Published online before print October 22, 2009 This Article
Articles by Wemheuer, W. M. Articles by Schulz-Schaeffer, W. J.
PubMed
PubMed Citation Articles by Wemheuer, W. M. Articles by Schulz-Schaeffer, W. J.
Copyright © 2009 American Society for Investigative Pathology American Journal of Pathology, doi:10.2353/ajpath.2009.090623
Accepted for publication August 19, 2009.
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Article
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, University Medical Center Goettingen, Goettingen, Germany; National Veterinary Institute, Department of Pathology, Oslo, Norway; Institute of Veterinary Medicine, Faculty for Agricultural Sciences, University of Goettingen, Goettingen, Germany; National Transmissible Spongiform Encephalopathies Reference Center, Department of Neurology, University Medical Center Goettingen, Goettingen, Germany; and Animal Health,¶ Ecole Nationale Vétérinaire de Toulouse, Toulouse, France
@ To whom correspondence should be addressed. E-mail: wjschulz@med.uni-goettingen.de.
Abstract
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.
http://ajp.amjpathol.org/cgi/content/abstract/ajpath.2009.090623v1
P.4.25
Human susceptibility to atypical scrapie
Chris Plinston, Rona Barron, Nora Hunter The Roslin Institute and R(D)SVS, University of Edinburgh, UK
Background: Isolates of classical sheep scrapie are thought to pose little risk to humans as there have been no documented links between presence of sheep scrapie and the development of human TSE disease. However, the link between BSE and the development of vCJD in humans proves that a risk does exist from ruminant TSE disease, and therefore all new ruminant TSEs may potentially be transmissible to humans. Due to increased sensitivity of TSE diagnostic assay systems, a new TSE of sheep termed 'atypical scrapie' has been identified. This disease has been difficult to identify, and is found mainly in sheep which are previously thought to have a genetic makeup that made them resistant to scrapie. It is unclear whether this is a new TSE of sheep, an old disease which has only been identified through increased surveillance, or if it represents the phenotype of classical scrapie in so called 'resistant' sheep PrP genotypes.
Objectives: The objective of the study is to assess relative transmissibility of atypical scrapie isolates to humans and the associated risk to the population.
Methods: In order to determine whether atypical scrapie poses a risk to human health we have transmitted isolates from three different sheep PrP genotypes to our gene targeted transgenic mice which express human PrP with the M129V polymorphism known to be important in human susceptibility to disease. Mice of all three PrP genotypes have been inoculated intracerebrally with atypical scrapie isolates.
Discussion: In order to prevent the emergence of a new human TSE, we need to be able to assess the risk to humans from new emerging TSEs in livestock. The study of atypical scrapie infection in these transgenic lines could therefore provide important information on the host range and disease characteristics associated with such isolates. Preventative measures could then be put in place before this disease gives rise to another human disease variant and an underlying level of infection in the population.
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
Wednesday, July 1, 2009
Nor98 scrapie identified in the United States J Vet Diagn Invest 21:454-463 (2009)
http://nor-98.blogspot.com/2009/07/nor98-scrapie-identified-in-united.html
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
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)
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.
http://www.pnas.org/content/102/44/16031.abstract
Monday, December 1, 2008
When Atypical Scrapie cross species barriers
Authors
Andreoletti O., Herva M. H., Cassard H., Espinosa J. C., Lacroux C., Simon S., Padilla D., Benestad S. L., Lantier F., Schelcher F., Grassi J., Torres, J. M., UMR INRA ENVT 1225, Ecole Nationale Veterinaire de Toulouse.France; ICISA-INlA, Madrid, Spain; CEA, IBiTec-5, DSV, CEA/Saclay, Gif sur Yvette cedex, France; National Veterinary Institute, Postboks 750 Sentrum, 0106 Oslo, Norway, INRA IASP, Centre INRA de Tours, 3738O Nouzilly, France.
Content
Atypical scrapie is a TSE occurring in small ruminants and harbouring peculiar clinical, epidemiological and biochemical properties. Currently this form of disease is identified in a large number of countries. In this study we report the transmission of an atypical scrapie isolate through different species barriers as modeled by transgenic mice (Tg) expressing different species PRP sequence.
The donor isolate was collected in 1995 in a French commercial sheep flock. inoculation into AHQ/AHQ sheep induced a disease which had all neuro-pathological and biochemical characteristics of atypical scrapie. Transmitted into Transgenic mice expressing either ovine or PrPc, the isolate retained all the described characteristics of atypical scrapie.
Surprisingly the TSE agent characteristics were dramatically different v/hen passaged into Tg bovine mice. The recovered TSE agent had biological and biochemical characteristics similar to those of atypical BSE L in the same mouse model. Moreover, whereas no other TSE agent than BSE were shown to transmit into Tg porcine mice, atypical scrapie was able to develop into this model, albeit with low attack rate on first passage.
Furthermore, after adaptation in the porcine mouse model this prion showed similar biological and biochemical characteristics than BSE adapted to this porcine mouse model. Altogether these data indicate.
(i) the unsuspected potential abilities of atypical scrapie to cross species barriers
(ii) the possible capacity of this agent to acquire new characteristics when crossing species barrier
These findings raise some interrogation on the concept of TSE strain and on the origin of the diversity of the TSE agents and could have consequences on field TSE control measures.
http://www.neuroprion.org/resources/pdf_docs/conferences/prion2008/abstract-book-prion2008.pdf
NOR-98 ATYPICAL SCRAPIE 5 cases documented in USA in 5 different states USA 2007
http://nor-98.blogspot.com/2008/04/seac-spongiform-encephalopathy-advisory.html
Tuesday, June 3, 2008 SCRAPIE USA UPDATE JUNE 2008 NOR-98 REPORTED PA
http://nor-98.blogspot.com/2008/06/scrapie-usa-update-june-2008-nor-98.html
Monday, September 1, 2008
RE-FOIA OF DECLARATION OF EXTRAORDINARY EMERGENCY BECAUSE OF AN ATYPICAL T.S.E. (PRION DISEASE) OF FOREIGN ORIGIN IN THE UNITED STATES [No. 00-072-1] September 1, 2008
http://foiamadsheepmadrivervalley.blogspot.com/2008/09/re-foia-of-declaration-of-extraordinary.html
http://nor-98.blogspot.com/
http://scrapie-usa.blogspot.com/
1: J Infect Dis 1980 Aug;142(2):205-8
Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.
Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.
Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation.
PMID: 6997404
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
12/10/76 AGRICULTURAL RESEARCH COUNCIL REPORT OF THE ADVISORY COMMITTE ON SCRAPIE Office Note CHAIRMAN: PROFESSOR PETER WILDY
snip...
A The Present Position with respect to Scrapie
A1 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://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
Epidemiology of Scrapie in the United States 1977
http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
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
http://nor-98.blogspot.com/
http://scrapie-usa.blogspot.com/
Monday, October 19, 2009
Atypical BSE, BSE, and other human and animal TSE in North America Update October 19, 2009
http://bse-atypical.blogspot.com/2009/10/atypical-bse-bse-and-other-human-and.html
Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518
Monday, October 26, 2009
Similarities between Forms of Sheep Scrapie and Creutzfeldt-Jakob Disease Are Encoded by Distinct Prion Types
Wednesday, July 8, 2009
Transgenic Mice Expressing Porcine Prion Protein Resistant to Classical Scrapie but Susceptible to Sheep BSE and Atypical Scrapie
DOI: 10.3201/eid1508.081218
Suggested citation for this article: Espinosa J-C, Herva M-E, Andréoletti O, Padilla D, Lacroux C, Cassard H, et al. Transgenic mice expressing porcine prion protein resistant to classical scrapie but susceptible to sheep bovine spongiform encephalopathy and atypical scrapie. Emerg Infect Dis. 2009 Aug; [Epub ahead of print]
Transgenic Mice Expressing Porcine Prion Protein Resistant to Classical Scrapie but Susceptible to Sheep Bovine Spongiform Encephalopathy and Atypical Scrapie
Juan-Carlos Espinosa,1 María-Eugenia Herva,1 Olivier Andréoletti, Danielle Padilla, Caroline Lacroux, Hervé Cassard, Isabelle Lantier, Joaquin Castilla, and Juan-María Torres
Author affiliations: Centro de Investigación en Sanidad Animal, Madrid, Spain (J.-C. Espinosa, M.-E. Herva, D. Padilla, J. Castilla, J.-M. Torres); École Nationale Vétérinaire de Toulouse, Toulouse, France (O. Andréoletti, C. Lacroux, H. Cassard); and Centre Institut National de la Recherche Agronomique de Tours, Nouzilly, France (I. Lantier)
1These authors contributed equally to this article.
How susceptible pigs are to infection with sheep prions is unknown. We show, through transmission experiments in transgenic mice expressing porcine prion protein (PrP), that the susceptibility of this mouse model to bovine spongiform encephalopathy (BSE) can be enhanced after its passage in ARQ sheep, indicating that the pathogenicity of the BSE agent is modified after passage in sheep. Transgenic mice expressing porcine PrP were, nevertheless, completely resistant to infection with a broad panel of classical scrapie isolates from different sheep PrP genotypes and with different biochemical characteristics. The atypical (Nor98 like) isolate (SC-PS152) was the only scrapie isolate capable of transmission in these mice, although with a marked transmission barrier. Unexpectedly, the atypical scrapie agent appeared to undergo a strain phenotype shift upon transmission to porcine-PrP transgenic mice and acquired new strain properties, suggesting that atypical scrapie agent may exhibit different phenotypes depending on the host cellular PrP or other genetic factors.
snip...
Discussion
In this study, transgenic mice expressing porcine PrP (8) were used to assess the transmission capacity of a wide range of TSE agents from sheep. Our results indicated that none of the classical scrapie isolates tested was transmitted to our porcine PrP mouse model after intracerebral inoculation (Table), suggesting a highly (if not completely) resistance to the classical scrapie strains tested independently of their origin and biochemical signature. The absence of successful transmission of the SC-PS48 isolates with an unglycosylated bands of 19 kDa-like BSE suggests a BSE-unrelated origin for these BSE-like scrapie strains.
The atypical isolate SC-PS152 was the only scrapie isolate able to infect the Po-PrP mouse model after intracerebral inoculation (Table), albeit with a low efficiency of infection in the first passage (attack rate 16%). These results suggest the potential ability of atypical scrapie prions to infect pigs, although with a strong transmission barrier. Given the increasing number of atypical scrapie cases found in Europe and in North America, the potential ability of atypical scrapie to adapt to the pig becoming more easily transmitted could raise concerns about the potential danger of feeding ruminant meat and bone meal to swine.
In our transmission experiments, an obviously shorter survival period (458 ± 11 dpi) and an increased attack rate (100%) were observed in PoPrP-Tg001 mice inoculated with sheep BSE (Table) compared with those inoculated with the original cattle BSE (>650 dpi, 19%). These last figures correlate well with those reported for other cattle BSE isolates (Table). Differences in survival times were maintained after subsequent passages in this mouse model (Table), suggesting that the increased infectivity of sheep BSE cannot be linked to a higher infectious titer in the initial inoculum but must be the outcome of a modification in the pathogenicity of the agent. We can also rule out that the primary amino acid sequence of the ovine PrPSC leads to more efficient conversion of porcine PrPC because scrapie isolates from sheep with the same ARQ-PrP genotype were not able to infect these mice (Table). Taken together, the increased infectivity of sheep BSE in the porcine PrP mouse model must be considered as increased pathogenicity of the agent attributable to its passage in sheep. These features support previous results indicating that the BSE agent modifies its biological properties after passage in sheep, with the result that its pathogenicity increases in transgenic mice expressing bovine PrP (24). An increased pathogenicity of ovine BSE was also reported in conventional RIII mice when compared with retrospective cattle BSE experiments (36). In other prion strains, passage through an intermediate species has also been noted to alter host susceptibility (37).
The enhanced infectivity of the BSE agent after its passage in ARQ sheep raises concern about its potential danger for other species, including humans. This question, as well as others related to the infectivity of the new porcine prion generated in this study, is currently being addressed in transmission experiments using transgenic mice expressing human PrP.
Upon passages in porcine PrP transgenic mice, the BSE agent retained most of its biochemical properties, except for its PrPres glycoprofile in which some differences were appreciable. Our comparative analysis of cattle BSE and sheep BSE upon transmission in porcine PrP transgenic mice showed that both agents exhibit similar molecular (Figure 2) and neuropathologic properties (Figure 4). These features were preserved after subsequent passages. These results suggest that, despite their modified pathogenicity, the 2 porcine prions generated share the same biochemical and neuropathologic properties, regardless of whether the BSE agent used to inoculate the mice was obtained from ARQ sheep or cows. In agreement with these results, the increased infectivity of sheep BSE previously observed upon transmission in bovine PrP transgenic mice was not reflected in its molecular or neuropathologic properties (24).
The atypical scrapie (SC-PS152) agent appeared to undergo a strain phenotype shift upon transmission to porcine PrP transgenic mice. Surprisingly, this novel strain phenotype was similar to that of sheep BSE propagated in the same mice in terms of several features: 1) survival times observed after stabilization in PoPrP-Tg001 mice (second passages) were similar (Table); 2) PrPres molecular profiles of the 2 agents in porcine PrP mice were indistinguishable (Figure 3); and 3) vacuolation profiles observed in second passages largely overlapped (Figure 4).
These findings could reflect the evolutionary potential of prion agents upon transmission to a foreign host able to promote strain shift and emergence of new properties (38,39). The converging molecular, neuropathologic, and biological properties of atypical scrapie and sheep BSE upon propagation in porcine transgenic mice could be the consequence of a restriction imposed by the porcine PrPC, which might only admit a few options as it changes its conformation to PrPSC.
Our results could also suggest a common origin for sheep BSE and atypical scrapie agents, which may exhibit different phenotypes depending on the host PrPC or other host factors.
Although this last explanation seems to be less likely, so far we cannot draw any definitive conclusion on this issue. Whichever the case, the ability of an atypical scrapie to infect other species and its potential capacity to undergo a strain phenotype shift in the new host prompts new concerns about the possible spread of this uncommon TSE in other species as a masked prion undistinguishable from other strains.
snip... see full text ;
http://www.cdc.gov/eid/content/15/8/pdfs/08-1218.pdf
Saturday, May 2, 2009
APHIS AND WHO PLAN TO EXEMPT THE ATYPICAL SCRAPIE NOR-98 FROM REGULATIONS AT MEETING THIS MONTH
http://nor-98.blogspot.com/2009/05/aphis-and-who-plan-to-exempt-atypical.html
1: J Infect Dis 1980 Aug;142(2):205-8
Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.
Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.
Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation.
PMID: 6997404
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
12/10/76 AGRICULTURAL RESEARCH COUNCIL REPORT OF THE ADVISORY COMMITTE ON SCRAPIE Office Note CHAIRMAN: PROFESSOR PETER WILDY
snip...
A The Present Position with respect to Scrapie
A1 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://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
Epidemiology of Scrapie in the United States 1977
http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
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
http://nor-98.blogspot.com/
http://scrapie-usa.blogspot.com/
see full text ;
Wednesday, July 1, 2009
Nor98 scrapie identified in the United States J Vet Diagn Invest 21:454-463 (2009)
http://nor-98.blogspot.com/2009/07/nor98-scrapie-identified-in-united.html
4.296 On 20 August 1990, a positive result was recorded in the CVL's experiment to transmit BSE to pigs. One pig had been diagnosed by post-mortem pathology as having developed a spongiform encephalopathy. A confidential pathology report submitted by Mr Gerald Wells, Head of the CVL's Neuropathology Section, to his colleague Mr Michael Dawson in the Virology Department, included the following remark:
The result, albeit confined to one animal in the experimental challenge group is incontrovertible evidence of the transmissibility of BSE to the pig by simultaneous intracerebral, intravenous and intraperitoneal inoculation routes. 11
http://www.bseinquiry.gov.uk/report/volume11/chapter8.htm#808467
http://www.bseinquiry.gov.uk/report/volume11/chapter8.htm#808471
http://www.bseinquiry.gov.uk/report/volume11/chapter8.htm#808475
http://www.bseinquiry.gov.uk/report/volume11/chapter8.htm#808479
http://www.bseinquiry.gov.uk/report/volume11/chapter8.htm#808483
http://www.bseinquiry.gov.uk/report/volume11/chapter8.htm#808487
4.303 The minutes of the meeting record that:
It was very difficult to draw conclusions from one experimental result for what may happen in the field. However it would be prudent to exclude specified bovine offals from the pig diet. Although any relationship between BSE and the finding of a spongiform encephalopathy in cats had yet to be demonstrated, the fact that this had occurred suggested that a cautious view should be taken of those species which might be susceptible. The 'specified offals' of bovines should therefore be excluded from the feed of all species. 17
http://www.bseinquiry.gov.uk/report/volume11/chapter8.htm#808491
4.308 SEAC issued formal advice on 20 September 1990, following its meeting on the previous day. The advice stated:
Since this result shows that pigs can get spongiform encephalopathy, even though there is no evidence that they have done so in the field, we believe that pigs should no longer be fed with protein derived from bovine tissues which might contain the BSE agent, ie, those 'specified' bovine offals that are already excluded from human consumption. It would make sense to extend this prohibition to feed for all species, including household pets, as other species have now developed spongiform encephalopathies. We are aware that many animal feed compounders and pet food manufacturers are already applying such a ban on a voluntary basis. 22
http://www.bseinquiry.gov.uk/report/volume11/chapter8.htm#808511
4.309 In a statement to the Inquiry, Dr Tyrrell said:
It was the rapid increase in the BSE epidemic, the occurrence of more cases of FSE and the results of the pig transmission experiment which led SEAC to give the advice we did on the extension of the SBO ban. Before then (September 1990), we were not asked to advise on the extension of the SBO ban. It was important to consider humans before other animals. It should be remembered that prior to the test results of the pig transmission experiment, pigs and poultry were not known to be susceptible to TSEs. Breeding pigs, in particular, were thought to have received a very high exposure to the same type of contaminated MBM as cattle but without any evidence of the occurrence of TSE. The issue of symptom-less hosts was considered very carefully because it could apply to all domestic and farmed animal species. 23
http://www.bseinquiry.gov.uk/report/volume11/chapter8.htm#808515
3.57 The experiment which might have determined whether BSE and scrapie were caused by the same agent (ie, the feeding of natural scrapie to cattle) was never undertaken in the UK. It was, however, performed in the USA in 1979, when it was shown that cattle inoculated with the scrapie agent endemic in the flock of Suffolk sheep at the United States Department of Agriculture in Mission, Texas, developed a TSE quite unlike BSE.339 The findings of the initial transmission, though not of the clinical or neurohistological examination, were communicated in October 1988 to Dr Watson, Director of the CVL, following a visit by Dr Wrathall, one of the project leaders in the Pathology Department of the CVL, to the United States Department of Agriculture.340 The results were not published at this point, since the attempted transmission to mice from the experimental cow brain had been inconclusive. The results of the clinical and histological differences between scrapie-affected sheep and cattle were published in 1995. Similar studies in which cattle were inoculated intracerebrally with scrapie inocula derived from a number of scrapie-affected sheep of different breeds and from different States, were carried out at the US National Animal Disease Centre.341 The results, published in 1994, showed that this source of scrapie agent, though pathogenic for cattle,
*** did not produce the same clinical signs of brain lesions characteristic of BSE. ***
3.58 There are several possible reasons why the experiment was not performed in the UK. It had been recommended by Sir Richard Southwood (Chairman of the Working Party on Bovine Spongiform Encephalopathy) in his letter to the Permanent Secretary of MAFF, Mr (now Sir) Derek Andrews, on 21 June 1988,342 though it was not specifically recommended in the Working Party Report or indeed in the Tyrrell Committee Report (details of the Southwood Working Party and the Tyrell Committee can be found in vol. 4: The Southwood Working Party, 1988–89 and vol. 11: Scientists after Southwood respectively). The direct inoculation of scrapie into calves was given low priority, because of its high cost and because it was known that it had already taken place in the USA.343 It was also felt that the results of such an experiment would be hard to interpret. While a negative result 337 Fraser, H., Bruce, M., Chree, A., McConnell, I. and Wells, G. (1992) Transmission of Bovine Spongiform Encephalopathy and Scrapie to Mice, Journal of General Virology, 73, 1891–7; Bruce, M., Chree, A., McConnell, I., Foster, J., Pearson, G. and Fraser, H. (1994) Transmission of Bovine Spongiform Encephalopathy and Scrapie to Mice: Strain Variation and the Species Barrier, Philosophical Transactions of the Royal Society of London, Series B, Biological Sciences, 343, 405–11 338 Bruce, M., Will, R., Ironside, J., McConell, I., Drummond, D., Suttie, A., McCordie, L., Chree, A., Hope, J., Birkett, C., Cousens, S., Fraser, H. and Bostock, C. (1997) Transmissions to Mice Indicate that ‘New Variant’ CJD is Caused by the BSE Agent, Nature, 389, 498–501 339 Clark, W., Hourrigan, J. and Hadlow, W. (1995) Encephalopathy in Cattle Experimentally Infected with the Scrapie Agent, American Journal of Veterinary Research, 56, 606–12 340 YB88/10.00/1.1 341 Cutlip, R., Miller, J., Race, R., Jenny, A., Katz, J., Lehmkuhl, H., Debey, B. and Robinson, M. (1994) Intracerebral Transmission of Scrapie to Cattle, Journal of Infectious Diseases, 169, 814–20 342 YB88/6.21/1.2 343 YB88/11.17/2.4 SCIENCE 84 would be informative, a positive result would need to demonstrate that when scrapie was transmitted to cattle, the disease which developed in cattle was the same as BSE.344 Given the large number of strains of scrapie and the possibility that BSE was one of them, it would be necessary to transmit every scrapie strain to cattle separately, to test the hypothesis properly. Such an experiment would be expensive. Secondly, as measures to control the epidemic took hold, the need for the experiment from the policy viewpoint was not considered so urgent. It was felt that the results would be mainly of academic interest.345 3.59 Nevertheless, from the first demonstration of transmissibility of BSE in 1988, the possibility of differences in the transmission properties of BSE and scrapie was clear. Scrapie was transmissible to hamsters, but by 1988 attempts to transmit BSE to hamsters had failed. Subsequent findings increased that possibility.
http://www.bseinquiry.gov.uk/pdf/volume2/chapter3.pdf
Monday, June 01, 2009
Biochemical typing of pathological prion protein in aging cattle with BSE
http://bse-atypical.blogspot.com/2009/06/biochemical-typing-of-pathological.html
Sunday, June 07, 2009
L-TYPE-BSE, H-TYPE-BSE, C-TYPE-BSE, IBNC-TYPE-BSE, TME, CWD, SCRAPIE, CJD, NORTH AMERICA
http://bse-atypical.blogspot.com/2009/06/l-type-bse-h-type-bse-c-type-bse-ibnc.html
Sunday, May 10, 2009
Identification and characterization of bovine spongiform encephalopathy cases diagnosed and NOT diagnosed in the United States
http://bse-atypical.blogspot.com/2009/05/identification-and-characterization-of.html
Sunday, December 28, 2008
MAD COW DISEASE USA DECEMBER 28, 2008 an 8 year review of a failed and flawed policy
http://bse-atypical.blogspot.com/2008/12/mad-cow-disease-usa-december-28-2008-8.html
Wednesday, August 20, 2008
Bovine Spongiform Encephalopathy Mad Cow Disease typical and atypical strains, was there a cover-up ?
http://bse-atypical.blogspot.com/2008/08/bovine-spongiform-encephalopathy-mad.html
Saturday, February 28, 2009
NEW RESULTS ON IDIOPATHIC BRAINSTEM NEURONAL CHROMATOLYSIS "All of the 15 cattle tested showed that the brains had abnormally accumulated PrP" 2009 SEAC 102/2
http://bse-atypical.blogspot.com/2009/02/new-results-on-idiopathic-brainstem.html
Saturday, June 13, 2009
BSE FEED VIOLATIONS USA UPDATE From 01/01/2009 To 06/10/2009
http://madcowfeed.blogspot.com/2009/06/bse-feed-violations-usa-update-from.html
Thursday, March 19, 2009
MILLIONS AND MILLIONS OF POUNDS OF MAD COW FEED IN COMMERCE USA
http://madcowfeed.blogspot.com/2009/03/millions-and-millions-of-pounds-of-mad.html
WHO WILL FOLLOW THE CHILDREN FOR CJD SYMPTOMS ???
Saturday, May 2, 2009
U.S. GOVERNMENT SUES WESTLAND/HALLMARK MEAT OVER USDA CERTIFIED DEADSTOCK DOWNER COW SCHOOL LUNCH PROGRAM
http://downercattle.blogspot.com/2009/05/us-government-sues-westlandhallmark.html
Sunday, April 12, 2009 BSE MAD COW TESTING USA 2009 FIGURES Month Number of Tests
Feb 2009 -- 1,891
Jan 2009 -- 4,620
http://www.aphis.usda.gov/newsroom/hot_issues/bse/surveillance/ongoing_surv_results.shtml
SEE FULL TEXT ;
http://madcowtesting.blogspot.com/2009/04/bse-mad-cow-testing-usa-2009-figures.html
Monday, May 4, 2009
Back to the Past With New TSE Testing Agricultural Research/May-June 2009
http://madcowtesting.blogspot.com/2009/05/back-to-past-with-new-tse-testing.html
Thursday, April 9, 2009
Docket No. FDA2002N0031 (formerly Docket No. 2002N0273) RIN 0910AF46 Substances Prohibited From Use in Animal Food or Feed; Final Rule: Proposed
http://madcowfeed.blogspot.com/2009/04/docket-no-fda2002n0031-formerly-docket.html
http://prionunitusaupdate2008.blogspot.com/2009/04/r-calf-and-usa-mad-cow-problem-dont.html#comments
Sunday, April 12, 2009 r-calf and the USA mad cow problem, don't look, don't find, and then blame Canada
http://prionunitusaupdate2008.blogspot.com/2009/04/r-calf-and-usa-mad-cow-problem-dont.html
http://prionunitusaupdate2008.blogspot.com/2009/04/cjd-foundation-sides-with-r-calfers-no.html#comments
Sunday, May 10, 2009
Meeting of the Transmissible Spongiform Encephalopathies Committee On June 12, 2009 (Singeltary submission)
http://tseac.blogspot.com/2009/05/meeting-of-transmissible-spongiform.html
Saturday, June 13, 2009
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States 2003 revisited 2009
snip...
http://cjdusa.blogspot.com/2009/06/monitoring-occurrence-of-emerging-forms.html
Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518
Suggested citation for this article: Espinosa J-C, Herva M-E, Andréoletti O, Padilla D, Lacroux C, Cassard H, et al. Transgenic mice expressing porcine prion protein resistant to classical scrapie but susceptible to sheep bovine spongiform encephalopathy and atypical scrapie. Emerg Infect Dis. 2009 Aug; [Epub ahead of print]
Transgenic Mice Expressing Porcine Prion Protein Resistant to Classical Scrapie but Susceptible to Sheep Bovine Spongiform Encephalopathy and Atypical Scrapie
Juan-Carlos Espinosa,1 María-Eugenia Herva,1 Olivier Andréoletti, Danielle Padilla, Caroline Lacroux, Hervé Cassard, Isabelle Lantier, Joaquin Castilla, and Juan-María Torres
Author affiliations: Centro de Investigación en Sanidad Animal, Madrid, Spain (J.-C. Espinosa, M.-E. Herva, D. Padilla, J. Castilla, J.-M. Torres); École Nationale Vétérinaire de Toulouse, Toulouse, France (O. Andréoletti, C. Lacroux, H. Cassard); and Centre Institut National de la Recherche Agronomique de Tours, Nouzilly, France (I. Lantier)
1These authors contributed equally to this article.
How susceptible pigs are to infection with sheep prions is unknown. We show, through transmission experiments in transgenic mice expressing porcine prion protein (PrP), that the susceptibility of this mouse model to bovine spongiform encephalopathy (BSE) can be enhanced after its passage in ARQ sheep, indicating that the pathogenicity of the BSE agent is modified after passage in sheep. Transgenic mice expressing porcine PrP were, nevertheless, completely resistant to infection with a broad panel of classical scrapie isolates from different sheep PrP genotypes and with different biochemical characteristics. The atypical (Nor98 like) isolate (SC-PS152) was the only scrapie isolate capable of transmission in these mice, although with a marked transmission barrier. Unexpectedly, the atypical scrapie agent appeared to undergo a strain phenotype shift upon transmission to porcine-PrP transgenic mice and acquired new strain properties, suggesting that atypical scrapie agent may exhibit different phenotypes depending on the host cellular PrP or other genetic factors.
snip...
Discussion
In this study, transgenic mice expressing porcine PrP (8) were used to assess the transmission capacity of a wide range of TSE agents from sheep. Our results indicated that none of the classical scrapie isolates tested was transmitted to our porcine PrP mouse model after intracerebral inoculation (Table), suggesting a highly (if not completely) resistance to the classical scrapie strains tested independently of their origin and biochemical signature. The absence of successful transmission of the SC-PS48 isolates with an unglycosylated bands of 19 kDa-like BSE suggests a BSE-unrelated origin for these BSE-like scrapie strains.
The atypical isolate SC-PS152 was the only scrapie isolate able to infect the Po-PrP mouse model after intracerebral inoculation (Table), albeit with a low efficiency of infection in the first passage (attack rate 16%). These results suggest the potential ability of atypical scrapie prions to infect pigs, although with a strong transmission barrier. Given the increasing number of atypical scrapie cases found in Europe and in North America, the potential ability of atypical scrapie to adapt to the pig becoming more easily transmitted could raise concerns about the potential danger of feeding ruminant meat and bone meal to swine.
In our transmission experiments, an obviously shorter survival period (458 ± 11 dpi) and an increased attack rate (100%) were observed in PoPrP-Tg001 mice inoculated with sheep BSE (Table) compared with those inoculated with the original cattle BSE (>650 dpi, 19%). These last figures correlate well with those reported for other cattle BSE isolates (Table). Differences in survival times were maintained after subsequent passages in this mouse model (Table), suggesting that the increased infectivity of sheep BSE cannot be linked to a higher infectious titer in the initial inoculum but must be the outcome of a modification in the pathogenicity of the agent. We can also rule out that the primary amino acid sequence of the ovine PrPSC leads to more efficient conversion of porcine PrPC because scrapie isolates from sheep with the same ARQ-PrP genotype were not able to infect these mice (Table). Taken together, the increased infectivity of sheep BSE in the porcine PrP mouse model must be considered as increased pathogenicity of the agent attributable to its passage in sheep. These features support previous results indicating that the BSE agent modifies its biological properties after passage in sheep, with the result that its pathogenicity increases in transgenic mice expressing bovine PrP (24). An increased pathogenicity of ovine BSE was also reported in conventional RIII mice when compared with retrospective cattle BSE experiments (36). In other prion strains, passage through an intermediate species has also been noted to alter host susceptibility (37).
The enhanced infectivity of the BSE agent after its passage in ARQ sheep raises concern about its potential danger for other species, including humans. This question, as well as others related to the infectivity of the new porcine prion generated in this study, is currently being addressed in transmission experiments using transgenic mice expressing human PrP.
Upon passages in porcine PrP transgenic mice, the BSE agent retained most of its biochemical properties, except for its PrPres glycoprofile in which some differences were appreciable. Our comparative analysis of cattle BSE and sheep BSE upon transmission in porcine PrP transgenic mice showed that both agents exhibit similar molecular (Figure 2) and neuropathologic properties (Figure 4). These features were preserved after subsequent passages. These results suggest that, despite their modified pathogenicity, the 2 porcine prions generated share the same biochemical and neuropathologic properties, regardless of whether the BSE agent used to inoculate the mice was obtained from ARQ sheep or cows. In agreement with these results, the increased infectivity of sheep BSE previously observed upon transmission in bovine PrP transgenic mice was not reflected in its molecular or neuropathologic properties (24).
The atypical scrapie (SC-PS152) agent appeared to undergo a strain phenotype shift upon transmission to porcine PrP transgenic mice. Surprisingly, this novel strain phenotype was similar to that of sheep BSE propagated in the same mice in terms of several features: 1) survival times observed after stabilization in PoPrP-Tg001 mice (second passages) were similar (Table); 2) PrPres molecular profiles of the 2 agents in porcine PrP mice were indistinguishable (Figure 3); and 3) vacuolation profiles observed in second passages largely overlapped (Figure 4).
These findings could reflect the evolutionary potential of prion agents upon transmission to a foreign host able to promote strain shift and emergence of new properties (38,39). The converging molecular, neuropathologic, and biological properties of atypical scrapie and sheep BSE upon propagation in porcine transgenic mice could be the consequence of a restriction imposed by the porcine PrPC, which might only admit a few options as it changes its conformation to PrPSC.
Our results could also suggest a common origin for sheep BSE and atypical scrapie agents, which may exhibit different phenotypes depending on the host PrPC or other host factors.
Although this last explanation seems to be less likely, so far we cannot draw any definitive conclusion on this issue. Whichever the case, the ability of an atypical scrapie to infect other species and its potential capacity to undergo a strain phenotype shift in the new host prompts new concerns about the possible spread of this uncommon TSE in other species as a masked prion undistinguishable from other strains.
snip... see full text ;
http://www.cdc.gov/eid/content/15/8/pdfs/08-1218.pdf
Saturday, May 2, 2009
APHIS AND WHO PLAN TO EXEMPT THE ATYPICAL SCRAPIE NOR-98 FROM REGULATIONS AT MEETING THIS MONTH
http://nor-98.blogspot.com/2009/05/aphis-and-who-plan-to-exempt-atypical.html
1: J Infect Dis 1980 Aug;142(2):205-8
Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.
Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.
Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation.
PMID: 6997404
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
12/10/76 AGRICULTURAL RESEARCH COUNCIL REPORT OF THE ADVISORY COMMITTE ON SCRAPIE Office Note CHAIRMAN: PROFESSOR PETER WILDY
snip...
