Antibiotic treatment of biofilm infections.

APMIS. 2017 Apr;125(4):304-319

Authors: Ciofu O, Rojo-Molinero E, Macià MD, Oliver A

Abstract
Bacterial biofilms are associated with a wide range of infections, from those related to exogenous devices, such as catheters or prosthetic joints, to chronic tissue infections such as those occurring in the lungs of cystic fibrosis patients. Biofilms are recalcitrant to antibiotic treatment due to multiple tolerance mechanisms (phenotypic resistance). This causes persistence of biofilm infections in spite of antibiotic exposure which predisposes to antibiotic resistance development (genetic resistance). Understanding the interplay between phenotypic and genetic resistance mechanisms acting on biofilms, as well as appreciating the diversity of environmental conditions of biofilm infections which influence the effect of antibiotics are required in order to optimize the antibiotic treatment of biofilm infections. Here, we review the current knowledge on phenotypic and genetic resistance in biofilms and describe the potential strategies for the antibiotic treatment of biofilm infections. Of note is the optimization of PK/PD parameters in biofilms, high-dose topical treatments, combined and sequential/alternate therapies or the use antibiotic adjuvants.

PMID: 28407419 [PubMed - in process]

Abnormal Rab11-Rab8-vesicles cluster in enterocytes of patients with Microvillus Inclusion Disease.

Traffic. 2017 Apr 13;:

Authors: Vogel GF, Janecke AR, Krainer IM, Gutleben K, Witting B, Mitton SG, Mansour S, Ballauff A, Roland JT, Engevik AC, Cutz E, Müller T, Goldenring JR, Huber LA, Hess MW

Abstract
Microvillus Inclusion Disease (MVID) is a congenital enteropathy characterized by accumulation of vesiculo-tubular endomembranes in the subapical cytoplasm of enterocytes, historically termed "secretory granules". However, neither their identity nor pathophysiological significance is well defined. Using immunoelectron microscopy and tomography we studied biopsies from MVID patients (3x Myosin 5b mutations, 1x Syntaxin3 mutation) and compared them to controls and genome-edited CaCo2 cell models, harboring relevant mutations. Duodenal biopsies from two patients with novel Myosin 5b mutations and typical clinical symptoms showed unusual ultrastructural phenotypes: aberrant subapical vesicles and tubules were prominent in the enterocytes, though other histological hallmarks of MVID were almost absent (ectopic intra-/intercellular microvilli, brush border atrophy). We identified these enigmatic vesiculo-tubular organelles as Rab11-Rab8-positive recycling compartments of altered size, shape and location harboring the apical SNARE Syntaxin3, apical transporters Sodium-Hydrogen Exchanger 3 (NHE3) and cystic fibrosis transmembrane conductance regulator (CFTR). Our data strongly indicate that in MVID disrupted trafficking between cargo vesicles and the apical plasma membrane is the primary cause of a defect of epithelial polarity and subsequent facultative loss of brush border integrity, leading to malabsorption. Furthermore, they support the notion that mislocalization of transporters, such as NHE3 substantially contributes to the reported sodium loss diarrhea.

PMID: 28407399 [PubMed - as supplied by publisher]

Clinical Outcomes Associated with Achromobacter Species Infection in Patients with Cystic Fibrosis.

Ann Am Thorac Soc. 2017 Apr 13;:

