Pulmonary aspiration in preschool children with cystic fibrosis.

Respir Res. 2018 Dec 17;19(1):255

Authors: Clarke D, Gorman I, Ringholz F, McDermott M, Cox DW, Greally P, Linnane B, Mc Nally P

Abstract
Pulmonary aspiration of gastric refluxate (PAGR) has been demonstrated in association with pulmonary inflammation in school aged children with Cystic Fibrosis (CF). We sought to determine if similar findings were present in preschool children. Pepsin was measured in Broncho-alveolar lavage (BAL) fluid collected from clinically stable preschool children with CF and controls. Elevated pepsin levels were found in a subgroup of children with CF, but this was not found to be associated with pulmonary infection, pulmonary inflammation or respiratory or gastrointestinal symptoms.

PMID: 30558606 [PubMed - in process]

A case report on filamin A gene mutation and progressive pulmonary disease in an infant: A lung tissued derived mesenchymal stem cell study.

Medicine (Baltimore). 2018 Dec;97(50):e13033

Authors: Calcaterra V, Avanzini MA, Mantelli M, Agolini E, Croce S, De Silvestri A, Re G, Collura M, Maltese A, Novelli A, Pelizzo G

Abstract
RATIONALE: Mesenchymal stem cells (MSC) play a crucial role in both the maintenance of pulmonary integrity and the pathogenesis of lung disease. Lung involvement has been reported in patients with the filamin A (FLNA) gene mutation. Considering FLNA's role in the intrinsic mechanical properties of MSC, we characterized MSCs isolated from FLNA-defective lung tissue, in order to define their pathogenetic role in pulmonary damage.
PATIENT CONCERNS: A male infant developed significant lung disease resulting in emphysematous lesions and perivascular and interstitial fibrosis. He also exhibited general muscular hypotonia, bilateral inguinal hernia, and deformities of the lower limbs (pes tortus congenitalis and hip dysplasia). Following lobar resection, chronic respiratory failure occurred.
DIAGNOSIS: Genetic testing was performed during the course of his clinical care and revealed a new pathogenic variant of the FLNA gene c.7391_7403del; (p.Val2464AlafsTer5). Brain magnetic resonance imaging revealed periventricular nodular heterotopia.
INTERVENTIONS AND OUTCOMES: Surgical thoracoscopic lung biopsy was performed in order to obtain additional data on the pathological pulmonary features. A small portion of the pulmonary tissue was used for MSC expansion. Morphology, immunophenotype, differentiation capacity, and proliferative growth were evaluated. Bone marrow-derived mesenchymal stem cells (BM-MSC) were employed as a control. MSCs presented the typical MSC morphology and phenotype while exhibiting higher proliferative capacity (P <.001) and lower migration potential (P=.02) compared to control BM-MSC.
LESSONS: The genetic profile and altered features of the MSCs isolated from FLNA-related pediatric lung tissue could be directly related to defects in cell migration during embryonic lung development and pulmonary damage described in FLNA-defective patients.

PMID: 30557962 [PubMed - in process]

Recombinant growth hormone therapy for cystic fibrosis in children and young adults.

