Literature Watch
Genetic Discoveries Highlight Environmental Factors as Key Drivers of Liver Disease.
Genetic Discoveries Highlight Environmental Factors as Key Drivers of Liver Disease.
Dig Dis. 2017 May 03;35(4):323-333
Authors: Chung BK, Karlsen TH
Abstract
BACKGROUND: Over the last 50 years, genetic studies have uncovered a spectrum of rare and common alleles that confer susceptibility to both Mendelian and complex forms of liver disease. For disorders of Mendelian inheritance, identification of the causal variants has demonstrated that common environmental exposures can elicit severe liver pathogenesis in predisposed individuals. Specific environmental triggers for complex liver disorders are largely unknown; however, large-scale association studies indicate that environmental triggers are the predominant factors in driving liver pathophysiology. Key Messages: In Mendelian liver disorders, a single rare variant of major effect is often responsible for disease development. Gene-sequencing technologies have greatly facilitated the discovery of causal variants for Mendelian diseases and are increasingly utilized in molecular and clinical genetics for diagnostic and counselling purposes. By contrast, genetic susceptibility for complex liver disorders is heterogeneous, as many different genes acting on multiple distinct pathways influence disease onset and severity. Risk variants for complex liver disorders are relatively common, typically of small effect size and detected by genome-wide association studies (GWAS), which compare the genetic variation of specific loci using thousands of patients and healthy controls. Thus far, GWAS have detected dozens of unique and overlapping risk alleles for complex liver disease, but these account for less than a quarter of the overall disease liability. These observations emphasize that environmental exposures on a background of genetic predisposition are significant drivers of liver pathophysiology. Rare variants of large effect size, undetectable by GWAS, may also affect the development of complex disease on a case-to-case basis but evidence for such a scenario remains to be determined.
CONCLUSIONS: Genetic technologies have identified numerous risk genes for Mendelian and complex liver disorders transforming disease recognition. For complex liver disorders, deciphering the interplay between genetic risk and environment determinants remains a significant challenge for unlocking the development of novel and personalized interventions.
PMID: 28468012 [PubMed - as supplied by publisher]
The anti-microbial peptide TP359 attenuates inflammation in human lung cells infected with Pseudomonas aeruginosa via TLR5 and MAPK pathways.
The anti-microbial peptide TP359 attenuates inflammation in human lung cells infected with Pseudomonas aeruginosa via TLR5 and MAPK pathways.
PLoS One. 2017;12(5):e0176640
Authors: Dosunmu EF, Emeh RO, Dixit S, Bakeer MK, Coats MT, Owen DR, Pillai SR, Singh SR, Dennis VA
Abstract
Pseudomonas aeruginosa infection induces vigorous inflammatory mediators secreted by epithelial cells, which do not necessarily eradicate the pathogen. Nonetheless, it reduces lung function due to significant airway damage, most importantly in cystic fibrosis patients. Recently, we published that TP359, a proprietary cationic peptide had potent bactericidal effects against P. aeruginosa, which were mediated by down-regulating its outer membrane biogenesis genes. Herein, we hypothesized that TP359 bactericidal effects could also serve to regulate P. aeruginosa-induced lung inflammation. We explored this hypothesis by infecting human A549 lung cells with live P. aeruginosa non-isogenic, mucoid and non-mucoid strains and assessed the capacity of TP359 to regulate the levels of elicited TNFα, IL-6 and IL-8 inflammatory cytokines. In all instances, the mucoid strain elicited higher concentrations of cytokines in comparison to the non-mucoid strain, and TP359 dose-dependently down-regulated their respective levels, suggesting its regulation of lung inflammation. Surprisingly, P. aeruginosa flagellin, and not its lipopolysaccharide moiety, was the primary inducer of inflammatory cytokines in lung cells, which were similarly down-regulated by TP359. Blocking of TLR5, the putative flagellin receptor, completely abrogated the capacity of infected lung cells to secrete cytokines, underscoring that TP359 regulates inflammation via the TLR5-dependent signaling pathway. Downstream pathway-specific inhibition studies further revealed that the MAPK pathway, essentially p38 and JNK are necessary for induction of P. aeruginosa elicited inflammatory cytokines and their down-regulation by TP359. Collectively, our data provides evidence to support exploring the relevancy of TP359 as an anti-microbial and anti-inflammatory agent against P. aeruginosa for clinical applications.