Authors: Somayaji R, Stanojevic S, Tullis DE, Stephenson AL, Ratjen F, Waters V

Abstract
RATIONALE: Achromobacter species are increasingly identified in individuals with cystic fibrosis (CF), but the clinical outcomes in these patients remain poorly understood.
OBJECTIVES: We aimed to determine the association of Achromobacter infection on clinical outcomes in pediatric and adult patients with CF.
METHODS: A cohort study of pediatric and adult CF patients was conducted from 1997 - 2014 in Toronto, Canada. Achromobacter spp infection was categorized as no history of infection, intermittent, and chronic infection (≥ 2 positive cultures in preceding 12 months). Cox models were used to estimate risk of death or transplantation. Mixed effects models were used to assess odds of pulmonary exacerbations (PEx) and effect on lung function (FEV1%) by Achromobacter spp category.
RESULTS: A total of 1103 patients were followed over 18 years; 88 patients (7.3%) had ≥ 1 culture for Achromobacter species. Chronic Achromobacter infection was associated with a greater risk of death or transplantation compared to patients with no history of infection (adjusted HR 2.03 [95% CI 1.05 - 3.95], p = 0.036). PEx were more common in patients with chronic infection but after adjusting for confounding factors, the effect was no longer significant. The chronic group had lower FEV1%, but it did not worsen after developing chronic infection.
CONCLUSIONS: Patients with CF and chronic Achromobacter infection are at increased risk of death or transplant.

PMID: 28406714 [PubMed - as supplied by publisher]

An Observational Study of Outcomes and Tolerances in Patients with Cystic Fibrosis Initiated on Lumacaftor/Ivacaftor.

Ann Am Thorac Soc. 2017 Apr 13;:

Authors: Jennings MT, Dezube R, Paranjape S, West NE, Hong G, Braun A, Grant J, Merlo CA, Lechtzin N

Abstract
RATIONALE: In July 2015, the FDA approved lumacaftor/ivacaftor for use in patients with CF. This drug targets the primary defect in the CFTR protein that is conferred by the F508del CFTR mutation.
OBJECTIVE: As there is limited experience with this therapy outside of clinical trials, this study aims to examine the clinical experience of this new drug in a CF population.
METHODS: Retrospective cohort study of individuals followed at the Johns Hopkins CF Center, who initiated treatment with lumacaftor/ivacaftor. Patients were followed from one year prior to drug initiation to up to 11 months post initiation. Key exclusion criteria include previous exposure to lumacaftor/ivacaftor through participation in a clinical trial.
RESULTS: 116 individuals were identified who started lumacaftor/ivacaftor treatment. 46 (39.7%) subjects reported side effects related to lumacaftor/ivacaftor with the vast majority (82.2%) being pulmonary side effects. 20 (17.2%) subjects discontinued lumacaftor/ivacaftor due to side effects. The mean change in FEV1 % predicted was 0.11% (range: range: -39% to +20%, p=0.9). 19 individuals had an FEV1 percent predicted ≤ 40% prior to treatment, and there was a higher percentage of patients in this subgroup that reported side effects (57.9%) and a higher percentage of patients who discontinued lumacaftor/ivacaftor (31.6%). Female gender was associated with a higher odds of drug discontinuation (adjusted odds ratio=3.12, 95% CI, 1.04-9.38).
CONCLUSIONS: This study highlights the prevalence of side effects in a CF population newly exposed to lumacaftor/ivacaftor, and demonstrates a relatively high rate of drug intolerance.

PMID: 28406713 [PubMed - as supplied by publisher]

The microbiome in respiratory medicine: current challenges and future perspectives.

Eur Respir J. 2017 Apr;49(4):

Authors: Faner R, Sibila O, Agustí A, Bernasconi E, Chalmers JD, Huffnagle GB, Manichanh C, Molyneaux PL, Paredes R, Pérez Brocal V, Ponomarenko J, Sethi S, Dorca J, Monsó E

Abstract
The healthy lung has previously been considered to be a sterile organ because standard microbiological culture techniques consistently yield negative results. However, culture-independent techniques report that large numbers of microorganisms coexist in the lung. There are many unknown aspects in the field, but available reports show that the lower respiratory tract microbiota: 1) is similar in healthy subjects to the oropharyngeal microbiota and dominated by members of the Firmicutes, Bacteroidetes and Proteobacteria phyla; 2) shows changes in smokers and well-defined differences in chronic respiratory diseases, although the temporal and spatial kinetics of these changes are only partially known; and 3) shows relatively abundant non-cultivable bacteria in chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis and bronchiectasis, with specific patterns for each disease. In all of these diseases, a loss of diversity, paralleled by an over-representation of Proteobacteria (dysbiosis), has been related to disease severity and exacerbations. However, it is unknown whether dysbiosis is a cause or a consequence of the damage to bronchoalveolar surfaces.Finally, little is known about bacterial functionality and the interactions between viruses, fungi and bacteria. It is expected that future research in bacterial gene expressions, metagenomics longitudinal analysis and host-microbiome animal models will help to move towards targeted microbiome interventions in respiratory diseases.