Cochrane Database Syst Rev. 2018 Dec 17;12:CD008901

Authors: Thaker V, Carter B, Putman M

Abstract
BACKGROUND: Cystic fibrosis (CF) is an inherited condition causing disease most noticeably in the lungs, digestive tract and pancreas. People with CF often have malnutrition and growth delay. Adequate nutritional supplementation does not improve growth optimally and hence an anabolic agent, recombinant human growth hormone (rhGH), has been proposed as a potential intervention. This is an update of a previously published review.
OBJECTIVES: To evaluate the effectiveness and safety of rhGH therapy in improving lung function, quality of life and clinical status of children and young adults with CF.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of latest search: 22 October 2018.We also searched ongoing trials registers in clinicaltrials.gov from the United States and WHO International Clinical Trials Registry Platform (ICTRP). Date of latest search: 05 March 2018.We conducted a search of relevant endocrine journals and proceedings of the Endocrinology Society meetings using Web of Science, Scopus and Proceedings First. Date of latest search: 04 March 2018.
SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of all preparations of rhGH compared to either no treatment, or placebo, or each other at any dose (high-dose and low-dose) or route and for any duration, in children or young adults (aged up to 25 years) diagnosed with CF (by sweat test or genetic testing).
DATA COLLECTION AND ANALYSIS: Two authors independently screened papers, extracted trial details and assessed their risk of bias. We assessed the quality of the evidence using the GRADE system.
MAIN RESULTS: We included eight trials (291 participants, aged between five and 23 years) in this revision of the review. Seven trials compared standard-dose rhGH (approximately 0.3 mg/kg/week) to no treatment and one three-arm trial (63 participants) compared placebo, standard-dose rhGH (0.3 mg/kg/week) and high-dose rhGH (0.5 mg/kg/week). Six trials lasted for one year and two trials for six months. We found that rhGH treatment may improve some of the pulmonary function outcomes but there was no difference between standard and high-dose levels (low-quality evidence, limited by inconsistency across the trials, small number of participants and short duration of therapy). The trials show evidence of improvement in the anthropometric parameters (height, weight and lean body mass) with rhGH therapy, again no differences between dose levels. We found improvement in height for all comparisons (very low- to low quality evidence), but improvements in weight and lean body mass were only reported for standard-dose rhGH versus no treatment (very low-quality evidence). There is some evidence indicating a change in the level of fasting blood glucose with rhGH therapy, however, it did not cross the clinical threshold for diagnosis of diabetes in the trials of short duration (low-quality evidence). There is low- to very low-quality evidence for improvement of pulmonary exacerbations with no further significant adverse effects, but this is limited by the short duration of trials and the small number of participants. One small trial provided inconsistent evidence on improvement in quality of life (very low-quality evidence). There is limited evidence from three trials in improvements in exercise capacity (low-quality evidence). None of the trials have systematically compared the expense of therapy on overall healthcare costs.
AUTHORS' CONCLUSIONS: When compared with no treatment, rhGH therapy is effective in improving the intermediate outcomes in height, weight and lean body mass. Some measures of pulmonary function showed moderate improvement, but no consistent benefit was seen across all trials. The significant change in blood glucose levels, although not causing diabetes, emphasizes the need for careful monitoring of this adverse effect with therapy in a population predisposed to CF-related diabetes. No significant changes in quality of life, clinical status or side-effects were observed in this review due to the small number of participants. Long-term, well-designed randomised controlled trials of rhGH in individuals with CF are required prior to routine clinical use of rhGH in CF.

PMID: 30557452 [PubMed - as supplied by publisher]

Diet-Induced Dysbiosis and Genetic Background Synergize With Cystic Fibrosis Transmembrane Conductance Regulator Deficiency to Promote Cholangiopathy in Mice.

Hepatol Commun. 2018 Dec;2(12):1533-1549

Authors: Debray D, El Mourabit H, Merabtene F, Brot L, Ulveling D, Chrétien Y, Rainteau D, Moszer I, Wendum D, Sokol H, Housset C

