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From: TSS (
Subject: An agreement with Japan on BSE and trade could set a precedent for agreements around the world (GOD HELP US)
Date: August 13, 2004 at 2:37 pm PST

-------- Original Message --------
Subject: An agreement with Japan on BSE and trade could set a precedent for agreements around the world (GOD HELP US)
Date: Fri, 13 Aug 2004 15:38:47 -0500
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy

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

8/12/2004 4:28:36 PM

USDA Official Hopes For Summer Japan Beef Market Opening

DENVER (Dow Jones)--U.S. Department of Agriculture Undersecretary J.B.

Penn Thursday reiterated his estimate that the Japanese market for U.S.

products will be at least partially reopened this summer.

Penn explained that some of the products at higher risk for bovine

spongiform encephalopathy, or mad-cow disease, may not be included. He
said he

thought an agreement for lower-risk products probably could be reached this


On Dec. 23, 2003, the Japanese markets, among others, were closed to U.S.

beef after a case of mad-cow disease was discovered in Washington state.

In 2003, the U.S. exported $1.7 billion worth of beef products to

Japan, its No. 1 beef market, he said.

In an interview with reporters at the annual summer meeting of the

National Cattlemen's Beef Association, Penn said a third working-group

among U.S. and Japanese officials was completed in April in Denver. The

Japanese delegation was quite large and included members of the Japanese


The Japanese delegation was treated to tours of U.S. packing plants,

laboratories and feedlots in addition to direct talks about the science of

BSE, Penn said. It was after this meeting that the working group said there

was little or nothing to be gained by testing younger animals for BSE,
he said.

That Japanese working group reported to its policy makers who then will

work out possible policy changes, Penn said.

There are ideas in the U.S. that the Japanese Food Safety Commission plans

to meet this month on the issue and that Penn will travel to Japan for

further discussions with the Food Safety Commission by the end of the month.

Penn, however, disavowed any knowledge of such plans. He might go to Tokyo

for high-level discussions, but no date has been set, he said.

Penn maintained his emphasis that any agreement with Japan on trade

resumption must be based on sound science. In his message to NCBA's Joint

International Markets Committee meeting, he said the U.S. should be a

in this area. An agreement with Japan on BSE and trade could set a

for agreements around the world.

One of the issues that needs to be resolved, Penn told reporters, is that

of an agreeable cut-off age for testing. He did not elaborate about what

Japanese want, but said the U.S. has maintained that 30 months of age is

appropriate to protect food safety.

End to U.S. beef import ban long way off: Kamei

Japan's farm minister hinted Tuesday that reaching a resolution in
beef-trade talks with the United States may take a long time, despite
the two countries' desire to settle the issue of Japan's beef import ban
this summer.

"It's difficult to tell the future schedule (of the talks) at this
stage," Yoshiyuki Kamei, minister of agriculture, forestry and
fisheries, said.

Noting that the Cabinet Office's Food Safety Commission has not yet made
any clear decisions in its review of domestic measures against mad cow
disease, Kamei said it will be hard to reach an early settlement.

Kamei repeated Japan's position that to remove its import ban, the
United States must implement safety measures similar to those Japan has
put into place against mad cow disease.

Tokyo imposed the ban after the first U.S. case of the brain-wasting
disease was confirmed in a Canadian-born cow in December.

"Taking measures equivalent of those in Japan is a basic requirement"
for the removal of the ban, Kamei said. "We will approach the talks in
such a way as to avoid damaging consumer trust."

Before removing its import ban, Tokyo wants the U.S. to agree to test
all slaughtered cattle for mad cow disease or provide equivalent safety
assurances. Washington maintains blanket testing is unscientific.

The Japan Times: Aug. 11, 2004
(C) All rights reserved

Release No. 0336.04

Office of Communications

Transcript of Remarks from Tele-news Conference with Agriculture
Secretary Ann M. Veneman, Under Secretary for Farm and Foreign
Agriculture Services J.B. Penn and Jerry Bange, Chairman, World Outlook
Board - Washington D.C. - August 13, 2004


ANNOUNCER: "Our next question will come from Bill Tomson from Oster Dow
Jones. Bill, go ahead."

QUESTION: "Hello. It's Bill Tomson with Dow Jones.

