Balkan Med J. 2021 Nov;38(6):357-364. doi: 10.5152/balkanmedj.2021.21199.

ABSTRACT

BACKGROUND: Cystic fibrosis, a pulmonary disease which is an autosomal recessive, inherited, multisystemic genetic disease commonly seen in the Caucasian race, is the most frequent cause of mortality and morbidity. So far, more than 2000 disease-causing gene variants have been found and this number has been increasing with the studies conducted. Although there is not yet enough data that include the Turkish population, the recent increase of studies is noteworthy.

AIMS: To discover the genetic variation in patients diagnosed with cystic fibrosis in the Central Anatolian region.

STUDY DESIGN: Cross-sectional study.

METHODS: The study was carried out in the Central Anatolian region in 3 pediatric pulmonology departments (Kayseri, Konya, and Ankara) in Turkey between July 2014 and December 2017. The Sanger and Next Generation Sequence analyses were used for exon and exon-intron boundaries in the cystic fibrosis transmembrane conductance regulatory (CFTR) gene, and in selected patients, mutation analysis was performed using the Multiplex Ligation-dependent Probe Amplification technique for large deletions and duplications.

RESULTS: CFTR gene analysis was performed for 316 patients and 215 of them were genetically diagnosed with cystic fibrosis. Sixtythree different variants were defined in these patients and 7 of these were large deletions/duplications detected with the MLPA method. The most frequent variants were F508del (29.6%), G85E (8.2%), N1303K (8.2%), Y515* (7.5%), and G542* (3.4%).

CONCLUSION: Using sequencing and Multiplex Ligation-dependent Probe Amplification methods, the identification of seven new mutations that were not previously reported in the literature contributes to a better understanding of the heterogeneous nature of CFTR mutations in the Turkish population. When no mutations are detected (pathogenic/probably pathogenic) in clinically compatible cases, Multiplex Ligationdependent Probe Amplification analysis contributes significantly to the diagnosis.

PMID:34860163 | DOI:10.5152/balkanmedj.2021.21199

Acc Chem Res. 2021 Dec 3. doi: 10.1021/acs.accounts.1c00601. Online ahead of print.

ABSTRACT

ConspectusmRNA drugs can preempt infectious disease and treat Mendelian disorders, such as sickle cell anemia, muscular dystrophy, and cystic fibrosis, as well as autoimmunity and cancer. The three major therapeutic areas for which mRNA delivery is currently being explored are antigen production, including the COVID-19 vaccine, protein replacement therapy, and genome engineering. It was demonstrated 30 years ago that introducing in vitro transcribed mRNA intramuscularly results in detectable protein expression for specific antigens protecting against the likes of influenza and cancer. Utilizing mRNA as a therapeutic modality, however, is challenging. mRNA is large and anionic and, as a result, cannot passively diffuse across the negatively charged plasma membrane. In addition, RNases present in the bloodstream and tissues rapidly degrade mRNA, and its administration induces the innate immune response. In consequence, lipid-, polymer-, dendrimer-, and natural membrane-based mRNA drug delivery systems have been developed to deliver mRNA to target cells. Significant efforts and investments have been made to translate some of these systems into the clinic. Specifically, systemically administered lipid nanoparticles (LNPs) have delivered mRNA to the liver, and intramuscularly administered LNPs have delivered mRNA to immune cells to protect against coronavirus disease of 2019. However, clinically relevant delivery in non-liver tissues such as the spleen, lungs, heart, eye, central nervous system, and lymphatics requires improved drug delivery systems.In this Account, we provide an overview of key advances that have led us to Food and Drug Administration approval for the Pfizer/BioNTech mRNA-based vaccine against SARS-CoV-2 and Emergency Use Authorization for the Moderna mRNA-based vaccine against the same disease, and we explain how these developments will contribute to the clinical translation of mRNA therapeutics targeted outside of the liver. We first focus on the chemical modifications and sequence optimization that can improve the potency of mRNA, resulting in greatly improved pharmacokinetics. After detailing what makes an ideal mRNA payload, we review drug delivery systems used to deliver the payload into target cells. We describe efforts to reduce clearance by the liver, a key obstacle to the development of non-liver therapies. We then consider recent examples of nanoparticles that have delivered mRNA to non-liver tissues. Finally, we discuss current clinical mRNA programs, focusing on the COVID vaccines and highlighting lessons that may be applied to future mRNA drugs.

