Investigating the role of the eosinophil in COPD

Now the third leading cause of death worldwide, chronic obstructive pulmonary disease (COPD) is characterised by unpredictable acute worsening of symptoms. A third of these crisis events are associated with an eosinophilic phenotype that has an unknown mechanism of injury. In this thesis, I have shown that RNA-sequencing of eosinophils isolated during exacerbations revealed upregulation of genes related to redox systems. Furthermore, eosinophils isolated during crisis events had increased capacity to produce reactive oxygen species (ROS), had a higher resting state of ROS generation, and released more mitochondrial specific ROS compared to neutrophils. Eosinophils also had comparatively low levels of the antioxidant enzyme glutathione, which appeared to be less oxidised, indicating that eosinophils have a weak ability to scavenge excess ROS. Finally, in a co-culture system, eosinophils were shown to disrupt epithelial barriers and induce hyperpermeability, which was further increased upon eosinophil stimulation. These findings would suggest that when COPD patients experience an eosinophilic exacerbation and consequently, an influx of activated eosinophils into the airways, there is damage caused to the local tissue milieu due to the release of ROS. This mechanism proposes a new therapeutic avenue at the point of an eosinophilic exacerbation. Additionally, analysis of serum and sputum samples highlighted IL-5 as a key eosinophil mediator released during eosinophilic exacerbations. Flow cytometry analysis identified the IL-3 receptor as a potential marker of eosinophil activation status

Rapid and Accurate Pressure Sensing Device for Direct Measurement of Intraocular Pressure.

PurposeIntraocular pressure (IOP) is the primary modifiable risk factor for glaucoma. Current devices measure IOP via the dynamic response of the healthy cornea and do not provide the accurate IOP measurements for patients with altered corneal biomechanics. We seek to develop and test an accurate needle-based IOP measurement device that is not cornea dependent.MethodsOur device combines a high-resolution pressure microsensor with 30- and 33-gauge Luer lock needles to provide IOP measurements via a microcontroller and USB interface to a computer. The device was calibrated in a membrane chamber and then tested and validated in the anterior chamber and post-vitrectomy vitreous chamber of rabbit eyes. The results were compared to Tonopen readings across a pressure range of 0 to 100 mm Hg, imposed in increments of 10 mm Hg.ResultsBoth the needle based sensor device and the Tonopen demonstrated a linear relationship with changes in imposed pressure. The Tonopen was found to consistently underestimate the IOP both in the anterior and vitreous chambers. The Tonopen exhibited a significantly greater error than our needle-based sensor device. With increased pressure (>30 mm Hg), the error of the Tonopen increased, whereas the error of our device did not. The 30-gauge needle produces an insignificant improvement in accuracy over the 33-gauge needle.ConclusionsA needle-based sensor device enables accurate IOP measurements over a broad range of induced IOP.Translational relevanceDirect measurement of IOP in the anterior chamber circumvents the influence of corneal parameters on IOP measurement

Using Diversity Ensembles with Time Limits to Handle Concept Drift

While traditional supervised learning focuses on static datasets, an increasing amount of data comes in the form of streams, where data is continuous and typically processed only once. A common problem with data streams is that the underlying concept we are trying to learn can be constantly evolving. This concept drift has been of interest to researchers the last few years and there is a need for improved machine learning algorithms that are capable of dealing with concept drifts. A promising approach involves using an ensemble of a diverse set of classifiers. The constituent classifiers are re-trained when a concept drift is detected. Decisions regarding the number of classifiers to maintain and the frequency of re-training classifiers are critical factors that determine classification accuracy in the presence of concept drift. This dissertation systematically investigated these issues in order to develop an improved classifier for online ensemble learning. The impact of reducing the time requiring additional ensembles was studied using artificial and real world datasets. Findings from these studies revealed that in many cases the number of time steps additional ensembles are in memory can be reduced without sacrificing prequential accuracy. It was also found that this new ensemble approach performed well in the presence of false concept drift

Student Perceptions of the Professional Behavior of Faculty Physicians

This study was conducted to obtain a baseline understanding of the professional behavior of clinical faculty physicians from the medical students’ perspective. Students completed a professionalism evaluation of supervising faculty at the end of each required third-year clerkship over a one year period. Results were analyzed by specific behaviors and across clerkships. Differences were noted in the frequency of the types of problems seen, and varied by clerkship discipline. The most common transgressions of professional behavior reported were the use of derogatory language towards other services or patients and the disrespectful treatment of others. Our study served to provide objective feedback to the faculty about student perceptions of faculty as role models for professionalism while on clinical rotations

