Emerging Infectious Diseases: CJD, BSE, SCRAPIE, CWD, PRION, TSE Evaluation to Implementation for Transfusion and Transplantation September 2010

Emerging Infectious Diseases: CJD, BSE, SCRAPIE, CWD, PRION, TSE Evaluation to Implementation for Transfusion and Transplantation September 2010

February 22, 2010: Vaccines and Related Biological Products Advisory Committee Transcripts (PDF - 193KB) Posted: 7/21/2010

snip...

Now let me just review quickly the status of bovine spongiform encephalopathy which has been the first of the animal diseases, clearly transmissible to human beings. The first case was diagnosed in 1986. Presumably animals were infected probably five or six years earlier. Feed ban, the first of several feed bans was imposed in the United Kingdom in 1990.

In 1988, the disease peaked among cattle. There were something over 37,000 cases a year in the U.K., in 1992 declined thereafter. Last year in the U.K. only 12 cases were seen.

There are 24 other countries that have had BSE, world total more than 187,000 cases diagnosed, reports there must have been many more that were not diagnosed.

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We have had in the United States three cases. One came in from Canada, diagnosed in 2003, one in 2006, and one in 2007. Canada has now had 18 recognized cases. So far as I know, all of those cases in Canada in the western part of the country.

There are only six cases that have high prevalence of BSE. And I -- but a number of other cases, there's -- and other countries, they are still seeing cases. Twelve countries have reported no cases since 2008 including the United States. But, unfortunately, last year there were 14 countries, and two have subsequently fallen off the list, Denmark and the Czech Republic. The point is that this disease is still around, and it's not clear when it will finally be eradicated.

In addition, the United Kingdom shows widespread exports of meat and bone meal, the presumed vector of this infection, sold all over the world including the United States. But large amounts where sold into the former Soviet Union and the Southeast Asia. They have reported no cases, but we wonder if their surveillance systems are very robust. And in any case, we must still consider this potentially a worldwide infection of cattle, fortunately

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coming under control in Western Europe and we hope in North America as well.

The World Organization for Animal Health, the OIE, has started to a system of BSE risk categorization. Two categories of interest, one negligible BSE risk, and the other controlled BSE risk. I won't go through the details of their criteria. There are in the slide; there are 11 negligible risk countries including Australia, New Zealand, some countries of northern Europe and South America; 32 controlled risk countries including the USA.

I must say I am a little uncomfortable categorizing the USA risk together with those of the U.K., Portugal, and Spain. But, so far as I know, the USDA has accepted their classification. It hasn't, not at least publicly, challenged them. The concern with BSE is that it is -- has transmitted disease to human beings, variant CJD, first described in the medical literature in 1996. The first teenager became ill probably in 1994, very different from sporadic CJD in its epidemiology. Much younger kids in their teens have been found with it in mean age 29 years or slightly shorter duration, some differences in clinical presentation and there are

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differences in the pathology.

Perhaps 15 percent of patients with Creutzfeldt-Jakob disease have amyloid plaques. All the patients with variant CJD have had amyloid plaques, often -- sorry always surrounded, at least some of them with these haloes or vacuoles called florid or flower like plaques. And their accumulations in variant CJD of prion protein in lymphoid tissues visible under the light microscope. And no one has to work very hard to find prion protein, never seen by you know, histo-chemistry in sporadic CJD. So it's a different looking disease.

As Sue summarized for you earlier today, there are now, I have got 218 cases of variant CJD, 172 of them in the United Kingdom, 46 outside the United Kingdom. Some of them were clearly acquired in the United Kingdom. We've had three cases in the United States, two of whom were long-time residents of the United Kingdom and one a long-term resident of Saudi Arabia; one case in Canada, also a long-time resident of the United Kingdom.

Deaths in the United Kingdom peaked about eight years after the peak of BSE diagnosed in cattle. One could use that to approximate a possible incubation

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period. Sue has already reported to you the four transfusion transmitted cases which were, what, on occasion are our concern in this group. And, as most of you know, in February of last year the United Kingdom reported a case of what appeared to be a pre-clinical infection in an elderly man who was a -- had hemophilia and had been receiving treatments with a plasma derived factor, factor 8.

One of the donors to the factor 8 he received was identified with variant CJD although an epidemiological study in the United Kingdom suggested that at least given some assumptions of prevalence, he might have been equally likely to have been infected from one of the non-implicated batches. Of course, it is not possible to know. The incubation periods are important because that lets us make some projections about how long someone might be carrying a transmissible agent in blood. To me, one of the most informative cases is a case in Japan, who spent only 24 days in the United Kingdom and three days in France, 12 years before returning Japan. Japan has some small amount of BSE on its own but the most probable

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source of his infection was the United Kingdom and it gives you a 12-year incubation period.

And the few other people who came down after exposures in the United Kingdom, their exposures were much longer so it's harder to calculate an incubation period. But they fall into that approximate range. The transfusions transmitted cases had somewhat shorter incubation period, anywhere from 6.3 to 8.5 years and the plasma derivative associated case, you can't see it on this projection, but it is 11 years if the implicated donor was, in fact, the source.

Steve Anderson and Hong Yang have done distributions of the likely incubation periods of persons with the methionine homonzygous and other genotypes. And the disturbing thing is it's certainly possible that there are going to be long tails to the number of people incubating variant CJD. And at the end of last year, Cosky (phonetic) and colleagues described typical variant CJD in a person heterozygous for methionine and valium at codon 129. Now we know that people with all genotypes presumably can be expected to come down with infection.

We hope that the peak will be much smaller in

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people with heterozygous genotype who make up about 50 percent of the population in the United Kingdom and probably about the same here. But if it is going to be like sporadic CJD, incubation periods may well exceed 35 years and even 40 years. And those folks are out there and we don't know how many of them are -- will have agent in blood or how long it will last or how much there would be.

I want to mention this because from a public health point of view keeping the cattle herd free of disease is probably the single most important thing that we can do. And in the context of the United States, the single most important measure taken is to prevent the feeding of contaminated material to a cattle, a feed ban line to affect here removing most mammalian proteins from cattle feed in 1997. And that was expanded in 2008, went into implementation last year to keep the highest risk material, that is brain and spinal cord of animals, over the age of 30 months from rendering for feeding to any kind of farm animals to prevent -- or pet food also to prevent cross-contamination on farms which was a problem

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in the United Kingdom.

There won't be time to talk about it, but there has been considerably more trouble with dura mater allograft which has infected over 150 recipients. Corneas have infected a couple of people with Creutzfeldt-Jakob disease and neuro surgical instruments. We have been over the both the blood red blood cells -- by the way, all four of the transfusion transmitted cases were in non-nuclear reduced to red cell concentrates. However, I think the plasma derivative case suggests that that is not going to be enough to remove risk to a safe level.

The general methods for managing risks we have already discussed. Risk can be accepted, reduced by restricting use of product or screening or manufacturing processes. And the FDA is particularly concerned with validating screening tests and validating methods that purport to remove infected material from final products. That's not just blood products; that's all biological products.

In January of 2007, the agency published a proposed medical products rule. I won't go into it except to express my own personal concern about fetal bovine

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serum because fetal bovine serum comes from the carcasses of gravid older cows which means that their nervous systems are at greater likelihood, if there is any BSE left in the country, of getting into the product and fetal calf serum is so widely used in vaccines and other biological products.

I have given you a timeline of the history of TSEs and FDA blood safety policies merged. Really the history of really begins in 1978 when Elias and Laura Manuelidis first detected CJD agent in blood of experimentally infected guinea pigs. This was confirmed in 1983 and in the 1983, the FDA issued its first guidance of recommending withdrawal of CJD implicated blood components when a donor had subsequently come down with CJD. I won't go into details, but as most of you know those deferral recommendations were made progressively more stringent over the years.

What do we know about the infection agent in the blood? Almost everything we know we have learned from the work of Bob Rohwer, originally with Paul Brown, later with Luisa Gregori, some work of Paul Brown with Larisa Cervenakova. In experimentally infected hamsters, the

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infectivity is first detectable in blood about 50 percent of the way through incubation period and the amounts detected continued to rise progressively until the animal becomes ill and has to be terminated.

But the amounts are very low. They almost never exceed 10 infectious doses per milliliter which is plenty to infect a recipient, but makes it very difficult to detect because of sampling problems. It makes it very difficult to detect the infectious agent.

In the blood, infectivity can be found in all components. But the components that seem to be intrinsically infected are the nucleated cells and the plasma. Considerable amount of infectivity appears to be intrinsic to the plasma which, of course, contaminates all the other components.

General methods to reducing the risk -- reduce the risk of exposure to the BSE agent through diet and that is what we try to do with the geographic deferrals or other exposures, deferring for use of U.K. bovine insulin, no longer marketed in this country, reduce the risk that the donor was exposed to vCJD of human origin and that means nobody transfused in U.K. after 1980. In 2005-2006,

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we proposed modifying that to defer for transfusion in France. There has also been some consideration, at least in the U.K., of deferring people who had risk surgical procedures. We haven't done that.

I won't go through the 2002 deferral guidance which is as most of you know still in force. The proposed modification, we hope, will be finalized this year. It's a striking difference between what's been seen with recipients of implicated transfusions in the United Kingdom and those receiving implicated sporadic CJD transfusions in the United States, described last year by Carrie Dorsey and colleagues from the American Red Cross building on work that was started, I believe, by Marion Sullivan supported by the CDC.

Out of the 26 recipients of labile components of receiving transfusion in the United Kingdom, four of them have already come down with variant CJD whereas 144 recipients have implicated components in the United States. Nobody has been recognized with CJD.

Now the intensity of surveillance is not as good here. A lot of the patients did not get autopsies and some of the recipients received blood collected more than

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five before onset. And then so it is not clear that all the donors would have had agent in their blood. But it is reassuring as far as it goes. Is it sufficiently reassuring to change FDA's guidance? It hasn't yet.

Mark Walderhaug showed you this sensitivity analysis performed by Steve Anderson and Hong Yang showing that for plasma derivatives the reduction of infectivity by manufacturing is the single most important factor in reducing the risk. And based on this, the division of hematology has entertained requests or has solicited efforts to validate those steps being used to manufacture various plasma, plasma derivatives and has entertained requests for label claims.

The model for concluding that a method for reducing infectivity is effective was taken from what is done with viruses. For viruses, a process has to -- in order to have a claim has to have at least two effective orthogonal steps to remove or inactivate virus. Each step should drop at least four logs. One of the steps should inactivate the virus. There should be mass balance that you should know where all of the virus that disappeared went, and you should be able to inactivate or remove at

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least three logs more than the amount that you think might be present in a worst case.

Of course, we can't do that for spongiform encephalopathies, but we have seen some clearance data presented, first to reiterate that PrPTSE clearance would be acceptable only as a preliminary assessment of probable effectiveness. That is if you do clearance study and you can't get rid of all the abnormal PrPTSE, then you might not want to waste time with that method of removal so that infectivity still required -- demonstration of removal of infectivity still requires bioassays in animals and, of course, it's infectivity that is the actual adverse event of concern.