PMID: 28467446 [PubMed - in process]
Low Beta-Adrenergic Sweat Responses in Cystic Fibrosis and Cystic Fibrosis Transmembrane Conductance Regulator-Related Metabolic Syndrome Children.
Low Beta-Adrenergic Sweat Responses in Cystic Fibrosis and Cystic Fibrosis Transmembrane Conductance Regulator-Related Metabolic Syndrome Children.
Pediatr Allergy Immunol Pulmonol. 2017 Mar 01;30(1):2-6
Authors: Salinas DB, Kang L, Azen C, Quinton P
Abstract
β-adrenergically stimulated sweat secretion depends on the function of the cystic fibrosis transmembrane conductance regulator (CFTR) and discriminates between cystic fibrosis (CF) patients and healthy controls. Therefore, we sought to determine the feasibility, safety, and efficacy of assaying β-adrenergic sweating in children identified by CF newborn screening to help determine prognoses for individuals with CFTR-related metabolic syndrome (CRMS). Preschool age children with a positive newborn screening test for CF participated in this cross-sectional study. Sweat rates were measured by evaporimetery (cyberDERM, inc.) as transepidermal water losses (g H2O/m(2)/h) before and after selectively stimulating sweat glands either cholinergically or β-adrenergically. Net peak sweat responses assayed as evaporation rates were compared between CF and CRMS cohorts. After a pilot test in adults, children between 4 and 6 years of age were evaluated (CF, n = 16; CRMS, n = 10). The test protocol was well tolerated; electrocardiograms and vital signs were within normal range for all subjects. The mean evaporative sweat rates in both groups in response to cholinergic stimulation were similar (CF, 60.3 ± 23.8; CRMS, 57.7 ± 13.9; p = 0.72) as well as to β-adrenergic stimulation (CF, 1.1 ± 1.7; CRMS, 2.0 ± 2.0; p = 0.14). The β-adrenergic sweat test is safe and well tolerated by young children. However, the β-adrenergic sweat secretion rates as measured by evaporimetery did not discriminate between CF and CRMS cohorts.
PMID: 28465863 [PubMed - in process]
Mashiningan improves opioid-induced constipation in rats by activating cystic fibrosis transmembrane conductance regulator chloride channel.
Mashiningan improves opioid-induced constipation in rats by activating cystic fibrosis transmembrane conductance regulator chloride channel.
J Pharmacol Exp Ther. 2017 May 02;:
Authors: Harada Y, Iizuka S, Saegusa Y, Mogami S, Fujitsuka N, Hattori T
Abstract
Opioid receptor stimulants are analgesics used in patients with and without cancer; however, they often cause constipation, resulting in poor adherence and deterioration of the quality of life. Hence, suitable treatments for constipation are required. In this study, we investigated the pharmacological mechanisms of action of mashiningan (MNG), a Kampo medicine used to treat constipation, and evaluated the effect of MNG on opioid-induced constipation in rats. MNG (100 or 300 mg/kg) was orally administered to normal or codeine phosphate (CPH)-induced constipation in rats, and its effect was evaluated on the basis of fecal counts, characteristics, and weight. Small intestinal fluid secretion was measured after treatment with MNG alone or co-administration with a cystic fibrosis transmembrane conductance regulator (CFTR) -specific inhibitor (CFTRinh-172). The effects of MNG on the CFTR and type-2 chloride channel were determined using patch clamp or short-circuit current experiments, respectively. MNG increased the fecal weight and proportion of soft feces in normal rats. CPH-induced constipation in rats decreased fecal counts and weight, whereas MNG prevented these effects and increased the proportion of soft feces. MNG increased the electronic chloride current, and this effect was inhibited by the CFTRinh-172 in the CFTR assay. Furthermore, MNG increased small intestinal fluid secretion, and this effect was abolished by co-administration with the CFTRinh-172. MNG improved opioid-induced constipation in rats, and this improvement may have been mediated by increasing intestinal fluid secretion via CFTR chloride channel activation. Therefore, MNG is expected as a medicine of the treatment for constipation in patients taking opioids.
