Investigation of the Binding Affinity of a Broad Array of l-Fucosides with Six Fucose-Specific Lectins of Bacterial and Fungal Origin.

Molecules. 2019 Jun 18;24(12):

Authors: Thai Le S, Malinovska L, Vašková M, Mező E, Kelemen V, Borbás A, Hodek P, Wimmerová M, Csávás M

Abstract
Series of multivalent α-l-fucoside containing glycoclusters and variously decorated l-fucosides were synthesized to find potential inhibitors of fucose-specific lectins and study the structure-binding affinity relationships. Tri- and tetravalent fucoclusters were built using copper-mediated azide-alkyne click chemistry. Series of fucoside monomers and dimers were synthesized using various methods, namely glycosylation, an azide-alkyne click reaction, photoinduced thiol-en addition, and sulfation. The interactions between compounds with six fucolectins of bacterial or fungal origin were tested using a hemagglutination inhibition assay. As a result, a tetravalent, α-l-fucose presenting glycocluster showed to be a ligand that was orders of magnitude better than a simple monosaccharide for tested lectins in most cases, which can nominate it as a universal ligand for studied lectins. This compound was also able to inhibit the adhesion of Pseudomonas aeruginosa cells to human epithelial bronchial cells. A trivalent fucocluster with a protected amine functional group also seems to be a promising candidate for designing glycoconjugates and chimeras.

PMID: 31216664 [PubMed - in process]

Absence of evidence that respiratory viral infections influence pediatric lung transplantation outcomes: results of the CTOTC-03 study.

Am J Transplant. 2019 Jun 19;:

Authors: Sweet SC, Chin H, Conrad C, Hayes D, Heeger PS, Faro A, Goldfarb S, Melicoff-Portillo E, Mohanakumar T, Odim J, Schecter M, Storch GA, Visner G, Williams NM, Kesler K, Danziger-Isakov L

Abstract
Based on reports in adult lung transplant recipients, we hypothesized that community acquired respiratory viral infections (CARV) would be a risk factor for poor outcome after pediatric lung transplant. We followed 61 pediatric lung transplant recipients for 2+ years or until they met a composite primary endpoint including bronchiolitis obliterans syndrome (BOS)/obliterative bronchiolitis, re-transplantation or death. Blood, bronchoalveolar lavage and nasopharyngeal specimens were obtained with standard of care visits. Nasopharyngeal specimens were obtained with respiratory viral symptoms. Respiratory specimens were interrogated for respiratory viruses using multiplex PCR. Donor-specific HLA antibodies, self-antigens, and Elispot reactivity were also evaluated. Survival was 84% (1 year) and 68% (3 years). BOS incidence was 20% (1 year) and 38% (3 years). The primary endpoint was met in 46% of patients. CARV was detected in 156 patient visits (74% enterovirus/rhinovirus). We did not find a relationship between CARV recovery from respiratory specimens and the primary endpoint (HR 0.64 (0.25, 1.59), P=0.335) or between CARV and the development of allo- or autoimmune humoral or cellular responses. These findings raise the possibility that the immunologic impact of CARV following pediatric lung transplant is different than that observed in adults. This article is protected by copyright. All rights reserved.

PMID: 31216376 [PubMed - as supplied by publisher]

Targeting bacterial biofilm: a new LecA multivalent ligand with inhibitory activity.

Chembiochem. 2019 Jun 19;:

Authors: Palmioli A, Sperandeo P, Polissi A, Airoldi C

Abstract
Biofilm formation by bacterial pathogens is a hallmark of chronic infections and is associated to increased antibiotic tolerance that makes pathogens difficult to eradicate with conventional antibiotic therapies. Infections caused by Pseudomonas aeruginosa are of great concern, especially for immunocompromised and cystic fibrosis patients. P. aeruginosa lectins LecA and LecB are virulence factors and play a key role in establishing biofilm; therefore, inhibition of the function of these proteins has potential in dismantling the bacterium from the protective biofilm environment and in restoring the activity of antibiotics. Here we report the NMR characterization of the binding of a galactose-based dendrimer (Gal18) to LecA. Moreover, we demonstrate the activity of Gal18 molecule in inhibiting P. aeruginosa biofilm formation in vitro.

