Research article
Transmission of sheep-bovine spongiform encephalopathy to
pigs
Carlos Hedman1, Rosa Bolea1*, Belén Marín1, Fabien Cobrière4, Hicham
Filali1, Francisco Vazquez2, José Luis Pitarch1, Antonia Vargas1, Cristina
Acín1, Bernardino Moreno1, Martí Pumarola3, Olivier Andreoletti4 and Juan José
Badiola1
* Corresponding author: Rosa Bolea rbolea@unizar.es
Author Affiliations
1 Veterinary Faculty, Centro de Investigación en Encefalopatías y
Enfermedades Transmisibles Emergentes (CIEETE), Universidad de Zaragoza,
Zaragoza, 50013, Spain
2 Veterinary Hospital, Universidad de Zaragoza, Zaragoza, 50013, Spain
3 Veterinary Faculty, Department of Animal Medicine and Surgery,
Universitat Autònoma de Barcelona, Barcelona, 08193, Spain
4 UMR INRA ENVT 1225, Interactions Hôtes Agents Pathogènes, Ecole Nationale
Vétérinaire de Toulouse, Toulouse, 31076, France
For all author emails, please log on.
Veterinary Research 2016, 47:14 doi:10.1186/s13567-015-0295-8
The electronic version of this article is the complete one and can be found
online at: http://www.veterinaryresearch.org/content/47/1/14
Received: 15 May 2015 Accepted: 21 September 2015 Published: 7 January 2016
© 2016 Hedman et al.
Open Access
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Abstract
Experimental transmission of the bovine spongiform encephalopathy
(BSE) agent has been successfully reported in pigs inoculated via three
simultaneous distinct routes (intracerebral, intraperitoneal and intravenous).
Sheep derived BSE (Sh-BSE) is transmitted more efficiently than the original
cattle-BSE isolate in a transgenic mouse model expressing porcine prion protein.
However, the neuropathology and distribution of Sh-BSE in pigs as natural hosts,
and susceptibility to this agent, is unknown. In the present study, seven pigs
were intracerebrally inoculated with Sh-BSE prions. One pig was euthanized for
analysis in the preclinical disease stage. The remaining six pigs developed
neurological signs and histopathology revealed severe spongiform changes
accompanied by astrogliosis and microgliosis throughout the central nervous
system. Intracellular and neuropil-associated pathological prion protein (PrP Sc
) deposition was consistently observed in different brain sections and
corroborated by Western blot. PrP Sc was detected by immunohistochemistry and
enzyme immunoassay in the following tissues in at least one animal: lymphoid
tissues, peripheral nerves, gastrointestinal tract, skeletal muscle, adrenal
gland and pancreas. PrP Sc deposition was revealed by immunohistochemistry alone
in the retina, optic nerve and kidney. These results demonstrate the efficient
transmission of Sh-BSE in pigs and show for the first time that in this species
propagation of bovine PrP Sc in a wide range of peripheral tissues is possible.
These results provide important insight into the distribution and detection of
prions in non-ruminant animals.
Introduction Transmissible spongiform encephalopathies (TSE) are chronic
neurodegenerative disorders that affect humans and animals and are associated
with the accumulation of an abnormal isoform (PrP Sc ) of the cellular prion
protein (PrP C ) in the central nervous system (CNS) [1]. TSE are characterized
by spongiform changes in the grey matter accompanied by astrocytosis and
microgliosis [2]–[4]. The new variant of Creutzfeldt-Jakob disease (nvCJD) in
humans [5] has been linked with the consumption of bovine spongiform
encephalopathy (BSE) contaminated meat or meat products during the BSE epidemic
in the UK and elsewhere. Moreover, one BSE natural case in a goat in France [6]
and another one in the UK [7], [8] have been reported. Sheep and goats can also
be experimentally infected using homogenized brain from affected animals as
inocula [9]–[11]. While BSE infection is largely restricted to the nervous
system in cattle [12], [13], PrP Sc is widely distributed in the lymphoid
tissues of sheep experimentally infected with BSE [10], [14], suggesting that
infected sheep could constitute a secondary and more dangerous source of BSE
infection for other species, including humans [15]–[17].
TSE has not been reported in natural conditions in pigs [18], and there is
no evidence of BSE transmission between pigs fed with brain material from cattle
[19]. However, despite the existence of a strong transmission barrier, signs of
TSE have been reported in pigs challenged simultaneously with BSE-derived
material via intraperitoneal, intravenous and intracerebral administration
[20]–[22]. Those studies demonstrated pathological changes and PrP Sc deposition
in the CNS, but reported no evidence of PrP Sc distribution in other organs.
Given the possible lifting of the European Union’s ban on feeding pigs and
poultry with animal meal, it is vital that TSE transmission be studied in
supposedly resistant species, such as swine, that form part of the human food
chain. Pigs are the source of a wide range of food products, and pork is one of
the most widely eaten meats in the world. Blood is frequently collected during
slaughter for blood sausage production and natural sausage casings are almost
exclusively prepared from different parts of the alimentary tract of pigs. The
use of pigs as graft donors is also a cause for concern, given a reported case
of CJD type 1 in a recipient of a porcine dura-mater graft [23]. It has also
been demonstrated that BSE experimentally passaged in sheep (Sh-BSE) homozygous
for the A 136 R 154 Q 171 allele of ovine prion protein (PrP) exhibits altered
pathobiological properties due to a decreased polymorphism barrier [24]. The
virulence of Sh-BSE in transgenic mice expressing porcine [15] and human PrP
[16], [25] is enhanced with respect to the original cattle BSE prion isolate.
This study is the first to describe the tissue distribution of PrP Sc in
pigs experimentally infected with BSE previously passaged in sheep, as well as
the clinical and neuropathological consequences.
snip...
Discussion This study was aimed at investigating the susceptibility and
neuropathological features of pigs intracerebrally inoculated with the BSE agent
after passage in sheep, as well as describing the PrP Sc distribution in
peripheral tissues in this species.
In the present study, seven pigs were intracerebrally inoculated with 0.5
mL of 10% Sh-BSE homogenate. Except in one animal (P-7), which was euthanized
for preclinical analysis, the transmission rate was 100%, with an incubation
period range of 77–109 wpi. Two previous studies in which bovine BSE has been
transmitted to pigs, reported 87.5% and 20% of rate attacks, with incubation
period ranges of 74–163 and 148–175 wpi, respectively [19], [20]. Sh-BSE
infected pigs show slightly shorter incubation periods. However, it is not
possible to compare the incubation period of our inoculated pigs with respect to
the incubation period found in the studies mentioned above, due to the lack of
titration of the original inoculum. Moreover, the incubation period could also
be modified in TSE due to the species barrier, which is modulated by specific
polymorphisms of the PRNP gene and plays a key role in susceptibility to prion
disease in other species such as sheep [35], [36], and goats [37]. Although some
studies show that there are no differences in the sequence of the porcine PRNP
gene [38]–[40], the possibility of changes in other regions of the gene or the
involvement of other genes in the incubation periods of BSE in pigs should not
be excluded. In addition, the restricted number of animals used does not allow
comparing difference on rate attacks in previous studies with the present
report. However, transmissible studies in porcine PRNP transgenic mice (Tgpo)
has demonstrated that the Sh-BSE agent reached rate attack of 100% and lower
survival time when compared to the original bovine BSE (19%) and other BSE
isolates at first passage [15]. At two subsequent passages, the transmission
rate of both Sh-BSE and bovine BSE was reported to be similar (100%) but always
with a lower survival time of the Sh-BSE infected mice [15]. Recent studies have
demonstrated an increase in the PrP-converting potency of Sh-BSE caused by
decreases in polymorphism barriers [24] and other specific cellular factors
[25], allowing Sh-BSE to be transmitted more efficiently than cattle BSE to
other species [16], [17] including supposedly less susceptible hosts such as
pigs [15]. The current study was in agreement with previous reports [20]–[22]
involving intracerebral inoculation of BSE prions to pigs demonstrating that
this species is susceptible to BSE. However, it is still unknown if pigs can
succumb to BSE after oral exposure which is the most likely route of inoculation
under natural conditions.
The clinical signs observed in the present study were similar to those
described in BSE-infected pigs [20]. Animals initially showed progressive
confusion, followed by motor deficits [19]. The behavioral and sensory changes
were also consistent with those observed in cattle infected naturally [41] and
experimentally with BSE [12]. The minimal neuropil vacuoles found in the control
pig are in total agreement with previous studies [21] and apparently does not
represent a clinical significant change [20]. The main pathological changes
observed were neuropil spongiosis, intraneuronal vacuolation and PrP Sc
deposition, all of which are characteristic of TSE [41]. The lesion distribution
pattern resembled that described previously in experimentally BSE- infected pigs
[21] and cattle [12]; the thalamus was the most affected area, followed by the
cerebellar and cerebral cortices, with the mildest effect observed in the spinal
cord. PrP Sc deposits were identified in the CNS of all clinically affected
pigs. PrP Sc deposits were typically associated with lesions in the fourth and
fifth layers of the cerebral cortex. Intracellular (ITNR, ITAS and ITMG) and
particulate/coalescing type PrP Sc deposition were the most commonly observed
patterns in the different CNS samples, in line with previous findings in sheep
[29], [30] and pigs [21] experimentally infected with BSE. Similarities in the
PrP Sc deposition types and distribution pattern could be explained by the high
stability of the BSE agent reported for different breeds and different genotypes
of the prion protein gene (PRNP) in sheep [30]. In addition, the porcine PRNP
gene has been described to be very homogenous [38]–[40].
