Otitis media (OM) is amongst the most common childhood diseases and is associated with multiple microbial pathogens within the middle ear. Global and temporal monitoring of predominant bacterial ...pathogens is important to inform new treatment strategies, vaccine development and to monitor the impact of vaccine implementation to improve progress toward global OM prevention.
A systematic review of published reports of microbiology of acute otitis media (AOM) and otitis media with effusion (OME) from January, 1970 to August 2014, was performed using PubMed databases.
This review confirmed that Streptococcus pneumoniae and Haemophilus influenzae, remain the predominant bacterial pathogens, with S. pneumoniae the predominant bacterium in the majority reports from AOM patients. In contrast, H. influenzae was the predominant bacterium for patients experiencing chronic OME, recurrent AOM and AOM with treatment failure. This result was consistent, even where improved detection sensitivity from the use of polymerase chain reaction (PCR) rather than bacterial culture was conducted. On average, PCR analyses increased the frequency of detection of S. pneumoniae and H. influenzae 3.2 fold compared to culture, whilst Moraxella catarrhalis was 4.5 times more frequently identified by PCR. Molecular methods can also improve monitoring of regional changes in the serotypes and identification frequency of S. pneumoniae and H. influenzae over time or after vaccine implementation, such as after introduction of the 7-valent pneumococcal conjugate vaccine.
Globally, S. pneumoniae and H. influenzae remain the predominant otopathogens associated with OM as identified through bacterial culture; however, molecular methods continue to improve the frequency and accuracy of detection of individual serotypes. Ongoing monitoring with appropriate detection methods for OM pathogens can support development of improved vaccines to provide protection from the complex combination of otopathogens within the middle ear, ultimately aiming to reduce the risk of chronic and recurrent OM in vulnerable populations.
Neurotrophins and their receptors modulate multiple signalling pathways to regulate neuronal survival and to maintain axonal and dendritic networks and synaptic plasticity. Neurotrophins have ...potential for the treatment of neurological diseases. However, their therapeutic application has been limited owing to their poor plasma stability, restricted nervous system penetration and, importantly, the pleiotropic actions that derive from their concomitant binding to multiple receptors. One strategy to overcome these limitations is to target individual neurotrophin receptors — such as tropomyosin receptor kinase A (TRKA), TRKB, TRKC, the p75 neurotrophin receptor or sortilin — with small-molecule ligands. Such small molecules might also modulate various aspects of these signalling pathways in ways that are distinct from the programmes triggered by native neurotrophins. By departing from conventional neurotrophin signalling, these ligands might provide novel therapeutic options for a broad range of neurological indications.
Abstract
Objective
to examine the associations of cardiovascular disease (CVD) and cardiovascular risk factors with frailty.
Design
a cross-sectional study.
Setting
the Irish Longitudinal Study on ...Ageing (TILDA).
Participants
frailty measures were obtained on 5,618 participants and a subset of 4,330 participants with no prior history of CVD.
Exposures for observational study
cardiovascular risk factors were combined in three composite CVD risk scores (Systematic Coronary Risk Evaluation SCORE, Ideal Cardiovascular Health ICH and Cardiovascular Health Metrics CHM).
Main outcome measures
a frailty index (40-items) was used to screen for frailty.
Methods
the associations of CVD risk factors with frailty were examined using logistic regression.
Results
overall, 16.4% of participants had frailty (7.6% at 50–59 years to 42.5% at 80+ years), and the prevalence was higher in those with versus those without prior CVD (43.0% vs. 10.7%). Among those without prior CVD, mean levels of CVD risk factors were closely correlated with higher frailty index scores. Combined CVD risk factors, assessed using SCORE, were linearly and positively associated with frailty. Compared to low-to-moderate SCOREs, the odds ratio (OR) (95% confidence interval, CI) of frailty for those with very high risk was 3.18 (2.38–4.25). Conversely, ICH was linearly and inversely associated with frailty, with an OR for optimal health of 0.29 (0.21–0.40) compared with inadequate health.
Conclusions
the concordant positive associations of SCORE and inverse associations of ICH and CHM with frailty highlight the potential importance of optimum levels of CVD risk factors for prevention of disability in frail older people.
Brain-derived neurotrophic factor (BDNF) activates the receptor tropomyosin-related kinase B (TrkB) with high potency and specificity, promoting neuronal survival, differentiation, and synaptic ...function. Correlations between altered BDNF expression and/or function and mechanism(s) underlying numerous neurodegenerative conditions, including Alzheimer disease and traumatic brain injury, suggest that TrkB agonists might have therapeutic potential. Using in silico screening with a BDNF loop-domain pharmacophore, followed by low-throughput in vitro screening in mouse fetal hippocampal neurons, we have efficiently identified small molecules with nanomolar neurotrophic activity specific to TrkB versus other Trk family members. Neurotrophic activity was dependent on TrkB and its downstream targets, although compound-induced signaling activation kinetics differed from those triggered by BDNF. A selected prototype compound demonstrated binding specificity to the extracellular domain of TrkB. In in vitro models of neurodegenerative disease, it prevented neuronal degeneration with efficacy equal to that of BDNF, and when administered in vivo, it caused hippocampal and striatal TrkB activation in mice and improved motor learning after traumatic brain injury in rats. These studies demonstrate the utility of loop modeling in drug discovery and reveal what we believe to be the first reported small molecules derived from a targeted BDNF domain that specifically activate TrkB.We propose that these compounds constitute a novel group of tools for the study of TrkB signaling and may provide leads for developing new therapeutic agents for neurodegenerative diseases.
