Study design considerations for the Standardized Treatment of Pulmonary Exacerbations 2 (STOP2): A trial to compare intravenous antibiotic treatment durations in CF.

Contemp Clin Trials. 2017 Nov 20;:

Authors: Heltshe SL, West NE, VanDevanter DR, Sanders DB, Beckett VV, Flume PA, Goss CH, STOP Study Group

Abstract
BACKGROUND: Pulmonary exacerbations (PEx) in cystic fibrosis (CF) are common and contribute to morbidity and mortality. Duration of IV antibiotic therapy to treat PEx varies widely in the US, and there are few data to guide treatment decisions.
METHODS: We combined a survey of CF stakeholders with retrospective analyses of a recent observational study of CF PEx to design a multicenter, randomized, prospective study comparing the efficacy and safety of different durations of IV antibiotics for PEx to meet the needs of people with CF and their caregivers.
RESULTS: IV antibiotic duration was cited as the most important PEx research question by responding CF physicians and top concern among surveyed CF patients/caregivers. During PEx, forced expiratory volume in 1s (FEV1% predicted) and symptom responses at 7-10days of IV antibiotics identified two distinct groups: early robust responders (ERR) who subsequently experienced greater FEV1 improvements compared to non-ERR (NERR). In addition to greater FEV1 and symptom responses, only 14% of ERR patients were treated with IV antibiotics for >15days, compared with 45% of NERR patients.
CONCLUSIONS: A divergent trial design that evaluates subjects' interim improvement in FEV1 and symptoms to tailor randomization to IV treatment duration (10 vs. 14days for ERR, 14 vs. 21days for NERR) may alleviate physician and patient concerns about excess or inadequate treatment. Such a study has the potential to provide evidence necessary to standardize IV antibiotic duration in CF PEx care -a first step to conducting PEx research of other treatment features.

PMID: 29170074 [PubMed - as supplied by publisher]

Immunohistochemical analysis of the distribution of molecules involved in ionic and pH regulation in the lancelet Branchiostoma floridae (Hubbs, 1922).

Acta Histochem. 2017 Nov 20;:

Authors: Cuoghi I, Lazzaretti C, Mandrioli M, Mola L, Pederzoli A

Abstract
The aim of present work is to analyse the distribution of carbonic anhydrase II (CAII), cystic fibrosis transmembrane regulator (CFTR), vacuolar-type H(+)-ATPase (V-H(+)-ATPase), Na(+)/K(+) ATPase, Na(+)/H(+) exchanger (NHE) and SLC26A6 (solute carrier family 26, member 6), also known as pendrin protein, in the lancelet Branchiostoma floridae in order to go in depth in the evolution of osmoregulation and pH regulation in Chordates. In view of their phylogenetic position, lancelets may indeed provide a critical point of reference for studies on osmoregulation evolution in Chordates. The results of present work demonstrated that, except to Na(+)/K(+) ATPase that is strongly expressed in nephridia only, all the other studied molecules are abundantly present in skin, coelomic epithelium, renal papillae and nephridia and hepatic coecum. Thus, it is possible to hypothesize that also in lancelet, as in fish, these organs are involved in pH control and ionic regulation. In the digestive tract of B. floridae, the intestine epithelium was weakly immune-reactive to all tested antibodies, while the hepatic coecum showed an intense immunoreactivity to all molecules. Since in amphioxus the hepatic coecum functions simultaneously as stomach, liver and pancreas, these immunohistochemical results proved the secretion of H+ and HCO3(-) ions, typical of digestive process. Colocalization studies indicated a co-expression of the studied proteins in all considered organs, excluding NHE and pendrin for renal papillae, since some renal papillae are NHE immunopositive only.

PMID: 29169695 [PubMed - as supplied by publisher]

Ivacaftor for cystic fibrosis: An evaluation of real world utilisation and expenditure in the Irish Healthcare Setting.

