SCRAPIE and TSE to human UPDATE 2008 (ambiguous terms of transition and reality set in)
The EFSA Journal (2008) 626, 1-11
© European Food Safety Authority, 2008
Scientific and technical clarification in the interpretation and consideration of some facets of the conclusions of its Opinion of 8 March 2007 on certain aspects related to the risk of Transmissible Spongiform Encephalopathies (TSEs) in ovine and caprine animals1
Scientific Report of the Scientific Panel on Biological Hazards
January 2008 - 37th Plenary meeting
Question EFSA-Q-2007-193
PANEL MEMBERS
Olivier Andreoletti, Herbert Budka, Sava Buncic, Pierre Colin, John D Collins, Aline De Koeijer, John Griffin, Arie Havelaar, James Hope, Günter Klein, Hilde Kruse, Simone Magnino, Antonio Martínez López, James McLauchlin, Christophe Nguyen-The, Karsten Noeckler, Birgit Noerrung, Miguel Prieto Maradona, Terence Roberts, Ivar Vågsholm, Emmanuel Vanopdenbosch.
ACKNOWLEDGEMENTS
The European Food Safety Authority wishes to thank the members of the Working Group for their contribution to this Scientific and Technical clarification: Olivier Andreoletti, Herbert Budka, Martin Groschup, James Hope, Danny Matthews, Marion Simmons, Emmanuel Vanopdenbosch (Chairman) and Kathy Webster.
1 For citation purposes: Scientific Report of the Panel on Biological Hazards on a request from the European Commission on “Scientific and technical clarification in the interpretation and consideration of some facets of the conclusions of its Opinion of 8 March 2007 on certain aspects related to the risk of Transmissible Spongiform Encephalopathies (TSEs) in ovine and caprine animals”. The EFSA Journal (2008), 626, 1-11. The EFSA Journal (2008) 626, 2-11
INTRODUCTORY STATEMENT FROM THE MEMBERS OF THE PANEL ON BIOLOGICAL HAZARDS ON COMMUNICATING SCIENTIFIC UNCERTAINTY
Scientific uncertainty results usually from five characteristics of the scientific method (EC, 2000): the variable chosen, the measurements made, the samples drawn, the models used and the causal relationship employed. This may also arise from a controversy on existing data or lack of some relevant data. Following appropriate scientific risk assessment, the expression of such uncertainty in complex settings, by simple and concise wording without sacrificing scientific exactness, is one of the major challenges of risk communication.
The following report is strictly limited to replying to the terms of reference as received from the European Commission by re-addressing the uncertainties that were reflected in the conclusions of the concerned EFSA 2007 opinion.
ANSWERS TO THE TERMS OF REFERENCE
1. In relation to conclusion 2 in page 7 the Authority is invited to clarify and substantiate if there is at this stage any scientific evidence about the presence of TSEs agents other than BSE, Classical and Atypical Scrapie agents in ovine or caprine animals.
Conclusion 2 in page 7 of the EFSA 2007 opinion states that: “The BSE agent is the only TSE agent identified as zoonotic. However, in view of their diversity it is currently not possible to exclude transmissibility to humans of other animal TSE agents.”
In the preamble of the EFSA 2007 opinion it is stated that:
• “Any positive case of TSE in small ruminants is termed as “TSE in small ruminants” which encompasses Classical Scrapie, Atypical Scrapie including Nor98 in sheep and goats as well as BSE in these species if found.”
It should be noted that, under 3.2.1 of the EFSA 2007 opinion it is stated that:
• “The introduction of active surveillance programmes in the European Union has led to the recognition of isolates that do not conform to previous phenotypes of BSE in cattle and Classical Scrapie in sheep. These are currently termed for operational reasons as “Atypical” BSE or Scrapie, but probably reflect part of a wider spectrum of isolates not previously recognised, and in the case of Atypical Scrapie affecting genotypes highly resistant to clinical Scrapie (Biacabe et al., 2004; Casalone et al., 2004; Benestad et al., 2003; Gavier- Widen et al., 2004; Buschmann et al., 2004).” Scrapie is a disease of ovine and caprine animals caused by a variety of TSE agents harbouring different biological properties that are still incompletely characterised, rather than by one specific transmissible entity. ‘Classical Scrapie’ and ‘Atypical Scrapie’ are operational rather than purely biological terms. (EFSA, 2005; Saegerman et al., 2007;
Benestad et al., 2008). The EFSA Journal (2008) 626, 3-11
Further on the EFSA 2007 opinion, under 3.2.3 the Panel acknowledges that there is a:
• “[…] lack of understanding of the true biodiversity of TSEs in small ruminants in terms of both Classical and Atypical agents […]”
This is in accordance to the approach taken by the Panel in the EFSA 2005 opinion when classifying the possible TSE cases in small ruminants. In fact, the EFSA 2007 opinion stresses that:
• “Practical definitions of TSE in small ruminants are summarized in the EFSA opinion on the classification of Atypical and Classical Scrapie and BSE in small ruminants (EFSA, 2005) in the Table “Criteria for the categorisation of TSEs in small ruminants” (in annex 1 of the said EFSA opinion).”
In Annex 1 of the EFSA 2005 opinion, a table for the categorisation of TSEs in small ruminants can be found. This opinion concludes that the definition of Atypical Scrapie:
• “[…] is provided in juxtaposition with similar definitions for Scrapie and BSE in small ruminants. Sub-categorisation of Scrapie and Atypical Scrapie is premature although this may become possible when more data are available.” Recent studies have identified TSE agents in cattle that differ from the original TSE agent type, which causes the disease commonly known as BSE that was detected since 1986 in the United Kingdom and is referred to as ‘Classical BSE’ in this document.
Based on their diagnostic phenotypes these more recently identified TSE agents in cattle are called L- and H-type BSE agents (Biacabe et al., 2004; Casalone et al., 2004; Baron et al., 2007). In conclusion, the reply to the ToR number 1 is:
• In ovine animals, no TSE agents other than those causing Classical Scrapie and Atypical Scrapie have been identified.
• In caprine animals, no TSE agents other than those causing BSE, Classical Scrapie and Atypical Scrapie have been identified.
• The operational term ‘BSE’ covers a TSE of bovine animals that could be caused by at least three distinct TSE agents with heterogeneous biological properties.
• The operational term ‘Classical Scrapie’ covers a TSE of ovine and caprine animals caused by several TSE agents with heterogeneous biological properties.
• The operational term ‘Atypical Scrapie’ covers a TSE of ovine and caprine animals that differs from Classical Scrapie. Currently, it is a subject for debate whether it is caused by one or more TSE agents. The EFSA Journal (2008) 626, 4-11
2. In relation to conclusion 2 in page 7 the Authority is invited to specify the scientific evidences which do not allow to exclude transmissibility to humans of “other TSE agents” other than BSE. Conclusion 2 in page 7 of the EFSA 2007 opinion states that: “The BSE agent is the only TSE agent identified as zoonotic. However, in view of their diversity it is currently not possible to exclude transmissibility to humans of other animal TSE agents.”
In the EFSA 2007 opinion under 3.2.3. the Panel states that:
• “There are significant uncertainties associated with the question whether TSE agents in their whole spectrum may cross the human transmission barrier under natural conditions”.
This statement is supported both by scientific evidence and considerations, referenced in the EFSA 2007 opinion:
• Scientific evidence from transmission studies to primates: - Transmission of Classical Scrapie from a TSE agent adapted in hamster was demonstrated by oral challenge in squirrel monkey (Saimiri sciureus) (Gibbs et al., 1980);
- Transmission of Classical Scrapie from two distinct sheep sources by intracerebral challenge in cynomologus monkey (Macaca fascicularis) and marmoset monkey (Callithrix jacchus) (Gibbs and Gajdusek, 1972; Baker et al., 1988).
• Scientific considerations on TSE epidemiology: - “The assumed lack of association between TSEs in humans and those in small ruminants […] may be biased by a number of factors: (i) The lack of a data on the historical real prevalence and distribution of small ruminant TSEs, at a time where only passive surveillance was performed; (ii) the lack of understanding of the true biodiversity of TSEs in small ruminants in terms of both Classical and Atypical agents; (iii) the lack of understanding of the diversity of TSEs in humans due to the limited molecular and bioassay characterisation of human TSEs also in relation to the number and spectrum of neurodegenerative diseases of humans; (iv) the predicted phenotype of disease that might arise should an animal derived TSE transmit to humans.” The EFSA Journal (2008) 626, 5-11
Further evidence is provided by:
• In vitro conversion assays: Raymond et al. (1997) studied whether there is a correlation between in vitro conversion efficiencies and known transmissibility of BSE, sheep Scrapie and CJD, and found limited conversion of human PrP-sen to PrP-res driven by PrP-res associated with both Scrapie (PrPSc) and BSE (PrPBSE). They concluded that “the inherent ability of these infectious agents of BSE and Scrapie to affect humans following equivalent exposure may be finite but similarly low”. Nevertheless, uncertainty arises from the fact that this is a simple in vitro model of a complex in vivo situation.
• Laboratory transmission studies with animal models: Since the publication of the Opinion new data have become available with regards to L type of BSE, which has now been identified in various EU members states (Biacabe et al., 2004; Casalone et al., 2004; Baron et al., 2007). This TSE agent, differing from that causing Classical BSE by its biochemical signature and transmission features in mouse models, has been transmitted to a Tg mouse model expressing Human M129 PRP gene (Beringue et al. 2007)2. Here again, uncertainty arises from the limitations of these animal models for the estimation of the human species barrier. These ‘proof of principle’ experiments provide data supporting the ability of TSE agents other than those causing Classical BSE to cross the human species barrier.
Even so, it is important to remember that as mentioned in the EFSA 2007 opinion, transmission to primates:
• “… does not allow to take into account the human gene PRNP polymorphisms (in particular the M/V 129), that have been identified to play a major role on relative susceptibility towards prion disease. In addition, genes other than the PrP gene may also be influential in determining overall susceptibility to TSEs.” Despite the interests in the area, studies of the transmissibility of currently known TSE agents using animal models will remain incomplete for several years.
In conclusion, the reply to the ToR number 2 is:
• Experimental transmissions to primate and to transgenic (Tg) mouse models expressing the human PrP gene, are currently used as to evaluate the potential capacity of a TSE agent to cross the human species barrier.
• TSE agents other than the Classical BSE agent from three field TSE cases (two Classical Scrapie cases and one L type BSE case) have been demonstrated to cross the modelled human species barrier.
• Some limitations to these models have to be considered, which include:
(i) The uncertainty of how well they represent the human species barrier. (ii) The uncertainty of how well the experimental inoculation route employed represents exposure under natural conditions. 2 Transmission of this TSE agent by intracerebral challenge to primates (Macaques) has been reported by Comoy et al. at the 2006 Prion Congress held in Torino. A scientific paper reporting this finding has been submitted for peer review publication. The EFSA Journal (2008) 626, 6-11
3. In relation to conclusion 3 in page 7, the Authority is invited:
a. To clarify if, although the diagnostic sensitivity and specificity of the discriminatory tests can not be assumed to be perfect, they are at this moment the diagnostic tool fit for the differentiation of the different TSE strains which can be present in ovine and caprine animals if they are performed according to the procedure described in point 3.2 (c) of Chapter C of Annex X to Regulation (EC) 999/2001.
Clarification of the ToR 3.a.: During the discussion of the WG it was clarified with the Commission services that when referring to differentiation of different TSE strains it was meant “identification of the TSE agent that causes Classical BSE versus any other TSE agent that can be present in ovine or caprine animals”.
Conclusion 3 in page 7 of the EFSA 2007 opinion states that:
• “Current discriminatory tests as described in the EC legislation to be used for discrimination between Scrapie and BSE appear, up to now, to be reliable for the differentiation of BSE from Classical and Atypical Scrapie. However, at the current stage of scientific knowledge, neither their diagnostic sensitivity nor their specificity can be assumed to be perfect.” Characterisation of TSE agents is based on biological and/or molecular methods. Molecular methods are based on the properties of the disease-specific proteaseresistant fragments of PrPSc or physico-chemical behaviour (e.g. proteinase K cleavage site, PrPSc glycosylation, relative proteinase K resistance, molecular conformation, etc). Biological methods identify the reproducibility and stability of the disease phenotype, including lesion profile and incubation period, on serial transmission in a specified mouse line, but also consider the phenotype of the disease in the host species. Discriminatory biochemical tests, as referred here, only represent a group of standardised methods (reagent protocols) allowing reproducible identification of certain abnormal PrP biochemical features associated with the TSE agent causing Classical BSE experimentally propagated in sheep. These biochemical methods cannot be considered to be appropriate tools for the differentiation of the different TSE agents (excluding the agent that causes Classical BSE), which can be present in ovine and caprine animals in the wider sense, as they have not been designed for that purpose.
In page 7 of the EFSA 2007 opinion, it is stated that based on the EFSA Opinion of 25 January 2007 on Quantitative Risk Assessment on the residual BSE risk in sheep meat and meat products (EFSA-Q-2005-235),
• “The Scrapie/BSE discriminatory tests are robust judging by their performance against a small number of samples in a blinded ring trial organised by the EU TSE Community Reference Laboratory (Stack et al., in preparation) and their application as part of small ruminant surveillance was continuing to improve the accuracy of these prevalence estimates. However, balanced against this optimistic scenario, the BIOHAZ Panel accepted that the sensitivity and specificity of the discriminatory tests had, for logistical reasons, not been experimentally evaluated and potential confounding factors, such as
The EFSA Journal (2008) 626, 7-11
concomitant infection of the same animal with Scrapie and BSE, remained to be investigated.” The result of that ring trial employing a limited number of different categories of samples3shows that all tests were able to discriminate between field cases of Classical Scrapie in sheep and the types of BSE in sheep available from experimental animals (Stack et al., 2008).
