Enhancement of ciliary beat amplitude by carbocisteine in ciliated human nasal epithelial cells.

Laryngoscope. 2019 Jul 11;:

Authors: Inui TA, Yasuda M, Hirano S, Ikeuchi Y, Kogiso H, Inui T, Marunaka Y, Nakahari T

Abstract
OBJECTIVE: Carbocisteine (CCis), a mucoactive agent, is used to improve the symptoms of sinonasal diseases. However, the effect of CCis on nasal ciliary beating remains uncertain. We examined the effects of CCis on ciliary beat distance (CBD, an index of amplitude), and ciliary beat frequency (CBF) in ciliated human nasal epithelial cells (cHNECs) in primary culture.
METHODS: The cHNECs were prepared from the nasal tissue resected from patients required surgery for chronic sinusitis (CS) or allergic rhinitis (AR). CBD and CBF were measured using videomicroscopy equipped with a high-speed camera.
RESULTS: CCis increased CBD by 30%, but not CBF, and decreased intracellular Cl- concentration ([Cl- ]i ) in cHNECs. The CCis' actions were mimicked by the Cl- -free NO3 - solution. In contrast, prior treatment of NPPB (20 μM) or CFTR(inh)-172 (1 μM), which increased [Cl- ]i by 20%, decreased CBF by 10% and CBD by 25% and inhibited the CCis' actions. However, prior treatment of T16Ainh-A01 (10 μM) did not inhibit the CCis' actions, although it decreased [Cl- ]i by 10% and CBD by 15%. Thus, CCis stimulates Cl- channels including cystic fibrosis transmembrane conductance regulator (CFTR). Moreover, CCis enhanced the transport of microbeads driven by the beating cilia in cHNECs. The CCis actions were similar in cHNECs from both types of pateints.
CONCLUSION: CCis increased CBD by 30% in cHNECs via an [Cl- ]i decrease stimulated by activation of Cl- channels, including CFTR. CCis may stimulate nasal mucociliary clearance by increasing CBD in patients contracting CS or AR.
LEVEL OF EVIDENCE: NA. Laryngoscope, 2019.

PMID: 31294840 [PubMed - as supplied by publisher]

Transient Elastography in the Evaluation of Cystic Fibrosis-Associated Liver Disease: Systematic Review and Meta-analysis.

J Can Assoc Gastroenterol. 2019 May;2(2):71-80

Authors: Lam S, Nettel-Aguirre A, Van Biervliet S, Roeb E, Sadler MD, Friedrich-Rust M, Karlas T, Kitson MT, deBruyn JCC

Abstract
Background and aims: Complications of cystic fibrosis-associated liver disease (CFLD) are a leading nonpulmonary cause of death. Transient elastography (TE) has recently been investigated to detect CFLD. This study reviews the current literature for TE in the detection CFLD. A meta-analysis was performed to determine the ideal liver stiffness measurement (LSM) cutoff.
Methods: PubMed, Medline, EMBASE and Web of Science were searched from inception until April 2016 for publications involving the detection of CFLD with TE. Data were extracted using a fixed protocol (a priori design) including study design, population characteristics, probe size and AST Platelet Ratio Index (APRI).
Results: Diagnostic properties were summarized from six studies of 605 patients. Cutoff for LSM was determined using pooled data submitted by authors. The cutoff for LSM and APRI were ≥5.95 kPa and ≥0.329 respectively, yielding a sensitivity, specificity and area under receiver operator characteristic of 55%, 87%, 0.76, 52%, 93% and 0.84 for LSM and APRI, respectively. When LSM ≥5.95 kPa and APRI ≥0.329, the sensitivity, specificity, positive predictive value and negative predictive value were 43%, 99%, 92% and 87% with a diagnostic odds ratio of 74.9. A bivariate metaregression model showed that pediatric specific cutoffs for liver stiffness and APRI may not be necessary.
Conclusion: Individually, LSM and APRI have poor sensitivity but good specificity for detecting CFLD. They are most useful when combined. We propose that patients with LSM ≥5.95 kPa and APRI ≥0.329 be investigated thoroughly for the presence of cystic fibrosis-associated liver disease.

PMID: 31294368 [PubMed]

Caffeine boosts Ataluren's readthrough activity.

