Abnormal leukocyte adhesion (i.e. leukostasis) to retinal vascular endothelial cells occurs in early diabetes. The processes of leukostasis have been clearly demonstrated in the vascular endothelium of patients with diabetes. In non-proliferative DR, clinical outcomes are manifested by excessive permeability from inflammatory progression leading to inner blood retinal barrier disruption, endothelial cell damage and widespread capillary nonperfusion. Diabetes promotes vascular leakage in DR by upregulation of adhesion molecules. Moreover, many of the pathological changes in NPDR are related to abnormalities in retinal blood flow. Studies have shown that specific circulating markers of inflammatory activity and endothelial dysfunction are associated with clinical signs of diabetic retinopathy. However, few have found an association between circulating levels of inflammatory and endothelial dysfunctional markers and abnormal retinal hemodynamics in patients with non-proliferative DR. The specific aims of this thesis are as follows: (Chapter 3)To correlate baseline levels of inflammatory and endothelial dysfunction markers and 1) baseline retinal arteriolar hemodynamics and 2) any disturbance in retinal hemodynamics over 6-month time in terms of vessel diameter, blood velocity, maximum-to-minimum velocity ratio and volumetric flow. In Chapter 4: To correlate circulating levels of inflammatory and endothelial dysfunction markers and 1) baseline vascular reactivity and 2) any disturbance in vascular reactivity after 6-month time in terms of vessel diameter, blood velocity, maximum-to-minimum velocity ratio and volumetric flow in patients with increasing non-proliferative diabetic retinopathy (NPDR) severity. Methods for Chapter 3: Diabetes subjects were stratified into either mild-to-moderate (Group 2) or moderate-to-severe (Group 3) NPDR based on their retinopathy status. Age-matched non-diabetics were recruited as controls (Group 1). Forearm blood sample was collected to determine baseline levels of inflammatory and endothelial dysfunctional markers. At visit 1, baseline retinal hemodynamics was acquired using Canon Laser Blood Flowmeter. Patients returned for a visit 2 (6 month follow-up visit) and retinal hemodynamics was reassessed. Baseline levels of inflammatory and endothelial dysfunctional markers compared between groups and correlated with both baseline and change in retinal hemodynamic parameters over 6-month time. For Chapter 4: Diabetes subjects were stratified into either mild-to-moderate NPDR or moderate-to-severe NPDR based on their retinopathy status. Age-matched non-diabetics were recruited as controls. At visit 1, forearm blood sample was collected to determine levels of inflammatory and endothelial dysfunctional markers and baseline vascular reactivity response was acquired. Retinal blood flow data was acquired while subjects breathed air. Retinal blood flow measurements were then acquired after exposure to isocapnic hyperoxic stimuli. At visit 2 (6 month follow-up), retinal vascular reactivity was reassessed. Baseline levels of inflammatory and endothelial dysfunctional markers compared between groups and correlated with both magnitude of baseline and change in vascular reactivity in terms of retinal hemodynamics. Results of Chapter 3: Maximum-to-minimum velocity ratio (max: min) was found to be significantly elevated in the group 3 compared to group 1 at baseline (0.72 vs. 0.49, after Bonferroni correction P<0.01). Both sICAM-1 and sE-selectin were significantly elevated as a function of group (ANOVA p=0.02 and p=0.04). A post hoc Bonferroni test showed that Group 3 had significantly higher in both sICAM-1 and sE-selectin levels compared to Group 1 (234.0 vs. 151.5 ng/ml, P=0.02 and 53.4 vs. 27.6 ng/ml, P<0.01, respectively). Hemoglobin A1c was significantly elevated across the groups (ANOVA p<0.01). A post hoc Bonferroni test showed that Group 3 had significantly higher hemoglobin A1c level compared to Group 1 (7.9 vs. 5.6 % , P<0.01). There were no significant associations found between baseline markers of inflammation and baseline retinal hemodynamics across all groups. The Δ velocity was correlated with the baseline sICAM-1 (r=0.42, p=0.02) and A1c levels (r=0.37, p=0.04) in patients with NPDR. After adjustment for all other variables (A1c, hsCRP and vWF), Δ velocity, sICAM-1 and A1c were found not to be reliable predictors of baseline retinal hemodynamics. For Chapter 4: There were no significant differences in magnitude of retinal vascular reactivity in hemodynamic parameters between groups at visit 1 or visit 2. Over 6 months time, compliance was found to be significantly reduced in patients of Group 3 compared to Group 2 (-0.4 vs. 0.1, t-test p<0.01). Both sICAM-1 and sE-selectin were significantly elevated as a function of group (ANOVA p=0.02 and p<0.01). A post hoc Bonferroni test showed that Group 3 had significantly higher in both sICAM-1 and sE-selectin levels compared to Group 1 (243.4 vs. 157.3ngml, P<0.01 and 57.0 vs. 29.3 ng/ml, P<0.01, respectively). Hemoglobin A1c was significantly elevated across the groups (ANOVA p<0.01). A post hoc Bonferroni test showed that Group 3 had significantly higher hemoglobin A1c level compared to Group 1 (8.8 vs. 5.6 % , P<0.01). Baseline VR in blood velocity weakly correlates with sE-selectin (r=0.31, p=0.04) across all groups while sVCAM-1 was associated with VR in terms of blood flow (r=-0.62, p<0.01) in patients with mild-to-moderate NPDR. The ∆ blood flow after 6 months was found to be weakly associated with sE-selectin (r=0.46, p=0.03) across all groups. Finally, the ∆ blood velocity after 6 month time was found to be moderately correlated with baseline vWF Ag level (r=-0.78, p=0.02). Multiple regression analysis found that vascular inflammatory and endothelial function markers had weak predictive power for Δ hemodynamic parameters. Conclusions Chapter 3: We found weak associations between circulating markers and baseline or the disturbance in retinal hemodynamics after 6 months time. Overall, we found both an increase in rigidity of the arteriolar circulation and elevated inflammatory adhesion markers (sICAM-1 and sE-selectin) within the same population sample. Change in velocity over the follow-up period was correlated with sICAM-1 and A1c levels in patients with NPDR but the level of association was such that neither sICAM-1 nor A1c proved to reliably predict retinal hemodynamics. Finally, in Chapter 4 we demonstrated two important characteristics in early NPDR; 1) a disturbance in vascular reactivity in terms of compliance and 2) an increase in systemic markers of inflammation were found in patients with NPDR. Although systemic markers of vascular inflammation and endothelial dysfunction are not predictive of hemodynamic parameters, our study found moderate associations between baseline and disturbances in VR after 6 months time. Therefore, there is evidence that inflammation and vascular function may be related with respect to their development in NPDR.