"I suppose this question is for Dr. Penn. Will you be traveling to Japan
later this month? And do you still believe that Japan will lift its beef
ban, the ban on U.S. beef by the end of the summer?"

SEC. J.B. PENN: "Bill, thanks for the question. As you know, we started
a process with the Japanese back in April, which we were to have a
series of technical working group meetings; and then that was to lead
into a report that would be evaluated by policy officials. That process
is still right on track, and I still plan to have consultations with my
counterparts in Japan.

"But we haven't set an exact date. As you know, there are lots of
discussions that are being held by various entities in the Japanese
government, and they're still evaluating the report from the working
group, and we want them to have ample time to do all of that before we

ANNOUNCER: "Our next question comes from Matt Kay from the Burns Bureau.
Go ahead, Matt."

QUESTION: "Thank you very much.

"Either for the Secretary or the Under Secretary, a follow-up on the
last question. And that is, based on the latest comments from Japan's
Farm Minister hinting that maybe it will take more time to conclude
these talks, is the situation worse now or better than it was when you
started these negotiations in terms of completing them in a timely fashion?

"And secondly, on the animal ID program, where are we on that now? And
how much of a total investment do you see before that's up and running?"

SEC. VENEMAN: "Well, let me just say a word about also what's going on
in Japan. First of all, I think it's very critical that people here
understand that Japan is working through this process, as are we on an
interagency basis. And so there have sometimes been comments by one
ministry or another, primarily the Ag Ministry, that I don't think
really reflect the inter-agency process that's going on.

"And so I know there have been some comments, but as Dr. Penn said he is
working very closely with his counterparts in Japan; and we are working
through the process that was laid out in April. And we feel that the
technical discussions have gone very well and are leading to good policy

"On animal ID, as you know last week we announced some initial grants,
primarily to states and tribes and other organizations, to begin to
implement this national identification program.

"This is the first tranche of such grants. We have put $33 million in
the budget for additional grants for this purpose in next year's budget.
We hope that that will pass through the Congress. And we anticipate that
we will begin to assign premise IDs sometime by the end of the summer,
maybe later by the end of the August. And so we think that the program
is progressing. It's going to take some time to implement on a
nationwide basis, but we're going to --as you know, many of the
livestock in this country already have some sort of identification. And
the first steps are really to take those animals that have
identification and put those into the national system. And this will be
a gradual process by which we will bring animals in and ultimately we
would anticipate that we would have a full-scale animal identification
system in this country which will help us track diseases very quickly
and that will help protect our livestock in this country from diseases."

ANNOUNCER: "Our next question comes from Ira Dreyfuss from Associated
Press. Ira, go ahead, please."

QUESTION: "Well, as always, I'd like to get two in. Are there any
specifics that you guys have lined up right now to deal with the
possibility that Charlie's going to come up the Coast, especially
through Georgia and South Carolina, North Carolina?

"The other is, what is the U.S. response to the suit that was filed
under NAFTA by the Canadian Cattle Group? Do they even have standing to
file? And has the U.S. government issued a formal response to it?"

SEC. VENEMAN: "If I might just, let me answer the first one, I mean the
second one first. And with regard to the Canadian case, we just saw
press reports of that today. We have not, as far as I know, seen any of
the actual documents that have been filed.

"I know that USTR will be looking closely at this as will the State

"But I don't think that at this point we have any more details than what
we've seen in press reports, which I'm sure you've seen as well.

"So again, we'll be, when we get the documents we'll have our lawyers
along with USTR lawyers and state lawyers looking at all of this to
determine what the grounds are for this action that they filed under NAFTA.

"As I mentioned at the end of my remarks, we are concerned about
Hurricane Charlie. We're watching it very closely. We have pictures of
the path of the hurricane which now looks like after it touches down in
Florida it will go up the East Coast hitting parts of Georgia, South
Carolina, North Carolina, Virginia and probably all the way up into New
York. And we are aware of certainly in Florida there are vegetable
crops, citrus, greenhouse that may be impacted. As you go further up,
poultry and hog houses, cotton, peanuts, corn, soybeans, tobacco could
all be impacted.

"This goes through the normal disaster process. A FEMA team will be
formed. Those will include USDA representatives to help farmers. It will
also include USDA representatives that help with people who are impacted
who need for example emergency food, Food Stamps and so forth.

