***Spontaneous appearance of infectivity reported in transgenic mice
expressing a mutated BoPrP and in mice expressing mutated mouse PrP reported by
Stöhr et al. (40) supports the hypothesis that infectious TSE prions, could
originate by a random genetic mutation that can induce de novo generation of
infectious prions, and that this mechanism could constitute a source of prion
diversity. ***These considerations enable us to hypothesize that the BSE
epidemic could have begun by a random genetic mutation that was able to generate
de novo infectious prions, which were included in meat and bone meal fed to
cattle and then broadly expanded in the cattle population. According to this
hypothesis, a key strategy for controlling BSE would involve preventing cows
from consuming products from cows with spontaneous cases of BSE.***
Volume 19, Number 12—December 2013 Research
Spontaneous Generation of Infectious Prion Disease in Transgenic Mice
Juan-MarÃa TorresComments to Author , JoaquÃn Castilla, Belén Pintado,
Alfonso Gutiérrez-Adan, Olivier Andréoletti, Patricia Aguilar-Calvo, Ana-Isabel
Arroba, Beatriz Parra-Arrondo, Isidro Ferrer, Jorge Manzanares, and Juan-Carlos
Espinosa Author affiliations: Instituto Nacional de Investigación y TecnologÃa
Agraria y Alimentaria, Madrid, Spain (J.-M. Torres, J. Castilla, B. Pintado, A.
Gutiérrez-Adán P. Aguilar-Calvo, A.-I. Arroba, B. Parra-Arrondo, J.-C.
Espinosa); Basque Foundation for Science, Bilbao, Spain (J. Castilla); Ecole
Nationale Vétérinaire de Toulouse, Toulouse, France (O. Andréoletti); Hospitalet
de Llobregat, Barcelona, Spain (I. Ferrer); Universidad Miguel Hernandez, Sant
Joan d´Alacant, Spain (J. Manzanares)
Abstract
We generated transgenic mice expressing bovine cellular prion protein
(PrPC) with a leucine substitution at codon 113 (113L). This protein is
homologous to human protein with mutation 102L, and its genetic link with
Gerstmann–Sträussler–Scheinker syndrome has been established. This mutation in
bovine PrPC causes a fully penetrant, lethal, spongiform encephalopathy. This
genetic disease was transmitted by intracerebral inoculation of brain homogenate
from ill mice expressing mutant bovine PrP to mice expressing wild-type bovine
PrP, which indicated de novo generation of infectious prions. Our findings
demonstrate that a single amino acid change in the PrPC sequence can induce
spontaneous generation of an infectious prion disease that differs from all
others identified in hosts expressing the same PrPC sequence. These observations
support the view that a variety of infectious prion strains might spontaneously
emerge in hosts displaying random genetic PrPC mutations.
snip...
The new 113L BSE prion generated shares some phenotypic features with the
classical BSE-C prion when inoculated in the same Tg110 mouse line according to
various criteria: 1) apparent molecular mass of PrPres, 2) PrPres glycosylation
pattern, 3) lack of immunoreactivity with mAb 12B2, 4) pattern of labeling with
mAbs Saf84 and R145, 5) detectable PrPres in spleens of infected animals, and 6)
spatial distribution of PrPres in brain. However, the vacuolation profile in
brain was distinct from those of all known bovine prion strains (classical
BSE-C, atypical BSE-H, and atypical BSE-L prions). These differences were
maintained after subsequent passages, indicating that the novel prion,
spontaneously produced by transgenic mice expressing mutant 113LBoPrP, is
distinct from all known bovine prion strains, although it shares many phenotypic
features with the classical BSE-C prion.
These observations demonstrate that mutations in bovine PrP can result in
spontaneous generation of infectious prion diseases and support the hypothesis
of a genetic origin for the epidemic BSE prion. Different features exhibited by
the new 113L-BSE prion, compared with those of the classical BSE prion, suggest
that if the origin of BSE was genetic, it is unlikely that the causal mutation
would be related to the 113L mutation. However, slight phenotypic differences
observed could be the results of evolution of the epidemic BSE prion in field
conditions in cattle, which must be different from those of our transgenic mouse
model. Although BoPrP with the 113L mutation has not been found in nature, a
potential pathogenic mutation (E211K) within PrP has been recently reported in a
cow with an H-type BSE phenotype (39). This mutation is equivalent to a common
mutation (E200K) in humans, which is associated with genetic TSEs.
Spontaneous appearance of infectivity reported in transgenic mice
expressing a mutated BoPrP and in mice expressing mutated mouse PrP reported by
Stöhr et al. (40) supports the hypothesis that infectious TSE prions, could
originate by a random genetic mutation that can induce de novo generation of
infectious prions, and that this mechanism could constitute a source of prion
diversity. These considerations enable us to hypothesize that the BSE epidemic
could have begun by a random genetic mutation that was able to generate de novo
infectious prions, which were included in meat and bone meal fed to cattle and
then broadly expanded in the cattle population. According to this hypothesis, a
key strategy for controlling BSE would involve preventing cows from consuming
products from cows with spontaneous cases of BSE.
