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From: TSS (wt-d6-158.wt.net)
Subject: Federal Veterinarian Volume 61 Number 10 October 2004 (TSE report)
Date: November 9, 2004 at 2:14 pm PST

-------- Original Message --------
Subject: Federal Veterinarian Volume 61 Number 10 October 2004 (TSE report)
Date: Tue, 9 Nov 2004 16:14:36 -0600
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy
To: BSE-L@UNI-KARLSRUHE.DE


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

Federal Veterinarian
Published in Washington, D.C. by
The National Association of Federal Veterinarians
Volume 61 Number 10 October 2004

snip...

October 2004 - Federal Veterinarian - Page 3

TSE Update

PStudy Lends Support to Mad Cow Theory
Scientists are reporting that, for the first time, they
have made an artificial prion, or misfolded protein,
that can by itself produce a deadly infectious disease
in mice and may help explain the roots of mad cow
disease.
The findings, being reported today in the Journal
Science, [Legname G., et al. Science, 305. 673 - 676
(2004)] are strong evidence for the "protein-only
hypothesis," the controversial idea that a protein,
acting alone without the help of DNA or RNA, a
cousin of DNA, can cause certain kinds of infectious
diseases.
The concept was introduced in 1982 by Dr Stanley
Prusiner, a neurology professor at the University of
California, San Francisco, who led the new study.
The hypothesis is still unsettling to many scientists
who have been taught that only bacteria and viruses
containing genetic information can spread infectious
diseases.
Over the years, the idea that a misfolded prion
protein, because of its shape alone, could trigger an
infectious disease has been gaining acceptance, but
it has never been conclusively proven. Proteins,
which are strings of amino acids, fold into distinct
shapes to carry out various functions in the body. It
is not completely known what makes proteins fold
incorrectly. But the theory is that when a misfolded
prion comes in contact with other prions, they, too,
become misfolded and a disease is spread.
In this study, Dr Prusiner said, researchers essentially
created a man-made prion and injected it into
mouse brains and produced disease. Then, they took
tissue from the diseased mice and injected it into
other mice, which also got the same disease.
Dr Prusiner said in a telephone interview that he
was "flabbergasted" that it took 22 years to prove the
hypothesis, but that his laboratory was able to overcome
earlier technical difficulties with a new set of
experiments. "We have compelling evidence," he
said. "We've done it all."
Dr Christopher Dobson, a professor of chemical
and structural biology at Cambridge University and
an expert on protein folding, said: "This is the key
experiment everyone was waiting for. While there is
never absolute proof in science, this experiment puts
the protein-only theory of transmission beyond
reasonable doubt."
Still, some said the evidence was not sufficient.
Dr Bruce Chesebro, chief of the Laboratory of
Persistent Viral Diseases at the federal Rocky Mountain
Laboratories, said the experiment showed that
the prion produced something in the mice. But he
said it was still unclear whether the prion was causing
the infection or just exposing an underlying
infectious process.
Dr Laura Manuelidis, a neuropathologist at the Yale
University Medical School, one of Dr Prusiner's most
vocal critics, said the prion strain that turned up in the
experiment looked like a mouse prion frequently used
in Dr Prusiner's laboratory. She said that meant that
something else might have caused the infection.
"Basically I think the data look like contamination,"
Dr Manuelidis said, possibly stemming from "inadequately
washed instruments."
Dr Prusiner, who won the 1997 Nobel Prize in
Physiology or Medicine for his prion research, said
some of his critics would never be satisfied. "They'll
say we need to do 10 more years of experiments," he
said. "It's just silly."
Dr Prusiner predicted that the newly gleaned
information would lead to more effective ways to
diagnose and treat a family of deadly diseases called
transmissible spongiform encephalopathies, or TSEs,
believed to be caused by aberrant proteins.
The stakes are enormous. Last week, a British
citizen who died from other causes was found to
have been infected by a human form of TSE from a
routine blood transfusion. The human form, called
variant Creutzfeldt-Jakob disease, is contracted from
eating cattle infected with mad cow disease. At least
2 people who died from the variant disease gave
blood before falling ill, which means many more
Britons could be infected. The disease can take years
to manifest itself in humans.
American agriculture officials are testing thousands
of cattle in an effort to determine whether mad cow
disease is a problem in this country, but the tests are
notoriously imperfect. A deeper understanding of
protein diseases should lead to tests that can diagnose
the disease even in cattle that show no symptoms.
The biology of protein diseases is new and often