"We're continuing to monitor this storm. That's part of what we do when
these kinds of situations are upon us. And we will be having USDA people
involved with necessary relief measures as expeditiously as possibly and
as effectively as possible."

ANNOUNCER: "Our next question comes from Jackie Thacker (sp) from Farm
Progress. Jackie, go ahead, please."

QUESTION: "Hello. Thank you. Again, this is Jackie Thacker from Farm

"My question is, is there any idea of when the rule might be released
for the Canadian border? I've heard some talk that it might be the end
of August or sometime in August."

SEC. VENEMAN: "Well, as you know this rule has had kind of a long
history. We first proposed it last fall. It was scheduled to have a
comment period that closed on January 5. We allowed that comment period
to end, but in the intervening time as you know we had the find of BSE
in this country.

"As a result, we reopened the rule for additional comment in the spring.
We have now been in the process of reviewing all of the comments. They
were much more numerous than we had originally anticipated. And we are
looking at the entire risk analysis that has to go along with such a
rule. And so at this point it is impossible to say how long this
rulemaking might take.

"We had initially thought that we could have a rule out much sooner. But
because of the number of comments and the complexity of the comments
that we received questioning the risk -- and you know some of what we
don't know in terms of prevalence, for example, we are trying to now
ascertain with our surveillance program. And we're getting good results
from that. But I think it will take us longer than August in order to
get this rule out."

ANNOUNCER: "Our next question is from Richard Cowan from Reuters, and
standing by should be Keith Merckx.

"Richard, go ahead, please."

QUESTION: "Yeah. Thank you.

"Back on Japan beef trade, Japanese officials have said it would be
impossible to have trade resuming quickly after any deal is reached,
that it could take several months. Have they told you anything
different, or are you still thinking as I think Dr. Penn said yesterday
that if there's a deal by late summer or early fall trade could resume
on that same timetable?"

DR. PENN: "Rick, this is JB. As I said earlier, this is a process. And
we have to work through the process. And as Secretary Veneman noted,
there are lots of comments by lots of officials, but it's still my
understanding that we are on track and working through our process. We
have said all along that we hope to conclude this process by the end of
summer and that it is our expectation that once we reach agreement on
the requirements for trade, resuming that trade, would actually resume
in a relatively short period after that.

"So I don't think anything has changed from what I've been saying all
along as we've tried to work through this process."


ANNOUNCER: "Our next question comes from Sally Schuff of Feedstuffs, and
standing by should be Lori Struve from Brownfield Network.

"Sally, go ahead, please."

QUESTION: "Thank you, Larry.

"Madam Secretary, my question concerns again the Canadian border. USDA
in conjunction with Mexico and Canada had appealed to OIE early on in
this BSE situation for some clarification on risk reach. Can you tell us
where that is and how that might impact the rule on reopening the border?"

SEC. VENEMAN: "Well, we have worked as you say closely together with
Mexico and Canada in the OIE. We've worked with a number of other
countries as well. And this is, for those of you who don't know the
initials OIE, this is the international standard setting body for animal
health. It's based in Paris. And it's been very helpful, particularly
with a disease like BSE, to help to bring together the latest science,
because as you know this is a disease that is relatively new. And the
science that we have keeps evolving.

"But the OIE, we have worked closely with Canada and with Mexico in
going to the OIE together and saying, give us some guidance on how this
kind of risk should be evaluated.

"And the meetings have been ongoing in that regard. We had meetings this
spring in the OIE, the regular spring meetings. There was a lot of
discussion with OIE. And we've continued to consult very closely with
the OIE folks in terms of the kinds of work that is coming within the
body of projects that they have on their plate.

"But again, as to your question about it impacting the rule, we are
undergoing a risk assessment. It doesn't have a direct effect on the
rule, but we want to follow OIE guidelines because it's an important
guideline of science with regard to this disease. We are going through a
process of sound science as we look at this rule and as we conduct
discussions within OIE science is what's guiding us."

ANNOUNCER: "Our next question will come from Lori Struve from Brownfield
Network. And standing by should be Jeff Nalley. Lori, go ahead with your
question, please."

QUESTION: "Yes, thank you. Actually my original question has already
been asked and answered. But I'm wondering what you're hearing back from
the animal ID hearings that are being held around the country right now,
and what in particular is standing out from the comments being heard?"

