Combined lung-liver-pancreas transplantation in a recipient with cystic fibrosis.

J Cyst Fibros. 2017 May 23;:

Authors: Barbas AS, Dib MJ, Al-Adra DP, Goldaracena N, Sapisochin G, Waddell TK, Keshavjee S, Selzner N, Chaparro C, Cattral MS

Abstract
Cystic fibrosis (CF) affects multiple organs including the lung, liver, and pancreas. Lung transplant, liver transplant, and combined lung-liver transplant have become well-established therapies for CF patients with end-stage organ failure. Thus far, however, there has been limited experience with pancreas transplantation in CF. In this report, we detail the clinical history, transplant procedure, and post-operative recovery of a patient who underwent combined lung-liver-pancreas transplant for advanced CF.

PMID: 28549610 [PubMed - as supplied by publisher]

Development and validation of CF-Medication Beliefs Questionnaire: A mixed-methods approach.

J Cyst Fibros. 2017 May 23;:

Authors: Eakin MN, Chung SE, Hoehn J, Borrelli B, Rand-Giovannetti D, Riekert KA

Abstract
BACKGROUND: Beliefs about medication have been associated with adherence in other diseases but there are no existing disease-specific medication beliefs questionnaires for CF. This mixed-methods validated the Cystic Fibrosis Medication Belief Questionnaire (CF-MBQ), based on social cognitive theory.
METHODS: Based on previous research, items were developed for five domains: motivation, self-efficacy, perceived importance, and decisional balance to take or miss medications. Cognitive interviews were conducted with 15 adult patients with CF to refine item development. 128 patients with CF completed an online survey and objective medication adherence was measured using pharmacy refill data.
RESULTS: The five subscales demonstrated strong psychometric properties, with adequate-to-good internal consistency scores. More importantly, each domain demonstrated construct validity with adherence.
CONCLUSIONS: These theoretically-derived measures may be important for clinical purposes to provide guidance on appropriate interventions to improve adherence and for research to provide enhanced understanding on patient determinants of medication adherence.

PMID: 28549609 [PubMed - as supplied by publisher]

Regulatory dynamics of 11p13 suggest a role for EHF in modifying CF lung disease severity.

Nucleic Acids Res. 2017 May 26;:

Authors: Stolzenburg LR, Yang R, Kerschner JL, Fossum S, Xu M, Hoffmann A, Lamar KM, Ghosh S, Wachtel S, Leir SH, Harris A

Abstract
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), but are not good predictors of lung phenotype. Genome-wide association studies (GWAS) previously identified additional genomic sites associated with CF lung disease severity. One of these, at chromosome 11p13, is an intergenic region between Ets homologous factor (EHF) and Apaf-1 interacting protein (APIP). Our goal was to determine the functional significance of this region, which being intergenic is probably regulatory. To identify cis-acting elements, we used DNase-seq and H3K4me1 and H3K27Ac ChIP-seq to map open and active chromatin respectively, in lung epithelial cells. Two elements showed strong enhancer activity for the promoters of EHF and the 5΄ adjacent gene E47 like ETS transcription factor 5 (ELF5) in reporter gene assays. No enhancers of the APIP promoter were found. Circular chromosome conformation capture (4C-seq) identified direct physical interactions of elements within 11p13. This confirmed the enhancer-promoter associations, identified additional interacting elements and defined topologically associating domain (TAD) boundaries, enriched for CCCTC-binding factor (CTCF). No strong interactions were observed with the APIP promoter, which lies outside the main TAD encompassing the GWAS signal. These results focus attention on the role of EHF in modifying CF lung disease severity.

PMID: 28549169 [PubMed - as supplied by publisher]

Outbreaks of nontuberculous mycobacteria.

