Disease-modifying drug therapy in cystic fibrosis.

Paediatr Respir Rev. 2017 Mar 14;:

Authors: Harman K, Dobra R, Davies JC

Abstract
Whilst substantial progress has been made in the treatment of cystic fibrosis, the disease still carries a significant burden in terms of symptoms, requirement for treatment and early mortality. The last decade has witnessed a new era in the development of small molecule drugs targeting the CFTR protein, which for the first time may provide a truly disease-modifying approach to treatment. This article reviews progress and highlights some of the current and future challenges in CFTR modulator therapies.

PMID: 28583720 [PubMed - as supplied by publisher]

Safety of endoscopic sinus surgery in children with cystic fibrosis.

Int J Pediatr Otorhinolaryngol. 2017 Jul;98:25-28

Authors: Tumin D, Hayes D, Kirkby SE, Tobias JD, McKee C

Abstract
INTRODUCTION: Data on the safety of endoscopic sinus surgery (ESS) are limited in children with cystic fibrosis (CF). We used a multi-institutional surgical registry to examine ESS outcomes in children with CF.
METHODS: The 2014-2015 American College of Surgeons' National Surgical Quality Improvement Program-Pediatric database was queried for patients age <18 years undergoing elective ESS. Prolonged hospital stay (>1 day), 30-day readmission, and 30-day unplanned reoperation were compared according to presence of CF diagnosis.
RESULTS: The data included 213 children with CF (age 10 ± 5 years, 105/108 male/female) and 821 children without CF (age 10 ± 5 years, 504/317 male/female). CF patients were more likely than non-CF patients to require prolonged hospital stay (30% vs. 9%, p < 0.001), yet had similar rates of readmission (6% vs. 4%; p = 0.189) and reoperation (0 vs. 1%; p = 0.133). All readmissions but one among CF patients were unrelated to ESS. In the non-CF cohort, reasons for ESS-related readmissions included recurrence of sinusitis, postoperative pain, and bleeding.
CONCLUSIONS: We demonstrate the safety of ESS in the largest cohort of children with CF reviewed to date. Multi-institutional review of ESS safety may contribute to monitoring expansion of this intervention in children with CF.

PMID: 28583497 [PubMed - in process]

Personalised medicine in asthma: from curative to preventive medicine.

Eur Respir Rev. 2017 Jan;26(143):

Authors: Guilleminault L, Ouksel H, Belleguic C, Le Guen Y, Germaud P, Desfleurs E, Leroyer C, Magnan A

Abstract
The concept of asthma has changed substantially in recent years. Asthma is now recognised as a heterogeneous entity that is complex to treat. The subdivision of asthma, provided by "cluster" analyses, has revealed various groups of asthma patients who share phenotypic features. These phenotypes underlie the need for personalised asthma therapy because, in contrast to the previous approach, treatment must be tailored to the individual patient. Determination of the patient's asthma phenotype is therefore essential but sometimes challenging, particularly in elderly patients with a multitude of comorbidities and a complex exposure history. This review first describes the various asthma phenotypes, some of which were defined empirically and others through cluster analysis, and then discusses personalisation of the patient's diagnosis and therapy, addressing in particular biological therapies and patient education. This personalised approach to curative medicine should make way in the coming years for personalised preventive and predictive medicine, focused on subjects at risk who are not yet ill, with the aim of preventing asthma before it occurs. The concept of personalised preventive medicine may seem a long way off, but is it really?

PMID: 28049124 [PubMed - indexed for MEDLINE]

The role of Nrf1 and Nrf2 in the regulation of glutathione and redox dynamics in the developing zebrafish embryo.

Redox Biol. 2017 May 30;13:207-218

Authors: Sant KE, Hansen JM, Williams LM, Tran NL, Goldstone JV, Stegeman JJ, Hahn ME, Timme-Laragy A