The glial reaction in all affected pigs was characterized by marked
astrocytosis and microgliosis. Astrocytosis was diffusely distributed throughout
the brain of affected pigs, perhaps caused by the accumulation of PrP Sc or by
cytokines secreted from astroglial or microglial cells [42]. Microgliosis was
present in the deeper layers of the gray matter in the cerebral cortex, which
also showed vacuolation and PrP Sc deposition, in accordance with previous
findings in mice [43]. The most extreme microglial activation was observed in
the hippocampus of all affected pigs, as previously described for CJD [44].
Numerous astrocytic processes and reactive microglia have been described in pigs
experimentally infected with BSE [45]. Our results suggest that astrogliosis and
microgliosis are common neuropathological features of Sh-BSE infection in pigs,
as described for TSE in other species [28], [43], [45]–[47].
Histopathological changes indicative of retinal degeneration were observed
in all clinically affected pigs. This has not been previously described in pigs
experimentally infected with BSE. Neuronal vacuolation in the GCL and
disorganization in the plexiform and nuclear layers have been reported in both
experimental [48] and natural scrapie infections in sheep [49] and goats [50],
chronic wasting disease (CWD) in mule deer [51] and in CJD-infected mice [52].
IHC revealed higher levels of PrP Sc in the retina than in the optic nerve,
where staining was less intense and more irregularly distributed, as described
in both sCJD and nvCJD [53]. The presence of PrP Sc in the optic nerve and
retina is consistent with the centrifugal spread of the agent from the brain,
presumably via the optic nerve [52]. This may indicate the existence of other
routes of PrP Sc migration to the retina (e.g., via the extracellular space
[54], the ad-axonal route along the optic nerve, or both [55]). Other authors
have suggested that the spread occurs from the subarachnoid space into the
perineural space of the optic nerve, and from there to the epichoroidal and
episcleral tissues of the eyeball [56]. Alternatively, the increased presence of
PrP Sc in the retina more than in the optic nerve could be attributed to the
higher presence of PrP c in the membranes of retinal neurons. Our detection of
PrP Sc in different retinal layers is in accordance with previous observations
in TSE in mice [52], feline spongiform encephalopathy (FSE) [57], scrapie [49],
CWD [51], BSE [56] and in patients with sporadic and nvCJD [53].
Western blot revealed a characteristic 3-band pattern that clearly differed
from the original inoculum, with a predominant monoclycosylated band. This
finding is consistent with previous Western blot findings in BSE-infected pigs
[58]. Our results reinforce the hypothesis that this particular signature is
associated with the porcine PrP c properties described in Tgpo mice [15].
The IDEXX enzyme immunoassay, which is not validated for PrP sc in pigs,
detected PrP Sc in samples that tested positive in other postmortem assays, but
detected no PrP sc in negative control tissues. Analysis of peripheral tissues
revealed widespread dissemination of PrP Sc in many organs other than the CNS.
This finding suggests that unlike in cattle where BSE is confined mainly in the
nervous system, in the pig, BSE prions can propagate in peripheral tissues as
reported in sheep [59]–[61]. However, it is not possible to ascertain that the
peripheral distribution of the agent is due to centrifugal dissemination from
the brain through the nerves as it is also probable that during an ic challenge
part of the inoculum enters into the blood circulation and can be disseminated
to the periphery where it can propagate in target tissues [62].
PrP Sc deposition in brachial and sciatic nerves has also been described in
cattle experimentally infected with L-type BSE [63] and in BSE-infected sheep
[64].
Immunohistochemistry demonstrated the presence of PrP Sc in the
lymphoreticular system of our Sh-BSE infected pigs. The assay revealed sporadic
intracytoplasmic accumulation within the tingible body macrophages in some lymph
nodes, findings that were subsequently corroborated by IDEXX, in good agreement
with previous findings in sheep experimentally infected with BSE [64]. In
contrast to our findings, previous studies reported no infectivity of lymphoid
tissues in BSE-infected pigs [19]. No PrP Sc was detected in the spleen or GALT
of our pigs, in line with previous studies of BSE-infected cattle [65] and FSE
[57].
PrP Sc accumulation in the gastrointestinal tract of Sh-BSE infected pigs
has not been described in similar experiments using this species. We observed
PrP Sc deposition in the myenteric plexi without apparent morphological
alterations of the enteric neurons, as seen in cattle experimentally infected
with BSE [65]. This finding is indicative of a potential centrifugal spread of
the Sh-BSE agent from the CNS via the vagus nerve to the peripheral nervous
system, and may account for the large deposits of PrP Sc observed in the dorsal
motor nucleus of the vagus nerve in the medulla oblongata.
We observed PrP Sc deposition in nerve fibers of the oculomotor muscle in
two pigs. In cattle naturally infected with BSE [66], PrP Sc has been detected
in intramuscular nerve fibers and muscle spindles. Although we found no PrP Sc
in the oculomotor muscle of any other clinically affected pigs, positive
labeling was observed in the oculomotor nuclei in the mesencephalon of all
clinically affected pigs.
Pancreatic PrP Sc staining was observed in 5 pigs. Analysis of pancreatic
nervous tissue has revealed PrP Sc deposition in the islets of Langerhans in
natural scrapie [34]. In natural BSE [56], PrP Sc deposition has been documented
in the nerve fibers of the adrenal gland. In agreement with previous findings in
natural scrapie [34], one pig showed PrP Sc immunolabeling in the medullary
region of the adrenal gland, associated with chromaffin cells, which are
considered modified sympathetic postganglionic neurons. Similarly, the presence
of PrP Sc within the epithelial tubular cells of the convoluted tubules and the
collecting ducts in the kidney in one pig has been described in FSE [67],
suggesting possible prionuria.
In addition to the large amount of PrP Sc observed in the CNS of
Sh-BSE-infected pigs, PrP Sc was widely distributed in the peripheral tissues,
although the extent of this distribution varied between animals. This variation
may be related to the distribution of PrP Sc within individual organs, the exact
anatomical location points at which samples were collected, and the detection
limits of the techniques used. More sensitive studies, such as in vitro protein
misfolding cyclic amplification (PMCA) and mouse bioassays will be needed to
clarify the distribution and infectivity of PrP Sc in peripheral tissues of
Sh-BSE infected pigs. These assays will most likely indicate a higher number of
PrP Sc -positive peripheral organs.
Comparison with previous studies of cattle-BSE in pigs revealed that the
incubation period of Sh-BSE in our pigs was generally shorter [20], [21] and
that PrP Sc was present in more peripheral tissue types [19]. We believe that
these differences may be due to a modification in the pathogenicity of the
cattle-BSE agent caused by its prior passage in sheep, as previously described
in TgPo mice [15]. However, studies of natural routes of transmission (e.g.,
oral) will be required to determine the real susceptibility of pigs to the
Sh-BSE agent.
Prion
Volume 9, Issue 4, 2015
Porcine prion protein amyloid
DOI:10.1080/19336896.2015.1065373Per Hammarströma & Sofie Nyströma*
pages 266-277
Received: 1 Jun 2015 Accepted: 17 Jun 2015 Accepted author version posted
online: 28 Jul 2015
© 2015 The Author(s). Published with license by Taylor & Francis Group,
LLC Additional license information
ABSTRACT
Mammalian prions are composed of misfolded aggregated prion protein (PrP)
with amyloid-like features. Prions are zoonotic disease agents that infect a
wide variety of mammalian species including humans. Mammals and by-products
thereof which are frequently encountered in daily life are most important for
human health. It is established that bovine prions (BSE) can infect humans while
there is no such evidence for any other prion susceptible species in the human
food chain (sheep, goat, elk, deer) and largely prion resistant species (pig) or
susceptible and resistant pets (cat and dogs, respectively). PrPs from these
species have been characterized using biochemistry, biophysics and neurobiology.
Recently we studied PrPs from several mammals in vitro and found evidence for
generic amyloidogenicity as well as cross-seeding fibril formation activity of
all PrPs on the human PrP sequence regardless if the original species was
resistant or susceptible to prion disease. Porcine PrP amyloidogenicity was
among the studied. Experimentally inoculated pigs as well as transgenic mouse
lines overexpressing porcine PrP have, in the past, been used to investigate the
possibility of prion transmission in pigs. The pig is a species with
extraordinarily wide use within human daily life with over a billion pigs
harvested for human consumption each year. Here we discuss the possibility that
the largely prion disease resistant pig can be a clinically silent carrier of
replicating prions.
SNIP...
CONCLUDING REMARKS Should the topic of porcine PrP amyloid be more of a
worry than of mere academic interest? Well perhaps. Prions are particularly
insidious pathogens. A recent outbreak of peripheral neuropathy in human,
suggests that exposure to aerosolized porcine brain is deleterious for human
health.43,44 Aerosolization is a known vector for prions at least under
experimental conditions.45-47 where a mere single exposure was enough for
transmission in transgenic mice. HuPrP is seedable with BoPrP seeds and even
more so with PoPrP seed (Fig. 1), indicating that humans could be infected by
porcine APrP prions while neurotoxicity associated with spongiform
encephalopathy if such a disease existed is even less clear. Importantly
transgenic mice over-expressing PoPrP are susceptible to BSE and BSE passaged
through domestic pigs implicating that efficient downstream neurotoxicity
pathways in the mouse, a susceptible host for prion disease neurotoxicity is
augmenting the TSE phenotype.25,26 Prions in silent carrier hosts can be
infectious to a third species. Data from Collinge and coworkers.21 propose that
species considered to be prion free may be carriers of replicating prions.
