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Retinitis pigmentosa (RP) defines a group of hereditary retinal dystrophies characterised by a progressive deterioration of night vision and reduction of the visual field due to photoreceptor degeneration. RP shows both clinical and genetic heterogeneity and has X- linked, autosomal recessive and autosomal dominant forms of inheritance. In addition, a 'digenic' form of inheritance had also been reported. To date, positional cloning and candidate gene approaches have identified more than 20 genes and gene loci responsible for RP, and the number is increasing. In the present study, three Scottish RP families were included in a linkage study, to determine if the disease locus in each of these families mapped to any of the known RP loci on chromosomes 7 (7p and 7q), 8 and 19. Significant positive LOD scores were obtained for family G-adRP, with markers mapping within the RPIO locus (7q31-q32). The highest LOD score obtained was 3.913 (at 0% recombination) with marker D7S514. Results for the remaining two families were generally inconclusive. However, LOD scores obtained indicated that linkage to 7p and 7q was significantly excluded for family F-adRP. No conclusive exclusion of linkage was obtained for family C-RP. Two candidate genes exist within the RPIO candidate region, namely the blue cone pigment gene (BCP) and the metabotropic glumate receptor 8 (GRM8) gene. Mutation screening was performed using SSCP analysis to evaluate the involvement of these genes in the pathogenesis of RP in family G-adRP. An A->C polymorphism was observed in the final base of codon 122 of the BCP gene (exon 2). The amino acid residue (glycine) is not altered, however, and is thus unlikely to be involved in the disease process. Furthermore, this polymorphism was noted in both affected and unaffected individuals of family G-adRP, as well as in control individuals. For the GRM8 gene, only eight out of ten exons were available for analysis at the time of study. SSCP mobility shifts were detected in 4 PCR fragments (exons IV, V and X, and exon VIIIb). Sequencing analysis of exon VIIIb revealed an A-C polymorphism in the first base of codon 561. The involvement of this polymorphism in the disease process is unlikely as the change does not alter the encoded amino acid (arginine) and it was detected in both affected and unaffected members of G- adRP. In exon X, a heterozygous C>T sequence transition was noted 29bp downstream of the stop codon. However, the shift was again found in both affected and unaffected individuals of family G-adRP, therefore unlikely to be pathogenic. Sequence analysis of the remaining two exons (exons IV and V) did not reveal any deviation from the published control sequence. The direct cDNA selection, technique was employed in the attempt to isolate transcripts from the candidate region. YACs spanning the region of interest were obtained and their inserts verified by FISH and PCR-based STS content screening. Selection was performed on human retinal cDNA library preparations, and the selected products were subcloned to create a selected-cDNA library for further analysis. Sequencing analysis of a subset (27clones) of the selected products indicated that some fragments were indeed derived from within the 7q3 l-q32 region, as shown by BLAST and FASTA sequence homology searches, although most were repetitive in origin. Hits to known genes or other transcribed sequences (ESTs or cloned cDNA) were also obtained, although several of these genes have been shown to map elsewhere in the genome. At present, family G-adRP is the fourth autosomal dominant RP family whose disease locus was mapped within the RPIO region (7q31-q32). All known candidate genes identified to date have been excluded, which necessitates positional cloning strategies to be employed. Using the direct cDNA selection technique, a library of cDNA fragments putatively isolated from a portion of the RPIO candidate region has been constructed in this study. However, time was a limiting factor, and as a result, only a minor subset (less than 15%) of the selected-cDNA library was analysed. Further analysis and characterisation of the selected cDNAs is warranted to identify clones that represent (novel) transcripts mapping within the 7q31-q32 candidate region, which will undoubtedly expedite the identification of the RPIO gene.

Retinal imaging with a confocal scanning laser Ophthalmoscope (cSLO) involves scanning a small laser beam over the retina and constructing an image from the reflected light. By applying the confocal principle, tomographic images can be produced by measuring a sequence of slices at different retinal depths. However, the thickness of such slices, when compared with the retinal thickness, is too large to give useful 3D retinal images, if no processing is done. In this work, a prototype cSLO was modified in terms hardware and software to give the ability of doing the tomographic measurements with the maximum theoretical axial resolution possible. A model eye was built to test the performance of the system. A novel algorithm has been developed which fits a double Gaussian curve to the axial intensity profiles generated from a stack of images slices. The underlying assumption is that the laser light has mainly been reflected by two structures in the retina, the internal limiting membrane and the retinal pigment epithelium. From the fitted curve topographic images and novel thickness images of the retina can be generated. Deconvolution algorithms have also been developed to improve the axial resolution of the system, using a theoretically predicted cSLO point spread function. The technique was evaluated using measurements made on a model eye, four normal eyes and seven eyes containing retinal pathology. The reproducibility, accuracy and physiological measurements obtained, were compared with available published data, and showed good agreement. The difference in the measurements when using a double rather than a single Gaussian model was also analysed.