Heliyon. 2019 Jun;5(6):e01963

Authors: Lentini L, Melfi R, Cancemi P, Pibiri I, Di Leonardo A

Abstract
The readthrough of nonsense mutations by small molecules like Ataluren is considered a novel therapeutic approach to overcome the gene defect in several genetic diseases as cystic fibrosis (CF). This pharmacological approach suppresses translation termination at premature termination codons (PTCs readthrough) thus restoring the expression of a functional protein. However, readthrough might be limited by the nonsense-mediated mRNA decay (NMD), a cell process that reduces the amount/level of PTCs containing mRNAs. Here we investigate the combined action of Ataluren and caffeine to enhance the readthrough of PTCs. IB3.1 CF cells with a nonsense mutation were treated with caffeine to attenuate the Nonsense-Mediated mRNA Decay (NMD) activity and thus enhance the stability of the nonsense (ns)-CFTR-mRNA to be targeted by Ataluren. Our results show that NMD attenuation by caffeine enhances mRNA stability and more importantly when combined with Ataluren increase the recovery of the full-length CFTR protein.

PMID: 31294114 [PubMed]

Hydrogels Embedded With Melittin and Tobramycin Are Effective Against Pseudomonas aeruginosa Biofilms in an Animal Wound Model.

Front Microbiol. 2019;10:1348

Authors: Maiden MM, Zachos MP, Waters CM

Abstract
We demonstrate that the antimicrobial peptide, melittin, is effective alone and in combination with the aminoglycosides tobramycin to kill Pseudomonas aeruginosa growing as biofilms both in vitro and in vivo. Melittin and tobramycin show enhanced in vitro activity in combination at micromolar concentrations, resulting in a 2-log10 reduction in the number of cells within mature PAO1 P. aeruginosa biofilms after 6-h of treatment. Alternatively, either agent alone resulted in half-a-log10 reduction. Time-killing assays demonstrated that the combination of melittin and tobramycin was effective at 2-h whereas tobramycin was not effective until after 6-h of treatment. We also found the combination was more effective than tobramycin alone against biofilms of 7 P. aeruginosa cystic fibrosis clinical isolates, resulting in a maximum 1.5-log10 cellular reduction. Additionally, melittin alone was effective at killing biofilms of 4 Staphylococcus aureus isolates, resulting in a maximum 2-log10 cellular reduction. Finally, melittin in combination with tobramycin embedded in an agarose-based hydrogel resulted in a 4-fold reduction in bioluminescent P. aeruginosa colonizing mouse wounds by 4-h. In contrast, tobramycin or melittin treatment alone did not cause a statistically significant reduction in bioluminescence. These data demonstrate that melittin in combination with tobramycin embedded in a hydrogel is a potential treatment for biofilm-associated wound infections.

PMID: 31293530 [PubMed]

Diagnostic value of chest ultrasound in children with cystic fibrosis - Pilot study.

PLoS One. 2019;14(7):e0215786

Authors: Strzelczuk-Judka L, Wojsyk-Banaszak I, Zakrzewska A, Jończyk-Potoczna K

Abstract
Cystic fibrosis (CF) is one of the most common genetic disorders among the White population. The disease has a progressive course and leads to a reduction in the quality of life and of life expectancy. Standard diagnostic procedures used in the monitoring of CF patients include methods which expose patients to ionizing radiation. With increasing life expectancy in CF the cumulative dose of ionising radiation increases, prompting clinicians' search for safer imaging studies. Despite its safety and availability lung ultrasound (LUS) is not routinely used in the diagnostic evaluation of CF patients. The aim of the study was to evaluate the diagnostic value of LUS in children with CF compared to a chest X-ray, and to assess the diagnostic value of the recently developed LUS score-CF-USS (Cystic Fibrosis Ultrasound Score). LUS was performed in 48 CF children and adolescents aged from 5 to 18 years (24 girls and 24 boys). LUS consisted of the assessment of the pleura, lung sliding, A-line and B-line artefacts, "lung rockets", alveolar consolidations, air bronchogram and pleural effusion. Chest radiography was performed in all patients and analyzed according to the modified Chrispin-Norman score. LUS was analyzed according to CF-USS. The correlation between the CF-USS and the modified Chrispin-Norman scores was moderate (R = 0.52, p = 0.0002) and strong in control studies. In 75% of patients undergoing LUS, small areas of subpleural consolidations were observed, which were not visible on x-rays. At the same time, LUS was not sensitive enough to visualize bronchial pathology, which plays an important role in assessing the progression of the disease. Conclusions: LUS constitutes an invaluable tool for the diagnosis of subpleural consolidations. CF-USS results correlate with the conventional x-ray modified Chrispin-Norman score. LUS should be considered a supplementary radiographic examination in the monitoring of CF patients, and CF-USS may provide clinicians with valuable information concerning the progression of the disease.