Abstract
Redox signaling is important for embryogenesis, guiding pathways that govern processes crucial for embryo patterning, including cell polarization, proliferation, and apoptosis. Exposure to pro-oxidants during this period can be deleterious, resulting in altered physiology, teratogenesis, later-life diseases, or lethality. We previously reported that the glutathione antioxidant defense system becomes increasingly robust, including a doubling of total glutathione and dynamic shifts in the glutathione redox potential at specific stages during embryonic development in the zebrafish, Danio rerio. However, the mechanisms underlying these changes are unclear, as is the effectiveness of the glutathione system in ameliorating oxidative insults to the embryo at different stages. Here, we examine how the glutathione system responds to the model pro-oxidants tert-butylhydroperoxide and tert-butylhydroquinone at different developmental stages, and the role of Nuclear factor erythroid 2-related factor (Nrf) proteins in regulating developmental glutathione redox status. Embryos became increasingly sensitive to pro-oxidants after 72h post-fertilization (hpf), after which the duration of the recovery period for the glutathione redox potential was increased. To determine whether the doubling of glutathione or the dynamic changes in glutathione redox potential are mediated by zebrafish paralogs of Nrf transcription factors, morpholino oligonucleotides were used to knock down translation of Nrf1 and Nrf2 (nrf1a, nrf1b, nrf2a, nrf2b). Knockdown of Nrf1a or Nrf1b perturbed glutathione redox state until 72 hpf. Knockdown of Nrf2 paralogs also perturbed glutathione redox state but did not significantly affect the response of glutathione to pro-oxidants. Nrf1b morphants had decreased gene expression of glutathione synthesis enzymes, while hsp70 increased in Nrf2b morphants. This work demonstrates that despite having a more robust glutathione system, embryos become more sensitive to oxidative stress later in development, and that neither Nrf1 nor Nrf2 alone appear to be essential for the response and recovery of glutathione to oxidative insults.

PMID: 28582729 [PubMed - as supplied by publisher]

Omalizumab effectively protects against early- and late allergic responses in asthma after 4 weeks.

Allergy. 2017 Jun 05;:

Authors: Trischler J, Lieb A, Arnold M, Schulze J, Rosewich M, Schubert R, Bottoli I, Zielen S

Abstract
Omalizumab is licensed for therapy in severe allergic asthma with an effect demonstrated after 8 weeks or longer treatment. Since new applications for omalizumab demand precise knowledge of the onset of effects, the objective of this study was to determine the time course of the early (EAR) and late allergic reaction (LAR). Ten patients (IgE >300 IU/mL and <700 IU/mL) with a significant response to allergen challenge were treated with omalizumab according to the approved dosing table. Bronchial allergen provocations (BAP) were repeated at week 1, 2, 4 and 8. EAR was significantly reduced after 4 weeks (ΔFEV1 28 vs. 11%; p<0.001), eNO (86 vs. 53ppb; p<0.05) and basophil activation after 2 weeks (CD63 expression 79 vs. 32%, p<0.05) and LAR already after 1 week (ΔFEV1 26 vs. 13%, p<0.05). These results demonstrate the onset of protective effects earlier than previously determined, potentially improving seasonal utilization and combination with immunotherapy. This article is protected by copyright. All rights reserved.

PMID: 28581121 [PubMed - as supplied by publisher]

Pancreatic lipomatosis in cystic fibrosis: Rare manifestation of an uncommon disease.

Intractable Rare Dis Res. 2017 May;6(2):150-151

Authors: Mandavdhare HS, Kumar A, Sharma V, Rana SS

Abstract
Cystic fibrosis is deemed to be uncommon in India. The presentation is usually in the childhood although more cases are now being recognized in adolescence and adulthood. We report a case of an adolescent male who had been treated for recurrent pulmonary infections and received anti-tubercular therapy for a possible diagnosis of sputum negative pulmonary tuberculosis and was evaluated for steatorrhea. The presence of pancreatic exocrine insufficiency along with pancreatic lipomatosis suggested the diagnosis of cystic fibrosis.

PMID: 28580220 [PubMed - in process]

Complications of long and intermediate term venous catheters in cystic fibrosis patients: A multicenter study.

J Cyst Fibros. 2017 Jun 01;:

Authors: May TL, Gifford AH, Lahiri T, Black A, Trang J, Cornell AG, Gonzalez K, Morin S, Napier M, Duarte CW, Zuckerman JB

