Learning's from the Editors Desk - 2017.

J Cyst Fibros. 2017 Nov;16(6):645-646

Authors: Bell SC, Castellani C, Flume PA

PMID: 29150008 [PubMed - in process]

The role of microRNAs in chronic respiratory disease: recent insights.

Biol Chem. 2017 Nov 27;:

Authors: Stolzenburg LR, Harris A

Abstract
Chronic respiratory diseases encompass a group of diverse conditions affecting the airways, which all impair lung function over time. They include cystic fibrosis, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and asthma, which together affect hundreds of millions of people worldwide. MicroRNAs (miRNAs), a class of small non-coding RNAs involved in post-transcriptional gene repression, are now recognized as major regulators in the development and progression of chronic lung disease. Alterations in miRNA abundance occur in lung tissue, inflammatory cells, and freely circulating in blood and are thought to function both as drivers and modifiers of disease. Their importance in lung pathology has prompted the development of miRNA-based therapies and biomarker tools. Here, we review current literature on miRNA expression and function in chronic respiratory disease and highlight further research that is needed to propel miRNA treatments for lung disorders towards the clinic.

PMID: 29148977 [PubMed - as supplied by publisher]

Discovery of N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-lH-pyrazole-5-carboxamide (GLPG1837), a Novel Potentiator which can open Class III Mutant Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Channels to a high extent.

J Med Chem. 2017 Nov 17;:

Authors: Van der Plas SE, Kelgtermans H, De Munck T, Martina SLX, Dropsit S, Quinton E, De Blieck A, Joannesse C, Tomaskovic L, Jans M, Christophe T, Van der Aar E, Borgonovi M, Nelles L, Gees M, Stouten PF, Van Der Schueren J, Mammoliti O, Conrath K, Andrews MJ

Abstract
Cystic fibrosis (CF) is caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Orkambi, it has been shown that CFTR function can be partially restored by administering one or more small molecules. These molecules aim at either enhancing the amount of CFTR on the cell surface (correctors) or at improving the gating function of the CFTR channel (potentiators). Here we describe the discovery of a novel potentiator GLPG1837 which shows enhanced efficacy on CFTR mutants harboring Class III mutations compared to Ivacaftor, the first marketed potentiator. The optimization of potency, efficacy and pharmacokinetic profile will be described.

PMID: 29148763 [PubMed - as supplied by publisher]

Exhaled markers of anti-oxidant activity and oxidative stress in stable cystic fibrosis patients with moderate lung disease.

J Breath Res. 2017 Nov 17;:

Authors: Spicuzza L, Parisi GF, Tardino L, Ciancio N, Nenna R, Midulla F, Leonardi S

Abstract
The sustained imbalance between oxidant and antioxidant species contributes to lung damage in patients with cystic fibrosis (CF). Glutathione (GSH) is an important component of the antioxidant defense in the airways epithelial lining fluid and its transportation out of the cells may be altered in CF. The aim of this study was to assess the oxidants/anti-oxidants balance in the airways of patients with CF. 
 We measured the concentrations of GSH, the total antioxidant capacity and the concentration of 8-iso-prostaglandin F2α (8-isoprostane), a marker of oxidative stress, in the exhaled breath condensate of 17 non-smoking patients with CF, in stable phase, and in 17 age-matched healthy subjects. 
 The levels of GSH and total anti-oxidant capacity in patients with CF were significantly lower than in healthy subjects (0.66 ± 0.07 μM vs 1.30 ± 0.08 μM, p<0.001, respectively for GSH; 0.157 ± 0.02 mM and 0.32 ± 0.01 mM, p<0.05, respectively for anti-oxidant capacity). The concentration of 8-isoprostane was higher in CF than in healthy controls (26.5 ± 0.1 pg/ml vs 10.8 ± 0.1 pg/ml; p<0.05). 
 A low concentration of anti-oxidant agents, particularly glutathione, and increased levels of 8-isoprostane in the exhaled breath suggest an altered oxidizing environment in the airways of patients with CF. This altered redox environment in the epithelial liquid surface may contribute to progressive lung disease.
 &#13.

PMID: 29146889 [PubMed - as supplied by publisher]

First Insight into the Genome Sequences of Two Linezolid-Resistant Nocardia farcinica Strains Isolated from Patients with Cystic Fibrosis.

