Research article
Experimental transmission of atypical scrapie to sheep
Marion M Simmons1 , Timm Konold1 , Hugh A Simmons3 , Yvonne I Spencer1 , Richard Lockey1 , John Spiropoulos1 , Sharon Everitt2 and Derek Clifford3
1Department of Pathology, Veterinary Laboratories Agency – Weybridge, Woodham Lane, New Haw, Addlestone, Surrey KT15 3NB, UK2Department of Molecular Pathogenesis and Genetics, Veterinary Laboratories Agency – Weybridge, Woodham Lane, New Haw, Addlestone, Surrey KT15 3NB, UK3Animal Services Unit, Veterinary Laboratories Agency – Weybridge, Woodham Lane, New Haw, Addlestone, Surrey KT15 3NB, UK
author email corresponding author email
BMC Veterinary Research 2007, 3:20doi:10.1186/1746-6148-3-20
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1746-6148/3/20
Received: 26 March 2007 Accepted: 28 August 2007 Published: 28 August 2007
© 2007 Crown copyright; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
AbstractBackgroundActive surveillance for transmissible spongiform encephalopathies in small ruminants has been an EU regulatory requirement since 2002. A number of European countries have subsequently reported cases of atypical scrapie, similar to previously published cases from Norway, which have pathological and molecular features distinct from classical scrapie. Most cases have occurred singly in flocks, associated with genotypes considered to be more resistant to classical disease. Experimental transmissibility of such isolates has been reported in certain ovinised transgenic mice, but has not previously been reported in the natural host. Information on the transmissibility of this agent is vital to ensuring that disease control measures are effective and proportionate.
ResultsThis report presents the successful experimental transmission, in 378 days, of atypical scrapie to a recipient sheep of homologous genotype with preservation of the pathological and molecular characteristics of the donor. This isolate also transmitted to ovinised transgenic mice (Tg338) with a murine phenotype indistinguishable from that of Nor 98.
ConclusionThis result strengthens the opinion that these cases result from a distinct strain of scrapie agent, which is potentially transmissible in the natural host under field conditions.
Background
snip...
DiscussionTo our knowledge this is the first report of the successful experimental transmission of atypical scrapie within the natural host. The retention of the molecular and pathological characteristics of the scrapie agent following this experimental transmission supports the hypothesis that disease in the donor animal was caused by a stable strain of the TSE agent which has phenotypic characteristics distinct from those associated with classical scrapie. Although clinical signs were not recorded from the donor animal because it presented dead (fallen stock), the signs seen in the challenged animal were consistent with those reported for the small number of passive surveillance cases so far identified in the UK [14,15] and elsewhere [6,16], which were characterised by gait abnormalities, abnormal behaviour and a relative lack of pruritic signs.
The transmission characteristics of atypical scrapie from different countries in Tg338 mice [12] and emerging data from similar transmissions of the isolate in this report indicate that at least one strain of atypical scrapie compatible with/indistinguishable from Nor98 is widespread across Europe, despite its relatively recent identification.
Although it has now been demonstrated to be experimentally transmissible within and between species via the intracerebral route, there is little epidemiological evidence for ease of transmission of this strain under field conditions, where scrapie is most likely transmitted via the oral route. This raises the question of how it came to be so geographically widespread. One hypothesis is that this represents a spontaneous genetic disease in sheep similar to the familial forms of TSE in man (e.g. GSS, familial CJD and FFI etc.), in which the resultant disease can subsequently be transmitted experimentally [17,18].
Horizontal transmission of classical scrapie has been shown to occur in adult sheep exposed to an affected flock [19] and even in animals which have had contact only with a contaminated environment (GI Dexter and SJ Bellworthy, personal communication). The environmental persistence of the classical scrapie agent is also supported by epidemiological evidence from Icelandic repopulation studies [20,21]. However, the low molecular mass (<14 kD) band of PrPSc seen in Western blots of atypical isolates is associated with a reduction in PK resistance of this disease-associated protein. It is possible that this relative protease susceptibility may make the agent less robust in field conditions and thereby reduce the extent to which it is transmissible by natural routes, and so limit the number of cases. It could be argued that this in turn supports the hypothesis that the natural disease may arise spontaneously. However, although genetic studies have indicated a PrP genotype host range for atypical scrapie which, for the majority of cases, is almost fully distinct from that of the classical forms of disease, they have not identified a single genetic feature (such as the point mutations in some human forms [22]) which might account for this.
This relative PrPSc fragility [23] compared to the PrPSc in classical scrapie, may also account for the total absence of intracellular PrPSc immunolabelling. The different PK cleavage sites in PrP associated with different strains of TSE infecting small ruminants can be used to differentiate them, both in blots and by immunohistochemistry. Intracellular immunostaining is significantly reduced in sheep infected with BSE compared to classical scrapie, when the appropriate monoclonal antibodies are applied, and it has been speculated that this demonstrates a partial digestion of the PrPSc molecule by the endogenous proteases within the cells [24]. If the PrPSc is more protease sensitive, then this loss of intracellular immunolabelling even with an antibody to the core of the protein (such as MAb 2G11) might indicate that cells can more effectively catabolise this abnormal form of the protein than more 'classical' forms, and therefore succumb to clinical disease much later, if at all. This may also account for the apparent absence of disease-related PrPSc in lymphoid tissues. It is interesting to note that in familial CJD (E200K mutation) also, PrP labelling was seen as a uniformly fine deposit throughout all cortical layers [25].
This study confirms that 'atypical scrapie' is transmissible within the natural host species, via the intracerebral route, without alteration of the pathological and molecular characteristics. This is the first report from a larger study which will explore more widely the effect of the PrP gene on the experimental susceptibility and resultant phenotype following intracerebral or oral challenge with this type of scrapie isolate.
