Tools and Methods Used for the Assessment of Body Composition in Patients With Cystic Fibrosis: A Systematic Review.

Nutr Clin Pract. 2019 Feb 07;:

Authors: Calella P, Valerio G, Brodlie M, Taylor J, Donini LM, Siervo M

Abstract
BACKGROUND: Cystic fibrosis (CF) is characterized by changes in fat mass and lean body mass that may have important prognostic value. We aim to appraise the type and frequency of application of body composition (BC) methods in child and adult patients with CF.
METHODS: We used 4 databases (Embase, PubMed, Scopus, and Web of Science) to perform the literature search. The search was conducted from January 2017 to February 2017. Two independent reviewers selected articles based on titles and abstracts to check eligibility for inclusion. All study designs or types of articles (abstract, full text) were considered.
RESULTS: Eighty-four full-text articles and 40 studies presented only as abstracts were selected. Sixty-four studies included children and adolescents (age range of 0.1-18 years), and 41 studies recruited adults (range of 18-57 years); 13 studies included both age groups. Dual-energy X-ray absorptiometry (DXA) was used in 56 studies (33.9%), and bioelectric impedance analysis (BIA) was used in 12 studies (9.7%), whereas 38 studies (30.6%) combined different methods (up to 5 different methods) to assess BC.
CONCLUSIONS: The results show a large variability in the application of BC methods in patients with CF that makes the comparison between studies difficult. The only methods with a sufficient body of literature are DXA and BIA.

PMID: 30729571 [PubMed - as supplied by publisher]

Association Between Fat-Free Mass and Pulmonary Function in Patients With Cystic Fibrosis: A Narrative Review.

Nutr Clin Pract. 2019 Feb 07;:

Authors: Gomes A, Hutcheon D, Ziegler J

Abstract
The association between body mass index (BMI) and pulmonary function in patients with cystic fibrosis (CF) is well established, yet BMI as the sole indicator of nutrition status fails to assess body composition, specifically fat-free mass (FFM). Reduced FFM is a characteristic of undernutrition and is associated with decreased pulmonary function. A critical review of the literature was undertaken to explore available evidence on the use of FFM derived from dual-energy X-ray absorptiometry (DXA), compared with BMI, to assess pulmonary function and thereby nutrition status in patients with CF. Four cross-sectional studies that met predefined inclusion and exclusion criteria were selected for review. Based on the evidence reviewed, reduced FFM was associated with reduced pulmonary function in both children and adults with CF. FFM was reduced among patients who may not otherwise be identified as at nutrition risk based on BMI alone. FFM, as compared with BMI, appears to be a better indicator of pulmonary function and nutrition status in patients with CF. Although future research is needed to identify and determine FFM measurements that are associated with improved pulmonary function and nutrition status in patients with CF, these findings highlight the potential value and clinical utility of using FFM measurements derived from DXA among patients with CF. Together, FFM and BMI may provide a more comprehensive picture of nutrition status during the nutrition assessment of the patient with CF.

PMID: 30729564 [PubMed - as supplied by publisher]

Therapeutic modulation of autophagy: which disease comes first?

Cell Death Differ. 2019 Feb 06;:

Authors: Maiuri MC, Kroemer G

Abstract
The relentless efforts of thousands of researchers have allowed deciphering the molecular machinery that regulates and executes autophagy, thus identifying multiple molecular targets to enhance or block the process, rendering autophagy "druggable". Autophagy inhibition may be useful for preserving the life of cells that otherwise would succumb to excessive self-digestion. Moreover, autophagy blockade may reduce the fitness of cancer cells or interrupt metabolic circuitries required for their growth. Autophagy stimulation is probably useful for the prevention or treatment of aging, cancer (when stimulation of immunosurveillance is the therapeutic goal), cardiovascular disease, cystic fibrosis, infection by intracellular pathogens, obesity, and intoxication by heavy metals, just to mention a few examples. Epidemiological evidence suggests broad health-improving effects for lifestyles, micronutrients, and drugs that favor autophagy. In this review, we discuss the role of autophagy in disease pathogenesis while focusing on the question, which disease will become the first clinically approved indication for therapeutic autophagy modulation.

PMID: 30728461 [PubMed - as supplied by publisher]

Phage therapy against Pseudomonas aeruginosa infections in a cystic fibrosis zebrafish model.

