60 results found
Kim SY, Mongey S, Wang P, et al., 2021, The Acid Injury and Repair (AIR) model: A new ex vivo tool to understand lung repair, Biomaterials, Vol: 267, ISSN: 0142-9612
Research into mechanisms underlying lung injury and subsequent repair responses is currently of paramount importance. There is a paucity of models that bridge the gap between in vitro and in vivo research. Such intermediate models are critical for researchers to decipher the mechanisms that drive repair and to test potential new treatments for lung repair and regeneration. Here we report the establishment of a new tool, the Acid Injury and Repair (AIR) model, that will facilitate studies of lung tissue repair. In this model, injury is applied to a restricted area of a precision-cut lung slice using hydrochloric acid, a clinically relevant driver. The surrounding area remains uninjured, thus mimicking the heterogeneous pattern of injury frequently observed in lung diseases. We show that in response to injury, the percentage of progenitor cells (pro surfactant protein C, proSP-C and TM4SF1 positive) significantly increases in the injured region. Whereas in the uninjured area, the percentage of proSP-C/TM4SF1 cells remains unchanged but proliferating cells (Ki67 positive) increase. These effects are modified in the presence of inhibitors of proliferation (Cytochalasin D) and Wnt secretion (C59) demonstrating that the AIR model is an important new tool for research into lung disease pathogenesis and potential regenerative medicine strategies.
Kim S, Mongey R, Griffiths M, et al., 2020, An ex vivo acid injury and repair (AIR) model using precision-cut lung slices to understand lung injury and repair, Current protocols in mouse biology, Vol: 10, Pages: e85-e85, ISSN: 2161-2617
Recent advances in cell culture models like air‒liquid interface culture and ex vivo models such as organoids have advanced studies of lung biology; however, gaps exist between these models and tools that represent the complexity of the three‐dimensional environment of the lung. Precision‐cut lung slices (PCLS) mimic the in vivo environment and bridge the gap between in vitro and in vivo models. We have established the acid injury and repair (AIR) model where a spatially restricted area of tissue is injured using drops of HCl combined with Pluronic gel. Injury and repair are assessed by immunofluorescence using robust markers, including Ki67 for cell proliferation and prosurfactant protein C for alveolar type 2/progenitor cells. Importantly, the AIR model enables the study of injury and repair in mouse lung tissue without the need for an initial in vivo injury, and the results are highly reproducible. Here, we present detailed protocols for the generation of PCLS and the AIR model. We also describe methods to analyze and quantify injury in AIR‐PCLS by immunostaining with established early repair markers and fluorescence imaging. This novel ex vivo model is a versatile tool for studying lung cell biology in acute lung injury and for semi‐high‐throughput screening of potential therapeutics. © 2020 Wiley Periodicals LLC.
Cheong SS, Akram K, Metellan C, et al., 2020, The planar polarity component Vangl2 is a key regulator of mechanosignaling, Frontiers in Cell and Developmental Biology, Vol: 8, ISSN: 2296-634X
VANGL2 is a component of the planar cell polarity (PCP) pathway, which regulates tissue polarity and patterning. The Vangl2Lp mutation causes lung branching defects due to dysfunctional actomyosin-driven morphogenesis. Since the actomyosin network regulates cell mechanics, we speculated that mechanosignaling could be impaired when VANGL2 is disrupted. Here, we used live-imaging of precision-cut lung slices (PCLS) from Vangl2Lp/+ mice to determine that alveologenesis is attenuated as a result of impaired epithelial cell migration. Vangl2Lp/+ tracheal epithelial cells (TECs) and alveolar epithelial cells (AECs) exhibited highly disrupted actomyosin networks and focal adhesions (FAs). Functional assessment of cellular forces confirmed impaired traction force generation in Vangl2Lp/+ TECs. YAP signaling in Vangl2Lp airway epithelium was reduced, consistent with a role for VANGL2 in mechanotransduction. Furthermore, activation of RhoA signaling restored actomyosin organization in Vangl2Lp/+, confirming RhoA as an effector of VANGL2. This study identifies a pivotal role for VANGL2 in mechanosignaling, which underlies the key role of the PCP pathway in tissue morphogenesis.
