porter, L. Juss, J. K. O'Callaghan, C. Chilvers, E. R. Condliffe, A. M. http://hdl.handle.net/2381/39035 2017-01-04T03:19:51Z 2017-01-03T15:05:13Z Title: Hypoxia upregulates neutrophil degranulation and potential for tissue injury. Authors: Hoenderdos, K.; Lodge, K. M.; Hirst, Robert A.; Chen, C.; Palazzo, S. G.; Emerenciana, A.; Summers, C.; Angyal, A.; Porter, L.; Juss, J. K.; O'Callaghan, C.; Chilvers, E. R.; Condliffe, A. M. Abstract: BACKGROUND: The inflamed bronchial mucosal surface is a profoundly hypoxic environment. Neutrophilic airway inflammation and neutrophil-derived proteases have been linked to disease progression in conditions such as COPD and cystic fibrosis, but the effects of hypoxia on potentially harmful neutrophil functional responses such as degranulation are unknown. METHODS AND RESULTS: Following exposure to hypoxia (0.8% oxygen, 3 kPa for 4 h), neutrophils stimulated with inflammatory agonists (granulocyte-macrophage colony stimulating factor or platelet-activating factor and formylated peptide) displayed a markedly augmented (twofold to sixfold) release of azurophilic (neutrophil elastase, myeloperoxidase), specific (lactoferrin) and gelatinase (matrix metalloproteinase-9) granule contents. Neutrophil supernatants derived under hypoxic but not normoxic conditions induced extensive airway epithelial cell detachment and death, which was prevented by coincubation with the antiprotease α-1 antitrypsin; both normoxic and hypoxic supernatants impaired ciliary function. Surprisingly, the hypoxic upregulation of neutrophil degranulation was not dependent on hypoxia-inducible factor (HIF), nor was it fully reversed by inhibition of phospholipase C signalling. Hypoxia augmented the resting and cytokine-stimulated phosphorylation of AKT, and inhibition of phosphoinositide 3-kinase (PI3K)γ (but not other PI3K isoforms) prevented the hypoxic upregulation of neutrophil elastase release. CONCLUSION: Hypoxia augments neutrophil degranulation and confers enhanced potential for damage to respiratory airway epithelial cells in a HIF-independent but PI3Kγ-dependent fashion. Description: Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/thoraxjnl-2015-207604) 2017-01-03T15:05:13Z Human macrophage inflammatory protein alpha (MIP-1 alpha) and MIP-1 beta chemokines attract distinct populations of lymphocytes. Schall, T. J. Bacon, K. Camp, R. D. Kaspari, J. W. Goeddel, D. V. http://hdl.handle.net/2381/38957 2016-12-16T03:14:10Z 2016-12-15T09:45:02Z Title: Human macrophage inflammatory protein alpha (MIP-1 alpha) and MIP-1 beta chemokines attract distinct populations of lymphocytes. Authors: Schall, T. J.; Bacon, K.; Camp, R. D.; Kaspari, J. W.; Goeddel, D. V. Abstract: Lymphocyte trafficking is an essential process in immune and inflammatory functions which can be thought to contain at least two main components: adhesion and migration. Whereas adhesion molecules such as the selections are known to mediate the homing of leukocytes from the blood to the endothelium, the chemoattractant substances responsible for the migration of specific subsets of lymphocytes to sites of infection or inflammation are largely unknown. Here we show that two molecules in the chemokine (for chemoattractant cytokine) superfamily, human macrophage inflammatory protein 1 alpha (MIP-1 alpha) and MIP-1 beta, do not share identical attractant activities for lymphocyte subpopulations. When analyzed in vitro in microchemotaxis experiments, HuMIP-1 beta tends to attract CD4+ T lymphocytes, with some preference for T cells of the naive (CD45RA) phenotype. HuMIP-1 alpha, when tested in parallel with HuMIP-1 beta, is a more potent lymphocyte chemoattractant with a broader range of concentration-dependent chemoattractant specificities. HuMIP-1 alpha at a concentration of 100 pg/ml attracts B cells and cytotoxic T cells, whereas at higher concentrations (10 ng/ml), the migration of these cells appears diminished, and the migration of CD4+ T cells is enhanced. Thus, in this assay system, HuMIP-1 alpha and -1 beta have differential attractant activities for subsets of immune effector cells, with HuMIP-1 alpha having greater effects than HuMIP-1 beta, particularly on B cells. 