Thursday, May 30, 2013

Statement from Agriculture Secretary Tom Vilsack Regarding World Organization for Animal Health (OIE) Upgrade of United States' BSE Risk Status

Release No. 0106.13 Contact: USDA Office of Communications (202) 720-4623



Statement from Agriculture Secretary Tom Vilsack Regarding World Organization for Animal Health (OIE) Upgrade of United States' BSE Risk Status



WASHINGTON, May 29, 2013–Agriculture Secretary Tom Vilsack made the following statement about notification received today from the World Organization for Animal Health (OIE) upgrading the United States' risk classification for bovine spongiform encephalopathy (BSE) to negligible risk: "I am very pleased with OIE's decision to grant the United States negligible risk status for BSE. This is a significant achievement that has been many years in the making for the United States, American beef producers and businesses, and federal and state partners who work together to maintain a system of interlocking safeguards against BSE that protect our public and animal health. This decision demonstrates OIE's belief that both our surveillance for, and safeguards against, BSE are strong. U.S. beef and beef products are of the highest quality, wholesome and produced to the highest safety standards in the world. Last year, exports of U.S.-origin beef and beef products totaled $5.5 billion. With our negligible risk classification from the OIE, we have a strong foundation in place to continue increasing exports of U.S.-origin beef and beef products. In doing so, we will continue to press trading partners to base their decisions on science, consistent with international standards. U.S. food and agricultural exporters and consumers worldwide benefit when countries adopt science-based international standards." #


USDA is an equal opportunity provider and employer. To file a complaint of discrimination, write: USDA, Office of the Assistant Secretary for Civil Rights, Office of Adjudication, 1400 Independence Ave., SW, Washington, DC 20250-9410 or call (866) 632-9992 (Toll-free Customer Service), (800) 877-8339 (Local or Federal relay), (866) 377-8642 (Relay voice users).












the new BSE TSE PRION MAD COW risk category the OIE gave the USA, puts everyone around the globe at more risk of a tse prion mad cow type disease now.


in my opinion, this new risk category was bought and paid for by your local cattle dealer, via fraud.


IT is of my opinion, that the OIE and the USDA et al, are the soul reason, and responsible parties, for Transmissible Spongiform Encephalopathy TSE prion diseases, including typical and atypical BSE, typical and atypical Scrapie, and all strains of CWD, and human TSE there from, spreading around the globe.


I have lost all confidence of this organization as a regulatory authority on animal disease, and consider it nothing more than a National Trading Brokerage for all strains of animal TSE, just to satisfy there commodity. AS i said before, OIE should hang up there jock strap now, since it appears they will buckle every time a country makes some political hay about trade protocol, commodities and futures. IF they are not going to be science based, they should do everyone a favor and dissolve there organization.


JUST because of low documented human body count with nvCJD and the long incubation periods, the lack of sound science being replaced by political and corporate science in relations with the fact that science has now linked some sporadic CJD with atypical BSE and atypical scrapie, and the very real threat of CWD being zoonosis, I believed the O.I.E. has failed terribly and again, I call for this organization to be dissolved. ...




IN A NUT SHELL ;


(Adopted by the International Committee of the OIE on 23 May 2006)


11. Information published by the OIE is derived from appropriate declarations made by the official Veterinary Services of Member Countries. The OIE is not responsible for inaccurate publication of country disease status based on inaccurate information or changes in epidemiological status or other significant events that were not promptly reported to the Central Bureau,







i pulled this comment off another board about the OIE and all it's lobby groups. please see ;



Having been to their offices in Paris and talked personally with the Head of the Animal Test Section, you would choke if you knew how many lobby groups attend that office daily. There is a steady stream of paid lobby groups that have one goal in life and that is to sway the Section Heads of each department within the OIE to suit the needs of different juristictions around the world, which curiously enough, also includes the USA and Canada. Anyone can go there and chat with them - providing they can privide valid cause to be let in. To say that the only goal of the OIE is animal health is actually only part of their function. They are more than that and my discussions with Dr. Diaz there has showed me that. But to blindly make a statement regarding what they do when you have no idea what they actually do is like eating the skin of the orange and not knowing what is actually under. Interstingly you state that the US Government applied pressure (to the OIE) I assume and that is a great example of the lobby groups doing their job. So, at the end of the day, one can safely assume that it is the pressure applied by certain influential lobby groups that will determine a likely aoutcome to an apparent OIE directive. Man alive, isn't it great to live in a democracy wherein the people get to make the choices and not just some "other" interested party or group - say like........Cargyll or Tyson for example?



So, one last question, question?



Who wags the tail of that dog?? And for what reason other than one that is purely associated with trade and international agreements and greed?



Location: Edmonton, Alberta, Canada



Occupation: CEO of BSE Prion Solutions Inc.



Interests: Prion Diseases and Live Animal Testing



end...tss





please see history of the USDA, OIE, mad cow follies and cover up and fraud there from here ;




Thursday, May 30, 2013







World Organization for Animal Health (OIE) has upgraded the United States' risk classification for mad cow disease to "negligible" from "controlled", and risk further exposing the globe to the TSE prion mad cow type disease







U.S. gets top mad-cow rating from international group







and risk further exposing the globe to the TSE prion mad cow type disease












Tuesday, May 21, 2013



Canada, USA, Bad feed, mad cows: Why we know three BSE cases had a common origin and why the SSS policy is in full force $$$








Tuesday, May 7, 2013



Feds want five-year paper trail for livestock NAIS COOL








Friday, April 19, 2013




APHIS 2013 Stakeholder Meeting (March 2013) BSE TSE PRION











Wednesday, February 20, 2013


World Organization for Animal Health Recommends United States' BSE Risk Status Be Upgraded

Statement from Agriculture Secretary Tom Vilsack:





http://madcowusda.blogspot.com/2013/02/world-organization-for-animal-health.html





 



Thursday, February 14, 2013



The Many Faces of Mad Cow Disease Bovine Spongiform Encephalopathy BSE and TSE prion disease




http://bse-atypical.blogspot.com/2013/02/the-many-faces-of-mad-cow-disease.html










Monday, October 10, 2011

EFSA Journal 2011 The European Response to BSE: A Success Story
 


snip...
 


EFSA and the European Centre for Disease Prevention and Control (ECDC) recently delivered a scientific opinion on any possible epidemiological or molecular association between TSEs in animals and humans (EFSA Panel on Biological Hazards (BIOHAZ) and ECDC, 2011). This opinion confirmed Classical BSE prions as the only TSE agents demonstrated to be zoonotic so far but the possibility that a small proportion of human cases so far classified as "sporadic" CJD are of zoonotic origin could not be excluded. Moreover, transmission experiments to non-human primates suggest that some TSE agents in addition to Classical BSE prions in cattle (namely L-type Atypical BSE, Classical BSE in sheep, transmissible mink encephalopathy (TME) and chronic wasting disease (CWD) agents) might have zoonotic potential.
 
 

snip...


 

 



 


 






Thursday, August 12, 2010
 

Seven main threats for the future linked to prions
 


First threat
 


The TSE road map defining the evolution of European policy for protection against prion diseases is based on a certain numbers of hypotheses some of which may turn out to be erroneous. In particular, a form of BSE (called atypical Bovine Spongiform Encephalopathy), recently identified by systematic testing in aged cattle without clinical signs, may be the origin of classical BSE and thus potentially constitute a reservoir, which may be impossible to eradicate if a sporadic origin is confirmed.
 

***Also, a link is suspected between atypical BSE and some apparently sporadic cases of Creutzfeldt-Jakob disease in humans. These atypical BSE cases constitute an unforeseen first threat that could sharply modify the European approach to prion diseases.
 


Second threat
 


snip...

 












Tuesday, March 05, 2013


A closer look at prion strains Characterization and important implications Prion

7:2, 99–108; March/April 2013; © 2013 Landes Bioscience



http://creutzfeldt-jakob-disease.blogspot.com/2013/03/a-closer-look-at-prion-strains.html










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








TSS









Terry S. Singeltary Sr.