PMID: 28465373 [PubMed - as supplied by publisher]
A multiple reader scoring system for Nasal Potential Difference parameters.
A multiple reader scoring system for Nasal Potential Difference parameters.
J Cyst Fibros. 2017 Apr 29;:
Authors: Solomon GM, Liu B, Sermet-Gaudelus I, Fajac I, Wilschanski M, Vermeulen F, Rowe SM
Abstract
BACKGROUND: Nasal Potential Difference (NPD) is a biomarker of CFTR activity used to diagnose CF and monitor experimental therapies. Limited studies have been performed to assess agreement between expert readers of NPD interpretation using a scoring algorithm.
METHODS: We developed a standardized scoring algorithm for "interpretability" and "confidence" for PD (potential difference) measures, and sought to determine the degree of agreement on NPD parameters between trained readers.
RESULTS: There was excellent agreement for interpretability between NPD readers for CF and fair agreement for normal tracings but slight agreement of interpretability in indeterminate tracings. Amongst interpretable tracings, excellent correlation of mean scores for Ringer's Baseline PD, Δamiloride, and ΔCl-free+Isoproterenol was observed. There was slight agreement regarding confidence of the interpretable PD tracings, resulting in divergence of the Ringers and Δamiloride, and ΔCl-free+Isoproterenol PDs between "high" and "low" confidence CF tracings.
CONCLUSION: A multi-reader process with adjudication is important for scoring NPDs for diagnosis and in monitoring of CF clinical trials.
PMID: 28465124 [PubMed - as supplied by publisher]
Prevalence of Burkholderia species, including members of Burkholderia cepacia complex, among UK cystic and non-cystic fibrosis patients.
Prevalence of Burkholderia species, including members of Burkholderia cepacia complex, among UK cystic and non-cystic fibrosis patients.
J Med Microbiol. 2017 Apr;66(4):490-501
Authors: Kenna DTD, Lilley D, Coward A, Martin K, Perry C, Pike R, Hill R, Turton JF
Abstract
PURPOSE: We aimed to establish the prevalence of different Burkholderia species among UK cystic fibrosis (CF) and non-CF patients over a 2 year period.
METHODOLOGY: Matrix-assisted laser desorption/ionization-time of flight mass spectrometry was used to identify isolates to genus level, followed by recA/gyrB sequence clustering or species-specific PCR. In all, 1047 Burkholderia isolates were submitted for identification from 361 CF patients and 112 non-CF patients, 25 from the hospital environment and three from a commercial company. Potential cross-infection was assessed by pulsed-field gel electrophoresis (PFGE) and multi- locus-sequence typing (MLST). MICs were determined for 161 Burkholderia cepacia complex (Bcc) isolates. CF Trust registry data were sought to examine clinical parameters relating to Bcc infection.
RESULTS: Burkholderia multivorans was the most prevalent species among CF patients affecting 56 % (192) patients, followed by Burkholderia cenocepacia IIIA (15 %; 52 patients). Five novel recA clusters were found. Among non-CF patients, Burkholderia cepacia was the most prevalent species (37/112; 34 %), with 18 of 40 isolates part of a UK-wide B. cepacia 'cluster'. This and three other clusters were investigated by PFGE and MLST. Cable-pili positive isolates included two novel sequence types and representatives of ET12. Antibiotic susceptibility varied between and within species and CF/non- CF isolates. CF Trust registry data suggested no significant difference in lung function between patients harbouring B. cenocepacia, B. multivorans and other Bcc species (P=0.81).
CONCLUSION: The dominance of B. multivorans in CF, the presence of a B. cepacia cluster among non-CF patients and the existence of putative novel species all highlighted the continuing role of Burkholderia species as opportunistic pathogens.
PMID: 28463663 [PubMed - in process]
Rab GTPases regulate the trafficking of channels and transporters - a focus on cystic fibrosis.
Rab GTPases regulate the trafficking of channels and transporters - a focus on cystic fibrosis.