Moreover, it should be noted that as previously reported under 3.2.3 of the 2007 EFSA opinion, the Panel acknowledged that there is a:
• “[…]lack of understanding of the true biodiversity of TSEs in small ruminants in terms of both Classical and Atypical agents […]”
In field cases of Classical Scrapie, more than one TSE agent can be isolated from a single animal (Pattison et al., 1961; Bruce, et al., 2002). The presence of one TSE agent can mask the presence of another as well as its manifestation with disease, when co-infecting the same individual. This phenomenon of “interference” has been studied in experimental models using different TSE agents (Manuelidis and Lu, 2003; Nishida et al., 2005; Bartz et al., 2007). Data reported by Baron and Biacabe (2001) indicated that intracerebral inoculation of C57Bl6 mice with a mixture of Scrapie and BSE agents, which were both already adapted to this mouse strain (i.e. species barrier effects had been ablated), resulted in the development of a TSE which presented with a Scrapie Western blot profile. Despite the fact that direct extrapolation of these observations to small ruminants is not possible, these results raise the possibility that the presence of BSE in sheep, if it occurred as a co-infecting TSE agent following established Scrapie, may remain undetected. As the likelihood of such a situation is uncertain at this moment, experiments designed to answer specifically to this question are currently ongoing in an EU funded program (QLK – CT –2001- 01309 BSE in sheep). The Panel recognises the uncertainty of performance of the discriminatory tests applied to small ruminants but also that it is pivotal to have some estimate of the likelihood of co-infection of BSE and Scrapie in the same animal. This would aid the understanding of the practical impact of this uncertainty.
In conclusion, the reply to the ToR number 3.a. is:
• Based on the limited data available, the discriminatory tests as implemented at EU level are practicable tools for screening of field TSE cases (as mentioned in Regulation 999/2001, Annex X, Chapter C, point 3.2. (c)), fulfilling the objective of rapid and reproducible identification of TSE cases that have a signature compatible with Classical BSE agent.
• These discriminatory tests cannot be considered to be perfect because of the current lack of understanding of both the true biodiversity of TSE agents in ovine and caprine animals and how the agents interact in case of co-infection. 3 These were: 4 Ovine BSE samples from ovine oral primary challenge with bovine BSE brain; 10 Ovine BSE samples, from intracerebral challenge with Cheviot AHQ/AHQ ovine BSE (1st sheep to sheep challenge); 12 Sheep Scrapie, positive by statutory tests; 9 Scrapie clinical suspects, negative by statutory tests; 2 Control sheep, negative samples; 2 confirmed bovine BSE positives; 2 Bovine negative controls.
The EFSA Journal (2008) 626, 8-11
b. To clarify if, although the diagnostic sensitivity and specificity of the discriminatory tests can not be assumed to be perfect, the absence of statistically sufficient data on the performance of the tests is not compensated by the procedure in place including a ring trial with additional molecular testing methods in different laboratories and an evaluation by an expert panel chaired by the Community Reference Laboratory for TSEs and taken into account the conclusion of the BIOHAZ Panel in its opinion dated 13 July 2006 that the proportion of sheep being infected by BSE is likely to be extremely small. In page 7 of the Opinion, it is stated that based in the EFSA Opinion of 25 January 2007 on Quantitative Risk Assessment on the residual BSE risk in sheep meat and meat products (EFSA-Q-2005-235, The EFSA Journal, 442, 1-44),
• “[…] the BIOHAZ Panel accepted that the sensitivity and specificity of the discriminatory tests had, for logistical reasons, not been experimentally evaluated and potential confounding factors, such as concomitant infection of the same animal with Scrapie and BSE, remained to be investigated.”
By definition the term diagnostic specificity means the number of correctly identified negative samples divided by the sum of the correctly identified negative and of the false positive samples. If it is uncertain to some degree whether the samples which are negative (this is non-BSE) in the discriminatory tests are correctly identified, an enlargement of the sample size does not add to the already existing data on their real diagnostic specificity.
By definition the term diagnostic sensitivity means the number of correctly identified positive samples divided by the sum of the correctly identified positive and of the false negative samples. Therefore, it is clear that in this case any increase of the number of negative samples is completely irrelevant for the determination of the diagnostic sensitivity of an assay.
To date, the discriminatory tests as described in Regulation (EC) 999/2001, Annex X, Chapter C, point 3.2 (c) have been only validated in the framework of a ring trial employing TSE agents isolated from sheep experimentally infected with Classical BSE agent. No confirmed ovine BSE field case has been detected through this process. Moreover, the tests have not been validated against a possible Classical BSE/other TSE agent co-infection.
In conclusion and also considering the content of the answer to ToR 3.a, the answer to ToR 3.b is:
• Despite consistent performance in ring trials employing samples from experimental ovine BSE cases, there is uncertainty on their performance in the field (because of the lack of detection of natural BSE in ovine or caprine animal).
• TSE positive cases go through the full discriminatory process (including bioassay) only when biochemical discriminatory testing is compatible with BSE signature. Therefore, data obtained through this process can not be used for the evaluation of the sensitivity or the specificity of the discriminatory tests.
The EFSA Journal (2008) 626, 9-11
• Increasing the number of negative results during the TSE discriminatory testing of ovine or caprine animals can not compensate for the absence of statistically sufficient data on the performance of the tests.
The EFSA Journal (2008) 626, 10-11
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Baron, T. G. M. and Biacabe, A. G. 2001. Molecular analysis of the abnormal prion protein during coinfection of mice by bovine spongiform encephalopathy and a Scrapie agent. Journal Of Virology 75 (1): 107-114.
Baron, T., Biacabe, A. G., Arsac, J. N., Benestad, S. and Groschup, M. H. 2007. Atypical transmissible spongiform encephalopathies (TSEs) in ruminants. Vaccine 25 (30): 5625-5630.
Bartz, J. C., Kramer, M. L., Sheehan, M. H., Hutter, J. A. L., Ayers, J. I., Bessen, R. A. and Kincaid, A. E. 2007. Prion interference is due to a reduction in strain-specific PrPSc levels. Journal Of Virology 81 (2): 689-697.
Benestad, S. L., Sarradin, P., Thu, B., Schonheit, J., Tranulis, M. A. and Bratberg, B. 2003. Cases of Scrapie with unusual features in Norway and designation of a new type, Nor98. Veterinary Record 153 (7): 202-+.
Benestad, S. L., Arsac, J. N., Goldmann, W. and Nöremark, M. 2008.Atypical-Nor98 Scrapie: properties of the agent, genetics, and epidemiology. Veterinary Research, 39:19. DOI: 10.1051- vetres:2007056.
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Beringue, V., Andreoletti, O., Le Dur, A., Essalmani, R., Vilotte, J. L., Lacroux, C., Reine, F., Herzog, L., Biacabe, A. G., Baron, T., Caramelli, M., Casalone, C. and Laude, H. 2007. A bovine prion acquires an epidemic bovine spongiform encephalopathy strain-like phenotype on interspecies transmission. Journal Of Neuroscience 27: 6965-6971.
Biacabe, A. G., Laplanche, J. L., Ryder, S. and Baron, T. 2004. Distinct molecular phenotypes in bovine prion diseases. Embo Reports 5 (1): 110-114.
Bruce, ME, Boyle, A, Cousens, S, McConnell, I, Foster, J, Goldmann, W and Fraser, H, 2002. Strain characterization of natural sheep Scrapie and comparison with BSE. Journal of General Virology, 83 (3): 695-704
Buschmann, A., Biacabe, A. G., Ziegler, U., Bencsik, A., Madec, J. Y., Erhardt, G., Luhken, G., Baron, T. and Groschup, M. H. 2004. Atypical Scrapie cases in Germany and France are identified by discrepant reaction patterns in BSE rapid tests. Journal Of Virological Methods 117 (1): 27-36.
Casalone, C., Zanusso, G., Acutis, P., Ferrari, S., Capucci, L., Tagliavini, F., Monaco, S. and Caramelli, M. 2004. Identification of a second bovine amyloidotic spongiform encephalopathy: Molecular similarities with sporadic Creutzfeldt-Jakob disease. Proceedings Of The National Academy Of Sciences Of The United States Of America 101 (9): 3065-3070. EC 2000. Communication from the Commission on the precautionary principle. COMM (2000)
1. http://ec.europa.eu/dgs/health_consumer/library/pub/pub07_en.pdf
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The EFSA Journal (2008) 626, 11-11
EFSA 2007. Opinion of the Scientific Panel on Biological Hazards on a request from the European Commission on certain aspects related to the risk of Transmissible Spongiform Encephalopathies (TSEs) in ovine and caprine animals. The EFSA Journal 466: 1-10.
http://www.efsa.europa.eu/EFSA/efsa_locale-1178620753812_1178620775196.htm
Gavier-Widen, D., Noremark, M., Benestad, S., Simmons, M., Renstrom, L., Bratberg, B., Elvander, M. and af Segerstad, C. H. 2004. Recognition of the Nor98 variant of Scrapie in the Swedish sheep population. Journal Of Veterinary Diagnostic Investigation 16 (6): 562-567.
Gibbs, C. J., Amyx, H. L., Bacote, A., Masters, C. L. and Gajdusek, D. C. 1980. Oral- Transmission Of Kuru, Creutzfeldt-Jakob Disease, And Scrapie To Nonhuman-Primates. Journal Of Infectious Diseases 142 (2): 205-208.
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Raymond, G. J., Hope, J., Kocisko, D. A., Priola, S. A., Raymond, L. D., Bossers, A., Ironside, J., Will, R. G., Chen, S. G., Petersen, R. B., Gambetti, P., Rubenstein, R., Smits, M. A., Lansbury, P. T. and Caughey, B. 1997. Molecular assessment of the potential transmissibilities of BSE and Scrapie to humans. Nature 388 (6639): 285-288.
Saegerman, C., Vanopdenbosch, E. and Berkvens, D. 2007. Current status of Scrapie. CAB Reviews: Perspectives in Agriculture, Veterinary Science, Nutrition and Natural Resources 2 (027): 20 pp.
Stack, M., Jeffrey, M., Deslys, J.P., Grassi, J., Baron, T., Safar, J., Groschup, M., Agrimi, U., Langeveld, J., Matthews, D., Hope, J. and Bostock, C., 2008. An evaluation of techniques for the discrimination of natural scrapie and experimental bovine spongiform encephalopathy in sheep. Document available at the Community Reference Laboratory for Transmissible Spongiform Encephalopathies.
http://www.defra.gov.uk/corporate/vla/science/documents/science-tse-rl-ringtrial.pdf
PLEASE READ ;
7 February 2008 - A Statement on the potential human health risk from changes to classical scrapie controls(41 KB) has been published.
http://www.seac.gov.uk/statements/scrapiestatement080207.pdf
16. There is no firm evidence for a link between human TSEs and classical scrapie. Although a link cannot be ruled out, even if there is a link, the human health risk from classical scrapie must be very low and result in very few human TSE cases per annum. This is because the incidence of human TSEs is very low and relatively constant world-wide (around one case per million people per year) showing that there must be at least a substantial, if not complete, barrier to transmission of classical scrapie to humans. Although it is not possible to quantify any increase in risk that would arise from the changes to classical scrapie controls, the increased risk is
6 © SEAC 2008
highly unlikely to be greater than the risk before classical scrapie controls were introduced. Indeed, given the apparent effect of the National Scrapie Plan (NSP) on reducing the incidence of classical scrapie in the UK, the risk, if it exists, is likely to be appreciably lower than prior to the implementation of the NSP controls. 17. It is possible that the changes to the EU controls may increase the level of atypical scrapie entering the food chain from classical scrapie affected flocks with concurrent atypical scrapie infections. However, given the low occurrence of atypical scrapie within flocks, any increase in the potential human health risk from atypical scrapie is likely to be very low.
Summary
18. Although the changes to the classical scrapie controls may increase the potential risks to human health from small ruminant TSEs, any risk that is present is currently very low or negligible and any increased risk likely to be very low or negligible. For classical scrapie, any increase in potential risk will be less than the longterm historic risk prior to the introduction of small ruminant TSE controls. A risk-benefit analysis is required to determine the proportionality of the changes in controls with respect to the increased potential risks. Such an analysis is not within the remit of SEAC.
SEAC February 2008
http://www.seac.gov.uk/statements/scrapiestatement080207.pdf
Thursday, January 31, 2008
SPONGIFORM ENCEPHALOPATHY ADVISORY COMMITTEE Draft minutes of the 99th meeting held on 14th December 2007
snip...
ITEM 8 – PUBLIC QUESTION AND ANSWER SESSION
40. The Chair explained that the purpose of the question and answer session was to give members of the public an opportunity to ask questions related to the work of SEAC. Mr Terry Singeltary (Texas, USA) had submitted a question prior to the meeting, asking: “With the Nor-98 now documented in five different states so far in the USA in 2007, and with the two atypical BSE H-base
13 © SEAC 2007
cases in Texas and Alabama, with both scrapie and chronic wasting disease (CWD) running rampant in the USA, is there any concern from SEAC with the rise of sporadic CJD in the USA from ''unknown phenotype'', and what concerns if any, in relations to blood donations, surgery, optical, and dental treatment, do you have with these unknown atypical phenotypes in both humans and animals in the USA? Does it concern SEAC, or is it of no concern to SEAC? Should it concern USA animal and human health officials?”
41. A member considered that this question ............
snip... please see full text, sources, and comments here ;
http://seac992007.blogspot.com/2008/01/spongiform-encephalopathy-advisory.html
USA MAD COW CASES IN ALABAMA AND TEXAS
***PLEASE NOTE***
USA BASE CASE, (ATYPICAL BSE), AND OR TSE (whatever they are calling it today), please note that both the ALABAMA COW, AND THE TEXAS COW, both were ''H-TYPE'', personal communication Detwiler et al Wednesday, August 22, 2007 11:52 PM. ...TSS
http://lists.ifas.ufl.edu/cgi-bin/wa.exe?A2=ind0708&L=sanet-mg&T=0&P=19779
P02.35 Molecular Features of the Protease-resistant Prion Protein (PrPres) in H- type BSE
Biacabe, A-G1; Jacobs, JG2; Gavier-Widén, D3; Vulin, J1; Langeveld, JPM2; Baron, TGM1 1AFSSA, France; 2CIDC-Lelystad, Netherlands; 3SVA, Sweden
Western blot analyses of PrPres accumulating in the brain of BSE- infected cattle have demonstrated 3 different molecular phenotypes regarding to the apparent molecular masses and glycoform ratios of PrPres bands. We initially described isolates (H-type BSE) essentially characterized by higher PrPres molecular mass and decreased levels of the diglycosylated PrPres band, in contrast to the classical type of BSE. This type is also distinct from another BSE phenotype named L-type BSE, or also BASE (for Bovine Amyloid Spongiform Encephalopathy), mainly characterized by a low representation of the diglycosylated PrPres band as well as a lower PrPres molecular mass. Retrospective molecular studies in France of all available BSE cases older than 8 years old and of part of the other cases identified since the beginning of the exhaustive surveillance of the disease in 20001 allowed to identify 7 H- type BSE cases, among 594 BSE cases that could be classified as classical, L- or H-type BSE. By Western blot analysis of H-type PrPres, we described a remarkable specific feature with antibodies raised against the C-terminal region of PrP that demonstrated the existence of a more C-terminal cleaved form of PrPres (named PrPres#2 ), in addition to the usual PrPres form (PrPres #1). In the unglycosylated form, PrPres #2 migrates at about 14 kDa, compared to 20 kDa for PrPres #1. The proportion of the PrPres#2 in cattle seems to by higher compared to the PrPres#1. Furthermore another PK–resistant fragment at about 7 kDa was detected by some more N-terminal antibodies and presumed to be the result of cleavages of both N- and C- terminal parts of PrP. These singular features were maintained after transmission of the disease to C57Bl/6 mice. The identification of these two additional PrPres fragments (PrPres #2 and 7kDa band) *** reminds features reported respectively in sporadic Creutzfeldt-Jakob disease and in Gerstmann-Sträussler-Scheinker (GSS) syndrome in humans.