PMID: 31216375 [PubMed - as supplied by publisher]

Hypertrophic osteoarthropathy presenting with joint pain in cystic fibrosis.

Arthritis Rheumatol. 2019 Jun 19;:

Authors: Clarke E, Bright-Thomas R

Abstract
A 19 year old man with cystic fibrosis (CF) presented with pain and swelling of both wrists in association with an infective respiratory exacerbation. His CF-related complications included clubbing, multilobar bronchiectasis, chronic infection with Pseudomonas aeruginosa, exocrine pancreatic insufficiency, cystic fibrosis related diabetes mellitus, and low body mass. This article is protected by copyright. All rights reserved.

PMID: 31216115 [PubMed - as supplied by publisher]

Emerging gene therapies for cystic fibrosis.

Expert Rev Respir Med. 2019 Jun 19;:

Authors: Miah KM, Hyde SC, Gill DR

Abstract
Introduction: Cystic fibrosis (CF) remains a life-threatening genetic disease, with few clinically effective treatment options. Gene therapy and gene editing strategies offer the potential for a one-time CF cure, irrespective of the CFTR mutation class. Areas covered: We review emerging gene therapies and gene delivery strategies for the treatment of CF particularly viral and non-viral approaches with potential to treat CF. Expert opinion: It was initially anticipated that the challenge of developing a gene therapy for CF lung disease would be met relatively easily. Following early proof-of-concept clinical studies, CF gene therapy has entered a new era with innovative vector designs, approaches to subvert the humoral immune system and increase gene delivery and gene correction efficiencies. Developments include integrating adenoviral vectors, rapamycin loaded nanoparticles and lung-tropic lentiviral vectors. The characterisation of novel cell types in the lung epithelium, including pulmonary ionocytes, may also encourage cell type-specific targeting for CF correction. We anticipate preclinical studies to further validate these strategies, which should pave the way for clinical trials. We also expect gene editing efficiencies to improve to clinically translatable levels, given advancements in viral and non-viral vectors. Overall, gene delivery technologies look more convincing in producing an effective CF gene therapy.

PMID: 31215818 [PubMed - as supplied by publisher]

Hepatocellular carcinoma in cystic fibrosis liver disease: a cautionary tale.

QJM. 2019 Jun 19;:

Authors: O'Brien C, Ramlaul N, Haughey A, Nolan N, Malone DE, Cormick AM

PMID: 31214693 [PubMed - as supplied by publisher]

Catabolism of Nucleic Acids by a Cystic Fibrosis Pseudomonas aeruginosa Isolate: An Adaptive Pathway to Cystic Fibrosis Sputum Environment.

Front Microbiol. 2019;10:1199

Authors: Kumar SS, Penesyan A, Elbourne LDH, Gillings MR, Paulsen IT

Abstract
Pseudomonas aeruginosa is a major cause of morbidity and mortality in patients with cystic fibrosis (CF). We undertook Biolog Phenotype Microarray testing of P. aeruginosa CF isolates to investigate their catabolic capabilities compared to P. aeruginosa laboratory strains PAO1 and PA14. One strain, PASS4, displayed an unusual phenotype, only showing strong respiration on adenosine and inosine. Further testing indicated that PASS4 could grow on DNA as a sole carbon source, with a higher biomass production than PAO1. This suggested that PASS4 was specifically adapted to metabolize extracellular DNA, a substrate present at high concentrations in the CF lung. Transcriptomic and proteomic profiling of PASS4 and PAO1 when grown with DNA as a sole carbon source identified a set of upregulated genes, including virulence and host-adaptation genes. PASS4 was unable to utilize N-Acetyl-D-glucosamine, and when we selected PASS4 mutants able to grow on this carbon source, they also displayed a gain in ability to catabolize a broad range of other carbon sources. Genome sequencing of the mutants revealed they all contained mutations within the purK gene, encoding a key protein in the de novo purine biosynthesis pathway. This suggested that PASS4 was a purine auxotroph. Growth assays in the presence of 2 mM adenosine and the complementation of PASS4 with an intact purK gene confirmed this conclusion. Purine auxotrophy may represent a viable microbial strategy for adaptation to DNA-rich environments such as the CF lung.

