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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
21

Imaging haemodynamic activity in the mouse visual cortex

Pisauro, M. A. January 2014 (has links)
Neurovascular coupling, the relationship between neural and haemodynamic activity, is not a fixed property of the brain. Physiological, behavioural and cognitive factors can strongly modulate the degree to which haemodynamic responses to perceptual stimuli reflect co-localized neural responses. Moreover, a significant part of the haemodynamic activity is not directly coupled with the spiking activity. Here we show how anaesthesia can influence the relationship between haemodynamic and neural activity and how the former can be expressed as the sum of two components: one which is well coupled with neuronal responses and the other which seem to be independent of them and which correlates with alertness. We used wide-field optical imaging of intrinsic signals in mouse primary visual cortex (V1). Haemodynamic responses could be used to obtain clear maps of retinotopy in both anaesthetized and awake mice. However, when the mice were awake, responses were four times larger and twice as fast compared to when they were anaesthetized. By measuring neural responses we could establish that the effects of anaesthesia on haemodynamic responses were due to changes in neurovascular coupling. By activating V1 via optogenetics, we replicated the effects of anaesthesia in terms of delay of the response but not of amplitude. We then asked whether haemodynamic activity can all be explained in terms of local neural activity. By imposing a precise spatiotemporal pattern of neural responses in visual cortex we were able to distinguish two component of the haemodynamic activity: one reflects responses to visual stimuli, and is local to the retinotopic region activated by the stimuli. The second correlates strongly with pupil diameter, which reflects a measure of arousal, and is shared simultaneously by large regions of cortex.
22

What are the major susceptibility factors for glaucoma progression?

Laskaratos, G. January 2014 (has links)
Elevated intraocular pressure (IOP) is a major risk factor for open angle glaucoma (OAG) and medical IOP reduction is the standard treatment, yet no randomised placebo-controlled study of medical IOP reduction has been undertaken previously. In the present thesis, the methodology, baseline characteristics and results from the United Kingdom Glaucoma Treatment Study (UKGTS), the first randomised, double-masked, placebo-controlled, multicentre treatment trial for OAG, are presented. Survival analysis shows a statistically significant difference in the time from baseline to the event of confirmed visual field progression in the medical treatment (latanoprost) group, as compared to placebo, over 24 months. The role of average IOP during follow-up, as a risk factor for progression, is evaluated. Median IOP, as measured by Goldmann Applanation Tonometry (GAT), Dynamic Contour Tonometry and the Ocular Response Analyzer, is significantly, but weakly, correlated with visual field progression. Corneal compensated IOP (IOPcc) is the best predictor of progression across all the UKGTS sites. While the addition of central corneal thickness (CCT) slightly improves the GAT IOP prediction model, CCT on its own is not a significant predictor of progression in the UKGTS. The role of mitochondrial dysfunction and oxidative stress as risk factors for glaucoma progression is investigated within an exploratory study. Experiments conducted on the lymphocytes of healthy subjects and patients, contrast individuals at the extremes of IOP susceptibility: rapidly progressing patients with Normal Tension Glaucoma (NTG) and non-progressing patients with Ocular Hypertension (OHT). The experimental data presented show, for the first time, that OHT patients may have more efficient mitochondria at a systemic level, when compared to age-similar NTG subjects and nonglaucomatous controls. Overall, OHT lymphocytes produce higher levels of ATP (Complex I and Complexes II/III), have higher mitochondrial membrane potential, enhanced capacity to deal with exogenous oxidative stress insults, higher serum levels of urate, a potent antioxidant, and are more capable of taking up and buffering cytosolic calcium, as compared to NTG and control lymphocytes. Lymphocytes from NTG patients, when compared to the OHT and control groups, show lower ATP synthesis from Complex IV, lower aconitase activity, lower serum levels of vitamin C, and enhanced antioxidant defence (SOD2). In conclusion, this study implicates the role of a) systemic oxidative damage and complex IV-linked mitochondrial defects in the pathogenesis of NTG and b) efficient systemic mitochondria in resistance to glaucomatous optic neuropathy development and progression, particularly in the context of OHT.
23