Genome Announc. 2017 Nov 16;5(46):

Authors: Valdezate S, Monzón S, Garrido N, Zaballos A, Medina-Pascual MJ, Azcona-Gutiérrez JM, Vilar B, Cuesta I

Abstract
The draft genome sequences of two Nocardia farcinica strains isolated from two patients with cystic fibrosis (CF), resistant to trimethoprim/sulfamethoxazole and linezolid, are reported here. The estimated genome sizes were 5.8 Mb with a 70.63% G+C content. Transposases from Tn916 were detected, but not 23S rRNA mutation (G2576T) related to linezolid resistance.

PMID: 29146850 [PubMed]

Draft Genome Sequence of the Mucoid Pseudomonas aeruginosa Clinical Isolate PA34.

Genome Announc. 2017 Nov 16;5(46):

Authors: Harrison LB, Hanson ND

Abstract
Pseudomonas aeruginosa is a serious threat to patients suffering from cystic fibrosis. These organisms are exposed to a unique set of selective pressures within the lung. Here, we report the draft genome sequence of a mucoid P. aeruginosa clinical isolate obtained from a cystic fibrosis patient colonized with P. aeruginosa.

PMID: 29146840 [PubMed]

Inflammation, age and changing microbiology: the search for causation in the cystic fibrosis airways.

Eur Respir J. 2017 Nov;50(5):

Authors: Rogers GB

PMID: 29146609 [PubMed - in process]

Airway microbiota across age and disease spectrum in cystic fibrosis.

Eur Respir J. 2017 Nov;50(5):

Authors: Zemanick ET, Wagner BD, Robertson CE, Ahrens RC, Chmiel JF, Clancy JP, Gibson RL, Harris WT, Kurland G, Laguna TA, McColley SA, McCoy K, Retsch-Bogart G, Sobush KT, Zeitlin PL, Stevens MJ, Accurso FJ, Sagel SD, Harris JK

Abstract
Our objectives were to characterise the microbiota in cystic fibrosis (CF) bronchoalveolar lavage fluid (BALF), and determine its relationship to inflammation and disease status.BALF from paediatric and adult CF patients and paediatric disease controls undergoing clinically indicated bronchoscopy was analysed for total bacterial load and for microbiota by 16S rDNA sequencing.We examined 191 BALF samples (146 CF and 45 disease controls) from 13 CF centres. In CF patients aged <2 years, nontraditional taxa (e.gStreptococcus, Prevotella and Veillonella) constituted ∼50% of the microbiota, whereas in CF patients aged ≥6 years, traditional CF taxa (e.gPseudomonas, Staphylococcus and Stenotrophomonas) predominated. Sequencing detected a dominant taxon not traditionally associated with CF (e.gStreptococcus or Prevotella) in 20% of CF BALF and identified bacteria in 24% of culture-negative BALF. Microbial diversity and relative abundance of Streptococcus, Prevotella and Veillonella were inversely associated with airway inflammation. Microbiota communities were distinct in CF compared with disease controls, but did not differ based on pulmonary exacerbation status in CF.The CF microbiota detected in BALF differs with age. In CF patients aged <2 years, Streptococcus predominates, whereas classic CF pathogens predominate in most older children and adults.

PMID: 29146601 [PubMed - in process]

Lumacaftor (VX-809) restores the ability of CF macrophages to phagocytose and kill Pseudomonas aeruginosa.

Am J Physiol Lung Cell Mol Physiol. 2017 Nov 16;:ajplung.00461.2017

Authors: Barnaby R, Koeppen K, Nymon A, Hampton TH, Berwin B, Ashare A, Stanton B

