Saturday, April 19, 2014

Exploring the zoonotic potential of animal prion diseases: In vivo and in vitro approaches

Exploring the zoonotic potential of animal prion diseases: In vivo and in vitro approaches
 
Marcelo A Barria*, James W Ironside, Mark W HeadView affiliations
 
 Submitted 4 Dec 2013
 
Revised 13 Jan 2014
 
Accepted 5 Feb 2014
 
Published Online 18 Feb 2014 Abstract
 
Following the discovery of a causal link between bovine spongiform encephalopathy (BSE) in cattle and variant Creutzfeldt–Jakob disease (vCJD) in humans, several experimental approaches have been used to try to assess the potential risk of transmission of other animal transmissible spongiform encephalopathies (TSEs) to humans. Experimental challenge of non-human primates, humanised transgenic mice and cell-free conversion systems have all been used as models to explore the susceptibility of humans to animal TSEs. In this review we compare and contrast in vivo and in vitro evidence of the zoonotic risk to humans from sheep, cattle and deer prions, focusing primarily on chronic wasting disease and our own recent studies using protein misfolding cyclic amplification.
 
*** These results would seem to suggest that CWD does indeed have zoonotic potential, at least as judged by the compatibility of CWD prions and their human PrPC target. Furthermore, extrapolation from this simple in vitro assay suggests that if zoonotic CWD occurred, it would most likely effect those of the PRNP codon 129-MM genotype and that the PrPres type would be similar to that found in the most common subtype of sCJD (MM1).
 
 
Greetings,
 
this study, I can’t figure out how the same studies between institutions and science using TG mice can vary so much.
 
this study seems to downplay all the typical and atypical TSE prion disease in different species, except the typical c-BSE, and CWD (elk strain only).
 
and under the section ;
 
Chronic Wasting Disease: A Risk As Yet Unquantified?
 
the theology that ;
 
‘’CJD surveillance systems in CWD affected countries have been alert to this possibility and have been vigilant for CJD patients with suspicious clinical signs and symptoms, a young age at onset and potential risk factors such as game hunting and venison consumption. The literature contains five such cases.40,41 The results of intensive investigation provided diagnoses of sCJD,40 familial CJD and early-onset Alzheimer disease41 and on balance the authors discounted a link to CWD, but conceded the difficulties involved in coming to this conclusion. It is important to note however that the specific features of an animal prion disease need not be conserved when zoonoses occur. Neither the characteristic vCJD neuropathology nor the pronounced peripheral tissue involvements of vCJD are features of BSE in cattle. The absence of neuropathological similarities between CWD and any individual cases of human prion disease is not sufficient grounds to discount CWD as a human pathogen.’’
 
so in my opinion as a layperson, the same should be said about atypical BSE strains, atypical scrapie strain, and even typical scrapie strains ;
 
(Gibbs et al *** The successful transmission of kuru, Creutzfeldt-Jakob disease, and scrapie by natural feeding to squirrel monkeys that we have reported provides further grounds for concern that scrapie-infected meat may occasionally give rise in humans to Creutzfeldt-Jakob disease.)
 
PMID: 6997404
 
 
but the same should hold true in my opinion from the paragraph above, for all TSE prion disease, there are just too many variables. I guess that’s the right word. ...tss
 
anyway, seems the this study discredits other studies that atypical L-type BSE and atypical H-BSE are ;
 
‘’To our knowledge, the only evidence comparing L-BSE and H-BSE in a cell free system comes from work by our group. A panel composed of several animal TSEs were tested for their ability to convert the human prion protein by PMCA. Human brain and humanized transgenic mouse brain homogenates of the PRNP codon 129 MM and VV genotypes all failed to support amplification when the PMCA reactions were seeded with L-BSE, H-BSE, scrapie and atypical scrapie. In contrast C-BSE and vCJD PrPSc efficiently converted the human PrPC, albeit in a codon 129 (M allele) dependent manner. These findings suggest that, at least at the molecular level, atypical scrapie and atypical BSE present a lower level of risk of zoonotic disease than classical BSE.37’’
 
well again, here they are using TG mice. I cannot see TG mice studies overriding studies done with human or non-human primates, and studies done with non-human primates have shown that indeed all these TSE prion strains have the potential to be infectious to humans, and transmit, even the atypical H-BSE i.e. KONG ET AL. ...tss
 
now to cwd from this study ;
 
Chronic Wasting Disease: A Risk As Yet Unquantified?
 
‘’The literature contains five such cases.40,41 The results of intensive investigation provided diagnoses of sCJD,40 familial CJD and early-onset Alzheimer disease41 and on balance the authors discounted a link to CWD, but conceded the difficulties involved in coming to this conclusion. It is important to note however that the specific features of an animal prion disease need not be conserved when zoonoses occur. Neither the characteristic vCJD neuropathology nor the pronounced peripheral tissue involvements of vCJD are features of BSE in cattle. The absence of neuropathological similarities between CWD and any individual cases of human prion disease is not sufficient grounds to discount CWD as a human pathogen...’’
 
please note ;
 
tss comment...PLEASE NOTE IN 2008 THIS WAS STATED ;
 
Thus far, *** twenty-seven CJD patients who regularly consumed venison were reported to the Surveillance Center***, however there have been no unusual or novel prion subtypes that might indicate the appearance of a new prion strain [7, 41].
 
 
 
‘’These results would seem to suggest that CWD does indeed have zoonotic potential, at least as judged by the compatibility of CWD prions and their human PrPC target. Furthermore, extrapolation from this simple in vitro assay suggests that if zoonotic CWD occurred, it would most likely effect those of the PRNP codon 129-MM genotype and that the PrPres type would be similar to that found in the most common subtype of sCJD (MM1).’’
 
‘’Figure 2. Human PMCA reactions with CWD prions. (A) CWD PrPSc amplification was conducted with substrates from three different sources (human brain, humanized transgenic mouse brain, human cell line,), each with both the PRNP codon 129 MM and the VV genotypes. The susceptibility of human PrPC to conversion was evaluated after a single round of PMCA. Irrespective to the origin, the three substrates supported amplification after one round (96 cycles) of PMCA. CWD amplification showed a preference for the MM genotype, with a robust amplification, compared with the VV genotype. Amplified sample (+), non-amplified sample (-). (B) PrPres typing of the CWD PrPSc amplified in a human brain substrate. vCJD, sCJD VV 2 subtype and sCJD MM1 subtype were used as PrPres type reference standards. The CWD PrPres material produced by PMCA (CWD-Hu PMCA) resemble type 1 human PrPres. PrP detection antibody was 3F4. M, Molecular marker.’’
 
Exploring the zoonotic potential of animal prion diseases: In vivo and in vitro approaches
 
 
as I said, what if ?
 
*** our results raise the possibility that CJD cases classified as VV1 may include cases caused by iatrogenic transmission of sCJD-MM1 prions or food-borne infection by type 1 prions from animals, e.g., chronic wasting disease prions in cervid. In fact, two CJD-VV1 patients who hunted deer or consumed venison have been reported (40, 41). The results of the present study emphasize the need for traceback studies and careful re-examination of the biochemical properties of sCJD-VV1 prions. ***
 
 
 ===========================================
 
Thursday, January 2, 2014
 
*** CWD TSE Prion in cervids to hTGmice, Heidenhain Variant Creutzfeldt-Jacob Disease MM1 genotype, and iatrogenic CJD ??? ***
 
WHAT IF ?
 
 
============================================
 
Sunday, April 06, 2014
 
SPORADIC CJD and the potential for zoonotic transmission there from, either directly or indirectly via friendly fire iatrogenic mode, evidence to date
 
 
Tuesday, April 01, 2014
 
Questions linger in U.S. CJD cases 2005, and still do in 2014
 
 
 *** PPo3-7: Prion Transmission from Cervids to Humans is Strain-dependent
 
*** Here we report that a human prion strain that had adopted the cervid prion protein (PrP) sequence through passage in cervidized transgenic mice efficiently infected transgenic mice expressing human PrP,
 
*** indicating that the species barrier from cervid to humans is prion strain-dependent and humans can be vulnerable to novel cervid prion strains.
 
PPo2-27:
 
Generation of a Novel form of Human PrPSc by Inter-species Transmission of Cervid Prions
 
*** Our findings suggest that CWD prions have the capability to infect humans, and that this ability depends on CWD strain adaptation, implying that the risk for human health progressively increases with the spread of CWD among cervids.
 
PPo2-7:
 
Biochemical and Biophysical Characterization of Different CWD Isolates
 
*** The data presented here substantiate and expand previous reports on the existence of different CWD strains.

Envt.07:
 
Pathological Prion Protein (PrPTSE) in Skeletal Muscles of Farmed and Free Ranging White-Tailed Deer Infected with Chronic Wasting Disease
 
***The presence and seeding activity of PrPTSE in skeletal muscle from CWD-infected cervids suggests prevention of such tissue in the human diet as a precautionary measure for food safety, pending on further clarification of whether CWD may be transmissible to humans.
 
 
>>>CHRONIC WASTING DISEASE , THERE WAS NO ABSOLUTE BARRIER TO CONVERSION OF THE HUMAN PRION PROTEIN<<<
 
*** PRICE OF CWD TSE PRION POKER GOES UP 2014 ***
 
Transmissible Spongiform Encephalopathy TSE PRION update January 2, 2014
 
Wednesday, January 01, 2014
 
Molecular Barriers to Zoonotic Transmission of Prions
 
*** chronic wasting disease, there was no absolute barrier to conversion of the human prion protein.
 
*** Furthermore, the form of human PrPres produced in this in vitro assay when seeded with CWD, resembles that found in the most common human prion disease, namely sCJD of the MM1 subtype.
 
 
 
PRION2013 CONGRESSIONAL ABSTRACTS CWD
 
Sunday, August 25, 2013
 
HD.13: CWD infection in the spleen of humanized transgenic mice
 
***These results indicate that the CWD prion may have the potential to infect human peripheral lymphoid tissues.
 
Oral.15: Molecular barriers to zoonotic prion transmission: Comparison of the ability of sheep, cattle and deer prion disease isolates to convert normal human prion protein to its pathological isoform in a cell-free system ***However, they also show that there is no absolute barrier ro conversion of human prion protein in the case of chronic wasting disease.
 
PRION2013 CONGRESSIONAL ABSTRACTS CWD
 
Sunday, August 25, 2013
 
***Chronic Wasting Disease CWD risk factors, humans, domestic cats, blood, and mother to offspring transmission
 
 
Friday, November 09, 2012
 
*** Chronic Wasting Disease CWD in cervidae and transmission to other species
 
 
there is in fact evidence that the potential for cwd transmission to humans can NOT be ruled out.
 
I thought your readers and hunters and those that consume the venison, should have all the scientific facts, personally, I don’t care what you eat, but if it effects me and my family down the road, it should then concern everyone, and the potential of iatrogenic transmission of the TSE prion is real i.e. ‘friendly fire’, medical, surgical, dental, blood, tissue, and or products there from...like deer antler velvet and TSE prions and nutritional supplements there from, all a potential risk factor that should not be ignored or silenced. ...
 
the prion gods at the cdc state that there is ;
 
''no strong evidence''
 
but let's see exactly what the authors of this cwd to human at the cdc state ;
 
now, let’s see what the authors said about this casual link, personal communications years ago. see where it is stated NO STRONG evidence. so, does this mean there IS casual evidence ????
 
“Our conclusion stating that we found no strong evidence of CWD transmission to humans”
 
From: TSS (216-119-163-189.ipset45.wt.net)
 
Subject: CWD aka MAD DEER/ELK TO HUMANS ???
 
Date: September 30, 2002 at 7:06 am PST
 
From: "Belay, Ermias"
 
To:
 
Cc: "Race, Richard (NIH)" ; ; "Belay, Ermias"
 
Sent: Monday, September 30, 2002 9:22 AM
 
Subject: RE: TO CDC AND NIH - PUB MED- 3 MORE DEATHS - CWD - YOUNG HUNTERS
 
Dear Sir/Madam,
 
In the Archives of Neurology you quoted (the abstract of which was attached to your email), we did not say CWD in humans will present like variant CJD.
 
That assumption would be wrong. I encourage you to read the whole article and call me if you have questions or need more clarification (phone: 404-639-3091). Also, we do not claim that "no-one has ever been infected with prion disease from eating venison." Our conclusion stating that we found no strong evidence of CWD transmission to humans in the article you quoted or in any other forum is limited to the patients we investigated.
 
Ermias Belay, M.D. Centers for Disease Control and Prevention
 
-----Original Message-----
 
From:
 
Sent: Sunday, September 29, 2002 10:15 AM
 
To: rr26k@nih.gov; rrace@niaid.nih.gov; ebb8@CDC.GOV
 
Subject: TO CDC AND NIH - PUB MED- 3 MORE DEATHS - CWD - YOUNG HUNTERS
 
Sunday, November 10, 2002 6:26 PM ......snip........end..............TSS
 
Thursday, April 03, 2008
 
A prion disease of cervids: Chronic wasting disease
 
2008 1: Vet Res. 2008 Apr 3;39(4):41
 
A prion disease of cervids: Chronic wasting disease
 
Sigurdson CJ.
 
snip...
 