PMID: 31291258 [PubMed - in process]

Amyloidosis in cystic fibrosis.

Paediatr Respir Rev. 2019 May 07;:

Authors: Simpson T, Elston C, Macedo P, Perrin F

Abstract
As the life expectancy of patients with cystic fibrosis has increased, greater attention has been paid towards the diagnosis and management of the longer term consequences of the condition. A recognised but rare complication of the disease is the development of secondary amyloidosis. Whilst deposition of amyloid protein has been reported in a high proportion of patients with cystic fibrosis at post-mortem [1] and Serum Amyloid A protein has been shown to correlate with disease activity and response to antibiotics [2], the manifestation of clinical disease remains extremely uncommon. The prognosis for patients with amyloid secondary to cystic fibrosis in published reports has been historically bleak [3-6], however there may be novel approaches in the era of biological therapies. The theoretical potential for an increase in the incidence of secondary amyloid amongst the population of cystic fibrosis patients who are experiencing much longer lifespans means that it is worthwhile to consider the condition and its possible treatments in more detail. We report a case and a review of the literature.

PMID: 31288987 [PubMed - as supplied by publisher]

Outpatient Parenteral Antimicrobial Treatment for Non-Cystic Fibrosis Bronchiectasis Exacerbations: A Prospective Multicentre Observational Cohort Study.

Respiration. 2019 Jul 09;:1-7

Authors: López-Cortés LE, Ayerbe-García R, Carrasco-Hernández L, Fraile-Ramos E, Carmona-Caballero JM, Quintana-Gallego E, Valido-Morales A, Praena J, Pachón-Diaz J, DOMUS OPAT Group

Abstract
BACKGROUND: The recently published guidelines of the Spanish Society of Pulmonology and Thoracic Surgery encourage physicians to use outpatient antimicrobial therapy to treat exacerbations in patients with non-cystic fibrosis bronchiectasis (NCFB). The published literature on this topic, however, is scarce.
METHODS: We report a prospective observational cohort study of patients with NCFB who received treatment at home for at least one exacerbation episode between September 2012 and September 2017 as part of an outpatient parenteral antimicrobial therapy (OPAT) program. Patients were included in the analysis if they fulfilled all of the following criteria: established diagnosis of bronchiectasis according to current guidelines criteria, clinical exacerbation, requiring intravenous antibiotics because of failure to respond to oral antibiotics, or isolation of a microorganism resistant to oral options.
OBJECTIVES: To evaluate the effectiveness and safety of the treatment of patients with NCFB exacerbations in an OPAT program under "real-world" conditions.
RESULTS: Sixty-seven patients were treated in the OPAT program due to bacterial exacerbations of NCFB. Forty-five (67.2%) patients were admitted to hospital for a median of 7 days before starting OPAT. Sixty-three (94%) patients achieved resolution of the exacerbation at the end of therapy. Four patients needed hospital readmission, and one died. The OPAT program saved 11,586 days of hospital admission, equivalent to EUR 7,866,904.
CONCLUSIONS: OPAT appears to be a safe, effective, and efficient strategy for treating patients with exacerbations of NCFB.

PMID: 31288243 [PubMed - as supplied by publisher]

Antibacterial and transfection activities of nebulized formulations incorporating long n-alkyl chain silver N-heterocyclic carbene complexes.