Especially this may be of concern for promiscuous prion strains such as
BSE.19,48 It is rather established that prions can exist in both replicating and
neurotoxic conformations.49,50 and this can alter the way in which new host
organisms can react upon cross-species transmission.51 The na€ıve host can
either be totally resistant to prion infection as well as remain non-infectious,
become a silent non-symptomatic but infectious carrier of disease or be
afflicted by disease with short or long incubation time. The host can harbor
and/or propagate the donor strain or convert the strain conformation to adapt it
to the na€ıve host species. The latter would facilitate infection and shorten
the incubation time in a consecutive event of intra-species transmission. It may
be advisable to avoid procedures and exposure without proper biosafety
precautions as the knowledge of silence carrier species is poor. One case of
iatrogenic CJD in recipient of porcine dura mater graft has been reported in the
literature.52 The significance of this finding is still unknown. The low public
awareness in this matter is exemplified by the practice of using proteolytic
peptide mixtures prepared from porcine brains (Cerebrolysin) as a nootropic
drug. While Cerebrolysin may be beneficial for treatment of severe diseases such
as vascular dementia,53 a long term follow-up of such a product for recreational
use is recommended.
The case for mad pigs in the US
From the Consumer Policy Institute and Consumers Union: March 24, 1997
Stephen F. Sundlof, D.V.M., Ph.D
Center for Veterinary Medicine Food and Drug Administration 7500 Standish
Place, Room 482, HFV 1 RockvLIle, MD 20855
Dear Dr. Sundlof:
We are writing to you to submit information that has recently come to our
attention which suggests that a TSE like disease (transmissible spongiform
encephalopathy) might exist in pigs in the U.S. We believe this new informantion
calls for intensive research and makes it urgent to ban the use of all mammalian
proteins, including swine, in the feed of all food animals, until better answers
are found.
The evidence for the potential PSE (porcine spongiform encephalopathy ) is
as follows. In 1979, an FSQS veternarian, Dr. Masuo Doi, noticed some unusual
central nervous system (CNS) symptoms in young (about 6 months old) hogs coming
into a slaughter plant In Albany, New York. Since the plant received hogs from a
wide variety of sources (New York, Canada, Indiana, Illinois, Ohio, and other
Midwestern states) and was not a plant used to dealing with diseased animals,
Dr. Doi thought that the problem might be affecting hogs slaughtered nationwide.
So, he decided to conduct a detailed study on central nervous system (CNS)
symptoms/disease in young hogs coming into that slaughter plant. The study ran
for 15 months (January, 1979 to March, 1980) and consisted of extended
observations of the behavior of animals with suspected CNS symptoms at the
plant, followed by pathological, histopatholpgical, and microbiological work on
tissues from various organs of particular animals after slaughter.
For his behavioral observational work, Dr. Doi extended the usual two day
observation period to three to four days, during which he took careful notes on
the animals' behavior and other vital signs. During the 15 month period of the
study, some 106 animals exhibiting CNS symptoms were retained during antemortem
inspection.
A 1980 paper that summarized Dr. Doi's findings on the clinical symptoms
and incidence of the 'disease," contained descriptions of these symptoms that
sound remarkably similar to the symptoms noted for bovine spongiform
encephalopathy (BSE):
"Excitable or nervous temperament to external stimuli such as touch to the
skin, handling and menacing approach to the animals is a common characteristic
sign among swine affected with the disease.... In the advanced stage of the
disease, manifestation of neurological signs are evidenced in the form of
general ataxia . . . Many animals have been found to be "downers' at first
observation; if the hindquarters of these downers are raised they may be able to
walk one or two steps and then fall to the ground" (Doi et al., 1980: 2, 4).
Indeed, a table of symptoms includes, for the early stage: "excitability and
nervousness (squealing, smacking of lips, grinding of teath, chewing, gnawing
ant foaming at mouth); stiffness of limbs . . . 'tic'; weakness of hindquarters;
focal tremors of skeletal muscles"; and for the advanced stage: depression;
ataxia; crossing over of limbs . . . kneeling posture . . . crawling". In
addition to his clinical observations, Dr. Doi also made an 8 mm film of
thirteen of the affected animals; film of two of the pigs was shown at the MPI
National Pathology Meeting in Seattle, Washington on flay 20, 1979.
Dr. Doi sent tissue samples from suspect cases to the USDA's Eastern
Laboratory in Athens, GA for pathological, histopathogical and microbiological
work. Known infectious diseases were ruled out. As Dr. Doi points out,
"Histopathological studies of tissue collected from the brain and spinal cord of
these animals in the early stage of the disease show congestion, hemorrhage and
neuronal degeneration. All animals in the advanced stage of the disease have
been confined to have Encephalitis or Meningitis by MPI laboratory" (Doi et al.,
1980: 5). Eventually some 60 animals were confirmed by the MPI Laboratory to
have encephalitis or meningitis, with no ldentifiable cause. As pointed out in a
paper presented at the 1979 MPI National Pathology Meetings,
"Since January, a number of hogs in this establishment have been found, in
antemortem, to show what appears to be CNS. Sets of tissue samples were sent to
the laboratory for examination, various tests were done which include
histological study (E H stain), fluorescence antibody technique, virus
neutralization and viral and bacteriological isolation. Differential diagnosis
was also done to exclude vitamin B deficiency, post vaccination reaction,
chlorinated hydrocarbon, arthritis, and transport stress" (Doi et al., 1979).
The brains of the 60 animals were examined. The brain of one of these pigs, on
histopathological analysis, exhibited signs reminiscent of a TSE. This
histopathological work was performed by Dr. Karl Langheinrich,
Pathologist-In-Charge at USDA's Eastern Laboratory in Athens, Georgia. According
to the USDA FSQS laboratory report, dated early November, 1979, Dr. Langheinrich
noted:
"Microscopic examination of the barrow tissues revealed a encephalopathy
and diffuse gliosis characterized by vacuolated neurons, loss of neurons and
gliosis in a confined region (nucleus) of the brain stem (anterior ventral
midbrain). Only an empty sometimes divided vacuole was present instead of the
normal morphology of a nerve cell. Occasionally a shriveled neuron was seen.
According to . . . Pathology of Domestic Animals, . . . 'The degeneration of
neurons, the reactivity of the glia .... are the classical hallmarks of viral
infection of the central nervous system' .... Scrapie of sheep, and
encephalopathy of mink, according to the literature, all produce focal
vacuolation of the neurons similar to the kind as described for this pig. I was
unable to locate any lead as to the cause of this interesting phenomenon in
other species including swine'' (Langheinrich, 1979). Indeed, Dr. Langheinrich's
main diagnosis was, " Encephalopathy and diffuse gliosis of undetermined
etiology." Portions of the brain were sent for microbiological testing to a
neurologist at the University of Georgia, where they came up negative for
pseudo-rabies. The brain was unique enough that USDA scientists, such as Dr.
Langheinrich and Or. Dot, mentioned it to student and scientific colleagues over
the years.
In 1979-1980, BSE was completely unknown. However, both the behavior of the
pigs, as well as the histopathology on at least one pig, both showed sign
consistent with a porcine TSE. This raises particular concern became the
affected animal was only 6 months old; in an animal this young, one would rust
expect to see any physical signs of TSE in the brain. Histopathology of TSEs can
be very variable, so that spongiform appearance (i.e. vacuolated neurons) are
not always present. Behavioral changes can be seen in TSE-infected animals
before any changes in brain morphology are visible. Dr. Clarence Gibbs, in
testimony before a Congressional hearing on the TSE issue on January 29, 1997
made just this point:
''In the mid-1960s, we demonstrated with our French and English
collaborators that during the early incubation of the TSEs, when the virus titer
in the brain was very low, there were already marked functional changes, even
though no pathology was yet detectable, even ultrastructurally. A month or hero
later, polynucleation of neurons appeared in spider monkeys, incubating kuru,
and somewhat later, microvacuolation and membrane changes visible only by
electron microscopy. This preceded the pest appearance of astrogliosis and
spongiform change. It was only much later that the classical scrapie TSE
pathology appeared with virus titers in brain of 10 -5 or higher" (Gibbs, 1997;
pg. 4). Given that TSEs can cause behavioral changes in infected animals before
any physical changes in the brain can be seen, that the manifestation of TSE in
the brain can be quite variable, and that changes in brain morphology are not
usually seen in 6 month old animals, we are concerned that the brain of one pig
actually showed physical evidence consistent with a TSE.
Following the announcement In March, 1996 of ten cases of new variant CJD
(Creutzfeldt-Jakob Disease) in the United Kingdom and their possible connection
to BSE, Drs. Doi, Langheinrich and others urged reinvestigation of this case.
In August, 1996, the USDA sent five slides, one of which was a
histopathology slide, to Dr. Janice Miller of USDA's Agricultural Research
Servicer . Dr. Miller stained four of the slides for prion protein (she didn't
stain the H&E slide). Dr. Miller told Consumers Union that Dr. Patrick
McCaskey, USDA/FSIS, in charge of the Research Center at Athens, GA, called her,
told her that he had five slides that all showed "problems" and asked her to
stain four of them. The H&E slide, which clearly show vacuoles in the
neurons (one sign of TSE), wasn't stained because to stain for PrP entails
removing the slide cover, baking the slide to destain it and then restaining it
for PrP; they didn't want to risk destroying the H&E slide.
Dr. Doi had kept frozen samples of the brain and spinal chord of the
suspect PSE pig in case the Eastern lab wanted more material for analysis.