Curr Opin Infect Dis. 2017 May 25;:

Authors: Sood G, Parrish N

Abstract
PURPOSE OF REVIEW: The purpose of this review is to summarize the emerging literature on nontuberculous mycobacteria outbreaks in healthcare settings. As our ability to identify mycobacterial species develops, we are better able to recognize epidemiologic connections and better understand the prevalence and importance of these outbreaks and pseudo-outbreaks in healthcare settings.
RECENT FINDINGS: The number of outbreaks related to nontuberculous outbreaks is increasing because of heightened awareness and better diagnostic tests for species level identification of mycobacteria. Outbreaks in healthcare settings have been related to cardiac surgery, plastic surgery, including medical tourism, colonized humidifiers and heater-cooler devices, imperfect disinfection, and hospital water sources. Mycobacteria have a predilection to form biofilms, are resistant to disinfection and are prevalent in hospital water systems. Patients with structural lung disease like cystic fibrosis patients are at particularly high risk for mycobacterial infection. It has been thought that acquisition in this patient population is from common environmental exposure; however, there is increasing evidence that transmission in this patient population can occur through either direct or indirect patient-to-patient spread.
SUMMARY: Mycobacteria outbreaks in healthcare settings have been underrecognized. As we identify additional clusters of infection with better diagnostic tools and heightened awareness, we will likely need better infection control practices to prevent infections in healthcare settings.

PMID: 28548990 [PubMed - as supplied by publisher]

Co-evolution with Staphylococcus aureus leads to lipopolysaccharide alterations in Pseudomonas aeruginosa.

ISME J. 2017 May 26;:

Authors: Tognon M, Köhler T, Gdaniec BG, Hao Y, Lam JS, Beaume M, Luscher A, Buckling A, van Delden C

Abstract
Detrimental and beneficial interactions between co-colonizing bacteria may influence the course of infections. In cystic fibrosis (CF) airways, Staphylococcus aureus prevails in childhood, whereas Pseudomonas aeruginosa progressively predominates thereafter. While a range of interactions has been identified, it is unclear if these represent specific adaptations or correlated responses to other aspects of the environment. Here, we investigate how P. aeruginosa adapts to S. aureus by evolving P. aeruginosa in the presence and absence of S. aureus. P. aeruginosa populations that evolved for 150 generations were sequenced and compared to the ancestor strain. Mutations in the Wsp signaling system were identified in both treatments and likely occurred because of low oxygen availability. Despite showing increased killing activity, wsp mutants were less fit in the presence of S. aureus. In contrast, mutations in lipopolysaccharide (LPS) biosynthesis occurred exclusively in co-cultures with S. aureus and conferred a fitness gain in its presence. Moreover, they increased resistance towards beta-lactam antibiotics. Strikingly, both mutations in wsp and LPS genes are observed in clinical isolates from CF-patients. Our results suggest that P. aeruginosa LPS mutations are a direct consequence of S. aureus imposed selection in vitro.The ISME Journal advance online publication, 26 May 2017; doi:10.1038/ismej.2017.83.

PMID: 28548661 [PubMed - as supplied by publisher]

Immunosuppression Drug Therapy in Lung Transplantation for Cystic Fibrosis.

Paediatr Drugs. 2017 May 25;:

Authors: Burcham P, Sarzynski L, Khalfoun S, Novak KJ, Miller JC, Tumin D, Hayes D

Abstract
Cystic fibrosis (CF) is a common indication for lung transplantation (LTx) in children and adults with severe and irreversible lung disease. In the setting of LTx in the CF population, immunosuppressive medications are used to prevent allograft rejection despite the majority of these patients being chronically infected with numerous, and often antibiotic-resistant, pathogens. There is limited evidence for the optimal post-LTx immunosuppression regimen in patients with CF, particularly in children. This article provides a review of immunosuppression regimens in the pediatric and adult CF post-LTx population, investigating drug dosing and monitoring, and medication combinations. Currently used immunosuppressive medications and related systemic adverse effects are reviewed. With limitations of data in the pediatric population, future research should address immunosuppression in these children to help guide pediatric drug management as a means to optimize clinical outcomes after LTx.

PMID: 28547678 [PubMed - as supplied by publisher]

Nationwide genetic analysis for molecularly unresolved cystic fibrosis patients in a multiethnic society: implications for preconception carrier screening.

