Structural and cellular characterization of Idiopathic Pulmonary Fibrosis

La Fibrosi Polmonare Idiopatica (IPF) è una malattia polmonare cronica, irreversibile la cui eziologia risulta essere ignota, caratterizzata da un processo fibrotico progressivo che inizia nel tratto respiratorio inferiore. Le persone affette da IPF presentano età media compresa tra 55 e 77 anni. L’incidenza annuale di IPF è stata recentemente stimata tra 14 e 42,7 casi per 100.000 persone e tale dato risulta essere in aumento. IPF fa parte delle malattie Polmonari Idiopatiche Interstiziali (IIP) che comprendono patologie con quadri istologici e clinici differenti. Le affezioni su cui si concentrerà questo studio sono: UIP (Usual Interstitial Pneumonia) caratterizzata da fibrosi interstiziale e dalla presenza di foci fibrotici connessi alla pleura e corrispondente al quadro anatomopatologico della maggior parte dei casi di IPF; NSIP (Non Specific Interstitial Pneumonia) simile alla UIP ma con maggiore uniformità temporale e spaziale delle manifestazioni; Sarcoidosi, malattia granulomatosa ad eziologia ignota. Attualmente la gravità della IPF, che implica una mortalità del 50% dei pazienti a 5 anni dall’esordio, e la scarsa efficacia farmacologica nel rallentarne la progressione vedono il trapianto polmonare come unica possibilità di sopravvivenza nelle forme più severe. Al momento non è chiaro il meccanismo patogenetico di insorgenza e progressione della IPF anche se sono stati individuati alcuni fattori scatenanti quali fumo di sigaretta, infezioni respiratorie e inquinanti atmosferici; tuttavia nessuno di tali elementi può da solo determinare un così esteso e progressivo rimodellamento del parenchima polmonare. Numerose sono le evidenze di come il substrato genetico, le alterazioni del rapporto morte/proliferazione cellulare e le citochine svolgano un ruolo nella genesi e nella progressione della malattia, ma non sono ancora chiari i fenomeni biologico-cellulari che la sostengono e, quindi, quali siano i punti di attacco per poter incidere terapeuticamente nel modificare l’evoluzione della IPF. Poiché il nostro laboratorio ha partecipato alla scoperta dell’esistenza di cellule staminali nel polmone umano normale, uno degli obiettivi finali di questo progetto si basa sull’ipotesi che un’alterazione del compartimento staminale svolga un ruolo cruciale nella eziopatogenesi di IPF. Per questo in precedenti esperienze abbiamo cercato di identificare nella IPF cellule che esprimessero antigeni associati a staminalità quali c-kit, CD34 e CD133. Questo lavoro di tesi si è proposto di condurre un’indagine morfometrica ed immunoistochimica su biopsie polmonari provenienti da 9 pazienti affetti da UIP, 3 da NSIP e 5 da Sarcoidosi al fine di valutare le alterazioni strutturali principali imputabili alle patologie. Preparati istologici di 8 polmoni di controllo sono stati usati come confronto. Come atteso, è stato osservato nelle tre patologie esaminate (UIP, NSIP e Sarcoidosi) un significativo incremento nella sostituzione del parenchima polmonare con tessuto fibrotico ed un ispessimento dei setti alveolari rispetto ai campioni di controllo. L’analisi dei diversi pattern di fibrosi presenti fa emergere come vi sia una netta differenza tra le patologie con una maggiore presenza di fibrosi di tipo riparativo e quindi altamente cellulata nei casi di UIP, e NSIP mentre nelle Sarcoidosi il pattern maggiormente rappresentato è risultato essere quello della fibrosi replacement o sostitutiva. La quantificazione delle strutture vascolari è stata effettuata tenendo separate le aree di polmone alveolare rispetto a quelle occupate da focolai sostitutivi di danno (componente fibrotica). Nei campioni patologici analizzati era presente un significativo riarrangiamento di capillari, arteriole e venule rispetto al polmone di controllo, fenomeno principalmente riscontrato nel parenchima fibrotico. Tali modifiche erano maggiormente presenti nei casi di NSIP da noi analizzati. Inoltre le arteriole subivano una diminuzione di calibro ed un aumento dello spessore in special modo nei polmoni ottenuti da pazienti affetti da Sarcoidosi. Rispetto ai controlli, nella UIP e nella Sarcoidosi i vasi linfatici risultavano inalterati nell’area alveolare mentre aumentavano nelle aree di estesa fibrosi; quadro differente si osservava nella NSIP dove le strutture linfatiche aumentavano in entrambe le componenti strutturali. Mediante indagini immunoistochimiche è stata documentata la presenza e distribuzione dei miofibroblasti, positivi per actina muscolare liscia e vimentina, che rappresentano un importante componente del danno tissutale nella IPF. La quantificazione di questo particolare fenotipo è attualmente in corso. Abbiamo inoltre analizzato tramite immunoistochimica la componente immunitaria presente nei campioni polmonari attraverso la documentazione dei linfociti T totali che esprimono CD3, andando poi a identificare la sottopopolazione di T citotossici esprimenti la glicoproteina CD8. La popolazione linfocitaria CD3pos risultava notevolmente aumentata nelle tre patologie analizzate soprattutto nei casi di UIP e Sarcoidosi sebbene l`analisi della loro distribuzione tra i vari distretti tissutali risultasse differente. Risultati simili si sono ottenuti per l`analisi dei linfociti CD8pos. La componente monocito-macrofagica è stata invece identificata tramite la glicoproteina CD68 che ha messo in evidenza una maggiore presenza di cellule positive nella Sarcoidosi e nella UIP rispetto ai casi di NSIP. I dati preliminari di questo studio indicano che il rimodellamento strutturale emo-linfatico e cellulare infiammatorio nella UIP si differenziano rispetto alle altre malattie interstiziali del polmone, avanzando l’ipotesi che il microambiente vascolare ed immunitario giochino un ruolo importante nella patogenesi della malattia