Our pilot studies with our U.S. licensed plasma-derived factor VIII have all showed substantial clearance of model TSE agents of at least four logs and the product used in the United Kingdom is not licensed in this country. Five products have been granted label claims. Unfortunately, none of those was based on an inactivation step, they were all removal steps of greater concern because, of course, that agent if it is not inactivated, is still available on the filters to infect a subsequent

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product if not discarded. And no claim of complete elimination of a TSE agent has been allowed.

It would be very good if we could do Andy Morton test. And you may recall that in 2006 we had a whole session of TSE advisory committee of tests that were in development. The desirable property is that they should be suitable to test individual donations, high throughput, highly analytical sensitivity that is to detect very low concentrations of PrPTSE and all of them that I am aware of are based on -- test and developmental based on the detection of abnormal PRP. They should have reasonable clinical sensitivity. We wouldn't require that every single infected donor be detected. I don't know how you determine that in the first place, but it should be able to eliminate a reasonable number of infected donors from the donor pool.

And it should to have a high specificity that is the inability to discriminate PrPTSE from other proteins yielding a low false-positive rate. And that's a problem. Luisa Gregori summarized at our last TSE meeting all the proteins that are present in human plasma, all of them in great excess to what one would expect for PrPTSE. The

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greatest problem is that there is perhaps ten to the fifth more normal PRP circulating in plasma than what you would expect based on the same -- based on the ratio determined from normal PRP to abnormal PRP in brain, you can predict, what if the ratio stays the same which we don't know, but what it would be in plasma and the PrPTSE would be present in an excess of a hundred thousand fold.

That's important because if you don't get rid of all the normal PRP, or if it is alive and it is supposed to be specific detects even a little bit of the normal PRP, there goes your specificity. And, in fact, nobody has successfully validated one of the tests yet.

Analytical studies, the U.K. has actually a committee that set up an algorithm for what it's going to take to get a test approved in the United Kingdom. There should be convincing analytical studies followed by spiking studies with blinded panels of human plasmas spiked with TSE infected brain tissues. If it does well on that, then with spleen tissue which is supposed to more like blood. Then the test should be able to detect endogenously infected blood from available animal models.

It would be even better if endogenously vCJD

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infected nonhuman primate blood could be detected because then exactly the same reagents that are proposed for human use could be used, which of course you can't do with rodents because of the failure of cross-reactivity. And it would nice to have a well characterized human vCJD blood reference material, but not even the U.K. has that.

I won't dwell on it, but there are a number of companies have advertised that they had promising tests and development. We had eight or perhaps it was nine presented in 2006, all except two or three have fallen silent now without bringing a test to market.

Luisa did a web search for the June meeting of last year and found that four other companies were still trying to develop a useful antemortem human blood test. The -- one of the companies, Amorfix, was reporting a specificity study using 10,000 reactive blood donors. Out of 10,000 tested -- six positives out of 10,000 tested in France. It might have been a little reassuring if they used a country that hadn't had 25 cases of variant Creutzfeldt-Jakob disease but that's what they had.

Two of the tests were based on an apparent amplification of abnormal protein. One of them used an

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interesting palindromic peptide. They have fallen silent now. The other one, Amprion, is using a very interesting technique called Protein Misfolding Cyclical Amplification. And the basic principle seems to work that as you take a very small amount of abnormal prion protein, abnormal brain tissue, do repeated sonications and the amount of protein increases to a level detectable by Western blot.

To my knowledge, this method has not been subjected to the traditional kind of analysis, comparative analysis side by side with blinded replica, unknown dilutions in plasma or serum compared with other detection methods. The developer of the method is going to be speaking at the FDA on the 26th of May. Perhaps he will have more information to share with us. You are all welcome. Well, not all of you, the room isn't that big. But some of you are welcome there, are welcome to come. We had mentioned that there is an absence of -- we have given up on human reference materials. They are just not going to be available but Corinne Lasmezas and colleagues have a very interesting model of infection of cynomolgus macaques with variant CJD agent. The infectivity is present in blood and Luisa Gregori is

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leading a new effort in the FDA. We finally have approvals and funding and the inoculum and she is going to be infecting cynomolgus macaques and collecting blood at intervals through symptomatic disease.

What we don't have is a well validated sensitive mouse assay because we certainly can't assay for infectivity in other cynomolgus monkeys which would have been the classical way to try to do it. I won't mention this, but she is also working on the use of urine as an alternative test material because in rodents infectivity can be detected in urine. But that's not been done in human urine, but it's very little -- very little investigation has been done with human urine. And in any case, it probably it isn't going to be a suitable donor screening testing in any case.

I share with Sue some sense of enthusiasm for the possibility of blood filters. There are two of them that have been described publicly. We think there may be others in development. The MacoPharma/Prometic: P-Capt Prion Reduction Filter and then the Pall Corporation has a filter. The U.K. Advisory Committee on Safety of Blood, Tissues, and Organs some months ago recommended using a --

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one of the filters with leuco reduction to treat blood for recipients in the U.K. under the age of 13.

But the filters are not available in the United States. And of course, here the risk-cost benefit ratio would be quite different from the U.K. because our prevalence is presumably much lower than it is in the U.K.

So to conclude we agree that ante-mortem assays for PrPTSE in blood and tissue donors would be useful. We encourage them; we don't have any available yet. I don't believe that any national authority has approved a test for practical use. There is no proof of concept that PrPTSE is even present in plasma and no test in development to my knowledge has convincingly identified vCJD infected or any other TSE infected human blood. There are some intriguing reports about animals.

There are unresolved issues regarding tests for TSE in blood. There are no TSE blood reference materials, human or nonhuman nor primate blood reference materials available. There has been no confirmatory assay described. And as for other infections of low prevalence, any analytically good but imperfect screening test, any such test would have a very low positive predictive value

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which means that most of the positives would be false positives leading to continuing significant donor deferrals and exceptionally difficult donor counseling.

PrP-removal filters have already been recommended in the U.K. but they are not available in the United States. The continued deferral of donors at increased risk for vCJD both food borne and blood borne seems reasonable. It's a low tech approach. It's probably been effective in reducing the risk of transfusion transmitted vCJD here. Of our three vCJD patients identified, two of them -- none of them was a blood donor but had they tried, two of them would have been deferred, the third would not.

It probably causes less emotional distress to be deferred for geographical reason than to get a false positive test result. But the default policy, we acknowledge, is extremely wasteful because it's deferring many otherwise suitable donors. We should probably continue deferring donors transfused in countries with possible high prevalence of preclinical variant CJD, currently the U.K. and France.

But the good news to me is that the need for

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donor deferrals and for testing and filtering would -- should decline as more countries implement effective anti-BSE food and animal feed precautions. And with that, I close. Sorry, if I ran a little bit over.

(Applause)

Q & A

DR. ALTER: Are there any questions? I think everybody wants -- Steve?

STEVE: Yeah, I have one quick one. I noticed from the slides on the actual FDA deferral policies from the guidance in 2002 that, if I read them correctly, the exclusion -- deferral criteria for visiting the U.K. are time limited, 1980 to 1996, but the criteria for visiting France or the rest of Europe are to the present. And I wonder if you have thought about reexamining whether to the present is still indicative given the low rates of vCJD these days?

DR. ASHER: Yes. We have thought about it. And I can only speak for myself but we have thought about it a lot. There are certain problems in Europe. We had a

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discussion of food protections in the European Union at the June meeting. And the problem is deciding when which country implemented the same level of food protection that we have considered acceptable in the United Kingdom. But in principle, you are absolutely, you are -- also the cross border exchange in food is greater in continental Europe than it is in spite of the Eurostar Britain is still separated geographically from the rest of -- it's a great train by the way to recommend, but at any rate there are certain difficulties in drawing a bright line between countries.

And I'm -- we didn't get a great deal of assistance from the European Union. Their feeling is they have the directives in place and every country is supposed to be following those directives, and therefore we should assume that they are following those directives and maybe we should. But, in principle, I think that you are absolutely right. When other countries reach the level of food chain protections we have considered acceptable, in the U.K. I can't see any reason for considering that risk to be any greater than that in the U.K. The problem is making the decision country by country.

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DR. ALTER: Okay. Well, we are little bit behind. We can all try to get --- (tape interruption.)

SESSION 3: ROUNDTABLE DISCUSSION

February 22, 2010: Vaccines and Related Biological Products Advisory Committee Transcripts (PDF - 193KB) Posted: 7/21/2010

Emerging Infectious Diseases: Evaluation to Implementation for Transfusion and Transplantation Safety Public Workshop Transcript - Day 1 (PDF - 572KB)

Emerging Infectious Diseases: Evaluation to Implementation for Transfusion and Transplantation Safety Public Workshop Transcript - Day 2 (PDF - 496KB)



http://www.fda.gov/downloads/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/UCM214030.pdf




http://www.fda.gov/downloads/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/UCM214031.pdf





PRION 2010

International Prion Congress: From agent to disease September 8–11, 2010 Salzburg, Austria


PPo3-11:

Blood Transmission Experiments in Primates: Squirrel Monkeys (the Baxter Study)

Paul Brown, James Ironside, Susan Gibson, Robert G. Will, Thomas R. Kreil and Christian Abee

Plasma and buffy coat samples from 2 sCJD and 3 vCJD cases were inoculated i.c. and i.v. into a total of 21 squirrel monkeys. Pooled brain from the 3 vCJD patients titered 106 LD50/g (i.c.). Whole blood from each of 4 monkeys inoculated with 10% vCJD brain homogenate was transfused i.v. to individual recipient monkeys at approximately 3-month intervals during the incubation and clinical stages of disease in the donor animals. Plasma, RBC’s, platelets, and purified leukocytes from 6 chimpanzees infected with either human sCJD or GSS were inoculated i.c. and i.v. into 12 monkeys. In the entire group of monkeys inoculated with blood or blood components, only a single neuropathologically-verified transmission occurred within a 5-year observation period, in an animal inoculated with leukocytes from a pair of GSS-infected chimpanzee.

Conclusions. In a primate model highly susceptible to TSE (the squirrel monkey), infectivity was not detected (<10>92%. Due to limited data and knowledge of vCJD, the model estimates are uncertain. This analysis identifies critical data gaps in understanding the risk of TTvC, and provides a tool to inform regulatory decision-making.




