MAD COW DISEASE

We all watch for mad cow disease, and any possibility that it has entered the U.S. food supply is front page news. But few people I speak to are as worried about chronic wasting disease (CWD), despite the fact that it is epidemic in the deer populations in the U.S. Even fewer people understand scrapie, which is epidemic in the goat and sheep populations. No one has heard about transmissible mink encephalopathy (TME), which has been in the U.S. since 1993. All we're worried about is mad cow, or bovine spongiform encephalopathy (BSE), because we know that can be transmitted to humans. Evidently, we are immune to the other illnesses because we have a species barrier, a magic genetic shield that keeps the bad prions out.

Prion diseases are very scary, because they cause brain wasting and are incurable. You only know you've got the disease years after you were infected, and at that point modern medicine doesn't have anything that can help. So the big goal is not to become infected.

Let me say at the outset that I recently attended a CDC infectious disease meeting in which I heard that neither sheep scrapie nor deer CWD can infect humans, but that we are monitoring the situation. Yesterday I had a patient tell me she got scrapie while farming goats. She said that the symptoms went away and were a lot like a herpes outbreak, but that she had gotten them right after immunizing her goats against scrapie. So to those who might say I have an axe to grind in this research, I would reply that my only interest is in finding the truth.

I am certain that infectious disease experts will howl when I say that these diseases all look like the same disease to me. I did not come to that idea from looking at the symptoms, but by looking at the way the disease can cross-infect different species with the same symptoms. Yes, they bear certain distinctions and genetic variations dependent on the particular species, but let us examine the cross-infection possibilities.

Sheep and goats can cross-infect each other with scrapie, and lambs can get scrapie from their mothers. Cattle, if injected, get scrapie. Sheep get mad cow BSE from injections of cow brain tissue (some sheep are resistant, more on this later). Mink got mink TME from eating downer cattle. When mink TME was injected back into cows, they developed mad cow. Sheep and goats also get mink TME when injected with it, with symptoms almost identical to scrapie. Cattle, sheep and goats injected with deer CWD brain tissue all develop deer CWD, which gives them symptoms similar to mad cow BSE and scrapie. So a sheep can get scrapie, mad cow BSE, mink TME, and deer CWD with pretty much the same symptoms. I'm going to keep using all the letters for the scientists out there, but for the non-scientist they all potentially mean "mad cow."

That mink TME is actually from mad cow BSE cattle is pretty clearly established, which means (oops!) "an unrecognized BSE-like disease in the United States" back in 1993. (Dev Biol Stand. 1993;80:111-8) I'm sure conspiracy theorists are going to go nuts with that information, particularly as it puts all the blame on Clinton. That BSE and CWD are just minor variations of scrapie (which has been around for hundreds of years) is a bit more of a stretch, but for the non-laboratory types the important thing is the disease can cross-infect different species. There are different incubation times until symptoms appear, but the results are the same.

What about different species? Raccoons get both mink TME and sheep scrapie, although scrapie takes longer to give symptoms. Rats and hamsters get scrapie. When six different species of animals infected with mad cow BSE had their brain material injected into mice, the mice produced almost the same symptoms.

For those of you who don't care about other species, the data don't look good for people. Deer CWD prions can alter human brain proteins in the laboratory. Everyone knows we can get mad cow BSE, which produces a variant of human Creutzfeldt-Jakob disease. When squirrel monkeys ate food infected with human Creutzfeldt-Jakob disease tissue or with sheep scrapie tissue, almost all developed similar neurological symptoms within three years. In other words, their brains reacted the same to the human disease and the sheep disease, even though officially these are two very different diseases. (Can I hear the price of mutton plummeting on the stock exchange?)

So the question of the hour is: why aren't we all dying from sheep scrapie? One enterprising researcher tracked down the fact that humans have a genetic variation that would make us the equivalent of scrapie-resistant sheep.

Someone high up has connected the dots and realized that sheep that get scrapie are sheep that can get mad cow BSE. The European Union has just put into place an agricultural initiative to breed only scrapie-resistant sheep, probably for this reason. They haven't yet connected the dots that the genetic shield we have as humans is that we are basically scrapie-resistant sheep. I wish they had, because the first cases of scrapie were just reported in a supposedly scrapie-resistant sheep. So much for our genetic shield against scrapie.

From what I have read, it is not clear that we ever had a shield, more like a sieve. Alzheimer's disease has amyloid plaques, scrapie has amyloid plaques. Mice given a single high dose of scrapie tissue did not develop the disease, but mice injected with the same dose broken into very small amounts over an extended period did. Mice injected with parts per million of scrapie daily all died of scrapie. In even lower doses, parts per billion, almost half the mice died of scrapie. What is the daily dose of scrapie necessary to produce symptoms in the human brain? We officially can't get scrapie, so no one has done the studies.

So what do we do about it? Well, prions resist boiling, alcohol, and radiation. Standard autoclaving is ineffective at inactivating them, so surgical instruments that undergo standard autoclaving would be a prime source of infection. But the prions can also be excreted in urine from an inflamed bladder. That means inflamed throats, or any blood borne route would be a possibility.

What protection do we have? The macrophages in the gut are effective at swallowing a prion before it can do any damage. So a combination of maximizing the immune system and minimizing exposure is still possible. If you eat meat, know your source. If you don't eat meat, don't pretend that you have no risk. But you have lowered your risk considerably.

I really wish I could be more optimistic about the information I found. I continue to eat meat, in denial of the facts. On the other hand, I know the meat farmer personally, and his cattle are all exclusively free range and grass fed. For those of you joining me in denial, write me for shipping. For those of you really in denial, please read all the research below. Again, I have no stake in anything but finding the truth, and I truly wish I had not found what I did. I have no interest or intention of defaming anyone or any organization, I just need to put this information out there for my patients to read.

BMC Infect Dis. 2006 Jan 11;6(1):5 [Epub ahead of print] Related Articles, Links
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Comparative evidence for a link between Peyer's patch development and susceptibility to transmissible spongiform encephalopathies.

St Rose SG, Hunter N, Matthews L, Foster JD, Chase-Topping ME, Kruuk LE, Shaw DJ, Rhind SM, Will RG, Woolhouse ME.

ABSTRACT: Background Epidemiological analyses indicate that the age distribution of natural cases of transmissible spongiform encephalopthies (TSEs) reflect age-related risk of infection, however, the underlying mechanisms remain poorly understood. Using a comparative approach, we tested the hypothesis that, there is a significant correlation between risk of infection for scrapie, bovine spongiform encephalopathy (BSE) and variant CJD (vCJD), and the development of lymphoid tissue in the gut. Methods Using anatomical data and estimates of risk of infection in mathematical models (which included results from previously published studies) for sheep, cattle and humans, we calculated the Spearman's rank correlation coefficient, rs, between available measures of Peyer's patch (PP) development and the estimated risk of infection for an individual of the corresponding age. Results There was a significant correlation between the measures of PP development and the estimated risk of TSE infection; the two age-related distributions peaked in the same age groups. This result was obtained for each of the three host species: for sheep, surface area of ileal PP tissue vs risk of infection, rs = 0.913 (n = 19, P < 0.001), and lymphoid follicle density vs risk of infection, rs = 0.933 (n = 19, P < 0.001); for cattle, weight of PP tissue vs risk of infection, rs = 0.693 (n = 94, P < 0.001); and for humans, number of PPs vs risk of infection, rs = 0.384 (n = 46, P = 0.008). In addition, when changes in exposure associated with BSE-contaminated meat were accounted for, the two age-related patterns for humans remained concordant: rs = 0.360 (n = 46, P = 0 .014). Conclusions Our findings suggest that, for sheep, cattle and humans alike there is an association between PP development (or a correlate of PP development) and susceptibility to natural TSE infection. This association may explain changes in susceptibility with host age, and differences in the age-susceptibility relationship between host species.

PMID: 16405727 [PubMed - as supplied by publisher]
CNS Drugs. 2006;20(1):15-28. Related Articles, Links

Prion diseases : current understanding of epidemiology and pathogenesis, and therapeutic advances.

Caramelli M, Ru G, Acutis P, Forloni G.

CEA-National TSE Reference Laboratory, Istituto Zooprofilattico Sperimentale del Piemonte, Turin, Italy.

The bovine spongiform encephalopathy (BSE) epidemic, along with the related threat to human health posed by the transmission of the BSE agent to humans, has highlighted the importance of prion diseases. These fatal neurodegenerative diseases are characterised by spongiform changes in the CNS, and comprise a wide spectrum of clinicopathological entities in humans and animals, such as Creutzfeldt-Jakob disease (CJD) and its emerging new variant (vCJD) in humans, and BSE and scrapie in animals. This article reviews the geographical distribution and the temporal trends of CJD and vCJD; the major events in the pathogenesis of prion diseases; the risk factors for sporadic CJD and vCJD; and the possible strategies for treating them.Worldwide statistics indicate that sporadic CJD has a stable incidence of one case per million people per year; in contrast, the incidence of vCJD appears to have increased exponentially from its characterisation in 1994 to a peak in 2000. As of December 2005, 183 definite or probable cases of vCJD had been reported worldwide.The crucial event in the pathogenesis of prion diseases is the conversion of the normally occurring cellular prion protein (PrP(c)) into a pathogenic form, called protease-resistant PrP (PrP(res)) or scrapie PrP (PrP(sc)). Pathogenetic studies in rodent models have shown that PrP(sc) is found in the enteric nervous system and in the gut-associated lymphoid tissue following oral scrapie ingestion. The role of the lymphoreticular system in the pathogenesis of TSE seems to be related to the strains of agents and the host genotype.Therapeutic approaches to vCJD are mainly based on the inhibition or prevention of the pathological change that creates PrP(sc). Derivatives of acridine (such as mepacrine [quinacrine]) and the phenothiazine psychotropics have been proposed as possible therapies because of their activity in cellular models; however, neither class was able to affect the protease resistance of preexisting PrP fibrils. More encouragingly, in animal models of prion disease, tetracyclines were found to reduce prion infectivity by direct inactivation of PrP(sc). While these findings are promising, the suitability of these compounds for clinical use is still limited by their low efficacy once symptoms are apparent. Treatments based on the vaccination approach have also produced positive results, but further investigations are necessary to establish their clinical application.

PMID: 16396521 [PubMed - in process]
J Virol. 2006 Jan;80(1):474-82. Related Articles, Links
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Resistance of neonatal mice to scrapie is associated with inefficient infection of the immature spleen.

Ierna M, Farquhar CF, Outram GW, Bruce ME.

Institute for Animal Health, Neuropathogenesis Unit, Ogston Building, West Mains Road, Edinburgh EH9 3JF, United Kingdom. moira.bruce@bbsrc.ac.uk.

Previous studies demonstrated that neonatal mice up to about a week old are less susceptible than adult mice to infection by intraperitoneal inoculation with mouse-passaged scrapie. In peripherally inoculated adult mice, scrapie replicates in lymphoid tissues such as the spleen before invading the central nervous system. Here, we investigated scrapie susceptibility in neonatal mice in more detail, concentrating on spleen involvement. First, we demonstrated that neonatal mice are about 10 times less susceptible than adults to intraperitoneal scrapie inoculation. Then we injected mice intraperitoneally with a scrapie dose that produced disease in all mice inoculated at 10 days or older but in only about a third of neonatally inoculated mice. In this experiment, spleens collected 70 days after scrapie injection of mice 10 days old or older almost all contained pathological prion protein, PrP(Sc), and those that were bioassayed all contained high infectivity levels. In contrast, at this early stage, only two of six spleens from neonatally inoculated mice had detectable, low infectivity levels; no PrP(Sc) was detected, even in the two spleens. Therefore, neonatal mice have an impaired ability to replicate scrapie in their spleens, suggesting that replication sites are absent or sparse at birth but mature within 10 days. The increase in susceptibility with age correlated with the first immunocytochemical detection of the normal cellular form of prion protein, PrP(c), on maturing follicular dendritic cell networks. As lymphoid tissues are more mature at birth in sheep, cattle, and humans than in mice, our results suggest that in utero infection with scrapie-like agents is theoretically possible in these species.

PMID: 16352571 [PubMed - in process]
Lancet Neurol. 2005 Oct;4(10):635-42. Related Articles, Links
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Prion diseases.

Johnson RT.

Pathology 627, The Johns Hopkins University School of Medicine & Bloomberg School of Public Health, Baltimore, MD 21287, USA. rtj@jhmi.edu

Prion diseases are degenerative disorders of the nervous system caused by transmissible particles that contain a pathogenic isoform of the prion protein, a normal constituent of cell membranes. The most common human prion disease is Creutzfeldt-Jakob disease (CJD). Most cases are sporadic with unknown mode of transmission, 10-15% of cases are inherited, and a small number have been transmitted by medical procedures. The spread of human prion diseases through consumption of infected material has been implicated historically in kuru and recently in variant CJD. Animal prion diseases (scrapie of sheep, transmissible mink encephalopathy, chronic wasting disease of cervids, and bovine spongiform encephalopathy) all seem to be laterally transmitted by contact with infected animals or by consumption of infected feed. The different modes of transmission of different prion diseases, the unpredictable species barriers, the variable distribution of infectivity in tissues, and strain variations found in some diseases all make risk assessment and predictions of future events difficult.

Publication Types:

* Review

PMID: 16168932 [PubMed - indexed for MEDLINE]
J Biol Chem. 2005 Dec 7; [Epub ahead of print] Related Articles, Links
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Chronic wasting disease of elk and deer and Creutzfeldt-Jakob disease: Comparative analysis of the scrapie prion protein.

Xie Z, O'rourke KI, Dong Z, Jenny AL, Langenberg JA, Belay ED, Schonberger LB, Petersen RB, Zou W, Kong Q, Gambetti P, Chen SG.

Dept. of Pathology, Case Western Reserve University, Cleveland, Ohio 44106.

Chronic wasting disease (CWD), a transmissible prion disease that affects elk and deer, poses new challenges to animal and human public health. Although the transmission of CWD to humans has not been proven, it remains a possibility. If this were to occur, it is important to know whether the "acquired" human prion disease would show a phenotype including the scrapie prion protein (PrPSc) features that differ from those associated with human sporadic prion disease. In this study, we have compared the pathological profiles and PrPSc characteristics in brains of CWD-affected elk and deer with that in subjects with sporadic Creutzfeldt-Jakob disease (CJD), as well as CJD-affected subjects who might have been exposed to CWD, using histopathology, immunohistochemistry, immunoblotting, conformation stability assay (CSA) and N-terminal protein sequencing. Spongiform changes and intense PrPSc staining were present in several brain regions of CWD-affected animals. Immunoblotting revealed three proteinase K (PK)-resistant bands in CWD, representing different glycoforms of PrPSc. Following deglycosylation, the unglycosylated PK-resistant PrPSc of CWD migrated at 21kDa with an electrophoretic mobility similar to that of type 1 human PrPSc present in sporadic CJD affecting subjects homozygous for methionine at codon 129 (sCJDMM1). N-terminal sequencing showed that the PK cleavage site of PrPSc in CWD occurred at residues 82 and 78, similar to that of PrPSc in sCJDMM1. Furthermore, CSA also showed no significant difference between elk CWD PrPSc and the PrPSc species associated with sCJDMM1. However, there was a major difference in glycoform ratio of PrPSc between CWD and sCJDMM1 affecting both CWD-exposed and non-exposed subjects. Moreover, PrPSc of CWD exhibited a distinct constellation of glycoforms distinguishable from that of sCJDMM1 in two-dimensional immunoblots. These findings underline the importance of detailed PrPSc characterization in trying to detect novel forms of acquired prion disease.

PMID: 16338930 [PubMed - as supplied by publisher]
J Gen Virol. 2005 Dec;86(Pt 12):3425-31. Related Articles, Links
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In vivo detection of scrapie cases from blood by infrared spectroscopy.

Carmona P, Monzon M, Monleon E, Badiola JJ, Monreal J.

Instituto de Estructura de la Materia (CSIC), Serrano 121, 28006 Madrid, Spain. p.carmona@iem.cfmac.csic.es

In the present study, infrared spectroscopy was shown to be able to distinguish healthy and scrapie-infected animals by analysis of the white-cell membranous fraction from blood. Infrared spectroscopy was able to detect not only clinical cases, but also animals at a preclinical stage of the disease. These findings suggest this technique as an accurate in vivo diagnostic tool that could be applied to animal as well as human samples. In addition to possibly avoiding the slaughter of a huge number of animals with the socio-economic consequences that this poses, the test could be expected to become useful in the prevention of human transmission by blood transfusion.

Publication Types:

* Evaluation Studies

PMID: 16298990 [PubMed - indexed for MEDLINE]
Microsc Res Tech. 2005 Nov;68(3-4):239-46. Related Articles, Links
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Slow virus disease: deciphering conflicting data on the transmissible spongiform encephalopathies (TSE) also called prion diseases.

Bastian FO, Fermin CD.

Tulane University Health Sciences Center, Department of Pathology & Lab Medicine, New Orleans, Louisian 70112, USa. fbastian@tulane.edu

The transmissible spongiform encephalopathies (TSE) that manifest as Creutzfeldt-Jakob disease in humans, as scrapie in sheep and goats, mad cow disease in cattle, or chronic wasting disease in cervids (deer) represent a serious human health crisis and a significant economical problem. Despite much research, the nature of the elusive pathogen directly involved with TSE is currently unresolved. This article reviews current pathogen-cell plasma membrane properties, showing that the primary biochemical marker of the prion disease is used as a receptor by the intracellular bacterium Brucella abortus. Such observation makes plausible the role for the prion in the pathogenesis of TSE, and supports the concept that Spiroplasma, a wall-less bacterium, may be a transmissible agent of TSE. Over the past three decades, we have published convincing evidence that Spiroplasma infection is associated with TSE. The bacterial-prion-receptor concept by other laboratories support a model for TSE wherein a Spiroplasma bacterium can bind to prion receptors (alone or with anchors) on the cell surface lipid raft, allowing entry of the microbe into the cell to initiate infection. The relevance of this new concept is that it offers a new window for future research involving a bacterium in the pathogenesis of TSE. Data from the bacterial-prion-receptor model will aid in the development diagnostic tests and/or treatment protocols for TSE. 2005 Wiley-Liss, Inc.

PMID: 16276518 [PubMed - in process]
Science. 2005 Oct 21;310(5747):493-6. Related Articles, Links
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Reciprocal interference between specific CJD and scrapie agents in neural cell cultures.

Nishida N, Katamine S, Manuelidis L.

Yale Medical School, New Haven, CT 06510, USA.

Infection of mice with an attenuated Creutzfeldt-Jakob disease agent (SY-CJD) interferes with superinfection by a more virulent human-derived CJD agent (FU-CJD) and does not require pathological prion protein (PrPres). Using a rapid coculture system, we found that a neural cell line free of immune system cells similarly supported substantial CJD agent interference without PrPres. In addition, SY-CJD prevented superinfection by sheep-derived Chandler (Ch) and 22L scrapie agents. However, only 22L and not Ch prevented FU-CJD infection, even though both scrapie strains provoked abundant PrPres. This relationship between particular strains of sheep- and human-derived agents is likely to affect their prevalence and epidemic spread.

PMID: 16239476 [PubMed - indexed for MEDLINE]
Med Hypotheses. 2005;64(5):919-24. Related Articles, Links
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Why don't humans get scrapie from eating sheep? A possible explanation based on secondary structure predictions.

Concepcion GP, David MP, Padlan EA.

Marine Science Institute, College of Science, University of the Philippines Diliman, Quezon City 1101, Philippines.

In an effort to find a structural explanation for the lack of direct transmission of scrapie from sheep to humans, secondary structure predictions are used to locate the segments of the prion sequence which may be involved in the transformation from the normal form of the prion protein, which has high helix content, to the pathogenic form, which has high beta-sheet content. The Chou-Fasman algorithm, which calculates propensities for both helix and sheet formation, was used to predict the secondary structures of the scrapie-resistant and the scrapie-susceptible variants of the ovine prion protein. The scrapie-susceptible variant, which has a glutamine at residue position 168 (human prion protein numbering), is predicted to have a propensity for sheet formation in that region of the molecule, while the scrapie-resistant variant, which has an arginine at position 168, does not. The valine at position 133, additionally present in the ovine variant which is the most susceptible to scrapie, is predicted to result in even more sheet formation. When the predicted secondary structure of the human prion protein is compared to those of the ovine prion protein variants, the human protein is found to be most similar to the scrapie-resistant variant. This result is proposed to provide a possible explanation for the observation that scrapie is not directly transmitted from sheep to humans.

PMID: 15780485 [PubMed - indexed for MEDLINE]

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Schweiz Arch Tierheilkd. 2001 Nov;143(11):539-47. Related Articles, Links

[Occurrence of scrapie in Switzerland: an anonymous cross-sectional study]

[Article in German]

Baumgarten L, Heim D, Zurbriggen A, Doherr MG.

Abteilung fur klinische Forschung, Departement fur klinische Veterinarmedizin der Universitat Bern.

Scrapie is a transmissible spongiform encephalopathy of sheep and goats, which leads to neurological signs and ends with the death of the infected animal. In Switzerland only a few cases were reported since 1982. In 1999, a questionnaire survey was conducted to increase information about neurological diseases in sheep and goat breeding farms. The aim was to estimate the frequency of neurological disorders including Scrapie and to increase the disease awareness of sheep and goat breeders. The main goal of the study was to increase the reporting of suspect cases of Scrapie and its differential diagnoses. Out of a database of all registered farms with at least five breeding sheep or breeding goats a random sample of 4711 was drawn to which anonymous questionnaires were sent. The return rate was 36%. In a parallel study, 150 voluntarily participants were interviewed using the same questionnaire. The results of both parts of the survey coincided. For the years 1997 and 1998, on average 1.0% of the breeding sheep and breeding goats showed neurological signs. 7.7% of the breeders indicated to have observed animals with neurological symptoms in their flock. At the population level, a total of 1954-2336 animals with neurological signs are observed in 691-929 flocks. The minority is reported to the veterinary authorities.

PMID: 11727673 [PubMed - indexed for MEDLINE]
Am J Vet Res. 1995 May;56(5):606-12. Related Articles, Links

Encephalopathy in cattle experimentally infected with the scrapie agent.

Clark WW, Hourrigan JL, Hadlow WJ.

USDA, Animal and Plant Health Inspection Service, Veterinary Services, Mission, TX 78572, USA.

Ten 8- to 10-month-old cattle were each inoculated intramuscularly, subcutaneously, intracerebrally, and orally with the scrapie agent to determine whether cattle are susceptible to it. Two inocula, both 10% homogenates of cerebrum, were used. One inoculum was from a sheep used for the second experimental ovine passage of the agent from 4 naturally affected Suffolk sheep. The other inoculum was from a goat used for the first experimental caprine passage of the agent from 2 naturally affected dairy goats living with the Suffolk sheep, the source of their infection. Between 27 and 48 months after inoculation, neurologic disease was observed in 1 of 5 cattle given the sheep brain homogenate and in 2 of 5 given the goat brain homogenate. In all 3 affected cattle, the disease was expressed clinically as increasing difficulty in rising from recumbency, stilted gait of the pelvic limbs, disorientation, and terminal recumbency during a 6- to 10-week course. Neurohistologic changes, though consistent with those of scrapie, were slight and subtle: moderate astrocytosis with sparse rod cells, some neuronal degeneration, a few vacuolated neurons, and scant spongiform change. Clinically and neurohistologically, the experimentally induced disease differed from bovine spongiform encephalopathy. The differences emphasize that such infections in cattle induce diverse responses, presumably depending largely on the strain of the agent. Pathologists should keep this variability in mind when looking for microscopic evidence of a scrapie-like encephalopathy in cattle.

PMID: 7661455 [PubMed - indexed for MEDLINE]
Vet Rec. 1993 Oct 2;133(14):339-41. Related Articles, Links

Transmission of bovine spongiform encephalopathy to sheep and goats.

Foster JD, Hope J, Fraser H.

Institute for Animal Health, AFRC, Edinburgh.

Spongiform encephalopathy has been confirmed in both 'positive' and 'negative' lines of Cheviot sheep (selected for their differential response on experimental exposure to scrapie) after intracerebral injection or oral dosing with brain homogenate derived from cattle with bovine spongiform encephalopathy (BSE). With either challenge the incubation period of the disease ranged from 440 to 994 days in both lines of sheep. In a similar experiment, three Anglo-Nubian goats developed the disease 506 to 570 days after intracerebral infection with the same BSE homogenate, and two of three goats developed the disease 941 and 1501 days after oral dosing; the other goat and some sheep from each of the experimental groups remain alive 1720 days after exposure. This is the first report of the experimental transmission of BSE to sheep and goats.

PMID: 8236676 [PubMed - indexed for MEDLINE]
Dev Biol Stand. 1993;80:111-8. Related Articles, Links

Epidemiologic and experimental studies on transmissible mink encephalopathy.

Marsh RF, Bessen RA.

Department of Animal Health and Biomedical Sciences, University of Wisconsin-Madison 53706.

Transmissible mink encephalopathy (TME) is a rare foodborne disease of ranch-raised mink produced by an as yet unidentified contaminated feed ingredient. Because of the clinicopathologic similarities to scrapie and the indistinguishable physicochemical properties of their transmissible agents, it was initially assumed that TME was caused by feeding mink scrapie-infected sheep. However, subsequent studies testing the oral susceptibility of mink to scrapie were unsuccessful. Epidemiologic investigations of individual incidents of TME have not identified an association between the occurrence of disease and the feeding of any particular ingredient. However, there are two incidents in which the rancher was confident that sheep were not fed. The most recent of these was in Stetsonville, Wisconsin in 1985 where the meat portion of the diet was composed almost exclusively of downer dairy cows. To examine the possibility that cattle may have been the source of infection on the Stetsonville ranch, mink brain was experimentally inoculated intracerebrally into two Holstein steers. Both of these animals developed fatal spongiform encephalopathies 18 and 19 months after inoculation. These findings are compatible with the Stetsonville incident of TME being caused by feeding mink infected cattle tissue and they suggest the presence of an unrecognized BSE-like disease in the United States. Further experimental studies on the Stetsonville source of TME have identified two distinct strains of the transmissible agent in Syrian hamsters. These strains vary in length of incubation period, clinical signs, endstage brain infectivity titre, and pathogenicity for mink.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 8270100 [PubMed - indexed for MEDLINE]
Philos Trans R Soc Lond B Biol Sci. 1994 Mar 29;343(1306):405-11. Related Articles, Links

Transmission of bovine spongiform encephalopathy and scrapie to mice: strain variation and the species barrier.

Bruce M, Chree A, McConnell I, Foster J, Pearson G, Fraser H.

IAH AFRC & MRC Neuropathogenesis Unit, Edinburgh, U.K.

