Are We Missing the Opportunity to Measure Muscle Mass on Computed Tomography Thorax?

J Thorac Imaging. 2020 Apr 28;:

Authors: Bryl B, Merrix S, Proud D, Marin A, Byrne A, Duckers J

Abstract
Hand grip strength (HGS) and fat free mass index (FFMI) are important indicators of skeletal muscle mass and correlate with prognosis in patients with respiratory diseases. It is also possible to estimate muscle mass by measuring muscle density and volume on cross sectional imaging. We reviewed all patients of the All Wales Cystic Fibrosis Centre who had a computed tomography thorax as part of routine clinical care between 2013 and 2017. By multiplying the volume and average Hounsfield units of the paraspinal muscles at T4 and T12 levels we were able to estimate the patients skeletal muscle mass. This was compared with their FFMI, HGS and forced expiratory volume in 1 second. Measurements of muscle mass at T4 and T12 showed significant correlation with HGS and FFMI, and T12 also showed significant correlation with forced expiratory volume in 1 second. This method may provide further prognostic information for patient with cystic fibrosis, particularly where equipment for HGS and FFMI assessments are lacking.

PMID: 32349054 [PubMed - as supplied by publisher]

Normal murine respiratory tract has its mucus concentrated in clouds based on the Muc5b mucin.

Am J Physiol Lung Cell Mol Physiol. 2020 Apr 29;:

Authors: Fakih DC, Rodríguez-Piñeiro AM, Trillo-Muyo S, Evans CM, Ermund A, Hansson GC

Abstract
The organization of the normal airway mucus system is different in small experimental animals from that in humans and large mammals. To address normal murine airway mucociliary clearance, Alcian blue-stained mucus transport was measured ex vivo on tracheal tissues of naïve C57BL/6, Muc5b-/-, Muc5ac-/-, and EGFP-tagged Muc5b reporter mice. Close to the larynx with a few submucosal glands, the mucus appeared as thick bundles. More distally in the trachea and in large bronchi, Alcian blue-stained mucus was organized in cloud-like formations based on the Muc5b mucin. On tilted tissue, the mucus clouds moved upwards towards the larynx with an average velocity of 12 µm/s compared to 20 µm/s for beads not associated with clouds. In Muc5ac-/- mice, Muc5b formed mucus strands attached to the tissue surface, while in Muc5b-/- mice, Muc5ac had a more variable appearance. The normal mouse lung mucus thus appear as discontinuous clouds, clearly different from the stagnant mucus layer in diseased lungs.

PMID: 32348677 [PubMed - as supplied by publisher]

The association between serum albumin/prealbumin level and disease severity in non-CF bronchiectasis.

Clin Exp Pharmacol Physiol. 2020 Apr 29;:

Authors: Li L, Li Z, Bi J, Li H, Wang S, Shao C, Song Y

Abstract
Non-cystic fibrosis (non-CF) bronchiectasis is a chronic pulmonary disease that can lead to malnutrition. Serum prealbumin and albumin level are related to inflammatory and nutritional status. Thus, we aimed to confirm our hypothesis that low serum albumin and prealbumin level, as well as BMI, is correlated to severe non-CF bronchiectasis. We conducted a retrospective cross-sectional study of 128 patients, including 75 patients with prealbumin test and 79 patients with albumin test. Detailed medical history was recorded, including pulmonary function tests and high-resolution computed tomography. BSI and FACED scores were calculated. Leicester Cough Questionnaire, Quality of Life Questionnaire-Bronchiectasis, COPD assessment test and Patient Health Questionnaire-9 questionnaires were used to assess patients' clinical symptoms. Correlation analysis showed that BSI score was more correlated to patients' clinical symptoms than FACED. Thus, patients were divided into 3 groups of different severity based on BSI score. Albumin, prealbumin and BMI showed a significant difference between 3 groups. Correlation and multivariable linear regression analysis showed that serum albumin and prealbumin level were correlated to BSI, FACED and questionnaires. The analysis between 3 indices and PFT/HRCT showed that prealbumin, albumin and BMI could reflect the PFT and modified Reiff score in non-CF bronchiectasis. In conclusion, BMI, albumin and prealbumin showed a significant correlation with the BSI, FACED, as well as patients' clinical symptoms. Among them, serum albumin was the indicator most strongly associated with the BSI and questionnaires, while prealbumin could better reflect lung function decline and radiological severity.