2016-12-15T09:45:02Z Evaluation of Antigens for Development of a Serological Test for Human African Trypanosomiasis Biéler, S. Waltenberger, H. Barrett, M. P. McCulloch, R. Mottram, J. C. Carrington, M. Schwaeble, Wilhelm McKerrow, J. Phillips, M. A. Michels, P. A. Büscher, P. Sanchez, J-C. Bishop, R. Robinson, D. R. Bangs, J. Ferguson, M. Nerima, B. Albertini, A. Michel, G. Radwandska, M. Mathu Ndung'u, J. http://hdl.handle.net/2381/38935 2016-12-15T03:20:20Z 2016-12-14T11:08:05Z Title: Evaluation of Antigens for Development of a Serological Test for Human African Trypanosomiasis Authors: Biéler, S.; Waltenberger, H.; Barrett, M. P.; McCulloch, R.; Mottram, J. C.; Carrington, M.; Schwaeble, Wilhelm; McKerrow, J.; Phillips, M. A.; Michels, P. A.; Büscher, P.; Sanchez, J-C.; Bishop, R.; Robinson, D. R.; Bangs, J.; Ferguson, M.; Nerima, B.; Albertini, A.; Michel, G.; Radwandska, M.; Mathu Ndung'u, J. Abstract: Background Control and elimination of human African trypanosomiasis (HAT) can be accelerated through the use of diagnostic tests that are more accurate and easier to deploy. The goal of this work was to evaluate the immuno-reactivity of antigens and identify candidates to be considered for development of a simple serological test for the detection of Trypanosoma brucei gambiense or T. b. rhodesiense infections, ideally both. Methodology/Principal Findings The reactivity of 35 antigens was independently evaluated by slot blot and ELISA against sera from both T. b. gambiense and T. b. rhodesiense infected patients and controls. The antigens that were most reactive by both tests to T. b. gambiense sera were the membrane proteins VSG LiTat 1.3, VSG LiTat 1.5 and ISG64. Reactivity to T. b. rhodesiense sera was highest with VSG LiTat 1.3, VSG LiTat 1.5 and SRA, although much lower than with T. b. gambiense samples. The reactivity of all possible combinations of antigens was also calculated. When the slot blot results of 2 antigens were paired, a VSG LiTat 1.3- ISG75 combination performed best on T. b. gambiense sera, while a VSG LiTat 1.3-VSG LiTat 1.5 combination was the most reactive using ELISA. A combination of SRA and either VSG LiTat 1.3 or VSG LiTat 1.5 had the highest reactivity on T. b. rhodesiense sera according to slot blot, while in ELISA, pairing SRA with either GM6 or VSG LiTat 1.3 yielded the best results. Conclusions This study identified antigens that were highly reactive to T. b. gambiense sera, which could be considered for developing a serological test for gambiense HAT, either individually or in combination. Antigens with potential for inclusion in a test for T. b. rhodesiense HAT were also identified, but because their reactivity was comparatively lower, a search for additional antigens would be required before developing a test for this form of the disease. 2016-12-14T11:08:05Z Effect of Immunosuppressive Drugs on the Changes of Serum Galactose-Deficient IgA1 in Patients with IgA Nephropathy. Kim, M. J. Schaub, S. Molyneux, Karen Koller, M. T. Stampf, S. Barratt, Jonathan http://hdl.handle.net/2381/38934 2016-12-15T03:20:23Z 2016-12-14T11:02:53Z Title: Effect of Immunosuppressive Drugs on the Changes of Serum Galactose-Deficient IgA1 in Patients with IgA Nephropathy. Authors: Kim, M. J.; Schaub, S.; Molyneux, Karen; Koller, M. T.; Stampf, S.; Barratt, Jonathan Abstract: Galactose-deficient IgA1 (Gd-IgA1) and IgA-IgG complexes are known to play an important role in the pathogenesis of IgA nephropathy (IgAN). We aimed therefore to determine the impact of immunosuppression on the serum levels of Gd-IgA1, total IgA1 and IgA-IgG complexes in IgAN patients. In a retrospective study, serum samples from IgAN patients collected before transplantation (t0) and at 3- and 6-month posttransplant (t3 & t6) were used to measure the levels of Gd-IgA1, total IgA1 and IgA-IgG complexes. The area under the curves (AUC) of immunosuppressants was calculated by the plot of plasma trough level or dosage of each immunosuppressant versus time and was interpreted as the extent of drug exposure. Thirty-six out of 64 IgAN