(American Journal of Pathology. 2009;175:2566-2573.) © 2009 American Society for Investigative Pathology DOI: 10.2353/ajpath.2009.090623
Similarities between Forms of Sheep Scrapie and Creutzfeldt-Jakob Disease Are Encoded by Distinct Prion Types
Wiebke M. Wemheuer*, Sylvie L. Benestad, Arne Wrede*, Ulf Schulze-Sturm*, Wilhelm E. Wemheuer, Uwe Hahmann*, Joanna Gawinecka, Ekkehard Schütz, Inga Zerr, Bertram Brenig, Bjørn Bratberg, Olivier Andréoletti¶ and Walter J. Schulz-Schaeffer* From the Prion and Dementia Research Unit,* Department of Neuropathology, and the National Transmissible Spongiform Encephalopathies Reference Center, Department of Neurology, University Medical Center Goettingen, Goettingen, Germany; the Department of Pathology, National Veterinary Institute, Oslo, Norway; the Institute of Veterinary Medicine, Faculty for Agricultural Sciences, University of Goettingen, Goettingen, Germany; and Animal Health,¶ Interactions Hôte Agent Pathogène, Ecole Nationale Vétérinaire de Toulouse, Toulouse, France
Transmissible spongiform encephalopathies such as scrapie in sheep, Creutzfeldt-Jakob disease (CJD) in humans, and bovine sporadic encephalopathy in cattle are characterized by the accumulation of a misfolded protein: the pathological prion protein. Ever since bovine sporadic encephalopathy was discovered as the likely cause of the new variant of CJD in humans, parallels between human and animal transmissible spongiform encephalopathies must be viewed under the aspect of a disease risk for humans. In our study we have compared prion characteristics of different forms of sheep scrapie with those of different phenotypes of sporadic CJD. The disease characteristics of sporadic CJD depend considerably on the prion type 1 or 2. Our results show that there are obvious parallels between sporadic CJD type 1 and the so-called atypical/Nor98 scrapie. These parelleles apply to the deposition form of pathological prion protein in the brain, detected by the paraffin-embedded-tissue blot and the prion aggregate stability with regard to denaturation by the chaotropic salt guanidine hydrochloride. The same applies to sporadic CJD type 2 and classical scrapie. The observed parallels between types of sporadic CJD and types of sheep scrapie demonstrate that distinct groups of prion disease exist in different species. This should be taken into consideration when discussing interspecies transmission.
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Different Scrapie Prion Types Show Similarities to Human Prion Types: PrPsc Deposition Pattern and Western Blot Results
After proteinase K-digestion and Western blot analysis, two different prion protein types were detectable in clinically distinct human Creutzfeldt-Jakob diseases.30 Depending on the PrPSc types 1 or 2 (Figure 1C) a difference in the form of PrPSc aggregates and the neuroanatomical distribution in the brain could be observed similar to differences identified in sheep scrapie. In patients with CJD that accumulate PrPSc type 1, reticular/synaptic were detected in cortical structures (Figure 3F), subcortical nuclei, and the cerebellar cortex (Figure 4D). By contrast, prion aggregates in patients accumulating PrPSc type 2 appeared to be complex as they displayed in particular perivacuolar, intra- and perineuronal, and/or plaque-like forms (Figures 3C and 5B). These differences concerning the deposition form of PrPSc aggregates were independent of the methionine/valine polymorphism at codon 129 of the PRNP. The topographical pattern of PrPSc distribution between these two prion types differed as follows: type 1 deposits were typically restricted to gray matter structures, while all type 2 patients showed deposits in the white matter. In patients with type 1 PrPSc the midbrain and brain stem structures were relatively spared, but in patients with type 2 PrPSc brain stem and midbrain were heavily affected. Although these prion type-related topographical differences are not completely identical to those in sheep scrapie, a comparable connection between prion type and deposition pattern is evident.
Aggregate Stability Regarding Denaturation
Similar to scrapie in sheep, the stability of PrPSc aggregates of human sporadic CJD against denaturation with GdnHCl showed two groups: denaturation-resistant and denaturation-sensitive PrPSc aggregates. This property correlated with the prion protein type according to Parchi et al8 and is independent from the physiologically occurring methionine/valine polymorphism at codon 129 of the PRNP. By membrane adsorption after GdnHCl denaturation and proteinase K-digestion, human PrPSc type 1 proved to be less stable than human PrPSc type 2. While human PrPSc type 2 was detectable up to GdnHCl concentrations between 3M and 4M, human PrPSc type 1 was stable up to 2M GdnHCl. Neither methionine nor valine at codon 129 in type 1 or type 2 seemed to alter the stability of the prion protein aggregates (Figure 5).
Summarizing the results, striking parallels between human PrPSc type 1 and atypical/Nor98 scrapie as well as human PrPSc type 2 and classical scrapie are observed with regard to PrPSc deposition and stability of the prion aggregates.
Discussion
In humans, different prion types are linked with clinically and neuropathologically distinct prion diseases.8 The present work emphasizes that the differences in deposition characteristics and stability with regard to denaturation between atypical/Nor98 and classical scrapie also account for different prion types. Moreover, the two scrapie types that have been characterized show a number of striking similarities with human PrPSc types in sporadic CJD. Hence, we propose that the existence of different PrPSc types might be a common denominator of prion diseases in humans and animals. Since these two prion types show an across-the-species comparability with similar biochemical and pathological characteristics, it is most likely that they exist due to a different conformational pattern of the disease-related prion protein.
Prion Types Depend on Conformation
The interpretation that the conformation of PrPSc accounts for prion types is supported by different proteinase K-cleavage sites of human prion types9 and the propagation of mutation-associated prion characteristics in human transgenic mice without PRNP-point mutation. 31 However, differences in protein stability as they have been found in this study, provide direct evidence for a conformational distinction between these molecules.32 Further support for the relation between type and conformation is also given by experiments focusing on the size of prion protein aggregates. Using virus removal filters, Kobayashi et al33 were able to show differences in the size of CJD type 1 and type 2 aggregates: PrPSc type 2 forms larger aggregates than PrPSc type 1, independent of whether the disease was sporadic, iatrogenic or acquired. This difference is clearly reflected by the morphology of the PrPSc depositions we have found in sheep scrapie and human CJD. Sporadic CJD type 1 and atypical/ Nor98 scrapie are characterized by fine (reticular) deposits, whereas CJD type 2 and classical scrapie display a complex aggregate pattern, regardless of the respective genotypes at the polymorphic positions of the PRNP that were investigated.
Prion Type Characteristics Versus Prion Strain Characteristics
Structural differences of the disease-associated protein have also been proposed as an explanation for the existence of strains. Partial digestion of the disease-associated protein with proteinase K as well as differences in antibody binding after the protein was partially denatured were used to identify structural characteristics in correlation with strain properties and different clinical TSE forms.23,34,35 It needs to be considered that the kinetics of proteinase K-digestion of PrPSc are markedly influenced by detergent effects in the buffer, demonstrating that the accessibility of the cleavage sites are variable.35 In contrast, differences in the stability against total unfolding of PrPSc seem to be a usable criterion to identify conformational differences or conformational motives. Whereas detergents affect the tertiary structure of a protein by interacting with hydrophilic and hydrophobic areas of protein molecules, chaotropic salts like GdnHCl destroy the hydrogen bonds in -helices and -sheets leading to an irregular coiled polypeptide chain.36 This is in line with the observation that detergents remove prion infectivity only partially, whereas chemicals that destroy secondary structures like chaotropic salts are highly effective. 37 However, detectable differences regarding the stability against denaturation with GdnHCl shown for various prion strains in hamsters seem to be very small compared with the ones that can be shown here for the prion types of human and ovine prion diseases. Strains could thus correspond to structural differences that are less marked than those defining types and are probably constant only under defined conditions. Influences of polymorphisms or interactions with other genetic factors like the promotor region, species-specific factors like the recently detected incorporation of polyanionic molecules into prions,38 glycosaminoglycans or other yet unknown factors of the original host may also lead to different strains in a new host within the prion types of the original species.5,39 The existence of prion types does not exclude the existence of strains. The same variations that account for strains might be the reason for differences in the clinical disease course of the natural host.
Two Different Prion Types also in BSE?
Parallel to human sporadic CJD and our results in sheep scrapie, there is increasing evidence that two prion types also exist in cattle BSE. Two presumably sporadic forms of BSE known as H-type BSE14 and bovine amyloidotic spongiform encephalopathy, also called L-type BSE,15 have been described in cattle in addition to typical/classical BSE.40 The small variation in the apparent molecular weight of the unglycosylated band of bovine amyloidotic spongiform encephalopathy is considered to be well within the range of classical BSE,41,42 which would leave H-type BSE with a considerably larger unglycosylated fragment in Western blot analysis than the second BSE type. Interestingly, bovine amyloidotic spongiform encephalopathy converts into classical BSE after serial passages in bovine-transgenic mice,43 although displaying clinically different diseases in cattle.44 From the latter experiment the authors concluded that different strains were responsible for different phenotypes. Obviously the different clinical diseases were generated by agents that belong to a single prion type. These results together with our observations emphasize the need to differentiate strictly between prion types and prion strains and demonstrate that even in cattle BSE, one prion type may contain different prion strains.
Prion Type Displays Parallels in the Pathophysiology of Disease between Species
Biochemical and morphological similarities have been used to draw parallels between forms of BSE and human prion diseases.15 Parallels between species can also be observed with regard to the route of prion infection: in classical BSE, variant CJD, and classical scrapie, all of which presumably belong to one class of prion type (type 2 in humans) according to the observations made above, the oral route of infection has been identified. These TSEs use the dorsal motor nucleus of the vagus nerve as an entry site into the brain.29,45,46 This observation suggests that distinct prion types in human and animal TSEs possibly have an impact on the pathogenesis of prion diseases.
Conclusion
As the prion protein is a highly conserved protein in terms of evolution, parallels between characteristics of prion types in TSEs of different species are of interest. In the present study, we report previously unknown similarities between sheep scrapie forms and human sporadic CJD types. We propose that the observed similarities between sheep scrapie and sporadic CJD in humans justify new interspecies groups of prion diseases in which prion types, not prion strains, are the major determinant for prion disease forms. While epidemiology implies that classical scrapie is not related to human TSEs,47 the atypical/Nor98 scrapie risk for human transmission has not yet been elucidated. Currently there is no compelling evidence that sCJD has a different origin than sporadic genesis. However, the finding of prion types with an across-the-species comparability might provide further understanding of the pathogenesis in prion diseases.
Acknowledgments We thank Tatjana Pfander, Nadine Rupprecht, and Kerstin Brekerbohm for their skillful technical assistance.
http://ajp.amjpathol.org/cgi/content/abstract/175/6/2566
hmmm, this is getting interesting now...
> Sporadic CJD type 1 and atypical/ Nor98 scrapie are characterized by fine (reticular) deposits,
see also ;
> All of the Heidenhain variants were of the methionine/ methionine type 1 molecular subtype.
http://cjdusa.blogspot.com/2009/09/co-existence-of-scrapie-prion-protein.html
Tuesday, July 29, 2008 Heidenhain Variant Creutzfeldt Jakob Disease Case Report
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Heidenhain Variant Creutzfeldt Jakob Disease autopsy case report 'MOM'
DIVISION OF NEUROPATHOLOGY University of Texas Medical Branch 114 McCullough Bldg. Galveston, Texas 77555-0785
FAX COVER SHEET
DATE: 4-23-98
TO: Mr. Terry Singeltary @ -------
FROM: Gerald Campbell
FAX: (409) 772-5315 PHONE: (409) 772-2881
Number of Pages (including cover sheet):
Message:
*CONFIDENTIALITY NOTICE*
This document accompanying this transmission contains confidential information belonging to the sender that is legally privileged. This information is intended only for the use of the individual or entry names above. If you are not the intended recipient, you are hereby notified that any disclosure, copying distribution, or the taking of any action in reliances on the contents of this telefaxed information is strictly prohibited. If you received this telefax in error, please notify us by telephone immediately to arrange for return of the original documents. -------------------------- Patient Account: 90000014-518 Med. Rec. No.: (0160)118511Q Patient Name: POULTER, BARBARA Age: 63 YRS DOB: 10/17/34 Sex: F Admitting Race: C
Attending Dr.: Date / Time Admitted : 12/14/97 1228 Copies to:
UTMB University of Texas Medical Branch Galveston, Texas 77555-0543 (409) 772-1238 Fax (409) 772-5683 Pathology Report
FINAL AUTOPSY DIAGNOSIS Autopsy' Office (409)772-2858
Autopsy NO.: AU-97-00435
AUTOPSY INFORMATION: Occupation: Unknown Birthplace: Unknown Residence: Crystal Beach Date/Time of Death: 12/14/97 13:30 Date/Time of Autopsy: 12/15/97 15:00 Pathologist/Resident: Pencil/Fernandez Service: Private Restriction: Brain only
FINAL AUTOPSY DIAGNOSIS
I. Brain: Creutzfeldt-Jakob disease, Heidenhain variant.
snip...see full text ;
http://creutzfeldt-jakob-disease.blogspot.com/2008/07/heidenhain-variant-creutzfeldt-jakob.html
P.5.21
Parallels between different forms of sheep scrapie and types of Creutzfeldt-Jakob disease (CJD)
Wiebke M. Wemheuer1, Sylvie L. Benestad2, Arne Wrede1, Wilhelm E. Wemheuer3, Tatjana Pfander1, Bjørn Bratberg2, Bertram Brenig3,Walter J. Schulz-Schaeffer1 1University Medical Center Goettingen, Germany; 2Institute of Veterinary Medicine Oslo, Norway; 3Institute of Veterinary Medicine Goettingen, Germany
Background: Scrapie in sheep and goats is often regarded as the archetype of prion diseases. In 1998, a new form of scrapie – atypical/Nor98 scrapie – was described that differed from classical scrapie in terms of epidemiology, Western blot profile, the distribution of pathological prion protein (PrPSc) in the body and its stability against proteinase K. In a similar way, distinct disease types exist in sporadic Creutzfeldt-Jakob disease (CJD). They differ with regard to their clinical outcome, Western blot profile and PrPSc deposition pattern in the central nervous system (CNS).
Objectives: The comparison of PrPSc deposits in sheep scrapie and human sporadic CJD.
Methods: Tissues of the CNS of sheep with classical scrapie, sheep with atypical/Nor98 scrapie and 20 patients with sporadic CJD were examined using the sensitive Paraffin Embedded Tissue (PET) blot method. The results were compared with those obtained by immunohistochemistry. With the objective of gaining information on the protein conformation, the PrPSc of classical and atypical/Nor98 sheep scrapie and sporadic CJD was tested for its stability against denaturation with guanidine hydrochloride (GdnHCl) using a Membrane Adsorption Assay.
Results: The PrPSc of atypical/Nor98 scrapie cases and of CJD prion type 1 patients exhibits a mainly reticular/synaptic deposition pattern in the brain and is relatively sensitive to denaturation with GdnHCl. In contrast classical scrapie cases and CJD prion type 2 patients have a more complex PrPSc deposition pattern in common that consists of larger PrPSc aggregates and the PrPSc itself is comparatively stable against denaturation.
Discussion: The similarity between CJD types and scrapie types indicates that at least two comparable forms of the misfolded prion protein exist beyond species barriers and can elicit prion diseases. It seems therefore reasonable to classify classical and atypical/Nor98 scrapie – in analogy to the existing CJD types – as different scrapie types.
http://www.prion2009.com/sites/default/files/Prion2009_Book_of_Abstracts.pdf
Monday, November 30, 2009
USDA AND OIE COLLABORATE TO EXCLUDE ATYPICAL SCRAPIE NOR-98 ANIMAL HEALTH CODE
http://nor-98.blogspot.com/2009/11/usda-and-oie-collaborate-to-exclude.html
Monday, December 1, 2008
When Atypical Scrapie cross species barriers
http://nor-98.blogspot.com/2008/12/when-atypical-scrapie-cross-species.html
EVIDENCE OF SCRAPIE IN SHEEP AS A RESULT OF FOOD BORNE EXPOSURE
This is provided by the statistically significant increase in the incidence of sheep scrape from 1985, as determined from analyses of the submissions made to VI Centres, and from individual case and flock incident studies. ........
http://web.archive.org/web/20010305222246/www.bseinquiry.gov.uk/files/yb/1994/02/07002001.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.
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The successful transmission of kuru, Creutzfeldt-Jakob disease, and scrapie by natural feeding to squirrel monkeys that we have reported provides further grounds for concern that scrapie-infected meat may occasionally give rise in humans to Creutzfeldt-Jakob disease.
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://web.archive.org/web/20010305223125/www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
Nature. 1972 Mar 10;236(5341):73-4.
Transmission of scrapie to the cynomolgus monkey (Macaca fascicularis). Gibbs CJ Jr, Gajdusek DC.
Nature 236, 73 - 74 (10 March 1972); doi:10.1038/236073a0
Transmission of Scrapie to the Cynomolgus Monkey (Macaca fascicularis)
C. J. GIBBS jun. & D. C. GAJDUSEK
National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland
SCRAPIE has been transmitted to the cynomolgus, or crab-eating, monkey (Macaca fascicularis) with an incubation period of more than 5 yr from the time of intracerebral inoculation of scrapie-infected mouse brain. The animal developed a chronic central nervous system degeneration, with ataxia, tremor and myoclonus with associated severe scrapie-like pathology of intensive astroglial hypertrophy and proliferation, neuronal vacuolation and status spongiosus of grey matter. The strain of scrapie virus used was the eighth passage in Swiss mice (NIH) of a Compton strain of scrapie obtained as ninth intracerebral passage of the agent in goat brain, from Dr R. L. Chandler (ARC, Compton, Berkshire).
http://www.nature.com/nature/journal/v236/n5341/abs/236073a0.html
Epidemiology of Scrapie in the United States 1977
http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
http://web.archive.org/web/20030513212324/http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
Tuesday, April 28, 2009
Nor98-like Scrapie in the United States of America
http://nor-98.blogspot.com/2009/04/nor98-like-scrapie-in-united-states-of.html
Scrapie USA
http://scrapie-usa.blogspot.com/
Like lambs to the slaughter
31 March 2001
by 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 ...
http://www.newscientist.com/article/mg16922840.300-like-lambs-to-the-slaughter.html
R.I.P. MOM hvCJD confirmed DECEMBER 14, 1997
TSS
Monday, December 14, 2009
Monday, November 30, 2009
USDA AND OIE COLLABORATE TO EXCLUDE ATYPICAL SCRAPIE NOR-98 ANIMAL HEALTH CODE
USDA AND OIE COLLABORATE TO EXCLUDE ATYPICAL SCRAPIE NOR-98 ANIMAL HEALTH CODE
OIE Scrapie Chapter Revision • Current draft recognizes Nor98-like scrapie as a separate disease from classical scrapie • USDA provided comments on the draft to OIE
http://www.animalagriculture.org/Solutions/Proceedings/Annual%20Meeting/2009/Sheep%20&%20Goat/Myers,%20Thomas.pdf
Atypical scrapie/Nor 98 October 2009
Last year, after examining member country submissions and investigating rigorous scientific research, the World Organisation for Animal Health (OIE) decided that Nor 98 should not be listed in its Terrestrial Animal Health Code. The Code sets out trade recommendations or restrictions for listed diseases or conditions, and the OIE determined there was no need for such recommendations around Nor 98.
http://www.nzfsa.govt.nz/publications/ce-column/ce-web-nor98.htm
http://www.biosecurity.govt.nz/files/pests/atypical-scrapie/atypical-scrapie-faq-oct09.pdf
Sutton reported that USDA has urged the World Organization for Animal Health (OIE) to categorize Nor98-like scrapie as a separate disease from classical scrapie. Currently, the OIE has proposed a draft revision of their scrapie chapter that would exclude Nor98-like scrapie from the chapter. USDA will be submitting it's comments on this proposal soon.
http://www.ohiosheep.org/Events/ScrapieNewsletterMarch09.pdf
SCRAPIE
The United States is unable to support the proposed new draft Code Chapter on Scrapie. The draft chapter, as written, departs significantly from the existing chapter, is confusing and is difficult to understand. This version of the scrapie chapter uses much of the same wording as the BSE chapter and is written as if the predominance of evidence revealed that scrapie was a food-borne disease similar to BSE in cattle which is inappropriate. Moreover, several of the new changes are not supported by current scientific evidence. As a result, detailed comments on individual articles would not meaningful at this time.