Sci Rep. 2019 Feb 06;9(1):1527

Authors: Cafora M, Deflorian G, Forti F, Ferrari L, Binelli G, Briani F, Ghisotti D, Pistocchi A

Abstract
Cystic fibrosis (CF) is a hereditary disease due to mutations in the CFTR gene and causes mortality in humans mainly due to respiratory infections caused by Pseudomonas aeruginosa. In a previous work we used phage therapy, which is a treatment with a mix of phages, to actively counteract acute P. aeruginosa infections in mice and Galleria mellonella larvae. In this work we apply phage therapy to the treatment of P. aeruginosa PAO1 infections in a CF zebrafish model. The structure of the CFTR channel is evolutionary conserved between fish and mammals and cftr-loss-of-function zebrafish embryos show a phenotype that recapitulates the human disease, in particular with destruction of the pancreas. We show that phage therapy is able to decrease lethality, bacterial burden, and the pro-inflammatory response caused by PAO1 infection. In addition, phage administration relieves the constitutive inflammatory state of CF embryos. To our knowledge, this is the first time that phage therapy is used to cure P. aeruginosa infections in a CF animal model. We also find that the curative effect against PAO1 infections is improved by combining phages and antibiotic treatments, opening a useful therapeutic approach that could reduce antibiotic doses and time of administration.

PMID: 30728389 [PubMed - in process]

Comparison of Subtyping Approaches and the Underlying Drivers of Microbial Signatures for Chronic Rhinosinusitis.

mSphere. 2019 Feb 06;4(1):

Authors: Biswas K, Cavubati R, Gunaratna S, Hoggard M, Waldvogel-Thurlow S, Hong J, Chang K, Wagner Mackenzie B, Taylor MW, Douglas RG

Abstract
Chronic rhinosinusitis (CRS) is a heterogeneous condition characterized by persistent sinus inflammation and microbial dysbiosis. This study aimed to identify clinically relevant subgroups of CRS patients based on distinct microbial signatures, with a comparison to the commonly used phenotypic subgrouping approach. The underlying drivers of these distinct microbial clusters were also investigated, together with associations with epithelial barrier integrity. Sinus biopsy specimens were collected from CRS patients (n = 23) and disease controls (n = 8). The expression of 42 tight junction genes was evaluated using quantitative PCR together with microbiota analysis and immunohistochemistry for measuring mucosal integrity and inflammation. CRS patients clustered into two distinct microbial subgroups using probabilistic modelling Dirichlet (DC) multinomial mixtures. DC1 exhibited significantly reduced bacterial diversity and increased dispersion and was dominated by Pseudomonas, Haemophilus, and Achromobacter DC2 had significantly elevated B cells and incidences of nasal polyps and higher numbers of Anaerococcus, Megasphaera, Prevotella, Atopobium, and Propionibacterium In addition, each DC exhibited distinct tight junction gene and protein expression profiles compared with those of controls. Stratifying CRS patients based on clinical phenotypic subtypes (absence or presence of nasal polyps [CRSsNP or CRSwNP, respectively] or with cystic fibrosis [CRSwCF]) accounted for a larger proportion of the variation in the microbial data set than with DC groupings. However, no significant differences between CRSsNP and CRSwNP cohorts were observed for inflammatory markers, beta-dispersion, and alpha-diversity measures. In conclusion, both approaches used for stratifying CRS patients had benefits and pitfalls, but DC clustering provided greater resolution when studying tight junction impairment. Future studies in CRS should give careful consideration to the patient subtyping approach used.IMPORTANCE Chronic rhinosinusitis (CRS) is a major human health problem that significantly reduces quality of life. While various microbes have been implicated, there is no clear understanding of the role they play in CRS pathogenesis. Another equally important observation made for CRS patients is that the epithelial barrier in the sinonasal cavity is defective. Finding a robust approach to subtype CRS patients would be the first step toward unravelling the pathogenesis of this heterogeneous condition. Previous work has explored stratification based on the clinical presentation of the disease (with or without polyps), inflammatory markers, pathology, or microbial composition. Comparisons between the different stratification approaches used in these studies have not been possible due to the different cohorts, analytical methods, or sample sites used. In this study, two approaches for subtyping CRS patients were compared, and the underlying drivers of the heterogeneity in CRS were also explored.

PMID: 30728283 [PubMed - in process]

Genetic and phenotypic traits of children and adolescents with cystic fibrosis in Southern Brazil.

