Biomedical subjects
Publications and source records attributed to A Garner.
The clinical and pathological findings of a 6-month-old infant with primary oxalosis, who died in renal failure, are presented. The oxalate crystalline deposition in the retinal pigment epithelium corresponded to the flecked retinopathy observed ophthalmoscopically. The difficulties in establishing a precise biochemical diagnosis are discussed and the relevant ophthalmic literature is reviewed.
The diagnostic potential of oxytalan fibre demonstration in differentiating between leiomyomas and spindle-cell malignant melanomas of the iris was investigated. It was found that oxytalan fibres were abundant in leiomyomata, both between and around the tumour cells, whereas they were found in small numbers only and usually near the iris muscle in malignant melanomata. Their presence and distribution, therefore, appear to offer a satisfactory method of differentiating between these tumours. Since the human choroid and ciliary body normally contain oxytalan fibres, the above findings are not relevant to malignant melanoma of these structures. Naevi and regressing aggregates of iris melanoma cells away from the main tumour mass may similarly be surrounded by misleading amounts of these fibres.
Imprints of choroidal malignant melanoma cells were treated with serum containing antibodies to a purified preparation of actin derived from skeletal muscle. Evidence of a positive reaction, as shown by indirect immunofluorescence, substantiated an impression based on morphological criteria that choroidal melanoma cells contain actin protein. The significance of this protein in tumour biology is discussed, and a possible interference by antiactin antibodies in the immunodiagnosis of choroidal melanoma is highlighted.
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Other contributors to this symposium will concern themselves with the stimulus to angiogenesis. My role is to review the character and topography of neovascularization with the eye. It would be redundant, however, if I were merely to recount the morphology of ocular new vessels and their location and not, in the process, draw attention to facets which may provide a clue to their pathogenesis and to attempt some sort of clinico-pathological correlation. This synopsis is confined to pathological angiogenesis involving the retina, iris, and cornea. Preretinal neovascularization alone will be discussed, since other papers will examine the intra-and subretinal locations.
Despite its importance as a cause of blindness, there is still much to be learned about the way in which onchocerciasis damages ocular tissues. Much of the difficulty encountered in investigating the problem is due to the lack of an adequate laboratory model amenable to study outside the endemic areas of O. volvulus infection. An attempt has been made to reproduce the ocular effects of O. volvulus in humans by infecting rabbits and guinea-pigs and bovine (O. gutturosa) and equine (O. cervicalis) strains of Onchocerca. The subconjunctival inoculation of rabbits with microfilariae of O. volvulus can produce a keratitis comparable to that seen in the naturally occurring disease and there is evidence that the intensity of the inflammatory response can be modified by pre-immunization. Injecting microfilariae into the posterior segment is equally able to produce choroido-retinal lesions, but evidence that immunological mechanisms are involved is less obvious.
The retest reaction is a variant of delayed hypersensitivity where in repeated application of an antigen at the same site leads to an intense eosinophil leucocytic infiltration. This reaction has been produced experimentally for the first time in the eyelids of rabbits and guinea-pigs and it is possible that such a mechanism is implicated in a variety of clinical ocular conditions in which IgE does not appear to feature. It was also found that tissue reaction was modified in the absence of suppressor cells, these having been temporarily inhibited by pretreatment of the animals with cyclophosphamide.
Long-term assessment of eyes in which silicone oil injection had been used in the treatment of retinal detachment with massive preretinal retraction was undertaken in 92 consecutive patients. While a high incidence of complications, particularly cataract, was confirmed, this study showed that they were probably caused not by any toxic effect of silicone oil but by obstruction of normal metabolic exchange at the silicone-tissue interface. The incidence of complications causing deterioration of vision or serious symptoms was not found to be high, and navigating vision was well preserved.
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A retrospective study of 55 patients with orbital lesions diagnosed on clinical grounds as cases of inflammatory pseudotumor was carried out to discover the relationship, if any, between the clinical and histological features and the response to treatment. It was found that few clinical parameters had a bearing on the subsequent progress of the lesion but B-scan ultrasonography was useful in identifying the lymphoproliferative mass. In 28 cases wherein histological material was available, the presence of follicles with germinal centres was found to indicate a good prognosis, whereas the presence of blast forms distributed randomly through the lymphoid tissue was associated with an inadequate response to corticosteroid therapy. Eosinophils were slightly more common in the corticosteroid-responsive lesions, but the presence of other leucocyte types was not helpful in determining prognosis.
The mechanism of the gastric cytoprotective action of prostaglandins is unknown but seems to be unrelated to inhibition of acid secretion. In the present study, effects of the prostaglandins, 16,16-dimethyl E2 and F2 alpha on H+ and HCO-3 secretion and electrical properties in amphibian-isolated gastric mucosa were studied. Spontaneous net secretion in fundic mucosa from Rana temporaria and Necturus was acid, whereas Necturus antrum secreted only HCO-3. The histamine H2-receptor antagonist, metiamide (10(-3) M), was used to inhibit acid secretion for studies on fundic alkalinization. Nutrient side administration of 16,16-dimethyl E2 (10(-6) M) for 60 min inhibited H+ secretion and stimulated HCO-3 secretion in Rana temporaria fundus. The drug (10(-5) M) also stimulated antral alkalinization. There was a dose-related increase in HCO-3 secretion in Necturus fundus after administration of F2 alpha (10(-5)-10(-4) M), but this drug had no significant effect on H+ secretion. Inhibition of acid secretion by 16,16-dimethyl E2 was associated with an increase in potential difference (PD), but there was no change in electrical resistance. Neither of the prostaglandins affected PD or resistance in alkaline-secreting tissues. Previous work has suggested that gastric HCO-3 secretion has a physiologic role in protecting the mucosal surface. The ability of prostaglandins to stimulate alkaline secretion may contribute to the cytoprotective action of these drugs in the stomach.
