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From: TSS ()
Subject: SEAC 96th MEETING ON TUESDAY 20 FEBRUARY 2007 AGENDA (HIGH SUSCEPTIBILITY OF A PRIMATE SPECIES TO THE BASE)
Date: February 13, 2007 at 2:46 pm PST


Agenda
96th meeting on Tuesday 20 February 2007


http://www.seac.gov.uk/minutes/95.pdf


CONFERENCE ON PRION DISEASES OF NEUROPRION, NETWORK OF EXCELLENCE, TURIN, ITALY, 3-6 OCTOBER 2006


BASE

OUR OBSERVATIONS UNDERLINE THE HIGH SUSCEPTIBILITY OF A PRIMATE SPECIES TO THE BASE PRION STRAIN AND PROVIDE A BIOCHEMICAL BASIS FOR THE IDENTIFICATION OF A POTENTIAL OCCURRENCE IN MAN. ...page 9...tss


http://www.seac.gov.uk/papers/96-2.pdf

UPDATE ATYPICAL SCRAPIE IN A TSE RESEARCH FLOCK

http://www.seac.gov.uk/papers/96-4.pdf


> Some unofficial information from a source on the inside looking out -
>
> Confidential!!!!
>
> As early as 1992-3 there had been long studies conducted on small
> pastures containing scrapie infected sheep at the sheep research station
> associated with the Neuropathogenesis Unit in Edinburgh, Scotland.
> Whether these are documented...I don't know. But personal recounts both
> heard and recorded in a daily journal indicate that leaving the pastures
> free and replacing the topsoil completely at least 2 feet of thickness
> each year for SEVEN years....and then when very clean (proven scrapie
> free) sheep were placed on these small pastures.... the new sheep also
> broke out with scrapie and passed it to offspring. I am not sure that TSE
> contaminated ground could ever be free of the agent!!
> A very frightening revelation!!!
>


http://www.microbes.info/forums/index.php?showtopic=306

Science 24 September 2004:
Vol. 305. no. 5692, pp. 1918 - 1921
DOI: 10.1126/science.1103581

Perspectives
BIOMEDICINE:
A Fresh Look at BSE
Bruce Chesebro*
Mad cow disease, or bovine spongiform encephalopathy (BSE), is the cattle
form of a family of progressive brain diseases. These diseases include
scrapie in sheep, Creutzfeldt-Jakob disease (CJD) in humans, and chronic
wasting disease (CWD) in deer and elk. They are also known as either "prion
diseases" because of the association of a misfolded cellular prion protein
in pathogenesis or "transmissible spongiform encephalopathies" (TSEs)
because of the spongelike nature of the damaged brain tissue (1).

The recent discovery of two BSE-infected cows, one in Canada and one in the
United States, has dramatically increased concern in North America among
meat producers and consumers alike over the extent to which BSE poses a
threat to humans as well as to domestic and wild animals. The European BSE
epidemic of the late-1980s seems to have been initiated a decade earlier in
the United Kingdom by changes in the production of meat and bone meal (MBM)
from rendered livestock, which led to contamination of MBM with the BSE
infectious agent. Furthermore, the fact that UK farmers fed this rendered
MBM to younger animals and that this MBM was distributed to many countries
may have contributed to the ensuing BSE epidemic in the United Kingdom and
internationally (2).

Despite extensive knowledge about the spread of BSE through contaminated
MBM, the source of BSE in Europe remains an unsolved mystery (2). It has
been proposed that BSE could be derived from a cross-species infection,
perhaps through contamination of MBM by scrapie-infected sheep tissues (see
the figure). Alternatively, BSE may have been an endemic disease in cattle
that went unnoticed because of its low level of horizontal transmission.
Lastly, BSE might have originated by "spontaneous" misfolding of the normal
cellular prion protein into the disease-associated abnormal isoform (3),
which is postulated to be the infectious agent or "prion."

Five possible sources of BSE in North American cattle. Sheep, deer, and elk
could spread prion diseases (TSEs) to cattle through direct animal contact
or contamination of pastures. Endemic BSE has not been proven to exist
anywhere in the world, but it is difficult to exclude this possibility
because of the inefficient spread of BSE infectivity between individual
animals (2). BSE caused by spontaneous misfolding of the prion protein has
not been proven.
CREDIT: KATHARINE SUTLIFF/SCIENCE

Spontaneous protein misfolding is not a new phenomenon as proteins are known
to sometimes misfold after synthesis. Cells in turn have devised ingenious
ways to deal with this problem. These include molecular chaperone proteins
that bind to misfolded proteins and help them to unfold, and organelles
called proteosomes that degrade misfolded or unwanted proteins. However,
although misfolded prion proteins have been generated in test tubes as well
as in cultured cells, it has been difficult to demonstrate that such
misfolded abnormal prion proteins are infectious (4, 5). Even the most
recent data do not prove conclusively that infectivity has been generated in
vitro because misfolded synthetic prion proteins were not able to transfer
disease directly to wild-type mice (6). To obtain infectivity and subsequent
prion disease, the misfolded proteins had to be inoculated and incubated for
1 to 2 years in transgenic mice that overexpressed a mutant version of the
prion protein. Previous data from this group showed that transgenic mice
expressing high amounts of prion protein developed neurological disease
without inoculation of misfolded prion protein (7). Thus, at the biochemical
level, the critical attributes of the misfolded prion protein required for
infectivity are not known, and misfolding of prion protein alone may not be
sufficient to generate an infectious agent (.
Nevertheless, the idea that BSE might originate due to the spontaneous
misfolding of prion proteins has received renewed interest in the wake of
reports suggesting the occurrence of atypical BSE (9-11). These results
imply that new strains of cattle BSE might have originated separately from
the main UK outbreak. Where and how might such strains have originated?
Although such rare events cannot be studied directly, any number of sources
of the original BSE strain could also explain the discovery of additional
BSE strains in cattle (see the figure). However, it would be worrisome if
spontaneous BSE were really a valid etiology because such a mechanism would
be impossible to prevent--unlike other possible scenarios that could be
controlled by large-scale eradication of TSE-positive animals.

Another way to look at this problem is to examine evidence for possible
spontaneous TSE disease in other animals besides cattle. Spontaneous BSE
would be extremely difficult to detect in cattle, where horizontal spread is
minimal. However, in the case of the sheep TSE disease, scrapie, which
spreads from ewes to lambs at birth as well as between adults, spontaneous
disease should be detectable as new foci of clinical infection. In the early
1950s scrapie was eradicated in both Australia and New Zealand, and the
mainland of both these countries has remained scrapie-free ever since. This
scrapie-free status is not the result of selection of sheep resistant to
scrapie because sheep from New Zealand are as susceptible as their UK
counterparts to experimental scrapie infection (12). These experiments of
man and nature appear to indicate that spontaneous clinical scrapie does not
occur in sheep. Similarly, because CWD is known to spread horizontally, the
lack of CWD in the deer or elk of eastern North America but its presence in
western regions would also argue against a spontaneous disease mechanism.
This is particularly noteworthy in New Zealand, where there are large
numbers of deer and elk farms and yet no evidence of spontaneous CWD. If
spontaneous scrapie does not occur in sheep or deer, this would suggest that
spontaneous forms of BSE and sporadic Creutzfeldt-Jakob disease (sCJD) are
unlikely to be found in cattle or humans. The main caveat to this notion is
that spontaneous disease may arise in some animal species but not others. In
humans, sCJD--which is considered by some researchers to begin by
spontaneous misfolding of the prion protein--usually takes more than 50
years to appear. Thus, in animals with a shorter life-span, such as sheep,
deer, and cattle, an analogous disease mechanism might not have time to
develop.

What can we conclude so far about BSE in North America? Is the BSE detected
in two North American cows sporadic or spontaneous or both? "Sporadic"
pertains to the rarity of disease occurrence. "Spontaneous" pertains to a
possible mechanism of origin of the disease. These are not equivalent terms.
The rarity of BSE in North America qualifies it as a sporadic disease, but
this low incidence does not provide information about cause. For the two
reported North American BSE cases, exposure to contaminated MBM remains the
most likely culprit. However, other mechanisms are still possible, including
cross-infection by sheep with scrapie or cervids with CWD, horizontal
transmission from cattle with endemic BSE, and spontaneous disease in
individual cattle. Based on our understanding of other TSEs, the spontaneous
mechanism is probably the least likely. Thus, "idiopathic" BSE--that is, BSE
of unknown etiology--might be a better term to describe the origin of this
malady.

