Cystic Fibrosis: A Risk Condition for Renal Disease.

J Ren Nutr. 2017 Nov;27(6):470-473

Authors: Santoro D, Postorino A, Lucanto C, Costa S, Cristadoro S, Pellegrino S, Conti G, Buemi M, Magazzù G, Bellinghieri G

Abstract
OBJECTIVE: Cystic fibrosis (CF) is the most common autosomal recessive disease affecting the Caucasian population, with a birth incidence ranging between 1:2,500 and 1:1,800. It is caused by mutations in the CF transmembrane regulator gene which is localized on 7 chromosomes. Renal disease is reported as a relatively rare complication in adult patient with CF. We evaluated proteinuria and chronic renal failure (CRF) in a population of patients with CF.
METHODS: A retrospective study was carried out in a referral center for CF at University of Messina in Italy. We identified all patients with renal disease, characterized by proteinuria and/or CRF, during the period 2007 to 2012 and reviewed their medical records to assess influence on renal disease of genotype, number of pulmonary exacerbation, pancreatic insufficiency, pulmonary function, CF-related diabetes, and antibiotics courses.
RESULTS: From a population of 77 adult patients with CF, we identified 9 patients with proteinuria (11.7%), and 11 patients (14.28%) with CRF. Mean age was 35.6 (+5.1 standard deviation) years, 55% were female and 33% had diabetes mellitus. Renal biopsy was performed in 3 patients because of nephrotic syndrome in 1 patient and proteinuria with renal failure in the other 2 patients. Renal amyloidosis was disclosed in 2, whereas IgA nephropathy in 1 patient. The ΔF508 mutation in homozygosis was present in 44% of patients with proteinuria (vs. 27% of our CF population, relative risk 2.07), whereas genotype ΔF508/N1303K in 22%. ΔF508 allele mutation was present in 77.7% of proteinuric patients.
CONCLUSIONS: Our study shows a higher prevalence of renal disease in patients with CF, than was previously described. The main reason may be related to increased life expectancy because of better management. Moreover, patients with ΔF508 homozygosis had higher risk of proteinuria.

PMID: 29056168 [PubMed - in process]

Vitamin A status and its determinants in patients with cystic fibrosis.

Acta Sci Pol Technol Aliment. 2017 Jul-Sep;16(3):345-354

Authors: Sapiejka E, Krzyżanowska P, Walkowiak D, Wenska-Chyży E, Szczepanik M, Cofta S, Pogorzelski A, Skorupa W, Walkowiak J

Abstract
BACKGROUND: Routine administration of vitamin A, recommended in CF patients, can help to prevent its deficiency. However, high vitamin A supplementation may lead to its excessive level and possible toxicity. Therefore, the aim of the present study was to assess the status of vitamin A and the determinants of its body resources in CF patients.
METHODS: In 196 CF patients aged from 4 months to 47 years, the following parameters  were analysed: nutritional status (standardized body weight and height, serum albumin concentration) and clinical expression of disease (lung function - spirometry; biochemical markers of liver function - ALT, AST, GGT; respiratory tract colonization by Pseudomonas aeruginosa; diabetes; cirrhosis, non-cirrhotic liver disease; exocrine pancreatic function - fecal elastase-1 concentration; blood clotting -  INR  and  vitamin  A supplementation).
RESULTS: Median vitamin A concentration in the study group was 383.0 ng/ml (1st-3rd quartile: 316.5-457.0). Vitamin A deficiency was found in 32 (16.3%) subjects studied. Vitamin A concentrations above the reference range were observed only in 3 (1.5%) CF patients. CF patients with vitamin A deficiency were significantly older and had lower values of FEV1 compared to CF subjects with normal vitamin A status. Moreover, vitamin A deficiency occurred more frequently in CF patients with diabetes, Pseudomonas aeruginosa colo- nization, worse lung function and in those without vitamin A supplementation. However, in multiple linear regression analyses, none of the independent variables was documented to be important for predicting vita- min A status.
CONCLUSIONS: Vitamin A body resources in CF patients are mostly normal. Moreover, there are no good de- terminants of vitamin A status in these patients. Further studies targeted at exploring potential toxicity and deficiencies of vitamin A in CF patients are needed.