Dean C, Taylor B, Rice A, et al., 2020, Mechanism of lung development in the aetiology of adult congenital pulmonary airway malformations, Thorax, Vol: 75, Pages: 1001-1003, ISSN: 0040-6376
Congenital pulmonary airway malformations (CPAMs) are rare lung abnormalities that result in cyst formation and are associated with respiratory distress in infants and malignant potential in adults. The pathogenesis of CPAMs remains unknown but data suggest disruption of the normal proximo-distal programme of airway branching and differentiation. Here, we demonstrate that adult human CPAM are lined with epithelium that retains SOX-2 and thyroid transcription factor-1 immunohistochemical markers, characteristic of the developing lung. However, RALDH-1, another key marker, is absent. This suggests a more complex aetiology for CPAM than complete focal arrest of lung development and may provide insight to the associated risk of malignancy.
RATIONALE: Poor lung health in adult life may occur partly through suboptimal growth and development, as suggested by epidemiological evidence pointing to early life risk factors. OBJECTIVES: To systematically investigate the effects of lung development genes on adult lung function. METHODS: Using UK Biobank data, we tested the association of 391 genes known to influence lung development with FVC and FEV1/FVC. We split the dataset into two random subsets of 207,616 and 138,411 individuals, using the larger to select the most promising signals and the smaller for replication. MEASUREMENTS AND MAIN RESULTS: We identified 55 genes, of which 36 (16 for FVC; 19 for FEV1/FVC; 1 for both) had not been identified in the largest, most recent genome-wide study of lung function. Most of these 36 signals were intronic variants; expression data from blood and lung tissue showed that the majority affect the expression of the genes they lie within. Further testing of 34 of these 36 signals in the CHARGE and SpiroMeta consortia showed that 16 replicated after Bonferroni correction and another 12 at nominal significance level. 53 of the 55 genes fell into four biological categories whose function is to regulate organ size and cell integrity (growth factors; transcriptional regulators; cell-cell adhesion; extra-cellular matrix), suggesting that these specific processes are important for adult lung health. CONCLUSIONS: Our study demonstrates the importance of lung development genes in regulating adult lung function and influencing both restrictive and obstructive patterns. Further investigation of these developmental pathways could lead to druggable targets.
Singh S, Hind M, Jordan S, et al., 2020, Weaning by surgical tracheostomy and portable ventilators released ICU ventilators during coronavirus disease 2019 surge in London., Critical Care Explorations, Vol: 2, Pages: 1-3, ISSN: 2639-8028
Price S, Singh S, Ledot S, et al., 2020, Respiratory management in severe acute respiratory syndrome coronavirus 2 infection., European Heart Journal: Acute Cardiovascular Care, Vol: 9, Pages: 229-238, ISSN: 2048-8734
The severe acute respiratory syndrome coronavirus 2 pandemic is to date affecting more than a million of patients and is challenging healthcare professionals around the world. Coronavirus disease 2019 may present with a wide range of clinical spectrum and severity, including severe interstitial pneumonia with high prevalence of hypoxic respiratory failure requiring intensive care admission. There has been increasing sharing experience regarding the patient's clinical features over the last weeks which has underlined the need for general guidance on treatment strategies. We summarise the evidence existing in the literature of oxygen and positive pressure treatments in patients at different stages of respiratory failure and over the course of the disease, including environment and ethical issues related to the ongoing coronavirus disease 2019 infection.
Akram K, Yates L, Mongey R, et al., 2019, Time-lapse imaging of alveologenesis in mouse precision-cut lung slices, Bio-protocol, Vol: 9, ISSN: 2331-8325
Alveoli are the gas-exchange units of lung. The process of alveolar development,alveologenesis, is regulated by a complex network of signaling pathways that act on various cell typesincluding alveolar type I and II epithelial cells, fibroblasts and the vascular endothelium. Dysregulatedalveologenesis results in bronchopulmonary dysplasia in neonates and in adults, disrupted alveolarregeneration is associated with chronic lung diseases including COPD and pulmonary fibrosis.Therefore, visualizing alveologenesis is critical to understand lung homeostasis and for thedevelopment of effective therapies for incurable lung diseases. We have developed a technique tovisualize alveologenesis in real-time using a combination of widefield microscopy and imagedeconvolution of precision-cut lung slices. Here, we describe this live imaging technique in step-by-stepdetail. This time-lapse imaging technique can be used to capture the dynamics of individual cells withintissue slices over a long time period (up to 16 h), with minimal loss of fluorescence or cell toxicity.
