Factors associated with changes in health-related quality of life in children with cystic fibrosis during 1-year follow-up.

Eur J Pediatr. 2017 Jun 09;:

Authors: van Horck M, Winkens B, Wesseling G, de Winter-de Groot K, de Vreede I, Jöbsis Q, Dompeling E

Abstract
There are limited data on health-related quality of life (HRQoL) changes over time in children with cystic fibrosis (CF). We investigated associations between clinical and treatment variables with changes in HRQoL during 1 year. Forty-nine children with CF aged 6-18 years were followed in this multicentre, observational cohort study during 1 year. HRQoL was measured by the validated disease specific cystic fibrosis questionnaire-revised (CFQ-R). The CFQ-R total score as well as most domain scores improved significantly (8.0 points and [3.3-31.7] points respectively) during the one-year follow-up. Age at baseline demonstrated a strong longitudinal association with the change of CFQ-R total score (2.853 points decrease of CFQ-R total score per year increase in age) and several domain scores. Below 12 years of age, CFQ-R total score improved in most children, whereas a deterioration was observed in most children above 12 years. The number of PEx was associated with an increase of treatment burden score (4.466 points decrease per extra PEx).
CONCLUSION: In the group as a whole, HRQoL improved significantly over time. However, changes over time were significantly influenced by age: below 12 years of age, HRQoL improved in most patients whereas a deterioration was observed in most children >12 years. Strategies how to preserve or ideally to improve HRQoL in adolescence should be developed. What is known: • Quality of life in patient with CF is diminished • Although CF is a chronic disease, longitudinal data on QoL in children with CF are scarce. What is new: • Below 12 years of age, quality of life improved in most children during the 1-year follow-up whereas a deterioration in quality of life was observed in most children above 12 years. • the treatment burden score of QoL correlated with the exacerbation rate.

PMID: 28597092 [PubMed - as supplied by publisher]

Long Persistence of a Streptococcus pneumoniae 23F Clone in a Cystic Fibrosis Patient.

mSphere. 2017 May-Jun;2(3):

Authors: Rieger M, Mauch H, Hakenbeck R

Abstract
Streptococcus pneumoniae isolates of serotype 23F with intermediate penicillin resistance were recovered on seven occasions over a period of 37 months from a cystic fibrosis patient in Berlin. All isolates expressed the same multilocus sequence type (ST), ST10523. The genome sequences of the first and last isolates, D122 and D141, revealed the absence of two phage-related gene clusters compared to the genome of another ST10523 strain, D219, isolated earlier at a different place in Germany. Genomes of all three strains carried the same novel mosaic penicillin-binding protein (PBP) genes, pbp2x, pbp2b, and pbp1a; these genes were distinct from those of other penicillin-resistant S. pneumoniae strains except for pbp1a of a Romanian S. pneumoniae isolate. All PBPs contained mutations that have been associated with the penicillin resistance phenotype. Most interestingly, a mosaic block identical to an internal pbp2x sequence of ST10523 was present in pbp2x of Streptococcus mitis strain B93-4, which was isolated from the same patient. This suggests interspecies gene transfer from S. pneumoniae to S. mitis within the host. Nearly all genes expressing surface proteins, which represent major virulence factors of S. pneumoniae and are typical for this species, were present in the genome of ST10523. One exception was the hyaluronidase gene hlyA, which contained a 12-nucleotide deletion within the promoter region and an internal stop codon. The lack of a functional hyaluronidase might contribute to the ability to persist in the host for an unusually long period of time. IMPORTANCEStreptococcus pneumoniae is a common resident in the human nasopharynx. However, carriage can result in severe diseases due to a unique repertoire of pathogenicity factors that are rare in closely related commensal streptococci. We investigated a penicillin-resistant S. pneumoniae clone of serotype 23F isolated from a cystic fibrosis patient on multiple occasions over an unusually long period of over 3 years that was present without causing disease. Genome comparisons revealed an apparent nonfunctional pneumococcus-specific gene encoding a hyaluronidase, supporting the view that this enzyme adds to the virulence potential of the bacterium. The 23F clone harbored unique mosaic genes encoding penicillin resistance determinants, the product of horizontal gene transfer involving the commensal S. mitis as donor species. Sequences identical to one such mosaic gene were identified in an S. mitis strain from the same patient, suggesting that in this case S. pneumoniae played the role of donor.

