Biomedical subjects
J V Forrester
Publications and source records attributed to J V Forrester.
Automated detection and quantification of microaneurysms in fluorescein angiograms.
Fluorescein angiograms from diabetics were digitised for analysis using digital image-processing techniques. Computer algorithms were written to detect and count microaneurysms present in the images. The accuracy, speed and reproducibility of the technique were assessed and compared with those of manual counts made by clinicians from both digitised and analogue images. Free-response ROC (receiver operating characteristic) curves were used to assess the performance of both the clinicians and the computer by comparing the results with "gold standards" compiled from prints of the original fluorescein angiograms. The computer performed as well as the clinicians when the latter were analysing the digitised images (512 x 512 pixel resolution), but only when one image was acquired at 4 times this resolution did the computer's performance match that of the clinicians analysing the analogue image. The automated technique was more reproducible than the manual method.
Low-dose cyclosporin therapy of ocular inflammation: preliminary report of a long-term follow-up study.
Cyclosporin A (CsA) is an effective therapy for severe intraocular inflammation but nephrotoxicity and hypertension are major side effects even in low dose in combination with oral corticosteroids and clinical studies on the long-term effects of low-dose CsA therapy outside the field of organ transplantation are lacking. This multicentre, open, longitudinal study has been established to evaluate the long-term efficacy and side effects of low-dose CsA therapy (initial dose less than or equal to 5 mg/kg/day, with a maximum dose of 7 mg/kg/day, and total treatment duration greater than 3 months) in severe ocular inflammation where conventional therapy had failed to control the disease or caused intolerable side effects. Visual response to treatment, clinical signs and symptoms of side effects, biochemical and haematological parameters have been recorded at 3-monthly intervals since January 1987 and will continue until December 1993. Data for 74 patients (age 35.5 +/- 16.6 years) and 293 follow up visits are presented in this preliminary report. [table: see text] Other side effects include (% of all visits): hypertrichosis (4.2), headache (2.8), cramps (1.8), arthropathy (1.8), paraesthesiae (1.8), abdominal pain (1.5), weakness (1.5), dyspepsia (1.4), nausea (1.4), others (4).
Immunocytochemical analysis of blood lymphocytes in uveitis.
We studied the surface expression of activation markers IL2-R, HLA-DR and CD45-RO on peripheral T-lymphocytes in two groups of patients (n = 26) with idiopathic uveoretinitis, compared with controls. Thirteen patients were analysed by alkaline phosphatase anti-alkaline phosphatase (APAAP) immunocytochemistry, which demonstrated a significant rise in expression of HLA-DR and IL2-R surface markers. Flow cytometric analysis was performed on a further 13 patients, which confirmed a significant rise in IL2-R expression in uveitis patients. Within this group systemic activation was confined to patients with idiopathic retinal vasculitis. Dual flow cytometry confirmed a CD4+,IL2--R+ T--lymphocyte phenotype. A further 4 patients with retinal vasculitis who had been treated with cyclosporin A demonstrated a 32% reduction in IL2-R expression over a 3-month period. Analysis of CD45-RO and CD5+ cells was found to be uninformative in this study. We have demonstrated activated peripheral lymphocytes in patients predominantly with retinal vasculitis, the significance of which is discussed.
Duke-Elder Lecture: new concepts on the role of autoimmunity in the pathogenesis of uveitis.
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Local anaesthesia for eye surgery.
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Sarcoidosis and inflammatory eye disease.
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Experimental autoimmune uveoretinitis: a model system for immunointervention: a review.
Experimental autoimmune uveoretinitis (EAU) is a useful model of human posterior uveitis and as such, permits the analysis of strategies for immuno-intervention. Modulation of the autoimmune response may be attempted at the stages of induction of EAU, during homing of autoreactive lymphocytes to the target organ, the retina, or during the effector stage of the disease. This paper presents a brief overview of current immuno-therapeutic modalities and assesses the usefulness for extrapolation to human disease.
Antigen processing and presentation in the eye: a review.
