Salinity-dependent expression of ncc2 in opercular epithelium and gill of mummichog (Fundulus heteroclitus).

J Comp Physiol B. 2020 Jan 24;:

Authors: Breves JP, Starling JA, Popovski CM, Doud JM, Tipsmark CK

Abstract
Mummichogs (Fundulus heteroclitus) can tolerate abrupt changes in environmental salinity because of their ability to rapidly adjust the activities of ionocytes in branchial and opercular epithelia. In turn, the concerted expression of sub-cellular effectors of ion transport underlies adaptive responses to fluctuating salinities. Exposure to seawater (SW) stimulates the expression of Na+/K+/2Cl- cotransporter 1 (nkcc1) and cystic fibrosis transmembrane regulator (cftr) mRNAs in support of ion extrusion by SW-type ionocytes. Given the incomplete understanding of how freshwater (FW)-type ionocytes actually operate in mummichogs, the transcriptional responses essential for ion absorption in FW environments remain unresolved. In a subset of species, a 'fish-specific' Na+/Cl- cotransporter denoted Ncc2 (Slc12a10) is responsible for the uptake of Na+ and Cl- across the apical surface of FW-type ionocytes. In the current study, we identified an ncc2 transcript that is highly expressed in gill filaments and opercular epithelium of FW-acclimated mummichogs. Within 1 day of transfer from SW to FW, ncc2 levels in both tissues increased in parallel with reductions in nkcc1 and cftr. Conversely, mummichogs transferred from FW to SW exhibited marked reductions in ncc2 concurrent with increases in nkcc1 and cftr. Immunohistochemical analyses employing a homologous antibody revealed apical Ncc2-immunoreactivity in Na+/K+-ATPase-immunoreactive ionocytes of FW-acclimated animals. Our combined observations suggest that Ncc2/ncc2-expressing ionocytes support the capacity of mummichogs to inhabit FW environments.

PMID: 31980891 [PubMed - as supplied by publisher]

Plasma microRNA levels in male and female children with cystic fibrosis.

Sci Rep. 2020 Jan 24;10(1):1141

Authors: Mooney C, McKiernan PJ, Raoof R, Henshall DC, Linnane B, McNally P, Glasgow AMA, Greene CM

Abstract
A gender gap exists in cystic fibrosis (CF). Here we investigate whether plasma microRNA expression profiles differ between the sexes in CF children. MicroRNA expression was quantified in paediatric CF plasma (n = 12; six females; Age range:1-6; Median Age: 3; 9 p.Phe508del homo- or heterozygotes) using TaqMan OpenArray Human miRNA Panels. Principal component analysis indicated differences in male versus female miRNA profiles. The miRNA array analysis revealed two miRNAs which were significantly increased in the female samples (miR-885-5p; fold change (FC):5.07, adjusted p value: 0.026 and miR-193a-5p; FC:2.6, adjusted p value: 0.031), although only miR-885-5p was validated as increased in females using specific qPCR assay (p < 0.0001). Gene ontology analysis of miR-885-5p validated targets identified cell migration, motility and fibrosis as processes potentially affected, with RAC1-mediated signalling featuring significantly. There is a significant increase in miR-885-5p in plasma of females versus males with CF under six years of age.

PMID: 31980676 [PubMed - in process]

Glycemic control and FEV1 recovery during pulmonary exacerbations in pediatric cystic fibrosis-related diabetes.

J Cyst Fibros. 2020 Jan 21;:

Authors: Okoniewski W, Hughan KS, Weiner GA, Weiner DJ, Forno E

Abstract
RATIONALE: Whether short-term glucose control in cystic fibrosis-related diabetes (CFRD) is associated with FEV1 recovery during acute pulmonary exacerbations is unclear.
METHODS: Data from all patients with CFRD ages 6-21 years hospitalized in 2010-2016 for pulmonary exacerbations at our CF Center were analyzed, including CFRD status at each encounter, all FEV1 recorded during each exacerbation, and relevant clinical covariates. Glucose control was analyzed using meter blood glucose area under the curve (AUC) indices. The primary outcome was FEV1 recovery.
RESULTS: Patients with CFRD who finished IV antibiotics at home were treated for longer than those fully treated in the hospital (22.2 vs. 13.8 days). In those who finished treatment at home, poor inpatient glycemic control was associated with lower lung function improvement: when comparing the 75th to the 25th percentile of each glycemic index (i.e., "poorer" vs. "better" glycemic control), FEV1 recovery at discharge was 20.1% lower for glucose AUC (95%CI -0.4%, -39.9%); 20.9% lower for 48-h AUC (95%CI -2.7%, -39.1%); and 28.2% lower for AUC/day (95%CI -7.1%, -49.3%). Similar results were found at the end of IV antibiotics and at clinic follow-up. Likewise, patients with poor glycemic control had a lower slope of inpatient FEV1 recovery. Analysis in patients with normal glucose tolerance was largely non-significant. No associations were found between hemoglobin A1c and FEV1 recovery.
CONCLUSIONS: In patients with CFRD who complete IV antibiotic treatment at home, poor inpatient glycemic control is associated with worse FEV1 recovery despite longer duration of treatment.

