Retinal blur experienced by myopes during near work has been linked to myopia development and progression. Whether poor responses to blur signals are due to poor perceptual blur sensitivity (subjective depth of focus), poor neural accommodation responses (objective depth of focus) to blur or optical differences such as higher order aberrations making blur detection difficult is yet unclear. This study investigates whether myopes respond to blur differently compared to emmetropes and whether filtering spatial frequencies in reading text influence accommodation responses. Accommodative functions were investigated using spatial frequency filtered text targets of two different sizes (N10 and N20). Monocular objective depth of focus (DOF), accommodative microfluctuations, and dynamic accommodation were measured. Subjective DOF after cycloplegia was also recorded with the same targets. Higher order aberration measurements explored optical contributions to blur. Peripheral refraction and accommodative lag were also measured to consider how in combination they might increase peripheral retinal blur for near tasks. Results showed that myopes demonstrated larger subjective DOF. Subjective DOF was larger when viewing the peak text spatial frequency in both refractive error groups. The optimum focus was more myopic for text peak spatial frequencies. Levels of spherical aberration were correlated with the point of optimum focus. Objective DOF and accommodative microfluctuations were larger in myopes when viewing the peak text spatial frequencies. Dynamic accommodation showed that while myopes were not poorer at initiating accommodation responses they had longer positive response times. Accommodative lag, although not different in myopes, increases the peripheral hyperopic blur experienced for near tasks. Conclusion: Myopes were poorer at using retinal blur cues to refine accommodation responses especially when viewing peak text spatial frequencies. Larger positive response times, DOF and accommodative microfluctuations in myopes resulted in accommodative error and hyperopic blur for near tasks. Spherical aberration, previously thought to provide a myopigenic stimulus, was not different between refractive groups and is unlikely to be large enough to enhance DOF during naturalistic viewing. Blur adaptation studies might consider using peak text spatial frequencies as adaptation targets to reduce accommodation differences in myopes and emmetropes. Optical treatment strategies aimed at correcting peripheral refraction to control myopia should consider the combined effect of accommodative lag which increases levels of hyperopic peripheral blur experienced by myopes.

Zhang Lin. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1999. / Includes bibliographical references (leaves 68-86). / Abstracts in English and Chinese. / ACKNOWLEDGEMENTS --- p.i / TABLE OF CONTENTS --- p.ii / ABBREVIATIONS --- p.v / LIST OF TABLES --- p.vi / LIST OF FIGURES --- p.vii / Chapter 1. --- ABSTRACT (ENGLISH/CHINESE) --- p.1 / Chapter 2. --- INTRODUCTION --- p.6 / Chapter 3. --- LITERATURE REVIEW --- p.9 / Chapter 3.1. --- MYOPIA IN HUMAN --- p.9 / Chapter 3.1.1. --- Different types of myopia --- p.9 / Chapter 3.1.2. --- The pathologic change of myopia --- p.10 / Chapter 3.1.3. --- The prevalence of myopia --- p.13 / Chapter 3.1.4. --- Hereditary influence in human myopia --- p.13 / Chapter 3.1.5. --- Environmental influence in human myopia --- p.15 / Chapter 3.1.6. --- Nutrition in human myopia --- p.16 / Chapter 3.1.7. --- Pharmacological agents used to prevent progression of myopia --- p.16 / Chapter 