Epithelial Na(+) channel inhibitors for the treatment of cystic fibrosis.

Pharm Pat Anal. 2017 Jul 11;:

Authors: Smith NJ, Solovay CF

Abstract
The epithelial Na(+) channel (ENaC) is a key regulator of the volume of airway surface liquid (ASL) and is found in the human airway epithelium. In cystic fibrosis (CF), Na(+) hyperabsorption through ENaC, in the absence of cystic fibrosis transmembrane conductance regulator mediated anion secretion, results in the dehydration of respiratory secretions and the impairment of mucociliary clearance. The hypothesis of utilizing an ENaC blocking molecule to facilitate restoration of the airway surface liquid volume sufficiently to allow normal mucociliary clearance is of interest in the management of lung disease in CF patients. This review summarizes the published patent applications from 2014 to the end of 2016 that claim approaches to inhibit the function of ENaC for the treatment of CF.

PMID: 28696180 [PubMed - as supplied by publisher]

Clinical Analysis of 77 Patients with Allergic Bronchopulmonary Aspergillosis in Peking Union Medical College Hospital.

Chin Med Sci J. 2017 Jun 20;39(3):352-357

Authors: Zhang M, Gao J

Abstract
Objective To summarize the clinical features of allergic bronchopulmonary aspergillosis(ABPA)to facilitate its early diagnosis and treatment. Methods We retrospectively analyzed the clinical data of 77 patients who had been admitted to Peking Union Medical College Hospital from January 1996 to July 2015 with ABPA. Results The average age of these 77 patients(38 men and 39 women)was(41.8±18.3)years. The co-morbidities included bronchial asthma(n=74,96%)and pulmonary cystic fibrosis(n=3,4%). The main symptoms and signs of ABPA were chronic cough(100%),sputum production(97%),wheeze(86%),sputum plugs(25%),blood-stained sputum(18%),hemoptysis(9%),chest pain(9%),fever(47%),weight loss(30%),and night sweat(12%). Laboratory tests revealed elevated levels of blood eosinophils absolute count(87%),anti-aspergillus antigen-specific IgE(89%)and specific IgG(57%)as well as a positive result of Aspergillus antigen skin test(88%). Pulmonary function testing showed that the incidences of obstructive ventilation and diffusion dysfunction were 66% and 65%,respectively;in addition,bronchodilatation test showed positive result in 60% of the patients. The most common CT findings were central bronchiectasis(81%),patchy infiltrations(79%),pleural thickening(49%),mediastinal adenopathy(35%),nodular opacities(25%),mucoid impaction(21%),and fleeting infiltrations(35%). In addition,44 cases(58%)were misdiagnosed as tuberculosis,pneumonia,lung abscess,and/or lung cancer autoimmune diseases. Conclusions ABPA can be easily misdiagnosed. ABPA should be carefully considered in patients with asthma or pulmonary cystic fibrosis who also suffer from wheeze,sputum plugs,elevated eosinophils central bronchiectasis,and fleeting infiltrations.

PMID: 28695805 [PubMed - in process]

Fenretinide differentially modulates the levels of long- and very long-chain ceramides by downregulating Cers5 enzyme: evidence from bench to bedside.

J Mol Med (Berl). 2017 Jul 10;:

Authors: Garić D, De Sanctis JB, Wojewodka G, Houle D, Cupri S, Abu-Arish A, Hanrahan JW, Hajduch M, Matouk E, Radzioch D