Cockbain B, Price LC, Hind M, 2019, Bony breathlessness: reversible pulmonary hypertension in melnick-needles syndrome using noninvasive ventilation, Circulation, Vol: 140, Pages: 880-885, ISSN: 0009-7322
Patient presentation: A 48-year-old woman with Melnick-Needles Syndrome (MNS, a congenital bony dysplasia) was referred because ofprogressive breathlessness and exertional presyncope.She described 12 months of progressive exertional dyspnea with reduced exercise tolerance. She could walk just 10 m on the flat and foundher office-based job unmanageable. There were features of exertional presyncope but no collapse, chest pain, cough, or palpitations. She reportedan inability to sleep supine, nocturia, morning headaches, and poor-quality, unrefreshing sleep.She had snored since childhood, improving after micrognathia surgeryin her 20s. Smoking history was modest: a 3 pack-year exposure quitting adecade earlier. She consumed minimal alcohol and no recreational drugs.She took no regular medication and reported no recent foreign travel.Aside from MNS, she had no other notable history.
Liew F, Gargoum F, Potter R, et al., 2019, Platypnoea-orthodeoxia syndrome: beware of investigations undertaken supine, Thorax, Vol: 74, Pages: 917-919, ISSN: 1468-3296
Platypnoea-orthodeoxia syndrome (POS) is a rare disorder, manifesting as deoxygenation occurring when the patient is in the upright position. Four broad mechanisms for the condition have been described: intracardiac shunts, intrapulmonary shunts, hepatopulmonary syndrome and pulmonary ventilation-perfusion mismatch. Here, we present the first case of POS in a patient with a proven right to left intracardiac shunt occurring in the context of postural hypotension and normal right heart pressures. We highlight the need to carry out investigations in the upright position before discounting intracardiac shunting as a cause for the syndrome. Short-term improvement of the syndrome was obtained with medical management of the patient's orthostatic hypotension and as such suggests a conservative management strategy for similar patients, which may delay the need for invasive procedures to close the anatomical defect.
Ng-Blichfeldt J-P, Gosens R, Dean C, et al., 2019, Regenerative pharmacology for COPD: breathing new life into old lungs, Thorax, Vol: 74, Pages: 890-897, ISSN: 1468-3296
Chronic obstructive pulmonary disease (COPD) is a major global health concern with few effective treatments. Widespread destruction of alveolar tissue contributes to impaired gas exchange in severe COPD, and recent radiological evidence suggests that destruction of small airways is a major contributor to increased peripheral airway resistance in disease. This important finding might in part explain the failure of conventional anti-inflammatory treatments to restore lung function even in patients with mild disease. There is a clear need for alternative pharmacological strategies for patients with COPD/emphysema. Proposed regenerative strategies such as cell therapy and tissue engineering are hampered by poor availability of exogenous stem cells, discouraging trial results, and risks and cost associated with surgery. An alternative therapeutic approach is augmentation of lung regeneration and/or repair by biologically active factors, which have potential to be employed on a large scale. In favour of this strategy, the healthy adult lung is known to possess a remarkable endogenous regenerative capacity. Numerous preclinical studies have shown induction of regeneration in animal models of COPD/emphysema. Here, we argue that given the widespread and irreversible nature of COPD, serious consideration of regenerative pharmacology is necessary. However, for this approach to be feasible, a better understanding of the cell-specific molecular control of regeneration, the regenerative potential of the human lung and regenerative competencies of patients with COPD are required.
Taylor BA, Hind M, Rice A, et al., 2019, Investigating the Molecular Mechanisms of Congenital Pulmonary Airway Malformation (CPAM), 211th Meeting of the Pathological-Society-of-Great-Britain-and-Ireland, Publisher: WILEY, Pages: S11-S11, ISSN: 0022-3417
Akram K, Yates L, Mongey R, et al., 2019, Live imaging of alveologenesis in precision-cut lung slices reveals dynamic epithelial cell behaviour, Nature Communications, Vol: 10, ISSN: 2041-1723
Damage to alveoli, the gas-exchanging region of the lungs, is a component of many chronic and acute lung diseases. In addition, insufficient generation of alveoli results in bronchopulmonary dysplasia, a disease of prematurity. Therefore visualising the process of alveolar development (alveologenesis) is critical for our understanding of lung homeostasis and for the development of treatments to repair and regenerate lung tissue. Using long-term, time-lapse imaging of precision-cut lung slices, we show alveologenesis for the first time. We reveal that during this process, epithelial cells are highly mobile and we identify specific cell behaviours that contribute to alveologenesis: cell clustering, hollowing and cell extension. Using the cytoskeleton inhibitors blebbistatin and cytochalasin D, we showed that cell migration is a key driver of alveologenesis. This study reveals important novel information about lung biology and provides a new system in which to manipulate alveologenesis genetically and pharmacologically.
