Beating the organ clock.

Nat Biotechnol. 2018 06 06;36(6):488-492

Authors: Senior M

PMID: 29874222 [PubMed - indexed for MEDLINE]

Recommended Reading from the Johns Hopkins University Pulmonary and Critical Care Fellows.

Am J Respir Crit Care Med. 2018 Dec 26;:

Authors: Montemayor K, Balasubramanian A, Simpson CE, Jennings MT, Fessler HE

PMID: 30586317 [PubMed - as supplied by publisher]

TMEM16A is indispensable for basal mucus secretion in airways and intestine.

FASEB J. 2018 Dec 26;:fj201801333RRR

Authors: Benedetto R, Cabrita I, Schreiber R, Kunzelmann K

Abstract
Transmembrane member 16A (TMEM16A) is the Ca2+-activated chloride channel in airways and intestine. It has been associated with goblet cell metaplasia, as expression of TMEM16A is strongly up-regulated in cystic fibrosis and asthma during mucus hypersecretion. However, the possible role of TMEM16A for mucus production or mucus secretion remains obscure, and whether TMEM16A controls the function of intestinal goblet cells is entirely unknown. Basal mucus secretion in lungs occurs through low levels of ATP in the airway surface liquid. Here, we report for the first time that TMEM16A is essential for basal secretion of mucus in airways and intestine. Airway-ciliated and intestinal epithelial-specific knockout of TMEM16A ( TMEM16Aflox/floxFoxJ1, TMEM16Aflox/floxVil1) leads to accumulation of mucus in airway club (Clara) cells and intestinal goblet cells, respectively. Acute ATP-induced mucus secretion by airway club cells is inhibited when TMEM16A is knocked out in ciliated cells, possibly as a result of compromised release of prosecretory cytokines. Knockdown or inhibition of TMEM16A in human Calu3 airway epithelial cells indicates compromised IL-8 release. In intestinal goblet cells lacking expression of TMEM16A, mucus accumulates as a result of compromised ATP-induced secretion. In contrast, cholinergic mucus secretion by compound exocytosis is independent of TMEM16A. The data demonstrate a previously unrecognized role of TMEM16A for membrane exocytosis and describe a novel, ATP-driven pathway for intestinal mucus secretion. We conclude that ATP-dependent mucus secretion in both airways and intestine requires TMEM16A. The present results may form the basis for a novel, therapeutic approach for the treatment of mucus hypersecretion in inflammatory airway and intestinal disease.-Benedetto, R., Cabrita, I., Schreiber, R., Kunzelmann, K. TMEM16A is indispensable for basal mucus secretion in airways and intestine.

PMID: 30586313 [PubMed - as supplied by publisher]

Modifier genes in cystic fibrosis-related liver disease.

Curr Opin Gastroenterol. 2018 Dec 20;:

Authors: Debray D, Corvol H, Housset C

Abstract
PURPOSE OF REVIEW: Cystic fibrosis (CF; OMIM 219700) is caused by variations in the cystic fibrosis transmembrane conductance regulator gene. CF-related liver disease (CFLD) affects approximately one-third of patients with CF, but the severity of CFLD is highly variable. This review provides the latest knowledge in the pathophysiology and CF genetic modifier research in CFLD.
RECENT FINDINGS: So far, the only modifier gene validated in CFLD is SERPINA1 (α-1-antitrypsin) Z allele. Recent studies support the view that cholangiopathy arising in CF is the result of an ill-adapted innate immune response to endotoxins coming from the intestine and triggering a pro-inflammatory response.
SUMMARY: The pathophysiology of liver disease remains uncertain and so far, no therapy has proven effective to prevent the progression of CFLD. A better understanding of the pathophysiology and the effect of environmental and non-cystic fibrosis transmembrane conductance regulator genetic influences in the context of CFLD development would help improve management and develop new drug therapies.

PMID: 30585791 [PubMed - as supplied by publisher]

Shwachman-Diamond syndrome with clonal interstitial deletion of the long arm of chromosome 20 in bone marrow: haematological features, prognosis and genomic instability.