Abstract
Cystic fibrosis is the most common genetic disease, in which symptoms may be alleviated but not fully eliminated. Ceramides have long been implicated in the inflammatory etiology of cystic fibrosis, with contradicting reports with regards to their role. Recently, significant biological and biophysical differences have been observed between long- and very long-chain ceramides. This work reveals that long-chain ceramides are upregulated whereas very long-chain ceramides are downregulated in cell lines, mouse animal model, and patients with cystic fibrosis, compared with their controls. Treatment with fenretinide decreases the levels of long-chain ceramides and increases the levels of very long-chain ceramides. Our results show that restoration of cystic fibrosis conductance regulator (CFTR) expression is associated with normalization of aberrant levels of specific ceramides. This demonstrates for the first time a correlation between CFTR protein expression and regulation of specific ceramide levels. Furthermore, using cystic fibrosis lung epithelial cell lines, we demonstrate that this effect can be attributed to the transcriptional downregulation of ceramide synthase 5 (Cers5) enzyme. We also discovered a partial synergism between fenretinide and zinc (Zn(2+)), which deficiency has been reported in patients with cystic fibrosis. Overall, in addition to having direct translational application, we believe that our findings contribute to the understanding of ceramide metabolism in cystic fibrosis, as well as other inflammatory diseases where imbalances of ceramides have also been observed.
KEY MESSAGES: Long- and very long-chain ceramides (LCCs and VLCCs) are biochemically distinct. LCCs are upregulated whereas VLCCs are downregulated in cystic fibrosis. Fenretinide downregulates the levels of LCCs and upregulates the levels of VLCCs. Fenretinide changes the balance of LCCs and VLCCs by downregulating Cers5 enzyme. Fenretinide and zinc ions cooperate in the modulation of ceramide levels.

PMID: 28695226 [PubMed - as supplied by publisher]

Family-centred care in cystic fibrosis: a pilot study in North Queensland, Australia.

Nurs Open. 2017 Jul;4(3):168-173

Authors: Smyth W, Abernethy G, Jessup M, Douglas T, Shields L, AREST‐CF

Abstract
AIMS: The aims were to: (i) examine perceptions of family-centred care of parents of children with cystic fibrosis and healthcare professionals who care for them; (ii) test design and tools in a regional population.
DESIGN: Quantitative pilot study of existing questionnaire.
METHODS: The methods involved were comparative, cross-sectional survey of parents of children with cystic fibrosis and health staff in North Queensland, using "Perceptions of Family Centered Care - Parent" and "Perceptions of Family Centered Care - Staff" questionnaires; and descriptive study of tools.
RESULTS: Eighteen staff, 14 parents (78%, 61%); using Mann-Whitney U, showed no significant differences in scores in categories: 'support' 'respect', 'collaboration'. Comments about suitability of questionnaires varied, but were largely positive.

PMID: 28694981 [PubMed - in process]

Descriptive analysis of cochrane child-relevant systematic reviews: an update and comparison between 2009 and 2013.

BMC Pediatr. 2017 Jul 11;17(1):155

Authors: Crick K, Thomson D, Fernandes RM, Nuspl M, Eurich DT, Rowe BH, Hartling L

Abstract
BACKGROUND: Systematic reviews support health systems and clinical decision-making by identifying and summarizing all existing studies on a particular topic. In 2009, a comprehensive description of child-relevant systematic reviews published in the Cochrane Database of Systematic Reviews was compiled. This study aims to provide an update, and to describe these systematic reviews according to their content and methodological approaches.
METHODS: All child-relevant systematic reviews published by the Cochrane Collaboration in the Cochrane Database of Systematic Reviews (CDSR) as of March, 2013 were identified and described in relation to their content and methodological approaches. This step equated to an update of the Child Health Field Review Register (CHFRR). The content of the updated CHFRR was compared to the published 2009 CHFRR description regarding clinical and methodological characteristics, using bivariate analyses. As the Cochrane Collaboration has recognized that disease burden should guide research prioritization, we extracted data from the Global and National Burden of Diseases and Injuries Among Children and Adolescents Between 1990 and 2013 study in order to map the distribution of the burden of disease in child health to the distribution of evidence across Review Groups in the CHFRR.
RESULTS: Of the 5,520 potential Cochrane systematic reviews identified, 1,293 (23.4%) were child-relevant (an increase of 24% since 2009). Overall, these reviews included 16,738 primary studies. The most commonly represented Review Groups were Airways (11.5%), Cystic Fibrosis and Genetic Diseases (7.9%), Acute Respiratory Infections (7.8%), Developmental, Psychological and Learning Problems (6.7%), and Infectious Diseases (6.2%). Corresponding authors were most often from Europe (51%), North America (15%), and Australia (15%). The majority of systematic reviews examined pharmacological interventions alone (52% compared to 59% in 2009). Out of 611 reviews that were assessed as up-to-date, GRADE was used in 204 (35%) reviews to assess the overall quality of the evidence, which was often moderate (35.6%) or low (37.8%) for primary outcomes. Ninety percent of reviews that were assessed as up to date used the Cochrane Risk of Bias tool, or a modified version, to assess methodological quality. Most reviews conducted one or more meta-analyses (73%). Among the 25 leading causes of death globally, the Review Groups associated with the largest number of causes were: 1) Infectious Diseases, 2) Anaesthesia, Critical, and Emergency Care, 3) Injuries, 4) Pregnancy and Childbirth (PC), and 5) Neonatal. There were large discrepancies between the number of causes of mortality that each Review Group was associated with and the total amount of evidence each Review Group contributed to the CHFRR. Ninety-eight percent of the causes of mortality in 2013 were from developing nations, but only 224 (17.3%) reviews had corresponding authors from developing countries.
CONCLUSION: The content and methodological characteristics of child-relevant systematic reviews in the Cochrane CHFRR have been described in detail. There were modest advances in methods between 2009 and 2013. Systematic reviews contained in the CDSR offer an important resource for researcher's, clinicians and policy makers by synthesizing an extensive body of primary research. Further content analysis will allow the identification of clinical topics of greatest priority for future systematic reviews in child health.

