Reactive oxygen: a novel antimicrobial mechanism for targeting biofilm-associated infection.

J Glob Antimicrob Resist. 2017 Feb 14;:

Authors: Dryden MS, Cooke J, Salib RJ, Holding RE, Biggs T, Salamat AA, Allan RN, Newby RS, Halstead F, Oppenheim B, Hall T, Cox SC, Grover LM, Al-Hindi Z, Novak-Frazer L, Richardson MD

Abstract
Reactive oxygen species (ROS) is a novel therapeutic strategy for topical or local application to wounds, mucosa or internal structures where there may be heavy bacterial bioburden with biofilm and chronic inflammation. Bacterial biofilms are a significant problem in clinical settings owing to their increased tolerance towards conventionally prescribed antibiotics and their propensity for selection of further antibacterial resistance. There is therefore a pressing need for the development of alternative therapeutic strategies that can improve antibiotic efficacy towards biofilms. ROS has been successful in treating chronic wounds and in clearing multidrug-resistant organisms, including methicillin-resistant Staphylococcus aureus (MRSA), and carbapenemase-producing isolates from wounds and vascular line sites. There is significant antifungal activity of ROS against planktonic and biofilm forms. Nebulised ROS has been evaluated in limited subjects to assess reductions in bioburden in chronically colonised respiratory tracts. The antibiofilm activity of ROS could have great implications for the treatment of a variety of persistent respiratory conditions. Use of ROS on internal prosthetic devices shows promise. A variety of novel delivery mechanisms are being developed to apply ROS activity to different anatomical sites.

PMID: 28213334 [PubMed - as supplied by publisher]

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Targeted therapy for chronic respiratory disease: a new paradigm.

Med J Aust. 2017 Feb 20;206(3):136-140

Authors: Gibson PG, Peters MJ, Wainwright CE

Abstract
Targeted therapy has emerged as a highly effective treatment approach for chronic respiratory diseases. Many of these conditions have dismal outcomes; however, targeted therapy shows great results for the subgroup who respond. This represents a new way to approach these conditions and offers great promise as a future treatment direction. In severe eosinophilic asthma, therapy that targets the interleukin-5 pathway with monoclonal antibodies leads to a 50% reduction in asthma exacerbations in previously refractory disease. In cystic fibrosis, lung function improves with therapy that targets specific molecular abnormalities in the cystic fibrosis transmembrane conductance regulator to increase the probability that this chloride channel is open. In lung cancer, specifically adenocarcinoma with epidermal growth factor receptor (EGFR) mutation and overexpression of EGFR tyrosine kinase, therapy that inhibits EGFR tyrosine kinase gives better outcomes than conventional chemotherapy.

PMID: 28208047 [PubMed - in process]

Faecal Calprotectin in Cystic Fibrosis and IT'S Relation to Disease Parameters - a Longitudinal Analysis Over 12 Years.

J Pediatr Gastroenterol Nutr. 2017 Feb 15;:

Authors: Ellemunter H, Engelhardt A, Schüller K, Steinkamp G

Abstract
OBJECTIVES: Faecal calprotectin (FC) is a marker of inflammation in the intestinal tract. We assessed FC levels longitudinally in patients with cystic fibrosis (CF) and evaluated the relation between FC results and relevant markers of disease.
METHODS: Calprotectin was measured in faecal samples starting in 2003 and values were stored in the centre's patient database. In this retrospective analysis we searched for associations of FC concentrations with disease severity and progression. Linear mixed effects models were used to model the logarithm of FC levels.
RESULTS: A total of 171 patients (0-61 years) had 2434 FC measurements between 2003 and 2015, with a total observation period of 1686 patient years. Median (IQR) FC concentrations were 60.9 (75.9) μg/g and 61% of the samples showed elevated FC concentrations (>50 μg/g). Despite some statistically significant effects, there was no clinically relevant association between FC and sex, age, FEV1 z-score, or BMI z-score. Pancreatic insufficiency (i.e. faecal elastase < 100 μg/g stool) was associated with considerably higher FC values compared to normal pancreatic function (median FC 68 vs. 29 μg/g, p < 0.0001). F508del homozygous subjects showed a trend to higher FC values than heterozygous patients (median 71 vs. 62 μg/g, p = 0.173). In addition, a significant association with increasing serum CRP concentrations (p < 0.0001) was observed.
CONCLUSIONS: FC was elevated in two thirds of stool specimens. Increased FC was more common in patients with pancreatic insufficiency. Whether increased faecal calprotectin reflects intestinal inflammation in patients with cystic fibrosis remains to be determined.

