Association of Vancomycin Trough Concentration With Response to Treatment for Acute Pulmonary Exacerbation of Cystic Fibrosis.

J Pediatric Infect Dis Soc. 2017 Sep 01;6(3):e103-e108

Authors: Fusco NM, Francisconi R, Meaney CJ, Duman D, Frederick CA, Prescott WA

Abstract
Background: Our goal was to determine the relationship between serum vancomycin trough concentrations (VTCs) and changes in pulmonary function among individuals with an acute pulmonary exacerbation (APE) of cystic fibrosis (CF).
Methods: We included subjects who were ≥6 years of age, were hospitalized for an APE of CF between May 1, 2012, and April 30, 2014, were administered vancomycin for ≥48 hours, and had a history of airway infection with methicillin-resistant Staphylococcus aureus. Pearson correlations were performed to characterize the relationship between VTC and pulmonary function.
Results: The mean final VTC (± standard deviation) was 12.6 ± 3.3 µg/mL; 40 (81.6%) of 49 final VTCs were in the range of 10 to <15 µg/mL. The mean change in forced expiratory volume in 1 second (FEV1) between admission and discharge was 24.5% ± 24.4% (P < .001) of predicted values. Forty-two (85.7%) patients returned to their baseline FEV1. No correlation between the change in FEV1 and VTC (Pearson r = -0.10; P = .49) was identified. Similarly, VTC, daily weight-adjusted vancomycin dose, and vancomycin area under the concentration-time curve normalized to the minimum inhibitory concentration (AUC/MIC) were not significant predictors of change in FEV1 or return to baseline FEV1 on multivariate analysis. One (2%) subject experienced acute kidney injury.
Conclusions: The majority of patients experienced improvement in pulmonary function and a return to their baseline FEV1 while achieving a VTC in the range of 10 to <15 µg/mL. We were unable to identify a correlation between markers of vancomycin exposure and change in pulmonary function test results. Additional studies are needed to reinforce the efficacy of VTCs of 10 to 15 µg/mL for treating APEs of CF.

PMID: 28903517 [PubMed - in process]

Dendrimer-based selective autophagy-induction rescues ΔF508-CFTR and inhibits Pseudomonas aeruginosa infection in cystic fibrosis.

PLoS One. 2017;12(9):e0184793

Authors: Brockman SM, Bodas M, Silverberg D, Sharma A, Vij N

Abstract
BACKGROUND: Cystic Fibrosis (CF) is a genetic disorder caused by mutation(s) in the CF-transmembrane conductance regulator (Cftr) gene. The most common mutation, ΔF508, leads to accumulation of defective-CFTR protein in aggresome-bodies. Additionally, Pseudomonas aeruginosa (Pa), a common CF pathogen, exacerbates obstructive CF lung pathology. In the present study, we aimed to develop and test a novel strategy to improve the bioavailability and potentially achieve targeted drug delivery of cysteamine, a potent autophagy-inducing drug with anti-bacterial properties, by developing a dendrimer (PAMAM-DEN)-based cysteamine analogue.
RESULTS: We first evaluated the effect of dendrimer-based cysteamine analogue (PAMAM-DENCYS) on the intrinsic autophagy response in IB3-1 cells and observed a significant reduction in Ub-RFP and LC3-GFP co-localization (aggresome-bodies) by PAMAM-DENCYS treatment as compared to plain dendrimer (PAMAM-DEN) control. Next, we observed that PAMAM-DENCYS treatment shows a modest rescue of ΔF508-CFTR as the C-form. Moreover, immunofluorescence microscopy of HEK-293 cells transfected with ΔF508-CFTR-GFP showed that PAMAM-DENCYS is able to rescue the misfolded-ΔF508-CFTR from aggresome-bodies by inducing its trafficking to the plasma membrane. We further verified these results by flow cytometry and observed significant (p<0.05; PAMAM-DEN vs. PAMAM-DENCYS) rescue of membrane-ΔF508-CFTR with PAMAM-DENCYS treatment using non-permeabilized IB3-1 cells immunostained for CFTR. Finally, we assessed the autophagy-mediated bacterial clearance potential of PAMAM-DENCYS by treating IB3-1 cells infected with PA01-GFP, and observed a significant (p<0.01; PAMAM-DEN vs. PAMAM-DENCYS) decrease in intracellular bacterial counts by immunofluorescence microscopy and flow cytometry. Also, PAMAM-DENCYS treatment significantly inhibits the growth of PA01-GFP bacteria and demonstrates potent mucolytic properties.
CONCLUSIONS: We demonstrate here the efficacy of dendrimer-based autophagy-induction in preventing sequestration of ΔF508-CFTR to aggresome-bodies while promoting its trafficking to the plasma membrane. Moreover, PAMAM-DENCYS decreases Pa infection and growth, while showing mucolytic properties, suggesting its potential in rescuing Pa-induced ΔF508-CF lung disease that warrants further investigation in CF murine model.