A The Present Position with respect to Scrapie
A1 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://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
Epidemiology of Scrapie in the United States 1977
http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
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
http://nor-98.blogspot.com/
http://scrapie-usa.blogspot.com/
see full text ;
Wednesday, July 1, 2009
Nor98 scrapie identified in the United States J Vet Diagn Invest 21:454-463 (2009)
http://nor-98.blogspot.com/2009/07/nor98-scrapie-identified-in-united.html
4.296 On 20 August 1990, a positive result was recorded in the CVL's experiment to transmit BSE to pigs. One pig had been diagnosed by post-mortem pathology as having developed a spongiform encephalopathy. A confidential pathology report submitted by Mr Gerald Wells, Head of the CVL's Neuropathology Section, to his colleague Mr Michael Dawson in the Virology Department, included the following remark:
The result, albeit confined to one animal in the experimental challenge group is incontrovertible evidence of the transmissibility of BSE to the pig by simultaneous intracerebral, intravenous and intraperitoneal inoculation routes. 11
http://www.bseinquiry.gov.uk/report/volume11/chapter8.htm#808467
http://www.bseinquiry.gov.uk/report/volume11/chapter8.htm#808471
http://www.bseinquiry.gov.uk/report/volume11/chapter8.htm#808475
http://www.bseinquiry.gov.uk/report/volume11/chapter8.htm#808479
http://www.bseinquiry.gov.uk/report/volume11/chapter8.htm#808483
http://www.bseinquiry.gov.uk/report/volume11/chapter8.htm#808487
4.303 The minutes of the meeting record that:
It was very difficult to draw conclusions from one experimental result for what may happen in the field. However it would be prudent to exclude specified bovine offals from the pig diet. Although any relationship between BSE and the finding of a spongiform encephalopathy in cats had yet to be demonstrated, the fact that this had occurred suggested that a cautious view should be taken of those species which might be susceptible. The 'specified offals' of bovines should therefore be excluded from the feed of all species. 17
http://www.bseinquiry.gov.uk/report/volume11/chapter8.htm#808491
4.308 SEAC issued formal advice on 20 September 1990, following its meeting on the previous day. The advice stated:
Since this result shows that pigs can get spongiform encephalopathy, even though there is no evidence that they have done so in the field, we believe that pigs should no longer be fed with protein derived from bovine tissues which might contain the BSE agent, ie, those 'specified' bovine offals that are already excluded from human consumption. It would make sense to extend this prohibition to feed for all species, including household pets, as other species have now developed spongiform encephalopathies. We are aware that many animal feed compounders and pet food manufacturers are already applying such a ban on a voluntary basis. 22
http://www.bseinquiry.gov.uk/report/volume11/chapter8.htm#808511
4.309 In a statement to the Inquiry, Dr Tyrrell said:
It was the rapid increase in the BSE epidemic, the occurrence of more cases of FSE and the results of the pig transmission experiment which led SEAC to give the advice we did on the extension of the SBO ban. Before then (September 1990), we were not asked to advise on the extension of the SBO ban. It was important to consider humans before other animals. It should be remembered that prior to the test results of the pig transmission experiment, pigs and poultry were not known to be susceptible to TSEs. Breeding pigs, in particular, were thought to have received a very high exposure to the same type of contaminated MBM as cattle but without any evidence of the occurrence of TSE. The issue of symptom-less hosts was considered very carefully because it could apply to all domestic and farmed animal species. 23
http://www.bseinquiry.gov.uk/report/volume11/chapter8.htm#808515
3.57 The experiment which might have determined whether BSE and scrapie were caused by the same agent (ie, the feeding of natural scrapie to cattle) was never undertaken in the UK. It was, however, performed in the USA in 1979, when it was shown that cattle inoculated with the scrapie agent endemic in the flock of Suffolk sheep at the United States Department of Agriculture in Mission, Texas, developed a TSE quite unlike BSE.339 The findings of the initial transmission, though not of the clinical or neurohistological examination, were communicated in October 1988 to Dr Watson, Director of the CVL, following a visit by Dr Wrathall, one of the project leaders in the Pathology Department of the CVL, to the United States Department of Agriculture.340 The results were not published at this point, since the attempted transmission to mice from the experimental cow brain had been inconclusive. The results of the clinical and histological differences between scrapie-affected sheep and cattle were published in 1995. Similar studies in which cattle were inoculated intracerebrally with scrapie inocula derived from a number of scrapie-affected sheep of different breeds and from different States, were carried out at the US National Animal Disease Centre.341 The results, published in 1994, showed that this source of scrapie agent, though pathogenic for cattle,
*** did not produce the same clinical signs of brain lesions characteristic of BSE. ***
3.58 There are several possible reasons why the experiment was not performed in the UK. It had been recommended by Sir Richard Southwood (Chairman of the Working Party on Bovine Spongiform Encephalopathy) in his letter to the Permanent Secretary of MAFF, Mr (now Sir) Derek Andrews, on 21 June 1988,342 though it was not specifically recommended in the Working Party Report or indeed in the Tyrrell Committee Report (details of the Southwood Working Party and the Tyrell Committee can be found in vol. 4: The Southwood Working Party, 1988–89 and vol. 11: Scientists after Southwood respectively). The direct inoculation of scrapie into calves was given low priority, because of its high cost and because it was known that it had already taken place in the USA.343 It was also felt that the results of such an experiment would be hard to interpret. While a negative result 337 Fraser, H., Bruce, M., Chree, A., McConnell, I. and Wells, G. (1992) Transmission of Bovine Spongiform Encephalopathy and Scrapie to Mice, Journal of General Virology, 73, 1891–7; Bruce, M., Chree, A., McConnell, I., Foster, J., Pearson, G. and Fraser, H. (1994) Transmission of Bovine Spongiform Encephalopathy and Scrapie to Mice: Strain Variation and the Species Barrier, Philosophical Transactions of the Royal Society of London, Series B, Biological Sciences, 343, 405–11 338 Bruce, M., Will, R., Ironside, J., McConell, I., Drummond, D., Suttie, A., McCordie, L., Chree, A., Hope, J., Birkett, C., Cousens, S., Fraser, H. and Bostock, C. (1997) Transmissions to Mice Indicate that ‘New Variant’ CJD is Caused by the BSE Agent, Nature, 389, 498–501 339 Clark, W., Hourrigan, J. and Hadlow, W. (1995) Encephalopathy in Cattle Experimentally Infected with the Scrapie Agent, American Journal of Veterinary Research, 56, 606–12 340 YB88/10.00/1.1 341 Cutlip, R., Miller, J., Race, R., Jenny, A., Katz, J., Lehmkuhl, H., Debey, B. and Robinson, M. (1994) Intracerebral Transmission of Scrapie to Cattle, Journal of Infectious Diseases, 169, 814–20 342 YB88/6.21/1.2 343 YB88/11.17/2.4 SCIENCE 84 would be informative, a positive result would need to demonstrate that when scrapie was transmitted to cattle, the disease which developed in cattle was the same as BSE.344 Given the large number of strains of scrapie and the possibility that BSE was one of them, it would be necessary to transmit every scrapie strain to cattle separately, to test the hypothesis properly. Such an experiment would be expensive. Secondly, as measures to control the epidemic took hold, the need for the experiment from the policy viewpoint was not considered so urgent. It was felt that the results would be mainly of academic interest.345 3.59 Nevertheless, from the first demonstration of transmissibility of BSE in 1988, the possibility of differences in the transmission properties of BSE and scrapie was clear. Scrapie was transmissible to hamsters, but by 1988 attempts to transmit BSE to hamsters had failed. Subsequent findings increased that possibility.
http://www.bseinquiry.gov.uk/pdf/volume2/chapter3.pdf
Monday, June 01, 2009
Biochemical typing of pathological prion protein in aging cattle with BSE
http://bse-atypical.blogspot.com/2009/06/biochemical-typing-of-pathological.html
Sunday, June 07, 2009
L-TYPE-BSE, H-TYPE-BSE, C-TYPE-BSE, IBNC-TYPE-BSE, TME, CWD, SCRAPIE, CJD, NORTH AMERICA
http://bse-atypical.blogspot.com/2009/06/l-type-bse-h-type-bse-c-type-bse-ibnc.html
Sunday, May 10, 2009
Identification and characterization of bovine spongiform encephalopathy cases diagnosed and NOT diagnosed in the United States
http://bse-atypical.blogspot.com/2009/05/identification-and-characterization-of.html
Sunday, December 28, 2008
MAD COW DISEASE USA DECEMBER 28, 2008 an 8 year review of a failed and flawed policy
http://bse-atypical.blogspot.com/2008/12/mad-cow-disease-usa-december-28-2008-8.html
Wednesday, August 20, 2008
Bovine Spongiform Encephalopathy Mad Cow Disease typical and atypical strains, was there a cover-up ?
http://bse-atypical.blogspot.com/2008/08/bovine-spongiform-encephalopathy-mad.html
Saturday, February 28, 2009
NEW RESULTS ON IDIOPATHIC BRAINSTEM NEURONAL CHROMATOLYSIS "All of the 15 cattle tested showed that the brains had abnormally accumulated PrP" 2009 SEAC 102/2
http://bse-atypical.blogspot.com/2009/02/new-results-on-idiopathic-brainstem.html
Saturday, June 13, 2009
BSE FEED VIOLATIONS USA UPDATE From 01/01/2009 To 06/10/2009
http://madcowfeed.blogspot.com/2009/06/bse-feed-violations-usa-update-from.html
Thursday, March 19, 2009
MILLIONS AND MILLIONS OF POUNDS OF MAD COW FEED IN COMMERCE USA
http://madcowfeed.blogspot.com/2009/03/millions-and-millions-of-pounds-of-mad.html
WHO WILL FOLLOW THE CHILDREN FOR CJD SYMPTOMS ???
Saturday, May 2, 2009
U.S. GOVERNMENT SUES WESTLAND/HALLMARK MEAT OVER USDA CERTIFIED DEADSTOCK DOWNER COW SCHOOL LUNCH PROGRAM
http://downercattle.blogspot.com/2009/05/us-government-sues-westlandhallmark.html
Sunday, April 12, 2009 BSE MAD COW TESTING USA 2009 FIGURES Month Number of Tests
Feb 2009 -- 1,891
Jan 2009 -- 4,620
http://www.aphis.usda.gov/newsroom/hot_issues/bse/surveillance/ongoing_surv_results.shtml
SEE FULL TEXT ;
http://madcowtesting.blogspot.com/2009/04/bse-mad-cow-testing-usa-2009-figures.html
Monday, May 4, 2009
Back to the Past With New TSE Testing Agricultural Research/May-June 2009
http://madcowtesting.blogspot.com/2009/05/back-to-past-with-new-tse-testing.html
Thursday, April 9, 2009
Docket No. FDA2002N0031 (formerly Docket No. 2002N0273) RIN 0910AF46 Substances Prohibited From Use in Animal Food or Feed; Final Rule: Proposed
http://madcowfeed.blogspot.com/2009/04/docket-no-fda2002n0031-formerly-docket.html
http://prionunitusaupdate2008.blogspot.com/2009/04/r-calf-and-usa-mad-cow-problem-dont.html#comments
Sunday, April 12, 2009 r-calf and the USA mad cow problem, don't look, don't find, and then blame Canada
http://prionunitusaupdate2008.blogspot.com/2009/04/r-calf-and-usa-mad-cow-problem-dont.html
http://prionunitusaupdate2008.blogspot.com/2009/04/cjd-foundation-sides-with-r-calfers-no.html#comments
Sunday, May 10, 2009
Meeting of the Transmissible Spongiform Encephalopathies Committee On June 12, 2009 (Singeltary submission)
http://tseac.blogspot.com/2009/05/meeting-of-transmissible-spongiform.html
Saturday, June 13, 2009
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States 2003 revisited 2009
snip...
http://cjdusa.blogspot.com/2009/06/monitoring-occurrence-of-emerging-forms.html
Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518
Wednesday, July 1, 2009
Nor98 scrapie identified in the United States J Vet Diagn Invest 21:454–463 (2009)
----- Original Message ----- From: Terry S. Singeltary Sr. To: TERRY SINGELTARY Sent: Tuesday, June 30, 2009 9:42 PM Subject: Nor98 scrapie identified in the United States
Nor98 scrapie identified in the United States
J Vet Diagn Invest 21:454–463 (2009)
Christie M. Loiacono,1 Bruce V. Thomsen, S. Mark Hall, Matti Kiupel, Diane Sutton, Katherine O’Rourke, Bradd Barr, Lucy Anthenill, Delwyn Keane
Abstract.
A distinct strain of scrapie identified in sheep of Norway in 1998 has since been identified in numerous countries throughout Europe. The disease is known as Nor98 or Nor98-like scrapie, among other names. Distinctions between classic scrapie and Nor98 scrapie are made based on histopathology and immunodiagnostic results. There are also differences in the epidemiology, typical signalment, and likelihood of clinical signs being observed. In addition, sheep that have genotypes associated with resistance to classic scrapie are not spared from Nor98 disease. The various differences between classic and Nor98 scrapie have been consistently reported in the vast majority of cases described across Europe. The current study describes in detail the pathologic changes and diagnostic results of the first 6 cases of Nor98 scrapie disease diagnosed in sheep of the United States.
Key words: Histopathology; Nor98; PrP immunolabeling; scrapie; sheep.
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The current study describes the diagnostic findings of the first 6 cases of Nor98 scrapie in sheep of the United States.
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Results
Case 1
The first case identified as consistent with Nor98 scrapie had nonclassic PrPSc distribution in brain tissue, no PrPSc in lymph tissue, and nonclassic migration of protein bands on a Western blot test. The animal was an aged, mottled-faced ewe that was traced back to a commercial flock in Wyoming. Individual animal records were not kept on the premises, so it was impossible to determine how long the ewe was on the farm, how many times she lambed on that farm, or her flock of origin. She was taken to a sale along with 88 other sheep and was tested at slaughter for scrapie as part of the RSSS program. No abnormal clinical signs were noted at the time of sale. The Prnp genotype of the case 1 ewe was AFRQ/ ALRQ (136 AA, 141 FL, 154 RR, 171 QQ). Evaluation of the brain by using HE revealed no lesions. IHC highlighted PrPSc bilaterally in the spinal nucleus of the trigeminal nerve and in the dorsal aspect of the dorsal horns of the cervical spinal cord (Fig. 1A, B). There was no PrPSc immunolabeling in the cerebellum, in the dorsal motor nucleus of the vagus nerve, or in lymphoid tissue. ELISA results were positive when using cerebellum and brainstem by the TSE sheep and goat kitk and negative for the same tissues when using the scrapie antigen kitl (Table 1). On Western blot, multiple distinct protein bands were present, including an unglycosylated band at ,15 kDa (Fig. 2A, lane 1). Subsequently, the entire flock was depopulated, and all 317 adult animals tested negative for Nor98 scrapie and classic scrapie.
Case 2
The second case was a clinically normal 8-year-old Suffolk ewe that had been in a quarantined flock for 5 years at a USDA facility in Iowa. The USDA flock, over the 5-year period, contained several hundred classic scrapie-exposed sheep that had been acquired over time from numerous private flocks designated as scrapie-infected or source flocks. A significant portion of the sheep in this quarantined flock ultimately died or was euthanized because of classic scrapie. The ewe and the entire remaining flock of 95 sheep were euthanized and tested for scrapie at the completion of a study that evaluated the use of third eyelid tissue for scrapie testing. The Prnp genotype of the case 2 ewe was ALRR/ALRR (136 AA, 141 LL, 154 RR, 171 RR). Evaluation of the brain by using HE revealed no lesions. IHC highlighted PrPSc bilaterally in the spinal nucleus of the trigeminal nerve (Fig. 1C) and in the dorsal aspect of the dorsal horns of the cervical spinal cord. There was also abundant PrPSc immunolabeling in the cerebellar molecular layer, mild-to-moderate immunolabeling in the cerebellar granular layer, and minimal scattered immunolabeling in the cerebellar white matter (Fig. 1D). PrPSc immunolabeling was absent from the dorsal motor nucleus of the vagus nerve and lymphoid tissue. ELISA results were positive when using cerebellum by both the TSE sheep and goat kitk and the scrapie antigen kitl (Table 1). Western blot results included multiple protein bands with an unglycosylated band at ,15 kDa (Fig. 2B, lanes 3 and 4). Digestion with PNGase after proteinase K treatment resulted in 3 unglycosylated bands (Fig. 2C, lane 4) comigrating with the lower 3 bands of the untreated sample (Fig. 2C, lane 3). A classic scrapie sample treated under identical conditions yielded a single band comigrating with the lowest band in the untreated sample (Fig. 2C, lanes 1 and 2). All sheep in this USDA-quarantined flock were tested for scrapie. No additional cases of Nor98 scrapie were detected, whereas 4 cases of classic scrapie were identified in the remaining 95 sheep.
Case 3
A 16-year-old, white-faced, cross-bred wether was born to a black-faced ewe. He lived his entire life as a pet on a farm in California, and was 1 of 6 wethers purchased as a group at 2 months of age. No other sheep were kept on the farm before this group, and none were introduced to the farm after the group was purchased. No clinical signs suggestive of scrapie disease were noted. The animal, with a history of having a large cervical mass, was submitted for necropsy. Samples were tested for scrapie as part of the national scrapie surveillance program through the National Animal Health Laboratory Network. The necropsy revealed a 15-cm cervical thymoma that had compressed the esophagus and resulted in aspiration pneumonia. The Prnp genotype of the case 4 wether was ALRQ/ALRQ (136 AA, 141 LL, 154 RR, 171 QQ). Evaluation of the brain by using HE revealed no lesions. IHC highlighted PrPSc bilaterally in the spinal nucleus of the trigeminal nerve and in the dorsal aspect of the dorsal horns of the cervical spinal cord (Fig. 1E). PrPSc immunolabeling in the dorsal motor nucleus of the vagus nerve and in lymphoid tissue was absent. The cerebellum was unavailable for evaluation. ELISA and Western blot tests were not done, because fresh tissue was unavailable. Brain samples were available from one other aged flock mate, and all tests were negative for Nor98 and classic scrapie.
Case 4
The fourth case of Nor98 scrapie was identified in an approximately 8-year-old Dorset ewe that was born into a flock of approximately 20 ewes in Indiana. After a flock dispersal sale, the ewe went to slaughter and was tested for scrapie as part of the RSSS program. No clinical signs suggestive of scrapie disease were noted. The Prnp genotype of the case 4 ewe was ALRQ/ALHQ (136 AA, 141 LL, 154 RH, 171 QQ). Evaluation of the brain by using HE revealed no lesions. IHC highlighted PrPSc bilaterally in the spinal nucleus of the trigeminal nerve and in the dorsal aspect of the dorsal horns of the cervical spinal cord. There was abundant PrPSc immunolabeling in the cerebellar molecular layer, moderate immunolabeling in the cerebellar granular layer, and minimal scattered immunolabeling in the cerebellar white matter (Fig. 1F), and no PrPSc immunolabeling in the dorsal motor nucleus of the vagus nerve or in lymphoid tissue. The ELISA results were positive for cerebellum by the TSE sheep and goat kitk and negative for the same tissue when using the scrapie antigen kitl (Table 1). Western blot results included multiple protein bands with an unglycosylated band at ,15 kDa (Fig. 2D, lane 6). Based on sale records, all of the animals sold at the dispersal sale went to slaughter, thus, no additional animals were available for scrapie testing.
Case 5
The fifth case was a clinically normal, approximately 3-year-old, white-faced, cross-bred ewe from an approximately 400 head commercial flock in Minnesota. The ewe was euthanized and tested for scrapie because the flock had previously been identified as a classic scrapie–infected flock. The Prnp genotype of the case 5 ewe was AFRQ/ALRQ (136 AA, 141 FL, 154 RR, 171 QQ). Evaluation of the brain by using HE revealed no lesions. IHC highlighted PrPSc bilaterally in the spinal nucleus of the trigeminal nerve and in the dorsal aspect of the dorsal horns of the cervical spinal cord. Abundant PrPSc immunolabeling was present in the cerebellar molecular layer, mild immunolabeling in the cerebellar granular layer, and minimal scattered immunolabeling in the cerebellar white matter (Fig. 1G). PrPSc immunolabeling in the dorsal motor nucleus of the vagus nerve and in lymphoid tissue was absent. The ELISA results were positive when using cerebellum by both the TSE sheep and goat kitk and the scrapie antigen kitl (Table 1). When using brainstem, ELISA was positive by the TSE sheep and goat kitk and negative by the scrapie antigen kitl (Table 1). Western blot produced multiple protein bands, including an unglycosylated band at ,15 kDa (Fig. 2E, lane 4). The flock was depopulated, and no additional cases of Nor98 or classic scrapie were identified in the adult sheep.
Case 6
The sixth case of Nor98 scrapie was identified in a 4-year-old, white-faced ewe that was purchased and added to a commercial flock in Pennsylvania that consisted of approximately 700 head of sheep and goats. Individual animal records were not kept on the premises, so it was impossible to determine exactly how long the ewe was on the farm or her flock of origin. It was estimated that she remained in this flock for approximately 1 month, was sent to slaughter, and was tested for PrPSc as part of the RSSS program. No clinical signs suggestive of scrapie disease were noted. The Prnp genotype of the case 6 ewe was AFRQ/ALRQ (136 AA, 141 FL, 154 RR, 171 QQ). Evaluation of the brain by using HE revealed no lesions. IHC highlighted PrPSc bilaterally in the spinal nucleus of the trigeminal nerve (Fig. 1H) and in the dorsal aspect of the dorsal horns of the cervical spinal cord. PrPSc immunolabeling in the dorsal motor nucleus of the vagus nerve and in lymphoid tissue was absent. Cerebellum was unavailable for evaluation. ELISA and Western blot tests were not done because fresh tissue was unavailable. The commercial flock was depopulated, and adult animals exposed to this ewe were tested for scrapie. No additional cases of Nor98 or classic scrapie were identified. A summary of relevant findings from all cases is shown in Table 1.
Discussion
Nor 98-like scrapie has significantly different diagnostic features when compared with classic scrapie.1,10 In the past, classic scrapie disease was confirmed by examination of the brain tissue for a triad of salient histopathologic changes, including vacuolation limited to gray matter referred to as spongiform change, loss of neurons, and accompanying gliosis.26 However, more recently, a presumptive histopathologic diagnosis was largely replaced by the more sensitive and confirmatory IHC and biochemical methods for detection of PrPSc in the brain or lymphoid tissues. In the case of Nor98 scrapie, there is generally little or no vacuolation in the brain, and, to date, no lymphoid accumulation of PrPSc has been detected.1 Classic scrapie has the earliest and most intense PrPSc immunolabeling at the motor nucleus of the vagus nerve as well as often abundant immunolabeling in numerous areas that contained lymphoid tissue, including retropharyngeal lymph nodes, tonsil, third eyelid, and rectal submucosa. Conversely, Nor98 scrapie–infected animals have no immunolabeling for PrPSc in the motor nucleus of the vagus nerve or in lymphoid tissues, but there typically is immunolabeling for PrPSc in the spinal nucleus of the trigeminal nerve and variable but often intense, immunolabeling for PrPSc in the cerebellum.1 Thus, the diagnosis of Nor98 disease can be based on IHC identification of PrPSc in specific regions of the brain, primarily the spinal nucleus of the trigeminal nerve and the cerebellum (Fig. 1) if there is a concurrent lack of immunolabeling for PrPSc in the dorsal motor nucleus of the vagus nerve or in any lymphoid tissues. In addition, there is a distinct diagnostic Western blot pattern for Nor98 scrapie that consists of multiple protein bands, including an unglycosylated band at ,15 kDa. This pattern remains unchanged for the lower 2–3 bands after enzymatic deglycosylation and is distinct from classic scrapie, in which the 3 protein bands that range from 20 to 30 kDa are reduced to a single unglycosylated 20 kDa band after treatment with PNGase.1,10,15
Nor98 scrapie was diagnosed in each of the 6 cases described in the present study based on IHC results (Table 1). In 4 of the cases that included fresh tissue, Western blot and ELISA results supported the diagnosis. All 6 cases had striking IHC features, including positive PrPSc immunolabeling in the spinal nucleus of the trigeminal nerve and positive PrPSc immunolabeling in the dorsal horns of the cervical spinal cord (Fig. 1). Positive PrPSc immunolabeling was less consistent in sections of cerebellum in the 4 cases that included this tissue for evaluation. Three of the 4 cases that included cerebellum were strongly positive with a similar distribution of PrPSc. The majority of PrPSc immunolabeling was present in the cerebellar molecular layer. Low-to-moderate PrPSc immunolabeling was present in the cerebellar granular layer, with only minimal scattered immunolabeling in the cerebellar white matter. The Purkinje cells were negative for immunolabeling in each of these cases. The fourth case, including cerebellum had no PrPSc immunolabeling present. None of the 6 cases had PrPSc immunolabeling in the dorsal motor nucleus of the vagus nerve, and none had PrPSc immunolabeling in lymphoid tissues. Western blot produced similar results for the 4 cases that had fresh tissue available for testing. In each case, there were multiple protein bands, including an unglycosylated band that measured ,15 kDa (Fig 2A, lane 1; B, lanes 3 and 4; D, lane 6; E, lane 4). A distinct feature in the analysis of Nor98 scrapie by Western blot testing is the presence of 3 different unglycosylated bands after PNGase treatment15 as observed in case 2 (Fig. 2C, lane 4), whereas, with classic scrapie, just 1 band is detected (Fig. 2C, lane 2). ELISA results were positive by the TSE sheep and goat kitk for all 4 cases that included fresh tissue but were positive by the scrapie antigen kitl for only 2 of these cases (Table 1).
The 6 U.S. cases were identified in a variety of testing scenarios that ranged from routine slaughter surveillance of healthy appearing animals to surveillance testing in an aged animal diagnosed with thoracic neoplasia and secondary pneumonia. None of the 6 cases had a clinical history that suggested the presence of a TSE. This is consistent with the findings in many European countries that have found Nor98 disease on a regular basis through slaughter surveillance of apparently healthy animals and fallen stock.1 Three of the sheep (cases 1, 4, and 6) were identified through the RSSS program. Of the remaining 3 animals, 2 sheep (cases 2 and 5) were found in flocks in which classic scrapie had been previously diagnosed, and the last case (case 3, a 16-year-old California wether) was presented for a routine diagnostic necropsy in which scrapie testing was included. Clinical signs are uncommon in the Nor98 strain of scrapie but most often include ataxia without pruritis, which is more commonly associated with classic scrapie.2 None of the 6 sheep described in the present study were reported to have had clinical signs, but it might be that subtle signs were not detected. This is a possibility with cases 1, 4, 5, and 6, because they were each part of large flocks with high rates of turnover. With regard to case 3, signs, including ataxia, may have been masked by other clinical signs associated with the unrelated disease processes of pneumonia and an obstructing tumor. Clinical signs in case 2 were unlikely to be missed, because the animal was closely scrutinized for scrapie signs as part of a scrapie study flock. Both Nor98 and classic scrapie can be diagnosed in a wide variety of age groups, but Nor98 appears to be more commonly found in older animals. In contrast to classic scrapie, which was diagnosed most commonly in 3–5-year-old sheep, Nor98 scrapie was found most frequently in animals more than 5 years of age.17 The U.S. cases described in the current report ranged in age from approximately 3 to 16 years, with a mean age of 7.8 years.
The 3 codons of the ovine Prnp gene at positions 136, 154, and 171, which are consistently reported to influence classic scrapie disease,14 also appear to have some influence on Nor98 scrapie. Sheep with genotypes known to be underrepresented in the classic scrapie-infected population are not spared from the Nor98 strain. Nor98 scrapie has been found in sheep that carry the A136H154Q171 haplotypes (A 5 alanine, H 5 histidine, and Q 5 glutamine) known to be less susceptible to classic scrapie and in sheep that carry the A136R154R171 haplotype (R 5 arginine) known to be associated with natural resistance to classic scrapie.8,16 Case 4 in the current study had the AHQ haplotype, and case 2 was homozygous for the ARR allele. The V136R154Q171 haplotype (V 5 valine) has been associated with higher susceptibility to classic scrapie but seems to offer at least partial resistance to Nor98 scrapie.14,16,17,24 None of the 6 cases reported in the present study had the VRQ haplotype. In addition, a fourth codon at position 141 has been identified that also appears to influence the presence of Nor98 scrapie disease.18 When phenylalanine (F) is present at position 141 with the ARQ haplotype (AF141RQ), the risk for developing Nor98 scrapie is highest, particularly when a sheep has 2 of this particular allele or has 1 AHQ allele along with the AFRQ allele.17,18,24 Cases 1, 5, and 6 presented in the current study each had an AFRQ haplotype with F residue at the 141 codon. Of the 6 cases presented, 4 had susceptible alleles. Cases 1, 5, and 6 had the AFRQ haplotype, and case 4 had the AHQ haplotype. Furthermore, case 2 had the ARR alleles reported to be susceptible to Nor98 scrapie but resistant to classic scrapie. In total, 5 of the 6 sheep identified in the current study had genotypes consistent with susceptibility to Nor98 scrapie. The sixth case, case 3, is homozygous for the ALRQ allele, which has been reported to be present in the Nor98 scrapie–infected population but is considered to have a low risk of susceptibility.17,18
The incidence of Nor98 scrapie is also reportedly different from that of classic scrapie. In a study that included 104 scrapie-infected flocks in Germany, the incidence of Nor98 scrapie was 0.2%, whereas the incidence of classic scrapie was 1.7%.17 The same study also found that, in more than 90% of the flocks infected with Nor98 scrapie, there was only a single infected animal within the flock. Similarly, each of the U.S. Nor98-positive animals was the only animal identified in their respective flock with this unique strain of scrapie. In another study that compared the prevalence of classic scrapie and Nor98 scrapie in 20 European countries, it was reported that, although the overall prevalence was low for both classic and Nor98 scrapie, there was greater variation in the prevalence of classic scrapie. Nor98 scrapie was relatively consistently present in all countries that participated in the study.12 Given this information and when considering how closely the 6 U.S. cases of Nor98 scrapie reported herein parallel European cases with regard to epidemiology and pathology, it is likely that a low but relatively consistent prevalence of Nor98 scrapie will be found wherever rigorous surveillance occurs.
Acknowledgements
The authors would like to thank Julie Lease, Sharon Lund, Dongyue Zhuang, Patricia Meinhardt, Troy Boyle, Jennifer Lamoreux, Donna Lester, and Jim Fosse for technical support. The authors also wish to thank the state and university veterinary diagnostic laboratories and their directors, especially Dr. James Collins, who test under contract to NVSL for TSE diseases and screen U.S. sheep for the presence of scrapie disease. Disclaimer: Mention of trade names or commercial products in this article is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the USDA. Sources and manufacturers
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full text ;
PDF Nor98 scrapie identified in the United States Loiacono et al. J Vet Diagn Invest.2009; 21: 454-463
http://jvdi.org/cgi/reprint/21/4/454?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=prion&searchid=1&FIRSTINDEX=0&volume=21&issue=4&resourcetype=HWCIT
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 (mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000161/!x-usc:mailto: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
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)
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.
http://www.pnas.org/content/102/44/16031.abstract
Monday, December 1, 2008
When Atypical Scrapie cross species barriers
Authors
Andreoletti O., Herva M. H., Cassard H., Espinosa J. C., Lacroux C., Simon S., Padilla D., Benestad S. L., Lantier F., Schelcher F., Grassi J., Torres, J. M., UMR INRA ENVT 1225, Ecole Nationale Veterinaire de Toulouse.France; ICISA-INlA, Madrid, Spain; CEA, IBiTec-5, DSV, CEA/Saclay, Gif sur Yvette cedex, France; National Veterinary Institute, Postboks 750 Sentrum, 0106 Oslo, Norway, INRA IASP, Centre INRA de Tours, 3738O Nouzilly, France.
Content
Atypical scrapie is a TSE occurring in small ruminants and harbouring peculiar clinical, epidemiological and biochemical properties. Currently this form of disease is identified in a large number of countries. In this study we report the transmission of an atypical scrapie isolate through different species barriers as modeled by transgenic mice (Tg) expressing different species PRP sequence.
The donor isolate was collected in 1995 in a French commercial sheep flock. inoculation into AHQ/AHQ sheep induced a disease which had all neuro-pathological and biochemical characteristics of atypical scrapie. Transmitted into Transgenic mice expressing either ovine or PrPc, the isolate retained all the described characteristics of atypical scrapie.
Surprisingly the TSE agent characteristics were dramatically different v/hen passaged into Tg bovine mice. The recovered TSE agent had biological and biochemical characteristics similar to those of atypical BSE L in the same mouse model. Moreover, whereas no other TSE agent than BSE were shown to transmit into Tg porcine mice, atypical scrapie was able to develop into this model, albeit with low attack rate on first passage.
Furthermore, after adaptation in the porcine mouse model this prion showed similar biological and biochemical characteristics than BSE adapted to this porcine mouse model. Altogether these data indicate.
(i) the unsuspected potential abilities of atypical scrapie to cross species barriers
(ii) the possible capacity of this agent to acquire new characteristics when crossing species barrier
These findings raise some interrogation on the concept of TSE strain and on the origin of the diversity of the TSE agents and could have consequences on field TSE control measures.
http://www.neuroprion.org/resources/pdf_docs/conferences/prion2008/abstract-book-prion2008.pdf
NOR-98 ATYPICAL SCRAPIE 5 cases documented in USA in 5 different states USA 2007
http://nor-98.blogspot.com/2008/04/seac-spongiform-encephalopathy-advisory.html
Tuesday, June 3, 2008
SCRAPIE USA UPDATE JUNE 2008 NOR-98 REPORTED PA
http://nor-98.blogspot.com/2008/06/scrapie-usa-update-june-2008-nor-98.html
http://nor-98.blogspot.com/
Monday, September 1, 2008
RE-FOIA OF DECLARATION OF EXTRAORDINARY EMERGENCY BECAUSE OF AN ATYPICAL T.S.E. (PRION DISEASE) OF FOREIGN ORIGIN IN THE UNITED STATES [No. 00-072-1] September 1, 2008
http://foiamadsheepmadrivervalley.blogspot.com/2008/09/re-foia-of-declaration-of-extraordinary.html
SEAC Position Statement
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Food standards agency atypical scrapie contingency plan Issue 1. In June 2006 the Food Standards Agency (FSA) Board considered current precautionary risk management measures for small ruminants. The Board agreed that current precautionary measures were sufficient. However, they wished to develop a contingency plan in case SEAC’s understanding of the risk of atypical scrapie for human health changed. To inform this contingency plan the FSA requested SEAC advice on potential outcomes of research on atypical scrapie, or surveillance results, that may lead to a change in SEAC’s estimate of the risk to human health.
Background 2. In February 2006 the SEAC sheep subgroup published a position statement on atypical scrapie1 which concluded that atypical scrapie should be considered a distinct transmissible spongiform encephalopathy (TSE) of small ruminants and not simply a variant of classical scrapie. While there was no evidence that atypical scrapie could infect humans, a theoretical risk could not be excluded. SEAC concluded, however, that there were insufficient data available to adequately assess the potential risks to human health. The subgroup recommended that an adequate assessment of the potential risk to human health of atypical scrapie might come from studies on the prevalence, transmission in animal models, tissue distribution and human health surveillance.
3. SEAC considered the potential significance of the outcomes of these areas of research for the human health risk from atypical scrapie, based on scenarios put forward by the FSA2.
Prevalence 4. The SEAC sheep subgroup statement concludes that there could be around 82,000 sheep in the UK infected with atypical scrapie. Future surveillance and epidemiological studies along with the analysis of sheep brain tissue samples dating back to 1964 may confirm the historical presence of the disease, changes in prevalence over time, and whether or not atypical scrapie may occur in countries previously thought to be free from classical and atypical scrapie. SEAC considered that the identification of historical cases, new cases in scrapie-free countries, and changes in prevalence of atypical scrapie would be significant from a public health perspective. If such data indicate that atypical scrapie has been present for many years, and is not increasing in prevalence then, by analogy with classical scrapie the human health risk would be considered low. However, if atypical scrapie were found to be spreading rapidly, this would imply it is a new disease and any human health risk would be more uncertain. It is therefore important to continue to assess the historic prevalence of atypical scrapie, and for archived sheep samples be analysed for the presence of the disease.
5. A human health risk would only be confirmed by concomitant changes in the prevalence of new types of Creutzfeldt-Jakob Disease (CJD). Because of the long incubation periods of prion diseases, such data may not become apparent for many years, although atypical scrapie has been identified in a UK sheep from 1989, implying that humans may have been exposed to atypical scrapie via the dietary route for a number of years. In the absence of data suggesting a link to a new type of CJD SEAC would be unlikely to change its current assessment of the human health risk.
Transmission studies 6. Results from transmission studies using non-human primates, particularly via the oral route, would strongly inform the understanding of human health risk. The immune and lymphoreticular systems of non-human primates are closely related to those of humans and the peripheral pathogenesis of TSEs in non-human primates mimics that in humans. However, non-human primates only provide data relating to one genotype, MM, which comprises about 37% of the UK population3. Assessment of the level of risk would require comparison with transmissions of other TSEs in the same models, in particular BSE, some of which are already available.
7. Humanised mice can provide data on all three human prion protein genotypes. It is important to be aware of the possibility that such mice may not show any clinical sign of infection after primary transmission of atypical scrapie, yet a secondary transmission from these animals to others may result in clinical disease due to loss of the interspecies transmission barrier. Although humanised mice are a good model for human disease, it will be critical to compare the behaviour of atypical scrapie with other TSEs, especially classical scrapie and BSE, in several mouse models after secondary transmission in order to obtain the most reliable risk assessments.
8. The barrier to transmission of atypical scrapie between animal and human can be tested in vitro by cell free conversion assays. However, care is needed in interpreting the significance of such experiments as ex vivo data do not always correlate well with in vivo studies. Nevertheless, they could provide data on whether conversion of the normal prion protein in humans to the abnormal form by the atypical scrapie prion is or is not possible.
Tissue Distribution 9. Little is known about the tissue distribution of abnormal prion protein (PrPsc) and infectivity in sheep with atypical scrapie. If atypical scrapie is found to be a health risk to humans, data from studies to assess the tissue distribution of PrPsc and infectivity are essential to allow an assessment of the risk under specific control measures.
Human Health 10. Establishing a definitive link between an animal and a human TSE is extremely difficult. Animal model data will only be indicative, and not definitive, although if carried out appropriately could be strongly indicative of a human health risk. The emergence of a new type of CJD which shows the same transmission characteristics as atypical scrapie in non-human primates and humanised mice would provide a strong indication that transmission had occurred through the consumption of infected material. Thus, ongoing human surveillance is critical.
11. It is difficult to conclude that atypical scrapie is not a human health risk from negative experimental or surveillance results. However, negative results from current and retrospective surveillance and transmission studies, over a significant period of time to allow for possibly long incubation periods, would imply a negligible human health risk.
Conclusion 12. It is not possible to assess the human health risk from atypical scrapie, or changes in risk, in the absence of hard scientific data. No single data set is likely to be definitive and it would be essential to consider all the information available, rather than data from single studies in isolation. Studies comparing the properties of atypical scrapie and other TSE agents using the same animal model, especially humanised mice or non-human primates, would be most informative in the short term. Surveillance data to assess any association between forms of CJD and atypical scrapie prevalence would be most persuasive but are unlikely to become available in the short term. SEAC would have to review experimental methods and results, should they emerge, before any conclusion of a change to the risk to human health from atypical scrapie could be made.
1 http://www.seac.gov.uk/pdf/positionstatement-sheep-subgroup.pdf (97 KB) 2 http://www.seac.gov.uk/papers/97-3.pdf (110 KB) 3 Palmer and Collinge (1993) Mutations and polymorphisms in the prion protein gene. Hum. Mutat. 2, 168-173.
Page updated: 6 September, 2007
http://www.seac.gov.uk/statements/fsa-scrapieplan.htm
Atypical scrapie
What does the term atypical scrapie mean?
Mankind has been aware of scrapie for over 250 years. In the past, infected sheep were usually detected when they became clinically affected, and were subjected to examination of brain tissue after death.
In the past 15-20 years, through the study of the genetics of sheep clinically affected with scrapie, it appeared that some were susceptible to scrapie, but others were apparently not as they were never represented in the clinical population (see TAFS Position paper on BSE in sheep for more extensive discussion). This absence of sheep of particular genotypes from the population of clinically affected sheep led to a belief that such sheep were at least resistant to clinical disease, and possibly resistant to infection by natural routes.
The expansion of research programmes due to concerns about BSE has demonstrated that such sheep are not totally resistant as they can be infected by inoculation directly into the brain (23).
Investigations into sheep that were ataxic (walking with difficulty, in an uncoordinated manner) in Norway identified a form of scrapie that seemed to differ from that seen in other flocks and countries. It occurred in genotypes of sheep that were rarely affected elsewhere. This form of scrapie was termed Nor98 (5). It is the first of the “atypical scrapie” isolates to be recognized.
When rapid tests were introduced into surveillance programmes in Europe in 2002, many of the sheep being tested were clinically healthy. Test results therefore had to be interpreted in isolation from data concerning clinical signs. Scientists in several countries faced a challenge to confirm positive results obtained by one test in particular, the BioRad Platelia® or TeSeETM test. Traditional test methods seemed ineffective in confirming the primary results. Equally challenging was the fact that the unconfirmed positive results were in genotypes of sheep that were previously assumed to be resistant. There were doubts about whether or not the fact that the tests had not been evaluated with sheep scrapie was a factor. The results could have been false
TAFS 3
positives due to reactions that would not have been recognized or anticipated by their prior evaluation solely on cattle BSE.
Verification of the results occurred quickly, but uncertainty as to their meaning led to the adoption of various terms – unclassified, atypical, discordant – to describe the cases, and eventually they collectively became known as “atypical”.
In a report to the European Commission, the Community Reference Laboratory Strain Typing Expert Group advised that it was likely that sheep were susceptible to infection with a spectrum of prion strains, only some of which had previously been detected and associated with what was known as classical scrapie. While it was possible that the atypical scrapie isolates were simply part of that spectrum, and had previously not been recognized because appropriate tests had not been available, there was also a possibility, albeit less likely, that they were a new phenomenon.