PPo4-20:

All Clinically Relevant Components, from Prion Infected Blood Donors, can Cause Disease Following a Single Transfusion

Sandra McCutcheon,1 Fiona E. Houston,2 Anthony R. Alejo-Blanco,1 Christopher de Wolf,1 Boon Chin Tan,1 Anthony Smith,3 Nora Hunter,1 Valerie S. Hornsey,4 Ian R. MacGregor,4 Christopher V. Prowse,4 Marc Turner5 and Jean C. Manson1 1The Roslin Institute; Roslin, Edinburgh UK; 2The University of Glasgow; Glasgow, UK; 3The Institute for Animal Health; Compton, Berkshire UK; 4National Science Laboratory; Scottish National Blood Transfusion Service (SNBTS); Edinburgh, UK; 5University of Edinburgh and SNBTS; Edinburgh, UK

Key words: blood, prion, BSE, transfusion

Introduction. To date, there have been over 220 cases of vCJD worldwide, likely acquired directly from bovine sources. There is concern that human to human transmission from individuals sub-clinically infected with vCJD may amplify/prolong a vCJD epidemic. The area of greatest concern in this respect is blood transfusion, of which there have been several reported cases. Here we examined which blood components are likely to pose the greatest risk of transmitting vCJD via blood transfusion using our sheep BSE model.

Results. 67% of donors have been confirmed as having BSE. We have recorded 25 positive transmissions of BSE following transfusion of non-leucodepleted blood components and 2 transmissions resulting from the transfusion of leucoreduced red cells and leucoreduced plasma.

Conclusion. We show that all components, prepared to the same criteria as used in human medicine, contain sufficient levels of infectivity to cause disease in recipients following a single blood transfusion. Leucoreduction of plasma and red cell concentrates does not remove infectivity. These data indicate the importance of devising appropriate control measures to minimise the risk of human to human transmission of vCJD by blood transfusion. Department of Health, UK (007/0162).

Methods. Sheep were orally infected with bovine BSE brain homogenate. We collected two full-sized donations of whole blood, before the onset of clinical signs. The following components were transfused into naive recipients: whole blood, red cell concentrates buffy coat, plasma and platelet units. We also transfused leucoreduced plasma, platelets and red cells. We collected a unit of whole blood from selected primary recipients for transfusion into secondary recipients.




PPo4-21:

The Risk of Variant Creutzfeldt-Jakob Disease (vCJD) Among UK Patients with Bleeding Disorders, Known to Have Received Clotting Factors Linked to Donors who Subsequently Developed vCJD

Syed M.A. Zaman,1 Nicky Connor,1 Noel Gill,1 Carolyn M. Millar,2,6 Mike Makris,3,6 Benedict Palmer4 and Frank G.H. Hill5,6 1CJD Section, Health Protection Agency Centre for Infections; London, UK; 2Department of Haematology; Imperial College; London, UK; 3University of Sheffield; Royal Hallamshire Hospital; Sheffield, UK; 4National Haemophilia Database; Manchester, UK; 5The Children’s Hospital NHS Foundation Trust; Birmingham, UK; 6Members of the Transfusion Transmitted Infection Working Party of the UK; Haemophilia Centre Doctors’ Organisation (UKHCDO); Sheffield, South Yorkshire UK

The risk of Creutzfeldt-Jakob Disease (vCJD) from potentially infected plasma products remains un-quantified. This risk has been assessed for 787 UK bleeding disorder patients prospectively followed-up for 10–20 years through the UK Haemophilia Centre Doctors’ Organisation (UKHCDO) Surveillance Study. These patients were treated with any of 25 ‘implicated’ clotting factor batches from 1987–1999, which included in their manufacture plasma from eight donors who subsequently developed vCJD. VCJD infectivity of these batches was estimated using plasma fraction infectivity estimates and batch manufacturing data. The quantity of implicated batches received by these patients was obtained. Total vCJD infectivity received by each patient has been estimated by cumulating infectivity from all doses received in their lifetime. Of 787 patients, 604 (77%) were followed-up for over 13 years since exposure to an implicated batch. By end 2008, none of these patients had developed vCJD. For these 604 patients, the estimated vCJD risk is <1%



http://www.prion2010.org/bilder/prion_2010_program_latest_w_posters_4_.pdf?139&PHPSESSID=a30a38202cfec579000b77af81be3099



some additional interesting studies.


O.10.5


A novel human prion disease affecting subjects with the three prion protein codon 129 genotypes: could it be the sporadic form of Gerstmann-Straussler?


Pierluigi Gambetti Case Western Reserve University, USA


Background: We recently described a novel prion disease, named protease-sensitive prionopathy or PSPr, characterized by the presence of an abnormal prion protein (PrP) that was 60 fold less protease resistant than that of sporadic Creutzfeldt-Jakob disease (sCJD) and on immunoblot generated a distinct ladder-like profile. All affected subjects where homozygous for valine at codon 129 (VV) and had no mutation in the PrP gene.


Methods: We have characterized several new cases in our surveillance and received from Europe.


Results: 1) A disease overall similar to that reported in the 129VV subjects also affects subjects that are methionine/valine heterozygous (MV) and methionine homozygous (MM) at codon 129 and have no PrP gene mutation; 2) The clinical and histopathological features of the new MV and MM PSPr cases are similar but distinguishable from those of the original VV cases; 3) The electrophoretic profiles generated by the abnormal PrP isoforms associated with the MV and MM cases are similar to VV cases but show increasing levels of proteaseresistance; 3) abnormal tau is present in all three genotypic forms of PSPr with features apparently similar to those of primary tauopathies placing PSPr at the intersection of tauopathies and prion diseases. Discussion: Will focus on: 1) the features of the abnormal PrP in the newly discovered 129MV and 129MM PSPr; 2) the effect of the 129 polymorphism on PSPr compared to that on sCJD; 3) the relationship of PSPr with tauopathies; 4) whether PSPr now with the three 129 genotypic forms is the long sought sporadic form of GSS.


(Supported by NIH AG-14359, NS052319, CDC UR8/CCU515004).


http://www.neuroprion.org/resources/pdf_docs/conferences/prion2009/prion2009_bookofabstracts.pdf



I ask Professor Kong ;


Thursday, December 04, 2008 3:37 PM
Subject: RE: re--Chronic Wating Disease (CWD) and Bovine Spongiform Encephalopathies (BSE): Public Health Risk Assessment


''IS the h-BSE more virulent than typical BSE as well, or the same as cBSE, or less virulent than cBSE? just curious.....''


Professor Kong reply ;


.....snip


''As to the H-BSE, we do not have sufficient data to say one way or another, but we have found that H-BSE can infect humans. I hope we could publish these data once the study is complete. Thanks for your interest.''


Best regards,


Qingzhong Kong,


PhD Associate Professor Department of Pathology Case Western Reserve University Cleveland, OH 44106 USA

END...TSS


P26


TRANSMISSION OF ATYPICAL BOVINE SPONGIFORM ENCEPHALOPATHY (BSE) IN HUMANIZED MOUSE MODELS


Liuting Qing1, Fusong Chen1, Michael Payne1, Wenquan Zou1, Cristina Casalone2, Martin Groschup3, Miroslaw Polak4, Maria Caramelli2, Pierluigi Gambetti1, Juergen Richt5*, and Qingzhong Kong1 1Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA; 2CEA, Istituto Zooprofilattico Sperimentale, Italy; 3Friedrich-Loeffler-Institut, Germany; 4National Veterinary Research Institute, Poland; 5Kansas State University, Diagnostic Medicine/Pathobiology Department, Manhattan, KS 66506, USA. *Previous address: USDA National Animal Disease Center, Ames, IA 50010, USA


Classical BSE is a world-wide prion disease in cattle, and the classical BSE strain (BSE-C) has led to over 200 cases of clinical human infection (variant CJD). Two atypical BSE strains, BSE-L (also named BASE) and BSE-H, have been discovered in three continents since 2004. The first case of naturally occurring BSE with mutated bovine PrP gene (termed BSE-M) was also found in 2006 in the USA. The transmissibility and phenotypes of these atypical BSE strains/isolates in humans were unknown. We have inoculated humanized transgenic mice with classical and atypical BSE strains (BSE-C, BSE-L, BSE-H) and the BSE-M isolate. We have found that the atypical BSE-L strain is much more virulent than the classical BSE-C. The atypical BSE-H strain is also transmissible in the humanized transgenic mice with distinct phenotype, but no transmission has been observed for the BSE-M isolate so far.


III International Symposium on THE NEW PRION BIOLOGY: BASIC SCIENCE, DIAGNOSIS AND THERAPY 2 - 4 APRIL 2009, VENEZIA (ITALY)


http://www.istitutoveneto.it/prion_09/Abstracts_09.pdf



P02.35


Molecular Features of the Protease-resistant Prion Protein (PrPres) in H-type BSE


Biacabe, A-G1; Jacobs, JG2; Gavier-Widén, D3; Vulin, J1; Langeveld, JPM2; Baron, TGM1 1AFSSA, France; 2CIDC-Lelystad, Netherlands; 3SVA, Sweden


Western blot analyses of PrPres accumulating in the brain of BSE-infected cattle have demonstrated 3 different molecular phenotypes regarding to the apparent molecular masses and glycoform ratios of PrPres bands. We initially described isolates (H-type BSE) essentially characterized by higher PrPres molecular mass and decreased levels of the diglycosylated PrPres band, in contrast to the classical type of BSE. This type is also distinct from another BSE phenotype named L-type BSE, or also BASE (for Bovine Amyloid Spongiform Encephalopathy), mainly characterized by a low representation of the diglycosylated PrPres band as well as a lower PrPres molecular mass. Retrospective molecular studies in France of all available BSE cases older than 8 years old and of part of the other cases identified since the beginning of the exhaustive surveillance of the disease in 20001 allowed to identify 7 H-type BSE cases, among 594 BSE cases that could be classified as classical, L- or H-type BSE. By Western blot analysis of H-type PrPres, we described a remarkable specific feature with antibodies raised against the C-terminal region of PrP that demonstrated the existence of a more C-terminal cleaved form of PrPres (named PrPres#2 ), in addition to the usual PrPres form (PrPres #1). In the unglycosylated form, PrPres #2 migrates at about 14 kDa, compared to 20 kDa for PrPres #1. The proportion of the PrPres#2 in cattle seems to by higher compared to the PrPres#1. Furthermore another PK-resistant fragment at about 7 kDa was detected by some more N-terminal antibodies and presumed to be the result of cleavages of both N- and C-terminal parts of PrP. These singular features were maintained after transmission of the disease to C57Bl/6 mice. The identification of these two additional PrPres fragments (PrPres #2 and 7kDa band) reminds features reported respectively in sporadic Creutzfeldt-Jakob disease and in Gerstmann-Sträussler-Scheinker (GSS) syndrome in humans.


http://www.neuroprion.com/pdf_docs/conferences/prion2007/abstract_book.pdf



MORE from this years PRION 2010 International Prion Congress: From agent to disease September 8–11, 2010 Salzburg, Austria


PPo2-17:


Atypical H-type BSE Infection in Bovine-PrP Transgenic Mice Let to the Emergence of Classical BSE Strain Features


Juan Carlos Espinosa,1 Olivier Andréoletti,2 Caroline Lacroux,2 Irene Prieto,1 Patricia Lorenzo,1 Magdalena Larska,1 Thierry Baron3 and Juan María Torres1 1Centro de Investigación en Sanidad Animal; INIA; Valdeolmos, Madrid Spain; 2UMR INRA-ENVT 1225; Interactions Hôte Agent Pathogène; Ecole Nationale Vétérinaire de; Toulouse, France; 3Agence Francaise de Sécurité Sanitaire des Aliments; Lyon Cedex, France


Key words: atypical BSE, PrPres, prion strain, prion transmission


Until identification of atypical cases of Bovine Spongiform Encephalopathy (BSE) in several countries it was assumed that BSE in cattle consisted of only a unique and biologically homogeneous strain type that caused BSE epidemic in Europe. Currently, beside the classical BSE strain associated to most described cases, atypical BSE cases are identified as H- or L-type based on the differences in the western blot profiles of abnormal protease-resistant prion protein (PrPres) according to the apparent molecular mass of its unglycosilated band. In the present study, we characterized five atypical BSE-H isolates by analyzing their molecular and neuropathological properties after transmission in transgenic mice expressing homologous bovine prion protein (PrP). The results showed that most of the inoculated animals conserved the atypical BSE-H strain features. However, a number of animals inoculated with two of these isolates showed prion strain features resembling those of classical BSE in this mouse model. On each case, the strain characteristics were preserved after subsequent passage in the same mice. These data suggest that atypical BSE-H prions, can acquire epidemic BSE-like properties during propagation in a homologous bovine PrP context. Beside a new view on BSE strains diversification, our observations support the hypothesis that atypical BSE-H, which could be a sporadic form of prion disease in cattle, may be at the origin of the foodborne BSE epizooty.



