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H Fraser

Publications and source records attributed to H Fraser.

At least 109 records · Page 6Linked to original sources
PubMed1989

Transport and targeting of scrapie infectivity and pathology in the optic nerve projections following intraocular infection.

The initial development of scrapie lesions can be seen following intraocular infection to be directly related to sequential infection of connecting neuronal relays within the projections of the optic nerve. For example, intraocular infection of VM mice with 22A virus produces lesions in the contralateral dorsal lateral geniculate nucleus (dLGN) and superior colliculus around halfway through the incubation period of about 360 days; the next lesions appear in the visual cortex, presumably as a result of the transport of infection through the geniculo-cortical tract. Infection of the same strain of mouse with 87V virus produces similar lesions in the dLGN slightly later in the incubation period of about 440 days, although cortical lesions are never seen with this agent. Subsequent lesions with both strains of the virus occur symmetrically in sites which are recognised targets with other routes of infection. Differences of this type provide the opportunity to relate levels of infectivity in sets of neurons directly to subsequent pathological changes. If the two murine Sinc genotypes (Sinc controls incubation period length) are compared after intraocular infection with ME7 virus, the timing of the appearance of the first lesions is in proportion to the length of the incubation period; this may provide a means of identifying the action of Sinc at a cellular level. Serial enucleation following infection of the right eye with ME7 virus has shown that infection takes between 7 and 14 days to reach the superior colliculus and initiate infection via this pathway. This slow rate of spread of infectivity suggests that ME7 is carried in an anterograde direction by the slow rate of axonal transport.

Animals↗
PubMed1989

The scrapie disease process is unaffected by ionising radiation.

The incubation period of scrapie, its degenerative neuropathology and the replication of its causal unconventional virus are all tightly controlled parameters of the experimental disease in mice. Each parameter can vary depending on the strain and dose of virus, on the route of infection, and on the host genotype. Exposure to whole-body gamma-irradiation from Caesium 137 has no effect on the progress or development of the disease, based on the three independent indices of incubation period, neuropathology, or infectibility by high or low doses of virus. These results are based on an extensive series of experiments in many mouse strains and are consistent using different strains (ME7, 22A, 79A, 87V) and doses of virus, routes of infection, timing and dose of radiation (3-15 Gy) administered as single or fractionated exposures with or without bone-marrow (b.m.) replacement therapy. Levels of infection in the spleen are unaltered after lethal whole-body irradiation of the scrapie-infected host, despite several-fold reductions in tissue mass due to the loss of proliferating myeloid and lymphoid precursor cells and their progeny. Contrary to our earlier suggestion, scrapie infection with the 22A virus does not reduce the effectiveness of post-exposure bone-marrow replacements to recolonise an infected host after repeated ionising radiation totalling 15Gy. This work narrows the search for the candidate cells and biosynthetic systems which replicate the virus in the lymphoreticular and central nervous systems. Many programmed cellular events are radiation sensitive but protein synthesis is extremely radioresistant.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

The molecular pathology of scrapie and the biological basis of lesion targeting.

Strains of scrapie virus can only be distinguished from the incubation period and neuropathology of the disease they induce in mice of different Sinc genotypes. There are two main aspects of the neuropathology: a spongiosis or degenerative vacuolation associated with the replication of virus, and cerebral amyloid plaques. The relationship between these two is unclear - they can occupy topographically quite different centres in the CNS and the timing of their occurrence is different. Surprisingly this is also the case using the very precise targeting provided by the intraocular infection route. Here the earliest spongiosis is very localised into the primary and secondary projections from the retina, but plaques, when they occur, occupy quite different sites. The relationship between plaques and spongy degeneration is probably a neuroanatomical one, similar to that suggested between plaques and tangle-bearing neurons in Alzheimer's disease. A third aspect of the pathology is the occurrence of SAF in negative-stained E.M. preparations, formed from the aggregation of a sialoglycoprotein called PrP or SAF-protein. Immunolabelling of plaques with antisera to SAF protein shows as yet that there is no antigenic variation in the protein prepared from different scrapie models with different strains of the virus based on available reagents. Strain variation is only recognised on biological criteria; as yet, there are no independent molecular markers or in vitro tests which can account for the biological variation.