This history is extensively discussed in two EFSA Opinions. One, in October 2005(16), describes attempts to classify isolates in small ruminants to ensure that there is consistency of approach between countries in terms of names applied to isolates. The second, in July 2006(17), describes much of the background especially in relation to the interrelationship with genotype and the likely impact on programmes to breed for resistance.
What are the differences between classical and atypical scrapie?
This is still an incomplete area of science, and therefore difficult to fully explain.
Both types of scrapie clearly involve the presence of abnormal prion protein, and are recognized as prion diseases.
Classical scrapie, identified in clinically affected sheep, occurs in certain genotypes of sheep. Historically there was only one recorded incident of a positive case in what was thought to be a fully resistant genotype (ARR/ARR) (24). There were doubts about the diagnosis in that case. Most classical scrapie cases have traditionally been in sheep carrying the VRQ and ARQ alleles (homozygous or heterozygous), occasionally in combination with ARR and AHQ. While it is still a point of debate as to whether a sheep can be classified as infected with classical scrapie if it is not exhibiting clinical signs, there is no doubt that the prion protein found, and the range of genotypes affected, are identical in healthy, found-dead or clinically affected sheep.
Atypical scrapie has been found predominantly in sheep carrying the AHQ, ARQ and ARR alleles, either homozygous or heterozygous. Full detail is given in the EFSA Opinions(1, 3, 4, 5, 9, 10, 13, 17, 18, 19, 20, 28, 29, 30, 31, 32, 33, 35).
The abnormal form of prion protein in atypical cases has been shown to be more susceptible to enzymatic digestion than in classical scrapie. Because most of the rapid diagnostic tests use enzymes to prepare the sample for testing, some at higher concentrations than others, they were unable to detect atypical scrapie while others could. The protein had been totally or partially digested during the processing for some tests, to the point where antibodies used in the tests were no longer able to recognize and bind to target sites on the prion protein. This phenomenon has subsequently been demonstrated more precisely(21).
Other methods based on ELISA or Western Blot techniques are now available which clearly can detect atypical scrapie, but as demonstrated by the evaluation of rapid tests for small ruminants conducted by EFSA in 2005, they are certainly not equally capable(14, 15).
TAFS 4
How was atypical scrapie found?
Nor98 was identified through the investigation of unusual clinical signs in sheep in Norway.
In the EU it was entirely as a result of the introduction of rapid testing for active surveillance, and initially particularly through the use of one test manufactured by a company called BioRad. Other tests have subsequently demonstrated that they can also detect atypical scrape following the evaluation of tests specifically for use on small ruminants.
Where has atypical scrapie been found?
This has been detailed in the EFSA Opinions described above, but it is clear that apart from Norway, where Nor98 was first identified, atypical scrapie has now been identified in several European and other countries - including the United Kingdom, France, Germany, Belgium, Finland, Iceland, Italy, Ireland, The Netherlands, Portugal, Sweden, Switzerland and the Falkland Islands(1, 3, 4, 5, 9, 10, 13, 17, 18, 19, 20, 28, 29, 30, 31, 32, 33, 35).
As rapid tests used for active surveillance are not all equally capable of detecting atypical scrapie, this will inevitably influence the apparent geographical distribution. In other words, countries that only use tests that are either unable or less able to detect atypical scrapie are unlikely to have reported cases. Only when the tests evaluated specifically on small ruminant tissues replace those previously evaluated on cattle tissue, will they be able to detect atypical cases with any certainty. This has already occurred in the European Union.
Is there more than one strain of atypical scrapie?
At the moment it is not possible to confirm this until further characterization has been completed, especially by bioassay in laboratory rodents.
While there is a degree of conformity between western immunoblotting results in most countries, there is also evidence for variability between animals when whole brains are examined by immunohistochemistry. Whether this is determined by the strain or the genotype of the sheep or goat, is not yet known.
Immunohistochemically the distribution of staining in the brain is quite different to classical scrapie, with only faint, focal, staining of the brain stem at the level of the obex, but more substantial staining of cerebellum of most animals, although in some it is the frontal cortex that is targeted. In some animals focal plaques are also seen in both grey and white matter.
Many of the cases are similar to Nor98 in terms of diagnostic criteria that have been characterized so far. The western blot below demonstrates how the banding pattern for classical and atypical scrapie differ.
Can atypical scrapie cause clinical signs?
Yes. In addition to Nor98 cases reported in Norway, a small number of cases have been detected in the UK. In Norway the most common sign was progressive incoordination (ataxia), together with some weight loss. There was no evidence of scratching. Scratching is not universally seen in classical scrapie however, and may depend on the strain of classical scrapie with which the sheep is infected(5).
In the British sheep the predominant sign was again ataxia, with inconsistent recording of changes in temperament, loss of condition, or circling, and in one case scratching(26, 27). Video clips of clinically affected sheep can be viewed via reference 24. Similar clinical cases have also been recorded in Ireland(32).
Is it transmissible?
Experimentally, it has been shown that it can be transmitted to genetically modified mice(28), and by intracerebral inoculation to sheep (unpublished work in progress). ?? These transmissions do not prove that it will transmit naturally from sheep to sheep, but studies involving oral infection of sheep are under way.
Although most atypical cases occur singly in flocks, there are some instances where two affected sheep have been identified in flocks. This may indicate that natural transmission may occur, or that the sheep were infected from a common alternative source(22, 29). Possible indications of an association with the feeding of vitamins and mineral feed supplements were detected in Norway, but remain to be proven(22). Does it represent a risk to human health?
This is currently unknown, but if atypical scrapie is not a new phenomenon, and has simply been discovered recently, then the lack of epidemiological association between
TAFS 6
prion diseases in humans and sheep, or consumption of sheep products, suggest that atypical scrapie does not represent a risk to humans. This is not however demonstration of absolute safety.
see full text ;
http://www.tseandfoodsafety.org/position_papers/TAFS_POSITION_PAPER_ON_ATYPICAL_SCRAPIE_AND_%20ATYPICAL_BSE_070516.pdf
experimental transmission of 171RR Nor98 brain to 5 RR recipients (Jan 2008)
http://www.sheepusa.org/index.phtml?page=site/get_file&print=1&file_id=f4d1b2a4739ab82d903cf042526bd9ee
http://www.eradicatescrapie.org/Educational%20Resources/PDFs%20&%20PPTs/Genotyping%20PPT/Slide%20Notes%20for%20Genotyping.pdf
http://www.eradicatescrapie.org/Educational%20Resources/PDFs%20&%20PPTs/Genotyping%20PPT/Genotyping%20A%20Tool%20for%20Controlling%20Classical%20Scrapie.ppt
P7.12 Co-existence of classical and atypical scrapie strains in a sheep from an Italian outbreak
Results: IHC revealed the simultaneous presence in the brain of pathological features characteristic of Nor98 and classical scrapie. This was confirmed by WB: PrPres fragments characteristic of Nor98 and scrapie were simultaneously present in all areas investigated, although in different proportions, with Nor98 being more abundant in the cortex and classical scrapie in the brainstem. The lymph node showed the presence of PrPsc with a molecular pattern referable only to classical scrapie, while the tongue resulted negative. Genetic analysis showed the following genotype: A136L141R154Q171/A136F141R154Q171.
Discussion: Our results suggest either the co-existence of Nor98 and classical scrapie in this sheep or the presence of a new scrapie phenotype. The presence of classical scrapie in the outbreak and the genotype of the animal support the first event, which might be explained by the different genetic and cellular targets of the two strains. The bioassay analysis in bank voles and Tg338 mice, at the moment in progress, will help to confirm this hypothesis.
also see ;
P9.18 First Report of Classical Scrapie in Portugal, including co-existence with atypical scrapie in the same flock
also see ;
P9.37 Sporadic Creutzfeldt-Jakob Disease in the Basque Country: Coexistence of prion protein strains in the same and different brain regions
Discussion: The Basque Country presents one of the highest annual incidences of confirmed sCJD in Spain and in Europe (1.87 per million inhabitants per annum). It also suffers the highest frequency of FFI (43.12%). Regarding regional pattern distribution, our results show a predominance of PrPsc type 1 in sCJD. Surprisingly, a high frequency of cases with both types of prion protein was observed, indicating that the coexistence of two different molecular patterns in the same individual is more common than expected.
http://www.neuroprion.org/resources/pdf_docs/conferences/prion2008/abstract-book-prion2008.pdf
Saturday, May 2, 2009
APHIS AND WHO PLAN TO EXEMPT THE ATYPICAL SCRAPIE NOR-98 FROM REGULATIONS AT MEETING THIS MONTH
http://nor-98.blogspot.com/2009/05/aphis-and-who-plan-to-exempt-atypical.html
2.1. European dimension of the problem.
Sheep and goats have suffered from scrapie for centuries in the EU and world wide but the current distribution and incidence of scrapie is largely unknown due to the inadequacy of the epidemiosurveillance networks in different Member States. Until the beginning of the BSE epidemic in the UK in the 1980s there was no particular concern about the national incidence of scrapie (or other TSEs in sheep). One reason was because it is generally accepted that there was no epidemiological relationship between the occurrence of scrapie in sheep and the incidence of Creutzfeldt-Jakob disease (CJD) in humans over a period of over 250 years. However, attention was drawn by the Scientific Veterinary Committee to the high incidence of familial CJD in the Orava region of Slovakia at a level of about 30 times the normal level of 1 per million adults per year. This form of familial CJD is attributed to mutations in the PrP gene at codon 200. This particular mutation is not fully penetrant and some of the workers in Slovakia have suggested that exposure to sheep scrapie may also be necessary for disease to result. This is partly because scrapie had been identified in sheep in the region following a period since the late XIXth century when scrapie was thought to be absent from the country.
http://ec.europa.eu/food/fs/sc/ssc/out48_en.html
http://www.springerlink.com/content/l564271136v7626t/
http://www.springerlink.com/content/v847132717217040/
1: Cent Eur J Public Health 2003 Mar;11(1):19-22
Analysis of unusual accumulation of Creutzfeldt-Jakob disease cases in Orava and Liptov regions (northern Slovak focus) 1983-2000.
Mad'ar R, Maslenova D, Ranostajova K, Straka S, Baska T.
Institute of Epidemiology, Jessenius Faculty of Medicine, Comenius University, Sklabinska 26, Martin, 037 53 Slovakia. mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000161/!x-usc:mailto:MADAR@jfmed.uniba.sk
While familial cases of Creutzfeldt-Jakob disease are extremely rare all over the world, 3 familial clusters were observed between 1983-2000 in a relatively small area situated in the North of Slovakia. Prevalence of CJD in this area exceeded the overall prevalence in Slovakia more than 8 times. The majority of CJD patients admitted consuming sheep brain. Most patients lived in small secluded villages with rather common familial intermarriage. CJD affected both sexes equally. All patients were prior to the disease mentally normal individuals. Shortly after the onset of CJD their mental status deteriorated remarkably with an average survival rate of 3.6 months.
PMID: 12690798
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12690798&dopt=Abstract
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1: Eur J Epidemiol 1991 Sep;7(5):520-3
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?db=PubMed&cmd=Display&dopt=pubmed_pubmed&from_uid=1761109
"Clusters" of CJD in Slovakia: the first laboratory evidence of scrapie.
Mitrova E, Huncaga S, Hocman G, Nyitrayova O, Tatara M.
Institute of Preventive and Clinical Medicine, Bratislava.
Epidemic-like occurrence of Creutzfeldt-Jakob disease was observed in 1987 in Slovakia (Orava). Search for the cause of CJD focus indicated a coincidence of genetic and environmental risks in clustering patients. Since Spongiform Encephalopathies might be transmitted orally, (Bovine Spongiform Encephalopathy), the possibility of zoonotic source of CJD cases in Orava was also considered. A deficient knowledge about the occurrence of scrapie in Slovakia stimulated an examination of sheep with signs of CNS disorders in two flocks of Valasky breed in Orava. In one flock, neurohistopathological examination revealed in sheep brains lesions characteristic for scrapie. Frozen brain tissue of these animals were used for the detection of scrapie associated fibrils. They were found in 2 animals from the same flock. This is the first laboratory confirmation of scrapie in Czecho-Slovakia. The possible epidemiological and economical implications are emphasized.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1761109&dopt=Abstract
STATEMENT OF DR HELEN GRANT MD FRCP ISSUED 13/05/1999
BSE INQUIRY
http://www.bseinquiry.gov.uk/files/ws/s410.pdf
http://www.bseinquiry.gov.uk/files/ws/s410x.pdf
http://www.bseinquiry.gov.uk/evidence/ws/ws8.htm
CWD to CJD in humans (why not?), as easy as BSE/Scrapie;
The EMBO Journal, Vol. 19, No. 17 pp. 4425-4430, 2000 © European Molecular Biology Organization
Evidence of a molecular barrier limiting susceptibility of humans, cattle and sheep to chronic wasting disease
G.J. Raymond1, A. Bossers2, L.D. Raymond1, K.I. O?Rourke3, L.E. McHolland4, P.K. Bryant III4, M.W. Miller5, E.S. Williams6, M. Smits2 and B. Caughey1,7
1NIAID/NIH Rocky Mountain Laboratories, Hamilton, MT 59840, 3USDA/ARS/ADRU, Pullman, WA 99164-7030, 4USDA/ARS/ABADRL, Laramie, WY 82071, 5Colorado Division of Wildlife, Wildlife Research Center, Fort Collins, CO 80526-2097, 6Department of Veterinary Sciences, University of Wyoming, Laramie, WY 82070, USA and 2ID-Lelystad, Institute for Animal Science and Health, Lelystad, The Netherlands 7Corresponding author e-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000161/!x-usc:mailto:bcaughey@nih.gov Received June 7, 2000; revised July 3, 2000; accepted July 5, 2000.
Abstract
Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) of deer and elk, and little is known about its transmissibility to other species. An important factor controlling interspecies TSE susceptibility is prion protein (PrP) homology between the source and recipient species/genotypes. Furthermore, the efficiency with which the protease-resistant PrP (PrP-res) of one species induces the in vitro conversion of the normal PrP (PrP-sen) of another species to the protease-resistant state correlates with the cross-species transmissibility of TSE agents. Here we show that the CWD-associated PrP-res (PrPCWD) of cervids readily induces the conversion of recombinant cervid PrP-sen molecules to the protease-resistant state in accordance with the known transmissibility of CWD between cervids. In contrast, PrPCWD-induced conversions of human and bovine PrP-sen were much less efficient, and conversion of ovine PrP-sen was intermediate. These results demonstrate a barrier at the molecular level that should limit the susceptibility of these non-cervid species to CWD.
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Clearly, it is premature to draw firm conclusions about CWD passing naturally into humans, cattle and sheep, but the present results suggest that CWD transmissions to humans would be as limited by PrP incompatibility as transmissions of BSE or sheep scrapie to humans. Although there is no evidence that sheep scrapie has affected humans, it is likely that BSE has caused variant CJD in 74 people (definite and probable variant CJD cases to date according to the UK CJD Surveillance Unit). Given the presumably large number of people exposed to BSE infectivity, the susceptibility of humans may still be very low compared with cattle, which would be consistent with the relatively inefficient conversion of human PrP-sen by PrPBSE. Nonetheless, since humans have apparently been infected by BSE, it would seem prudent to take reasonable measures to limit exposure of humans (as well as sheep and cattle) to CWD infectivity as has been recommended for other animal TSEs.
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http://www.emboj.org/current.shtml
Scrapie to Humans USA?
1: Neuroepidemiology. 1985;4(4):240-9.
Sheep consumption: a possible source of spongiform encephalopathy in humans.
Davanipour Z, Alter M, ***el E, Callahan M.
A fatal spongiform encephalopathy of sheep and goats (scrapie) shares many characteristics with Creutzfeldt-Jakob disease (CJD), a similar dementing illness of humans. To investigate the possibility that CJD is acquired by ingestion of contaminated sheep products, we collected information on production, slaughtering practices, and marketing of sheep in Pennsylvania. The study revealed that sheep were usually marketed before central nervous system signs of scrapie are expected to appear; breeds known to be susceptible to the disease were the most common breeds raised in the area; sheep were imported from other states including those with a high frequency of scrapie; use of veterinary services on the sheep farms investigated and, hence, opportunities to detect the disease were limited; sheep producers in the area knew little about scrapie despite the fact that the disease has been reported in the area, and animal organs including sheep organs were sometimes included in processed food. Therefore, it was concluded that in Pennsylvania there are some 'weak links' through which scrapie-infected animals could contaminate human food, and that consumption of these foods could perhaps account for spongiform encephalopathy in humans. The weak links observed are probably not unique to Pennsylvania.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3915057&dopt=Abstract
Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.
Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.
Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation.
PMID: 6997404
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
Libyan Jews
A countrywide search for CJD in Israel uncovered 29 cases with onset between 1963–72.25 The incidence in various ethnic groups varied from 0.4 to 1.9 per million, except among Jewish immigrants from Libya, among whom the incidence was 31.3 per million. The eating of lightly cooked sheep brain, a delicacy amongst Mediterranean Jews, was at first postulated to be responsible, but the incidence of CJD amongst other ethnic groups with the same dietary habits was only 1–2 cases per million of the population.
The Chilean cluster
A cluster in Chile, involving four cases of histologically-proven CJD in three farmers and one housewife, occurred in 1982–3. The four lived in small rural communities situated within a 20-km radius of the town of Chillian. They were unrelated and did not know each other. Their life long dietary habits are of interest, but uncertain relevance. They all consumed uncooked sheep blood and poorly-cooked sheep blood and brain.
http://qjmed.oxfordjournals.org/cgi/content/full/93/9/617
Mutation of the prion protein in Libyan Jews with Creutzfeldt-Jakob disease Article Abstract:
Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disease of a class referred to as the spongiform encephalopathies. The disease can be transmitted experimentally and has also been transmitted accidentally. The causative agent in these transmissions is unlike any well characterized infectious agent and is referred to by many as a prion. Creutzfeldt-Jakob disease may occur in families, but is usually sporadic. The incidence of Creutzfeldt-Jakob disease is about one or two cases per million people. However, among Jews from Libya, the incidence is 100 times higher. Many possible explanations have been put forward to account for this unusually high incidence, but none has sustained any scrutiny. One of the more popular notions was that the eating of sheep brains, a popular delicacy in the region, infected people with scrapie, a prion disease of sheep similar to CJD. However, the eating of sheep brain is popular throughout the Mediterranean, and cannot explain the specificity of the increased incidence to Libyan Jews. Mediterranean sheep, if anything, have a lower rate of scrapie than other areas of Europe and North America. A study was undertaken to determine if the increased incidence of CJD among these people might be accounted for by genetic factors. The prion protein genes were analyzed in 11 Libyan Jews with Creutzfeldt-Jakob disease. Investigation of one patient revealed that a mutation had occurred in the 200th codon of the gene, that is, the 200th set of three DNA bases. The net result of this change would be to substitute a lysine for glutamine in the resulting protein. After this mutation was identified, it was confirmed in the other 10 Libyan patients. It is interesting to note that the mutation was not present in a Moroccan Jew with CJD. The results suggest that the increased incidence of Creutzfeldt-Jakob disease in this population is the result of a gene carried by this group. In eight of the present cases, a family history of CJD could be confirmed. Although not all families were cooperative in providing information of the ancestral heritage, all the families for which such information was available could be traced to Djerba, which is an island off the coast of Tunisia. (Consumer Summary produced by Reliance Medical Information, Inc.)
author: Scarlato, Guglielmo, Prusiner, Stanley B., Hsiao, Karen, Meiner, Zeev, Kahana, Esther, Cass, Carin, Kahana, Irit, Avrahami, Dana, Abramsky, Oded, Gabizon, Ruth Publisher: Massachusetts Medical Society Publication Name: The New England Journal of Medicine Subject: Health ISSN: 0028-4793 Year: 1991
http://www.faqs.org/abstracts/Health/Mutation-of-the-prion-protein-in-Libyan-Jews-with-Creutzfeldt-Jakob-disease.html
Friday, August 22, 2008
Creutzfeldt Jakob Disease and Veterans and how they are treated at death
They worry that he may have gotten it from eating sheep brains locals served to soldiers as an honor in Oman two years ago.
http://creutzfeldt-jakob-disease.blogspot.com/2008/08/creutzfeldt-jakob-disease-and-veterans.html
SCRAPIE DETECTED IN ANOTHER GOAT USA UPDATE MARCH 2009
http://scrapie-usa.blogspot.com/2009/04/scrapie-detected-in-another-goat-usa.html
Full Scientific Reports
Experimental oral transmission of United States origin scrapie to neonatal sheep
Amir N. Hamir1, Robert A. Kunkle, Justin J. Greenlee and Juergen A. Richt Correspondence: 1Corresponding Author: Amir N. Hamir, National Animal Disease Center, ARS, USDA, 2300 Dayton Avenue, PO Box 70, Ames, IA 50010. mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000161/!x-usc:mailto:amir.hamir@ars.usda.gov
Scrapie, a transmissible spongiform encephalopathy (TSE), is a naturally occurring fatal neurodegenerative disease of sheep and goats. The current study documents incubation periods, pathologic findings, and distribution of abnormal prion proteins (PrPSc) by immunohistochemistry and Western blot in tissues of genetically susceptible and resistant neonatal lambs inoculated with pooled brain homogenates from 13 U.S. origin scrapie-affected ewes. Nine Suffolk lambs with genotypes AA/RR/QQ (n = 5) and AA/RR/QR (n = 4) at codons 136, 154, and 171, respectively) were orally inoculated, within 12 hr of birth, with 1 ml of a 10% (w/v) brain homogenate prepared from scrapie-affected sheep brains. Inoculated animals were euthanized when advanced clinical signs of scrapie were observed. All QQ sheep developed clinical signs of scrapie, with a mean survival time of 24 months. Spongiform lesions in the brains and PrPSc deposits in the central nervous system and lymphoid tissues were present in these sheep. None of the QR sheep succumbed to the disease. A previous study that used a larger volume (30 ml of 10% brain suspension) of the same inoculum in 4-month-old Suffolk lambs of susceptible genotype documented longer survival periods (average 32 months), and only 5 of 9 inoculated sheep developed scrapie. Findings of this study suggest that orally exposed neonatal lambs of a susceptible (QQ) genotype exhibit a higher attack rate and shorter incubation period than older (4-month-old) lambs exposed to a larger dose (30x) of the same inoculum.
Key Words: Immunohistochemistry • neonatal sheep • scrapie • spongiform encephalopathy • Western blot
http://jvdi.org/cgi/content/abstract/21/1/64?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=prion&searchid=1&FIRSTINDEX=0&volume=21&issue=1&resourcetype=HWCIT
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://www.bseinquiry.gov.uk/files/yb/1994/02/07002001.pdf
Title: Characterization of a U.S. Sheep Scrapie Isolate with Short Incubation Time
Authors
Hamir, Amirali Richt, Juergen Kunkle, Robert Greenlee, Justin Bulgin, M - UNIVERSITY OF IDAHO Gregori, L - VA MEDICAL CENTER, MD Rohwer, R - VA MEDICAL CENTER, MD
Submitted to: Veterinary Pathology Publication Type: Peer Reviewed Journal Publication Acceptance Date: April 16, 2009 Publication Date: N/A
Interpretive Summary: Scrapie is a naturally occurring fatal disease of sheep and goats. In a previous study it was shown that sheep inoculated with US scrapie inoculum (No. 13-7) induced terminal disease within an average of 19 months. We have since produced an inoculum, No. X124 from pooled brains of US origin sheep scrapie, that results in incubations nearly 3 fold shorter. The present study documents laboratory findings in tissues of sheep inoculated with No. X124. All inoculated sheep developed clinical disease and were euthanized within an average of 7.7 months post inoculation (MPI). Sheep that were genetically susceptible developed the disease faster (within 6 months). Also, the inoculum was able to induce disease in a short time (7 MPI) in a sheep that was supposed to be highly resistant to scrapie. This indicates that inoculum No. X124 appears to be more virulent than inoculum No. 13-7. Importantly this strain of scrapie represents a significant development in that it provides a natural model that requires less than 25 percent of the time for the disease to develop, thus enabling a faster pace for research investigating prion disease pathogenesis and inactivation. Technical Abstract: Scrapie is a naturally occurring fatal neurodegenerative disease of sheep and goats. Susceptibility to the disease is partly dependent upon the genetic makeup of the host. In a previous study it was shown that sheep intracerebrally inoculated with US scrapie inoculum (No. 13-7) developed terminal disease within an average of 19 months. We have since produced an inoculum, No. x124 from pooled brains of US origin sheep scrapie, that results in incubations nearly 3 fold shorter. The present study documents clinicopathological findings and the distribution of abnormal prion proteins (PrP**Sc) by immunohistochemical (IHC) and Western blot (WB) techniques, in tissues of sheep inoculated with No. x124. All inoculated sheep developed clinical disease and were euthanized within an average of 7.7 months post-inoculation (MPI). Sheep that had VV or AV at codon 136 of prion protein (PRNP) gene developed the disease faster and were euthanized at an average of 4.3 and 5.6 MPI, respectively. Also, the inoculum was able to induce disease in a short time (7 MPI) in a sheep that was relatively resistant (QR at codon 171) to scrapie. This indicates that inoculum No. x124 appears to induce scrapie in shorter time than inoculum No. 13-7, especially in sheep homozygous or heterozygous for valine at codon 136.
http://www.ars.usda.gov/research/publications/publications.htm?seq_no_115=230885
1: J Infect Dis 1980 Aug;142(2):205-8
Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.
Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.
Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation.
PMID: 6997404
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
12/10/76 AGRICULTURAL RESEARCH COUNCIL REPORT OF THE ADVISORY COMMITTE ON SCRAPIE Office Note CHAIRMAN: PROFESSOR PETER WILDY
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A The Present Position with respect to Scrapie
A1 The Problem
Scrapie is a natural disease of sheep and goats. It is a slow and inexorably progressive degenerative disorder of the nervous system and it ia fatal. It is enzootic in the United Kingdom but not in all countries.
The field problem has been reviewed by a MAFF working group (ARC 35/77). It is difficult to assess the incidence in Britain for a variety of reasons but the disease causes serious financial loss; it is estimated that it cost Swaledale breeders alone $l.7 M during the five years 1971-1975. A further inestimable loss arises from the closure of certain export markets, in particular those of the United States, to British sheep.
It is clear that scrapie in sheep is important commercially and for that reason alone effective measures to control it should be devised as quickly as possible.
Recently the question has again been brought up as to whether scrapie is transmissible to man. This has followed reports that the disease has been transmitted to primates. One particularly lurid speculation (Gajdusek 1977) conjectures that the agents of scrapie, kuru, Creutzfeldt-Jakob disease and transmissible encephalopathy of mink are varieties of a single "virus". The U.S. Department of Agriculture concluded that it could "no longer justify or permit scrapie-blood line and scrapie-exposed sheep and goats to be processed for human or animal food at slaughter or rendering plants" (ARC 84/77)" The problem is emphasised by the finding that some strains of scrapie produce lesions identical to the once which characterise the human dementias"
Whether true or not. the hypothesis that these agents might be transmissible to man raises two considerations. First, the safety of laboratory personnel requires prompt attention. Second, action such as the "scorched meat" policy of USDA makes the solution of the acrapie problem urgent if the sheep industry is not to suffer grievously.
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76/10.12/4.6
http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
Epidemiology of Scrapie in the United States 1977
http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
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
http://nor-98.blogspot.com/
http://scrapie-usa.blogspot.com/
Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518
Nor98 scrapie identified in the United States
J Vet Diagn Invest 21:454–463 (2009)
Christie M. Loiacono,1 Bruce V. Thomsen, S. Mark Hall, Matti Kiupel, Diane Sutton, Katherine O’Rourke, Bradd Barr, Lucy Anthenill, Delwyn Keane
Abstract.
A distinct strain of scrapie identified in sheep of Norway in 1998 has since been identified in numerous countries throughout Europe. The disease is known as Nor98 or Nor98-like scrapie, among other names. Distinctions between classic scrapie and Nor98 scrapie are made based on histopathology and immunodiagnostic results. There are also differences in the epidemiology, typical signalment, and likelihood of clinical signs being observed. In addition, sheep that have genotypes associated with resistance to classic scrapie are not spared from Nor98 disease. The various differences between classic and Nor98 scrapie have been consistently reported in the vast majority of cases described across Europe. The current study describes in detail the pathologic changes and diagnostic results of the first 6 cases of Nor98 scrapie disease diagnosed in sheep of the United States.
Key words: Histopathology; Nor98; PrP immunolabeling; scrapie; sheep.
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The current study describes the diagnostic findings of the first 6 cases of Nor98 scrapie in sheep of the United States.
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Results
Case 1
The first case identified as consistent with Nor98 scrapie had nonclassic PrPSc distribution in brain tissue, no PrPSc in lymph tissue, and nonclassic migration of protein bands on a Western blot test. The animal was an aged, mottled-faced ewe that was traced back to a commercial flock in Wyoming. Individual animal records were not kept on the premises, so it was impossible to determine how long the ewe was on the farm, how many times she lambed on that farm, or her flock of origin. She was taken to a sale along with 88 other sheep and was tested at slaughter for scrapie as part of the RSSS program. No abnormal clinical signs were noted at the time of sale. The Prnp genotype of the case 1 ewe was AFRQ/ ALRQ (136 AA, 141 FL, 154 RR, 171 QQ). Evaluation of the brain by using HE revealed no lesions. IHC highlighted PrPSc bilaterally in the spinal nucleus of the trigeminal nerve and in the dorsal aspect of the dorsal horns of the cervical spinal cord (Fig. 1A, B). There was no PrPSc immunolabeling in the cerebellum, in the dorsal motor nucleus of the vagus nerve, or in lymphoid tissue. ELISA results were positive when using cerebellum and brainstem by the TSE sheep and goat kitk and negative for the same tissues when using the scrapie antigen kitl (Table 1). On Western blot, multiple distinct protein bands were present, including an unglycosylated band at ,15 kDa (Fig. 2A, lane 1). Subsequently, the entire flock was depopulated, and all 317 adult animals tested negative for Nor98 scrapie and classic scrapie.
Case 2
The second case was a clinically normal 8-year-old Suffolk ewe that had been in a quarantined flock for 5 years at a USDA facility in Iowa. The USDA flock, over the 5-year period, contained several hundred classic scrapie-exposed sheep that had been acquired over time from numerous private flocks designated as scrapie-infected or source flocks. A significant portion of the sheep in this quarantined flock ultimately died or was euthanized because of classic scrapie. The ewe and the entire remaining flock of 95 sheep were euthanized and tested for scrapie at the completion of a study that evaluated the use of third eyelid tissue for scrapie testing. The Prnp genotype of the case 2 ewe was ALRR/ALRR (136 AA, 141 LL, 154 RR, 171 RR). Evaluation of the brain by using HE revealed no lesions. IHC highlighted PrPSc bilaterally in the spinal nucleus of the trigeminal nerve (Fig. 1C) and in the dorsal aspect of the dorsal horns of the cervical spinal cord. There was also abundant PrPSc immunolabeling in the cerebellar molecular layer, mild-to-moderate immunolabeling in the cerebellar granular layer, and minimal scattered immunolabeling in the cerebellar white matter (Fig. 1D). PrPSc immunolabeling was absent from the dorsal motor nucleus of the vagus nerve and lymphoid tissue. ELISA results were positive when using cerebellum by both the TSE sheep and goat kitk and the scrapie antigen kitl (Table 1). Western blot results included multiple protein bands with an unglycosylated band at ,15 kDa (Fig. 2B, lanes 3 and 4). Digestion with PNGase after proteinase K treatment resulted in 3 unglycosylated bands (Fig. 2C, lane 4) comigrating with the lower 3 bands of the untreated sample (Fig. 2C, lane 3). A classic scrapie sample treated under identical conditions yielded a single band comigrating with the lowest band in the untreated sample (Fig. 2C, lanes 1 and 2). All sheep in this USDA-quarantined flock were tested for scrapie. No additional cases of Nor98 scrapie were detected, whereas 4 cases of classic scrapie were identified in the remaining 95 sheep.
Case 3
A 16-year-old, white-faced, cross-bred wether was born to a black-faced ewe. He lived his entire life as a pet on a farm in California, and was 1 of 6 wethers purchased as a group at 2 months of age. No other sheep were kept on the farm before this group, and none were introduced to the farm after the group was purchased. No clinical signs suggestive of scrapie disease were noted. The animal, with a history of having a large cervical mass, was submitted for necropsy. Samples were tested for scrapie as part of the national scrapie surveillance program through the National Animal Health Laboratory Network. The necropsy revealed a 15-cm cervical thymoma that had compressed the esophagus and resulted in aspiration pneumonia. The Prnp genotype of the case 4 wether was ALRQ/ALRQ (136 AA, 141 LL, 154 RR, 171 QQ). Evaluation of the brain by using HE revealed no lesions. IHC highlighted PrPSc bilaterally in the spinal nucleus of the trigeminal nerve and in the dorsal aspect of the dorsal horns of the cervical spinal cord (Fig. 1E). PrPSc immunolabeling in the dorsal motor nucleus of the vagus nerve and in lymphoid tissue was absent. The cerebellum was unavailable for evaluation. ELISA and Western blot tests were not done, because fresh tissue was unavailable. Brain samples were available from one other aged flock mate, and all tests were negative for Nor98 and classic scrapie.
Case 4
The fourth case of Nor98 scrapie was identified in an approximately 8-year-old Dorset ewe that was born into a flock of approximately 20 ewes in Indiana. After a flock dispersal sale, the ewe went to slaughter and was tested for scrapie as part of the RSSS program. No clinical signs suggestive of scrapie disease were noted. The Prnp genotype of the case 4 ewe was ALRQ/ALHQ (136 AA, 141 LL, 154 RH, 171 QQ). Evaluation of the brain by using HE revealed no lesions. IHC highlighted PrPSc bilaterally in the spinal nucleus of the trigeminal nerve and in the dorsal aspect of the dorsal horns of the cervical spinal cord. There was abundant PrPSc immunolabeling in the cerebellar molecular layer, moderate immunolabeling in the cerebellar granular layer, and minimal scattered immunolabeling in the cerebellar white matter (Fig. 1F), and no PrPSc immunolabeling in the dorsal motor nucleus of the vagus nerve or in lymphoid tissue. The ELISA results were positive for cerebellum by the TSE sheep and goat kitk and negative for the same tissue when using the scrapie antigen kitl (Table 1). Western blot results included multiple protein bands with an unglycosylated band at ,15 kDa (Fig. 2D, lane 6). Based on sale records, all of the animals sold at the dispersal sale went to slaughter, thus, no additional animals were available for scrapie testing.
Case 5
The fifth case was a clinically normal, approximately 3-year-old, white-faced, cross-bred ewe from an approximately 400 head commercial flock in Minnesota. The ewe was euthanized and tested for scrapie because the flock had previously been identified as a classic scrapie–infected flock. The Prnp genotype of the case 5 ewe was AFRQ/ALRQ (136 AA, 141 FL, 154 RR, 171 QQ). Evaluation of the brain by using HE revealed no lesions. IHC highlighted PrPSc bilaterally in the spinal nucleus of the trigeminal nerve and in the dorsal aspect of the dorsal horns of the cervical spinal cord. Abundant PrPSc immunolabeling was present in the cerebellar molecular layer, mild immunolabeling in the cerebellar granular layer, and minimal scattered immunolabeling in the cerebellar white matter (Fig. 1G). PrPSc immunolabeling in the dorsal motor nucleus of the vagus nerve and in lymphoid tissue was absent. The ELISA results were positive when using cerebellum by both the TSE sheep and goat kitk and the scrapie antigen kitl (Table 1). When using brainstem, ELISA was positive by the TSE sheep and goat kitk and negative by the scrapie antigen kitl (Table 1). Western blot produced multiple protein bands, including an unglycosylated band at ,15 kDa (Fig. 2E, lane 4). The flock was depopulated, and no additional cases of Nor98 or classic scrapie were identified in the adult sheep.
Case 6
The sixth case of Nor98 scrapie was identified in a 4-year-old, white-faced ewe that was purchased and added to a commercial flock in Pennsylvania that consisted of approximately 700 head of sheep and goats. Individual animal records were not kept on the premises, so it was impossible to determine exactly how long the ewe was on the farm or her flock of origin. It was estimated that she remained in this flock for approximately 1 month, was sent to slaughter, and was tested for PrPSc as part of the RSSS program. No clinical signs suggestive of scrapie disease were noted. The Prnp genotype of the case 6 ewe was AFRQ/ALRQ (136 AA, 141 FL, 154 RR, 171 QQ). Evaluation of the brain by using HE revealed no lesions. IHC highlighted PrPSc bilaterally in the spinal nucleus of the trigeminal nerve (Fig. 1H) and in the dorsal aspect of the dorsal horns of the cervical spinal cord. PrPSc immunolabeling in the dorsal motor nucleus of the vagus nerve and in lymphoid tissue was absent. Cerebellum was unavailable for evaluation. ELISA and Western blot tests were not done because fresh tissue was unavailable. The commercial flock was depopulated, and adult animals exposed to this ewe were tested for scrapie. No additional cases of Nor98 or classic scrapie were identified. A summary of relevant findings from all cases is shown in Table 1.
