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From: TSS ()
Subject: Re: Chronic wasting disease of elk and deer and Creutzfeldt-Jakob disease: Comparative analysis of the scrapie prion protein
Date: December 18, 2005 at 9:31 am PST

In Reply to: Chronic wasting disease of elk and deer and Creutzfeldt-Jakob disease: Comparative analysis of the scrapie prion protein posted by TSS on December 13, 2005 at 4:14 pm:


----- Original Message -----
From: "Terry S. Singeltary Sr."
To: "Jim Woodward" ; "'Shu Chen'"
Sent: Sunday, December 18, 2005 9:51 AM
Subject: Re: Human resistance to scrapie?


> Greetings Jim and Dr. Chen,
>
>
> as far as amplification and transmission, this is not rocket science, just
> junk science and or denial $ ;-)
> there are plenty of references in science 'sound science' to show that
> indeed the potential for scrapie transmission
> to man (who knows which strain of scrapie or all of them) is as real is as
> BSE or CWD. to continue with the myth
> that scrapie will not transmit to humans, under the pretence of 200 years of
> scrapie and no documented transmision
> to humans, is like saying that we have never had BSE/TSE in USA cattle herds
> until Dec. 2003. it's simply not true.
> the truth is they never looked until then, thus it was never documented. two
> different things, not here and not documented.
>
>
> but just look at the science just off the top of my head here, and then try
> referencing scrapie transmission studies to
> humans and or primates to dispute it. ......TSS
>
>
> Gerald Wells: Report of the Visit to USA, April-May 1989
>
> snip...
>
> The general opinion of those present was that BSE, as an
> overt disease phenomenon, _could exist in the USA, but if it did,
> it was very rare. The need for improved and specific surveillance
> methods to detect it as recognised...
>
> snip...
>
> It is clear that USDA have little information and _no_ regulatory
> responsibility for rendering plants in the US...
>
> snip...
>
> 3. Prof. A. Robertson gave a brief account of BSE. The US approach
> was to accord it a _very low profile indeed_. Dr. A Thiermann showed
> the picture in the ''Independent'' with cattle being incinerated and thought
> this was a fanatical incident to be _avoided_ in the US _at all costs_...
>
> snip...
>
> http://www.bseinquiry.gov.uk/files/mb/m11b/tab01.pdf
>
> To be published in the Proceedings of the
> Fourth International Scientific Congress in
> Fur Animal Production. Toronto, Canada,
> August 21-28, 1988
>
> Evidence That Transmissible Mink Encephalopathy
> Results from Feeding Infected Cattle
>
> R.F. Marsh* and G.R. Hartsough
>
> .Department of Veterinary Science, University of Wisconsin-Madison, Madison,
> Wisconsin 53706; and ^Emba/Creat Lakes Ranch Service, Thiensville, Wisconsin
> 53092
>
> ABSTRACT
> Epidemiologic investigation of a new incidence of
> transmissible mink encephalopathy (TME) in Stetsonville, Wisconsin
> suggests that the disease may have resulted from feeding infected
> cattle to mink. This observation is supported by the transmission of
> a TME-like disease to experimentally inoculated cattle, and by the
> recent report of a new bovine spongiform encephalopathy in
> England.
>
> INTRODUCTION
>
> Transmissible mink encephalopathy (TME) was first reported in 1965 by
> Hartsough
> and Burger who demonstrated that the disease was transmissible with a long
> incubation
> period, and that affected mink had a spongiform encephalopathy similar to
> that found in
> scrapie-affecied sheep (Hartsough and Burger, 1965; Burger and Hartsough,
> 1965).
> Because of the similarity between TME and scrapie, and the subsequent
> finding that the
> two transmissible agents were indistinguishable (Marsh and Hanson, 1969), it
> was
> concluded that TME most likely resulted from feeding mink scrapie-infecied
> sheep.
> The experimental transmission of sheep scrapie to mink (Hanson et al., 1971)
> confirmed the close association of TME and scrapie, but at the same time
> provided
> evidence that they may be different. Epidemiologic studies on previous
> incidences of
> TME indicated that the incubation periods in field cases were between six
> months and
> one year in length (Harxsough and Burger, 1965). Experimentally, scrapie
> could not be
> transmitted to mink in less than one year.
> To investigate the possibility that TME may be caused by a (particular
> strain of
> scrapie which might be highly pathogenic for mink, 21 different strains of
> the scrapie
> agent, including their sheep or goat sources, were inoculated into a total
> of 61 mink.
> Only one mink developed a progressive neurologic disease after an incubation
> period of
> 22 mon..s (Marsh and Hanson, 1979). These results indicated that TME was
> either caused
> by a strain of sheep scrapie not yet tested, or was due to exposure to a
> scrapie-like agent
> from an unidentified source.
>
> OBSERVATIONS AND RESULTS
>
> A New Incidence of TME. In April of 1985, a mink rancher in Stetsonville,
> Wisconsin
> reported that many of his mink were "acting funny", and some had died. At
> this time, we
> visited the farm and found that approximately 10% of all adult mink were
> showing
> typical signs of TME: insidious onset characterized by subtle behavioral
> changes, loss of
> normal habits of cleanliness, deposition of droppings throughout the pen
> rather than in a
> single area, hyperexcitability, difficulty in chewing and swallowing, and
> tails arched over
> their _backs like squirrels. These signs were followed by progressive
> deterioration of
> neurologic function beginning with locomoior incoordination, long periods of
> somnolence
> in which the affected mink would stand motionless with its head in the
> corner of the
> cage, complete debilitation, and death. Over the next 8-10 weeks,
> approximately 40% of
> all the adult mink on the farm died from TME.
> Since previous incidences of TME were associated with common or shared
> feeding
> practices, we obtained a careful history of feed ingredients used over the
> past 12-18
> months. The rancher was a "dead stock" feeder using mostly (>95%) downer or
> dead dairy
> cattle and a few horses. Sheep had never been fed.
>
> Experimental Transmission. The clinical diagnosis of TME was confirmed by
> histopaihologic examination and by experimental transmission to mink after
> incubation
> periods of four months. To investigate the possible involvement of cattle in
> this disease
> cycle, two six-week old castrated Holstein bull calves were inoculated
> intracerebrally
> with a brain suspension from affected mink. Each developed a fatal
> spongiform
> encephalopathy after incubation periods of 18 and 19 months.
>
> DISCUSSION
> These findings suggest that TME may result from feeding mink infected cattle
> and
> we have alerted bovine practitioners that there may exist an as yet
> unrecognized
> scrapie-like disease of cattle in the United States (Marsh and Hartsough,
> 1986). A new
> bovine spongiform encephalopathy has recently been reported in England
> (Wells et al.,
> 1987), and investigators are presently studying its transmissibility and
> possible
> relationship to scrapie. Because this new bovine disease in England is
> characterized by
> behavioral changes, hyperexcitability, and agressiveness, it is very likely
> it would be
> confused with rabies in the United Stales and not be diagnosed. Presently,
> brains from
> cattle in the United States which are suspected of rabies infection are only
> tested with
> anti-rabies virus antibody and are not examined histopathologically for
> lesions of
> spongiform encephalopathy.