Amyloidosis↗
PubMed1988

Altered clinical and histological features of male MM mouse pyelonephritis associated with a change in its microbiology.

Radical changes in the clinical, microbiological and histological features of spontaneous pyelonephritis in MM male mice occurred when they were transferred to a new environment after Caesarean derivation. Although the incidence of pyelonephritis remained the same, the survival age was increased. The renal histology indicated a shift to a more chronic form of pyelonephritis with renal amyloidosis as a common feature. At autopsy much more renal scarring was seen, resulting in the 'shrunken' kidney typical of chronic pyelonephritis. Renal lymphocytic accumulations were commonly found in MM mice, but they were also seen frequently in C57BL mice and in germfree stocks of both strains: no association was found between these lesions and pyelonephritis.

Amyloidosis↗
PubMed1987

Amyloid scrapie plaques in mice, and Alzheimer senile plaques, share common antigens with tau, a microtubule-associated protein.

Immunolabelling was performed on brain sections of scrapie-infected mice with antibodies against tau, a microtubule-associated protein, and against the paired helical filaments of Alzheimer's disease. Both kinds of antibodies have been shown previously to label paired helical filaments in neurons and in abnormal neurites associated with the senile plaques of Alzheimer's disease. Amyloid plaques in murine scrapie were labelled by both antisera. The structural substrate for the immunolabelling was probably the dystrophic neurites in the periphery of the plaques, leaving the amyloid core unstained. These results emphasize that similar mechanisms are likely to be involved in the pathogenesis of plaques in both diseases.

Alzheimer Disease↗
PubMed1987

Scrapie associated fibrils in the diagnosis of scrapie in sheep.

Previous research has consistently demonstrated by electron microscopy the presence of scrapie associated fibrils in brain extracts prepared from mice and hamsters with clinical signs of experimental scrapie. In the present study similar fibrils were seen in all the brain extracts prepared from 11 Cheviot or Suffolk sheep with natural or experimental scrapie that had been diagnosed clinically and confirmed neuropathologically. They were not found in the brain extracts of nine sheep that did not have scrapie and which included four that had been injected with infected material but did not develop the disease. The presence of such fibrils can therefore be used as an additional diagnostic criterion for natural scrapie in sheep.

Animals↗
PubMed1987

No evidence for involvement of plasma proteins or blood-borne cells in amyloid plaque formation in scrapie-affected mice. An immunohistoperoxidase study.

The present study was designed to investigate blood-brain permeability and the possible involvement of plasma proteins and blood-borne cells in amyloid plaque formation in scrapie-affected mice. No abnormal extravasation of intravenously injected horseradish peroxidase (HRP) was found and with immunocytochemical techniques no plasma proteins were detected in neuropil from scrapie-affected mice. In contrast to an earlier report, these findings suggest that the blood-brain barrier is essentially intact in scrapie-affected mice. Using immunohistochemical and enzyme histochemical methods no cells belonging to the monocyte-macrophage lineage were detected in association with amyloid plaques. Thus, by these methods there was no evidence that plasma proteins or blood-borne cells are involved in amyloid plaque formation in scrapie-affected mice. However, astrocytes were consistently found to be associated with amyloid plaques at all stages of their development.

Amyloid↗
PubMed1987

Ionising radiation has no influence on scrapie incubation period in mice.

Scrapie has an early non-clinical stage when replication of agent occurs in lymphoreticular organs. Whole-body irradiation failed to alter the incubation or neuropathology of the disease. Many experiments were carried out with different strains of scrapie agent and host, doses and timing of irradiation. The results suggest that mitotically quiescent cells are involved in agent replication.

Animals↗
PubMed1986

Primary retinopathy in scrapie in mice deprived of light.