Discussion
Nor 98-like scrapie has significantly different diagnostic features when compared with classic scrapie.1,10 In the past, classic scrapie disease was confirmed by examination of the brain tissue for a triad of salient histopathologic changes, including vacuolation limited to gray matter referred to as spongiform change, loss of neurons, and accompanying gliosis.26 However, more recently, a presumptive histopathologic diagnosis was largely replaced by the more sensitive and confirmatory IHC and biochemical methods for detection of PrPSc in the brain or lymphoid tissues. In the case of Nor98 scrapie, there is generally little or no vacuolation in the brain, and, to date, no lymphoid accumulation of PrPSc has been detected.1 Classic scrapie has the earliest and most intense PrPSc immunolabeling at the motor nucleus of the vagus nerve as well as often abundant immunolabeling in numerous areas that contained lymphoid tissue, including retropharyngeal lymph nodes, tonsil, third eyelid, and rectal submucosa. Conversely, Nor98 scrapie–infected animals have no immunolabeling for PrPSc in the motor nucleus of the vagus nerve or in lymphoid tissues, but there typically is immunolabeling for PrPSc in the spinal nucleus of the trigeminal nerve and variable but often intense, immunolabeling for PrPSc in the cerebellum.1 Thus, the diagnosis of Nor98 disease can be based on IHC identification of PrPSc in specific regions of the brain, primarily the spinal nucleus of the trigeminal nerve and the cerebellum (Fig. 1) if there is a concurrent lack of immunolabeling for PrPSc in the dorsal motor nucleus of the vagus nerve or in any lymphoid tissues. In addition, there is a distinct diagnostic Western blot pattern for Nor98 scrapie that consists of multiple protein bands, including an unglycosylated band at ,15 kDa. This pattern remains unchanged for the lower 2–3 bands after enzymatic deglycosylation and is distinct from classic scrapie, in which the 3 protein bands that range from 20 to 30 kDa are reduced to a single unglycosylated 20 kDa band after treatment with PNGase.1,10,15
Nor98 scrapie was diagnosed in each of the 6 cases described in the present study based on IHC results (Table 1). In 4 of the cases that included fresh tissue, Western blot and ELISA results supported the diagnosis. All 6 cases had striking IHC features, including positive PrPSc immunolabeling in the spinal nucleus of the trigeminal nerve and positive PrPSc immunolabeling in the dorsal horns of the cervical spinal cord (Fig. 1). Positive PrPSc immunolabeling was less consistent in sections of cerebellum in the 4 cases that included this tissue for evaluation. Three of the 4 cases that included cerebellum were strongly positive with a similar distribution of PrPSc. The majority of PrPSc immunolabeling was present in the cerebellar molecular layer. Low-to-moderate PrPSc immunolabeling was present in the cerebellar granular layer, with only minimal scattered immunolabeling in the cerebellar white matter. The Purkinje cells were negative for immunolabeling in each of these cases. The fourth case, including cerebellum had no PrPSc immunolabeling present. None of the 6 cases had PrPSc immunolabeling in the dorsal motor nucleus of the vagus nerve, and none had PrPSc immunolabeling in lymphoid tissues. Western blot produced similar results for the 4 cases that had fresh tissue available for testing. In each case, there were multiple protein bands, including an unglycosylated band that measured ,15 kDa (Fig 2A, lane 1; B, lanes 3 and 4; D, lane 6; E, lane 4). A distinct feature in the analysis of Nor98 scrapie by Western blot testing is the presence of 3 different unglycosylated bands after PNGase treatment15 as observed in case 2 (Fig. 2C, lane 4), whereas, with classic scrapie, just 1 band is detected (Fig. 2C, lane 2). ELISA results were positive by the TSE sheep and goat kitk for all 4 cases that included fresh tissue but were positive by the scrapie antigen kitl for only 2 of these cases (Table 1).
The 6 U.S. cases were identified in a variety of testing scenarios that ranged from routine slaughter surveillance of healthy appearing animals to surveillance testing in an aged animal diagnosed with thoracic neoplasia and secondary pneumonia. None of the 6 cases had a clinical history that suggested the presence of a TSE. This is consistent with the findings in many European countries that have found Nor98 disease on a regular basis through slaughter surveillance of apparently healthy animals and fallen stock.1 Three of the sheep (cases 1, 4, and 6) were identified through the RSSS program. Of the remaining 3 animals, 2 sheep (cases 2 and 5) were found in flocks in which classic scrapie had been previously diagnosed, and the last case (case 3, a 16-year-old California wether) was presented for a routine diagnostic necropsy in which scrapie testing was included. Clinical signs are uncommon in the Nor98 strain of scrapie but most often include ataxia without pruritis, which is more commonly associated with classic scrapie.2 None of the 6 sheep described in the present study were reported to have had clinical signs, but it might be that subtle signs were not detected. This is a possibility with cases 1, 4, 5, and 6, because they were each part of large flocks with high rates of turnover. With regard to case 3, signs, including ataxia, may have been masked by other clinical signs associated with the unrelated disease processes of pneumonia and an obstructing tumor. Clinical signs in case 2 were unlikely to be missed, because the animal was closely scrutinized for scrapie signs as part of a scrapie study flock. Both Nor98 and classic scrapie can be diagnosed in a wide variety of age groups, but Nor98 appears to be more commonly found in older animals. In contrast to classic scrapie, which was diagnosed most commonly in 3–5-year-old sheep, Nor98 scrapie was found most frequently in animals more than 5 years of age.17 The U.S. cases described in the current report ranged in age from approximately 3 to 16 years, with a mean age of 7.8 years.
The 3 codons of the ovine Prnp gene at positions 136, 154, and 171, which are consistently reported to influence classic scrapie disease,14 also appear to have some influence on Nor98 scrapie. Sheep with genotypes known to be underrepresented in the classic scrapie-infected population are not spared from the Nor98 strain. Nor98 scrapie has been found in sheep that carry the A136H154Q171 haplotypes (A 5 alanine, H 5 histidine, and Q 5 glutamine) known to be less susceptible to classic scrapie and in sheep that carry the A136R154R171 haplotype (R 5 arginine) known to be associated with natural resistance to classic scrapie.8,16 Case 4 in the current study had the AHQ haplotype, and case 2 was homozygous for the ARR allele. The V136R154Q171 haplotype (V 5 valine) has been associated with higher susceptibility to classic scrapie but seems to offer at least partial resistance to Nor98 scrapie.14,16,17,24 None of the 6 cases reported in the present study had the VRQ haplotype. In addition, a fourth codon at position 141 has been identified that also appears to influence the presence of Nor98 scrapie disease.18 When phenylalanine (F) is present at position 141 with the ARQ haplotype (AF141RQ), the risk for developing Nor98 scrapie is highest, particularly when a sheep has 2 of this particular allele or has 1 AHQ allele along with the AFRQ allele.17,18,24 Cases 1, 5, and 6 presented in the current study each had an AFRQ haplotype with F residue at the 141 codon. Of the 6 cases presented, 4 had susceptible alleles. Cases 1, 5, and 6 had the AFRQ haplotype, and case 4 had the AHQ haplotype. Furthermore, case 2 had the ARR alleles reported to be susceptible to Nor98 scrapie but resistant to classic scrapie. In total, 5 of the 6 sheep identified in the current study had genotypes consistent with susceptibility to Nor98 scrapie. The sixth case, case 3, is homozygous for the ALRQ allele, which has been reported to be present in the Nor98 scrapie–infected population but is considered to have a low risk of susceptibility.17,18
The incidence of Nor98 scrapie is also reportedly different from that of classic scrapie. In a study that included 104 scrapie-infected flocks in Germany, the incidence of Nor98 scrapie was 0.2%, whereas the incidence of classic scrapie was 1.7%.17 The same study also found that, in more than 90% of the flocks infected with Nor98 scrapie, there was only a single infected animal within the flock. Similarly, each of the U.S. Nor98-positive animals was the only animal identified in their respective flock with this unique strain of scrapie. In another study that compared the prevalence of classic scrapie and Nor98 scrapie in 20 European countries, it was reported that, although the overall prevalence was low for both classic and Nor98 scrapie, there was greater variation in the prevalence of classic scrapie. Nor98 scrapie was relatively consistently present in all countries that participated in the study.12 Given this information and when considering how closely the 6 U.S. cases of Nor98 scrapie reported herein parallel European cases with regard to epidemiology and pathology, it is likely that a low but relatively consistent prevalence of Nor98 scrapie will be found wherever rigorous surveillance occurs.
Acknowledgements
The authors would like to thank Julie Lease, Sharon Lund, Dongyue Zhuang, Patricia Meinhardt, Troy Boyle, Jennifer Lamoreux, Donna Lester, and Jim Fosse for technical support. The authors also wish to thank the state and university veterinary diagnostic laboratories and their directors, especially Dr. James Collins, who test under contract to NVSL for TSE diseases and screen U.S. sheep for the presence of scrapie disease. Disclaimer: Mention of trade names or commercial products in this article is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the USDA. Sources and manufacturers
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PDF Nor98 scrapie identified in the United States Loiacono et al. J Vet Diagn Invest.2009; 21: 454-463
http://jvdi.org/cgi/reprint/21/4/454?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=prion&searchid=1&FIRSTINDEX=0&volume=21&issue=4&resourcetype=HWCIT
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 (mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000161/!x-usc:mailto: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
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)
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.
http://www.pnas.org/content/102/44/16031.abstract
Monday, December 1, 2008
When Atypical Scrapie cross species barriers
Authors
Andreoletti O., Herva M. H., Cassard H., Espinosa J. C., Lacroux C., Simon S., Padilla D., Benestad S. L., Lantier F., Schelcher F., Grassi J., Torres, J. M., UMR INRA ENVT 1225, Ecole Nationale Veterinaire de Toulouse.France; ICISA-INlA, Madrid, Spain; CEA, IBiTec-5, DSV, CEA/Saclay, Gif sur Yvette cedex, France; National Veterinary Institute, Postboks 750 Sentrum, 0106 Oslo, Norway, INRA IASP, Centre INRA de Tours, 3738O Nouzilly, France.
Content
Atypical scrapie is a TSE occurring in small ruminants and harbouring peculiar clinical, epidemiological and biochemical properties. Currently this form of disease is identified in a large number of countries. In this study we report the transmission of an atypical scrapie isolate through different species barriers as modeled by transgenic mice (Tg) expressing different species PRP sequence.
The donor isolate was collected in 1995 in a French commercial sheep flock. inoculation into AHQ/AHQ sheep induced a disease which had all neuro-pathological and biochemical characteristics of atypical scrapie. Transmitted into Transgenic mice expressing either ovine or PrPc, the isolate retained all the described characteristics of atypical scrapie.
Surprisingly the TSE agent characteristics were dramatically different v/hen passaged into Tg bovine mice. The recovered TSE agent had biological and biochemical characteristics similar to those of atypical BSE L in the same mouse model. Moreover, whereas no other TSE agent than BSE were shown to transmit into Tg porcine mice, atypical scrapie was able to develop into this model, albeit with low attack rate on first passage.
Furthermore, after adaptation in the porcine mouse model this prion showed similar biological and biochemical characteristics than BSE adapted to this porcine mouse model. Altogether these data indicate.
(i) the unsuspected potential abilities of atypical scrapie to cross species barriers
(ii) the possible capacity of this agent to acquire new characteristics when crossing species barrier
These findings raise some interrogation on the concept of TSE strain and on the origin of the diversity of the TSE agents and could have consequences on field TSE control measures.
http://www.neuroprion.org/resources/pdf_docs/conferences/prion2008/abstract-book-prion2008.pdf
NOR-98 ATYPICAL SCRAPIE 5 cases documented in USA in 5 different states USA 2007
http://nor-98.blogspot.com/2008/04/seac-spongiform-encephalopathy-advisory.html
Tuesday, June 3, 2008
SCRAPIE USA UPDATE JUNE 2008 NOR-98 REPORTED PA
http://nor-98.blogspot.com/2008/06/scrapie-usa-update-june-2008-nor-98.html
http://nor-98.blogspot.com/
Monday, September 1, 2008
RE-FOIA OF DECLARATION OF EXTRAORDINARY EMERGENCY BECAUSE OF AN ATYPICAL T.S.E. (PRION DISEASE) OF FOREIGN ORIGIN IN THE UNITED STATES [No. 00-072-1] September 1, 2008
http://foiamadsheepmadrivervalley.blogspot.com/2008/09/re-foia-of-declaration-of-extraordinary.html
SEAC Position Statement
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Food standards agency atypical scrapie contingency plan Issue 1. In June 2006 the Food Standards Agency (FSA) Board considered current precautionary risk management measures for small ruminants. The Board agreed that current precautionary measures were sufficient. However, they wished to develop a contingency plan in case SEAC’s understanding of the risk of atypical scrapie for human health changed. To inform this contingency plan the FSA requested SEAC advice on potential outcomes of research on atypical scrapie, or surveillance results, that may lead to a change in SEAC’s estimate of the risk to human health.
Background 2. In February 2006 the SEAC sheep subgroup published a position statement on atypical scrapie1 which concluded that atypical scrapie should be considered a distinct transmissible spongiform encephalopathy (TSE) of small ruminants and not simply a variant of classical scrapie. While there was no evidence that atypical scrapie could infect humans, a theoretical risk could not be excluded. SEAC concluded, however, that there were insufficient data available to adequately assess the potential risks to human health. The subgroup recommended that an adequate assessment of the potential risk to human health of atypical scrapie might come from studies on the prevalence, transmission in animal models, tissue distribution and human health surveillance.
3. SEAC considered the potential significance of the outcomes of these areas of research for the human health risk from atypical scrapie, based on scenarios put forward by the FSA2.
Prevalence 4. The SEAC sheep subgroup statement concludes that there could be around 82,000 sheep in the UK infected with atypical scrapie. Future surveillance and epidemiological studies along with the analysis of sheep brain tissue samples dating back to 1964 may confirm the historical presence of the disease, changes in prevalence over time, and whether or not atypical scrapie may occur in countries previously thought to be free from classical and atypical scrapie. SEAC considered that the identification of historical cases, new cases in scrapie-free countries, and changes in prevalence of atypical scrapie would be significant from a public health perspective. If such data indicate that atypical scrapie has been present for many years, and is not increasing in prevalence then, by analogy with classical scrapie the human health risk would be considered low. However, if atypical scrapie were found to be spreading rapidly, this would imply it is a new disease and any human health risk would be more uncertain. It is therefore important to continue to assess the historic prevalence of atypical scrapie, and for archived sheep samples be analysed for the presence of the disease.
5. A human health risk would only be confirmed by concomitant changes in the prevalence of new types of Creutzfeldt-Jakob Disease (CJD). Because of the long incubation periods of prion diseases, such data may not become apparent for many years, although atypical scrapie has been identified in a UK sheep from 1989, implying that humans may have been exposed to atypical scrapie via the dietary route for a number of years. In the absence of data suggesting a link to a new type of CJD SEAC would be unlikely to change its current assessment of the human health risk.
Transmission studies 6. Results from transmission studies using non-human primates, particularly via the oral route, would strongly inform the understanding of human health risk. The immune and lymphoreticular systems of non-human primates are closely related to those of humans and the peripheral pathogenesis of TSEs in non-human primates mimics that in humans. However, non-human primates only provide data relating to one genotype, MM, which comprises about 37% of the UK population3. Assessment of the level of risk would require comparison with transmissions of other TSEs in the same models, in particular BSE, some of which are already available.
7. Humanised mice can provide data on all three human prion protein genotypes. It is important to be aware of the possibility that such mice may not show any clinical sign of infection after primary transmission of atypical scrapie, yet a secondary transmission from these animals to others may result in clinical disease due to loss of the interspecies transmission barrier. Although humanised mice are a good model for human disease, it will be critical to compare the behaviour of atypical scrapie with other TSEs, especially classical scrapie and BSE, in several mouse models after secondary transmission in order to obtain the most reliable risk assessments.
8. The barrier to transmission of atypical scrapie between animal and human can be tested in vitro by cell free conversion assays. However, care is needed in interpreting the significance of such experiments as ex vivo data do not always correlate well with in vivo studies. Nevertheless, they could provide data on whether conversion of the normal prion protein in humans to the abnormal form by the atypical scrapie prion is or is not possible.
Tissue Distribution 9. Little is known about the tissue distribution of abnormal prion protein (PrPsc) and infectivity in sheep with atypical scrapie. If atypical scrapie is found to be a health risk to humans, data from studies to assess the tissue distribution of PrPsc and infectivity are essential to allow an assessment of the risk under specific control measures.
Human Health 10. Establishing a definitive link between an animal and a human TSE is extremely difficult. Animal model data will only be indicative, and not definitive, although if carried out appropriately could be strongly indicative of a human health risk. The emergence of a new type of CJD which shows the same transmission characteristics as atypical scrapie in non-human primates and humanised mice would provide a strong indication that transmission had occurred through the consumption of infected material. Thus, ongoing human surveillance is critical.
11. It is difficult to conclude that atypical scrapie is not a human health risk from negative experimental or surveillance results. However, negative results from current and retrospective surveillance and transmission studies, over a significant period of time to allow for possibly long incubation periods, would imply a negligible human health risk.
Conclusion 12. It is not possible to assess the human health risk from atypical scrapie, or changes in risk, in the absence of hard scientific data. No single data set is likely to be definitive and it would be essential to consider all the information available, rather than data from single studies in isolation. Studies comparing the properties of atypical scrapie and other TSE agents using the same animal model, especially humanised mice or non-human primates, would be most informative in the short term. Surveillance data to assess any association between forms of CJD and atypical scrapie prevalence would be most persuasive but are unlikely to become available in the short term. SEAC would have to review experimental methods and results, should they emerge, before any conclusion of a change to the risk to human health from atypical scrapie could be made.
1 http://www.seac.gov.uk/pdf/positionstatement-sheep-subgroup.pdf (97 KB) 2 http://www.seac.gov.uk/papers/97-3.pdf (110 KB) 3 Palmer and Collinge (1993) Mutations and polymorphisms in the prion protein gene. Hum. Mutat. 2, 168-173.
Page updated: 6 September, 2007
http://www.seac.gov.uk/statements/fsa-scrapieplan.htm
Atypical scrapie
What does the term atypical scrapie mean?
Mankind has been aware of scrapie for over 250 years. In the past, infected sheep were usually detected when they became clinically affected, and were subjected to examination of brain tissue after death.
In the past 15-20 years, through the study of the genetics of sheep clinically affected with scrapie, it appeared that some were susceptible to scrapie, but others were apparently not as they were never represented in the clinical population (see TAFS Position paper on BSE in sheep for more extensive discussion). This absence of sheep of particular genotypes from the population of clinically affected sheep led to a belief that such sheep were at least resistant to clinical disease, and possibly resistant to infection by natural routes.
The expansion of research programmes due to concerns about BSE has demonstrated that such sheep are not totally resistant as they can be infected by inoculation directly into the brain (23).
Investigations into sheep that were ataxic (walking with difficulty, in an uncoordinated manner) in Norway identified a form of scrapie that seemed to differ from that seen in other flocks and countries. It occurred in genotypes of sheep that were rarely affected elsewhere. This form of scrapie was termed Nor98 (5). It is the first of the “atypical scrapie” isolates to be recognized.
When rapid tests were introduced into surveillance programmes in Europe in 2002, many of the sheep being tested were clinically healthy. Test results therefore had to be interpreted in isolation from data concerning clinical signs. Scientists in several countries faced a challenge to confirm positive results obtained by one test in particular, the BioRad Platelia® or TeSeETM test. Traditional test methods seemed ineffective in confirming the primary results. Equally challenging was the fact that the unconfirmed positive results were in genotypes of sheep that were previously assumed to be resistant. There were doubts about whether or not the fact that the tests had not been evaluated with sheep scrapie was a factor. The results could have been false
TAFS 3
positives due to reactions that would not have been recognized or anticipated by their prior evaluation solely on cattle BSE.
Verification of the results occurred quickly, but uncertainty as to their meaning led to the adoption of various terms – unclassified, atypical, discordant – to describe the cases, and eventually they collectively became known as “atypical”.
In a report to the European Commission, the Community Reference Laboratory Strain Typing Expert Group advised that it was likely that sheep were susceptible to infection with a spectrum of prion strains, only some of which had previously been detected and associated with what was known as classical scrapie. While it was possible that the atypical scrapie isolates were simply part of that spectrum, and had previously not been recognized because appropriate tests had not been available, there was also a possibility, albeit less likely, that they were a new phenomenon.
This history is extensively discussed in two EFSA Opinions. One, in October 2005(16), describes attempts to classify isolates in small ruminants to ensure that there is consistency of approach between countries in terms of names applied to isolates. The second, in July 2006(17), describes much of the background especially in relation to the interrelationship with genotype and the likely impact on programmes to breed for resistance.
What are the differences between classical and atypical scrapie?
This is still an incomplete area of science, and therefore difficult to fully explain.
Both types of scrapie clearly involve the presence of abnormal prion protein, and are recognized as prion diseases.
Classical scrapie, identified in clinically affected sheep, occurs in certain genotypes of sheep. Historically there was only one recorded incident of a positive case in what was thought to be a fully resistant genotype (ARR/ARR) (24). There were doubts about the diagnosis in that case. Most classical scrapie cases have traditionally been in sheep carrying the VRQ and ARQ alleles (homozygous or heterozygous), occasionally in combination with ARR and AHQ. While it is still a point of debate as to whether a sheep can be classified as infected with classical scrapie if it is not exhibiting clinical signs, there is no doubt that the prion protein found, and the range of genotypes affected, are identical in healthy, found-dead or clinically affected sheep.
Atypical scrapie has been found predominantly in sheep carrying the AHQ, ARQ and ARR alleles, either homozygous or heterozygous. Full detail is given in the EFSA Opinions(1, 3, 4, 5, 9, 10, 13, 17, 18, 19, 20, 28, 29, 30, 31, 32, 33, 35).
The abnormal form of prion protein in atypical cases has been shown to be more susceptible to enzymatic digestion than in classical scrapie. Because most of the rapid diagnostic tests use enzymes to prepare the sample for testing, some at higher concentrations than others, they were unable to detect atypical scrapie while others could. The protein had been totally or partially digested during the processing for some tests, to the point where antibodies used in the tests were no longer able to recognize and bind to target sites on the prion protein. This phenomenon has subsequently been demonstrated more precisely(21).
Other methods based on ELISA or Western Blot techniques are now available which clearly can detect atypical scrapie, but as demonstrated by the evaluation of rapid tests for small ruminants conducted by EFSA in 2005, they are certainly not equally capable(14, 15).
TAFS 4
How was atypical scrapie found?
Nor98 was identified through the investigation of unusual clinical signs in sheep in Norway.
In the EU it was entirely as a result of the introduction of rapid testing for active surveillance, and initially particularly through the use of one test manufactured by a company called BioRad. Other tests have subsequently demonstrated that they can also detect atypical scrape following the evaluation of tests specifically for use on small ruminants.
Where has atypical scrapie been found?
This has been detailed in the EFSA Opinions described above, but it is clear that apart from Norway, where Nor98 was first identified, atypical scrapie has now been identified in several European and other countries - including the United Kingdom, France, Germany, Belgium, Finland, Iceland, Italy, Ireland, The Netherlands, Portugal, Sweden, Switzerland and the Falkland Islands(1, 3, 4, 5, 9, 10, 13, 17, 18, 19, 20, 28, 29, 30, 31, 32, 33, 35).
As rapid tests used for active surveillance are not all equally capable of detecting atypical scrapie, this will inevitably influence the apparent geographical distribution. In other words, countries that only use tests that are either unable or less able to detect atypical scrapie are unlikely to have reported cases. Only when the tests evaluated specifically on small ruminant tissues replace those previously evaluated on cattle tissue, will they be able to detect atypical cases with any certainty. This has already occurred in the European Union.
Is there more than one strain of atypical scrapie?
At the moment it is not possible to confirm this until further characterization has been completed, especially by bioassay in laboratory rodents.
While there is a degree of conformity between western immunoblotting results in most countries, there is also evidence for variability between animals when whole brains are examined by immunohistochemistry. Whether this is determined by the strain or the genotype of the sheep or goat, is not yet known.
Immunohistochemically the distribution of staining in the brain is quite different to classical scrapie, with only faint, focal, staining of the brain stem at the level of the obex, but more substantial staining of cerebellum of most animals, although in some it is the frontal cortex that is targeted. In some animals focal plaques are also seen in both grey and white matter.
Many of the cases are similar to Nor98 in terms of diagnostic criteria that have been characterized so far. The western blot below demonstrates how the banding pattern for classical and atypical scrapie differ.
Can atypical scrapie cause clinical signs?
Yes. In addition to Nor98 cases reported in Norway, a small number of cases have been detected in the UK. In Norway the most common sign was progressive incoordination (ataxia), together with some weight loss. There was no evidence of scratching. Scratching is not universally seen in classical scrapie however, and may depend on the strain of classical scrapie with which the sheep is infected(5).
In the British sheep the predominant sign was again ataxia, with inconsistent recording of changes in temperament, loss of condition, or circling, and in one case scratching(26, 27). Video clips of clinically affected sheep can be viewed via reference 24. Similar clinical cases have also been recorded in Ireland(32).
Is it transmissible?
Experimentally, it has been shown that it can be transmitted to genetically modified mice(28), and by intracerebral inoculation to sheep (unpublished work in progress). ?? These transmissions do not prove that it will transmit naturally from sheep to sheep, but studies involving oral infection of sheep are under way.
Although most atypical cases occur singly in flocks, there are some instances where two affected sheep have been identified in flocks. This may indicate that natural transmission may occur, or that the sheep were infected from a common alternative source(22, 29). Possible indications of an association with the feeding of vitamins and mineral feed supplements were detected in Norway, but remain to be proven(22). Does it represent a risk to human health?
This is currently unknown, but if atypical scrapie is not a new phenomenon, and has simply been discovered recently, then the lack of epidemiological association between
TAFS 6
prion diseases in humans and sheep, or consumption of sheep products, suggest that atypical scrapie does not represent a risk to humans. This is not however demonstration of absolute safety.
see full text ;
http://www.tseandfoodsafety.org/position_papers/TAFS_POSITION_PAPER_ON_ATYPICAL_SCRAPIE_AND_%20ATYPICAL_BSE_070516.pdf
experimental transmission of 171RR Nor98 brain to 5 RR recipients (Jan 2008)
http://www.sheepusa.org/index.phtml?page=site/get_file&print=1&file_id=f4d1b2a4739ab82d903cf042526bd9ee
http://www.eradicatescrapie.org/Educational%20Resources/PDFs%20&%20PPTs/Genotyping%20PPT/Slide%20Notes%20for%20Genotyping.pdf
http://www.eradicatescrapie.org/Educational%20Resources/PDFs%20&%20PPTs/Genotyping%20PPT/Genotyping%20A%20Tool%20for%20Controlling%20Classical%20Scrapie.ppt
P7.12 Co-existence of classical and atypical scrapie strains in a sheep from an Italian outbreak
Results: IHC revealed the simultaneous presence in the brain of pathological features characteristic of Nor98 and classical scrapie. This was confirmed by WB: PrPres fragments characteristic of Nor98 and scrapie were simultaneously present in all areas investigated, although in different proportions, with Nor98 being more abundant in the cortex and classical scrapie in the brainstem. The lymph node showed the presence of PrPsc with a molecular pattern referable only to classical scrapie, while the tongue resulted negative. Genetic analysis showed the following genotype: A136L141R154Q171/A136F141R154Q171.
Discussion: Our results suggest either the co-existence of Nor98 and classical scrapie in this sheep or the presence of a new scrapie phenotype. The presence of classical scrapie in the outbreak and the genotype of the animal support the first event, which might be explained by the different genetic and cellular targets of the two strains. The bioassay analysis in bank voles and Tg338 mice, at the moment in progress, will help to confirm this hypothesis.
also see ;
P9.18 First Report of Classical Scrapie in Portugal, including co-existence with atypical scrapie in the same flock
also see ;
P9.37 Sporadic Creutzfeldt-Jakob Disease in the Basque Country: Coexistence of prion protein strains in the same and different brain regions
Discussion: The Basque Country presents one of the highest annual incidences of confirmed sCJD in Spain and in Europe (1.87 per million inhabitants per annum). It also suffers the highest frequency of FFI (43.12%). Regarding regional pattern distribution, our results show a predominance of PrPsc type 1 in sCJD. Surprisingly, a high frequency of cases with both types of prion protein was observed, indicating that the coexistence of two different molecular patterns in the same individual is more common than expected.
http://www.neuroprion.org/resources/pdf_docs/conferences/prion2008/abstract-book-prion2008.pdf
Saturday, May 2, 2009
APHIS AND WHO PLAN TO EXEMPT THE ATYPICAL SCRAPIE NOR-98 FROM REGULATIONS AT MEETING THIS MONTH
http://nor-98.blogspot.com/2009/05/aphis-and-who-plan-to-exempt-atypical.html
2.1. European dimension of the problem.
Sheep and goats have suffered from scrapie for centuries in the EU and world wide but the current distribution and incidence of scrapie is largely unknown due to the inadequacy of the epidemiosurveillance networks in different Member States. Until the beginning of the BSE epidemic in the UK in the 1980s there was no particular concern about the national incidence of scrapie (or other TSEs in sheep). One reason was because it is generally accepted that there was no epidemiological relationship between the occurrence of scrapie in sheep and the incidence of Creutzfeldt-Jakob disease (CJD) in humans over a period of over 250 years. However, attention was drawn by the Scientific Veterinary Committee to the high incidence of familial CJD in the Orava region of Slovakia at a level of about 30 times the normal level of 1 per million adults per year. This form of familial CJD is attributed to mutations in the PrP gene at codon 200. This particular mutation is not fully penetrant and some of the workers in Slovakia have suggested that exposure to sheep scrapie may also be necessary for disease to result. This is partly because scrapie had been identified in sheep in the region following a period since the late XIXth century when scrapie was thought to be absent from the country.
http://ec.europa.eu/food/fs/sc/ssc/out48_en.html
http://www.springerlink.com/content/l564271136v7626t/
http://www.springerlink.com/content/v847132717217040/
1: Cent Eur J Public Health 2003 Mar;11(1):19-22
Analysis of unusual accumulation of Creutzfeldt-Jakob disease cases in Orava and Liptov regions (northern Slovak focus) 1983-2000.
Mad'ar R, Maslenova D, Ranostajova K, Straka S, Baska T.
Institute of Epidemiology, Jessenius Faculty of Medicine, Comenius University, Sklabinska 26, Martin, 037 53 Slovakia. mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000161/!x-usc:mailto:MADAR@jfmed.uniba.sk
While familial cases of Creutzfeldt-Jakob disease are extremely rare all over the world, 3 familial clusters were observed between 1983-2000 in a relatively small area situated in the North of Slovakia. Prevalence of CJD in this area exceeded the overall prevalence in Slovakia more than 8 times. The majority of CJD patients admitted consuming sheep brain. Most patients lived in small secluded villages with rather common familial intermarriage. CJD affected both sexes equally. All patients were prior to the disease mentally normal individuals. Shortly after the onset of CJD their mental status deteriorated remarkably with an average survival rate of 3.6 months.
PMID: 12690798
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12690798&dopt=Abstract
------------------------------------------------------------------------
1: Eur J Epidemiol 1991 Sep;7(5):520-3
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?db=PubMed&cmd=Display&dopt=pubmed_pubmed&from_uid=1761109
"Clusters" of CJD in Slovakia: the first laboratory evidence of scrapie.
Mitrova E, Huncaga S, Hocman G, Nyitrayova O, Tatara M.
Institute of Preventive and Clinical Medicine, Bratislava.
Epidemic-like occurrence of Creutzfeldt-Jakob disease was observed in 1987 in Slovakia (Orava). Search for the cause of CJD focus indicated a coincidence of genetic and environmental risks in clustering patients. Since Spongiform Encephalopathies might be transmitted orally, (Bovine Spongiform Encephalopathy), the possibility of zoonotic source of CJD cases in Orava was also considered. A deficient knowledge about the occurrence of scrapie in Slovakia stimulated an examination of sheep with signs of CNS disorders in two flocks of Valasky breed in Orava. In one flock, neurohistopathological examination revealed in sheep brains lesions characteristic for scrapie. Frozen brain tissue of these animals were used for the detection of scrapie associated fibrils. They were found in 2 animals from the same flock. This is the first laboratory confirmation of scrapie in Czecho-Slovakia. The possible epidemiological and economical implications are emphasized.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1761109&dopt=Abstract
STATEMENT OF DR HELEN GRANT MD FRCP ISSUED 13/05/1999
BSE INQUIRY
http://www.bseinquiry.gov.uk/files/ws/s410.pdf
http://www.bseinquiry.gov.uk/files/ws/s410x.pdf
http://www.bseinquiry.gov.uk/evidence/ws/ws8.htm
CWD to CJD in humans (why not?), as easy as BSE/Scrapie;
The EMBO Journal, Vol. 19, No. 17 pp. 4425-4430, 2000 © European Molecular Biology Organization
Evidence of a molecular barrier limiting susceptibility of humans, cattle and sheep to chronic wasting disease
G.J. Raymond1, A. Bossers2, L.D. Raymond1, K.I. O?Rourke3, L.E. McHolland4, P.K. Bryant III4, M.W. Miller5, E.S. Williams6, M. Smits2 and B. Caughey1,7
1NIAID/NIH Rocky Mountain Laboratories, Hamilton, MT 59840, 3USDA/ARS/ADRU, Pullman, WA 99164-7030, 4USDA/ARS/ABADRL, Laramie, WY 82071, 5Colorado Division of Wildlife, Wildlife Research Center, Fort Collins, CO 80526-2097, 6Department of Veterinary Sciences, University of Wyoming, Laramie, WY 82070, USA and 2ID-Lelystad, Institute for Animal Science and Health, Lelystad, The Netherlands 7Corresponding author e-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000161/!x-usc:mailto:bcaughey@nih.gov Received June 7, 2000; revised July 3, 2000; accepted July 5, 2000.
Abstract
Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) of deer and elk, and little is known about its transmissibility to other species. An important factor controlling interspecies TSE susceptibility is prion protein (PrP) homology between the source and recipient species/genotypes. Furthermore, the efficiency with which the protease-resistant PrP (PrP-res) of one species induces the in vitro conversion of the normal PrP (PrP-sen) of another species to the protease-resistant state correlates with the cross-species transmissibility of TSE agents. Here we show that the CWD-associated PrP-res (PrPCWD) of cervids readily induces the conversion of recombinant cervid PrP-sen molecules to the protease-resistant state in accordance with the known transmissibility of CWD between cervids. In contrast, PrPCWD-induced conversions of human and bovine PrP-sen were much less efficient, and conversion of ovine PrP-sen was intermediate. These results demonstrate a barrier at the molecular level that should limit the susceptibility of these non-cervid species to CWD.
snip...
Clearly, it is premature to draw firm conclusions about CWD passing naturally into humans, cattle and sheep, but the present results suggest that CWD transmissions to humans would be as limited by PrP incompatibility as transmissions of BSE or sheep scrapie to humans. Although there is no evidence that sheep scrapie has affected humans, it is likely that BSE has caused variant CJD in 74 people (definite and probable variant CJD cases to date according to the UK CJD Surveillance Unit). Given the presumably large number of people exposed to BSE infectivity, the susceptibility of humans may still be very low compared with cattle, which would be consistent with the relatively inefficient conversion of human PrP-sen by PrPBSE. Nonetheless, since humans have apparently been infected by BSE, it would seem prudent to take reasonable measures to limit exposure of humans (as well as sheep and cattle) to CWD infectivity as has been recommended for other animal TSEs.
snip...
http://www.emboj.org/current.shtml
Scrapie to Humans USA?
1: Neuroepidemiology. 1985;4(4):240-9.
Sheep consumption: a possible source of spongiform encephalopathy in humans.
Davanipour Z, Alter M, ***el E, Callahan M.
A fatal spongiform encephalopathy of sheep and goats (scrapie) shares many characteristics with Creutzfeldt-Jakob disease (CJD), a similar dementing illness of humans. To investigate the possibility that CJD is acquired by ingestion of contaminated sheep products, we collected information on production, slaughtering practices, and marketing of sheep in Pennsylvania. The study revealed that sheep were usually marketed before central nervous system signs of scrapie are expected to appear; breeds known to be susceptible to the disease were the most common breeds raised in the area; sheep were imported from other states including those with a high frequency of scrapie; use of veterinary services on the sheep farms investigated and, hence, opportunities to detect the disease were limited; sheep producers in the area knew little about scrapie despite the fact that the disease has been reported in the area, and animal organs including sheep organs were sometimes included in processed food. Therefore, it was concluded that in Pennsylvania there are some 'weak links' through which scrapie-infected animals could contaminate human food, and that consumption of these foods could perhaps account for spongiform encephalopathy in humans. The weak links observed are probably not unique to Pennsylvania.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3915057&dopt=Abstract
Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.
Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.
Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation.
PMID: 6997404
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
Libyan Jews
A countrywide search for CJD in Israel uncovered 29 cases with onset between 1963–72.25 The incidence in various ethnic groups varied from 0.4 to 1.9 per million, except among Jewish immigrants from Libya, among whom the incidence was 31.3 per million. The eating of lightly cooked sheep brain, a delicacy amongst Mediterranean Jews, was at first postulated to be responsible, but the incidence of CJD amongst other ethnic groups with the same dietary habits was only 1–2 cases per million of the population.