PMID: 28207476 [PubMed - as supplied by publisher]

Molecular modeling in the age of clinical genomics, the enterprise of the next generation.

J Mol Model. 2017 Mar;23(3):75

Authors: Prokop JW, Lazar J, Crapitto G, Smith DC, Worthey EA, Jacob HJ

Abstract
Protein modeling and molecular dynamics hold a unique toolset to aide in the characterization of clinical variants that may result in disease. Not only do these techniques offer the ability to study under characterized proteins, but they do this with the speed that is needed for time-sensitive clinical cases. In this paper we retrospectively study a clinical variant in the XIAP protein, C203Y, while addressing additional variants seen in patients with similar gastrointestinal phenotypes as the C203Y mutation. In agreement with the clinical tests performed on the C203Y patient, protein modeling and molecular dynamics suggest that direct interactions with RIPK2 and Caspase3 are altered by the C203Y mutation and subsequent loss of Zn coordination in the second BIR domain of XIAP. Interestingly, the variant does not appear to alter interactions with SMAC, resulting in further damage to the caspase and NOD2 pathways. To expand the computational strategy designed when studying XIAP, we have applied the molecular modeling tools to a list of 140 variants seen in CFTR associated with cystic fibrosis, and a list of undiagnosed variants in 17 different genes. This paper shows the exciting applications of molecular modeling in the classification and characterization of genetic variants identified in next generation sequencing. Graphical abstract XIAP in Caspase 3 and NOD2 signaling pathways.

PMID: 28204942 [PubMed - in process]

High incidence of non-tuberculous mycobacteria-positive cultures among adolescent with cystic fibrosis.

J Cyst Fibros. 2017 Feb 12;:

Authors: Cavalli Z, Reynaud Q, Bricca R, Nove-Josserand R, Durupt S, Reix P, Perceval M, de Montclos MP, Lina G, Durieu I

Abstract
BACKGROUND: We evaluated the prevalence of non-tuberculous mycobacteria (NTM)-positive cultures among our cystic fibrosis (CF) center patients, reviewed risk factors for NTM positivity, and determined its impact on lung function evolution.
METHODS: From 2009 to 2014, CF adults and children attending the CF center of Lyon (France) and having at least one positive NTM isolate were included. Each case was matched by age and gender with two CF patients with no NTM isolate (controls).
RESULTS: 48 CF patients with NTM-positive isolates were matched to 96 controls. The age group for whom incident NTM was higher was young adolescents aged 13 to 17. A significant association for NTM positivity was found with Staphylococcusaureus in multivariate analysis and with allergic bronchopulmonary aspergillosis, corticosteroid and itraconazole in univariate analysis. Mean annual FEV1 decline was faster for NTM-positive patients compared to controls.
CONCLUSION: These data highlight the high incidence of NTM-positive cultures among young adolescents with CF.

PMID: 28202251 [PubMed - as supplied by publisher]

Beyond cystic fibrosis transmembrane conductance regulator (CFTR) single channel kinetics: implications for therapeutic intervention.

J Physiol. 2017 Feb 15;595(4):1015-1016

Authors: McNicholas CM

PMID: 28198020 [PubMed - in process]

Genomic profiling of acute lymphoblastic leukemia in ataxia telangiectasia patients reveals tight link between ATM mutations and chromothripsis.