Dr Torres is lead researcher scientist in the Prions Group at the Centro
de Investigación en Sanidad Animal–Instituto Nacional de Investigación y
TecnologÃa Agraria y Alimentaria, Madrid, Spain. His research interests include
prion strain characterization and evolution and the pathogenesis of prion
diseases and their effects on human and animal health.
Acknowledgment
This study was supported by grants from the Spanish Ministerio de Ciencia e
Innovación (EET2002-5168 and AGL2009-11553-C02-02) and the European Union
(FP7-2009-CT-222887 and FP7-2009-CT-228394).
let's take a closer look at this new prionpathy or prionopathy, and then
let's look at the g-h-BSEalabama mad cow.
This new prionopathy in humans? the genetic makeup is IDENTICAL to the
g-h-BSEalabama mad cow, the only _documented_ mad cow in the world to date like
this, ......wait, it get's better. this new prionpathy is killing young and old
humans, with LONG DURATION from onset of symptoms to death, and the symptoms are
very similar to nvCJD victims, OH, and the plaques are very similar in some
cases too, bbbut, it's not related to the g-h-BSEalabama cow, WAIT NOW, it gets
even better, the new human prionpathy that they claim is a genetic TSE, has no
relation to any gene mutation in that family. daaa, ya think it could be related
to that mad cow with the same genetic make-up ??? there were literally tons and
tons of banned mad cow protein in Alabama in commerce, and none of it
transmitted to cows, and the cows to humans there from ??? r i g h t $$$
ALABAMA MAD COW g-h-BSEalabama
In this study, we identified a novel mutation in the bovine prion protein
gene (Prnp), called E211K, of a confirmed BSE positive cow from Alabama, United
States of America. This mutation is identical to the E200K pathogenic mutation
found in humans with a genetic form of CJD. This finding represents the first
report of a confirmed case of BSE with a potential pathogenic mutation within
the bovine Prnp gene. We hypothesize that the bovine Prnp E211K mutation most
likely has caused BSE in "the approximately 10-year-old cow" carrying the E221K
mutation.
***Spontaneous appearance of infectivity reported in transgenic mice
expressing a mutated BoPrP and in mice expressing mutated mouse PrP reported by
Stöhr et al. (40) supports the hypothesis that infectious TSE prions, could
originate by a random genetic mutation that can induce de novo generation of
infectious prions, and that this mechanism could constitute a source of prion
diversity. ***These considerations enable us to hypothesize that the BSE
epidemic could have begun by a random genetic mutation that was able to generate
de novo infectious prions, which were included in meat and bone meal fed to
cattle and then broadly expanded in the cattle population. According to this
hypothesis, a key strategy for controlling BSE would involve preventing cows
from consuming products from cows with spontaneous cases of BSE.***
her healthy calf also carried the mutation (J. A. Richt and S. M. Hall PLoS
Pathog. 4, e1000156; 2008).
This raises the possibility that the disease could occasionally be genetic
in origin. Indeed, the report of the UK BSE Inquiry in 2000 suggested that the
UK epidemic had most likely originated from such a mutation and argued against
the scrapierelated assumption. Such rare potential pathogenic PRNP mutations
could occur in countries at present considered to be free of BSE, such as
Australia and New Zealand. So it is important to maintain strict surveillance
for BSE in cattle, with rigorous enforcement of the ruminant feed ban (many
countries still feed ruminant proteins to pigs). Removal of specified risk
material, such as brain and spinal cord, from cattle at slaughter prevents
infected material from entering the human food chain. Routine genetic screening
of cattle for PRNP mutations, which is now available, could provide additional
data on the risk to the public. Because the point mutation identified in the
Alabama animals is identical to that responsible for the commonest type of
familial (genetic) CJD in humans, it is possible that the resulting infective
prion protein might cross the bovine–human species barrier more easily. Patients
with vCJD continue to be identified. The fact that this is happening less often
should not lead to relaxation of the controls necessary to prevent future
outbreaks.
Malcolm A. Ferguson-Smith Cambridge University Department of Veterinary
Medicine, Madingley Road, Cambridge CB3 0ES, UK e-mail: maf12@cam.ac.uk Jürgen
A. Richt College of Veterinary Medicine, Kansas State University, K224B Mosier
Hall, Manhattan, Kansas 66506-5601, USA
NATURE|Vol 457|26 February 2009
Saturday, August 14, 2010
***BSE Case Associated with Prion Protein Gene Mutation (g-h-BSEalabama)
and VPSPr PRIONPATHY
*** (see mad cow feed in COMMERCE IN ALABAMA...TSS)
However, a BSE expert said that consumption of infected material is the
only known way that cattle get the disease under natural conditons.
***“In view of what we know about BSE after almost 20 years experience,
contaminated feed has been the source of the epidemic,” said Paul Brown, a
scientist retired from the National Institute of Neurological Diseases and
Stroke.
BSE is not caused by a microbe. It is caused by the misfolding of the
so-called “prion protein” that is a normal constituent of brain and other
tissues. If a diseased version of the protein enters the brain somehow, it can
slowly cause all the normal versions to become misfolded. It is possible the
disease could arise spontaneously, though such an event has never been recorded,
Brown said.
*** What irks many scientists is the USDA’s April 25 statement that the
rare disease is “not generally associated with an animal consuming infected
feed.”
