Evaluation of different molecular and phenotypic methods for identification of environmental Burkholderia cepacia complex.

World J Microbiol Biotechnol. 2019 Feb 09;35(3):39

Authors: Furlan JPR, Pitondo-Silva A, Braz VS, Gallo IFL, Stehling EG

Abstract
The correct identification of different genera and bacterial species is essential, especially when these bacteria cause infections and appropriate therapies need to be chosen. Bacteria belonging to the Burkholderia cepacia complex are considered important opportunistic pathogens, causing different types of infections in immunocompromised, principally in patients with cystic fibrosis. Twenty-one isolates were obtained from different soil samples and identified by sequencing of 16S rRNA, 23S rRNA, recA gene, MLST and by VITEK 2 and MALDI-TOF MS systems. Then, statistical analyses were performed. VITEK 2 and MALDI-TOF MS systems showed different bacterial genera. Sequencing of the 16S rRNA, 23S rRNA gene and amplification of recA gene showed that all the isolates belong to the B. cepacia complex. Sequencing of the recA gene showed a predominance of B. cenocepacia. The PCR of the recA gene showed a high specificity when it is necessary to identify the bacteria belonging to the B. cepacia complex in comparison with 16S and 23S rRNA genes sequencing. MLST analyzes showed a diversity of STs, which have not yet been correlated to the species. Phenotypic identification was not suitable for the identification of these pathogens since in many cases different genera have been reported, including identification by using MALDI-TOF MS.

PMID: 30739255 [PubMed - in process]

Coexistence of Candida species and bacteria in patients with cystic fibrosis.

Eur J Clin Microbiol Infect Dis. 2019 Feb 09;:

Authors: Haiko J, Saeedi B, Bagger G, Karpati F, Özenci V

Abstract
Cystic fibrosis (CF) patients become colonized by pathogenic bacteria as well as by Candida species. The interplay between different microorganisms may play a key role in the prognosis of CF. The aim of the study was to analyze the coexistence patterns of bacteria and Candida spp. in sputum samples of patients with CF and to compare these patterns with the results of patients with other respiratory disorders (ORD). Sputum samples from 130 patients with CF and 186 patients with ORD were cultured on six different agar plates promoting the growth of bacteria and yeasts. Bacterial and Candida species were identified with MALDI-TOF MS. Pathogenic bacteria were found in 69.2% of the sputum samples of the CF patients, and in 44.1% the patients with ORD. CF patients tended to have growth of Pseudomonas aeruginosa and Staphylococcus aureus in sputum more often than patients with ORD. Overall, there was no difference in the coexistence of pathogenic bacteria and Candida spp. in these patient groups. However, when analyzed at the species level, P. aeruginosa and S. aureus coexisted with Candida spp. more frequently in sputum samples of CF patients compared with patients with ORD. Also, when analyzed according to age, it was shown that the adult (≥ 18 years) CF patients had a higher rate of coexistence of any pathogenic bacteria and Candida spp. than the children with CF and the adult patients with ORD. The rate for colonization with Candida together with pathogenic bacteria is increased in adult patients with CF.

PMID: 30739228 [PubMed - as supplied by publisher]

Incretin dysfunction and hyperglycemia in cystic fibrosis: Role of acyl-ghrelin.

J Cyst Fibros. 2019 Feb 06;:

Authors: Sun X, Yi Y, Liang B, Yang Y, He N, Ode KL, Uc A, Wang K, Gibson-Corley KN, Engelhardt JF, Norris AW

Abstract
BACKGROUND: Insulin secretion is insufficient in cystic fibrosis (CF), even before diabetes is present, though the mechanisms involved remain unclear. Acyl-ghrelin (AG) can diminish insulin secretion and is elevated in humans with CF.
METHODS: We tested the hypothesis that elevated AG contributes to reduced insulin secretion and hyperglycemia in CF ferrets.
RESULTS: Fasting AG was elevated in CF versus non-CF ferrets. Similar to its effects in other species, AG administration in non-CF ferrets acutely reduced insulin, increased growth hormone, and induced hyperglycemia. During oral glucose tolerance testing, non-CF ferrets had responsive insulin, glucagon like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels and maintained normal glucose levels, whereas CF ferrets had insufficient responses and became hyperglycemic. Interestingly in wild-type ferrets, the acyl-ghrelin receptor antagonist [D-Lys3]-GHRP-6 impaired glucose tolerance, and abolished insulin, GLP-1, and GIP responses during glucose tolerance testing. By contrast, in CF ferrets [D-Lys3]-GHRP-6 improved glucose tolerance, enhanced the insulin-to-glucose ratio, but did not impact the already low GLP-1 and GIP levels.
CONCLUSIONS: These results suggest a mechanism by which elevated AG contributes to CF hyperglycemia through inhibition of insulin secretion, an effect magnified by low GLP-1 and GIP. Interventions that lower ghrelin, ghrelin action, and/or raise GLP-1 or GIP might improve glycemia in CF.

