Atypical BSE (BASE) Transmitted from Asymptomatic Aging Cattle to a Primate
Atypical BSE (BASE) Transmitted from Asymptomatic Aging Cattle to a Primate Emmanuel E. Comoy1*, Cristina Casalone2, Nathalie Lescoutra-Etchegaray1, Gianluigi Zanusso3, Sophie Freire1, Dominique Marcé1, Frédéric Auvré1, Marie-Magdeleine Ruchoux1, Sergio Ferrari3, Salvatore Monaco3, Nicole Salès4, Maria Caramelli2, Philippe Leboulch1,5, Paul Brown1, Corinne I. Lasmézas4, Jean-Philippe Deslys1
1 Institute of Emerging Diseases and Innovative Therapies, CEA, Fontenay-aux-Roses, France, 2 Istituto Zooprofilattico Sperimentale del Piemonte, Turin, Italy, 3 Policlinico G.B. Rossi, Verona, Italy, 4 Scripps Florida, Jupiter, Florida, United States of America, 5 Genetics Division, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
Abstract Background Human variant Creutzfeldt-Jakob Disease (vCJD) results from foodborne transmission of prions from slaughtered cattle with classical Bovine Spongiform Encephalopathy (cBSE). Atypical forms of BSE, which remain mostly asymptomatic in aging cattle, were recently identified at slaughterhouses throughout Europe and North America, raising a question about human susceptibility to these new prion strains.
Methodology/Principal Findings Brain homogenates from cattle with classical BSE and atypical (BASE) infections were inoculated intracerebrally into cynomolgus monkeys (Macacca fascicularis), a non-human primate model previously demonstrated to be susceptible to the original strain of cBSE. The resulting diseases were compared in terms of clinical signs, histology and biochemistry of the abnormal prion protein (PrPres). The single monkey infected with BASE had a shorter survival, and a different clinical evolution, histopathology, and prion protein (PrPres) pattern than was observed for either classical BSE or vCJD-inoculated animals. Also, the biochemical signature of PrPres in the BASE-inoculated animal was found to have a higher proteinase K sensitivity of the octa-repeat region. We found the same biochemical signature in three of four human patients with sporadic CJD and an MM type 2 PrP genotype who lived in the same country as the infected bovine.
Conclusion/Significance Our results point to a possibly higher degree of pathogenicity of BASE than classical BSE in primates and also raise a question about a possible link to one uncommon subset of cases of apparently sporadic CJD. Thus, despite the waning epidemic of classical BSE, the occurrence of atypical strains should temper the urge to relax measures currently in place to protect public health from accidental contamination by BSE-contaminated products.
Citation: Comoy EE, Casalone C, Lescoutra-Etchegaray N, Zanusso G, Freire S, et al. (2008) Atypical BSE (BASE) Transmitted from Asymptomatic Aging Cattle to a Primate. PLoS ONE 3(8): e3017. doi:10.1371/journal.pone.0003017
Editor: Neil Mabbott, University of Edinburgh, United Kingdom
Received: April 24, 2008; Accepted: August 1, 2008; Published: August 20, 2008
Copyright: © 2008 Comoy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work has been supported by the Network of Excellence NeuroPrion.
Competing interests: CEA owns a patent covering the BSE diagnostic tests commercialized by the company Bio-Rad.
* E-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000065/!x-usc:mailto:emmanuel.comoy@cea.fr
Introduction Classical Bovine Spongiform Encephalopathy (cBSE), the first prion disease identified in cattle, was initially reported in 1986 in the UK. Food-borne transmission of cBSE to humans was observed ten years later as a variant form of Creutzfeldt-Jakob Disease (vCJD) [1], leading to a major public health crisis.
This strain of cBSE is now rapidly disappearing as a result of appropriate containment measures. However, atypical forms of BSE have recently been identified in Europe and North America as a consequence of cBSE testing performed in these countries [2]–[4]. Because these cases are only found sporadically in older animals (=8 years) coming to slaughter with few or no signs of disease, it would be plausible to suppose that atypical forms of BSE may have a lower virulence than cBSE and be innocuous to humans. However, recent studies suggest that one of the two main forms of atypical BSE, initially discovered in Italy and referred to as the bovine amyloidotic spongiform encephalopathy (BASE), might be at the origin of the cBSE epidemic: inoculation of the BASE strain into transgenic and inbred mice showed an apparent natural evolution towards the typical BSE strain [5], [6]. Moreover, a possible link has been suggested between BASE and one subtype (MV2) of human sporadic CJD (sCJD) on the basis of biochemical similarities [2], [7]. In contrast to vCJD, sCJD is believed to occur de novo without food-borne transmission. However, specific contaminating events by ingestion are difficult to rule out because human prion diseases can have silent incubation periods exceeding 50 years, as demonstrated for kuru [8].
One strategy to evaluate the risk of BASE for humans consists in assessing the susceptibility to disease transmission and the degree of pathogenicity in a non-human primate model that has already been shown to have characteristic clinical signs, histopathological lesions and PrPres profiles following infections with either BSE or vCJD [9], [10]. We therefore inoculated cynomolgus macaque monkeys (Macacca fascicularis) intracerebrally with BASE, cBSE and vCJD prion strains. The BASE strain, prepared from brain extract of a 15-year-old asymptomatic cow induced a distinctive and more rapidly fatal disease than cBSE, and showed a biochemical signature similar to that of the MM2 cortical subtype of human sCJD.
Methods Cattle and human samples The BASE inoculum (mix of brainstem and thalamus) from an asymptomatic 15 year-old Italian Piemontese cow [2]: 250 µl of a 10% brain homogenate in 5% glucose were inoculated intracerebrally (i.c.) to a single macaque monkey. As controls, we used two macaques inoculated i.c. with cBSE (brainstem from infected UK cattle) and 4 macaques inoculated i.c. with human vCJD [9], [11]. Twenty-one subjects with a diagnosis of definite sCJD were referred to the Medical Center in Verona, Italy during the period 2000–2004. Tissues were processed 4–18 hours post-mortem according to established guidelines regarding safety and ethics. Brains were cut longitudinally into two halves. Hemi-brains were frozen and stored at -80°C until biochemical studies were performed. The patient group encompassed all of the different Western blot subtypes of sCJD described by Parchi et al [7]: MM1 (5 cases), MV1 (2), VV1 (1), MM2 (4), MV2 (6) and VV2 (3).
Non-human primate model Cynomolgus macaques (Macacca fascicularis), captive-bred from the Centre de Recherche en Primatologie (Mauritius), were checked for the absence of common primate pathogens before importation and handling in accordance to national guidelines. Animals were maintained in biological security level 3 animal facilities and clinical examinations were performed regularly. They were humanely euthanized at the terminal stage of the disease, and tissues were either fixed in Carnoy's fluid for histological examination or snap-frozen in liquid nitrogen and stored at -80°C for biochemical analyses.
Neuropathology and immunochemistry Neuropathology and immunochemical detection of proteinase-resistant prion protein (PrPres) and Glial fibrillary acidic protein (GFAP) was performed on brain sections as previously described [12].
PrPres analysis Tissues were homogenized to 20% (w/v) final concentration in a 5% sterile glucose solution. PrPres was purified according to a protocol optimized for strain discrimination in ruminants [13], [14] (Discriminatory kit ref 3551177, BioRad, Marnes la Coquette, France). Briefly, brain homogenates were first subjected to proteolysis using either 0.4 µg (“low” concentration) or 4 µg (“high” concentration) of proteinase K/mg of brain (final concentration) in a special buffer that partially protects the N-terminal part of PrPres in order to increase strain discrimination, and then purified PrPres was concentrated by centrifugation. Purified, non-human primate and human samples were processed for Western blot analysis as previously described: briefly, samples were separated by electrophoresis on a 12% SDS polyacrylamide gel, blotted onto a nitrocellulose membrane and detected by two mouse monoclonal antibodies: the antibody from the BioRad Discriminatory kit, which targets the epitope WGQPHGGX within the N-Terminal octarepeat region at position 57–88, and 3F4, which targets the epitope MKHM in the hydrophobic core at position 109–112. The protein bands were visualized using a peroxidase-conjugated goat anti-mouse antibody and chemiluminescence.
Results Transmission characteristics of BASE and BSE Clinical features. The BASE-inoculated macaque developed clinical signs after a 21 months incubation period. Clinical signs evolved slowly during the first four months, being limited to mild tremor and myoclonus, without impairment in coordination or locomotion, and without anxiety or aggressiveness. In the last month, the clinical picture rapidly worsened with evidence of major spatial disorientation (the animal did not recognize its environment and seemed lost in its cage), cognitive troubles (no recall of food location and at intervals unaccountably stopped eating) and the appearance of incoordination and disequilibrium; however, appetite and general fitness were maintained. Euthanasia was performed at the terminal stage of illness at 26 months post inoculation (Table 1). The two cBSE-inoculated animals had longer incubations periods (37.5 months) and survivals (40 months) despite a presumably larger infecting dose (100 mg containing a 10-fold higher PrPres concentration). Moreover, the clinical presentation was very different: animals exhibited aggressiveness and anxiety in combination with incoordination, severe ataxic tremor, and loss of appetite to the point of near starvation. The four animals inoculated with human vCJD had a clinical evolution similar to that of animals inoculated with BSE, though with less prolonged survivals (25 to 37 months).