PPo3-9:


Potential of Cell Substrates used for Production of Biologics to Propagate Transmissible Spongiform Encephalopathy (TSE) Agents: 5-year Update


P. Piccardo,1,* L. Cervenakova,2 I. Vasilyeva,2 O. Yakovleva,2 I. Bacik,1 J. Cervenak,1 L. Gregori,1 K. Pomeroy,1 L. Kurillova,1 C. McKenzie2 and D.M. Asher1 1Laboratory of Bacterial and TSE Agents; CBER; FDA; USA; 2J. Holland Laboratory; American Red Cross; USA *Presenting Author


Key words: cell culture, animal models, biologics, prion, TSE-agent


Background. TSE agents have contaminated human-tissue-derived therapeutics and animal vaccines. Many biologics are prepared in cell cultures. Although most cultures studied resisted infection with TSE agents, a few were susceptible.


Objectives. We are investigating susceptibility of several cell lines to infection with TSE agents. Results. We studied Vero, CHO, MDCK, HEK-393 and WI-38 cells. We also studied SH-SY5Y cells overexpressing wild-type PrP and mutant PrPs. Cells exposed to TSE agents were serially propagated for 30 passages and samples tested for TSE-associated PrP (PrPTSE) and infectivity by intracerebral inoculation into transgenic mice and squirrel monkeys (BSE-exposed cells only). No exposed cell substrate has transmitted TSE to mice or monkeys to date. No PrPTSE was found in any exposed cells after 30 passages. Known susceptible murine cells exposed to mouse-adapted scrapie agent as positive controls accumulated PrPTSE. Three monkeys inoculated with BSE reference material have developed TSE to date.


Discussion. To date, no candidate cell substrate exposed to 3 TSE agents accumulated PrPTSE or propagated a TSE agent. Squirrel monkeys provide a new model to study BSE pathogenesis.


Methods. We inoculated brain suspensions containing agents of bovine spongiform encephalopathy (BSE), variant Creutzfeldt-Jakob disease (vCJD) or sporadic CJD into several cell lines important in manufacture of biologics. Serial dilutions of the BSE reference material used as inoculum were also inoculated into mice and squirrel monkeys.

The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Administration determination or policy. Acknowledgements Support. NIAID-NIH AI-4893-02/FDA 224-05-1307



PPo2-27:


Generation of a Novel form of Human PrPSc by Inter-species Transmission of Cervid Prions


Marcelo A. Barria,1 Glenn C. Telling,2 Pierluigi Gambetti,3 James A. Mastrianni4 and Claudio Soto1 1Mitchell Center for Alzheimer’s disease and related Brain disorders; Dept of Neurology; University of Texas Houston Medical School; Houston, TX USA; 2Dept of Microbiology, Immunology & Molecular Genetics and Neurology; Sanders Brown Center on Aging; University of Kentucky Medical Center; Lexington, KY USA; 3Institute of Pathology; Case western Reserve University; Cleveland, OH USA; 4Dept of Neurology; University of Chicago; Chicago, IL USA


Prion diseases are infectious neurodegenerative disorders affecting humans and animals that result from the conversion of normal prion protein (PrPC) into the misfolded and infectious prion (PrPSc). Chronic wasting disease (CWD) of cervids is a prion disorder of increasing prevalence within the United States that affects a large population of wild and captive deer and elk. CWD is highly contagious and its origin, mechanism of transmission and exact prevalence are currently unclear. The risk of transmission of CWD to humans is unknown. Defining that risk is of utmost importance, considering that people have been infected by animal prions, resulting in new fatal diseases. To study the possibility that human PrPC can be converted into the infectious form by CWD PrPSc we performed experiments using the Protein Misfolding Cyclic Amplification (PMCA) technique, which mimic in vitro the process of prion replication. Our results show that cervid PrPSc can induce the pathological conversion of human PrPC, but only after the CWD prion strain has been stabilized by successive passages in vitro or in vivo. Interestingly, this newly generated human PrPSc exhibits a distinct biochemical pattern that differs from any of the currently known forms of human PrPSc, indicating that it corresponds to a novel human prion strain. Our findings suggest that CWD prions have the capability to infect humans, and that this ability depends on CWD strain adaptation, implying that the risk for human health progressively increases with the spread of CWD among cervids.


PPo3-7:


Prion Transmission from Cervids to Humans is Strain-dependent


Qingzhong Kong, Shenghai Huang,*Fusong Chen, Michael Payne, Pierluigi Gambetti and Liuting Qing Department of Pathology; Case western Reserve University; Cleveland, OH USA *Current address: Nursing Informatics; Memorial Sloan-Kettering Cancer Center; New York, NY USA


Key words: CWD, strain, human transmission


Chronic wasting disease (CWD) is a widespread prion disease in cervids (deer and elk) in North America where significant human exposure to CWD is likely and zoonotic transmission of CWD is a concern. Current evidence indicates a strong barrier for transmission of the classical CWD strain to humans with the PrP-129MM genotype. A few recent reports suggest the presence of two or more CWD strains. What remain unknown is whether individuals with the PrP-129VV/MV genotypes are also resistant to the classical CWD strain and whether humans are resistant to all natural or adapted cervid prion strains. Here we report that a human prion strain that had adopted the cervid prion protein (PrP) sequence through passage in cervidized transgenic mice efficiently infected transgenic mice expressing human PrP, indicating that the species barrier from cervid to humans is prion strain-dependent and humans can be vulnerable to novel cervid prion strains. Preliminary results on CWD transmission in transgenic mice expressing human PrP-129V will also be discussed.

Acknowledgement Supported by NINDS NS052319 and NIA AG14359.


http://www.prion2010.org/bilder/prion_2010_program_latest_w_posters_4_.pdf?139&PHPSESSID=a30a38202cfec579000b77af81be3099




Greetings Everyone !


Confucius ponders, IS GSS and the g-h-BSEalabama mad cow case, the birth of nvCJD-like disease from cattle to humans in the USA ???


Could it be from the ever growing cases of the Nor-98 atypical scrapie in the USA, with 6 cases documented already this year ???


Could it be possible from one of the CWD strains here in the USA ???


ARE GAMBETTI'S INFAMOUS 2ND 10+ AND GROWING, simply USA MAD COW strain in humans ???


WHY not, if US sheep scrapie transmitted to US cattle did not produce a c-BSE (UK type), then why would it produce an nvCJD strain in humans ???


THE ever growing strains of TSE in humans and animals, and classification there from, does not compute. now we are seeing atypical h-BSE cases, and atypical l-BSE cases, atypical human TSE cases that look like these atypical BSE cases, so why in the name of science is all this not acceptable to conclude that these atypical human TSE are a by-product of these atypical animal TSE $$$ and how can it be that the science that concluded IRONSIDES 1st 10+ in 1995, does not correspond with Gambetti's 2nd 10+, in that Gambetti's 2nd 10+ is not a cause from anything, just a happenstance of bad luck on a funked out twisted protein that spontaneously twist to a bad protein on it's own, or, it is familial CJD, but not related to any common family mutation, like sporadic FFI or sporadic GSS $$$ this does not compute either. JUST HOW long can Gambetti et al hold off on a final analysis of the ever growing numbers of human TSE in the USA $$$


National Prion Disease Pathology Surveillance Center Cases Examined1 (July 31, 2010)


5 Includes

16 cases in which the diagnosis is pending, and 18 inconclusive cases;

6 Includes 21 (19 from 2010) cases with type determination pending in which the diagnosis of vCJD has been excluded.


http://www.cjdsurveillance.com/pdf/case-table.pdf



CAN the blood from these atypical CJD cases transmit TSE prions ???


WHAT if these strange atypical case of human TSE in the USA are from USA cattle, deer, elk, sheep, goat, will blood products transmit, and why wouldn't they ???


Have there been extensive transmission studies done with blood and all it's products there from ???


WHAT about vaccines ???


>>> Results. We studied Vero, CHO, MDCK, HEK-393 and WI-38 cells. We also studied SH-SY5Y cells overexpressing wild-type PrP and mutant PrPs. Cells exposed to TSE agents were serially propagated for 30 passages and samples tested for TSE-associated PrP (PrPTSE) and infectivity by intracerebral inoculation into transgenic mice and squirrel monkeys (BSE-exposed cells only). No exposed cell substrate has transmitted TSE to mice or monkeys to date. No PrPTSE was found in any exposed cells after 30 passages. Known susceptible murine cells exposed to mouse-adapted scrapie agent as positive controls accumulated PrPTSE. Three monkeys inoculated with BSE reference material have developed TSE to date. <<< ???


Thursday, August 12, 2010


USA Blood products, collected from a donor who was at risk for vCJD, were distributed July-August 2010


http://creutzfeldt-jakob-disease.blogspot.com/2010/08/usa-blood-products-collected-from-donor.html


Sunday, August 01, 2010


Blood product, collected from a donors possibly at increased risk for vCJD only, was distributed USA JULY 2010


http://vcjdtransfusion.blogspot.com/2010/08/blood-product-collected-from-donors.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.