FC5.5.1 BASE Transmitted to Primates and MV2 sCJD Subtype Share PrP27-30 and PrPSc C-terminal Truncated Fragments
Zanusso, G1; Commoy, E2; Fasoli, E3; Fiorini, M3; Lescoutra, N4; Ruchoux, MM4; Casalone, C5; Caramelli, M5; Ferrari, S3; Lasmezas, C6; Deslys, J-P4; Monaco, S3 1University of Verona, of Neurological and Visual Sciences, Italy; 2CEA, IMETI/SEPIA, France; 3University of Verona, Neurological and Visual Sciences, Italy; 4IMETI/SEPIA, France; 5IZSPLVA, Italy; 6The Scripps Research Insitute, USA
The etiology of sporadic Creutzfeldt-Jakob disease (sCJD), the most frequent human prion disease, remains still unknown. The marked disease phenotype heterogeneity observed in sCJD is thought to be influenced by the type of proteinase K- resistant prion protein, or PrPSc (type 1 or type 2 according to the electrophoretic mobility of the unglycosylated backbone), and by the host polymorphic Methionine/Valine (M/V) codon 129 of the PRNP. By using a two-dimensional gel electrophoresis (2D-PAGE) and imunoblotting we previously showed that in sCJD, in addition to the PrPSc type, distinct PrPSc C-terminal truncated fragments (CTFs) correlated with different sCJD subtypes. Based on the combination of CTFs and PrPSc type, we distinguished three PrPSc patterns: (i) the first was observed in sCJD with PrPSc type 1 of all genotypes,;
(ii) the second was found in M/M-2 (cortical form); (iii) the third in amyloidogenic M/V- 2 and V/V-2 subtypes (Zanusso et al., JBC 2004) . Recently, we showed that sCJD subtype M/V-2 shared molecular and pathological features with an atypical form of BSE, named BASE, thus suggesting a potential link between the two conditions. This connection was further confirmed after 2D-PAGE analysis, which showed an identical PrPSc signature, including the biochemical pattern of CTFs. To pursue this issue, we obtained brain homogenates from Cynomolgus macaques intracerebrally inoculated with brain homogenates from BASE. Samples were separated by using a twodimensional electrophoresis (2D-PAGE) followed by immunoblotting. We here show that the PrPSc pattern obtained in infected primates is identical to BASE and sCJD MV-2 subtype. *** These data strongly support the link, or at least a common ancestry, between a sCJD subtype and BASE. This work was supported by Neuroprion (FOOD-CT-2004-506579)
FC5.5.2 Transmission of Italian BSE and BASE Isolates in Cattle Results into a Typical BSE Phenotype and a Muscle Wasting Disease
Zanusso, G1; Lombardi, G2; Casalone, C3; D’Angelo, A4; Gelmetti, D2; Torcoli, G2; Barbieri, I2; Corona, C3; Fasoli, E1; Farinazzo, A1; Fiorini, M1; Gelati, M1; Iulini, B3; Tagliavini, F5; Ferrari, S1; Monaco, S1; Caramelli, M3; Capucci, L2 1University of Verona, Neurological and Visual Sciences, Italy; 2IZSLER, Italy; 3IZSPLVA, Italy; 4University of Turin, Animal Pathology, Italy; 5Isituto Carlo Besta, Italy
The clinical phenotype of bovine spongiform encephalopathy has been extensively reported in early accounts of the disorder. Following the introduction of statutory active surveillance, almost all BSE cases have been diagnosed on a pathological/molecular basis, in a pre-symptomatic clinical stage. In recent years, the active surveillance system has uncovered atypical BSE cases, which are characterized by distinct conformers of the PrPSc, named high-type (BSE-H) and low-type (BSE-L), whose clinicopathological phenotypes remain unknown. We recently reported two Italian atypical cases with a PrPSc type similar to BSE-L, pathologically characterized by PrP amyloid plaques. Experimental transmission to TgBov mice has recently disclosed that BASE is caused by a distinct prion strain which is extremely virulent. A major limitation of transmission studies to mice is the lack of reliable information on clinical phenotype of BASE in its natural host. In the present study, we experimentally infected Fresian/Holstein and Alpine/Brown cattle with Italian BSE and BASE isolates by i.c. route. BASE infected cattle showed survival times significantly shorter than BSE, a finding more readily evident in Fresian/Holstein, and in keeping with previous observations in TgBov mice. Clinically, BSE-infected cattle developed a disease phenotype highly comparable with that described in field BSE cases and in experimentally challenged cattle. On the contrary, BASE-inoculated cattle developed an amyotrophic disorder accompanied by mental dullness. The molecular and neuropathological profiles, including PrP deposition pattern, closely matched those observed in the original cases. This study further confirms that BASE is caused by a distinct prion isolate and discloses a novel disease phenotype in cattle, closely resembling the phenotype previous reported in scrapie-inoculated cattle *** and in some subtypes of inherited and sporadic Creutzfeldt-Jakob disease. Oral Abstracts 14
P04.27
Experimental BSE Infection of Non-human Primates: Efficacy of the Oral Route
Holznagel, E1; Yutzy, B1; Deslys, J-P2; Lasmézas, C2; Pocchiari, M3; Ingrosso, L3; Bierke, P4; Schulz-Schaeffer, W5; Motzkus, D6; Hunsmann, G6; Löwer, J1 1Paul-Ehrlich-Institut, Germany; 2Commissariat à l´Energie Atomique, France; 3Instituto Superiore di Sanità, Italy; 4Swedish Institute for Infectious Disease control, Sweden; 5Georg August University, Germany; 6German Primate Center, Germany
Background:
In 2001, a study was initiated in primates to assess the risk for humans to contract BSE through contaminated food. For this purpose, BSE brain was titrated in cynomolgus monkeys.
Aims:
The primary objective is the determination of the minimal infectious dose (MID50) for oral exposure to BSE in a simian model, and, by in doing this, to assess the risk for humans. Secondly, we aimed at examining the course of the disease to identify possible biomarkers.
Methods:
Groups with six monkeys each were orally dosed with lowering amounts of BSE brain: 16g, 5g, 0.5g, 0.05g, and 0.005g. In a second titration study, animals were intracerebrally (i.c.) dosed (50, 5, 0.5, 0.05, and 0.005 mg).
Results:
In an ongoing study, a considerable number of high-dosed macaques already developed simian vCJD upon oral or intracerebral exposure or are at the onset of the clinical phase. However, there are differences in the clinical course between orally and intracerebrally infected animals that may influence the detection of biomarkers.
Conclusions:
Simian vCJD can be easily triggered in cynomolgus monkeys on the oral route using less than 5 g BSE brain homogenate. The difference in the incubation period between 5 g oral and 5 mg i.c. is only 1 year (5 years versus 4 years). However, there are rapid progressors among orally dosed monkeys that develop simian v CJD as fast as intracerebrally inoculated animals.
The work referenced was performed in partial fulfilment of the study “BSE in primates“ supported by the EU (QLK1-2002-01096).
Subject: Aspects of the Cerebellar Neuropathology in Nor98
Date: September 26, 2007 at 4:06 pm PST
P03.141
Aspects of the Cerebellar Neuropathology in Nor98
Gavier-Widén, D1; Benestad, SL2; Ottander, L1; Westergren, E1 1National Veterinary Insitute, Sweden; 2National Veterinary Institute, Norway
Nor98 is a prion disease of old sheep and goats. This atypical form of scrapie was first described in Norway in 1998. Several features of Nor98 were shown to be different from classical scrapie including the distribution of disease associated prion protein (PrPd) accumulation in the brain. The cerebellum is generally the most affected brain area in Nor98. The study here presented aimed at adding information on the neuropathology in the cerebellum of Nor98 naturally affected sheep of various genotypes in Sweden and Norway. A panel of histochemical and immunohistochemical (IHC) stainings such as IHC for PrPd, synaptophysin, glial fibrillary acidic protein, amyloid, and cell markers for phagocytic cells were conducted. The type of histological lesions and tissue reactions were evaluated. The types of PrPd deposition were characterized. The cerebellar cortex was regularly affected, even though there was a variation in the severity of the lesions from case to case. Neuropil vacuolation was more marked in the molecular layer, but affected also the granular cell layer. There was a loss of granule cells. Punctate deposition of PrPd was characteristic. It was morphologically and in distribution identical with that of synaptophysin, suggesting that PrPd accumulates in the synaptic structures. PrPd was also observed in the granule cell layer and in the white matter. *** The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.
http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf
IS THERE A SCRAPIE-LIKE DISEASE IN CATTLE ?
In April of 1985, a mink rancher in Wisconsin reported a debilitating neurologic disease in his herd which we diagnosed as TME by histopathologic findings confirmed by experimental transmission to mink and squirrel monkeys. The rancher was a ''dead stock'' feeder using mostly (>95%) downer or dead dairy cattle and a few horses. She had never been fed.
We believe that these findings may indicate the presence of a previously unrecognized scrapie-like disease in cattle and wish to alert dairy practitioners to this possibility.
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PROCEEDINGS OF THE SEVENTH ANNUAL WESTERN CONFERENCE FOR FOOD ANIMAL VETERINARY MEDICINE, University of Arizona, March 17-19, 1986
http://www.bseinquiry.gov.uk/files/mb/m09a/tab01.pdf
1: J Infect Dis 1980 Aug;142(2):205-8
Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.
Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.
Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation.
PMID: 6997404
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
12/10/76 AGRICULTURAL RESEARCH COUNCIL REPORT OF THE ADVISORY COMMITTE ON SCRAPIE Office Note CHAIRMAN: PROFESSOR PETER WILDY
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A The Present Position with respect to Scrapie A] The Problem
Scrapie is a natural disease of sheep and goats. It is a slow and inexorably progressive degenerative disorder of the nervous system and it ia fatal. It is enzootic in the United Kingdom but not in all countries.
The field problem has been reviewed by a MAFF working group (ARC 35/77). It is difficult to assess the incidence in Britain for a variety of reasons but the disease causes serious financial loss; it is estimated that it cost Swaledale breeders alone $l.7 M during the five years 1971-1975. A further inestimable loss arises from the closure of certain export markets, in particular those of the United States, to British sheep.
It is clear that scrapie in sheep is important commercially and for that reason alone effective measures to control it should be devised as quickly as possible.
Recently the question has again been brought up as to whether scrapie is transmissible to man. This has followed reports that the disease has been transmitted to primates. One particularly lurid speculation (Gajdusek 1977) conjectures that the agents of scrapie, kuru, Creutzfeldt-Jakob disease and transmissible encephalopathy of mink are varieties of a single "virus". The U.S. Department of Agriculture concluded that it could "no longer justify or permit scrapie-blood line and scrapie-exposed sheep and goats to be processed for human or animal food at slaughter or rendering plants" (ARC 84/77)" The problem is emphasised by the finding that some strains of scrapie produce lesions identical to the once which characterise the human dementias"
Whether true or not. the hypothesis that these agents might be transmissible to man raises two considerations. First, the safety of laboratory personnel requires prompt attention. Second, action such as the "scorched meat" policy of USDA makes the solution of the acrapie problem urgent if the sheep industry is not to suffer grievously.
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76/10.12/4.6
http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
Epidemiology of Scrapie in the United States 1977
http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
SCRAPIE PROGRAM FY REPORT 2007
Prepared by National Center for Animal Health Programs Ruminant Health Programs Team November 15, 2007
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Infected and Source Flocks
During FY 2007, there were a total of 76 new infected or source flocks identified. Of those new flocks identified, 30 were infected flocks and 46 were source flocks (Figure 2). As of September 30, 2007, there were 38 scrapie infected and source flocks with open statuses (Figure 3). ...
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In FY 2007, 331 scrapie cases have been confirmed and reported by the National Veterinary Services Laboratories (NVSL), including 59* Regulatory Scrapie Slaughter Surveillance (RSSS) cases (Figure 5 and Slide 16). In FY 2007, two field cases, one validation case, and two RSSS cases were consistent with Nor-98 scrapie. The Nor98-like cases originated from flocks in California, Minnesota, Colorado, Wyoming and Indiana respectively. Nineteen cases of scrapie in goats have been reported since 1990 (Figure 6). The last goat case was reported in September 2007.
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see full report here ;
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/yearly_report.pps
Like lambs to the slaughter
31 March 2001 Debora MacKenzie Magazine issue 2284
FOUR years ago, Terry Singeltary watched his mother die horribly from a degenerative brain disease. Doctors told him it was Alzheimer's, but Singeltary was suspicious. The diagnosis didn't fit her violent symptoms, and he demanded an autopsy. It showed she had died of sporadic Creutzfeldt-Jakob disease.
Most doctors believe that sCJD is caused by a prion protein deforming by chance into a killer. But Singeltary thinks otherwise. He is one of a number of campaigners who say that some sCJD, like the variant CJD related to BSE, is caused by eating meat from infected animals. Their suspicions have focused on sheep carrying scrapie, a BSE-like disease that is widespread in flocks across Europe and North America.
Now scientists in France have stumbled across new evidence that adds weight to the campaigners' fears. To their complete surprise, the researchers found that one strain of scrapie causes the same brain damage in mice as sCJD.
"This means we cannot rule out that at least some sCJD may be caused by some strains of scrapie," says team member Jean-Philippe Deslys of the French Atomic Energy Commission's medical research laboratory in Fontenay-aux-Roses, south-west of Paris.
