)
=> b-fold)
of the normal prion glycoprotein (PrPc) into a
disease-causing
conformer (PrPres / PrPSc) which
aggregates into
protease-resistant b-sheets. Host
RNA molecules
are cofactors for prion replicationref.
Induction of b-sheet structures in
recombinant
prion proteins is associated with increased solvent
accessibility of tyrosine
: antibodies directed against the prion protein repeat motif,
tyrosine-tyrosine-arginine,
recognize PrPSc but not the PrPc isoform
(antibody
binding to the pathological can be created in vitro by partial
denaturation
of PrPc). PrP contains 2 conserved N-glycosylation
sites, which are partially occupied by a highly
heterogeneous array
of complex-type oligosaccharides carrying sialylated and
fucosylated antennae.
It has been proposed that the occupancy of the N-glycosylation
sites
can be correlated with differente strains of prions, but this
hypothesis
remains controversial. For example, prions isolated from the
brains of
patients with "classical" forms of CJD were found to have a very
different
sugar pattern from those isolated from patients with a variant
form of
CJD that struck some patients much earlier in life. But the
sugar pattern
of variant CJD prions was identical to those that cause BSE - a
finding
key to establishing that variant CJD was in fact the human form
mad cow
disease. Deletions of one or both glycosylation sites in
transgenic mice
result in unusual patterns of PrPSc deposition,
suggesting that
might play a role in the diseases process, but the functions of
the sugars
remain enigmatic. MALDI-MS molecular weight profiling of N-oligosaccharides
released
from hamster PrP and PrPSc revealed decreased amounts
of oligosaccharides with bisecting GlcNAc residues, and
increased amounts
of tri- and tetraantennary sugars, in the PrPSc
oligosaccharides
compared with those from normal PrP. ES methodology, including
ultrahigh-sensitivity
MS/MS experiments on a Q-TOF instrument was used to provide
detailed information
on the occupancy of the second glycosylation site (Asn196)
of
murine PrP, thus complementing a previous MS investigation of
glycosylation
at Asn181 in the hamster. The 2 sites are substituted
with more
than 60 bi-, tri-, and tetraantennary core-fucosylated
structures, many
of which are bisected. The oligosaccharides carry a limited
number of antennae
types. The diversity and difference in site occupancy arise
largely from
the arrangements of the antennae types in individual
oligosaccharides.
The NTD binds Cu+ preventing oxidative stress. It's
the conversion
process, not the accumulation of protein, that is key to the
disease :
depleting neuronal PrP in prion infection prevents disease and
reverses
spongiosis. The switch may produce a toxic by-product, an
intermediate
form, or may deplete a factor that is crucial to brain-cell
survivalref.
Prnp-/-
animals
don't have the disease and the gene loss itself don't create any
syndrome
: so it may be presumed that PrPc has no importance
in cell
metabolism or its functions are substituted by
PRND
/ prion protein 2 / dublet, which codes for doppel
(as the
latter has no NTD, Prnp-/- animals suffer
more from oxidative
stress).
: transmissible
mink
encephalopathy (TME)
: feline
spongiform
encephalopathy (FSE)
: scrapie
: bovine
spongiform
encephalopathy (BSE) / mad-cow disease,
Gallus
gallus,
turtles (Testudines)
and frogs (Xenopus
laevis),
which
also harbour prions, suffer diseases as a result. This is
partly
because they don't know what symptoms to look for.,
dysarthria,
head, trunk and limbs tremors disappearing during sleeping =>
flaccid paralysis,
dysphagia
and cerebellar
ataxia,
progressive insomnia,
hallucinations, stupor, and coma; autonomic and motor
disturbances are
also present.
in the brain. 6 types exist :
and dementia,
dementia,
rigidity,
tremor, and hyperreflexia,
there are progressive short-term memory loss and clumsiness.,
dysarthria,
ataxia,
athetoid movements, and generalized rigidity,
but less damage in the cingulate gyrus and basal ganglia
compared with
patients with CJD who have cerebral
ataxia as the leading clinical sign. The CSF assay
for the 14-3-3 protein
may be normal. Disease course : 5.7 months
of long duration : different genotypes at codon
129 and "type 2" protease-resistant
prion protein.
patients actually had CJDref.
