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Dr. Stanley Prusiner Changes His Story!

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Kathy

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In searching out new patents, and patent applications, I have found out that the Nobel Prize winner Stanley Prusiner, the inventor/discoverer? of the PRION, has changed his story.

In an older patent, he states:

Patent #6,166,187 US Patent and Trademark Office, dated December 26, 2000

“Prions are infectious pathogens that cause central nervous system spongiform encephalopathies in humans and animals. Prions are distinct from bacteria, viruses and viroids. The predominant hypothesis at present is that no nucleic acid component is necessary for infectivity of prion protein. Further, a prion which infects one species of animal (e.g., a human) will not readily infect another (e.g., a mouse).”


In Prusiner’s most recent patent #6,916,419, dated July 12, 2005, he clarifies and changes his hypothesis:

“Prions are infectious pathogens that cause central nervous system spongiform encephalopathies in humans and animals. Prions are distinct from bacteria, viruses and viroids. The predominant hypothesis at present is that no nucleic acid component is necessary for infectivity of prion protein. Further, a prion which infects one species of animal (e.g., a human) will not infect another (e.g., a mouse).”

What’s that Doc?

“A prion which infects one species of animal (e.g., a human) will not infect another (e.g., a mouse).”

This means, according to Stanley Prusiner’s latest research, on which he based this new patent - “Device for removal of prions from blood, plasma and other liquids.”),

BSE does not (and cannot) cause vCJD.
 

flounder

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>>> This means, according to Stanley Prusiner’s latest research, on which he based this new patent - “Device for removal of prions from blood, plasma and other liquids.”),

BSE does not (and cannot) cause vCJD.<<<


cathy, can you please reference where stanley prusiner states

''BSE does not (and cannot) cause vCJD'' ???


thanks, terry
 

Mike

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I think what he is saying here is that a mutation must take place before it will
infect another species. Not much of a Revelation here.

Not much difference between "not readily" and "will not".
 

Tam

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BSE does not (and cannot) cause vCJD.
:D :D

Not much difference between "not readily" and "will not".

"Will not" in my book is it won't happen "Not readily" means it could happen. Thats a big different when it comes to a genuine risk of death there Mike.
 

flounder

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Published online before print March 20, 2001, 10.1073/pnas.041490898


Neurobiology
Adaptation of the bovine spongiform encephalopathy agent to primates and comparison with Creutzfeldt- Jakob disease: Implications for human health
Corinne Ida Lasmézas*,, Jean-Guy Fournier*, Virginie Nouvel*, Hermann Boe*, Domíníque Marcé*, François Lamoury*, Nicolas Kopp, Jean-Jacques Hauw§, James Ironside¶, Moira Bruce, Dominique Dormont*, and Jean-Philippe Deslys*
* Commissariat à l'Energie Atomique, Service de Neurovirologie, Direction des Sciences du Vivant/Département de Recherche Medicale, Centre de Recherches du Service de Santé des Armées 60-68, Avenue du Général Leclerc, BP 6, 92 265 Fontenay-aux-Roses Cedex, France; Hôpital Neurologique Pierre Wertheimer, 59, Boulevard Pinel, 69003 Lyon, France; § Laboratoire de Neuropathologie, Hôpital de la Salpêtrière, 83, Boulevard de l'Hôpital, 75013 Paris, France; ¶ Creutzfeldt-Jakob Disease Surveillance Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, United Kingdom; and Institute for Animal Health, Neuropathogenesis Unit, West Mains Road, Edinburgh EH9 3JF, United Kingdom

Edited by D. Carleton Gajdusek, Centre National de la Recherche Scientifique, Gif-sur-Yvette, France, and approved December 7, 2000 (received for review October 16, 2000)


Abstract

There is substantial scientific evidence to support the notion that bovine spongiform encephalopathy (BSE) has contaminated human beings, causing variant Creutzfeldt-Jakob disease (vCJD). This disease has raised concerns about the possibility of an iatrogenic secondary transmission to humans, because the biological properties of the primate-adapted BSE agent are unknown. We show that (i) BSE can be transmitted from primate to primate by intravenous route in 25 months, and (ii) an iatrogenic transmission of vCJD to humans could be readily recognized pathologically, whether it occurs by the central or peripheral route. Strain typing in mice demonstrates that the BSE agent adapts to macaques in the same way as it does to humans and confirms that the BSE agent is responsible for vCJD not only in the United Kingdom but also in France. The agent responsible for French iatrogenic growth hormone-linked CJD taken as a control is very different from vCJD but is similar to that found in one case of sporadic CJD and one sheep scrapie isolate. These data will be key in identifying the origin of human cases of prion disease, including accidental vCJD transmission, and could provide bases for vCJD risk assessment.



snip...





