Volume 13, Number 12–December 2007
Phenotypic Similarity of Transmissible Mink Encephalopathy in Cattle and L-type Bovine Spongiform Encephalopathy in a Mouse Model
Thierry Baron,* Anna Bencsik,* Anne-Gaëlle Biacabe,* Eric Morignat,* andRichard A. Bessen†*Agence Française de Sécurité Sanitaire des Aliments–Lyon, Lyon, France; and†Montana State University, Bozeman, Montana, USA
Transmissible mink encepholapathy (TME) is a foodborne transmissiblespongiform encephalopathy (TSE) of ranch-raised mink; infection with aruminant TSE has been proposed as the cause, but the precise origin of TMEis unknown. To compare the phenotypes of each TSE, bovine-passaged TMEisolate and 3 distinct natural bovine spongiform encephalopathy (BSE) agents(typical BSE, H-type BSE, and L-type BSE) were inoculated into an ovinetransgenic mouse line (TgOvPrP4). Transgenic mice were susceptible toinfection with bovine-passaged TME, typical BSE, and L-type BSE but not toH-type BSE. Based on survival periods, brain lesions profiles,disease-associated prion protein brain distribution, and biochemicalproperties of protease-resistant prion protein, typical BSE had a distintphenotype in ovine transgenic mice compared to L-type BSE and bovine TME.The similar phenotypic properties of L-type BSE and bovine TME in TgOvPrP4mice suggest that L-type BSE is a much more likely candidate for the originof TME than is typical BSE.
These studies provide experimental evidence that the Stetsonville TME agentis distinct from typical BSE but has phenotypic similarities to L-type BSEin TgOvPrP4 mice. Our conclusion is that L-type BSE is a more likelycandidate for a bovine source of TME infection than typical BSE. In thescenario that a ruminant TSE is the source for TME infection in mink, thiswould be a second example of transmission of a TSE from ruminants tonon-ruminants under natural conditions or farming practices in addition totransmission of typical BSE to humans, domestic cats, and exotic zoo animals(37). The potential importance of this finding is relevant to L-type BSE,which based on experimental transmission into humanized PrP transgenic miceand macaques, suggests that L-type BSE is more pathogenic for humans thantypical BSE (24,38).
J. Biol. Chem., Vol. 282, Issue 49, 35878-35886, December 7, 2007
High Titers of Transmissible Spongiform Encephalopathy InfectivityAssociated with Extremely Low Levels of PrPSc in Vivo*
Rona M. Barron12, Susan L. Campbell13, Declan King, Anne Bellon, Karen E.Chapman¶, R. Anthony Williamson, and Jean C. MansonFrom the Neuropathogenesis Unit, Roslin Institute, Ogston Building, WestMains Road, Edinburgh EH9 3JF, Scotland, United Kingdom, the Department ofImmunology, Scripps Research Institute, La Jolla, California 92037, and the¶Centre for Cardiovascular Sciences, Queen's Medical Research Institute,University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ,Scotland, United Kingdom
Diagnosis of transmissible spongiform encephalopathy (TSE) disease in humansand ruminants relies on the detection in post-mortem brain tissue of theprotease-resistant form of the host glycoprotein PrP. The presence of thisabnormal isoform (PrPSc) in tissues is taken as indicative of the presenceof TSE infectivity. Here we demonstrate conclusively that high titers of TSEinfectivity can be present in brain tissue of animals that show clinical andvacuolar signs of TSE disease but contain low or undetectable levels ofPrPSc. This work questions the correlation between PrPSc level and the titerof infectivity and shows that tissues containing little or no proteinaseK-resistant PrP can be infectious and harbor high titers of TSE infectivity.Reliance on protease-resistant PrPSc as a sole measure of infectivity maytherefore in some instances significantly underestimate biologicalproperties of diagnostic samples, thereby undermining efforts to contain anderadicate TSEs.
Received for publication, May 25, 2007 , and in revised form, September 24,2007.
* This work was supported by United Kingdom Department for Environment,Food, and Rural Affairs Grant SE1437. The costs of publication of thisarticle were defrayed in part by the payment of page charges. This articlemust therefore be hereby marked "advertisement" in accordance with 18 U.S.C.Section 1734 solely to indicate this fact.
The on-line version of this article (available at http://www.jbc.org )contains supplemental Figs. S1–S3 and Table S1.