Br J Haematol. 2018 Dec 26;:

Authors: Valli R, Minelli A, Galbiati M, D'Amico G, Frattini A, Montalbano G, Khan AW, Porta G, Millefanti G, Olivieri C, Cipolli M, Cesaro S, Pasquali F, Danesino C, Cazzaniga G, Maserati E

Abstract
In Shwachman-Diamond syndrome (SDS), deletion of the long arm of chromosome 20, del(20)(q), often acquired in bone marrow (BM), may imply a lower risk of developing myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), due to the loss of the EIF6 gene. The genes L3MBTL1 and SGK2, also on chromosome 20, are in a cluster of imprinted genes, and their loss implies dysregulation of BM function. We report here the results of array comparative genomic hybridization (a-CGH) performed on BM DNA of six patients which confirmed the consistent loss of EIF6 gene. Interestingly, array single nucleotide polymorphisms (SNPs) showed copy neutral loss of heterozygosity for EIF6 region in cases without del(20)(q). No preferential parental origin of the deleted chromosome 20 was detected by microsatellite analysis in six SDS patients. Our patients showed a very mild haematological condition, and none evolved into BM aplasia or MDS/AML. We extend the benign prognostic significance of del(20)(q) and loss of EIF6 to the haematological features of these patients, consistently characterized by mild hypoplastic BM, no or mild neutropenia, anaemia and thrombocytopenia. Some odd results obtained in microsatellite and SNP-array analysis demonstrate a peculiar genomic instability, in an attempt to improve BM function through the acquisition of the del(20)(q).

PMID: 30585299 [PubMed - as supplied by publisher]

Ivacaftor, a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator, Enhances Ciprofloxacin Activity Against Pseudomonas aeruginosa.

Am J Rhinol Allergy. 2018 Dec 25;:1945892418815615

Authors: Cho DY, Lim DJ, Mackey C, Skinner D, Zhang S, McCormick J, Woodworth BA

Abstract
BACKGROUND: Methods to improve the clinical efficacy of currently available antibiotics against multidrug resistant bacteria in cystic fibrosis (CF) chronic rhinosinusitis (CRS) are greatly needed. Ivacaftor, a cystic fibrosis transmembrane conductance regulator potentiator, was recently identified as having potentially beneficial off-target effects as a weak inhibitor of bacterial DNA gyrase and topoisomerase IV. The objective of the current study is to evaluate whether ivacaftor enhances the antimicrobial activity of ciprofloxacin against Pseudomonas aeruginosa.
METHODS: The planktonic growth of the PAO-1 strain of P. aeruginosa was studied in the presence of ciprofloxacin and/or ivacaftor. Effects were measured according to optical density of cultured PAO-1 at 600 nm. For a static PAO-1 biofilm assay, the PAO-1 strain was inoculated and cultured for 72 h in the presence of the drugs. Formed PAO-1 biofilms were quantified by crystal violet staining and imaged with confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM).
RESULTS: PAO-1 growth was significantly reduced in the presence of ivacaftor (8 or 16 µg/mL) and ciprofloxacin (0.02 or 0.05 µg/mL) compared to ciprofloxacin alone ( P < .001). Similarly, ivacaftor (8 or 16 µg/mL) showed a significant reduction of PAO-1 biofilms when treated with 0.05 µg/mL of ciprofloxacin. Significant synergism was noted between ciprofloxacin and 16 µg/mL of ivacaftor ( P < .0001) in reducing planktonic growth and biofilm formation. Quantitative measurements with crystal violet staining were correlated to CLSM and SEM images.
CONCLUSION: Ivacaftor enhanced ciprofloxacin's antimicrobial activity against P. aeruginosa. Further studies evaluating the efficacy of ivacaftor/ciprofloxacin combination for P. aeruginosa for CF CRS are warranted.

PMID: 30585080 [PubMed - as supplied by publisher]

Triplet CFTR modulators: future prospects for treatment of cystic fibrosis.