PMID: 28693463 [PubMed - in process]

[Chinese expert consensus for non-antiinfective effects and clinical use of macrolides].

Zhonghua Nei Ke Za Zhi. 2017 Jul 01;56(7):546-557

Authors: Lin JT, Zhang YM, Zhou X, Wang CZ, Huang M, Liu CT, Wu CG, Wan HY, Yu WC, Dai YR

Abstract
Important/potential value of macrolides has been proved in the management of chronic respiratory diseases by increasing basic and clinical trials.Through three face-to-face discussions, 10 experts examined important data and drafted this consensus related to macrolides: (1) mechanism of non-antiinfective effects; (2) clinical use in chronic respiratory diseases; (3) cautions of long-term use.The mechanism out of non-antiinfective effects includes anti-inflammatory effect, modifying airway secretion, immune-regulation related to antibacterial effect, corticoid saving effect and anti-viral effect.The efficacy of long-term use of low-dose macrolides is definitely confirmed in diffuse panbronchiolitis, chronic rhinosinusitis. It is considerably used in bronchiectasia, cystic fibrosis, severe asthma and chronic obstructive pulmonary disease. Further studies should be conducted in cryptogenic organizing pneumonia and respiratory viral infection. It should be paid attention to its possible adverse effects (including drug interactions, cardiac toxicity, ototoxicity and disturbance of intestinal flora) and drug resistance in long-term use.A Chinese consensus for non-antiinfective effects and clinical use of macrolides is developed for the first time, which aims to expand their rational use and the further research.

PMID: 28693067 [PubMed - in process]

Diversity, Prevalence, and Longitudinal Occurrence of Type II Toxin-Antitoxin Systems of Pseudomonas aeruginosa Infecting Cystic Fibrosis Lungs.

Front Microbiol. 2017;8:1180

Authors: Andersen SB, Ghoul M, Griffin AS, Petersen B, Johansen HK, Molin S

Abstract
Type II toxin-antitoxin (TA) systems are most commonly composed of two genes encoding a stable toxin, which harms the cell, and an unstable antitoxin that can inactivate it. TA systems were initially characterized as selfish elements, but have recently gained attention for regulating general stress responses responsible for pathogen virulence, formation of drug-tolerant persister cells and biofilms-all implicated in causing recalcitrant chronic infections. We use a bioinformatics approach to explore the distribution and evolution of type II TA loci of the opportunistic pathogen, Pseudomonas aeruginosa, across longitudinally sampled isolates from cystic fibrosis lungs. We identify their location in the genome, mutations, and gain/loss during infection to elucidate their function(s) in stabilizing selfish elements and pathogenesis. We found (1) 26 distinct TA systems, where all isolates harbor four in their core genome and a variable number of the remaining 22 on genomic islands; (2) limited mutations in core genome TA loci, suggesting they are not under negative selection; (3) no evidence for horizontal transmission of elements with TA systems between clone types within patients, despite their ability to mobilize; (4) no gain and limited loss of TA-bearing genomic islands, and of those elements partially lost, the remnant regions carry the TA systems supporting their role in genomic stabilization; (5) no significant correlation between frequency of TA systems and strain ability to establish as chronic infection, but those with a particular TA, are more successful in establishing a chronic infection.