1 Both authors contributed equally to this work.
3 Current address: Medical Research Council Clinical Sciences Centre,Imperial College, Hammersmith Campus, Du Cane Road, London W12 0NN, UnitedKingdom.
2 To whom correspondence should be addressed. Tel.: 44-131-667-5204; Fax:44-131-668-3872; E-mail: firstname.lastname@example.org .
Transmissible Mink Encephalopathy TMESubject: In Confidence - Perceptions of unconventional slow virus diseasesof animals in the USA - APRIL-MAY 1989 - G A H Wells
Gerald Wells: Report of the Visit to USA, April-May 1989
The general opinion of those present was that BSE, as anovert disease phenomenon, _could exist in the USA, but if it did,it was very rare. The need for improved and specific surveillancemethods to detect it as recognised...
It is clear that USDA have little information and _no_ regulatoryresponsibility for rendering plants in the US...
3. Prof. A. Robertson gave a brief account of BSE. The US approachwas to accord it a _very low profile indeed_. Dr. A Thiermann showedthe picture in the ''Independent'' with cattle being incinerated and thoughtthis was a fanatical incident to be _avoided_ in the US _at all costs_...
snip...please read this old full text document !
To be published in the Proceedings of theFourth International Scientific Congress inFur Animal Production. Toronto, Canada,August 21-28, 1988
Evidence That Transmissible Mink EncephalopathyResults from Feeding Infected Cattle
R.F. Marsh* and G.R. Hartsough
•Department of Veterinary Science, University of Wisconsin-Madison, Madison,Wisconsin 53706; and ^Emba/Creat Lakes Ranch Service, Thiensville, Wisconsin53092
ABSTRACTEpidemiologic investigation of a new incidence oftransmissible mink encephalopathy (TME) in Stetsonville, Wisconsinsuggests that the disease may have resulted from feeding infectedcattle to mink. This observation is supported by the transmission ofa TME-like disease to experimentally inoculated cattle, and by therecent report of a new bovine spongiform encephalopathy inEngland.
Transmissible mink encephalopathy (TME) was first reported in 1965 by Hartsoughand Burger who demonstrated that the disease was transmissible with a long incubationperiod, and that affected mink had a spongiform encephalopathy similar to that found inscrapie-affecied sheep (Hartsough and Burger, 1965; Burger and Hartsough, 1965).Because of the similarity between TME and scrapie, and the subsequent finding that thetwo transmissible agents were indistinguishable (Marsh and Hanson, 1969), it wasconcluded that TME most likely resulted from feeding mink scrapie-infecied sheep.The experimental transmission of sheep scrapie to mink (Hanson et al., 1971)confirmed the close association of TME and scrapie, but at the same time providedevidence that they may be different. Epidemiologic studies on previous incidences ofTME indicated that the incubation periods in field cases were between six months andone year in length (Harxsough and Burger, 1965). Experimentally, scrapie could not betransmitted to mink in less than one year.To investigate the possibility that TME may be caused by a (particular strain ofscrapie which might be highly pathogenic for mink, 21 different strains of the scrapieagent, including their sheep or goat sources, were inoculated into a total of 61 mink.Only one mink developed a progressive neurologic disease after an incubation period of22 mon..s (Marsh and Hanson, 1979). These results indicated that TME was either causedby a strain of sheep scrapie not yet tested, or was due to exposure to a scrapie-like agentfrom an unidentified source.
OBSERVATIONS AND RESULTS
A New Incidence of TME. In April of 1985, a mink rancher in Stetsonville, Wisconsinreported that many of his mink were "acting funny", and some had died. At this time, wevisited the farm and found that approximately 10% of all adult mink were showingtypical signs of TME: insidious onset characterized by subtle behavioral changes, loss ofnormal habits of cleanliness, deposition of droppings throughout the pen rather than in asingle area, hyperexcitability, difficulty in chewing and swallowing, and tails arched overtheir _backs like squirrels. These signs were followed by progressive deterioration ofneurologic function beginning with locomoior incoordination, long periods of somnolencein which the affected mink would stand motionless with its head in the corner of thecage, complete debilitation, and death. Over the next 8-10 weeks, approximately 40% ofall the adult mink on the farm died from TME.Since previous incidences of TME were associated with common or shared feedingpractices, we obtained a careful history of feed ingredients used over the past 12-18months. The rancher was a "dead stock" feeder using mostly (>95%) downer or dead dairycattle and a few horses. Sheep had never been fed.