Mol Genet Genomic Med. 2017 May;5(3):223-236

Authors: Behar DM, Inbar O, Shteinberg M, Gur M, Mussaffi H, Shoseyov D, Ashkenazi M, Alkrinawi S, Bormans C, Hakim F, Mei-Zahav M, Cohen-Cymberknoh M, Dagan A, Prais D, Sarouk I, Stafler P, Bar Aluma BE, Akler G, Picard E, Aviram M, Efrati O, Livnat G, Rivlin J, Bentur L, Blau H, Kerem E, Singer A

Abstract
BACKGROUND: Preconception carrier screening for cystic fibrosis (CF) is usually performed using ethnically targeted panels of selected mutations. This has been recently challenged by the use of expanded, ethnically indifferent, pan-population panels. Israel is characterized by genetically heterogeneous populations carrying a wide range of CFTR mutations. To assess the potential of expanding the current Israeli preconception screening program, we sought the subset of molecularly unresolved CF patients listed in the Israeli CF data registry comprising ~650 patients.
METHODS: An Israeli nationwide genotyping of 152 CF cases, representing 176 patients lacking molecular diagnosis, was conducted. Molecular analysis included Sanger sequencing for all exons and splice sites, multiplex ligation probe amplification (MLPA), and next-generation sequencing of the poly-T/TG tracts.
RESULTS: We identified 54 different mutations, of which only 16 overlapped the 22 mutations included in the Israeli preconception screening program. A total of 29/54 (53.7%) mutations were already listed as CF causing by the CFTR2 database, and only 4/54 (7.4%) were novel. Molecular diagnosis was reached in 78/152 (51.3%) cases. Prenatal diagnosis of 24/78 (30.8%) cases could have been achieved by including all CFTR2-causing mutations in the Israeli panel.
CONCLUSIONS: Our data reveal an overwhelming hidden abundance of CFTR gene mutations suggesting that expanded preconception carrier screening might achieve higher preconception detection rates.

PMID: 28546993 [PubMed - in process]

Direct Binding of the Corrector VX-809 to human CFTR NBD1: Evidence of an Allosteric Coupling between the Binding Site and the NBD1:CL4 interface.

Mol Pharmacol. 2017 May 25;:

Authors: Hudson RP, Dawson JE, Chong PA, Yang Z, Millen L, Thomas PJ, Brouillette CG, Forman-Kay JD

Abstract
Understanding the mechanism of action of modulator compounds for the cystic fibrosis transmembrane conductance regulator (CFTR) is key for optimization of therapeutics as well as obtaining insights into the molecular mechanisms of CFTR function. We demonstrate direct binding of VX-809 to the first nucleotide-binding domain (NBD1) of human CFTR. Disruption of the interaction between C-terminal helices and the NBD1 core upon VX-809 binding is observed from chemical shift changes in the NMR spectra of residues in the helices and on the surface of β-strands S3, S9 and S10. Binding to VX-809 leads to a significant negative shift in NBD1 thermal melting temperature (Tm), pointing to direct VX-809 interaction shifting the NBD1 conformational equilibrium. An inter-residue correlation analysis of the chemical shift changes provides evidence of allosteric coupling between the direct binding site and the NBD1:CL4 interface, thus enabling effects on the interface in the absence of direct binding in that location. These NMR binding data and the negative Tm shifts are very similar to those previously reported by us for binding of the dual corrector-potentiator CFFT-001 to NBD1 (Hudson, Chong et al. 2012), suggesting that the two compounds may share some aspects of their mechanisms of action. While previous studies have shown an important role for VX-809 in modulating the conformation of the first membrane spanning domain (MSD1) (Aleksandrov, Kota et al. 2012, Ren, Grove et al. 2013), this additional mode of VX-809 binding provides insight into conformational dynamics and allostery within CFTR.

PMID: 28546419 [PubMed - as supplied by publisher]

Pediatric Lung Transplantation.