PMID:34859663 | DOI:10.1021/acs.accounts.1c00601

Pediatr Pulmonol. 2021 Dec 3. doi: 10.1002/ppul.25781. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a multisystem disorder that results in the buildup of mucus in various organs. Ninety percent of CF patients are classified as pancreatic insufficient, leading to malabsorption of nutrients and fat-soluble vitamins without the assistance of exogenous pancreatic enzymes. This study was designed to determine if serum 25-hydroxyvitamin D concentrations were impacted by initiation of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA).

METHODS: Serum 25-hydroxyvitamin D concentrations were measured prior to and 1 year post-ELX/TEZ/IVA initiation. A Wilcoxon signed-rank test was used to compare values.

RESULTS: Seventy-six patients were included in the final analysis. The average age of our population was 25.8 years (SD = 13.2 years) with a majority being male, homozygous F508del, pancreatic insufficient, and not modulator-naive. The median increase of serum vitamin D concentration after initiating ELX/TEZ/IVA was 5 ng/mL ((IQR) = -4, 13; p = 0.0035).

CONCLUSIONS: We suggest that ELX/TEZ/IVA may improve fat-soluble vitamin absorption, specifically serum 25-hydroxyvitamin D. These results may lead to adjustments in vitamin supplementation in patients receiving cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy. This article is protected by copyright. All rights reserved.

PMID:34859619 | DOI:10.1002/ppul.25781

Front Vet Sci. 2021 Nov 11;8:728849. doi: 10.3389/fvets.2021.728849. eCollection 2021.

ABSTRACT

Lactobacillus plantarum CGMCC 1258 and Lactobacillus reuteri LR1 are two important strains of probiotics. However, their different advantages in the probiotic effect of weaned pigs are still poorly understood. Therefore, the study was to investigate the comparative effects of dietary supplementation of L. plantarum CGMCC 1258 and L. reuteri LR1 on growth performance, antioxidant function, and intestinal immunity in weaned pigs. Ninety barrows [initial body weight (BW) = 6.10 ± 0.1 kg] 21 days old were randomly divided into 3 treatments with 5 replicates, each replicate containing 6 pigs. Pigs in control (CON) were fed a basal diet, and the basal diets supplemented with 5 × 1010 CFU/kg L. plantarum CGMCC 1258 (LP) or L. reuteri LR1 (LR) for 42 days, respectively. The results showed that LP increased (p < 0.05) serum superoxide dismutase (SOD), and decreased (p < 0.05) serum malondialdehyde (MDA) and the expression and secretion of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) in intestinal mucosa, but has no significant effect on growth performance and diarrheal incidence. However, LR increased (p < 0.05) final BW and average daily gain (ADG), reduced (p < 0.05) 29-42-day diarrheal incidence, decreased (p < 0.05) the expression and secretion of IL-1β, IL-6, TNF-α, and IFN-γ, and increased (p < 0.05) the expression of transforming growth factor-β (TGF-β) in intestinal mucosa. In addition, the serum glutathione peroxidase (GSH-PX), mRNA relative expression of Na+-K+-2Cl- co-transporter 1 (NKCC1) and cystic fibrosis transmembrane conductance regulator (CFTR) and the content of toll-like relative (TLR2) and TLR4 in the jejunum, and secretory immunoglobulin (sIgA) content of ileal mucosa were higher (p < 0.05) than LP. Collectively, dietary L. plantarum CGMCC 1258 improved intestinal morphology, intestinal permeability, intestinal immunity, and antioxidant function in weaned pigs. Dietary L. reuteri LR1 showed better growth performance, a lower incidence of diarrhea, better intestinal morphology, and a higher extent of immune activation in weaned pigs.

PMID:34859082 | PMC:PMC8632148 | DOI:10.3389/fvets.2021.728849

Front Cell Infect Microbiol. 2021 Nov 9;11:800847. doi: 10.3389/fcimb.2021.800847. eCollection 2021.