3.1.8. --- Contact lens in the prevention of progression human myopia --- p.17 / Chapter 3.2. --- ANIMAL MODELS OF EXPERIMENTAL MYOPIA --- p.19 / Chapter 3.2.1. --- Experimental myopia in monkeys --- p.19 / Chapter 3.2.2. --- Experimental myopia in three shrew --- p.21 / Chapter 3.2.3. --- Experimental myopia in marmosets and guinea pigs --- p.23 / Chapter 3.2.4. --- Experimental myopia in chicks --- p.24 / Chapter 3.2.5. --- Summary --- p.26 / Chapter 3.3. --- PHARMACOLOGICAL STUDIES --- p.27 / Chapter 4. --- OBJECTIVES --- p.32 / Chapter 5. --- materials and methods --- p.34 / Chapter 5.1. --- ANIMALS AND INDUCTION OF FORM DEPRIVATION MYOPIA --- p.34 / Chapter 5.2. --- EYE GROWTH AND MYOPIC STUDY --- p.35 / Chapter 5.2.1. --- Refractive measurements --- p.35 / Chapter 5.2.2. --- Ultrasonographic measurements of eye size in vivo --- p.35 / Chapter 5.2.3. --- Measurements with calipers on enucleated eyes --- p.36 / Chapter 5.2.4. --- Weight of eye globes --- p.36 / Chapter 5.3. --- RETINAL CHANGE --- p.36 / Chapter 5.3.1. --- Light microscopy --- p.36 / Chapter 5.3.2. --- Calretinin immuno-reactivity study of the myopic retina --- p.37 / Chapter 5.4. --- DETECTION OF APOPTOTIC CELL DEATH --- p.38 / Chapter 5.4.1. --- TUNEL --- p.38 / Chapter 5.5. --- EFFECT OF RETINAL TOXINS ON MYOPIC EYES --- p.39 / Chapter 5.5.1. --- Intravitreal injection of iodoacetic acid (IAA) --- p.39 / Chapter 5.5.2. --- Intravitreal injection of glutamic acid --- p.40 / Chapter 5.5.3. --- "Intravitreal injection of 5,7-dihydrowytryptamine (5,7-DHT)" --- p.40 / Chapter 5.6. --- EFFECT OF LIGHTING ON MYOPIC EYES --- p.41 / Chapter 6. --- RESULTS --- p.42 / Chapter 6.1. --- REFRACTIVE STATES --- p.42 / Chapter 6.2. --- EYE SIZE MEASUREMENTS --- p.42 / Chapter 6.2.1. --- Ultrasonographic measurements in vivo --- p.42 / Chapter 6.2.2. --- Caliper measurements of chick eyes ex vivo --- p.43 / Chapter 6.3. --- WEIGHT OF EYE GLOBES --- p.45 / Chapter 6.4. --- RETINAL CHANGE --- p.45 / Chapter 6.4.1. --- Morphological features --- p.45 / Chapter 6.4.2. --- Morphometry of calretinin immuno-positive cells --- p.46 / Chapter 6.5. --- EFFECT OF RETINAL TOXINS ON MYOPIC EYE --- p.46 / Chapter 6.5.1. --- Intravitreal injection of iodoacetic acid (IAA) --- p.46 / Chapter 6.5.1.1. --- Eye growth measurements --- p.47 / Chapter 6.5.1.2. --- Retinal histological features --- p.47 / Chapter 6.5.2. --- Intravitreal injection of glutamic acid --- p.48 / Chapter 6.5.2.1. --- Eye growth measurements --- p.48 / Chapter 6.5.2.2. --- Retinal histological features --- p.49 / Chapter 6.5.3. --- "Intravitreal injection of 5,7,-dihydrowytryptamine (5,7-DHT)" --- p.50 / Chapter 6.5.3.1. --- Eye growth measurements --- p.50 / Chapter 6.5.3.2. --- Retinal histological features --- p.50 / Chapter 6.6. --- EFFECT OF LIGHTING ON MYOPIC EYES --- p.51 / Chapter 6.6.1. --- Eye growth measurements --- p.51 / Chapter 6.6.2. --- Retinal histological features --- p.51 / Chapter 7. --- DISCUSSION --- p.53 / Chapter 7.1. --- REFRACTIVE STATES --- p.55 / Chapter 7.2. --- CHANGE IN EYE SIZE --- p.56 / Chapter 7.2.1. --- The rate of eye growth --- p.56 / Chapter 7.2.2. --- Ultrasonographic measurements --- p.57 / Chapter 7.2.3. --- Axial length change with caliper measurements --- p.58 / Chapter 7.3. --- MORPHOLOGY AND MORPHOMETRY OF MYOPIC RETINA --- p.58 / Chapter 7.4. --- EFFECT OF RETINAL TOXINS ON MYOPIC EYES --- p.60 / Chapter 7.4.1. --- Intravitreal injection of iodoacetic acid --- p.60 / Chapter 7.4.2. --- Intravitreal injection of glutamic acid --- p.61 / Chapter 7.4.3. --- "Intravitreal injection of 5,7-DHT" --- p.63 / Chapter 7.5. --- EFFECT OF LIGHTING ON MYOPIC EYES --- p.64 / Chapter 8. --- CONCLUSION --- p.66 / BIBLIOGRAPHY --- p.68