PMID: 32347970 [PubMed - as supplied by publisher]

The Role of Noninvasive Ventilation in Cystic Fibrosis: A Cochrane Review Summary With Commentary.

Respir Care. 2020 May;65(5):719-721

Authors: Willis LD

PMID: 32345763 [PubMed - in process]

2019 Year in Review: Aerosol Therapy.

Respir Care. 2020 May;65(5):705-712

Authors: Berlinski A

Abstract
Relevant publications related to medicinal and toxic aerosols are discussed in this review. Treatment of COPD includes a combination of long-acting bronchodilators and long-acting muscarinic antagonists. A combination of aclidinium bromide and formoterol fumarate was approved in the United States. The combination was superior to its components alone, as well as tiotropium and a salmeterol-fluticasone combination. Increased risk of an asthma exacerbation was reported in children exposed to electronic nicotine delivery systems. A smart inhaler capable of recording inspiratory flow was approved in the United States. The use of as-needed budesonide-formoterol was reported to be superior to scheduled budesonide and as-needed terbutaline for the treatment of adults with mild-to-moderate asthma. A survey among teens with asthma and their caregivers revealed a disagreement in the number of inhaled controller medications the teen was taking. Treatment with inhaled hypertonic saline resulted in a decreased lung clearance index in infants and preschool children with cystic fibrosis. Surgical masks were well tolerated and significantly decreased the burden of aerosolized bacteria generated by coughing in adults with cystic fibrosis. Inhaled liposomal amikacin in addition to guideline-based therapy was reported to be superior to guideline-based therapy alone in achieving negative sputum cultures in adult subjects with Mycobacterium avium complex pulmonary disease. During 2019, lung injury associated to e-cigarette or vaping was reported, including 60 casualties.

PMID: 32345761 [PubMed - in process]

Commensal Oral Rothia mucilaginosa Produces Enterobactin, a Metal-Chelating Siderophore.

mSystems. 2020 Apr 28;5(2):

Authors: Uranga CC, Arroyo P, Duggan BM, Gerwick WH, Edlund A

Abstract
Next-generation sequencing studies of saliva and dental plaque from subjects in both healthy and diseased states have identified bacteria belonging to the Rothia genus as ubiquitous members of the oral microbiota. To gain a deeper understanding of molecular mechanisms underlying the chemical ecology of this unexplored group, we applied a genome mining approach that targets functionally important biosynthetic gene clusters (BGCs). All 45 genomes that were mined, representing Rothia mucilaginosa, Rothia dentocariosa, and Rothia aeria, harbored a catechol-siderophore-like BGC. To explore siderophore production further, we grew the previously characterized R. mucilaginosa ATCC 25296 in liquid cultures, amended with glycerol, which led to the identification of the archetype siderophore enterobactin by using tandem liquid chromatography-mass spectrometry (LC-MS/MS), high-performance liquid chromatography (HPLC), and nuclear magnetic resonance (NMR) spectroscopy. Normally attributed to pathogenic gut bacteria, R. mucilaginosa is the first commensal oral bacterium found to produce enterobactin. Cocultivation studies including R. mucilaginosa or purified enterobactin revealed that enterobactin reduced growth of certain strains of cariogenic Streptococcus mutans and pathogenic strains of Staphylococcus aureus Commensal oral bacteria were either unaffected, reduced in growth, or induced to grow adjacent to enterobactin-producing R. mucilaginosa or the pure compound. Taken together with Rothia's known capacity to ferment a variety of carbohydrates and amino acids, our findings of enterobactin production add an additional level of explanation to R. mucilaginosa's prevalence in the oral cavity. Enterobactin is the strongest Fe(III) binding siderophore known, and its role in oral health requires further investigation.IMPORTANCE The communication language of the human oral microbiota is vastly underexplored. However, a few studies have shown that specialized small molecules encoded by BGCs have critical roles such as in colonization resistance against pathogens and quorum sensing. Here, by using a genome mining approach in combination with compound screening of growth cultures, we identified that the commensal oral community member R. mucilaginosa harbors a catecholate-siderophore BGC, which is responsible for the biosynthesis of enterobactin. The iron-scavenging role of enterobactin is known to have positive effects on the host's iron pool and negative effects on host immune function; however, its role in oral health remains unexplored. R. mucilaginosa was previously identified as an abundant community member in cystic fibrosis, where bacterial iron cycling plays a major role in virulence development. With respect to iron's broad biological importance, iron-chelating enterobactin may explain R. mucilaginosa's colonization success in both health and disease.