Leukemia. 2017 Feb 15;:

Authors: Ratnaparkhe M, Hlevnjak M, Kolb T, Jauch A, Maass KK, Devens F, Rode A, Hovestadt V, Korshunov A, Pastorczak A, Mlynarski W, Sungalee S, Korbel J, Hoell J, Fischer U, Milde T, Kramm C, Nathrath M, Chrzanowska K, Tausch E, Takagi M, Taga T, Constantini S, Loeffen J, Meijerink J, Zielen S, Gohring G, Schlegelberger B, Maass E, Siebert R, Kunz J, Kulozik AE, Worst B, Jones DT, Pfister SM, Zapatka M, Lichter P, Ernst A

Abstract
Recent developments in sequencing technologies led to the discovery of a novel form of genomic instability, termed chromothripsis. This catastrophic genomic event, involved in tumorigenesis, is characterized by tens to hundreds of simultaneously acquired locally clustered rearrangements on one chromosome. We hypothesized that leukemias developing in individuals with Ataxia Telangiectasia, who are born with two mutated copies of the ATM gene, an essential guardian of genome stability, would show a higher prevalence of chromothripsis due to the associated defect in DNA double-strand break repair. Using whole-genome sequencing, fluorescence in situ hybridization and RNA sequencing, we characterized the genomic landscape of Acute Lymphoblastic Leukemia (ALL) arising in patients with Ataxia Telangiectasia. We detected a high frequency of chromothriptic events in these tumors, specifically on acrocentric chromosomes, as compared to tumors from individuals with other types of DNA repair syndromes (27 cases total, 10 with Ataxia Telangiectasia). Our data suggest that the genomic landscape of Ataxia Telangiectasia ALL is clearly distinct from that of sporadic ALL. Mechanistically, short telomeres and compromised DNA damage response in cells of Ataxia Telangiectasia patients may be linked with frequent chromothripsis. Furthermore, we show that ATM loss is associated with increased chromothripsis prevalence in additional tumor entities.Leukemia accepted article preview online, 15 February 2017. doi:10.1038/leu.2017.55.

PMID: 28196983 [PubMed - as supplied by publisher]

Vardenafil reduces macrophage pro-inflammatory overresponses in Cystic Fibrosis through PDE5- and CFTR-dependent mechanisms.

Clin Sci (Lond). 2017 Feb 14;:

Authors: Noel S, Panin N, Beka M, Dhooghe B, Huaux F, Leal T

Abstract
Chronic inflammation that progressively disrupts the lung tissue is a hallmark of Cystic Fibrosis (CF). In mice, vardenafil, an inhibitor of phosphodiesterase type 5 (PDE5), restores transepithelial ion transport and corrects mislocalization of the most common CF mutation, F508del-CFTR. It also reduces lung pro-inflammatory responses in mice and in patients with CF. To test the hypothesis that macrophages are target effector cells of the immunomodulatory effect of vardenafil, we isolated lung macrophages from mice homozygous for the F508del mutation or invalidated for the cftr gene and from their corresponding wild-type littermates. We then evaluated the effect of vardenafil on the classical M1 polarization, mirroring release of pro-inflammatory cytokines. We confirmed that macrophages from different body compartments express CFTR and showed that vardenafil targets the cells through PDE5- and CFTR-dependent mechanisms. In the presence of the F508del mutation, vardenafil downregulated overresponses of the M1 markers, tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (NOS)-2. Our study identifies lung macrophages as target cells of the anti-inflammatory effect of vardenafil in CF and supports the view that the drug is potentially beneficial for treating CF as it combines rescue of CFTR protein and anti-inflammatory properties.

PMID: 28196856 [PubMed - as supplied by publisher]

R248G cystic fibrosis transmembrane conductance regulator mutation in three siblings presenting with recurrent acute pancreatitis and reproductive issues: a case series.