Reading is one of the most important activities in most people’s life. For children, reading is a window to knowledge, good educational achievement and better job opportunities in the future. Thus reading fluency is a very important factor in the child’s education. Children and young adults with low vision usually use a close working distance to gain relative distance magnification. Unlike adults, they have active accommodation. Many studies, however, have shown that children and young adults with low vision have reduced accommodation response compared to the norms of their age. Reading additions (high plus lenses) can correct for this reduction in accommodation and may be an optimum method of prescribing magnification in younger adults with low vision. There have been no studies to verify the best method of prescribing reading additions in young adults with low vision and few studies of their effect on reading performance. This is the first study to compare different methods to determine reading additions and their effect on reading performance in young adults with low vision. The aims of the present study are 1) to investigate if three different methods to determine reading additions would lead to significantly different dioptric powers 2) to determine which method (if any) would lead to better reading performance. Reading performance was assessed by measuring the maximum reading speed, critical print size (CPS), print size threshold and the area under the reading speed curve. This was an experimental study involving thirty participants with low vision aged between 8 to 35 years. Participants were recruited from the Low Vision Clinic at the School of Optometry, University of Waterloo, Canadian National Institute for the Blind (CNIB) and the Vision Institute of Canada. All participants underwent a routine clinical examination including distance visual acuity, near visual acuity, Pelli-Robson contrast sensitivity, unilateral cover test, static retinoscopy, subjective refraction and measurement of the habitual reading distance. A questionnaire was used to determine their usage of any low vision aids, their perceived difficulty with reading and time spent reading. Reading additions were determined by 1) an objective method using Nott dynamic retinoscopy 2) an age-based formula 3) a subjective method based on the participant’s response to lenses. Reading tasks and dynamic retinoscopy were conducted at a fixed working distance of 12.5cm. Reading performance was assessed using MNREAD-style reading charts with each of the reading additions and without a reading addition, in a random order. Sentences were arranged in way that no sentence was repeated by the same participant. Participants were timed with a stop watch in order to calculate the reading speed in correct words per minute (CWPM). Reading speeds were plotted against print size to calculate the maximum reading speed, the critical print size, MNREAD threshold and the area under the reading speed curve. The participant’s mean age was 16 (± 6) years. There were equal number of males and females. The mean distance visual acuity of the tested eye ranged from 0.357 to 1.184 logMAR with a mean of 0.797 ± 0.220 logMAR. The near visual acuity ranged between 0.301 to 1.301 logMAR with a mean of 0.80 ± 0.26 logMAR. There were six participants who already had a reading addition. Maximum reading speed ranged between 52 to 257 wpm (165 ± 61 wpm). Critical print size ranged between 0.325 to 1.403 logMAR (0.965 ± 0.279 logMAR). Repeated measures ANOVA on the whole group showed that there was a significant difference between the reading additions (p=0.001). The retinoscopy reading addition power was significantly lower than the age add (p=0.002) and the subjective add (p=0.038). Repeated measures ANOVA did not show any improvement of any of the reading measures with the reading additions compared to without the reading addition. A re-analysis was undertaken excluding participants who had normal accommodation at 12.5cm. The results of repeated measures ANOVA showed that there was no significant difference in the dioptric powers obtained by the three methods, although, all reading addition power were significantly greater than zero (t-test <0.0005). There was a significant difference in the area under the reading speed curve (p=0.035), which was greater with the subjective addition than with no reading addition (p=0.048). The MNREAD threshold significantly improved with the age addition compared to no addition (p=0.012). There was a large variability between the participants in their response to a reading addition. Analysis of individual data showed that some participants showed a clear improvement in reading performance with a reading addition. Other participants did not demonstrate any obvious improvement in reading performance with reading additions. Of those participants who showed an improvement, all but one participant had abnormal accommodation. However, not all participants who