Wednesday, November 18, 2009

A Novel Protective Prion Protein Variant that Colocalizes with Kuru Exposure

A Novel Protective Prion Protein Variant that Colocalizes with Kuru Exposure

Simon Mead, M.R.C.P., Jerome Whitfield, M.A., Mark Poulter, B.Sc., Paresh Shah, Ph.D., James Uphill, B.Sc., Tracy Campbell, B.Sc., Huda Al-Dujaily, B.Sc., Holger Hummerich, Ph.D., Jon Beck, B.Sc., Charles A. Mein, Ph.D., Claudio Verzilli, Ph.D., John Whittaker, Ph.D., Michael P. Alpers, F.R.S., and John Collinge, F.R.S.


Background Kuru is a devastating epidemic prion disease that affected a highly restricted geographic area of the Papua New Guinea highlands; at its peak, it predominantly affected adult women and children of both sexes. Its incidence has steadily declined since the cessation of its route of transmission, endocannibalism.

Methods We performed genetic and selected clinical and genealogic assessments of more than 3000 persons from Eastern Highland populations, including 709 who participated in cannibalistic mortuary feasts, 152 of whom subsequently died of kuru.

Results Persons who were exposed to kuru and survived the epidemic in Papua New Guinea are predominantly heterozygotes at the known resistance factor at codon 129 of the prion protein gene (PRNP). We now report a novel PRNP variant — G127V — that was found exclusively in people who lived in the region in which kuru was prevalent and that was present in half of the otherwise susceptible women from the region of highest exposure who were homozygous for methionine at PRNP codon 129. Although this allele is common in the area with the highest incidence of kuru, it is not found in patients with kuru and in unexposed population groups worldwide. Genealogic analysis reveals a significantly lower incidence of kuru in pedigrees that harbor the protective allele than in geographically matched control families.

Conclusions The 127V polymorphism is an acquired prion disease resistance factor selected during the kuru epidemic, rather than a pathogenic mutation that could have triggered the kuru epidemic. Variants at codons 127 and 129 of PRNP demonstrate the population genetic response to an epidemic of prion disease and represent a powerful episode of recent selection in humans.

Source Information

From the Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology (S.M., J. Whitfield, M.P., P.S., J.U., T.C., H.A.-D., H.H., J.B., M.P.A., J.C.); the Genome Centre, Barts and the London Queen Mary's School of Medicine and Dentistry, John Vane Science Centre (C.A.M.); and the Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine (C.V., J. Whittaker) — all in London; Papua New Guinea Institute of Medical Research, Goroka, Eastern Highlands Province, Papua New Guinea (J. Whitfield, M.P.A.); and the Centre for International Health, Curtin University, Perth, WA, Australia (M.P.A.).

Address reprint requests to Dr. Collinge at the Department of Neurodegenerative Disease, Institute of Neurology, Queen Sq., London WC1N 3BG, United Kingdom, or at

Brain disease “resistance gene” could offer insights into CJD19 November 2009 A community in Papua New Guinea that suffered a major epidemic of a CJD-like fatal brain disease called kuru has developed strong genetic resistance to the disease, according to new research by Medical Research Council (MRC) scientists.

Kuru is a fatal prion disease, similar to CJD in humans and BSE in animals, and is geographically unique to an area in Papua New Guinea. In the mid 20th Century, an epidemic of kuru devastated a population in the Eastern Highlands of Papua New Guinea. The infection was passed on at mortuary feasts, where mainly women and children consumed their deceased relatives as a mark of respect and mourning. This practice was banned and ceased in the late 1950s.

Scientists from the MRC Prion Unit, a national centre of excellence in prion diseases, assessed over 3000 people from the affected and surrounding Eastern Highland populations, including 709 who had participated in cannibalistic mortuary feasts, 152 of whom subsequently died of kuru. They discovered a novel and unique variation in the prion protein gene called G127V in people from the Purosa valley region where kuru was most rife.

This gene mutation, which is found nowhere else in the world, seems to offer high or even complete protection against the development of kuru and has become frequent in this area through natural selection over recent history, in direct response to the epidemic. This is thought be perhaps the strongest example yet of recent natural selection in humans.

Lead author Professor John Collinge, Director of the MRC Prion Unit said:

“It’s absolutely fascinating to see Darwinian principles at work here. This community of people has developed their own biologically unique response to a truly terrible epidemic. The fact that this genetic evolution has happened in a matter of decades is remarkable. Kuru comes from the same disease family as CJD so the discovery of this powerful resistance factor opens up new areas for research taking us closer to understanding, treating and hopefully preventing a range of prion diseases.”

The study “A Novel Protective Prion Protein Variant that Colocalizes with Kuru Exposure”, which began in 1996, will be published in the New England Journal of Medicine on 19 November 2009.


Notes to editors 1. Study available on request.

2. For almost 100 years the Medical Research Council has improved the health of people in the UK and around the world by supporting the highest quality science. The MRC invests in world-class scientists. It has produced 29 Nobel Prize winners and sustains a flourishing environment for internationally recognised research. The MRC focuses on making an impact and provides the financial muscle and scientific expertise behind medical breakthroughs, including the first antibiotic penicillin, the structure of DNA and the lethal link between smoking and cancer. Today MRC funded scientists tackle research into the major health challenges of the 21st century.

3. Prion diseases or transmissible spongiform encephalopathies (TSEs) belong to group of progressive conditions that affect the nervous system in humans and animals. In humans, prion diseases impair brain function, causing memory changes, personality changes, a decline in intellectual function (dementia), and problems with movement that worsen over time. They are fatal conditions. Familial prion diseases of humans include classic Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS) fatal insomnia (FI) and Kuru.

4. Kuru was restricted to the Fore linguistic groups and their immediate neighbours which whom they intermarried. It was the practice in the Fore society for kinship groups to consume deceased relatives at mortuary feasts, a practice that resulted in human-to-human prion transmission. On the whole, men and children over 8 years of age did not participate in the feast, with the result that kuru at its peak predominantly affected women and children. As recorded in oral history the first cases appeared in the early 20th century and thereafter the number of cases increased in incidence. A peak annual mortality of more than 2% was recorded in some villages. Some villages became largely devoid of young women. More information on the Papua New Guinea Institute of Medical Research is available here

5. The study was lead by the Medical Research Council Prion Unit, and involved scientists from the University College London Institute of Neurology; Papua New Guinea Institute of Medical Research; and Curtin University Australia. Other institutions participating; the Genome Centre, Barts the London Queen Mary’s School of Medicine and Dentistry; London School of Hygiene and Tropical Medicine.

Press contact: 020 7637 6011

November 19, 2009

Brain-eating tribe enriches understanding of mad cow disease

Mark Henderson, Science Editor Recommend? A cannibalistic ritual in which the brains of dead tribespeople were eaten by their relatives has triggered one of the most striking examples of rapid human evolution on record, scientists have discovered.

In the middle of the 20th century the Fore tribe of the Eastern Highlands province of Papua New Guinea was devastated by a CJD-like disease called kuru, which was passed on by mortuary feasts in which the brains of the dead were consumed.

Although the practice was banned in the 1950s and kuru has disappeared, it has left an imprint on the tribe’s DNA. Research has now identified a genetic mutation unique to the Fore that protects against the brain disease and which has spread swiftly through the population by natural selection.

As the mutation confers high or almost complete resistance to kuru, carriers have a survival advantage and have had more descendants. About 8 per cent of people from the Purosa Valley region, where kuru hit hardest, now have the gene, which is unknown anywhere else in the world.

Related Links Daniel Gajdusek New wave of mad cow disease feared What the cannibals taught us The findings, from a team led by Simon Mead, of the Medical Research Council Prion Unit at University College London, show how quickly human evolution can respond to new environmental pressures.

They are described today in The New England Journal of Medicine as scientists prepare to celebrate the 150th anniversary of the publication of Charles Darwin’s On the Origin of Species on Tuesday.

Professor John Collinge, the director of the prion unit, said: “It’s absolutely fascinating to see Darwinian principles at work here. This community of people have developed their own biologically unique response to a truly terrible epidemic. The fact that this genetic evolution has happened in a matter of decades is remarkable.”

