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My mother was murdered by what I call corporate and political homicide i.e. FOR PROFIT! she died from a rare phenotype of CJD i.e. the Heidenhain Variant of Creutzfeldt Jakob Disease i.e. sporadic, simply meaning from unknown route and source. I have simply been trying to validate her death DOD 12/14/97 with the truth. There is a route, and there is a source. There are many here in the USA. WE must make CJD and all human TSE, of all age groups 'reportable' Nationally and Internationally, with a written CJD questionnaire asking real questions pertaining to route and source of this agent. Friendly fire has the potential to play a huge role in the continued transmission of this agent via the medical, dental, and surgical arena. We must not flounder any longer. ...TSS

Sunday, August 01, 2010

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

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

PRODUCT 1) Red Blood Cells Leukocytes Reduced. Recall # B-1432-10; 2) Recovered Plasma. Recall # B-1433-10 CODE 1) and 2) Units: X73159; X48910 RECALLING FIRM/MANUFACTURER Blood Assurance Inc., Chattanooga, TN, by fax on September 15, 2009, September 29, 2009 and September 30, 2009. Firm initiated recall is complete. REASON Blood products, collected from a donor considered to be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed. VOLUME OF PRODUCT IN COMMERCE 4 units DISTRIBUTION TN, GA, Korea

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PRODUCT 1) Red Blood Cells Leukocytes Reduced. Recall # B-1720-10; 2) Recovered Plasma. Recall # B-1721-10 CODE 1) and 2) Unit: GP53048 RECALLING FIRM/MANUFACTURER Blood Bank Of San Bernardino and Riverside Counties, San Bernardino, CA, by letter and email on February 19, 2010. Firm initiated recall is complete. REASON Blood products, collected from a donor considered to be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed. VOLUME OF PRODUCT IN COMMERCE 2 units DISTRIBUTION CA, Austria

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PRODUCT Recovered Plasma. Recall # B-1769-10 CODE Unit: P87454 RECALLING FIRM/MANUFACTURER Tacoma Pierce County Blood Bank, Tacoma, WA, by electronic notification on April 9, 2010. Firm initiated recall is complete. REASON Blood product, collected from a donor who was at risk for variant Creutzfeldt-Jakob Disease (vCJD), was distributed. VOLUME OF PRODUCT IN COMMERCE 1 unit DISTRIBUTION Switzerland

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PRODUCT Recovered Plasma. Recall # B-1833-10 CODE Unit: W036509031626 RECALLING FIRM/MANUFACTURER LifeShare Blood Centers, Alexandria, LA, by e-mail on February 18, 2010. Firm initiated recall is complete. REASON Blood product, collected from a donor considered to be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), was distributed. VOLUME OF PRODUCT IN COMMERCE 1 unit DISTRIBUTION Switzerland

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PRODUCT 1) Plasma Frozen. Recall # B-1838-10; 2) Red Blood Cells. Recall # B-1839-10; 3) Fresh Frozen Plasma. Recall # B-1840-10 CODE 1) Units: W038509801565; W038508331750; 2) Units: W038509801565; W038508331750; 4133133; 3) Unit: 4133133 RECALLING FIRM/MANUFACTURER Walter L. Shepeard Community Blood Center, Inc., Augusta, GA, by fax on October 9, 2009. Firm initiated recall is complete. REASON Blood products, collected from a donor considered to be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed. VOLUME OF PRODUCT IN COMMERCE 6 units DISTRIBUTION GA, SC

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END OF ENFORCEMENT REPORT FOR JULY 28, 2010

http://www.fda.gov/Safety/Recalls/EnforcementReports/ucm220487.htm


PRODUCT 1) Recovered Plasma. Recall # B-1772-10; 2) Red Blood Cells Leukocytes Reduced. Recall # B-1773-10; 3) Fresh Frozen Plasma. Recall # B-1774-10 CODE 1) Unit: 6174086; 2) Units: 6205935, 6174086, 6142542; 3) Units: 6205935, 6142542 RECALLING FIRM/MANUFACTURER South Texas Blood and Tissue Center, San Antonio, TX, by facsimile on September 29, 2009, October 6, 2009, November 3, 2009, and November 4, 2009. Firm initiated recall is complete. REASON Blood products, collected from a donor who was at risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed. VOLUME OF PRODUCT IN COMMERCE 6 units DISTRIBUTION Austria, TX

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PRODUCT 1) Red Blood Cells Leukocytes Reduced. Recall # B-1826-10; 2) Platelets. Recall # B-1827-10; 3) Plasma Frozen. Recall # B-1828-10 CODE 1), 2) and 3) Unit: P51128 RECALLING FIRM/MANUFACTURER Blood Assurance Inc., Chattanooga, TN, by facsimile on January 27, 2010. Firm initiated recall is complete. REASON Blood products collected from a donor who may have warranted deferral for residency in an area at risk for Creutzfeldt-Jakob Disease (vCJD) were distributed. VOLUME OF PRODUCT IN COMMERCE 3 units DISTRIBUTION TN, GA

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END OF ENFORCEMENT REPORT FOR JULY 21, 2010

http://www.fda.gov/Safety/Recalls/EnforcementReports/ucm219893.htm


PRODUCT 1) Red Blood Cells Leukocytes Reduced. Recall # B-1683-10; 2) Plasma Frozen. Recall # B-1684-10 CODE 1) and 2) Unit: 9352826 RECALLING FIRM/MANUFACTURER Blood Centers of the Pacific - Irwin Center, San Francisco, CA, by telephone on February 22, 2010. Firm initiated recall is complete. REASON Unit: Blood products, collected from a donor who was at risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed. VOLUME OF PRODUCT IN COMMERCE 2 units DISTRIBUTION CA

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PRODUCT Red Blood Cells Leukocytes Reduced. Recall # B-1736-10 CODE Unit: W038110023096 RECALLING FIRM/MANUFACTURER Florida's Blood Centers, Inc, Orlando, FL, by telephone on January 21, 2010. Firm initiated recall is complete. REASON Blood product, collected from a donor possibly at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), was distributed. VOLUME OF PRODUCT IN COMMERCE 1 unit DISTRIBUTION FL

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END OF ENFORCEMENT REPORT FOR JULY 14, 2010

http://www.fda.gov/Safety/Recalls/EnforcementReports/ucm219025.htm


Saturday, July 17, 2010

Variant Creutzfeldt-Jakob disease Ironside JW., Haemophilia. 2010 Jul;16 Suppl 5:175-80

REVIEW ARTICLE

http://vcjdtransfusion.blogspot.com/2010/07/variant-creutzfeldtjakob-disease.html


Research Paper Transcription of Alu DNA elements in blood cells of sporadic Creutzfeldt-Jakob disease (sCJD) Petra Kiesel, Toby J. Gibson, Barbara Ciesielczyk, Monika Bodemer, Franz-Josef Kaup, Walter Bodemer, Hans Zischler and Inga Zerr Volume 4, Issue 2 April/May/June 2010 Pages 87 - 93

Purchase "Transcription of Alu DNA elements in blood cells of sporadic Creutzfeldt-Jakob disease (sCJD)" for $19 Subscribe to this journal » Log in

Alu DNA elements were long considered to be of no biological significance and thus have been only poorly defined. However, in the past Alu DNA elements with well-defined nucleotide sequences have been suspected to contribute to disease, but the role of Alu DNA element transcripts has rarely been investigated. For the first time, we determined in a real-time approach Alu DNA element transcription in buffy coat cells isolated from the blood of humans suffering from sporadic Creutzfeldt-Jakob disease (sCJD) and other neurodegenerative disorders. The reverse transcribed Alu transcripts were amplified and their cDNA sequences were aligned to genomic regions best fitted to database genomic Alu DNA element sequences deposited in the UCSC and NCBI data bases. Our cloned Alu RNA/cDNA sequences were widely distributed in the human genome and preferably belonged to the "young" Alu Y family. We also observed that some RNA/cDNA clones could be aligned to several chromosomes because of the same degree of identity and score to resident genomic Alu DNA elements. These elements, called paralogues, have purportedly been recently generated by retrotransposition. Along with cases of sCJD we also included cases of dementia and Alzheimer's disease (AD). Each group revealed a divergent pattern of transcribed Alu elements. Chromosome 2 was the most preferred site in sCJD cases, besides chromosome 17; in AD cases chromosome 11 was overrepresented whereas chromosomes 2, 3 and 17 were preferred active Alu loci in controls. Chromosomes 2, 12 and 17 gave rise to Alu transcripts in dementia cases. The detection of putative Alu paralogues widely differed depending on the disease. A detailed data search revealed that some cloned Alu transcripts originated from RNA polymerase III transcription since the genomic sites of their Alu elements were found between genes. Other Alu DNA elements could be located close to or within coding regions of genes. In general, our observations suggest that identification and genomic localization of active Alu DNA elements could be further developed as a surrogate marker for differential gene expression in disease. A sufficient number of cases are necessary for statistical significance before Alu DNA elements can be considered useful to differentiate neurodegenerative diseases from controls.

Authors Petra Kiesel German Primate Center Toby J. Gibson EMBL Heidelberg, Heidelberg, Germany Barbara Ciesielczyk Georg-August University Göttingen, Göttingen, Germany Monika Bodemer Georg-August University Göttingen, Göttingen, Germany Franz-Josef Kaup German Primate Center Walter Bodemer German Primate Center Hans Zischler Dept. of Anthropology, Mainz University, Germany Inga Zerr Corresponding author: IngaZerr@med.uni-goettingen.de Georg-August University Göttingen, Göttingen, Germany

http://www.landesbioscience.com/journals/prion/article/11965


2002

BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein

Emmanuel A. Asante, Jacqueline M. Linehan, Melanie Desbruslais, Susan Joiner, Ian Gowland, Andrew L. Wood, Julie Welch, Andrew F. Hill, Sarah E. Lloyd, Jonathan D.F. Wadsworth, and John Collinge1 MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College, Queen Square, London WC1N 3BG, UK 1Corresponding author e-mail: j.collinge@prion.ucl.ac.ukReceived August 1, 2002; Revised September 24, 2002; Accepted October 17, 2002. This article has been cited by other articles in PMC. Other Sections?

Abstract

Variant Creutzfeldt-Jakob disease (vCJD) has been recognized to date only in individuals homozygous for methionine at PRNP codon 129. Here we show that transgenic mice expressing human PrP methionine 129, inoculated with either bovine spongiform encephalopathy (BSE) or variant CJD prions, may develop the neuropathological and molecular phenotype of vCJD, consistent with these diseases being caused by the same prion strain. Surprisingly, however, BSE transmission to these transgenic mice, in addition to producing a vCJD-like phenotype, can also result in a distinct molecular phenotype that is indistinguishable from that of sporadic CJD with PrPSc type 2. These data suggest that more than one BSE-derived prion strain might infect humans; it is therefore possible that some patients with a phenotype consistent with sporadic CJD may have a disease arising from BSE exposure.

