TSEAC Meeting August 1, 2011 donor deferral Saudi Arabia vCJD risk blood and blood products

Meeting of the Transmissible Spongiform Encephalopathies Advisory Committee

Center Date Time Location

CBER August 1, 2011 9:00 a.m. - 4:30 p.m.

Hilton Washington DC/North, 620 Perry Pkwy., Gaithersburg, MD

Agenda

On August 1, 2011, in the morning, the committee will discuss donor deferral for time spent in Saudi Arabia to reduce the risk of variant Creutzfeldt-Jakob disease (vCJD) by blood and blood products and human cells, tissues and cellular and tissue-based products.

Meeting Materials

Materials for this meeting will be available at:

http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/default.htm1

Public Participation Information

Interested persons may present data, information, or views, orally or in writing, on issues pending before the committee.

Written submissions may be made to the contact person on or before July 25, 2011

Oral presentations from the public will be scheduled between approximately 2:15 p.m. and 2:45 p.m. Those individuals interested in making formal oral presentations should notify the contact person and submit a brief statement of the general nature of the evidence or arguments they wish to present, the names and addresses of proposed participants, and an indication of the approximate time requested to make their presentation on or before July 15, 2011. Time allotted for each presentation may be limited. If the number of registrants requesting to speak is greater than can be reasonably accommodated during the scheduled open public hearing session, FDA may conduct a lottery to determine the speakers for the scheduled open public hearing session. The contact person will notify interested persons regarding their request to speak by July 18, 2011.

Contact Information

Bryan Emery or Rosanna Harvey 1401 Rockville Pike, HFM-71, Rockville, MD 20852 301-827-1277 FAX: 301-827-0294 e-mail: Bryan.Emery@fda.hhs.gov or email: Rosanna.Harvey@fda.hhs.gov

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Greetings Doctor Emery et al @ TSEAC,


I wish to kindly submit the following Meeting August 1, 2011 donor deferral Saudi Arabia vCJD risk blood and blood products.

My main concern is the denial of the same risk factors from atypical CJDs here in the USA from the many overly abundant strains of TSE in animals and man.

IF the study below (see Transmissibility of BSE-L and Cattle-Adapted TME Prion Strain to Cynomolgus Macaque "BSE-L in North America may have existed for decades", IF this comes to be true, as i have believed it to be for years and years, IT is not Saudi Arabia risk factor you should be addressing, it should be the risk factor there from here in the USA and all of North America.

AS the strains, sub-strains of TSE continue to emerge and spread, more and more humans and animals for human and animal consumption will be exposed.

WE know there is some sort of risk factor from the BAXTER study on GSS and blood. WE see now that the Nor-98 atypical scrapie, H-BSE, L-BSE, TME, GSS and some sporadic CJD, all seem to be connected in some way to each other. all of which have been documented in North America. it would be negligent in my opinion to omit this from risk factor assessments. by the time the dots are connected, it will be too late. If accumulation plays a roll, and we accumulate enough of different typical and atypical TSE, what is the threshold from exposure to sub-clinical to clinical (especially now that we know more than one type of TSE can infect a species) ? you cannot answer that. nor can anyone else. so you continue to roll the dice for everyone. we must include all human Transmissible Spongiform Encephalopathy in donor deferral, and we must take an urgent and serious look at Alzheimer's and blood donor risk factor there from, in my opinion.

I hope you can submit this to the TSEAC meeting. if not, please.........PLEASE take time to read the recent scientific studies. the tides turning, however slow it may be, and the science seems to be coming together to show what i have been saying for 14 years. however, it may take another 2 decades for officials and industry to connect the dots$ or admit$ by then it will be much too late.

(please note, the blogs i post my research of data on TSE too, please note i do NOT advertise. i make no money. i simply made a promise to my Mother. i also think science and the truth there from, should be free. i simply use these blogs as a tool to educate the public. ...tss)



please see the follow ;



Bio.108: Transmission of Prion Disease by Multiple, Clinically-Relevant Blood Components Following a Single Blood Transfusion

Sandra McCutcheon,2,† Anthony R. Alejo Blanco,2 E. Fiona Houston,1 Christopher de Wolf,2 Boon Chin Tan,2 Nora Hunter,2 Valerie Hornsey,3 Ian R. MacGregor,3 Christopher V. Prowse,3 Marc Turner3, 4 and Jean C. Manson2

1The University of Glasgow; Glasgow, UK; 2The Roslin Institute and R(D)SVS, University of Edinburgh; Edinburgh, UK; 3Scottish National Blood Transfusion Service; Edinburgh, UK; 4The University of Edinburgh; Edinburgh, UK;†Presenting author; Email: sandra.mccutcheon@roslin.ed.ac.uk

Variant CJD (vCJD) is an incurable, infectious human disease, likely arising from the consumption of BSE-contaminated meat products. While the epidemic appears to be waning, there is much concern that vCJD infection may be amplified/prolonged in humans by the transfusion of contaminated blood products. Since 2004, several cases of transfusion-associated vCJD transmission have been reported. Using the most appropriate animal model available, in which the disease manifested resembles that of humans affected with vCJD, we examined which blood components used in human medicine are likely to pose the greatest risk of transmitting vCJD via transfusion. We collected two full units of blood from BSE-infected donor animals during the pre-clinical phase of infection. Using methods employed by transfusion services we prepared red cell concentrates, plasma and platelets units (including leucoreduced equivalents). Following transfusion to recipients, we showed that all components contain sufficient levels of infectivity to cause disease following only a single transfusion and also that leucoreduction did not prevent disease transmission. These data suggest that all blood components can act as potential vectors for prion transmission and highlight the importance of multiple control measures to minimize the risk of human to human transmission of vCJD by blood transfusion.


PPPM.18: Induction of Ab Amyloidogenesis In Vivo by Blood Transfusion

Rodrigo Morales,1,† Claudia Duran-Aniotz,1, 2 Akihiko Urayama,1 Lisbell Estrada,3 Diego Morales-Scheihing1, 2 and Claudio Soto1

1University of Texas Health Science Center at Houston; Houston, TX USA; 2Universidad de Los Andes; Santiago, Chile; 3Universidad Catolica de Chile; Santiago, Chile†Presenting author; Email: Rodrigo.MoralesLoyola@uth.tmc.edu

Alzheimer disease (AD) is the most common type of senile dementia. Disease manifestation is characterized by progressive impairment of memory and cognition which is triggered by synaptic dysfunction and neuronal loss. Compelling evidence suggests that misfolding and aggregation of Ab is a hallmark event in the disease pathogenesis. An important unanswered question related to AD involves its etiology since over 90% of the AD cases arise sporadically. Interestingly, misfolding and aggregation of proteins is the main feature of other diseases -termed Protein Misfolding Disorders (PMDs)] which include Transmissible Spongiform Encephalopathies (TSEs), among others. Convincing experimental evidences have shown that the only component of the infectious agent in TSEs is the misfolded form of the prion protein. Strikingly, the molecular mechanisms responsible for prion replication are very similar to the process of amyloid formation in all PMDs, suggesting that all these diseases have the inherent capability of being transmissible. Recent reports have shown that intra-cerebral and intra-peritoneal administration of brain homogenates containing Ab aggregates can accelerate the generation of senile plaques in mice models of AD. However, it remains to be demonstrated if this phenomenon can occur by more relevant routes of administration. The aim of this study was to assess whether AD pathogenesis can be induced intravenously, mimicking the know transmission of prion diseases through blood transfusion. For this purpose we used young tg2576 mice which were injected with blood obtained from 12 months old tg2576 mice (AD-blood) that contains a substantial quantity of cerebral Ab deposits. Mice were sacrificed at 250 days old, a time in which these animals scarcely develop Ab deposits. Interestingly, we observed that infusion of AD-blood induces substantial Ab accumulation in animals that without treatment or injected with wild type blood would barely have any detectable Ab lesion. Plaque deposition was mainly present in cortex and hippocampus, being more abundant in the former. In addition, we observed a decrease in memory in mice challenged with AD-blood. Other features such as brain inflammation and synaptic integrity were also measured. Importantly, similar results were obtained in a second and independent experiment performed in a double transgenic mouse model that develops AD plaques as early as 4 months old. Our results indicate that an AD-like pathogenesis can be induced by intravenous administration of AD-blood, presumably through induction of protein misfolding in a similar way as prion diseases. These findings may open a new avenue to understand the origin of sporadic AD and may provide new strategies for disease intervention and prevention.


http://www.prion2011.ca/files/PRION_2011_-_Posters_(May_5-11).pdf


Sunday, June 26, 2011

Risk Analysis of Low-Dose Prion Exposures in Cynomolgus Macaque

http://transmissiblespongiformencephalopathy.blogspot.com/2011/06/risk-analysis-of-low-dose-prion.html



