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Mammalian transmissible spongiform encephalopathies (TSEs) display marked activation of astrocytes and microglia that precedes neuronal loss. Investigation of clinical parallels between TSEs and other neurodegenerative protein misfolding diseases, such as Alzheimer's disease, has revealed similar patterns of neuroinflammatory responses to the accumulation of self-propagating amyloids. The contribution of glial activation to the progression of protein misfolding diseases is incompletely understood, with evidence for mediation of both protective and deleterious effects. Glial populations are heterogeneously distributed throughout the brain and capable of dynamic transitions along a spectrum of functional activation states between pro- and antiinflammatory polarization extremes. Using a murine model of Rocky Mountain Laboratory scrapie, the neuroinflammatory response to prion infection was characterized by evaluating glial activation across 15 brain regions over time and correlating it to traditional markers of prion neuropathology, including vacuolation and PrPSc deposition. Quantitative immunohistochemistry was used to evaluate glial expression of iNOS and Arg1, markers of classical and alternative glial activation, respectively. The results indicate progressive upregulation of iNOS in microglia and a mixed astrocytic profile featuring iNOS expression in white matter tracts and detection of Arg1-positive populations throughout the brain. These data establish a temporospatial lesion profile for this prion infection model and demonstrate evidence of multiple glial activation states. [ABSTRACT FROM AUTHOR]

Prion diseases are neurodegenerative diseases characterized by the accumulation of misfolded prion protein (PrPSc) in the brain and other tissues. Animal prion diseases include scrapie in sheep, chronic wasting disease (CWD) in cervids, and transmissible mink encephalopathy (TME) in ranch-raised mink. We investigated the susceptibility of raccoons to various prion disease agents and compared the clinicopathologic features of the resulting disease. Raccoon kits were inoculated intracranially with the agents of raccoon-passaged TME (TMERac), bovine-passaged TME (TMEBov), hamster-adapted drowsy (TMEDY) or hyper TME (TMEHY), CWD from white-tailed deer (CWDWtd) or elk (CWDElk), or atypical (Nor98) scrapie. Raccoons were euthanized when they developed clinical signs of prion disease or at study endpoint (<82 mo post-inoculation). Brain was examined for the presence of spongiform change, and disease-associated PrPSc was detected using an enzyme immunoassay, western blot, and immunohistochemistry. All raccoons inoculated with the agents of TMERac and TMEBov developed clinical disease at ~6.6 mo post-inoculation, with widespread PrPSc accumulation in central nervous system tissues. PrPSc was detected in the brain of 1 of 4 raccoons in each of the CWDWtd-, CWDElk-, and TMEHY-inoculated groups. None of the raccoons inoculated with TMEDY or atypical scrapie agents developed clinical disease or detectable PrPSc accumulation. Our results indicate that raccoons are highly susceptible to infection with raccoon- and bovine-passaged TME agents, whereas CWD isolates from white-tailed deer or elk and hamster-adapted TMEHY transmit poorly. Raccoons appear to be resistant to infection with hamster-adapted TMEDY and atypical scrapie agents. [ABSTRACT FROM AUTHOR]

H-type bovine spongiform encephalopathy (H-BSE) is an atypical form of BSE in cattle. During passaging of H-BSE in transgenic bovinized (TgBoPrP) mice, a novel phenotype of BSE, termed BSE-SW emerged and was characterized by a short incubation time and host weight loss. To investigate the biological and biochemical properties of the BSE-SW prion, a transmission study was conducted in cattle, which were inoculated intracerebrally with brain homogenate from BSE-SW–infected TgBoPrP mice. The disease incubation period was approximately 15 months. The animals showed characteristic neurological signs of dullness, and severe spongiform changes and a widespread, uniform distribution of disease-associated prion protein (PrPSc) were observed throughout the brain of infected cattle. Immunohistochemical PrPSc staining of the brain revealed the presence of intraglial accumulations and plaque-like deposits. No remarkable differences were identified in vacuolar lesion scores, topographical distribution patterns, and staining types of PrPSc in the brains of BSE-SW– vs H-BSE–infected cattle. PrPSc deposition was detected in the ganglia, vagus nerve, spinal nerve, cauda equina, adrenal medulla, and ocular muscle. Western blot analysis revealed that the specific biochemical properties of the BSE-SW prion, with an additional 10- to 12-kDa fragment, were well maintained after transmission. These findings indicated that the BSE-SW prion has biochemical properties distinct from those of H-BSE in cattle, although clinical and pathologic features of BSW-SW in cattle are indistinguishable from those of H-BSE. The results suggest that the 2 infectious agents, BSE-SW and H-BSE, are closely related strains. [ABSTRACT FROM AUTHOR]