*** twenty-seven CJD patients who regularly consumed venison were reported to the Surveillance Center***,
 
snip...
 
full text ;
 
 
 
 
***********CJD REPORT 1994 increased risk for consumption of veal and venison and lamb***********
 
CREUTZFELDT JAKOB DISEASE SURVEILLANCE IN THE UNITED KINGDOM THIRD ANNUAL REPORT AUGUST 1994
 
Consumption of venison and veal was much less widespread among both cases and controls. For both of these meats there was evidence of a trend with increasing frequency of consumption being associated with increasing risk of CJD. (not nvCJD, but sporadic CJD...tss)
 
These associations were largely unchanged when attention was restricted to pairs with data obtained from relatives. ...
 
Table 9 presents the results of an analysis of these data.
 
There is STRONG evidence of an association between ‘’regular’’ veal eating and risk of CJD (p = .0.01).
 
Individuals reported to eat veal on average at least once a year appear to be at 13 TIMES THE RISK of individuals who have never eaten veal.
 
There is, however, a very wide confidence interval around this estimate. There is no strong evidence that eating veal less than once per year is associated with increased risk of CJD (p = 0.51).
 
The association between venison eating and risk of CJD shows similar pattern, with regular venison eating associated with a 9 FOLD INCREASE IN RISK OF CJD (p = 0.04).
 
There is some evidence that risk of CJD INCREASES WITH INCREASING FREQUENCY OF LAMB EATING (p = 0.02).
 
The evidence for such an association between beef eating and CJD is weaker (p = 0.14). When only controls for whom a relative was interviewed are included, this evidence becomes a little STRONGER (p = 0.08).
 
snip...
 
It was found that when veal was included in the model with another exposure, the association between veal and CJD remained statistically significant (p = < 0.05 for all exposures), while the other exposures ceased to be statistically significant (p = > 0.05).
 
snip...
 
In conclusion, an analysis of dietary histories revealed statistical associations between various meats/animal products and INCREASED RISK OF CJD. When some account was taken of possible confounding, the association between VEAL EATING AND RISK OF CJD EMERGED AS THE STRONGEST OF THESE ASSOCIATIONS STATISTICALLY. ...
 
snip...
 
In the study in the USA, a range of foodstuffs were associated with an increased risk of CJD, including liver consumption which was associated with an apparent SIX-FOLD INCREASE IN THE RISK OF CJD. By comparing the data from 3 studies in relation to this particular dietary factor, the risk of liver consumption became non-significant with an odds ratio of 1.2 (PERSONAL COMMUNICATION, PROFESSOR A. HOFMAN. ERASMUS UNIVERSITY, ROTTERDAM). (???...TSS)
 
snip...see full report ;
 
 
Thursday, October 10, 2013
 
*************CJD REPORT 1994 increased risk for consumption of veal and venison and lamb**************
 
 
CJD9/10022
 
October 1994
 
Mr R.N. Elmhirst Chairman British Deer Farmers Association Holly Lodge Spencers Lane BerksWell Coventry CV7 7BZ
 
Dear Mr Elmhirst,
 
CREUTZFELDT-JAKOB DISEASE (CJD) SURVEILLANCE UNIT REPORT
 
Thank you for your recent letter concerning the publication of the third annual report from the CJD Surveillance Unit. I am sorry that you are dissatisfied with the way in which this report was published.
 
The Surveillance Unit is a completely independant outside body and the Department of Health is committed to publishing their reports as soon as they become available. In the circumstances it is not the practice to circulate the report for comment since the findings of the report would not be amended. In future we can ensure that the British Deer Farmers Association receives a copy of the report in advance of publication.
 
The Chief Medical Officer has undertaken to keep the public fully informed of the results of any research in respect of CJD. This report was entirely the work of the unit and was produced completely independantly of the the Department.
 
The statistical results reqarding the consumption of venison was put into perspective in the body of the report and was not mentioned at all in the press release. Media attention regarding this report was low key but gave a realistic presentation of the statistical findings of the Unit. This approach to publication was successful in that consumption of venison was highlighted only once by the media ie. in the News at one television proqramme.
 
I believe that a further statement about the report, or indeed statistical links between CJD and consumption of venison, would increase, and quite possibly give damaging credence, to the whole issue. From the low key media reports of which I am aware it seems unlikely that venison consumption will suffer adversely, if at all.
 
 
JUST OUT !!!
 
*** this just out cdc, be sure to read what Bradley said about chimps, and why we should not use them. ...tss ***
 
Sunday, March 30, 2014
 
*** Chronic Wasting Disease Agents in Nonhuman Primates ***
 
 
NOW WHAT ABOUT atypical H-type and L-type BASE BSE, and other studies showing different results ;
 
Thursday, August 12, 2010
 
Seven main threats for the future linked to prions
 
First threat
 
The TSE road map defining the evolution of European policy for protection against prion diseases is based on a certain numbers of hypotheses some of which may turn out to be erroneous. In particular, a form of BSE (called atypical Bovine Spongiform Encephalopathy), recently identified by systematic testing in aged cattle without clinical signs, may be the origin of classical BSE and thus potentially constitute a reservoir, which may be impossible to eradicate if a sporadic origin is confirmed.
 
***Also, a link is suspected between atypical BSE and some apparently sporadic cases of Creutzfeldt-Jakob disease in humans. These atypical BSE cases constitute an unforeseen first threat that could sharply modify the European approach to prion diseases.
 
Second threat
 
snip...
 
 
EFSA Journal 2011 The European Response to BSE: A Success Story
 
This is an interesting editorial about the Mad Cow Disease debacle, and it's ramifications that will continue to play out for decades to come ;
 
Monday, October 10, 2011
 
EFSA Journal 2011 The European Response to BSE: A Success Story
 
snip...
 
EFSA and the European Centre for Disease Prevention and Control (ECDC) recently delivered a scientific opinion on any possible epidemiological or molecular association between TSEs in animals and humans (EFSA Panel on Biological Hazards (BIOHAZ) and ECDC, 2011). This opinion confirmed Classical BSE prions as the only TSE agents demonstrated to be zoonotic so far ***but the possibility that a small proportion of human cases so far classified as "sporadic" CJD are of zoonotic origin could not be excluded. Moreover, transmission experiments to non-human primates suggest that some TSE agents in addition to Classical BSE prions in cattle (namely L-type Atypical BSE, Classical BSE in sheep, transmissible mink encephalopathy (TME) and chronic wasting disease (CWD) agents) might have zoonotic potential.
 
snip...
 
 
 
see follow-up here about North America BSE Mad Cow TSE prion risk factors, and the ever emerging strains of Transmissible Spongiform Encephalopathy in many species here in the USA, including humans ;
 
 
*** 2010-2011 ***
 
When L-type BSE was inoculated into ovine transgenic mice and Syrian hamster the resulting molecular fingerprint had changed, either in the first or a subsequent passage, from L-type into C-type BSE. In addition, non-human primates are specifically susceptible for atypical BSE as demonstrated by an approximately 50% shortened incubation time for L-type BSE as compared to C-type. Considering the current scientific information available, it cannot be assumed that these different BSE types pose the same human health risks as C-type BSE or that these risks are mitigated by the same protective measures.
 
This study will contribute to a correct definition of specified risk material (SRM) in atypical BSE. The incumbent of this position will develop new and transfer existing, ultra-sensitive methods for the detection of atypical BSE in tissue of experimentally infected cattle.
 
 
Monday, September 26, 2011 L-BSE BASE prion and atypical sporadic CJD
 
Risk.12:
 
Transmission of Atypical Italian sCJD Case to Humanized Mice Reveals a Novel Infectious Strain
 
Roberta Galeno,1,† Marco Sbriccoli,1 Loredana Ingrosso,1 Silvia Graziano,1 Angelina Valanzano,1 Anna Poleggi,1 Angela De Pascalis,1 Anna Ladogana,1 Franco Cardone,1 Maria Puopolo,1 Gianluigi Zanusso2 and Maurizio Pocchiari1
 
1Istituto Superiore di Sanità; Rome, Italy; 2University of Verona; Verona, Italy†Presenting author; Email: roberta.galeno@iss.it
 
Sporadic Creutzfeldt-Jakob disease (sCJD) is a neurodegenerative prion disorder with uncertain etiology characterized by a typical combination of clinical symptoms, neuropathological lesions, and by the deposition of the pathological protein PrPTSE in the brain.
 
The vast majority of patients affected by sCJD can be categorized according to the genotype at the polymorphic position 129 of PrP (methionine or valine) and to the molecular mass of PrPTSE (type 1 or 2, corresponding to 21 or 19 kDa), yielding six possible combinations (MM1, MM2, VV1, VV2, MV1, and MV2) that associate with five clinico-pathological variants. Transmission studies of these sCJD subtypes into transgenic mice expressing the human prion protein allowed to identify four different infectious strains, which can partly explain the heterogeneity observed in sCJD patients.1
 
We recently described a novel molecular and pathological phenotype of sCJD (MV at position 129 of PrP), associated with an unprecedented electrophoretic pattern of PrPTSE characterized by the absence of the highly glycosylated isoform. In this work, we sought to characterize the prion strain associated with this atypical case by intracerebral inoculation into gene-targeted transgenic mice (HuTg) carrying the human PRNP gene with the three 129 genotype combinations. For comparison, three Italian sCJD cases heterozygous at position 129 of the prion protein, belonging to different subtypes (MV1, MV1/2, MV2), were transmitted to the same panel of transgenic mice. Survival times, attack rates, lesion profiles, and molecular analysis of the PrPTSE type recovered from mouse brains injected with the atypical case were compared with data from control animals. Mice inoculated with the atypical case displayed a restricted host tropism, with only a small number of VV animals that resulted PrPTSE-positive after an exceedingly long survival time. Interestingly, PrPTSE accumulated in brains from these mice lacks the diglycosylated band similar to that in sCJD inoculum, yet dissimilar to any other PrPTSE observed in HuTg mice by us and by other authors.1,2 Overall, *** these results strongly indicate that our atypical case associates with a new infectious strain of sCJD. Further investigations are needed to understand the possible connection with other human and animal prion diseases.
 
References
 
1. Bishop MT, Will RG, Manson JC. Defining sporadic Creutzfeldt-Jakob disease strains and their transmission properties. Proc Natl Acad Sci USA 2010; 107:12005-10.
 
2. Bishop MT, Hart P, Aitchison L, Baybutt HN, Plinston C, Thomson V, et al. Predicting susceptibility and incubation time of human-to-human transmission of vCJD. Lancet Neurol 2006; 5:393-8.
 
 
url changed to ;
 
 
Saturday, June 25, 2011
 
Transmissibility of BSE-L and Cattle-Adapted TME Prion Strain to Cynomolgus Macaque
 
"BSE-L in North America may have existed for decades"
 
 
Sunday, June 26, 2011
 
Risk Analysis of Low-Dose Prion Exposures in Cynomolgus Macaque
 
 
2011 Monday, September 26, 2011
 
L-BSE BASE prion and atypical sporadic CJD
 
 
 *** October 2009 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.
 
 
*** The discovery of previously unrecognized prion diseases in both humans and animals (i.e., Nor98 in small ruminants) demonstrates that the range of prion diseases might be wider than expected and raises crucial questions about the epidemiology and strain properties of these new forms. We are investigating this latter issue by molecular and biological comparison of VPSPr, GSS and Nor98.
 
 
Wednesday, March 28, 2012
 
VARIABLY PROTEASE-SENSITVE PRIONOPATHY IS TRANSMISSIBLE, price of prion poker goes up again $
 
 
Saturday, August 14, 2010
 
BSE Case Associated with Prion Protein Gene Mutation (g-h-BSEalabama) and VPSPr PRIONPATHY
 
(see mad cow feed in COMMERCE IN ALABAMA...TSS)
 
 
UPDATE
 
I ask Professor Kong ; Thursday, December 04, 2008 3:37 PM
 
Subject: RE: re--Chronic Wating Disease (CWD) and Bovine Spongiform Encephalopathies (BSE): Public Health Risk Assessment
 
''IS the h-BSE more virulent than typical BSE as well, or the same as cBSE, or less virulent than cBSE? just curious.....''
 
Professor Kong reply ;
 
.....snip
 
''As to the H-BSE, we do not have sufficient data to say one way or another, but we have found that H-BSE can infect humans. I hope we could publish these data once the study is complete. Thanks for your interest.''
 
Best regards, Qingzhong Kong, PhD Associate Professor Department of Pathology Case Western Reserve University Cleveland, OH 44106 USA
 
END...TSS
 
Thursday, December 04, 2008 2:37 PM
 
"we have found that H-BSE can infect humans."
 
personal communication with Professor Kong. ...TSS
 
BSE-H is also transmissible in our humanized Tg mice. The possibility of more than two atypical BSE strains will be discussed.
 
Supported by NINDS NS052319, NIA AG14359, and NIH AI 77774.
 
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.
 