Keywords: BSE/Creutzfeldt-Jakob disease/prion/transgenic

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC136957/?tool=pubmed


2004

Originally published in Science Express on 11 November 2004 Science 3 December 2004: Vol. 306. no. 5702, pp. 1793 - 1796 DOI: 10.1126/science.1103932

Reports Human Prion Protein with Valine 129 Prevents Expression of Variant CJD Phenotype Jonathan D. F. Wadsworth, Emmanuel A. Asante, Melanie Desbruslais, Jacqueline M. Linehan, Susan Joiner, Ian Gowland, Julie Welch, Lisa Stone, Sarah E. Lloyd, Andrew F. Hill,* Sebastian Brandner, John Collinge

Variant Creutzfeldt-Jakob disease (vCJD) is a unique and highly distinctive clinicopathological and molecular phenotype of human prion disease associated with infection with bovine spongiform encephalopathy (BSE)-like prions. Here, we found that generation of this phenotype in transgenic mice required expression of human prion protein (PrP) with methionine 129. Expression of human PrP with valine 129 resulted in a distinct phenotype and, remarkably, persistence of a barrier to transmission of BSE-derived prions on subpassage. Polymorphic residue 129 of human PrP dictated propagation of distinct prion strains after BSE prion infection. Thus, primary and secondary human infection with BSE-derived prions may result in sporadic CJD-like or novel phenotypes in addition to vCJD, depending on the genotype of the prion source and the recipient.

Medical Research Council (MRC) Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.

* Present address: Department of Biochemistry and Molecular Biology and Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia.

To whom correspondence should be addressed. E-mail: j.collinge@prion.ucl.ac.uk

http://www.sciencemag.org/cgi/content/abstract/306/5702/1793


2008

Prominent and Persistent Extraneural Infection in Human PrP Transgenic Mice Infected with Variant CJD

The evolution of the variant Creutzfeldt-Jakob disease (vCJD) epidemic is hazardous to predict due to uncertainty in ascertaining the prevalence of infection and because the disease might remain asymptomatic or produce an alternate, sporadic-like phenotype.

Transgenic mice were produced that overexpress human prion protein with methionine at codon 129, the only allele found so far in vCJD-affected patients. These mice were infected with prions derived from variant and sporadic CJD (sCJD) cases by intracerebral or intraperitoneal route, and transmission efficiency and strain phenotype were analyzed in brain and spleen. We showed that

i) the main features of vCJD infection in humans, including a prominent involvement of the lymphoid tissues compared to that in sCJD infection were faithfully reproduced in such mice;

ii) transmission of vCJD agent by intracerebral route could lead to the propagation of either vCJD or sCJD-like prion in the brain, whereas vCJD prion was invariably propagated in the spleen,

iii) after peripheral exposure, inefficient neuroinvasion was observed, resulting in an asymptomatic infection with life-long persistence of vCJD prion in the spleen at stable and elevated levels.

Our findings emphasize the possibility that human-to-human transmission of vCJD might produce alternative neuropathogical phenotypes and that lymphoid tissue examination of CJD cases classified as sporadic might reveal an infection by vCJD-type prions. They also provide evidence for the strong propensity of this agent to establish long-lasting, subclinical vCJD infection of lymphoreticular tissues, thus amplifying the risk for iatrogenic transmission.

snip...

Discussion Top In this study we used tg650 mice, a newly developed transgenic line expressing human PrPC, to investigate some aspects of the pathogenesis of vCJD infection. As main findings, we demonstrate that prion strain divergence can occur upon transmission of human, primary vCJD to such mice, and that peripheral challenge leads to an asymptomatic, life-long infection of the lymphoid compartment. A feature of tg650 mice is that following primary intracerebral vCJD challenge they developed a neurological disease with typically 100% attack rate, unlike for previously established PrP129Met, including overexpressing lines [16], [19]. The mean survival time - typically around 500 days in homozygous mice - did not change notably on subpassaging, implying that vCJD agent might clinically infect the tg650 mice with little or no transmission barrier. This discrepant result may reflect the use of different constructs and genetic backgrounds (Text S1), and the transgene expression levels, although the latter does not seem to greatly differ as far as the tg650+/- and tg45 mice [16] are concerned.

A surprising result of these studies is the alternate pattern of disease that was induced by one of the inoculated vCJD cases, a WHO reference case here designated vCJD no. 4. Indeed, while vCJD strain features were faithfully propagated in the majority of tg650 mice, almost half of the vCJD 4-inoculated mice were found to propagate a prion replicating faster than vCJD agent, and exhibiting sCJD-like PrPres and neuropathological features. Although strain divergence upon transmission of BSE/vCJD agent to mice was reported to occur in earlier studies [16], [24], it was unprecedented within a context of homotypic transmission, i.e. full matching between the donor and receiver PrP sequences. To address the issue of a possible contamination, we performed independent transmission experiments, involving separate inoculum batches of the incriminated case, which all produced consistent results. Therefore, we consider the data inconsistent with contamination of the VCJD no. 4 material by a sCJD infectious source within our laboratory. An alternate possibility, i.e. a cross-contamination of the source material, was judged highly improbable owing to the procedures applied during the collect of the specimen and the preparation of the homogenates ([25] and P. Minor, personal communication). On the other hand, our observation intriguingly parallels the phenotypic disjunction observed upon transmission of BSE agent to human PrP129Met mice (tg35 line [16]). Together, these findings lend support to the hypothesis that a minor strain component might be created upon cattle-to-human transmission of BSE agent and could emerge upon subsequent human-to-human transmission. It is also worth mentioning that, while the probability to detect such a variant through mouse bioassay would be expected to depend on the amount - and possibly the regions - of brain tissue taken to establish the source material, the vCJD-4 homogenate was prepared using a larger amount of tissue from the same brain than for the other homogenates analyzed in this study (i.e. 100 mg instead of 1 mg of frontal cortex [25]).

The above finding has obvious implications in terms of public health as it raises the concern that some humans iatrogenically infected by vCJD agent may develop a clinical disease that would not be recognized as of vCJD origin [17], [26]. Strikingly however, all vCJD-4-inoculated mice, notwithstanding the strain phenotype divergence propagated bona fide vCJD agent in their spleen, based on the PrPres pattern and the disease phenotype produced by secondary transmission to tg650 mice. This result is of direct relevance to the diagnosis of variant and sporadic CJD. Indeed, looking for peripheral lymphoreticular deposition of abnormal PrP on cases diagnosed as sporadic CJD might reveal a vCJD infection resulting from human-to-human, or cattle-to-human transmission. In this respect, it would be of interest to examine whether BSE-inoculated tg35 mice showing discordant PrPres signatures [16], or vCJD-challenged PrP129Val transgenic mice producing 'type 5' prion in their brain [17] do accumulate PrPvCJD in their spleens. In any case, our findings provide clear evidence that, as a consequence of strain-related tropism disparities, the same mouse can propagate different prions in different tissues following a single infection event.

Another salient finding emerging from this study was the remarkable ability of vCJD agent to establish asymptomatic infection despite sustained, life-long propagation in extraneural tissues. When challenged peripherally, tg650 mice remained asymptomatic over the whole observation period, and did not accumulate PrPres at detectable levels in their brain before 750 days pi, near the life end-stage. In the spleen of these mice however, PrPres accumulation reached its maximum at an early stage of infection, and remained at stable and substantial levels until death. Plateauing of prion infection in the spleen is consistent with earlier observations, and has been suggested to reflect an exhaustion of target cells (for review [22]) Importantly, the spleen tissue was highly infectious as it killed 100% of intracerebrally challenged mice within the minimal mean incubation time (~500 days). Altogether these data support the view that the sustained multiplication of the vCJD prion in lymphoid tissues was not accompanied by an efficient neuroinvasion in tg650 mice. Such an extremely delayed neuroinvasion appears to be rare in TSE rodent models, and to our knowledge was only reported for the mouse-adapted strain 87V on IM mice infected intraperitoneally with diluted inoculum [27]. Clearly, while early accumulation of prions in lymphoid tissues may be essential for efficient neuroinvasion [22], efficient lymphoinvasion does not inevitably lead to rapid neuroinvasion. This finding strengthens the notion that humans infected by vCJD from a human source - including individuals of the MM genotype - might remain clinically asymptomatic for a very prolonged period of time while harboring relatively high levels of prion infectivity in their lymphoid tissues from an early stage of infection on, thereby amplifying the risk of iatrogenic transmission. It also supports the view that the large-scale survey of lymphoreticular tissues [28] may lead to a reliable assessment of the actual prevalence of vCJD infection in the UK population.

Finally, the human PrP transgenic model described in this study may help to further our understanding of peripheral vCJD pathogenesis, for instance in trying to identify factors that might enhance neuroinvasion efficiency, or modulate the shedding of prion infectivity from the lymphoreticular to the blood compartment. Moreover, preliminary results indicate that the search for abnormal PrP in the spleen of such mice culled at time intervals post infection [29], [30] could allow the detection of low levels of vCJD infectivity within a reasonably short time scale.

Citation: Béringue V, Le Dur A, Tixador P, Reine F, Lepourry L, et al. (2008) Prominent and Persistent Extraneural Infection in Human PrP Transgenic Mice Infected with Variant CJD. PLoS ONE 3(1): e1419. doi:10.1371/journal.pone.0001419

Academic Editor: Adam Ratner, Columbia University, United States of America

Received: September 20, 2007; Accepted: December 17, 2007; Published: January 9, 2008

Copyright: © 2008 Beringue 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 was supported by INRA, Institut de Veille Sanitaire (InVS) and the Ministry of Research, France. The sponsors of this study had no role in study conduct, collection analysis, interpretation of the data, writing of the report or approval of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

* To whom correspondence should be addressed. E-mail: hubert.laude@jouy.inra.fr (HL); vincent.beringue@jouy.inra.fr (VB)

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001419




Let's look at just how many risk factors there are in North America from mad cow type disease i.e. prion disease i.e. Transmissible Spongiform Encephalopathy, from all strains. North America has more documented TSE in different species than any other continent on the globe. they have all been circulating for years, decades, and we have all been exposed. the medical and surgical arenas are awash with exposure there from. this is not to scare folks, this is fact. For those interested, i have listed a few studies below, new and old, for you to study, there from, you can make a better decision as to how much risk there might be.

Thank You,

Kind Regards, terry


Journal of Virology, May 2010, p. 5097-5107, Vol. 84, No. 10 0022-538X/10/$012.00+0 doi:10.1128/JVI.02169-09 Copyright © 2010, American Society for Microbiology. All Rights Reserved.

B Cells and Platelets Harbor Prion Infectivity in the Blood of Deer Infected with Chronic Wasting Disease

Candace K. Mathiason,1 Jeanette Hayes-Klug,1 Sheila A. Hays,1 Jenny Powers,2 David A. Osborn,3 Sallie J. Dahmes,4 Karl V. Miller,3 Robert J. Warren,3 Gary L. Mason,1 Glenn C. Telling,5 Alan J. Young,6 and Edward A. Hoover1* Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado,1 National Park Service, Fort Collins, Colorado,2 Warnell School of Forestry and Natural Resources, University of Georgia, Athens, Georgia,3 WASCO Inc., Monroe, Georgia,4 University of Kentucky Medical Center, Lexington, Kentucky,5 South Dakota State University, Brookings, South Dakota6

Received 13 October 2009/ Accepted 23 February 2010

Substantial evidence for prion transmission via blood transfusion exists for many transmissible spongiform encephalopathy (TSE) diseases. Determining which cell phenotype(s) is responsible for trafficking infectivity has important implications for our understanding of the dissemination of prions, as well as their detection and elimination from blood products. We used bioassay studies of native white-tailed deer and transgenic cervidized mice to determine (i) if chronic wasting disease (CWD) blood infectivity is associated with the cellular versus the cell-free/plasma fraction of blood and (ii) in particular if B-cell (MAb 2-104+), platelet (CD41/61+), or CD14+ monocyte blood cell phenotypes harbor infectious prions. All four deer transfused with the blood mononuclear cell fraction from CWD+ donor deer became PrPCWD positive by 19 months postinoculation, whereas none of the four deer inoculated with cell-free plasma from the same source developed prion infection. All four of the deer injected with B cells and three of four deer receiving platelets from CWD+ donor deer became PrPCWD positive in as little as 6 months postinoculation, whereas none of the four deer receiving blood CD14+ monocytes developed evidence of CWD infection (immunohistochemistry and Western blot analysis) after 19 months of observation. Results of the Tg(CerPrP) mouse bioassays mirrored those of the native cervid host. These results indicate that CWD blood infectivity is cell associated and suggest a significant role for B cells and platelets in trafficking CWD infectivity in vivo and support earlier tissue-based studies associating putative follicular B cells with PrPCWD. Localization of CWD infectivity with leukocyte subpopulations may aid in enhancing the sensitivity of blood-based diagnostic assays for CWD and other TSEs.