Ther Clin Risk Manag. 2018;14:2375-2383

Authors: Chaudary N

Abstract
Cystic fibrosis (CF) is an autosomal recessive genetic disease characterized by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is a chloride channel responsible for ion flow across epithelial surfaces of lung, sinuses, pancreas, intestine, and liver. Researchers have grouped CFTR genetic mutations into various protein defects: reduced protein synthesis (class 1 mutations), abnormal protein folding and maturation (class 2 mutation), and abnormal gating (class 3 mutation). These mutations usually present as severe forms of CF due to complete absence of CFTR at cell surfaces. Milder forms (eg, protein maturation and conductance defects, classes 4-6) present as less severe forms of CF related to the presence of CFTR at the cell surface. Differences in severity are directly due to CFTR function which is based on the severity of CFTR mutation. This knowledge has proven useful for designing therapy for individual mutations and mutation classes. The discovery and US Food and Drug Administration approval of Kalydeco® (ivacaftor) in early 2011 marked the beginning of a new era of therapies that are focused on improving defective CFTR protein function. However, due to its specificity for the G551D mutation, ivacaftor only benefitŝ5% of CF patients. Approximately 50% of CF patients have two copies of the F508Del mutation, while other CF patients carry only one copy of this gene. More recently, Orkambi®, a two compound medication composed of lumacaftor and ivacaftor, has provided the foundation necessary to further build on molecular concepts of: correction of trafficking, potentiation, and amplification of defective CFTR. These new concepts will form the basis of future CF therapies and extend CFTR treatment to almost 50% of CF patients. Evolving knowledge of the molecular mechanisms responsible for defective CFTR has prompted new research focused on "repair" of each phase of CFTR expression and function, thus creating a new class of combination "CFTR correctors" referred to as "triplet CFTR compounds." This article will review how patients can be selected and treated with these newer agents that are based on specific mutations. In the future, many CF practitioners have expectations that initiation of treatment for CF patients will occur simply by use of biomarkers of CFTR expression (eg, sweat chloride, nasal potential difference, rectal organoids) rather than testing for specific mutations. As continued research identifies biomarkers with greater specificity and which predict clinical response, therapies can potentially be tailored to individual responses.

PMID: 30584312 [PubMed]

Worsening anemia associated with volvulus in a stable neonate with intestinal obstruction.

J Neonatal Perinatal Med. 2018;11(4):417-422

Authors: Moore GP, Byrne A, Davila J, Sarfi E, Bettolli M

Abstract
Intrauterine intestinal obstruction complicated by midgut volvulus is a serious life-threatening diagnosis. Immediate surgical intervention is generally the course of action upon diagnosis to prevent morbidity and mortality. We report a case of intrauterine intestinal obstruction where the neonate then presented with an unusual onset of volvulus within the first 12 hours of life. The patient was born with generalized edema, a distended abdomen, and pallor. Unlike many cases, the patient did not present with typical signs of volvulus. Diagnostic imaging preceding delivery and the stable postnatal clinical course did not offer a justification for immediate laparotomy. Less than 24 hours later, the patient's hemoglobin significantly dropped leading to an emergent laparotomy. Findings included a volvulus of the terminal ileum and large amounts of intraluminal blood. Our case report includes an analysis of clinical observations that should be considered so that patients presenting with similar signs receive earlier surgical intervention.

PMID: 30584174 [PubMed - in process]

A multicenter evaluation of sweat chloride concentration and variation in infants with cystic fibrosis.

J Cyst Fibros. 2018 Dec 21;:

Authors: LeGrys VA, Moon TC, Laux J, Accurso F, Martiniano SA

Abstract
Fifty-nineCF infants' sweat chloride concentrations were analyzed to answer the questions: What is the biological and analytical variation in sweat chloride concentrations collected from the 32 infants homozygous for the F508 deletion? Do sweat chloride concentrations change in the first year of life beyond the variance previously established for adults with similar CFTR mutations? The biological and analytical variation of the infants' sweat chloride concentration was similar to that seen in adult CF patients. While there was a statistically significant difference between sweat chloride concentration in early (89.8 mmol/L) and late (95.0 mmol/L) infancy, this change is not likely clinically significant. This suggests that sweat chloride concentrations in CF patients do not change in a meaningful way during the first year of life. Determining variability in infants with CF is the necessary first step for future design of clinical trials of CFTR modulators in younger patients.