The Chilean cluster
A cluster in Chile, involving four cases of histologically-proven CJD in three farmers and one housewife, occurred in 1982–3. The four lived in small rural communities situated within a 20-km radius of the town of Chillian. They were unrelated and did not know each other. Their life long dietary habits are of interest, but uncertain relevance. They all consumed uncooked sheep blood and poorly-cooked sheep blood and brain.
http://qjmed.oxfordjournals.org/cgi/content/full/93/9/617
Mutation of the prion protein in Libyan Jews with Creutzfeldt-Jakob disease Article Abstract:
Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disease of a class referred to as the spongiform encephalopathies. The disease can be transmitted experimentally and has also been transmitted accidentally. The causative agent in these transmissions is unlike any well characterized infectious agent and is referred to by many as a prion. Creutzfeldt-Jakob disease may occur in families, but is usually sporadic. The incidence of Creutzfeldt-Jakob disease is about one or two cases per million people. However, among Jews from Libya, the incidence is 100 times higher. Many possible explanations have been put forward to account for this unusually high incidence, but none has sustained any scrutiny. One of the more popular notions was that the eating of sheep brains, a popular delicacy in the region, infected people with scrapie, a prion disease of sheep similar to CJD. However, the eating of sheep brain is popular throughout the Mediterranean, and cannot explain the specificity of the increased incidence to Libyan Jews. Mediterranean sheep, if anything, have a lower rate of scrapie than other areas of Europe and North America. A study was undertaken to determine if the increased incidence of CJD among these people might be accounted for by genetic factors. The prion protein genes were analyzed in 11 Libyan Jews with Creutzfeldt-Jakob disease. Investigation of one patient revealed that a mutation had occurred in the 200th codon of the gene, that is, the 200th set of three DNA bases. The net result of this change would be to substitute a lysine for glutamine in the resulting protein. After this mutation was identified, it was confirmed in the other 10 Libyan patients. It is interesting to note that the mutation was not present in a Moroccan Jew with CJD. The results suggest that the increased incidence of Creutzfeldt-Jakob disease in this population is the result of a gene carried by this group. In eight of the present cases, a family history of CJD could be confirmed. Although not all families were cooperative in providing information of the ancestral heritage, all the families for which such information was available could be traced to Djerba, which is an island off the coast of Tunisia. (Consumer Summary produced by Reliance Medical Information, Inc.)
author: Scarlato, Guglielmo, Prusiner, Stanley B., Hsiao, Karen, Meiner, Zeev, Kahana, Esther, Cass, Carin, Kahana, Irit, Avrahami, Dana, Abramsky, Oded, Gabizon, Ruth Publisher: Massachusetts Medical Society Publication Name: The New England Journal of Medicine Subject: Health ISSN: 0028-4793 Year: 1991
http://www.faqs.org/abstracts/Health/Mutation-of-the-prion-protein-in-Libyan-Jews-with-Creutzfeldt-Jakob-disease.html
Friday, August 22, 2008
Creutzfeldt Jakob Disease and Veterans and how they are treated at death
They worry that he may have gotten it from eating sheep brains locals served to soldiers as an honor in Oman two years ago.
http://creutzfeldt-jakob-disease.blogspot.com/2008/08/creutzfeldt-jakob-disease-and-veterans.html
SCRAPIE DETECTED IN ANOTHER GOAT USA UPDATE MARCH 2009
http://scrapie-usa.blogspot.com/2009/04/scrapie-detected-in-another-goat-usa.html
Full Scientific Reports
Experimental oral transmission of United States origin scrapie to neonatal sheep
Amir N. Hamir1, Robert A. Kunkle, Justin J. Greenlee and Juergen A. Richt Correspondence: 1Corresponding Author: Amir N. Hamir, National Animal Disease Center, ARS, USDA, 2300 Dayton Avenue, PO Box 70, Ames, IA 50010. mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000161/!x-usc:mailto:amir.hamir@ars.usda.gov
Scrapie, a transmissible spongiform encephalopathy (TSE), is a naturally occurring fatal neurodegenerative disease of sheep and goats. The current study documents incubation periods, pathologic findings, and distribution of abnormal prion proteins (PrPSc) by immunohistochemistry and Western blot in tissues of genetically susceptible and resistant neonatal lambs inoculated with pooled brain homogenates from 13 U.S. origin scrapie-affected ewes. Nine Suffolk lambs with genotypes AA/RR/QQ (n = 5) and AA/RR/QR (n = 4) at codons 136, 154, and 171, respectively) were orally inoculated, within 12 hr of birth, with 1 ml of a 10% (w/v) brain homogenate prepared from scrapie-affected sheep brains. Inoculated animals were euthanized when advanced clinical signs of scrapie were observed. All QQ sheep developed clinical signs of scrapie, with a mean survival time of 24 months. Spongiform lesions in the brains and PrPSc deposits in the central nervous system and lymphoid tissues were present in these sheep. None of the QR sheep succumbed to the disease. A previous study that used a larger volume (30 ml of 10% brain suspension) of the same inoculum in 4-month-old Suffolk lambs of susceptible genotype documented longer survival periods (average 32 months), and only 5 of 9 inoculated sheep developed scrapie. Findings of this study suggest that orally exposed neonatal lambs of a susceptible (QQ) genotype exhibit a higher attack rate and shorter incubation period than older (4-month-old) lambs exposed to a larger dose (30x) of the same inoculum.
Key Words: Immunohistochemistry • neonatal sheep • scrapie • spongiform encephalopathy • Western blot
http://jvdi.org/cgi/content/abstract/21/1/64?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=prion&searchid=1&FIRSTINDEX=0&volume=21&issue=1&resourcetype=HWCIT
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://www.bseinquiry.gov.uk/files/yb/1994/02/07002001.pdf
Title: Characterization of a U.S. Sheep Scrapie Isolate with Short Incubation Time
Authors
Hamir, Amirali Richt, Juergen Kunkle, Robert Greenlee, Justin Bulgin, M - UNIVERSITY OF IDAHO Gregori, L - VA MEDICAL CENTER, MD Rohwer, R - VA MEDICAL CENTER, MD
Submitted to: Veterinary Pathology Publication Type: Peer Reviewed Journal Publication Acceptance Date: April 16, 2009 Publication Date: N/A
Interpretive Summary: Scrapie is a naturally occurring fatal disease of sheep and goats. In a previous study it was shown that sheep inoculated with US scrapie inoculum (No. 13-7) induced terminal disease within an average of 19 months. We have since produced an inoculum, No. X124 from pooled brains of US origin sheep scrapie, that results in incubations nearly 3 fold shorter. The present study documents laboratory findings in tissues of sheep inoculated with No. X124. All inoculated sheep developed clinical disease and were euthanized within an average of 7.7 months post inoculation (MPI). Sheep that were genetically susceptible developed the disease faster (within 6 months). Also, the inoculum was able to induce disease in a short time (7 MPI) in a sheep that was supposed to be highly resistant to scrapie. This indicates that inoculum No. X124 appears to be more virulent than inoculum No. 13-7. Importantly this strain of scrapie represents a significant development in that it provides a natural model that requires less than 25 percent of the time for the disease to develop, thus enabling a faster pace for research investigating prion disease pathogenesis and inactivation. Technical Abstract: Scrapie is a naturally occurring fatal neurodegenerative disease of sheep and goats. Susceptibility to the disease is partly dependent upon the genetic makeup of the host. In a previous study it was shown that sheep intracerebrally inoculated with US scrapie inoculum (No. 13-7) developed terminal disease within an average of 19 months. We have since produced an inoculum, No. x124 from pooled brains of US origin sheep scrapie, that results in incubations nearly 3 fold shorter. The present study documents clinicopathological findings and the distribution of abnormal prion proteins (PrP**Sc) by immunohistochemical (IHC) and Western blot (WB) techniques, in tissues of sheep inoculated with No. x124. All inoculated sheep developed clinical disease and were euthanized within an average of 7.7 months post-inoculation (MPI). Sheep that had VV or AV at codon 136 of prion protein (PRNP) gene developed the disease faster and were euthanized at an average of 4.3 and 5.6 MPI, respectively. Also, the inoculum was able to induce disease in a short time (7 MPI) in a sheep that was relatively resistant (QR at codon 171) to scrapie. This indicates that inoculum No. x124 appears to induce scrapie in shorter time than inoculum No. 13-7, especially in sheep homozygous or heterozygous for valine at codon 136.
http://www.ars.usda.gov/research/publications/publications.htm?seq_no_115=230885
1: J Infect Dis 1980 Aug;142(2):205-8
Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.
Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.
Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation.
PMID: 6997404
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
12/10/76 AGRICULTURAL RESEARCH COUNCIL REPORT OF THE ADVISORY COMMITTE ON SCRAPIE Office Note CHAIRMAN: PROFESSOR PETER WILDY
snip...
A The Present Position with respect to Scrapie
A1 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://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
Epidemiology of Scrapie in the United States 1977
http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
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
http://nor-98.blogspot.com/
http://scrapie-usa.blogspot.com/
Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518
Saturday, May 2, 2009
APHIS AND WHO PLAN TO EXEMPT THE ATYPICAL SCRAPIE NOR-98 FROM REGULATIONS AT MEETING THIS MONTH
APHIS AND WHO PLAN TO EXEMPT THE ATYPICAL SCRAPIE NOR-98 FROM REGULATIONS AT MEETING THIS MONTH and expose the globe to yet more Transmissible Spongiform Encephalopathies, just for trade, when science shows otherwise $$$
It's all about trade, to hell with human health. if the body bag count is low, due to a slow incubating disease, so be it, let the trading of this slow disease continue. Just because the
atypical Nor-98 scrapie is more like sporadic CJD in humans, no big deal. ...
still disgusted in Bacliff, Texas ...TSS
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
OH WELL, as with the BSE MRR policy, big ag changes animal health zootic disease policy again. scapie transmits to primate by its non-forced oral consumption, and the atypical Nor-98 scrapie looks like some sub-types of the sporadic CJD, so what did you expect. just ignor the science and snow the public, they'll eat anything. ...TSS
Nor98-like Scrapie in the United States of America
was presented by Drs. Christina M. Loiacono, S. Mark Hall, and Bruce V. Thomsen, National Veterinary Services Laboratory, USDA-APHIS-VS.
This paper describes the first six sheep diagnosed with Nor98-like disease in the United States and serves to acknowledge the increased efforts of diagnosticians and the USDA program to control and eradicate scrapie disease. Classical scrapie, a fatal neurodegenerative disease affecting the central nervous system of sheep and goats, is among a number of diseases classified as transmissible spongiform encephalopathies (TSEs). Recently, a distinct strain of scrapie was diagnosed in sheep in Norway1 and has been identified in numerous countries of the European Union (EU). The disease has been identified, among other names, as Nor98 or Nor98-like scrapie. Distinctions between classical scrapie and Nor98-like scrapie are made based on signalment, clinical signs, histopathology and immunodiagnostic results. In the past, the classical scrapie disease was confirmed by examination of the brain tissue for a triad of histopathological signs - vacuolation, loss of neurons and gliosis - and, more recently, by immunohistochemical (IHC) or biochemical detection of abnormal prion protein (PrPSc) in the brain, or lymphoid tissues. In the case of Nor98-like scrapie there is generally little or no vacuolation in the brain and, to date, no lymphoid accumulation of PrPSc has been detected. Classical scrapie typically has the most intense PrPSc immunostaining at the obex (motor nucleus of the vagus), while this area is spared in Nor98-like scrapie. Alternatively, Nor98-like scrapie consistently has PrPSc immunostaining in the spinal nucleus of the trigeminal nerve and variable, but often an intense immunostaining for PrPSc in the cerebellum. Thus the diagnosis of Nor98 and Nor98-like disease can be based on immunohistochemistry identifying abnormal prion protein in regions of the brain not typically associated with classical scrapie. Additionally there is a distinct diagnostic western blot pattern for Nor98 and Nor-98 like disease consisting of three or more protein bands with the unglycosylated band being less than 15 kd, compared to classical scrapie in which the unglycosylated band is greater than 15 kd. Nor98 and Nor-98 like disease is associated with older sheep, usually greater than four years of age, while sheep in the range of three to five years of age are more commonly affected by classical scrapie. Clinical signs are uncommon with Nor98 and Nor98-like disease but when present most often include ataxia without pruritis. Genotypes known to provide sheep with resistance to classical scrapie are not spared from Nor98 and Nor98-like disease.
The six U.S. cases had no clinical signs reported. Three cases were detected during slaughter surveillance, two were detected as a result of classical scrapie being found in the flock, one found during testing associated with diagnostic necropsy. Five of the 6 cases had genotypes that are susceptible to classical scrapie and one was AARR. Only one Nor98-like scrapie case was found per flock.
1. Benestad SL, Sarradin P, Thu B, Schönheit J, Tranulis MA, Bratberg B., Cases of scrapie with unusual features in Norway and designation of a new type, Nor98. Vet. Rec.
http://www.usaha.org/committees/reports/2008/report-scr-2008.pdf
http://www.sheepusa.org/index.phtml?page=site/get_file&print=1&file_id=a565d8d1480eca6400d3a2adff9d89bc
http://www.sheepusa.org/index.phtml?page=site/get_file&print=1&file_id=f4d1b2a4739ab82d903cf042526bd9ee
http://www.animalagriculture.org/Proceedings/2008AM/Tuesday/S&G/O'Rourke,%20Katherine.pdf
NOW, if there have been more of the Nor-98 documented to date, know one would know since NO MAP for the Nor-98 total cases in the USA is posted on the USDA/APHIS scrapie maps monthly report. ...TSS
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
NOR-98 ATYPICAL SCRAPIE 5 cases documented in USA in 5 different states USA 007
http://nor-98.blogspot.com/2008/04/seac-spongiform-encephalopathy-advisory.html
Tuesday, June 3, 2008 SCRAPIE USA UPDATE JUNE 2008 NOR-98 REPORTED PA
http://nor-98.blogspot.com/2008/06/scrapie-usa-update-june-2008-nor-98.html
http://nor-98.blogspot.com/
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://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.
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://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
Epidemiology of Scrapie in the United States 1977
http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
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
FULL TEXT ;
http://www.organicconsumers.org/meat/scrapiecjd.cfm
TSS
----- Original Message -----
From: "Terry S. Singeltary Sr."
To:Sent: Sunday, April 26, 2009 3:15 PM
Subject: [BSE-L] SCRAPIE DETECTED IN ANOTHER GOAT USA UPDATE MARCH 2009
-------------------- BSE-L@LISTS.AEGEE.ORG --------------------
SCRAPIE DETECTED IN ANOTHER GOAT USA UPDATE MARCH 2009
SEE MARCH 2009 SCRAPIE UPDATE PPS ;
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/monthly_scrapie_rpt.pps
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/
Greetings BSE-L,
I find it disturbing that the Nor-98 atypical cases of scrapie in the USA are NOT documented on the APHIS web page. this makes no sense, and i have ask about it before in the past, APHIS et al refuse to post a seperate map showing the documented Nor98-like atypical cases here in the USA, all of them ? said they would look into it years ago. it's like out of sight, out of mind, like the TSE in the USA bovine. THE ONLY mention of the Nor-98 like scrapie that has been documented in the USA to date was on CHART 3, and then it is very very misleading as to the actual number of cases. it states ;
* Through March 31, 2009 - does not include the Nor-98-like Scrapie cases found through RSSS (2 in FY 2007 and 1 in FY 2008). <>To:Sent: Sunday, April 26, 2009 3:15 PM Subject: [BSE-L] SCRAPIE DETECTED IN ANOTHER GOAT USA UPDATE MARCH 2009
-------------------- BSE-L@LISTS.AEGEE.ORG --------------------
SCRAPIE DETECTED IN ANOTHER GOAT USA UPDATE MARCH 2009
SEE MARCH 2009 SCRAPIE UPDATE PPS ;
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/monthly_scrapie_rpt.pps
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/
Greetings BSE-L,
I find it disturbing that the Nor-98 atypical cases of scrapie in the USA are NOT documented on the APHIS web page. this makes no sense, and i have ask about it before in the past, APHIS et al refuse to post a seperate map showing the documented Nor98-like atypical cases here in the USA, all of them ? said they would look into it years ago. it's like out of sight, out of mind, like the TSE in the USA bovine. THE ONLY mention of the Nor-98 like scrapie that has been documented in the USA to date was on CHART 3, and then it is very very misleading as to the actual number of cases. it states ;
* Through March 31, 2009 - does not include the Nor-98-like Scrapie cases found through RSSS (2 in FY 2007 and 1 in FY 2008). <
SO, were just going to forget about the other 3 cases of the Nor-98-like scrapie in the USA ??? or, are there more ???
WHY not a seperate map showing Nor-98-like atypical Scrapie cases (all of them), state by state ???
HAVE the actual number of cases grown in the USA from the 6 cases I was aware of ???
BY my records, to date, there have been 6 cases of the Nor-98-like atypical scrapie documented in the USA.
Maybe one of the USDA followers here on the BSE-L, that is in the Scrapie department, would be so kind as to help us clear this up?
NOR-98 ATYPICAL SCRAPIE 5 cases documented in USA in 5 different states USA
http://nor-98.blogspot.com/2008/04/seac-spongiform-encephalopathy-advisory.html
Tuesday, June 3, 2008 SCRAPIE USA UPDATE JUNE 2008 NOR-98 REPORTED PA
http://nor-98.blogspot.com/2008/06/scrapie-usa-update-june-2008-nor-98.html
http://nor-98.blogspot.com/
http://scrapie-usa.blogspot.com/
SCRAPIE DETECTED IN ANOTHER GOAT USA UPDATE MARCH 2009
http://scrapie-usa.blogspot.com/2009/04/scrapie-detected-in-another-goat-usa.html
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
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
TSS
It's all about trade, to hell with human health. if the body bag count is low, due to a slow incubating disease, so be it, let the trading of this slow disease continue. Just because the
atypical Nor-98 scrapie is more like sporadic CJD in humans, no big deal. ...
still disgusted in Bacliff, Texas ...TSS
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
OH WELL, as with the BSE MRR policy, big ag changes animal health zootic disease policy again. scapie transmits to primate by its non-forced oral consumption, and the atypical Nor-98 scrapie looks like some sub-types of the sporadic CJD, so what did you expect. just ignor the science and snow the public, they'll eat anything. ...TSS
Nor98-like Scrapie in the United States of America
was presented by Drs. Christina M. Loiacono, S. Mark Hall, and Bruce V. Thomsen, National Veterinary Services Laboratory, USDA-APHIS-VS.
This paper describes the first six sheep diagnosed with Nor98-like disease in the United States and serves to acknowledge the increased efforts of diagnosticians and the USDA program to control and eradicate scrapie disease. Classical scrapie, a fatal neurodegenerative disease affecting the central nervous system of sheep and goats, is among a number of diseases classified as transmissible spongiform encephalopathies (TSEs). Recently, a distinct strain of scrapie was diagnosed in sheep in Norway1 and has been identified in numerous countries of the European Union (EU). The disease has been identified, among other names, as Nor98 or Nor98-like scrapie. Distinctions between classical scrapie and Nor98-like scrapie are made based on signalment, clinical signs, histopathology and immunodiagnostic results. In the past, the classical scrapie disease was confirmed by examination of the brain tissue for a triad of histopathological signs - vacuolation, loss of neurons and gliosis - and, more recently, by immunohistochemical (IHC) or biochemical detection of abnormal prion protein (PrPSc) in the brain, or lymphoid tissues. In the case of Nor98-like scrapie there is generally little or no vacuolation in the brain and, to date, no lymphoid accumulation of PrPSc has been detected. Classical scrapie typically has the most intense PrPSc immunostaining at the obex (motor nucleus of the vagus), while this area is spared in Nor98-like scrapie. Alternatively, Nor98-like scrapie consistently has PrPSc immunostaining in the spinal nucleus of the trigeminal nerve and variable, but often an intense immunostaining for PrPSc in the cerebellum. Thus the diagnosis of Nor98 and Nor98-like disease can be based on immunohistochemistry identifying abnormal prion protein in regions of the brain not typically associated with classical scrapie. Additionally there is a distinct diagnostic western blot pattern for Nor98 and Nor-98 like disease consisting of three or more protein bands with the unglycosylated band being less than 15 kd, compared to classical scrapie in which the unglycosylated band is greater than 15 kd. Nor98 and Nor-98 like disease is associated with older sheep, usually greater than four years of age, while sheep in the range of three to five years of age are more commonly affected by classical scrapie. Clinical signs are uncommon with Nor98 and Nor98-like disease but when present most often include ataxia without pruritis. Genotypes known to provide sheep with resistance to classical scrapie are not spared from Nor98 and Nor98-like disease.
The six U.S. cases had no clinical signs reported. Three cases were detected during slaughter surveillance, two were detected as a result of classical scrapie being found in the flock, one found during testing associated with diagnostic necropsy. Five of the 6 cases had genotypes that are susceptible to classical scrapie and one was AARR. Only one Nor98-like scrapie case was found per flock.
1. Benestad SL, Sarradin P, Thu B, Schönheit J, Tranulis MA, Bratberg B., Cases of scrapie with unusual features in Norway and designation of a new type, Nor98. Vet. Rec.
http://www.usaha.org/committees/reports/2008/report-scr-2008.pdf
http://www.sheepusa.org/index.phtml?page=site/get_file&print=1&file_id=a565d8d1480eca6400d3a2adff9d89bc
http://www.sheepusa.org/index.phtml?page=site/get_file&print=1&file_id=f4d1b2a4739ab82d903cf042526bd9ee
http://www.animalagriculture.org/Proceedings/2008AM/Tuesday/S&G/O'Rourke,%20Katherine.pdf
NOW, if there have been more of the Nor-98 documented to date, know one would know since NO MAP for the Nor-98 total cases in the USA is posted on the USDA/APHIS scrapie maps monthly report. ...TSS
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
NOR-98 ATYPICAL SCRAPIE 5 cases documented in USA in 5 different states USA 007
http://nor-98.blogspot.com/2008/04/seac-spongiform-encephalopathy-advisory.html
Tuesday, June 3, 2008 SCRAPIE USA UPDATE JUNE 2008 NOR-98 REPORTED PA
http://nor-98.blogspot.com/2008/06/scrapie-usa-update-june-2008-nor-98.html
http://nor-98.blogspot.com/
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://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.
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://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
Epidemiology of Scrapie in the United States 1977
http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
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
FULL TEXT ;
http://www.organicconsumers.org/meat/scrapiecjd.cfm
TSS
----- Original Message -----
From: "Terry S. Singeltary Sr."
To:
Subject: [BSE-L] SCRAPIE DETECTED IN ANOTHER GOAT USA UPDATE MARCH 2009
-------------------- BSE-L@LISTS.AEGEE.ORG --------------------
SCRAPIE DETECTED IN ANOTHER GOAT USA UPDATE MARCH 2009
SEE MARCH 2009 SCRAPIE UPDATE PPS ;
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/monthly_scrapie_rpt.pps
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/
Greetings BSE-L,
I find it disturbing that the Nor-98 atypical cases of scrapie in the USA are NOT documented on the APHIS web page. this makes no sense, and i have ask about it before in the past, APHIS et al refuse to post a seperate map showing the documented Nor98-like atypical cases here in the USA, all of them ? said they would look into it years ago. it's like out of sight, out of mind, like the TSE in the USA bovine. THE ONLY mention of the Nor-98 like scrapie that has been documented in the USA to date was on CHART 3, and then it is very very misleading as to the actual number of cases. it states ;
* Through March 31, 2009 - does not include the Nor-98-like Scrapie cases found through RSSS (2 in FY 2007 and 1 in FY 2008). <>To:
-------------------- BSE-L@LISTS.AEGEE.ORG --------------------
SCRAPIE DETECTED IN ANOTHER GOAT USA UPDATE MARCH 2009
SEE MARCH 2009 SCRAPIE UPDATE PPS ;
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/monthly_scrapie_rpt.pps
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/
Greetings BSE-L,
I find it disturbing that the Nor-98 atypical cases of scrapie in the USA are NOT documented on the APHIS web page. this makes no sense, and i have ask about it before in the past, APHIS et al refuse to post a seperate map showing the documented Nor98-like atypical cases here in the USA, all of them ? said they would look into it years ago. it's like out of sight, out of mind, like the TSE in the USA bovine. THE ONLY mention of the Nor-98 like scrapie that has been documented in the USA to date was on CHART 3, and then it is very very misleading as to the actual number of cases. it states ;
* Through March 31, 2009 - does not include the Nor-98-like Scrapie cases found through RSSS (2 in FY 2007 and 1 in FY 2008). <
SO, were just going to forget about the other 3 cases of the Nor-98-like scrapie in the USA ??? or, are there more ???
WHY not a seperate map showing Nor-98-like atypical Scrapie cases (all of them), state by state ???
HAVE the actual number of cases grown in the USA from the 6 cases I was aware of ???
BY my records, to date, there have been 6 cases of the Nor-98-like atypical scrapie documented in the USA.
Maybe one of the USDA followers here on the BSE-L, that is in the Scrapie department, would be so kind as to help us clear this up?
NOR-98 ATYPICAL SCRAPIE 5 cases documented in USA in 5 different states USA
http://nor-98.blogspot.com/2008/04/seac-spongiform-encephalopathy-advisory.html
Tuesday, June 3, 2008 SCRAPIE USA UPDATE JUNE 2008 NOR-98 REPORTED PA
http://nor-98.blogspot.com/2008/06/scrapie-usa-update-june-2008-nor-98.html
http://nor-98.blogspot.com/
http://scrapie-usa.blogspot.com/
SCRAPIE DETECTED IN ANOTHER GOAT USA UPDATE MARCH 2009
http://scrapie-usa.blogspot.com/2009/04/scrapie-detected-in-another-goat-usa.html
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
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
TSS
Tuesday, April 28, 2009
Nor98-like Scrapie in the United States of America
>>>BY my records, to date, there have been 6 cases of the Nor-98-like atypical scrapie documented in the USA.<<<
>>>Maybe one of the USDA followers here on the BSE-L, that is in the Scrapie department, would be so kind as to help us clear this up?<<<
oh well, so much for the USDA followers here........ however, i did find this ;
Nor98-like Scrapie in the United States of America
was presented by Drs. Christina M. Loiacono, S. Mark Hall, and Bruce V. Thomsen, National Veterinary Services Laboratory, USDA-APHIS-VS.
This paper describes the first six sheep diagnosed with Nor98-like disease in the United States and serves to acknowledge the increased efforts of diagnosticians and the USDA program to control and eradicate scrapie disease. Classical scrapie, a fatal neurodegenerative disease affecting the central nervous system of sheep and goats, is among a number of diseases classified as transmissible spongiform encephalopathies (TSEs). Recently, a distinct strain of scrapie was diagnosed in sheep in Norway1 and has been identified in numerous countries of the European Union (EU). The disease has been identified, among other names, as Nor98 or Nor98-like scrapie. Distinctions between classical scrapie and Nor98-like scrapie are made based on signalment, clinical signs, histopathology and immunodiagnostic results. In the past, the classical scrapie disease was confirmed by examination of the brain tissue for a triad of histopathological signs – vacuolation, loss of neurons and gliosis – and, more recently, by immunohistochemical (IHC) or biochemical detection of abnormal prion protein (PrPSc) in the brain, or lymphoid tissues. In the case of Nor98-like scrapie there is generally little or no vacuolation in the brain and, to date, no lymphoid accumulation of PrPSc has been detected. Classical scrapie typically has the most intense PrPSc immunostaining at the obex (motor nucleus of the vagus), while this area is spared in Nor98-like scrapie. Alternatively, Nor98-like scrapie consistently has PrPSc immunostaining in the spinal nucleus of the trigeminal nerve and variable, but often an intense immunostaining for PrPSc in the cerebellum. Thus the diagnosis of Nor98 and Nor98-like disease can be based on immunohistochemistry identifying abnormal prion protein in regions of the brain not typically associated with classical scrapie. Additionally there is a distinct diagnostic western blot pattern for Nor98 and Nor-98 like disease consisting of three or more protein bands with the unglycosylated band being less than 15 kd, compared to classical scrapie in which the unglycosylated band is greater than 15 kd. Nor98 and Nor-98 like disease is associated with older sheep, usually greater than four years of age, while sheep in the range of three to five years of age are more commonly affected by classical scrapie. Clinical signs are uncommon with Nor98 and Nor98-like disease but when present most often include ataxia without pruritis. Genotypes known to provide sheep with resistance to classical scrapie are not spared from Nor98 and Nor98-like disease. The six U.S. cases had no clinical signs reported. Three cases were detected during slaughter surveillance, two were detected as a result of classical scrapie being found in the flock, one found during testing associated with diagnostic necropsy. Five of the 6 cases had genotypes that are susceptible to classical scrapie and one was AARR. Only one Nor98-like scrapie case was found per flock. 1. Benestad SL, Sarradin P, Thu B, Schönheit J, Tranulis MA, Bratberg B., Cases of scrapie with unusual features in Norway and designation of a new type, Nor98. Vet. Rec.
http://www.usaha.org/committees/reports/2008/report-scr-2008.pdf
http://www.sheepusa.org/index.phtml?page=site/get_file&print=1&file_id=a565d8d1480eca6400d3a2adff9d89bc
http://www.sheepusa.org/index.phtml?page=site/get_file&print=1&file_id=f4d1b2a4739ab82d903cf042526bd9ee
http://www.animalagriculture.org/Proceedings/2008AM/Tuesday/S&G/O'Rourke,%20Katherine.pdf
NOW, if there have been more of the Nor-98 documented to date, know one would know since NO MAP for the Nor-98 total cases in the USA is posted on the USDA/APHIS scrapie maps monthly report. ...TSS
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
NOR-98 ATYPICAL SCRAPIE 5 cases documented in USA in 5 different states USA 007
http://nor-98.blogspot.com/2008/04/seac-spongiform-encephalopathy-advisory.html
Tuesday, June 3, 2008 SCRAPIE USA UPDATE JUNE 2008 NOR-98 REPORTED PA
http://nor-98.blogspot.com/2008/06/scrapie-usa-update-june-2008-nor-98.html
http://nor-98.blogspot.com/
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://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. PMID: 6997404
http://www.ncbi.nlm.nih.gov/entrez/query.fcgicmd=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://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
Epidemiology of Scrapie in the United States 1977
http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
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
FULL TEXT ;
http://www.organicconsumers.org/meat/scrapiecjd.cfm
TSS
----- Original Message ----- From: "Terry S. Singeltary Sr."To: Sent: Sunday, April 26, 2009 3:15 PM Subject: [BSE-L] SCRAPIE DETECTED IN ANOTHER GOAT USA UPDATE MARCH 2009
-------------------- BSE-L@LISTS.AEGEE.ORG --------------------
SCRAPIE DETECTED IN ANOTHER GOAT USA UPDATE MARCH 2009
SEE MARCH 2009 SCRAPIE UPDATE PPS ;
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/monthly_scrapie_rpt.pps
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/
Greetings BSE-L,
I find it disturbing that the Nor-98 atypical cases of scrapie in the USA are NOT documented on the APHIS web page. this makes no sense, and i have ask about it before in the past, APHIS et al refuse to post a seperate map showing the documented Nor98-like atypical cases here in the USA, all of them ? said they would look into it years ago. it's like out of sight, out of mind, like the TSE in the USA bovine. THE ONLY mention of the Nor-98 like scrapie that has been documented in the USA to date was on CHART 3, and then it is very very misleading as to the actual number of cases. it states ;
>* Through March 31, 2009 - does not include the Nor-98-like Scrapie cases found through RSSS (2 in FY 2007 and 1 in FY 2008). <
SO, were just going to forget about the other 3 cases of the Nor-98-like scrapie in the USA ???
or, are there more ???
WHY not a seperate map showing Nor-98-like atypical Scrapie cases (all of them), state by state ???
HAVE the actual number of cases grown in the USA from the 6 cases I was aware of ???
BY my records, to date, there have been 6 cases of the Nor-98-like atypical scrapie documented in the USA. Maybe one of the USDA followers here on the BSE-L, that is in the Scrapie department, would be so kind as to help us clear this up?
SEE FULL TEXT ;
SCRAPIE DETECTED IN ANOTHER GOAT USA UPDATE MARCH 2009
http://scrapie-usa.blogspot.com/2009/04/scrapie-detected-in-another-goat-usa.html
>>>Maybe one of the USDA followers here on the BSE-L, that is in the Scrapie department, would be so kind as to help us clear this up?<<<
oh well, so much for the USDA followers here........ however, i did find this ;
Nor98-like Scrapie in the United States of America
was presented by Drs. Christina M. Loiacono, S. Mark Hall, and Bruce V. Thomsen, National Veterinary Services Laboratory, USDA-APHIS-VS.
This paper describes the first six sheep diagnosed with Nor98-like disease in the United States and serves to acknowledge the increased efforts of diagnosticians and the USDA program to control and eradicate scrapie disease. Classical scrapie, a fatal neurodegenerative disease affecting the central nervous system of sheep and goats, is among a number of diseases classified as transmissible spongiform encephalopathies (TSEs). Recently, a distinct strain of scrapie was diagnosed in sheep in Norway1 and has been identified in numerous countries of the European Union (EU). The disease has been identified, among other names, as Nor98 or Nor98-like scrapie. Distinctions between classical scrapie and Nor98-like scrapie are made based on signalment, clinical signs, histopathology and immunodiagnostic results. In the past, the classical scrapie disease was confirmed by examination of the brain tissue for a triad of histopathological signs – vacuolation, loss of neurons and gliosis – and, more recently, by immunohistochemical (IHC) or biochemical detection of abnormal prion protein (PrPSc) in the brain, or lymphoid tissues. In the case of Nor98-like scrapie there is generally little or no vacuolation in the brain and, to date, no lymphoid accumulation of PrPSc has been detected. Classical scrapie typically has the most intense PrPSc immunostaining at the obex (motor nucleus of the vagus), while this area is spared in Nor98-like scrapie. Alternatively, Nor98-like scrapie consistently has PrPSc immunostaining in the spinal nucleus of the trigeminal nerve and variable, but often an intense immunostaining for PrPSc in the cerebellum. Thus the diagnosis of Nor98 and Nor98-like disease can be based on immunohistochemistry identifying abnormal prion protein in regions of the brain not typically associated with classical scrapie. Additionally there is a distinct diagnostic western blot pattern for Nor98 and Nor-98 like disease consisting of three or more protein bands with the unglycosylated band being less than 15 kd, compared to classical scrapie in which the unglycosylated band is greater than 15 kd. Nor98 and Nor-98 like disease is associated with older sheep, usually greater than four years of age, while sheep in the range of three to five years of age are more commonly affected by classical scrapie. Clinical signs are uncommon with Nor98 and Nor98-like disease but when present most often include ataxia without pruritis. Genotypes known to provide sheep with resistance to classical scrapie are not spared from Nor98 and Nor98-like disease. The six U.S. cases had no clinical signs reported. Three cases were detected during slaughter surveillance, two were detected as a result of classical scrapie being found in the flock, one found during testing associated with diagnostic necropsy. Five of the 6 cases had genotypes that are susceptible to classical scrapie and one was AARR. Only one Nor98-like scrapie case was found per flock. 1. Benestad SL, Sarradin P, Thu B, Schönheit J, Tranulis MA, Bratberg B., Cases of scrapie with unusual features in Norway and designation of a new type, Nor98. Vet. Rec.
http://www.usaha.org/committees/reports/2008/report-scr-2008.pdf
http://www.sheepusa.org/index.phtml?page=site/get_file&print=1&file_id=a565d8d1480eca6400d3a2adff9d89bc
http://www.sheepusa.org/index.phtml?page=site/get_file&print=1&file_id=f4d1b2a4739ab82d903cf042526bd9ee
http://www.animalagriculture.org/Proceedings/2008AM/Tuesday/S&G/O'Rourke,%20Katherine.pdf
NOW, if there have been more of the Nor-98 documented to date, know one would know since NO MAP for the Nor-98 total cases in the USA is posted on the USDA/APHIS scrapie maps monthly report. ...TSS
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
NOR-98 ATYPICAL SCRAPIE 5 cases documented in USA in 5 different states USA 007
http://nor-98.blogspot.com/2008/04/seac-spongiform-encephalopathy-advisory.html
Tuesday, June 3, 2008 SCRAPIE USA UPDATE JUNE 2008 NOR-98 REPORTED PA
http://nor-98.blogspot.com/2008/06/scrapie-usa-update-june-2008-nor-98.html
http://nor-98.blogspot.com/
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://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. PMID: 6997404
http://www.ncbi.nlm.nih.gov/entrez/query.fcgicmd=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://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
Epidemiology of Scrapie in the United States 1977
http://www.bseinquiry.gov.uk/files/mb/m08b/tab64.pdf
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
FULL TEXT ;
http://www.organicconsumers.org/meat/scrapiecjd.cfm
TSS
----- Original Message ----- From: "Terry S. Singeltary Sr."
-------------------- BSE-L@LISTS.AEGEE.ORG --------------------
SCRAPIE DETECTED IN ANOTHER GOAT USA UPDATE MARCH 2009
SEE MARCH 2009 SCRAPIE UPDATE PPS ;
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/monthly_scrapie_rpt.pps
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/
Greetings BSE-L,
I find it disturbing that the Nor-98 atypical cases of scrapie in the USA are NOT documented on the APHIS web page. this makes no sense, and i have ask about it before in the past, APHIS et al refuse to post a seperate map showing the documented Nor98-like atypical cases here in the USA, all of them ? said they would look into it years ago. it's like out of sight, out of mind, like the TSE in the USA bovine. THE ONLY mention of the Nor-98 like scrapie that has been documented in the USA to date was on CHART 3, and then it is very very misleading as to the actual number of cases. it states ;
>* Through March 31, 2009 - does not include the Nor-98-like Scrapie cases found through RSSS (2 in FY 2007 and 1 in FY 2008). <
SO, were just going to forget about the other 3 cases of the Nor-98-like scrapie in the USA ???
or, are there more ???
WHY not a seperate map showing Nor-98-like atypical Scrapie cases (all of them), state by state ???
HAVE the actual number of cases grown in the USA from the 6 cases I was aware of ???
BY my records, to date, there have been 6 cases of the Nor-98-like atypical scrapie documented in the USA. Maybe one of the USDA followers here on the BSE-L, that is in the Scrapie department, would be so kind as to help us clear this up?
SEE FULL TEXT ;
SCRAPIE DETECTED IN ANOTHER GOAT USA UPDATE MARCH 2009
http://scrapie-usa.blogspot.com/2009/04/scrapie-detected-in-another-goat-usa.html
Wednesday, February 11, 2009
Atypical scrapie in sheep from a UK research flock which is free from classical scrapie
Research article
Atypical scrapie in sheep from a UK research flock which is free from classical scrapie
Hugh A Simmons , Marion M Simmons , Yvonne I Spencer , Melanie J Chaplin , Gill Povey , Andrew Davis , Angel Ortiz-Pelaez , Nora Hunter , Danny Matthews and Anthony E Wrathall
BMC Veterinary Research 2009, 5:8doi:10.1186/1746-6148-5-8
Published: 10 February 2009
Abstract (provisional) Background In the wake of the epidemic of bovine spongiform encephalopathy the British government established a flock of sheep from which scrapie-free animals are supplied to laboratories for research. Three breeds of sheep carrying a variety of different genotypes associated with scrapie susceptibility/resistance were imported in 1998 and 2001 from New Zealand, a country regarded as free from scrapie. They are kept in a purpose-built Sheep Unit under strict disease security and are monitored clinically and post mortem for evidence of scrapie. It is emphasised that atypical scrapie, as distinct from classical scrapie, has been recognised only relatively recently and differs from classical scrapie in its clinical, neuropathological and biochemical features. Most cases are detected in apparently healthy sheep by post mortem examination.