PMID: 28902888 [PubMed - in process]

Repeated high-intensity cycling performance is unaffected by timing of carbohydrate ingestion.

J Strength Cond Res. 2017 Sep 06;:

Authors: Shei RJ, Paris HL, Beck CP, Chapman RF, Mickleborough TD

Abstract
To determine whether carbohydrate feeding taken immediately before, early, or late in a series of high-intensity cycling exercises affected cycling performance 16 trained, male cyclists (> 6hr post-prandial) performed three, 4-km cycling time trials (TT1, TT2, TT3) separated by 15 min of active recovery on four separate occasions. Carbohydrate feeding (80g) was given either before TT1 (PRE1), before TT2 (PRE2), before TT3 (PRE3), or not at all (control, CTL). Treatment order was randomized. Sweet-placebo was given prior to the other time trials. Blood glucose concentration (BG) was measured before each trial. Mean power output (Pmean) and time to completion (TTC) were recorded. Pmean was higher in TT1 compared to TT2 (p=0.001) and TT3 (p=0.004) in all conditions, but no differences were observed between treatments. TTC was lower in TT1 compared to TT2 (p=0.01) but no other differences in TTC (within or between treatments) were observed. Within CTL and PRE1, BG did not differ between TT1, TT2, and TT3. In PRE2, BG was significantly higher in TT2 compared to TT1 (p=0.006), in TT3 compared to TT1 (p=0.001), and in TT3 compared to TT2 (p=0.01). In PRE3, BG was significantly higher in TT3 compared to TT1 and TT2 (p=0.001 for both). Given that performance was not influenced by the timing of carbohydrate ingestion, athletes engaging in repeated, high-intensity cycling exercise do not need to ingest carbohydrate prior to-, or between- exercise bouts; furthermore, athletes should refrain from ingesting carbohydrate between bouts if they wish to avoid a rise in BG.

PMID: 28902115 [PubMed - as supplied by publisher]

Phenotypic plasticity in gene expression and physiological response in red drum Sciaenops ocellatus exposed to a long-term freshwater environment.

Fish Physiol Biochem. 2017 Sep 12;:

Authors: Gullian Klanian M, Zapata Pérez O, Vela-Magaña MA

Abstract
Red drum (Sciaenops ocellatus) is a euryhaline fish commonly found in the Gulf of Mexico and along the Atlantic coast of North America. Because of high commercial demand and its euryhaline characteristics, aquaculture of this species has diversified from marine to low-salinity aquaculture systems. In recent years, interest in the feasibility of producing red drum in inland freshwater systems has grown and this prompted us to investigate its osmoregulatory capacity after rearing for 8 months in a freshwater aquaculture system. We compared the activities of several genes and enzymes involved in the osmoregulatory process in freshwater-acclimatized (FW) and seawater (SW) red drum. The gene expression profiles were variable: the expression of genes encoding Na(+)/K(+)-ATPase (NKA) and the cystic fibrosis transmembrane regulator (CFTR) was slightly higher in SW than FW fish, while phosphoenolpyruvate carboxykinase (PEPCK) and the glucocorticoid receptor messenger RNA (mRNA) levels were higher in FW red drum. The total plasma K concentration was 60.3% lower, and gill NKA activity was 63.5% lower in FW than in SW fish. PEPCK activity was twofold higher in FW than in SW red drum. Similarly, liver glycogen was 60% higher in FW fish. In summary, both gene expression and the enzyme activity data support the phenotypic plasticity of red drum and suggest that the limited capacity for ion homeostasis observed, in particular the low plasma K concentration, was due to the composition of freshwater and does not necessarily reflect a physiological inability to osmoregulate.

PMID: 28900798 [PubMed - as supplied by publisher]

Predicted effects of observed changes in the mRNA and microRNA transcriptome of lung neutrophils during S. pneumoniae pneumonia in mice.