PMID: 30738804 [PubMed - as supplied by publisher]

Authors' response: Letter to the Editor 'Comparison of lung clearance index determined by washout of N2 and SF6 in infants and preschool children with cystic fibrosis'.

J Cyst Fibros. 2019 Feb 06;:

Authors: Stahl M, Joachim C, Wielpütz MO, Mall MA

PMID: 30738803 [PubMed - as supplied by publisher]

Lumacaftor-rescued F508del-CFTR has a modified bicarbonate permeability.

J Cyst Fibros. 2019 Feb 06;:

Authors: Ferrera L, Baroni D, Moran O

Abstract
Deletion of phenylalanine at position 508, F508del, the most frequent mutation among Cystic fibrosis (CF) patients, destabilizes the protein, thus causing both a folding and a trafficking defect, resulting in a dramatic reduction in expression of CFTR. In vitro treatment with lumacaftor produces an enhancement of anion transport in cells. We studied the permeability properties of the CFTR mutant F508del treated with the corrector lumacaftor, showing that the rescued protein has selectivity properties different than the wild type CFTR, showing an augmented bicarbonate permeability. This difference would indicate a diverse conformation of the rescued F508del-CFTR, that is plausibly reflected on an improper regulation of the airway surface liquid, lessening the efficacy of the corrector. Our findings rather support the idea that a combination of correctors would be required to address the CFTR-dependent bicarbonate permeability.

PMID: 30738802 [PubMed - as supplied by publisher]

Health economic modelling in Cystic Fibrosis: A systematic review.

J Cyst Fibros. 2019 Feb 06;:

Authors: Mohindru B, Turner D, Sach T, Bilton D, Carr S, Archangelidi O, Bhadhuri A, Whitty JA

Abstract
INTRODUCTION: Cystic Fibrosis (CF) is a heritable chronic condition. Due to the genetic and progressive nature of CF, a number of interventions are available for the condition. In the United Kingdom (U.K.) average annual cost of CF treatment is between €49,000 to €76,000 (2012) per patient [1]. A review of health economic modelling studies is warranted to provide decision makers and researchers with an in depth understanding of modelling practices in CF and guidance for future research.
METHODS: Online searches were performed in the 5 databases, studies were included if they were: a) Model based economic evaluation for management of Cystic Fibrosis. Articles were restricted to English language only, but no restriction was applied on publication year.
RESULTS: Nine studies were reviewed, most were Markov cohort models. Models evaluated pharmaceutical interventions and drug adherence. Modelling structure was consistent across most articles and a range of sources were used to populate the models. Cost and utility data were based on different sources and elicitation methods respectively. The majority of models failed to incorporate significant health events which impact both cost and disease progression.
CONCLUSION: In our review we observed a lack of, application of European Medicines Agency (EMA) guidelines for clinical trial endpoints, model structure justifications and lastly, health-related quality of life derived utility information around important clinical events. Future work around conceptual modelling of CF progression, utility valuation of significant health events and meeting EMA guidelines for trial reporting is encouraged.

PMID: 30738801 [PubMed - as supplied by publisher]

CFTR structure, stability, function and regulation.