The United States is not supportive of the proposed draft chapter for the following reasons: 1. Inclusion of “atypical” scrapie: The scientific evidence indicates that “atypical” scrapie, also referred to as Nor-98, Nor-98-like, or non-classical scrapie, is not the same disease as classical scrapie. Further, “atypical” scrapie does not meet the criteria for listing diseases of trade concern by the OIE, as described in Chapter 2.1.1 of the Code. The United States recommends that the scope of this chapter be limited to classical scrapie in sheep and goats. Further, the United States recommends that OIE clearly adopt the position that “atypical” scrapie represents a distinct disease entity from classical scrapie and that it not be a listed disease.
• There is no evidence that “atypical” scrapie is a contagious disease. If it is contagious, available evidence suggests that it has a much lower transmission efficiency. (Hopp, et al, 2006; Green, et al, 2007; Benestad, et al 2008; McIntyre, et al, 2008)
• The disease appears to be ubiquitous in that it has been found wherever sufficient surveillance has been conducted. (Buschmann et al, 2004; De Bosschere et al, 2004; Orge, et al, 2004; Everest et al, 2006; Arsac, 2007; Benestad, et al 2008; Fediaevsky, et al, 2008)
• The disease does not appear to be economically significant in that the prevalence of clinical disease is low and it typically occurs in older animals. (Luhken, et al., 2007; Benestad, et al 2008).
• The disease is as likely as not to be the result of a spontaneous conversion of normal prion protein. (Benestad, et al 2008, De Bosschere et al 2007)
• Removal of exposed sheep is unlikely to reduce the prevalence of “atypical” scrapie infection and removing only those exposed sheep that are phenylalanine (F) at codon 141 is scientifically unsound since the disease is known to affect sheep of most other genotypes. Further, sheep with AHQ alleles have a similar risk of infection with “atypical” strains as sheep with F at codon 141. (Luhken, et al., 2007).
• If “atypical” scrapie is included as a listed disease, the surveillance and diagnostic requirements which are needed to identify these cases should be described in detail in both this Chapter and the Manual of Diagnostic Tests and Vaccines for Terrestrial
2
Animals. Data from Europe illustrates that using the proper test(s) is essential for the identification of atypical scrapie (Fediaevsky et al., 2008).
SNIP...
6. Overemphasis on importation and use of bovine meat and bone meal as a route of scrapie transmission: Given that the draft Chapter is not intended to address risk mitigation for BSE in small ruminants, we believe there is an over-emphasis on this potential route of transmission in the current draft.
The United States recommends that the requirements in this chapter be limited to the inclusion of products from sheep and goats (instead of from all ruminants) in feed or feed ingredients intended for consumption by animals.
• The use of products from sheep and goats as feed or feed ingredients for ruminant or non-ruminant animals represent one possible route of transmission (Philippe, et al, 2005) and a source of environmental contamination with the classical scrapie agent. However, this is not the primary route of transmission for the scrapie agent.
• The need for the exclusion of cattle-derived protein or other animal protein to mitigate BSE risk should be based on a country’s BSE risk status and should be addressed in Chapter 2.3.13 of the Code.
SNIP...
14. Failure to provide scientific justification for the list of permitted commodities in Item 1 of Article 2.4.8.1. .
We recommend that the list be re-evaluated and those items that have not been substantiated as presenting no risk be excluded or those with some risk but where the intended use mitigates the risk the use be specified.
• There is no known human health risk associated with scrapie. As such, if meat and meat products for human consumption are included in this list, sheep and/or goat milk intended for human consumption should also be added to the list of permitted commodities in Item 1 of Article 2.4.8.1.
• In the vast majority of sheep infected with classical scrapie, actual infectivity or PrPres has been identified in most tissues including the lymphoreticular system (tonsils, spleen, lymph nodes), the gastrointestinal tract, brain, and spinal cord (Hadlow et. al. 1979; Hadlow et al., 1980; van Kuelen et al., 1996; van Kuelen et al., 1999, Andreoletti et al., 2000; Heggebø et al., 2002; Caplazi et al., 2004). Infectivity and/or PrPres has also been identified in the placenta (see Hourrigan et al., 1979; Onodera et al., 1993; Pattison et al., 1972; Pattison et al., 1974; Race et al., 1998), blood (Hunter et al., 2002; Houston et al. 2008); peripheral nerves (Groschup et al., 1996), muscle (Pattison and Millson, 1962; Andreoletti et al., 2004; Casalone et al., 2005), salivary gland (Hadlow et al., 1980; Vascellari et al., 2007), kidney (Siso et al., 2006), and skin ( Thomzig et al., 2007). In addition, recent work has shown milk and/or colostrum from scrapie infected ewes transmitted the disease to 17 of 18 lambs (Konold et al., 2008).
• The data on the risk of low protein tallow made from scrapie infected tissues particularly for use in milk replacer is limited and some epidemiologic studies suggest an association of milk replacer use with scrapie risk. Taylor et al., 1997 examined the inactivation capacity of different rendering system in regards to scrapie. The presence of infectivity was determined by bioassay into mice. From the onset of this study, it was assumed that tallow was not the vehicle for the transmission of TSE. Hence only 2 tallow samples were examined.
http://www.aphis.usda.gov/import_export/animals/oie/downloads/tahc_mar-sep08/tahc-scrapie-77-mar08_cmt.pdf
• Most critical is that atypical scrapie shows higher prevalence in so-called resistant ARR homozygote and heterozygote genotypes, compared with classical scrapie. • Atypical scrapie has not been found naturally in VRQ/VRQ sheep, although such sheep can be infected artificially. VRQ sheep are, in contrast, highly susceptible to classical scrapie. In the UK, one case of atypical scrapie has been found in VRQ heterozygote (AF141RQ/VRQ) sheep. It is important to ascertain whether or not VRQ-carrying sheep are significantly resistant to infection with atypical scrapie or whether the data might result from a failure to detect PrPres in atypical scrapie due to a different pattern of PrP distribution in tissues. • Increased incidence of atypical scrapie in sheep with PrP alleles carrying the variant phenylalanine (F) at position 141 (leucine(L)/phenylalanine) has also been observed compared with classical scrapie. • It will be important to clarify the genotype effect, particularly in relation to ARR and L141F in transmission studies. • In classical scrapie, there is clear evidence for a PrP genotype effect on tissue distribution patterns of PrPres. This might also be true for atypical scrapie although the data are less complete. 4. Transmission of atypical scrapie It has recently18 been demonstrated that atypical scrapie is experimentally transmissible to mice and sheep, primarily through intracerebral injection. There are some data suggesting that it may also be transmissible orally to sheep of different genotypes. The subgroup noted that challenge experiments with atypical scrapie in sheep were underway in the UK, with one successful intracerebral challenge to date. The subgroup was informed that positive transmission of infectivity from atypical scrapie isolated from sheep with a range of genotypes had been observed in mice. This included ovinised transgenic mice overexpressing the VRQ allele. Nor98 atypical scrapie had also transmitted to ARR ovinised mice, with transmission experiments in AF141RQ ovinised mice planned. Biochemical features of the isolates were maintained after transmission, and were distinct from BSE and classical scrapie. High infectivity titres were observed in brain tissue from atypical scrapie, including from ARR/ARR sheep. Brain transmission experiments in mice carrying the human PrP gene were at an early stage. 18 Le Dur A., Béringue V., Andréoletti O., Reine F., Laï T.H., Baron T., Bratberg B., Vilotte J.- L., Sarradin P., Benestad S.L. and Laude H.(2005) A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes. PNAS 102, 16031-16036
http://www.seac.gov.uk/pdf/positionstatement-sheep-subgroup.pdf
A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes
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*,†† + Author Affiliations
*Virologie Immunologie Moléculaires and ?Génétique Biochimique et Cytogénétique, Institut National de la Recherche Agronomique, 78350 Jouy-en-Josas, France; ‡Unité Mixte de Recherche, Institut National de la Recherche Agronomique-Ecole Nationale Vétérinaire de Toulouse, Interactions Hôte Agent Pathogène, 31066 Toulouse, France; §Agence Française de Sécurité Sanitaire des Aliments, Unité Agents Transmissibles Non Conventionnels, 69364 Lyon, France; **Pathologie Infectieuse et Immunologie, Institut National 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 (received for review March 21, 2005)
Next Section Abstract 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 a misfolded 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 to the 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 goat flocks and may have important implications in terms of scrapie control and public health.
SNIP...
Our study demonstrates that an authentic TSE infectious agent is responsible in sheep and goats of sporadic atypical infections that remained unnoticed until recently. This raises important issues with regard to control of scrapie infection in small ruminants. Of major concern, ARR/ARR sheep can no longer be regarded as free of natural TSE infection. This finding challenges, at least to some extent, the foundation of the selective breeding programs engaged in several European Union member states (47, 48) and may call for a reappraisal of possible consequences of this strategy in the long term. Finally, more information about this newly discovered type of TSE agent, its prevalence in countries free of scrapie or BSE disease, and its potential to across-species transmission would be needed for a comprehensive evaluation of its implications in terms of public health.
http://www.pnas.org/content/102/44/16031.long
http://www.pnas.org/content/102/44/16031.figures-only
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.
***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
PR-26
NOR98 SHOWS MOLECULAR FEATURES REMINISCENT OF GSS
R. Nonno1, E. Esposito1, G. Vaccari1, E. Bandino2, M. Conte1, B. Chiappini1, S. Marcon1, M. Di Bari1, S.L. Benestad3, U. Agrimi1 1 Istituto Superiore di Sanità, Department of Food Safety and Veterinary Public Health, Rome, Italy (romolo.nonno@iss.it); 2 Istituto Zooprofilattico della Sardegna, Sassari, Italy; 3 National Veterinary Institute, Department of Pathology, Oslo, Norway
Molecular variants of PrPSc are being increasingly investigated in sheep scrapie and are generally referred to as "atypical" scrapie, as opposed to "classical scrapie". Among the atypical group, Nor98 seems to be the best identified. We studied the molecular properties of Italian and Norwegian Nor98 samples by WB analysis of brain homogenates, either untreated, digested with different concentrations of proteinase K, or subjected to enzymatic deglycosylation. The identity of PrP fragments was inferred by means of antibodies spanning the full PrP sequence. We found that undigested brain homogenates contain a Nor98-specific PrP fragment migrating at 11 kDa (PrP11), truncated at both the C-terminus and the N-terminus, and not N-glycosylated. After mild PK digestion, Nor98 displayed full-length PrP (FL-PrP) and N-glycosylated C-terminal fragments (CTF), along with increased levels of PrP11. Proteinase K digestion curves (0,006-6,4 mg/ml) showed that FL-PrP and CTF are mainly digested above 0,01 mg/ml, while PrP11 is not entirely digested even at the highest concentrations, similarly to PrP27-30 associated with classical scrapie. Above 0,2 mg/ml PK, most Nor98 samples showed only PrP11 and a fragment of 17 kDa with the same properties of PrP11, that was tentatively identified as a dimer of PrP11. Detergent solubility studies showed that PrP11 is insoluble in 2% sodium laurylsorcosine and is mainly produced from detergentsoluble, full-length PrPSc. Furthermore, among Italian scrapie isolates, we found that a sample with molecular and pathological properties consistent with Nor98 showed plaque-like deposits of PrPSc in the thalamus when the brain was analysed by PrPSc immunohistochemistry. Taken together, our results show that the distinctive pathological feature of Nor98 is a PrP fragment spanning amino acids ~ 90-155. This fragment is produced by successive N-terminal and C-terminal cleavages from a full-length and largely detergent-soluble PrPSc, is produced in vivo and is extremely resistant to PK digestion.
*** Intriguingly, these conclusions suggest that some pathological features of Nor98 are reminiscent of Gerstmann-Sträussler-Scheinker disease.
119
http://www.neuroprion.com/pdf_docs/conferences/prion2006/abstract_book.pdf
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 goat flocks and may have important implications in terms of scrapie control and public health.
Edited by Stanley B. Prusiner, University of California, San Francisco, CA, and approved September 12, 2005 (received for review March 21, 2005)
http://www.pnas.org/cgi/content/abstract/0502296102v1
Prions: Protein Aggregation and Infectious Diseases
ADRIANO AGUZZI AND ANNA MARIA CALELLA
Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland
snip...
3. Sporadic Creutzfeldt-Jakob disease Approximately 85% of all human prion diseases are sporadic forms of CJD. For sCJD, there is no association with a mutant PRNP allele, nor is there any epidemiological evidence for exposure to a TSE agent through contact with people or animals infected with TSEs. sCJD cases are currently subclassified according to the methionine/valine polymorphism at codon 129 of the PRNP gene and the size and glycoform ratio of proteaseresistant prion protein identified on western blot (type 1 or type 2) (174). Heterozygosity (Met/Val) at PrP codon 129 appears to be associated with a lower risk (378) and/or prolonged incubation time (119, 387). The lack of routine laboratory testing for preclinical diagnosis makes the search for agent sources and other risk factors extremely difficult. At present, the means of acquisition of a TSE agent in these patients remains a mystery. So far, there is no evidence for spontaneous PrPSc formation in any animal or human TSE. In humans, the peak age incidence of sporadic CJD is 55–60 years. However, if spontaneous misfolding were the primary event, one might expect a continuously increasing incidence with age because more time would allow more opportunity for rare misfolding events.
snip...
Physiol Rev • VOL 89 • OCTOBER 2009 • www.prv.org
http://physrev.physiology.org/cgi/content/abstract/89/4/1105
Monday, December 1, 2008
When Atypical Scrapie cross species barriers
http://nor-98.blogspot.com/2008/12/when-atypical-scrapie-cross-species.html
EVIDENCE OF SCRAPIE IN SHEEP AS A RESULT OF FOOD BORNE EXPOSURE
This is provided by the statistically significant increase in the incidence of sheep scrape from 1985, as determined from analyses of the submissions made to VI Centres, and from individual case and flock incident studies. ........
http://web.archive.org/web/20010305222246/www.bseinquiry.gov.uk/files/yb/1994/02/07002001.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.
snip...
The successful transmission of kuru, Creutzfeldt-Jakob disease, and scrapie by natural feeding to squirrel monkeys that we have reported provides further grounds for concern that scrapie-infected meat may occasionally give rise in humans to Creutzfeldt-Jakob disease.
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
snip...
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.
snip...
76/10.12/4.6
http://web.archive.org/web/20010305223125/www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
Nature. 1972 Mar 10;236(5341):73-4.
Transmission of scrapie to the cynomolgus monkey (Macaca fascicularis). Gibbs CJ Jr, Gajdusek DC.
Nature 236, 73 - 74 (10 March 1972); doi:10.1038/236073a0
Transmission of Scrapie to the Cynomolgus Monkey (Macaca fascicularis)
C. J. GIBBS jun. & D. C. GAJDUSEK
National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland
SCRAPIE has been transmitted to the cynomolgus, or crab-eating, monkey (Macaca fascicularis) with an incubation period of more than 5 yr from the time of intracerebral inoculation of scrapie-infected mouse brain. The animal developed a chronic central nervous system degeneration, with ataxia, tremor and myoclonus with associated severe scrapie-like pathology of intensive astroglial hypertrophy and proliferation, neuronal vacuolation and status spongiosus of grey matter. The strain of scrapie virus used was the eighth passage in Swiss mice (NIH) of a Compton strain of scrapie obtained as ninth intracerebral passage of the agent in goat brain, from Dr R. L. Chandler (ARC, Compton, Berkshire).
http://www.nature.com/nature/journal/v236/n5341/abs/236073a0.html
Epidemiology of Scrapie in the United States 1977
http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
http://web.archive.org/web/20030513212324/http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
Tuesday, April 28, 2009
Nor98-like Scrapie in the United States of America
http://nor-98.blogspot.com/2009/04/nor98-like-scrapie-in-united-states-of.html
Scrapie USA
http://scrapie-usa.blogspot.com/
Monday, November 23, 2009
A case of atypical scrapie/Nor98 in a sheep from New Zealand
http://nor-98.blogspot.com/2009/11/case-of-atypical-scrapienor98-in-sheep.html
Monday, November 23, 2009
BSE GBR RISK ASSESSMENTS UPDATE NOVEMBER 23, 2009 COMMISSION OF THE EUROPEAN COMMUNITIES AND O.I.E.
http://docket-aphis-2006-0041.blogspot.com/2009/11/bse-gbr-risk-assessments-update.html
IN A NUT SHELL ;
(Adopted by the International Committee of the OIE on 23 May 2006)
11. Information published by the OIE is derived from appropriate declarations made by the official Veterinary Services of Member Countries. The OIE is not responsible for inaccurate publication of country disease status based on inaccurate information or changes in epidemiological status or other significant events that were not promptly reported to the Central Bureau,
http://www.oie.int/eng/Session2007/RF2006.pdf
----- Original Message -----
From: Terry S. Singeltary Sr.