ConclusionAt present the significance of this result, in terms of the transmissibility or pathogenicity under 'field conditions' of this agent strain in any species remains speculative, but it supports the need for appropriate control measures protecting both the animal and the human food chain to encompass atypical scrapie cases specifically.
snip...END...TSS
http://www.biomedcentral.com/1746-6148/3/20
Tissue distribution. For atypical scrapie, what is PrPres andinfectivity distribution within sheep of different genotypes,particularly with respect to SRM removal? For classicalscrapie and experimental BSE in sheep, tissue distribution ofinfectivity is widespread. Thus, even with SRM controls inplace, an infected sheep poses around 1000 times the risk tohuman health than does an infected cow22. Does thedistribution depend on whether infection is by the oral or21 Gubbins S. Prevalence of BSE in sheep: interpreting the results ofretrospective andprospective testing of sheep TSE cases. SEAC 84 open meeting22 paper presented to Food Standards Agency board on 9 December 2004.http://www.foodstandards.gov.uk/multimedia/pdfs/fsa041204.pdfAlso see paper SEAC/84/2 Annex 2: McLean, A.Page 13© SEAC 27 February 2006intracerebral route? Are some VRQ sheep carriers with noneurological symptoms?
SEAC SHEEP SUBGROUPPOSITION STATEMENT
http://www.seac.gov.uk/pdf/positionstatement-sheep-subgroup.pdf
Published online before print October 20, 2005Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0502296102Medical Sciences
A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes
( sheep prion transgenic mice )Annick Le Dur *, Vincent Béringue *, Olivier Andréoletti , Fabienne Reine *,Thanh Lan Laï *, Thierry Baron , Bjørn Bratberg ¶, Jean-Luc Vilotte ,Pierre Sarradin **, Sylvie L. Benestad ¶, and Hubert Laude **Virologie Immunologie Moléculaires and Génétique Biochimique etCytogénétique, Institut National de la Recherche Agronomique, 78350Jouy-en-Josas, France; Unité Mixte de Recherche, Institut National de laRecherche Agronomique-Ecole Nationale Vétérinaire de Toulouse, InteractionsHôte Agent Pathogène, 31066 Toulouse, France; Agence Française de SécuritéSanitaire des Aliments, Unité Agents Transmissibles Non Conventionnels,69364 Lyon, France; **Pathologie Infectieuse et Immunologie, InstitutNational de la Recherche Agronomique, 37380 Nouzilly, France; and¶Department of Pathology, National Veterinary Institute, 0033 Oslo, Norway
Edited by Stanley B. Prusiner, University of California, San Francisco, CA,and approved September 12, 2005 (received for review March 21, 2005)
Scrapie in small ruminants belongs to transmissible spongiform encephalopathies (TSEs), or prion diseases, a family of fatal neurodegenerative disorders that affect humans and animals and can transmit within and between species by ingestion or inoculation. Conversion of the host-encoded prion protein (PrP), normal cellular PrP (PrPc), into amisfolded form, abnormal PrP (PrPSc), plays a key role in TSE transmission and pathogenesis. The intensified surveillance of scrapie in the European Union, together with the improvement of PrPSc detection techniques, has led to the discovery of a growing number of so-called atypical scrapie cases. These include clinical Nor98 cases first identified in Norwegian sheep on the basis of unusual pathological and PrPSc molecular features and "cases" that produced discordant responses in the rapid tests currently applied tothe large-scale random screening of slaughtered or fallen animals. Worryingly, a substantial proportion of such cases involved sheep with PrP genotypes known until now to confer natural resistance to conventional scrapie. Here we report that both Nor98 and discordant cases, including three sheep homozygous for the resistant PrPARR allele (A136R154R171), efficiently transmitted the disease to transgenic mice expressing ovine PrP, and that they shared unique biological and biochemical features upon propagation in mice. These observations support the view that a truly infectious TSE agent, unrecognized until recently, infects sheep and goatflocks andmay have important implications in terms of scrapie control andpublic health.
--------------------------------------------------------------------------------
Author contributions: H.L. designed research; A.L.D., V.B., O.A., F.R.,T.L.L., J.-L.V., and H.L. performed research; T.B., B.B., P.S., and S.L.B.contributed new reagents/analytic tools; V.B., O.A., and H.L. analyzed data;and H.L. wrote the paper.A.L.D. and V.B. contributed equally to this work.To whom correspondence should be addressed.Hubert Laude,
E-mail: laude@jouy.inra.fr
www.pnas.org/cgi/doi/10.1073/pnas.0502296102
http://www.pnas.org/cgi/content/abstract/0502296102v1
OF COURSE, the USDA et al once was concerned for human health from typical scrapie, and rightly so, typical scrapie transmits to primates by there NON-FORCED ORAL CONSUMPTION ;
76/10.12/4.6
http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
http://www.ncbi.nlm.nih.gov/entrez/query.fcgicmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
ALSO, The agent responsible for French iatrogenic growth hormone-linked CJD taken as a control is very different from vCJD but is similar to that found in one case of sporadic CJD and one sheep scrapie isolate.
http://www.pnas.org/cgi/content/full/041490898v1
TAFS
INTERNATIONAL FORUM FOR TRANSMISSIBLE ANIMAL DISEASES AND FOOD SAFETY
a non-profit Swiss Foundation(May 16, 2007)TAFS1
Position Paper on Atypical scrapie and Atypical BSE
Although most atypical cases occur singly in flocks, there are some instances where two affected sheep have been identified in flocks. This may indicate that natural transmission may occur, or that the sheep were infected from a common alternative source(22, 29). Possible indications of an association with the feeding of vitamins and mineral feed supplements were detected in Norway, but remain to be proven(22).
snip...
Atypical BSE may arise spontaneously in a small proportion of cattle. The existence of sporadic CJD in humans has led to postulation that disease could arise spontaneously in any animal, but this is still not proven to happen. Despitethe small numbers of atypical BSE detected so far, in some countries the numbers are too great to suggest that they all arise spontaneously, if it were assumed that such a phenomenon occurred at the same frequency as sporadic CJD in humans.
http://www.tseandfoodsafety.org/position_papers/TAFS_POSITION_PAPER_ON_ATYPICAL_SCRAPIE_AND_%20ATYPICAL_BSE_070516.pdf
TSS
Thursday, November 22, 2007
Tuesday, October 9, 2007
NOR-98 SCRAPIE UPDATE AUGUST 31, 2007 RISES TO 5 DOCUMENTED CASES
Thursday, November 01, 2007 6:38 AM UPDATE
ATYPICAL NOR-98 SCRAPIE LOCATION UPDATE ON 5 DOCUMENTED CASES THIS YEAR ;
The flocks of origin are WY, CO, CA, IN, and MN.
personal communication USDA et al. ...TSS
USA NOR-98 SCRAPIE UPDATE AUGUST 31, 2007 RISES TO 5 DOCUMENTED CASES
http://nor-98.blogspot.com/
Government Accountability Project
https://www.blogger.com/comment.g?blogID=3995372399492420922&postID=295754279213239559
TSS
Subject: NOR-98 SCRAPIE UPDATE AUGUST 31, 2007 (RISES TO 5 DOCUMENTED CASES IN USA)
Date: October 9, 2007 at 7:15 am PST
Greetings, seems the NOR-98 atypical scrapie cases are the rise in the USA. ...tss
INFECTED AND SOURCE FLOCKS AS of August 31, 2007, there were 33 scrapie infected and source flocks with open statuses (Figure 3). Five new source flocks and one new infected flock were reported n August (Figure 4) with a total of 64 reported for FY 2007(Figure 5).
snip...