Ir Med J. 2017 Aug 12;110(7):619

Authors: Corcoran A, Hickey N, Barry M, Usher C, McCullagh LM

Abstract
In Ireland, Ivacaftor is reimbursed, on the High-Tech Drug Scheme, for the treatment of cystic fibrosis in patients age 6 years and older who have the G551D mutation. The aim of this study was to analyse the utilisation and expenditure of Ivacaftor on this scheme in the 12 month period post-reimbursement. All patients who had received Ivacaftor (regardless of General Medical Services Scheme eligibility/ineligibility) were included. A total of 140 individuals (male=74; 53%) received Ivacaftor over the defined 12 month study period (from January 2015 to December 2015 inclusive). The cohort ranged in age from 6 years to 61 years. The mean age was 22 years; a positive skew in age distribution indicated that a greater number of the cohort were in the younger age groups. No statistically significant difference was detected in the mean ages of the male and female subgroups. Drug acquisition expenditure by the Health Services Executive on Ivacaftor over the 12 month study period was €29.81 million.

PMID: 29169001 [PubMed - in process]

TGFβ as a therapeutic target in cystic fibrosis.

Expert Opin Ther Targets. 2017 Nov 23;:

Authors: Kramer E, Clancy JP

Abstract
INTRODUCTION: Cystic fibrosis (CF) is a genetic disease characterized by progressive lung disease. Most CF therapies focus on treating secondary pulmonary complications rather than addressing the underlying processes inducing airway remodeling and ineffective response to infection. Transforming growth factor beta (TGFβ) is a cytokine involved in fibrosis, inflammation, and injury response as well as a genetic modifier and biomarker of CF lung disease. Targeting the TGFβ pathway has been pursued in other diseases, but the mechanism of TGFβ effects in CF is less well understood. Areas Covered: In this review, we discuss CF lung disease pathogenesis with a focus on potential links to TGFβ. TGFβ signaling in lung health and disease is reviewed. Recent studies investigating TGFβ's impact in CF airway epithelial cells are highlighted. Finally, an overview of potential therapies to target TGFβ signaling relevant to CF are addressed. Expert Opinion: The broad impact of TGFβ signaling on numerous cellular processes in homeostasis and disease is both a strength and a challenge to developing TGFβ dependent therapeutics in CF. We discuss the challenges inherent in developing TGFβ-targeted therapy, identifying appropriate patient populations, and questions regarding the timing of treatment. Future directions for research into TGFβ focused therapeutics are discussed.

PMID: 29168406 [PubMed - as supplied by publisher]

Normal sweat chloride test does not rule out cystic fibrosis.

Turk J Pediatr. 2017;59(1):68-70

Authors: Başaran AE, Karataş-Torun N, Maslak İC, Bingöl A, Alper ÖM

Abstract
Başaran AE, Karataş-Torun N, Maslak İC, Bingöl A, Alper ÖM. Normal sweat chloride test does not rule out cystic fibrosis. Turk J Pediatr 2017; 59: 68-70. A 5-month-old patient presented with complaints of fever and cough. He was hospitalized with the diagnosis of bronchopneumonia and pseudo-Bartter's syndrome. Patient was further investigated for diagnosis of cystic fibrosis. The chloride (Cl) level in sweat was determined within the normal range (25.1 mmol/L, 20.3 mmol/L). CFTR (Cystic Fibrosis Transmembrane Regulator gene; NM_000492.2) genotyping results were positive for p.E92K; p.F1052V mutations. The patient was diagnosed with cystic fibrosis. In our patient, with features of CF and normal sweat test, mutation analysis was helpful for the diagnosis of cystic fibrosis.

PMID: 29168366 [PubMed - in process]

Hyperoxia induces paracellular leak and alters claudin expression by neonatal alveolar epithelial cells.