difficult to grasp, Dr Prusiner said. He said that many
proteins cause disease when they adopt an abnormal
shape and form toxic fibrils that create havoc in the
brain or body. Alzheimer's disease, Parkinson's
disease, Type 2 diabetes, and at least 2 dozen other
human disorders may be caused by misshapen
proteins, he said. Those diseases, however, do not
involve prions, which are the only misfolded proteins
known to be infectious.
The hallmarks of a TSE are spongy holes and
inflammation in the brain. Some of the diseases also
feature clumps of fibrils called amyloids.
When Dr Prusiner introduced the protein-only
hypothesis, he was greeted with skepticism. Laboratories
around the world have tried many times to
inject synthetic prions into mice, but the experiments
never worked, because the mice never got sick, Dr
Prusiner said. But this time, he said, the mice did get
sick from the synthetic prion. The protein fragment
was synthetic to avoid the possibility that something
in a live cell might have contributed to the disease.
In this experiment, Dr Prusiner injected a protein
fragment that he reasoned could be the core source
of the infection.
"We waited," he said. "And waited. At 300 days,
none of the animals had gotten sick. We thought the
experiment had not worked."
But over the next 200 days, every animal developed
spongiform degeneration, Dr Prusiner said. A
brain extract from a sick animal was injected into
normal mice with different prion structures. They, too,
got sick.
PPrion Finding Offers Insight into
Spontaneous Protein Diseases
UCSF [Univ of California at San Francisco] scientists
are reporting what they say is compelling evidence
that the infectious agent known as prion is
composed solely of protein. Their findings promise to
create new tools for early diagnosis of prions causing
bovine spongiform encephalopathy, or "mad cow"
disease, in cattle and Creutzfeldt-Jakob disease in
people, they say. The researchers believe that their
work may also help advance investigations of more
common neurodegenerative diseases, such as
Alzheimer's disease, Parkinson's disease and amyotrophic
lateral sclerosis.
The finding is reported in the 30 Jul 2004 issue of
Science.
In the study, the researchers created a large
fragment of the normal prion protein -- a harmless
protein found in all mammals examined. They then
folded this fragment into the abnormal shape that
they suspected would give it the infectious properties
of the prion. Next, they injected the folded protein
fragment into the brains of mice genetically engineered
to over-express the same fragment, but with
the shape of the normal prion protein. After a year,
the mice developed prion disease, and brain tissue
from the inoculated mice was injected into wild-type
mice, which subsequently developed prion disease in
about half a year.
"Our study demonstrates that misfolding a particular
segment of the normal prion protein is sufficient to
transform the protein into infectious prions," says the
lead author of the study, Giuseppe Legname, PhD,
UCSF assistant adjunct professor of neurology in the
laboratory of the senior author Stanley B. Prusiner,
MD, CSF professor of neurology and director of the
UCSF Institute for Neurodegenerative Diseases.
"A great deal of evidence indicates that prions are
composed only of protein, but this is the first time that
this has been directly shown in mammals. The
challenge in the last few years has been to figure out
exactly how to demonstrate that prions are made
entirely of protein."
PSpontaneous Prion Diseases
The discovery that a small change in the condition
of a cell can cause the development of a prion offers
an explanation, says Prusiner, for the sporadic form
of Creutzfeldt Jakob disease (CJD), which is responsible
for 85 percent of cases of prion disease in
humans (occurring in 1 or 2 people per million) and is
believed to develop spontaneously. It also supports
his belief, he says, that sporadic forms of prion
disease are caused by prion strains that are different
from the one causing bovine spongiform encephalopathy
(BSE) in cattle in Britain. He says he thinks that
sporadic BSE will be found in one to 5 cattle per
million and predicts such numbers will be found with
increased testing for BSE.
"The finding represents a renaissance in prion
biology," says Prusiner. "For the first time, we can
create prions in the test tube, which will change the
way scientists do experiments in the field. We now
have a tool for exploring the mechanism by which a
protein can spontaneously fold into a shape that
causes disease."
More broadly, he says, the advance may lead to
similar changes in the way studies are conducted for
other neurodegenerative diseases that involve
protein misprocessing, including Alzheimer's disease,
Parkinson's disease, and amyotrophic lateral sclerosis.
While it is not clear that a protein changes shape
in all these diseases, each involves a particular
protein that undergoes some form of misprocessing,
in terms of a shape change, metabolism or degradation,
or proteolysis. It is not clear [cont pg 4, col 1]