Experimental Transmission. The clinical diagnosis of TME was confirmed byhistopaihologic examination and by experimental transmission to mink after incubationperiods of four months. To investigate the possible involvement of cattle in this diseasecycle, two six-week old castrated Holstein bull calves were inoculated intracerebrallywith a brain suspension from affected mink. Each developed a fatal spongiformencephalopathy after incubation periods of 18 and 19 months.
These findings suggest that TME may result from feeding mink infected cattle andwe have alerted bovine practitioners that there may exist an as yet unrecognizedscrapie-like disease of cattle in the United States (Marsh and Hartsough, 1986). A newbovine spongiform encephalopathy has recently been reported in England (Wells et al.,1987), and investigators are presently studying its transmissibility and possiblerelationship to scrapie. Because this new bovine disease in England is characterized bybehavioral changes, hyperexcitability, and agressiveness, it is very likely it would beconfused with rabies in the United Stales and not be diagnosed. Presently, brains fromcattle in the United States which are suspected of rabies infection are only tested withanti-rabies virus antibody and are not examined histopathologically for lesions ofspongiform encephalopathy.We are presently pursuing additional studies to further examine the possibleinvolvement of cattle in the epidemiology of TME. One of these is the backpassage ofour experimental bovine encephalopathy to mink. Because (here are as yet no agent-specific proteins or nucleic acids identified for these transmissible neuropathogens, onemeans of distinguishing them is by animal passage and selection of the biotype whichgrows best in a particular host. This procedure has been used to separate hamster-adapted and mink-udapted TME agents (Marsh and Hanson, 1979). The intracerebralbackpassage of the experimental bovine agent resulted in incubations of only four monthsindicating no de-adaptation of the Stetsonville agent for mink after bovine passage.Mink fed infected bovine brain remain normal after six months. It will be essential todemonstrate oral transmission fiom bovine to mink it this proposed epidemiologicassociation is to be confirmed.
These studies were supported by the College of Agricultural and Life Sciences,University of Wisconsin-Madison and by a grant (85-CRCR-1-1812) from the UnitedStates Department of Agriculture. The authors also wish to acknowledge the help andencouragement of Robert Hanson who died during the course of theseinvestigations.
Burger, D. and Hartsough, G.R. 1965. Encephalopathy of mink. II.Experimental andnatural transmission. J. Infec. Dis. 115:393-399.Hanson, R.P., Eckroade, R.3., Marsh, R.F., ZuRhein, C.M., Kanitz, C.L. andGustatson,D.P. 1971. Susceptibility of mink to sheep scrapie. Science 172:859-861.Hansough, G.R. and Burger, D. 1965. Encephalopathy of mink. I.Epizoociologic andclinical observations. 3. Infec. Dis. 115:387-392.Marsh, R.F. and Hanson, R.P. 1969. Physical and chemical properties of thetransmissible mink encephalopathy agent. 3. ViroL 3:176-180.Marsh, R.F. and Hanson, R.P. 1979. On the origin of transmissible minkencephalopathy. In Hadlow, W.J. and Prusiner, S.P. (eds.) Slow transmissiblediseases of the nervous system. Vol. 1, Academic Press, New York, pp451-460.Marsh, R.F. and Hartsough, G.R. 1986. Is there a scrapie-like disease incattle?Proceedings of the Seventh Annual Western Conference for Food AnimalVeterinaryMedicine. University of Arizona, pp 20.Wells, G.A.H., Scott, A.C., Johnson, C.T., Cunning, R.F., Hancock, R.D.,Jeffrey, M.,Dawson, M. and Bradley, R. 1987. A novel progressive spongiformencephalopathyin cattle. Vet. Rec. 121:419-420.
In Confidence - Perceptions of unconventional slow virus diseasesof animals in the USA - APRIL-MAY 1989 - G A H Wells
SEE FULL TEXT TME
TME hyper/drowsy, INTER-SPECIES TRANSMISSION CWD and strain properties
NOR-98 ATYPICAL SCRAPIE USA UPDATE AS AT OCT 2007
ABSTRACTS SPORADIC CJD AND H BASE MAD COW ALABAMA AND TEXAS SEPTEMBER 2007Date: Mon, 24 Sep 2007 21:31:55 -0500
I suggest that you all read the data out about h-BASE and sporadic CJD,GSS,blood, and some of the other abstracts from the PRION2007. ...