 
 
 
The present study demonstrated successful intraspecies transmission of H-type BSE to cattle and the distribution and immunolabeling patterns of PrPSc in the brain of the H-type BSE-challenged cattle. TSE agent virulence can be minimally defined by oral transmission of different TSE agents (C-type, L-type, and H-type BSE agents) [59]. Oral transmission studies with H-type BSEinfected cattle have been initiated and are underway to provide information regarding the extent of similarity in the immunohistochemical and molecular features before and after transmission. *** In addition, the present data will support risk assessments in some peripheral tissues derived from cattle affected with H-type BSE. http://www.veterinaryresearch.org/content/pdf/1297-9716-42-79.pdf
 
Thursday, June 23, 2011
 
Experimental H-type bovine spongiform encephalopathy characterized by plaques and glial- and stellate-type prion protein deposits
 
 
Saturday, June 25, 2011
 
Transmissibility of BSE-L and Cattle-Adapted TME Prion Strain to Cynomolgus Macaque
 
Emmanuel Comoy,1,† Valérie Durand,1 Evelyne Correia,1 Sophie Freire,1 Jürgen Richt,2 Justin Greenlee,3 Juan-Maria Torres,4 Paul Brown,1 Bob Hills5 and Jean-Philippe Deslys1
 
1Atomic Energy Commission; Fontenay-aux-Roses, France; 2Kansas State University; Manhattan, KS USA; 3USDA; Ames, IA USA; 4INIA; Madrid, Spain; 5Health Canada; Ottawa, ON Canada†Presenting author; Email: emmanuel.comoy@cea.fr
 
The epidemiology of Transmissible mink encephalopathy (TME) indicates an alimentary origin. Several inter-species transmission experiments have not succeeded in establishing with certainty any natural reservoir of this prion strain, although both ovine and bovine sources have been suspected. Cattle exposed to TME develop a spongiform encephalopathy that is distinct from classical Bovine Spongiform Encephalopathy (c-BSE).
 
Inoculation of c-BSE to cynomolgus macaque provided early evidence of a possible risk to humans, and remains an important model to define the risk of both primary (oral transmission from cattle to primate) and secondary (intravenous intra-species transmission) exposures. We have also evaluated the transmissibility of other cattle prion strains to macaques, including L- and H- atypical forms of BSE, namely BSE-L and BSE-H, and cattle-adapted TME.
 
BSE-L induced a neurological disease distinct from c-BSE. Peripheral exposures demonstrate the transmissibility of BSE-L by oral, intravenous, and intra-cerebral routes, with incubation periods similar to c-BSE. Cattle-adapted TME also induced a rapid disease in cynomolgus macaque. The clinical features, lesion profile, and biochemical signature of the induced disease was similar to the features observed in animals exposed to BSE-L, suggesting a link between the two prion strains. Secondary transmissions to a common host (transgenic mouse overexpressing bovine PrP) of cattle-TME and BSE-L before or after passage in primates induced diseases with similar incubation periods: like the c-BSE strain, these cattle strains maintained their distinctive features regardless of the donor species and passages.
 
If the link between TME and BSE-L is confirmed, our results would suggest that BSE-L in North America may have existed for decades, and highlight a possible preferential transmission of animal prion strains to primates after passage in cattle.
 
=====================end...tss====================
 
Risk.16: Clinical Disease in Cattle Experimentally Inoculated with All Types of BSE
 
Catherine Graham,1,† Michel Levy,2 Ed Pajor,2 Garth McGregor,1 Rheana Flitton1 and Stefanie Czub1
 
1Canadian Food Inspection Agency; Lethbridge, AB Canada; 2Faculty of Veterinary Medicine; University of Calgary; Calgary, AB Canada†Presenting author; Email: catherine.graham@inspection.gc.ca
 
Background. Classical, or C-type, bovine spongiform encephalopathy (BSE) has been extensively described in the literature. Recently, two novel forms of BSE, termed atypical BSE, have been reported in a number of countries. These new forms show differences in the biochemical characteristics of the prion protein and, where reported, tend to occur in aged animals but descriptions of clinical presentation are incomplete or absent.
 
 Materials and Methods. Female Hereford/Angus cross calves were intracranially challenged at approximately five months of age with 1 ml of a 10% brain homogenate originating from Canadian field cases of BSE which had been previously classified as C-, L-, or H- type.
 
 The animals were monitored during incubation period, and clinical disease is described using a standardized examination protocol. Incubation period, description and progression of clinical signs was recorded and videotaped for objective evaluation.
 
 Results. All L- and H- type atypical BSE challenged animals began to display signs of clinical disease at approximately 11 months post inoculation, and disease progression was slow but constant until animals were euthanized. Clinical signs in all atypical BSE inoculated animals included hesitation at doors and gates, spontaneous muscle fasciculations and sensitivity to touch. Teeth grinding and excessive salivation are occasionally noted. Animals with L-type BSE are very anxious and show high levels of sensitivity to hand movement. One H-type animal shows periods of somnolence. Both H-type inoculated animals go down during handling and have difficulty rising and show sensitivity to movement around their head and neck area, but to a lesser degree than the L-type BSE inoculated animals. Interestingly, no locomotor abnormalities have been observed in either group.
 
 C-type challenged animals remain normal at approximately 18 months post inoculation. Clinical disease in C-type inoculated animals from a previous transmission study was typically slow and intermittently displayed during the initial stages and after a period of two to four months was more consistent and progressive. Clinical signs in C-type BSE were as previously reported in the literature.
 
 Discussion. The spectrum of clinical signs for all three types of BSE examined is similar. Incubation period is shorter for H- and L-type BSE as compared with C-type. Once clinical signs begin, progression is slow but relentless in atypical BSE, and more insidious in classical BSE. A summary of clinical signs presented in the three different types of BSE will be presented, and video of clinical disease will be displayed.
 
 link url not available, please see PRION 2011 ;
 
 
PRION2011
 
ORAL PRESENTATIONS
 
 
PRION BIOLOGY
 
 
=========================end...tss================
 
 
PLEASE NOTE *
 
Over the next 8-10 weeks, approximately 40% of all the adult mink on the farm died from TME.
 
snip...
 
*** The rancher was a ''dead stock'' feeder using mostly (>95%) downer or dead dairy cattle...
 
 
 
please see below from PRION2013 ;
 
 
*** This study imply the possibility that the novel BSE prions with high virulence in cattle will be emerged during intraspecies transmission.
 
AD.56: The emergence of novel BSE prions by serial passages of H-type BSE in bovinized mice
 
Kentaro Masujin, Naoko Tabeta, Ritsuko Miwa, Kohtaro Miyazawa, Hiroyuki Okada, Shirou Mohri and Takashi Yokoyama National Institute of Animal Health; Tsukuba, Japan
 
H-type bovine spongiform encephalopathy (BSE) is an atypical form of BSE, and has been detected in several European countries, and North America. Transmission studies of H-type BSE led to the emergence of the classical BSE (C-BSE) phenotypes during passages in inbred wild type and bovinized PrP-overexpressing transgenic mice. In this study, we conducted serial passages of Canadian H-type BSE isolate in bovinized PrP-overexpressing transgenic mice (TgBoPrP). H-type BSE isolate was transmitted to TgBoPrP with incubation periods of 320 ± 12.2 d at primary passage. The incubation period of 2nd and 3rd passage were constant (~= 220 d), no clear differences were observed in their biological and biochemical properties. However, at the forth passage, 2 different BSE phenotypes were confirmed; one is shorter survival times (109 ± 4 d) and the other is longer survival times. TgBoPrP mice with longer incubation period showed the H-type phenotype of PrPsc profile and pathology. However, those of shorter incubation period were different phenotypes from previously existed BSE prions (C-BSE, L-type BSE, and H-type BSE).
 
*** This study imply the possibility that the novel BSE prions with high virulence in cattle will be emerged during intraspecies transmission.
 
 
 
 
please see ;
 
Thursday, August 15, 2013
 
The emergence of novel BSE prions by serial passages of H-type BSE in bovinized mice
 
 
 
please see below from PRION2013 ;
 
*** This study imply the possibility that the novel BSE prions with high virulence in cattle will be emerged during intraspecies transmission.
 
AD.56: The emergence of novel BSE prions by serial passages of H-type BSE in bovinized mice
 
Kentaro Masujin, Naoko Tabeta, Ritsuko Miwa, Kohtaro Miyazawa, Hiroyuki Okada, Shirou Mohri and Takashi Yokoyama National Institute of Animal Health; Tsukuba, Japan
 
H-type bovine spongiform encephalopathy (BSE) is an atypical form of BSE, and has been detected in several European countries, and North America. Transmission studies of H-type BSE led to the emergence of the classical BSE (C-BSE) phenotypes during passages in inbred wild type and bovinized PrP-overexpressing transgenic mice. In this study, we conducted serial passages of Canadian H-type BSE isolate in bovinized PrP-overexpressing transgenic mice (TgBoPrP). H-type BSE isolate was transmitted to TgBoPrP with incubation periods of 320 ± 12.2 d at primary passage. The incubation period of 2nd and 3rd passage were constant (~= 220 d), no clear differences were observed in their biological and biochemical properties. However, at the forth passage, 2 different BSE phenotypes were confirmed; one is shorter survival times (109 ± 4 d) and the other is longer survival times. TgBoPrP mice with longer incubation period showed the H-type phenotype of PrPsc profile and pathology. However, those of shorter incubation period were different phenotypes from previously existed BSE prions (C-BSE, L-type BSE, and H-type BSE).
 
*** This study imply the possibility that the novel BSE prions with high virulence in cattle will be emerged during intraspecies transmission.
 
 
www.landesbioscience.com
 
please see ;
 
Thursday, August 15, 2013
 
The emergence of novel BSE prions by serial passages of H-type BSE in bovinized mice
 
 
Sunday, September 1, 2013
 
*** Evaluation of the Zoonotic Potential of Transmissible Mink Encephalopathy
 
We previously described the biochemical similarities between PrPres derived from L-BSE infected macaque and cortical MM2 sporadic CJD: those observations suggest a link between these two uncommon prion phenotypes in a primate model (it is to note that such a link has not been observed in other models less relevant from the human situation as hamsters or transgenic mice overexpressing ovine PrP [28]). We speculate that a group of related animal prion strains (L-BSE, c-BSE and TME) would have a zoonotic potential and lead to prion diseases in humans with a type 2 PrPres molecular signature (and more specifically type 2B for vCJD)
 
snip...
 
Together with previous experiments performed in ovinized and bovinized transgenic mice and hamsters [8,9] indicating similarities between TME and L-BSE, the data support the hypothesis that L-BSE could be the origin of the TME outbreaks in North America and Europe during the mid-1900s.
 
 
Identification of a second bovine amyloidotic spongiform encephalopathy: Molecular similarities with sporadic Creutzfeldt–Jakob disease
 
Cristina Casalone*†, Gianluigi Zanusso†‡, Pierluigi Acutis*, Sergio Ferrari‡, Lorenzo Capucci§, Fabrizio Tagliavini¶, Salvatore Monaco‡ , and Maria Caramelli* *Centro di Referenza Nazionale per le Encefalopatie Animali, Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d’Aosta, Via Bologna, 148, 10195 Turin, Italy; ‡Department of Neurological and Visual Science, Section of Clinical Neurology, Policlinico G.B. Rossi, Piazzale L.A. Scuro, 10, 37134 Verona, Italy; §Istituto Zooprofilattico Sperimentale della Lombardia ed Emilia Romagna, Via Bianchi, 9, 25124 Brescia, Italy; and ¶Istituto Nazionale Neurologico ‘‘Carlo Besta,’’ Via Celoria 11, 20133 Milan, Italy Edited by Stanley B. Prusiner, University of California, San Francisco, CA, and approved December 23, 2003 (received for review September 9, 2003)
 
Transmissible spongiform encephalopathies (TSEs), or prion diseases, are mammalian neurodegenerative disorders characterized by a posttranslational conversion and brain accumulation of an insoluble, protease-resistant isoform (PrPSc) of the host-encoded cellular prion protein (PrPC). Human and animal TSE agents exist as different phenotypes that can be biochemically differentiated on the basis of the molecular mass of the protease-resistant PrPSc fragments and the degree of glycosylation. Epidemiological, molecular, and transmission studies strongly suggest that the single strain of agent responsible for bovine spongiform encephalopathy (BSE) has infected humans, causing variant Creutzfeldt–Jakob disease. The unprecedented biological properties of the BSE agent, which circumvents the so-called ‘‘species barrier’’ between cattle and humans and adapts to different mammalian species, has raised considerable concern for human health. To date, it is unknown whether more than one strain might be responsible for cattle TSE or whether the BSE agent undergoes phenotypic variation after natural transmission. Here we provide evidence of a second cattle TSE. The disorder was pathologically characterized by the presence of PrP-immunopositive amyloid plaques, as opposed to the lack of amyloid deposition in typical BSE cases, and by a different pattern of regional distribution and topology of brain PrPSc accumulation. In addition, Western blot analysis showed a PrPSc type with predominance of the low molecular mass glycoform and a protease- resistant fragment of lower molecular mass than BSE-PrPSc. Strikingly, the molecular signature of this previously undescribed bovine PrPSc was similar to that encountered in a distinct subtype of sporadic Creutzfeldt–Jakob disease.
 
SNIP...
 
Discussion
 
In natural and experimental TSEs, PrPSc deposition represents an early event that occurs weeks to months before the development of spongiform changes (20, 21). As a consequence, the detection of PrPSc by Western immunoblot provides a unique opportunity in the diagnosis of BSE early in the incubation period and, therefore, in presymptomatic animals. The identification of the present cattle by postmortem biochemical tests, in the absence of clear neurological involvement, suggests that the disorder was detected at early stages, and this may also explain the lack of widespread vacuolar changes.
 
Previous pathological studies in clinically suspect cases of BSE in Great Britain have provided evidence for a uniform pattern in the severity and distribution of vacuolar lesions in affected animals, with medulla oblongata nuclei being the most involved (22). While confirming that the BSE epidemic has been sustained by a single agent, these studies have assessed the validity of statutory criteria for the diagnosis of BSE, which is currently based on both histopathological and immunobiochemical exam- ination of the medulla. However, the prevailing involvement of cortical regions in the cattle with amyloid deposition suggests that postmortem brain sampling should not be limited to the obex. In addition, a careful analysis of PrPSc glycoform profiles at the confirmatory Western immunoblot may provide a molecular means of identifying atypical cases of bovine TSE.
 