Page 4 - Federal Veterinarian - October 2004
TSE Update cont from pg 3
which of these forms of misprocessing occurs in each
disease, says Prusiner. However, as in prion diseases,
the misprocessing involves a profound conformational
change that most often occurs spontaneously.
"The insights that scientists have made into the
spontaneous misprocessing of prion proteins have
already aided progress in studies of other neurodegenerative
diseases," says Prusiner. "But we hope
that our new findings with synthetic prions will help
scientists investigating other neurodegenerative
diseases to move one step further in understanding
how misprocessing is spontaneously initiated, and
how it progresses."
The production of synthetic prions is the latest
milestone in the 30-year effort by UCSF scientists to
move in on the biochemical composition of the
elusive agent, which causes a variety of similar rare,
fatal, brain-destroying diseases, including sporadic
CJD and variant CJD, in humans, BSE, or "mad cow"
disease, in cattle, scrapie in sheep, and like illnesses
in deer, elk and mink.
PPrion's Fatal Dance
The researchers have long maintained that a prion
does not contain nucleic acid, the genetic material of
life (DNA or RNA). Viruses, which have a nucleic acid
core, replicate by hijacking the machinery of a cell
and using it to synthesize more nucleic acid. In
contrast, prions are an aberrant form of a normal
protein (thus composed of amino acids) that form
when a particular segment of normal prion protein in
the brain's nerve cells, or neurons, loses its
corkscrew-shape structure (known as an alpha helix)
and flattens into so-called beta sheets. They suspect
that individual normal prion proteins (PrPC) occasionally
misform in all people and relevant animals, but
are routinely "cleared," or removed, from brain cells.
However, in rare cases, they suspect, the abnormal
protein, or prion (PrPSc), is not cleared.
Once conversion occurs, they hypothesize, the
prion moves on to other normal prion proteins,
pinning and flattening their spirals, and thus, initiating
a process that occurs repeatedly, akin to a deadly
Virginia reel in the brain. The accumulation and
aggregation of the flattened beta sheets leads to
structural damage of the nerve cells, causing cell
degradation that generally leads to death in less than
a year. Prions can arise spontaneously, result from
an inherited mutation in prion protein gene or develop
through infection from an exogenous source.
When the protein-only theory was postulated by
Prusiner, in 1982, it was met with skepticism. In
subsequent years, the UCSF scientists and numerous
other groups have reported substantial evidence
to support the hypothesis, reflected in the fact that
Prusiner was awarded the Lasker Prize, in 1994, and
the Nobel Prize in Physiology or Medicine, in 1997,
for the discovery "of prions -- a new biological principal
of infection," which he named prion (PREE-on),
for proteinaceous infectious protein. Still, despite the
wealth of scientific studies producing evidence to
support the theory, a direct, straightforward test of
the prion theory has eluded researchers until now.
The goal has been to create a bonafide prion in the
lab, which would be proven to be such by its ability to
infect animals and cause a fatal illness. The challenge,
says Prusiner, has been the inability to determine
the details of the prion's 3-dimensional structure
at the atomic level.
"If we knew this," he says, "we could have designed
a physical assay that would tell us we are now
making PrPSc in the test tube."
The new study represents the latest tactic by
Prusiner and his colleagues to get around this block:
working from the belief that beta-sheet-rich structures
harbor prion infectivity, but without knowing which
segments are responsible, the team set out to create
a synthetic agent made up of a subset of beta-sheetrich
structures that assemble into amyloid fibers,
which they hypothesized might have some prion
infectivity.
PThe Research
Following the strategy used to establish that a virus
or bacterium is the cause of a particular infectious
disease, UCSF scientists reported 20 years ago that
prions purified from brains of rodents that were
clumped into amyloid fibrils triggered disease when
injected into the brains of healthy animals, and
produced mad cow-like brain pathology.
Because prions are unprecedented, UCSF scientists
wanted to go one step further and produce
synthetic prions. The scientists chose to produce a
fragment of the normal PrP in E. coli, since bacteria
are known not to carry prions. The fragment was
chosen because it corresponds in length to the
truncated PrP that assembles infectious amyloid
fibrils when purified from infected brains.
The scientists purified the PrP fragment from E. coli
and then altered its conformation so that it might
become an infectious prion. They did this by taking
the segment of the protein that they know has the
capacity to form amyloid, and placing it in a shaking
device to promote amyloid formation. They tracked
the process with thioflavin T, a dye that fluoresces in
the presence of amyloid.
After 40 hours, amyloid was detected. To accelerate
the reaction time, the team then took some of
these amyloid fibrils and used them as a "seed" for
the production of nascent amyloid fibrils in a 2nd
shaking tube. This time amyloid fibrils were detected
after 10 hours. These were called "seeded" amyloid
fibrils.
To determine whether the PrP fragment was
infectious, Prusiner and his colleagues used transgenic
mice making the same PrP fragment. Importantly,
the mice express truncated PrP at 16 times
the level that PrP is normally made in wild-type mice.
The overexpression of the PrP fragment in these
mice shortens the incubation times, which already
approach the lifespan of mice. Prusiner and his
colleagues also thought that if the truncated PrP
expressed in the transgenic mice corresponded
precisely to the PrP fragment produced in bacteria,
this would provide the most sensitive system for
detecting newly formed prions.
Notably, amyloid is a structure that, depending on
the protein it contains, has been implicated in a
number of brain diseases including Alzheimer's and
Parkinson's. After about 300 days, with none of the
transgenic mice sick, the researchers were ready to
declare the study a failure. But then, at 380 days, one
of the mice showed symptoms of a prion-like disease.
Eventually, all of the inoculated mice showed
neurologic disease, the last one 660 days after
injection.
Prusiner and his colleagues then inoculated more
transgenic as well as wild-type mice with brain
extract prepared from one of the sick mice. The
prions in the brain extract caused disease in about
150 days in the wild-type mice and in about 90 days
in transgenic mice expressing full-length PrP.
In each case, on the primary passage, the scientists
detected 4 hallmarks of prion disease -- (1)
clinical signs of neurologic dysfunction (ataxia, or
loss of motor coordination, and rigidity), (2) neuropathologic
changes in the brain (vacuolation, deposits
of PrPSc and astrocytic gliosis), (3) resistance of
PrPSc to breakdown by protease and (4) -- most
importantly -- serial transmission of prion infectivity to
wild-type and other transgenic mice.
While the results strongly indicate that the subset
of beta-sheet-rich structure represented by amyloid
harbors prion infectivity, the scientists report that they
have preliminary evidence that other beta-sheet-rich
structures may also harbor prion rion preparations
that have much higher levels of prion infectivity than
the two reported.
"Our findings give us the opportunity to start exploring
prions on a new level," says Legname.
Coauthors of the study were Ilia V. Baskakov, PhD,
who, at the time the study was started was a postdoctoral
fellow in the UCSF Institute for Neuro degenerative
Diseases (IND), and is now at University of
Maryland in Baltimore; Hoang-Oanh B. Nguyen, a
staff research assistant in the UCSF/IND; Detlev
Riesner, professor of biochemistry at the Institut fur
Physikalische Biologie, Heinrich-Heine Universitat,
Dussedldorf, Germany; Fred E. Cohen, PhD, UCSF
adjunct professor of pharmacology, and Stephen J.
DeArmond, PhD, UCSFprofessor of pathology and
neuropathology.
PFood Makers Trying to Reassure BSEconscious
Consumers
While the government has implemented various
measures since the outbreak of mad cow disease in
Japan 3 years ago, Japanese food makers are going
a step further to ensure the safety of beef and beefproducts.
The food industry uses not only beef but also cowderived
materials such as beef tallow, beef extract
and gelatin, to produce various food products.
After Japan's first case of bovine spongiform
encephalopathy (BSE) was confirmed in 2001, the
government made mandatory the testing of all domestically
grown cattle for the disease and the
incineration of certain cattle parts, such as brains and
spinal marrow that are likely to spread the disease.
It has also banned sales of foods made from the
specified cattle parts, except for those imported from
countries where no BSE cases have been confirmed.
As a result of these and other measures, the initial
extreme consumer caution in the mad cow scare has
waned.
But Japanese consumers, said to be some of the
world's most sensitive about food safety, still remain
vaguely concerned.
In response, Japanese food makers have gone a
step further than observing government regulations
based on a scientific point of view and have begun to
focus on giving consumers [cont pg 5, col 1]

