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A personal message to the Board from Mark Purdey!

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Kathy

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Mark sent this message for the Board to me today. Apparently, for whatever computer glitch reason, he is unable to post it himself.
*******************************************************
(from Mark Purdey, Somerset, UK)

I was greatly saddened to read some of the wildly irrelevant and impertinent comments that have been posted about my research data and hypotheses on the origins of TSE.

I feel that my critics need to do their homework first, before launching into their tirade of speculative and misguided comments about the authenticity of my first hand research into TSEs. Since most of the critics are professing to hail from an academic background, then they should study the true basis of my work, by educating themselves with my peer reviewed published papers ( chartered on the pubmed and other databases ). They will see that my hypotheses are based upon a raft of real life analytical observations which I have amassed from the numerous field excursions that I have undertaken in the main TSE cluster zones around the world . They are also based upon a cross linking of many other research works in the field of TSE science - these studies being duly referenced in my publications.

I therefore am at a loss to understand how my work can be outcast as 'suspicious' , when I have devoted twenty years of my life to an extremely intensive and thorough hands on investigation into the origins of TSEs I am insulted by such comments. Whatever information is cited in my writings ( whether nerve agent dumping in the UK seas , hand clap tests for clinical BSE , etc ), I have always utilized a valid reference in support of my statements .

And then another commentator goes on to say that " we all agree that rogue metals play a role in the cause of TSEs, but Purdey's ideas are simply.................."

What a short memory this commentator has. If they had studied the scientific literature in the proper way, they would be aware that it was my own original paper - published in Medical Hypotheses 2000 which presented my novel analytical data from Iceland , Colorado, Slovakia (recieved at the Elsevier editorial office - 1st April 1998 ) and was the first paper to propose that a rogue metal replacement of the copper / zinc domains on native prion protein was responsible for the origins of TSEs. Shouldn't I therefore get some recognition for this groundbreaking observation ????

The fact that other researchers have subsequently plagiarized my data and hypotheses does not destroy the hard historical reality of my intellectual copyright, my original research investigations and publications ( internationally broadcast on a BBC world film for God's sake ) .

In this respect, I feel that it is totally unfair that my work is being subjected to this misappropriated assault on your pages.

Others go on to say that i am ever changing my theories, as and when they are refuted by the establishment.

Please describe the work by the establishment that has successfully refuted my position? The only study that I was aware of involved the exposure of recombinant prion protein to the DFP type of organo-phosphate , and this trial was totally irrelevant to the testing of my hypothesis on the following grounds ;

Firstly, because the toxicological properties of the DFP molecule are totally different to the toxicological properties of Phosmet - the OP insecticide used upon UK farms during the relevant period , and secondly, because the recombinant prion protein does not contain a glycolipid anchor - the actual region of the prion protein amino acid chain which represents a target for OP induced phosphorylation and protein misfolding . So the whole experiment was worthless.

Likewise, several other attempts to refute my work have employed equally irrelevant research protocols .

Since new research discoveries are arising on a virtual weekly basis in the area of TSE research, my own environmental theory on TSE cause needs to be open to change in order to remain viable. Like any other theory, it has to be capable of accommodating these advancements. This is the healthy evolution of a scientific theory at work. I therefore feel unfairly criticized on grounds that my theory has evolved (eg: changed ) over the years .

What is so wrong with that - for god's sake? Wouldn't we all be better off if the establishment's theory had remained open to change over the years . In this respect, progress would be made towards resolving many of the missing links in the aetiology of these diseases.

Others have expanded their criticism of my work, by erroneously stating that I have moved from pesticides, to heavy metals, to sonic waves, etc, as a cause of BSE. But these people are wholly ignorant of my work. They have failed to get the most basic gist of what i am actually saying.

Clearly a straight forward metal or pesticide toxicity does not provide an adequate explanation for the cause of these unique TSE diseases - since mammalian exposure to the various metals, and to some extent, the pesticides, has obviously gone on for years prior to the emergence of TSEs. To suggest that my research has not recognized this basic factor is completely inaccurate and unfair. It’s insulting of my intelligence.

However, I have advanced upon this basic tenet, after collecting further analytical data of the levels of magnetic susceptibility , radioactivity, piezoelectic capacity of the soils, hard tissues etc, in the TSE cluster and TSE-free areas. So whilst the same specific elements (eg; phosphorous , manganese , barium, etc) remain the central nucleating agents in the aetiology of these diseases, it is the piezoelectric capacity of the specific crystalline metal-protein conglomerates which are subsequently formed within the contaminated tissues that represent the pathogenic driving force within these diseases - eg; representing the heat resistant, transmissible , pathogenic capacity that interweaves with the other environmental prerequisites into a unified , viable hypothesis which fits all of the well recognized idiosyncratic properties that define the causal agent in TSEs.

Furthermore, my work is not a case of the egg before the chicken - I have never started off with a theory, and then tried to force subsequent observations to fit the picture as some are suggesting. I have allowed my first hand environmental observations in the cluster environments to gradually assemble the right theory that would seem to fit all of the facts. There are bound to be cul de sacs, and false leads, but the theory has kept on evolving. Nobody is going to hit the nail on the head; particularly if they are operating without the benefits of government or corporate backed funding, like myself.

I would strongly recommend to those critics who profess to hail from a scholarly background, that they should actually begin to make the effort to read my academic publications in the first instance, rather than relying upon the misguided hearsay.

I also feel that your readers should be aware of the personal and financial hardship that entrepreneurial researchers such as myself have had to endure for the 'crime' of launching fresh observations and ideas into the public arena - particularly if those findings should threaten the reputations or vested interests of the status quo scientists in any way.

Whilst many reputable scientific establishments are currently making a small fortune out of the fruits of my own pioneering work, my own life has ironically degenerated into a state of total collapse. All I ask is for a bit of basic human respect, and not for the accolades of acidity that are sent my way nearly everyday. Thank you Kathy, for being the only intelligent and open minded contributor to ranchers.com

Yours,

Mark Purdey
 

Kathy

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There are many more on the board who support Mark's work. I don't think there are any as "into it" as myself; but, your support is still very much appreciated.

Kathy
 

bse-tester

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Well done Kathy for taking the time to encourage Mark Prdey to post his comments. It is sad to see that minds are indeed closed - I see it constantly and it is this failure of the human spirit that allows contempt for those who are trying to put forward ideas, to grow. I applaud you for your steadfastness in this matter and would like to thank Mark for coming to the table and posting his words. It should be said that it not so much important that we agree or not that is the point here. It is however, important that we allow all to voice their opinions, regardless of whether or not we agree with them. Having said that, I would further suggest that we should be able to do this in a manner that is worthy of good open discussion and sharing of opinions. Although I do not necessarily agree with all who post here, as I am sure not all agree with my postings, I am able to say that I feel I am capable of reading, absorbing and then forming an opinion that is hopefully without rhetoric or condemnation. It is in this forum that we may learn to appreciate the efforts of those who are trying to show us a new path, a new ideology or protocol and it is here that we can learn and share our findings and/or opinions. Well done Kathy and thank you Mark for your response.
 

cedardell

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Thank-You Kathy for bringing Mark Purdey's commentary to the board. It was the best way I know to put us in touch with reality.
 

Kathy

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I am truly sorry for your loss and suffering R2, however, you have so over-stepped the lines on these comments that - indeed - you are the one that must be ignored from now on.

Everyone hear has acknowledged that CJD can be transmitted iagtrogenically (in a clinical setting). You have lied when you stated:

...deny that CJD is transmissable from person to person, e.g., via contaminated surgical instruments or tissue or blood donations

what you refuse to get, no matter how many times you are told this, is that the agent being tranferred from one person to another is not a lonely infectious protein. That these misfolded protein aggregates must have a nucleating center consisting of metals in order for them to form. Without these metallic centers there is no protein aggregation.

Your second statement:

it is they who are perverting your theories and therefore subjecting you to ridicule.

The only person who has consistently, and perversely, subjected Mark Purdey's work to ridicule on this message board, is YOU.

Perhaps, you may actually be admitting to yourself, that some of his findings of fact have, and are, leading to answers in the varying fields of neurological disease. Certainly, there are enough researchers out there taking up more of his line of questioning.

When you comment:
you reject a hypothesis that must be accepted for the time being

you fail to realize that many of the areas of science that are now seeing the light of day (finally), were brought up by this man 25 years ago. Others, like Dr. D. Brown, and BS Wong clearly proved an association with metals and CJD and they to have been ignored.

I am only glad that the science is digging deeper into things now. A sense of more open-ness is apparent. But as long as the egos of people stand in the way of progress, we will continue to accept the status quo.

Do not throw stones R2! People are trying to discover the truth. But that does not mean that some in the scientific field want us to "know" the truth. Your absolute insistence to make others on this board "ignore" Mark Purdey because you say, is sad!
 

Kathy

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Since we agree on many issues, yet disagree on the most important issue, we may have to tolerate our differences. Eventually, we may be able to come to the same conclusions, visa our different routes.

You have brought forward, over the past while, many postings which have confounded me, until they led to further information, such as how nanotechnology affects prion disease.