PMID: 32345739 [PubMed]

Drosophila as a model for studying cystic fibrosis pathophysiology of the gastrointestinal system.

Proc Natl Acad Sci U S A. 2020 Apr 28;:

Authors: Kim K, Lane EA, Saftien A, Wang H, Xu Y, Wirtz-Peitz F, Perrimon N

Abstract
Cystic fibrosis (CF) is a recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The most common symptoms include progressive lung disease and chronic digestive conditions. CF is the first human genetic disease to benefit from having five different species of animal models. Despite the phenotypic differences among the animal models and human CF, these models have provided invaluable insight into understanding disease mechanisms at the organ-system level. Here, we identify a member of the ABCC4 family, CG5789, that has the structural and functional properties expected for encoding the Drosophila equivalent of human CFTR, and thus refer to it as Drosophila CFTR (Dmel\CFTR). We show that knockdown of Dmel\CFTR in the adult intestine disrupts osmotic homeostasis and displays CF-like phenotypes that lead to intestinal stem cell hyperplasia. We also show that expression of wild-type human CFTR, but not mutant variants of CFTR that prevent plasma membrane expression, rescues the mutant phenotypes of Dmel\CFTR Furthermore, we performed RNA sequencing (RNA-Seq)-based transcriptomic analysis using Dmel\CFTR fly intestine and identified a mucin gene, Muc68D, which is required for proper intestinal barrier protection. Altogether, our findings suggest that Drosophila can be a powerful model organism for studying CF pathophysiology.

PMID: 32345720 [PubMed - as supplied by publisher]

Molecular mechanisms of action of naringenin in chronic airway diseases.

Eur J Pharmacol. 2020 Apr 25;:173139

Authors: Chin LH, Hon CM, Chellappan DK, Chellian J, Madheswaran T, Zeeshan F, Awasthi R, Aljabali AA, Tambuwala MM, Dureja H, Negi P, Kapoor DN, Goyal R, Paudel KR, Satija S, Gupta G, Hsu A, Wark P, Mehta M, Wadhwa R, Hansbro PM, Dua K

Abstract
Chronic airway inflammatory diseases are characterized by persistent proinflammatory responses in the respiratory tract. Although, several treatment strategies are currently available, lifelong therapy is necessary for most of these diseases. In recent years, phytophenols, namely, flavonoids, derived from fruits and vegetables have been gaining tremendous interest and have been extensively studied due to their low toxicological profile. Naringenin is a bioflavonoid abundantly found in citrus fruits. This substance has shown notable therapeutic potential in various diseases due to its promising diverse biological activities. In this review, we have attempted to review the published studies from the available literature, discussing the molecular level mechanisms of naringenin in different experimental models of airway inflammatory diseases including asthma, chronic obstructive pulmonary disease (COPD), lung cancer, pulmonary fibrosis and cystic fibrosis. Current evidences have proposed that the anti-inflammatory properties of naringenin play a major role in ameliorating inflammatory disease states. In addition, naringenin also possesses several other biological properties. Despite the proposed mechanisms suggesting remarkable therapeutic benefits, the clinical use of naringenin is, however, hampered by its low solubility and bioavailability. Furthermore, this review also discusses on the studies that utilise nanocarriers as a drug delivery system to address the issue of poor solubility.