FC5.1.2


Interim Transmission Results in Cynomolgus Macaques Inoculated with BSE and vCJD Blood Specimens


Lasmezas, C1; Lescoutra, N2; Comoy, E2; Holznagel, E3; Loewer, J3; Motzkus, D4; Hunsmann, G4; Ingrosso, L5; Bierke, P6; Pocchiari, M5; Ironside, J7; Will, R7; Deslys, JP2 1Scripps Florida, Infectology, USA; 2CEA, France; 3PEI, Germany; 4DPZ, Germany; 5Istituto Superiore di Sanita, Italy; 6SMI, Sweden; 7CJD Surveillance Unit, UK


BSE and vCJD transmitted to cynomolgus macaques reproduce many features of human vCJD, including clinical symptoms, neuropathological hallmarks of vCJD, PrPres electrophoretical pattern and, most importantly, the wide distribution of infectivity in peripheral organs. The latter characteristic distinguishes vCJD from sCJD in both humans and cynomolgus macaques, and prompted us to use this non-human primate model for further investigations of vCJD and its risk for human health. The occurrence of four vCJD infections in humans transfused with blood from patients who later developed vCJD has raised concern about blood transfusion safety in countries with vCJD. In this collaborative European study, we investigated the infectivity of blood components and whole blood administered by intracerebral (ic) and intravenous (iv) routes. Buffy-coat and whole blood was inoculated by ic and iv route, respectively, from two vCJD patients and from two clinical vCJD-inoculated macaques. Transfusions were also performed from whole blood and blood leucodepleted according to hospital practice standards from two clinical BSE inoculated macaques. Blood infectivity during the preclinical phase is being examined in orally infected macaques. Whole blood was collected and transfused from one such animal two years after oral challenge, whereas buffy-coat and plasma from two animals at 2 and 4.5 years post-challenge, respectively, have been inoculated by the ic route. This is an ongoing study in which recipient animals continue to be observed at various times post-inoculation. So far, we have had one positive transmission in one animal transfused 65 months earlier with 40 ml of whole blood from a vCJD macaque (the characteristics of the disease in this animal will be shown in a separate poster by E. Comoy). This positive transmission reproduces transfusion transmission of vCJD in humans, with an incubation of 5.5 years compatible with incubation periods observed in humans.


http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf



Saturday, September 5, 2009


TSEAC MEETING FEBRUARY 12, 2004 THE BAXTER STUDY GSS


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



Thursday, July 08, 2010

Nosocomial transmission of sporadic Creutzfeldt-Jakob disease: results from a risk-based assessment of surgical interventions Public release date: 8-Jul-2010


http://creutzfeldt-jakob-disease.blogspot.com/2010/07/nosocomial-transmission-of-sporadic.html



National Prion Disease Pathology Surveillance Center Cases Examined1 (July 31, 2010)


(please see video at the bottom of this url...tss)


http://prionunitusaupdate2008.blogspot.com/2010/08/national-prion-disease-pathology.html



Sunday, July 11, 2010


CJD or prion disease 2 CASES McLennan County Texas population 230,213 both cases in their 40s


http://creutzfeldt-jakob-disease.blogspot.com/2010/07/cjd-2-cases-mclennan-county-texas.html



Thursday, July 08, 2010 GLOBAL CLUSTERS OF CREUTZFELDT JAKOB DISEASE - A REVIEW 2010


http://creutzfeldt-jakob-disease.blogspot.com/2010/07/global-clusters-of-creutzfeldt-jakob.html



Tuesday, August 03, 2010


Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein


http://creutzfeldt-jakob-disease.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.html



Monday, August 9, 2010


Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein or just more Prionbaloney ?


http://prionunitusaupdate2008.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.html



Friday, November 30, 2007


CJD QUESTIONNAIRE USA CWRU AND CJD FOUNDATION


http://cjdquestionnaire.blogspot.com/




ALABAMA MAD COW g-h-BSEalabama


In this study, we identified a novel mutation in the bovine prion protein gene (Prnp), called E211K, of a confirmed BSE positive cow from Alabama, United States of America. This mutation is identical to the E200K pathogenic mutation found in humans with a genetic form of CJD. This finding represents the first report of a confirmed case of BSE with a potential pathogenic mutation within the bovine Prnp gene. We hypothesize that the bovine Prnp E211K mutation most likely has caused BSE in "the approximately 10-year-old cow" carrying the E221K mutation.


http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000156


http://www.plospathogens.org/article/fetchObjectAttachment.action?uri=info%3Adoi%2F10.1371%2Fjournal.ppat.1000156&representation=PDF



let's take a closer look at this new prionpathy or prionopathy, and then let's look at the g-h-BSEalabama mad cow.


This new prionopathy in humans? the genetic makeup is IDENTICAL to the g-h-BSEalabama mad cow, the only _documented_ mad cow in the world to date like this, ......wait, it get's better. this new prionpathy is killing young and old humans, with LONG DURATION from onset of symptoms to death, and the symptoms are very similar to nvCJD victims, OH, and the plaques are very similar in some cases too, bbbut, it's not related to the g-h-BSEalabama cow, WAIT NOW, it gets even better, the new human prionpathy that they claim is a genetic TSE, has no relation to any gene mutation in that family. daaa, ya think it could be related to that mad cow with the same genetic make-up ??? there were literally tons and tons of banned mad cow protein in Alabama in commerce, and none of it transmitted to cows, and the cows to humans there from ??? r i g h t $$$



Saturday, August 14, 2010


BSE Case Associated with Prion Protein Gene Mutation (g-h-BSEalabama) and VPSPr PRIONPATHY (see mad cow feed in COMMERCE IN ALABAMA...TSS)


http://prionpathy.blogspot.com/2010/08/bse-case-associated-with-prion-protein.html



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



CJD TEXAS 38 YEAR OLD FEMALE WORKED SLAUGHTERING CATTLE EXPOSED TO BRAIN AND SPINAL CORD MATTER




>>>Up until about 6 years ago, the pt worked at Tyson foods where she worked on the assembly line, slaughtering cattle and preparing them for packaging. She was exposed to brain and spinal cord matter when she would euthanize the cattle. <<<



Irma Linda Andablo CJD Victim, she died at 38 years old on February 6, 2010 in Mesquite Texas


Irma Linda Andablo CJD Victim, she died at 38 years old on February 6, 2010 in Mesquite Texas. She left 6 Kids and a Husband. The Purpose of this web is to give information in Spanish to the Hispanic community, and to all the community who want's information about this terrible disease.-


Physician Discharge Summary, Parkland Hospital, Dallas Texas


Admit Date: 12/29/2009


Discharge Date: 1/20/2010


Attending Provider: Greenberg, Benjamin Morris;


General Neurology Team: General Neurology Team


Linda was a Hispanic female with no past medical history presents with 14 months of incresing/progressive altered mental status, generalized weakness, inability to walk, loss of appetite, inability to speak, tremor and bowel/blader incontinence. She was, in her usual state of health up until February, 2009, when her husbans notes that she began forgetting things like names and short term memories. He also noticed mild/vague personality changes such as increased aggression. In March, she was involved in a hit and run MVA,although she was not injured. The police tracked her down and ticketed her. At that time, her son deployed to Iraq with the Army and her husband assumed her mentation changes were due to stress over these two events. Also in March, she began to have weakness in her legs, making it difficult to walk. Over the next few months, her mentation and personality changes worsened, getting to a point where she could no longer recognized her children. She was eating less and less. She was losing more weight. In the last 2-3 months, she reached the point where she could not walk without an assist, then 1 month ago, she stopped talking, only making grunting/aggressive sounds when anyone came near her. She also became both bowel and bladder incontinent, having to wear diapers. Her '"tremor'" and body jerks worsened and her hands assumed a sort of permanent grip position, leading her family to put tennis balls in her hands to protect her fingers. The husband says that they have lived in Nebraska for the past 21 years. They had seen a doctor there during the summer time who prescribed her Seroquel and Lexapro, Thinking these were sx of a mood disorder. However, the medications did not help and she continued to deteriorate clinically. Up until about 6 years ago, the pt worked at Tyson foods where she worked on the assembly line, slaughtering cattle and preparing them for packaging. She was exposed to brain and spinal cord matter when she would euthanize the cattle. The husband says that he does not know any fellow workers with a similar illness. He also says that she did not have any preceeding illness or travel.


http://www.recordandoalinda.com/index.php?option=com_content&view=article&id=19:cjd-english-info&catid=9:cjd-ingles&Itemid=8


Our condolences go out to the family and friends of Irma Linda Andablo, and a great big Thank You for this report from the family and the hospital. WE, the public would never have known about this case other wise. Thank you ! ...TSS



>>>Up until about 6 years ago, the pt worked at Tyson foods where she worked on the assembly line, slaughtering cattle and preparing them for packaging. She was exposed to brain and spinal cord matter when she would euthanize the cattle. <<<


Monday, March 29, 2010

Irma Linda Andablo CJD Victim, she died at 38 years old on February 6, 2010 in Mesquite Texas


http://creutzfeldt-jakob-disease.blogspot.com/2010/03/irma-linda-andablo-cjd-victim-she-died.html


CJD TEXAS 38 YEAR OLD FEMALE WORKED SLAUGHTERING CATTLE EXPOSED TO BRAIN AND SPINAL CORD MATTER


http://cjdtexas.blogspot.com/2010/03/cjd-texas-38-year-old-female-worked.html




Terry S. Singeltary Sr. has added the following comment: "According to the World Health Organisation, the future public health threat of vCJD in the UK and Europe and potentially the rest of the world is of concern and currently unquantifiable. However, the possibility of a significant and geographically diverse vCJD epidemic occurring over the next few decades cannot be dismissed .


The key word here is diverse. What does diverse mean?

If USA scrapie transmitted to USA bovine does not produce pathology as the UK c-BSE, then why would CJD from there look like UK vCJD?"

SEE FULL TEXT ;


http://www.promedmail.org/pls/apex/f?p=2400:1001:568933508083034::NO::F2400_P1001_BACK_PAGE,F2400_P1001_PUB_MAIL_ID:1000,82101



.57 The experiment which might have determined whether BSE and scrapie were caused by the same agent (ie, the feeding of natural scrapie to cattle) was never undertaken in the UK. It was, however, performed in the USA in 1979, when it was shown that cattle inoculated with the scrapie agent endemic in the flock of Suffolk sheep at the United States Department of Agriculture in Mission, Texas, developed a TSE quite unlike BSE. 32 The findings of the initial transmission, though not of the clinical or neurohistological examination, were communicated in October 1988 to Dr Watson, Director of the CVL, following a visit by Dr Wrathall, one of the project leaders in the Pathology Department of the CVL, to the United States Department of Agriculture. 33 The results were not published at this point, since the attempted transmission to mice from the experimental cow brain had been inconclusive. The results of the clinical and histological differences between scrapie-affected sheep and cattle were published in 1995. Similar studies in which cattle were inoculated intracerebrally with scrapie inocula derived from a number of scrapie-affected sheep of different breeds and from different States, were carried out at the US National Animal Disease Centre. 34 The results, published in 1994, showed that this source of scrapie agent, though pathogenic for cattle, did not produce the same clinical signs of brain lesions characteristic of BSE.