PMID: 28596991 [PubMed - in process]

Review: Quality of Life in Children with Non-cystic Fibrosis Bronchiectasis.

Front Pediatr. 2017;5:84

Authors: Nathan AM, de Bruyne JA, Eg KP, Thavagnanam S

Abstract
Non-cystic fibrosis bronchiectasis (NCFB) has gained renewed interest, due to its increasing health-care burden. Annual mortality statistics in England and Wales showed that under 1,000 people die from bronchiectasis each year, and this number is increasing by 3% yearly. Unfortunately, there is a severe lack of well-powered, randomized controlled trials to guide clinicians how to manage NCFB effectively. Quality-of-life (QOL) measures in NCFB are an important aspect of clinical care that has not been studied well. Commonly used disease-specific questionnaires in children with NCFB are the St George's Respiratory Questionnaire, Short Form-36, the Leicester Cough Questionnaire, and the Parent Cough-Specific Quality of Life questionnaire (PC-QOL). Of these, only the PC-QOL can be used in young children, as it is a parent-proxy questionnaire. We reviewed pediatric studies looking at QOL in children with NCFB and cystic fibrosis. All types of airway clearance techniques appear to be safe and have no significant benefit over each other. Number of exacerbations and hospitalizations correlated with QOL scores, while symptom subscales correlated with lung function, worse QOL, frequent antibiotic requirements, and duration of regular follow-up in only one study. There was a correlation between QOL and age of diagnosis in children with primary ciliary dyskinesia. Other studies have shown no relationship between QOL scores and etiology of NCFB as well as CT changes. As for treatments, oral azithromycin and yoga have demonstrated some improvement in QOL scores. In conclusion, more studies are required to accurately determine important factors contributing to QOL.

PMID: 28596950 [PubMed - in process]

The challenge of defining exacerbation in bronchiectasis.

Eur Respir J. 2017 Jun;49(6):

Authors: Martínez-García MÁ, Máiz-Carro L

PMID: 28596429 [PubMed - in process]

A smartphone-based chloridometer for point-of-care diagnostics of cystic fibrosis.

Biosens Bioelectron. 2017 May 27;97:164-168

Authors: Zhang C, Kim JP, Creer M, Yang J, Liu Z

Abstract
Chloride in sweat is an important diagnostic marker for cystic fibrosis (CF), but the implementation of point-of-care systems for diagnosis is hindered by the prohibitive costs of existing chloride sensors. To enable low cost diagnostic solutions, we recently established a citrate-derived synthesis platform for the development of new fluorescence sensors with high selectivity for chloride. As a next step, we herein designed a smartphone operated chloridometer that optimizes the analytical performance of the citrate-derived sensor materials for the detection of chloride in sweat. The sensor material demonstrated a wide linear range of 0.8-200mM chloride and a diffusion-limited response time; sweat chloride levels corresponded to measurable changes in fluorescence emission that was captured by a smartphone. Clinical validation was performed with sweat from individuals with and without CF, demonstrating convenient sweat diagnostics with reliable detection of cystic fibrosis. To our knowledge, this is the first clinical study of a smartphone-based chloride sensor, paving the way for point-of-care diagnostic systems for CF.

PMID: 28595077 [PubMed - as supplied by publisher]

The Meanings of Helping: An Analysis of Cystic Fibrosis Patients' Reasons for Participating in Biomedical Research.

J Empir Res Hum Res Ethics. 2017 Jun 01;:1556264617713098

Authors: Christofides E, Stroud K, Tullis DE, O'Doherty K

Abstract
Research participants often report wanting to help as a reason for participation, but who they want to help and why is rarely explored. We examined meanings associated with helping among 21 adults with cystic fibrosis (CF)-a group with high participation in research. Meanings included helping to advance research, helping others with CF, helping as their job, helping themselves, helping because they are special, and helping to give back. While some meanings were primarily oriented toward helping others, some also involved hoping for benefits for oneself, and some included feelings of responsibility. Despite indicating that they understood that research is not designed to help them directly, participants nevertheless hoped that it might. We discuss implications for research ethics oversight.

PMID: 28593817 [PubMed - as supplied by publisher]

Erratum to: The evidence on tiotropium bromide in asthma: from the rationale to the bedside.