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Discussion We have shown that BASE, the first identified atypical strain of BSE [2], originating from asymptomatic cattle, is transmissible by i.c. inoculation to a species of non-human primate. Although this observation concerned only one animal, its survival was substantially shorter than for all the macaques inoculated with classical BSE as well as the majority of those inoculated with human vCJD. Moreover, in earlier experiments by others on a total of 6 macaques inoculated i.c. with 50 mg of cBSE brain, none had an incubation period of less than 30 months [17], and humanized transgenic mice have been found to be highly susceptible to infection with BASE, and completely resistant to infection with cBSE [18]. If BASE is more pathogenic than classical BSE for primates, it could indicate a more readily transmissible infection from cattle to humans than previously suspected. A preliminary trial of oral transmission is currently ongoing for alimentary risk assessment: 49 months after oral dosing there is no indication of transmission; however, the incubation period following similar oral challenge with cBSE in an already completed experiment was 60 months.
The disease induced by BASE was different in all respects from that induced by classical BSE. The clinical presentation was characterized by mild tremors and myoclonus, progressing to a marked cognitive disorder, including spatial disorientation but without anxiety, aggressiveness or loss of appetite. In contrast, cBSE presented signs of anxiety and aggressiveness together with progressive difficulties in locomotion as well as cerebellar signs (major ataxia), and severe decrease of appetite with concurrent weight loss. The widespread spongiform lesions and loss of pyramidal cells in the third and fifth layers of the frontal cortex together with the severe parietal lesions could explain the prominent cognitive signs and the spatial disorientation seen in the BASE-infected monkey, contrasting with the severity of lesions in the obex and cerebellum consistent with the incoordination seen in animals inoculated with cBSE. Amyloid plaques, the hallmark of BASE in cattle, are not produced in the Macaque monkey, and conversely, cBSE does not produce plaques in cattle, but does so in the Macaque [9], a clear indication that plaque deposition depends as much on the host as the prion strain.
At the molecular level, under conditions of high proteinase pre-treatment and detection using two antibodies reacting with either an epitope in the N terminal octapeptide repeat region or the core of PrP, BASE and cBSE were clearly distinguishable in primate. BASE was detectable only by the core antibody, whereas cBSE was detectable by both antibodies. We estimated that the proportion of octapeptide-resistant PrPres molecules in the BASE brain homogenate was only a small fraction (=1/10) of that of the cBSE brain homogenate. The difference in octapeptide sensitivity to PK between cBSE and vCJD in macaques on the one hand, and Type 1 sporadic CJD in humans on the other hand, is similar to what was observed between cBSE and classical scrapie in sheep. This method can now be used to test both ruminant and human samples to identify similarities and differences in their molecular protein signatures, and to implement the classification of ruminant and possibly human strains.
Although classical epidemiological studies have not found any link between scrapie in sheep and goats and human CJD, newer molecular biological studies now indicate that about half of all cases of scrapie are due to previously undetected atypical strains [19] that are experimentally transmissible to sheep and mice [20]. Their risk for humans is unknown and is the subject of current studies in experimental models, including primates. cBSE has been shown to be responsible for human cases of vCJD, but the comparative risk for humans of BASE and other atypical strains of BSE is still unknown, and its clarification will require many years of epidemiological surveillance and molecular biological testing of both bovine and human populations.
The first cases of BASE in cattle had PrPres electrophoretic profiles similar to the MV2 subtype of sporadic CJD patients [2] that, together with the presence of amyloid plaques in both the cattle and the patients, suggested a possible link between BASE and this subtype of sCJD. However, our PrPres typing technique has shown that, in the primate, PrPres of other MV2 sCJD patients exhibited a resistance to proteolysis different from the BASE-infected primate, whereas PrPres from vCJD-infected patients and primates behave similarly. This observation, together with the absence of amyloid plaques in the BASE-infected primate, weakens the likelihood of a direct link between BASE and MV2 subtype sCJD patients.
In contrast, the specific signature of PrPres in the BASE-infected primate was similar to that seen in three of four patients with the MM2 cortical subtype of sporadic CJD [7]. It is interesting that an important feature of the clinical-pathological syndrome in this BASE-infected macaque –the absence of cerebellar involvement – is also a common element in patients with the MM2 subtype of human sporadic CJD (Supplementary Figure S2). However, as illustrated by the clinical details of our four tested MM2 cases, there is considerable patient-to-patient variation, just as there can be variation among individual animals experimentally inoculated with a given strain of TSE. [21], [22].
It is not known whether atypical strains of BSE have been circulating for years, or represent new forms of disease, and continuing research is clearly needed to answer both this and the equally important question about a possible relationship to at least certain forms of what are presently regarded as sporadic cases of human disease (sCJD) [4], [23]. Moreover, the BASE strain has been described to evolve naturally towards BSE after successive transmissions in inbred mice [6]. The stability and pathogenicity of this strain in humans remains to be determined, and it is worth recalling that the stability of the cBSE/vCJD strain, which retains its specific molecular signature in different infected hosts, is the exception rather than the rule. As has been previously observed [24]–[26], one patient (Case No. 4, cf. figure 5 sample MM2#4) exhibited both types of PrP, i.e. type 2 typical of the MM2 subtype and type 1 observed in the MM1 subtype. On the one hand, this demonstrates the interest of such a simple biochemical test to refine PrP analysis, and on the other hand it raises a question about the existence of different PrPres signatures in the same patient, i.e., different prion strains linked to multiple infections or to variants selected by the host.
In summary, we have transmitted one atypical form of BSE (BASE) to a cynomolgus macaque monkey that had a shorter incubation period than monkeys infected with classical BSE, with distinctive clinical, neuropathological, and biochemical features; and have shown that the molecular biological signature resembled that seen in a comparatively uncommon subtype of sporadic CJD. We cannot yet say whether BASE is more pathogenic for primates (including humans) than cBSE, nor can we predict whether its molecular biological features represent a clue to one cause of apparently sporadic human CJD. However, the evidence presented here and by others justifies concern about a potential human health hazard from undetected atypical forms of BSE, and despite the waning epizoonosis of classical BSE, it would be premature to abandon the precautionary measures that have been so successful in reversing the impact of cBSE. We would instead urge a gradual, staged reduction that takes into account the evolving knowledge about atypical ruminant diseases, and both a permanent ban on the use of bovine central nervous system tissue for either animal or human use, and its destruction so as to eliminate any risk of environmental contamination.
Supporting Information Figure S1. (2.51 MB TIF)
Resistance to proteolysis of different prion strains in sheep. PrPres from brain homogenates of sheep infected with classical scrapie, experimental cBSE, or atypical Nor-98 scrapie, and of an uninfected control sheep. Samples were purified using low (odd lanes) or high (even lanes) concentrations of proteinase K, and visualized with monoclonal antibodies that recognize either the core region (Panel A) or the octapeptide region (Panel B) of the protein. With the lower concentration of PK used in the purification step (in order to maximize test sensitivity) of one widely utilized BSE screening test [13], all three strains gave a positive result with both the anti-core and anti-octapeptide antibodies (odd lanes). Using a higher concentration of PK (even lanes) did not alter the positivity with either antibody for classical scrapie, but the cBSE strain no longer reacted with the anti-octapeptide antibody while Nor98 did not react with either antibody. Thus, by using the higher concentration of PK and two different antibodies, it is possible to discriminate between all three strains.
Figure S2. (1.52 MB TIF)
Lesion profiles in cBSE- and BASE-infected macaque, and in MM2 sporadic CJD patients. The lesions were scored from 0 to 4 (negative, light, mild, moderate, and severe) for the different following gray matter regions: frontal (FC), temporal (TC), parietal (PC) and occipital (OC) neocortices, hippocampus (HI), parasubiculum and entorhinal cortex (EC), neostriatum (ST) (nuclei caudatus and putamen), thalamus (TH), substantia nigra (SN), midbrain periventricular gray (PG), locus ceruleus (LC), medulla (ME) (periventricular gray and inferior olive) and cerebellum (CE). Scoring for MME sCJD patient was issued from Parchi et al. [7].
Acknowledgments We thank Sebastien Jacquin for careful maintenance of primates, and Aurore Jolit for her precious help for histological studies; we thank Richard Kascsak (New York State Institute for Basic Research in Developmental Disabilities), Jacques Grassi, Eric Quemeneur and their colleagues (CEA/DSV) who provided the anti-PrP antibodies. We thank Sylvie Benestad (National Veterinary Institute, Oslo, Norway) for Nor-98 sheep samples, and Danny Matthews (VLA, Weybridge, UK) for the sheep sample inoculated with experimental cBSE.