Accommodation and vergence are two interacting ocular motor systems that function to maintain clear and single vision across a wide range of distances. Sustained fixation results in the adaptation of these ocular motor systems and has been widely investigated in adults but not in children. Moreover, limited reports have measured adaptation to disparities induced by ophthalmic lenses. This thesis used near addition lenses as a means to investigate binocular adaptation in children. The specific aims of this thesis were three-fold. First, the thesis aimed to gain insight into the mechanism of changes to accommodation and vergence during binocular adaptation in children. The second objective was to determine the role of vergence-bias category (eso/exo/normals) on adaptation. Lastly, this thesis evaluated the influence of myopia on binocular adaptation. Thirty- eight myopic and 38 emmetropic children between 7-14 years of age were examined for the purpose of this thesis. A series of studies were performed to evaluate adaptation using varying demands for accommodation and vergence, stimulated by binocular fixation at near (33 cm), through the addition of +2D and -2D over corrective lenses (closed loop accommodation) and using 10 base-out prisms (open-loop accommodation at 4M). In each closed-loop condition, measures of binocular and monocular accommodation (PowerRefractor, Multichannel systems) and near phoria (modified Thorington technique) were recorded at frequent intervals when children binocularly fixated a high contrast near target (33 cm) for 20 min. For the open-loop condition (obtained using 0.5 mm pinhole pupils), binocular accommodation and tonic vergence (distance heterophoria through pinhole pupils) were determined at frequent intervals when binocular fixation was sustained at 4M for 20 min. For all conditions, tonic accommodation was measured before and after the near task to measure accommodative adaptation. The results of this thesis make three major contributions to the literature. First, it outlines that the addition of +2D and -2D lenses alters both accommodation and near phoria during sustained binocular fixation, which can be explained based on the models of accommodation and vergence. Second, it shows that the direction of phoria influences the pattern of binocular vs. monocular accommodation in closed-loop conditions and alters the degree of vergence adaptation in both closed and open-loop accommodation. These changes have been primarily attributed to the varying demands on fusional vergence. Lastly, this thesis demonstrates that myopic children show reduced vergence adaptation when fusional convergence was initiated through plus adds or base-out prisms but not when fusional divergence was initiated through minus addition lenses. Further, myopic children also showed variations in other ocular motor parameters such as higher accommodative lags, greater variability of accommodative response, larger accommodative after-effects, and higher AV/A ratios compared to emmetropes. Consistent with the models of accommodation and vergence, the thesis highlights that it is necessary to measure changes to both accommodation and vergence when evaluating the response of the ocular motor system. The direction of phoria and type of refractive error play a significant role in determining binocular adaptation in children. Future studies should differentiate these parameters when evaluating adaptation of the ocular motor system.

No description available.