October 2004 - Federal Veterinarian - Page 5
TSE Update cont from pg 4
"sense of security" from a psychological point of
view.
Morinaga & Co, for instance, has switched from
cattle gelatin to other gelatins for the production of
confectioneries.
The major Japanese confectionery company is
doing so despite the fact that the safety of gelatin
made from cattle has been ensured by government
requirements regarding the use of materials from
countries other than those affected by BSE.
"Gelatin is safe in the first place," a Morinaga public
relations officer said. "But we had to take consumers'
rising concern over food safety into account."
S&B Foods Inc., a major manufacturer of condiments
and prepared foods, has stopped using beef
tallow and beef extract in the thickener of its longselling
"Golden Curry."
"We have examined cow-derived materials and
confirmed their safety, but stopped using them in
some products because some customers are still
concerned about BSE," said a company official.
The Japanese Consumers' Cooperative Union
(JCCU) has asked the government to ensure food
safety, while striving to maintain the safety of its Coop
brand products.
With regard to the resumption of beef imports from
the United States, the 20-million-strong cooperative
has been pressing the government to urge Washington
to take sufficient safety measures to eliminate the
chance of exporting BSE-infected beef to Japan.
"In Japan, the word "anzen" (safety) is often confused
with "anshin" (peace of mind)," said Kazuo
Onitake, a JCCU official in charge of promoting food
safety measures.
"Under ordinary circumstances, all we are supposed
to do is to ensure the safety of foods scientifically,"
Onitake said. "But due to the government's
poor handling of the BSE scare in the initial stage, we
are being forced to give consideration to consumers'
peace of mind."
P5th Case of BSE Suspected in Slovenia
A new, 5th case of mad cow disease is being
suspected in Slovenia, the Veterinary Administration
said on Friday [16 July]. As the 6-year-old cow from
a farm in the northeast of Slovenia was born in
Germany, the competent authorities in that country
have been notified as well.
After the preliminary tests confirmed that this could
be a case of BSE, the Veterinary Administration
introduced all the precautionary measures at the farm
that imported the animal in 2001.
The case was discovered through preventive
testing at the national veterinary institute, when a
sample of the spinal cord was tested with Enfer and
Prionics Check Western tests. After both tests came
out positive, the sample will be tested further with
more detailed methods.
The first BSE case was discovered in Slovenia in
December 2001, another followed in January 2002,
the 3rd case was reported in March 2003, while the
last confirmed case was discovered in March 2004.
There were a number of other BSE scares in the
country. However, comprehensive tests later established
other neurological diseases.
[The first case of BSE in native cattle was reported
from Germany in 2000. However, according to EU's
Geographical BSE-Risk (GBR) opinion, exported
German cattle could have been contaminated since
1988. The number of BSE-positive cases detected in
Germany since 2001, according to their respective
years of birth, is as follows: 1992 -- 2; 1993 -- 3; 1994
-- 13; 1995 -- 80; 1996 -- 123; 1997 -- 29; 1998 -- 18;
1999 -- 13; 2000 -- 0. If finally confirmed, the 5th
Slovenian case could be added to Germany's 1998
cohort figures. - Mod.AS] [ProMED-mail promed@
promedmail.org]
PEFSA Publishes Geographical BSE-risk
(GBR Assessments for Australia, Canada,
Mexico, Norway, South Africa, Sweden and
USA
The European Food Safety Authority (EFSA) has
issued today seven up-to-date scientific reports on
the Geographical Bovine Spongiform Encephalopathy
(BSE) Risk (GBR) assessments for Australia,
Canada, Mexico, Norway, South Africa Sweden and
the United States of America. While Australia’’s GBR
level I (ie presence of BSE in domestic cattle is highly
unlikely) is maintained, that of Norway has been
raised to level II (presence of BSE unlikely but not
excluded), Sweden remains at GBR level II and
those of Canada and the United States have been
raised to level III (presence of BSE likely but not
confirmed, or confirmed at a lower level) following a
new assessment taking into account the most recent
evidence. EFSA’s Scientific Expert Working Group
on geographic BSE risk assessment also evaluated
the status of Mexico and South Africa which were
classified as level III.
In 2003 EFSA was requested by the European
Commission (EC) to re-assess the Geographical
Bovine Spongiform Encephalopathy (BSE) risk
(GBR) for 13 countries: Australia, Botswana,Canada,
Costa Rica, El Salvador, Nicaragua, Namibia, Norway,
Mexico, Panama, Swaziland, Sweden and the
United States. Although the European Commission
did not specifically seek advice from EFSA relating to
the appearance of BSE in South Africa, the working
group decided to carry out a risk assessment for this
country under a self-tasking mandate in order to
allow for a meaningful evaluation of the three other
countries in the Southern African Region for which a
GBR assessment was requested (ie Botswana,
Namibia, Swaziland). EFSA’s Scientific Expert
Working Group on the Assessment of the GBR has
completed to date those assessments relating to
Australia, Canada, Mexico, Norway, South Africa,
Sweden and the United States of America. The GBR
assessments for the remaining countries will be
finalized by the end of 2004.
In conducting the GBR assessments, EFSA’s GBR
working group followed the methodology developed
by the former Scientific Steering Committee of DG
Health and Consumer Safety (DG SANCO) of the
European Commission which is described in its final
opinion on GBR assessment . The risk assessments
published today are based on up-to-date data provided
by the countries concerned as well as other
sources of data (ie Eurostat and country export data)
covering the period of 1980 to 2003.
Making the simple complicated is commonplace;
making the complicated simple, awesomely simple,
that’s creativity. Charles Mingus (1922-79)
[Cited in Bits & Pieces] Musician and composer
PUSDA Proposes to Amend Regulations for
Interstate Movement of Sheep and Goats
Washington, 26 Aug 2004 The US Department of
Agriculture’s Animal and Plant Health Inspection
Service proposes to require livestock facilities that
handle sheep and goats in interstate commerce to
follow certain procedures to minimize the potential
spread of scrapie. The approval process will ensure
that certain uniform practices relating to the identification,
recordkeeping and handling of sheep and goats
are followed.
Scrapie is a degenerative and eventually fatal
disease affecting the central nervous systems of
sheep and goats. This proposal includes stockyards,
livestock markets, buying stations, concentration
points or any other premises where sheep or goats
are assembled. APHIS approval of livestock facilities
is intended to ensure that they are constructed and
operated in a manner that will help prevent the
interstate transmission of livestock diseases. APHIS
approval would be contingent on the facility operator
meeting certain minimum standards and other conditions
relating to the receipt, handling and release of
sheep and goats at the facility. The national scrapie
eradication program includes a mandatory identification
component for sheep and goats.

