Mechanistic Insights From Global Metabolomics Studies into Synergistic Bactericidal Effect of a Polymyxin B Combination With Tamoxifen Against Cystic Fibrosis MDR Pseudomonas aeruginosa.

Comput Struct Biotechnol J. 2018;16:587-599

Authors: Hussein M, Han ML, Zhu Y, Schneider-Futschik EK, Hu X, Zhou QT, Lin YW, Anderson D, Creek DJ, Hoyer D, Li J, Velkov T

Abstract
Polymyxins are amongst the most important antibiotics in modern medicine, in recent times their clinical utility has been overshadowed by nosocomial outbreaks of polymyxin resistant MDR Gram-negative 'superbugs'. An effective strategy to surmount polymyxin resistance is combination therapy with FDA-approved non-antibiotic drugs. Herein we used untargeted metabolomics to investigate the mechanism(s) of synergy between polymyxin B and the selective estrogen receptor modulator (SERM) tamoxifen against a polymyxin-resistant MDR cystic fibrosis (CF) Pseudomonas aeruginosa FADDI-PA006 isolate (polymyxin B MIC=8 mg/L , it is an MDR polymyxin resistant P. aeruginosa isolated from the lungs of a CF patient). The metabolome of FADDI-PA006 was profiled at 15 min, 1 and 4 h following treatment with polymyxin B (2 mg/L), tamoxifen (8 mg/L) either as monotherapy or in combination. At 15 min, the combination treatment induced a marked decrease in lipids, primarily fatty acid and glycerophospholipid metabolites that are involved in the biosynthesis of bacterial membranes. In line with the polymyxin-resistant status of this strain, at 1 h, both polymyxin B and tamoxifen monotherapies produced little effect on bacterial metabolism. In contrast to the combination which induced extensive reduction (≥ 1.0-log2-fold, p ≤ 0.05; FDR ≤ 0.05) in the levels of essential intermediates involved in cell envelope biosynthesis. Overall, these novel findings demonstrate that the primary mechanisms underlying the synergistic bactericidal effect of the combination against the polymyxin-resistant P. aeruginosa CF isolate FADDI-PA006 involves a disruption of the cell envelope biogenesis and an inhibition of aminoarabinose LPS modifications that confer polymyxin resistance.

PMID: 30546859 [PubMed]

Use of a Primary Epithelial Cell Screening Tool to Investigate Phage Therapy in Cystic Fibrosis.

Front Pharmacol. 2018;9:1330

Authors: Trend S, Chang BJ, O'Dea M, Stick SM, Kicic A, WAERP, AusREC, AREST CF

Abstract
Antimicrobial-resistant microbes are an increasing threat to human health. In cystic fibrosis (CF), airway infections with Pseudomonas aeruginosa remain a key driver of lung damage. With few new antibiotics on the development horizon, alternative therapeutic approaches are needed against antimicrobial-resistant pathogens. Phage therapy, or the use of viruses that infect bacteria, is one proposed novel therapy to treat bacterial infections. However, the airways are complex microenvironments with unique characteristics that may affect the success of novel therapies. Here, three phages of P. aeruginosa (E79, F116, and one novel clinically derived isolate, designated P5) were screened for activity against 21 P. aeruginosa strains isolated from children with CF. Of these, phage E79 showed broad antibacterial activity (91% of tested strains sensitive) and was selected for further assessment. E79 genomic DNA was extracted, sequenced, and confirmed to contain no bacterial pathogenicity genes. High titre phage preparations were then purified using ion-exchange column chromatography and depleted of bacterial endotoxin. Primary airway epithelial cells derived from children with CF (n = 8, age range 0.2-5.5 years, 5 males) or healthy non-CF controls (n = 8, age range 2.5-4.0 years, 4 males) were then exposed to purified phage for 48 h. Levels of inflammatory IL-1β, IL-6, and IL-8 cytokine production were measured in culture supernatant by immunoassays and the extent of cellular apoptosis was measured using a ssDNA kit. Cytokine and apoptosis levels were compared between E79-stimulated and unstimulated controls, and, encouragingly, purified preparations of E79 did not stimulate any significant inflammatory cytokine responses or induce apoptosis in primary epithelial cells derived from children with or without CF. Collectively, this study demonstrates the feasibility of utilizing pre-clinical in vitro culture models to screen therapeutic candidates, and the potential of E79 as a therapeutic phage candidate in CF.