The USDA’s conclusion is a “gross oversimplification,” said Dr. Paul Brown,
one of the world’s experts on this type of disease who retired recently from the
National Institutes of Health. "(The agency) has no foundation on which to base
that statement.”
However, a BSE expert said that consumption of infected material is the
only known way that cattle get the disease under natural conditons.
“In view of what we know about BSE after almost 20 years experience,
contaminated feed has been the source of the epidemic,” said Paul Brown, a
scientist retired from the National Institute of Neurological Diseases and
Stroke.
BSE is not caused by a microbe. It is caused by the misfolding of the
so-called “prion protein” that is a normal constituent of brain and other
tissues. If a diseased version of the protein enters the brain somehow, it can
slowly cause all the normal versions to become misfolded. It is possible the
disease could arise spontaneously, though such an event has never been recorded,
Brown said.
*** Saturday, November 2, 2013 ***
Exploring the risks of a putative transmission of BSE to new species
Wednesday, September 25, 2013
Presence of subclinical infection in gene-targeted human prion protein
transgenic mice exposed to atypical BSE
I ask Professor Kong ; Thursday, December 04, 2008 3:37 PM
Subject: RE: re--Chronic Wating Disease (CWD) and Bovine Spongiform
Encephalopathies (BSE): Public Health Risk Assessment ''IS the h-BSE more
virulent than typical BSE as well, or the same as cBSE, or less virulent than
cBSE? just curious.....'' Professor Kong reply ;
.....snip
''As to the H-BSE, we do not have sufficient data to say one way or
another, but we have found that H-BSE can infect humans. I hope we could publish
these data once the study is complete. Thanks for your interest.''
Best regards, Qingzhong Kong, PhD Associate Professor Department of
Pathology Case Western Reserve University Cleveland, OH 44106 USA END...TSS
Thursday, December 04, 2008 2:37 PM
"we have found that H-BSE can infect humans."
personal communication with Professor Kong. ...TSS
BSE-H is also transmissible in our humanized Tg mice. The possibility of
more than two atypical BSE strains will be discussed.
Supported by NINDS NS052319, NIA AG14359, and NIH AI 77774.
please see below from PRION2013 ;
*** This study imply the possibility that the novel BSE prions with high
virulence in cattle will be emerged during intraspecies transmission.
AD.56: The emergence of novel BSE prions by serial passages of H-type BSE
in bovinized mice
Kentaro Masujin, Naoko Tabeta, Ritsuko Miwa, Kohtaro Miyazawa, Hiroyuki
Okada, Shirou Mohri and Takashi Yokoyama National Institute of Animal Health;
Tsukuba, Japan
H-type bovine spongiform encephalopathy (BSE) is an atypical form of BSE,
and has been detected in several European countries, and North America.
Transmission studies of H-type BSE led to the emergence of the classical BSE
(C-BSE) phenotypes during passages in inbred wild type and bovinized
PrP-overexpressing transgenic mice. In this study, we conducted serial passages
of Canadian H-type BSE isolate in bovinized PrP-overexpressing transgenic mice
(TgBoPrP). H-type BSE isolate was transmitted to TgBoPrP with incubation periods
of 320 ± 12.2 d at primary passage. The incubation period of 2nd and 3rd passage
were constant (~= 220 d), no clear differences were observed in their biological
and biochemical properties. However, at the forth passage, 2 different BSE
phenotypes were confirmed; one is shorter survival times (109 ± 4 d) and the
other is longer survival times. TgBoPrP mice with longer incubation period
showed the H-type phenotype of PrPsc profile and pathology. However, those of
shorter incubation period were different phenotypes from previously existed BSE
prions (C-BSE, L-type BSE, and H-type BSE).
*** This study imply the possibility that the novel BSE prions with high
virulence in cattle will be emerged during intraspecies transmission.
www.landesbioscience.com
please see ;
Thursday, August 15, 2013
The emergence of novel BSE prions by serial passages of H-type BSE in
bovinized mice
Sunday, September 1, 2013
*** Evaluation of the Zoonotic Potential of Transmissible Mink
Encephalopathy
We previously described the biochemical similarities between PrPres derived
from L-BSE infected macaque and cortical MM2 sporadic CJD: those observations
suggest a link between these two uncommon prion phenotypes in a primate model
(it is to note that such a link has not been observed in other models less
relevant from the human situation as hamsters or transgenic mice overexpressing
ovine PrP [28]). We speculate that a group of related animal prion strains
(L-BSE, c-BSE and TME) would have a zoonotic potential and lead to prion
diseases in humans with a type 2 PrPres molecular signature (and more
specifically type 2B for vCJD)
snip...
Together with previous experiments performed in ovinized and bovinized
transgenic mice and hamsters [8,9] indicating similarities between TME and
L-BSE, the data support the hypothesis that L-BSE could be the origin of the TME
outbreaks in North America and Europe during the mid-1900s.
Monday, October 10, 2011
EFSA Journal 2011 The European Response to BSE: A Success Story
snip...