Lesion Profiles in C57BL/6 Mice of sCJD, iCJD, and Natural Scrapie. Both French natural scrapie and the U.S. scrapie strain C506 M3 produced lesion profiles that were clearly distinct from that of BSE (Fig. 2e). Also, sCJD was readily distinguishable from vCJD (Fig. 2f). However, the lesion profiles of iCJD and sCJD had a similar shape despite a slight difference in intensity (Fig. 2g), and the latter shape was also identical to that of the French natural scrapie strain (Fig. 2h).

PrPres Analyses. We were ideally placed to perform biochemical strain typing because we could analyze the PrPres induced by the different agents in syngeneic C57BL/6 mice carrying a single PrP sequence. We clearly distinguished two types of PrPres: that of cattle/macaque BSE and vCJD (corresponding to a type 2 or 4 depending on the classification used; refs. 5 and 14) and that of scrapie, sCJD, and iCJD, which had a higher molecular weight most clearly seen in the un- and monoglycosylated bands (type 1 PrPres, Fig. 3, lanes 4 and 5 versus lanes 2, 3, and 6).





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Fig. 3. Electrophoretic analysis of PrPres of vCJD, BSE, sCJD, iCJD, and scrapie transmitted to C57BL/6 mice. Western blot detection of PrPres purified from the brains of C57BL/6 mice at the terminal stage of the disease (except for the control) after inoculation of normal mouse brain homogenate (lane 1); French case of iCJD linked to the administration of growth hormone (lane 2); French case of sCJD (lane 3); first of the three French vCJD cases (lane 4); cattle-BSE (lane 5); and natural sheep scrapie (French Romanov flock) (lane 6). The mouse brain equivalent loads were 0.6 mg (lanes 4 and 6), 1.2 mg (lanes 3 and 5), and 12 mg (lanes 1 and 2).




Transmissions of vCJD and BSE to Nonhuman Primates. Secondary transmission of BSE to macaques by the i.c. route led to a shortening of the incubation period to half that of the primary passage (18 versus 36 months, Fig. 1). The vCJD-inoculated primates died 25 and 30 months after inoculation, as compared to the 20 and 21 months observed with macaque BSE at the same inoculation concentration. Macaque-adapted kuru transmitted after 24 months.

Titration by homologous i.c. inoculation of a limited number of macaques revealed the presence of >105.4 infectious units/g of BSE-infected macaque brain. BSE-infected macaque brain (40 mg) was also injected i.v. into another macaque, which died of the disease after 25 months.


The duration of the clinical phase was as follows: 1-3.5 months for BSE (i.c.), 4 months (i.v.); 5.5 months for vCJD (i.c.); and 3.5 months for kuru (i.c.). For vCJD and BSE, clinical signs were similar to the first passage of BSE (2); the disease began with behavioral signs (with variable relative intensity depending on the animals: depression, nervousness, teeth grinding, yawning, alterations of the grooming activity, voracious appetite) and evolved rapidly to a truncal ataxia with tremors, incoordination of movements, and imbalance. Later on, the animals became aggressive; the ataxia was extremely severe; and myoclonic jerks were observed. In the monkey inoculated with kuru, cerebellar signs were prominent, and behavioral changes (which were early signs of illness for BSE) appeared later in the course of the disease, apparently as a consequence of wasting.


Phenotype in Nonhuman Primates of vCJD and BSE After Secondary Transmission. The pathology of the second passage of BSE in nonhuman primates was similar to that of vCJD transmitted to macaques and resembled that described for the first passage in macaques (2). Thus, the second passage of BSE in primates is characterized pathologically by severe vacuolation and astrocytosis in the thalamus (Fig. 4 b, c, and f); vacuolation and PrP deposition in the granular and molecular layers of the cerebellum; a patchy distribution of vacuolation in the cortex (mainly cingulate and occipital) accompanied by the presence of dense plaques, some of them harboring a florid morphology (Fig. 4 g, h, and i); and cellular and granular PrP deposition in deep cortical layers, in the basal ganglia and thalamus (Fig. 4 b and c). No difference in pathology was observed between macaques inoculated i.c. and i.v. (Fig. 4 g and h).





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Fig. 4. Immunopathology of BSE, vCJD, and kuru in cynomolgus macaques. All panels show the pattern of PrP deposition with the 3F4 antibody, except f, which depicts glial fibrillary acidic protein immunohistochemistry. (a, b, and c) Thalamus in kuru, BSE, and vCJD, ×20. (d and e) Cerebral cortex in kuru, ×2.5 and ×10. (f) Thalamus in BSE, ×10. (g) Cerebral cortex in BSE (i.v.), ×2.5. (h) Cerebral cortex in BSE (i.c.), ×2.5. (i) Immature florid plaque with a dense core of PrP surrounded by few vacuoles in the cerebral cortex (BSE, i.c.), ×20.