PMID: 31214142 [PubMed]

Inhaled corticosteroids, blood eosinophils, and FEV1 decline in patients with COPD in a large UK primary health care setting.

Int J Chron Obstruct Pulmon Dis. 2019;14:1063-1073

Authors: Whittaker HR, Müllerova H, Jarvis D, Barnes NC, Jones PW, Compton CH, Kiddle SJ, Quint JK

Abstract
Background: Inhaled corticosteroid (ICS)-containing medications slow rate of decline of FEV1. Blood eosinophil (EOS) levels are associated with the degree of exacerbation reduction with ICS. Purpose: We investigated whether FEV1 decline differs between patients with and without ICS, stratified by blood EOS level. Patients and methods: The UK Clinical Practice Research Datalink (primary care records) and Hospital Episode Statistics (hospital records) were used to identify COPD patients aged 35 years or older, who were current or ex-smokers with ≥2 FEV1 measurements ≥6 months apart. Prevalent ICS use and the nearest EOS count to start of follow-up were identified. Patients were classified at baseline as higher stratum EOS (≥150 cell/µL) on ICS; higher stratum EOS not on ICS; lower stratum EOS (<150 cells/µL) on ICS; and lower stratum EOS not on ICS. In addition, an incident ICS cohort was used to investigate the rate of FEV1 change by EOS and incident ICS use. Mixed-effects linear regression was used to compare rates of FEV1 change in mL/year. Results: A total of 26,675 COPD patients met our inclusion criteria (median age 69, 46% female). The median duration of follow up was 4.2 years. The rate of FEV1 change in prevalent ICS users was slower than non-ICS users (-12.6 mL/year vs -21.1 mL/year; P =0.001). The rate of FEV1 change was not significantly different when stratified by EOS level. The rate of FEV1 change in incident ICS users increased (+4.2 mL/year) vs -21.2 mL/year loss in non-ICS users; P<0.001. In patients with high EOS, incident ICS patients showed an increase in FEV1 (+12 mL/year) compared to non-ICS users whose FEV1 decreased (-20.8 mL/year); P<0.001. No statistical difference was seen in low EOS patients. Incident ICS use is associated with an improvement in FEV1 change, however, over time this association is lost. Conclusion: Regardless of blood EOS level, prevalent ICS use is associated with slower rates of FEV1 decline in COPD.

PMID: 31213788 [PubMed - in process]

Interactions between Aspergillus fumigatus and Pulmonary Bacteria: Current State of the Field, New Data, and Future Perspective.

J Fungi (Basel). 2019 Jun 12;5(2):

Authors: Briard B, Mislin GLA, Latgé JP, Beauvais A

Abstract
Aspergillus fumigatus and Pseudomonas aeruginosa are central fungal and bacterial members of the pulmonary microbiota. The interactions between A. fumigatus and P. aeruginosa have only just begun to be explored. A balance between inhibitory and stimulatory effects on fungal growth was observed in mixed A. fumigatus-P. aeruginosa cultures. Negative interactions have been seen for homoserine-lactones, pyoverdine and pyochelin resulting from iron starvation and intracellular inhibitory reactive oxidant production. In contrast, several types of positive interactions were recognized. Dirhamnolipids resulted in the production of a thick fungal cell wall, allowing the fungus to resist stress. Phenazines and pyochelin favor iron uptake for the fungus. A. fumigatus is able to use bacterial volatiles to promote its growth. The immune response is also differentially regulated by co-infections.

PMID: 31212791 [PubMed]

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Non-invasive ventilation versus oxygen therapy in cystic fibrosis: A 12-month randomized trial.