SEC. VENEMAN: "Well, I think that they're being very well-received. I
think Bill Hawks has done at least probably 10 or 12 of these so far and
has more scheduled. He's doing some this week as we speak. And his
response has been very positive in terms of -- I think one of the most
important things that's coming out of these hearings is an opportunity
for dialog and understanding about how this process will work.

"Obviously, producers are concerned about things like confidentiality.
And we're concerned about that as well. We're working very closely with
the Congress in terms of changes that will have to be made in the law.
And our lawyers are very involved in that.

"We're trying to work with people that are knowledgeable about
technology. We're working to try to get a system of identifying premises
so that there can be a common definition of premises that can be used
throughout the country.

"So there are a number of issues. And I think these hearings have been
very helpful in allowing people to discuss concerns and discuss how the
operation of this implementation will work.

"It's going to take some time, there's no question; but I think we're
off to a good start. And we're pleased that we're going to be able to
assign premise numbers hopefully by the end of the month."

ANNOUNCER: "And our final question today will come from Jeff Nalley,
Cromwell Ag Radio Network.

"Jeff, go ahead, please."

QUESTION: "Thank you, Madam Secretary, Larry, Mr. Penn and Mr. Bange.
Thanks for sharing time with us.

"The question might have been answered. I had to step away to do
markets, but I'll ask this.

"Mr. Penn, when we were talking about working in the negotiations with
the Japanese it was clear that we wanted those negotiations to take
place on a scientific level. I think I remember the Japanese saying they
wanted a scientific answer, a scientific base for these negotiations.

"Now as this element is becoming more politicized or becoming more known
in Japan, do you still feel like the opening of that market will be
based more on science and the facts, or the political attributes of the
consumers accepting the science?"

SEC. PENN: "I think, Jeff, you had it exactly right in the first part of
your question. The reason that we engaged in this process with the
Japanese is to try to develop the science and to help improve
understanding on both our parts as to what's involved with this disease.
This is a disease about which we're still learning lots. We're still
learning about the amelioration measures that need to be taken, how they
help reduce risk.

"So the working group discussions that we had with the Japanese were to
focus on a relatively small number of questions, all related to BSE. We
have worked through a lot of those and amazingly we have come to a much
better understanding on both sides.

"So what remains now is to work out details that reflect the scientific
basis that we have been able to establish on both our parts.

"So I think the ultimate result is going to be as we have wanted all
along, and that is that it be based on science-- because we are setting
precedents here and how we resolve this trade matter will I think be
important in determining how beef is traded globally for a long time to



GOD may not help us, but Japan just might, if it sticks to sound
science, not the BSee this administration is handing out ;

> One of the issues that needs to be resolved, Penn told reporters, is that
> of an agreeable cut-off age for testing. He did not elaborate about
> what the
> Japanese want, but said the U.S. has maintained that 30 months of age is
> appropriate to protect food safety.

the youngest age of BSE case to date is 20 months old; As at: 31 May
2003 Year of onset Age youngest case (mnths) Age 2nd youngest case
(mnths) Age 2nd oldest case (yrs.mnths) Age oldest case (yrs.mnths) 1986
30 33 5.03 5.07 1987 30 31 9.09 10.00 1988 24 27 10.02 11.01(2) 1989 21
24(4) 12.00(2) 15.04 1990 24(2) 26 13.03 14.00 1991 24 26(3) 14.02 17.05
1992 20 26 15.02 16.02 1993 29 30(3) 14.10 18.10 1994 30(2) 31(2) 14.05
16.07 1995 24 32 14.09 15.05 1996 29 30 15.07 17.02 1997 37(7) 38(3)
14.09 15.01 1998 34 36 14.07 15.05 1999 39(2) 41 13.07 13.10 2000 40 42
17.08 19.09 2001 48(2) 56 14.10 14.11 2002 51 52 15.08 15.09(2) 2003 50
62 11.11 14.11

The implications of the Swiss result for Britain, which has had the most
BSE, are complex. Only cattle aged 30 months or younger are eaten in
Britain, on the assumption, based on feeding trials, that cattle of that
age, even if they were infected as calves, have not yet accumulated
enough prions to be infectious. But the youngest cow to develop BSE on
record in Britain was 20 months old, showing some are fast incubators.
Models predict that 200-300 cattle under 30 months per year are infected
with BSE and enter the food chain currently in Britain. Of these 3-5
could be fast incubators and carrying detectable quantities of prion.