Proudfoot A, Bayliffe A, O'Kane CM, et al., 2018, Novel anti-tumour necrosis factor receptor-1 (TNFR1) domain antibody prevents pulmonary inflammation in experimental acute lung injury, Thorax, Vol: 73, Pages: 723-730, ISSN: 1468-3296
BACKGROUND: Tumour necrosis factor alpha (TNF-α) is a pleiotropic cytokine with both injurious and protective functions, which are thought to diverge at the level of its two cell surface receptors, TNFR1 and TNFR2. In the setting of acute injury, selective inhibition of TNFR1 is predicted to attenuate the cell death and inflammation associated with TNF-α, while sparing or potentiating the protective effects of TNFR2 signalling. We developed a potent and selective antagonist of TNFR1 (GSK1995057) using a novel domain antibody (dAb) therapeutic and assessed its efficacy in vitro, in vivo and in a clinical trial involving healthy human subjects. METHODS: We investigated the in vitro effects of GSK1995057 on human pulmonary microvascular endothelial cells (HMVEC-L) and then assessed the effects of pretreatment with nebulised GSK1995057 in a non-human primate model of acute lung injury. We then tested translation to humans by investigating the effects of a single nebulised dose of GSK1995057 in healthy humans (n=37) in a randomised controlled clinical trial in which subjects were subsequently exposed to inhaled endotoxin. RESULTS: Selective inhibition of TNFR1 signalling potently inhibited cytokine and neutrophil adhesion molecule expression in activated HMVEC-L monolayers in vitro (P<0.01 and P<0.001, respectively), and also significantly attenuated inflammation and signs of lung injury in non-human primates (P<0.01 in all cases). In a randomised, placebo-controlled trial of nebulised GSK1995057 in 37 healthy humans challenged with a low dose of inhaled endotoxin, treatment with GSK1995057 attenuated pulmonary neutrophilia, inflammatory cytokine release (P<0.01 in all cases) and signs of endothelial injury (P<0.05) in bronchoalveolar lavage and serum samples. CONCLUSION: These data support the potential for pulmonary delivery of a selective TNFR1 dAb as a novel therapeutic approach for the prevention of acute respiratory distress syndrome. TRI
Allen CJ, Freeman T, Perera W, et al., 2018, Thoracic Park: cardiac MRI reveals massive thoracic varices as consequence of inferior vena cava ligation, EHJ Cardiovascular Imaging / European Heart Journal - Cardiovascular Imaging, Vol: 19, Pages: 359-360, ISSN: 2047-2412
Pavitt MJ, Nevett J, Swanton LL, et al., 2017, London Ambulance source data on choking incidence for the calendar year 2016 – an observational study., BMJ Open Respiratory Research, Vol: 4, ISSN: 2052-4439
Introduction Complete foreign body airway obstruction is a life-threatening emergency, but there are limited data on its epidemiology.Methods We conducted a retrospective analysis of data collected routinely from London Ambulance Service calls coded as being for choking was undertaken for the calendar year of 2016.Results There were 1916 choking episodes of significant severity to call for emergency assessment in London during 2016, 0.2% of total calls requiring an ambulance response, an average of 5.2 per day. The incidence increased at the extremes of age. Calls coded as choking occurred at times consistent with lunch and dinner and less frequently at breakfast. Peak incidence occurred at Sunday lunchtimes and on Wednesday evenings.Conclusions Choking is a substantial health problem for Londoners to seek emergency assistance. Choking is more frequent at the extremes of age with a higher incidence at lunch and dinner time. Greater public awareness of choking and its management could help to prevent avoidable deaths.