IN FY 2007 TWO FIELD CASES, ONE VALIDATION CASE, AND TWO RSSS CASES WERE CONSISTENT WITH NOR-98 SCRAPIE. ...
(BRINGS A TOTAL OF 5 NOR-98 CASES DOCUMENTED IN 2007 IN USA. ...TSS)
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/monthly_scrapie_rpt.pps
please note sporadic cjd cases on the rise with 'unknown type' increasing drastically. ...tss
NOW, why in the world is no one much speaking about the lates 3 cases of theNOR-98 case in the USA, and what are the potential ramifications thereof;
Subject: Aspects of the Cerebellar Neuropathology in Nor98
Date: September26, 2007 at 4:06 pm PST
P03.141
Aspects of the Cerebellar Neuropathology in Nor98
Gavier-Widén, D1; Benestad, SL2; Ottander, L1; Westergren, E1 1NationalVeterinary 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 studyhere presented aimed at adding information on the neuropathology in the cerebellum of Nor98 naturally affected sheep of various genotypes in Swedenand 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 thegranule cell layer and in the white matter.
*** The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.
http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf
what does the Nobel Prize Winner Stanely Prusiner say about atypical scrapie, lets look at that first ;
Published online before print October 20, 2005Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0502296102Medical Sciences
A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes
( sheep prion transgenic mice )Annick Le Dur *, Vincent Béringue *, Olivier Andréoletti , Fabienne Reine *,Thanh Lan Laï *, Thierry Baron , Bjørn Bratberg ¶, Jean-Luc Vilotte ,Pierre Sarradin **, Sylvie L. Benestad ¶, and Hubert Laude **Virologie Immunologie Moléculaires and Génétique Biochimique etCytogénétique, Institut National de la Recherche Agronomique, 78350Jouy-en-Josas, France; Unité Mixte de Recherche, Institut National de laRecherche Agronomique-Ecole Nationale Vétérinaire de Toulouse, InteractionsHôte Agent Pathogène, 31066 Toulouse, France; Agence Française de SécuritéSanitaire des Aliments, Unité Agents Transmissibles Non Conventionnels,69364 Lyon, France; **Pathologie Infectieuse et Immunologie, InstitutNational de la Recherche Agronomique, 37380 Nouzilly, France; and¶Department of Pathology, National Veterinary Institute, 0033 Oslo, Norway
Edited by Stanley B. Prusiner, University of California, San Francisco, CA,and approved September 12, 2005 (received for review March 21, 2005)
Scrapie in small ruminants belongs to transmissible spongiform encephalopathies (TSEs), or prion diseases, a family of fatal neurodegenerative disorders that affect humans and animals and can transmit within and between species by ingestion or inoculation. Conversion of the host-encoded prion protein (PrP), normal cellular PrP (PrPc), into amisfolded form, abnormal PrP (PrPSc), plays a key role in TSE transmission and pathogenesis. The intensified surveillance of scrapie in the European Union, together with the improvement of PrPSc detection techniques, has led to the discovery of a growing number of so-called atypical scrapie cases. These include clinical Nor98 cases first identified in Norwegian sheep on the basis of unusual pathological and PrPSc molecular features and "cases" that produced discordant responses in the rapid tests currently applied tothe large-scale random screening of slaughtered or fallen animals. Worryingly, a substantial proportion of such cases involved sheep with PrP genotypes known until now to confer natural resistance to conventional scrapie. Here we report that both Nor98 and discordant cases, including three sheep homozygous for the resistant PrPARR allele (A136R154R171), efficiently transmitted the disease to transgenic mice expressing ovine PrP, and that they shared unique biological and biochemical features upon propagation in mice. These observations support the view that a truly infectious TSE agent, unrecognized until recently, infects sheep and goatflocks and
may have important implications in terms of scrapie control andpublic health.
--------------------------------------------------------------------------------
Author contributions: H.L. designed research; A.L.D., V.B., O.A., F.R.,T.L.L., J.-L.V., and H.L. performed research; T.B., B.B., P.S., and S.L.B.contributed new reagents/analytic tools; V.B., O.A., and H.L. analyzed data;and H.L. wrote the paper.A.L.D. and V.B. contributed equally to this work.To whom correspondence should be addressed.Hubert Laude,
E-mail: laude@jouy.inra.fr
www.pnas.org/cgi/doi/10.1073/pnas.0502296102
http://www.pnas.org/cgi/content/abstract/0502296102v1
OF COURSE, the USDA et al once was concerned for human health from typical scrapie, and rightly so, typical scrapie transmits to primates by there NON-FORCED ORAL CONSUMPTION ;
76/10.12/4.6
http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
J Infect Dis. 2004 Aug 1;190(3):653-60.
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.