Int J Pharm. 2019 Jul 06;:118500

Authors: Mottais A, Berchel M, Le Gall T, Sibiril Y, d'Arbonneau F, Laurent V, Jaffrès PA, Montier T

Abstract
The development of new antibacterial molecules is essential in view of the emergence of pathogenic strains resistant to multiple antibiotics. Among the infectious pathologies, pulmonary infections are particularly difficult to treat due to the complexity of lung anatomy and the presence of natural barriers such as mucus. At present, the aerosol delivery of antibacterial compounds is still poorly employed. Furthermore, the presence of bacteria in lungs negatively affects aerosolized Cystic Fibrosis gene therapy efficiency. A multi-functional formulation (antibacterial and transfection activities) could increase the therapeutic effect. This work reports the synthesis of new N-heterocyclic carbene silver complexes (Ag-NHC) featuring a lipid chain and the evaluation of their antibacterial potency, especially when delivered following aerosolization. When formulated alone in water, these Ag-NHC displayed remarkable antibacterial activities against some Staphyloccocus aureus strains and Pseudomonas aeruginosa clinical strains. Moreover, combined with cationic lipid and DNA (ternary combination), they could be used to deliver therapeutic genes via aerosolization in infected lungs. Altogether, the data reported herein support n-alkyl chain Ag-NHC as a possible alternative to conventional antibiotics for treating respiratory infections and to combat the emergence of multi-resistant bacteria.

PMID: 31288056 [PubMed - as supplied by publisher]

Optimization of dosing regimens of intravenous colistin in patients with cystic fibrosis: What data are required?

Pediatr Pulmonol. 2019 Jul 08;:

Authors: Nation RL, Landersdorfer CB

PMID: 31286687 [PubMed - as supplied by publisher]

Targeting DNAJB9, a novel ER luminal co-chaperone, to rescue ΔF508-CFTR.

Sci Rep. 2019 Jul 08;9(1):9808

Authors: Huang Y, Arora K, Mun KS, Yang F, Moon C, Yarlagadda S, Jegga A, Weaver T, Naren AP

Abstract
The molecular mechanism of Endoplasmic Reticulum-associated degradation (ERAD) of Cystic fibrosis transmembrane-conductance regulator (CFTR) is largely unknown. Particularly, it is unknown what ER luminal factor(s) are involved in ERAD. Herein, we used ProtoArray to identify an ER luminal co-chaperone, DNAJB9, which can directly interact with CFTR. For both WT- and ΔF508 (deletion of phenylalanine at position 508, the most common CF-causing mutant)-CFTR, knockdown of DNAJB9 by siRNA increased their expression levels on the cell surface and, consequently, upregulated their function. Furthermore, genetic ablation of DNAJB9 in WT mice increased CFTR expression and enhanced CFTR-dependent fluid secretion in enteroids. Importantly, DNAJB9 deficiency upregulated enteroids' fluid secretion in CF mice (homozygous for ΔF508), and silencing one allele of DNAJB9 is sufficient to rescue ΔF508-CFTR in vitro and in vivo, suggesting that DNAJB9 may be a rate-limiting factor in CFTR ERAD pathway. Our studies identified the first ER luminal co-chaperone involved in CFTR ERAD, and DNAJB9 could be a novel therapeutic target for CF.

PMID: 31285458 [PubMed - in process]

Nanotechnology based therapeutics for lung disease.

Thorax. 2019 Jul 08;:

Authors: Doroudian M, MacLoughlin R, Poynton F, Prina-Mello A, Donnelly SC

Abstract
Nanomedicine is a multidisciplinary research field with an integration of traditional sciences such as chemistry, physics, biology and materials science. The application of nanomedicine for lung diseases as a relatively new area of interdisciplinary science has grown rapidly over the last 10 years. Promising research outcomes suggest that nanomedicine will revolutionise the practice of medicine, through the development of new approaches in therapeutic agent delivery, vaccine development and nanotechnology-based medical detections. Nano-based approaches in the diagnosis and treatment of lung diseases will, in the not too distant future, change the way we practise medicine. This review will focus on the current trends and developments in the clinical translation of nanomedicine for lung diseases, such as in the areas of lung cancer, cystic fibrosis, asthma, bacterial infections and COPD.

PMID: 31285360 [PubMed - as supplied by publisher]

Influence of the lung microbiome on antibiotic susceptibility of cystic fibrosis pathogens.