EFSA and the European Centre for Disease Prevention and Control (ECDC)
recently delivered a scientific opinion on any possible epidemiological or
molecular association between TSEs in animals and humans (EFSA Panel on
Biological Hazards (BIOHAZ) and ECDC, 2011). This opinion confirmed Classical
BSE prions as the only TSE agents demonstrated to be zoonotic so far but the
possibility that a small proportion of human cases so far classified as
"sporadic" CJD are of zoonotic origin could not be excluded. Moreover,
transmission experiments to non-human primates suggest that some TSE agents in
addition to Classical BSE prions in cattle (namely L-type Atypical BSE,
Classical BSE in sheep, transmissible mink encephalopathy (TME) and chronic
wasting disease (CWD) agents) might have zoonotic potential.
snip...
see follow-up here about North America BSE Mad Cow TSE prion risk factors,
and the ever emerging strains of Transmissible Spongiform Encephalopathy in many
species here in the USA, including humans ;
Thursday, August 12, 2010
Seven main threats for the future linked to prions
First threat
The TSE road map defining the evolution of European policy for protection
against prion diseases is based on a certain numbers of hypotheses some of which
may turn out to be erroneous. In particular, a form of BSE (called atypical
Bovine Spongiform Encephalopathy), recently identified by systematic testing in
aged cattle without clinical signs, may be the origin of classical BSE and thus
potentially constitute a reservoir, which may be impossible to eradicate if a
sporadic origin is confirmed.
***Also, a link is suspected between atypical BSE and some apparently
sporadic cases of Creutzfeldt-Jakob disease in humans. These atypical BSE cases
constitute an unforeseen first threat that could sharply modify the European
approach to prion diseases.
Second threat
snip...
PRIONOPATHY OR PRIONOBALONEY $$$
Conclusion/Significance: Our results point to a possibly higher degree of
pathogenicity of BASE than classical BSE in primates and also raise a question
about a possible link to one uncommon subset of cases of apparently sporadic
CJD. Thus, despite the waning epidemic of classical BSE, the occurrence of
atypical strains should temper the urge to relax measures currently in place to
protect public health from accidental contamination by BSE-contaminated
products.
SPONTANEOUS TSE
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
snip...
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. ...
snip...full text ;
DR. DEHAVEN: “All right. I think we've got three different questions in
there, and I'll try to touch on each one of them.
“First of all, let me correct just a technical issue, and that is you
mentioned 1 in 10,000. And actually our surveillance system currently is
designed, the one that we have in place now is designed to detect 1 positive in
1 million cattle, and I gave some numbers between 200,000 and 268,000 that would
allow us to detect 1 in 10 million as opposed to 1 in 10,000.
“So we would, if we were able to collect in the ballpark of those numbers
of samples then we with increasing numbers of samples have an increasingly
statistically valid sample from which to determine, one, whether or not the
disease exists and, if so, at what prevalence level.
“So our real emphasis is to test as many of those animals as we can, ensure
that we get an appropriate geographical distribution, but not setting a specific
number as far as a target. Again, consistent with the recommendation from the
International Review Team, their recommendation was to test all of them.
“So that's consistent with where we're going is to test as many as we
possibly can.
*** “As far as spontaneous cases, that is a very difficult issue. There is
no evidence to prove that spontaneous BSE occurs in cattle; but here again it's
an issue of proving a negative. We do know that CJD, the human version of the
disease, does occur spontaneously in humans at the rate of about 1 in 1 million.
We don't have enough data to definitively say that spontaneous cases of BSE in
cattle occur or do not occur.
“Again, it's a very difficult situation to prove a negative.
“So a lot of research is ongoing. Certainly if we do come up with any
positive samples in the course of this surveillance we will be looking at that
question in evaluating those samples but no scientifically hard evidence to
confirm or refute whether or not spontaneous cases of BSE occur.
snip...
Thursday, August 12, 2010
Seven main threats for the future linked to prions
First threat
The TSE road map defining the evolution of European policy for protection
against prion diseases is based on a certain numbers of hypotheses some of which
may turn out to be erroneous. In particular, a form of BSE (called atypical
Bovine Spongiform Encephalopathy), recently identified by systematic testing in
aged cattle without clinical signs, may be the origin of classical BSE and thus
potentially constitute a reservoir, which may be impossible to eradicate if a
sporadic origin is confirmed.
***Also, a link is suspected between atypical BSE and some apparently
sporadic cases of Creutzfeldt-Jakob disease in humans. These atypical BSE cases
constitute an unforeseen first threat that could sharply modify the European
approach to prion diseases.
Second threat
snip...
Thursday, August 12, 2010
Seven main threats for the future linked to prions
Tuesday, November 02, 2010
BSE – ATYPICAL LESION DISTRIBUTION (RBSE 92-21367) statutory (obex only)
diagnostic criteria CVL 1992
Atypical BSE in Cattle
BSE has been linked to the human disease variant Creutzfeldt Jakob Disease
(vCJD). The known exposure pathways for humans contracting vCJD are through the
consumption of beef and beef products contaminated by the BSE agent and through
blood transfusions. However, recent scientific evidence suggests that the BSE
agent may play a role in the development of other forms of human prion diseases
as well. These studies suggest that classical type of BSE may cause type 2
sporadic CJD and that H-type atypical BSE is connected with a familial form of
CJD.