Hind M, Polkey MI, Simonds AK, 2017, Homeward bound: a centenary of home mechanical ventilation, American Journal of Respiratory and Critical Care Medicine, Vol: 195, Pages: 1140-1149, ISSN: 1073-449X
The evolution of home mechanical ventilation is an intertwined chronicle of negative and positive pressure modes and their role in managing ventilatory failure in neuromuscular diseases and other chronic disorders. The uptake of noninvasive positive pressure ventilation has resulted in widespread growth in home ventilation internationally and fewer patients being ventilated invasively. As with many applications of domiciliary medical technology, home ventilatory support has either led or run in parallel with acute hospital applications and has been influenced by medical and societal shifts in the approach to chronic care, the creation of community support teams, a preference of recipients to be treated at home, and economic imperatives. This review summarizes the trends and growing evidence base for ventilatory support outside the hospital.
Hind M, Jordan S, Hansell DM, et al., 2017, A man with progressive type II respiratory failure, Lancet Respiratory Medicine, Vol: 5, Pages: 456-456, ISSN: 2213-2600
Pavitt MJ, Swanton LL, Hind M, et al., 2017, Choking on a foreign body: a physiological study of the effectiveness of abdominal thrust manoeuvres to increase thoracic pressure, THORAX, Vol: 72, Pages: 576-578, ISSN: 0040-6376
The Heimlich manoeuvre is a well-known intervention for the management of choking due to foreign body airway occlusion, but the evidence base for guidance on this topic is limited and guidelines differ. We measured pressures during abdominal thrusts in healthy volunteers. The angle at which thrusts were performed (upthrust vs circumferential) did not affect intrathoracic pressure. Self-administered abdominal thrusts produced similar pressures to those performed by another person. Chair thrusts, where the subject pushed their upper abdomen against a chair back, produced higher pressures than other manoeuvres. Both approaches should be included in basic life support teaching.
Poobalasingam T, Yates LL, Walker SA, et al., 2017, Heterozygous Vangl2 looptail mice reveal novel roles for the planar cell polarity pathway in adult lung homeostasis and repair, Disease Models & Mechanisms, Vol: 10, Pages: 409-423, ISSN: 1754-8403
Lung diseases impose a huge economic and health burden worldwide. A key aspect of several adult lung diseases, such as Idiopathic pulmonary fibrosis (IPF) and Chronic Obstructive pulmonary Disease (COPD), including emphysema, is aberrant tissue repair, which leads to an accumulation of damage and impaired respiratory function. Currently, there are few effective treatments available for these diseases and their incidence is rising.The Planar Cell Polarity (PCP) pathway is critical for the embryonic development of many organs, including kidney and lung. We have previously shown that perturbation of the PCP pathway impairs tissue morphogenesis, which disrupts the number and shape of epithelial tubes formed within these organs during embryogenesis. However, very little is known about the role of the PCP pathway beyond birth, partly due to the perinatal lethality of many PCP mouse mutant lines.Here we have investigated heterozygous Looptail (Lp) mice, in which a single copy of the core PCP gene, Vangl2, is disrupted. We show that these mice are viable but display severe airspace enlargement and impaired adult lung function. Underlying these defects, we find that Vangl2Lp/+ lungs exhibit altered distribution of actin microfilaments and abnormal regulation of the actin modifying protein cofilin. In addition, we show that Vangl2Lp/+ lungs exhibit many of the hallmarks of tissue damage including an altered macrophage population, abnormal elastin deposition and elevated levels of the elastin-modifying enzyme, Mmp12, all of which are observed in the lung disease, emphysema.In vitro, VANGL2 disruption impairs directed cell migration and reduces the rate of repair following scratch wounding of human alveolar epithelial cells. Moreover, using population data from a birth cohort of young adults, all aged 31, we found evidence of an interactive effect between VANGL2 and smoking (a tissue damaging insult) on lung function. Finally, we show that that PCP genes VANGL2 and SCRIBBLE (SC
Ng-Blichfeldt JP, Alçada J, Montero MA, et al., 2017, Deficient retinoid-driven angiogenesis may contribute to failure of adult human lung regeneration in emphysema, Thorax, Vol: 72, Pages: 510-521, ISSN: 0040-6376
BACKGROUND: Molecular pathways that regulate alveolar development and adult repair represent potential therapeutic targets for emphysema. Signalling via retinoic acid (RA), derived from vitamin A, is required for mammalian alveologenesis, and exogenous RA can induce alveolar regeneration in rodents. Little is known about RA signalling in the human lung and its potential role in lung disease. OBJECTIVES: To examine regulation of human alveolar epithelial and endothelial repair by RA, and characterise RA signalling in human emphysema. METHODS: The role of RA signalling in alveolar epithelial repair was investigated with a scratch assay using an alveolar cell line (A549) and primary human alveolar type 2 (AT2) cells from resected lung, and the role in angiogenesis using a tube formation assay with human lung microvascular endothelial cells (HLMVEC). Localisation of RA synthetic (RALDH-1) and degrading (cytochrome P450 subfamily 26 A1 (CYP26A1)) enzymes in human lung was determined by immunofluorescence. Regulation of RA pathway components was investigated in emphysematous and control human lung tissue by quantitative real-time PCR and Western analysis. RESULTS: RA stimulated HLMVEC angiogenesis in vitro; this was partially reproduced with a RAR-α agonist. RA induced mRNA expression of vascular endothelial growth factor A (VEGFA) and VEGFR2. RA did not modulate AT2 repair. CYP26A1 protein was identified in human lung microvasculature, whereas RALDH-1 partially co-localised with vimentin-positive fibroblasts. CYP26A1 mRNA and protein were increased in emphysema. CONCLUSIONS: RA regulates lung microvascular angiogenesis; the endothelium produces CYP26A1 which is increased in emphysema, possibly leading to reduced RA availability. These data highlight a role for RA in maintenance of the human pulmonary microvascular endothelium.