PMID: 31980357 [PubMed - as supplied by publisher]

18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2020/01/25

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Development of mutant human immunoreactive trypsinogen 1 (IRT1) and mutant human immunoreactive trypsinogen 2 (IRT2) for use in immunoassays.

Protein Expr Purif. 2020 Jan 20;:105572

Authors: Divyapicigil M, Pirincci Gokturk SS, Ergenoglu B, Yucel F, Akcael EA

Abstract
Immunoreactive Trypsinogen (IRT) is a protein-based pancreatic proenzyme that has an important role in protein digestion in humans. In human body, once IRT present in the small intestine, the proteolytic cleavage activates trypsinogen into trypsin. When IRT is in the active form, it is capable to cleave antibodies, other proteins and even itself while it is desired to use in immunoassays. According to the literature, there are three important IRT isoforms called Immunoreactive Trypsinogen 1 (IRT1), Immunoreactive Trypsinogen 2 (IRT2), and Immunoreactive Trypsinogen 3 (IRT3). However, trypsinogen 1 (cationic trypsinogen, IRT1) and trypsinogen 2 (anionic trypsinogen, IRT2) are the major isoforms in human pancreatic juice and used in the diagnosis of cystic fibrosis (CF). In this study, it is aimed to restrain its proteolytic activity with K23D mutation, which changes lysine (K) residue at the 23rd position to aspartic acid (D). Because we wanted to produce a hassle-free human recombinant immune reactive trypsinogen proenzyme which has similar antigenic properties with the native form. It is also aimed that the mutant IRTs do not exhibit proteolytic activity for the development of durable detection kits with a longer shelf life for both two isoforms. The innovation was actualized in order to use IRTs as a standard antigen in Immunoassays such as ELISA kits. The gene was synthesized as mutated and expressed in P. pastoris X-33 strain. The loss of proteolytic activity has been proven with the BAEE test. Antigenic properties of K23D IRTs and the effect of proteolytic inactivation on their performance in immunoassays were assessed with ELISA and Western Blot. In ELISA results K23D mutated IRTs showed higher signals than Wild-Type forms.

PMID: 31972264 [PubMed - as supplied by publisher]

Stop codon context influences genome-wide stimulation of termination codon readthrough by aminoglycosides.

Elife. 2020 Jan 23;9:

Authors: Wangen JR, Green R

Abstract
Stop codon readthrough (SCR) occurs when the ribosome miscodes at a stop codon. Such readthrough events can be therapeutically desirable when a premature termination codon (PTC) is found in a critical gene. To study SCR in vivo in a genome-wide manner, we treated mammalian cells with aminoglycosides and performed ribosome profiling. We find that in addition to stimulating readthrough of PTCs, aminoglycosides stimulate readthrough of normal termination codons (NTCs) genome-wide. Stop codon identity, the nucleotide following the stop codon, and the surrounding mRNA sequence context all influence the likelihood of SCR. In comparison to NTCs, downstream stop codons in 3'UTRs are recognized less efficiently by ribosomes, suggesting that targeting of critical stop codons for readthrough may be achievable without general disruption of translation termination. Finally, we find that G418-induced miscoding alters gene expression with substantial effects on translation of histone genes, selenoprotein genes, and S-adenosylmethionine decarboxylase (AMD1).

PMID: 31971508 [PubMed - as supplied by publisher]

Advances in the diagnosis and management of pulmonary aspergillosis.

Adv Respir Med. 2019;87(6):231-243

Authors: Gao Y, Soubani A

Abstract
Aspergillus is a mould that is ubiquitous in nature and may lead to a variety of infectious and allergic diseases depending on the host's immune status or pulmonary structure. Invasive pulmonaryaspergillosisoccurs primarily in patients with severe immunodeficiency. The significance of this infection has dramatically increased with growing numbers of patients with impaired immune state associated with the management of malignancy, organ transplantation, autoimmune and inflammatory conditions; critically ill patients appear to be at an increased risk as well. The introduction of new noninvasive tests, combined with more effective and better-tolerated antifungal agents, has resulted in lower mortality rates associated with this infection. Chronic pulmonary aspergillosis is a locally invasive disease described in patients with chronic lung disease or mild immunodeficiency. Recently, the European Society for Clinical Microbiology and Infectious Diseases provided a more robust sub-classification of this entity that allows for a straightforward approach to diagnosis and management. Allergic bronchopulmonaryaspergillosis, a hypersensitivity reaction to Aspergillus antigens, is generally seen in patients with atopy, asthma or cystic fibrosis. This review provides an update on the evolving epidemiology and risk factors of the major manifestations of Aspergillus lung disease and the clinical manifestations that should prompt the clinician to consider these conditions. It also details the role of noninvasive tests in the diagnosis of Aspergillus related lung diseases and advances in the management of these disorders.

