Thrombocytopenia associated with diclofenac therapy.
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Biomedical subjects
Publications and source records attributed to A H Rahi.
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Unusual giant nodules on the posterior surface of Descemet's membrane were observed in two out of over 400 corneae examined during routine histopathological reporting. Both of the patients, a 60-year-old man and a 26-year-old woman, had histories of corneal trauma. Neither was associated with chronic keratitis or corneal dystrophy. Light microscopy showed these nodules to be composed of material resembling Descemet's membrane. Histochemical and electron microscopical preparations identified oxytalan fibres within the outer layers of the nodules. These fibres are not a feature of the normal adult Descemet's membrane. The findings are discussed and compared with other nodular lesions of Descemet's membrane.
This study documents for the first time light and electron microscopical changes in the retinal pigment epithelium (RPE) following treatment with high dose desferrioxamine for systemic iron overload. The changes include loss of microvilli from the apical surface, patchy depigmentation, vacuolation of the cytoplasm, swelling and calcification of mitochondria, and disorganisation of the plasma membrane. In addition, Bruch's membrane overlying degenerate RPE cells appeared abnormally thickened owing to the accumulation of large amounts of mature elastic fibres, pre-elastic oxytalan, and long spacing collagen. The specificity of these changes and the mechanism of toxicity are discussed.
Sheets of vitreous membrane (scar tissue) and associated retinal detachment were produced in the right eye of 86 adult New Zealand white rabbits by intravitreal injection of cultured autologous skin fibroblasts. The membranes were examined by light and electron microscopy and time-lapse cinephotomicrography. Immunohistochemistry was used to demonstrate alterations in the distribution of cytoplasmic contractile proteins. While retinal detachment and membrane contraction were taking place, there was pronounced increase in the numbers of fibroblasts with an elongated spindle shape. These spindle-shaped cells had some similarities to myofibroblasts including the presence of 'stress cables'. However, the myofibroblast-like cells stained much less avidly for cytoplasmic (actin) microfilaments than migratory fibroblasts seen at early stages of membrane development. The significance of migrating fibroblasts and myofibroblasts in scar contraction is discussed.
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Cell surface carbohydrates play an important role in several biological, immunological, and neoplastic phenomena including development, growth regulation, cellular locomotion, receptor activation, and tumour metastasis. Fluorescein labelled lectins which bind to specific carbohydrate residues in glycoproteins and glycolipids are being increasingly used as chemical probes to study cell components. Several different preparations of ocular tissues from human, rabbit, and rat were examined for the distribution of N-acetyl-D-galactosamine (D-gal NAc) by means of fluorescein-labelled lectin from soybean (glycine max). A very strong fluorescence was observed in the corneal epithelium; Descemet's membrane and corneal endothelium were also strongly fluorescent. The conjunctival epithelium similarly showed a strong reaction, as did the goblet cells. The iris epithelium and the dilator pupillae were only weakly fluorescent, but the ciliary body showed strong fluorescence, as did the blood vessels. As compared with lens fibres the lens epithelium was strongly fluorescent. The outer retina, that is, the photoreceptors, the pigment epithelium, and Bruch's membrane, showed a very strong reactivity. The optic nerve showed moderate fluorescence, but reaction with extraocular muscles was variable. The skin of the upper and lower eyelids, hair follicles, and blood vessels showed strong lectin binding. Sections of retinoblastoma and malignant melanoma showed no reaction. The physiological and pathological significance of these findings is discussed.
Recent advances in the field of cellular immunology have enabled us to recognise a complex homeostatic mechanism controlling inflammation, allowing us to understand the aetiopathogenesis of many systemic disease processes. This immune regulatory mechanism involves the interaction of positive and negative messages passing between the different subsets of peripheral blood lymphocytes. Quantitative or qualitative defects in the suppressor cell subset of thymus derived T-lymphocytes are believed to be responsible (at least in part) for chronic inflammation and autoimmune disease. A variety of peripheral blood lymphocyte parameters were examined in four ill-understood inflammatory ophthalmological conditions: acute anterior uveitis, heterochromic cyclitis, acute lepromatous uveitis and Mooren's ulcer. Defects in the number or function of suppressor T-cells were found in all conditions studied. These findings make it possible to explain some of the immunological aberrations previously reported in these conditions. As abnormalities have been found in the immune regulatory mechanism of patients with inflammatory eye conditions of unknown aetiology, the way is now open to explore new lines of treatment using drugs which have the properties to allow selective manipulation of T-lymphocyte subsets.