Respir Care. 2017 Jun;62(6):776-798

Authors: Sweet SC

Abstract
Pediatric lung transplant is a viable option for treatment of end-stage lung disease in children, with > 100 pediatric lung transplants reported to the Registry of the International Society of Heart and Lung Transplantation each year. Long-term success is limited by availability of donor organs, debilitation as a result of chronic disease, impaired mucus clearance resulting from both surgical and pharmacologic interventions, increased risk for infection resulting from immunosuppression, and most importantly late complications, such as chronic lung allograft dysfunction. Opportunities for investigation and innovation remain in all of these domains: (1) Ex vivo lung perfusion is a promising technology with the potential for increasing the lung donor pool, (2) evolving extracorporeal support strategies coupled with effective rehabilitation will effectively bridge critically ill patients to transplant, and most importantly, (3) research efforts intended to increase our understanding of the underlying mechanisms of chronic lung allograft dysfunction will ultimately lead to the development of effective therapies to prevent or treat the variety of chronic lung allograft dysfunction presentations.

PMID: 28546378 [PubMed - in process]

MRI of cystic fibrosis lung manifestations: sequence evaluation and clinical outcome analysis.

Clin Radiol. 2017 May 22;:

Authors: Scholz O, Denecke T, Böttcher J, Schwarz C, Mentzel HJ, Streitparth F, Maurer MH, Pfeil A, Huppertz A, Mehl A, Staab D, Hamm B, Renz DM

Abstract
AIM: To evaluate different magnetic resonance imaging (MRI) sequences for diagnosis of pulmonary manifestations of cystic fibrosis (CF) in comparison to chest computed tomography (CT), including an extended outcome analysis.
MATERIALS AND METHODS: Twenty-eight patients with CF (15 male, 13 female, mean age 30.5±9.4 years) underwent CT and MRI of the lung. MRI (1.5 T) included different T2- and T1-weighted sequences: breath-hold HASTE (half Fourier acquisition single shot turbo spin echo) and VIBE (volumetric interpolated breath-hold examination, before and after contrast medium administration) sequences and respiratory-triggered PROPELLER (periodically rotated overlapping parallel lines with enhanced reconstruction) sequences with and without fat signal suppression, and perfusion imaging. CT and MRI images were evaluated by the modified Helbich and the Eichinger scoring systems. The clinical follow-up analysis assessed pulmonary exacerbations within 24 months.
RESULTS: The highest concordance to CT was achieved for the PROPELLER sequences without fat signal suppression (concordance correlation coefficient CCC of the overall modified Helbich score 0.93 and of the overall Eichinger score 0.93). The other sequences had the following concordance: PROPELLER with fat signal suppression (CCCs 0.91 and 0.92), HASTE (CCCs 0.87 and 0.89), VIBE (CCCs 0.84 and 0.85) sequences. In the outcome analysis, the combined MRI analysis of all five sequences and a specific MRI protocol (PROPELLER without fast signal suppression, VIBE sequences, perfusion imaging) reached similar correlations to the number of pulmonary exacerbations as the CT examinations.
CONCLUSION: An optimum lung MRI protocol in patients with CF consists of PROPELLER sequences without fat signal suppression, VIBE sequences, and lung perfusion analysis to enable high diagnostic efficacy and outcome prediction.

PMID: 28545684 [PubMed - as supplied by publisher]

A simple, fast and inexpensive method for mutation scanning of CFTR gene.

BMC Med Genet. 2017 May 25;18(1):58

Authors: Figueredo Lago JE, Armas Cayarga A, González González YJ, Collazo Mesa T

Abstract
BACKGROUND: Mutation scanning methods in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene may not distinguish between a Cystic Fibrosis (CF) causing mutation and a benign variant. We have developed a simple and fast method for scanning 14 selected CF-causing mutations which have high frequency in Latin America.
METHODS: In a group of 35 samples coming from CF patients previously characterized and using two allele-specific real-time multiplex PCRs targeting wild-type and mutant alleles respectively, we detect the presence of mutations by analyzing the Ct variation. Twenty-five samples without mutations considered non-carrier samples, were also included in this study. High Resolution Melting Analysis (HRMA) was performed to confirm the result of the scanning method and in most cases allowed the genotype determination.
RESULTS: The results validate this method for CF diagnosis. A least one CFTR gene mutation was detected in the samples of CF patients, as predicted by their ΔCt values. The ΔCt value also indicated the zygosity of the sample according to the distribution of CFTR gene mutations. In most cases, HRMA allowed the identification of the mutation(s), thereby confirming the efficiency of this scanning strategy.
CONCLUSIONS: This strategy simplifies the detection of CF, reducing the analysis of 14 CF-causing mutations to two parallel reactions and making the procedure compatible with the analysis of a large number of samples. As the method is fast, inexpensive and highly reliable, it is advisable for scanning CFTR gene mutations in newborns, patients with a clinical suspicion of CF as well as in the preconception carrier screening.