PMID: 31970725 [PubMed - in process]

Mechanical forces induce an asthma gene signature in healthy airway epithelial cells.

Sci Rep. 2020 Jan 22;10(1):966

Authors: Kılıç A, Ameli A, Park JA, Kho AT, Tantisira K, Santolini M, Cheng F, Mitchel JA, McGill M, O'Sullivan MJ, De Marzio M, Sharma A, Randell SH, Drazen JM, Fredberg JJ, Weiss ST

Abstract
Bronchospasm compresses the bronchial epithelium, and this compressive stress has been implicated in asthma pathogenesis. However, the molecular mechanisms by which this compressive stress alters pathways relevant to disease are not well understood. Using air-liquid interface cultures of primary human bronchial epithelial cells derived from non-asthmatic donors and asthmatic donors, we applied a compressive stress and then used a network approach to map resulting changes in the molecular interactome. In cells from non-asthmatic donors, compression by itself was sufficient to induce inflammatory, late repair, and fibrotic pathways. Remarkably, this molecular profile of non-asthmatic cells after compression recapitulated the profile of asthmatic cells before compression. Together, these results show that even in the absence of any inflammatory stimulus, mechanical compression alone is sufficient to induce an asthma-like molecular signature.

PMID: 31969610 [PubMed - in process]

Procalcitonin predicts the severity of cystic fibrosis pulmonary exacerbations and readmissions in adult patients: a prospective cohort study.

J Investig Med. 2020 Jan 21;:

Authors: Bailey KL, Murphy PJ, Lineberry OK, Haack MR, Dickinson JD, Kalil AC

Abstract
Patients with cystic fibrosis (CF) experience multiple pulmonary exacerbations throughout their lifetime, resulting in repeated antibiotic exposure and hospital admissions. Reliable diagnostic markers to guide antibiotic treatment in patients with CF, however, are lacking. Given that the CF airway is characterized by persistent and frequent bacterial infection, our goal was to determine if procalcitonin (PCT) could be used as a severity and prognostic marker of CF exacerbation. We enrolled 40 participants at the time of diagnosis of CF pulmonary exacerbation. Inclusion criteria: age ≥19 years with exacerbation requiring antibiotics as determined by the treating physician. Exclusion criteria: antibiotics initiated more than 48 hours prior to enrollment, and pregnancy. Blood samples were collected on enrollment day and after 7-10 days of treatment. Of the 40 patients enrolled, 23 (57.5%) had detectable levels of PCT (≥0.05 ng/mL). PCT levels were significantly associated with pulmonary exacerbation scores (p=0.01) and per cent decrease in forced expiratory volume in 1 second (FEV1) (p=0.01) compared with the best in the last 12 months. Those who had worsening PCT during treatment had less improvement in FEV1 (p=0.001) and were more likely to be readmitted to the hospital sooner (p<0.0001). Likewise, those who had a detectable PCT at the time of admission were more likely to be readmitted sooner (p=0.03). PCT elevation during antibiotic treatment is associated with less improvement in FEV1 and earlier readmission. A detectable PCT level occurs only in more severe CF exacerbations. Multicenter trials are needed to confirm whether PCT may play a role in the clinical care of patients with CF.

PMID: 31969379 [PubMed - as supplied by publisher]

Prevalence of hypermutator isolates of Achromobacter spp. from cystic fibrosis patients.