PMID: 29055982 [PubMed - in process]

Prevalence of Burkholderia cepacia complex species in cystic fibrosis patients in Argentina during the period 2011-2015.

Enferm Infecc Microbiol Clin. 2017 Oct 18;:

Authors: Cipolla L, Rocca F, Martinez C, Aguerre L, Barrios R, Prieto M

Abstract
INTRODUCTION: Burkholderia cepacia (B. cepacia) complex is composed of 20 phylogenetically closely related bacterial species. Some species have emerged as opportunistic pathogens in immunocompromised patients and are responsible for nosocomial outbreaks. The B. cepacia complex is a recognized respiratory pathogen in patients with cystic fibrosis. Burkholderia cenocepacia and Burkholderia multivorans (B. multivorans) are the most prevalent species in the world, according to the literature. However, research groups in Argentina have described a particular local epidemiology, with prevalence of Burkholderia contaminans (B. contaminans).
METHODS: A total of 68 isolates of B. cepacia complex recovered of 46 cystic fibrosis patients attended at 14 hospitals distributed in 9 provinces of the country were studied. Identification was carried out by conventional phenotypic methods and was confirmed by recA gene sequencing. Sequences were analysed using the BLASTN program and comparing with B. cepacia complex type strains sequences deposited in GenBank. Antibiotic susceptibility tests were performed on isolates of the most prevalent species according to CLSI M45 guidelines.
RESULTS: The prevalent specie was B. contaminans (49%, n = 33) followed by B. cenocepacia (25%; n = 17). The remaining species were Burkholderia seminalis (B. seminalis) (7%, n = 5), B. cepacia (7%, n = 5), B. multivorans (6%, n = 4), Burkholderia vietnamensis (5%, n=3) and Burkholderia pyrrocinia (1%; n = 1). The 46% of B. contaminans isolates were resistant to SXT and 76% sensitive to MIN, MEM and CAZ. The isolates of B. cenocepacia were 100% resistant to SXT and MIN and 47% to CAZ and MEM. B. seminalis showed high levels of resistance to TMS (80%), CAZ (60%) and MIN (60%), and 60% of the isolates showed intermediate sensitivity to MEM.
CONCLUSION: Previous reports have described the prevalence of B. contaminans isolation from cystic fibrosis patients in Argentina, Spain and Portugal, and a case of two patients with cystic fibrosis in Ireland has recently been reported. Due to the high frequency with which B. contaminans is isolated in our country, it is necessary to promote the investigation of possible sources of infection and to understand the factors and mechanisms involved in the apparent greater transmissibility of this species. Different antimicrobial resistance profiles were detected between the species.

PMID: 29055510 [PubMed - as supplied by publisher]

Singing as an adjunct therapy for children and adults with cystic fibrosis.

Int J Nurs Stud. 2017 Sep 15;:

Authors: Whitehead L, Arabiat RND, Foster M

PMID: 29055499 [PubMed - as supplied by publisher]

Vitamin K deficit and elastolysis theory in pulmonary elasto-degenerative diseases.

Med Hypotheses. 2017 Oct;108:38-41

Authors: Janssen R, Vermeer C

Abstract
Elastin is a unique protein providing deformability and resilience to dynamic tissues, such as arteries and lungs. It is an absolute basic requirement for circulation and respiration. Elastin can be degraded by elastases and has a high calcium affinity. Elastin calcification and elastin degradation are two pathological processes that impair elastin's functioning. Furthermore, elastin degradation can be associated to elastin calcification. Matrix Gla Protein (MGP) is probably the most potent natural inhibitor of elastin calcification and requires vitamin K for its activation. Measuring circulating levels of inactive MGP (dp-ucMGP) is a frequently used method to assess vitamin K status. Dp-ucMGP reflects the burden of vitamin K-dependent proteins that have not been activated by vitamin K and could therefore best be regarded as a biomarker of a vitamin K deficit. Dp-ucMGP levels decrease after vitamin K supplementation. Since the amino acids desmosine and isodesmosine (DES) are unique to crosslinked elastin fibers, systemic elastin degradation can be assessed with the plasma DES assay. Recently, we discovered a strong correlation between plasma dp-ucMGP and plasma DES levels in both patients with chronic obstructive pulmonary disease (COPD) and controls. The 'Vitamin K deficit and elastolysis theory' posits that elastin degradation causes a rise in the vitamin K deficit and implies that vitamin K supplementation could be preventing elastin degradation. If this hypothesis holds true and is universally found in every state and condition, it will have an unprecedented impact on the management of every single pulmonary disease characterized by accelerated elastin degradation, such as alpha-1 antitrypsin deficiency, bronchiectasis, COPD and cystic fibrosis. Theoretically, a plasma dp-ucMGP concentration of zero would be associated with a near-complete standstill of elastin degradation and disease progression in patients with any of these debilitating conditions.