PMID: 28545452 [PubMed - in process]

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Research and progress on ClC‑2 (Review).

Mol Med Rep. 2017 May 18;:

Authors: Wang H, Xu M, Kong Q, Sun P, Yan F, Tian W, Wang X

Abstract
Chloride channel 2 (ClC-2) is one of the nine mammalian members of the ClC family. The present review discusses the molecular properties of ClC‑2, including CLCN2, ClC‑2 promoter and the structural properties of ClC‑2 protein; physiological properties; functional properties, including the regulation of cell volume. The effects of ClC‑2 on the digestive, respiratory, circulatory, nervous and optical systems are also discussed, in addition to the mechanisms involved in the regulation of ClC‑2. The review then discusses the diseases associated with ClC‑2, including degeneration of the retina, Sjögren's syndrome, age‑related cataracts, degeneration of the testes, azoospermia, lung cancer, constipation, repair of impaired intestinal mucosa barrier, leukemia, cystic fibrosis, leukoencephalopathy, epilepsy and diabetes mellitus. It was concluded that future investigations of ClC‑2 are likely to be focused on developing specific drugs, activators and inhibitors regulating the expression of ClC‑2 to treat diseases associated with ClC‑2. The determination of CLCN2 is required to prevent and treat several diseases associated with ClC‑2.

PMID: 28534947 [PubMed - as supplied by publisher]

Differences in Gene Expression Profiles between Early and Late Isolates in Monospecies Achromobacter Biofilm.

Pathogens. 2017 May 19;6(2):

Authors: Nielsen SM, Meyer RL, Nørskov-Lauritsen N

Abstract
Bacteria of genus Achromobacter are emerging pathogens in cystic fibrosis (CF) capable of biofilm formation and development of antimicrobial resistance. Evolutionary adaptions in the transition from primary to chronic infection were assessed by transcriptomic analysis of successive isolates of Achromobacter xylosoxidans from a single CF patient. Several efflux pump systems targeting antimicrobial agents were upregulated during the course of the disease, whereas all genes related to motility were downregulated. Genes annotated to subsystems of sulfur metabolism, protein metabolism and potassium metabolism exhibited the strongest upregulation. K+ channel genes were hyperexpressed, and a putative sulfite oxidase was more than 1500 times upregulated. The transcriptome patterns indicated a pivotal role of sulfur metabolism and electrical signalling in Achromobacter biofilms during late stage CF lung disease.

PMID: 28534862 [PubMed - in process]

Classical activation of macrophages and vardenafil.

Clin Sci (Lond). 2017 Jun 01;131(11):1141-1145

Authors: Muimo R

Abstract
Inhibitors of phosphodiesterase 5 (PDE5) - sildenafil citrate (Viagra; Pfizer) and vardenafil hydrochloride (Levitra; Bayer/GlaxoSmithKline) - approved for the treatment of erectile dysfunction and pulmonary arterial hypertension also rescue the loss of cystic fibrosis (CF) chloride channel function and the mislocalization of F508del-CFTR in affected tissues in CF. Can PDE5 inhibitors provide a therapeutic strategy which combines ability to correct the basic ion transport defect and to control de-regulated lung inflammation in CF?

PMID: 28533270 [PubMed - in process]

Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD.

PLoS Genet. 2016 Aug;12(8):e1006011

Authors: Sun W, Kechris K, Jacobson S, Drummond MB, Hawkins GA, Yang J, Chen TH, Quibrera PM, Anderson W, Barr RG, Basta PV, Bleecker ER, Beaty T, Casaburi R, Castaldi P, Cho MH, Comellas A, Crapo JD, Criner G, Demeo D, Christenson SA, Couper DJ, Curtis JL, Doerschuk CM, Freeman CM, Gouskova NA, Han MK, Hanania NA, Hansel NN, Hersh CP, Hoffman EA, Kaner RJ, Kanner RE, Kleerup EC, Lutz S, Martinez FJ, Meyers DA, Peters SP, Regan EA, Rennard SI, Scholand MB, Silverman EK, Woodruff PG, O'Neal WK, Bowler RP, SPIROMICS Research Group, COPDGene Investigators

Abstract
Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p < 8 X 10-10) pQTLs in 38 (43%) of blood proteins tested. Most pQTL SNPs were novel with low overlap to eQTL SNPs. The pQTL SNPs explained >10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10-392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group.