PMID: 28404649 [PubMed - in process]

Costs of treatment of adult patients with cystic fibrosis in Poland and internationally.

Public Health. 2017 Apr 07;148:49-55

Authors: Kopciuch D, Zaprutko T, Paczkowska A, Nowakowska E

Abstract
OBJECTIVES: Despite its low prevalence, cystic fibrosis (CF) may have a considerable impact on healthcare system expenditures in terms of direct healthcare costs and lost productivity. This study was aimed at calculation of costs associated with CF treatment in Poland, as well as at comparison of average costs of treatment of CF patients in selected countries, taking into account the purchasing power parity.
STUDY DESIGN: Retrospective study.
METHODS: The researchers undertook a retrospective study of adult patients with CF taking into account the broadest social perspective possible. Medical and non-medical direct costs as well as indirect costs were calculated. CF costs estimated by researchers from other countries over the last 15 years were also compared.
RESULTS: Total annual treatment cost per one CF patient in Poland was on average EUR 19,581.08. Costs of treatment of CF patients over the last 15 years varied between the countries and ranged from EUR 23,330.82 in Bulgaria to EUR 68,696.42 in the United States.
CONCLUSIONS: CF is an international problem. The data in this study could be the baseline for integrated and harmonised approaches for periodical assessment of the future impact of new public policies and interventions for rare diseases at the national and international levels.

PMID: 28404533 [PubMed - as supplied by publisher]

Type 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer.

Lancet Gastroenterol Hepatol. 2016 Nov;1(3):226-237

Authors: Hart PA, Bellin MD, Andersen DK, Bradley D, Cruz-Monserrate Z, Forsmark CE, Goodarzi MO, Habtezion A, Korc M, Kudva YC, Pandol SJ, Yadav D, Chari ST, Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer(CPDPC)

Abstract
Diabetes mellitus is a group of diseases defined by persistent hyperglycaemia. Type 2 diabetes, the most prevalent form, is characterised initially by impaired insulin sensitivity and subsequently by an inadequate compensatory insulin response. Diabetes can also develop as a direct consequence of other diseases, including diseases of the exocrine pancreas. Historically, diabetes due to diseases of the exocrine pancreas was described as pancreatogenic or pancreatogenous diabetes mellitus, but recent literature refers to it as type 3c diabetes. It is important to note that type 3c diabetes is not a single entity; it occurs because of a variety of exocrine pancreatic diseases with varying mechanisms of hyperglycaemia. The most commonly identified causes of type 3c diabetes are chronic pancreatitis, pancreatic ductal adenocarcinoma, haemochromatosis, cystic fibrosis, and previous pancreatic surgery. In this Review, we discuss the epidemiology, pathogenesis, and clinical relevance of type 3c diabetes secondary to chronic pancreatitis and pancreatic ductal adenocarcinoma, and highlight several important knowledge gaps.

PMID: 28404095 [PubMed - in process]

Plasma metabolomics in adults with cystic fibrosis during a pulmonary exacerbation: A pilot randomized study of high-dose vitamin D3 administration.

