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M Jeffrey

Publications and source records attributed to M Jeffrey.

At least 73 records · Page 4Linked to original sources
PubMed1997

In vivo toxicity of prion protein in murine scrapie: ultrastructural and immunogold studies.

Prion protein (PrP) is a cell surface, host coded, sialoglycoprotein which accumulates in excess in scrapie, Creutzfeldt-Jakob disease, bovine spongiform encephalopathy and other transmissible spongiform encephalopathies. Infection of mice with the 87 V or ME7 scrapie strains results in distinctive and very different light microscopical patterns of vacuolation and disease specific PrP accumulation. In both of these scrapie strains immunogold electron microscopy was used to locate PrP to the plasmalemma of neurons from where it was released into the neuropil. Initial PrP accumulation around neurons and in early plaques lacking amyloid fibrils was generally not associated with morphological changes either of the neuron or dendrite releasing the PrP or in the adjacent neuropil in which excess PrP accumulated. However, accumulation of pre-amyloid PrP in some brain areas was associated with specific degeneration of dendritic spines and axon terminals. Initial PrP aggregation into fibrils was also associated with tissue damage with both ME7 and 87 V plaques and diffuse accumulations. Tissue damage associated with fibrillogenesis was localized and would not be expected to have clinical significance. We conclude that pre-amyloid PrP release and accumulation is not invariably toxic, either to the neuron releasing PrP or to the neuropil into which it is released. However, axon terminal degeneration and dendritic spine loss in some neuroanatomical areas may be indicative of specific PrP toxicity and may be the main cause of neurological dysfunction in murine scrapie.

Animals↗
PubMed1996

BSE in Great Britain: consistency of the neurohistopathological findings in two random annual samples of clinically suspect cases.

Two annual, random samples of clinically suspect cases of bovine spongiform encephalopathy (BSE) were taken in 1992-93 (year 1, 1500 cases) and 1993-94 (year 2, 1000 cases). From each sample, 100 positive cases were examined in detail to establish the severity of the vacuolation in 17 specific neuroanatomical locations. The resultant 'lesion profiles' were compared with the profile obtained from a similar sample of BSE-affected cattle from early in the epidemic (1987-89); the comparison showed that the distribution and severity of vacuolation in BSE has remained unchanged. The cases not confirmed as BSE on histological examination (172 in year 1 and 162 in year 2) were examined for evidence of any alternative neurohistological diagnosis. As in previous studies, the majority of these cases showed no significant lesions (61.6 and 61.7 per cent). The remainder consisted of bilateral focal spongiosis of unknown significance (26.7 and 21.0 per cent), inflammatory conditions (8.1 and 11.1 per cent) and a small number of cases with tumours, cerebrocortical necrosis or idiopathic brainstem neuronal chromatolysis. No evidence was found of any cases of BSE with an atypical distribution of lesions. These findings support the theory that the BSE epidemic is sustained by a single, stable strain of the BSE agent, and confirm that the existing statutory diagnostic criteria continue to be appropriate.

Animals↗
PubMed1996

Ultrastructural immuno-localization of synthetic prion protein peptide antibodies in 87V murine scrapie.

Disease specific forms of a host encoded cell surface sialoglycoprotein called prion protein (PrP) accumulate during this incubation period of the transmissible spongiform encephalopathies. A 33-35 kDa disease specific form of PrP is partially resistant to protease digestion whereas the normal form of PrP can be completely digested. Proteinase K digestion of the murine disease specific form of PrP produces diverse forms of low molecular weight PrP, some of which are N-terminally truncated at amino acid residue 49 or 57 within the octapeptide repeat segment. Amyloid plaques are a pathological feature of many of the transmissible spongiform encephalopathies and are composed of PrP. Using synthetic peptide antibodies to the N-terminus of PrP (which is not present in truncated disease specific PrP) and antibodies to the protease resistant fraction of PrP we have immunostained plaques and pre-amyloid deposits in the brains of mice, experimentally infected with the 87V strain of scrapie, for examination by light and electron microscopy. Classical fibrillar amyloid deposits in plaques as well as pre-amyloid deposits were both immunostained by antibodies to the N-terminus of PrP and to the protease resistant core of the PrP molecule. This suggests that both N-terminal and core amino acid residues are present in disease specific PrP released from scrapie infected cells in vivo. The results also suggest that N-terminal truncation of PrP may not be essential for formation of amyloid fibrils.

Amyloid↗
PubMed1995

A survey of the incidence of Neospora caninum infection in aborted and stillborn bovine fetuses in England and Wales.

Selected brains and fetal viscera from 190 aborted or stillborn bovine fetuses submitted to Veterinary Investigation Centres in England and Wales between August 1992 and January 1993 were examined histologically. Non-suppurative inflammation of the brain and/or myocardium and placental cotyledons was identified by light microscopy in 20 (10.5 per cent). An immunocytochemical examination of fixed tissue sections using antisera against Neospora caninum, Toxoplasma gondii and Sarcocystis species revealed positive immunolabelling for N caninum in the brains of eight (4.2 per cent), but no labelling with anti-T gondii or anti-Sarcocystis species antisera was evident. These results suggest that N caninum may be an important cause of reproductive failure in cattle in England and Wales.