Studies suggest that natural autoantibodies may be part of an immunological network which maintains the normal homeostatic response seen in controls. Any defect in this network leading to autoimmunity may be represented in the anti-retinal antibody response observed in patients. Characterisation of the humoral autoimmune response occurring during active uveitis may provide valuable information on the immune mechanisms, both humoral and cellular, involved in uveitis. Serum titres and ELISA based tests can only partially describe an antibody response, a more complete description requires access to the B-cell repertoire constituting the response. In the past hybridoma technology has generated a wealth of vital information on antibody responses in animals, but with limited success when applied to humans, producing unstable cell lines with poor antigen affinity. Using scFv phage display antibody technology we attempted to isolate the immune response occurring during active uveitis using a phage display library derived from peripheral blood lymphocyte mRNA of a patient with active uveitis. In this study, we report the isolation and characterisation of human autoimmune recombinant scFv's from two libraries, a uveitis patient derived library and a healthy non uveitis donor derived library. Anti-IRBP and S-Antigen autoantibodies were successfully selected from both libraries. Sequence analysis of these selected autoantibodies revealed possible differential epitope targeting of disease associated anti-S-Ag autoantibodies, and exclusive use of the VH segment, DP49 was revealed among selected anti-S-Ag scFv's. In addition ELISA studies using the selected scFv's, and both patient and control serum, indicated that it may be possible to distinguish the 'natural' and disease associated anti-S-Ag responses at the idiotype/anti-idiotype network level.

Silicone Oil for the management of complicated retinal detachments was introduced by Cibis and associates . Its clinical use was later prohibited in the United States because of significant post-operative complications. Experimental studies indicated that silicone oil might be retino toxic. Scott 2 in Cambridge, for many years continued to advocate the use of Silicone Oil and he slowly convinced retinal surgeons that there might be a place for Silicone Oil in detachment s u r g e r y . Because of a better understanding of vltreoretinal abnormalities and improved surgical techniques, the use of Silicone Oil is now being re-evaluated in many centres including the United States.

Xu Ge-Zhi. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1995. / Includes bibliographical references (leaves 56-69). / List of figures --- p.IV / Abstract --- p.V / Chapter Chapter1 --- Introduction --- p.1 / Literature review --- p.2 / Chapter 1. --- Necrosis --- p.2 / Chapter 2. --- Apoptosis --- p.3 / Chapter 2.1. --- Morphologic features of apoptosis --- p.4 / Chapter 2.2. --- Biochemical mechanism of apoptosis --- p.5 / Chapter 2.3. --- Genetic regulation of apoptosis --- p.7 / Chapter 2.4. --- Techniques for identifying apoptosis --- p.7 / Chapter 3. --- Retinal degeneration --- p.9 / Chapter 3.1. --- Pathologic myopia --- p.9 / Chapter 3.2. --- Age-related macular degeneration (ARM) --- p.11 / Chapter 3.3. --- Retinal detachment --- p.12 / Chapter 4. --- Apoptosis and retinal degeneration --- p.14 / Chapter 5. --- Scope and definition of the thesis problem --- p.15 / Chapter Chapter2 --- Materials and methods --- p.16 / Chapter 1. --- Cases selection and tissue preparation --- p.16 / Chapter 2. --- TdT-mediated dUTP-biotin nick-end Labelling (TUNEL) --- p.17 / Chapter Chapter3 --- Results --- p.20 / Chapter 1. --- Pathologic myopia group --- p.20 / Chapter 2. --- Age-related macular degeneration group --- p.22 / Chapter 3. --- Retinal detachment group --- p.23 / Chapter 4. --- Peripheral retinal degeneration group --- p.26 / Chapter Chapter4 --- Discussion --- p.44 / References --- p.56

