Difference between revisions of "PrP prions: Dose Response Models"

Revision as of 18:42, 5 October 2011

Prion

General overview of prion and prion diseases

Scrapie is a prion agent. Prions are 'self-replicating' basic proteins of small molecular weight. Prions form a new class of infectious agents responsible for a number of slow degenerative central nervous system diseases of humans and other animal species. The transmissible spongiform encephalopathies (TSEs) are a group of progressive neurological prion diseases, including scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle and Creutzfeldt-Jakob disease (CJD) in humans (Gale 2006).

Public awareness of prion diseases have been raised after an outbreak of BSE occurred among cattle in many European countries and scientific evidence indicated the foodborne transmission of BSE to humans (Will et al. 1996; Smith and Bradley 2003).

The disease is most easily transmitted to humans via consuming food contaminated with the brain or spinal cord of infected carcasses.

Summary Data

Diringer et al. (1998) inoculated outbred Syrian hamsters orally with graded doses of scrapie agent. The infectious agent was prepared from the brains of scrapied hamsters at the terminal stage of disease.

Jacquemot et al. (2005) exposed C57BL/6 mice to mouse-adapted scrapie strain C506M3 via the intraperitoneal route. The inoculum was a brain homogenate at 10% (wt/vol) in 5% glucose solution from a mouse with scrapie at the terminal stage of disease

Taylor et al. (1995) injected Weanling RIII/FaDk-ro mice with pooled BSE-infected brain. They measured the titer of infectivity by bioassay in mice. The infectious agent was prepared from the brains of 861cattle with suspected BSE obtained between August and November 1990 from five veterinary centers throughout England.

Table 1.1. Summary of the prion data and best fits

The data were not able to be statistically pooled.

^*Recommended Model

It is recommended that experiment 1 should be used as the best dose response model. The exposure was oral route which is a better representation of an actual release scenario.

Optimized Models and Fitting Analyses

Optimization Output for experiment 1

Figure 1.1 Parameter scatter plot for beta Poisson model ellipses signify the 0.9, 0.95 and 0.99 confidence of the parameters.

Figure 1.2 beta Poisson model plot, with confidence bounds around optimized model

Optimization Output for experiment 2

Figure 1.3 Parameter histogram for exponential model (uncertainty of the parameter)

Figure 1.4 Exponential model plot, with confidence bounds around optimized model

Optimization Output for experiment 3

Figure 1.5 Parameter histogram for exponential model (uncertainty of the parameter)

Figure 1.6 Exponential model plot, with confidence bounds around optimized model

Summary

One should note that the dose unit in the literature was not given as organism number or cfu/pfu, so the relative units were presented.

References

Diringer, H., roehmel, J. and Beekes, M. (1998) Effect of repeated oral infection of hamsters with scrapie. Journal of General Virology 79, 609-612.

Gale, P. (2006) The infectivity of transmissible spongiform encephalopathy agent at low doses: The importance of phospholipid. Journal of Applied Microbiology 101, 261-274.

Jacquemot, C., Cuche, C., Dormont, D. and Lazarini, F. (2005) High incidence of scrapie induced by repeated injections of subinfectious prion doses. Journal of Virology, 8904–8908.

Smith, P. and Bradley, R. (2003) Bovine spongiform encephalopathy (bse) and its epidemiology. British Medical Bulletin 66, 185–198.

Taylor, D.M., Woodgate, S.L. and Atkinson, M.J. (1995) Inactivation of the bovine spongiform encephalopathy agent by rendering procedures. Veterinary Record 137, 605-610.

Will, R., Ironside, J., Zeidler, M., Cousens, S., Estibeiro, K., Alperovitch, A., Poser, S., Pocchiari, M., Hofman, A. and Smith, P. (1996) A new variant of creutzfeldt-jakob disease in the uk. Lancet 347, 921-925.