Multidiscip Respir Med. 2017;12:17

Authors: Radovanovic D, Santus P, Blasi F, Mantero M

Abstract
[This corrects the article DOI: 10.1186/s40248-017-0094-3.].

PMID: 28593046 [PubMed - in process]

Bacterial Sphingomyelinase is a State-Dependent Inhibitor of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR).

Sci Rep. 2017 Jun 07;7(1):2931

Authors: Stauffer BB, Cui G, Cottrill KA, Infield DT, McCarty NA

Abstract
Sphingomyelinase C (SMase) inhibits CFTR chloride channel activity in multiple cell systems, an effect that could exacerbate disease in CF and COPD patients. The mechanism by which sphingomyelin catalysis inhibits CFTR is not known but evidence suggests that it occurs independently of CFTR's regulatory "R" domain. In this study we utilized the Xenopus oocyte expression system to shed light on how CFTR channel activity is reduced by SMase. We found that the pathway leading to inhibition is not membrane delimited and that inhibited CFTR channels remain at the cell membrane, indicative of a novel silencing mechanism. Consistent with an effect on CFTR gating behavior, we found that altering gating kinetics influenced the sensitivity to inhibition by SMase. Specifically, increasing channel activity by introducing the mutation K1250A or pretreating with the CFTR potentiator VX-770 (Ivacaftor) imparted resistance to inhibition. In primary bronchial epithelial cells, we found that basolateral, but not apical, application of SMase leads to a redistribution of sphingomyelin and a reduction in forskolin- and VX-770-stimulated currents. Taken together, these data suggest that SMase inhibits CFTR channel function by locking channels into a closed state and that endogenous CFTR in HBEs is affected by SMase activity.

PMID: 28592822 [PubMed - in process]

The added value of exhaled breath temperature in respiratory medicine.

J Breath Res. 2017 Jun 08;:

Authors: Popov TA, Kralimarkova T, Labor M, Plavec D

Abstract
Recognition of the huge economic burden chronic respiratory diseases pose for society motivated fundamental and clinical research leading to insight into the role of airway inflammation in various disease entities and their phenotypes. However, no easy, cheap and patient-friendly methods to assess it have found a place in routine clinical practice. Measurement of exhaled breath temperature (EBT) has been suggested as a non-invasive method to detect inflammatory processes in the airways as a result of increased blood flow within the airway walls. As EBT values are within a narrow range, the thermometers designed for the purpose of assessing it need to be precise and very sensitive. EBT increases linearly over the pediatric age range and seems to be influenced by gender, but not by height and body weight. In non-smoking individuals with no history of respiratory disease EBT has a natural circadian peak about noon and increases with food intake and physical exercise. When interpreting EBT in subjects with alleged airway pathology, the possibilities of tissue destruction (chronic obstructive pulmonary disease, cystic fibrosis) or excessive bronchial obstruction and air trapping (severe asthma) need to be considered, as these conditions drive (force) EBT down. A prominent advantage of the method is to assess EBT when patients are in a steady state of their disease and to use this "personal best" to monitor them and guide their treatment. Individual devices outfitted with microprocessors and memory have been created, which can be used for personalized monitoring and disease management by telemedicine.

PMID: 28592704 [PubMed - as supplied by publisher]

Linaclotide activates guanylate cyclase-C/cGMP/protein kinase-II-dependent trafficking of CFTR in the intestine.

Physiol Rep. 2017 Jun;5(11):

Authors: Ahsan MK, Tchernychev B, Kessler MM, Solinga RM, Arthur D, Linde CI, Silos-Santiago I, Hannig G, Ameen NA