Abortion, Veterinary↗
PubMed1995

A new form of ovine GM1-gangliosidosis.

Neurological signs were observed in 3 lambs at approximately 1 month of age, in a flock of 1 ram and 29 ewes with 43 lambs. Deterioration occurred such that the lambs had either died or been killed by 4 months of age. Necropsies of two of these lambs revealed a diffuse encephalopathy in which the most prominent feature was ballooned neurons. Sections of frozen brain showed PAS-positive, oil red O-negative, and weak Sudan Black-positive material in the swollen neuronal cytoplasm. The ultrastructure of the neuronal inclusions showed characteristic whorled membranes, suggesting diagnosis of a gangliosidosis. The underlying enzymic defect was investigated by assaying 11 lysosomal enzymes in extracts of kidney from an affected lamb and from normal lambs. A deficiency (90%) of acidic beta-D-galactosidase was found in the affected lamb. All other activities, including N-acetylneuraminidase, were normal. A specific deficiency of lysosomal beta-D-galactosidase was demonstrated by separating the lysosomal and cytosolic beta-D-galactosidase by chromatography on concanavalin A-Sepharose. Diagnosis of GM1-gangliosidosis, analogous to the severe infantile form of the human disease, was made on the basis of the pathology and enzymology. The beta-D-galactosidase activity in the white blood cells of the ram and several of the ewes was consistent with their being heterozygotes. This disorder is different from a previously described lipidosis in sheep, in which there was a combined deficiency of beta-D-galactosidase and alpha-neuraminidase.

Animals↗
PubMed1995

Pathology of the transmissible spongiform encephalopathies with special emphasis on ultrastructure.

The transmissible spongiform encephalopathies are a group of genetic and infectious disorders which are exemplified by scrapie in animals and Creutzfeldt-Jakob disease in humans. The spongiform encephalopathies are characterized by symmetrical vacuolation of neurons and neuropil. Amyloid plaque formation similar to that found in Alzheimer's disease is conspicuous in many, but not all, of these diseases. The sub-cellular pathology features of the spongiform encephalopathies have been studied by conventional transmission electron microscopy, scanning electron microscopy, freeze fracture, negative staining and most recently by application of immunogold labelling methods. Although these studies have revealed many unusual structures, convincing virus-like particles have not been demonstrated. Considerable data, including important transgenic mouse studies, now suggest that a single cellular protein, designated prion protein, is necessary for infection. Ultrastructural immunogold studies have shown that prion protein is released from the surface of neurons and neurites, diffuses through the extracellular space around infected cells where it accumulates and finally becomes aggregated as amyloid fibrils. It is likely that the accumulation of prion protein within the extracellular space is instrumental in causing nerve cell dysfunction and, ultimately, neurological disease.

Amyloid↗
PubMed1995

Early unsuspected neuron and axon terminal loss in scrapie-infected mice revealed by morphometry and immunocytochemistry.

Neuronal loss is often quoted as an element of the pathology of the transmissible spongiform encephalopathies, but few data are published. To determine whether neuronal loss is a salient feature of murine scrapie, and whether there is a relationship with the other hallmark lesions of scrapie we compared the numbers of neurons, severity of vacuolation, axonal bouton density and distribution of prion protein (PrP) in the dorsal lateral geniculate nucleus (dLGN) following intraocular infection of C57BL/FaBtDk mice with ME7 scrapie. This route of infection limits the initial spread of infection to the retinal efferents, thus directing infectivity and subsequent pathological changes to the dLGN which is a major projection of the optic nerve. Morphometric assessment of neuron number in the dLGN was made on semi-serial sections from five infected and five normal brain injected controls at four 50-day intervals during the incubation period, and on terminally affected mice. The number of neurons decreased from around 20,000 at 50 days to under 1000 in the terminal group. Significant loss was identified in individual mice at 150 days post-infection, coincident with the onset of vacuolation: neuron number was found to have an inverse relationship to the severity of vacuolation. Axonal boutons in the dLGN (demonstrated by synaptophysin immunolabelling) were reduced at 200 days, and virtually absent in terminal mice. The intensity of PrP immunostaining progressively increased from 150 days, and in a separate experiment PrP was detected from 175 days by polyacrylamide gel electrophoresis of brain extracts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Correlative light and electron microscopy studies of PrP localisation in 87V scrapie.