Biol Chem. 2018 Dec 01;:

Authors: Meng X, Clews J, Cuitaa AD, Martin ER, Ford RC

Abstract
CFTR (Cystic Fibrosis transmembrane conductance regulator) is a unique member of the ATP-binding cassette family of proteins because it has evolved into a channel. Mutations in CFTR cause cystic fibrosis, the most common genetic disease in people of European origins. The F508del mutation is found in about 90% of patients and here we present data that suggest its main effect is on CFTR stability rather than on the 3D folded state. A survey of recent cryo-electron microscopy studies was carried out and this highlighted differences in terms of CFTR conformation despite similarities in experimental conditions. We further studied CFTR structure under various phosphorylation states and with the CFTR-interacting protein NHERF1. The coexistence of outward-facing and inward-facing conformations under a range of experimental conditions was suggested from these data. These results are discussed in terms of structural models for channel gating, and favour the model where the mostly disordered regulatory-region of the protein acts as a channel plug.

PMID: 30738013 [PubMed - as supplied by publisher]

A black-blood ultra-short echo time (UTE) sequence for 3D isotropic resolution imaging of the lungs.

Magn Reson Med. 2019 Feb 08;:

Authors: Delacoste J, Feliciano H, Yerly J, Dunet V, Beigelman-Aubry C, Ginami G, van Heeswijk RB, Piccini D, Stuber M, Sauty A

Abstract
PURPOSE: Ultra-short echo time MRI is a promising alternative to chest CT for cystic fibrosis patients. Black-blood imaging in particular could help discern small-sized anomalies, such as mucoid plugging, which may otherwise be confused with neighboring blood vessels, particularly when contrast agent is not used. We, therefore, implemented and tested an ultra-short echo time sequence with black-blood preparation. Additionally, this sequence may also be used to generate bright-blood angiograms.
METHODS: Using this sequence, data was acquired during free breathing in 10 healthy volunteers to obtain respiratory-motion-resolved 3D volumes covering the entire thorax with an isotropic resolution of (1 mm)3 . The magnitude of signal suppression relative to a bright-blood reference acquisition was quantified and compared with that obtained with a turbo-spin echo (TSE) acquisition. Bright-blood angiograms were also generated by subtraction. Finally, an initial feasibility assessment was performed in 2 cystic fibrosis patients, and images were visually compared with contrast-enhanced images and with CT data.
RESULTS: Black-blood preparation significantly decreased the average normalized signal intensity in the vessel lumen (-66%; P < 0.001). Similarly, blood signal was significantly lowered (-60%; P = 0.001) compared with the TSE acquisition. In patients, mucoid plugging could be emphasized in the black-blood datasets. An intercostal artery could also be visualized in the subtraction angiograms.
CONCLUSION: Black-blood free-breathing ultra-short echo time imaging was successfully implemented and motion-resolved full volumetric coverage of the lungs with high spatial resolution was achieved, while obtaining an angiogram without contrast agent injection. Encouraging initial results in patients prompt further investigations in a larger cohort.

PMID: 30737836 [PubMed - as supplied by publisher]

Defective proteostasis in celiac disease as a new therapeutic target.

Cell Death Dis. 2019 Feb 08;10(2):114

Authors: Maiuri L, Villella VR, Piacentini M, Raia V, Kroemer G

Abstract
Cystic fibrosis (CF) is a disease caused by loss-of-function mutations affecting the CF transmembrane conductance regulator (CFTR), a chloride channel. Recent evidence indicates that CFTR is inhibited by a gluten/gliadin-derived peptide (P31-43), causing an acquired state of CFTR inhibition within the gut that contributes to the pathogenesis of celiac disease (CD). Of note, CFTR inhibition does not only cause intra- and extracellular ion imbalances but also affects proteostasis by activating transglutaminase-2 (TGM2) and by disabling autophagy. These three phenomena (CFTR inhibition, TGM2 activation, and autophagy impairment) engage in multiple self-amplifying circuitries, thus forming an "infernal trio". The trio hinders enterocytes from returning to homeostasis and instead locks them in an irreversible pro-inflammatory state that ultimately facilitates T lymphocyte-mediated immune responses against another gluten/gliadin-derived peptide (P57-68), which,upon deamidation by activated TGM2, becomes fully antigenic. Hence, the pathogenic protein gliadin exemplifies a food constituent the exceptional immunogenicity of which arises from a combination of antigenicity (conferred by deaminated P57-68) and adjuvanticity (conferred by P31-43). CF can be treated by agents targeting the "infernal trio" including CFTR potentiators, TGM2 inhibitors, and autophagy enhancers. We speculate that such agents may also be used for CD therapy and indeed could constitute close-to-etiological treatments of this enteropathy.