did not show an improvement had normal accommodation. Univariate analysis and forward step-wise linear regression analysis were used to investigate if any improvement in reading performance and the habitual reading performance without a reading addition could be predicted by factors that were measured in the study. These factors included distance visual acuity, near visual acuity, contrast sensitivity, lag of accommodation, age, time spent on reading each day, perceived difficulty of reading regular print and whether or not the participant received training for the usage of his/her low vision aids. Improvement in reading performance could not be predicted by any of these factors. Habitual reading performance without a reading addition was correlated with some factors. Univariate analysis showed that critical print size was associated with MNREAD threshold (r=0.904. p<0.0005), distance visual acuity (r=0.681, p<0.0005) and contrast sensitivity (r=-0.428, p=0.018) and MNREAD threshold without an addition was associated with the contrast sensitivity (r=-0.431, p=0.017,) and distance visual acuity (r=0.728, p<0.0005). Difficulty of reading correlated with near visual acuity (Spearman correlation coefficient=0.620, p=0.0009), MNREAD threshold (Spearman correlation coefficient=0.450, p=0.02) and maximum reading speed (Spearman correlation coefficient=-0.472, p=0.014). Time spent on reading each day correlated with the area under the reading speed curve (Spearman correlation coefficient=0.659, p=0.0024). The multiple regression analysis showed that MNREAD threshold was best predicted by distance visual acuity (R=0.728, p <0.0005), critical print size could be predicted by distance visual acuity (R=0.681, p <0.0005) and age (R=0.748, p=0.022) and the power of the subjective addition could be predicted by age (R=0.583, p=0.001) and near visual acuity (R=0.680, p=0.028). There was evidence that a reading addition improved reading performance as measured by the area under the curve and MNREAD (reading acuity) thresholds, but this was not predicted by any visual factor, except that all those who gained improvement had poor accommodation. Therefore, it is recommended that an eye care practitioner should demonstrate a reading addition in a low vision assessment of children and young adults, particularly with patients who have reduced accommodation.

Abstract Purpose: Interocular inhibitory interactions appear to underlie the establishment of ocular dominance. The inhibitory effect leads to suppression of the non dominant eye in certain conditions. While these processes are not fully understood, the relative differences in image contrast appear to be fundamental. By titrating the relative contrast presented to each eye, a balance in the relative inhibitory effects of each eye can be defined. This research looked at whether the interocular contrast ratio at perceptual balance could be used as an index of the ocular dominance in binocular normal population, and the suppression typically found in the amblyopic population. Contrast variation was compared to luminance variation as well as the application of neutral density filters. Methods: Balance point measures were obtained by varying the interocular levels of contrast for a global motion task viewed dichoptically. One eye received signal dots moving in a given direction while the other eye received noise dots moving randomly. Subjects were tasked with determining the direction of movement of the signal dots. Balanced dichoptic motion sensitivity was achieved under a specific contrast ratio (or the balance point), depending on the observer’s binocular functions. This test was conducted on a control group (n=23) having normal vision and a strabismic amblyopic group (n=10). In addition, a variation of this test was designed with interocular luminance (rather than interocular contrast) serving as the independent variable was conducted to both the control (n=5) and amblyopic groups (n=8). Concurrent eye tracking measures measured changes in eye alignment at the balance point. Results: Although most normal vision subjects showed a balance point at close to equal levels of contrast between the eyes, a minority of them were significantly imbalanced. The suppression measured in the strabismic amblyopic group was significantly greater than that of the control group. Varying the interocular luminance instead of contrast failed to affect the coherence motion thresholds. Ocular alignment was not changed when the balance point was reached. Conclusion: Consistent with the current model of binocular integration, interocular contrast are uniquely important in establishing sensory dominance and suppression. This suggests that the interocular suppression found in amblyopia could be attenuated by methods that allow the reduction of contrast to the fellow fixing eye. Amblyopia therapy might then be improved where such contrast balancing methods are employed instead of the complete patching of the fellow eye.