P.O. Box 42


Bacliff, Texas USA 77518


Friday, May 24, 2013

Asynchronous Onset of Clinical Disease in BSE-Infected Macaques

Volume 19, Number 7—July 2013


Dispatch



Asynchronous Onset of Clinical Disease in BSE-Infected Macaques



Judith Montag1, Walter Schulz-Schaeffer, Annette Schrod, Gerhard Hunsmann, and Dirk Motzkus Author affiliations: German Primate Center, Göttingen, Germany (J. Montag, A. Schrod, G. Hunsmann, D. Motzkus); University of Göttingen, Göttingen (W. Schulz-Schaeffer)




Abstract



To estimate the effect of the variability of prion disease onset on primary bovine spongiform encephalopathy transmission to humans, we studied 6 cynomolgus macaques. The preclinical incubation period was significantly prolonged in 2 animals, implying that onset of variant Creutzfeldt-Jacob disease in humans could be more diverse than previously expected.




Prion diseases, such as bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep, and Creutzfeldt-Jakob disease (CJD) in humans, are fatal, transmissible, neurodegenerative disorders associated with the aggregation of an infectivity-associated isoform (PrPSc) of the cellular prion protein (PrP) (1). Seventeen years ago, it became apparent that the BSE-infectious agent had entered the food chain and was identified as the causative agent for a new variant CJD (vCJD) (2). Since then, several risk assessment studies have investigated the number of expected vCJD cases in human populations (reviewed in [3]). Although thousands to millions of consumers of beef products were estimated to be affected, thus far only a few more than 200 vCJD cases have been observed worldwide.




This discrepancy was assumed to be attributable to the so-called species barrier, defined as the hindrance of an infectious agent to change its natural host. Upon crossing the species barrier, prion diseases often show a low attack rate in conjunction with a high variability in the preclinical incubation time. Thus, the consumption of BSE-contaminated products may have led either to a restricted infection or to a prolonged asymptomatic phase in some exposed persons. Therefore, concerns have been raised that asymptomatic carriers of vCJD might exist, posing a risk for unintentional human-to-human transmission.




First indications that transmission of BSE to primates may lead to variances in the preclinical incubation times were obtained by inoculating cynomolgus macaques with cattle-derived BSE material (4–6), even though in those studies not more than 3 animals were used. We have now used a group of 6 macaques that were infected with BSE at a comparable age and kept under identical and controlled experimental conditions.




The Study Six captive-bred female cynomolgus macaques (Macaca fascicularis, purchased from the Centre de Recherche en Primatologie, Mauritius) were inoculated intracerebrally with 1 dose of 50 mg brain homogenate (10% wt/vol) derived from 11 BSE-infected cattle. Animal experimentation was performed in accordance with section 8 of the German Animal Protection Law in compliance with Directive 86/609/EEC. Macaques were housed in a social group, and behavioral changes were assessed on a daily basis by experienced animal care takers.




After inoculation, all 6 macaques remained healthy and asymptomatic for >30 months (Table). At 931 days postinfection, 1 animal showed indications of slight coordination disorders. Within a few days, afferent ataxia developed, and when the animal was separated from the others animals, she apparently became tame. After 2 weeks, the animal showed severe dysmetria of the extremities without obvious myoclonia. Dementia was apparent but could not be diagnosed by objective measures. For ethical reasons, the animal was euthanized 17 days after disease onset. Within the next 14 weeks, 3 more animals became symptomatic. After appearance of neurologic symptoms (ataxia, tremors), the affected animals were occasionally separated from the group when symptoms became more severe or attacks from asymptomatic animals occurred. The disease course in these animals was comparable to that of the first animal, but the progression was slower (91–103 days).




Figure 1




Figure 1. . Survival of intracerebrally BSE-infected cynomolgus macaques. Six age- and sex-matched cynomolgus macaques were inoculated intracerebrally with 50 mg brain homogenate (10% in sucrose) derived from 11 BSE-infected cattle. Macaques were...




Two of the 6 animals remained asymptomatic for ≈1 additional year. Although daily monitoring was facilitated by the fact that only 2 macaques remained and that the caretakers were more experienced to recognize minor changes in behavior, symptoms were first detected 1,340 and 1,398 days postinfection, respectively. Clinical signs were similar to those observed in the previous 4 animals. The symptomatic periods before euthanasia for these macaques lasted 103 and 143 days, respectively (Table). Direct comparison revealed that the difference between the short (931–1,025 days) and the long (1,340–1,398 days) preclinical incubation time was statistically significant (Figure 1, log-rank [Mantel-Cox] test, p<0 .05="" div="">



Test results of brain samples from all animals were positive for macaque-adapted BSE by Western blot analysis. In brief, brain tissue from each animal was homogenized and subjected to proteinase K (PK) treatment for 1 h at 37°C. Samples were separated on acrylamide gels and transferred to nitrocellulose membranes. Macaque-adapted BSE (PrPSc) was detected by using the monoclonal anti-PrP antibody 11C6. PK-resistant PrP was detected in all 6 macaques, confirming that BSE was transmitted to the animals.




Figure 2



Figure 2. . PrPSc profile of macaque-adapted BSE in comparison to human CJD. Brain homogenates from human sCJD type 1, sCJD type 2, vCJD, and BSE-infected macaques were subjected to PK treatment, separated...




The individual glycopattern and band migration of macaque-adapted PrPSc was compared with human sporadic CJD (sCJD) type 1, sCJD type 2, and vCJD. PK-resistant PrP from BSE-infected macaques co-migrated with type 2 sCJD and was clearly distinguishable from type 1 sCJD (Figure 2). The glycosylation pattern of macaque-adapted BSE was comparable with vCJD (6,7), which is characterized by an overrepresentation of diglycosylated PrPSc (8,9). Using 11C6 antibody (10), we detected a slightly decreased signal of the diglycosylated PrPSc isoform for sCJD, vCJD, and macaque-adapted BSE. We assume that this effect is related to a reduced affinity of the diglycosylated isoform to 11C6 that otherwise shows high sensitivity to macaque-adapted PrPSc. Nevertheless, direct comparison showed a higher amount of the diglysosylated PrPSc isoform in vCJD and macaque-adapted BSE than sCJD, which was also shown with a different monoclonal antibody, 3F4. This finding confirms that BSE transmission to macaques is comparable with, and can be used as a model for, human vCJD infection.




Conclusions




Several susceptibility studies using nonhuman primates as a model for human prion diseases hint to heterogeneity of the preclinical incubation period upon crossing the species barrier (5,11,12). However, because of the low number of no more than 3 animals, this variability was not always evident (4). Therefore, there was an urgent need to determine whether the transmission of BSE to humans is likely to lead to a similar diversity.




Our study using 6 cynomolgus macaques shows that the transmission of BSE to primates led to a significantly prolonged asymptomatic phase in 2 animals. Disease onset is influenced by several factors (13). Our study design enabled us to exclude that the route of transmission influenced the disease progression because the infectious agent was injected into the same brain region of each animal. Also, a limited infectious dose cannot be responsible, as shown by the attack rate of 100%. In addition, endogenous factors, such as age, the MM genotype at codon 129 (Table), and housing conditions, were comparable for all macaques.




Thus, we conclude that the variable asymptomatic phase is most likely influenced by the infectious agent (14) or the genomic diversity of the macaques (13). The animals in our study were not inbred. Therefore, differences in the genomic background may have influenced the time of disease onset. In contrast, the PrPSc migration patterns of the animals give no indications for different types or strains that evolved from the mixed BSE inoculum. However, further studies will have to verify this.




Nevertheless, during the BSE epidemics, the human population with its natural genomic diversity was also exposed to a nonhomogenous prion source. Therefore, our study closely mimics the human situation. Our results imply that a prolonged asymptomatic phase can be expected for vCJD. In light of the transmissibility of vCJD through blood transfusions (15), our findings emphasize the need for continued attention to the risks of secondary human-to-human transmission.




Dr Montag is a microbiologist at the Department of Molecular and Cell Physiology at the Hannover Medical School. Her primary research interests are the molecular mechanisms of disease pathology, including prion disorders and inherited cardiac diseases.




Acknowledgments We thank J.P. Deslys for providing vCJD material.




This study was supported by European Union grant QLK1-CT-2002-01096 and BMH4-CT-98-6029.