PMID: 28690609 [PubMed - in process]

Investigating the variation in the incidence of new Pseudomonas aeruginosa infection between paediatric cystic fibrosis centres.

J Cyst Fibros. 2017 Jul 06;:

Authors: Gilchrist FJ, Jones AM, Smyth AR, Southern KW, Webb AK, Lenney W

PMID: 28690130 [PubMed - as supplied by publisher]

Pneumocystis jirovecii and Cystic Fibrosis in Brittany, France.

Mycopathologia. 2017 Jul 07;:

Authors: Nevez G, Robert-Gangneux F, Pougnet L, Virmaux M, Belleguic C, Deneuville E, Rault G, Chevrier S, Ramel S, Le Bihan J, Guillaud-Saumur T, Calderon E, Le Govic Y, Gangneux JP, Le Gal S

Abstract
Pneumocystis jirovecii is a transmissible fungus with a high pulmonary tropism. The prevalence of P. jirovecii in patients with cystic fibrosis (CF) has been estimated in Germany at 7.4%, in Spain at 21.5% and in Brazil at 38.2%. Data on the prevalence of P. jirovecii in CF patients in France remain scarce, particularly in Brittany, where the prevalence of CF is high (from 1/1600 to 1/4500). Our objectives were to determine the prevalence of colonization of the airways by P. jirovecii in Brittany in CF patients monitored at the "Centre de Ressources et de Compétences de la Mucoviscidose (CRCM)" of Rennes compared to that previously observed at the CRCM of Roscoff-Brest. Sputa from 86 patients (178 specimens) followed in Rennes were analyzed retrospectively. The detection of P. jirovecii was performed using real-time PCR targeting the gene encoding the mitochondrial large subunit of ribosomal RNA. Pneumocystis jirovecii DNA was detected in 3/86 patients (3.5%) monitored at Rennes, whereas it had previously been detected in 1/76 patients (1.3%) monitored at Roscoff-Brest, thus showing an overall prevalence of 2.5% in Brittany. These results obtained from two Breton centers taken together show that P. jirovecii prevalence in patients with CF in Brittany is lower than those observed in Germany, Spain, Brazil or in other regions of France. This study is a preliminary step in determining the risk factors for P. jirovecii acquisition, its epidemiological and clinical significance in CF patients through a prospective multicenter study.

PMID: 28688008 [PubMed - as supplied by publisher]

Expanded carrier screening for monogenic disorders: Where are we now?

Prenat Diagn. 2017 Jul 06;:

Authors: Chokoshvili D, Vears D, Borry P

Abstract
BACKGROUND: Expanded carrier screening (ECS), which can identify carriers of a large number of recessive disorders in the general population, has grown in popularity and is now widely accessible to prospective parents. This article presents a comprehensive overview of the characteristics of currently available ECS tests.
METHODS: To identify relevant ECS providers, we employed a multi-step approach, which included online searching, review of the recent literature, and consultations with researchers familiar with the current landscape of ECS.
RESULTS: As of January 2017, there were sixteen providers of ECS tests: 13 commercial companies, two medical hospitals and one academic diagnostic laboratory. We observed drastic differences in the characteristics of ECS tests, with the number of conditions ranging from 41 to 1700. Only three conditions (Cystic fibrosis, Maple syrup urine disease 1b, and Niemann-Pick disease) were screened for by all providers. Where the same disease gene was included by multiple providers, substantial differences existed in the mutations screened and/or variant interpretation/reporting strategies.
CONCLUSION: Given the importance of carrier screening results in reproductive decision-making, the observed heterogeneity across ECS panels is concerning. Efforts should be made to ensure that clear and concrete criteria are in place to guide the development of ECS panels.

PMID: 28685505 [PubMed - as supplied by publisher]

Rituximab for treating inhibitors in people with inherited severe hemophilia.