Hans Kretschmar of the University of Göttingen, who coordinates CJD surveillance in Germany, is so concerned by the findings that he now wants to trawl back through past sCJD cases to see if any might have been caused by eating infected mutton or lamb. ...
http://www.newscientist.com/article/mg16922840.300-like-lambs-to-the-slaughter.html
Tissue distribution. For atypical scrapie, what is PrPres and infectivity distribution within sheep of different genotypes, particularly with respect to SRM removal? For classical scrapie and experimental BSE in sheep, tissue distribution of infectivity is widespread. Thus, even with SRM controls in place, an infected sheep poses around 1000 times the risk to human health than does an infected cow22. Does the distribution depend on whether infection is by the oral or 21 Gubbins S. Prevalence of BSE in sheep: interpreting the results of retrospective and prospective testing of sheep TSE cases. SEAC 84 open meeting 22 paper presented to Food Standards Agency board on 9 December 2004.
http://www.foodstandards.gov.uk/multimedia/pdfs/fsa041204.pdf
Also see paper SEAC/84/2 Annex 2: McLean, A. Page 13 © SEAC 27 February 2006 intracerebral route? Are some VRQ sheep carriers with no neurological symptoms?
SEAC SHEEP SUBGROUP POSITION STATEMENT
http://www.seac.gov.uk/pdf/positionstatement-sheep-subgroup.pdf
NOR-98 ATYPICAL SCRAPIE USA UPDATE AS AT OCT 2007
http://nor-98.blogspot.com/
SCRAPIE USA
http://scrapie-usa.blogspot.com/
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Singeltary, Sr et al. JAMA.2001; 285: 733-734.
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Since this article does not have an abstract, we have provided the first 150 words of the full text and any section headings.
To the Editor: In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.
Terry S. Singeltary, Sr Bacliff, Tex
1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323. FREE FULL TEXT
http://jama.ama-assn.org/cgi/content/extract/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=singeltary&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT
APHIS-2006-0041-0006 TSE advisory committee for the meeting December 15, 2006
http://www.regulations.gov/fdmspublic/ContentViewer?objectId=09000064801f3413&disposition=attachment&contentType=msw8
[Docket No. FSIS-2006-0011] FSIS Harvard Risk Assessment of Bovine Spongiform Encephalopathy (BSE)
http://www.fsis.usda.gov/OPPDE/Comments/2006-0011/2006-0011-1.pdf
[Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk Materials for Human Food and Requirement for the Disposition of Non-Ambulatory Disabled Cattle
http://www.fsis.usda.gov/OPPDE/Comments/03-025IFA/03-025IFA-2.pdf
Attachment to Singeltary comment
January 28, 2007
Greetings APHIS,
I would kindly like to submit the following to ;
BSE; MRR; IMPORTATION OF LIVE BOVINES AND PRODUCTS DERIVED FROM BOVINES [Docket No. APHIS-2006-0041] RIN 0579-AC01
[Federal Register: January 9, 2007 (Volume 72, Number 5)] [Proposed Rules] [Page 1101-1129] From the Federal Register Online via GPO Access [wais.access.gpo.gov] [DOCID:fr09ja07-21]
http://www.regulations.gov/fdmspublic/component/main?main=DocumentDetail&o=09000064801f8152
BSE; MRR; IMPORTATION OF LIVE BOVINES AND PRODUCTS DERIVED FROM BOVINES [Docket No. APHIS-2006-0041] RIN 0579-AC01 Date: January 9, 2007 at 9:08 am PST
http://www.regulations.gov/fdmspublic/component/main?main=DocumentDetail&o=09000064801f3412
USDA CERTIFIED H-BASE MAD COW SCHOOL LUNCH PROGRAM
http://cjdmadcowbaseoct2007.blogspot.com/2008/02/usda-certified-h-base-mad-cow-school.html
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518
Friday, February 15, 2008
Monday, January 21, 2008
Atypical/Nor98 scrapie: properties of the agent, genetics, and epidemiology
Vet. Res. (2008) 39:19 DOI: 10.1051/vetres:2007056
Atypical/Nor98 scrapie: properties of the agent, genetics, and epidemiology
Sylvie L. Benestad1, Jean-Noël Arsac2, Wilfred Goldmann3 and Maria Nöremark4
1 National Veterinary Institute, PO Box 8156 Dep., Oslo, Norway 2 Agence Française de Sécurité Sanitaire des Aliments, 31 av. Tony Garnier, 69364 Lyon Cedex 07, France 3 Neuropathogenesis Unit, Roslin Institute, Ogston Bldg, West Mains Rd, Edinburgh, EH9 3JF, UK 4 National Veterinary Institute, 75189 Uppsala, Sweden
(Received 23 July 2007; accepted 23 October 2007 ; published online 11 January 2008)
Abstract - Atypical/Nor98 scrapie cases in sheep were diagnosed for the first time in Norway in 1998. They are now identified in small ruminants in most European countries and represent an increasingly large proportion of the scrapie cases diagnosed in Europe. Atypical/Nor98 scrapie isolates have shown to be experimentally transmissible into transgenic mice and sheep but the properties of the TSE agent involved, like its biological and biochemical features, are so clearly distinct from the agent involved in classical scrapie that they have provided a challenging diagnostic for many years. No strain diversity has yet been identified among the atypical/Nor98 scrapie sample cases. The genetic predisposition of the sheep affected by atypical/Nor98 scrapie is almost inverted compared to classical scrapie, and the exact origin of this sporadic TSE strain is still speculative, but a spontaneous, non-contagious origin, like sporadic Creutzfeldt-Jakob disease in humans, can not be excluded. Further transmission and epidemiological studies are needed to better address this hypothesis.
Key words: atypical scrapie / Nor98 / transmissible spongiform encephalopathies TSE / genetics / epidemiology
Corresponding author: sylvie.benestad@vetinst.no
© INRA, EDP Sciences 2008
http://www.vetres.org/index.php?option=article&access=doi&doi=10.1051/vetres:2007056
The genetic predisposition of the sheep affected by atypical/Nor98 scrapie is almost inverted compared to classical scrapie, and the exact origin of this
sporadic TSE strain is still speculative, but a spontaneous, non-contagious origin, like sporadic Creutzfeldt-Jakob disease in humans, can not be excluded.
there are 26790 hits on 'sporadic' at pub-med.
there are 12830 hits on 'sporadic disease' at pub-med.
with the first few being ;
Comparison Analysis of Gene Expression Patterns between Sporadic Alzheimer's and Parkinson's Disease.
http://www.ncbi.nlm.nih.gov/pubmed/18198416?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
Sporadic ALS with early onset respiratory failure is not associated with IGHMBP2 gene mutations.
http://www.ncbi.nlm.nih.gov/pubmed/18187479?ordinalpos=10&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
Sporadic Multiple Cerebral Cavernomatosis: Report of a Case and Review of Literature
http://www.ncbi.nlm.nih.gov/pubmed/18195658?ordinalpos=7&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
A sporadic disease is one that occurs only occasionally in a population (i.e., prevalence is zero).
http://mansfield.osu.edu/~sabedon/biol2045.htm
sporadic CJD is NOT a single strain, phenotype.
sporadic CJD is simply a human TSE, which routes, sources, strains, are unknown.
there are 6 different documented phenotypes of the sporadic CJD, with 'UNKNOWN' sub-types growing.
spontaneous TSE in the field ??? never has been proven, and highly unlikely that 85%+ of all human TSE i.e. sporadic CJD, just happen without route and source.
Volume 12, Number 12–December 2006
Perspective
On the Question of Sporadic or Atypical Bovine Spongiform Encephalopathy and Creutzfeldt-Jakob Disease
Paul Brown,* Lisa M. McShane,† Gianluigi Zanusso,‡ and Linda Detwiler§
*Bethesda, Maryland, USA; †National Institutes of Health, Bethesda, Maryland, USA; ‡University of Verona, Verona, Italy; and §Virginia-Maryland Regional College of Veterinary Medicine, College Park, Maryland, USA
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Sporadic CJD
The possibility that at least some cases of apparently sporadic CJD might be due to infection by sporadic cases of BSE cannot be dismissed outright. Screening programs needed to identify sporadic BSE have yet to be implemented, and we know from already extant testing programs that at least a proportion of infected animals have no symptoms and thus would never be identified in the absence of systematic testing. Thus, sporadic BSE (or for that matter, sporadic disease in any mammalian species) might be occurring on a regular basis at perhaps the same annual frequency as sporadic CJD in humans, that is, in the range of 1 case per million animals.
Whether humans might be more susceptible to atypical forms of BSE cannot be answered at this time. Experimentally transmitted BASE shows shorter incubation periods than BSE in at least 1 breed of cattle, bovinized transgenic mice, and Cynomolgus monkeys (12,13). In humanized transgenic mice, BASE transmitted, whereas typical BSE did not transmit (13). Paradoxically, the other major phenotype (H) showed an unusually long incubation period in bovinized transgenic mice (12).
The limited experimental evidence bearing on a possible relationship between BSE and sporadic CJD is difficult to interpret. The original atypical BASE strain of BSE had a molecular protein signature very similar to that of 1 subtype (type 2 M/V) of sporadic CJD in humans (5). In another study, a strain of typical BSE injected into humanized mice encoding valine at codon 129 showed a glycopattern indistinguishable from the same subtype of sporadic CJD (15). In a third study, the glycopatterns of both the H and L strains of atypical BSE evidently did not resemble any of the known sporadic CJD subtypes (12).
To these molecular biology observations can be added the epidemiologic data accumulated during the past 30 years. The hypothesis that at least some cases of apparently sporadic CJD are due to unrecognized BSE infections cannot be formally refuted, but if correct, we might expect by now to have some epidemiologic evidence linking BSE to at least 1 cluster of apparently sporadic cases of CJD. Although only a few clusters have been found (and still fewer published), every proposed cluster that has been investigated has failed to show any common exposure to bovines. For that matter, no common exposure has been shown to any environmental vehicles of infection, including the consumption of foodstuffs from bovine, ovine, and porcine sources, the 3 livestock species known to be susceptible to transmissible spongiform encephalopathies. Additional negative evidence comes from several large case-control studies in which no statistically significant dietary differences were observed between patients with sporadic CJD and controls (16,17).
On the other hand, the difficulty of establishing a link between BSE and CJD may be compounded by our ignorance of the infectious parameters of a sporadic form of BSE (e.g., host range, tissue distribution of infectivity, route of transmission, minimum infectious dose for humans, whether single or multiple). Presumably, these parameters would resemble those of variant CJD; that is, high infectivity central nervous system and lymphoreticular tissues of an infected cow find their way into products consumed by humans. Transmissions that might have occurred in the past would be difficult to detect because meat products are generally not distributed in a way that results in detectable geographic clusters.
Barring the discovery of a specific molecular signature (as in variant CJD), the most convincing clue to an association will come from the observation of trends over time of the incidence of typical and atypical BSE and of sporadic and variant CJD. With 4 diseases, each of which could have increasing, unchanging, or decreasing trends, there could be 81 (34) possible different combinations. However, it is highly likely that the trends for typical BSE and variant CJD will both decrease in parallel as feed bans continue to interrupt recycled contamination. The remaining combinations are thus reduced to 9 (32), and some of them could be highly informative.
For example, if the incidence of atypical BSE declines in parallel with that of typical BSE, its candidacy as a sporadic form of disease would be eliminated (because sporadic disease would not be influenced by current measures to prevent oral infection). If, on the other hand, atypical BSE continues to occur as typical BSE disappears, this would be a strong indication that it is indeed sporadic, and if in addition at least 1 form of what is presently considered as sporadic CJD (such as the type 2 M/V subtype shown to have a Western blot signature like BASE) were to increase, this would suggest (although not prove) a causal relationship (Figure 5).
Recognition of the different forms of BSE and CJD depends upon continuing systematic testing for both bovines and humans, but bovine testing will be vulnerable to heavy pressure from industry to dismantle the program as the commercial impact of declining BSE cases ceases to be an issue. Industry should be aware, however, of the implications of sporadic BSE. Its occurrence would necessitate the indefinite retention of all of the public health measures that exclude high-risk bovine tissues from the animal and human food chains, whereas its nonoccurrence would permit tissues that are now destroyed to be used as before, once orally acquired BSE has disappeared.
http://www.cdc.gov/ncidod/EID/vol12no12/06-0965.htm
THE USDA JUNE 2004 ENHANCED BSE SURVEILLANCE PROGRAM WAS TERRIBLY FLAWED ;
CDC DR. PAUL BROWN TSE EXPERT COMMENTS 2006
The U.S. Department of Agriculture was quick to assure the public earlier this week that the third case of mad cow disease did not pose a risk to them, but what federal officials have not acknowledged is that this latest case indicates the deadly disease has been circulating in U.S. herds for at least a decade.
The second case, which was detected last year in a Texas cow and which USDA officials were reluctant to verify, was approximately 12 years old.
These two cases (the latest was detected in an Alabama cow) present a picture of the disease having been here for 10 years or so, since it is thought that cows usually contract the disease from contaminated feed they consume as calves. The concern is that humans can contract a fatal, incurable, brain-wasting illness from consuming beef products contaminated with the mad cow pathogen.
"The fact the Texas cow showed up fairly clearly implied the existence of other undetected cases," Dr. Paul Brown, former medical director of the National Institutes of Health's Laboratory for Central Nervous System Studies and an expert on mad cow-like diseases, told United Press International. "The question was, 'How many?' and we still can't answer that."
Brown, who is preparing a scientific paper based on the latest two mad cow cases to estimate the maximum number of infected cows that occurred in the United States, said he has "absolutely no confidence in USDA tests before one year ago" because of the agency's reluctance to retest the Texas cow that initially tested positive.
USDA officials finally retested the cow and confirmed it was infected seven months later, but only at the insistence of the agency's inspector general.
"Everything they did on the Texas cow makes everything USDA did before 2005 suspect," Brown said. ...snip...end
http://www.upi.com/
CDC - Bovine Spongiform Encephalopathy and Variant Creutzfeldt ... Dr. Paul Brown is Senior Research Scientist in the Laboratory of Central Nervous System ... Address for correspondence: Paul Brown, Building 36, Room 4A-05, ...
http://www.cdc.gov/ncidod/eid/vol7no1/brown.htm
PAUL BROWN COMMENT TO ME ON THIS ISSUE
Tuesday, September 12, 2006 11:10 AM
"Actually, Terry, I have been critical of the USDA handling of the mad cow issue for some years, and with Linda Detwiler and others sent lengthy detailed critiques and recommendations to both the USDA and the Canadian Food Agency." ........
Archive Number 20071105.3602 Published Date 05-NOV-2007 Subject PRO/AH/EDR> Prion disease update 2007 (07)
PRION DISEASE UPDATE 2007 (07)
snip...