Sci Rep. 2017 Sep 12;7(1):11258

Authors: Gomez JC, Dang H, Kanke M, Hagan RS, Mock JR, Kelada SNP, Sethupathy P, Doerschuk CM

Abstract
The complex role of neutrophils in modulating the inflammatory response is increasingly appreciated. Our studies profiled the expression of mRNAs and microRNAs (miRs) in lung neutrophils in mice during S. pneumoniae pneumonia and performed in depth in silico analyses. Lung neutrophils were isolated 24 hours after intratracheal instillation of PBS or S. pneumoniae, and differentially expressed (DE) mRNAs and miRs were identified. Lung neutrophils from mice with S. pneumoniae pneumonia contained 4127 DE mRNAs, 36% of which were upregulated at least 2-fold. During pneumonia, lung neutrophils increase expression of pattern recognition receptors, receptors for inflammatory mediators, transcription factors including NF-κB and AP-1, Nrf2 targets, cytokines, chemokines and other inflammatory mediators. Interestingly, neutrophils responded to Type I interferons, whereas they both produced and responded to Type II interferon. Expression of regulators of the inflammatory and immune response was verified at the mRNA and protein level. Of approximately 1100 miRs queried, 31 increased and 67 decreased more than 2-fold in neutrophils from S. pneumoniae pneumonia. Network analyses of potential DE miR-target DE mRNA interactions revealed candidate key regulatory miRs. Thus, S. pneumoniae modulates mRNA and miR expression by lung neutrophils, increasing their ability to respond and facilitating host defense.

PMID: 28900269 [PubMed - in process]

Severe Pneumococcal Pneumonia Causes Acute Cardiac Toxicity and Subsequent Cardiac Remodeling.

Am J Respir Crit Care Med. 2017 Sep 01;196(5):609-620

Authors: Reyes LF, Restrepo MI, Hinojosa CA, Soni NJ, Anzueto A, Babu BL, Gonzalez-Juarbe N, Rodriguez AH, Jimenez A, Chalmers JD, Aliberti S, Sibila O, Winter VT, Coalson JJ, Giavedoni LD, Dela Cruz CS, Waterer GW, Witzenrath M, Suttorp N, Dube PH, Orihuela CJ

Abstract
RATIONALE: Up to one-third of patients hospitalized with pneumococcal pneumonia experience major adverse cardiac events (MACE) during or after pneumonia. In mice, Streptococcus pneumoniae can invade the myocardium, induce cardiomyocyte death, and disrupt cardiac function following bacteremia, but it is unknown whether the same occurs in humans with severe pneumonia.
OBJECTIVES: We sought to determine whether S. pneumoniae can (1) translocate the heart, (2) induce cardiomyocyte death, (3) cause MACE, and (4) induce cardiac scar formation after antibiotic treatment during severe pneumonia using a nonhuman primate (NHP) model.
METHODS: We examined cardiac tissue from six adult NHPs with severe pneumococcal pneumonia and three uninfected control animals. Three animals were rescued with antibiotics (convalescent animals). Electrocardiographic, echocardiographic, and serum biomarkers of cardiac damage were measured (troponin T, N-terminal pro-brain natriuretic peptide, and heart-type fatty acid binding protein). Histological examination included hematoxylin and eosin staining, immunofluorescence, immunohistochemistry, picrosirius red staining, and transmission electron microscopy. Immunoblots were used to assess the underlying mechanisms.
MEASUREMENTS AND MAIN RESULTS: Nonspecific ischemic alterations were detected by electrocardiography and echocardiography. Serum levels of troponin T and heart-type fatty acid binding protein were increased (P < 0.05) after pneumococcal infection in both acutely ill and convalescent NHPs. S. pneumoniae was detected in the myocardium of all NHPs with acute severe pneumonia. Necroptosis and apoptosis were detected in the myocardium of both acutely ill and convalescent NHPs. Evidence of cardiac scar formation was observed only in convalescent animals by transmission electron microscopy and picrosirius red staining.
CONCLUSIONS: S. pneumoniae invades the myocardium and induces cardiac injury with necroptosis and apoptosis, followed by cardiac scarring after antibiotic therapy, in an NHP model of severe pneumonia.

PMID: 28614669 [PubMed - indexed for MEDLINE]

The fermentation product 2,3-butanediol alters P. aeruginosa clearance, cytokine response and the lung microbiome.