PMID: 29055397 [PubMed - in process]

Correcting CFTR folding defects by small-molecule correctors to cure cystic fibrosis.

Curr Opin Pharmacol. 2017 Oct 18;34:83-90

Authors: Mijnders M, Kleizen B, Braakman I

Abstract
Pharmacological intervention to treat the lethal genetic disease cystic fibrosis has become reality, even for the severe, most common folding mutant F508del CFTR. CFTR defects range from absence of the protein, misfolding that leads to degradation rather than cell-surface localization (such as F508del), to functional chloride-channel defects on the cell surface. Corrector and potentiator drugs improve cell-surface location and channel activity, respectively, and combination therapy of two correctors and a potentiator have shown synergy. Several combinations are in the drug-development pipeline and although the primary defect is not repaired, rescue levels are reaching those resembling a cure for CF. Combination therapy with correctors may also improve functional CFTR mutants and benefit patients on potentiator therapy.

PMID: 29055231 [PubMed - as supplied by publisher]

Cystic fibrosis transmembrane regulator haplotypes in households of patients with cystic fibrosis.

Gene. 2017 Oct 17;:

Authors: Furgeri DT, Marson FAL, Correia CAA, Ribeiro JD, Bertuzzo CS

Abstract
INTRODUCTION: Nearly 2000 mutations in the cystic fibrosis transmembrane regulator (CFTR) gene have been reported. The F508del mutation occurs in approximately 50-65% of patients with cystic fibrosis (CF). However, molecular diagnosis is not always possible. Therefore, silent polymorphisms can be used to label the mutant allele in households of patients with CF.
OBJECTIVE: To verify the haplotypes of four polymorphisms at the CFTR locus in households of patients with CF for pre-fertilization, pre-implantation, and prenatal indirect mutation diagnosis to provide better genetic counseling for families and patients with CF and to associate the genotypes/haplotypes with the F508del mutation screening.
METHODS: GATT polymorphism analysis was performed using direct polymerase chain reaction amplification, and the Mp6d-9, TUB09 and TUB18 polymorphism analyses were performed using restriction fragment length polymorphism.
RESULTS: Nine haplotypes were found in 37 CFTR alleles, and of those, 24 were linked with the F508del mutation and 13 with other CFTR mutations. The 6 (GATT), C (Mp6d-9), G (TUB09), and C (TUB18) haplotypes showed the highest prevalence (48%) of the mutant CFTR allele and were linked to the F508del mutation (64%). In 43% of households analyzed, at least one informative polymorphism can be used for the indirect diagnostic test.
CONCLUSION: CFTR polymorphisms are genetic markers that are useful for identifying the mutant CFTR alleles in households of patients with CF when it is not possible to establish the complete CFTR genotype. Moreover, the polymorphisms can be used for indirect CFTR mutation identification in cases of pre-fertilization, pre-implantation and prenatal analysis.

PMID: 29054758 [PubMed - as supplied by publisher]

Substitution of Yor1p NBD1 residues improves the thermal stability of Human Cystic Fibrosis Transmembrane Conductance Regulator.