NO ABSTRACT

PMID:34858886 | PMC:PMC8630675 | DOI:10.3389/fcimb.2021.800847

Biomed Opt Express. 2021 Oct 7;12(11):6796-6813. doi: 10.1364/BOE.435870. eCollection 2021 Nov 1.

ABSTRACT

A non-invasive diagnostic tool to assess remodeling of the lung airways caused by disease is currently missing in the clinic. Measuring key features such as airway smooth muscle (ASM) thickness would increase the ability to improve diagnosis and enable treatment evaluation. In this research, polarization-sensitive optical coherence tomography (PS-OCT) has been used to image a total of 24 airways from two healthy lungs and four end-stage diseased lungs ex vivo, including fibrotic sarcoidosis, chronic obstructive pulmonary disease (COPD), fibrotic hypersensitivity pneumonitis, and cystic fibrosis. In the diseased lungs, except COPD, the amount of measured airway smooth muscle was increased. In COPD, airway smooth muscle could not be distinguished from surrounding collagen. COPD lungs showed increased alveolar size. 3D pullbacks in the same lumen provided reproducible assessment of airway smooth muscle (ASM). Image features such as thickened ASM and size/presence of alveoli were recognized in histology. The results of this study are preliminary and must be confirmed with further ex vivo and in vivo studies. PS-OCT is applicable for in vivo assessment of peribronchial and peribronchiolar lung structures and may become a valuable tool for diagnosis in pulmonology.

PMID:34858681 | PMC:PMC8606143 | DOI:10.1364/BOE.435870

Front Immunol. 2021 Nov 9;12:704391. doi: 10.3389/fimmu.2021.704391. eCollection 2021.

ABSTRACT

Cystic fibrosis (CF) is an autosomal recessive gene disorder that affects tens of thousands of patients worldwide. Individuals with CF often succumb to progressive lung disease and respiratory failure following recurrent infections with bacteria. Viral infections can also damage the lungs and heighten the CF patient's susceptibility to bacterial infections and long-term sequelae. Vitamin A is a key nutrient important for immune health and epithelial cell integrity, but there is currently no consensus as to whether vitamin A should be monitored in CF patients. Here we evaluate previous literature and present results from a CF mouse model, showing that oral vitamin A supplements significantly reduce lung lesions that would otherwise persist for 5-6 weeks post-virus exposure. Based on these results, we encourage continued research and suggest that programs for the routine monitoring and regulation of vitamin A levels may help reduce virus-induced lung pathology in CF patients.

PMID:34858393 | PMC:PMC8630690 | DOI:10.3389/fimmu.2021.704391

Front Pharmacol. 2021 Nov 8;12:746710. doi: 10.3389/fphar.2021.746710. eCollection 2021.

ABSTRACT

Objectives: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators, Kalydeco® (ivacaftor), Orkambi® (lumacaftor/ivacaftor) and Symkevi® (tezacaftor/ivacaftor), have substantially improved patients' lives yet significantly burden healthcare budgets. This analysis aims to compare pricing and reimbursement of aforementioned cystic fibrosis medicines, across European countries. Methods: Clinical trial registries, national databases, health technology assessment reports and grey literature of Austria, Belgium, Denmark, France, Germany, Ireland, Poland, Spain, Sweden, Switzerland, Netherlands, the United Kingdom were consulted. Publicly available prices, reimbursement statuses, economic evaluations, budget impact analyses and managed entry agreements of CFTR modulators were examined. Results: In Belgium, lowest list prices were observed for Kalydeco® (ivacaftor) and Symkevi® (tezacaftor/ivacaftor) at €417 per defined daily dose (DDD) and €372 per average daily dose (ADD), respectively. Whereas, Switzerland had the lowest price for Orkambi® (lumacaftor/ivacaftor) listed at €309 per DDD. Spain had the highest prices for Kalydeco® (ivacaftor) and Symkevi® (tezacaftor/ivacaftor) at €850 per DDD and €761 per ADD, whereas Orkambi® (lumacaftor/ivacaftor) was most expensive in Poland at €983 per DDD. However, list prices were subject to confidential discounts and likely varied from actual costs. In all countries, these treatments were deemed not to be cost-effective. The annual budget impact of the CFTR modulators varied between countries and depended on factors such as local product prices, size of target population, scope of costs and discounting. However, all modulators were fully reimbursed in ten of the evaluated countries except for Sweden and Poland that, respectively, granted reimbursement to one and none of the therapies. Managed entry agreements were confidential but commonly adopted to address financial uncertainties. Conclusion: Discrepancies concerning prices, reimbursement and access were detected for Kalydeco® (ivacaftor), Orkambi® (lumacaftor/ivacaftor) and Symkevi® (tezacaftor/ivacaftor) across European countries.