[In submitting these data, Terry S. Singeltary Sr. draws attention to the steady increase in the "type unknown" category, which, according to their definition, comprises cases in which vCJD could be excluded. The total of 26 cases for the current year (2007) is disturbing, possibly symptomatic of the circulation of novel agents. Characterization of these agents should be given a high priority. - Mod.CP]
http://www.promedmail.org/pls/askus/f?p=2400:1001:6833194127530602005::NO::F2400_P1001_BACK_PAGE,F2400_P1001_PUB_MAIL_ID:1010,39963
There is a growing number of human CJD cases, and they were presented last week in San Francisco by Luigi Gambatti(?) from his CJD surveillance collection.
He estimates that it may be up to 14 or 15 persons which display selectively SPRPSC and practically no detected RPRPSC proteins.
http://www.fda.gov/ohrms/dockets/ac/06/transcripts/1006-4240t1.htm
http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4240t1.pdf
JOURNAL OF NEUROLOGY
MARCH 26, 2003
RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob
disease in the United States
Email Terry S. Singeltary:
flounder@wt.net
I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to
comment on the CDC's attempts to monitor the occurrence of emerging
forms of CJD. Asante, Collinge et al [1] have reported that BSE
transmission to the 129-methionine genotype can lead to an alternate
phenotype that is indistinguishable from type 2 PrPSc, the commonest
sporadic CJD. However, CJD and all human TSEs are not reportable
nationally. CJD and all human TSEs must be made reportable in every
state and internationally. I hope that the CDC does not continue to
expect us to still believe that the 85%+ of all CJD cases which are
sporadic are all spontaneous, without route/source. We have many TSEs in
the USA in both animal and man. CWD in deer/elk is spreading rapidly and
CWD does transmit to mink, ferret, cattle, and squirrel monkey by
intracerebral inoculation. With the known incubation periods in other
TSEs, oral transmission studies of CWD may take much longer. Every
victim/family of CJD/TSEs should be asked about route and source of this
agent. To prolong this will only spread the agent and needlessly expose
others. In light of the findings of Asante and Collinge et al, there
should be drastic measures to safeguard the medical and surgical arena
from sporadic CJDs and all human TSEs. I only ponder how many sporadic
CJDs in the USA are type 2 PrPSc?
http://www.neurology.org/cgi/eletters/60/2/176#535
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Singeltary, Sr et al. JAMA.2001; 285: 733-734.
http://jama.ama-assn.org/http://www.neurology.org/cgi/eletters/60/2/176#535
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States
http://cjdusa.blogspot.com/
Creutzfeldt Jakob Disease
http://creutzfeldt-jakob-disease.blogspot.com/
CJD QUESTIONNAIRE
http://cjdquestionnaire.blogspot.com/
SEAC 99th meeting on Friday 14th December 2007
http://seac992007.blogspot.com/
16 January 2008 - The final minutes of the 98th SEAC meeting have been published.
PUBLIC QUESTION AND ANSWER SESSION 2© SEAC 2007SEAC considered a question about possible links between CJD cases and animal TSEs in the United States of America (USA).
http://www.seac.gov.uk/summaries/seac99_summary.pdf
vCJD case study highlights blood transfusion risk
http://vcjdblood.blogspot.com/
vCJD transfusion-associated Fourth Case UK
http://vcjdtransfusion.blogspot.com/
risk factors for sporadic CJD
http://creutzfeldt-jakob-disease.blogspot.com/2008/01/risk-factors-for-sporadic-creutzfeldt.html
Creutzfeldt-Jakob Disease, Prion Protein Gene Codon 129VV, and a Novel PrPSc Type in a Young British Woman
http://creutzfeldt-jakob-disease.blogspot.com/2008/01/creutzfeldt-jakob-disease-prion-protein.html
BSE (Mad Cow) Update: Do Reports of sCJD Clusters Matter?
snip... see full text ;
http://cjdtexas.blogspot.com/
THE PATHOLOGICAL PROTEIN Hardcover, 304 pages plus photos and illustrations. ISBN 0-387-95508-9 June 2003 BY Philip Yam
CHAPTER 14 LAYING ODDS
Answering critics like Terry Singeltary, who feels that the U.S. under-counts CJD, Schonberger conceded that the current surveillance system has errors but stated that most of the errors will be confined to the older population.
http://www.thepathologicalprotein.com/
doi:10.1016/S1473-3099(03)00715-1Copyright © 2003 Published by Elsevier Ltd.
Newsdesk
Tracking spongiform encephalopathies in North America
Xavier Bosch
Available online 29 July 2003. Volume 3, Issue 8, August 2003, Page 463
"My name is Terry S Singeltary Sr, and I live in Bacliff, Texas. I lost my mom to hvCJD (Heidenhain variant CJD) and have been searching for answers ever since. What I have found is that we have not been told the truth. CWD in deer and elk is a small portion of a much bigger problem." ...
http://www.thelancet.com/journals/laninf/article/PIIS1473309903007151/fulltext
http://download.thelancet.com/pdfs/journals/1473-3099/PIIS1473309903007151.pdf
ANIMAL HEALTH REPORT 2006 (BSE h-BASE EVENT IN ALABAMA, Scrapie, and CWD)
http://animalhealthreport2006.blogspot.com/
P03.141
Aspects of the Cerebellar Neuropathology in Nor98
Gavier-Widén, D1; Benestad, SL2; Ottander, L1; Westergren, E11National Veterinary Insitute, Sweden; 2National Veterinary Institute, Norway
Nor98 is a prion disease of old sheep and goats. This atypical form of scrapie was first described in Norway in 1998. Several features of Nor98 were shown to be different from classical scrapie including the distribution of disease associated prion protein (PrPd) accumulation in the brain. The cerebellum is generally the most affected brain area in Nor98. The study here presented aimed at adding information on the neuropathology in the cerebellum of Nor98 naturally affected sheep of various genotypes in Sweden and Norway. A panel of histochemical and immunohistochemical (IHC) stainings such as IHC for PrPd, synaptophysin, glial fibrillary acidic protein, amyloid, and cell markers for phagocytic cells were conducted. The type of histological lesions and tissue reactions were evaluated. The types of PrPd deposition were characterized. The cerebellar cortex was regularly affected, even though there was avariation in the severity of the lesions from case to case. Neuropil vacuolation was more marked in the molecular layer, but affected also the granular cell layer. There was a loss of granule cells. Punctate deposition of PrPd was characteristic. It was morphologically and in distribution identical with that of synaptophys in, suggesting that PrPd accumulates in the synaptic structures. PrPd was also observed in the granule cell layer and in the white matter. The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.
http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf
NOR-98 ATYPICAL SCRAPIE USA UPDATE AS AT OCT 2007
typical scrapie transmits to primates by there NON-FORCED ORAL CONSUMPTION ;
76/10.12/4.6
http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=6997404&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus
full text ;
http://nor-98.blogspot.com/
http://scrapie-usa.blogspot.com/
CREUTZFELDT JAKOB DISEASE MAD COW BASE UPDATE USA
http://cjdmadcowbaseoct2007.blogspot.com/
Transmissible Mink Encephalopathy TME
http://transmissible-mink-encephalopathy.blogspot.com/
CHRONIC WASTING DISEASE
http://chronic-wasting-disease.blogspot.com/
ONE other question from Confucius,
IF we are to believe as some has so persistently tried to claim without any proof, if we are to believe that these TSE just happen spontaneous, then why have there been NO other cases of TME in the USA ???
WHERE are these cases of spontaneous BSE/BASE in the USA ???
WHAT about the FSE cases, none in the USA either, no feline spongiform encephalopathy in USA documented to date ???
IF the spontaneous TSE truely exist, would we have not seen these species with TSE here in the USA ???
WHAT about Europe, if the spontanous TSE truely happened, would CWD, TME, not happen in the EU countries as well ???
OR is it just the USDA certified BASE mad cows that are spontaneous ;-) $$$
Saturday, December 01, 2007
Phenotypic Similarity of Transmissible Mink Encephalopathy in Cattle and L-type Bovine Spongiform Encephalopathy in a Mouse Model
http://transmissible-mink-encephalopathy.blogspot.com/
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518
Atypical/Nor98 scrapie: properties of the agent, genetics, and epidemiology
Sylvie L. Benestad1, Jean-Noël Arsac2, Wilfred Goldmann3 and Maria Nöremark4
1 National Veterinary Institute, PO Box 8156 Dep., Oslo, Norway 2 Agence Française de Sécurité Sanitaire des Aliments, 31 av. Tony Garnier, 69364 Lyon Cedex 07, France 3 Neuropathogenesis Unit, Roslin Institute, Ogston Bldg, West Mains Rd, Edinburgh, EH9 3JF, UK 4 National Veterinary Institute, 75189 Uppsala, Sweden
(Received 23 July 2007; accepted 23 October 2007 ; published online 11 January 2008)
Abstract - Atypical/Nor98 scrapie cases in sheep were diagnosed for the first time in Norway in 1998. They are now identified in small ruminants in most European countries and represent an increasingly large proportion of the scrapie cases diagnosed in Europe. Atypical/Nor98 scrapie isolates have shown to be experimentally transmissible into transgenic mice and sheep but the properties of the TSE agent involved, like its biological and biochemical features, are so clearly distinct from the agent involved in classical scrapie that they have provided a challenging diagnostic for many years. No strain diversity has yet been identified among the atypical/Nor98 scrapie sample cases. The genetic predisposition of the sheep affected by atypical/Nor98 scrapie is almost inverted compared to classical scrapie, and the exact origin of this sporadic TSE strain is still speculative, but a spontaneous, non-contagious origin, like sporadic Creutzfeldt-Jakob disease in humans, can not be excluded. Further transmission and epidemiological studies are needed to better address this hypothesis.
Key words: atypical scrapie / Nor98 / transmissible spongiform encephalopathies TSE / genetics / epidemiology
Corresponding author: sylvie.benestad@vetinst.no
© INRA, EDP Sciences 2008
http://www.vetres.org/index.php?option=article&access=doi&doi=10.1051/vetres:2007056
The genetic predisposition of the sheep affected by atypical/Nor98 scrapie is almost inverted compared to classical scrapie, and the exact origin of this
sporadic TSE strain is still speculative, but a spontaneous, non-contagious origin, like sporadic Creutzfeldt-Jakob disease in humans, can not be excluded.
there are 26790 hits on 'sporadic' at pub-med.
there are 12830 hits on 'sporadic disease' at pub-med.
with the first few being ;
Comparison Analysis of Gene Expression Patterns between Sporadic Alzheimer's and Parkinson's Disease.
http://www.ncbi.nlm.nih.gov/pubmed/18198416?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
Sporadic ALS with early onset respiratory failure is not associated with IGHMBP2 gene mutations.
http://www.ncbi.nlm.nih.gov/pubmed/18187479?ordinalpos=10&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
Sporadic Multiple Cerebral Cavernomatosis: Report of a Case and Review of Literature
http://www.ncbi.nlm.nih.gov/pubmed/18195658?ordinalpos=7&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
A sporadic disease is one that occurs only occasionally in a population (i.e., prevalence is zero).
http://mansfield.osu.edu/~sabedon/biol2045.htm
sporadic CJD is NOT a single strain, phenotype.
sporadic CJD is simply a human TSE, which routes, sources, strains, are unknown.
there are 6 different documented phenotypes of the sporadic CJD, with 'UNKNOWN' sub-types growing.
spontaneous TSE in the field ??? never has been proven, and highly unlikely that 85%+ of all human TSE i.e. sporadic CJD, just happen without route and source.
Volume 12, Number 12–December 2006
Perspective
On the Question of Sporadic or Atypical Bovine Spongiform Encephalopathy and Creutzfeldt-Jakob Disease
Paul Brown,* Lisa M. McShane,† Gianluigi Zanusso,‡ and Linda Detwiler§
*Bethesda, Maryland, USA; †National Institutes of Health, Bethesda, Maryland, USA; ‡University of Verona, Verona, Italy; and §Virginia-Maryland Regional College of Veterinary Medicine, College Park, Maryland, USA
snip...
Sporadic CJD
The possibility that at least some cases of apparently sporadic CJD might be due to infection by sporadic cases of BSE cannot be dismissed outright. Screening programs needed to identify sporadic BSE have yet to be implemented, and we know from already extant testing programs that at least a proportion of infected animals have no symptoms and thus would never be identified in the absence of systematic testing. Thus, sporadic BSE (or for that matter, sporadic disease in any mammalian species) might be occurring on a regular basis at perhaps the same annual frequency as sporadic CJD in humans, that is, in the range of 1 case per million animals.
Whether humans might be more susceptible to atypical forms of BSE cannot be answered at this time. Experimentally transmitted BASE shows shorter incubation periods than BSE in at least 1 breed of cattle, bovinized transgenic mice, and Cynomolgus monkeys (12,13). In humanized transgenic mice, BASE transmitted, whereas typical BSE did not transmit (13). Paradoxically, the other major phenotype (H) showed an unusually long incubation period in bovinized transgenic mice (12).
The limited experimental evidence bearing on a possible relationship between BSE and sporadic CJD is difficult to interpret. The original atypical BASE strain of BSE had a molecular protein signature very similar to that of 1 subtype (type 2 M/V) of sporadic CJD in humans (5). In another study, a strain of typical BSE injected into humanized mice encoding valine at codon 129 showed a glycopattern indistinguishable from the same subtype of sporadic CJD (15). In a third study, the glycopatterns of both the H and L strains of atypical BSE evidently did not resemble any of the known sporadic CJD subtypes (12).
To these molecular biology observations can be added the epidemiologic data accumulated during the past 30 years. The hypothesis that at least some cases of apparently sporadic CJD are due to unrecognized BSE infections cannot be formally refuted, but if correct, we might expect by now to have some epidemiologic evidence linking BSE to at least 1 cluster of apparently sporadic cases of CJD. Although only a few clusters have been found (and still fewer published), every proposed cluster that has been investigated has failed to show any common exposure to bovines. For that matter, no common exposure has been shown to any environmental vehicles of infection, including the consumption of foodstuffs from bovine, ovine, and porcine sources, the 3 livestock species known to be susceptible to transmissible spongiform encephalopathies. Additional negative evidence comes from several large case-control studies in which no statistically significant dietary differences were observed between patients with sporadic CJD and controls (16,17).
On the other hand, the difficulty of establishing a link between BSE and CJD may be compounded by our ignorance of the infectious parameters of a sporadic form of BSE (e.g., host range, tissue distribution of infectivity, route of transmission, minimum infectious dose for humans, whether single or multiple). Presumably, these parameters would resemble those of variant CJD; that is, high infectivity central nervous system and lymphoreticular tissues of an infected cow find their way into products consumed by humans. Transmissions that might have occurred in the past would be difficult to detect because meat products are generally not distributed in a way that results in detectable geographic clusters.