Abstract
The transmembrane receptor guanylyl cyclase-C (GC-C), expressed on enterocytes along the intestine, is the molecular target of the GC-C agonist peptide linaclotide, an FDA-approved drug for treatment of adult patients with Irritable Bowel Syndrome with Constipation and Chronic Idiopathic Constipation. Polarized human colonic intestinal cells (T84, CaCo-2BBe) rat and human intestinal tissues were employed to examine cellular signaling and cystic fibrosis transmembrane conductance regulator (CFTR)-trafficking pathways activated by linaclotide using confocal microscopy, in vivo surface biotinylation, and protein kinase-II (PKG-II) activity assays. Expression and activity of GC-C/cGMP pathway components were determined by PCR, western blot, and cGMP assays. Fluid secretion as a marker of CFTR cell surface translocation was determined using in vivo rat intestinal loops. Linaclotide treatment (30 min) induced robust fluid secretion and translocation of CFTR from subapical compartments to the cell surface in rat intestinal loops. Similarly, linaclotide treatment (30 min) of T84 and CaCo-2BBe cells increased cell surface CFTR levels. Linaclotide-induced activation of the GC-C/cGMP/PKGII signaling pathway resulted in elevated intracellular cGMP and pVASP(ser239) phosphorylation. Inhibition or silencing of PKGII significantly attenuated linaclotide-induced CFTR trafficking to the apical membrane. Inhibition of protein kinase-A (PKA) also attenuated linaclotide-induced CFTR cell surface trafficking, implying cGMP-dependent cross-activation of PKA pathway. Together, these findings support linaclotide-induced activation of the GC-C/cGMP/PKG-II/CFTR pathway as the major pathway of linaclotide-mediated intestinal fluid secretion, and that linaclotide-dependent CFTR activation and recruitment/trafficking of CFTR from subapical vesicles to the cell surface is an important step in this process.

PMID: 28592587 [PubMed - in process]

Knockdown of CFTR enhances sensitivity of prostate cancer cells to cisplatin via inhibition of autophagy.

Neoplasma. 2017 Jun 08;:

Authors: Zhu Q, Li H, Liu Y, Jiang L

Abstract
Prostate cancer is one of the most lethal diseases in men worldwide. Although the survival rate of men diagnosed with prostate cancer has increased with the improvement of treatments, drug resistance still remains a big challenge for improving overall survival. Cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated anion channel, has been reported to have a pivotal role in the pathogenesis of various cancers, but its role in chemoresistance of prostate cancer cells is poorly understood. In our study, we found that CFTR expression was significantly increased in prostate cancer tissues associated the chemoresistance, and in the cisplatin-resistant cell line LNCaP/CP compared with their respective parental cells. Cisplatin treatment inhibited CFTR expression in a concentration-dependent manner, which was correlated with a decrease in cell viability. Moreover, inhibition of CFTR by transfection of small interfering RNA enhanced cisplatin-induced the decrease of cell viability. Autophagy was dramatically increased in LNCaP/CP cells, as evidenced by autopaphgic markers as well as fluorescence microscopy analysis of GFP-LC3, MDC and AO staining. Of note, inhibiting autophagy by 3MA induced LNCaP/CP cell apoptosis, showed by MTT assay and Hoechst 33258 staining. In addition, blockade of CFTR also inhibited LNCaP/CP cell viability and autophagy. Furthermore, the dephosphorylation of AKT and mTOR was reversed by CFTR inhibition, indicating the knockdown of CFTR might inhibit autophagy in LNCaP/CP cells via activation of AKT/mTOR signaling. Altogether, these results provide a novel understanding of the mechanism for acquired cisplatin. Inhibition of CFTR may be a useful strategy to increase the efficacy of cisplatin to treat prostate cancer by preventing the protective response of autophagy.

PMID: 28592122 [PubMed - as supplied by publisher]

Keratin 8 knockdown leads to loss of the chloride transporter DRA in the colon.

Am J Physiol Gastrointest Liver Physiol. 2016 Jun 01;310(11):G1147-54

Authors: Asghar MN, Priyamvada S, Nyström JH, Anbazhagan AN, Dudeja PK, Toivola DM