Bovine Amyloidotic Spongiform Encephalopathy (BASE): A Second Bovine TSE. The present findings show that a previously undescribed pathological and immunohistochemical phenotype, associated with cattle TSE, is related to the presence of a PrPSc type with biochemical properties, including the gel mobility of the protease-resistant fragment and glycoform ratios, different from those encountered in cattle BSE. Brain deposition of this pathological isoform of cattle PrP correlates with the formation of PrP-amyloid plaques, as opposed to typical BSE cases. Although in several natural and experimental recipients of the BSE agent, including humans (13), neuropathological changes are characterized by the presence of PrP-positive amyloid deposits with surrounding vacuolation, cattle BSE is not associated with PrP-amyloid plaque formation. On the basis of the above features, we propose to name the disease described here BASE. Although observed in only two cattle, the BASE phenotype could be more common than expected. In previous studies, amyloid congophilic plaques were found in 1 of 20 BSE cases examined systematically for amyloid (23), and it was reported that focal cerebral amyloidosis is present in a small proportion of BSE cases (24). Although no biochemical analysis of PrPSc glycotype is available for these animals with ‘‘atypical BSE phenotype,’’ our present results underscore the importance of performing a strain-typing in bovine TSE with amyloid deposition.
 
In sCJD, the neuropathological phenotype largely correlates with the molecular type of PrPSc and distinct polymorphic sites of PRNP (9, 19). This is in contrast with the situation in cattle, where different genotypes have been reported based on the variable numbers of octapeptide repeats in each allele, but no evidence for single-codon polymorphisms in the PrP gene has been established (25, 26). Because the present animals shared a similar genetic background and breed, differences in disease phenotypes between cattle with BSE and BASE can be tentatively related only to distinct PrPSc types or alternative routes of infection and spread of prion pathology. Accordingly, the lack of involvement of the motor dorsal nucleus of the vagus and the slight involvement of the brainstem in BASE, suggests a route for spreading of the agent other than the alimentary tract. Therefore, unless the BASE agent propagates throughout the olfactory pathway or other peripheral routes, it is possible that this disorder represents a sporadic form of cattle TSE, which would also explain the difference in ages between the two groups of affected animals.
 
Phenotypic Similarities Between BASE and sCJD. The transmissibility of CJD brains was initially demonstrated in primates (27), and classification of atypical cases as CJD was based on this property (28). To date, no systematic studies of strain typing in sCJD have been provided, and classification of different subtypes is based on clinical, neuropathological, and molecular features (the polymorphic PRNP codon 129 and the PrPSc glycotype) (8, 9, 15, 19).
 
The importance of molecular PrPSc characterization in assessing the identity of TSE strains is underscored by several studies, showing that the stability of given disease-specific PrPSc types is maintained upon experimental propagation of sCJD, familial CJD, and vCJD isolates in transgenic PrP-humanized mice (8, 29). Similarly, biochemical properties of BSE- and vCJDassociated PrPSc molecules remain stable after passage to mice expressing bovine PrP (30). Recently, however, it has been reported that PrP-humanized mice inoculated with BSE tissues may also propagate a distinctive PrPSc type, with a ‘‘monoglycosylated- dominant’’ pattern and electrophoretic mobility of the unglycosylated fragment slower than that of vCJD and BSE (31). Strikingly, this PrPSc type shares its molecular properties with the a PrPSc molecule found in classical sCJD. This observation is at variance with the PrPSc type found in M V2 sCJD cases and in cattle BASE, showing a monoglycosylated-dominant pattern but faster electrophoretic mobility of the protease-resistant fragment as compared with BSE. In addition to molecular properties of PrPSc, BASE and M V2 sCJD share a distinctive pattern of intracerebral PrP deposition, which occurs as plaque-like and amyloid-kuru plaques. Differences were, however, observed in the regional distribution of PrPSc. While inM V2 sCJD cases the largest amounts of PrPSc were detected in the cerebellum, brainstem, and striatum, in cattle BASE these areas were less involved and the highest levels of PrPSc were recovered from the thalamus and olfactory regions.
 
In conclusion, decoding the biochemical PrPSc signature of individual human and animal TSE strains may allow the identification of potential risk factors for human disorders with unknown etiology, such as sCJD. However, although BASE and sCJD share several characteristics, caution is dictated in assessing a link between conditions affecting two different mammalian species, based on convergent biochemical properties of diseaseassociated PrPSc types. Strains of TSE agents may be better characterized upon passage to transgenic mice. In the interim until this is accomplished, our present findings suggest a strict epidemiological surveillance of cattle TSE and sCJD based on molecular criteria.
 
 
 
SUMMARY REPORT CALIFORNIA BOVINE SPONGIFORM ENCEPHALOPATHY CASE INVESTIGATION JULY 2012 (ATYPICAL L-TYPE BASE)
 
Summary Report BSE 2012
 
Executive Summary
 
 
Saturday, August 4, 2012
 
*** Final Feed Investigation Summary - California BSE Case - July 2012 ***
 
 
Saturday, August 4, 2012
 
Update from APHIS Regarding Release of the Final Report on the BSE Epidemiological Investigation
 
 
Atypical BSE (BASE) Transmitted from Asymptomatic Aging Cattle to a Primate
 
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.
 
 
Sunday, September 1, 2013
 
*** Evaluation of the Zoonotic Potential of Transmissible Mink Encephalopathy
 
We previously described the biochemical similarities between PrPres derived from L-BSE infected macaque and cortical MM2 sporadic CJD: those observations suggest a link between these two uncommon prion phenotypes in a primate model (it is to note that such a link has not been observed in other models less relevant from the human situation as hamsters or transgenic mice overexpressing ovine PrP [28]). We speculate that a group of related animal prion strains (L-BSE, c-BSE and TME) would have a zoonotic potential and lead to prion diseases in humans with a type 2 PrPres molecular signature (and more specifically type 2B for vCJD)
 
snip...
 
Together with previous experiments performed in ovinized and bovinized transgenic mice and hamsters [8,9] indicating similarities between TME and L-BSE, the data support the hypothesis that L-BSE could be the origin of the TME outbreaks in North America and Europe during the mid-1900s.
 
 
TEXAS ATYPICAL H-BSE MAD COW CASE
 
On June 24, 2005, the USDA announced receipt of final results from The Veterinary Laboratories Agency in Weybridge, England, confirming BSE in a cow that had conflicting test results in 2004. This cow was from Texas, died at approximately 12 years of age, and represented the first endemic case of BSE in the United States. (see Texas BSE Investigation, Final Epidemiology Report, August 2005 External Web Site Policy PDF Document Icon (PDF – 83 KB))
 
ALABAMA ATYPICAL H-TYPE GENETIC BSE
 
On March 15, 2006, the USDA announced the confirmation of BSE in a cow in Alabama. The case was identified in a non-ambulatory (downer) cow on a farm in Alabama. The animal was euthanized by a local veterinarian and buried on the farm. The age of the cow was estimated by examination of the dentition as 10-years-old. It had no ear tags or distinctive marks; the herd of origin could not be identified despite an intense investigation (see second featured item above and Alabama BSE Investigation, Final Epidemiology Report, May 2006 External Web Site PolicyPDF Document Icon (PDF – 104 KB)).
 
In August 2008, several ARS investigators reported that a rare, genetic abnormality that may persist within the cattle population "is considered to have caused" BSE in this atypical (H-type) BSE animal from Alabama. (See Identification of a Heritable Polymorphism in Bovine PRNP Associated with Genetic Transmissible Spongiform Encephalopathy: Evidence of Heritable BSE External Web Site Policy. Also see BSE Case Associated with Prion Protein Gene Mutation External Web Site Policy.)
 
On December 23, 2003, the U.S. Department of Agriculture (USDA) announced a presumptive diagnosis of the first known case of BSE in the United States. It was in an adult Holstein cow from Washington State. This diagnosis was confirmed by an international reference laboratory in Weybridge, England, on December 25. Trace-back based on an ear-tag identification number and subsequent genetic testing confirmed that the BSE-infected cow was imported into the United States from Canada in August 2001. Because the animal was non-ambulatory (a "downer cow") at slaughter, brain tissue samples were taken by USDA's Animal and Plant Health Inspection Service as part of its targeted surveillance for BSE. However the animal's condition was attributed to complications from calving. After the animal was examined by a USDA Food Safety and Inspection Service (FSIS) veterinary medical officer both before and after slaughter, the carcass was released for use as food for human consumption. During slaughter, the tissues considered to be at high risk for the transmission of the BSE agent were removed. On December 24, 2003, FSIS recalled beef from cattle slaughtered in the same plant on the same day as the BSE positive cow. (see Bovine Spongiform Encephalopathy in a Dairy Cow - Washington State, 2003.)
 
 
Tuesday, August 22, 2006
 
BSE ATYPICAL TEXAS AND ALABAMA UPDATE JANUARY 20, 2007
 
 
 LAST MAD COW IN USA, IN CALIFORNIA, WAS ATYPICAL L-TYPE BASE BSE TSE PRION DISEASE Thursday, February 20, 2014
 
Unnecessary precautions BSE MAD COW DISEASE Dr. William James FSIS VS Dr. Linda Detwiler 2014
 
 
Saturday, August 14, 2010
 
***BSE Case Associated with Prion Protein Gene Mutation (g-h-BSEalabama) and VPSPr PRIONPATHY
 
*** (see mad cow feed in COMMERCE IN ALABAMA...TSS)
 
 
*** What irks many scientists is the USDA’s April 25 statement that the rare disease is “not generally associated with an animal consuming infected feed.”
 
The USDA’s conclusion is a “gross oversimplification,” said Dr. Paul Brown, one of the world’s experts on this type of disease who retired recently from the National Institutes of Health. "(The agency) has no foundation on which to base that statement.”
 
 
Owens, Julie
 
From: Terry S. Singeltary Sr. [flounder9@verizon.net]
 
Sent: Monday, July 24, 2006 1:09 PM
 
To: FSIS RegulationsComments
 
Subject: [Docket No. FSIS-2006-0011] FSIS Harvard Risk Assessment of Bovine Spongiform Encephalopathy (BSE) Page 1 of 98
 
 
FSIS, USDA, REPLY TO SINGELTARY
 
 
Sunday, December 15, 2013
 
*** FDA PART 589 -- SUBSTANCES PROHIBITED FROM USE IN ANIMAL FOOD OR FEED VIOLATIONS OFFICIAL ACTION INDICATED OIA UPDATE DECEMBER 2013 UPDATE
 
 
 FDA et al thinks as much as 5.5 grams of SRM is just fine for a heifer weighing about 600 lbs ;
 
''FDA has determined that each animal could have consumed, at most and in total, five-and-one-half grams - approximately a quarter ounce -- of prohibited material. These animals weigh approximately 600 pounds.''
 
 
 Saturday, December 21, 2013 **** Complementary studies detecting classical bovine spongiform encephalopathy infectivity in jejunum, ileum and ileocaecal junction in incubating cattle **** http://madcowusda.blogspot.com/2013/12/complementary-studies-detecting.html Wednesday, May 2, 2012 ARS FLIP FLOPS ON SRM REMOVAL FOR ATYPICAL L-TYPE BASE BSE RISK HUMAN AND ANIMAL HEALTH http://transmissiblespongiformencephalopathy.blogspot.com/2012/05/ars-flip-flops-on-srm-removal-for.html Saturday, June 12, 2010 PUBLICATION REQUEST AND FOIA REQUEST Project Number: 3625-32000-086-05 Study of Atypical Bse http://bse-atypical.blogspot.com/2010/06/publication-request-and-foia-request.html Wednesday, July 28, 2010 re-Freedom of Information Act Project Number 3625-32000-086-05, Study of Atypical BSE UPDATE July 28, 2010 http://bse-atypical.blogspot.com/2010/07/re-freedom-of-information-act-project.html
 
PRION 2009 CONGRESS BOOK OF ABSTRACTS
 
O.4.3
 
Spread of BSE prions in cynomolgus monkeys (Macaca fascicularis) after oral transmission
 
Edgar Holznagel1, Walter Schulz-Schaeffer2, Barbara Yutzy1, Gerhard Hunsmann3, Johannes Loewer1 1Paul-Ehrlich-Institut, Federal Institute for Sera and Vaccines, Germany; 2Department of Neuropathology, Georg-August University, Göttingen, Germany, 3Department of Virology and Immunology, German Primate Centre, Göttingen, Germany
 
Background: BSE-infected cynomolgus monkeys represent a relevant animal model to study the pathogenesis of variant Creutzfeldt-Jacob disease (vCJD).
 
Objectives: To study the spread of BSE prions during the asymptomatic phase of infection in a simian animal model.
 
Methods: Orally BSE-dosed macaques (n=10) were sacrificed at defined time points during the incubation period and 7 orally BSE-dosed macaques were sacrificed after the onset of clinical signs. Neuronal and non-neuronal tissues were tested for the presence of proteinase-K-resistant prion protein (PrPres) by western immunoblot and by paraffin-embedded tissue (PET) blot technique.
 