Although autopsies once were performed on approximately 50%
of all corpses,
the frequency has dropped to < 15% in the United States.
The National
Center for Health Statistics (NCHS) -- a branch of the CDC
-- stopped collecting
autopsy data in 1995. While autopsies have been declining,
the number of
deaths attributed to Alzheimer's has increased more than
50-fold since
1979, going from 857 deaths then to nearly 50 000 in 2000,
partly due to
the aging
of the population. Switzerland discovered in 2002 that its
CJD rate was
twice that of any other country in the world. Switzerland
had been seeing
8 to 11 cases per year from 1997 to 2000. Then the incidence
more than
doubled, to 19 cases in 2001 and 18 cases in 2002. In the
18-year period
between 1979 and 1996 USA saw a jump from 1 case of sporadic
CJD in people
under the age of 30 (a warning sign for vCJD) to 5 cases in
5 years between
1997 and 2001. There have been increases in sporadic CJD in
France, Germany,
and Italy, all of which have detected mad cow disease in
their cattle.
PrPSc is deposited in the neuroepithelium of the
olfactory mucosa
in patients with sporadic CJD, and olfactory biopsy may
provide diagnostic
information in living patients. The olfactory pathway may
represent a route
of infection and a means of spreading prions.
(n = 46), brain
hemorrhage
(n = 14), Jannetta procedure for facial
palsy
(n = 13) and for trigeminal
neuralgia
(n = 6), intracranial
aneurysm
(n = 8), unspecified anomalies (n = 5), intracranial
hematoma (n = 3), injury (n = 1), and
ossification of the spinal posterior
longitudinal ligament (n = 1). Latency periods
ranged from 14 months (receipt
in 1987 and onset in 1989) to 275 months (receipt
in 1978 and onset in
2001). The median and mean latency periods were
122 and 125 months, respectively.
During 1983 to 1987, the estimated minimum risk
for CJD within 17 years
of receipt of the implicated product in Japan was
approximately 1 case
per 1250 grafts (0.04%). No cases have been
reported among patients who
received their first dural graft after 1991;
however, because of the long
latency period between graft placement and symptom
onset, additional cases
of graft-associated CJD are likely to be reported.
That all Lyodura®-associated
CJD cases to date occurred among patients who
received grafts before 1992
suggests that all implicated grafts likely were
processed before 1987;
the implicated product's expiration date is 5
years after processing. In
1997, the report of 43 cases of dura mater
graft-associated CJD in Japan
represented the largest cluster of such cases in
any one country. In one
of the CJD cases reported in Japan, the implicated
graft was used in a
spinal (not an intracranial) procedure : this case
suggests that transmission
from contaminated dura might occur in areas of the
neuraxis outside of
the cranial vault. Subsequently, numerous other
dura mater graft-associated
cases were identified worldwide; nearly all
patients had received the implicated
product, including one additional U.S. patient
(see below)
(33%)
(25%)ref,
may also harbor prions and contaminate surgical
instruments
transplantation or the associated albumin transfusionsref)
affected with BSE
: in 1996 the human PrPSc was found to
resemble the PrPSc
found in BSE. The Committee for Proprietary Medical
Products (CPMP) of
the European Agency for the Evaluation of Medicinal
Products (EMEA) established,
in 2001, 4 BSE risk categories on the basis of
examinations of cows and
other animals that became infected with similar diseases
(for example,
sheep which contracted scrapie). These categories have
been summarized
in the "Note for guidance on minimizing the risk of
transmitting animal
spongiform encephalopathy agents via medicinal
products," as follows :
(lower part of the small intestine)
(e.g. from the peripheral nerve tissue and the
suprarenal gland of the
BSE positive 94 month old cow that had died on 9 Mar
2004ref.)
(proximal)
("hard" meninges)
could carry infectious prions from the brain to
: anyway mice injected with nerve cells from
infected cow tongue remain
healthy.
Indeed, since prions are believed to be associated
with neural tissue,
then it stands to reason prions can travel along
any nerve path. One needs
to understand the fundamentals of US Slaughter
facilities to comprehend
the situation. Cattle are humanely stunned with a
captive bolt stunner
that penetrates or piths the brain rendering the
animal unable to feel
pain. However, the animal is not dead. Depending
upon the speed of the
slaughter plant the animal remains alive, but
unable to comprehend or feel
pain, for an average of 2 to 7 minutes before the
throat is cut, exsanguinating
the animal. During that 2 to 7 minutes the
neurological tissue that captive
bolt compressed into the brain and into the blood
stream can circulate
throughout the body, as long as the heart beats.