To: Debra.Beasley@aphis.usda.gov
Sent: Tuesday, November 24, 2009 11:01 AM
Subject: OIE has recently published its proposed animal welfare guidelines for public comment
Greetings USDA/APHIS et al,
I would kindly like to comment on OIE proposed guidelines.
AS I said before, OIE should hang up there jock strap now, since it appears they will buckle every time a country makes some political hay about trade protocol, commodities and futures. IF they are not going to be science based, they should do everyone a favor and dissolve there organization. THE reason most every country around the globe came down with BSE/TSE in their cattle, were due to the failed and flawed BSE/TSE testing and surveillance policy of the O.I.E. NOW, they don't even acknowledge atypical scrapie it seems, as one for concern $
Monday, November 23, 2009
BSE GBR RISK ASSESSMENTS UPDATE NOVEMBER 23, 2009 COMMISSION OF THE EUROPEAN COMMUNITIES AND O.I.E.
http://docket-aphis-2006-0041.blogspot.com/2009/11/bse-gbr-risk-assessments-update.html
Wednesday, November 18, 2009
R-CALF: 40 Groups Disagree With USDA's Latest BSE Court Submission
http://bse-atypical.blogspot.com/2009/11/r-calf-40-groups-disagree-with-usdas.html
Monday, November 23, 2009
A case of atypical scrapie/Nor98 in a sheep from New Zealand
http://nor-98.blogspot.com/2009/11/case-of-atypical-scrapienor98-in-sheep.html
MY comments/questions are as follows ; 1. SINCE the first Harvard BSE Risk Assessment was so flawed and fraught with error after the PEER REVIEW assessment assessed this fact, how do you plan on stopping this from happening again, will there be another peer review with top TSE Scientist, an impartial jury so-to-speak, to assess this new and updated Harvard BSE/TSE risk assessment and will this assessment include the Atypical TSE and SRM issues ?
*** Suppressed peer review of Harvard study October 31, 2002 ***
http://www.fsis.usda.gov/oa/topics/BSE_Peer_Review.pdf
***
http://www.scribd.com/doc/1490709/USDA-200600111
***
http://www.fsis.usda.gov/OPPDE/Comments/2006-0011/2006-0011-1.pdf
***
http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648027c28e&disposition=attachment&contentType=pdf
***
http://www.fsis.usda.gov/OPPDE/Comments/2006-0011/2006-0011-1.pdf
***
Response to Public Comments on the Harvard Risk Assessment of BSE USA
RESPONSE TO COMMENTS FROM TERRY S. SINGELTARY SR. Comment #1: SINCE the first Harvard BSE Risk Assessment was so flawed and fraught ...
http://www.fsis.usda.gov/PDF/BSE_Risk_Assess_Response_Public_Comments.pdf
IT ALL STARTED, LEGALLY, RIGHT HERE ;
Docket APHIS-2006-0026 Docket Title Bovine Spongiform Encephalopathy; Animal Identification and Importation of Commodities Docket Type Rulemaking Document APHIS-2006-0026-0001 Document Title Bovine Spongiform Encephalopathy; Minimal-Risk Regions, Identification of Ruminants and Processing and Importation of Commodities Public Submission APHIS-2006-0026-0012 Public Submission Title Comment from Terry S Singletary
http://www.regulations.gov/fdmspublic/component/main?main=DocumentDetail&o=09000064801e47e1
Docket APHIS-2006-0041 Docket Title Bovine Spongiform Encephalopathy; Minimal-Risk Regions; Importation of Live Bovines and Products Derived from Bovines Commodities Docket Type Rulemaking Document APHIS-2006-0041-0001 Document Title Bovine Spongiform Encephalopathy; Minimal-Risk Regions; Importation of Live Bovines and Products Derived From Bovines Public Submission APHIS-2006-0041-0028 Public Submission Title Comment from Terry S Singletary
Comment 2006-2007 USA AND OIE POISONING GLOBE WITH BSE MRR POLICY
THE USA is in a most unique situation, one of unknown circumstances with human and animal TSE. THE USA has the most documented TSE in different species to date, with substrains growing in those species (BSE/BASE in cattle and CWD in deer and elk, there is evidence here with different strains), and we know that sheep scrapie has over 20 strains of the typical scrapie with atypical scrapie documented and also BSE is very likely to have passed to sheep. all of which have been rendered and fed back to animals for human and animal consumption, a frightening scenario. WE do not know the outcome, and to play with human life around the globe with the very likely TSE tainted products from the USA, in my opinion is like playing Russian roulette, of long duration, with potential long and enduring consequences, of which once done, cannot be undone. These are the facts as I have come to know through daily and extensive research of TSE over 9 years, since 12/14/97. I do not pretend to have all the answers, but i do know to continue to believe in the ukbsenvcjd only theory of transmission to humans of only this one strain from only this one TSE from only this one part of the globe, will only lead to further failures, and needless exposure to humans from all strains of TSE, and possibly many more needless deaths from TSE via a multitude of proven routes and sources via many studies with primates and rodents and other species.
MY personal belief, since you ask, is that not only the Canadian border, but the USA border, and the Mexican border should be sealed up tighter than a drum for exporting there TSE tainted products, until a validated, 100% sensitive test is available, and all animals for human and animal consumption are tested. all we are doing is the exact same thing the UK did with there mad cow poisoning when they exported it all over the globe, all the while knowing what they were doing. this BSE MRR policy is nothing more than a legal tool to do just exactly what the UK did, thanks to the OIE and GW, it's legal now. and they executed Saddam for poisoning ???
go figure. ...
http://www.regulations.gov/fdmspublic/component/main?main=DocumentDetail&o=09000064801f8151
Docket APHIS-2006-0041 Docket Title Bovine Spongiform Encephalopathy; Minimal-Risk Regions; Importation of Live Bovines and Products Derived from Bovines Commodities Docket Type Rulemaking Document APHIS-2006-0041-0001 Document Title Bovine Spongiform Encephalopathy; Minimal-Risk Regions; Importation of Live Bovines and Products Derived From Bovines Public Submission APHIS-2006-0041-0028.1 Public Submission Title Attachment to Singletary 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
http://www.regulations.gov/fdmspublic/ContentViewer?objectId=09000064801f8152&disposition=attachment&contentType=msw8
Monday, October 26, 2009
MAD COW DISEASE, AND U.S. BEEF TRADE
MAD COW DISEASE, CJD, TSE, SOUND SCIENCE, COMMERCE, AND SELLING YOUR SOUL TO THE DEVIL
http://usdameatexport.blogspot.com/2009/10/mad-cow-disease-and-us-beef-trade.html
Tuesday, November 10, 2009
Surveillance On the Bovine Spongiform Encephalopathy and rabies in Taiwan and USA
http://usdavskorea.blogspot.com/2009/11/surveillance-on-bovine-spongiform.html
Tuesday, November 17, 2009
SEAC NEW RESULTS ON IDIOPATHIC BRAINSTEM NEURONAL CHROMATOLYSIS (IBNC) FROM THE VETERINARY LABORATORIES AGENCY (VLA) SEAC 103/1
http://bse-atypical.blogspot.com/2009/11/seac-new-results-on-idiopathic.html
Tuesday, November 17, 2009
SEAC EFFECT OF AGE ON THE PATHOGENESIS OF TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES SEAC 103/2
http://downercattle.blogspot.com/2009/11/seac-effect-of-age-on-pathogenesis-of.html
Terry S. Singeltary Sr
P.O. Box 42
Bacliff, Texas USA 77518
----- Original Message -----
From:
Sent: Tuesday, November 24, 2009 12:00 PM
Subject: Fw: OIE Animal Welfare documents for comment re: TAHSC September 2009 Report
>
> OIE Animal Welfare documents for comment re: TAHSC September 2009 Report
>
> *Please note the instructions below for formatting comments. The OIE will
> not consider comments that are not submitted in the appropriate format.
>
OIE Scrapie Chapter Revision • Current draft recognizes Nor98-like scrapie as a separate disease from classical scrapie • USDA provided comments on the draft to OIE
http://www.animalagriculture.org/Solutions/Proceedings/Annual%20Meeting/2009/Sheep%20&%20Goat/Myers,%20Thomas.pdf
Atypical scrapie/Nor 98 October 2009
Last year, after examining member country submissions and investigating rigorous scientific research, the World Organisation for Animal Health (OIE) decided that Nor 98 should not be listed in its Terrestrial Animal Health Code. The Code sets out trade recommendations or restrictions for listed diseases or conditions, and the OIE determined there was no need for such recommendations around Nor 98.
http://www.nzfsa.govt.nz/publications/ce-column/ce-web-nor98.htm
http://www.biosecurity.govt.nz/files/pests/atypical-scrapie/atypical-scrapie-faq-oct09.pdf
Sutton reported that USDA has urged the World Organization for Animal Health (OIE) to categorize Nor98-like scrapie as a separate disease from classical scrapie. Currently, the OIE has proposed a draft revision of their scrapie chapter that would exclude Nor98-like scrapie from the chapter. USDA will be submitting it's comments on this proposal soon.
http://www.ohiosheep.org/Events/ScrapieNewsletterMarch09.pdf
SCRAPIE
The United States is unable to support the proposed new draft Code Chapter on Scrapie. The draft chapter, as written, departs significantly from the existing chapter, is confusing and is difficult to understand. This version of the scrapie chapter uses much of the same wording as the BSE chapter and is written as if the predominance of evidence revealed that scrapie was a food-borne disease similar to BSE in cattle which is inappropriate. Moreover, several of the new changes are not supported by current scientific evidence. As a result, detailed comments on individual articles would not meaningful at this time.
The United States is not supportive of the proposed draft chapter for the following reasons: 1. Inclusion of “atypical” scrapie: The scientific evidence indicates that “atypical” scrapie, also referred to as Nor-98, Nor-98-like, or non-classical scrapie, is not the same disease as classical scrapie. Further, “atypical” scrapie does not meet the criteria for listing diseases of trade concern by the OIE, as described in Chapter 2.1.1 of the Code. The United States recommends that the scope of this chapter be limited to classical scrapie in sheep and goats. Further, the United States recommends that OIE clearly adopt the position that “atypical” scrapie represents a distinct disease entity from classical scrapie and that it not be a listed disease.
• There is no evidence that “atypical” scrapie is a contagious disease. If it is contagious, available evidence suggests that it has a much lower transmission efficiency. (Hopp, et al, 2006; Green, et al, 2007; Benestad, et al 2008; McIntyre, et al, 2008)
• The disease appears to be ubiquitous in that it has been found wherever sufficient surveillance has been conducted. (Buschmann et al, 2004; De Bosschere et al, 2004; Orge, et al, 2004; Everest et al, 2006; Arsac, 2007; Benestad, et al 2008; Fediaevsky, et al, 2008)
• The disease does not appear to be economically significant in that the prevalence of clinical disease is low and it typically occurs in older animals. (Luhken, et al., 2007; Benestad, et al 2008).
• The disease is as likely as not to be the result of a spontaneous conversion of normal prion protein. (Benestad, et al 2008, De Bosschere et al 2007)
• Removal of exposed sheep is unlikely to reduce the prevalence of “atypical” scrapie infection and removing only those exposed sheep that are phenylalanine (F) at codon 141 is scientifically unsound since the disease is known to affect sheep of most other genotypes. Further, sheep with AHQ alleles have a similar risk of infection with “atypical” strains as sheep with F at codon 141. (Luhken, et al., 2007).
• If “atypical” scrapie is included as a listed disease, the surveillance and diagnostic requirements which are needed to identify these cases should be described in detail in both this Chapter and the Manual of Diagnostic Tests and Vaccines for Terrestrial
2
Animals. Data from Europe illustrates that using the proper test(s) is essential for the identification of atypical scrapie (Fediaevsky et al., 2008).
SNIP...
6. Overemphasis on importation and use of bovine meat and bone meal as a route of scrapie transmission: Given that the draft Chapter is not intended to address risk mitigation for BSE in small ruminants, we believe there is an over-emphasis on this potential route of transmission in the current draft.
The United States recommends that the requirements in this chapter be limited to the inclusion of products from sheep and goats (instead of from all ruminants) in feed or feed ingredients intended for consumption by animals.
• The use of products from sheep and goats as feed or feed ingredients for ruminant or non-ruminant animals represent one possible route of transmission (Philippe, et al, 2005) and a source of environmental contamination with the classical scrapie agent. However, this is not the primary route of transmission for the scrapie agent.
• The need for the exclusion of cattle-derived protein or other animal protein to mitigate BSE risk should be based on a country’s BSE risk status and should be addressed in Chapter 2.3.13 of the Code.
SNIP...
14. Failure to provide scientific justification for the list of permitted commodities in Item 1 of Article 2.4.8.1. .
We recommend that the list be re-evaluated and those items that have not been substantiated as presenting no risk be excluded or those with some risk but where the intended use mitigates the risk the use be specified.
• There is no known human health risk associated with scrapie. As such, if meat and meat products for human consumption are included in this list, sheep and/or goat milk intended for human consumption should also be added to the list of permitted commodities in Item 1 of Article 2.4.8.1.
• In the vast majority of sheep infected with classical scrapie, actual infectivity or PrPres has been identified in most tissues including the lymphoreticular system (tonsils, spleen, lymph nodes), the gastrointestinal tract, brain, and spinal cord (Hadlow et. al. 1979; Hadlow et al., 1980; van Kuelen et al., 1996; van Kuelen et al., 1999, Andreoletti et al., 2000; Heggebø et al., 2002; Caplazi et al., 2004). Infectivity and/or PrPres has also been identified in the placenta (see Hourrigan et al., 1979; Onodera et al., 1993; Pattison et al., 1972; Pattison et al., 1974; Race et al., 1998), blood (Hunter et al., 2002; Houston et al. 2008); peripheral nerves (Groschup et al., 1996), muscle (Pattison and Millson, 1962; Andreoletti et al., 2004; Casalone et al., 2005), salivary gland (Hadlow et al., 1980; Vascellari et al., 2007), kidney (Siso et al., 2006), and skin ( Thomzig et al., 2007). In addition, recent work has shown milk and/or colostrum from scrapie infected ewes transmitted the disease to 17 of 18 lambs (Konold et al., 2008).
• The data on the risk of low protein tallow made from scrapie infected tissues particularly for use in milk replacer is limited and some epidemiologic studies suggest an association of milk replacer use with scrapie risk. Taylor et al., 1997 examined the inactivation capacity of different rendering system in regards to scrapie. The presence of infectivity was determined by bioassay into mice. From the onset of this study, it was assumed that tallow was not the vehicle for the transmission of TSE. Hence only 2 tallow samples were examined.
http://www.aphis.usda.gov/import_export/animals/oie/downloads/tahc_mar-sep08/tahc-scrapie-77-mar08_cmt.pdf
• Most critical is that atypical scrapie shows higher prevalence in so-called resistant ARR homozygote and heterozygote genotypes, compared with classical scrapie. • Atypical scrapie has not been found naturally in VRQ/VRQ sheep, although such sheep can be infected artificially. VRQ sheep are, in contrast, highly susceptible to classical scrapie. In the UK, one case of atypical scrapie has been found in VRQ heterozygote (AF141RQ/VRQ) sheep. It is important to ascertain whether or not VRQ-carrying sheep are significantly resistant to infection with atypical scrapie or whether the data might result from a failure to detect PrPres in atypical scrapie due to a different pattern of PrP distribution in tissues. • Increased incidence of atypical scrapie in sheep with PrP alleles carrying the variant phenylalanine (F) at position 141 (leucine(L)/phenylalanine) has also been observed compared with classical scrapie. • It will be important to clarify the genotype effect, particularly in relation to ARR and L141F in transmission studies. • In classical scrapie, there is clear evidence for a PrP genotype effect on tissue distribution patterns of PrPres. This might also be true for atypical scrapie although the data are less complete. 4. Transmission of atypical scrapie It has recently18 been demonstrated that atypical scrapie is experimentally transmissible to mice and sheep, primarily through intracerebral injection. There are some data suggesting that it may also be transmissible orally to sheep of different genotypes. The subgroup noted that challenge experiments with atypical scrapie in sheep were underway in the UK, with one successful intracerebral challenge to date. The subgroup was informed that positive transmission of infectivity from atypical scrapie isolated from sheep with a range of genotypes had been observed in mice. This included ovinised transgenic mice overexpressing the VRQ allele. Nor98 atypical scrapie had also transmitted to ARR ovinised mice, with transmission experiments in AF141RQ ovinised mice planned. Biochemical features of the isolates were maintained after transmission, and were distinct from BSE and classical scrapie. High infectivity titres were observed in brain tissue from atypical scrapie, including from ARR/ARR sheep. Brain transmission experiments in mice carrying the human PrP gene were at an early stage. 18 Le Dur A., Béringue V., Andréoletti O., Reine F., Laï T.H., Baron T., Bratberg B., Vilotte J.- L., Sarradin P., Benestad S.L. and Laude H.(2005) A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes. PNAS 102, 16031-16036
http://www.seac.gov.uk/pdf/positionstatement-sheep-subgroup.pdf
A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes
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*,†† + Author Affiliations
*Virologie Immunologie Moléculaires and ?Génétique Biochimique et Cytogénétique, Institut National de la Recherche Agronomique, 78350 Jouy-en-Josas, France; ‡Unité Mixte de Recherche, Institut National de la Recherche Agronomique-Ecole Nationale Vétérinaire de Toulouse, Interactions Hôte Agent Pathogène, 31066 Toulouse, France; §Agence Française de Sécurité Sanitaire des Aliments, Unité Agents Transmissibles Non Conventionnels, 69364 Lyon, France; **Pathologie Infectieuse et Immunologie, Institut National 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 (received for review March 21, 2005)
Next Section Abstract 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 a misfolded 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 to the 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 goat flocks and may have important implications in terms of scrapie control and public health.
SNIP...
Our study demonstrates that an authentic TSE infectious agent is responsible in sheep and goats of sporadic atypical infections that remained unnoticed until recently. This raises important issues with regard to control of scrapie infection in small ruminants. Of major concern, ARR/ARR sheep can no longer be regarded as free of natural TSE infection. This finding challenges, at least to some extent, the foundation of the selective breeding programs engaged in several European Union member states (47, 48) and may call for a reappraisal of possible consequences of this strategy in the long term. Finally, more information about this newly discovered type of TSE agent, its prevalence in countries free of scrapie or BSE disease, and its potential to across-species transmission would be needed for a comprehensive evaluation of its implications in terms of public health.
http://www.pnas.org/content/102/44/16031.long
http://www.pnas.org/content/102/44/16031.figures-only
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.