1: Vet Rec. 1998 Jan 31;142(5):103-6. Related Articles,


Preliminary observations on the pathogenesis of experimental bovine
spongiform encephalopathy (BSE): an update.

Wells GA, Hawkins SA, Green RB, Austin AR, Dexter I, Spencer YI, Chaplin
MJ, Stack MJ, Dawson M.

Veterinary Laboratories Agency, Central Veterinary Laboratory, New Haw,
Addlestone, Surrey.

> Previous reported observations have included the presence of
> infectivity in the distal ileum of cattle killed after six to 18
> months, the earliest onset of clinical signs in an exposed animal
> after 35 months, and diagnostic histopathological changes in the
> brain, in association with clinical disease, after 36, 38 and 40 months.


Early accumulation of PrPSc in gut-associated lymphoid and
nervous tissues of susceptible sheep from a Romanov flock
with natural scrapie
Olivier Andre! oletti,1 Patricia Berthon,2 Daniel Marc,2 Pierre
Sarradin,2 Jeanne Grosclaude,3
Lucien van Keulen,4 François Schelcher,1 Jean-Michel Elsen5 and Fre! de!
ric Lantier2
1UMR INRA-ENVT, Physiopathologie Infectieuse et Parasitaire des
Ruminants, Ecole Nationale Ve! te! rinaire de Toulouse, Toulouse, France
2 INRA, Laboratoire de Pathologie Infectieuse et Immunologie, F-37380
Nouzilly, France
3 INRA, Virologie et Immunologie Mole! culaires, Jouy-en-Josas, France
4 Department of Immunology, Pathobiology and Epidemiology, Institute for
Animal Science and Health (ID-Lelystad), Lelystad,
The Netherlands
5 INRA, Station dAme! lioration Ge! ne! tique des Animaux, Auzeville,