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* Corresponding author. Mailing address: Colorado State University, Pathology 1619, Fort Collins, CO 80523. Phone: (970) 491-7587. Fax: (970) 491-0523.
E-mail: Edward.Hoover@ColoState.edu

Published ahead of print on 10 March 2010.

Supplemental material for this article may be found at http://jvi.asm.org/.

http://jvi.asm.org/cgi/content/abstract/84/10/5097


Infectious Prions in Pre-Clinical Deer and Transmission of Chronic Wasting Disease Solely by Environmental Exposure

Candace K. Mathiason1, Sheila A. Hays1, Jenny Powers2, Jeanette Hayes-Klug1, Julia Langenberg3, Sallie J. Dahmes4, David A. Osborn5, Karl V. Miller5, Robert J. Warren5, Gary L. Mason1, Edward A. Hoover1* 1 Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America, 2 National Park Service, Fort Collins, Colorado, United States of America, 3 Wisconsin Department of Natural Resources, Madison, Wisconsin, United States of America, 4 WASCO Inc., Monroe, Georgia, United States of America, 5 Warnell School of Forestry and Natural Resources, University of Georgia, Athens, Georgia, United States of America

Abstract

Key to understanding the epidemiology and pathogenesis of prion diseases, including chronic wasting disease (CWD) of cervids, is determining the mode of transmission from one individual to another. We have previously reported that saliva and blood from CWD-infected deer contain sufficient infectious prions to transmit disease upon passage into nai¨ve deer. Here we again use bioassays in deer to show that blood and saliva of pre-symptomatic deer contain infectious prions capable of infecting nai¨ve deer and that nai¨ve deer exposed only to environmental fomites from the suites of CWD-infected deer acquired CWD infection after a period of 15 months post initial exposure. These results help to further explain the basis for the facile transmission of CWD, highlight the complexities associated with CWD transmission among cervids in their natural environment, emphasize the potential utility of blood-based testing to detect pre-clinical CWD infection, and could augur similar transmission dynamics in other prion infections.

snip...

Infectious prions in blood of CWD+ deer

Blood-borne transmission of TSEs has long been feared, and the identification of a prion pathogen associated with blood-borne transmission has been pursued with disparate results [33,45,46]. Here we report the induction of CWD infection by a single blood transfusion from each of two pre-clinical CWD+ blood donors. This result is consistent with previous findings in substantiating the transmission of infectious prions by the blood of asymptomatic animal [27,32] and human [28-30,47,48] donors, thus providing support for a subclinical hematogenous carrier state in TSE infections.

Direct detection of blood-borne PrPRES has been difficult. Saa et al were the first to use protein misfolding cyclic amplification assay (PMCA) [49,50] to detect protease-resistant prion protein in the blood of asymptomatic scrapie-infected hamsters [51]. More recently, Thorne et al reported PMCA amplification of PrPSC from the blood of scrapie-infected sheep [52]. Continued efforts toward the development of sensitive, noninvasive, diagnostic tools are paramount. We are presently re-examining by serial PMCA the tissues of exposed but conventional PrPCWD test negative animals that may harbor infectious prions not manifested in the observation periods used in our CWD studies.

Hunter and colleagues [33,34] provided the first evidence for blood-borne TSE transmission for bovine spongiform encephalopathy (BSE) and scrapie by transfusion of whole blood [33,34] and buffy-coat white blood cells [34] from infected donor sheep to nai¨ve sheep. Sparse but compelling evidence has accumulated for blood transmission of variant Creutzfeldt-Jakob Disease (vCJD) [28-30,48] and PrPRES has been found in peripheral organs of some sporadic CJD patients [53], raising the possibility that peripheral distribution of PrPRES is not limited to vCJD. In an ongoing study of sixty-six individuals who received blood products from asymptomatic blood donors who later developed vCJD [54], three of the 66 blood transfusion recipients developed vCJD 6.5 to 8.5 years after receiving blood [28,30,48] and a fourth blood recipient died of causes unrelated to vCJD five years after receiving the blood donation. Upon autopsy of this individual, PrPRES was detected in lymphoid tissue but not brain, thus providing presumptive evidence for a case of subclinical infection [29]. Our findings with CWD further support the tenet that blood products from subclinical prion-infected individuals may transmit disease.

Additional cases of subclinical human prion disease may exist. While in vitro conversion studies have indicated an inefficient conversion of human PrP into a protease-resistant form [26,55] and no evidence exists of CWD transmission to non-cervid species cohabitating with or on CWD contaminated environments [24,56-58], it is reasonable to surmise that cross-species transmission of prions may require extenuating circumstances, i.e. origin of specific strains [59,60], prolonged incubation time [61], and permissive genotypes [62]. At least two studies provide information bearing on these concerns. The first study, an ongoing longitudinal study to closely monitor 81 Americans who inadvertently consumed, or were exposed to, CWD+ venison at an upstate New York sportsman's feast, will conduct health evaluations of these individuals over the next six years [63]. The second, a retrospective study using western blot analysis of human tonsil and appendix samples collected in the United Kingdom (UK) to investigate possible exposure to the BSE agent, reported the detection of abnormal prion protein in three of 12,674 samples [64]. Mathematical modeling based on the results of this study predicts a minimum estimate of 3000 BSE infected people in the UK between 10-30 years of age. If this model is accurate, it predicts that 93% of these individuals could develop long-term subclinical infection [65].

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2691594/pdf/pone.0005916.pdf


TRANSFUSION MEDICINE

Prion diseases are efficiently transmitted by blood transfusion in sheep

Fiona Houston1, Sandra McCutcheon1, Wilfred Goldmann2, Angela Chong2, James Foster2, Silvia Sisó3, Lorenzo González3, Martin Jeffrey3, and Nora Hunter2 1 Neuropathogenesis Division, Roslin Institute, Compton, United Kingdom; 2 Neuropathogenesis Division, Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom; and 3 Lasswade Laboratory, Veterinary Laboratories Agency, Penicuik, United Kingdom

The emergence of variant Creutzfeld-Jakob disease, following on from the bovine spongiform encephalopathy (BSE) epidemic, led to concerns about the potential risk of iatrogenic transmission of disease by blood transfusion and the introduction of costly control measures to protect blood supplies. We previously reported preliminary data demonstrating the transmission of BSE and natural scrapie by blood transfusion in sheep. The final results of this experiment, reported here, give unexpectedly high transmission rates by transfusion of 36% for BSE and 43% for scrapie. A proportion of BSE-infected tranfusion recipients (3 of 8) survived for up to 7 years without showing clinical signs of disease. The majority of transmissions resulted from blood collected from donors at more than 50% of the estimated incubation period. The high transmission rates and relatively short and consistent incubation periods in clinically positive recipients suggest that infectivity titers in blood were substantial and/or that blood transfusion is an efficient method of transmission. This experiment has established the value of using sheep as a model for studying transmission of variant Creutzfeld-Jakob disease by blood products in humans.

http://bloodjournal.hematologylibrary.org/cgi/content/abstract/112/12/4739


Although recent data in humanized mice suggested that BSE-L agent is likely to be lymphotropic (12)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2634647/


Although it is difficult to compare results from different mouse lines, these findings suggest that the BASE strain has higher transmissibility than BSE-C does for humanized Tg mice with PrP-129M and possibly for humans with PrP-129MM. The BASE strain also appears to be more virulent than BSE-C in bovinized Tg mice, since the incubation time for the BASE strain is 185 ± 12 days, whereas that for BSE-C is 230 ± 7 days (7). Nevertheless, compared with the 100% attack rate and incubation times of ~9 months for sCJDMM1 and sCJDMM2 in the Tg40 line (Table 1), the 60% attack rate and unusually long incubation times (20 to 22 months) for the BASE strain in the same Tg line suggest that the transmission barrier from the BASE strain to humans with PrP-129MM is still quite significant.PK-resistant PrPSc was also detected in the spleen in 4 out of 18 BASE strain-infected Tg40 mice. In contrast, no spleen involvement could be demonstrated for the Tg40 mice following i.c. inoculation with human PrPSc from sCJDMM1. This is the first report of the presence of PrPSc in the spleens of humanized Tg mice after i.c. inoculation with a BSE strain, suggesting that the BASE strain, like BSE-C, where at least in vCJD-infected subjects PrPSc and prion infectivity have been detected in spleens and tonsils (6, 11), is intrinsically lymphotropic. Therefore, lymphoid tissues of BASE strain-infected individuals might also carry prion infectivity.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268471/


Wednesday, March 31, 2010

Atypical BSE in Cattle North America

Topic: Emerging Infectious Diseases Preferred type of presentation:

International Scientific Exchange

This abstract has been ACCEPTED. #0670:

Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009

Authors: T. Singeltary; Bacliff, TX/US

Title: Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009

Body: Background An update on atypical BSE and other TSE in North America.

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

Methods 12 years independent research of available data

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

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

Keywords: Transmissible Spongiform Encephalopathy Creutzfeldt Jakob Disease Prion

see page 114 ;

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


http://www.isid.org/14th_icid/


http://www.isid.org/publications/ICID_Archive.shtml


http://ww2.isid.org/Downloads/IMED2009_AbstrAuth.pdf


http://bse-atypical.blogspot.com/2010/03/atypical-bse-in-cattle-position-post.html



*****URGENT NOTE HERE ABOUT OIE AND ATYPICAL BSE*****

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.


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



Thursday, June 24, 2010

Accumulation of L-type Bovine Prions in Peripheral Nerve Tissues

Volume 16, Number 7-July 2010

http://bse-atypical.blogspot.com/2010/06/accumulation-of-l-type-bovine-prions-in.html



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



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



P02.35

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

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

Western blot analyses of PrPres accumulating in the brain of BSE-infected cattle have demonstrated 3 different molecular phenotypes regarding to the apparent molecular masses and glycoform ratios of PrPres bands. We initially described isolates (H-type BSE) essentially characterized by higher PrPres molecular mass and decreased levels of the diglycosylated PrPres band, in contrast to the classical type of BSE. This type is also distinct from another BSE phenotype named L-type BSE, or also BASE (for Bovine Amyloid Spongiform Encephalopathy), mainly characterized by a low representation of the diglycosylated PrPres band as well as a lower PrPres molecular mass.