PMID: 32343971 [PubMed - as supplied by publisher]

Palliative drug treatments for breathlessness in cystic fibrosis.

Cochrane Database Syst Rev. 2020 Apr 28;4:CD011855

Authors: Jaiswal N, Singh M, Agarwal A, Chauhan A, Jaiswal N

Abstract
BACKGROUND: Cystic fibrosis is a life-limiting autosomal recessive genetic illness. A feeling of shortness of breath is common in cystic fibrosis, especially as the disease progresses. Reversing the underlying cause is the priority when treating breathlessness (dyspnoea), but when it is not feasible, palliation (easing) becomes the primary goal to improve an individual's quality of life. A range of drugs administered by various routes have been used, but no definite guidelines are available. A systematic review is needed to evaluate such treatments.
OBJECTIVES: To assess the efficacy and safety of drugs used to ease breathlessness in people with cystic fibrosis.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. Date of last search: 18 November 2019. We searched databases (clinicaltrials.gov, the ISRCTN registry, the Clinical Trials Registry India and WHO ICTRP) for ongoing trials. These searches were last run on 06 March 2020.
SELECTION CRITERIA: We planned to include randomised and quasi-randomised controlled trials in people with cystic fibrosis (diagnosed by a positive sweat chloride test or genetic testing) who have breathlessness. We considered studies comparing any drugs used for easing breathlessness to another drug administered by any route (inhaled (nebulised), intravenous, oral, subcutaneous, transmucosal (including buccal, sublingual and intra-nasal) and transdermal).
DATA COLLECTION AND ANALYSIS: The authors assessed the search results according to the pre-defined inclusion criteria.
MAIN RESULTS: The new searches in 2020 yielded two ongoing studies that were not relevant to the review question. Previous searches had found only one study (cross-over in design), which did not fulfil the inclusion criteria as no data were available from the first treatment period alone.
AUTHORS' CONCLUSIONS: Due to the lack of available evidence, this review cannot provide any information for clinical practice. The authors call for specific research in this area after taking into account relevant ethical considerations. The research should focus on the efficacy and safety of the drugs with efficacy being measured in terms of improvement in quality of life, dyspnoea scores and hospital stay.

PMID: 32343850 [PubMed - as supplied by publisher]

Three-dimensional Ultrashort Echo Time MRI for Functional Lung Imaging in Cystic Fibrosis.

Radiology. 2020 Apr 28;:192251

Authors: Heidenreich JF, Weng AM, Metz C, Benkert T, Pfeuffer J, Hebestreit H, Bley TA, Köstler H, Veldhoen S