The recognition event between self-antigen, the MHC and the T cell receptor has become the target for potential immunotherapy of T cell mediated autoimmune disease. For this approach to succeed in uveoretinitis, uniformity in T cell receptor usage, restricted MHC usage and limited epitope recognition by individuals would be required. In this study we have shown that despite clonal heterogeneity of response to multideterminate retinal extract antigens, proliferation to the antigens tested was restricted by the IA MHC class II molecule. Different patterns of reactivity to retinal antigens in the presence of various protease inhibitors was observed. Natural processing of IRBP appears to be complex, requiring a number of enzymes to generate immunogenic fragments, in contrast, for S-antigen, plasmin alone may suffice. The RPE cells which are potential processors and presenters of retinal antigens produce PGE2 and may act as suppressors of ocular inflammation.
Epitopes and idiotypes in experimental autoimmune uveitis: a review.
Retinal S-antigen (SAg) and interphotoreceptor retinol-binding protein (IRBP) induced experimental autoimmune uveitis (EAU) and experimental autoimmune pinealitis (EAP) are good models for studying the mechanisms involved in autoimmune diseases. Many immunogenetically active epitopes have been identified in these proteins but immunodominance of one or more epitopes in vivo, has not yet been established. In this paper we present and discuss some experiments that led to the discovery of a dominant "tolerogenic" epitope in SAg. We also demonstrate the presence of cross reactive epitopes in the two potent retinal antigens, SAg and IRBP and finally introduce early data on a unique anti S2.4.c5 idiotypic (Id) monoclonal antibody (MAb) which appears to be a site non associated antibody that binds not only to s2.4.c5 but also to SAg.
Induction of experimental autoimmune uveitis by the retinal photoreceptor cell protein, phosducin.
Experimental autoimmune uveitis (EAU) and experimental autoimmune pinealitis (EAP) are CD4+ T cell mediated inflammatory diseases of the retina and uveal tract of the eye and the pineal gland respectively. They can be induced in experimental animals by immunization with several well characterized retinal autoantigens. We induced a mild to moderate EAU and EAP in Lewis rats by immunization with phosducin, a 33K retinal phosphoprotein which is involved in the phototransduction of vision. In contrast to the severe EAU induced by other retinal antigens like S-antigen (SAg) or interstitial retinoid binding protein (IRBP), the clinical disease was late in onset, low grade in severity and predominantly affected the posterior segment of the eye. Our study demonstrates that another photoreceptor cell protein, phosducin, is capable of eliciting EAU and EAP.
Interphotoreceptor retinoid binding protein induced experimental autoimmune uveitis: an immunophenotypic analysis using alkaline phosphatase anti-alkaline phosphatase staining, dual immunofluorescence and confocal microscopy.
Using a Lewis rat model of IRBP induced EAU, we have examined the progress of leucocytes infiltrating the uveitic eye. APAAP and dual immunofluorescence were used to show that ED7 and 8 (CD11b/CD18) positive monocytes, W3/25 and OX8 (CD4 and CD8) lymphocytes were prominent in the initial inflammatory exudate around the retinal vessels and in the choroid. ED1 positive monocytes were also observed in the choroid. As disease progressed, these cells moved into the inner retina, vitreous and ROS. ED8 positive cells were the first to appear in the ROS. This was followed by the later appearance of ED2 tissue macrophages in the vitreous and ED3 inflammatory macrophages in the vitreous and ROS.
The use of lithium clearance studies in the early detection of cyclosporin A (CsA) nephrotoxicity: a protocol of renal function assessment with CsA therapy.
Cyclosporin A nephrotoxicity was studied with the use of lithium and creatinine clearance tests in 18 patients with chronic intraocular inflammation (duration of treatment 3-48 months). In 11 patients lithium clearance and fractional excretion of lithium were significantly reduced (compared with pretreatment levels) within the first six months of treatment. There was no significant change in either serum creatinine or creatinine clearance within this period. In 14/18 patients there was a significant reduction in lithium clearance and fractional excretion of lithium during the treatment period. 7 patients whose therapy was stopped because of continuing nephrotoxicity despite dose reduction, demonstrated some reversibility of renal function on cessation of cyclosporin A. We propose a protocol for the assessment of renal function in these patients so that with dose modulation the changes in these parameters can be minimised, reducing the risk of renal impairment, whilst maximising immunosuppressive treatment.
Ultrastructural pathology of experimental autoimmune uveitis. Quantitative evidence of activation and possible high endothelial venule-like changes in retinal vascular endothelium.