This "nanotechnology" is what it is coming down to. The metal nanoclusters which Dr. Vodyanoy writes about in his report, "Novel Metal Clusters Lethal to Cancer Cells", are the initiating mechanism required for prion disease, and other misfolding protein disorders. To say that someone iatrogenically injected with blood products containing the harmful forms of these metal clusters, has been "infected" with them, is just wrong.

Infectious agents are living organisms which invade our cells and destroy them. These metal clusters - are not living. Contamination by metals is a toxin. They can be passed onto anything which is utilizing them, this can include feed, blood transfusions, vaccinations, etc. However, there are other factors such as utilizing stainless steel instruments during intimate contact surgery (eg holding the skull open for several hours). The disinfectants used during surgery are caustic and have been shown to dislodge metal particals from instruments. A paper I've mentioned before, failed to show some of the results from their control, which was a plain stainless steel wire. This, in my opinion, is because the control also initiated the conversion of PrPC to PrPSc.

The fact that the transmission experiments must first utilize such extreme methodology such as homogenization, denaturing, sonication are classic examples of exciting these metal molecule clusters in order that they may more quickly scavenge the proteins associatied with them.

I have always stated that any of the prion disorders can be transmitted iatrogenically.

The fact that prions, in naturally occurring BSE cases, have ONLY been found to accummulate in the retina of the eyes, brain and spinal cord - as compared to the iatrogenic transmission experiments, where it has shown up in a few other places like the distal ileum, is not to be ignored.

But, on the side of caution, industry and government openly ignore this fact. Behind the scenes however, they know that the lab procedure experiments are not the same as the natural cases; and this is why we see their contrasting information, like the re-introduction of intestines (minus the distal ileum) to the food chain.

We continue to ignore the evidence which proves that our environment (air, food, water, soil) are contaminated with naturally occurring, and more so, man-made pollutants. Why are these unhealthy metals accummulating in our bodies now, more so than ever before?

Would you be willing to explore these areas, or are you only concerned only with CJD?

I want these toxic and chemical pollutants cleaned-up and out of our environment. BSE is the head-line classic example of a man-made catastrophe which is being blamed on the "unknown" factor. Herein lies the real BS! Because more is known than is being told, and if all were told which were known, there would be hell to pay.

I may not stay in the cattle industry very long; but this will not stop me from investigating and exposing the truth. I have survived cancer, and I have seen the halls of the hospitals which are jam packed with men and women suffering from this plague. There is a reason for it all.

The most common denominator found in human disease, is the lack of accountability for our own health. People need to stand up for themselves; they need to stop the polluters, they need to eat better; and they need to stop using harmful chemicals like they are candy.

Cattle were exposed to increasing concentrations of OPs in the UK just before, and at the same time BSE erupted. When they stopped using this chemical, the numbers dropped accordingly. Cases still pop up long after the feed bans. If stopping the feeding of MBM to animals is the answer, explain these cases which continue to show up in the UK, Japan, France, etc.

Maybe you should ask experts like Dr. Jean-Phillippe Deslys, of the French Atomic Energy Commission (CEA for short). Ironically, it was the French Atomic Energy Commission who first developed a rapid test for BSE.
 

Kathy

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R2, what is with your last comment?
Let's not clean up Love Canal because it's a coincidence that so many people living near it came down with cancer. It's not really provable so let's not bother. Hmmm...

Perhaps you should read the info posted by Mike under the Beyond Treason thread. The US government and Department of Defence knowingly and carelessly released radiation from one of their weapons facilities on the unknowing people "down-wind". The article written by lawyers, apparently:
Downwinders' still press their case against Hanford

By RICHARD A. DU BEY, CONNIE SUE MARTIN and R. BRENT WALTON
Short Cressman & Burgess


You have to catch them and prove your case before anything is done about it. With BSE, we have been declared guilty. The evidence if fabricated to make it look clear-cut and simple. It is not as simple as it appears.
 

Mike

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Kathy wrote:
The fact that the transmission experiments must first utilize such extreme methodology such as homogenization......

I fail to see the extreme in "homogenization". Simply put, in BSE experimentation, (from what I have read), brain (or other) matter is placed in a blender so that the material may be drawn into a syringe for inoculation into, for instance, mice or other cattle, etc.

"Homogenization" is not some scientific term that alters the state in any way except for the ability to inject it. Or, a better way to describe it is: "making a liquid out of a solid".

How is this "extreme methodology"?
 

flounder

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Greetings Ranchers and board members,


Kathy wrote in another thread, but yet never documented;

> didn't say that OPs caused prion disease, but that they contributed greatly
> to the UK experience,

and again, could your please reference this materials with scientific data, instead
of hearsay please ???


you can argue the origin of TSE until all the mad cows on earth come home to roost.


i.e. ;


Phosmet induces up-regulation of surface levels of the cellular prion protein.
Neuroreport. 9(7):1391-1395, May 11, 1998.
Gordon, Irit 1; Abdulla, Elizabeth M. 1; Campbell, Iain C. 1; Whatley, Stephen A. 1,2
Abstract:
CHRONIC (2 day) exposure of human neuroblastoma cells to the organophosphate pesticide phosmet induced a marked concentration-dependent increase in the levels of PrP present on the cell surface as assessed by biotin labelling and immunoprecipitation. Levels of both phospholipase C (PIPLC)-releasable and non-releasable forms of PrP were increased on the plasma membrane. These increases appear to be due to post-transcriptional mechanisms, since PrP mRNA levels as assessed by Northern blotting were unaffected by phosmet treatment. These data raise the possibility that phosmet exposure could increase the susceptibility to the prion agent by altering the levels of accessible PrP.

(C) Lippincott-Raven Publishers.



http://www.neuroreport.com/pt/re/neuroreport/abstract.00001756-199805110-00026.htm;jsessionid=DOEcw0d3vPau1LEbPM42DrGrWVZnF06cF115hTGLe07ro2BZx8d3!586698740!-949856144!9001!-1





BUT, amplification and transmission is the most important factor in stopping the

spread of the TSE agent. WE have known for decades what factors involve the amplification

and transmission, yet the industries involved CHOSE to ignore this science until the incubation

period in humans and animals started to catch up with society.



would it not have been more easy and very much less expensive for MAFF/USDA et al to jump on the OP
bandwagon and save the industry, if OP theory had any credence to it at all? and why did they not?


transmission studies DO NOT LIE !

show me the data that ops are in all the primate/mouse transmission studies?


EUROPEAN COMMISSION
HEALTH & CONSUMER PROTECTION DIRECTORATE-GENERAL
Scientific Steering Committee
OPINION ON
ORGANOPHOSPHATE (OP) POISONING AND
HYPOTHETICAL INVOLVEMENT IN THE ORIGIN OF BSE
Background
In its opinion on possible links between BSE and Organophosphates adopted on 25-26 June
1998 and in its opinion on Hypotheses on the origin and transmission of BSE adopted on 29-
30 November 2001 the SSC concluded that there is no scientific evidence in support of the
hypothesis of an OP origin of BSE.
The issue of organophosphate poisoning has not been dealt with by the SSC so far. The
concerns expressed in the enquiries cover mainly intoxication by occupational exposure of
shepherds and farmers to OPs upon use against ecto-parasites, especially in sheep dipping and
treatment of cattle against Warble Fly infestation. Risks from residues are addressed to a
lesser extend.
In early 2003, a large number of additional enquiries on the issue have been addressed to
European Commission’s Health and Consumer Directorate General. Four of these with
substantial enclosures were by one person. Most of them are addressing both issues: chronic
organophosphate (OP) poisoning and the origin of BSE.
Information provided with the enquiries
In addition to numerous newspaper and magazine articles the enclosures to the enquiries
provide the Material Safety Data Sheet on diazinon, the OHSA Occupational Safety and
Health Guideline for Tetraethylpyrophosphate (TEPP), an US agency Hazardous Substances
Fact Sheet on crufomate, company safety information sheets, some correspondence with UK
authorities including their activities to improve safe use of these chemicals. The information
regarding claimed OP chronic poisoning of cases presented does not provide evidence, neither
for OPs being the cause for diseases nor for their exclusion (i.e., “very low” bloodcholinesterase
levels, provided without data or comparison with the normal distribution of
values; successful treatment of a patient for OP clearance without giving any OP data). It
C:\WINNT\Temporary Internet Files\SSC_Last_OP_Final.doc 2
seems however, that due to insufficient, non-prudent use of the safety requirements undue
exposures of shepherds and farmers have occurred.
There is no additional information on the claimed involvement of OPs in the origin of BSE.
This applies for both, the hypotheses on the direct effect of OPs as well as on their
hypothetical role for Cu-deficiency to be involved in the origin of BSE (Cu binding of prion
protein is known). New publications are mentioned in one enquiry but they have not yet been
provided. In an Internet search no recent scientifically valid publications were traceable. The
SSC had been informed that research would be launched on this hypothesis, but no
information has been provided so far on its status or on results.
Conclusions
a) As regards the involvement of organophosphates in the origin of BSE, no new scientific
information providing evidence or supporting the hypothesis by valid data became
available after the adoption of the last opinion of the SSC on this issue. Consequently
there is no reason for modifying the existing opinions.
b) Regarding the possibility of OP poisoning, the European legislation for registration of
plant protection products and veterinary medicines – addressed in the enquiries – provide
the basis for safe use of registered compounds and their formulations. Regarding the
alleged intoxication cases reported and OP exposure it must be concluded that safety
measures may not have been strictly followed.
References
Brown, D.R., Qin, K., Herms, J.W., Madlung, A., Manson, J., Strome, R., Fraser, P.E., Kruck, T., von
Bohlen, A., Schulz- Schaeffer, W., Giese, A., Westaway, D. and Kretzschmar, H. (1997) The Cellular
Prion Protein Binds Copper In Vivo, Nature, 390, 684-7.
Purdey, M. (2000) Ecosystems Supporting Clusters of Sporadic TSEs Demonstrate Excesses of the Radical-
Generating Divalent Cation Manganese and Deficiencies of Antioxidant Co-Factors Cu, Se, Fe, Zn Medical
Hypotheses, 54, 278-306.
Scientific Steering Committee, 1998. Opinion on possible links between BSE and Organophosphates. Adopted
on 25-26 June 1998
Scientific Steering Committee, 2001. Opinion on Hypotheses on the origin and transmission of BSE. Adopted
on 29-30 November 2001.