Respirology. 2019 Jun 17;:

Authors: Milross MA, Piper AJ, Dwyer TJ, Wong K, Bell SC, Bye PTP, Non-Invasive Ventilation in Cystic Fibrosis (NIVCF) Study Group

Abstract
BACKGROUND AND OBJECTIVE: No published studies have examined the long-term effects of non-invasive ventilation (NIV) in cystic fibrosis (CF). Our primary aim was to determine if adults with CF and sleep desaturation were less likely to develop hypercapnia with NIV ± O2 compared to low-flow oxygen therapy (LFO2 ) or meet the criteria for failure of therapy over 12 months. We studied event-free survival, hospitalizations, lung function, arterial blood gases (ABG), sleep quality and health-related quality of life.
METHODS: A prospective, randomized, parallel group study in adult patients with CF and sleep desaturation was conducted, comparing 12 months of NIV ± O2 to LFO2 . Event-free survival was defined as participants without events. Events included: failure of therapy with PaCO2  > 60 mm Hg, or increase in PaCO2  > 10 mm Hg from baseline, increases in TcCO2  > 10 mm Hg, lung transplantation or death. Outcomes were measured at baseline, 3, 6 and 12 months, including lung function, ABG, Pittsburgh Sleep Quality Inventory (PSQI), SF36 and hospitalizations.
RESULTS: A total of 29 patients were randomized to NIV ± O2 (n = 14) or LFO2 (n = 15) therapy for 12 months. Of the 29 patients, 18 met the criteria for event-free survival over 12 months. NIV ± O2 group had 33% (95% CI: 5-58%) and 46% (95% CI: 10-68%) more event-free survival at 3 and 12 months than LFO2 group. No statistically significant differences were seen in spirometry, ABG, questionnaires or hospitalizations.
CONCLUSION: NIV ± O2 during sleep increases event-free survival over 12 months in adults with CF. Further studies are required to determine which subgroups benefit the most from NIV.

PMID: 31206975 [PubMed - as supplied by publisher]

A multi-scale model of gas transport in the lung to study heterogeneous lung ventilation during the multiple-breath washout test.

PLoS Comput Biol. 2019 Jun 17;15(6):e1007079

Authors: Hasler D, Anagnostopoulou P, Nyilas S, Latzin P, Schittny J, Obrist D

Abstract
The multiple-breath washout (MBW) is a lung function test that measures the degree of ventilation inhomogeneity (VI). The test is used to identify small airway impairment in patients with lung diseases like cystic fibrosis. However, the physical and physiological factors that influence the test outcomes and differentiate health from disease are not well understood. Computational models have been used to better understand the interaction between anatomical structure and physiological properties of the lung, but none of them has dealt in depth with the tracer gas washout test in a whole. Thus, our aim was to create a lung model that simulates the entire MBW and investigate the role of lung morphology and tissue mechanics on the tracer gas washout procedure. To this end, we developed a multi-scale lung model to simulate the inert gas transport in airways of all size. We then applied systematically different modifications to geometrical and mechanical properties of the lung model (compliance, residual airway volume and flow resistance) which have been associated with VI. The modifications were applied to distinct parts of the model, and their effects on the gas distribution within the lung and on the gas concentration profile were assessed. We found that variability in compliance and residual volume of the airways, as well as the spatial distribution of this variability in the lung had a direct influence on gas distribution among airways and on the MBW pattern (washout duration, characteristic concentration profile during each expiration), while the effects of variable flow resistance were negligible. Based on these findings, it is possible to classify different types of inhomogeneities in the lung and relate them to specific features of the MBW pattern, which builds the basis for a more detailed association of lung function and structure.

PMID: 31206515 [PubMed - as supplied by publisher]

The First Report of Total Pancreatectomy and Islet Cell Autotransplantation for Pancreatic Cystosis in Patient With Cystic Fibrosis.

Pancreas. 2019 Jul;48(6):e54-e55

Authors: Desai CS, Vonderau JS, Ma X, Hanson M, Xu X, Khan A

PMID: 31206471 [PubMed - in process]

Respiratory Fungal Diseases in Adult Patients With Cystic Fibrosis.