Hopkinson NS, Polkey, Shah P, et al., 2016, Endobronchial valves for patients with heterogeneous emphysema and without interlobar collateral ventilation – open label treatment following the BeLieVeR-HIFi study, Thorax, Vol: 72, Pages: 277-279, ISSN: 1468-3296
Outcomes in early trials of bronchoscopic lung volume reduction using endobronchial valves for the treatment of patients with advanced emphysema were inconsistent. However improvements in patient selection with focus on excluding those with interlobar collateral ventilation and homogeneous emphysema resulted in significant benefits in the BeLieVeR-HIFi study compared to sham treated controls. In this manuscript we present data from the control patients in the BeLieVeR-HIFi study who went on to have open label endobronchial valve treatment after completion of the clinical trial (n=12), combined with data from those in the treatment arm who did not have collateral ventilation (n=19). Three months after treatment the forced expiratory volume in the 1st second increased by 27.3(36.4)%, residual volume reduced by 0.49(0.76)L, the 6 minute walk distance increased by 32.6(68.7) m, and the St George Respiratory Questionnaire for COPD score improved by 8.2(20.2) points. These data extend the evidence for endobronchial valve placement in appropriately selected patients with COPD.
Hadjiphilippou S, Shah PL, Rice A, et al., 2016, Bronchial Dieulafoy lesion. A 20-year history of unexplained hemoptysis, American Journal of Respiratory and Critical Care Medicine, Vol: 195, Pages: 397-397, ISSN: 1073-449X
Minelli C, Dean CH, Hind M, et al., 2016, Association of Forced Vital Capacity with the Developmental Gene NCOR2, PLOS One, Vol: 11, ISSN: 1932-6203
BackgroundForced Vital Capacity (FVC) is an important predictor of all-cause mortality in the absenceof chronic respiratory conditions. Epidemiological evidence highlights the role of early lifefactors on adult FVC, pointing to environmental exposures and genes affecting lung developmentas risk factors for low FVC later in life. Although highly heritable, a small number ofgenes have been found associated with FVC, and we aimed at identifying further geneticvariants by focusing on lung development genes.PLOS ONE | DOI:10.1371/journal.pone.0147388 February 2, 2016 1 / 17OPEN ACCESSCitation: Minelli C, Dean CH, Hind M, Alves AC,Amaral AFS, Siroux V, et al. (2016) Association ofForced Vital Capacity with the Developmental GeneNCOR2. PLoS ONE 11(2): e0147388. doi:10.1371/journal.pone.0147388Editor: Philipp Latzin, University Children's HospitalBasel, SWITZERLANDReceived: August 28, 2015Accepted: January 4, 2016Published: February 2, 2016Copyright: © 2016 Minelli et al. This is an openaccess article distributed under the terms of theCreative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in anymedium, provided the original author and source arecredited.Data Availability Statement: All relevant data arewithin the paper and its Supporting Information files.Funding: The authors have no support or funding toreport.Competing Interests: The authors have declaredthat no competing interests exist.MethodsPer-allele effects of 24,728 SNPs in 403 genes involved in lung development were tested in7,749 adults from three studies (NFBC1966, ECRHS, EGEA). The most significant SNP forthe top 25 genes was followed-up in 46,103 adults (CHARGE and SpiroMeta consortia) and5,062 children (ALSPAC). Associations were considered replicated if the replication p-valuesurvived Bonferroni correction (p<0.002; 0.05/25), with a nominal p-value considered assuggestive evidence. For SNPs with evidence of replication, effects on the expression levelsof n
Davey C, Zoumot Z, Jordan S, et al., 2015, Bronchoscopic lung volume reduction with endobronchial valves for patients with heterogeneous emphysema and intact interlobar fissures (the BeLieVeR-HIFi study): a randomised controlled trial, Lancet, Vol: 386, Pages: 1066-1073, ISSN: 1474-547X