Myopia: structural and functional correlates

Ocular dimensions are widely recognised as key variants of refractive error. Previously, accurate depiction of eye shape in vivo was largely restricted by limitations in the imaging techniques available. This thesis describes unique applications of the recently introduced 3-dimensional magnetic resonance imaging (MRI) approach to evaluate human eye shape in a group of young adult subjects (n=76) with a range of ametropia (MSE= -19.76 to +4.38D). Specific MRI derived parameters of ocular shape are then correlated with measures of visual function. Key findings include the significant homogeneity of ocular volume in the anterior eye for a range of refractive errors, whilst significant volume changes occur in the posterior eye as a function of ametropia. Anterior vs. posterior eye differences have also been shown through evaluations of equivalent spherical radius; the posterior 25% cap of the eye was shown to be relatively steeper in myopes compared to emmetropes. Further analyses showed differences in retinal quadrant profiles; assessments of the maximum distance from the retinal surface to the presumed visual axes showed exaggerated growth of the temporal quadrant in myopic eyes. Comparisons of retinal contour values derived from transformation of peripheral refraction data were made with MRI; flatter retinal curvature values were noted when using the MRI technique. A distinctive feature of this work is the evaluation of the relationship between ocular structure and visual function. Multiple aspects of visual function were evaluated through several vehicles: multifocal electroretinogram testing, visual field sensitivity testing, and the use of psychophysical methods to determine ganglion cell density. The results show that many quadrantic structural and functional variations exist. In general, the data could not demonstrate a significant correlation between visual function and associated measures of ocular conformation either within or between myopic and emmetropic groups.

Lubrication efficiency and die design in wire drawing

With the competitive challenge facing business today, the need to keep cost down and quality up is a matter of survival. One way in which wire manufacturers can meet this challenge is to possess a thorough understanding of deformation, friction and lubrication during the wire drawing process, and therefore to make good decisions regarding the selection and application of lubricants as well as the die design. Friction, lubrication and die design during wire drawing thus become the subject of this study. Although theoretical and experimental investigations have been being carried out ever since the establishment of wire drawing technology, many problems remain unsolved. It is therefore necessary to conduct further research on traditional and fundamental subjects such as the mechanics of deformation, friction, lubrication and die design in wire drawing. Drawing experiments were carried out on an existing bull-block under different cross-sectional area reductions, different speeds and different lubricants. The instrumentation to measure drawing load and drawing speed was set up and connected to the wire drawing machine, together with a data acquisition system. A die box connected to the existing die holder for using dry soap lubricant was designed and tested. The experimental results in terms of drawing stress vs percentage area reduction curves under different drawing conditions were analysed and compared. The effects on drawing stress of friction, lubrication, drawing speed and pressure die nozzle are discussed. In order to determine the flow stress of the material during deformation, tensile tests were performed on an Instron universal test machine, using the wires drawn under different area reductions. A polynomial function is used to correlate the flow stress of the material with the plastic strain, on which a general computer program has been written to find out the coefficients of the stress-strain function. The residual lubricant film on the steel wire after drawing was examined both radially and longitudinally using an SEM and optical microscope. The lubricant film on the drawn wire was clearly observed. Therefore, the micro-analysis by SEM provides a way of friction and lubrication assessment in wire drawing.