PMID: 30583934 [PubMed - as supplied by publisher]

Standardized clinical criteria and sweat test combined as a tool to diagnose Cystic Fibrosis.

Heliyon. 2018 Dec;4(12):e01050

Authors: González-Andrade F

Abstract
Context: CF is under-diagnosed in Ecuador; one out of every 11,252 live births born in Ecuador could have CF.
Aim: To analyze the clinical findings, based on previously established criteria, with the results of the sweat test, in circumstances where we do not have the routine molecular study.
Methods: Epidemiological, observational, analytic, cross-sectional study. It analyzed 180 patients clinically suspected of CF. Inclusion criteria: children of both sexes older than 30 days and younger than 12 years, who meet at least three clinical criteria suggestive for CF, outpatient and referred by a specialist physician who made a preliminary diagnosis. This is a pilot study.
Results: The combination of criteria pneumonia, chronic cough and chronic obstructive bronchial syndrome is the most frequent, with not a significant relationship with a positive sweat test. On the contrary, a significant relationship was found between the clinical combinations of pneumonia with cough and rhinosinusitis; pneumonia with cough; presence of Pseudomonas aeruginosa; and pneumonia with digital cough and clubbing, so it is recommended to perform the test in all these associations. The most frequent clinical criterion for the reference and performance of the electrolyte test in sweat is pneumonia to repeat for two or more episodes.
Conclusion: Clinical combinations of pneumonia with cough and rhinosinusitis; pneumonia with cough; presence of Pseudomonas aeruginosa; and pneumonia with digital cough and clubbing are pathognomonic for CF and indication for the sweat test. The predictive performance in CF diagnosis, defined as compatible clinical presence plus high values of chloride in sweat test, was 91.1%.

PMID: 30582056 [PubMed]

Bowel-associated dermatosis-arthritis syndrome (BADAS) in a patient with cystic fibrosis.

JAAD Case Rep. 2019 Jan;5(1):37-39

Authors: Rosen JD, Stojadinovic O, McBride JD, Rico R, Cho-Vega JH, Nichols AJ

PMID: 30581933 [PubMed]

Human Cellular Models for the Investigation of Lung Inflammation and Mucus Production in Cystic Fibrosis.

Anal Cell Pathol (Amst). 2018;2018:3839803

Authors: Castellani S, Di Gioia S, di Toma L, Conese M

Abstract
Chronic inflammation, oxidative stress, mucus plugging, airway remodeling, and respiratory infections are the hallmarks of the cystic fibrosis (CF) lung disease. The airway epithelium is central in the innate immune responses to pathogens colonizing the airways, since it is involved in mucociliary clearance, senses the presence of pathogens, elicits an inflammatory response, orchestrates adaptive immunity, and activates mesenchymal cells. In this review, we focus on cellular models of the human CF airway epithelium that have been used for studying mucus production, inflammatory response, and airway remodeling, with particular reference to two- and three-dimensional cultures that better recapitulate the native airway epithelium. Cocultures of airway epithelial cells, macrophages, dendritic cells, and fibroblasts are instrumental in disease modeling, drug discovery, and identification of novel therapeutic targets. Nevertheless, they have to be implemented in the CF field yet. Finally, novel systems hijacking on tissue engineering, including three-dimensional cocultures, decellularized lungs, microfluidic devices, and lung organoids formed in bioreactors, will lead the generation of relevant human preclinical respiratory models a step forward.

PMID: 30581723 [PubMed - in process]

Human Primary Epithelial Cell Models: Promising Tools in the Era of Cystic Fibrosis Personalized Medicine.