Protein Eng Des Sel. 2017 Oct 19;:1-13

Authors: Xavier BM, Hildebrandt E, Jiang F, Ding H, Kappes JC, Urbatsch IL

Abstract
The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a plasma membrane chloride channel protein that regulates vertebrate fluid homeostasis. The inefficiency of wild type human CFTR protein folding/trafficking is exacerbated by genetic mutations that can cause protein misfolding in the endoplasmic reticulum (ER) and subsequent degradation. This project investigates small changes in protein sequence that can alter the thermal stability of the large multi-domain CFTR protein. We target a conserved 70-residue α-subdomain located in the first nucleotide-binding domain that hosts the common misfolding mutation ∆F508. To investigate substitutions that can stabilize this domain, we constructed chimeras between human CFTR and its closest yeast homolog Yor1p. The α-subdomain of Yor1p was replaced with that of CFTR in Saccharomyces cerevisiae. Cellular localization of green fluorescence protein-tagged Yor1p-CFTR chimeras was analyzed by fluorescence microscopy and quantitative multispectral imaging flow cytometry, steady-state protein levels were compared by SDS-PAGE and protein function probed by a phenotypic oligomycin resistance assay. The chimeras exhibited ER retention in yeast characteristic of defective protein folding/processing. Substitution of seven CFTR α-subdomain residues that are highly conserved in Yor1p and other transporters but differ in CFTR (S495P/R516K/F533L/A534P/K536G/I539T/R553K) improved Yor1p-CFTR chimera localization to the yeast plasma membrane. When introduced into human CFTR expressed in mammalian cells, the same substitutions improve the purified protein thermal stability. This stabilized human CFTR protein will be directly useful for structural and biophysical studies that have been limited by the thermal sensitivity of wild type CFTR. The insights into critical structural residues within CFTR could facilitate development of effective therapeutics for CF-causing mutations.

PMID: 29053845 [PubMed - as supplied by publisher]

Tailored Approach to Surgical Exposure Reduces Surgical Site Complications after Bilateral Lung Transplantation.

Surg Infect (Larchmt). 2017 Oct 20;:

Authors: Elde S, Huddleston S, Jackson S, Kelly R, Shumway S, Loor G

Abstract
BACKGROUND: We evaluated the effects of tailoring the operative approach on major surgical site complications and outcomes in lung transplant recipients.
PATIENTS AND METHODS: Beginning in July 2013, bilateral lung transplants at a single institution were performed either through sternotomy or clamshell depending on proximity of hilar structures by computed tomography (CT), anticipated complexity, past surgical history, and surgeon experience. Patient demographics and outcomes were collected in the institution's Transplant Information Services (TIS). A major surgical site complication was defined as a sterile or infected incision requiring operative intervention.
RESULTS: One hundred six bilateral lung transplants (68 via clamshell and 38 via median sternotomy) were performed between July 2013 and June 2016. Median sternotomy patients were older (mean age 55 vs. 50 y, p = 0.04), and less likely to have cystic fibrosis (5 [13%] vs. 19 [28%], p = 0.21) or diabetes (5 [13%] vs. 26 [38%], p = 0.01). There was no statistically significant difference in mean lung allocation score (LAS) (45 vs. 48, p = 0.39) and body mass index (BMI; kg/m(2); 25.3 vs. 24.4, p = 0.29) between the sternotomy and clamshell group. Fifteen (14.2%) patients experienced a total of 25 surgical site complications (19 major and 6 minor). No sternotomy patient had a major surgical site complication and 11 (16.2%) clamshell patients had a major surgical site complication (p = 0.01). Of these 11 patients, 5 (45%) required multiple operative revisions related to the surgical site. Freedom from major surgical site complications at three years was 100% for sternotomy patients and 80% for clamshell patients (p = 0.017).
CONCLUSIONS: Tailoring the operative approach can reduce surgical site complications in lung transplant patients by avoiding a clamshell whenever feasible.

PMID: 29053438 [PubMed - as supplied by publisher]

Aerosolizing Lipid Dispersions Enables Antibiotic Transport Across Mimics of the Lung Airway Surface Even in the Presence of Pre-existing Lipid Monolayers.