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=6997404&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus
ALSO, The agent responsible for French iatrogenic growth hormone-linked CJD taken as a control is very different from vCJD but is similar to that found in one case of sporadic CJD and one sheep scrapie isolate.
http://www.pnas.org/cgi/content/full/041490898v1
SO, in my opinion, the _myth_ that typical scrapie does not transmit to humans, is just that, a myth. there have never been transmission studies done on man, and I would bet my last bottom dollar, anyone making the statement, would not eat a handful of scrapie infected brains. you do know about james alford don't you, whether or not it was the sheep brains he was fed in the middle east, or something else, this war hero has cjd, and he is very young. this was a tragic story too. dont hear much of that now either. ...
http://www.blackfive.net/main/2004/10/a_dying_hero_ss.html
http://www.blackfive.net/main/2004/03/ssg_james_alfor.html
PLEASE NOTE IN USA CJD UPDATE AS AT JUNE 2007, please note steady increase in
''TYPE UNKNOWN''. ...TSS
1 Acquired in the United Kingdom; 2 Acquired in Saudi Arabia; 3 Includes 17 inconclusive and 9 pending (1 from 2006, 8from 2007); 4 Includes 17 non-vCJD type unknown (2 from 1996, 2 from 1997, 1 from 2001, 1 from 2003, 4 from 2004, 3 from 2005, 4 from 2006) and 36 type pending (2 from 2005, 8 from 2006, 26 from 2007)
http://www.cjdsurveillance.com/pdf/case-table.pdf
TSS
From: "Terry S. Singeltary Sr."
Sent: Tuesday, August 21, 2007 9:50 AM
Subject: TWO MORE Nor98 atypical Scrapie cases detected in USA bringingtotal to 3 cases to date
Infected and Source Flocks As of June 30, 2007, there were .....
snip...
One field case and one validation case were consistent with Nor-98 scrapie.
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/monthly_scrapie_rpt.pps
IN the February 2007 Scrapie report it only mentions; ''One case was consistent with Nor98 scrapie.''
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/
(please note flocks of origin were in WY, CO, AND CA. PERSONAL COMMUNCATIONS USDA, APHIS, VS ET AL. ...TSS)
NOR98 SHOWS MOLECULAR FEATURES REMINISCENT OF GSS
http://lists.ifas.ufl.edu/cgi-bin/wa.exe?A2=ind0708&L=sanet-mg&T=0&P=14553
An evaluation of scrapie surveillance in the United States
http://lists.ifas.ufl.edu/cgi-bin/wa.exe?A2=ind0708&L=sanet-mg&T=0&P=3427
FOIA REQUEST FOR ATYPICAL TSE INFORMATION ON VERMONT SHEEP
http://lists.ifas.ufl.edu/cgi-bin/wa.exe?A2=ind0708&L=sanet-mg&T=0&P=10451
NEW SCIENTIST MAGAZINE 4/02/01
NEW SCIENTIST EDITORIAL PAGE 3MAD SHEEP DISEASE?
IF THERE is one categorical pronouncement you can safely make about prion diseases like BSE or CJD, it is that one should not make categorical pronouncements. "British beef is safe" and "there is no BSE in Germany" come to mind. Now there are two more: "scrapie is safe", and "people don't catch sporadic CJD". Scrapie is the most widespread prion disease, infecting untold numbers of sheep worldwide. Sporadic CJD is theold-fashioned pre-BSE kind that is supposed to happen spontaneously in unlucky people. But a surprise observation in France suggests some sCJD cases--though by no means all--maybe linked to scrapie after all (see p 4). For years, British authorities asserted that BSE was harmless because it was a form of scrapie. In fact, the only evidence scrapie is safe is some broad-brush epidemiology, good as far as it goes but unable to reveal occasional risks for some people from some sheep. Alarm bells should have rung in 1980 when researchers gave monkeys scrapie by feeding them infected brains. But that research, like so much other work on prion diseases, was never followed up. We still have little idea what BSE does in pigs and chickens. The Queniborough vCJD outbreak (see p 5) would be easier to understand if we knew how much brain we must eat to be infected. As for scrapie, it shouldn't take a chance finding to tell us that there may be dangerous sheep out there.
Suspect symptoms
What if you can catch old-fashioned CJD by eating meat from a sheep infected with scrapie?
Exclusive from New Scientist magazine
Four years ago, Terry Singeltary watched his mother die horribly from a degenerative brain disease.................
full text url follows
By Debora MacKenzie
Suspect Symptoms
http://www.newscientist.com/channel/health/bse/mg16922840.300
if url dead, go here for 'SUSPECT SYMPTOMS'
you can access article here also;
http://www.mad-cow.org/UKCJD/CJD_news52.html#29%20Mar%2001%20-%20CJD%20-%20Suspect%20symptoms
http://www.organicconsumers.org/meat/scrapiecjd.cfm
Then follow up with PNAS studies from which new scientist article written from;
Published online before print March 20, 2001
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.041490898
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Lasmézas, C. I. Deslys, J.-P.Alert me when: new articles cite this article Download to Citation Manager Neurobiology
Adaptation of the bovine spongiform encephalopathy agent to primates andcomparison with Creutzfeldt- Jakob disease: Implications for human health
Corinne Ida Lasmézas*, [dagger] , Jean-Guy Fournier*, Virginie Nouvel*,Hermann Boe*, Domíníque Marcé*, François Lamoury*, Nicolas Kopp [Dagger] , Jean-Jacques Hauw§, James Ironside¶, Moira Bruce [] , DominiqueDormont*, and Jean-Philippe Deslys** Commissariat à l'Energie Atomique, Service de Neurovirologie,Direction des Sciences du Vivant/Département de Recherche Medicale,Centre de Recherches du Service de Santé des Armées 60-68, Avenue duGénéral Leclerc, BP 6, 92 265 Fontenay-aux-Roses Cedex, France; [Dagger] Hôpital Neurologique Pierre Wertheimer, 59, Boulevard Pinel, 69003Lyon, France; § Laboratoire de Neuropathologie, Hôpital de laSalpêtrière, 83, Boulevard de l'Hôpital, 75013 Paris, France; ¶Creutzfeldt-Jakob Disease Surveillance Unit, Western General Hospital,Crewe Road, Edinburgh EH4 2XU, United Kingdom; and [] Institute forAnimal Health, Neuropathogenesis Unit, West Mains Road, Edinburgh EH93JF, United KingdomEdited by D. Carleton Gajdusek, Centre National de la RechercheScientifique, Gif-sur-Yvette, France, and approved December 7, 2000(received for review October 16, 2000)
Abstract
There is substantial scientific evidence to support the notion that bovine spongiform encephalopathy (BSE) has contaminated human beings, causing variant Creutzfeldt-Jakob disease (vCJD). This disease has raised concerns about the possibility of an iatrogenic secondary transmission to humans, because the biological properties of the primate-adapted BSE agent are unknown. We show that (i) BSE can be transmitted from primate to primate by intravenous route in 25 months, and (ii) an iatrogenic transmission of vCJD to humans could be readily recognized pathologically, whether it occurs by the central or peripheral route. Strain typing in mice demonstrates that the BSE agent adapts to macaques in the same way as it does to humans and confirms that the BSE agent is responsible for vCJD not only in the United Kingdom but also in France. The agent responsible for French iatrogenic growth hormone-linked CJD taken as a control is very different from vCJD but is similar to that found in one case of sporadic CJD and one sheep scrapie isolate. These data will be key in identifying the origin of human cases of prion disease, including accidental vCJD transmission, and could provide bases for vCJD risk assessment.