What does all this imply about testing cattle for BSE in North America?
Current testing in the United States indicates that BSE is rare (one
positive result in 40,000 cattle tested). However, additional testing of
200,000 head of slaughtered cattle over the next 1 to 2 years, as recently
proposed by the U.S. Department of Agriculture (USDA), should tell us the
incidence more precisely. Nevertheless, if any rare cases are detected, we
may still not know their origin. If evidence arises of a focal occurrence of
BSE, we might gain important insight into unexpected sources of
contamination. However, because current tests do not seem to be able to
detect BSE in infected animals less than 30 months of age, even more
extensive testing will not completely guarantee the negative status of
younger animals in the food chain. Therefore, the alternative option of
testing all slaughtered cattle, as implemented in some countries such as
Japan, would appear to provide little additional benefit. This fact has been
acknowledged as the basis for a new agreement between the United States and
Japan aimed at reestablishing the beef trade between the two countries.

One problem with the current U.S. testing program was the announcement a few
months ago of unconfirmed positive BSE tests in two additional North
American animals that were subsequently found to be negative when tested
with the more accurate method of Western blotting. The public release of
information about unconfirmed positive tests detected by the rapid test used
for mass screening may be a good idea in the interest of openness, but it ha
s the potential to create unwarranted anxiety. If unconfirmed positives are
a frequent occurrence, it would seem reasonable to follow a more cautious
approach and wait until confirmatory testing is complete before publicly
announcing the details.

Based on the experience of many European countries, the mainstays of
controlling BSE in cattle and avoiding spread to humans are threefold:
first, eliminate feeding of ruminant tissues to ruminants; second, remove
high-risk cattle tissues from human food; and third, continue to test for
BSE in cattle in order to monitor progress with the elimination of the
disease on a local and national basis. In the next 12 months, after
extensive USDA test results are available, the extent of any possible BSE
spread in the United States will be better documented. But, in fact, the
United States and Canada have already instituted the most important steps to
prevent the spread of cattle BSE in advance of the results--that is, a ban
on feeding ruminant MBM to other ruminants and removal of high-risk tissues
from meat for human consumption. It is hoped that the new data will not
deviate enough from previous predictions to require further measures for
management of this problem. The most important line of defense against any
possible spread of BSE will be to maintain strict vigilance in the
implementation of the current regulations.

References


S. B. Prusiner, Proc. Natl. Acad. Sci. U.S.A 95, 13363 (1998) [Medline].
P. G. Smith, R. Bradley, Br. Med. Bull. 66, 185 (2003) [Medline].
C. Weissmann, A. Aguzzi, Curr. Opin. Neurobiol. 7, 695 (1997) [Medline].
A. F. Hill et al., J. Gen. Virol. 80, 11 (1999) [Medline].
R. Chiesa et al., J. Virol. 77, 7611 (2003) [Medline].
G. Legname et al., Science 305, 673 (2004).
D. Westaway et al., Cell 76, 117 (1994) [Medline].
B. Chesebro, Science 279, 42 (1998).
A. G. Biacabe et al., EMBO Rep. 5, 110 (2004) [Medline].
Y. Yamakawa et al., Jpn. J. Infect. Dis. 56, 221 (2003) [Medline].
C. Casalone et al., Proc. Natl. Acad. Sci. U.S.A. 101, 3065 (2004)
[Medline].
E. F. Houston et al., J. Gen. Virol. 83, 1247 (2002) [Medline].

http://www.sciencemag.org/cgi/content/full/305/5692/1918

However, Phillips did not have an explanation of how the first cow got BSE and other

explanations continue to be put forward. One journalist commented on the idea favoured

by the Phillips Committee that BSE started with a spontaneous mutation:

However, apart from there being little evidence for the idea, a random mutation

could not explain why Britain alone has suffered the problem. America, for

instance, has 10 times the number of cattle, and so must in theory run ten times

the risk of a similar random event leading to BSE and so being passed on in

recycled meat and bone meal.13

http://www.parliament.uk/commons/lib/research/rp2001/rp01-089.pdf

Evaluation of the Potential for Bovine Spongiform

Encephalopathy in the United States

Joshua T. Cohen

Keith Duggar

George M. Gray

Silvia Kreindel

Harvard Center for Risk Analysis

Harvard School of Public Health

Hatim Abdelrahman

Tsegaye HabteMariam

David Oryang

Berhanu Tameru

Center for Computational Epidemiology

College of Veterinary Medicine

Tuskegee University

November 26, 2001

snip...

2.3.1 Spontaneous BSE

A potential way in which BSE could be introduced into the United States is the

development of a spontaneous case of a BSE in a native animal. A “spontaneous case” is one that

occurs in an animal with no known risk factors for development of BSE. The presumed

mechanism by which a BSE could occur spontaneously is by the mutation of the PrP gene to a

Section 2

- 20 -

form that codes for PrPsc, and subsequent recruitment of PrPc until disease is manifest (Prusiner,

1989); (for review see: (Chesebro, 1999). There is no direct evidence of this mechanism,

although some argue that all mammals might have a low spontaneous rate of TSE (Hueston,

1997). In addition, a transgenic animal over-expressing the PrP gene has apparently replicated

the human TSE GSS (Hsiao et al., 1991). Recent results, in which mice expressing the same

point mutation but at normal levels failed to develop disease (Manson et al., 1999), suggest the

mutations may increase susceptibility rather than directly cause the disease. Although at this time

there is no scientific evidence suggesting that spontaneous BSE exists, the BSE Inquiry suggested

that TSEs could possibly develop sporadically in other species, as they do in humans (BSE

Inquiry, 2000). In contrast, the Review of the origin of BSE (Horn et al., 2001) concluded that

although the spontaneous case hypothesis cannot be excluded, there is no evidence supporting the

presence of sporadic form prion disease in cattle or sheep.

snip...

http://www.aphis.usda.gov/lpa/issues/bse/risk_assessment/mainreporttext.pdf

http://www.aphis.usda.gov/lpa/issues/bse/madcow.pdf

REPORT ON : THE RISK BORN BY RECYCLING ANIMAL BY-PRODUCTS AS FEED WITH
REGARD TO PROPAGATING TSE'S IN NON-RUMINANT FARMED ANIMALS. PREPARED BY A
WORKING GROUP FOR THE SCIENTIFIC STEERING COMMITTEE AS AN INPUT IN THE
ELABORATION OF THE OPINION ON THE SAME SUBJECT ADOPTED ON 16-17 SEPTEMBER
1999.
September 1999
The European Commission


snip...