References




snip...see full text ;








Monday, October 10, 2011


EFSA Journal 2011 The European Response to BSE: A Success Story


snip...


EFSA and the European Centre for Disease Prevention and Control (ECDC) recently delivered a scientific opinion on any possible epidemiological or molecular association between TSEs in animals and humans (EFSA Panel on Biological Hazards (BIOHAZ) and ECDC, 2011). This opinion confirmed Classical BSE prions as the only TSE agents demonstrated to be zoonotic so far but the possibility that a small proportion of human cases so far classified as "sporadic" CJD are of zoonotic origin could not be excluded. Moreover, transmission experiments to non-human primates suggest that some TSE agents in addition to Classical BSE prions in cattle (namely L-type Atypical BSE, Classical BSE in sheep, transmissible mink encephalopathy (TME) and chronic wasting disease (CWD) agents) might have zoonotic potential.



snip...













Thursday, August 12, 2010



Seven main threats for the future linked to prions



First threat



The TSE road map defining the evolution of European policy for protection against prion diseases is based on a certain numbers of hypotheses some of which may turn out to be erroneous. In particular, a form of BSE (called atypical Bovine Spongiform Encephalopathy), recently identified by systematic testing in aged cattle without clinical signs, may be the origin of classical BSE and thus potentially constitute a reservoir, which may be impossible to eradicate if a sporadic origin is confirmed.



***Also, a link is suspected between atypical BSE and some apparently sporadic cases of Creutzfeldt-Jakob disease in humans. These atypical BSE cases constitute an unforeseen first threat that could sharply modify the European approach to prion diseases.



Second threat



snip...













Tuesday, March 05, 2013


A closer look at prion strains Characterization and important implications Prion


7:2, 99–108; March/April 2013; © 2013 Landes Bioscience









Friday, April 19, 2013


APHIS 2013 Stakeholder Meeting (March 2013) BSE TSE PRION









Monday, May 6, 2013


Warning of mad cow disease threat to blood transfusions









Sunday, May 19, 2013


CJD BLOOD SCREENING, DONORS, AND SILENT CARRIERS House of Commons Written Answers 16 May 2013









Tuesday, May 21, 2013


CJD, TSE, PRION, BLOOD Abstracts of the 23rd Regional Congress of the International Society of Blood Transfusion, Amsterdam, The Netherlands, June 2-5, 2013










Sunday, February 10, 2013


Creutzfeldt-Jakob disease (CJD) biannual update (February 2013) Infection report/CJD









Saturday, December 15, 2012


Bovine spongiform encephalopathy: the effect of oral exposure dose on attack rate and incubation period in cattle -- an update 5 December 2012










Thursday, February 14, 2013


The Many Faces of Mad Cow Disease Bovine Spongiform Encephalopathy BSE and TSE prion disease










Tuesday, March 5, 2013


Use of Materials Derived From Cattle in Human Food and Cosmetics; Reopening of the Comment Period FDA-2004-N-0188-0051 (TSS SUBMISSION)


FDA believes current regulation protects the public from BSE but reopens comment period due to new studies









Tuesday, November 02, 2010


BSE - ATYPICAL LESION DISTRIBUTION (RBSE 92-21367) statutory (obex only) diagnostic criteria CVL 1992











Wednesday, April 24, 2013


Chimpanzees Released After 30 Years Of Testing, Brace Yourself For Smiles









TSS

Tuesday, May 21, 2013

CJD, TSE, PRION, BLOOD Abstracts of the 23rd Regional Congress of the International Society of Blood Transfusion, Amsterdam, The Netherlands, June 2-5, 2013

Abstracts of the 23rd Regional Congress of the International Society of Blood Transfusion, Amsterdam, The Netherlands, June 2-5, 2013 Oral Abstracts Oral Abstracts (pages 1–64) Article first published online: 20 MAY 2013 | DOI: 10.1111/vox.12047





1D-H08-02




CURRENT PERSPECTIVES IN TRANSFUSION-TRANSMITTED INFECTIOUS DISEASES: EMERGING AND IMPORTED INFECTIONS, INCLUDING PARASITES


Stramer SL


American Red Cross, Gaithersburg, MD, United States of America


Background: In August 2009, a group from the AABB (Stramer et al., Transfusion 2009;99:1S-29S, Emerging Infectious Disease Agents and their Potential Threat to Transfusion Safety; http://www.aabb.org/resources/bct/eid/Pages/default.aspx) published a Supplement to Transfusion that reviewed the definition and background of emerging infectious disease (EID) agents that pose a real or theoretical threat to transfusion safety, but for which an existing effective intervention is lacking. The necessary attributes for transfusion transmission were outlined including: presence of the agent in blood during an asymptomatic phase in the donor, the agent’s survival/ persistence in blood during processing/storage, and lastly that the agent must be recognized as responsible for a clinically apparent outcome in at least a proportion of recipients who become infected. Without these attributes, agents are not considered as a transfusion-transmission threat and were excluded. Sixty-eight such agents were identified with enough evidence/likelihood of transfusion transmission (e.g. blood phase) and potential for clinical disease to warrant further consideration. In the Supplement, Fact Sheets (FS) were published providing information on: agent classification; background on the disease agent’s importance; the clinical syndromes/ diseases caused; transmission modes (including vectors/reservoirs); likelihood of transfusion transmission, and if proven to be transfusion transmitted, information on known cases; the feasibility and predicted success of interventions that could be used donor screening (questioning) and tests available for diagnostics or that could be adapted for donor screening; and finally, the efficacy, if known, of inactivation methods for plasma-derived products. The Supplement also included a separate section on pathogen reduction technologies for all blood components using published data.
 
 
Agents were prioritized relative to their scientific/epidemiologic threat as well as their perceived threat to the community including concerns expressed by the regulators of blood.
 
 
Agents given the highest priority due to a known transfusiontransmission threat and severe/fatal disease in recipients were the vCJD prion, dengue viruses and the obligate red-cell parasite that causes babesiosis (B. microti and related babesia).
 
 
Although the focus of the Supplement was towards the United States and Canada, many of the agents (and the process) are applicable worldwide. Next steps: Since the publication of the Supplement, five new FSs (yellow fever viruses-including vaccine breakthrough infections, miscellaneous arboviruses, XMRV-including a comprehensive table of published literature, and human parvoviruses/ bocaviruses other than B19) were added and 11 existing FSs updated (babesia, bartonella, chronic wasting disease-CWD, human prions other than vCJD, vCJD, Coxiella burnetii-the agent of Q fever, dengue viruses, HEV, Japanese encephalitis- JE complex, tick-borne encephalitis viruses-TBEV, and human parvovirus B19). Also, tables were released outlining pathogen reduction clinical trials/results (published) and availability/commercial routine use of such technologies by country for platelets, plasma, red cells and whole blood. Of necessity, the list of EID agents is not, and can never be, exhaustive due to the nature of emergence. We recognized that a system of assessing the risk/threat of EIDs for their potential impact on blood safety and availability must include a process for monitoring, identification, evaluation, estimating severity, risk assessments and intervention development. Thus, we are now developing a ‘toolkit’ containing the necessary ‘tools’ from EID monitoring (horizon scanning) to validation/effectiveness evaluations of interventions. Our goal is, ‘to develop a systematic approach to risk assessment and intervention development for the impact of emerging infectious upon blood safety in North America. The system is primarily intended to educate and advise AABB members about risks and interventions in a timely and accurate fashion. Secondary audiences include North American blood systems, blood services and transfusion services’. Certainly this toolkit may be adapted to the needs of ISBT members. Conclusions: The process and final product (toolkit) including methods to monitor EID agent emergence, identification/recognition of a transfusion-transmission threat, methods for quantitative risk assessments, and the appropriate management of such threats should be considered for implementation by all blood systems.