PMID: 30546305 [PubMed]

Impact of CFTR modulation with Ivacaftor on Gut Microbiota and Intestinal Inflammation.

Sci Rep. 2018 Dec 13;8(1):17834

Authors: Ooi CY, Syed SA, Rossi L, Garg M, Needham B, Avolio J, Young K, Surette MG, Gonska T

Abstract
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Next to progressive airway disease, CF is also associated with intestinal inflammation and dysbiosis. Ivacaftor, a CFTR potentiator, has improved pulmonary and nutritional status but its effects on the intestinal microbiota and inflammation are unclear. Hence, we assessed the changes on the intestinal microbial communities (16S rRNA variable 3 gene region) and inflammatory markers (calprotectin and M2-pyruvate kinase [M2-PK]) in 16 CF individuals (8 children and 8 adults) before and after (median 6.1 months) ivacaftor. Stool calprotectin significantly decreased following ivacaftor (median [IQR]: 154.4 [102.1-284.2] vs. 87.5 [19.5-190.2] mg/kg, P = 0.03). There was a significant increase in Akkermansia with ivacaftor. Increased abundance of Akkermansia was associated with normal stool M2-PK concentrations, and decreased abundances of Enterobacteriaceae correlated with decreased stool calprotectin concentrations. In summary, changes in the gut microbiome and decrease in intestinal inflammation was associated with Ivacaftor treatment among individuals with CF carrying at least one gating CFTR mutation. Thus, CFTR-modifying therapy may adequately improve the aberrant pathophysiology and milieu of the CF gut to favor a more healthy microbiota, which in turn reduces intestinal inflammation.

PMID: 30546102 [PubMed - in process]

Publisher Correction: Early detection of pulmonary exacerbations in children with Cystic Fibrosis by electronic home monitoring of symptoms and lung function.

Sci Rep. 2018 Dec 13;8(1):17946

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

Abstract
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

PMID: 30546045 [PubMed - in process]

Influence of Inspiratory/Expiratory CT Registration on Quantitative Air Trapping.

Acad Radiol. 2018 Dec 10;:

Authors: Weinheimer O, Hoff BA, Fortuna AB, Fernández-Baldera A, Konietzke P, Wielpütz MO, Robinson TE, Galbán CJ

Abstract
RATIONALE AND OBJECTIVES: The aim of this study was to assess variability in quantitative air trapping (QAT) measurements derived from spatially aligned expiration CT scans.
MATERIALS AND METHODS: Sixty-four paired CT examinations, from 16 school-age cystic fibrosis subjects examined at four separate time intervals, were used in this study. For each pair, visually inspected lobe segmentation maps were generated and expiration CT data were registered to the inspiration CT frame. Measurements of QAT, the percentage of voxels on the expiration CT scan below a set threshold were calculated for each lobe and whole-lung from the registered expiration CT and compared to the true values from the unregistered data.
RESULTS: A mathematical model, which simulates the effect of variable regions of lung deformation on QAT values calculated from aligned to those from unaligned data, showed the potential for large bias. Assessment of experimental QAT measurements using Bland-Altman plots corroborated the model simulations, demonstrating biases greater than 5% when QAT was approximately 40% of lung volume. These biases were removed when calculating QAT from aligned expiration CT data using the determinant of the Jacobian matrix. We found, by Dice coefficient analysis, good agreement between aligned expiration and inspiration segmentation maps for the whole-lung and all but one lobe (Dice coefficient > 0.9), with only the lingula generating a value below 0.9 (mean and standard deviation of 0.85 ± 0.06).
CONCLUSION: The subtle and predictable variability in corrected QAT observed in this study suggests that image registration is reliable in preserving the accuracy of the quantitative metrics.

