Biomedical subjects
C Farquhar
Publications and source records attributed to C Farquhar.
Lysosomes as key organelles in the pathogenesis of prion encephalopathies.
The causation, structural origin, and mechanism of formation of spongiform lesions in transmissible encephalopathies are unknown. We have used immunogold electron microscopy to locate ubiquitin conjugates, hsp 70, and beta-glucuronidase (markers of the lysosomal compartment) and prion protein (PrP) in both control and scrapie-infected mouse brain. In scrapie-infected brain, lysosomes and lysosome-related structures (multivesicular and tubulovesicular dense bodies) are present in abnormally high numbers in neuronal cell processes. These structures contain PrP, together with the lysosomal markers ubiquitin conjugates, hsp 70, and beta-glucuronidase, which could also be identified spilling from tubulovesicular dense bodies into areas of early rarefaction in neuronal processes; we suggest that these areas of rarefaction are the precursor lesions of spongiform change. We advance the hypothesis that spongiform change is brought about by cytoskeletal disruption in neuronal processes caused by liberation of hydrolytic enzymes from lysosomes overloaded with the abnormal isoform of PrP (PrPsc). We suggest that the lysosomal system is probably acting as the bioreactor for processing of normal PrP to the abnormal isoform. The continuous production of increasing quantities of abnormal PrPsc in lysosome-related bodies will eventually cause disruption of the lysosomal membrane with destruction of the neuronal cytoskeleton and the initiation of vacuolation. Later, death of the cell will be associated with release of the PrPsc isoform into the extracellular environment. Repeated rounds of phagocytosis, lysosomal biogenesis of PrPsc, lysosomal membrane rupture, hydrolytic enzyme release, and neuronal lysis will lead to an exponential increase in cell damage and cell death.(ABSTRACT TRUNCATED AT 250 WORDS)
Immunoreactivity to ubiquitin-protein conjugates is present early in the disease process in the brains of scrapie-infected mice.
Brains from mice infected with either the 87V or the ME7 strains of mouse-passaged sheep scrapie were taken at stages during the disease process and immunostained to show the localization of ubiquitin-protein conjugates. In both models, conjugates were seen as fine, dot-like structures; as coarser, granular lesions within or adjacent to neurones; and in areas surrounding plaques. The dot-like structures were visible at 28 days post-ME7 infection and at 55 days in 87V-infected mice. In both models, the extent of immunoreactive changes increased as the disease progressed and terminal infection was as described earlier by us (Lowe et al., J. Pathol 1990; 162: 61-66). The patterns of development of these features were distinctive in two ways: progression from region to region was observable and the density of the pathological lesions grew exponentially as the clinical symptoms appeared. The earliest pathological dot-like structures corresponded temporally with the earliest detection of PrPSC by Western blotting, and immunogold electron microscopic investigation of the dot-like lesions indicated that they were the multi-vesicular, lysosome-related, dense bodies that we have described previously in terminal disease (Laszlo et al., J Pathol 1992; 166: 333-341). Until now, ubiquitin-protein conjugates were seen mainly in inclusion bodies associated with the terminal stages of a range of human degenerative diseases. This study establishes that ubiquitin-protein conjugates accumulate in lysosome-related bodies very early and appear to be intimately related to the pathological processes in the animal disorders that we have studied.
Identification of linear epitopes of the BPV-1 L1 protein recognized by sera of infected or immunized animals.
Sera from cattle that had been inoculated with BPV-1 virions or with recombinant L1 proteins and serum from a rabbit that had been immunized with SDS-denatured virions were evaluated for their reactivity with 466 overlapping synthetic peptides corresponding to 95% of the BPV-1 L1 protein. The late serological response of cattle to both intact virions and recombinant L1 proteins exhibited a similar profile of reactivity with approximately 70% (7 of 10) of L1 antigenic sites. However, the L1 serological response of the rabbit to SDS-denatured virions exhibited a significant difference from bovine serum antibodies in the profile of epitopes recognized, including a relative lack of response to major bovine epitopes located between L1 amino acids (AAs) 300-400. Importantly, only the sera from animals inoculated/immunized with intact virions was capable of neutralizing BPV-1 infectivity of murine C127 cells, suggesting that nonlinear epitopes are important for papillomavirus neutralization.
Teacher expectations in infant school: associations with attainment and progress, curriculum coverage and classroom interaction.
There is still much debate, particularly in North America, about whether teachers' expectations have an effect on pupils' achievement, and through which factors expectations might be mediated. This paper reports on associations between teachers' academic expectations at the beginning, and children's attainments at the end of the school year. The study took place in infant schools in London. Associations were significant during all three years of infant school, and were not explained by children's attainments at the time of the expectation rating. Range of effects, in standard deviation units, of associations between expectations and progress over the school year ranged from 0.4 to 0.8. Two possible mediating factors between expectations and attainment were explored: differential curriculum coverage and differential classroom behaviour. It was found that children for whom teachers had higher expectations were given a wider range of activities in written language and mathematics, and this was so over and above attainments at the beginning of the school year. In contrast, there was no evidence that expectations were related to measures of classroom interaction like teacher praise and instructional contact.
Bovine spongiform encephalopathy: a scrapie-like disease of British cattle.
Scrapie is a CNS degenerative infection of sheep and goats, which is invariably fatal after incubation periods of several months to years. Related disorders are found naturally in man and other species. There is a impairment of protein catabolism in scrapie and related diseases which leads to the accumulation of sparingly-soluble protein deposits in brain. These protein aggregates may share with the amyloid of Alzheimer's disease (AD) some common stage in the biochemical pathways of their formation, although different proteins are affected in scrapie (the PrP protein) and AD (the A4-precursor protein). Recently, cattle with the clinical signs and brain pathology of a neurodegenerative disease have been reported, and this cattle disorder has been called bovine spongiform encephalopathy (BSE). BSE-affected brains contain abnormal forms of the bovine homologue of PrP. This provides biochemical evidence that BSE is cattle scrapie rather than cattle AD.
Low dose aspirin treatment in late pregnancy differentially inhibits cyclo-oxygenase in maternal platelets.
Eighteen pregnant women were treated with aspirin, 37.5 mg once daily by mouth. Treatment was started two weeks before the expected date of delivery, and continued until delivery. Seventeen untreated women were studied concurrently. Platelet thromboxane (TX) production was determined by radioimmunoassay of TXB2 in serum from blood incubated for one hour with thrombin at 37 degrees C. Maternal blood was studied before treatment and at delivery. Fetal blood, from the cord, was studied at delivery. Prostacyclin (PGI2) production by rings of umbilical artery incubated in Hanks' solution at 37 degrees C for one hour was determined by radio-immunoassay of its hydrolysis product, 6-oxo-prostaglandin (PG) F1 alpha. Maternal and fetal blood from untreated women produced similar amounts of TXB2. Aspirin, in the dose regimen used, significantly inhibited TXB2 production in maternal but not in fetal blood, and did not impair PGI2 synthesis by umbilical artery rings. This differential effect on the cyclo-oxygenase of maternal platelets is probably due to the unusual kinetic properties of aspirin, and may prove therapeutically useful.