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Report of the first oral inoculation of BSE prion UPDATE

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flounder

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Subject: Report of the first oral inoculation of BSE prion UPDATE
Date: January 4, 2006 at 7:00 am PST

[January 04, 2006]


Hokkaido lab may have succeeded in 1st artificial BSE infection+

(Japan Economic Newswire Via Thomson Dialog NewsEdge)SAPPORO, Jan. 4_(Kyodo) _ Japan may have succeeded for the first time in artificially triggering the onset of mad cow disease as several cows inoculated with abnormal prions have shown symptoms of the disease at the Hokkaido Animal Research Center, its official said Wednesday.


The center plans to dissect three of the cows in February to see if they were indeed infected with bovine spongiform encephalopathy. If confirmed, it will be the first successful case of human-induced BSE in Japan, which researchers hope will contribute to further studies of the disease-causing abnormal proteins and cure methods.

According to the prefectural research center, the experiment began in February 2004 when 14 female Holstein calves, kept in an isolated facility, were inoculated in the brain with 0.1 gram of abnormal prions extracted from BSE infected cows.

Researchers kept a close watch on the calves, including their behavior and blood samples. Around the end of last year, several calves began to show early symptoms of the brain-wasting disease such as wobbling and overreacting to sounds, the official said.

"Until now, we have only had (samples from) dead infected cows," the official said. "If it becomes possible to analyze blood and other samples from infected cows that are alive, then we can understand what kinds of changes occur before the infection develops and enable earlier detection of the disease."

Researchers in Britain have already succeeded in similar experiments. Elsewhere in Japan, the National Institute of Animal Health in Ibaraki Prefecture is conducting a similar test by injecting abnormal prions into the stomachs of cows.


http://www.tmcnet.com/usubmit/2006/jan/1260423.htm


Report of the first oral inoculation of BSE prion
into cattle in Japan

Ryoko Irie, Hiroyuki Okada, Hiroko Hayashi, Yoshifumi Iwamaru, Taka-
shi Yokoyama and Morikazu Shinagawa

Prion Disease Research Center, National Institute of Animal Health, 3-1-5
Kannondai, Tsukuba 305-0856 Japan [email protected]

Abstract

A Prion Disease Research Center at the National Institute of Animal
Health (NIAH) was established to conduct comprehensive research on
BSE in response to the discovery of bovine spongiform encephalopathy
(BSE) in Japan. A new research facility for the center has been con-
structed. It was designed as a biosafety level (BSL) 3 facility with the
capacity to inoculate and hold experimental animals. Experiments have
begun to infect cattle with BSE orally. This route of inoculation simu-
lates the feeding of contaminated meat and bone meal that caused pan-
demic occurrence of BSE in the UK. An abnormal isoform of the prion
protein (PrPSc) accumulates in BSE affected cattle. The purpose of this
study is to examine the spread of the abnormal prion from digestive tract to
the central nervous system and to describe the pathological changes in cat-
tle during the course of infection. Atypical BSE and young BSE cases
have been found in the abattoir surveillance program. As a result the cat-
tle used in this experiment were imported from Australia, a country free of
BSE, to exclude the possibility of prior BSE infection before inoculation.
Each calf (Holstein heifer, 10-months old) was inoculated orally with 5g of
brain stem from BSE infected cattle (courtesy provided by Veterinary
Laboratory Agency, Weybridge, UK) into the rumen with a catheter. The
cattle will be euthanized at intervals during the clinical stages of disease.
Infectivity from different tissues at different stages of clinical disease as
well as the deposition of PrPSc will be analyzed. Other factors that may
be related to the pathogenesis of the BSE prion will be investigated.

181

PRIONS
Food and Drug Safety
Springer
T. Kitamoto (Ed.)
TSS
 

Econ101

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Flounder, has there been much success of infection by animal feed in trials? This might be a factor of the ruminant's digestive system like abcesses or something. Don't know, just wondering.
 

rkaiser

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TSS research tells us that -
According to the prefectural research center, the experiment began in February 2004 when 14 female Holstein calves, kept in an isolated facility, were inoculated in the brain with 0.1 gram of abnormal prions extracted from BSE infected cows.

In other words folks, watch for cows with syringes in their posession. They could be inoculating herd mates causing this horrific BSE situation. They seem to be in the know about which cows have abnormal prions (unlike our CFIA or USDA) and are going about sucking bits of brain out of them and injecting it in cows from Washington, Texas, and Alberta. :wink:
 

flounder

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PLEASE read carefully ;


''Experiments have
begun to infect cattle with BSE _orally_.''


''Each calf (Holstein heifer, 10-months old) was inoculated orally with 5g of
brain stem from BSE infected cattle (courtesy provided by Veterinary
Laboratory Agency, Weybridge, UK) into the rumen with a catheter.''



http://www.fda.gov/cvm/FdaVetJulAug2005.htm







> The investigation concluded that the 1997 feed rule, which prohibits the feeding of



> most mammalian protein to cattle and other ruminants, was being followed.



NOT !!!




FOR IMMEDIATE RELEASE
P01-05
January 30, 2001
Print Media: 301-827-6242
Consumer Inquiries: 888-INFO-FDA



--------------------------------------------------------------------------------

Note: On Dec. 23, 2003, the U.S. Department of Agriculture reported that a cow in Washington state had tested positive for bovine spongiform encephalopathy (BSE, or mad cow disease). As a result, information on this Web page stating that no BSE cases had been found in the United States is now incorrect. However, because other information on this page continues to have value, the page will remain available for viewing.

FDA ANNOUNCES TEST RESULTS FROM TEXAS FEED LOT


Today the Food and Drug Administration announced the results of tests taken on feed used at a Texas feedlot that was suspected of containing meat and bone meal from other domestic cattle -- a violation of FDA's 1997 prohibition on using ruminant material in feed for other ruminants. Results indicate that a very low level of prohibited material was found in the feed fed to cattle.

FDA has determined that each animal could have consumed, at most and in total, five-and-one-half grams - approximately a quarter ounce -- of prohibited material. These animals weigh approximately 600 pounds.

It is important to note that the prohibited material was domestic in origin (therefore not likely to contain infected material because there is no evidence of BSE in U.S. cattle), fed at a very low level, and fed only once. The potential risk of BSE to such cattle is therefore exceedingly low, even if the feed were contaminated.

According to Dr. Bernard Schwetz, FDA's Acting Principal Deputy Commissioner, "The challenge to regulators and industry is to keep this disease out of the United States. One important defense is to prohibit the use of any ruminant animal materials in feed for other ruminant animals. Combined with other steps, like U.S. Department of Agriculture's (USDA) ban on the importation of live ruminant animals from affected countries, these steps represent a series of protections, to keep American cattle free of BSE."

Despite this negligible risk, Purina Mills, Inc., is nonetheless announcing that it is voluntarily purchasing all 1,222 of the animals held in Texas and mistakenly fed the animal feed containing the prohibited material. Therefore, meat from those animals will not enter the human food supply. FDA believes any cattle that did not consume feed containing the prohibited material are unaffected by this incident, and should be handled in the beef supply clearance process as usual.

FDA believes that Purina Mills has behaved responsibly by first reporting the human error that resulted in the misformulation of the animal feed supplement and then by working closely with State and Federal authorities.

This episode indicates that the multi-layered safeguard system put into place is essential for protecting the food supply and that continued vigilance needs to be taken, by all concerned, to ensure these rules are followed routinely.

FDA will continue working with USDA as well as State and local officials to ensure that companies and individuals comply with all laws and regulations designed to protect the U.S. food supply.




--------------------------------------------------------------------------------


http://www.fda.gov/bbs/topics/NEWS/2001/NEW00752.html


NEWS RELEASE

Texas Animal Health Commission

Box l2966 •Austin, Texas 78711 •(800) 550-8242• FAX (512) 719-0719

Linda Logan, DVM, PhD• Executive Director

For info, contact Carla Everett, information officer, at 1-800-550-8242, ext. 710,

or [email protected]

For Immediate Release--

Feed Contamination Issue Resolved by FDA

Although many of you may have heard the latest regarding the resolution of the cattle feed

contamination situation in Texas, I wanted to ensure that you received this statement issued

by the Food and Drug Administration (FDA), the agency in charge of regulating feed

components. The FDA has said the cattle involved are to be rendered and the material will not

enter ruminant or human food channels. The Texas Animal Health Commission (TAHC) will

provided assistance to the FDA as requested and needed.

FDA ANNOUNCES TEST RESULTS FROM TEXAS FEED LOT

Today (Tuesday, Jan. the Food and Drug Administration announced the results of tests taken

on feed used at a Texas feedlot that was suspected of containing meat and bone meal from

other domestic cattle -- a violation of FDA's 1997 prohibition on using ruminant material in

feed for other ruminants. Results indicate that a very low level of prohibited material was

found in the feed fed to cattle.