Front Pharmacol. 2018;9:1429

Authors: Awatade NT, Wong SL, Hewson CK, Fawcett LK, Kicic A, Jaffe A, Waters SA

Abstract
Cystic fibrosis (CF) is an inherited disorder where individual disease etiology and response to therapeutic intervention is impacted by CF transmembrane regulator (CFTR) mutations and other genetic modifiers. CFTR regulates multiple mechanisms in a diverse range of epithelial tissues. In this Review, we consolidate the latest updates in the development of primary epithelial cellular model systems relevant for CF. We discuss conventional two-dimensional (2-D) airway epithelial cell cultures, the backbone of in vitro cellular models to date, as well as improved expansion protocols to overcome finite supply of the cellular source. We highlight a range of strategies for establishment of three dimensional (3-D) airway and intestinal organoid models and evaluate the limitations and potential improvements in each system, focusing on their application in CF. The in vitro CFTR functional assays in patient-derived organoids allow for preclinical pharmacotherapy screening to identify responsive patients. It is likely that organoids will be an invaluable preclinical tool to unravel disease mechanisms, design novel treatments, and enable clinicians to provide personalized management for patients with CF.

PMID: 30581387 [PubMed]

Differences in the lower airway microbiota of infants with and without cystic fibrosis.

J Cyst Fibros. 2018 Dec 20;:

Authors: Frayman KB, Wylie KM, Armstrong DS, Carzino R, Davis SD, Ferkol TW, Grimwood K, Storch GA, Ranganathan SC

Abstract
BACKGROUND: Cystic fibrosis (CF) lung disease commences in infancy, and understanding the role of the microbiota in disease pathogenesis is critical. This study examined and compared the lower airway microbiota of infants with and without CF and its relationship to airway inflammation in the first months of life.
METHODS: Infants newly-diagnosed with CF were recruited into a single-centre study in Melbourne, Australia from 1992 to 2001. Bronchoalveolar lavage was performed at study entry. Healthy infants undergoing bronchoscopy to investigate chronic stridor acted as controls. Quantitative microbiological culture was performed and inflammatory markers were measured contemporaneously. 16S ribosomal RNA gene analysis was performed on stored samples.
RESULTS: Thirteen bronchoalveolar samples from infants with CF and nine from control infants, collected at median ages of 1.8-months (25th-75th percentile 1.5 to 3.1-months) and 5-months (25th-75th percentile 2.9 to 8.2-months) respectively, provided 16S rRNA gene data. Bacterial biomass was positively associated with inflammation. Alpha diversity was reduced in infants with CF and between-group compositional differences were apparent. These differences were driven by increased Staphylococcus and decreased Fusobacterium and were most apparent in symptomatic infants with CF.
CONCLUSION: In CF lung disease, differences in lower airway microbial community composition and structure are established by age 6-months.

PMID: 30580994 [PubMed - as supplied by publisher]

CFTR Modulator Use is Associated with Higher Hemoglobin Levels in Individuals with Cystic Fibrosis.

Ann Am Thorac Soc. 2018 Dec 22;:

Authors: Gifford AH, Heltshe SL, Goss CH

Abstract
RATIONALE: Understanding how CFTR modulators influence comorbid conditions like anemia is of interest to the CF community.
OBJECTIVE: To test the hypothesis that CFTR modulators are associated with higher hemoglobin (Hgb) levels.
METHODS: Annualized Hgb and other laboratory, demographic, and anthropometric data were abstracted from the U.S. CF Foundation Patient Registry for adult and pediatric registrants before and after therapy with ivacaftor (IVA) or lumacaftor/ivacaftor (LUM/IVA) between January 2010 and December 2016. Univariate and multivariate linear mixed models were used to examine the effect of IVA on Hgb in G551D-CFTR patients and the effect of LUM/IVA on Hgb in F508del-CFTR homozygotes. Linear regression was used to characterize change in mean Hgb over time.
RESULTS: A total of 1,347 registrants (707 males, 640 females) with G551D-CFTR and 12,582 F508del-CFTR homozygotes (6,640 males, 5,942 females) were identified who had never undergone lung transplant and had contemporaneous data on Hgb and CFTR modulator use. IVA was associated with average Hgb increases of 0.54 gm/dl (95% CI 0.39, 0.69, p <0.0001) and 0.18 gm/dl (95% CI 0.01, 0.35, p = 0.037) for males and females, respectively, with G551D-CFTR. LUM/IVA was associated with average Hgb increases of 0.58 gm/dl (95% CI 0.48, 0.68, p <0.0001) and 0.26 gm/dl (95% CI 0.20, 0.33, p <0.0001) for male and female F508del-CFTR homozygotes, respectively. In multivariate models, IVA positively affected Hgb in males but not females, and LUM/IVA positively affected Hgb in both sexes.
CONCLUSIONS: Ivacaftor and lumacaftor/ivacaftor use are both associated with higher Hgb levels in CF patients.

