Measuring function and mobility among clients with diabetes in Samoa

The aim of the thesis was to collect baseline data and to investigating suitable physical tests and a self-rapport questionnaire. Collected data was used to find a routine measurement when investigating foot health, function and mobility among clients suffering from diabetes in Samoa. Twenty-one participants suffering from diabetes were included in the study. Clients answered the Foot function index (FFI) questionnaire and performed physical tests, consisting of Bergs balance scale (BBS) and Time up and go (TUG). Results from the physical tests revealed a great balance disturbance and mobility limitations among the majority of the clients. General high weight and BMI was measured among both genders. Subjects with the highest BMI performed lowest time during TUG test. The statistic analyze revealed a strong correlation between the two physical tests, indicating that one of the tests could be applied as a routine measurement in the future, when evaluating function and mobility in Samoa. The compilation of self-report questionnaires indicated a general good foot health with a low amount of pain, disabilities and activity limitations.

The urokinase plasminogen activating system in thyroid cancer: clinical implications

The urokinase plasminogen activator (uPA) system (uPAS) comprises the uPA, its cell membrane receptor (uPAR) and two specific inhibitors, the plasminogen activator inhibitor 1 (PAI-1) and 2 (PAI-2). The uPA converts the plasminogen in the serine protease plasmin, involved in a number of physiopathological processes requiring basement membrane (BM) or extracellular matrix (ECM) remodelling, including tumor progression and metastasis. The tumor-promoting role of PAS is not limited to the degradation of ECM and BM required for local diffusion and spread to distant sites of malignant cells, but widens to tumor cell proliferation, adhesion and migration, intravasation, growth at the metastatic site and neoangiogenesis. The relevance of uPAS in cancer progression has been confirmed by several studies which documented an increased expression of uPA, uPAR and PAI-1 in different human malignancies, and a positive correlation between the levels of one or more of them and a poor prognosis. For these reasons, the uPAS components have aroused considerable interest as suitable targets for anticancer therapy, and several pharmacological approaches aimed at inhibiting the uPA and/or uPAR expression or function in preclinical and clinical settings have been described. In the present manuscript, we will first glance at uPAS biological functions in human cancer progression and its clinical significance in terms of prognosis and therapy. We will then review the main findings regarding expression and function of uPAS components in thyroid cancer tissues along with the experimental and clinical evidence suggesting its potential value as molecular prognostic marker and therapeutic target in thyroid cancer patients.

Computer-based tools for assessing micro-longitudinal patterns of cognitive function in older adults

Patterns of cognitive change over micro-longitudinal timescales (i.e., ranging from hours to days) are associated with a wide range of age-related health and functional outcomes. However, practical issues with conducting high-frequency assessments make investigations of micro-longitudinal cognition costly and burdensome to run. One way of addressing this is to develop cognitive assessments that can be performed by older adults, in their own homes, without a researcher being present. Here, we address the question of whether reliable and valid cognitive data can be collected over micro-longitudinal timescales using unsupervised cognitive tests.In study 1, 48 older adults completed two touchscreen cognitive tests, on three occasions, in controlled conditions, alongside a battery of standard tests of cognitive functions. In study 2, 40 older adults completed the same two computerized tasks on multiple occasions, over three separate week-long periods, in their own homes, without a researcher present. Here, the tasks were incorporated into a wider touchscreen system (Novel Assessment of Nutrition and Ageing (NANA)) developed to assess multiple domains of health and behavior. Standard tests of cognitive function were also administered prior to participants using the NANA system.Performance on the two “NANA” cognitive tasks showed convergent validity with, and similar levels of reliability to, the standard cognitive battery in both studies. Completion and accuracy rates were also very high. These results show that reliable and valid cognitive data can be collected from older adults using unsupervised computerized tests, thus affording new opportunities for the investigation of cognitive function.

Quantitative evaluation of visual function 12 months after bilateral implantation of a diffractive trifocal IOL

