Chronic obstructive pulmonary disease (COPD) was traditionally thought to be caused by tobacco smoking. However, recognition of the importance of non-smoking-related risk factors for COPD has ...increased over the past decade, with evidence on the burden, risk factors, and clinical presentations of COPD in never-smokers. About half of all COPD cases worldwide are due to non-tobacco-related risk factors, which vary by geographical region. These factors include air pollution, occupational exposures, poorly controlled asthma, environmental tobacco smoke, infectious diseases, and low socioeconomic status. Impaired lung growth during childhood, caused by a range of early-life exposures, is associated with an increased risk of COPD. Potential mechanisms for the pathogenesis of COPD in never-smokers include inflammation, oxidative stress, airway remodelling, and accelerated lung ageing. Compared with smokers who develop COPD, never-smokers with COPD have relatively mild chronic respiratory symptoms, little or no emphysema, milder airflow limitation, and fewer comorbidities; however, exacerbations can still be frequent. Further research-including epidemiological, translational, clinical, and implementation studies-is needed to address gaps in understanding and to advance potential solutions to reduce the burden of COPD in never-smokers.
Chronic obstructive pulmonary disease (COPD) is the third commonest cause of death globally, and manifests as a progressive inflammatory lung disease with no curative treatment. The lung microbiome ...contributes to COPD progression, but the function of the gut microbiome remains unclear. Here we examine the faecal microbiome and metabolome of COPD patients and healthy controls, finding 146 bacterial species differing between the two groups. Several species, including Streptococcus sp000187445, Streptococcus vestibularis and multiple members of the family Lachnospiraceae, also correlate with reduced lung function. Untargeted metabolomics identifies a COPD signature comprising 46% lipid, 20% xenobiotic and 20% amino acid related metabolites. Furthermore, we describe a disease-associated network connecting Streptococcus parasanguinis_B with COPD-associated metabolites, including N-acetylglutamate and its analogue N-carbamoylglutamate. While correlative, our results suggest that the faecal microbiome and metabolome of COPD patients are distinct from those of healthy individuals, and may thus aid in the search for biomarkers for COPD.
The opium poppy genome and morphinan production Guo, Li; Winzer, Thilo; Yang, Xiaofei ...
Science (American Association for the Advancement of Science),
10/2018, Letnik:
362, Številka:
6412
Journal Article
Recenzirano
Odprti dostop
Morphinan-based painkillers are derived from opium poppy (
L.). We report a draft of the opium poppy genome, with 2.72 gigabases assembled into 11 chromosomes with contig N50 and scaffold N50 of 1.77 ...and 204 megabases, respectively. Synteny analysis suggests a whole-genome duplication at ~7.8 million years ago and ancient segmental or whole-genome duplication(s) that occurred before the Papaveraceae-Ranunculaceae divergence 110 million years ago. Syntenic blocks representative of phthalideisoquinoline and morphinan components of a benzylisoquinoline alkaloid cluster of 15 genes provide insight into how this cluster evolved. Paralog analysis identified P450 and oxidoreductase genes that combined to form the
gene fusion essential for morphinan biosynthesis in opium poppy. Thus, gene duplication, rearrangement, and fusion events have led to evolution of specialized metabolic products in opium poppy.
The design of proteins that bind to a specific site on the surface of a target protein using no information other than the three-dimensional structure of the target remains a challenge
. Here we ...describe a general solution to this problem that starts with a broad exploration of the vast space of possible binding modes to a selected region of a protein surface, and then intensifies the search in the vicinity of the most promising binding modes. We demonstrate the broad applicability of this approach through the de novo design of binding proteins to 12 diverse protein targets with different shapes and surface properties. Biophysical characterization shows that the binders, which are all smaller than 65 amino acids, are hyperstable and, following experimental optimization, bind their targets with nanomolar to picomolar affinities. We succeeded in solving crystal structures of five of the binder-target complexes, and all five closely match the corresponding computational design models. Experimental data on nearly half a million computational designs and hundreds of thousands of point mutants provide detailed feedback on the strengths and limitations of the method and of our current understanding of protein-protein interactions, and should guide improvements of both. Our approach enables the targeted design of binders to sites of interest on a wide variety of proteins for therapeutic and diagnostic applications.