Unfortunately, these samples were discarded when the packing plant in Albany, NY
closed in 1991. It appears that the brain material sent to the Univcrsity of
Georgia may have been discarded. [pers com.. Dr. Doi 3/13/97]
Dr. Miller found that the PrP stained in the four pig slides was found only
on the inside of neurons, while a positive control slide from a scrapie sheep
showed massive amounts of extraneuronal staining. In a letter summarizing her
results (copy attached), she concludes that the PrP stained in this pig was
normal: "In the pig sections you will see a small particulate type of staining
that is confined to neurons and as I indicated on the phone, I would interpret
as normal PrP. It is in marked contrast to the massive amount of extraneuronal
staining seen in the scrapie section" (Miller, 1996).
Unfortunately, Dr. Miller's finding toes not conclusively rule out a TSE.
We are concerned that while British BSE and serapie create a massive amount of
extraneuronal staining, there are TSEs where this isn't the case. Three
experiments were done in He U.S. -- in Mission, TX (APHIS work), Pullman,
Washington (ARS work), and Ames, Iowa (ARS work) -- to see whether sheep scrapie
can possibly infect cows. In all the experiments, cattle were inoculated with
tissue from scrapie -infected sheep primarily by intra-cranial injection, but in
the case of the Texas and Iowa studies also by oral feeding -- to see if cattle
were susceptible to scrapie at all. In all three experiments, the majority of
cows injected in the brain with scrapie-infected sheep material (usually brains)
also developed a fatal spongiform encephalopathy.
However, in all three examples, the symptoms of the spongifonn
encephalopathy differed from "mad cow" disease ~ England, as did the appearances
of slides from their brains. The brain lesions seen in ail these animals were
more variable than those seen in England. When Dr. Miller did similar staining
for PrP from these brains (what she called "bovine scrapie") she only found PrP
stains on the inside of the neurons, not the massive extraneuronal staining seen
in BSE (Miller, pers. comm., March 7, 1997). Thus, Dr. Miller's finding of PrP
stains only inside the neurons in the suspect pigs is not particularly
reassuring.
In November 1996, USDA sent the single histopathology slide to Dr. William
Hadlow, one of the foremost spongiform encephalopathy pathologists in the world.
(For unknown reasons, Dr. Hadlow was only sent the one slide; he was not told of
the existence of the other slides, nor of Dr. Miller's findings, nor was he told
or given the behavioral report from Dr. Doi or the morphology work by Dr.
Langheinrich, or shown film of the affected pigs [Dr. Hadlow, pers. com.,
3/13/97] From this single slide, Dr. Hadlow found some evidence consistent with
TSEs but not enough for a conclusive diagnosis. He noted that the slide
contained vacuoles inside neurons, one of the signs of a TSE (Dr. Langheinrich
had noted this as well).
However, since such vacuoles occasionally occur normally in pigs, he
thought that was not something special: "About twelve (12) neurons in the
parasympathetic nucleus have unilocular optically empty vacuoles in the
perikaryon. This is the site where such vacuolated neurons have been seen in the
swine (as well as in cats and sheep) as an incidental finding. So I do not think
such cells have any significance in this pig" (Hadlow, 1996). However, he did
see evidence, Including changes in astrocytes, that suggested a TSE, but without
examining other parts of the brain to look for other evidence of TSE, he
couldn't be sure:
"I am impressed, though, with what seems to be an increase in the number of
astrocytes in the section. Some astrocytes are in clusters, some are enlarged
and vesicular. Where they are most numerous, a few rod cells (activated
microglia) are seen. These findings suggest some perturbation of the nervous
tissue. Although such a global response occurs in the transmissible spongifonn
encephalopathies, I do no! know its significance in this case without examining
other parts of the brain for changes characteristic of these diseases. Thus,
from looking; at this one (1) section of brain, I cannot conclude that the pig
was affected with a scrapie-like spongiform encephalopathy" (Hadlow, 1996). In
sum, Dr. Hadlow~s letter does not rule out the possibility of a TSE. He says
that there is suggestive evidence, but that he would need to look at other
slides/sections of the brain, to make a conclusive diagnosis.
In our view, the implications of this data are extremely serious.
Experiments in the United Kingdom have shown that pigs are susceptible to BSE.
Pigs inoculated with BSE develop a TSE (Dawson et al., 1990). Feeding
experiments are underway in the UK to see if BSE can be orally transmitted to
pigs; as of March, 1997, some 6 years after the start of the experiment, none of
the pigs fed BSE brain have come down with a TSE. Unfortunately the design of
this experiment severely limits what we will learn from it, and will most likely
not tell us conclusively if pigs can get BSE from feed. It turns out that the
pigs were not fed BSE brain continuously. Rather, the pigs were only fed BSE
brain material on three days, over a three week period (i.e.. one day each
week). Following these three doses, the pigs were never fed contaminated
material again. The total amount of infective material given to the pigs was
therefore quite small. Thus, a negative finding would be hard to interpret and
would not mean that BSE is not orally active in pigs.
We believe that as a top priority USDA should conduct follow-up studies to
look for potential CNS/PSE cases in pigs (we plan to communicate about this to
USDA separately). In brief, we feel that the following kinds of studies need to
be done:
i) TSE pathology experts should examine all the slides from the suspect pig
(2709). To our knowledge, at least 12 separate slides exist.
ii) Determine if any brain material from the suspect pig (2709) still
exists at the Unlverslty of Georgia. If so, this material should be retrieved
and used for transmission studies. In particular, suckling pigs should be
inoculated with the material and then permitted to live unto they die of a
disease or old age, at which point their brains should be examined for physical
signs of a TSE as well as for immunchistochemical evidence (i.e. staining
looking for the abnormal PrP).
iii) Increase antemortem inspection for CNS symptoms at hog facilities.
Inspectors should be trained to detect the subtle CNS symptoms seen in the Doi
et al. study. At a select number of slaughter facilities, animals exhibiting CNS
symptoms should be removed and held for observation until they die, at which
time their brains should be examined for evidence of a TSE.
iv) Research on CNS symptoms among Me 6,000 or so breeding sows which are
permitted to live for 3+ years. Sows exhibiting CNS symptoms should be removed
and held for observation until they die, at which time then brains should be
exernined for evidence of a TSE.
While such work is underway, given the above inforrnabon, we believe that
as a precutionary measure the FDA must expand the proposed ruminant plus
mink-to-ruminnant feed ban to prevent protein from any material, including hogs,
being fed to any food animal.
Sincerely,
Michael Hansen, Ph.D Research Associate
Jean Halloran Director
References
Dawson, M., Wells, G.A.H., Parker, B.N;J. and A.C Scott. 1990. Primary
parental transmission of bovine spongiform encephalopathy to the pig. Veternary
Record, pg. 338.
Doi, M., Matzner, N.D. and C. Rothaug. 1979. Observation of CNS disease in
market hogs at Est. 893 Tobin Packing Co., Inc. Albany, New York. United States
Department of Agriculture, Food Safety and Quality.Service, Meat and Poultry
Inspection Service. 7pp.
Doi, M, Langheinrich, K. and F. Rellosa. 1980. Observations of CNS signs in
hogs at Est. 893 Tobin Packing C:o., Inc. Presented by Dr. Lngheinrich at the
MPI National Pathology Meeting in Seattle, Washington on July 20, 1979.
Gibbs, C. 1997. Statement to the Committee on Governnent Reform and
Oversight, Subcommittee on Human Resources and Intergovernmental Relations, U.S.
House of Representatives. January 29,1997.
Hadlow, WJ. 1996. Letter to Patrick McCaskey, USDA/FSIS/Eastem Lab, dated
November 13, 1996.
Langheinrich, KA. 1979. USDA/FSQS Laboratory report on specimen 2709. Dated
November 8, 1979
Miller, J. 1996. Letter to Patrick McCaskey, USDA/ESIS/Eastern Lab, dated
September 6, 1996.
Dr. Janice Miller, ARS< USDA responds Mon, 31 Mar 1997 Correspondence My
involvement in the "pig incident" (I refuse to say "mad pig disease" since no
such disease has been recognized):
I was asked by Dr. Al Jenny at the National Veterinary Services Laboratory
if I had ever done immunohistochemistry on slides that had already been stained
by hematoxylin and eosin, the standard stain used for histopathology. I had done
it on a few scrapie cases so he asked if I would do the procedure on some pig
brain slides that he had received from Dr. Pat McCaskey, an FSIS pathologist in
Athens, GA.
At the time I didn't know the history of the situation but Dr. Jenny said I
should call Dr. McCaskey and discuss it with him before proceeding. Only then
did I learn a little about the history of the case. We decided that I wouldn't
try to stain all of the slides because I was afraid the procedure required to
remove the cover slips might damage the sections and Dr. McCaskey was concerned
about preserving the sections for other pathology consultations, if necessary.
We agreed that I would stain 4 of the 5 slides, leaving the slide with the
best lesions untouched. I was also concerned that I didn't know whether the
antiserum we use would stain pig PrP but decided it was worth a try. When I
completed the staining procedure the only positive material I observed was a
small amount of particulate staining within the cell body of some neurons. We
have occasionally observed that kind of staining in brains from control cattle
and sheep in our experiments and interpret it to be normal PrP. (A similar
finding was reported by Dr. Haritani, who first described the technique for
BSE).
That observation was reported in our 1994 paper and we stated that
consequently we could not interpret intraneuronal staining as indicative of
scrapie (although it may be present, the bulk of staining is in neuropil, around
vessels and neurons, etc). In that study I think our interpretation was somewhat
validated by the very close correlation we had between immunohistochemistry and
western blot results. At any rate, I told Dr. McCaskey that my interpretation on
the slides was that the only staining present was consistent with normal PrP.