Scrapie is a naturally occurring transmissible spongiform encephalopathy of sheep and goats. There are different strains of sheep scrapie that are associated with unique molecular, transmission, and phenotype characteristics. However, in the United States, very little is known about the potential presence of scrapie strains. Scrapie strain and PRNP genotype could both affect susceptibility, potential for transmission, incubation period (IP), and control measures required for eliminating scrapie from a flock. The investigators evaluated 2 US scrapie isolates, No. 13-7 and x124, after intranasal inoculation to compare clinical signs, IPs, spongiform lesions, and patterns of PrPSc deposition in sheep with scrapie-susceptible PRNP genotypes (QQ171). After inoculation with x124, susceptibility and IP were associated with valine at codon 136 (V136) of the prion protein: VV136 sheep had short IPs (6.9 months), those in AV136 sheep were 11.9 months, and AA136 sheep did not develop scrapie. All No. 13-7 inoculated sheep developed scrapie, with IPs of 20.1 months for AA136 sheep, 22.8 months for AV136 sheep, and 26.7 months for VV136 sheep. Patterns of immunoreactivity in the brain were influenced by inoculum isolate and host genotype. Differences in PrPSc profiles versus isolate were most striking when examining brains from sheep with the VV136 genotype. Inoculation into C57BL/6 mice resulted in markedly different attack rates (90.5% for x124 and 5.9% for No. 13-7). Taken together, these data demonstrate that No. 13-7 and x124 represent 2 distinct strains of scrapie with different IPs, genotype susceptibilities, and PrPSc deposition profiles. [ABSTRACT FROM AUTHOR]

Bovine spongiform encephalopathy (BSE) is a prion disease that is invariably fatal in cattle and has been implicated as a significant human health risk. As a transmissible disease of livestock, it has impacted food safety, production practices, global trade, and profitability. Genetic polymorphisms that alter the prion protein in humans and sheep are associated with transmissible spongiform encephalopathy susceptibility or resistance. In contrast, there is no strong evidence that nonsynonymous mutations in the bovine prion gene (PRNP) are associated with classical BSE (C-BSE) disease susceptibility, though two bovine PRNP insertion/deletion polymorphisms, in the putative region, are associated with susceptibility to C-BSE. However, these associations do not explain the full extent of BSE susceptibility, and loci outside of PRNP appear to be associated with disease incidence in some cattle populations. This article provides a review of the current state of genetic knowledge regarding prion diseases in cattle. [ABSTRACT FROM AUTHOR]

The article discusses the intraspecies transmission studies of transmissible spongiform encephalopathies (TSE) to cattle. The results show cattle's susceptibility to intracerebrally (IC) inoculation of scrapie, transmissible mink encephalopathy (TME), and chronic wasting disease (CWD). Cattle develop spongiform lesions or clinical disease similar to bovine spongiform encephalopathy (BSE) only when inoculated with TME. Cattle's resistance to oral transmission of scrapie or CWD is also noted.

The article discusses the level of knowledge on the spectrum of transmissible spongiform encephalopathies (TSEs) in cattle and small ruminants. Diagnostic methods for TSE in ruminants include screening, confirmatory and discriminatory tests. Clinical signs, incubation period, neuroanatomical distribution and intensity of lesions and biochemical characteristics are some of the criteria established to describe the phenotype of a TSE.

We present a back-calculation analysis of the variant Creutzfeldt-Jakob (vCJD) epidemic in the UK to estimate the number of infected individuals and to explore the likely future incidence of the disease. The main features of the model are that the hazard of infection was assumed proportional to the incidence of BSE in the UK with allowance for precautionary control measures taken in 1988 and in 1996, and that the incubation period distribution of vCJD follows an offset generalized F distribution. Our results indicate that current the numbers of cases with onset up to 31 December 2000 data are broadly compatible with numbers of primary infections ranging from a few hundred to several million. However, if a very large number of persons were infected, the model suggests that the mean incubation period is likely to be well beyond the human lifespan, resulting in a disease epidemic of much smaller size (maximum several thousand). A sensitivity analysis indicates that our results are sensitive to the underreporting of vCJD cases before 1996. Finally, we show that, in the absence of a reliable test for asymptomatic infection, uncertainty in estimates of the total number of infections is likely to remain for at least several years, even if the number of clinical cases remains low. [ABSTRACT FROM AUTHOR]

The causative agents of variant Creutzfeldt-Jakob disease (vCJD) and of bovine spongiform encephalopathy (BSE) are currently indistinguishable. However, the route(s) by which humans became infected remain unknown. The path by which humans were infected with the BSE agent might impact on the geographical distribution of cases and we therefore sought evidence of regional variation and local clustering of vCJD cases. With the notable exception of a group of five cases in Leicestershire, the absence of local clustering of vCJD cases is compatible with most human exposure to the vCJD agent arising through routes that result in the risk of infection being similar over wide geographical areas, rather than through small-scale local events. Infection through the consumption of mechanically recovered meat (MRM) contaminated with the BSE agent was a potential route for such widespread exposure. An ecological analysis relating the regional incidence of vCJD to historical dietary data does not provide a dear evidence that humans became infected through consumption of MRM. [ABSTRACT FROM AUTHOR]