Pediatr Pulmonol. 2017 Nov 23;:

Authors: Vyas-Read S, Vance RJ, Wang W, Colvocoresses-Dodds J, Brown LA, Koval M

Abstract
BACKGROUND: Premature neonates frequently require oxygen supplementation as a therapeutic intervention that, while necessary, also exposes the lung to significant oxidant stress. We hypothesized that hyperoxia has a deleterious effect on alveolar epithelial barrier function rendering the neonatal lung susceptible to injury and/or bronchopulmonary dysplasia (BPD).
MATERIALS AND METHODS: We examined the effects of exposure to 85% oxygen on neonatal rat alveolar barrier function in vitro and in vivo. Whole lung was measured using wet-to-dry weight ratios and bronchoalveolar lavage protein content and cultured primary neonatal alveolar epithelial cells (AECs) were measured using transepithelial electrical resistance (TEER) and paracellular flux measurements. Expression of claudin-family tight junction proteins, E-cadherin and the Snail transcription factor SNAI1 were measured by Q-PCR, immunoblot and confocal immunofluorescence microscopy.
RESULTS: Cultured neonatal AECs exposed to 85% oxygen showed impaired barrier function. This oxygen-induced increase in paracellular leak was associated with altered claudin expression, where claudin-3 and -18 were downregulated at both the mRNA and protein level. Claudin-4 and -5 mRNA were also decreased, although protein expression of these claudins was largely maintained. Lung alveolarization and barrier function in vivo were impaired in response to hyperoxia. Oxygen exposure also significantly decreased E-cadherin expression and induced expression of the SNAI1 transcription factor in vivo and in vitro.
CONCLUSIONS: These data support a model in which hyperoxia has a direct impact on alveolar tight and adherens junctions to impair barrier function. Strategies to antagonize the effects of high oxygen on alveolar junctions may potentially reverse this deleterious effect.

PMID: 29168340 [PubMed - as supplied by publisher]

Fungus-Specific CD4 T Cells as Specific Sensors for Identification of Pulmonary Fungal Infections.

Mycopathologia. 2017 Nov 22;:

Authors: Scheffold A, Schwarz C, Bacher P

Abstract
Patients with cystic fibrosis (CF) suffer from chronic lung infections, caused by bacterial, viral or fungal pathogens, which determine morbidity and mortality. The contribution of individual pathogens to chronic disease and acute lung exacerbations is often difficult to determine due to the complex composition of the lung microbiome in CF. In particular, the relevance of fungal pathogens in CF airways remains poorly understood due to limitations of current diagnostics to identify the presence of fungal pathogens and to resolve the individual host-pathogen interaction status. T-lymphocytes play an essential role in host defense against pathogens, but also in inappropriate immune reactions such as allergies. They have the capacity to specifically recognize and discriminate the different pathogens and orchestrate a diverse array of effector functions. Thus, the analysis of the fungus-specific T cell status of an individual can in principle provide detailed information about the identity of the fungal pathogen(s) encountered and the actual fungus-host interaction status. This may allow to classify patients, according to appropriate (protective) or inappropriate (pathology-associated) immune reactions against individual fungal pathogens. However, T cell-based diagnostics are currently not part of the clinical routine. The identification and characterization of fungus-specific T cells in health and disease for diagnostic purposes are associated with significant challenges. Recent technological developments in the field of fungus-specific T helper cell detection provide new insights in the host T cell-fungus interaction. In this review, we will discuss basic principles and the potential of T cell-based diagnostics, as well as the perspectives and further needs for use of T cells for improved clinical diagnostics of fungal diseases.

PMID: 29168073 [PubMed - as supplied by publisher]

Prenatal maternal plasma DNA screening for cystic fibrosis: A computer modelling study of screening performance.