Immunohistochemical techniques were used to examine the distribution of cells containing glial fibrillary acidic protein (GFAP) in normal and pathological human specimens, including 22 globes (13 of which contained epiretinal membranes 'in situ'), 16 surgically excised epiretinal membranes, and monolayers of cells obtained from five epiretinal membranes placed in tissue culture. The astrocytic cells of normal and pathological retinae stained with the glial-cell marker, but Müller cells were GFAP-negative in normal retinae at the antisera dilutions used. Müller cells did, however, stain in retinae from glaucomatous eyes and in eyes with prolonged retinal detachment. Electron microscopy did not reveal any obvious morphological difference between the intermediate filaments of normal (GFAP-negative) and GFAP-positive Müller cells. Ten of the 13 epiretinal membranes 'in situ', all 16 excised membranes, and three of the five monolayers contained glial cells. Purely glial membranes were not associated with retinal puckering or detachment, while all membranes causing tractional complications had a prominent fibrous, non-glial component. Our findings suggest that glial cells do not contribute significantly to the contractile forces generated by epiretinal membranes. They may, however, provide a scaffold on which other cells proliferate and contract and an anchorage by means of which tangential forces are transmitted into and through the retina.
Following an inconclusive study of differential lymphocyte counts in uveitis in which the peripheral blood was examined only once in the course of each case a longitudinal study has been carried out in patients with acute anterior uveitis. Venous blood lymphocytes were examined at intervals throughout the course of the illness, from presentation until six months later. No changes in E-rosetting T cells or total lymphocyte values have been found, nor any variations from normal in the helper (OKT4)/suppressor (OKT8) T-cell ratio. Random studies performed in a sample of patients with heterochromic cyclitis have also failed to reveal consistent abnormalities in peripheral blood lymphocyte parameters.
Mooren's ulcer is a chronic, painful corneal ulceration of unknown aetiology. Recent histological and immunological studies suggest an autoimmune basis. It is now becoming clear that the immune system plays an intricate role in maintaining homoeostasis in health and disease. Regulation of the immune response appears to involve a subset of peripheral blood T lymphocytes known as suppressor cells. A qualitative or quantitative deficiency of suppressor cells may therefore be responsible for chronic inflammation, autoimmune disease, and immunodeficiency states. To explain the reported immunological aberrations the number of suppressor T cells in addition to other immunological parameters were studied in a patient with bilateral Mooren's ulcers. A deficiency of suppressor T cells was found in the peripheral blood. This deficit in the immunoregulatory mechanism explains some of the immunological abnormalities reported in previous studies. Furthermore this study provides additional evidence for an autoimmune aetiology. In the light of these findings the possibility of a new line of treatment has been raised.
The aetiology of acute anterior uveitis (AAU) in the great majority of cases is unclear. Various infective agents have been postulated, however, as playing a direct or indirect part in the disease process, possibly via an immune-complex vasculitis. In an earlier study we concluded that, contrary to a previous report, hepatitis B virus (HBV) played only a small role, if any, in the pathogenesis of uveitis in Great Britain. Since we did not look for other markers of HBV infection other than hepatitis B surface antigen (HBsAg), it is possible that some cases of recent HBV infection may have been missed. In the present study 49 patients with AAU were tested for markers of hepatitis B infection. Sera from all patients tested were found to be negative for HBsAg and for antibody to the HBV core (anti-HBc), excluding HBV as a significant cause of AAU in this country. Since the quest for an infective agent in AAU may remain unproductive, future research on the aetiopathogenesis of AAU should include the study of tissue 'vulnerability' and the local and systemic immunoregulatory factors which modulate inflammatory responses.
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Viruses have been demonstrated or suspected as the causative agents of various types of uveitis. Hepatitis B virus (HBV), apart from causing hepatitis, has also been implicated in the pathogenesis of systemic vasculitis, for example in glomerulonephritis and polyarteritis nodosa. It is therefore possible to postulate that a similar vasculitic process might occur in the eye leading to intraocular inflammation. A recent report from Switzerland suggests that HBV may be implicated in the aetiology of uveitis, as hepatitis B surface antigen (HBsAg) was found in the serum of 13% of cases of uveitis. Since the status of HBV in the aetiology of uveitis in Great Britain has not been investigated, we have examined serum from 200 cases of uveitis of various clinical types for the presence of circulating HBsAg. Only 4 cases (2%) were found to be HBsAg positive. This study failed, therefore, to confirm HBV as an important cause of uveitis in this country, but one cannot exclude the possibility that it may play a pathogenetic role in a small proportion of such cases.
