Dornase alfa during lower respiratory tract infection post-lung transplantation: a randomized controlled trial.

Transpl Int. 2019 Jun;32(6):603-613

Authors: Tarrant BJ, Snell G, Ivulich S, Button B, Thompson B, Holland A

Abstract
Lung transplant (LTx) recipients are at risk of lower respiratory tract infection (LRTI), while altered physiology may lead to difficulty clearing sputum. Mucoactive agents alter sputum properties and facilitate mucociliary clearance; however, there are no randomized controlled trials (RCTs) studying this post-LTx. This RCT evaluated the safety and efficacy of nebulized dornase alfa during LRTI post-LTx. Inpatient adults with LRTI and abnormal sputum following bilateral sequential LTx were eligible. Participants received 5 ml of isotonic saline, or 2.5 ml of dornase alfa, nebulized once daily for 1 month followed by 2 months symptom diary. Primary outcome was lung clearance index (LCI2%). Secondary outcomes included spirometry, quality of life, readmission, length of stay, self-reported exacerbations, and adverse events at baseline, 1 and 3 months. Thirty-two participated, 16 in each group, baseline mean (SD) FEV1 % 58 (22), median (IQR) length of stay 7 (5) days, time since LTx 3.49 (6.80) years. There were no significant between-group differences in LCI2% at any point (1 month mean difference -0.34, 95% confidence interval (CI) -1.57 to 0.89; 3 months -0.76, 95% CI -2.29 to 0.78, favoring dornase alfa). Secondary outcomes were not different between groups. These results do not support the routine use of dornase alfa during LRTI in LTx recipients.

PMID: 30632208 [PubMed - indexed for MEDLINE]

Towards automated <i>in vivo</i> tracheal mucociliary transport measurement: detecting and tracking particle movement in synchrotron phase-contrast X-ray images.

Phys Med Biol. 2020 Feb 11;:

Authors: Gardner M, Parsons D, Morgan KS, McCarron A, Cmielewski P, Gradl R, Donnelley M

Abstract
Accurate in vivo quantification of airway mucociliary transport (MCT) in animal models is important for understanding diseases such as cystic fibrosis, as well as for developing therapies. A non-invasive method of measuring MCT behaviour, based on tracking the position of micron sized particles using Synchrotron X-ray imaging, has previously been described. In previous studies, the location (and path) of each particle was tracked manually, which is a time consuming and subjective process. Here we describe particle tracking methods that were developed to reduce the need for manual particle tracking. The MCT marker particles were detected in the Synchrotron X-ray images using cascade classifiers. The particle trajectories along the airway surface were generated by linking the detected locations between frames using a modified particle linking algorithm. The developed methods were compared with the manual tracking method on simulated X-ray images, as well as on in vivo images of rat airways acquired at the SPring-8 Synchrotron. The results for the simulated and in vivo images showed that the semi-automatic algorithm reduced the time required for particle tracking when compared with the manual tracking method, and was able to detect MCT marker particle locations and measure particle speeds more accurately than the manual tracking method. Future work will examine the modification of methods to improve particle detection and particle linking algorithms to allow for more accurate fully-automatic particle tracking.

PMID: 32045895 [PubMed - as supplied by publisher]

Circulating biomarkers of antioxidant status and oxidative stress in people with cystic fibrosis: A systematic review and meta-analysis.

Redox Biol. 2020 Jan 23;:101436

Authors: Causer AJ, Shute JK, Cummings MH, Shepherd AI, Gruet M, Costello JT, Bailey S, Lindley M, Pearson C, Connett G, Allenby MI, Carroll MP, Daniels T, Saynor ZL

Abstract
INTRODUCTION: Oxidative stress may play an important role in the pathophysiology of cystic fibrosis (CF). This review aimed to quantify CF-related redox imbalances.
METHODS: Systematic searches of the Medline, CINAHL, CENTRAL and PsycINFO databases were conducted. Mean content of blood biomarkers from people with clinically-stable CF and non-CF controls were used to calculate the standardized mean difference (SMD) and 95% confidence intervals (95% CI).
RESULTS: Forty-nine studies were eligible for this review including a total of 1792 people with CF and 1675 controls. Meta-analysis revealed that protein carbonyls (SMD: 1.13, 95% CI: 0.48 to 1.77), total F2-isoprostane 8-iso-prostaglandin F2α (SMD: 0.64, 95% CI: 0.23 to 1.05) and malondialdehyde (SMD: 1.34, 95% CI: 0.30 to 2.39) were significantly higher, and vitamins A (SMD: -0.66, 95% CI -1.14 to -0.17) and E (SMD: -0.74, 95% CI: -1.28 to -0.20), β-carotene (SMD: -1.80, 95% CI: -2.92 to -0.67), lutein (SMD: -1.52, 95% CI: -1.83 to -1.20) and albumin (SMD: -0.98, 95% CI: -1.68 to -0.27) were significantly lower in the plasma or serum of people with CF versus controls.
CONCLUSIONS: This systematic review and meta-analysis found good evidence for reduced antioxidant capacity and elevated oxidative stress in people with clinically-stable CF.