Results The occurrence of atypical scrapie in three sheep in (or derived from) the Sheep Unit is reported. Significant features of the affected sheep included their relatively high ages (6y 1mo, 7y 9mo, 9y 7mo respectively), their breed (all Cheviots) and their similar PRNP genotypes (AFRQ/AFRQ, AFRQ/ALRQ, and AFRQ/AFRQ, respectively). Two of the three sheep showed no clinical signs prior to death but all were confirmed as having atypical scrapie by immunohistochemistry and Western immunoblotting. Results of epidemiological investigations are presented and possible aetiologies of the cases are discussed.
Conclusions By process of exclusion, a likely explanation for the three cases of atypical scrapie is that they arose spontaneously and were not infected from an exterior source. If correct, this raises challenging issues for countries which are currently regarded as free from scrapie. It would mean that atypical scrapie is liable to occur in flocks worldwide, especially in older sheep of susceptible genotypes. To state confidently that both the classical and atypical forms of scrapie are absent from a population it is necessary for active surveillance to have taken place.
http://www.biomedcentral.com/1746-6148/5/8/abstract
Discussion
It is noteworthy that a clinical presentation was evident only in the index case, G320, and the other two cases, Y71 and D337, were diagnosed retrospectively after they had been killed. The latter two had apparently been healthy immediately prior to their euthanasia and we do not know if they would have eventually developed clinical disease. The apparent blindness of sheep G320 prior to death was unusual in that previous cases of atypical scrapie have mostly presented with loss of body condition, sometimes with incoordination [12]. There are several possible origins of these atypical scrapie cases: exposure from the environment or infected animals (or, in the case of D337, from the experimental challenge), and spontaneous development of the disease within the sheep themselves. From our own investigations, and the currently available published evidence, none of these possibilities can be ruled out. We must point out, however, that if D337 had been infected by transfusion of blood from the BSE challenged sheep, we would have expected her IHC and WB test results to be characteristic of BSE rather than, as was the case, characteristic of atypical scrapie [4].
With regard to the possibility of exposure, we are aware that the most important risk factor for introduction of classical scrapie into a flock appears to be the purchase of infected animals [13] but, as yet, we do not know if this is also the case for introduction of atypical scrapie. Experimental transmission of atypical scrapie by intracranial inoculation of brain homogenate from affected cases has been demonstrated in transgenic (ovinised) mice [14], and in sheep with the AHQ/AHQ genotype which succumbed after a very variable incubation period ranging from 378 to 1057 days [9; unpublished observations]. This leaves open the question of whether the infection can be transmitted naturally between sheep or via a contaminated environment. To our knowledge, experimental transmission of atypical scrapie has not yet been achieved by the oral route, although studies are ongoing.
Our retrospective analyses and testing did not enable us to determine whether atypical scrapie infection was present among the sheep when they were imported from New Zealand or whether exposure and/or infection occurred after the Sheep Unit was established in the UK. With regard to the latter possibility, we believe that because the Sheep Unit is completely closed with strict biosecurity measures, the risk of introducing scrapie from the outside is very low indeed. At the time of writing (May 2008) only six cases of classical scrapie (and none of atypical scrapie) had been confirmed in the county (Cambridgeshire) in the past ten years, and all of these were beyond a 20 km radius of the Sheep Unit. Furthermore, all sheep and goats tested under the Fallen Stock and Abattoir surveys from holdings in Cambridgeshire have been negative. According to the 2005 agricultural census Cambridgeshire has less than 31 sheep per km2, which is one of the lowest densities in the UK, so contact between sheep in the Unit and other sheep is extremely unlikely. Nevertheless the Unit is not a high-security laboratory premises but a barriered isolation unit where humans (and occasionally wildlife such as birds and rodents) come into contact with its livestock. Therefore we cannot claim that sheep within the Unit are totally isolated from their environment. Comprehensive monitoring by IHC and/or WB is undertaken in animals culled from the flock, and also, where possible, through follow-up of animals leaving for other reasons. However, due to the age and genotype structure of the flock, only a relatively small number of sheep of genotypes that are now known to be at high risk of atypical scrapie [5;15] have been tested, and, of those that have been tested, few were aged four years and over.
Another possible explanation for the three cases of atypical scrapie is that they arose spontaneously and were not infected from an external source. The ‘spontaneous aetiology’ hypothesis for atypical scrapie in sheep has been mentioned by several authors [e.g. 7;10;16;17] but there is no published evidence for it, and it would be difficult to test experimentally. In support of this hypothesis is the relatively consistent prevalence of atypical scrapie in national sheep flocks throughout the European Union (EU), despite significant variations in breed and management methods [15]. This suggests that atypical scrapie is potentially spontaneous at a consistent rate, or, alternatively, that it is poorly contagious.
Although atypical scrapie has been shown to be transmissible by experimental inoculation (see above), if it is a spontaneous genetic disease it may be similar in origin to the familial forms of TSE in man such as Gerstmann-Sträussler-Scheinker syndrome, Creutzfeldt-Jacob disease and fatal familial insomnia in which the resultant diseases can subsequently be transmitted experimentally [18;19]). In a recent article McIntyre [20] refers to the possibility of a spontaneous aetiology but also restates New Zealand’s position as being free from classical scrapie and other TSEs of ruminants. For suppliers and users of TSE negative control sheep and cattle, and of TSE-free biological materials, the spontaneous aetiology hypothesis raises challenging nomenclature and certification issues. If the hypothesis is correct, one would expect sheep of susceptible genotypes in flocks across the world to be prone to develop atypical scrapie spontaneously, especially in old age. To state confidently that atypical scrapie is absent from a population, specific surveillance is required. It is not sufficient to have shown an absence of the classical disease because atypical scrapie has been shown to exist in sheep populations in which classical scrapie has not been detected [21;22]). Additionally, the low prevalence of atypical scrapie in the EU, and its widespread recognition only following the introduction of certain rapid tests into large surveillance programmes, argues that it may occur below the limit of detection even in countries that do carry out scrapie surveillance. As reported by Lühken et al. [17] and Moreno et al. [9], the AFRQ allele appears to confer the highest susceptibility to atypical scrapie, so the probability of detecting the disease is likely to be greatest in sheep of this genotype.
Conclusions
In view of the fact that the three sheep affected with atypical scrapie reported here were carriers of the AFRQ allele, and were of relatively advanced ages, we are of the opinion that the spontaneous origin explanation is the one that should be given the most credence. Disease monitoring, as outlined above, is continuing and the barriers to introduction of disease from outside the Sheep Unit will be maintained. However, with the low recorded incidence of atypical scrapie and the late age at onset, it will be a challenge to establish the true origin of the disease in this flock.
snip...end...TSS
http://www.biomedcentral.com/content/pdf/1746-6148-5-8.pdf
HOW would one explain 'spontaneously', the high morbidity rate 21.05% in these older sheep with scrapie ?
Thursday, March 5, 2009
INVESTIGATION of an OUTBREAK of SCRAPIE in
PALESTINE
Salameh Barhoom
Clinical studies , Faculty of Veterinary Medicine. An-Najah National University ,
Nablus –Palestie P.O Box 7, e-mail address: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000295/!x-usc:mailto:bsalameh@najah.edu
Abstract:-
This study documents an outbreak of scrapie in adult sheep (East – Friesian Breed) in Palestine with high morbidity rate 21.5% . The clinical findings of the disease were abnormal behavior, ataxia, tremor, incoordination of locomotion, pruritus, loss of wool, nibbling, recumbency and hyperaesthesia to noise, movement or touch. The clinical diagnosis is supported by histopathological lesions and immuno-detection of prion proteins in central nervous system by immunohistochemistry using a reference specific staining monoclonal antibody RIDA Mab L42.
Introduction
Scrapie is a fatal degenerative disease of sheep and goats affecting the central nervous system of an incubation period 2-5 years. The onset of clinical disease is insidious, affected sheep show subtle changes, excitable, tremor of head and neck which may be elicited by sudden noise or movement, shortly thereafter animal develop intense pruritus with wool loss and skin rubbed raw. After 1-3 months of progressive deterioration which characterized by emaciation, weakness, ataxia, staring eyes, recumbence death occur (1). A disease affecting man and some animals known as transmissible spongiform encephalopathy (TSE) and is the prototype of the prion disease, the heterogenons group of PrP-sc associated disorders notably bovine spongiform encephalopathy (BSE), related humans disorders variant creutzfeldot-jakob disease of Captive and free ranging mule deer, white tailed deer and Elk(2). Animal prion diseases all seem to be laterally transmitted by contact with infected animals or by consumption of infected feed(2). The disease is caused by a novel transmissible agent largely composed of prion protein (PrP) Prsc,an abnormal folded isoform of the normal cellular PrP, PrPc. The PrP is very resistant to many environmental insults, chemicals and physical condition that would destroy any virus or microorganism and it does not evoke any detectable immune response or inflammatory reaction in sheep and goats (3,4). The diagnosis of the disease currently based on a clinical history, histopathological changes in the brain and demonstration the presence of PrP – containing Plaque by immunohistochemistry (5). This study deals for the first time with an outbreak of scrapie in sheep ( East –Fresian Breed) recently encountered in Palestine where clinical, pathological and immunohisto_chemistry studies were conducted.
Material and Methods
An outbreak of scrapie occurring in a private Farm with 95 adult sheep age about 2-5 years (East – Fresian Breed) was investigated, the disease appeared in Azzon area –East of Qalqelia Governorate, North Palestine.
Complete clinical examination was performed on the affected animals in April 2005 and Five recumbent animals were euthanized and subjected to thorough post-mortem examination.Specimens from the pons, medulla, Midbrain, thalamus, cerebellum, anterior spinal cord, hippocampus and cerebrum were collected and fixed in 10% neutral buffered formalin for routine scrapie histopathology, Hematoxylin – Eosine stain (6).
Immunohistochemistry assay: slides with samples collected from suspected cases and uninfected control sheep were stained by a standard protocol developed for PrP-sc detection in central nervous system tissues according (7).Briefly slides were dewaxed, rehydrated and treated in 98% formic a cid for 20 min prior to hydreated autoclaving for 30 min at 122c? . After blocking with normal goat serum ( dilution, 1:66) sections staining monoclonal antibody (RIDA MAbL42) the sections were rinsed and treated with biotinylated goat anti-rabbit immunoglobulin G diluted 1:200, followed by treatment with vector Elite ABC and the color was developed with diaminobenzidine.
Results
This study was conducted on a flock of 95 adult sheep (East – Friesian Breed), all animals were treated with Ivermectin and vaccinated annually against the following enzootic infectious diseases Sheeppox, Pest Des Petit Ruminants, Foot and Mouth Disease. The table (1) illustrate the distribution of animals according to clinical signs and their ages.
Table 1:Distribution of animals on the bases of clinical signs and age.
Number &% of clinically affected animals Number &% of clinically healthy animals
Number of animals 25 (21.05%) 70 (73.7%)
Age in years 3-5 1-2
Clinical findings : The clinical signs of the disease appear at age 3-5 years old, morbidity rate 21.05%, affected animals starts by abnormal behaviour tendency where it separate itself from the flock then return normally if left undisturbed at rest, howere when stimulated by excessive movement like handling or abnormal noise, animals tremble or fall down, ataxia, tremor of the head and neck, incoordination of locomotion, pruritus, loss wool, emaciation despite retention of appetite and recumbency. The recumbent animals are hyperexcitable, tends to carry its head high and has fixed stare, nibble at the affected area of the skin, wool loss and denudation of skin. The course of the disease from onset until recumbency lasts 3-6 months .
Gross Pathology ; There were no characteristic gross lesions.
Histopathology; Vacuolation of neurons in medulla, Pons and midbrain, surrounding cytoplasm showed signs of degeneration and Interstitial spongy degeneration often found and amyloid plaques (sometimes) as in Fig: "(1)
Immunohistochemistry: Positive staining of medulla oblingata, pons and midbrain tissues were identified as strong Particulate and cytoplasmic staining in neurons of tissues as seen in Fig (2) while negative antibody were seen in control tissue.
Fig.1: Vacuolation of several neurons with neuronal degeneration in the medulla oblongata of sheep. Hematoxyline and Eosine. X40.
Fig. 2: Positive immunohistochemistry of medulla oblongata of sheep showed abnormal accumulation of PrP. X40
Discussion
Scrapie recognized as a distinct disease of sheep in many countries, its distributed widely in Europe, North America and occur sporadically in countries in Africa and Asia (8), According to OIE International Animal Health code, scrapie can be found under list B and within the European Unoin countries, the disease has been a notifiable since January 1993(5). Most breeds of sheep are affected although in some there is a clear genetic basis for resistance or low prevalence of clinical disease, scrapie has also been described in Moufflon (Ovis musimon) a primitive type of sheep such animal incubating the disease and that animal never develop clinical signs may still be a source of infection to others (9). Sheep are considered the natural hosts for scrapie agent, a considerable body of evidence indicate that most sheep with scrapie were infected early in life and the agent has persisted within them in quiescent state during intervening period (1) Most Cases of clinical scrapie occur in sheep 2-5 years of age (10) Rarely Cases present in sheep under one year of age because in some instances the commercial lifespan of sheep may be too short to allow the clinical disease to develop (8) and these findings were similar to that found in comparing with the present study. The encountered clinical findings in sheep were characterized by insidious onset, abnormal behavior, affected animal may lead or trail the rest of flock, tremor, nibbling, ataxia, incoordination of the gait, pruritus, lose weights and recumbency, all these findings, were in accordance with those previously reported(1,5,11,12).A particular interest of this outbreak is its appearance among adult sheep with high morbidity rate 21.05% in comparing with sporadically occurance in Europe(5). The Pathological findings reported in this outbreak were prominent in the medulla, Pons, Mid-brain which characterized by interstitial spongy degeneration and all of these findings were in agreed with those previously reported (13,14,15) . The presence of prion protein in body cells with a high concentration on the surface of nerve cells in the brain due to proteinase K resistance which deposite on to the brain killing other nerve cells which leads to holes in spongiform diseases (16).Immunohistochemistry appears to be useful in detecting scrapie in affected animals and remains promising as it is widely available and inexpensive(17). The final diagnosis was based on the characteristic clinical signs, histopathological findings and identification of the prion by immunohistochemistry.
References
1- Fraser H. Scrapie in sheep and goats and related diseases. In:Diseases of sheep. Third edition. Martin W.B., and Aitken I.D. Black-well scientific Ltd. Oxford. U.K. 2000, 207-218.
2- Richard T Johnson. .Review. Prion diseases. Lancet Neurol. 2005.4: b35-42.
3- Prusiner S.B. Novel Proteinaceaus infectious Particle Cause Scrapie. 1982, Science: 216:136-44.
4- Prusiner S.B. Prion: Novel infectious Pathogen. 1984 Advance virus. Res. a,29; 1-56.
5- Office International Des Epizootics. Manual of Diagnostic tests and Vaccine for Terrestrial animals- Scrapie. 5th edition, 2004.
6- Luna LG.Manual of histologic staining methods of the Armed Force Institute of Pathology. 3rd .ed. Newyork; M.C.Grow-Hill Book company.
7- Miller J,M., Jenny A,l., Taylor W,D., Race R,E., Ernst D,R., Katz J,B., and Rubenstein R. Detection of prion protein in Formalin-Fixed brain by hydrated autoclaving immunohistochemistry for diagnosis of Scrapie in sheep. 1994 J.vet.Diagn. Investing., 16:366-368.
8- Frederic A Murphy, E Paul J Gibbs, Marinac Hozinek,Michael J studdert. Veterinary virology.3rd ed Academic press Newyork ,2003 P575-576.
9- Wood J L.N., Lund L.J., and Done S.H., The natural occurrence of scrapie in Moufflon. 1992 Vet. Rec-, 130, 25-27.
10- Hoinville L.J.A review of the epidemiology of Scrapie in sheep. Rev. sci tech off. Int.Epiz. 1996, 15, 827-852.
11- Kimberline R.H. Scrapie Disease 1981 Br. Vet .J.. 137, 105-112.
12- Parry H.B. Scrapie Disease in sheep. Historical Clinical Epidemiological, pathological and practical Aspects of the natural disease.Oppenheimer DR, ed. Academic press London . UK, 1983, pp192.
13- Jubb K.V.F, Kennedy P.C, and Palmer N. Pathology of Domestic Animals -3rd ed. Vol-I.Academic Prees, Newyork 1985 PP 305-307.
14- Wood J.L.,N,MCGill I.S., Done S.H., and Bradley R. Neuro Pathology of Scrapie: a Study of the distribution patterns of brain lesions in 222 cases of natural scrapie in sheep, 1982-1991 .1997 vet. Rec., 140,167-174.
15- Jeffry M.,Martins., Gonzalezt., Ryder S.J., Bellwothy S.J.,and Jackman R. Differential diagnosis of infections with the Bovine Spongiform Encephalopathy (BSE) and Scrapie agents in sheep. 2001 J. comp. Pathol., 125,271-284.
16- Pousiner S.B. Prions. Proc Natl Acad sci USA. 1998., 95; 13363-83
17- Belt, P.B .G.M, Muileman I.H., Schreuder B.E.C., Gielken A.L.J.,and Smith M.A. Identification of Five allelic, Variants of the sheep PrP gene and their association with natural scrapie. 1995 Journal of general virology, , 76, 509-517.
http://blogs.najah.edu/staff/emp_2364/article/INVESTIGATION-of-an-OUTBREAK-of-SCRAPIE-in-
OR, remember the infamous Louping-ill vaccine that caused some many scrapie cases here ;
From: TSS (216-119-138-163.ipset18.wt.net) Subject: Louping-ill vaccine documents from November 23rd, 1946 Date: September 10, 2000 at 8:57 am PST
Subject: Louping-ill vaccine documents from November 23rd, 1946 Date: Sat, 9 Sep 2000 17:44:57 -0700 From: "Terry S. Singeltary Sr." Reply-To: Bovine Spongiform Encephalopathy To: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000295/!x-usc:mailto:BSE-L@uni-karlsruhe.de
######### Bovine Spongiform Encephalopathy #########
THE VETERINARY RECORD 516 No 47. Vol. 58 November 23rd, 1946
NATIONAL VETERINARY MEDICAL ASSOCIATION OF GREAT BRITAIN AND IRELAND
ANNUAL CONGRESS, 1946
The annual Congress, 1946, was held at the Royal Veterinary College, Royal College Street, London, N.W.I. from September 22nd to September 27th.
Opening Meeting
[skip to scrapie vaccine issue...tss]
Papers Presented to Congress
The papers presented to this year's Congress had as their general theme the progressive work of the profession during the war years. Their appeal was clearly demonstrated by the large and remarkably uniform attendance in the Grand Hall of the Royal Veterinary College throughout the series; between 200 and 250 members were present and they showed a keen interest in every paper, which was reflected in the expression of some disappointment that the time available for discussion did not permit of the participation of more than a small proportion of would-be contributors.
In this issue we publish (below) the first to be read and discussed, that by Dr. W. S. Gordon, M.R.C.V.S., F.R.S.E., "Advances in Veterinary Research." Next week's issue will contain the paper on "Some Recent Advances in Veterinary Medicine and Surgery in Large-Animal Practice" by Mr. T. Norman Gold, M.R.C.V.S. In succeeding numbers of the Record will be reproduced, also with reports of discussions, that by Mr. W. L. Weipers, M.R.C.V.S., D.V.S.M., on the same subject as relating to small-animal practice, and the papers by Mr. J. N. Ritchie, B.SC., M.R.C.V.S., D.V.S.M., and Mr. H.W. Steele-Bodger, M.R.C.V.S., on "War-time Achievements of the British Home Veterinary Services."
The first scientific paper of Congress was read by Dr. W. S. Gordon, M.R.C.V.S., F.R.S.E. on Monday, September 23rd, 1946, when Professor J. Basil Buxton, M.A., F.R.C.V.S, D.V.H., Prinicipal of the Royal Veterinary College, presided.
Advances in Veterinary Research
by
W.S. GORDON, PH.D., M.R.C.V.S., F.R.S.E.
Agriculteral Research Council, Field Station, Compton, Berks.
Louping-ill, Tick-borne Fever and Scrapie
In 1930 Pool, Browniee & Wilson recorded that louping-ill was a transmissible disease. Greig et al, (1931) showed that the infective agent was a filter-passing virus with neurotropic characters and Browniee & Wilson (1932) that the essential pathology was that of an encephalomyelitis. Gordon, Browniee, Wilson & MacLeod (1932) and MacLeod & Gordon (1932) confirmed and extended this work. It was shown that on louping-ill farms the virus was present in the blood of many sheep which did not show clinical symptoms indicating involvement of the central nervous system and that for the perpetuation and spread of the disease these subclinical cases were probably of greater importance that the frank clinical cases because, in Nature, the disease was spread by the tick, lxodes ricinus L. More recently Wilson (1945, 1946) has described the cultivation of the virus in a chick embryo medium, the pathogenic properties of this culture virus and the preparation of louping-ill antiserum.
Between 1931 and 1934 I carried out experiments which resulted in the development of an effective vaccine for the prevention of louping-ill.* This vaccine has been in general use since 1935 and in his annual report to the Animal Diseases Research Association this year, Dr. Greig stated that about 227,000 doses of vaccine had been issued from Moredun alone.
Dr. Gordon illustrated this portion of his paper by means of graphs and diagrams projected by the epidiascope.
This investigation, however, did not begin and end with the study of louping-ill; it had, by good fortune, a more romantic turn and less fortunately a final dramtic twist which led almost to catastrope. After it had been established that a solid immunity to louping-ill could be induced in sheep, a group of immunized and a group of susceptible animals were placed together on the tick-infected pasture of a louping-ill farm. Each day all the animals were gathered and their temperatures were recorded. It was anticipated that febrile reactions with some fatalities would develop in the controls while the louping-ill immunes would remain normal. Contrary to expectation, however, every sheep, both immune and control, developed a febrile reaction. This unexpected result made neccessary further investigation which showed that the febrile reaction in the louping-ill immunes was due to a hitherto undescribed infective agent, a Rickettsia-like organism which could be observed in the cytoplasm of the grannular leucocytes, especially the neutrophil polymorphs (MacLeod (1932), Gordon, Browniee, Wilson & MacLeod. MacLeod & Gordon (1933). MacLeod (1936). MacLeod collected ticks over many widely separated parts of Scotland and all were found to harbour the infective agent of tick-borne fever, and it is probable that all sheep on tick-infested farms develop this disease, at least on the first occasion that they become infested with ticks. When the infection is passed in series through susceptible adult sheep it causes a sever, febrile reaction, dullness and loss of bodily condition but it rarely, if ever, proves fatal. It is clear, however, that it aggravates the harmful effects of a louping-ill infection and it is a serious additional complication to such infections as pyaemia and the anacrobic infections which beset lambs on the hill farms of Northern Britain.
Studying the epidemiology of louping-ill on hill farms it became obvious that the pyaemic condition of lambs described by M'Fadyean (1894) was very prevalent on tick infested farms Pyaemia is a crippling condition of lambs associated with tick-bite and is often confused with louping-ill. It is caused by infection with Staphylococcus aureus and affected animals may show abscess formation on the skin, in the joints, viscera, meninges and elsewhere in the body. It was thought that tick-borne fever might have ben a predisposing factor in this disease and unsuccessful attempts were made by Taylor, Holman & Gordon (1941) to reproduce the condition by infecting lambs subcutaneously with the staphylococcus and concurrently produceing infections with tickborne fever and louping-ill in the same lambs. Work on pyaemia was then continued by McDiarmid (1946a, 1946b, 1946c), who succeeded in reproducing a pyaemic disease in mice, guinea-pigs and lambs similar to the naturally occuring condition by intravenous inoculation of Staphylococcus aureus. He also found a bacteraemic form of the disease in which no gross pyaemic lesions were observed. The prevention or treatment of this condition presents a formidable problem. It is unlikely that staphylococcal ???oid will provide an effective immunity and even if penicillin proved to be a successful treatment, the difficulty of applying it in adequate and sustained dosage to young lambs on hill farms would be almost insurmountable.
From 1931 to 1934 field trials to test the immunizing value and harmlessness of the loup-ill vaccine were carried out on a gradually increasing scale. Many thousands of sheep were vaccinated and similar numbers, living under identical conditions were left as controls. The end result showed that an average mortability of about 9 percent in the controls was reduced to less than 1 percent in the vaccinated animals. While the efficiency of the vaccine was obvious after the second year of work, previous bitter experience had shown the wisdom of withholding a biological product from widespread use until it had been successfully produced in bulk, as opposed to small-scale experimental production and until it had been thoroughly tested for immunizing efficiency and freedom from harmful effects. It was thought that after four years testing this stage had been reached in 1935, and in the spring of that year the vaccine was issued for general use. It comprised a 10 percent saline suspension of brain, spinal cord and spleen tissues taken from sheep five days after infection with louping-ill virus by intracerebral inoculation. To this suspension 0-35 percent of formalin was added to inactivate the virus and its safety for use as a vaccine was checked by intracerbral inoculation of mice and sheep and by the inoculation of culture medium. Its protective power was proved by vaccination sheep and later subjecting them, along with controls, to a test dose of living virus.
Vaccine for issue had to be free from detectable, living virus and capable of protecting sheep against a test dose of virus applied subcutaneously. The 1935 vaccine conformed to these standards and was issued for inoculation in March as three separate batches labelled 1, 2, and 3. The tissues of 140 sheep were employed to make batch 1 of which 22,270 doses were used; 114 to make batch 2 of which 18,000 doses were used and 44 to make batch 3 of which 4,360 doses were used. All the sheep tissues incorporated in the vaccine were obtained from yearling sheep. During 1935 and 1936 the vaccine proved highly efficient in the prevention of loup-ill and no user observed an ill-effect in the inoculated animals. In September, 1937, two and a half years after vaccinating the sheep, two owners complained that scrapie, a disease which had not before been observed in the Blackface breed, was appearing in their stock of Blackface sheep and further that it was confined to animals vaccinated with louping-ill vaccine in 1935. At that stage it was difficult to conceive that the occurrence could be associated with the injection of the vaccine but in view of the implications, I visited most of the farms on which sheep had been vaccinated in 1935. It was at this point that the investigation reached its dramatic phase; I shall not forget the profound effect on my emotions when I visited these farms and was warmly welcomed because of the great benefits resulting from the application of louping-ill vaccine, wheras the chief purpose of my visit was to determine if scrapie was appearing in the inoculated sheep. The enquiry made the position clear. Scrapie was developing in the sheep vaccinated in 1935 and it was only in a few instances that the owner was associating the occurrence with louping-ill vaccination. The disease was affecting all breeds and it was confined to the animals vaccinated with batch 2. This was clearly demonstrated on a number of farms on which batch 1 had been used to inoculate the hoggs in 1935 and batch 2 to inoculate the ewes. None of the hoggs, which at this time were three- year-old ewes. At this time it was difficult to forecast whether all of the 18,000 sheep which had received batch 2 vaccine would develop scrapie. It was fortunate, however, that the majority of the sheep vaccinated with batch 2 were ewes and therfore all that were four years old and upwards at the time of vaccination had already been disposed of and there only remained the ewes which had been two to three years old at the time of vaccination, consequently no accurate assessment of the incidence of scrapie could be made. On a few farms, however, where vaccination was confined to hoggs, the incidence ranged from 1 percent, to 35 percent, with an average of about 5 percent. Since batch 2 vaccine had been incriminated as a probable source of scrapie infection, an attempt was made to trace the origin of the 112 sheep whose tissues had been included in the vaccine. It was found that they had been supplied by three owners and that all were of the Blackface or Greyface breed with the exception of eight which were Cheviot lambs born in 1935 from ewes which had been in contact with scrapie infection. Some of these contact ewes developed scrapie in 1936-37 and three surviving fellow lambs to the eight included in the batch 2 vaccine of 1935 developed scrapie, one in September, 1936, one in February, 1937, and one in November, 1937. There was, therefore, strong presumptive evidence that the eight Cheviot lambs included in the vaccine althought apparently healthy were, in fact, in the incubative stage of a scrapie infection and that in their tissues there was an infective agent which had contaminated the batch 2 vaccine, rendering it liable to set up scrapie. If that assumption was correct then the evidence indicated that:-
(1) the infective agent of scrapie was present in the brain, spinal cord and or spleen of infected sheep: (2) it could withstand a concentration of formalin of 0-35 percent, which inactivated the virus of louping-ill: (3) it could be transmitted by subcutaneous inoculation; (4) it had an incubative period of two years and longer.
Two Frenchmen, Cuille & Chelle (1939) as the result of experiments commenced in 1932, reported the successful infection of sheep by inoculation of emulsions of spinal cord or brain material by the intracerebral, epidural, intraocular and subcutaneous routes The incubation period varied according to the route employed, being one year intracerebrally, 15 months intraocularly and 20 months subcutaneously. They failed to infect rabbits but succeeded in infecting goats. Another important part of their work showed that the infective agent could pass throught a chamberland 1.3 filter, thus demonstrating that the infective agent was a filtrable virus. It was a curious coincidence that while they were doing their transmission experiments their work was being confirmed by the unforeseeable infectivity of a formalinized tissue vaccine.
As a result of this experience a large-scale transmision experiment involving the ue of 788 sheep was commenced in 1938 on a farm specially taken for the purpose by the Animal Diseases Research Association with funds provided by the Agricultural Research Council. The experiment was designed to determine the nature of the infective agent and the pathogenesis of the disease. It is only possible here to give a summary of the result which showed that (1) saline suspensions of brain and spinal cord tissue of sheep affected with scrapie were infective to normal sheep when inoculatted intracerebrally or subcutaneously; (2) the incubation period after intracerebral inoculation was seven months and upwards and only 60 percent of the inoculated sheep developed scrapie during a period of four and a half years; (3) the incubation period after subcutaneous inoculation was 15 months and upwards and only about 30 percent of the inoculated sheep developed the disease during the four and a half years: (4) the infective agent was of small size and probably a filtrable virus.
The prolonged incubative period of the disease and the remarkable resistance of the causal agent to formalin are features of distinct interest. It still remains to determine if a biological test can be devised to detect infected animals so that they can be killed for food before they develop clinical symptoms and to explore the possibilities of producing an immunity to the disease. ==================================================================
Greetings List Members,
pretty disturbing document. now, what would stop this from happening with the vaccineCJD in children???
kind regards, Terry S. Singeltary Sr., Bacliff, Texas USA
http://www.whale.to/v/singeltary.html
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Subject: VACCINES/CHILDREN/TSE'S -- 'CONFIDENTIAL' From: "Terry S. Singeltary Sr." <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000295/!x-usc:mailto:flounder@wt.net> Reply-To: Bovine Spongiform Encephalopathy <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000295/!x-usc:mailto:BSE-L@UNI-KARLSRUHE.DE> Date: Tue, 5 Sep 2000 12:00:34 -0700 Content-Type: text/plain Parts/Attachments: text/plain (148 lines)
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Greetings list members,
this document is very disturbing, considering if they continued to use these vaccines, the U.K. could loose a generation of children. If they continue to force these vaccines on children, they could loose more than just one generation, looking at the inventory. I did not know, that a Government body or bodies, if you include the United States, could be so stupid to this disease, with the evidence they have to date. It's as blatant and negligent as you can get. You may think the BSE Inquiry is almost over, but that was only the beginning.
The Truth Will Come... (just hope i'm alive to see it)
kind regards, Terry S. Singeltary Sr., Bacliff, Texas USA ============================================
BSE3/1 0250
Dr Harris (MED)
From: Dr Adams (MB3B)
cc - Dr. Pickles
Date: 14 February 1989
BOVINE SPONGIFORM ENCEPHALOPATHY
This minute details the information received on human vaccines in response to telephone enquires, and details of forthcoming expert group meetings during February 1989.
Vaccines
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Subject: VACCINES and CJD -- FDA says Mothers to stupid to understand... 7/27/2000 TSE Advisory Committee From: "Terry S. Singeltary Sr." <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000295/!x-usc:mailto:flounder@wt.net> Reply-To: Bovine Spongiform Encephalopathy <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000295/!x-usc:mailto:BSE-L@UNI-KARLSRUHE.DE> Date: Tue, 19 Sep 2000 11:12:39 -0700
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Greetings List Members,
"Ninety million Americans are either marginally or low literate, meaning they can't understand a bus map or can't understand a bus schedule or locate their intersection on a map." We can't communicate with the same message to them that we might communicate to people who are making vaccine decisions at the state or county or other levels."
But I think the Mothers are smart enough to know, that the scrapie agent has been the model for CJD research since day one. So, I think the Louping-ill vaccine and Scrapie episode, which killed many sheep, from a vaccine made from scrapie-infected brain, is most important, and I think these Mothers are smart enough to understand that...
snip...
TSE Advisory Committee 7/27/2000
259 I feel the need to say something. It's theoretical. I agree with your sense of how often it's going to occur totally. What could we do? What could they do?
DR. SNIDER: This is Dixie Snider. Yeah, we can hear from him, but you made a criticism of my comment, and I just want -- I thought it might be useful to have something to go along with their U.S. Today story that they were reading. That's all. Something that's authoritative from the FDA.
CHAIRMANBROWN: I'm glad I'm the Chairman of this committee, not this committee.
DR. RATZAN: If I could try to answer that, there is a scientific nature to how do you look at communication. You don't overreact to infinitesimal risks, and at the same time you don't under-react when there is a real risk that's involved, because that does undermine the public trust.
What I heard today were some of the steps that were being taken by some of the manufacturers, the two that presented, that they are trying to embody the public trust in terms of their processes. I think more of the open nature, even meetings like this of being able to have advisory meetings, meetings also that might have the professional associations where you have opinion leaders who might be able to defuse the information appropriately.
A blanket communication -- We often say Marshall McCluhan, a Canadian scholar in media, said, if you try to reach everybody, you reach nobody. By doing that, it's really key in thinking about communicating with the people that need to know.
Ninety million Americans are either marginally or low literate, meaning they can't understand a bus map or can't understand a bus schedule or locate their intersection on a map. We can't communicate with the same message to them that we might communicate to people who are making vaccine decisions at the state or county or other levels.
So I'm answering in a circuitous way, because I think we've heard some of the right steps being taken today, the open hearing, some of the voluntary efforts that are being done in good faith by the manufacturers, and some of the other ways that continue to monitor the open disclosure. I think the surveillance systems that we've put in place not only here in the United States but now abroad in looking at BSE and looking at the CJD that we heard from CDC and others where the numbers are.
So I would say, by all means, keep the surveillance. Keep the voluntary efforts. Continue to focus upon the science, and communicate that appropriately on, whether it's a quarterly basis, or use the different channels, the Institute of Medicine channels that are out there.
I think there's a variety of different expert committees as well. So, thank you.
CHAIRMAN BROWN: Thank you very much. Yes?
MS. FISHER: You may not want to communicate this theoretical risk to the public, but that doesn't mean it's the right thing to do. I think that part of what the National Childhood Injury Act of 1986 was all about, the safety provisions, was communicating risk to parents before they get their children vaccinated.
I think that, you know, the FDA's charge is to ensure the purity and potency of vaccines. It seems to me that the least that we can do at this juncture when we know something is to let the people know we know, rather than keeping it from them.
CHAIRMAN BROWN: Hold on, Dave. Shirley?
MS. WALKER: There's an old German proverb, "Don't point the devil on the wall; otherwise, he will jump off." I think the devil has already jumped off.
The inserts in the packets for pharmaceuticals are great. Notification to the doctor is great. But I represent something like 79,000 mothers who have children in Dallas County who we actively promote to get vaccinated.
So Monday morning when I go back to work, I'm going to have to tell someone, a percentage of these young mothers, that, hey, your child is at risk for whatever that minute amount is for CJD. So what do we do at this particular point? Do we remain mute and say nothing or do we promote and give some type of information?
So I am saying to FDA that we do need some kind of general information that we can impart to our constituents.
CHAIRMAN BROWN: Thank you. I'm going to ask for just a couple of more comments in this discussion, and then in the event that a number of people on the committee may have to leave, there are two or three very specific questions that the FDA would like some discussion-on, and I want to move to them. We've touched on some of them already, but if there's anything more to say on this -- Yes, go ahead.
263 DR. STEPHENS: I guess I'm really concerned that this discussion is kind of spinning out of control in terms of the risk. I must agree with the consumer advocate who spoke a minute ago --
CHAIRMAN BROWN: Dr. Ratzan.
DR. STEPHENS: -- that, you know, this is -- We are at some -- We have a duty, in my view, to protect the vaccine system in this country. I think that this discussion has gotten to the point of at least suggesting that we believe that this is a significant problem. The data suggests that the risk is in the billions, that there have not -- there's not been a single case of new variant CJD in this country, despite the use of vaccines manufactured in this way for years.
So I think the issue is we need public disclosure. That's not the question. I think we all are in agreement on this committee, but I think to emphasize this point where you're concerned about going back to your group of mothers and saying there's a risk -- I think that's something we don't want to send. That's a message we do not want to send.
CHAIRMAN BROWN: I opened this whole seminar with the notion that we're starting from a very, very small amount of infectivity, if there is any, and that there is a tradeoff between, as several people have said, a theoretical risk and a real risk, which would be discrediting in some way vaccines or causing vaccine shortages or difficulties or refusal to get vaccines.
In other words, this is the tradeoff. Right at the outset, this was the scene that I hoped to set. But you're right. All of our committee discussion meetings tend to spin out of control at about this time of the afternoon, and sometimes it's in one direction, and sometimes it's in another direction.
I think the word risk has enlarged as the afternoon has progressed, and maybe we should shrink it down a little bit and get a little better perspective or a little different perspective. So I tend to agree with you. Let me --
DR. BOLTON: Paul, can I get in my comment?
CHAIRMAN BROWN: I'm sorry? Go ahead.