J Aerosol Med Pulm Drug Deliv. 2017 Oct 20;:

Authors: Iasella SV, Stetten AZ, Corcoran TE, Garoff S, Przybycien TM, Tilton RD

Abstract
BACKGROUND: Secondary lung infections are the primary cause of morbidity associated with cystic fibrosis lung disease. Aerosolized antibiotic inhalation is potentially advantageous but has limited effectiveness due to altered airway aerodynamics and deposition patterns that limit drug access to infected regions. One potential strategy to better reach infected areas is to formulate aerosols with surfactants that induce surface tension gradients and drive postdeposition drug dispersal via Marangoni transport along the airway surface liquid (ASL). Since this relies on surfactant-induced surface tension reduction, the presence of endogenous lipid monolayers may hinder drug dispersal performance.
METHODS: Tobramycin solutions were formulated with dipalmitoylphosphatidylcholine (DPPC), a major component of endogenous pulmonary surfactant, to drive postdeposition aerosol dispersal across a model ASL based on a liquid layer or "subphase" of aqueous porcine gastric mucin (PGM) solution with predeposited DPPC monolayers to mimic the endogenous surfactant. In vitro subphase samples were collected from regions outside the aerosol deposition zone and assayed for tobramycin concentration using a closed enzyme donor immunoassay. The motion of a tracking bead across the subphase surface and the corresponding decrease in surface tension on aerosol deposition were tracked both with and without a predeposited DPPC monolayer. The surface tension/area isotherm for DPPC on PGM solution subphase was measured to aid in the interpretation of the tobramycin dispersal behavior.
RESULTS AND CONCLUSIONS: Transport of tobramycin away from the deposition region occurs in aerosols formulated with DPPC whether or not predeposited lipid is present, and tobramycin concentrations are similar in both cases across biologically relevant length scales (∼8 cm). When DPPC is deposited from an aerosol, it induces ultralow surface tensions (<5 mN/m), which drive Marangoni flows, even in the presence of a dense background layer of DPPC. Therefore, aerosolized phospholipids, such as DPPC, will likely be effective spreading agents in the human lung.

PMID: 29053080 [PubMed - as supplied by publisher]

Genome-wide association study identifies the SERPINB gene cluster as a susceptibility locus for food allergy.

Nat Commun. 2017 Oct 20;8(1):1056

Authors: Marenholz I, Grosche S, Kalb B, Rüschendorf F, Blümchen K, Schlags R, Harandi N, Price M, Hansen G, Seidenberg J, Röblitz H, Yürek S, Tschirner S, Hong X, Wang X, Homuth G, Schmidt CO, Nöthen MM, Hübner N, Niggemann B, Beyer K, Lee YA

Abstract
Genetic factors and mechanisms underlying food allergy are largely unknown. Due to heterogeneity of symptoms a reliable diagnosis is often difficult to make. Here, we report a genome-wide association study on food allergy diagnosed by oral food challenge in 497 cases and 2387 controls. We identify five loci at genome-wide significance, the clade B serpin (SERPINB) gene cluster at 18q21.3, the cytokine gene cluster at 5q31.1, the filaggrin gene, the C11orf30/LRRC32 locus, and the human leukocyte antigen (HLA) region. Stratifying the results for the causative food demonstrates that association of the HLA locus is peanut allergy-specific whereas the other four loci increase the risk for any food allergy. Variants in the SERPINB gene cluster are associated with SERPINB10 expression in leukocytes. Moreover, SERPINB genes are highly expressed in the esophagus. All identified loci are involved in immunological regulation or epithelial barrier function, emphasizing the role of both mechanisms in food allergy.

PMID: 29051540 [PubMed - in process]

Breathing Easier; a Well-tolerated Corrector for F508del.

Am J Respir Crit Care Med. 2017 Oct 19;:

Authors: Nichols DP

PMID: 29048931 [PubMed - as supplied by publisher]

Family-centred care for families living with cystic fibrosis in a rural setting: A qualitative study.