The final outcome should contribute to the assessment of the possibility
of transmission of TSE to fish, the evaluation of the potential risk
connected to fish derived foods for human and animal, the establishment of
analytical protocols for PrP detection in fresh fish food and the
comparison of the molecular properties of normal and abnormal isoforms of
PrP. d. Ruminants A large number of experiments, abundantly reported on
in the scientific literature, has shown that cattle and sheep are
susceptible to TSE's originating from their own species and that ruminants
in general fed with infectious material originating from the same species
can be infected with TSE's. Also, experimental evidence (EC, 1998) shows
that BSE can be transmitted to sheep (and goats) via the oral route7. If
a spontaneous TSE occurred in cattle, one might reasonable have expected
this to have occurred in detectable levels of a BSE-like disease in a much
larger number of countries than presently is the case, and where the
rendering systems used are very much alike those used in the EU prior to
1992, that implies not in accordance with the EU rendering directive
90/667. The potential occurrence of spontaneous TSE in cattle has till yet
not lead to detectable levels of cattle TSE in most countries, and in
countries where TSE in cattle occurs, this has so far not been attributed
to spontaneous cases. In fact, most of the BSE incidence in countries
where native BSE occurs, is accounted for by feeding of infected or
contaminated feedstufs. It must nevertheless be mentioned that, following
epidemiological investigations after the occurrence of a case, not all BSE
cases can always be brought back to proven feeding practices.
(E.Vanopdenbosch, 1998, personal communication) If scrapie would also
spontaneously occur in sheep, it would more likely occur in those sheep
with the most susceptible PrP genotypes. However, it is now known that a
significant proportion of Australian and New Zealand sheep have such
genotypes, but have not developed scrapie (Hunter et al, 1997). e. Pigs,
poultry and fish as possible silent carriers Marsh et al (1969) reported
the recovery of transmissible mink encephalopathy (TME) infectivity from
the spleen of one chicken and from the spleen, caecum, tonsil and bursa of
Fabricius of a second chicken of two chickens challenged experimentally by
i/v inoculation of fourth passage mink brain with TME. They noted that
infectivity administered either intra-cranial, intra-venous,
intra-muscular or subcutaneously, persisted for extended periods (30 and
50 days in the case of chickens) in lymphoid tissues of rhesus monkeys,
chickens, mice, cats, ferrets, goats and calves that were studied. No
experimental data are available about oral infectivity tests. Race and
Chesebro (1998), reported the results of i/c challenge of mice with
hamster scrapie strain 263K that produces no clinical disease in mice,
followed by sub-passage from brain and spleen into further mice and into
scrapie susceptible hamsters. Infectivity was detected in the spleen and
brain tissues by the hamsters, but not by the mice. The authors' view was
that the mice had not replicated the agent. They noted that they had not
tested to see if the same results were obtained after oral challenge.
However, they suggested that food animal species resistant to BSE, such as
poultry, exposed to BSE infectivity via feed but might show persistent
infectivity in their tissues without replication. Over 80% of pig meat
and 80% of poultry meat produced in the EU originates from pigs less than
8 months of age and broilers less than 2 months of age respectively.
However, the life expectancy of both pigs and chickens raised for
slaughter may be too short to show any signs of SE-s whenever they are
infected. Taking account of all our knowledge on prion diseases in
animals, it is unlikely that clinical evidence of disease would occur at
such a young age. Only adult breeding pigs would be expected to be old
enough to exhibit clinical signs if ever a TSE of pigs was found. However,
it can be hypothesized that infectivity of extra-neural tissues,
particularly lymphoreticular tissues, could theoretically arise in these
species exposed to TSE infection via feed whether or not replication and
neuroinvasion subsequently occurred. The results of the studies using the
BSE agent mentioned above do not support the hypothesis that infectivity
can be sequestered in the manner described and particularly this is a
unlikely event in pigs exposed to the BSE agent by the oral route two
years earlier. It is noted however, that these studies used mice to detect
any infectivity, cattle would be more susceptible. Furthermore the results
of bioassays done at the termination of the porcine studies are still
awaited as are those from poultry (see also sections 7.a and 7.b).
However, special attention should be drawn to the eventuality that in pigs
under natural conditions the intestinal barrier is would be very
efficacious in respect to the development of clinical TSE, but that by
feeding infected ruminant MBM and/or intraspecies recycling of pigs with
low levels of infectivity, an increasing level of infectivity could be
built up in the intestine. Such low levels could only be detected by the
most sensitive methods i.e. intracerebral inoculation of calves with
intestinal tissue of orally exposed pigs. This would be in accordance with
the results of the experiments of Race and Cesebro to detect infectivity
in resistant species. f. Risks related to the content of the gut and to
manure (faeces) The content of the gut and manure represent an increased
risk, if the animals were fed with (possibly TSE-contaminated) ruminant
material even if it was previously treated at "133!C/20'/3 bars", because
this standard is considered not to eliminate all possible TSE infectivity
if the initial titer was high. If the presence of a BSE risk is not
excluded, these materials should therefore be considered as "condemned
materials" as described in the SSC's opinion on "Fallen stock" of 24-25
June 1999. Provided they are appropriately processed and if any TSE risk
is excluded, they could be recycled into industrial products or
fertilizers. However, if a TSE risk exists, they should be disposed of.

