Ophthalmology, Eye and Vision Research Collected Works

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    Oral administration of antigen in the treatment of eye disease
    (BMJ Publishing Group - http://bjo.bmjjournals.com/, 1997-09) Williams, Keryn Anne
    Comment on the Oral administration of antigen in the treatment of eye disease
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    Influence of advanced recipient and donor age on the outcome of corneal transplantation. Australian Corneal Graft Registry.
    (BMJ Publishing Group - http://bjo.bmjjournals.com/, 1997-10) Williams, Keryn Anne ; Muehlberg, S M ; Lewis, R F ; Coster, Douglas John
    AIMS: The aims of this study were to examine the influence of advanced recipient and donor age on the long term outcome of corneal transplantation. METHODS: Records of 1036 penetrating corneal grafts in recipients aged > or = 80 years at surgery (defined as the elderly subset) and 8092 donor corneas used for transplantation were obtained from the Australian Corneal Graft Register database, Kaplan-Meier graft survival plots were compared using log rank statistics. RESULTS: Elderly recipients constituted 15% of the recipient pool. The major indication for corneal transplantation in the elderly was bullous keratopathy. Graft survival fell with increasing recipient age (p < 0.00001); the major cause of graft failure was rejection (33%). The desired outcome in 51% of cases was to improve vision and in 42% of cases to relieve pain; 23% of elderly recipients achieved a Snellen acuity of 6/18 or better in the grafted eye and 66% recorded improved acuity after transplantation. Elderly recipients suffered more complications and comorbidities in the grafted eye than did younger recipients. Donor age (stratified in 10 year intervals) did not influence corneal graft survival significantly (p = 0.10). CONCLUSIONS: Elderly graft recipients fared less well after corneal transplantation than did younger recipients, but outcomes in terms of long term graft survival and visual rehabilitation were still good. Donor age did not affect graft survival.
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    A simple corneal perfusion chamber for drug penetration and toxicity studies
    (BMJ Publishing Group - http://bjo.bmjjournals.com/, 2001-04) Thiel, Michael A ; Morlet, N ; Schulz, D ; Edelhauser, HF ; Dart, JK ; Coster, Douglas John ; Williams, Keryn Anne
    AIMS: Corneal perfusion chambers are important tools in the development and assessment of ophthalmic drugs. The aim of this study was to design and test a modified perfusion chamber suitable for topical application of drugs to isolated corneoscleral preparations, and which allowed continuous monitoring of endothelial cell function. METHODS: A polycarbonate and stainless steel perfusion chamber was designed to clamp corneas in a horizontal plane suitable for topical drug delivery. Endothelial cell function was assessed by ultrasonic pachymetry and specular microscopy during perfusion. Epithelial barrier function was assessed by penetration of fluorescein. Leakage was examined by measuring penetration of a large protein, IgG. Tissue architecture after perfusion was examined by conventional histology. RESULTS: Corneas maintained a functionally and morphologically intact endothelial monolayer during perfusion periods of up to 14 hours. The epithelial barrier function was well preserved. The tissue clamp sealed the preparation effectively against leakage of macromolecules. CONCLUSION: The new chamber device forms a reliable tool for in vitro drug penetration and toxicity studies in isolated perfused corneoscleral tissue.
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    Investigation of crystallin genes in familial cataract, and report of two disease associated mutations.
    (BMJ Publishing Group - http://bjo.bmjjournals.com/, 2004-01) Burdon, Kathryn Penelope ; Wirth, M Gabriela ; Mackey, David A ; Russell-Eggit, Isabelle M ; Craig, Jamie E ; Elder, James E ; Dickinson, Joanne L ; Sale, Michele M
    AIMS: Mutations of seven crystallin genes have been shown to cause familial cataract. The authors aimed to identify disease causing crystallin mutations in paediatric cataract families from south eastern Australia. METHODS: 38 families with autosomal dominant or recessive paediatric cataract were examined. Three large families were studied by linkage analysis. Candidate genes at regions providing significant LOD scores were sequenced. Single stranded conformational polymorphism (SSCP) analysis was used to screen five crystallin genes in the probands, followed by direct sequencing of observed electrophoretic shifts. Mutations predicted to affect the coding sequence were subsequently investigated in the entire pedigree. RESULTS: A LOD score of 3.72 was obtained at the gamma-crystallin locus in one pedigree. Sequencing revealed a P23T mutation of CRYGD, found to segregate with disease. A splice site mutation at the first base of intron 3 of the CRYBA1/A3 gene segregating with disease was identified by SSCP in another large family. Five polymorphisms were also detected. CONCLUSIONS: Although mutations in the five crystallin genes comprehensively screened in this study account for 38% of paediatric cataract mutations in the literature, only two causative mutations were detected in 38 pedigrees, suggesting that crystallin mutations are a relatively rare cause of the cataract phenotype in this population.