Introduction
The recognition of a variant of the human transmissible spongiform encephalopathy (TSE) Creutzfeldt-Jakob Disease (vCJD) in the U.K. in 1996 raised the major concern that it would correspond to human infection with the agent responsible for bovine spongiform encephalopathy (BSE; ref. 1). Transmission of BSE to macaques provided the first experimental evidence as it produced a disease close to vCJD in humans (2). Strain typing in inbred mice (consisting of measuring the incubation period and establishing lesion profiles corresponding to the strain-specific distribution of brain vacuolation) allows reliable identification of TSE strains (3). This method, together with biochemical methods, has revealed a single phenotype for the agents ofBSE and the British cases of vCJD (4-6). Mice expressing only the bovine prion protein (PrP) were highly susceptible to vCJD and BSE, which induced the same disease (7). Thus, it is now well established that BSE has caused vCJD, probably by alimentary contamination. In this respect,the finding of abnormal PrP labeling in the gastrointestinal tract and lymphatic tissues of orally BSE-contaminated lemurs shows that the BSE agent can infect primates by the oral route (8). About 1 million contaminated cattle may have entered the human food chain, and thefuture number of vCJD cases could range from 63 to 136,000 depending on the incubation period of BSE in humans (9). Unlike sporadic CJD (sCJD) and iatrogenic CJD (iCJD) linked to the administration of contaminated growth hormone extracted from human hypophyses, in vCJD, the infectious agent seems to be widely distributed in lymphoid organs, as pathological PrP (PrPres) can be detected in tonsils, lymph nodes, spleen, and appendix even in the preclinical phase of the disease (10, 11). This raises a public health issue with regard to the risk of iatrogenic transmission of vCJD through surgical instruments, grafts, blood transfusion, or parenteral administration of biological products of human origin. However, this risk is difficult to assess, because it largely depends on factors such as the virulence of the BSE agent adapted to primates and the efficiency of secondary transmission to humans by a peripheral route such as the i.v. one. A further issue is whether vCJD accidentally acquired from humans would be recognized. The latter poses the question of a phenotypic variation of the BSE agentafter successive transmissions in humans: does it retain its strain characteristics, and does it induce a pathology similar to that observed in the previous host? A 9-year history of transmission of BSE to primates and mice enables us today to clarify a number of these important points. Although BSE has mainly affected the U.K., two definite cases and one probable case of vCJD have now been reported in France in people who have never resided in the U.K. (12, 13). We strain-typed the first of these cases to establish its origin. Strain typing in C57BL/6 mice of BSE, French, and British vCJD was compared with that of BSE passaged in nonhuman primates, thus allowing us to study the effect of serial passages in primates. Comparisons were also made with French cases of sCJD and iCJD and two strains of scrapie (one of French and one of U.S. origin).
Our findings provide experimental demonstration that the same agent, namely that responsible for the cattle disease BSE, has causedvCJD both in France and in the U.K., in line with biochemical data and with the fact that, until 1996, about 10% of the beef consumed in France was imported from the U.K. We found that the BSE agent in nonhuman primates is similar to that causing vCJD in humans and tends to evolve rapidly toward a primate-adapted variant.
Furthermore, we showed that the strain responsible for iCJD is closely related to that of one patient with sCJD, and, more unexpectedly, that these agents were similar to the French scrapie strain studied (but different from theU.S. scrapie strain). This finding requires a cautious interpretation for several reasons, not least because of the inevitably limited number of TSE strains that can be studied by such a cumbersome method as straintyping. Nonetheless, it also prompts reconsideration of the possibility that, in some instances, sheep and human TSEs can share a common origin.
snip...
http://www.pnas.org/cgi/content/full/041490898v1
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 ScrapieA]
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 duringthe 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 ofAgriculture 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 one 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 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
Subject: FSIS NOTICE SAMPLE COLLECTION FROM CATTLE UNDER THE BOVINESPONGIFORM ENCEPHALOPATHY (BSE)ONGOING SURVEILLANCE PROGRAMFrom: "Terry S. Singeltary Sr."Reply-To: Sustainable Agriculture Network Discussion GroupDate: Fri, 2 Feb 2007 17:32:58 -0600
http://lists.ifas.ufl.edu/cgi-bin/wa.exe?A2=ind0702&L=sanet-mg&P=720
ABSTRACTS SPORADIC CJD AND H BASE MAD COW ALABAMA AND TEXAS SEPTEMBER 2007 Date: Mon, 24 Sep 2007 21:31:55 -0500
I suggest that you all read the data out about h-BASE and sporadic CJD, GSS,blood, and some of the other abstracts from the PRION2007. ...
http://lists.ifas.ufl.edu/cgi-bin/wa.exe?A2=ind0709&L=sanet-mg&T=0&F=&S=&P=19744
*** PLEASE READ AND UNDERSTAND THE RAMIFICATIONS OF THIS !!!
THE PRICE OF POKER INDEED GOES UP. ...TSS
USA BASE CASE, (ATYPICAL BSE), AND OR TSE (whatever they are calling it today), please note that both the ALABAMA COW, AND THE TEXAS COW, both were''H-TYPE'', personal communication Detwiler et al Wednesday, August 22, 200711:52 PM. ...TSS
http://lists.ifas.ufl.edu/cgi-bin/wa.exe?A2=ind0708&L=sanet-mg&T=0&P=19779
see full text 143 pages ;
http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf
Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518
ATYPICAL NOR-98 SCRAPIE LOCATION UPDATE ON 5 DOCUMENTED CASES THIS YEAR ;
The flocks of origin are WY, CO, CA, IN, and MN.
personal communication USDA et al. ...TSS
USA NOR-98 SCRAPIE UPDATE AUGUST 31, 2007 RISES TO 5 DOCUMENTED CASES
http://nor-98.blogspot.com/
Government Accountability Project
https://www.blogger.com/comment.g?blogID=3995372399492420922&postID=295754279213239559
TSS
Subject: NOR-98 SCRAPIE UPDATE AUGUST 31, 2007 (RISES TO 5 DOCUMENTED CASES IN USA)
Date: October 9, 2007 at 7:15 am PST
Greetings, seems the NOR-98 atypical scrapie cases are the rise in the USA. ...tss
INFECTED AND SOURCE FLOCKS AS of August 31, 2007, there were 33 scrapie infected and source flocks with open statuses (Figure 3). Five new source flocks and one new infected flock were reported n August (Figure 4) with a total of 64 reported for FY 2007(Figure 5).
snip...