PMID:34858177 | PMC:PMC8630624 | DOI:10.3389/fphar.2021.746710

J Biosci. 2021;46:111.

ABSTRACT

S-nitrosothiols (SNOs) are small naturally occurring thiol and nitric oxide adducts that participate in many cell signaling pathways in living organisms. SNOs receive widespread attention in cell biology, biochemistry and chemistry because they can donate nitric oxide and/or nitrosonium ions in S-nitrosylation reactions, which are comparable to phosphorylation, acetylation, glutathionylation, and palmitoylation reactions. SNOs have advantageous effects in respiratory diseases and other systems in the body. S-nitrosylation signaling is a metabolically regulated physiological process that leads to specific post-translational protein modifications. S-nitrosylation signaling is faulty in cystic fibrosis (CF) and many other lung diseases. CF is an inherited, lethal autosomal recessive multisystem disease resulting from mutations in the gene encoding the CF transmembrane conductance regulatory (CFTR) protein. F508del CFTR is the most common mutation associated with CF, which results in CFTR misfolding because a phenylalanine is deleted from the primary structure of CFTR. The majority of wild-type CFTR and almost all F508del is degraded before reaching the cell surface. Ultimately, CF researchers have been looking to correct the mutated CFTR protein in the CF patients. Remarkably, researchers have found that SNOs levels are low in the CF lower airway compared to non-CF patients. We have been interested in determining whether SNOs increase CFTR maturation through S-nitrosylation. Maturation of both wild type and mutant F508del CFTR increases SNOs, which up-regulate CFTR maturation. In this review, we summarized our current knowledge of S-nitrosothiols signaling in cystic fibrosis airways.

PMID:34857676

Eur Respir J. 2021 Dec 2;58(6):2102735. doi: 10.1183/13993003.02735-2021. Print 2021 Dec.

NO ABSTRACT

PMID:34857588 | DOI:10.1183/13993003.02735-2021

BMJ Open Respir Res. 2021 Dec;8(1):e000998. doi: 10.1136/bmjresp-2021-000998.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a genetic, multisystemic, progressive and life-shortening disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Different genotypes have been linked to variations in disease progression among people with CF. The burden of illness (BOI) in children with CF is incompletely characterised, particularly as it relates to CFTR genotypes prior to the availability of the first CFTR modulators. This retrospective, cross-sectional, descriptive study evaluated the BOI in US children with CF <12 years of age prior to the first approval of CFTR modulators.

METHODS: Data from the US Cystic Fibrosis Foundation Patient Registry from 2011 were used to summarise key patient and disease characteristics using descriptive statistics, overall and grouped by age (0 to <2 years, 2 to <6 years and 6 to <12 years) and genotype (F508del/F508del, F508del/minimal function (MF), MF/MF, gating mutation on ≥1 allele, residual function mutation on ≥1 allele and R117H on ≥1 allele) group.

RESULTS: The analysis included 9185 children. Among 6-year-olds to <12-year-olds, mean (SD) per cent predicted FEV1 in 1 s was 92.6% (17.5%). Among all children <12 years of age, the mean (SD) all-cause hospitalisation and pulmonary exacerbation rates in 2011 were 0.4 (1.0) and 0.3 (0.8), respectively. Most (93.6%) had ≥1 positive lung microbiology culture. CF-related medication and nutritional supplementation use was common across all ages and genotypes. More than half (54.7%) had ≥1 CF-related complication. Evidence of disease burden was observed across the age and genotype groups studied.