5. Conclusions from the Working Group Concerning the susceptibility of
pigs, poultry and fish to become infected with TSE's, there is evidence
that pigs can become infected with BSE through intra-cerebral inoculation
with infectious BSE material. Infectivity could be recovered from poultry
inoculated via the i/v route with TME. No evidence was found of TSE's in
fish. Till date no experiments have shown that pigs, poultry and fish
could be infected with TSE through the oral route. The hypothesis
proposed that orally TSE-inoculated non-ruminants without any signs of
disease could carry over the TSE-infection through there tissues has till
date not been proven. Concerning ruminants, a large number of
experiments, abundantly reported on in the scientific literature, has
shown that cattle and sheep are susceptible to TSE's originating from
their own species and that ruminants in general fed8 with infectious
material originating from the same species can be infected with TSE's.
Should a country be free of any animal TSE, epidemiological evidence
suggests that the onset of an endemic of a certain TSE based on a
spontaneous native case of TSE is very unlikely.9 6. General remark on the
safety of derived products. Recycling of animal by-products processed
into basic biochemical substances as fat and protein is recognised as an
effective way of re-use of valuable materials. When an animal is
decomposed through processing into protein, fat and other basic
biochemical materials, consumption of this material is not anymore
recognised as being intra-species recycling. Besides the feed-value of
these slaughter by-products, effective disposal and processing is of
importance to protect human and animal health and to preserve the
environment. An effective system that prevents the uncontrolled dispersion
of slaughter by-products in the environment is important to preserve human
and animal health. Longitudinal integrated safety assurance (LISA) should
be implemented based on the HACCP concept to assure the safety of the
processed products and to make them available for the market. From
environmental point of view protection strategies should be directed
towards: firstly a reduction of waste and secondly towards a full re-use
of waste. The use of energy and the production of waste water and odour
should be implemented in the strategies to comply with these policies.
Intra-species recycling can be acceptable when the material of origin is
from epidemiological point of view safely sourced with regard to TSE's and
treated accordingly to prevent any spread of conventional diseases. 7.
Non-exhaustive list of the consulted literature and documents Agrimi U.,
Ru G., Cardone, F., Pocchiari, M, Caramelli, M., 1999. Epidemic of
transmissible spongiform encephalopathy in sheep and goats in Italy. The
Lancet 353, 560-561 Animal Health, 1996. Report of the Chief Veterinary
Officer. HMSO, London, pp22-45. Animal Health, 1997. Report of the Chief
Veterinary Officer. HMSO, London, pp22-45. Capucchio MT, Guarda F, Isaia
MC, Caracappa S, Di Marco, V., 1998. Natural occurrence of scrapie in
goats in Italy. The Veterinary Record, 143, 452-453 Dawson, M., Wells,
G.A.H., Parker, B.N.J., Francis, M.E., Scott, A.,C., 1991. Transmission
studies of BSE in cattle, hamsters, pigs and domestic fowl. In: Current
topics in Vet. Med. and Anim. Sci., Sub-acute spongiform encephalopathies,
Bradley R., Savey M., Marchant B., eds. 55, 25-32. Kluwer Academic
Publishers, Dordrecht. Dawson, M., Wells, G.A.H., Parker, B.N.J.,
Francis, M.E., Scott, A.,C., Hawkins, S.A.C., Martin, T.C., Simmons, M.,
Austin, A.R., 1994. Transmission studies of BSE in cattle, pigs and
domestic fowl. In: Proceedings of a Consultation on BSE with the
Scientific Veterinary Committee of the EC, Brussels, 14-15 Sep 1993.
Bradley R., Savey M., Marchant B., eds. pp 161-167. EC, Brussels. Dawson,
M., Wells, G.A.H., Parker, B.N.J., Scott, A.,C., 1990. Primary,
parenteral transmission of BSE to a pig. Vet. Rec. 127, 338.
Environmental Agency, 1998. Processes Subject to Integrated Pollution
Control. IPC Guidance Note S2 1.05. Amplification Note N! 1.Combustion of
Meat-and-bone meal (MBM). 23 pp. FIN (Fishmeal Information Network),
1998. Information package on fishmeal provided to the Secretariat of the
Scientific Steering Committee. FIN (Fishmeal Information Network), 1999.
Letter and annexes of 1 March 1999 of C.Trotman to the SSC secretariat
providing information on (1) the processing of fish, including trimmins,
for use in animal feed, (2) the heat sensitivity of fish pathogens and (3)
the possible occurrence of TSEs in fish. Fransen, N.G., Urlings, H.A.P.,
Bijker, P.G.H., van Logtestijn, J.G., 1996. The use of slaughterhouse
sludge. Fleischwirtschaft, 76, 1179-1184. Gibbs, C.J., Gajdusek, C.J.,
Amyx, 1979. Strain variation in the viruses of Creutzfeldt-Jakob disease
and kuru. In :Slow Transmissible Diseases of the Nervous System. (S.B.
Prusiner and W.J. Hadlow, Eds), Vol.2, pp 87-110, Academic Press, New
York. Gordon, W.S., 1946. Advances in veterinary research: louping ill,
tick-borne fever and scrapie. Vet Rec 58, 516-525. Greig, J.R., 1950.
Scrapie in sheep. J Comp Path, 60, 263-266. Hansen, M., Halloran, J.,
1997. Letter of 24 March 1997 of Hansen and Halloran (Consumer Policy
Institute, Consumer Union, US) to Dr. S.F.Sundlof (Centre for veterinary
Medicine, USFood and Drug Administration, Rockville, US). Hawkins,
S.A.C., Ryder, S.J., Wells, G.A.H., Austin, A.R., Dawson, M., 1998.
Studies of the experimental transmissibility of BSE and scrapie to pigs.
In: Proceedings of the 15th IVPS Congress, Birmingham, England, 5-9 July
1998. P. 186. Hunter, N., Cairns, D., Foster, J., Smith, G., Goldmann, W.
and Donnelly, K. 1997. Is scrapie a genetic disease? Evidence from
scrapie-free countries. Nature, 386, 137. Marsh, R.F., Burger, D.,
Eckroade, R., ZuRhein, G.M., Hanson, R.P., 1969. A preliminary report on
the experimental host range of transmissible mink encephalopathy agent. J.
Inf. Dis. 120 713-719. Race, R., Chesebro, B., 1998. Scrapie infectivity
found in resistant species. Nature, 392, 770. Robinson, M.M., Hallow,
W.J., Huff, T.P., Wells, G.A., Dawson,M., Marsh,R.F., Gorham,J.R.; 1994:
Experimental infection of mink with BSE. Journal of General Virology,
(75), 1994, pp. 2151-2155 Schoon, H.-A., Brunckhorst, D., Pohlenz J.,
1991a. Spongiforme Enzephalopathie beim Rothalsstraus (Struthio camelus)
Ein kasuistischer Beitrag. Tier
rztl. Praxis, 19, 263-265.
Schoon, H.-A., Brunckhorst, D. & Pohlenz, J., 1991b. Beitrag zur
Neuropathologie beim Rothalsstrauss (Struthio camelus) - Spongiforme
Enzephalopathie. Verh. ber. Erkrg. Zootiere, 33, 309-313.
SSC (Scientific Steering Committee of the European Commission):
Scientific opinions :
* Safety of Gelatine, last update,19/2/99
* Safety of Meat and Bone Meal (MBM) from mammalian animals, naturally
or experimentally susceptible to Transmissible
Spongiform Encephalopathies. 27/3/98
* Safety of Tallow, 27/3/98
* Safety of Dicalcium Phosphate precipitated from ruminant bones and
used as an animal feed, 26/6/98
* Safety of Hydrolysed Proteins produced from bovine hides,
23/10/98
* Safety of Organic Fertilizers derived from mammalian animals, 25/9/98
* Risk of Infection of Sheep and Goats with the Bovine Spongiform
Encephalopathy agent, 25/9/98
* "Fallen Stock": The risks of non conventional transmissible agents,
conventional infectious agents or other hazards such as toxic substances
entering the human food or animal feed chains via raw material from fallen
stock and dead animals (including also: ruminants, pigs, poultry, fish,
wild/exotic/zoo animals, fur animals, cats, laboratory animals and fish)
or via condemned materials, 23/7/99
Reports of Working Groups
* Report on the safety of meat and bone meal derived from mammalian
animals fed to non-ruminant food-producing farm animals, 25/9/98
* Report on the possible vertical transmission of Bovine Spongiform
Encephalopathy (BSE),19/3/99.
Opinions of the SSC and related Reports of Working Group are published on
the Internet under
http://europa.eu.int/comm/dg24/health/sc/ssc/outcome_en.html as soon as
possible after the adoption of the opinions by the SSC. Van Sonsbeek,
J.Th.M., van Beek, P., Urlings, H.A.P., Bijker, P.G.H., Hagelaar, J.F.L.,
1997. Mixed integer programming for strategic decision support in
slaughter by-product chain. OR Spektrum, 19, 159-168.
Wells, G.A.H., Hawkins,S.A.C. and Dawson, M. 1998. Transmissible
Spongiforme Encephalopathy in Pigs: Did natural exposure to BSE
lead to infection. In: Proceedings of the 15th IPVS Congress,
Birmingham, England, 5-9 July 1998
8. Acknowledgements
The present report was prepared by a Working Group chaired by Dr. H.A.P.
Urlings. Other members of the working group were:
Prof.Dr. R.Bhm, Prof.Dr.Mac Johnston, Prof.Dr. Milhaud, Prof.D.V.M. Esko
Nurmi, Prof. Dr. A.-L. Parodi, Prof.Dr.G.Piva, Dr. M.Riedinger, Prof.Soren
Alexandersen, Dr. J.Schlatter, Prof.Dr.D.W.Taylor, Dr.D.M.Taylor,
Prof.Dr.M.Vanbelle, Prof.Dr. M.Wierup, Prof.Dr. P.Willeberg.
Contributions were also received from Dr.R.Bradley, Dr.L.Detwiler and
Dr.N.Hunter.
----------------------------------------
1 Intra-species recycling of fur animals is discussed in the SSC opinion
on "Fallen stock", adopted on 24-25.06.99 2 See the "Fallen stock"
opinion.
3 Healthy animals are defined as animals which have undergone an ante
mortem inspection by an official veterinarian where it was determined that
the animals were not suffering from a disease which is communicable to man
and animals and that they do not show symptoms or are in a general
condition such as to indicate that such disease may occur and they show no
symptoms of disease or of a disorder of their general conditions which is
likely to make their meat unfit for human consumption. (Definition as
given in Directive 64/433/EEC, laying down the rules for ante mortem
inspection)
4 Based also on the following USA documents: (1) Dr.W.J.Hadlow's Report of
10.04.97 on the microscopic examination of pig brain N! 2709, (2)
Dr.J.Miller's comments of 31.03.97 on the incident and (3) H.W.Moon's
review of 31 March of the pathology reports of the pigs.
5 According to Alderman (1996) there are a few recognised diseases of
viral and protozoal aetiology which affect nervous tissues of farmed and
wild fish which result in pathologies and which, whilst they may be
described as encephalopathies, can not in any way be confused with
spongiform encephalopathy group of diseases, which include BSE, CJD and
scrapie either in their gross, behavioural or pathological
characteristics. Such viruses and protozoans are regarded as being
extremely host specific and adapted for cold blooded animals.
6 It is easier to section the entire head, thus including the brain, than
to concentrate only on gill.
7 See also Section 2 Scope, on other ways of transmission.
8 See also Section 2 Scope, on other routes of transmission. 9 On the
latter sentence, there was no consensus, as some found it misleading: if
epidemic BSE originated from recycling of sporadic BSE, this could have
happened everywhere with the right conditions.

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http://209.85.165.104/search?q=cache:OYo6dIyFZuYJ:www.foodcontamination.ca/animalnet/1999/9-1999/an-09-26-99-01.txt+spontaneous+TSE+bse+inquiry+little+evidence&hl=en&ct=clnk&cd=29&gl=us

The ongoing BSE surveillance program will sample approximately 40,000 animals each year. Under the program, USDA will continue to collect samples from a variety of sites and from the cattle populations where the disease is most likely to be detected, similar to the enhanced surveillance program procedures.