Results: In clinically diseased macaques (5 years p.i. + 6 mo.), PrPres deposits were widely spread in neuronal tissues (including the peripheral sympathetic and parasympathetic nervous system) and in lymphoid tissues including tonsils. In asymptomatic disease carriers, PrPres deposits could be detected in intestinal lymph nodes as early as 1 year p.i., but CNS tissues were negative until 3 – 4 years p.i. Lumbal/sacral segments of the spinal cord and medulla oblongata were PrPres positive as early as 4.1 years p.i., whereas sympathetic trunk and all thoracic/cervical segments of the spinal cord were still negative for PrPres. However, tonsil samples were negative in all asymptomatic cases.
 
Discussion: There is evidence for an early spread of BSE to the CNS via autonomic fibres of the splanchnic and vagus nerves indicating that trans-synaptical spread may be a time-limiting factor for neuroinvasion. Tonsils were predominantly negative during the main part of the incubation period indicating that epidemiological vCJD screening results based on the detection of PrPres in tonsil biopsies may mostly tend to underestimate the prevalence of vCJD among humans.
 
 
 Simian vCJD can be easily triggered in cynomolgus monkeys on the oral route using less than 5 g BSE brain homogenate.
 
 
Atypical L-Type Bovine Spongiform Encephalopathy (L-BSE) Transmission to Cynomolgus Macaques, a Non-Human Primate
 
 Jpn. J. Infect. Dis., 64 (1), 81-84, 2011
 
To see a printable version of the article in the Adobe file format, click this [PDF] link.
 
Short Communication
 
Atypical L-Type Bovine Spongiform Encephalopathy (L-BSE) Transmission to Cynomolgus Macaques, a Non-Human Primate
 
Fumiko Ono, Naomi Tase1, Asuka Kurosawa3, Akio Hiyaoka, Atsushi Ohyama, Yukio Tezuka, Naomi Wada2, Yuko Sato3, Minoru Tobiume3, Ken'ichi Hagiwara4, Yoshio Yamakawa4*, Keiji Terao1, and Tetsutaro Sata3
 
The Corporation for Production and Research of Laboratory Primates, Tsukuba 305-0843; 1Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Tsukuba 305-0843; 2Department of Veterinary Medicine, Yamaguchi University, Yamaguchi 753-8515; and 3Department of Pathology and 4Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
 
(Received December 9, 2010. Accepted December 22, 2010)
 
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*Corresponding author: Mailing address: Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan. Tel: +81-3-5285-1111 ext. 2127, Fax: +81-3-5285-1157, E-mail: yamakawa@nih.go.jp
 
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SUMMARY: A low molecular weight type of atypical bovine spongiform encephalopathy (L-BSE) was transmitted to two cynomolgus macaques by intracerebral inoculation of a brain homogenate of cattle with atypical BSE detected in Japan. They developed neurological signs and symptoms at 19 or 20 months post-inoculation and were euthanized 6 months after the onset of total paralysis. Both the incubation period and duration of the disease were shorter than those for experimental transmission of classical BSE (C-BSE) into macaques. Although the clinical manifestations, such as tremor, myoclonic jerking, and paralysis, were similar to those induced upon C-BSE transmission, no premonitory symptoms, such as hyperekplexia and depression, were evident. Most of the abnormal prion protein (PrPSc) was confined to the tissues of the central nervous system, as determined by immunohistochemistry and Western blotting. The PrPSc glycoform that accumulated in the monkey brain showed a similar profile to that of L-BSE and consistent with that in the cattle brain used as the inoculant. PrPSc staining in the cerebral cortex showed a diffuse synaptic pattern by immunohistochemistry, whereas it accumulated as fine and coarse granules and/or small plaques in the cerebellar cortex and brain stem. Severe spongiosis spread widely in the cerebral cortex, whereas florid plaques, a hallmark of variant Creutzfeldt-Jakob disease in humans, were observed in macaques inoculated with C-BSE but not in those inoculated with L-BSE.
 
snip...
 
To date, 27 cases of L-BSE and 24 cases of H-BSE have been report­ed worldwide (16), thus meaning that the prevalence of atypical BSE is considerably lower than that of C-BSE. However, recent studies showed that L-BSE is easily transmissible to transgenic mice expressing human (17,18) or bovine (19,20) prion protein, as well as to non-human primates (21), with shorter incubation periods than for the transmission of C-BSE to these animals. The virulent nature of L-BSE has stimulated new concern for human public health since the transmis­sion of C-BSE to humans resulted in variant Creutz­feldt-Jakob disease (vCJD) (4-7), a new emergent prion disease.
 
snip...
 
Two macaques simultaneously developed neurologi­cal signs and symptoms 19-20 months post-inoculation (mpi) with the brain homogenate of BSEI JP24. The monkeys entered the terminal stage of the disease (total paralysis) at 24-25 mpi, Both the onset and duration of the disease were shorter than those reported for the transmission of C-BSE to macaques by us and other groups (27,28). The clinical manifestations such as tremor, myoclonic jerking, and paralysis were similar to those observed during the transmission of C-BSE to ma- caques, whereas the premonitory abnormal behaviors, such as hyperekplexia and depression, seen upon trans­mission of C-BSE to macaques were not evident (27).
 
Histopathological analysis and IHC, performed as described previously (29), showed that severe spon­giform changes and the accumulation of Prpsc with various patterns were detectable in the brains of both monkeys (Fig. 1). Vacuolization was profound throughout the cerebral cortex, from the frontal to the occipital lobes (Fig. la). Likewise, synaptic-type Prpsc precipitation (30) was observed in the whole cerebral cortex and basal ganglia by IHC (Figs. Ib and c). Dense precipitates and plaques of Prpsc, which had been ob­served in cattle (JP24) brain (13), were not detected in the cerebrum of the monkeys. Prpsc, in the form of small plaques or coarse granules, was, however, detect­ed in the molecular layer of the cerebellum (Fig. Ie). Despite the severe spongiosis in the cerebral cortex, florid plaques, which are large Prpsc plaques surround­ed by vacuoles, a hallmark ofvCJD (4-7,30) and C-BSE transmission to macaques (27,28), were not observed. The histopathology of the brain was therefore similar to that reported for the brain of L-BSE (BASE)-transmit­ted macaques (21).
 
snip...
 
see full text ;
 
 
Monday, September 13, 2010
 
atypical BSE strains and sporadic CJD strains, is there a connection and why shouldn't there be $
 
 
Monday, September 13, 2010
 
atypical BSE strains and sporadic CJD strains, is there a connection and why shouldn't there be $ A Surprisingly High Number of the Plaque-Like VV sCJD Subtype Among the Polish sCJD-is There a Connection with BASE?
 
PPo4-15:
 
A Surprisingly High Number of the Plaque-Like VV sCJD Subtype Among the Polish sCJD—is There a Connection with BASE?
 
Beata Sikorska and Pawel P. Liberski Department of Molecular Pathology and Neuropathology; Medical University of Lodz; Lodz, Poland
 
Recently described bovine amyloidotic spongiform encephalopathy (BASE) or L type BSE—was is overrepresented in Poland (15% of all cases of BSE). Moreover, the number of BASE cases in Poland per million bovines is the highest in Europe. A potential human risk from BASE is evident from experimental transmission to “humanized” transgenic animals and primates. Taking into consideration that non-human primate inoculated with BASE had a shorter incubation period than monkeys infected with classical BSE, and that humanized Tg mice have been found to be highly susceptible to infection with atypical form of BSE, it seems probable that BASE may be more pathogenic for humans than BSE, but the transmitted disease may differ from BSE-derived vCJD. Among 47 cases which have been diagnosed as definite in our laboratory, in 19 cases complete histopathological examination and codon 129 status were available. On the basis of the histological pattern and codon 129 status the cases of sCJD were divided into subtypes according to the Parchi&Gambetti classification. The results are as follows: type 1 (MMorMV)- 42%, type 2 (VV)-32%, type 3 (MV)-10.5%, type 4c (MM)- 10.5% and type 5 (VV)-5 %. Although the number of cases is too low to conclude a significantly different distribution of sCJD subtypes in Polish population those data show surprisingly high number of the plaque-like VV sCJD subtype. Interestingly, it was shown before that Tg mice inoculated with BASE showed granular and plaque-like aggregates or PrPSc in brains resembling those observed in VV2 subtype of sCJD.
 
PPo2-26:
 
Transmission of Classical and Atypical (L-type) Bovine Spongiform Encephalopathy (BSE) Prions to Cynomolgus macaques
 
Fumiko Ono,1 Yoshio Yamakawa,2 Minoru Tobiume,3 Yuko Sato,3 Harutaka Katano,3 Kenichi Hagiwara,2 Iori Itagaki,1 Akio Hiyaoka,1 Katuhiko Komatuzaki,1 Yasunori Emoto,1 Hiroaki Shibata,4 Yuichi Murayama,5 Keiji Terao,4 Yasuhiro Yasutomi4 and Tetsutaro Sata3
 
1The Corporation for Production and Research of Laboratory Primates; Tsukuba City, Japan; 2Departments of Cell Biology and Biochemistry; and 3Pathology; National Institute of Infectious Diseases; Tokyo, Japan; 4Tsukuba Primate Research Center; National Institute of Biomedical Innovation; Tsukuba City, Japan; 5Prion Disease Research Team; National Institute of Animal Health; Tsukuba City, Japan
 
Key words: L-type BSE, cBSE, cynomolgus macaques, transmission
 
BSE prion derived from classical BSE (cBSE) or L-type BSE was characterized by inoculation into the brain of cynomolgus macaques. The neurologic manifestation was developed in all cynomolgus macaques at 27–43 months after intracerebral inoculation of brain homogenate from cBSE-affected cattle (BSE JP/6). Second transmission of cBSE from macaque to macaque shortened incubation period to 13–18 months. cBSE-affected macaques showed the similar clinical signs including hyperekplexia, tremor and paralysis in both primary and second transmission.
 
Two macaques were intracerebrally inoculated brain homogenate from the L-type BSE-affected cattle (BSE JP/24). The incubation periods were 19–20 months in primary transmission.
 
The clinical course of the L-type BSE-affected macaques differed from that in cBSE-affected macaques in the points of severe myoclonus without hyperekplexia. The glycoform profile of PrPSc detected in macaque CNS was consistent with original pattern of either cBSE or L-typeBSE PrPSc, respectively. Although severe spongiform change in the brain was remarkable in all BSE-affected macaques, severe spongiform spread widely in cerebral cortex in L-type BSE-affected macaques. Heavy accumulation of PrPSc surrounded by vacuola formed florid plaques in cerebral cortex of cBSE-affected macaques. Deposit of PrPSc in L-type BSE-affected macaque was weak and diffuse synaptic pattern in cerebrum, but large PrPSc plaques were evident at cerebellum. MRI analysis, T2, T1, DW and flair sequences, at the time of autopsy revealed that brain atrophy and dilatation of cerebral ventricles were significantly severe in L-type BSE-affected macaques. These results suggest that L-type BSE is more virulent strain to primates comparing to cBSE.
 
SP1-4:
 
Evidence from Molecular Strain Typing
 
Gianluigi Zanusso Department of Neurological and Visual Sciences; Section of Clinical Neurology; University of Verona; Verona, Italy
 
Key words: molecular analysis, strain typing, atypical BSE, CJD
 
In 2001, active surveillance for bovine spongiform encephalopathy (BSE) led to the discovery of atypical BSE phenotypes in aged cattle distinct from classical BSE (C-type). These atypical BSE cases had been classified as low L-type (BASE) or high H-type BSE based on the molecular mass and the degree of glycosylation of of the pathological prion protein (PrPSc). Transmission studies in TgBov mice showed that H-type BSE, C-type BSE and BASE behave as distinct prion strains with different incubation periods, PrPSc molecular patterns and pathological phenotypes. A still unclear issue concerns the potential transmissibility and phenotypes of atypical BSEs in humans. We previously indicated that BASE was similar to a distinct subgroup of sporadic form of Creutzfeldt-Jakob disease (sCJD) MV2, based on molecular similarities and on neuropathological pattern of PrP deposition. To investigate a possible link between BASE and sCJD, Kong et al. and Comoy et al. experimentally inoculated TgHu mice (129MM) and a non-human primate respectively, showing in both models that BASE was more virulent compare to BSE. Further, non-human primate reproduced a clinical phenotype resembling to that of sCJD subtype MM2. Here, we presented a comparative analysis of the biochemical fingerprints of PrPSc between the different sCJD subtypes and animal TSEs and after experimental transmission to animals.
 



====UPDATED...TSS===


PO-028: Oral transmission of L-type bovine spongiform encephalopathy (L-BSE) in primate model Microcebus murinus

 Nadine Mestre-Frances,1 Simon Nicot,2 Sylvie Rouland,1 Anne-Gaëlle Biacabe,2 Isabelle Quadrio,3 Armand Perret-Liaudet,3 Thierry Baron,2 Jean-Michel Verdier1 1IN SER M UM2; Montpellier, France; 2Anses; Lyon, France; 3Hopitaux Civils de Lyon; Lyon, France

 An atypical form of bovine spongiform encephalopathy has been identified in cattle in Europe, North America and Japan and was designed as L-type BSE (L-BSE) due to the lower apparent molecular mass of the unglycosylated, protease-resistant prion protein (PrPres) detected by western blot compared with classical BSE. Experimental evidences from studies in transgenic mice expressing human PrP and in primate models suggest a higher risk of transmission to humans of the L-BSE form than for classical BSE agent. However, a major unresolved issue concerns the potential transmissibility of the L-BSE agent by oral route. To address this question, we infected mouse lemurs (Microcebus murinus), a non-human primate model, with L-BSE by intracerebral or oral route.