FDA has determined that each animal could have consumed, at most and in total,

five-and-one-half grams - approximately a quarter ounce -- of prohibited material. These

animals weigh approximately 600 pounds.

It is important to note that the prohibited material was domestic in origin (therefore not likely

to contain infected material because there is no evidence of BSE in U.S. cattle), fed at a very

low level, and fed only once. The potential risk of BSE to such cattle is therefore exceedingly

low, even if the feed were contaminated.

According to Dr. Bernard Schwetz, FDA's Acting Principal Deputy Commissioner, "The

challenge to regulators and industry is to keep this disease out of the United States. One

important defense is to prohibit the use of any ruminant animal materials in feed for other

ruminant animals. Combined with other steps, like U.S. Department of Agriculture's (USDA)

ban on the importation of live ruminant animals from affected countries, these steps represent

a series of protections, to keep American cattle free of BSE."

Despite this negligible risk, Purina Mills, Inc., is nonetheless announcing that it is voluntarily

purchasing all 1,222 of the animals held in Texas and mistakenly fed the animal feed

containing the prohibited material. Therefore, meat from those animals will not enter the

human food supply. FDA believes any cattle that did not consume feed containing the

prohibited material are unaffected by this incident, and should be handled in the beef supply

clearance process as usual.

FDA believes that Purina Mills has behaved responsibly by first reporting the human error

that resulted in the misformulation of the animal feed supplement and then by working

closely with State and Federal authorities.

This episode indicates that the multi-layered safeguard system put into place is essential for

protecting the food supply and that continued vigilance needs to be taken, by all concerned, to

ensure these rules are followed routinely.

FDA will continue working with USDA as well as state and local officials to ensure that

companies and individuals comply with all laws and regulations designed to protect the U.S.

food supply.

---30--



http://www.tahc.state.tx.us/news/pr/2001/101FEED_ISSUE_RESOLVED.pdf



as little as 1 mg (or 0.001 gm) caused 7% (1 of 14) of the cows to come down with BSE



Risk of oral infection with bovine spongiform

encephalopathy agent in primates

Corinne Ida Lasmézas, Emmanuel Comoy, Stephen Hawkins, Christian Herzog, Franck Mouthon, Timm Konold, Frédéric Auvré, Evelyne Correia,

Nathalie Lescoutra-Etchegaray, Nicole Salès, Gerald Wells, Paul Brown, Jean-Philippe Deslys

The uncertain extent of human exposure to bovine spongiform encephalopathy (BSE)—which can lead to variant

Creutzfeldt-Jakob disease (vCJD)—is compounded by incomplete knowledge about the efficiency of oral infection

and the magnitude of any bovine-to-human biological barrier to transmission. We therefore investigated oral

transmission of BSE to non-human primates. We gave two macaques a 5 g oral dose of brain homogenate from a

BSE-infected cow. One macaque developed vCJD-like neurological disease 60 months after exposure, whereas the

other remained free of disease at 76 months. On the basis of these findings and data from other studies, we made a

preliminary estimate of the food exposure risk for man, which provides additional assurance that existing public

health measures can prevent transmission of BSE to man.



snip...



BSE bovine brain inoculum

100 g 10 g 5 g 1 g 100 mg 10 mg 1 mg 0·1 mg 0·01 mg

Primate (oral route)* 1/2 (50%)

Cattle (oral route)* 10/10 (100%) 7/9 (78%) 7/10 (70%) 3/15 (20%) 1/15 (7%) 1/15 (7%)

RIII mice (icip route)* 17/18 (94%) 15/17 (88%) 1/14 (7%)

PrPres biochemical detection

The comparison is made on the basis of calibration of the bovine inoculum used in our study with primates against a bovine brain inoculum with a similar PrPres concentration that was

inoculated into mice and cattle.8 *Data are number of animals positive/number of animals surviving at the time of clinical onset of disease in the first positive animal (%). The accuracy of

bioassays is generally judged to be about plus or minus 1 log. icip=intracerebral and intraperitoneal.

Table 1: Comparison of transmission rates in primates and cattle infected orally with similar BSE brain inocula



snip...



www.thelancet.com Published online January 27, 2005 http://image.thelancet.com/extras/05let1056web.pdf







#1 TEJAS MAD COW THAT WAS NOT TESTED AT ALL!

FDA Statement
FOR IMMEDIATE RELEASE
Statement
May 4, 2004
Media Inquiries: 301-827-6242
Consumer Inquiries: 888-INFO-FDA



Statement on Texas Cow With Central Nervous System Symptoms
On Friday, April 30 th , the Food and Drug Administration learned that a cow with central nervous system symptoms had been killed and shipped to a processor for rendering into animal protein for use in animal feed.

FDA, which is responsible for the safety of animal feed, immediately began an investigation. On Friday and throughout the weekend, FDA investigators inspected the slaughterhouse, the rendering facility, the farm where the animal came from, and the processor that initially received the cow from the slaughterhouse.

FDA's investigation showed that the animal in question had already been rendered into "meat and bone meal" (a type of protein animal feed). Over the weekend FDA was able to track down all the implicated material. That material is being held by the firm, which is cooperating fully with FDA.

Cattle with central nervous system symptoms are of particular interest because cattle with bovine spongiform encephalopathy or BSE, also known as "mad cow disease," can exhibit such symptoms. In this case, there is no way now to test for BSE. But even if the cow had BSE, FDA's animal feed rule would prohibit the feeding of its rendered protein to other ruminant animals (e.g., cows, goats, sheep, bison).

FDA is sending a letter to the firm summarizing its findings and informing the firm that FDA will not object to use of this material in swine feed only. If it is not used in swine feed, this material will be destroyed. Pigs have been shown not to be susceptible to BSE. If the firm agrees to use the material for swine feed only, FDA will track the material all the way through the supply chain from the processor to the farm to ensure that the feed is properly monitored and used only as feed for pigs.

To protect the U.S. against BSE, FDA works to keep certain mammalian protein out of animal feed for cattle and other ruminant animals. FDA established its animal feed rule in 1997 after the BSE epidemic in the U.K. showed that the disease spreads by feeding infected ruminant protein to cattle.

Under the current regulation, the material from this Texas cow is not allowed in feed for cattle or other ruminant animals. FDA's action specifying that the material go only into swine feed means also that it will not be fed to poultry.

FDA is committed to protecting the U.S. from BSE and collaborates closely with the U.S. Department of Agriculture on all BSE issues. The animal feed rule provides crucial protection against the spread of BSE, but it is only one of several such firewalls. FDA will soon be improving the animal feed rule, to make this strong system even stronger.


OOPS!..........TSS


http://www.fda.gov/bbs/topics/news/2004/NEW01061.html



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


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



snip...


Conclusions

From BSE and vCJD transmissions in nonhuman primates, a number of conclusions can be drawn that are of major importance for human health: (i) human-adapted BSE appears to be a variant of the BSE agent that is more virulent for humans than cattle BSE and is efficiently transmitted by the peripheral route; (ii) the detection of vCJD in unusually young patients is probably not because of a lack of diagnosis of cases in older patients, thus raising the question of the source of human contamination with BSE early in life; and (iii) iatrogenic transmissions from patients with vCJD would be readily recognized by using the same diagnostic criteria as those applied to vCJD [clinical and pathological criteria (27) comprising neuronal loss and gliosis in the thalamus correlated with high MRI signal (28, 29)], whether such contaminations had occurred by the central or i.v. route. Primary and iatrogenic cases of vCJD could be distinguished on the basis of the patient's clinical history.