BOLTON: I agree that it would be important to communicate known risks or even good estimates of risk to the public, but I'm not sure what that estimate would be at this point. I don't think that we really have enough information to communicate to the public and have it be meaningful and not simply scare people away.
I can't imagine the negative impact on the program in this country if parents started thinking that, if I vaccinate my child, he or she may come down with new variant CJD.
To me, the other way that we communicate is by action. It seems to me that there are actions that can be taken in terms of looking at the process of vaccine manufacture and where the real -- the greatest of the theoretical risks are. It seems to me that the viral/bacterial master seeds are really at the very lowest end, as are the master cell banks, and also trying to change those creates the biggest problem.
From that point on, from the working seeds on down through production, I think that the manufacturers have issues that they can address in terms of removing the use of at-risk bovine materials from that point on.
I guess my question to anybody at the FDA is: Are at-risk bovine materials currently in use at the -- certainly from the production step on, and even at the production of the working seeds and working cell lines, are they in use now, and how long before they will be phased out?
CHAIRMANBROWN: I guess what you're -- to add to that, are the sources of anything currently coming from BSE designated countries?
DR. STEPHENS: When I say at risk, I really mean those bovine materials are coming from Europe or at-risk countries.
CHAIRMAN BROWN: Right. Does the FDA -- You might be better off --
DR. EGAN: As I mentioned in my opening talk, for some bacterial vaccines there was bovine derived fermentation media where that skeletal muscle and pancreas derived from several European countries. I think it was Germany, Denmark, Poland, the Netherlands.
CHAIRMAN BROWN: Right. So they are currently in use in this country.
DR. EGAN: They have all agreed to -- That will be changed, but as I mentioned, by the time -- You know, they've gotten new sources, but that comes into new vaccines -- What?
DR. BOLTON: Is that the only material that's now sourced from at-risk countries?
DR. EGAN: That's used in the production. I think I also mentioned hemin. I think that was it, but I'd have to go back to it.
DR. BOLTON: So I guess my recommendation would be that the FDA work with the manufacturers to set a definite timeline to phase out all those materials. In terms of the master virus seeds and the bacterial stocks and the master cell lines, I think that the risk is so small as to be really counterproductive to try to change those, because the risk of changing the product by changing those is much, much greater than any risk that there would be from proceeding.
CHAIRMAN BROWN: One of the questions that the FDA specifically wanted some judgment on was: Is it necessary to re-derive bacterial master seeds? I mean, I'm getting the sense -- Every time I get the sense of something, the sense changes. You know, we had a consensus about informed consent, and now we have a consensus about not smother it, but be awfully, awfully, awfully careful.
Now I thought we had pretty much decided that, at least for current products, that it will not be necessary to re-derive bacterial master seeds. That was my sense. Dr. Huang?
DR. HUANG: I completely agree. I think that the derivation of new master seed stocks would be more dangerous than this perceived danger that we are facing now.
CHAIRMAN BROWN: Does anybody -- As I asked before, does anybody differ from that opinion? All right. We have answered one definitive question that the FDA wanted to asked.
They also want an answer to a question I think should be very easy to answer. That is: Is 1980, form all that you have heard, an appropriate cutoff date before which one need not worry about anything in terms of sourcing of the products we are talking about?
We always worry about something, but 1980 -- is that an appropriate date before which not to be concerned? That's a pretty focused question. Is there anybody that feels that one should be concerned about products produced before 1980 from anywhere? Yes?
DR. ROOS: I think 1980 sounds like a good year, Paul, and with respect to our blood donation pool in the United States,'we were concerned about BSE and started with 1980.
CHAIRMAN BROWN: It has the merit of consistency as well. All right. That's two questions.
The third question they were concerned about was: Do we think that the small amount of fetal calf serum from the U.K. around 1985 used in the production of master cell banks constitutes a negligible or -- well, the phrase was "a negligible or a significant risk"? Again, a question about fetal calf serum, sourced from the U.K. in the middle of the 1980s, use in the production of master cell banks constitutes any kind of significant risk? Yes?
DR. CLIVER: May I start by saying negligible. We'll see if anybody disagrees.
CHAIRMAN BROWN: Do I hear significant? Negligible?
[[[sounds like a damn auction...tss]]]
DR. BOLTON: I agree that it's negligible.
CHAIRMAN BROWN: Okay. Any differing opinion that fetal calf serum used for the production -- just for this specific purpose, used in the production of master cell banks? Well, that answers the three questions that you most wanted some judgment on Dr. Ewenstein?
Dr. EWENSTEIN: There was also the products that are still under investigation. I think, you know, we should address that. I think one of the comments before was, I think, right on the point. That is that it's different if you have a licensed drug or product that has, therefore, documented benefit versus recruited volunteers.
I think we should think about what we should answer for number 3. I think that it's appropriate to include again, with the correct caveat, about theoretical and negligibly small risk in a consent form. but I certainly wouldn't like to see all clinical trials stopped of such vaccines.
CHAIRMAN BROWN: Yes. This is the idea about an investigational drugs. We haven't touched on that, and we might just continue that discussion a bit. Peter?
DR. LURIE: Yes. I think Dr. Ewenstein is right, if I understood him correctly. I think that it is indeed a different situation. For one thing, not only is the benefit of the vaccine unknown, but for another, one actually does know the name of the patients, and one is personal contact with those patients on a semi-regular basis.
I think that the ethical responsibility toward those people is quite different than is owed to the population at large......
FULL TEXT AT URL BELOW PDF FORM (about 79 pages)......TSS
http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3635t1c.pdf
############ http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html ############
https://lists.aegee.org/cgi-bin/wa?A2=ind0009&L=BSE-L&T=0&F=&S=&X=528A4F31A528740893&Y=flounder9%40verizon.net&P=15635
The Old Days
https://lists.aegee.org/cgi-bin/wa?A1=ind0009&L=BSE-L&X=528A4F31A528740893&Y=flounder9%40verizon.net
Sunday, May 18, 2008
MAD COW DISEASE BSE CJD CHILDREN VACCINES
http://bseinquiry.blogspot.com/2008/05/mad-cow-disease-bse-cjd-children.html
Sunday, May 18, 2008 BSE, CJD, and Baby foods (the great debate 1999 to 2005)
http://bseinquiry.blogspot.com/2008/05/bse-cjd-and-baby-foods-great-debate.html
Back to reality
When Atypical Scrapie cross species barriers
Authors
Andreoletti O., Herva M. H., Cassard H., Espinosa J. C., Lacroux C., Simon S., Padilla D., Benestad S. L., Lantier F., Schelcher F., Grassi J., Torres, J. M., UMR INRA ENVT 1225, Ecole Nationale Veterinaire de Toulouse.France; ICISA-INlA, Madrid, Spain; CEA, IBiTec-5, DSV, CEA/Saclay, Gif sur Yvette cedex, France; National Veterinary Institute, Postboks 750 Sentrum, 0106 Oslo, Norway, INRA IASP, Centre INRA de Tours, 3738O Nouzilly, France.
Content
Atypical scrapie is a TSE occurring in small ruminants and harbouring peculiar clinical, epidemiological and biochemical properties. Currently this form of disease is identified in a large number of countries. In this study we report the transmission of an atypical scrapie isolate through different species barriers as modeled by transgenic mice (Tg) expressing different species PRP sequence.
The donor isolate was collected in 1995 in a French commercial sheep flock. inoculation into AHQ/AHQ sheep induced a disease which had all neuro-pathological and biochemical characteristics of atypical scrapie. Transmitted into Transgenic mice expressing either ovine or PrPc, the isolate retained all the described characteristics of atypical scrapie.
Surprisingly the TSE agent characteristics were dramatically different v/hen passaged into Tg bovine mice. The recovered TSE agent had biological and biochemical characteristics similar to those of atypical BSE L in the same mouse model. Moreover, whereas no other TSE agent than BSE were shown to transmit into Tg porcine mice, atypical scrapie was able to develop into this model, albeit with low attack rate on first passage.
Furthermore, after adaptation in the porcine mouse model this prion showed similar biological and biochemical characteristics than BSE adapted to this porcine mouse model. Altogether these data indicate.
(i) the unsuspected potential abilities of atypical scrapie to cross species barriers
(ii) the possible capacity of this agent to acquire new characteristics when crossing species barrier
These findings raise some interrogation on the concept of TSE strain and on the origin of the diversity of the TSE agents and could have consequences on field TSE control measures.
http://www.neuroprion.org/resources/pdf_docs/conferences/prion2008/abstract-book-prion2008.pdf
SCRAPIE USA
INFECTED AND SOURCE FLOCKS
There were 20 scrapie infected and source flocks with open statuses (Figure 3) as of April, 30, 2008. Twenty eight new infected and source flocks have been designated in FY 2008 (Figure 4); three source flocks were reported in April. ...snip
POSITIVE SCRAPIE CASES
As of April 30, 2008, 122 new scrapie cases have been confirmed and reported by the National Veterinary Services Laboratories (NVSL) in FY 2008 (Figure 6). Of these, 103 were field cases and 19* were Regulatory Scrapie Slaughter Surveillance (RSSS) cases (collected in FY 2008 and reported by May 20, 2008). Positive cases reported for April 2008 are depicted in Figure 7. Eighteen cases of scrapie in goats have been confirmed by NVSL since implementation of the regulatory changes in FY 2002 (Figure 8). The most recent positive goat case was confirmed in February 2008 and originated from the same herd in Michigan as the other FY 2008 goat cases. ...snip
CAPRINE SCRAPIE PREVALENCE STUDY (CSPS)
snip...
However, four positive goats have been identified this fiscal year through field investigations. One was a clinical suspect submitted for testing and the other three originated from the birth herd of the clinical case.
ANIMALS SAMPLED FOR SCRAPIE TESTING
As of April 30, 2008, 26,703 animals have been sampled for scrapie testing: 23,378 RSSS, 1,517 goats for the CSPS study, 1,466 regulatory field cases, 270 regulatory third eyelid biopsies, and 72 regulatory rectal biopsies (chart 8).
TESTING OF LYMPHOID TISSUE OBTAINED BY RECTAL BIOPSY WAS APPROVED BY USDA AS AN OFFICIAL LIVE-ANIMAL TEST ON JANUARY 11, 2008. ...
PLEASE NOTE, (FIGURE 6), Scrapie Confirmed Cases in FY 2008 MAP, PA 3, 1**, Two cases-state of ID UNKNOWN, 1 case Nor98-like**
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/monthly_scrapie_rpt.pps
http://scrapie-usa.blogspot.com/
CHAPTER 3 Animal Disease Eradication Programs and Control and Certification Programs
snip...
In FY 2007, two field cases, one validation study case, and two RSSS cases were consistent with a variant of the disease known as Nor98 scrapie.1 These five cases originated from flocks in California, Minnesota, Colorado, Wyoming, and Indiana, respectively.
snip...
http://www.aphis.usda.gov/publications/animal_health/content/printable_version/AHR_Web_PDF_07/D_Chapter_3.pdf
NOR-98 Scrapie FY 2008 to date 1
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/monthly_scrapie_rpt.pps
Monday, September 1, 2008
RE-FOIA OF DECLARATION OF EXTRAORDINARY EMERGENCY BECAUSE OF AN ATYPICAL T.S.E. (PRION DISEASE) OF FOREIGN ORIGIN IN THE UNITED STATES [No. 00-072-1]
September 1, 2008
http://foiamadsheepmadrivervalley.blogspot.com/2008/09/re-foia-of-declaration-of-extraordinary.html
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
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
NOR-98 ATYPICAL SCRAPIE 5 cases documented in USA in 5 different states USA 007
http://nor-98.blogspot.com/2008/04/seac-spongiform-encephalopathy-advisory.html
Tuesday, June 3, 2008 SCRAPIE USA UPDATE JUNE 2008 NOR-98 REPORTED PA
http://nor-98.blogspot.com/2008/06/scrapie-usa-update-june-2008-nor-98.html
http://nor-98.blogspot.com/
Monday, December 1, 2008 When Atypical Scrapie cross species barriers
http://nor-98.blogspot.com/2008/12/when-atypical-scrapie-cross-species.html
CONFIDENTIAL PAPER No: SEAC 78/9 Amendment 2 2 In March 2002, a SEAC Sub-Group considered the risks associated with certain genotypes entering the food chain if BSE were ever isolated from sheep. In contrast to the SSC opinion, SEAC concluded that: • In line with previous SEAC advice, only animals carrying the ARR allele should enter the food chain • On a precautionary basis, the 12 month cut off previously advised by SEAC remained appropriate for ARR heterozygotes. However, in view of existing SRM regulations there was no justification for any age cut off in ARR homozygotes • In line with SEAC advice in 2001, only milk from ARR homozygous sheep could be considered as highly unlikely to contain the infectious agent. Further experimental work was required before potential risks from small ruminant milk from goats and semi-resistant or susceptible sheep could be excluded. There is therefore a disparity of opinion between the SSC and SEAC on this issue. Whilst recognising the uncertainties relating to the science in this area, it is important that contingency planning is based on the most up to date scientific developments and assessments of risk that are available. SEAC will be presented with an update on the ongoing BSE in sheep studies, funded by Defra (Annex 31). This covering paper also provides a history of previous SEAC advice on this issue. BACKGROUND...snip...end
http://www.seac.gov.uk/papers/78-9-closed.pdf
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 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 is 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 emphasized by the finding that some strains of scrapie produce lesions identical to the once which characterize 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 scrapie problem urgent if the sheep industry is not to suffer grievously.
snip...
76/10.12/4.6
http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
1: J Infect Dis 1980 Aug;142(2):205-8
Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.
Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.
Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation.
PMID: 6997404
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=6997404&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus
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://www.bseinquiry.gov.uk/files/yb/1994/02/07002001.pdf
http://nor-98.blogspot.com/
Wednesday, January 28, 2009TAFS1 Position Paper on BSE in small ruminants (January 2009)
http://scrapie-usa.blogspot.com/2009/01/tafs1-position-paper-on-bse-in-small.html
TSS
Atypical scrapie in sheep from a UK research flock which is free from classical scrapie
Hugh A Simmons , Marion M Simmons , Yvonne I Spencer , Melanie J Chaplin , Gill Povey , Andrew Davis , Angel Ortiz-Pelaez , Nora Hunter , Danny Matthews and Anthony E Wrathall
BMC Veterinary Research 2009, 5:8doi:10.1186/1746-6148-5-8
Published: 10 February 2009
Abstract (provisional) Background In the wake of the epidemic of bovine spongiform encephalopathy the British government established a flock of sheep from which scrapie-free animals are supplied to laboratories for research. Three breeds of sheep carrying a variety of different genotypes associated with scrapie susceptibility/resistance were imported in 1998 and 2001 from New Zealand, a country regarded as free from scrapie. They are kept in a purpose-built Sheep Unit under strict disease security and are monitored clinically and post mortem for evidence of scrapie. It is emphasised that atypical scrapie, as distinct from classical scrapie, has been recognised only relatively recently and differs from classical scrapie in its clinical, neuropathological and biochemical features. Most cases are detected in apparently healthy sheep by post mortem examination.
Results The occurrence of atypical scrapie in three sheep in (or derived from) the Sheep Unit is reported. Significant features of the affected sheep included their relatively high ages (6y 1mo, 7y 9mo, 9y 7mo respectively), their breed (all Cheviots) and their similar PRNP genotypes (AFRQ/AFRQ, AFRQ/ALRQ, and AFRQ/AFRQ, respectively). Two of the three sheep showed no clinical signs prior to death but all were confirmed as having atypical scrapie by immunohistochemistry and Western immunoblotting. Results of epidemiological investigations are presented and possible aetiologies of the cases are discussed.
Conclusions By process of exclusion, a likely explanation for the three cases of atypical scrapie is that they arose spontaneously and were not infected from an exterior source. If correct, this raises challenging issues for countries which are currently regarded as free from scrapie. It would mean that atypical scrapie is liable to occur in flocks worldwide, especially in older sheep of susceptible genotypes. To state confidently that both the classical and atypical forms of scrapie are absent from a population it is necessary for active surveillance to have taken place.
http://www.biomedcentral.com/1746-6148/5/8/abstract
Discussion
It is noteworthy that a clinical presentation was evident only in the index case, G320, and the other two cases, Y71 and D337, were diagnosed retrospectively after they had been killed. The latter two had apparently been healthy immediately prior to their euthanasia and we do not know if they would have eventually developed clinical disease. The apparent blindness of sheep G320 prior to death was unusual in that previous cases of atypical scrapie have mostly presented with loss of body condition, sometimes with incoordination [12]. There are several possible origins of these atypical scrapie cases: exposure from the environment or infected animals (or, in the case of D337, from the experimental challenge), and spontaneous development of the disease within the sheep themselves. From our own investigations, and the currently available published evidence, none of these possibilities can be ruled out. We must point out, however, that if D337 had been infected by transfusion of blood from the BSE challenged sheep, we would have expected her IHC and WB test results to be characteristic of BSE rather than, as was the case, characteristic of atypical scrapie [4].
With regard to the possibility of exposure, we are aware that the most important risk factor for introduction of classical scrapie into a flock appears to be the purchase of infected animals [13] but, as yet, we do not know if this is also the case for introduction of atypical scrapie. Experimental transmission of atypical scrapie by intracranial inoculation of brain homogenate from affected cases has been demonstrated in transgenic (ovinised) mice [14], and in sheep with the AHQ/AHQ genotype which succumbed after a very variable incubation period ranging from 378 to 1057 days [9; unpublished observations]. This leaves open the question of whether the infection can be transmitted naturally between sheep or via a contaminated environment. To our knowledge, experimental transmission of atypical scrapie has not yet been achieved by the oral route, although studies are ongoing.
Our retrospective analyses and testing did not enable us to determine whether atypical scrapie infection was present among the sheep when they were imported from New Zealand or whether exposure and/or infection occurred after the Sheep Unit was established in the UK. With regard to the latter possibility, we believe that because the Sheep Unit is completely closed with strict biosecurity measures, the risk of introducing scrapie from the outside is very low indeed. At the time of writing (May 2008) only six cases of classical scrapie (and none of atypical scrapie) had been confirmed in the county (Cambridgeshire) in the past ten years, and all of these were beyond a 20 km radius of the Sheep Unit. Furthermore, all sheep and goats tested under the Fallen Stock and Abattoir surveys from holdings in Cambridgeshire have been negative. According to the 2005 agricultural census Cambridgeshire has less than 31 sheep per km2, which is one of the lowest densities in the UK, so contact between sheep in the Unit and other sheep is extremely unlikely. Nevertheless the Unit is not a high-security laboratory premises but a barriered isolation unit where humans (and occasionally wildlife such as birds and rodents) come into contact with its livestock. Therefore we cannot claim that sheep within the Unit are totally isolated from their environment. Comprehensive monitoring by IHC and/or WB is undertaken in animals culled from the flock, and also, where possible, through follow-up of animals leaving for other reasons. However, due to the age and genotype structure of the flock, only a relatively small number of sheep of genotypes that are now known to be at high risk of atypical scrapie [5;15] have been tested, and, of those that have been tested, few were aged four years and over.
Another possible explanation for the three cases of atypical scrapie is that they arose spontaneously and were not infected from an external source. The ‘spontaneous aetiology’ hypothesis for atypical scrapie in sheep has been mentioned by several authors [e.g. 7;10;16;17] but there is no published evidence for it, and it would be difficult to test experimentally. In support of this hypothesis is the relatively consistent prevalence of atypical scrapie in national sheep flocks throughout the European Union (EU), despite significant variations in breed and management methods [15]. This suggests that atypical scrapie is potentially spontaneous at a consistent rate, or, alternatively, that it is poorly contagious.
Although atypical scrapie has been shown to be transmissible by experimental inoculation (see above), if it is a spontaneous genetic disease it may be similar in origin to the familial forms of TSE in man such as Gerstmann-Sträussler-Scheinker syndrome, Creutzfeldt-Jacob disease and fatal familial insomnia in which the resultant diseases can subsequently be transmitted experimentally [18;19]). In a recent article McIntyre [20] refers to the possibility of a spontaneous aetiology but also restates New Zealand’s position as being free from classical scrapie and other TSEs of ruminants. For suppliers and users of TSE negative control sheep and cattle, and of TSE-free biological materials, the spontaneous aetiology hypothesis raises challenging nomenclature and certification issues. If the hypothesis is correct, one would expect sheep of susceptible genotypes in flocks across the world to be prone to develop atypical scrapie spontaneously, especially in old age. To state confidently that atypical scrapie is absent from a population, specific surveillance is required. It is not sufficient to have shown an absence of the classical disease because atypical scrapie has been shown to exist in sheep populations in which classical scrapie has not been detected [21;22]). Additionally, the low prevalence of atypical scrapie in the EU, and its widespread recognition only following the introduction of certain rapid tests into large surveillance programmes, argues that it may occur below the limit of detection even in countries that do carry out scrapie surveillance. As reported by Lühken et al. [17] and Moreno et al. [9], the AFRQ allele appears to confer the highest susceptibility to atypical scrapie, so the probability of detecting the disease is likely to be greatest in sheep of this genotype.
Conclusions
In view of the fact that the three sheep affected with atypical scrapie reported here were carriers of the AFRQ allele, and were of relatively advanced ages, we are of the opinion that the spontaneous origin explanation is the one that should be given the most credence. Disease monitoring, as outlined above, is continuing and the barriers to introduction of disease from outside the Sheep Unit will be maintained. However, with the low recorded incidence of atypical scrapie and the late age at onset, it will be a challenge to establish the true origin of the disease in this flock.
snip...end...TSS
http://www.biomedcentral.com/content/pdf/1746-6148-5-8.pdf
HOW would one explain 'spontaneously', the high morbidity rate 21.05% in these older sheep with scrapie ?
Thursday, March 5, 2009
INVESTIGATION of an OUTBREAK of SCRAPIE in
PALESTINE
Salameh Barhoom
Clinical studies , Faculty of Veterinary Medicine. An-Najah National University ,
Nablus –Palestie P.O Box 7, e-mail address: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000295/!x-usc:mailto:bsalameh@najah.edu
Abstract:-
This study documents an outbreak of scrapie in adult sheep (East – Friesian Breed) in Palestine with high morbidity rate 21.5% . The clinical findings of the disease were abnormal behavior, ataxia, tremor, incoordination of locomotion, pruritus, loss of wool, nibbling, recumbency and hyperaesthesia to noise, movement or touch. The clinical diagnosis is supported by histopathological lesions and immuno-detection of prion proteins in central nervous system by immunohistochemistry using a reference specific staining monoclonal antibody RIDA Mab L42.
Introduction
Scrapie is a fatal degenerative disease of sheep and goats affecting the central nervous system of an incubation period 2-5 years. The onset of clinical disease is insidious, affected sheep show subtle changes, excitable, tremor of head and neck which may be elicited by sudden noise or movement, shortly thereafter animal develop intense pruritus with wool loss and skin rubbed raw. After 1-3 months of progressive deterioration which characterized by emaciation, weakness, ataxia, staring eyes, recumbence death occur (1). A disease affecting man and some animals known as transmissible spongiform encephalopathy (TSE) and is the prototype of the prion disease, the heterogenons group of PrP-sc associated disorders notably bovine spongiform encephalopathy (BSE), related humans disorders variant creutzfeldot-jakob disease of Captive and free ranging mule deer, white tailed deer and Elk(2). Animal prion diseases all seem to be laterally transmitted by contact with infected animals or by consumption of infected feed(2). The disease is caused by a novel transmissible agent largely composed of prion protein (PrP) Prsc,an abnormal folded isoform of the normal cellular PrP, PrPc. The PrP is very resistant to many environmental insults, chemicals and physical condition that would destroy any virus or microorganism and it does not evoke any detectable immune response or inflammatory reaction in sheep and goats (3,4). The diagnosis of the disease currently based on a clinical history, histopathological changes in the brain and demonstration the presence of PrP – containing Plaque by immunohistochemistry (5). This study deals for the first time with an outbreak of scrapie in sheep ( East –Fresian Breed) recently encountered in Palestine where clinical, pathological and immunohisto_chemistry studies were conducted.
Material and Methods
An outbreak of scrapie occurring in a private Farm with 95 adult sheep age about 2-5 years (East – Fresian Breed) was investigated, the disease appeared in Azzon area –East of Qalqelia Governorate, North Palestine.
Complete clinical examination was performed on the affected animals in April 2005 and Five recumbent animals were euthanized and subjected to thorough post-mortem examination.Specimens from the pons, medulla, Midbrain, thalamus, cerebellum, anterior spinal cord, hippocampus and cerebrum were collected and fixed in 10% neutral buffered formalin for routine scrapie histopathology, Hematoxylin – Eosine stain (6).
Immunohistochemistry assay: slides with samples collected from suspected cases and uninfected control sheep were stained by a standard protocol developed for PrP-sc detection in central nervous system tissues according (7).Briefly slides were dewaxed, rehydrated and treated in 98% formic a cid for 20 min prior to hydreated autoclaving for 30 min at 122c? . After blocking with normal goat serum ( dilution, 1:66) sections staining monoclonal antibody (RIDA MAbL42) the sections were rinsed and treated with biotinylated goat anti-rabbit immunoglobulin G diluted 1:200, followed by treatment with vector Elite ABC and the color was developed with diaminobenzidine.
Results
This study was conducted on a flock of 95 adult sheep (East – Friesian Breed), all animals were treated with Ivermectin and vaccinated annually against the following enzootic infectious diseases Sheeppox, Pest Des Petit Ruminants, Foot and Mouth Disease. The table (1) illustrate the distribution of animals according to clinical signs and their ages.
Table 1:Distribution of animals on the bases of clinical signs and age.
Number &% of clinically affected animals Number &% of clinically healthy animals
Number of animals 25 (21.05%) 70 (73.7%)
Age in years 3-5 1-2
Clinical findings : The clinical signs of the disease appear at age 3-5 years old, morbidity rate 21.05%, affected animals starts by abnormal behaviour tendency where it separate itself from the flock then return normally if left undisturbed at rest, howere when stimulated by excessive movement like handling or abnormal noise, animals tremble or fall down, ataxia, tremor of the head and neck, incoordination of locomotion, pruritus, loss wool, emaciation despite retention of appetite and recumbency. The recumbent animals are hyperexcitable, tends to carry its head high and has fixed stare, nibble at the affected area of the skin, wool loss and denudation of skin. The course of the disease from onset until recumbency lasts 3-6 months .
Gross Pathology ; There were no characteristic gross lesions.
Histopathology; Vacuolation of neurons in medulla, Pons and midbrain, surrounding cytoplasm showed signs of degeneration and Interstitial spongy degeneration often found and amyloid plaques (sometimes) as in Fig: "(1)
Immunohistochemistry: Positive staining of medulla oblingata, pons and midbrain tissues were identified as strong Particulate and cytoplasmic staining in neurons of tissues as seen in Fig (2) while negative antibody were seen in control tissue.
Fig.1: Vacuolation of several neurons with neuronal degeneration in the medulla oblongata of sheep. Hematoxyline and Eosine. X40.
Fig. 2: Positive immunohistochemistry of medulla oblongata of sheep showed abnormal accumulation of PrP. X40
Discussion
Scrapie recognized as a distinct disease of sheep in many countries, its distributed widely in Europe, North America and occur sporadically in countries in Africa and Asia (8), According to OIE International Animal Health code, scrapie can be found under list B and within the European Unoin countries, the disease has been a notifiable since January 1993(5). Most breeds of sheep are affected although in some there is a clear genetic basis for resistance or low prevalence of clinical disease, scrapie has also been described in Moufflon (Ovis musimon) a primitive type of sheep such animal incubating the disease and that animal never develop clinical signs may still be a source of infection to others (9). Sheep are considered the natural hosts for scrapie agent, a considerable body of evidence indicate that most sheep with scrapie were infected early in life and the agent has persisted within them in quiescent state during intervening period (1) Most Cases of clinical scrapie occur in sheep 2-5 years of age (10) Rarely Cases present in sheep under one year of age because in some instances the commercial lifespan of sheep may be too short to allow the clinical disease to develop (8) and these findings were similar to that found in comparing with the present study. The encountered clinical findings in sheep were characterized by insidious onset, abnormal behavior, affected animal may lead or trail the rest of flock, tremor, nibbling, ataxia, incoordination of the gait, pruritus, lose weights and recumbency, all these findings, were in accordance with those previously reported(1,5,11,12).A particular interest of this outbreak is its appearance among adult sheep with high morbidity rate 21.05% in comparing with sporadically occurance in Europe(5). The Pathological findings reported in this outbreak were prominent in the medulla, Pons, Mid-brain which characterized by interstitial spongy degeneration and all of these findings were in agreed with those previously reported (13,14,15) . The presence of prion protein in body cells with a high concentration on the surface of nerve cells in the brain due to proteinase K resistance which deposite on to the brain killing other nerve cells which leads to holes in spongiform diseases (16).Immunohistochemistry appears to be useful in detecting scrapie in affected animals and remains promising as it is widely available and inexpensive(17). The final diagnosis was based on the characteristic clinical signs, histopathological findings and identification of the prion by immunohistochemistry.
References
1- Fraser H. Scrapie in sheep and goats and related diseases. In:Diseases of sheep. Third edition. Martin W.B., and Aitken I.D. Black-well scientific Ltd. Oxford. U.K. 2000, 207-218.
2- Richard T Johnson. .Review. Prion diseases. Lancet Neurol. 2005.4: b35-42.
3- Prusiner S.B. Novel Proteinaceaus infectious Particle Cause Scrapie. 1982, Science: 216:136-44.
4- Prusiner S.B. Prion: Novel infectious Pathogen. 1984 Advance virus. Res. a,29; 1-56.
5- Office International Des Epizootics. Manual of Diagnostic tests and Vaccine for Terrestrial animals- Scrapie. 5th edition, 2004.
6- Luna LG.Manual of histologic staining methods of the Armed Force Institute of Pathology. 3rd .ed. Newyork; M.C.Grow-Hill Book company.
7- Miller J,M., Jenny A,l., Taylor W,D., Race R,E., Ernst D,R., Katz J,B., and Rubenstein R. Detection of prion protein in Formalin-Fixed brain by hydrated autoclaving immunohistochemistry for diagnosis of Scrapie in sheep. 1994 J.vet.Diagn. Investing., 16:366-368.
8- Frederic A Murphy, E Paul J Gibbs, Marinac Hozinek,Michael J studdert. Veterinary virology.3rd ed Academic press Newyork ,2003 P575-576.
9- Wood J L.N., Lund L.J., and Done S.H., The natural occurrence of scrapie in Moufflon. 1992 Vet. Rec-, 130, 25-27.
10- Hoinville L.J.A review of the epidemiology of Scrapie in sheep. Rev. sci tech off. Int.Epiz. 1996, 15, 827-852.
11- Kimberline R.H. Scrapie Disease 1981 Br. Vet .J.. 137, 105-112.
12- Parry H.B. Scrapie Disease in sheep. Historical Clinical Epidemiological, pathological and practical Aspects of the natural disease.Oppenheimer DR, ed. Academic press London . UK, 1983, pp192.
13- Jubb K.V.F, Kennedy P.C, and Palmer N. Pathology of Domestic Animals -3rd ed. Vol-I.Academic Prees, Newyork 1985 PP 305-307.
14- Wood J.L.,N,MCGill I.S., Done S.H., and Bradley R. Neuro Pathology of Scrapie: a Study of the distribution patterns of brain lesions in 222 cases of natural scrapie in sheep, 1982-1991 .1997 vet. Rec., 140,167-174.
15- Jeffry M.,Martins., Gonzalezt., Ryder S.J., Bellwothy S.J.,and Jackman R. Differential diagnosis of infections with the Bovine Spongiform Encephalopathy (BSE) and Scrapie agents in sheep. 2001 J. comp. Pathol., 125,271-284.
16- Pousiner S.B. Prions. Proc Natl Acad sci USA. 1998., 95; 13363-83
17- Belt, P.B .G.M, Muileman I.H., Schreuder B.E.C., Gielken A.L.J.,and Smith M.A. Identification of Five allelic, Variants of the sheep PrP gene and their association with natural scrapie. 1995 Journal of general virology, , 76, 509-517.
http://blogs.najah.edu/staff/emp_2364/article/INVESTIGATION-of-an-OUTBREAK-of-SCRAPIE-in-
OR, remember the infamous Louping-ill vaccine that caused some many scrapie cases here ;
From: TSS (216-119-138-163.ipset18.wt.net) Subject: Louping-ill vaccine documents from November 23rd, 1946 Date: September 10, 2000 at 8:57 am PST
Subject: Louping-ill vaccine documents from November 23rd, 1946 Date: Sat, 9 Sep 2000 17:44:57 -0700 From: "Terry S. Singeltary Sr." Reply-To: Bovine Spongiform Encephalopathy To: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000295/!x-usc:mailto:BSE-L@uni-karlsruhe.de
######### Bovine Spongiform Encephalopathy #########
THE VETERINARY RECORD 516 No 47. Vol. 58 November 23rd, 1946
NATIONAL VETERINARY MEDICAL ASSOCIATION OF GREAT BRITAIN AND IRELAND
ANNUAL CONGRESS, 1946
The annual Congress, 1946, was held at the Royal Veterinary College, Royal College Street, London, N.W.I. from September 22nd to September 27th.
Opening Meeting
[skip to scrapie vaccine issue...tss]
Papers Presented to Congress
The papers presented to this year's Congress had as their general theme the progressive work of the profession during the war years. Their appeal was clearly demonstrated by the large and remarkably uniform attendance in the Grand Hall of the Royal Veterinary College throughout the series; between 200 and 250 members were present and they showed a keen interest in every paper, which was reflected in the expression of some disappointment that the time available for discussion did not permit of the participation of more than a small proportion of would-be contributors.
In this issue we publish (below) the first to be read and discussed, that by Dr. W. S. Gordon, M.R.C.V.S., F.R.S.E., "Advances in Veterinary Research." Next week's issue will contain the paper on "Some Recent Advances in Veterinary Medicine and Surgery in Large-Animal Practice" by Mr. T. Norman Gold, M.R.C.V.S. In succeeding numbers of the Record will be reproduced, also with reports of discussions, that by Mr. W. L. Weipers, M.R.C.V.S., D.V.S.M., on the same subject as relating to small-animal practice, and the papers by Mr. J. N. Ritchie, B.SC., M.R.C.V.S., D.V.S.M., and Mr. H.W. Steele-Bodger, M.R.C.V.S., on "War-time Achievements of the British Home Veterinary Services."
The first scientific paper of Congress was read by Dr. W. S. Gordon, M.R.C.V.S., F.R.S.E. on Monday, September 23rd, 1946, when Professor J. Basil Buxton, M.A., F.R.C.V.S, D.V.H., Prinicipal of the Royal Veterinary College, presided.
Advances in Veterinary Research
by
W.S. GORDON, PH.D., M.R.C.V.S., F.R.S.E.
Agriculteral Research Council, Field Station, Compton, Berks.
Louping-ill, Tick-borne Fever and Scrapie
In 1930 Pool, Browniee & Wilson recorded that louping-ill was a transmissible disease. Greig et al, (1931) showed that the infective agent was a filter-passing virus with neurotropic characters and Browniee & Wilson (1932) that the essential pathology was that of an encephalomyelitis. Gordon, Browniee, Wilson & MacLeod (1932) and MacLeod & Gordon (1932) confirmed and extended this work. It was shown that on louping-ill farms the virus was present in the blood of many sheep which did not show clinical symptoms indicating involvement of the central nervous system and that for the perpetuation and spread of the disease these subclinical cases were probably of greater importance that the frank clinical cases because, in Nature, the disease was spread by the tick, lxodes ricinus L. More recently Wilson (1945, 1946) has described the cultivation of the virus in a chick embryo medium, the pathogenic properties of this culture virus and the preparation of louping-ill antiserum.
Between 1931 and 1934 I carried out experiments which resulted in the development of an effective vaccine for the prevention of louping-ill.* This vaccine has been in general use since 1935 and in his annual report to the Animal Diseases Research Association this year, Dr. Greig stated that about 227,000 doses of vaccine had been issued from Moredun alone.
Dr. Gordon illustrated this portion of his paper by means of graphs and diagrams projected by the epidiascope.
This investigation, however, did not begin and end with the study of louping-ill; it had, by good fortune, a more romantic turn and less fortunately a final dramtic twist which led almost to catastrope. After it had been established that a solid immunity to louping-ill could be induced in sheep, a group of immunized and a group of susceptible animals were placed together on the tick-infected pasture of a louping-ill farm. Each day all the animals were gathered and their temperatures were recorded. It was anticipated that febrile reactions with some fatalities would develop in the controls while the louping-ill immunes would remain normal. Contrary to expectation, however, every sheep, both immune and control, developed a febrile reaction. This unexpected result made neccessary further investigation which showed that the febrile reaction in the louping-ill immunes was due to a hitherto undescribed infective agent, a Rickettsia-like organism which could be observed in the cytoplasm of the grannular leucocytes, especially the neutrophil polymorphs (MacLeod (1932), Gordon, Browniee, Wilson & MacLeod. MacLeod & Gordon (1933). MacLeod (1936). MacLeod collected ticks over many widely separated parts of Scotland and all were found to harbour the infective agent of tick-borne fever, and it is probable that all sheep on tick-infested farms develop this disease, at least on the first occasion that they become infested with ticks. When the infection is passed in series through susceptible adult sheep it causes a sever, febrile reaction, dullness and loss of bodily condition but it rarely, if ever, proves fatal. It is clear, however, that it aggravates the harmful effects of a louping-ill infection and it is a serious additional complication to such infections as pyaemia and the anacrobic infections which beset lambs on the hill farms of Northern Britain.