Cochrane Database Syst Rev. 2017 Jul 07;7:CD010810

Authors: Jiang L, Liu Y, Zhang L, Santoro C, Rodriguez A

Abstract
BACKGROUND: Hemophilia A and B are inherited coagulation disorders characterized by a reduced or absent level of factor VIII or factor IX respectively. The severe form is characterized by a factor level less than 0.01 international units (IU) per milliliter. The development of inhibitors in hemophilia is the main complication of treatment, because the presence of these antibodies, reduces or even nullifies the efficacy of replacement therapy, making it very difficult to control the bleeding. People with inhibitors continue to have significantly higher risks of morbidity and mortality, with considerable treatment costs. Given the wide 'off-label' use of rituximab for treating people with hemophilia and inhibitors, its efficacy and safety need to be evaluated. This is an update of a previously published Cochrane Review.
OBJECTIVES: To assess the efficacy and safety of rituximab for treating inhibitors in people with inherited severe hemophilia A or B.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, complied from electronic database searches and handsearching of journals and conference abstract books. We searched the reference lists of relevant articles and reviews and also searched for ongoing or unpublished studies. We also undertook further searches of other bibliographic databases and trial registries.Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register: 16 February 2017.
SELECTION CRITERIA: Randomized controlled trials and controlled clinical trials investigating the efficacy and safety of rituximab for treating inhibitors in people with hemophilia.
DATA COLLECTION AND ANALYSIS: No randomized controlled trials matching the selection criteria were eligible for inclusion.
MAIN RESULTS: No randomized controlled trials on rituximab for treating inhibitors in people with hemophilia were identified.
AUTHORS' CONCLUSIONS: We were unable to identify any relevant trials on the efficacy and safety of rituximab for treating inhibitors in people with hemophilia. The research evidence available is from case reports and case series. Randomized controlled trials are needed to evaluate the efficacy and safety of rituximab for this condition. However, prior to the publication of any possible future randomized controlled trials, meta-analysis of case reports and case series may provide some evidence.

PMID: 28685500 [PubMed - as supplied by publisher]

Chronic Diseases as Barriers to Oxygen Delivery: A Unifying Hypothesis of Tissue Reoxygenation Therapy.

Adv Exp Med Biol. 2017;977:15-20

Authors: Perdrizet GA

Abstract
Modern medical practice has resulted in the accumulation of a growing number of incurable chronic diseases, many of which are inflammatory in nature. Inflammation establishes a hypoxic microenvironment within tissues, a condition of inflammatory hypoxia (IH). Tissues thus affected become severely compromised, are unable to elicit adaptive responses and eventually develop fibrosis and fixed microvascular deficits. Previous work has demonstrated that tissue hypoxia exits even within the simple human model of self-resolving inflammation, the tuberculin reaction. Failed resolution of IH establishes a vicious cycle within tissues that perpetuates tissue hypoxia and resists standard drug therapies. Diseases such as sepsis, chronic cutaneous wounds, kidney disease, traumatic brain injury, solid tumors, inflammatory bowel disease, and chronic bacterial infections (urinary tract infection, cystic fibrosis) are tissue specific manifestations of chronic IH. Successful reversal of IH, through tissue re-oxygenation therapy (TROT), will break this vicious cycle and restore tissue homeostasis. The examples of solid tumors and inflammatory bowel disease are presented to illustrate a theoretical framework to support this hypothesis. Re-oxygenation of compromised tissues must occur before successful treatment of these diverse chronic disease s can be expected.

PMID: 28685422 [PubMed - in process]

Reorganization of gene network for degradation of polycyclic aromatic hydrocarbons (PAHs) in Pseudomonas aeruginosa PAO1 under several conditions.

J Appl Genet. 2017 Jul 07;:

Authors: Yan S, Wu G

Abstract
Although polycyclic aromatic hydrocarbons (PAHs) are harmful to human health, their elimination from the environment is not easy. Biodegradation of PAHs is promising since many bacteria have the ability to use hydrocarbons as their sole carbon and energy sources for growth. Of various microorganisms that can degrade PAHs, Pseudomonas aeruginosa is particularly important, not only because it causes a series of diseases including infection in cystic fibrosis patients, but also because it is a model bacterium in various studies. The genes that are responsible for degrading PAHs have been identified in P. aeruginosa, however, no gene acts alone as various stresses often initiate different metabolic pathways, quorum sensing, biofilm formation, antibiotic tolerance, etc. Therefore, it is important to study how PAH degradation genes behave under different conditions. In this study, we apply network analysis to investigating how 46 PAH degradation genes reorganized among 5549 genes in P. aeruginosa PAO1 under nine different conditions using publicly available gene coexpression data from GEO. The results provide six aspects of novelties: (i) comparing the number of gene clusters before and after stresses, (ii) comparing the membership in each gene cluster before and after stresses, (iii) defining which gene changed its membership together with PAH degradation genes before and after stresses, (iv) classifying membership-changed-genes in terms of category in Pseudomonas Genome Database, (v) postulating unknown gene's function, and (vi) proposing new mechanisms for genes of interests. This study can shed light on understanding of cooperative mechanisms of PAH degradation from the level of entire genes in an organism, and paves the way to conduct the similar studies on other genes.