F1000Res. 2017;6:1896

Authors: Old RW, Bestwick JP, Wald NJ

Abstract
Background: Prenatal cystic fibrosis (CF) screening is currently based on determining the carrier status of both parents. We propose a new method based only on the analysis of DNA in maternal plasma. Methods: The method relies on the quantitative amplification of the CF gene to determine the percentage of DNA fragments in maternal plasma at targeted CF mutation sites that carry a CF mutation. Computer modelling was carried out to estimate the distributions of these percentages in pregnancies with and without a fetus affected with CF. This was done according to the number of DNA fragments counted and fetal fraction, using the 23 CF mutations recommended by the American College of Medical Genetics for parental carrier testing. Results: The estimated detection rate (sensitivity) is 70% (100% of those detected using the 23 mutations), the false-positive rate 0.002%, and the odds of being affected given a positive screening result 14:1, compared with 70%, 0.12%, and 1:3, respectively, with current prenatal screening based on parental carrier testing. Conclusions: Compared with current screening practice based on parental carrier testing, the proposed method would substantially reduce the number of invasive diagnostic procedures (amniocentesis or chorionic villus sampling) without reducing the CF detection rate. The expected advantages of the proposed method justify carrying out the necessary test development for use in a clinical validation study.

PMID: 29167740 [PubMed]

miR-200b downregulates CFTR during hypoxia in human lung epithelial cells.

Cell Mol Biol Lett. 2017;22:23

Authors: Bartoszewska S, Kamysz W, Jakiela B, Sanak M, Króliczewski J, Bebok Z, Bartoszewski R, Collawn JF

Abstract
Background: Hypoxic conditions induce the expression of hypoxia-inducible factors (HIFs) that allow cells to adapt to the changing conditions and alter the expression of a number of genes including the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is a low abundance mRNA in airway epithelial cells even during normoxic conditions, but during hypoxia its mRNA expression decreases even further.
Methods: In the current studies, we examined the kinetics of hypoxia-induced changes in CFTR mRNA and protein levels in two human airway epithelial cell lines, Calu-3 and 16HBE14o-, and in normal primary bronchial epithelial cells. Our goal was to examine the posttranscriptional modifications that affected CFTR expression during hypoxia. We utilized in silico predictive protocols to establish potential miRNAs that could potentially regulate CFTR message stability and identified miR-200b as a candidate molecule.
Results: Analysis of each of the epithelial cell types during prolonged hypoxia revealed that CFTR expression decreased after 12 h during a time when miR-200b was continuously upregulated. Furthermore, manipulation of the miRNA levels during normoxia and hypoxia using miR-200b mimics and antagomirs decreased and increased CFTR mRNA levels, respectively, and thus established that miR-200b downregulates CFTR message levels during hypoxic conditions.
Conclusion: The data suggest that miR-200b may be a suitable target for modulating CFTR levels in vivo.

PMID: 29167681 [PubMed - in process]

ADAGE signature analysis: differential expression analysis with data-defined gene sets.

BMC Bioinformatics. 2017 Nov 22;18(1):512

Authors: Tan J, Huyck M, Hu D, Zelaya RA, Hogan DA, Greene CS

Abstract
BACKGROUND: Gene set enrichment analysis and overrepresentation analyses are commonly used methods to determine the biological processes affected by a differential expression experiment. This approach requires biologically relevant gene sets, which are currently curated manually, limiting their availability and accuracy in many organisms without extensively curated resources. New feature learning approaches can now be paired with existing data collections to directly extract functional gene sets from big data.
RESULTS: Here we introduce a method to identify perturbed processes. In contrast with methods that use curated gene sets, this approach uses signatures extracted from public expression data. We first extract expression signatures from public data using ADAGE, a neural network-based feature extraction approach. We next identify signatures that are differentially active under a given treatment. Our results demonstrate that these signatures represent biological processes that are perturbed by the experiment. Because these signatures are directly learned from data without supervision, they can identify uncurated or novel biological processes. We implemented ADAGE signature analysis for the bacterial pathogen Pseudomonas aeruginosa. For the convenience of different user groups, we implemented both an R package (ADAGEpath) and a web server ( http://adage.greenelab.com ) to run these analyses. Both are open-source to allow easy expansion to other organisms or signature generation methods. We applied ADAGE signature analysis to an example dataset in which wild-type and ∆anr mutant cells were grown as biofilms on the Cystic Fibrosis genotype bronchial epithelial cells. We mapped active signatures in the dataset to KEGG pathways and compared with pathways identified using GSEA. The two approaches generally return consistent results; however, ADAGE signature analysis also identified a signature that revealed the molecularly supported link between the MexT regulon and Anr.
CONCLUSIONS: We designed ADAGE signature analysis to perform gene set analysis using data-defined functional gene signatures. This approach addresses an important gap for biologists studying non-traditional model organisms and those without extensive curated resources available. We built both an R package and web server to provide ADAGE signature analysis to the community.