Down syndrome (DS) is the most common genetic cause of mental challenge in individuals and is associated with many ocular disorders. One of these anomalies which is frequently present in this population is reduced accommodation and many studies have reported this. Accommodation is the ability of the crystalline lens in the eye to focus for objects at different distances. Prescribing bifocals could potentially help in correcting the resultant inaccurate focus, although this modality of treatment is not very commonly practiced. The impact of bifocals on reading and literacy skills (academic skills) as well as visual-perceptual skills in individuals with DS has not been studied previously. The aim of this study was to investigate the impact of bifocals on the educational attainment of children and young adults with DS who have reduced accommodation and monitor their performance longitudinally. This is the first time that the impact of bifocal provision on the functional performance of children and young adults with DS has been studied. Also for the first time in children with DS, frequent measures of performance have been used to control for progression with time before and after bifocal prescription. A battery of tests comprising early literacy and visual-perceptual skills was administered before and after bifocal prescription. Accommodation and printing skills were also measured periodically. It was expected that the prescription of bifocals would help to improve near visual acuity and that the improved near acuity would result in educational achievements at school. Compliance with spectacle wear and school reports were also considered. A longitudinal observational study design was utilized with each child acting as his/her own control. Fourteen children and teenagers aged 8-18 with DS were recruited and underwent a basic optometric exam including measurement of their accommodative ability and a cycloplegic refraction. Seventy nine percent required a change in their spectacle prescription and were prescribed single vision (SV) lenses. One hundred percent had reduced accommodation both before and after new SV glasses were prescribed. Distance visual acuity did not significantly improve with SV lenses (p>0.05) but near visual acuity showed a significant improvement (p-=0.015) from 0.64±0.25 logMAR to 0.54±0.20 logMAR. A high prevalence of high refractive errors, including both hyperopia and myopia, was observed t andnear visual acuity even with a habitual correctionwas reduced compared to distance VA. A full battery of reading and visual-perceptual tests was administered with SV lenses. Thereafter the participants were followed for 6 months and monthly subtests (probes) of literacy skills and printing tasks were administered. These “probes” acted as immediate indicators of the child’s performance with his/her correction and change in performance over this time period was monitored. Over the 6 months the participants showed no noteworthy progression in their literacy skills. The group of participants performed at an age-equivalent between 3-10 years. The quality of printing formation in this population has been studied for the first time and showed no significant change over time. It was observed that some aspects of visual-perceptual and early literacy skills could be measured in all the participants. Chronological age and receptive vocabulary were significantly correlated with visual motor integration and Word Identification. Eighty five percent of the participants were prescribed bifocals with additions ranging from +1.00D to +3.50D at the 6th month after the provision of SV lenses. Post-bifocal measures of visual acuity, accommodation, visual-perceptual and early literacy skills were taken 1-2 weeks, and finally 5 months, after bifocal correction. Throughout the pre- and post-bifocal period, verbal compliance with spectacle wear was assessed through school and parental reports. The mean near logMAR VA improved with bifocals (p=0.007) compared to SV lenses. Accommodative accuracy improved with bifocals (less accommodative lag) compared to SV lenses (p=0.002) but there was no change in the accommodation exerted through the distance portion of the lens compared to SV lenses (p=0.423). There was a main effect of bifocals on sight words (p=0.013), Word Identification (p=0.047), and 2 out of 3 tests of visual perception (p<0.05). It was observed that bifocals have a positive impact on the children’s visual and school performance and this was supported by reports of improved performance in school for nine out of eleven individuals who were prescribed bifocals. The children adapted to bifocals more readily than the SV glasses, wearing them for the majority of their waking time. All the sessions of early literacy and visual-perceptual skills administered throughout the duration of the study were videotaped and were then analyzed by a naïve examiner. The time taken to perform each task was calculated and compared between the main single vision and bifocal visits. There was a significant decrease in the completion times on the test battery with bifocals for Word Identification (p=0.0015) and the Dolch sight words (p=0.048). All participants who completed the monthly probes took less time to complete the Dolch sight words (p= 0.025) and the number writing task (p=0.001) with bifocals. Similar results were not observed for the visual-perceptual tests. Performance in the monthly probes was compared before and after bifocal prescription in terms of the average raw scores and time taken. The rate of improvement in performance with bifocals was calculated by plotting the test scores against time and determing the regression lines. There was an overall significant improvement in the monthly probe scores of Word Identification (p=0.050), Dolch sight words (p=0.025) and the number test (p=0.023) with bifocals. The rate of progression in scores increased with bifocals for the Word Identification (p=0.008). Evidence of improved and faster performance with bifocals on some literacy skills was seen. It was concluded that bifocals, which result in improved near focusing, help individuals with DS to maximize their educational potential. It is suggested that more children and teenagers with DS will benefit from bifocal prescription, as they were observed to improve near visual acuity and enable better focusing for near. This thesis has provided a comprehensive analysis of the some tests of literacy, visual- perceptual and early printing skills before and after a bifocal prescription in a group of children and teenagers with Down syndrome. This is the first study to longitudinally monitor the educational impact of bifocals in a population with Down syndrome. Furthermore, the quality of printing formation in this population is a previously unstudied area and was studied longitudinally prior to and after bifocal intervention. The impact of bifocals on printing skills is also discussed. Another novel approach was that all the literacy, writing and visual-perceptual tasks sessions were videotaped to calculate the time taken to complete each task pre- and post-bifocals. This thesis is an addition to the existing literature on bifocal prescription in Down syndrome populations. From the findings in this thesis, the following recommendations are made in order to improve the standard of clinical eye care in this population. Measurement of accommodation should be considered a routine test in the clinical ocular examination for young individuals with DS, now that it is known that many of them present with accommodative deficits. When accommodation is found to be reduced, prescription of bifocals is indicated and should also become the standard of care in this population.