> We are presently pursuing additional studies to further examine the possible
> involvement of cattle in the epidemiology of TME. One of these is the
> backpassage of
> our experimental bovine encephalopathy to mink. Because (here are as yet no
> agent-
> specific proteins or nucleic acids identified for these transmissible
> neuropathogens, one
> means of distinguishing them is by animal passage and selection of the
> biotype which
> grows best in a particular host. This procedure has been used to separate
> hamster-
> adapted and mink-udapted TME agents (Marsh and Hanson, 1979). The
> intracerebral
> backpassage of the experimental bovine agent resulted in incubations of only
> four months
> indicating no de-adaptation of the Stetsonville agent for mink after bovine
> passage.
> Mink fed infected bovine brain remain normal after six months. It will be
> essential to
> demonstrate oral transmission fiom bovine to mink it this proposed
> epidemiologic
> association is to be confirmed.
>
> ACKNOWLEDGEMENTS
> These studies were supported by the College of Agricultural and Life
> Sciences,
> University of Wisconsin-Madison and by a grant (85-CRCR-1-1812) from the
> United
> States Department of Agriculture. The authors also wish to acknowledge the
> help and
> encouragement of Robert Hanson who died during the course of these
> investigations.
>
> REFERENCES
> Burger, D. and Hartsough, G.R. 1965. Encephalopathy of mink. II.
> Experimental and
> natural transmission. J. Infec. Dis. 115:393-399.
> Hanson, R.P., Eckroade, R.3., Marsh, R.F., ZuRhein, C.M., Kanitz, C.L. and
> Gustatson,
> D.P. 1971. Susceptibility of mink to sheep scrapie. Science 172:859-861.
> Hansough, G.R. and Burger, D. 1965. Encephalopathy of mink. I.
> Epizoociologic and
> clinical observations. 3. Infec. Dis. 115:387-392.
> Marsh, R.F. and Hanson, R.P. 1969. Physical and chemical properties of
> the
> transmissible mink encephalopathy agent. 3. ViroL 3:176-180.
> Marsh, R.F. and Hanson, R.P. 1979. On the origin of transmissible mink
> encephalopathy. In Hadlow, W.J. and Prusiner, S.P. (eds.) Slow
> transmissible
> diseases of the nervous system. Vol. 1, Academic Press, New York, pp
> 451-460.
> Marsh, R.F. and Hartsough, G.R. 1986. Is there a scrapie-like disease in
> cattle?
> Proceedings of the Seventh Annual Western Conference for Food Animal
> Veterinary
> Medicine. University of Arizona, pp 20.
> Wells, G.A.H., Scott, A.C., Johnson, C.T., Cunning, R.F., Hancock, R.D.,
> Jeffrey, M.,
> Dawson, M. and Bradley, R. 1987. A novel progressive spongiform
> encephalopathy
> in cattle. Vet. Rec. 121:419-420.
>
> MARSH
>
> http://www.bseinquiry.gov.uk/files/mb/m09/tab05.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
> 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
>
>
> Like lambs to the slaughter
> 31 March 2001
> Debora MacKenzie
> Magazine issue 2284
> What if you can catch old-fashioned CJD by eating meat from a sheep infected
> with scrapie?
> 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 ...
>
> The complete article is 889 words long.
>
> full text;
>
> http://www.newscientist.com/article.ns?id=mg16922840.300
>
>
>
> Neurobiology
> Adaptation of the bovine spongiform encephalopathy agent to primates and
> comparison with Creutzfeldt- Jakob disease: Implications for human health
> Corinne Ida Lasmézas*,, Jean-Guy Fournier*, Virginie Nouvel*, Hermann Boe*,
> Domíníque Marcé*, François Lamoury*, Nicolas Kopp, Jean-Jacques Hauw§, James
> Ironside¶, Moira Bruce, Dominique Dormont*, 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 du Général Leclerc,
> BP 6, 92 265 Fontenay-aux-Roses Cedex, France; Hôpital Neurologique Pierre
> Wertheimer, 59, Boulevard Pinel, 69003 Lyon, France; § Laboratoire de
> Neuropathologie, Hôpital de la Salpêtrière, 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 for Animal Health, Neuropathogenesis Unit, West Mains Road,
> Edinburgh EH9 3JF, United Kingdom
>
> Edited by D. Carleton Gajdusek, Centre National de la Recherche
> Scientifique, Gif-sur-Yvette, France, and approved December 7, 2000
> (received for review October 16, 2000)
>
>
> Abstract
> Top
> Abstract
> Introduction
> Materials and Methods
> Results
> Discussion
> Conclusions
> References
> 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.
>
>
> http://www.pnas.org/cgi/content/full/041490898v1TSS
>
>
> 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. 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_ui
> ds=12690798&dopt=Abstract
>
> ------------------------------------------------------------------------
>
> 1: Eur J Epidemiol 1991 Sep;7(5):520-3
> > =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_ui
> ds=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: 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, Sobel 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_ui
> ds=6997404&dopt=Abstract
>
>
>
>
> Approved-By: tom
> Message-ID:
> Date: Mon, 19 Jul 1999 11:21:25 -0800
> Reply-To: Bovine Spongiform Encephalopathy
> Sender: Bovine Spongiform Encephalopathy
> From: tom
> Subject: iatrogenic scrapie from sheep dura mater?
> Someone kindly sent me the full text of a very curious 1993 Lancet article.
> This is available from the Ovid service -- Lancet itself ironically does not
> offer an electronic version this far back.
>
> An orthopaedic surgeon employed by the lyodura company [Braun Melsungen]
> extracted dura mater from sheep and human cadavers and came down with fast
> CJD 22 years later. The ratio of sheep to human dura mater he collected
> was150 sheep to 12 humans. Apparently the surgeon and the sheep were German.
> Scrapie has long been present in Germany but reported levels are very low,
> about a flock a year has to be destroyed. I am not aware of any high
> sensitivity tests or random screening every being used in Germany to assess
> the levels of preclinical animals.
>
> This raises the question, what did the lyodura company do with so much dura
> mater from sheep? The market for specialty surgical products was
> overwelmingly in humans in 1968. The Lancet article only says it was for
> research -- but in what species? Perhaps dura mater gives an immune
> response across species after processing, ruling out its use in humans.
> But as far as I know, blood type or other genetic differences do not matter
> within humans, ie, there is no tissue matching with dura mater.