 Four adult lemurs were intracerebrally (IC) inoculated with 5mg of L-BSE infected brain homogenate of an atypical French BSE case (02-2528). Four young and four adult animals were fed with 5 mg or 50 mg of infected brain. After sacrifice, the brain tissues were biochemically and immunocytochemically investigated for PrPres.

 The 4 animals IC inoculated died at 19 and 22 months postinoculation (mpi). They developed blindness, tremor, abnormal posture, incoordinated movements, balance loss. Symptoms get worse according to the disease progression, until severe ataxia. Severe spongiosis was evidenced into the thalamus, the striatum, the mesencephalon, and the brainstem, whereas into the cortex the vacuolisation was weaker. Strong deposits of PrPres were detected into the thalamus, the striatum, and the hippocampus whereas in the cerebral cortex, PrPres was prominently accumulated in plaques.

 The orally inoculated animals showed similar clinical symptoms occurring between 27 and 34 mpi. Disease was characterized by progressive prostration, loss of appetite and poor appearance of the fur. Only one adult animal showed disequilibrium. PrPres was strongly accumulated only in the striatum and thalamus and weakly into the cortex. No plaques were evidenced. Two animals that were orally challenged at the age of two years are still alive and healthy 34 months after inoculation. The western blot analysis showed uniform molecular profiles, irrespective of the route or dose of infection, and included notably a PrPres form with low apparent molecular mass (~19 kDa) similar to the PrPres in the original cattle brain. However, the PrPres profile in lemurs was characterized by a higher proportion of di- and mono-glycosylated species (up to 95% of the total signal) than in the bovine L-BSE inoculum (~80%). In addition, small amounts of PrPres were detected by western blotting in the spleen of three animals (one intra-cerebrally inoculated and two fed with 5 mg of cattle brain).

 Here, we demonstrate that the L-BSE agent can be transmitted by oral route from cattle to young and adult mouse lemurs. In comparison to IC inoculated animals, orally challenged lemurs were characterized by longer survival periods as expected with this route of infection.

 

Opinion of the Scientific Steering Committee on the GEOGRAPHICAL RISK OF BOVINE SPONGIFORM ENCEPHALOPATHY (GBR) in POLAND Adopted on 30/03/2001
 
It is concluded that it is likely but not confirmed that one or several cattle that are (pre-clinically or clinically) infected with the BSE agent are currently present in the domestic herd of Poland (GBR III).
 
 
 
 Atypical BSE (BASE) Transmitted from Asymptomatic Aging Cattle to a Primate
 
Emmanuel E. Comoy1*, Cristina Casalone2, Nathalie Lescoutra-Etchegaray1, Gianluigi Zanusso3, Sophie Freire1, Dominique Marcé1, Frédéric Auvré1, Marie-Magdeleine Ruchoux1, Sergio Ferrari3, Salvatore Monaco3, Nicole Salès4, Maria Caramelli2, Philippe Leboulch1,5, Paul Brown1, Corinne I. Lasmézas4, Jean-Philippe Deslys1
 
1 Institute of Emerging Diseases and Innovative Therapies, CEA, Fontenay-aux-Roses, France, 2 Istituto Zooprofilattico Sperimentale del Piemonte, Turin, Italy, 3 Policlinico G.B. Rossi, Verona, Italy, 4 Scripps Florida, Jupiter, Florida, United States of America, 5 Genetics Division, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
 
Abstract Top Background Human variant Creutzfeldt-Jakob Disease (vCJD) results from foodborne transmission of prions from slaughtered cattle with classical Bovine Spongiform Encephalopathy (cBSE). Atypical forms of BSE, which remain mostly asymptomatic in aging cattle, were recently identified at slaughterhouses throughout Europe and North America, raising a question about human susceptibility to these new prion strains.
 
Methodology/Principal Findings Brain homogenates from cattle with classical BSE and atypical (BASE) infections were inoculated intracerebrally into cynomolgus monkeys (Macacca fascicularis), a non-human primate model previously demonstrated to be susceptible to the original strain of cBSE. The resulting diseases were compared in terms of clinical signs, histology and biochemistry of the abnormal prion protein (PrPres). The single monkey infected with BASE had a shorter survival, and a different clinical evolution, histopathology, and prion protein (PrPres) pattern than was observed for either classical BSE or vCJD-inoculated animals. Also, the biochemical signature of PrPres in the BASE-inoculated animal was found to have a higher proteinase K sensitivity of the octa-repeat region. We found the same biochemical signature in three of four human patients with sporadic CJD and an MM type 2 PrP genotype who lived in the same country as the infected bovine.
 
Conclusion/Significance Our results point to a possibly higher degree of pathogenicity of BASE than classical BSE in primates and also raise a question about a possible link to one uncommon subset of cases of apparently sporadic CJD. Thus, despite the waning epidemic of classical BSE, the occurrence of atypical strains should temper the urge to relax measures currently in place to protect public health from accidental contamination by BSE-contaminated products.
 
Citation: Comoy EE, Casalone C, Lescoutra-Etchegaray N, Zanusso G, Freire S, et al. (2008) Atypical BSE (BASE) Transmitted from Asymptomatic Aging Cattle to a Primate. PLoS ONE 3(8): e3017. doi:10.1371/journal.pone.0003017
 
Editor: Neil Mabbott, University of Edinburgh, United Kingdom
 
Received: April 24, 2008; Accepted: August 1, 2008; Published: August 20, 2008
 
Copyright: © 2008 Comoy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
 
Funding: This work has been supported by the Network of Excellence NeuroPrion.
 
Competing interests: CEA owns a patent covering the BSE diagnostic tests commercialized by the company Bio-Rad.
 
* E-mail: emmanuel.comoy@cea.fr
 
 
Session I - Prions: Structure, Strain and Detection (II)
 
Searching for BASE Strain Signature in Sporadic Creutzfedlt-Jakob Disease
 
Gianluigi Zanusso
 
Department of Neurological and Visual Sciences, Section of Clinical Neurology University of Verona, Verona, Italy.
 
Bovine amyloidotic spongiform encephalopathy (BASE) is a newly recognized form of bovine prion disease, which was originally detected in Italy in 2004 as an effect of active surveillance. BASE or BSE L-type (L is referred to the lower electrophoretic PrPSc migration than classical BSE) has now been reported in several countries, including Japan. All field cases of BASE were older than 8 years and neurologically normal at the time of slaughtered. By experimental transmission, we defined the disease phenotype of cattle BASE, which is quite distinct from that seen in typical BSE and characterized by mental dullness and amyotrophy. Surprisingly, following intraspecies and interspecies transmission the incubation period of BASE was shorter than BSE. The relatively easy transmission of BASE isolate as well as the molecular similarity with sporadic Creutzfeldt-Jakob disease (sCJD) have raised concern regarding its potential passage to humans. Tg humanized mice Met/Met at codon 129 challenged with both BSE and BASE isolates, showed a resistance to BSE but a susceptibility to BASE at a 60% rate; in addition, BASE-inoculated Cynomolgus (129 Met/Met) had shorter incubation periods than BSE-inoculated primates. In this study we compared the biochemical properties of PrPSc in Cynomolgus and in TgHu Met/Met mice challenged with BSE and BASE strains, by conventional SDS-PAGE analysis and 2D separation. The results obtained disclose distinct conformational changes in PrPSc, which are dependent on the inoculated host but not on the codon 129 genotype.
 
This work was supported by Neuroprion contract n. FOOD CT 2004 -506579 (NOE)
 
 
 WE know now, and we knew decades ago, that 5.5 grams of suspect feed in TEXAS was enough to kill 100 cows.
 
look at the table and you'll see that as little as 1 mg (or 0.001 gm) caused 7% (1 of 14) of the cows to come down with BSE;
 
Risk of oral infection with bovine spongiform encephalopathy agent in primates
 
Corinne Ida Lasmézas, Emmanuel Comoy, Stephen Hawkins, Christian Herzog, Franck Mouthon, Timm Konold, Frédéric Auvré, Evelyne Correia, Nathalie Lescoutra-Etchegaray, Nicole Salès, Gerald Wells, Paul Brown, Jean-Philippe Deslys Summary The uncertain extent of human exposure to bovine spongiform encephalopathy (BSE)--which can lead to variant Creutzfeldt-Jakob disease (vCJD)--is compounded by incomplete knowledge about the efficiency of oral infection and the magnitude of any bovine-to-human biological barrier to transmission. We therefore investigated oral transmission of BSE to non-human primates. We gave two macaques a 5 g oral dose of brain homogenate from a BSE-infected cow. One macaque developed vCJD-like neurological disease 60 months after exposure, whereas the other remained free of disease at 76 months. On the basis of these findings and data from other studies, we made a preliminary estimate of the food exposure risk for man, which provides additional assurance that existing public health measures can prevent transmission of BSE to man.
 
snip...
 
BSE bovine brain inoculum
 
100 g 10 g 5 g 1 g 100 mg 10 mg 1 mg 0·1 mg 0·01 mg
 
Primate (oral route)* 1/2 (50%)
 
Cattle (oral route)* 10/10 (100%) 7/9 (78%) 7/10 (70%) 3/15 (20%) 1/15 (7%) 1/15 (7%)
 
RIII mice (ic ip route)* 17/18 (94%) 15/17 (88%) 1/14 (7%)
 
PrPres biochemical detection
 
The comparison is made on the basis of calibration of the bovine inoculum used in our study with primates against a bovine brain inoculum with a similar PrPres concentration that was inoculated into mice and cattle.8 *Data are number of animals positive/number of animals surviving at the time of clinical onset of disease in the first positive animal (%). The accuracy of bioassays is generally judged to be about plus or minus 1 log. ic ip=intracerebral and intraperitoneal.
 
Table 1: Comparison of transmission rates in primates and cattle infected orally with similar BSE brain inocula
 
Published online January 27, 2005
 
 
 It is clear that the designing scientists must also have shared Mr Bradley’s surprise at the results because all the dose levels right down to 1 gram triggered infection.
 
 
 it is clear that the designing scientists must have also shared Mr Bradleyâs surprise at the results because all the dose levels right down to 1 gram triggered infection.
 
 
 OIE AND USDA OUT OF TOUCH WITH RISK FACTORS OF ATYPICAL TSE, AND PUT ALL COUNTRIES AT RISK WITH THIS JUNK SCIENCE
 
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.
 
 
“The U.S. has lower sanitary and phyto-sanitary standards (SPS) for imports than many other countries, especially those concerning bovine spongiform encephalopathy (BSE). These low standards have made the U.S. a dumping ground for beef from the countries that have experienced BSE problems. Food Safety and SPS issues continue to be problematic for our industry, as some countries comply with OIE standards, while others ignore them either for cultural reasons, or too often use them as trade barriers. The USITC October 7, 2008 release reported, ‘U.S. beef processors and beef cattle ranchers lose billions of dollars in export opportunities each year because of animal health and food safety measures in other countries that are inconsistent with international standards and vary by country.
 
 
 18.173 page 189
 
Experimental Challenge of Cattle with H-type and L-type Atypical BSE
 
A. Buschmann1, U. Ziegler1, M. Keller1, R. Rogers2, B. Hills3, M.H. Groschup1. 1Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany, 2Health Canada, Bureau of Microbial Hazards, Health Products & Food Branch, Ottawa, Canada, 3Health Canada, Transmissible Spongiform Encephalopathy Secretariat, Ottawa, Canada
 
Background: After the detection of two novel BSE forms designated H-type and L-type atypical BSE the question of the pathogenesis and the agent distribution of these two types in cattle was fully open. From initial studies of the brain pathology, it was already known that the anatomical distribution of L-type BSE differs from that of the classical type where the obex region in the brainstem always displays the highest PrPSc concentrations. In contrast in L-type BSE cases, the thalamus and frontal cortex regions showed the highest levels of the pathological prion protein, while the obex region was only weakly involved.
 
Methods:We performed intracranial inoculations of cattle (five and six per group) using 10%brainstemhomogenates of the two German H- and L-type atypical BSE isolates. The animals were inoculated under narcosis and then kept in a free-ranging stable under appropriate biosafety conditions.At least one animal per group was killed and sectioned in the preclinical stage and the remaining animals were kept until they developed clinical symptoms. The animals were examined for behavioural changes every four weeks throughout the experiment following a protocol that had been established during earlier BSE pathogenesis studies with classical BSE.
 
Results and Discussion: All animals of both groups developed clinical symptoms and had to be euthanized within 16 months. The clinical picture differed from that of classical BSE, as the earliest signs of illness were loss of body weight and depression. However, the animals later developed hind limb ataxia and hyperesthesia predominantly and the head. Analysis of brain samples from these animals confirmed the BSE infection and the atypical Western blot profile was maintained in all animals. Samples from these animals are now being examined in order to be able to describe the pathogenesis and agent distribution for these novel BSE types. Conclusions: A pilot study using a commercially avaialble BSE rapid test ELISA revealed an essential restriction of PrPSc to the central nervous system for both atypical BSE forms. A much more detailed analysis for PrPSc and infectivity is still ongoing.
 