Retrospective molecular studies in France of all available BSE cases older than 8 years old and of part of the other cases identified since the beginning of the exhaustive surveillance of the disease in 20001 allowed to identify 7 H-type BSE cases, among 594 BSE cases that could be classified as classical, L- or H-type BSE.

By Western blot analysis of H-type PrPres, we described a remarkable specific feature with antibodies raised against the C-terminal region of PrP that demonstrated the existence of a more C-terminal cleaved form of PrPres (named PrPres#2 ), in addition to the usual PrPres form (PrPres #1). In the unglycosylated form, PrPres #2 migrates at about 14 kDa, compared to 20 kDa for PrPres #1. The proportion of the PrPres#2 in cattle seems to by higher compared to the PrPres#1. Furthermore another PK-resistant fragment at about 7 kDa was detected by some more N-terminal antibodies and presumed to be the result of cleavages of both N- and C-terminal parts of PrP. These singular features were maintained after transmission of the disease to C57Bl/6 mice.

The identification of these two additional PrPres fragments (PrPres #2 and 7kDa band) reminds features reported respectively in sporadic Creutzfeldt-Jakob disease and in Gerstmann-Sträussler-Scheinker (GSS) syndrome in humans.

O.11.3

Infectivity in skeletal muscle of BASE-infected cattle

Silvia Suardi1, Chiara Vimercati1, Fabio Moda1, Ruggerone Margherita1, Ilaria Campagnani1, Guerino Lombardi2, Daniela Gelmetti2, Martin H. Groschup3, Anne Buschmann3, Cristina Casalone4, Maria Caramelli4, Salvatore Monaco5, Gianluigi Zanusso5, Fabrizio Tagliavini1 1Carlo Besta" Neurological Institute,Italy; 2IZS Brescia, Italy; 33FLI Insel Riems, D, Germany; 4CEA-IZS Torino, Italy; 5University of Verona, Italy

Background: BASE is an atypical form of bovine spongiform encephalopathy caused by a prion strain distinct from that of BSE. Upon experimental transmission to cattle, BASE induces a previously unrecognized disease phenotype marked by mental dullness and progressive atrophy of hind limb musculature. Whether affected muscles contain infectivity is unknown. This is a critical issue since the BASE strain is readily transmissible to a variety of hosts including primates, suggesting that humans may be susceptible.

Objectives: To investigate the distribution of infectivity in peripheral tissues of cattle experimentally infected with BASE. Methods: Groups of Tg mice expressing bovine PrP (Tgbov XV, n= 7-15/group) were inoculated both i.c. and i.p. with 10% homogenates of a variety of tissues including brain, spleen, cervical lymph node, kidney and skeletal muscle (m. longissimus dorsi) from cattle intracerebrally infected with BASE. No PrPres was detectable in the peripheral tissues used for inoculation either by immunohistochemistry or Western blot.

Results: Mice inoculated with BASE-brain homogenates showed clinical signs of disease with incubation and survival times of 175±15 and 207±12 days. Five out of seven mice challenged with skeletal muscle developed a similar neurological disorder, with incubation and survival times of 380±11 and 410±12 days. At present (700 days after inoculation) mice challenged with the other peripheral tissues are still healthy. The neuropathological phenotype and PrPres type of the affected mice inoculated either with brain or muscle were indistinguishable and matched those of Tgbov XV mice infected with natural BASE.

Discussion: Our data indicate that the skeletal muscle of cattle experimentally infected with BASE contains significant amount of infectivity, at variance with BSE-affected cattle, raising the issue of intraspecies transmission and the potential risk for humans. Experiments are in progress to assess the presence of infectivity in skeletal muscles of natural BASE.

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


O.2.4

Detection of prions in blood leucocytes

Linda A. Terry, Laurence Howells, Jeremy Hawthorn, Sally Everest, Sarah Jo Moore, Jane C. Edwards Veterinary Laboratories Agency, UK

Background: Infected human blood has been implicated in the iatrogenic transmission of vCJD in four reported cases. Experimental transmission studies have demonstrated that blood from scrapie and BSE infected sheep also contains infectivity. Rodent models of prion disease implicated both cellular and plasma fractions. However, direct detection of PrPsc from blood in the absence of in vitro amplification or bioassay has proved difficult. Methods for the direct detection of PrPsc in blood would be advantageous for the study of the pathogenesis of TSEs and as a basis for a blood test. Objectives: To develop a method for the direct detection of PrPsc in blood cells from scrapie and BSE infected sheep; to study the temporal distribution of PrPsc in blood and to determine the identity of the cells bearing prions in blood. Methods: Peripheral blood mononuclear cells (PBMC) were isolated from sheep naturally infected with scrapie or experimentally infected with BSE at the clinical stage of disease and from scrapie infected sheep from 3 months of age through to clinical end-point. PBMCs were tested for PrPsc content by a direct immunoassay based on the IDEXX CWD HerdChek kit. Different subsets of PBMCs were isolated by subset specific cell surface markers and magnetic bead separation and analysed for PrPsc content. Results: PrPSc was detected in 54% of sheep with clinical scrapie and 71% of sheep with clinical BSE. A longitudinal study of the temporal distribution of blood PBMC associated PrPsc showed that the detection rate increases during the course of disease and is more likely to be observed during the second half of the incubation period. Additionally detection is more likely in scrapie infected sheep if they carry the PRNP genotype of VRQ/VRQ. Cell separation studies showed that the PrPsc is associated with a specific cell subset implicating a subset of B lymphocytes. Discussion. This is the first report of the direct detection of PrPsc in cells isolated from sheep blood in the absence of in vitro amplification or bioassay. Since PrPsc can be detected from as early as 3 months of age in sheep naturally infected with scrapie, correlating with initial replication in the gut-associated lymphoid tissue, the assay could be the basis of a preclinical test. The identification of the cell subset carrying PrPsc progresses our understanding of the pathogenesis of the disease. However, it remains unclear whether this cell subset is responsible for the dissemination of prions or in clearance of circulating PrPsc. Funded by defra, UK and IDEXX.

O.2.6

Human urine and PrP

Silvio Notari1*, Liuting Qing1*, Ayuna Dagdanova1*, Sergei Ilchenko1, Mark E. Obrenovich1, Wen-Quan Zou1, Maurizio Pocchiari2, Pierluigi Gambetti1, Qingzhong Kong1, Shu G. Chen1 1Case Western Reserve University, USA; 2Istituto Superiore di Sanità, Italy

Background: The presence and the characteristics of prion protein (PrP) in human urine under normal conditions are controversial. Similarly, there are no definite data on the presence of infectivity in urine in the course of naturally occurring human prion diseases. Objectives: 1) To definitely determine the presence and characteristics of PrPC in normal urine. 2) To evaluate the prion infectivity in human urine in sporadic Creutzfeldt-Jakob disease (sCJD), we have carried out a set of bioassays in humanized transgenic mouse with urine samples collected from sCJD subjects. Methods: 1) Advanced mass spectrometry and experimental treatments have been used to demonstrate the presence, primary structure and posttranslational modifications of purified urinary PrPC (uPrP). 2) Bioassays were performed by intracerebral inoculation of 100 times concentrated and dialyzed urine, collected from three sCJD-MM1 cases to humanized transgenic mice and from appropriate controls. Results: We found that human urine contains significant amount of PrP (approximately 10 ng/ml) that is truncated with the major N-terminus at residue 112 as the PrPC fragment identified as C1, and it carries an anchor, which is soluble because likely lacks the phosholipid component. None of the humanized transgenic mice inoculated with sCJD concentrated urine had evidence of prion disease during a period of over 700 days (their normal life expectancy) leading to the conclusion that prion infectivity in sCJD urine, if present, must be less than 6 infectious units/100ml. Discussion: The issues raised in the discussion will include: 1) The origin of the truncated uPrP; 2) How the present data compare with the experimental studies published to date that indicate presence of infectivity; 3) The practical implications of our findings. *

O.4.6

All separated components, prepared from BSE-infected sheep blood, are infectious upon transfusion

Sandra McCutcheon1, Anthony Richard Alejo Blanco1, Christopher de Wolf1, Boon Chin Tan1, Nora Hunter1, Valerie Hornsey2, Christopher Prowse2, Marc Turner2, Martin H Groschup3, Dietmar Becher4, Fiona Houston5, Jean C Manson1 1The Roslin Institute and R (D) SVS, University of Edinburgh, UK; 2Scottish National Blood Transfusion Service, UK; 3FLIFederal Research Institute for Animal Health, Germany; 4Micromun, Germany; 5University of Glasgow, UK

Background: The possibility that vCJD may be transmitted by blood transfusion is serious public health issue, of which 4 probable (3 clinical) cases have been attributed. Recently a case of asymptomatic vCJD infection was identified in a haemophiliac; following treatment with clotting factors from UK plasma pools. Sheep orally infected with BSE provide a suitable model, to assess vCJD infection in humans & risk reduction methods, as the distribution of PrPSc & infectivity in lymphoid tissues resembles that of vCJD patients.

Objectives: To determine qualitative and quantitative data on the changes in infectivity in blood and its clinically relevant components with time, to assess the effect of leucodepletion of such products and the potential for secondary transmission by blood transfusion.

Methods: We orally infected sheep with bovine BSE brain homogenate and collected two full-sized donations of whole blood, before the onset of clinical signs. The following components were transfused into naive recipients: whole blood, buffy coat and leucoreduced and non leucoreduced plasma, platelets and red cells. A sub sample of all components was inoculated into TgShpXI mice for determination of infectivity titers. A unit of whole blood from selected primary recipients was transfused into secondary recipients. We are creating a blood archive throughout this study.

Results: 33% of the infected donors have been confirmed as having BSE. We have 4 transmissions of BSE-infectivity following the transfusion of whole blood, buffy coat and plasma. Short incubation times were recorded in these recipients (468, 513, 567 and 594 days) & were similar to those seen in their respective donors (534, 628, 614 and 614 days). The donor of buffy coat also donated both leucodepleted and non leucodepleted blood components to other recipients.

Discussion: Our study will provide invaluable data on the safety of blood products, in relation to TSE infection, used in human medicine (DoH 007/0162)

O.8.1

Variant CJD and plasma products

Robert G. Will National CJD Surveillance Unit, Edinburgh, UK

Evidence from the Transfusion Medicine Epidemiology Review (TMER) project indicates that variant CJD is transmissible through transfusion of labile blood components. The question as to whether plasma products sourced from vCJD contaminated plasma pools has been addressed by a number of risk assessments, with conflicting conclusions. Recently a case of possible vCJD infection in an individual with haemophilia has been described and analysis has suggested that infection may have been related to prior treatment with vCJD implicated Factor VIII. The details of this case will be described together with an analysis of plasma product exposures in UK clinical cases of vCJD.

O.8.2

Blood safety: from screening tests to prion removal

Marc Turner Scottish National Blood Transfusion Service and Department of Haematology, Royal Infirmary, Edinburgh, UK

Although the number of clinical cases of variant CJD continues to fall, concern remains within UK and Western European Blood Services in relation to the risk of transmission of variant CJD due to the estimated prevalence of sub-clinical infection in the general population and the clinical cases of transmission of variant CJD prions by blood components and plasma products. The UK Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO) has considered a number of further precautionary measures including reducing exposure to blood transfusion, importation of blood components, implementation of prion assays and prion reduction for red cell concentrates. The latter two technologies are currently under independent evaluation and it is expected that contingent on the outcome of these an initial decision on whether or not to recommend implementation of these technologies will be made by SaBTO in Autumn 2009.