Abstract
Cystic Fibrosis (CF), the most common lethal genetic disease in Caucasians, is characterized by chronic bacterial lung infection and excessive inflammation, which leads to progressive loss of lung function, and premature death. Although ivacaftor (VX-770) and the combination of ivacaftor and lumacaftor (VX-809) improve lung function in CF patients with the Gly551Asp and del508Phe mutation, respectively, the effects of these drugs on the function of human CF macrophages are unknown. Thus, studies were conducted to examine the effects of lumacaftor alone and in combination with ivacaftor (i.e., Orkambi) on the ability of human CF (del508Phe/del508Phe) monocyte derived macrophages (MDMs) to phagocytose and kill P. aeruginosa. Lumacaftor alone restored the ability of CF MDMs to phagocytose and kill P. aeruginosa to levels observed in MDMs obtained from non-CF donors (WT-CFTR). This effect contrasts with the partial correction (~15%) of del508Phe Cl- secretion of airway epithelial cells by lumacaftor. Ivacaftor reduced the ability of lumacaftor to stimulate phagocytosis and killing of P. aeruginosa. Lumacaftor had no effect on P. aeruginosa-stimulated cytokine secretion by CF MDMs. Ivacaftor (5 µM) alone, or in combination with lumacaftor, reduced the secretion of several pro-inflammatory cytokines. The clinical efficacy of Orkambi may be related in part to the ability of lumacaftor to stimulate phagocytosis and killing of P. aeruginosa by macrophages.

PMID: 29146575 [PubMed - as supplied by publisher]

Buserelin alleviates chloride transport defect in human cystic fibrosis nasal epithelial cells.

PLoS One. 2017;12(11):e0187774

Authors: Calvez ML, Benz N, Huguet F, Saint-Pierre A, Rouillé E, Coraux C, Férec C, Kerbiriou M, Trouvé P

Abstract
Cystic fibrosis (CF) is the most common autosomal recessive disease in Caucasians caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) chloride (Cl-) channel regulated by protein kinases, phosphatases, divalent cations and by protein-protein interactions. Among protein-protein interactions, we previously showed that Annexin A5 (AnxA5) binds to CFTR and is involved in the channel localization within membranes and in its Cl- channel function. The deletion of phenylalanine at position 508 (F508del) is the most common mutation in CF which leads to an altered protein (F508del-CFTR) folding with a nascent protein retained within the ER and is quickly degraded. We previously showed that AnxA5 binds to F508del-CFTR and that its increased expression due to a Gonadoliberin (GnRH) augments Cl- efflux in cells expressing F508del-CFTR. The aim of the present work was to use the GnRH analog buserelin which is already used in medicine. Human nasal epithelial cells from controls and CF patients (F508del/F508del) were treated with buserelin and we show here that the treatment alleviates Cl- channel defects in CF cells. Using proteomics we highlighted some proteins explaining this result. Finally, we propose that buserelin is a potential new pharmaceutical compound that can be used in CF and that bronchus can be targeted since we show here that they express GnRH-R.

PMID: 29145426 [PubMed - in process]

Investigating the preventive effects of baicalin and gallocatechin aginst glyoxal induced cystatin aggregation.

J Biomol Struct Dyn. 2017 Nov 16;:1-31

Authors: Sohail A, Bhat WF, Furkan M, Shah A, Bano B

Abstract
Several mammalian proteins form pathological deposits under nonphysiological conditions that are associated with many degenerative diseases. Protein aggregation is associated with aging, as well as a variety of diseases, including cystic fibrosis, amyotrophic lateral sclerosis (ALS), and hypertrophic cardiomyopathy. There is a lack of any potential anti-amyloidogenic agents and therapeutics till date. Polyphenols have been accredited with myriad biological effects. An analysis of the effects of natural agents like baicalin (BC) and gallocatechin (GC) on aggregation process can open new avenues for the treatment of protein misfolding diseases. Thus, investigation of the effects of these flavonoids on Buffalo Heart Cystatin (BHC) aggregation induced by a reactive metabolic dialdehyde, glyoxal (GO), was taken up. Results have shown that elevated concentration of GO forms aggregates of BHC, which was characterized by an increase in the ANS fluorescence intensity, an increase in ThT fluorescence intensity, red shift in Congo red absorbance, negative ellipticity peak at 217 nm in the far-UVCD and BHC aggregates displaying by TEM. Using fluorescence spectroscopic analysis with Thioflavin T, CD and electron microscopic studies, anti-aggregation effects of polyphenols, BC and GC were analyzed. The study showed that BC and GC produced concentration-dependent anti-aggregation effects with GC producing a more pronounced effect than BC. The study proposed a mechanistic approach assuming structural constraints and specific aromatic interactions of polyphenols with sheets of BHC aggregates.