Int J Med Microbiol. 2020 Jan 16;:151393

Authors: Ridderberg W, Jensen Handberg K, Nørskov-Lauritsen N

Abstract
Bacteria colonising the lungs of cystic fibrosis (CF) patients encounter high selective pressures. Hypermutation facilitates adaptation to fluctuating environments, and hypermutator strains are frequently isolated from CF patients. We investigated the prevalence of hypermutator isolates of Achromobacter spp. among patients affiliated with the CF Centre in Aarhus, Denmark. By exposure to rifampicin, the mutation frequency was determined for 90 isolates of Achromobacter spp. cultured from 42 CF patients; 20 infections were categorised as chronic, 22 as intermittent. The genetic mechanisms of hypermutation were examined by comparing DNA repair gene sequences from hypermutator and normomutator isolates. Achromobacter spp. cultured from 11 patients were categorised as hypermutators, and this phenotype was exclusively associated with chronic infections. Isolates of the Danish epidemic strain (DES) of Achromobacter ruhlandii cultured from patients from both Danish CF centres showed elevated mutation frequencies. The hypermutator state of Achromobacter spp. was most commonly associated with nonsynonymous mutations in the DNA mismatch repair gene mutS; a single clone had developed a substitution in the S-adenosyl-L-methionine-dependent methyltransferase putatively involved in DNA repair mechanisms, but not previously linked to the hypermutator phenotype. Hypermutation is prevalent among clinical isolates of Achromobacter spp. and could be a key determinant for the extraordinary adaptation and persistence of DES.

PMID: 31969255 [PubMed - as supplied by publisher]

Dextran Microparticulate Inhalable Dry Powder for the Treatment of Cystic Fibrosis and Mucopolysaccharidosis.

Curr Drug Deliv. 2020 Jan 22;:

Authors: Solanki NR, Patel DH, Talele DR

Abstract
BACKGROUND: Cystic fibrosis (CF) is genetic disease that affects the patient's lungs, pancreas, liver, kidney and intestine and lacks sulfatase enzyme, which lead to mucopolysaccharidosis. Colistin sulfate acts by interacting with phospholipids of bacterial cell membranes. Sulfatase enzyme reduces the high levels of sulfated glycosaminoglycans and glycolipids by hydrolysis of sulfate esters in lysosome.
OBJECTIVE: The aim of the present investigation was to prepare and evaluate dextran microparticulate inhalable dry powder for the efficient targeting of colistin sulfate at affected area of lung without causing the side effects in the treatment of CF and mucopolysaccharidosis.
METHODS: Microparticulate dry powder was prepared by lyophilization method and evaluated for particle size, % yield, % drug content, solid state characterization, in-vitro lung deposition study, and in-vitro drug release study.
RESULTS: Particle size, % yield and % drug content were found to be 4.03 ±0.196 µm, 94.02 % and 99.45± 0.015%. Bulk density, tapped density, hausner's ratio, carr's index and angle of repose of optimized batch were found to be 0.216±0.025 g/cm3, 0.236±0.035 g/cm3, 1.09±0.026, 8.47±0.025 % and 26.10±0.029˚ respectively. A fine particle fraction, fine particle dose, mass median aerodynamic diameter, geometric standard deviation and emitted dose were found to be 66.78%, 16.45 mg, 4.89 µm, 1.32 and 246.33 mg respectively. The % CDR of optimized batch was found to be 96.12± 0.049 % at 24 h.
CONCLUSION: Based on the obtained results, we conclude that dextran microparticulate inhalable dry powder might be suitable carrier for delivery of colistin sulfate and sulfatase in combination via pulmonary route for treatment of cystic fibrosis and mucopolysaccharidosis.

PMID: 31969100 [PubMed - as supplied by publisher]

Potentially lethal cystic fibrosis gene variant in the orangutan.

Am J Primatol. 2020 Jan 22;:e23097

Authors: Taylor-Cousar JL, Evans TA, Cutting GR, Sharma N

Abstract
A syndrome of chronic upper and lower airway disease leading to increased morbidity and mortality occurs primarily in captive orangutans. Similarities in symptoms to the inherited human respiratory disease, cystic fibrosis, led us to hypothesize that orangutan respiratory disease is a result of variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. We identified the nonsense variant, c.484A>T (p.Lys162X), in heterozygosity in an unaffected orangutan. Analysis of the pedigree of this orangutan confirmed that both his sire and deceased fetus also harbored the c.484A>T allele. An expression minigene harboring c.484A>T produced no full-length CFTR protein in HEK293 cells. Finally, the c.484A>T CFTR messenger RNA abundance was severely reduced in primary nasal epithelial cells of the orangutan indicating that c.484A>T (p.Lys162X) is potentially lethal. Genetic screening of the captive orangutan population could be used to prevent transmission of this potentially lethal variant, and thus aid in the conservation of this critically endangered species.

PMID: 31967360 [PubMed - as supplied by publisher]

Lumacaftor/ivacaftor therapy is associated with reduced hepatic steatosis in cystic fibrosis patients.