PrPSc deposits are associated with TSE pathogenesis and
IHC detection of this pathological PrP isoform is routinely
used as a hallmark of these diseases (Kitamoto et al., 1987;
Lantos et al., 1992). In our study, similar patterns of PrPSc
accumulation were observed using either the rabbit antiserum
R521 or the mouse MAb 2G11. R521 has been used previously
for IHC studies on ovine scrapie (van Keulen et al., 1995,
1996; Schreuder et al., 1996, 1998). Moreover, MAb 2G11
appears to be highly speciÆc for PrPSc, with no labelling of the
cellular PrP under our experimental conditions (Andre! oletti et
al., 1999), and therefore constitutes a useful tool for the IHC
detection of ovine PrPSc. Our method, using the rabbit
antiserum R521, has been evaluated in a procedure for the
standardization of IHC protocols for PrPSc detection in ovine
palatin tonsils (European proposal FAIR-PL 97±6013) and
showed a marked improvement in the quality of ovine PrPSclabelling
compared to other methods.
At the clinical stage of the disease, PrPSc was detected in
both the lymphoid tissues and in the CNS of VRQ}VRQ
sheep, whereas in VRQ}ARR sheep, PrPSc deposits were seen
only in the CNS. Similar Ændings have been reported
previously in natural scrapie of Texel sheep (van Keulen et al.,
1996; Schreuder et al., 1996, 1998). Taken together, these data
suggest that sheep carrying the PrP allele ARR do not
accumulate PrPSc in the lymphoid tissues.
The kinetics of scrapie dissemination in ovine lymphoid
tissues have only been slightly documented to date (Hadlow et
al., 1982). Our study revealed a very early PrPSc deposition in
VRQ}VRQ sheep. In one animal of this genotype, PrPSc was
detected as early as 2 months of age in the ileal Peyer's patches
and in the ileal mesenteric lymph node. Between 2 and 6
months of age, PrPSc-labelling extended to all other GALT, the
palatine tonsils and their draining lymph nodes. During this
time, GALT-unrelated lymphoid tissues became positive in
some individuals, although PrPSc-labelling was still weaker
both in its intensity and in its extent. Finally, at 9 months of
age, PrPSc was deposited in all the investigated lymphoid
tissues, except for the thymus.
PrPSc accumulation in the palatine tonsil biopsies has been
previously observed in naturally exposed Texel VRQ}VRQ
Early oral contamination in natural scrapie
sheep at the age of 4 months, more than 20 months before the
occurrence of clinical signs (Schreuder et al., 1998). In our
study, tonsils were found to be already PrPSc-positive in most
of the VRQ}VRQ sheep at the age of 3 months. All these data
strongly argue for a very early scrapie infection by the oral
route under natural conditions and point to the ileal Peyer's
patch as a likely primary entry site of the scrapie agent. After
experimental oral ingestion of infectious brain material in mice
(Maignien et al., 1999) and in deer (Sigurdson et al., 1999),
Peyer's patches and the draining mesenteric lymph nodes
became PrPSc-positive 45 days post-inoculation. Comparison
of our results to these data suggests that, at least for the oral
route, natural contamination may be as eæcient as experimental
The distribution of PrPSc deposits among Peyer's patch
cells showed a sequential pattern : early steps of scrapie
infection Ærst involved cells located in dome areas between the
specialized lymphoepithelium and B follicles. Subsequently,
PrPSc deposits were visualized in both mantle and centrofollicular
cells of B follicles and, at later times, were detected
mainly in centrofollicular cells. During this later period, PrPSc
deposits in the domes of the Peyer's patches decreased
progressively. It seems therefore, that after penetration
through Peyer's patches, PrPSc spreads to the centrofollicular
area where it can persist in its target follicular dendritic cells.
In the domes of the Peyer's patches, double-labelling
techniques demonstrated an exclusive localization of PrPSc
granulation in CD68 cells and no PrPSc accumulation was seen
in B or T lymphocytes. In humans, the CD68 epitope deÆned
with the MAb Ki-M6 is speciÆcally expressed by macrophages
(Parwaresch et al., 1986). In sheep lymphoid tissues, some
CD68 cells showed a morphology indicative of interdigitating
dendritic cells rather than macrophages, although these two
cell types are derived from a common progenitor (Randolph et
al., 1999). Nevertheless, it has been proposed that phagocytic
cells present in the domes of the Peyer's patches, such as CD68
cells, could act as antigen-transporting cells from the lymphoepithelium
to follicular dendritic cells (Szakal et al., 1983;Berney
et al., 1999). Therefore, the presence of PrPSc deposits in these
cells may provide a clue to the early stages of infection. Uptake
of the scrapie infectious agent from the digestive tract could be
achieved by lymphoepithelial M cells, just as with the uptake
of bacteria or inert particles (Owen, 1999; Beekes & McBride,
2000). Then CD68 cells may transport the infectious agent to
follicular dendritic cells where a primary replication, or at least
a concentration, may occur. Whether PrPSc granulation in
CD68 cells results from a passive transport of an exogenous
PrPSc or from an endogenous replication is still unknown,
although the amount of PrPSc accumulated in those cells may
favour the second hypothesis. According to recent studies in
mice, prion replication depends on PrP-expressing follicular
dendritic cells without any direct involvement of bone marrowderived
cells such as lymphocytes or myeloid cells (Brown et
al., 1999). However, cellular mechanisms of scrapie pathogenesis
could diåer from one species to another and, in our