IN FY 2007 TWO FIELD CASES, ONE VALIDATION CASE, AND TWO RSSS CASES WERE CONSISTENT WITH NOR-98 SCRAPIE. ...
(BRINGS A TOTAL OF 5 NOR-98 CASES DOCUMENTED IN 2007 IN USA. ...TSS)
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/monthly_scrapie_rpt.pps
please note sporadic cjd cases on the rise with 'unknown type' increasing drastically. ...tss
NOW, why in the world is no one much speaking about the lates 3 cases of theNOR-98 case in the USA, and what are the potential ramifications thereof;
Subject: Aspects of the Cerebellar Neuropathology in Nor98
Date: September26, 2007 at 4:06 pm PST
P03.141
Aspects of the Cerebellar Neuropathology in Nor98
Gavier-Widén, D1; Benestad, SL2; Ottander, L1; Westergren, E1 1NationalVeterinary 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 studyhere presented aimed at adding information on the neuropathology in the cerebellum of Nor98 naturally affected sheep of various genotypes in Swedenand 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 thegranule cell layer and in the white matter.
*** The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.
http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf
what does the Nobel Prize Winner Stanely Prusiner say about atypical scrapie, lets look at that first ;
Published online before print October 20, 2005Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0502296102Medical Sciences
A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes
( sheep prion transgenic mice )Annick Le Dur *, Vincent Béringue *, Olivier Andréoletti , Fabienne Reine *,Thanh Lan Laï *, Thierry Baron , Bjørn Bratberg ¶, Jean-Luc Vilotte ,Pierre Sarradin **, Sylvie L. Benestad ¶, and Hubert Laude **Virologie Immunologie Moléculaires and Génétique Biochimique etCytogénétique, Institut National de la Recherche Agronomique, 78350Jouy-en-Josas, France; Unité Mixte de Recherche, Institut National de laRecherche Agronomique-Ecole Nationale Vétérinaire de Toulouse, InteractionsHôte Agent Pathogène, 31066 Toulouse, France; Agence Française de SécuritéSanitaire des Aliments, Unité Agents Transmissibles Non Conventionnels,69364 Lyon, France; **Pathologie Infectieuse et Immunologie, InstitutNational de la Recherche Agronomique, 37380 Nouzilly, France; and¶Department of Pathology, National Veterinary Institute, 0033 Oslo, Norway
Edited by Stanley B. Prusiner, University of California, San Francisco, CA,and approved September 12, 2005 (received for review March 21, 2005)
Scrapie in small ruminants belongs to transmissible spongiform encephalopathies (TSEs), or prion diseases, a family of fatal neurodegenerative disorders that affect humans and animals and can transmit within and between species by ingestion or inoculation. Conversion of the host-encoded prion protein (PrP), normal cellular PrP (PrPc), into amisfolded form, abnormal PrP (PrPSc), plays a key role in TSE transmission and pathogenesis. The intensified surveillance of scrapie in the European Union, together with the improvement of PrPSc detection techniques, has led to the discovery of a growing number of so-called atypical scrapie cases. These include clinical Nor98 cases first identified in Norwegian sheep on the basis of unusual pathological and PrPSc molecular features and "cases" that produced discordant responses in the rapid tests currently applied tothe large-scale random screening of slaughtered or fallen animals. Worryingly, a substantial proportion of such cases involved sheep with PrP genotypes known until now to confer natural resistance to conventional scrapie. Here we report that both Nor98 and discordant cases, including three sheep homozygous for the resistant PrPARR allele (A136R154R171), efficiently transmitted the disease to transgenic mice expressing ovine PrP, and that they shared unique biological and biochemical features upon propagation in mice. These observations support the view that a truly infectious TSE agent, unrecognized until recently, infects sheep and goatflocks and
may have important implications in terms of scrapie control andpublic health.
--------------------------------------------------------------------------------
Author contributions: H.L. designed research; A.L.D., V.B., O.A., F.R.,T.L.L., J.-L.V., and H.L. performed research; T.B., B.B., P.S., and S.L.B.contributed new reagents/analytic tools; V.B., O.A., and H.L. analyzed data;and H.L. wrote the paper.A.L.D. and V.B. contributed equally to this work.To whom correspondence should be addressed.Hubert Laude,
E-mail: laude@jouy.inra.fr
www.pnas.org/cgi/doi/10.1073/pnas.0502296102
http://www.pnas.org/cgi/content/abstract/0502296102v1
OF COURSE, the USDA et al once was concerned for human health from typical scrapie, and rightly so, typical scrapie transmits to primates by there NON-FORCED ORAL CONSUMPTION ;
76/10.12/4.6
http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf
J Infect Dis. 2004 Aug 1;190(3):653-60.
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.