***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
PR-26
NOR98 SHOWS MOLECULAR FEATURES REMINISCENT OF GSS
R. Nonno1, E. Esposito1, G. Vaccari1, E. Bandino2, M. Conte1, B. Chiappini1, S. Marcon1, M. Di Bari1, S.L. Benestad3, U. Agrimi1 1 Istituto Superiore di Sanità, Department of Food Safety and Veterinary Public Health, Rome, Italy (romolo.nonno@iss.it); 2 Istituto Zooprofilattico della Sardegna, Sassari, Italy; 3 National Veterinary Institute, Department of Pathology, Oslo, Norway
Molecular variants of PrPSc are being increasingly investigated in sheep scrapie and are generally referred to as "atypical" scrapie, as opposed to "classical scrapie". Among the atypical group, Nor98 seems to be the best identified. We studied the molecular properties of Italian and Norwegian Nor98 samples by WB analysis of brain homogenates, either untreated, digested with different concentrations of proteinase K, or subjected to enzymatic deglycosylation. The identity of PrP fragments was inferred by means of antibodies spanning the full PrP sequence. We found that undigested brain homogenates contain a Nor98-specific PrP fragment migrating at 11 kDa (PrP11), truncated at both the C-terminus and the N-terminus, and not N-glycosylated. After mild PK digestion, Nor98 displayed full-length PrP (FL-PrP) and N-glycosylated C-terminal fragments (CTF), along with increased levels of PrP11. Proteinase K digestion curves (0,006-6,4 mg/ml) showed that FL-PrP and CTF are mainly digested above 0,01 mg/ml, while PrP11 is not entirely digested even at the highest concentrations, similarly to PrP27-30 associated with classical scrapie. Above 0,2 mg/ml PK, most Nor98 samples showed only PrP11 and a fragment of 17 kDa with the same properties of PrP11, that was tentatively identified as a dimer of PrP11. Detergent solubility studies showed that PrP11 is insoluble in 2% sodium laurylsorcosine and is mainly produced from detergentsoluble, full-length PrPSc. Furthermore, among Italian scrapie isolates, we found that a sample with molecular and pathological properties consistent with Nor98 showed plaque-like deposits of PrPSc in the thalamus when the brain was analysed by PrPSc immunohistochemistry. Taken together, our results show that the distinctive pathological feature of Nor98 is a PrP fragment spanning amino acids ~ 90-155. This fragment is produced by successive N-terminal and C-terminal cleavages from a full-length and largely detergent-soluble PrPSc, is produced in vivo and is extremely resistant to PK digestion.
*** Intriguingly, these conclusions suggest that some pathological features of Nor98 are reminiscent of Gerstmann-Sträussler-Scheinker disease.
119
http://www.neuroprion.com/pdf_docs/conferences/prion2006/abstract_book.pdf
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 goat flocks and may have important implications in terms of scrapie control and public health.
Edited by Stanley B. Prusiner, University of California, San Francisco, CA, and approved September 12, 2005 (received for review March 21, 2005)
http://www.pnas.org/cgi/content/abstract/0502296102v1
Prions: Protein Aggregation and Infectious Diseases
ADRIANO AGUZZI AND ANNA MARIA CALELLA
Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland
snip...
3. Sporadic Creutzfeldt-Jakob disease Approximately 85% of all human prion diseases are sporadic forms of CJD. For sCJD, there is no association with a mutant PRNP allele, nor is there any epidemiological evidence for exposure to a TSE agent through contact with people or animals infected with TSEs. sCJD cases are currently subclassified according to the methionine/valine polymorphism at codon 129 of the PRNP gene and the size and glycoform ratio of proteaseresistant prion protein identified on western blot (type 1 or type 2) (174). Heterozygosity (Met/Val) at PrP codon 129 appears to be associated with a lower risk (378) and/or prolonged incubation time (119, 387). The lack of routine laboratory testing for preclinical diagnosis makes the search for agent sources and other risk factors extremely difficult. At present, the means of acquisition of a TSE agent in these patients remains a mystery. So far, there is no evidence for spontaneous PrPSc formation in any animal or human TSE. In humans, the peak age incidence of sporadic CJD is 55–60 years. However, if spontaneous misfolding were the primary event, one might expect a continuously increasing incidence with age because more time would allow more opportunity for rare misfolding events.
snip...
Physiol Rev • VOL 89 • OCTOBER 2009 • www.prv.org
http://physrev.physiology.org/cgi/content/abstract/89/4/1105
Monday, December 1, 2008
When Atypical Scrapie cross species barriers
http://nor-98.blogspot.com/2008/12/when-atypical-scrapie-cross-species.html
EVIDENCE OF SCRAPIE IN SHEEP AS A RESULT OF FOOD BORNE EXPOSURE
This is provided by the statistically significant increase in the incidence of sheep scrape from 1985, as determined from analyses of the submissions made to VI Centres, and from individual case and flock incident studies. ........
http://web.archive.org/web/20010305222246/www.bseinquiry.gov.uk/files/yb/1994/02/07002001.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.
snip...
The successful transmission of kuru, Creutzfeldt-Jakob disease, and scrapie by natural feeding to squirrel monkeys that we have reported provides further grounds for concern that scrapie-infected meat may occasionally give rise in humans to Creutzfeldt-Jakob disease.
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
snip...
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.
snip...
76/10.12/4.6
http://web.archive.org/web/20010305223125/www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
Nature. 1972 Mar 10;236(5341):73-4.
Transmission of scrapie to the cynomolgus monkey (Macaca fascicularis). Gibbs CJ Jr, Gajdusek DC.
Nature 236, 73 - 74 (10 March 1972); doi:10.1038/236073a0
Transmission of Scrapie to the Cynomolgus Monkey (Macaca fascicularis)
C. J. GIBBS jun. & D. C. GAJDUSEK
National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland
SCRAPIE has been transmitted to the cynomolgus, or crab-eating, monkey (Macaca fascicularis) with an incubation period of more than 5 yr from the time of intracerebral inoculation of scrapie-infected mouse brain. The animal developed a chronic central nervous system degeneration, with ataxia, tremor and myoclonus with associated severe scrapie-like pathology of intensive astroglial hypertrophy and proliferation, neuronal vacuolation and status spongiosus of grey matter. The strain of scrapie virus used was the eighth passage in Swiss mice (NIH) of a Compton strain of scrapie obtained as ninth intracerebral passage of the agent in goat brain, from Dr R. L. Chandler (ARC, Compton, Berkshire).
http://www.nature.com/nature/journal/v236/n5341/abs/236073a0.html
Epidemiology of Scrapie in the United States 1977
http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
http://web.archive.org/web/20030513212324/http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
Tuesday, April 28, 2009
Nor98-like Scrapie in the United States of America
http://nor-98.blogspot.com/2009/04/nor98-like-scrapie-in-united-states-of.html
Scrapie USA
http://scrapie-usa.blogspot.com/
Monday, November 23, 2009
A case of atypical scrapie/Nor98 in a sheep from New Zealand
http://nor-98.blogspot.com/2009/11/case-of-atypical-scrapienor98-in-sheep.html
Monday, November 23, 2009
BSE GBR RISK ASSESSMENTS UPDATE NOVEMBER 23, 2009 COMMISSION OF THE EUROPEAN COMMUNITIES AND O.I.E.
http://docket-aphis-2006-0041.blogspot.com/2009/11/bse-gbr-risk-assessments-update.html
IN A NUT SHELL ;
(Adopted by the International Committee of the OIE on 23 May 2006)
11. Information published by the OIE is derived from appropriate declarations made by the official Veterinary Services of Member Countries. The OIE is not responsible for inaccurate publication of country disease status based on inaccurate information or changes in epidemiological status or other significant events that were not promptly reported to the Central Bureau,
http://www.oie.int/eng/Session2007/RF2006.pdf
----- Original Message -----
From: Terry S. Singeltary Sr.
To: Debra.Beasley@aphis.usda.gov
Sent: Tuesday, November 24, 2009 11:01 AM
Subject: OIE has recently published its proposed animal welfare guidelines for public comment
Greetings USDA/APHIS et al,
I would kindly like to comment on OIE proposed guidelines.
AS I said before, OIE should hang up there jock strap now, since it appears they will buckle every time a country makes some political hay about trade protocol, commodities and futures. IF they are not going to be science based, they should do everyone a favor and dissolve there organization. THE reason most every country around the globe came down with BSE/TSE in their cattle, were due to the failed and flawed BSE/TSE testing and surveillance policy of the O.I.E. NOW, they don't even acknowledge atypical scrapie it seems, as one for concern $
Monday, November 23, 2009
BSE GBR RISK ASSESSMENTS UPDATE NOVEMBER 23, 2009 COMMISSION OF THE EUROPEAN COMMUNITIES AND O.I.E.
http://docket-aphis-2006-0041.blogspot.com/2009/11/bse-gbr-risk-assessments-update.html
Wednesday, November 18, 2009
R-CALF: 40 Groups Disagree With USDA's Latest BSE Court Submission
http://bse-atypical.blogspot.com/2009/11/r-calf-40-groups-disagree-with-usdas.html
Monday, November 23, 2009
A case of atypical scrapie/Nor98 in a sheep from New Zealand
http://nor-98.blogspot.com/2009/11/case-of-atypical-scrapienor98-in-sheep.html
MY comments/questions are as follows ; 1. SINCE the first Harvard BSE Risk Assessment was so flawed and fraught with error after the PEER REVIEW assessment assessed this fact, how do you plan on stopping this from happening again, will there be another peer review with top TSE Scientist, an impartial jury so-to-speak, to assess this new and updated Harvard BSE/TSE risk assessment and will this assessment include the Atypical TSE and SRM issues ?
*** Suppressed peer review of Harvard study October 31, 2002 ***
http://www.fsis.usda.gov/oa/topics/BSE_Peer_Review.pdf
***
http://www.scribd.com/doc/1490709/USDA-200600111
***
http://www.fsis.usda.gov/OPPDE/Comments/2006-0011/2006-0011-1.pdf
***
http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648027c28e&disposition=attachment&contentType=pdf
***
http://www.fsis.usda.gov/OPPDE/Comments/2006-0011/2006-0011-1.pdf
***
Response to Public Comments on the Harvard Risk Assessment of BSE USA
RESPONSE TO COMMENTS FROM TERRY S. SINGELTARY SR. Comment #1: SINCE the first Harvard BSE Risk Assessment was so flawed and fraught ...
http://www.fsis.usda.gov/PDF/BSE_Risk_Assess_Response_Public_Comments.pdf
IT ALL STARTED, LEGALLY, RIGHT HERE ;
Docket APHIS-2006-0026 Docket Title Bovine Spongiform Encephalopathy; Animal Identification and Importation of Commodities Docket Type Rulemaking Document APHIS-2006-0026-0001 Document Title Bovine Spongiform Encephalopathy; Minimal-Risk Regions, Identification of Ruminants and Processing and Importation of Commodities Public Submission APHIS-2006-0026-0012 Public Submission Title Comment from Terry S Singletary
http://www.regulations.gov/fdmspublic/component/main?main=DocumentDetail&o=09000064801e47e1
Docket APHIS-2006-0041 Docket Title Bovine Spongiform Encephalopathy; Minimal-Risk Regions; Importation of Live Bovines and Products Derived from Bovines Commodities Docket Type Rulemaking Document APHIS-2006-0041-0001 Document Title Bovine Spongiform Encephalopathy; Minimal-Risk Regions; Importation of Live Bovines and Products Derived From Bovines Public Submission APHIS-2006-0041-0028 Public Submission Title Comment from Terry S Singletary
Comment 2006-2007 USA AND OIE POISONING GLOBE WITH BSE MRR POLICY
THE USA is in a most unique situation, one of unknown circumstances with human and animal TSE. THE USA has the most documented TSE in different species to date, with substrains growing in those species (BSE/BASE in cattle and CWD in deer and elk, there is evidence here with different strains), and we know that sheep scrapie has over 20 strains of the typical scrapie with atypical scrapie documented and also BSE is very likely to have passed to sheep. all of which have been rendered and fed back to animals for human and animal consumption, a frightening scenario. WE do not know the outcome, and to play with human life around the globe with the very likely TSE tainted products from the USA, in my opinion is like playing Russian roulette, of long duration, with potential long and enduring consequences, of which once done, cannot be undone. These are the facts as I have come to know through daily and extensive research of TSE over 9 years, since 12/14/97. I do not pretend to have all the answers, but i do know to continue to believe in the ukbsenvcjd only theory of transmission to humans of only this one strain from only this one TSE from only this one part of the globe, will only lead to further failures, and needless exposure to humans from all strains of TSE, and possibly many more needless deaths from TSE via a multitude of proven routes and sources via many studies with primates and rodents and other species.
MY personal belief, since you ask, is that not only the Canadian border, but the USA border, and the Mexican border should be sealed up tighter than a drum for exporting there TSE tainted products, until a validated, 100% sensitive test is available, and all animals for human and animal consumption are tested. all we are doing is the exact same thing the UK did with there mad cow poisoning when they exported it all over the globe, all the while knowing what they were doing. this BSE MRR policy is nothing more than a legal tool to do just exactly what the UK did, thanks to the OIE and GW, it's legal now. and they executed Saddam for poisoning ???
go figure. ...
http://www.regulations.gov/fdmspublic/component/main?main=DocumentDetail&o=09000064801f8151
Docket APHIS-2006-0041 Docket Title Bovine Spongiform Encephalopathy; Minimal-Risk Regions; Importation of Live Bovines and Products Derived from Bovines Commodities Docket Type Rulemaking Document APHIS-2006-0041-0001 Document Title Bovine Spongiform Encephalopathy; Minimal-Risk Regions; Importation of Live Bovines and Products Derived From Bovines Public Submission APHIS-2006-0041-0028.1 Public Submission Title Attachment to Singletary 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
http://www.regulations.gov/fdmspublic/ContentViewer?objectId=09000064801f8152&disposition=attachment&contentType=msw8
Monday, October 26, 2009
MAD COW DISEASE, AND U.S. BEEF TRADE
MAD COW DISEASE, CJD, TSE, SOUND SCIENCE, COMMERCE, AND SELLING YOUR SOUL TO THE DEVIL
http://usdameatexport.blogspot.com/2009/10/mad-cow-disease-and-us-beef-trade.html
Tuesday, November 10, 2009
Surveillance On the Bovine Spongiform Encephalopathy and rabies in Taiwan and USA
http://usdavskorea.blogspot.com/2009/11/surveillance-on-bovine-spongiform.html
Tuesday, November 17, 2009
SEAC NEW RESULTS ON IDIOPATHIC BRAINSTEM NEURONAL CHROMATOLYSIS (IBNC) FROM THE VETERINARY LABORATORIES AGENCY (VLA) SEAC 103/1
http://bse-atypical.blogspot.com/2009/11/seac-new-results-on-idiopathic.html
Tuesday, November 17, 2009
SEAC EFFECT OF AGE ON THE PATHOGENESIS OF TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES SEAC 103/2
http://downercattle.blogspot.com/2009/11/seac-effect-of-age-on-pathogenesis-of.html
Terry S. Singeltary Sr
P.O. Box 42
Bacliff, Texas USA 77518
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Subject: Fw: OIE Animal Welfare documents for comment re: TAHSC September 2009 Report
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> OIE Animal Welfare documents for comment re: TAHSC September 2009 Report
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Monday, November 23, 2009
A case of atypical scrapie/Nor98 in a sheep from New Zealand
----- Original Message ----- From: Terry S. Singeltary Sr. To: TERRY SINGELTARY Sent: Sunday, November 22, 2009 9:21 PM Subject: A case of atypical scrapie/Nor98 in a sheep from New Zealand
A case of atypical scrapie/Nor98 in a sheep from New Zealand
Abnormal prion protein consistent with atypical scrapie/Nor98 has been detected in the brain of a New Zealand sheep that was part of a large consignment of brains sent to Europe for use as negative control material. Nature of atypical scrapie/Nor98 Accumulated scientific knowledge to date has demonstrated that atypical scrapie, also known as Nor98, is clinically, pathologically, biochemically and epidemiologically different from classical scrapie (1). The majority of atypical scrapie/Nor98 cases have been identified in clinically normal sheep sampled at slaughter (1-3). Cases have been reported from Norway, Sweden, Finland, the UK, Germany, France, Portugal, Belgium, the Netherlands, Ireland, Denmark(4), the United States (5) and Canada (6). The apparent prevalence of the cases in the European Union (EU) Member States is very low, for example for the UK it is less than 0.1%. Active surveillance programmes have led to the detection of atypical scrapie/Nor98 cases even in the absence of any case of classical scrapie in sheep in Portugal, Denmark, Sweden and Finland(4), and in the Falkland Islands(7), the first region in the Southern Hemisphere to report such a case. Atypical scrapie/Nor98 appears to be a non-contagious, sporadic degenerative condition of older sheep. A spontaneous aetiology, possibly with a genetic determinant, environmental influences and metabolic factors, has been suggested in a number of studies based on epidemiological evidence (2-4, 8). Contributing to this suggestion is the observation that atypical scrapie/Nor98 cases have been detected by active surveillance programmes, wherever such programmes have been initiated (4). Most cases which have been detected in a flock have been the only case and this lead to early speculation that the condition is not naturally infectious (1-3). Experimental oral transmission to sheep has been unsuccessful, to date. Experimental oral transmission into standard mice and into bank voles also failed (1). Only experimental intracerebral transmission to transgenic mice expressing the ovine (9, 10) or porcine (11) prion gene and experimental intracerebral challenge in sheep were successful (12). Unlike classical scrapie, abnormal prion protein has not been detected in peripheral tissues of sheep affected by atypical scrapie/Nor98 (1, 4). The OIE Terrestrial Animal Health Code chapter on scrapie specifically excludes atypical scrapie/Nor98 and explicitly states that the condition is unrelated to ‘classical’ scrapie, is probably not contagious and may be a spontaneously occurring condition (13). Draft for submission to Surveillance magazine 27/10/2009 2 It seems that wherever scrapie surveillance in sheep raising countries is intensified and suitable tests are used, atypical scrapie/Nor98 is found. Recently, three cases of atypical scrapie/Nor98 were reported in a UK research sheep flock derived from animals of New Zealand origin (14). Subsequent investigations in the UK did not find any evidence that the condition was either acquired in the UK or introduced from New Zealand. Thus the discovery of an atypical scrapie/Nor98 case in an otherwise healthy New Zealand sheep is not entirely unexpected (15); and reinforces the view that atypical scrapie/Nor 98 occurs spontaneously or naturally in very small numbers of older sheep in every population.
http://www.biosecurity.govt.nz/files/pests/atypical-scrapie/background-paper.pdf
2009 BSE AND SCRAPIE NZ
http://www.biosecurity.govt.nz/files/pests/atypical-scrapie/literature-review.pdf
Nevertheless, the incidence of atypical scrapie is much higher than that of sporadic CJD in humans. Long-term studies on the occurrence and genetics of atypical scrapie, combined with the development of more sensitive methods for detection of infectivity, are needed to elucidate these aspects. Atypical scrapie is not confined to sheep, as it has also been diagnosed in goats in a few European countries including Norway (Benestad et al. 2006). Currently the molecular characteristics of atypical scrapie in goats and sheep are indistinguishable (Le Dur et al. 2005). However, only a few cases have been found in goats to date, so any epidemiological link between the diseases in these two species is presently unknown. 4
http://www.vkm.no/dav/7f33267b4e.pdf
This position has been accepted by the OIE and the Animal Health Code Article 14.9.1 states “The chapter does not cover so-called ‘atypical’ scrapie which is clinically, pathologically, biochemically and epidemiologically unrelated to ‘classical’ scrapie, may not be contagious and may, in fact, be a spontaneous degenerative condition of older sheep.” This position has been supported by the scientific panel on biological hazards of the European Food Safety Authority 3.
snip...