PMID: 29166858 [PubMed - in process]

Biological Significance of the Suppression of Oxidative Phosphorylation in Induced Pluripotent Stem Cells.

Cell Rep. 2017 Nov 21;21(8):2058-2065

Authors: Zhang C, Skamagki M, Liu Z, Ananthanarayanan A, Zhao R, Li H, Kim K

Abstract
We discovered that induced pluripotent stem cell (iPSC) clones generated from aged tissue donors (A-iPSCs) fail to suppress oxidative phosphorylation. Compared to embryonic stem cells (ESCs) and iPSCs generated from young donors (Y-iPSCs), A-iPSCs show poor expression of the pluripotent stem cell-specific glucose transporter 3 (GLUT3) and impaired glucose uptake, making them unable to support the high glucose demands of glycolysis. Persistent oxidative phosphorylation in A-iPSCs generates higher levels of reactive oxygen species (ROS), which leads to excessive elevation of glutathione (a ROS-scavenging metabolite) and a blunted DNA damage response. These phenotypes were recapitulated in Y-iPSCs by inhibiting pyruvate dehydrogenase kinase (PDK) or supplying citrate to activate oxidative phosphorylation. In addition, oxidative phosphorylation in A-iPSC clones depletes citrate, a nuclear source of acetyl group donors for histone acetylation; this consequently alters histone acetylation status. Expression of GLUT3 in A-iPSCs recovers the metabolic defect, DNA damage response, and histone acetylation status.

PMID: 29166598 [PubMed - in process]

Early-Life Pseudomonas aeruginosa Infection in Cystic Fibrosis and Lung Disease Progression.

Glob Pediatr Health. 2017;4:2333794X17738465

Authors: Petrocheilou A, Papagrigoriou-Theodoridou M, Michos A, Doudounakis SE, Loukou I, Kaditis A

Abstract
Lung disease in cystic fibrosis (CF) starts early, with studies identifying abnormalities on chest computed tomography (CT) scan even in infancy. In this retrospective study, abnormal chest CT was the main outcome; body mass index (BMI) z score and forced expiratory volume percent predicted (FEV1%) predicted at age 6 to 7 years were secondary outcomes. Pseudomonas aeruginosa infection prior to 12 months of age was the main explanatory variable. There was no association between early P aeruginosa infection and abnormal CT after adjustment for CFTR (cystic fibrosis transmembrane conductance regulator) functional mutation class, gender, and other pathogens (odds ratio = 0.30; 95% confidence interval = 0.07-1.35; P = .11). No significant associations were demonstrated for BMI z score and FEV1% predicted. Children with class I-III CFTR mutations had increased risk of abnormal CT findings (odds ratio = 11.67; 95% confidence interval = 1.11-115.06; P = .035) and lower FEV1% predicted (P = .04). In the current era, early-life P aeruginosa infection in CF might not influence the severity of lung disease in school age as much as previously. Larger studies are needed to confirm this finding.

PMID: 29164174 [PubMed]

Aspergillus fumigatus-specific immunoglobulin levels in BALF of CF patients.

ERJ Open Res. 2017 Oct;3(4):

Authors: Goña-Höpler M, Pfaller B, Argeny J, Kanolzer S, Gruber S, Schmidthaler K, Renner S, Nachbaur E, Fucik P, Glaser AG, Debiasi M, Szépfalusi Z, Crameri R, Rhyner C, Eiwegger T

Abstract
IgE responses to Aspergillus fumigatus in cystic fibrosis lungs http://ow.ly/XXwv30furqs.

PMID: 29164145 [PubMed]

Intensive care unit patients with lower respiratory tract nosocomial infections: the ENIRRIs project.