Abstract
The most typical expression of cystic fibrosis (CF)-related liver disease is a cholangiopathy that can progress to cirrhosis. We aimed to determine the potential impact of environmental and genetic factors on the development of CF-related cholangiopathy in mice. Cystic fibrosis transmembrane conductance regulator (Cftr)-/- mice and Cftr +/+ littermates in a congenic C57BL/6J background were fed a high medium-chain triglyceride (MCT) diet. Liver histopathology, fecal microbiota, intestinal inflammation and barrier function, bile acid homeostasis, and liver transcriptome were analyzed in 3-month-old males. Subsequently, MCT diet was changed for chow with polyethylene glycol (PEG) and the genetic background for a mixed C57BL/6J;129/Ola background (resulting from three backcrosses), to test their effect on phenotype. C57BL/6J Cftr -/- mice on an MCT diet developed cholangiopathy features that were associated with dysbiosis, primarily Escherichia coli enrichment, and low-grade intestinal inflammation. Compared with Cftr +/+ littermates, they displayed increased intestinal permeability and a lack of secondary bile acids together with a low expression of ileal bile acid transporters. Dietary-induced (chow with PEG) changes in gut microbiota composition largely prevented the development of cholangiopathy in Cftr -/- mice. Regardless of Cftr status, mice in a mixed C57BL/6J;129/Ola background developed fatty liver under an MCT diet. The Cftr -/- mice in the mixed background showed no cholangiopathy, which was not explained by a difference in gut microbiota or intestinal permeability, compared with congenic mice. Transcriptomic analysis of the liver revealed differential expression, notably of immune-related genes, in mice of the congenic versus mixed background. In conclusion, our findings suggest that CFTR deficiency causes abnormal intestinal permeability, which, combined with diet-induced dysbiosis and immune-related genetic susceptibility, promotes CF-related cholangiopathy.

PMID: 30556040 [PubMed]

CHAC1 Is Differentially Expressed in Normal and Cystic Fibrosis Bronchial Epithelial Cells and Regulates the Inflammatory Response Induced by Pseudomonas aeruginosa.

Front Immunol. 2018;9:2823

Authors: Perra L, Balloy V, Foussignière T, Moissenet D, Petat H, Mungrue IN, Touqui L, Corvol H, Chignard M, Guillot L

Abstract
In cystic fibrosis (CF), Pseudomonas aeruginosa (Pa) colonizes the lungs, leading to chronic inflammation of the bronchial epithelium. ChaC glutathione-specific γ-glutamylcyclotransferase 1 (CHAC1) mRNA is differentially expressed in primary human airway epithelial cells from bronchi (hAECBs) from patients with CF and healthy patients at baseline and upon infection with Pa. CHAC1 degrades glutathione and is associated with ER stress and apoptosis pathways. In this study, we examined the roles of CHAC1 in the inflammatory response and apoptosis in lung epithelial cells. First, we confirmed by reverse transcription quantitative polymerase chain reaction that CHAC1 mRNA was overexpressed in hAECBs from patients without CF compared with the expression in hAECBs from patients with CF upon Pa (PAK strain) infection. Moreover, the Pa virulence factors LPS and flagellin were shown to induce CHAC1 expression in cells from patients without CF. Using NCI-H292 lung epithelial cells, we found that LPS-induced CHAC1 mRNA expression was PERK-independent and involved ATF4. Additionally, using CHAC1 small interfering RNA, we showed that reduced CHAC1 expression in the context of LPS and flagellin stimulation was associated with modulation of inflammatory markers and alteration of NF-κB signaling. Finally, we showed that Pa was not able to induce apoptosis in NCI-H292 cells. Our results suggest that CHAC1 is involved in the regulation of inflammation in bronchial cells during Pa infection and may explain the excessive inflammation present in the respiratory tracts of patients with CF.

PMID: 30555487 [PubMed - in process]

Burkholderia cepacia complex outbreaks among non-cystic fibrosis patients in the intensive care units: A review of adult and pediatric literature.