PMID: 28685384 [PubMed - as supplied by publisher]

Treatment of high-grade osteoblastic osteosarcoma of the humerus in a 5-year-old boy with cystic fibrosis: A case report.

Mol Clin Oncol. 2017 Jul;7(1):148-150

Authors: Okuda KV, Hammermann J, Lange BS, Fischer JC, Thielemann F, Knöfler R, Suttorp M

Abstract
Antineoplastic treatment of osteoblastic osteosarcoma in a patient with cystic fibrosis (CF) may harbor a high risk of neutropenia-associated complications, and, to the best of our knowledge, has not been previously reported. Diagnosis of CF was confirmed in a 6-week-old boy following pathological newborn screening. The patient had a stable course of CF under standardized continuous therapy. At the age of 5 years, osteosarcoma of the left proximal humerus was diagnosed without evidence of metastases. Neoadjuvant chemotherapy, including doxorubicin, cisplatin and methotrexate, was administered for 10 weeks. The patient tolerated this therapy relatively well, with a continuous antibiotic prophylaxis of cefuroxime without experiencing major complications; in particular, no pulmonary exacerbations were observed as a consequence of immunosuppression or mucosal toxicity. The tumor responded well, and amputation of the limb was avoided via the use of 'clavicle per humerus' osteosynthesis. Postoperatively, compartmental syndrome occurred, requiring management by fasciotomy. Adjuvant chemotherapy was applied thereafter again, without major toxicity that would have required dose reduction. Under intensive physiotherapy, the mobility of the left arm and hand was deemed to be satisfactory. The coincidence of CF with osteosarcoma is extremely rare, and, to the best of our knowledge, has not been previously described. Under antibiotic prophylaxis, antineoplastic treatment was possible without major complications during neutropenia.

PMID: 28685094 [PubMed - in process]

Modifications of Pseudomonas aeruginosa cell envelope in the cystic fibrosis airway alters interactions with immune cells.

Sci Rep. 2017 Jul 06;7(1):4761

Authors: Hill PJ, Scordo JM, Arcos J, Kirkby SE, Wewers MD, Wozniak DJ, Torrelles JB

Abstract
Pseudomonas aeruginosa is a ubiquitous environmental organism and an opportunistic pathogen that causes chronic lung infections in the airways of cystic fibrosis (CF) patients as well as other immune-compromised individuals. During infection, P. aeruginosa enters the terminal bronchioles and alveoli and comes into contact with alveolar lining fluid (ALF), which contains homeostatic and antimicrobial hydrolytic activities, termed hydrolases. These hydrolases comprise an array of lipases, glycosidases, and proteases and thus, they have the potential to modify lipids, carbohydrates and proteins on the surface of invading microbes. Here we show that hydrolase levels between human ALF from healthy and CF patients differ. CF-ALF influences the P. aeruginosa cell wall by reducing the content of one of its major polysaccharides, Psl. This CF-ALF induced Psl reduction does not alter initial bacterial attachment to surfaces but reduces biofilm formation. Importantly, exposure of P. aeruginosa to CF-ALF drives the activation of neutrophils and triggers their oxidative response; thus, defining human CF-ALF as a new innate defense mechanism to control P. aeruginosa infection, but at the same time potentially adding to the chronic inflammatory state of the lung in CF patients.

PMID: 28684799 [PubMed - in process]

Air trapping in early cystic fibrosis lung disease-Does CT tell the full story?