Abstract
Background In cystic fibrosis (CF), recurrent imaging and pulmonary function tests (PFTs) are needed for the assessment of lung function during disease management. Purpose To assess the clinical feasibility of pulmonary three-dimensional ultrashort echo time (UTE) MRI at breath holding for quantitative image analysis of ventilation inhomogeneity and hyperinflation in CF compared with PFT. Materials and Methods In this prospective study from May 2018 to June 2019, participants with CF and healthy control participants underwent PFTs and functional lung MRI by using a prototypical single breath-hold three-dimensional UTE sequence. Fractional ventilation (FV) was calculated from acquired data in normal inspiration and normal expiration. FV of each voxel was normalized to the whole lung mean (FVN), and interquartile range of normalized ventilation (IQRN; as a measure of ventilation heterogeneity) was calculated. UTE signal intensity (SI) was assessed in full expiration (SIN, normalized to aortic blood). Obtained metrics were compared between participants with CF and control participants. For participants with CF, MRI metrics were correlated with the standard lung clearance index (LCI) and PFT. Mann-Whitney U tests and Spearman correlation were used for statistical analysis. Results Twenty participants with CF (mean age, 17 years ± 9 [standard deviation]; 12 men) and 10 healthy control participants (24 years ± 8; five men) were included. IQRN was higher for participants with CF than for control participants (mean, 0.66 ± 0.16 vs 0.50 ± 0.04, respectively; P = .007). In the 20 participants with CF, IQRN correlated with obstruction markers forced expiratory volume in 1 second-to-forced vital capacity ratio (r = -0.70; 95% confidence interval [CI]: -0.92, -0.28; P < .001), mean expiratory flow 25% (r = 0.78; 95% CI: -0.95, -0.39; P < .001), and with the ventilation inhomogeneity parameter LCI (r = 0.90; 95% CI: 0.69, 0.96; P < .001). Mean SIN in full expiration was lower in participants with CF than in control participants (0.34 ± 0.08 vs 0.39 ± 0.03, respectively; P = .03). Conclusion Three-dimensional ultrashort echo time MRI in the lungs allowed for functional imaging of ventilation inhomogeneity within a few breath holds in patients with cystic fibrosis. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Wielpütz in this issue.

PMID: 32343212 [PubMed - as supplied by publisher]

Gene therapy for haemophilia.

Cochrane Database Syst Rev. 2020 Apr 28;4:CD010822

Authors: Sharma A, Easow Mathew M, Sriganesh V, Reiss UM

Abstract
BACKGROUND: Haemophilia is a genetic disorder characterized by spontaneous or provoked, often uncontrolled, bleeding into joints, muscles and other soft tissues. Current methods of treatment are expensive, challenging and involve regular administration of clotting factors. Gene therapy for haemophilia is a curative treatment modality currently under investigation. This is an update of a published Cochrane Review.
OBJECTIVES: To evaluate the safety and efficacy of gene therapy for treating people with haemophilia A or B.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis & Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews. Date of last search: 17 April 2020.
SELECTION CRITERIA: Eligible trials include randomised or quasi-randomised clinical trials, including controlled clinical trials comparing gene therapy (with or without standard treatment) with standard treatment (factor replacement) or other 'curative' treatment such as stem cell transplantation for individuals with haemophilia A or B of all ages who do not have inhibitors to factor VIII or IX.
DATA COLLECTION AND ANALYSIS: No trials of gene therapy for haemophilia matching the inclusion criteria were identified.
MAIN RESULTS: No trials of gene therapy for haemophilia matching the inclusion criteria were identified.
AUTHORS' CONCLUSIONS: No randomised or quasi-randomised clinical trials of gene therapy for haemophilia were identified. Thus, we are unable to determine the safety and efficacy of gene therapy for haemophilia. Gene therapy for haemophilia is still in clinical investigation and there is a need for well-designed clinical trials to assess the long-term feasibility, success and risks of gene therapy for people with haemophilia.

PMID: 32342499 [PubMed - in process]

Exercise and Cystic Fibrosis.

Adv Exp Med Biol. 2020;1228:381-391

Authors: Ding S, Zhong C

Abstract
Cystic fibrosis (CF) is an autosomal recessive, inherited congenital disease caused by the mutation of the family autosomal CF gene, with cumulative exocrine secretion characterized by inflammation, tracheal remodeling, and mucus accumulation. With the development of modern medical technology, CF patients are living longer lives and receiving more and more treatments, including traditional drugs, physical therapy, and gene therapy. Exercise is widely used to prevent and treat metabolic diseases such as cardiovascular diseases, obesity, diabetes, and metabolic syndrome. Regular exercise is beneficial to aerobic capacity and lung health. Exercise therapy has been of great interest since people realized that CF can be affected by exercise. Exercise alone can be used as an ACT (airway clearance technique), which promotes the removal of mucosal cilia. Exercise therapy is more easily accepted by any society, which helps to normalize the lives of CF patients, rather than placing a psychological burden on them. In this chapter, we will review the latest research progress about exercise in CF.