>
> I always wondered how CJD could show up from a handful of human dura mater
> donations with sporadic CJD supposedly so rare -- on the other hand, there
> would be no surprise at all if a case of subclinical scrapie showed up in
> 150 sheep.
>
> This raises the question, have dura mater recipients or the surgeon
> subsequently been strain-typed? This might give a very different outcome
> than other forms of iatrogenic CJD or simply co-classify with pituitary
> growth hormone if route of infection (injected, oral, hereditary, etc.) is
> more important than strain source.
>
> Otherwise, iatrogenic scrapie (like cwdCJD) is somwhat unpredictable in its
> gel pattern (though strains of scrapie in other primate species might be
> re-examined). The original scrapie strain is not be identifiable directly
> because material was not likely retained. Strain-typing was not available
> at the time of the article -- but Collinge was one of the authors.
>
> There is little doubt that scrapie could be transfered to humans by
> intracerebral injection (based on lack of species barrier in primates) and
> that processed pooled (human?) dura mater can carry sufficient infectivity
> to cause CJD. I am not aware of animal experiments that specifically used
> sheep dura mater as experimental dose source.
>
>
> tom
>
> -=-=-=-=-=-=-
>
>
> Transmission of Creutzfeldt-Jakob disease by handling of dura mater.
> The Lancet Volume 341(8837) January 9, 1993 pp
> 123-124
> Weber, Thomas; Tumani, Hayrettin; Holdorff, Bernd; Collinge, John; Palmer,
> Mark; Kretzschmar, Hans A.; Felgenhauer, Klaus
>
>
> Sir,- Creutzfeldt-Jakob disease (CJD) can be transmitted iatrogenically by
> human pituitary growth hormone, corneal transplants, and dura mater grafts
> (1). Possible accidental transmission has been reported in only four
> people-a neurosurgeon (2), a pathologist (3), and two laboratory technicians
> (4,5) . We have encountered an unusually rapid case of CJD probably acquired
> through handling of sheep and human dura mater.
> In May, 1992, a 55-year-old orthopaedic surgeon developed paraesthesia of
> the left arm. A few days later he had spatial disorientation, apraxia, and
> gait ataxia. In June he was admitted and a neurologist suspected CJD on the
> basis of the clinical signs, typical electroencephalogram (EEG) pattern, and
> history. An EEG in June revealed a typical pattern of periodic biphasic and
> triphasic sharp wave complexes. We saw the patient in July, 1992. He was
> awake and oriented, with dyscalculia, dysgraphia, disturbed vision, apraxia
> mainly of the left side, rigidity of wrists, spasticity of all muscles,
> myoclonus of the left arm, increased tendon reflexes, ataxia of limbs and
> trunk, and incoordination of left arm. Within 3 weeks he had impaired
> consciousness and attention, mildly impaired memory, and threatening visual
> hallucinations with restless turning. He had periodic states with movements
> of his head and eye-bulbs resembling tonic adversive seizures. During sleep
> these motor disturbances stopped. 2 1/2 months later the patient died.
>
> This patient had worked with sheep and human dura mater from 1968 to 1972.
> He handled about 150 specimens of ovine origin and at least a dozen human
> preparations for research. Handling involved opening skulls with a band saw,
> removing dura, and testing them either fresh (usually), preserved, or
> lyophilised for mechanical qualities. These specimens were sent to a company
> that has sold dura mater preparations by which CJD was transmitted in six
> instances. No information was available from the company about a possible
> connection with this patient's disease and the earlier cases of transmitted
> CJD. Brain biopsy was consistent with diagnosis of CJD. Cerebrospinal fluid
> obtained in July showed neuron-specific enolase (NSE) at 82.0 ng/mL,
> compared with 16.7 ng/mL in serum of other cases (6). Proton magnetic
> resonance spectroscopy of parieto-occipital and temporal grey matter,
> parietal white matter, and thalamus revealed a 20-30% reduction of
> N-acetylaspartate, as described (7). DNA was genotyped with allele-specific
> oligonucleotides (8) and was homozygous for methionine at the polymorphic
> codon 129. Subsequent direct DNA sequencing for the PrP gene open-reading
> frame demonstrated normal sequence on both alleles, excluding known or novel
> pathogenic PrP mutations.
>
> It is tempting to speculate that prions were transmitted to this patient
> from sheep or human dura mater through small lacerations of his skin, but
> the patient and his wife did not remember any significant injury during his
> four years of working with these samples. It cannot be excluded that this
> was a case of sporadic CJD although this assumption is unlikely in view of
> the clinical course which was similar to iatrogenic CJD transmitted by
> peripheral inoculation, such as with human pituitary growth hormone or
> gonadotropin or to kuru (1). Iatrogenic cases resulting from intracerebral
> inoculation with the transmissible agent, for instance following dura mater
> grafts (2-5), present with a dementing picture, as is usual in sporadic CJD,
> rather than with ataxia as in this case.
>
>
> 1. Brown P, Preece MA, Will RG. "Friendly fire" in medicine: hormones,
> homografts, and Creutzfeldt-Jakob disease. Lancet 1992; 340: 24-27. [Medline
> Link] [Context Link]
>
> 2. Schoene WC, Masters CL, Gibbs CJ Jr, et al. Transmissible spongiform
> encephalopathy (Creutzfeldt-Jakob Disease): atypical clinical and
> pathological findings. Arch Neurol 1981; 38: 473-77. [Medline Link] [Context
> Link]
>
> 3. Gorman DG, Benson DF, Vogel DG, Vinters HV. Creutzfeldt-Jakob disease in
> a pathologist. Neurology 1992; 42: 463. [Medline Link] [Context Link]
>
> 4. Miller DC. Creutzfeldt-Jakob disease in histopathology technicians. N
> Engl J Med 1988; 318: 853-54. [Medline Link] [Context Link]
>
> 5. Sitwell L, Lach B, Atack E, Atack D, Izukawa D. Creutzfeldt-Jakob disease
> in histopathology technicians. N Engl J Med 1988; 318: 854. [Medline Link]
> [Context Link]
>
> 6. Wakayama Y, Shibuya S, Kawase J, Sagawa F, Hashizume Y. High
> neuron-specific enolase level of cerebrospinal fluid in the early stage of
> Creutzfeldt-Jakob disease. Klin Wochenschr 1987; 65: 798-801. [Medline Link]
> [Context Link]
>
> 7. Bruhn H, Weber T, Thorwirth V, Frahm J. In-vivo monitoring of neuronal
> loss in Creutzfeldt-Jakob disease by proton magnetic resonance spectroscopy.