Infez Med. 2018 Dec 01;26(4):299-307

Authors: Abdallah M, Abdallah HA, Memish ZA

Abstract
Burkholderia cepacia complex (Bcc) is a Gram-negative bacterium commonly found in moist environments and soil. Bcc species are associated with many outbreaks in intensive care units (ICUs). In this review, we describe the sources of Bcc outbreaks among non-cystic fibrosis (CF) patients in various ICUs that include neonatal intensive care units, pediatric intensive care units and adult ICUs. Also we summarize the risk factors and outcome predictors of Bcc infection or colonization in non-CF critically ill patients. Finally, we describe the infection control measures that are used to manage and prevent the spread of Bcc outbreaks. PubMed was searched from 1 January 1994 and 31 December 2017. We found 30 outbreaks of Bcc among non-cystic fibrosis patients in ICUs; 17 outbreaks occurred in adult ICUs. The source was identified in 22 outbreaks. B. cepacia was the most common Bcc species causing outbreaks in ICUs; it was detected in 21 outbreaks. Indwelling central lines, presence of renal failure on hemodialysis, multiple bronchoscopic procedures, and recent abdominal surgery are independently associated with the development of B. cepacia bacteremia, while prolonged duration on a mechanical ventilator, a large number of nebulized albuterol therapies delivered, and prescription of beta-lactam, aztreonam, or macrolide-vancomycin antibiotics are risk factors for respiratory tract acquisition of B. cepacia. Disease severity and age were the main significant independent predictors of 14-day mortality in adult ventilated non-CF patients with Bcc acquisition. Bcc species have been linked to many outbreaks in non-CF patients in ICUs. Strict application of infection control standards is critical to limit the emergence and spread of Bcc in ICU settings.

PMID: 30555132 [PubMed - in process]

Deducing the presence of proteins and proteoforms in quantitative proteomics.

Nat Commun. 2018 06 13;9(1):2320

Authors: Bamberger C, Martínez-Bartolomé S, Montgomery M, Pankow S, Hulleman JD, Kelly JW, Yates JR

Abstract
The human genome harbors just 20,000 genes suggesting that the variety of possible protein products per gene plays a significant role in generating functional diversity. In bottom-up proteomics peptides are mapped back to proteins and proteoforms to describe a proteome; however, accurate quantitation of proteoforms is challenging due to incomplete protein sequence coverage and mapping ambiguities. Here, we demonstrate that a new software tool called ProteinClusterQuant (PCQ) can be used to deduce the presence of proteoforms that would have otherwise been missed, as exemplified in a proteomic comparison of two fly species, Drosophila melanogaster and D. virilis. PCQ was used to identify reduced levels of serine/threonine protein kinases PKN1 and PKN4 in CFBE41o- cells compared to HBE41o- cells and to elucidate that shorter proteoforms of full-length caspase-4 and ephrin B receptor are differentially expressed. Thus, PCQ extends current analyses in quantitative proteomics and facilitates finding differentially regulated proteins and proteoforms.

PMID: 29899466 [PubMed - indexed for MEDLINE]

Granule-stored MUC5B mucins are packed by the non-covalent formation of N-terminal head-to-head tetramers.

J Biol Chem. 2018 04 13;293(15):5746-5754

Authors: Trillo-Muyo S, Nilsson HE, Recktenwald CV, Ermund A, Ridley C, Meiss LN, Bähr A, Klymiuk N, Wine JJ, Koeck PJB, Thornton DJ, Hebert H, Hansson GC

Abstract
Most MUC5B mucin polymers in the upper airways of humans and pigs are produced by submucosal glands. MUC5B forms N-terminal covalent dimers that are further packed into larger assemblies because of low pH and high Ca2+ in the secretory granule of the mucin-producing cell. We purified the recombinant MUC5B N-terminal covalent dimer and used single-particle electron microscopy to study its structure under intracellular conditions. We found that, at intragranular pH, the dimeric MUC5B organized into head-to-head noncovalent tetramers where the von Willebrand D1-D2 domains hooked into each other. These N-terminal tetramers further formed long linear complexes from which, we suggest, the mucin domains and their C termini project radially outwards. Using conventional and video microscopy, we observed that, upon secretion into the submucosal gland ducts, a flow of bicarbonate-rich fluid passes the mucin-secreting cells. We suggest that this unfolds and pulls out the MUC5B assemblies into long linear threads. These further assemble into thicker mucin bundles in the glandular ducts before emerging at the gland duct opening. We conclude that the combination of intracellular packing of the MUC5B mucin and the submucosal gland morphology creates an efficient machine for producing linear mucin bundles.

PMID: 29440393 [PubMed - indexed for MEDLINE]

Efficacy and Safety of CFTR Corrector and Potentiator Combination Therapy in Patients with Cystic Fibrosis for the F508del-CFTR Homozygous Mutation: A Systematic Review and Meta-analysis.