3B-PL6


EVALUATION OF NEURODEGENERATIVE DISEASES AS A THREAT TO THE BLOOD SUPPLY


Edgren G1,2 1Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden 2Department of Hematology, Karolinska University Hospital, Stockholm, Sweden


Background: During recent years, evidence has been accumulating that protein misfolding is central in the causation of a range of neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Considering for example AD, where one of the hallmark features is the aggregation of aberrantly misfolded proteins in the brain, which seems to propagate through the brain in an infectionlike process. Similar observations have been made for Parkinson’s disease, where intrastriatal inoculation of misfolded a-Synuclein – the principal component of Lewy bodies – initiates Parkinson-like neurodegeneration in mice. Similarities with prion diseases have been noted. This is especially disconcerting in light of evidence that variant Creutzfeldt-Jakob disease (vCJD), which could also be characterized as a misfolded protein disease, is transfusion transmittable in sheep – even with blood taken during the symptom free phase of infection – and might have been transmitted by transfusions in humans. As such, the possibility of transfusion transmission of several neurodegenerative disorders is a relevant concern. Aims: To investigate the possible consequences for the blood supply, we assessed the occurrence of a selected range of neurodegenerative diseases in Scandinavian blood donors and possible transfusion transmission of AD.


Methods: The analyses were all based on the Scandinavian donations and transfusions (SCANDAT) database which records the entire computerized blood donation and transfusion history in Sweden and Denmark. We identified all blood donors who had performed at least one whole blood, plasma or platelet donation between 1968 and 2002, and their respective transfusion recipients. Data on donors and transfused patients was linked with national inpatient and cause of death registers to ascertain the occurrence of AD, PD, Amyotrophic lateral sclerosis (ALS) and Dementia of any type. The probability that a particular donation was made by a donor who later developed one of these disorders within 10, 20 or 25 years, was estimated as cumulative incidences using the Kaplan–Meier method. Follow-up was extended until death, emigration or end of follow-up. We also investigated possible transmission of AD by comparing the incidence of AD in recipients of blood from donors who went on to develop AD and recipients of blood from donors who did not develop AD. Transmission analyses were adjusted for necessary confounding factors.


Results: In all, we included 1.1 million blood donors, followed over 13 million person years. A total of 730 donors developed AD, 827 PD, 338 ALS and 2418 Dementia. The probability that a donation was made by a donor who developed AD within 10, 20 and 25 years was 0.03%, 0.19% and 0.45%. For PD, probabilities were 0.03%, 0.22% and 0.45%, and for ALS, 0.02%, 0.07%, and 0.11%. For Dementia, estimates were 0.08%, 0.63%, and 1.44%. Finally, there was no evidence of AD transmission (relative risk, 1.00; 95% CI, 0.78–1.28)


Conclusions: Even when considering latencies as long as 25 years, very few donations are made by donors who go on to develop a neurodegenerative disease. Importantly, we see no association between AD occurrence in donors and their respective recipients, indicating that such transmission is unlikely.




Donor Health and Safey – Infectious Uncertainties





3D-S26-01


AN AMPLIFICATION ASSAY FOR THE PRESYMPTOMATIC DETECTION OF PRION IN BLOOD


Segarra C1, Bougard D1, Beringue V2 and Coste J1 1Etablissement Francais du Sang Pyr en ees-M editerran ee R&D TransDiag, Montpellier, France 2UR892 VIM, Institut National de Recherche Agronomique, Jouy-en-Josas, France


Background: Prion diseases or Transmissible Spongiform Encephalopathies (TSEs) are neurodegenerative diseases including the variant of Creutzfeldt-Jakob disease (vCJD) in humans. The central event of these diseases would be the conformational change of a normal cellular protein PrPC into an infectious form PrPTSE. It is now evident that TSEs are transmissible by blood transfusion and this has raised concerns that a reservoir of infectious asymptomatic people could exist in the blood donor population. Until now, no screening test could detect the infectious agent in blood before the onset of clinical signs of disease.


Aims: The objective of this study is to develop a sensitive and specific test that enables the detection of PrPTSE in the blood during the presymptomatic phase of TSE.


Methods: The detection assay comprises three major steps: (i) a ligand-coated bead pre-analytical step in order to concentrate PrPTSE from the different blood components and to remove inhibitory factors which can interfere in the amplification; (ii) a PrPTSE amplification by serial PMCA using transgenic mouse brain homogenate as substrate and (iii) a specific detection of the amplified PrPTSE by immuno-blotting after partial proteinase K digestion. The sample volume has been optimized for 500 ll of plasma and for 25–50 ll of buffy-coat. Whole blood samples from infected sheep collected during preclinical and clinical phases of scrapie were processed in buffy-coat, white blood cells (WBC) and plasma.


Results: PMCA assay allowed detection of PrPTSE in: (i) the WBC of four sheep at the acute phase of scrapie with a 100% sensitivity and specificity, (ii) in the plasma and buffy coat collected in the asymptomatic phase of the disease. Summary/Conclusions: The expected level of sensitivity for the detection of prion in the blood was reached. This assay is currently evaluated as a confirmatory detection test for the presence of the vCJD agent in human blood. The next step will be to perform prevalence studies by analysing panels of at-risk populations.










Poster Abstracts Poster Abstracts (pages 65–299)


Article first published online: 20 MAY 2013 | DOI: 10.1111/vox.12048






P-368


IS ALZHEIMER’S DISEASE A PRION DISEASE?


Segarra C and Coste J


Etablissement Francais du Sang Pyr en ees-M editerran ee R&D TransDiag, Montpellier, France


Alzheimer’s disease (AD) is the most common type of senile dementia, mainly affecting individuals over 65 years old. Disease manifestation is characterized by progressive impairment of memory and cognition, mainly produced by synaptic dysfunction and neuronal loss. This fatal neurodegenerative disease is a matter of great interest because since its first description in 1906 by the psychiatrist A. Alzheimer the AD cases doesn’t stop to increase and more than 90% of disease arise sporadically. Cerebral accumulation of misfofded protein aggregates composed of amyloid b (Ab) proteins and hyperphosphorylated tau protein have been associated to the disease. In the past decade, there has been renewed interest in the possibility that the proteins causing neurodegenerative disorders are all prions. Recently, the origin of the disease, described until now as linked to aging, was re-evaluated by S. Prusiner (Nobel Prize). In animal models he has shown that, when the neurodegenerative process had been started, it propagates over all the brain, by a prion-like mechanism – prion is the responsible agent of Transmissible Spongiform Encephalopathy (TSE) such as Creutzfeldt-Jacob Disease (CJD).


The misfolding and aggregation mechanisms and structural intermediates are very similar in both AD and TSE. The starting point would be a normal protein, PrPC (Cellular Prion) for TSE and APP (Amyloid Precursor Protein) for AD, which would be converted into pathological misfolded proteins (MFP): PrPSc (scrapie Prion) and Ab protein respectively. These MFP would be then implicated in a process of selfaggregation, leading to the formation of amyloid plaques in the brain. Moreover the mechanism of aggregation follows the same seeding-nucleation process.


Several studies in animal models had shown that:


1 For TSE, the PrPSc aggregates generated by this process were infectious.


2 Ab deposition can be induced by injection of AD brain extracts into animals which without exposure to this material will never develop brain alterations.


3 The transfusion of blood from mice with amyloid plaques in brain accelerates the neuro-degenerative phenomenon and the memory loss in two different models of healthy transgenic mice.


In conclusion, questions on the infectivity of Ab protein in Alzheimer’s disease and the possible secondary transmission by blood transfusion are posed.






P-382


REMOVAL OF EXOGENOUS PRION INFECTIVITY IN LEUCOREDUCED RED BLOOD CELLS UNIT BY P-CAPTTM PRION REMOVAL FILTER


Lescoutra N1, Sumian C1, Culeux A1, Durand V2, Deslys JP2 and Comoy EE2 1MacoPharma, Fontenay-aux-Roses, France 2CEA, Prion Research Group, DSV/ IMETI/SEPIA, Fontenay-aux-Roses, France


Background: Five cases of variant Creutzfeldt-Jakob Disease (vCJD) infections were probably linked to infusion of contaminated blood components, turning to real the inter-human transmissibility of this prion disease from asymptomatic carriers. Corresponding preventive policies are currently limited to exclusion from blood donation, but also take advantage of leucoreduction initially implemented against leucotropic viruses. In the absence of available antemortem diagnostic tests, the updated prevalence of silent vCJD infections (1/2000 in the UK) urges the necessity to enforce blood safety with more efficient active measures able to remove remaining infectivity.


