Environmental Burkholderia cenocepacia Strain Enhances Fitness by Serial Passages during Long-Term Chronic Airways Infection in Mice.

Int J Mol Sci. 2017 Nov 14;18(11):

Authors: Bragonzi A, Paroni M, Pirone L, Coladarci I, Ascenzioni F, Bevivino A

Abstract
Burkholderia cenocepacia is an important opportunistic pathogen in cystic fibrosis (CF) patients, and has also been isolated from natural environments. In previous work, we explored the virulence and pathogenic potential of environmental B. cenocepacia strains and demonstrated that they do not differ from clinical strains in some pathogenic traits. Here, we investigated the ability of the environmental B. cenocepacia Mex1 strain, isolated from the maize rhizosphere, to persist and increase its virulence after serial passages in a mouse model of chronic infection. B. cenocepacia Mex1 strain, belonging to the recA lineage IIIA, was embedded in agar beads and challenged into the lung of C57Bl/6 mice. The mice were sacrificed after 28 days from infection and their lungs were tested for bacterial loads. Agar beads containing the pool of B. cenocepacia colonies from the four sequential passages were used to infect the mice. The environmental B. cenocepacia strain showed a low incidence of chronic infection after the first passage; after the second, third and fourth passages in mice, its ability to establish chronic infection increased significantly and progressively up to 100%. Colonial morphology analysis and genetic profiling of the Mex1-derived clones recovered after the fourth passage from infected mice revealed that they were indistinguishable from the challenged strain both at phenotypic and genetic level. By testing the virulence of single clones in the Galleria mellonella infection model, we found that two Mex1-derived clones significantly increased their pathogenicity compared to the parental Mex1 strain and behaved similarly to the clinical and epidemic B. cenocepacia LMG16656(T). Our findings suggest that serial passages of the environmental B. cenocepacia Mex1 strain in mice resulted in an increased ability to determine chronic lung infection and the appearance of clonal variants with increased virulence in non-vertebrate hosts.

PMID: 29135920 [PubMed - in process]

Cerebral artery myogenic reactivity: The next frontier in developing effective interventions for subarachnoid hemorrhage.

J Cereb Blood Flow Metab. 2017 Jan 01;:271678X17742548

Authors: Lidington D, Kroetsch JT, Bolz SS

Abstract
Aneurysmal subarachnoid hemorrhage (SAH) is a devastating cerebral event that kills or debilitates the majority of those afflicted. The blood that spills into the subarachnoid space stimulates profound cerebral artery vasoconstriction and consequently, cerebral ischemia. Thus, once the initial bleeding in SAH is appropriately managed, the clinical focus shifts to maintaining/improving cerebral perfusion. However, current therapeutic interventions largely fail to improve clinical outcome, because they do not effectively restore normal cerebral artery function. This review discusses emerging evidence that perturbed cerebrovascular "myogenic reactivity," a crucial microvascular process that potently dictates cerebral perfusion, is the critical element underlying cerebral ischemia in SAH. In fact, the myogenic mechanism could be the reason why many therapeutic interventions, including "Triple H" therapy, fail to deliver benefit to patients. Understanding the molecular basis for myogenic reactivity changes in SAH holds the key to develop more effective therapeutic interventions; indeed, promising recent advancements fuel optimism that vascular dysfunction in SAH can be corrected to improve outcome.

PMID: 29135346 [PubMed - as supplied by publisher]

Evaluation of Tobramycin Exposure Predictions in Three Bayesian Forecasting Programmes Compared with Current Clinical Practice in Children and Adults with Cystic Fibrosis.