BackgroundLung volume reduction surgery improves survival in selected patients with emphysema, and has generated interest in bronchoscopic approaches that might achieve the same effect with less morbidity and mortality. Previous trials with endobronchial valves have yielded modest group benefits because when collateral ventilation is present it prevents lobar atelectasis.MethodsWe did a single-centre, double-blind sham-controlled trial in patients with both heterogeneous emphysema and a target lobe with intact interlobar fissures on CT of the thorax. We enrolled stable outpatients with chronic obstructive pulmonary disease who had a forced expiratory volume in 1 s (FEV1) of less than 50% predicted, significant hyperinflation (total lung capacity >100% and residual volume >150%), a restricted exercise capacity (6 min walking distance <450 m), and substantial breathlessness (MRC dyspnoea score ≥3). Participants were randomised (1:1) by computer-generated sequence to receive either valves placed to achieve unilateral lobar occlusion (bronchoscopic lung volume reduction) or a bronchoscopy with sham valve placement (control). Patients and researchers were masked to treatment allocation. The study was powered to detect a 15% improvement in the primary endpoint, the FEV1 3 months after the procedure. Analysis was on an intention-to-treat basis. The trial is registered at controlled-trials.com, ISRCTN04761234.Findings50 patients (62% male, FEV1 [% predicted] mean 31·7% [SD 10·2]) were enrolled to receive valves (n=25) or sham valve placement (control, n=25) between March 1, 2012, and Sept 30, 2013. In the bronchoscopic lung volume reduction group, FEV1 increased by a median 8·77% (IQR 2·27–35·85) versus 2·88% (0–8·51) in the control group (Mann-Whitney p=0·0326). There were two deaths in the bronchoscopic lung volume reduction group and one control patient was unable to attend for follow-up asse
Nanzer AM, Janssen J, Hind M, 2014, Sniffing out a hidden cause of breathlessness., BMJ Case Rep, Vol: 2014
A 78-year-old man presented with severe exertional dyspnoea. He suffered from mild chronic obstructive pulmonary disease, congestive cardiac failure and seropositive myasthaenia gravis. Clinical examination of his chest and heart were unremarkable but he had speech dyspnoea and was unable to count to 20 in a single breath. Consecutive sniff nasal inspiratory measurements (SNIP) fell from 55 to 33 cm H2O and forced vital capacity (FVC) fell from 3.4 to 2.4 L. A diagnosis of myasthenic crisis was carried out and treatment with non-invasive ventilation, intravenous immunoglobulis and high-dose oral prednisolone was initiated. The patient responded well and was discharged following a short period of rehabilitation. A high index of suspicion and a careful clinical examination with the help of two simple bedside tests, FVC and SNIP, allowed correct and timely treatment of his condition.
Proudfoot AG, O'Kane CM, Bayliffe A, et al., 2014, A Novel Tnfr1-Targeting Domain Antibody Attenuates Pulmonary Inflammation In A Human Model Of Lung Injury, Via Actions On The Lung Micro-Vascular Endothelium, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 189, ISSN: 1073-449X
Dean C, Bingle C, Hind M, 2013, Delivering and phenotyping mouse models for the respiratory community: a report on the Biochemical Society Workshop, CLINICAL SCIENCE, Vol: 125, Pages: 495-500, ISSN: 0143-5221
Hare A, Chatwin M, Hind M, et al., 2013, Percutaneous gastrostomy (PEG) insertion under general anaesthesia (GA) in ventilator-dependent patients with neuromuscular disease (NMD), EUROPEAN RESPIRATORY JOURNAL, Vol: 42, ISSN: 0903-1936
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