PMID: 30737369 [PubMed - in process]

Methylomic correlates of autophagy activity in cystic fibrosis.

J Cyst Fibros. 2019 Feb 05;:

Authors: Caution K, Pan A, Krause K, Badr A, Hamilton K, Vaidya A, Gosu H, Daily K, Estfanous S, Gavrilin MA, Drew ME, Cormet-Boyaka E, Chen X, Frankhouser DE, Bundschuh R, Yan P, Dakhlallah D, Amer AO

Abstract
Autophagy is a highly regulated, biological process that provides energy during periods of stress and starvation. This conserved process also acts as a defense mechanism and clears microbes from the host cell. Autophagy is impaired in Cystic Fibrosis (CF) patients and CF mice, as their cells exhibit low expression levels of essential autophagy molecules. The genetic disorder in CF is due to mutations in the cystic fibrosis transmembrane conductance regulator (cftr) gene that encodes for a chloride channel. CF patients are particularly prone to infection by pathogens that are otherwise cleared by autophagy in healthy immune cells including Burkholderia cenocepacia (B. cenocepacia). The objective of this study is to determine the mechanism underlying weak autophagic activity in CF macrophages and find therapeutic targets to correct it. Using reduced representation bisulfite sequencing (RRBS) to determine DNA methylation profile, we found that the promoter regions of Atg12 in CF macrophages are significantly more methylated than in the wild-type (WT) immune cells, accompanied by low protein expression. The natural product epigallocatechin-3-gallate (EGCG) significantly reduced the methylation of Atg12 promoter improving its expression. Accordingly, EGCG restricted B. cenocepacia replication within CF mice and their derived macrophages by improving autophagy and preventing dissemination. In addition, EGCG improved the function of CFTR protein. Altogether, utilizing RRBS for the first time in the CF field revealed a previously unrecognized mechanism for reduced autophagic activity in CF. Our data also offers a mechanism by which EGCG exerts its positive effects in CF.

PMID: 30737168 [PubMed - as supplied by publisher]

Cav3.2 calcium channel interactions with the epithelial sodium channel ENaC.

Mol Brain. 2019 Feb 08;12(1):12

Authors: Garcia-Caballero A, Gandini MA, Huang S, Chen L, Souza IA, Dang YL, Stutts MJ, Zamponi GW

Abstract
This study describes the functional interaction between Cav3.2 calcium channels and the Epithelial Sodium Channel (ENaC). β-ENaC subunits showed overlapping expression with endogenous Cav3.2 calcium channels in the thalamus and hypothalamus as detected by immunostaining. Moreover, β- and γ-ENaC subunits could be co-immunoprecipitated with Cav3.2 calcium channels from brain lysates, dorsal horn and lumbar dorsal root ganglia. Mutation of a cluster of lysines present in the intracellular N-terminus region of β-ENaC (K4R/ K5R/ K9R/ K16R/ K23R) reduced interactions with Cav3.2 calcium channels. Αβγ-ENaC channels enhanced Cav3.2 calcium channel trafficking to the plasma membrane in tsA-201 cells. This effect was reciprocal such that Cav3.2 channel expression also enhanced β-ENaC trafficking to the cell surface. T-type current density was increased when fully assembled αβγ-ENaC channels were transiently expressed in CAD cells, a neuronal derived cell line. Altogether, these findings reveal ENaC as an interactor and potential regulator of Cav3.2 calcium channels expressed in neuronal tissues.

PMID: 30736831 [PubMed - in process]

Retro-1-Oligonucleotide Conjugates. Synthesis and Biological Evaluation.

Molecules. 2019 Feb 06;24(3):

Authors: Agramunt J, Pedroso E, Kreda SM, Juliano RL, Grandas A

Abstract
Addition of small molecule Retro-1 has been described to enhance antisense and splice switching oligonucleotides. With the aim of assessing the effect of covalently linking Retro-1 to the biologically active oligonucleotide, three different derivatives of Retro-1 were prepared that incorporated a phosphoramidite group, a thiol or a 1,3-diene, respectively. Retro-1⁻oligonucleotide conjugates were assembled both on-resin (coupling of the phosphoramidite) and from reactions in solution (Michael-type thiol-maleimide reaction and Diels-Alder cycloaddition). Splice switching assays with the resulting conjugates showed that they were active but that they provided little advantage over the unconjugated oligonucleotide in the well-known HeLa Luc705 reporter system.