O.9.3

Updated risk assessment of variant Creutzfeldt-Jakob disease (vCJD) risks for recipients of plasma-derived blood clotting products in the U.S.

Hong Yang, Richard Forshee, Mark Walderhaug, Steven Anderson US Food and Drug Administration, USA

Background: A recent announcement by UK health authorities of a case of vCJD infection in a >70 year old person with hemophilia has prompted the US Food & Drug Administration (FDA) to re-evaluate vCJD risks in the U.S. via plasma-derived Factor VIII (pdFVIII) and to update its 2006 risk assessment. As of May 2009, confirmed vCJD deaths have occurred in persons who are homozygous methionine (MM) at codon 129 of the PRP gene. Several reports in the last few years have indicated signs of vCJD infection in persons of methionine-valine (MV) and homozygous valine (VV) genotypes. FDA updated risk assessment by assuming all genotypes are susceptible to vCJD and modeling the incubation periods for all three genotypes.

Objectives: To evaluate the vCJD risk for pdFVIII recipients with severe hemophilia and vonWillebrand diseases.

Methods: The model assumed equal susceptibility of three genotypes, a median incubation period of 12 years for the MM and 32 years for MV and VV genotypes, and vCJD infectivity was present in the blood of infected donors during the last 50% to 90% of incubation period. Model used statistical distributions for inputs including susceptibility to the disease, donation rates, frequency and duration of travel to the UK, France and other countries in Europe since 1980, the effectiveness of donor deferral policies and infectivity clearance during manufacturing processes.

Results: For severe hemophilia patients at the highest risk (prophylaxis, with inhibitor, with immune tolerance) the model estimated annual mean exposure to be ~7 x 10-8 iv ID50 or ~1 in 270,000 with the lower prevalence (4 per million) assumption, and ~1 x 10-4 iv ID50 or ~1 in 12,000 with the higher prevalence (1 per 4,225) assumption. Donor deferral policies reduce the risk by >92%.

Discussion: Due to limited data and knowledge of vCJD, the model estimates are uncertain. However, it suggests the risk is small, and donor deferral and manufacturing processes greatly reduce the risk.

P.10.7

Serial passage of sCJD in humanised transgenic mice indicates two major transmission strains associated with PrPSc of either type 1 or 2

Matthew Bishop, Robert Will, Enrico Cancellotti, Jean Manson University of Edinburgh, UK

Background: Questions remain about the aetiology of sporadic CJD and whether phenotypic variation is solely controlled by factors such as codon 129 genotype and biochemistry of PrPC. Variation in infective strain has not been clearly demonstrated in sCJD.

Objectives: By serial passage of sCJD in transgenic mice expressing human prion protein with MM, MV, and VV codon 129 genotypes we aimed to understand strain transmission characteristics for the three most commonly observed phenotypes of sCJD.

Methods: We performed intracerebral inoculation of humanised transgenic mice with brain homogenates derived from similar mice previously inoculated with frontal cortex from sCJD patients of subgroups MM1, MV2, and VV2. These mice were assessed for clinical TSE signs, for TSE vacuolation, and deposition of PrPSc.

Results: sCJD(MM1) passage via all mice showed transmission profiles similar to primary inoculation. sCJD(MV2) passage via HuMM and HuVV mice showed a transmission profile similar to primary inoculation. Passage via a HuMV mouse showed transmission properties similar to not only the primary inoculum but also sCJD(MM1). sCJD(VV2) passage via HuMV and HuVV mice showed transmission profiles similar to the primary inoculation. Passage via a HuMM mouse showed transmission properties similar to not only the sCJD(VV2) primary inoculum but also sCJD(MM1). Cluster analysis of the lesion profile data showed that three clusters seen after primary inoculation were reduced to two following second passage, identified by the biochemical type of PrPSc (1 or 2) found in the host mice.

Discussion: Serial passage of sCJD subgroups MM1, MV2, and VV2 shows that PrPSc type and mouse codon 129 genotype determine the secondary transmission profile, independently of the originating inoculum strain. There are associations between type 1 PrPSc and C129-Met, and type 2 PrPSc and C129-Val. This should allow us to investigate further the relationship between PrPSc, genotype, infection, and pathology.

P.5.1

Detection of cellular prion protein (PrPc) in plasma from healthy cynomolgus monkeys (Macaca fascicularis) and changes observed after BSE infection

Barbara Yutzy, Edgar Holznagel, Johannes Löwer Paul-Ehrlich-Institut, Germany

Background: Orally BSE-dosed cynomolgus monkeys represent a valuable model to examine the kinetic of blood infectivity and to assess the risk of blood-borne transmission of variant Creutzfeldt-Jacob disease (vCJD).

Methods: Blood samples were collected monthly from BSE-infected (n = 18) and non-infected female cynomolgus monkeys (n = 8) over a period of up to 9 years. PrPc concentrations were retrospectively analyzed in plasma samples by a dot blot assay and by a sandwich ELISA using a highly sensitive dissociation- enhanced lanthanide fluoro-immunoassay (DELFIA) for detection. Different blood preparation protocols were evaluated to obtain plasma.

Objective: To detect changes in the levels of soluble plasmaderived PrPc. Results: Different blood preparation protocols had a significant effect on the measured plasma PrPc concentrations. In non-infected macaques, concentrations of soluble, plasmaderived PrPc were at least 10-fold lower compared to plasma concentrations in healthy humans. Levels of plasma PrPc increased 6 - 12 months after experimental BSE infection, remained high during the asymptomatic phase, and dropped towards the clinical phase. Soluble, plasma-derived PrPc molecules were PK-sensitive in BSE-infected macaques.

Discussion: There is a species-specific difference in the PrPc concentrations between human and macaque. At least a part of the plasma-derived PrPc fraction originates from blood cells. Andfinally, BSE infection caused an increase in plasma PrPc levels during the asymptomatic phase of infection. Blood transfusion studies have been initiated to examine whether these PK-sensitive PrP molecules carry infectivity.

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


FC5.1.1

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

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

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

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

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

Conclusion: No infectivity was found in small volumes of blood components from 4 patients with sporadic CJD and 3 patients with variant CJD.

However, a single transmission from a chimpanzee-passaged strain of GSS shows that infectivity may be present in leukocytes, and the 'shock' of general anaesthesia and plasmspheresis appears to have triggered the onset of illness in pre-clinical donor chimpanzees.

FC5.1.2

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

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

BSE and vCJD transmitted to cynomolgus macaques reproduce many features of human vCJD, including clinical symptoms, neuropathological hallmarks of vCJD, PrPres electrophoretical pattern and, most importantly, the wide distribution of infectivity in peripheral organs. The latter characteristic distinguishes vCJD from sCJD in both humans and cynomolgus macaques, and prompted us to use this non-human primate model for further investigations of vCJD and its risk for human health. The occurrence of four vCJD infections in humans transfused with blood from patients who later developed vCJD has raised concern about blood transfusion safety in countries with vCJD.

In this collaborative European study, we investigated the infectivity of blood components and whole blood administered by intracerebral (ic) and intravenous (iv) routes. Buffy-coat and whole blood was inoculated by ic and iv route, respectively, from two vCJD patients and from two clinical vCJD-inoculated macaques. Transfusions were also performed from whole blood and blood leucodepleted according to hospital practice standards from two clinical BSE inoculated macaques. Blood infectivity during the preclinical phase is being examined in orally infected macaques. Whole blood was collected and transfused from one such animal two years after oral challenge, whereas buffy-coat and plasma from two animals at 2 and 4.5 years post-challenge, respectively, have been inoculated by the ic route.

This is an ongoing study in which recipient animals continue to be observed at various times post-inoculation. So far, we have had one positive transmission in one animal transfused 65 months earlier with 40 ml of whole blood from a vCJD macaque (the characteristics of the disease in this animal will be shown in a separate poster by E. Comoy). This positive transmission reproduces transfusion transmission of vCJD in humans, with an incubation of 5.5 years compatible with incubation periods observed in humans.

http://www.neuroprion.org/resources/pdf_docs/conferences/prion2007/abstract_book.pdf


P03.106

Detection of Chronic Wasting Disease Prions in Saliva, Blood, and Excreta of Deer

Mathiason, C1; Powers, J2; Dahmes, S3; Osborn, D4; Miller, K4; Warren, R4; Mason, G1; Hays, S1; Hayes-Klug, J1; Seelig, D1; Wild, M2; Wolfe, L5; Spraker, T6; Miller, M5; Sigurdson, C1; Telling, G7; Hoover, E1 1Colorado State University, Microbiology, Immunology and Pathology, USA; 2National Park Service, Biological Resource Management Division, USA; 3Wildlife Artist Supply Company (WASCO, Inc.), USA; 4University of Georgia, Athens, Warnell School of Forestry and Natural Resources, USA; 5Colorado Division of Wildlife, Wildlife Research Center, USA; 6Colorado State University, Veterinary Diagnostic Laboratory, CVMBS, USA; 7University of Kentucky, Microbiology, Immunology and Molecular Genetics, USA

Background: The potential presence of prions in body fluids is perhaps most relevant to chronic wasting disease (CWD) of cervids, owing to its facile transmission, geographic expansion, and the relatively large amount of aberrant prion protein in peripheral lymphoid tissues. Nevertheless the exact mode by which the CWD prions are shed and transmitted has remained unknown. Objective: To determine whether infectious CWD prions are present in saliva, blood or urine and feces of CWD-positive deer.

Methods: Two bioassay studies comprising three cohorts for a total of n = 6 naïve deer/cohort were exposed either orally to 50 ml saliva, or 50 ml urine and 50 gram feces, or via intravenous transfusion of 250 ml whole blood from CWD-positive deer. Study controls included positive control cohorts totalling (n = 8) deer exposed to brain from CWD-positive deer and a negative control cohort consisting of (n = 2) deer receiving inocula from CWD-negative deer. The recipient animals were maintained under rigorous indoor isolation conditions to exclude potential adventitious prion exposure and monitored for CWD infection for a minimum of 18 months post infection by serial tonsil biopsy and terminal necropsy.

Results: Infectious prions capable of transmitting CWD were detected in saliva (by the oral route) and in blood (by transfusion). PrPCWD was first detected in tonsils between 3 and 12 months post inoculation. To our surprise, no deer fed urine and feces from CWD-positive donors developed CWD infection, despite multiple exposures.

Conclusion: Infectious prions in saliva may explain the efficient transmission of CWD in nature. Infectious prions in the blood of CWD-positive deer establishes a basis for developing antemortem detection of the disease by blood-based assay methods and emphasizes the widespread distribution of infectivity in CWD-positive deer.

O.9.3

Updated risk assessment of variant Creutzfeldt-Jakob disease (vCJD) risks for recipients of plasma-derived blood clotting products in the U.S.

Hong Yang, Richard Forshee, Mark Walderhaug, Steven Anderson

US Food and Drug Administration, USA

Background: A recent announcement by UK health authorities of a case of vCJD infection in a >70 year old person with hemophilia has prompted the US Food & Drug Administration (FDA) to re-evaluate vCJD risks in the U.S. via plasma-derived Factor VIII (pdFVIII) and to update its 2006 risk assessment. As of May 2009, confirmed vCJD deaths have occurred in persons who are homozygous methionine (MM) at codon 129 of the PRP gene. Several reports in the last few years have indicated signs of vCJD infection in persons of methionine-valine (MV) and homozygous valine (VV) genotypes. FDA updated risk assessment by assuming all genotypes are susceptible to vCJD and modeling the incubation periods for all three genotypes.