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    Late onset post-keratoplasty astigmatism in patients with keratoconus
    (BMJ Publishing Group - http://bjo.bmjjournals.com/, 2004-03) Lim, L ; Pesudovs, Konrad ; Goggin, M ; Coster, Douglas John
    AIM: 10 eyes of 10 patients are reported where progression of keratoconus in the host cornea occurred more than 10 years after penetrating keratoplasty with resultant increase in astigmatism. The technique and results of graft refractive surgery in seven eyes are presented. METHODS: The clinical features and management of these patients were retrospectively analysed. Graft refractive surgery involved an incision at the graft-host junction adjacent to the host thinning with compressive resuturing. Astigmatic changes were calculated using vector analysis. RESULTS: There were seven men and three women with a mean age of 41.2 years. The average age when undergoing penetrating keratoplasty in the affected eye was 28.4 years and the average time after penetrating keratoplasty until keratoconus appeared in the host cornea defined by host thinning was 13.5 years. The mean cylinder power before host thinning was noted was 5.07 D (SD 2.19) and the mean after host thinning was 11.0 D (2.53). The mean vector calculated disease induced astigmatism magnitude was 7.59 D (3.09). Graft refractive surgery was performed in seven eyes. The mean cylinder power before and after graft refractive surgery was 11.28 D (2.15) and 7.09 D (5.53) respectively. The surgically induced astigmatism vector magnitude was 7.36 D (4.88). CONCLUSION: Progression of keratoconus in the host cornea late after penetrating keratoplasty is characterised by a large astigmatic change where the flat axis of astigmatism passes through an area of host thinning visible on slit lamp examination. Compressive resuturing performed in the area of host thinning resulted in satisfactory reduction of astigmatism.
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    Contrast and glare testing in keratoconus and after penetratin keratoplasty
    (BMJ Publishing Group - http://bjo.bmjjournals.com/, 2004-05) Pesudovs, Konrad ; Schoneveld, P ; Seto, R J ; Coster, Douglas John
    AIM: To compare the performance of keratoconus, penetrating keratoplasty (PK), and control subjects on clinical tests of contrast and glare vision, to determine whether differences in vision were independent of visual acuity (VA), and thereby establish which vision tests are the most useful for outcome studies of PK for keratoconus. METHODS: All PK subjects had keratoconus before grafting and no subjects had any other eye disease. The keratoconus (n = 11, age 35.0 (SD 11.1) years), forme fruste keratoconus (n = 6, 33.0 (13.0)), PK (n = 21, 41.2 (7.9)), and control (n = 24, 33.7 (8.6)) groups were similar in age. Vision testing, conducted with optimal refractive correction in place, included low contrast visual acuity (LCVA) and Pelli-Robson contrast sensitivity (PRCS) both with and without glare, as well as VA. RESULTS: Normal subjects saw better than PK subjects who in turn saw better than keratoconus subjects on all raw measures. However, when adjusted for VA, the normal group only saw significantly better than the keratoconus group on LCVA (low contrast loss 0.05 (0.04) v 0.15 (0.12), F(2,48) = 6.16; p<0.01, post hoc Sheffe p<0.05), and the decrements to glare were no worse than for normals. The forme fruste keratoconus group were indistinguishable from normals on all measures. CONCLUSIONS: PK subjects have superior vision to keratoconus subjects, but not as good as normal subjects. Including mild keratoconus subjects within a keratoconus group could confound these differences in vision. While VA is an excellent test for comparing normal, keratoconus and PK groups, additional information can be provided by LCVA and PRCS, but not by glare testing. Outcomes research into keratoconus management should include a measure in the contrast domain.
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    The impact of corneal allograft rejection on the long-term outcome of corneal transplantation
    ( 2005) Coster, Douglas John ; Williams, Keryn Anne
    To examine the influence of corneal allograft rejection on the survival of penetrating corneal transplantation, to review the status of conventional therapies to improve graft survival, and to consider prospects for alternative approaches to reduce the impact of rejection. Perspective, including prospective, observational cohort study. An examination of the literature on human corneal graft rejection and data from the Australian Corneal Graft Registry, reviewed in the context of clinical experience. Corneal graft outcome is not improving with era. The sequelae of inflammation, whether occurring before corneal transplantation or subsequently, exert a profound influence by predisposing the graft to rejection. Of the developments that have been instrumental in reducing rejection in vascularized organ transplantation, living-related donation is not an option for corneal transplantation. However, HLA matching may be beneficial and requires reassessment. The evidence base to support the use of systemic immunosuppressive agents in corneal transplantation is thin, and topical glucocorticosteroids remain the drugs of choice to prevent or reverse rejection episodes. Experimental approaches to local allospecific immunosuppression, including the use of antibody-based reagents and gene therapy, are being developed but may be difficult to translate from the laboratory bench to the clinic. Corneal allograft rejection remains a major cause of graft failure. High-level evidence to vindicate the use of a particular approach or treatment to prevent or treat corneal graft rejection is lacking. In the absence of extensive data from randomized, controlled clinical trials, corneal graft registers and extrapolation from experimental models provide some clinically useful information.
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    In vitro adenovirus mediated gene transfer to the human cornea
    (BMJ Publishing Group - http://bjo.bmjjournals.com/, 2005-06) Jessup, Claire Frances ; Brereton, Helen Mary ; Coster, Douglas John ; Williams, Keryn Anne
    BACKGROUND/AIMS: Replication deficient adenovirus is an efficient vector for gene transfer to the cornea. The aim was to optimise the transduction of human corneal endothelium with adenoviral vectors and to measure transgene production from transduced corneas. METHODS: Adenoviral vectors (AdV) encoding enhanced green fluorescent protein (eGFP) or a transgenic protein (scFv) were used to transfect 34 human corneas. Reporter gene expression was assessed after 72-96 hours of organ culture. The kinetics of scFv production was monitored in vitro for 1 month by flow cytometric analysis of corneal supernatants. RESULTS: Transduction of human corneas with high doses (5 x 10(7)-3 x 10(8) pfu) of AdV caused eGFP expression in 12-100% of corneal endothelial cells. Corneas were efficiently transduced following up to 28 days in cold storage. Very high AdV doses (2 x 10(9) pfu) reduced endothelial cell densities to 98 (SD 129) nuclei/mm(2) (compared to 2114 (716) nuclei/mm(2) for all other groups). Transgenic protein production peaked at 2.4 (0.9) microg/cornea/day at 2 weeks post-transduction, and decreased to 1.2 (0.4) microg/cornea/day by 33 days, at which time endothelial cell density had decreased to 431 (685) nuclei/mm(2). CONCLUSION: Human corneas can be efficiently transduced by AdV following extended periods of cold storage, and transgene expression is maintained for at least 1 month in vitro.
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    The telomere of human chromosome 1p contains at least two independent autosomal dominant congenital cataract genes.
    (BMJ Publishing Group - http://bjo.bmjjournals.com/, 2005-07) McKay, James D ; Patterson, B ; Craig, Jamie E ; Russell-Eggit, Isabelle M ; Wirth, M Gabriela ; Burdon, Kathryn Penelope ; Hewitt, Alex W ; Cohn, Amy C ; Kerdraon, Y ; Mackey, David A
    AIMS: Multiple genetic causes of congenital cataract have been identified, both as a component of syndromes and in families that present with isolated congenital cataract. Linkage analysis was used to map the genetic locus in a six generation Australian family presenting with total congenital cataract. METHODS: Microsatellite markers located across all known autosomal dominant congenital cataract loci were genotyped in all recruited family members of the Tasmanian family. Both two point and multipoint linkage analysis were used to assess each locus under an autosomal dominant model. RESULTS: Significant linkage was detected at the telomere of the p arm of chromosome 1, with a maximum two point LOD of 4.21 at marker D1S507, a maximum multipoint exact LOD of 5.44, and an estimated location score of 5.61 at marker D1S507. Haplotype analysis places the gene inside a critical region between D1S228 and D1S199, a distance of approximately 6 megabases. The candidate gene PAX7 residing within the critical interval was excluded by direct sequencing in affected individuals. CONCLUSION: This is the third report of congenital cataract linkage to 1ptel. The critical region as defined by the shared haplotype in this family is clearly centromeric from the Volkmann cataract locus identified through study of a Danish family, indicating that two genes causing autosomal dominant congenital cataract map to the telomeric region of chromosome 1p.
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    Influence of format on in vitro penetration of antibody fragments through porcine cornea
    (BMJ Publishing Group - http://bjo.bmjjournals.com/, 2005-09) Brereton, Helen Mary ; Taylor, Susan D ; Farrall, Alexandra L ; Hocking, Dianna M ; Thiel, Michael A ; Tea, Melinda Nay ; Coster, Douglas John ; Williams, Keryn Anne
    AIM: Antibody fragments, appropriately formulated, can penetrate through the ocular surface and thus have potential as therapeutic agents. The aim was to investigate the influence of protein fragment format on the kinetics and extent of ocular penetration in vitro. METHODS: Immunoglobulin single chain variable domain fragments of a murine monoclonal antibody with specificity for rat CD4 were engineered with a 20 or 11 amino acid linker by assembly polymerase chain reaction, expressed in Escherichia coli and purified by chromatography. Fab fragments of the parental antibody were prepared by papain digestion. Antibody fragments were formulated with a penetration and a viscosity enhancer and were applied to the surface of perfused pig corneas for up to 10 hours in vitro. Penetration was quantified by flow cytometry on rat thymocytes. RESULTS: 20-mer antibody fragments formed natural monomers and dimers following purification that could be separately isolated, while 11-mer fragments were dimeric. All formats of fragment (20-mer monomers and dimers, 11-mer dimers, Fab) showed penetration through the pig cornea after 6 hours of intermittent topical administration. CONCLUSION: Antibody fragments of different shapes and sizes can penetrate the cornea after topical administration, thereby increasing the potential of this class of proteins for topical ophthalmic use.
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    The PITX3 gene in posterior polar congenital cataract in Australia
    ( 2006) Burdon, Kathryn Penelope ; McKay, James D ; Wirth, M Gabriela ; Ruddle, Jonathan B ; Russell-Eggit, Isabelle M ; Bhatti, Samira ; Dimasi, David Paul ; Mackey, David A ; Craig, Jamie E
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    The Australian Corneal Graft Registry 2004 annual report
    ( 2006-06-20T03:38:28Z) Williams, Keryn Anne ; Hornsby, Ngaere B ; Bartlett, Christine Mary ; Holland, Helene K ; Esterman, Adrian Jeffrey ; Coster, Douglas John
    The Australian Corneal Graft Registry (ACGR) opened in May 1985 and has now been in operation for 18 years. In that time, we have collected data on over 14,000 corneal grafts. At the time of transplantation, we seek information on the recipient, the donor and the operative procedure. Follow-up then occurs at approximately yearly intervals for an indefinite period. Follow-up only ceases upon loss of the graft, or death or loss-to-follow-up of the patient. At each round of follow-up, we request information on graft and visual outcome, and upon relevant events and treatments. The data are entered into a database and checked for consistency. Descriptive, univariate and multivariate analyses are performed, and the report collated.
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    The Australian Corneal Graft Registry 2007 Report
    (Flinders University Press, 2007) Williams, Keryn Anne ; Lowe, Marie Therese ; Bartlett, Christine Mary ; Kelly, L ; Coster, Douglas John
    The Australian Corneal Graft Registry opened in May 1985 and thus has now been in operation for over 22 years. The census date for this report was 01/09/2006. Over the years, we have collected data on more than 18,500 corneal grafts. The majority of corneal grafts registered have been penetrating, but increasing numbers of lamellar and limbal grafts have also been registered over recent years, as patterns of surgical practice change. At registration, we seek information on the recipient, the donor, the eye bank practices and the operative procedure. Follow-up then occurs at approximately yearly intervals for an indefinite period, and ceases upon loss of the graft, or the death or loss-to-follow-up of the patient. At each round of follow-up, we request information on the graft and visual outcome, and upon relevant post-operative events and treatments. The data are entered into an Access database and checked for consistency. Descriptive, univariate and multivariate analyses are subsequently performed using SPSS and Stata software, and the report is eventually collated.
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    Novel causative mutations in patients with Nance-Horan Syndrome and altered localization of the mutant NHS-A protein isoform
    ( 2008) Sharma, Shiwani ; Burdon, Kathryn Penelope ; Craig, Jamie E ; Dave, Alpana ; Jamieson, Robyn ; Yaron, Yuval ; Billson, Frank ; Maldergem, Lionel ; Lorenz, Birgit ; Gecz, Jozef
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    Genetic analysis of the clusterin gene in pseudoexfoliation syndrome.
    ( 2008) Sharma, Shiwani ; Burdon, Kathryn Penelope ; Craig, Jamie E ; Hewitt, Alex W ; Wang, Jie Jin ; Mackey, David A ; Mitchell, Paul ; McMellon, Amy E
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    Investigation of eight candidate genes on chromosome 1p36 for autosomal dominant total congenital cataract
    ( 2008) Mackey, David A ; Craig, Jamie E ; Burdon, Kathryn Penelope ; Lachke, Salil A ; Hattersely, Kathryn ; Laurie, Kate ; Maas, Richard L
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    A novel locus for X-lined congenital cataract on Xq24
    ( 2008) Craig, Jamie E ; Friend, K ; Gecz, Jozef ; Rattray, K M ; Troski, Mark ; Mackey, David A ; Burdon, Kathryn Penelope
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    Repeatability of corneal first-surface wavefront aberrations measured with Pentacam corneal topography [Post print]
    (Elsevier, 2008-05) Shankar, Hema ; Taranath, Deepa A ; Santhirathelagan, Chandramalar T ; Pesudovs, Konrad
    PURPOSE: To assess the repeatability of corneal wavefront aberrations derived from Pentacam (Oculus) corneal topography. SETTING: Flinders Eye Centre, Flinders Medical Centre, Bedford Park, South Australia, Australia. METHODS: Forty-five normal participants and 10 participants with keratoconus were tested. Intraobserver and interobserver repeatability was determined using 4 observers within and between sessions. Topographical maps were exported to external software, and corneal first-surface wavefront aberrations were calculated using a 10th-order Zernike expansion over a 6.0 mm optical zone. Repeatability was determined with Bland-Altman limits of agreement and expressed as the coefficient of repeatability (COR). RESULTS: Initial data showed high wavefront aberrations in normal participants and poor repeatability. Topographical maps showed extrapolated topography in zones without data acquisition; maps with less than 6.0 mm of complete data were excluded in the final analysis. The mean wavefront aberrations for normal participants remained high, but repeatability improved. The COR relative to the magnitude of wavefront aberrations was high (average 100%) across all modal pairs and orders, although best for total higher-order root mean square. Participants with keratoconus had higher magnitude wavefront aberrations and poorer repeatability but similar COR to average wavefront aberration ratios. Examination of raw elevation data showed poor repeatability. CONCLUSIONS: Wavefront aberrations calculated from Pentacam corneal topography were large in magnitude, and reliability was poor, largely due to variability in corneal elevation data. Intraobserver and interobserver reliability within and between sessions was comparable. The Pentacam was not reliable in measuring corneal wavefront aberrations.
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    Rejection and acceptance of corneal allografts
    (Lippincott, Williams & Wilkins, 2009) Klebe, Sonja ; Coster, Douglas John ; Williams, Keryn Anne
    PURPOSE OF REVIEW: Corneal transplantation is successful in the short-term, but the long-term prognosis has not improved over the past 20 years. Here, we review recent findings that may contribute to improved corneal allograft survival. RECENT FINDINGS: A better understanding of the molecular pathways affecting corneal graft survival has led to more targeted approaches to immune modulation. Costimulatory molecule blockade, inhibition of chemokine-chemokine receptor interactions, modulation of apoptotic pathways, and reduction of corneal neovascularization and lymphangiogenesis have been shown to prolong corneal graft survival in animal models. Conventional immunosuppressive drugs have been tested in new combinations and formulations with some success. Two randomized prospective clinical trials in clinical penetrating corneal transplantation have been reported, but there remains little evidence on the long-term outcomes of the newer lamellar corneal graft procedures. SUMMARY: New approaches to reducing the impact of rejection on corneal graft survival have focussed on topical rather than systemic therapies, and on component corneal transplantation. The most successful experimental strategies have been those in which more than one pathway has been targeted; it now seems likely that to improve clinical allograft survival, simultaneous modulation of multiple axes of the rejection process will be necessary.
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    Optic neuritis - more than a loss of vision
    (Royal Australian College of General Practitioners, 2009) Chu, Edward R ; Chen, Celia Shin Wen
    Optic neuritis (ON) is the presence of an acute inflammation of the optic nerve that results in painful loss of vision. It is the most commonly encountered optic neuropathy in general practice, and is often associated with multiple sclerosis (MS). Studies show that in about 15–20% of MS cases, ON was the presenting symptom and more than half of people with MS experience at least one episode of ON during their disease. The risk of developing MS can be stratified by appropriate imaging investigations at the diagnosis of ON. Therefore, early recognition is important to ensure timely referral, investigation and treatment; prompt treatment can hasten visual recovery.