ERJ Open Res. 2017 Oct;3(4):

Authors: De Pascale G, Ranzani OT, Nseir S, Chastre J, Welte T, Antonelli M, Navalesi P, Garofalo E, Bruni A, Coelho LM, Skoczynski S, Longhini F, Taccone FS, Grimaldi D, Salzer HJF, Lange C, Froes F, Artigas A, Díaz E, Vallés J, Rodríguez A, Panigada M, Comellini V, Fasano L, Soave PM, Spinazzola G, Luyt CE, Alvarez-Lerma F, Marin J, Masclans JR, Chiumello D, Pezzi A, Schultz M, Mohamed H, Van Der Eerden M, Hoek RAS, Gommers DAMPJ, Pasquale MD, Civljak R, Kutleša M, Bassetti M, Dimopoulos G, Nava S, Rios F, Zampieri FG, Povoa P, Bos LD, Aliberti S, Torres A, Martín-Loeches I

Abstract
The clinical course of intensive care unit (ICU) patients may be complicated by a large spectrum of lower respiratory tract infections (LRTI), defined by specific epidemiological, clinical and microbiological aspects. A European network for ICU-related respiratory infections (ENIRRIs), supported by the European Respiratory Society, has been recently established, with the aim at studying all respiratory tract infective episodes except community-acquired ones. A multicentre, observational study is in progress, enrolling more than 1000 patients fulfilling the clinical, biochemical and radiological findings consistent with a LRTI. This article describes the methodology of this study. A specific interest is the clinical impact of non-ICU-acquired nosocomial pneumonia requiring ICU admission, non-ventilator-associated LRTIs occurring in the ICU, and ventilator-associated tracheobronchitis. The clinical meaning of microbiologically negative infectious episodes and specific details on antibiotic administration modalities, dosages and duration are also highlighted. Recently released guidelines address many unresolved questions which might be answered by such large-scale observational investigations. In light of the paucity of data regarding such topics, new interesting information is expected to be obtained from our network research activities, contributing to optimisation of care for critically ill patients in the ICU.

PMID: 29164144 [PubMed]

Iron Acquisition Mechanisms and Their Role in the Virulence of Burkholderia Species.

Front Cell Infect Microbiol. 2017;7:460

Authors: Butt AT, Thomas MS

Abstract
Burkholderia is a genus within the β-Proteobacteriaceae that contains at least 90 validly named species which can be found in a diverse range of environments. A number of pathogenic species occur within the genus. These include Burkholderia cenocepacia and Burkholderia multivorans, opportunistic pathogens that can infect the lungs of patients with cystic fibrosis, and are members of the Burkholderia cepacia complex (Bcc). Burkholderia pseudomallei is also an opportunistic pathogen, but in contrast to Bcc species it causes the tropical human disease melioidosis, while its close relative Burkholderia mallei is the causative agent of glanders in horses. For these pathogens to survive within a host and cause disease they must be able to acquire iron. This chemical element is essential for nearly all living organisms due to its important role in many enzymes and metabolic processes. In the mammalian host, the amount of accessible free iron is negligible due to the low solubility of the metal ion in its higher oxidation state and the tight binding of this element by host proteins such as ferritin and lactoferrin. As with other pathogenic bacteria, Burkholderia species have evolved an array of iron acquisition mechanisms with which to capture iron from the host environment. These mechanisms include the production and utilization of siderophores and the possession of a haem uptake system. Here, we summarize the known mechanisms of iron acquisition in pathogenic Burkholderia species and discuss the evidence for their importance in the context of virulence and the establishment of infection in the host. We have also carried out an extensive bioinformatic analysis to identify which siderophores are produced by each Burkholderia species that is pathogenic to humans.

PMID: 29164069 [PubMed - in process]

Commentary: Cytokine-Regulation of Na(+)-K(+)-Cl(-) Cotransporter 1 and Cystic Fibrosis Transmembrane Conductance Regulator-Potential Role in Pulmonary Inflammation and Edema Formation.