Aquatic birds harbor diverse influenza A viruses and are a major viral reservoir in nature. The recent discovery of influenza viruses of a new H17N10 subtype in Central American fruit bats suggests ...that other New World species may similarly carry divergent influenza viruses. Using consensus degenerate RT-PCR, we identified a novel influenza A virus, designated as H18N11, in a flat-faced fruit bat (Artibeus planirostris) from Peru. Serologic studies with the recombinant H18 protein indicated that several Peruvian bat species were infected by this virus. Phylogenetic analyses demonstrate that, in some gene segments, New World bats harbor more influenza virus genetic diversity than all other mammalian and avian species combined, indicative of a long-standing host-virus association. Structural and functional analyses of the hemagglutinin and neuraminidase indicate that sialic acid is not a ligand for virus attachment nor a substrate for release, suggesting a unique mode of influenza A virus attachment and activation of membrane fusion for entry into host cells. Taken together, these findings indicate that bats constitute a potentially important and likely ancient reservoir for a diverse pool of influenza viruses.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Display omitted
•Levels of ambient PM2.5 are stable or increasing in many low and middle-income countries.•We assessed associations between childrens’ long-term PM2.5 exposure and acute respiratory ...infection (ARI)•We found a significant association between annual PM and ARI in the preceding two weeks.•Boys and children living in rural areas appeared to be at greater risk of adverse effects.
Evidence from developed countries suggests that fine particulate matter (≤2.5 µm PM2.5) contributes to childhood respiratory morbidity and mortality. However, few analyses have focused on resource-limited settings, where much of this burden occurs. We aimed to investigate the cross-sectional associations between annual average exposure to ambient PM2.5 and acute respiratory infection (ARI) in children aged <5 years living in low- and middle-income countries (LMICs).
We combined Demographic and Health Survey (DHS) data from 35 countries with gridded global estimates of annual PM2.5 mass concentrations. We analysed the association between PM2.5 and maternal-reported ARI in the two weeks preceding the survey among children aged <5 years living in 35 LMICs. We used multivariable logistic regression models that adjusted for child, maternal, household and cluster-level factors. We also fitted multi-pollutant models (adjusted for nitrogen dioxide NO2 and surface-level ozone O3), among other sensitivity analyses. We assessed whether the associations between PM2.5 and ARI were modified by sex, age and place of residence.
The analysis comprised 573,950 children, among whom the prevalence of ARI was 22,506 (3.92%). The mean (±SD) estimated annual concentration of PM2.5 to which children were exposed was 48.2 (±31.0) µg/m3. The 5th and 95th percentiles of PM2.5 were 9.8 µg/m3 and 110.9 µg/m3, respectively. A 10 µg/m3 increase in PM2.5 was associated with greater odds of having an ARI (OR: 1.06; 95% CI: 1.05–1.07). The association between PM2.5 and ARI was robust to adjustment for NO2 and O3. We observed evidence of effect modification by sex, age and place of residence, suggesting greater effects of PM2.5 on ARI in boys, in younger children, and in children living in rural areas.
Annual average ambient PM2.5, as an indicator for long-term exposure, was associated with greater odds of maternal-reported ARI in children aged <5 years living in 35 LMICs. Longitudinal studies in LMICs are required to corroborate our cross-sectional findings, to further elucidate the extent to which lowering PM2.5 may have a role in the global challenge of reducing ARI-related morbidity and mortality in children.