> Lancet 1991; 337: 1610-11. [Medline Link] [Context Link]
>
> 8. Collinge J, Palmer MS, Dryden AJ. Genetic predisposition to iatrogenic
> Creutzfeldt-Jakob disease. Lancet 1991; 337: 1444-42. [Medlin
>
> Issues raised by a subsequent comment letter seem dubious at best in the
> case of this surgeon:
>
>
> Ridley: Lancet, Volume 341(8845).Mar 6, 1993.pp 641-642.
> The Lancet Volume 341(8845) Mar 6, 1993 pp 641-642
>
> Occupational risk of Creutzfeldt-Jakob disease.
> [Letters to the Editor]
> Ridley, R.M.; Baker,H.F.
> Division of Psychiatry, Clinical Research Centre, Harrrow, Middlesex HA1
> 3UJ, UK.
>
>
> Sir,- Readers should be cautious about Dr Weber and colleagues' (Jan 9, p
> 123) suggestion that occupational transmission of Creutzfeldt-Jakob disease
> (CJD) may have taken place in a neurosurgeon, a pathologist, 2 histology
> technicians, and an orthopaedic surgeon. Large epidemiological surveys
> (1,2) have failed to find a link between occupation and CJD. This disease
> has been reported in several people working in occupations in which exposure
> to neural tissue could have happened (eg, butchers, farmers, and various
> health professionals (3) ) but the number of these cases is not in excess
> of that which would be expected by random association. In the absence of a
> clear excess of cases, as has occurred in the iatrogenic transmission of
> spongiform encephalopathy by exposure to human derived growth hormone (4),
> the occurrence of CJD in people from the medical and paramedical professions
> is no more remarkable than its occurence in people of any other profession.
> Brown et al (1) rep!
> orted six cases among clerics, but this does not necessarily implicate their
> occupation in their ultimate demise.
>
> The notion that CJD is always acquired (as opposed to idiopathic) and that
> the existence of any hypothetical risk factor must therefore be the cause of
> the disease led to the much cited claim that the high incidence of CJD among
> Libyan Jews was due to their consumption of sheep's eyeballs (5), despite a
> lack of evidence that their dietary habits differed from their ethnic
> neighbours in whom no increased incidence of this disease was recorded. The
> high frequency of CJD in the Libyan Jews is now known to be due to a codon
> 200 mutation in the PrP gene in affected families in that ethnic group (6).
>
> CJD is a peculiar disease that does not fit into any single pattern of
> distribution. The great majority of cases cannot be attributed to
> environmental exposure. Very particular precautions are required to prevent
> transmission from cases of human and animal spongiform encephalopathy since,
> when this does occur, a major outbreak of disease can arise. Under these
> circumstances it is especially important that the occurrence of CJD is
> viewed from an epidemiological rather than an anecdotal perspective.
>
> REFERENCES
>
> 1. Brown P, Cathala F, Raubertas RF, et al. The epidemiology of
> Creutzfeldt-Jakob: conclusion of a 15-year investigation in France and a
> review of the world literature. Neurology 1987; 37: 895-904. [Medline
> Link] [Context Link]
>
> 2. Harries-Jones R, Knight R, Will RG, et al. Creutzfeldt-Jakob disease in
> England and Wales, 1980-1984; a case control study of potential risk
> factors. J Neurol Neurosurg Psychiatry 1988; 51: 1113-19. [Medline Link]
> [Context Link]
>
> 3. Masters CL, Harris JO, Gajdusek C, et al. Creutzfeldt-Jakob disease:
> patterns of worldwide occurrence and the significance of familial and
> sporadic clustering. Ann Neurol 1978; 5: 177-88. [Medline Link] [Context
> Link]
>
> 4. Brown P, Gajdusek C, Gibbs CJ, Asher DM. Potential epidemic of
> Creutzfeldt-Jakob disease from human growth hormone therapy. N Engl J Med
> 1985; 313: 728-31. [Medline Link] [Context Link]
>
> 5. Kahana E, Alter M, Braham J, Sofer D. Creutzfeldt-Jakob disease: focus
> among Libyan Jews in Israel. Science 1974; 183: 90-91. [Medline Link]
> [Context Link]
>
> 6. Hsiao K, Meiner Z, Kahana E, et al. Mutation of the prion protein in
> Libyan Jews with Creutzfeldt-Jakob disease. N Engl J Med 1991; 324: 1091-97.
>
>
> ----------------------------------------------------------------------------
> ----
>
>
>
>
> Approved-By: "Roland Heynkes @ T-Online"
> Message-ID: <006a01bed26b$d48e9400$31be9ec1@pentium>
> Date: Mon, 19 Jul 1999 23:28:00 +0200
> Reply-To: Bovine Spongiform Encephalopathy
> Sender: Bovine Spongiform Encephalopathy
> From: "Roland Heynkes @ T-Online"
> Subject: Re: iatrogenic scrapie from sheep dura mater?
> Dear Tom,
>
> >An orthopaedic surgeon employed by the lyodura company [Braun Melsungen]
> >extracted dura mater from sheep and human cadavers and came down with
> >fast CJD 22 years later.
> >
> the article does not say that he was an employee of Braun Melsungen, but
> sent et least some of the lyodoras to the company. Do you have additional
> information from one of the authors and do you know if the company got
> the ovine dura maters too?
>
> >Scrapie has long been present in Germany but reported levels are very
> >low, about a flock a year has to be destroyed. I am not aware of any
> >high sensitivity tests or random screening every being used in Germany
> >to assess the levels of preclinical animals.
> >
> I don't know if the Groschup group in Tuebingen does use a sensitive
> scrapie test like the dutch test in order to perform a random screening
> program. When I asked last time a few years ago, they "only" tested animals
> with unclear neurological symptoms.
> Scrapie still occurs in Germany, but we have less than one recorded case
> per year.
>
> >This raises the question, what did the lyodura company do with so much
> >dura mater from sheep? The market for specialty surgical products was
> >overwelmingly in humans in 1968. The Lancet article only says it was for
> >research -- but in what species?
> >
> Are you sure that this research with the ovine dura mater has been done
> at Braun Melsungen?
>
> best regards
>
> Roland Heynkes
>
> Erkwiesenstr. 19
> D-52072 Aachen (Germany)
> Tel.: +49 (0)241/932070
> Fax: +49 (0)241/932071
> email: roland.heynkes@t-online.de
> http://home.t-online.de/home/Roland.Heynkes
>
>
> ----------------------------------------------------------------------------
> ----
>
>
>
>
> Approved-By: tom
> Message-ID:
> Date: Tue, 20 Jul 1999 11:48:17 -0800
> Reply-To: Bovine Spongiform Encephalopathy
> Sender: Bovine Spongiform Encephalopathy
> From: tom
> Subject: Re: iatrogenic scrapie from sheep dura mater?
> In-Reply-To: <006a01bed26b$d48e9400$31be9ec1@pentium>
>
> >
> >>An orthopaedic surgeon employed by the lyodura company [Braun Melsungen]
> >>extracted dura mater from sheep and human cadavers and came down with
> >>fast CJD 22 years later.