Pediatr Pulmonol. 2017 Jul 06;:

Authors: Rosenow T, Ramsey K, Turkovic L, Murray CP, Mok LC, Hall GL, Stick SM, AREST CF

Abstract
INTRODUCTION: Mosaic attenuation on expiratory chest computed tomography (CT) is common in early life cystic fibrosis (CF) and often referred to as "air trapping". It is presumed to be localized hyperinflation due to small airway obstruction. In order to test this assumption, we compared air trapping extent to lung volumes measured on CT in young children with CF.
MATERIALS AND METHODS: Children aged below 7 years undergoing inspiratory/expiratory CT were recruited from the Australian Respiratory Early Surveillance Team for Cystic Fibrosis cohort. Automated lung segmentation was used to determine functional residual capacity (FRC), total lung capacity (TLC), and their ratio (FRC/TLC). Structural lung disease (%Disease) and air trapping (%TrappedAir) extent were assessed using PRAGMA-CF. Lung clearance index (LCI), an index of ventilation heterogeneity, was measured. Linear mixed model analysis was used to determine associations.
RESULTS: Seventy-three scans from 55 patients were obtained. %TrappedAir was associated with %Disease (0.19 [0.07, 0.31]; P = 0.003) and LCI (0.22 [0.04, 0.39]; P = 0.016), but not FRC/TLC (0.00 [-0.02, 0.02]; P = 0.931).
DISCUSSION: CT mosaic attenuation is associated with CF lung disease, however it is not always accompanied by physiologic hyperinflation. Other pathologies may contribute to mosaic attenuation. A better understanding of these factors could guide future therapies.

PMID: 28682006 [PubMed - as supplied by publisher]

An outbreak of Burkholderia cepacia complex in the paediatric unit of a tertiary care hospital.

Indian J Med Microbiol. 2017 Apr-Jun;35(2):216-220

Authors: Mali S, Dash L, Gautam V, Shastri J, Kumar S

Abstract
INTRODUCTION: Burkholderia cepacia complex (Bcc) has emerged as a serious nosocomial pathogen worldwide especially in patients with indwelling catheters and cystic fibrosis. Bcc is a common contaminant of pharmaceutical products. We describe an outbreak of Bcc bacteraemia amongst children admitted in Paediatric Intensive Care Unit (PICU) and paediatric ward at a tertiary care hospital, Mumbai, in Western India.
MATERIALS AND METHODS: Blood culture samples from paediatric patients yielded growth of non-fermenting, oxidase positive, motile, Gram negative bacilli (NFGNB) (76/909) over a period of 8 months. Based on conventional biochemical tests and antimicrobial susceptibility testing, these isolates were provisionally identified as Bcc. The increased, repeated and continued isolation of Bcc alerted the possibility of an outbreak confined to PICU and paediatric ward. Active surveillance was undertaken to trace the source and contain the outbreak. Isolates were subjected to recA polymerase chain reaction (PCR) and Expanded multilocus sequence typing (EMLST).
RESULTS: Surveillance revealed the presence of Bcc on the upper surface of rubber stopper of sealed multidose amikacin vials. Isolates from blood culture and rubber stoppers were confirmed as Bcc by recA PCR. EMLST revealed that these isolates shared an identical novel sequence type 824 proving clonality. Timely interventions instituted led to control of the outbreak.
CONCLUSION: This study highlights the importance of identification and molecular characterization of Bcc to establish its role in infection and outbreak.

PMID: 28681809 [PubMed - in process]

Biofilm-Induced Type 2 Innate Immunity in a Cystic Fibrosis Model of Pseudomonas aeruginosa.

Front Cell Infect Microbiol. 2017;7:274

Authors: Bielen K, 's Jongers B, Boddaert J, Raju TK, Lammens C, Malhotra-Kumar S, Jorens PG, Goossens H, Kumar-Singh S