The new program will not only comply with the science-based international guidelines set forth by the World Animal Health organization (OIE), it will provide testing at a level ten times higher than the OIE recommended level.

http://www.usda.gov/wps/portal/usdahome?contentidonly=true&contentid=2006/07/0255.xml

To: tse-conference@netlink.co.nz, tse%MAFHO.HOWGTN@cogs.maf.govt.nz
From: "Howard Pharo"
Subject: TSE Conference: BSE SURVEILLANCE IN FRANCE (2)
MIME-Version: 1.0
Content-Type: Text/Plain; Charset=US-ASCII
Content-Transfer-Encoding: 7BIT
Sender: owner-tse-conference@netlink.co.nz

Moderators' comment on paper by Savey et.
al., posted on 26/5/97 by B.Toma entitled
BSE SURVEILLANCE IN FRANCE.


Following the conclusions of the paper is a
section entitled ALTERNATIVE CALCULATION,
which requires some further explanation.

<<1. N is the minimum number of
investigations required,
2. Ntot is the size of the population where
the screening is done,
3. Cases is the expected number of BSE
cases,
4. Alpha is the probability to detect one or
more BSE cases (0.90, 0.95, or 0.99).

N = (Ntot - [Cases/2] + 0.5) * (1 - Alpha[1/
Cases] )>>

I would like to see either a reference
explaining the basis for this formula or
else a derivation of it.

The three tables which follow this formula
require some clarification also.

I note that one of the assumptions on
generating the tables from this formula is
that the laboratory testing is 100%
sensitive. Bearing in mind that we appear to
be talking here about sampling of clinically
normal animals [is my understandiung of that
point correct?] then I would question the
validity of this assumption.

I note also the following assumption:
<prevalence of BSE is 1 per 1000000 cattle.>>

Could the authors please explain which OIE
proposal is referred to here? I believe that
the OIE proposal is that progressive nervous
disease can be expected to occur at a rate
of 100 per million cattle per year, and that
1% of the cases of such progressive nervous
disease which occur in cattle over 20 months
of age is the miniumum level that a
surveillance system should be able to
detect.

==========
Howard Pharo

To: tse-conference@netlink.co.nz
From: Martin Hugh-Jones
Subject: TSE Conference: SOME COMMENTS
Sender: owner-tse-conference@netlink.co.nz

Martin Hugh-Jones
Dept Epidemiology & Community Health,
School of Veterinary Medicine, LSU, USA

I have held back from commenting earlier because I am not in the
arena and those who are will always provide more valuable comments
than us mere spectators. However:

[1] QUALITY CONTROL OF BSE TESTING: There has been a marked absence
of any comments on this other than to say that folk had been sent for
training at Weybridge and secondly that all calculations assumed a
100% sensitivity. Phew! I, like every other epidemiologist, have been
let down occasionally by a diagnostic lab - it happens - but to be
frank I now take precautions to check out any lab before I trust its
data. How often has it been built into the system to submit covert
positives ("ringers") to check whether one's lab is correctly (1)
identifying them and (2) reporting them? They should never be sent in
as specials because that immediately warns everyone what they are.
How often is the brain-sampling checked to ensure that the correct
part is being submitted and properly fixed & sectioned? When ringers
are correctly identified and reported, it generates confidence in all
concerned nationally and internationally. When they are missed but
admitted, this is also confidence building because of the
intellectual honesty and that it follows that corrections will be
made to improve the system. Similarly, there have been delays between
training and finding the first BSE case. Has this been followed up to
find out why. What can we learn from, say, the Netherlands in this
regard?

[2] WHAT HAPPENS IF?: I have also seen an absence of any indications
of what plans had been roughed out in the event that a negative
country should come across a positive TSE bovine. From talking with
the late Dick Marsh and subsequently with some of his colleagues, it
was abundantly clear that he believed that a bovine TSE (had) existed
in Wisconsin. I see no reason to doubt his view. One wonders what US
plans exist in the event that one of these animals should be
discovered in the current on-going US surveillance scheme. Similarly,
as this search has come up with no positives yet, has it affected the
epidemiological sensitivity of the search. One should remember that
the more sensitive the search the stronger can be the claim that any
positives must be "sporadic". And if a US positive is found, will the
response be to immediately slaughter out the herd or to quarantine it
and sort out how it came about? Similarly, what are the Canadian
plans now that all imported UK cattle are dead? The Argentines and
the Brasilians are in the same boat. I am not being naive in asking
what may be a politically loaded question because if reasonable plans
have been made and are shared, the potential damage of this
unfortunate event may be reduced.

[3] SURVEILLANCE: "Passive" surveillance is an oxymoron. I would
prefer to use "Targetted" and "Untargetted" surveillance, the latter
refering to population / statistically based surveys. On the latter
subject many excellent comments have been made already. As far as BSE
goes, such searches will only work when a very cheap & rapid
laboratory test has been developed, as for brucellosis and warble fly
infestations, so that very large numbers of samples can be processed,
as in 1-5 million per year. Until then they are clearly a total waste
of time, money, and effort for this disease. The objective of a
targetted surveillance is to pick a circumstance in which the
probability of finding your condition is realistic. So if one were to
use cattle demonstrating neurological signs, broadly defined maybe,
if BSE exists it will be in that group, hopefully. This plays to
Quality Control. The pattern of the reported diagnostic repetoire
will largely reflect the quality of the pathological observations,
quite apart from providing useful information in its own right and
possibly thereby paying for the work. If one normally expects to see
Condition A and it is missing or excessive, it tells one something
about the refering clinicians and examining pathologists, and their
need for retraining.

[4] THE NEXT DISEASE: In a few years there will be another disease.
If we don't learn from the mistakes made and the true successes in
dealing with BSE, we will relearn them the hard way. This must be
done honestly because, as I tell my students, God is illiterate. She
cannot read the literature and certainly never reads any ministerial
statements. Reality is separate from the scientific and political
literature.

=================
Martin Hugh-Jones

From: Noel Murray
To: tse-conference@netlink.co.nz
Subject: TSE Conference: SCRAPIE SURVEILLANCE IN THE UNITED STATES (4)
Sender: owner-tse-conference@netlink.co.nz

Linda Detwiler's posting of 23 May provided some clarification on the
tests used for the diagnosis of scrapie in the USA, viz:

1. both histopathology and immunohistochemistry (IHC) are used
routinely

2. western blotting, is used in the event that the other tests are
inconclusive.

As indicated in her posting these tests are usually undertaken on
sheep with clinical signs suggestive of scrapie. These tests are
interpreted in parallel so that a positive result to any of these
leads to a diagnosis of scrapie.

It is obviously important when interpreting test results to first of
all decide upon a case definition, taking into account the
sensitivity and specificity of the tests employed. In many
circumstances however these values may not be known. Nevertheless it
is still important to keep in mind how test interpretation can
influence the final diagnosis. For example by applying these tests to
clinically normal sheep in a low risk population (no recorded cases
of scrapie) erroneous conclusions may be reached, particularly where
the specificity of the tests is less than 100% and tests are
interpreted in parallel.

I would like to ascertain if Dr Detwiler is able to provide estimates
of the sensitivity or specificity for these tests and if so what was
the gold standard to which the tests were compared.

I certainly look forward with interest to hearing the results of the
slaughterhouse survey of clinically normal sheep and in particular
how the results are interpreted.

*****************************
At the risk of appearing to preach to the converted ... some
reminders
*****************************

The predictive value of a positive test is defined as the proportion
of diseased animals among those that test positive i.e. p(D+/T+). In
other words we are trying to answer the question: Given that the
animal has a positive test what is the likelihood that it has the
disease in question?

There are a number of methods available to improve the positive
predictive value:

1. screening high risk populations, for example sheep with clinical
signs consistent with scrapie from infected flocks

2. use more than one screening test

a) apply a relatively sensitive inexpensive screening test to
all suspect cases then use a more sensitive but expensive test on a
limited number of cases positive to the first test.

b) apply two or more tests simultaneously and interpret the test
results in parallel (animal is positive if it reacts positively to
any of the test applied) or in series (animal must be positive to all
tests to be considered positive).

Parallel interpretation increases the sensitivity but tends to
decrease the specificity of the combined tests whilst series
interpretation will increase specificity but decrease sensitivity.