Adv Ther. 2018 Dec 15;:

Authors: Wu HX, Zhu M, Xiong XF, Wei J, Zhuo KQ, Cheng DY

Abstract
INTRODUCTION: Cystic fibrosis (CF) is a progressive, genetic disease that causes persistent lung infections and limits the ability to breathe over time. The combination of a cystic fibrosis transmembrane conductance regulator (CFTR) corrector and potentiator has provided a benefit by decreasing sweat chloride concentration in CF for the F508del-CFTR homozygous mutation, but it remains controversial in lung function, nutritional status, clinical score and safety.
METHODS: The authors performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of combination therapy on lung function, nutritional status, clinical score and safety in CF for the F508del-CFTR homozygous mutation. Web of Science, Cochrane Central Register of Controlled Trials, Medline, and Embase were searched. The registered PROSPERO number was CRD42018085875.
RESULTS: Five RCTs, including a total of 1637 participants with the F508del-CFTR homozygous mutation who accepted CFTR corrector and potentiator combination therapy along with basic treatment were enrolled in this analysis. Primary analysis revealed that combination therapy improved the percent of predicted FEV1 (ppFEV1) (MD 2.38, 1.62-3.15, P < 0.00001), Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score (MD 2.59, 0.96-4.22, P = 0.002) and body-mass index (BMI) (MD 0.21, 0.03-0.39, P = 0.02). In the secondary analysis, combination therapy had no impact on the number of participants reporting adverse events (OR 0.88, 0.58-1.33, P = 0.53), but increased the proportion of discontinued treatments due to adverse events (OR 2.71, 1.3-5.63, P = 0.008).
CONCLUSIONS: CFTR corrector and potentiator combination therapy effectively improves lung function, nutritional status and clinical score in CF patients with the F508del-CFTR homozygous mutation, and has an acceptable safety profile.

PMID: 30554331 [PubMed - as supplied by publisher]

Parental awareness of newborn bloodspot screening in Ireland.

Ir J Med Sci. 2018 Dec 15;:

Authors: Fitzpatrick P, Fitzgerald C, Somerville R, Linnane B

Abstract
BACKGROUND: There is little known regarding how familiar parents are with the newborn bloodspot screening (NBS) test or how well parents of a child with a screen-detected condition understand that condition initially.
AIM: The study aim was to examine parental NBS awareness and conditions screened.
METHODS: Two studies were conducted: [1] Parents of children with cystic fibrosis (CF) detected via NBS and subsequently, diagnosed (n = 124) completed a telephone questionnaire regarding information they received at the time of NBS. [2] A cross-sectional study of women (n = 662 (58%) antenatal; n = 480 (42%) postnatal) attending three large maternity hospitals completed a questionnaire addressing NBS awareness.
RESULTS: Mothers incorrectly identified diabetes/asthma (35% postnatal; 70% antenatal) and sickle cell disease (26%) as conditions on NBS in Ireland. Phenylketonuria was correctly identified by 48/26%, CF by 82/64%, and congenital hypothyroidism by 35/13% postnatal and antenatal women respectively. Of parents of children screen-detected and subsequently, diagnosed with CF, only half (n = 63; 51%) reported awareness at the time of NBS that CF was included. These results should be used to improve the information provided to expectant mothers and to inform health professionals' initial discussions with parents about their child's diagnosis, building on parents' pre-existing knowledge.

PMID: 30554310 [PubMed - as supplied by publisher]

Letter to the editor: Cystic fibrosis in the Middle East: An awareness analysis.

J Cyst Fibros. 2018 Dec 12;:

Authors: Hider AM

PMID: 30553744 [PubMed - as supplied by publisher]

Unilateral segmental dysplasia of the vas deferens.