Abstract
BACKGROUND: Totally implantable venous access devices (TIVADs) or peripherally inserted central venous catheters (PICCs) are commonly used in the care of patients with cystic fibrosis (CF), but they are associated with various complications, including thrombosis, infection, and insertion site symptoms.
METHODS: We conducted a retrospective review of PICC and TIVAD use in adults and children with CF over an 8-year period at 3 accredited care centers. Patient attributes included CFTR genotype, comorbidities, lung function, body mass index, use of anticoagulation, and respiratory tract microbiology. Catheter data included line type, caliber, and lumen number. We assessed practice variation by surveying physicians.
RESULTS: In a population of 592 CF patients, 851 PICC and 61 TIVADs were placed between January 1, 2003 and July 1, 2011. Larger catheter caliber and increased lumen number were risk factors for PICC complications in adults. Patient-related risk factors for PICC complications included poor nutritional status, infection with Burkholderia cepacia spp., and having ≥5 lines inserted during the study period. The probability of a PICC complication varied across centers (2.6% to 14.1%, p=0.001) and remained significant after adjustment for patient-and line-related risk factors. The median complication-free survival of TIVADs, however, did not vary significantly by center (p=0.85).
CONCLUSIONS: This is the first longitudinal, multicenter assessment of complication rates for PICCs and TIVADs in a large cohort of adults and children with CF. Specific patient- and catheter-related characteristics were associated with increased risk of complications. Center effects on complication rates were observed for PICCs.

PMID: 28579360 [PubMed - as supplied by publisher]

Filtration and Normalization of Sequencing Read Data in Whole-Metagenome Shotgun Samples.

PLoS One. 2016;11(10):e0165015

Authors: Chouvarine P, Wiehlmann L, Moran Losada P, DeLuca DS, Tümmler B

Abstract
Ever-increasing affordability of next-generation sequencing makes whole-metagenome sequencing an attractive alternative to traditional 16S rDNA, RFLP, or culturing approaches for the analysis of microbiome samples. The advantage of whole-metagenome sequencing is that it allows direct inference of the metabolic capacity and physiological features of the studied metagenome without reliance on the knowledge of genotypes and phenotypes of the members of the bacterial community. It also makes it possible to overcome problems of 16S rDNA sequencing, such as unknown copy number of the 16S gene and lack of sufficient sequence similarity of the "universal" 16S primers to some of the target 16S genes. On the other hand, next-generation sequencing suffers from biases resulting in non-uniform coverage of the sequenced genomes. To overcome this difficulty, we present a model of GC-bias in sequencing metagenomic samples as well as filtration and normalization techniques necessary for accurate quantification of microbial organisms. While there has been substantial research in normalization and filtration of read-count data in such techniques as RNA-seq or Chip-seq, to our knowledge, this has not been the case for the field of whole-metagenome shotgun sequencing. The presented methods assume that complete genome references are available for most microorganisms of interest present in metagenomic samples. This is often a valid assumption in such fields as medical diagnostics of patient microbiota. Testing the model on two validation datasets showed four-fold reduction in root-mean-square error compared to non-normalized data in both cases. The presented methods can be applied to any pipeline for whole metagenome sequencing analysis relying on complete microbial genome references. We demonstrate that such pre-processing reduces the number of false positive hits and increases accuracy of abundance estimates.

PMID: 27760173 [PubMed - indexed for MEDLINE]

Photoactivatable fluorescent probes reveal heterogeneous nanoparticle permeation through biological gels at multiple scales.

J Control Release. 2017 May 31;:

Authors: Schuster BS, Allan DB, Kays JC, Hanes J, Leheny RL

Abstract
Diffusion through biological gels is crucial for effective drug delivery using nanoparticles. Here, we demonstrate a new method to measure diffusivity over a large range of length scales - from tens of nanometers to tens of micrometers - using photoactivatable fluorescent nanoparticle probes. We have applied this method to investigate the length-scale dependent mobility of nanoparticles in fibrin gels and in sputum from patients with cystic fibrosis (CF). Nanoparticles composed of poly(lactic-co-glycolic acid), with polyethylene glycol coatings to resist bioadhesion, were internally labeled with caged rhodamine to make the particles photoactivatable. We activated particles within a region of sample using brief, targeted exposure to UV light, uncaging the rhodamine and causing the particles in that region to become fluorescent. We imaged the subsequent spatiotemporal evolution in fluorescence intensity and observed the collective particle diffusion over tens of minutes and tens of micrometers. We also performed complementary multiple particle tracking experiments on the same particles, extending significantly the range over which particle motion and its heterogeneity can be observed. In fibrin gels, both methods showed an immobile fraction of particles and a mobile fraction that diffused over all measured length scales. In the CF sputum, particle diffusion was spatially heterogeneous and locally anisotropic but nevertheless typically led to unbounded transport extending tens of micrometers within tens of minutes. These findings provide insight into the mesoscale architecture of these gels and its role in setting their permeability on physiologically relevant length scales, pointing toward strategies for improving nanoparticle drug delivery.