PMID: 29143574 [PubMed - as supplied by publisher]

[Inhaled antibiotics for the management of non cystic fibrosis bronchiectasis].

Rev Med Suisse. 2017 Nov 15;13(583):2001-2004

Authors: Berra G, Chappuis-Gisin É, Soccal PM, Plojoux J

Abstract
Bronchiectasis is irreversible bronchial dilatation associated with chronic respiratory symptoms. Management is aimed at reducing symptoms and slowing the progression of the disease by interrupting the vicious circle: bronchial infection, inflammation, altered mucociliary clearance, lung destruction. Unlike the literature on inhaled antibiotics in cystic fibrosis, literature data are limited and of low quality for bronchiectasis of other causes. However, new recommendations from the European Respiratory Society propose the conditional use of inhaled antibiotics to prevent repeated infectious exacerbations and to eradicate Pseudomonas aeruginosa colonization.

PMID: 29143505 [PubMed - in process]

K2P TASK-2 and KCNQ1/KCNE3 K(+) channels are major players contributing to intestinal anion and fluid secretion.

J Physiol. 2017 Nov 16;:

Authors: Julio-Kalajzić F, Villanueva S, Burgos J, Ojeda M, Cid LP, Jentsch TJ, Sepúlveda FV

Abstract
Anion and fluid secretion across the intestinal epithelium, a process altered in cystic fibrosis and secretory diarrhoea, is mediated by cAMP-activated CFTR Cl(-) channels and requires the simultaneous activity of basolateral K(+) channels to maintain cellular ionic homeostasis and membrane potential. This function is fulfilled by the cAMP-activated K(+) channel formed by the association of pore-forming KCNQ1 with its obligatory KCNE3 β-subunit. Studies using mice show sizable cAMP-activated intestinal anion secretion in the absence of either KCNQ1 or KCNE3 suggesting that an alternative K(+) conductance must compensate for the loss of KCNQ1/KCNE3 activity. We now use double mutant mouse and pharmacological approaches to identify such conductance. Ca(2+) -dependent anion secretion can also be supported by Ca(2+) -dependent KCa 3.1 channels after independent CFTR activation, but cAMP-dependent anion secretion is not further decreased in the combined absence of KCa 3.1 and KCNQ1/KCNE3 K(+) channel activity. We show that K2P K(+) channel TASK-2 is expressed in the epithelium of the small and large intestine. Tetrapentylammonium, a TASK-2 inhibitor, abolishes anion secretory current remaining in the absence of KCNQ1/KCNE3 activity. A double mutant mouse lacking both KCNQ1/KCNE3 and TASK-2 showed a much reduced cAMP-mediated anion secretion compared to that observed in the single KCNQ1/KCNE3 deficient mouse. We conclude that KCNQ1/KCNE3 and TASK-2 play major roles in the intestinal anion and fluid secretory phenotype. The persistence of an, admittedly reduced, secretory activity in the absence of these two conductances suggests that further additional K(+) channel(s) as yet unidentified contribute to the robustness of the intestinal anion secretory process. This article is protected by copyright. All rights reserved.

PMID: 29143340 [PubMed - as supplied by publisher]

Structural and perfusion magnetic resonance imaging of the lung in cystic fibrosis.

Pediatr Radiol. 2017 Nov 15;:

Authors: Amaxopoulou C, Gnannt R, Higashigaito K, Jung A, Kellenberger CJ

Abstract
BACKGROUND: Because of its absence of ionising radiation and possibility for obtaining functional information, MRI is promising for assessing lung disease in children who require repetitive imaging for long-term follow-up.
OBJECTIVE: To describe MRI findings in children with cystic fibrosis and evaluate semi-quantitative dynamic contrast-enhanced lung perfusion.
MATERIALS AND METHODS: We retrospectively compared lung MRI in 25 children and young adults with cystic fibrosis (median age 3.7 years) to 12 children (median age 2 years) imaged for other pathologies. MRI at 1.5 T included respiratory-gated sequences and contrast-enhanced lung perfusion imaging. We described and graded any morphologic change. Signal enhancement and time to peak values of perfusion abnormalities were compared to those of normally enhancing lung parenchyma.
RESULTS: Frequent findings in patients with cystic fibrosis were bronchial wall thickening (24/25, 96%), areas of consolidation (22/25, 88%), enlarged lymph nodes (20/25, 80%), bronchiectasis (5/25, 20%) and mucus plugging (3/25, 12%). Compared to normally enhancing lung, perfusion defects (21/25, 84%), characterised by decreased enhancement, showed prolonged time to peak. Areas of consolidation showed increased enhancement. While time to peak of procedure-related atelectasis was not significantly different from that of normal lung, disease-related consolidation showed prolonged time to peak (P=0.01).
CONCLUSION: Lung MRI demonstrates structural and perfusion abnormalities in children and young people with cystic fibrosis. Semi-quantitative assessment of dynamic contrast-enhanced perfusion imaging might allow differentiation between procedure-related atelectasis and disease-related consolidation.

PMID: 29143200 [PubMed - as supplied by publisher]

Elevated p53 Activities Restrict Differentiation Potential of MicroRNA-Deficient Pluripotent Stem Cells.

Stem Cell Reports. 2017 Nov 14;9(5):1604-1617

Authors: Liu Z, Zhang C, Skamagki M, Khodadadi-Jamayran A, Zhang W, Kong D, Chang CW, Feng J, Han X, Townes TM, Li H, Kim K, Zhao R

Abstract
Pluripotent stem cells (PSCs) deficient for microRNAs (miRNAs), such as Dgcr8(-/-) or Dicer(-/-) embryonic stem cells (ESCs), contain no mature miRNA and cannot differentiate into somatic cells. How miRNA deficiency causes differentiation defects remains poorly understood. Here, we report that miR-302 is sufficient to enable neural differentiation of differentiation-incompetent Dgcr8(-/-) ESCs. Our data showed that miR-302 directly suppresses the tumor suppressor p53, which is modestly upregulated in Dgcr8(-/-) ESCs and serves as a barrier restricting neural differentiation. We demonstrated that direct inactivation of p53 by SV40 large T antigen, a short hairpin RNA against Trp53, or genetic ablation of Trp53 in Dgcr8(-/-) PSCs enables neural differentiation, while activation of p53 by the MDM2 inhibitor nutlin-3a in wild-type ESCs inhibits neural differentiation. Together, we demonstrate that a major function of miRNAs in neural differentiation is suppression of p53 and that modest activation of p53 blocks neural differentiation of miRNA-deficient PSCs.

PMID: 29141234 [PubMed - in process]

CFTR Genotype and Maximal Exercise Capacity in Cystic Fibrosis: A Cross-sectional Study.

Ann Am Thorac Soc. 2017 Nov 15;:

Authors: Radtke T, Hebestreit H, Gallati S, Schneiderman JE, Braun J, Stevens D, Hulzebos EH, Takken T, Boas SR, Urquhart DS, Lands LC, Tejero S, Sovtic A, Dwyer T, Petrovic M, Harris RA, Karila C, Savi D, Usemann J, Mei-Zahav M, Hatziagorou E, Ratjen F, Kriemler S, CFTR-Exercise study group

Abstract
RATIONALE: Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in human skeletal muscle cells. Variations of CFTR dysfunction among patients with CF may present an important determinant of aerobic exercise capacity in CF. Previous studies on the relationship between CFTR genotype and aerobic exercise capacity are scarce and contradictory.
OBJECTIVES: This study was designed to explore factors influencing aerobic exercise capacity, expressed as peak oxygen consumption (VO2peak) with a specific focus on CFTR genotype in children and adults with CF.
METHODS: In an international, multicenter cross-sectional study we collected data on CFTR genotype and cardiopulmonary exercise tests (CPET) in patients with CF eight years and older. CFTR mutations were classified into functional classes I-V.
RESULTS: The final analysis included 726 patients (45% females, age 8 to 61 years, FEV1 16 to 123 % predicted) from 17 CF centers in North America, Europe, Australia and Asia whom all had both valid maximal CPET and complete CFTR genotype data. Overall, patients exhibited exercise intolerance (VO2peak, 77.3±19.1 % predicted), but values were comparable among different CFTR classes. Using linear regression analysis adjusted for relevant confounders, lung function and body mass index, but not CFTR genotype were the main predictors of VO2peak.
CONCLUSIONS: We conclude that lung disease severity and reduced nutritional status rather than CFTR genotypes are the major determinants of aerobic exercise capacity in patients with CF.