Barring the discovery of a specific molecular signature (as in variant CJD), the most convincing clue to an association will come from the observation of trends over time of the incidence of typical and atypical BSE and of sporadic and variant CJD. With 4 diseases, each of which could have increasing, unchanging, or decreasing trends, there could be 81 (34) possible different combinations. However, it is highly likely that the trends for typical BSE and variant CJD will both decrease in parallel as feed bans continue to interrupt recycled contamination. The remaining combinations are thus reduced to 9 (32), and some of them could be highly informative.
For example, if the incidence of atypical BSE declines in parallel with that of typical BSE, its candidacy as a sporadic form of disease would be eliminated (because sporadic disease would not be influenced by current measures to prevent oral infection). If, on the other hand, atypical BSE continues to occur as typical BSE disappears, this would be a strong indication that it is indeed sporadic, and if in addition at least 1 form of what is presently considered as sporadic CJD (such as the type 2 M/V subtype shown to have a Western blot signature like BASE) were to increase, this would suggest (although not prove) a causal relationship (Figure 5).
Recognition of the different forms of BSE and CJD depends upon continuing systematic testing for both bovines and humans, but bovine testing will be vulnerable to heavy pressure from industry to dismantle the program as the commercial impact of declining BSE cases ceases to be an issue. Industry should be aware, however, of the implications of sporadic BSE. Its occurrence would necessitate the indefinite retention of all of the public health measures that exclude high-risk bovine tissues from the animal and human food chains, whereas its nonoccurrence would permit tissues that are now destroyed to be used as before, once orally acquired BSE has disappeared.
http://www.cdc.gov/ncidod/EID/vol12no12/06-0965.htm
THE USDA JUNE 2004 ENHANCED BSE SURVEILLANCE PROGRAM WAS TERRIBLY FLAWED ;
CDC DR. PAUL BROWN TSE EXPERT COMMENTS 2006
The U.S. Department of Agriculture was quick to assure the public earlier this week that the third case of mad cow disease did not pose a risk to them, but what federal officials have not acknowledged is that this latest case indicates the deadly disease has been circulating in U.S. herds for at least a decade.
The second case, which was detected last year in a Texas cow and which USDA officials were reluctant to verify, was approximately 12 years old.
These two cases (the latest was detected in an Alabama cow) present a picture of the disease having been here for 10 years or so, since it is thought that cows usually contract the disease from contaminated feed they consume as calves. The concern is that humans can contract a fatal, incurable, brain-wasting illness from consuming beef products contaminated with the mad cow pathogen.
"The fact the Texas cow showed up fairly clearly implied the existence of other undetected cases," Dr. Paul Brown, former medical director of the National Institutes of Health's Laboratory for Central Nervous System Studies and an expert on mad cow-like diseases, told United Press International. "The question was, 'How many?' and we still can't answer that."
Brown, who is preparing a scientific paper based on the latest two mad cow cases to estimate the maximum number of infected cows that occurred in the United States, said he has "absolutely no confidence in USDA tests before one year ago" because of the agency's reluctance to retest the Texas cow that initially tested positive.
USDA officials finally retested the cow and confirmed it was infected seven months later, but only at the insistence of the agency's inspector general.
"Everything they did on the Texas cow makes everything USDA did before 2005 suspect," Brown said. ...snip...end
http://www.upi.com/
CDC - Bovine Spongiform Encephalopathy and Variant Creutzfeldt ... Dr. Paul Brown is Senior Research Scientist in the Laboratory of Central Nervous System ... Address for correspondence: Paul Brown, Building 36, Room 4A-05, ...
http://www.cdc.gov/ncidod/eid/vol7no1/brown.htm
PAUL BROWN COMMENT TO ME ON THIS ISSUE
Tuesday, September 12, 2006 11:10 AM
"Actually, Terry, I have been critical of the USDA handling of the mad cow issue for some years, and with Linda Detwiler and others sent lengthy detailed critiques and recommendations to both the USDA and the Canadian Food Agency." ........
Archive Number 20071105.3602 Published Date 05-NOV-2007 Subject PRO/AH/EDR> Prion disease update 2007 (07)
PRION DISEASE UPDATE 2007 (07)
snip...
[In submitting these data, Terry S. Singeltary Sr. draws attention to the steady increase in the "type unknown" category, which, according to their definition, comprises cases in which vCJD could be excluded. The total of 26 cases for the current year (2007) is disturbing, possibly symptomatic of the circulation of novel agents. Characterization of these agents should be given a high priority. - Mod.CP]
http://www.promedmail.org/pls/askus/f?p=2400:1001:6833194127530602005::NO::F2400_P1001_BACK_PAGE,F2400_P1001_PUB_MAIL_ID:1010,39963
There is a growing number of human CJD cases, and they were presented last week in San Francisco by Luigi Gambatti(?) from his CJD surveillance collection.
He estimates that it may be up to 14 or 15 persons which display selectively SPRPSC and practically no detected RPRPSC proteins.
http://www.fda.gov/ohrms/dockets/ac/06/transcripts/1006-4240t1.htm
http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4240t1.pdf
JOURNAL OF NEUROLOGY
MARCH 26, 2003
RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob
disease in the United States
Email Terry S. Singeltary:
flounder@wt.net
I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to
comment on the CDC's attempts to monitor the occurrence of emerging
forms of CJD. Asante, Collinge et al [1] have reported that BSE
transmission to the 129-methionine genotype can lead to an alternate
phenotype that is indistinguishable from type 2 PrPSc, the commonest
sporadic CJD. However, CJD and all human TSEs are not reportable
nationally. CJD and all human TSEs must be made reportable in every
state and internationally. I hope that the CDC does not continue to
expect us to still believe that the 85%+ of all CJD cases which are
sporadic are all spontaneous, without route/source. We have many TSEs in
the USA in both animal and man. CWD in deer/elk is spreading rapidly and
CWD does transmit to mink, ferret, cattle, and squirrel monkey by
intracerebral inoculation. With the known incubation periods in other
TSEs, oral transmission studies of CWD may take much longer. Every
victim/family of CJD/TSEs should be asked about route and source of this
agent. To prolong this will only spread the agent and needlessly expose
others. In light of the findings of Asante and Collinge et al, there
should be drastic measures to safeguard the medical and surgical arena
from sporadic CJDs and all human TSEs. I only ponder how many sporadic
CJDs in the USA are type 2 PrPSc?
http://www.neurology.org/cgi/eletters/60/2/176#535
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Singeltary, Sr et al. JAMA.2001; 285: 733-734.
http://jama.ama-assn.org/http://www.neurology.org/cgi/eletters/60/2/176#535
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States
http://cjdusa.blogspot.com/
Creutzfeldt Jakob Disease
http://creutzfeldt-jakob-disease.blogspot.com/
CJD QUESTIONNAIRE
http://cjdquestionnaire.blogspot.com/
SEAC 99th meeting on Friday 14th December 2007
http://seac992007.blogspot.com/
16 January 2008 - The final minutes of the 98th SEAC meeting have been published.
PUBLIC QUESTION AND ANSWER SESSION 2© SEAC 2007SEAC considered a question about possible links between CJD cases and animal TSEs in the United States of America (USA).
http://www.seac.gov.uk/summaries/seac99_summary.pdf
vCJD case study highlights blood transfusion risk
http://vcjdblood.blogspot.com/
vCJD transfusion-associated Fourth Case UK
http://vcjdtransfusion.blogspot.com/
risk factors for sporadic CJD
http://creutzfeldt-jakob-disease.blogspot.com/2008/01/risk-factors-for-sporadic-creutzfeldt.html
Creutzfeldt-Jakob Disease, Prion Protein Gene Codon 129VV, and a Novel PrPSc Type in a Young British Woman
http://creutzfeldt-jakob-disease.blogspot.com/2008/01/creutzfeldt-jakob-disease-prion-protein.html
BSE (Mad Cow) Update: Do Reports of sCJD Clusters Matter?
snip... see full text ;
http://cjdtexas.blogspot.com/
THE PATHOLOGICAL PROTEIN Hardcover, 304 pages plus photos and illustrations. ISBN 0-387-95508-9 June 2003 BY Philip Yam
CHAPTER 14 LAYING ODDS
Answering critics like Terry Singeltary, who feels that the U.S. under-counts CJD, Schonberger conceded that the current surveillance system has errors but stated that most of the errors will be confined to the older population.
http://www.thepathologicalprotein.com/
doi:10.1016/S1473-3099(03)00715-1Copyright © 2003 Published by Elsevier Ltd.
Newsdesk
Tracking spongiform encephalopathies in North America
Xavier Bosch
Available online 29 July 2003. Volume 3, Issue 8, August 2003, Page 463
"My name is Terry S Singeltary Sr, and I live in Bacliff, Texas. I lost my mom to hvCJD (Heidenhain variant CJD) and have been searching for answers ever since. What I have found is that we have not been told the truth. CWD in deer and elk is a small portion of a much bigger problem." ...
http://www.thelancet.com/journals/laninf/article/PIIS1473309903007151/fulltext
http://download.thelancet.com/pdfs/journals/1473-3099/PIIS1473309903007151.pdf
ANIMAL HEALTH REPORT 2006 (BSE h-BASE EVENT IN ALABAMA, Scrapie, and CWD)
http://animalhealthreport2006.blogspot.com/
P03.141
Aspects of the Cerebellar Neuropathology in Nor98
Gavier-Widén, D1; Benestad, SL2; Ottander, L1; Westergren, E11National Veterinary Insitute, Sweden; 2National Veterinary Institute, Norway
Nor98 is a prion disease of old sheep and goats. This atypical form of scrapie was first described in Norway in 1998. Several features of Nor98 were shown to be different from classical scrapie including the distribution of disease associated prion protein (PrPd) accumulation in the brain. The cerebellum is generally the most affected brain area in Nor98. The study here presented aimed at adding information on the neuropathology in the cerebellum of Nor98 naturally affected sheep of various genotypes in Sweden and Norway. A panel of histochemical and immunohistochemical (IHC) stainings such as IHC for PrPd, synaptophysin, glial fibrillary acidic protein, amyloid, and cell markers for phagocytic cells were conducted. The type of histological lesions and tissue reactions were evaluated. The types of PrPd deposition were characterized. The cerebellar cortex was regularly affected, even though there was avariation in the severity of the lesions from case to case. Neuropil vacuolation was more marked in the molecular layer, but affected also the granular cell layer. There was a loss of granule cells. Punctate deposition of PrPd was characteristic. It was morphologically and in distribution identical with that of synaptophys in, suggesting that PrPd accumulates in the synaptic structures. PrPd was also observed in the granule cell layer and in the white matter. The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.
http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf
NOR-98 ATYPICAL SCRAPIE USA UPDATE AS AT OCT 2007
typical scrapie transmits to primates by there NON-FORCED ORAL CONSUMPTION ;
76/10.12/4.6
http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=6997404&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus
full text ;
http://nor-98.blogspot.com/
http://scrapie-usa.blogspot.com/
CREUTZFELDT JAKOB DISEASE MAD COW BASE UPDATE USA
http://cjdmadcowbaseoct2007.blogspot.com/
Transmissible Mink Encephalopathy TME
http://transmissible-mink-encephalopathy.blogspot.com/
CHRONIC WASTING DISEASE
http://chronic-wasting-disease.blogspot.com/
ONE other question from Confucius,
IF we are to believe as some has so persistently tried to claim without any proof, if we are to believe that these TSE just happen spontaneous, then why have there been NO other cases of TME in the USA ???
WHERE are these cases of spontaneous BSE/BASE in the USA ???
WHAT about the FSE cases, none in the USA either, no feline spongiform encephalopathy in USA documented to date ???
IF the spontaneous TSE truely exist, would we have not seen these species with TSE here in the USA ???
WHAT about Europe, if the spontanous TSE truely happened, would CWD, TME, not happen in the EU countries as well ???
OR is it just the USDA certified BASE mad cows that are spontaneous ;-) $$$
Saturday, December 01, 2007
Phenotypic Similarity of Transmissible Mink Encephalopathy in Cattle and L-type Bovine Spongiform Encephalopathy in a Mouse Model
http://transmissible-mink-encephalopathy.blogspot.com/
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518
Tuesday, December 4, 2007
SCRAPIE PROGRAM FY REPORT 2007
SCRAPIE PROGRAM FY REPORT 2007
Prepared by National Center for Animal Health Programs Ruminant Health Programs Team November 15, 2007
snip...
Infected and Source Flocks
During FY 2007, there were a total of 76 new infected or source flocks identified. Of those new flocks identified, 30 were infected flocks and 46 were source flocks (Figure 2). As of September 30, 2007, there were 38 scrapie infected and source flocks with open statuses (Figure 3). ...
snip...