Transmissions of bovine spongiform encephalopathy (BSE) from seven unrelated cattle sources have given remarkably uniform disease characteristics in mice, differing from over twenty previous and contemporary transmissions of sheep and goat scrapie. Transmissions to mice of spongiform encephalopathy from six species (including sheep and goats) which have been experimentally or naturally infected with BSE have given similar results to direct BSE transmissions from cattle. Therefore the BSE agent has retained its identity when passaged through a range of species and the 'donor' species has little specific influence on disease characteristics in mice, adding to evidence for an agent-specific informational molecule. On transmission of BSE or scrapie to mice the incubation periods are long compared with subsequent mouse-to-mouse passages (the 'species barrier'). Contributing factors include a low efficiency of infection on interspecies transmission, the apparent failure of intracerebrally injected 'foreign' inoculum to establish infection directly in mouse brain and the selection of variant strains of agent which replicate most readily in the new host species.

Publication Types:

* Review

PMID: 7913758 [PubMed - indexed for MEDLINE]
Vet Rec. 1992 Aug 1;131(5):93-6. Related Articles, Links

Natural scrapie in goats: neuropathology.

Wood JL, Done SH.

Pathology Department, Central Veterinary Laboratory, Weybridge, Surrey.

The brains of the 20 goats affected with natural scrapie received at the Central Veterinary-Laboratory, Weybridge, since 1975 were examined microscopically. Lesions of a spongiform encephalopathy were found in the brainstem, cerebellum, diencephalon, corpus striatum, and also in the neopallium or cerebral cortex. The lesions in the neopallium have not previously been reported in natural scrapie in goats. Deposits of amyloid were present in the thalamus in three of the 20 goats.

PMID: 1523800 [PubMed - indexed for MEDLINE] Vet Rec. 1992 Jul 25;131(4):66-8. Related Articles, Links

Natural scrapie in goats: case histories and clinical signs.

Wood JN, Done SH, Pritchard GC, Wooldridge MJ.

Pathology Department, Central Veterinary Laboratory, New Haw, Weybridge, Surrey.

The case histories of the 20 goats affected with natural scrapie which have been examined since 1975 at the Central Veterinary Laboratory, Weybridge, are reviewed. Their ages ranged from two to seven years (median three years, four months) and 85 per cent of them were between two and four years old. The most common clinical signs were hyperaesthesia, ataxia and pruritus. The histories indicated that scrapie can occur in goats which have not been in contact with sheep.

Publication Types:

* Case Reports

PMID: 1529502 [PubMed - indexed for MEDLINE]
Can J Vet Res. 1987 Jan;51(1):135-44. Related Articles, Links
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Experimental infection of sheep and goats with transmissible mink encephalopathy virus.

Hadlow WJ, Race RE, Kennedy RC.

In a study to learn more about the pathogenicity of transmissible mink encephalopathy virus for the natural hosts of scrapie, 20 Cheviot sheep and 19 dairy goats were inoculated intracerebrally with the Idaho strain of the virus. Five sheep and nine goats became affected with a progressive neurological disease. The incubation period in the sheep varied from 45 to 80 months (mean, 65 months) and in the goats from 31 to 40 months (mean, 35 months). Except for degeneration of the cerebral cortex (neocortex), the disease was indistinguishable clinically and neurohistologically from scrapie. During two more passages of the virus in goats, the incubation period was shortened to 12 to 15 months, the morbidity rate rose to 100% (6/6 dairy goats and 3/3 African pygmy goats), and the cortical lesion became constant and more pronounced. By the intracerebral inoculation of pastel mink, transmissible mink encephalopathy virus was detected in the brains of several affected sheep and goats but not in extraneural sites (lymphoid tissues and intestine), except for a trace amount in the proximal colon of one goat. Even after two passages in goats, the virus remained nonpathogenic for the laboratory mouse. Despite the essential likeness of the experimental disease and scrapie, the common identity of their causal viruses remains to be determined. Even so, the results of this study are still compatible with the view that transmissible mink encephalopathy virus almost certainly is scrapie virus whose biological properties became altered by chance passage in mink, a carnivore and an aberrant host.

PMID: 2952237 [PubMed - indexed for MEDLINE]
Vet Pathol. 1986 Sep;23(5):543-9. Related Articles, Links

Cerebrocortical degeneration in goats inoculated with mink-passaged scrapie virus.

Hadlow WJ, Race RE.

Widespread spongiform degeneration of the cerebral cortex occurred in four African pygmy goats that became affected with scrapie after intracerebral inoculation with scrapie virus (Suffolk sheep brain origin) that had been passed three times in ranch mink. The occurrence of such cerebrocortical degeneration was a distinct departure from the topographic pattern of neuropathologic changes that characterizes scrapie in sheep and goats. But the cortical lesion was identical to the one found in goats that became affected with a disease otherwise indistinguishable from scrapie after intracerebral inoculation with transmissible mink encephalopathy (TME) virus that had been passed twice in mink. If TME originated from infection with wild scrapie virus, as is generally thought, then the viruses used in these two instances would be equivalent in their passage history in this aberrant host. Given this similarity, the common occurrence of the cortical lesion is thought to be consistent with the view that TME virus almost certainly is scrapie virus whose biologic properties became altered by chance passage in ranch mink.

PMID: 2946103 [PubMed - indexed for MEDLINE]
Ann Neurol. 1980 Dec;8(6):628-32. Related Articles, Links

Brain tissue from persons dying of Creutzfeldt-Jakob disease causes scrapie-like encephalopathy in goats.

Hadlow WJ, Prusiner SB, Kennedy RC, Race RE.

Two goats became affected with an encephalopathy indistinguishable from scrapie 43 months after they were inoculated intracerebrally with 10% suspensions of brain from two persons dying of Creutzfeldt-Jakob disease. Although this observation does not establish the common identity of Creutzfeldt-Jakob disease virus and scrapie virus, it is thought to provide strong evidence of a close etiological relationship between the two diseases.

PMID: 7011169 [PubMed - indexed for MEDLINE]
J Infect Dis. 1980 Aug;142(2):205-8. Related Articles, Links

Comment in:

* J Infect Dis. 2004 Aug 1;190(3):653-60.

Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.

Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.

Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation.

PMID: 6997404 [PubMed - indexed for MEDLINE]
N Engl J Med. 1977 Dec 8;297(23):1253-8. Related Articles, Links

Precautions in medical care of, and in handling materials from, patients with transmissible virus dementia (Creutzfeldt-Jakob disease).

Gajdusek DC, Gibbs CJ Jr, Asher DM, Brown P, Diwan A, Hoffman P, Nemo G, Rohwer R, White L.

We have formulated a series of precautions to be observed in caring for patients with Creutzfeldt-Jakob disease and in handling their tissues. The virus resists inactivation by simple boiling in water. Also ineffective are 10 per cent formalin, 70 per cent alcohol and ionizing and ultraviolet radiation. Autoclaving for one hour at 121 degrees C and 20 psi inactivates the agent completely. Five per cent hypochlorite, 0.03 per cent permanganate, phenolics and iodine solutions are adequate disinfectants inactivating large infective doses of the virus. Special isolation wards for afflicted patients seem unwarranted. Workers exposed to infected saliva, nasopharyngeal secretions, urine or feces need to and should wash thoroughly with ordinary soap. Needles and needle electrodes should be autoclaved or incinerated and discarded. Demented persons should not be used for donations of blood or other tissues. Although precautions are necessary, the epidemiologic evidence does not suggest an unusual risk of Creutzfeldt-Jakob disease for medical workers.

PMID: 335248 [PubMed - indexed for MEDLINE]
Mater Med Pol. 1976 Jan-Mar;8(1):3-12. Related Articles, Links

Introduction to the scrapie diseases: self-replicating agents surviving standard autoclaving for an hour and 10% formalin for a year.

Kast RE.

Publication Types:

* Review

PMID: 817091 [PubMed - indexed for MEDLINE]
Chandler RL. Related Articles, Links
No abstract Experimental transmission of scrapie to voles and Chinese hamsters.
Lancet. 1971 Jan 30;1(7692):232-3. No abstract available.
PMID: 4099889 [PubMed - indexed for MEDLINE]
Fitzsimmons WM, Pattison IH. Related Articles, Links
No abstract Unsuccessful attempts to transmit scrapie by nematode parasites.
Res Vet Sci. 1968 May;9(3):281-3. No abstract available.
PMID: 5690146 [PubMed - indexed for MEDLINE]
Field EJ. Related Articles, Links
No abstract Transmission experiments with multiple sclerosis: an interim report.
Br Med J. 1966 Sep 3;2(513):564-5. No abstract available.
PMID: 5950508 [PubMed - indexed for MEDLINE]
ZLOTNIK I, RENNIE JC. Related Articles, Links
No abstract EXPERIMENTAL TRANSMISSION OF MOUSE PASSAGED SCRAPIE TO GOATS, SHEEP, RATS AND HAMSTERS.
J Comp Pathol. 1965 Apr;75:147-57. No abstract available.
PMID: 14319384 [PubMed - OLDMEDLINE for Pre1966]
HUNTER GD, MILLSON GC, MEEK G. Related Articles, Links
No abstract THE INTRACELLULAR LOCATION OF THE AGENT OF MOUSE SCRAPIE.
J Gen Microbiol. 1964 Feb;34:319-25. No abstract available.
PMID: 14135538 [PubMed - OLDMEDLINE for Pre1966]
Vet Pathol. 2005 Nov;42(6):844-51. Related Articles, Links
Ligios C, Sigurdson CJ, Santucciu C, Carcassola G, Manco G, Basagni M, Maestrale C, Cancedda MG, Madau L, Aguzzi A. Related Articles, Links
No abstract PrPSc in mammary glands of sheep affected by scrapie and mastitis.
Nat Med. 2005 Nov;11(11):1137-8. No abstract available.
PMID: 16270061 [PubMed - indexed for MEDLINE]
Click here to read
Second passage of sheep scrapie and transmissible mink encephalopathy (TME) agents in raccoons (Procyon lotor).

Hamir AN, Kunkle RA, Miller JM, Richt JA.

National Animal Disease Center, ARS, USDA, 2300 Dayton Avenue, Ames, IA 50010, USA. ahamir@nadc.ars.usda.gov

To determine the transmissibility and pathogenicity of sheep scrapie and transmissible mink encephalopathy (TME) agents derived from raccoons (first passage), raccoon kits were inoculated intracerebrally with either TME (one source) or scrapie (two sources-each in separate groups of raccoons). Two uninoculated raccoon kits served as controls. All animals in the TME-inoculated group developed clinical signs of neurologic dysfunction and were euthanatized between postinoculation month (PIM) 6 and 8. Raccoons in the two scrapie-inoculated groups manifested similar clinical signs of disease, but such signs were observed much later and the animals were euthanized between PIM 12 and 18. Necropsy revealed no gross lesions in any of the raccoons. Spongiform encephalopathy was observed by use of light microscopy, and the presence of protease-resistant prion protein (PrPres) was detected by use of immunohistochemical (IHC) and Western blot analytic techniques. Results of IHC analysis indicated a distinct pattern of anatomic distribution of PrPres in the TME- and scrapie-inoculated raccoons. These findings confirm that TME and sheep scrapie are experimentally transmissible to raccoons and that the incubation periods and IHC distribution for both agents are distinct. Therefore, it may be possible to use raccoons for differentiating unknown transmissible spongiform encephalopathy (TSE) agents. Further studies, with regard to the incubation period and the pattern of PrPres deposition by use of IHC analysis in bovine spongiform encephalopathy and for other isolates of scrapie, chronic wasting disease, and TME in raccoons are needed before the model can be further characterized for differentiation of TSE agents.

PMID: 16301585 [PubMed - in process]
J Virol. 2005 Dec;79(23):14971-5. Related Articles, Links
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Breaking an absolute species barrier: transgenic mice expressing the mink PrP gene are susceptible to transmissible mink encephalopathy.

Windl O, Buchholz M, Neubauer A, Schulz-Schaeffer W, Groschup M, Walter S, Arendt S, Neumann M, Voss AK, Kretzschmar HA.

University of Munich, Istitute of Neuropathology, Munchen, Germany.

Transmissible mink encephalopathy (TME) is a rare disease of the North American mink, which has never been successfully transmitted to laboratory mice. We generated transgenic mice expressing the mink prion protein (PrP) and inoculated them with TME or the mouse-adapted scrapie strain 79A. TME infected mink PrP-transgenic mice on a murine PrP knockout background. The absolute species barrier between the infectious agent of TME and mice was therefore broken. Following TME and 79A infection of mice carrying both mink and murine PrP(C), only proteinase-resistant PrP homologous to the incoming agent was detectable. The presence of the murine PrP(C) prolonged the incubation time of TME substantially.

PMID: 16282497 [PubMed - in process]
Microsc Res Tech. 2005 Nov;68(3-4):239-46. Related Articles, Links
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Slow virus disease: deciphering conflicting data on the transmissible spongiform encephalopathies (TSE) also called prion diseases.

Bastian FO, Fermin CD.

Tulane University Health Sciences Center, Department of Pathology & Lab Medicine, New Orleans, Louisian 70112, USa. fbastian@tulane.edu

The transmissible spongiform encephalopathies (TSE) that manifest as Creutzfeldt-Jakob disease in humans, as scrapie in sheep and goats, mad cow disease in cattle, or chronic wasting disease in cervids (deer) represent a serious human health crisis and a significant economical problem. Despite much research, the nature of the elusive pathogen directly involved with TSE is currently unresolved. This article reviews current pathogen-cell plasma membrane properties, showing that the primary biochemical marker of the prion disease is used as a receptor by the intracellular bacterium Brucella abortus. Such observation makes plausible the role for the prion in the pathogenesis of TSE, and supports the concept that Spiroplasma, a wall-less bacterium, may be a transmissible agent of TSE. Over the past three decades, we have published convincing evidence that Spiroplasma infection is associated with TSE. The bacterial-prion-receptor concept by other laboratories support a model for TSE wherein a Spiroplasma bacterium can bind to prion receptors (alone or with anchors) on the cell surface lipid raft, allowing entry of the microbe into the cell to initiate infection. The relevance of this new concept is that it offers a new window for future research involving a bacterium in the pathogenesis of TSE. Data from the bacterial-prion-receptor model will aid in the development diagnostic tests and/or treatment protocols for TSE. 2005 Wiley-Liss, Inc.

PMID: 16276518 [PubMed - in process]
Schweiz Arch Tierheilkd. 2005 Oct;147(10):425-33. Related Articles, Links

[Swiss scrapie surveillance. I. Clinical aspects of neurological diseases in sheep and goats]

[Article in German]

Maurer E, Botteron C, Ehrensperger F, Fatzer R, Jaggy A, Kolly C, Meylan M, Zurbriggen A, Doherr MG.

Abteilung Klinische Forschung der Universitat Bern.

Small ruminants infected with scrapie show a large range of often unspecific clinical symptoms. The most-often described signs, locomotion, sensibility and behavioural disorders and emaciation, rarely occur together, and cases have been described in which only one of those signs was detectable.Thus, formulating a well-circumscribed definition of a clinical suspect case is difficult. Most animals with CNS-effecting diseases such as listeriosis, polioencephalomacia, cerebrospinal nematidiasis and enterotoxemia will, in a thorough neurological examination, show at least some scrapie-like symptoms. Among the 22 neurological field cases examined in this study, a goat with cerebral gliomatosis and hair lice showed the closest similarity to clinical scrapie. The unilateral deficiency of the cerebral nerves has potential as an clinical exclusion criterion for scrapie. However, the laboratory confirmation--or exclusion--of scrapie remains important. It thus needs to be realized that a consistent and thorough examination of neurologically diseased small ruminants (including fallen stock) is the backbone of a good surveillance system for these diseases. This should be a motivation for submitting adult sheep and goats for neuropathological examination.

PMID: 16259408 [PubMed - indexed for MEDLINE]
Schweiz Arch Tierheilkd. 2005 Oct;147(10):435-43. Related Articles, Links

[Swiss scrapie surveillance. II. Epidemiologic aspects of the detection of neurological diseases in sheep and goats]

[Article in German]

Maurer E, Botteron C, Zurbriggen A, Doherr MG.

Abteilung klinische Forschung, Dept. klinischeVeterinarmedizin der Universitat Bern.

Monitoring of transmissible spongiform encephalopathy (TSE) in Swiss sheep and goats is based on the examination of animals from different sources. In this study, frequencies and proportions of the different diagnoses were compared between routinely submitted sheep and goats, notified scrapie suspects as well as fallen stock. Meningitis/ encephalitis cases were significantly more frequent (OR = 2.2) in the scrapie suspect group when compared to the routine submissions. Metabolic-toxic encephalopathy was seen more frequently within the fallen stock. Rare neurological diagnoses were more frequent among scrapie suspects and routine submissions when compared to fallen stock. Listeriosis was diagnosed equally frequent among the scrapie suspects and routine submissions but less frequent in fallen stock. Scrapie prevalence among the fallen stock and the routine submissions was 0 (zero), with 95% certainty that prevalence is < 1%. The examined animals are representative for most of the Swiss regions with considerable sheep and goat production. Continuation of the detailed neuropathological examination of small ruminants from these three groups, substituted by actively testing a sufficiently large sample of fallen stock and possibly also healthy-slaughtered adult sheep and goats for transmissible spongiform encephalopathies would ensure a good surveillance within the small ruminant population.

PMID: 16259409 [PubMed - indexed for MEDLINE]
Science. 2005 Oct 14;310(5746):324-6. Related Articles, Links
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Coincident scrapie infection and nephritis lead to urinary prion excretion.

Seeger H, Heikenwalder M, Zeller N, Kranich J, Schwarz P, Gaspert A, Seifert B, Miele G, Aguzzi A.

Institute of Neuropathology, University Hospital of Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland.

Prion infectivity is typically restricted to the central nervous and lymphatic systems of infected hosts, but chronic inflammation can expand the distribution of prions. We tested whether chronic inflammatory kidney disorders would trigger excretion of prion infectivity into urine. Urinary proteins from scrapie-infected mice with lymphocytic nephritis induced scrapie upon inoculation into noninfected indicator mice. Prionuria was found in presymptomatic scrapie-infected and in sick mice, whereas neither prionuria nor urinary PrP(Sc) was detectable in prion-infected wild-type or PrP(C)-overexpressing mice, or in nephritic mice inoculated with noninfectious brain. Thus, urine may provide a vector for horizontal prion transmission, and inflammation of excretory organs may influence prion spread.

PMID: 16224026 [PubMed - indexed for MEDLINE]
Am J Pathol. 2005 Oct;167(4):1033-42. Related Articles, Links
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Bovine prion is endocytosed by human enterocytes via the 37 kDa/67 kDa laminin receptor.

Morel E, Andrieu T, Casagrande F, Gauczynski S, Weiss S, Grassi J, Rousset M, Dormont D, Chambaz J.

UMR505 INSERM/UPMC, 15 rue de l'ecole de Medecine, 75006 Paris, France.

Some forms of transmissible spongiform encephalopathies result from oral infection. We have thus analyzed the early mechanisms that could account for an uptake of infectious prion particles by enterocytes, the major cell population of the intestinal epithelium. Human Caco-2/TC7 enterocytes cultured on microporous filters were incubated with different prion strains and contaminated brain homogenates in the apical compartment. Internalization of infectious particles was analyzed by Western blotting and immunofluorescence. We observed internalization by enterocytes of prion particles from bovine spongiform encephalopathy brain homogenates but not from mouse-adapted scrapie-strain brain homogenates or purified bovine spongiform encephalopathy scrapie-associated fibrils. Bovine prion particles were internalized via endocytosis within minutes of infection and were associated with subapical vesicular structures related to early endosomes. The endocytosis of the infectious bovine PrP(Sc) was reduced by preincubating the cells with an anti-LRP/LR blocking antibody, identifying the 37 kDa/67 kDa laminin receptor (LRP/LR), which is apically expressed in Caco-2/TC7 cells, as the receptor for the infectious prion protein. Altogether, our results underscore a potential role of enterocytes in the absorption of bovine prions during oral infection through specific LRP/LR-dependent endocytosis.

PMID: 16192638 [PubMed - indexed for MEDLINE]
Res Vet Sci. 2005 Sep 21; [Epub ahead of print] Related Articles, Links
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Scrapie infection alters the distribution of plasma metabolites in diseased Cheviot sheep indicating a change in energy metabolism.

Charlton AJ, Jones S, Heasman L, Davis AM, Dennis MJ.

Department for Environment, Food and Rural Affairs Central Science Laboratory, Sand Hutton, North Yorkshire YO41 1LZ, UK.

Nuclear magnetic resonance (NMR) spectroscopy has been used to profile the metabolic status of plasma from; sheep showing clinical signs of scrapie, those known to be infected with scrapie but yet to show clinical signs, and control animals. The NMR measurements have shown that energy metabolism in scrapie infected animals is altered before the onset of clinical symptoms. These metabolic changes may provide the foundation for a pre-clinical diagnostic test for scrapie in sheep.

PMID: 16183088 [PubMed - as supplied by publisher] Prev Vet Med. 2005 Sep 15; [Epub ahead of print] Related Articles, Links
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Breeding programmes for TSE resistance in British sheep I. Assessing the impact on prion protein (PrP) genotype frequencies.

Roden JA, Nieuwhof GJ, Bishop SC, Jones DA, Haresign W, Gubbins S.

Institute of Rural Sciences, University of Wales, Llanbadarn Fawr, Aberystwyth, Ceredigon SY23 2AL, UK.

From April 2005, member states of the European Union were required to implement a compulsory breeding programme for resistance to transmissible spongiform encephalopathies (TSEs) in sheep as part of measures to eradicate TSEs from national flocks. In this paper, we assessed the impact of four different breeding strategies on prion protein (PrP) genotype frequencies using a mathematical model which describes in detail gene flow in the British sheep flock. These strategies ranged from the minimum requirements laid down in by EU legislation to compulsory implementation of the current National Scrapie Plan for Great Britain (NSP) ram genotyping scheme. All four strategies were predicted to substantially reduce the frequency of the VRQ allele, which is associated with the highest risk of scrapie, although schemes with more stringent requirements produced a larger reduction. However, there were marked differences in the impact of the strategies on the frequency of other PrP alleles. In particular, restrictions beyond those required by EU legislation were necessary to change the frequency of other PrP alleles substantially. Consequently, a breeding programme which aims to reduce the risk to human health by reducing the frequency of the ARQ allele (associated with the highest risk of BSE in sheep) must place restrictions on ARQ-bearing animals. Similarly, a programme which seeks to increase the frequency of the ARR allele (associated with the lowest risk of TSE) must favour ARR-bearing animals.

PMID: 16169614 [PubMed - as supplied by publisher]
Vet J. 2005 Sep 15; [Epub ahead of print] Related Articles, Links
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TSE detected in a Belgian ARR-homozygous sheep via active surveillance.

De Bosschere H, Roels S, Dechamps P, Vanopdenbosch E.

Veterinary Agrochemical Research Centre (VAR), Department of Biocontrol, Groeselenberg 99, B-1180 Brussels (Ukkel), Belgium.

It is commonly accepted that scrapie-resistance and -susceptibility in sheep are genetically controlled. Consequently, the selection of sheep with scrapie-resistant genotypes is currently one of the most important objectives of the sheep breeding associations. However, during the last two years, new data have become available on transmissible spongiform encephalopathy (TSE) cases in TSE-resistant sheep in several European Union member states. The present paper describes the first Belgian natural "atypical" TSE case in a sheep with a scrapie-resistant genotype (ARR/ARR) detected via active surveillance. No other infections or diseases were detected in the source flock. The continued finding of new "atypical" TSE cases in sheep with scrapie-resistant genotypes undermines the purpose and efficacy of the breeding programs.

PMID: 16169265 [PubMed - as supplied by publisher]
Vet Pathol. 2005 Sep;42(5):530-49. Related Articles, Links
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Chronic wasting disease.

Williams ES.

Department of Veterinary Sciences, University of Wtoming, Laramie, USA.

Chronic wasting disease (CWD) is a unique transmissible spongiform encephalopathy (TSE) of mule deer (Odocoileus hemionus), white-tailed deer (O. virginianus), and Rocky Mountain elk (Cervus elaphus nelsoni). The natural history of CWD is incompletely understood, but it differs from scrapie and bovine spongiform encephalopathy (BSE) by virtue of its occurrence in nondomestic and free-ranging species. CWD has many features in common with scrapie, including early widespread distribution of disease-associated prion protein (PrP(d)) in lymphoid tissues, with later involvement of central nervous system (CNS) and peripheral tissues. This distribution likely contributes to apparent efficiency of horizontal transmission and, in this, is similar to scrapie and differs from BSE. Clinical features and lesions of CWD are qualitatively similar to the other animal TSEs. Microscopically, marked spongiform lesions occur in the central nervous system (CNS) after a prolonged incubation period and variable course of clinical disease. During incubation, PrP(d) can be identified in tissues by antibody-based detection systems. Although CWD can be transmitted by intracerebral inoculation to cattle, sheep, and goats, ongoing studies have not demonstrated that domestic livestock are susceptible via oral exposure, the presumed natural route of exposure to TSEs. Surveillance efforts for CWD in captive and free-ranging cervids will continue in concert with similar activities for scrapie and BSE. Eradication of CWD in farmed cervids is the goal of state, federal, and industry programs, but eradication of CWD from free-ranging populations of cervids is unlikely with currently available management techniques.

Publication Types:

* Review

PMID: 16145200 [PubMed - indexed for MEDLINE]
Lancet. 2005 Sep 3-9;366(9488):856-61. Related Articles, Links

Comment in:

* Lancet. 2005 Sep 3-9;366(9488):790-1.

Click here to read
The origin of bovine spongiform encephalopathy: the human prion disease hypothesis.

Colchester AC, Colchester NT.

Kent Institute of Medicine and Health Sciences, University of Kent, Canterbury CT2 7PD, UK. a.colchester@kent.ac.uk

The cause of the original case or cases of bovine spongiform encephalopathy (BSE) remains an enigma. Sheep scrapie or a previously undetected sporadic bovine transmissible spongiform encephalopathy (TSE) have long been considered as candidates, but no convincing evidence to support these proposals has come to light. We present a new theory, with three related hypotheses: (1) that BSE was acquired from a human TSE (prion disease); (2) that the route of infection was oral, through animal feed containing imported mammalian raw materials contaminated with human remains; and (3) that the origin was the Indian subcontinent, from which large amounts of mammalian material were imported during the relevant time period. Human remains are known to be incorporated into meal made locally, and may still be entering exported material. Further investigations are needed into the sources of animal by-products used in animal feed manufacture, and into the the transmissibility of human TSEs to cattle.

PMID: 16139661 [PubMed - indexed for MEDLINE]
Nat Med. 2005 Sep;11(9):982-5. Epub 2005 Aug 28. Related Articles, Links
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Detection of prions in blood.

Castilla J, Saa P, Soto C.

Department of Neurology, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas, 77555-0646, USA.

Prion diseases are caused by an unconventional infectious agent termed prion, composed mainly of the misfolded prion protein (PrP(Sc)). The development of highly sensitive assays for biochemical detection of PrP(Sc) in blood is a top priority for minimizing the spread of the disease. Here we show that the protein misfolding cyclic amplification (PMCA) technology can be automated and optimized for high-efficiency amplification of PrP(Sc). We show that 140 PMCA cycles leads to a 6,600-fold increase in sensitivity over standard detection methods. Two successive rounds of PMCA cycles resulted in a 10 million-fold increase in sensitivity and a capability to detect as little as 8,000 equivalent molecules of PrP(Sc). Notably, serial PMCA enables detection of PrP(Sc) in blood samples of scrapie-afflicted hamsters with 89% sensitivity and 100% specificity. These findings represent the first time that PrP(Sc) has been detected biochemically in blood, offering promise for developing a noninvasive method for early diagnosis of prion diseases.

PMID: 16127436 [PubMed - indexed for MEDLINE]
Bull Acad Natl Med. 2005 Feb;189(2):389-98. Related Articles, Links

[Update on transmissible spongiform subacute encephalopathies (TSSE)]

[Article in French]

Brugere-Picoux J, Adjou K, Brugere H.

Ecole Nationale Veterinaire d'Alfort, 7 avenue du General de Gaulle, 94704 Maisons-Alfort, France.

This update concerns human and ruminant transmissible spongiform subacute encephalopathies (TSSE). The latest data on variant Creutzfeldt-Jakob disease confirm that new cases are less frequent than feared some years ago, but subclinical carriers could be a source of iatrogenic infection. The macaque is a good model of human oral transmission of bovine spongiform encephalopathy (BSE). The latest data on BSE in Europe confirm the effectiveness of precautionary measures taken in 1996 and 2000. Concerns in other ruminants include a chronic wasting disease of Cervidae in North America, the discovery of a BSE-like agent associated with natural scrapie in a French goat, maternal transmission of natural scrapie in sheep, with an exceptionally short incubation period (6.5 months), and doubts over the efficacy of genetic selection for combating ovine scrapie (atypical cases in " resistant " sheep, especially with the scrapie strain Nor 98 in Europe). These data demonstrate the value of active European surveillance of scrapie in small ruminants.

Publication Types:

* Review

PMID: 16114866 [PubMed - indexed for MEDLINE]
Dev Biol (Basel). 2005;120:27-33. Related Articles, Links

Pathogenesis and transfusion risk of transmissible spongiform encephalopathies.

Brown P.

NINDS/NIH, Bethesda MD, USA. paulbrown@comcast.net

The genesis (and pathogenesis) of sporadic and familial forms of human transmissible spongiform encephalopathy (TSE) is unknown, but the disease process may originate spontaneously in the brain as a statistically random event involving misfolding and amyloid formation of the "prion" protein. The pathogenesis of environmentally acquired TSE depends on the route of infection and is likely to involve both neural and haematogenous paths of neuro-invasion. Blood infectivity is well documented in experimental rodent models of TSE and in natural scrapie infections, but has not yet been proved to occur in humans. The knowledge that many plasma pools have included donations from individuals who later died of sporadic Creutzfeldt-Jakob disease (sCJD), together with the failure to identify any affected recipients, implies that the risk is either negligible or absent. In sharp contrast, two out of 26 recipients of labile blood products from individuals who later died from the variant form of CJD (vCJD) have became infected, and the still-living at-risk recipients are under continuing surveillance.

Publication Types:

* Review

PMID: 16050152 [PubMed - indexed for MEDLINE]
Res Vet Sci. 2006 Feb;80(1):33-44. Epub 2005 Jul 19. Related Articles, Links
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The Shetland Islands scrapie monitoring and control programme: Analysis of the clinical data collected from 772 scrapie suspects 1985-1997.

Cockcroft PD, Clark AM.

Farm Animal Epidemiology and Informatics Unit, Department of Clinical Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, United Kingdom.

There were 574 scrapie positive suspects (histopathological scrapie lesions present) and 198 scrapie negative suspects (histopathological scrapie lesions absent). The greatest number of scrapie cases were recorded in sheep of 2, 3 and 4 years of age which represented 17%, 36% and 23% of the scrapie positive suspects, respectively. The sign sensitivities and specificities for the ten recorded signs were, respectively: pruritus (62%, 42%), ataxia (23%, 74%), hyperaesthesia (32%, 74%), wool loss (25%, 73%), fleece discolouration (29%, 85%), bruxism (23%, 69%), nibbling reflex (17%, 58%), head rubbing (47%, 78%), poll rubbing (25%, 83%). These single signs had poor discriminatory values with likelihood ratios close to one (range 0.89-1.21); combinations of the four signs, pruritus, wool loss, ataxia, hyperaesthesia and emaciation were more discriminatory (range 0.30-4.3). This study covered a time period when bovine spongiform encephalopathy (BSE) might have been introduced into the sheep population on the Shetland Islands via contaminated feed. No temporal changes could be detected in the age structure of the affected animals.

PMID: 16045948 [PubMed - in process]
Ann N Y Acad Sci. 2005 Jun;1050:417-28. Related Articles, Links
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Bovine spongiform encephalopathy, multiple sclerosis, and creutzfeldt-jakob disease are probably autoimmune diseases evoked by Acinetobacter bacteria.

Ebringer A, Rashid T, Wilson C.

Infection and Immunity Group, Division of Health and Life Sciences, King's College London, 150 Stamford Street, London SE1 9NN, United Kingdom. alan.ebringer@kcl.ac.uk

Bovine spongiform encephalopathy (BSE) belongs to a group of conditions named together as transmissible spongiform encephalopathies (TSE). They are fatal neurodegenerative diseases that include "scrapie" in sheep, Creutzfeldt-Jakob disease (CJD) and kuru in humans, and chronic wasting disease in deers. BSE-affected animals suffer from "hindquarters" paralysis, which is also one of the main features of "experimental allergic encephalomyelitis" (EAE). EAE is considered an animal model of multiple sclerosis (MS) and lower limb ataxia is often observed in MS patients. The presence of clinical and histopathological similarities in these diseases suggests a common pathology. Specific brain peptides, which produce EAE, were shown to have "molecular mimicry" with the soil and skin saprophytic microbe, Acinetobacter. BSE-affected animals and patients suffering from MS have been found to have elevated levels of antibodies to both Acinetobacter and Pseudomonas bacteria, as well as autoantibodies to both white and gray matter brain components. The hypothesis is proposed that Acinetobacter/Pseudomonas bacteria may have evoked both BSE and MS through the mechanism of "molecular mimicry" and autoimmunity in a similar way to Streptococcus microbes producing rheumatic fever and Sydenham's chorea. The possibility that CJD patients may show similar features remains to be determined.

Publication Types:

* Review

PMID: 16014559 [PubMed - indexed for MEDLINE]
J Virol. 2005 Jul;79(14):8904-8. Related Articles, Links
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High incidence of scrapie induced by repeated injections of subinfectious prion doses.

Jacquemot C, Cuche C, Dormont D, Lazarini F.

Neurovirologie et Regeneration du Systeme Nerveux, Dpt Neurosciences, Institut Pasteur, Paris, France.

To clarify the mechanisms leading to the development of Creutzfeldt-Jakob disease in some recipients of pituitary-derived human growth hormone (hGH), we investigated the effects of repeated injections of low prion doses in mice. The injections were performed, as in hGH-treated children, by a peripheral route at short intervals and for an extended period. Twelve groups of 24 mice were intraperitoneally inoculated one, two, or five times per week for 200 days with 2 x 10(-5) to 2 x 10(-8) dilutions of brain homogenate containing the mouse-adapted C506M3 scrapie strain. Sixteen control mice were injected once a week for 200 days with a 2 x 10(-4) dilution of normal brain homogenate. Of mice injected in a single challenge with a scrapie inoculum of a 2 x 10(-4), 2 x 10(-5), or 2 x 10(-6) dilution, 2/10, 1/10, and 0/10 animals developed scrapie, respectively. Control mice remained healthy. One hundred thirty-five of 135 mice injected with repeated prion doses of a 2 x 10(-5) or 2 x 10(-6) dilution succumbed to scrapie. Of mice injected with repeated scrapie doses of a 2 x 10(-7) or 2 x 10(-8) dilution, 52/59 and 38/67 animals died of scrapie, respectively. A high incidence of scrapie was observed in mice receiving repeated doses at low infectivity, whereas there was no disease in mice that were injected once with the same doses. Repeated injections of low prion doses thus constitute a risk for development of prion disease even if the same total dose inoculated in a single challenge does not induce the disease.

PMID: 15994784 [PubMed - indexed for MEDLINE]
Curr Drug Targets CNS Neurol Disord. 2005 Jun;4(3):235-48. Related Articles, Links
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Amyloid associated proteins in Alzheimer's and prion disease.

Veerhuis R, Boshuizen RS, Familian A.