Author Contributions Conceived and designed the experiments: CC CIL. Performed the experiments: NLE SF DM FA. Analyzed the data: EEC NLE MMR SF JPD. Contributed reagents/materials/analysis tools: CC GZ MMR MC. Wrote the paper: EEC GZ PB JPD. Participated to the final reviewing of the manuscript: CC SM NS MC PL CIL.
References
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http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0003017
>>>"the biochemical signature of PrPres in the BASE-inoculated animal was found to have a higher proteinase K sensitivity of the octa-repeat region. We found the same biochemical signature in three of four human patients with sporadic CJD and an MM type 2 PrP genotype who lived in the same country as the infected bovine."<<<
just another one of those sporadic CJD coincidences i suppose $$$ NOT to forget ;
Thursday, June 05, 2008
Review on the epidemiology and dynamics of BSE epidemics Vet. Res. (2008) 39:15 http://www.vetres.org/
DOI: 10.1051/vetres:2007053 c INRA, EDP Sciences, 2008 Review article
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And last but not least, similarities of PrPres between Htype BSE and human prion diseases like CJD or GSS have been put forward [10], as well as between L-type BSE and CJD [17]. These findings raise questions about the origin and inter species transmission of these prion diseases that were discovered through the BSE active surveillance.
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Cases of atypical BSE have only been found in countries having implemented large active surveillance programs. As of 1st September 2007, 36 cases (16 H, 20 L) have been described all over the world in cattle: Belgium (1 L) [23], Canada (1 H)15, Denmark (1 L)16, France (8 H, 6 L)17, Germany (1 H, 1 L) [13], Italy (3 L)18, Japan (1 L) [71], Netherlands (1 H, 2 L)19, Poland (1 H, 6 L)20, Sweden (1 H)21, United Kingdom (1 H)22, and USA (2 H)23. Another H-type case has been found in a 19 year old miniature zebu in a zoological park in Switzerland [56]. It is noteworthy that atypical cases have been found in countries that did not experience classical BSE so far, like Sweden, or in which only few cases of classical BSE have been found, like Canada or the USA.
And last but not least, similarities of PrPres between Htype BSE and human prion diseases like CJD or GSS have been put forward [10], as well as between L-type BSE and CJD [17]. These findings raise questions about the origin and inter species transmission of these prion diseases that were discovered through the BSE active surveillance.
full text 18 pages ;
http://www.vetres.org/index.php?option=article&access=standard&Itemid=129&url=/articles/vetres/pdf/2008/04/v07232.pdf
please see full text ;
http://bse-atypical.blogspot.com/2008/06/review-on-epidemiology-and-dynamics-of.html
***Atypical forms of BSE have emerged which, although rare, appear to be more virulent than the classical BSE that causes vCJD.***
Progress Report from the National Prion Disease Pathology Surveillance Center
An Update from Stephen M. Sergay, MB, BCh & Pierluigi Gambetti, MD
April 3, 2008
http://www.aan.com/news/?event=read&article_id=4397&page=72.45.45
Sunday, March 16, 2008
MAD COW DISEASE terminology UK c-BSE (typical), atypical BSE H or L, and or Italian L-BASE
http://bse-atypical.blogspot.com/2008/03/mad-cow-disease-terminology-uk-c-bse.html
HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory JUNE 2008
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Tissue infectivity and strain typing of the many variants Manuscript of the human and animal TSEs are paramount in all variants of all TSE. There must be a proper classification that will differentiate between all these human TSE in order to do this. With the CDI and other more sensitive testing coming about, I only hope that my proposal will some day be taken seriously. ...
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http://cjdmadcowbaseoct2007.blogspot.com/2008/06/human-and-animal-tse-classifications-ie.html
NOT to forget the 5 cases of the NOR-98 atypical scrapie documented in the USA in 2007, in five different states. WHICH pathologically looks like some sub-types of sporadic CJD, of which Stanely Prusiner warns of a public health risk ;
***The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.
http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf
Here we report that both Nor98 and discordant cases, including three sheep homozygous for the resistant PrPARR allele (A136R154R171), efficiently transmitted the disease to transgenic mice expressing ovine PrP, and that they shared unique biological and biochemical features upon propagation in mice. These observations support the view that a truly infectious TSE agent, unrecognized until recently, infects sheep and goat flocks and may have important implications in terms of scrapie control and public health.
Edited by Stanley B. Prusiner, University of California, San Francisco, CA, and approved September 12, 2005 (received for review March 21, 2005)
http://www.pnas.org/cgi/content/abstract/0502296102v1
Tuesday, June 3, 2008 SCRAPIE USA UPDATE JUNE 2008 NOR-98 REPORTED PA
http://nor-98.blogspot.com/2008/06/scrapie-usa-update-june-2008-nor-98.html
NOR-98 ATYPICAL SCRAPIE 5 cases documented in USA in 5 different states USA 007
http://nor-98.blogspot.com/2008/04/seac-spongiform-encephalopathy-advisory.html
http://nor-98.blogspot.com/
SCRAPIE USA
http://scrapie-usa.blogspot.com/
Sunday, June 15, 2008
A descriptive study of the prevalence of atypical and classical scrapie in sheep in 20 European countries
Research article
http://nor-98.blogspot.com/2008/06/descriptive-study-of-prevalence-of.html
Thursday, April 24, 2008
RE-FOIA OF DECLARATION OF EXTRAORDINARY EMERGENCY BECAUSE OF AN ATYPICAL T.S.E. OF FOREIGN ORIGIN IN THE UNITED STATES [Docket No. 00-072-1]
http://foiamadsheepmadrivervalley.blogspot.com/2008/04/re-foia-of-declaration-of-extraordinary.html
another question, just how long have these atypical BSE TSEs been around in the bovine ???
let's look at another case of atypical BSE in Germany way back in 1992 ;
Subject: atypical BSE reported in 1992 and conviently slaughterd and incinerated and then swept under rug for about 12 years Date: April 26, 2007 at 1:08 pm PST 1992
NEW BRAIN DISORDER
3. WHAT ABOUT REPORTS OF NEW FORM OF BSE?
THE VETERINARY RECORD HAS PUBLISHED AN ARTICLE ON A NEW BRAIN DISORDER OF CATTLE DISCOVERED THROUGH OUR CONTROL MEASURES FOR BSE. ALTHOUGH IT PRESENTS SIMILAR CLINICAL SIGNS TO BSE THERE ARE MAJOR DIFFERENCES IN THE HISTOPATHOLOGY AND INCUBATION PERIODS BETWEEN THE TWO. MUST EMPHASISE THAT THIS IS NOT BSE.
4. IS THIS NEW BRAIN DISORDER A THREAT?
WE DO NOT EVEN KNOW WHETHER THE AGENT OF THIS DISEASE IS TRANSMISSIBLE. IN ANY CASE, CASES SO FAR IDENTIFIED HAD SHOWN SIMILAR SYMPTOMS TO THOSE OF BSE, AND THEREFORE HAVE BEEN SLAUGHTERED AND INCINERATED, SO THAT IF A TRANSMISSIBLE AGENT WERE INVOLVED IT WOULD HAVE BEEN ELIMINATED. .......
http://www.bseinquiry.gov.uk/files/yb/1992/10/26001001.pdf
2. The Collinge/Will dispute appears to rumble on. Dr. Collinge had told Dr. Tyrrell that Dr. Will's response to his criticism about sharing material had been ''quite unacceptable'' (in spite of it's apparently conciliatory tone). Apparently Professor Allen was now going to try and arrange a meeting to resolve the dispute. No action here for MAFF, although Mr. Murray may be interested.
3. Dr. Tyrrell regretted that the Committee had not seen the article on BBD. However he felt that for the time being NO specific action was called for. The most important need was to consider the possibility that the condition might be transmissible. As we have discussed, I suggested that we might circulate a paper to the members of the committee giving our appreciation of this condition (and perhaps of other non-BSE neurological conditions that had been identified in negative cases) and of any necessary follow up action. IF any Committee member felt strongly about this, or if the issue CAME TO A HEAD, we would call an interim meeting. He was happy with this approach. I would be grateful if Mr. Maslin could, in discussion with CVL and veterinary colleagues draft such a note, which will presumably very largely follow what Mr. Bradley's briefing paper has already said, taking account of DOH comments, We can then clear a final version with DOH before circulating it to Committee members.
http://www.bseinquiry.gov.uk/files/yb/1992/10/29005001.pdf
IN CONFIDENCE
This is a highly competitive field and it really will be a pity if we allow many of the key findings to be published by overseas groups while we are unable to pursue our research findings because of this disagreement, which I hope we can make every effort to solve.
http://www.bseinquiry.gov.uk/files/yb/1992/10/26002001.pdf
COLLINGE THREATENS TO GO TO MEDIA
http://www.bseinquiry.gov.uk/files/yb/1992/12/16005001.pdf
2. The discovery might indicate the existence of a different strain of BSE from that present in the general epidemic or an unusual response by an individual host.
3. If further atypical lesion distribution cases are revealed in this herd then implications of misdiagnosis of 'negative' cases in other herds may not be insignificant.
