Tumour necrosis factor-alpha (TNF alpha) is a major proinflammatory cytokine which appears in the cerebrospinal fluid very early after endotoxin challenge, and is likely to be produced locally. Following in vivo and in vitro challenge with endotoxin, we have demonstrated immunocytochemically and by in situ hybridization that pig and guinea-pig choroid plexus ependymal cells can produce TNF alpha. Immuno-electron microscopy shows that this protein is localized within ependymal cells to the cytoplasm and microvilli. We suggest that this TNF alpha may be important in the initiation of the inflammatory response in bacterial meningitis.
Guinea pigs were treated with a single dose of Cisplatin (5 mg IP). After 2-4 days the cochleas were prepared for morphological analysis by scanning electron microscopy and chemical analysis by X-ray dispersive microanalysis. Following Cisplatin, the bundles of stereocilia on the hair cells were found to be rough, disarrayed, fused, and finally absorbed. Significant increases were found in the levels of calcium, sulphur, and phosphorus in the abnormal hair cells. It is suggested that the high calcium levels might be due to the inhibition of enzymes which normally keep cytoplasmic calcium low, and that some of the changes in the stereocilia might be secondary to this.
An apparently unique form of cochlear damage was produced in guinea pigs by perfusing the cochlea or injecting the cerebrospinal fluid with bacterial endotoxin. This developed rapidly (within two hours) and was characterised by sweiling of the tectorial membrane and damage to both inner and outer hair cells, with parallel functional damage demonstrable electrophysiologicaily. AU these changes could be attenuated by pretreatment with dexamethasone. Such endotoxin mediated lesions may be the mechanism by which hearing loss occurs in bacterial meningitis.Deafness is a well recognised complication of bacterial meningitis. 'Treonic' microinfusion pump (IP-3, Vickers Medical) was inserted into the basal hole in the scala tympani and fitted tightly into it. Artificial perilymph containing endotoxin (Escherichia coli 026:B6 lipopolysaccharide (Sigma Chemicals), 100 ng-l sg) was introduced into the cochlea in a total volume of 17 ,ul over a period of one minute. Some leakage occurred from the apical hole, and this was mopped up with a tissue wick.Recordings of cochlear microphonics and compound action potentials were made at 30 minute intervals for at least two hours using an electrode sealed within the glass micropipette.9At the end of the experiment the cochlea was immediately fixed by intravital perfusion of glutaraldehyde and prepared for scanning electron microscopy as previously described.'0 The opposite cochlea was similarly fixed immediately after death. These studies were repeated after pretreatment of the guinea pigs with dexamethasone (1 mg/kg intraperitoneally) one hour before the infusion of endotoxin. Similar experiments were performed in which 100 ng-l ,tg of E coli endotoxin were injected intracisternally into the cerebrospinal fluid. These studies too were repeated after pretreatment with dexamethasone. Control studies were performed perfusing the cochlea with artificial perilymph alone, without endotoxin. Each experiment was repeated several times.
Results
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