Aims: Several affinity resins were proved to experimentally reduce high levels of brain-spiked infectivity from human leucoreduced red blood cell concentrates (L-RBC). One was integrated in a device adapted to field constraints (volumes, duration) of human transfusion. We aimed here to assess the ability of the final device, in its real conditions of use, i.e. the real conditions of filtration with human leucoreduced red cell concentrates (L-RBC), to remove infectivity from human L-RBC unit spiked with scrapie-infected hamster brain.


Methods: A standardized method for preparation of clarified brain homogenate from 263 K infected hamsters, allowing elimination of large aggregates of PrPres without modification of apparent infectivity, was selected for spiking human L-RBC unit. Filtration by gravity, according to the manufacturer’s recommendations, of a 0.0001% spiked L-RBC unit was carried out on day 1 at room temperature. Pre- and post- blood filtration sample aliquots were removed for infectivity studies (intracerebral inoculation of hamsters). Results: Incubation periods of recipient animals suggest around 3 log10 removal of brain-derived prion infectivity by filtration through the P-Capt[TRADEMARK].


Conclusion: On brain-derived spiked infectivity, the P-Capt[TRADEMARK] filter provided similar performances as columns used for initial proof-of-concept studies (Gregori et al., Lancet 2006), suggesting an appropriate scale-up to efficiently remove infectivity from an individual human blood bag. According to the ability of resin to completely remove apparent endogenous infectivity from hamster leucoreduced blood, the implementation of such a filter, now commercially available, might seriously improve blood safety towards prion.






P-383


UPDATE ON THE ABILITY OF THE PRION CAPTURE FILTER, P-CAPTTM, TO DELAY ONSET OF AN ORIGINAL MYELOPATHIC DISEASE OBSERVED IN PRIMATES EXPOSED TO PRION INFECTED BLOOD PRODUCTS


Lescoutra N1, Jaffre N2, Culeux A1, Sumian C1, Durand V2, Mikol JP2, Luccantoni S2, Deslys JP2 and Comoy EE2


1MacoPharma, Fontenay-aux-Roses, France 2CEA, Prion Research Group, DSV/ IMETI/SEPIA, Fontenay-aux-Roses, France


Background: In the United Kingdom, the recent report of four human cases of variant of Creutzfeldt-Jakob disease (vCJD) through transfusion has justified the implementation of measures to secure blood and blood products towards prions. Leucoreduction, implemented against blood-borne viruses, is not sufficient to remove the entire prion blood infectivity, halved between white cells and plasma. In absence of antemortem diagnostic tests, several devices, including P-Capt[TRADEMARK] filter, were designed to remove prions. This filter incorporates an affinity resin specific for PrP, which has already demonstrated its efficiency in removing both exogenous and endogenous prion infectivity in the experimental model of hamster infected with the experimental 263 K strain. The ability of the P-Capt [TRADEMARK] filter was also previously assessed with human L-RBC artificially contaminated with 263 K clarified brain extracts and demonstrated comparable efficiency.


Aims: We aimed to complete the evaluation of the P-Capt[TRADEMARK] filter with blood-borne infectivity in the cynomolgus macaque considered as an utmost relevant model for the investigation of human prion diseases. Methods: Two independent experiments were performed 1 year apart. First, five donor primates were intravenously (iv) inoculated with high amounts of clarified brain homogenate from a BSE-infected primate to maximize their blood infectivity. At the onset of first clinical signs, their blood was drawn and pooled to reach a volume equivalent to a human blood donation. After whole blood leucoreduction, Red Blood Cell Concentrate (L-RBC) was prepared following routine blood human procedures. L-RBC was suspended in plasma according to conditions used for pediatric transfusion in the UK. Twenty-seven milliliters were transfused to two or three recipient primates prior or after P-Capt[TRADEMARK] filtration respectively. In the second experiment designed for the evaluation of a combined filter for leucoreduction and prion removal, the same scheme was applied with RBC (suspended in Sag-M) issued from six animals intravenously infected with clarified brain homogenate from a vCJD-infected primate.


Results: In the BSE experiment, both primates injected with L-RBC before filtration developed an original neurological disease 30 and 31 months post inoculation and died 2 months later. This original neurodegenerative disease is described by E. Comoy et al. as an atypical form of prion disease. Conversely, all the three animals transfused with P-Capt[TRADEMARK] filtrated L-RBC still remained asymptomatic 54 months post transfusion. In the v-CJD experiment, first clinical signs evocative of the myelopathic syndrome were detected in both primates before filtration 20– 27 months post inoculation. One of them was subject to euthanasia 42 mpi, and pathological examination confirmed the occurrence of the myelopathic syndrome. The others animals are still asymptomatic.


Conclusions: The P-Capt was shown to be able to retain classical prion strains. Here in two independent experiments, we demonstrate that this filter is also able to retain atypical strains recently identified in primates after exposition to human blood products.




P-384


CONTAMINATED BLOOD PRODUCTS INDUCE AN ATYPICAL PRION DISEASE IN PRIMATES IN THE ABSENCE OF DETECTABLE ABNORMAL PRION PROTEIN


Comoy EEC1, Jaffre N1, Mikol J1, Durand V1, Luccantoni S1, Correia E1, Jas-Duval C2, Cheval J3, Eloit M4 and Deslys JP1


1Atomic Energy Commission, Fontenay-aux-Roses, France 2EFS, Lille, France 3Pathoquest, Paris, France 4Pasteur Institute, Paris, France


Background: Concerns about the blood-borne risk of prion infection have been confirmed by the occurrence in the UK of four transfusion-related infections of vCJD (variant Creutzfeldt-Jakob disease), and an apparently silent infection in an hemophiliac patient. Asymptomatic incubation periods in prion diseases can extend over decades in humans. Several parameters, including factors driving blood infectivity, remain poorly understand.


Aims: We used a validated non-human primate model of prion disease to evaluate the transfusional risk linked to v-CJD in human.


Methods: Cynomolgus macaques were inoculated with brain or blood specimens from vCJD infected humans and vCJD or BSE-infected monkeys. Neuropathological and biochemical findings were obtained using current methods used for human patients.


Results: Six out of 12 primates exposed to human or macaque blood-derived components exhibited after a long silent incubation period exceeding 5 years an original neurological disease (myelopathy) previously not described either in humans or primates, and which is devoid of the classical clinical and lesional features of prion disease (front leg paresis in the absence of central involvement, lesions concentrated in anterior horns of lower cervical cord, with no spongiosis or inflammation), while the nine brain-inoculated donor animals and one transfused animal exhibited the classical vCJD pattern, and the five other primates exposed to blood-derived components remain asymptomatic. No abnormal prion protein (PrPres) was detected by standard tests in use for human prion diagnosis. No alternative cause has been found in an exhaustive search for metabolic, endocrine, toxic, nutritional, vascular and infectious etiologies, including a search for pathogen genotypes (‘deep sequencing’). In secondary transmission experiments in primates, after shorter incubation periods (<2 a="" accumulation.="" and="" cord="" disease="" div="" induced="" inoculation="" intracerebral="" myelopathic="" of="" plasma="" prion="" prpres="" same="" spinal="" spongiosis="" syndrome="" the="" transfusion="" transmitted="" typical="" whereas="" with="" years="">

Conclusion: We describe a new neurological syndrome in monkeys exposed to various vCJD/BSE-infected blood components. Secondary transmission in primates confirm first the transmissibility of this myelopathy, and second its prion origin which could not be diagnosed as such in the first recipients. This myelopathy might be compared under some aspects to certain forms of human lower motor neuron diseases including neuromyelitis optica, the flail arm syndrome of ALS and the recently described FOSMN. Similar human infections, were they to occur, would not be identified as a prion disease by current diagnostic investigations.