The pattern of PrP deposition and plaque morphology were identical to those observed at first passage of BSE in the animals inoculated as adults. There were many dense plaques with no or few vacuoles, quite obviously representing immature forms of florid plaques. Typical florid plaques were more numerous in the young animal inoculated as a neonate (2). This may be related to the longer duration of the clinical phase in the young animal, which allowed greater pathology development.


In contrast, in kuru there were few vacuoles in the thalamus and cerebellum (notwithstanding the presence of PrP deposition, Fig. 4a); vacuolation was more severe than in BSE and was uniform throughout the cortex (Fig. 4d); and PrP immunohistochemistry revealed mainly punctate deposits in all cortical layers with few plaques (Fig. 4 d and e).



Discussion
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
Conclusions
References

One aim of this study was to determine the risk of secondary transmission to humans of vCJD, which is caused not by a primarily human strain of TSE agent but by the BSE strain having passed the species barrier to humans. This risk is tightly linked to the capacity of the BSE agent to adapt to primates and harbor enhanced virulence (i.e., induce disease after a short incubation period and provoke disease even if highly diluted) and to its pathogenicity after inoculation by the peripheral route. With respect to the latter, there are huge variations between different TSE agent strains and hosts. For example, the BSE agent is pathogenic to pigs after i.c. inoculation but not after oral administration (23). Thus, we wanted to know to what extent the BSE/vCJD agent is pathogenic to humans by the i.c. and i.v. routes. To achieve this, we used the macaque model. To monitor the evolution of the BSE agent in primates, but also to verify the identity of French vCJD, we conducted parallel transmission to C57BL/6 mice, allowing strain-typing. The experimental scheme is depicted in Fig. 1.

Characterization of the BSE Agent in Primates. The identity of the lesion profiles obtained from the brains of the French patient with vCJD, two British patients with vCJD, and nonhuman primates infected with BSE provides experimental demonstration of the fact that the BSE agent strain has been transmitted to humans both in the U.K. and in France. Further, it lends support to the validity of the macaque model as a powerful tool for the study of vCJD. As far as the evolution of the BSE agent in primates is concerned, we observed an interesting phenomenon: at first passage of BSE in macaques and with vCJD, there was a polymorphism of the lesion profile in mice in the hippocampal region, with about half of them harboring much more severe vacuolation than the mice inoculated with cattle BSE. At second passage, the polymorphism tended to disappear, with all mice showing higher vacuolation scores in the hippocampus than cattle BSE mice. This observation suggests the appearance of a variant of the BSE agent at first passage in primates and its clonal selection during second passage in primates. The lesion profiles showed that it was still the BSE agent, but the progressive appearance of a "hippocampal signature" hallmarked the evolution toward a variant by essence more virulent to primates.

Characterization of the CJD and Scrapie Strains. Controls were set up by transmitting one French and one U.S. scrapie isolate from ruminants as well as French sCJD and iCJD cases from humans. None of these revealed a lesion profile or transmission characteristics similar or close to those of BSE or vCJD, respectively, thus extending to the present French scrapie isolate the previous observation that the BSE agent was different from all known natural scrapie strains (4, 24).

The lesion profiles of sCJD and iCJD differed only slightly in severity of the lesions, but not in shape of the profile, revealing the identity of the causative agents. One of us reported the absence of similarity between sCJD (six cases) and U.K. scrapie (eight cases) in transmission characteristics in mice (4). Herein, we made the striking observation that the French natural scrapie strain (but not the U.S. scrapie strain) has the same lesion profile and transmission times in C57BL/6 mice as do the two human TSE strains studied. This strain "affiliation" was confirmed biochemically. There is no epidemiological evidence for a link between sheep scrapie and the occurrence of CJD in humans (25). However, such a link, if it is not a general rule, would be extremely difficult to establish because of the very low incidence of CJD as well as the existence of different isolates in humans and multiple strains in scrapie. Moreover, scrapie is transmissible to nonhuman primates (26). Thus, there is still a possibility that in some instances TSE strains infecting humans do share a common origin with scrapie, as pointed out by our findings.


Transmission of vCJD and BSE to Nonhuman Primates. vCJD transmitted readily to the cynomolgus macaque after 2 years of incubation, which was comparable to the transmission obtained from first-passaged macaque BSE and much shorter than the interspecies transmission of BSE. Starting with 100 mg of BSE-macaque brain material, dilutions up to 4 µg still provoked disease. These data suggest that the BSE agent rapidly adapts to primates accompanied by enhanced virulence.

Examination of macaque brain inoculated with vCJD revealed a similar pathology to that with second-passage BSE. The distribution of vacuolation and gliosis, as well as the pattern of PrP deposition, including the dense, sometimes florid plaques, were similar to the human vCJD and the BSE hallmarks of the first passage (1, 2). These data show that the phenotype of BSE in primates is conserved over two passages. Moreover, they confirm that the BSE agent behaves similarly in humans and macaques, a precious finding that will prove useful in the near future for the design of pathogenesis or therapeutic studies.