J Clin Nurs. 2017 Oct 19;:

Authors: Jessup M, Smyth W, Abernethy G, Shields L, Douglas T, AREST-CF

Abstract
AIMS AND OBJECTIVES: This study aimed to explore experience of family-centred care among parents of children with cystic fibrosis living far from tertiary treatment centres and to understand what such distances mean to their care.
BACKGROUND: Australia is a large continent. However, many families with a child with cystic fibrosis live in regional areas, often thousands of kilometres away from the primary treatment centres located in Australia's coastal capital cities.
DESIGN: A qualitative, phenomenological design utilising a van Manen (1990) approach.
METHODS: Individual, semi-structured interviews were conducted with parents (n=7) of a child with cystic fibrosis who lived in regional Australia. Thematic content data analysis was used.
RESULTS: The essence of the participants' experience was their seeking certainty and continuity in the changeable realm of cystic fibrosis while negotiating a collaborative approach to their child's care. Five core themes and two subthemes were identified: 'Daily care: a family affair', including the subtheme 'Accessing expert care'; 'Family centred care: seeking inclusion'; 'Control versus collaboration: seeking mutual trust', with the subtheme 'The team who grows with you'; 'Future projections'; and 'The CF circle'.
CONCLUSION: Some concerns are not unlike those of their city counterparts, but can be intensified by their sense of distance and isolation. This article is protected by copyright. All rights reserved.

PMID: 29048768 [PubMed - as supplied by publisher]

Use of taurolidine in lung transplantation for cystic fibrosis and impact on bacterial colonization.

Eur J Cardiothorac Surg. 2017 Oct 18;:

Authors: Zeriouh M, Sabashnikov A, Patil NP, Schmack B, Zych B, Mohite PN, García Sáez D, Koch A, Mansur A, Soresi S, Weymann A, Marczin N, Wahlers T, De Robertis F, Simon AR, Popov AF

Abstract
OBJECTIVES: The presence of bacterial colonization that causes chronic pulmonary infections in cystic fibrosis (CF) patients remains a key issue before lung transplantation. We sought to assess the impact of intraoperative taurolidine lavage on bacterial colonization and long-term outcomes following lung transplantation in CF patients.
METHODS: Between 2007 and 2013, 114 CF patients underwent lung transplantation at our institute, and taurolidine 2% bronchial lavage was applied in a substantial proportion of patients (n = 42). A detailed analysis of donor and recipient bacterial colonization status in treatment and control groups and their impact on outcome was performed.
RESULTS: The proportion of recipients colonized with Pseudomonas aeruginosa was lower in the taurolidine group at 3 months (P < 0.001) and at 1 year (P = 0.053) postoperatively, despite no differences before transplant (P = 1.000). Moreover, a complete eradication of Burkholderia cepacia and Stenotrophomonas maltophilias colonizations could be achieved in the taurolidine group, whereas in the non-taurolidine group, persistent B. cepacia and S. maltophilias colonizations were observed. Early outcome in the taurolidine group was superior regarding fraction of expired volume in 1 s at 3 and 6 months after surgery with 74.5 ± 14.6 vs 60.4 ± 17.5 (P < 0.001) and 80.6 ± 16.9 vs 67.2 ± 19.4 (P = 0.005) percent of predicted values, respectively. In terms of long-term overall survival (P = 0.277) and freedom from bronchiolitis obliterans syndrome (P = 0.979), both groups were comparable.
CONCLUSIONS: Taurolidine might be associated with a reduced proportion of CF patients colonized with multiresistant pathogens, particularly with P. aeruginosa. Long-term results should be further assessed in larger multicentre trials.

PMID: 29048473 [PubMed - as supplied by publisher]

Multifocal Fixed Drug Eruption to ceftazidime in a child with cystic fibrosis.

Pediatr Allergy Immunol. 2017 Oct 19;:

Authors: Ben Mansour A, Bellon N, Frassati-Biaggi A, Sermet-Gaudelus I, Ponvert C, de Blic J, Lezmi G

Abstract
Fixed drug eruption (FDE) is a cutaneous adverse drug reaction characterized by well-delimited pigmented lesions of the skin and/or mucosa [1,2]. FDE is rare and frequently misdiagnosed leading to recurrent eruptions after the offending drug is re-administered [1,2]. The diagnosis hallmark is its recurrence in previously affected sites leading to a residual hyperpigmentation, however some cases without residual pigmentation have been described [2]. Many drugs have been shown to induce FDE, especially antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs) [3]. To our knowledge, there is no report of FDE to ceftazidime. This article is protected by copyright. All rights reserved.