PMID: 30545681 [PubMed - as supplied by publisher]

Novel features in the structure of P-glycoprotein (ABCB1) in the post-hydrolytic state as determined at 7.9 Å resolution.

BMC Struct Biol. 2018 Dec 13;18(1):17

Authors: Thonghin N, Collins RF, Barbieri A, Shafi T, Siebert A, Ford RC

Abstract
BACKGROUND: P-glycoprotein (ABCB1) is an ATP-binding cassette transporter that plays an important role in the clearance of drugs and xenobiotics and is associated with multi-drug resistance in cancer. Although several P-glycoprotein structures are available, these are either at low resolution, or represent mutated and/or quiescent states of the protein.
RESULTS: In the post-hydrolytic state the structure of the wild-type protein has been resolved at about 8 Å resolution. The cytosolic nucleotide-binding domains (NBDs) are separated but ADP remains bound, especially at the first NBD. Gaps in the transmembrane domains (TMDs) that connect to an inner hydrophilic cavity are filled by density emerging from the annular detergent micelle. The NBD-TMD linker is partly resolved, being located between the NBDs and close to the Signature regions involved in cooperative NBD dimerization. This, and the gap-filling detergent suggest steric impediment to NBD dimerization in the post-hydrolytic state. Two central regions of density lie in two predicted drug-binding sites, implying that the protein may adventitiously bind hydrophobic substances even in the post-hydrolytic state. The previously unresolved N-terminal extension was observed, and the data suggests these 30 residues interact with the headgroup region of the lipid bilayer.
CONCLUSION: The structural data imply that (i) a low basal ATPase activity is ensured by steric blockers of NBD dimerization and (ii) allocrite access to the central cavity may be structurally linked to NBD dimerization, giving insights into the mechanism of drug-stimulation of P-glycoprotein activity.

PMID: 30545335 [PubMed - in process]

Regulators of A20 (TNFAIP3) - new drug-able targets in inflammation.

Am J Physiol Lung Cell Mol Physiol. 2018 Dec 13;:

Authors: Momtazi G, Lambrecht B, Naranjo JR, Schock BC

Abstract
Persistent activation of the transcription factor Nuclear Factor-kappaB (NF-κB) is central to the pathogenesis of many inflammatory disorders, including those of the lung such as cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease (COPD). Despite recent advances in treatment, management of the inflammatory component of these diseases still remains suboptimal. A20 is an endogenous negative regulator of NF-κB signaling, which has been widely described in several autoimmune and inflammatory disorders and more recently in terms of chronic lung disorders. However, the underlying mechanism for the apparent lack of A20 in CF, COPD and asthma has not been investigated. Transcriptional regulation of A20 is complex and requires co-ordination of different transcription factors. In this review we examine the existing body of research evidence on the regulation of A20, concentrating on pulmonary inflammation. Special focus is given to the repressor DREAM and its nuclear and cytosolic action to regulate inflammation. We provide evidence that would suggest the A20-DREAM axis to be an important player in (airway) inflammatory responses and point to DREAM as a potential future therapeutic target for the modification of phenotypic changes in airway inflammatory disorders. A schematic summary describing the role of DREAM in inflammation with a focus on chronic lung diseases as well as the possible consequences of altered DREAM expression on immune responses is provided.

PMID: 30543305 [PubMed - as supplied by publisher]

Interactions of Aspergillus fumigatus and Stenotrophomonas maltophilia in an in vitro Mixed Biofilm Model: Does the Strain Matter?

