PubMed Health⌕ Search

Biomedical subjects

J B Cavanagh

Publications and source records attributed to J B Cavanagh.

At least 19 recordsLinked to original sources
PubMed1992

Ubiquitin, PGP 9.5 and dense body formation in trimethyltin intoxication: differential neuronal responses to chemically induced cell damage.

Ubiquitin in normal cells may be important in degrading or transferring short-lived or aberrant proteins to lysosomal dense bodies. To examine its role in degrading proteins produced by a chemical insult, changes in the distribution of ubiquitin and the carboxy-terminal hydrolase, PGP 9.5, have been studied in rat hippocampal neurons and cerebellar Purkinje cells in trimethyltin intoxication. Here tubulovesicular dense bodies (TVBs) form from 12h onwards associated with vacuolation of the Golgi apparatus. Striking accumulations of lysosomal dense bodies follow in hippocampal pyramidal cells but not in cerebellar Purkinje cells; many of the hippocampal neurons later die, while the Purkinje cells generally survive. Ubiquitin immunoreactivity was diffusely increased in hippocampal pyramidal and Purkinje cells 6 h after dosing. By 12 h both diffuse and granular ubiquitin immunoreactivity was present that intensified over 24 and 48 h. Both by light and electron microscopy TVBs showed ubiquitin immunoreactivity, but dense bodies in hippocampal perikarya did not stain with an anti-ubiquitin antibody. PGP 9.5 immunoreactivity was not altered in hippocampal cells at any time, while Purkinje and Golgi cell dendrites and perikarya showed intensified labelling at 3 h that reached a peak of 12 h. At 48 h Western blot analysis of hippocampal homogenates showed significant increases in high molecular weight (HMW) ubiquitin conjugates, while cerebellar homogenates showed an increase in ubiquitin-histone conjugates. Northern blot analyses showed no change in ubiquitin or PGP9.5 gene expression in hippocampus or cerebellum. These findings suggest that the material in the TVBs in hippocampal cells is not being degraded by the ubiquitin system but passes ubiquitinated into the lysosomal system, while material in Purkinje cell TVBs is degraded by the ubiquitin system, suggesting it may have a different composition in each type of neuron.

Animals↗
PubMed1992

Methyl bromide intoxication and acute energy deprivation syndromes.

The case reported in this issue of symmetrical brain stem damage associated with exposure to methylbromide has affinities with a number of analogous syndromes associated with tissue energy deprivation. Attention is drawn to topographical and metabolic similarities and differences in these conditions, and suggestions are made for possible ways of mitigating the damage in future cases that may also be of value in Wernicke and Leigh's diseases.

Acute Disease↗
PubMed1992

Chronic low-dose exposure of sodium nitrite in VM-strain mice: central nervous system changes.

1. There is suggestive evidence that nitrite may be a causative factor in cerebral glioma. 2. To test this hypothesis we selected the VM mouse strain, known for its susceptibility to spontaneous glioma formation, and exposed 300 animals to 0.2% sodium nitrite in their drinking water. One hundred of this group were exposed both in utero and throughout their adult lives. The remaining 200 animals received nitrite from the time of weaning. A further 200 mice were used as controls and received distilled water. 3. All animals were maintained until their natural death and were then subjected to autopsy and routine histological examination. 4. There was no excess of nervous system tumours in the experimental groups.

Administration, Oral↗
PubMed1992

Functional/metabolic modulation of the brain stem lesions caused by 1,3-dinitrobenzene in the rat.

To determine whether neuronal activity plays a role in the localisation of brain stem lesions in 1,3-dinitrobenzene intoxication we produced asymmetrical changes in auditory input by rupturing the left tympanic membrane in Fischer rats. This raised the auditory threshold on that side from 57-63 dB to 104-122 dB. It also decreased glucose utilisation in the ipsilateral cochlear nucleus and significantly increased utilisation in the contralateral nucleus, resulting in a relative deficit of 72 +/- 6%. Similarly, tympanic membrane rupture led to decreased glucose utilisation in the contralateral and increased utilisation in the ipsilateral inferior colliculus. Additional exposure to "white noise" prevented the decrease in glucose utilisation in the contralateral inferior colliculus. Dosing with dinitrobenzene (10 mg/kg in 4 doses over 48 hr) to otherwise normal rats produces symmetrical vasculonecrotic lesions in these regions, but in animals with left tympanic membrane rupture the severity of morphological changes in the ipsilateral cochlear nucleus and the contralateral inferior colliculus were substantially reduced. Additional exposure to "white noise" increased the degree of damage in the ipsilateral cochlear nucleus and contralateral inferior colliculus. These findings indicate that altered auditory function in rats, with its associated metabolic consequences exercises a significant role in the development of brain stem damage in auditory pathways following dinitrobenzene intoxication.

Acoustic Stimulation↗
PubMed1991

What have we learnt from Graham Frederick Young? Reflections on the mechanism of thallium neurotoxicity.