http://europa.eu.int/comm/food/fs/sc/ssc/out356_en.pdf



Studies on the Putative Interactions between the Organophosphorus Insecticide Phosmet and Recombinant Mouse PrP and its Implication in the BSE Epidemic
I. Shaw1, C. Berry2, E. Lane1, P. Fitzmaurice1, D. Clarke3 and A. Holden1

(1) Centre for Toxicology, University of Central Lancashire, Preston, UK
(2) Department of Morbid Anatomy, The Royal London Hospital, London, UK
(3) CLRC Daresbury Laboratory, Warrington, UK


Abstract It has been suggested that exposure of cattle to the ectoparasiticide Phosmet in the 1980s caused a conformational change in the cellular prion protein (PrPC) to form the BSE prion (PrPSC), which initiated the epidemic of bovine spongiform encephalopathy (BSE).
Recombinant mouse cellular prion (r[mouse]PrPC) was exposed to the organophosphorus pesticide Phosmet in vitro and the conformation of the prion before and after exposure was monitored using circular dichroism (CD) spectroscopy, utilizing synchrotron radiation at the Council for the Central Laboratory of the Research Councils (CLRC) facilities at Daresbury, UK. Metabolites of Phosmet, generated in situ by rat microsomes, were investigated in the same way, to determine whether they might initiate the conformational change due to their high chemical reactivity.
Our studies showed that exposure of r[mouse]PrPC to Phosmet or microsomes-generated metabolites of Phosmet did not result in the conformational change in the protein from -helix to -pleated sheet that is characteristic of the PrPC to PrPSC conversion and, therefore, Phosmet is very unlikely to have initiated the BSE epidemic by a simple direct mechanism of conformational change in the prion protein.
bovine spongiform encephalopathy - circular dichroism spectroscopy - insecticide - organophosphate - Phosmet - prion - protein conformation



http://www.springerlink.com/(bmbpjj55ksv02p2wiismj555)/app/home/contribution.asp?referrer=parent&backto=issue,3,9;journal,31,74;linkingpublicationresults,1:103009,1



transmission studies do not lie, amplification and transmission!


i see NO properties of high levels of Manganese in the diet, combined with low levels of copper, in any of these primate
transmission studies.

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


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

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

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

PMID: 6997404

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


Oral Transmission And Early Lymphoid Tropism Of Chronic Wasting Disease
Prpres In Mule Deer Fawns

Publication: Journal Of General Virology
Publication Request Approval Date: June 25, 1999

Interpretive Summary: Chronic wasting disease is a transmissible
spongiform encephalopathy or prion disease of deer and elk. CWD is a
member of the family of diseases that includes sheep scrapie and bovine
spongiform encephalopathy (BSE). The natural route of transmission of
these diseases in ruminant animals is unknown but oral exposure to
contaminated feeds, bedding, or tissues is presumed to be a major source
of infection. In this study, mule deer fawns were orally fed an
infectious homogenate and sacrificed at intervals to examine the
lymphoid tissue of the alimentary tract for signs of infection. Prion
protein was detected as early as 42 days and was evident in all fawns
after 53 days. This paper provides an improved procedure for detecting
prions in early infection, establishes a protocol for accelerated study
of transmission routes, and supports the hypothesis that oral exposure
may reflect the initial pathway of CWD infection in deer.

Technical Abstract: Mule deer fawns were inoculated orally with a brain
homogenate prepared from mule deer with naturally occurring chronic
wasting disease (CWD), a prion induced transmissible spongiform
encephalopathy. Fawns were necropsies and examined for PrP-res, a
protein marker for infection, at 10, 42, 53, 77, 78 and 80 days post
inoculation using an immunohistochemistry assay modified to enhance
sensitivity. PrP-res was detected in alimentary-tract- associated
lymphoid tissues as early as 42 days post inoculation and in all fawns
after 53 days. These results indicated that CWD PrP-res can be detected
at least 16 months before clinical signs would be expected to appear and
may reflect the initial pathway of CWD infection in deer.

http://nps.ars.usda.gov/publication...gnum=0000103091

Establishing the transmission of BSE to mink

44. Transmissible mink encephalopathy ("TME") is a rare disease of ranch
reared mink, first recognised in the USA. It had been assumed to be
scrapie in mink and, like BSE, outbreaks have epidemiological
features consistent with a foodborne infection, but it has never been
possible to demonstrate that scrapie infected sheep brain tissue is
pathogenic to mink by oral exposure. In an incident of TME in
Stetsonville, Wisconsin, USA in 1985 Dr Richard Marsh observed that
although the rancher fed 'dead stock', mainly in the form of cattle
carcasses, sheep tissues had never been fed. Studies in the USA of
this incident showed not only that cattle inoculated intracerebrally
with the mink brain developed a fatal spongiform encephalopathy, but
also that the cattle passaged agent remained pathogenic for
mink by either intracerebral inoculation or feeding. In the absence of
reports of a clinical disease homologous to BSE in domestic cattle,
these findings prompted the suggestion that a rare or occult
form of such a disease might exist in the USA. Comparison of the
biological properties of the BSE
12
pathogen with those of the Stetsonville isolate was therefore of
considerable interest in relation to hypotheses concerning possible
origins of BSE and potential for subclinical infection in cattle.
45. Proposals to carry out studies with mink in the USA were developed
in collaboration with, the United States Department of Agriculture
("USDA") Agricultural Research Service ("ARS") and the
Department of Veterinary Science, University of Wisconsin, Madison,
Wisconsin, USA. On 30th October, 1990 I attended a CVL/NPU BSE R&D
meeting at the NPU in Edinburgh (YB90/10.30/1.1). I reported that brain
material from BSE affected cows and a control cow (not fed meat and
bonemeal) had been sent coded to Mr Mark Robinson (USDA) for
transmission studies in mink. The studies were conducted from February
1991 under the control and principal funding of USDA-ARS. The results,
discussed at the tenth CVL/NPU BSE R&D meeting on 27th April, 1993
(YB93/4.27/1.1) indicated that mink were indeed susceptible to BSE and,
in contrast to previous attempts to transmit scrapie to the species,
were susceptible by the oral route of inoculation. The collaboration
resulted in the publication of a paper: Robinson, M.M. et al (1994)
Experimental infection of mink with bovine spongiform encephalopathy.
Journal of General Virology 75, 2151-2155 (J/JVIR /75/2151).

snip...


http://www.bseinquiry.gov.uk/files/ws/s065a.pdf

BSE TO MINK CONFIRMED

http://www.bseinquiry.gov.uk/files/yb/1993/04/27001001.pdf


1: Proc Natl Acad Sci U S A 2001 Mar 27;98(7):4142-7

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

Lasmezas CI, Fournier JG, Nouvel V, Boe H, Marce D, Lamoury F, Kopp N,
Hauw JJ, Ironside J, Bruce M, Dormont D, Deslys JP.

Commissariat a l'Energie Atomique, Service de Neurovirologie, Direction
des Sciences du Vivant/Departement de Recherche Medicale, Centre de
Recherches du Service de Sante des Armees 60-68, Fontenay-aux-Roses,
France. [email protected]

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.


http://www.ncbi.nlm.nih.gov/entrez/...1&dopt=Abstract

this next one frightens me the most, you might want to read
it twice, and really think about it...TSS

1: J Neurol Neurosurg Psychiatry 1994 Jun;57(6):757-8

Transmission of Creutzfeldt-Jakob disease to a chimpanzee by electrodes
contaminated during neurosurgery.

Gibbs CJ Jr, Asher DM, Kobrine A, Amyx HL, Sulima MP, Gajdusek DC.

Laboratory of Central Nervous System Studies, National Institute of
Neurological Disorders and Stroke, National Institutes of Health,
Bethesda, MD 20892.