Front Microbiol. 2018;9:2850

Authors: Melloul E, Roisin L, Durieux MF, Woerther PL, Jenot D, Risco V, Guillot J, Dannaoui E, Decousser JW, Botterel F

Abstract
Introduction: Aspergillus fumigatus (Af) and Stenotrophomonas maltophilia (Sm) are pathogenic microorganisms, which coexist in the respiratory tract of cystic fibrosis (CF) patients. We recently developed an in vitro model of mixed biofilm associating Af ATCC 13073-GFP (Af13073) and Sm ATCC 13637 (Sm13637) and described an antibiosis effect. The present study aim was to assess the antibiosis of Sm on Af using different strains and to analyze the potential synergistic virulence of these strains in an in vivo Galleria mellonella model. Methods: The effect of Sm13637 was evaluated on eight Af strains and the effect of nine Sm strains was evaluated on Af13073. The strains originated from clinical cases (human and animal) and from environment. Fungal and bacterial inocula were simultaneously inoculated to initiate mixed biofilm formation. Fungal growth inhibition was analyzed by qPCR and CLSM and the fungal cell wall modifications by TEM analysis. The virulence of different Sm strains was assessed in association with Af in G. mellonella larvae. Results: All strains of Af and Sm were able to produce single and mixed biofilms. The antibiosis effect of Sm13637 was similar whatever the Af strain tested. On the other hand, the antibiosis effect of Sm strains was bacterial-fitness and strain dependent. One strain (1/9) originated from animal clinical case was never able to induce an antibiosis, even with high bacterial concentration. In the G. mellonella model, co-inoculation with Sm13637 and Af13073 showed synergism since the mortality was 50%, i.e., more than the summed virulence of both. Conclusion: Human clinical strains of Sm yielded in higher antibiosis effect on Af and in a thinner mixed biofilm, probably due to an adaptive effect of these strains. Further research covering Af increased wall thickness in the presence of Sm strains, and its correlation with modified antifungal susceptibility is encouraged in patients with chronic respiratory infections by these 2 microorganisms.

PMID: 30542331 [PubMed]

Vitamin E Increases Antimicrobial Sensitivity by Inhibiting Bacterial Lipocalin Antibiotic Binding.

mSphere. 2018 Dec 12;3(6):

Authors: Naguib MM, Valvano MA

Abstract
Burkholderia cenocepacia is an opportunistic Gram-negative bacterium that causes serious respiratory infections in patients with cystic fibrosis. Recently, we discovered that B. cenocepacia produces the extracellular bacterial lipocalin protein BcnA upon exposure to sublethal concentrations of bactericidal antibiotics. BcnA captures a range of antibiotics outside bacterial cells, providing a global extracellular mechanism of antimicrobial resistance. In this study, we investigated water-soluble and liposoluble forms of vitamin E as inhibitors of antibiotic binding by BcnA. Our results demonstrate that in vitro, both vitamin E forms bind strongly to BcnA and contribute to reduce the MICs of norfloxacin (a fluoroquinolone) and ceftazidime (a β-lactam), both of them used as model molecules representing two different chemical classes of antibiotics. Expression of BcnA was required for the adjuvant effect of vitamin E. These results were replicated in vivo using the Galleria mellonella larva infection model whereby vitamin E treatment, in combination with norfloxacin, significantly increased larva survival upon infection in a BcnA-dependent manner. Together, our data suggest that vitamin E can be used to increase killing by bactericidal antibiotics through interference with lipocalin binding.IMPORTANCE Bacteria exposed to stress mediated by sublethal antibiotic concentrations respond by adaptive mechanisms leading to an overall increase of antibiotic resistance. One of these mechanisms involves the release of bacterial proteins called lipocalins, which have the ability to sequester antibiotics in the extracellular space before they reach bacterial cells. We speculated that interfering with lipocalin-mediated antibiotic binding could enhance the efficacy of antibiotics to kill bacteria. In this work, we report that when combined with bactericidal antibiotics, vitamin E contributes to enhance bacterial killing both in vitro and in vivo. This adjuvant effect of vitamin E requires the presence of BcnA, a bacterial lipocalin produced by the cystic fibrosis pathogen Burkholderia cenocepacia Since most bacteria produce lipocalins like BcnA, we propose that our findings could be translated into making novel antibiotic adjuvants to potentiate bacterial killing by existing antibiotics.

PMID: 30541778 [PubMed - in process]

Dual Transcriptomics of Host-Pathogen Interaction of Cystic Fibrosis Isolate Pseudomonas aeruginosa PASS1 With Zebrafish.