Background Asthma pathophysiology and treatment responsiveness are predicted by inflammatory phenotype. However, the relationship between airway microbiology and asthma phenotype is poorly ...understood. Objective We aimed to characterize the airway microbiota in patients with symptomatic stable asthma and relate composition to airway inflammatory phenotype and other phenotypic characteristics. Methods The microbial composition of induced sputum specimens collected from adult patients screened for a multicenter randomized controlled trial was determined by using 16S rRNA gene sequencing. Inflammatory phenotypes were defined by sputum neutrophil and eosinophil cell proportions. Microbiota were defined by using α- and β-diversity measures, and interphenotype differences were identified by using similarity of percentages, network analysis, and taxon fold change. Phenotypic predictors of airway microbiology were identified by using multivariate linear regression. Results Microbiota composition was determined in 167 participants and classified as eosinophilic (n = 84), neutrophilic (n = 14), paucigranulocytic (n = 60), or mixed neutrophilic-eosinophilic (n = 9) asthma phenotypes. Airway microbiology was significantly less diverse ( P = .022) and more dissimilar ( P = .005) in neutrophilic compared with eosinophilic participants. Sputum neutrophil proportions, but not eosinophil proportions, correlated significantly with these diversity measures (α-diversity: Spearman r = −0.374, P < .001; β-diversity: r = 0.238, P = .002). Interphenotype differences were characterized by a greater frequency of pathogenic taxa at high relative abundance and reduced Streptococcus , Gemella , and Porphyromonas taxa relative abundance in patients with neutrophilic asthma. Multivariate regression confirmed that sputum neutrophil proportion was the strongest predictor of microbiota composition. Conclusions Neutrophilic asthma is associated with airway microbiology that is significantly different from that seen in patients with other inflammatory phenotypes, particularly eosinophilic asthma. Differences in microbiota composition might influence the response to antimicrobial and steroid therapies and the risk of lung infection.
Acute exacerbation of COPD Ko, Fanny W.; Chan, Ka Pang; Hui, David S. ...
Respirology (Carlton, Vic.),
October 2016, Letnik:
21, Številka:
7
Journal Article
Recenzirano
Odprti dostop
The literature of acute exacerbation of chronic obstructive pulmonary disease (COPD) is fast expanding. This review focuses on several aspects of acute exacerbation of COPD (AECOPD) including ...epidemiology, diagnosis and management. COPD poses a major health and economic burden in the Asia‐Pacific region, as it does worldwide. Triggering factors of AECOPD include infectious (bacteria and viruses) and environmental (air pollution and meteorological effect) factors. Disruption in the dynamic balance between the ‘pathogens’ (viral and bacterial) and the normal bacterial communities that constitute the lung microbiome likely contributes to the risk of exacerbations. The diagnostic approach to AECOPD varies based on the clinical setting and severity of the exacerbation. After history and examination, a number of investigations may be useful, including oximetry, sputum culture, chest X‐ray and blood tests for inflammatory markers. Arterial blood gases should be considered in severe exacerbations, to characterize respiratory failure. Depending on the severity, the acute management of AECOPD involves use of bronchodilators, steroids, antibiotics, oxygen and noninvasive ventilation. Hospitalization may be required, for severe exacerbations. Nonpharmacological interventions including disease‐specific self‐management, pulmonary rehabilitation, early medical follow‐up, home visits by respiratory health workers, integrated programmes and telehealth‐assisted hospital at home have been studied during hospitalization and shortly after discharge in patients who have had a recent AECOPD. Pharmacological approaches to reducing risk of future exacerbations include long‐acting bronchodilators, inhaled steroids, mucolytics, vaccinations and long‐term macrolides. Further studies are needed to assess the cost‐effectiveness of these interventions in preventing COPD exacerbations.
The macrolide antibiotic azithromycin reduces exacerbations in adults with persistent symptomatic asthma. However, owing to the pleotropic properties of macrolides, unintended bacteriological ...consequences such as augmented pathogen colonization or dissemination of antibiotic-resistant organisms can occur, calling into question the long-term safety of azithromycin maintenance therapy.
To assess the effects of azithromycin on the airway microbiota, pathogen abundance, and carriage of antibiotic resistance genes.
16S rRNA sequencing and quantitative PCR were performed to assess the effect of azithromycin on sputum microbiology from participants of the AMAZES (Asthma and Macrolides: The Azithromycin Efficacy and Safety) trial: a 48-week, double-blind, placebo-controlled trial of thrice-weekly 500 mg oral azithromycin in adults with persistent uncontrolled asthma. Pooled-template shotgun metagenomic sequencing, quantitative PCR, and isolate whole-genome sequencing were performed to assess antibiotic resistance.