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=6997404&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus
ALSO, The agent responsible for French iatrogenic growth hormone-linked CJD taken as a control is very different from vCJD but is similar to that found in one case of sporadic CJD and one sheep scrapie isolate.
http://www.pnas.org/cgi/content/full/041490898v1
SO, in my opinion, the _myth_ that typical scrapie does not transmit to humans, is just that, a myth. there have never been transmission studies done on man, and I would bet my last bottom dollar, anyone making the statement, would not eat a handful of scrapie infected brains. you do know about james alford don't you, whether or not it was the sheep brains he was fed in the middle east, or something else, this war hero has cjd, and he is very young. this was a tragic story too. dont hear much of that now either. ...
http://www.blackfive.net/main/2004/10/a_dying_hero_ss.html
http://www.blackfive.net/main/2004/03/ssg_james_alfor.html
PLEASE NOTE IN USA CJD UPDATE AS AT JUNE 2007, please note steady increase in
''TYPE UNKNOWN''. ...TSS
1 Acquired in the United Kingdom; 2 Acquired in Saudi Arabia; 3 Includes 17 inconclusive and 9 pending (1 from 2006, 8from 2007); 4 Includes 17 non-vCJD type unknown (2 from 1996, 2 from 1997, 1 from 2001, 1 from 2003, 4 from 2004, 3 from 2005, 4 from 2006) and 36 type pending (2 from 2005, 8 from 2006, 26 from 2007)
http://www.cjdsurveillance.com/pdf/case-table.pdf
TSS
From: "Terry S. Singeltary Sr."
Sent: Tuesday, August 21, 2007 9:50 AM
Subject: TWO MORE Nor98 atypical Scrapie cases detected in USA bringingtotal to 3 cases to date
Infected and Source Flocks As of June 30, 2007, there were .....
snip...
One field case and one validation case were consistent with Nor-98 scrapie.
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/monthly_scrapie_rpt.pps
IN the February 2007 Scrapie report it only mentions; ''One case was consistent with Nor98 scrapie.''
http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/
(please note flocks of origin were in WY, CO, AND CA. PERSONAL COMMUNCATIONS USDA, APHIS, VS ET AL. ...TSS)
NOR98 SHOWS MOLECULAR FEATURES REMINISCENT OF GSS
http://lists.ifas.ufl.edu/cgi-bin/wa.exe?A2=ind0708&L=sanet-mg&T=0&P=14553
An evaluation of scrapie surveillance in the United States
http://lists.ifas.ufl.edu/cgi-bin/wa.exe?A2=ind0708&L=sanet-mg&T=0&P=3427
FOIA REQUEST FOR ATYPICAL TSE INFORMATION ON VERMONT SHEEP
http://lists.ifas.ufl.edu/cgi-bin/wa.exe?A2=ind0708&L=sanet-mg&T=0&P=10451
NEW SCIENTIST MAGAZINE 4/02/01
NEW SCIENTIST EDITORIAL PAGE 3MAD SHEEP DISEASE?
IF THERE is one categorical pronouncement you can safely make about prion diseases like BSE or CJD, it is that one should not make categorical pronouncements. "British beef is safe" and "there is no BSE in Germany" come to mind. Now there are two more: "scrapie is safe", and "people don't catch sporadic CJD". Scrapie is the most widespread prion disease, infecting untold numbers of sheep worldwide. Sporadic CJD is theold-fashioned pre-BSE kind that is supposed to happen spontaneously in unlucky people. But a surprise observation in France suggests some sCJD cases--though by no means all--maybe linked to scrapie after all (see p 4). For years, British authorities asserted that BSE was harmless because it was a form of scrapie. In fact, the only evidence scrapie is safe is some broad-brush epidemiology, good as far as it goes but unable to reveal occasional risks for some people from some sheep. Alarm bells should have rung in 1980 when researchers gave monkeys scrapie by feeding them infected brains. But that research, like so much other work on prion diseases, was never followed up. We still have little idea what BSE does in pigs and chickens. The Queniborough vCJD outbreak (see p 5) would be easier to understand if we knew how much brain we must eat to be infected. As for scrapie, it shouldn't take a chance finding to tell us that there may be dangerous sheep out there.
Suspect symptoms
What if you can catch old-fashioned CJD by eating meat from a sheep infected with scrapie?
Exclusive from New Scientist magazine
Four years ago, Terry Singeltary watched his mother die horribly from a degenerative brain disease.................
full text url follows
By Debora MacKenzie
Suspect Symptoms
http://www.newscientist.com/channel/health/bse/mg16922840.300
if url dead, go here for 'SUSPECT SYMPTOMS'
you can access article here also;
http://www.mad-cow.org/UKCJD/CJD_news52.html#29%20Mar%2001%20-%20CJD%20-%20Suspect%20symptoms
http://www.organicconsumers.org/meat/scrapiecjd.cfm
Then follow up with PNAS studies from which new scientist article written from;
Published online before print March 20, 2001
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.041490898
Abstract of this ArticleReprint (PDF) Version of this ArticleSimilar articles found in:
PNAS OnlinePubMedPubMed CitationSearch Medline for articles by:
Lasmézas, C. I. Deslys, J.-P.Alert me when: new articles cite this article Download to Citation Manager Neurobiology
Adaptation of the bovine spongiform encephalopathy agent to primates andcomparison with Creutzfeldt- Jakob disease: Implications for human health
Corinne Ida Lasmézas*, [dagger] , Jean-Guy Fournier*, Virginie Nouvel*,Hermann Boe*, Domíníque Marcé*, François Lamoury*, Nicolas Kopp [Dagger] , Jean-Jacques Hauw§, James Ironside¶, Moira Bruce [] , DominiqueDormont*, and Jean-Philippe Deslys** Commissariat à l'Energie Atomique, Service de Neurovirologie,Direction des Sciences du Vivant/Département de Recherche Medicale,Centre de Recherches du Service de Santé des Armées 60-68, Avenue duGénéral Leclerc, BP 6, 92 265 Fontenay-aux-Roses Cedex, France; [Dagger] Hôpital Neurologique Pierre Wertheimer, 59, Boulevard Pinel, 69003Lyon, France; § Laboratoire de Neuropathologie, Hôpital de laSalpêtrière, 83, Boulevard de l'Hôpital, 75013 Paris, France; ¶Creutzfeldt-Jakob Disease Surveillance Unit, Western General Hospital,Crewe Road, Edinburgh EH4 2XU, United Kingdom; and [] Institute forAnimal Health, Neuropathogenesis Unit, West Mains Road, Edinburgh EH93JF, United KingdomEdited by D. Carleton Gajdusek, Centre National de la RechercheScientifique, Gif-sur-Yvette, France, and approved December 7, 2000(received for review October 16, 2000)
Abstract
There is substantial scientific evidence to support the notion that bovine spongiform encephalopathy (BSE) has contaminated human beings, causing variant Creutzfeldt-Jakob disease (vCJD). This disease has raised concerns about the possibility of an iatrogenic secondary transmission to humans, because the biological properties of the primate-adapted BSE agent are unknown. We show that (i) BSE can be transmitted from primate to primate by intravenous route in 25 months, and (ii) an iatrogenic transmission of vCJD to humans could be readily recognized pathologically, whether it occurs by the central or peripheral route. Strain typing in mice demonstrates that the BSE agent adapts to macaques in the same way as it does to humans and confirms that the BSE agent is responsible for vCJD not only in the United Kingdom but also in France. The agent responsible for French iatrogenic growth hormone-linked CJD taken as a control is very different from vCJD but is similar to that found in one case of sporadic CJD and one sheep scrapie isolate. These data will be key in identifying the origin of human cases of prion disease, including accidental vCJD transmission, and could provide bases for vCJD risk assessment.