Objectives: To evaluate the vCJD risk for pdFVIII recipients with severe hemophilia and vonWillebrand diseases.

Methods: The model assumed equal susceptibility of three genotypes, a median incubation period of 12 years for the MM and 32 years for MV and VV genotypes, and vCJD infectivity was present in the blood of infected donors during the last 50% to 90% of incubation period. Model used statistical distributions for inputs including susceptibility to the disease, donation rates, frequency and duration of travel to the UK, France and other countries in Europe since 1980, the effectiveness of donor deferral policies and infectivity clearance during manufacturing processes.

Results: For severe hemophilia patients at the highest risk (prophylaxis, with inhibitor, with immune tolerance) the model estimated annual mean exposure to be ~7 x 10-8 iv ID50 or ~1 in 270,000 with the lower prevalence (4 per million) assumption, and ~1 x 10-4 iv ID50 or ~1 in 12,000 with the higher prevalence (1 per 4,225) assumption. Donor deferral policies reduce the risk by >92%.

Discussion: Due to limited data and knowledge of vCJD, the model estimates are uncertain. However, it suggests the risk is small, and donor deferral and manufacturing processes greatly reduce the risk.

FC5.3

Assessing the Risk of vCJD Transmission by Dentistry; Distribution of Infectivity in Oral Tissues of VM Mice after Simulated Oral Feeding of BSE-301V

Sutton, JM1; Kirby, E1; Dickinson, J1; Dennis, M1; Cornwall, M1; Vassey, MJ1; Smith, A2; Marsh, PD3; Walker, JT1; Raven, NDH1

1Health Protection Agency, Centre for Emergency Preparedness and Response,, TSE Research group, UK; 2University of Glasgow, Dental School, UK; 3Health Protection Agency, Centre for Emergency Preparedness and Response,, UK

Background: Ongoing concerns about the prevalence of variant Creutzfeldt Jakob Disease (vCJD) in the UK population has heightened concerns about the risks of iatrogenic transmission of the disease. Although there have been no cases to date of transmission by surgery there have been 4 cases involving blood transfusion. This study aims to assess the potential of transmission of the disease by dental procedures. Whilst the risks are undoubtably low the very large numbers of procedures carried out annually have the potential to amplify the risks considerably and there is very little data in this area to form the basis for accurate risk assessments.

Aim(s)/Objective(s): To assess the relative levels of infectivity in oral tissues from a murine model following exposure to BSE-301V through the small intestine. Methods. The study uses a BSE-301V, VM mouse model as a clinically relevant model for assessing iatrogenic vCJD transmission between humans. Infectious mouse brain homogenate was prepared and inoculated into a loop of the duodenum, to prevent direct contamination of the oral tissues. Mice were sacrificed at 3-weekly intervals and at appearance of clinical symptoms. A range of oral tissues, including dental pulp, gingival margin, salivary gland, saliva, lingual tonsil and trigeminal ganglia, together with brain and spleen tissues were removed, processed as homogenates and reinoculated intracranially (ic.) into indicator mice.

Results: The primary challenge proved to be a very efficient route of infection with a 100% attack rate and a mean incubation to clinical disease of 157 ± 17 days (compared to 120 days for the same titre inoculum ic.). Infectivity was observed in all oral and control tissues with varying time-courses and titres estimated from incubation period.

Discussion: The results throw new light on the potential routes of dissemination and spread of infectivity from the small intestine to the oral cavity and its implications for possible iatrogenic transmission of vCJD via dental, endoscopic or other forms of surgery.

Conclusion: The data generated from the study provides support for ongoing risk assessments to look at the potential for vCJD transmission via dental procedures alongside other elements of studies looking at effectiveness of decontamination and re-use of dental instruments.

FC5.5.1

BASE Transmitted to Primates and MV2 sCJD Subtype Share PrP27-30 and PrPSc C-terminal Truncated Fragments

Zanusso, G1; Commoy, E2; Fasoli, E3; Fiorini, M3; Lescoutra, N4; Ruchoux, MM4; Casalone, C5; Caramelli, M5; Ferrari, S3; Lasmezas, C6; Deslys, J-P4; Monaco, S3 1University of Verona, of Neurological and Visual Sciences, Italy; 2CEA, IMETI/SEPIA, France; 3University of Verona, Neurological and Visual Sciences, Italy; 4IMETI/SEPIA, France; 5IZSPLVA, Italy; 6The Scripps Research Insitute, USA

The etiology of sporadic Creutzfeldt-Jakob disease (sCJD), the most frequent human prion disease, remains still unknown. The marked disease phenotype heterogeneity observed in sCJD is thought to be influenced by the type of proteinase K-resistant prion protein, or PrPSc (type 1 or type 2 according to the electrophoretic mobility of the unglycosylated backbone), and by the host polymorphic Methionine/Valine (M/V) codon 129 of the PRNP. By using a two-dimensional gel electrophoresis (2D-PAGE) and imunoblotting we previously showed that in sCJD, in addition to the PrPSc type, distinct PrPSc C-terminal truncated fragments (CTFs) correlated with different sCJD subtypes. Based on the combination of CTFs and PrPSc type, we distinguished three PrPSc patterns: (i) the first was observed in sCJD with PrPSc type 1 of all genotypes,; (ii) the second was found in M/M-2 (cortical form); (iii) the third in amyloidogenic M/V- 2 and V/V-2 subtypes (Zanusso et al., JBC 2004) . Recently, we showed that sCJD subtype M/V-2 shared molecular and pathological features with an atypical form of BSE, named BASE, thus suggesting a potential link between the two conditions. This connection was further confirmed after 2D-PAGE analysis, which showed an identical PrPSc signature, including the biochemical pattern of CTFs. To pursue this issue, we obtained brain homogenates from Cynomolgus macaques intracerebrally inoculated with brain homogenates from BASE. Samples were separated by using a twodimensional electrophoresis (2D-PAGE) followed by immunoblotting.

We here show that the PrPSc pattern obtained in infected primates is identical to BASE and sCJD MV-2 subtype. These data strongly support the link, or at least a common ancestry, between a sCJD subtype and BASE.

This work was supported by Neuroprion (FOOD-CT-2004-506579)

FC5.5.2

Transmission of Italian BSE and BASE Isolates in Cattle Results into a Typical BSE Phenotype and a Muscle Wasting Disease

Zanusso, G1; Lombardi, G2; Casalone, C3; D'Angelo, A4; Gelmetti, D2; Torcoli, G2; Barbieri, I2; Corona, C3; Fasoli, E1; Farinazzo, A1; Fiorini, M1; Gelati, M1; Iulini, B3; Tagliavini, F5; Ferrari, S1; Monaco, S1; Caramelli, M3; Capucci, L2

1University of Verona, Neurological and Visual Sciences, Italy; 2IZSLER, Italy; 3IZSPLVA, Italy; 4University of Turin, Animal Pathology, Italy; 5Isituto Carlo Besta, Italy

The clinical phenotype of bovine spongiform encephalopathy has been extensively reported in early accounts of the disorder. Following the introduction of statutory active surveillance, almost all BSE cases have been diagnosed on a pathological/molecular basis, in a pre-symptomatic clinical stage. In recent years, the active surveillance system has uncovered atypical BSE cases, which are characterized by distinct conformers of the PrPSc, named high-type (BSE-H) and low-type (BSE-L), whose clinicopathological phenotypes remain unknown. We recently reported two Italian atypical cases with a PrPSc type similar to BSE-L, pathologically characterized by PrP amyloid plaques. Experimental transmission to TgBov mice has recently disclosed that BASE is caused by a distinct prion strain which is extremely virulent. A major limitation of transmission studies to mice is the lack of reliable information on clinical phenotype of BASE in its natural host. In the present study, we experimentally infected Fresian/Holstein and Alpine/Brown cattle with Italian BSE and BASE isolates by i.c. route. BASE infected cattle showed survival times significantly shorter than BSE, a finding more readily evident in Fresian/Holstein, and in keeping with previous observations in TgBov mice. Clinically, BSE-infected cattle developed a disease phenotype highly comparable with that described in field BSE cases and in experimentally challenged cattle. On the contrary, BASE-inoculated cattle developed an amyotrophic disorder accompanied by mental dullness.

The molecular and neuropathological profiles, including PrP deposition pattern, closely matched those observed in the original cases. This study further confirms that BASE is caused by a distinct prion isolate and discloses a novel disease phenotype in cattle, closely resembling the phenotype previous reported in scrapie-inoculated cattle and in some subtypes of inherited and sporadic Creutzfeldt-Jakob disease.

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


http://www.neuroprion.org/resources/pdf_docs/conferences/prion2007/abstract_book.pdf


O.2.2

vCJD infection in an asymptomatic UK haemophilic patient

Alexander Peden1, Graham Fairfoul1, Suzanne Lowrie1, Linda McCardle1, Mark Head1, Seth Love2, Hester Ward1, Simon Cousens3, David Keeling4, Carolyn Millar5, FGH Hill6, James Ironside1 1University of Edinburgh, UK; 2Frenchay Hospital, Bristol, UK; 3London School of Hygiene and Tropical Medicine, UK; 4Churchill Hospital, Oxford, UK; 5Imperial College London, UK; 6Birmingham Children's Hospital, Birmingham, UK

We describe a study of 17 UK patients with haemophilia considered to be at increased risk of vCJD through exposure to UK plasma products.

10 autopsy cases and 7 biopsy cases were analysed for disease- associated, protease-resistant prion protein (PrPres). The tissues available from each case were variable, ranging from a single biopsy sample to a wide range of autopsy tissues. A single specimen from the spleen of one autopsy case gave a strong positive result on repeated testing for PrPres by Western blot analysis. This tissue came from a 73 year-old male with no history of neurological disease, who was heterozygous (methionine/valine) at codon 129 in the prion protein gene. He had received over 9,000 units of Factor VIII concentrate prepared from plasma pools known to include donations from a vCJD-infected donor, and some 400,000 units not known to include donations from vCJD-infected donors. He had also received 14 units of red blood cells and had undergone several surgical and invasive endoscopic procedures. Estimates of the relative risks of exposure though diet, surgery, endoscopy, blood transfusion and receipt of UK plasma products suggest that by far the most likely route of infection was receipt of UK plasma products.

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


P04.36

Enhanced Surveillance of Persons Identified as at Increased Risk of CJD Due to Blood Transfusion or Healthcare Procedures

Brookes, D1; Chow, Y1; Ward, HJT2; Will, RG2; Hewitt, P3; Gill, ON1 1HPA, CJD, UK; 2National CJD Surveillance Unit, UK; 3Colindale, NHS Blood and Tissue, UK

Introduction: Reports of four iatrogenic transmissions of variant-CJD (vCJD) infection in the UK (all due to transfusion of blood from donors who later developed vCJD), evidence from iatrogenic transmissions of sporadic CJD and experimental work on CJD infectivity in tissues and on healthcare instruments have given rise to concern about the risks of iatrogenic transmission of CJD. This risk warrants a) certain public health precautions, and b) follow-up of individuals with identified risks in order to gain evidence about their risks and ensure appropriate management of these risks. Evidence of transmission via iatrogenic routes is important to inform public health measures and so prevent ongoing transmission of CJD.