PMID: 28578189 [PubMed - as supplied by publisher]

Ammonia exposure affects the mRNA and protein expression levels of certain Rhesus glycoproteins in the gills of climbing perch.

J Exp Biol. 2017 Jun 02;:

Authors: Chen XL, Zhang B, Chng YR, Ong JLY, Chew SF, Wong WP, Lam SH, Nakada T, Ip YK

Abstract
The freshwater climbing perch, Anabas testudineus, is an obligate air-breathing and euryhaline teleost capable of active ammonia excretion and tolerance of high concentrations of environmental ammonia. As Rhesus glycoproteins (RhGP/Rhgp) are known to transport ammonia, this study aimed to obtain the complete cDNA coding sequences of various rhgp isoforms from the gills of A. testudineus, and to determine their mRNA and protein expression levels during 6 days of exposure to 100 mmol l(-1) NH4Cl. The subcellular localization of Rhgp isoforms in the branchial epithelium was also examined in order to elucidate the type of ionocyte involved in active ammonia excretion. Four rhgp (rhag, rhbg, rhcg1 and rhcg2) had been identified from the gills of A. testudineus They had conserved amino acid residues for NH4(+) binding, NH4(+) deprotonation, channel gating and lining of the vestibules. Despite inwardly-directed NH3 and NH4(+) gradients, there were significant increases in the mRNA expression levels of the four branchial rhgp in A. testudineus at certain time points during 6 days of ammonia exposure, with significant increases in the protein abundances of Rhag and Rhcg2 on day 6. Immunofluorescence microscopy revealed a type of ammonia-inducible Na(+)/K(+)-ATPase α1c-immunoreactive ionocyte with apical Rhag and basolateral Rhcg2 in the gills of fish exposed to ammonia for 6 days. Hence, active ammonia excretion may involve NH4(+) entering the ionocyte through the basolateral Rhcg2 and being excreted through the apical Rhag, driven by a transapical membrane electrical potential generated by the apical cystic fibrosis transmembrane conductance regulator Cl(-) channel as suggested previously.

PMID: 28576822 [PubMed - as supplied by publisher]

The diagnosis of cystic fibrosis.

Presse Med. 2017 May 30;:

Authors: De Boeck K, Vermeulen F, Dupont L

Abstract
Establishing the diagnosis of cystic fibrosis (CF) is straight forward in the majority of patients: they present with a clear clinical picture (most frequently chronic respiratory symptoms plus malabsorption), the sweat chloride value is>60mmol/L and two known disease causing CFTR mutations are identified. In less than 5% of subjects, mainly those with a milder or limited phenotype, the diagnostic process is more complex, because initial diagnostic test results are inconclusive: sweat chloride concentration in the intermediate range, less than 2 CF causing mutations identified or both. These patients should be referred to expert centers where bioassays of CFTR function like nasal potential difference measurement or intestinal current measurement can be done. Still, in some patients, despite symptoms compatible with CF and some indication of CFTR dysfunction (e.g. only intermediate sweat chloride value), diagnostic criteria are not met (e.g. only 1 CFTR mutation identified). For these subjects, the term CFTR related disorder (CFTR-RD) is used. Patients with disseminated bronchiectasis, congenital bilateral absence of the vas deferens and acute or recurrent pancreatitis may fall in this category. CF has a very wide disease spectrum and increasingly the diagnosis is being made during adult life, mainly in subjects with milder phenotypes. In many countries, nationwide CF newborn screening (NBS) has been introduced. In screen positive babies, the diagnosis of CF must be confirmed by a sweat test demonstrating a sweat chloride concentration above 60mmol/L. To achieve the benefit of NBS, every baby in whom the diagnosis of CF is confirmed must receive immediate follow-up and treatment in a CF reference center. CF NBS is not full proof: some diagnoses will be missed and in some babies the diagnosis cannot be confirmed nor ruled out with certainty. Screening algorithms that include gene sequencing will detect a high number of such babies that are screen positive with an inconclusive diagnosis (CFSPID). Even in 2016, the most reliable and widely available diagnostic test for CF is the measurement of chloride concentration in sweat. The method of choice is sweat induction by pilocarpine iontophoresis, followed by sweat collection on a gauze or filter paper or in a Macroduct coil. Since mutation specific therapies have become available, it is important to identify the mutations responsible for CF in each individual patient.