PMID: 32044291 [PubMed - as supplied by publisher]

Variable cellular ivacaftor concentrations in people with cystic fibrosis on modulator therapy.

J Cyst Fibros. 2020 Feb 07;:

Authors: Guimbellot JS, Ryan KJ, Anderson JD, Liu Z, Kersh L, Esther CR, Rowe SM, Acosta EP

Abstract
The development of CFTR modulators has transformed the care of patients with cystic fibrosis (CF). Although the clinical efficacy of modulators depends on their concentrations in target tissues, the pharmacokinetic properties of these drugs in epithelia are not utilized to guide patient care. We developed assays to quantitate ivacaftor in cells and plasma from patients on modulator therapy, and our analyses revealed that cellular ivacaftor concentrations differ from plasma concentrations measured concurrently, with evidence of in vivo accumulation of ivacaftor in the cells of patients. While the nature of this study is exploratory and limited by a small number of patients, these findings suggest that techniques to measure modulator concentrations in vivo will be essential to interpreting their clinical impact, particularly given the evidence that ivacaftor concentrations influence the activity and stability of restored CFTR protein.

PMID: 32044246 [PubMed - as supplied by publisher]

Pseudomonas aeruginosa antibody response in cystic fibrosis decreases rapidly following lung transplantation.

J Cyst Fibros. 2020 Feb 07;:

Authors: Schwensen HF, Moser C, Perch M, Pressler T, Høiby N

Abstract
BACKGROUND: Specific Pseudomonas aeruginosa (PA) precipitating immunoglobulin G antibodies in serum are correlated with PA biofilm infection and are used as diagnostic and prognostic markers in cystic fibrosis (CF). The aim of this study was to examine the change of PA antibody response in CF patients after bilateral sequential lung transplantation (LTx).
METHODS: PA antibodies and airway bacteriology were retrospectively evaluated in 20 chronically infected CF patients, who underwent LTx between 2001 and 2016 at Rigshospitalet, Copenhagen. Yearly precipitin counts from one year before LTx and up to five years after LTx were compared. Monthly airway cultures were examined in the five-year period after LTx. In addition, crossed immunoelectrophoresis (CIE) were analysed for each patient for antigenic similarities from time of infection, pre-LTx and post-LTx.
RESULTS: All patients experienced a significant drop in PA antibodies from one year pre-LTx to one year post-LTx (p < 0.0001). The PA antibody level did not differ between those, who became reinfected immediately after LTx, and those, who did not. No patients regained the high pre-LTx precipitin levels in the following five years. The antigenic specificities of the sera post-LTx were in each patient similar to the antigenic specificities at the beginning of infection indicating a decades long memory of their immune response like an "immunological fingerprint".
CONCLUSIONS: After LTx a significant and continuous reduction in PA antibodies was observed. The reduction was independent of immediate reinfection after LTx. A novel three-factor explanatory model is presented.

PMID: 32044245 [PubMed - as supplied by publisher]

Minimal change in structural, functional and inflammatory markers of lung disease in newborn screened infants with cystic fibrosis at one year.