Stereotactic multicontact electrodes used to probe the cerebral cortex
of a middle aged woman with progressive dementia were previously
implicated in the accidental transmission of Creutzfeldt-Jakob disease
(CJD) to two younger patients. The diagnoses of CJD have been confirmed
for all three cases. More than two years after their last use in humans,
after three cleanings and repeated sterilisation in ethanol and
formaldehyde vapour, the electrodes were implanted in the cortex of a
chimpanzee. Eighteen months later the animal became ill with CJD. This
finding serves to re-emphasise the potential danger posed by reuse of
instruments contaminated with the agents of spongiform encephalopathies,
even after scrupulous attempts to clean them.

http://www.ncbi.nlm.nih.gov/entrez/...4&dopt=Abstract

Proc Natl Acad Sci U S A 1999 Mar 30;96(7):4046-51

Natural and experimental oral infection of nonhuman primates by bovine
spongiform encephalopathy agents.

Bons N, Mestre-Frances N, Belli P, Cathala F, Gajdusek DC, Brown P.

Ecole Pratique des Hautes Etudes, Laboratoire de Neuromorphologie
Fonctionnelle, Universite Montpellier II, 34095-Montpellier cedex 5, France.

Experimental lemurs either were infected orally with the agent of bovine
spongiform encephalopathy (BSE) or were maintained as uninfected control
animals. Immunohistochemical examination for proteinase-resistant
protein (prion protein or PrP) was performed on tissues from two
infected but still asymptomatic lemurs, killed 5 months after infection,
and from three uninfected control lemurs. Control tissues showed no
staining, whereas PrP was detected in the infected animals in tonsil,
gastrointestinal tract and associated lymphatic tissues, and spleen. In
addition, PrP was detected in ventral and dorsal roots of the cervical
spinal cord, and within the spinal cord PrP could be traced in nerve
tracts as far as the cerebral cortex. Similar patterns of PrP
immunoreactivity were seen in two symptomatic and 18 apparently healthy
lemurs in three different French primate centers, all of which had been
fed diets supplemented with a beef protein product manufactured by a
British company that has since ceased to include beef in its veterinary
nutritional products. This study of BSE-infected lemurs early in their
incubation period extends previous pathogenesis studies of the
distribution of infectivity and PrP in natural and experimental scrapie.
The similarity of neuropathology and PrP immunostaining patterns in
experimentally infected animals to those observed in both symptomatic
and asymptomatic animals in primate centers suggests that BSE
contamination of zoo animals may have been more widespread than is
generally appreciated.

http://www.ncbi.nlm.nih.gov/entrez/...0&dopt=Abstract

1: Vet Rec 1993 Apr 17;132(16):403-6

Experimental transmission of BSE and scrapie to the common marmoset.

Baker HF, Ridley RM, Wells GA.

Division of Psychiatry, Clinical Research Centre, Harrow, Middlesex.

Two young male common marmosets (Callithrix jacchus) were injected
intracerebrally and intraperitoneally with a crude brain homogenate
prepared from a cow with bovine spongiform encephalopathy (BSE). Two
other marmosets were similarly injected with brain homogenate from a
sheep with natural scrapie. The two animals injected with scrapie
material developed neurological signs 38 and 42 months after injection
and the two animals injected with BSE material developed neurological
signs after 46 and 47 months. Post mortem examination of the brains
revealed spongiform encephalopathy especially in the basal nuclei and
diencephalon of all the animals and, in addition, involvement of the
cerebral cortex of the marmosets injected with scrapie material. The
experiment extends the host range of experimental BSE to include a
primate species.

http://www.ncbi.nlm.nih.gov/entrez/...8&dopt=Abstract


1: J Gen Virol 1991 Mar;72 ( Pt 3):589-94

Epidemiological and experimental studies on a new incident of
transmissible mink encephalopathy.

Marsh RF, Bessen RA, Lehmann S, Hartsough GR.

Department of Veterinary Science, University of Wisconsin-Madison 53706.

Epidemiological investigation of a new incident of transmissible mink
encephalopathy (TME) in Stetsonville, Wisconsin, U.S.A. in 1985 revealed
that the mink rancher had never fed sheep products to his mink but did
feed them large amounts of products from fallen or sick dairy cattle. To
investigate the possibility that this occurrence of TME may have
resulted from exposure to infected cattle, two Holstein bull calves were
injected intracerebrally with mink brain from the Stetsonville ranch.
Each bull developed a fatal spongiform encephalopathy 18 and 19 months
after inoculation, respectively, and both bovine brains passaged back
into mink were highly pathogenic by either intracerebral or oral
inoculation. These results suggest the presence of a previously
unrecognized scrapie-like infection in cattle in the United States.

http://www.ncbi.nlm.nih.gov/entrez/...3&dopt=Abstract

1: Ital J Neurol Sci 1983 Apr;4(1):61-4

Creutzfeld-Jakob disease in the province of Siena: two cases transmitted
to monkeys.

Fieschi C, Orzi F, Pocchiari M, Nardini M, Rocchi F, Asher D, Gibbs C,
Gajdusek D.

Two cases of histopathologically documented Creutzfeldt-Jakob disease
were observed in the same area of the province of Siena in 1974-1975.
The transmission of the disease was obtained through brain homogenates
and lymphnodes in one of the two cases. This confirms that the agent is
present in other tissues besides the brain and underlines further the
analogies between Creutzfeld-Jakob disease and scrapie.

http://www.ncbi.nlm.nih.gov/entrez/...0&dopt=Abstract


1: Dev Biol Stand 1993;80:9-13

Transmission of human spongiform encephalopathies to experimental
animals: comparison of the chimpanzee and squirrel monkey.

Asher DM, Gibbs CJ Jr, Sulima MP, Bacote A, Amyx H, Gajdusek DC.

Laboratory of Central Nervous System Studies, National Institute of
Neurological Disorders and Stroke, NIH, Bethesda, MD 20992.

The agents of kuru and Creutzfeldt-Jakob disease have been consistently
transmitted from patients with those diseases to chimpanzees and
squirrel monkeys, as well as to other new-world primates, with average
incubation periods of two or three years. No other animals have been
found so consistently susceptible to the agents in human tissues. More
rapid and convenient assays for the infectious agents would greatly
facilitate research on the spongiform encephalopathies of humans.

http://www.ncbi.nlm.nih.gov/entrez/...9&dopt=Abstract


1: J Vet Diagn Invest 2001 Jan;13(1):91-6

Preliminary findings on the experimental transmission of chronic wasting
disease agent of mule deer to cattle.

Hamir AN, Cutlip RC, Miller JM, Williams ES, Stack MJ, Miller MW,
O'Rourke KI, Chaplin MJ.

National Animal Disease Center, ARS, USDA, Ames, IA 50010, USA.

To determine the transmissibility of chronic wasting disease (CWD) to
cattle and to provide information about clinical course, lesions, and
suitability of currently used diagnostic procedures for detection of CWD
in cattle, 13 calves were inoculated intracerebrally with brain
suspension from mule deer naturally affected with CWD. Between 24 and 27
months postinoculation, 3 animals became recumbent and were euthanized.
Gross necropsies revealed emaciation in 2 animals and a large pulmonary
abscess in the third. Brains were examined for protease-resistant prion
protein (PrP(res)) by immunohistochemistry and Western blotting and for
scrapie-associated fibrils (SAFs) by negative-stain electron microscopy.
Microscopic lesions in the brain were subtle in 2 animals and absent in
the third case. However, all 3 animals were positive for PrP(res) by
immunohistochemistry and Western blot, and SAFs were detected in 2 of
the animals. An uninoculated control animal euthanized during the same
period did not have PrP(res) in its brain. These are preliminary
observations from a currently in-progress experiment. Three years after
the CWD challenge, the 10 remaining inoculated cattle are alive and
apparently healthy. These preliminary findings demonstrate that
diagnostic techniques currently used for bovine spongiform
encephalopathy (BSE) surveillance would also detect CWD in cattle should
it occur naturally.

http://www.ncbi.nlm.nih.gov/entrez/...4&dopt=Abstract

P.S. the study above confirmed 5 cows and 1 goat transmission of CWD to cattle,
of the final stages of the study. ...tss

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*,dagger, Jean-Guy Fournier*, Virginie Nouvel*, Hermann Boe*, Domíníque Marcé*, François Lamoury*, Nicolas KoppDagger , Jean-Jacques Hauw§, James Ironside¶, Moira Bruce||, Dominique Dormont*, and Jean-Philippe Deslys*

snip...


Discussion

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

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.

snip...

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



MRC-43-00 [ ] [Text only version of this site] [Print this page]
Issued: Monday, 28 August 2000
NEW EVIDENCE OF SUB-CLINICAL PRION INFECTION: IMPORTANT RESEARCH FINDINGS RELEVANT TO CJD AND BSE

A team of researchers led by Professor John Collinge at the Medical Research Council Prion Unit1 report today in the Proceedings of the National Academy of Sciences, on new evidence for the existence of a ?sub-clinical? form of BSE in mice which was unknown until now.

The scientists took a closer look at what is known as the ?species barrier? - the main protective factor which limits the ability of prions2 to jump from one species to infect another. They found the mice had a ?sub-clinical? form of disease where they carried high levels of infectivity but did not develop the clinical disease during their normal lifespan. The idea that individuals can carry a disease and show no clinical symptoms is not new. It is commonly seen in conventional infectious diseases.

Researchers tried to infect laboratory mice with hamster prions3 called Sc237 and found that the mice showed no apparent signs of disease. However, on closer inspection they found that the mice had high levels of mouse prions in their brains. This was surprising because it has always been assumed that hamster prions could not cause the disease in mice, even when injected directly into the brain.