Eur Respir Rev. 2019 Jun 30;28(152):

Authors: Vandeplassche E, Tavernier S, Coenye T, Crabbé A

Abstract
The lungs of patients with cystic fibrosis (CF) are colonised by a microbial community comprised of pathogenic species, such as Pseudomonas aeruginosa and Staphylococcus aureus, and microorganisms that are typically not associated with worse clinical outcomes (considered as commensals). Antibiotics directed at CF pathogens are often not effective and a discrepancy is observed between activity of these agents in vitro and in the patient. This review describes how interspecies interactions within the lung microbiome might influence the outcome of antibiotic treatment targeted at common CF pathogens. Protective mechanisms by members of the microbiome such as antibiotic degradation (indirect pathogenicity), alterations of the cell wall, production of matrix components decreasing antibiotic penetration, and changes in metabolism are discussed. Interspecies interactions that increase bacterial susceptibility are also addressed. Furthermore, we discuss how experimental conditions, such as culture media, oxygen levels, incorporation of host-pathogen interactions, and microbial community composition may influence the outcome of microbial interaction studies related to antibiotic activity. Hereby, the importance to create in vitro conditions reflective of the CF lung microenvironment is highlighted. Understanding the role of the CF lung microbiome in antibiotic efficacy may help find novel therapeutic and diagnostic approaches to better tackle chronic lung infections in this patient population.

PMID: 31285289 [PubMed - in process]

Genomic analysis identifies novel Pseudomonas aeruginosa resistance genes under selection during inhaled aztreonam therapy in vivo.

Antimicrob Agents Chemother. 2019 Jul 08;:

Authors: McLean K, Lee D, Holmes EA, Penewit K, Waalkes A, Ren M, Lee SA, Gasper J, Manoil C, Salipante SJ

Abstract
Inhaled aztreonam is increasingly used for chronic Pseudomonas aeruginosa suppression in patients with cystic fibrosis, but the potential for that organism to evolve aztreonam resistance remains incompletely explored. Here we performed genomic analysis of clonally related pre- and post-treatment clinical isolate pairs to identify genes that are under positive selection during aztreonam therapy in vivo We identified 16 frequently mutated genes associated with aztreonam resistance, the most prevalent being ftsI and ampC, 13 of which increased aztreonam resistance when introduced as single gene transposon mutants. Several previously implicated aztreonam resistance genes were found to be under positive selection in clinical isolates even in the absence of inhaled aztreonam exposure, indicating that other selective pressures in the CF airway can promote aztreonam resistance. Given its potential to confer plasmid-mediated resistance, we further characterized mutant ampC alleles and performed artificial evolution of ampC for maximal activity against aztreonam. We found that naturally occurring ampC mutants could confer variably increased resistance to aztreonam (2- to 64- fold) and other β-lactam agents, but that its maximal evolutionary capacity for hydrolyzing aztreonam was considerably higher (512- to 1,024- fold increases) and could be achieved while maintaining or increasing resistance to other drugs. These studies implicate novel chromosomal aztreonam resistance determinants while highlighting that different mutations are favored during selection in vivo and in vitro, show that ampC has a high maximal potential to hydrolyze aztreonam, and provide an approach to disambiguate mutations promoting specific resistance phenotypes from those more generally increasing bacterial fitness in vivo.

PMID: 31285231 [PubMed - as supplied by publisher]

Anti-quorum sensing and anti-biofilm activity of 5-hydroxymethylfurfural against Pseudomonas aeruginosa PAO1: Insights from in vitro, in vivo and in silico studies.

Microbiol Res. 2019 Sep;226:19-26

Authors: Rajkumari J, Borkotoky S, Reddy D, Mohanty SK, Kumavath R, Murali A, Suchiang K, Busi S

Abstract
Pseudomonas aeruginosa is one of the most common pathogens associated with nosocomial infections and a great concern to immunocompromised individuals especially in the cases of cystic fibrosis, AIDS and burn wounds. The pathogenicity of P. aeruginosa is largely directed by the quorum sensing (QS) system. Hence, QS may be considered an important therapeutic target to combat P. aeruginosa infections. The anti-quorum sensing and anti-biofilm efficacy of aromatic aldehyde, 5-hydroxymethylfurfural (5-HMF) against P. aeruginosa PAO1 were assessed. At the sub-inhibitory concentration, 5-HMF suppressed the production of QS-controlled virulence phenotypes and biofilm formation in P. aeruginosa. It was also able to significantly enhance the survival rate of C. elegans infected with P. aeruginosa. The in silico studies revealed that 5-HMF could serve as a competitive inhibitor for the auto-inducer molecules as it exhibited a strong affinity for the regulatory proteins of the QS-circuits i.e. LasR and RhlR. In addition, a significant down-regulation in the expression of QS-related genes was observed suggesting the ability of 5-HMF in mitigating the pathogenicity of P. aeruginosa.