patients, who underwent kidney transplantation between 2005 and 2012, were enrolled. From t0 to t3, serum Gd-IgA1 and total IgA1 decreased significantly (24.7 AU (18.6-36.1) to 17.2 (13.1-29.5) (p<0.0001); 4.1 mg/ml (3.6-5.1) to 3.4 (3.0-4.1) (p = 0.0005)), whereas IgA-IgG complexes remained similar. From t3 to t6, Gd-IgA1 and IgA-IgG complexes significantly increased (17.2 AU (13.1-29.5) to 23.9 (16.8-32.0) (p = 0.0143); OD 0.16 (0.06-0.31) to 0.26 (0.14-0.35) (p = 0.0242)), while total IgA1 remained similar. According to median regression analysis, AUC of prednisone t0-6 was significantly associated with the decrease of Gd-IgA1 t0-6 (P = 0.01) and IgA1 t0-6 (p = 0.002), whereas AUC of tacrolimus t0-6 was associated with the decrease of IgA1 t0-6 (p = 0.02). AUC of prednisone t0-3 was associated with the decrease of IgA-IgG complexes t0-3 (p = 0.0036). The association of AUC prednisone t0-6 with Gd-IgA1 t0-6 remained highly significant after adjustment for other immunosuppressants (p = 0.0036). Serum levels of Gd-IgA1, total IgA1 and IgA-IgG in patients with IgAN vary according to the changing degrees of immunosuppression. The exposure to prednisone most clearly influenced the serum levels of Gd-IgA1. 2016-12-14T11:02:53Z Dietary fat in relation to fatty acid composition of red cells and adipose tissue in colorectal cancer Neoptolemos, J. P. Clayton, H. Heagerty, A. M. Nicholson, M. J. Johnson, B. Mason, J. Manson, K. James, R. F. L. Bell, P. R. F. http://hdl.handle.net/2381/38926 2016-12-14T03:21:05Z 2016-12-13T16:00:02Z Title: Dietary fat in relation to fatty acid composition of red cells and adipose tissue in colorectal cancer Authors: Neoptolemos, J. P.; Clayton, H.; Heagerty, A. M.; Nicholson, M. J.; Johnson, B.; Mason, J.; Manson, K.; James, R. F. L.; Bell, P. R. F. Abstract: Fatty acids were determined in erthrocytes in 49 patients with colorectal cancer and compared with age and sex-matched controls. Marginally increased levels of stearic acid (P = 0.057) and oleic acid (P = 0.064) and decreased arachidonic acid (P = 0.043) occurred in cancer patients. There was no difference in the stearic to oleic acid ratio between the two groups. Dietary intake, assessed by dietary recall and adipose tissue analysis was also not different. In control subjects the polyunsaturated:saturated (P:S) fatty acid ratio correlated between diet and adipose tissue (P less than 0.01, at least). In contrast cancer patients showed different correlations; in particular dietary and erythrocyte P:S fatty acid ratios correlated (P less than 0.01). These findings may indicate disturbed fat metabolism in cancer patients. The erythrocyte stearic to oleic acid ratio is of no diagnostic value. 2016-12-13T16:00:02Z Human activated macrophages and hypoxia: a comprehensive review of the literature Sotoodehnejadnematalahi, F. Burke, Bernard http://hdl.handle.net/2381/38900 2016-12-13T03:22:41Z 2016-12-12T17:02:13Z Title: Human activated macrophages and hypoxia: a comprehensive review of the literature Authors: Sotoodehnejadnematalahi, F.; Burke, Bernard Abstract: Macrophages accumulate in poorly vascularised and hypoxic sites including solid tumours, wounds and sites of infection and inflammation where they can be exposed to low levels of oxygen for long periods. Up to date, different studies have shown that a number of transcription factors are activated by hypoxia which in turn activate a broad array of mitogenic, pro-invasive, pro-angiogenic, and pro-metastatic genes. On the other hand, macrophages respond to hypoxia by up-regulating several genes which are chief factors in angiogenesis and tumorigenesis. Therefore, in this review article we focus mainly on the role of macrophages during inflammation and discuss their response to hypoxia by regulating a diverse array of transcription factors. We also review the existing literatures on hypoxia and its cellular and molecular mechanism which mediates macrophages activation. 