> >>
> >the article does not say that he was an employee of Braun Melsungen, but
> >sent et least some of the lyodoras to the company. Do you have additional
> >information from one of the authors and do you know if the company got
> >the ovine dura maters too?
>
> I really do not know any more at this time than what was in the article.
> The way I read it, he was not an internal employee but an independent
> orthopaedic surgeon who had a contract to supply dura mater to the company.
> The victim's wife may be able to supply details, however the family name is
> not given.
>
> >
> >>Scrapie has long been present in Germany but reported levels are very
> >>low, about a flock a year has to be destroyed. I am not aware of any
> >>high sensitivity tests or random screening every being used in Germany
> >>to assess the levels of preclinical animals.
> >>
> >I don't know if the Groschup group in Tuebingen does use a sensitive
> >scrapie test like the dutch test in order to perform a random screening
> >program. When I asked last time a few years ago, they "only" tested animals
> >with unclear neurological symptoms.
> >Scrapie still occurs in Germany, but we have less than one recorded case
> >per year.
>
> Sure. According to this, it was a bit of extraordinary bad luck that any of
> 150 sheep + 12 humans could have carried the disease, but we know not to
> equate recorded cases with incidence. Portugal had very few recorded cases
> per year of BSE too.
>
> In your opinion, how exactly has it been possible for scrapie to persist in
> Germany for all these decades at this vanishingly small level? Cases are
> probably not geographically or farm-exchange linked. Surely the
> authorities don't allow live imports from England.
>
> >
> >>This raises the question, what did the lyodura company do with so much
> >>dura mater from sheep? The market for specialty surgical products was
> >>overwelmingly in humans in 1968. The Lancet article only says it was for
> >>research -- but in what species?
> >>
> >Are you sure that this research with the ovine dura mater has been done
> >at Braun Melsungen?
>
> I would guess that they did not do the research there but sold it to the
> marketplace. Perhaps you could give the German authors a call (Weber,
> Thomas; Tumani, Hayrettin; Holdorff, Bernd all in Hamburg I think) I will
> shop around on Internet catalogues, see which companies today sell sheep
> dura mater for research (my guess is no one).
>
> It is annoying that so many details relevent to interpretation were left out
> of the paper. Still, any forward tracing of the dura mater will soon hit a
> brick wall at the company, Braun Melsungen- B. Carl-Braun-Str. 1
> D-34212 Melsungen Germany Tel: ++49 5661 - 71-1739, Fax: ++49 5661 -
> 71-1632. If any humans received sheep dura mater, I doubt that this will be
> disclosed or that specific recipients will be identified to their doctors.
> It is probably better to trace backwards from affected recipients -- see if
> they strain-type out to be sheep.
>
> Japan has been particularly hard hit by dura mater CJD (curious in itself)
> and researchers there might be motivated to find out what happened. I am
> not aware of agricultural agencies that would impede research over there.
>
> tom
>
> P.S. The US would never think of pooling dura mater in the same container.
> However, even after the lyodura experience, apparently we thought it safe to
> use the same rinse water on 26 consecutive dura mater donations:
>
> Creutzfeldt-Jakob Disease (CJD) in a Recipient of a U.S.-Processed Dura
> Mater Graft: Cause or Coincidence? Belay E.D.1, Dobbins, J.G.1, Malecki,
> J.2, Buck, B.E.3, Bell, M.1, Cobb, J.2, Schonberger, L.B.1, 1Centers for
> Disease Control and Prevention (CDC), Atlanta, GA; 2Palm Beach County Health
> Department, West Palm Beach, FL; 3Department of Orthopedics and
> Rehabilitation, University of Miami School of Medicine, Miami, FL.
> http://www.life.umd.edu/jifsan/tse/belay.htm
>
> In 1997, CDC was notified about a 72-year-old man who developed CJD 54
> months after he received a dura mater graft during removal of a meningioma.
> CDC confirmed that CJD diagnosis was based on standard clinical criteria,
> including typical electroencephalographic changes. Investigation of patients
> who underwent craniotomy within 4 months before or after the case-patient's
> surgery revealed no evidence for nosocomial transmission of CJD. The dura
> donor was a previously healthy 34-year-old man with no known risk factors
> fore CJD who had died in a motor vehicle collision. The dura was processed
> in the United States with no direct contact with other dura. However,
> possible indirect contact through water used to rinse dural grafts from
> about 25 other donors simultaneously could not be ruled out; tracing of
> recipients of these grafts is in progress. If this case-patient remains the
> only recipient of a U.S.-processed dural graft with CJD, then this graft-CJD
> association is more likely to be coincidental than causal. This report
> underscores the potential importance of recent recommendations to minimize
> the risk of CJD transmission by such grafts, including neuropathologic
> screening of all donors and removal of opportunities for cross-contamination
> among grafts.
>
>
>
> IA#84-03 --- 6/27/87
> http://www.fda.gov/ora/fiars/ora_import_ia8403.html
>
> BACKGROUND
>
> A recent reported case of Creutzfeldt-Jakob Disease (CJD) in a 28 year-old
> patient who had received a human dura mater graft indicates that the graft
> may
> have been the source of this always fatal disease. The woman died 22 months
> after receiving the lyophilized, irradiated human cadaveric dura mater
> graft.
> The dura mater used in the graft was packaged in October 1982 under lot
> #2105
> by B. Braun Melsungen AG of West Germany, shipped to Tri Hawk International,
> Inc., Montreal, Quebec, Canada and sold to Saint Francis Hospital, Hartford,
> Connecticut, on April 4, 1985.
>
> This is the first known case of CJD transmission associated with a dura
> mater
> graft. Present methods of sterilizing the dura mater do not completely
> inactivate the CJD agent.
>
> The dura mater is manufactured by the West German firm under the trade name
> Lyodura. Although the material is primarily used in neurosurgery, it is
> also
> used in orthopedic, otologic, dental, urologic, gynecologic, and cardiac
> surgical procedures.
>
> We have been unable to determine the total number of packages of Lyodura
> that
> were imported into the United States because the Canadian distributor failed
> to maintain adequate records of distribution for all lots which may have
> been
> distributed by mail to hospitals in the United States and Canada.
>
> As stated in the FDA Safety Alert which issued April 28, 1987, we strongly
> recommend that users of dura mater choose only products from known sources
> which retrieve, process and handle the material according to guidelines such
> as those of the American Association of Tissue Banks.
>
> To report cases or for further information, please contact:
>
> Gordon C. Johnson, M.D.
> Center for Devices and Radiological Health
> Food and Drug Administration
> 8757 Georgia Ave,
> Silver Spring, Maryland 20910
>
>
> GUIDANCE
>
> Alert your local Customs office to be aware of this import alert and to
> monitor mail shipments for this product.