opinion, myeloid cells (such as macrophages or interdigitating
dendritic cells) could also be involved in scrapie replication in
sheep. Further investigations are required to address this
Entry of the scrapie agent into ileal Peyer's patches was
followed by its spread within the whole GALT. Numerous
cells with cytoplasmic PrPSc granulation were observed
apparently migrating through lymph node sinusal formations,
indicating a lymphatic}vascular dissemination pathway. A less
extensive PrPSc accumulation was observed in more systemic
lymphoid organs such as the spleen. This suggests that prion
dissemination depends on cells migrating preferentially
through gut-associated lymphoid formations.
PrPSc deposits were observed in the autonomic myenteric
nervous system only after their dissemination in lymphoid
tissues. It must be noted that the dissemination through the
enteric nervous system showed a pattern similar to that
observed in the GALT, with a primary involvement of ileal
structures, followed by a spread to more proximal and distal
segments. On this point, our observations are in agreement
with those previously obtained in Texel sheep (van Keulen et
al., 1999a, b). Furthermore, the preferential accumulation of
PrPSc in neurons close to PrPSc-positive Peyer's patches could
suggest that a scrapie passage from lymphoid structures to the
nervous system occurs there at the level of the nervous Æbres
innervating these lymphoid tissues (Beekes & McBride, 2000).
Lymphoid organs could thus act as a primary replication site
and as a reservoir for the scrapie agent, facilitating infection of
the nervous system. Comparison of VRQ}ARR and VRQ}
VRQ sheep in the Langlade Øock may oåer some facts
supporting this view. VRQ}ARR animals, of which fewer than
5% eventually develop the disease, do not accumulate PrPSc in
their lymphoid tissues, whereas VRQ}VRQ animals, of which
80% die of scrapie after a relatively short incubation period, do
accumulate PrPSc in their lymphoid system. Thus, it seems that
replication and accumulation of the scrapie agent in lymphoid
tissues is required for an eæcient and rapid spread of infection
to the nervous system. After reaching the autonomous nervous
system, the scrapie agent could reach the CNS through an
axonal pathway (Race et al., 2000). Our observation of a
primary deposition in the nucleus parasympathicus nervi X,
which is the origin of the autonomic nervous system
innervating the digestive tract, is a clue which supports this
hypothesis. In contrast to a previous report (van Keulen et al.,
1999b), in which spinal cord was described as the Ærst site of
CNS accumulation in sheep with natural scrapie, we did not
observe any PrPSc deposition in spinal cord segments. This is
probably due to a non-systematic sampling of the spinal cord
in our study and does not interfere with our hypothesis.
Furthermore, in hamsters orally infected with scrapie an
independent pathway to the brain has been demonstrated,
bypassing the spinal cord after the uptake of the scrapie agent
via the gastro-intestinal tract (Baldauf et al., 1997).
O. Andre! oletti and others
The incubation period and pathogenesis of scrapie results
from interactions of the agent isolate with the host PrP
genotype. Several scrapie strains have been identiÆed in sheep
(Bruce & Fraser, 1991; Bruce et al., 1997) and the allelic
distribution of the PrP gene diåers between Øocks and breeds
of sheep (Dawson et al., 1998). In the context of our naturally
scrapie-infected Øock of Romanov sheep (Elsen et al., 1999), the
data obtained from the VRQ}VRQ sheep strongly suggest
that an early natural scrapie infection occurs via the oral route
and point to the ileal Peyer's patch as a likely primary entry site
of the scrapie agent. Subsequently, it appears that replication
and dissemination of the infectious agent takes place in the
secondary lymphoid organ system via the lymphatic}vascular
pathway. Infection of the autonomic myenteric nervous
system, possibly facilitated through infection of the GALT,
could Ænally lead to a spread of the scrapie agent to the CNS.
The level of infectivity in the GALT could inØuence the
eæciency of infection of the autonomic nervous system and its
spread to the CNS. However, our model, which is supported
by the experimental data from our Romanov Øock, does not
rule out the possibility of other alternative peripheral routes of
infection, such as skin lesions (Dickinson et al., 1968; Goldmann
et al., 1994; Taylor et al., 1996). Further investigations are
clearly needed for us to understand the early events of scrapie
contamination and to evaluate the role of alternative pathways.
Nevertheless, infection of the GALT may lead to the shedding
of scrapie infectivity to the environment and thus indirectly
contribute to the horizontal transmission of scrapie that is
observed under natural Æeld conditions.
This work has been supported by the EU (grant FAIR-PL 97±6013)
and the French TSE Interministerial Committee (grant ACC2).
The authors wish to deeply thank Dr E. Monks (Veterinary Research
Laboratories, Dublin, Ireland) for critical reading of the manuscript. We
gratefully acknowledge the Experimental Unit of Langlade (De! partement
de Ge! ne! tique Animale, INRA), especially Francis Eychenne and Eric
Lecloux, for their expert care of the provided animals. We should like also
to acknowledge Thierry Delaunay for production of MAb 2G11. We are
grateful to the assistants of the National Veterinary School of Toulouse
for their help in sheep necropsies. Many thanks to Colette Chetcutti and
Abdelkader Bouzar for their technical assistance in performing all the IHC
tissue sections and to Labogena (Jouy-en-Josas, France) for ovine PrP