The risk assessment of biological products of human origin, notably those derived from blood, has been deeply modified by the appearance of vCJD. We confirm that the BSE agent has contaminated humans not only in the U.K. and the Republic of Ireland but also in France, and we show that its pathogenic properties for primates are being enhanced by a primary passage in humans. Considering the flow of potentially contaminated bovine-derived products between 1980 and 1996, it is obvious that further vCJD cases may occur outside the U.K. Thus, and in the light of the present study, it is necessary to sustain worldwide CJD surveillance regardless of national BSE incidence and to take all precautionary measures to avoid iatrogenic transmissions from vCJD.


http://www.pnas.org/cgi/content/full/041490898v1



It is clear that the designing scientists must

also have shared Mr Bradley?s surprise at the results because all the dose

levels right down to 1 gram triggered infection.


http://www.bseinquiry.gov.uk/files/ws/s145d.pdf


2

6. It also appears to me that Mr Bradley?s answer (that it would take less
than say 100

grams) was probably given with the benefit of hindsight; particularly if one

considers that later in the same answer Mr Bradley expresses his surprise
that it

could take as little of 1 gram of brain to cause BSE by the oral route
within the

same species. This information did not become available until the "attack
rate"

experiment had been completed in 1995/96. This was a titration experiment

designed to ascertain the infective dose. A range of dosages was used to
ensure

that the actual result was within both a lower and an upper limit within the
study

and the designing scientists would not have expected all the dose levels to
trigger

infection. The dose ranges chosen by the most informed scientists at that
time

ranged from 1 gram to three times one hundred grams. It is clear that the
designing

scientists must have also shared Mr Bradley?s surprise at the results
because all the

dose levels right down to 1 gram triggered infection.


http://www.bseinquiry.gov.uk/files/ws/s147f.pdf


Re: BSE .1 GRAM LETHAL NEW STUDY SAYS via W.H.O. Dr Maura Ricketts

[BBC radio 4 FARM news]

http://www.maddeer.org/audio/BBC4farmingtoday2_1_03.ram

http://www.fda.gov/ohrms/dockets/ac/03/slides/3923s1_OPH.htm


2) Infectious dose:

To cattle: 1 gram of infected brain material (by oral ingestion)

http://www.inspection.gc.ca/english/sci/bio/bseesbe.shtml




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Articles by Lasmézas, C. I.

Journal of Virology, November 2005, p. 14339-14345, Vol. 79, No. 22
0022-538X/05/$08.00+0 doi:10.1128/JVI.79.22.14339-14345.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.


PrPTSE Distribution in a Primate Model of Variant, Sporadic, and Iatrogenic Creutzfeldt-Jakob Disease
Christian Herzog, Julie Rivière, Nathalie Lescoutra-Etchegaray, Aurore Charbonnier, Virginie Leblanc, Nicole Salès, Jean-Philippe Deslys, and Corinne Ida Lasmézas*

Commissariat à l'Energie Atomique, Département de Recherche Médicale, BP6, 92265 Fontenay-aux-Roses, France

Received 13 May 2005/ Accepted 25 August 2005

Human prion diseases, such as Creutzfeldt-Jakob disease (CJD), are neurodegenerative and fatal. Sporadic CJD (sCJD) can be transmitted between humans through medical procedures involving highly infected organs, such as the central nervous system. However, in variant CJD (vCJD), which is due to human contamination with the bovine spongiform encephalopathy (BSE) agent, lymphoreticular tissue also harbors the transmissible spongiform encephalopathy-associated prion protein (PrPTSE), which poses a particularly acute risk for iatrogenic transmission. Two blood transfusion-related cases are already documented. In addition, the recent observation of PrPTSE in spleen and muscle in sCJD raised the possibility that peripheral PrPTSE is not limited to vCJD cases. We aimed to clarify the peripheral pathogenesis of human TSEs by using a nonhuman primate model which mimics human diseases. A highly sensitive enzyme-linked immunosorbent assay was adapted to the detection of extraneural PrPTSE. We show that affected organs can be divided into two groups. The first is peripheral organs accumulating large amounts of PrPTSE, which represent a high risk of iatrogenic transmission. This category comprises only lymphoreticular organs in the vCJD/BSE model. The second is organs with small amounts of PrPTSE associated with nervous structures. These are the muscles, adrenal glands, and enteric nervous system in the sporadic, iatrogenic, and variant CJD models. In contrast to the first set of organs, this low level of tissue contamination is not strain restricted and seems to be linked to secondary centrifugal spread of the agent through nerves. It might represent a risk for iatrogenic transmission, formerly underestimated despite previous reports of low rates of transmission from peripheral organs of humans to nonhuman primates (5, 10). This study provides an additional experimental basis for the classification of human organs into different risk categories and a rational re-evaluation of current risk management measures.



--------------------------------------------------------------------------------

* Corresponding author. Present address: The Scripps Research Institute, Department of Infectology, 33458 Jupiter, FL. Phone: (561) 799-8895. Fax: (561) 799-8960. E-mail: [email protected]




--------------------------------------------------------------------------------



http://jvi.asm.org/cgi/content/abstract/79/22/14339



another frightening potential route and source (remember, we are still in the prehistoric ages of ''detectibility'' and ''sensitivity'' of ''diagnosing'' ANY TSE. ...TSS



Science, Vol 310, Issue 5746, 324-326 , 14 October 2005

[DOI: 10.1126/science.1118829]

Reports
Coincident Scrapie Infection and Nephritis Lead to Urinary Prion Excretion
Harald Seeger,1* Mathias Heikenwalder,1* Nicolas Zeller,1 Jan Kranich,1 Petra Schwarz,1 Ariana Gaspert,2 Burkhardt Seifert,3 Gino Miele,1 Adriano Aguzzi1


Prion infectivity is typically restricted to the central nervous and lymphatic systems of infected hosts, but chronic inflammation can expand the distribution of prions. We tested whether chronic inflammatory kidney disorders would trigger excretion of prion infectivity into urine. Urinary proteins from scrapie-infected mice with lymphocytic nephritis induced scrapie upon inoculation into noninfected indicator mice. Prionuria was found in presymptomatic scrapie-infected and in sick mice, whereas neither prionuria nor urinary PrPSc was detectable in prion-infected wild-type or PrPC-overexpressing mice, or in nephritic mice inoculated with noninfectious brain. Thus, urine may provide a vector for horizontal prion transmission, and inflammation of excretory organs may influence prion spread.

1 Institute of Neuropathology, University Hospital of Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland.
2 Institute of Clinical Pathology, University Hospital of Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland.
3 Institute of Biostatistics, University of Zürich, Sumatrastrasse 30, CH-8006 Zürich, Switzerland.

* These authors contributed equally to this work.

To whom correspondence should be addressed. E-mail: [email protected]



--------------------------------------------------------------------------------

The prion, the infectious agent of transmissible spongiform encephalopathies (TSEs), is detectable at extraneural sites long before clinical symptoms appear (1). PrPSc,



snip...





How do prions enter the urine? Upon extrarenal replication, blood-borne prions may be excreted by a defective filtration apparatus. Alternatively, prions may be produced locally and excreted during leukocyturia. Although prionemia occurs in many paradigms of peripheral prion pathogenesis (15, 16), the latter hypothesis appears more likely, because prionuria was invariably associated with local prion replication within kidneys.

Urine from one CJD patient was reported to elicit prion disease in mice (17, 18), but not in primates (19). Perhaps unrecognized nephritic conditions may underlie these discrepant observations. Inflammation-associated prionuria may also contribute to horizontal transmission among sheep, deer, and elk, whose high efficiency of lateral transmission is not understood.


References and Notes





snip...end



MY favorite study here. please note ;



''by their nonforced consumption of known infectious tissues''



J Infect Dis 1980 Aug;142(2):205-8



Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.

Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.

Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation.

PMID: 6997404
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract


TSS
 

TimH

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Econ101 said:
Flounder, has there been much success of infection by animal feed in trials? This might be a factor of the ruminant's digestive system like abcesses or something. Don't know, just wondering.

Good question, Econ!!! How about it , Flounder?? (the word "feed" is also a verb)
I'm also wondering if there has been any any proven scientific link between vCJD and consumption of beef. I'm aware that there are implied,infered and circumstantial links, but I'd like to hear about any actual scientific links.
 

TimH

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flounder said:
Subject: Report of the first oral inoculation of BSE prion UPDATE
Date: January 4, 2006 at 7:00 am PST

[January 04, 2006]


Hokkaido lab may have succeeded in 1st artificial BSE infection+

(Japan Economic Newswire Via Thomson Dialog NewsEdge)SAPPORO, Jan. 4_(Kyodo) _ Japan may have succeeded for the first time in artificially triggering the onset of mad cow disease as several cows inoculated with abnormal prions have shown symptoms of the disease at the Hokkaido Animal Research Center, its official said Wednesday.


The center plans to dissect three of the cows in February to see if they were indeed infected with bovine spongiform encephalopathy. If confirmed, it will be the first successful case of human-induced BSE in Japan, which researchers hope will contribute to further studies of the disease-causing abnormal proteins and cure methods.

According to the prefectural research center, the experiment began in February 2004 when 14 female Holstein calves, kept in an isolated facility, were inoculated in the brain with 0.1 gram of abnormal prions extracted from BSE infected cows.

Researchers kept a close watch on the calves, including their behavior and blood samples. Around the end of last year, several calves began to show early symptoms of the brain-wasting disease such as wobbling and overreacting to sounds, the official said.

"Until now, we have only had (samples from) dead infected cows," the official said. "If it becomes possible to analyze blood and other samples from infected cows that are alive, then we can understand what kinds of changes occur before the infection develops and enable earlier detection of the disease."