>
> Detain all shipments of Lyodura (dura mater) received from Tri Hawk
> International, Inc., Montreal, Quebec, Canada or from B. Braun Melsungen AG
> of
> West Germany. Charge: "The article is subject to refusal of admission
> pursuant to section 801(a)(1) in that it appears to be adulterated under
> section 501(h), because the methods and controls used for the storage and
> distribution of Lyodura (dura mater) are not in conformance with current
> good
> manufacturing practice requirements under section 520(f)(1)."
>
> -=-=-=-=-
>
> DR. MARTIN ZEIDLER:
> http://www.life.umd.edu/jifsan/tse/zeidler.htm
> 8 June 1998
>
> Thank you very much and I'd like to start this by thanking JIFSAN for kindly
> inviting me here today.
>
> I became involved in the whole issue of Creutzfeldt-Jakob disease and dura
> mater grafts about a year ago when I had the good fortune to be working with
> the World Health Organization. It was at this time that WHO had a
> consultation addressing the issue of safety of medicinal and other products
> in relation to human and animal TSEs. This meeting recommended that dura
> mater grafts could no longer be used, which caused some controversy and I
> was involved in the debate which ensued with various dura mater
> manufacturers....
>
> So, what is dura mater? Well, it's the outer covering of the meninges, this
> is the fibrous sheath which encircles the central nervous system. It really
> has two functions, first, to keep the spinal fluid in, and, second, to stop
> infection from getting into the central nervous system. Surgical procedures
> or trauma that broach the dura mater may result in a hole, that because of
> the fibrous, inelastic nature of dura, may not be possible shut by primary
> closure. If the defect is to be filled, perhaps the obvious tissue to do
> this is a dural graft.
>
> Since the 1950s, dura mater grafts have been utilised ; some of the first
> grafts came from the U.S. Navy's Medical School here in the United States.
> The popularity of dural grafts came to the fore in the 1970s and 1980s when
> they were commercially produced. It appeared that surgeons were actually
> very happy with these particular materials - they provided a good barrier to
> infection and stopped the leakage of CSF.
>
> It was in 1987 that the first case was reported of a person with CJD who
> had previously been known to have received a dura mater graft. The patient
> was a 28-year-old woman who had an operation 18 months previously to remove
> a cholesteatoma and she subsequently developed histologically confirmed CJD.
> To date I've managed to find a total of 83 case reports of dura mater
> related CJD cases, and I am grateful Dr Paul Brown for providing me with
> data. There are 3 additions to the number which Paul mentioned during his
> talk earlier, although these three cases are slightly questionable. Two of
> these were reported from France, and both had undergone embolisation
> procedures with dura mater rather than receiving a conventional graft. The
> third case is from Thailand and has not yet been pathologically confirmed.
>
> The clinical phenotype of patients with dura mater-associated CJD is similar
> to that seen in the classical sporadic form of CJD: rapidly progressive
> dementia, myoclonus, and in the majority of patients a characteristic EEG.
> However, there are some differences: dura-associated cases tend to have more
> prominent early cerebellar symptoms and a somewhat more prolonged clinical
> course. In sporadic CJD the median illness duration is 4 1/2 months and this
> is doubled on average in dura mater cases. The age at onset is about 10-15
> years younger on average than we see with sporadic CJD.
>
> I think the youngest dura mater case documented was 16 or 17. The average
> incubation period from the time the patient received their graft to onset of
> their illness is approximately 6 years, but ranges from 16 months to 16
> years. Although most of these cases have arisen through the use of dura
> mater for cranial surgery, there are some cases which have been known to
> have resulted from ear, nose and throat surgery or from spinal surgery. Two
> cases from France, as mentioned, followed embolism procedures, in one case
> the patient had a nasopharyngeal tumor and dura mater was cut up into lots
> of little pieces and injected into the external carotid artery to embolise
> this, and in the other case the dura mater was inoculated into an artery in
> the chest to embolise an area of infection.
>
> I would like to just go back and show you the countries which are known to
> have had dura mater cases of CJD. Most of the reports come from Japan, and
> we were rather surprised at the WHO consultation last year in Geneva, to
> hear reports from Dr Tateishi of a recent study conducted in Japan which had
> shown the presence of 43 cases of dura mater CJD.
>
> I think you will agree looking at the slide that the other cases have been
> reported really quite widely throughout the world. Virtually all of these
> patients received one particular form of dura mater graft that was
> commercially manufactured by a single German company. The product was called
> Lyodura, and most of the patients had received grafts that had been
> manufactured during a 4 year period between 1983 and 1987. Lyodura was
> pooled during this time, so there was a potential for cross contamination
> and the sterilization procedures used involved 10% hydrogen peroxide for 24
> hours and ionizing radiation. Subsequent animal experiments have shown that
> this is not an adequate form of sterilization.
>
> An important question is whether any of the dura mater cases were recipients
> of grafts that were treated with more thorough and adequate sterilisation.
> By this, I mean treatment with 1N sodium hydroxide, which is in the standard
> step which was introduced in the treatment of Lyodura after 1987. There are
> four cases out of this series of 83 which perhaps I'll talk about in a
> little bit more detail. Two cases were clearly not Lyodura. These were
> locally procured grafts, one from Italy and the other from the United
> Kingdom - these were used between 1969 and 1981.
>
> Furthermore, there was the a recently reported case from America which we
> heard about yesterday. Perhaps the case of most interest is one from the
> Japanese series. This was a lady in her mid-60s who received a graft in 1991
> and later developed clinically probable CJD, but this was not histologically
> confirmed. The hospital records did not note whether or not her graft was
> Lyodura or the other form of dura used in that hospital at that time. It was
> concluded in the report of the Japanese cases that it was unlikely that this
> patient had received Lyodura produced before 1987.
>
> So the possibility exists that this patient had received a form of dura
> which was considered to be adequately sterilised. It is important to note
> two points, first, as this case did not undergo histological examination the
> diagnosis of CJD is not 100% certain, and second, we can not be absolutely
> sure that in this or some of the of other 82 cases that the history of
> receiving a dural mater graft is coincidental. In none of these cases is
> there data which tells if the graft donor had CJD.
>
> Following the announcement of the first case here in the United States,
> doctors in the United Kingdom, Australia and New Zealand decided that they
> were going to use alternatives to cadaveric dura homografts, and here in the
> States I believe there was an importation ban on Lyodura.
>
> So what alternatives are there to cadaveric-derived dura? There are
> several - I'll just run through these. One of the most popular is fascia
> lata, this is the fibrous covering of the lateral thigh muscle. The removal
> of this can add about 30 minutes to the length of the operation and of
> course leaves a wound which, as with all wounds, can potentially become
> infected or have other complications.