PMID: 30736307 [PubMed - in process]

Comparison of different conditions for DNA extraction in sputum - a pilot study.

Multidiscip Respir Med. 2019;14:6

Authors: Oriano M, Terranova L, Teri A, Sottotetti S, Ruggiero L, Tafuro C, Marchisio P, Gramegna A, Amati F, Nava F, Franceschi E, Cariani L, Blasi F, Aliberti S

Abstract
Background: The analysis of microbiome in respiratory samples is a topic of great interest in chronic respiratory diseases. The method used to prepare sputum samples for microbiome analysis is very heterogeneous. The selection of the most suitable methodology for DNA extraction is fundamental to have the most representative data. The objective of this study was to compare different conditions for DNA extraction from sputum in adult patients with bronchiectasis.
Methods: Five sputum samples from bronchiectasis patients were collected at the Policlinico Hospital in Milan, Italy. Eighteen conditions for DNA extraction were compared, including two enzyme-based (Roche and Zymo) and one beads-based (Mobio) technique. These techniques were tested with/without Dithiothreitol (DTT) and with/without lysostaphin (0.18 and 0.36 mg/mL) step. DNA was quantified, tested using Real-time PCR for 16S rDNA and S. aureus and, then, microbiome was evaluated.
Results: Although 16S rDNA was similarly detected across all the different techniques, Roche kit gave the highest DNA yield. The lowest Ct values for Real-time PCR for S. aureus was identified when lysostaphin was added. Considering genera from microbiome, alpha diversity indices did not show any significant differences between techniques, while relative abundances were more similar in presence of DTT.
Conclusions: None of the conditions emerged to be superior to the others even if enzyme-based kits seem to be needed in order to have a higher extraction yield.

PMID: 30733864 [PubMed]

Controlled light-induced gas phase nitric oxide release from S-nitrosothiol-doped silicone rubber films.

Nitric Oxide. 2019 Feb 05;:

Authors: Lautner G, Stringer B, Brisbois EJ, Meyerhoff ME, Schwendeman SP

Abstract
The light induced nitric oxide (NO) release properties of S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathione (GSNO) NO donors doped within polydimethylsiloxane (PDMS) films (PDMS-SNAP and PDMS-GSNO respectively) for potential inhaled NO (iNO) applications is examined. To achieve photolytic release of gas phase NO from the PDMS-SNAP and PDMS-GSNO films, narrow band LED light sources are employed and the NO concentration in a N2 sweep gas above the film is monitored with an electrochemical NO sensor. The NO release kinetics using LED sources with different nominal wavelengths and optical power densities are reported. The effect of the NO donor loading within the PDMS films is also examined. The NO release levels can be controlled by the LED triggered release from the NO donor-doped silicone rubber films in order to generate therapeutic levels in a sweep gas for suitable durations potentially useful for iNO therapy. Hence this work may lay the groundwork for future development of a highly portable iNO system for treatment of patients with pulmonary hypertension, hypoxemia, and cystic fibrosis.

PMID: 30735785 [PubMed - as supplied by publisher]

Evolutionary highways to persistent bacterial infection.

Nat Commun. 2019 Feb 07;10(1):629

Authors: Bartell JA, Sommer LM, Haagensen JAJ, Loch A, Espinosa R, Molin S, Johansen HK

Abstract
Persistent infections require bacteria to evolve from their naïve colonization state by optimizing fitness in the host via simultaneous adaptation of multiple traits, which can obscure evolutionary trends and complicate infection management. Accordingly, here we screen 8 infection-relevant phenotypes of 443 longitudinal Pseudomonas aeruginosa isolates from 39 young cystic fibrosis patients over 10 years. Using statistical modeling, we map evolutionary trajectories and identify trait correlations accounting for patient-specific influences. By integrating previous genetic analyses of 474 isolates, we provide a window into early adaptation to the host, finding: (1) a 2-3 year timeline of rapid adaptation after colonization, (2) variant "naïve" and "adapted" states reflecting discordance between phenotypic and genetic adaptation, (3) adaptive trajectories leading to persistent infection via three distinct evolutionary modes, and (4) new associations between phenotypes and pathoadaptive mutations. Ultimately, we effectively deconvolute complex trait adaptation, offering a framework for evolutionary studies and precision medicine in clinical microbiology.