Can J Urol. 2018 Dec;25(6):9620-9622

Authors: Saitz TR, Thomas AA

Abstract
A healthy 35-year-old male presented for vasectomy after fathering two children. Due to difficulty palpating the left vas, the patient was taken to the operating room for scrotal exploration and vasectomy. The left vas was absent; however, a 1.2 cm pearly nodule was identified in the scrotum along its suspected course. This nodule was excised, found to contain thick white pasty fluid, and confirmed vas deferens by pathology. The patient was found to have normal kidneys on renal ultrasound and was indeed a carrier for cystic fibrosis gene mutations. We herein discuss management and implications of vasal anomalies.

PMID: 30553290 [PubMed - in process]

Safety of Peripherally Inserted Central Catheter Use in Children From Rural Versus Urban Settings Receiving Long-term Parenteral Antimicrobial Therapy.

Hosp Pediatr. 2018 Dec 14;:

Authors: Beachum N, Dehority W

Abstract
OBJECTIVES: To determine the safety of peripherally inserted central catheter (PICC) use for delivery of outpatient parenteral antimicrobial therapy (PAT) in children discharged to rural or urban locales. We hypothesized that children from rural settings would experience higher complication rates.
PATIENTS AND METHODS: We conducted a retrospective cohort study of children admitted to an academic medical center in the Southwestern United States over 9 years who were discharged with a PICC to complete a course of PAT with follow-up at our institution. To classify rural versus urban residence, we used rural-urban continuum codes from the US Department of Agriculture, the driving time in hours to the nearest trauma center, and the discharging center using Google Maps.
RESULTS: In total, 221 children met inclusion criteria (mean age 9.8 years). Osteoarticular infections and cystic fibrosis exacerbations were the most common indications for PICC use (68.8%). The mean driving time to the discharging hospital was significantly longer for those children residing in the most rural regions of the state (3.6 vs 0.8 hours; P < .001) as well as to the nearest level 1, 2, or 3 trauma center (2.2 vs 0.4 hours; P < .001). PICC complications occurred in 47 children (21.3%). No association was found between rural-urban continuum codes, driving times to the discharging hospital, or nearest trauma center with any complication nor with complications overall.
CONCLUSIONS: In our study, we demonstrate an equivalent safety profile for children in rural and urban settings with PICCs for receipt of outpatient PAT.

PMID: 30552090 [PubMed - as supplied by publisher]

Modulation of the unfolded protein response pathway as an antiviral approach in airway epithelial cells.

Antiviral Res. 2018 Dec 11;:

Authors: Schögler A, Caliaro O, Brügger M, Oliveira Esteves BI, Nita I, Gazdhar A, Geiser T, Alves MP

Abstract
INTRODUCTION: Rhinovirus (RV) infection is a major cause of cystic fibrosis (CF) lung morbidity with limited therapeutic options. Various diseases involving chronic inflammatory response and infection are associated with endoplasmic reticulum (ER) stress and subsequent activation of the unfolded protein response (UPR), an adaptive response to maintain cellular homeostasis. Recent evidence suggests impaired ER stress response in CF airway epithelial cells, this might be a reason for recurrent viral infection in CF. Therefore, assuming that ER stress inducing drugs have antiviral properties, we evaluated the activation of the UPR by selected ER stress inducers as an approach to control virus replication in the CF bronchial epithelium.
METHODS: We assessed the levels of UPR markers, namely the glucose-regulated protein 78 (Grp78) and the C/EBP homologous protein (CHOP), in primary CF and control bronchial epithelial cells and in a CF and control bronchial epithelial cell line before and after infection with RV. The cells were also pretreated with ER stress-inducing drugs and RV replication and shedding was measured by quantitative RT-PCR and by a TCID50 assay, respectively. Cell death was assessed by a lactate dehydrogenate (LDH) activity test in supernatants.
RESULTS: We observed a significantly impaired induction of Grp78 and CHOP in CF compare to control cells following RV infection. The ER stress response could be significantly induced in CF cells by pharmacological ER stress inducers Brefeldin A, Tunicamycin, and Thapsigargin. The chemical induction of the UPR pathway prior to RV infection of CF and control cells reduced viral replication and shedding by up to two orders of magnitude and protected cells from RV-induced cell death.
CONCLUSION: RV infection causes an impaired activation of the UPR in CF cells. Rescue of the ER stress response by chemical ER stress inducers reduced significantly RV replication in CF cells. Thus, pharmacological modulation of the UPR might represent a strategy to control respiratory virus replication in the CF bronchial epithelium.