<p>The visual system in humans provides the ability to interpret our surroundings from many distances. This complex system serves as a powerful sense which can drastically impact the quality of life when threatened or eliminated. While the mechanisms involved in visual interpretation are largely understood, many of the mechanisms of ocular diseases remain elusive. The most common ocular disorders are refractive errors, where failure of normal growth processes results in eye components with shape and sizes that are not matched to provide uncorrected sharp visual acuity without correction. Myopia, or nearsightedness, is a refractive error with prevalence rates of epidemic proportions in some urban Asian settings, and rising in other developed countries. Pathological, or high myopia, has an increased risk for potentially blinding ocular morbidities which can be irreversible and further negatively impact quality of life. Myopia, like other common ocular disorders, results from a combination of environmental and genetic factors. Over 20 candidate genomic regions have been identified as involved in myopic development progression. </p><p>One such locus, <italic>MYP3</italic>, on chromosome 12q21-23 spans nearly 44 Mb with more than 200 protein-encoding genes mapped within. Sizable candidate disease genomic regions typically require refinement to identify genes or variants within them which may contribute to disease development. Without an understanding of the underlying mechanistic framework of a disease, as is the case with myopia, biological inferences are difficult to make in prioritizing candidates, which can make finding true disease causing variants seem like finding a needle in a haystack. A better understanding of human ocular growth, as it relates to refractive error, may lead to more knowledgeable approaches to identifying the cause(s) of myopic development and associated ocular diseases. </p><p>To identify genes involved in ocular growth and development, whole genome expression patterns were assessed in human ocular tissues of fetal versus adult eyes, and adult posterior versus peripheral tissues. No database exists of fetal ocular tissue gene expression. In addition to providing insights into expression patterns during ocular development, these tissues were also compared as a surrogate to study rapid eye growth states such as in myopia. Only ocular tissue types with clinical phenotypes associated with myopic development were considered. Human retina/retinal pigment epithelium (RPE), choroid, sclera, cornea* and optic nerve* tissues were isolated from fetal (N=9; *N= 6) and adult (N=6) normal donor eyes. The Illumina® whole genome expression microarray platform was used to assess differential expression of genes. Fetal tissues were compared to their adult counterparts while adult posterior tissues were compared to their peripheral counterparts, and the differences in each were assessed using Ingenuity Pathway Analysis (IPA) for enriched functional groups and canonical pathways. Statistical significance for all tissue comparisons was determined using the Benjamin and Hochberg False Discovery Rate (FDR, 5%). Differentially expressed genes were compared to previously identified candidates for myopic development.</p><p>Additionally, qualitative and quantitative association studies in a large family (N=82) based high myopia cohort by genotyping 768 single nucleotide polymorphisms (SNPs) in the peak linkage area was performed to fine map the <italic>MYP3</italic> linkage peak. Qualitative testing for high myopia (&#8804; -5 diopter (D) affected, > -5 D unaffected) and quantitative testing on the average (avg) dioptric sphere (SPH) was performed. Five candidate SNPs were genotyped in a replicate high myopia cohort for independent validation. Additionally, the most significant SNPs were screened in a previously genotyped twin cohort as a second independent validation cohort.</p><p>Ocular growth expression data were used to help prioritize the resulting association candidates as supporting evidence and was not used on its own to identify or exclude candidates. Candidate genes (within 100 kilobases (kb) of highly associated SNPs) identified through either qualitative or quantitative association testing were screened in the most disease relevant tissues (retina/ retinal pigment epithelium (RPE), choroid and sclera) for differential expression during ocular growth and by physical regions of the tissues within the eye. Genes that were identified by microarray studies as being differentially expressed in one or more tissue were validated using quantitative real time PCR (RT-qPCR). </p><p>Significant gene expression changes with fold changes > 1.5 were found in adult versus fetal retina/RPE (N=1185), choroid (N=6446), sclera (N=1349), and cornea (N=3872), but not the optic nerve nor any of the central versus peripheral tissues. In all adult versus fetal tissues, differentially expressed genes belonging to cancer, development, and cell death/growth functional groups, as well as signaling canonical pathways were enriched. Seventeen genes previously associated with increased susceptibility for non-syndromic high myopia were in the most significant functional assignments for at least one adult versus fetal ocular tissue. In adult central versus peripheral tissues, there was considerably more variation by tissue in enriched functions and canonical