PMID: 31284940 [PubMed - in process]

Strategies against Nonsense: Oxadiazoles as Translational Readthrough-Inducing Drugs (TRIDs).

Int J Mol Sci. 2019 Jul 06;20(13):

Authors: Campofelice A, Lentini L, Di Leonardo A, Melfi R, Tutone M, Pace A, Pibiri I

Abstract
This review focuses on the use of oxadiazoles as translational readthrough-inducing drugs (TRIDs) to rescue the functional full-length protein expression in mendelian genetic diseases caused by nonsense mutations. These mutations in specific genes generate premature termination codons (PTCs) responsible for the translation of truncated proteins. After a brief introduction on nonsense mutations and their pathological effects, the features of various classes of TRIDs will be described discussing differences or similarities in their mechanisms of action. Strategies to correct the PTCs will be presented, particularly focusing on a new class of Ataluren-like oxadiazole derivatives in comparison to aminoglycosides. Additionally, recent results on the efficiency of new candidate TRIDs in restoring the production of the cystic fibrosis transmembrane regulator (CFTR) protein will be presented. Finally, a prospectus on complementary strategies to enhance the effect of TRIDs will be illustrated together with a conclusive paragraph about perspectives, opportunities, and caveats in developing small molecules as TRIDs.

PMID: 31284579 [PubMed - in process]

[Allergies to non-betalactam antibiotics: a challenge in practice].

Ther Umsch. 2019 Jul;75(1):13-21

Authors: Scherer Hofmeier K

Abstract
Allergies to non-betalactam antibiotics: a challenge in practice Abstract. The heterogeneous group of non-betalactam antibiotics can in part trigger very severe immunologically mediated hypersensitivity reactions. The risks are very differently distributed among the different representatives and a genetic predisposition to the development of Stevens-Johnson syndrome / toxic epidermal necrolysis or Drug rash with eosinophilia and systemic symptoms (DRESS syndrome) can be observed. Individual patient groups are particularly frequently affected, including patients with HIV or cystic fibrosis. In this overview, the individual drug groups and corresponding risk situations as well as the available diagnostic means are discussed.

PMID: 31282834 [PubMed - in process]

Development of inhibitors against Mycobacterium abscessus tRNA (m1G37) methyltransferase (TrmD) using fragment-based approaches.

J Med Chem. 2019 Jul 08;:

Authors: Whitehouse A, Thomas SE, Brown KP, Fanourakis A, Chan D, Libardo MDJ, Mendes V, Boshoff HIM, Floto RA, Abell C, Blundell TL, Coyne AG

Abstract
Mycobacterium abscessus (Mab) is a rapidly growing species of multidrug-resistant nontuberculous mycobacteria (NTM) that has emerged as a growing threat to individuals with cystic fibrosis, and other pre-existing chronic lung diseases. Mab pulmonary infections are difficult, or sometimes impossible, to treat and result in accelerated lung function decline and premature death. There is therefore an urgent need to develop novel antibiotics with improved efficacy. tRNA (m1G37) methyltransferase (TrmD) is a promising target for novel antibiotics. It is essential in Mab and other mycobacteria, improving reading frame maintenance on the ribosome to prevent frameshift errors. In this work a fragment-based approach was employed with the merging of two fragments bound to the active site, followed by structure-guided elaboration to design potent nanomolar inhibitors against Mab TrmD. Several of these compounds exhibit promising activity against mycobacterial species, including Mycobacterium tuberculosis and Mycobacterium leprae in addition to Mab, supporting the use of TrmD as a target for the development of antimycobacterial compounds.

PMID: 31282680 [PubMed - as supplied by publisher]

Effects of Exercise Intervention Program on Bone Mineral Accretion in Children and Adolescents with Cystic Fibrosis: A Randomized Controlled Trial.