Abstract
Keratins (K) are intermediate filament proteins important in protection from stress. The roles of keratins in the intestine are not clear, but K8 knockout (K8(-/-)) mice develop a Th2-type colonic inflammation, epithelial hyperproliferation, and mild diarrhea caused by a keratin level-dependent decrease in short-circuit current and net sodium and chloride absorption in the distal colon. The lack of K8 leads to mistargeting or altered levels of membrane proteins in colonocytes; however, the main transporter responsible for the keratin-related ion transport defect is unknown. We here analyzed protein and mRNA levels of candidate ion transporters CFTR, PAT-1, NHE-3, and DRA in ileum, cecum, and proximal and distal colon. Although no differences were observed for CFTR, PAT-1, or NHE-3, DRA mRNA levels were decreased by three- to fourfold and DRA protein was almost entirely lost in K8(-/-) cecum and proximal and distal colon compared with K8(+/+), whereas the levels in ileum were normal. In K8(+/-) mice, DRA mRNA levels were unaltered, while decreased DRA protein levels were detected in the proximal colon. Immunofluorescence staining confirmed the loss of DRA in K8(-/-) distal colon, while K8(+/-) displayed a similar but more patchy apical DRA distribution compared with K8(+/+) DRA was similarly decreased when K8 was knocked down in Caco-2 cells, confirming that K8 levels modulate DRA levels in an inflammation-independent manner. Taken together, the loss of DRA in the K8(-/-) mouse colon and cecum explains the dramatic chloride transport defect and diarrheal phenotype after K8 inactivation and identifies K8 as a novel regulator of DRA.

PMID: 27125276 [PubMed - indexed for MEDLINE]

Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: II. Cephalosporins and penicillins update.

Pediatr Pulmonol. 2017 Jun 07;:

Authors: Zobell JT, Epps KL, Young DC

PMID: 28590594 [PubMed - as supplied by publisher]

Exercise Testing, Supplemental Oxygen and Hypoxia.

Ann Am Thorac Soc. 2017 Jun 07;:

Authors: Ward SA, Grocott MP, Levett DZ

Abstract
Cardiopulmonary exercise testing (CPET) in hyperoxia and hypoxia has several applications, stemming from characterization of abnormal physiological response profiles associated with exercise intolerance. As altered oxygenation can impact on the performance of gas-concentration and flow sensors and pulmonary gas exchange algorithms, integrated CPET system function requires validation under these conditions. Also, as oxygenation status can influence peak O2 uptake, care should be taken in the selection of work-rate incrementation rates when CPET performance is to be compared with sea-level. CPET has been used to evaluate the effects of supplemental O2 on exercise intolerance in chronic obstructive pulmonary disease, interstitial pulmonary fibrosis and cystic fibrosis at sea-level. However, identification of those CPET indices likely to be predictive of supplemental O2 outcomes for exercise tolerance at altitude in such patients is lacking. CPET performance with supplemental O2 in respiratory patients residing at high altitudes is poorly studied. Finally, CPET has the potential to give physiological and clinical information about acute and chronic mountain sickness, high-altitude pulmonary edema, and high-altitude cerebral edema. It can translate high-altitude acclimatization and adaptive processes in healthy individuals into intensive care medical practice.

PMID: 28590162 [PubMed - as supplied by publisher]

Challenges in Laboratory Detection of Fungal Pathogens in the Airways of Cystic Fibrosis Patients.

Mycopathologia. 2017 Jun 06;:

Authors: Chen SC, Meyer W, Pashley CH

Abstract
Study of the clinical significance of fungal colonization/infection in the airways of cystic fibrosis (CF) patients, especially by filamentous fungi, is challenged by the absence of standardized methodology for the detection and identification of an ever-broadening range of fungal pathogens. Culture-based methods remain the cornerstone diagnostic approaches, but current methods used in many clinical laboratories are insensitive and unstandardized, rendering comparative studies unfeasible. Guidelines for standardized processing of respiratory specimens and for their culture are urgently needed and should include recommendations for specific processing procedures, inoculum density, culture media, incubation temperature and duration of culture. Molecular techniques to detect fungi directly from clinical specimens include panfungal PCR assays, multiplex or pathogen-directed assays, real-time PCR, isothermal methods and probe-based assays. In general, these are used to complement culture. Fungal identification by DNA sequencing methods is often required to identify cultured isolates, but matrix-assisted laser desorption/ionization time-of-flight mass spectrometry is increasingly used as an alternative to DNA sequencing. Genotyping of isolates is undertaken to investigate relatedness between isolates, to pinpoint the infection source and to study the population structure. Methods range from PCR fingerprinting and amplified fragment length polymorphism analysis, to short tandem repeat typing, multilocus sequencing typing (MLST) and whole genome sequencing (WGS). MLST is the current preferred method, whilst WGS offers best case resolution but currently is understudied.

PMID: 28589247 [PubMed - as supplied by publisher]

Is sweat chloride predictive of severity of cystic fibrosis lung disease assessed by chest computed tomography?

Pediatr Pulmonol. 2017 Jun 06;:

Authors: Caudri D, Zitter D, Bronsveld I, Tiddens H

Abstract
BACKGROUND: Cystic Fibrosis (CF) lung disease is characterized by a marked heterogeneity. Sweat chloride-level is a functional marker of the CF Transmembrane Regulator (CFTR) protein and could be an important predictor of later disease severity.
METHODS: In this retrospective analysis children from the Rotterdam CF clinic with available sweat chloride level at diagnosis and at least one routine spirometry-controlled volumetric chest CT scan in follow-up were included. CT scans were scored using the CF-CT scoring system (% of maximum). Associations between sweat chloride-levels and CF-CT scores were calculated using linear regression models, adjusting for age at sweat test and age at follow-up. Because structural lung damage develops over the course of many years, effect modification by the age at follow-up CT-scan was tested for by age-stratification.
RESULTS: In 59 children (30 male) sweat chloride was measured at diagnosis (median age 0.5 years, range 0-13) and later chest CT performed (median age 14 years, range 6-18). Sweat chloride was associated with significantly higher CT-CT total score, bronchiectasis score, and mucus plugging score. Stratification for age at follow-up in tertiles showed this association remained only in the oldest age group (range 15-18 years). In that subgroup associations were found with all but one of the CF-CT subscores, as well as with all tested lung functions parameters.
CONCLUSION: Sweat chloride-level is a significant predictor of CF lung disease severity as determined by chest CT and lung function. This association could only be demonstrated in children with follow-up to age 15 years and above.

PMID: 28586522 [PubMed - as supplied by publisher]

Impact of enzymatic digestion on bacterial community composition in CF airway samples.

PeerJ. 2017;5:e3362

Authors: Williamson KM, Wagner BD, Robertson CE, Johnson EJ, Zemanick ET, Harris JK

Abstract
BACKGROUND: Previous studies have demonstrated the importance of DNA extraction methods for molecular detection of Staphylococcus, an important bacterial group in cystic fibrosis (CF). We sought to evaluate the effect of enzymatic digestion (EnzD) prior to DNA extraction on bacterial communities identified in sputum and oropharyngeal swab (OP) samples from patients with CF.
METHODS: DNA from 81 samples (39 sputum and 42 OP) collected from 63 patients with CF was extracted in duplicate with and without EnzD. Bacterial communities were determined by rRNA gene sequencing, and measures of alpha and beta diversity were calculated. Principal Coordinate Analysis (PCoA) was used to assess differences at the community level and Wilcoxon Signed Rank tests were used to compare relative abundance (RA) of individual genera for paired samples with and without EnzD.
RESULTS: Shannon Diversity Index (alpha-diversity) decreased in sputum and OP samples with the use of EnzD. Larger shifts in community composition were observed for OP samples (beta-diversity, measured by Morisita-Horn), whereas less change in communities was observed for sputum samples. The use of EnzD with OP swabs resulted in significant increase in RA for the genera Gemella (p < 0.01), Streptococcus (p < 0.01), and Rothia (p < 0.01). Staphylococcus (p < 0.01) was the only genus with a significant increase in RA from sputum, whereas the following genera decreased in RA with EnzD: Veillonella (p < 0.01), Granulicatella (p < 0.01), Prevotella (p < 0.01), and Gemella (p = 0.02). In OP samples, higher RA of Gram-positive taxa was associated with larger changes in microbial community composition.
DISCUSSION: We show that the application of EnzD to CF airway samples, particularly OP swabs, results in differences in microbial communities detected by sequencing. Use of EnzD can result in large changes in bacterial community composition, and is particularly useful for detection of Staphylococcus in CF OP samples. The enhanced identification of Staphylococcus aureus is a strong indication to utilize EnzD in studies that use OP swabs to monitor CF airway communities.

PMID: 28584706 [PubMed - in process]

Immunonutrition in patients with cyctic fibrosis leads to drop of serum amyloid A and increase of oxidative stress.

J Clin Biochem Nutr. 2017 May;60(3):176-179

Authors: Hloch O, Charvat J, Fila L, Jan H

Abstract
The aim of the present study is to evaluate of the impact of immunonutrition on parameters of oxidative stress and inflammation in patients with cystic fibrosis and malnutrition. In the 30 patients with cystic fibrosis and long-term enteral nutrition support for malnutrition the effect of standard and immunonutrion sipping on oxidative stress and inflammatory activity parameters was compared. Malonyldialdehyde (MDA) as parameter of oxidative stress and serum amyloid A (SAA), interleukin 1 and 6, hsCRP, IgM, IgA, IgG as parameters of inflammatory activity were examined. Immunonutrition decreased SAA to 17.6 mg/L comparing to 25.6 mg/L when standard nutrition was given (p = 0.014). MDA was 0.66 µM on standard and 0.96 µM on immunonutrition support (p<0.01). The significant negative correlation was recorded between MDA and SAA, hs-CRP, interleukin 6, IgA and IgG. In conclusion, the application of immunonutrition in patients with cystic fibrosis and malnutrition is associated with drop of SAA but with the rise of MDA.

PMID: 28584399 [PubMed - in process]

The role of AxyZ transcriptional regulator in the overproduction of AxyXY-OprZ multidrug efflux system in Achromobacter spp. mutants selected by tobramycin.

Antimicrob Agents Chemother. 2017 Jun 05;:

Authors: Bador J, Neuwirth C, Grangier N, Muniz M, Germé L, Bonnet J, Pillay VG, Llanes C, de Curraize C, Amoureux L

Abstract
AxyXY-OprZ is an RND-type efflux system that confers innate aminoglycoside resistance to Achromobacter spp. We investigated here about a putative TetR family transcriptional regulator encoded by the axyZ gene located upstream of axyXY-oprZ In-frame axyZ gene deletion assay led to increased MICs of antibiotic substrates of the efflux system: aminoglycosides, cefepime, fluoroquinolones, tetracyclines and erythromycin, indicating that the product of axyZ negatively regulates expression of axyXY-oprZ Moreover we identified an amino-acid substitution at position 29 of AxyZ (V29G) in a clinical Achromobacter strain that occurred during the course of chronic respiratory tract colonization in a cystic fibrosis (CF) patient. This substitution, also detected in 3 other strains exposed in vitro to tobramycin, led to the increase in axyY transcription level (5 to 17-fold) together with the increase in antibiotic resistance level. This overproduction of AxyXY-OprZ is the first description of antibiotic resistance acquisition due to modification of a chromosomally encoded mechanism in Achromobacter and might have potential impact on the management of infected CF patients. Indeed tobramycin is widely used for aerosol therapy within this population and we have demonstrated that it easily selects mutants with increased minimal inhibitory concentrations of aminoglycosides but also fluoroquinolones, cefepime and tetracyclines.

PMID: 28584156 [PubMed - as supplied by publisher]

Crystal structures of the Burkholderia multivorans hopanoid transporter HpnN.

Proc Natl Acad Sci U S A. 2017 Jun 05;:

Authors: Kumar N, Su CC, Chou TH, Radhakrishnan A, Delmar JA, Rajashankar KR, Yu EW

Abstract
Strains of the Burkholderia cepacia complex (Bcc) are Gram-negative opportunisitic bacteria that are capable of causing serious diseases, mainly in immunocompromised individuals. Bcc pathogens are intrinsically resistant to multiple antibiotics, including β-lactams, aminoglycosides, fluoroquinolones, and polymyxins. They are major pathogens in patients with cystic fibrosis (CF) and can cause severe necrotizing pneumonia, which is often fatal. Hopanoid biosynthesis is one of the major mechanisms involved in multiple antimicrobial resistance of Bcc pathogens. The hpnN gene of B. multivorans encodes an integral membrane protein of the HpnN family of transporters, which is responsible for shuttling hopanoids to the outer membrane. Here, we report crystal structures of B. multivorans HpnN, revealing a dimeric molecule with an overall butterfly shape. Each subunit of the transporter contains 12 transmembrane helices and two periplasmic loops that suggest a plausible pathway for substrate transport. Further analyses indicate that HpnN is capable of shuttling hopanoid virulence factors from the outer leaflet of the inner membrane to the periplasm. Taken together, our data suggest that the HpnN transporter is critical for multidrug resistance and cell wall remodeling in Burkholderia.

PMID: 28584102 [PubMed - as supplied by publisher]