Segmentation quality evaluation for large scale mapping purposes in Flanders, Belgium

In Flanders the large scale reference database called GRB, takes care of the layout, exchange and management of large scale geographic information with respect to, amongst others, roads, buildings and parcels. As Flanders is extremely urbanized (average population density of about 450 inhabitants per square kilometer), the large scale maps need to be highly accurate. Currently, accuracies at the centimeter level are guaranteed due to topographic field measurements aided by standard photogrammetry based on analogue aerial photographs. In order to speed up the GRB production and to ensure large scale map products at the long term, it is essential to automate this labour-intensive, but highly accurate production process. Segmentation of very high resolution digital images could be an alternative approach for maintaining and updating the Flemish GRB as long as high accuracy segmentation results are obtained. Based on DMC images (8 cm ground resolution) and several reference buildings, a comprehensive sensitivity analysis is performed testing different segmentation parameter settings in order to gain insight into their impact on segmentation accuracy. The segmentation quality is evaluated using similarity measures focusing on aspects of presence, shape and positional accuracy where emphasis is placed on interpretability of the measures with respect to operational conditions put on the reference data. The end user should be able to read the measures and link this to the return-on-investment he will gain by using a given segmentation process on his data

Preliminary Characterization of Voltage-Activated Whole-Cell Currents in Developing Human Vestibular Hair Cells and Calyx Afferent Terminals

We present preliminary functional data from human vestibular hair cells and primary afferent calyx terminals during fetal development. Whole-cell recordings were obtained from hair cells or calyx terminals in semi-intact cristae prepared from human fetuses aged between 11 and 18 weeks gestation (WG). During early fetal development (11–14 WG), hair cells expressed whole-cell conductances that were qualitatively similar but quantitatively smaller than those observed previously in mature rodent type II hair cells. As development progressed (15–18 WG), peak outward conductances increased in putative type II hair cells but did not reach amplitudes observed in adult human hair cells. Type I hair cells express a specific low-voltage activating conductance, G(K,L). A similar current was first observed at 15 WG but remained relatively small, even at 18 WG. The presence of a “collapsing” tail current indicates a maturing type I hair cell phenotype and suggests the presence of a surrounding calyx afferent terminal. We were also able to record from calyx afferent terminals in 15–18 WG cristae. In voltage clamp, these terminals exhibited fast inactivating inward as well as slower outward conductances, and in current clamp, discharged a single action potential during depolarizing steps. Together, these data suggest the major functional characteristics of type I and type II hair cells and calyx terminals are present by 18 WG. Our study also describes a new preparation for the functional investigation of key events that occur during maturation of human vestibular organs

Reliability of histopathologic diagnosis of fibrotic interstitial lung disease: an international collaborative standardization project

Malaltia pulmonar intersticial; Fibrosi pulmonar; Pneumònia intersticial habitualEnfermedad pulmonar intersticial; Fibrosis pulmonar; Neumonía intersticial habitualInterstitial lung disease; Pulmonary fibrosis; Usual interstitial pneumoniaBackground Current interstitial lung disease (ILD) diagnostic guidelines assess criteria across clinical, radiologic and pathologic domains. Significant interobserver variation in histopathologic evaluation has previously been shown but the specific source of these discrepancies is poorly documented. We sought to document specific areas of difficulty and develop improved criteria that would reduce overall interobserver variation. Methods Using an internet-based approach, we reviewed selected images of specific diagnostic features of ILD histopathology and whole slide images of fibrotic ILD. After an initial round of review, we confirmed the presence of interobserver variation among our group. We then developed refined criteria and reviewed a second set of cases. Results The initial round reproduced the existing literature on interobserver variation in diagnosis of ILD. Cases which were pre-selected as inconsistent with usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF) were confirmed as such by multi-observer review. Cases which were thought to be in the spectrum of chronic fibrotic ILD for which UIP/IPF were in the differential showed marked variation in nearly all aspects of ILD evaluation including extent of inflammation and extent and pattern of fibrosis. A proposed set of more explicit criteria had only modest effects on this outcome. While we were only modestly successful in reducing interobserver variation, we did identify specific reasons that current histopathologic criteria of fibrotic ILD are not well defined in practice. Conclusions Any additional classification scheme must address interobserver variation in histopathologic diagnosis of fibrotic ILD order to remain clinically relevant. Improvements to tissue-based diagnostics may require substantial resources such as larger datasets or novel technologies to improve reproducibility. Benchmarks should be established for expected outcomes among clinically defined subgroups as a quality metric.This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors