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Ian J Constable

Publications and source records attributed to Ian J Constable.

At least 19 recordsLinked to original sources
PubMed2005

Retinal microvascular patency in the diabetic rat.

PURPOSE: To study whether the patency to erythrocytes in retinal microvessels of diabetic rats is reduced or blocked before the vessels lose their patency to plasma flow. METHODS: We used recognized techniques to induce diabetic and galactose related microvascular retinal lesions in rats: (1) alloxan induction (2) streptozotocin induction (3) galactose-containing diet. The rats were followed up to 17 months. We used our vascular trichrome technique to observe the effects of the ongoing diabetes on the retinal microcirculation. RESULTS: A focal leakage of a plasma-borne fluorescent dye was noted around the junction of the deep retinal capillaries and the ascending venules to the superficial retinal circulation in the streptozotocin and alloxan diabetic rats by the 14th month, and, by the 16th month, retinal capillary non-perfusion and retinal vascular malformations were present. The affected vessels showed patency to microspheres (0.2 microm in diameter) but no perfusion of erythrocytes. No such changes were seen in the galactose-fed rats. CONCLUSIONS: (1) The location between the deep retinal capillary net and the ascending venules may be the site of early vascular leakage in the diabetic rat model, (2) the erythrocytes' passage in the affected retinal microcirculation was blocked before the development of complete blockage to plasma in diabetic rats. The logical assumption that during the development stage of retinal capillary occlusion there may be a transient stage of microvascular insufficiency was examined. The lathyrogen, imino-diproprionitrile (IDPN), had previously been effective for creating a fast-developing model of retinal vasculopathy. Using that model, we demonstrated a stage in which the retinal microvasculature was blocked to erythrocytes but not to plasma [1]. However, we questioned the applicability of our findings to more slowly developing microvasculopathies, such as diabetic retinopathy. We designed the current study to examine the presence of such stage in slowly developing microvasculopathy. Animal models that are known to induce "diabetic retinopathy-like" changes used [2-4]. The diabetic animals were followed for a period of 17 months. Starting at the 12th month, a few animals of each group were killed and the retains were examined with our trichrome method [1] for relative capillary patency to erythrocytes and plasma, for functionality of endothelial cells, and for disturbances in the blood-retinal barrier. The results of this study support the hypothesis that retinal microvascular insufficiency does exist as a temporary stage that precedes the development of complete capillary blockage in long-term developing rat models of diabetic retinopathy.

Alloxan↗
PubMed2005

Retinal image analysis: concepts, applications and potential.

As digital imaging and computing power increasingly develop, so too does the potential to use these technologies in ophthalmology. Image processing, analysis and computer vision techniques are increasing in prominence in all fields of medical science, and are especially pertinent to modern ophthalmology, as it is heavily dependent on visually oriented signs. The retinal microvasculature is unique in that it is the only part of the human circulation that can be directly visualised non-invasively in vivo, readily photographed and subject to digital image analysis. Exciting developments in image processing relevant to ophthalmology over the past 15 years includes the progress being made towards developing automated diagnostic systems for conditions, such as diabetic retinopathy, age-related macular degeneration and retinopathy of prematurity. These diagnostic systems offer the potential to be used in large-scale screening programs, with the potential for significant resource savings, as well as being free from observer bias and fatigue. In addition, quantitative measurements of retinal vascular topography using digital image analysis from retinal photography have been used as research tools to better understand the relationship between the retinal microvasculature and cardiovascular disease. Furthermore, advances in electronic media transmission increase the relevance of using image processing in 'teleophthalmology' as an aid in clinical decision-making, with particular relevance to large rural-based communities. In this review, we outline the principles upon which retinal digital image analysis is based. We discuss current techniques used to automatically detect landmark features of the fundus, such as the optic disc, fovea and blood vessels. We review the use of image analysis in the automated diagnosis of pathology (with particular reference to diabetic retinopathy). We also review its role in defining and performing quantitative measurements of vascular topography, how these entities are based on 'optimisation' principles and how they have helped to describe the relationship between systemic cardiovascular disease and retinal vascular changes. We also review the potential future use of fundal image analysis in telemedicine.

Animals↗
PubMed2005

Management and outcomes of postoperative endophthalmitis since the endophthalmitis vitrectomy study: the Endophthalmitis Population Study of Western Australia (EPSWA)'s fifth report.

PURPOSE: To examine if changes in the diagnosis and management of postoperative endophthalmitis have occurred since 1995, and to identify factors that might predict final visual outcome. DESIGN: Retrospective, population-based, noncomparative, consecutive case series. PARTICIPANTS: Patients with clinically diagnosed endophthalmitis after cataract surgery and lens-related surgery in Western Australia from 1980 to 2000. METHODS: Endophthalmitis cases were identified using record linkage and cross-referencing with the surgical logbooks of vitreoretinal surgeons before validation by medical record review. MAIN OUTCOME MEASURES: Microbiological data (microorganisms isolated and antibiotic susceptibilities), diagnostic interventions, surgical procedures, therapeutic interventions, and visual acuity (VA). RESULTS: During the 21-year period, 213 episodes of endophthalmitis occurred after cataract surgery. Since 1995, both anterior chamber sampling and vitreous sampling have increased significantly. The overall use of vitrectomy has also increased, but we did not observe a difference according to presenting VA. Intravitreal antibiotic use increased significantly, whereas the use of both subconjunctival and IV antibiotics decreased. In one third of patients, the VA at least 6 months after admission for endophthalmitis was worse than 6/18. This was associated with treatment that did not include the use of oral antibiotics (odds ratio [OR], 3.86; 95% confidence interval [CI], 1.21-12.39; P = 0.02), growth from intraocular samples of organisms other than coagulase-negative staphylococci (OR, 9.84; 95% CI, 2.84-34.09; P<0.001), and a discharge VA worse than 6/18 (OR, 6.10; 95% CI, 1.63-22.89; P = 0.01). CONCLUSIONS: Although we observed noticeable changes in the diagnosis and management of endophthalmitis since 1995, visual outcomes have not improved and remain poor. Our finding that treatment with oral antibiotics may be associated with a better visual outcome warrants further investigation.

Aged↗
PubMed2005

Long-term evaluation of AAV-mediated sFlt-1 gene therapy for ocular neovascularization in mice and monkeys.

Vascular endothelial growth factor (VEGF) is one of the major mediators of retinal ischemia-associated neovascularization. We have shown here that adeno-associated virus (AAV)-mediated expression of sFlt-1, a soluble form of the Flt-1 VEGF receptor, was maintained for up to 8 and 17 months postinjection in mice and in monkeys, respectively. The expression of sFlt-1 was associated with the long-term (8 months) regression of neovascular vessels in 85% of trVEGF029 eyes. In addition, it resulted in the maintenance of retinal morphology, as the majority of the treated trVEGF029 eyes (75%) retained high numbers of photoreceptors, and in retinal function as measured by electroretinography. AAV-mediated expression of sFlt-1 prevented the development of laser photocoagulation-induced choroidal neovascularization in all treated monkey eyes. There were no clinically or histologically detectable signs of toxicity present in either animal model following AAV.sFlt injection. These results suggest that AAV-mediated secretion gene therapy could be considered for treatment of retinal and choroidal neovascularizations.

Animals↗
PubMed2005

A risk score as part of an evidence-based approach to the selection of corneal replacement surgery.

PURPOSE: There is currently no standardized methodology that permits preoperative prediction of the surgical technique or drug regimen for corneal grafting most likely to succeed for an individual patient. A score factor related to the chance of successful penetrating keratoplasty (PK) may assist in standardization of graft outcome reporting and evidence-based management. METHODS: The Risk Score (RS) is based on factors shown to reduce the probability of 1-year survival of conventional PK in increments, using published Australian Corneal Graft Registry data. To asses its validity, Kaplan-Meier survival curves from 156 corneal replacement surgeries, stratified by preoperative RS, were used to derive the probability of survival at 1 year for donor PK, with or without systemic immunosuppression, and for synthetic PK with the AlphaCor artificial cornea. The probability of survival was then plotted against RS for each regimen, producing a family of curves. RESULTS: The mean RS for immunosuppressed cases was higher than for nonimmunosuppressed cases. The AlphaCor group had the highest scores. AlphaCor survival is little affected by the factors that affect the risk of graft survival, whereas the probability of donor graft survival, immunosuppressed or not, is inversely related to RS. CONCLUSIONS: This study was designed to test a method that allows objective comparison of outcomes of different methods of corneal replacement for different risk categories. Analysis of this small dataset supports the validity of the concept and suggests that the Risk Score is a useful descriptive statistic. With a sufficient sample size, statistically significant evidence of the optimum management method for an individual patient with a particular risk profile could be determined such that a prospective patient's preoperative RS could be used to assist management decisions. In particular, data allowing separation of different immunosuppression regimes would be useful. Functional outcomes such as visual acuity would be more significant clinically than the survival end point used in this study and the system also could be adapted to different follow-up periods.

Artificial Organs↗
PubMed2004

Predilection of the macular region to high incidence of choroidal neovascularization after intense laser photocoagulation in the monkey.

OBJECTIVE: To determine the key factors for creating a high incidence model of choroidal neovascularization (CNV) in the monkey. METHODS: Intense laser photocoagulation was performed in 8 eyes of 4 monkeys using krypton red and green-yellow and Alcon frequency-doubled diode ophthalmic lasers. Eight to 13 lesions were delivered to an area between the temporal vascular arcades in each eye. Development of CNV was monitored by fluorescein angiography at 2 and 4 weeks after laser treatment, and the results were correlated with histological analysis. RESULTS: A much higher incidence of CNV occurred in the macular region, which refers to an anatomic area equivalent to a mean +/- SD 2.5 +/- 0.4 times the horizontal diameter of the optic disc in the fundus. Regardless of the type of ophthalmic laser used, 72% of lesions developed fluorescein leakage within the macula, compared with 12% outside the macula (P<.001). By histological analysis, 89% of lesions developed microscopic CNV within the macula vs 22% outside the macula (P<.001). CONCLUSION: The macular region is predisposed to creation of laser-induced CNV in the monkey.Clinical Relevance The predilection of the macular region to a high incidence of laser-induced CNV may account for the high recurrence rate of subfoveal CNV after laser treatment in humans.

Animals↗
PubMed2004

Deposits in artificial corneas: risk factors and prevention.

PURPOSE: To identify risk factors for calcium deposition and pigmented staining within AlphaCor artificial corneas. METHODS: Retrospective analysis of data from 72 AlphaCor implantations was conducted. Histological analysis of explants was performed. RESULTS: Eight cases of either intraoptic calcium or pigment deposition occurred in AlphaCor patients between 2.5 and 21 months after implantation. Four cases had diffuse white deposits, confirmed to be calcium and associated with prior coadministration of topical steroids and beta-blockers. The other four cases had brown deposits, associated with cigarette smoking and topical levobunolol. CONCLUSION: These findings led to changes in patient management protocols, surgeon training and patient information so as to minimize the risk of further occurrences. No further cases of white deposition have occurred after warning surgeons of the risk associated with certain topical therapy combinations. The risk of brown staining may be difficult to remove completely as it appears that environmental exposure to chemicals may cause deposition in addition to personal smoking habits and topical medications.

Adrenergic beta-Antagonists↗
PubMed2003

Differentiation of marrow stromal cells into photoreceptors in the rat eye.

Retinal degenerations and dystrophies are the major causes of genetically inherited blindness that are characterized by the apoptotic death of the photoreceptor cell layer of the retina. To date, no treatment exists for these diseases and only recently have they been considered as candidates for gene and stem cell therapies. Here we report the ability of adult CD90+ marrow stromal cells (MSCs) to be induced by activin A, taurine, and EGF into cells (20-32%) expressing photoreceptor-specific markers rhodopsin, opsin, and recoverin in vitro. CD90+ cells were either transduced with recombinant adeno-associated virus expressing green fluorescent protein (GFP) or bromodeoxyuridine (BrdU) labeled and then injected into the subretinal space of adult Royal College of Surgeons rats. Fundus photography and angiography showed no adverse effects of CD90+ MSC transplantation. GFP-expressing cells or BrdU-positive cells covered approximately 30% of the entire retinal area. By 2 weeks after injection, CD90+ MSCs integrated into the host retina, forming structures similar to the photoreceptor layer and expressed a photoreceptor-specific marker. No teratoma formation was observed in the recipient retina. The subretinally delivered CD90+ MSCs did not stain for proliferating cell nuclear antigen, indicating that they primarily undergo differentiation rather than proliferation. In addition, we established that transplanted cells can attract synaptic vesicles and hence are potentially capable of signal transduction. This study demonstrates for the first time the partial differentiation of adult CD90+ MSCs into photoreceptors in vitro and in vivo. Our results establish a proof of concept for CD90+ MSC differentiation with autologous transplantation, which may provide a promising therapeutic strategy for the treatment of some forms of genetically inherited retinal degenerations.