In addition the researchers showed that this new sub-clinical infection could be easily passed on when injected into healthy mice and hamsters.

The height of the species barrier varies widely between different combinations of animals and also varies with the type or strain of prions. While some barriers are quite small (for instance BSE easily infects mice), other combinations of strain and species show a seemingly impenetrable barrier. Traditionally, the particular barrier studied here was assumed to be robust.

Professor John Collinge said: "These results have a number of important implications. They suggest that we should re-think how we measure species barriers in the laboratory, and that we should not assume that just because one species appears resistant to a strain of prions they have been exposed to, that they do not silently carry the infection. This research raises the possibility, which has been mentioned before, that apparently healthy cattle could harbour, but never show signs of, BSE.

"This is a timely and unexpected result, increasing what we know about prion disease. These new findings have important implications for those researching prion disease, those responsible for preventing infected material getting into the food chain and for those considering how best to safeguard health and reduce the risk that theoretically, prion disease could be contracted through medical and surgical procedures."

ISSUED FRIDAY 25 AUGUST UNDER EMBARGO. PLEASE NOTE THAT THE EMBARGO IS SET BY THE JOURNAL.

FOR FURTHER INFORMATION CONTACT THE MRC PRESS OFFICE ON 020 7637 6011 (OFFICE HOURS) OR 07818 428297 OR 0385 774357 (OUT-OF-OFFICE-HOURS) OR PROFESSOR JOHN COLLINGE ON 020 7594 3760. PLEASE NOTE THAT OWING TO TRAVEL COMMITMENTS PROFESSOR COLLINGE WILL ONLY BE AVAILABLE UNTIL 16.30 ON FRIDAY 25 AUGUST AND CONTACTABLE AGAIN ON MONDAY 28 AUGUST VIA THE MRC PRESS OFFICE. DR ANDREW HILL (A CO-AUTHOR ON THE PAPER) FROM THE DEPARTMENT OF PATHOLOGY AT THE UNIVERSITY OF MELBOURNE WILL BE AVAILABLE ON 00 61 3 8344 3995 (DURING OFFICE HOURS) OR 00 61 3 9443 0009 (OUT-OF-OFFICE HOURS). PLEASE NOTE THAT AUSTRALIA IS TEN HOURS AHEAD OF UK TIME.

NOTES FOR EDITORS

Professor Collinge is a consultant neurologist and Director of the newly formed MRC Prion Unit based at The Imperial College School of Medicine at St Mary?s Hospital. He is also a member of the UK Government?s Spongiform Encephalopathy Advisory Committee (SEAC). The MRC prion unit is was set up in 1999, and its work includes molecular genetic studies of human prion disease and transgenic modelling of human prion diseases.

Prions are unique infectious agents that cause fatal brain diseases such as Creutzfeldt-Jakob disease (CJD) in humans and scrapie and BSE (mad cow disease) in animals. In some circumstances prions from one species of animals can infect another and it is clear that BSE has done this to cause the disease variant CJD in the UK and France. It remains unclear how large an epidemic of variant CJD will occur over the years ahead.

The strain of prion used here to infect the mice is the Sc237 strain (also known as 263K) which infects hamsters, and until now was assumed not to infect mice.

This research was funded by the Medical Research Council and Wellcome Trust.

The Medical Research Council (MRC) is a national organisation funded by the UK tax-payer. Its business is medical research aimed at improving human health; everyone stands to benefit from the outputs. The research it supports and the scientists it trains meet the needs of the health services, the pharmaceutical and other health-related industries and the academic world. MRC has funded work which has led to some of the most significant discoveries and achievements in medicine in the UK. About half of the MRC?s expenditure of £345 million is invested in over 50 of its Institutes and Units, where it employs its own research staff. The remaining half goes in the form of grant support and training awards to individuals and teams in universities and medical schools.

The Wellcome Trust is the world's largest medical research charity with a spend of some £600 million in the current financial year 1999/2000. The Wellcome Trust supports more than 5,000 researchers, at 400 locations, in 42 different countries to promote and foster research with the aim of improving human and animal health. As well as funding major initiatives in the public understanding of science, the Wellcome Trust is the country's leading supporter of research into the history of medicine.

©2002 Medical Research Council

http://www.mrc.ac.uk/index/public_interest/public-press_office/public-press_releases_2000/public-mrc-43-00.htm


and for Gods sake, if someone is smearing this [email protected] all over there kids
heads for lice and did not come up with a TSE, i would say this is good case study;


1) None of our animals that contracted BSE were treated with OP's, even
in utero.
2) My kids were treated with OP's as infants to control head lice. This
seems to be endemic as infection waves in UK primary schools (and
possibly elsewhere).
3) One might argue if the continued use of british beef in the UK was
ethical, none the less it happened. We have a duty to learn from it, not
least a duty to learn on behalf of those people who died so horribly....


NOPE, greed and money is the name of the game, they have known for decades;


STRICTLY PRIVATE AND CONFIDENTIAL 25, AUGUST 1995

snip...

To minimise the risk of farmers' claims for compensation from feed
compounders.

To minimise the potential damage to compound feed markets through adverse publicity.

To maximise freedom of action for feed compounders, notably by
maintaining the availability of meat and bone meal as a raw
material in animal feeds, and ensuring time is available to make any
changes which may be required.

snip...

THE FUTURE

4..........

MAFF remains under pressure in Brussels and is not skilled at
handling potentially explosive issues.

5. Tests _may_ show that ruminant feeds have been sold which
contain illegal traces of ruminant protein. More likely, a few positive
test results will turn up but proof that a particular feed mill knowingly
supplied it to a particular farm will be difficult if not impossible.

6. The threat remains real and it will be some years before feed
compounders are free of it. The longer we can avoid any direct
linkage between feed milling _practices_ and actual BSE cases,
the more likely it is that serious damage can be avoided. ...

SEE full text ;

http://www.bseinquiry.gov.uk/files/yb/1995/08/24002001.pdf



BUT, i applaud ranchers that understand the TSE science and not the hype that surrounds it such as 'reader the second' ;


>>>Look, Mark Purdey, I applaud you for your perserverance, your bravery in taking on the establishment, and your creativity. It may well be that you were instrumental in bringing the familial and other genetic clusters in Slovenia to the attention of science.

I acknowledge that you suffered but your suffering sir is NOTHING compared to the suffering of the families afflicted with CJD and variant CJD and to the extent that your writings are used to ignore public health threats and to avoid taking public health measures that may well protect humans from CJD, then your writings are being ill used. You should acknowledge that and if you do not, I will pay no further attention to you.

Your supporters use your writings to (1) deny that CJD is transmissable from person to person, e.g., via contaminated surgical instruments or tissue or blood donations; (2) reject totally the strong hypothesis that variant CJD is due to the BSE epidemic in the UK being "pushed" over the species barrier. They claim that all cases of human CJD are due to metal contamination. It is they who are perverting your theories and therefore subjecting you to ridicule. Unless you deny these things as well and in which case, you should be ignored since in the case of (1) you deny fact and in the case of (2) you reject a hypothesis that must be accepted for the time being and must lead our public health measures given its strength.

NO ONE has denied that the ultimate cause of TSEs is unknown. However TSEs ARE transmissable between species, albeit not easily, and they are certainly transmissable among the same species. The suffering of the individual and his/her family who contracts CJD or variant CJD is hideous beyond description. If TSEs are your life work, you had better be taking that into consideration.<<<


>>>This is a danger to ranchers and to all humans<<<


INDEED there is;


CJD FARMERS WIFE 1989

http://www.bseinquiry.gov.uk/files/yb/1989/10/13007001.pdf

http://www.bseinquiry.gov.uk/files/yb/1989/10/13003001.pdf


20 year old died from sCJD in USA in 1980 and a 16 year
old in 1981. A 19 year old died from sCJD in
France in 1985. There is no evidence of an iatrogenic
cause for those cases....

http://www.bseinquiry.gov.uk/files/yb/1995/10/04004001.pdf

cover-up of 4th farm worker ???

http://www.bseinquiry.gov.uk/files/yb/1995/10/23006001.pdf

http://www.bseinquiry.gov.uk/files/yb/1995/10/20006001.pdf

CONFIRMATION OF CJD IN FOURTH FARMER

http://www.bseinquiry.gov.uk/files/yb/1995/11/03008001.pdf

now story changes from;

SEAC concluded that, if the fourth case were confirmed, it would be
worrying, especially as all four farmers with CJD would have had BSE
cases on their farms.

to;

This is not unexpected...

was another farmer expected?

http://www.bseinquiry.gov.uk/files/yb/1995/11/13010001.pdf

4th farmer, and 1st teenager

http://www.bseinquiry.gov.uk/files/yb/1996/02/27003001.pdf

2. snip...
Over a 5 year period, which is the time period on which the advice
from Professor Smith and Dr. Gore was based, and assuming a
population of 120,000 dairy farm workers, and an annual incidence
of 1 per million cases of CJD in the general population, a
DAIRY FARM WORKER IS 5 TIMES MORE LIKELY THAN
an individual in the general population to develop CJD. Using the
actual current annual incidence of CJD in the UK of 0.7 per
million, this figure becomes 7.5 TIMES.