PMID: 30580531 [PubMed - as supplied by publisher]

CFTR Modulators: Deciding What Is Best for Individuals in an Era of Precision Medicine.

Ann Am Thorac Soc. 2018 03;15(3):298-300

Authors: Elborn JS

PMID: 29493341 [PubMed - indexed for MEDLINE]

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Positive mental health and wellbeing in adults with cystic fibrosis: A cross sectional study.

J Psychosom Res. 2018 Nov 27;:

Authors: Cronly J, Duff A, Riekert K, Horgan A, Lehane E, Perry I, Fitzgerald A, Howe B, Chroinin MN, Savage E

Abstract
OBJECTIVE: Screening for depression and anxiety in people with cystic fibrosis (CF) is recommended but this alone can miss the opportunity to assess and promote positive mental health and wellbeing. This cross-sectional study assessed positive mental health and wellbeing, and associations with physical health and health-related quality of life (HRQoL) in adults with CF.
METHODS: Adults (n = 147) with CF from 9 CF centres in the Republic of Ireland completed the Warwick Edinburgh Mental Well-being scale, the Hospital Anxiety and Depression Scale and the Cystic Fibrosis Questionnaire-Revised. Demographic and physical health outcome data were also collected.
RESULTS: High levels of positive mental health and wellbeing were reported in this sample. There were significant associations between positive 'mental health and wellbeing' and pulmonary function, self-reported physical health and recent hospitalizations. Positive mental health was significantly associated with 11 of the 12 CFQ-R domains assessing HRQoL.
CONCLUSION: Assessing and promoting positive mental health and wellbeing may contribute to improving or maintaining physical and mental health, and HRQoL in patients with cystic fibrosis. It provides valuable clinical information to complement depression and anxiety screening and has potential to track the effectiveness of mental health promotion strategies by assessing and monitoring positive mental health and wellbeing over time. Individuals with CF may benefit from interventions that promote positive mental health and wellbeing by enhancing coping and problem-solving skills and fostering hope and optimism. Future research should focus on the development and testing of positive mental health and wellbeing promotion interventions in people with CF.

PMID: 30579560 [PubMed - as supplied by publisher]

Positive mental health and wellbeing in adolescents with cystic fibrosis.

J Psychosom Res. 2018 Nov 27;:

Authors: Cronly J, Savage E

PMID: 30579558 [PubMed - as supplied by publisher]

Cluster and CART analyses identify large subgroups of adults with cystic fibrosis at low risk of 10-year death.

Eur Respir J. 2018 Dec 21;:

Authors: Burgel PR, Lemonnier L, Dehillotte C, Sykes J, Stanojevic S, Stephenson AL, Paillasseur JL

Abstract
Our goal was to identify subgroups of cystic fibrosis (CF) adults at low risk of death within 10 years.Factor analysis for mixed data followed by Ward's cluster analysis were conducted using 25 variables from 1572 French CF adults in 2005. Rates of death by subgroups were analysed over 10 years. An algorithm was developed using classification and regression tree (CART) to provide rules for the identification of subgroups of CF adults with low rates of death within 10 years. This algorithm was validated in 1376 Canadian CF adults.Seven subgroups were identified by cluster analysis in French CF adults, including two subgroups with low (∼5%) rates of death at 10 years: one subgroup (22% of patients) was composed of patients with non-classic CF, the other subgroup (17% of patients) was composed of patients with classic CF but low rates of P. aeruginosa infection and diabetes. An algorithm based on CART analysis of data in 2005 allowed to identify most French adults with low rates of death. When tested using data from Canadian CF adults in 2005, the algorithm identified 287/1376 (21%) patients at low risk (10-year death, 7.7%).Large subgroups of CF adults share low risk of 10-year mortality.

PMID: 30578399 [PubMed - as supplied by publisher]