pathways of differentially expressed genes. The only functional category shared by all three tissue types was development. </p><p><italic>MYP3</italic> association testing yielded several genetic markers as nominally significant in association with high myopia in qualitative testing including <italic>rs3803036</italic> (p=9.1X10-4), a missense mutation in <italic>PTPRR</italic>; and <italic>rs4764971</italic> (p = 6.1X10-4), an intronic SNP in <italic>UHRF1BP1L</italic>. After correction for multiple testing, quantitative tests found statistically significant SNPs<italic> rs4764971</italic> (p = 3.1x10-6), also found by qualitative testing; <italic>rs7134216</italic> (p = 5.4X10-7), in the 3<super>1</super> UTR of <italic>DEPDC4</italic>; and <italic>rs17306116<iitalic> (p < 9X10-4), intronic within <italic>PPFIA2<italic>. The intronic SNP in <italic>UHRF1BP1L</italic>, <italic>rs4764971</italic>, was validated for association with the quantitative trait of sphere (SPH) using an independently collected non-syndromic, high myopia cohort. SNPs within <italic>PTPRR</italic> (for quantitative association) and <italic>PPFIA2</italic> (for qualitative and quantitative association) both approached significance in the independent high myopia cohort.</p><p>As with screening genes previously implicated in myopic development, qualitative and quantitative association candidates were screened in the independent whole genome expression array analyses, comparing normal rapidly growing fetal to normal grown adult ocular tissues. <italic>PTPRR</italic> and <italic>PPFIA2<italic>, candidates from qualitative and quantitative association respectively, were both validated by RT-qPCR with differential expression in at least one disease relevant ocular tissue. <italic>PTPRR</italic> and <italic>PPFIA2<italic> belong to the same gene family- that of protein tyrosine phosphatase (PTP) genes. This family of genes relays extracellular signals that regulate cell growth, division, maturation and function, and its differential expression is consistent with our myopia surrogate model. </p><p>Many genes implicated in either syndromic or non-syndromic myopia were present in the most significantly enriched adult versus fetal functional and/or canonical pathways together. The adult versus fetal choroid and cornea tissue types had the most overlap with known non-syndromic myopic-associated genes in the most significantly enriched functional groups. Further exploration of the connections amongst these known genes may elucidate possible mechanistic roles for disease progression and/or reveal related novel candidate genes. Differentially expressed genes in central versus peripheral tissues yielded minimal overlap with genes implicated in myopia; however, in addition to broadening our understanding of the spatial variances in these tissues they may contain clues to the development and/or progression of other ocular diseases such as retinopathy of prematurity development.</p><p>The overlap with previously identified myopia-associated genes supports the model of eye growth for studying myopic development in human tissues. This expression data can be used both in prioritizing candidate genes other proposed genomic myopia loci, and also in detailed pathway analyses to identify potential biological mechanisms for candidates within these loci. Our most strongly associated candidate gene both in the discovery and replicate cohort was <italic>UHRF1BP1L</italic>, which was not differentially expressed in our data; however, interacting genes regulate the expression of at least one differentially expressed gene, indicating a possibly pathway connection. It is possible that differential expression may have been missed by the microarray data, or it may not be differentially expressed and affects myopic development through alternative or indirect means. While the expression data is a useful tool in prioritizing and inferring mechanistic roles for candidates, it cannot be used to exclude candidates. Deeper study of the pathways of candidate genes for myopic development may reveal connections to genes involved in ocular growth. Despite these potential limitations, two of the three novel candidates, <italic>PTPRR</italic> and <italic>PPFIA2</italic>, were supported by genomic convergence with the expression data, in addition to our discovery genetic association data. The other novel candidate, <italic>UHRF1BP1L</italic>, was validated in an independent Caucasian high-grade myopia cohort. Further validation and refinement of these three novel <italic>MYP3<italic> candidate genes is necessary to make further claims about their possible involvement in myopic progression.</p> / Dissertation