PMID: 29140739 [PubMed - as supplied by publisher]

Treatment Setting and Outcomes of Cystic Fibrosis Pulmonary Exacerbations.

Ann Am Thorac Soc. 2017 Nov 15;:

Authors: Schechter MS, VanDevanter DR, Pasta DJ, Short SA, Morgan WJ, Konstan MW, Scientific Advisory Group and the Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis

Abstract
RATIONALE: There are important gaps in our knowledge of the optimal treatment of cystic fibrosis (CF) pulmonary exacerbations. Previous observational studies comparing inpatient to outpatient treatment have suffered from methodological weaknesses, especially indication bias.
OBJECTIVES: We analyzed data from the Epidemiologic Study of CF using techniques to control for indication bias to determine whether there is an advantage to inpatient treatment of CF pulmonary exacerbations.
METHODS: We identified typical pulmonary exacerbations in patients ≥6 years of age during the 3-year observation period ending in 2005. Our primary analysis used the instrumental variables method, implemented using 2-stage least squares (2SLS) regression, to evaluate the effect of the proportion of total time that IV treatment was administered inpatient (vs. outpatient) on the likelihood of return of percent predicted FEV1 (ppFEV1) to ≥90% of baseline post-treatment. We also evaluated two other indicators of treatment setting, three other measures of treatment response, and two alternative modelling techniques, and additionally looked for differences between children and adults.
RESULTS: Our final analysis included 4497 pulmonary exacerbations, in 2773 individual patients from 75 sites. We calculated the mean proportion of IV treatment time that was provided in the hospital setting at each site; the median across sites was 0.581 (IQR, 0.396-0.753). The median treatment success rate across sites was 74.2% (IQR 67.9%-79.2%). Univariate analysis and 2SLS models showed a positive relationship between treatment success and proportion of inpatient treatment days. Our primary model found an absolute increase of 9.08% (95% confidence interval 2.55, 15.61, p=0.006) in the achievement of a return of ppFEV1 to ≥90% of baseline comparing complete inpatient treatment with no inpatient treatment. Treatment response was not related to duration of IV therapy. Similar results were found for all our modelling techniques and outcomes.
CONCLUSIONS: CF patients treated at sites with more reliance on inpatient treatment were more likely to achieve successful FEV1 recovery. There was no relationship between treatment duration and recovery of FEV1.

PMID: 29140726 [PubMed - as supplied by publisher]

The Antibacterial and Anti-inflammatory Activity of Chicken Cathelicidin-2 combined with Exogenous Surfactant for the Treatment of Cystic Fibrosis-Associated Pathogens.

Sci Rep. 2017 Nov 14;7(1):15545

Authors: Banaschewski BJH, Baer B, Arsenault C, Jazey T, Veldhuizen EJA, Delport J, Gooyers T, Lewis JF, Haagsman HP, Veldhuizen RAW, Yamashita C

Abstract
Cystic fibrosis (CF) is characterized by recurrent airway infections with antibiotic-resistant bacteria and chronic inflammation. Chicken cathelicin-2 (CATH-2) has been shown to exhibit antimicrobial activity against antibiotic-resistant bacteria and to reduce inflammation. In addition, exogenous pulmonary surfactant has been suggested to enhance pulmonary drug delivery. It was hypothesized that CATH-2 when combined with an exogenous surfactant delivery vehicle, bovine lipid extract surfactant (BLES), would exhibit antimicrobial activity against CF-derived bacteria and downregulate inflammation. Twelve strains of CF-pathogens were exposed to BLES+CATH-2 in vitro and killing curves were obtained to determine bactericidal activity. Secondly, heat-killed bacteria were administered in vivo to elicit a pro-inflammatory response with either a co-administration or delayed administration of BLES+CATH-2 to assess the antimicrobial-independent, anti-inflammatory properties of BLES+CATH-2. CATH-2 alone exhibited potent antimicrobial activity against all clinical strains of antibiotic-resistant bacteria, while BLES+CATH-2 demonstrated a reduction, but significant antimicrobial activity against bacterial isolates. Furthermore, BLES+CATH-2 reduced inflammation in vivo when either co-administered with killed bacteria or after delayed administration. The use of a host-defense peptide combined with an exogenous surfactant compound, BLES+CATH-2, is shown to exhibit antimicrobial activity against antibiotic-resistant CF bacterial isolates and reduce inflammation.