SENSITIVITY is the probability that a diseased animal will actually
give a positive test result

SPECIFICITY is the probability that a non-diseased animal will
actually give a negative test result

*****************************

Noel Murray
Ministry of Agriculture
New Zealand

From: Vicki Bridges
To: tse-conference@netlink.co.nz
Subject: TSE Conference: TARGETTING SURVEILLANCE FOR TSE'S IN CATTLE
Sender: owner-tse-conference@netlink.co.nz

The NAHMS Dairy 1996 study collected health and management
information from producers in 20 states, representing 83.1% of all US
dairy cows. From this survey it was estimated that 0.1% of all dairy
cows died on farm due to "lack of coordination or severe depression".
These clinical signs include dairy cows with rabies, listeriosis,
tetanus, nervous ketosis, and a variety of other neurologic diseases.
An additional 0.2% of dairy cows were culled for slaughter due to
"aggressiveness or belligerence". Although it is possible that some
neurologic diseases are included in this group, many of these cows
have temperaments that don*t fit the milking management of the
producer (i.e., kickers). These reports, along with many others, are
available on the web site of the Centers for Epidemiology and Animal
Health (CEAH) (www.aphis.usda.gov/vs/ceah). An estimate of the
number of beef cows with CNS signs is expected to come from NAHMS
Beef 1997 study. The relevant question asked for number of cows in
1996 that had "neurologic problems (such as lack of coordination,
tremors, nervousness, or weakness)". These data are currently being
analyzed and results will be posted on the CEAH web site this summer.

The results of these studies can be used as an estimate of the number
of cows in the US exhibiting clinical signs that are consistent with
those of a TSE. Because of the general wording of the questions,
responses include animals that do not truly have clinical signs
consistent with a TSE, such as kickers or animals with
non-progressive clinical signs, resulting in an overestimate. Even
so, the results from these surveys can provide an estimate (albeit an
overestimate) for the target number of at-risk animals to base TSE
surveillance upon.

==============================
Vicki Bridges and Chris Kopral
Centers for Epidemiology and Animal Health
Ft. Collins, CO USA


From: Janice Miller
To: tse-conference@netlink.co.nz
Subject: TSE Conference: SCRAPIE SURVEILLANCE IN THE UNITED STATES (5)
Sender: owner-tse-conference@netlink.co.nz

I was contacted by Dr. Linda Detwiler regarding a request from Noel
Murray (29 May) for sensitivity and specificity estimates on the
immunohistochemical (IHC) and western blot (WB) tests used to
diagnose scrapie in the United States. She asked me to respond
because I co-authored a paper with scientists at the U.S. Department of
Agriculture's Animal and Plant Health Inspection Service (APHIS), in
which we described a comparison between these techniques and
histopathologic diagnosis (J Vet Diagn Invest 6:366-368, 1994). In that
comparison we only had 10 brain samples that we could consider as
true negative controls with any reasonable degree of confidence. They
were sheep from a flock maintained here at the National Animal Disease
Center for many years with no cases of scrapie having been observed.
Although no positive reactions were observed with either the IHC or WB
tests, we don't think that would be a sufficient number to use for a
specificity determination.

With regard to sensitivity, our question was what the "gold standard"
should be. Because we were examining field material, there was no
way to determine with absolute confidence that a particular sheep
actually had scrapie, although all had been considered suspicious based
on clinical observations. Our primary concern, therefore, was to see
how the IHC and WB tests for PrP would compare, not to determine the
sensitivity of these tests. We also wanted to see how the PrP test
results would compare to histopathologic findings.

We had 108 brains from which both formalin fixed and frozen samples
were available. Results of the IHC and WB tests for PrP agreed on 100
samples (58 positive and 42 negative). Of the 8 cases with differing
results, 2 were positive by WB only and 6 were positive by IHC only. The
histopathologic findings were not helpful in determining whether any of
these reactions were "false positives" because only 1 of the 8 sheep
had been diagnosed as scrapie by histopathology (1 of the WB positive
cases). In the absence of a bioassay or additional PrP tests to confirm
the other cases, we didn't feel it was appropriate to calculate sensitivity
estimates using such information. As we stated in our paper, "a more
accurate comparison of test sensitivity might be possible in a time-course
study of experimentally inoculated sheep, especially if samples were
carefully collected to minimize the effects of nonuniform PrP-res
distribution." The last point should be emphasized because when
comparing tests for PrP it is important to remember that the amount of PrP
can vary considerably from one area of the brain to another. Our
samples were collected in the field by many different people so we could
not be assured that formalin-fixed and frozen samples were always
taken from the same area. Considering this fact, we were pleasantly
surprised that the IHC and WB results correlated so well.

While the correlation of IHC and WB results for PrP was quite good (in
our opinion), we did not find such good correlation between PrP positivity
and the histopathologic diagnosis. We examined a total of 196 different
brains by IHC and 107 were considered PrP positive. However, only 42
of these 107 cases had been diagnosed as scrapie by histopathology.

Based on our earlier comparison of IHC with WB, we felt reasonably
confident that the IHC results were valid and therefore concluded that
the IHC test was considerably more sensitive than histopathologic
examination for diagnosing scrapie. I should, however, insert a caveat
here, because the criteria used by APHIS for histopathologic diagnosis of
scrapie may have been more stringent than those used by other
pathologists. In fact, almost half of the 65 IHC positive cases that were
not diagnosed as scrapie by histopathology had been considered
suspicious because they met some (but not all) of the 4 required criteria
(intracytoplasmic vacuolation of neurons, neuronal degeneration,
vacuolation of gray matter neuropil and astrocytosis).

============
Janice M. Miller
Veterinary Medical Officer
U. S. Department of Agriculture
Agricultural Research Service
National Animal Disease Center
Ames, IA
U.S.A.


From: Reinhold Kittelberger
To: tse-conference@netlink.co.nz
Subject: TSE Conference: DIAGNOSTIC TESTS FOR TSEs (10)
Sender: owner-tse-conference@netlink.co.nz

The primary concern for a country, especially when claiming to be
free from animal TSEs, will be the type of survey to be conducted.
This issue was and still is extensively discussed in this conference.
Following from this arises the question on what diagnostic
capability a country should have in order to run TSE surveys?

>From the postings on surveillance in various countries to this
conference and from personal contacts to various research groups, I
have compiled the table below, showing the diagnostic test methods
available in individual countries for animal TSE testing (mainly BSE
and scrapie). Unfortunately, not all postings to this conference
have identified the methods used for their TSE surveillance schemes
and many countries have not submitted data at all. Nevertheless, the
table gives an impression on the diagnostic capability of a number of
countries.

It is quite clear that any TSE surveillance to date is primarily
based on histopathology. For the purpose of confirmatory testing
immunohistochemistry is widely used, in at least 12 of the 21
countries listed below. Nine countries have the capability to run
Western blots and 7 to look for scrapie-associated fibrils. I would
like to ask this conference if it is considered necessary for a major
sheep/cattle raising country to be able to perform all tests for
surveillance purposes, keeping in mind that histopathology and
immunohistochemistry cannot be used on autolysed tissues.

Another issue is the safety of the diagnostic laboratory performing
TSE diagnosis. According to the recommendations of the Advisory
Committee on Dangerous Pathogens/UK, for scrapie a containment level
of 1 and for BSE a level of 2 is sufficient. What are the safety
standards for scrapie and BSE testing laboratories in other
countries? Should a contry considered free from animal TSEs follow
more stringent rules than countries where the dieseases are present?


********************************************
[note: to see correct allignment of the columns in the following
table, switch your mailer to a non-proportional font, such as courier
- mod]
********************************************

Table: Diagnostic test methods used in various countries for animal
TSE surveillance.


Country Methods
HP IHC SAF WB BA

Argentina 1) xxx
Australia xxx xxx xxx xxx xxx
Belgium xxx xxx xxx
Canada xxx xxx xxx xxx
Cyprus xxx
Denmark 2)
Finland xxx
France 2)
Germany 3) xxx xxx xxx xxx xxx
Iceland xxx xxx xxx xxx
Ireland xxx xxx
Israel xxx xxx xxx
Japan xxx xxx xxx xxx
Mexico xxx xxx
Netherlands xxx xxx xxx xxx
New Zealand xxx xxx4)
Norway xxx
Sweden 2)
Switzerland 2) xxx
UK xxx xxx xxx xxx xxx
USA xxx xxx xxx xxx
********************************************

Notes:
xxx = method used in a country.
HP = histopathology;
IHC = immunohistochemistry;
SAF = scrapie-associated fibril isolation;
WB = Western blot;
BA = bioassay.