3. You will recall that the advice provided by Professor Smith in
1993 and by Dr. Gore this month used the sub-population of dairy
farm workers who had had a case of BSE on their farms -
63,000, which is approximately half the number of dairy farm
workers - as a denominator. If the above sums are repeated using
this denominator population, taking an annual incidence in the general
population of 1 per million the observed rate in this sub-population
is 10 TIMES, and taking an annual incidence of 0.7 per million,
IT IS 15 TIMES (THE ''WORST CASE'' SCENARIO) than
that in the general population...

http://www.bseinquiry.gov.uk/files/yb/1995/01/31004001.pdf



and for those that believe this was a spontaneous event or a happen-stance of bad luck from a spontatneous misfolding PrP, well, dream on. ...TSS


TSS submissions to federal dockets and peer review journals
Importation of Whole Cuts of Boneless Beef from Japan [Docket No. 05-004-1] RIN 0579-AB93 TSS SUBMISSION


http://docket.epa.gov/edkfed/do/EDKStaffItemDetailView?objectId=090007d480993808



http://docket.epa.gov/edkfed/do/EDKStaffAttachDownloadPDF?objectId=090007d480993808



http://docket.epa.gov/edkfed/do/EDKStaffCollectionDetailView?objectId=0b0007d48096b40d



========================================================

========================================================

OLD TSS SUBMISSIONS;



Docket No, 04-047-l Regulatory Identification No. (RIN) 091O-AF46 NEW BSE SAFEGUARDS (comment submission)

https://web01.aphis.usda.gov/regpublic.nsf/0/eff9eff1f7c5cf2b87256ecf000df08d?OpenDocument



Docket No. 03-080-1 -- USDA ISSUES PROPOSED RULE TO ALLOW LIVE ANIMAL
IMPORTS FROM CANADA


https://web01.aphis.usda.gov/BSEcom.nsf/0/b78ba677e2b0c12185256dd300649f9d?OpenDocument&AutoFramed


Docket No. 2003N-0312 Animal Feed Safety System [TSS SUBMISSION]

http://www.fda.gov/ohrms/dockets/dockets/03n0312/03N-0312_emc-000001.txt

Docket Management Docket: 02N-0273 - Substances Prohibited From Use in

Animal Food or Feed; Animal Proteins Prohibited in Ruminant Feed

Comment Number: EC -10

Accepted - Volume 2


http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004be07.html



PART 2


http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004be09.html



PDF]Freas, William TSS SUBMISSION

File Format: PDF/Adobe Acrobat -

Page 1. J Freas, William From: Sent: To: Subject: Terry S. Singeltary

Sr. [[email protected]] Monday, January 08,200l 3:03 PM freas ...



http://www.fda.gov/ohrms/dockets/ac/01/slides/3681s2_09.pdf



Asante/Collinge et al, that BSE transmission to the 129-methionine

genotype can lead to an alternate phenotype that is indistinguishable

from type 2 PrPSc, the commonest _sporadic_ CJD;



http://www.fda.gov/ohrms/dockets/ac/03/slides/3923s1_OPH.htm



Docket Management Docket: 96N-0417 - Current Good Manufacturing Practice
in Manufacturing, Packing, or Holding Dietary Ingredients a
Comment Number: EC -2
Accepted - Volume 7

http://www.fda.gov/ohrms/dockets/dailys/03/Mar03/031403/96N-0417-EC-2.htm


[PDF] Appendices to PL107-9 Inter-agency Working Group Final Report 1-1
File Format: PDF/Adobe Acrobat - View as HTML
Agent, Weapons of Mass Destruction Operations Unit Federal Bureau of
those who provided comments in response to Docket No. ...
Meager 8/18/01 Terry S. Singeltary Sr ...


http://www.aphis.usda.gov/lpa/pubs/pubs/PL107-9_Appen.pdf

Docket No. 2003N-0312 Animal Feed Safety System [TSS SUBMISSION
TO DOCKET 2003N-0312]

http://www.fda.gov/ohrms/dockets/dockets/03n0312/03N-0312_emc-000001.txt

# Docket No: 02-088-1 RE-Agricultural Bioterrorism Protection Act of
2002; [TSS SUBMISSION ON POTENTIAL FOR BSE/TSE & FMD 'SUITCASE BOMBS'] -
TSS 1/27/03 (0)

Docket Management

Docket: 02N-0276 - Bioterrorism Preparedness; Registration of Food Facilities, Section 305
Comment Number: EC-254 [TSS SUBMISSION]

http://www.fda.gov/ohrms/dockets/dockets/02n0276/02N-0276-EC-254.htm


Dockets Entered On October 2, 2003 Table of Contents, Docket #,
Title, 1978N-0301,

OTC External Analgesic Drug Products, ... EMC 7, Terry S. Singeltary Sr.
Vol #: 1, ...

http://www.fda.gov/ohrms/dockets/dailys/03/oct03/100203/100203.htm


Daily Dockets Entered on 02/05/03

DOCKETS ENTERED on 2/5/03. ... EMC 4 Terry S. Singeltary Sr. Vol#: 2.
... Vol#: 1.

03N-0009 Federal Preemption of State & Local Medical Device Requireme. ...


http://www.fda.gov/ohrms/dockets/dailys/03/Feb03/020503/020503.htm


Docket Management

Docket: 02N-0370 - Neurological Devices; Classification of Human Dura Mater

Comment Number: EC -1

Accepted - Volume 1


http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004be11.html


http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004bdfe.html


http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004bdfc.html


Daily Dockets - 04/10/03

... 00D-1662 Use of Xenotransplantation Products in Humans.
EMC 98 Terry S. Singeltary Sr. Vol#: 3. 01F ...
http://www.fda.gov/ohrms/dockets/dailys/03/Apr03/041003/041003.htm - 05-20-2003
- Cached


2003D-0186
Guidance for Industry: Use of Material From Deer and Elk In Animal Feed




EMC 1
Terry S. Singeltary Sr.
Vol #:
1

http://www.fda.gov/ohrms/dockets/dailys/03/Jun03/060903/060903.htm


2003D-0186
Guidance for Industry: Use of Material From Deer and Elk In Animal Feed


EMC 7
Terry S. Singeltary Sr.
Vol #:
1

2003D-0186
Guidance for Industry: Use of Material From Deer and Elk In Animal Feed


EMC 7
Terry S. Singeltary Sr.
Vol #:
1


http://www.fda.gov/ohrms/dockets/dailys/03/oct03/100203/100203.htm

01N-0423 Substances Prohibited from use in animal food/Feed Ruminant

APE 5 National Renderers Association, Inc. Vol#: 2

APE 6 Animal Protein Producers Industry Vol#: 2

APE 7 Darling International Inc. Vol#: 2

EMC 1 Terry S. Singeltary Sr. Vol#: 3

http://www.fda.gov/ohrms/dockets/dailys/01/Oct01/101501/101501.htm

Send Post-Publication Peer Review to journal:


Re: RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob

disease in the United States


Email Terry S. Singeltary:


[email protected]



I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to

comment on the CDC's attempts to monitor the occurrence of emerging

forms of CJD. Asante, Collinge et al [1] have reported that BSE

transmission to the 129-methionine genotype can lead to an alternate

phenotype that is indistinguishable from type 2 PrPSc, the commonest

sporadic CJD. However, CJD and all human TSEs are not reportable

nationally. CJD and all human TSEs must be made reportable in every

state and internationally. I hope that the CDC does not continue to

expect us to still believe that the 85%+ of all CJD cases which are

sporadic are all spontaneous, without route/source. We have many TSEs in

the USA in both animal and man. CWD in deer/elk is spreading rapidly and

CWD does transmit to mink, ferret, cattle, and squirrel monkey by

intracerebral inoculation. With the known incubation periods in other

TSEs, oral transmission studies of CWD may take much longer. Every

victim/family of CJD/TSEs should be asked about route and source of this

agent. To prolong this will only spread the agent and needlessly expose

others. In light of the findings of Asante and Collinge et al, there

should be drastic measures to safeguard the medical and surgical arena

from sporadic CJDs and all human TSEs. I only ponder how many sporadic

CJDs in the USA are type 2 PrPSc?


http://www.neurology.org/cgi/eletters/60/2/176#535



LANCET INFECTIOUS DISEASE JOURNAL


Volume 3, Number 8 01 August 2003


Newsdesk


Tracking spongiform encephalopathies in North America


Xavier Bosch

My name is Terry S Singeltary Sr, and I live in Bacliff, Texas. I lost

my mom to hvCJD (Heidenhain variant CJD) and have been searching for

answers ever since. What I have found is that we have not been told the

truth. CWD in deer and elk is a small portion of a much bigger problem.


49-year-old Singeltary is one of a number of people who have remained

largely unsatisfied after being told that a close relative died from a

rapidly progressive dementia compatible with spontaneous

Creutzfeldt-Jakob disease (CJD). So he decided to gather hundreds of

documents on transmissible spongiform encephalopathies (TSE) and

realised that if Britons could get variant CJD from bovine spongiform

encephalopathy (BSE), Americans might get a similar disorder from

chronic wasting disease (CWD)the relative of mad cow disease seen among

deer and elk in the USA. Although his feverish search did not lead him

to the smoking gun linking CWD to a similar disease in North American

people, it did uncover a largely disappointing situation.


