Between Bovine Spongiform Encephalopathy Research Articles

Chronic wasting disease and atypical forms of bovine spongiform encephalopathy and scrapie are not transmissible to mice expressing wild-type levels of human prion protein

The association between bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) has demonstrated that cattle transmissible spongiform encephalopathies (TSEs) can pose a risk to human health and raises the possibility that other ruminant TSEs may be transmissible to humans. In recent years, several novel TSEs in sheep, cattle and deer have been described and the risk posed to humans by these agents is currently unknown. In this study, we inoculated two forms of atypical BSE (BASE and H-type BSE), a chronic wasting disease (CWD) isolate and seven isolates of atypical scrapie into gene-targeted transgenic (Tg) mice expressing the human prion protein (PrP). Upon challenge with these ruminant TSEs, gene-targeted Tg mice expressing human PrP did not show any signs of disease pathology. These data strongly suggest the presence of a substantial transmission barrier between these recently identified ruminant TSEs and humans.

Joint Scientific Opinion on any possible epidemiological or molecular association between TSEs in animals and humans

The existing scientific evidence that links animal and human TSEs is reviewed and discussed. The challenges involved in identifying TSEs as zoonoses are described and the example of the process that led to the establishment of a link between Bovine Spongiform Encephalopathy (BSE) and variant Creutzfeldt-Jakob Disease (vCJD) is reviewed. The strain diversity of animal and human TSE agents and the factors influencing the capacity of TSE agents to cross the species transmission barrier are also discussed. The scientific opinion critically assesses the tools and methodologies currently available to study and evaluate the possible association of animal and human TSEs, focussing on epidemiological and laboratory methods. The available scientific evidence on Classical BSE, Atypical BSE (H-type and L-type), Classical scrapie, Atypical scrapie, Chronic Wasting Disease (CWD), Transmissible Mink Encephalopathy (TME) and human TSEs is reviewed. The conclusions state that, at present, the only TSE agent demonstrated to be zoonotic is the Classical BSE agent. Active screening has allowed the identification of three new forms of animal TSEs (H-type Atypical BSE, L-type Atypical BSE and Atypical scrapie), but the information obtained has major limitations due to the unknown sensitivity of the current monitoring system for these TSEs. There is no epidemiological evidence to suggest that Classical scrapie is zoonotic. The epidemiological data are too limited to conclude whether the Atypical scrapie agent has a zoonotic potential. Transmission experiments to human PrP transgenic mice or primates suggest that some TSE agents other than the Classical BSE agent in cattle (namely L-type Atypical BSE, Classical BSE in sheep, TME, CWD agents) might have zoonotic potential and indicate that that of the L-type Atypical BSE agent appears similar or even higher than that of the Classical BSE agent. A single study reported efficient transmission of a natural sheep Classical scrapie isolate to primates

Frequencies of PRNP Gene Polymorphisms in Vietnamese Dairy Cattle for Potential Association with BSE

Summary Since 2004, significant associations between bovine spongiform encephalopathy (BSE) susceptibility in cattle and frequencies of insertion/deletion (ins/del; indel) polymorphisms within the bovine prion protein gene (PRNP) have been reported. In this study, we investigated the frequencies of indel polymorphisms within two variable sites, a 23-bp indel polymorphism in the promoter region (23indel) and a 12-bp indel polymorphism in intron 1 region (12indel), in the PRNP in 206 Vietnamese dairy cattle and seven Japanese BSE-affected cattle. In Vietnamese dairy cattle, the frequency distributions of del allele and del/del genotypic polymorphisms in the 23indel site, which are thought to be associated with BSE susceptibility, were significantly higher, whereas the frequencies of del allelic and del/del genotypic polymorphisms in the 12indel site, which have been reported to confer BSE susceptibility, were significantly lower. We have provided evidence that Vietnamese dairy cattle have a unique genetic background in the PRNP gene in comparison with cattle or sires previously reported in other countries.

Genotype distribution of the prion protein gene (PRNP) promoter polymorphisms in Korean cattle

Recently, an association between bovine spongiform encephalopathy (BSE) and insertion/deletion (indel) polymorphisms in the bovine prion protein gene (PRNP) promoter region has been reported in German cattle. These PRNP polymorphisms cause changes in PRNP expression and are thought to play an important role in BSE susceptibility. BSE has been reported in British and Japanese Holstein cattle but has not been diagnosed in Hanwoo cattle (Bos taurus coreanae) up to now. These results prompted us to investigate the genotype distributions of these PRNP promoter polymorphisms in 107 Hanwoo cattle and 52 Holstein cattle and compare the results with those of previous studies. A significant difference (P=0.0249) in allele frequency of the 23 bp indel polymorphism was observed between Hanwoo and the BSE-affected German cattle previously investigated. There were no significant differences in the genotype (P=0.2095) or allele (P=0.8875) frequencies of the 12 bp indel polymorphism between Hanwoo and BSE-affected German cattle. Interestingly, the genotype and allele frequencies of the 23 bp indel polymorphism in Korean Holsteins were very similar to those previously reported for BSE-affected German cattle and healthy US cattle sires.