Abstract
Biofilm-producing strains of Pseudomonas aeruginosa are a major cause of morbidity and mortality in cystic fibrosis (CF) patients. In these patients, increased levels of IL-17 as well as of IL-5 and IL-13 along with arginase (Arg)-positive macrophages have been observed in bronchoalveolar lavage fluid. While IL-17 is a strong proinflammatory cytokine associated with host defense against bacterial and fungal infections and is also elevated in several autoimmune diseases, IL-5/IL-13 and Arg1-positive M2 macrophages are part of the anti-inflammatory type 2 (Th2) immunity. To study whether increased IL-5 and IL-13 levels are related to biofilm formation, which is frequently observed in CF patients colonized by P. aeruginosa, we utilized an agarose bead-embedded P. aeruginosa rat model commonly employed in in vivo biofilm studies. We showed that "sterile" agarose bead instillation in rat notably increased lung transcript levels of IL-5 and IL-13 at two post-instillation study-points, day 1 and day 3. Concurrently, increased infiltration of type 2 innate cells such as eosinophils and Arg1 positive M2 activated macrophages (Arg1+CD68+) was also observed both at day 1 and day 3 while the proportion of M1 activated macrophages (iNOS+CD68+) at these time-points decreased. In contrast, P. aeruginosa-loaded beads caused a drastic elevation of proinflammatory Th1 (IFNγ, TNFα, IL-12a) and antibacterial Th17 (IL-17a, IL-17f, IL-22, IL-23a) cytokines along with a high influx of neutrophils and M1 macrophages, while Th2 cytokines (IL-5 and IL-13) drastically declined at day 1 post-infection. Interestingly, at day 3 post-infection, both Th1 and Th17 cytokines sharply declined and corroborated with decreased M1 and increased M2 macrophages. These data suggest that while IL-17 is linked to episodes of acute exacerbations of infection in CF patients, the increased Th2 cytokines and M2 macrophages observed in these patients are largely due to the biofilm matrix. The data presented here has important implications for clinical management of CF patients.

PMID: 28680858 [PubMed - in process]

Molecular Simulations of Carbohydrates with a Fucose-Binding Burkholderia ambifaria Lectin Suggest Modulation by Surface Residues Outside the Fucose-Binding Pocket.

Front Pharmacol. 2017;8:393

Authors: Dingjan T, Imberty A, Pérez S, Yuriev E, Ramsland PA

Abstract
Burkholderia ambifaria is an opportunistic respiratory pathogen belonging to the Burkholderia cepacia complex, a collection of species responsible for the rapidly fatal cepacia syndrome in cystic fibrosis patients. A fucose-binding lectin identified in the B. ambifaria genome, BambL, is able to adhere to lung tissue, and may play a role in respiratory infection. X-ray crystallography has revealed the bound complex structures for four fucosylated human blood group epitopes (blood group B, H type 1, H type 2, and Le(x) determinants). The present study employed computational approaches, including docking and molecular dynamics (MD), to extend the structural analysis of BambL-oligosaccharide complexes to include four additional blood group saccharides (A, Le(a), Le(b), and Le(y)) and a library of blood-group-related carbohydrates. Carbohydrate recognition is dominated by interactions with fucose via a hydrogen-bonding network involving Arg15, Glu26, Ala38, and Trp79 and a stacking interaction with Trp74. Additional hydrogen bonds to non-fucose residues are formed with Asp30, Tyr35, Thr36, and Trp74. BambL recognition is dominated by interactions with fucose, but also features interactions with other parts of the ligands that may modulate specificity or affinity. The detailed computational characterization of the BambL carbohydrate-binding site provides guidelines for the future design of lectin inhibitors.

PMID: 28680402 [PubMed - in process]

Proteomic profile of cystic fibrosis sputum cells in adults chronically infected with Pseudomonas aeruginosa.

Eur Respir J. 2017 Jul;50(1):

Authors: Pattison SH, Gibson DS, Johnston E, Peacock S, Rivera K, Tunney MM, Pappin DJ, Elborn JS

Abstract
Lung disease is the main cause of morbidity and mortality in cystic fibrosis (CF), and involves chronic infection and perturbed immune responses. Tissue damage is mediated mostly by extracellular proteases, but other cellular proteins may also contribute to damage through their effect on cell activities and/or release into sputum fluid by means of active secretion or cell death.We employed MudPIT (multidimensional protein identification technology) to identify sputum cellular proteins with consistently altered abundance in adults with CF, chronically infected with Pseudomonas aeruginosa, compared with healthy controls. Ingenuity Pathway Analysis, Gene Ontology, protein abundance and correlation with lung function were used to infer their potential clinical significance.Differentially abundant proteins relate to Rho family small GTPase activity, immune cell movement/activation, generation of reactive oxygen species, and dysregulation of cell death and proliferation. Compositional breakdown identified high abundance of proteins previously associated with neutrophil extracellular traps. Furthermore, negative correlations with lung function were detected for 17 proteins, many of which have previously been associated with lung injury.These findings expand our current understanding of the mechanisms driving CF lung disease and identify sputum cellular proteins with potential for use as indicators of disease status/prognosis, stratification determinants for treatment prescription or therapeutic targets.

PMID: 28679606 [PubMed - in process]