Recent studies have shown experimental transmission of atypical scrapie in sheep and laboratory animals (Simmons et al 2007) but there is as yet no evidence to confirm that transmission can occur naturally in the field. Another recent paper by Espinosa et al (Espinosa, Herva, 2009) has shown that atypical scrapie can be transmitted with low efficiency to genetically engineered mice over expressing the porcine prion protein. They concluded there was a marked species transmission barrier. Further the agent appeared to undergo a strain phenotype shift upon transmission to the transgenic mice. This is the first report of this occurring.
http://www.biosecurity.govt.nz/files/pests/atypical-scrapie/literature-review.pdf
• Most critical is that atypical scrapie shows higher prevalence in so-called resistant ARR homozygote and heterozygote genotypes, compared with classical scrapie. • Atypical scrapie has not been found naturally in VRQ/VRQ sheep, although such sheep can be infected artificially. VRQ sheep are, in contrast, highly susceptible to classical scrapie. In the UK, one case of atypical scrapie has been found in VRQ heterozygote (AF141RQ/VRQ) sheep. It is important to ascertain whether or not VRQ-carrying sheep are significantly resistant to infection with atypical scrapie or whether the data might result from a failure to detect PrPres in atypical scrapie due to a different pattern of PrP distribution in tissues. • Increased incidence of atypical scrapie in sheep with PrP alleles carrying the variant phenylalanine (F) at position 141 (leucine(L)/phenylalanine) has also been observed compared with classical scrapie. • It will be important to clarify the genotype effect, particularly in relation to ARR and L141F in transmission studies. • In classical scrapie, there is clear evidence for a PrP genotype effect on tissue distribution patterns of PrPres. This might also be true for atypical scrapie although the data are less complete. 4. Transmission of atypical scrapie It has recently18 been demonstrated that atypical scrapie is experimentally transmissible to mice and sheep, primarily through intracerebral injection. There are some data suggesting that it may also be transmissible orally to sheep of different genotypes. The subgroup noted that challenge experiments with atypical scrapie in sheep were underway in the UK, with one successful intracerebral challenge to date. The subgroup was informed that positive transmission of infectivity from atypical scrapie isolated from sheep with a range of genotypes had been observed in mice. This included ovinised transgenic mice overexpressing the VRQ allele. Nor98 atypical scrapie had also transmitted to ARR ovinised mice, with transmission experiments in AF141RQ ovinised mice planned. Biochemical features of the isolates were maintained after transmission, and were distinct from BSE and classical scrapie. High infectivity titres were observed in brain tissue from atypical scrapie, including from ARR/ARR sheep. Brain transmission experiments in mice carrying the human PrP gene were at an early stage. 18 Le Dur A., Béringue V., Andréoletti O., Reine F., Laï T.H., Baron T., Bratberg B., Vilotte J.- L., Sarradin P., Benestad S.L. and Laude H.(2005) A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes. PNAS 102, 16031-16036
http://www.seac.gov.uk/pdf/positionstatement-sheep-subgroup.pdf
A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes
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*,†† + Author Affiliations
*Virologie Immunologie Moléculaires and ?Génétique Biochimique et Cytogénétique, Institut National de la Recherche Agronomique, 78350 Jouy-en-Josas, France; ‡Unité Mixte de Recherche, Institut National de la Recherche Agronomique-Ecole Nationale Vétérinaire de Toulouse, Interactions Hôte Agent Pathogène, 31066 Toulouse, France; §Agence Française de Sécurité Sanitaire des Aliments, Unité Agents Transmissibles Non Conventionnels, 69364 Lyon, France; **Pathologie Infectieuse et Immunologie, Institut National 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 (received for review March 21, 2005)
Next Section Abstract 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 a misfolded 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 to the 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 goat flocks and may have important implications in terms of scrapie control and public health.
SNIP...
Our study demonstrates that an authentic TSE infectious agent is responsible in sheep and goats of sporadic atypical infections that remained unnoticed until recently. This raises important issues with regard to control of scrapie infection in small ruminants. Of major concern, ARR/ARR sheep can no longer be regarded as free of natural TSE infection. This finding challenges, at least to some extent, the foundation of the selective breeding programs engaged in several European Union member states (47, 48) and may call for a reappraisal of possible consequences of this strategy in the long term. Finally, more information about this newly discovered type of TSE agent, its prevalence in countries free of scrapie or BSE disease, and its potential to across-species transmission would be needed for a comprehensive evaluation of its implications in terms of public health.
http://www.pnas.org/content/102/44/16031.long
http://www.pnas.org/content/102/44/16031.figures-only
Transmissibility of Atypical Scrapie in Ovine Transgenic Mice: Major Effects of Host Prion Protein Expression and Donor Prion Genotype
Atypical scrapie or Nor98 has been identified as a transmissible spongiform encephalopathy (TSE) that is clearly distinguishable from classical scrapie and BSE, notably regarding the biochemical features of the protease-resistant prion protein PrPres and the genetic factors involved in susceptibility to the disease. In this study we transmitted the disease from a series of 12 French atypical scrapie isolates in a transgenic mouse model (TgOvPrP4) overexpressing in the brain ~0.25, 1.5 or 6× the levels of the PrPARQ ovine prion protein under the control of the neuron-specific enolase promoter. We used an approach based on serum PrPc measurements that appeared to reflect the different PrPc expression levels in the central nervous system. We found that transmission of atypical scrapie, much more than in classical scrapie or BSE, was strongly influenced by the PrPc expression levels of TgOvPrP4 inoculated mice. Whereas TgOvPrP4 mice overexpressing ~6× the normal PrPc level died after a survival periods of 400 days, those with ~1.5× the normal PrPc level died at around 700 days. The transmission of atypical scrapie in TgOvPrP4 mouse line was also strongly influenced by the prnp genotypes of the animal source of atypical scrapie. Isolates carrying the AF141RQ or AHQ alleles, associated with increased disease susceptibility in the natural host, showed a higher transmissibility in TgOvPrP4 mice. The biochemical analysis of PrPres in TgOvPrP4 mouse brains showed a fully conserved pattern, compared to that in the natural host, with three distinct PrPres products. Our results throw light on the transmission features of atypical scrapie and suggest that the risk of transmission is intrinsically lower than that of classical scrapie or BSE, especially in relation to the expression level of the prion protein.
Article Metrics Related Content Comments: 0 Formal Correction: This article has been formally corrected to address the following errors.
To add a note, highlight some text. Hide notes Make a general comment Jump to Jean-Noël Arsac1, Dominique Bétemps1, Eric Morignat1, Cécile Féraudet2, Anna Bencsik1, Denise Aubert3, Jacques Grassi2, Thierry Baron1*
1 Agence Française de Sécurité Sanitaire des Aliments, Lyon, France, 2 Commissariat à l'Energie Atomique, Service de Pharmacologie et d'Immunoanalyse, Gif sur Yvette, France, 3 Ecole Normale Supérieure de Lyon, CNRS/INRA, Lyon, France
Abstract Top Atypical scrapie or Nor98 has been identified as a transmissible spongiform encephalopathy (TSE) that is clearly distinguishable from classical scrapie and BSE, notably regarding the biochemical features of the protease-resistant prion protein PrPres and the genetic factors involved in susceptibility to the disease. In this study we transmitted the disease from a series of 12 French atypical scrapie isolates in a transgenic mouse model (TgOvPrP4) overexpressing in the brain ~0.25, 1.5 or 6× the levels of the PrPARQ ovine prion protein under the control of the neuron-specific enolase promoter. We used an approach based on serum PrPc measurements that appeared to reflect the different PrPc expression levels in the central nervous system. We found that transmission of atypical scrapie, much more than in classical scrapie or BSE, was strongly influenced by the PrPc expression levels of TgOvPrP4 inoculated mice. Whereas TgOvPrP4 mice overexpressing ~6× the normal PrPc level died after a survival periods of 400 days, those with ~1.5× the normal PrPc level died at around 700 days. The transmission of atypical scrapie in TgOvPrP4 mouse line was also strongly influenced by the prnp genotypes of the animal source of atypical scrapie. Isolates carrying the AF141RQ or AHQ alleles, associated with increased disease susceptibility in the natural host, showed a higher transmissibility in TgOvPrP4 mice. The biochemical analysis of PrPres in TgOvPrP4 mouse brains showed a fully conserved pattern, compared to that in the natural host, with three distinct PrPres products. Our results throw light on the transmission features of atypical scrapie and suggest that the risk of transmission is intrinsically lower than that of classical scrapie or BSE, especially in relation to the expression level of the prion protein.
SNIP...
Discussion Top Characterization of the infectious agents involved in TSEs has historically required transmission in inbred wild-type mice, such as C57Bl, VM or RIII [4], [22], [23]. However some TSEs, such as the CH1641 experimental scrapie source [24] or some human TSEs [25] fail to transmit to wild-type mice of any genotype. The recent availability of transgenic mice expressing the prion gene of the natural host of the disease has facilitated TSE transmission studies, as in the use of ovine transgenic mice for scrapie or BSE [5], [20], [21]. The strain-specific molecular diversity of the classical scrapie or BSE sources was faithfully reproduced in the TgOvPrP4 ovine transgenic mouse model that we have developed. However, a novel TSE, called atypical scrapie or Nor98, has recently been identified in sheep and goats throughout Europe [12]. In several countries this disease is now more frequent than classical scrapie and in some countries atypical scrapie has been recognized in the absence of classical scrapie [26]–[28]. The experimental transmissibility of this disease was established in a transgenic mouse model (tg338) that strongly over-expresses (8- to 10-fold) the VRQ allele of ovine prion protein, from a series of 10 French atypical scrapie cases and 2 Norwegian Nor98 isolates [17]. In contrast, experimental transmission was not achieved in wild-type mice [12], [17] or in bank voles [29]. Overall this clearly confirmed that atypical scrapie is a genuine TSE associated with infectious prions.
In this study we confirmed the transmissibility of atypical scrapie, after intracerebral challenge, in another ovine transgenic mouse model (TgOvPrP4), but failed to transmit the disease from 2 cases into wild-type mice. Twelve cases, including the 10 French isolates previously transmitted to the tg338 mouse line [17], were successfully transmitted to TgOvPrP4 mice that over-expressed the AL141RQ prion protein. Although this prnp genotype of TgOvPrP4 mice is only rarely identified in sheep with atypical scrapie [13]–[16], [26], [30]–[33], most of the inoculated mice accumulated the pathological prion protein in their brain. Biochemical analysis of PrPres showed a fully conserved pattern comparable to that previously described in the natural host [15], i.e. a similar complex pattern including 5 major bands derived from 3 distinct PrPres products. Both PrPres fragments cleaved at both N- and C-terminal ends, and the uncleaved (or marginally cleaved) PrPres, were consistently maintained after transmission into ovine transgenic mice (Figure 4). The consistency of the Western blot profiles, whatever the isolate, and in line with previous studies in tg338 ovine transgenic mice, does not suggest any diversity in atypical scrapie. This consistent PrPres glycoprofile is somewhat reminiscent of certain PrPres features in patients with Gerstmann-Straüssler-Scheinker syndrome [34]–[36].
This study enabled us to extend the descriptive profile of our TgOvPrP4 mouse model and examine TSE transmission factors in relation to the level of expression of the prion protein by the infected host. After long-term breeding of the mouse line we indeed found three TgOvPrP4 mice subpopulations expressing in their brain ~0.25, 1.5 or 6× the PrPc level measured in a sheep brain control. We then decided to evaluate the possible influence of these differences in PrPc levels in the central nervous system on TSE development, following the inoculation of 3 mouse-adapted strains (BSE, C506M3, 87V), 3 experimental small ruminants isolates (SSBP1, CH1641, BSEOVINE) and 22 small ruminant natural isolates collected by active surveillance of TSEs in sheep and goats (10 classical scrapie isolates, including 3 usual isolates as shown by PrPres molecular analysis and 7 “CH1641-like” isolates; 12 atypical scrapie isolates). This panel of samples thus represents the molecular diversity of TSEs in small ruminants, especially with the three basic PrPres phenotypes possibly demonstrated by Western blot in natural scrapie. Strikingly the influence of the PrPc expression level was much more obvious for the atypical scrapie isolates, and a considerable delay in disease onset was associated with a decrease in PrPc expression levels,. TgOvPrP4 mice with higher PrPc levels (~6×) died after shorter periods (around 400 days) than mice with lower PrPc levels (~1.5×) (around 700 days). Comparisons of different transgenic mouse lines already indicated that the expression levels of the prion protein were inversely related to the incubation period in classical scrapie [6]. Nevertheless, to the best of our knowledge, the variable influence of PrPc expression levels according to the form of prion disease defined by its essential molecular features, has never been described and is here reported between different animals in a same transgenic mouse line. However, although the development of atypical scrapie appears to be much more facilitated by increased PrPc expression, this also suggests that the risk of transmission in animals expressing physiological levels of the protein would be relatively low. This characteristic, in addition to the species barrier, would help to explain the failure to transmit atypical scrapie to wild-type mice (RIII, VM and C56Bl mice) [17] or bank voles [29], unlike classical scrapie. Besides, a major influence of the PrPc expression levels has been demonstrated in transgenic mice over-expressing (i) mutated human prion protein linked to Gerstmann–Sträussler-Scheinker syndrome [37], [38] or (ii) a prion protein with a nine-octapeptide insertion associated with a human familial prion disease [39], [40]. In both cases disease development was strongly conditioned by the levels of transgene expressions, not only following inoculations of brain tissues from affected patients, but also spontaneously.
Our demonstration that atypical scrapie was much more influenced by PrPc expression levels than classical scrapie or BSE was possible in this mouse model solely because our approach was based on serum PrPc measurements. These were indeed found to reflect the levels of PrPc expression in the brain. In this model protein expression was controlled by the neuron-specific enolase promoter and neither RT-PCR or Western blot analyses were able to detect expression of the prnp gene in non nervous tissues [5], [41]. One explanation of the close relationship between serum and cerebral PrPc might be related to a release of PrPc from the central nervous system into the blood, as was also shown for some other neuronal proteins [42]. It is noteworthy that the plasma concentration of PrPc in wild-type C57Bl mice (~70+/-15 ng/ml) is much higher than in TgOvPrP4 mice, even in [TgOvPrP4 (x6)] with the highest level of expression (48+/-10 ng/ml). This suggests that a fraction of the PrPc in the serum of wild-type mice could originate from the nervous system, under physiological conditions. Importantly, direct evidence that PrPc readily crosses the blood brain barrier in both brain-to-blood and blood-to-brain directions has recently been reported [43]. Regarding the TgOvPrP4 mouse line, the presence of [TgOvPrP4 (x0.25)] animals which express low levels of PrPc clearly represents a drawback for transmission studies of TSEs. This can however be circumvented by assessing the PrPc expression levels in each individual mouse prior to its use in animal experiments. Furthermore, although this subpopulation increased following long-term random breeding of the mouse line, blood testing is also used to monitor PrPc expression levels during breeding in order to eliminate those breeders that produce progeny with a high proportion of poorly expressing animals. It should be noted that no indication of variation of transgene expression was found in a similarly produced mouse line (TgOvPrP59) originating from different founders [44], [45], which makes it unlikely that our observations in the TgOvPrP4 mouse line result from factors intrinsic to the transgene construct and/or the genetic background of the mice. However, the loss of transgene expression in a transgenic line is not unprecedented and two types of explanation are generally provided to account for such a loss. These include (1) integration of the transgene in an heterochromatin-rich region which results in silencing of the transgene in some cells (position effect variegation) [46] or (2) the repetitive nature of the transgene arrays which induces the formation of heterochromatin at the sites of integration and leads to gene silencing [47]. In addition, our genetic construction does not contain any insulators, which suggests that heterochromatin propagation might be a cause of transgene extinction in some animals [48].
Concerning the factors involved in the transmission of atypical scrapie, we were also surprised to demonstrate the influence of the prnp genotypes of the sheep or goat donors on development of the disease in TgOvPrP4 inoculated mice. This had not been observed in tg338 mice, which overall showed more rapid incubation of the disease [17]. Lower PrPc expression levels in TgOvPrP4 mice were required to transmit atypical scrapie, when the isolates carried the AF141RQ or AHQ alleles associated with increased susceptibility to the disease in sheep [14]. The same analysis of possible differences associated with the susceptible or resistant genotype, as here reported in atypical scrapie, could not be done for classical scrapie or BSE considering the available isolates. Among these sources only one classical scrapie isolates (Classusual 2) carried the ARR allele known to be associated with resistance to clinical scrapie [49], [50]. Although the ARR allele is rarely observed in classical scrapie we here confirmed, by both PrPres analyses in sheep and bioassays in wild-type and ovine transgenic mice, that it is possible to detect classical scrapie in relatively resistant animals during the implementation of flock analysis of scrapie cases [51]. Overall, given the limited number of samples available we cannot exclude a possible influence of the prnp genotypes for classical scrapie or BSE. The results observed with atypical scrapie are difficult to explain and we cannot exclude differences in infectious titres between the two groups of samples examined, in relation to (i) possible differences in the distribution of infectivity within the CNS [52] and/or (ii) different stages in the incubation periods in sheep and goats. On the other hand the AF141RQ or AHQ prnp alleles were associated with a lower conformational stability of the ovine PrPc protein [53], which might be associated with an increased capacity of the PrPsc of such genotypes to transconform PrPc. It is noteworthy that only one successful experimental transmission of atypical scrapie has so far been reported in sheep, which was obtained in an AHQ homozygous sheep intracerebrally inoculated with an atypical scrapie isolate from an AHQ homozygous sheep [18]. However the apparently spontaneous occurrence of three cases of atypical scrapie in genetically susceptible sheep was also reported in a flock derived from sheep imported from New Zealand, a country regarded as scrapie-free [54].