Metabolism. 2017 May;70:31-41

Authors: Alvarez JA, Chong EY, Walker DI, Chandler JD, Michalski ES, Grossmann RE, Uppal K, Li S, Frediani JK, Tirouvanziam R, Tran VT, Tangpricha V, Jones DP, Ziegler TR

Abstract
BACKGROUND: Cystic fibrosis (CF) is a chronic catabolic disease often requiring hospitalization for acute episodes of worsening pulmonary exacerbations. Limited data suggest that vitamin D may have beneficial clinical effects, but the impact of vitamin D on systemic metabolism in this setting is unknown.
OBJECTIVE: We used high-resolution metabolomics (HRM) to assess the impact of baseline vitamin D status and high-dose vitamin D3 administration on systemic metabolism in adults with CF with an acute pulmonary exacerbation.
DESIGN: Twenty-five hospitalized adults with CF were enrolled in a randomized trial of high-dose vitamin D3 (250,000IU vitamin D3 bolus) versus placebo. Age-matched healthy subjects served as a reference group for baseline comparisons. Plasma was analyzed with liquid chromatography/ultra-high resolution mass spectrometry. Using recent HRM bioinformatics and metabolic pathway enrichment methods, we examined associations with baseline vitamin D status (sufficient vs. deficient per serum 25-hydroxyvitamin D concentrations) and the 7-day response to vitamin D3 supplementation.
RESULTS: Several amino acids and lipid metabolites differed between CF and healthy control subjects, indicative of an overall catabolic state. In CF subjects, 343 metabolites differed (P<0.05) by baseline vitamin D status and were enriched within 7 metabolic pathways including fatty acid, amino acid, and carbohydrate metabolism. A total of 316 metabolites, which showed enrichment for 15 metabolic pathways-predominantly representing amino acid pathways-differed between the vitamin D3- and placebo-treated CF subjects over time (P<0.05). In the placebo group, several tricarboxylic acid cycle intermediates increased while several amino acid-related metabolites decreased; in contrast, little change in these metabolites occurred with vitamin D3 treatment.
CONCLUSIONS: Numerous metabolic pathways detected by HRM varied in association with vitamin D status and high-dose vitamin D3 supplementation in adults with CF experiencing a pulmonary exacerbation. Overall, these pilot data suggest an anti-catabolic effect of high-dose vitamin D3 in this clinical setting.

PMID: 28403943 [PubMed - in process]

Lung structure and function similarities between primary ciliary dyskinesia and mild cystic fibrosis: a pilot study.

Ital J Pediatr. 2017 Apr 12;43(1):34

Authors: Maglione M, Montella S, Mollica C, Carnovale V, Iacotucci P, De Gregorio F, Tosco A, Cervasio M, Raia V, Santamaria F

Abstract
BACKGROUND: Primary ciliary dyskinesia (PCD) and cystic fibrosis (CF) are increasingly compared. There are no chest magnetic resonance imaging (MRI) comparative studies of PCD and CF. We assessed clinical, functional, microbiological and MRI findings in PCD and mild CF patients in order to evaluate different expression of lung disease.
METHODS: Twenty PCD (15.1 years) and 20 CF subjects with mild respiratory impairment (16 years, 70% with pancreatic insufficiency) underwent MRI, spirometry, and sputum cultures when clinically stable. MRI was scored using the modified Helbich system.
RESULTS: PCD was diagnosed later than CF (9.9 versus 0.6 years, p = 0.03), despite earlier symptoms (0.1 versus 0.6 years, p = 0.02). In the year preceding the study, patients from both groups underwent two systemic antibiotic courses (p = 0.48). MRI total scores were 11.6 ± 0.7 and 9.1 ± 1 in PCD and CF, respectively. FEV1 and FVC Z-scores were -1.75 (range, -4.6-0.7) and -0.6 (-3.9-1.8) in PCD, and -0.9 (range, -5.4-2.3) and -0.3 (-3.4-2.5) in CF, respectively. No difference was found between lung function or structure, despite a higher MRI subscore of collapse/consolidation in PCD versus CF (1.6 ± 0.1 and 0.6 ± 0.2, p < 0.001). These findings were confirmed after data-control for diagnostic delay. Pseudomonas aeruginosa and Staphylococcus aureus were more frequent in CF than in PCD (p = 0.05 and p = 0.003, respectively).
CONCLUSIONS: MRI is a valuable radiation-free tool for comparative PCD and CF lung disease assessment. Patients with PCD may exhibit similar MRI and lung function changes as CF subjects with mild pulmonary disease. Delay in PCD diagnosis is unlikely the only determinant of similarities.