PMID: 32342472 [PubMed - in process]

Allelic polymorphism shapes community function in evolving Pseudomonas aeruginosa populations.

ISME J. 2020 Apr 27;:

Authors: Azimi S, Roberts AEL, Peng S, Weitz JS, McNally A, Brown SP, Diggle SP

Abstract
Pseudomonas aeruginosa is an opportunistic pathogen that chronically infects the lungs of individuals with cystic fibrosis (CF) by forming antibiotic-resistant biofilms. Emergence of phenotypically diverse isolates within CF P. aeruginosa populations has previously been reported; however, the impact of heterogeneity on social behaviors and community function is poorly understood. Here we describe how this heterogeneity impacts on behavioral traits by evolving the strain PAO1 in biofilms grown in a synthetic sputum medium for 50 days. We measured social trait production and antibiotic tolerance, and used a metagenomic approach to analyze and assess genomic changes over the duration of the evolution experiment. We found that (i) evolutionary trajectories were reproducible in independently evolving populations; (ii) over 60% of genomic diversity occurred within the first 10 days of selection. We then focused on quorum sensing (QS), a well-studied P. aeruginosa trait that is commonly mutated in strains isolated from CF lungs. We found that at the population level, (i) evolution in sputum medium selected for decreased the production of QS and QS-dependent traits; (ii) there was a significant correlation between lasR mutant frequency, the loss of protease, and the 3O-C12-HSL signal, and an increase in resistance to clinically relevant β-lactam antibiotics, despite no previous antibiotic exposure. Overall, our findings provide insights into the effect of allelic polymorphism on community functions in diverse P. aeruginosa populations. Further, we demonstrate that P. aeruginosa population and evolutionary dynamics can impact on traits important for virulence and can lead to increased tolerance to β-lactam antibiotics.

PMID: 32341475 [PubMed - as supplied by publisher]

Environmental fungal sensitisation associates with poorer clinical outcomes in COPD.

Eur Respir J. 2020 Apr 27;:

Authors: Tiew PY, Ko FWS, Pang SL, Matta SA, Sio YY, Poh ME, Lau KJX, Mac Aogáin M, Jaggi TK, Ivan FX, Gaultier NE, Uchida A, Drautz-Moses DI, Xu H, Koh MS, Hui DSC, Tee A, Abisheganaden JA, Schuster SC, Chew FT, Chotirmall SH

Abstract
INTRODUCTION: Allergic sensitisation to fungi such as Aspergillus are associated to poor clinical outcomes in asthma, bronchiectasis and cystic fibrosis, however, clinical relevance in COPD remains unclear.
METHODS: Patients with stable COPD (n=446) and non-diseased controls (n=51) were prospectively recruited across three countries (Singapore, Malaysia and Hong Kong) and screened against a comprehensive allergen panel including house dust mites, pollens, cockroach and fungi. For the first time, using a metagenomics approach, we assess outdoor and indoor environmental allergen exposure in COPD. We identify key fungi in outdoor air and develop specific-IgE assays against the top culturable fungi, linking sensitisation responses to COPD outcomes. Indoor air and surface allergens were prospectively evaluated by metagenomics in the homes of n=11 COPD patients and linked to clinical outcome.
RESULTS: High frequencies of sensitisation to a broad range of allergens occurs in COPD. Fungal sensitisation associates with frequent exacerbations, and, unsupervised clustering reveals a "highly sensitised fungal predominant" sub-group demonstrating significant symptomatology, frequent exacerbations and poor lung function. Outdoor and indoor environments serve as important reservoirs of fungal allergen exposure in COPD, and, promote a sensitisation response to outdoor air fungi. Indoor (home) environments with high fungal allergens associate with greater COPD symptoms and poorer lung function illustrating the importance of environmental exposures on clinical outcomes in COPD.
CONCLUSION: Fungal sensitisation is prevalent in COPD and associates with frequent exacerbations representing a potential treatable trait. Outdoor and indoor (home) environments represent a key source of fungal allergen exposure, amenable to intervention, in "sensitised" COPD.