1) biochemical detection mentioned. Not clear what test is meant.
2) detailed data not given.
3) this information is derived from a laboratory visit to Germany.
4) done at CVL, UK


[moderators' comment: in addition to the above table, under NZ's
scrapie freedom assurance programme, our sheep imports require that
all parent stock be subjected to the bioassay before the offspring
are released from quarantine]

================
Reinhold Kittelberger
Scientist
Central Animal Health Laboratory
New Zealand

From: Dorothy Preslar
To: tse-conference@netlink.co.nz
Subject: TSE Conference: TSEs IN EXOTIC ANIMALS
Sender: owner-tse-conference@netlink.co.nz

While I know that this conference is limited to TSE in livestock, I thought
you might be interested in the following posting on ProMED-mail;

TSE - UK: EXOTIC ANIMALS
************************

Date: Sat, 7 Jun 1997
From: Dorothy Preslar
Source: UK media source, 2 Jun 1997

In a written reply to the House of Commons, Agriculture Minister of State
Jeff Rooker has provided details of Transmissible Spongiform
Encephalopathy in animals other than livestock. His report includes
confirmed cases of TSE in 2 ankole cows, one bison, three cheetah, six
eland, one gemsbok, six kudu, one nyala, two ocelot, one Arabian oryx,
one scimitar horned oryx, three pumas and one tiger, in addition to 77
domestic cats.


From: Bernard TOMA
To: tse-conference@netlink.co.nz
Subject: TSE Conference: BSE SURVEILLANCE IN FRANCE (3)
Sender: owner-tse-conference@netlink.co.nz

REPLIES TO THE MODERATOR AND FURTHER COMMENTS.
M. Savey, B. Durand, F. Moutou et B. Toma.

In a posting on 29 May, the moderator wrote:
>I would like to see either a reference
>explaining the basis for this formula or
>else a derivation of it.

The formula we used is described in Veterinary Epidemiology - Principles
and Methods MARTIN S.W., MEEK A.H., WILLEBERG P. 1987, Iowa State
Press p. 37

Unfortunately, an error occured when transcribing the formula in our
e-mail.
The correct formula is :
N = [Ntot - (C / 2) + 0.5][1 - (1 - Alpha)^(1 / C)]
Where :
N is the size of the sample,
Ntot is the size of the population where random sampling is done
C is the number of cases in this population
Alpha is the confidence level

We apologize for this error.

>I note that one of the assumptions on
>generating the tables from this formula is
>that the laboratory testing is 100%
>sensitive. Bearing in mind that we appear to
>be talking here about sampling of clinically
>normal animals [is my understanding of that
>point correct?] then I would question the
>validity of this assumption.

No, the random sampling (for laboratory investigations) is not done within
the set of the clinically normal animals, but, in case of table 1 in the set of
adult cattle presenting a progressive nervous disease (as in the OIE
proposals), in case of table 2 in the set of adult cattle affected by any
nervous disease, and in case of table 3 in the set of dead adult cattle
(see below).

>I note also the following assumption:
><>prevalence of BSE is 1 per 1000000 cattle.>>
>Could the authors please explain which OIE
>proposal is referred to here? I believe that
>the OIE proposal is that progressive nervous
>disease can be expected to occur at a rate
>of 100 per million cattle per year, and that
>1% of the cases of such progressive nervous
>disease which occur in cattle over 20 months
>of age is the miniumum level that a
>surveillance system should be able to
>detect.

First, in our posting, the terms "expected prevalence of BSE" must of
course be understood as "minimum prevalence that a surveillance
system should be able to detect".

We have made 3 different kinds of calculations, each of them based on
different assumptions.

Table 1 simply extended the OIE proposals to confidence levels of 95%
and 99% (notice that the column for a confidence level of 90% is the
same as in the OIE draft text), the random sampling being done (as for
the OIE proposals)within the population of the cattle affected by a
progressive nervous disease (1 case per 10000 cattle per year), and the
minimum level of detection being 1% of these cases.

----------------------------------------------------------------
TABLE 1: Population where screening is done : deaths caused by a
neurologic disease.
Rate of expected neurologic disease : 1 case per 10 000 cattle.

Pop. Neur. Dis. BSE 90% 95% 99%
500 000 50 .5 50 50 50
700 000 70 .7 68 69 70
1 000 000 100 1 91 95 99
2 500 000 250 2.5 151 174 210
5 000 000 500 5 184 224 300
7 000 000 700 7 196 243 336
10 000 000 1 000 10 205 258 367
20 000 000 2 000 20 217 277 409
30 000 000 3 000 30 221 284 425
40 000 000 4 000 40 224 287 433
----------------------------------------------------------------

In the two following tables, our hypothesis was that progressive
nervous diseases are not easy to identify. At a large scale, one can think
that this population would include not only progressive nervous
diseases, but also other diseases. The assumption made in OIE
proposals is 1 case of progressive nervous disease per 10,000 cattle,
and a minimum level of detection of 1% of these cases. Thus, this
proposal defines the minimum detection level of BSE cases as a fraction
of the real cases of progressive nervous diseases. What should be this
number if our hypothesis is true ? Our choice was to define the minimum
detection level as a fraction of the set of adult cattle (which is a more
classical method and seems to be more transparent).

Expressing in this way the value proposed by OIE gives 1 BSE case per
1000000 cattle. This is the value we used in the following calculations.

In table 2 the hypothesis was that the population where random sampling
is done is the set of adult cattle affected by any nervous disease. We
assumed that the size of this population was 10% of the annual mortality
rate (1%), that is 1 case per 1 000
cattle.

----------------------------------------------------------------
TABLE 2: Population where screening is done :deaths caused by a
neurologic disease.
Rate of expected neurologic disease : 1 case per 1000 cattle. (Mortality
of 1 per 100, 10 deaths per 100 caused by a neurologic disease).

Pop. Neur. Dis. BSE 90% 95% 99%
500 000 500 .5 495 499 500
700 000 700 .7 674 690 699
1 000 000 1 000 1 900 950 990
2 500 000 2 500 2.5 1 504 1 745 2 103
5 000 000 5 000 5 1 844 2 253 3 008
7 000 000 7 000 7 1 961 2 436 3 373
10 000 000 10 000 10 2 056 2 587 3 689
20 000 000 20 000 20 2 174 2 781 4 111
30 000 000 30 000 30 2 215 2 850 4 267
40 000 000 40 000 40 2 236 2 885 4 348
----------------------------------------------------------------

Finally, a more provocative point of view was that the set of adult cattle
affected by a progressive nervous disease (or by any nervous disease)
is not a good basis for random sampling (because these diseases are
difficult to identify, especially in extensive farming), and that this sampling
should be done in the set of dead adult cattle. It is of course an
unrealistic point of view because - among other reasons - if an animal is
found dead, it's brain will probably not be a good material for laboratory
examinations. Nevertheless, is was interesting to calculate, under this
assumption, the minimal size of the samples needed to detect 1 case of
BSE per 1 000 000 cattle.

----------------------------------------------------------------
TABLE 3: Population where screening is done : deaths.
Mortality of 1 per 100.

Pop. Scr. pop. BSE 90% 95% 99%
500 000 5 000 .5 4 950 4 988 5 000
700 000 7 000 .7 6 739 6 903 6 990
1 000 000 10 000 1 9 000 9 500 9 900
2 500 000 25 000 2.5 15 047 17 457 21 037
5 000 000 50 000 5 18 451 22 535 30 093
7 000 000 70 000 7 19 621 24 370 33 742
10 000 000 100 000 10 20 566 25 885 36 903
20 000 000 200 000 20 21 748 27 820 41 132
30 000 000 300 000 30 22 163 28 508 42 689
40 000 000 400 000 40 22 375 28 862 43 497
----------------------------------------------------------------


The OIE proposes a targetted surveillance scheme. The objective of such
a scheme is, following Martin Hugh-Jones (29/05/97) "to pick a
circumstance in which the probability of finding your condition is
realistic". These criteria define a sub-set of the population where
laboratory investigations are done. All the problem is then to define these
criteria. It seems to us that there are two options.