Because of the number of macaques examined in this study, we can now reliably state that the pathology, in particular the PrP deposition pattern provoked by BSE, is similar in older and very young animals. However, plaque deposition is greater, and mature florid plaques were more numerous, in the young, which may be correlated with a longer duration of the clinical phase observed in this animal (2). This is important with regard to the fact that vCJD has been diagnosed mainly in teenagers and young adults, which raises the concern that older patients may have been misdiagnosed because of an alternative phenotype of the disease.


One should bear in mind, however, that cynomolgus macaques are all homozygotes for methionine at codon 129 of the PrP gene. Thus, our observations may not be relevant to humans carrying one or both valine alleles; however, all patients with vCJD reported to date have been M/M at this position (27).


Intravenous Transmissions to Nonhuman Primates. Brain pathology was identical in macaques inoculated i.c. and i.v. The i.v. route proved to be very efficient for the transmission of BSE, as shown by the 2-year survival of the animals, which is only 5 months longer than that obtained after inoculating the same amount of agent i.c. As the i.v. injection of the infectious agent implies per se a delayed neuroinvasion compared with a direct inoculation in the brain, this slight lengthening of the incubation period cannot, at this stage, be interpreted as a lower efficiency of infection as regards the i.c. route.

These data should be taken into account in the risk assessment of iatrogenic vCJD transmission by i.v. administration of biological products of human origin. They also constitute an incentive for a complete i.v. titration.



Conclusions
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
Conclusions
References

From BSE and vCJD transmissions in nonhuman primates, a number of conclusions can be drawn that are of major importance for human health: (i) human-adapted BSE appears to be a variant of the BSE agent that is more virulent for humans than cattle BSE and is efficiently transmitted by the peripheral route; (ii) the detection of vCJD in unusually young patients is probably not because of a lack of diagnosis of cases in older patients, thus raising the question of the source of human contamination with BSE early in life; and (iii) iatrogenic transmissions from patients with vCJD would be readily recognized by using the same diagnostic criteria as those applied to vCJD [clinical and pathological criteria (27) comprising neuronal loss and gliosis in the thalamus correlated with high MRI signal (28, 29)], whether such contaminations had occurred by the central or i.v. route. Primary and iatrogenic cases of vCJD could be distinguished on the basis of the patient's clinical history.

The risk assessment of biological products of human origin, notably those derived from blood, has been deeply modified by the appearance of vCJD. We confirm that the BSE agent has contaminated humans not only in the U.K. and the Republic of Ireland but also in France, and we show that its pathogenic properties for primates are being enhanced by a primary passage in humans. Considering the flow of potentially contaminated bovine-derived products between 1980 and 1996, it is obvious that further vCJD cases may occur outside the U.K. Thus, and in the light of the present study, it is necessary to sustain worldwide CJD surveillance regardless of national BSE incidence and to take all precautionary measures to avoid iatrogenic transmissions from vCJD.


Acknowledgements




snip...



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



For personal use. Only reproduce with permission from Elsevier Ltd
Research Letters

Published online
January 27, 2005

Risk of oral infection with bovine spongiform
encephalopathy agent in primates

Corinne Ida Lasmézas, Emmanuel Comoy, Stephen Hawkins, Christian Herzog,
Franck Mouthon, Timm Konold, Frédéric Auvré, Evelyne Correia,
Nathalie Lescoutra-Etchegaray, Nicole Salès, Gerald Wells, Paul Brown,
Jean-Philippe Deslys


The uncertain extent of human exposure to bovine spongiform
encephalopathy (BSE)which can lead to variant
Creutzfeldt-Jakob disease (vCJD)is compounded by incomplete knowledge
about the efficiency of oral infection
and the magnitude of any bovine-to-human biological barrier to
transmission. We therefore investigated oral
transmission of BSE to non-human primates. We gave two macaques a 5 g
oral dose of brain homogenate from a
BSE-infected cow. One macaque developed vCJD-like neurological disease
60 months after exposure, whereas the
other remained free of disease at 76 months. On the basis of these
findings and data from other studies, we made a
preliminary estimate of the food exposure risk for man, which provides
additional assurance that existing public
health measures can prevent transmission of BSE to man.

Up to 400 000 cows with undiagnosed bovine spongiform
encephalopathy (BSE) infection are estimated to
have been slaughtered for food before brain and spinal
cord were banned from human consumption in 1989.
More restricted exposure to BSE could have continued
through 1995 from consumption of processed meat
products containing mechanically recovered meat
contaminated with central nervous system (CNS) tissue
and spinal ganglia.1 The discovery of BSE in Canada and
the USA, where consumption of brain and other viscera
was allowed until 2003, and of secondary cases of variant
Creutzfeldt-Jakob disease (vCJD) in the UK, possibly
attributable to contaminated blood donated by people
with pre-clinical primary infection, reinforces the need
for an experimental assessment of the risk of oral
exposure to BSE. We therefore investigated oral
transmission of BSE to non-human primates.