J Cyst Fibros. 2020 Feb 07;:

Authors: Davies G, Thia LP, Stocks J, Bush A, Hoo AF, Wade A, Nguyen TTD, Brody AS, Calder A, Klein NJ, Carr SB, Wallis C, Suri R, Pao CS, Ruiz G, Balfour-Lynn IM, London Cystic Fibrosis Collaboration (LCFC)

Abstract
BACKGROUND: With the widespread introduction of newborn screening for cystic fibrosis (CF), there has been considerable emphasis on the need to develop objective markers of lung health that can be used during infancy. We hypothesised that in a newborn screened (NBS) UK cohort, evidence of airway inflammation and infection at one year would be associated with adverse structural and functional outcomes at the same age.
METHODS: Infants underwent lung function testing, chest CT scan and bronchoscopy with bronchoalveolar lavage (BAL) at 1 year of age when clinically well. Microbiology cultures were also available from routine cough swabs.
RESULTS: 65 infants had lung function, CT and BAL. Mean (SD) lung clearance index and forced expiratory volume in 0.5 s z-scores were 0.9(1.2) and -0.6(1.1) respectively; median Brody II CF-CT air trapping score on chest CT =0 (interquartile range 0-1, maximum possible score 27). Infants isolating any significant pathogen by 1 yr of age had higher LCI z-score (mean difference 0.9; 95%CI:0.4-1.4; p = 0.001) and a trend towards higher air trapping scores on CT (p = 0.06). BAL neutrophil elastase was detectable in 23% (10/43) infants in whom BAL supernatant was available. This did not relate to air trapping score on CT.
CONCLUSIONS: In this UK NBS cohort at one year of age, lung and airway damage is much milder and associations between inflammation, abnormal physiology and structural changes were at best weak, contrary to our hypothesis and previously published reports. Continued follow-up will clarify longer term implications of these very mild structural, functional and inflammatory changes.

PMID: 32044244 [PubMed - as supplied by publisher]

Influence of lung transplantation on the essential fatty acid profile in cystic fibrosis.

Prostaglandins Leukot Essent Fatty Acids. 2020 Jan 23;:102060

Authors: Hanssens L, Duchateau J, Namane SA, Malfroot A, Knoop C, Casimir G

Abstract
Lung transplantation is assumed to normalize essential fatty acid (EFA) profile in the plasma, described as abnormal in patients with cystic fibrosis (CF). This study sought to evaluate the EFA profile in both the plasma and erythrocyte membrane according to lung status by comparing CF patients with or without a lung transplant. A total of 50 homozygous F508del patients (33 CF patients [CF group] and 17 CF patients with a lung transplant [TX CF group]) were included. In comparison with the CF group, in the plasma, the levels of total n-3, α-linolenic, eicosapentaenoic, and docosahexaenoic acids were higher and the n-6/n-3 ratio was lower in the TX CF group. Yet, these differences were not observed in the erythrocyte membrane. This study supports that lung transplantation improves the EFA profile in the plasma but not in the erythrocyte membrane by means of the different mechanisms suggested in this article.

PMID: 32044180 [PubMed - as supplied by publisher]

Collaboration is key: identification of a novel cystic fibrosis mutation in three patients of South Asian descent.

Clin Respir J. 2020 Feb 11;:

Authors: Semple A, Clark T, Allen N, Krishnananthan T, Nwokoro C, Girodon E, Porzio M, Herzig M

Abstract
INTRODUCTION: The Cystic Fibrosis (CF) clinical profile and associated CFTR mutation spectrum is poorly understood in the South Asian population. This is likely due to lack of diagnostic resources and the absence of a centralised cystic fibrosis database and screening programme, despite a relatively large proportion of the global population.
METHODS: Following identification of a previously unreported CFTR mutation (c.2805_2810delinsTCAGA; p.(Pro936Ginfs*6)) in a newly diagnosed patient of Indian descent, we interrogated national registries for other cases.
RESULTS: We identified three European-born subjects of South Asian descent with CF due to a novel CFTR mutation. All three subjects presented in infancy, and each had a severe phenotype with intestinal complications as a presenting feature. Two subjects were diagnosed prior to the advent of universal screening. Preliminary genetic screening failed to identify the causative mutation in all three patients.
CONCLUSION: Our work highlights the value of extended or targeted genotyping in selected populations. It also demonstrates the benefit of routine collaboration between national registries. This will promote identification of novel mutations; leading to greater understanding of genotype-phenotype associations, improved individual prognostication, and ultimately the improved availability of novel precision therapies. This collaboration is essential if we are to achieve health equality for people with CF living in resource-limited settings.

PMID: 32043836 [PubMed - as supplied by publisher]

Assessing and responding to stress related to pulmonary function testing in cystic fibrosis through quality improvement.