ISME J. 2016 Dec;10(12):2978-2983

Authors: Nguyen M, Sharma A, Wu W, Gomi R, Sung B, Hospodsky D, Angenent LT, Worgall S

Abstract
Diseases that favor colonization of the respiratory tract with Pseudomonas aeruginosa are characterized by an altered airway microbiome. Virulence of P. aeruginosa respiratory tract infection is likely influenced by interactions with other lung microbiota or their products. The bacterial fermentation product 2,3-butanediol enhances virulence and biofilm formation of P. aeruginosa in vitro. This study assessed the effects of 2,3-butanediol on P. aeruginosa persistence, inflammatory response, and the lung microbiome in vivo. Here, P. aeruginosa grown in the presence of 2,3-butanediol and encapsulated in agar beads persisted longer in the murine respiratory tract, induced enhanced TNF-α and IL-6 responses and resulted in increased colonization in the lung tissue by environmental microbes. These results led to the following hypothesis that now needs to be tested with a larger study: fermentation products from the lung microbiota not only have a role in P. aeruginosa virulence and abundance, but also on the increased colonization of the respiratory tract with environmental microbes, resulting in dynamic shifts in microbiota diversity and disease susceptibility.

PMID: 27177192 [PubMed - indexed for MEDLINE]

Respiratory research networks in Europe and beyond: aims, achievements and aspirations for the 21st century.

Breathe (Sheff). 2017 Sep;13(3):209-215

Authors: Martin-Loeches I, Zampieri F, Povoa P, Ranzani O, Bos LD, Aliberti S, Torres A

Abstract
Healthcare-associated infection, such as intensive care unit (ICU)-related respiratory infections, remain the most frequently encountered morbidity of ICU admission, prolonging hospital stay and increasing mortality rates. The epidemiology of ICU-related respiratory infections, particularly nonventilated ICU-associated pneumonia and ventilator-associated tracheobronchitis, appears to be quite different among different countries. European countries have different prevalence, patterns and mechanism of resistance, as well as different treatments chosen by different attending physicians. The classical clinical research process in respiratory infections consists of the following loop: 1) identification of knowledge gaps; 2) systematic review and search for adequate answers; 3) generation of study hypotheses; 4) design of study protocols; 5) collection clinical data; 6) analysis and interpretation of the results; and 7) implementation of the results in clinical practice.

PMID: 28894481 [PubMed]

Use of a High-Throughput Phenotypic Screening Strategy to Identify Amplifiers, a Novel Pharmacological Class of Small Molecules That Exhibit Functional Synergy with Potentiators and Correctors.

SLAS Discov. 2017 Sep 01;:2472555217729790

Authors: Giuliano KA, Wachi S, Drew L, Dukovski D, Green O, Bastos C, Cullen MD, Hauck S, Tait BD, Munoz B, Lee PS, Miller JP

Abstract
Cystic fibrosis (CF) is a lethal genetic disorder caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Despite recent groundbreaking approval of genotype-specific small-molecule drugs, a significant portion of CF patients still lack effective therapeutic options that address the underlying cause of the disease. Through a phenotypic high-throughput screen of approximately 54,000 small molecules, we identified a novel class of CFTR modulators called amplifiers. The identified compound, the characteristics of which are represented here by PTI-CH, selectively increases the expression of immature CFTR protein across different CFTR mutations, including F508del-CFTR, by targeting the inefficiencies of early CFTR biosynthesis. PTI-CH also augments the activity of other CFTR modulators and was found to possess novel characteristics that distinguish it from CFTR potentiator and corrector moieties. The PTI-CH-mediated increase in F508del-CFTR did not elicit cytosolic or endoplasmic reticulum-associated cellular stress responses. Based on these data, amplifiers represent a promising new class of CFTR modulators for the treatment of CF that can be used synergistically with other CFTR modulators.

PMID: 28898585 [PubMed - as supplied by publisher]

Maturation of arousals during day and night in infants with non-smoking and smoking mothers.

Early Hum Dev. 2017 Sep 08;115:46-50

Authors: Gillioen B, Plancoulaine S, Montemitro E, Flori S, Lin JS, Guyon A, Stagnara C, Bat-Pitault F, Patural H, Gustin MP, Franco P

PMID: 28892739 [PubMed - as supplied by publisher]

Membrane Mucin Muc4 promotes blood cell association with tumor cells and mediates efficient metastasis in a mouse model of breast cancer.