The good news was that the antiserum did in fact stain something and that it was
in the correct location for normal PrP, indicating that the antiserum would have
detected abnormal PrP, had it been present. Subsequently, I called Dr. Richard
Rubenstein, who provided the antibody we use, and asked if he knew whether it
would react with pig PrP and he said he didn't know. However, he said it reacted
with almost all mammalian species, except ferret and mink, that he had tried so
he would be surprised if it wasn't reactive with pig PrP.
So, having all of this information at hand, people can decide whether the
immunohistochemical test means anything or not. The lack of a positive control
pig tissue (positive sheep tissue is included in every test) may be viewed by
some people as diminishing the value of a negative result, but feel we did the
best we could under the circumstances.
The above recitation describes my experience with the case in question. I
did not photograph the slides and returned all 5 to Dr. McCaskey. It was later
that he had Dr. Hadlow look at the case for histopathologic interpretation. I
did not examine the slides for that purpose because I do not have experience in
scrapie diagnosis and would not consider my observations meaningful.
I appreciated the additional information about the original study done by
Dr. Doi. Although I've heard bits and pieces of the story from different people,
this was the first time I had heard that 60 of the pigs were diagnosed as having
encephalitis or meningitis. I think that fact, plus the fact that the pigs were
only about 6 months old, should certainly indicate that it's highly unlikey that
a spongiform encephalopathy epidemic was causing the CNS signs observed. Whether
the 1 pig with the questionable encephalopathy lesions was a TSE could be
debated, I suppose. The age would seem to argue against it and the
immunohistochemistry result would also (at least that's my opinion).
We disagree about the implications of age regarding the liklihood of TSE in
a 6-month old pig. Certainly dose has an effect on incubation period in
experimental transmissions and probably also in the "natural" acquired
transmissions. However, regardless of the manner of transmission, I don't know
of any first passage experimental interspecies transmission where the incubation
period was as short as 6 months.
Early onset in mice were achieved only after adaptation through at least 1
intraspecies transfer. I believe the same is true for development of the hamster
models. With regard to acquired transmissions, Linda Detwiler's review on
scrapie cites research that indicated infectivity was found in CNS tissues of
lambs as early as 4 months of age: however, they were not showing clinical
signs. From what I can find in the literature, a clinical case of scrapie under
2 years of age would be exceptional, but with the amount of material published
on that disease I wouldn't want to say it hasn't happened.
With TME the shortest incubation I've seen reported was 9 months. Elizabeth
Williams has indicated that the youngest case of CWD observed in their wildlife
facilities was 18 months old. You stated that in England calves were getting BSE
by one year. In the experimental BSE transmissions cattle didn't develop
clinical signs until the second year of observation and the earlest sign we
observed in cattle inoculated with sheep scrapie was 14 months.
With respect to swine, the only model we have is the experimental
transmission of BSE. The animal first developed signs about 17 months after
inoculation. I think that it would be highly unlikely for a 6 month old pig to
be showing CLINICAL signs of a TSE (the claim in this particular situation). One
can never say never but it seems reasonable to at least examine what is known
and make an educated estimate about what is likely.
A case-control study of CJD. Dietary risk factors. Am J Epidemiol 122 (3):
443-451 (1985) Davanipour Z, Alter M, Sobel E, Asher DM, Gajdusek DC The mode of
natural transmission of Creutzfeldt-Jakob disease remains unknown. In a
case-control study conducted in 1981-1983 to evaluate possible dietary and other
sources of the disease, 26 cases were ascertained in the mid-Atlantic region of
the United States, 23 of which were obtained from accumulated records of the
Laboratory of Central Nervous System Studies of the National Institutes of
Health. Controls included 18 family members and 22 hospital-matched individuals
(total sample size, 66). An increased consumption among patients was found for
roast pork, ham, hot dogs (p less than 0.05), roast lamb, pork chops, smoked
pork, and scrapple (p less than 0.1). An excess consumption of rare meat (p less
than 0.01) and raw oysters/clams (p less than 0.1) was also reported among the
patients. Liver consumption, among organ foods, was greater (p less than 0.1)
among the cases. If Creutzfeldt-Jakob disease is acquired through ingestion of
foods containing the agent, then the food items identified may be among those
which need to be evaluated more intensively. Larger case-control studies with
more focused dietary questions are warranted.
Sundlof can't comment From: Dr. Stephen Sundlof D.V.M., Ph.D. Director,
Center for Veterinary Medicine Food and Drug Administration :
At the present time FDA is in the process of developing a final rule which
will regulate the feeding of certain animal-derived protein to other animals. In
addition to studying the scientific literature pertaining to TSE's, we have
received 700 comments relating the proposed rule that was published in the
Federal Register on January 3, 1977. The information provided by Dr. Hansen and
others will be considered in developing the final rule along with all of the
other information and comments that have been officially submitted to FDA. Until
the final rule is published, FDA is prohibited from commenting on information
that might impact the final rule. Therefore, I am unable to respond to the
documents in Dr. Hansen's letter.
I do not have access to the photomicrographs of the histopathology slides,
and I was unaware of their existance until Dr. Hansen brought the issue to my
attention. Furthermore, I do not have addresses or telephone numbers for Drs.
Doi. Langheinrich, or Hadlow. Someone from the USDA would have this information
but I am not sure who that would be.
Webmaster had written: " Do photomicrographs of any of the 12 slides exist?
If you have any of them, I would like to scan a few of these and post them at
high resolution on the internet so that pathologists world-wide could view and
comment on them.
Primary parenteral transmission of bovine spongiform encephalopathy to the
pig. Veterinary Record 1990 127 13 338 Dawson, M.; Wells, G. A. H.; Parker, B.
N. J.; Scott, A. C. Ten, weaned one- to two-week old piglets from a specific
pathogen free breeding herd were inoculated under halothane anaesthesia by
simultaneous injections intracerebrally (0.5 ml) intravenously (1 to 2 ml) and
intraperitoneally (8 to 9 ml) with an inoculum consisting of 10% saline
suspension of pooled homogenised brainstem from 4 natural bovine spongiform
encephalopathy cases. Control piglets were similarly inoculated with saline.
After 69 weeks one challenged pig showed mild aggressive behaviour towards the
animal attendants. Intermittent inappetence and depression were also noted.
Within one week the behavioural changes included aimless biting activity and
there was mild symmetrical ataxia. The ataxia progressed and 5 weeks after onset
of signs the gait ataxia was generalised with hypermetria and wide-based stance.
At this time the pig was killed. Histopathological examination of the brain
revealed spongiosis of grey matter neuropil with greatest intensity in the
medial geniculate body, superior colliculus and corpus striatum. There was
sparse vacuolation of neuronal perikarya in the dorsal nucleus of the vagina
nerve and widespread astrocytic reaction. Characteristic fibrils associated with
transmissible spongiform encephalopathies were detected by electron microscopy.
One good question is what _pooled_ medical products do they make from pigs.
The key issues for spread of this disease are the amplification cycle and
distribution pooling. That is, one rotten apple by itself is less of a problem
than if it is in a barrel. – webmaster
IN CONFIDENCE
EXPERIMENTAL PORCINE SPONGIFORM ENCEPHALOPATHY 1. CMO should be aware that
a pig inoculated experimentally (ic, iv, and ip) with BSE brain suspension has
after 15 months developed an illness, now confirmed as a spongiform
encephalopathy. This is the first ever description of such a disease in a pig,
although it seems there ar no previous attempts at experimental inoculation with
animal material. The Southwood group had thought igs would not be susceptible.
Most pigs are slaughtered when a few weeks old but there have been no reports of
relevant neurological illness in breeding sows or other elderly pigs.
...see full text ;
IN CONFIDENCE
So it is plausible pigs could be preclinically affected with BSE but since
so few are allowed to reach adulthood this has not been recognised through
clinical disease. ...
snip...
CONFIDENTIAL EXPERIMENTAL PORCINE SPONGIFORM ENCEPHALOPATHY
PLEASE NOTE, these old BSE Inquiry links take a while to open with the
wayback machine, so be patient. ...tss Title: Experimental Intracerebral and
Oral Inoculation of Scrapie to Swine: Preliminary Report In the United States,
feeding of ruminant by-products to ruminants is prohibited, but feeding of
ruminant materials to swine and poultry still occurs. The potential for swine to
have access to scrapie-contaminated feedstuffs exists, but the potential for
swine to serve as a host for replication/accumulation of the agent of scrapie is
unknown. The purpose of this study was to perform oral and intracerebral
inoculation of the U.S. scrapie agent to determine the potential of swine as a
host for the scrapie agent and their clinical susceptibility. snip... IN
CONFIDENCE EXPERIMENTAL PORCINE SPONGIFORM ENCEPHALOPATHY 1. CMO should be aware
that a pig inoculated experimentally (ic, iv, and ip) with BSE brain suspension
has after 15 months developed an illness, now confirmed as a spongiform
encephalopathy. This is the first ever description of such a disease in a pig,
although it seems there ar no previous attempts at experimental inoculation with
animal material. The Southwood group had thought igs would not be susceptible.
Most pigs are slaughtered when a few weeks old but there have been no reports of
relevant neurological illness in breeding sows or other elderly pigs. ...see
full text ;
we cannot rule out the possibility that unrecognised subclinical spongiform
encephalopathy could be present in British pigs though there is no evidence for
this: only with parenteral/implantable pharmaceuticals/devices is the
theoretical risk to humans of sufficient concern to consider any action.
May I, at the outset, reiterate that we should avoid dissemination of
papers relating to this experimental finding to prevent premature release of the
information. ...