Singeltary was greatly demoralised at the few attempts to monitor the

occurrence of CJD and CWD in the USA. Only a few states have made CJD

reportable. Human and animal TSEs should be reportable nationwide and

internationally, he complained in a letter to the Journal of the

American Medical Association (JAMA 2003; 285: 733). I hope that the CDC

does not continue to expect us to still believe that the 85% plus of all

CJD cases which are sporadic are all spontaneous, without route or source.


Until recently, CWD was thought to be confined to the wild in a small

region in Colorado. But since early 2002, it has been reported in other

areas, including Wisconsin, South Dakota, and the Canadian province of

Saskatchewan. Indeed, the occurrence of CWD in states that were not

endemic previously increased concern about a widespread outbreak and

possible transmission to people and cattle.


To date, experimental studies have proven that the CWD agent can be

transmitted to cattle by intracerebral inoculation and that it can cross

the mucous membranes of the digestive tract to initiate infection in

lymphoid tissue before invasion of the central nervous system. Yet the

plausibility of CWD spreading to people has remained elusive.


Part of the problem seems to stem from the US surveillance system. CJD

is only reported in those areas known to be endemic foci of CWD.

Moreover, US authorities have been criticised for not having performed

enough prionic tests in farm deer and elk.


Although in November last year the US Food and Drug Administration

issued a directive to state public-health and agriculture officials

prohibiting material from CWD-positive animals from being used as an

ingredient in feed for any animal species, epidemiological control and

research in the USA has been quite different from the situation in the

UK and Europe regarding BSE.


Getting data on TSEs in the USA from the government is like pulling

teeth, Singeltary argues. You get it when they want you to have it,

and only what they want you to have.


Norman Foster, director of the Cognitive Disorders Clinic at the

University of Michigan (Ann Arbor, MI, USA), says that current

surveillance of prion disease in people in the USA is inadequate to

detect whether CWD is occurring in human beings; adding that, the

cases that we know about are reassuring, because they do not suggest the

appearance of a new variant of CJD in the USA or atypical features in

patients that might be exposed to CWD. However, until we establish a

system that identifies and analyses a high proportion of suspected prion

disease cases we will not know for sure. The USA should develop a

system modelled on that established in the UK, he points out.



Ali Samii, a neurologist at Seattle VA Medical Center who recently

reported the cases of three hunterstwo of whom were friendswho died

from pathologically confirmed CJD, says that at present there are

insufficient data to claim transmission of CWD into humans; adding that

[only] by asking [the questions of venison consumption and deer/elk

hunting] in every case can we collect suspect cases and look into the

plausibility of transmission further. Samii argues that by making both

doctors and hunters more aware of the possibility of prions spreading

through eating venison, doctors treating hunters with dementia can

consider a possible prion disease, and doctors treating CJD patients

will know to ask whether they ate venison.


CDC spokesman Ermias Belay says that the CDC will not be investigating

the [Samii] cases because there is no evidence that the men ate

CWD-infected meat. He notes that although the likelihood of CWD

jumping the species barrier to infect humans cannot be ruled out 100%

and that [we] cannot be 100% sure that CWD does not exist in humans&

the data seeking evidence of CWD transmission to humans have been very

limited.




http://infection.thelancet.com/journal/journal.isa




he complained in a letter to the Journal of the American Medical



Association (JAMA 2003; 285: 733). I hope that the CDC does not

continue to expect us to still believe that the 85% plus of all CJD

cases which are sporadic are all spontaneous, without route or source.<<<



actually, that quote was from a more recent article in the Journal of

Neurology (see below), not the JAMA article...



Full Text

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

Singeltary, Sr et al. JAMA.2001; 285: 733-734.



http://jama.ama-assn.org/


BRITISH MEDICAL JOURNAL



SOMETHING TO CHEW ON



BMJ



http://www.bmj.com/cgi/eletters/319/7220/1312/b#EL2



BMJ



http://www.bmj.com/cgi/eletters/320/7226/8/b#EL1



THE PATHOLOGICAL PROTEIN

BY Philip Yam

Yam Philip Yam News Editor Scientific American www.sciam.com
http://www.thepathologicalprotein.com/

IN light of Asante/Collinge et al findings that BSE transmission to the
129-methionine genotype can lead to an alternate phenotype that is
indistinguishable from type 2 PrPSc, the commonest _sporadic_ CJD;

-------- Original Message -------- Subject: re-BSE prions propagate as

either variant CJD-like or sporadic CJD Date: Thu, 28 Nov 2002 10:23:43

-0000 From: "Asante, Emmanuel A" To:
"'[email protected]'"

Dear Terry,

I have been asked by Professor Collinge to respond to your request. I am

a Senior Scientist in the MRC Prion Unit and the lead author on the

paper. I have attached a pdf copy of the paper for your attention. Thank

you for your interest in the paper.

In respect of your first question, the simple answer is, yes. As you

will find in the paper, we have managed to associate the alternate

phenotype to type 2 PrPSc, the commonest sporadic CJD.

It is too early to be able to claim any further sub-classification in

respect of Heidenhain variant CJD or Vicky Rimmer's version. It will

take further studies, which are on-going, to establish if there are

sub-types to our initial finding which we are now reporting. The main

point of the paper is that, as well as leading to the expected new

variant CJD phenotype, BSE transmission to the 129-methionine genotype

can lead to an alternate phenotype which is indistinguishable from type

2 PrPSc.



I hope reading the paper will enlighten you more on the subject. If I

can be of any further assistance please to not hesitate to ask. Best wishes.



Emmanuel Asante

<> ____________________________________

Dr. Emmanuel A Asante MRC Prion Unit & Neurogenetics Dept. Imperial

College School of Medicine (St. Mary's) Norfolk Place, LONDON W2 1PG

Tel: +44 (0)20 7594 3794 Fax: +44 (0)20 7706 3272 email:

[email protected] (until 9/12/02)

New e-mail: [email protected] (active from now)

____________________________________

snip...

full text ;

http://www.fda.gov/ohrms/dockets/ac/03/slides/3923s1_OPH.htm


AND the new findings of BASE in cattle in Italy of Identification of a
second bovine amyloidotic spongiform encephalopathy: Molecular
similarities with sporadic

Creutzfeldt-Jakob disease


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


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

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

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

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

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

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

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

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


ALL animals for human/animal consumption must be tested for TSE.

ALL human TSEs must be made reportable Nationally and Internationally, OF ALL AGES...TSS
 

Kathy

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Since the studies done on the effects of Phosmet, did not utilize the same Phosmet formula which was used in the UK, the evidence is not fully substantiated. Yet, this still showed an up-regulation of PrPC on the nerve cell membrane which would allow for more interaction of this protein with the seeds (metallic nanoclusters) causing the crystalline growth.
...induced a marked concentration-dependent increase in the levels of PrP present on the cell

You cannot have prion disease without the host PrPC protein.

Flounder wrote:
would it not have been more easy and very much less expensive for MAFF/USDA et al to jump on the OP bandwagon and save the industry, if OP theory had any credence to it at all? and why did they not?

Why don't you ask them? Maybe the fact that the UK government mandated its use, would lead to lawsuits by the farmers and industry against the government.

There are many false statements about Phosmets use floating about which the UK government promulgates, like - we've been using this chemical since the '60s. However, the concentration of this chemical was steadily increasing over the years. The concentration levels used in the 1982 warble eradication program were never utilized before. Then there was the matter of the suggested half dose treatment two weeks after the first full dose.

Don't forget that Phosmet wasn't only used on cattle. Pigs were treated with it as well for parasites.

flounder writes:
show me the data that ops are in all the primate/mouse transmission studies?

How about you show us! Are there any? I don't think so. You see when you don't want to find something, you just don't look!

Read your own posting again flounder. At the time, there was no evidence to support or exclude their involvement. I would disagree slightly on that, as the Whatley study showed that a modified version of Phosmet did cause the up-regulation of PrPC - this was a good start, but it was never follow through by MAFF.

Ray Bradley, of MAFF, also a paid consultant of ICI - the manufacturer of Phosmet, might be a good person to ask why there wasn't more testing done. And while your talking to him, ask him how come ICI couldn't provide the original formula for Phosmet to be tested; as well, why they couldn't provide the mandated information which listed where and when Phosmet was distributed and sold. Pretty sloppy record keeping.

flounder also reported:
Recombinant mouse cellular prion (r[mouse]PrPC) was exposed to the organophosphorus pesticide Phosmet

The use of "recombinant" mouse prions, come on flounder. We both know that the recombinant form does not utilize the C-terminus of the PrPC or PrPSc protein, which is the most extensive site of copper adherence. Also, tests which do not utilize the active living nerve cells, will not tell the whole story.

As for homogenation. This does not simply mean breaking it apart in a blender to liquify it. The pulvarization of the brain tissue by ceramic beads for long periods of time, along with protease K treatment which denatures proteins causes the breaking apart of aggregates of protease resistant proteins. When they are broken apart to this extreme level, the metallic nanocluster nuclei are once again activated because their binding capacity is restored.