PMID: 30733448 [PubMed - in process]

Can't see the wood for the trees: confounders, colliders and causal inference - a statistician's approach.

Thorax. 2019 Feb 07;:

Authors: Huang B, Szczesniak R

PMID: 30733328 [PubMed - as supplied by publisher]

Outcomes in cystic fibrosis lung transplant recipients infected with organisms labeled aspan-resistant: An ISHLT Registry‒based analysis.

J Heart Lung Transplant. 2019 Jan 25;:

Authors: Lay C, Law N, Holm AM, Benden C, Aslam S

Abstract
BACKGROUND: The presence of pan-resistant organisms in patients with cystic fibrosis (CF) potentially impacts mortality after lung transplant (LT). In this study we aimed to study LT mortality in CF patients with and without pan-resistant infection.
METHODS: The International Society for Heart and Lung Transplantation (ISHLT) Thoracic Transplant Registry was used to identify adults with CF, first-time, bilateral LT from 1991 to 2015. Extracted data included demographics, clinical characteristics, post-transplant outcomes, and mortality (infection-related, overall). Multivariate binary logistic regression models were created with 90-day and 1-year mortality as primary outcomes.
RESULTS: Among 3,256 LT recipients with CF, 697 were labeled as having pan-resistant infection, the others were included as controls (n = 2,649). Pre-transplant, those labeled as pan-resistant were more likely to require ventilator support, have an infection requiring intravenous antibiotics, and have had ≥2 pneumonia episodes within 1 year. Ninety-day and 1-year mortality was similar between groups, but infection-related mortality at 90 days (3.3% vs 1.88%, p = 0.01) and 1 year (6.6% vs 4.6%, p < 0.001) was higher in those labeled as pan-resistant. In multivariate analysis, presence of organisms labeled as pan-resistant was not associated with 90-day (odds ratio [OR] 1.5, 95% confidence interval [CI] 0.93 to 2.42, p = 0.09) or 1-year mortality (OR 1.32, 95% CI 0.95 to 1.83, p = 0.097).
CONCLUSIONS: CF patients with pre-transplant infection from organisms labeled as pan-resistant had similar 90-day and 1-year mortality as those without. Despite increased infection-related mortality in these patients, it was not predictive of mortality in multivariate analysis. The higher occurrence of post-transplant infections in these patients warrants diligent follow-up. A multicenter cohort study will be required to validate the findings of our study.

PMID: 30733155 [PubMed - as supplied by publisher]

Impact of colonizing organism in the respiratory tract on the incidence, duration, and time between subsequent hospitalizations among patients with cystic fibrosis.

Am J Infect Control. 2019 Feb 04;:

Authors: Cios K, Cohen B, Quittell LM, Liu J, Larson EL

Abstract
BACKGROUND: This study aimed to examine the association between colonizing respiratory tract organism and frequency, duration, and time between subsequent hospitalizations among hospitalized patients with cystic fibrosis (CF).
METHODS: This retrospective cohort study of 312 CF patients from 2 New York City hospitals (2006-2016) examined the effects of colonization with Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus aureus (MSSA) or methicillin-resistant S aureus (MRSA), co-colonization on incidence of hospitalization, time to next hospitalization, and total length of stay (LOS).
RESULTS: Annual rate of subsequent hospitalizations was highest in patients with P aeruginosa: adjusted incidence rate ratios (aIRRs) were 2.75 (95% confidence interval [CI], 1.72-4.41) for P aeruginosa versus MSSA, 2.57 (95% CI, 1.52-4.31) for co-colonization versus MSSA, and 1.77 (95% CI, 1.04-3.01) for P aeruginosa versus MRSA. Time to readmission was shortest for P aeruginosa: aIRRs were 1.75 (95% CI, 1.05-2.94) for MRSA versus P aeruginosa, 1.64 (95% CI, 1.03-2.59) for MSSA versus P aeruginosa, and 1.61 (95% CI, 1.04-2.47) for co-colonization versus P aeruginosa. LOS was longest for P aeruginosa: aIRRs were 3.41 (95% CI, 2.19-5.32) for P aeruginosa versus MSSA, 1.66 (95% CI, 1.01-2.75) for co-colonization versus MSSA, 2.50 (95% CI, 1.58-3.93) for P aeruginosa versus MRSA, and 2.05 (95% CI, 1.32-3.18) for P aeruginosa versus co-colonization.
CONCLUSIONS: CF patients with P aeruginosa alone experienced more hospitalizations, longer LOS, and shorter time to readmission versus patients with S aureus or both organisms.