We chose cynomolgus macaques for the study because
these old-world monkeys have a digestive physiology
similar to that of human beings, are methionine
homozygous at codon 129 of the PRNP gene, and have a
BSE neuropathology similar to that of vCJD.2,3 We gave
two 4-year-old adult macaques a 5 g oral dose of brain
homogenate from a BSE-affected cow. We tested for
proteinase-resistant prion protein (PrPres) in this
homogenate with a commercial BSE-testing ELISA kit
(Bio-Rad, Marnes-la-Coquette, France). A sample of the
100% homogenate brain paste inoculum that was fed to
the primates was rehomogenised at 20% weight-pervolume
in the kit buffer. Serial dilutions were made with
a pool of 20% weight-per-volume BSE-negative brain
homogenate in the same buffer. Testing was done
according to the manufacturers instructions and results
were confirmed by a western blot test (Bio-Rad) with a
similar process of PrPres dilution. With both methods,
dilutions of up to 1 in 300 provided a positive signal
(figure A).

One macaque developed neurological disease
60 months after exposure and was killed at 63 months
because of recumbency. Histopathological examination
of the brain of this animal showed the typical pathology
of vCJD (figure B) and an accumulation of PrPres
associated with the follicular dendritic cells in tonsils
(figure C), spleen, and intestine. A western blot showed
similar patterns of PrPres in a brain sample from the
macaque and the BSE-infected bovine inoculum
(figure D). The other macaque remained free of clinical
signs 76 months after exposure, and a tonsil biopsy done
at 72 months was negative (figure E).

In a previous study, two macaques orally dosed with
5 g of brain from a macaque with terminal clinical BSE
became ill after 44 and 47 months.4 The results of the
present study suggest that the incubation period for
interspecies transmission of BSE can be considerably
longer than that of intraspecies transmission (60 months
vs 44 and 47 months, representing 36% and 28%
increases, respectively). The interval between the period of
peak exposure to infectious BSE tissue and the hitherto
peak incidence of vCJD is about 1015 years, but
incubation periods of up to 40 years have followed oral
infection with kuru between human beings.5 Therefore,
maximum incubation periods might exceed 50 years in
cases of oral transmission of BSE from cattle to man.

The present data do not provide a definitive minimum
infective dose for transmission of cattle BSE to primates,
but they do give enough information for a preliminary
assessment of the adequacy of existing measures to
protect the human food chain. Results of ongoing
experiments provide a rough estimation of the intraspecies
transmission rates in cattle. The BSE brain
inoculum to which the cattle were exposed had an
infectivity titre of 103·5 mouse infectious (intracerebral
and intraperitoneal) units ID50 per g (ID50 is the dose at
which 50% of animals become infected). Interim results
at 6 years after exposure suggest that the oral ID50 in
cattle may be between 100 mg and 1 g (table 1; S A C
Hawkins, T Konold, G A H Wells, unpublished data).

Since the brain of a cow weighs 500 g and a spinal cord
200 g, CNS tissues from a cow with clinical signs of BSE
could contain enough infective agent to transmit disease
orally to 4901400 cows (70% of 700 g if 1g is needed, or
20% of 700 g if 100 mg is sufficient), or to 70 primates
(50% of 700 g if 5 g represents the oral ID50).

The accuracy of estimates of the oral ID50 for man will
not be improved until completion, several years from
now, of a large dose-response European study (QLK1-
2002-01096) in macaques, in which the minimum dose
is 50 mg. However, because similar inocula were used in
both the cattle and macaque studies,6 a tentative comparison
can be made between the efficiency of oral infection
in cattle and that in primates. On this basis, a factor of
720 could be considered as the range of magnitude of a
bovine-to-primate species barrier for oral BSE infection
(70 primates infected compared with 490 or 1400 cows,
with a similar dose).