Clin Med Insights Circ Respir Pulm Med. 2019;13:1179548419849939

Authors: Delfino E, Del Puente F, Briano F, Sepulcri C, Giacobbe DR

Abstract
Clinical manifestations of respiratory fungal diseases in adult cystic fibrosis (CF) patients are very heterogeneous, ranging from asymptomatic colonization to chronic infections, allergic disorders, or invasive diseases in immunosuppressed CF patients after lung transplantation. In this narrative review, mainly addressed to clinicians without expertise in CF who may nonetheless encounter adult CF patients presenting with acute and chronic respiratory syndromes, we briefly summarize the most representative clinical aspects of respiratory fungal diseases in adult CF patients.

PMID: 31205434 [PubMed]

Cystic fibrosis drug ivacaftor stimulates CFTR channels at picomolar concentrations.

Elife. 2019 Jun 17;8:

Authors: Csanády L, Töröcsik B

Abstract
The devastating inherited disease cystic fibrosis (CF) is caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) anion channel. The recent approval of the CFTR potentiator drug ivacaftor (Vx-770) for the treatment of CF patients has marked the advent of causative CF therapy. Currently, thousands of patients are being treated with the drug, and its molecular mechanism of action is under intensive investigation. Here we determine the solubility profile and true stimulatory potency of Vx-770 towards wild-type (WT) and mutant human CFTR channels in cell-free patches of membrane. We find that its aqueous solubility is ~200-fold lower (~60 nanomolar), whereas the potency of its stimulatory effect is >100-fold higher, than reported, and is unexpectedly fully reversible. Strong, but greatly delayed, channel activation by picomolar Vx-770 identifies multiple sequential slow steps in the activation pathway. These findings provide solid guidelines for the design of in vitro studies using Vx-770.

PMID: 31205003 [PubMed - as supplied by publisher]

A case report of successful eradication of new isolates of Burkholderia cenocepacia in a child with cystic fibrosis.

Acta Clin Belg. 2019 Jun 15;:1-4

Authors: Sputael V, Van Schandevyl G, Hanssens L

Abstract
Chronic respiratory infection with Burkholderia cenocepacia (Bc) in patients with cystic fibrosis (CF) is associated with accelerated decline in lung function and increased mortality. It is therefore important to attempt to eradicate new isolates, especially in children. However, there are no standardized guidelines to eradicate Bc. We report a case of successful eradication of new isolates of Bc in a 2-year-old child with CF using a combination of IV, nebulized antibiotics and sinus surgery.

PMID: 31204617 [PubMed - as supplied by publisher]

Effectiveness and safety of biologics in pediatric inflammatory boweldisease: Real-life data from the Sicilian Network.

Clin Res Hepatol Gastroenterol. 2019 Jun 13;:

Authors: Romeo AC, Ventimiglia M, Dipasquale V, Orlando A, Citrano M, Pellegrino S, Accomando S, Cottone M, Romano C

Abstract
BACKGROUND: Biological therapies have modified the disease course of pediatric inflammatory bowel disease (IBD) and are routinely used in clinical practice. Our observational study aims to evaluate effectiveness and safety of biologics in IBD.
METHOD: Clinical benefit and safety data of 93 children with IBD, receiving biologics (Infliximab - IFX, Adalimumab - ADA, Golimumab - GOL) from January 2013 to December 2017, were extracted from the cohort of the Sicilian Network of IBD.
RESULTS: Among 87 children aged 7-17 years (63 Crohn's disease [CD], 24 Ulcerative colitis [UC]), 101 out of 108 biologic treatments were considered. Evaluation of 74 biologic treatments in CD patients at 26, 52, 104 weeks showed clinical benefit rates of 84.2%, 93.3%, 66.7% with IFX (n= 38) and 88.9%, 84.4%, 65.2% with ADA (n= 36). Biologic treatments (n=27) evaluated in the UC group at 26, 52, 104 weeks, led to clinical benefit rates of 85.7%, 83.3%, 50% in IFX subgroup (n=21) and 40%, 50%, 33% in the ADA subgroup (n=5), respectively. One patient treated with GOL showed 100% clinical benefit at 26 and 52 weeks. Overall adverse events (AEs) rate was 9.25%. Six younger children, <6 years, receiving 8 treatments (4 ADA, 4 IFX) presented a clinical remission rate of 75% at 12 weeks and 25% at 52 weeks. AEs rate was 25% in this group.
CONCLUSION: Our data show that biologic therapy in children, even at a younger age, is effective in allowing long-term remission with a good safety profile.