The prion is smaller than
a red blood cell. Therefore, it would appear that
the prion agent can be
in muscle tissue.
(distal).)
fed 5 mg of BSE-infected material had lambs that died of
BSE after showing
signs of infection in their tonsils 546 days after birth.
Their mothers
had shown no outward signs of the disease at lambing, one
showing them
73 days after lambing, and the other 198 days after. But
it is still not
certain that the lambs were infected while in the uterus,
or shortly before
or after lambing. The disease may have spread through the
birthing fluids
or in some other way. The evidence so far suggests this is
far more likely
than the lambs catching the disease from other apparently
unaffected sheep.
It is already known that BSE-like diseases can be
transmitted via blood
in humans as well as animals, but there has been no
evidence that it has
been handed from dam to calf in cattle, or mother to baby
in people. The
sheep involved were of a genetic type that in lab tests
previously appeared
most susceptible to BSE. But it is unclear how many such
sheep are in flocks
on farms. There are 15 different genotypes, and unlike in
BSE in cattle,
genetic type seems important. Unfortunately at present
there would be no
way of identifying resistant sheep in time for them to go
into food, while
banning others. The fear about sheep has existed for years
because, until
the late 1980s, they were fed the same sort of feed as
cattle. However
if it was ever in sheep, there is no suggestion that it
ever existed on
a large scale. There is some good news. The lambs that
seem to have inherited
BSE showed a brain signature similar to BSE in cattle.
Officials have been
worried that some BSE in sheep, if it existed, might have
been masked by
a similar disease called scrapie, not known to be
dangerous to humansref
: efforts to find the infectious prion in the muscle of
infected animals
by seeing whether antibodies to the prion could find any
and bind to them
have previously failed. But Telling's lab has now shown,
using transgenic
mice, that disease prions can reside in the muscle of
deer infected with
CWD. The team replaced the gene for the normal mouse
version of the prion
protein with the normal gene from deer, so the mice made
the normal, healthy
deer protein. They then injected the mouse brains with
tissue from infected
deer. 12 to 18 months later, the mice developed
encephalopathy. Tissues
from both the infected deer's brains and thigh muscles
caused disease.
Muscle took slightly longer to cause disease than brain
tissue, showing
it had slightly less prion. We don't know that it is
transmitted in the
wild by animals eating muscle from infected animals. We
now have to see
where else the prion might be, including saliva and even
excrement, using
more transgenic mice. Because we tested deer that were
already ill, we
don't know what the distribution of prion is in animals
that are still
incubating the disease. Hunters have been warned by
wildlife agencies not
to kill and eat obviously ill animals, but an animal not
yet showing signs
of the disease might still carry the abnormal prion,
albeit less of it.
It is also unknown whether people can catch
encephalopathy by eating
CWD-infected meat, as they can from eating BSE-tainted
meatref
began in 1989. Parenteral inoculation of the agent by
three routes simultaneously
(intracranially, intravenously and intraperitoneally)
produced disease
with an incubation period range of 69-150 weeks.
Pre-clinical pathological
changes were detected in 2 pigs killed electively at 105
and 106 weeks
post-inoculation. Infectivity was detected by bioassay
in inbred mice in
the CNS of those pigs that developed spongiform
encephalopathy. Infectivity
was also found in the stomach, jejunum, distal ileum and
pancreas of terminally
affected pigs. These findings show that pigs are
susceptible to BSE. In
contrast, disease failed to occur in pigs retained for 7
years after exposure
by feeding BSE-affected brain on three separate days, at
1-2 week intervals.
The amounts fed each day were equivalent to the maximum
daily intake of
meat and bone meal in rations for pigs aged 8 weeks. No
infectivity was
found in tissues assayed from the pigs exposed orally.
This included tissues
of the alimentary tract. It is suggested that these pigs
did not become
infected. The relatively high oral exposure used in
these experiments compared
with feed-borne exposure in the field may explain the
absence of an epidemic
of spongiform encephalopathy in domestic pigs concurrent
with the BSE epidemic
in the UKref.