Effects of antiinflammatory agents and prostaglandins on H+ and HCO-3 secretions and electrical properties were investigated in the amphibian-isolated gastric mucosa. Gastric HCO-3 transport was studied in Rana temporaria fundus, in which H+ secretion had been inhibited with the histamine H2-receptor antagonists metiamide or cimetidine (10(-3) M), and in Necturus antrum, which secreted HCO-3 spontaneously. Hydrocortisone (100-500 microgram/ml) had no effect on H+ or HCO-3 secretion in the fundus. Indomethacin (10(-4) M) was a considerably more potent inhibitor of HCO-3 secretion than of H+ secretion in the fundus and also inhibited HCO-3 transport in the antrum. Fenclofenac (3 x 10(-3) M) almost abolished fundic HCO-3 transport and also depressed H+ secretion. There was a marked fall in transmucosal potential difference and a decrease in electrical resistance in fenclofenac-treated mucosae whereas indomethacin had less effect on electrical properties at the concentrations used here. The prostaglandins, E2, 16,16-dimethyl E2 and I2 all inhibited H+ secretion but only 16,16-dimethyl E2 stimulated HCO-3 secretion. The inhibitory action of indomethacin on HCO-3 secretion was prevented by co-administration of 16,16-dimethyl PGE2 (10(-6) M). It is proposed that the inhibitory action of nonsteroidal antiinflammatory drugs and the stimulatory action of some prostaglandins on HCO-3 secretion contributes to their ulcerogenic and anti-ulcer actions on the gastric mucosa.
Amongst other properties, malignant neoplasms are characterized by having antigenic determinants not normally found in mature healthy tissue. Consequently an immune response is usual on the part of the host and in recent years interest has centred on the twin possibilities of putting this property to diagnostic and therapeutic use. In our own laboratory we have concentrated on the diagnostic potential of immunological techniques in the investigation of pigmented tumours of the uvea. We have found that not only malignant melanomata, but also many naevi, can provoke an immunological reaction and we have shown that this is directed largely against contractile elements in the cytoplasm. Such reactions, which are not strictly tumour-specific, may be a source of diagnostic confusion and need to be excluded if immunology is to be of value in distinguishing malignant lesions of the uveal melanocytes from innocuous naevi.
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Fifty-five patients, suspected on clinical grounds of having an inflammatory orbital pseudotumor, were studied retrospectively. Clinical groups based on natural history or response to corticosteroid therapy were correlated with available histopathological findings. These findings were interpreted without knowledge of clinical grouping or previous pathology reports. Although dogmatic statements are not possible, several conclusions are warranted. (1) Bilaterality was not significantly related to response to steroids or development of systemic disease. (2) B-scan ultrasonography, while not diagnostic, provided a worthwhile investigative technique. (3) Germinal follicles are associated with a good prognosis and indicate a reactive lesion, while diffusely distributed lymphoblasts are associated with steroid unresponsiveness and a probable neoplastic lymphoid lesions. (4) Eosinophils are more common in reactive lesions than in presumed lymphomas. Other cellular components showed no preferential distribution in either neoplastic or nonneoplastic groups.
Sera from patients with proved and suspected melanoma of the uvea and from patients with innocuous uveal naevi were found by immunohistological techniques to have an affinity for the cytoplasm of malignant choroidal melanoma cells in an appreciable proportion of cases. The responsible antibodies were subsequently shown to react with smooth muscle protein in a variety of tissues and not to be melanoma-specific. It was also shown by electron microscopy that microfilaments consistent with contractile protein are a feature of the cytoplasm of malignant choroidal melanoma cells. The latter observations, which do not appear to have been reported previously, mean that false positives are to be expected if immunodiagnostic techniques are used for the recognition of malignant disease of the uvea, especially as smooth muscle antibodies can occur in non-neoplastic ocular diseases.
Measurement of gastric intraluminal PCO2 and pH in the anesthetized guinea pig enabled simultaneous determination of total H+ and HCO3- gastric secretions. There was quantitative agreement between the release of CO2 and decrease in HCO3- after intragastric instillation of HCl. The basal rate of HCO3- secretion (approximately 40 mueq-h-1) was, in most cases, smaller than spontaneous H+ secretion, but gastric net secretory output was alkaline (HCO3- greater than H+) after inhibition of acid secretion with histamine H2-receptor antagonists (cimetidine 20 mg-kg-1 or metiamide 35 mg-kg-1). Carbachol (1-2 microgram-kg-1) stimulated secretion of both HCO3- and H+; only the latter response was sensitive to the histamine antagonists. Atropin (100 microgram-kg-1) blocked stimulation of HCO3- secretion but did not affect the basal output of HCO3-. An increase in HCO3- secretion was associated with an equivalent increase in net Na+ influx and an increase in the net influx of Cl- with H+ plus K+. Intragastric neutralization of H+ by HCO3- is likely to occur at the mucosal surface and may protect the mucosa from the damaging effects of intraluminal acid.
The effects of oxidants (sensitizers) in the radiolysis of aqueous solutions of pyrimidine and purine bases have been investigated. Their influence on the nature of the permanent radiolysis products and on the kinetics of disappearance of transient intermediates is reported. Particular attention has been paid to the chemical fates of carbocationic intermediates which can be produced from radical-sensitizer interaction.