PMID: 29047164 [PubMed - as supplied by publisher]

Enhancement of lung gene delivery after aerosol: a new strategy using non-viral complexes with antibacterial properties.

Biosci Rep. 2017 Oct 18;:

Authors: Mottais A, Le Gall T, Sibiril Y, Ravel J, Laurent V, d'Arbonneau F, Montier T

Abstract
The pathophysiology of obstructive pulmonary diseases, such as cystic fibrosis, leads to the development of chronic infections in the respiratory tract. Thus, the symptomatic management of the disease requires, in particular, repetitive antibiotherapy. Besides these antibacterial treatments, certain pathologies, such as cystic fibrosis or chronic obstructive pulmonary disease, require the intake of many drugs. This simultaneous absorption may lead to undesired drug interactions. For example, Orkambi® (lumacaftor/Ivacaftor, Vertex), a pharmacological drug employed to treat F508del patients, cannot be used with antibiotics such as rifampicin or rifabutin (rifamycin family) which are necessary to treat Mycobacteriaceae. As far as gene therapy is concerned, bacteria and/or biofilm in the airways present an additional barrier for gene transfer. Thus, aerosol administrations of nanoparticles have to overcome many obstacles before allowing a cellular penetration of therapeutic compounds. This review focuses on the development of aerosol formulations adapted to the respiratory tract and its multiple barriers. Then, formulations that are currently used in clinical applications are summarized depending on the active molecule delivered. Finally, we focus on new therapeutic approaches to reduce possible drug interactions by transferring the antibacterial activity to the nanocarrier while ensuring the transfection efficiency.

PMID: 29046368 [PubMed - as supplied by publisher]

The shedding-derived soluble receptor for advanced glycation endproducts sustains inflammation during acute Pseudomonas aeruginosa lung infection.

Biochim Biophys Acta. 2017 02;1861(2):354-364

Authors: Antonelli A, Di Maggio S, Rejman J, Sanvito F, Rossi A, Catucci A, Gorzanelli A, Bragonzi A, Bianchi ME, Raucci A

Abstract
BACKGROUND: The membrane-bound isoform of the receptor for advanced glycation end products (FL-RAGE) is primarily expressed by alveolar epithelial cells and undergoes shedding by the protease ADAM10, giving rise to soluble cleaved RAGE (cRAGE). RAGE has been associated with the pathogenesis of several acute and chronic lung disorders. Whether the proteolysis of FL-RAGE is altered by a given inflammatory stimulus is unknown. Pseudomonas aeruginosa causes nosocomial infections in hospitalized patients and is the major pathogen associated with chronic lung diseases.
METHODS: P. aeruginosa was injected in Rage-/- and wild-type mice and the impact on RAGE expression and shedding, levels of inflammation and bacterial growth was determined.
RESULTS: Acute P. aeruginosa lung infection in mice induces a reduction of the active form of ADAM10, which determines an increase of FL-RAGE expression on alveolar cells and a concomitant decrease of pulmonary cRAGE levels. This was associated with massive recruitment of leukocytes and release of pro-inflammatory factors, tissue damage and relocation of cRAGE in the alveolar and bronchial cavities. The administration of sRAGE worsened bacterial burden and neutrophils infiltration. RAGE genetic deficiency reduced the susceptibility to P. aeruginosa infection, mitigating leukocyte recruitment, inflammatory molecules production, and bacterial growth.
CONCLUSIONS: These data are the first to suggest that inhibition of FL-RAGE shedding, by affecting the FL-RAGE/cRAGE levels, is a novel mechanism for controlling inflammation to acute P. aeruginosa pneumonia. sRAGE in the alveolar space sustains inflammation in this setting.
GENERAL SIGNIFICANCE: RAGE shedding may determine the progression of inflammatory lung diseases.

PMID: 27913191 [PubMed - indexed for MEDLINE]

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F508del CFTR gene mutation in patients with allergic bronchopulmonary aspergillosis.