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This minute is re-issued with a wider distribution. The information contained herein should NOT be disseminated further except on the basis of ''NEED TO KNOW''.
R Bradley
http://www.bseinquiry.gov.uk/files/yb/1993/02/17001001.pdf
IN CONFIDENCE
BSE ATYPICAL LESION DISTRIBUTION
http://www.bseinquiry.gov.uk/files/yb/1993/03/14001001.pdf
In this context, a word is in order about the US testing program. After the discovery of the first (imported) cow in 2003, the magnitude of testing was much increased, reaching a level of >400,000 tests in 2005 (Figure 4). Neither of the 2 more recently indigenously infected older animals with nonspecific clinical features would have been detected without such testing, and neither would have been identified as atypical without confirmatory Western blots. Despite these facts, surveillance has now been decimated to 40,000 annual tests (USDA news release no. 0255.06, July 20, 2006) and invites the accusation that the United States will never know the true status of its involvement with BSE.
In short, a great deal of further work will need to be done before the phenotypic features and prevalence of atypical BSE are understood. More than a single strain may have been present from the beginning of the epidemic, but this possibility has been overlooked by virtue of the absence of widespread Western blot confirmatory testing of positive screening test results; or these new phenotypes may be found, at least in part, to result from infections at an older age by a typical BSE agent, rather than neonatal infections with new "strains" of BSE. Neither alternative has yet been investigated.
http://www.cdc.gov/ncidod/EID/vol12no12/06-0965.htm
IF BSE is not in the USA (just not documented for many different reasons), and only atypical BSE is in the USA (plus CWD, plus, many strains of Scrapie, and Now the Nor-98 documented in 5 different states, plus TME, then why would human mad cow in the USA look like the UK nvCJD from UK BSE cows ? it was shown long ago in studies at Mission Texas that experimental transmission of USA Scrapie to USA Bovine, DID NOT LOOK LIKE UK BSE. so again, in short, why would human mad cow in the USA look like human mad cow in the UK i.e. the (nvCJD). however, I believe that BSE has been in the USA untested and undocumented for years. why on earth then does the USDA refuse to allow creekstone or anyone else test their product? simple, if you don't look/test, you don't find.
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He added that because the CDC only provide information on diseases, they have no plans
to make a separate press release on the issue including the result of the investigation.
and that is the way they plan to keep it, all spontaneous, sporadic, no route, no source $$$
USDA, CDC, NIH, ET AL INVOKE THE UKBSEnvCJD ONLY RULE $$$
Virginia Woman Did not Die of vCJD
Updated Jun.17,2008 08:34 KST
The MBC news program "PD Diary" reported that Aretha Vinson died of variant Creutzfeldt-Jakob Disease (vCJD) in early April when in an interview, Vinson's mother actually said, "The results had come in from the MRI and it appeared that our daughter could possibly have CJD," not vCJD.
please see full text ;
http://cjdmadcowbaseoct2007.blogspot.com/2008/06/portsmouth-woman-did-not-die-of-mad-cow.html
NEW SOLUTIONS: A Journal of Environmental and Occupational Health Policy
Issue: Volume 18, Number 2 / 2008 Pages: 145 - 156 URL: Linking Options
Mad Cows and Computer Models: The U.S. Response to BSE
Frank Ackerman and Wendy A. Johnecheck
Abstract:
The proportion of slaughtered cattle tested for BSE is much smaller in the U.S. than in Europe and Japan, leaving the U.S. heavily dependent on statistical models to estimate both the current prevalence and the spread of BSE. We examine the models relied on by USDA, finding that the prevalence model provides only a rough estimate, due to limited data availability. Reassuring forecasts from the model of the spread of BSE depend on the arbitrary constraint that worst-case values are assumed by only one of 17 key parameters at a time. In three of the six published scenarios with multiple worst-case parameter values, there is at least a 25% probability that BSE will spread rapidly. In public policy terms, reliance on potentially flawed models can be seen as a gamble that no serious BSE outbreak will occur. Statistical modeling at this level of abstraction, with its myriad, compound uncertainties, is no substitute for precautionary policies to protect public health against the threat of epidemics such as BSE.
http://baywood.metapress.com/app/home/contribution.asp?referrer=parent&backto=issue,5,18;journal,1,41;linkingpublicationresults,1:300327,1
Owner and Corporation Plead Guilty to Defrauding Bovine Spongiform Encephalopathy (BSE) Surveillance Program
PLEASE SEE FULL TEXT ;
Monday, June 16, 2008 Mad Cows and Computer Models: The U.S. Response to BSE
http://bse-atypical.blogspot.com/
Sunday, March 16, 2008 MAD COW DISEASE terminology UK c-BSE (typical), atypical BSE H or L, and or Italian L-BASE March 16, 2008
http://bse-atypical.blogspot.com/2008/03/mad-cow-disease-terminology-uk-c-bse.html
Sunday, August 10, 2008
Thursday, July 10, 2008 A Novel Human Disease with Abnormal Prion Protein Sensitive to Protease update July 10, 2008
http://cjdmadcowbaseoct2007.blogspot.com/2008/07/novel-human-disease-with-abnormal-prion.html
Thursday, July 10, 2008 A New Prionopathy update July 10, 2008
http://cjdmadcowbaseoct2007.blogspot.com/2008/07/new-prionopathy-update-july-10-2008.html
MY COMMENTS, for whatever they are worth ;
A New Prionopathy OR more of the same old BSe and sporadic CJD
http://creutzfeldt-jakob-disease.blogspot.com/2008/08/new-prionopathy-or-more-of-same-old-bse.html
Communicated by: Terry S. Singeltary Sr.
[In submitting these data, Terry S. Singeltary Sr. draws attention to the steady increase in the "type unknown" category, which, according to their definition, comprises cases in which vCJD could be excluded. The total of 26 cases for the current year (2007) is disturbing, possibly symptomatic of the circulation of novel agents. Characterization of these agents should be given a high priority. - Mod.CP]
http://pro-med.blogspot.com/2007/11/proahedr-prion-disease-update-2007-07.html
http://www.promedmail.org/pls/askus/f?p=2400:1001:6833194127530602005::NO::F2400_P1001_BACK_PAGE,F2400_P1001_PUB_MAIL_ID:1010,39963
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
JOURNAL OF NEUROLOGY
MARCH 26, 2003
RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob
disease in the United States
Email Terry S. Singeltary:
mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000065/!x-usc:mailto:flounder@wt.net
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
THE PATHOLOGICAL PROTEIN
Hardcover, 304 pages plus photos and illustrations. ISBN 0-387-95508-9
June 2003
BY Philip Yam
CHAPTER 14 LAYING ODDS
Answering critics like Terry Singeltary, who feels that the U.S. under- counts CJD, Schonberger conceded that the current surveillance system has errors but stated that most of the errors will be confined to the older population.
http://www.thepathologicalprotein.com/
Diagnosis and Reporting of Creutzfeldt-Jakob Disease Singeltary, Sr et al. JAMA.2001; 285: 733-734. Vol. 285 No. 6, February 14, 2001 JAMA
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
To the Editor: In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.
Terry S. Singeltary, Sr Bacliff, Tex
1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323. FREE FULL TEXT
http://jama.ama-assn.org/cgi/content/extract/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=singeltary&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT
http://jama.ama-assn.org/cgi/content/full/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=singeltary&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT
2 January 2000
British Medical Journal U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well
http://www.bmj.com/cgi/eletters/320/7226/8/b#6117
15 November 1999
British Medical Journal vCJD in the USA * BSE in U.S.
http://www.bmj.com/cgi/eletters/319/7220/1312/b#5406
Creutzfeldt Jakob Disease
http://creutzfeldt-jakob-disease.blogspot.com/
http://creutzfeldt-jakob-disease.blogspot.com/2008/01/cjd-hgh-body-snatchers.html
http://creutzfeldt-jakob-disease.blogspot.com/2008/01/tubulovesicular-structures-are.html
http://creutzfeldt-jakob-disease.blogspot.com/2008/01/risk-factors-for-sporadic-creutzfeldt.html
http://creutzfeldt-jakob-disease.blogspot.com/2008/01/creutzfeldt-jakob-disease-prion-protein.html
http://creutzfeldt-jakob-disease.blogspot.com/2007/12/risk-assessment-of-transmission-of.html
http://creutzfeldt-jakob-disease.blogspot.com/2007/12/risk-factors-for-sporadic-creutzfeldt.html
http://creutzfeldt-jakob-disease.blogspot.com/2006/11/on-question-of-sporadic-or-atypical.html
USA PRION UNIT BLOG
http://prionunitusaupdate2008.blogspot.com/
Sunday, April 20, 2008 Progress Report from the National Prion Disease Pathology Surveillance Center April 3, 2008
Atypical forms of BSE have emerged which, although rare, appear to be more virulent than the classical BSE that causes vCJD.
see full text ;
http://prionunitusaupdate2008.blogspot.com/2008/04/progress-report-from-national-prion.html
CJD TEXAS (cjd clusters)
http://cjdtexas.blogspot.com/
USA WRITTEN CJD QUESTIONNAIRE ???
http://cjdquestionnaire.blogspot.com/
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
to be continued. ...TSS
1 Institute of Emerging Diseases and Innovative Therapies, CEA, Fontenay-aux-Roses, France, 2 Istituto Zooprofilattico Sperimentale del Piemonte, Turin, Italy, 3 Policlinico G.B. Rossi, Verona, Italy, 4 Scripps Florida, Jupiter, Florida, United States of America, 5 Genetics Division, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
Abstract Background Human variant Creutzfeldt-Jakob Disease (vCJD) results from foodborne transmission of prions from slaughtered cattle with classical Bovine Spongiform Encephalopathy (cBSE). Atypical forms of BSE, which remain mostly asymptomatic in aging cattle, were recently identified at slaughterhouses throughout Europe and North America, raising a question about human susceptibility to these new prion strains.