Introduction
The recognition of a variant of the human transmissible spongiform encephalopathy (TSE) Creutzfeldt-Jakob Disease (vCJD) in the U.K. in 1996 raised the major concern that it would correspond to human infection with the agent responsible for bovine spongiform encephalopathy (BSE; ref. 1). Transmission of BSE to macaques provided the first experimental evidence as it produced a disease close to vCJD in humans (2). Strain typing in inbred mice (consisting of measuring the incubation period and establishing lesion profiles corresponding to the strain-specific distribution of brain vacuolation) allows reliable identification of TSE strains (3). This method, together with biochemical methods, has revealed a single phenotype for the agents ofBSE and the British cases of vCJD (4-6). Mice expressing only the bovine prion protein (PrP) were highly susceptible to vCJD and BSE, which induced the same disease (7). Thus, it is now well established that BSE has caused vCJD, probably by alimentary contamination. In this respect,the finding of abnormal PrP labeling in the gastrointestinal tract and lymphatic tissues of orally BSE-contaminated lemurs shows that the BSE agent can infect primates by the oral route (8). About 1 million contaminated cattle may have entered the human food chain, and thefuture number of vCJD cases could range from 63 to 136,000 depending on the incubation period of BSE in humans (9). Unlike sporadic CJD (sCJD) and iatrogenic CJD (iCJD) linked to the administration of contaminated growth hormone extracted from human hypophyses, in vCJD, the infectious agent seems to be widely distributed in lymphoid organs, as pathological PrP (PrPres) can be detected in tonsils, lymph nodes, spleen, and appendix even in the preclinical phase of the disease (10, 11). This raises a public health issue with regard to the risk of iatrogenic transmission of vCJD through surgical instruments, grafts, blood transfusion, or parenteral administration of biological products of human origin. However, this risk is difficult to assess, because it largely depends on factors such as the virulence of the BSE agent adapted to primates and the efficiency of secondary transmission to humans by a peripheral route such as the i.v. one. A further issue is whether vCJD accidentally acquired from humans would be recognized. The latter poses the question of a phenotypic variation of the BSE agentafter successive transmissions in humans: does it retain its strain characteristics, and does it induce a pathology similar to that observed in the previous host? A 9-year history of transmission of BSE to primates and mice enables us today to clarify a number of these important points. Although BSE has mainly affected the U.K., two definite cases and one probable case of vCJD have now been reported in France in people who have never resided in the U.K. (12, 13). We strain-typed the first of these cases to establish its origin. Strain typing in C57BL/6 mice of BSE, French, and British vCJD was compared with that of BSE passaged in nonhuman primates, thus allowing us to study the effect of serial passages in primates. Comparisons were also made with French cases of sCJD and iCJD and two strains of scrapie (one of French and one of U.S. origin).
Our findings provide experimental demonstration that the same agent, namely that responsible for the cattle disease BSE, has causedvCJD both in France and in the U.K., in line with biochemical data and with the fact that, until 1996, about 10% of the beef consumed in France was imported from the U.K. We found that the BSE agent in nonhuman primates is similar to that causing vCJD in humans and tends to evolve rapidly toward a primate-adapted variant.
Furthermore, we showed that the strain responsible for iCJD is closely related to that of one patient with sCJD, and, more unexpectedly, that these agents were similar to the French scrapie strain studied (but different from theU.S. scrapie strain). This finding requires a cautious interpretation for several reasons, not least because of the inevitably limited number of TSE strains that can be studied by such a cumbersome method as straintyping. Nonetheless, it also prompts reconsideration of the possibility that, in some instances, sheep and human TSEs can share a common origin.
snip...
http://www.pnas.org/cgi/content/full/041490898v1
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 ScrapieA]
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 duringthe 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 ofAgriculture 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 one 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 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
Subject: FSIS NOTICE SAMPLE COLLECTION FROM CATTLE UNDER THE BOVINESPONGIFORM ENCEPHALOPATHY (BSE)ONGOING SURVEILLANCE PROGRAMFrom: "Terry S. Singeltary Sr."Reply-To: Sustainable Agriculture Network Discussion GroupDate: Fri, 2 Feb 2007 17:32:58 -0600
http://lists.ifas.ufl.edu/cgi-bin/wa.exe?A2=ind0702&L=sanet-mg&P=720
ABSTRACTS SPORADIC CJD AND H BASE MAD COW ALABAMA AND TEXAS SEPTEMBER 2007 Date: Mon, 24 Sep 2007 21:31:55 -0500
I suggest that you all read the data out about h-BASE and sporadic CJD, GSS,blood, and some of the other abstracts from the PRION2007. ...
http://lists.ifas.ufl.edu/cgi-bin/wa.exe?A2=ind0709&L=sanet-mg&T=0&F=&S=&P=19744
*** PLEASE READ AND UNDERSTAND THE RAMIFICATIONS OF THIS !!!
THE PRICE OF POKER INDEED GOES UP. ...TSS
USA BASE CASE, (ATYPICAL BSE), AND OR TSE (whatever they are calling it today), please note that both the ALABAMA COW, AND THE TEXAS COW, both were''H-TYPE'', personal communication Detwiler et al Wednesday, August 22, 200711:52 PM. ...TSS
http://lists.ifas.ufl.edu/cgi-bin/wa.exe?A2=ind0708&L=sanet-mg&T=0&P=19779
see full text 143 pages ;
http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf
Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518
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