As Vodyanoy stated, the PNCs (proteon nucleating centers) which he examined, had the scavenging capacity of approximately 100,000 hemoglobin molecules. Homogenization breaks these aggragates apart, allowing the energy of the PNC to bind proteins or protein fragments all over again. This is exactly how Dr. Claudio Soto's protein amplification procedure works, except that he adds "sonication" to the mix.
 

Kathy

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Just out in Nature:

Nature 437, 1053-1056 (13 October 2005) | doi: 10.1038/nature04054

Solution structure of a protein denatured state and folding intermediate
T. L. Religa1, J. S. Markson1, U. Mayor1,2, S. M. V. Freund1 and A. R. Fersht1

Top of pageThe most controversial area in protein folding concerns its earliest stages. Questions such as whether there are genuine folding intermediates, and whether the events at the earliest stages are just rearrangements of the denatured state1 or progress from populated transition states2, remain unresolved. The problem is that there is a lack of experimental high-resolution structural information about early folding intermediates and denatured states under conditions that favour folding because competent states spontaneously fold rapidly. Here we have solved directly the solution structure of a true denatured state by nuclear magnetic resonance under conditions that would normally favour folding, and directly studied its equilibrium and kinetic behaviour. We engineered a mutant of Drosophila melanogaster Engrailed homeodomain that folds and unfolds reversibly just by changing ionic strength. At high ionic strength, the mutant L16A is an ultra-fast folding native protein, just like the wild-type protein; however, at physiological ionic strength it is denatured. The denatured state is a well-ordered folding intermediate, poised to fold by docking helices and breaking some non-native interactions. It unfolds relatively progressively with increasingly denaturing conditions, and so superficially resembles a denatured state with properties that vary with conditions. Such ill-defined unfolding is a common feature of early folding intermediate states and accounts for why there are so many controversies about intermediates versus compact denatured states in protein folding.

Top of pageMRC Centre for Protein Engineering and Cambridge University Chemical Laboratories, MRC Centre, Hills Road, Cambridge CB2 2QH, UK
†Present address: Wellcome Trust Cancer Research UK Gurdon Institute, Tennis Court Road, Cambridge CB2 1QN, UK
Correspondence to: A. R. Fersht1 Correspondence and requests for materials should be addressed to A.R.F. (Email: [email protected]).

Received 11 March 2005; Accepted 19 July 2005
 

flounder

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kathy, you conviently ignore my request for documents of the false statement you made? can you please provide this proof?


Kathy wrote in another thread, but yet never documented;

> didn't say that OPs caused prion disease, but that they contributed greatly
> to the UK experience,

and again, could your please reference this materials with scientific data, instead
of hearsay please ???


TSS
 

Mike

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As for homogenation. This does not simply mean breaking it apart in a blender to liquify it. The pulvarization of the brain tissue by ceramic beads for long periods of time, along with protease K treatment which denatures proteins causes the breaking apart of aggregates of protease resistant proteins. When they are broken apart to this extreme level, the metallic nanocluster nuclei are once again activated because their binding capacity is restored.

One "Homogenization" method:
Special care is taken to ensure that the sample contains gray matter since this has the greatest concentration of prions. The sample and a special buffer are placed in an easy–to-use homogenizer bag and subjected to a gentle homogenization. The approximately two-minute homogenization process ensures that the tissue is broken down and the prions are solubilized.

After homogenization, the liquid homogenate is centrifuged. The supernatant of the sample is transferred to a multiple-well plate containing a special enzyme solution called Proteinase K. During incubation, Proteinase K digests the normal prion proteins in the sample, while the abnormal prion proteins (BSE agent) remain intact and bind to the sample well. The sample is now ready for the immunoassay procedure.
 

Kathy

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Apparently flounder can't read!!!!!!!!!!!!!!!!!!!!!!!!!!

Mike, the homogenization procedure used to test for prions is far different from that used to do transmission experiments. Of course in the testing for the presence of prions, you do not want to destroy them. The presence of the PrP amino acid chains attached to the PNCs is necessary to bind to the monoclonal antibodies used in the test kits.
 

bse-tester

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After homogenization, the liquid homogenate is centrifuged. The supernatant of the sample is transferred to a multiple-well plate containing a special enzyme solution called Proteinase K. During incubation, Proteinase K digests the normal prion proteins in the sample, while the abnormal prion proteins (BSE agent) remain intact and bind to the sample well. The sample is now ready for the immunoassay procedure.

Mike, you are quoting almost verbatum from our test protocol. PK resistance is an essential part of the process and the fact that PrPsc is resistant to PK Digestion is crucial to the identification process - period! Homogenization is a commonly accepted testing procedure that is used throughout the world to speed up the testing process through duplication of infectivity. Otherwise, we would all have to wait until the clinical symptoms appeared - if at all- and that would not be a good thing. [Decades in the case of CJD]in humans or months in the lab mouse] Time is most certainly of the essence in the lab especially when trying to develop a protocol that will put forward new and exciting ideas and procedures.
 

flounder

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flounder reads just fine.

apparently kathy can not back up what she states. ...

TSS
 

bse-tester

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Kathy wrote:

the homogenization procedure used to test for prions is far different from that used to do transmission experiments. Of course in the testing for the presence of prions, you do not want to destroy them. The presence of the PrP amino acid chains attached to the PNCs is necessary to bind to the monoclonal antibodies used in the test kits.

This is not exactly correct Kathy. It is possible to use the same homogenate to create an infectivity test as one would use to test for the presence of PrPsc. I am assuming that you are referring to the fact that the formal PrPsc testing procedure includes all of the digestion processes along with separation of the suspended particals and the infectivity test doesn't? An homogenate is nothing more than a glorified, but deadly milkshake so to speak. Also, it is not necessary to use monoclonal antibody to conduct testing for PrPsc. The one advantage of using a mono antibody is that it need not be made when your sample has expired or run out. We produce a specific antibody for our test kit and it can be produced in a quantity that will provide approximately 1 million samples at a cost of about $0.03 per sample. [3 Cents each] Also, I do not know of any PrPsc detection procedure and/or test protocol anywhere that can actually destroy prions in and during the normal test procedures used to identify the presence of PrPsc. In fact Kathy, as you know, prions are virtually indestructable, but, I should add, not completely indestructable though.
 

bse-tester

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Mike, you know that the basic principles of prion testing are virtually the same in all tests. The meat and spuds of the tests that actually work is in the final stages of the protocol and coupled with the correct antibodies and some other rather ingenius methods inserted into the formula, we can set our test apart from the rest as it works each and every time and is able to be replicated by any who wish to try it. The Enfer Test and those tests performed by Dr. Ruth G, are all so similar that they appear to have been written by the same person. It is the nature of the beast that prion tests are so alike, but the one's that work have that something extra that makes them what they are, like ours.
 

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reader (the Second) said:
Kathy said:
Mark sent this message for the Board to me today. Apparently, for whatever computer glitch reason, he is unable to post it himself.
*******************************************************
(from Mark Purdey, Somerset, UK)

I was greatly saddened to read some of the wildly irrelevant and impertinent comments that have been posted about my research data and hypotheses on the origins of TSE.

I feel that my critics need to do their homework first, before launching into their tirade of speculative and misguided comments about the authenticity of my first hand research into TSEs.
...

In this respect, I feel that it is totally unfair that my work is being subjected to this misappropriated assault on your pages.



I also feel that your readers should be aware of the personal and financial hardship that entrepreneurial researchers such as myself have had to endure for the 'crime' of launching fresh observations and ideas into the public arena ...

Whilst many reputable scientific establishments are currently making a small fortune out of the fruits of my own pioneering work, my own life has ironically degenerated into a state of total collapse. All I ask is for a bit of basic human respect, and not for the accolades of acidity that are sent my way nearly everyday. Thank you Kathy, for being the only intelligent and open minded contributor to ranchers.com

Yours,

Mark Purdey

Look, Mark Purdey, I applaud you for your perserverance, your bravery in taking on the establishment, and your creativity. It may well be that you were instrumental in bringing the familial and other genetic clusters in Slovenia to the attention of science.

I acknowledge that you suffered but your suffering sir is NOTHING compared to the suffering of the families afflicted with CJD and variant CJD and to the extent that your writings are used to ignore public health threats and to avoid taking public health measures that may well protect humans from CJD, then your writings are being ill used. You should acknowledge that and if you do not, I will pay no further attention to you.

Your supporters use your writings to (1) deny that CJD is transmissable from person to person, e.g., via contaminated surgical instruments or tissue or blood donations; (2) reject totally the strong hypothesis that variant CJD is due to the BSE epidemic in the UK being "pushed" over the species barrier. They claim that all cases of human CJD are due to metal contamination. It is they who are perverting your theories and therefore subjecting you to ridicule. Unless you deny these things as well and in which case, you should be ignored since in the case of (1) you deny fact and in the case of (2) you reject a hypothesis that must be accepted for the time being and must lead our public health measures given its strength.

NO ONE has denied that the ultimate cause of TSEs is unknown. However TSEs ARE transmissable between species, albeit not easily, and they are certainly transmissable among the same species. The suffering of the individual and his/her family who contracts CJD or variant CJD is hideous beyond description. If TSEs are your life work, you had better be taking that into consideration.
 

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