Pediatr Pulmonol. 2020 Feb 10;:

Authors: Nusbaum K, Filigno SS, Feldstein J, Hente E, Koch E, Mullen L, Weiland J, Boat T, Siracusa C

Abstract
BACKGROUND: Pulmonary function tests (PFTs) are performed routinely to evaluate lung function in patients with cystic fibrosis (CF). Staff at the Cincinnati Children's Hospital Medical Center CF Center observed stress in patients before PFTs. An interdisciplinary quality improvement (QI) team was assembled to address this clinical issue.
METHODS: The Plan-Do-Study-Act method of QI was used to investigate feasibility of assessing stress and offering brief interventions to reduce stress before PFTs. Interventions included listening to music, covering the PFT screen, or doing breathing meditation before PFTs. Patients rated stress levels on a 1 to 5 Likert scale before and after testing.
RESULTS: Of 75 patient encounters, interventions were trialed in 20. Fifteen patients who tried an intervention reported wanting to use the intervention again (five encounters had missing data); patients reported that the intervention benefited performance on PFTs in eight encounters (40%). The average pre-PFT stress rating for encounters that trialed an intervention was 2.1 and post-PFT rating was 2.0. Average stress pre-PFT and post-PFT ratings were 1.7 and 1.6 respectively, for encounters that did not trial an intervention. Median length of PFT encounter was 15  minutes regardless of whether intervention was trialed.
CONCLUSION: Some patients with CF utilized interventions, while many opted out. This QI effort identified feasible outpatient clinic interventions that did not negatively impact clinic flow. Finding ways to reduce stress associated with PFTs could have a meaningful impact on patient performance and emotional well-being for a subset of patients.

PMID: 32040891 [PubMed - as supplied by publisher]

The Effects of the Anti-aging Protein Klotho on Mucociliary Clearance.

Front Med (Lausanne). 2019;6:339

Authors: Garth J, Easter M, Skylar Harris E, Sailland J, Kuenzi L, Chung S, Dennis JS, Baumlin N, Adewale AT, Rowe SM, King G, Faul C, Barnes JW, Salathe M, Krick S

Abstract
α-klotho (KL) is an anti-aging protein and has been shown to exert anti-inflammatory and anti-oxidative effects in the lung and pulmonary diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis. The current study investigated the direct effect of KL on the bronchial epithelium in regards to mucociliary clearance parameters. Primary human bronchial and murine tracheal epithelial cells, cultured, and differentiated at the air liquid interface (ALI), were treated with recombinant KL or infected with a lentiviral vector expressing KL. Airway surface liquid (ASL) volume, airway ion channel activities, and expression levels were analyzed. These experiments were paired with ex vivo analyses of mucociliary clearance in murine tracheas from klotho deficient mice and their wild type littermates. Our results showed that klotho deficiency led to impaired mucociliary clearance with a reduction in ASL volume in vitro and ex vivo. Overexpression or exogenous KL increased ASL volume, which was paralleled by increased activation of the large-conductance, Ca2+-activated, voltage-dependent potassium channel (BK) without effect on the cystic fibrosis transmembrane conductance regulator (CFTR). Furthermore, KL overexpression downregulated IL-8 levels and attenuated TGF-β-mediated downregulation of LRRC26, the γ subunit of BK, necessary for its function in non-excitable cells. In summary, we show that KL regulates mucociliary function by increasing ASL volume in the airways possibly due to underlying BK activation. The KL mediated BK channel activation may be a potentially important target to design therapeutic strategies in inflammatory airway diseases when ASL volume is decreased.

PMID: 32039219 [PubMed]

Evaluation of a radiographer-led peripherally inserted central catheter insertion service.

J Med Imaging Radiat Oncol. 2020 Feb 09;:

Authors: De Boo DW, Marshall E, Erskine B, Koukounaras J, Kavnoudias H, Thomson KR

Abstract
INTRODUCTION: To evaluate a radiographer-led peripherally inserted central catheter (PICC) insertion service within an interventional radiology suite using ultrasound and fluoroscopic guidance.
METHODS: Data from 366 consecutive PICC insertions by five trained angiography-specialized radiographers were prospectively collected over a 12-month period. For each PICC insertion, patient demographics, including past medical history of cystic fibrosis (CF), number of punctures, vein used, final tip position, contrast administration and screening time were recorded. Institutional review board approval was obtained.
RESULTS: The overall PICC insertion success rate was 100%. Fifty-five (15%) had a known medical history of CF. Three hundred and thirty-one (90%) PICC insertions required a single puncture and 32 (9%) required two punctures. The remaining three insertions required three punctures. The basilic vein was most commonly used (69%) followed by the brachial vein (29%), and the cephalic vein was used only in 2%. Administration of contrast medium was necessary during 27 (7%) PICC insertions. Mean screening time was 10.7 s.
CONCLUSION: Our specifically trained, radiographer-led PICC insertion service proved to be successful. Both straightforward and complex insertions, for example in CF patients could be adequately and efficiently performed.