Preclinical deposition of pathological prion protein PrPSc in muscles of
hamsters orally exposed to scrapie
Achim Thomzig,1 Walter Schulz-Schaeffer,2 Christine Kratzel,1 Jessica
Mai,1 and Michael Beekes1

1Robert Koch-Institut, P26  Pathogenese und Diagnostik Transmissibler
Spongiformer Enzephalopathien, Berlin, Germany. 2Universitätsklinikum
Göttingen, Institut für Neuropathologie, Göttingen, Germany.

Address correspondence to: Michael Beekes, Robert Koch-Institut (P26 
Pathogenese und Diagnostik Transmissibler Spongiformer
Enzephalopathien), Nordufer 20, 13353 Berlin, Germany. Phone:
49-30-4547-2396; Fax: 49-30-4547-2267; E-mail:

Received January 15, 2004; Accepted April 2, 2004.


Our studies demonstrate that PrPSc can be detected in skeletal muscles
of hamsters fed with scrapie before the animals show clinical signs of
disease. Preclinical detection of pathological prion protein in muscle
tissues was confined to relatively late stages of the asymptomatic phase
of incubation, however. The bulk of muscle-associated PrPSc accumulated
during clinical disease and all examined skeletal muscles and tongue
specimens from terminally ill hamsters contained substantial amounts of
PrPSc in accordance with previous observations (12
The accumulation of PrPSc found in the latter group of animals was
accompanied by the consistent presence of at least 2 ? 103 to 10 ? 103
LD50ic of scrapie agent per gram of tissue in the M. biceps femoris, M.
trapezius, M. psoas major, and lingual muscle. PET blot and IHC
examinations corroborated the Western blot findings in our hamsters and
provided new detailed information on the distribution and location of
PrPSc in muscle tissue. Since the animal model used in this study in the
past has been frequently found to exhibit key pathogenetic features of
peripheral PrPSc routing (4
in several different alimentarily acquired and naturally occurring TSEs
of animals and humans (14
the findings reported here may well have several relevant implications:

The experimental study of the pathogenesis of BSE after oral exposure of
cattle conducted in the UK (Wells et al 1994, Wells et al. 1996, Wells
et al.,
1998, EC 2002, Terry et al., 2003) has examined certain PNS tissues. Thirty
Friesian/Holstein calves, were each dosed orally at four months of age with
100g of pooled brain stems from cases of BSE. Groups of exposed animals
and controls were killed sequentially at mainly 4 month intervals, with the
final kill at 40 months p.i. Tissues were sampled aseptically for
assays in conventional/wild type mice. After each sequential kill,
inocula were
prepared from 44 tissues, representing principally the lymphoreticular
(LRS), the peripheral nervous system (PNS) and the central nervous system
(CNS), alimentary tract, striated muscles and major viscera (see Table 3.1,
Wells and others, 1996). Inoculum pools of each tissue were made from all of
the exposed cattle at each time point. Infectivity was detected in the
ileum from 6 to 18 and from 36 to 40 months after exposure.


F:\WebDev\Autonomic nervous system_OPINION_0303_FINAL.doc- 7
Evidence from the British
pathogenesis study of BSE (Wells et al., 1998, Update of the Opinion on
Tissue Infectivity Distribution in Ruminant Tissues, EC 2002b) also suggests
SSC meeting of 6-7 March 2003 / 6.2.e
that there is no clear disparity in the temporal involvement (as
indicated by
mouse infectivity and PrP immunohistochemistry) in the spinal cord (and
DRG) and the brain stem, an observation which can best be explained, as in
the rodent models and in natural scrapie, by dual routes of
neuroinvasion, but
in BSE with the neuroinvasion of brain resulting from sensory pathways. The
recent finding of infectivity in tonsil 10 months after oral exposure in the
pathogenesis study (see, Update of the Opinion on Tissue Infectivity
Distribution in Ruminant Tissues, EC 2002b) , raises the possibility
that such
a pathway for infection could arise in the innervation of the soft
It is also of interest that in an experimental model of transmissible mink
encephalopathy (TME) in the hamster (Bartz et al 2003) rapid neuroinvasion
of the CNS resulted from inoculation of prions into the tongue,
implicating a
cranial nerve route of spread which was more efficient than other non neural
routes, including another intramuscular route of inoculation.

> An agreement with Japan on BSE and trade could set a precedent for
> agreements around the world (GOD HELP US)

THIS would only lead to the further spreading and enhancement of
increased spreading of the TSE agent to
both animals and humans.

AS i said, only Japan can help us here in the USA, we cannot depend on


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