Studying the epidemiology of louping-ill on hill farms it became obvious that the pyaemic condition of lambs described by M'Fadyean (1894) was very prevalent on tick infested farms Pyaemia is a crippling condition of lambs associated with tick-bite and is often confused with louping-ill. It is caused by infection with Staphylococcus aureus and affected animals may show abscess formation on the skin, in the joints, viscera, meninges and elsewhere in the body. It was thought that tick-borne fever might have ben a predisposing factor in this disease and unsuccessful attempts were made by Taylor, Holman & Gordon (1941) to reproduce the condition by infecting lambs subcutaneously with the staphylococcus and concurrently produceing infections with tickborne fever and louping-ill in the same lambs. Work on pyaemia was then continued by McDiarmid (1946a, 1946b, 1946c), who succeeded in reproducing a pyaemic disease in mice, guinea-pigs and lambs similar to the naturally occuring condition by intravenous inoculation of Staphylococcus aureus. He also found a bacteraemic form of the disease in which no gross pyaemic lesions were observed. The prevention or treatment of this condition presents a formidable problem. It is unlikely that staphylococcal ???oid will provide an effective immunity and even if penicillin proved to be a successful treatment, the difficulty of applying it in adequate and sustained dosage to young lambs on hill farms would be almost insurmountable.
From 1931 to 1934 field trials to test the immunizing value and harmlessness of the loup-ill vaccine were carried out on a gradually increasing scale. Many thousands of sheep were vaccinated and similar numbers, living under identical conditions were left as controls. The end result showed that an average mortability of about 9 percent in the controls was reduced to less than 1 percent in the vaccinated animals. While the efficiency of the vaccine was obvious after the second year of work, previous bitter experience had shown the wisdom of withholding a biological product from widespread use until it had been successfully produced in bulk, as opposed to small-scale experimental production and until it had been thoroughly tested for immunizing efficiency and freedom from harmful effects. It was thought that after four years testing this stage had been reached in 1935, and in the spring of that year the vaccine was issued for general use. It comprised a 10 percent saline suspension of brain, spinal cord and spleen tissues taken from sheep five days after infection with louping-ill virus by intracerebral inoculation. To this suspension 0-35 percent of formalin was added to inactivate the virus and its safety for use as a vaccine was checked by intracerbral inoculation of mice and sheep and by the inoculation of culture medium. Its protective power was proved by vaccination sheep and later subjecting them, along with controls, to a test dose of living virus.
Vaccine for issue had to be free from detectable, living virus and capable of protecting sheep against a test dose of virus applied subcutaneously. The 1935 vaccine conformed to these standards and was issued for inoculation in March as three separate batches labelled 1, 2, and 3. The tissues of 140 sheep were employed to make batch 1 of which 22,270 doses were used; 114 to make batch 2 of which 18,000 doses were used and 44 to make batch 3 of which 4,360 doses were used. All the sheep tissues incorporated in the vaccine were obtained from yearling sheep. During 1935 and 1936 the vaccine proved highly efficient in the prevention of loup-ill and no user observed an ill-effect in the inoculated animals. In September, 1937, two and a half years after vaccinating the sheep, two owners complained that scrapie, a disease which had not before been observed in the Blackface breed, was appearing in their stock of Blackface sheep and further that it was confined to animals vaccinated with louping-ill vaccine in 1935. At that stage it was difficult to conceive that the occurrence could be associated with the injection of the vaccine but in view of the implications, I visited most of the farms on which sheep had been vaccinated in 1935. It was at this point that the investigation reached its dramatic phase; I shall not forget the profound effect on my emotions when I visited these farms and was warmly welcomed because of the great benefits resulting from the application of louping-ill vaccine, wheras the chief purpose of my visit was to determine if scrapie was appearing in the inoculated sheep. The enquiry made the position clear. Scrapie was developing in the sheep vaccinated in 1935 and it was only in a few instances that the owner was associating the occurrence with louping-ill vaccination. The disease was affecting all breeds and it was confined to the animals vaccinated with batch 2. This was clearly demonstrated on a number of farms on which batch 1 had been used to inoculate the hoggs in 1935 and batch 2 to inoculate the ewes. None of the hoggs, which at this time were three- year-old ewes. At this time it was difficult to forecast whether all of the 18,000 sheep which had received batch 2 vaccine would develop scrapie. It was fortunate, however, that the majority of the sheep vaccinated with batch 2 were ewes and therfore all that were four years old and upwards at the time of vaccination had already been disposed of and there only remained the ewes which had been two to three years old at the time of vaccination, consequently no accurate assessment of the incidence of scrapie could be made. On a few farms, however, where vaccination was confined to hoggs, the incidence ranged from 1 percent, to 35 percent, with an average of about 5 percent. Since batch 2 vaccine had been incriminated as a probable source of scrapie infection, an attempt was made to trace the origin of the 112 sheep whose tissues had been included in the vaccine. It was found that they had been supplied by three owners and that all were of the Blackface or Greyface breed with the exception of eight which were Cheviot lambs born in 1935 from ewes which had been in contact with scrapie infection. Some of these contact ewes developed scrapie in 1936-37 and three surviving fellow lambs to the eight included in the batch 2 vaccine of 1935 developed scrapie, one in September, 1936, one in February, 1937, and one in November, 1937. There was, therefore, strong presumptive evidence that the eight Cheviot lambs included in the vaccine althought apparently healthy were, in fact, in the incubative stage of a scrapie infection and that in their tissues there was an infective agent which had contaminated the batch 2 vaccine, rendering it liable to set up scrapie. If that assumption was correct then the evidence indicated that:-
(1) the infective agent of scrapie was present in the brain, spinal cord and or spleen of infected sheep: (2) it could withstand a concentration of formalin of 0-35 percent, which inactivated the virus of louping-ill: (3) it could be transmitted by subcutaneous inoculation; (4) it had an incubative period of two years and longer.
Two Frenchmen, Cuille & Chelle (1939) as the result of experiments commenced in 1932, reported the successful infection of sheep by inoculation of emulsions of spinal cord or brain material by the intracerebral, epidural, intraocular and subcutaneous routes The incubation period varied according to the route employed, being one year intracerebrally, 15 months intraocularly and 20 months subcutaneously. They failed to infect rabbits but succeeded in infecting goats. Another important part of their work showed that the infective agent could pass throught a chamberland 1.3 filter, thus demonstrating that the infective agent was a filtrable virus. It was a curious coincidence that while they were doing their transmission experiments their work was being confirmed by the unforeseeable infectivity of a formalinized tissue vaccine.
As a result of this experience a large-scale transmision experiment involving the ue of 788 sheep was commenced in 1938 on a farm specially taken for the purpose by the Animal Diseases Research Association with funds provided by the Agricultural Research Council. The experiment was designed to determine the nature of the infective agent and the pathogenesis of the disease. It is only possible here to give a summary of the result which showed that (1) saline suspensions of brain and spinal cord tissue of sheep affected with scrapie were infective to normal sheep when inoculatted intracerebrally or subcutaneously; (2) the incubation period after intracerebral inoculation was seven months and upwards and only 60 percent of the inoculated sheep developed scrapie during a period of four and a half years; (3) the incubation period after subcutaneous inoculation was 15 months and upwards and only about 30 percent of the inoculated sheep developed the disease during the four and a half years: (4) the infective agent was of small size and probably a filtrable virus.
The prolonged incubative period of the disease and the remarkable resistance of the causal agent to formalin are features of distinct interest. It still remains to determine if a biological test can be devised to detect infected animals so that they can be killed for food before they develop clinical symptoms and to explore the possibilities of producing an immunity to the disease. ==================================================================
Greetings List Members,
pretty disturbing document. now, what would stop this from happening with the vaccineCJD in children???
kind regards, Terry S. Singeltary Sr., Bacliff, Texas USA
http://www.whale.to/v/singeltary.html
https://lists.aegee.org/cgi-bin/wa?A2=ind0009&L=BSE-L&T=0&F=&S=&X=528A4F31A528740893&Y=flounder9%40verizon.net&P=5205
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Subject: VACCINES/CHILDREN/TSE'S -- 'CONFIDENTIAL' From: "Terry S. Singeltary Sr." <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000295/!x-usc:mailto:flounder@wt.net> Reply-To: Bovine Spongiform Encephalopathy <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000295/!x-usc:mailto:BSE-L@UNI-KARLSRUHE.DE> Date: Tue, 5 Sep 2000 12:00:34 -0700 Content-Type: text/plain Parts/Attachments: text/plain (148 lines)
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Greetings list members,
this document is very disturbing, considering if they continued to use these vaccines, the U.K. could loose a generation of children. If they continue to force these vaccines on children, they could loose more than just one generation, looking at the inventory. I did not know, that a Government body or bodies, if you include the United States, could be so stupid to this disease, with the evidence they have to date. It's as blatant and negligent as you can get. You may think the BSE Inquiry is almost over, but that was only the beginning.
The Truth Will Come... (just hope i'm alive to see it)
kind regards, Terry S. Singeltary Sr., Bacliff, Texas USA ============================================
BSE3/1 0250
Dr Harris (MED)
From: Dr Adams (MB3B)
cc - Dr. Pickles
Date: 14 February 1989
BOVINE SPONGIFORM ENCEPHALOPATHY
This minute details the information received on human vaccines in response to telephone enquires, and details of forthcoming expert group meetings during February 1989.
Vaccines
https://lists.aegee.org/cgi-bin/wa?A2=ind0009&L=BSE-L&T=0&F=&S=&X=528A4F31A528740893&Y=flounder9%40verizon.net&P=2065
Subject: VACCINES and CJD -- FDA says Mothers to stupid to understand... 7/27/2000 TSE Advisory Committee From: "Terry S. Singeltary Sr." <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000295/!x-usc:mailto:flounder@wt.net> Reply-To: Bovine Spongiform Encephalopathy <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000295/!x-usc:mailto:BSE-L@UNI-KARLSRUHE.DE> Date: Tue, 19 Sep 2000 11:12:39 -0700
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Greetings List Members,
"Ninety million Americans are either marginally or low literate, meaning they can't understand a bus map or can't understand a bus schedule or locate their intersection on a map." We can't communicate with the same message to them that we might communicate to people who are making vaccine decisions at the state or county or other levels."
But I think the Mothers are smart enough to know, that the scrapie agent has been the model for CJD research since day one. So, I think the Louping-ill vaccine and Scrapie episode, which killed many sheep, from a vaccine made from scrapie-infected brain, is most important, and I think these Mothers are smart enough to understand that...
snip...
TSE Advisory Committee 7/27/2000
259 I feel the need to say something. It's theoretical. I agree with your sense of how often it's going to occur totally. What could we do? What could they do?
DR. SNIDER: This is Dixie Snider. Yeah, we can hear from him, but you made a criticism of my comment, and I just want -- I thought it might be useful to have something to go along with their U.S. Today story that they were reading. That's all. Something that's authoritative from the FDA.
CHAIRMANBROWN: I'm glad I'm the Chairman of this committee, not this committee.
DR. RATZAN: If I could try to answer that, there is a scientific nature to how do you look at communication. You don't overreact to infinitesimal risks, and at the same time you don't under-react when there is a real risk that's involved, because that does undermine the public trust.
What I heard today were some of the steps that were being taken by some of the manufacturers, the two that presented, that they are trying to embody the public trust in terms of their processes. I think more of the open nature, even meetings like this of being able to have advisory meetings, meetings also that might have the professional associations where you have opinion leaders who might be able to defuse the information appropriately.
A blanket communication -- We often say Marshall McCluhan, a Canadian scholar in media, said, if you try to reach everybody, you reach nobody. By doing that, it's really key in thinking about communicating with the people that need to know.
Ninety million Americans are either marginally or low literate, meaning they can't understand a bus map or can't understand a bus schedule or locate their intersection on a map. We can't communicate with the same message to them that we might communicate to people who are making vaccine decisions at the state or county or other levels.
So I'm answering in a circuitous way, because I think we've heard some of the right steps being taken today, the open hearing, some of the voluntary efforts that are being done in good faith by the manufacturers, and some of the other ways that continue to monitor the open disclosure. I think the surveillance systems that we've put in place not only here in the United States but now abroad in looking at BSE and looking at the CJD that we heard from CDC and others where the numbers are.
So I would say, by all means, keep the surveillance. Keep the voluntary efforts. Continue to focus upon the science, and communicate that appropriately on, whether it's a quarterly basis, or use the different channels, the Institute of Medicine channels that are out there.
I think there's a variety of different expert committees as well. So, thank you.
CHAIRMAN BROWN: Thank you very much. Yes?
MS. FISHER: You may not want to communicate this theoretical risk to the public, but that doesn't mean it's the right thing to do. I think that part of what the National Childhood Injury Act of 1986 was all about, the safety provisions, was communicating risk to parents before they get their children vaccinated.
I think that, you know, the FDA's charge is to ensure the purity and potency of vaccines. It seems to me that the least that we can do at this juncture when we know something is to let the people know we know, rather than keeping it from them.
CHAIRMAN BROWN: Hold on, Dave. Shirley?
MS. WALKER: There's an old German proverb, "Don't point the devil on the wall; otherwise, he will jump off." I think the devil has already jumped off.
The inserts in the packets for pharmaceuticals are great. Notification to the doctor is great. But I represent something like 79,000 mothers who have children in Dallas County who we actively promote to get vaccinated.
So Monday morning when I go back to work, I'm going to have to tell someone, a percentage of these young mothers, that, hey, your child is at risk for whatever that minute amount is for CJD. So what do we do at this particular point? Do we remain mute and say nothing or do we promote and give some type of information?
So I am saying to FDA that we do need some kind of general information that we can impart to our constituents.
CHAIRMAN BROWN: Thank you. I'm going to ask for just a couple of more comments in this discussion, and then in the event that a number of people on the committee may have to leave, there are two or three very specific questions that the FDA would like some discussion-on, and I want to move to them. We've touched on some of them already, but if there's anything more to say on this -- Yes, go ahead.
263 DR. STEPHENS: I guess I'm really concerned that this discussion is kind of spinning out of control in terms of the risk. I must agree with the consumer advocate who spoke a minute ago --
CHAIRMAN BROWN: Dr. Ratzan.
DR. STEPHENS: -- that, you know, this is -- We are at some -- We have a duty, in my view, to protect the vaccine system in this country. I think that this discussion has gotten to the point of at least suggesting that we believe that this is a significant problem. The data suggests that the risk is in the billions, that there have not -- there's not been a single case of new variant CJD in this country, despite the use of vaccines manufactured in this way for years.
So I think the issue is we need public disclosure. That's not the question. I think we all are in agreement on this committee, but I think to emphasize this point where you're concerned about going back to your group of mothers and saying there's a risk -- I think that's something we don't want to send. That's a message we do not want to send.
CHAIRMAN BROWN: I opened this whole seminar with the notion that we're starting from a very, very small amount of infectivity, if there is any, and that there is a tradeoff between, as several people have said, a theoretical risk and a real risk, which would be discrediting in some way vaccines or causing vaccine shortages or difficulties or refusal to get vaccines.
In other words, this is the tradeoff. Right at the outset, this was the scene that I hoped to set. But you're right. All of our committee discussion meetings tend to spin out of control at about this time of the afternoon, and sometimes it's in one direction, and sometimes it's in another direction.
I think the word risk has enlarged as the afternoon has progressed, and maybe we should shrink it down a little bit and get a little better perspective or a little different perspective. So I tend to agree with you. Let me --
DR. BOLTON: Paul, can I get in my comment?
CHAIRMAN BROWN: I'm sorry? Go ahead.
BOLTON: I agree that it would be important to communicate known risks or even good estimates of risk to the public, but I'm not sure what that estimate would be at this point. I don't think that we really have enough information to communicate to the public and have it be meaningful and not simply scare people away.
I can't imagine the negative impact on the program in this country if parents started thinking that, if I vaccinate my child, he or she may come down with new variant CJD.
To me, the other way that we communicate is by action. It seems to me that there are actions that can be taken in terms of looking at the process of vaccine manufacture and where the real -- the greatest of the theoretical risks are. It seems to me that the viral/bacterial master seeds are really at the very lowest end, as are the master cell banks, and also trying to change those creates the biggest problem.
From that point on, from the working seeds on down through production, I think that the manufacturers have issues that they can address in terms of removing the use of at-risk bovine materials from that point on.
I guess my question to anybody at the FDA is: Are at-risk bovine materials currently in use at the -- certainly from the production step on, and even at the production of the working seeds and working cell lines, are they in use now, and how long before they will be phased out?
CHAIRMANBROWN: I guess what you're -- to add to that, are the sources of anything currently coming from BSE designated countries?
DR. STEPHENS: When I say at risk, I really mean those bovine materials are coming from Europe or at-risk countries.
CHAIRMAN BROWN: Right. Does the FDA -- You might be better off --
DR. EGAN: As I mentioned in my opening talk, for some bacterial vaccines there was bovine derived fermentation media where that skeletal muscle and pancreas derived from several European countries. I think it was Germany, Denmark, Poland, the Netherlands.
CHAIRMAN BROWN: Right. So they are currently in use in this country.
DR. EGAN: They have all agreed to -- That will be changed, but as I mentioned, by the time -- You know, they've gotten new sources, but that comes into new vaccines -- What?
DR. BOLTON: Is that the only material that's now sourced from at-risk countries?
DR. EGAN: That's used in the production. I think I also mentioned hemin. I think that was it, but I'd have to go back to it.
DR. BOLTON: So I guess my recommendation would be that the FDA work with the manufacturers to set a definite timeline to phase out all those materials. In terms of the master virus seeds and the bacterial stocks and the master cell lines, I think that the risk is so small as to be really counterproductive to try to change those, because the risk of changing the product by changing those is much, much greater than any risk that there would be from proceeding.
CHAIRMAN BROWN: One of the questions that the FDA specifically wanted some judgment on was: Is it necessary to re-derive bacterial master seeds? I mean, I'm getting the sense -- Every time I get the sense of something, the sense changes. You know, we had a consensus about informed consent, and now we have a consensus about not smother it, but be awfully, awfully, awfully careful.
Now I thought we had pretty much decided that, at least for current products, that it will not be necessary to re-derive bacterial master seeds. That was my sense. Dr. Huang?
DR. HUANG: I completely agree. I think that the derivation of new master seed stocks would be more dangerous than this perceived danger that we are facing now.
CHAIRMAN BROWN: Does anybody -- As I asked before, does anybody differ from that opinion? All right. We have answered one definitive question that the FDA wanted to asked.
They also want an answer to a question I think should be very easy to answer. That is: Is 1980, form all that you have heard, an appropriate cutoff date before which one need not worry about anything in terms of sourcing of the products we are talking about?
We always worry about something, but 1980 -- is that an appropriate date before which not to be concerned? That's a pretty focused question. Is there anybody that feels that one should be concerned about products produced before 1980 from anywhere? Yes?
DR. ROOS: I think 1980 sounds like a good year, Paul, and with respect to our blood donation pool in the United States,'we were concerned about BSE and started with 1980.
CHAIRMAN BROWN: It has the merit of consistency as well. All right. That's two questions.
The third question they were concerned about was: Do we think that the small amount of fetal calf serum from the U.K. around 1985 used in the production of master cell banks constitutes a negligible or -- well, the phrase was "a negligible or a significant risk"? Again, a question about fetal calf serum, sourced from the U.K. in the middle of the 1980s, use in the production of master cell banks constitutes any kind of significant risk? Yes?
DR. CLIVER: May I start by saying negligible. We'll see if anybody disagrees.
CHAIRMAN BROWN: Do I hear significant? Negligible?
[[[sounds like a damn auction...tss]]]
DR. BOLTON: I agree that it's negligible.
CHAIRMAN BROWN: Okay. Any differing opinion that fetal calf serum used for the production -- just for this specific purpose, used in the production of master cell banks? Well, that answers the three questions that you most wanted some judgment on Dr. Ewenstein?
Dr. EWENSTEIN: There was also the products that are still under investigation. I think, you know, we should address that. I think one of the comments before was, I think, right on the point. That is that it's different if you have a licensed drug or product that has, therefore, documented benefit versus recruited volunteers.
I think we should think about what we should answer for number 3. I think that it's appropriate to include again, with the correct caveat, about theoretical and negligibly small risk in a consent form. but I certainly wouldn't like to see all clinical trials stopped of such vaccines.
CHAIRMAN BROWN: Yes. This is the idea about an investigational drugs. We haven't touched on that, and we might just continue that discussion a bit. Peter?
DR. LURIE: Yes. I think Dr. Ewenstein is right, if I understood him correctly. I think that it is indeed a different situation. For one thing, not only is the benefit of the vaccine unknown, but for another, one actually does know the name of the patients, and one is personal contact with those patients on a semi-regular basis.
I think that the ethical responsibility toward those people is quite different than is owed to the population at large......
FULL TEXT AT URL BELOW PDF FORM (about 79 pages)......TSS
http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3635t1c.pdf
############ http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html ############
https://lists.aegee.org/cgi-bin/wa?A2=ind0009&L=BSE-L&T=0&F=&S=&X=528A4F31A528740893&Y=flounder9%40verizon.net&P=15635
The Old Days
https://lists.aegee.org/cgi-bin/wa?A1=ind0009&L=BSE-L&X=528A4F31A528740893&Y=flounder9%40verizon.net
Sunday, May 18, 2008
MAD COW DISEASE BSE CJD CHILDREN VACCINES
http://bseinquiry.blogspot.com/2008/05/mad-cow-disease-bse-cjd-children.html
Sunday, May 18, 2008 BSE, CJD, and Baby foods (the great debate 1999 to 2005)
http://bseinquiry.blogspot.com/2008/05/bse-cjd-and-baby-foods-great-debate.html
Back to reality
When Atypical Scrapie cross species barriers
Authors
Andreoletti O., Herva M. H., Cassard H., Espinosa J. C., Lacroux C., Simon S., Padilla D., Benestad S. L., Lantier F., Schelcher F., Grassi J., Torres, J. M., UMR INRA ENVT 1225, Ecole Nationale Veterinaire de Toulouse.France; ICISA-INlA, Madrid, Spain; CEA, IBiTec-5, DSV, CEA/Saclay, Gif sur Yvette cedex, France; National Veterinary Institute, Postboks 750 Sentrum, 0106 Oslo, Norway, INRA IASP, Centre INRA de Tours, 3738O Nouzilly, France.
Content
Atypical scrapie is a TSE occurring in small ruminants and harbouring peculiar clinical, epidemiological and biochemical properties. Currently this form of disease is identified in a large number of countries. In this study we report the transmission of an atypical scrapie isolate through different species barriers as modeled by transgenic mice (Tg) expressing different species PRP sequence.
The donor isolate was collected in 1995 in a French commercial sheep flock. inoculation into AHQ/AHQ sheep induced a disease which had all neuro-pathological and biochemical characteristics of atypical scrapie. Transmitted into Transgenic mice expressing either ovine or PrPc, the isolate retained all the described characteristics of atypical scrapie.
Surprisingly the TSE agent characteristics were dramatically different v/hen passaged into Tg bovine mice. The recovered TSE agent had biological and biochemical characteristics similar to those of atypical BSE L in the same mouse model. Moreover, whereas no other TSE agent than BSE were shown to transmit into Tg porcine mice, atypical scrapie was able to develop into this model, albeit with low attack rate on first passage.
Furthermore, after adaptation in the porcine mouse model this prion showed similar biological and biochemical characteristics than BSE adapted to this porcine mouse model. Altogether these data indicate.
(i) the unsuspected potential abilities of atypical scrapie to cross species barriers
(ii) the possible capacity of this agent to acquire new characteristics when crossing species barrier
These findings raise some interrogation on the concept of TSE strain and on the origin of the diversity of the TSE agents and could have consequences on field TSE control measures.
http://www.neuroprion.org/resources/pdf_docs/conferences/prion2008/abstract-book-prion2008.pdf
SCRAPIE USA
INFECTED AND SOURCE FLOCKS
There were 20 scrapie infected and source flocks with open statuses (Figure 3) as of April, 30, 2008. Twenty eight new infected and source flocks have been designated in FY 2008 (Figure 4); three source flocks were reported in April. ...snip
POSITIVE SCRAPIE CASES
As of April 30, 2008, 122 new scrapie cases have been confirmed and reported by the National Veterinary Services Laboratories (NVSL) in FY 2008 (Figure 6). Of these, 103 were field cases and 19* were Regulatory Scrapie Slaughter Surveillance (RSSS) cases (collected in FY 2008 and reported by May 20, 2008). Positive cases reported for April 2008 are depicted in Figure 7. Eighteen cases of scrapie in goats have been confirmed by NVSL since implementation of the regulatory changes in FY 2002 (Figure 8). The most recent positive goat case was confirmed in February 2008 and originated from the same herd in Michigan as the other FY 2008 goat cases. ...snip
CAPRINE SCRAPIE PREVALENCE STUDY (CSPS)
snip...
However, four positive goats have been identified this fiscal year through field investigations. One was a clinical suspect submitted for testing and the other three originated from the birth herd of the clinical case.
ANIMALS SAMPLED FOR SCRAPIE TESTING
As of April 30, 2008, 26,703 animals have been sampled for scrapie testing: 23,378 RSSS, 1,517 goats for the CSPS study, 1,466 regulatory field cases, 270 regulatory third eyelid biopsies, and 72 regulatory rectal biopsies (chart 8).
TESTING OF LYMPHOID TISSUE OBTAINED BY RECTAL BIOPSY WAS APPROVED BY USDA AS AN OFFICIAL LIVE-ANIMAL TEST ON JANUARY 11, 2008. ...
PLEASE NOTE, (FIGURE 6), Scrapie Confirmed Cases in FY 2008 MAP, PA 3, 1**, Two cases-state of ID UNKNOWN, 1 case Nor98-like**
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/monthly_scrapie_rpt.pps
http://scrapie-usa.blogspot.com/
CHAPTER 3 Animal Disease Eradication Programs and Control and Certification Programs
snip...
In FY 2007, two field cases, one validation study case, and two RSSS cases were consistent with a variant of the disease known as Nor98 scrapie.1 These five cases originated from flocks in California, Minnesota, Colorado, Wyoming, and Indiana, respectively.
snip...
http://www.aphis.usda.gov/publications/animal_health/content/printable_version/AHR_Web_PDF_07/D_Chapter_3.pdf
NOR-98 Scrapie FY 2008 to date 1
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/monthly_scrapie_rpt.pps
Monday, September 1, 2008
RE-FOIA OF DECLARATION OF EXTRAORDINARY EMERGENCY BECAUSE OF AN ATYPICAL T.S.E. (PRION DISEASE) OF FOREIGN ORIGIN IN THE UNITED STATES [No. 00-072-1]
September 1, 2008
http://foiamadsheepmadrivervalley.blogspot.com/2008/09/re-foia-of-declaration-of-extraordinary.html
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
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
NOR-98 ATYPICAL SCRAPIE 5 cases documented in USA in 5 different states USA 007
http://nor-98.blogspot.com/2008/04/seac-spongiform-encephalopathy-advisory.html
Tuesday, June 3, 2008 SCRAPIE USA UPDATE JUNE 2008 NOR-98 REPORTED PA
http://nor-98.blogspot.com/2008/06/scrapie-usa-update-june-2008-nor-98.html
http://nor-98.blogspot.com/
Monday, December 1, 2008 When Atypical Scrapie cross species barriers
http://nor-98.blogspot.com/2008/12/when-atypical-scrapie-cross-species.html
CONFIDENTIAL PAPER No: SEAC 78/9 Amendment 2 2 In March 2002, a SEAC Sub-Group considered the risks associated with certain genotypes entering the food chain if BSE were ever isolated from sheep. In contrast to the SSC opinion, SEAC concluded that: • In line with previous SEAC advice, only animals carrying the ARR allele should enter the food chain • On a precautionary basis, the 12 month cut off previously advised by SEAC remained appropriate for ARR heterozygotes. However, in view of existing SRM regulations there was no justification for any age cut off in ARR homozygotes • In line with SEAC advice in 2001, only milk from ARR homozygous sheep could be considered as highly unlikely to contain the infectious agent. Further experimental work was required before potential risks from small ruminant milk from goats and semi-resistant or susceptible sheep could be excluded. There is therefore a disparity of opinion between the SSC and SEAC on this issue. Whilst recognising the uncertainties relating to the science in this area, it is important that contingency planning is based on the most up to date scientific developments and assessments of risk that are available. SEAC will be presented with an update on the ongoing BSE in sheep studies, funded by Defra (Annex 31). This covering paper also provides a history of previous SEAC advice on this issue. BACKGROUND...snip...end
http://www.seac.gov.uk/papers/78-9-closed.pdf
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 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 is 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 emphasized by the finding that some strains of scrapie produce lesions identical to the once which characterize 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 scrapie problem urgent if the sheep industry is not to suffer grievously.
snip...
76/10.12/4.6
http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
1: J Infect Dis 1980 Aug;142(2):205-8
Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.
Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.
Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation.
PMID: 6997404
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=6997404&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus
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://www.bseinquiry.gov.uk/files/yb/1994/02/07002001.pdf
http://nor-98.blogspot.com/
Wednesday, January 28, 2009TAFS1 Position Paper on BSE in small ruminants (January 2009)
http://scrapie-usa.blogspot.com/2009/01/tafs1-position-paper-on-bse-in-small.html
TSS
Monday, December 1, 2008
When Atypical Scrapie cross species barriers
When Atypical Scrapie cross species barriers
Authors
Andreoletti O., Herva M. H., Cassard H., Espinosa J. C., Lacroux C., Simon S., Padilla D., Benestad S. L., Lantier F., Schelcher F., Grassi J., Torres, J. M., UMR INRA ENVT 1225, Ecole Nationale Veterinaire de Toulouse.France; ICISA-INlA, Madrid, Spain; CEA, IBiTec-5, DSV, CEA/Saclay, Gif sur Yvette cedex, France; National Veterinary Institute, Postboks 750 Sentrum, 0106 Oslo, Norway, INRA IASP, Centre INRA de Tours, 3738O Nouzilly, France.
Content
Atypical scrapie is a TSE occurring in small ruminants and harbouring peculiar clinical, epidemiological and biochemical properties. Currently this form of disease is identified in a large number of countries. In this study we report the transmission of an atypical scrapie isolate through different species barriers as modeled by transgenic mice (Tg) expressing different species PRP sequence.
The donor isolate was collected in 1995 in a French commercial sheep flock. inoculation into AHQ/AHQ sheep induced a disease which had all neuro-pathological and biochemical characteristics of atypical scrapie. Transmitted into Transgenic mice expressing either ovine or PrPc, the isolate retained all the described characteristics of atypical scrapie.
Surprisingly the TSE agent characteristics were dramatically different v/hen passaged into Tg bovine mice. The recovered TSE agent had biological and biochemical characteristics similar to those of atypical BSE L in the same mouse model. Moreover, whereas no other TSE agent than BSE were shown to transmit into Tg porcine mice, atypical scrapie was able to develop into this model, albeit with low attack rate on first passage.
Furthermore, after adaptation in the porcine mouse model this prion showed similar biological and biochemical characteristics than BSE adapted to this porcine mouse model. Altogether these data indicate.
(i) the unsuspected potential abilities of atypical scrapie to cross species barriers
(ii) the possible capacity of this agent to acquire new characteristics when crossing species barrier
These findings raise some interrogation on the concept of TSE strain and on the origin of the diversity of the TSE agents and could have consequences on field TSE control measures.
http://www.neuroprion.org/resources/pdf_docs/conferences/prion2008/abstract-book-prion2008.pdf
SCRAPIE USA
INFECTED AND SOURCE FLOCKS
There were 20 scrapie infected and source flocks with open statuses (Figure 3) as of April, 30, 2008. Twenty eight new infected and source flocks have been designated in FY 2008 (Figure 4); three source flocks were reported in April. ...snip
POSITIVE SCRAPIE CASES
As of April 30, 2008, 122 new scrapie cases have been confirmed and reported by the National Veterinary Services Laboratories (NVSL) in FY 2008 (Figure 6). Of these, 103 were field cases and 19* were Regulatory Scrapie Slaughter Surveillance (RSSS) cases (collected in FY 2008 and reported by May 20, 2008). Positive cases reported for April 2008 are depicted in Figure 7. Eighteen cases of scrapie in goats have been confirmed by NVSL since implementation of the regulatory changes in FY 2002 (Figure 8). The most recent positive goat case was confirmed in February 2008 and originated from the same herd in Michigan as the other FY 2008 goat cases. ...snip
CAPRINE SCRAPIE PREVALENCE STUDY (CSPS)
snip...
However, four positive goats have been identified this fiscal year through field investigations. One was a clinical suspect submitted for testing and the other three originated from the birth herd of the clinical case.
ANIMALS SAMPLED FOR SCRAPIE TESTING
As of April 30, 2008, 26,703 animals have been sampled for scrapie testing: 23,378 RSSS, 1,517 goats for the CSPS study, 1,466 regulatory field cases, 270 regulatory third eyelid biopsies, and 72 regulatory rectal biopsies (chart 8).
TESTING OF LYMPHOID TISSUE OBTAINED BY RECTAL BIOPSY WAS APPROVED BY USDA AS AN OFFICIAL LIVE-ANIMAL TEST ON JANUARY 11, 2008. ...
PLEASE NOTE, (FIGURE 6), Scrapie Confirmed Cases in FY 2008 MAP, PA 3, 1**, Two cases-state of ID UNKNOWN, 1 case Nor98-like**
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/monthly_scrapie_rpt.pps
http://scrapie-usa.blogspot.com/
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
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
NOR-98 ATYPICAL SCRAPIE 5 cases documented in USA in 5 different states USA 007
http://nor-98.blogspot.com/2008/04/seac-spongiform-encephalopathy-advisory.html
Tuesday, June 3, 2008 SCRAPIE USA UPDATE JUNE 2008 NOR-98 REPORTED PA
http://nor-98.blogspot.com/2008/06/scrapie-usa-update-june-2008-nor-98.html
http://nor-98.blogspot.com/
TSS
Authors
Andreoletti O., Herva M. H., Cassard H., Espinosa J. C., Lacroux C., Simon S., Padilla D., Benestad S. L., Lantier F., Schelcher F., Grassi J., Torres, J. M., UMR INRA ENVT 1225, Ecole Nationale Veterinaire de Toulouse.France; ICISA-INlA, Madrid, Spain; CEA, IBiTec-5, DSV, CEA/Saclay, Gif sur Yvette cedex, France; National Veterinary Institute, Postboks 750 Sentrum, 0106 Oslo, Norway, INRA IASP, Centre INRA de Tours, 3738O Nouzilly, France.
Content
Atypical scrapie is a TSE occurring in small ruminants and harbouring peculiar clinical, epidemiological and biochemical properties. Currently this form of disease is identified in a large number of countries. In this study we report the transmission of an atypical scrapie isolate through different species barriers as modeled by transgenic mice (Tg) expressing different species PRP sequence.
The donor isolate was collected in 1995 in a French commercial sheep flock. inoculation into AHQ/AHQ sheep induced a disease which had all neuro-pathological and biochemical characteristics of atypical scrapie. Transmitted into Transgenic mice expressing either ovine or PrPc, the isolate retained all the described characteristics of atypical scrapie.
Surprisingly the TSE agent characteristics were dramatically different v/hen passaged into Tg bovine mice. The recovered TSE agent had biological and biochemical characteristics similar to those of atypical BSE L in the same mouse model. Moreover, whereas no other TSE agent than BSE were shown to transmit into Tg porcine mice, atypical scrapie was able to develop into this model, albeit with low attack rate on first passage.
Furthermore, after adaptation in the porcine mouse model this prion showed similar biological and biochemical characteristics than BSE adapted to this porcine mouse model. Altogether these data indicate.
(i) the unsuspected potential abilities of atypical scrapie to cross species barriers
(ii) the possible capacity of this agent to acquire new characteristics when crossing species barrier
These findings raise some interrogation on the concept of TSE strain and on the origin of the diversity of the TSE agents and could have consequences on field TSE control measures.
http://www.neuroprion.org/resources/pdf_docs/conferences/prion2008/abstract-book-prion2008.pdf
SCRAPIE USA
INFECTED AND SOURCE FLOCKS
There were 20 scrapie infected and source flocks with open statuses (Figure 3) as of April, 30, 2008. Twenty eight new infected and source flocks have been designated in FY 2008 (Figure 4); three source flocks were reported in April. ...snip
POSITIVE SCRAPIE CASES
As of April 30, 2008, 122 new scrapie cases have been confirmed and reported by the National Veterinary Services Laboratories (NVSL) in FY 2008 (Figure 6). Of these, 103 were field cases and 19* were Regulatory Scrapie Slaughter Surveillance (RSSS) cases (collected in FY 2008 and reported by May 20, 2008). Positive cases reported for April 2008 are depicted in Figure 7. Eighteen cases of scrapie in goats have been confirmed by NVSL since implementation of the regulatory changes in FY 2002 (Figure 8). The most recent positive goat case was confirmed in February 2008 and originated from the same herd in Michigan as the other FY 2008 goat cases. ...snip
CAPRINE SCRAPIE PREVALENCE STUDY (CSPS)
snip...
However, four positive goats have been identified this fiscal year through field investigations. One was a clinical suspect submitted for testing and the other three originated from the birth herd of the clinical case.
ANIMALS SAMPLED FOR SCRAPIE TESTING
As of April 30, 2008, 26,703 animals have been sampled for scrapie testing: 23,378 RSSS, 1,517 goats for the CSPS study, 1,466 regulatory field cases, 270 regulatory third eyelid biopsies, and 72 regulatory rectal biopsies (chart 8).
TESTING OF LYMPHOID TISSUE OBTAINED BY RECTAL BIOPSY WAS APPROVED BY USDA AS AN OFFICIAL LIVE-ANIMAL TEST ON JANUARY 11, 2008. ...
PLEASE NOTE, (FIGURE 6), Scrapie Confirmed Cases in FY 2008 MAP, PA 3, 1**, Two cases-state of ID UNKNOWN, 1 case Nor98-like**
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/monthly_scrapie_rpt.pps
http://scrapie-usa.blogspot.com/
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
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
NOR-98 ATYPICAL SCRAPIE 5 cases documented in USA in 5 different states USA 007
http://nor-98.blogspot.com/2008/04/seac-spongiform-encephalopathy-advisory.html
Tuesday, June 3, 2008 SCRAPIE USA UPDATE JUNE 2008 NOR-98 REPORTED PA
http://nor-98.blogspot.com/2008/06/scrapie-usa-update-june-2008-nor-98.html
http://nor-98.blogspot.com/
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