Clin Pharmacokinet. 2017 Nov 13;:

Authors: Burgard M, Sandaradura I, van Hal SJ, Stacey S, Hennig S

Abstract
BACKGROUND AND OBJECTIVES: Bayesian forecasting (BF) methods for tobramycin dose individualisation has not seen widespread clinical adoption, despite being endorsed by clinical practice guidelines. Several freeware and commercial programmes using BF methods are available to support personalised dosing. This study evaluated exposure estimates, dose recommendations, and predictive performance compared with current clinical practice.
METHODS: Data from 105 patients (50 adults and 55 children) with cystic fibrosis who received intravenous tobramycin treatment and had paired concentration-time measurements were analysed using (1) log-linear regression analysis, and (2) three BF programmes: TDMx, InsightRX, and DoseMe. Exposure estimates and dose recommendations were compared using the Wilcoxon signed-rank test and Bland-Altman analysis. Predictive performance of BF programmes was compared based on bias and imprecision.
RESULTS: Median estimated tobramycin exposure with current clinical practice was significantly lower (87.8 vs. 92.5, 94.0 and 90.3 mg h l(-1); p ≤ 0.01), hence median subsequent dose recommendations were significantly higher (10.1 vs. 9.4, 9.4 and 9.2 mg kg(-1); p ≤ 0.01) compared with BF programmes. Furthermore, median relative dose-adjustment differences were higher in adults (> 10%) compared with children (4.4-7.8%), and differences in individual dose recommendations were > 20% on 19.1-27.4% of occasions. BF programmes showed low bias (< 7%) and imprecision (< 20%), and none of the programmes made consistently significantly different recommendations compared with each other.
CONCLUSIONS: On average, the predictions made by the BF programmes were similar, however substantial individual differences were observed for some patients. This suggests the need for detailed investigations of true tobramycin exposure.

PMID: 29134570 [PubMed - as supplied by publisher]

Secretin-stimulated ultrasound estimation of pancreatic secretion in cystic fibrosis validated by magnetic resonance imaging.

Eur Radiol. 2017 Nov 13;:

Authors: Engjom T, Tjora E, Wathle G, Erchinger F, Lærum BN, Gilja OH, Haldorsen IS, Dimcevski G

Abstract
OBJECTIVES: Secretin-stimulated magnetic resonance imaging (s-MRI) is the best validated radiological modality assessing pancreatic secretion. The purpose of this study was to compare volume output measures from secretin-stimulated transabdominal ultrasonography (s-US) to s-MRI for the diagnosis of exocrine pancreatic failure in cystic fibrosis (CF).
METHODS: We performed transabdominal ultrasonography and MRI before and at timed intervals during 15 minutes after secretin stimulation in 21 CF patients and 13 healthy controls. To clearly identify the subjects with reduced exocrine pancreatic function, we classified CF patients as pancreas-sufficient or -insufficient by secretin-stimulated endoscopic short test and faecal elastase.
RESULTS: Pancreas-insufficient CF patients had reduced pancreatic secretions compared to pancreas-sufficient subjects based on both imaging modalities (p < 0.001). Volume output estimates assessed by s-US correlated to that of s-MRI (r = 0.56-0.62; p < 0.001). Both s-US (AUC: 0.88) and s-MRI (AUC: 0.99) demonstrated good diagnostic accuracy for exocrine pancreatic failure.
CONCLUSIONS: Pancreatic volume-output estimated by s-US corresponds well to exocrine pancreatic function in CF patients and yields comparable results to that of s-MRI. s-US provides a simple and feasible tool in the assessment of pancreatic secretion.
KEY POINTS: • Cystic fibrosis patients with affected pancreas have reduced pancreatic secretions. • Secretin-stimulated sonography is a simple and feasible method to assess pancreatic output. • Secretin-simulated MRI is a more precise method to assess pancreatic secretions. • The sonographic and MRI methods yielded comparable pancreatic secretory output estimates.

PMID: 29134356 [PubMed - as supplied by publisher]

Diminished Susceptibility of African-Americans to Non-tuberculous Mycobacterial Disease.

Lung. 2017 Nov 13;:

Authors: Reich JM, Kim JS

Abstract
The incidence of three granulomatous response diseases-sarcoidosis, tuberculosis, and non-tuberculous mycobacterial pulmonary disease-differ markedly in African-Americans versus Caucasians. In reviewing a large compendium of non-cystic-fibrosis bronchiectasis, we noted that complicating infection with non-tuberculous mycobacteria was relatively infrequent among individuals of African-American descent, confirming previous observations of their inherent resistance. Disease-specific variance among African-Americans in the efficacy of their granulomatous response suggests a nexus, a mediating, immunological mechanism. Environmentally conditioned selection of SLC11A1 (Nramp1) alleles may account for this ethnic variance.