Elimination from the human food chain of CNS
tissues from cows with clinical BSE is estimated to have
reduced the risk of human exposure to the disease by
about 90%.7 Risk was further reduced in continental
Europe by systematic screening for the diagnostic
presence of PrPres in the brainstem of all cattle older than
30 months, and in the UK by the total interdiction of
cows older than 30 months. In an oral exposure study to
assess the pathogenesis of BSE in cattle, in which the
same European Union-evaluated test as we used in the
present study was applied to CNS tissues, some
preclinical cases of the disease were diagnosed.8

Using the same test, pooled brainstem from cows with
clinical BSE has yielded a endpoint titre of PrPres
corresponding to a 1-in-300 to 1-in-1000 dilution of
positive brainstem.6,9 If people were to eat CNS tissues
from a cow with preclinical BSE with a concentration of
PrPres just below the test detection limit of 1 in 300, they
would need to ingest at least 1·5 kg to reach the degree
of exposure equivalent to that in the 5 g of brain used for
oral transmission to the macaque in the present study. If
the oral ID50 for man was one log below this dose (ie,
similar to that in cattle, and not accounting for any
species barrier between cattle and man; see table), 150 g
of CNS tissue that tested falsely negative could represent
an infective dose. Because use of cattle brain and spinal
cord for human consumption is prohibited, and in view
of the existing mechanically recovered meat regulations,
a person would be very unlikely to ingest this amount of
cattle CNS tissue.

The minimum sensitivity of screening tests to detect
100% of BSE-infected animals has yet to be ascertained.
However, our results provide reassurance that BSE
screening procedures combined with CNS removal are
effective measures to protect the human food chain.


Published online
January 27, 2005
http://image.thelancet.com/
extras/05let1056web.pdf
Commissariat à lEnergie
Atomique/Direction des
Sciences du Vivant/Départment
de Recherche Médicale,
18 Route du Panorama, 92265
Fontenay-aux-Roses, France
(C I Lasmézas DrMedVet,
E Comoy DrMedVet,
C Herzog DipBiol,
F Mouthon DipBiol, F Auvré,
E Correia,
N Lescoutra-Etchegaray DipBiol,
Prof N Salès PhD, J-P Deslys MD);
Veterinary Laboratories
Agency, New Haw, Addlestone,
UK (S Hawkins MIBiol,
T Konold DrMedVet,
G Wells BVetMed); and 7815
Exeter Road, Bethesda, MD
20814, USA (P Brown PhD)
Correspondence to:
Dr Jean-Philippe Deslys
e-mail: [email protected]
www.thelancet.com Published online January 27, 2005
http://image.thelancet.com/extras/05let1056web.pdf 1

Risk of oral infection with bovine spongiform
encephalopathy agent in primates

Corinne Ida Lasmézas, Emmanuel Comoy, Stephen Hawkins, Christian Herzog,
Franck Mouthon, Timm Konold, Frédéric Auvré, Evelyne Correia,
Nathalie Lescoutra-Etchegaray, Nicole Salès, Gerald Wells, Paul Brown,
Jean-Philippe Deslys

B
C
E
A
Dilution
D
3·215
1·989
0·984
0·302
0·131
0·065
0·052
1/10
1/30
1/100
1/300
1/1000
1/3000
Neg
36 kDa
36 kDa
22 kDa
22 kDa
16 kDa
1 2 3 4
ELISA detection of PrPres (absorbance units)
Figure: PrPres content of brain homogenate and histopathological
assessment of macaque tissues
(A) Results of in-vitro testing for PrPres in BSE-infected inoculum by
ELISA and western blot. Neg=normal bovine
brain material. (B) Typical florid plaque in the occipital cortex of the
macaque that developed disease.
PrPres detected by proteinase K treatment with SAF32 anti PrP monoclonal
antibody (kindly provided by Jacques
Grassi, CEA Saclay). The dense core of PrPres is surrounded by several
vacuoles in a fibrillar proteinaceous corona;
bar=10 m. (C) Positive PrPres staining in tonsil (80% of follicules
stained positive) of the macaque that developed
disease; bar=50 m. (E) Negative PrPres staining in tonsil of the
macaque that did not develop disease; bar=50 m.
(D) Western blot showing similar PrPres patterns in samples from a
patient with vCJD (lane 1), the macaque that
developed disease (lane 3), and the bovine BSE inoculum (lane 4). By
contrast, a macaque inoculated intracerebrally
with material from a patient with sporadic CJD showed a different PrPres
pattern (lane 2).
For personal use. Only reproduce with permission from Elsevier Ltd
Research Letters