PMID: 30550797 [PubMed - as supplied by publisher]

Inhaled antibiotic use is associated with Scedosporium/Lomentospora species isolation in cystic fibrosis.

Pediatr Pulmonol. 2018 Dec 14;:

Authors: Hong G, Lechtzin N, Hadjiliadis D, Kawut SM

Abstract
INTRODUCTION: Prevalence of fungi has been rising in the cystic fibrosis (CF) population. Scedosporium species (spp) is the second most common mold seen in the CF respiratory tract. However, the characteristics associated with Scedosporium isolation and its clinical implications are poorly understood. The goal of this study was to determine clinical factors associated with Scedosporium spp to better understand the mechanisms that may contribute to the emergence of filamentous fungi in CF.
METHODS: We conducted a retrospective cohort study of subjects followed in the CF Foundation Patient Registry between January 1, 2010 and December 31, 2012. Patients under 6 years of age, history of solid organ transplantation, and insufficient respiratory culture data were excluded. We used a multivariable logistic regression model to determine demographic data and baseline disease characteristics, medications and co-infections associated with Scedosporium spp recovery in CF sputum.
RESULTS: Among 19 023 subjects, prevalence of Scedosporium spp was 615 (3.2%). Older age (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.07, 1.26) and white race (OR 1.69, 95% CI 1.09, 2.63) were the demographic factors associated with Scedosporium spp isolation. Inhaled antibiotic use had a significant association with Scedosporium isolation (OR 2.01, 95% CI 1.61, 2.52). For every additional course of intravenous antibiotics, the odds of Scedosporium isolation increased by 8% (OR 1.08, 95% CI 1.03, 1.14).
CONCLUSIONS: The association between inhaled antibiotics and Scedosporium informs us that chronic inhaled antibiotics may be playing a role in Scedosporium isolation. Further investigation to better characterize this relationship is necessary.

PMID: 30549449 [PubMed - as supplied by publisher]

Impact of high- versus low-risk genotype on sinonasal radiographic disease in cystic fibrosis.

Laryngoscope. 2018 Dec 14;:

Authors: Halderman AA, Lee S, London NR, Day A, Jain R, Moore JA, Lin SY

Abstract
OBJECTIVE: Understanding of how specific mutations impact the cystic fibrosis transmembrane conductance regulator (CFTR) protein has given rise to the classification of CF patients into low-risk and high-risk genotypes. Few prior studies have investigated differences in sinonasal disease between low-risk and high-risk CF genotypes. This multi-institutional review aimed to evaluate radiographic sinus disease severity based on genotype.
METHODS: A review was conducted on adult patients with CF evaluated between 2005 to 2017 at three academic institutions. Data including age, gender, CFTR mutation, and presence of a maxillofacial/sinus computed tomography scan was collected. A modified Lund-Mackay score (MLMS) was assigned to each scan, and the presence of sinus aplasia or hypoplasia was determined. Patients were further grouped depending on genotype into low- or high-risk for comparison.
RESULTS: A total of 126 patients were included with 99 patients in the high-risk and 21 in the low-risk groups. The high-risk group had significantly higher MLMS than the low-risk group (mean 13.88 vs. 8.06, P < 0.0001, 95% CI -8.196 to -3.462) The rate of frontal (P < 0.01), maxillary (P = 0.04), and sphenoid (P < 0.001) hypoplasia/aplasia was significantly higher in high-risk patients compared to low-risk.
CONCLUSION: This is one of the largest studies to date evaluating the impact of CF genotype on paranasal sinus development and disease. Genotype appears to impact sinonasal disease severity and also potentially paranasal sinus cavity development to a degree, although the exact mechanism is unknown.
LEVEL OF EVIDENCE: 4. Laryngoscope, 2018.