32 Clark, W., Hourrigan, J. and Hadlow, W. (1995) Encephalopathy in Cattle Experimentally Infected with the Scrapie Agent, American Journal of Veterinary Research, 56, 606-12

33 YB88/10.00/1.1

http://web.archive.org/web/20040823105233/www.bseinquiry.gov.uk/files/yb/1988/10/00001001.pdf



34 Cutlip, R., Miller, J., Race, R., Jenny, A., Katz, J., Lehmkuhl, H., Debey, B. and Robinson, M. (1994) Intracerebral Transmission of Scrapie to Cattle, Journal of Infectious Diseases, 169, 814-20




Friday, August 27, 2010

NEW ATYPICAL NOR-98 SCRAPIE CASE DETECTED IDAHO NOW 5 CASES DOCUMENTED 2010

http://nor-98.blogspot.com/2010/08/new-atypical-nor-98-scrapie-case.html





PR-26


NOR98 SHOWS MOLECULAR FEATURES REMINISCENT OF GSS


R. Nonno1, E. Esposito1, G. Vaccari1, E. Bandino2, M. Conte1, B. Chiappini1, S. Marcon1, M. Di Bari1, S.L. Benestad3, U. Agrimi1 1 Istituto Superiore di Sanità, Department of Food Safety and Veterinary Public Health, Rome, Italy (romolo.nonno@iss.it); 2 Istituto Zooprofilattico della Sardegna, Sassari, Italy; 3 National Veterinary Institute, Department of Pathology, Oslo, Norway

Molecular variants of PrPSc are being increasingly investigated in sheep scrapie and are generally referred to as "atypical" scrapie, as opposed to "classical scrapie". Among the atypical group, Nor98 seems to be the best identified. We studied the molecular properties of Italian and Norwegian Nor98 samples by WB analysis of brain homogenates, either untreated, digested with different concentrations of proteinase K, or subjected to enzymatic deglycosylation. The identity of PrP fragments was inferred by means of antibodies spanning the full PrP sequence. We found that undigested brain homogenates contain a Nor98-specific PrP fragment migrating at 11 kDa (PrP11), truncated at both the C-terminus and the N-terminus, and not N-glycosylated. After mild PK digestion, Nor98 displayed full-length PrP (FL-PrP) and N-glycosylated C-terminal fragments (CTF), along with increased levels of PrP11. Proteinase K digestion curves (0,006-6,4 mg/ml) showed that FL-PrP and CTF are mainly digested above 0,01 mg/ml, while PrP11 is not entirely digested even at the highest concentrations, similarly to PrP27-30 associated with classical scrapie. Above 0,2 mg/ml PK, most Nor98 samples showed only PrP11 and a fragment of 17 kDa with the same properties of PrP11, that was tentatively identified as a dimer of PrP11. Detergent solubility studies showed that PrP11 is insoluble in 2% sodium laurylsorcosine and is mainly produced from detergentsoluble, full-length PrPSc. Furthermore, among Italian scrapie isolates, we found that a sample with molecular and pathological properties consistent with Nor98 showed plaque-like deposits of PrPSc in the thalamus when the brain was analysed by PrPSc immunohistochemistry. Taken together, our results show that the distinctive pathological feature of Nor98 is a PrP fragment spanning amino acids ~ 90-155. This fragment is produced by successive N-terminal and C-terminal cleavages from a full-length and largely detergent-soluble PrPSc, is produced in vivo and is extremely resistant to PK digestion.

*** Intriguingly, these conclusions suggest that some pathological features of Nor98 are reminiscent of Gerstmann-Sträussler-Scheinker disease.

119

http://www.neuroprion.com/pdf_docs/conferences/prion2006/abstract_book.pdf





Sunday, May 18, 2008


MAD COW DISEASE BSE CJD CHILDREN VACCINES Sunday, May 18, 2008

MAD COW DISEASE BSE CJD CHILDREN VACCINES

TIP740203/l 0424 CONFIDENTIAL


http://bseinquiry.blogspot.com/2008/05/mad-cow-disease-bse-cjd-children.html





Monday, December 14, 2009

Similarities between Forms of Sheep Scrapie and Creutzfeldt-Jakob Disease Are Encoded by Distinct Prion Types


http://nor-98.blogspot.com/2009/12/similarities-between-forms-of-sheep.html




http://nor-98.blogspot.com/2010/08/scrapie-canada-update-current-as-of.html




PPo2-27:

Generation of a Novel form of Human PrPSc by Inter-species Transmission of Cervid Prions

Marcelo A. Barria,1 Glenn C. Telling,2 Pierluigi Gambetti,3 James A. Mastrianni4 and Claudio Soto1 1Mitchell Center for Alzheimer’s disease and related Brain disorders; Dept of Neurology; University of Texas Houston Medical School; Houston, TX USA; 2Dept of Microbiology, Immunology & Molecular Genetics and Neurology; Sanders Brown Center on Aging; University of Kentucky Medical Center; Lexington, KY USA; 3Institute of Pathology; Case western Reserve University; Cleveland, OH USA; 4Dept of Neurology; University of Chicago; Chicago, IL USA

Prion diseases are infectious neurodegenerative disorders affecting humans and animals that result from the conversion of normal prion protein (PrPC) into the misfolded and infectious prion (PrPSc). Chronic wasting disease (CWD) of cervids is a prion disorder of increasing prevalence within the United States that affects a large population of wild and captive deer and elk. CWD is highly contagious and its origin, mechanism of transmission and exact prevalence are currently unclear. The risk of transmission of CWD to humans is unknown. Defining that risk is of utmost importance, considering that people have been infected by animal prions, resulting in new fatal diseases. To study the possibility that human PrPC can be converted into the infectious form by CWD PrPSc we performed experiments using the Protein Misfolding Cyclic Amplification (PMCA) technique, which mimic in vitro the process of prion replication. Our results show that cervid PrPSc can induce the pathological conversion of human PrPC, but only after the CWD prion strain has been stabilized by successive passages in vitro or in vivo. Interestingly, this newly generated human PrPSc exhibits a distinct biochemical pattern that differs from any of the currently known forms of human PrPSc, indicating that it corresponds to a novel human prion strain. Our findings suggest that CWD prions have the capability to infect humans, and that this ability depends on CWD strain adaptation, implying that the risk for human health progressively increases with the spread of CWD among cervids.



PPo3-7:

Prion Transmission from Cervids to Humans is Strain-dependent

Qingzhong Kong, Shenghai Huang,*Fusong Chen, Michael Payne, Pierluigi Gambetti and Liuting Qing Department of Pathology; Case western Reserve University; Cleveland, OH USA *Current address: Nursing Informatics; Memorial Sloan-Kettering Cancer Center; New York, NY USA

Key words: CWD, strain, human transmission

Chronic wasting disease (CWD) is a widespread prion disease in cervids (deer and elk) in North America where significant human exposure to CWD is likely and zoonotic transmission of CWD is a concern. Current evidence indicates a strong barrier for transmission of the classical CWD strain to humans with the PrP-129MM genotype. A few recent reports suggest the presence of two or more CWD strains. What remain unknown is whether individuals with the PrP-129VV/MV genotypes are also resistant to the classical CWD strain and whether humans are resistant to all natural or adapted cervid prion strains. Here we report that a human prion strain that had adopted the cervid prion protein (PrP) sequence through passage in cervidized transgenic mice efficiently infected transgenic mice expressing human PrP, indicating that the species barrier from cervid to humans is prion strain-dependent and humans can be vulnerable to novel cervid prion strains. Preliminary results on CWD transmission in transgenic mice expressing human PrP-129V will also be discussed.

Acknowledgement Supported by NINDS NS052319 and NIA AG14359.



http://www.prion2010.org/bilder/prion_2010_program_latest_w_posters_4_.pdf?139&PHPSESSID=a30a38202cfec579000b77af81be3099





http://chronic-wasting-disease.blogspot.com/2010/07/comments-sought-on-revised-plan-to.html





http://chronic-wasting-disease.blogspot.com/2009/09/experimental-oral-transmission-of.html





http://chronic-wasting-disease.blogspot.com/2009/08/susceptibilities-of-nonhuman-primates.html





http://chronic-wasting-disease.blogspot.com/





Wednesday, September 08, 2010

CWD PRION CONGRESS SEPTEMBER 8-11 2010


http://chronic-wasting-disease.blogspot.com/2010/09/cwd-prion-2010.html





Sunday, September 6, 2009

MAD COW USA 1997 SECRET VIDEO


http://madcowusda.blogspot.com/2009/09/mad-cow-usa-1997-video.html





U.S.A. HIDING MAD COW DISEASE VICTIMS AS SPORADIC CJD ? see video at bottom


http://creutzfeldt-jakob-disease.blogspot.com/2009/07/usa-hiding-mad-cow-disease-victims-as.html





Rural and Regional Affairs and Transport References Committee The possible impacts and consequences for public health, trade and agriculture of the Government’s decision to relax import restrictions on beef Final report June 2010

2.65 At its hearing on 14 May 2010, the committee heard evidence from Dr Alan Fahey who has recently submitted a thesis on the clinical neuropsychiatric, epidemiological and diagnostic features of Creutzfeldt-Jakob disease.48 Dr Fahey told the committee of his concerns regarding the lengthy incubation period for transmissible spongiform encephalopathies, the inadequacy of current tests and the limited nature of our current understanding of this group of diseases.49

2.66 Dr Fahey also told the committee that in the last two years a link has been established between forms of atypical CJD and atypical BSE. Dr Fahey said that: They now believe that those atypical BSEs overseas are in fact causing sporadic Creutzfeldt-Jakob disease. They were not sure if it was due to mad sheep disease or a different form. If you look in the textbooks it looks like this is just arising by itself. But in my research I have a summary of a document which states that there has never been any proof that sporadic Creutzfeldt-Jakob disease has arisen de novo—has arisen of itself. There is no proof of that. The recent research is that in fact it is due to atypical forms of mad cow disease which have been found across Europe, have been found in America and have been found in Asia. These atypical forms of mad cow disease typically have even longer incubation periods than the classical mad cow disease.50

http://www.aph.gov.au/senate/committee/rrat_ctte/mad_cows/report/report.pdf





Wednesday, August 11, 2010

Heterozygosity at Polymorphic Codon 219 in Variant Creutzfeldt-Jakob Disease

Vol. 67 No. 8, August 2010

http://creutzfeldt-jakob-disease.blogspot.com/2010/08/heterozygosity-at-polymorphic-codon-219.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





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





Title:

HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory



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



http://cjdusa.blogspot.com/2009/06/monitoring-occurrence-of-emerging-forms.html





Saturday, June 13, 2009

Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States 2003 revisited 2009



http://cjdusa.blogspot.com/2009/06/monitoring-occurrence-of-emerging-forms.html




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 PART III]

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




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




VACCINES AND TSE I.E. PRION DISEASE AKA MAD COW TYPE DISEASE CONFIDENTIAL

NOW, the vaccine TSE issue ;

NON-LICENSED HUMAN TISSUE DEVICES WERE NOT COMMERCIALLY AVAILABLE

snip...