The structural and electrochemical consequences of hydrogenating Copper N2S2 Schiff base macrocycles

A series of cis and trans tetradentate copper macrocyclic complexes, of ring size fourteen - sixteen, which employ amine and thioether donor groups are reported. Apart from 5,6,15,16-bisbenzo-8,13-diaza-1,4-dithia-cyclohexadecane copper(I) (cis-[Cu(H4NbuSen)]+) all of the complexes are obtained in the copper(II) form. Crystallographic analysis shows that the copper(II) complexes all adopt a distorted planar geometry around the copper. In contrast, cis-[Cu(H4NbuSen)]+ is found to adopt a distorted tetrahedral geometry. The complexes were subjected to electrochemical analysis in water and acetonitrile. The effect of the solvent, positions of the donor atoms (cis/trans) on E1/2 is discussed as is the comparison of the electrochemical behaviour of these complexes with their parent Schiff base macrocycles.

Impact of senescence and disease on the structural and functional performance of the visual pathway

The diagnosis and monitoring of ocular disease presents considerable clinical difficulties for two main reasons i) the substantial physiological variation of anatomical structure of the visual pathway and ii) constraints due to technical limitations of diagnostic hardware. These are further confounded by difficulties in detecting early loss or change in visual function due to the masking of disease effects, for example, due to a high degree of redundancy in terms of nerve fibre number along the visual pathway. This thesis addresses these issues across three areas of study: 1. Factors influencing retinal thickness measures and their clinical interpretation As the retina is the principal anatomical site for damage associated with visual loss, objective measures of retinal thickness and retinal nerve fibre layer thickness are key to the detection of pathology. In this thesis the ability of optical coherence tomography (OCT) to provide repeatable and reproducible measures of retinal structure at the macula and optic nerve head is investigated. In addition, the normal physiological variations in retinal thickness and retinal nerve fibre layer thickness are explored. Principal findings were: • Macular retinal thickness and optic nerve head measurements are repeatable and reproducible for normal subjects and diseased eyes • Macular and retinal nerve fibre layer thickness around the optic nerve correlate negatively with axial length, suggesting that larger eyes have thinner retinae, potentially making them more susceptible to damage or disease • Foveola retinal thickness increases with age while retinal nerve fibre layer thickness around the optic nerve head decreases with age. Such findings should be considered during examination of the eye with suspect pathology or in long-term disease monitoring 2. Impact of glucose control on retinal anatomy and function in diabetes Diabetes is a major health concern in the UK and worldwide and diabetic retinopathy is a major cause of blindness in the working population. Objective, quantitative measurements of retinal thickness. particularly at the macula provide essential information regarding disease progression and the efficacy of treatment. Functional vision loss in diabetic patients is commonly observed in clinical and experimental studies and is thought to be affected by blood glucose levels. In the first study of its kind, the short term impact of fluctuations in blood glucose levels on retinal structure and function over a 12 hour period in patients with diabetes are investigated. Principal findings were: • Acute fluctuations in blood glucose levels are greater in diabetic patients than normal subjects • The fluctuations in blood glucose levels impact contrast sensitivity scores. SWAP visual fields, intraocular pressure and diastolic pressure. This effect is similar for type 1 and type 2 diabetic patients despite the differences in their physiological status. • Long-term metabolic control in the diabetic patient is a useful predictor in the fluctuation of contrast sensitivity scores. • Large fluctuations in blood glucose levels and/or visual function and structure may be indicative of an increased risk of development or progression of retinopathy 3. Structural and functional damage of the visual pathway in glaucomatous optic neuropathy The glaucomatous eye undergoes a number of well documented pathological changes including retinal nerve fibre loss and optic nerve head damage which is correlated with loss of functional vision. In experimental glaucoma there is evidence that glaucomatous damage extends from retinal ganglion cells in the eye, along the visual pathway, to vision centres in the brain. This thesis explores the effects of glaucoma on retinal nerve fibre layer thickness, ocular anterior anatomy and cortical structure, and its correlates with visual function in humans. Principal findings were: • In the retina, glaucomatous retinal nerve fibre layer loss is less marked with increasing distance from the optic nerve head, suggesting that RNFL examination at a greater distance than traditionally employed may provide invaluable early indicators of glaucomatous damage • Neuroretinal rim area and retrobulbar optic nerve diameter are strong indicators of visual field loss • Grey matter density decreases at a rate of 3.85% per decade. There was no clear evidence of a disease effect • Cortical activation as measured by fMRI was a strong indicator of functional damage in patients with significant neuroretinal rim loss despite relatively modest visual field defects These investigations have shown that the effects of senescence are evident in both the anterior and posterior visual pathway. A variety of anatomical and functional diagnostic protocols for the investigation of damage to the visual pathway in ocular disease are required to maximise understanding of the disease processes and thereby optimising patient care.