PMID: 32037725 [PubMed - as supplied by publisher]

Centralised versus outreach models of cystic fibrosis care should be tailored to the needs of the individual patient.

Intern Med J. 2020 Feb;50(2):232-235

Authors: Geake J, Ballard E, O'Rourke P, Wainwright CE, Reid DW, Bell SC

Abstract
Cystic fibrosis (CF) is a common life-limiting genetic condition. As the disease progresses access to specialist tertiary multi-disciplinary care services may become necessary. For patients living in regional/remote Australia, accessing such services may be a challenge. Here, we describe long-term outcomes for CF patients according to their access to specialist CF centre care in childhood.

PMID: 32037704 [PubMed - in process]

A Prospective Study of Hematologic Complications and Long-Term Survival of Italian Patients Affected by Shwachman-Diamond Syndrome.

J Pediatr. 2020 Feb 06;:

Authors: Cesaro S, Pegoraro A, Sainati L, Lucidi V, Montemitro E, Corti P, Ramenghi U, Nasi C, Menna G, Zecca M, Danesino C, Nicolis E, Pasquali F, Perobelli S, Tridello G, Farruggia P, Cipolli M

Abstract
OBJECTIVE: To describe the hematologic outcome and long-term survival of patients enrolled in the Shwachman-Diamond syndrome Italian Registry.
STUDY DESIGN: A retrospective and prospective study of patients recorded in the Shwachman-Diamond syndrome Italian Registry.
RESULTS: The study population included 121 patients, 69 males and 52 females, diagnosed between 1999 and 2018. All patients had the clinical diagnosis confirmed by mutational analysis on the SBDS gene. During the study period, the incidence of SDS was 1 in 153 000 births. The median age of patients with SDS at diagnosis was 1.3 years (range, 0-35.6 years). At the first hematologic assessment, severe neutropenia was present in 25.8%, thrombocytopenia in 25.5%, and anemia in 4.6% of patients. A normal karyotype was found in 40 of 79 patients, assessed whereas the most frequent cytogenetic abnormalities were isochromosome 7 and interstitial deletion of the long arm of chromosome 20. The cumulative incidence of severe neutropenia, thrombocytopenia, and anemia at 30 years of age were 59.9%, 66.8%, and 20.2%, respectively. The 20-year cumulative incidence of myelodysplastic syndrome/leukemia and of bone marrow failure/severe cytopenia was 9.8% and 9.9%, respectively. Fifteen of 121 patients (12.4%) underwent allogeneic stem cell transplantation. Fifteen patients (12.4%) died; the probability of overall survival at 10 and 20 years was 95.7% and 87.4%, respectively.
CONCLUSIONS: Despite an improvement in survival, hematologic complications still cause death in patients with SDS. Further studies are needed to optimize type and modality of hematopoietic stem cell transplantation and to assess the long-term outcome in nontransplanted patients.

PMID: 32037152 [PubMed - as supplied by publisher]

Nontuberculous mycobacterial infections in a Brazilian pediatric population: a seven-year survey.

Pathog Glob Health. 2020 Feb 08;:1-5

Authors: Mauch RM, Mansinho AAS, Rocha PMO, Zaccariotto TR, Levy CE, Nolasco da Silva MT

Abstract
The aim of this study was to describe the frequency of nontuberculous mycobacteria (NTM) isolation and their related outcomes among pediatric patients of a Brazilian university hospital from 2012 to 2019. NTM were identified in different clinical samples by microbiological culture and molecular-based methods. NTM were isolated from 14 patients, out of whom four (27%) were infected and were treated accordingly. Two were infected with Mycobacterium avium complex (MAC), two with M. abscessus complex (MABSC) and one with M. intracellulare. Two patients had cystic fibrosis-related lung disease and improved after successful NTM eradication. One patient was HIV-positive and died. One patient had severe combined immunodeficiency (SCID)-related pneumonia and is currently being followed-up. We conclude that NTM frequency in our center was low among pediatric patients. Whether this is inherent to Brazilian patients, due to the broad coverage of the Bacille Calmette-Guérin (BCG) vaccine in Brazil, or a result of underdiagnosis remains to be elucidated.

PMID: 32036778 [PubMed - as supplied by publisher]

Reply to Finotti et al.: Enhancing the Expression of CFTR Using Antisense Molecules against MicroRNA miR-145-5p.

Am J Respir Crit Care Med. 2019 06 01;199(11):1444-1445

Authors: Lutful Kabir F, Harris WT

PMID: 30811947 [PubMed - indexed for MEDLINE]

Topical Pilocarpine Formulation for diagnosis of Cystic Fibrosis.

J Pharm Sci. 2020 Feb 06;:

Authors: Fatima T, Ajjarapu S, Shankar VK, Rangappa S, Kumar HNS, Biswas SK, Hoque M, Murthy SN

Abstract
Cystic fibrosis is diagnosed in infants by estimating the levels of chloride ions present in the sweat induced by iontophoresis of pilocarpine solution. Elevated levels of chloride (≥ 60 mMol/L) in sweat is indicative of cystic fibrosis. However, the iontophoretic method of delivering pilocarpine is cumbersome and usually is associated with several side effects such as skin burn, skin rashes, erythema etc., The objective of this study was therefore to develop a topical formulation that delivers adequate amount of pilocarpine. The drug delivery of formulation was compared with iontophoresis of aqueous solution of pilocarpine nitrate in vitro using porcine skin model. The pilocarpine levels in the skin exposed to topical pilocarpine solution under mild hyperthermia was 152.04 ± 52.23 μg/cm2 after 10 min of application, while it was 97.05 ± 27.93 μg/cm2 in the skin after 10 min of iontophoresis. The topical formulation was subjected to clinical evaluation to assess the efficacy of the product to induce sweat production. The average amount of the sweat secreted on application of topical formulation was found to be 77.28 ± 18.97 mg. Based on these results, it was found that the topical formulation was successful in delivering pilocarpine and to stimulate sweat secretion.

PMID: 32035925 [PubMed - as supplied by publisher]

A comparative study of the pancreas in pediatric patients with cystic fibrosis and healthy children using two-dimensional shear wave elastography.

J Ultrasound. 2020 Feb 07;:

Authors: Piskin FC, Yavuz S, Kose S, Cagli C, Dogruel D, Tumgor G, Aikimbaev K

Abstract
PURPOSE: To compare sonographic parameters of the pancreas between healthy children and pediatric cystic fibrosis (CF) patients with pancreatic involvement using shear wave elastography (SWE) and to investigate the efficacy of SWE in the diagnosis of pancreatic involvement in pediatric CF patients.
METHODS: The pancreas was evaluated in 38 patients with CF and 38 healthy children using conventional B-mode ultrasonography (US) and two-dimensional (2D)-SWE.
RESULTS: The pancreatic 2D-SWE values of the CF group were significantly lower than those of the healthy control group (1.01 ± 0.16 vs. 1.31 ± 0.01 m/s for the head, 1.03 ± 0.05 vs. 1.28 ± 0.08 m/s for the pancreatic body, and 1.02 ± 0.05 vs. 1.30 ± 0.10 m/s for the tail; p < 0.005 for all the comparisons). When the threshold values were obtained for the pancreatic head, body, and tail segments for the differentiation of the CF patients and healthy controls, the sensitivity of the test was determined as 81.5%, 76.3%, and 73.3%, respectively, and the specificity as 97.3%, 100%, and 100%, respectively. When the patients were divided into two groups based on the presence of B-mode US characteristics (homogeneity, sharp demarcation, and hyperechoic pancreas), there was a significant difference in the 2D-SWE values of the pancreatic head between the patients with and the patients without these characteristics (p = 0.048 for homogeneity, p = 0.021 for sharp demarcation, and p = 0.006 for hyperechoic pancreas).
CONCLUSION: The measurement of 2D-SWE values was found to be an easily applicable non-invasive test with high sensitivity and specificity for the demonstration of changes in the pancreas of pediatric CF patients.

PMID: 32034705 [PubMed - as supplied by publisher]

Exendin-4 restores airway mucus homeostasis through the GLP1R-PKA-PPARγ-FOXA2-phosphatase signaling.