snip...

Scrapie Program Continues Progress
Regulatory Scrapie Slaughter, which began 1 April
2003, is a targeted slaughter surveillance program
designed to identify infected flocks for clean-up. The
foundation for the targeted regulatory slaughter
surveillance program (RSSS) evolved from the
findings of the Scrapie: Ovine Slaughter Surveillance
(SOSS) Program. Since its inauguration, samples
have been collected from 23,643 sheep, of which
results have been reported for 21,497 of them.
Samples have been submitted from 29 plants.
The latest numbers are as follows:
• 61 confirmed positive sheep identified by the
National Veterinary services Laboratory (NVSL).
• 42 confirmed positive cases from NVSL in FY 2004.
Face colors include 37 black, 3 mottled and 2 white.
• During July 2004, 2,147 sheep were tested; 12 new
confirmed positives reported by NVSL.
As a result of RSSS tracebacks of positive animals
and on-farm surveillance by producers and veterinarians,
new infected and source flocks have been
identified. As of 31 July 2004, there were 71 flocks
with a scrapie infected or source status with a total of
90 newly infected and source flocks reported for FY
2004. The total of infected and source flocks that
have been released in FY 2004 is 60 with the ratio of
infected and source flocks released to newly infected
and source flocks for FY 2004 being 0.68 to one. As
of 31 July, 282 scrapie cases have been confirmed
and reported by the NVSL in FY 2004, of which 42
were RSSS cases. Thirteen cases of scrapie in goats
have been reported since 1990. One new goat case
was reported in FY 2004.
Scrapie Testing
To date, 17,742 animals have been sampled and/or
tested for scrapie; 15,656 RSSS; 1,711 regulatory
field cases; 279 regulatory third eyelid biopsies; 13
third eyelid validations and 72 necropsy validations
for FY 2004.
Animal ID
A total of 86,825 sheep and goat premises have
been assigned identification numbers in the Scrapie
National Generic Database. Official eartags have
been issued to 61,098 of these premises.
The Scrapie Flock Certification Program
The July report shows 1,859 flocks participating in
the Scrapie Flock Certification Program (SVCP). Of
these flocks, 133 were certified flocks, while 1,728
were complete-monitored flocks. There were seven
flocks newly enrolled or certified in June.
The scrapie eradication program focuses on
four main action areas:
1. A targeted slaughter surveillance program for cull
sheep with demonstrated higher risk for the disease;
2. The encouragement and support of programs
aimed at increasing the genetic resistance of at-risk
flocks to scrapie infection;
3. The education of sheep producers to be alert to
the signs of scrapie in their sheep and goats and
report any suspects to an accredited or regulatory
veterinarian and to properly use scrapie program ID
devices on animals within their flocks; and
4. The continued encouragement of seed stock
producers to enroll in and utilize the Scrapie Flock
Certification Program to provide breeding stock with
a very low risk of scrapie infection.
[Sheep & Goat Health Rpt, Spg/Sum 04]

snip...