Tuesday, May 21, 2013


IS ALZHEIMER’S DISEASE A PRION DISEASE? the possible secondary transmission by blood transfusion are posed








Sunday, May 19, 2013


CJD BLOOD SCREENING, DONORS, AND SILENT CARRIERS House of Commons Written Answers 16 May 2013






Monday, May 6, 2013


Warning of mad cow disease threat to blood transfusions








Tuesday, April 30, 2013


Mad cow infected blood 'to kill 1,000’








Friday, June 29, 2012


Highly Efficient Prion Transmission by Blood Transfusion








Tuesday, March 5, 2013


Use of Materials Derived From Cattle in Human Food and Cosmetics; Reopening of the Comment Period FDA-2004-N-0188-0051 (TSS SUBMISSION)


FDA believes current regulation protects the public from BSE but reopens comment period due to new studies








Tuesday, March 05, 2013


A closer look at prion strains Characterization and important implications Prion


7:2, 99–108; March/April 2013; © 2013 Landes Bioscience









Sunday, February 10, 2013


Creutzfeldt-Jakob disease (CJD) biannual update (February 2013) Infection report/CJD








Tuesday, May 7, 2013


Proteinopathies, a core concept for understanding and ultimately treating degenerative disorders?











TSS

Monday, May 6, 2013

Warning of mad cow disease threat to blood transfusions

Warning of mad cow disease threat to blood transfusions


Ben Riley-Smith Reporter Monday 6 May 2013


patients could contract the human form of Creutzfeldt-Jakob Disease (CJD) from blood transfusions because current tests cannot detect a dormant strain of the virus, a leading scientist has warned.

Professor Marc Turner, medical director for the Scottish National Blood Transfusion Service, said shortfalls in technology mean blood donors are not screened for the passive form of variant (vCJD), otherwise known as mad cow disease.


Some 2500 Scots are estimated to be "silent" carriers of defective proteins that have caused people to develop the deadly brain-wasting illness, which can kill sufferers in 12 to 18 months.

The lack of understanding about the variant form means it is impossible to know which carriers of the proteins – known as prions – will go on to develop the disease, or if new cases will emerge.

Humans cannot now contract vCJD from eating British beef, following the culling of millions of cows in the late 1980s.


However, UK Government experts fear one in 20,000 Britons carry a dormant form that could be passed on in blood donations.

Mr Turner said: "We know vCJD can pass through blood transfusion... what's unknown is whether what we've done collectively so far in terms of precautionary measures has been enough to mitigate the risk of transmission. The key issue is whether [donors] have any evidence of infection in their blood.


Unfortunately it has proved very technically demanding to develop a vCJD blood test due to the very low levels of abnormal prions you might find in the blood of such individuals."


Mr Turner said most people over the age of 16 or 17 would have been exposed to BSE in the food chain, especially during the 1980s, and warned that in principle those exposed could have been infected with a form of vCJD.


He said these kind of diseases could have an incubation period of up to 50 years but there was no certainty the dormant form would ever become active.


The comments follow reports that up to 1000 people could die from the disease through infected blood given to them in hospitals, according to a risk assessment by the UK Government's Health Protection Analytical team. The total death toll from vCJD currently stands at 176.


Last month Nick Baxter, 65, the founder and former chief executive of leading Scottish social care charity Cornerstone, died after contracting sporadic CJD, one of four forms of the disease. Mr Baxter did not have the human form of mad cow disease.


Politicians and experts said the findings in the Government's report were worrying and called for nationwide screening of blood donors to be established.


Asked if he wanted to see such a system, Mr Turner said: "If we can get a test which we know is sensitive enough to pick up people who are incubating the illness and specific enough not to falsely identify positive people then yes, that would be clearly a good thing."


A Department of Health spokesman said it continues to encourage everyone to give blood, adding the UK has one of the safest blood supplies in the world.


He added: "There is no evidence of any UK clinical cases of vCJD being linked to a blood transfusion given after 1999. There have been no new cases in the UK for more than two years."
 
 
 


Monday, May 6, 2013

BSE-associated Prion-Amyloid Cardiomyopathy in Primates

Volume 19, Number 6—June 2013

 
 
 

Tuesday, April 30, 2013

Mad cow infected blood 'to kill 1,000’

http://vcjdtransfusion.blogspot.com/2013/04/mad-cow-infected-blood-to-kill-1000.html




Monday, April 15, 2013

Dr. Stephen B. Thacker Director Centers for Disease Control and Prevention′s Office of Science, Epidemiology and Laboratory Services (OSELS) dies from Creutzfeldt Jakob Disease CJD

http://creutzfeldt-jakob-disease.blogspot.com/2013/04/dr-stephen-b-thacker-director-centers.html




Tuesday, March 5, 2013

Use of Materials Derived From Cattle in Human Food and Cosmetics; Reopening of the Comment Period FDA-2004-N-0188-0051 (TSS SUBMISSION)

FDA believes current regulation protects the public from BSE but reopens comment period due to new studies

http://transmissiblespongiformencephalopathy.blogspot.com/2013/03/use-of-materials-derived-from-cattle-in_6452.html




Sunday, February 10, 2013

Creutzfeldt-Jakob disease (CJD) biannual update (February 2013) Infection report/CJD

http://creutzfeldt-jakob-disease.blogspot.com/2013/02/creutzfeldt-jakob-disease-cjd-biannual.html




Sunday, June 3, 2012

A new neurological disease in primates inoculated with prion-infected blood or blood components

http://transmissiblespongiformencephalopathy.blogspot.com/2012/06/new-neurological-disease-in-primates.html




Thursday, August 16, 2012

Blood products, collected from a donor who was at risk for variant Creutzfeldt-Jakob disease ( vCJD) USA JUNE, JULY, AUGUST 2012

http://vcjdtransfusion.blogspot.com/2012/08/blood-products-collected-from-donor-who.html

http://transmissiblespongiformencephalopathy.blogspot.com/




Wednesday, August 24, 2011

All Clinically-Relevant Blood Components Transmit Prion Disease following a Single Blood Transfusion: A Sheep Model of vCJD

http://transmissiblespongiformencephalopathy.blogspot.com/2011/08/all-clinically-relevant-blood.html




Sunday, May 1, 2011

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

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




Monday, February 7, 2011

FDA’s Currently-Recommended Policies to Reduce the Possible Risk of Transmission of CJD and vCJD by Blood and Blood Products 2011 ???

http://tseac.blogspot.com/2011/02/fdas-currently-recommended-policies-to.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




Tuesday, September 14, 2010

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

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




nothing like missing the bigger picture, but they been missing (ignroing) it since 1985 $$$


*** The discovery of previously unrecognized prion diseases in both humans and animals (i.e., Nor98 in small ruminants) demonstrates that the range of prion diseases might be wider than expected and raises crucial questions about the epidemiology and strain properties of these new forms. We are investigating this latter issue by molecular and biological comparison of VPSPr, GSS and Nor98.

http://www.landesbioscience.com/journals/prion/01-Prion6-2-OralPresentations.pdf?nocache=1216084967




Wednesday, March 28, 2012

VARIABLY PROTEASE-SENSITVE PRIONOPATHY IS TRANSMISSIBLE, price of prion poker goes up again $

http://prionopathy.blogspot.com/2012/03/variably-protease-sensitve-prionopathy.html



Thursday, August 12, 2010

Seven main threats for the future linked to prions

First threat

The TSE road map defining the evolution of European policy for protection against prion diseases is based on a certain numbers of hypotheses some of which may turn out to be erroneous. In particular, a form of BSE (called atypical Bovine Spongiform Encephalopathy), recently identified by systematic testing in aged cattle without clinical signs, may be the origin of classical BSE and thus potentially constitute a reservoir, which may be impossible to eradicate if a sporadic origin is confirmed.

***Also, a link is suspected between atypical BSE and some apparently sporadic cases of Creutzfeldt-Jakob disease in humans. These atypical BSE cases constitute an unforeseen first threat that could sharply modify the European approach to prion diseases.

Second threat

snip...

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


Thursday, August 12, 2010

Seven main threats for the future linked to prions

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




Monday, October 10, 2011

EFSA Journal 2011 The European Response to BSE: A Success Story

snip...