Abnormal leukocyte adhesion (i.e. leukostasis) to retinal vascular endothelial cells occurs in early diabetes. The processes of leukostasis have been clearly demonstrated in the vascular endothelium of patients with diabetes. In non-proliferative DR, clinical outcomes are manifested by excessive permeability from inflammatory progression leading to inner blood retinal barrier disruption, endothelial cell damage and widespread capillary nonperfusion. Diabetes promotes vascular leakage in DR by upregulation of adhesion molecules. Moreover, many of the pathological changes in NPDR are related to abnormalities in retinal blood flow. Studies have shown that specific circulating markers of inflammatory activity and endothelial dysfunction are associated with clinical signs of diabetic retinopathy. However, few have found an association between circulating levels of inflammatory and endothelial dysfunctional markers and abnormal retinal hemodynamics in patients with non-proliferative DR. The specific aims of this thesis are as follows: (Chapter 3)To correlate baseline levels of inflammatory and endothelial dysfunction markers and 1) baseline retinal arteriolar hemodynamics and 2) any disturbance in retinal hemodynamics over 6-month time in terms of vessel diameter, blood velocity, maximum-to-minimum velocity ratio and volumetric flow. In Chapter 4: To correlate circulating levels of inflammatory and endothelial dysfunction markers and 1) baseline vascular reactivity and 2) any disturbance in vascular reactivity after 6-month time in terms of vessel diameter, blood velocity, maximum-to-minimum velocity ratio and volumetric flow in patients with increasing non-proliferative diabetic retinopathy (NPDR) severity. Methods for Chapter 3: Diabetes subjects were stratified into either mild-to-moderate (Group 2) or moderate-to-severe (Group 3) NPDR based on their retinopathy status. Age-matched non-diabetics were recruited as controls (Group 1). Forearm blood sample was collected to determine baseline levels of inflammatory and endothelial dysfunctional markers. At visit 1, baseline retinal hemodynamics was acquired using Canon Laser Blood Flowmeter. Patients returned for a visit 2 (6 month follow-up visit) and retinal hemodynamics was reassessed. Baseline levels of inflammatory and endothelial dysfunctional markers compared between groups and correlated with both baseline and change in retinal hemodynamic parameters over 6-month time. For Chapter 4: Diabetes subjects were stratified into either mild-to-moderate NPDR or moderate-to-severe NPDR based on their retinopathy status. Age-matched non-diabetics were recruited as controls. At visit 1, forearm blood sample was collected to determine levels of inflammatory and endothelial dysfunctional markers and baseline vascular reactivity response was acquired. Retinal blood flow data was acquired while subjects breathed air. Retinal blood flow measurements were then acquired after exposure to isocapnic hyperoxic stimuli. At visit 2 (6 month follow-up), retinal vascular reactivity was reassessed. Baseline levels of inflammatory and endothelial dysfunctional markers compared between groups and correlated with both magnitude of baseline and change in vascular reactivity in terms of retinal hemodynamics. Results of Chapter 3: Maximum-to-minimum velocity ratio (max: min) was found to be significantly elevated in the group 3 compared to group 1 at baseline (0.72 vs. 0.49, after Bonferroni correction P<0.01). Both sICAM-1 and sE-selectin were significantly elevated as a function of group (ANOVA p=0.02 and p=0.04). A post hoc Bonferroni test showed that Group 3 had significantly higher in both sICAM-1 and sE-selectin levels compared to Group 1 (234.0 vs. 151.5 ng/ml, P=0.02 and 53.4 vs. 27.6 ng/ml, P<0.01, respectively). Hemoglobin A1c was significantly elevated across the groups (ANOVA p<0.01). A post hoc Bonferroni test showed that Group 3 had significantly higher hemoglobin A1c level compared to Group 1 (7.9 vs. 5.6 % , P<0.01). There were no significant associations found between baseline markers of inflammation and baseline retinal hemodynamics across all groups. The Δ velocity was correlated with the baseline sICAM-1 (r=0.42, p=0.02) and A1c levels (r=0.37, p=0.04) in patients with NPDR. After adjustment for all other variables (A1c, hsCRP and vWF), Δ velocity, sICAM-1 and A1c were found not to be reliable predictors of baseline retinal hemodynamics. For Chapter 4: There were no significant differences in magnitude of retinal vascular reactivity in hemodynamic parameters between groups at visit 1 or visit 2. Over 6 months time, compliance was found to be significantly reduced in patients of Group 3 compared to Group 2 (-0.4 vs. 0.1, t-test p<0.01). Both sICAM-1 and sE-selectin were significantly elevated as a function of group (ANOVA p=0.02 and p<0.01). A post hoc Bonferroni test showed that Group 3 had significantly higher in both sICAM-1 and sE-selectin levels compared to Group 1 (243.4 vs. 157.3ngml, P<0.01 and 57.0 vs. 29.3 ng/ml, P<0.01, respectively). Hemoglobin A1c was significantly elevated across the groups (ANOVA p<0.01). A post hoc Bonferroni test showed that Group 3 had significantly higher hemoglobin A1c level compared to Group 1 (8.8 vs. 5.6 % , P<0.01). Baseline VR in blood velocity weakly correlates with sE-selectin (r=0.31, p=0.04) across all groups while sVCAM-1 was associated with VR in terms of blood flow (r=-0.62, p<0.01) in patients with mild-to-moderate NPDR. The ∆ blood flow after 6 months was found to be weakly associated with sE-selectin (r=0.46, p=0.03) across all groups. Finally, the ∆ blood velocity after 6 month time was found to be moderately correlated with baseline vWF Ag level (r=-0.78, p=0.02). Multiple regression analysis found that vascular inflammatory and endothelial function markers had weak predictive power for Δ hemodynamic parameters. Conclusions Chapter 3: We found weak associations between circulating markers and baseline or the disturbance in retinal hemodynamics after 6 months time. Overall, we found both an increase in rigidity of the arteriolar circulation and elevated inflammatory adhesion markers (sICAM-1 and sE-selectin) within the same population sample. Change in velocity over the follow-up period was correlated with sICAM-1 and A1c levels in patients with NPDR but the level of association was such that neither sICAM-1 nor A1c proved to reliably predict retinal hemodynamics. Finally, in Chapter 4 we demonstrated two important characteristics in early NPDR; 1) a disturbance in vascular reactivity in terms of compliance and 2) an increase in systemic markers of inflammation were found in patients with NPDR. Although systemic markers of vascular inflammation and endothelial dysfunction are not predictive of hemodynamic parameters, our study found moderate associations between baseline and disturbances in VR after 6 months time. Therefore, there is evidence that inflammation and vascular function may be related with respect to their development in NPDR.

