1,721,061 research outputs found
Epithelial-biofilm interaction in primary ciliary dyskinesia
No full textPrimary ciliary dyskinesia (PCD) is an inherited disorder of motile cilia that affects around 1 in
15,000 live births and its defining feature is a lack of mucociliary clearance. This results in
progressive lung disease, upper airway symptoms and, potentially, situs inversus and infertility.
PCD is characterised by early colonisation of the lower airways with bacteria, resulting in
progressive lung function decline. Non-typeable Haemophilus influenzae (NTHi) is the
commonest of these colonising bacteria in children and is also cultured in many other lung
conditions such as cystic fibrosis, chronic obstructive pulmonary disease and bronchiectasis.
NTHi forms biofilms on airway epithelium; a phenotype associated with increased tolerance to
antibiotic treatment and resistance to host immunity.
This work hypothesised that, in addition to lack of mucociliary clearance, the PCD airway has
intrinsically dysregulated responses to colonising bacteria. This may be, in part, due to
extremely low airway nitric oxide (NO). Thus, exogenous NO may represent a potential
therapeutic adjunct in the treatment of lower airway infection. Systematic review and metaanalysis
were used to define NO levels in PCD airway and healthy/disease controls. Then an
established model of a 72h NTHi biofilm in vitro and on cultured primary respiratory
epithelium was employed. NO treatment of these biofilms was investigated using a targeted
NO compound (PYRRO-C3D) with the NO-treated NTHi in vitro biofilms subjected to label-free
proteomic analyses to identify mechanisms underlying these treatment effects. Label-free
proteomic analysis was also employed to identify differences in healthy and PCD epithelial
proteome following exposure to 72h NTHi biofilm, as well as identifying NTHi proteins present.
Systematic review and meta-analysis showed that PCD patients had extremely low nasal NO
(mean 19.4nl/min) compared to healthy (265nl/min) and CF patients (123.2nl/min). This was
independent of genotype or ultrastructural defect, thus there was a common epithelial defect
across almost all PCD patients. PYRRO-C3D was effective in enhancing antibiotic treatment of
NTHi biofilms in vitro and on cultured respiratory epithelium (p<0.05). This effect was more
pronounced on PCD epithelium (2 log fold CFU drop) than healthy (1 log fold). Inhibition of NO
release and scavenging of NO showed the effect to be NO mediated. Proteomic analysis
revealed NO-induced upregulation of metabolic pathways and translational machinery, as well
as a D-methionine uptake lipoprotein and iron metabolism. However, methionine isomers
reversed the antibiotic enhancing effect of PYRRO-C3D. Pathway analysis of proteomic data
from the co-culture model demonstrated that healthy epithelium responds to NTHi
colonisation by cytoskeletal remodelling, metabolic upregulation and initial hyper-proliferation
as well as suppression of acute inflammation via downregulation of S100 proteins. PCD
epithelium appears to show a lesser degree of hyper-proliferation and fails to downregulate
pro-inflammatory S100 proteins to the same extent. NTHi proteins were also identified in the
analysis, with 14 present in both the co-culture samples and in vitro work, suggesting they
warrant further investigation. OMPp5 (a HSP70 protein) is of particular interest as a potential
biomarker or vaccine target.
In conclusion, almost all PCD patients have extremely low airway NO regardless of underlying
genotype, suggesting a common epithelial dysfunction. PCD epithelium may not respond
adequately to NTHi colonisation as there is a failure of both normal proliferation and
inflammatory suppression through downregulation of S100 proteins. Changes in intracellular
calcium flux is a potential common mechanism behind failure of ciliary beat, low nitric oxide
and S100/innate immune dysfunction. NO can also be successfully used as a targeted
therapeutic adjunct in NTHi biofilms and may be particularly effective in PCD due to the
constitutively low NO during colonisation. NO induces metabolic and translational changes in
NTHi that make it more sensitive to treatment with macrolides and, potentially, other
translation-targeting antibiotics. Proteins such as OMPp5 are common to in vitro and ex vivo
biofilm models, suggesting the validity of in vitro models and showing promise as potential
biomarkers of significant NTHi colonisation or targets of vaccines
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Nasal nitric oxide screening for primary ciliary dyskinesia: systematic review and meta-analysis
No full textNasal nitric oxide (nNO) concentrations are low in patients with primary ciliary dyskinesia (PCD) providing a noninvasive screening test. We conducted a systematic review of the literature to examine the utility of nNO in screening for PCD, in particular 1) different respiratory manoeuvres during sampling (velum closure, tidal breathing, etc.), 2) accuracy in screening young/uncooperative children, 3) stationary versus portable analysers, and 4) nNO in "atypical" PCD. 96 papers were assessed according to modified PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria and 22 were included in this review. Meta-analysis of 11 studies comparing nNO during a velum closure breath hold gave a mean±sd nNO of 19.4±18.6 nL·min(-1) in PCD (n = 478) and 265.0±118.9 nL·min(-1) in healthy controls (n = 338). Weighted mean difference for PCD versus healthy controls was 231.1 nL·min(-1) (95% CI 193.3-268.9; n = 338) and 114.1 nL·min(-1) (95% CI 101.5-126.8; n = 415) for PCD versus cystic fibrosis. Five studies of nNO measurement during tidal breathing demonstrated that this is an acceptable manoeuvre in young children where velum closure is not possible, but the discriminatory value was reduced. Four small studies of portable NO analysers suggest these are reliable tools for screening for PCD. However, nNO must be interpreted alongside clinical suspicion. Future studies should focus on standardising sampling techniques and reporting
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Genetic testing in the diagnosis of primary ciliary dyskinesia: state-of-the-art and future perspectives
No full textPrimary ciliary dyskinesia (PCD) is a heterogeneous autosomal recessive condition affecting around 1:15,000. In people with PCD, microscopic motile cilia do not move normally resulting in impaired clearance of mucus and debris leading to repeated sinopulmonary infection. If diagnosis is delayed, permanent bronchiectasis and deterioration of lung function occurs. Other complications associated with PCD include congenital heart disease, hearing impairment and infertility. A small number of longitudinal studies suggest that lung function deteriorates before diagnosis of PCD but may stabilise following diagnosis with subsequent specialist management. Early diagnosis is therefore essential, but for a number of reasons referral for diagnostic testing is often delayed until older childhood or even adulthood. Functional diagnostic tests for PCD are expensive, time consuming and require specialist equipment and scientists. In the last few years, there have been considerable developments to identify genes associated with PCD, currently enabling 65% of patients to be identified by bi-allelic mutations. The rapid identification of new genes continues. This review will consider the evidence that early diagnosis of PCD is beneficial. It will review the recent advances in identification of PCD-associated genes and will discuss the role of genetic testing in PCD. It will then consider whether screening for PCD antenatally or in the new born is likely to become a feasible and acceptable for this rare disease
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
- …