BACKGROUND: Experimental autoimmune uveitis (EAU) is a highly organ-specific autoimmune disease in which the target is the retinal photoreceptors. It is well recognized as a model of uveoretinitis in humans. The mechanisms that control the homing of sensitized lymphocytes and other leukocytes to the retina is unknown. The aim of this study was to investigate changes in the retinal vasculature that may be involved with aiding leukocyte-endothelial cell interactions and subsequent extravasation of leukocytes into the retina. EXPERIMENTAL DESIGN: Lewis rats immunized with S-antigen were used to produce EAU. The retinal vasculature was assessed by morphologic (light and electron microscopy) and morphometric techniques at various stages in the generation and course of the disease (days 3, 7, 11, 14, 21, 28 and 49 postimmunization) for evidence of endothelial cell (EC) activation and leukocyte-EC interaction. Image analysis of the retinal vessels at the electron microscopic level was performed to detect alterations in the thickness and irregularity of the EC surface, both considered to be important in lymphocyte homing in the high endothelial venules (HEVs) of lymphoid tissues. Control values were obtained from normal eyes, pertussis-only treated animals, and normal lymph node HEVs. RESULTS: The clinical and histopathologic changes in the eyes were consistent with previous descriptions of EAU and included perivasculitis, focal mononuclear infiltrate in the outer retina, and choroid with destruction of the photoreceptor outer segments and eventually loss of large portions of the outer retina. During the course of EAU, a significant proportion of retinal venules underwent both qualitative and quantitative morphologic changes including EC activation evident as increased cytoplasmic organelles, a 230% average increase in mean EC thickness, and a concomitant 4-fold increase in irregularity of the EC, that produced plump irregular EC with deep intercellular clefts. These alterations were maximal at day 21, however from day 11 onward, large numbers of lymphocytes and monocytes were observed adhering to or lodged in the clefts of plump EC, migrating through the EC cytoplasm, or lying beneath the EC. CONCLUSIONS: The characteristics acquired by the retinal venules during EAU are reminiscent of HEVs. This study suggests that tissue-specific changes in the endothelial cells of retinal venules may be responsible for the homing of S-antigen specific autoreactive lymphocytes to the target organ in this model of retinal autoimmunity.
Detection and quantification of hyperfluorescent leakage by computer analysis of fundus fluorescein angiograms.
Digital imaging systems can be used for direct acquisition of images of the ocular fundus or for their indirect acquisition from fundus photographs or transparencies. Computerised image processing techniques can then be used to manipulate and quantify features of interest. We describe a method for the detection and quantification of macular leakage in fluorescein angiograms. The rate of change in fluorescence over time is examined on a pixel-by-pixel basis and used to provide a gradient threshold that discriminates pixels displaying leakage from normal pixels. A region-growing technique is then used to enhance the detection of leakage missed by gradient thresholding alone. This report discusses the potential applications of the technique and highlights the methodology required to obtain reproducible results.
Quantification of diabetic maculopathy by digital imaging of the fundus.
Measurement of the extent of diabetic retinopathy is an essential part of assessing the efficacy of local or systemic treatment regimens. Current clinical studies use empirical grading of retinopathy which is performed by a trained observer using standard photographs. This method is relatively arbitrary, as well as time consuming and vulnerable to observer error. We have developed a digital fundus imaging system and image processing programs which provide objective, quantitative measures of macular oedema, retinal exudates, and microaneurysms in diabetic retinopathy. Using fluorescein angiograms, the degree of macular oedema is quantified both in terms of area of fundus involved and severity of oedema by analysis of the temporal changes in intensity of fluorescence. Fluorescein angiograms are also used for the detection and counting of microaneurysms, by a combination of shade correction, matched filtering, and shape algorithms. For detection and measurement of retinal exudates, a colour transparency projected through a red free filter is analysed using a combination of shade correction and thresholding techniques. The system described is in clinical use, and has potential for a wide variety of applications. With further development, digital analysis of fundus images should supercede the currently used manual semi-quantitative methods, providing faster, more accurate, objective quantitative results.
The oval pupil.
The dynamics of pupillary dilation induced by Phenylephrine 10% and Cyclopentolate 1% have been examined by flash photography. A correlation between anterior chamber depth and the pupil shape on dilation with Phenylephrine Hydrochloride 10% is described. It is postulated that these pupillary dilation dynamics support a sympathetic abnormality as a trigger for acute primary angle closure glaucoma.