PMID: 27532455 [PubMed - indexed for MEDLINE]

Allergic Bronchopulmonary Aspergillosis in Cystic Fibrosis: MR Imaging of Airway Mucus Contrasts as a Tool for Diagnosis.

Radiology. 2017 May 22;:162350

Authors: Dournes G, Berger P, Refait J, Macey J, Bui S, Delhaes L, Montaudon M, Corneloup O, Chateil JF, Marthan R, Fayon M, Laurent F

Abstract
Purpose To assess the diagnostic accuracy of mucus contrast characterization by using magnetic resonance (MR) imaging to discriminate allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF). Materials and Methods The study was approved by the local Ethics Committee, and all patients or their parents gave written informed consent. One hundred ten consecutive patients with CF were screened between January 2014 and July 2015. All patients underwent a non-contrast material-enhanced MR protocol that included routine T1-weighted and T2-weighted sequences. The presence of mucus with both high T1 and low T2 signal intensities and the so-called inverted mucoid impaction signal (IMIS) sign was qualitatively and quantitatively assessed by two physicians who were blinded to all other data. The reference standard for a diagnosis of ABPA was the criteria of the Cystic Fibrosis Foundation Consensus Conference. ABPA status was followed up for 1 year. Reproducibility was assessed by using the κ test, correlation was assessed by using the Spearman coefficient, and diagnostic accuracy was assessed by calculating the sensitivity and specificity of IMIS. Results One hundred eight patients with CF were included (mean age, 20 years ± 11 [standard deviation]; range, 6-53 years): 18 patients with ABPA and 90 patients without ABPA. At the lobar level, inter- and intrareader reproducibility were very good (κ > 0.90). IMIS had 94% sensitivity (95% confidence interval [CI]: 73%, 99%) and 100% specificity (95% CI: 96%, 100%) for the diagnosis of ABPA. A complete resolution of IMIS was observed in patients with ABPA after 3 months of specific treatment that was significantly correlated with decrease in total immunoglobulin E level (ρ = 0.47; P = .04). Conclusion The IMIS sign was both specific and sensitive for the diagnosis of ABPA in CF. Allergic fungal inflammation appears to induce characteristic modifications of mucus contrasts that are assessable by using a noninvasive, contrast material-free, and radiation-free method. (©) RSNA, 2017 Online supplemental material is available for this article.

PMID: 28530849 [PubMed - as supplied by publisher]

EIT based pulsatile impedance monitoring during spontaneous breathing in cystic fibrosis.