 
 
 
 
P03.141
 
Aspects of the Cerebellar Neuropathology in Nor98
 
Gavier-Widén, D1; Benestad, SL2; Ottander, L1; Westergren, E1 1National Veterinary Insitute, Sweden; 2National Veterinary Institute,
 
Norway Nor98 is a prion disease of old sheep and goats. This atypical form of scrapie was first described in Norway in 1998. Several features of Nor98 were shown to be different from classical scrapie including the distribution of disease associated prion protein (PrPd) accumulation in the brain. The cerebellum is generally the most affected brain area in Nor98. The study here presented aimed at adding information on the neuropathology in the cerebellum of Nor98 naturally affected sheep of various genotypes in Sweden and Norway. A panel of histochemical and immunohistochemical (IHC) stainings such as IHC for PrPd, synaptophysin, glial fibrillary acidic protein, amyloid, and cell markers for phagocytic cells were conducted. The type of histological lesions and tissue reactions were evaluated. The types of PrPd deposition were characterized. The cerebellar cortex was regularly affected, even though there was a variation in the severity of the lesions from case to case. Neuropil vacuolation was more marked in the molecular layer, but affected also the granular cell layer. There was a loss of granule cells. Punctate deposition of PrPd was characteristic. It was morphologically and in distribution identical with that of synaptophysin, suggesting that PrPd accumulates in the synaptic structures. PrPd was also observed in the granule cell layer and in the white matter. The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.
 
***The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.
 
 
PR-26
 
NOR98 SHOWS MOLECULAR FEATURES REMINISCENT OF GSS
 
R. Nonno1, E. Esposito1, G. Vaccari1, E. Bandino2, M. Conte1, B. Chiappini1, S. Marcon1, M. Di Bari1, S.L. Benestad3, U. Agrimi1 1 Istituto Superiore di Sanità, Department of Food Safety and Veterinary Public Health, Rome, Italy (romolo.nonno@iss.it); 2 Istituto Zooprofilattico della Sardegna, Sassari, Italy; 3 National Veterinary Institute, Department of Pathology, Oslo, Norway
 
Molecular variants of PrPSc are being increasingly investigated in sheep scrapie and are generally referred to as "atypical" scrapie, as opposed to "classical scrapie". Among the atypical group, Nor98 seems to be the best identified. We studied the molecular properties of Italian and Norwegian Nor98 samples by WB analysis of brain homogenates, either untreated, digested with different concentrations of proteinase K, or subjected to enzymatic deglycosylation. The identity of PrP fragments was inferred by means of antibodies spanning the full PrP sequence. We found that undigested brain homogenates contain a Nor98-specific PrP fragment migrating at 11 kDa (PrP11), truncated at both the C-terminus and the N-terminus, and not N-glycosylated. After mild PK digestion, Nor98 displayed full-length PrP (FL-PrP) and N-glycosylated C-terminal fragments (CTF), along with increased levels of PrP11. Proteinase K digestion curves (0,006-6,4 mg/ml) showed that FL-PrP and CTF are mainly digested above 0,01 mg/ml, while PrP11 is not entirely digested even at the highest concentrations, similarly to PrP27-30 associated with classical scrapie. Above 0,2 mg/ml PK, most Nor98 samples showed only PrP11 and a fragment of 17 kDa with the same properties of PrP11, that was tentatively identified as a dimer of PrP11. Detergent solubility studies showed that PrP11 is insoluble in 2% sodium laurylsorcosine and is mainly produced from detergentsoluble, full-length PrPSc. Furthermore, among Italian scrapie isolates, we found that a sample with molecular and pathological properties consistent with Nor98 showed plaque-like deposits of PrPSc in the thalamus when the brain was analysed by PrPSc immunohistochemistry. Taken together, our results show that the distinctive pathological feature of Nor98 is a PrP fragment spanning amino acids ~ 90-155. This fragment is produced by successive N-terminal and C-terminal cleavages from a full-length and largely detergent-soluble PrPSc, is produced in vivo and is extremely resistant to PK digestion.
 
*** Intriguingly, these conclusions suggest that some pathological features of Nor98 are reminiscent of Gerstmann-Sträussler-Scheinker disease.
 
119
 
 
A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes
 
Annick Le Dur*,?, Vincent Béringue*,?, Olivier Andréoletti?, Fabienne Reine*, Thanh Lan Laï*, Thierry Baron§, Bjørn Bratberg¶, Jean-Luc Vilotte?, Pierre Sarradin**, Sylvie L. Benestad¶, and Hubert Laude*,?? +Author Affiliations
 
*Virologie Immunologie Moléculaires and ?Génétique Biochimique et Cytogénétique, Institut National de la Recherche Agronomique, 78350 Jouy-en-Josas, France; ?Unité Mixte de Recherche, Institut National de la Recherche Agronomique-Ecole Nationale Vétérinaire de Toulouse, Interactions Hôte Agent Pathogène, 31066 Toulouse, France; §Agence Française de Sécurité Sanitaire des Aliments, Unité Agents Transmissibles Non Conventionnels, 69364 Lyon, France; **Pathologie Infectieuse et Immunologie, Institut National de la Recherche Agronomique, 37380 Nouzilly, France; and ¶Department of Pathology, National Veterinary Institute, 0033 Oslo, Norway
 
***Edited by Stanley B. Prusiner, University of California, San Francisco, CA (received for review March 21, 2005)
 
Abstract Scrapie in small ruminants belongs to transmissible spongiform encephalopathies (TSEs), or prion diseases, a family of fatal neurodegenerative disorders that affect humans and animals and can transmit within and between species by ingestion or inoculation. Conversion of the host-encoded prion protein (PrP), normal cellular PrP (PrPc), into a misfolded form, abnormal PrP (PrPSc), plays a key role in TSE transmission and pathogenesis. The intensified surveillance of scrapie in the European Union, together with the improvement of PrPSc detection techniques, has led to the discovery of a growing number of so-called atypical scrapie cases. These include clinical Nor98 cases first identified in Norwegian sheep on the basis of unusual pathological and PrPSc molecular features and "cases" that produced discordant responses in the rapid tests currently applied to the large-scale random screening of slaughtered or fallen animals. Worryingly, a substantial proportion of such cases involved sheep with PrP genotypes known until now to confer natural resistance to conventional scrapie. 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.
 
 
Monday, December 1, 2008
 
When Atypical Scrapie cross species barriers
 
Authors
 
Andreoletti O., Herva M. H., Cassard H., Espinosa J. C., Lacroux C., Simon S., Padilla D., Benestad S. L., Lantier F., Schelcher F., Grassi J., Torres, J. M., UMR INRA ENVT 1225, Ecole Nationale Veterinaire de Toulouse.France; ICISA-INlA, Madrid, Spain; CEA, IBiTec-5, DSV, CEA/Saclay, Gif sur Yvette cedex, France; National Veterinary Institute, Postboks 750 Sentrum, 0106 Oslo, Norway, INRA IASP, Centre INRA de Tours, 3738O Nouzilly, France.
 
Content
 
Atypical scrapie is a TSE occurring in small ruminants and harbouring peculiar clinical, epidemiological and biochemical properties. Currently this form of disease is identified in a large number of countries. In this study we report the transmission of an atypical scrapie isolate through different species barriers as modeled by transgenic mice (Tg) expressing different species PRP sequence.
 
The donor isolate was collected in 1995 in a French commercial sheep flock. inoculation into AHQ/AHQ sheep induced a disease which had all neuro-pathological and biochemical characteristics of atypical scrapie. Transmitted into Transgenic mice expressing either ovine or PrPc, the isolate retained all the described characteristics of atypical scrapie.
 
*** Surprisingly the TSE agent characteristics were dramatically different v/hen passaged into Tg bovine mice. The recovered TSE agent had biological and biochemical characteristics similar to those of atypical BSE L in the same mouse model.
 
*** Moreover, whereas no other TSE agent than BSE were shown to transmit into Tg porcine mice, atypical scrapie was able to develop into this model, albeit with low attack rate on first passage.
 
*** Furthermore, after adaptation in the porcine mouse model this prion showed similar biological and biochemical characteristics than BSE adapted to this porcine mouse model. Altogether these data indicate.
 
*** (i) the unsuspected potential abilities of atypical scrapie to cross species barriers
 
*** (ii) the possible capacity of this agent to acquire new characteristics when crossing species barrier
 
*** These findings raise some interrogation on the concept of TSE strain and on the origin of the diversity of the TSE agents and could have consequences on field TSE control measures.
 
 
Friday, February 11, 2011
 
Atypical/Nor98 Scrapie Infectivity in Sheep Peripheral Tissues
 
 
 
 
 Monday, June 27, 2011
 
Comparison of Sheep Nor98 with Human Variably Protease-Sensitive Prionopathy and Gerstmann-Sträussler-Scheinker Disease
 
 
 Increased Atypical Scrapie Detections
 
Press reports indicate that increased surveillance is catching what otherwise would have been unreported findings of atypical scrapie in sheep. In 2009, five new cases have been reported in Quebec, Ontario, Alberta, and Saskatchewan. With the exception of Quebec, all cases have been diagnosed as being the atypical form found in older animals. Canada encourages producers to join its voluntary surveillance program in order to gain scrapie-free status. The World Animal Health will not classify Canada as scrapie-free until no new cases are reported for seven years. The Canadian Sheep Federation is calling on the government to fund a wider surveillance program in order to establish the level of prevalence prior to setting an eradication date. Besides long-term testing, industry is calling for a compensation program for farmers who report unusual deaths in their flocks.
 
 
Thursday, March 29, 2012
 
atypical Nor-98 Scrapie has spread from coast to coast in the USA 2012
 
NIAA Annual Conference April 11-14, 2011San Antonio, Texas
 
 
Monday, December 14, 2009
 
Similarities between Forms of Sheep Scrapie and Creutzfeldt-Jakob Disease Are Encoded by Distinct Prion Types
 
(hmmm, this is getting interesting now...TSS)
 
Sporadic CJD type 1 and atypical/ Nor98 scrapie are characterized by fine (reticular) deposits,
 
see also ;
 
All of the Heidenhain variants were of the methionine/ methionine type 1 molecular subtype.
 
 
see full text ;
 
Monday, December 14, 2009
 
Similarities between Forms of Sheep Scrapie and Creutzfeldt-Jakob Disease Are Encoded by Distinct Prion Types
 
 
 
From: xxxx
 
To: Terry Singeltary
 
Sent: Saturday, December 05, 2009 9:09 AM
 
Subject: 14th ICID - abstract accepted for 'International Scientific Exchange'
 
Your preliminary abstract number: 670
 
Dear Mr. Singeltary,
 
On behalf of the Scientific Committee, I am pleased to inform you that your abstract
 
'Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009'
 
WAS accepted for inclusion in the INTERNATIONAL SCIENTIFIC EXCHANGE (ISE) section of the 14th International Congress on Infectious Diseases. Accordingly, your abstract will be included in the "Intl. Scientific Exchange abstract CD-rom" of the Congress which will be distributed to all participants.
 
Abstracts accepted for INTERNATIONAL SCIENTIFIC EXCHANGE are NOT PRESENTED in the oral OR poster sessions.
 
Your abstract below was accepted for: INTERNATIONAL SCIENTIFIC EXCHANGE
 
#0670: Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009
 
Author: T. Singeltary; Bacliff, TX/US
 
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
 
page 114 ;
 
 
 
 
 
 Wednesday, February 24, 2010
 
Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America 14th
 
ICID International Scientific Exchange Brochure -
 
 
TSE
 
 
Atypical neuropathological sCJD-MM phenotype with abundant white matter Kuru-type plaques sparing the cerebellar cortex
 
Ellen Gelpi1,*, Josep Ma Soler Insa2, Piero Parchi8, Daniela Saverioni8, Jordi Yagüe3, Carlos Nos5, Elena Martínez- Saez6, Teresa Ribalta1,3, Isidre Ferrer7, Raquel Sanchez-Valle3,4
 
Article first published online: 5 AUG 2012
 
DOI: 10.1111/j.1440-1789.2012.01341.x
 
Keywords:
 
atypical sCJD; Kuru plaques; mixed PrP; molecular subtypes; white matter
 
We describe an atypical neuropatholgical phenotype of sporadic Creutzfeldt-Jakob disease (sCJD) in a 64-year-old man presenting with a 5-month history of rapidly progressive dementia, comprising behavioral disturbances, memory complaints, disorientation and language alterations. MRI showed diffuse atrophy and hyperintensities in parietal, occipital, temporal and frontal cortices and left caudate nucleus on T2-weighted and fluid-attenuated inversion recovery images. No typical EEG alterations were observed. Repeated 14-3-3 assay was positive after a first negative test. Neuropathology showed classical CJD changes with small cortical foci of large confluent vacuoles and relatively well-preserved cerebellar cortex. The most striking feature was the presence of abundant Kuru-type plaques in both cerebral cortex and subcortical white matter. Sparse Kuru-type plaques were also seen in cerebellum, although only in white matter. Immunohistochemistry showed, in addition to unicentric plaques, diffuse synaptic and patchy perivacuolar, as well as plaque-like and periaxonal pathological prion protein deposits (PrPres). Western blot studies demonstrated the co-occurrence of PrPres types 1 and 2 in frontal cortex and a relatively weak type 2 signal in cerebellum. PRNP genotyping revealed methionine homozygosity at codon 129 and excluded mutations. This case shows a previously undescribed combination of histopathological features which preclude its classification according to the current phenotypic and molecular sCJD classification. The observation demonstrates that Kuru-type amyloid plaques mainly involving the cerebral white matter may also occur in sCJD cases with short clinical course and the co-existence of PrPres types 1 and 2. This case further highlights the complexity of the correlations between histopathological phenotype and PrPres isotype in prion diseases.
 