Small GTPases. 2017 May 02;:0
Authors: Farinha CM, Matos P
Abstract
The amount of ion channels and transporters present at the plasma membrane is a crucial component of the overall regulation of ion transport. The number of channels present result from an intricate network of proteins that controls the late events of channel trafficking, such as endocytosis, recycling and targeting to lysosomal degradation. Small GTPases of the Rab family are key players in these processes thus contributing to regulation of fluid secretion and ion homeostasis. In epithelia, this involves mainly the balance between the chloride channel CFTR and the sodium channel ENaC, whose misfunction is a hallmark of cystic fibrosis - the commonest recessive disorder in Caucasians. Here, we review the role of GTPases in regulating trafficking of ion channels and transporters, comparing what is known for CFTR and ENaC with other types of channels. We also discuss how feasible would be to target the Rab machinery to handle a disorder such as CF.
PMID: 28463591 [PubMed - as supplied by publisher]
Does current reporting of lung function by the UK cystic fibrosis registry allow a fair comparison of adult centres?
Does current reporting of lung function by the UK cystic fibrosis registry allow a fair comparison of adult centres?
J Cyst Fibros. 2017 Apr 24;:
Authors: Nightingale JA, Osmond C
Abstract
BACKGROUND: Outcome data for UK cystic fibrosis centres are publicly available in an annual report, which ranks centres by median FEV1% predicted. We wished to assess whether there are differences in lung function outcomes between adult centres that might imply differing standards of care.
METHODS: UK Registry data from 4761 subjects at 34 anonymised adult centres were used to calculate mean FEV1% and rate of change of lung function for 2007-13. These measures were used to rank centres and compare outcomes.
RESULTS: There are minor differences between centres for mean FEV1% for some years of the study and for rate of change of lung function over the study period. However, rankings are critically dependent on the outcome measure chosen and centre variation becomes negligible once patient population characteristics are taken into account.
CONCLUSIONS: We have demonstrated that the ranking of centres is biased and any apparent difference in respiratory outcomes is unlikely to be related to differing standards of care between centres.
PMID: 28462874 [PubMed - as supplied by publisher]
Animal models of hospital-acquired pneumonia: current practices and future perspectives.
Animal models of hospital-acquired pneumonia: current practices and future perspectives.
Ann Transl Med. 2017 Mar;5(6):132
Authors: Bielen K, 's Jongers B, Malhotra-Kumar S, Jorens PG, Goossens H, Kumar-Singh S
Abstract
Lower respiratory tract infections are amongst the leading causes of mortality and morbidity worldwide. Especially in hospital settings and more particularly in critically ill ventilated patients, nosocomial pneumonia is one of the most serious infectious complications frequently caused by opportunistic pathogens. Pseudomonas aeruginosa is one of the most important causes of ventilator-associated pneumonia as well as the major cause of chronic pneumonia in cystic fibrosis patients. Animal models of pneumonia allow us to investigate distinct types of pneumonia at various disease stages, studies that are not possible in patients. Different animal models of pneumonia such as one-hit acute pneumonia models, ventilator-associated pneumonia models and biofilm pneumonia models associated with cystic fibrosis have been extensively studied and have considerably aided our understanding of disease pathogenesis and testing and developing new treatment strategies. The present review aims to guide investigators in choosing appropriate animal pneumonia models by describing and comparing the relevant characteristics of each model using P. aeruginosa as a model etiology for hospital-acquired pneumonia. Key to establishing and studying these animal models of infection are well-defined end-points that allow precise monitoring and characterization of disease development that could ultimately aid in translating these findings to patient populations in order to guide therapy. In this respect, and discussed here, is the development of humanized animal models of bacterial pneumonia that could offer unique advantages to study bacterial virulence factor expression and host cytokine production for translational purposes.
PMID: 28462212 [PubMed]
Ets Homologous Factor (EHF) has Critical Roles in Epithelial Dysfunction in Airway Disease.
Ets Homologous Factor (EHF) has Critical Roles in Epithelial Dysfunction in Airway Disease.