Contributors
J-P Deslys, C Lasmézas, and E Comoy were responsible for design and
management of this study. G Wells, S Hawkins, and T Konold were
responsible for the pathogenesis study in ruminants. C Lasmézas,
C Herzog, and N Lescoutra-Etchegaray were in charge of the primate
experiments. F Auvré undertook the biochemical analyses. N Salès was
responsible for the immunohistochemical analyses, which were done
by E Correia. C Lasmézas, E Comoy, F Mouthon, G Wells, P Brown, and
J-P Deslys drafted the manuscript.
Conflict of interest statement
Commissariat à lEnergie Atomique owns a patent covering the BSE
diagnostic test commercialised by Bio-Rad. All authors had full access to
all data and had responsibility to submit for publication. The funding
sources had no role in the collection, analysis, and interpretation of
data, writing of the report, or decision to submit the paper for
publication.
2 www.thelancet.com Published online January 27, 2005
http://image.thelancet.com/extras/05let1056web.pdf
BSE bovine brain inoculum
100 g 10 g 5 g 1 g 100 mg 10 mg 1 mg 0·1 mg 0·01 mg
Primate (oral route)* 1/2 (50%)
Cattle (oral route)* 10/10 (100%) 7/9 (78%) 7/10 (70%) 3/15 (20%) 1/15
(7%) 1/15 (7%)
RIII mice (icip route)* 17/18 (94%) 15/17 (88%) 1/14 (7%)
PrPres biochemical detection
The comparison is made on the basis of calibration of the bovine
inoculum used in our study with primates against a bovine brain inoculum
with a similar PrPres concentration that was
inoculated into mice and cattle.8 *Data are number of animals
positive/number of animals surviving at the time of clinical onset of
disease in the first positive animal (%). The accuracy of
bioassays is generally judged to be about plus or minus 1 log.
icip=intracerebral and intraperitoneal.
Table 1: Comparison of transmission rates in primates and cattle
infected orally with similar BSE brain inocula
For personal use. Only reproduce with permission from Elsevier Ltd
Research Letters
Acknowledgments
We gratefully acknowledge the expert care of the primate animals
provided by René Rioux, Sébastien Jacquin, and Anthony Fort, and the
technical expertise of Dominique Marcé, Capucine Dehen,
Sophie Freire, and Aurore Jolit Charbonnier. This work has received
financial support from the French Ministry of Research (GIS Prion). It is
now continued within the framework of the EU consortium QLK1-2002-
01096 and the European network of Excellence NeuroPrion. Ongoing
studies by the Veterinary Laboratories Agency in cattle are funded by the
UK Department for Environment, Food, and Rural Affairs.
References
1Anderson RM, Donnelly CA, Ferguson NM, et al. Transmission
dynamics and epidemiology of BSE in British cattle. Nature 1996;
382: 77988.
2 Lasmézas CI, Deslys JP, Demaimay R, et al. BSE transmission to
macaques. Nature 1996; 381: 74344.
3 Lasmézas CI, Fournier JG, Nouvel V, et al. Adaptation of the bovine
spongiform encephalopathy agent to primates and comparison with
Creutzfeldt-Jakob disease: implications for human health. Proc Natl
Acad Sci USA 2001; 98: 414247.
4 Herzog C, Salès N, Etchegaray N, et al. Tissue distribution of bovine
spongiform encephalopathy agent in primates after intravenous or
oral infection. Lancet 2004; 363: 42228.
5 Klitzman RL, Alpers MP, Gajdusek DC. The natural incubation
period of kuru and the episodes of transmission in three clusters of
patients. Neuroepidemiol 1984; 3: 320.
6 Deslys JP, Comoy E, Hawkins S, et al. Screening slaughtered cattle
for BSE. Nature 2001; 409: 47678.
7 European Commission. Opinion of the Scientific Steering
Committee on the Human Exposure Risk via food with respect to
BSE. Adopted on 10 December 1999. http://europa.eu.int./comm/
food/fs/sc/ssc/out67_en.pdf (accessed Jan 17, 2004).
8 Grassi J, Comoy E, Simon S, et al. Rapid test for the preclinical
postmortem diagnosis of BSE in central nervous system tissue.
Vet Rec 2001; 149: 57782.
9 Moynagh J, Schimmel H. Tests for BSE evaluated. Bovine
spongiform encephalopathy. Nature 1999; 400: 105.
www.thelancet.com Published online January 27, 2005
http://image.thelancet.com/extras/05let1056web.pdf 3TSS
 

Twotimer

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Kathy said:
In searching out new patents, and patent applications, I have found out that the Nobel Prize winner Stanley Prusiner, the inventor/discoverer? of the PRION, has changed his story.

In an older patent, he states:

Patent #6,166,187 US Patent and Trademark Office, dated December 26, 2000

“Prions are infectious pathogens that cause central nervous system spongiform encephalopathies in humans and animals. Prions are distinct from bacteria, viruses and viroids. The predominant hypothesis at present is that no nucleic acid component is necessary for infectivity of prion protein. Further, a prion which infects one species of animal (e.g., a human) will not readily infect another (e.g., a mouse).”


In Prusiner’s most recent patent #6,916,419, dated July 12, 2005, he clarifies and changes his hypothesis:

“Prions are infectious pathogens that cause central nervous system spongiform encephalopathies in humans and animals. Prions are distinct from bacteria, viruses and viroids. The predominant hypothesis at present is that no nucleic acid component is necessary for infectivity of prion protein. Further, a prion which infects one species of animal (e.g., a human) will not infect another (e.g., a mouse).”

What’s that Doc?

“A prion which infects one species of animal (e.g., a human) will not infect another (e.g., a mouse).”