Saturday, June 25, 2011

Transmissibility of BSE-L and Cattle-Adapted TME Prion Strain to Cynomolgus Macaque

"BSE-L in North America may have existed for decades"

http://transmissiblespongiformencephalopathy.blogspot.com/2011/06/transmissibility-of-bse-l-and-cattle.html



Thursday, June 23, 2011

Experimental H-type bovine spongiform encephalopathy characterized by plaques and glial- and stellate-type prion protein deposits

http://transmissiblespongiformencephalopathy.blogspot.com/2011/06/experimental-h-type-bovine-spongiform.html



Monday, June 27, 2011

Comparison of Sheep Nor98 with Human Variably Protease-Sensitive Prionopathy and Gerstmann-Sträussler-Scheinker Disease

http://prionopathy.blogspot.com/2011/06/comparison-of-sheep-nor98-with-human.html


IN reference to the above study, please see ;


Bio.001: Protease-Sensitive Synthetic Prions and Evidence that Tg9949 Mice Do Not Spontaneously Generate Prions

David Colby1,† and Stanley Prusiner2

1University of Delaware; Newark, DE USA; 2University of California, San Francisco; San Francisco, CA USA†Presenting author; Email: colby@udel.edu

The resistance of many forms of PrPSc to protease digestion provides a convenient assay used to identify the presence of prions in tissue samples. However, protease-sensitive prions (sPrPSc) have also been isolated, and many prion strains have been found to be composed of mixtures of sPrPSc and protease resistant prions (rPrPSc). We have generated novel synthetic prions, composed of wild-type PrP, which are serially transmissible in two lines of transgenic mice, result in neuropathology indicative of prion disease, and cause a conformational change in PrP that is not accompanied by resistance to proteinase K. Inoculation of recombinant PrP of residues 89-230, refolded into an amyloid conformation, into Tg9949 mice resulted in the generation of these protease-sensitive prions. In control experiments, Tg9949 mice, which overexpress an N-terminally truncated form of PrP, were found to be prone to late onset neurological dysfunction distinct from prion disease. Control Tg9949 mice lacked both prion neuropathology and any detectable change in the conformation of PrP. Repeated serial passage of age-matched brain material from control Tg9949 mice did not generate prions. Our results demonstrate that sPrPSc of wild-type sequence can be pathogenic and transmissible and suggest that the contribution of sPrPSc may be overlooked in many studies that rely on the measurement of rPrPSc alone.

http://www.prion2011.ca/files/PRION_2011_-_Posters_(May_5-11).pdf


Monday, May 23, 2011

Atypical Prion Diseases in Humans and Animals 2011

Top Curr Chem (2011)

DOI: 10.1007/128_2011_161

# Springer-Verlag Berlin Heidelberg 2011

Michael A. Tranulis, Sylvie L. Benestad, Thierry Baron, and Hans Kretzschmar

Abstract

Although prion diseases, such as Creutzfeldt-Jakob disease (CJD) in humans and scrapie in sheep, have long been recognized, our understanding of their epidemiology and pathogenesis is still in its early stages. Progress is hampered by the lengthy incubation periods and the lack of effective ways of monitoring and characterizing these agents. Protease-resistant conformers of the prion protein (PrP), known as the "scrapie form" (PrPSc), are used as disease markers, and for taxonomic purposes, in correlation with clinical, pathological, and genetic data. In humans, prion diseases can arise sporadically (sCJD) or genetically (gCJD and others), caused by mutations in the PrP-gene (PRNP), or as a foodborne infection, with the agent of bovine spongiform encephalopathy (BSE) causing variant CJD (vCJD). Person-to-person spread of human prion disease has only been known to occur following cannibalism (kuru disease in Papua New Guinea) or through medical or surgical treatment (iatrogenic CJD, iCJD). In contrast, scrapie in small ruminants and chronic wasting disease (CWD) in cervids behave as infectious diseases within these species. Recently, however, so-called atypical forms of prion diseases have been discovered in sheep (atypical/Nor98 scrapie) and in cattle, BSE-H and BSE-L. These maladies resemble sporadic or genetic human prion diseases and might be their animal equivalents. This hypothesis also raises the significant public health question of possible epidemiological links between these diseases and their counterparts in humans.

M.A. Tranulis (*)

Norwegian School of Veterinary Science, Oslo, Norway

e-mail: Michael.Tranulis@nvh.no

S.L. Benestad

Norwegian Veterinary Institute, Oslo, Norway

T. Baron

Agence Nationale de Se´curite´ Sanitaire, ANSES, Lyon, France

H. Kretzschmar

Ludwig-Maximilians University of Munich, Munich, Germany

Keywords Animal Atypical Atypical/Nor98 scrapie BSE-H BSE-L Human Prion disease Prion strain Prion type

http://resources.metapress.com/pdf-preview.axd?code=f433r34h34ugg617&size=largest


snip...

SEE FULL TEXT AND MUCH MORE HERE;

Monday, May 23, 2011

Atypical Prion Diseases in Humans and Animals 2011

http://bse-atypical.blogspot.com/2011/05/atypical-prion-diseases-in-humans-and.html


Monday, June 27, 2011

Zoonotic Potential of CWD: Experimental Transmissions to Non-Human Primates

http://chronic-wasting-disease.blogspot.com/2011/06/zoonotic-potential-of-cwd-experimental.html



Tuesday, June 14, 2011

Clinical research in CJD at a U.S. clinical prion research center: CJD Quinacrine Study results and improved diagnosis of prion disease

http://transmissiblespongiformencephalopathy.blogspot.com/2011/06/clinical-research-in-cjd-at-us-clinical.html


Sunday, May 01, 2011

STUDY OF ATYPICAL BSE 2010 Annual Report May 2011

http://bse-atypical.blogspot.com/2011/05/study-of-atypical-bse-2010-annual.html


Friday, June 03, 2011

Estimation of variant Creutzfeldt-Jakob disease infectivity titers in human blood

http://vcjdtransfusion.blogspot.com/2011/06/estimation-of-variant-creutzfeldt-jakob.html


Saturday, May 14, 2011

USA Blood products, collected from a donor who was at risk for vCJD, were distributed Nationally and Internationally MAY 11, 2011

http://vcjdtransfusion.blogspot.com/2011/05/usa-blood-products-collected-from-donor.html


Sunday, May 1, 2011

W.H.O. T.S.E. PRION Blood products and related biologicals May 2011

http://transmissiblespongiformencephalopathy.blogspot.com/2011/05/who-tse-prion-blood-products-and.html


Saturday, April 30, 2011

Blood product, collected from a donor who was at risk for variant Creutzfeldt-Jakob disease (vCJD), was distributed APRIL 27, 2011

http://vcjdtransfusion.blogspot.com/2011/04/blood-product-collected-from-donor-who.html


Sunday, March 6, 2011

U.K. and U.S.A. vCJD, CJD, TSE screen (a) the blood supply and (b) blood donors Commons Hansard Written Answers and FDA March 2011

http://transmissiblespongiformencephalopathy.blogspot.com/2011/03/uk-and-usa-vcjd-cjd-tse-screen-the.html


Saturday, March 5, 2011

MAD COW ATYPICAL CJD PRION TSE CASES WITH CLASSIFICATIONS PENDING ON THE RISE IN NORTH AMERICA

http://transmissiblespongiformencephalopathy.blogspot.com/2011/03/mad-cow-atypical-cjd-prion-tse-cases.html


Tuesday, April 26, 2011

sporadic CJD RISING Text and figures of the latest annual report of the NCJDRSU covering the period 1990-2009 (published 11th March 2011)

http://creutzfeldt-jakob-disease.blogspot.com/2011/04/sporadic-cjd-rising-text-and-figures-of.html


Tuesday, March 29, 2011

TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY EXPOSURE SPREADING VIA HOSPITALS AND SURGICAL PROCEDURES AROUND THE GLOBE

http://transmissiblespongiformencephalopathy.blogspot.com/2011/03/transmissible-spongiform-encephalopathy.html


FC5.1.1

Transmission Results in Squirrel Monkeys Inoculated with Human sCJD, vCJD, and GSS Blood Specimens: the Baxter Study

Brown, P1; Gibson, S2; Williams, L3; Ironside, J4; Will, R4; Kreil, T5; Abee, C3 1Fondation Alliance BioSecure, France; 2University of South Alabama, USA; 3University of Texas MD Anderson Cancer Center, USA; 4Western General Hospital, UK; 5Baxter BioSience, Austria

Background: Rodent and sheep models of Transmissible Spongiform Encephalopathy (TSE) have documented blood infectivity in both the pre-clinical and clinical phases of disease. Results in a (presumably more appropriate) non-human primate model have not been reported.

Objective: To determine if blood components (red cells, white cells, platelets, and plasma) from various forms of human TSE are infectious.