3. It is particularly important that this information is not passed outside
the Department, until Ministers have decided how they wish it to be handled. ...
But it would be easier for us if pharmaceuticals/devices are not directly
mentioned at all. ...
Our records show that while some use is made of porcine materials in
medicinal products, the only products which would appear to be in a
hypothetically ''higher risk'' area are the adrenocorticotrophic hormone for
which the source material comes from outside the United Kingdom, namely America
China Sweden France and Germany. The products are manufactured by Ferring and
Armour. A further product, ''Zenoderm Corium implant'' manufactured by Ethicon,
makes use of porcine skin - which is not considered to be a ''high risk''
tissue, but one of its uses is described in the data sheet as ''in dural
replacement''. This product is sourced from the United Kingdom.....
snip...
It was not until . . . August 1990, that the result from the pig persuaded
both SEAC and us to change our view and to take out of pig rations any residual
infectivity that might have arisen from the SBOs.
4.303 The minutes of the meeting record that: It was very difficult to draw
conclusions from one experimental result for what may happen in the field.
However it would be prudent to exclude specified bovine offals from the pig
diet. Although any relationship between BSE and the finding of a spongiform
encephalopathy in cats had yet to be demonstrated, the fact that this had
occurred suggested that a cautious view should be taken of those species which
might be susceptible. The 'specified offals' of bovines should therefore be
excluded from the feed of all species. 17
http://web.archive.org/web/20031026084516/http://www.bseinquiry.gov.uk/files/yb/1990/09/07001001.pdf
7 OF 10 LITTLE PIGGIES WENT ON TO DEVELOP BSE;
1: J Comp Pathol. 2000 Feb-Apr; 122(2-3): 131-43. Related Articles, Links
Click here to read
The neuropathology of experimental bovine spongiform encephalopathy in the
pig.
Ryder SJ, Hawkins SA, Dawson M, Wells GA. Veterinary Laboratories Agency
Weybridge, Woodham Lane, New Haw, Addlestone, Surrey, KT15 3NB, UK.
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 animals. PMID: 10684682
[PubMed - indexed for MEDLINE]
Transgenic mice expressing porcine prion protein resistant to classical
scrapie but susceptible to sheep bovine spongiform encephalopathy and atypical
scrapie.
Emerg Infect Dis. 2009 Aug; [Epub ahead of print]
Wednesday, July 06, 2011
Swine Are Susceptible to Chronic Wasting Disease by Intracerebral
Inoculation snip... In the US, feeding of ruminant by-products to ruminants is
prohibited, but feeding of ruminant materials to swine, mink and poultry still
occurs. Although unlikely, the potential for swine to have access to
TSE-contaminated feedstuffs exists.
snip...
Wednesday, July 06, 2011
Swine Are Susceptible to Chronic Wasting Disease by Intracerebral
Inoculation (see tonnage of mad cow feed in commerce USA...tss)
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.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?holding=npg&cmd=Retrieve&db=PubMed&list_uids=10684682&dopt=Abstract
Title: Experimental Intracerebral and Oral Inoculation of Scrapie to Swine:
Preliminary Report
In the United States, feeding of ruminant by-products to ruminants is
prohibited, but feeding of ruminant materials to swine and poultry still occurs.
The potential for swine to have access to scrapie-contaminated feedstuffs
exists, but the potential for swine to serve as a host for
replication/accumulation of the agent of scrapie is unknown. The purpose of this
study was to perform oral and intracerebral inoculation of the U.S. scrapie
agent to determine the potential of swine as a host for the scrapie agent and
their clinical susceptibility. snip... snip... In the United States, feeding of
ruminant by-products to ruminants is prohibited, but feeding of ruminant
materials to swine and poultry still occurs. The potential for swine to have
access to scrapie-contaminated feedstuffs exists, but the potential for swine to
serve as a host for replication/accumulation of the agent of scrapie is unknown.
The purpose of this study was to perform oral and intracerebral inoculation of
the U.S. scrapie agent to determine the potential of swine as a host for the
scrapie agent and their clinical susceptibility.
see full text and more transmission studies here ;
snip... see full text ;
Thursday, November 10, 2011
National Meat Association v. Harris Docket No., 10-224 DEADSTOCK DOWNER
PIGS AND PORCINE SPONGIFORM ENCEPHALOPATHY PSE Court Likely to Overturn Calif.
Law on Livestock
Friday, April 20, 2012
Ultrastructural findings in pigs experimentally infected with bovine
spongiform encephalopathy agent
Wednesday, July 29, 2015
Porcine Prion Protein Amyloid or mad pig disease PSE
Monday, August 10, 2015
Detection and Quantification of beta-Amyloid, Pyroglutamyl A beta, and Tau
in Aged Canines
http://caninespongiformencephalopathy.blogspot.com/2015/08/detection-and-quantification-of-beta.html
Friday, August 7, 2015
Transgenic Mouse Bioassay: Evidence That Rabbits Are Susceptible to a
Variety of Prion Isolates
PRION 2015 CONFERENCE FT. COLLINS CWD RISK FACTORS TO HUMANS
*** LATE-BREAKING ABSTRACTS PRION 2015 CONFERENCE ***
O18
Zoonotic Potential of CWD Prions
Liuting Qing1, Ignazio Cali1,2, Jue Yuan1, Shenghai Huang3, Diane Kofskey1,
Pierluigi Gambetti1, Wenquan Zou1, Qingzhong Kong1 1Case Western Reserve
University, Cleveland, Ohio, USA, 2Second University of Naples, Naples, Italy,
3Encore Health Resources, Houston, Texas, USA
***These results indicate that the CWD prion has the potential to infect
human CNS and peripheral lymphoid tissues and that there might be asymptomatic
human carriers of CWD infection.***
P.105: RT-QuIC models trans-species prion transmission
Kristen Davenport, Davin Henderson, Candace Mathiason, and Edward Hoover
Prion Research Center; Colorado State University; Fort Collins, CO USA
Additionally, human rPrP was competent for conversion by CWD and fCWD.
***This insinuates that, at the level of protein:protein interactions, the
barrier preventing transmission of CWD to humans is less robust than previously
estimated.***
From: Terry S. Singeltary Sr.
Sent: Saturday, November 15, 2014 9:29 PM
To: Terry S. Singeltary Sr.
Subject: THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE R. G. WILL 1984
THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE
R. G. WILL
1984
*** The association between venison eating and risk of CJD shows similar
pattern, with regular venison eating associated with a 9 FOLD INCREASE IN RISK
OF CJD (p = 0.04). (SEE LINK IN REPORT HERE...TSS) PLUS, THE CDC DID NOT PUT
THIS WARNING OUT FOR THE WELL BEING OF THE DEER AND ELK ;
snip...
*** These results would seem to suggest that CWD does indeed have zoonotic
potential, at least as judged by the compatibility of CWD prions and their human
PrPC target. Furthermore, extrapolation from this simple in vitro assay suggests
that if zoonotic CWD occurred, it would most likely effect those of the PRNP
codon 129-MM genotype and that the PrPres type would be similar to that found in
the most common subtype of sCJD (MM1).***
*** The potential impact of prion diseases on human health was greatly
magnified by the recognition that interspecies transfer of BSE to humans by beef
ingestion resulted in vCJD. While changes in animal feed constituents and
slaughter practices appear to have curtailed vCJD, there is concern that CWD of
free-ranging deer and elk in the U.S. might also cross the species barrier.
Thus, consuming venison could be a source of human prion disease. Whether BSE
and CWD represent interspecies scrapie transfer or are newly arisen prion
diseases is unknown. Therefore, the possibility of transmission of prion disease
through other food animals cannot be ruled out. There is evidence that vCJD can
be transmitted through blood transfusion. There is likely a pool of unknown size
of asymptomatic individuals infected with vCJD, and there may be asymptomatic
individuals infected with the CWD equivalent. These circumstances represent a
potential threat to blood, blood products, and plasma supplies.
O.05: Transmission of prions to primates after extended silent incubation
periods: Implications for BSE and scrapie risk assessment in human populations
Emmanuel Comoy, Jacqueline Mikol, Val erie Durand, Sophie Luccantoni,
Evelyne Correia, Nathalie Lescoutra, Capucine Dehen, and Jean-Philippe Deslys
Atomic Energy Commission; Fontenay-aux-Roses, France
Prion diseases (PD) are the unique neurodegenerative proteinopathies
reputed to be transmissible under field conditions since decades. The
transmission of Bovine Spongiform Encephalopathy (BSE) to humans evidenced that
an animal PD might be zoonotic under appropriate conditions. Contrarily, in the
absence of obvious (epidemiological or experimental) elements supporting a
transmission or genetic predispositions, PD, like the other proteinopathies, are
reputed to occur spontaneously (atpical animal prion strains, sporadic CJD
summing 80% of human prion cases). Non-human primate models provided the first
evidences supporting the transmissibiity of human prion strains and the zoonotic
potential of BSE. Among them, cynomolgus macaques brought major information for
BSE risk assessment for human health (Chen, 2014), according to their
phylogenetic proximity to humans and extended lifetime. We used this model to
assess the zoonotic potential of other animal PD from bovine, ovine and cervid
origins even after very long silent incubation periods. *** We recently observed
the direct transmission of a natural classical scrapie isolate to macaque after
a 10-year silent incubation period, ***with features similar to some reported
for human cases of sporadic CJD, albeit requiring fourfold longe incubation than
BSE. Scrapie, as recently evoked in humanized mice (Cassard, 2014), ***is the
third potentially zoonotic PD (with BSE and L-type BSE), ***thus questioning the
origin of human sporadic cases. We will present an updated panorama of our
different transmission studies and discuss the implications of such extended
incubation periods on risk assessment of animal PD for human health.