J Med Case Rep. 2017 Feb 15;11(1):42

Authors: Villalona S, Glover-López G, Ortega-García JA, Moya-Quiles R, Mondejar-López P, Martínez-Romero MC, Rigabert-Montiel M, Pastor-Vivero MD, Sánchez-Solís M

Abstract
BACKGROUND: Mutational combinations of the cystic fibrosis transmembrane conductance regulator, CFTR, gene have different phenotypic manifestations at the molecular level with varying clinical consequences for individuals possessing such mutations. Reporting cystic fibrosis transmembrane conductance regulator mutations is important in understanding the genotype-phenotype correlations and associated clinical presentations in patients with cystic fibrosis. Understanding the effects of mutations is critical in developing appropriate treatments for individuals affected with cystic fibrosis, non-classic cystic fibrosis, or cystic fibrosis transmembrane conductance regulator-related disorders. This is the first report of related individuals possessing the R248G missense cystic fibrosis transmembrane conductance regulator mutation and we present their associated clinical histories.
CASE PRESENTATION: All three patients are of Spanish descent. Deoxyribonucleic acid analysis revealed that all three siblings possessed a novel c.742A>G mutation, resulting in a p.Arg248Gly (R248G) amino acid change in exon 6 in trans with the known N1303K mutant allele. Case 1 patient is a 39-year-old infertile man presenting with congenital unilateral absence of the vas deferens and recurrent episodes of epigastric pain. Case 2 patient is a 32-year-old woman presenting with periods of infertility, two previous spontaneous abortions, recurrent epigastric pain, and recurrent pancreatitis. Case 3 patient is a 29-year-old woman presenting with recurrent pancreatitis and epigastric pain.
CONCLUSIONS: We report the genotype-phenotype correlations and clinical manifestations of a novel R248G cystic fibrosis transmembrane conductance regulator mutation: congenital unilateral absence of the vas deferens in males, reduced female fertility, and recurrent acute pancreatitis. In addition, we discuss the possible functional consequences of the mutations at the molecular level.

PMID: 28196530 [PubMed - in process]

CHEER National Study of Chronic Rhinosinusitis Practice Patterns.

Otolaryngol Head Neck Surg. 2017 Feb 01;:194599817691476

Authors: Chapurin N, Pynnonen MA, Roberts R, Schulz K, Shin JJ, Witsell DL, Parham K, Langman A, Carpenter D, Vambutas A, Nguyen-Huynh A, Wolfley A, Lee WT

Abstract
Objectives (1) Describe national patterns of chronic rhinosinusitis (CRS) care across academic and community practices. (2) Determine the prevalence of comorbid disorders in CRS patients, including nasal polyposis, allergic rhinitis, asthma, and cystic fibrosis. (3) Identify demographic, clinical, and practice type factors associated with endoscopic sinus surgery (ESS). Study Design Multisite cross-sectional study. Setting Otolaryngology's national research network CHEER (Creating Healthcare Excellence through Education and Research). Subjects and Methods A total of 17,828 adult patients with CRS were identified, of which 10,434 were seen at community practices (59%, n = 8 sites) and 7394 at academic practices (41%, n = 10 sites). Multivariate logistic regression was used to evaluate the association between demographic, practice type, and clinical factors and the odds of a patient undergoing ESS. Results The average age was 50.4 years; 59.5% of patients were female; and 88.3% were Caucasian. The prevalence of comorbid diseases was as follows: allergic rhinitis (35.1%), nasal polyposis (13.3%), asthma (4.4%), and cystic fibrosis (0.2%). In addition, 24.8% of patients at academic centers underwent ESS, as compared with 12.3% at community sites. In multivariate analyses, nasal polyposis (odds ratio [OR], 4.28), cystic fibrosis (OR, 2.42), and academic site type (OR, 1.86) were associated with ESS ( P < .001), while adjusting for other factors. Conclusions We describe practice patterns of CRS care, as well as demographic and clinical factors associated with ESS. This is the first study of practice patterns in CRS utilizing the CHEER network and may be used to guide future research.

PMID: 28195023 [PubMed - as supplied by publisher]

Differential Responses of Human Dendritic Cells to Metabolites from the Oral/Airway Microbiome.