Researchers in Britain have already succeeded in similar experiments. Elsewhere in Japan, the National Institute of Animal Health in Ibaraki Prefecture is conducting a similar test by injecting abnormal prions into the stomachs of cows.


http://www.tmcnet.com/usubmit/2006/jan/1260423.htm


Report of the first oral inoculation of BSE prion
into cattle in Japan

Ryoko Irie, Hiroyuki Okada, Hiroko Hayashi, Yoshifumi Iwamaru, Taka-
shi Yokoyama and Morikazu Shinagawa

Prion Disease Research Center, National Institute of Animal Health, 3-1-5
Kannondai, Tsukuba 305-0856 Japan [email protected]

Abstract

A Prion Disease Research Center at the National Institute of Animal
Health (NIAH) was established to conduct comprehensive research on
BSE in response to the discovery of bovine spongiform encephalopathy
(BSE) in Japan. A new research facility for the center has been con-
structed. It was designed as a biosafety level (BSL) 3 facility with the
capacity to inoculate and hold experimental animals. Experiments have
begun to infect cattle with BSE orally. This route of inoculation simu-
lates the feeding of contaminated meat and bone meal that caused pan-
demic occurrence of BSE in the UK. An abnormal isoform of the prion
protein (PrPSc) accumulates in BSE affected cattle. The purpose of this
study is to examine the spread of the abnormal prion from digestive tract to
the central nervous system and to describe the pathological changes in cat-
tle during the course of infection. Atypical BSE and young BSE cases
have been found in the abattoir surveillance program. As a result the cat-
tle used in this experiment were imported from Australia, a country free of
BSE, to exclude the possibility of prior BSE infection before inoculation.
Each calf (Holstein heifer, 10-months old) was inoculated orally with 5g of
brain stem from BSE infected cattle (courtesy provided by Veterinary
Laboratory Agency, Weybridge, UK) into the rumen with a catheter. The
cattle will be euthanized at intervals during the clinical stages of disease.
Infectivity from different tissues at different stages of clinical disease as
well as the deposition of PrPSc will be analyzed. Other factors that may
be related to the pathogenesis of the BSE prion will be investigated.

181

PRIONS
Food and Drug Safety
Springer
T. Kitamoto (Ed.)
TSS

"PLEASE read carefully" is right!! Because if you do , you will easily recognize that this article is citing two separate experiments.
One in which 14 calves were intra-cranially injected .Nothing "oral" about that one.
And another study in which 10 calves were "innoculated into the rumen using a catheter".

:roll: :roll: :roll: :roll: :roll: :roll: :roll: :roll:
 

flounder

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thanks tim, here is the other study. one was on page 181 and the other was on 183, and i failed to post the second study, meant to though ;


The development of the intracerebral inoculation
method and BSE experimental transmissions to
calves

Shigeo Fukuda, Satoshi Nikaido, Yoshitaka Matsui, Soichi Kageyama and
Sadao Onoe

Hokkaido Animal Research Center, 5-39 Shintoku-nishi, Shintoku-cho,
Kamikawa-gun 081-0038 Japan <e-mail> [email protected]

Abstract

It is very difficult to obtain cattle infected with bovine spongiform en-
cephalopathy (BSE) because there is no means of diagnosing BSE in live
animals. This has been the obstacle of the BSE research. It is pressing
need to make sure of enough cattle and bovine tissues infected with BSE
for it. An intracerebral (i.e.) inoculation is the most efficient route of a
prion disease transmission in each animal. However there are few reports
about methods of i.e. inoculation to cattle. We developed the efficient
and safe method of an i.e. inoculation to calves. In addition, we chal-
lenged BSE brain tissues to calves. It is the first BSE experimental
transmission to cattle in Japan.

The inoculation site was decided using heads of carcass calves. A
frontal bone was drilled by a pin-drill with a diameter of 2 mm on the spot
of 1 cm nose side from the front edge of the bulge between horns and 2 cm
right side from the median line. The tip of the disposable needle (70 mm,
18G) could penetrate a midbrain of calves. Four calves were injected in-
tracerebrally with stained normal brain tissue homogenates to this site un-
der mollification and local anesthesia. Clinical symptoms of these calves
were observed for 3 or 4 hours and the distribution of the inoculated brain
homogenate were investigated on the postmortem.

There were no calves presenting obvious neurological symptoms after
challenges. The almost of all homogenate spread ventricles and cerebral
aqueduct. Cerebrospinal fluid flowed over from the hole of inoculation
site by intracranial pressure, which leads to the leakage of infectious fac-
tors and the secondary infection for calves. Using a 3 x 8 mm stainless
screw has settled this problem.

183



as far as the whom and what to believe, youll have to make your own mind up on that. each of us interpret science differently, and some interpret it to fit there needs. personally, i believe the oral route is only one of many routes and source of infection with TSEs, and in each species, strains will vary and when those strains mutate and transmit, they too may
infect and transmit differently. just my opinion. ...tss
 

flounder

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also, there is just as much need to be concerned with sheep scrapie as with BSE and or BASE in cattle. the myth that sheep scrapie will not transmit to humans is just that, a myth. ..........


----- Original Message -----
From: "Terry S. Singeltary Sr." <[email protected]>
To: "Jim Woodward" <[email protected]>; "'Shu Chen'" <[email protected]>
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. [email protected]
>
> 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
> <http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?db=PubMed&cmd=Display&dopt
> =pubmed_pubmed&from_uid=1761109>
>
>
> "Clusters" of CJD in Slovakia: the first laboratory evidence of scrapie.
>
> Mitrova E, Huncaga S, Hocman G, Nyitrayova O, Tatara M.
>
> Institute of Preventive and Clinical Medicine, Bratislava.
>
> Epidemic-like occurrence of Creutzfeldt-Jakob disease was observed in
> 1987 in Slovakia (Orava). Search for the cause of CJD focus indicated a
> coincidence of genetic and environmental risks in clustering patients.
> Since Spongiform Encephalopathies might be transmitted orally, (Bovine
> Spongiform Encephalopathy), the possibility of zoonotic source of CJD
> cases in Orava was also considered. A deficient knowledge about the
> occurrence of scrapie in Slovakia stimulated an examination of sheep
> with signs of CNS disorders in two flocks of Valasky breed in Orava. In
> one flock, neurohistopathological examination revealed in sheep brains
> lesions characteristic for scrapie. Frozen brain tissue of these animals
> were used for the detection of scrapie associated fibrils. They were
> found in 2 animals from the same flock. This is the first laboratory
> confirmation of scrapie in Czecho-Slovakia. The possible epidemiological
> and economical implications are emphasized.
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_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: [email protected] 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 <[email protected]>
> Message-ID: <[email protected][12.7.122.68]>
> Date: Mon, 19 Jul 1999 11:21:25 -0800
> Reply-To: Bovine Spongiform Encephalopathy <[email protected]>
> Sender: Bovine Spongiform Encephalopathy <[email protected]>
> From: tom <[email protected]>
> 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" <[email protected]>
> Message-ID: <[email protected]>
> Date: Mon, 19 Jul 1999 23:28:00 +0200
> Reply-To: Bovine Spongiform Encephalopathy <[email protected]>
> Sender: Bovine Spongiform Encephalopathy <[email protected]>
> From: "Roland Heynkes @ T-Online" <[email protected]>
> 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: [email protected]
> http://home.t-online.de/home/Roland.Heynkes
>
>
> ----------------------------------------------------------------------------
> ----
>
>
>
>
> Approved-By: tom <[email protected]>
> Message-ID: <[email protected][12.7.122.68]>
> Date: Tue, 20 Jul 1999 11:48:17 -0800
> Reply-To: Bovine Spongiform Encephalopathy <[email protected]>
> Sender: Bovine Spongiform Encephalopathy <[email protected]>
> From: tom <[email protected]>
> Subject: Re: iatrogenic scrapie from sheep dura mater?
> In-Reply-To: <[email protected]>
>
> >
> >>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
 

flounder

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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"
<[email protected]>
Message-ID: <[email protected]>
Date: Wed, 21 Jul 1999 11:33:00 +0200
Reply-To: Bovine Spongiform Encephalopathy <[email protected]>
Sender: Bovine Spongiform Encephalopathy <[email protected]>
From: "Roland Heynkes @ T-Online" <[email protected]>
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: [email protected]
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: [email protected]

www.pnas.org/cgi/doi/10.1073/pnas.0502296102


http://www.pnas.org/cgi/content/abstract/0502296102v1


TSS




----- Original Message -----
From: "Jim Woodward" <[email protected]>
To: "'Shu Chen'" <[email protected]>
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:[email protected]]
> > 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
> > [email protected]
> >
> > ----- Original Message -----
> > From: Jim Woodward <[email protected]>
> > 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
> > >
> > >
> > >
> >
>
 

flounder

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hi kathy,

kathy writes;

Terry, can the VLA, or any of these labs, provide an analysis of the metals found in the prion samples used to inoculate these animals???

im sure they can. i have pasted some urls below. one of them i think at bottom has some emails for vla diagnostic;


http://www.defra.gov.uk/corporate/vla/science/documents/science-tesee-prot290104.pdf



http://64.233.187.104/search?q=cache:y1V_rOumrCgJ:www.defra.gov.uk/corporate/vla/science/documents/science-tesee-prot290104.pdf+vla+lab+PROTOCOL+METALS&hl=en





Page 1 1 SEAC 86/1 SPONGIFORM ENCEPHALOPATHY ADVISORY COMMITTEE ...