I was quite prepared to believe in unofficial pituitary hormones, also in the 1970's, whether as described by Dr. Little, or in other circumstances, for animal use.

snip...

The fact that there were jars of pituitaries (or extract) around on shelves is attested by the still potent 1943 pituitaries, described in Stockell Hartree et al. (J/RF/17/291) which had come from the lab. at Mill Hill. Having taken the trouble to collect them, they were not lightly thrown out...



http://collections.europarchive.org/tna/20080102174454/http://www.bseinquiry.gov.uk/files/ws/s467bx.pdf




B.S.E. and Veterinary Medicines

Thank you very much indeed for your letter of the 26th of January outlining to me the various steps that are proposing to take in order to reduce the risk from B.S.E. in veterinary medicines. It is, as you say, and extremely difficult problem. ....


http://web.archive.org/web/20030526124448/http://www.bseinquiry.gov.uk/files/yb/1989/01/30008001.pdf




Draft cover letter to product licence holders (considered by Human and Vet Medicines including deer)


http://collections.europarchive.org/tna/20080103002832/http://www.bseinquiry.gov.uk/files/yb/1989/02/22008001.pdf




http://collections.europarchive.org/tna/20080102155758/http://www.bseinquiry.gov.uk/files/yb/1989/02/22011001.pdf




(It was noted with concern that hormone extracts could be manufactured by a veterinary surgeon for administration to animals under his care without any Medicines Act Control.)

PITUITARY EXTRACT

This was used to help cows super ovulate. This tissue was considered to be of greatest risk of containing BSE and consequently transmitting the disease.

BEEF BRAIN AND BRAIN INFUSION BROTHS

Considered to be of great risk.


http://collections.europarchive.org/tna/20080102164725/http://www.bseinquiry.gov.uk/files/yb/1988/06/08011001.pdf




COMMERCIAL IN CONFIDENCE

MEDICINES ACT - VETERINARY PRODUCTS COMMITTEE

5 BLANK PAGES. ...TSS

7. Any Other Business


http://collections.europarchive.org/tna/20080102164736/http://www.bseinquiry.gov.uk/files/yb/1988/06/07010001.pdf




TWA LITTLE STATEMENT 331

8 June 1988 Internal CVL meeting to discuss the implications of BSE to Biologicals Products containing bovine extracted material (Annex 6). (YB 88/06.08/11.1-11.2) Following a detailed review of situation the following recommendations were made:

1. Specific concern over use of pituitary gland products by veterinary surgeons and companies. Paper to be produced for Tolworth (Veterinary Medicines Division).

2. Urgent review of all products both immunological and pharmaceutical for possible inclusion of ingredients of bovine origin.

3. Draft guidelines to be presented in full to the National Office of Animal Health (NOAH), the trade body representing the Veterinary Medicines part of the pharmaceutical industry, at next meeting on 11 July 1988


http://collections.europarchive.org/tna/20080102163939/http://www.bseinquiry.gov.uk/files/ws/s331.pdf




TWA LITTLE minute

2. We have identified one problem over where we are unable to act and this is the use of gonadotrophins in embryo transfer work. Some veterinary surgeons are quite legally using this exemption from the Medicines Act contained in Section 9(2) to prepare gonadotrophins from pituitary glands from various species, including cattle. These hormones are used to stimulate superovulation in donor cows.



http://collections.europarchive.org/tna/20080102164806/http://www.bseinquiry.gov.uk/files/yb/1988/06/10001001.pdf




http://collections.europarchive.org/tna/20080102164811/http://www.bseinquiry.gov.uk/files/yb/1988/06/13010001.pdf




http://collections.europarchive.org/tna/20080103031215/http://www.bseinquiry.gov.uk/files/yb/1988/06/14006001.pdf




COMMERCIAL IN CONFIDENCE

3.2 Minute 5.3 - 5.4 Bovine Spongiform Encephalopathy

It was reported that some replies had been received from Companies using pituitary glands in their products. Copies of the BSE document had also been sent to DHSS and NIBSC.

and then another 3 + pages of blank space. ...TSS


http://collections.europarchive.org/tna/20080102164813/http://www.bseinquiry.gov.uk/files/yb/1988/09/06005001.pdf




COMMERCIAL IN CONFIDENCE

BSE - CURRENT POSITION WITH VETERINARY LICENCED PRODUCTS (MA.1968)

There are three areas of particular concern, vaccines (including emergency vaccines), pharmaceuticals which are covered by MA licences and unlicenses hormonal products produced under exemptions claimed under (Section 9(2) Medicines Act).

1) Vaccines


http://collections.europarchive.org/tna/20080103033809/http://www.bseinquiry.gov.uk/files/yb/1988/10/06005001.pdf




NOT FOR PUBLICATION

another 6 pages of blank space. ...TSS


http://collections.europarchive.org/tna/20080103032658/http://www.bseinquiry.gov.uk/files/yb/1988/11/01012001.pdf




http://collections.europarchive.org/tna/20080103032631/http://www.bseinquiry.gov.uk/files/yb/1988/11/04003001.pdf




http://collections.europarchive.org/tna/20080103033926/http://www.bseinquiry.gov.uk/files/yb/1988/04/00007001.pdf




COMMERCIAL IN CONFIDENCE


http://collections.europarchive.org/tna/20080103034137/http://www.bseinquiry.gov.uk/files/yb/1988/07/00007001.pdf




COMMERCIAL IN CONFIDENCE

Medicines Act - Veterinary Products Committee

http://collections.europarchive.org/tna/20080103034140/http://www.bseinquiry.gov.uk/files/yb/1988/09/00004001.pdf




COMMERCIAL IN CONFIDENCE

http://collections.europarchive.org/tna/20080102164744/http://www.bseinquiry.gov.uk/files/yb/1988/10/00003001.pdf




MANAGEMENT IN CONFIDENCE

CERTIFIED BSE-FREE HERDS FOR SOURCE OF MATERIAL FOR BIOLOGICAL PRODUCTS

http://collections.europarchive.org/tna/20080102184729/http://www.bseinquiry.gov.uk/files/yb/1989/01/04001001.pdf




Subject: BSE--U.S. 50 STATE CONFERENCE CALL Jan. 9, 2001

Date: Tue, 9 Jan 2001 16:49:00 -0800

From: "Terry S. Singeltary Sr."

Reply-To: Bovine Spongiform Encephalopathy

To: BSE-L@uni-karlsruhe.de

[host Richard Barns] and now a question from Terry S. Singeltary of CJD Watch.

[TSS] yes, thank you, U.S. cattle, what kind of guarantee can you give for serum or tissue donor herds?

[no answer, you could hear in the back ground, mumbling and 'we can't. have him ask the question again.]

[host Richard] could you repeat the question?

[TSS] U.S. cattle, what kind of guarantee can you give for serum or tissue donor herds?

[not sure whom ask this] what group are you with?

[TSS] CJD Watch, my Mom died from hvCJD and we are tracking CJD world-wide.

[not sure who is speaking] could you please disconnect Mr. Singeltary

[TSS] you are not going to answer my question?

[not sure whom speaking] NO

from this point, i was still connected, got to listen and tape the whole conference. at one point someone came on, a woman, and ask again;

[unknown woman] what group are you with?

[TSS] CJD Watch and my Mom died from hvCJD we are trying to tract down CJD and other human TSE's world wide. i was invited to sit in on this from someone inside the USDA/APHIS and that is why i am here. do you intend on banning me from this conference now?

at this point the conference was turned back up, and i got to finish listening. They never answered or even addressed my one question, or even addressed the issue. BUT, i will try and give you a run-down for now, of the conference.

snip...full text ;


http://bse-atypical.blogspot.com/2010/01/14th-international-congress-on.html




COMMERCIAL IN CONFIDENCE

NOT FOR PUBLICATION

COMMITTEE ON SAFETY OF MEDICINES

another 6 pages or so that are blank. ...TSS

http://collections.europarchive.org/tna/20080102185137/http://www.bseinquiry.gov.uk/files/yb/1989/01/26007001.pdf




http://collections.europarchive.org/tna/20080102184613/http://www.bseinquiry.gov.uk/files/yb/1989/01/30001001.pdf




COMMERCIAL IN CONFIDENCE

NOT FOR PUBLICATION

COMMITTEE ON SAFETY OF MEDICINES

WORKING PARTY ON BOVINE SPONGIFORM ENCEPHALOPATHY

7.2.1. Products with bovine brain/lymphoid tissue as ingredients and administered by injection...[111]

7.2.2 Products with bovine ingredients (other than brain/lymphoid tissue) and administered by injection...[135]

7.2.3 Tissue implants, open wound dressings, surgical materials, dental and opthalmic products with bovine ingredients...[27]

7.2.4. Products with bovine ingredients and administered topically...[5]

7.2.5 Products with bovine ingredients and administered orally...[9]

7.2.6 Products with other animal/insect/bird ingredients and administered:

a. by injection a: 117

b. by topically b: 6

c. orally c: 8

7.2.7 Products with materials produced from animal material by chemical processes, eg stearic acid, gelatin and lanolin...[156]

With two exceptions, the replies to date have not given any immediate cause for concern, although 176 products do not conform to the CSM/VPC guidelines.

8. The first exception was from which gave very limited information about a very large number of homoepathic medicines with material obtained from cattle and a number with material from the brain. Of these, 53 were injectable products of which 20 were derived from cattle brain. A list of these products is attached as Appendix 1 to Annex D. The second exception relates to the product, 'Surgical Catgut', which is sourced from UK bovine intestines and will contain lymphoid material...

see full text ;

http://collections.europarchive.org/tna/20080102164420/http://www.bseinquiry.gov.uk/files/yb/1989/09/06011001.pdf




please see ;

Sunday, December 16, 2007

Risk factors for sporadic Creutzfeldt-Jakob disease

Increased risk was not associated with surgical categories chosen a priori but was confined to the residual category other surgery, in which the increase in risk appeared most marked for three subcategories: skin stitches, nose/throat operations, and removal of growths/cysts/moles.

snip...

which the increase in risk appeared most marked for three subcategories:

skin stitches, nose/throat operations, and removal of growths/cysts/moles.

10 January 1990

Other US BSE risks: the imported products picture

24 Jul 00 Trade Statistics: UK to US

Compiled by Terry S.Singeltary Sr of Bacliff, Texas

[Opinion (webmaster): The US has focused for years on tracing, containing, and eradicating live animal imports from the UK or other countries with acknowledged BSE like Belgium, including some 499 cattle and the Vermont sheep. This strategy does not acknowledge imports of rendered bovine products from England during the BSE period nor secondary products such as surgical catgut, which is to say surgical cowgut, or dairy cattle embryos, vaccines for veterinarian and human medicines. What has become of these?