The innate inflammatory response contributes to secondary injury in brain trauma and other disorders. Metabolic factors such as caloric restriction, ketogenic diet, and hyperglycemia influence the ...inflammatory response, but how this occurs is unclear. Here, we show that glucose metabolism regulates pro-inflammatory NF-κB transcriptional activity through effects on the cytosolic NADH:NAD
ratio and the NAD(H) sensitive transcriptional co-repressor CtBP. Reduced glucose availability reduces the NADH:NAD
ratio, NF-κB transcriptional activity, and pro-inflammatory gene expression in macrophages and microglia. These effects are inhibited by forced elevation of NADH, reduced expression of CtBP, or transfection with an NAD(H) insensitive CtBP, and are replicated by a synthetic peptide that inhibits CtBP dimerization. Changes in the NADH:NAD
ratio regulate CtBP binding to the acetyltransferase p300, and regulate binding of p300 and the transcription factor NF-κB to pro-inflammatory gene promoters. These findings identify a mechanism by which alterations in cellular glucose metabolism can influence cellular inflammatory responses.Several metabolic factors affect cellular glucose metabolism as well as the innate inflammatory response. Here, the authors show that glucose metabolism regulates pro-inflammatory responses through effects on the cytosolic NADH:NAD+ ratio and the NAD(H)-sensitive transcription co-repressor CtBP.
Little is known about the within-person variability of different frailty instruments, their agreement over time, and whether use of repeat assessments could improve the strength of associations with ...adverse health outcomes. Repeat measurements recorded in 2010-2011 (Wave 1) and 2012 (Wave 2) from The Irish Longitudinal Study on Ageing (TILDA) were used to classify individuals with frailty using the frailty phenotype (FP) and frailty index (FI). Within-person variability and agreement of frailty classifications were assessed using ANOVA and kappa (K) statistics, respectively. Associations of each frailty measure (wave 1, wave 2, or mean of both waves) with risk of falls, hospitalisations and all-cause mortality were assessed using logistic regression. Among 7455 individuals (mean age 64.7 SD 9.9 years), within-person SD was 0.664 units (95% CI 0.654-0.671) for FP and 2 health deficits (SD 0.050 0.048-0.051) for FI. Agreement of frailty was modest for both measures, but higher for FI (K 0.600 0.584-0.615) than FP (K 0.370 0.348-0.401). The odds ratios (ORs) for all-cause mortality were higher for frailty assessed using the mean of two versus single measurements for FI (ORs for mortality 3.5 2.6-4.9 vs. 2.7 1.9-3.4, respectively) and FP (ORs for mortality 6.9 4.6-10.3 vs. 4.0 2.8-5.635, respectively). Frailty scores based on single measurements had substantial within-person variability, but the agreement in classification of frailty was higher for FI than FP. Frailty assessed using the mean of two or more measurements recorded at separate visits was more strongly associated with adverse health outcomes than those recorded at a single visit.
The Lieutenant of Koutais the first novel in Massa Makan Diabaté's award-winning trilogy. Featuring an introduction by leading Diabaté scholar Cheick M. Chérif Keïta and Shane Auerbach, it tells the ...story, part tragicomic and part hagiographic, of an African lieutenant in the French Army who returns as a decorated hero from the battlefields of Europe to Kouta, a fictionalized version of the author's own birthplace, the Malian town of Kita. Upon his return, Siriman Keita finds it difficult to adjust to village life as he navigates traditional customs in his attempts to create his place in the predominantly Muslim Kouta. The novel offers a rich and nuanced representation of Mali on the brink of independence; it is a tapestry of traditional Mandinka society and the French colonial apparatus, illustrating the dynamic interplay between the two. This text is, ultimately, a story of one man's transformation coinciding with that of his country.
The paper presents an extensive review of topographic effects in seismology taking into account the knowledge of 40 yr of scientific literature. An overview of topographic effects based on ...experimental observations and numerical modelling is presented with the aim of highlighting meaning and causes of these phenomena as well as possible correlations between site response (fundamental frequency, amplification level) and geometrical (width and shape ratio of a relief) parameters. After a thorough summary of topographic effects, the paper focuses on five Italian sites whose seismic response is potentially affected by local morphology, as already evidenced by previous studies. In this study, seismic data recorded at these sites are analysed computing directional spectral ratios both in terms of horizontal to vertical spectral ratios (HVSRs) and, wherever possible, in terms of standard spectral ratios (SSRs). The analysis lead to the conclusion that wavefield tends to be polarized along a direction perpendicular to the main axis of a topographic irregularity, direction along which ground motion amplification is maximum. The final section of the article compares and contrasts different spectral ratio techniques in order to examine their effectiveness and reliability in detecting topographic effects. The examples discussed in the paper show that site responses based on HVSRs rather than SSR measurements could lead to misinterpretation of ground response results, both as concerns the definition of the site fundamental frequency and amplification level.
Results and findings of this work will be used as starting point to discuss the influence of topographic effects on ground motion prediction equations and regulations for design. These topics will be discussed in the companion article.
Gene set analysis using biological pathways has become a widely used statistical approach for gene expression analysis. A biological pathway can be represented through a graph where genes and their ...interactions are, respectively, nodes and edges of the graph. From a biological point of view only some portions of a pathway are expected to be altered; however, few methods using pathway topology have been proposed and none of them tries to identify the signal paths, within a pathway, mostly involved in the biological problem. Here, we present a novel algorithm for pathway analysis clipper, that tries to fill in this gap. clipper implements a two-step empirical approach based on the exploitation of graph decomposition into a junction tree to reconstruct the most relevant signal path. In the first step clipper selects significant pathways according to statistical tests on the means and the concentration matrices of the graphs derived from pathway topologies. Then, it identifies within these pathways the signal paths having the greatest association with a specific phenotype. We test our approach on simulated and two real expression datasets. Our results demonstrate the efficacy of clipper in the identification of signal transduction paths totally coherent with the biological problem.
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