Methods: Blood components were inoculated intra-cerebrally (0.1 ml) and intravenously (0.5 ml) into squirrel monkeys from 2 patients with sporadic Creutzfeldt- Jakob disease (sCJD) and 3 patients with variant Creutzfeldt-Jakob disease (vCJD). Additional monkeys were inoculated with buffy coat or plasma samples from chimpanzees infected with either sCJD or Gerstmann-Sträussler-Scheinker disease (GSS). Animals were monitored for a period of 5 years, and all dying or sacrificed animals had post-mortem neuropathological examinations and Western blots to determine the presence or absence of the misfolded prion protein (PrPTSE).

Results: No transmissions occurred in any of the animals inoculated with blood components from patients with sporadic or variant CJD. All donor chimpanzees (sCJD and GSS) became symptomatic within 6 weeks of their pre-clinical phase plasmapheresis, several months earlier than the expected onset of illness. One monkey inoculated with purified leukocytes from a pre-clinical GSS chimpanzee developed disease after 36 months.

Conclusion: No infectivity was found in small volumes of blood components from 4 patients with sporadic CJD and 3 patients with variant CJD. ***However, a single transmission from a chimpanzee-passaged strain of GSS shows that infectivity may be present in leukocytes, and the shock of general anaesthesia and plasmspheresis appears to have triggered the onset of illness in pre-clinical donor chimpanzees.



Saturday, September 5, 2009

TSEAC MEETING FEBRUARY 12, 2004 THE BAXTER STUDY GSS

snip...

But the first thing is our own study, and as I mentioned, it's a Baxter primate study, and those are the major participants. And the goal was twofold, and here is the first one: to see whether CJD, either sporadic or familial -- actually it turns out to be the familial CJD is incorrect. It really should be the Fukuoka strain of Gerstmann-Straussler-Scheinker disease. So it's really GSS instead of familial CJD -- when passaged through chimps into squirrel monkeys using purified blood components, very pure blood components.

So this addresses the question that was raised just recently about whether or not red cell infectivity that's been found in rodents is really in the red cells or is it contaminated.

We prepared these samples with exquisite care, and they are ultra-ultra-ultra purified. There's virtually no contamination of any of the components that we looked at ? platelets, red cells, plasma, white cells -- with any other component.

These are a sort of new set of slides, and what I've tried to do is make them less complicated and more clear, but I'm afraid I haven't included the build. So you'll just have to try and follow what I explain with this little red pointer.

There were three initial patients. Two of them had sporadic CJD. One of them had Gerstmann-Straussler-Scheinker syndrome. Brain tissue from each individual patient was inoculated intracerebrally into a pair of chimpanzees. All right?

From those chimps, either plasma or ultra purified -- in fact, everything is ultra-purified. I'll just talk about purified plasma, purified white cells -- were inoculated intracerebrally and intravenously to get the maximum amount of infective load into a pair of squirrel monkeys.

The same thing was done for each of these three sets. This monkey died from non-CJD causes at 34 months post inoculation.

Let me go back for a second. I didn't point out the fact that these were not sacrificed at this point. These chimpanzees were apheresed at 27 weeks when they were still asymptomatic. In this instance, we apheresed them terminally when they were symptomatic.

And before I forget, I want to mention just a little sidelight of this. Chimpanzees in our experience -- and I think we may be the only people that have ever inoculated chimpanzees, and that's no longer a possibility, so this was 20, 30 years ago -- the shortest incubation period of any chimpanzee that we have ever seen with direct intracerebral inoculation is 13 months.

So we chose 27 weeks, which is about seven months, and incidentally typically the incubation period is more like 16 or 18 months. The shortest was 13 months. We chose the 27th week, which is about six and a half months, thinking that this would be about halfway through the incubation period, which we wanted to check for the presence or absence of infectivity.

But within four weeks after the apheresis, which was conducted under general anesthesia for three or four hours apiece, every single one of the six chimpanzees became symptomatic. That is another experiment that I would love to conclude, perhaps because this is simply not heard of, and it very much smells like we triggered clinical illness. We didn't trigger the disease, but it certainly looks like we triggered symptomatic disease at a point that was much earlier than one would have possibly expected.

Maybe it will never be done because it would probably open the floodgates of litigation. There's no end of little things that you can find out from CJD patients after the fact. For example, the neighbor's dog comes over, barks at a patient, makes him fall down, and three weeks later he gets CJD. So you have a lawsuit against the neighbor.

I mean, this is not an unheard of matter, but I do think that physical stress in the form of anesthesia and four hours of whatever goes on with anesthesia, low blood pressure, sometimes a little hypoxemia looks like it's a bad thing.

So here we have the 31st week. All of the chimps are symptomatic, and here what we did was in order to make the most use of the fewest monkeys, which is always a problem in primate research, we took these same three patients and these six chimps. Only now we pooled these components; that is to say, we pooled the plasma from all six chimps. We pooled ultra-purified white cells from all six chimps because here we wanted to see whether or not we could distinguish a difference between intracerebral route of infection and intravenous route of infection.

With respect to platelets and red blood cells, we did not follow that. We inoculated both intracerebral and intravenously, as we had done earlier because nobody has any information on whether or not platelets and red cells are infectious, and so we wanted again to get the maximum.

This is an IV versus IC goal. This one, again, is just getting the maximum load in to see whether there is, in fact, any infectivity in pure platelets, in pure red cells.

And of all of the above, the only transmission of disease related to the inoculation was in a squirrel monkey that received pure leukocytes from the presymptomatic apheresis. So that goes some way to address the question as to whether or not it's a matter of contamination. To date the red cells have not been -- the monkeys that receive red cells have not been observed for more than a year because that was a later experiment.

So we still can't say about red cells, but we're about four and a half years down the road now, and we have a single transmission from purified leukocytes, nothing from plasma and nothing from platelets.

That was the first part of the experiment. The second part was undertaken with the cooperation of Bob Will and others supplying material to us. These were a couple of human, sporadic cases of CJD and three variant cases of CJD from which we obtained buffy coat and plasma separated in a normal way. That is, these are not purified components.

The two cases of sporadic CJD, the plasma was pooled from both patients. The buffy coat was pooled from both patients, and then inoculated intracerebrally and intravenously into three squirrel monkeys each. This is a non-CJD death five years after inoculation. The other animals are still alive.

For variant CJD we decided not to pool. It was more important to eliminate the possibility that there was just a little bit of infectivity in one patient that would have been diluted to extinction, if you like, by mixing them if it were to so occur with two patients, for example, who did not have infectivity. So each one of these was done individually, but the principle was the same: plasma and buffy coat for each patient was inoculated into either two or three squirrel monkeys. This is, again, a non-CJD related death.

In addition to that, we inoculated rain as a positive control from the two sporadic disease cases of human -- from the two human sporadic cases at ten to the minus one and ten to the minus three dilutions. We have done this many, many times in the past with other sporadic patients. So we knew what to expect, and we got exactly what we did expect, namely, after an incubation period not quite two years, all four monkeys developed disease at this dilution and at the minus three dilution, not a whole lot of difference between the two.

Now, these are the crucial monkeys because each one of these monkeys every three to four months was bled and the blood transfused into a new healthy monkey, but the same monkey all the time. So this monkey, for example, would have received in the course of 21 months about six different transfusions of blood from this monkey into this monkey, similarly with this pair, this pair, and this pair. So you can call these buddies. This is sort of the term that was used. These monkeys are still alive.

In the same way, the three human variant CJD specimens, brain, were inoculated into four monkeys, and again, each one of these monkeys has been repeatedly bled at three to four month intervals and that blood transfused into a squirrel monkey, the same one each time. Ideally we would love to have taken bleeding at three months and inoculated a monkey and then let him go, watch him, and then done the same thing at six months. It would have increased the number of monkeys eightfold and just unacceptably expensive. So we did the best we could.

That, again, is a non-CJD death, as is this.

This was of interest mainly to show that the titer of infectivity in brain from variant CJD is just about the same as it from sporadic. We didn't do a minus five and a minus seven in sporadic because we have an enormous experience already with sporadic disease in squirrel monkeys, and we know that this is exactly what happens. It disappears at about ten to the minus five. So the brain titer in monkeys receiving human vCJD is identical to the brain titer in monkeys that have been inoculated with sporadic CJD.

That's the experiment. All of the monkeys in aqua are still alive. They are approaching a five-year observation period, and I think the termination of this experiment will now need to be discussed very seriously in view of a probable six-year incubation period in the U.K. case. The original plan was to terminate the experiment after five years of observation with the understanding that ideally you would keep these animals for their entire life span, which is what we used to do when had unlimited space, money, and facilities. We can't do that anymore.