Clin Exp Immunol. 2017 Feb 14;:

Authors: Whiteson K, Agrawal S, Agrawal A

Abstract
Small molecule metabolites that are produced or altered by host-associated microbial communities are emerging as significant immune response modifiers. However, there is a key gap in our knowledge of how oral microbial metabolites affect the immune response. Here, we examined the effects of metabolites from five bacterial strains commonly found in the oral/airway microbial communities of humans. The five strains, each isolated from cystic fibrosis patient sputum, were Pseudomonas aeruginosa FLR01 non-mucoid (P1) and FLR02 mucoid (P2) forms, Streptococcus pneumoniae (Sp), Streptococcus salivarius (Ss), and Rothia mucilaginosa (Rm). The effect of bacterial metabolites on dendritic cell (DC) activation, T cell priming and cytokine secretion was determined by exposing DCs to bacterial supernatants and individual metabolites of interest. Supernatants from P1 and P2 induced high levels of TNF-α, IL-12 and IL-6 from DCs and primed T cells to secrete IFN-γ, IL-22 compared to supernatants from Sp, Ss and Rm. Investigations into the composition of supernatants using GC-MS revealed signature metabolites for each of the strains. Supernatants from P1 and P2 contained high levels of putrescine and glucose while Sp and Ss contained high levels of 2,3-butanediol. The individual metabolites replicated the results of whole supernatants though the magnitudes of their effects were significantly reduced. Altogether, our data demonstrate for the first time that the signature metabolites produced by different bacteria have different effects on DC functions. The identification of signature metabolites and their effects on the host immune system can provide mechanistic insights into diseases and may also be developed as biomarkers. This article is protected by copyright. All rights reserved.

PMID: 28194750 [PubMed - as supplied by publisher]

Role of CFTR mutation analysis in the diagnostic algorithm for cystic fibrosis.

World J Pediatr. 2017 Feb 14;:

Authors: Ratkiewicz M, Pastore M, McCoy KS, Thompson R, Hayes D, Sheikh SI

Abstract
BACKGROUND: The cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation identification is being used with increased frequency to aid in the diagnosis of cystic fibrosis (CF) in those suspected with CF. Aim of this study was to identify diagnostic outcomes when CFTR mutational analysis was used in CF diagnosis. CFTR mutational analysis results were also compared with sweat chloride results.
METHODS: This study was done on all patients at our institution who had CFTR mutation analysis over a sevenyear period since August 2006.
RESULTS: A total of 315 patients underwent CFTR mutational analysis. Fifty-one (16.2%) patients had two mutations identified. Among them 32 had positive sweat chloride levels (≥60 mmol/L), while seven had borderline sweat chloride levels (40-59 mmol/L). An additional 70 patients (22.3%) had only one mutation identified. Among them eight had positive sweat chloride levels, and 17 had borderline sweat chloride levels. Fifty-five patients (17.5%) without CFTR mutations had either borderline (n=45) or positive (n=10) sweat chloride results. Three patients with a CF phenotype had negative CFTR analysis but elevated sweat chloride levels. In eighty-three patients (26.4%) CFTR mutational analysis was done without corresponding sweat chloride testing.
CONCLUSIONS: Although CFTR mutation analysis has improved the diagnostic capability for CF, its use either as the first step or the only test to diagnose CFTR dysfunction should be discouraged and CF diagnostic guidelines need to be followed.

PMID: 28194692 [PubMed - as supplied by publisher]

Wearable Potentiometric Chloride Sweat Sensor: The Critical Role of the Salt Bridge.

Anal Chem. 2016 Dec 20;88(24):12241-12247

Authors: Choi DH, Kim JS, Cutting GR, Searson PC

Abstract
The components of sweat provide an array of potential biomarkers for health and disease. Sweat chloride is of interest as a biomarker for cystic fibrosis, electrolyte metabolism disorders, electrolyte balance, and electrolyte loss during exercise. Developing wearable sensors for biomarkers in sweat is a major technological challenge. Potentiometric sensors provide a relatively simple technology for on-body sweat chloride measurement, however, equilibration between reference and test solutions has limited the time over which accurate measurements can be made. Here, we report on a wearable potentiometric chloride sweat sensor. We performed parametric studies to show how the salt bridge geometry determines equilibration between the reference and test solutions. From these results, we show a sweat chloride sensor can be designed to provide accurate measurements over extended times. We then performed on-body tests on healthy subjects while exercising to establish the feasibility of using this technology as a wearable device.