PMID: 31204314 [PubMed - as supplied by publisher]

Healthcare professionals' perceptions of risky health behaviours: A qualitative evaluation of preventative measures for populations with cystic fibrosis.

Chronic Illn. 2019 Jun 15;:1742395319856395

Authors: Keyte R, Egan H, Mantzios M

PMID: 31203674 [PubMed - as supplied by publisher]

Genetic predisposition in pancreatitis.

Curr Opin Pediatr. 2018 10;30(5):660-664

Authors: Gonska T

Abstract
PURPOSE OF REVIEW: Genetic mutations are the primary cause for acute recurrent (ARP) and chronic pancreatitis in children. Further, our medical approach for many diseases is changing from a one-drug therapy to more individualized therapeutic strategies. In respect to the therapeutic management of ARP/chronic pancreatitis, this entails an understanding of the individual, mainly genetic, risk factors that led to pancreatitis disease.
RECENT FINDINGS: New pancreatitis-associated genes are continuously emerging from increasingly large genetic cohort studies. Furthermore, newer research findings demonstrate that multiple genetic and nongenetic factors are required to increase the individual risk for developing ARP/chronic pancreatitis. Last, there is new exciting development towards targeted pancreatitis therapy in the future.
SUMMARY: This review introduces the current concept of ARP/chronic pancreatitis as a complex disease caused by multiple genetic and nongenetic factors. This warrants careful evaluation of these patients and ideally consultation of a pancreas expert to help understand individual genetic risk profiles and to provide more effective patient consultation.

PMID: 30015686 [PubMed - indexed for MEDLINE]

Pseudomonas aeruginosa eradication therapy and risk of acquiring Aspergillus in young children with cystic fibrosis.

Thorax. 2019 Jun 15;:

Authors: Harun SN, Holford NHG, Grimwood K, Wainwright CE, Hennig S, Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) study group

Abstract
BACKGROUND: While Aspergillus detection rates in adults, adolescents and older children with cystic fibrosis (CF) have increased, the risk of acquiring this fungal pathogen in young children is unknown.
AIM: To determine the risk and explanatory factors of acquiring Aspergillus in children with CF by age 5 years.
METHODS: Cross-sectional analysis of clinical, bronchoalveolar lavage and treatment data from the Australasian Cystic Fibrosis Bronchoalveolar Lavage study was used to identify predictive factors for detecting Aspergillus at age 5 years. A parametric repeated time-to-event model quantitatively described the risk and factors associated with acquiring Aspergillus and Pseudomonas aeruginosa from birth until age 5 years.
RESULTS: Cross-sectional analysis found that the number of P. aeruginosa eradication courses increased the odds of detecting Aspergillus at age 5 years (OR 1.61, 95% CI 1.23 to 2.12). The median (IQR) age for the first P. aeruginosa positive culture was 2.38 (1.32-3.79) years and 3.69 (1.68-4.74) years for the first Aspergillus positive culture. The risk of P. aeruginosa and Aspergillus events changes with time after the first year of study entry. It also decreases for P. aeruginosa after completing P. aeruginosa eradication (HR 0.15, 95% CI 0.00 to 0.79), but increases for Aspergillus events (HR 2.75, 95% CI 1.45 to 5.41). The risk of acquiring both types of events increases after having had a previous event.
CONCLUSION: In young children with CF, completing P. aeruginosa eradication therapy and previous Aspergillus events are associated with increased risk of acquiring Aspergillus.

PMID: 31203197 [PubMed - as supplied by publisher]