Age-related macular degeneration : pathogenesis and drug delivery

Anderson, O. A. January 2014 (has links)
Age related macular degeneration (AMD) is the leading cause of blindness amongst the elderly in the developed world. There is currently no effective treatment for the atrophic (dry) form of the disease. The aims of this thesis are twofold: Firstly to investigate the pathogenesis of atrophic AMD, a chronic inflammatory disease, with a view to identifying new potential treatment targets. Secondly to develop a novel method of sustained drug delivery with a view to using this mode of delivery to deliver immune modulating therapy in the treatment of atrophic AMD. We discovered that A2E, the major fluorophore of lipofuscin, induces the release of multiple chemokines and cytokines by retinal pigment epithelial cells in vitro. We showed that IL-1 1 was produced following activation of the NLRP3 inflammasome. Increased levels of IL-1 1 were also seen in the retinal-choroidal interface of ABCA4 knockout mice, known to contain high levels of A2E. A2E appears to be proinflammatory and therefore may be involved in the pathogenesis of age related macular degeneration. We also assessed the use of hyaluronic acid binding peptides as a mode of sustained intravitreal drug delivery. This was with the intention of linking them to a pharmacological agent, hence prolonging the intravitreal half-life of that agent. With regards to the peptide HABP35, we showed that hyaluronic acid binding translated into prolonged retention in the vitreous, in both an in vitro and in vivo setting. We then proposed a method of demonstrating its efficacy in vivo using IL-1 1 as a potential target. In conclusion our results provide novel data concerning a potential inflammatory role of A2E in the pathogenesis of AMD as well as introducing hyaluronic acid binding peptides into the field of ocular drug delivery.
24

Objective imaging technologies and their use in assessing retinal diseases

Normando, E. January 2014 (has links)
Confocal Scanning Laser Ophthalmoscopy (cSLO), Optical Coherence Tomography (OCT) and Scanning Laser Polarimerty (SLP) imaging techniques have greatly increased our ability to monitor retinal diseases, providing objective and structural measures. However, their role in evaluation of experimental models is not fully established, nor their application in identifying early changes. This thesis aims to provide new insights into the use of these objective retinal imaging techniques in the assessment of both human and experimental retinal diseases. cSLO, OCT, and SLP were used in clinical and animal studies to assess structural retinal modifications and Retinal Ganglion Cells apoptosis. Two groups of patients were assessed: Acute Primary Angle Closure (APAC) and those referred as glaucoma suspects (GS). Five retinal disease models were also evaluated: a rat model of ocular hypertension (OHT), a rotenone rat and transgenic model of Parkinson’s disease (PD), and transgenic models of Retinitis Pigmentosa (RP) and Alzheimer Disease (AD). Progressive SLO and SLP changes with partial agreement between the two techniques were documented following APAC. Similarly, HRT and OCT showed some agreement in a cross-sectional study of GS patients, especially with respect to Posterior Pole analysis. All experimental models showed RGC apoptosis and retinal structural modifications, including retinal layer thickness, with significant changes recorded over time. These novel DARC (Detection of Apoptosing Retinal Cells) and OCT findings suggest that RGC apoptosis and retinal structural alterations could be an early marker of PD, AD and RP, and a possible endpoint for neuroprotective strategies to prevent cell loss in human retinal and neurodegenerative diseases. This is exemplified by the studies reported here, evaluating rosiglitazone treatment in PD-rat models. In conclusion, the studies performed in this thesis, highlight the usefulness of state-of-the-art retinal imaging technology to assess and monitor glaucoma patients. Furthermore, these same technologies are effective in the in vivo assessment of experimental models of neurodegenerative diseases, providing new and real-time objective outcome measures, which can be readily translated to the clinic.
25