PMID: 28403885 [PubMed - in process]

Patient-derived Airway Secretion Dissociation Technique to Isolate and Concentrate Immune cells using Closed-loop Inertial Microfluidics.

Anal Chem. 2017 Apr 12;:

Authors: Ryu H, Choi K, Qu Y, Kwon T, Lee JS, Han J

Abstract
Assessment of airway secretion cells, both for research and clinical purposes, is a highly desired goal in patients with acute and chronic pulmonary diseases. However, lack of proper cell isolation and enrichment techniques hinder downstream evaluation and characterization of cells found in airway secretions. Here, we demonstrate a novel enrichment method to capture immune-related cells from clinical airway secretions using closed-loop separation of spiral inertial microfluidics (C-sep). By recirculating the output focusing stream back to the input reservoir, and running continuously with a high flow processing rate, one can achieve optimal concentration, recovery and purity of airway immune cells from a large volume of diluent, which was not readily possible in the single-pass operation. Our method reproducibly recovers 94.0% of polymorphonuclear leukocytes (PMNs), with up to 105 PMNs in clear diluted buffer from 50 µl of airway secretions obtained from mechanically ventilated patients. We show that C-sep isolated PMNs show higher neutrophil elastase (NE) release following activation by phorbol 12-myristate 13-acetate (PMA) than cells isolated by conventional mucolytic method. By capturing cells without chemically disrupting their potential function, our method is expected to expand the possibility of clinical in-vitro cell based biological assays for various pulmonary diseases such as acute respiratory distress syndrome, pneumonia, cystic fibrosis and bronchiectasis.

PMID: 28402103 [PubMed - as supplied by publisher]

SANI-Severe Asthma Network in Italy: a way forward to monitor severe asthma.

Clin Mol Allergy. 2017;15:9

Authors: Senna G, Guerriero M, Paggiaro PL, Blasi F, Caminati M, Heffler E, Latorre M, Canonica GW, SANI

Abstract
Even if severe asthma (SA) accounts for 5-10% of all cases of the disease, it is currently a crucial unmet need, owing its difficult clinical management and its high social costs. For this reason several networks, focused on SA have been organized in some countries, in order to select these patients, to recognize their clinical features, to evaluate their adherence, to classify their biological/clinical phenotypes, to identify their eligibility to the new biologic therapies and to quantify the costs of the disease. Aim of the present paper is to describe the ongoing Italian Severe Asthma Network (SANI). Up today 49 centres have been selected, widespread on the national territory. Sharing the same diagnostic protocol, data regarding patients with SA will be collected and processed in a web platform. After their recruitment, SA patients will be followed in the long term in order to investigate the natural history of the disease. Besides clinical data, the cost/benefit evaluation of the new biologics will be verified as well as the search of peculiar biomarker(s) of the disease.

PMID: 28400707 [PubMed - in process]

Within-Host Evolution of Burkholderia pseudomallei during Chronic Infection of Seven Australasian Cystic Fibrosis Patients.

MBio. 2017 Apr 11;8(2):

