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The main eye condition associated with diabetes is called diabetic retinopathy and is, the main cause of blindness. The earliest signs of this disease include damage to retinal blood vessels and then the formation of lesions such as exudates and red spots. Such lesions are normally detected manually by clinicians in intensive and time-consuming processes. Computer:-_aided detection and grading of such conditions could facilitate an immediate and accurate Criagnosis. Whilst some progress has been made to detect these diseases, there is no complete system for automated detection and grading of diabetic retinopathy and this is hindering the development of automated methods to support assessment of diabetic eye disease. The aim of this work is to develop computer algorithms that can be used in the medical screening system for evaluating the condition of the retina leading to successful treatment. This work comprises five stages: 1) image pre-processing, 2) retinal structure extraction; 3) hard exudate detection, 4) red lesion detection and 5) grading of diabetic retinopathy. The aim of image pre-processing is to prepare the image with better quality where shade correction using morphological processes and contrast enhancement using fuzzy logic-based method are applied to the image. In the retinal structure extraction, multi-scale morphological technique and classification procedure are proposed for blood vessel detection. Vasculature loop-based method for the optic disc localisation is proposed, while for fovea localisation, a method based on its features and geometric relationships with the other retinal structures is developed. These methods have the advantage of lower computational complexity and competitive performance compared to the existing related methods. A novel coarse to fine strategy is proposed to detect hard exudates, where a local variation operator is used to calculate the standard deviation around each pixel followed by automated thresholding, morphological operations, and classification to segment coarse hard exudates. To fine-tune the result of coarse hard exudates, two region-based segmentation techniques are investigated to detect fine hard exudates. The significance of this method is manifested by its superior performance, lower computational complexity (compared to the current state of the art) and the ability to deal with a variety of image qualities. A novel red lesion detection method is proposed using mathematical morphology to segment candidate red lesions followed by refining them from traces of retinal structures and then a classification based on red lesion features is used to detect red lesions with high degree of discrimination between genuine red lesions and artifacts and as a result its detection performance has proved to be favourable. Grading of diabetic retinopathy is a very important stage after the detection of retinal lesions to evaluate their severity and to decide appropriate treatment. The most reliable medical approaches to diabetic retinopathy grading were investigated to build a novel computer-aided model for automated grading based on the clinical criteria and results of the earlier lesion segmentation. This model quantifies the nature, extent and spatial distribution of all the detected features and provides a clinical grading assessment. This is among the first of such models published and as such the novelty is considered to be one of the main contributions of this thesis.

The aim of this thesis was to investigate the prevalence and impact of age-related macular degeneration (AMD) causing visual impairment in people aged 75 years and above in the UK. A secondary objective was to investigate a small number of potential risk factors for AMD. This was an add-on study to the MRC Trial of the Assessment and Management of Older People in the Community. The prevalence of AMD causing visual impairment was estimated at 3.7% (95% confidence interval 3.2% to 4.2%) in people aged 75 years and above. This prevalence increased sharply with age. There was a higher risk of AMD causing visual impairment in women. There were estimated to be approximately 192,000 people aged 75 years and above in the UK living in the community with visual impairment due to AMD (95% confidence interval 144,000 to 239,000) of whom 60,000 are aged 90 years or above. The prevalence of AMD causing visual impairment did not vary by socio-economic group or region. After controlling for appropriate confounding factors, compared to people not visually impaired, people visually impaired due to AMD were more likely to have functional difficulties, report poor health and be depressed. They were more likely to be in the worst quintile for the home management and mobility dimensions of the Sickness Impact Profile (SIP). After controlling for appropriate confounding factors including binocular acuity score, compared to people visually impaired due to other causes, people visually impaired due to AMD were more likely to have functional difficulties and report poor health and less likely to be in the worst quintile for SIP body care and movement dimension or die. There was an association between smoking status and risk of being visually impaired due to AMD. This effect was particularly strong in people aged 75-79 years of age. In these people there was a dose-response relationship between pack years of smoking and risk of AMD causing visual impairment. There were no statistically significant associations between alcohol consumption, cardiovascular disease and reproductive factors (in women) and AMD causing visual impairment.

The overall objective of this work was to compare the effect of pre-treatment and catalysts on the quality of liquid products from fast pyrolysis of biomass. This study investigated the upgrading of bio-oil in terms of its quality as a bio-fuel and/or source of chemicals. Bio-oil used directly as a biofuel for heat or power needs to be improved particularly in terms of temperature sensitivity, oxygen content, chemical instability, solid content, and heating values. Chemicals produced from bio-oil need to be able to meet product specifications for market acceptability. There were two main objectives in this research. The first was to examine the influence of pre-treatment of biomass on the fast pyrolysis process and liquid quality. The relationship between the method of pre-treatment of biomass feedstock to fast pyrolysis oil quality was studied. The thermal decomposition behaviour of untreated and pretreated feedstocks was studied by using a TGA (thermogravimetric analysis) and a Py-GC/MS (pyroprobe-gas chromatography/mass spectrometry). Laboratory scale reactors (100g/h, 300g/h, 1kg/h) were used to process untreated and pretreated feedstocks by fast pyrolysis. The second objective was to study the influence of numerous catalysts on fast pyrolysis liquids from wheat straw. The first step applied analytical pyrolysis (Py-GC/MS) to determine which catalysts had an effect on fast pyrolysis liquid, in order to select catalysts for further laboratory fast pyrolysis. The effect of activation, temperature, and biomass pre-treatment on catalysts were also investigated. Laboratory experiments were also conducted using the existing 300g/h fluidised bed reactor system with a secondary catalytic fixed bed reactor. The screening of catalysts showed that CoMo was a highly active catalyst, which particularly reduced the higher molecular weight products of fast pyrolysis. From these screening tests, CoMo catalyst was selected for larger scale laboratory experiments. With reference to the effect of pre-treatment work on fast pyrolysis process, a significant effect occurred on the thermal decomposition of biomass, as well as the pyrolysis products composition, and the proportion of key components in bio-oil. Torrefaction proved to have a mild influence on pyrolysis products, when compared to aquathermolysis and steam pre-treatment.

It is now well established that vascular endothelial growth factor-A (VEGF-A or VEGF), originally described as a key angiogenic factor, plays a crucial cytoprotective role for non- endothelial cell types, including the retinal pigmented epithelium and neuronal cell types. Anti-VEGF therapy has been approved to treat a number of angiogenic-dependent diseases, for example neovascular age-related macular degeneration and renal cell carcinoma, but neutralizing VEGF can cause detrimental effects such as retinal damage, sensory neuropathy and/or pain. Alternative splicing of VEGF mRNA produces two functionally distinct families of proteins, the conventional pro-angiogenic family, VEGFxxxa, and an anti-angiogenic family, VEGFxxxb. Using in vitro cytotoxicity assays, I investigated the cytoprotective effect of the predominant VEGFxxxb isoform, VEGF 165b, on retinal pigment epithelial (RPE) cells, hippocampal and dorsal root ganglion (DRG) neurons. Like its sister isoform VEGF 165a, VEGF 165b was cytoprotective for RPE cells and, hippocampal and DRG neurons against various insults and the underlying mechanism was explored. I investigated the effect of VEGF 165a, VEGF 165b and a VEGF neutralizing antibody on mechanical withdrawal nociceptive behaviour in normal and nerve-injured mice. Key findings were that VEGF isoforms affected nociceptive behaviour in an opposing and isoform-specific manner and the pro-nociceptive effect of VEGF 165a was dependent the ion channel, transient receptor potential- vanilloid-l (TRPVl). The VEGF isoforms also affected TRPVI channel activity in an opposing and isoform-specific manner in vitro. VEGFxxxb proteins make up a significant proportion of total VEGF in adult physiology and the adverse events that arise from anti- VEGF therapy may arise from the disruption of VEGFxxxb-mediated cytoprotection and anti- nociception. The novel effects of VEGF 165b, identified in this thesis, also indicate a potential use for the protein in degenerative conditions and painful neuropathies.

Introduction: Age-related macular degeneration (AMD) results in the deterioration of the retinal pigment epithelial (RPE) layer under the macula. A potential surgical treatment involves the replacement of the diseased RPE cells with healthy cells. Clinically, this requires identification of the appropriate cells to use and the optimal substrate for use as a transplant vehicle. The material under investigation was polyurethane (PU) and ways to manufacture porous PU were explored. Iris pigment epithelium (IPE) is derived from the same embryonic origin as RPE and has been shown to have several of the same functions. IPE can be harvested more easily than RPE. The aim of this study was to compare the behaviour of primary bovine RPE (bRPE), IPE (bIPE) and human RPE (hRPE) cultured on PU membranes with the objective of optimising the cell/substrate combination for transplantation. Morphology and functionality of the cells attaching on the membranes were also evaluated. Methods: The PU used in this study were Z3Ai and Z9Ai (b9'" Biomer Technology Ltd.) membranes with thickness <lOOllm. Several ways of producing porous PU were investigated. One of which was mixing Z3Ai with (dimethyl acetamide) DMAC in a concentration of 5% (vol/vol) and 5% icing sugar (by weight). The mixture was then dried in an oven at 75°C for 24 hours and then rinsed with distilled water. The surface topography was investigated using SEM. Properties of the membranes such as tensile strength, modulus of elasticity and wettability were examined. Freshly harvested bRPE, blPE and hRPE cells were seeded on the b9 films, porous PU membrane and tissue culture polystyrene (TCPS) as control. The monolayer formation of the cells on the surfaces were controlled by optimising the correct harvesting technique, using the correct amount of seeding, controlling the amount of serum and the addition of retinoic acid. The cell morphology was assessed by phase contrast microscopy and stained for F-actin, zonula occludens-I (ZO-i) tight junction marker and DAPI for nuclei distribution. Cytokeratin staining was used to confirm the epithelial phenotype. Phagocytosis assays, selectivity of phagocytosis assay and dextran transport studies were conducted to evaluate the functionalities of the cells on the membranes. An In vitro injury model of the cells attaching on the membranes was also investigated. Results: The porous PU membranes produced were shown to have suitable properties as a replacement of a native Bruch's membrane with Sum thickness and good porosities. All cell types demonstrated good epithelial phenotype, confirmed by cytokeratin expression when attached on the membrane. Nuclei were dispersed evenly, F-actin belt formation with ZO-i at the cell borders were observed. Phagocytosis of photoreceptor outer segments (PaS) demonstrated that the cells attaching on these surfaces were able to phagocytose in a time-dependant manner and show selectivity in phagocytosis when tested with polystyrene beads and blocking with the aVI35-integrin. Dextran transport revealed a reduction in the transport of higher molecular weight dextran through the porous membrane-cells complex. The preliminary In vitro injury model study showed inconsistent cell integration. Conclusion: This project has developed a porous PU with appropriate mechanical properties and porosities. The project has demonstrated that primary BRPE and BIPE were successfully harvested and differentiated into a functional monolayer in vitro. Primary bovine and human RPE and IPE were shown to grow as a differentiated monolayer on non-porous and porous PU substrates. The differentiated monolayer of primary cells on PU substrate displayed functional activities in the ability to phagocytose pas and transporting different sized dextran molecules.

Purpose: Inflammation may play a role in the development of diabetic retinopathy (DR). Monocytes/macrophages have been implicated in the initiation of microvascular damage in diabetes. In addition, leukocytes from diabetes have been shown to have increased expression of adhesion molecules and greater adhesion to endothelial cells (EC). The aims of this study were to determine which leukocyte subsets were involved in the inflammatory response in DR and how.