The management & medical treatment of thyroid eye disease

Rajendram, R. January 2014 (has links)
Thyroid eye disease (TED) is a disfiguring autoimmune orbital inflammatory condition that may result in loss of vision and intractable diplopia. Optimal treatment is highly debated as current evidence is conflicting, and long-term outcomes of management within the UK is lacking as a result of small cohorts and variability in individual physician:s treatment plans. I performed a retrospective casenote review of 425 patients presenting to Moorfields Eye Hospital under one consultant between 1997 and 2002 inclusively. Approximately two-thirds of patients (69%) with initial and final exophthalmometer readings (n=257) had a reduction in proptosis of 2mm or more and 67% of the 206 with diplopia at presentation improved by their final visit. Smokers at presentation required strabismus surgery more often than non-smokers (hazard ratio 1.8; p = 0.02, 95% confidence interval 1.08 – 3.22). These results indicate that there is room for improvement in outcomes and that smoking cessation should be emphasised. Orbital radiotherapy is the most controversial of current therapies used worldwide. I performed a systematic review which suggested that radiotherapy is superior to sham radiotherapy (natural history) with a relative risk of 1.92. To provide further Level 1 evidence, I established a multicentre factorial-designed 3 year follow-up randomised controlled trial (RCT) addressing the use of steroids in combination with either radiotherapy, a steroid sparing agent (azathioprine) or both (www.cirted.org). A high screening failure rate early on led to review of entry criteria and appropriate modifications of the protocol increased the proportion of eligible patients progressing to randomisation. At the time of writing recruitment is complete with 512 patients assessed for eligibility, 298 screened, 167 recruited and given a 2 week steroid trial leading to 127 responding and being randomised. The high conversion from recruitment to randomisation (76%) suggested the clinical enrolment criteria were effective for detecting active disease. To identify a novel objective measure of disease activity a nested magnetic resonance imaging (MRI) study was performed to explore the use of diffusion-weighted imaging. This technique was found to be subject to significant artefact and difficult to interpret, and therefore not of benefit in clinical practice. Taken together, the studies in this thesis show that, despite treatment deemed best management, proptosis or diplopia persists in one third of patients and additional medical treatments in the active stage are required to improve outcomes; robust RCTs are needed to provide evidence. Such RCTs are complex and our trial provides a template on which other collaborative work could be based, and therefore encourage homogeneity of outcome measures to allow future meta-analyses.
26

Predictors of disease extension and progression in patients with granulomatosis with polyangiitis (GPA)

Mohammad Isa, H. January 2015 (has links)
Granulomatosis with Polyangiitis (GPA) is a granulomatous inflammatory disease. It is generally described as a systemic disorder which can present with a localized presentation like the orbit. Orbital GPA can be the initial manifestation of GPA where over time the disease may progress and become severe, involving vital organs. This study aimed to look for biomarkers in orbital GPA biopsies that could indicate diagnosis and be a predictor for the progression of the disease. To identify GPA patients, retrospective examination of patients’ medical records, who had undergone orbital biopsies for orbital inflammatory disease (OID), over a 21 year period, was performed. Long term outcomes of these patients were studied. Further subjective and objective histology analyses were done on haemotoxylin and eosin (H&E) tissue preparations. Comparison of cellular activity in biopsies of GPA and other OID were performed. Further T cells, B cells and macrophage phenotypes and their cytokines, were investigated with immunohistochemistry (IHC). IHC cell count comparisons were performed between GPA, sarcoidosis and idiopathic inflammatory orbital diseases (IIOD) biopsies. Results showed that in patients who presented with orbital GPA with no systemic manifestations, the disease remained localised and did not progress to systemic form, over time. H&E tissue biopsies examination showed that GPA tissues had a higher cellular activity compared to OIDs. Vasculitis and necrosis were found to be independently associated with the diagnosis of orbital GPA but these features were unreliable for diagnosis as a number of the biopsies did not exhibit these features. In immunohistochemistry staining, T cells, B cells and macrophage subtypes counts were comparable between GPA, sarcoidosis and IIOD. Nonetheless cytokines IL-17, IL-23 and BAFF-receptor (BAFF-R), were found significantly more in GPA compared to sarcoidosis and IIOD. This suggests that these cytokines possibly have a role in the pathogenesis of GPA and may have diagnostic value.
27