Front Cell Infect Microbiol. 2018;8:406

Authors: Kumar SS, Tandberg JI, Penesyan A, Elbourne LDH, Suarez-Bosche N, Don E, Skadberg E, Fenaroli F, Cole N, Winther-Larsen HC, Paulsen IT

Abstract
Pseudomonas aeruginosa is a significant cause of mortality in patients with cystic fibrosis (CF). To explore the interaction of the CF isolate P. aeruginosa PASS1 with the innate immune response, we have used Danio rerio (zebrafish) as an infection model. Confocal laser scanning microscopy (CLSM) enabled visualization of direct interactions between zebrafish macrophages and P. aeruginosa PASS1. Dual RNA-sequencing of host-pathogen was undertaken to profile RNA expression simultaneously in the pathogen and the host during P. aeruginosa infection. Following establishment of infection in zebrafish embryos with PASS1, 3 days post infection (dpi), there were 6739 genes found to be significantly differentially expressed in zebrafish and 176 genes in PASS1. A range of virulence genes were upregulated in PASS1, including genes encoding pyoverdine biosynthesis, flagellin, non-hemolytic phospholipase C, proteases, superoxide dismutase and fimbrial subunits. Additionally, iron and phosphate acquisition genes were upregulated in PASS1 cells in the zebrafish. Transcriptional changes in the host immune response genes highlighted phagocytosis as a key response mechanism to PASS1 infection. Transcriptional regulators of neutrophil and macrophage phagocytosis were upregulated alongside transcriptional regulators governing response to tissue injury, infection, and inflammation. The zebrafish host showed significant downregulation of the ribosomal RNAs and other genes involved in translation, suggesting that protein translation in the host is affected by PASS1 infection.

PMID: 30524971 [PubMed - in process]

Sex and Relationships Education for Individuals with Cystic Fibrosis: A Service-Based Approach.

Sex Disabil. 2018;36(4):363-376

Authors: Norris E, Phillips S, Butler C, James K

Abstract
Increasing life expectancy within cystic fibrosis (CF) raises challenges around previously neglected topics such as sexual and reproductive health (SRH). The study aimed to gather retrospective experiences of service provision around SRH to consider the role of the CF service, age of information provision and unmet needs highlighting possible improvements to provision. A mixed-methods retrospective survey-based design was employed. An Adult CF team participated in a consultation session generating survey questions around SRH. A 20-item online survey was constructed and disseminated to adult CF patients. Unmet needs were found in SRH provision in pediatric and adult CF services, with further information required by patients on topics including parenthood and fertility. Results support previous research findings highlighting the need for standardized provision around SRH. Age of SRH provision suggested individual differences in need within the pediatric service. Further research could explore format and specific age of SRH information provision.

PMID: 30524155 [PubMed]

Dropping acid: why is cystic fibrosis mucus abnormal?

Eur Respir J. 2018 Dec;52(6):

Authors: Rubin BK, Thornton DJ

PMID: 30523208 [PubMed - in process]

A Personal Reflection from London.

Hum Gene Ther. 2017 11;28(11):959

Authors: Thrasher AJ

PMID: 29035116 [PubMed - indexed for MEDLINE]

FGF23 Induction of O-Linked N-Acetylglucosamine Regulates IL-6 Secretion in Human Bronchial Epithelial Cells.

Front Endocrinol (Lausanne). 2018;9:708

Authors: Krick S, Helton ES, Hutcheson SB, Blumhof S, Garth JM, Denson RS, Zaharias RS, Wickham H, Barnes JW