PMID: 29134263 [PubMed - as supplied by publisher]

Pseudo-Bartter Syndrome in a Chinese Infant with Cystic Fibrosis Caused by c.532G>A Mutation in CFTR.

Chin Med J (Engl). 2017 Nov 20;130(22):2771-2772

Authors: Yao Y, Feng XL, Xu BP, Shen KL

PMID: 29133775 [PubMed - in process]

Mutations in gene fusA1 as a novel mechanism of aminoglycoside resistance in clinical strains of Pseudomonas aeruginosa.

Antimicrob Agents Chemother. 2017 Nov 13;:

Authors: Bolard A, Plesiat P, Jeannot K

Abstract
Resistance of clinical strains of Pseudomonas aeruginosa to aminoglycosides can result from production of transferable aminoglycoside-modifying enzymes, of 16S rRNA methylases, and/or mutational derepression of intrinsic multidrug efflux pump MexXY(OprM). The present study reports on characterization of a new type of mutants 4- to 8-fold more resistant to 2-deoxystreptamine derivatives (e.g., gentamicin, amikacin, tobramycin), as compared with wild-type strain PAO1. The genetic alterations of three in vitro mutants were mapped on fusA1, and found to result in single amino acid substitutions in domains II, III and V of elongation factor G (EF-G1A), a key component of translational machinery. Transfer of the mutated fusA1 alleles into PAO1 reproduced the resistance phenotype. Interestingly, fusA1 mutants with other amino acid changes in domains G, IV and V of EF-G1A were identified among clinical strains with decreased susceptibility to aminoglycosides. Allelic exchange experiments confirmed the relevance of these latter mutations and of three other previously reported alterations located in domains G and IV. Pump MexXY(OprM) was found to partly contribute to the resistance conferred by the mutated EF-G1A variants, and to have additive effects on aminoglycosides MICs when mutationally up-regulated. Altogether, our data demonstrate that cystic fibrosis (CF) and non-CF strains of P. aeruginosa can acquire a therapeutically significant resistance to important aminoglycosides, via a new mechanism involving mutations in elongation factor EF-G1A.

PMID: 29133559 [PubMed - as supplied by publisher]

Primary ciliary dyskinesia: keep it on your radar.

Thorax. 2017 Nov 13;:

Authors: Rosenfeld M, Ostrowski LE, Zariwala MA

PMID: 29133352 [PubMed - as supplied by publisher]

Clinical effects of probiotics in cystic fibrosis patients: A systematic review.

Clin Nutr ESPEN. 2017 Apr;18:37-43

Authors: Van Biervliet S, Declercq D, Somerset S

Abstract
Cystic fibrosis (CF) is characterised by a build-up of thick, intransient mucus linings of the digestive and respiratory mucosa, which disrupts digestive system functioning and microbiota composition. In view of the potential for probiotics to enhance microbiota composition in other contexts, this study investigated the current evidence for probiotics as an adjunct to usual therapy for CF. Electronic clinical databases were interrogated for human randomised, controlled, intervention trials (1985-2015) testing the effects of probiotics on clinical endpoints in CF were reviewed. From 191 articles identified in initial searches, six studies met the critical inclusion criteria, and were reviewed in detail. These studies varied in size (n = 22 to 61) but were generally small and showed substantial diversity in protocol, specific probiotic species used and range of clinical outcomes measured. Probiotic administration showed beneficial effects on fecal calprotectin levels, pulmonary exacerbation risk, and quality of life indicators. In one study, such changes were associated with variations in gut microbiota composition. Despite encouraging preliminary results, the limited number of small and highly varied studies to date do not justify the addition of probiotics as an adjunct to current CF treatment protocols. Importantly, very minimal adverse effects of probiotics have been reported.

PMID: 29132736 [PubMed - in process]

The therapeutic potential of CFTR modulators for COPD and other airway diseases.