PMID: 28576637 [PubMed - as supplied by publisher]

The treatment of the pulmonary and extrapulmonary manifestations of cystic fibrosis.

Presse Med. 2017 May 30;:

Authors: Chin M, Aaron SD, Bell SC

Abstract
Cystic fibrosis (CF) is a complex multisystem disease with considerable between patient variability in its manifestations and severity. In the past several decades, the range of treatments and the evidence to support their use for the pulmonary and extrapulmonary manifestations of CF have increased dramatically, contributing to the improved median survival of patients. As therapy for CF has evolved, new challenges including treatment adherence, medication intolerance and allergy, medical complications and coping with the burden of disease in the context of having a family and managing employment have arisen. While the majority of current therapy focuses primarily on improving symptoms, new therapies (CFTR modulators) target the underlying genetic defect.

PMID: 28576636 [PubMed - as supplied by publisher]

Characterization of circadian COPD symptoms by phenotype: Methodology of the STORICO observational study.

Eur J Intern Med. 2017 May 30;:

Authors: Canonica GW, Blasi F, Scichilone N, Simoni L, Zullo A, Giovannetti C, Briguglio C, Barsanti S, Antonelli Incalzi R, STORICO study group

Abstract
Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality worldwide. The symptoms of COPD are troublesome, variable, can occur during all parts of the 24-h day and have a substantial impact on patients' health status, quality of life and healthcare resource utilization. Reducing symptoms, improving health status and increasing physical activity are major goals in the management of stable COPD. In order to provide effective, patient-oriented care, patients should be evaluated on the basis of lung function, frequency of symptoms and patient-perceived impact of symptoms on their lives and treatment decisions made on a case-by-case basis. The identification of COPD phenotypes is an evolving debate and literature data about the circadian variation of COPD symptoms according to phenotypes are nowadays lacking. The ongoing STORICO (STudio Osservazionale sulla caratteRizzazione dei sIntomi delle 24 ore nei pazienti con BPCO) study (NCT03105999) is aimed to describe by clinically defined phenotypes the frequency and 12-month evolution of early-morning, day- and night-time COPD symptoms in a cohort of 600 Italian patients with stable COPD. Secondary objectives include the description of the 12-month variation of outcomes of interest according to phenotypes and of the healthcare resources utilization (overall and by phenotype) during 12-month observation. An exploratory analysis will be conducted aimed to phenotype COPD patients in an alternative researcher-independent way based on circadian pattern of symptoms combined with measures of respiratory function, health-related quality of life and comorbidity. The present paper describes the methodology of the STORICO study.

PMID: 28576398 [PubMed - as supplied by publisher]

Cystic Fibrosis Transmembrane Regulator Modulators: Implications for the Management of Depression and Anxiety in Cystic Fibrosis.

Psychosomatics. 2017 Apr 05;:

Authors: Talwalkar JS, Koff JL, Lee HB, Britto CJ, Mulenos AM, Georgiopoulos AM

Abstract
BACKGROUND: Individuals with cystic fibrosis (CF) are at high risk for depression and anxiety, which are associated with worse medical outcomes. Novel therapies for CF hold great promise for improving physical health, but the effects of these therapies on mental health remain poorly understood.
OBJECTIVE: This review aims to familiarize psychiatrists with the potential effect of novel CF therapies on depression and anxiety.
METHODS: We discuss novel therapies that directly target the mutant CF protein, the CF transmembrane regulator (CFTR), which are called CFTR modulators. We summarize depression and anxiety screening and treatment guidelines under implementation in accredited CF centers. Case vignettes highlight the complexities of caring for individuals with CF with comorbid depression and anxiety, including patients experiencing worsening depression and anxiety proximate to initiation of CFTR modulator therapy, and management of drug-drug interactions.
CONCLUSIONS: Although CFTR modulator therapies provide hope for improving clinical outcomes, worsening depression and anxiety occurs in some patients when starting these novel agents. This phenomenon may be multifactorial, with hypothesized contributions from CFTR modulator-psychotropic medication interactions, direct effects of CFTR modulators on central nervous system function, the psychologic effect of starting a potentially life-altering drug, and typical triggers of depression and anxiety such as stress, pain, and inflammation. The medical and psychiatric complexity of many individuals with CF warrants more direct involvement of mental health specialists on the multidisciplinary CF team. Inclusion of mental health variables in patients with CF registries will facilitate further examination at an epidemiologic level.