Mr. Singeltary, who lost his mother to CJD of unexplained origin a few years back and went on to became a well-known TSE activist, has tracked down voluminous pertinent import data through correspondence with UK officials and searches of government web sites. Imports of such products are frequently cited by Europeans in rating BSE risks in the US and in shutting out US exports.

Many people's eyes glaze over when reviewing reams of sometimes older trade statistics. There is no proof that any of the imported products was contaminated with BSE nor if so, any evidence that any BSE product lead to infection in US livestock, surgical patients, or what not. Nonetheless, the data obtained by Mr. Singeltary establish that an appalling variety and tonnage of products that were imported by the US from the UK and othr BSE-affected countries during the peak of the BSE epidemic years.]

10 January 1990

NOT FOR PUBLICATION

COMMITTEE ON SAFETY OF MEDICINES

WORKING PARTY ON BOVINE SPONGIFORM ENCEPHALOPATHY

SURGICAL CATGUT SUTURES

2.1 At the first meeting of the Working Party on Bovine Spongiform Encephalopathy on 6 September 1989, detailed consideration was given to XXXXX Surgical Catgut. This arose from the Company's response to the Letter to License Holders, indicating that the bovine small intestine source material was derived from UK cattle, unlike 8 other licensed catgut sutures. In contrast XXXXX Surgical Catgut was stated to hold over 90% share of the market for catgut sutures, and to constitute approximately 83% of all sutures used in U.K.

IMPORTS OF SUTURES FROM THE KNOWN BSE COUNTRY;

3006.10.0000: STERILE SURGICAL CATGUT, SIMILAR STERILE SUTURE MATERIALS AND STERILETISSUE ADHESIVES FOR SURGICAL WOUND CLOSURE; AND SIMILAR STERILE MATERIAL

U.S. Imports for Consumption: December 1998 and 1998 Year-to-Date (Customs Value, in Thousands of Dollars) (Units of Quantity: Kilograms)

<--- Dec 1998 ---> <--- 1998 YTD --->

Country Quantity Value Quantity Value

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

WORLD TOTAL . . . . . . . 10,801 3,116 143,058 40,068

Belgium . . . . . . . . . --- --- 107 14

France . . . . . . . . . 81 49 2,727 1,132

Switzerland . . . . . . . --- --- 1,357 1,693

United Kingdom . . . . . 1,188 242 35,001 5,564


http://www.mad-cow.org/00/jul00_dont_eat_sheep.html#hhh




see url now available at ;


http://collections.europarchive.org/tna/20080102182449/http://www.bseinquiry.gov.uk/files/yb/1990/01/10008001.pdf




Part II

2.1 Bovine Small Intestine

This is the largest single category, comprising 9 product licenses for surgical catgut, held by 3 Companies ;


http://collections.europarchive.org/tna/20080102182349/http://www.bseinquiry.gov.uk/files/yb/1990/01/10010001.pdf




2.2 Skin

Bovine dermal collagen is present in 2 products for correction of tissue contour deformities by injection and 4 implantable haemostates.

Source USA, USA, W Germany, W. Germany, France. ...


http://collections.europarchive.org/tna/20080102182349/http://www.bseinquiry.gov.uk/files/yb/1990/01/10010001.pdf




UPDATE ON SURGICAL CATGUT

MAY 1990


http://collections.europarchive.org/tna/20080102222354/http://www.bseinquiry.gov.uk/files/yb/1990/05/00011001.pdf




40,000 human heart valves a year from BSE herds

Sun, 3 Sep 2000.

Unpublished Inquiry documents obtained by CJD activist Terry S. Singeltary Sr. of Bacliff, Texas


http://www.mad-cow.org/00/sep00_news.html#hhh




The documents below were provided by Terry S. Singeltary Sr on 8 May 2000. They are optically character read (scanned into computer) and so may contain typos and unreadable parts.

TIP740203/l 0424 CONFIDENTIAL

snip...

The responses by the companies were presented by Ms Turner and were categorised by MCA standards, the products that were discussed were all low volume usage products eg sutures, heart valves.

8. As the responses included some materials of human origin it was decided that more information should be sought about CJD. There had been 2 recent deaths reported associated with human growth hormone. These were being investigated.

snip...


http://www.mad-cow.org/00/may00_news.html#aaa




5.3.3 The greatest risk, in theory, would be from parenteral injection of material derived from bovine brain or lymphoid tissue. Medicinal products for injection or surgical implantation which are prepared from bovine tissues, or which utilise bovine serum albumin or similar agents in their manufacture, might also be capable of transmitting infectious agents. All medicinal products are licensed under the Medicines Act by the Licensing Authority following guidance, for example from the Committee on Safety of Medicines (CSM), the Committee on Dental and Surgical Materials (CDSM) and their subcommittees. The Licensing Authority have been alerted to potential concern about BSE in medicinal products and will ensure that scrutiny of source materials and manufacturing processes now takes account of BSE agent.

see all 76 pages ;


http://collections.europarchive.org/tna/20080102132706/http://www.bseinquiry.gov.uk/files/ib/ibd1/tab02.pdf




EXPORT OF BRITISH BIOLOGICAL PHARMACEUTICALS

1. Please see the attached note of a recent meeting in Brussels. For Dr. Purford should read Dr. Purves (I think). If the Germans get their way, and it looks as if they might, because of worries about BSE we could end up with a ban on certain bovine materials being exported from the UK for pharmaceutical manufacture. Thse materials include cell cultures of bovine origin (? and also any cultures which have been fed bovine nutrient material), bovine serum, and fetal calf serum.

2. Whilst export of these raw materials may be very limited, it is only a small step to include in this export ban any finished product made from such materials. This would include virtually all biologicals and vaccines. This could have very serious effects on the export trade of British Manufacturers of biologicals because even where they source their bovine ingredients outside the UK it might be impossible or at least very difficult to bypass any export ban.

3. Our own line is that we have not used regulations to restrict the use of British bovine material for non-food use, although certain offals cannot be used for human consumption. ...


http://collections.europarchive.org/tna/20080102220244/http://www.bseinquiry.gov.uk/files/yb/1990/03/13002001.pdf




Export of British 'Biological' Pharmaceuticals


http://collections.europarchive.org/tna/20080102220202/http://www.bseinquiry.gov.uk/files/yb/1990/03/13008001.pdf




http://collections.europarchive.org/tna/20080102215829/http://www.bseinquiry.gov.uk/files/yb/1990/03/13009001.pdf




No papers were presented by our American guests and none covered the subject of pharmaceuticals. ...


http://collections.europarchive.org/tna/20080102220453/http://www.bseinquiry.gov.uk/files/yb/1990/04/02002001.pdf




STANDING COMMITTEE MEETING ON BSE

Thanks for your note. I am disappointed not to have been informed about this meeting in advance and am surprised that Dr. Tyrrell was not involved either. I find it insulting to be told the proceedings were in confidence and find your excuse about only hosting the meeting unconvincing.


http://collections.europarchive.org/tna/20080102220555/http://www.bseinquiry.gov.uk/files/yb/1990/04/06002001.pdf




The documents below were provided by Terry S. Singeltary Sr on 8 May 2000. They are optically character read (scanned into computer) and so may contain typos and unreadable parts.

TIP740203/l 0424 CONFIDENTIAL

Mr Cunningham CMP3 From: D O Hagger MBI Dr Salisbury MED/IMCD3 Mr Burton PD/STB/PG1B B/17/2 Date: 15.02.1989 Mr Dudley PD/AD4

snip...

89/06.19/8.1 BSE3/1 0191 Hr J Maslin (MAFF) Ref: Maslin3g

From: Dr H Pickles Med SEB/B Date: 3 July 1989

CATTLE BY-PRODUCTS AND BSE

I was interested to see the list of by-products sent to the HSE. Those of particular concern included:

* small intestines: sutures (I thought the source was ovine but you are checking this)

* spinal cord: pharmaceuticals

* thymus: pharmaceuticals

Are you able to give me more information on which UK manufacturers use these materials? Our proposed ban on bovine offal for human consumption would not affect these uses, I assume.

snip...see full text ;


http://www.mad-cow.org/00/may00_news.html




http://www.javno.com/en/world/clanak.php?id=32047




http://creutzfeldt-jakob-disease.blogspot.com/2007/12/risk-factors-for-sporadic-creutzfeldt.html




http://bseinquiry.blogspot.com/2008/05/mad-cow-disease-bse-cjd-children.html




Research Lead: Dr. David Westaway, University of Alberta

Project: "Extending the spectrum of Prionopathies to Amyotrophic Lateral Sclerosis and Autism"

This project proposes to link the chemistry of the prion protein to the new territory of other nervous system diseases, such as ALS (Lou Gehrig's disease) and the socialization disorder autism-diseases which are at least one thousand times more common than prion diseases. It is believed that a different type or prion protein may operate in other types of brain diseases, which could lead to new ways of thinking about incurable disorders. The project will create changes in the amounts of the various forms of the new membrane protein, and then perform an array of analyses on the behavior and nervous system transmission of laboratory mice. Nervous transmission by electrical impulse can be measured in isolated brain cells, a system that is also convenient to study the effect of stress by adding small amounts of toxins to the fluids bathing the cultures. By these means, the project aims to extend the boundaries of what is considered "prion disease."

Funding: $520,500


http://www.prioninstitute.ca/index.php?page=webpages&menucat=42&id=26&action=displaypage&side=1




Unfolding the Prion Mystery Building and Growing Research Expertise in Alberta Year 4 2008-2009 Annual Report

Dr. David Westaway, University of Alberta Extending the spectrum of prionopathies to amyotrophic lateral sclerosis (ALS) and autism Dr. Westaway’s study aims to extend the boundaries of what is considered prion disease. His project takes the chemistry of the prion protein into the territory of nervous system diseases such as ALS (Lou Gehrig’s disease) and socialization disorder diseases such as autism. These brain diseases are at least 1,000 times more common than diseases currently accepted as prion related. Dr. Westaway hypothesizes that a different type of protein misfolding may operate in brain diseases such as Lou Gehrig’s and autism. This type of protein misfolding may occur in response to stresses in the brain. Unlike misfolded prions, other misfolded proteins may be noninfectious and not viable outside of the affected animal. Dr. Westaway’s research team will investigate these hypotheses by inducing changes in the brain cells of laboratory mice, measuring the resulting electrical impulses in the animals’ nervous systems and analyzing the effect on behaviour. Because nervous transmission by electrical impulse can be measured in isolated brain cells, adding small amounts of toxins to the fluids bathing the cell cultures will make it possible to study the effect of stress. The results could lead to new ways of thinking about nervous system disorders.


http://www.prioninstitute.ca/forms/WEBSITE%20AR.pdf




Wednesday, February 3, 2010

Import Alert 62-07 Sygen Injectable (Bovine-Extracted GMI Monosialoganglioside) manufactured from bovine brain starting material


http://bseusa.blogspot.com/2010/02/import-alert-62-07-sygen-injectable.html




Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518 flounder@verizon.net