Pigs and poultry in the United Kingdom have undeniably
been exposed to
the BSE agent. They consumed the same ruminant protein
that gave rise to
the BSE epidemic in cattle, but there has been no
evidence of an epidemic
in these species. Experimental investigations have shown
pigs to be susceptible
to infection by multiple parenteral challenge, but
resistant to oral exposure
with BSE-infected cattle brain. Current but incomplete
evidence suggests
that they are also resistant to oral challenge with
sheep scrapie. Studies
in domestic chickens indicate that they are resistant to
both parenteral
and oral challenge. Unfortunately, no published data
exists on the susceptibility
of fish to infection. Incidental findings in the brains
of unexposed pigs
are described that could otherwise give rise to concerns
aboutthe presence
of a transmissible spongiform encephalopathy in pig
populations around
the worldref.
In an experimental study of the transmissibility of BSE
to the pig, seven
of 10 pigs, infected at 1-2 weeks of age by
multiple-route parenteral inoculation
with a homogenate of bovine brain from natural BSE cases
developed lesions
typical of spongiform encephalopathy. The lesions
consisted principally
of severe neuropil vacuolation affecting most areas of
the brain, but mainly
the forebrain. In addition, some vacuolar change was
identified in the
rostral colliculi and hypothalamic areas of normal
control pigs. PrP accumulations
were detected immunocytochemically in the brains of
BSE-infected animals.
PrP accumulation was sparse in many areas and its
density was not obviously
related to the degree of vacuolation. The patterns of
PrP immunolabelling
in control pigs differed strikingly from those in the
infected animalsref.
A new study details transplanting swine organs to people
and the possibility
of TSE disease being transmitted. Research
Project:
Transmission, Differentiation, and Pathobiology of
Transmissible
Spongiform Encephalopathies, National
Animal
Disease Center Virus and Prion Diseases of Livestock,
Evaluation
of a diet free of animal protein in germfree swine. 2
experiments were
conducted in which germfree pigs or pigs monoassociated
with Lactobacillus
paracasei subspecies paracasei were fed
either a traditional
milk-based diet (Esbilac) or an experimental diet free
of animal protein
(DFAP). Throughout the 16-day study, animals' clinical
condition, total
weight gain, feed conversion, and bacterial
contamination were monitored.
At the conclusion of the study the animals were killed,
necropsied and
tissues sampled for L. paracasei isolation.
General pig disposition
remained consistent between treatment groups and trials,
except for two
animals that developed mild diarrhoea during trial 1.
All pigs remained
viable during the study irrespective the diet fed or
probiotic inoculation.
Germfree pigs fed the Esbilac diet gained on average a
total of 1034 +/-
63.0 g, and had a feed conversion ratio of 0.17 +/- 0.01
g of gain per
1 ml of diet. Germfree pigs fed the experimental diet
gained on average
a total of 599 +/- 151 g, and had a feed conversion
ratio of 0.10 +/- 0.02
g of gain per 1 ml of diet. Monoassociated pigs fed the
Esbilac diet gained
on average a total of 862 +/- 70.3 g, and had a feed
conversion ratio 0.14
+/- 0.01 g of gain per 1 ml of diet. Monoassociated pigs
fed the experimental
diet gained on average a total of 563 +/- 96.8 g, and
had a feed conversion
ratio of 0.09 +/- 0.02 g of gain per 1 ml of diet.
Lactobacillus paracasei
established extensively in pigs fed either the Esbilac
or experimental
diets.
Lactobacillus paracasei had no effect (P
>0.05) on
piglet growth and did not display any interactions based
on the diet fed.
Measured growth parameters were statistically different
(P <0.05) based
on the diet fed and variance seen between trials. In
conclusion, a DFAP
has been developed and has been shown to be capable of
sustaining life
in piglets up to 16 days of ageref.,
which is abundant in meat. The 2 proteins seem to stick
together. By attaching
fluorescent tags to the 2 proteins, they showed that they
are transported
through a growing sheet of human Caco-2 intestinal
epithelial cells
hand-in-handref.
Prions can also pass through the gut unaided, through M
cellsref.