After the discovery of variant Creutzfeldt-Jakob disease (vCJD), scientific advances quickly led to postmortem tests to identify late-stage bovine spongiform encephalopathy (BSE) disease. These were first used in Switzerland in 1999 for active BSE surveillance of a) fallen and emergency-slaughter bovines (risk stock) and b) 5% sample of routinely slaughtered cattle over 30 months of age. In 1999 and 2000, Switzerland's estimated 103 BSE positives per 1 000 000 adult cattle put it in the same BSE risk classification as UKand Portugal. In July2000, the European Union's Scientific Steering Committee published its methodology (and first vetted results) for geographical BSE risk (GBR) assessment in cattle. Member states with no BSE cases found themselves, on rational assessment, classified as GBR III (BSE likely but not confirmed, or confirmed at a lower level). Because of Europe's thus highly assessed BSE risks, active BSE surveillance of adult cattle in all member states began in January2001 using one of three validated post-mortem tests. Implementation was variable across member states in January to March 2001 but, where operational, active surveillance was typically achieved for around 13 300 routinely slaughtered and 1000 risk stock per month per 1 000 000 adult cattle; BSE positive rates were 60 and 600 per 1 000 000 routinely slaughtered and risk cattle, respectively. By the second half of 2001, active BSE surveillance was operating reasonably in most member states, although anomalies persisted. Performance and results for July to December 2001 and for January to June 2002 are considered in detail. The BSE positive rate decreased substantially in UK, Portugal and Ireland between semesters, whereas Spain's rates increased for both routinely slaughtered and risk bovines. Based on 1 450 000 routinely slaughtered and 135 000 risk stock as standard, France could have expected 153 BSE positives in July to December 2001 (109 in January to June 2002); Italy 154 (67); and Germany only 39 (48). When sample-based surveillance data were scaled up and combined with clinical BSE cases, Great Britain's BSE positives were estimated at around 400 per 1 000 000 adult cattle in 2002 compared with over 1000 per 1 000 000 adult cattle in 2000. Age distributions for cattle subject to active BSE surveillance have been underexploited. The major transmissible spongiform encephalopathy (TSE) which affects sheep and goats is scrapie. Passive surveillance of scrapie is associated with substantial under-reporting. Susceptibility to scrapie depends strongly on sheep genotype; but resistance to scrapie does not necessarily confer resistance of sheep to BSE. Because of uncertainty about the true prevalence of scrapie-infected adult sheep and concern that BSE in sheep may be missed, the European Union pre-empted its planned evaluation of rapid post-mortem TSE tests in sheep by requiring the rapid TSE testing of small ruminants from April 2002 with one of the three cattle-validated tests. Basic requirements for active TSE surveillance in sheep were: random sample of 6000 fallen sheep and of 60 000 routinely slaughtered adult native sheep to be tested per member state by end March 2003. Lower surveillance targets were set for countries with under 1 000 000 adult sheep. Adequately to map scrapie-susceptible genotypes and identify resistant genotypes, a random sample of 500 routinely slaughtered native adult sheep was to be genotyped, together with each TSE rapid test positive adult sheep and two sets of three suitably sampled controls. By the end of August 2002, when 41% of the initial surveillance time had elapsed, only 20% of the European joint target for routinely slaughtered adult sheep had been completed, but that for fallen sheep was exceeded. Except in Ireland, the upper 95% confidence bound on TSE prevalence exceeded 500 per 1 000 000 routinely slaughtered adult sheep in reporting-compliant countries with more than 1 000 000 adult sheep. The UK, Greece, Italy and France were likely to approach the goal of 100 TSE rapid test positives on completion of their assigned first-year surveillance target for sheep. Results from the recommended genotyping of TSE positive adult sheep and controls for use in inferring differential TSE-positive susceptibility by genotype are awaited. Only by genotyping 5000-50 000 TSE-positive adult sheep, a massive undertaking even on the European scale, will it become clear whether scrapie resistance is relative rather than absolute. This paper details Europe's quantitative evolution in TSE surveillance. [ABSTRACT FROM AUTHOR]

The paper presents a practical approach to assessing the risks of exposure to the infective agents from transmissible spongiform encephalopathies. Current data on the infectivity of bovine tissues have been reviewed and values for use in risk assessment studies proposed for the infectivity of central nervous system and other tissues, the development of infectivity through the incubation period and the cattle-human species barrier. A study to assess the risk of exposure to BSE infectivity in cattle disposed of during the 2001 foot and mouth epidemic in the UK by burning in pyres or burial is used to illustrate the application of TSE risk assessment and the way in which it can be used as an input to decision making. [ABSTRACT FROM AUTHOR]

The author reflects on the threat brought by the epidemic of variant Creutzfeldt-Jakob disease in cattle in Great Britain. He cites that the occurrence of the disease in cattle would lead to the prohibition in trading meat for safety of consumers. The Spongiform Encephalopathy Advisory Committee conducted a meeting to the public to give additional information about the existence of the so-called disease.