PMID: 30732978 [PubMed - as supplied by publisher]

Novel cystamine-core dendrimer-formulation rescues ΔF508-CFTR and inhibits Pseudomonas aeruginosa infection by augmenting autophagy.

Expert Opin Drug Deliv. 2019 Feb 07;:1-10

Authors: Faraj J, Bodas M, Pehote G, Swanson D, Sharma A, Vij N

Abstract
BACKGROUND: Cystic fibrosis (CF) is challenged with pathophysiological barriers for effective airway drug-delivery. Hence, we standardized the therapeutic efficacy of the novel dendrimer-based autophagy-inducing anti-oxidant drug, cysteamine.
RESEARCH DESIGN AND METHODS: Human primary-CF epithelial-cells, CFBE41o-cells were used to standardize the efficacy of the dendrimer-cystamine in correcting impaired-autophagy, rescuing ΔF508-CFTR and Pseudomonas-aeruginosa (Pa) infection.
RESULTS: We first designed a novel cystamine-core dendrimer formulation (G4-CYS) that significantly increases membrane-ΔF508CFTR expression in CFBE41o-cells (p < 0.05) by forming its reduced-form cysteamine, in vivo. Additionally, G4-CYS treatment corrects ΔF508-CFTR-mediated impaired-autophagy as observed by a significant decrease (p < 0.05) in Ub-LC3-positive aggresome-bodies. Next, we verified that in non-permeabilized CFBE41o-cells, G4-CYS significantly (p < 0.05) induces ΔF508-CFTR's forward-trafficking to the plasma membrane. Furthermore, cysteamine's known antibacterial and anti-biofilm properties against Pa were enhanced as our findings demonstrate that both G4-CYS and its control DAB-core dendrimer, G4-DAB, exhibited significant (p < 0.05) bactericidal-activity against Pa. We also found that both G4-CYS and G4-DAB exhibit marked mucolytic-activity against porcine-mucus (p < 0.05). Finally, we demonstrate that G4-CYS not only corrects the autophagy-impairment by rescuing ΔF508-CFTR in CFBE41o-cells but also corrects the intrinsic phagocytosis defect (p < 0.05).
CONCLUSIONS: Overall, our data demonstrates the efficacy of novel cystamine-dendrimer formulation in rescuing ΔF508-CFTR to the plasma membrane and inhibiting Pa bacterial-infection by augmenting autophagy.

PMID: 30732491 [PubMed - as supplied by publisher]

Fast up-dosing with a birch allergoid is safe and well tolerated in allergic rhinitis patients with or without asthma.

Immunotherapy. 2019 Feb;11(3):177-187

Authors: Zielen S, Plückhahn K, Akboga Y, Rieker-Schwienbacher J, Thieme U, Rosewich M

Abstract
AIM: Subcutaneous immunotherapy is effective in treating allergic rhinoconjunctivitis and asthma, but is still inconvenient when heavy schedules are used. A faster dose escalation is desirable.
MATERIALS & METHODS: In this open-label, Phase II trial, 130 adults were randomized 1:1 to receive a birch pollen allergoid subcutaneous immunotherapy. Group I with four weekly injections and Group II with seven weekly injections. Safety, tolerability and immunogenicity were assessed.
RESULTS: Mild-to-moderate treatment-related adverse events were reported for 57.7% of the patients (Group I: 36, Group II: 39). Tolerability was assessed by physicians and rated as 'good' or 'very good' for 55 patients in Group I (87.3%) and for 63 patients in Group II (94.0%). Levels of IgG and IgG4 increased before and after treatment significantly (p < 0.0001) in both groups.
CONCLUSION: Standard versus fast dose escalation is comparable in terms of safety and tolerability.

PMID: 30730274 [PubMed - in process]