===============
***thus questioning the origin of human sporadic cases...TSS
===============
Research Project: TRANSMISSION, DIFFERENTIATION, AND PATHOBIOLOGY OF
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
Title: Transmission of scrapie prions to primate after an extended silent
incubation period
Authors
item Comoy, Emmanuel - item Mikol, Jacqueline - item Luccantoni-Freire,
Sophie - item Correia, Evelyne - item Lescoutra-Etchegaray, Nathalie - item
Durand, Valérie - item Dehen, Capucine - item Andreoletti, Olivier - item
Casalone, Cristina - item Richt, Juergen item Greenlee, Justin item Baron,
Thierry - item Benestad, Sylvie - item Hills, Bob - item Brown, Paul - item
Deslys, Jean-Philippe -
Submitted to: Scientific Reports Publication Type: Peer Reviewed Journal
Publication Acceptance Date: May 28, 2015 Publication Date: June 30, 2015
Citation: Comoy, E.E., Mikol, J., Luccantoni-Freire, S., Correia, E.,
Lescoutra-Etchegaray, N., Durand, V., Dehen, C., Andreoletti, O., Casalone, C.,
Richt, J.A., Greenlee, J.J., Baron, T., Benestad, S., Brown, P., Deslys, J.
2015. Transmission of scrapie prions to primate after an extended silent
incubation period. Scientific Reports. 5:11573.
Interpretive Summary:
The transmissible spongiform encephalopathies (also called prion diseases)
are fatal neurodegenerative diseases that affect animals and humans. The agent
of prion diseases is a misfolded form of the prion protein that is resistant to
breakdown by the host cells. Since all mammals express prion protein on the
surface of various cells such as neurons, all mammals are, in theory, capable of
replicating prion diseases. One example of a prion disease, bovine spongiform
encephalopathy (BSE; also called mad cow disease), has been shown to infect
cattle, sheep, exotic undulates, cats, non-human primates, and humans when the
new host is exposed to feeds or foods contaminated with the disease agent. The
purpose of this study was to test whether non-human primates (cynomologous
macaque) are susceptible to the agent of sheep scrapie. After an incubation
period of approximately 10 years a macaque developed progressive clinical signs
suggestive of neurologic disease. Upon postmortem examination and microscopic
examination of tissues, there was a widespread distribution of lesions
consistent with a transmissible spongiform encephalopathy. This information will
have a scientific impact since it is the first study that demonstrates the
transmission of scrapie to a non-human primate with a close genetic relationship
to humans. This information is especially useful to regulatory officials and
those involved with risk assessment of the potential transmission of animal
prion diseases to humans.
Technical Abstract:
Classical bovine spongiform encephalopathy (c-BSE) is an animal prion
disease that also causes variant Creutzfeldt-Jakob disease in humans. Over the
past decades, c-BSE's zoonotic potential has been the driving force in
establishing extensive protective measures for animal and human health. In
complement to the recent demonstration that humanized mice are susceptible to
scrapie, we report here the first observation of direct transmission of a
natural classical scrapie isolate to a macaque after a 10-year incubation
period. Neuropathologic examination revealed all of the features of a prion
disease: spongiform change, neuronal loss, and accumulation of PrPres throughout
the CNS.
***This observation strengthens the questioning of the harmlessness of
scrapie to humans, at a time when protective measures for human and animal
health are being dismantled and reduced as c-BSE is considered controlled and
being eradicated. Our results underscore the importance of precautionary and
protective measures and the necessity for long-term experimental transmission
studies to assess the zoonotic potential of other animal prion strains.
O35
J. Mikol1, S. Luccantoni-Freire1, E. Correia1, N. Lescoutra-Etchegaray1, V.
Durand1, C. Dehen1, J.P. Deslys1, E. Comoy1
1Institute of Emerging Diseases and Innovative Therapies, Service of Prion
Diseases, Atomic Energy Commission, 18 Route du Panorama 92265 Fontenayaux-
Roses, France
E-mail: jacqueline.mikol@wanadoo.fr
Uncommon prion disease induced in macaque ten years after scrapie
inoculation
Introduction: Bovine Spongiform Encephalopathy (BSE) is the single animal
prion disease reputed to be zoonotic, inducing variant of Creutzfeldt-Jakob
Disease (vCJD) in man, and therefore strongly conditioned the protective
measures. Among different sources of animal prion diseases, we show here that
after more than ten years of incubation, intracerebral injection of a sheep
scrapie isolate can induce a prion disease in cynomolgus macaque, a relevant
model of human situation towards several prion strains. Neuropathological
studies showed classical and uncommon data.
Material and method: The cynomolgus macaque was intracerebrally exposed to
a classical scrapie isolate issued from a naturally infected sheep flock. Upon
onset of clinical signs, euthanasia was performed for ethical reasons. Classical
methods of biochemistry and neuropathology were used.
Results: The three elements of the triad were present:
spongiosis was predominant in the cortex, the striatum, the cerebellum.
Neuronal loss and gliosis were moderate.
The notable data were the following
(i) the brain was small, the atrophy involved mostly the temporal lobe in
which axonal loss was histologically demonstrated
(ii) the spongiosis of the Purkinje cells was so intense that most of them
were destroyed
(iii) there was a neuronal loss and a massive gliosis of the dorsomedialis
nucleus of the thalamus
(iv) iron deposits were present in the lenticular nucleus. PrPres heavily
distributed in the cortex, the basal ganglia and the cerebellum consisted in
synaptic deposits and aggregates. Western Blot exhibited a type 1 PrPres in all
parts of the brain.
Conclusion: We described here the successful transmission of a scrapie
prion disease to a non-human primate after an extended incubation period,
leading to a fatal, non-relapsing neurological disease with all the features of
a prion disease. The cerebral lesional profile we observed was original in
comparison to other animal prion diseases (c-BSE, L-type BSE, TME) we previously
experimentally transmitted in this model.
Tuesday, December 16, 2014
Evidence for zoonotic potential of ovine scrapie prions
Hervé Cassard,1, n1 Juan-Maria Torres,2, n1 Caroline Lacroux,1, Jean-Yves
Douet,1, Sylvie L. Benestad,3, Frédéric Lantier,4, Séverine Lugan,1, Isabelle
Lantier,4, Pierrette Costes,1, Naima Aron,1, Fabienne Reine,5, Laetitia
Herzog,5, Juan-Carlos Espinosa,2, Vincent Beringue5, & Olivier Andréoletti1,
Affiliations Contributions Corresponding author Journal name: Nature
Communications Volume: 5, Article number: 5821 DOI: doi:10.1038/ncomms6821
Received 07 August 2014 Accepted 10 November 2014 Published 16 December 2014
Article tools Citation Reprints Rights & permissions Article metrics
Abstract
Although Bovine Spongiform Encephalopathy (BSE) is the cause of variant
Creutzfeldt Jakob disease (vCJD) in humans, the zoonotic potential of scrapie
prions remains unknown. Mice genetically engineered to overexpress the human
prion protein (tgHu) have emerged as highly relevant models for gauging the
capacity of prions to transmit to humans. These models can propagate human
prions without any apparent transmission barrier and have been used used to
confirm the zoonotic ability of BSE. Here we show that a panel of sheep scrapie
prions transmit to several tgHu mice models with an efficiency comparable to
that of cattle BSE. The serial transmission of different scrapie isolates in
these mice led to the propagation of prions that are phenotypically identical to
those causing sporadic CJD (sCJD) in humans. These results demonstrate that
scrapie prions have a zoonotic potential and raise new questions about the
possible link between animal and human prions.
Subject terms: Biological sciences• Medical research At a glance
why do we not want to do TSE transmission studies on chimpanzees $
5. A positive result from a chimpanzee challenged severly would likely
create alarm in some circles even if the result could not be interpreted for
man. I have a view that all these agents could be transmitted provided a large
enough dose by appropriate routes was given and the animals kept long enough.
Until the mechanisms of the species barrier are more clearly understood it might
be best to retain that hypothesis.
snip...
R. BRADLEY
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.
snip...
The successful transmission of kuru, Creutzfeldt-Jakob disease, and scrapie
by natural feeding to squirrel monkeys that we have reported provides further
grounds for concern that scrapie-infected meat may occasionally give rise in
humans to Creutzfeldt-Jakob disease.
PMID: 6997404
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
Recently the question has again been brought up as to whether scrapie is
transmissible to man. This has followed reports that the disease has been
transmitted to primates. One particularly lurid speculation (Gajdusek 1977)
conjectures that the agents of scrapie, kuru, Creutzfeldt-Jakob disease and
transmissible encephalopathy of mink are varieties of a single "virus". The U.S.
Department of Agriculture concluded that it could "no longer justify or permit
scrapie-blood line and scrapie-exposed sheep and goats to be processed for human
or animal food at slaughter or rendering plants" (ARC 84/77)" The problem is
emphasized by the finding that some strains of scrapie produce lesions identical
to the once which characterize the human dementias"
Whether true or not. the hypothesis that these agents might be
transmissible to man raises two considerations. First, the safety of laboratory
personnel requires prompt attention. Second, action such as the "scorched meat"
policy of USDA makes the solution of the scrapie problem urgent if the sheep
industry is not to suffer grievously.
snip...
76/10.12/4.6
Nature. 1972 Mar 10;236(5341):73-4.
Transmission of scrapie to the cynomolgus monkey (Macaca fascicularis).