Abstract
The hexosamine biosynthetic pathway (HBP) generates the substrate for the O-linked β-N-acetylglucosamine (O-GlcNAc) modification of proteins. The HBP also serves as a stress sensor and has been reported to be involved with nuclear factor of activated T-cells (NFAT) activation, which can contribute to multiple cellular processes including cell metabolism, proliferation, and inflammation. In our previously published report, Fibroblast Growth Factor (FGF) 23, an important endocrine pro-inflammatory mediator, was shown to activate the FGFR4/phospholipase Cγ (PLCγ)/nuclear factor of activated T-cells (NFAT) signaling in chronic inflammatory airway diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Here, we demonstrate that FGF23 increased the O-GlcNAc modification of proteins in HBECs. Furthermore, the increase in O-GlcNAc levels by FGF23 stimulation resulted in the downstream activation of NFAT and secretion of interleukin-6 (IL-6). Conversely, inhibition of FGF23 signaling and/or O-GlcNAc transferase (OGT)/O-GlcNAc reversed these effects. Collectively, these data suggest that FGF23 induced IL-6 upregulation and secretion is, at least, partially mediated via the activation of the HBP and O-GlcNAc levels in HBECs. These findings identify a novel link whereby FGF23 and the augmentation of O-GlcNAc levels regulate airway inflammation through NFAT activation and IL-6 upregulation in HBECs. The crosstalk between these signaling pathways may contribute to the pathogenesis of chronic inflammatory airway diseases such as COPD and CF as well as metabolic syndromes, including diabetes.

PMID: 30538676 [PubMed]

Gene Therapy for Cystic Fibrosis Lung Disease: Overcoming the Barriers to Translation to the Clinic.

Front Pharmacol. 2018;9:1381

Authors: Donnelley M, Parsons DW

Abstract
Cystic fibrosis (CF) is a progressive, chronic and debilitating genetic disease caused by mutations in the CF Transmembrane-Conductance Regulator (CFTR) gene. Unrelenting airway disease begins in infancy and produces a steady deterioration in quality of life, ultimately leading to premature death. While life expectancy has improved, current treatments for CF are neither preventive nor curative. Since the discovery of CFTR the vision of correcting the underlying genetic defect - not just treating the symptoms - has been developed to where it is poised to become a transformative technology. Addition of a properly functioning CFTR gene into defective airway cells is the only biologically rational way to prevent or treat CF airway disease for all CFTR mutation classes. While new gene editing approaches hold exciting promise, airway gene-addition therapy remains the most encouraging therapeutic approach for CF. However, early work has not yet progressed to large-scale clinical trials. For clinical trials to begin in earnest the field must demonstrate that gene therapies are safe in CF lungs; can provide clear health benefits and alter the course of lung disease; can be repeatedly dosed to boost effect; and can be scaled effectively from small animal models into human-sized lungs. Demonstrating the durability of these effects demands relevant CF animal models and accurate and reliable techniques to measure benefit. In this review, illustrated with data from our own studies, we outline recent technological developments and discuss these key questions that we believe must be answered to progress CF airway gene-addition therapies to clinical trials.

PMID: 30538635 [PubMed]

Corticosteroid use and increased CXCR2 levels on leukocytes are associated with lumacaftor/ivacaftor discontinuation in cystic fibrosis patients homozygous for the F508del CFTR mutation.

PLoS One. 2018;13(12):e0209026

Authors: Pohl K, Nichols DP, Taylor-Cousar JL, Saavedra MT, Strand MJ, Nick JA, Bratcher PE

Abstract
Cystic fibrosis (CF) is the most common life-shortening genetic disease and is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Several current therapies aim at improving availability and/or function of the mutant CFTR proteins. The combination therapeutic lumacaftor/ivacaftor (Orkambi, luma/iva) partially corrects folding and potentiates CFTR function impaired by the F508del mutation. Despite the potential for clinical benefit, a substantial number of patients discontinue treatment due to intolerable adverse effects. The aim of the present study is to identify differences between individuals who continued treatment and those who discontinued due to adverse respiratory effects to potentially inform treatment decisions. Clinical data from the year prior to treatment initiation were analyzed from 82 patients homozygous for the F508del mutation treated at the Colorado Adult CF Program. Blood samples were collected from 30 of these subjects before initiation of treatment to examine expression of circulating leukocyte surface antigens and cytokines. Clinical and demographic characteristics were analyzed along with inflammatory markers to determine biomarkers of drug discontinuation. The use of oral prednisone and/or nasal budesonide in the year prior to luma/iva initiation was more prevalent in CF subjects who did not tolerate luma/iva (82% vs. 43%). Increased age, but not gender or initial lung function, was associated with higher probability of discontinuing treatment due to side effects overall. Worse lung function (lower ppFEV1, ppFEF25-75 ≤ 60%) was associated with higher incidence of discontinuing treatment due to pulmonary adverse effects. In a nested cohort of patients, increased surface levels of CXCR2 on CD14+CD16- monocytes were associated with discontinuation. Overall, the patients who tolerated luma/iva were distinguishable from those who did not tolerate the drug based on clinical and cellular markers obtained prior to treatment initiation.