Front Immunol. 2017;8:1490

Authors: Eisenhut M

PMID: 29163549 [PubMed]

Nucleotide-Binding Oligomerization Domain 2 Contributes to Limiting Growth of Mycobacterium abscessus in the Lung of Mice by Regulating Cytokines and Nitric Oxide Production.

Front Immunol. 2017;8:1477

Authors: Lee JY, Lee MS, Kim DJ, Yang SJ, Lee SJ, Noh EJ, Shin SJ, Park JH

Abstract
Mycobacterium abscessus is a prominent cause of pulmonary infection in immunosuppressed patients and those with cystic fibrosis. Nucleotide-binding oligomerization domain (NOD) 2 is a cytosolic receptor which senses a bacterial peptidoglycan component, muramyl dipeptide (MDP). Although nucleotide-binding oligomerization domain 2 (NOD2) contributes to protect host against various microbial infections, it is still unclear whether NOD2 is essential to regulate host immune responses against M. abscessus infection. In this study, we sought to clarify the role of NOD2 and the underlying mechanism in host defense against M. abscessus infection. Mice were infected intranasally with M. abscessus and sacrificed at indicated time points. Bacterial survival, cytokines production, and pathology in the lungs were determined. Bone marrow-derived macrophages were used to clarify cellular mechanism of NOD2-mediated immune response. Bacterial clearance was impaired, and pathology was more severe in the lungs of NOD2-deficient mice compared with the wild-type mice. In macrophages, NOD2-mediated activation of p38 and JNK were required for production of proinflammatory cytokines and nitric oxide (NO) and expression of iNOS in response to M. abscessus. NO was critical for limiting intracellular growth of the pathogen. Intranasal administration of MDP reduced in vivo bacterial replication and thus improved lung pathology in M. abscessus-infected mice. This study offers important new insights into the potential roles of the NOD2 in initiating and potentiating innate immune response against M. abscessus pulmonary infection.

PMID: 29163541 [PubMed]

Lipoprotein Glycosylation by Protein-O-Mannosyltransferase (MAB_1122c) Contributes to Low Cell Envelope Permeability and Antibiotic Resistance of Mycobacterium abscessus.

Front Microbiol. 2017;8:2123

Authors: Becker K, Haldimann K, Selchow P, Reinau LM, Dal Molin M, Sander P

Abstract
Lipoproteins are important components of the mycobacterial cell envelope due to their function in cell wall homeostasis and bacterial virulence. They are post-translationally modified with lipid- and glycosyl-residues in various species and interference with acylation or glycosylation leads to reduced growth and attenuated virulence in Mycobacterium tuberculosis. Lipoproteins are also expressed in the emerging and highly drug resistant pathogen Mycobacterium abscessus which frequently affects the lungs of patients with chronic pulmonary disease or cystic fibrosis. We investigated post-translational modification, acylation and glycosylation, of heterologously expressed (M. tuberculosis LppX and Mpt83) and endogenous (SodC) lipoproteins at the molecular level in M. abscessus and identified MAB_1122c as protein O-mannosyltransferase (Pmt). Both, heterologous and endogenous lipoproteins carried a characteristic lipid anchor with palmitic acid (C16), palmitoleic acid (C16:1), oleic acid (C18), or tuberculostearic acid (C19) modifications. Multiple hexose-moieties were detected in the N-terminal region of the model lipoproteins expressed in M. abscessus. Conservation of lipoprotein glycosylation in M. tuberculosis and M. abscessus was revealed and points toward the existence of an O-glycosylation motif or other regulatory mechanisms regarding this post-translational modification. Deletion of MAB_1122c prevented glycosylation and affected susceptibility to specific antibiotics which are large or target peptidoglycan synthesis and to lysozyme. Cell envelope permeability of M. abscessus Δpmt was increased and mutant bacteria showed reduced survival inside macrophages. The results provide a link between post-translational modification of lipoproteins and the permeability of the mycobacterial cell envelope which stresses the importance of lipoproteins as components of this complex structure.