Authors: Viberg LT, Sarovich DS, Kidd TJ, Geake JB, Bell SC, Currie BJ, Price EP

Abstract
Cystic fibrosis (CF) is a genetic disorder characterized by progressive lung function decline. CF patients are at an increased risk of respiratory infections, including those by the environmental bacterium Burkholderia pseudomallei, the causative agent of melioidosis. Here, we compared the genomes of B. pseudomallei isolates collected between ~4 and 55 months apart from seven chronically infected CF patients. Overall, the B. pseudomallei strains showed evolutionary patterns similar to those of other chronic infections, including emergence of antibiotic resistance, genome reduction, and deleterious mutations in genes involved in virulence, metabolism, environmental survival, and cell wall components. We documented the first reported B. pseudomallei hypermutators, which were likely caused by defective MutS. Further, our study identified both known and novel molecular mechanisms conferring resistance to three of the five clinically important antibiotics for melioidosis treatment. Our report highlights the exquisite adaptability of microorganisms to long-term persistence in their environment and the ongoing challenges of antibiotic treatment in eradicating pathogens in the CF lung. Convergent evolution with other CF pathogens hints at a degree of predictability in bacterial evolution in the CF lung and potential targeted eradication of chronic CF infections in the future.IMPORTANCEBurkholderia pseudomallei, the causative agent of melioidosis, is an environmental opportunistic bacterium that typically infects immunocompromised people and those with certain risk factors such as cystic fibrosis (CF). Patients with CF tend to develop chronic melioidosis infections, for reasons that are not well understood. This report is the first to describe B. pseudomallei evolution within the CF lung during chronic infection. We show that the pathways by which B. pseudomallei adapts to the CF lung are similar to those seen in better-studied CF pathogens such as Pseudomonas aeruginosa, Staphylococcus aureus, and Burkholderia cepacia complex species. Adaptations include the accumulation of antibiotic resistance, loss of nonessential genes, metabolic alterations, and virulence factor attenuation. Known and novel mechanisms of resistance to three of the five antibiotics used in melioidosis treatment were identified. Similar pathways of evolution in CF pathogens, including B. pseudomallei, provide exciting avenues for more-targeted treatment of chronic, recalcitrant infections.

PMID: 28400528 [PubMed - in process]

The impact of co-morbidity in childhood Cystic Fibrosis.

Paediatr Respir Rev. 2017 Mar 14;:

Authors: Duncan JA, Brown SM

Abstract
A number of risk factors have been identified for deterioration of lung disease in children with Cystic Fibrosis (CF), and current management strategies are based on the prevention and treatment of such elements. Further challenge ensues when a patient has co-morbid disease in addition to CF, particularly when faced with rapidly deteriorating pulmonary status. It is difficult to measure the contribution of other pathologies to this decline and optimisation of both CF care and co-morbidity is paramount. This review explores the challenges faced when treating children with CF and co-morbid conditions, focussing on gastroesophageal reflux disease pre- and post-lung transplantation.

PMID: 28400242 [PubMed - as supplied by publisher]

Highlights from the 30th North American Cystic Fibrosis Conference, Orlando 2016.

Paediatr Respir Rev. 2017 Mar 14;:

Authors: Shawcross A, Barry PJ

Abstract
This is a selection of papers presented at the 30th North American Cystic Fibrosis Conference held in Orlando in October 2016. The papers discussed are thought to be of particular interest to CF caregivers in the UK. We highlight the major themes covered in the conference including novel therapies, recently published and proposed guidelines and insights from registry studies.

PMID: 28400241 [PubMed - as supplied by publisher]

Mucoactive agents for chronic, non-cystic fibrosis lung disease: A systematic review and meta-analysis.

Respirology. 2017 Apr 11;:

Authors: Tarrant BJ, Le Maitre C, Romero L, Steward R, Button BM, Thompson BR, Holland AE

Abstract
Inhaled mucoactive agents are used in respiratory disease to improve mucus properties and enhance secretion clearance. The effect of mannitol, recombinant human deoxyribonuclease/dornase alfa (rhDNase) and hypertonic saline (HS) or normal saline (NS) are not well described in chronic lung conditions other than cystic fibrosis (CF). The aim of this review was to determine the benefit and safety of inhaled mucoactive agents outside of CF. We searched Medline, Embase, CINAHL and CENTRAL for randomized controlled trials investigating the effects of mucoactive agents on lung function, adverse events (AEs), health-related quality of life (HRQOL), hospitalization, length of stay, exacerbations, sputum clearance and inflammation. There were detrimental effects of rhDNase in bronchiectasis, with average declines of 1.9-4.3% in forced expiratory volume in 1 s (FEV1 ) and 3.7-5.4% in forced vital capacity (FVC) (n = 410, two studies), and increased exacerbation risk (relative risk = 1.35, 95% CI = 1.01-1.79 n = 349, one study). Some participants exhibited a reduction in FEV1 (≥10-15%) with mucoactive agents on screening (mannitol = 158 of 1051 participants, rhDNase = 2 of 30, HS = 3 of 80). Most AEs were mild and transient, including bronchospasm, cough and breathlessness. NS eased symptomatic burden in COPD, while NS and HS improved spirometry, HRQOL and sputum burden in non-CF bronchiectasis. Mannitol improved mucociliary clearance in asthma and bronchiectasis, while the effects of N-acetylcysteine were unclear. In chronic lung diseases outside CF, there are small benefits of mannitol, NS and HS. Adverse effects of rhDNase suggest this should not be administered in non-CF bronchiectasis.