Based on our findings, the possibility that variations in the expression of ovine PrPc might be factors involved in susceptibility to atypical scrapie in sheep and goats, is open to question. A second proposal could question whether a failure of the protein quality-control systems might also be involved in susceptibility to atypical scrapie. Recent studies have provided new evidence for a role of these systems in the conversion of PrPc to an abnormal form of prion protein, with either impairment of proteasomal degradation or endoplasmic reticulum stress, leading to the generation of a misfolded form of prion protein [55]–[57]. Transgenic mice were also reported to develop a spontaneous neurological disease in the absence of PrPsc when preferentially expressing a transmembrane form of prion protein (PrPCtm) [58], [59], which would imply that CtmPrP is a key component in the pathway of neurodegeneration as in Gerstmann–Sträussler-Scheinker syndrome.
However our data do emphasize the unresolved questions regarding the origin of atypical scrapie, which as yet remains unknown. A spontaneous origin of the disease is suspected, and importantly, no evidence of natural transmissibility in small ruminants has been observed [33], [60]. The results of our novel approach, based on monitoring prion protein expression in animals from the same transgenic mouse line, suggest that the risk of transmission of atypical scrapie is intrinsically lower than that of classical scrapie or BSE, especially in relation to the expression level of the prion protein.
http://www.plosone.org/article/info:doi%2F10.1371%2Fjournal.pone.0007300
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.
***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
PR-26
NOR98 SHOWS MOLECULAR FEATURES REMINISCENT OF GSS
R. Nonno1, E. Esposito1, G. Vaccari1, E. Bandino2, M. Conte1, B. Chiappini1, S. Marcon1, M. Di Bari1, S.L. Benestad3, U. Agrimi1 1 Istituto Superiore di Sanità, Department of Food Safety and Veterinary Public Health, Rome, Italy (romolo.nonno@iss.it); 2 Istituto Zooprofilattico della Sardegna, Sassari, Italy; 3 National Veterinary Institute, Department of Pathology, Oslo, Norway
Molecular variants of PrPSc are being increasingly investigated in sheep scrapie and are generally referred to as "atypical" scrapie, as opposed to "classical scrapie". Among the atypical group, Nor98 seems to be the best identified. We studied the molecular properties of Italian and Norwegian Nor98 samples by WB analysis of brain homogenates, either untreated, digested with different concentrations of proteinase K, or subjected to enzymatic deglycosylation. The identity of PrP fragments was inferred by means of antibodies spanning the full PrP sequence. We found that undigested brain homogenates contain a Nor98-specific PrP fragment migrating at 11 kDa (PrP11), truncated at both the C-terminus and the N-terminus, and not N-glycosylated. After mild PK digestion, Nor98 displayed full-length PrP (FL-PrP) and N-glycosylated C-terminal fragments (CTF), along with increased levels of PrP11. Proteinase K digestion curves (0,006-6,4 mg/ml) showed that FL-PrP and CTF are mainly digested above 0,01 mg/ml, while PrP11 is not entirely digested even at the highest concentrations, similarly to PrP27-30 associated with classical scrapie. Above 0,2 mg/ml PK, most Nor98 samples showed only PrP11 and a fragment of 17 kDa with the same properties of PrP11, that was tentatively identified as a dimer of PrP11. Detergent solubility studies showed that PrP11 is insoluble in 2% sodium laurylsorcosine and is mainly produced from detergentsoluble, full-length PrPSc. Furthermore, among Italian scrapie isolates, we found that a sample with molecular and pathological properties consistent with Nor98 showed plaque-like deposits of PrPSc in the thalamus when the brain was analysed by PrPSc immunohistochemistry. Taken together, our results show that the distinctive pathological feature of Nor98 is a PrP fragment spanning amino acids ~ 90-155. This fragment is produced by successive N-terminal and C-terminal cleavages from a full-length and largely detergent-soluble PrPSc, is produced in vivo and is extremely resistant to PK digestion.
*** Intriguingly, these conclusions suggest that some pathological features of Nor98 are reminiscent of Gerstmann-Sträussler-Scheinker disease.
119
http://www.neuroprion.com/pdf_docs/conferences/prion2006/abstract_book.pdf
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 goat flocks and may have important implications in terms of scrapie control and public health.
Edited by Stanley B. Prusiner, University of California, San Francisco, CA, and approved September 12, 2005 (received for review March 21, 2005)
http://www.pnas.org/cgi/content/abstract/0502296102v1
>>> So far, there is no evidence for spontaneous PrPSc formation in any animal or human TSE.
Prions: Protein Aggregation and Infectious Diseases
ADRIANO AGUZZI AND ANNA MARIA CALELLA
Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland
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3. Sporadic Creutzfeldt-Jakob disease Approximately 85% of all human prion diseases are sporadic forms of CJD. For sCJD, there is no association with a mutant PRNP allele, nor is there any epidemiological evidence for exposure to a TSE agent through contact with people or animals infected with TSEs. sCJD cases are currently subclassified according to the methionine/valine polymorphism at codon 129 of the PRNP gene and the size and glycoform ratio of proteaseresistant prion protein identified on western blot (type 1 or type 2) (174). Heterozygosity (Met/Val) at PrP codon 129 appears to be associated with a lower risk (378) and/or prolonged incubation time (119, 387). The lack of routine laboratory testing for preclinical diagnosis makes the search for agent sources and other risk factors extremely difficult. At present, the means of acquisition of a TSE agent in these patients remains a mystery. So far, there is no evidence for spontaneous PrPSc formation in any animal or human TSE. In humans, the peak age incidence of sporadic CJD is 55–60 years. However, if spontaneous misfolding were the primary event, one might expect a continuously increasing incidence with age because more time would allow more opportunity for rare misfolding events.
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Physiol Rev • VOL 89 • OCTOBER 2009 • www.prv.org
http://physrev.physiology.org/cgi/content/abstract/89/4/1105
Monday, December 1, 2008
When Atypical Scrapie cross species barriers
http://nor-98.blogspot.com/2008/12/when-atypical-scrapie-cross-species.html
EVIDENCE OF SCRAPIE IN SHEEP AS A RESULT OF FOOD BORNE EXPOSURE
This is provided by the statistically significant increase in the incidence of sheep scrape from 1985, as determined from analyses of the submissions made to VI Centres, and from individual case and flock incident studies. ........
http://web.archive.org/web/20010305222246/www.bseinquiry.gov.uk/files/yb/1994/02/07002001.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.
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The successful transmission of kuru, Creutzfeldt-Jakob disease, and scrapie by natural feeding to squirrel monkeys that we have reported provides further grounds for concern that scrapie-infected meat may occasionally give rise in humans to Creutzfeldt-Jakob disease.
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://web.archive.org/web/20010305223125/www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
Nature. 1972 Mar 10;236(5341):73-4.
Transmission of scrapie to the cynomolgus monkey (Macaca fascicularis). Gibbs CJ Jr, Gajdusek DC.
Nature 236, 73 - 74 (10 March 1972); doi:10.1038/236073a0
Transmission of Scrapie to the Cynomolgus Monkey (Macaca fascicularis)
C. J. GIBBS jun. & D. C. GAJDUSEK
National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland
SCRAPIE has been transmitted to the cynomolgus, or crab-eating, monkey (Macaca fascicularis) with an incubation period of more than 5 yr from the time of intracerebral inoculation of scrapie-infected mouse brain. The animal developed a chronic central nervous system degeneration, with ataxia, tremor and myoclonus with associated severe scrapie-like pathology of intensive astroglial hypertrophy and proliferation, neuronal vacuolation and status spongiosus of grey matter. The strain of scrapie virus used was the eighth passage in Swiss mice (NIH) of a Compton strain of scrapie obtained as ninth intracerebral passage of the agent in goat brain, from Dr R. L. Chandler (ARC, Compton, Berkshire).
http://www.nature.com/nature/journal/v236/n5341/abs/236073a0.html
Epidemiology of Scrapie in the United States 1977
http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
http://web.archive.org/web/20030513212324/http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
Tuesday, April 28, 2009
Nor98-like Scrapie in the United States of America
http://nor-98.blogspot.com/2009/04/nor98-like-scrapie-in-united-states-of.html
Scrapie USA
http://scrapie-usa.blogspot.com/
SCRAPIE
The United States is unable to support the proposed new draft Code Chapter on Scrapie. The draft chapter, as written, departs significantly from the existing chapter, is confusing and is difficult to understand. This version of the scrapie chapter uses much of the same wording as the BSE chapter and is written as if the predominance of evidence revealed that scrapie was a food-borne disease similar to BSE in cattle which is inappropriate. Moreover, several of the new changes are not supported by current scientific evidence. As a result, detailed comments on individual articles would not meaningful at this time.
The United States is not supportive of the proposed draft chapter for the following reasons:
1. Inclusion of “atypical” scrapie: The scientific evidence indicates that “atypical” scrapie, also referred to as Nor-98, Nor-98-like, or non-classical scrapie, is not the same disease as classical scrapie. Further, “atypical” scrapie does not meet the criteria for listing diseases of trade concern by the OIE, as described in Chapter 2.1.1 of the Code. The United States recommends that the scope of this chapter be limited to classical scrapie in sheep and goats. Further, the United States recommends that OIE clearly adopt the position that “atypical” scrapie represents a distinct disease entity from classical scrapie and that it not be a listed disease.
• There is no evidence that “atypical” scrapie is a contagious disease. If it is contagious, available evidence suggests that it has a much lower transmission efficiency. (Hopp, et al, 2006; Green, et al, 2007; Benestad, et al 2008; McIntyre, et al, 2008)
• The disease appears to be ubiquitous in that it has been found wherever sufficient surveillance has been conducted. (Buschmann et al, 2004; De Bosschere et al, 2004; Orge, et al, 2004; Everest et al, 2006; Arsac, 2007; Benestad, et al 2008; Fediaevsky, et al, 2008)
• The disease does not appear to be economically significant in that the prevalence of clinical disease is low and it typically occurs in older animals. (Luhken, et al., 2007; Benestad, et al 2008).
• The disease is as likely as not to be the result of a spontaneous conversion of normal prion protein. (Benestad, et al 2008, De Bosschere et al 2007)
• Removal of exposed sheep is unlikely to reduce the prevalence of “atypical” scrapie infection and removing only those exposed sheep that are phenylalanine (F) at codon 141 is scientifically unsound since the disease is known to affect sheep of most other genotypes. Further, sheep with AHQ alleles have a similar risk of infection with “atypical” strains as sheep with F at codon 141. (Luhken, et al., 2007).
• If “atypical” scrapie is included as a listed disease, the surveillance and diagnostic requirements which are needed to identify these cases should be described in detail in both this Chapter and the Manual of Diagnostic Tests and Vaccines for Terrestrial
2
Animals. Data from Europe illustrates that using the proper test(s) is essential for the identification of atypical scrapie (Fediaevsky et al., 2008).
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6. Overemphasis on importation and use of bovine meat and bone meal as a route of scrapie transmission: Given that the draft Chapter is not intended to address risk mitigation for BSE in small ruminants, we believe there is an over-emphasis on this potential route of transmission in the current draft.
The United States recommends that the requirements in this chapter be limited to the inclusion of products from sheep and goats (instead of from all ruminants) in feed or feed ingredients intended for consumption by animals
• The use of products from sheep and goats as feed or feed ingredients for ruminant or non-ruminant animals represent one possible route of transmission (Philippe, et al, 2005) and a source of environmental contamination with the classical scrapie agent. However, this is not the primary route of transmission for the scrapie agent.
• The need for the exclusion of cattle-derived protein or other animal protein to mitigate BSE risk should be based on a country’s BSE risk status and should be addressed in Chapter 2.3.13 of the Code.
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14. Failure to provide scientific justification for the list of permitted commodities in Item 1 of Article 2.4.8.1. .
We recommend that the list be re-evaluated and those items that have not been substantiated as presenting no risk be excluded or those with some risk but where the intended use mitigates the risk the use be specified.
• There is no known human health risk associated with scrapie. As such, if meat and meat products for human consumption are included in this list, sheep and/or goat milk intended for human consumption should also be added to the list of permitted commodities in Item 1 of Article 2.4.8.1.
• In the vast majority of sheep infected with classical scrapie, actual infectivity or PrPres has been identified in most tissues including the lymphoreticular system (tonsils, spleen, lymph nodes), the gastrointestinal tract, brain, and spinal cord (Hadlow et. al. 1979; Hadlow et al., 1980; van Kuelen et al., 1996; van Kuelen et al., 1999, Andreoletti et al., 2000; Heggebø et al., 2002; Caplazi et al., 2004). Infectivity and/or PrPres has also been identified in the placenta (see Hourrigan et al., 1979; Onodera et al., 1993; Pattison et al., 1972; Pattison et al., 1974; Race et al., 1998), blood (Hunter et al., 2002; Houston et al. 2008); peripheral nerves (Groschup et al., 1996), muscle (Pattison and Millson, 1962; Andreoletti et al., 2004; Casalone et al., 2005), salivary gland (Hadlow et al., 1980; Vascellari et al., 2007), kidney (Siso et al., 2006), and skin ( Thomzig et al., 2007). In addition, recent work has shown milk and/or colostrum from scrapie infected ewes transmitted the disease to 17 of 18 lambs (Konold et al., 2008).
• The data on the risk of low protein tallow made from scrapie infected tissues particularly for use in milk replacer is limited and some epidemiologic studies suggest an association of milk replacer use with scrapie risk. Taylor et al., 1997 examined the inactivation capacity of different rendering system in regards to scrapie. The presence of infectivity was determined by bioassay into mice. From the onset of this study, it was assumed that tallow was not the vehicle for the transmission of TSE. Hence only 2 tallow samples were examined.
http://www.aphis.usda.gov/import_export/animals/oie/downloads/tahc_mar-sep08/tahc-scrapie-77-mar08_cmt.pdf
USDA's Deputy Secretary Talks with Sheep Producers
May 1, 2009 - "Life in rural America is intimately integrated with production agriculture," said Kathleen Merrigan, deputy secretary for the U.S. Department of Agriculture (USDA), when she addressed the more than 50 sheep producers from around the country who were in Washington, D.C., this week. "I am very interested in looking for new ways for farmers to market their products and for them to grab a little more of the food dollar. The connection between the food that consumers eat and the farms that the food is grown on must be closer, and I look forward to working with producers to affect that."
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According to Jere Dick, DVM, associate deputy administrator and chief of field operations for the Animal and Plant Health Inspection Service (APHIS), "We anticipate discussions and hopefully revisions of the scrapie chapter at the World Organization for Animal Health meeting this month. The revisions will likely exclude Nor-98 like scrapie from classical scrapie regulations. If this is done, APHIS will be able to exempt flocks with Nor-98 like scrapie cases, should they occur, from extensive flock depopulation actions."
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http://sheepusa.org/?page=site/newsandevents&nav_id=c806da768c6fcc2652eee0967bc96b5a#772efce63bd783bb5da167cf744f349a
Monday, November 23, 2009
BSE GBR RISK ASSESSMENTS UPDATE NOVEMBER 23, 2009 COMMISSION OF THE EUROPEAN COMMUNITIES AND O.I.E.
http://docket-aphis-2006-0041.blogspot.com/2009/11/bse-gbr-risk-assessments-update.html
Tuesday, November 17, 2009
SEAC NEW RESULTS ON IDIOPATHIC BRAINSTEM NEURONAL CHROMATOLYSIS (IBNC) FROM THE VETERINARY LABORATORIES AGENCY (VLA) SEAC 103/1
http://bse-atypical.blogspot.com/2009/11/seac-new-results-on-idiopathic.html
Tuesday, November 17, 2009
SEAC EFFECT OF AGE ON THE PATHOGENESIS OF TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES SEAC 103/2
http://downercattle.blogspot.com/2009/11/seac-effect-of-age-on-pathogenesis-of.html
Thursday, November 05, 2009
Incidence and spectrum of sporadic Creutzfeldt-Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification
http://creutzfeldt-jakob-disease.blogspot.com/2009/11/incidence-and-spectrum-of-sporadic.html
J Neurol Neurosurg Psychiatry 1994;57:757-758 doi:10.1136/jnnp.57.6.757 Research Article
Transmission of Creutzfeldt-Jakob disease to a chimpanzee by electrodes contaminated during neurosurgery.