Mucosal Immunol. 2020 Feb 07;:

Authors: Choi W, Choe S, Lin J, Borchers MT, Kosmider B, Vassallo R, Limper AH, Lau GW

Abstract
Goblet cell hyperplasia and metaplasia and excessive mucus are prominent pathologies of chronic airway diseases such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and chronic bronchitis. Chronic infection by respiratory pathogens, including Pseudomonas aeruginosa, exacerbates cyclical proinflammatory responses and mucus hypersecretion. P. aeruginosa and its virulence factor pyocyanin contribute to these pathologies by inhibiting FOXA2, a key transcriptional regulator of mucus homeostasis, through activation of antagonistic signaling pathways EGFR-AKT/ERK1/2 and IL-4/IL-13-STAT6-SPDEF. However, FOXA2-targeted therapy has not been previously explored. Here, we examined the feasibility of repurposing the incretin mimetic Exendin-4 to restore FOXA2-mediated airway mucus homeostasis. We have found that Exendin-4 restored FOXA2 expression, attenuated mucin production in COPD and CF-diseased airway cells, and reduced mucin and P. aeruginosa burden in mouse lungs. Mechanistically, Exendin-4 activated the GLP1R-PKA-PPAR-γ-dependent phosphatases PTEN and PTP1B, which inhibited key kinases within both EGFR and STAT6 signaling cascades. Our results may lead to the repurposing of Exendin-4 and other incretin mimetics to restore FOXA2 function and ultimately regulate excessive mucus in diseased airways.

PMID: 32034274 [PubMed - as supplied by publisher]

Optimized plant compound with potent anti-biofilm activity across gram-negative species.

Bioorg Med Chem. 2020 Jan 24;:115229

Authors: Lawrence JA, Huang Z, Rathinavelu S, Hu JF, Garo E, Ellis M, Norman VL, Buckle R, Williams RB, Starks CM, Eldridge GR

Abstract
Many human diseases, including cystic fibrosis lung infections, are caused or exacerbated by bacterial biofilms. Specialized modes of motility, including swarming and twitching, allow gram-negative bacteria to spread across surfaces and form biofilms. Compounds that inhibit these motilities could slow the spread of biofilms, thereby allowing antibiotics to work better. We previously demonstrated that a set of plant-derived triterpenes, including oleanolic acid and ursolic acid, inhibit formation of Escherichia coli and Pseudomonas aeruginosa biofilms, and alter expression of genes involved in chemotaxis and motility. In the present study, we have prepared a series of analogs of oleanolic acid. The analogs were evaluated against clinical isolates of E. coli and P. aeruginosa in biofilm formation assays and swarming assays. From these analogs, compound 9 was selected as a lead compound for further development. Compound 9 inhibits E. coli biofilm formation at 4 µg/mL; it also inhibits swarming at ≤1 µg/mL across multiple clinical isolates of P. aeruginosa, E. coli, Burkholderia cepacia, and Salmonella enterica, and at <0.5 µg/mL against multiple agricultural strains. Compound 9 also potentiates the activity of the antibiotics tobramycin and colistin against swarming P. aeruginosa; this is notable, as tobramycin and colistin are inhaled antibiotics commonly used to treat P. aeruginosa lung infections in people with cystic fibrosis. qPCR experiments suggested that 9 alters expression of genes involved in regulating Type IV pili; western blots confirmed that expression of Type IV pili components PilA and PilY1 decreases in P. aeruginosa in the presence of 9.

PMID: 32033878 [PubMed - as supplied by publisher]

β11-12 linker isomerization governs Acid-sensing ion channel desensitization and recovery.

Elife. 2020 Feb 07;9:

Authors: Rook ML, Williamson A, Lueck JD, Musgaard M, Maclean DM

Abstract
Acid-sensing ion channels (ASICs) are neuronal sodium-selective channels activated by reductions in extracellular pH. Structures of the three presumptive functional states, high-pH resting, low-pH desensitized, and toxin-stabilized open, have all been solved for chicken ASIC1. These structures, along with prior functional data, suggest that the isomerization or flipping of the β11-12 linker in the extracellular, ligand-binding domain is an integral component of the desensitization process. To test this, we combined fast perfusion electrophysiology, molecular dynamics simulations and state-dependent non-canonical amino acid cross-linking. We find that both desensitization and recovery can be accelerated by orders of magnitude by mutating resides in this linker or the surrounding region. Furthermore, desensitization can be suppressed by trapping the linker in the resting state, indicating that isomerization of the β11-12 linker is not merely a consequence of, but a necessity for the desensitization process in ASICs.

PMID: 32031522 [PubMed - as supplied by publisher]