Molecular profiling and comparison of field transmissible spongiform encephalopathy cases diagnosed in Catalunya

Molecular profiling of the proteinase K resistant prion protein (PrP res) is a technique that has been applied to the characterisation of transmissible spongiform encephalopathy (TSE) strains. An interesting example of the application of this technique is the ability to differentiate, at the experimental level, between bovine spongiform encephalopathy (BSE) and scrapie infection in sheep, and to distinguish between classical and atypical BSE and scrapie cases. Twenty-six BSE cases and two scrapie cases from an active TSE surveillance program and diagnosed at the PRIOCAT, TSE Reference Laboratory (Centre de Recerca en Sanitat Animal, Universitat Autònoma de Barcelona, Catalunya, Spain) were examined by Western blotting. Molecular profiling was achieved by comparing the glycosylation profile, deglycosylated PrP molecular weight and 6H4/P4 monoclonal antibody binding ratio. The results obtained during the characterisation of these field cases indicated an absence of atypical BSE cases in Catalunya.

Phenotype of disease-associated PrP accumulation in the brain of bovine spongiform encephalopathy experimentally infected sheep

In view of the established link between bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease and of the susceptibility of sheep to experimental BSE, the detection of potential cases of naturally occurring BSE in sheep has become of great importance. In this study, the immunohistochemical (IHC) phenotype of disease-associated prion protein (PrP(d)) accumulation has been determined in the brain of 64 sheep, of various breeds and PrP genotypes, that had developed neurological disease after experimental BSE challenge with different inocula by a range of routes. Sheep BSE was characterized by neuron-associated intra- and extracellular PrP(d) aggregates and by conspicuous and consistent deposits in the cytoplasm of microglia-like cells. The stellate PrP(d) type was also prominent in most brain areas and marked linear deposits in the striatum and midbrain were distinctive. Sheep of the ARR/ARR and ARQ/AHQ genotypes displayed lower levels of PrP(d) than other sheep, and intracerebral BSE challenge resulted in higher levels of PrP(d) accumulating in the brain compared with other routes. The PrP genotype and the route of challenge also appeared to affect the incubation period of the disease, giving rise to complex combinations of magnitude of PrP(d) accumulation and incubation period. Despite these differences, the phenotype of PrP(d) accumulation was found to be very consistent across the different factors tested (notably after subpassage of BSE in sheep), thus highlighting the importance of detailed IHC examination of the brain of clinically affected sheep for the identification of potential naturally occurring ovine BSE.

Prion protein gene (PRNP) variants and evidence for strong purifying selection in functionally important regions of bovine exon 3

Amino acid replacements encoded by the prion protein gene (PRNP) have been associated with transmissible and hereditary spongiform encephalopathies in mammalian species. However, an association between bovine spongiform encephalopathy (BSE) and bovine PRNP exon 3 has not been detected. Moreover, little is currently known regarding the mechanisms of evolution influencing the bovine PRNP gene. Therefore, in this study we evaluated the patterns of nucleotide variation associated with PRNP exon 3 for 36 breeds of domestic cattle and representative samples for 10 additional species of Bovinae. The results of our study indicate that strong purifying selection has intensely constrained PRNP over the long-term evolutionary history of the subfamily Bovinae, especially in regions considered to be of functional, structural, and pathogenic importance in humans as well as other mammals. The driving force behind this intense level of purifying selection remains to be explained.