PMID: 29163413 [PubMed]

The involvement of musculoskeletal system and its influence on postural stability in children and young adults with cystic fibrosis.

Ital J Pediatr. 2017 Nov 21;43(1):106

Authors: Kenis-Coskun O, Karadag-Saygi E, Bahar-Ozdemir Y, Gokdemir Y, Karadag B, Kayhan O

Abstract
BACKGROUND: Cystic fibrosis (CF) affects the musculoskeletal system via a multifactorial pathway that includes vitamin D deficiency and involvement of respiratory muscles such as intercostals due to recurrent upper and lower respiratory tract infections. Eventual result is the deterioration of musculoskeletal health and posture in CF patients. Postural stability is directly affected by posture and can be compromised in every musculoskeletal problem. The aim of this study is to evaluate musculoskeletal system and postural stability in patients with CF.
METHODS: Patients with CF over six years of age and age and sex-matched control groups were included in the study. Cobb angle and thoracic kyphosis angles were measured on the spine radiographs. Both patients and control group were examined with pediatric gait, arms, legs and spine scale (pGALS). They also were evaluated with a NeuroCom Balance Master for their postural stability.
RESULTS: Fifty-one patients with CF and 94 healthy controls participated in the study. In results of the pGALS examination, CF group had significantly more pathological findings than the control group in lower extremity appearance and movement (p = 0.006 and p = 0.01) and spine appearance and movement (p = 0.001 and p = 0.022) domains. The tandem walking speed was significantly higher in controls with a mean of 24.45 ± 7.79 while it was 20.47 ± 6.95 in the CF group (p = 0.03). Various limits of stability parameters also showed significant differences. Medium correlations were found between musculoskeletal examination and postural stability parameters.
CONCLUSION: In patients with CF, a systematic but simple musculoskeletal examination can detect pathologies, which are more frequent than the normal population. These pathologies show a medium correlation with the involvement of postural stability.

PMID: 29162121 [PubMed - in process]

Bolus weekly vitamin D3 supplementation impacts gut and airway microbiota in adults with cystic fibrosis: a double-blind, randomized, placebo-controlled clinical trial.

J Clin Endocrinol Metab. 2017 Nov 16;:

Authors: Kanhere M, He J, Chassaing B, Ziegler TR, Alvarez JA, Ivie EA, Hao L, Hanfelt J, Gewirtz AT, Tangpricha V

Abstract
Background: Disruption of gut microbiota may exacerbate severity of cystic fibrosis (CF). Vitamin D deficiency is a common co-morbidity in patients with CF that may influence composition of the gut microbiota.
Objectives: Compare microbiota of vitamin D sufficient and insufficient CF patients, and assess impact of a weekly high-dose vitamin D3 bolus regimen on gut and airway microbiome in adults with CF and vitamin D insufficiency (25(OH)D <30 ng/mL).
Design: Forty-one subjects with CF were classified into two groups - vitamin D insufficient (n=23) and vitamin D sufficient (n=18). Subjects with vitamin D insufficiency were randomized to receive 50,000 IU of oral vitamin D3 or placebo weekly for 12 weeks. Sputum and stool samples were obtained pre and post intervention and 16S rRNA genes sequenced using Illumina MiSeq technology.
Results: Gut microbiota differed significantly based on vitamin D status with Gammaproteobacteria, which contain numerous potentially pathogenic species, being enriched in the vitamin D insufficient group. PCoA analysis showed differential gut microbiota composition within the vitamin D insufficient patients following 12 weeks treatment with placebo or vitamin D3 (Permanova = 0.024) with Lactococcus significantly enriched in subjects treated with vitamin D3, whereas Vellionella and Erysipelotrichacea were significantly enriched in patients treated with placebo.
Conclusion: This exploratory study suggests vitamin D insufficiency is associated with alterations in microbiota composition that may promote inflammation and that supplementation with vitamin D has the potential to impact microbiota composition. Additional studies to determine vitamin D's impact on the microbiota benefits clinical outcomes in CF are warranted.

PMID: 29161417 [PubMed - as supplied by publisher]