World J Hepatol. 2019 Dec 27;11(12):761-772

Authors: Kutney K, Donnola SB, Flask CA, Gubitosi-Klug R, O'Riordan M, McBennett K, Sferra TJ, Kaminski B

Abstract
BACKGROUND: Hepatic steatosis is a common form of cystic fibrosis associated liver disease (CFLD) seen in an estimated 15%-60% of patients with cystic fibrosis (CF). The pathophysiology and health implications of hepatic steatosis in cystic fibrosis remain largely unknown. In the general population, hepatic steatosis is strongly associated with insulin resistance and type 2 diabetes. Cystic fibrosis related diabetes (CFRD) impacts 40%-50% of CF adults and is characterized by both insulin insufficiency and insulin resistance. We hypothesized that patients with CFRD would have higher levels of hepatic steatosis than cystic fibrosis patients without diabetes.
AIM: To determine whether CFRD is associated with hepatic steatosis and to explore the impact of lumacaftor/ivacaftor therapy on hepatic steatosis in CF.
METHODS: Thirty patients with CF were recruited from a tertiary care medical center for this cross-sectional study. Only pancreatic insufficient patients with CFRD or normal glucose tolerance (NGT) were included. Patients with established CFLD, end stage lung disease, or persistently elevated liver enzymes were excluded. Mean magnetic resonance imaging (MRI) proton density fat fraction (PDFF) was obtained for all participants. Clinical characteristics [age, sex, body mass index, percent predicted forced expiratory volume at 1 s (FEV1), lumacaftor/ivacaftor use] and blood chemistries were assessed for possible association with hepatic steatosis. Hepatic steatosis was defined as a mean MRI PDFF > 5%. Patients were grouped by diabetes status (CFRD, NGT) and cystic fibrosis transmembrane conductance regulator (CFTR) modulator use (lumacaftor/ivacaftor, no lumacaftor/ivacaftor) to determine between group differences. Continuous variables were analyzed with a Wilcoxon rank sum test and discrete variables with a Chi square test or Fisher's exact test.
RESULTS: Twenty subjects were included in the final analysis. The median age was 22.3 years (11.3-39.0) and median FEV1 was 77% (33%-105%). Twelve subjects had CFRD and 8 had NGT. Nine subjects were receiving lumacaftor/ivacaftor. The median PDFF was 3.0% (0.0%-21.0%). Six subjects (30%) had hepatic steatosis defined as PDFF > 5%. Hepatic fat fraction was significantly lower in patients receiving lumacaftor/ivacaftor (median, range) (2.0%, 0.0%-6.4%) than in patients not receiving lumacaftor/ivacaftor (4.1%, 2.7-21.0%), P = 0.002. Though patients with CFRD had lower PDFF (2.2%, 0.0%-14.5%) than patients with NGT (4.9%, 2.4-21.0%) this did not reach statistical significance, P = 0.06. No other clinical characteristic was strongly associated with hepatic steatosis.
CONCLUSION: Use of the CFTR modulator lumacaftor/ivacaftor was associated with significantly lower hepatic steatosis. No association between CFRD and hepatic steatosis was found in this cohort.

PMID: 31966908 [PubMed]

A Phase I, dose-escalating study of safety and pharmacokinetics of inhaled dry powder vancomycin (AeroVanc) in volunteers and patients with cystic fibrosis: a new approach to therapy for methicillin-resistant Staphylococcus aureus.

Antimicrob Agents Chemother. 2020 Jan 21;:

Authors: Waterer G, Lord J, Hofmann T, Jouhikainen T

Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) has become a significant acute and chronic respiratory pathogen. While vancomycin is effective against MRSA, its relatively poor penetration into lung secretions and dose-limiting renal toxicity make it less effective in the respiratory setting. As inhaled administration of vancomycin would overcome these limitations, we developed a dry powder formulation suitable for inhalation (AeroVanc). Here we report a Phase I, single-dose, dose-escalating study aimed at demonstrating safety and tolerability of AeroVanc. In Part I, 18 healthy subjects received a single dose of 16 mg, 32 mg or 80 mg of AeroVanc. Two subjects also received a 250 mg dose of intravenous vancomycin. In Part 2 of the study, 32 mg and 80 mg AeroVanc was administered to subjects with cystic fibrosis as single doses. There were no serious side effects. A small drop in FEV1 was observed in 3 subjects with cystic fibrosis, one of whom required salbutamol. Vancomycin was rapidly absorbed after inhalation. Peak and mean plasma concentrations of vancomycin were dose proportional. The average minimum concentration of vancomycin in sputum remained above the usual MIC values for MRSA for up to 24 hours (Cmin: 32mg dose = 3.05 μg/ml, 80mg dose = 8.0 μg/ml). In conclusion, AeroVanc was well tolerated and achieved high levels in sputum with a mean systemic absorption of 49%, making it a potential therapeutic strategy for respiratory infection with MRSA.

PMID: 31964790 [PubMed - as supplied by publisher]

Probiotics for people with cystic fibrosis.

Cochrane Database Syst Rev. 2020 Jan 22;1:CD012949

Authors: Coffey MJ, Garg M, Homaira N, Jaffe A, Ooi CY

Abstract
BACKGROUND: Cystic fibrosis (CF) is a multisystem disease and the importance of growth and nutrition has been well established, given its implications for lung function and overall survival. It has been established that intestinal dysbiosis (i.e. microbial imbalance) and inflammation is present in people with CF. Probiotics are commercially available (over-the-counter) and may improve both intestinal and overall health.
OBJECTIVES: To assess the efficacy and safety of probiotics for improving health outcomes in children and adults with CF.
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 register search: 20 January 2020. We also searched ongoing trials registries and the reference lists of relevant articles and reviews. Date of last search: 29 January 2019.
SELECTION CRITERIA: Randomised or quasi-randomised controlled trials (RCTs) assessing efficacies and safety of probiotics in children and adults with CF. Cross-over RCTs with a washout phase were included and for those without a washout period, only the first phase of each trial was analysed.
DATA COLLECTION AND ANALYSIS: We independently extracted data and assessed the risk of bias of the included trials; we used GRADE to assess the certainty of the evidence. We contacted trial authors for additional data. Meta-analyses were undertaken on outcomes at several time points.
MAIN RESULTS: We identified 17 trials and included 12 RCTs (11 completed and one trial protocol - this trial was terminated early) (464 participants). Eight trials included only children, whilst four trials included both children and adults. Trial duration ranged from one to 12 months. Nine trials compared a probiotic (seven single strain and three multistrain preparations) with a placebo preparation, two trials compared a synbiotic (multistrain) with a placebo preparation and one trial compared two probiotic preparations. Overall we judged the risk of bias in the 12 trials to be low. Three trials had a high risk of performance bias, two trials a high risk of attrition bias and six trials a high risk of reporting bias. Only two trials were judged to have low or unclear risk of bias for all domains. Four trials were sponsored by grants only, two trials by industry only, two trials by both grants and industry and three trials had an unknown funding source. Combined data from four trials (225 participants) suggested probiotics may reduce the number of pulmonary exacerbations during a four to 12 month time-frame, mean difference (MD) -0.32 episodes per participant (95% confidence interval (CI) -0.68 to 0.03; P = 0.07) (low-certainty evidence); however, the 95% CI includes the possibility of both an increased and a reduced number of exacerbations. Additionally, two trials (127 participants) found no evidence of an effect on the duration of antibiotic therapy during the same time period. Combined data from four trials (177 participants) demonstrated probiotics may reduce faecal calprotectin, MD -47.4 µg/g (95% CI -93.28 to -1.54; P = 0.04) (low-certainty evidence), but the results for other biomarkers mainly did not show any difference between probiotics and placebo. Two trials (91 participants) found no evidence of effect on height, weight or body mass index (low-certainty evidence). Combined data from five trials (284 participants) suggested there was no difference in lung function (forced expiratory volume at one second (FEV1) % predicted) during a three- to 12-month time frame, MD 1.36% (95% CI -1.20 to 3.91; P = 0.30) (low-certainty evidence). Combined data from two trials (115 participants) suggested there was no difference in hospitalisation rates during a three- to 12-month time frame, MD -0.44 admissions per participant (95% CI -1.41 to 0.54; P = 0.38) (low-certainty evidence). One trial (37 participants) reported health-related quality of life and while the parent report favoured probiotics, SMD 0.87 (95% CI 0.19 to 1.55) the child self-report did not identify any effect, SMD 0.59 (95% CI -0.07 to 1.26) (low-certainty evidence). There were limited results for gastrointestinal symptoms and intestinal microbial profile which were not analysable. Only four trials and one trial protocol (298 participants) reported adverse events as a priori hypotheses. No trials reported any deaths. One terminated trial (12 participants and available as a protocol only) reported a severe allergic reaction (severe urticaria) for one participant in the probiotic group. Two trials reported a single adverse event each (vomiting in one child and diarrhoea in one child). The estimated number needed to harm for any adverse reaction (serious or not) is 52 people (low-certainty evidence).
AUTHORS' CONCLUSIONS: Probiotics significantly reduce faecal calprotectin (a marker of intestinal inflammation) in children and adults with CF, however the clinical implications of this require further investigation. Probiotics may make little or no difference to pulmonary exacerbation rates, however, further evidence is required before firm conclusions can be made. Probiotics are associated with a small number of adverse events including vomiting, diarrhoea and allergic reactions. In children and adults with CF, probiotics may be considered by patients and their healthcare providers. Given the variability of probiotic composition and dosage, further adequately-powered multicentre RCTs of at least 12 months duration are required to best assess the efficacy and safety of probiotics for children and adults with CF.

PMID: 31962375 [PubMed - in process]

Mucus plugging, air trapping, and bronchiectasis are important outcome measures in assessing progressive childhood cystic fibrosis lung disease.

Pediatr Pulmonol. 2020 Jan 21;:

Authors: Robinson TE, Goris ML, Moss RB, Tian L, Kan P, Yilma M, McCoy KS, Newman B, de Jong PA, Long FR, Brody AS, Behrje R, Yates DP, Cornfield DN

Abstract
OBJECTIVE: To determine which outcome measures could detect early progression of disease in school-age children with mild cystic fibrosis (CF) lung disease over a two-year time interval utilizing chest computed tomography (CT) scores, quantitative CT air trapping (QAT), and spirometric measurements.
METHODS: Thirty-six school-age children with mild CF lung disease (median [interquartile range] age 12 [3.7] years; percent predicted forced expiratory volume in 1 second (ppFEV1 ) 99 [12.5]) were evaluated by serial spirometer-controlled chest CT scans and spirometry at baseline, 3-month, 1- and 2-years.
RESULTS: No significant changes were noted at 3-month for any variable except for decreased ppFEV1 . Mucus plugging score (MPS) and QATA1 and A2 increased at 1- and 2-years. The bronchiectasis score (BS), and total score (TS) were increased at 2-year. All variables tested with the exception of bronchial wall thickness score, parenchymal score (PS), and ppFEV1 , were consistent with longitudinal worsening of lung disease. Multivariate analysis revealed baseline PS, baseline TS, and 1-year changes in BS and air trapping score were predictive of 2-year changes in BS.
CONCLUSIONS: MPS and QATA1-A2 were the most sensitive indicators of progressive childhood CF lung disease. The 1-year change in the bronchiectasis score had the most positive predictive power for 2-year change in bronchiectasis.

PMID: 31962004 [PubMed - as supplied by publisher]

CFTR dysregulation drives active selection of the gut microbiome.

PLoS Pathog. 2020 Jan 21;16(1):e1008251

Authors: Meeker SM, Mears KS, Sangwan N, Brittnacher MJ, Weiss EJ, Treuting PM, Tolley N, Pope CE, Hager KR, Vo AT, Paik J, Frevert CW, Hayden HS, Hoffman LR, Miller SI, Hajjar AM

Abstract
Patients with cystic fibrosis (CF) have altered fecal microbiomes compared to those of healthy controls. The magnitude of this dysbiosis correlates with measures of CF gastrointestinal (GI) disease, including GI inflammation and nutrient malabsorption. However, whether this dysbiosis is caused by mutations in the CFTR gene, the underlying defect in CF, or whether CF-associated dysbiosis augments GI disease was not clear. To test the relationships between CFTR dysfunction, microbes, and intestinal health, we established a germ-free (GF) CF mouse model and demonstrated that CFTR gene mutations are sufficient to alter the GI microbiome. Furthermore, flow cytometric analysis demonstrated that colonized CF mice have increased mesenteric lymph node and spleen TH17+ cells compared with non-CF mice, suggesting that CFTR defects alter adaptive immune responses. Our findings demonstrate that CFTR mutations modulate both the host adaptive immune response and the intestinal microbiome.

PMID: 31961914 [PubMed - as supplied by publisher]

Cystic fibrosis transmembrane conductance regulator dysfunction in platelets drives lung hyperinflammation.

J Clin Invest. 2020 Jan 21;:

Authors: Ortiz-Munoz G, Yu MA, Lefrançais E, Mallavia B, Valet C, Tian JJ, Ranucci S, Wang KM, Liu Z, Kwaan N, Dawson D, Kleinhenz ME, Khasawneh FT, Haggie PM, Verkman AS, Looney MR

Abstract
Cystic fibrosis (CF) lung disease is characterized by an inflammatory response that can lead to terminal respiratory failure. The cystic fibrosis transmembrane regulator (CFTR) is mutated in CF and we hypothesized that dysfunctional CFTR in platelets, which are key participants in immune responses, is a central determinant of CF inflammation. We found that deletion of CFTR in platelets produced exaggerated acute lung inflammation and platelet activation after intratracheal LPS or Pseudomonas aeruginosa challenge. CFTR loss of function in mouse or human platelets resulted in agonist-induced hyperactivation and increased calcium entry into platelets. Inhibition of the transient receptor potential cation channel 6 (TRPC6) reduced platelet activation and calcium flux, and reduced lung injury in CF mice after intratracheal LPS or Pseudomonas aeruginosa challenge. CF subjects receiving CFTR modulator therapy showed partial restoration of CFTR function in platelets, which may be a convenient approach to monitoring biological responses to CFTR modulators. We conclude that CFTR dysfunction in platelets produces aberrant TRPC6-dependent platelet activation, which is a major driver of CF lung inflammation and impaired bacterial clearance. Platelets, and TRPC6, are what we believe to be novel therapeutic targets in the treatment of CF lung disease.