Curr Opin Pharmacol. 2017 Nov 09;34:132-139

Authors: Solomon GM, Fu L, Rowe SM, Collawn JF

Abstract
Airways diseases, especially chronic obstructive pulmonary disease (COPD) and asthma, are common causes of morbidity and mortality worldwide. There is an ongoing unmet need for novel and effective therapies. There is an established pathophysiological link and phenotypic similarity between the chronic bronchitis phenotype of COPD and cystic fibrosis (CF). New evidence suggests that CFTR dysfunction may play a role in other common airways diseases such as COPD, non-atopic asthma and non-CF bronchiectasis. Newly approved and investigational drugs that target both mutant and wildtype CFTR channels have provided a new treatment opportunity addressing the mucus defect in pulmonary diseases that share the same pathophysiology with CF.

PMID: 29132121 [PubMed - as supplied by publisher]

Optimized approach for the identification of highly efficient correctors of nonsense mutations in human diseases.

PLoS One. 2017;12(11):e0187930

Authors: Benhabiles H, Gonzalez-Hilarion S, Amand S, Bailly C, Prévotat A, Reix P, Hubert D, Adriaenssens E, Rebuffat S, Tulasne D, Lejeune F

Abstract
About 10% of patients with a genetic disease carry a nonsense mutation causing their pathology. A strategy for correcting nonsense mutations is premature termination codon (PTC) readthrough, i.e. incorporation of an amino acid at the PTC position during translation. PTC-readthrough-activating molecules appear as promising therapeutic tools for these patients. Unfortunately, the molecules shown to induce PTC readthrough show low efficacy, probably because the mRNAs carrying a nonsense mutation are scarce, as they are also substrates of the quality control mechanism called nonsense-mediated mRNA decay (NMD). The screening systems previously developed to identify readthrough-promoting molecules used cDNA constructs encoding mRNAs immune to NMD. As the molecules identified were not selected for the ability to correct nonsense mutations on NMD-prone PTC-mRNAs, they could be unsuitable for the context of nonsense-mutation-linked human pathologies. Here, a screening system based on an NMD-prone mRNA is described. It should be suitable for identifying molecules capable of efficiently rescuing the expression of human genes harboring a nonsense mutation. This system should favor the discovery of candidate drugs for treating genetic diseases caused by nonsense mutations. One hit selected with this screening system is presented and validated on cells from three cystic fibrosis patients.

PMID: 29131862 [PubMed - in process]

Equivalence in outcomes between Draf 2B vs Draf 3 frontal sinusotomy for refractory chronic frontal rhinosinusitis.

Int Forum Allergy Rhinol. 2017 Nov 13;:

Authors: Patel VS, Choby G, Shih LC, Patel ZM, Nayak JV, Hwang PH

Abstract
BACKGROUND: Endoscopic Draf 2B and Draf 3 frontal sinusotomies are frequently performed for chronic refractory frontal rhinosinusitis. The purpose of this study was to compare outcomes between Draf 2B and Draf 3 procedures.
METHODS: A retrospective cohort study was conducted comparing patients undergoing bilateral Draf 2B vs Draf 3 procedures from 2000 to 2016. Patients with neoplasia, dysplasia, mucocele, cystic fibrosis, or ciliary dyskinesia were excluded. Preoperative disease parameters included number of prior surgeries, presence of polyps, preoperative 22-item Sino-Nasal Outcome Test (SNOT-22) score, frontal Lund-Mackay score, anterior-posterior diameter of the frontal ostium, and Global Osteitis Scoring Scale (GOSS). Postoperative outcomes included SNOT-22 score, neo-ostium patency, surgical revision rates, and complications.
RESULTS: A total of 21 patients with bilateral Draf 2B and 17 patients with Draf 3 surgeries were compared. Mean follow-up time was 15.6 months. No significant differences were seen between groups for any preoperative disease parameter. Both cohorts showed statistically significant (p = 0.0001 [Draf 2B]; p = 0.0001 [Draf 3]) and clinically meaningful (Δ = 24.1; Δ = 24.9) improvements in SNOT-22 at last follow-up vs preoperatively. The Draf 2B group had greater improvement in SNOT-22 score than the Draf 3 group at 1 to 3 months (p = 0.003), but the magnitude of improvement equalized at 5 to 9 months (p = 0.66) and last follow-up (p = 0.90). No significant differences were noted between groups regarding patency, revision rates, or complications.
CONCLUSION: Both Draf 2B and Draf 3 procedures offer durable symptomatic improvement for patients with refractory frontal CRS. The Draf 2B is associated with earlier postoperative symptom improvement and overall shows comparable long-term outcomes to the Draf 3 sinusotomy.