EFSA and the European Centre for Disease Prevention and Control (ECDC) recently delivered a scientific opinion on any possible epidemiological or molecular association between TSEs in animals and humans (EFSA Panel on Biological Hazards (BIOHAZ) and ECDC, 2011). This opinion confirmed Classical BSE prions as the only TSE agents demonstrated to be zoonotic so far but the possibility that a small proportion of human cases so far classified as "sporadic" CJD are of zoonotic origin could not be excluded. Moreover, transmission experiments to non-human primates suggest that some TSE agents in addition to Classical BSE prions in cattle (namely L-type Atypical BSE, Classical BSE in sheep, transmissible mink encephalopathy (TME) and chronic wasting disease (CWD) agents) might have zoonotic potential.

snip...

http://www.efsa.europa.eu/en/efsajournal/pub/e991.htm?emt=1

http://www.efsa.europa.eu/en/efsajournal/doc/e991.pdf




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




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




P.4.23

Transmission of atypical BSE in humanized mouse models

Liuting Qing1, Wenquan Zou1, Cristina Casalone2, Martin Groschup3, Miroslaw Polak4, Maria Caramelli2, Pierluigi Gambetti1, Juergen Richt5, Qingzhong Kong1 1Case Western Reserve University, USA; 2Instituto Zooprofilattico Sperimentale, Italy; 3Friedrich-Loeffler-Institut, Germany; 4National Veterinary Research Institute, Poland; 5Kansas State University (Previously at USDA National Animal Disease Center), USA

Background: 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). Atypical BSE cases have been discovered in three continents since 2004; they include the L-type (also named BASE), the H-type, and the first reported case of naturally occurring BSE with mutated bovine PRNP (termed BSE-M). The public health risks posed by atypical BSE were largely undefined.

Objectives: To investigate these atypical BSE types in terms of their transmissibility and phenotypes in humanized mice. Methods: Transgenic mice expressing human PrP were inoculated with several classical (C-type) and atypical (L-, H-, or Mtype) BSE isolates, and the transmission rate, incubation time, characteristics and distribution of PrPSc, symptoms, and histopathology were or will be examined and compared.

Results: Sixty percent of BASE-inoculated humanized mice became infected with minimal spongiosis and an average incubation time of 20-22 months, whereas only one of the C-type BSE-inoculated mice developed prion disease after more than 2 years. Protease-resistant PrPSc in BASE-infected humanized Tg mouse brains was biochemically different from bovine BASE or sCJD. PrPSc was also detected in the spleen of 22% of BASE-infected humanized mice, but not in those infected with sCJD. Secondary transmission of BASE in the humanized mice led to a small reduction in incubation time.*** The atypical BSE-H strain is also transmissible with distinct phenotypes in the humanized mice, but no BSE-M transmission has been observed so far.

Discussion: Our results demonstrate that BASE is more virulent than classical BSE, has a lymphotropic phenotype, and displays a modest transmission barrier in our humanized mice. BSE-H is also transmissible in our humanized Tg mice. The possibility of more than two atypical BSE strains will be discussed.

Supported by NINDS NS052319, NIA AG14359, and NIH AI 77774.

http://www.prion2009.com/sites/default/files/Prion2009_Book_of_Abstracts.pdf




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




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

Thursday, December 04, 2008 2:37 PM

"we have found that H-BSE can infect humans."

personal communication with Professor Kong. ...TSS

BSE-H is also transmissible in our humanized Tg mice.

The possibility of more than two atypical BSE strains will be discussed.

Supported by NINDS NS052319, NIA AG14359, and NIH AI 77774.

http://www.prion2009.com/sites/default/files/Prion2009_Book_of_Abstracts.pdf

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

http://bse-atypical.blogspot.com/2012/03/experimental-h-type-and-l-type-bovine.html




Atypical BSE (BASE) Transmitted from Asymptomatic Aging Cattle to a Primate

Emmanuel E. Comoy1*, Cristina Casalone2, Nathalie Lescoutra-Etchegaray1, Gianluigi Zanusso3, Sophie Freire1, Dominique Marcé1, Frédéric Auvré1, Marie-Magdeleine Ruchoux1, Sergio Ferrari3, Salvatore Monaco3, Nicole Salès4, Maria Caramelli2, Philippe Leboulch1,5, Paul Brown1, Corinne I. Lasmézas4, Jean-Philippe Deslys1

1 Institute of Emerging Diseases and Innovative Therapies, CEA, Fontenay-aux-Roses, France, 2 Istituto Zooprofilattico Sperimentale del Piemonte, Turin, Italy, 3 Policlinico G.B. Rossi, Verona, Italy, 4 Scripps Florida, Jupiter, Florida, United States of America, 5 Genetics Division, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America

Abstract Top Background Human variant Creutzfeldt-Jakob Disease (vCJD) results from foodborne transmission of prions from slaughtered cattle with classical Bovine Spongiform Encephalopathy (cBSE). Atypical forms of BSE, which remain mostly asymptomatic in aging cattle, were recently identified at slaughterhouses throughout Europe and North America, raising a question about human susceptibility to these new prion strains.

Methodology/Principal Findings Brain homogenates from cattle with classical BSE and atypical (BASE) infections were inoculated intracerebrally into cynomolgus monkeys (Macacca fascicularis), a non-human primate model previously demonstrated to be susceptible to the original strain of cBSE. The resulting diseases were compared in terms of clinical signs, histology and biochemistry of the abnormal prion protein (PrPres). The single monkey infected with BASE had a shorter survival, and a different clinical evolution, histopathology, and prion protein (PrPres) pattern than was observed for either classical BSE or vCJD-inoculated animals. Also, the biochemical signature of PrPres in the BASE-inoculated animal was found to have a higher proteinase K sensitivity of the octa-repeat region. We found the same biochemical signature in three of four human patients with sporadic CJD and an MM type 2 PrP genotype who lived in the same country as the infected bovine.

Conclusion/Significance Our results point to a possibly higher degree of pathogenicity of BASE than classical BSE in primates and also raise a question about a possible link to one uncommon subset of cases of apparently sporadic CJD. Thus, despite the waning epidemic of classical BSE, the occurrence of atypical strains should temper the urge to relax measures currently in place to protect public health from accidental contamination by BSE-contaminated products.

Citation: Comoy EE, Casalone C, Lescoutra-Etchegaray N, Zanusso G, Freire S, et al. (2008) Atypical BSE (BASE) Transmitted from Asymptomatic Aging Cattle to a Primate. PLoS ONE 3(8): e3017. doi:10.1371/journal.pone.0003017

Editor: Neil Mabbott, University of Edinburgh, United Kingdom

Received: April 24, 2008; Accepted: August 1, 2008; Published: August 20, 2008

Copyright: © 2008 Comoy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work has been supported by the Network of Excellence NeuroPrion.

Competing interests: CEA owns a patent covering the BSE diagnostic tests commercialized by the company Bio-Rad.

* E-mail: mailto:emmanuel.comoy%40cea.fr

snip...

In summary, we have transmitted one atypical form of BSE (BASE) to a cynomolgus macaque monkey that had a shorter incubation period than monkeys infected with classical BSE, with distinctive clinical, neuropathological, and biochemical features; and have shown that the molecular biological signature resembled that seen in a comparatively uncommon subtype of sporadic CJD. We cannot yet say whether BASE is more pathogenic for primates (including humans) than cBSE, nor can we predict whether its molecular biological features represent a clue to one cause of apparently sporadic human CJD. However, the evidence presented here and by others justifies concern about a potential human health hazard from undetected atypical forms of BSE, and despite the waning epizoonosis of classical BSE, it would be premature to abandon the precautionary measures that have been so successful in reversing the impact of cBSE. We would instead urge a gradual, staged reduction that takes into account the evolving knowledge about atypical ruminant diseases, and both a permanent ban on the use of bovine central nervous system tissue for either animal or human use, and its destruction so as to eliminate any risk of environmental contamination.