23. One member explained that some researchers in the USA had

suggested that the prevalence of CWD could be modified by levels

of trace elements in the environment, such as copper and

manganese, which when absorbed could influence PrP conversion.

The Chair asked whether the member considered that this theory

might provide an alternative to lateral transmission as a mechanism

of propagation of the disease. In response, the member explained

that in a feeding study in elk, dietary copper had reduced the

incidence of CWD in an experimental herd compared with a control

herd. Thus, it is possible that trace elements could either reduce

the severity of the symptoms or prevent infection. The committee

noted that there was strong evidence for lateral transmission of

CWD via the environment, from studies of cervids inhabiting

paddocks previously inhabited by infected animals or contaminated

with infected carcases.





snip...



28. In response to questions about the possible transmission of CWD

to cows and sheep, Dr Bourne explained that transmission of CWD

by intracerebral inoculation of cows and sheep was inefficient. In

addition, an oral transmission experiment of CWD to cows, whilst

incomplete, had not shown transmission of the disease after six

years. Additionally, no signs of infection were found from

surveillance of cows living in a CWD endemic area for a number of

years.



(FACTS are, CWD HAS transmitted to cattle and sheep by innoculation in the lab, oral infection will take much longer, if and when it takes place. ...TSS)



http://www.seac.gov.uk/papers/minutes301104.pdf


http://www.food.gov.uk/multimedia/pdfs/reslistapril05.pdf

http://www.vmd.gov.uk/mavis/publications/mavis24.pdf


http://64.233.187.104/search?q=cache:Q834BRiJXkcJ:www.defra.gov.uk/corporate/vla/comserv/documents/comserv-insight15.pdf+vla+lab+PROTOCOL+METALS&hl=en


TSS
 

Kathy

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Fact: Doctor Matthews at the VLA has REFUSED to answer our inquiries about the levels of metals in the prions being used for innoculation experiments.

Fact: Dr. McDonnell's controlled experiments with CWD and copper, which I have posted here before, proved that supplementation with copper (at adequate dietary levels) completely eliminated CWD in elk being raised on land which previously, elk had been diagnosed with CWD.

The other two pens tested received NO COPPER or only SOME COPPER BUT NOT SUFFICIENT DIETARY AMOUNTS. They showed cased of CWD which related to copper consumption. The animals in the pen with no copper, had a 55% CWD recurrence, and the animals with some copper but not enough had a 7.5% recurrence; the animals with adequate copper in their diet had no further recurrence in them, even though they were being raised on so-called "prion contaminated" land.

If you don't believe me, I suggest you ask someone at the VLA to answer my question.
 

flounder

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1st kathy writes;

Terry, can the VLA, or any of these labs, provide an analysis of the metals found in the prion samples used to inoculate these animals???



THEN kathy writes;

Fact: Doctor Matthews at the VLA has REFUSED to answer our inquiries about the levels of metals in the prions being used for innoculation experiments. ...

don't have time for trick questions kathy. FACT is your OP and metals theory on the
CAUSE of CWD/BSE/TSE and or completely eliminated CWD in elk is total hogwash. we have discussed this before, i have posted the data that disputes this, no need to wasted the space here to do it again and again.


kind regards,
terry
 

flounder

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RECAP;


Oral transmission and early lymphoid tropism of chronic wasting disease
PrPres in mule deer fawns (Odocoileus hemionus )
Christina J. Sigurdson1, Elizabeth S. Williams2, Michael W. Miller3,
Terry R. Spraker1,4, Katherine I. O'Rourke5 and Edward A. Hoover1

Department of Pathology, College of Veterinary Medicine and Biomedical
Sciences, Colorado State University, Fort Collins, CO 80523- 1671, USA1
Department of Veterinary Sciences, University of Wyoming, 1174 Snowy
Range Road, University of Wyoming, Laramie, WY 82070, USA 2
Colorado Division of Wildlife, Wildlife Research Center, 317 West
Prospect Road, Fort Collins, CO 80526-2097, USA3
Colorado State University Veterinary Diagnostic Laboratory, 300 West
Drake Road, Fort Collins, CO 80523-1671, USA4
Animal Disease Research Unit, Agricultural Research Service, US
Department of Agriculture, 337 Bustad Hall, Washington State University,
Pullman, WA 99164-7030, USA5

Author for correspondence: Edward Hoover.Fax +1 970 491 0523. e-mail
[email protected]

Mule deer fawns (Odocoileus hemionus) were inoculated orally with a
brain homogenate prepared from mule deer with naturally occurring
chronic wasting disease (CWD), a prion-induced transmissible spongiform
encephalopathy. Fawns were necropsied and examined for PrP res, the
abnormal prion protein isoform, at 10, 42, 53, 77, 78 and 80 days
post-inoculation (p.i.) using an immunohistochemistry assay modified to
enhance sensitivity. PrPres was detected in alimentary-tract-associated
lymphoid tissues (one or more of the following: retropharyngeal lymph
node, tonsil, Peyer's patch and ileocaecal lymph node) as early as 42
days p.i. and in all fawns examined thereafter (53 to 80 days p.i.). No
PrPres staining was detected in lymphoid tissue of three control fawns
receiving a control brain inoculum, nor was PrPres detectable in neural
tissue of any fawn. PrPres-specific staining was markedly enhanced by
sequential tissue treatment with formic acid, proteinase K and hydrated
autoclaving prior to immunohistochemical staining with monoclonal
antibody F89/160.1.5. These results indicate that CWD PrP res can be
detected in lymphoid tissues draining the alimentary tract within a few
weeks after oral exposure to infectious prions and may reflect the
initial pathway of CWD infection in deer. The rapid infection of deer
fawns following exposure by the most plausible natural route is
consistent with the efficient horizontal transmission of CWD in nature
and enables accelerated studies of transmission and pathogenesis in the
native species.

snip...

These results indicate that mule deer fawns develop detectable PrP res
after oral exposure to an inoculum containing CWD prions. In the
earliest post-exposure period, CWD PrPres was traced to the lymphoid
tissues draining the oral and intestinal mucosa (i.e. the
retropharyngeal lymph nodes, tonsil, ileal Peyer's patches and
ileocaecal lymph nodes), which probably received the highest initial
exposure to the inoculum. Hadlow et al. (1982) demonstrated scrapie
agent in the tonsil, retropharyngeal and mesenteric lymph nodes, ileum
and spleen in a 10-month-old naturally infected lamb by mouse bioassay.
Eight of nine sheep had infectivity in the retropharyngeal lymph node.
He concluded that the tissue distribution suggested primary infection
via the gastrointestinal tract. The tissue distribution of PrPres in the
early stages of infection in the fawns is strikingly similar to that
seen in naturally infected sheep with scrapie. These findings support
oral exposure as a natural route of CWD infection in deer and support
oral inoculation as a reasonable exposure route for experimental studies
of CWD.

snip...

http://vir.sgmjournals.org/cgi/content/full/80/10/2757



Subject: MAD DEER/ELK DISEASE AND POTENTIAL SOURCES
Date: Sat, 25 May 2002 18:41:46 -0700
From: "Terry S. Singeltary Sr."
Reply-To: BSE-L
To: BSE-L

8420-20.5% Antler Developer
For Deer and Game in the wild
Guaranteed Analysis Ingredients / Products Feeding Directions

snip...

_animal protein_

http://www.surefed.com/deer.htm

BODE'S GAME FEED SUPPLEMENT #400
A RATION FOR DEER
NET WEIGHT 50 POUNDS
22.6 KG.

snip...