It's not cheap, but I think in view of the U.K. case, it will be very important to think very seriously about allowing at least these buddies and the buddies from the sporadic CJD to go on for several more years because although you might think that the U.K. case has made experimental work redundant, in point of fact, anything that bears on the risk of this disease in humans is worthwhile knowing, and one of the things we don't know is frequency of infection. We don't know whether this case in the U.K. is going to be unique and never happen again or whether all 13 or 14 patients have received blood components are ultimately going to die. Let's hope not.

The French primate study is primarily directed now by Corinne Lasmezas. As you know, the late Dominique Dromont was the original, originally initiated this work, and they have very active primate laboratory in France, and I'm only going to show two very simple slides to summarize what they did.

The first one is simply to show you the basis of their statement that the IV route of infection looks to be pretty efficient because we all know that the intracerebral route of infection is the most efficient, and if you look at this where they inoculated the same infective load either intracerebrally or intravenously, the incubation periods were not substantially different, which suggests but doesn't prove, but doesn't prove that the route of infection is pretty efficient.

Lower doses of brain material given IV did extend the incubation period and presumably it's because of the usual dose response phenomenon that you see in any infectious disease.

With a whopping dose of brain orally, the incubation period was even lower. Again, just one more example of inefficiency of the route of infection and the necessity to use more infective material to get transmissions.

And they also have blood inoculated IV which is on test, and the final slide or at least the penultimate slide shows you what they have on test and the time of observation, that taken human vCJD and like us inoculated buffy coat, they've also inoculated whole blood which we did not do.

So to a great extent their studies are complementary to ours and makes it all worthwhile.

We have about -- oh, I don't know -- a one to two-year lead time on the French, but they're still getting into pretty good observation periods. Here's three-plus years.

They have variant CJD adapted to the macaque. That is to say this one was passaged in macaque monkeys, the cynomolgus, and they did the same thing. Again, we're talking about a study here in which like ours there are no transmissions. I mean, we have that one transmission from leukocytes, and that's it.

Here is a BSE adapted to the macaque. Whole blood, and then they chose to inoculate leukodepleted whole blood, in both instances IV. Here they are out to five years without a transmission.

And then finally oral dosing of the macaque, which had been infected with -- which was infected with BSE, but a macaque passaged BSE, whole blood buffy coat and plasma, all by the IC route, and they're out to three years.

So with the single exception of the leukocyte transmission from our chimp that was inoculated with a sporadic case of CJD or -- excuse me -- with a GSS, Gerstmann-Straussler, in neither our study nor the French study, which are not yet completed have we yet seen a transmission.

And I will just close with a little cartoon that appeared in the Washington Post that I modified slightly lest you get too wound up with these questions of the risk from blood. This should be a "corrective."

(Laughter.)

DR. BROWN: Thanks.

Questions?

CHAIRPERSON PRIOLA: Yes. Any questions for Dr. Brown? Dr. Linden.

DR. LINDEN: I just want to make sure I understand your study design correctly. When you mention the monkeys that have the IV and IC inoculations, the individual monkeys had both or --

DR. BROWN: Yes, yes, yes. That's exactly right.

DR. LINDEN: So an individual monkey had both of those as opposed to some monkeys had one and some had the other?

DR. BROWN: Correct, correct. Where IC and IV are put down together was IC plus IV into a given monkey.

DR. LINDEN: Into a given monkey. Okay.

And the IC inoculations, where were those given?

DR. BROWN: Right parietal cortex, Southern Alabama.

(Laughter.)

DR. BROWN: Oh, it can't be that clear. Yeah, here, Pierluigi.

CHAIRPERSON PRIOLA: Dr. Epstein.

DR. BROWN: Pierluigi always damns me with feint praise. He always says that's a very interesting study, but. I'm waiting for that, Pierluigi.

I think Jay Epstein --

DR. GAMBETTI: I will say that there's an interesting study and will say, but I just --

(Laughter.)

DR. GAMBETTI: -- I just point of review. You talk about a point of information. You say that -- you mention GSS, I guess, and the what, Fukuowa (phonetic) --

DR. BROWN: Yes, Fukuoka 1.

DR. GAMBETTI: Fukuowa, and is that from the 102, if I remember correctly, of the --

DR. BROWN: Yes, that is correct.

DR. GAMBETTI: Because that is the only one that also --

DR. BROWN: No, it's not 102. It's 101. It's the standard. It's a classical GSS. Oh, excuse me. You're right. One, oh, two is classical GSS. It's been so long since I've done genetics. You're right.

DR. GAMBETTI: Because that is the only one I know, I think, that I can remember that has both the seven kv fragment that is characteristic of GSS, but also the PrPsc 2730. So in a sense, it can be stretching a little bit compared to the sporadic CJD.

DR. BROWN: Yeah, I think that's right. That's why I want to be sure that I made you aware on the very first slide that that was not accurate, that it truly was GSS.

There's a GSS strain that has been adapted to mice, and it's a hot strain, and therefore, it may not be translatable to sporadic disease, correct. All we can say for sure is that it is a human TSE, and it is not variant. I think that's about it.

DR. GAMBETTI: I agree, but this is also not perhaps the best --

DR. BROWN: No, it is not the best. We understand --

DR. GAMBETTI: -- of GSS either.

DR. BROWN: Yeah. If we had to do it over again, we'd look around for a -- well, I don't know. We'd probably do it the same way because we have two sporadics already on test they haven't transmitted, and so you can take your pick of what you want to pay attention to.

Jay?

DR. EPSTEIN: Yes, Paul. Could you just comment? If I understood you correctly, when you did the pooled apheresis plasma from the six chimps when they were symptomatic at 31 weeks, you also put leukocytes into squirrel monkeys in that case separately IV and IC, but in that instance you have not seen an infection come down in squirrel monkey, and the question is whether it's puzzling that you got transmission from the 27-week asymptomatic sampling, whereas you did not see transmission from the 31-week sampling in symptomatic animals.

DR. BROWN: Yes, I think there are two or three possible explanations, and I don't know if any of them are important. The pre-symptomatic animal was almost symptomatic as it turned out so that we were pretty close to the period at which symptoms would being, and whether you can, you know, make much money on saying one was incubation period and the other was symptomatic in this particular case because both bleedings were so close together. That's one possibility.

The other possibility is we're dealing with a very irregular phenomenon and you're not surprised at all by surprises, so to speak so that a single animal, you could see it almost anywhere.

The third is that we, in fact, did just what I suggested we didn't want to do for the preclinical, namely, by pooling we got under the threshold. See?

You can again take that for what it's worth. It is a possible explanation, and again, until we know what the levels of infectivity are and whether by pooling we get under the threshold of transmission, we simply cannot make pronouncements.

CHAIRPERSON PRIOLA: Dr. DeArmond.

DR. DeARMOND: Yeah, it was very interesting data, but the --

(Laughter.)

DR. BROWN: I just love it. Go ahead.

DR. DeARMOND: Two comments. The first one was that the GSS cases, as I remember from reading your publications -- I think Gibbs was involved with them -- when you transmitted the GSS into animals, into monkeys, perhaps I think it was chimps, the transmission was more typical of CJD rather than GSS. There were no amyloid plaques. It was vacuolar degeneration so that you may be transmitting a peculiar form, as I criticized once in Bali and then you jumped all over me about.

DR. BROWN: I may do it again.

DR. DeARMOND: Calling me a bigot and some other few things like that.

(Laughter.)

DR. BROWN: Surely not. I wouldn't have said that.

DR. DeARMOND: So there could be something strange about that particular --

DR. BROWN: Yeah. I think you and Pierluigi are on the same page here. This may be an unusual strain from a number of points of view.

DR. DeARMOND: The other question though has to do with species barrier because the data you're showing is kind of very reassuring to us that it's hard to transmit from blood, but the data from the sheep and from the hamsters and some of the work, I think, that has been done by others, that it's easy in some other animals to transmit, hamster to hamster, mouse to mouse.

Could you comment on the --

DR. BROWN: That's exactly why we went to primates. That's exactly it, because a primate is closer to a human than a mouse is, and that's just common sense.

And so to try and get a little closer to the human situation and not totally depend on rodents for transferrable data, that is why you would use a primate. Otherwise you wouldn't use them. They're too expensive and they cause grief to animal care study people and protocol makers and the whole thing.

Primate studies are a real pain.

DR. DeARMOND: But right now it's inconclusive and you need more time on it.

DR. BROWN: I believe that's true. I think if we cut it off at six years you could still say it was inconclusive, and cutting it off at all will be to some degree inconclusive, and that's just the way it is.

DR. DeARMOND: So what has to be done? Who do you have to convince, or who do we all have to convince to keep that going?

DR. BROWN: Thomas?

Without trying to be flip at all, the people that would be the first people to try to convince would be the funders of the original study. If that fails, and it might for purely practical reasons of finance, then we will have to look elsewhere because I really don't want to see those animals sacrificed, not those eight buddies. Those are crucial animals, and they don't cost a whole lot to maintain. You can maintain eight -- well, they cost a lot from my point of view, but 15 to $20,000 a year would keep them going year after year.