The transmissible neurodegenerative diseases, of which scrapie is the archetype, are caused by unconventional infectious agents. Prion protein (PrP), a widespread host coded, cell surface sialoglycoprotein, is thought to be an essential or, controversially, sole component of these agents. During infection, disease specific accumulations of PrP may be observed in immunostained brain sections of mice infected with the 87V scrapie strain as amyloid plaques or as diffuse or granular foci within the neuropil. Using serial light and electron microscopical preparations we determined immunocytochemically that infection specific PrP is present in amyloid fibrils, and accumulates on the plasmalemma of neurites at the periphery of plaques and in the neuropil, irrespective of the morphological form of PrP accumulation when viewed by light microscopy. In some brain areas with dense granular PrP expression complete disruption of neuropil with loss of neurites was associated with fibrils lying free in expanded extracellular space. These results suggest that normal PrP may be converted to its pathological form at the neuronal plasmalemma or in the extracellular space and, furthermore, that amyloid fibrils are formed following the accumulation and aggregation of subunit proteins at these sites.

Animals↗
PubMed1994

Murine scrapie-infected neurons in vivo release excess prion protein into the extracellular space.

An originally heretical proposition that the transmissible spongiform encephalopathies are caused by a host-coded protein (the prion hypothesis) is now current dogma. Indeed these disorders are commonly called prion diseases but the prion hypothesis provides no readily acceptable explanation for the source of the informational component of the agent necessary to code for the diversity of strains of scrapie. Ultrastructural immunolocalisation of prion protein (PrP) in murine scrapie shows that PrP accumulates in association with the plasmalemma of neurones, diffusing from the neuronal cell surface into the extracellular space around small neurites prior to aggregation and fibril assembly. These events occur without the involvement of other cell types. The area of neuropil infiltrated with extracellular PrP around infected neurons and neurites indicates that the form of PrP initially produced is not immediately amyloidogenic.

Animals↗
PubMed1994

Infection-specific prion protein (PrP) accumulates on neuronal plasmalemma in scrapie-infected mice.

Prion protein (PrP) is an abundant membrane-associated host protein which accumulates in abnormal, relatively protease-resistant forms in the brains of animals with scrapie and related diseases. Using correlative light and electron microscopy we determined the sites of subcellular localization of PrP in mice infected with the 87V strain of scrapie. Disease-specific accumulation of PrP was observed at light microscopy as amyloid plaques or as diffuse or granular staining within the neuropil, often clearly associated with individual neurons. Serial electron microscopical preparations were immunostained for PrP by the immunogold method. Gold particles were located on amyloid fibrils and on the plasmalemma of neurites at the periphery of plaques and in the neuropil, irrespective of the morphological form of PrP accumulation when viewed by light microscopy. This suggests the amyloid fibrils are formed following the accumulation and aggregation of sub-unit proteins at the plasmalemma and, furthermore, that normal PrP may be converted to its pathological form at this site.

Animals↗
PubMed1994

Unsuspected early neuronal loss in scrapie-infected mice revealed by morphometric analysis.

This study was undertaken to determine to what extent neuronal loss is a feature of scrapie pathology, using an experimental model in which infectivity and subsequent vacuolar lesions are well characterized but in which neuronal loss has not been previously identified. Intraocular infection with ME7 scrapie directs infection through the major projections of the optic nerve, which include the dorsal lateral geniculate nucleus (dLGN) on the contralateral side to the infected eye. Infectivity can be detected in the dLGN at 77 days post-infection and vacuolar lesions are first seen around halfway through the incubation period of 240 days. Morphometric assessment of neuron number in the dLGN was made on gallocyanin stained semi-serial sections from 5 infected and 5 normal brain-injected controls at 4 fifty-day intervals during the incubation period, and on clinically terminal mice. The number of neurons in the dLGN of the infected mice decreased steadily from around 20,000 at 50 days post-infection to under 2,000 in the terminal group. The loss was delayed in the ipsilateral dLGN, although terminal counts were the same for both sides. The onset of neuronal loss was coincident with initial vacuolar changes, and neuronal numbers were inversely proportional to the severity of vacuolation. It is concluded that scrapie infection causes a progressive neuronal loss that can be identified some 30-80 days after infectivity can be detected in the dLGN, long before the onset of clinical disease.

Animals↗
PubMed1994

Polioencephalomalacia associated with the ingestion of ammonium sulphate by sheep and cattle.

In the latter part of 1991 an unusual neurological disease was recognised on several farms in England. This report describes the case histories and clinical, biochemical and pathological findings in six calves and two lambs aged from two to 44 weeks obtained from five of these farms. Laminar cerebrocortical necrosis and severe bilateral necrosis of the thalamus and/or striatum progressing to cavitation were recognised in their brains. These changes are similar to those of experimental sulphate toxicity. Morbidity rates of 16 to 48 per cent and mortality rates of 0 to 8 per cent were recorded. The affected animals did not respond to vitamin B1 treatment; the erythrocyte transketolase levels of in-contact cattle and of one untreated affected calf and one untreated lamb were within the normal range. All five farms had recently introduced a proprietary concentrate ration containing ammonium bicarbonate. After this ration was withdrawn no new cases of nervous clinical disease were observed. It is suggested that, in at least some cases, the morphology and topography of lesions may distinguish sulphate induced polioencephalomalacia from that of sporadic thiamine-dependent cerebrocortical necrosis.

Ammonium Sulfate↗