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0003017


Proc Natl Acad Sci U S A. 2004 March 2; 101(9): 3065–3070. Published online 2004 February 17. doi: 10.1073/pnas.0305777101 PMCID: PMC365745 Medical Sciences

Identification of a second bovine amyloidotic spongiform encephalopathy: Molecular similarities with sporadic Creutzfeldt-Jakob disease

Cristina Casalone,*† Gianluigi Zanusso,†‡ Pierluigi Acutis,* Sergio Ferrari,‡ Lorenzo Capucci,§ Fabrizio Tagliavini,¶ Salvatore Monaco,‡ and Maria Caramelli*

Abstract

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are mammalian neurodegenerative disorders characterized by a posttranslational conversion and brain accumulation of an insoluble, protease-resistant isoform (PrPSc) of the host-encoded cellular prion protein (PrPC). Human and animal TSE agents exist as different phenotypes that can be biochemically differentiated on the basis of the molecular mass of the protease-resistant PrPSc fragments and the degree of glycosylation. Epidemiological, molecular, and transmission studies strongly suggest that the single strain of agent responsible for bovine spongiform encephalopathy (BSE) has infected humans, causing variant Creutzfeldt-Jakob disease. The unprecedented biological properties of the BSE agent, which circumvents the so-called ”species barrier” between cattle and humans and adapts to different mammalian species, has raised considerable concern for human health. To date, it is unknown whether more than one strain might be responsible for cattle TSE or whether the BSE agent undergoes phenotypic variation after natural transmission. Here we provide evidence of a second cattle TSE. The disorder was pathologically characterized by the presence of PrP-immunopositive amyloid plaques, as opposed to the lack of amyloid deposition in typical BSE cases, and by a different pattern of regional distribution and topology of brain PrPSc accumulation. In addition, Western blot analysis showed a PrPSc type with predominance of the low molecular mass glycoform and a protease-resistant fragment of lower molecular mass than BSE-PrPSc. Strikingly, the molecular signature of this previously undescribed bovine PrPSc was similar to that encountered in a distinct subtype of sporadic Creutzfeldt-Jakob disease.

snip...

Phenotypic Similarities Between BASE and sCJD. The transmissibility of CJD brains was initially demonstrated in primates (27), and classification of atypical cases as CJD was based on this property (28). To date, no systematic studies of strain typing in sCJD have been provided, and classification of different subtypes is based on clinical, neuropathological, and molecular features (the polymorphic PRNP codon 129 and the PrPSc glycotype) (8, 9, 15, 19). The importance of molecular PrPSc characterization in assessing the identity of TSE strains is underscored by several studies, showing that the stability of given disease-specific PrPSc types is maintained upon experimental propagation of sCJD, familial CJD, and vCJD isolates in transgenic PrP-humanized mice (8, 29). Similarly, biochemical properties of BSE- and vCJD-associated PrPSc molecules remain stable after passage to mice expressing bovine PrP (30). Recently, however, it has been reported that PrP-humanized mice inoculated with BSE tissues may also propagate a distinctive PrPSc type, with a ”monoglycosylated-dominant” pattern and electrophoretic mobility of the unglycosylated fragment slower than that of vCJD and BSE (31). Strikingly, this PrPSc type shares its molecular properties with the a PrPSc molecule found in classical sCJD. This observation is at variance with the PrPSc type found in M/V2 sCJD cases and in cattle BASE, showing a monoglycosylated-dominant pattern but faster electrophoretic mobility of the protease-resistant fragment as compared with BSE. In addition to molecular properties of PrPSc, BASE and M/V2 sCJD share a distinctive pattern of intracerebral PrP deposition, which occurs as plaque-like and amyloid-kuru plaques. Differences were, however, observed in the regional distribution of PrPSc. While in M/V2 sCJD cases the largest amounts of PrPSc were detected in the cerebellum, brainstem, and striatum, in cattle BASE these areas were less involved and the highest levels of PrPSc were recovered from the thalamus and olfactory regions.

In conclusion, decoding the biochemical PrPSc signature of individual human and animal TSE strains may allow the identification of potential risk factors for human disorders with unknown etiology, such as sCJD. However, although BASE and sCJD share several characteristics, caution is dictated in assessing a link between conditions affecting two different mammalian species, based on convergent biochemical properties of disease-associated PrPSc types. Strains of TSE agents may be better characterized upon passage to transgenic mice. In the interim until this is accomplished, our present findings suggest a strict epidemiological surveillance of cattle TSE and sCJD based on molecular criteria.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC365745/



FC5.1.1

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

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

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

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

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

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

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

Saturday, September 5, 2009

TSEAC MEETING FEBRUARY 12, 2004 THE BAXTER STUDY GSS

snip...

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



Saturday, September 5, 2009

TSEAC MEETING FEBRUARY 12, 2004 THE BAXTER STUDY GSS

snip...

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(Laughter.)

DR. BROWN: Thanks.

Questions?

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

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

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

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

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

DR. LINDEN: Into a given monkey. Okay.

And the IC inoculations, where were those given?

DR. BROWN: Right parietal cortex, Southern Alabama.

(Laughter.)

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

CHAIRPERSON PRIOLA: Dr. Epstein.

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

I think Jay Epstein --

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

(Laughter.)

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

DR. BROWN: Yes, Fukuoka 1.

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

DR. BROWN: Yes, that is correct.

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

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

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

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

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

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

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

DR. GAMBETTI: -- of GSS either.

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

Jay?

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

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

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

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

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

CHAIRPERSON PRIOLA: Dr. DeArmond.

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

(Laughter.)

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

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

DR. BROWN: I may do it again.

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

(Laughter.)

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

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

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

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

Could you comment on the --

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

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

Primate studies are a real pain.

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

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

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

DR. BROWN: Thomas?

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

CHAIRPERSON PRIOLA: Dr. Johnson.

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

DR. BROWN: Brand new.

MR. JOHNSON: Brand new. Okay.

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

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

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

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

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

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

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

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

(Laughter.)

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

(Laughter.)

CHAIRPERSON PRIOLA: Dr. Bracey.

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

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

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

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

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

snip...

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



snip...

see full text ;

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




(Laughter.)

Saturday, January 20, 2007

Fourth case of transfusion-associated vCJD infection in the United Kingdom

http://vcjdtransfusion.blogspot.com/2007/01/fourth-case-of-transfusion-associated.html





(Laughter.)


Friday, June 29, 2012

Highly Efficient Prion Transmission by Blood Transfusion

http://transmissiblespongiformencephalopathy.blogspot.com/2012/06/highly-efficient-prion-transmission-by.html




(Laughter.)


Wednesday, August 24, 2011

All Clinically-Relevant Blood Components Transmit Prion Disease following a Single Blood Transfusion: A Sheep Model of vCJD

http://transmissiblespongiformencephalopathy.blogspot.com/2011/08/all-clinically-relevant-blood.html





(Laughter.)

Sunday, July 20, 2008

Red Cross told to fix blood collection or face charges 15 years after warnings issued, few changes made to ensure safety

http://vcjdblood.blogspot.com/2008/07/red-cross-told-to-fix-blood-collection.html




Saturday, December 08, 2007

Transfusion Transmission of Human Prion Diseases

http://vcjdblood.blogspot.com/2006/12/vcjd-case-study-highlights-blood.html





Tuesday, October 09, 2007

nvCJD TSE BLOOD UPDATE

http://vcjdblood.blogspot.com/2007/10/nvcjd-tse-blood-update.html





Saturday, December 08, 2007

Transfusion Transmission of Human Prion Diseases

http://vcjdblood.blogspot.com/2007/12/transfusion-transmission-of-human-prion.html





Saturday, January 20, 2007

Fourth case of transfusion-associated vCJD infection in the United Kingdom

http://vcjdtransfusion.blogspot.com/2007/01/fourth-case-of-transfusion-associated.html





vCJD case study highlights blood transfusion risk 9 Dec 2006 by Terry S. Singeltary Sr.

THIS was like closing the barn door after the mad cows got loose. not only the red cross, but the FDA has failed the public in protecting them from the TSE aka mad cow agent. TSE agent ie bse, base, cwd, scrapie, tme, ...

vCJD case study highlights blood transfusion risk -

http://www.mrc.ac.uk/Newspublications/News/MRC003431

http://vcjdblood.blogspot.com/2006/12/vcjd-case-study-highlights-blood.html

http://vcjdblood.blogspot.com/




Friday, April 19, 2013

APHIS 2013 Stakeholder Meeting (March 2013) BSE TSE PRION

http://madcowusda.blogspot.com/2013/04/aphis-2013-stakeholder-meeting-march.html




TSS