PMID: 30540818 [PubMed - in process]

Antiemetic Drug Use in Children: What the Clinician Needs to Know.

J Pediatr Gastroenterol Nutr. 2018 Dec 11;:

Authors: Romano C, Dipasquale V, Scarpignato C

Abstract
Vomiting is not only unpleasant for both children and families, but can lead to frequent hospital admission. The persistent vomiting hampers oral intake and increases the risk of dehydration so the proper use of antiemetic drugs can be useful. The pharmacological treatment of vomiting in children remains a challenge for the pediatrician because several antiemetics are prescribed as "off-label", outside their authorized drug label. Domperidone and ondansetron are the most commonly known antiemetic drugs. A single oral dose of ondansetron has been shown to reduce the risk of recurrent vomiting, the need for intravenous fluids and hospital admissions in children with acute gastroenteritis. There is enough evidence to support ondansetron administration in children, so the clinical use can be defined as "off-label/on evidence". This review aims to provide an overview of therapeutic use, safety and main pharmacological properties of antiemetic drugs in children. A comprehensive search of published literature using the PubMed MEDLINE database was carried out to identify all papers published in English from 1998 to February 2018. At present time, the "off-label/on-evidence" use of some antiemetics could improve the success rate of oral rehydration therapy in pediatric emergency settings and to change the management of vomiting with the prevention of the complications.

PMID: 30540713 [PubMed - as supplied by publisher]

Identification of molecular signatures of cystic fibrosis disease status using plasma-based functional genomics.

Physiol Genomics. 2018 Dec 12;:

Authors: Levy H, Jia S, Pan A, Zhang X, Kaldunski ML, Nugent ML, Reske M, Feliciano RA, Quintero D, Renda MM, Woods KJ, Murkowski K, Johnson K, Verbsky J, Dasu T, Ideozu JE, McColley S, Quasney MW, Dahmer MK, Avner ED, Farrell PM, Cannon CL, Jacob H, Simpson PM, Hessner MJ

Abstract
Although cystic fibrosis (CF) is attributed to dysfunction of a single gene, the relationships between the abnormal gene product and development of inflammation and progression of lung disease are not fully understood, limiting our ability to predict an individual patient's clinical course and treatment response. To better understand CF progression, we characterized the molecular signatures of CF disease status using plasma-based functional genomics. Peripheral blood mononuclear cells (PBMCs) from healthy donors were cultured with plasma samples from CF patients (n=103) and unrelated, healthy controls (n=31). Gene expression levels were measured with an Affymetrix microarray (GeneChip Human Genome U133 Plus 2.0). Peripheral blood samples from a subset of the CF patients (n=40) were immunophenotyped by flow cytometry, and the data were compared to historical data for age-matched healthy controls (n=351). Plasma samples from another subset of CF patients (n=56) and healthy controls (n=16) were analyzed by a multiplex enzyme-linked immunosorbent assay (ELISA) that included assays for numerous cytokines and chemokines. Principal component analysis and hierarchical clustering of induced transcriptional data revealed disease-specific plasma-induced PBMC profiles. Among 1094 differentially expressed probe sets, 51 genes were associated with pancreatic sufficient status, and 224 genes were associated with infection with Pseudomonas aeruginosa. The flow cytometry and ELISA data confirmed that various immune modulators are relevant contributors to the CF molecular signature. This study provides evidence for distinct molecular signatures among CF patients. An understanding of these molecular signatures may lead to unique molecular markers that will enable more personalized prognoses, individualized treatment, and monitoring.