J Biol Chem. 2017 May 01;:
Authors: Fossum SL, Mutolo MJ, Tugores A, Ghosh S, Randell SH, Jones LC, Leir SH, Harris A
Abstract
The airway epithelium forms a barrier between the internal and external environments. Epithelial dysfunction is critical in the pathology of many respiratory diseases including cystic fibrosis (CF). Ets homologous factor (EHF) is a key member of the transcription factor (TF) network that regulates gene expression in the airway epithelium in response to endogenous and exogenous stimuli. EHF, which has altered expression in inflammatory states, maps to the 5 ' end of an intergenic region on Chr11p13 that was implicated as a modifier of CF airway disease. Here we determine the functions of EHF in primary human bronchial epithelial (HBE) cells and relevant airway cell lines. Using EHF chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) and RNA-seq after EHF depletion, we show that EHF targets in HBE cells are enriched for genes involved in inflammation and wound repair. Furthermore, changes in gene expression impact cell phenotype, since EHF depletion alters epithelial secretion of a neutrophil chemokine and slows wound closure in HBE cells. EHF activates expression of the SAM pointed domain-containing ETS transcription factor (SPDEF), which contributes to goblet cell hyperplasia. Our data reveal a critical role for EHF in regulating epithelial function in lung disease.
PMID: 28461336 [PubMed - as supplied by publisher]
Population Pharmacokinetic Modeling as a Tool to Characterize the Decrease in Ciprofloxacin free Interstitial Levels Caused by Pseudomonas aeruginosa Biofilm Lung Infection in Wistar Rats.
Population Pharmacokinetic Modeling as a Tool to Characterize the Decrease in Ciprofloxacin free Interstitial Levels Caused by Pseudomonas aeruginosa Biofilm Lung Infection in Wistar Rats.
Antimicrob Agents Chemother. 2017 May 01;:
Authors: Torres BGS, Helfer VE, Bernardes PM, Macedo AJ, Nielsen EI, Friberg LE, Dalla Costa T
Abstract
Biofilm formation plays an important role in the persistence of pulmonary infections, for example in cystic fibrosis patients. So far, little is known about antimicrobials lung disposition in biofilm-associated pneumonia. This study aimed to evaluate, by microdialysis, ciprofloxacin (CIP) penetration into the lungs of healthy and Pseudomonas aeruginosa biofilm infected rats and to develop a comprehensive model to describe the CIP disposition in both conditions. P. aeruginosa was immobilized into alginate beads and intratracheally inoculated 14 days before CIP administration (20 mg/kg). Plasma and microdialysate were sampled in different animal groups and the observations were evaluated by noncompartmental analysis (NCA) and population pharmacokinetic (popPK) analysis. The final model, that successfully described all data, consisted of an arterial and a venous central compartment, two peripheral distribution compartments and lung disposition was modeled as a two-compartment model structure linked to the venous compartment. Plasma clearance was approximately 32% lower in infected animals leading to a significant higher plasma CIP exposure (AUC0-∞ 27.3 ± 12.1 μg⋅h/mL and 13.3 ± 3.5 μg⋅h/mL, infected and healthy, respectively). Despite the plasma exposure, infected animals showed a four times lower tissue/plasma ratio (fT = 0.44 and fT = 1.69, infected and healthy, respectively), a lung clearance was added to the model for these animals (CLlung = 0.643 L h(-1) kg(-1)) to explain the lower tissue concentrations. Our results indicate that P. aeruginosa biofilm infection reduces CIP free interstitial lung concentrations and increases plasma exposure, suggesting that plasma concentrations alone are not a good surrogate of lung concentrations.
PMID: 28461311 [PubMed - as supplied by publisher]
Singing Lessons for Respiratory Health: A Literature Review.
Singing Lessons for Respiratory Health: A Literature Review.
J Voice. 2017 Apr 28;:
Authors: Goldenberg RB
Abstract
OBJECTIVE: Several studies have explored the role of music and singing as a treatment for respiratory symptoms. The objective of this paper was to review the current body of literature in regard to the use of singing as both a physiological and a psychological therapy for respiratory disease and assess the role the singing teacher might play in this treatment.
STUDY DESIGN: This is a literature review, discussion of results and directions for further research.
METHOD: Multiple databases were searched using keywords such as "respiratory," "physiotherapy," and "pulmonary" in conjunction with "singing." Studies that met selection criteria were summarized and analyzed.