_animal protein_

http://www.bodefeed.com/prod7.htm

Ingredients

Grain Products, Plant Protein Products, Processed Grain By-Products,
Forage Products, Roughage Products 15%, Molasses Products,
__Animal Protein Products__,
Monocalcium Phosphate, Dicalcium Pyosphate, Salt,
Calcium Carbonate, Vitamin A Acetate with D-activated Animal Sterol
(source of Vitamin D3), Vitamin E Supplement, Vitamin B12 Supplement,
Riboflavin Supplement, Niacin Supplement, Calcium Panothenate, Choline
Chloride, Folic Acid, Menadione Soduim Bisulfite Complex, Pyridoxine
Hydorchloride, Thiamine Mononitrate, d-Biotin, Manganous Oxide, Zinc
Oxide, Ferrous Carbonate, Calcium Iodate, Cobalt Carbonate, Dried
Sacchoromyces Berevisiae Fermentation Solubles, Cellulose gum,
Artificial Flavors added.

http://www.bodefeed.com/prod6.htm
===================================

MORE ANIMAL PROTEIN PRODUCTS FOR DEER

Bode's #1 Game Pellets
A RATION FOR DEER
F3153

GUARANTEED ANALYSIS
Crude Protein (Min) 16%
Crude Fat (Min) 2.0%
Crude Fiber (Max) 19%
Calcium (Ca) (Min) 1.25%
Calcium (Ca) (Max) 1.75%
Phosphorus (P) (Min) 1.0%
Salt (Min) .30%
Salt (Max) .70%


Ingredients

Grain Products, Plant Protein Products, Processed Grain By-Products,
Forage Products, Roughage Products, 15% Molasses Products,
__Animal Protein Products__,
Monocalcium Phosphate, Dicalcium Phosphate, Salt,
Calcium Carbonate, Vitamin A Acetate with D-activated Animal Sterol
(source of Vitamin D3) Vitamin E Supplement, Vitamin B12 Supplement,
Roboflavin Supplement, Niacin Supplement, Calcium Pantothenate, Choline
Chloride, Folic Acid, Menadione Sodium Bisulfite Complex, Pyridoxine
Hydrochloride, Thiamine Mononitrate, e - Biotin, Manganous Oxide, Zinc
Oxide, Ferrous Carbonate, Calcium Iodate, Cobalt Carbonate, Dried
Saccharyomyces Cerevisiae Fermentation Solubles, Cellulose gum,
Artificial Flavors added.

FEEDING DIRECTIONS
Feed as Creep Feed with Normal Diet

http://www.bodefeed.com/prod8.htm

INGREDIENTS

Grain Products, Roughage Products (not more than 35%), Processed Grain
By-Products, Plant Protein Products, Forage Products,
__Animal Protein Products__,
L-Lysine, Calcium Carbonate, Salt, Monocalcium/Dicalcium
Phosphate, Yeast Culture, Magnesium Oxide, Cobalt Carbonate, Basic
Copper Chloride, Manganese Sulfate, Manganous Oxide, Sodium Selenite,
Zinc Sulfate, Zinc Oxide, Sodium Selenite, Potassium Iodide,
Ethylenediamine Dihydriodide, Vitamin E Supplement, Vitamin A
Supplement, Vitamin D3 Supplement, Mineral Oil, Mold Inhibitor, Calcium
Lignin Sulfonate, Vitamin B12 Supplement, Menadione Sodium Bisulfite
Complex, Calcium Pantothenate, Riboflavin, Niacin, Biotin, Folic Acid,
Pyridoxine Hydrochloride, Mineral Oil, Chromium Tripicolinate

DIRECTIONS FOR USE

Deer Builder Pellets is designed to be fed to deer under range
conditions or deer that require higher levels of protein. Feed to deer
during gestation, fawning, lactation, antler growth and pre-rut, all
phases which require a higher level of nutrition. Provide adequate
amounts of good quality roughage and fresh water at all times.

http://www.profilenutrition.com/Products/Specialty/deer_builder_pellets.html
===================================================

DEPARTMENT OF HEALTH & HUMAN SERVICES
PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION

April 9, 2001 WARNING LETTER

01-PHI-12
CERTIFIED MAIL
RETURN RECEIPT REQUESTED

Brian J. Raymond, Owner
Sandy Lake Mills
26 Mill Street
P.O. Box 117
Sandy Lake, PA 16145
PHILADELPHIA DISTRICT

Tel: 215-597-4390

Dear Mr. Raymond:

Food and Drug Administration Investigator Gregory E. Beichner conducted
an inspection of your animal feed manufacturing operation, located in
Sandy Lake, Pennsylvania, on March 23,
2001, and determined that your firm manufactures animal feeds including
feeds containing prohibited materials. The inspection found significant
deviations from the requirements set forth in
Title 21, code of Federal Regulations, part 589.2000 - Animal Proteins
Prohibited in Ruminant Feed. The regulation is intended to prevent the
establishment and amplification of Bovine Spongiform Encephalopathy
(BSE) . Such deviations cause products being manufactured at this
facility to be misbranded within the meaning of Section 403(f), of the
Federal Food, Drug, and Cosmetic
Act (the Act).

Our investigation found failure to label your
swine feed with the required cautionary statement "Do Not Feed to cattle
or other Ruminants" The FDA suggests that the statement be
distinguished
by different type-size or color or other means of highlighting the
statement so that it is easily noticed by a purchaser.

In addition, we note that you are using approximately 140 pounds of
cracked corn to flush your mixer used in the manufacture of animal
feeds containing prohibited material. This
flushed material is fed to wild game including deer, a ruminant animal.
Feed material which may potentially contain prohibited material should
not be fed to ruminant animals which may become part of the food chain.

The above is not intended to be an all-inclusive list of deviations from
the regulations. As a manufacturer of materials intended for animal
feed use, you are responsible for assuring that your overall operation
and the products you manufacture and distribute are in compliance with
the law. We have enclosed a copy of FDA's Small Entity Compliance Guide
to assist you with complying with the regulation... blah, blah, blah...

http://www.fda.gov/foi/warning_letters/g1115d.pdf



1: J Infect Dis 1980 Aug;142(2):205-8 Related Articles, Links

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/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract>




Greetings Ranchers and board members,


Kathy wrote in another thread, but yet never documented;

> didn't say that OPs caused prion disease, but that they contributed greatly
> to the UK experience,

and again, could your please reference this materials with scientific data, instead
of hearsay please ???


you can argue the origin of TSE until all the mad cows on earth come home to roost.


i.e. ;


Phosmet induces up-regulation of surface levels of the cellular prion protein.
Neuroreport. 9(7):1391-1395, May 11, 1998.
Gordon, Irit 1; Abdulla, Elizabeth M. 1; Campbell, Iain C. 1; Whatley, Stephen A. 1,2
Abstract:
CHRONIC (2 day) exposure of human neuroblastoma cells to the organophosphate pesticide phosmet induced a marked concentration-dependent increase in the levels of PrP present on the cell surface as assessed by biotin labelling and immunoprecipitation. Levels of both phospholipase C (PIPLC)-releasable and non-releasable forms of PrP were increased on the plasma membrane. These increases appear to be due to post-transcriptional mechanisms, since PrP mRNA levels as assessed by Northern blotting were unaffected by phosmet treatment. These data raise the possibility that phosmet exposure could increase the susceptibility to the prion agent by altering the levels of accessible PrP.

(C) Lippincott-Raven Publishers.



http://www.neuroreport.com/pt/re/neuroreport/abstract.00001756-199805110-00026.htm;jsessionid=DOEcw0d3vPau1LEbPM42DrGrWVZnF06cF115hTGLe07ro2BZx8d3!586698740!-949856144!9001!-1





BUT, amplification and transmission is the most important factor in stopping the

spread of the TSE agent. WE have known for decades what factors involve the amplification

and transmission, yet the industries involved CHOSE to ignore this science until the incubation

period in humans and animals started to catch up with society.



would it not have been more easy and very much less expensive for MAFF/USDA et al to jump on the OP
bandwagon and save the industry, if OP theory had any credence to it at all? and why did they not?


transmission studies DO NOT LIE !

show me the data that ops are in all the primate/mouse transmission studies?