PMID: 29138462 [PubMed - in process]

Antibacterial Effect and DNA Delivery Using a Combination of an Arsonium-Containing Lipophosphoramide with an N-Heterocyclic Carbene-Silver Complex - Potential Benefits for Cystic Fibrosis Lung Gene Therapy.

Int J Pharm. 2017 Nov 11;:

Authors: Mottais A, Berchel M, Sibiril Y, Laurent V, Gill D, Hyde S, Jaffrès PA, Montier T, Le Gall T

Abstract
Cystic Fibrosis (CF), the most common chronic genetic disorder among the Caucasian population, is a life-threatening disease mainly due to respiratory failures resulting from chronic infections and inflammation. Although research in the pharmacological field has recently made significant progress, gene therapy still remains a promising strategy to cure CF, especially because it should be applicable to any patient whatever the mutation profile. Until now, little attention has been paid to bacterial lung infections with regard to gene delivery to the airways; yet, this could greatly impact on the success of gene therapy. Previously, we have reported arsonium-containing lipophosphoramides as poly-functional nanocarriers capable of simultaneous antibacterial action against Gram-positive bacteria and gene transfer into eukaryotic cells. In the present work, we show that such nanoparticles can also be combined with an N-heterocyclic carbene-silver complex in order to extend the spectrum of antibacterial activity, including towards the Gram-negative Pseudomonas aeruginosa. Importantly, this is demonstrated not only using standard in vitro protocols but also a clinically-relevant aerosol delivery method. Furthermore, antibacterial effects are compatible with efficient and safe gene delivery into human bronchial epithelial cells. The poly-functionality of combinations of such chemical compounds may thus show benefits for CF lung gene therapy.

PMID: 29138047 [PubMed - as supplied by publisher]

Oral glucose tolerance test and continuous glucose monitoring to assess diabetes development in cystic fibrosis patients.

Endocrinol Diabetes Nutr. 2017 Nov 11;:

Authors: Clemente León M, Bilbao Gassó L, Moreno-Galdó A, Campos Martorrell A, Gartner Tizzano S, Yeste Fernández D, Carrascosa Lezcano A

Abstract
INTRODUCTION: Patients with cystic fibrosis (CF) undergo a slow and progressive process toward diabetes. Oral glucose tolerance test (OGTT) is recommended to diagnose impaired glucose levels in these patients. Continuous glucose monitoring (CGM) measures glucose profiles under real-life conditions.
OBJECTIVE: To compare OGTT and CGM results in CF patients.
METHODS: Paired OGTT and 6-day CGM profiles (146.2±9.1h/patient) were performed in 30 CF patients aged 10-18 years.
RESULTS: According to OGTT, 14 patients had normal glucose tolerance (NGT), 14 abnormal glucose tolerance (AGT), and two cystic fibrosis-related diabetes (CFRD). In 27 patients (13 NGT, 13 AGT, 1 CFRD), CGM showed glucose values ranging from 140 to 200mg/dL during similar monitoring times (2%-14% with NGT, 1%-16.9% with AGT, and 3% with CFRD). Glucose peak levels ≥200mg/dL were seen in seven patients (3 NGT, 3 AGT, 1 CFRD). According to CGM, two patients had all glucose values under 140mg/dL (1 NGT, 1 AGT). Seventeen patients had glucose levels ranging from 140 to 200mg/dL (10 NGT, 6 AGT, 1 CFRD). Ten patients (3 NGT, 7 AGT) had glucose values ≥200mg/dL for ≤1% of the monitoring time and one (CFRD) for >1% of the monitoring time.
CONCLUSIONS: OGTT results did not agree with those of the CGM. CGM allows for diagnosis of glucose changes not detected by OGTT. Such changes may contribute to optimize pre-diabetes management in CF patients.

PMID: 29137964 [PubMed - as supplied by publisher]