The research is also significant because it promises to shed light on the rogue prion proteins that cause Creutzfeldt-Jakob disease (vCJD), the human form of mad cow disease.

Dr Mead said: “It isn’t going to lead to a drug tomorrow but it would improve our background understanding of how prion diseases work and how they might be prevented.”

Oral histories provided by elderly members of the Fore tribe suggest that kuru emerged in the early 20th century and developed into a serious epidemic with an annual mortality rate of more than 2 per cent in some villages.

It mainly affected women and children, who would eat the remains of dead relatives. Kuru disappeared when cannibal rituals were stopped in the 1950s under the influence of missionaries.

In the new study scientists analysed the DNA of more than 3,000 people from affected and unaffected parts of the Eastern Highlands, including 709 who had taken part in cannibalistic rituals and 152 who had died of kuru.

The variant in the prion protein gene, called G127V, appears to have emerged about 1800 and then became advantageous with the arrival of kuru.

Dr Mead said that the variant would have spread rapidly for two reasons: “First, if you’re a carrier you’re resistant to the disease. More subtly, it also had benefits in terms of the relatives eaten. If you were in a family protected against kuru and ate auntie’s brain you were less likely to be eating an infected brain.”

In the genes

Sickle-cell anaemia This genetic disease is more common among African and Mediterranean people because the gene responsible also confers resistance to malaria

Blood groups People with blood group O are more vulnerable to cholera but less susceptible to malaria, spread by mosquitoes

HIV There is evidence that a variant of a gene called CCR5-32, which offers resistance against HIV, is increasing in frequency in Africa

Lactose tolerance Common in ethnic groups with a strong pastoral tradition such as North Europeans and East Africans

Skin colour Natural selection favours dark skins at equatorial latitudes for cancer protection, but pale skins at high latitudes, because they allow greater production of vitamin D

Source: Times database

Tuesday, July 28, 2009

The kuru infectious agent is a unique geographic isolate distinct from Creutzfeldt–Jakob disease and scrapie agents

Kuru in the 21st century—an acquired human prion disease Thu Jun 22, 2006 19:44

The Lancet 2006; 367:2068-2074


Kuru in the 21st century—an acquired human prion disease with very long incubation periods John Collinge a , Jerome Whitfield a b, Edward McKintosh a, John Beck a, Simon Mead a, Dafydd J Thomas a and Michael P Alpers a c

Summary Background Kuru provides the principal experience of epidemic human prion disease. Its incidence has steadily fallen after the abrupt cessation of its route of transmission (endocannibalism) in Papua New Guinea in the 1950s. The onset of variant Creutzfeldt-Jakob disease (vCJD), and the unknown prevalence of infection after the extensive dietary exposure to bovine spongiform encephalopathy (BSE) prions in the UK, has led to renewed interest in kuru. We investigated possible incubation periods, pathogenesis, and genetic susceptibility factors in kuru patients in Papua New Guinea.

Methods We strengthened active kuru surveillance in 1996 with an expanded field team to investigate all suspected patients. Detailed histories of residence and exposure to mortuary feasts were obtained together with serial neurological examination, if possible.

Findings We identified 11 patients with kuru from July, 1996, to June, 2004, all living in the South Fore. All patients were born before the cessation of cannibalism in the late 1950s. The minimum estimated incubation periods ranged from 34 to 41 years. However, likely incubation periods in men ranged from 39 to 56 years and could have been up to 7 years longer. PRNP analysis showed that most patients with kuru were heterozygous at polymorphic codon 129, a genotype associated with extended incubation periods and resistance to prion disease.