Gibbs CJ Jr, Gajdusek DC.
Nature 236, 73 - 74 (10 March 1972); doi:10.1038/236073a0
Transmission of Scrapie to the Cynomolgus Monkey (Macaca fascicularis)
C. J. GIBBS jun. & D. C. GAJDUSEK
National Institute of Neurological Diseases and Stroke, National Institutes
of Health, Bethesda, Maryland
SCRAPIE has been transmitted to the cynomolgus, or crab-eating, monkey
(Macaca fascicularis) with an incubation period of more than 5 yr from the time
of intracerebral inoculation of scrapie-infected mouse brain. The animal
developed a chronic central nervous system degeneration, with ataxia, tremor and
myoclonus with associated severe scrapie-like pathology of intensive astroglial
hypertrophy and proliferation, neuronal vacuolation and status spongiosus of
grey matter. The strain of scrapie virus used was the eighth passage in Swiss
mice (NIH) of a Compton strain of scrapie obtained as ninth intracerebral
passage of the agent in goat brain, from Dr R. L. Chandler (ARC, Compton,
Berkshire).
Friday, January 30, 2015
*** Scrapie: a particularly persistent pathogen ***
Thursday, March 26, 2015
Increased Infectivity of Anchorless Mouse Scrapie Prions in Transgenic Mice
Overexpressing Human Prion Protein
Increased susceptibility of human-PrP transgenic mice to bovine spongiform
encephalopathy following passage in sheep
J. Virol. doi:10.1128/JVI.01578-10 Copyright (c) 2010, American Society for
Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.
Increased susceptibility of human-PrP transgenic mice to bovine spongiform
encephalopathy following passage in sheep.
Chris Plinston, Patricia Hart, Angela Chong, Nora Hunter, James Foster,
Pedro Piccardo, Jean C. Manson, and Rona M Barron* Neuropathogenesis Division,
The Roslin Institute and R(D)SVS, University of Edinburgh, Roslin, Midlothian,
UK; Laboratory of Bacterial and TSE Agents, Food and Drug Administration,
Rockville, MD, USA
* To whom correspondence should be addressed. Email:
rona.barron@roslin.ed.ac.uk .
Abstract
The risk of transmission of ruminant transmissible spongiform
encephalopathy (TSE) to humans was thought to be low due to the lack of
association between sheep scrapie and incidence of human TSE. However a single
TSE agent strain has been shown to cause both bovine spongiform encephalopathy
(BSE) and human vCJD, indicating that some ruminant TSEs may be transmissible to
humans. While the transmission of cattle BSE to humans in transgenic mouse
models has been inefficient, indicating the presence of a significant
transmission barrier between cattle and humans, BSE has been transmitted to a
number of other species. Here we aimed to further investigate the human
transmission barrier following passage of BSE in a sheep. Following inoculation
with cattle BSE, gene targeted transgenic mice expressing human PrP showed no
clinical or pathological signs of TSE disease. However following inoculation
with an isolate of BSE that had been passaged through a sheep, TSE associated
vacuolation and proteinase-K resistant PrP deposition were observed in mice
homozygous for the codon 129-methionine PRNP gene. This observation may be due
to higher titres of the BSE agent in sheep, or an increased susceptibility of
humans to BSE prions following passage through a sheep. ***However these data
confirm that, contrary to previous predictions, it is possible that a sheep
prion may be transmissible to humans and that BSE from other species may be a
public health risk.
BSE: TIME TO TAKE H.B. PARRY SERIOUSLY
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. ...
Tuesday, August 4, 2015
FDA U.S. Measures to Protect Against BSE
Thursday, August 20, 2015 Doctor William J. Hadlow RIP
William J. Hadlow Dr. Hadlow (Ohio State ’48), 94, Hamilton, Montana, died
June 20, 2015.
Friday, August 21, 2015
Porcine prion protein amyloid or mad pig disease PSE Porcine Spongiform
Encephalopathy ?
Sunday, October 18, 2015
World Organisation for Animal Health (OIE) and the Institut Pasteur
Cooperating on animal disease and zoonosis research
Thursday, December 17, 2015
Annual report of the Scientific Network on BSE-TSE 2015 EFSA-Q-2015-00738
10 December 2015
Saturday, December 12, 2015
*** BOVINE SPONGIFORM ENCEPHALOPATHY BSE TSE PRION REPORT DECEMBER 14, 2015
Friday, January 1, 2016
South Korea Lifts Ban on Beef, Veal Imports From Canada
US CONGRESS, another failed entity...tss
Tuesday, December 29, 2015
*** Congress repeals country-of-origin labeling rule for beef and pork
December 28, 2015 at 2:21am
*** Australian government assessing risk of importing beef from US, Japan
and the Netherlands
Thursday, December 24, 2015
Infectious disease spread is fueled by international trade
*** you can find some history of the BSE cases in Canada and Klein’s BSE
SSS policy comment here ;
Monday, January 4, 2016
Long live the OIE, or time to close the doors on a failed entity?
http://transmissiblespongiformencephalopathy.blogspot.com/2016/01/long-live-oie-or-time-to-close-doors-on.html
Tuesday, December 29, 2015
TEXAS MONTHLY CHRONIC WASTING DISEASE CWD JANUARY 2016 DEER BREEDERS STILL
DON'T GET IT $
Chronic Wasting Unease
The emergence of a deadly disease has wildlife officials and deer breeders
eyeing each other suspiciously.
Saturday, December 12, 2015
CHRONIC WASTING DISEASE CWD TSE PRION REPORT DECEMBER 14, 2015
Wednesday, January 06, 2016
CREUTZFELDT JAKOB DISEASE SURVEILLANCE IN THE U.K. 23rd ANNUAL REPORT 2014
(published 18th November 2015)
Saturday, December 12, 2015
CREUTZFELDT JAKOB DISEASE CJD TSE PRION REPORT DECEMBER 14, 2015
MOM
Thursday, December 24, 2015
Revisiting the Heidenhain Variant of Creutzfeldt-Jakob Disease: Evidence
for Prion Type Variability Influencing Clinical Course and Laboratory Findings
Article type: Research Article
Evidence for human transmission of amyloid-β pathology and cerebral amyloid
angiopathy
07 02:27 AM
Terry S. Singeltary Sr. said:
re-Evidence for human transmission of amyloid-? pathology and cerebral
amyloid angiopathy
Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26
April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated
online 11 September 2015 Erratum (October, 2015)
*** I would kindly like to comment on the Nature Paper, the Lancet reply,
and the newspaper articles.
snip...see full text ;
Subject: 1992 IN CONFIDENCE TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO
PRIMATES POSSIBILITY ON A TRANSMISSIBLE PRION REMAINS OPEN
BSE101/1 0136
IN CONFIDENCE
CMO
From: . Dr J S Metiers DCMO
4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have
recognised the public sensitivity of these findings and intend to report them in
their proper context. 'This hopefully will avoid misunderstanding and possible
distortion by the media to portray the results as having more greater
significance than the findings so far justify.
2. Using a highly unusual route of transmission (intra-cerebral injection)
the researchers have demonstrated the transmission of a pathological process
from two cases one of severe Alzheimer's disease the other of
Gerstmann-Straussler disease to marmosets. However they have not demonstrated
the transmission of either clinical condition as the "animals were behaving
normally when killed". As the report emphasises the unanswered question is
whether the disease condition would have revealed itself if the marmosets had
lived longer. They are planning further research to see if the conditions, as
opposed to the partial pathological process, is transmissible.
what are the implications for public health?
3. The route 'of transmission is very specific and in the natural state of
things highly unusual. However it could be argued that the results reveal a
potential risk, in that brain tissue from these two patients has been shown to
transmit a pathological process. Should therefore brain tissue from such cases
be regarded as potentially infective? Pathologists, morticians, neuro surgeons
and those assisting at neuro surgical procedures and others coming into contact
with "raw" human brain tissue could in theory be at risk. However, on a priori
grounds given the highly specific route of transmission in these experiments
that risk must be negligible if the usual precautions for handling brain tissue
are observed.
1
92/11.4/1.1
BSE101/1 0137
4. The other dimension to consider is the public reaction. To some extent
the GSS case demonstrates little more than the transmission of BSE to a pig by
intra-cerebral injection. If other prion diseases can be transmitted in this way
it is little surprise that some pathological findings observed in GSS were also
transmissible to a marmoset. But the transmission of features of Alzheimer's
pathology is a different matter, given the much greater frequency of this
disease and raises the unanswered question whether some cases are the result of
a transmissible prion. The only tenable public line will be that "more research
is required’’ before that hypothesis could be evaluated. The possibility on a
transmissible prion remains open. In the meantime MRC needs carefully to
consider the range and sequence of studies needed to follow through from the
preliminary observations in these two cases. Not a particularly comfortable
message, but until we know more about the causation of Alzheimer's disease the
total reassurance is not practical.
J S METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH
832 llllYc!eS 2 92/11.4/1.2
>>> The only tenable public line will be that "more research is
required’’ <<<
>>> possibility on a transmissible prion remains open<<<
O.K., so it’s about 23 years later, so somebody please tell me, when is
"more research is required’’ enough time for evaluation ?
Self-Propagative Replication of Ab Oligomers Suggests Potential
Transmissibility in Alzheimer Disease
Received July 24, 2014; Accepted September 16, 2014; Published November 3,
2014
*** Singeltary comment PLoS ***
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion
disease, Iatrogenic, what if ?
Posted by flounder on 05 Nov 2014 at 21:27 GMT
Terry S. Singeltary Sr.