 
Re: vCJD in the USA * BSE in U.S. 15 November 1999 Terry S Singeltary, NA
 
CWD is just a small piece of a very big puzzle. I have seen while deer hunting, deer, squirrels and birds, eating from cattle feed troughs where they feed cattle, the high protein cattle by products, at least up until Aug. 4, 1997. So why would it be so hard to believe that this is how they might become infected with a TSE. Or, even by potentially infected land. It's been well documented that it could be possible, from scrapie.
 
It was proven in Oprah Winfrey's trial, that Cactus Cattle feeders, sent neurologically ill cattle, some with encephalopathy stamped on the dead slips, were picked up and sent to the renders, along with sheep carcasses.
 
 
U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well...
 
2 January 2000 Terry S Singeltary
 
The exact same recipe for B.S.E. existed in the U.S. for years and years. In reading over the Qualitative Analysis of BSE Risk Factors-1, this is a 25 page report by the USDA:APHIS:VS. It could have been done in one page. The first page, fourth paragraph says it all;
 
"Similarities exist in the two countries usage of continuous rendering technology and the lack of usage of solvents, however, large differences still remain with other risk factors which greatly reduce the potential risk at the national level."
 
Then, the next 24 pages tries to down-play the high risks of B.S.E. in the U.S., with nothing more than the cattle to sheep ratio count, and the geographical locations of herds and flocks. That's all the evidence they can come up with, in the next 24 pages.
 
Something else I find odd, page 16;
 
"In the United Kingdom there is much concern for a specific continuous rendering technology which uses lower temperatures and accounts for 25 percent of total output. This technology was _originally_ designed and imported from the United States. However, the specific application in the production process is _believed_ to be different in the two countries."
 
A few more factors to consider, page 15;
 
"Figure 26 compares animal protein production for the two countries. The calculations are based on slaughter numbers, fallen stock estimates, and product yield coefficients. This approach is used due to variation of up to 80 percent from different reported sources. At 3.6 million tons, the United States produces 8 times more animal rendered product than the United Kingdom."
 
"The risk of introducing the BSE agent through sheep meat and bone meal is more acute in both relative and absolute terms in the United Kingdom (Figures 27 and 28). Note that sheep meat and bone meal accounts for 14 percent, or 61 thousand tons, in the United Kingdom versus 0.6 percent or 22 thousand tons in the United States. For sheep greater than 1 year, this is less than one-tenth of one percent of the United States supply."
 
"The potential risk of amplification of the BSE agent through cattle meat and bone meal is much greater in the United States where it accounts for 59 percent of total product or almost 5 times more than the total amount of rendered product in the United Kingdom."
 
Considering, it would only take _one_ scrapie infected sheep to contaminate the feed. Considering Scrapie has run rampant in the U.S. for years, as of Aug. 1999, 950 scrapie infected flocks. Also, Considering only one quarter spoonful of scrapie infected material is lethal to a cow. Considering all this, the sheep to cow ration is meaningless. As I said, it's 24 pages of B.S.e.
 
To be continued...
 
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA
 
Competing interests: None declared
 
 
Letters
 
JAMA. 2001;285(6):733-734. doi: 10.1001/jama.285.6.733
 
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
 
Terry S. Singeltary, Sr Bacliff, Tex
 
Since this article does not have an abstract, we have provided the first 150 words of the full text.
 
KEYWORDS: creutzfeldt-jakob disease, diagnosis. 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.
 
References 1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323.
 
 
Published March 26, 2003
 
RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States
 
Terry S. Singeltary, retired (medically)
 
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?
 
Published March 26, 2003
 
 
14th ICID International Scientific Exchange Brochure - Final Abstract Number: ISE.114
 
Session: International Scientific Exchange
 
Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009
 
T. Singeltary Bacliff, TX, USA
 
Background: An update on atypical BSE and other TSE in North America. Please remember, the typical U.K. c-BSE, the atypical l-BSE (BASE), and h-BSE have all been documented in North America, along with the typical scrapie's, and atypical Nor-98 Scrapie, and to date, 2 different strains of CWD, and also TME. All these TSE in different species have been rendered and fed to food producing animals for humans and animals in North America (TSE in cats and dogs ?), and that the trading of these TSEs via animals and products via the USA and Canada has been immense over the years, decades.
 
Methods: 12 years independent research of available data
 
Results: I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2009. With all the science to date refuting it, to continue to validate this old myth, will only spread this TSE agent through a multitude of potential routes and sources i.e. consumption, medical i.e., surgical, blood, dental, endoscopy, optical, nutritional supplements, cosmetics etc.
 
Conclusion: I would like to submit a review of past CJD surveillance in the USA, and the urgent need to make all human TSE in the USA a reportable disease, in every state, of every age group, and to make this mandatory immediately without further delay. The ramifications of not doing so will only allow this agent to spread further in the medical, dental, surgical arena's. Restricting the reporting of CJD and or any human TSE is NOT scientific. Iatrogenic CJD knows NO age group, TSE knows no boundaries. I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Gajdusek, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route.
 
 
The Lancet Infectious Diseases, Volume 3, Issue 8, Page 463, August 2003 doi:10.1016/S1473-3099(03)00715-1Cite or Link Using DOI
 
Tracking spongiform encephalopathies in North America
 
Original
 
Xavier Bosch
 
“My name is Terry S Singeltary Sr, and I live in Bacliff, Texas. I lost my mom to hvCJD (Heidenhain variant CJD) and have been searching for answers ever since. What I have found is that we have not been told the truth. CWD in deer and elk is a small portion of a much bigger problem.” 49-year—old Singeltary is one of a number of people who have remained largely unsatisfied after being told that a close relative died from a rapidly progressive dementia compatible with spontaneous Creutzfeldt—Jakob ...
 
 
 
SEE FULL TEXT ;
 
-------- Original Message --------
 
Subject: Tracking spongiform encephalopathies in North America LANCET INFECTIOUS DISEASE Volume 3, Number 8 01 August 2003
 
Date: Tue, 29 Jul 2003 17:35:30 –0500
 
From: "Terry S. Singeltary Sr." Reply-To: Bovine Spongiform Encephalopathy
 
To: BSE-L@uni-karlsruhe.de
 
Volume 3, Number 8 01 August 2003
 
Previous
 
Next
 
Newsdesk
 
Tracking spongiform encephalopathies in North America
 
Xavier Bosch
 
My name is Terry S Singeltary Sr, and I live in Bacliff, Texas. I lost my mom to hvCJD (Heidenhain variant CJD) and have been searching for answers ever since. What I have found is that we have not been told the truth. CWD in deer and elk is a small portion of a much bigger problem.
 
49-year-old Singeltary is one of a number of people who have remained largely unsatisfied after being told that a close relative died from a rapidly progressive dementia compatible with spontaneous Creutzfeldt-Jakob disease (CJD). So he decided to gather hundreds of documents on transmissible spongiform encephalopathies (TSE) and realised that if Britons could get variant CJD from bovine spongiform encephalopathy (BSE), Americans might get a similar disorder from chronic wasting disease (CWD)the relative of mad cow disease seen among deer and elk in the USA. Although his feverish search did not lead him to the smoking gun linking CWD to a similar disease in North American people, it did uncover a largely disappointing situation.
 
Singeltary was greatly demoralised at the few attempts to monitor the occurrence of CJD and CWD in the USA. Only a few states have made CJD reportable. Human and animal TSEs should be reportable nationwide and internationally, he complained in a letter to the Journal of the American Medical Association (JAMA 2003; 285: 733). I hope that the CDC does not continue to expect us to still believe that the 85% plus of all CJD cases which are sporadic are all spontaneous, without route or source.
 
Until recently, CWD was thought to be confined to the wild in a small region in Colorado. But since early 2002, it has been reported in other areas, including Wisconsin, South Dakota, and the Canadian province of Saskatchewan. Indeed, the occurrence of CWD in states that were not endemic previously increased concern about a widespread outbreak and possible transmission to people and cattle.
 
To date, experimental studies have proven that the CWD agent can be transmitted to cattle by intracerebral inoculation and that it can cross the mucous membranes of the digestive tract to initiate infection in lymphoid tissue before invasion of the central nervous system. Yet the plausibility of CWD spreading to people has remained elusive.
 
Part of the problem seems to stem from the US surveillance system. CJD is only reported in those areas known to be endemic foci of CWD. Moreover, US authorities have been criticised for not having performed enough prionic tests in farm deer and elk.
 
Although in November last year the US Food and Drug Administration issued a directive to state public-health and agriculture officials prohibiting material from CWD-positive animals from being used as an ingredient in feed for any animal species, epidemiological control and research in the USA has been quite different from the situation in the UK and Europe regarding BSE.
 
Getting data on TSEs in the USA from the government is like pulling teeth, Singeltary argues. You get it when they want you to have it, and only what they want you to have.
 
Norman Foster, director of the Cognitive Disorders Clinic at the University of Michigan (Ann Arbor, MI, USA), says that current surveillance of prion disease in people in the USA is inadequate to detect whether CWD is occurring in human beings; adding that, the cases that we know about are reassuring, because they do not suggest the appearance of a new variant of CJD in the USA or atypical features in patients that might be exposed to CWD. However, until we establish a system that identifies and analyses a high proportion of suspected prion disease cases we will not know for sure. The USA should develop a system modelled on that established in the UK, he points out.
 
Ali Samii, a neurologist at Seattle VA Medical Center who recently reported the cases of three hunterstwo of whom were friendswho died from pathologically confirmed CJD, says that at present there are insufficient data to claim transmission of CWD into humans; adding that [only] by asking [the questions of venison consumption and deer/elk hunting] in every case can we collect suspect cases and look into the plausibility of transmission further. Samii argues that by making both doctors and hunters more aware of the possibility of prions spreading through eating venison, doctors treating hunters with dementia can consider a possible prion disease, and doctors treating CJD patients will know to ask whether they ate venison.
 
CDC spokesman Ermias Belay says that the CDC will not be investigating the [Samii] cases because there is no evidence that the men ate CWD-infected meat. He notes that although the likelihood of CWD jumping the species barrier to infect humans cannot be ruled out 100% and that [we] cannot be 100% sure that CWD does not exist in humans& the data seeking evidence of CWD transmission to humans have been very limited.
 
 
LANCET SINGELTARY ET AL CWD TSE PRION NORTH AMERICA
 
 
Singeltary submission to PLOS ;
 
No competing interests declared.
 
see full text ;
 
 
CANADA SEE STEADY INCREASE OF THE SPORADIC CJD’S AND THE VPSPR’S (sporadic CJD’s). ...tss
 
PLEASE NOTE, type determination pending Creutzfeldt Jakob Disease (tdpCJD) in Canada is also on a steady increase.
 
please see ;
 
> 3. Final classification of 50 cases from 2009, 2010, 2011 and 2012 is pending.
 
CJD Deaths Reported by CJDSS1, 1994-20122
 
CJD Deaths Reported by CJDSS1, 1994-20122
 
As of May 31, 2012
 
 
 
SEE DECEMBER 2012 CANADA
 
 
USA SEE STEADY INCREASE OF THE SPORADIC CJD’S AND THE VPSPR’S (sporadic CJD’s). ...tss
 
National Prion Disease Pathology Surveillance Center
 
Cases Examined1
 
(May 18, 2012)
 
5 Includes 14 cases in which the diagnosis is pending, and 18 inconclusive cases;
 
6 Includes 17 (16 from 2012) cases with type determination pending in which the diagnosis of vCJD has been excluded. The Sporadic cases include 16 cases of sporadic Fatal Insomnia (sFI) and 42 cases of Variably Protease-Sensitive Prionopathy (VPSPr) and 2118 cases of sporadic Creutzfeldt-Jakob disease (sCJD).
 
Rev 5/18/2012
 
 
> 6 Includes
 
> 17 (16 from 2012) cases with type determination pending in which the diagnosis of vCJD has been excluded.
 
> The Sporadic cases include 16 cases of sporadic Fatal Insomnia (sFI) and 42 cases of Variably Protease-Sensitive Prionopathy (VPSPr) and 2118 cases of sporadic Creutzfeldt-Jakob disease (sCJD).
 
WELL, it seems the USA mad cow strains in humans classified as type determination pending tdpCJD, VPSPr, sFFI, and sCJD) have steadily increased over the years, and the same old song and dance continues with sporadic CJD cases $$$
 
 
Creutzfeldt-Jakob Disease CJD cases rising North America updated report August 2013
 
*** Creutzfeldt-Jakob Disease CJD cases rising North America with Canada seeing an extreme increase of 48% between 2008 and 2010 ***
 
 
Sunday, October 13, 2013
 
*** CJD TSE Prion Disease Cases in Texas by Year, 2003-2012
 
 
Sunday, March 09, 2014
 
A Creutzfeldt-Jakob Disease (CJD) Lookback Study: Assessing the Risk of Blood Borne Transmission of Classic Forms of Creutzfeldt-Jakob Disease
 
FDA TSEAC CIRCUS AND TRAVELING ROAD SHOW FOR THE TSE PRION DISEASES
 
 
 
Wednesday, October 09, 2013
 
*** WHY THE UKBSEnvCJD ONLY THEORY IS SO POPULAR IN IT'S FALLACY, £41,078,281 in compensation REVISED ***
 
 
 
CJD...Straight talk with...James Ironside...and...Terry Singeltary... 2009
 
 
 
Tuesday, August 18, 2009
 
* BSE-The Untold Story - joe gibbs and singeltary 1999 - 2009
 
 
 
TSS

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