J Asthma. 2017 Oct 16;:1-7

Authors: Gamaletsou MN, Hayes G, Harris C, Brock J, Muldoon EG, Denning DW

Abstract
OBJECTIVE: The F508del mutation occurs in approximately 3.5% of Caucasian population of Northern Europe. Heterozygotes have increased risk for asthma and reduced pulmonary function. Allergic bronchopulmonary aspergillosis (ABPA) is more common in patients with cystic fibrosis (CF). We aimed to establish the frequency of F508del mutation in adult patients with ABPA.
METHODS: A retrospective matched case-control study of CF genotyped patients with ABPA seen at the National Aspergillosis Centre was undertaken. Key data were collected retrospectively from medical records, including respiratory comorbidities, total IgE, Aspergillus IgG and IgE, and immunoglobulins. Cystic fibrosis transmembrane regulator (CFTR) gene mutation analysis included multiplex PCR and sequencing.
RESULTS: From a cohort of 189 ABPA patients, 156 were screened for common mutations and variants in the CFTR gene. Eighteen were heterozygous for at least one CFTR mutation; 12 (7.7%) were heterozygous for the F508del, notably; 3 were heterozygous for the intron 8 5T variant; and 1 for an intronic variant of uncertain significance, c.3139 + 18C>T. Eight (67%) had asthma, 7 (58%) had CT-defined bronchiectasis, 4 (33%) hypergammaglobulinemia (>16 g/L), 3 (25%) sinusitis and 1 (8%) chronic pulmonary aspergillosis. Eight (67%) had elevated Aspergillus IgG antibodies (42-98 mg/L), and 8 (67%) had total IgE above 1,000 KIU/L. Two individuals heterozygous for the F508del mutation and the TG12T5 variant were diagnosed with CF, leading to a de novo CF discovery rate of 1.3%.
CONCLUSIONS: In our ABPA patient cohort, the presence of the delta F508 mutation was higher than that seen in general population. Genetic counseling for CFTR genotyping might be appropriate for these patients.

PMID: 29035608 [PubMed - as supplied by publisher]

Homogeneity of Aerosol Deposition and Mucociliary Clearance are Improved Following Ivacaftor Treatment in Cystic Fibrosis.

J Aerosol Med Pulm Drug Deliv. 2017 Oct 16;:

Authors: Bennett WD, Zeman KL, Laube BL, Wu J, Sharpless G, Mogayzel PJ, Donaldson SH

Abstract
BACKGROUND: Using planar gamma scintigraphy of inhaled radioaerosols, we have developed new analytical methods for assessing homogeneity of aerosol deposition and time-dependent particle clearance on a pixel-by-pixel basis, and applied them to a therapeutic cystic fibrosis (CF) study.
METHODS: At baseline and 1 month after beginning treatment with ivacaftor, a cystic fibrosis transmembrane regulator modulator for CF patients with at least one copy of the G551D mutation (n = 13), initial deposition and subsequent mucociliary clearance (MCC) of radiolabeled particles ((99m)Technetium-sulfur colloid, 5 μm mass median aerodynamic diameter) inhaled under controlled breathing conditions were measured.
RESULTS: Improved homogeneity of deposition, that is, decreased areas of higher and lower particle deposition in the lungs, was observed following ivacaftor treatment. The mean number ratio (NR) of pixels with higher deposition, relative to lung size, decreased from 0.14 to 0.09 (p = 0.003) and mean NR of colder pixels decreased from 0.23 to 0.19 (p = 0.004). Particle clearance was also improved following treatment, with mean MCC through 60 minutes equal to 12% versus 24%, without and with treatment, respectively (p = 0.010). Pixel-level analysis of MCC showed that (1) the fraction of pixels clearing >30% at 60 minutes was increased from 0.13 to 0.32 (p = 0.007); and (2) the fraction of pixels clearing <5% at 60 minutes was decreased from 0.54 to 0.37 (p = 0.014), indicating an overall recruitment of more fast-clearing lung regions with ivacaftor treatment.
CONCLUSION: These detailed pixel analyses of deposition and clearance homogeneity may supplement traditional methods that use large regions of interest for assessing efficacy and mechanisms of therapeutic intervention in patients with airways disease.

PMID: 29035122 [PubMed - as supplied by publisher]