CHAIRPERSON PRIOLA: Dr. Johnson.

DR. JOHNSON: Yeah, Paul, I'm intrigued as you are by the shortening of the incubation period. Have you in all of the other years of handling these animals when they were transfused, when they were flown out to Louisiana at night -- a lot of the stressful things have happened to some of these chimps. Have you ever noticed that before or is this a new observation?

DR. BROWN: Brand new.

MR. JOHNSON: Brand new. Okay.

CHAIRPERSON PRIOLA: Bob, did you want to say something? Dr. Rohwer.

DR. ROHWER: The Frederick fire, wasn't that correlated with a lot of --

DR. BROWN: Not that I k now of, but you may --

DR. ROHWER: Well, that occurred shortly after I came to NIH, and what I remember is that there were a whole bunch of conversions that occurred within the few months following the fire. That was fire that occurred adjacent to the NINDS facility, but in order to protect it, they moved the monkeys out onto the tarmac because they weren't sure it wouldn't burn as well.

DR. BROWN: Well, if you're right, then it's not brand new, but I mean, I'm not sure how we'll ever know because if I call Carlton and ask him, I'm not sure but what I would trust the answer that he gives me, short of records.

You know, Carlot is a very enthusiastic person, and he might say, "Oh, yeah, my God, the whole floor died within three days," but I would want to verify that.

On the other hand, it may be verifiable. There possibly are records that are still extant.

DR. ROHWER: Actually I thought I heard the story from you.

(Laughter.)

DR. BROWN: You didn't because it's brand new for me. I mean, either that or I'm on the way

(Laughter.)

CHAIRPERSON PRIOLA: Dr. Bracey.

DR. BRACEY: I was wondering if some of the variability in terms of the intravenous infection route may be related to intraspecies barriers, that is, the genetic differences, the way the cells, the white leukocytes are processed, whether or not microchimerism is established, et cetera.

DR. BROWN: I don't think that processing is at fault, but the question, the point that you raise is a very good one, and needless to say, we have material with which we can analyze genetically all of the animals, and should it turn out that we get, for example, -- I don't know -- a transmission in one variant monkey and no transmissions in another and a transmission in three sporadic monkeys, we will at that point genetically analyze every single animal that has been used in this study, but we wanted to wait until we could see what would be most useful to analyze.

but the material is there, and if need be, we'll do it.

CHAIRPERSON PRIOLA: Okay. Thank you very much, Dr. Brown.

I think we'll move on to the open public hearing section of the morning.

snip...

http://www.fda.gov/ohrms/dockets/ac/04/transcripts/4019t1.DOC



snip...

see full text ;

http://tseac.blogspot.com/2009/09/tseac-meeting-february-12-2004-baxter.html


Friday, June 03, 2011

Estimation of variant Creutzfeldt-Jakob disease infectivity titers in human blood

http://vcjdtransfusion.blogspot.com/2011/06/estimation-of-variant-creutzfeldt-jakob.html


Wednesday, March 2, 2011

Transmissible Spongiform Encephalopathies Advisory Committee Meeting Transcript Posted: 3/2/2011 Posted: 3/2/2011

October 28, 2010

http://tseac.blogspot.com/2011/03/transmissible-spongiform.html


Tuesday, September 14, 2010

Transmissible Spongiform Encephalopathies Advisory Committee; Notice of Meeting October 28 and 29, 2010 (COMMENT SUBMISSION)

http://tseac.blogspot.com/2010/09/transmissible-spongiform_14.html


Sunday, May 10, 2009

Meeting of the Transmissible Spongiform Encephalopathies Committee On June 12, 2009 (Singeltary submission)

TO : william.freas@fda.hhs.gov

May 8, 2009

Greetings again Dr. Freas, TSEAC et al,

I would kindly, once again, wish to comment at this meeting about the urgent actions that need to be taken asap, to the Meeting of the Transmissible Spongiform Encephalopathies Committee On June 12, 2009. Due to my disability from my neck injury, I will not be attending this meeting either, however I hope for my submission to be read and submitted. ...

IN reply to ;

http://tseac.blogspot.com/2009/05/meeting-of-transmissible-spongiform.html


Friday, June 12, 2009

vCJD-related abnormal prion protein in a person with haemophilia - an update

http://vcjdtransfusion.blogspot.com/2009/06/vcjd-related-abnormal-prion-protein-in.html


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


PDF]Freas, William TSS SUBMISSION

File Format: PDF/Adobe Acrobat -

Page 1. J Freas, William From: Sent: To: Subject: Terry S. Singeltary Sr. [flounder@wt.net]

Monday, January 08,200l 3:03 PM freas ...

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


-----Original Message-----

From: Terry S. Singeltary Sr. [mailto:flounder@wt.net]

Sent: Tuesday, February 18, 2003 12:45 PM

To: Freas, William

Cc: Langford, Sheila

Subject: Re: re-vCJD/blood and meeting of Feb. 20, 2003

Greetings FDA,

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


Tuesday, February 8, 2011

U.S.A. 50 STATE BSE MAD COW CONFERENCE CALL Jan. 9, 2001

http://tseac.blogspot.com/2011/02/usa-50-state-bse-mad-cow-conference.html


Suppressed peer review of Harvard study October 31, 2002.

October 31, 2002 Review of the Evaluation of the Potential for Bovine Spongiform Encephalopathy in the United States Conducted by the Harvard Center for Risk Analysis, Harvard School of Public Health and Center for Computational Epidemiology, College of Veterinary Medicine, Tuskegee University Final Report Prepared for U.S. Department of Agriculture Food Safety and Inspection Service Office of Public Health and Science Prepared by RTI Health, Social, and Economics Research Research Triangle Park, NC 27709 RTI Project Number 07182.024

http://www.fsis.usda.gov/oa/topics/BSE_Peer_Review.pdf


Sunday, February 14, 2010

[Docket No. FSIS-2006-0011] FSIS Harvard Risk Assessment of Bovine Spongiform Encephalopathy (BSE)

http://bseusa.blogspot.com/2010/02/docket-no-fsis-2006-0011-fsis-harvard.html


PLEASE SEE FULL TEXT 98 PAGES HERE ;

[Docket No. FSIS-2006-0011] FSIS Harvard Risk Assessment of Bovine Spongiform Encephalopathy (BSE)

http://www.fsis.usda.gov/OPPDE/Comments/2006-0011/2006-0011-1.pdf


Response to Public Comments on the Harvard Risk Assessment of Bovine Spongiform Encephalopathy

Update, October 31, 2005 INTRODUCTION The United States Department of Agriculture’s Food Safety and Inspection Service (FSIS) held a public meeting on July 25, 2006 in Washington, D.C. to present findings from the Harvard Risk Assessment of Bovine Spongiform Encephalopathy Update, October 31, 2005 (report and model located on the FSIS website: http://www.fsis.usda.gov/Science/Risk_Assessments/index.asp).

Comments on technical aspects of the risk assessment were then submitted to FSIS. Comments were received from Food and Water Watch, Food Animal Concerns Trust (FACT), Farm Sanctuary, R-CALF USA, Linda A Detwiler, and Terry S. Singeltary.

This document provides itemized replies to the public comments received on the 2005 updated Harvard BSE risk assessment. Please bear the following points in mind:

http://www.fsis.usda.gov/PDF/BSE_Risk_Assess_Response_Public_Comments.pdf


From: Terry S. Singeltary Sr.

To: FREAS@CBER.FDA.GOV

Cc: william.freas@fda.hhs.gov ; rosanna.harvey@fda.hhs.gov

Sent: Friday, December 01, 2006 2:59 PM

Subject: Re: TSE advisory committee for the meeting December 15, 2006 [TSS SUBMISSION]

snip...

ONE FINAL COMMENT PLEASE, (i know this is long Dr. Freas but please bear with me)

THE USA is in a most unique situation, one of unknown circumstances with human and animal TSE. THE USA has the most documented TSE in different species to date, with substrains growing in those species (BSE/BASE in cattle and CWD in deer and elk, there is evidence here with different strains), and we know that sheep scrapie has over 20 strains of the typical scrapie with atypical scrapie documented and also BSE is very likely to have passed to sheep. all of which have been rendered and fed back to animals for human and animal consumption, a frightening scenario. WE do not know the outcome, and to play with human life around the globe with the very likely TSE tainted blood from the USA, in my opinion is like playing Russian roulette, of long duration, with potential long and enduring consequences, of which once done, cannot be undone.

These are the facts as i have come to know through daily and extensive research of TSE over 9 years, since 12/14/97. I do not pretend to have all the answers, but i do know to continue to believe in the ukbsenvcjd only theory of transmission to humans of only this one strain from only this one TSE from only this one part of the globe, will only lead to further failures, and needless exposure to humans from all strains of TSE, and possibly many more needless deaths from TSE via a multitude of proven routes and sources via many studies with primates and rodents and other species. ...

Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518

snip... 48 pages...page 1 starts on page 13, then come back to page 1 to finish.....tss

http://www.regulations.gov/fdmspublic/ContentViewer?objectId=09000064801f3413&disposition=attachment&contentType=msw8


TSEAC JUNE 2, 1999

Welcome to the FDA traveling road show

From: TSS

snip...

CHAIRMAN BROWN: A couple of points just to bring your experimental data up to speed. Unpublished further experiments on the mouse model have produced good news and bad news.

The bad news is that we have a disappointingly large number of transmissions following intravenous inoculation of either plasma or Buffy coat. We also have a transmission using whole blood as a transfusion into these mice. So that's not good news.

The other thing that is not too good is that we have now got in this particular model a ratio of five to one, as opposed to ten to one, which was also disappointing.

The only piece of good news in that in terms of experimental data is that we found that, again, in this model, the level of infectivity during the entire incubation period is almost negligible compared to the level of infectivity during the clinical phase of illness. And that is very good news indeed. So these are data that are not yet published but ??

snip...

snip...page 154

CHAIRMAN BROWN: Well, this is exactly why we're here today. Dr. Satcher and the other groups have already decided that this is not worth significant worry with respect to classical CJD, and that new variant was an unknown. And so that's why we're considering specifically new variant because we don't have information specifically on it. I mean, everything we don't have information on becomes a subject for this committee. (Laughter.)

snip...

snip...page 218

MS. HARRELL: Well, I asked him the question, was there a deferral ?? was there deferral criteria for blood donors for classic CJD for people who have either resided or visited the UK.

CHAIRMAN BROWN: I'm sorry. Repeat that, the question.

MS. HARRELL: Is there a deferral policy for blood donors to attempt to reduce the risk of transmitting classic CJD for people who either resided or visited the UK?

DR. SCHONBERGER: The answer is no.

MS. HARRELL: And if there is no risk, if we think that there is no risk of transmitting the whatever to ?? for CJD, what makes this different, for new variant CJD much different?

CHAIRMAN BROWN: That's the first time, Stan, you'll ever hear of prion referred to as a whatever. (Laughter.)

CHAIRMAN BROWN: I mean, I've heard it referred to as a lot of different things. I'm ??

DR. PRUSINER: You've said that many times, Paul. (Laughter.)

CHAIRMAN BROWN: It may be that ??

DR. PRUSINER: Is that in the Congressional Record?

CHAIRMAN BROWN: The issue is not about sporadic CJD. That is the issue we can sort of generically say CJD. Presumably, if the blood from a patient with new variant CJD were infectious, the disease that it would transmit would be new variant CJD. So it's not ??

MS. HARRELL: Okay. So CJD is not transmitted through the blood is what you're saying?

CHAIRMAN BROWN: We have no evidence from looking at populations that that has ever happened. The question is: since we know it can happen when we use experimental models of CJD, we can take CJD blood from one animal and produce the disease in another animal.

So there is the "theoretical possibility" that this might also happen in humans, particularly with a different strain of the disease, which new variant is, about which we don't know a whole lot. That's the question.

DR. SCHONBERGER: Isn't the answer to her question that the incidence of CJD, REDS, classic CJD, is not influenced by whether or not you've lived in the UK between 1980 and 1996 ??

CHAIRMAN BROWN: Yes.

DR. SCHONBERGER: ?? but the incidence of new variant CJD is?

CHAIRMAN BROWN: Yes, 40-love. (Laughter.)


snip...


see more here ;

http://tseac.blogspot.com/2011/06/tseac-june-2-1999-welcome-to-fda.html



Saturday, January 2, 2010

Human Prion Diseases in the United States January 1, 2010 ***FINAL***

http://prionunitusaupdate2008.blogspot.com/2010/01/human-prion-diseases-in-united-states.html


Manuscript Draft Manuscript Number: Title: HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory Article Type: Personal View Corresponding Author: Mr. Terry S. Singeltary, Corresponding Author's Institution: na First Author: Terry S Singeltary, none Order of Authors: Terry S Singeltary, none; Terry S. Singeltary Abstract: TSEs have been rampant in the USA for decades in many species, and they all have been rendered and fed back to animals for human/animal consumption. I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2007.

http://www.regulations.gov/fdmspublic/ContentViewer?objectId=090000648027c28e&disposition=attachment&contentType=pdf


my comments to PLosone here ;

http://www.plosone.org/annotation/listThread.action?inReplyTo=info%3Adoi%2F10.1371%2Fannotation%2F04ce2b24-613d-46e6-9802-4131e2bfa6fd&root=info%3Adoi%2F10.1371%2Fannotation%2F04ce2b24-613d-46e6-9802-4131e2bfa6fd


Wednesday, March 31, 2010

Atypical BSE in Cattle

To date the OIE/WAHO assumes that the human and animal health standards set out in the BSE chapter for classical BSE (C-Type) applies to all forms of BSE which include the H-type and L-type atypical forms. This assumption is scientifically not completely justified and accumulating evidence suggests that this may in fact not be the case. Molecular characterization and the spatial distribution pattern of histopathologic lesions and immunohistochemistry (IHC) signals are used to identify and characterize atypical BSE. Both the L-type and H-type atypical cases display significant differences in the conformation and spatial accumulation of the disease associated prion protein (PrPSc) in brains of afflicted cattle. Transmission studies in bovine transgenic and wild type mouse models support that the atypical BSE types might be unique strains because they have different incubation times and lesion profiles when compared to C-type BSE. When L-type BSE was inoculated into ovine transgenic mice and Syrian hamster the resulting molecular fingerprint had changed, either in the first or a subsequent passage, from L-type into C-type BSE. In addition, non-human primates are specifically susceptible for atypical BSE as demonstrated by an approximately 50% shortened incubation time for L-type BSE as compared to C-type. Considering the current scientific information available, it cannot be assumed that these different BSE types pose the same human health risks as C-type BSE or that these risks are mitigated by the same protective measures.

This study will contribute to a correct definition of specified risk material (SRM) in atypical BSE. The incumbent of this position will develop new and transfer existing, ultra-sensitive methods for the detection of atypical BSE in tissue of experimentally infected cattle.

http://www.prionetcanada.ca/detail.aspx?menu=5&dt=293380&app=93&cat1=387&tp=20&lk=no&cat2


Thursday, August 12, 2010

Seven main threats for the future linked to prions

First threat

The TSE road map defining the evolution of European policy for protection against prion diseases is based on a certain numbers of hypotheses some of which may turn out to be erroneous. In particular, a form of BSE (called atypical Bovine Spongiform Encephalopathy), recently identified by systematic testing in aged cattle without clinical signs, may be the origin of classical BSE and thus potentially constitute a reservoir, which may be impossible to eradicate if a sporadic origin is confirmed. ***Also, a link is suspected between atypical BSE and some apparently sporadic cases of Creutzfeldt-Jakob disease in humans. These atypical BSE cases constitute an unforeseen first threat that could sharply modify the European approach to prion diseases.

Second threat

snip...

http://www.neuroprion.org/en/np-neuroprion.html


http://prionpathy.blogspot.com/2010/08/seven-main-threats-for-future-linked-to.html


14th ICID International Scientific Exchange Brochure -

Final Abstract Number: ISE.114

Session: International Scientific Exchange

Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America

update October 2009

T. Singeltary

Bacliff, TX, USA

Background:

An update on atypical BSE and other TSE in North America. Please remember, the typical U.K. c-BSE, the atypical l-BSE (BASE), and h-BSE have all been documented in North America, along with the typical scrapie's, and atypical Nor-98 Scrapie, and to date, 2 different strains of CWD, and also TME. All these TSE in different species have been rendered and fed to food producing animals for humans and animals in North America (TSE in cats and dogs ?), and that the trading of these TSEs via animals and products via the USA and Canada has been immense over the years, decades.

Methods:

12 years independent research of available data

Results:

I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2009. With all the science to date refuting it, to continue to validate this old myth, will only spread this TSE agent through a multitude of potential routes and sources i.e. consumption, medical i.e., surgical, blood, dental, endoscopy, optical, nutritional supplements, cosmetics etc.