PMID: 28397992 [PubMed - as supplied by publisher]

Rifabutin Is Active Against Mycobacterium abscessus Complex.

Antimicrob Agents Chemother. 2017 Apr 10;:

Authors: Aziz DB, Low JL, Wu ML, Gengenbacher M, Teo JW, Dartois V, Dick T

Abstract
Lung infections with Mycobacterium abscessus are emerging as a global threat to individuals with cystic fibrosis and other patient groups. Recent evidence for human-to-human transmission worsens the situation. M. abscessus is an intrinsically multidrug resistant pathogen showing resistance even against standard anti tuberculosis drugs such as rifampicin. Here, our objective was to identify existing drugs that may be employed for the treatment of M. abscessus lung disease. A collection of more than 2700 approved drugs was screened at a single point concentration against an M. abscessus clinical isolate. Hits were confirmed with fresh solids in dose response experiments. For the most attractive hit, growth inhibition and bactericidal activities against reference strains of the three M. abscessus subspecies and a collection of clinical isolates were determined. Surprisingly, the rifampicin derivative rifabutin had an MIC of 3 ± 2 μM (3 μg/mL) against the screening strain, the reference strains M. abscessus subsp. abscessus ATCC 19977, M. abscessus subsp. bolletii CCUG 50184-T and M. abscesuss subsp. massiliense CCUG 48898-T, as well as a collection of clinical isolates. Furthermore, rifabutin was active against clarithromycin resistant strains. In conclusion, rifabutin - in contrast to rifampicin - is active against the Mycobacterium abscessus complex bacteria in vitro and may be considered for treatment of M. abscessus lung disease.

PMID: 28396540 [PubMed - as supplied by publisher]

Diagnosed cataracts in patients with cystic fibrosis in a United States administrative database.

Ophthalmic Genet. 2017 Apr 10;:1-6

Authors: Everage NJ, Bai Y, Loop B, Volkova N, Liu N, Enger C

Abstract
BACKGROUND: We estimated the incidence and prevalence of diagnosed cataracts among patients with cystic fibrosis (CF) versus the general population (GP).
METHODS: Using a large US health insurance claims database, we identified a CF cohort and a GP cohort matched with respect to age, gender, and calendar year. The prevalence and incidence of diagnosed cataract (primary outcome) for both cohorts were calculated, as well as the incidence rate ratios (IRRs).
RESULTS: The prevalence of diagnosed cataracts among patients with CF alive and enrolled in the health plan on August 31, 2012 was 4.8% versus 2.8% in the GP. The incidence in the CF cohort was higher than in the GP and increased with age in both cohorts. The adjusted IRR comparing the CF and GP cohorts was 1.5 (95% CI: 1.2-1.8).
CONCLUSIONS: The study suggests that the risk of developing cataract was higher among patients with CF than among the GP.

PMID: 28394650 [PubMed - as supplied by publisher]

Thymosin α1 represents a potential potent single-molecule-based therapy for cystic fibrosis.