Oncogene. 2017 Sep 11;:

Authors: Rowson-Hodel AR, Wald JH, Hatakeyama J, O'Neal WK, Stonebraker JR, VanderVorst K, Saldana MJ, Borowsky AD, Sweeney C, Carraway KL

Abstract
Mucin-4 (Muc4) is a large cell surface glycoprotein implicated in the protection and lubrication of epithelial structures. Previous studies suggest that aberrantly expressed Muc4 can influence the adhesiveness, proliferation, viability and invasiveness of cultured tumor cells, as well as the growth rate and metastatic efficiency of xenografted tumors. Although it has been suggested that one of the major mechanisms by which Muc4 potentiates tumor progression is via its engagement of the ErbB2/HER2 receptor tyrosine kinase, other mechanisms exist and remain to be delineated. Moreover, the requirement for endogenous Muc4 for tumor growth progression has not been previously explored in the context of gene ablation. To assess the contribution of endogenous Muc4 to mammary tumor growth properties, we first created a genetically engineered mouse line lacking functional Muc4 (Muc4(ko)), and then crossed these animals with the NDL (Neu DeLetion mutant) model of ErbB2-induced mammary tumorigenesis. We observed that Muc4(ko) animals are fertile and develop normally, and adult mice exhibit no overt tissue abnormalities. In tumor studies, we observed that although some markers of tumor growth such as vascularity and cyclin D1 expression are suppressed, primary mammary tumors from Muc4(ko)/NDL female mice exhibit similar latencies and growth rates as Muc4(wt)/NDL animals. However, the presence of lung metastases is markedly suppressed in Muc4(ko)/NDL mice. Interestingly, histological analysis of lung lesions from Muc4(ko)/NDL mice revealed a reduced association of disseminated cells with platelets and white blood cells. Moreover, isolated cells derived from Muc4(ko)/NDL tumors interact with fewer blood cells when injected directly into the vasculature or diluted into blood from wild type mice. We further observed that blood cells more efficiently promote the viability of non-adherent Muc4(wt)/NDL cells than Muc4(ko)/NDL cells. Together, our observations suggest that Muc4 may facilitate metastasis by promoting the association of circulating tumor cells with blood cells to augment tumor cell survival in circulation.Oncogene advance online publication, 11 September 2017; doi:10.1038/onc.2017.327.

PMID: 28892049 [PubMed - as supplied by publisher]

Mounier Kuhn syndrome presenting with recurrent atelectasis.

Acta Clin Belg. 2017 Sep 11;:1-3

Authors: Quentin C, Lefevre N, Bodart E, Hanssens L

Abstract
Objective and importance Mounier Kuhn syndrome is usually diagnosed in adulthood, and only a few cases have been described in childhood. Clinical presentation We present the case of a seven-year-old boy suffering from recurrent pneumonia and atelectasis. Intervention Previously performed chest X-rays showed bilateral hyperinflation and tracheobronchomegaly. Chest computed tomography (CT) confirmed the presence of distal enlargement of trachea and bronchi. Tracheobronchomegaly associated with recurrent respiratory tract infections is consistent with Mounier Kuhn syndrome. Pseudomonas aeruginosa was isolated from the sputum of the patient. He was then treated according to the guidelines for P. aeruginosa management in cystic fibrosis patients considering the similarities in clinical presentations and pathophysiology of both diseases. Antibiotic treatment resulted in a remarkable reduction of events of pulmonary exacerbation and hospitalizations. There are no specific guidelines for treatment options in case of pulmonary exacerbation of Mounier Kuhn syndrome. Case reports discussing the choice and efficiency of antibiotic treatment are random. Conclusion headings We share our experience of treating pulmonary exacerbation caused by P. aeruginosa in a patient with Mounier Kuhn syndrome suggesting a possible treatment option of pseudomonas infections in this syndrome.

PMID: 28891754 [PubMed - as supplied by publisher]

Ursodeoxycholic acid for cystic fibrosis-related liver disease.