The recent death of the psychopathic poisoner, Graham Frederick Young, prompts the question: has our knowledge of the toxic effects of thallium been increased as a result of his activities? The answer is 'yes' but very little. However, the poisonings led to a re-examination of the topography and pathogenesis of thallium intoxication and the suggestion that there are close similarities with chronic thiamine deficiency neuropathy and arsenical neuropathy. They might be termed chronic energy deprivation neuropathies and are associated with damage to other organs with high energy requirements, namely skin and its appendages, testis and heart. While the exact metabolic 'lesion' in thallium intoxication is not yet known, circumstantial evidence continues to suggest that it may be related to the known interaction of this ion with riboflavin, with consequent effects upon energy generation mechanisms associated with tissue flavoproteins.

Crime↗
PubMed1991

Alfred Meyer.

Explore the source record for details and available documents.

Germany↗
PubMed1991

Vascular factors in the neurotoxic damage caused by 1,3-dinitrobenzene in the rat.

Using a 3 x 10 mg/kg dose schedule of 1,3-dinitrobenzene (DNB) over two days in Fischer rats, we have found the following changes in vascular function and structure during the early phase of the symmetrical brain stem lesions. 1. Marked increase in cerebral blood flow generally but especially in the inferior colliculi, from 6 h after the final dose of DNB. 2. Increasing incidence of petechial haemorrhages in inferior colliculi, cerebellar roof, vestibular and superior olivary nuclei from 12 h. 3. Focal leakage of horseradish peroxidase and many sleeve-like arteriolar haemorrhages seen in vibratome sections and by scanning electron microscopy (SEM) in these regions from 12 h. 4. Periarteriolar oedema and protein leakage present in step-serial sections in these regions from 12 h, with astrocyte swelling and occasional small infarcts. These changes suggest that the vascular bed may play an important role in the pathogenesis of these lesions, perhaps in parallel with early astroglial damage. They are discussed in relation to (i) the known presence of xanthine oxidase in the vascular bed of the brain and the likelihood of "useless redox cycling' with free radical generation from this enzyme's interaction with nitroheterocyclic compounds, and (ii) the possible role of free radical damage to endothelial cells in this intoxication and in the analogous lesions of natural and experimental Wernicke's encephalopathy.

Animals↗
PubMed1990

Regional variations in nerve cell responses to trimethyltin intoxication in Mongolian gerbils and rats; further evidence for involvement of the Golgi apparatus.

The different responses of neurons with distinctive variations in morphology and function, confirm earlier observations of the lack of uniformity in the reaction of nerve cells to trimethyltin. Thus, hippocampal pyramidal and cortical neurons in both rat and Mongolian gerbil (M. unguiculatus) show abundant lysosomal dense bodies and disorganisation of the protein-synthesising apparatus. Cerebellar Purkinje cells in gerbil, but not in rat, show striking increases in smooth membrane systems, while dense bodies are insignificant in both species; large motor-type neurons in brain stem and spinal cord in both species do not accumulate dense bodies, but their rough endoplasmic reticulum (RER) may undergo intense vacuolation with or without subsequent cell death; and by contrast, spinal ganglion cells of both species may form an excess of dense bodies and, in the gerbil, vacuolation of RER. In contrast with these varied responses to trimethyltin most neurons, large and small, in both species regularly undergo striking vacuolation of the Golgi apparatus in the earliest phase of the intoxication, a constant feature that probably reflects the site of the primary cytotoxic lesion; all other changes we consider are secondary to such damage to the Golgi apparatus, however this may come about. These observations are discussed in relation to earlier reports of the variable effects of trimethyltin and with the metabolic changes reported in trimethyltin intoxication that in general accord with these morphological conclusions.

Animals↗
PubMed1990

Selective degeneration of cerebellar cortical neurons caused by cycad neurotoxin, L-beta-methylaminoalanine (L-BMAA), in rats.

Both the racemate and the L-form of BMAA (beta-methylaminoalanine), when injected intraperitoneally into young rats, produced acute signs of cerebellar dysfunction and degeneration of cerebellar stellate, basket, Purkinje and Golgi cells, but not granule cells. Degenerative changes were also occasionally seen in cerebellar roof nuclei which may be secondary in nature. No other changes were found in the remainder of the central nervous system. The doses of the L-form of BMAA producing these changes were from 6 to 14 mumols/g body weight, i.e. the lower and upper levels of the dose range used by Vega and Bell (1967) and equivalent to 75 and 183 mg/rat. Doses of 1 to 4 mg/g body weight of the racemate were given to young rats less than 100 g in weight, but no changes were apparent after daily doses of the racemate of 0.5 mg/g body weight. Damage to cerebellar neurons is considered to be the result of excitotoxic activity. All cells showing degeneration are GABAergic, although not all are known to possess N-methyl-D-aspartate (NMDA) receptors. The present finding of selective cerebellar neuron damage may not conflict with the earlier findings of others, but our results suggest that L-BMAA has unusual glutamate receptor binding properties.