CWD Developments
The Plan for Assiting States, Federal Agencies,
and Tribes in Managing Chronic Wasting Disease in
Wild and Captive Cervids (GWD National Management
Plan) was completed in June 2002. The first
progress report on the plan was released in May
2004. The progress report Iists accomplishments and
the next steps necessary to achieve the objectives
set forth in the CWD National Management Plan.
According to the report, nearly 118,000 wild whitetailed
deer, mule deer and elk were tested in the
United States from October 2002 to September 2003,
with 592 animals testing positive for the CWD prion
More than $38,000,000 was spent by federal and
state wildlife and animal health agencies on CWDrelated
activities during this same period. Surveillance
data from individual states are contained in the
report, which also includes a list of ongoing and
completed CWD research projects conducted since
1978. The complete report and the CWD National
Management Plan can be accessed at the CWD
Alliance website (www.cwd.info.org).
Several research papers contributing to the body of
information available on CWD have been published
in recent months. Two CWD articles appeared in the
June 2004 issue of the journal Emerging Infectious
Diseases. In Chronic Wasting Disease and Potential
Transmission to Humans, the authors reported on
epidemiological studies of cases of fatal human
neurological disease to identify any links to exposure
to CWD. Cases that were investigated included prion
disease in unusually young patients, Creutzfeldt-
Jakob disease (CJD) in two persons with a history of
exposure to venison obtained from the known CWD
endemic areas, the highly publicized fatal neurological
diseases in three persons who attended a wild
game feast and others. Additionally, the incidence
and age distribution of CJD patients in Colorado and
Wyoming, where CWD has been endemic for decades,
was compared to other parts of the United
States. The study showed, “...no human cases of
prion disease with strong evidence of a link with
CWD were identified,” and the authors concluded, “...
lack of evidence of a link between CWD transmission
and unusual cases of CJD. despite several
epidemiologic investigations, and the absence of an
increase in CJD incidence in Colorado and Wyoming
suggest that the risk, if any, of transmission of CWD
to humans is low.” However, they recommended that
additional epidemiologic studies be conducted and
that hunters minimize their risk for exposure to the
CWD agent by following the recommendations of
public health authorities and wildlife agencies.
In the second article in Emerging Infectious Diseases,
Environmental Sources of Prion Transmission
in Mule Deer, investigators reported on a study to
determine if CWD can be transmitted to susceptible
animals indirectly from environments contaminated
by excreta or decomposed carcasses. Their findings
are as follows: “Under experimental conditions, mule
deer became infected in two of [cont pg 9, col 1]

October 2004 - Federal Veterinarian - Page 9
CWD Developments cont from pg 8
three paddocks containing naturally infected deer, in
two of three paddocks where infected deer carcasses
had decomposed in situ approximately 1.8 years
earlier, and in one of three paddocks where infected
deer had last resided 2.2 years earlier,” The authors
concluded, “Although live deer and elk represent the
most plausible mechanisms for geographic spread of
CWD, our data show that environmental sources
could contribute to maintaining or prolonging local
epidemics, even when all infected animals are
eliminated.” Both articles in Emerging Infectious
Diseases can be found at www.cdc.gov/ncidod/EID.
Two additional publications have provided information
on the epidemiology of CWD in captive deer. In
the September 4, 2003, issue of the journal Nature,
in an article entitled Prion Disease: Horizontal Prion
Transmission in Mule Deer, it was reported, “...horizontal
transmission is remarkably efficient, producing
a high incidence of disease (87%) in a cohort of mule
deer in which maternal transmission was improbable,
indicating that horizontal transmission is likely to be
more important [than maternal transmission] in
sustaining CWD epidemics.” Furthermore, the authors
stated, “...direct and indirect transmission of
CWD can probably occur, and concentrating deer in
captivity or by feeding them artificially may facilitate
transmission.”
In a paper published in the April 2004 issue of the
Journal of Wildlife Diseases, entitled Epidemiology of
Chronic Wasting Disease in Captive White-tailed and
Mule Deer, the authors found similar patterns in both
species. They concluded, “...sustained horizontal
transmission of CWD most plausibly explained
epidemic dynamics.... It follows that CWD epidemic
dynamics in sympatric. free-ranging white-tailed deer
and mule deer in western North American ranges
also may be similar.”
Although some gaps remain, the contributions of
seasoned CWD researchers are adding to the body
of knowledge on CWD. For example, Dr Mike Miller
with the Colorado Division of Wildlife authored or
coauthored all four publications listed above and Dr
Beth Williams with the Wyoming State Veterinary
Laboratory coauthored three of the four publication.
Research is an integral component or the CWD
National Management Plan, and projects are underway
to elucidate additional epidemiological aspects
that are essential to our understanding of the disease
and to the development of practical control measures.
[SCWDS Briefs, 7/04]

http://users.erols.com/nafv/fedvet.htm

VETERINARIAN'S OATH

Being admitted to the profession of veterinary medicine, I
solemnly swear to use my scientific knowledge and skills for the
benefit of society through the protection of animal health, the
relief of animal suffering, the conservation of animal
resources, the promotion of public health, and the advancement
of medical knowledge.