Conclusion:

I would like to submit a review of past CJD surveillance in the USA, and the urgent need to make all human TSE in the USA a reportable disease, in every state, of every age group, and to make this mandatory immediately without further delay. The ramifications of not doing so will only allow this agent to spread further in the medical, dental, surgical arena's. Restricting the reporting of CJD and or any human TSE is NOT scientific. Iatrogenic CJD knows NO age group, TSE knows no boundaries. I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Gajdusek, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route.

http://ww2.isid.org/Downloads/14th_ICID_ISE_Abstracts.pdf



Thursday, February 24, 2011

The risk of variant Creutzfeldt-Jakob disease among UK patients with bleeding disorders, known to have received potentially contaminated plasma products

http://vcjdtransfusion.blogspot.com/2011/02/risk-of-variant-creutzfeldt-jakob.html


Saturday, January 22, 2011

Alzheimer's, Prion, and Neurological disease, and the misdiagnosis there of, a review 2011

http://transmissiblespongiformencephalopathy.blogspot.com/2011/01/alzheimers-prion-and-neurological.html



CJD1/9 0185

Ref: 1M51A

IN STRICT CONFIDENCE

Dr McGovern From: Dr A Wight

Date: 5 January 1993

Copies: Dr Metters

Dr Skinner

Dr Pickles

Dr Morris

Mr Murray

TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES

1. CMO will wish to be aware that a meeting was held at DH yesterday, 4 January, to discuss the above findings. It was chaired by Professor Murray (Chairman of the MRC Co-ordinating Committee on Research in the Spongiform Encephalopathies in Man), and attended by relevant experts in the fields of Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the spongiform encephalopathies, and by representatives of the MRC and AFRC.

2. Briefly, the meeting agreed that:

i) Dr Ridley et als findings of experimental induction of p amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegenerative disorders;

ii) there were no immediate implications for the public health, and no further safeguards were thought to be necessary at present; and

iii) additional research was desirable, both epidemiological and at the molecular level. Possible avenues are being followed up by DH and the MRC, but the details will require further discussion.

93/01.05/4.1tss

http://collections.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf



BSE101/1 0136

IN CONFIDENCE

5 NOV 1992

CMO From: Dr J S Metters DCMO 4 November 1992

TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES

1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have recognized the public sensitivity of these findings and intend to report them in their proper context. This hopefully will avoid misunderstanding and possible distortion by the media to portray the results as having more greater significance than the findings so far justify.

2. Using a highly unusual route of transmission (intra-cerebral injection) the researchers have demonstrated the transmission of a pathological process from two cases one of severe Alzheimer's disease the other of Gerstmann-Straussler disease to marmosets. However they have not demonstrated the transmission of either clinical condition as the "animals were behaving normally when killed'. As the report emphasizes the unanswered question is whether the disease condition would have revealed itself if the marmosets had lived longer. They are planning further research to see if the conditions, as opposed to the partial pathological process, is transmissible.

What are the implications for public health?

3. . The route of transmission is very specific and in the natural state of things highly unusual. However it could be argued that the results reveal a potential risk, in that brain tissue from these two patients has been shown to transmit a pathological process. Should therefore brain tissue from such cases be regarded as potentially infective? Pathologists, morticians, neuro surgeons and those assisting at neuro surgical procedures and others coming into contact with "raw" human brain tissue could in theory be at risk. However, on a priori grounds given the highly specific route of transmission in these experiments that risk must be negligible if the usual precautions for handling brain tissue are observed.

92/11.4/1-1

BSE101/1 0137

4. The other dimension to consider is the public reaction. To some extent the GSS case demonstrates little more than the transmission of BSE to a pig by intra-cerebral injection. If other prion diseases can be transmitted in this way it is little surprise that some pathological findings observed in GSS were also transmissible to a marmoset. But the transmission of features of Alzheimer's pathology is a different matter, given the much greater frequency of this disease and raises the unanswered question whether some cases are the result of a transmissible prion. The only tenable public line will be that "more research is required" before that hypothesis could be evaluated. The possibility on a transmissible prion remains open. In the meantime MRC needs carefully to consider the range and sequence of studies needed to follow through from the preliminary observations in these two cases. Not a particularly comfortable message, but until we know more about the causation of Alzheimer's disease the total reassurance is not practical.

JS METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832

121/YdeStss

92/11.4/1.2

http://collections.europarchive.org/tna/20080102232842/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf



http://betaamyloidcjd.blogspot.com/


Oral presentations

Oral.01: Changing Spectrum of Prions

Stanley Prusiner

University of California San Francisco, Institute for Neurodegenerative Diseases; San Francisco, CA USA

Prions are self-propagating forms of proteins found in eukaryotes. Prions are created from benign, cellular precursor proteins by a posttranslational modification that is self-perpetuating. Often the prion form of the protein is aggregated and assembles into amyloid polymers. Prions can be inherited both genetically and epigenetically. In neurodegenerative diseases, the formation of prions is heritable through mutations in the gene encoding the cellular form of the prion protein. In fungi, the prion state is epigenetically transferred from mother to daughter cells.

Historically, prions were confined to a small group of infectious CNS illnesses including Creutzfeldt-Jakob disease (CJD) and kuru of humans, scrapie of sheep, bovine spongiform encephalopathy, and chronic wasting disease of deer and elk. CJD can present as an infectious, inherited or sporadic illness. In all three manifestations of the disease, the cellular prion protein (PrPC) refolds into the disease-causing isoform (PrPSc). A truncated form of PrPSc readily polymerizes into amyloid fibrils and forms PrP amyloid plaques. Prion strains composed of different conformers of PrPScSc have been identified. Subsequently, prions were recognized in fungi and studied extensively using yeast. Recently, self-propagation of altered proteins that cause several neurodegenerative diseases, including Alzheimer disease and the tauopathies, has been demonstrated using cultured cell and transgenic mouse models. Increasing evidence argues that the Ab peptide acts as a prion in that it stimulates the de-novo formation of more Ab peptide. Similarly, the aggregates of Tau provoke the assembly of more aggregated Tau. In addition, fetal grafts of substantia nigra in patients with advanced Parkinson’s disease exhibit Lewy bodies, arguing that a-synuclein may act as a prion. Misfolded a-synuclein is thought to transit from the patient’s neurons to those in the graft, where it stimulates the de-novo formation of aberrantly folded a-synuclein into Lewy bodies.

The spread of misprocessed proteins in the human CNS is also consistent with the Ab peptide, hyperphosphorylated Tau and misfolded a-synuclein being prions. In Alzheimer disease, Ab plaques and neurofibrillary tangles (NFTs) begin in the entorhinal cortex and spread throughout the brain. In a delayed form of traumatic brain injury, NFTs appear to spread outward from points of impact. Misfolded a-synuclein has been found along the vagus nerve where it appears to migrate retrograde into the CNS.

Increasing evidence that posttranslationally altered proteins are responsible for the major neurodegenerative diseases widens the spectrum of prion disorders. Moreover, prions with glutamine/asparagine-rich regions like those in yeast and aplysia have given unique insights into the normal function of alternatively processed, self-propagating proteins.

http://www.prion2011.ca/files/PRION_2011_-_Posters_(May_5-11).pdf


Wednesday, January 5, 2011

ENLARGING SPECTRUM OF PRION-LIKE DISEASES Prusiner Colby et al 2011 Prions

David W. Colby1,* and Stanley B. Prusiner1,2

http://cshperspectives.cshlp.org/content/3/1/a006833.full.pdf+html


http://betaamyloidcjd.blogspot.com/2011/01/enlarging-spectrum-of-prion-like.html


Friday, September 3, 2010

Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids, Prionpathy, Prionopathy, TSE

http://betaamyloidcjd.blogspot.com/2010/09/alzheimers-autism-amyotrophic-lateral.html


Thursday, December 23, 2010

Alimentary prion infections: Touch-down in the intestine, Alzheimer, Parkinson disease and TSE mad cow diseases $ The Center for Consumer Freedom

http://betaamyloidcjd.blogspot.com/2010/12/alimentary-prion-infections-touch-down.html


Saturday, March 22, 2008

10 Million Baby Boomers to have Alzheimer's in the coming decades

snip...

Alzheimer’s disease is the seventh leading cause of all deaths in the United States and the fifth leading cause of death in Americans older than the age of 65 years. More than 5 million Americans are estimated to have Alzheimer’s disease. Every 71 seconds someone in America develops Alzheimer’s disease; by 2050 it is expected to occur every 33 seconds. During the coming decades, baby boomers are projected to add 10 million people to these numbers. By 2050, the incidence of Alzheimer’s disease is expected to approach nearly a million people per year, with a total estimated prevalence of 11 to 16 million persons. Significant cost implications related to Alzheimer’s disease and other dementias include an estimated $148 billion annually in direct (Medicare/Medicaid) and indirect (eg, caregiver lost wages and out-of-pocket expenses, decreased business productivity) costs. Not included in these figures are the estimated 10 million caregivers who annually provide $89 billion in unpaid services to individuals with Alzheimer’s disease.

snip...

http://www.alzheimersanddementia.org/webfiles/images/journals/jalz/JALZ_739.pdf



see full text and more ;

http://betaamyloidcjd.blogspot.com/2008/03/10-million-baby-boomers-to-have.html


http://betaamyloidcjd.blogspot.com/


TSS



UPDATE JULY 27, 2011


August 1, 2011 Transmissible Spongiform Encephalopathies Advisory Committee Meeting Draft Agenda (PDF - 18KB)




Posted: 7/27/2011



http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/TransmissibleSpongiformEncephalopathiesAdvisoryCommittee/UCM265683.pdf


August 1, 2011 Transmissible Spongiform Encephalopathies Advisory Committee Meeting: Issue Summary (PDF - 154KB)
Posted: 7/27/2011


http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/TransmissibleSpongiformEncephalopathiesAdvisoryCommittee/UCM265682.pdf



----- Original Message -----



From: Emery, Bryan (CBER)



To: 'Terry S. Singeltary Sr.'