Molecular genetic basis of recessively inherited retinal dystrophies in the Saudi population

Alrashed, M. M. M. January 2014 (has links)
Inherited retinal dystrophies (IRD) are a remarkably genetically and phenotypically heterogeneous group of inherited eye diseases, with over 190 causative genes identified to date. In the highly consanguineous Saudi population, autosomal recessive forms of IRD are thought to account for the overwhelming majority of cases. Consanguinity is known to increase the frequency of recessive disorders since it increases the coefficient of inbreeding, which is a measure of the percentage of the genome that is identical by descent. Homozygosity mapping, targeted candidate gene analysis and whole exome sequencing were used to identify the causes of IRD in the Saudi population. Retinitis pigmentosa (RP) is the most common form of IRD, and mutations in the RP1 gene cause both recessive and dominant RP. Mutations in RP1 were found to be a common cause of recessive RP in the Saudi population. Novel and previously identified homozygous mutations in the KCNV2 gene were identified in a cohort of patients with a distinct recessive retinal disorder, ‘cone dystrophy with supranormal rod response,’ demonstrating phenotype/genotype correlation. In addition, a founder homozygous CABP4 mutation was identified in four consanguineous Saudi families with clinical features including congenital nystagmus, stable low vision, photophobia and a normal or near-normal fundus appearance, and no symptom of night blindness. Causative homozygous mutations were also found in the IRD genes RBP3, RDH12, CRB1, BBS4, CNGA3, CNGB1, EYS, RLBP1, ABCA4 and PCDH12 in Saudi patients. Four novel candidate genes for retinal degeneration were identified in this study. Potentially pathogenic homozygous variants were identified in EMC1 (c.G430A, p.A144T), KIAA1549 (c.2399_2400insAA, p.T800fs809X), GPR125 (c.C2504G, p.S835C) and DHX29 (c.C2738T, p.A913V). In the majority of cases (31 families) the genetic cause of IRD was identified, demonstrating the power of homozygosity mapping and whole exome sequencing. In four families (3 multiplex and 1 simplex case), however, no potentially pathogenic homozygous variants were identified, indicating that other novel loci and genes may be implicated as causing IRD in the Saudi population.
28

Leber Congenital Amaurosis and other autosomal recessive retinal dystrophies : a clinical and molecular genetic study

Moradi, P. January 2014 (has links)
Leber congenital amaurosis (LCA) and the early onset retinal dystrophies (EORD) are a spectrum of autosomal recessively inherited genetic conditions affecting children who have visual impairment starting under the age of five years. There are currently 19 known genes that account for approximately two thirds of cases. Only two of these 19 genes (IMPDH 1 and CRX; not studied in this project) have been found to cause autosomal dominant LCA. This genetic heterogeneity makes the identification of these causative genes expensive and time consuming. Phenotype-genotype correlations are therefore important in directing efforts to determine the molecular cause of disease. The aims of this research project were to recruit and clinically characterise a large panel of LCA and EORD patients and to identify the underlying genetic cause of autosomal recessive disease. Patients were recruited from Moorfields Eye Hospital and Great Ormond Street Hospital. A full clinical examination was carried out. DNA samples were analysed using the Asper Ophthalmics LCA microarray chip and by direct sequencing. Large families, with several affected members, were examined using the Affymetrix gene chip arrays for regions of homozygosity and candidate gene sequencing was performed. DNA samples from 158 patients were obtained and 117 patients were examined clinically. A definitive molecular diagnosis was obtained for 26% of patients. Of the cohort of 158 patients with one or two mutated alleles identified and genotyped: RPE65 accounts for 1% of this cohort, 6% are due to mutations in CRB1, 15% are due to RDH12 mutations and 11% are due to mutations in CEP290. Two families were identified with novel CRALBP mutations. The genotype yield from the period of this research, August 2006- August 2008, is lower than that expected with newer technologies in 2014; such as next generation sequencing (NGS) or whole exome sequencing. Useful prognostic information gained will help future patients with these disorders. Patients with a molecular diagnosis may be eligible for clinical trials of gene replacement therapy.
29