PMID: 28193033 [PubMed - in process]

Inhibition of cyst growth in PCK and Wpk rat models of polycystic kidney disease with low doses of peroxisome proliferator-activated receptor γ agonists.

J Transl Int Med. 2016 Sep 01;4(3):118-126

Authors: Flaig SM, Gattone VH, Blazer-Yost BL

Abstract
BACKGROUND AND OBJECTIVES: The studies were designed to test the efficacy of two peroxisome proliferator-activated receptor γ (PPARγ) agonists in two rodent models of polycystic kidney disease (PKD).
MATERIALS AND METHODS: The PCK rat is a slowly progressing cystic model while the Wpk(-/-) rat is a rapidly progressing model. PCK rats were fed with a pharmacological (0.4 mg/kg body weight [BW]) and a sub-pharmacological (0.04 mg/kg BW) dose of rosiglitazone (week 4-28). Wpk(-/-) rats were fed with pharmacological (2.0 mg/kg BW) and sub-pharmacologic (0.2 mg/kg BW) doses of pioglitazone from day 5 to 18. At termination, kidney weights of treated versus untreated cystic animals were used to determine efficacy. The current studies were also compared with previous studies containing higher doses of PPARγ agonists. The concentrations used in the animals were calculated with reference to equivalent human doses for both drugs.
RESULTS: The current studies demonstrate: 1) that low, pharmacologically relevant, doses of the PPARγ agonists effectively inhibit cyst growth; 2) there is a class action of the drugs with both commercially available PPARγ agonists, rosiglitazone, and pioglitazone, inhibiting cyst growth; 3) the drugs showed efficacy in two different preclinical cystic models. In the PCK rat, animals fed with a sub-pharmacological dose of rosiglitazone for 24 weeks had significantly lower kidney weights than untreated animals (3.68 ± 0.13 g vs. 4.17 ± 0. 11 g, respectively, P < 0.01) while treatment with a pharmacologic dose had no significant effect on kidney weight. The rapidly progressing Wpk(-/-) rats were fed with pharmacological and sub-pharmacologic doses of pioglitazone from day 5 to 18 and the kidneys were compared with non-treated, cystic animals. Kidney weights on the pharmacologic dose were not statistically lower than the untreated animals while rats fed a sub-pharmacologic dose showed a significant decrease compared with untreated animals (3.35 ± 0.15 g vs. 4.55 ± 0.46 g, respectively, P = 0.045).
CONCLUSION: Concentrations of PPARγ agonists below the human equivalent diabetic doses are effective in slowing cyst growth in two rodent models of PKD.

PMID: 28191533 [PubMed - in process]

Pregnancy among cystic fibrosis women in the era of CFTR modulators.

J Cyst Fibros. 2017 Feb 09;:

Authors: Heltshe SL, Godfrey EM, Josephy T, Aitken ML, Taylor-Cousar JL

Abstract
BACKGROUND: Little is known about how new therapies that partially correct the basic cystic fibrosis (CF) defect (ivacaftor and lumacaftor) might alter hormonal contraceptive effectiveness, impact pregnancy outcomes, or affect pregnancy timing. Examination of pregnancy rates among CF women during periods of CFTR modulator therapy initiation will provide foundation for further research in this area.
METHODS: The Cystic Fibrosis Foundation Patient Registry was used to examine pregnancy rates and outcomes by genotype class before, during, and after the introduction of CFTR modulator therapies between 2005 and 2014.
RESULTS: Among women with CF, ages 15-44years, there was a slight downward trend in annual pregnancy rates from 2005 to 2014 (2% reduction per year, p=0.041). Among women with G551D, pregnancy rates during phase 3 ivacaftor trial years was 14.4/1000 women-years compared to 34.0/1000 prior to the trial period (relative risk [RR]=0.65; 95% CI=0.43-0.96; p=0.011) and 38.4/1000 after drug approval in June 2012 (RR=1.52 post-approval compared to trial period; 95% CI=1.26, 1.83; p<0.001). Pregnancy outcomes did not significantly change between 2005 and 2014 for any genotype class.
CONCLUSION: Evidence of significantly increased numbers of pregnancies among women taking approved CFTR modulators is important because of the unknown risk to pregnancy and fetal outcomes. Increases may be temporary following pregnancy prevention during controlled clinical trials, or from altered perceptions about maternal survival with new approved treatments. As more women with CF become eligible to receive modulators, the CF community must study their effect on contraceptive efficacy and safety during pregnancy. With increased health and survival due to modulation, family planning topics will become more common in CF.

PMID: 28190780 [PubMed - as supplied by publisher]

Dietary Genistein Rescues Reduced Basal Chloride Secretion in Diabetic Jejunum via Sex-Dependent Mechanisms.

Cell Physiol Biochem. 2016;40(1-2):335-346

Authors: Catmull S, Masood F, Schacht S, Dolan R, Stegman D, Leung L, Al-Nakkash L

Abstract
BACKGROUND/AIMS: The goal of this study was to determine the effect of dietary genistein (naturally occurring phytoestrogen) on jejunal secretory function in a clinically relevant model of diabetes and obesity, the leptin-defIcient ob/ob mouse.
METHODS: We measured transepithelial short circuit current (Isc), across freshly isolated segments of jejunum from 12-week old male and female ob/ob and lean C57Bl/6J mice fed a genistein diet (600 mg genistein/kg diet) for 4-weeks. Separate segments of jejunum were frozen for western blot determination of key proteins involved in secretory transport.
RESULTS: Basal Isc was signifIcantly decreased (by 33%, P<0.05) in ob/ob females versus leans, and genistein-diet reversed this. Similarly, in males, basal Isc was decreased (by 47%, P<0.05) in ob/ob mice versus leans, and genistein-diet reversed this. Inhibition with either clotrimazole (100 µM, bilateral) or ouabain (100 µM, basolateral) was signifIcantly reduced in ob/ob mice compared to leans (P<0.05), and genistein-diet reversed clotrimazole-sensitive inhibition in ob/ob females, and reversed the ouabain-sensitive inhibition in males (indicating sex-dependent mechanisms). Our data suggested that PDE3 levels were dysregulated in ob/ob females and genistein reversed this. Expression of total CFTR (normalized to actin) was signifIcantly decreased ∼80% (P<0.05) in all ob/ob mice compared to leans, and genistein-diet was without effect. Expression of total NKCC1 (normalized to actin) was signifIcantly decreased ∼80% (P<0.05) in ob/ob male mice versus leans, and genistein-diet reversed this.
CONCLUSIONS: Our data suggests that the reduced basal jejunal Isc in ob/ob female mice is a consequence of reduced CFTR expression, decreased activities of the basolateral KCa channel and Na+/K+-ATPase, and in male mice reduced basal jejunal Isc is a consequence of reduced CFTR and NKCC1 expression, along with decreased activities of the basolateral KCa channel and Na+/K+-ATPase. Genistein-diet has beneficial effects on basal Isc mediated by sex-dependent mechanisms in diabetic mice: in females via increased KCa-sensitive Isc and in males via increased Na+/K+-ATPase activity and increased NKCC1 expression. Improved understanding of intestinal dysfunctions in the ob/ob jejunum, may allow for the development of novel drug targets to treat obesity and diabetes, and may also be of benefit in CF-related diabetes.

PMID: 27866192 [PubMed - indexed for MEDLINE]

Consensus on the diagnosis and treatment of cholestatic liver diseases (2015, China).