Paired sputum samples were available from 61 patients (
= 34 placebo,
= 27 azithromycin). Azithromycin did not affect bacterial load (
= 0.37) but did significantly decrease Faith's phylogenetic diversity (
= 0.026) and
load (
< 0.0001). Azithromycin did not significantly affect levels of
,
,
, or
. Of the 89 antibiotic resistance genes detected, five macrolide resistance genes and two tetracycline resistance genes were increased significantly.
In patients with persistent uncontrolled asthma, azithromycin reduced airway
load compared with placebo but did not change total bacterial load. Macrolide resistance increased, reflecting previous studies. These results highlight the need for studies assessing the efficacy of nonantibiotic macrolides as a long-term therapy for patients with persistent uncontrolled asthma.
Background
The role of inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD) has been the subject of much controversy. Major international guidelines recommend selective use ...of ICS. Recently published meta‐analyses have reported conflicting findings on the effects of inhaled steroid therapy in COPD.
Objectives
To determine the efficacy and safety of inhaled corticosteroids in stable patients with COPD, in terms of objective and subjective outcomes.
Search methods
A pre‐defined search strategy was used to search the Cochrane Airways Group Specialised Register for relevant literature. Searches are current as of July 2011.
Selection criteria
We included randomised trials comparing any dose of any type of inhaled steroid with a placebo control in patients with COPD. Acute bronchodilator reversibility to short‐term beta2‐agonists and bronchial hyper‐responsiveness were not exclusion criteria. The a priori primary outcome was change in lung function. We also analysed data on mortality, exacerbations, quality of life and symptoms, rescue bronchodilator use, exercise capacity, biomarkers and safety.
Data collection and analysis
Two review authors independently assessed trial quality and extracted data. We contacted study authors for additional information. We collected adverse effects information from the trials.
Main results
Fifty‐five primary studies with 16,154 participants met the inclusion criteria. Long‐term use of ICS (more than six months) did not consistently reduce the rate of decline in forced expiratory volume in one second (FEV1) in COPD patients (generic inverse variance analysis: mean difference (MD) 5.80 mL/year with ICS over placebo, 95% confidence interval (CI) ‐0.28 to 11.88, 2333 participants; pooled means analysis: 6.88 mL/year, 95% CI 1.80 to 11.96, 4823 participants), although one major trial demonstrated a statistically significant difference. There was no statistically significant effect on mortality in COPD patients (odds ratio (OR) 0.98, 95% CI 0.83 to 1.16, 8390 participants). Long‐term use of ICS reduced the mean rate of exacerbations in those studies where pooling of data was possible (generic inverse variance analysis: MD ‐0.26 exacerbations per patient per year, 95% CI ‐0.37 to ‐0.14, 2586 participants; pooled means analysis: MD ‐0.19 exacerbations per patient per year, 95% CI ‐0.30 to ‐0.08, 2253 participants). ICS slowed the rate of decline in quality of life, as measured by the St George's Respiratory Questionnaire (MD ‐1.22 units/year, 95% CI ‐1.83 to ‐0.60, 2507 participants). Response to ICS was not predicted by oral steroid response, bronchodilator reversibility or bronchial hyper‐responsiveness in COPD patients. There was an increased risk of oropharyngeal candidiasis (OR 2.65, 95% CI 2.03 to 3.46, 5586 participants) and hoarseness. In the long‐term studies, the rate of pneumonia was increased in the ICS group compared to placebo, in studies that reported pneumonia as an adverse event (OR 1.56, 95% CI 1.30 to 1.86, 6235 participants). The long‐term studies that measured bone effects generally showed no major effect on fractures and bone mineral density over three years.
Authors' conclusions
Patients and clinicians should balance the potential benefits of inhaled steroids in COPD (reduced rate of exacerbations, reduced rate of decline in quality of life and possibly reduced rate of decline in FEV1) against the potential side effects (oropharyngeal candidiasis and hoarseness, and risk of pneumonia).
PDF