>
> Other alternatives include pericranium (the covering of the skull bone),
> temporalis fascia (the membrane which surrounds the temporalis muscle at the
> side of the head) and synthetic materials - a number of such materials have
> been tried over the years including gold foils, cellophane, and dacron
> grafts. However, there has been some concern about the safety of synthetic
> materials and neurosurgeons have felt that these were rather inferior,
> although I think with the newer materials that's not so clearly the case. I
> should note that there is no controlled trial that has ever been conducted
> to answer the question as to whether or not these substitutes are better or
> worse than cadaveric-derived dura.
>
> I think there are two key questions that need to be addressed, first, are
> there situations where cadaveric dura is better than available alternatives?
> If the answer is no then we need to question why we are using cadaveric
> dural grafts at all. If the answer is yes, then the next question is how can
> dura be made as safe as possible? I'd like to show you some of the report
> from the WHO meeting over a year ago. I'll read it to you.
>
> "Because over 50 cases of CJD have resulted from cadaveric dura mater
> grafts, the group strongly recommended that dura mater no longer be used,
> especially in the case of neurosurgery, unless no alternative is available.
> If dura mater is to be used, only material which is from non-pooled sources
> originating from carefully screened donors subjected to validated
> inactivated treatment should be considered."
>
> Following this recommendation the Japanese authorities decided that they
> were no longer going to issue a license for the use of dura mater and the
> TSE Advisory Committee here in the States met again to discuss the issue of
> dura mater. I just want to run through their recommendations, there were
> some differences from WHO's: although they also discouraged use of dura
> mater, the final decision on its usage was left up to the individual
> physicians, but certain additional safeguards were put into place.
>
> For instance, it was felt mandatory that for every donor a full brain
> autopsy should be performed and examined histologically and with
> immunocytochemistry, which is probably the most sensitive method that we
> have, other than transmission studies. It was further recommended that a
> sample of the dura and the brain should be kept for further testing as
> needed.
>
> Additionally, standard protocols for determining donors eligibility and
> tissue procurement were recommended, and dura should be collected before the
> brain at autopsy - which obviously makes sense to avoid contamination of the
> graft. Furthermore, decontamination with 1N sodium hydroxide for one hour
> should be used. This had previously been confirmed by Paul Brown and
> colleagues to be an effective decontamination procedure. There should be no
> pooling of grafts, to prevent cross-contamination and there should be
> documentation to allow tracking from the donor to the recipient and from the
> recipients to the donor. I think there can be little doubt that if these
> recommendations are adopted, then the safety of dura mater grafts will be
> dramatically improved.
>
> However, I would like to just play the devil's advocate here and to mention
> a few cautions. We know from animal experiments that infectivity can predate
> any pathological changes and this includes immunocytological changes as
> well. We also know that standard decontamination procedures using sodium
> hydroxide, as David Taylor mentioned yesterday, may not completely be
> effective. I think we have to remember that dura is a potentially high-risk
> material, and that studies also performed by David Taylor have shown that
> dura mater can have 106 ID50 per gram. Perhaps through the use of current
> decontamination procedures we will produce grafts which are much safer than
> those previously used, with but with low-level residual infectivity which
> may lead to disease with a potentially long incubation period. (For TSE
> agents it is known that dose administered is inversely proportional to
> incubation period)...
>
>
> http://www.life.umd.edu/jifsan/tse/brown.htm
>
> 3 corneal
> 2 sterotactic
> 4 neurosurgery
> 80 dura mater
> 106 growth hormone
> ...25 US (includes 5 New Zealand + 1 Brazilian case using US-prepared
> hormone)
> ...28 UK
> ...53 France
> 4 gonadotrophin Approved-By: "Roland Heynkes @ T-Online"
>
> Message-ID: <001601bed3c7$60a91940$0f2d9c3e@pentium>
> Date: Wed, 21 Jul 1999 11:33:00 +0200
> Reply-To: Bovine Spongiform Encephalopathy
> Sender: Bovine Spongiform Encephalopathy
> From: "Roland Heynkes @ T-Online"
> Subject: Re: iatrogenic scrapie from sheep dura mater?
> Dear Tom,
>
> >>>An orthopaedic surgeon employed by the lyodura company [Braun Melsungen]
> >>>extracted dura mater from sheep and human cadavers and came down with
> >>>fast CJD 22 years later.
> >
> >>the article does not say that he was an employee of Braun Melsungen, but
> >>sent et least some of the lyodoras to the company. Do you have additional
> >>information from one of the authors and do you know if the company got
> >>the ovine dura maters too?
> >
> >I really do not know any more at this time than what was in the article.
> >The way I read it, he was not an internal employee but an independent
> >orthopaedic surgeon who had a contract to supply dura mater to the company.
> >The victim's wife may be able to supply details, however the family name
> >is not given.
> >
> Perhaps the journal's editors were happy to demonstrate with this ambiguous
> letter the advantages of peer reviewing.
>
> >>>Scrapie has long been present in Germany but reported levels are very
> >>>low, about a flock a year has to be destroyed. I am not aware of any
> >>>high sensitivity tests or random screening every being used in Germany
> >>>to assess the levels of preclinical animals.
> >
> >>I don't know if the Groschup group in Tuebingen does use a sensitive
> >>scrapie test like the dutch test in order to perform a random screening
> >>program. When I asked last time a few years ago, they "only" tested
> animals
> >>with unclear neurological symptoms.
> >>Scrapie still occurs in Germany, but we have less than one recorded case
> >>per year.
> >
> >Sure. According to this, it was a bit of extraordinary bad luck that any
> >of 150 sheep + 12 humans could have carried the disease, but we know not
> >to equate recorded cases with incidence. Portugal had very few recorded
> >cases per year of BSE too.
> >
> Of course the incidence must be higher than the number of recorded cases
> and the Lelystad-scrapie-test should be used in order to approach the real
> incidence of scrapie in Germany. But in Germany sheep unlike cows are not
> high productivity farm animals that become killed very young and especially
> when their productivity decreases. Therefore in my opinion scrapie infected
> sheep have a good chance to develop symptomes and if a vet observes such
> neurological symptomes, governmental vets including the central German lab
> for scrapie diagnosis in Tuebingen will check it histopathologically.
>
> >In your opinion, how exactly has it been possible for scrapie to persist
> >in Germany for all these decades at this vanishingly small level?
> >
> A good question that I can not answer. One reason may be the use of
> occationally contaminated animal meal. But of course a much higher
> incidence of sublethal infected sheep is also possible.
>
> >Cases are probably not geographically or farm-exchange linked.
> >Surely the authorities don't allow live imports from England.
> >
> Unfortunately importing british sheep has never been forbidden in
> Germany. In my opinion this is extreemly stupid and may be a further
> reason for scrapie in Germany.