The ferritin protein is almost identical in a wide range of
species, which
might allow it to latch on to and ferry foreign prions from
cows : ferritin
might transport prions to humans from other animals with
prion disease,
such as deer and elk suffering from chronic wasting disease.
Hobbling the
transport of ferritin might block prions from entering the
body, but this
would be difficult to use therapeutically because people
would have to
be treated at the time when they were being exposed, which
is many years
before symptoms of the disease emerge.
from infected donor|
|
|
|
|
| foodborne | Canada | 1987–1990 | 11–14 |
| Ireland | 1989–1995 | 5–10 | |
| Japan (patient was reported to have stayed in the United Kingdom 24 days) | 1989 | 12 | |
| United Kingdom (Leicestershire, England) | 1980–1985 | 10–16 | |
| United States | 1980–1992 | 9–21 | |
| bloodborne | United Kingdom | 1996 | 6.5 |
| United Kingdom (atient with presumed bloodborne transmission died of a nonneurologic disease. The presence of the vCJD agent was detected in the spleen and cervical lymph node; the patient was heterozygous for methionine and valine at the polymorphic codon 129 of the prion protein genep) | 1999 | >5 |
are the main immune reservoir for prions and the distance
between the FDCs
and the enervated areas of the spleen determines the
velocity and efficiency
of neuroinvasion : anything that reduces the distance
between FDCs and
sympathetic nerves—inflammatory conditions or infections,
for instance—could
enhance prion disease susceptibility (genetically
engineered CXCR5-/-
mice in which prion-rich cells are abnormally close to
nerve endings in
the spleen develop disease symptoms around 30 days earlier
than normal
mice). There is a long lag period during which the
infectious agent replicates
in the FDCs before moving on to brain : switching off the
FDCs is a pretty
mild treatment as it does not lead to severe
immunosuppressionref.
or intercurring infections
shows periodic sharp wave complexes (PSWC) (specificity =
74% in sporadic
CJDref)
: in sCJD patients hyperintense signal in T2-weighted
sequences was found
to be present in the neostriatum (the caudate nucleus and
putamen) with
specificity of 93%, while in vCJD cases signal
hyperintensity was found
in pulvinar thalami. The "pulvinar sign" was
evidenced to be highly
sensitive (79%) and specific (100%) for the diagnosis of the
latter form
of CJD. An MRI result with symmetrically increased signal
intensity in
the pulvinar region relative to the signal intensity in
other deep and
cortical gray mater areas has been reported in >75% of
vCJD patients. The
presence of the pulvinar sign may suggest a vCJD diagnosis
in the appropriate
clinical context.
: sensitivity, specificity, and positive and negative
predictive values
of PSWCs are 64%, 91%, 95%, and 49%, respectively. In the
falsely positive
cases, Alzheimer's
disease
and vascular
dementia
are the underlying diseases. However, only in 20% of cases
both clinical
and EEG data would have led to the false-positive result to
diagnose probable
CJDref.
with the addition of phosphotungstic acid precipitation step
(Bio-Rad Deslys
et al.)ref1,
ref2
symptoms appears 2 years after inoculation of cerebral
samples from infected
bovines, but incubation period shortens with sequential
passages within
a species.
has an incubation period of only 6 months.
Every few weeks the pump is filled up with the drug. A
Belfast patient
is the only person known to have survived 3 years while
suffering from
the disease : as his health rapidly declined his family went
to court for
him to be allowed to take PPS. The patient has since
undergone 2 years
of having PPS injected i.c.. Because the drug, which is used
in the USA
to treat cystitis, has anticoagulant blood thinner and
anti-inflammatory
properties, it was thought to carry the risk of side
effects. About 22
people have been treated so far (10 in Japan) : 1 died
despite treatment,
some have continued without improvement but the condition of
about 6 has
stabilisedref.
PPS may prolong life (the average survival in vCJD is
generally believed
to be about 13 months) but does not seem to halt progressive
deterioration
of the brain, a study of 7 British patients who took the
drug has found.
Of the 7 patients, 3 had vCJD; 2 had iatrogenic prion
disease from GH;
and 2 had the hereditary form of CJD. All were aged under
35. 3 of the
7 died before the study's endref
: in 2001, one British vCJD patient was reported to have made
an astonishing
recovery during a trial, but the woman has since died| BSE and CJD news
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