2016-12-12T17:02:13Z The Effects of Exercise and Sport in Solid Organ Transplant Recipients: A Review. Neale, Jill Smith, Alice C. Bishop, Nicolette C. http://hdl.handle.net/2381/38895 2016-12-13T03:22:39Z 2016-12-12T14:55:17Z Title: The Effects of Exercise and Sport in Solid Organ Transplant Recipients: A Review. Authors: Neale, Jill; Smith, Alice C.; Bishop, Nicolette C. Abstract: Solid organ transplantation is the criterion standard treatment for many with end-organ failure and can offer a new independence from the burden of disease. However solid organ transplant recipients (SOTRs) remain at high risk of cardiovascular (CV) disease, and poor quality of life and physical functioning. Increasing physical activity and exercise can improve the health of the general population; however, the effects on those with a transplant remain unclear. Intensive exercise and sporting activity has the potential to be beneficial, although there remain concerns particularly around the effects on immune function and the CV system. This review summarizes what is known about the effects of exercise on determinants of health in SOTRs and then collates the available literature investigating the consequences of intensive exercise and sport on the health of SOTR. There is a paucity of high-quality research, with most evidence being case studies or anecdotal; this is understandable given the relatively few numbers of SOTRs who are performing sport and exercise at a high level. However, if suitable evidence-based guidelines are to be formed and SOTRs are to be given reassurances that their activity levels are not detrimental to their transplanted organ and overall health, then more high-quality studies are required. 2016-12-12T14:55:17Z Intradermal grass pollen immunotherapy increases Th2 and IgE Responses and worsens respiratory allergic symptoms Slovick, A. Douiri, A. Muir, R. Guerra, A. Tsiouslos, K. Hay, E. Lam, E. P. S. Kelly, J. Peacock, J. L. Ying, S. Shamji, M. H. Cousins, David J. Durham, S. R. Till, S. J. http://hdl.handle.net/2381/38808 2016-12-03T03:57:46Z 2016-12-02T12:53:58Z Title: Intradermal grass pollen immunotherapy increases Th2 and IgE Responses and worsens respiratory allergic symptoms Authors: Slovick, A.; Douiri, A.; Muir, R.; Guerra, A.; Tsiouslos, K.; Hay, E.; Lam, E. P. S.; Kelly, J.; Peacock, J. L.; Ying, S.; Shamji, M. H.; Cousins, David J.; Durham, S. R.; Till, S. J. Abstract: Background Repeated low-dose grass pollen intradermal allergen injection suppresses allergen-induced cutaneous late-phase responses comparably with conventional subcutaneous and sublingual immunotherapy. Objective We sought to evaluate the efficacy and safety of grass pollen intradermal immunotherapy in the treatment of allergic rhinitis. Methods We randomly assigned 93 adults with grass pollen–induced allergic rhinitis to receive 7 preseasonal intradermal allergen injections (containing 7 ng of Phl p 5 major allergen) or a histamine control. The primary end point was daily combined symptom-medication scores during the 2013 pollen season (area under the curve). Analysis was by intention to treat. Skin biopsy specimens were collected after intradermal allergen challenges, and late-phase responses were measured 4 and 7, 10, or 13 months after treatment. Results There was no significant difference in the primary end point between treatment arms (active, n = 46; control, n = 47; median difference, 14; 95% CI, −172.5 to 215.1; P = .80). Among secondary end points, nasal symptoms were worse in the intradermal treatment group, as measured based on daily (median difference, 35; 95% CI, 4.0-67.5; P = .03) and visual analog scale (median difference, 53; 95% CI, −11.6 to 125.2; P = .05) scores. In a per-protocol analysis intradermal immunotherapy was further associated with worse asthma symptoms and fewer symptom-free days. Intradermal immunotherapy increased serum Phleum pratense–specific IgE levels (P = .001) compared with those in the control arm. T cells cultured from biopsy specimens of subjects undergoing intradermal immunotherapy had higher expression of the TH2 surface marker CRTH2 (P = .04) and lower expression of the TH1 marker CXCR3 (P = .01), respectively. Late-phase responses remained inhibited 7 months after treatment (P = .03). Conclusion Intradermal allergen immunotherapy suppressed skin late-phase responses but was not clinically effective and resulted in worsening of respiratory allergic symptoms. 