I will practice my profession conscientiously, with dignity, and
in keeping with the principles of veterinary medical ethics.

I accept as a lifelong obligation the continual improvement of
my professional knowledge and competence.

http://users.erols.com/nafv/vetoath.htm

Greetings List members,

I have mixed emotions with Prusiner and his spontaneous sporadic CJD in
85%+ of all cases (or any spontaneous TSE)?
IS he serious about believing this, or is he pushing this theory to sell
his test once validated and marketed$
WHAT better way to make manditory BSE/TSE of all bovine for human/animal
consumption.
AND i cannot believe i just said that, but i would almost say i believe
it just to get them to do it
(test all cattle)...

Published online before print August 5, 2004, 10.1073/pnas.0404650101
PNAS | August 17, 2004 | vol. 101 | no. 33 | 12207-12211

Autocatalytic self-propagation of misfolded prion protein

Jan Bieschke *, {dagger} , Petra Weber *, Nikolaus Sarafoff *, Michael
Beekes {ddagger} , Armin Giese * and Hans Kretzschmar *

*Center for Neuropathology and Prion Research, Ludwig Maximilians
University of Munich, Feodor-Lynen-Strasse 23, 81377 Munich, Germany;
and {ddagger} Robert Koch Institute, Nordufer 20, 13353 Berlin, Germany

Communicated by Manfred Eigen, Max Planck Institute for Biophysical
Chemistry, Göttingen, Germany, June 30, 2004 (received for review March
1, 2004)

Prions are thought to replicate in an autocatalytic process that
converts cellular prion protein (PrPC) to the disease-associated
misfolded PrP isoform (PrPSc). Our study scrutinizes this hypothesis by
in vitro protein misfolding cyclic amplification (PMCA). In serial
transmission PMCA experiments, PrPSc was inoculated into healthy hamster
brain homogenate containing PrPC. Misfolded PrP was amplified by rounds
of sonication and incubation and reinoculated into fresh brain
homogenate every 10 PMCA rounds. The amplification depended on PrPC
substrate and could be inhibited by recombinant hamster PrP. In serial
dilution experiments, newly formed misfolded and proteinase K-resistant
PrP (PrPres) catalyzed the structural conversion of PrPC as efficiently
as PrPSc from brain of scrapie (263K)-infected hamsters, yielding an
{approx} 300-fold total amplification of PrPres after 100 rounds, which
confirms an autocatalytic PrP-misfolding cascade as postulated by the
prion hypothesis. PrPres formation was not paralleled by replication of
biological infectivity, which appears to require factors additional to
PrP-misfolding autocatalysis.

------------------------------------------------------------------------
Abbreviations: PMCA, protein misfolding cyclic amplification; PrP, prion
protein; PrpC, cellular PrP; PrPSc, scrapie-associated PrP isoform;
PrPres, proteinase K-resistant PrP; LD50i.c., 50% intracerebral lethal
dose; rPrP, recombinant PrP; SHa, Syrian hamster.

{dagger} To whom correspondence should be sent at the present address:
The Scripps Research Institute, BCC 265, 10550 North Torrey Pines Road,
La Jolla, CA 92037. E-mail: jbiesch@scripps.edu
.

© 2004 by The National Academy of Sciences
of the USA

http://www.pnas.org/cgi/content/abstract/101/33/12207?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=prion&searchid=1092795682466_476&stored_search=&FIRSTINDEX=0&volume=101&issue=33


Protein-only prion proposal

Stanley Prusiner first put forward the
protein-only hypothesis of prion
propagation in 1982. Now, 22 years
later, his research group has moved a
step closer to proving once and for all
that the infectious properties of prions
are due to the propagation of protein
misfolding. The present article from
Prusiners group comes close to being
this final proof, Claudio Soto
(University of Texas Medical Center,
TX, USA) told The Lancet Neurology.
However, a number of technical
issues minimise my enthusiasm.
Most experts agree that the
hypothesis would be proven if a
synthetic infectious protein engineered
in vitro was shown to be capable of
causing disease in vivo. Prusiners
team, which is based at the University
of California, San Francisco,
engineered Escherichia coli to express a
truncated version of mouse prion
protein; E Coli does not normally
produce prion proteins.
The researchers then folded the
protein into a beta-sheet rich conformation
that was likely to be infectious
and injected the protein into
transgenic mice that make the same
mutated prion fragment (called
TG9949 mice). 380 days later, one of
the mice showed symptoms of a prionlike
disease. By 660 days, all the mice
had neurological symptoms. Importantly,
TG9949 mice that were injected
with saline as controls failed to show
any signs of disease 620 days after
injection (Science 2004; 305: 67376).
Sotos main criticism is that
Prusiners team injected the synthetic
prion into a transgenic model that
expresses high levels of the truncated
version of the prion protein. It is
well-known in the field that most of
this type of animal develop clinical
signs and scrapie-like pathology
spontaneously, says Soto. The
injection of the recombinant protein
may have merely accelerated a process
that was set to occur spontaneously
anyway. For me it would have been
very convincing if the disease was
transmitted to wild-type animals in a
first passage. In addition, Soto notes
that the disease characteristics were
different to those normally obtained in
these animals.
Unsurprisingly, Prusiner is more
upbeat: The finding represents a
renaissance in prion biology. For the
first time, we can create prions in the
test tube, which will change the way
scientists do experiments in the field.
We now have a tool for exploring the
mechanism by which a protein can
spontaneously fold into a shape that
causes disease.