PURPOSE: To quantitatively evaluate visual function 12 months after bilateral implantation of the Physiol FineVision® trifocal intraocular lens (IOL) and to compare these results with those obtained in the first postoperative month. METHODS: In this prospective case series, 20 eyes of 10 consecutive patients were included. Monocular and binocular, uncorrected and corrected visual acuities (distance, near, and intermediate) were measured. Metrovision® was used to test contrast sensitivity under static and dynamic conditions, both in photopic and low-mesopic settings. The same software was used for pupillometry and glare evaluation. Motion, achromatic, and chromatic contrast discrimination were tested using 2 innovative psychophysical tests. A complete ophthalmologic examination was performed preoperatively and at 1, 3, 6, and 12 months postoperatively. Psychophysical tests were performed 1 month after surgery and repeated 12 months postoperatively. RESULTS: Final distance uncorrected visual acuity (VA) was 0.00 ± 0.08 and distance corrected VA was 0.00 ± 0.05 logMAR. Distance corrected near VA was 0.00 ± 0.09 and distance corrected intermediate VA was 0.00 ± 0.06 logMAR. Glare testing, pupillometry, contrast sensitivity, motion, and chromatic and achromatic contrast discrimination did not differ significantly between the first and last visit (p>0.05) or when compared to an age-matched control group (p>0.05). CONCLUSIONS: The Physiol FineVision® trifocal IOL provided satisfactory full range of vision and quality of vision parameters 12 months after surgery. Visual acuity and psychophysical tests did not vary significantly between the first and last visit.

Assessing microvascular function with breathing maneuvers : an oxygenation-sensitive CMR study

Ce projet illustre cinq études, mettant l'emphase sur le développement d'une nouvelle approche diagnostique cardiovasculaire afin d'évaluer le niveau d’oxygène contenu dans le myocarde ainsi que sa fonction microvasculaire. En combinant une séquence de résonance magnétique cardiovasculaire (RMC) pouvant détecter le niveau d’oxygène (OS), des manœuvres respiratoires ainsi que des analyses de gaz artériels peuvent être utilisés comme procédure non invasive destinée à induire une réponse vasoactive afin d’évaluer la réserve d'oxygénation, une mesure clé de la fonction vasculaire. Le nombre de tests diagnostiques cardiaques prescrits ainsi que les interventions, sont en pleine expansion. L'imagerie et tests non invasifs sont souvent effectués avant l’utilisation de procédures invasives. L'imagerie cardiaque permet d’évaluer la présence ou absence de sténoses coronaires, un important facteur économique dans notre système de soins de santé. Les techniques d'imagerie non invasives fournissent de l’information précise afin d’identifier la présence et l’emplacement du déficit de perfusion chez les patients présentant des symptômes d'ischémie myocardique. Néanmoins, plusieurs techniques actuelles requièrent la nécessité de radiation, d’agents de contraste ou traceurs, sans oublier des protocoles de stress pharmacologiques ou physiques. L’imagerie RMC peut identifier une sténose coronaire significative sans radiation. De nouvelles tendances d’utilisation de RMC visent à développer des techniques diagnostiques qui ne requièrent aucun facteur de stress pharmacologiques ou d’agents de contraste. L'objectif principal de ce projet était de développer et tester une nouvelle technique diagnostique afin d’évaluer la fonction vasculaire coronarienne en utilisant l' OS-RMC, en combinaison avec des manœuvres respiratoires comme stimulus vasoactif. Ensuite, les objectifs, secondaires étaient d’utilisés l’OS-RMC pour évaluer l'oxygénation du myocarde et la réponse coronaire en présence de gaz artériels altérés. Suite aux manœuvres respiratoires la réponse vasculaire a été validée chez un modèle animal pour ensuite être utilisé chez deux volontaires sains et finalement dans une population de patients atteints de maladies cardiovasculaires. Chez le modèle animal, les manœuvres respiratoires ont pu induire un changement significatif, mesuré intrusivement par débit sanguin coronaire. Il a été démontré qu’en présence d'une sténose coronarienne hémodynamiquement significative, l’OS-RMC pouvait détecter un déficit en oxygène du myocarde. Chez l’homme sain, l'application de cette technique en comparaison avec l'adénosine (l’agent standard) pour induire une vasodilatation coronarienne et les manœuvres respiratoires ont pu induire une réponse plus significative en oxygénation dans un myocarde sain. Finalement, nous avons utilisé les manœuvres respiratoires parmi un groupe de patients atteint de maladies coronariennes. Leurs myocardes étant altérées par une sténose coronaire, en conséquence modifiant ainsi leur réponse en oxygénation. Par la suite nous avons évalué les effets des gaz artériels sanguins sur l'oxygénation du myocarde. Ils démontrent que la réponse coronarienne est atténuée au cours de l’hyperoxie, suite à un stimuli d’apnée. Ce phénomène provoque une réduction globale du débit sanguin coronaire et un déficit d'oxygénation dans le modèle animal ayant une sténose lorsqu’un supplément en oxygène est donné. En conclusion, ce travail a permis d'améliorer notre compréhension des nouvelles techniques diagnostiques en imagerie cardiovasculaire. Par ailleurs, nous avons démontré que la combinaison de manœuvres respiratoires et l’imagerie OS-RMC peut fournir une méthode non-invasive et rentable pour évaluer la fonction vasculaire coronarienne régionale et globale.