Introduction: Oxygen delivery, or utilization, is a function of retinal blood flow and blood oxygen saturation. The retinal pigment epithelium (RPE), in particular, has been shown to have the highest levels of metabolic activity within the human body. Oxygen delivery is therefore of extreme importance to the maintenance of the health and integrity of the retina. Animal models presuppose that the oxygen tension in the retina is highest in the innermost layers at the level of the choriocapillaris, less in the photoreceptors and further decreases throughout the outer retinal structures. The choroid provides by far the largest component of the oxygen for consumption by the photoreceptors. A lack of oxygen stores in the inner retina therefore makes a constant supply crucial for its normal functioning. Blood flow dysfunction and subsequent hypoxia are both a feature in the pathogenesis of several major ocular diseases such as retinopathy of prematurity (ROP), age-related macular degeneration (ARMD), diabetic retinopathy (DR) and glaucoma. The development of methods to measure retinal blood flow and blood oxygen saturation is crucial to improve understanding of the patho-physiology of major ocular diseases. Purpose: The aims of this work were, firstly, to determine the least variable (range ± standard deviation) wavelength combination (610/548, 600/569 and 605/586) and subsequent ODR with the prototype HRC device. Secondly, using the ODR with the lowest measurement variability, we sought to quantify retinal blood SO2 in arterioles and venules and investigate the relationship between retinal blood SO2 and total retinal blood flow (TRBF) in response to stepwise changes in PETO2 in healthy participants. Retinal blood SO2 and TRBF were assessed using the IRIS HRC (Photon etc. Inc. Montreal, Canada) and the RTvue Doppler Fourier Domain OCT (Optovue Inc, Freemont, CA) instruments, respectively. Methods: Ten healthy participants between the ages of 23 and 37, with an average age of 28.3 years were evaluated in two descriptive cross-sectional studies. Two gas provocation protocols; hyperoxia (end-tidal oxygen; PETO2 of 100, 200, 300, 400mmHg) and hypoxia (PETO2 of 100, 80, 60, 50mmHg) were administered in a fixed sequential order. In each phase of gas provocation (via modulation of PETO2), retinal blood SO2 and TRBF measurements were acquired with the HRC and Doppler FD-OCT. The precise and repeated control of the partial end tidal pressures of oxygen (PETO2) and carbon dioxide (PETCO2) over the pre-determined phase duration, irrespective of the individuals’ respiratory rate, was made possible with the RespirAct (Thornhill Research Inc., Toronto, Canada); a sequential re-breathing gas delivery Results: In arterioles, the group range (±SD) of ODR values for baseline measurements (PETO2 of 100mmHg) was 0.169±0.061 for the 605/586 wavelength combination, 0.371±0.099 for the 600/569 wavelength combination and 0.340±0.104 for the 610/548 wavelength combination. In venules, the group range (±SD) of ODR values was 0.600±0.198 for the 605/586 wavelength combination, 0.569±0.169 for the 600/569 wavelength combination and 0.819±0.274 for the 610/548 wavelength combination. With the 605/586 combination at baseline 1 and 2 in arterioles, the group range (±SD) of ODR values was 0.607 ± 0.224 and 0.619 ± 0.158, respectively (p = 0.370), while in venules the group range (±SD) of ODR at baseline 1 and 2 was 0.289±0.750 and 0.284 ± 0.729, respectively (p = 0.714). For the 600/569 combination at baseline 1 and 2 in arterioles, the group range (±SD) of ODR values was 0.747±0.350 and 0.761±0.391, respectively (p = 0.424) while in venules the group range (±SD) of ODR at baseline 1 and 2 was 0.329±0.675 and 0.366±0.659, respectively (p = 0.372). For the 610/548 combination at baseline 1 and 2 in arterioles, the group range (±SD) of ODR values was 0.604±0.263 and 0.685±0.450, respectively (p = 0.056) while in venules, the group range (±SD) of ODR at baseline 1 and 2 was 0.292±0.746 and 0.285±1.009, respectively (p = 0.131). There was no statistical difference found between baseline ODR values (baseline 1 and 2) across all three wavelength combinations in both arterioles and venules. The mean retinal blood SO2 value at baseline in arterioles for 4 participants was 95.19% ± 31.04% and venules was 53.89% ± 17.24% (p = 0.115). There was a negative linear relationship between group retinal blood SO2 and TRBF values in the 10 participants studied, although the results of any of the 10 individuals did not show evidence of such a relationship using the described methodology. The Pearson’s correlation coefficient (r) between TRBF and SaO2 was r = -0.354 and p = 0.001 and between TRBF and SvO2 was r = - 0.295, p = 0.008 Conclusion: Of the three wavelength combinations investigated (605/586, 600/569 and 610/548), the 605/586 combination was shown to have the overall least variability. It would be unwise at this stage to adopt this wavelength combination for clinical usage, however, since it is presupposed that the 605/586 combination is also the most reliable combination to detect change in retinal blood SO2 i.e. lower variability of the 605/586 combination may be irrelevant if this combination proves to be insensitive to change in retinal blood SO2. The absolute mean ± SD retinal blood SO2 in the arterioles (SaO2) was 95.19% ± 31.04% and in the venules (SvO2) was 53.89% ± 17.24%. These values fell within the range expected and described in the literature. The magnitude of the difference between the SaO2 and SvO2 was also consistent with the literature. These findings were all appropriate for a low flow, high oxygen exchange vascular network typical of the inner retinal vascular system. Using group rather than individual data, TRBF was found in this study to relate inversely with SaO2 (r = -0.354 and p = 0.001) and SvO2 (r = – 0.295 and p=0.008), respectively. This relationship between TRBF and SaO2 and SvO2, was as expected based upon data derived primarily from animal models. This study is ground-breaking and unique, in that, it is the first study to concomitantly measure both retinal blood SO2 and TRBF in human participants. Individual data showed extensive variability and noise, thus limiting the strength of the association between TRBF and SaO2 and SvO2..