Methodology/Principal Findings Brain homogenates from cattle with classical BSE and atypical (BASE) infections were inoculated intracerebrally into cynomolgus monkeys (Macacca fascicularis), a non-human primate model previously demonstrated to be susceptible to the original strain of cBSE. The resulting diseases were compared in terms of clinical signs, histology and biochemistry of the abnormal prion protein (PrPres). The single monkey infected with BASE had a shorter survival, and a different clinical evolution, histopathology, and prion protein (PrPres) pattern than was observed for either classical BSE or vCJD-inoculated animals. Also, the biochemical signature of PrPres in the BASE-inoculated animal was found to have a higher proteinase K sensitivity of the octa-repeat region. We found the same biochemical signature in three of four human patients with sporadic CJD and an MM type 2 PrP genotype who lived in the same country as the infected bovine.
Conclusion/Significance Our results point to a possibly higher degree of pathogenicity of BASE than classical BSE in primates and also raise a question about a possible link to one uncommon subset of cases of apparently sporadic CJD. Thus, despite the waning epidemic of classical BSE, the occurrence of atypical strains should temper the urge to relax measures currently in place to protect public health from accidental contamination by BSE-contaminated products.
Citation: Comoy EE, Casalone C, Lescoutra-Etchegaray N, Zanusso G, Freire S, et al. (2008) Atypical BSE (BASE) Transmitted from Asymptomatic Aging Cattle to a Primate. PLoS ONE 3(8): e3017. doi:10.1371/journal.pone.0003017
Editor: Neil Mabbott, University of Edinburgh, United Kingdom
Received: April 24, 2008; Accepted: August 1, 2008; Published: August 20, 2008
Copyright: © 2008 Comoy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work has been supported by the Network of Excellence NeuroPrion.
Competing interests: CEA owns a patent covering the BSE diagnostic tests commercialized by the company Bio-Rad.
* E-mail: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000065/!x-usc:mailto:emmanuel.comoy@cea.fr
Introduction Classical Bovine Spongiform Encephalopathy (cBSE), the first prion disease identified in cattle, was initially reported in 1986 in the UK. Food-borne transmission of cBSE to humans was observed ten years later as a variant form of Creutzfeldt-Jakob Disease (vCJD) [1], leading to a major public health crisis.
This strain of cBSE is now rapidly disappearing as a result of appropriate containment measures. However, atypical forms of BSE have recently been identified in Europe and North America as a consequence of cBSE testing performed in these countries [2]–[4]. Because these cases are only found sporadically in older animals (=8 years) coming to slaughter with few or no signs of disease, it would be plausible to suppose that atypical forms of BSE may have a lower virulence than cBSE and be innocuous to humans. However, recent studies suggest that one of the two main forms of atypical BSE, initially discovered in Italy and referred to as the bovine amyloidotic spongiform encephalopathy (BASE), might be at the origin of the cBSE epidemic: inoculation of the BASE strain into transgenic and inbred mice showed an apparent natural evolution towards the typical BSE strain [5], [6]. Moreover, a possible link has been suggested between BASE and one subtype (MV2) of human sporadic CJD (sCJD) on the basis of biochemical similarities [2], [7]. In contrast to vCJD, sCJD is believed to occur de novo without food-borne transmission. However, specific contaminating events by ingestion are difficult to rule out because human prion diseases can have silent incubation periods exceeding 50 years, as demonstrated for kuru [8].
One strategy to evaluate the risk of BASE for humans consists in assessing the susceptibility to disease transmission and the degree of pathogenicity in a non-human primate model that has already been shown to have characteristic clinical signs, histopathological lesions and PrPres profiles following infections with either BSE or vCJD [9], [10]. We therefore inoculated cynomolgus macaque monkeys (Macacca fascicularis) intracerebrally with BASE, cBSE and vCJD prion strains. The BASE strain, prepared from brain extract of a 15-year-old asymptomatic cow induced a distinctive and more rapidly fatal disease than cBSE, and showed a biochemical signature similar to that of the MM2 cortical subtype of human sCJD.
Methods Cattle and human samples The BASE inoculum (mix of brainstem and thalamus) from an asymptomatic 15 year-old Italian Piemontese cow [2]: 250 µl of a 10% brain homogenate in 5% glucose were inoculated intracerebrally (i.c.) to a single macaque monkey. As controls, we used two macaques inoculated i.c. with cBSE (brainstem from infected UK cattle) and 4 macaques inoculated i.c. with human vCJD [9], [11]. Twenty-one subjects with a diagnosis of definite sCJD were referred to the Medical Center in Verona, Italy during the period 2000–2004. Tissues were processed 4–18 hours post-mortem according to established guidelines regarding safety and ethics. Brains were cut longitudinally into two halves. Hemi-brains were frozen and stored at -80°C until biochemical studies were performed. The patient group encompassed all of the different Western blot subtypes of sCJD described by Parchi et al [7]: MM1 (5 cases), MV1 (2), VV1 (1), MM2 (4), MV2 (6) and VV2 (3).
Non-human primate model Cynomolgus macaques (Macacca fascicularis), captive-bred from the Centre de Recherche en Primatologie (Mauritius), were checked for the absence of common primate pathogens before importation and handling in accordance to national guidelines. Animals were maintained in biological security level 3 animal facilities and clinical examinations were performed regularly. They were humanely euthanized at the terminal stage of the disease, and tissues were either fixed in Carnoy's fluid for histological examination or snap-frozen in liquid nitrogen and stored at -80°C for biochemical analyses.
Neuropathology and immunochemistry Neuropathology and immunochemical detection of proteinase-resistant prion protein (PrPres) and Glial fibrillary acidic protein (GFAP) was performed on brain sections as previously described [12].
PrPres analysis Tissues were homogenized to 20% (w/v) final concentration in a 5% sterile glucose solution. PrPres was purified according to a protocol optimized for strain discrimination in ruminants [13], [14] (Discriminatory kit ref 3551177, BioRad, Marnes la Coquette, France). Briefly, brain homogenates were first subjected to proteolysis using either 0.4 µg (“low” concentration) or 4 µg (“high” concentration) of proteinase K/mg of brain (final concentration) in a special buffer that partially protects the N-terminal part of PrPres in order to increase strain discrimination, and then purified PrPres was concentrated by centrifugation. Purified, non-human primate and human samples were processed for Western blot analysis as previously described: briefly, samples were separated by electrophoresis on a 12% SDS polyacrylamide gel, blotted onto a nitrocellulose membrane and detected by two mouse monoclonal antibodies: the antibody from the BioRad Discriminatory kit, which targets the epitope WGQPHGGX within the N-Terminal octarepeat region at position 57–88, and 3F4, which targets the epitope MKHM in the hydrophobic core at position 109–112. The protein bands were visualized using a peroxidase-conjugated goat anti-mouse antibody and chemiluminescence.
Results Transmission characteristics of BASE and BSE Clinical features. The BASE-inoculated macaque developed clinical signs after a 21 months incubation period. Clinical signs evolved slowly during the first four months, being limited to mild tremor and myoclonus, without impairment in coordination or locomotion, and without anxiety or aggressiveness. In the last month, the clinical picture rapidly worsened with evidence of major spatial disorientation (the animal did not recognize its environment and seemed lost in its cage), cognitive troubles (no recall of food location and at intervals unaccountably stopped eating) and the appearance of incoordination and disequilibrium; however, appetite and general fitness were maintained. Euthanasia was performed at the terminal stage of illness at 26 months post inoculation (Table 1). The two cBSE-inoculated animals had longer incubations periods (37.5 months) and survivals (40 months) despite a presumably larger infecting dose (100 mg containing a 10-fold higher PrPres concentration). Moreover, the clinical presentation was very different: animals exhibited aggressiveness and anxiety in combination with incoordination, severe ataxic tremor, and loss of appetite to the point of near starvation. The four animals inoculated with human vCJD had a clinical evolution similar to that of animals inoculated with BSE, though with less prolonged survivals (25 to 37 months).