C J Gibbs, Jr, D M Asher, A Kobrine, H L Amyx, M P Sulima, D C Gajdusek + Author Affiliations
Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892. Abstract Stereotactic multicontact electrodes used to probe the cerebral cortex of a middle aged woman with progressive dementia were previously implicated in the accidental transmission of Creutzfeldt-Jakob disease (CJD) to two younger patients. The diagnoses of CJD have been confirmed for all three cases. More than two years after their last use in humans, after three cleanings and repeated sterilisation in ethanol and formaldehyde vapour, the electrodes were implanted in the cortex of a chimpanzee. Eighteen months later the animal became ill with CJD. This finding serves to re-emphasise the potential danger posed by reuse of instruments contaminated with the agents of spongiform encephalopathies, even after scrupulous attempts to clean them.
http://jnnp.bmj.com/content/57/6/757.abstract
TSS
A case of atypical scrapie/Nor98 in a sheep from New Zealand
Abnormal prion protein consistent with atypical scrapie/Nor98 has been detected in the brain of a New Zealand sheep that was part of a large consignment of brains sent to Europe for use as negative control material. Nature of atypical scrapie/Nor98 Accumulated scientific knowledge to date has demonstrated that atypical scrapie, also known as Nor98, is clinically, pathologically, biochemically and epidemiologically different from classical scrapie (1). The majority of atypical scrapie/Nor98 cases have been identified in clinically normal sheep sampled at slaughter (1-3). Cases have been reported from Norway, Sweden, Finland, the UK, Germany, France, Portugal, Belgium, the Netherlands, Ireland, Denmark(4), the United States (5) and Canada (6). The apparent prevalence of the cases in the European Union (EU) Member States is very low, for example for the UK it is less than 0.1%. Active surveillance programmes have led to the detection of atypical scrapie/Nor98 cases even in the absence of any case of classical scrapie in sheep in Portugal, Denmark, Sweden and Finland(4), and in the Falkland Islands(7), the first region in the Southern Hemisphere to report such a case. Atypical scrapie/Nor98 appears to be a non-contagious, sporadic degenerative condition of older sheep. A spontaneous aetiology, possibly with a genetic determinant, environmental influences and metabolic factors, has been suggested in a number of studies based on epidemiological evidence (2-4, 8). Contributing to this suggestion is the observation that atypical scrapie/Nor98 cases have been detected by active surveillance programmes, wherever such programmes have been initiated (4). Most cases which have been detected in a flock have been the only case and this lead to early speculation that the condition is not naturally infectious (1-3). Experimental oral transmission to sheep has been unsuccessful, to date. Experimental oral transmission into standard mice and into bank voles also failed (1). Only experimental intracerebral transmission to transgenic mice expressing the ovine (9, 10) or porcine (11) prion gene and experimental intracerebral challenge in sheep were successful (12). Unlike classical scrapie, abnormal prion protein has not been detected in peripheral tissues of sheep affected by atypical scrapie/Nor98 (1, 4). The OIE Terrestrial Animal Health Code chapter on scrapie specifically excludes atypical scrapie/Nor98 and explicitly states that the condition is unrelated to ‘classical’ scrapie, is probably not contagious and may be a spontaneously occurring condition (13). Draft for submission to Surveillance magazine 27/10/2009 2 It seems that wherever scrapie surveillance in sheep raising countries is intensified and suitable tests are used, atypical scrapie/Nor98 is found. Recently, three cases of atypical scrapie/Nor98 were reported in a UK research sheep flock derived from animals of New Zealand origin (14). Subsequent investigations in the UK did not find any evidence that the condition was either acquired in the UK or introduced from New Zealand. Thus the discovery of an atypical scrapie/Nor98 case in an otherwise healthy New Zealand sheep is not entirely unexpected (15); and reinforces the view that atypical scrapie/Nor 98 occurs spontaneously or naturally in very small numbers of older sheep in every population.
http://www.biosecurity.govt.nz/files/pests/atypical-scrapie/background-paper.pdf
2009 BSE AND SCRAPIE NZ
http://www.biosecurity.govt.nz/files/pests/atypical-scrapie/literature-review.pdf
Nevertheless, the incidence of atypical scrapie is much higher than that of sporadic CJD in humans. Long-term studies on the occurrence and genetics of atypical scrapie, combined with the development of more sensitive methods for detection of infectivity, are needed to elucidate these aspects. Atypical scrapie is not confined to sheep, as it has also been diagnosed in goats in a few European countries including Norway (Benestad et al. 2006). Currently the molecular characteristics of atypical scrapie in goats and sheep are indistinguishable (Le Dur et al. 2005). However, only a few cases have been found in goats to date, so any epidemiological link between the diseases in these two species is presently unknown. 4
http://www.vkm.no/dav/7f33267b4e.pdf
This position has been accepted by the OIE and the Animal Health Code Article 14.9.1 states “The chapter does not cover so-called ‘atypical’ scrapie which is clinically, pathologically, biochemically and epidemiologically unrelated to ‘classical’ scrapie, may not be contagious and may, in fact, be a spontaneous degenerative condition of older sheep.” This position has been supported by the scientific panel on biological hazards of the European Food Safety Authority 3.
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Recent studies have shown experimental transmission of atypical scrapie in sheep and laboratory animals (Simmons et al 2007) but there is as yet no evidence to confirm that transmission can occur naturally in the field. Another recent paper by Espinosa et al (Espinosa, Herva, 2009) has shown that atypical scrapie can be transmitted with low efficiency to genetically engineered mice over expressing the porcine prion protein. They concluded there was a marked species transmission barrier. Further the agent appeared to undergo a strain phenotype shift upon transmission to the transgenic mice. This is the first report of this occurring.
http://www.biosecurity.govt.nz/files/pests/atypical-scrapie/literature-review.pdf
• Most critical is that atypical scrapie shows higher prevalence in so-called resistant ARR homozygote and heterozygote genotypes, compared with classical scrapie. • Atypical scrapie has not been found naturally in VRQ/VRQ sheep, although such sheep can be infected artificially. VRQ sheep are, in contrast, highly susceptible to classical scrapie. In the UK, one case of atypical scrapie has been found in VRQ heterozygote (AF141RQ/VRQ) sheep. It is important to ascertain whether or not VRQ-carrying sheep are significantly resistant to infection with atypical scrapie or whether the data might result from a failure to detect PrPres in atypical scrapie due to a different pattern of PrP distribution in tissues. • Increased incidence of atypical scrapie in sheep with PrP alleles carrying the variant phenylalanine (F) at position 141 (leucine(L)/phenylalanine) has also been observed compared with classical scrapie. • It will be important to clarify the genotype effect, particularly in relation to ARR and L141F in transmission studies. • In classical scrapie, there is clear evidence for a PrP genotype effect on tissue distribution patterns of PrPres. This might also be true for atypical scrapie although the data are less complete. 4. Transmission of atypical scrapie It has recently18 been demonstrated that atypical scrapie is experimentally transmissible to mice and sheep, primarily through intracerebral injection. There are some data suggesting that it may also be transmissible orally to sheep of different genotypes. The subgroup noted that challenge experiments with atypical scrapie in sheep were underway in the UK, with one successful intracerebral challenge to date. The subgroup was informed that positive transmission of infectivity from atypical scrapie isolated from sheep with a range of genotypes had been observed in mice. This included ovinised transgenic mice overexpressing the VRQ allele. Nor98 atypical scrapie had also transmitted to ARR ovinised mice, with transmission experiments in AF141RQ ovinised mice planned. Biochemical features of the isolates were maintained after transmission, and were distinct from BSE and classical scrapie. High infectivity titres were observed in brain tissue from atypical scrapie, including from ARR/ARR sheep. Brain transmission experiments in mice carrying the human PrP gene were at an early stage. 18 Le Dur A., Béringue V., Andréoletti O., Reine F., Laï T.H., Baron T., Bratberg B., Vilotte J.- L., Sarradin P., Benestad S.L. and Laude H.(2005) A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes. PNAS 102, 16031-16036
http://www.seac.gov.uk/pdf/positionstatement-sheep-subgroup.pdf
A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes
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*,†† + Author Affiliations
*Virologie Immunologie Moléculaires and ?Génétique Biochimique et Cytogénétique, Institut National de la Recherche Agronomique, 78350 Jouy-en-Josas, France; ‡Unité Mixte de Recherche, Institut National de la Recherche Agronomique-Ecole Nationale Vétérinaire de Toulouse, Interactions Hôte Agent Pathogène, 31066 Toulouse, France; §Agence Française de Sécurité Sanitaire des Aliments, Unité Agents Transmissibles Non Conventionnels, 69364 Lyon, France; **Pathologie Infectieuse et Immunologie, Institut National 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 (received for review March 21, 2005)
Next Section Abstract 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 a misfolded 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 to the 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 goat flocks and may have important implications in terms of scrapie control and public health.
SNIP...
Our study demonstrates that an authentic TSE infectious agent is responsible in sheep and goats of sporadic atypical infections that remained unnoticed until recently. This raises important issues with regard to control of scrapie infection in small ruminants. Of major concern, ARR/ARR sheep can no longer be regarded as free of natural TSE infection. This finding challenges, at least to some extent, the foundation of the selective breeding programs engaged in several European Union member states (47, 48) and may call for a reappraisal of possible consequences of this strategy in the long term. Finally, more information about this newly discovered type of TSE agent, its prevalence in countries free of scrapie or BSE disease, and its potential to across-species transmission would be needed for a comprehensive evaluation of its implications in terms of public health.
http://www.pnas.org/content/102/44/16031.long
http://www.pnas.org/content/102/44/16031.figures-only
Transmissibility of Atypical Scrapie in Ovine Transgenic Mice: Major Effects of Host Prion Protein Expression and Donor Prion Genotype
Atypical scrapie or Nor98 has been identified as a transmissible spongiform encephalopathy (TSE) that is clearly distinguishable from classical scrapie and BSE, notably regarding the biochemical features of the protease-resistant prion protein PrPres and the genetic factors involved in susceptibility to the disease. In this study we transmitted the disease from a series of 12 French atypical scrapie isolates in a transgenic mouse model (TgOvPrP4) overexpressing in the brain ~0.25, 1.5 or 6× the levels of the PrPARQ ovine prion protein under the control of the neuron-specific enolase promoter. We used an approach based on serum PrPc measurements that appeared to reflect the different PrPc expression levels in the central nervous system. We found that transmission of atypical scrapie, much more than in classical scrapie or BSE, was strongly influenced by the PrPc expression levels of TgOvPrP4 inoculated mice. Whereas TgOvPrP4 mice overexpressing ~6× the normal PrPc level died after a survival periods of 400 days, those with ~1.5× the normal PrPc level died at around 700 days. The transmission of atypical scrapie in TgOvPrP4 mouse line was also strongly influenced by the prnp genotypes of the animal source of atypical scrapie. Isolates carrying the AF141RQ or AHQ alleles, associated with increased disease susceptibility in the natural host, showed a higher transmissibility in TgOvPrP4 mice. The biochemical analysis of PrPres in TgOvPrP4 mouse brains showed a fully conserved pattern, compared to that in the natural host, with three distinct PrPres products. Our results throw light on the transmission features of atypical scrapie and suggest that the risk of transmission is intrinsically lower than that of classical scrapie or BSE, especially in relation to the expression level of the prion protein.
Article Metrics Related Content Comments: 0 Formal Correction: This article has been formally corrected to address the following errors.
To add a note, highlight some text. Hide notes Make a general comment Jump to Jean-Noël Arsac1, Dominique Bétemps1, Eric Morignat1, Cécile Féraudet2, Anna Bencsik1, Denise Aubert3, Jacques Grassi2, Thierry Baron1*
1 Agence Française de Sécurité Sanitaire des Aliments, Lyon, France, 2 Commissariat à l'Energie Atomique, Service de Pharmacologie et d'Immunoanalyse, Gif sur Yvette, France, 3 Ecole Normale Supérieure de Lyon, CNRS/INRA, Lyon, France
Abstract Top Atypical scrapie or Nor98 has been identified as a transmissible spongiform encephalopathy (TSE) that is clearly distinguishable from classical scrapie and BSE, notably regarding the biochemical features of the protease-resistant prion protein PrPres and the genetic factors involved in susceptibility to the disease. In this study we transmitted the disease from a series of 12 French atypical scrapie isolates in a transgenic mouse model (TgOvPrP4) overexpressing in the brain ~0.25, 1.5 or 6× the levels of the PrPARQ ovine prion protein under the control of the neuron-specific enolase promoter. We used an approach based on serum PrPc measurements that appeared to reflect the different PrPc expression levels in the central nervous system. We found that transmission of atypical scrapie, much more than in classical scrapie or BSE, was strongly influenced by the PrPc expression levels of TgOvPrP4 inoculated mice. Whereas TgOvPrP4 mice overexpressing ~6× the normal PrPc level died after a survival periods of 400 days, those with ~1.5× the normal PrPc level died at around 700 days. The transmission of atypical scrapie in TgOvPrP4 mouse line was also strongly influenced by the prnp genotypes of the animal source of atypical scrapie. Isolates carrying the AF141RQ or AHQ alleles, associated with increased disease susceptibility in the natural host, showed a higher transmissibility in TgOvPrP4 mice. The biochemical analysis of PrPres in TgOvPrP4 mouse brains showed a fully conserved pattern, compared to that in the natural host, with three distinct PrPres products. Our results throw light on the transmission features of atypical scrapie and suggest that the risk of transmission is intrinsically lower than that of classical scrapie or BSE, especially in relation to the expression level of the prion protein.
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Discussion Top Characterization of the infectious agents involved in TSEs has historically required transmission in inbred wild-type mice, such as C57Bl, VM or RIII [4], [22], [23]. However some TSEs, such as the CH1641 experimental scrapie source [24] or some human TSEs [25] fail to transmit to wild-type mice of any genotype. The recent availability of transgenic mice expressing the prion gene of the natural host of the disease has facilitated TSE transmission studies, as in the use of ovine transgenic mice for scrapie or BSE [5], [20], [21]. The strain-specific molecular diversity of the classical scrapie or BSE sources was faithfully reproduced in the TgOvPrP4 ovine transgenic mouse model that we have developed. However, a novel TSE, called atypical scrapie or Nor98, has recently been identified in sheep and goats throughout Europe [12]. In several countries this disease is now more frequent than classical scrapie and in some countries atypical scrapie has been recognized in the absence of classical scrapie [26]–[28]. The experimental transmissibility of this disease was established in a transgenic mouse model (tg338) that strongly over-expresses (8- to 10-fold) the VRQ allele of ovine prion protein, from a series of 10 French atypical scrapie cases and 2 Norwegian Nor98 isolates [17]. In contrast, experimental transmission was not achieved in wild-type mice [12], [17] or in bank voles [29]. Overall this clearly confirmed that atypical scrapie is a genuine TSE associated with infectious prions.
In this study we confirmed the transmissibility of atypical scrapie, after intracerebral challenge, in another ovine transgenic mouse model (TgOvPrP4), but failed to transmit the disease from 2 cases into wild-type mice. Twelve cases, including the 10 French isolates previously transmitted to the tg338 mouse line [17], were successfully transmitted to TgOvPrP4 mice that over-expressed the AL141RQ prion protein. Although this prnp genotype of TgOvPrP4 mice is only rarely identified in sheep with atypical scrapie [13]–[16], [26], [30]–[33], most of the inoculated mice accumulated the pathological prion protein in their brain. Biochemical analysis of PrPres showed a fully conserved pattern comparable to that previously described in the natural host [15], i.e. a similar complex pattern including 5 major bands derived from 3 distinct PrPres products. Both PrPres fragments cleaved at both N- and C-terminal ends, and the uncleaved (or marginally cleaved) PrPres, were consistently maintained after transmission into ovine transgenic mice (Figure 4). The consistency of the Western blot profiles, whatever the isolate, and in line with previous studies in tg338 ovine transgenic mice, does not suggest any diversity in atypical scrapie. This consistent PrPres glycoprofile is somewhat reminiscent of certain PrPres features in patients with Gerstmann-Straüssler-Scheinker syndrome [34]–[36].
This study enabled us to extend the descriptive profile of our TgOvPrP4 mouse model and examine TSE transmission factors in relation to the level of expression of the prion protein by the infected host. After long-term breeding of the mouse line we indeed found three TgOvPrP4 mice subpopulations expressing in their brain ~0.25, 1.5 or 6× the PrPc level measured in a sheep brain control. We then decided to evaluate the possible influence of these differences in PrPc levels in the central nervous system on TSE development, following the inoculation of 3 mouse-adapted strains (BSE, C506M3, 87V), 3 experimental small ruminants isolates (SSBP1, CH1641, BSEOVINE) and 22 small ruminant natural isolates collected by active surveillance of TSEs in sheep and goats (10 classical scrapie isolates, including 3 usual isolates as shown by PrPres molecular analysis and 7 “CH1641-like” isolates; 12 atypical scrapie isolates). This panel of samples thus represents the molecular diversity of TSEs in small ruminants, especially with the three basic PrPres phenotypes possibly demonstrated by Western blot in natural scrapie. Strikingly the influence of the PrPc expression level was much more obvious for the atypical scrapie isolates, and a considerable delay in disease onset was associated with a decrease in PrPc expression levels,. TgOvPrP4 mice with higher PrPc levels (~6×) died after shorter periods (around 400 days) than mice with lower PrPc levels (~1.5×) (around 700 days). Comparisons of different transgenic mouse lines already indicated that the expression levels of the prion protein were inversely related to the incubation period in classical scrapie [6]. Nevertheless, to the best of our knowledge, the variable influence of PrPc expression levels according to the form of prion disease defined by its essential molecular features, has never been described and is here reported between different animals in a same transgenic mouse line. However, although the development of atypical scrapie appears to be much more facilitated by increased PrPc expression, this also suggests that the risk of transmission in animals expressing physiological levels of the protein would be relatively low. This characteristic, in addition to the species barrier, would help to explain the failure to transmit atypical scrapie to wild-type mice (RIII, VM and C56Bl mice) [17] or bank voles [29], unlike classical scrapie. Besides, a major influence of the PrPc expression levels has been demonstrated in transgenic mice over-expressing (i) mutated human prion protein linked to Gerstmann–Sträussler-Scheinker syndrome [37], [38] or (ii) a prion protein with a nine-octapeptide insertion associated with a human familial prion disease [39], [40]. In both cases disease development was strongly conditioned by the levels of transgene expressions, not only following inoculations of brain tissues from affected patients, but also spontaneously.
Our demonstration that atypical scrapie was much more influenced by PrPc expression levels than classical scrapie or BSE was possible in this mouse model solely because our approach was based on serum PrPc measurements. These were indeed found to reflect the levels of PrPc expression in the brain. In this model protein expression was controlled by the neuron-specific enolase promoter and neither RT-PCR or Western blot analyses were able to detect expression of the prnp gene in non nervous tissues [5], [41]. One explanation of the close relationship between serum and cerebral PrPc might be related to a release of PrPc from the central nervous system into the blood, as was also shown for some other neuronal proteins [42]. It is noteworthy that the plasma concentration of PrPc in wild-type C57Bl mice (~70+/-15 ng/ml) is much higher than in TgOvPrP4 mice, even in [TgOvPrP4 (x6)] with the highest level of expression (48+/-10 ng/ml). This suggests that a fraction of the PrPc in the serum of wild-type mice could originate from the nervous system, under physiological conditions. Importantly, direct evidence that PrPc readily crosses the blood brain barrier in both brain-to-blood and blood-to-brain directions has recently been reported [43]. Regarding the TgOvPrP4 mouse line, the presence of [TgOvPrP4 (x0.25)] animals which express low levels of PrPc clearly represents a drawback for transmission studies of TSEs. This can however be circumvented by assessing the PrPc expression levels in each individual mouse prior to its use in animal experiments. Furthermore, although this subpopulation increased following long-term random breeding of the mouse line, blood testing is also used to monitor PrPc expression levels during breeding in order to eliminate those breeders that produce progeny with a high proportion of poorly expressing animals. It should be noted that no indication of variation of transgene expression was found in a similarly produced mouse line (TgOvPrP59) originating from different founders [44], [45], which makes it unlikely that our observations in the TgOvPrP4 mouse line result from factors intrinsic to the transgene construct and/or the genetic background of the mice. However, the loss of transgene expression in a transgenic line is not unprecedented and two types of explanation are generally provided to account for such a loss. These include (1) integration of the transgene in an heterochromatin-rich region which results in silencing of the transgene in some cells (position effect variegation) [46] or (2) the repetitive nature of the transgene arrays which induces the formation of heterochromatin at the sites of integration and leads to gene silencing [47]. In addition, our genetic construction does not contain any insulators, which suggests that heterochromatin propagation might be a cause of transgene extinction in some animals [48].