Multiterminal DC wind farm collection grid internal fault analysis and protection design

The multiterminal dc wind farm is a promising topology with a voltage-source inverter (VSI) connection at the onshore grid. Voltage-source converters (VSCs) are robust to ac-side fault conditions. However, they are vulnerable to dc faults on the dc side of the converter. This paper analyzes dc faults, their transients, and the resulting protection issues. Overcurrent faults are analyzed in detail and provide an insight into protection system design. The radial wind farm topology with star or string connection is considered. The outcomes may be applicable for VSCs in the multi-VSC dc wind farm collection grid and VSC-based high-voltage direct current (HVDC) offshore transmission systems.

Engineering the future! Inspiring student engagement through innovative course and programme design:an empirical approach

An analysis of a bespoke learning and teaching approach developed for use in engineering education

Agent-orientated auction mechanism and strategy design

Agent-based technology is playing an increasingly important role in today’s economy. Usually a multi-agent system is needed to model an economic system such as a market system, in which heterogeneous trading agents interact with each other autonomously. Two questions often need to be answered regarding such systems: 1) How to design an interacting mechanism that facilitates efficient resource allocation among usually self-interested trading agents? 2) How to design an effective strategy in some specific market mechanisms for an agent to maximise its economic returns? For automated market systems, auction is the most popular mechanism to solve resource allocation problems among their participants. However, auction comes in hundreds of different formats, in which some are better than others in terms of not only the allocative efficiency but also other properties e.g., whether it generates high revenue for the auctioneer, whether it induces stable behaviour of the bidders. In addition, different strategies result in very different performance under the same auction rules. With this background, we are inevitably intrigued to investigate auction mechanism and strategy designs for agent-based economics. The international Trading Agent Competition (TAC) Ad Auction (AA) competition provides a very useful platform to develop and test agent strategies in Generalised Second Price auction (GSP). AstonTAC, the runner-up of TAC AA 2009, is a successful advertiser agent designed for GSP-based keyword auction. In particular, AstonTAC generates adaptive bid prices according to the Market-based Value Per Click and selects a set of keyword queries with highest expected profit to bid on to maximise its expected profit under the limit of conversion capacity. Through evaluation experiments, we show that AstonTAC performs well and stably not only in the competition but also across a broad range of environments. The TAC CAT tournament provides an environment for investigating the optimal design of mechanisms for double auction markets. AstonCAT-Plus is the post-tournament version of the specialist developed for CAT 2010. In our experiments, AstonCAT-Plus not only outperforms most specialist agents designed by other institutions but also achieves high allocative efficiencies, transaction success rates and average trader profits. Moreover, we reveal some insights of the CAT: 1) successful markets should maintain a stable and high market share of intra-marginal traders; 2) a specialist’s performance is dependent on the distribution of trading strategies. However, typical double auction models assume trading agents have a fixed trading direction of either buy or sell. With this limitation they cannot directly reflect the fact that traders in financial markets (the most popular application of double auction) decide their trading directions dynamically. To address this issue, we introduce the Bi-directional Double Auction (BDA) market which is populated by two-way traders. Experiments are conducted under both dynamic and static settings of the continuous BDA market. We find that the allocative efficiency of a continuous BDA market mainly comes from rational selection of trading directions. Furthermore, we introduce a high-performance Kernel trading strategy in the BDA market which uses kernel probability density estimator built on historical transaction data to decide optimal order prices. Kernel trading strategy outperforms some popular intelligent double auction trading strategies including ZIP, GD and RE in the continuous BDA market by making the highest profit in static games and obtaining the best wealth in dynamic games.

Advanced manufacturing technology and work design:towards a theoretical framework

This paper introduces a theoretical framework to guide research into the psychological effects of advanced manufacturing technology (AMT) on shopfloor operators. The framework has two main aspects. First, based on the emerging literature on the job content implications of AMT, it identifies four key constructs, namely: control, cognitive demand, production responsibility and social interaction. Second, by drawing on the more established job design, stress and related literatures, it predicts how these independent variables differentially affect system performance, job-related strain and job satisfaction. The wider implications and limitations of the theoretical framework are discussed.