J Bras Pneumol. 2018 Nov-Dec;44(6):498-504

Authors: Rosa KMD, Lima EDS, Machado CC, Rispoli T, Silveira VD, Ongaratto R, Comaru T, Pinto LA

Abstract
OBJECTIVES: To characterize the main identified mutations on cystic fibrosis transmembrane conductance regulator (CFTR) in a group of children and adolescents at a cystic fibrosis center and its association with the clinical and laboratorial characteristics.
METHOD: Descriptive cross-sectional study including patients with cystic fibrosis who had two alleles identified with CFTR mutation. Clinical, anthropometrical, laboratorial and pulmonary function (spirometry) data were collected from patients' records in charts and described with the results of the sample genotyping.
RESULTS: 42 patients with cystic fibrosis were included in the study. The most frequent mutation was F508del, covering 60 alleles (71.4%). The second most common mutation was G542X (six alleles, 7.1%), followed by N1303K and R1162X mutations (both with four alleles each). Three patients (7.14%) presented type III and IV mutations, and 22 patients (52.38%) presented homozygous mutation for F508del. Thirty three patients (78.6%) suffered of pancreatic insufficiency, 26.2% presented meconium ileus, and 16.7%, nutritional deficit. Of the patients in the study, 59.52% would be potential candidates for the use of CFTR-modulating drugs.
CONCLUSIONS: The mutations of CFTR identified more frequently were F508del and G542X. These are type II and I mutations, respectively. Along with type III, they present a more severe cystic fibrosis phenotype. More than half of the sample (52.38%) presented homozygous mutation for F508del, that is, patients who could be treated with Lumacaftor/Ivacaftor. Approximately 7% of the patients (7.14%) presented type III and IV mutations, therefore becoming candidates for the treatment with Ivacaftor.

PMID: 30726326 [PubMed - in process]

Parenteral administration of oral medications in lung transplant recipients: An under-recognized problem.

Am J Transplant. 2019 Feb 06;:

Authors: Carney JM, Gray AL, Howell DN, Pavlisko EN

Abstract
Microcrystalline cellulose (MCC) is an insoluble material commonly used as a binder and filler in oral medications. Identification of pulmonary intravascular deposition of MCC in transbronchial biopsies from lung transplant (LT) recipients following parenteral injection of oral medications has only been reported once. A search of our surgical pathology electronic database was performed from 1/1/2000 to 11/1/2017 using the text "transplant transbronchial". The diagnosis field for all cases retrieved was then searched for the text "cellulose." These cases were queried for patient demographics and outcomes. Between 1/1/2000 and 11/1/2017, 1558 lung transplants were performed in 1476 individual patients at our institution; 12 were identified to have MCC in their lung tissue. Patients with MCC identified on biopsies were more likely to be transplanted for cystic fibrosis versus other indications and younger versus older. MCC identified in two of our cases was favored to be donor-derived. Of the 12 patients, 6 (50%) are deceased. MCC within the pulmonary vasculature may be an indicator of increased complications, mortality, or shortened survival in LT recipients. Detecting intravascular MCC and distinguishing it from aspirated foreign material can be challenging. Awareness of the differential diagnosis for pulmonary foreign material is of paramount importance for the pathologist. This article is protected by copyright. All rights reserved.

PMID: 30725518 [PubMed - as supplied by publisher]

Improved Clinical Outcome Following Treatment of Mycobacterium abscessus Complex Pulmonary Disease in Children with Cystic Fibrosis.

Pediatr Infect Dis J. 2019 Feb 04;:

Authors: Chacko A, Wen SC, Hartel G, Kapur N, Wainwright CE, Clark JE

Abstract
BACKGROUND: Mycobacterium abscessus complex pulmonary disease (M. abscessus PD) in cystic fibrosis (CF) is challenging to treat. Current guideline therapeutic regimens involving an intensive phase of intravenous antibiotics followed by a consolidation phase of inhaled and oral antibiotics are not evidence-based. The objectives of this study were to characterize the clinical outcomes and clearance of Mycobacterium abscessus complex (M. abscessus) from respiratory cultures in children with CF M. abscessus PD.
METHODS: This retrospective longitudinal cohort analysis evaluated the first course of treatment for M. abscessus PD in 33 children in Queensland, Australia between 2001-2015. Spirometry and nutritional outcomes 2 years prior to and 1-year post-treatment were compared to clearance or relapse/persistence of M. abscessus from respiratory cultures.
RESULTS: 9/18 children who completed therapy, cleared infection. 3/7 children who completed only intensive therapy cleared sputum compared with 0/8 children who did not. The trajectory of the percent predicted forced expiratory volume in one second and age standardized body mass index (BMI) significantly improved post-treatment in those that cleared sputum (p<0.0001).
CONCLUSIONS: These results suggest that current treatment recommendations for M. abscessus PD are associated with some success in clearing infection in children with CF and improvement in lung function and BMI. Clinical trials are required to determine the best treatment approaches.

PMID: 30724835 [PubMed - as supplied by publisher]

Alpha-1 Antitrypsin Substitution for Extrapulmonary Conditions in Alpha-1 Antitrypsin Deficient Patients.

Chronic Obstr Pulm Dis. 2018 Sep 19;5(4):267-276

Authors: Baranovski BM, Schuster R, Nisim O, Brami I, Lior Y, Lewis EC

Abstract
Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder which most commonly manifests as pulmonary emphysema. Accordingly, alpha-1 antitrypsin (AAT) augmentation therapy aims to reduce the progression of emphysema, as achieved by life-long weekly slow-drip infusions of plasma-derived affinity-purified human AAT. However, not all AATD patients will receive this therapy, due to either lack of medical coverage or low patient compliance. To circumvent these limitations, attempts are being made to develop lung-directed therapies, including inhaled AAT and locally-delivered AAT gene therapy. Lung transplantation is also an ultimate therapy option. Although less common, AATD patients also present with disease manifestations that extend beyond the lung, including vasculitis, diabetes and panniculitis, and appear to experience longer and more frequent hospitalization times and more frequent pneumonia bouts. In the past decade, new mechanism-based clinical indications for AAT therapy have surfaced, depicting a safe, anti-inflammatory, immunomodulatory and tissue-protective agent. Introduced to non-AATD individuals, AAT appears to provide relief from steroid-refractory graft-versus-host disease, from bacterial infections in cystic fibrosis and from autoimmune diabetes; preclinical studies show benefit also in multiple sclerosis, ulcerative colitis, rheumatoid arthritis, acute myocardial infarction and stroke, as well as ischemia-reperfusion injury and aberrant wound healing processes. While the current augmentation therapy is targeted towards treatment of emphysema, it is suggested that AATD patients may benefit from AAT augmentation therapy geared towards extrapulmonary pathologies as well. Thus, development of mechanism-based, context-specific AAT augmentation therapy protocols is encouraged. In the current review, we will discuss extrapulmonary manifestations of AATD and the potential of AAT augmentation therapy for these conditions.

PMID: 30723784 [PubMed]

Pulmonary exacerbations in patients with primary ciliary dyskinesia: an expert consensus definition for use in clinical trials.

ERJ Open Res. 2019 Feb;5(1):

Authors: Lucas JS, Gahleitner F, Amorim A, Boon M, Brown P, Constant C, Cook S, Crowley S, Destouches DMS, Eber E, Mussaffi H, Haarman E, Harris A, Koerner-Rettberg C, Kuehni CE, Latzin P, Loebinger MR, Lorent N, Maitre B, Moreno-Galdó A, Nielsen KG, Özçelik U, Philipsen LKD, Pohunek P, Polverino E, Rademacher J, Robinson P, Snijders D, Yiallouros P, Carr SB

Abstract
Pulmonary exacerbations are a cause of significant morbidity in patients with primary ciliary dyskinesia (PCD) and are frequently used as an outcome measure in clinical research into chronic lung diseases. So far, there has been no consensus on the definition of pulmonary exacerbations in PCD. 30 multidisciplinary experts and patients developed a consensus definition for children and adults with PCD. Following a systematic review, the panel used a modified Delphi process with a combination of face-to-face meetings and e-surveys to develop a definition that can be used in research settings for children and adults with PCD. A pulmonary exacerbation was defined by the presence of three or more of the following seven items: 1) increased cough, 2) change in sputum volume and/or colour, 3) increased shortness of breath perceived by the patient or parent, 4) decision to start or change antibiotic treatment because of perceived pulmonary symptoms, 5) malaise, tiredness, fatigue or lethargy, 6) new or increased haemoptysis, and 7) temperature >38°C. The consensus panel proposed that the definition should be used for future clinical trials. The definition should be validated and the usability assessed during these studies.

PMID: 30723730 [PubMed]

Post-infective bronchiectasis by measles prior infection - A case report.

Respir Med Case Rep. 2019;26:203-205

Authors: Braz M, Ferreira AC, Sousa AS, Barata F

Abstract
Bronchiectasis (BE) refers to an abnormal and irreversible dilatation of the bronchi. Post-infectious etiology still remains an important and frequent cause. Associated the anti-vaccine movement, measles resurfaces and with all the outcomes that comes from the disease. The present case illustrates one of the possible complication of measles - BE, underlining the importance of vaccination.

PMID: 30723668 [PubMed]

Pseudomonas aeruginosa stimulates nuclear sphingosine-1-phosphate generation and epigenetic regulation of lung inflammatory injury.

Thorax. 2019 Feb 05;:

Authors: Ebenezer DL, Berdyshev EV, Bronova IA, Liu Y, Tiruppathi C, Komarova Y, Benevolenskaya EV, Suryadevara V, Ha AW, Harijith A, Tuder RM, Natarajan V, Fu P

Abstract
INTRODUCTION: Dysregulated sphingolipid metabolism has been implicated in the pathogenesis of various pulmonary disorders. Nuclear sphingosine-1-phosphate (S1P) has been shown to regulate histone acetylation, and therefore could mediate pro-inflammatory genes expression.
METHODS: Profile of sphingolipid species in bronchoalveolar lavage fluids and lung tissue of mice challenged with Pseudomonas aeruginosa (PA) was investigated. The role of nuclear sphingosine kinase (SPHK)2 and S1P in lung inflammatory injury by PA using genetically engineered mice was determined.
RESULTS: Genetic deletion of Sphk2, but not Sphk1, in mice conferred protection from PA-mediated lung inflammation. PA infection stimulated phosphorylation of SPHK2 and its localisation in epithelial cell nucleus, which was mediated by protein kinase C (PKC) δ. Inhibition of PKC δ or SPHK2 activity reduced PA-mediated acetylation of histone H3 and H4, which was necessary for the secretion of pro-inflammatory cytokines, interleukin-6 and tumour necrosis factor-α. The clinical significance of the findings is supported by enhanced nuclear localisation of p-SPHK2 in the epithelium of lung specimens from patients with cystic fibrosis (CF).
CONCLUSIONS: Our studies define a critical role for nuclear SPHK2/S1P signalling in epigenetic regulation of bacterial-mediated inflammatory lung injury. Targeting SPHK2 may represent a potential strategy to reduce lung inflammatory pulmonary disorders such as pneumonia and CF.

PMID: 30723184 [PubMed - as supplied by publisher]

StatPearls

Book. 2018 01

Authors:

Abstract
N-acetylcysteine (NAC) is the mainstay of therapy for acetaminophen toxicity. NAC has FDA approval for the treatment of potentially hepatotoxic doses of acetaminophen (APAP), and it is almost 100% effective if given within 8 hours post-ingestion.[1] It is also approved for use in conditions with abnormal, viscid or inspissated mucous secretions such as pneumonia, bronchitis, tracheobronchitis, cystic fibrosis, tracheostomy patients, postoperative pulmonary complications, posttraumatic chest conditions and before diagnostic bronchoscopy to help with mucous plugging. Off-label indications include acute hepatic failure, prevention of contrast-induced nephropathy and topical treatment of keratoconjunctivitis sicca.

PMID: 30725868

StatPearls

Book. 2018 01

Authors:

Abstract
In neonates, meconium Ileus (MI) is one of the earliest manifestations in patients with cystic fibrosis (CF). It presents in up to 20% of patients with CF. The inspissated meconium obstructs the small intestine at the level of the terminal ileum. If left untreated, the prognosis is poor.[1] 

PMID: 30725693

Different Munc18 proteins mediate baseline and stimulated airway mucin secretion.

JCI Insight. 2019 Feb 05;:

Authors: Jaramillo AM, Piccotti L, Velasco WV, Huerta Delgado AS, Azzegagh Z, Chung FS, Nazeer UI, Farooq J, Brenner JM, Parker-Thornburg J, Scott BL, Evans CM, Adachi R, Burns AR, Kreda SM, Tuvim MJ, Dickey BF