Rodents infected with some strains of scrapie develop a severe retinopathy in which the photoreceptor cells are destroyed. The possibility that this results from light-induced damage as a secondary consequence of the disease was tested by maintaining scrapie-infected albino mice in total darkness. Photoreceptor loss occurred in terminal scrapie-infected mice maintained in both total darkness and in normal lighting conditions establishing that the retinopathy is a primary lesion with this strain of scrapie agent.

Animals↗
PubMed1986

Brain tumours in mice, with particular reference to astrocytoma.

In a survey of 75,000 brains from 23 inbred mouse strains studied during research work on scrapie, astrocytoma was by far the commonest neuroectodermal tumour. It occurred in VM and BRVR mice at a 1% incidence, but was virtually absent from other strains. In VM mice it occurred nearly twice as often in males as in females, sometimes causing neurological signs of circling, depression or spinal paralysis, but more often showing no clinical effects and being discovered only during routine neuropathology carried out for other purposes. Astrocytomas occurred in mice in the spinal cord or in the brain, with equal frequency in the fore-, mid- and hindbrain. A dual origin has never been confirmed, but astrocytomas occasionally co-existed with other central nervous system tumours. Macroscopically they cause no distortion of the brain; this contrasts with the rare oligodendroglioma, in cases of which the brain is sometimes swollen and misshapen. Astrocytomas characteristically spread through white-matter tracts, but in some grey-matter localities neoplastic astrocytes can co-exist with viable neurons, suggesting that they may subserve some functions of normal astrocytes. The astrocytomas found in this study often co-existed with scrapie lesions. Scrapie-induced vacuolation penetrated some astrocytomas in grey matter, and the specific scrapie-associated argyrophilic (amyloid) plaques occurred in the middle of an astrocytoma in several mice. However, there is no relationship between the occurrence of astrocytoma and scrapie infection, and the neoplasm also occurs independently both of the Sinc gene, which controls the pathogenesis of scrapie, and of the histocompatibility type of the strains concerned. The spontaneous VM astrocytoma is transplantable intracerebrally and, in the early series of in vivo subpassages, it only grew in the brains of mice of the strain of origin and its crosses. The age occurrence of astrocytoma and the incidence of other CNS tumours in mice are discussed in this paper.

Age Factors↗
PubMed1985

Targeting of scrapie lesions and spread of agent via the retino-tectal projection.

Scrapie infectivity and degenerative vacuolation was initially localized within the contralateral superior colliculus following intraocular injection. The time course of these events was prolonged. With the ME7 strain of scrapie in Sincs7 genotype mice, infectivity began to rise in the superior colliculus from about 70 days, followed by the earliest asymmetrical lesions there from 120 days, with death occurring at about 250 days, at which time vacuolar degeneration was widespread in the brain. With other mouse Sinc genotype mouse/agent strain combinations the process was even further prolonged. With 87V scrapie strain in Sincp7 genotype mice the first lesions to appear were in the contralateral tectum at 300 days. It is concluded that scrapie agent can spread within ganglion cell axons.

Animals↗
PubMed1984

Degenerative hippocampal pathology in mice infected with scrapie.

The lesions of scrapie are confined to the CNS, and the most characteristic histopathological change in mice terminally infected with scrapie is vacuolation. With most laboratory strains of scrapie, one of the regions affected by this lesion is the cerebral cortex, including the hippocampus. Under some circumstances, however, a more destructive degeneration occurs in the hippocampus, with pyramidal cell necrosis accompanied by glial reactions, which can extend to a severe hippocampal sclerosis especially when an intracerebral route of infection has been used. The purpose of this paper is to identify some of the factors involved in these differences in the pathology of the hippocampus and their interdependence; this has necessitated the development and use of a scoring system for sclerosis in the hippocampus, in conjunction with an already established scoring system for vacuolation. Comparison of average hippocampal sclerosis scores and the vacuolation index (an estimate of the severity of grey matter vacuolation throughout the brain) reveals that hippocampal sclerosis is generally associated with scrapie models which produce intense vacuolation in the hippocampus, and also in the brain as a whole. Scrapie-induced hippocampal sclerosis provides an experimental system for investigating the basis for similar lesions, which occur in a variety of conditions, such as Alzheimer's disease and epilepsy.

Animals↗