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Discussion We have shown that BASE, the first identified atypical strain of BSE [2], originating from asymptomatic cattle, is transmissible by i.c. inoculation to a species of non-human primate. Although this observation concerned only one animal, its survival was substantially shorter than for all the macaques inoculated with classical BSE as well as the majority of those inoculated with human vCJD. Moreover, in earlier experiments by others on a total of 6 macaques inoculated i.c. with 50 mg of cBSE brain, none had an incubation period of less than 30 months [17], and humanized transgenic mice have been found to be highly susceptible to infection with BASE, and completely resistant to infection with cBSE [18]. If BASE is more pathogenic than classical BSE for primates, it could indicate a more readily transmissible infection from cattle to humans than previously suspected. A preliminary trial of oral transmission is currently ongoing for alimentary risk assessment: 49 months after oral dosing there is no indication of transmission; however, the incubation period following similar oral challenge with cBSE in an already completed experiment was 60 months.
The disease induced by BASE was different in all respects from that induced by classical BSE. The clinical presentation was characterized by mild tremors and myoclonus, progressing to a marked cognitive disorder, including spatial disorientation but without anxiety, aggressiveness or loss of appetite. In contrast, cBSE presented signs of anxiety and aggressiveness together with progressive difficulties in locomotion as well as cerebellar signs (major ataxia), and severe decrease of appetite with concurrent weight loss. The widespread spongiform lesions and loss of pyramidal cells in the third and fifth layers of the frontal cortex together with the severe parietal lesions could explain the prominent cognitive signs and the spatial disorientation seen in the BASE-infected monkey, contrasting with the severity of lesions in the obex and cerebellum consistent with the incoordination seen in animals inoculated with cBSE. Amyloid plaques, the hallmark of BASE in cattle, are not produced in the Macaque monkey, and conversely, cBSE does not produce plaques in cattle, but does so in the Macaque [9], a clear indication that plaque deposition depends as much on the host as the prion strain.
At the molecular level, under conditions of high proteinase pre-treatment and detection using two antibodies reacting with either an epitope in the N terminal octapeptide repeat region or the core of PrP, BASE and cBSE were clearly distinguishable in primate. BASE was detectable only by the core antibody, whereas cBSE was detectable by both antibodies. We estimated that the proportion of octapeptide-resistant PrPres molecules in the BASE brain homogenate was only a small fraction (=1/10) of that of the cBSE brain homogenate. The difference in octapeptide sensitivity to PK between cBSE and vCJD in macaques on the one hand, and Type 1 sporadic CJD in humans on the other hand, is similar to what was observed between cBSE and classical scrapie in sheep. This method can now be used to test both ruminant and human samples to identify similarities and differences in their molecular protein signatures, and to implement the classification of ruminant and possibly human strains.
Although classical epidemiological studies have not found any link between scrapie in sheep and goats and human CJD, newer molecular biological studies now indicate that about half of all cases of scrapie are due to previously undetected atypical strains [19] that are experimentally transmissible to sheep and mice [20]. Their risk for humans is unknown and is the subject of current studies in experimental models, including primates. cBSE has been shown to be responsible for human cases of vCJD, but the comparative risk for humans of BASE and other atypical strains of BSE is still unknown, and its clarification will require many years of epidemiological surveillance and molecular biological testing of both bovine and human populations.
The first cases of BASE in cattle had PrPres electrophoretic profiles similar to the MV2 subtype of sporadic CJD patients [2] that, together with the presence of amyloid plaques in both the cattle and the patients, suggested a possible link between BASE and this subtype of sCJD. However, our PrPres typing technique has shown that, in the primate, PrPres of other MV2 sCJD patients exhibited a resistance to proteolysis different from the BASE-infected primate, whereas PrPres from vCJD-infected patients and primates behave similarly. This observation, together with the absence of amyloid plaques in the BASE-infected primate, weakens the likelihood of a direct link between BASE and MV2 subtype sCJD patients.
In contrast, the specific signature of PrPres in the BASE-infected primate was similar to that seen in three of four patients with the MM2 cortical subtype of sporadic CJD [7]. It is interesting that an important feature of the clinical-pathological syndrome in this BASE-infected macaque –the absence of cerebellar involvement – is also a common element in patients with the MM2 subtype of human sporadic CJD (Supplementary Figure S2). However, as illustrated by the clinical details of our four tested MM2 cases, there is considerable patient-to-patient variation, just as there can be variation among individual animals experimentally inoculated with a given strain of TSE. [21], [22].
It is not known whether atypical strains of BSE have been circulating for years, or represent new forms of disease, and continuing research is clearly needed to answer both this and the equally important question about a possible relationship to at least certain forms of what are presently regarded as sporadic cases of human disease (sCJD) [4], [23]. Moreover, the BASE strain has been described to evolve naturally towards BSE after successive transmissions in inbred mice [6]. The stability and pathogenicity of this strain in humans remains to be determined, and it is worth recalling that the stability of the cBSE/vCJD strain, which retains its specific molecular signature in different infected hosts, is the exception rather than the rule. As has been previously observed [24]–[26], one patient (Case No. 4, cf. figure 5 sample MM2#4) exhibited both types of PrP, i.e. type 2 typical of the MM2 subtype and type 1 observed in the MM1 subtype. On the one hand, this demonstrates the interest of such a simple biochemical test to refine PrP analysis, and on the other hand it raises a question about the existence of different PrPres signatures in the same patient, i.e., different prion strains linked to multiple infections or to variants selected by the host.
In summary, we have transmitted one atypical form of BSE (BASE) to a cynomolgus macaque monkey that had a shorter incubation period than monkeys infected with classical BSE, with distinctive clinical, neuropathological, and biochemical features; and have shown that the molecular biological signature resembled that seen in a comparatively uncommon subtype of sporadic CJD. We cannot yet say whether BASE is more pathogenic for primates (including humans) than cBSE, nor can we predict whether its molecular biological features represent a clue to one cause of apparently sporadic human CJD. However, the evidence presented here and by others justifies concern about a potential human health hazard from undetected atypical forms of BSE, and despite the waning epizoonosis of classical BSE, it would be premature to abandon the precautionary measures that have been so successful in reversing the impact of cBSE. We would instead urge a gradual, staged reduction that takes into account the evolving knowledge about atypical ruminant diseases, and both a permanent ban on the use of bovine central nervous system tissue for either animal or human use, and its destruction so as to eliminate any risk of environmental contamination.
Supporting Information Figure S1. (2.51 MB TIF)
Resistance to proteolysis of different prion strains in sheep. PrPres from brain homogenates of sheep infected with classical scrapie, experimental cBSE, or atypical Nor-98 scrapie, and of an uninfected control sheep. Samples were purified using low (odd lanes) or high (even lanes) concentrations of proteinase K, and visualized with monoclonal antibodies that recognize either the core region (Panel A) or the octapeptide region (Panel B) of the protein. With the lower concentration of PK used in the purification step (in order to maximize test sensitivity) of one widely utilized BSE screening test [13], all three strains gave a positive result with both the anti-core and anti-octapeptide antibodies (odd lanes). Using a higher concentration of PK (even lanes) did not alter the positivity with either antibody for classical scrapie, but the cBSE strain no longer reacted with the anti-octapeptide antibody while Nor98 did not react with either antibody. Thus, by using the higher concentration of PK and two different antibodies, it is possible to discriminate between all three strains.
Figure S2. (1.52 MB TIF)
Lesion profiles in cBSE- and BASE-infected macaque, and in MM2 sporadic CJD patients. The lesions were scored from 0 to 4 (negative, light, mild, moderate, and severe) for the different following gray matter regions: frontal (FC), temporal (TC), parietal (PC) and occipital (OC) neocortices, hippocampus (HI), parasubiculum and entorhinal cortex (EC), neostriatum (ST) (nuclei caudatus and putamen), thalamus (TH), substantia nigra (SN), midbrain periventricular gray (PG), locus ceruleus (LC), medulla (ME) (periventricular gray and inferior olive) and cerebellum (CE). Scoring for MME sCJD patient was issued from Parchi et al. [7].
Acknowledgments We thank Sebastien Jacquin for careful maintenance of primates, and Aurore Jolit for her precious help for histological studies; we thank Richard Kascsak (New York State Institute for Basic Research in Developmental Disabilities), Jacques Grassi, Eric Quemeneur and their colleagues (CEA/DSV) who provided the anti-PrP antibodies. We thank Sylvie Benestad (National Veterinary Institute, Oslo, Norway) for Nor-98 sheep samples, and Danny Matthews (VLA, Weybridge, UK) for the sheep sample inoculated with experimental cBSE.
Author Contributions Conceived and designed the experiments: CC CIL. Performed the experiments: NLE SF DM FA. Analyzed the data: EEC NLE MMR SF JPD. Contributed reagents/materials/analysis tools: CC GZ MMR MC. Wrote the paper: EEC GZ PB JPD. Participated to the final reviewing of the manuscript: CC SM NS MC PL CIL.