2016-12-02T12:53:58Z Development of an In Vitro Assay for Detection of Drug-Induced Resuscitation-Promoting-Factor-Dependent Mycobacteria. Loraine, Jessica Pu, Feifei Turapov, Obolbek Mukamolova, Galina V. http://hdl.handle.net/2381/38785 2017-03-10T11:42:48Z 2016-12-01T14:39:57Z Title: Development of an In Vitro Assay for Detection of Drug-Induced Resuscitation-Promoting-Factor-Dependent Mycobacteria. Authors: Loraine, Jessica; Pu, Feifei; Turapov, Obolbek; Mukamolova, Galina V. Abstract: Tuberculosis is a major infectious disease that requires prolonged chemotherapy with a combination of four drugs. Here we present data suggesting that treatment of Mycobacterium tuberculosis, the causative agent of tuberculosis, and Mycobacterium smegmatis, a model organism widely used for the screening of antituberculosis agents, with first-line drugs resulted in the generation of substantial populations that could be recovered only by the addition of a culture supernatant from growing mycobacteria. These bacilli failed to grow in standard media, resulting in significant underestimation of the numbers of viable mycobacteria in treated samples. We generated M. smegmatis strains overexpressing M. tuberculosis resuscitation-promoting factors (Rpfs) and demonstrated their application for the detection of Rpf-dependent mycobacteria generated after drug exposure. Our data offer novel opportunities for validation of the sterilizing activity of antituberculosis agents. Description: Supplemental material for this article may be found at http://dx.doi.org/10.1128/AAC.00518-16. 2016-12-01T14:39:57Z Differential Effects of p38, MAPK, PI3K or Rho Kinase Inhibitors on Bacterial Phagocytosis and Efferocytosis by Macrophages in COPD. Bewley, M. A. Belchamber, K. B. Chana, K. K. Budd, R. C. Donaldson, G. Wedzicha, J. A. Brightling, Christopher E. Kilty, I. Donnelly, L. E. Barnes, P. J. Singh, D. Whyte, M. K. Dockrell, D. H. COPDMAP http://hdl.handle.net/2381/38781 2016-12-02T03:20:14Z 2016-12-01T12:17:27Z Title: Differential Effects of p38, MAPK, PI3K or Rho Kinase Inhibitors on Bacterial Phagocytosis and Efferocytosis by Macrophages in COPD. Authors: Bewley, M. A.; Belchamber, K. B.; Chana, K. K.; Budd, R. C.; Donaldson, G.; Wedzicha, J. A.; Brightling, Christopher E.; Kilty, I.; Donnelly, L. E.; Barnes, P. J.; Singh, D.; Whyte, M. K.; Dockrell, D. H.; COPDMAP Abstract: Pulmonary inflammation and bacterial colonization are central to the pathogenesis of chronic obstructive pulmonary disease (COPD). Defects in macrophage phagocytosis of both bacteria and apoptotic cells contribute to the COPD phenotype. Small molecule inhibitors with anti-inflammatory activity against p38 mitogen activated protein kinases (MAPKs), phosphatidyl-inositol-3 kinase (PI3K) and Rho kinase (ROCK) are being investigated as novel therapeutics in COPD. Concerns exist, however, about off-target effects. We investigated the effect of p38 MAPK inhibitors (VX745 and SCIO469), specific inhibitors of PI3K α (NVS-P13K-2), δ (NVS-P13K-3) or γ (NVS-P13K-5) and a ROCK inhibitor PF4950834 on macrophage phagocytosis, early intracellular killing of bacteria and efferocytosis of apoptotic neutrophils. Alveolar macrophages (AM) obtained from broncho-alveolar lavage (BAL) or monocyte-derived macrophages (MDM) from COPD patients (GOLD stage II/III) enrolled from a well characterized clinical cohort (MRC COPD-MAP consortium) or from healthy ex-smoker controls were studied. Both COPD AM and MDM exhibited lower levels of bacterial phagocytosis (using Streptococcus pneumoniae and non-typeable Haemophilus influenzae) and efferocytosis than healthy controls. None of the inhibitors altered bacterial internalization or early intracellular bacterial killing in AM or MDM. Conversely PF4950834, but not other inhibitors, enhanced efferocytosis in COPD AM and MDM. These results suggest none of these inhibitors are likely to exacerbate phagocytosis-related defects in COPD, while confirming ROCK inhibitors can enhance efferocytosis in COPD. 2016-12-01T12:17:27Z