PMID: 29131540 [PubMed - as supplied by publisher]

Comparison of two different assays and the predictive value of allergen components in house dust mite allergy.

Immunotherapy. 2017 Nov;9(15):1253-1262

Authors: Schulze J, Leberkuehne L, Salzmann-Manrique E, Schubert R, Zielen S, Rosewich M

Abstract
AIM: In house dust mite (HDM) allergy diagnostics, the IMMULITE, ImmunoCAP and assays for allergen components (nDer p 1 and rDer p 2) are available.
METHODS: Serum sIgE levels were compared and the predictive values for the detection of an early asthmatic response (EAR) were calculated with receiver operating characteristics and a log-logistic regression model.
RESULTS: sIgE levels of IMMULITE and ImmunoCAP were similar (Dermatophagoides pteronyssinus [D. pter.] 47.3 ± 35.7 and 42.9 ± 34.4 kU.l(-1); p = 0.23). ImmunoCAP slgEs exhibited similar accuracy in detecting an EAR, area under the curves (AUCs): D. pter. (0.76); Dermatophagoides farinae (0.79); nDer p 1 (0.69); and rDer p 2 (0.72). At low sIgE concentrations (3.5 kU.l(-1)), rDer p 2 was more specific and better predicted an EAR (probability rDer p 2: 62%; D. pter.: 19%).

PMID: 29130795 [PubMed - in process]

Depression, Social Support, and Clinical Outcomes following Lung Transplantation.

Transpl Int. 2017 Nov 12;:

Authors: Smith PJ, Snyder LD, Palmer SM, Hoffman BM, Stonerock GL, Ingle KK, Saulino CK, Blumenthal JA

Abstract
BACKGROUND: Depressive symptoms are common among lung transplant candidates and have been associated with poorer clinical outcomes in some studies. Previous studies have been plagued by methodologic problems, including small sample sizes, few clinical events, and uncontrolled confounders, particularly perioperative complications. In addition, few studies have examined social support as a potential protective factor. We therefore examined the association between pre-transplant depressive symptoms, social support, and mortality in a large sample of lung transplant recipients. As a secondary aim, we also examined the associations between psychosocial factors, perioperative outcomes (indexed by hospital length of stay [LOS]), and mortality. We hypothesized that depression would be associated with longer LOS and that the association between depression, social support, and mortality would be moderated by LOS.
METHODS: Participants included lung transplant recipients, transplanted at Duke University Medical Center from January 2009 to December 2014. Depressive symptoms were evaluated using the Beck Depression Inventory (BDI-II) and social support using the Perceived Social Support Scale (PSSS). Medical risk factors included forced vital capacity (FVC), partial pressure of carbon dioxide (PCO2 ), donor age, acute rejection, and transplant type. Functional status was assessed using six-minute walk distance (6MWD). We also controlled for demographic factors, including age, gender, and native disease. Transplant hospitalization LOS was examined as a marker of perioperative clinical outcomes.
RESULTS: Participants included 273 lung recipients (174 restrictive, 67 obstructive, 26 cystic fibrosis, and 6 'other'). Pre-transplant depressive symptoms were common, with 56 participants (21%) exhibiting clinically elevated levels (BDI-II > 14). Greater depressive symptoms were associated with longer LOS (adjusted b = 0.20 [2 days per 7-point higher BDI-II score], P <.01). LOS moderated the associations between depressive symptoms (P = .019), social support (P<.001), and mortality, such that greater depressive symptoms and lower social support were associated with greater mortality only among individuals with longer LOS. For individuals with LOS > 1-month, clinically elevated depressive symptoms (BDI-II > 14) were associated with a three-fold increased risk of mortality (HR = 2.97).
CONCLUSIONS: Greater pre-transplant depressive symptoms and lower social support may be associated with greater mortality among a subset of individuals with worse perioperative outcomes. This article is protected by copyright. All rights reserved.

PMID: 29130541 [PubMed - as supplied by publisher]

Rapid Electrochemical Detection of Pseudomonas aeruginosa Signaling Molecules by Boron-Doped Diamond Electrode.

Methods Mol Biol. 2018;1673:107-116

Authors: Buzid A, Luong JHT, Reen FJ, O'Gara F, Glennon JD, McGlacken GP

Abstract
As the leading cause of morbidity and mortality of cystic fibrosis (CF) patients, early detection of Pseudomonas aeruginosa (PA) is critical in the clinical management of this pathogen. Herein, we describe rapid and sensitive electroanalytical methods using differential pulse voltammetry (DPV) at a boron-doped diamond (BDD) electrode for the detection of PA signaling biomolecules. Monitoring the production of key signaling molecules in bacterial cultures of P. aeruginosa PA14 over 8 h is described, involving sample pretreatment by liquid-liquid and solid-phase extraction. In addition, direct electrochemical detection approach of PA signaling molecules is also reported in conjunction with hexadecyltrimethylammonium bromide (CTAB) to disrupt the bacterial membrane.

PMID: 29130168 [PubMed - in process]

Atomic Force Microscopy: A Promising Tool for Deciphering the Pathogenic Mechanisms of Fungi in Cystic Fibrosis.

Mycopathologia. 2017 Nov 11;:

Authors: Cuenot S, Bouchara JP

Abstract
During the past decades, atomic force microscopy (AFM) has emerged as a powerful tool in microbiology. Although most of the works concerned bacteria, AFM also permitted major breakthroughs in the understanding of physiology and pathogenic mechanisms of some fungal species associated with cystic fibrosis. Complementary to electron microscopies, AFM offers unprecedented insights to visualize the cell wall architecture and components through three-dimensional imaging with nanometer resolution and to follow their dynamic changes during cell growth and division or following the exposure to drugs and chemicals. Besides imaging, force spectroscopy with piconewton sensitivity provides a direct means to decipher the forces governing cell-cell and cell-substrate interactions, but also to quantify specific and non-specific interactions between cell surface components at the single-molecule level. This nanotool explores new ways for a better understanding of the structures and functions of the cell surface components and therefore may be useful to elucidate the role of these components in the host-pathogen interactions as well as in the complex interplay between bacteria and fungi in the lung microbiome.

PMID: 29128932 [PubMed - as supplied by publisher]

Lack of efficacy of Lactobacillus GG in reducing pulmonary exacerbations and hospital admissions in children with cystic fibrosis: A randomised placebo controlled trial.

J Cyst Fibros. 2017 Nov 08;:

Authors: Bruzzese E, Raia V, Ruberto E, Scotto R, Giannattasio A, Bruzzese D, Cavicchi MC, Francalanci M, Colombo C, Faelli N, Daccò V, Magazzù G, Costa S, Lucidi V, Majo F, Guarino A