>
>
> >>>This raises the question, what did the lyodura company do with so much
> >>>dura mater from sheep? The market for specialty surgical products was
> >>>overwelmingly in humans in 1968. The Lancet article only says it was for
> >>>research -- but in what species?
> >
> >>Are you sure that this research with the ovine dura mater has been done
> >>at Braun Melsungen?
> >
> >I would guess that they did not do the research there but sold it to
> >the marketplace. Perhaps you could give the German authors a call
> >(Weber, Thomas; Tumani, Hayrettin; Holdorff, Bernd all in Hamburg I
> >think)
> >
> Thomas Weber at least was at the Institut for Neurology, University of
> Goettingen, but we have hundreds of Thomas Weber in Germany and at least
> seven around Goettingen. But perhaps I can find an email-address on the
> Institute site.
>
> >It is annoying that so many details relevent to interpretation were
> >left out of the paper. Still, any forward tracing of the dura mater
> >will soon hit a brick wall at the company, Braun Melsungen- B.
> >Carl-Braun-Str. 1 D-34212 Melsungen Germany Tel: ++49 5661 - 71-1739,
> >Fax: ++49 5661 - 71-1632. If any humans received sheep dura mater,
> >I doubt that this will be disclosed or that specific recipients will
> >be identified to their doctors. It is probably better to trace
> >backwards from affected recipients -- see if they strain-type out
> >to be sheep.
> >
> This letter to the editor is indeed of such a low quality that it hardly
> could be worse if it were published on internet instead of a well known
> journal.
>
> >P.S. The US would never think of pooling dura mater in the same container.
> >However, even after the lyodura experience, apparently we thought it safe
> >to use the same rinse water on 26 consecutive dura mater donations:
> >
> unbelievable clever!
>
> best regards
>
> Roland Heynkes
>
> Erkwiesenstr. 19
> D-52072 Aachen (Germany)
> Tel.: +49 (0)241/932070
> Fax: +49 (0)241/932071
> email: roland.heynkes@t-online.de
> http://home.t-online.de/home/Roland.Heynkes
> ----------------------------------------------------------------------------
> ---->Cases are probably not geographically or farm-exchange linked.
> >Surely the authorities don't allow live imports from England.
> >
> Unfortunately importing british sheep has never been forbidden in
> Germany. In my opinion this is extreemly stupid and may be a further
> reason for scrapie in Germany. ...
>
>
>
> 0208h023: UK exports of sheep, goats and sheep/goat meats and meat products
> (1988 - 2001)
>
>
> http://www.vegsource.com/articles/sheep_exports.htm
>
>
>
> Infected and Source Flocks
>
> As of August 31, 2005, there were 115 scrapie infected and source flocks
> (figure 3). There were 3 new infected and source flocks reported in August
> (Figure 4) with a total of 148 flocks reported for FY 2005 (Figure 5). The
> total infected and source flocks that have been released in FY 2005 are 102
> (Figure 6), with 5 flocks released in August. The ratio of infected and
> source flocks released to newly infected and source flocks for FY 2005 =
> 0.69 :
> 1. In addition, as of August 31, 2005, 574 scrapie cases have been confirmed
> and reported by the National Veterinary Services Laboratories (NVSL), of
> which 122 were RSSS cases (Figure 7). This includes 55 newly confirmed cases
> in August 2005 (Figure 8). Fifteen cases of scrapie in goats have been
> reported since 1990 (Figure 9). The last goat case was reported in May 2005.
>
> snip...
>
> full text ;
>
> http://www.aphis.usda.gov/vs/nahps/scrapie/monthly_report/monthly-report.htm
> l
>
>
>
>
> Published online before print October 20, 2005
>
> Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0502296102
> Medical 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 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,
> 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 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.
>
>
>
> ----------------------------------------------------------------------------
> ----
>
> 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
>
>
> TSS
>
>
>
>
> ----- Original Message -----
> From: "Jim Woodward"
> To: "'Shu Chen'"
> Sent: Saturday, December 17, 2005 11:02 PM
> Subject: RE: Human resistance to scrapie?
>
>
> > Dr. Chen,
> >
> > Thanks for your reply. The human lifespan at the end of the eighteenth
> > century was in the mid-30s, and was only about ten years higher at the end
> > of the nineteenth century. That would not seem to be long enough for the
> > onset of scrapie-induced CJD. In fact, CJD was not described as a disease
> > until the 1920s. Is it appropriate to make such a blanket statement about
> > human resistance to scrapie and to dismiss the Marsh experiments?
> >
> > Kind regards,
> >
> > Jim
> >
> >
> >
> > > -----Original Message-----
> > > From: Shu Chen [mailto:shu.chen@case.edu]
> > > Sent: Saturday, December 17, 2005 8:49 AM
> > > To: Jim Woodward
> > > Subject: Re: Human resistance to scrapie?
> > >
> > > Jim,
> > > Thank you for your interest. The resistance of humans to
> > > scrapie is due to the fact that sheep naturally develop
> > > scrapie and consumption of sheep by humans in several
> > > hundreds of years since scrapie is known does not seem to be
> > > a cause for CJD. I have no specific reference on this, but
> > > you may refer to many prion reviews by Prusiner, some of
> > > which may have mentioned this.
> > > Best,
> > > Shu G. Chen, Ph.D.
> > > Institute of Pathology, Rm 406
> > > Case Western Reserve University
> > > 2085 Adelbert Road
> > > Cleveland, OH 44106-4907
> > > 216)368-8925; (216)368-2546-fax
> > > sxc59@cwru.edu
> > >
> > > ----- Original Message -----
> > > From: Jim Woodward
> > > Date: Friday, December 16, 2005 0:41 am
> > > Subject: Human resistance to scrapie?
> > > > Dear Dr. Chen,
> > > >
> > > > I recently read your very interesting paper, CHRONIC
> > > WASTING DISEASE
> > > > OF ELK AND DEER AND CREUTZFELDT-JAKOB DISEASE: COMPARATIVE
> > > ANALYSIS OF
> > > > THE SCRAPIE PRION PROTEIN. Near the end of the discussion section,
> > > > you assert that the transmission of CWD to squirrel monkey
> > > by Marsh,
> > > > et al. is not relevant to the question of human
> > > susceptibility to CWD
> > > > since squirrel monkeys are "very permissive to prions of different
> > > > species including sheep scrapie to which humans are resistant". In
> > > > contrast to the rest of your paper which is carefully
> > > referenced, your
> > > > statement that humans are resistant to scrapie is not
> > > referenced. Was
> > > > this an oversight? Are there data to support thisstatement?
> > > >
> > > > Regards,
> > > >
> > > > Jim Woodward
> > > > Wellington, Colorado
> > > >
> > > >
> > > >
> > >
> >
> >
> >
>



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