Methods: The Health Protection Agency and Health Protection Scotland holds details of persons identified as 'at-risk' of vCJD due to blood transfusion and of persons identified as 'at-risk' of CJD (of any type) from other healthcare procedures. The GPs/clinicians of all persons identified as 'at-risk' for public health purposes are provided with: information; risk assessment updates; advice on public health precautions and advice on referral to specialist care. Procedures are being established to obtain enhanced surveillance data on these individuals, including: clinical status updates, date and cause of death, surplus tissue and blood specimens, and postmortem investigations.

Results: Persons 'at-risk' of CJD have experienced a range of exposures. Estimated risks are uncertain and overlapping. Some individuals - recipients of vCJD implicated blood components - are considered to be at a clearly higher risk of infection: active follow-up is currently conducted for these individuals. In time, the enhanced surveillance of persons at increased risk of CJD will provide estimates of transmission risks and of the impact of iatrogenic exposures on mortality.

Conclusion: Knowledge about iatrogenic transmission of CJD is being gained by the follow-up of individuals who have been identified as 'at-risk' of CJD in the UK. This enhanced surveillance may need to be sustained for many years.

http://www.neuroprion.org/resources/pdf_docs/conferences/prion2007/abstract_book.pdf


P04.49

Case Report of Variant Creutzfeldt-Jakob Disease in a Macaque after Blood

Transfusion

Lescoutra-Etchegaray, N1; Ruchoux, MM1; Correia, E1; Jolit, A1; Freire, S1; Lasmezas, CI2; Deslys, JP1; Comoy, E1 1CEA/DSV/IMETI/SEPIA, France; 2Scripps Florida, USA

A fourth human case of probable transmission of vCJD through transfusion has now been reported but a number of features affecting transfusion-related infection remain imprecise, including infectious dose, length of incubation period and critical infectious window of blood donors.

We report here the first case of experimental transmission of vCJD in primates by blood transfusion. Experimental infection of Cynomolgus macaque has been demonstrated to be a sensitive model for the investigation of human prion diseases, inducing similar distribution of infectivity in peripheral lymphoid tissues and equivalent brain pathology. In our study, transfusion was performed with 40 ml of whole blood drawn from a vCJD-infected macaque at the terminal stage of the disease. Clinical symptoms of vCJD appeared in the recipient animal after five years of incubation. The total amount of infectivity in the transfused blood was approximately 106 fold lower than in the brain (titration still in progress). In several animals infected intravenously with brain homogenate, the presence of PrPres in serial lymph nodes biopsies and in other organs at autopsy was examined and results will be presented.

P04.51

Atypical Presentation of Variant Creutzfeldt-Jakob Disease in a 73 Year Old Blood Transfusion

Recipient Wroe, S1; Pal, S1; Webb, T1; Alner, K2; Hewitt, P3; Brander, S4; Wadsworth, JD5; Collinge, J1 1National Hospital for Neurology and Neurosurgery, National Prion Clinic, UK; 2National Hospital for Neurology and Neurosurgery, Department of Neuropsychology, UK; 3Health Protection Agency, UK; 4National Hospital for Neurology and Neurosurgery, Department of Neuropathology, UK; 5Institute of Neurology, UCL, UK

We report atypical presentation of variant Creutzfeldt-Jakob Disease (vCJD) identified ante-mortem in a 73 year-old recipient of blood products. This patient was transfused following orthopaedic surgery in December 1997. Tracing of blood products identified a single unit of non-leucodepleted red cells from an individual who developed neuropathologically confirmed vCJD eleven months after donation. Nine years post transfusion, this individual was referred to the National Prion Clinic for specialist investigation. Six years post transfusion the recipient complained of fluctuating fatigue and impaired concentration. At this time neurological examination and MRI brain (T1/T2 weighted/DWI) were normal. Progressive symptoms emerged six months later with imbalance and deteriorating cognition. Examination two months after onset of neurological symptoms demonstrated cognitive deficits, dyspraxia or visuospatial dysfunction and normal motor, sensory and gait examination. Six weeks later cognitive impairment was identified alongside tremulousness, impaired manual dexterity and limb ataxia. Serological investigations were normal. MRI (T1/T2 weighted/FLAIR/DWI) demonstrated prominent signal change throughout the dorsal thalamus, consistent with vCJD. PRNP genotyping revealed no mutations and homozygosity for methionine at codon 129. The prolonged incubation period of vCJD and possibility of asymptomatic carrier states pose major public health concerns. This case highlights the significant risk encountered by recipients of contaminated blood products and the necessity for their specialist monitoring.

P04.73

Whole-body Biodistribution and Tissue Uptake Kinetics of PrPSc in the Initial Phase of the Infection

Urayama, A; Morales, R; Soto, C University of Texas Medical Branch, USA

Although prion diseases have been a public health concern for decades, the lack of knowledge about the pharmacokinetics and biodistribution of prions complicates the risk assessment. In our prior studies, we found that the level of PrPSc in blood was undetectable several weeks after inoculation, then it became detectable during the early pre-symptomatic phase, disappeared from blood right before the symptomatic phase and raised to its highest at the clinical stage of the disease. These data suggest that there are several stages of the movement of PrPSc in the body during the progression of the disease. The aim of the current study was to analyze the biodisribution and tissue uptake kinetics of PrPSc in the initial phase of the infection in mice.

After an intravenous injection of [131I]PrPSc (together with [125I]albumin as a vascular space marker), the levels of [131I]PrPSc in serum decreased biphasically with time, whereas albumin levels did not significantly change during the course of the experiment. Elimination half-lives of [131I]PrPSc and [125I]albumin were 3.44 ± 0.42 and 17.6 ± 8.6 hr, respectively. These results suggest that the level of [131I]PrPSc in serum 24 hr after the injection is less than 1 % of the injected dose (ID). The rate for albumin was consistent with previous reports. The volumes of distribution for [131I]PrPSc (3.34 ± 0.16 ml) suggest that PrPSc was well distributed in the extracellular space in the body, whereas the majority of albumin was in the serum space. [131I]PrPSc showed higher systemic clearance rates than that of [125I]albumin. The uptake of [131I]PrPSc was also investigated in various tissues. The quantity of PrPSc taken up by brain was around 0.2 %ID, indicating that the protein can penetrate across the blood-brain barrier with a medium efficiency compared to other proteins. The higher levels of [131I]PrPSc were found in liver, spleen, kidney, lung, heart, and skeletal muscle when compared to the levels in the brain. Interestingly, TCAprecipitable [131I]PrPSc was clearly detected in urine. These results provide a fundamental pharmacokinetic characterization of PrPSc in animals that may be relevant to estimate tissue risks, mechanisms of prion neuroinvassion and to develop novel therapeutic strategies.

P04.102

Has vCJD been Transmitted by Human Blood Plasma Products? 20 Years and Counting

Foster, P

Scottish National Blood Transfusion Service, Protein Fractionation Centre, UK The diagnosis of vCJD in a patient whose plasma had previously been used in the preparation of blood plasma products by the NHS led to the decision in 1998 that the preparation of plasma derivatives from UK-donor plasma should cease as a precautionary measure. Since then, plasma products have either been manufactured by the NHS, using plasma purchased from the USA and Europe, or purchased directly from commercial companies.

It is now known that donations from 11 individuals, later diagnosed with vCJD, had been included in the preparation of a total of 175 batches of different plasma products that were released for use between June 1987 and September 1998. No cases of vCJD have been associated with these products, although 20 years have elapsed since the first implicated batches were released for use. This contrasts with 3 instances of probable transmission of vCJD by red cells in which symptoms of vCJD developed in recipients 6.5 years, 7.8 years and 8.3 years after transfusion.

There are a number of possible explanations for the apparent absence of transmision by plasma products.

(1) Prion infectivity was not present in the donated plasma.

(2) Prion infectivity was present in the donated plasma but not in the manufactured products, due to dilution or removal of infectivity by the manufacturing process.

(3) Prion infectivity was present in manufactured product(s) but has not resulted in clinical symptoms of vCJD because of either a prolonged incubation period or a lack of suceptibility in recipients.

The methods used for the manufacture of blood plasma products by the Scottish National Blood Transfusion Service have been examined to determine the extent to which removal of prions might have occurred. These experiments indicate a possible overall prion reduction of 2.7 logs for intermediate-purity factor VIII concentrate (Z8), 3.0 logs for intermediate-purity factor IX concentrate (DEFIX), 5.8 logs for thrombin, ³6.2 logs for fibrinogen, ³6.5 logs for immunoglobulin, 7.4 logs for high-purity factor IX concentrate and ³11.5 logs for albumin.

http://www.neuroprion.org/resources/pdf_docs/conferences/prion2007/abstract_book.pdf


P04.36

Enhanced Surveillance of Persons Identified as at Increased Risk of CJD Due to Blood Transfusion or Healthcare Procedures

Brookes, D1; Chow, Y1; Ward, HJT2; Will, RG2; Hewitt, P3; Gill, ON1 1HPA, CJD, UK; 2National CJD Surveillance Unit, UK; 3Colindale, NHS Blood and Tissue, UK

Introduction: Reports of four iatrogenic transmissions of variant-CJD (vCJD) infection in the UK (all due to transfusion of blood from donors who later developed vCJD), evidence from iatrogenic transmissions of sporadic CJD and experimental work on CJD infectivity in tissues and on healthcare instruments have given rise to concern about the risks of iatrogenic transmission of CJD. This risk warrants a) certain public health precautions, and b) follow-up of individuals with identified risks in order to gain evidence about their risks and ensure appropriate management of these risks. Evidence of transmission via iatrogenic routes is important to inform public health measures and so prevent ongoing transmission of CJD.

Methods: The Health Protection Agency and Health Protection Scotland holds details of persons identified as 'at-risk' of vCJD due to blood transfusion and of persons identified as 'at-risk' of CJD (of any type) from other healthcare procedures. The GPs/clinicians of all persons identified as 'at-risk' for public health purposes are provided with: information; risk assessment updates; advice on public health precautions and advice on referral to specialist care. Procedures are being established to obtain enhanced surveillance data on these individuals, including: clinical status updates, date and cause of death, surplus tissue and blood specimens, and postmortem investigations.

Results: Persons 'at-risk' of CJD have experienced a range of exposures. Estimated risks are uncertain and overlapping. Some individuals - recipients of vCJD implicated blood components - are considered to be at a clearly higher risk of infection: active follow-up is currently conducted for these individuals. In time, the enhanced surveillance of persons at increased risk of CJD will provide estimates of transmission risks and of the impact of iatrogenic exposures on mortality.