To date the OIE/WAHO assumes that the human and animal health standards
set out in the BSE chapter for classical BSE (C-Type) applies to all forms of
BSE which include the H-type and L-type atypical forms. This assumption is
scientifically not completely justified and accumulating evidence suggests that
this may in fact not be the case. Molecular characterization and the spatial
distribution pattern of histopathologic lesions and immunohistochemistry (IHC)
signals are used to identify and characterize atypical BSE. Both the L-type and
H-type atypical cases display significant differences in the conformation and
spatial accumulation of the disease associated prion protein (PrPSc) in brains
of afflicted cattle. Transmission studies in bovine transgenic and wild type
mouse models support that the atypical BSE types might be unique strains because
they have different incubation times and lesion profiles when compared to C-type
BSE. When L-type BSE was inoculated into ovine transgenic mice and Syrian
hamster the resulting molecular fingerprint had changed, either in the first or
a subsequent passage, from L-type into C-type BSE. In addition, non-human
primates are specifically susceptible for atypical BSE as demonstrated by an
approximately 50% shortened incubation time for L-type BSE as compared to
C-type. Considering the current scientific information available, it cannot be
assumed that these different BSE types pose the same human health risks as
C-type BSE or that these risks are mitigated by the same protective measures.
snip...see full text ;
Friday, April 19, 2013
Bovine Spongiform Encephalopathy (BSE) Feed Safety Support Program Grants
Fiscal Year 2011: October 1, 2010 - September 30, 2011 FDA
J. clin. Path., 25, Suppi. (Roy. Coll. Path.), 6, 110-114
Scrapie-a personal view
l. H. PATTISON
From the ARC Institute for Research on Animal Diseases, Compton, Newbury,
Berkshire
The first published reference to the transmissible agent as something other
than a virus was by Parry (1962), who called it a provirus, defined as something
that was formed inside an affected animal but had no independent outside
existence. The next published suggestion that the scrapie agent might be odd was
my own (Pattison, 1965) when I said that ' . . . if the transmissible agent of
scrapie is a living virus, it is a virus of a kind as yet unrecognized.' This
conclusion was based on a long series of unsuccessful attempts to inactivate the
scrapie agent by heroic methods, including treatment with 12% formalin for 28
months. But what is a 'virus'? If by 'virus' is meant something that will
negotiate an antibacterial filter and can be passed indefinitely through
animals, apparently increasing in quantity as it goes, then the scrapie agent is
a virus. If, however, a virus has to contain nucleic acid, then I believe that
D. A. Haig and M. C. Clarke at Compton and their collaborator Tikvah Alper at
the Hammersmith Hospital have shown beyond reasonable doubt by their studies
with ultraviolet irradiation that the scrapie agent does not contain nucleic
acid and is not a virus (Alper, Haig, and Clarke, 1966; Alper, Cramp, Haig, and
Clarke,
114
1967; Haig, Clarke, Blum, and Alper, 1969; Latarjet, Muel, Haig, Clarke,
and Alper, 1970).
References
Alper, T., Cramp, W. A., 1faig, D. A., and Clarke, M. C. (1967). Does the
agent of scrapie replicate without nucleic acid? Nature (Lond.), 214,
764-766.
Alper. T., Haig, D. A., and Clarke, M. C. (1966). The exceptionally small
size of the scrapie agent. Biochem. biophys. Res. Comnmun., 22, 278-284.
Bertrand, I., Carre, ff., and Lucam, F. (1937). La 'tremblante' du mouton.
Ann. Anat. path. med.-chir., 14, 565-586.
Besnoit, C., and Morel, C. (1898). Note sur les lesions nerveuses de Ia
tremblante du mouton. Rev. vet. Toulouse, 23, 397-400.
Brownlee, A. (1940). Histopathological studies of scrapie, an obscure
disease of sheep. Vet. J., 96, 254-264.
Chandler, R. L. (1961). Encephalopathy in mice produced by inoculation with
scrapie brain material. Lancet, 1, 1378-1379. Chandler, R. L. (1962).
Encephalopathy in mice. (Letter). Lancet, 1, 107-108.
Cuille, J., and Chelle, P. L. (1936). La maladie dite tremblante du mouton
est-elle inoculable? C.R. Acad. Sci. (Paris), 203, 1552-1554.
Cuille, J. and Chelle, P. L. (1938). La tremblante du mouton est-elle
determinee par un virus filterable? C.R. Acad. Sci. (Paris), 206,
1687-1688.
Cuille, J., and Chelle, P. L. (1939). Transmission experimentale de la
tremblante a la chevre. C.R. Acad. Sci. (Paris), 208, 1058-1060.
Field, E. J. (1969). Slow virus infections of the nervous system. Int. Rev.
exp. Path., 8, 129-239.
I. H. Pattison Field, E. J., and Windsor, G. D. (1965). Cultural characters
of scrapie mouse brain. Res. vet. Sci., 6, 130-132.
Gajdusek, D. C., Gibbs, C. J., Jr., and Alpers, M. (1966). Experimental
transmission of a kuru-like syndrome to chimpanzees. Nature (Lond.), 209,
794-796.
Gordon, W. S. (1957). Discussion to Palmer, A. C. Studies in scrapie. Vet.
Rec., 69, 1324-1327.
Gordon, W. S. (1966). Review of work on scrapie at Compton, England,
1952-1964. In Report of Scrapie Seminar, Washington D.C., ARS 91-53, pp.
19-36.