Animals↗
PubMed2003

Practical considerations of recombinant adeno-associated virus-mediated gene transfer for treatment of retinal degenerations.

BACKGROUND: Photoreceptor (PR) and retinal pigment epithelium (RPE) are the principal cell targets in retinal gene therapy. Recombinant adeno-associated virus (rAAV) has emerged as a very promising vector for gene therapy in hereditary retinal diseases. Gene transfer at different stages of the disease is a practical consideration for future clinical application. METHODS: A rAAV carrying the enhanced green fluorescent protein gene driven by a cytomegalovirus promoter was produced by either co-infecting the 293 cell line with E1-defective adenovirus and purified by CsCl(2) density gradient (CsCl(2)-rAAV), or by transfecting with an adenoviral helper plasmid and purified by iodixanol density gradient followed by heparin column chromatography (heparin-rAAV). The impact of different virus preparations on the patterns of transgene expression was investigated after subretinal injection. Furthermore, rAAV-mediated gene transfer was evaluated at both early and advanced stages of retinal degeneration in four disease models including the RCS rat, rd, RPE(65) (-)/(-) and cathepsin D mutant mice that are associated with PR- or RPE-related gene defects. RESULTS: CsCl(2)-rAAV predominantly transduced RPE and with less efficiency in PR. In contrast, heparin-rAAV predominantly transduced PR but with much less efficiency in RPE. Subretinal injection of either rAAV preparation induced no changes to retinal morphology and retinal-choroidal vasculature. The product of transgene, however, could be observed in multiple tracts in the brain. In the four disease models, target cells were efficiently transduced not only at the early stage, but also at the late stage of disease as long as the target cells were present. CONCLUSIONS: Different preparations of rAAV have an impact on the patterns of transgene expression after subretinal injection. Patients at advanced stages of retinal degeneration may still benefit from rAAV-mediated gene therapy. The possible side effects of transgenic products on the central nervous system should be carefully monitored once therapeutic genes are employed.

Animals↗
PubMed2003

Quantitative model demonstrating that recombinant adeno-associated virus and green fluorescent protein are non-toxic to the rat retina.

BACKGROUND: Recombinant adeno-associated virus (rAAV) is one of the most promising recombinant viral vectors for delivering therapeutic agents to the retina. The present study aims to quantify any effect that an rAAV construct may have on the retina. To be able to use rAAV for therapeutic purposes, the potentially toxic effect of the vector and an associated green fluorescent protein (gfp) marker has to be investigated. METHODS: By combining histological analysis with computer scanning techniques, the local toxicity of rAAV and gfp can be measured. This will have obvious implications for its role as a carrier in the rapidly developing world of gene therapy. RESULTS: It is shown that a construct consisting of rAAV and gfp, delivered subretinally to rat eyes, causes no more histological damage than injection with saline alone. Furthermore, via fluorescent fundus photography and computer scanning techniques it is seen that the area exposed to the rAAV-gfp construct is significantly greater than the area of histological change. CONCLUSIONS: It is thus concluded that the rAAV-gfp construct has no significant toxic effect, at an anatomical level, on the retina 12 months after injection.

Animals↗
PubMed2003

AlphaCor cases: comparative outcomes.

PURPOSE: To describe clinical outcomes after a novel type of corneal surgery, implantation of an artificial cornea, AlphaCor , and to evaluate outcomes in comparison with alternative keratoprostheses and high-risk grafts. METHODS: Case reports and data from a noncontrolled clinical trial and a literature review. RESULTS: The probability of AlphaCor retention to 1 year is 80%. Postoperative best corrected visual acuity ranges from Perception Light to 20/30. The most significant complications are stromal melts and optic depositions, for both of which the main risk factors have been identified. Complications can be managed without loss of the eye. CONCLUSION: Results from the clinical trial period have helped to determine the indications and risk factors for AlphaCor surgery and to refine surgical techniques. Continued monitoring of outcomes as the series increases will allow a more accurate determination of comparative outcomes. The series provides preliminary evidence that AlphaCor may have a lower incidence of complications than traditional keratoprostheses and may prove to be preferable to a donor graft in high-risk cases.

Aged↗