Conclusion: Knowledge about iatrogenic transmission of CJD is being gained by the follow-up of individuals who have been identified as 'at-risk' of CJD in the UK. This enhanced surveillance may need to be sustained for many years.

http://www.neuroprion.org/resources/pdf_docs/conferences/prion2007/abstract_book.pdf


Saturday, January 20, 2007

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

http://vcjdtransfusion.blogspot.com/2007_01_01_archive.html


sadly, with unknown phenotypes of cjd roaming around in North American humans and animals, the risk factors from blood products from these individuals are unknown. IF you look at the L-type BSE, which has been documented in North America, which has exposed humans, what would CJD there from look like ? and since it is much more virulent, is blood much more virulent as well not only from L-type BSE, but from humans that have been exposed to L-type BSE from the bovine as well ? are they more virulent ? something to ponder for sure...TSS

OLDER STUDIES ;

Transmission of Creutzfeldt-Jakob Disease from Blood and Urine Into Mice

The Lancet, November 9, 1985

Sir,--Professor Manuelidis and his colleagues (Oct 19, p896) report transmission to animals of Creutzfeldt-Jakob disease (CJD) from the buffy coat from two patients. We also transmitted the disease from whole blood samples of a patient (and of mice) infected with CJD.1 Brain, Cornea, and urine from this patient were also infectious, and the clinicopathological findings2 are summarised as follows.

A 70-year-old man was noted to have a slowing of speech and writing and some disorientation, all of which progressed rapidly. Decorticate rigidity, forced grasping, positive snout reflex, and myoclonus appeared within 2 months. Electroencephalogram revealed typical periodic synchronous discharge, and he died of pneumonia and upper gastrointestinal haemorrhage, about 3 months after onset of the symptoms. The Brain weighed 1290g and showed severe histological changes diagnostic of CJD, including spongiform change, loss of nerve cells, and diffuse proliferation of astrocytes. There were no inflammatory cells, microglia, neurofibrillary tangles, and amyloid plaques, although virus-like particles were detected by electron microscopy.

Results of inoculation in Mice

Inocula NO* Incubation period (days)+ Brain 7/10 (4) 789 (+ or - 112) Cornea 1/6 (0) 1037 Blood 2/13 (0) 1080 (+ or - 69) Urine 5/10 (1) 880 (+ or - 55) CSF 0/10

* Number of mice with CJD change/number examined histologically. Number with amyloid plaques shown in parentheses.

+ means + or - SD

Samples were taken aseptically at necropsy. 10% crude homogenates of brain and cornea in saline, whole blood (after crushing a clot), and untreated CSF and urine were inoculated intracerebrally into CF1 strain mice (20 ul per animal). Some mice showed emaciation, bradykinesia, rigidity of the body and tail, and sometimes tremor after long incubation periods. Tissues obtained after the animal died (or was killed) were studied histologically (table). Animals infected by various inocula showed common pathological changes, consisting of severe spongiform changes, glial proliferation, and a moderate loss of nerve cells. A few mice inoculated with brain tissue or urine had the same amyloid plaques found in patients and animals with CJD.3

In our long-term experiments, inoculating materials taken from twenty patients with CJD or Gerstmann-Straussler-Scheinker's disease (GSS) into rodents, positive results were obtained in seventeen cases, including this patient. Brain tissue transmitted the disease most frequently within the shortes incubation period, except for one case where the lymph node was the most infectious. Transmission through the cornea has been noted in man4 and in guineapigs.5 Whole blood samples taken from three patients were inoculated and a positive transmission occurred only in the case recorded here. Mouse-to-mouse transmission through blood inoculation was successful after a mean incubation period of 365 days.1 Transmission through urine was positive in this patient only, and negative in one other patient and in many infected animals. Transmission through the CSF from eight patients was negative, yet transmission via the CSF of infected rats was positive.1

As viraemia has been proved in guineapigs,6 mice,1,7 and lately in patients with CJD, blood for transfusion or blood products for medical use must be tested for unconventional pathogens. For this purpose, we inoculated blood products into rodents.8 The CJD pathogen was not found in the products examined. However, this approach takes too long to be of practical value. More efficient methods must be developed to detect pathogens and to eliminate them from blood. One proposal9 is to apply membrane filtration to the purification protocol of human growth hormone suspected of being contaminated with CJD. Similar methods are needed for blood contamination.

Department of Neuropathology, Neurological Institute, Faculty of Medicine, Kyushu University, Fukuoka812, Japan

JUN TATEISHI

1. Tateishi J, Sato Y, Kaga M. Doi H, Ohta M. Experimental transmission of human subacute spongiform encephalopathy to small rodents 1: Clinical and histological observations. Acta Neuropathol (Berl) 1980; 51: 127.

2. Shibayama Y, Sakaguchi Y, Nakata K, et al, Creutzfeldt-Jakob disease with demonstration of virus-like particles. Acta pathol Jpn 1982;32: 695.

3. Tateishi J, Nagara H, Hikita K, Sato Y. Amyloid plaques in the brains of mice with Creutzfeldt-Jakob disease. Ann Neurol 1984; 15: 278.

4. Duffy P, Wolf J, Colings G, DeVoe AG, Streeten B, Cowen D. Possible person-to-person transmission of Creutzfeldt-Jakob disease. N Engl J Med 1974; 290: 692.

5. Manuelidis EE, Angelo JN, Gorgacz EJ, Kim JH, Manuelidis L. Experimental Creutzfeldt-Jakob disease transmitted via the eye with infected cornea. N Engl J Med 1977; 296: 1334.

6. Manuelidis EE, Gorgacz EJ, Manuelidis L. Viremia in experimental Creutzfeldt-Jakob disease. Science 1978: 200: 1069.

7. Kuroda Y, Gibbs CJ Jr, Amyx HL, Gajdusek DC. Creutzfeldt-Jakob disease in mice. Persistent viremiam and preferential replication of virus in low-density lymphocytes. Infect Immun 1983; 41: 154.

8. Tateishi J, Tsuji S. Unconventional pathogens causing spongiform encephalopathis absent in blood products. J Med Virol 1985; 15: 11.

9. Tateishi J, Kitamoto T, Hiratani H. Creutzfeldt-Jakob disease pathogen in growth hormone preparations is eliminatable. Lancet (in press).

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

also, this from the Her Majesty's Government...TSS

Subject: Transmission of TSEs through blood
Date: Tue, 28 Mar 2000 14:48:35 +0100
From: Ralph Lucas Reply-To: Bovine Spongiform Encephalopathy
To: BSE-L@uni-karlsruhe.de

######### Bovine Spongiform Encephalopathy #########

The Lord Lucas asked Her Majesty's Government:

Whether there is any evidence that any Transmissible Spongiform Encephalopathy in any species can be transmitted through blood; and whether they will place in the Library of the House copies of the principal relevant scientific papers. (HL1545)

The Parliamentary Under-Secretary of State, Department of Health (Lord Hunt of Kings Heath):

Some animal studies have shown that certain transmissible spongiform encephalopathies can be experimentally transmitted from animal to animal through blood components. However, the Spongiform Encephalopathy Advisory Committee at its February meeting reviewed recent research undertaken in this area and did not consider any measures were necessary, in addition to those already in place, to reduce any potential risk to public health from human blood and blood products.

Copies of the following relevant scientific papers are being placed in the Library.

Brown P, 1995, "Can Creutzfeldt-Jakob Disease be transmitted by Transfusion?" Haematology 2: 472 - 477.

Brown et al 1999, Further studies of blood infectivity in an experimental model of transmissible spongiform encephalopathy, with an explanation of why blood components do not transmit Creutzfeldt - Jakob disease in humans.

Transfusion Vol. 39, November/December 1169 - 1178.

RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States 26 March 2003

I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to comment on the CDC's attempts to monitor the occurrence of emerging forms of CJD. Asante, Collinge et al [1] have reported that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype that is indistinguishable from type 2 PrPSc, the commonest sporadic CJD. However, CJD and all human TSEs are not reportable nationally. CJD and all human TSEs must be made reportable in every state and internationally. I hope that the CDC does not continue to expect us to still believe that the 85%+ of all CJD cases which are sporadic are all spontaneous, without route/source. We have many TSEs in the USA in both animal and man. CWD in deer/elk is spreading rapidly and CWD does transmit to mink, ferret, cattle, and squirrel monkey by intracerebral inoculation. With the known incubation periods in other TSEs, oral transmission studies of CWD may take much longer. Every victim/family of CJD/TSEs should be asked about route and source of this agent. To prolong this will only spread the agent and needlessly expose others. In light of the findings of Asante and Collinge et al, there should be drastic measures to safeguard the medical and surgical arena from sporadic CJDs and all human TSEs. I only ponder how many sporadic CJDs in the USA are type 2 PrPSc?

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


re-Human Prion Diseases in the United States

Posted by flounder on 01 Jan 2010 at 18:11 GMT

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

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


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


Saturday, June 13, 2009

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


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


IF you consider the many different TSE strains in different species in North America, and then think 'friendly fire' there from. For a few years now there seems to be a rise here in the U.S.A. of sporadic CJD strains of 'unknown phenotype', with ;

5 Includes 28 cases in which the diagnosis is pending, and 17 inconclusive cases;

6 Includes 28 (24 from 2010) cases with type determination pending in which the diagnosis of vCJD has been excluded


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


There is a growing number of human CJD cases, and they were presented last week in San Francisco by Luigi Gambatti(?) from his CJD surveillance collection.

He estimates that it may be up to 14 or 15 persons which display selectively SPRPSC and practically no detected RPRPSC proteins.


http://www.fda.gov/ohrms/dockets/ac/06/transcripts/1006-4240t1.htm


http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4240t1.pdf


ATYPICAL BSE MORE VIRULENT TO HUMANS THAN UK STRAIN

18 January 2007 - Draft minutes of the SEAC 95 meeting (426 KB) held on 7 December 2006 are now available.

snip...

64. A member noted that at the recent Neuroprion meeting, a study was presented showing that in transgenic mice BSE passaged in sheep may be more virulent and infectious to a wider range of species than bovine derived BSE.

Other work presented suggested that BSE and bovine amyloidotic spongiform encephalopathy (BASE) MAY BE RELATED. A mutation had been identified in the prion protein gene in an AMERICAN BASE CASE THAT WAS SIMILAR IN NATURE TO A MUTATION FOUND IN CASES OF SPORADIC CJD.

snip...

http://www.seac.gov.uk/minutes/95.pdf


2008 - 2010

The statistical incidence of CJD cases in the United States has been revised to reflect that there is one case per 9000 in adults age 55 and older. Eighty-five percent of the cases are sporadic, meaning there is no known cause at present.

http://www.cjdfoundation.org/fact.html


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

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

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

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

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


Creutzfeldt-Jakob Disease Surveillance in Texas

http://cjdtexas.blogspot.com/


Friday, February 05, 2010

New Variant Creutzfelt Jakob Disease case reports United States 2010 A Review

http://vcjd.blogspot.com/2010/02/new-variant-creutzfelt-jakob-disease.html


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

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


Tuesday, June 1, 2010

USA cases of dpCJD rising with 24 cases so far in 2010

http://cjdtexas.blogspot.com/2010/06/usa-cases-of-dpcjd-rising-with-24-cases.html


Saturday, July 17, 2010

Variant Creutzfeldt-Jakob disease Ironside JW., Haemophilia. 2010 Jul;16 Suppl 5:175-80

REVIEW ARTICLE

http://vcjdtransfusion.blogspot.com/2010/07/variant-creutzfeldtjakob-disease.html


Tuesday, August 18,

2009 BSE-The Untold Story - joe gibbs and singeltary 1999 - 2009

http://madcowusda.blogspot.com/2009/08/bse-untold-story-joe-gibbs-and.html



Friday, November 30, 2007

CJD QUESTIONNAIRE USA CWRU AND CJD FOUNDATION

http://cjdquestionnaire.blogspot.com/




TSS

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