In FY 2007, 331 scrapie cases have been confirmed and reported by the National Veterinary Services Laboratories (NVSL), including 59* Regulatory Scrapie Slaughter Surveillance (RSSS) cases (Figure 5 and Slide 16). In FY 2007, two field cases, one validation case, and two RSSS cases were consistent with Nor-98 scrapie. The Nor98-like cases originated from flocks in California, Minnesota, Colorado, Wyoming and Indiana respectively. Nineteen cases of scrapie in goats have been reported since 1990 (Figure 6). The last goat case was reported in September 2007.
snip...
see full report here ;
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/yearly_report.pps
P03.141
Aspects of the Cerebellar Neuropathology in Nor98
Gavier-Widén, D1; Benestad, SL2; Ottander, L1; Westergren, E11National Veterinary Insitute, Sweden; 2National Veterinary Institute, Norway
Nor98 is a prion disease of old sheep and goats. This atypical form of scrapie was firstdescribed in Norway in 1998. Several features of Nor98 were shown to be differentfrom classical scrapie including the distribution of disease associated prion protein(PrPd) accumulation in the brain. The cerebellum is generally the most affected brainarea in Nor98. The study here presented aimed at adding information on theneuropathology in the cerebellum of Nor98 naturally affected sheep of variousgenotypes in Sweden and Norway. A panel of histochemical and immunohistochemical(IHC) stainings such as IHC for PrPd, synaptophysin, glial fibrillary acidic protein,amyloid, and cell markers for phagocytic cells were conducted. The type of histologicallesions and tissue reactions were evaluated. The types of PrPd deposition werecharacterized. The cerebellar cortex was regularly affected, even though there was avariation in the severity of the lesions from case to case. Neuropil vacuolation wasmore marked in the molecular layer, but affected also the granular cell layer. There wasa loss of granule cells. Punctate deposition of PrPd was characteristic. It wasmorphologically and in distribution identical with that of synaptophysin, suggestingthat PrPd accumulates in the synaptic structures. PrPd was also observed in thegranule cell layer and in the white matter. The pathology features of Nor98 in thecerebellum of the affected sheep showed similarities with those of sporadicCreutzfeldt-Jakob disease in humans.
http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf
NOR-98 ATYPICAL SCRAPIE USA UPDATE AS AT OCT 2007
typical scrapie transmits to primates by there NON-FORCED ORAL CONSUMPTION ;
76/10.12/4.6
http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=6997404&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus
full text ;
http://nor-98.blogspot.com/
http://scrapie-usa.blogspot.com/
CREUTZFELDT JAKOB DISEASE MAD COW BASE UPDATE USA
http://cjdmadcowbaseoct2007.blogspot.com/
Transmissible Mink Encephalopathy TME
http://transmissible-mink-encephalopathy.blogspot.com/
CHRONIC WASTING DISEASE
http://chronic-wasting-disease.blogspot.com/
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease inthe United States
http://cjdusa.blogspot.com/
i am reminded of a few things deep throat (high ranking official at usda)told me years ago;
==========================================
The most frightening thing I have read all day is the report of Gambetti's finding of a new strain of sporadic cjd in young people.........Dear God,
https://www.blogger.com/comment.g?blogID=7842737484277562285&postID=5759550357128128100
CJD QUESTIONNAIRE
http://cjdquestionnaire.blogspot.com/
TSS
Prepared by National Center for Animal Health Programs Ruminant Health Programs Team November 15, 2007
snip...
Infected and Source Flocks
During FY 2007, there were a total of 76 new infected or source flocks identified. Of those new flocks identified, 30 were infected flocks and 46 were source flocks (Figure 2). As of September 30, 2007, there were 38 scrapie infected and source flocks with open statuses (Figure 3). ...
snip...
In FY 2007, 331 scrapie cases have been confirmed and reported by the National Veterinary Services Laboratories (NVSL), including 59* Regulatory Scrapie Slaughter Surveillance (RSSS) cases (Figure 5 and Slide 16). In FY 2007, two field cases, one validation case, and two RSSS cases were consistent with Nor-98 scrapie. The Nor98-like cases originated from flocks in California, Minnesota, Colorado, Wyoming and Indiana respectively. Nineteen cases of scrapie in goats have been reported since 1990 (Figure 6). The last goat case was reported in September 2007.
snip...
see full report here ;
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/yearly_report.pps
P03.141
Aspects of the Cerebellar Neuropathology in Nor98
Gavier-Widén, D1; Benestad, SL2; Ottander, L1; Westergren, E11National Veterinary Insitute, Sweden; 2National Veterinary Institute, Norway
Nor98 is a prion disease of old sheep and goats. This atypical form of scrapie was firstdescribed in Norway in 1998. Several features of Nor98 were shown to be differentfrom classical scrapie including the distribution of disease associated prion protein(PrPd) accumulation in the brain. The cerebellum is generally the most affected brainarea in Nor98. The study here presented aimed at adding information on theneuropathology in the cerebellum of Nor98 naturally affected sheep of variousgenotypes in Sweden and Norway. A panel of histochemical and immunohistochemical(IHC) stainings such as IHC for PrPd, synaptophysin, glial fibrillary acidic protein,amyloid, and cell markers for phagocytic cells were conducted. The type of histologicallesions and tissue reactions were evaluated. The types of PrPd deposition werecharacterized. The cerebellar cortex was regularly affected, even though there was avariation in the severity of the lesions from case to case. Neuropil vacuolation wasmore marked in the molecular layer, but affected also the granular cell layer. There wasa loss of granule cells. Punctate deposition of PrPd was characteristic. It wasmorphologically and in distribution identical with that of synaptophysin, suggestingthat PrPd accumulates in the synaptic structures. PrPd was also observed in thegranule cell layer and in the white matter. The pathology features of Nor98 in thecerebellum of the affected sheep showed similarities with those of sporadicCreutzfeldt-Jakob disease in humans.
http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf
NOR-98 ATYPICAL SCRAPIE USA UPDATE AS AT OCT 2007
typical scrapie transmits to primates by there NON-FORCED ORAL CONSUMPTION ;
76/10.12/4.6
http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=6997404&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus
full text ;
http://nor-98.blogspot.com/
http://scrapie-usa.blogspot.com/
CREUTZFELDT JAKOB DISEASE MAD COW BASE UPDATE USA
http://cjdmadcowbaseoct2007.blogspot.com/
Transmissible Mink Encephalopathy TME
http://transmissible-mink-encephalopathy.blogspot.com/
CHRONIC WASTING DISEASE
http://chronic-wasting-disease.blogspot.com/
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease inthe United States
http://cjdusa.blogspot.com/
i am reminded of a few things deep throat (high ranking official at usda)told me years ago;
==========================================
The most frightening thing I have read all day is the report of Gambetti's finding of a new strain of sporadic cjd in young people.........Dear God,
https://www.blogger.com/comment.g?blogID=7842737484277562285&postID=5759550357128128100
CJD QUESTIONNAIRE
http://cjdquestionnaire.blogspot.com/
TSS
Thursday, November 22, 2007
UPDATE ATYPICAL SCRAPIE NOR-98 RESEARCH ARTICLES
Research article
Experimental transmission of atypical scrapie to sheep
Marion M Simmons1 , Timm Konold1 , Hugh A Simmons3 , Yvonne I Spencer1 , Richard Lockey1 , John Spiropoulos1 , Sharon Everitt2 and Derek Clifford3
1Department of Pathology, Veterinary Laboratories Agency – Weybridge, Woodham Lane, New Haw, Addlestone, Surrey KT15 3NB, UK2Department of Molecular Pathogenesis and Genetics, Veterinary Laboratories Agency – Weybridge, Woodham Lane, New Haw, Addlestone, Surrey KT15 3NB, UK3Animal Services Unit, Veterinary Laboratories Agency – Weybridge, Woodham Lane, New Haw, Addlestone, Surrey KT15 3NB, UK
author email corresponding author email
BMC Veterinary Research 2007, 3:20doi:10.1186/1746-6148-3-20
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1746-6148/3/20
Received: 26 March 2007 Accepted: 28 August 2007 Published: 28 August 2007
© 2007 Crown copyright; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
AbstractBackgroundActive surveillance for transmissible spongiform encephalopathies in small ruminants has been an EU regulatory requirement since 2002. A number of European countries have subsequently reported cases of atypical scrapie, similar to previously published cases from Norway, which have pathological and molecular features distinct from classical scrapie. Most cases have occurred singly in flocks, associated with genotypes considered to be more resistant to classical disease. Experimental transmissibility of such isolates has been reported in certain ovinised transgenic mice, but has not previously been reported in the natural host. Information on the transmissibility of this agent is vital to ensuring that disease control measures are effective and proportionate.
ResultsThis report presents the successful experimental transmission, in 378 days, of atypical scrapie to a recipient sheep of homologous genotype with preservation of the pathological and molecular characteristics of the donor. This isolate also transmitted to ovinised transgenic mice (Tg338) with a murine phenotype indistinguishable from that of Nor 98.
ConclusionThis result strengthens the opinion that these cases result from a distinct strain of scrapie agent, which is potentially transmissible in the natural host under field conditions.
Background
snip...
DiscussionTo our knowledge this is the first report of the successful experimental transmission of atypical scrapie within the natural host. The retention of the molecular and pathological characteristics of the scrapie agent following this experimental transmission supports the hypothesis that disease in the donor animal was caused by a stable strain of the TSE agent which has phenotypic characteristics distinct from those associated with classical scrapie. Although clinical signs were not recorded from the donor animal because it presented dead (fallen stock), the signs seen in the challenged animal were consistent with those reported for the small number of passive surveillance cases so far identified in the UK [14,15] and elsewhere [6,16], which were characterised by gait abnormalities, abnormal behaviour and a relative lack of pruritic signs.
The transmission characteristics of atypical scrapie from different countries in Tg338 mice [12] and emerging data from similar transmissions of the isolate in this report indicate that at least one strain of atypical scrapie compatible with/indistinguishable from Nor98 is widespread across Europe, despite its relatively recent identification.
Although it has now been demonstrated to be experimentally transmissible within and between species via the intracerebral route, there is little epidemiological evidence for ease of transmission of this strain under field conditions, where scrapie is most likely transmitted via the oral route. This raises the question of how it came to be so geographically widespread. One hypothesis is that this represents a spontaneous genetic disease in sheep similar to the familial forms of TSE in man (e.g. GSS, familial CJD and FFI etc.), in which the resultant disease can subsequently be transmitted experimentally [17,18].
Horizontal transmission of classical scrapie has been shown to occur in adult sheep exposed to an affected flock [19] and even in animals which have had contact only with a contaminated environment (GI Dexter and SJ Bellworthy, personal communication). The environmental persistence of the classical scrapie agent is also supported by epidemiological evidence from Icelandic repopulation studies [20,21]. However, the low molecular mass (<14 kD) band of PrPSc seen in Western blots of atypical isolates is associated with a reduction in PK resistance of this disease-associated protein. It is possible that this relative protease susceptibility may make the agent less robust in field conditions and thereby reduce the extent to which it is transmissible by natural routes, and so limit the number of cases. It could be argued that this in turn supports the hypothesis that the natural disease may arise spontaneously. However, although genetic studies have indicated a PrP genotype host range for atypical scrapie which, for the majority of cases, is almost fully distinct from that of the classical forms of disease, they have not identified a single genetic feature (such as the point mutations in some human forms [22]) which might account for this.
This relative PrPSc fragility [23] compared to the PrPSc in classical scrapie, may also account for the total absence of intracellular PrPSc immunolabelling. The different PK cleavage sites in PrP associated with different strains of TSE infecting small ruminants can be used to differentiate them, both in blots and by immunohistochemistry. Intracellular immunostaining is significantly reduced in sheep infected with BSE compared to classical scrapie, when the appropriate monoclonal antibodies are applied, and it has been speculated that this demonstrates a partial digestion of the PrPSc molecule by the endogenous proteases within the cells [24]. If the PrPSc is more protease sensitive, then this loss of intracellular immunolabelling even with an antibody to the core of the protein (such as MAb 2G11) might indicate that cells can more effectively catabolise this abnormal form of the protein than more 'classical' forms, and therefore succumb to clinical disease much later, if at all. This may also account for the apparent absence of disease-related PrPSc in lymphoid tissues. It is interesting to note that in familial CJD (E200K mutation) also, PrP labelling was seen as a uniformly fine deposit throughout all cortical layers [25].
This study confirms that 'atypical scrapie' is transmissible within the natural host species, via the intracerebral route, without alteration of the pathological and molecular characteristics. This is the first report from a larger study which will explore more widely the effect of the PrP gene on the experimental susceptibility and resultant phenotype following intracerebral or oral challenge with this type of scrapie isolate.
ConclusionAt present the significance of this result, in terms of the transmissibility or pathogenicity under 'field conditions' of this agent strain in any species remains speculative, but it supports the need for appropriate control measures protecting both the animal and the human food chain to encompass atypical scrapie cases specifically.
snip...END...TSS
http://www.biomedcentral.com/1746-6148/3/20
Tissue distribution. For atypical scrapie, what is PrPres andinfectivity distribution within sheep of different genotypes,particularly with respect to SRM removal? For classicalscrapie and experimental BSE in sheep, tissue distribution ofinfectivity is widespread. Thus, even with SRM controls inplace, an infected sheep poses around 1000 times the risk tohuman health than does an infected cow22. Does thedistribution depend on whether infection is by the oral or21 Gubbins S. Prevalence of BSE in sheep: interpreting the results ofretrospective andprospective testing of sheep TSE cases. SEAC 84 open meeting22 paper presented to Food Standards Agency board on 9 December 2004.http://www.foodstandards.gov.uk/multimedia/pdfs/fsa041204.pdfAlso see paper SEAC/84/2 Annex 2: McLean, A.Page 13© SEAC 27 February 2006intracerebral route? Are some VRQ sheep carriers with noneurological symptoms?
SEAC SHEEP SUBGROUPPOSITION STATEMENT
http://www.seac.gov.uk/pdf/positionstatement-sheep-subgroup.pdf
Published online before print October 20, 2005Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0502296102Medical Sciences
A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes
( sheep prion transgenic mice )Annick Le Dur *, Vincent Béringue *, Olivier Andréoletti , Fabienne Reine *,Thanh Lan Laï *, Thierry Baron , Bjørn Bratberg ¶, Jean-Luc Vilotte ,Pierre Sarradin **, Sylvie L. Benestad ¶, and Hubert Laude **Virologie Immunologie Moléculaires and Génétique Biochimique etCytogénétique, Institut National de la Recherche Agronomique, 78350Jouy-en-Josas, France; Unité Mixte de Recherche, Institut National de laRecherche Agronomique-Ecole Nationale Vétérinaire de Toulouse, InteractionsHôte Agent Pathogène, 31066 Toulouse, France; Agence Française de SécuritéSanitaire des Aliments, Unité Agents Transmissibles Non Conventionnels,69364 Lyon, France; **Pathologie Infectieuse et Immunologie, InstitutNational de la Recherche Agronomique, 37380 Nouzilly, France; and¶Department of Pathology, National Veterinary Institute, 0033 Oslo, Norway
Edited by Stanley B. Prusiner, University of California, San Francisco, CA,and approved September 12, 2005 (received for review March 21, 2005)
Scrapie in small ruminants belongs to transmissible spongiform encephalopathies (TSEs), or prion diseases, a family of fatal neurodegenerative disorders that affect humans and animals and can transmit within and between species by ingestion or inoculation. Conversion of the host-encoded prion protein (PrP), normal cellular PrP (PrPc), into amisfolded form, abnormal PrP (PrPSc), plays a key role in TSE transmission and pathogenesis. The intensified surveillance of scrapie in the European Union, together with the improvement of PrPSc detection techniques, has led to the discovery of a growing number of so-called atypical scrapie cases. These include clinical Nor98 cases first identified in Norwegian sheep on the basis of unusual pathological and PrPSc molecular features and "cases" that produced discordant responses in the rapid tests currently applied tothe large-scale random screening of slaughtered or fallen animals. Worryingly, a substantial proportion of such cases involved sheep with PrP genotypes known until now to confer natural resistance to conventional scrapie. Here we report that both Nor98 and discordant cases, including three sheep homozygous for the resistant PrPARR allele (A136R154R171), efficiently transmitted the disease to transgenic mice expressing ovine PrP, and that they shared unique biological and biochemical features upon propagation in mice. These observations support the view that a truly infectious TSE agent, unrecognized until recently, infects sheep and goatflocks andmay have important implications in terms of scrapie control andpublic health.