PMID: 32341102 [PubMed - as supplied by publisher]

Ivacaftor decreases monocyte sensitivity to interferon-γ in people with cystic fibrosis.

ERJ Open Res. 2020 Apr;6(2):

Authors: Hisert KB, Birkland TP, Schoenfelt KQ, Long ME, Grogan B, Carter S, Liles WC, McKone EF, Becker L, Manicone AM

Abstract
This study demonstrates that initiation of the CFTR modulator ivacaftor in people with cystic fibrosis and susceptible CFTR mutations causes an acute reduction in blood monocyte sensitivity to the key proinflammatory cytokine IFN-γ http://bit.ly/2TeI6LG.

PMID: 32337217 [PubMed]

Enhanced inflammasome activation and reduced sphingosine-1 phosphate S1P signalling in a respiratory mucoobstructive disease model.

J Inflamm (Lond). 2020;17:16

Authors: Tran HB, Macowan MG, Abdo A, Donnelley M, Parsons D, Hodge S

Abstract
Background: Inflammasomes and sphingosine-1-phosphate (S1P) signalling are increasingly subject to intensive research in human diseases. We hypothesize that in respiratory muco-obstructive diseases, mucus obstruction enhances NLRP3 inflammasome activation and dysregulated S1P signalling.
Methods: Lung tissues from mice overexpressing the beta-unit of the epithelial sodium channel (βENaC) and their littermate controls were examined by histology, immunofluorescence and confocal microscopy, followed by ImageJ quantitative analysis.
Results: Lower airways in βENaC mice showed patchy patterns of mucus obstruction and neutrophil-dominant infiltrations. In contrast to a ubiquitous distribution of TNFα specks, significantly (p < 0.05) increased specks of bronchiolar NLRP3, IL-1β, and IgG in the βENaC mouse lungs were localized to the vicinity of mucus obstruction sites. Bright Spinster homologue 2 (SPNS2) at the epithelial apex and positive correlation with sphingosine kinase 1 (SPHK1) (R2 = 0.640; p < 0.001) supported the normal bronchial epithelium as an active generator of extracellular S1P. SPNS2 in βENaC mice was sharply reduced (38%, p < 0.05) and lost apical localization at sites of mucus obstruction. A significant (34%; p < 0.01) decrease in epithelial SPHK2 was also noted at mucus obstruction sites.
Conclusion: These results support that mucus obstruction may enhance NLRP3 inflammasome activation and dysregulated S1P signaling.

PMID: 32336954 [PubMed]

Targeted Killing of Pseudomonas aeruginosa by Pyocin G Occurs via the Hemin Transporter Hur.

J Mol Biol. 2020 Apr 24;:

Authors: Atanaskovic I, Mosbahi K, Sharp C, Housden NG, Kaminska R, Walker D, Kleanthous C

Abstract
Pseudomonas aeruginosa is a priority pathogen for the development of new antibiotics, particularly because multi-drug resistant strains of this bacterium cause serious nosocomial infections and are the leading cause of death in cystic fibrosis patients. Pyocins, bacteriocins of P. aeruginosa, are potent and diverse protein antibiotics that are deployed during bacterial competition. Pyocins are produced by more than 90% of P. aeruginosa strains and may have utility as last resort antibiotics against this bacterium. In this study, we explore the antimicrobial activity of a newly discovered pyocin called pyocin G (PyoG). We demonstrate that PyoG has broad killing activity against a collection of clinical P. aeruginosa isolates and is active in a Galleria mellonella infection model. We go on to identify cell envelope proteins that are necessary for the import of PyoG and its killing activity. PyoG recognises bacterial cells by binding to Hur, an outer membrane TonB dependent transporter. Both pyocin and Hur interact with TonB1, which in complex with ExbB-ExbD links the proton motive force generated across the inner membrane with energy dependent pyocin translocation across the outer membrane. Inner membrane translocation of PyoG is dependent on the conserved inner membrane AAA+ ATPase/protease, FtsH. We also report a functional exploration of the PyoG receptor. We demonstrate that Hur can bind to hemin in vitro and that this interaction is blocked by PyoG, confirming the role of Hur in hemin acquisition.