Nat Med. 2017 Apr 10;:

Authors: Romani L, Oikonomou V, Moretti S, Iannitti RG, D'Adamo MC, Villella VR, Pariano M, Sforna L, Borghi M, Bellet MM, Fallarino F, Pallotta MT, Servillo G, Ferrari E, Puccetti P, Kroemer G, Pessia M, Maiuri L, Goldstein AL, Garaci E

Abstract
Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that compromise its chloride channel activity. The most common mutation, p.Phe508del, results in the production of a misfolded CFTR protein, which has residual channel activity but is prematurely degraded. Because of the inherent complexity of the pathogenetic mechanisms involved in CF, which include impaired chloride permeability and persistent lung inflammation, a multidrug approach is required for efficacious CF therapy. To date, no individual drug with pleiotropic beneficial effects is available for CF. Here we report on the ability of thymosin alpha 1 (Tα1)-a naturally occurring polypeptide with an excellent safety profile in the clinic when used as an adjuvant or an immunotherapeutic agent-to rectify the multiple tissue defects in mice with CF as well as in cells from subjects with the p.Phe508del mutation. Tα1 displayed two combined properties that favorably opposed CF symptomatology: it reduced inflammation and increased CFTR maturation, stability and activity. By virtue of this two-pronged action, Tα1 has strong potential to be an efficacious single-molecule-based therapeutic agent for CF.

PMID: 28394330 [PubMed - as supplied by publisher]

How are the ancient cystic fibrosis patients? Cystic fibrosis diagnosed over 60 years-old.

Respir Med Case Rep. 2017;21:49-51

Authors: Prados C, Lerín M, Cabanillas JJ, Gómez-Carrera L, Álvarez-Sala R, cystic fibrosis group of Neumomadrid

Abstract
BACKGROUND AND AIMS: To specify the prevalence of patients diagnosed with CF at age of ≥60 year-old and to analyze their characteristics.
PATIENTS AND METHODS: Observational study of CF patients which were diagnosed at age ≥60 year-old. The analyzed variables were: age, sex, nationality, lung function parameters, conditions present at diagnosis, microbiological characteristics and genetic findings.
RESULTS: eight patients were included. 7 patients were female (87.5%) with a mean age of 70.6 years (median 71.5 years, range 60-78 years). The most important findings were: sweat test >60 mEq/l; heterozygotes F508del; bronchiectasis in CT; methicillin-sensitive Staphylococcus aureus (50%) in sputum. The most patients presented a normal or mild obstructive lung function.
CONCLUSIONS: CF must also be considered a disease diagnosed in adulthood, incorporating the sweat test within the usual techniques of differential diagnosis in patients with different diseases associated with CF, because genetic counselling is esencial.

PMID: 28393935 [PubMed - in process]

The role of S-nitrosoglutathione reductase (GSNOR) in human disease and therapy.

Crit Rev Biochem Mol Biol. 2017 Apr 10;:1-15

Authors: Barnett SD, Buxton IL

Abstract
S-nitrosoglutathione reductase (GSNOR), or ADH5, is an enzyme in the alcohol dehydrogenase (ADH) family. It is unique when compared to other ADH enzymes in that primary short-chain alcohols are not its principle substrate. GSNOR metabolizes S-nitrosoglutathione (GSNO), S-hydroxymethylglutathione (the spontaneous adduct of formaldehyde and glutathione), and some alcohols. GSNOR modulates reactive nitric oxide (•NO) availability in the cell by catalyzing the breakdown of GSNO, and indirectly regulates S-nitrosothiols (RSNOs) through GSNO-mediated protein S-nitrosation. The dysregulation of GSNOR can significantly alter cellular homeostasis, leading to disease. GSNOR plays an important regulatory role in smooth muscle relaxation, immune function, inflammation, neuronal development and cancer progression, among many other processes. In recent years, the therapeutic inhibition of GSNOR has been investigated to treat asthma, cystic fibrosis and interstitial lung disease (ILD). The direct action of •NO on cellular pathways, as well as the important regulatory role of protein S-nitrosation, is closely tied to GSNOR regulation and defines this enzyme as an important therapeutic target.

PMID: 28393572 [PubMed - as supplied by publisher]