EUROPEAN COMMISSION
HEALTH & CONSUMER PROTECTION DIRECTORATE-GENERAL
Scientific Steering Committee
OPINION ON
ORGANOPHOSPHATE (OP) POISONING AND
HYPOTHETICAL INVOLVEMENT IN THE ORIGIN OF BSE
Background
In its opinion on possible links between BSE and Organophosphates adopted on 25-26 June
1998 and in its opinion on Hypotheses on the origin and transmission of BSE adopted on 29-
30 November 2001 the SSC concluded that there is no scientific evidence in support of the
hypothesis of an OP origin of BSE.
The issue of organophosphate poisoning has not been dealt with by the SSC so far. The
concerns expressed in the enquiries cover mainly intoxication by occupational exposure of
shepherds and farmers to OPs upon use against ecto-parasites, especially in sheep dipping and
treatment of cattle against Warble Fly infestation. Risks from residues are addressed to a
lesser extend.
In early 2003, a large number of additional enquiries on the issue have been addressed to
European Commission’s Health and Consumer Directorate General. Four of these with
substantial enclosures were by one person. Most of them are addressing both issues: chronic
organophosphate (OP) poisoning and the origin of BSE.
Information provided with the enquiries
In addition to numerous newspaper and magazine articles the enclosures to the enquiries
provide the Material Safety Data Sheet on diazinon, the OHSA Occupational Safety and
Health Guideline for Tetraethylpyrophosphate (TEPP), an US agency Hazardous Substances
Fact Sheet on crufomate, company safety information sheets, some correspondence with UK
authorities including their activities to improve safe use of these chemicals. The information
regarding claimed OP chronic poisoning of cases presented does not provide evidence, neither
for OPs being the cause for diseases nor for their exclusion (i.e., “very low” bloodcholinesterase
levels, provided without data or comparison with the normal distribution of
values; successful treatment of a patient for OP clearance without giving any OP data). It
C:\WINNT\Temporary Internet Files\SSC_Last_OP_Final.doc 2
seems however, that due to insufficient, non-prudent use of the safety requirements undue
exposures of shepherds and farmers have occurred.
There is no additional information on the claimed involvement of OPs in the origin of BSE.
This applies for both, the hypotheses on the direct effect of OPs as well as on their
hypothetical role for Cu-deficiency to be involved in the origin of BSE (Cu binding of prion
protein is known). New publications are mentioned in one enquiry but they have not yet been
provided. In an Internet search no recent scientifically valid publications were traceable. The
SSC had been informed that research would be launched on this hypothesis, but no
information has been provided so far on its status or on results.
Conclusions
a) As regards the involvement of organophosphates in the origin of BSE, no new scientific
information providing evidence or supporting the hypothesis by valid data became
available after the adoption of the last opinion of the SSC on this issue. Consequently
there is no reason for modifying the existing opinions.
b) Regarding the possibility of OP poisoning, the European legislation for registration of
plant protection products and veterinary medicines – addressed in the enquiries – provide
the basis for safe use of registered compounds and their formulations. Regarding the
alleged intoxication cases reported and OP exposure it must be concluded that safety
measures may not have been strictly followed.
References
Brown, D.R., Qin, K., Herms, J.W., Madlung, A., Manson, J., Strome, R., Fraser, P.E., Kruck, T., von
Bohlen, A., Schulz- Schaeffer, W., Giese, A., Westaway, D. and Kretzschmar, H. (1997) The Cellular
Prion Protein Binds Copper In Vivo, Nature, 390, 684-7.
Purdey, M. (2000) Ecosystems Supporting Clusters of Sporadic TSEs Demonstrate Excesses of the Radical-
Generating Divalent Cation Manganese and Deficiencies of Antioxidant Co-Factors Cu, Se, Fe, Zn Medical
Hypotheses, 54, 278-306.
Scientific Steering Committee, 1998. Opinion on possible links between BSE and Organophosphates. Adopted
on 25-26 June 1998
Scientific Steering Committee, 2001. Opinion on Hypotheses on the origin and transmission of BSE. Adopted
on 29-30 November 2001.

http://europa.eu.int/comm/food/fs/sc/ssc/out356_en.pdf



Studies on the Putative Interactions between the Organophosphorus Insecticide Phosmet and Recombinant Mouse PrP and its Implication in the BSE Epidemic
I. Shaw1, C. Berry2, E. Lane1, P. Fitzmaurice1, D. Clarke3 and A. Holden1

(1) Centre for Toxicology, University of Central Lancashire, Preston, UK

(2) Department of Morbid Anatomy, The Royal London Hospital, London, UK

(3) CLRC Daresbury Laboratory, Warrington, UK


Abstract It has been suggested that exposure of cattle to the ectoparasiticide Phosmet in the 1980s caused a conformational change in the cellular prion protein (PrPC) to form the BSE prion (PrPSC), which initiated the epidemic of bovine spongiform encephalopathy (BSE).
Recombinant mouse cellular prion (r[mouse]PrPC) was exposed to the organophosphorus pesticide Phosmet in vitro and the conformation of the prion before and after exposure was monitored using circular dichroism (CD) spectroscopy, utilizing synchrotron radiation at the Council for the Central Laboratory of the Research Councils (CLRC) facilities at Daresbury, UK. Metabolites of Phosmet, generated in situ by rat microsomes, were investigated in the same way, to determine whether they might initiate the conformational change due to their high chemical reactivity.
Our studies showed that exposure of r[mouse]PrPC to Phosmet or microsomes-generated metabolites of Phosmet did not result in the conformational change in the protein from -helix to -pleated sheet that is characteristic of the PrPC to PrPSC conversion and, therefore, Phosmet is very unlikely to have initiated the BSE epidemic by a simple direct mechanism of conformational change in the prion protein.
bovine spongiform encephalopathy - circular dichroism spectroscopy - insecticide - organophosphate - Phosmet - prion - protein conformation



http://www.springerlink.com/(bmbpjj55ksv02p2wiismj555)/app/home/contribution.asp?referrer=parent&backto=issue,3,9;journal,31,74;linkingpublicationresults,1:103009,1



transmission studies do not lie, amplification and transmission!



Vol. 96, Issue 7, 4046-4051, March 30, 1999


Neurobiology
Natural and experimental oral infection of nonhuman primates by bovine spongiform encephalopathy agents
Nöelle Bons*,, Nadine Mestre-Frances*, Patrick Belli, Françoise Cathala§, D. Carleton Gajdusek¶, and Paul Brown

* Ecole Pratique des Hautes Etudes, Laboratoire de Neuromorphologie Fonctionnelle, Université Montpellier II, 34095-Montpellier cedex 5, France; Centre National d'Etudes Veterinaires et Alimentaires, Pathologie Bovine, 31 Av. Tony Garnier, 69342-Lyon cedex 07, France; § 68 Bd Saint-Michel, 75006-Paris, France; ¶ Institut Alfred Fessard, Centre National de la Recherche Scientifique, 91198-Gif-sur-Yvette, France; and Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892

Contributed by D. Carleton Gajdusek, December 21, 1998

ABSTRACT


Experimental lemurs either were infected orally with the agent of bovine spongiform encephalopathy (BSE) or were maintained as uninfected control animals. Immunohistochemical examination for proteinase-resistant protein (prion protein or PrP) was performed on tissues from two infected but still asymptomatic lemurs, killed 5 months after infection, and from three uninfected control lemurs. Control tissues showed no staining, whereas PrP was detected in the infected animals in tonsil, gastrointestinal tract and associated lymphatic tissues, and spleen. In addition, PrP was detected in ventral and dorsal roots of the cervical spinal cord, and within the spinal cord PrP could be traced in nerve tracts as far as the cerebral cortex. Similar patterns of PrP immunoreactivity were seen in two symptomatic and 18 apparently healthy lemurs in three different French primate centers, all of which had been fed diets supplemented with a beef protein product manufactured by a British company that has since ceased to include beef in its veterinary nutritional products. This study of BSE-infected lemurs early in their incubation period extends previous pathogenesis studies of the distribution of infectivity and PrP in natural and experimental scrapie. The similarity of neuropathology and PrP immunostaining patterns in experimentally infected animals to those observed in both symptomatic and asymptomatic animals in primate centers suggests that BSE contamination of zoo animals may have been more widespread than is generally appreciated.



snip...



DISCUSSION


Pathogenesis has been a continuing subject of importance in the study of transmissible spongiform encephalopathies, having been first addressed systematically by Hadlow et al. (8-10) in a landmark set of experiments in which the sequential appearance of infectivity in different organs was determined in both naturally and experimentally acquired disease, continued by Kimberlin and Walker (11, 12) in a series of experiments on orally infected mice, and most recently extended by Beekes et al. (13, 14) to include parallel studies of PrP in tissues after oral infection and by Klein et al. (15) with particular attention to the role of B cells in neuroinvasion. All of these studies were undertaken by using scrapie as the model of infection, but preliminary investigations also have been reported on BSE in naturally and experimentally infected cattle (16).

From the ensemble of these studies it has become clear that, after oral infection, infectivity and pathologic PrP first appear in the digestive tract and its contained or proximate lymphoid tissues (tonsils, lymph nodes, Peyer's patches, and spleen), before moving, presumably through autonomic nervous system fibers, to the spinal cord and up to the brain. Natural and experimental BSE in bovines is notable in the comparatively limited distribution of infectivity outside the central nervous system, having been demonstrated only in the trigeminal and dorsal root ganglia, distal ileum, and (possibly) bone marrow and retina.