Inexpensive high quality fundus camera systems enable imaging of retina for vision related health management and diagnosis at large scale. A computer based analysis system can help establish the general baseline of normal conditions vs. anomalous ones, so that different classes of retinal conditions can be classified. Advanced applications, ranging from disease screening algorithms, aging vs. disease trend modeling and prediction, and content-based retrieval systems can be developed. In this dissertation, I propose an analytical framework for the modeling of retina blood vessels to capture their statistical properties, so that based on these properties one can develop blood vessel mapping algorithms with self-optimized parameters. Then, other image objects can be registered based on vascular topology modeling techniques. On the basis of these low level analytical models and algorithms, the third major element of this dissertation is a high level population statistics application, in which texture classification of macular patterns is correlated with vessel structures, which can also be used for retinal image retrieval. The analytical models have been implemented and tested based on various image sources. Some of the algorithms have been used for clinical tests. The major contributions of this dissertation are summarized as follows: (1) A concise, accurate feature representation of retinal blood vessel on retinal images by proposing two feature descriptors Sp and Ep derived from radial contrast transform. (2) A new statistical model of lognormal distribution, which captures the underlying physical property of the levels of generations of the vascular network on retinal images. (3) Fast and accurate detection algorithms for retinal objects, which include retinal blood vessel, macular-fovea area and optic disc, and (4) A novel population statistics based modeling technique for correlation analysis of blood vessels and other image objects that only exhibit subtle texture changes.

OBJECTIVE To determine whether grading for AMD during a diabetic retinopathy (DR) screening program would be cost-effective in Hong Kong. METHODS A cost-effectiveness analysis based on a Markov model with six mutually exclusive health states was undertaken. It included grading for AMD and treatment with vitamin therapy for those with intermediate AMD. The outcome of the model was cost per quality-adjusted life year (QALY) gained. A public provider perspective was used. The measures of effectiveness were mostly taken from a local DR screening project except the transition probabilities and the utility values which were taken from overseas data. Costs were mainly taken from the Hospital Authority and salary scale 2009. The main assumptions and estimates were tested in sensitivity analyses. In this model, only subjects with non-sight threatening diabetic retinopathy were included and the possibility of disease regression and treatment benefit for those with advanced AMD were not considered. Both costs and benefits were discounted at 3%. RESULTS The cost per QALY gained through grading for AMD at the time of DR screening and treatment with vitamins of appropriate cases was HK$47,397 after discounting. This would be considered highly cost-effective based on the World Health Organization’s threshold of willingness-to-pay (WTP) for a QALY, e.g. less than the annual per capita GDP HK$300,000. One way sensitivity analyses revealed that the cost per QALY was most sensitive to utility value, discount rate, progression rate from intermediate to advanced AMD, and compliance rate for the treatment. The cost-effectiveness acceptability curve showed that at a WTP for a QALY of $100,000 or more, this AMD screening programme has over 90% of probability of being cost-effective compared with no screening. CONCLUSION Our cost-effectiveness analysis demonstrated that grading for AMD at the time of DR screening among diabetic patients would probably be cost-effective in a Hong Kong public hospital setting. / published_or_final_version / Public Health / Master / Master of Public Health

Retinal diseases are a major cause of blindness worldwide. Although widely studied, disease mechanisms are not completely understood, and diagnostic tests may not detect disease early enough for timely intervention. The goal of this research is to contribute to research for more sensitive diagnostic tests that might use the interaction of polarized light with retinal tissue to detect subtle changes in the microstructure. This dissertation describes the GDx-MM, a scanning laser polarimeter which measures a complete 16-element Mueller matrix image of the retina. This full polarization signature may provide new comparative information on the structure of healthy and diseased retinal tissue by highlighting depolarizing structures as well as structures with varying magnitudes and orientations of retardance and diattenuation.The three major components of this dissertation are: 1. Development of methods for polarimeter optimization and error analysis; 2. Design, optimization, assembly, calibration, and validation of the GDx-MM polarimeter; and 3. Analysis of data for several human subjects. Development involved modifications to a Laser Diagnostics GDx, a commercially available scanning laser ophthalmoscope with incomplete polarization capability. Modifications included installation of polarization components, development of a data acquisition system, and implementation of algorithms to convert raw data into polarization parameter images. Optimization involved visualization of polarimeter state trajectories on the Poincaré sphere and a condition number analysis of the instrument matrix. Retinal images are collected non-invasively at 20 ?m resolution over a 15° visual field in four seconds. Validation of the polarimeter demonstrates a polarimetric measurement accuracy of approximately ± 5%.Retinal polarization data was collected on normal human subjects at the University of Arizona and at Indiana University School of Optometry. Calculated polarization parameter images reveal properties of the tissue microstructure. For example, retardance images indicate nerve fiber layer thickness and orientation, and depolarization images (uniform for these normal subjects), are predicted to indicate regions of disease-related tissue disruption. This research demonstrates a method for obtaining a full polarization signature of the retina in one measurement using a polarimetrically optimized instrument, and provides a step toward the use of complete retinal imaging polarimetry in the diagnosis and monitoring of retinal disease.