PMID: 30540547 [PubMed - as supplied by publisher]

Snow angels - the microbiology of freshly fallen snow: implications for immunocompromised patients.

J Water Health. 2018 Dec;16(6):1029-1032

Authors: Moore JE, McCaughan J, Stirling J, Bell J, Millar BC

Abstract
The frequency of seasonal snowfall results in the transient covering of gardens/amenity sites/open public spaces, which encourages recreational interaction mainly with children. No data is available demonstrating the microbiological composition of such fallen snow and therefore a study was undertaken to examine the microbiology of snow from 37 sites, estimating (i) total viable count (TVC), (ii) identification of bacteria, and (iii) the presence of Pseudomonas aeruginosa. Mean TVC count of 8.3 colony-forming units (cfu)/ml snow melt water, 51.7 cfu/ml, 865 cfu/ml and 2,197 cfu/ml, was obtained for public amenity sites, domestic gardens, public open spaces and melting snow from public footpaths, respectively. No bacterial organisms (<10 cfu/ml) were detected in 5/14 (35.7%) open public spaces, 2/5 (40%) amenity sites and in 1/10 (10%) domestic gardens. Pseudomonas aeruginosa was not detected from any snow sample examined. Bacterial diversity consisted of 15 bacterial species (11 Gram-positive/four Gram-negative). The six Gram-positive genera identified from snow were Actinomyces, Bacillus, Brevibacillus, Micrococcus, Staphylococcus and Streptococcus. The four Gram-negative genera identified were Enterobacter, Pantoea, Pseudomonas and Xanthomonas. Bacillus licheniformis was the most commonly isolated organism from snow; it was isolated from every snow type. Snow may contain a diverse range of bacteria, many of which are capable of causing human infections.

PMID: 30540276 [PubMed - in process]

THE USE OF ULTRASONOGRAPHY TO EVALUATE MUSCLE THICKNESS AND SUBCUTANEOUS FAT IN CHILDREN AND ADOLESCENTS WITH CYSTIC FIBROSIS.

Rev Paul Pediatr. 2018 Oct-Dec;36(4):457-465

Authors: Souza RP, Donadio MVF, Heinzmann-Filho JP, Baptista RR, Pinto LA, Epifanio M, Marostica PJC

Abstract
OBJECTIVE: To compare muscle thickness and subcutaneous fat in cystic fibrosis (CF) patients and healthy controls using ultrasonography (US), and to correlate US findings with nutritional, clinical and functional variables.
METHODS: Patients aged 6 to 18 years old with a diagnosis of CF and healthy controls were included. Participants underwent anthropometric measurements, an ultrasonographic evaluation of muscle thickness and subcutaneous fat in the triceps, quadriceps, and gastrocnemius regions, and skinfold thickness measurements. Body fat percentage was estimated using skinfold measurement. Subjects with CF also underwent a pulmonary function assessment using spirometry.
RESULTS: We studied 39 CF patients and 45 controls. Alower body mass index was observed in CF patients (p=0.011). Body composition and muscle thickness were similar between the groups. Only calf (p=0.023) circumference and femur diameter (p<0.001) were lower in CF patients. Although there were no significant between-group differences in the comparison of US measurements of subcutaneous fat, CF patients exhibited decreased skinfold thickness in the triceps (p=0.031) and quadriceps (p=0.019). Moreover, there were weak and moderate correlations of US quadricep thickness with forced vital capacity (FVC) and lean mass, respectively. Moderate correlations of the triceps, quadriceps and gastrocnemius between US subcutaneous fat and skinfold measurements were found.
CONCLUSIONS: Patients with CF presented a reduction in subcutaneous fat content. Muscle thickness correlated with FVC and nutritional parameters. In addition, US findings correlated positively with skinfold measurements.

PMID: 30540111 [PubMed - in process]