James Butcher
Protein-only prion proposal
Neurology Vol 3 September 2004
http://neurology.thelancet.com


> that can by itself produce a deadly infectious disease
> in mice and may help explain the roots of mad cow
> disease.


> Spontaneous Prion Diseases
> The discovery that a small change in the condition
> of a cell can cause the development of a prion offers
> an explanation, says Prusiner, for the sporadic form
> of Creutzfeldt Jakob disease (CJD), which is responsible
> for 85 percent of cases of prion disease in
> humans (occurring in 1 or 2 people per million) and is
> believed to develop spontaneously.


THEN how do we explain;

BSE prions propagate as either variant CJD-like or sporadic CJD-like
prion strains in transgenic mice expressing human prion protein

Emmanuel A. Asante, Jacqueline M. Linehan, Melanie Desbruslais, Susan
Joiner, Ian Gowland, Andrew L. Wood, Julie Welch, Andrew F. Hill, Sarah
E. Lloyd, Jonathan D.F. Wadsworth and John Collinge1

MRC Prion Unit and Department of Neurodegenerative Disease, Institute of
Neurology, University College, Queen Square, London WC1N 3BG, UK 1
Corresponding author e-mail: j.collinge@prion.ucl.ac.uk


Received August 1, 2002; revised September 24, 2002; accepted October
17, 2002

Abstract


Variant CreutzfeldtJakob disease (vCJD) has been recognized to date
only in individuals homozygous for methionine at PRNP codon 129. Here we
show that transgenic mice expressing human PrP methionine 129,
inoculated with either bovine spongiform encephalopathy (BSE) or variant
CJD prions, may develop the neuropathological and molecular phenotype of
vCJD, consistent with these diseases being caused by the same prion
strain. Surprisingly, however, BSE transmission to these transgenic
mice, in addition to producing a vCJD-like phenotype, can also result in
a distinct molecular phenotype that is indistinguishable from that of
sporadic CJD with PrPSc type 2. These data suggest that more than one
BSE-derived prion strain might infect humans; it is therefore possible
that some patients with a phenotype consistent with sporadic CJD may
have a disease arising from BSE exposure...

http://embojournal.npgjournals.com/cgi/content/full/21/23/6358

THE new findings of BASE in cattle in Italy of Identification of a
second bovine amyloidotic spongiform encephalopathy: Molecular
similarities with sporadic Creutzfeldt-Jakob disease


http://www.pnas.org/cgi/content/abstract/0305777101v1


Adaptation of the bovine spongiform encephalopathy agent to primates
and comparison with Creutzfeldt- Jakob disease: Implications for
human health

THE findings from Corinne Ida Lasmézas*, [dagger] , Jean-Guy Fournier*,
Virginie Nouvel*,

Hermann Boe*, Domíníque Marcé*, François Lamoury*, Nicolas Kopp [Dagger

] , Jean-Jacques Hauw§, James Ironside¶, Moira Bruce [||] , Dominique

Dormont*, and Jean-Philippe Deslys* et al, that The agent responsible
for French iatrogenic growth hormone-linked CJD taken as a control is
very different from vCJD but is similar to that found in one case of
sporadic CJD and one sheep scrapie isolate;

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

Characterization of two distinct prion strains
derived from bovine spongiform encephalopathy
transmissions to inbred mice

Sarah E. Lloyd, Jacqueline M. Linehan, Melanie Desbruslais,
Susan Joiner, Jennifer Buckell, Sebastian Brandner,
Jonathan D. F. Wadsworth and John Collinge

Correspondence
John Collinge
j.collinge@prion.ucl.ac.uk

MRC Prion Unit and Department of Neurodegenerative Disease, Institute of
Neurology,
University College, London WC1N 3BG, UK
Received 9 December 2003
Accepted 27 April 2004

Distinct prion strains can be distinguished by differences in incubation
period, neuropathology
and biochemical properties of disease-associated prion protein (PrPSc)
in inoculated mice.
Reliable comparisons of mouse prion strain properties can only be
achieved after passage in
genetically identical mice, as host prion protein sequence and genetic
background are known
to modulate prion disease phenotypes. While multiple prion strains have
been identified in
sheep scrapie and CreutzfeldtJakob disease, bovine spongiform
encephalopathy (BSE) is
thought to be caused by a single prion strain. Primary passage of BSE
prions to different lines
of inbred mice resulted in the propagation of two distinct PrPSc types,
suggesting that two
prion strains may have been isolated. To investigate this further, these
isolates were
subpassaged in a single line of inbred mice (SJL) and it was confirmed
that two distinct prion
strains had been identified. MRC1 was characterized by a short
incubation time (110±3 days),
a mono-glycosylated-dominant PrPSc type and a generalized diffuse
pattern of PrP-immunoreactive
deposits, while MRC2 displayed a much longer incubation time (155±1 days),
a di-glycosylated-dominant PrPSc type and a distinct pattern of
PrP-immunoreactive deposits
and neuronal loss. These data indicate a crucial involvement of the host
genome in modulating
prion strain selection and propagation in mice. It is possible that
multiple disease phenotypes
may also be possible in BSE prion infection in humans and other animals.

http://vir.sgmjournals.org/cgi/content/abstract/85/8/2471

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


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

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

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

PMID: 6997404

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


comments anyone ?

TSS

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