1. The criteria are not especially targetted at BSE but define a set of
syndromes which includes BSE clinical signs. This set must then be the
set of nervous diseases, broadly defined (note that the OIE draft text
talks -art.3.2.13.1, clause 4- talks of "neurologic diseases", not of
"progressive nervous diseases"). Available data show that an annual
incidence of 1/10 000 under-estimates the incidence of these diseases,
and that a number of 1/1 000 (cf our preceding contribution) would be
more appropriate. This is also the number obtained for US dairy cows
(see the posting of Vicky Bridges, 30/05/97), with an estimate of 0.1% of
all dairy cows which died on farm (in 1996) due to "lack of coordination
or severe depression". The USDA report from which this number comes
indicates also that 0.6% of all dairy cows died on farm due to an
"unknown reason". This annual incidence leads to a great number of
laboratory investigations
(cf table 3 in our preceding contribution). Moreover, this first approach
assumes that a sufficient proportion of nervous diseases are reported
for further investigations. A value can be given to this "sufficient
proportion", using a simple mathematical approach (see table 4 below,
the details of the calculations are explained at the end of this posting).

----------------------------------------------------------------
TABLE 4: Minimal percentage of nervous diseases that must be
detected in order to garantee an annual BSE incidence less than
1 case per 1 000 000 cattle (of 20 months age or older) with
confidence levels of 90%, 95% and 99%.

Cattle pop of Confidence
20 months age level
or older 90% 95% 99%
500 000 99.00 99.75 99.99
700 000 96.27 98.62 99.86
1 000 000 90.00 95.00 99.00
2 500 000 60.19 69.83 84.15
5 000 000 36.90 45.07 60.19
7 000 000 28.03 34.82 48.21
10 000 000 20.57 25.89 36.90
20 000 000 10.87 13.91 20.57
30 000 000 7.39 9.50 14.23
40 000 000 5.59 7.22 10.87
----------------------------------------------------------------

One can see that the minimal level of detection of nervous diseases is
very high for countries with a low number of adult cattle.


2. The criteria are targetted at BSE and define "valid BSE suspicions". All
of these suspicions are investigated at laboratory. This approach
supposes awareness campaigns for practitioners dealing with cattle and
the help of experts of the
clinical signs of BSE. The annual expected number of suspect cases is
much lower than in the preceding approach. The outcome of such a
surveillance scheme is no more a probability of absence of BSE (i.e. a
confidence level), but a number of clinical BSE
suspicions and of BSE cases.

Thus, our opinion is that this second approach is, for scientific and
practical reasons, the most realistic surveillance scheme for BSE. Going
further in defining measures to be adopted to permit the safe trade in
bovine animals and products is a matter of quality assurance and control,
as other pointed out.

CALCULATION METHOD USED IN TABLE 4.

Following John Morton's contribution to this conference (16/05/97), the
actual number of cases which occured in the population during a time
period (n)is a function of the sensitivity of the total diagnostic procedure
(Se_overall)and the
confidence level (c) (the certainty of detection of at least 1 case of
disease in the population under surveillance during the time period):
n = log(1 - c) / log(1 - Se_overall)

Solving this formula for Se_overall gives:
Se_overall = 1 - ((1 - c)^(1 / n)) (1)
Se_overall is the probability that a case is diagnosed, assuming a given
confidence level (c) and a desired detection level (n : the minimum
number of cases that the surveillance system should be able to detect).

The surveillance scheme proposed by OIE can be roughly described as
follow:
Real nervous diseases
---Clinical detection---> Observed nervous diseases
---Random sampling---> Lab investigations
---Lab sensitivity---> Diagnostic

Assuming that all the brain of all suspect cases are examined in the lab
(the propability that a case is in the sample is 1), and that the sensitivity
of the lab investigations is 1, Se_overall is the probability that a case is
clinically detected as a suspect case. Thus, the formula (1) gives the
minimal percentage of nervous diseases that must be clinically detected
in order to garantee a given annual BSE incidence with a given
confidence level.

===================
Unite Epidemiologie
Laboratoire Central de Recherches Veterinaires
Centre National d'Etudes Veterinaire et Alimentaires
22, rue Pierre Curie BP 67 F-94703 MAISONS-ALFORT Cedex FRANCE

Bernard TOMA
Ecole veterinaire d'Alfort, 94703 Maisons-Alfort, France
Tel:(33)(0)143687334 Fax: (33)(0)143967131


END...TSS FILES

WHY would several strains of TSE in feed not be a plausible theory rather than a theory never proven, the spontaneous theory $$$

WHY is it not plausible to think that BASE might have come from feed too ???

WHY WOULD ONE STRAIN AMPLIFY AND TRANSMIT, AND THE OTHER NOT ???

WHY would one strain of TSE in cattle transmit orally via feed i.e. BSE, and the other i.e. BASE not transmit orally ???

answer =

STRICTLY PRIVATE AND CONFIDENTIAL 25, AUGUST 1995

snip...

To minimise the risk of farmers' claims for compensation from feed
compounders.

To minimise the potential damage to compound feed markets through adverse publicity.

To maximise freedom of action for feed compounders, notably by
maintaining the availability of meat and bone meal as a raw
material in animal feeds, and ensuring time is available to make any
changes which may be required.

snip...

THE FUTURE

4..........

MAFF remains under pressure in Brussels and is not skilled at
handling potentially explosive issues.

5. Tests _may_ show that ruminant feeds have been sold which
contain illegal traces of ruminant protein. More likely, a few positive
test results will turn up but proof that a particular feed mill knowingly
supplied it to a particular farm will be difficult if not impossible.

6. The threat remains real and it will be some years before feed
compounders are free of it. The longer we can avoid any direct
linkage between feed milling _practices_ and actual BSE cases,
the more likely it is that serious damage can be avoided. ...

SEE full text ;

http://www.bseinquiry.gov.uk/files/yb/1995/08/24002001.pdf


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


Other work presented suggested that BSE and bovine amyloidotic spongiform
encephalopathy (BASE) MAY BE RELATED. A mutation had been identified in the
prion protein gene in an AMERICAN BASE CASE THAT WAS SIMILAR IN NATURE TO A
MUTATION FOUND IN CASES OF SPORADIC CJD.

snip...

http://www.seac.gov.uk/minutes/95.pdf


3:30 Transmission of the Italian Atypical BSE (BASE) in Humanized Mouse

Models Qingzhong Kong, Ph.D., Assistant Professor, Pathology, Case Western Reserve
University

Bovine Amyloid Spongiform Encephalopathy (BASE) is an atypical BSE strain
discovered recently in Italy, and similar or different atypical BSE cases
were also reported in other countries. The infectivity and phenotypes of
these atypical BSE strains in humans are unknown. In collaboration with
Pierluigi Gambetti, as well as Maria Caramelli and her co-workers, we have
inoculated transgenic mice expressing human prion protein with brain
homogenates from BASE or BSE infected cattle. Our data shows that about half
of the BASE-inoculated mice became infected with an average incubation time
of about 19 months; in contrast, none of the BSE-inoculated mice appear to
be infected after more than 2 years.

***These results indicate that BASE is transmissible to humans and suggest that BASE is more virulent than
classical BSE in humans.***


6:30 Close of Day One


http://www.healthtech.com/2007/tse/day1.asp


SEE STEADY INCREASE IN SPORADIC CJD IN THE USA FROM
1997 TO 2006. SPORADIC CJD CASES TRIPLED, with phenotype
of 'UNKNOWN' strain growing. ...


http://www.cjdsurveillance.com/resources-casereport.html

There is a growing number of human CJD cases, and they were presented last
week in San Francisco by Luigi Gambatti(?) from his CJD surveillance
collection.

He estimates that it may be up to 14 or 15 persons which display selectively
SPRPSC and practically no detected RPRPSC proteins.


http://www.fda.gov/ohrms/dockets/ac/06/transcripts/1006-4240t1.htm


http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4240t1.pdf

TSS



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