RESULTS: Seventeen studies pertaining to multiple conditions including chronic obstructive pulmonary disease, asthma, cystic fibrosis, cancer, Parkinson disease, quadriplegia, and multiple sclerosis were analyzed. All studies reported trends of positive physical and/or quality of life outcomes after a series of singing lessons, regardless of statistical significance. Several noted improvements in maximum expiratory pressure and overall breathing technique. Many studies included open-ended interviews revealing participants' perception of singing as an effective therapy that was fun, improved mood, taught breathing and breath control, was a good exercise for the lungs, and had improved physical functioning.
CONCLUSIONS: Singing can be used as an adjunctive treatment for respiratory disease, with the best results occurring after long-term study. Group lessons and a strong teacher relationship feed the need for social interaction and support, which can facilitate treatment compliance. Further research is warranted.
PMID: 28461167 [PubMed - as supplied by publisher]
Standardized Treatment of Pulmonary Exacerbations (STOP) study: Observations at the initiation of intravenous antibiotics for cystic fibrosis pulmonary exacerbations.
Standardized Treatment of Pulmonary Exacerbations (STOP) study: Observations at the initiation of intravenous antibiotics for cystic fibrosis pulmonary exacerbations.
J Cyst Fibros. 2017 Apr 28;:
Authors: Sanders DB, Solomon GM, Beckett VV, West NE, Daines CL, Heltshe SL, VanDevanter DR, Spahr JE, Gibson RL, Nick JA, Marshall BC, Flume PA, Goss CH, STOP Study Group
Abstract
BACKGROUND: The Standardized Treatment of Pulmonary Exacerbations (STOP) program has the intent of defining best practices in the treatment of pulmonary exacerbations (PEx) in patients with cystic fibrosis (CF). The objective of this analysis was to describe the clinical presentations of patients admitted for intravenous (IV) antibiotics and enrolled in a prospective observational PEx study as well as to understand physician treatment goals at the start of the intervention.
METHODS: We enrolled adolescents and adults admitted to the hospital for a PEx treated with IV antibiotics. We recorded patient and PEx characteristics at the time of enrollment. We surveyed treating physicians on treatment goals as well as their willingness to enroll patients in various study designs. Additional demographic and clinical data were obtained from the CF Foundation Patient Registry.
RESULTS: Of 220 patients enrolled, 56% were female, 19% were adolescents, and 71% were infected with P. aeruginosa. The mean (SD) FEV1 at enrollment was 51.1 (21.6)% predicted. Most patients (85%) experienced symptoms for ≥7days before admission, 43% had received IV antibiotics within the previous 6months, and 48% received oral and/or inhaled antibiotics prior to IV antibiotic initiation. Forty percent had ≥10% FEV1 decrease from their best value recorded in the previous 6months, but for 20% of patients, their enrollment FEV1 was their best FEV1 recorded within the previous 6months. Physicians reported that their primary treatment objectives were lung function recovery (53%) and improvement of symptoms (47%) of PEx. Most physicians stated they would enroll patients in studies involving 10-day (72%) or 14-day (87%), but not 7-day (29%), treatment regimens.
CONCLUSIONS: Based on the results of this study, prospective studies are feasible and physician willingness for interventional studies of PEx exists. Results of this observational study will help design future PEx trials.
PMID: 28460885 [PubMed - as supplied by publisher]
Notice of NCI's Participation on PA-17-226, Advancing the Science of Geriatric Palliative Care (R21)
Notice of Correction to Key Dates for PAR-16-201 " Improving Smoking Cessation in Socioeconomically Disadvantaged Populations via Scalable Interventions (R21)"
Notice of Frequently Asked Questions for RFA-HL-18-020 Integrative Computational Biology for Analysis of NHLBI TOPMed Data (R01)
Notice of Change in the Expiration Date for PA-15-081 Drug Abuse Prevention Intervention Research (R03)
Notice of Intent to Publish a Funding Opportunity Announcement for NCCIH Natural Product Early Phase Clinical Trials (R33)
Center for Inherited Disease Research (CIDR) High Throughput Sequencing and Genotyping Resource Access (X01)
Cystic Fibrosis Research and Translation Center (P30)
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