Indian J Pediatr. 2019 Jul 08;:

Authors: Gupta S, Mukherjee A, Lodha R, Kabra M, Deepak KK, Khadgawat R, Talwar A, Kabra SK

Abstract
OBJECTIVE: To evaluate effect of one year exercise intervention program on bone mineral accrual in children and adolescent with cystic fibrosis (CF).
METHODS: Fifty-two CF children (mean age 149.79 mo) were randomized into experimental (15 boys and 10 girls) and control groups (15 boys and 12 girls). Experimental group performed prescribed exercises three times/week, while control group continued with routine physical activities for one year. Following were assessed at baseline and at one year: Bone mineral density (BMD) of whole body and lumbar spine, pulmonary function, exercise capacity, quality of life and habitual activity.
RESULTS: Change in whole body and lumbar spine BMD over 12 mo in experimental group was lower by 0.006 g/cm2 (95% CI -0.02 to 0.02) and higher by 0.001 g/cm2 (95% CI -0.04 to 0.03) than controls, respectively. However, difference between groups was non-significant for both parameters. Experimental group had a significant improvement in their exercise capacity (p = 0.006), quality of life, and serum vitamin D (p = 0.007) levels. Differences between groups for changes in pulmonary function and habitual activity were non-significant.
CONCLUSIONS: Exercise regime was not associated with significant improvement in BMD of CF patients, but it had a positive impact on both physical and psychological health of these patients.

PMID: 31281938 [PubMed - as supplied by publisher]

Synthesis and evaluation of tetrahydropyrazolopyridine inhibitors of anion exchange protein SLC26A4 (pendrin).

Bioorg Med Chem Lett. 2019 Jul 03;:

Authors: Zhu JS, Lu JY, Tan JA, Rivera AA, Phuan PW, Shatskikh ME, Son JH, Haggie PM, Verkman AS, Kurth MJ

Abstract
Pendrin is a transmembrane chloride/anion antiporter that is strongly upregulated in the airways in rhinoviral infection, asthma, cystic fibrosis and chronic rhinosinusitis. Based on its role in the regulation of airway surface liquid depth, pendrin inhibitors have potential indications for treatment of inflammatory airways diseases. Here, a completely regioselective route to tetrahydro-pyrazolopyridine pendrin inhibitors based on 1,3-diketone and substituted hydrazine condensation was been developed. Structure-activity relationships at the tetrahydropyridyl nitrogen were investigated using a focused library, establishing the privileged nature of N-phenyl ureas and improving inhibitor potency by greater than 2-fold.

PMID: 31281021 [PubMed - as supplied by publisher]

Cost-effectiveness of home mechanical ventilation in children living in a developing country.

Anaesthesiol Intensive Ther. 2019;51(1):35-40

Authors: Hassani SA, Navaei S, Shirzadi R, Rafiemanesh H, Masiha F, Keivanfar M, Tahernia L, Moazzami B, Azizi G, Aghaali M, Modaresi M

Abstract
BACKGROUND: Home mechanical ventilation is a promising option for children requiring long-term mechanical-assisted ventilation, while data on cost-effectiveness of this approach is limited.
AIMS: To investigate the cost-effectiveness of home mechanical ventilation in children requiring long-term mechanical-assisted ventilation.
METHODS: A retrospective cohort was conducted on 67 children (32 girls, 47.7%) requiring mechanical-assisted ventilation. Underlying diseases of children were congenital airway malformations in 24, cystic fibrosis in 4, severe laryngomalacia in 16, poly neuropathy syndrome in 6, mitochondrial myopathy in 5, hypoxic ischemic encephalopathy in 6, and cerebral palsy in 2. Children were admitted in pediatric intensive care units (ICU) for 2 weeks. After discharge, they were on home mechanical ventilation and were followed for 1 year. Data on daily costs of admission at ICU, rehospitalizations, weaning, educational performance and muscle strength were gathered.
RESULTS: Mean age of children at time of initiation of mechanical-assisted ventilation was 5.8 years (ranged from 2 months to 15 years). Mean number of re-hospitalizations was 3.4_4.9 times with mean duration of 9.44_2.53 days. Of children on mechanical ventilation, 1 attended school, 2 were weaned, and 21 experienced improvement in muscle strength. No fatal or serious complications were observed while children were on home mechanical ventilation. Mean costs of daily ICU admission was 912_1028 $, while the mean daily cost of home mechanical ventilation was 60.86_4.95 $ (p < 0.001).
CONCLUSIONS: Home mechanical ventilation is more cost-effective compared to ICU admission for only mechanical-assisted ventilation. < p > < /p >.

PMID: 31280550 [PubMed - in process]