Accommodation and vergence are two interacting ocular motor systems that function to maintain clear and single vision across a wide range of distances. Sustained fixation results in the adaptation of these ocular motor systems and has been widely investigated in adults but not in children. Moreover, limited reports have measured adaptation to disparities induced by ophthalmic lenses. This thesis used near addition lenses as a means to investigate binocular adaptation in children. The specific aims of this thesis were three-fold. First, the thesis aimed to gain insight into the mechanism of changes to accommodation and vergence during binocular adaptation in children. The second objective was to determine the role of vergence-bias category (eso/exo/normals) on adaptation. Lastly, this thesis evaluated the influence of myopia on binocular adaptation. Thirty- eight myopic and 38 emmetropic children between 7-14 years of age were examined for the purpose of this thesis. A series of studies were performed to evaluate adaptation using varying demands for accommodation and vergence, stimulated by binocular fixation at near (33 cm), through the addition of +2D and -2D over corrective lenses (closed loop accommodation) and using 10 base-out prisms (open-loop accommodation at 4M). In each closed-loop condition, measures of binocular and monocular accommodation (PowerRefractor, Multichannel systems) and near phoria (modified Thorington technique) were recorded at frequent intervals when children binocularly fixated a high contrast near target (33 cm) for 20 min. For the open-loop condition (obtained using 0.5 mm pinhole pupils), binocular accommodation and tonic vergence (distance heterophoria through pinhole pupils) were determined at frequent intervals when binocular fixation was sustained at 4M for 20 min. For all conditions, tonic accommodation was measured before and after the near task to measure accommodative adaptation. The results of this thesis make three major contributions to the literature. First, it outlines that the addition of +2D and -2D lenses alters both accommodation and near phoria during sustained binocular fixation, which can be explained based on the models of accommodation and vergence. Second, it shows that the direction of phoria influences the pattern of binocular vs. monocular accommodation in closed-loop conditions and alters the degree of vergence adaptation in both closed and open-loop accommodation. These changes have been primarily attributed to the varying demands on fusional vergence. Lastly, this thesis demonstrates that myopic children show reduced vergence adaptation when fusional convergence was initiated through plus adds or base-out prisms but not when fusional divergence was initiated through minus addition lenses. Further, myopic children also showed variations in other ocular motor parameters such as higher accommodative lags, greater variability of accommodative response, larger accommodative after-effects, and higher AV/A ratios compared to emmetropes. Consistent with the models of accommodation and vergence, the thesis highlights that it is necessary to measure changes to both accommodation and vergence when evaluating the response of the ocular motor system. The direction of phoria and type of refractive error play a significant role in determining binocular adaptation in children. Future studies should differentiate these parameters when evaluating adaptation of the ocular motor system.

This research investigated underlying issues that were critical to the success of the bifocal trial and comprised of three studies. The first study evaluated if Chinese-Canadian children were suitable subjects for the bifocal trial. The high prevalence of myopia in Chinese children suggests that genetic input plays a role in myopia development, but the rapid increase in prevalence over the last few decades indicates environmental factors are also important. Since this bifocal trial was conducted in Canada, this work aimed to determine whether Chinese children who had migrated to Canada would still have high myopia prevalence and a high rate of myopia progression. The second study determined the optimal bifocal lens power for myopia treatment and the effect of incorporating base-in prism into the bifocal. In the majority of published myopia control studies, the power of the prescribed near addition was usually predetermined in the belief that the near addition would always help to improve the near focus. In fact, the effect of near addition on the accommodative error might be quite different even for individuals in which the same magnitude of accommodation lag had been measured. Therefore, this work was necessary to guide the selection of bifocal and prism powers most suitable for the subsequent bifocal trial. The third study, the ultimate goal of this research, was to conduct a longitudinal clinical trial to determine if bifocals and prismatic bifocals could control myopia progression in children.

Thesis (M.S.)--New England College of Optometry, 2009. / Includes bibliographical references (p. 94-96).

Thesis (Ph. D.)--University of Hong Kong, 2010. / Includes bibliographical references (p. 103-132). Also available in print.

Prior research shows returns are positive when firms meet or beat analysts’ consensus forecasts but negative when firms miss. Past studies also show managers frequently cut R&D expenses in order to meet the consensus forecast. Despite these findings, there is limited evidence about how the market responds when firms beat the forecast by cutting R&D. This study shows the stock market penalizes firms that use R&D cuts to manage earnings and exacts a discount to the market reward if beating the forecast requires cutting R&D. The discount is only partial and firms are still better off doing so in the short run. Furthermore, this study shows the R&D cuts used to manage earnings are concentrated in specific industries and are likely temporary, as firms tend to increase R&D spending in the subsequent period. Investors appear to recognize these short-term cuts and treat them similar to accruals. / 10000-01-01