Cochrane Database Syst Rev. 2017 Sep 11;9:CD000222

Authors: Cheng K, Ashby D, Smyth RL

Abstract
BACKGROUND: Abnormal biliary secretion leads to the thickening of bile and the formation of plugs within the bile ducts; the consequent obstruction and abnormal bile flow ultimately results in the development of cystic fibrosis-related liver disease. This condition peaks in adolescence with up to 20% of adolescents with cystic fibrosis developing chronic liver disease. Early changes in the liver may ultimately result in end-stage liver disease with people needing transplantation. One therapeutic option currently used is ursodeoxycholic acid. This is an update of a previous review.
OBJECTIVES: To analyse evidence that ursodeoxycholic acid improves indices of liver function, reduces the risk of developing chronic liver disease and improves outcomes in general in cystic fibrosis.
SEARCH METHODS: We searched the Cochrane CF and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. We also contacted drug companies and searched online trial registries.Date of the most recent search of the Group's trials register: 09 April 2017.
SELECTION CRITERIA: Randomised controlled trials of the use of ursodeoxycholic acid for at least three months compared with placebo or no additional treatment in people with cystic fibrosis.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility and quality. The authors used GRADE to assess the quality of the evidence.
MAIN RESULTS: Twelve trials have been identified, of which four trials involving 137 participants were included; data were only available from three of the trials (118 participants) since one cross-over trial did not report appropriate data. The dose of ursodeoxycholic acid ranged from 10 to 20 mg/kg/day for up to 12 months. The complex design used in two trials meant that data could only be analysed for subsets of participants. There was no significant difference in weight change, mean difference -0.90 kg (95% confidence interval -1.94 to 0.14) based on 30 participants from two trials. Improvement in biliary excretion was reported in only one trial and no significant change after treatment was shown. There were no data available for analysis for long-term outcomes such as death or need for liver transplantation.
AUTHORS' CONCLUSIONS: There are few trials assessing the effectiveness of ursodeoxycholic acid. The quality of the evidence identified ranged from low to very low. There is currently insufficient evidence to justify its routine use in cystic fibrosis.

PMID: 28891588 [PubMed - as supplied by publisher]

Lumacaftor/ivacaftor, a novel agent for the treatment of cystic fibrosis patients who are homozygous for the F580del CFTR mutation.

Expert Rev Clin Pharmacol. 2017 Sep 11;:

Authors: Bulloch MN, Hanna C, Giovane R

Abstract
INTRODUCTION: Cystic Fibrosis (CF) is an autosomal recessive disease affecting up to 90,000 people worldwide. Approximately 73% of patients are homozygous for the F508del cystic fibrosis transmembrane conductance regulator [CFTR] mutation. Traditionally treatment has only included supportive care. Therefore, there is a need for safe and effective novel therapies targeting the underlying molecular defects seen with CF. Areas covered: In 2016, the Food and Drug Administration and the European Commission approved LUM/IVA (Orkambi), a CFTR modulator that includes both a CFTR corrector and potentiator, for CF patients homozygous for the F508del CFTR mutation. This article reviews the pharmacologic features, clinical efficacy, and safety of LUM/IVA and summarize the available pre-clinical and clinical data of LUM/IVA use. Expert Commentary: LUM/IVA showed modest, but significant improvements from baseline in percent predicted FEV1 (ppFEV1) as well as a reduction in pulmonary exacerbations by 35% It was shown to be safe for short- and long-term use. Currently, LUM/IVA is the only oral agent in its class available and represents a milestone the development of therapies for the management of CF. Nonetheless, pharmacoeconomic data are necessary to justify its high cost before is use becomes standard of care.

PMID: 28891346 [PubMed - as supplied by publisher]

Evaluation of severity score-guided approaches to macrolide use in community-acquired pneumonia.

Eur Respir J. 2017 Sep;50(3):

Authors: Singanayagam A, Aliberti S, Cillóniz C, Torres A, Blasi F, Chalmers JD

Abstract
International guidelines including those in the UK, Japan, Australia and South Africa recommend the avoidance of macrolides in patients with low-severity community-acquired pneumonia (CAP). We hypothesised that severity scores are poor predictors of atypical pneumonia and response to macrolide therapy, and thus, inadequate tools for guiding antibiotic prescriptions.Secondary analysis of four independent prospective CAP datasets was conducted. The predictive values of the CURB-65 and pneumonia severity index (PSI) for clinically important groups of causative pathogens were evaluated. The effect of macrolide use according to risk class was assessed by multivariable analysis. Patients (3297) were evaluated, and the predictive values of CURB-65 and PSI for atypical pathogens were poor (AUC values of 0.37 and 0.42, respectively). No significant differences were noted among the effects of macrolide use on mortality in patients with mild, moderate and severe CAP, according to either CURB-65 (interaction testing severe versus mild disease OR=0.74 (0.29-1.89)) or PSI (severe versus mild disease OR=3.4 (0.055-2.10)), indicating that severity scores were not significant modifiers of response to macrolide therapy.Severity scores did not accurately predict response to macrolide therapy in CAP, suggesting that current guidance to use these tools for empirical antibiotic choices might not be justified.

PMID: 28890433 [PubMed - in process]

Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids.