This means, according to Stanley Prusiner’s latest research, on which he based this new patent - “Device for removal of prions from blood, plasma and other liquids.”),

BSE does not (and cannot) cause vCJD.

Even if you can never bring yourself to admit that BSE caused vCJD, the recent cases of BSE in sheep and goats are indisputable. As others said, you are splitting semantic hairs here and quite possibly reading way more into Prusiner's words than was meant, all agree that the species barrier is luckily hard to cross and that in the case of BSE there had to be an epidemic caused by ruminant-to-ruminant feed that PUSHED BSE across the barrier.
 

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According another prion specialist, in order to test for CJD using a cyclical amplification procedure such as Claudio Soto's, you would have to use human brain homogenate.

I agree with Tam, when "Prusiner" says "will not" this is a big change.

Transmission experiments using homogenated brain tissue, subjected to sonication, etc. are flawed, unrealistic, and conjure up a false picture.

Factor X is soon to be revealed, don't blink.
 

Mike

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Kathy said:
According another prion specialist, in order to test for CJD using a cyclical amplification procedure such as Claudio Soto's, you would have to use human brain homogenate.

I agree with Tam, when "Prusiner" says "will not" this is a big change.

Transmission experiments using homogenated brain tissue, subjected to sonication, etc. are flawed, unrealistic, and conjure up a false picture.

Factor X is soon to be revealed, don't blink.

Oh, I see. Everyone questions Prusiner about his Prion Theory and gives him very little credit. But when he makes a small change in his assessment of the species barrier SUDDENLY HE BECOMES THE GOSPEL?

You folks are amazing.

:wink:
 

Tam

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this just proves one thing he is human just like the rest of us and he makes mistakes too and is willing to admit them
 

Kathy

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You fail to see what I see here, and that is oky-doky with me.

Change of thought process, or identification of reality?

It takes alot of guts to admit that you weren't 100% right, and, of course, most of us are never 100% sure of anything.

All of the phrases: "thought to be" and "believed to be" are there for a purpose. Stan isn't the gospel; but his latest work is leaning away from the protein only theory.

I hope that I glean good from all the reports that are out there. Not just one gospel. Homogenate studies can transmit lots of non-transmissible conditions.

What's amazing here is a big change in the terminology and definitions. They don't go as far as I'd like to see them change, but this is a sign of movement in the right direction.
 

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To place a more human version of events on this topic, one could easily explain flatulance as being the unwarranted passing of normal or often copious amounts of gas at times when one would create the most embarrassing moments. However, when one also exhales, is one not also passing gas? The event is nonetheless described as that of passing gas and yet there is discussion that identifies the type of gas being passed and the manner in which it is being done. One method is considered rude and often ill-timed, yet the other is quite normal in that we all do it regularly with each exhale of breath. But, in the cold light of the early morning, we all pass gas in many ways but refrain from telling people, and yet we are often explaining something to another human while passing gas at that very moment and actually using it to form words. Stanly Prusiner is prone to reformation of words and this change in the subtle manner in which he describes something can be misread and misinterpreted to a point where the true meaning if his hypothesis is lost to a new argument as to what he actually meant by making such a change when perhaps he meant nothing at all but to draw one's attention to a new form of interpretation to an already existing hypothesis seen from an entirely new perspective. He may change his terminology yet further as his desire to acquire more patents grows as I am sure it will. Patents and prions make for nothing but swollen egos and very little contributions to real science other than to allow a name to acquire more cause-celeb status - but that is just an opinion that has been floated many times before. We can no more patent the wind than the difference between similar words. But then, I wish I had applied for a patent on the known English language and then all of you would be paying me simply just to make arguments come to life. Perchance to be poor and to live a simple life. Oh well, back into the shadows I go and hopefully you will take these words with somewhat of a chuckle, for that is all they are meant to create. Do not take them too seriously. But consider this - if one is harboring prions in one's blood, and suffers bleeding into the lungs, is it possible that with each exhale of breath, we can actually also send out in that shower of moisture, a few prions held within the mix?? Mmmmm, most interesting. Puts a whole new spin on waiting in the Doctor's office with all those people coughing their collective heads off.
 

Kathy

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Another amuzing conversation for the board. Maybe?

Stan Prusiner is the king of "bending definitions". The illusion of reality is all that is needed in our society.

Care to guess when S. B. Prusiner will make his conformational change -from calling prions infectious to identifiying his elusive Factor X (a possible unknown product within the aggregates) as the true pathogen. We will all have a great chuckle over it.

But I do this research with ernest, and bse-tester you never addressed the comment regarding CJD. Is it true (to your knowledge), that to test for CJD or vCJD using a cyclical protein amplification process (like Dr. Claudio Soto's), you MUST use human brain homogenate, and no other?
 

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