Previous studies have demonstrated that observers may ignore highly salient feature singletons during a conjunction search task through focusing the attentional window (Belopolsky, Zwaan, Theeuwes, & Kramer, 2007), or by the suppression of bottom-up information (Treisman & Sato, 1990). In the current study, observers’ eye movements were monitored while performing a search task in which a feature singleton was present and corresponded with the target at a chance level. With practice, observers were less likely to make an initial saccade toward the singleton item, but initial saccades directed at the target were likely throughout. Results demonstrate that, in an effort to ignore the singleton, observers were more likely to suppress bottom-up information than adjust the size of the attentional window.

Reading is one of the most important activities in most people’s life. For children, reading is a window to knowledge, good educational achievement and better job opportunities in the future. Thus reading fluency is a very important factor in the child’s education. Children and young adults with low vision usually use a close working distance to gain relative distance magnification. Unlike adults, they have active accommodation. Many studies, however, have shown that children and young adults with low vision have reduced accommodation response compared to the norms of their age. Reading additions (high plus lenses) can correct for this reduction in accommodation and may be an optimum method of prescribing magnification in younger adults with low vision. There have been no studies to verify the best method of prescribing reading additions in young adults with low vision and few studies of their effect on reading performance. This is the first study to compare different methods to determine reading additions and their effect on reading performance in young adults with low vision. The aims of the present study are 1) to investigate if three different methods to determine reading additions would lead to significantly different dioptric powers 2) to determine which method (if any) would lead to better reading performance. Reading performance was assessed by measuring the maximum reading speed, critical print size (CPS), print size threshold and the area under the reading speed curve. This was an experimental study involving thirty participants with low vision aged between 8 to 35 years. Participants were recruited from the Low Vision Clinic at the School of Optometry, University of Waterloo, Canadian National Institute for the Blind (CNIB) and the Vision Institute of Canada. All participants underwent a routine clinical examination including distance visual acuity, near visual acuity, Pelli-Robson contrast sensitivity, unilateral cover test, static retinoscopy, subjective refraction and measurement of the habitual reading distance. A questionnaire was used to determine their usage of any low vision aids, their perceived difficulty with reading and time spent reading. Reading additions were determined by 1) an objective method using Nott dynamic retinoscopy 2) an age-based formula 3) a subjective method based on the participant’s response to lenses. Reading tasks and dynamic retinoscopy were conducted at a fixed working distance of 12.5cm. Reading performance was assessed using MNREAD-style reading charts with each of the reading additions and without a reading addition, in a random order. Sentences were arranged in way that no sentence was repeated by the same participant. Participants were timed with a stop watch in order to calculate the reading speed in correct words per minute (CWPM). Reading speeds were plotted against print size to calculate the maximum reading speed, the critical print size, MNREAD threshold and the area under the reading speed curve. The participant’s mean age was 16 (± 6) years. There were equal number of males and females. The mean distance visual acuity of the tested eye ranged from 0.357 to 1.184 logMAR with a mean of 0.797 ± 0.220 logMAR. The near visual acuity ranged between 0.301 to 1.301 logMAR with a mean of 0.80 ± 0.26 logMAR. There were six participants who already had a reading addition. Maximum reading speed ranged between 52 to 257 wpm (165 ± 61 wpm). Critical print size ranged between 0.325 to 1.403 logMAR (0.965 ± 0.279 logMAR). Repeated measures ANOVA on the whole group showed that there was a significant difference between the reading additions (p=0.001). The retinoscopy reading addition power was significantly lower than the age add (p=0.002) and the subjective add (p=0.038). Repeated measures ANOVA did not show any improvement of any of the reading measures with the reading additions compared to without the reading addition. A re-analysis was undertaken excluding participants who had normal accommodation at 12.5cm. The results of repeated measures ANOVA showed that there was no significant difference in the dioptric powers obtained by the three methods, although, all reading addition power were significantly greater than zero (t-test <0.0005). There was a significant difference in the area under the reading speed curve (p=0.035), which was greater with the subjective addition than with no reading addition (p=0.048). The MNREAD threshold significantly improved with the age addition compared to no addition (p=0.012). There was a large variability between the participants in their response to a reading addition. Analysis of individual data showed that some participants showed a clear improvement in reading performance with a reading addition. Other participants did not demonstrate any obvious improvement in reading performance with reading additions. Of those participants who showed an improvement, all but one participant had abnormal accommodation. However, not all participants who did not show an improvement had normal accommodation. Univariate analysis and forward step-wise linear regression analysis were used to investigate if any improvement in reading performance and the habitual reading performance without a reading addition could be predicted by factors that were measured in the study. These