References
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http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0003017
>>>"the biochemical signature of PrPres in the BASE-inoculated animal was found to have a higher proteinase K sensitivity of the octa-repeat region. We found the same biochemical signature in three of four human patients with sporadic CJD and an MM type 2 PrP genotype who lived in the same country as the infected bovine."<<<
just another one of those sporadic CJD coincidences i suppose $$$ NOT to forget ;
Thursday, June 05, 2008
Review on the epidemiology and dynamics of BSE epidemics Vet. Res. (2008) 39:15 http://www.vetres.org/
DOI: 10.1051/vetres:2007053 c INRA, EDP Sciences, 2008 Review article
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And last but not least, similarities of PrPres between Htype BSE and human prion diseases like CJD or GSS have been put forward [10], as well as between L-type BSE and CJD [17]. These findings raise questions about the origin and inter species transmission of these prion diseases that were discovered through the BSE active surveillance.
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Cases of atypical BSE have only been found in countries having implemented large active surveillance programs. As of 1st September 2007, 36 cases (16 H, 20 L) have been described all over the world in cattle: Belgium (1 L) [23], Canada (1 H)15, Denmark (1 L)16, France (8 H, 6 L)17, Germany (1 H, 1 L) [13], Italy (3 L)18, Japan (1 L) [71], Netherlands (1 H, 2 L)19, Poland (1 H, 6 L)20, Sweden (1 H)21, United Kingdom (1 H)22, and USA (2 H)23. Another H-type case has been found in a 19 year old miniature zebu in a zoological park in Switzerland [56]. It is noteworthy that atypical cases have been found in countries that did not experience classical BSE so far, like Sweden, or in which only few cases of classical BSE have been found, like Canada or the USA.
And last but not least, similarities of PrPres between Htype BSE and human prion diseases like CJD or GSS have been put forward [10], as well as between L-type BSE and CJD [17]. These findings raise questions about the origin and inter species transmission of these prion diseases that were discovered through the BSE active surveillance.
full text 18 pages ;
http://www.vetres.org/index.php?option=article&access=standard&Itemid=129&url=/articles/vetres/pdf/2008/04/v07232.pdf
please see full text ;
http://bse-atypical.blogspot.com/2008/06/review-on-epidemiology-and-dynamics-of.html
***Atypical forms of BSE have emerged which, although rare, appear to be more virulent than the classical BSE that causes vCJD.***
Progress Report from the National Prion Disease Pathology Surveillance Center
An Update from Stephen M. Sergay, MB, BCh & Pierluigi Gambetti, MD
April 3, 2008
http://www.aan.com/news/?event=read&article_id=4397&page=72.45.45
Sunday, March 16, 2008
MAD COW DISEASE terminology UK c-BSE (typical), atypical BSE H or L, and or Italian L-BASE
http://bse-atypical.blogspot.com/2008/03/mad-cow-disease-terminology-uk-c-bse.html
HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory JUNE 2008
snip...
Tissue infectivity and strain typing of the many variants Manuscript of the human and animal TSEs are paramount in all variants of all TSE. There must be a proper classification that will differentiate between all these human TSE in order to do this. With the CDI and other more sensitive testing coming about, I only hope that my proposal will some day be taken seriously. ...
snip...
http://cjdmadcowbaseoct2007.blogspot.com/2008/06/human-and-animal-tse-classifications-ie.html
NOT to forget the 5 cases of the NOR-98 atypical scrapie documented in the USA in 2007, in five different states. WHICH pathologically looks like some sub-types of sporadic CJD, of which Stanely Prusiner warns of a public health risk ;
***The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.
http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf
Here we report that both Nor98 and discordant cases, including three sheep homozygous for the resistant PrPARR allele (A136R154R171), efficiently transmitted the disease to transgenic mice expressing ovine PrP, and that they shared unique biological and biochemical features upon propagation in mice. These observations support the view that a truly infectious TSE agent, unrecognized until recently, infects sheep and goat flocks and may have important implications in terms of scrapie control and public health.
Edited by Stanley B. Prusiner, University of California, San Francisco, CA, and approved September 12, 2005 (received for review March 21, 2005)
http://www.pnas.org/cgi/content/abstract/0502296102v1
Tuesday, June 3, 2008 SCRAPIE USA UPDATE JUNE 2008 NOR-98 REPORTED PA
http://nor-98.blogspot.com/2008/06/scrapie-usa-update-june-2008-nor-98.html
NOR-98 ATYPICAL SCRAPIE 5 cases documented in USA in 5 different states USA 007
http://nor-98.blogspot.com/2008/04/seac-spongiform-encephalopathy-advisory.html
http://nor-98.blogspot.com/
SCRAPIE USA
http://scrapie-usa.blogspot.com/
Sunday, June 15, 2008
A descriptive study of the prevalence of atypical and classical scrapie in sheep in 20 European countries
Research article
http://nor-98.blogspot.com/2008/06/descriptive-study-of-prevalence-of.html
Thursday, April 24, 2008
RE-FOIA OF DECLARATION OF EXTRAORDINARY EMERGENCY BECAUSE OF AN ATYPICAL T.S.E. OF FOREIGN ORIGIN IN THE UNITED STATES [Docket No. 00-072-1]
http://foiamadsheepmadrivervalley.blogspot.com/2008/04/re-foia-of-declaration-of-extraordinary.html
another question, just how long have these atypical BSE TSEs been around in the bovine ???
let's look at another case of atypical BSE in Germany way back in 1992 ;
Subject: atypical BSE reported in 1992 and conviently slaughterd and incinerated and then swept under rug for about 12 years Date: April 26, 2007 at 1:08 pm PST 1992
NEW BRAIN DISORDER
3. WHAT ABOUT REPORTS OF NEW FORM OF BSE?
THE VETERINARY RECORD HAS PUBLISHED AN ARTICLE ON A NEW BRAIN DISORDER OF CATTLE DISCOVERED THROUGH OUR CONTROL MEASURES FOR BSE. ALTHOUGH IT PRESENTS SIMILAR CLINICAL SIGNS TO BSE THERE ARE MAJOR DIFFERENCES IN THE HISTOPATHOLOGY AND INCUBATION PERIODS BETWEEN THE TWO. MUST EMPHASISE THAT THIS IS NOT BSE.
4. IS THIS NEW BRAIN DISORDER A THREAT?
WE DO NOT EVEN KNOW WHETHER THE AGENT OF THIS DISEASE IS TRANSMISSIBLE. IN ANY CASE, CASES SO FAR IDENTIFIED HAD SHOWN SIMILAR SYMPTOMS TO THOSE OF BSE, AND THEREFORE HAVE BEEN SLAUGHTERED AND INCINERATED, SO THAT IF A TRANSMISSIBLE AGENT WERE INVOLVED IT WOULD HAVE BEEN ELIMINATED. .......
http://www.bseinquiry.gov.uk/files/yb/1992/10/26001001.pdf
2. The Collinge/Will dispute appears to rumble on. Dr. Collinge had told Dr. Tyrrell that Dr. Will's response to his criticism about sharing material had been ''quite unacceptable'' (in spite of it's apparently conciliatory tone). Apparently Professor Allen was now going to try and arrange a meeting to resolve the dispute. No action here for MAFF, although Mr. Murray may be interested.
3. Dr. Tyrrell regretted that the Committee had not seen the article on BBD. However he felt that for the time being NO specific action was called for. The most important need was to consider the possibility that the condition might be transmissible. As we have discussed, I suggested that we might circulate a paper to the members of the committee giving our appreciation of this condition (and perhaps of other non-BSE neurological conditions that had been identified in negative cases) and of any necessary follow up action. IF any Committee member felt strongly about this, or if the issue CAME TO A HEAD, we would call an interim meeting. He was happy with this approach. I would be grateful if Mr. Maslin could, in discussion with CVL and veterinary colleagues draft such a note, which will presumably very largely follow what Mr. Bradley's briefing paper has already said, taking account of DOH comments, We can then clear a final version with DOH before circulating it to Committee members.
http://www.bseinquiry.gov.uk/files/yb/1992/10/29005001.pdf
IN CONFIDENCE
This is a highly competitive field and it really will be a pity if we allow many of the key findings to be published by overseas groups while we are unable to pursue our research findings because of this disagreement, which I hope we can make every effort to solve.
http://www.bseinquiry.gov.uk/files/yb/1992/10/26002001.pdf
COLLINGE THREATENS TO GO TO MEDIA
http://www.bseinquiry.gov.uk/files/yb/1992/12/16005001.pdf
2. The discovery might indicate the existence of a different strain of BSE from that present in the general epidemic or an unusual response by an individual host.
3. If further atypical lesion distribution cases are revealed in this herd then implications of misdiagnosis of 'negative' cases in other herds may not be insignificant.
snip...
This minute is re-issued with a wider distribution. The information contained herein should NOT be disseminated further except on the basis of ''NEED TO KNOW''.