Abstract
Airway mucin secretion is necessary for ciliary clearance of inhaled particles and pathogens, but can be detrimental in pathologies such as asthma and cystic fibrosis. Exocytosis in mammals requires a Munc18 scaffolding protein, and airway secretory cells express all three Munc18 isoforms. Using conditional airway epithelial deletant mice, we found that Munc18a has the major role in baseline mucin secretion, Munc18b has the major role in stimulated mucin secretion, and Munc18c does not function in mucin secretion. In an allergic asthma model, Munc18b deletion reduced airway mucus occlusion and airflow resistance. In a cystic fibrosis model, Munc18b deletion reduced airway mucus occlusion and emphysema. Munc18b deficiency in the airway epithelium did not result in any abnormalities of lung structure, particle clearance, inflammation, or bacterial infection. Our results show that regulated secretion in a polarized epithelial cell may involve more than one exocytic machine at the apical plasma membrane, and that the protective roles of mucin secretion can be preserved while therapeutically targeting its pathologic roles.

PMID: 30721150 [PubMed - as supplied by publisher]

Defective exocytosis and processing of insulin in a cystic fibrosis mouse model.

J Endocrinol. 2019 Feb 01;:

Authors: Edlund A, Barghouth M, Huhn M, Abels M, Esguerra J, Mollet I, Svedin E, Wendt A, Renstrom E, Zhang E, Wierup N, Scholte BJ, Flodström-Tullberg M, Eliasson L

Abstract
Cystic fibrosis-related diabetes (CFRD) is a common complication for patients with cystic fibrosis (CF), a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). The cause of CFRD is unclear, but a commonly observed reduction in first-phase insulin secretion suggests defects at the beta cell level. Here we aimed to examine beta- and alpha-cell function in the Cftrtm1EUR/F508del mouse model (C57BL/6J), which carries the most common human mutation in CFTR, the F508del mutation. CFTR expression, beta cell mass, insulin granule distribution, hormone secretion and single cell capacitance changes were evaluated using islets (or beta cells) from F508del mice and age-matched wild-type mice aged 7-10 weeks. Granular pH was measured with DND-189 fluorescence. Serum glucose, insulin and glucagon levels were measured in vivo, and glucose tolerance was assessed using IPGTT. We show increased secretion of proinsulin and concomitant reduced secretion of C-peptide in islets from F508del mice compared to WT mice. Exocytosis and number of docked granules was reduced. We confirmed reduced granular pH by CFTR stimulation. We detected decreased pancreatic beta cell area, but unchanged beta cell number. Moreover, the F508del mutation caused failure to suppress glucagon secretion leading to hyperglucagonemia. In conclusion, F508del mice have beta cell defects resulting in 1) reduced number of docked insulin granules and reduced exocytosis, and 2) potential defective proinsulin cleavage and secretion of immature insulin. These observations provide insight into the functional role of CFTR in pancreatic islets and contribute to increased understanding of the pathogenesis of CFRD.

PMID: 30721137 [PubMed - as supplied by publisher]

Pediatric Chest MRI: A Review.

Indian J Pediatr. 2019 Feb 05;:

Authors: Kapur S, Bhalla AS, Jana M

Abstract
Chest radiographs and CT scans have been the cornerstone of pulmonary imaging given their advantages of being rapid and easily available techniques. However, a significant concern with their use in the pediatric population is the associated ionisation radiation. The use of magnetic resonance imaging (MRI) in pulmonary imaging has lagged behind its adoption in other organ systems. Previously, the lung parenchyma was considered difficult to evaluate by magnetic resonance due to low proton density in the pulmonary tissue, susceptibility artefacts within the lungs, and respiratory motion artefacts. However, in recent years, there have been a multitude of technical advancements to overcome these limitations. MRI can be an excellent radiation-free alternative in patients who require protracted follow-up like in cases such as cystic fibrosis, complicated pneumonias, tuberculosis and mediastinal neoplasms. An added advantage of MRI is that it can provide functional information in addition to the structural information provided by traditional imaging techniques. One of the major reasons of limited use of MRI despite its established utility is the lack of clarity regarding its indications, and a paucity of data on tailored MRI protocols customised to clinical needs. This article aims to review the basic MRI techniques, indications and terminologies used in chest imaging, with special emphasis on imaging findings of common pathologies in the pediatric population.

PMID: 30719641 [PubMed - as supplied by publisher]

Pseudomonas aeruginosa Can Inhibit Growth of Streptococcal Species via Siderophore Production.