Nat Med. 2017 Aug;23(8):954-963

Authors: Sampaziotis F, Justin AW, Tysoe OC, Sawiak S, Godfrey EM, Upponi SS, Gieseck RL, de Brito MC, Berntsen NL, Gómez-Vázquez MJ, Ortmann D, Yiangou L, Ross A, Bargehr J, Bertero A, Zonneveld MCF, Pedersen MT, Pawlowski M, Valestrand L, Madrigal P, Georgakopoulos N, Pirmadjid N, Skeldon GM, Casey J, Shu W, Materek PM, Snijders KE, Brown SE, Rimland CA, Simonic I, Davies SE, Jensen KB, Zilbauer M, Gelson WTH, Alexander GJ, Sinha S, Hannan NRF, Wynn TA, Karlsen TH, Melum E, Markaki AE, Saeb-Parsy K, Vallier L

Abstract
The treatment of common bile duct (CBD) disorders, such as biliary atresia or ischemic strictures, is restricted by the lack of biliary tissue from healthy donors suitable for surgical reconstruction. Here we report a new method for the isolation and propagation of human cholangiocytes from the extrahepatic biliary tree in the form of extrahepatic cholangiocyte organoids (ECOs) for regenerative medicine applications. The resulting ECOs closely resemble primary cholangiocytes in terms of their transcriptomic profile and functional properties. We explore the regenerative potential of these organoids in vivo and demonstrate that ECOs self-organize into bile duct-like tubes expressing biliary markers following transplantation under the kidney capsule of immunocompromised mice. In addition, when seeded on biodegradable scaffolds, ECOs form tissue-like structures retaining biliary characteristics. The resulting bioengineered tissue can reconstruct the gallbladder wall and repair the biliary epithelium following transplantation into a mouse model of injury. Furthermore, bioengineered artificial ducts can replace the native CBD, with no evidence of cholestasis or occlusion of the lumen. In conclusion, ECOs can successfully reconstruct the biliary tree, providing proof of principle for organ regeneration using human primary cholangiocytes expanded in vitro.

PMID: 28671689 [PubMed - indexed for MEDLINE]

European Respiratory Society guidelines for the management of adult bronchiectasis.

Eur Respir J. 2017 Sep;50(3):

Authors: Polverino E, Goeminne PC, McDonnell MJ, Aliberti S, Marshall SE, Loebinger MR, Murris M, Cantón R, Torres A, Dimakou K, De Soyza A, Hill AT, Haworth CS, Vendrell M, Ringshausen FC, Subotic D, Wilson R, Vilaró J, Stallberg B, Welte T, Rohde G, Blasi F, Elborn S, Almagro M, Timothy A, Ruddy T, Tonia T, Rigau D, Chalmers JD

Abstract
Bronchiectasis in adults is a chronic disorder associated with poor quality of life and frequent exacerbations in many patients. There have been no previous international guidelines.The European Respiratory Society guidelines for the management of adult bronchiectasis describe the appropriate investigation and treatment strategies determined by a systematic review of the literature.A multidisciplinary group representing respiratory medicine, microbiology, physiotherapy, thoracic surgery, primary care, methodology and patients considered the most relevant clinical questions (for both clinicians and patients) related to management of bronchiectasis. Nine key clinical questions were generated and a systematic review was conducted to identify published systematic reviews, randomised clinical trials and observational studies that answered these questions. We used the GRADE approach to define the quality of the evidence and the level of recommendations. The resulting guideline addresses the investigation of underlying causes of bronchiectasis, treatment of exacerbations, pathogen eradication, long term antibiotic treatment, anti-inflammatories, mucoactive drugs, bronchodilators, surgical treatment and respiratory physiotherapy.These recommendations can be used to benchmark quality of care for people with bronchiectasis across Europe and to improve outcomes.

PMID: 28889110 [PubMed - in process]

Hepatobiliary disease in children and adolescents with cystic fibrosis.

J Pediatr (Rio J). 2017 Sep 07;:

Authors: Nascimento FS, Sena NA, Ferreira TDA, Marques CDF, Silva LR, Souza ELS

Abstract
OBJECTIVES: The aims of the study were to determine the frequency of hepatobiliary disease in patients with CF and to describe the sociodemographic, clinical, and laboratory profile of these patients.
METHODS: This was a retrospective, descriptive, and analytical study of 55 patients diagnosed with CF fibrosis, aged between 3 months and 21 years, followed-up from January 2008 to June 2016 in a referral center. Medical records were consulted, including sociodemographic, clinical and laboratory data, including hepatobiliary alterations, imaging studies, genetic studies, liver biopsies, and upper digestive endoscopies.
RESULTS: Hepatobiliary disease was diagnosed in 16.4% of the patients and occurred as an initial manifestation of CF in 55.6% of these cases. The diagnosis of hepatopathy occurred before or concomitantly with the diagnosis of CF in 88.9% of the children. All patients with hepatobiliary disease were considered non-white, with a predominance of females (77.8%) and median (IQR) of 54 (27-91) months. Compared with the group without hepatobiliary disease, children with liver disease had a higher frequency of severe mutations identified in the CFTR gene (77.8% vs. 39.6%, p=0.033) and severe pancreatic insufficiency (88.9% vs. 31.6%, p=0.007).
CONCLUSION: The frequency of hepatobiliary disease was high, with a very early diagnosis of the disease and its complications in the studied series. A statistical association was observed between the occurrence of hepatobiliary disease and the presence of pancreatic insufficiency and severe mutations in the CFTR gene. It is emphasized that CF is an important differential diagnosis of liver diseases in childhood.

PMID: 28888897 [PubMed - as supplied by publisher]

Neutrophil-Derived Cytosolic PLA2α Contributes to Bacterial-Induced Neutrophil Transepithelial Migration.

J Immunol. 2017 Sep 08;:

Authors: Yonker LM, Pazos MA, Lanter BB, Mou H, Chu KK, Eaton AD, Bonventre JV, Tearney GJ, Rajagopal J, Hurley BP

Abstract
Eicosanoids are a group of bioactive lipids that are shown to be important mediators of neutrophilic inflammation; selective targeting of their function confers therapeutic benefit in a number of diseases. Neutrophilic airway diseases, including cystic fibrosis, are characterized by excessive neutrophil infiltration into the airspace. Understanding the role of eicosanoids in this process may reveal novel therapeutic targets. The eicosanoid hepoxilin A3 is a pathogen-elicited epithelial-produced neutrophil chemoattractant that directs transepithelial migration in response to infection. Following hepoxilin A3-driven transepithelial migration, neutrophil chemotaxis is amplified through neutrophil production of a second eicosanoid, leukotriene B4 (LTB4). The rate-limiting step of eicosanoid generation is the liberation of arachidonic acid by phospholipase A2, and the cytosolic phospholipase A2 (cPLA2)α isoform has been specifically shown to direct LTB4 synthesis in certain contexts. Whether cPLA2α is directly responsible for neutrophil synthesis of LTB4 in the context of Pseudomonas aeruginosa-induced neutrophil transepithelial migration has not been explored. Human and mouse neutrophil-epithelial cocultures were used to evaluate the role of neutrophil-derived cPLA2α in infection-induced transepithelial signaling by pharmacological and genetic approaches. Primary human airway basal stem cell-derived epithelial cultures and micro-optical coherence tomography, a new imaging modality that captures two- and three-dimensional real-time dynamics of neutrophil transepithelial migration, were applied. Evidence from these studies suggests that cPLA2α expressed by neutrophils, but not epithelial cells, plays a significant role in infection-induced neutrophil transepithelial migration by mediating LTB4 synthesis during migration, which serves to amplify the magnitude of neutrophil recruitment in response to epithelial infection.

PMID: 28887431 [PubMed - as supplied by publisher]

Reactive oxygen therapy: a novel antimicrobial.

Int J Antimicrob Agents. 2017 Sep 05;:

Authors: Dryden M

Abstract
The main solution to the global antibiotic resistance crisis is reducing the volume of antibiotic use in medicine, agriculture and the environment. However there is also a pressing need for novel antimicrobials. Despite much rhetoric, there are few entirely novel agents in development. One such therapy to reach clinical use is an agent using Reactive Oxygen Species (ROS), oxygen radicals, as an antimicrobial mechanism. ROS can be delivered to the site of infection in various formats. ROS is highly antimicrobial against Gram positive and negative bacteria, viruses and fungi. It prevents and breaks down biofilm. These functions make ROS potentially highly suitable for chronic inflammatory conditions, where antibiotics are frequently overused and relatively ineffective: chronic wounds, ulcers and burns; chronic rhinosinusitis, chronic bronchitis, bronchiectasis, cystic fibrosis, ventilated airways; recurrent cystitis; and prosthetic device infection. ROS could have an important role in infection prevention and antimicrobial stewardship. Much clinical investigation remains to be delivered on ROS therapy but in vitro work on infection models and early clinical evaluations are extremely promising.

PMID: 28887201 [PubMed - as supplied by publisher]