--------------------------------------------------------------------------------
Author contributions: H.L. designed research; A.L.D., V.B., O.A., F.R.,T.L.L., J.-L.V., and H.L. performed research; T.B., B.B., P.S., and S.L.B.contributed new reagents/analytic tools; V.B., O.A., and H.L. analyzed data;and H.L. wrote the paper.A.L.D. and V.B. contributed equally to this work.To whom correspondence should be addressed.Hubert Laude,
E-mail: laude@jouy.inra.fr
www.pnas.org/cgi/doi/10.1073/pnas.0502296102
http://www.pnas.org/cgi/content/abstract/0502296102v1
OF COURSE, the USDA et al once was concerned for human health from typical scrapie, and rightly so, typical scrapie transmits to primates by there NON-FORCED ORAL CONSUMPTION ;
76/10.12/4.6
http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
http://www.ncbi.nlm.nih.gov/entrez/query.fcgicmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
ALSO, The agent responsible for French iatrogenic growth hormone-linked CJD taken as a control is very different from vCJD but is similar to that found in one case of sporadic CJD and one sheep scrapie isolate.
http://www.pnas.org/cgi/content/full/041490898v1
TAFS
INTERNATIONAL FORUM FOR TRANSMISSIBLE ANIMAL DISEASES AND FOOD SAFETY
a non-profit Swiss Foundation(May 16, 2007)TAFS1
Position Paper on Atypical scrapie and Atypical BSE
Although most atypical cases occur singly in flocks, there are some instances where two affected sheep have been identified in flocks. This may indicate that natural transmission may occur, or that the sheep were infected from a common alternative source(22, 29). Possible indications of an association with the feeding of vitamins and mineral feed supplements were detected in Norway, but remain to be proven(22).
snip...
Atypical BSE may arise spontaneously in a small proportion of cattle. The existence of sporadic CJD in humans has led to postulation that disease could arise spontaneously in any animal, but this is still not proven to happen. Despitethe small numbers of atypical BSE detected so far, in some countries the numbers are too great to suggest that they all arise spontaneously, if it were assumed that such a phenomenon occurred at the same frequency as sporadic CJD in humans.
http://www.tseandfoodsafety.org/position_papers/TAFS_POSITION_PAPER_ON_ATYPICAL_SCRAPIE_AND_%20ATYPICAL_BSE_070516.pdf
TSS
Experimental transmission of atypical scrapie to sheep
Marion M Simmons1 , Timm Konold1 , Hugh A Simmons3 , Yvonne I Spencer1 , Richard Lockey1 , John Spiropoulos1 , Sharon Everitt2 and Derek Clifford3
1Department of Pathology, Veterinary Laboratories Agency – Weybridge, Woodham Lane, New Haw, Addlestone, Surrey KT15 3NB, UK2Department of Molecular Pathogenesis and Genetics, Veterinary Laboratories Agency – Weybridge, Woodham Lane, New Haw, Addlestone, Surrey KT15 3NB, UK3Animal Services Unit, Veterinary Laboratories Agency – Weybridge, Woodham Lane, New Haw, Addlestone, Surrey KT15 3NB, UK
author email corresponding author email
BMC Veterinary Research 2007, 3:20doi:10.1186/1746-6148-3-20
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1746-6148/3/20
Received: 26 March 2007 Accepted: 28 August 2007 Published: 28 August 2007
© 2007 Crown copyright; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
AbstractBackgroundActive surveillance for transmissible spongiform encephalopathies in small ruminants has been an EU regulatory requirement since 2002. A number of European countries have subsequently reported cases of atypical scrapie, similar to previously published cases from Norway, which have pathological and molecular features distinct from classical scrapie. Most cases have occurred singly in flocks, associated with genotypes considered to be more resistant to classical disease. Experimental transmissibility of such isolates has been reported in certain ovinised transgenic mice, but has not previously been reported in the natural host. Information on the transmissibility of this agent is vital to ensuring that disease control measures are effective and proportionate.
ResultsThis report presents the successful experimental transmission, in 378 days, of atypical scrapie to a recipient sheep of homologous genotype with preservation of the pathological and molecular characteristics of the donor. This isolate also transmitted to ovinised transgenic mice (Tg338) with a murine phenotype indistinguishable from that of Nor 98.
ConclusionThis result strengthens the opinion that these cases result from a distinct strain of scrapie agent, which is potentially transmissible in the natural host under field conditions.
Background
snip...
DiscussionTo our knowledge this is the first report of the successful experimental transmission of atypical scrapie within the natural host. The retention of the molecular and pathological characteristics of the scrapie agent following this experimental transmission supports the hypothesis that disease in the donor animal was caused by a stable strain of the TSE agent which has phenotypic characteristics distinct from those associated with classical scrapie. Although clinical signs were not recorded from the donor animal because it presented dead (fallen stock), the signs seen in the challenged animal were consistent with those reported for the small number of passive surveillance cases so far identified in the UK [14,15] and elsewhere [6,16], which were characterised by gait abnormalities, abnormal behaviour and a relative lack of pruritic signs.
The transmission characteristics of atypical scrapie from different countries in Tg338 mice [12] and emerging data from similar transmissions of the isolate in this report indicate that at least one strain of atypical scrapie compatible with/indistinguishable from Nor98 is widespread across Europe, despite its relatively recent identification.
Although it has now been demonstrated to be experimentally transmissible within and between species via the intracerebral route, there is little epidemiological evidence for ease of transmission of this strain under field conditions, where scrapie is most likely transmitted via the oral route. This raises the question of how it came to be so geographically widespread. One hypothesis is that this represents a spontaneous genetic disease in sheep similar to the familial forms of TSE in man (e.g. GSS, familial CJD and FFI etc.), in which the resultant disease can subsequently be transmitted experimentally [17,18].
Horizontal transmission of classical scrapie has been shown to occur in adult sheep exposed to an affected flock [19] and even in animals which have had contact only with a contaminated environment (GI Dexter and SJ Bellworthy, personal communication). The environmental persistence of the classical scrapie agent is also supported by epidemiological evidence from Icelandic repopulation studies [20,21]. However, the low molecular mass (<14 kD) band of PrPSc seen in Western blots of atypical isolates is associated with a reduction in PK resistance of this disease-associated protein. It is possible that this relative protease susceptibility may make the agent less robust in field conditions and thereby reduce the extent to which it is transmissible by natural routes, and so limit the number of cases. It could be argued that this in turn supports the hypothesis that the natural disease may arise spontaneously. However, although genetic studies have indicated a PrP genotype host range for atypical scrapie which, for the majority of cases, is almost fully distinct from that of the classical forms of disease, they have not identified a single genetic feature (such as the point mutations in some human forms [22]) which might account for this.
This relative PrPSc fragility [23] compared to the PrPSc in classical scrapie, may also account for the total absence of intracellular PrPSc immunolabelling. The different PK cleavage sites in PrP associated with different strains of TSE infecting small ruminants can be used to differentiate them, both in blots and by immunohistochemistry. Intracellular immunostaining is significantly reduced in sheep infected with BSE compared to classical scrapie, when the appropriate monoclonal antibodies are applied, and it has been speculated that this demonstrates a partial digestion of the PrPSc molecule by the endogenous proteases within the cells [24]. If the PrPSc is more protease sensitive, then this loss of intracellular immunolabelling even with an antibody to the core of the protein (such as MAb 2G11) might indicate that cells can more effectively catabolise this abnormal form of the protein than more 'classical' forms, and therefore succumb to clinical disease much later, if at all. This may also account for the apparent absence of disease-related PrPSc in lymphoid tissues. It is interesting to note that in familial CJD (E200K mutation) also, PrP labelling was seen as a uniformly fine deposit throughout all cortical layers [25].
This study confirms that 'atypical scrapie' is transmissible within the natural host species, via the intracerebral route, without alteration of the pathological and molecular characteristics. This is the first report from a larger study which will explore more widely the effect of the PrP gene on the experimental susceptibility and resultant phenotype following intracerebral or oral challenge with this type of scrapie isolate.
ConclusionAt present the significance of this result, in terms of the transmissibility or pathogenicity under 'field conditions' of this agent strain in any species remains speculative, but it supports the need for appropriate control measures protecting both the animal and the human food chain to encompass atypical scrapie cases specifically.
snip...END...TSS
http://www.biomedcentral.com/1746-6148/3/20
Tissue distribution. For atypical scrapie, what is PrPres andinfectivity distribution within sheep of different genotypes,particularly with respect to SRM removal? For classicalscrapie and experimental BSE in sheep, tissue distribution ofinfectivity is widespread. Thus, even with SRM controls inplace, an infected sheep poses around 1000 times the risk tohuman health than does an infected cow22. Does thedistribution depend on whether infection is by the oral or21 Gubbins S. Prevalence of BSE in sheep: interpreting the results ofretrospective andprospective testing of sheep TSE cases. SEAC 84 open meeting22 paper presented to Food Standards Agency board on 9 December 2004.http://www.foodstandards.gov.uk/multimedia/pdfs/fsa041204.pdfAlso see paper SEAC/84/2 Annex 2: McLean, A.Page 13© SEAC 27 February 2006intracerebral route? Are some VRQ sheep carriers with noneurological symptoms?
SEAC SHEEP SUBGROUPPOSITION STATEMENT
http://www.seac.gov.uk/pdf/positionstatement-sheep-subgroup.pdf
Published online before print October 20, 2005Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0502296102Medical Sciences
A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes
( sheep prion transgenic mice )Annick Le Dur *, Vincent Béringue *, Olivier Andréoletti , Fabienne Reine *,Thanh Lan Laï *, Thierry Baron , Bjørn Bratberg ¶, Jean-Luc Vilotte ,Pierre Sarradin **, Sylvie L. Benestad ¶, and Hubert Laude **Virologie Immunologie Moléculaires and Génétique Biochimique etCytogénétique, Institut National de la Recherche Agronomique, 78350Jouy-en-Josas, France; Unité Mixte de Recherche, Institut National de laRecherche Agronomique-Ecole Nationale Vétérinaire de Toulouse, InteractionsHôte Agent Pathogène, 31066 Toulouse, France; Agence Française de SécuritéSanitaire des Aliments, Unité Agents Transmissibles Non Conventionnels,69364 Lyon, France; **Pathologie Infectieuse et Immunologie, InstitutNational de la Recherche Agronomique, 37380 Nouzilly, France; and¶Department of Pathology, National Veterinary Institute, 0033 Oslo, Norway
Edited by Stanley B. Prusiner, University of California, San Francisco, CA,and approved September 12, 2005 (received for review March 21, 2005)
Scrapie in small ruminants belongs to transmissible spongiform encephalopathies (TSEs), or prion diseases, a family of fatal neurodegenerative disorders that affect humans and animals and can transmit within and between species by ingestion or inoculation. Conversion of the host-encoded prion protein (PrP), normal cellular PrP (PrPc), into amisfolded form, abnormal PrP (PrPSc), plays a key role in TSE transmission and pathogenesis. The intensified surveillance of scrapie in the European Union, together with the improvement of PrPSc detection techniques, has led to the discovery of a growing number of so-called atypical scrapie cases. These include clinical Nor98 cases first identified in Norwegian sheep on the basis of unusual pathological and PrPSc molecular features and "cases" that produced discordant responses in the rapid tests currently applied tothe large-scale random screening of slaughtered or fallen animals. Worryingly, a substantial proportion of such cases involved sheep with PrP genotypes known until now to confer natural resistance to conventional scrapie. Here we report that both Nor98 and discordant cases, including three sheep homozygous for the resistant PrPARR allele (A136R154R171), efficiently transmitted the disease to transgenic mice expressing ovine PrP, and that they shared unique biological and biochemical features upon propagation in mice. These observations support the view that a truly infectious TSE agent, unrecognized until recently, infects sheep and goatflocks andmay have important implications in terms of scrapie control andpublic health.
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Author contributions: H.L. designed research; A.L.D., V.B., O.A., F.R.,T.L.L., J.-L.V., and H.L. performed research; T.B., B.B., P.S., and S.L.B.contributed new reagents/analytic tools; V.B., O.A., and H.L. analyzed data;and H.L. wrote the paper.A.L.D. and V.B. contributed equally to this work.To whom correspondence should be addressed.Hubert Laude,
E-mail: laude@jouy.inra.fr
www.pnas.org/cgi/doi/10.1073/pnas.0502296102
http://www.pnas.org/cgi/content/abstract/0502296102v1
OF COURSE, the USDA et al once was concerned for human health from typical scrapie, and rightly so, typical scrapie transmits to primates by there NON-FORCED ORAL CONSUMPTION ;
76/10.12/4.6
http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
http://www.ncbi.nlm.nih.gov/entrez/query.fcgicmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
ALSO, The agent responsible for French iatrogenic growth hormone-linked CJD taken as a control is very different from vCJD but is similar to that found in one case of sporadic CJD and one sheep scrapie isolate.
http://www.pnas.org/cgi/content/full/041490898v1
TAFS
INTERNATIONAL FORUM FOR TRANSMISSIBLE ANIMAL DISEASES AND FOOD SAFETY
a non-profit Swiss Foundation(May 16, 2007)TAFS1
Position Paper on Atypical scrapie and Atypical BSE
Although most atypical cases occur singly in flocks, there are some instances where two affected sheep have been identified in flocks. This may indicate that natural transmission may occur, or that the sheep were infected from a common alternative source(22, 29). Possible indications of an association with the feeding of vitamins and mineral feed supplements were detected in Norway, but remain to be proven(22).
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Atypical BSE may arise spontaneously in a small proportion of cattle. The existence of sporadic CJD in humans has led to postulation that disease could arise spontaneously in any animal, but this is still not proven to happen. Despitethe small numbers of atypical BSE detected so far, in some countries the numbers are too great to suggest that they all arise spontaneously, if it were assumed that such a phenomenon occurred at the same frequency as sporadic CJD in humans.
http://www.tseandfoodsafety.org/position_papers/TAFS_POSITION_PAPER_ON_ATYPICAL_SCRAPIE_AND_%20ATYPICAL_BSE_070516.pdf
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