A prospective immunological study of patients with proptosis due to intraorbital lesions composed largely or exclusively of lymphoid tissue indicates that the use of antisera to specific heavy and light chain antibody components can be helpful in distinguishing between polyclonal and truly neoplastic monoclonal disorders. On the basis of combined histological and immunological information it is possible to delineate 4 categories of patient: those with unequivocal chronic inflammation, those with a virtually pure lymphoproliferative lesion and a polyclonal profile, and those with a monoclonal lymphomatous disorder which may be histologically comparable to the previous category or, in a fourth group, be unmistakably malignant on cytological grounds. The first of these groups will normally respond to corticosteroid treatment, but the others, including the polyclonal lymphoproliferative masses, need radiotherapy. The finding of reduced numbers of circulating T cells in the presence of low plasma levels of IgA, and of autoantibodies in the serum of a third of the patients, could mean that individuals developing lymphoproliferative lesions in the orbit, whether hyperplastic or neoplastic, are partially immunodeficient.
Monolayers of cells were grown from epiretinal membranes using standard tissue culture techniques. The growing cells were filmed by time-lapse cinephotomicrography to record their locomotory characteristics and cell-to-cell interactions. The established layers of cells were examined in the scanning electron microscope. In addition, the cultured cells were studied immunohistochemically to identify specific cell types and the distribution of contractile elements (e.g. actin). The locomotory patterns, the topography and the immunohistochemistry of cells from epiretinal membranes were compared to the movement, appearance and staining characteristics of a wide range of normal cells in culture. From the growth characteristics in tissue culture, early membranes appeared more hypercellular than longer standing membranes. Cell outgrowth was established more quickly and was more widespread in the young epiretinal membranes than in older, more fibrous, specimens. The locomotory and immunohistochemical studies demonstrated that a wide variety of cell types may contribute to epiretinal membranes. A remarkably wide range of cell forms were observed in cultures of individual membranes. Epithelial and glial cells were found in many of the monolayers. However, they did not constitute the majority of cells in the cultures. The predominating cell types had the morphological and locomotory characteristics of fibroblasts or macrophages.
Structurally and therefore antigenically the retina is a complex tissue. Since it develops as an extension from the neural tube it shares with the brain several cell membranes and cytoplasm associated antigens including those present in neurofilaments of the various neurones and the glial filaments of the astrocytes. The advent of monoclonal antibodies has helped to dissect, in detail, the antigenic makeup of the retina. Nervous system antigens (NS-3, 4 and 7) are generously represented in the retina. At least in the chick eye there seems to be a concentration gradient of retinal antigens along a dorsoventral axis which is believed to provide means by which neurones of developing retinal signal and receive the positional information necessary for the formation of specific synapses. It now seems certain that organ-specific antigens are presented not only in the photoreceptors and the retinal pigment epithelium but also in the retinal ganglion cells and the astrocytes. Photoreceptor outer-segment contains soluble antigens which when injected in rats, rabbits, guinea-pigs or monkeys produce varying degrees of intraocular inflammation leading to uveitis, retinal detachment, photoreceptor degeneration and occasionally retinal vasculitis. Both cell-mediated and humoral immunity to photoreceptor antigen has been demonstrated in various types of uveitis (including toxoplasmosis and sarcoidosis), pars planitis, vitriitis, Behçets disease, sympathetic ophthalmitis, Vogt-Koyanagi-Harada syndrome, birdshot retinopathy, retinitis pigmentosa and retinal vasculitis. Retinal autoimmunity is also found in retinal detachment and diabetic retinopathy, particularly after Argon laser photocoagulation. Antibodies to retinal antigens are also found in patients with systemic lupus erythematosus and other systemic immune disorders without ocular involvement. The precise pathogenetic role of retinal autoimmunity in eye disease is therefore uncertain. It may simply represent an epiphenomenon which develops afer retinal damage due to physical, micro-organismal or immunological insult. Alternatively it is possible that although autoimmunity does not initiate ocular inflammation it perpetuates and maintains the inflammatory state and produces further damage to ocular tissues.