PMID: 31961827 [PubMed - as supplied by publisher]

Oxidative and inflammatory effects of pulmonary rehabilitation in patients with bronchiectasis. A prospective, randomized study.

Nutr Hosp. 2020 Jan 21;:

Authors: Olveira C, García-Escobar E, Doña E, Palenque FJ, Porras N, Dorado A, Godoy AM, Rubio-Martín E, Bermúdez-Silva FJ, Romero-Zerbo SY, Rojo Martínez G, Martín-Valero R, Abuín Fernández J, Olveira G

Abstract
BACKGROUND: systemic inflammation and oxidative stress are important factors in the pathogenesis of bronchiectasis. Pulmonary rehabilitation (PR) is recommended for bronchiectasis, but there is no data about its effect on the inflammatory and REDOX status of these patients.
AIMS: to investigate the effect of PR in non-cystic-fibrosis bronchiectasis (NCFB) patients, and to compare it with the effect of PR plus a hyperproteic oral nutritional supplement (PRS) enriched with beta-hydroxy-beta-methylbutyrate (HMB) on serum inflammatory and oxidative biomarkers.
MATERIALS AND METHODS: this was an open randomized, controlled trial. Thirty individuals (65 years old or younger with a body mass index over 18.5, older than 65 years with a body mass index over 20) were recruited from September 2013 to September 2014, and randomly assigned to receive PR or PRS. Total neutrophils, and inflammatory and oxidative biomarker levels were measured at baseline, and then at 3 and 6 months.
RESULTS: in the PRS group neutrophil levels were decreased from baseline at 6 months. A significantly different fold change was found between the PR and PRS groups. In the PR group, IL-6 and adiponectin were increased by the end of the study while TNFα levels were decreased from baseline at 6 months. REDOX biomarkers remained stable throughout the study except for 8-isoprostane levels, which were increased from baseline at 6 months in both groups of patients.
CONCLUSIONS: a PR program induced a pro-oxidative effect accompanied by changes in circulating inflammatory cytokine levels in NCFB patients. Our results would also suggest a possible beneficial effect of the HMB enriched supplement on neutrophil level regulation in these patients. The information provided in this study could be useful for choosing the right therapeutic approach in the management of bronchiectasis.

PMID: 31960695 [PubMed - as supplied by publisher]

A human ciliopathy reveals essential functions for NEK10 in airway mucociliary clearance.

Nat Med. 2020 Jan 20;:

Authors: Chivukula RR, Montoro DT, Leung HM, Yang J, Shamseldin HE, Taylor MS, Dougherty GW, Zariwala MA, Carson J, Daniels MLA, Sears PR, Black KE, Hariri LP, Almogarri I, Frenkel EM, Vinarsky V, Omran H, Knowles MR, Tearney GJ, Alkuraya FS, Sabatini DM

Abstract
Mucociliary clearance, the physiological process by which mammalian conducting airways expel pathogens and unwanted surface materials from the respiratory tract, depends on the coordinated function of multiple specialized cell types, including basal stem cells, mucus-secreting goblet cells, motile ciliated cells, cystic fibrosis transmembrane conductance regulator (CFTR)-rich ionocytes, and immune cells1,2. Bronchiectasis, a syndrome of pathological airway dilation associated with impaired mucociliary clearance, may occur sporadically or as a consequence of Mendelian inheritance, for example in cystic fibrosis, primary ciliary dyskinesia (PCD), and select immunodeficiencies3. Previous studies have identified mutations that affect ciliary structure and nucleation in PCD4, but the regulation of mucociliary transport remains incompletely understood, and therapeutic targets for its modulation are lacking. Here we identify a bronchiectasis syndrome caused by mutations that inactivate NIMA-related kinase 10 (NEK10), a protein kinase with previously unknown in vivo functions in mammals. Genetically modified primary human airway cultures establish NEK10 as a ciliated-cell-specific kinase whose activity regulates the motile ciliary proteome to promote ciliary length and mucociliary transport but which is dispensable for normal ciliary number, radial structure, and beat frequency. Together, these data identify a novel and likely targetable signaling axis that controls motile ciliary function in humans and has potential implications for other respiratory disorders that are characterized by impaired mucociliary clearance.

PMID: 31959991 [PubMed - as supplied by publisher]