J Bacteriol. 2019 Feb 04;:

Authors: Scott JE, Li K, Filkins LM, Zhu B, Kuchma SL, Schwartzman JD, O'Toole GA

Abstract
Cystic Fibrosis (CF) is a genetic disease that causes patients to accumulate thick, dehydrated mucus in the lung and develop chronic, polymicrobial infections due to reduced mucociliary clearance. These chronic polymicrobial infections and subsequent decline in lung function are significant factors in the morbidity and mortality of CF. Pseudomonas aeruginosa and Streptococcus spp. are among the most prevalent organisms in the CF lung; the presence of P. aeruginosa correlates with lung function decline and the Streptococcus milleri group (SMG), a subgroup of the viridans streptococci, is associated with exacerbations in patients with CF. Here we characterize the interspecies interactions that occur between these two genera. We demonstrated that multiple P. aeruginosa laboratory strains and clinical CF isolates promote the growth of multiple SMG strains and oral streptococci in an in vitro coculture system. We investigated the mechanism by which P. aeruginosa enhances growth of streptococci by screening for mutants of P. aeruginosa PA14 unable to enhance Streptococcus growth, and we identified the P. aeruginosa pqsL::TnM mutant, which failed to promote growth of S. constellatus and S. sanguinis Characterization of the P. aeruginosa ΔpqsL mutant revealed that this strain cannot promote Streptococcus growth. Our genetic data and growth studies support a model whereby the P. aeruginosa ΔpqsL mutant overproduces siderophores, and thus likely outcompetes Streptococcus sanguinis for limited iron. We propose a model whereby competition for iron represents one important means of interaction between P. aeruginosa and Streptococcus spp.ImportanceCystic fibrosis (CF) lung infections are increasingly recognized for their polymicrobial nature. These polymicrobial infections may alter the biology of the organisms involved in CF-related infections, leading to changes in growth, virulence and/or antibiotic tolerance, and could thereby affect patient health and response to treatment. In this study, we demonstrate interactions between P. aeruginosa and streptococci using a coculture model, and show that one interaction between these microbes is likely competition for iron. Thus, these data indicate that one CF pathogen may influence the growth of another and add to our limited knowledge of polymicrobial interactions in the CF airway.

PMID: 30718303 [PubMed - as supplied by publisher]

"Resurrecting old β-lactams": the potent inhibitory activity of temocillin against multi-drug resistant Burkholderia spp. isolates from the United States.

Antimicrob Agents Chemother. 2019 Feb 04;:

Authors: Zeiser ET, Becka SA, Barnes MD, Taracila MA, LiPuma JJ, Papp-Wallace KM

Abstract
Burkholderia spp. are opportunistic human pathogens that infect persons with cystic fibrosis and the immunocompromised. Burkholderia spp. express class A and C β-lactamases, which are transcriptionally regulated by PenRA through linkage to cell wall metabolism and β-lactam exposure. The potency of temocillin, a 6-methoxy-β-lactam was tested against a panel of multi-drug resistant (MDR) Burkholderia spp. In addition, the mechanistic basis of temocillin activity was assessed and compared to ticarcillin. Susceptibility testing with temocillin and ticarcillin was conducted, as well as biochemical analysis of the PenA1 class A β-lactamase and AmpC1 class C β-lactamase. Molecular dynamics simulations (MDS) were performed using PenA1 with temocillin and ticarcillin. The majority (86.7%) of 150 MDR Burkholderia strains were susceptible to temocillin, while only 4% of the strains were susceptible to ticarcillin. Neither temocillin nor ticarcillin induced bla expression. Ticarcillin was hydrolyzed by PenA1 (k cat/K m = 1.7±0.2 μM-1s-1), while temocillin was slow to form a favorable complex (K iapp = ∼2 mM). Ticarcillin and temocillin were both potent inhibitors of AmpC1, with K i app values of 4.9±1.0 μM and 4.3±0.4 μM, respectively. MDS of PenA revealed that ticarcillin is in an advantageous position for acylation and deacylation. Conversely, with temocillin, active site residues K73 and S130 are rotated and the catalytic water molecule is displaced, thereby slowing acylation and allowing the 6-methoxy of temocillin to block deacylation. Temocillin is a β-lactam with potent activity against Burkholderia spp. as it does not induce bla expression and is poorly hydrolyzed by endogenous β-lactamases.

PMID: 30718248 [PubMed - as supplied by publisher]

Comment on "repeated hot water and steam disinfection of pari LC Plus® nebulizers alter nebulizer output".

J Cyst Fibros. 2019 Feb 01;:

Authors: Millar BC, Bell J

PMID: 30718163 [PubMed - as supplied by publisher]