PMID: 30549259 [PubMed - as supplied by publisher]

Cystic fibrosis vigilance in Arab countries: The role of genetic epidemiology.

Respirology. 2018 Dec 13;:

Authors: Pallin M

PMID: 30548951 [PubMed - as supplied by publisher]

Comprehensive genotyping reveals novel CFTR variants in cystic fibrosis patients from the Russian Federation.

Clin Genet. 2018 Dec 12;:

Authors: Petrova NV, Marakhonov AV, Vasilyeva TA, Kashirskaya NY, Ginter EK, Kutsev SI, Zinchenko RA

Abstract
Single nucleotide variants are represented as lines. The height of the line corresponds to the allele frequency. Gross chromosomal copy number variations are shown as arrows. Color corresponds to the mutation type. Complex alleles represented with a clip. Previously reported variants are located above the schematic gene representation. Their names are presented in Table 1 in main text. Novel variants are depicted beneath the schematic gene representation.

PMID: 30548586 [PubMed - as supplied by publisher]

A case of pan-resistant burkholderia cepacia complex bacteraemic pneumonia, after lung transplantation treated with a targeted combination therapy.

Transpl Infect Dis. 2018 Dec 12;:e13034

Authors: Cantón-Bulnes ML, Hurtado Martínez Á, López-Cerero L, Arenzana Seisdedos Á, Merino-Bohorquez V, de Farmacia S, Garnacho-Montero J

Abstract
We describe a case of one patient with cystic fibrosis who developed a pan-resistant Burkholderia Cepacia Complex rapidly progressive bacteraemic pneunonia, following bilateral lung transplantation. Patient was treated with a targeted combination antibiotic therapy (meropenem plus ceftazidime/avibactam plus high doses of nebulized colistimethate sodium). The disease evolution was complicated by multiple organ system dysfunction. Finally, clinical improvement and microbiological cure was achieved. This article is protected by copyright. All rights reserved.

PMID: 30548546 [PubMed - as supplied by publisher]

Increases in cytosolic Ca2+ induce dynamin- and calcineurin-dependent internalisation of CFTR.

Cell Mol Life Sci. 2018 Dec 13;:

Authors: Patel W, Moore PJ, Sassano MF, Lopes-Pacheco M, Aleksandrov AA, Amaral MD, Tarran R, Gray MA

Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated, apical anion channel that regulates ion and fluid transport in many epithelia including the airways. We have previously shown that cigarette smoke (CS) exposure to airway epithelia causes a reduction in plasma membrane CFTR expression which correlated with a decrease in airway surface hydration. The effect of CS on CFTR was dependent on an increase in cytosolic Ca2+. However, the underlying mechanism for this Ca2+-dependent, internalisation of CFTR is unknown. To gain a better understanding of the effect of Ca2+ on CFTR, we performed whole cell current recordings to study the temporal effect of raising cytosolic Ca2+ on CFTR function. We show that an increase in cytosolic Ca2+ induced a time-dependent reduction in whole cell CFTR conductance, which was paralleled by a loss of cell surface CFTR expression, as measured by confocal and widefield fluorescence microscopy. The decrease in CFTR conductance and cell surface expression were both dynamin-dependent. Single channel reconstitution studies showed that raising cytosolic Ca2+ per se had no direct effect on CFTR. In fact, the loss of CFTR plasma membrane activity correlated with activation of calcineurin, a Ca2+-dependent phosphatase, suggesting that dephosphorylation of CFTR was linked to the loss of surface expression. In support of this, the calcineurin inhibitor, cyclosporin A, prevented the Ca2+-induced decrease in cell surface CFTR. These results provide a hitherto unrecognised role for cytosolic Ca2+ in modulating the residency of CFTR at the plasma membrane through a dynamin- and calcineurin-dependent mechanism.

PMID: 30547226 [PubMed - as supplied by publisher]