Physiol Meas. 2017 Jun;38(6):1214-1225

Authors: Krueger-Ziolek S, Schullcke B, Gong B, Müller-Lisse U, Moeller K

Abstract
OBJECTIVE: Evaluating the lung function in patients with obstructive lung disease by electrical impedance tomography (EIT) usually requires breathing maneuvers containing deep inspirations and forced expirations. Since these maneuvers strongly depend on the patient's co-operation and health status, normal tidal breathing was investigated in an attempt to develop continuous maneuver-free measurements.
APPROACH: Ventilation related and pulsatile impedance changes were systematically analyzed during normal tidal breathing in 12 cystic fibrosis (CF) patients and 12 lung-healthy controls (HL). Tidal breaths were subdivided into three inspiratory (In1, In2, In3) and three expiratory (Ex1, Ex2, Ex3) sections of the same amplitude of global impedance change. Maximal changes of the ventilation and the pulsatile impedance signal occurring during these sections were determined (▵I V and ▵I P). Differences in ▵I V and ▵I P among sections were ascertained in relation to the first inspiratory section. In addition, ▵I V/▵I P was calculated for each section.
MAIN RESULTS: Medians of changes in ▵I V were  <0.05% in all sections for both subject groups. Both groups showed a similar pattern of ▵I P changes during tidal breathing. Changes in ▵I P first decreased during inspiration (In2), then increased towards the end of inspiration (In3) and reached a maximum at the beginning of expiration (Ex1). During the last two sections of expiration (Ex2, Ex3) ▵I P changes decreased. The CF patients showed higher variations in ▵I P changes compared to the controls (CF:  -426.5%, HL:  -158.1%, coefficient of variation). Furthermore, ▵I V/▵I P significantly differed between expiratory sections for the CF patients (Ex1-Ex2, p  <  0.01; Ex1-Ex3, p  <  0.001; Ex2-Ex3, p  <  0.05), but not for the controls. No significant differences in ▵I V/▵I P between inspiratory sections were determined for both groups.
SIGNIFICANCE: Differences in ▵I P changes and in ▵I V/▵I P between both subject groups were speculated to be caused by higher breathing efforts of the CF patients due to airway obstruction leading to higher intrathoracic pressures, and thus to greater changes in lung perfusion.

PMID: 28530203 [PubMed - in process]

[LONG TERM TREATMENT WITH MACROLIDES IN CHRONIC LUNG DISEASES].

Harefuah. 2016 Sep;155(9):567-571

Authors: Shteinberg M, Schneer S, Lavon O, Adir Y

Abstract
INTRODUCTION: Macrolide agents have both antibacterial properties as well as various effects on the inflammatory system. In recent years there is growing evidence regarding the favourable effects of macrolides in a range of chronic respiratory conditions. Historically, erythromycin and clarithromycin were found to stabilize pulmonary deterioration in diffuse panbronchiolitis. In cystic fibrosis patients colonized with pseudomonas aeruginosa, long term treatment with azithromycin reduces exacerbations and presents improved lung function. A similar effect on prevention of exacerbations has been demonstrated in noncystic fibrosis bronchiectasis. In patients undergoing lung transplantation, long term azithromycin prevents bronchiolitis obliterans syndrome. In patients with chronic obstructive pulmonary disease (COPD), azithromycin prevents acute exacerbations. Chronic treatment with macrolides is associated with adverse effects including gastrointestinal symptoms, interactions with other drugs and cardiovascular complications. Of the macrolides, azithromycin is associated with the lowest interactions and adverse effects and is also the most investigated.

PMID: 28530085 [PubMed - in process]

Role of the CXCL8-CXCR1/2 Axis in Cancer and Inflammatory Diseases.

Theranostics. 2017;7(6):1543-1588

Authors: Ha H, Debnath B, Neamati N

Abstract
The chemokine receptors CXCR1/2 and their ligand CXCL8 are essential for the activation and trafficking of inflammatory mediators as well as tumor progression and metastasis. The CXCL8-CXCR1/2 signaling axis is involved in the pathogenesis of several diseases including chronic obstructive pulmonary diseases (COPD), asthma, cystic fibrosis and cancer. Interaction between CXCL8 secreted by select cancer cells and CXCR1/2 in the tumor microenvironment is critical for cancer progression and metastasis. The CXCL8-CXCR1/2 axis may play an important role in tumor progression and metastasis by regulating cancer stem cell (CSC) proliferation and self-renewal. During the past two decades, several small-molecule CXCR1/2 inhibitors, CXCL8 releasing inhibitors, and neutralizing antibodies against CXCL8 and CXCR1/2 have been reported. As single agents, such inhibitors are expected to be efficacious in various inflammatory diseases. Several preclinical studies suggest that combination of CXCR1/2 inhibitors along with other targeted therapies, chemotherapies, and immunotherapy may be effective in treating select cancers. Currently, several of these inhibitors are in advanced clinical trials for COPD, asthma, and metastatic breast cancer. In this review, we provide a comprehensive analysis of the role of the CXCL8-CXCR1/2 axis and select genes co-expressed in this pathway in disease progression. We also discuss the latest progress in developing small-molecule drugs targeting this pathway.

PMID: 28529637 [PubMed - in process]