*** PLEASE READ AND UNDERSTAND THE RAMIFICATIONS OF THIS !!!THE PRICE OF POKER INDEED GOES UP. ...TSS
USA BASE CASE, (ATYPICAL BSE), AND OR TSE (whatever they are calling ittoday), please note that both the ALABAMA COW, AND THE TEXAS COW, bothwere''H-TYPE'', personal communication Detwiler et al Wednesday, August 22,200711:52 PM. ...TSS
see full text 143 pages ;
full text ;
****** USA: National Prion Disease Pathology Surveillance CenterDate: June 2007Source: National Prion Disease Pathology Surveillance Center (USA) [edited]< http://www.cjdsurveillance.com/pdf/case-table.pdf >
CJD Cases examined----------------------Year / Referrals / Prion disease / Sporadic / Familial / Iatrogenic / vCJD
1996 / 42 / 32 / 26 / 4 / 0 / 01997 / 115 / 68 / 57 / 9 / 0 / 01998 / 93 / 53 / 45 / 7 / 1 / 01999 / 114 / 69 / 61 / 8 / 0 / 02000 / 151 / 103 / 89 / 14 / 0 / 02001 / 208 / 116 / 106 / 9 / 0 / 02002 / 255 / 143 / 118 / 23 / 2 / 02003 / 272 / 174 / 132 / 41 / 0 / 02004 / 334 / 183 / 157 / 21 / 0 / 1*2005 / 352 / 195 / 152 / 37 / 1 / 02006 / 372 / 186 / 143 / 30 / 0 / 1**2007 / 120 / 68 / 35 / 7 / 0 / 0TOTAL / 2428*** / 1390**** / 1121 / 210 / 4 / 2
*Acquired in UK** Acquired in Saudi Arabia*** Includes 17 inconclusive and 9 pending (1 from 2006, 8 from 2007.**** Includes 17 non-vCJD type unknown (2 from 1996, 2 from 1997, 1from 2001, 1 from 2003, 4 from 2004, 3 from 2005, 4 from 2006) and 36type pending (2 from 2005, 8 from 2006, 26 from 2007).
-- Cases are listed based on the year of death when available. If theyear of death is not available, the year of sample receipt is used.
-- Referrals: Cases with possible or probable prion disease fromwhich brain tissue or blood in the case of familial disease were submitted.
-- Inconclusive: Cases in which the samples were not sufficient tomake a diagnosis.
-- Non-vCJD type unknown are cases in which the tissue submitted wasadequate to establish the presence but not the type; in all cases,vCJD could be excluded.
--Communicated by:Terry S. Singeltary Sr. < email@example.com >
[In submitting these data, Terry S. Singeltary Sr. draws attention tothe steady increase in the "type unknown" category, which, accordingto their definition, comprises cases in which vCJD could be excluded.The total of 26 cases for the current year (2007) is disturbing,possibly symptomatic of the circulation of novel agents.Characterization of these agents should be given a high priority. - Mod.CP]
************************************************************Become a ProMED-mail Premium Subscriber at< http://www.isid.org/ProMEDMail_Premium.shtml >************************************************************Visit ProMED-mail's web site at < http://www.promedmail.org >.
SEE STEADY INCREASE IN SPORADIC CJD IN THE USA FROM1997 TO 2006. SPORADIC CJD CASES TRIPLED, with phenotypeof 'UNKNOWN' strain growing. ...
There is a growing number of human CJD cases, and they were presented lastweek in San Francisco by Luigi Gambatti(?) from his CJD surveillancecollection.
He estimates that it may be up to 14 or 15 persons which display selectivelySPRPSC and practically no detected RPRPSC proteins.
PLEASE NOTE IN USA CJD UPDATE AS AT JUNE 2007, please note steady increasein ''TYPE UNKNOWN''. ...TSS
1 Acquired in the United Kingdom; 2 Acquired in Saudi Arabia; 3 Includes 17inconclusive and 9 pending (1 from 2006, 8from 2007); 4 Includes 17 non-vCJD type unknown (2 from 1996, 2 from 1997, 1from 2001, 1 from 2003, 4 from 2004, 3from 2005, 4 from 2006) and 36 type pending (2 from 2005, 8 from 2006,
*** 26 from 2007)
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Singeltary, Sr et al. JAMA.2001; 285: 733-734.