Amino Acids, Diamino↗
PubMed1990

Glial cell intrusions actively remove detritus due to toxic chemicals from within nerve cells.

It has been observed that when neurons are acutely damaged by toxic chemicals leading to accumulations of effete materials, glial supporting cells insert cytoplasmic processes into neuronal cytoplasm and appear to transfer this material into themselves. Essentially the same phenomenon has now been seen in several situations, namely in peripheral nerve axons in a number of experimental peripheral nerve intoxications, especially in spinal roots, as well as occasionally in normal axons in paranodal regions and more frequently above a nerve ligation. It has been seen, too, in cerebellar Purkinje cells after acrylamide intoxication and in hippocampal pyramidal neurons and in neurons of the pyriform cortex after triethyllead and trimethyltin intoxications. A similar process may also be taking place regularly both in normal and chemically damaged spinal ganglion cells through their satellite cell sheath. While probing of neurons by glia has also been noted normally in pre-synaptic regions of mammalian neurons as well as in the perikarya of certain goldfish neurons, the purpose for this is less apparent. Such findings in relation to removal of bulk residual material from neurons raise intriguing questions as to the signals required between cells to enable such evidently cooperative intercellular events to take place, and whether this process, that is apparently so inefficient in removing lipofuscin pigment from ageing neurons, may not, perhaps, be adversely influenced by environmental agents.

Animals↗
PubMed1989

Motoneuron disease: a disorder secondary to solvent exposure?

There seems to be a statistically significant association between work in the leather industry and subsequent development of motoneuron disease. The reason for this association may be occupational exposure to solvents, which may damage motoneurons either directly or through activation of latent virus.

Adolescent↗
PubMed1989

Trichloroethylene cranial neuropathy: is it really a toxic neuropathy or does it activate latent herpes virus?

The mechanism of the cranial neuropathy associated with heavy exposure to trichloroethylene (or dichloroethylene) is unknown. In severe cases there is destructive spread of the neuropathic process from the Vth cranial nerve nuclei up and down the brain stem in a manner that is difficult to explain on accepted neurotoxicological principles. However, there is a close association reported of this form of trigeminal neuropathy with reactivation of orofacial herpes simplex that suggests the possibility that the chemical, which readily gains entrance into the nervous system, may be responsible for reactivating the latent virus. This novel hypothesis is discussed in the light of current understanding of latency in herpes simplex infection in nervous tissue.

Cranial Nerve Diseases↗
PubMed1988

Lesion localisation: implications for the study of functional effects and mechanisms of action.

In some toxic neuropathies we see only distal "dying back" of longer and larger diameter axons, the perikaryon appearing to be intact. Some of these are the result of chronic energy deprivation, others are not. In other neuropathies sensory and autonomic neuron cell bodies are damaged without apparent selectivity. Toxic neuropathies often mimic the neurological effects of vitamin deficiencies by causing juxtaposed lesions in the same metabolic pathways. In acute energy deprivation toxic syndromes in the CNS, the pattern of damage is restricted to specific grey centres: there are variations in this pattern according to the site of the metabolic lesion, the species studied, the development of seizures, and other factors. Such toxic responses mimic human and animal disease states, such as Wernicke's encephalopathy and Leigh's disease, both of which are essentially acute energy deprivation syndromes.

Animals↗
PubMed1986

The axon reaction in spinal ganglion neurons of acrylamide-treated rats.

Rats were given acrylamide in doses of either 30 or 50 mg/kg (5 days each week) for up to 3 weeks and killed at weekly intervals. The right sciatic nerve was tied tightly at the level of the major trochanter 4 days before killing the animals by perfusion fixation when ipsilateral and contralateral sensory ganglia (L5 and L6) were removed. The effects on neuronal perikarya of axotomy alone, of acrylamide alone and of these combined were studied by light and electron microscopy. The responses to axotomy and to acrylamide intoxication shared certain features, namely peripheral Nissl substance and to a lesser degree nuclear eccentricity, nucleolemmal crenation and mitochondrial enlargement. Neurofilament loss was present only with acrylamide. In combined axotomy and acrylamide all these five features were prominent. These findings indicate firstly that the individual responses to axotomy and to acrylamide, while sharing several features, are subtly different and secondly that acrylamide appears to impede the vital neuronal responses directed towards repair of the axon.

Acrylamide↗
PubMed1979

Studies on the early changes in acute isoniazid neuropathy in the rat.

Large single doses if isoniazid by mouth (1--2g/kg) have been shown to produce in rats Wallerian degeneration visible with the light microscope from the third day onwards. By contrast, changes in axons are seen from 24 h onwards by electron microscopy. The earliest ultrastructural changes are associated with vacuoles appearing between axon and Schwann cells. These are large and focal, and often compress the axon. The adjacent axon may show changes in smooth ER, and in microtubular arrangement. Alterations in smooth membranes and in mitochondria are visible in Schwann cell cytoplasm, not necessarily related to the vacuole formation and axonal features. It is suggested that INH neuropathy is essentially a multifocal axonal lesion.

Acute Disease↗