Concerning the factors involved in the transmission of atypical scrapie, we were also surprised to demonstrate the influence of the prnp genotypes of the sheep or goat donors on development of the disease in TgOvPrP4 inoculated mice. This had not been observed in tg338 mice, which overall showed more rapid incubation of the disease [17]. Lower PrPc expression levels in TgOvPrP4 mice were required to transmit atypical scrapie, when the isolates carried the AF141RQ or AHQ alleles associated with increased susceptibility to the disease in sheep [14]. The same analysis of possible differences associated with the susceptible or resistant genotype, as here reported in atypical scrapie, could not be done for classical scrapie or BSE considering the available isolates. Among these sources only one classical scrapie isolates (Classusual 2) carried the ARR allele known to be associated with resistance to clinical scrapie [49], [50]. Although the ARR allele is rarely observed in classical scrapie we here confirmed, by both PrPres analyses in sheep and bioassays in wild-type and ovine transgenic mice, that it is possible to detect classical scrapie in relatively resistant animals during the implementation of flock analysis of scrapie cases [51]. Overall, given the limited number of samples available we cannot exclude a possible influence of the prnp genotypes for classical scrapie or BSE. The results observed with atypical scrapie are difficult to explain and we cannot exclude differences in infectious titres between the two groups of samples examined, in relation to (i) possible differences in the distribution of infectivity within the CNS [52] and/or (ii) different stages in the incubation periods in sheep and goats. On the other hand the AF141RQ or AHQ prnp alleles were associated with a lower conformational stability of the ovine PrPc protein [53], which might be associated with an increased capacity of the PrPsc of such genotypes to transconform PrPc. It is noteworthy that only one successful experimental transmission of atypical scrapie has so far been reported in sheep, which was obtained in an AHQ homozygous sheep intracerebrally inoculated with an atypical scrapie isolate from an AHQ homozygous sheep [18]. However the apparently spontaneous occurrence of three cases of atypical scrapie in genetically susceptible sheep was also reported in a flock derived from sheep imported from New Zealand, a country regarded as scrapie-free [54].
Based on our findings, the possibility that variations in the expression of ovine PrPc might be factors involved in susceptibility to atypical scrapie in sheep and goats, is open to question. A second proposal could question whether a failure of the protein quality-control systems might also be involved in susceptibility to atypical scrapie. Recent studies have provided new evidence for a role of these systems in the conversion of PrPc to an abnormal form of prion protein, with either impairment of proteasomal degradation or endoplasmic reticulum stress, leading to the generation of a misfolded form of prion protein [55]–[57]. Transgenic mice were also reported to develop a spontaneous neurological disease in the absence of PrPsc when preferentially expressing a transmembrane form of prion protein (PrPCtm) [58], [59], which would imply that CtmPrP is a key component in the pathway of neurodegeneration as in Gerstmann–Sträussler-Scheinker syndrome.
However our data do emphasize the unresolved questions regarding the origin of atypical scrapie, which as yet remains unknown. A spontaneous origin of the disease is suspected, and importantly, no evidence of natural transmissibility in small ruminants has been observed [33], [60]. The results of our novel approach, based on monitoring prion protein expression in animals from the same transgenic mouse line, suggest that the risk of transmission of atypical scrapie is intrinsically lower than that of classical scrapie or BSE, especially in relation to the expression level of the prion protein.
http://www.plosone.org/article/info:doi%2F10.1371%2Fjournal.pone.0007300
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.
***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
PR-26
NOR98 SHOWS MOLECULAR FEATURES REMINISCENT OF GSS
R. Nonno1, E. Esposito1, G. Vaccari1, E. Bandino2, M. Conte1, B. Chiappini1, S. Marcon1, M. Di Bari1, S.L. Benestad3, U. Agrimi1 1 Istituto Superiore di Sanità, Department of Food Safety and Veterinary Public Health, Rome, Italy (romolo.nonno@iss.it); 2 Istituto Zooprofilattico della Sardegna, Sassari, Italy; 3 National Veterinary Institute, Department of Pathology, Oslo, Norway
Molecular variants of PrPSc are being increasingly investigated in sheep scrapie and are generally referred to as "atypical" scrapie, as opposed to "classical scrapie". Among the atypical group, Nor98 seems to be the best identified. We studied the molecular properties of Italian and Norwegian Nor98 samples by WB analysis of brain homogenates, either untreated, digested with different concentrations of proteinase K, or subjected to enzymatic deglycosylation. The identity of PrP fragments was inferred by means of antibodies spanning the full PrP sequence. We found that undigested brain homogenates contain a Nor98-specific PrP fragment migrating at 11 kDa (PrP11), truncated at both the C-terminus and the N-terminus, and not N-glycosylated. After mild PK digestion, Nor98 displayed full-length PrP (FL-PrP) and N-glycosylated C-terminal fragments (CTF), along with increased levels of PrP11. Proteinase K digestion curves (0,006-6,4 mg/ml) showed that FL-PrP and CTF are mainly digested above 0,01 mg/ml, while PrP11 is not entirely digested even at the highest concentrations, similarly to PrP27-30 associated with classical scrapie. Above 0,2 mg/ml PK, most Nor98 samples showed only PrP11 and a fragment of 17 kDa with the same properties of PrP11, that was tentatively identified as a dimer of PrP11. Detergent solubility studies showed that PrP11 is insoluble in 2% sodium laurylsorcosine and is mainly produced from detergentsoluble, full-length PrPSc. Furthermore, among Italian scrapie isolates, we found that a sample with molecular and pathological properties consistent with Nor98 showed plaque-like deposits of PrPSc in the thalamus when the brain was analysed by PrPSc immunohistochemistry. Taken together, our results show that the distinctive pathological feature of Nor98 is a PrP fragment spanning amino acids ~ 90-155. This fragment is produced by successive N-terminal and C-terminal cleavages from a full-length and largely detergent-soluble PrPSc, is produced in vivo and is extremely resistant to PK digestion.
*** Intriguingly, these conclusions suggest that some pathological features of Nor98 are reminiscent of Gerstmann-Sträussler-Scheinker disease.
119
http://www.neuroprion.com/pdf_docs/conferences/prion2006/abstract_book.pdf
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 goat flocks and may have important implications in terms of scrapie control and public health.
Edited by Stanley B. Prusiner, University of California, San Francisco, CA, and approved September 12, 2005 (received for review March 21, 2005)
http://www.pnas.org/cgi/content/abstract/0502296102v1
>>> So far, there is no evidence for spontaneous PrPSc formation in any animal or human TSE.
Prions: Protein Aggregation and Infectious Diseases
ADRIANO AGUZZI AND ANNA MARIA CALELLA
Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland
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3. Sporadic Creutzfeldt-Jakob disease Approximately 85% of all human prion diseases are sporadic forms of CJD. For sCJD, there is no association with a mutant PRNP allele, nor is there any epidemiological evidence for exposure to a TSE agent through contact with people or animals infected with TSEs. sCJD cases are currently subclassified according to the methionine/valine polymorphism at codon 129 of the PRNP gene and the size and glycoform ratio of proteaseresistant prion protein identified on western blot (type 1 or type 2) (174). Heterozygosity (Met/Val) at PrP codon 129 appears to be associated with a lower risk (378) and/or prolonged incubation time (119, 387). The lack of routine laboratory testing for preclinical diagnosis makes the search for agent sources and other risk factors extremely difficult. At present, the means of acquisition of a TSE agent in these patients remains a mystery. So far, there is no evidence for spontaneous PrPSc formation in any animal or human TSE. In humans, the peak age incidence of sporadic CJD is 55–60 years. However, if spontaneous misfolding were the primary event, one might expect a continuously increasing incidence with age because more time would allow more opportunity for rare misfolding events.
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Physiol Rev • VOL 89 • OCTOBER 2009 • www.prv.org
http://physrev.physiology.org/cgi/content/abstract/89/4/1105
Monday, December 1, 2008
When Atypical Scrapie cross species barriers
http://nor-98.blogspot.com/2008/12/when-atypical-scrapie-cross-species.html
EVIDENCE OF SCRAPIE IN SHEEP AS A RESULT OF FOOD BORNE EXPOSURE
This is provided by the statistically significant increase in the incidence of sheep scrape from 1985, as determined from analyses of the submissions made to VI Centres, and from individual case and flock incident studies. ........
http://web.archive.org/web/20010305222246/www.bseinquiry.gov.uk/files/yb/1994/02/07002001.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.
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The successful transmission of kuru, Creutzfeldt-Jakob disease, and scrapie by natural feeding to squirrel monkeys that we have reported provides further grounds for concern that scrapie-infected meat may occasionally give rise in humans to Creutzfeldt-Jakob disease.
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://web.archive.org/web/20010305223125/www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
Nature. 1972 Mar 10;236(5341):73-4.
Transmission of scrapie to the cynomolgus monkey (Macaca fascicularis). Gibbs CJ Jr, Gajdusek DC.
Nature 236, 73 - 74 (10 March 1972); doi:10.1038/236073a0
Transmission of Scrapie to the Cynomolgus Monkey (Macaca fascicularis)
C. J. GIBBS jun. & D. C. GAJDUSEK
National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland
SCRAPIE has been transmitted to the cynomolgus, or crab-eating, monkey (Macaca fascicularis) with an incubation period of more than 5 yr from the time of intracerebral inoculation of scrapie-infected mouse brain. The animal developed a chronic central nervous system degeneration, with ataxia, tremor and myoclonus with associated severe scrapie-like pathology of intensive astroglial hypertrophy and proliferation, neuronal vacuolation and status spongiosus of grey matter. The strain of scrapie virus used was the eighth passage in Swiss mice (NIH) of a Compton strain of scrapie obtained as ninth intracerebral passage of the agent in goat brain, from Dr R. L. Chandler (ARC, Compton, Berkshire).
http://www.nature.com/nature/journal/v236/n5341/abs/236073a0.html
Epidemiology of Scrapie in the United States 1977
http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
http://web.archive.org/web/20030513212324/http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
Tuesday, April 28, 2009
Nor98-like Scrapie in the United States of America
http://nor-98.blogspot.com/2009/04/nor98-like-scrapie-in-united-states-of.html
Scrapie USA
http://scrapie-usa.blogspot.com/
SCRAPIE
The United States is unable to support the proposed new draft Code Chapter on Scrapie. The draft chapter, as written, departs significantly from the existing chapter, is confusing and is difficult to understand. This version of the scrapie chapter uses much of the same wording as the BSE chapter and is written as if the predominance of evidence revealed that scrapie was a food-borne disease similar to BSE in cattle which is inappropriate. Moreover, several of the new changes are not supported by current scientific evidence. As a result, detailed comments on individual articles would not meaningful at this time.
The United States is not supportive of the proposed draft chapter for the following reasons:
1. Inclusion of “atypical” scrapie: The scientific evidence indicates that “atypical” scrapie, also referred to as Nor-98, Nor-98-like, or non-classical scrapie, is not the same disease as classical scrapie. Further, “atypical” scrapie does not meet the criteria for listing diseases of trade concern by the OIE, as described in Chapter 2.1.1 of the Code. The United States recommends that the scope of this chapter be limited to classical scrapie in sheep and goats. Further, the United States recommends that OIE clearly adopt the position that “atypical” scrapie represents a distinct disease entity from classical scrapie and that it not be a listed disease.
• There is no evidence that “atypical” scrapie is a contagious disease. If it is contagious, available evidence suggests that it has a much lower transmission efficiency. (Hopp, et al, 2006; Green, et al, 2007; Benestad, et al 2008; McIntyre, et al, 2008)
• The disease appears to be ubiquitous in that it has been found wherever sufficient surveillance has been conducted. (Buschmann et al, 2004; De Bosschere et al, 2004; Orge, et al, 2004; Everest et al, 2006; Arsac, 2007; Benestad, et al 2008; Fediaevsky, et al, 2008)
• The disease does not appear to be economically significant in that the prevalence of clinical disease is low and it typically occurs in older animals. (Luhken, et al., 2007; Benestad, et al 2008).
• The disease is as likely as not to be the result of a spontaneous conversion of normal prion protein. (Benestad, et al 2008, De Bosschere et al 2007)
• Removal of exposed sheep is unlikely to reduce the prevalence of “atypical” scrapie infection and removing only those exposed sheep that are phenylalanine (F) at codon 141 is scientifically unsound since the disease is known to affect sheep of most other genotypes. Further, sheep with AHQ alleles have a similar risk of infection with “atypical” strains as sheep with F at codon 141. (Luhken, et al., 2007).
• If “atypical” scrapie is included as a listed disease, the surveillance and diagnostic requirements which are needed to identify these cases should be described in detail in both this Chapter and the Manual of Diagnostic Tests and Vaccines for Terrestrial
2
Animals. Data from Europe illustrates that using the proper test(s) is essential for the identification of atypical scrapie (Fediaevsky et al., 2008).
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6. Overemphasis on importation and use of bovine meat and bone meal as a route of scrapie transmission: Given that the draft Chapter is not intended to address risk mitigation for BSE in small ruminants, we believe there is an over-emphasis on this potential route of transmission in the current draft.
The United States recommends that the requirements in this chapter be limited to the inclusion of products from sheep and goats (instead of from all ruminants) in feed or feed ingredients intended for consumption by animals
• The use of products from sheep and goats as feed or feed ingredients for ruminant or non-ruminant animals represent one possible route of transmission (Philippe, et al, 2005) and a source of environmental contamination with the classical scrapie agent. However, this is not the primary route of transmission for the scrapie agent.
• The need for the exclusion of cattle-derived protein or other animal protein to mitigate BSE risk should be based on a country’s BSE risk status and should be addressed in Chapter 2.3.13 of the Code.
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14. Failure to provide scientific justification for the list of permitted commodities in Item 1 of Article 2.4.8.1. .
We recommend that the list be re-evaluated and those items that have not been substantiated as presenting no risk be excluded or those with some risk but where the intended use mitigates the risk the use be specified.
• There is no known human health risk associated with scrapie. As such, if meat and meat products for human consumption are included in this list, sheep and/or goat milk intended for human consumption should also be added to the list of permitted commodities in Item 1 of Article 2.4.8.1.
• In the vast majority of sheep infected with classical scrapie, actual infectivity or PrPres has been identified in most tissues including the lymphoreticular system (tonsils, spleen, lymph nodes), the gastrointestinal tract, brain, and spinal cord (Hadlow et. al. 1979; Hadlow et al., 1980; van Kuelen et al., 1996; van Kuelen et al., 1999, Andreoletti et al., 2000; Heggebø et al., 2002; Caplazi et al., 2004). Infectivity and/or PrPres has also been identified in the placenta (see Hourrigan et al., 1979; Onodera et al., 1993; Pattison et al., 1972; Pattison et al., 1974; Race et al., 1998), blood (Hunter et al., 2002; Houston et al. 2008); peripheral nerves (Groschup et al., 1996), muscle (Pattison and Millson, 1962; Andreoletti et al., 2004; Casalone et al., 2005), salivary gland (Hadlow et al., 1980; Vascellari et al., 2007), kidney (Siso et al., 2006), and skin ( Thomzig et al., 2007). In addition, recent work has shown milk and/or colostrum from scrapie infected ewes transmitted the disease to 17 of 18 lambs (Konold et al., 2008).
• The data on the risk of low protein tallow made from scrapie infected tissues particularly for use in milk replacer is limited and some epidemiologic studies suggest an association of milk replacer use with scrapie risk. Taylor et al., 1997 examined the inactivation capacity of different rendering system in regards to scrapie. The presence of infectivity was determined by bioassay into mice. From the onset of this study, it was assumed that tallow was not the vehicle for the transmission of TSE. Hence only 2 tallow samples were examined.
http://www.aphis.usda.gov/import_export/animals/oie/downloads/tahc_mar-sep08/tahc-scrapie-77-mar08_cmt.pdf
USDA's Deputy Secretary Talks with Sheep Producers
May 1, 2009 - "Life in rural America is intimately integrated with production agriculture," said Kathleen Merrigan, deputy secretary for the U.S. Department of Agriculture (USDA), when she addressed the more than 50 sheep producers from around the country who were in Washington, D.C., this week. "I am very interested in looking for new ways for farmers to market their products and for them to grab a little more of the food dollar. The connection between the food that consumers eat and the farms that the food is grown on must be closer, and I look forward to working with producers to affect that."
snip...
According to Jere Dick, DVM, associate deputy administrator and chief of field operations for the Animal and Plant Health Inspection Service (APHIS), "We anticipate discussions and hopefully revisions of the scrapie chapter at the World Organization for Animal Health meeting this month. The revisions will likely exclude Nor-98 like scrapie from classical scrapie regulations. If this is done, APHIS will be able to exempt flocks with Nor-98 like scrapie cases, should they occur, from extensive flock depopulation actions."
snip...end
http://sheepusa.org/?page=site/newsandevents&nav_id=c806da768c6fcc2652eee0967bc96b5a#772efce63bd783bb5da167cf744f349a
Monday, November 23, 2009
BSE GBR RISK ASSESSMENTS UPDATE NOVEMBER 23, 2009 COMMISSION OF THE EUROPEAN COMMUNITIES AND O.I.E.
http://docket-aphis-2006-0041.blogspot.com/2009/11/bse-gbr-risk-assessments-update.html
Tuesday, November 17, 2009
SEAC NEW RESULTS ON IDIOPATHIC BRAINSTEM NEURONAL CHROMATOLYSIS (IBNC) FROM THE VETERINARY LABORATORIES AGENCY (VLA) SEAC 103/1
http://bse-atypical.blogspot.com/2009/11/seac-new-results-on-idiopathic.html
Tuesday, November 17, 2009
SEAC EFFECT OF AGE ON THE PATHOGENESIS OF TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES SEAC 103/2
http://downercattle.blogspot.com/2009/11/seac-effect-of-age-on-pathogenesis-of.html
Thursday, November 05, 2009
Incidence and spectrum of sporadic Creutzfeldt-Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification
http://creutzfeldt-jakob-disease.blogspot.com/2009/11/incidence-and-spectrum-of-sporadic.html
J Neurol Neurosurg Psychiatry 1994;57:757-758 doi:10.1136/jnnp.57.6.757 Research Article
Transmission of Creutzfeldt-Jakob disease to a chimpanzee by electrodes contaminated during neurosurgery.
C J Gibbs, Jr, D M Asher, A Kobrine, H L Amyx, M P Sulima, D C Gajdusek + Author Affiliations
Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892. Abstract Stereotactic multicontact electrodes used to probe the cerebral cortex of a middle aged woman with progressive dementia were previously implicated in the accidental transmission of Creutzfeldt-Jakob disease (CJD) to two younger patients. The diagnoses of CJD have been confirmed for all three cases. More than two years after their last use in humans, after three cleanings and repeated sterilisation in ethanol and formaldehyde vapour, the electrodes were implanted in the cortex of a chimpanzee. Eighteen months later the animal became ill with CJD. This finding serves to re-emphasise the potential danger posed by reuse of instruments contaminated with the agents of spongiform encephalopathies, even after scrupulous attempts to clean them.
http://jnnp.bmj.com/content/57/6/757.abstract
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