PMID: 28576305 [PubMed - as supplied by publisher]

Identification of the Amino Acids Inserted During Suppression of CFTR Nonsense Mutations and Determination of Their Functional Consequences.

Hum Mol Genet. 2017 May 31;:

Authors: Xue X, Mutyam V, Thakerar A, Mobley J, Bridges RJ, Rowe SM, Keeling KM, Bedwell DM

Abstract
In-frame premature termination codons (PTCs) account for ∼11% of all disease-associated mutations. PTC suppression therapy utilizes small molecules that suppress translation termination at a PTC to restore synthesis of a full-length protein. PTC suppression is mediated by the base pairing of a near-cognate aminoacyl-tRNA with a PTC and subsequently, the amino acid becomes incorporated into the nascent polypeptide at the site of the PTC. However, little is known about the identity of the amino acid(s) inserted at a PTC during this process in mammalian cells, or how the surrounding sequence context influences amino acid incorporation. Here we determined the amino acids inserted at the CFTR W1282X PTC (a UGA codon) in the context of its three upstream and downstream CFTR codons during G418-mediated suppression. We found that leucine, cysteine, and tryptophan are inserted during W1282X suppression. Interestingly, these amino acids (and their proportions) are significantly different from those recently identified following G418-mediated suppression of the CFTR G542X UGA mutation. These results demonstrate for the first time that local mRNA sequence context plays a key role in near-cognate aminoacyl-tRNA selection during PTC suppression. We also found that some variant CFTR proteins generated by PTC suppression exhibit reduced maturation and activity, indicating the complexity of nonsense suppression therapy. However, both a CFTR corrector and potentiator enhanced activity of protein variants generated by G418-mediated suppression. These results suggest that PTC suppression in combination with CFTR modulators may be beneficial for the treatment of CF patients with PTCs.

PMID: 28575328 [PubMed - as supplied by publisher]

Assessment of pathologic increase in liver stiffness enables earlier diagnosis of CFLD: Results from a prospective longitudinal cohort study.

PLoS One. 2017;12(6):e0178784

Authors: Klotter V, Gunchick C, Siemers E, Rath T, Hudel H, Naehrlich L, Roderfeld M, Roeb E

Abstract
About 30% of patients with Cystic Fibrosis (CF) develop CF-associated liver disease (CFLD). Recent studies have shown that transient elastography (TE), as a method to quantify liver stiffness, allows non-invasive diagnosis of CFLD in adults and children with CF. Within this study we aimed to prospectively identify patients at risk for development of CFLD by longitudinal analysis of liver stiffness and fibrosis scores in a 5-year follow-up. 36 pediatric and 16 adult patients with initial liver stiffness below the cut-off value indicative of CFLD (6.3 kPa) were examined by transient elastography for 4-5 years. TE, APRI-, and FIB-4-scores were assessed and compared by Kruskal-Wallis test and receiver operating characteristic (ROC)-analysis. Frequencies were compared by Chi2-test. Among the 36 patients participating in this study, a subgroup of 9 patients developed liver stiffness >6.3 kPa after 4-5 years with an increase of ΔTE >0.38 kPa/a (the group with increasing liver stiffness was labelled TEinc). APRI- and FIB-4 scores confirmed the rationale for grouping. The frequency of CFLD assessed by conventional diagnosis was significantly higher in TEinc-group compared to the control group (TEnorm). None of the adult CF patients matched criteria for TEinc-group. For the first time it was shown that the non-invasive longitudinal assessment of TE allows identification of patients with progression of CFLD in a subgroup of juvenile but not in adult CF patients. Comparing TE to conventional fibrosis-scores underlined the strength of the continuous assessment of liver stiffness for the exact diagnosis of progressive CFLD. The newly described cut-off for pathologic increase of liver stiffness, ΔTEcutoff = 0.38kPa/a, might enable to detect developing CFLD using consequent follow up TE measurements before reaching the level of stiffness indicating established CFLD. Nevertheless, the limited size of the analyzed cohort should encourage a prospective, multi-center, long term follow up study to confirm the suggested cut-off for the rise in liver stiffness.