PMID: 32339530 [PubMed - as supplied by publisher]

Combination antifungal therapy for Scedosporium species in cystic fibrosis.

Pediatr Pulmonol. 2020 Apr 27;:

Authors: Bentley S, Davies JC, Carr SB, Balfour-Lynn IM

Abstract
OBJECTIVE: To evaluate safety and efficacy of oral posaconazole and terbinafine for Lomentospora prolificans and Scedosporium apiospermum in children with cystic fibrosis.
METHODS: Retrospective case review.
RESULTS: There were five children (four girls), median age 15.0 years; three had S. apiospermum and two had L. prolificans. Treatment duration: median 5 months (range: 5-18 m). In no patient was eradication achieved, with the follow-up range being 6 months to 4 years. Effect on lung function was variable but encouraging. No adverse effects were reported, one child had transient elevation of liver enzymes.
CONCLUSIONS: While the combination therapy was well tolerated, it was unsuccessful at eradication.

PMID: 32339450 [PubMed - as supplied by publisher]

Secondary Pulmonary Hypertension Among Patients Qualified for Lung Transplantation: Single-Center Study.

Transplant Proc. 2020 Apr 23;:

Authors: Stącel T, Urlik M, Nęcki M, Antończyk R, Latos M, Wajda-Pokrontka M, Tatoj Z, Zawadzki F, Przybyłowski P, Zembala M, Ochman M

Abstract
INTRODUCTION: Secondary pulmonary hypertension (PH) is a serious complication of end-stage lung disease and is associated with unfavorable prognosis. The aim of the study was to evaluate the incidence and severity of secondary PH among patients qualified for lung transplantation (LTx).
MATERIAL AND METHODS: The study population consisted of 143 patients qualified for LTx between 2004 and 2019. Analyzed medical records included results collected during the qualification process (eg, echocardiography parameters, right heart catherization [RHC]). There were 37.8% (n = 54) of patients with chronic obstructive pulmonary disease (COPD), 58.7% (n = 84) of patients with interstitial lung diseases (ILDs), and 3.5% (n = 5) of patients with combined pulmonary fibrosis and emphysema (CPFE). The inclusion criteria were ILDs, COPD or CPFE diagnosis, and the presence of RHC data preformed during qualification for LTx. The exclusion criteria were lack of RHC results and diagnosis of idiopathic pulmonary artery hypertension, pulmonary artery hypertension associated with connective tissue disease, cystic fibrosis, or bronchiectasis.
RESULTS: PH was detected among 60.1% (n = 86) of patients qualified for LTx. The prevalence of PH was 39% (n = 18) vs 76.19% (n = 64) in the COPD vs ILDs groups, respectively. Both ILDs and COPD patients presented with similar mean artery pulmonary pressure (36.3 ± 9.61 vs 34.78 ± 11.47 mm Hg; not statistically significant). Severe PH was more frequent in the ILDs group than in the COPD group (60.94% vs 38.89%).
CONCLUSIONS: PH is commonly diagnosed in patients with chronic lung diseases qualified for LTx and more often observed among patients qualified because of ILDs. It is important to assess the pulmonary pressure because of frequent occurrence of PH among patients referred for LTx.

PMID: 32336653 [PubMed - as supplied by publisher]

Tackling bias in clinical trials.

J Cyst Fibros. 2019 07;18(4):445-446

Authors: van Koningsbruggen-Rietschel S, Downey DG

PMID: 31230796 [PubMed - indexed for MEDLINE]