Gustafson, D. P., and Kanitz, C. L. (1965). Evidence of the presence of
scrapie in cell cultures of brain. In Slow, Latent and Temperate Virus
Infections (NINDB Monograph No. 2), pp. 221-236, edited by D. C. Gajdusek, C. J.
Gibbs, Jr., and M. Alpers, National Institute of Health, Washington D.C.
Hadlow, W. J. (1959). Scrapie and kuru. Lancet, 2, 289-290.
Haig, D. A., and Clarke, M. C. (1971). Multiplication of the scrapie agent.
Nature (Lond.), 234, 106-107.
Haig, D. A., Clarke, M. C., Blum, E., and Alper, T. (1969). Further studies
on the inactivation of the scrapie agent by ultraviolet light. J. gen. Virol.,
5, 455-457.
Haig, D. A., and Pattison, I. H. (1967) In-vitro growth of pieces of brain
from scrapie-affected mice. J. Path. Bact., 93, 724-727.
Latarjet, R., Muel, B., 1-faig, D. A., Clarke, M. C., and Alper, T. (1970).
Inactivation of the scrapie agent by near monochromatic ultraviolet light.
Nature (Lond.), 227, 1341-1343.
Morris, J. A., and Gajdusek, D. C. (1963). Encephalopathy in mice following
inoculation of scrapie sheep brain. Nature (Lond.), 197, 1084-1086.
Parry, H. B. (1962). Scrapie: a transmissible and hereditary disease of
sheep. Heredity, 17, 75-105.
Pattison, I. H. (1965). Resistance of the scrapie agent to formalin. J.
comp. Path., 75, 159-164.
Pattison, I. H., Gordon, W. S., and Millson, G. C. (1959). Experimental
production of scrapie in goats. J. comp. Path., 69, 300-312.
Pattison, 1. H., and Millson, G. C. (1961). Scrapie produced experimentally
in goats with special reference to the clinical syndrome. J. comp. Path., 71,
101-108.
Roche-Lubin (1848). Memoire pratique sur la maladie des b8tes a laine
connue sous les noms de prurigo lombaire, maladie convulsive, trembleuse,
tremblante, etc. Rec. Med. vet. Ser 3, 5, 698-7 14.
Stamp, J. T. (1960). Scrapie and scrapie research at Animal Diseases
Research Association, Moredun Institute, Edinburgh. In U.S. Department of
Agriculture Special Meetings on Scrapie, ARS 91-22, pp. 13-22.
Stamp, J. T., Brotherston, J. G., Ziotnik, I., Mackay, J. M. K., and Smith,
W. (1959). Further studies on scrapie. J. comp. Path., 69, 268-280.
Stockman, S. (1926). Contribution to the study of the disease known as
scrapie. J. comp. Path., 39, 42-71.
Thormar, H. (1971). Slow infections of the central nervous system. Z.
Neurol., 199, 1-23 and 151-166.
Wilson, D. R. (1952). Scrapie. Vet. Rec., 64, 468.
Wilson, D. R., Anderson, R. D., and Smith, W. (1950). Studies in scrapie.
J. comp. Path., 60, 267-282.
4.2.9 A further hypothesis to explain the occurrence of BSE is the
emergence or selection of a strain or strains of the scrapie agent pathogenic
for cattle. Mutations of the scrapie agent. which can occur after a single
passage in mice. have been well documented (9). This phenomenon cannot be
dismissed for BSE. but given the form of the epidemic and the geographically
widespread occurrence of BSE, such a hypothesis" would require the emergence of
a mutant scrapie strain simultaneously in a large . number of sheep flocks, or
cattle. throughout the country. Also. if it resulted "from a localised chance
transmission of the scrapie strain from sheep to cattle giving rise , . to a
mutant. a different pattern of disease would have been expected: its range would
'. have increased with time. Thus the evidence from Britain is against the
disease being due to a new strain of the agent, but we note that in the United
States from 1984 to 1988 outbreaks of scrapie in sheep flocks are reported to
have Increased markedly. now being nearly 3 times as high as during any previous
period (18).
If the scrapie agent is generated from ovine DNA and thence causes disease
in other species, then perhaps, bearing in mind the possible role of scrapie in
CJD of humans (Davinpour et al, 1985), scrapie and not BSE should be the
notifiable disease. ...