CONCLUSIONS: Prior to the approval of the first CFTR modulator therapies in children <12 years of age, CF was associated with substantial BOI from an early age-including respiratory infections, hospitalisations/pulmonary exacerbations, need for supplemental nutrition and pharmacological treatments-irrespective of genotype.

PMID:34857524 | DOI:10.1136/bmjresp-2021-000998

J Cyst Fibros. 2021 Nov 29:S1569-1993(21)02151-2. doi: 10.1016/j.jcf.2021.11.009. Online ahead of print.

ABSTRACT

BACKGROUND: In the STOP2 (Standardized Treatment of Pulmonary Exacerbations-2) study, intravenous (IV) antimicrobial treatment duration for adults with cystic fibrosis (CF) experiencing pulmonary exacerbations (PEx) was determined based on initial treatment response. The impact of home vs hospital care remains an important clinical question in CF. Our hypothesis was that STOP2 participants treated at home would have less improvement in lung function compared to those treated in the hospital.

METHODS: Treating clinicians determined PEx treatment location, which was a stratification factor for STOP2 randomization. Lung function, weight, and symptom recovery were evaluated by treatment location. Propensity scores and inverse probability treatment weighting were used to test for differences in clinical response by treatment location.

RESULTS: In all, 33% of STOP2 participants received IV antimicrobials in the hospital only, 46% both in the hospital and at home, and 21% at home only. Mean (95% CI) ppFEV1 improvement was significantly (p < 0.05) lower for those treated at home only, 5.0 (3.5, 6.5), compared with at home and in the hospital, 7.0 (5.9, 8.1), and in the hospital only, 8.0 (6.7, 9.4). Mean weight (p < 0.001) and symptom (p < 0.05) changes were significantly smaller for those treated at home only compared to those treated in the hospital only.

CONCLUSIONS: Compared to PEx treatment at home only, treatment in the hospital was associated with greater mean lung function, respiratory symptom, and weight improvements. The limitations of home IV therapy should be addressed in order to optimize outcomes for adults with CF treated at home.

PMID:34857494 | DOI:10.1016/j.jcf.2021.11.009

Clin Nutr ESPEN. 2021 Dec;46:527-531. doi: 10.1016/j.clnesp.2021.08.009. Epub 2021 Aug 28.

ABSTRACT

BACKGROUND: Previous studies have emphasized the effects of vitamin D on the lung function of cystic fibrosis (CF) adult patients. The main aim of the present study sought to determine the association between circulating 25-hydroxyvitamin D (25-OH D) concentration and clinical outcomes in non-cystic fibrosis (non-CF) bronchiectasis subjects. Secondary, we assessed the possible relationship between body composition and respiratory dysfunction in these patients.

MATERIALS AND METHODS: Sixty-two non-CF bronchiectasis patients (24 male/38 female), aged 18-72, were recruited in this cross-sectional study. Anthropometric indices, lung function tests, and bronchiectasis severity valuations were determined. Body composition, including Mid-arm muscle circumference (MAMC, cm) was calculated using triceps skinfold (TSF,mm) and mid-arm circumference (MAC,cm) under the reference formula. Then serum 25-hydroxyvitamin D concentration and C-reactive protein level were measured. The correlation between vitamin D level and pulmonary function and disease exacerbation tests was primarily assessed. Additionally, we evaluated the correlation between body composition and lung function tests.

RESULTS: Circulating 25-hydroxyvitamin D status positively was correlated with lung function tests, including FEV1 (r = 0.30, p value = 0.035) and FVC (r = 0.36, p value = 0.011), and also be associated with the extent of pulmonary involvement (r = -0.34, p value = 0.03). There was a significant negative correlation between percentage body fat and respiratory function, FEV1/FVC ratio (r = -0.43, p value < 0.001). In contrast, there was a strong correlation between skeletal muscle mass and pulmonary function tests (r = 0.26, p value = 0.04).