PMID: 28575039 [PubMed - in process]

Targeting Mycolic Acid Transport by Indole-2-carboxamides for the Treatment of Mycobacterium abscessus Infections.

J Med Chem. 2017 Jun 02;:

Authors: Kozikowski AP, Onajole OK, Stec J, Dupont C, Viljoen A, Richard M, Chaira T, Lun S, Bishai WR, Raj VS, Ordway D, Kremer L

Abstract
Mycobacterium abscessus is a fast-growing, multidrug-resistant organism that has emerged as a clinically significant pathogen in cystic fibrosis (CF) patients. The intrinsic resistance of M. abscessus to most commonly available antibiotics seriously restricts chemotherapeutic options. Herein, we report the potent activity of a series of indolecarboxamides against M. abscessus. The lead compounds, 6 and 12, exhibited strong activity in vitro against a wide panel of M. abscessus isolates and in infected macrophages. High resistance levels to the indolecarboxamides appear to be associated with an A309P mutation in the mycolic acid transporter MmpL3. Biochemical analyses demonstrated that while de novo mycolic acid synthesis remained unaffected, the indolecarboxamides strongly inhibited the transport of trehalose monomycolate, resulting in the loss of trehalose dimycolate production and abrogating mycolylation of arabinogalactan. Our data introduce a hereto unexploited chemical structure class active against M. abscessus infections with promising translational development possibilities for the treatment of CF patients.

PMID: 28574259 [PubMed - as supplied by publisher]

Pulmonary microRNA profiling: implications in upper lobe predominant lung disease.

Clin Epigenetics. 2017;9:56

Authors: Armstrong DA, Nymon AB, Ringelberg CS, Lesseur C, Hazlett HF, Howard L, Marsit CJ, Ashare A

Abstract
BACKGROUND: Numerous pulmonary diseases manifest with upper lobe predominance including cystic fibrosis, smoking-related chronic obstructive pulmonary disease, and tuberculosis. Zonal hypoxia, characteristic of these pulmonary maladies, and oxygen stress in general is known to exert profound effects on various important aspects of cell biology. Lung macrophages are major participants in the pulmonary innate immune response and regional differences in macrophage responsiveness to hypoxia may contribute in the development of lung disease. MicroRNAs are ubiquitous regulators of human biology and emerging evidence indicates altered microRNA expression modulates respiratory disease processes. The objective of this study is to gain insight into the epigenetic and cellular mechanisms influencing regional differences in lung disease by investigating effect of hypoxia on regional microRNA expression in the lung. All studies were performed using primary alveolar macrophages (n = 10) or bronchoalveolar lavage fluid (n = 16) isolated from human subjects. MicroRNA was assayed via the NanoString nCounter microRNA assay.
RESULTS: Divergent molecular patterns of microRNA expression were observed in alternate lung lobes, specifically noted was disparate expression of miR-93 and miR-4454 in alveolar macrophages along with altered expression of miR-451a and miR-663a in bronchoalveolar lavage fluid. Gene ontology was used to identify potential downstream targets of divergent microRNAs. Targets include cytokines and matrix metalloproteinases, molecules that could have a significant impact on pulmonary inflammation and fibrosis.
CONCLUSIONS: Our findings show variant regional microRNA expression associated with hypoxia in alveolar macrophages and BAL fluid in the lung-upper vs lower lobe. Future studies should address whether these specific microRNAs may act intracellularly, in a paracrine/endocrine manner to direct the innate immune response or may ultimately be involved in pulmonary host-to-pathogen trans-kingdom cross-talk.

PMID: 28572860 [PubMed - in process]

Standard operating procedures for tuberculosis care.

Eur Respir J. 2017 Jun;49(6):

Authors: Solovic I, Abubakar I, Sotgiu G, Dara M, Goletti D, Duarte R, Aliberti S, de Benedictis FM, Ward B, Teixeira V, Gratziou C, Migliori GB

PMID: 28572129 [PubMed - in process]

The effect of 100% oxygen on tidal breathing parameters in preschool children.

Eur Respir J. 2017 Jun;49(6):

Authors: Foong RE, Harper AJ, Hall GL, Ramsey KA, AREST CF

PMID: 28572125 [PubMed - in process]