Cc: Emery, Bryan (CBER)



Sent: Friday, July 22, 2011 9:47 AM



Subject: RE: TSEAC Meeting August 1, 2011 donor deferral Saudi Arabia vCJD risk blood and blood products



Hi Mr. Singeltary,



Your statement will be provided to the members and will be placed in the meetings display folder for the public to see. Come or attend via webcast.



thanks for your public participation



LCDR Bryan Emery



--------------------------------------------------------------------------------



From: Terry S. Singeltary Sr. [mailto:flounder9@verizon.net]



Sent: Wednesday, June 29, 2011 3:54 PM



To: Emery, Bryan (CBER)



Cc: Harvey, Rosanna; BSE-L@LISTS.AEGEE.ORG; CJD-L@LISTS.AEGEE.ORG; cjdvoice@yahoogroups.com; BLOODCJD@YAHOOGROUPS.COM; Advocatejr@aol.com; COTTWEST@SILCOM.COM; Dave Cavenaugh



Subject: TSEAC Meeting August 1, 2011 donor deferral Saudi Arabia vCJD risk blood and blood products



Meeting of the Transmissible Spongiform Encephalopathies Advisory Committee



Center Date Time Location



CBER August 1, 2011 9:00 a.m. - 4:30 p.m.



Hilton Washington DC/North, 620 Perry Pkwy., Gaithersburg, MD



Agenda



snip...end...TSS



Wednesday, June 29, 2011



TSEAC Meeting August 1, 2011 donor deferral Saudi Arabia vCJD risk blood and blood products



http://tseac.blogspot.com/2011/06/tseac-meeting-august-1-2011-donor.html




Bio.108: Transmission of Prion Disease by Multiple, Clinically-Relevant Blood Components Following a Single Blood Transfusion



Sandra McCutcheon,2,† Anthony R. Alejo Blanco,2 E. Fiona Houston,1 Christopher de Wolf,2 Boon Chin Tan,2 Nora Hunter,2 Valerie Hornsey,3 Ian R. MacGregor,3 Christopher V. Prowse,3 Marc Turner3, 4 and Jean C. Manson2



1The University of Glasgow; Glasgow, UK; 2The Roslin Institute and R(D)SVS, University of Edinburgh; Edinburgh, UK; 3Scottish National Blood Transfusion Service; Edinburgh, UK; 4The University of Edinburgh; Edinburgh, UK;†Presenting author; Email: sandra.mccutcheon@roslin.ed.ac.uk



Variant CJD (vCJD) is an incurable, infectious human disease, likely arising from the consumption of BSE-contaminated meat products. While the epidemic appears to be waning, there is much concern that vCJD infection may be amplified/prolonged in humans by the transfusion of contaminated blood products. Since 2004, several cases of transfusion-associated vCJD transmission have been reported. Using the most appropriate animal model available, in which the disease manifested resembles that of humans affected with vCJD, we examined which blood components used in human medicine are likely to pose the greatest risk of transmitting vCJD via transfusion. We collected two full units of blood from BSE-infected donor animals during the pre-clinical phase of infection. Using methods employed by transfusion services we prepared red cell concentrates, plasma and platelets units (including leucoreduced equivalents). Following transfusion to recipients, we showed that all components contain sufficient levels of infectivity to cause disease following only a single transfusion and also that leucoreduction did not prevent disease transmission. These data suggest that all blood components can act as potential vectors for prion transmission and highlight the importance of multiple control measures to minimize the risk of human to human transmission of vCJD by blood transfusion.



PPPM.18: Induction of Ab Amyloidogenesis In Vivo by Blood Transfusion



Rodrigo Morales,1,† Claudia Duran-Aniotz,1, 2 Akihiko Urayama,1 Lisbell Estrada,3 Diego Morales-Scheihing1, 2 and Claudio Soto1



1University of Texas Health Science Center at Houston; Houston, TX USA; 2Universidad de Los Andes; Santiago, Chile; 3Universidad Catolica de Chile; Santiago, Chile†Presenting author; Email: Rodrigo.MoralesLoyola@uth.tmc.edu



Alzheimer disease (AD) is the most common type of senile dementia. Disease manifestation is characterized by progressive impairment of memory and cognition which is triggered by synaptic dysfunction and neuronal loss. Compelling evidence suggests that misfolding and aggregation of Ab is a hallmark event in the disease pathogenesis. An important unanswered question related to AD involves its etiology since over 90% of the AD cases arise sporadically. Interestingly, misfolding and aggregation of proteins is the main feature of other diseases -termed Protein Misfolding Disorders (PMDs)] which include Transmissible Spongiform Encephalopathies (TSEs), among others. Convincing experimental evidences have shown that the only component of the infectious agent in TSEs is the misfolded form of the prion protein. Strikingly, the molecular mechanisms responsible for prion replication are very similar to the process of amyloid formation in all PMDs, suggesting that all these diseases have the inherent capability of being transmissible. Recent reports have shown that intra-cerebral and intra-peritoneal administration of brain homogenates containing Ab aggregates can accelerate the generation of senile plaques in mice models of AD. However, it remains to be demonstrated if this phenomenon can occur by more relevant routes of administration. The aim of this study was to assess whether AD pathogenesis can be induced intravenously, mimicking the know transmission of prion diseases through blood transfusion. For this purpose we used young tg2576 mice which were injected with blood obtained from 12 months old tg2576 mice (AD-blood) that contains a substantial quantity of cerebral Ab deposits. Mice were sacrificed at 250 days old, a time in which these animals scarcely develop Ab deposits. Interestingly, we observed that infusion of AD-blood induces substantial Ab accumulation in animals that without treatment or injected with wild type blood would barely have any detectable Ab lesion. Plaque deposition was mainly present in cortex and hippocampus, being more abundant in the former. In addition, we observed a decrease in memory in mice challenged with AD-blood. Other features such as brain inflammation and synaptic integrity were also measured. Importantly, similar results were obtained in a second and independent experiment performed in a double transgenic mouse model that develops AD plaques as early as 4 months old. Our results indicate that an AD-like pathogenesis can be induced by intravenous administration of AD-blood, presumably through induction of protein misfolding in a similar way as prion diseases. These findings may open a new avenue to understand the origin of sporadic AD and may provide new strategies for disease intervention and prevention.



http://www.prion2011.ca/files/PRION_2011_-_Posters_(May_5-11).pdf





Tuesday, July 26, 2011



Irhad Rizvo Durakovic has lost his fight to nvCJD R.I.P.



http://creutzfeldt-jakob-disease.blogspot.com/2011/07/irhad-rizvo-durakovic-has-lost-his.html



http://transmissiblespongiformencephalopathy.blogspot.com/



http://vcjdtransfusion.blogspot.com/



http://creutzfeldt-jakob-disease.blogspot.com/




Wednesday, July 27, 2011



HIQA says vCJD blood filter not justified



[Posted: Wed 27/07/2011 http://www.irishhealth.com/]





http://vcjdtransfusion.blogspot.com/2011/07/hiqa-says-vcjd-blood-filter-not.html




----- Original Message -----



From: "Terry S. Singeltary Sr."



To:



Sent: Wednesday, June 29, 2011 2:54 PM



Subject: [CJD-L] TSEAC Meeting August 1, 2011 donor deferral Saudi Arabia vCJD risk blood and blood products



Meeting of the Transmissible Spongiform Encephalopathies Advisory Committee



Center Date Time Location



CBER August 1, 2011 9:00 a.m. - 4:30 p.m.



Hilton Washington DC/North, 620 Perry Pkwy., Gaithersburg, MD



Agenda



On August 1, 2011, in the morning, the committee will discuss donor deferral for time spent in Saudi Arabia to reduce the risk of variant Creutzfeldt-Jakob disease (vCJD) by blood and blood products and human cells, tissues and cellular and tissue-based products.



SNIP...



Wednesday, June 29, 2011



TSEAC Meeting August 1, 2011 donor deferral Saudi Arabia vCJD risk blood and blood products



http://tseac.blogspot.com/2011/06/tseac-meeting-august-1-2011-donor.html





TSS