JOURNAL OF NEUROLOGY
MARCH 26, 2003
RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob
disease in the United States
Email Terry S. Singeltary
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  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?
doi:10.1016/S1473-3099(03)00715-1Copyright © 2003 Published by Elsevier Ltd.Newsdesk
Tracking spongiform encephalopathies in North America
Available online 29 July 2003.
Volume 3, Issue 8, August 2003, Page 463
“My name is Terry S Singeltary Sr, and I live in Bacliff, Texas. I lost mymom to hvCJD (Heidenhain variant CJD)and have been searching for answers ever since. What I have found is that wehave not been told the truth. CWDin deer and elk is a small portion of a much bigger problem.”............................
see history of cjd questionnaire
Sent: Monday May 28, 2007
Subject: THE BIG LIE SPORADIC CJD AND MAD COW DISEASEs i.e. TSE
Subject: HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and theUKBSEnvCJD only theoryDate: January 29, 2006 at 9:03 am PST
Comments sent via JAMA Feedback Page------------------------------------------------------------NAME: Terry S. Singeltary Sr.E-MAIL: firstname.lastname@example.org IP ADDRESS: xxxxxxxxHOSTNAME: xxxxxxxxPREVIOUS PAGE: http://jama.ama-assn.org/misc/authors.dtl BROWSER: Mozilla/5.0 (Windows; U; Win98; en-US; rv:1.0.2) Gecko/20030208Netscape/7.02PROMOTIONAL USE: (not answered)
HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJDonly theory
TSEs have been rampant in the USA for decades in many species, and they allhave been rendered and fed back to animals for human/animal consumption.propose that the current diagnostic criteria for human TSEs only enhancesand helps the spreading of human TSE from the continued belief of theUKBSEnvCJD only theory in 2007. With all the science to date refuting it, tocontinue to validate this myth, will only spread this TSE agent through amultitude of potential routes and sources i.e. consumption, surgical, blood,medical, cosmetics etc. I propose as with Aguzzi, Asante, Collinge, Caughey,Deslys, Dormont, Gibbs, Ironside, Manuelidis, Marsh, et al and many more,that the world of TSE Transmissible Spongiform Encephalopathy is far from anexact science, but there is enough provenscience to date that this myth should be put to rest once and for all, andthat we move forward with a new classification for human and animal TSE thatwould properly identify the infected species, the source species, and thenthe route.
This would further have to be broken down to strain of species and then theroute of transmission would further have to be broken down. Accumulation andTransmission are key to the threshold from sub-clinical to clinical disease,and key to all this, is to stop the amplification and transmission of thisagent, the spreading of, no matter what strain. In my opinion, to continuewith this myth that the U.K. strain of BSE (one strain TSE in cows), and thenv/v CJD (one strain TSE humans) and that all the rest of human TSE are justone single strain i.e. sporadic CJD (when to date there are 6 differentphenotypes of sCJD, and growing per Gambetti et al), and that no otheranimal TSE transmits to humans, to continue with this masquerade will onlycontinue to spread, expose, and kill, who knows how many more in the yearsand decades to come. ONE was enough for me, My Mom, hvCJD i.e. HeidenhainVariant CJD, DOD 12/14/97 confirmed, which is nothing more than another mansname added to CJD, like CJD itself, Jakob and Creutzfeldt, orGerstmann-Straussler-Scheinker syndrome, just another CJD or human TSE,named after another human.
WE are only kidding ourselves with the current diagnostic criteria for humanand animal TSE, especially differentiating between the nvCJD vs the sporadicCJDstrains and then the GSS strains and also the FFI fatal familial insomniastrains or the ones that mimics one or the other of those TSE? Tissueinfectivity and strain typing of the many variants of the human and animalTSEs are paramount in all variants of all TSE. There must be a properclassification that will differentiate between all these human TSE in orderto do this. With the CDI and other more sensitive testing coming about, Ionly hope that my proposal will some day be taken seriously. ...
Terry S. Singeltary Sr.P.O. Box 42Bacliff, Texas USA 77518 email@example.com
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease inthe United States
i am reminded of a few things deep throat (high ranking official at usda)told me years ago;
The most frightening thing I have read all day is thereport of Gambetti's finding of a new strain ofsporadic cjd in young people.........Dear God,