Roles of the small leucine-rich repeat proteoglycans OMD and PRELP in development and cancer

Papadaki, V. January 2014 (has links)
Osteomodulin (OMD) and Proline/arginine-rich and Leucine-rich Repeat protein (PRELP) belong to the small leucine-rich repeat proteoglycan (SLRP) family and as extracellular matrix components have the ability to influence various cellular functions, including cell growth, migration and proliferation, while their mutation or aberrant expression can cause developmental disorders and cancer. This thesis extends previous work in further understanding the roles of OMD and PRELP in cancer and also during mouse development. In the current project OMD and PRELP are overexpressed in a bladder cancer cell line where they are found to alter cell morphology, reduce cell invasion and anchorage-independent growth, while they also inhibit tumour growth in xenograft mouse models. Additionally, we show that OMD and PRELP mediate their effects by cross-regulating different signalling pathways and also by affecting tight junction formation. Furthermore, novel knock-out mouse models of OMD and PRELP were generated, where a Lac-Z cassette has been inserted in the coding regions of the two genes, allowing us to follow their expression under X-gal staining. Therefore a detailed analysis of expression patterns was initially conducted. OMD and PRELP were both expressed in skeletal elements during mouse development, while in adult mice they were differentially expressed in neurons and epithelia of the brain and the eye, and in the urothelium of the bladder. Finally, the novel knock-out mice were used to assess any cancer-related aberrant phenotypes arising from OMD and PRELP deficiency. The bladders of the knock-out mice presented with early stages of urothelial papillary formations, where the junctional complexes were also disrupted, suggesting that lack of OMD and/or PRELP is permissive for cancer initiation. Overall, with our current findings we hope to improve the understanding of SLRP biology in carcinogenesis, and we would like to propose OMD and PRELP as potential targets for the development of cancer therapies.
30

Quantifying functional impairment and metamorphopsia in a low vision population

Wiecek, E. K. January 2015 (has links)
Visual perception is required to interact with our environment on a daily basis. Pathological vision loss can disrupt perception and cause systematic functional changes. Quantifying these changes is essential to monitor deficits associated with visual disease, but measurement is complicated by retinotopic impairment, an overlap of symptoms, and influence from higher visual processes. Visual search provides a way to examine visual functioning in a ubiquitous task that involves an interplay between high-resolution central vision and low-resolution peripheral vision. We examined visual search performance in 12 participants with peripheral visual field loss (PVFL) and eight participants with central visual field loss (CVFL). Visual search behavior in PVFL participants was significantly different from age-matched controls with no field loss; yet oculomotor parameters were not significantly different. This suggests that PVFL impairs eye movement strategies, but not dynamics of oculomotor control. CVFL participants completed a visual search task with a set of image modifications designed to improve common perceptual deficits of CVFL patients. There was no significant benefit of image modification on performance, but a multivariate model accurately predicted performance on the basis of age, acuity and extent of field loss. Attempts to improve search may be more successful if they are tailored to the individual’s deficits. Metamorphopsia (visual distortion) often precedes visual field loss, may be caused by retinal layer displacement, and can be used to study the progression of retinal disease. A retrospective study of more than 7,000 Amsler grids showed systematic variations in the spatial pattern of distortion across different etiologies and concluded that metamorphopsia is a prevalent symptom that varies across disease type. However, a study of patient reported outcomes determined that metamorphopsia is under-reported in retinal disease patients, which may impact self-referral and clinical management. We also developed novel psychophysical methods to quantify metamorphopsia, yet found that measures across methods were uncorrelated. This suggests that metamorphopsia is not simply a consequence of pathological retinal displacement, but involves higher visual processes. Finally, we considered how metamorphopsia interacts with visual acuity and found a nonlinear relationship between the spatial properties of distortion and performance on a letter recognition task.

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