CONCLUSION: There is a positive association between low 25-hydroxyvitamin D status and lung dysfunction in participants with non-CF bronchiectasis. The pulmonary dysfunction also correlated with more percentage body fat and low skeletal muscle mass in these patients. Therefore, the evaluation of body composition and serum vitamin D are suggested in the disease management of the patients with non-CF bronchiectasis. However, these associations should be interpreted with caution due to the likelihood of reverse causation. More high-quality prospective studies are warranted to confirm our observations and determine the mechanisms underlying these findings.

PMID:34857245 | DOI:10.1016/j.clnesp.2021.08.009

Anal Chim Acta. 2022 Jan 15;1190:339215. doi: 10.1016/j.aca.2021.339215. Epub 2021 Oct 27.

ABSTRACT

In this work electrochemical sensors fabricated from compact disc material (waste or new) are used to quantify chloride ions in different types of samples. All three electrodes, working, counter, and pseudo-reference electrodes, were fabricated from the compact disc and directly used. Different parameters were studied in order to demonstrate the possibility of using this waste material for efficient and low-cost electrochemical sensors. Chloride sensing performance was evaluated using linear scan voltammetry as the detection technique. A sensitivity of 0.174 mA mM-1 cm-2 with a limit of detection of 20 μM and excellent selectivity against many interferents was observed. Selectivity and reproducibility tests were also carried out, showing excellent results. Sensors were also validated with real samples (drinking and sea water, milk, sweat and physiological solutions) with results comparable to conventional techniques. Our results show the applicability and suitability of these low-cost sensors, for detection of those analytes for which, silver, has high sensitivity and selectivity.

PMID:34857136 | DOI:10.1016/j.aca.2021.339215

BMC Pulm Med. 2021 Dec 2;21(1):394. doi: 10.1186/s12890-021-01764-4.

ABSTRACT

BACKGROUND: Home mechanical ventilation (HMV) is a viable and effective strategy for patients with chronic respiratory failure (CRF). The Chilean Ministry of Health started a program for adults in 2008.

METHODS: This study examined the following data from a prospective cohort of patients with CRF admitted to the national HMV program: characteristics, mode of admission, quality of life, time in the program and survival.

RESULTS: A total of 1105 patients were included. The median age was 59 years (44-58). Women accounted for 58.1% of the sample. The average body mass index (BMI) was 34.9 (26-46) kg/m2. A total of 76.2% of patients started HMV in the stable chronic mode, while 23.8% initiated HMV in the acute mode. A total of 99 patients were transferred from the children's program. There were 1047 patients on non-invasive ventilation and 58 patients on invasive ventilation. The median baseline PaCO2 level was 58.2 (52-65) mmHg. The device usage time was 7.3 h/d (5.8-8.8), and the time in HMV was 21.6 (12.2-49.5) months. The diagnoses were COPD (35%), obesity hypoventilation syndrome (OHS; 23.9%), neuromuscular disease (NMD; 16.3%), non-cystic fibrosis bronchiectasis or tuberculosis (non-CF BC or TBC; 8.3%), scoliosis (5.9%) and amyotrophic lateral sclerosis (ALS; 5.24%). The baseline score on the Severe Respiratory Insufficiency questionnaire (SRI) was 47 (± 17.9) points and significantly improved over time. The lowest 1- and 3-year survival rates were observed in the ALS group, and the lowest 9-year survival rate was observed in the non-CF BC or TB and COPD groups. The best survival rates at 9 years were OHS, scoliosis and NMD. In 2017, there were 701 patients in the children's program and 722 in the adult´s program, with a prevalence of 10.4 per 100,000 inhabitants.

CONCLUSION: The most common diagnoses were COPD and OHS. The best survival was observed in patients with OHS, scoliosis and NMD. The SRI score improved significantly in the follow-up of patients with HMV. The prevalence of HMV was 10.4 per 100,000 inhabitants. Trial registration This study was approved by and registered at the ethics committee of North Metropolitan Health Service of Santiago, Chile (N° 018/2021).

PMID:34856963 | DOI:10.1186/s12890-021-01764-4

Indian J Med Microbiol. 2021 Nov 29:S0255-0857(21)04718-6. doi: 10.1016/j.ijmmb.2021.11.010. Online ahead of print.