R Bradley
http://www.bseinquiry.gov.uk/files/yb/1993/02/17001001.pdf
IN CONFIDENCE
BSE ATYPICAL LESION DISTRIBUTION
http://www.bseinquiry.gov.uk/files/yb/1993/03/14001001.pdf
In this context, a word is in order about the US testing program. After the discovery of the first (imported) cow in 2003, the magnitude of testing was much increased, reaching a level of >400,000 tests in 2005 (Figure 4). Neither of the 2 more recently indigenously infected older animals with nonspecific clinical features would have been detected without such testing, and neither would have been identified as atypical without confirmatory Western blots. Despite these facts, surveillance has now been decimated to 40,000 annual tests (USDA news release no. 0255.06, July 20, 2006) and invites the accusation that the United States will never know the true status of its involvement with BSE.
In short, a great deal of further work will need to be done before the phenotypic features and prevalence of atypical BSE are understood. More than a single strain may have been present from the beginning of the epidemic, but this possibility has been overlooked by virtue of the absence of widespread Western blot confirmatory testing of positive screening test results; or these new phenotypes may be found, at least in part, to result from infections at an older age by a typical BSE agent, rather than neonatal infections with new "strains" of BSE. Neither alternative has yet been investigated.
http://www.cdc.gov/ncidod/EID/vol12no12/06-0965.htm
IF BSE is not in the USA (just not documented for many different reasons), and only atypical BSE is in the USA (plus CWD, plus, many strains of Scrapie, and Now the Nor-98 documented in 5 different states, plus TME, then why would human mad cow in the USA look like the UK nvCJD from UK BSE cows ? it was shown long ago in studies at Mission Texas that experimental transmission of USA Scrapie to USA Bovine, DID NOT LOOK LIKE UK BSE. so again, in short, why would human mad cow in the USA look like human mad cow in the UK i.e. the (nvCJD). however, I believe that BSE has been in the USA untested and undocumented for years. why on earth then does the USDA refuse to allow creekstone or anyone else test their product? simple, if you don't look/test, you don't find.
snip...
He added that because the CDC only provide information on diseases, they have no plans
to make a separate press release on the issue including the result of the investigation.
and that is the way they plan to keep it, all spontaneous, sporadic, no route, no source $$$
USDA, CDC, NIH, ET AL INVOKE THE UKBSEnvCJD ONLY RULE $$$
Virginia Woman Did not Die of vCJD
Updated Jun.17,2008 08:34 KST
The MBC news program "PD Diary" reported that Aretha Vinson died of variant Creutzfeldt-Jakob Disease (vCJD) in early April when in an interview, Vinson's mother actually said, "The results had come in from the MRI and it appeared that our daughter could possibly have CJD," not vCJD.
please see full text ;
http://cjdmadcowbaseoct2007.blogspot.com/2008/06/portsmouth-woman-did-not-die-of-mad-cow.html
NEW SOLUTIONS: A Journal of Environmental and Occupational Health Policy
Issue: Volume 18, Number 2 / 2008 Pages: 145 - 156 URL: Linking Options
Mad Cows and Computer Models: The U.S. Response to BSE
Frank Ackerman and Wendy A. Johnecheck
Abstract:
The proportion of slaughtered cattle tested for BSE is much smaller in the U.S. than in Europe and Japan, leaving the U.S. heavily dependent on statistical models to estimate both the current prevalence and the spread of BSE. We examine the models relied on by USDA, finding that the prevalence model provides only a rough estimate, due to limited data availability. Reassuring forecasts from the model of the spread of BSE depend on the arbitrary constraint that worst-case values are assumed by only one of 17 key parameters at a time. In three of the six published scenarios with multiple worst-case parameter values, there is at least a 25% probability that BSE will spread rapidly. In public policy terms, reliance on potentially flawed models can be seen as a gamble that no serious BSE outbreak will occur. Statistical modeling at this level of abstraction, with its myriad, compound uncertainties, is no substitute for precautionary policies to protect public health against the threat of epidemics such as BSE.
http://baywood.metapress.com/app/home/contribution.asp?referrer=parent&backto=issue,5,18;journal,1,41;linkingpublicationresults,1:300327,1
Owner and Corporation Plead Guilty to Defrauding Bovine Spongiform Encephalopathy (BSE) Surveillance Program
PLEASE SEE FULL TEXT ;
Monday, June 16, 2008 Mad Cows and Computer Models: The U.S. Response to BSE
http://bse-atypical.blogspot.com/
Sunday, March 16, 2008 MAD COW DISEASE terminology UK c-BSE (typical), atypical BSE H or L, and or Italian L-BASE March 16, 2008
http://bse-atypical.blogspot.com/2008/03/mad-cow-disease-terminology-uk-c-bse.html
Sunday, August 10, 2008
Thursday, July 10, 2008 A Novel Human Disease with Abnormal Prion Protein Sensitive to Protease update July 10, 2008
http://cjdmadcowbaseoct2007.blogspot.com/2008/07/novel-human-disease-with-abnormal-prion.html
Thursday, July 10, 2008 A New Prionopathy update July 10, 2008
http://cjdmadcowbaseoct2007.blogspot.com/2008/07/new-prionopathy-update-july-10-2008.html
MY COMMENTS, for whatever they are worth ;
A New Prionopathy OR more of the same old BSe and sporadic CJD
http://creutzfeldt-jakob-disease.blogspot.com/2008/08/new-prionopathy-or-more-of-same-old-bse.html
Communicated by: Terry S. Singeltary Sr.
[In submitting these data, Terry S. Singeltary Sr. draws attention to the steady increase in the "type unknown" category, which, according to their definition, comprises cases in which vCJD could be excluded. The total of 26 cases for the current year (2007) is disturbing, possibly symptomatic of the circulation of novel agents. Characterization of these agents should be given a high priority. - Mod.CP]
http://pro-med.blogspot.com/2007/11/proahedr-prion-disease-update-2007-07.html
http://www.promedmail.org/pls/askus/f?p=2400:1001:6833194127530602005::NO::F2400_P1001_BACK_PAGE,F2400_P1001_PUB_MAIL_ID:1010,39963
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
JOURNAL OF NEUROLOGY
MARCH 26, 2003
RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob
disease in the United States
Email Terry S. Singeltary:
mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000065/!x-usc:mailto:flounder@wt.net
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
THE PATHOLOGICAL PROTEIN
Hardcover, 304 pages plus photos and illustrations. ISBN 0-387-95508-9
June 2003
BY Philip Yam
CHAPTER 14 LAYING ODDS
Answering critics like Terry Singeltary, who feels that the U.S. under- counts CJD, Schonberger conceded that the current surveillance system has errors but stated that most of the errors will be confined to the older population.
http://www.thepathologicalprotein.com/
Diagnosis and Reporting of Creutzfeldt-Jakob Disease Singeltary, Sr et al. JAMA.2001; 285: 733-734. Vol. 285 No. 6, February 14, 2001 JAMA
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
To the Editor: In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.
Terry S. Singeltary, Sr Bacliff, Tex
1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323. FREE FULL TEXT
http://jama.ama-assn.org/cgi/content/extract/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=singeltary&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT
http://jama.ama-assn.org/cgi/content/full/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=singeltary&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT
2 January 2000
British Medical Journal U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well
http://www.bmj.com/cgi/eletters/320/7226/8/b#6117
15 November 1999
British Medical Journal vCJD in the USA * BSE in U.S.
http://www.bmj.com/cgi/eletters/319/7220/1312/b#5406
Creutzfeldt Jakob Disease
http://creutzfeldt-jakob-disease.blogspot.com/
http://creutzfeldt-jakob-disease.blogspot.com/2008/01/cjd-hgh-body-snatchers.html
http://creutzfeldt-jakob-disease.blogspot.com/2008/01/tubulovesicular-structures-are.html
http://creutzfeldt-jakob-disease.blogspot.com/2008/01/risk-factors-for-sporadic-creutzfeldt.html
http://creutzfeldt-jakob-disease.blogspot.com/2008/01/creutzfeldt-jakob-disease-prion-protein.html
http://creutzfeldt-jakob-disease.blogspot.com/2007/12/risk-assessment-of-transmission-of.html
http://creutzfeldt-jakob-disease.blogspot.com/2007/12/risk-factors-for-sporadic-creutzfeldt.html
http://creutzfeldt-jakob-disease.blogspot.com/2006/11/on-question-of-sporadic-or-atypical.html
USA PRION UNIT BLOG
http://prionunitusaupdate2008.blogspot.com/
Sunday, April 20, 2008 Progress Report from the National Prion Disease Pathology Surveillance Center April 3, 2008
Atypical forms of BSE have emerged which, although rare, appear to be more virulent than the classical BSE that causes vCJD.
see full text ;
http://prionunitusaupdate2008.blogspot.com/2008/04/progress-report-from-national-prion.html
CJD TEXAS (cjd clusters)
http://cjdtexas.blogspot.com/
USA WRITTEN CJD QUESTIONNAIRE ???
http://cjdquestionnaire.blogspot.com/
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
to be continued. ...TSS
Labels: atypical bse, korea, prion, SCRAPIE, SPORADIC CJD, USA
posted by Terry S. Singeltary Sr. at
7:46 PM
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