ALSO, SEE Scrapie Mission, Texas, did not produce _typical_ BSE... see
page 17 here ;
3.57 The experiment which might have determined whether BSE and scrapie
were caused by the same agent (ie, the feeding of natural scrapie to cattle) was
never undertaken in the UK. It was, however, performed in the USA in 1979, when
it was shown that cattle inoculated with the scrapie agent endemic in the flock
of Suffolk sheep at the United States Department of Agriculture in Mission,
Texas, developed a TSE quite unlike BSE.339 The findings of the initial
transmission, though not of the clinical or neurohistological examination, were
communicated in October 1988 to Dr Watson, Director of the CVL, following a
visit by Dr Wrathall, one of the project leaders in the Pathology Department of
the CVL, to the United States Department of Agriculture.340 The results were not
published at this point, since the attempted transmission to mice from the
experimental cow brain had been inconclusive. The results of the clinical and
histological differences between scrapie-affected sheep and cattle were
published in 1995. Similar studies in which cattle were inoculated
intracerebrally with scrapie inocula derived from a number of scrapie-affected
sheep of different breeds and from different States, were carried out at the US
National Animal Disease Centre.341 The results, published in 1994, showed that
this source of scrapie agent, though pathogenic for cattle,
*** did not produce the same clinical signs of brain lesions characteristic
of BSE. ***
3.58 There are several possible reasons why the experiment was not
performed in the UK. It had been recommended by Sir Richard Southwood (Chairman
of the Working Party on Bovine Spongiform Encephalopathy) in his letter to the
Permanent Secretary of MAFF, Mr (now Sir) Derek Andrews, on 21 June 1988,342
though it was not specifically recommended in the Working Party Report or indeed
in the Tyrrell Committee Report (details of the Southwood Working Party and the
Tyrell Committee can be found in vol. 4: The Southwood Working Party, 1988–89
and vol. 11: Scientists after Southwood respectively). The direct inoculation of
scrapie into calves was given low priority, because of its high cost and because
it was known that it had already taken place in the USA.343 It was also felt
that the results of such an experiment would be hard to interpret. While a
negative result 337 Fraser, H., Bruce, M., Chree, A., McConnell, I. and Wells,
G. (1992) Transmission of Bovine Spongiform Encephalopathy and Scrapie to Mice,
Journal of General Virology, 73, 1891–7; Bruce, M., Chree, A., McConnell, I.,
Foster, J., Pearson, G. and Fraser, H. (1994) Transmission of Bovine Spongiform
Encephalopathy and Scrapie to Mice: Strain Variation and the Species Barrier,
Philosophical Transactions of the Royal Society of London, Series B, Biological
Sciences, 343, 405–11 338 Bruce, M., Will, R., Ironside, J., McConell, I.,
Drummond, D., Suttie, A., McCordie, L., Chree, A., Hope, J., Birkett, C.,
Cousens, S., Fraser, H. and Bostock, C. (1997) Transmissions to Mice Indicate
that ‘New Variant’ CJD is Caused by the BSE Agent, Nature, 389, 498–501 339
Clark, W., Hourrigan, J. and Hadlow, W. (1995) Encephalopathy in Cattle
Experimentally Infected with the Scrapie Agent, American Journal of Veterinary
Research, 56, 606–12 340 YB88/10.00/1.1 341 Cutlip, R., Miller, J., Race, R.,
Jenny, A., Katz, J., Lehmkuhl, H., Debey, B. and Robinson, M. (1994)
Intracerebral Transmission of Scrapie to Cattle, Journal of Infectious Diseases,
169, 814–20 342 YB88/6.21/1.2 343 YB88/11.17/2.4 SCIENCE 84 would be
informative, a positive result would need to demonstrate that when scrapie was
transmitted to cattle, the disease which developed in cattle was the same as
BSE.344 Given the large number of strains of scrapie and the possibility that
BSE was one of them, it would be necessary to transmit every scrapie strain to
cattle separately, to test the hypothesis properly. Such an experiment would be
expensive. Secondly, as measures to control the epidemic took hold, the need for
the experiment from the policy viewpoint was not considered so urgent. It was
felt that the results would be mainly of academic interest.345 3.59
Nevertheless, from the first demonstration of transmissibility of BSE in 1988,
the possibility of differences in the transmission properties of BSE and scrapie
was clear. Scrapie was transmissible to hamsters, but by 1988 attempts to
transmit BSE to hamsters had failed. Subsequent findings increased that
possibility.
In Confidence - Perceptions of unconventional slow virus diseases of
animals in the USA - APRIL-MAY 1989 - G A H Wells
snip...
PAGE 31
Appendix I
VISIT TO USA - DR A E WRATHALL - INFO ON BSE AND SCRAPIE
1. Dr Clark lately of the Scrapie Research Unit, Mission Texas has
successfully transmitted ovine and caprine scrapie to cattle. The experimental
results have not been published but there are plans to do this. This work was
initiated in 1978. A summary of it is:-
Expt A 6 Her x Jer calves born in 1978 were inoculated as follows with a
2nd Suffolk scrapie passage:-
i/c 1ml i/m, 5ml; s/c 5ml; oral 30ml.
1/6 went down after 48 months with a scrapie/BSE-like disease.
Expt B 6 Her or Jer or HxJ calves were inoculated with angora Goat virus
2/6 went down similarly after 36 months.
Expt C Mice inoculated from brains of calves/cattle in expts A & B were
resistant, only 1/20 going down with scrapie and this was the reason given for
not publishing.
Diagnosis in A, B, C was by histopath. No reports on SAF were given.
Dr Warren Foote indicated success so far in eliminating scrapie in
offspring from experimentally- (and naturally) infected sheep by ET. He had
found difficulty in obtaining emhryos from naturally infected sheep (cf SPA).
3. Prof. A Robertson gave a brief account of BSE. The US approach was to
PAGE 32
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. BSE was not reported in USA.
4. Scrapie incidents (ie affected flocks) have shown a dramatic increase
since 1978. In 1953 when the National Control Scheme was started there were
10-14 incidents, in 1978 - 1 and in 1988 so far 60.
5. Scrapie agent was reported to have been isolated from a solitary fetus.
6. A western blotting diagnostic technique (? on PrP} shows some promise.
7. Results of a questionnaire sent to 33 states on the subject of the
national sheep scrapie programme survey indicated;
17/33 wished to drop it 6/33 wished to develop it 8/33 had few sheep and
were neutral
Information obtained from Dr Wrathall's notes of a meeting of the U.S.
Animal Health Association at Little Rock, Arkansas Nov. 1988.
please see ;
In Confidence - Perceptions of unconventional slow virus diseases of
animals in the USA - APRIL-MAY 1989 - G A H Wells
PAGE 31
Appendix I
VISIT TO USA - DR A E WRATHALL - INFO ON BSE AND SCRAPIE
1. Dr Clark lately of the Scrapie Research Unit, Mission Texas has
successfully transmitted ovine and caprine scrapie to cattle. The experimental
results have not been published but there are plans to do this. This work was
initiated in 1978. A summary of it is:-
Expt A 6 Her x Jer calves born in 1978 were inoculated as follows with a
2nd Suffolk scrapie passage:-
i/c 1ml i/m, 5ml; s/c 5ml; oral 30ml.
1/6 went down after 48 months with a scrapie/BSE-like disease.
Expt B 6 Her or Jer or HxJ calves were inoculated with angora Goat virus
2/6 went down similarly after 36 months.
Expt C Mice inoculated from brains of calves/cattle in expts A & B were
resistant, only 1/20 going down with scrapie and this was the reason given for
not publishing.
Diagnosis in A, B, C was by histopath. No reports on SAF were given.
Dr Warren Foote indicated success so far in eliminating scrapie in
offspring from experimentally- (and naturally) infected sheep by ET. He had
found difficulty in obtaining emhryos from naturally infected sheep (cf SPA).
3. Prof. A Robertson gave a brief account of BSE. The US approach was to
PAGE 32
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. BSE was not reported in USA.
4. Scrapie incidents (ie affected flocks) have shown a dramatic increase
since 1978. In 1953 when the National Control Scheme was started there were
10-14 incidents, in 1978 - 1 and in 1988 so far 60.
5. Scrapie agent was reported to have been isolated from a solitary
fetus.
6. A western blotting diagnostic technique (? on PrP} shows some promise.
7. Results of a questionnaire sent to 33 states on the subject of the
national sheep scrapie programme survey indicated;
17/33 wished to drop it 6/33 wished to develop it 8/33 had few sheep and
were neutral
Information obtained from Dr Wrathall's notes of a meeting of the U.S.
Animal Health Association at Little Rock, Arkansas Nov. 1988.
kind regards,
Terry S. Singeltary Sr., Bacliff, Texas USA -July 29, 2000-
please see ;
Their concern deepened as they experimented with ways to sanitize the
holding pens in Fort Collins and Sybille. All the deer and elk in the
contaminated pens at Sybille were killed, and the pens were left empty for six
months to a year. When deer and elk were reintroduced to the pens, they were
animals that weren't known to have had direct contact with infected deer and
elk. In spite of these efforts, elk in the pens came down with chronic wasting
disease within five years after the attempt at sterilizing the facility.
In Fort Collins, the effort was even more intense. All the deer and elk in
the facility were killed and buried. Then personnel plowed up the soil in the
pens in an effort to bury possible disease organisms and sprayed structures and
pastures repeatedly with a strong disinfectant. A year later, they took twelve
elk calves from the wild and released them in the sanitized holding areas. In
the next five years, two of these elk died from chronic wasting disease.
Saturday, June 25, 2011
Transmissibility of BSE-L and Cattle-Adapted TME Prion Strain to Cynomolgus
Macaque
"BSE-L in North America may have existed for decades"
Over the next 8-10 weeks, approximately 40% of all the adult mink on the
farm died from TME.
snip...
The rancher was a ''dead stock'' feeder using mostly (>95%) downer or
dead dairy cattle...
*** Saturday, November 2, 2013 ***
Exploring the risks of a putative transmission of BSE to new species
Wednesday, October 30, 2013
SPECIFIED RISK MATERIAL (SRM) CONTROL VERIFICATION TASK FSIS NOTICE 70-13
10/30/13
***Together with previous experiments performed in ovinized and bovinized
transgenic mice and hamsters [8,9] indicating similarities between TME and
L-BSE, the data support the hypothesis that L-BSE could be the origin of the TME
outbreaks in North America and Europe during the mid-1900s.
Tuesday, September 24, 2013
NORDION (US), INC., AND BIOAXONE BIOSCIENCES, INC., Settles $90M Mad Cow
TSE prion Contamination Suit Cethrin(R)
*** Case 0:12-cv-60739-RNS Document 1 Entered on FLSD Docket 04/26/2012
Page 1 of 15 ***
with great sadness and disgust, I must inform you that our federal
government has failed us again, and chose the industry over sound science, with
regards to TSE prion disease, aka mad cow type disease...tss
Saturday, November 2, 2013
APHIS Finalizes Bovine Import Regulations in Line with International Animal
Health Standards while enhancing the spread of BSE TSE prion mad cow type
disease around the Globe
Monday, November 4, 2013
R-CALF Bullard new BSE rule represents the abrogation of USDA’s
responsibility to protect U.S. consumers and the U.S. cattle herd from the
introduction of foreign animal disease
TSS