ABSTRACT

Cystic fibrosis is characterized by abnormal mucous secretions in the lungs that favor the proliferation of colonizing bacteria, with Pseudomonas aeruginosa and Staphylococcus aureus being the most isolated, however, other less known species could also have an impact on the health of the patient. Here we demonstrate the isolation and antibiotic resistance profiles of Inquilinus limosus, a rarely reported multidrug resistant bacterium, and compare them to a co-infectant strain of Pseudomonas aeruginosa. Likewise, we found that co-infection with both bacteria promotes increased formation of neutrophil extracellular traps, which can have an impact on the disease severity and make treatment difficult.

PMID:34856324 | DOI:10.1016/j.ijmmb.2021.11.010

Am J Respir Crit Care Med. 2021 Dec 2. doi: 10.1164/rccm.202110-2446ED. Online ahead of print.

NO ABSTRACT

PMID:34856109 | DOI:10.1164/rccm.202110-2446ED

Chron Respir Dis. 2021 Jan-Dec;18:14799731211061600. doi: 10.1177/14799731211061600.

ABSTRACT

Objectives: Primary ciliary dyskinesia (PCD) is a rare congenital disease with defective mucociliary clearance causing frequent and often persistent pulmonary infections. Achromobacter species are opportunistic pathogens renowned for the difficulty of effective treatments and deteriorating effects on lung function. We aimed to describe the occurrence, treatment, and rate of successful eradication of Achromobacter species in patients with PCD. Methods: We retrospectively reviewed 18 years of historical microbiological samples and 10 years of electronic health records for PCD patients in Denmark. Results: We included 136 patients. Twenty-six patients had isolates of Achromobacter species. On average, 5% of the cohort had at least one annual isolate. Infections became persistent in 38% with a median length of 6.6 years leading to a significant number of antibiotic treatments. Resistance toward tobramycin and ciprofloxacin was prevalent. Overall, successful eradication was achieved in 62% of patients. We found the course of lung function significantly worse during persistent Achromobacter species infection than during the two preceding years, but not different to the course in unaffected age-matched controls. Conclusion The prevalence of Achromobacter species in patients with PCD is in line with what has been reported in cystic fibrosis and can occur transiently, intermittently, or develop into a serious persistent lung infection associated with long-term antibiotic treatment.

PMID:34854775 | DOI:10.1177/14799731211061600

Sci Rep. 2021 Dec 1;11(1):23256. doi: 10.1038/s41598-021-02420-x.

ABSTRACT

There is evidence that the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel is highly expressed at the apical pole of ciliated cells in human bronchial epithelium (HBE), however recent studies have detected little CFTR mRNA in those cells. To understand this discrepancy we immunostained well differentiated primary HBE cells using CFTR antibodies. We confirmed apical immunofluorescence in ciliated cells and quantified the covariance of the fluorescence signals and that of an antibody against the ciliary marker centrin-2 using image cross-correlation spectroscopy (ICCS). Super-resolution stimulated emission depletion (STED) imaging localized the immunofluorescence in distinct clusters at the bases of the cilia. However, similar apical fluorescence was observed when the monoclonal CFTR antibodies 596, 528 and 769 were used to immunostain ciliated cells expressing F508del-CFTR, or cells lacking CFTR due to a Class I mutation. A BLAST search using the CFTR epitope identified a similar amino acid sequence in the ciliary protein rootletin X1. Its expression level correlated with the intensity of immunostaining by CFTR antibodies and it was detected by 596 antibody after transfection into CFBE cells. These results may explain the high apparent expression of CFTR in ciliated cells and reports of anomalous apical immunofluorescence in well differentiated cells that express F508del-CFTR.

PMID:34853321 | DOI:10.1038/s41598-021-02420-x

Thorax. 2021 Dec 1:thoraxjnl-2021-218240. doi: 10.1136/thoraxjnl-2021-218240. Online ahead of print.

NO ABSTRACT

PMID:34853158 | DOI:10.1136/thoraxjnl-2021-218240