Institute for Clinical and Experimental Neurosciences-VU, Departments of Psychiatry Vrije Universiteit University Medical Center, 1007 MB Amsterdam, The Netherlands. r.veerhuis@vumc.nl

Clustering of activated microglia in Abeta deposits is related to accumulation of amyloid associated factors and precedes the neurodegenerative changes in AD. Microglia-derived pro-inflammatory cytokines are suggested to be the driving force in AD pathology. Inflammation-related proteins, including complement factors, acute-phase proteins, pro-inflammatory cytokines, that normally are locally produced at low levels, are increasingly synthesized in Alzheimer's disease (AD) brain. Similar to AD, in prion diseases (Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease and experimentally scrapie infected mouse brain) amyloid associated factors and activated glial cells accumulate in amyloid deposits of conformational changed prion protein (PrPres). Biological properties of Abeta and prion (PrP) peptides, including their potential to activate microglia, relate to Abeta and PrP peptide fibrillogenic abilities that are influenced by certain amyloid associated factors. However, since small oligomers of amyloid forming peptides are more toxic to neurons than large fibrils, certain amyloid associated factors that enhance fibril formation, may sequester the potentially harmful Abeta and PrP peptides from the neuronal microenvironment. In this review the positive and negative actions of amyloid associated factors on amyloid peptide fibril formation and on the fibrillation state related activation of microglia will be discussed. Insight in these mechanisms will enable the design of specific therapies to prevent neurodegenerative diseases in which amyloid accumulation and glial activation are prominent early features.

Publication Types:

* Review

PMID: 15975027 [PubMed - indexed for MEDLINE]
J Neurol Neurosurg Psychiatry. 2005 Jul;76(7):906-19. Related Articles, Links
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Molecular neurology of prion disease.

Collinge J.

MRC Prion Unit and National Prion Clinic, Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK. j.collinge@prion.ucl.ac.uk

Prions are infectious pathogens principally composed of abnormal forms of a protein encoded in the host genome. They cause lethal neurodegenerative conditions including CJD, GSS, and kuru in humans and scrapie and bovine spongiform encephalopathy in domestic animals. Remarkably, distinct strains of prions occur despite absence of an agent-specific genome: misfolded proteins themselves may encode strain diversity--with wide implications in biology. The arrival of variant CJD, and the experimental confirmation that it is caused by infection with BSE-like prions, has focussed research on early diagnosis and treatment. Recent advances lead to considerable optimism that effective human therapies may now be developed. While several drugs have been tried in small numbers of patients, there is no clear evidence of efficacy of any agent and controlled clinical trials are urgently needed. Importantly, there is increasing recognition that fundamental processes involved in prion propagation--seeded aggregation of misfolded host proteins--are of far wider significance, not least in understanding the commoner neurodegenerative diseases that pose such a major and increasing challenge for healthcare in an ageing population.

Publication Types:

* Review

PMID: 15965195 [PubMed - indexed for MEDLINE]
Int J Pharm. 2005 Jul 25;298(2):293-304. Related Articles, Links
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Role of gut macrophages in mice orally contaminated with scrapie or BSE.

Maignien T, Shakweh M, Calvo P, Marce D, Sales N, Fattal E, Deslys JP, Couvreur P, Lasmezas CI.

CEA, Service de Neurovirologie, CRSSA, B.P.6, Fontenay-aux-Roses Cedex, France.

While there is a growing consensus on the understanding of the propagation pathways after oral infection of transmissible spongiform encephalopathy (TSE) agents and even if the central role of follicular dendritic cells is identified, little is known about the key players in the first steps of the infection and about the site of the disease development. We investigated the role of gut macrophages, which are capable of capturing aggregates of the prion protein. PLGA particles containing clodronate were designed in order to be orally administered and to target Peyer's patches for inducing gut-associated macrophages suicide in mice. Mice were subsequently infected with scrapie or BSE by the oral route. It was found that the efficacy of macrophage suppression in the Peyer's patches correlated well with an earlier appearance of PrPres in these formations and with a higher amount of PrPres at a later stage of the infection. Thus, the capture of infectious particles that have crossed the epithelial gut barrier and their elimination by macrophages seems to be a key event to restrict the amount of agent initiating the infection.

PMID: 15964722 [PubMed - indexed for MEDLINE]
Science. 2005 Jun 3;308(5727):1435-9. Related Articles, Links

Comment in:

* Science. 2005 Jun 3;308(5727):1420-1.

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Anchorless prion protein results in infectious amyloid disease without clinical scrapie.

Chesebro B, Trifilo M, Race R, Meade-White K, Teng C, LaCasse R, Raymond L, Favara C, Baron G, Priola S, Caughey B, Masliah E, Oldstone M.

Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT 59840, USA. bchesebro@niaid.nih.gov

In prion and Alzheimer's diseases, the roles played by amyloid versus nonamyloid deposits in brain damage remain unresolved. In scrapie-infected transgenic mice expressing prion protein (PrP) lacking the glycosylphosphatidylinositol (GPI) membrane anchor, abnormal protease-resistant PrPres was deposited as amyloid plaques, rather than the usual nonamyloid form of PrPres. Although PrPres amyloid plaques induced brain damage reminiscent of Alzheimer's disease, clinical manifestations were minimal. In contrast, combined expression of anchorless and wild-type PrP produced accelerated clinical scrapie. Thus, the PrP GPI anchor may play a role in the pathogenesis of prion diseases.

PMID: 15933194 [PubMed - indexed for MEDLINE]
Med Hypotheses. 2005;65(1):47-54. Related Articles, Links
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Risk analysis of ectoparasites acting as vectors for chronic wasting disease.

Lupi O.

Department of Medical Clinics, Microcirculation Research Laboratory, Universidade do Estado do Rio de Janeiro, Rua Frei Leandro, 16\501, 22.470-210 Rio de Janeiro, RJ, Brazil. omarlupi@globo.com

Prion diseases are rare neurodegenerative diseases of humans and animals with a lethal evolution. Animal prion infections, such as chronic wasting disease (CWD) and scrapie (sheep) have shown a pattern of horizontal transmission. CWD is an endemic disease that has been affecting thousands of domestic and wild cervids in US for the last three decades. The mode of contamination is not known, although direct contact between infected and non-infected animals via saliva, urine and feces have been considered. Increasing spread of CWD has raised concerns about the potential transmission to humans and the conversion of human prion protein by CWD-associated prions has been demonstrated in laboratory experiments. Fly larvae exposed to brain infected material were able to readily transmit scrapie to hamsters. Prion rods were identified in both larvae and fly pupae. New lines of evidence confirmed that adult flies are also able to express prion proteins. The most prevalent species of myiasis in cattle, sheep and wild cervids (Hypoderma spp.) present a very different life cycle from human myiasis, with a long contact with neurologic structures, such as the spinal canal and epidural fat, that are potentially rich in prion rods. Considering the huge amount of fly larvae that affects each animal, it is important to discuss the possibility that these ectoparasites could theoretically act as reservoirs and vectors for CWD and other prion diseases. It is critical to recognize all the possible factors involved in CWD transmission since ectoparasites could be handled in an easier way than the environmental persistence of infectious prions.

PMID: 15893117 [PubMed - indexed for MEDLINE]

J Immunol. 2005 Nov 15;175(10):6443-9. Related Articles, Links
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The murine B cell repertoire is severely selected against endogenous cellular prion protein.

Gregoire S, Bergot AS, Feraudet C, Carnaud C, Aucouturier P, Rosset MB.

Institut National de la Sante et de la Recherche Medicale Unite 712 and Universite Pierre et Marie Curie, Hopital Saint-Antoine, Paris, France.

Abs to the prion protein (PrP) can protect against experimental prion infections, but efficient Ab responses are difficult to generate because PrP is expressed on many tissues and induces a strong tolerance. We previously showed that immunization of wild-type mice with PrP peptides and CpG oligodeoxynucleic acid overcomes tolerance and induces cellular and humoral responses to PrP. In this study, we compared Ab and T cell repertoires directed to PrP in wild-type and PrP knockout (Prnp o/o) C57BL/6 mice. Animals were immunized with mouse PrP-plasmid DNA or with 30-mer overlapping peptides either emulsified in CFA or CpG/IFA. In Prnp o/o mice, Abs raised by PrP-plasmid DNA immunization recognized only N-terminal PrP peptides; analyses of Ab responses after PrP peptide/CFA immunization allowed us to identify six distinct epitopes, five of which were also recognized by Abs raised by PrP peptides/CpG. By contrast, in wild-type mice, no Ab response was detected after PrP-plasmid DNA or peptide/CFA immunization. However, when using CpG, four C-terminal peptides induced Abs specific for distinct epitopes. Importantly, immune sera from Prnp o/o but not from wild-type mice bound cell surface PrP. Abs of IgG1 and IgG2b subclasses predominated in Prnp o/o mice while the strongest signals were for IgG2b in wild-type mice. Most anti-PrP Th cells were directed to a single epitope in both Prnp o/o and wild-type mice. We conclude that endogenous PrPC expression profoundly affects the Ab repertoire as B cells reactive for epitopes exposed on native PrPC are strongly tolerized. Implications for immunotherapy against prion diseases are discussed.

PMID: 16272297 [PubMed - indexed for MEDLINE]