factors included distance visual acuity, near visual acuity, contrast sensitivity, lag of accommodation, age, time spent on reading each day, perceived difficulty of reading regular print and whether or not the participant received training for the usage of his/her low vision aids. Improvement in reading performance could not be predicted by any of these factors. Habitual reading performance without a reading addition was correlated with some factors. Univariate analysis showed that critical print size was associated with MNREAD threshold (r=0.904. p<0.0005), distance visual acuity (r=0.681, p<0.0005) and contrast sensitivity (r=-0.428, p=0.018) and MNREAD threshold without an addition was associated with the contrast sensitivity (r=-0.431, p=0.017,) and distance visual acuity (r=0.728, p<0.0005). Difficulty of reading correlated with near visual acuity (Spearman correlation coefficient=0.620, p=0.0009), MNREAD threshold (Spearman correlation coefficient=0.450, p=0.02) and maximum reading speed (Spearman correlation coefficient=-0.472, p=0.014). Time spent on reading each day correlated with the area under the reading speed curve (Spearman correlation coefficient=0.659, p=0.0024). The multiple regression analysis showed that MNREAD threshold was best predicted by distance visual acuity (R=0.728, p <0.0005), critical print size could be predicted by distance visual acuity (R=0.681, p <0.0005) and age (R=0.748, p=0.022) and the power of the subjective addition could be predicted by age (R=0.583, p=0.001) and near visual acuity (R=0.680, p=0.028). There was evidence that a reading addition improved reading performance as measured by the area under the curve and MNREAD (reading acuity) thresholds, but this was not predicted by any visual factor, except that all those who gained improvement had poor accommodation. Therefore, it is recommended that an eye care practitioner should demonstrate a reading addition in a low vision assessment of children and young adults, particularly with patients who have reduced accommodation.

Inherited retinal degenerative diseases can affect various components of the retina leading to blindness. Five different mutant strains of chicken have been studied extensively as potential models for inherited retinal degeneration. The Smoky Joe (SJ) chicken is a sixth genetically blind strain of White Leghorns that shows various degrees of blindness at hatch and by 8 weeks post-hatch, have complete blindness for those that are homozygous. The objective of this study was to characterize the retinal degeneration in these birds by histology, both during embryonic and post-hatch development, and to the retinal function using electroretinograms (ERG). For both embryonic and post-hatch development, a significantly lower number of cells were found in the retina of blind birds compared to sighted (both p<0.0001). The significant contributor to cell number decrease was the loss of amacrine cells located in the inner nuclear layer. Photoreceptors were also found to potentially decrease in number, but at a later stage. ERG recordings revealed decreases in amplitudes of b-waves and oscillatory potentials in blind birds, but not in sighted. Both histology and ERG findings support the idea that the inner retinal cells are affected. The results indicate that degeneration in the Smoky Joe retina occurs mostly within the inner nuclear layer affecting amacrine cells. This hampers the functional capacity of the retina, causing blindness.

Abstract Purpose: Interocular inhibitory interactions appear to underlie the establishment of ocular dominance. The inhibitory effect leads to suppression of the non dominant eye in certain conditions. While these processes are not fully understood, the relative differences in image contrast appear to be fundamental. By titrating the relative contrast presented to each eye, a balance in the relative inhibitory effects of each eye can be defined. This research looked at whether the interocular contrast ratio at perceptual balance could be used as an index of the ocular dominance in binocular normal population, and the suppression typically found in the amblyopic population. Contrast variation was compared to luminance variation as well as the application of neutral density filters. Methods: Balance point measures were obtained by varying the interocular levels of contrast for a global motion task viewed dichoptically. One eye received signal dots moving in a given direction while the other eye received noise dots moving randomly. Subjects were tasked with determining the direction of movement of the signal dots. Balanced dichoptic motion sensitivity was achieved under a specific contrast ratio (or the balance point), depending on the observer’s binocular functions. This test was conducted on a control group (n=23) having normal vision and a strabismic amblyopic group (n=10). In addition, a variation of this test was designed with interocular luminance (rather than interocular contrast) serving as the independent variable was conducted to both the control (n=5) and amblyopic groups (n=8). Concurrent eye tracking measures measured changes in eye alignment at the balance point. Results: Although most normal vision subjects showed a balance point at close to equal levels of contrast between the eyes, a minority of them were significantly imbalanced. The suppression measured in the strabismic amblyopic group was significantly greater than that of the control group. Varying the interocular luminance instead of contrast failed to affect the coherence motion thresholds. Ocular alignment was not changed when the balance point was reached. Conclusion: Consistent with the current model of binocular integration, interocular contrast are uniquely important in establishing sensory dominance and suppression. This suggests that the interocular suppression found in amblyopia could be attenuated by methods that allow the reduction of contrast to the fellow fixing eye. Amblyopia therapy might then be improved where such contrast balancing methods are employed instead of the complete patching of the fellow eye.