The present study, which extends our earlier investigations of two lemurs and one monkey dying with spongiform encephalopathy in the Montpellier zoo (1, 2), contributes two additional pieces of information about oral infection by transmissible spongiform encephalopathy agents. First, the immunohistochemical results of our experimental study of BSE-fed lemurs has precisely defined the distribution and localization of PrP within a variety of tissues early in the incubation period of disease. PrP (and by implication, the infectious agent) evidently is taken up by epithelial cells lining the lumen of the digestive tract (including those of the tonsil), initiating a reaction of the M cells and lymphocytes within the tissues of the digestive tract and in their lymphatic drainage system (including lymph nodes and spleen). Our observations also show that even before PrP can be detected in the central nervous system in the pattern typical of terminal illness, it can be traced along nerve pathways from ventral and dorsal root ganglia through the spinal cord into the brain cortex. These results are consistent with the observed distribution and progression of infectivity and PrP during the evolution of scrapie, as measured by infectivity assays (12) and Western blots of extracted PrP (14).

Second, the similar neuropathology and distribution of PrP in orally infected experimental lemurs and spontaneously affected zoo lemurs, together with the epidemiological observations confirming the occurrence of spongiform encephalopathy in animals fed a diet supplemented with meat protein that until 1996 had very likely included rendered British beef, leave little room for doubt that cases of spongiform encephalopathy in French primates resulted from infection by BSE-contaminated meat, just as in felines and ungulates in zoos elsewhere. Our unexpected finding that the same patterns of PrP distribution and brain degeneration were present in asymptomatic lemurs from two other French primate facilities suggests that BSE-contaminated diets may have been far more widespread than appreciated and mandates continued surveillance of primates in European zoos and breeding facilities.


snip...

http://www.pnas.org/cgi/content/full/96/7/4046




Journal of General Virology, Vol 72, 589-594, Copyright © 1991 by Society for General Microbiology


--------------------------------------------------------------------------------

ARTICLES


Epidemiological and experimental studies on a new incident of transmissible mink encephalopathy
RF Marsh, RA Bessen, S Lehmann and GR Hartsough
Department of Veterinary Science, University of Wisconsin-Madison 53706.

Epidemiological investigation of a new incident of transmissible mink encephalopathy (TME) in Stetsonville, Wisconsin, U.S.A. in 1985 revealed that the mink rancher had never fed sheep products to his mink but did feed them large amounts of products from fallen or sick dairy cattle. To investigate the possibility that this occurrence of TME may have resulted from exposure to infected cattle, two Holstein bull calves were injected intracerebrally with mink brain from the Stetsonville ranch. Each bull developed a fatal spongiform encephalopathy 18 and 19 months after inoculation, respectively, and both bovine brains passaged back into mink were highly pathogenic by either intracerebral or oral inoculation. These results suggest the presence of a previously unrecognized scrapie-like infection in cattle in the United States.



http://vir.sgmjournals.org/cgi/content/abstract/72/3/589


TSS
 

Kathy

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Terry when the studies you quote can provide an analysis of all the metal components in the innoculant, along with testing for radio-activity levels - we may have something worth looking at.

For now, I can agree with the studies which you posted which showed that Phosmet caused an up-regulation of the PrP protein which the cells producing them could not handle and the PrP protein lingered on the cell surface membrane for a long time.

You can deny the metal imbalance connection all you want. You can deny that OPs and other chemicals can cause up-regulation of the PrP protein too.

AS for asking the VLA, ask them yourself. But you don't want to do that, why? maybe you don't want to know the truth. What protein causes the innoculant to spread disease after the innoculant has been chard to nothing after heating to temperatures above 660 degrees celcius, only simple elements (with no proteins, amino acids components) remain. Nothing but carbon and metals.
 

flounder

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1st kathy writes;

>Terry, can the VLA, or any of these labs, provide an analysis of the metals found in the prion samples used to inoculate these animals???
<

THEN kathy answers her own question with;

>Fact: Doctor Matthews at the VLA has REFUSED to answer our inquiries about the levels of metals in the prions being used for innoculation experiments. ... <


TSS WRITES;
don't have time for trick questions kathy. FACT is your OP and metals theory on the
CAUSE of CWD/BSE/TSE and or completely eliminated CWD in elk is total hogwash.
we have discussed this before, i have posted the data that disputes this, no need to wasted
the space here to do it again and again.


then kathy writes;


>Fact: Doctor Matthews at the VLA has REFUSED to answer our inquiries about the levels of metals in the prions being used for innoculation experiments. <


then tries to insinuate that it was me wanting to know something from vla ;


>AS for asking the VLA, ask them yourself. But you don't want to do that, why?<


FACT is, kathy, it is you that seems confused, so you need to ask vla yourself.
it is YOU they will not answer.
i have my answers. furthermore, instead of wasting my time, come back and talk
to us when your OPs and or metals become infectious/transmissible,
THEN well have something to discuss. ...TSS
 

Kathy

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Terry, I want you to ask the VLA this question because you believe VLA is perfect and forthcoming with all the evidence that there need be. The complete lack of metal analysis of any innoculant in "transmission" studies is pathetic. The fact that the UK government withheld 30% of the information they had on BSE during the BSE Inquiry, is also pathetic.

Here is one for you which explains why a copper deficiency/ zinc deficiency (less) could lead to disease. It sounds alot like Dr. D. R. Browns research where manganese bound to PrPC when the cellular environment was depleted of copper. If the copper is bound to these proteins, they are kinetically stable. If the nerve cell continues to up-regulate the PrPC protein (for whatever reason) and no copper is available to bind with the octapeptide repeats, then another metal will take those positions. It is not the same protein then, and it accummulates on the nerve cell's surface until it the buildup blocks absorption and expulsion of anything else, thereby starving the cell, and building up toxins within the cell.

Your lack of interest in asking VLA shows me that you are not interested in looking for answers.

Biochem Biophys Res Commun 2006 Feb 10;340(2):457-61. Epub 2005 Dec 15.

Dominant role of copper in the kinetic stability of Cu/Zn superoxide dismutase.

Lynch SM, Colon W.

Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA.

Mutations in Cu/Zn superoxide dismutase (SOD) are involved in some cases of familial amyotrophic lateral sclerosis, and it appears that misfolding and aggregation, perhaps mediated by abnormal binding or loss of copper (Cu) and/or zinc (Zn), may play a pathological role. It is known that the absence of both metals kinetically destabilizes wild type and mutant SOD leading to a 60-fold increase in their rate of unfolding. Here, the individual contributions of Cu and Zn to the kinetic stability of SOD were investigated, and the results show that Cu plays a greater role. Thus, the deficiency of Cu or Zn, especially the former, will compromise the kinetic stability of SOD, thereby increasing the probability that pathogenic mutants and even the WT protein may misfold and self-assemble into toxic species.

Do you also deny that OPs chelate copper; binding with it, making copper unavailable for many cellular functions?
 

flounder

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kathy writes;


>Terry, I want you to ask the VLA this question because you believe VLA is perfect and forthcoming with all the evidence that there need be.<

again, it was YOU that said vla refuses to answer YOUR questions.
YOUR problem. as far as your other false statement;


>you believe VLA is perfect and forthcoming with all the evidence that there need be<


can you please show me where i said this?
i have never stated this. ...

tss
 

flounder

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##################### Bovine Spongiform Encephalopathy #####################

[January 17, 2006]


LEAD: Japanese researchers trigger onset of mad cow disease in cows+

(Japan Economic Newswire Via Thomson Dialog NewsEdge)SAPPORO, Jan. 18_(Kyodo) _ (EDS: ADDING DETAILS)

Japanese researchers have succeeded for the first time in Japan in infecting cows with mad cow disease in an experiment, an animal laboratory in Hokkaido said Wednesday.

The Hokkaido Animal Research Center said the researchers triggered the onset of bovine spongiform encephalopathy in three cows in an experiment in which the cows were injected with abnormal prions extracted from BSE-infected cows.

The researchers said they believe the breakthrough will help shed light on the mechanism of abnormal prions -- which cause BSE -- building up inside the animal. They said they also think the achievement will help them develop a method of diagnosing whether a cow is infected with the disease.


Researchers in Britain have already succeeded in similar experiments. In Japan's Ibaraki Prefecture, the National Institute of Animal Health is conducting a similar test, injecting abnormal prions into the stomachs of cows.

According to the center, the experiment has been conducted since February 2004 on 14 female Holstein calves. A tenth of a gram of abnormal prions was injected into each of their brains.

Late last year, three of them began showing initial symptoms of the brain-wasting disease such as wobbling and overreacting to sound. Autopsies conducted on them at the National Institute of Animal Health confirmed the three were infected, the center said.


http://www.tmcnet.com/usubmit/2006/01/17/1293527.htm


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