Design for placement of modified optodes to non-invasively map cerebral function

By using near infrared spectroscopy (NIRS) and by modifying the current Somanetics® optodes being used with the INVOS oximeter, the modified optodes are made to be fairly functional not only across the forehead, but across the hairy regions of the scalp as well. A major problem arises in the positioning of these optodes on the patients scalp and holding them in place while recording data. Another problem arises in the inconsistent repeatability of the trends displayed in the recorded data. A method was developed to facilitate the easy placement of these optodes on the patients scalp keeping in mind thepatient's comfort. The sensitivity of the optodes, too, was improved by incorporating better refined techniques for manufacturing the fiber optic brushes and fixing the same to the optode transmitting and receiving windows. The modified and improved optodes, in the single as well as in the multiplexed modes, were subjected to various tests on different areas of the brain to determine their efficiency and functionality.

MicroRNA modulation of aldosterone production in the adrenal gland

Hypertension is the major risk factor for coronary disease worldwide. Primary hypertension is idiopathic in origin but is thought to arise from multiple risk factors including genetic, lifestyle and environmental influences. Secondary hypertension has a more definite aetiology; its major single cause is primary aldosteronism (PA), the greatest proportion of which is caused by aldosteroneproducing adenoma (APA), where aldosterone is synthesized at high levels by an adenoma of the adrenal gland. There is strong evidence to show that high aldosterone levels cause adverse effects on cardiovascular, cerebrovascular, renal and other systems. Extensive studies have been conducted to analyse the role that regulation of CYP11B2, the gene encoding the aldosterone synthase enzyme plays in determining aldosterone production and the development of hypertension. One significant regulatory factor that has only recently emerged is microRNA (miRNA). miRNAs are small non-coding RNAs, synthesized by a series of enzymatic processes, that negatively regulate gene expression at the posttranscriptional level. Detection and manipulation of miRNA is now known to be a viable method in the treatment, prevention and prognosis of certain diseases. The aim of the present study was to identify miRNAs likely to have a role in the regulation of corticosteroid biosynthesis. To achieve this, the miRNA profile of APA and normal human adrenal tissue was compared, as was the H295R adrenocortical cell line model of adrenocortical function, under both basal conditions and following stimulation of aldosterone production. Key differentially-expressed miRNAs were then identified and bioinformatic tools used to identify likely mRNA targets and pathways for these miRNAs, several of which were investigated and validated using in vitro methods. The background to this study is set out in Chapter 1 of this thesis, followed by a description of the major technical methods employed in Chapter 2. Chapter 3 presents the first of the study results, analysing differences in miRNA profile between APA and normal human adrenal tissue. Microarray was implemented to detect the expression of miRNAs in these two tissue types and several miRNAs were found to vary significantly and consistently between them. Furthermore, members of several miRNA clusters exhibited similar changes in expression pattern between the two tissues e.g. members of cluster miR-29b-1 (miR-29a-3p and miR-29b-3p) and of cluster miR-29b-2 (miR-29b-3p and miR-29c- 3p) are downregulated in APA, while members of cluster let-7a-1 (let-7a-5p and let-7d-5p), cluster let-7a-3 (let-7a-5p and let-7b-5p) and cluster miR-134 (miR- 134 and miR-382) are upregulated. Further bioinformatic analysis explored the possible biological function of these miRNAs using Ingenuity® Systems Pathway Analysis software. This led to the identification of validated mRNAs already known to be targeted by these miRNAs, as well as the prediction of other mRNAs that are likely targets and which are involved in processes relevant to APA pathology including cholesterol synthesis (HMGCR) and corticosteroidogenesis (CYP11B2). It was therefore hypothesised that increases in miR-125a-5p or miR- 335-5p would reduce HMGCR and CYP11B2 expression. Chapter 4 describes the characterisation of H295R cells of different strains and sources (H295R Strain 1, 2, 3 and HAC 15). Expression of CYP11B2 was assessed following application of 3 different stimulants: Angio II, dbcAMP and KCl. The most responsive strain to stimulation was Strain 1 at lower passage numbers. Furthermore, H295R proliferation increased following Angio II stimulation. In Chapter 5, the hypothesis that increases in miR-125a-5p or miR-335-5p reduces HMGCR and CYP11B2 expression was tested using realtime quantitative RT-PCR and transfection of miRNA mimics and inhibitors into the H295R cell line model of adrenocortical function. In this way, miR-125a-5p and miR-335-5p were shown to downregulate CYP11B2 and HMGCR expression, thereby validating certain of the bioinformatic predictions generated in Chapter 3. The study of miRNA profile in the H295R cell lines was conducted in Chapter 6, analysing how it changes under conditions that increase aldosterone secretion, including stimulation Angiotensin II, potassium chloride or dibutyryl cAMP (as a substitute for adrenocorticotropic hormone). miRNA profiling identified 7 miRNAs that are consistently downregulated by all three stimuli relative to basal cells: miR-106a-5p, miR-154-3p, miR-17-5p, miR-196b-5p, miR-19a-3p, miR-20b- 5p and miR-766-3p. These miRNAs include those derived from cluster miR-106a- 5p/miR-20b-5p and cluster miR-17-5p/miR-19a-3p, each producing a single polycistronic transcript. IPA bioinformatic analysis was again applied to identify experimentally validated and predicted mRNA targets of these miRNAs and the key biological pathways likely to be affected. This predicted several interactions between miRNAs derived from cluster miR-17-5p/miR-19a-3p and important mRNAs involved in cholesterol biosynthesis: LDLR and ABCA1. These predictions were investigated by in vitro experiment. miR-17-5p/miR-106a-p and miR-20b-5p were found to be consistently downregulated by stimulation of aldosterone biosynthesis. Moreover, miR-766-3p was upregulation throughout. Furthermore, I was able to validate the downregulation of LDLR by miR-17 transfection, as predicted by IPA. In summary, this study identified key miRNAs that are differentially-expressed in vivo in cases of APA or in vitro following stimulation of aldosterone biosynthesis. The many possible biological actions these miRNAs could have were filtered by bioinformatic analysis and selected interactions validated in vitro. While direct actions of these miRNAs on steroidogenic enzymes were identified, cholesterol handling also emerged as an important target and may represent a useful point of intervention in future therapies designed to modulate aldosterone biosynthesis and reduce its harmful effects.

An approximate method for the solution of an influence function foil rolling model

Fleck and Johnson (Int. J. Mech. Sci. 29 (1987) 507) and Fleck et al. (Proc. Inst. Mech. Eng. 206 (1992) 119) have developed foil rolling models which allow for large deformations in the roll profile, including the possibility that the rolls flatten completely. However, these models require computationally expensive iterative solution techniques. A new approach to the approximate solution of the Fleck et al. (1992) Influence Function Model has been developed using both analytic and approximation techniques. The numerical difficulties arising from solving an integral equation in the flattened region have been reduced by applying an Inverse Hilbert Transform to get an analytic expression for the pressure. The method described in this paper is applicable to cases where there is or there is not a flat region.

Study on microwave dielectric properties of epoxy resin mixtures used for rapid product development

This paper presents a preliminary study on the dielectric properties and curing of three different types of epoxy resins mixed at various stichiometric mixture of hardener, flydust and aluminium powder under microwave energy. In this work, the curing process of thin layers of epoxy resins using microwave radiation was investigated as an alternative technique that can be implemented to develop a new rapid product development technique. In this study it was observed that the curing time and temperature were a function of the percentage of hardener and fillers presence in the epoxy resins. Initially dielectric properties of epoxy resins with hardener were measured which was directly correlated to the curing process in order to understand the properties of cured specimen. Tensile tests were conducted on the three different types of epoxy resins with hardener and fillers. Modifying dielectric properties of the mixtures a significant decrease in curing time was observed. In order to study the microstructural changes of cured specimen the morphology of the fracture surface was carried out by using scanning electron microscopy.

Smoothing a Discrete Hazard Function for the Number of Patients Colonized with Methicillin-Resistance Staphylococcus Aureus in an Intensive Care Unit

A new method for estimating the time to colonization of Methicillin-resistant Staphylococcus Aureus (MRSA) patients is developed in this paper. The time to colonization of MRSA is modelled using a Bayesian smoothing approach for the hazard function. There are two prior models discussed in this paper: the first difference prior and the second difference prior. The second difference prior model gives smoother estimates of the hazard functions and, when applied to data from an intensive care unit (ICU), clearly shows increasing hazard up to day 13, then a decreasing hazard. The results clearly demonstrate that the hazard is not constant and provide a useful quantification of the effect of length of stay on the risk of MRSA colonization which provides useful insight.