Abstract
BACKGROUND: Intestinal dysbiosis has been described in Cystic Fibrosis (CF) and probiotics have been proposed to restore microbial composition. Aim of the study was to investigate the effects of Lactobacillus rhamnosus GG (LGG) on clinical outcomes in children with cystic fibrosis (CF).
METHODS: A multicentre, randomised double-blind, clinical trial was conducted in children with CF. After 6months of baseline assessment, enrolled children (2 to 16years of age) received Lactobacillus GG (6×10(9)CFU/day) or placebo for 12months. Primary outcomes were proportion of subjects with at least one pulmonary exacerbation and hospitalisation over 12months. Secondary endpoints were total number of exacerbations and hospitalisations, pulmonary function, and nutritional status.
RESULTS: Ninety-five patients were enrolled (51/95 female; median age of 103±50months). In a multivariate GEE logistic analysis, the odds of experiencing at least one exacerbation was not significantly different between the two groups, also after adjusting for the presence of different microbial organisms and for the number of pulmonary exacerbations within 6months before randomisation (OR 0.83; 95% CI 0.38 to 1.82, p=0.643). Similarly, LGG supplementation did not significantly affect the odds of hospitalisations (OR 1.67; 95% CI 0.75 to 3.72, p=0.211). No significant difference was found for body mass index and FEV1.
CONCLUSIONS: LGG supplementation had no effect on respiratory and nutritional outcomes in this large study population of children with CF under stringent randomised clinical trial conditions. Whether earlier interventions, larger doses, or different strains of probiotics may be effective is unknown.

PMID: 29128317 [PubMed - as supplied by publisher]

Fecal calprotectin concentrations in young children with cystic fibrosis: Authors response.

J Cyst Fibros. 2017 Nov 08;:

Authors: Garg M, Leach ST, Day AS, Ooi CY

PMID: 29128316 [PubMed - as supplied by publisher]

Changes in the lung bacteriome in relation to antipseudomonal therapy in children with cystic fibrosis.

Folia Microbiol (Praha). 2017 Nov 10;:

Authors: Kramná L, Dřevínek P, Lin J, Kulich M, Cinek O

Abstract
The lung in cystic fibrosis (CF) is home to numerous pathogens that shorten the lives of patients. The aim of the present study was to assess changes in the lung bacteriome following antibiotic therapy targeting Pseudomonas aeruginosa in children with CF. The study included nine children (9-18 years) with CF who were treated for their chronic or intermittent positivity for Pseudomonas aeruginosa. The bacteriomes were determined in 16 pairs of sputa collected at the beginning and at the end of a course of intravenous antibiotic therapy via deep sequencing of the variable region 4 of the 16S rRNA gene, and the total bacterial load and selected specific pathogens were assessed using quantitative real-time PCR. The effect of antipseudomonal antibiotics was observable as a profound decrease in the total 16S rDNA load (p = 0.001) as well as in a broad range of individual taxa including Staphylococcus aureus (p = 0.03) and several members of the Streptococcus mitis group (S. oralis, S. mitis, and S. infantis) (p = 0.003). Improvements in forced expiratory volume (FEV1) were associated with an increase in Granulicatella sp. (p = 0.004), whereas a negative association was noted between the total bacterial load and white blood cell count (p = 0.007). In conclusion, the data show how microbial communities differ in reaction to antipseudomonal treatment, suggesting that certain rare species may be associated with clinical parameters. Our work also demonstrates the utility of absolute quantification of bacterial load in addition to the 16S rDNA profiling.

PMID: 29127619 [PubMed - as supplied by publisher]

The role of TRPV4 in fibrosis.

Gene. 2017 Nov 07;:

Authors: Zhan L, Li J

Abstract
The transient receptor potential vanilloid 4 (TRPV4) is a highly Ca(2+)-permeable non-selective cation channel in TRPV family. Accumulating evidence hints that TRPV4 play a significant role in a wide diversity of pathologic changes. Fibrosis is a kind of chronic disease which was characterized by the formation of excessive accumulation of extracellular matrix (ECM) components in tissues and organs. In recent years, a growing body of studies showed that TRPV4 acted as a crucial regulator in the progression of fibrosis including myocardial fibrosis, cystic fibrosis, pulmonary fibrosis, hepatic fibrosis and pancreatic fibrosis, suggesting TRPV4 may be a potential therapeutic vehicle in fibrotic diseases. However, the mechanisms by which TRPV4 regulates fibrosis are still undefined. In this review, firstly, we intend to sum up the collective knowledge of TRPV4. Then we provided the latent mechanism between TRPV4 and fibrosis. We also elaborated the distinct signaling pathways focus on TRPV4 with fibrosis. Finally, we discussed its potential as a novel therapeutic target for fibrosis.

PMID: 29126921 [PubMed - as supplied by publisher]