Comparative PRNP genotyping of U.S. cattle sires for potential association with BSE

The recent discovery of significant associations between bovine spongiform encephalopathy (BSE) susceptibility in German cattle and the frequency distributions of insertion/deletion (indel) polymorphisms within the bovine PRNP gene prompted an evaluation of 132 commercial U.S. artificial insemination (AI) sires from 39 breeds. Forward primer sequences from published primer sets targeting indels within the putative bovine PRNP promoter, intron 1, and the 3' UTR (untranslated region) were synthesized with unique 5' fluorescent labels and utilized to develop a rapid multiplexed PCR assay for identifying BSE-associated indels as well as facilitating polymorphism analyses and/or marker-assisted selection. Significant differences ( p < 0.05 all tests) were detected between the frequencies of bovine PRNP promoter alleles for 48 healthy German cattle previously described and 132 commercial U.S. cattle sires. The frequency of the 23-bp promoter allele observed for commercial U.S. cattle sires strongly resembled that recently described for 43 BSE-affected German cattle. No significant difference ( p = 0.051) was detected between the distributions of promoter genotypes for healthy German cattle and our panel of commercial U.S. cattle sires. Interestingly, significant differences ( p < 0.01; p < 0.02) were also noted between the frequencies and distributions of intron 1 alleles and genotypes, respectively, for BSE-affected German cattle and our panel of U.S. cattle sires. No significant allelic or genotypic differences were detected for the 14-bp 3' UTR indel for any given comparison between German cattle and commercial U.S. cattle sires.

Risk management of the transmissible spongiform encephalopathies in North America.

As North American Free Trade Agreement partners, Canada, the United States of America (USA) and Mexico apply independent but harmonised transmissible spongiform encephalopathy (TSE) risk management strategies in observance of Office International des Epizooties guidelines. The divergence between bovine spongiform encephalopathy (BSE) risk management approaches in North American and Europe reflects comparatively reduced external and internal BSE risks in North America. The external quarantine and internal surveillance measures adopted for BSE respond to several iterations of national risk assessments initiated in the early 1990s and revised as recently as 2002. Feed bans applied since 1997 to preclude establishment of BSE also bear the potential to limit intra-species and inter-species exposure to scrapie, chronic wasting disease (CWD) and transmissible mink encephalopathy (TME). Surveillance continues for the four TSEs through collaborative efforts of national and sub-national veterinary infrastructures and accompanying laboratory networks. Mexico has never identified the presence of any TSE. The last diagnosed case of TME in North America dates back to 1985. Since the only recognised appearance in Canada through an import from Great Britain in 1993, BSE has not been detected in North America. Scrapie and CWD remain at generally low prevalence in Canada and the USA. Independent but harmonised eradication programmes target elimination of the latter two diseases.

Molecular advances in understanding inherited prion diseases.

The prion diseases are neurodegenerative disorders that have attracted great interest because of the possible link between bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (CTD) in humans. Possible transmission of these diseases has been linked to a single protein termed the prion protein. This protein is an abnormal isoform of a normal synaptic glycoprotein. The majority of prion diseases does not appear to be caused by transmission of an infectious agent but occur spontaneously with no known cause. The strongest supporting evidence that the prion protein is the causative agent in prion disease comes from specific inheritable forms of prion disease which are linked to single point mutations in the prion protein gene. Paradoxically, these point mutations, although autosomal dominant with 100% penetrance do not lead to disease until late in life. Molecular techniques are now being used extensively to determine how these point-mutations alter the prion protein's normal structure and activity. This review deals with the latest insights into how inherited mutations in the prion protein gene lead to neurodegenerative disease.

Visualizing latent domain knowledge

Knowledge discovery and data mining commonly rely on finding salient patterns of association from a vast amount of data. Traditional citation analysis of scientific literature draws insights from strong citation patterns. Latent domain knowledge, in contrast to the mainstream domain knowledge, often consists of highly relevant but relatively infrequently cited scientific works. Visualizing latent domain knowledge presents a significant challenge to knowledge discovery and quantitative studies of science. We build upon a citation-based knowledge visualization procedure and develop an approach that not only captures knowledge structures from prominent and highly cited works, but also traces latent domain knowledge through low-frequency citation chains. We apply this approach to two cases: (1) identifying cross-domain applications of Pathfinder networks (PFNETs) and (2) clarifying the current status of scientific inquiry of a possible link between Bovine spongiform encephalopathy (BSE), also known as mad cow disease, and a new variant Creutzfeldt-Jakob disease (vCJD), a type of brain disease in humans.

Communication failure on environmental and health issues

Theories of cognition and communication are used to illustrate their usefulness in understanding two controversies: the link between bovine spongiform encephalopathy (BSE) and Creutzfeldt-Jakob disease (CJD), and the implications of building a waste incinerator. Examples of six types of cognitive error are considered in the debate surrounding the BSE-CJD controversy. Personal construct theory is used to illustrate the advantages in modelling divergent responses to a proposed waste incinerator. It is concluded, first, that psychology has much to offer by way of improvements to thinking about, and communicating, complex environmental information; and second, the often incomprehensible magnitude of environmental problems present challenges to contemporary theories of cognition and communication which have often been formulated and tested against problems of relatively modest scale.