J Dig Dis. 2016 Mar;17(3):137-54

Authors: Chinese Society of Hepatology, Chinese Society of Gastroenterology, and Chinese Society of Infectious Diseases of the Chinese Medical Association

PMID: 26950044 [PubMed - indexed for MEDLINE]

Effectiveness of a stepwise Pseudomonas aeruginosa eradication protocol in children with cystic fibrosis.

J Cyst Fibros. 2017 Feb 09;:

Authors: Blanchard AC, Horton E, Stanojevic S, Taylor L, Waters V, Ratjen F

Abstract
INTRODUCTION: Antibiotic eradication therapy (AET) for initial Pseudomonas aeruginosa (Pa) infection is standard of care in children with cystic fibrosis (CF), but information is limited on treatment for patients who fail initial AET. The aim of this study was to evaluate the effectiveness of a multi-step protocol for AET for new-onset Pa infections in children with CF.
METHODS: A three-step AET protocol which includes: (step 1) 28days of tobramycin inhalation solution (TIS) for new-onset Pa infection; (step 2) a second course of TIS for patients with positive respiratory tract culture after step 1; (step 3) 14days of intravenous antibiotics followed by 28days of TIS for patients with a subsequent positive culture. We conducted a retrospective review of all pediatric CF patients who underwent the eradication protocol between January 2010 and December 2015. The success rate of each step and of the overall protocol was recorded.
RESULTS: During the study period, 128 patients had a total of 213 new-onset Pa infections. Of 195 asymptomatic episodes, 150 (76.9%, 95% CI 70.4; 82.6) cleared after step 1 and 12 cleared after step 2 (33.3% (95% CI 18.6; 50.9) stepwise success rate and 87.1% (95% CI 77.1; 88.1) cumulative success rate). Intravenous antibiotics followed by 28days of TIS were administered in 24 episodes; this was successful in 10 episodes (41.7%; 95% CI 22.1; 63.4). The regimen in asymptomatic patients failed in fourteen episodes (7.5%; 95% CI 4.2; 12.3) then considered chronically infected with Pa. Overall, the cumulative success rate of the asymptomatic arm was 88.2% (95% CI 82.8; 92.4).
CONCLUSION: The first step of the AET protocol led to the greatest eradication success. Subsequent eradication attempts have a success rate below 50%. Prospective studies of eradication protocols for this population are needed to determine the most effective treatment strategy.

PMID: 28189634 [PubMed - as supplied by publisher]

Calumenin contributes to ER-Ca(2+) homeostasis in bronchial epithelial cells expressing WT and F508del mutated CFTR and to F508del-CFTR retention.

Cell Calcium. 2017 Feb 04;:

Authors: Philippe R, Antigny F, Buscaglia P, Norez C, Huguet F, Castelbou C, Trouvé P, Becq F, Frieden M, Férec C, Mignen O

Abstract
Cystic Fibrosis (CF) is the most frequent fatal genetic disease in Caucasian populations. Mutations in the chloride channel CF Transmembrane Conductance Regulator (CFTR) gene are responsible for functional defects of the protein and multiple associated dysregulations. The most common mutation in patients with CF, F508del-CFTR, causes defective CFTR protein folding. Thus minimal levels of the receptor are expressed at the cell surface as the mutated CFTR is retained in the endoplasmic reticulum (ER) where it correlates with defective calcium (Ca(2+)) homeostasis. In this study, we discovered that the Ca(2+) binding protein Calumenin (CALU) is a key regulator in the maintenance of ER-Ca(2+) calcium homeostasis in both wild type and F508del-CFTR expressing cells. Calumenin modulates SERCA pump activity without drastically affecting ER-Ca(2+) concentration. In addition, reducing Calumenin expression in CF cells results in a partial restoration of CFTR activity, highlighting a potential function of Calumenin in CFTR maturation. These findings demonstrate a pivotal role for Calumenin in CF cells, providing insights into how modulation of Calumenin expression or activity may be used as a potential therapeutic tool to correct defects in F508del-CFTR.

PMID: 28189267 [PubMed - as supplied by publisher]