Interpretation Incubation periods of infection with human prions can exceed 50 years. In human infection with BSE prions, species-barrier effects, which are characteristic of cross-species transmission, would be expected to further increase the mean and range of incubation periods, compared with recycling of prions within species. These data should inform attempts to model variant CJD epidemiology.


a. MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, London WC1N 3BG, UK b. Papua New Guinea Institute of Medical Research, Goroka, EHP, Papua New Guinea c. Centre for International Health, Curtin University, Perth, Australia

Correspondence to: Prof John Collinge


Listen to The Lancet This week's audio summary discusses an Article entitled "Kuru in the 21st century - an acquired human prion disease with very long incubation periods". Also covered is a Lecture assessing climate change and its impact on health, and an Editorial about the roll-out of cervical cancer vaccines worldwide. >>

further into this study;


The early clinical, epidemiological, and anthropological study of kuru; the recognition of its neuropathological, and then causal parallels to ovine scrapie;20 and then crucially, the experimental transmission of the disease

to primates,21 originated the concept of the human transmissible spongiform encephalopathies, which was followed in turn by the eventual unifying concept of the mammalian prion diseases. However, in addition to the central historical importance of kuru, study of the end-stage of this epidemic offers a unique opportunity to study the variables of a near-complete epidemic of human prion disease. In particular, recognition of the incubation periods possible after natural prion infection in people is important in providing an insight (from actual case histories rather than from mathematical models) into the probable span of the vCJD epidemic in the UK. Although estimation of kuru incubation periods early in the epidemic was difficult, and the timing of the actual infecting event for an individual can rarely be determined, the abrupt and permanent interruption of the source of infection, endocannibalism, in the late 1950s, has progressively allowed recognition of an enormous span of possible incubation periods, at its shortest extreme bracketed by the rare onset of disease in children as young as 5 years and extending up to (and perhaps beyond) the incubations covering more than half a century, as we describe here.In our field studies, we have interviewed many individuals who participated in traditional mortuary feasting or who described the participation of family members from the preceding generation. These detailed descriptions will be published elsewhere but have reaffirmed the oral histories of endocannibalism in the Fore recorded previously12,22–24 and that this practice ceased abruptly at the time of Australian administrative control over the kuru areas. Although isolated events might have occurred for a few years after this prohibition, we are confident that new exposures of individuals to kuru at mortuary feasts would not have occurred after 1960. Not only have no cases of kuru been recorded in people born after 1959 (and only nine were recorded in those born after 1956); but also all the 11 last recorded cases of kuru that we report here were born before 1950. If any source of infection remained, whether from surreptitious cannibalism, possible ground contam-ination with human prions at sites where food was prepared, or other lateral routes, we would expect individuals born after this period to have kuru—especially since children are thought to have had shorter incubation periods than adults. However, no such cases have been observed. Additionally, although a fraction of hamster-adapted scrapie prions have been shown to survive in soil for at least 3 years,25 the mortuary feast practices (during which the entire body would be consumed) were undertaken so that any substantial contamination of soil would not have occurred, and traditional bamboo knives and leaf plates were burned after the feast. Furthermore, no clusters of kuru cases, as seen earlier in the epidemic,26 have been recorded for many years. We have also reviewed the assertion that maternal transmission of kuru did not occur, and saw no evidence for maternal transmission from kuru archives, interviews of colleagues who have practised medicine in the Fore, or local oral history. Again, any possible vertical route of kuru transmission would have resulted in the presence of kuru in children born after 1960, especially since kuru was common in women of childbearing age; no such cases have occurred.With respect to extrapolation of incubation periods of BSE prion infection in people, we should recognise that the kuru epidemic arose from intraspecies recycling of infectious prions. However, transmission of prions between different mammalian species is associated with a species barrier, which is better described as a transmission barrier, because of the importance of within-species prion strain type, in addition to species-specific differences in its determination.27 The biological effects of such a barrier are: extended mean incubation period; increased spread of incubation periods in individual animals; and reduced attack rate (in which only a fraction of inoculated animals will succumb), by comparison with the 100% mortality generally associated with within-species inoculation with high-titre infectivity. Incubation periods approaching the natural lifespan of the inoculated species are often seen in such primary cross-species transmissions of prions. Second and subsequent passage of prions within the new species is always associated with adaptation involving a considerable shortening of the mean and spread of incubation periods and high or total lethality to high-titre inocula. Thus, estimation of the range of possible incubation periods in human BSE infection needs superimposition of the effect of a transmission barrier onto these findings of natural human incubation periods. The mean incubation period for kuru has been estimated to be around 12 years,27 with a similar estimate in iatrogenic CJD associated with the use of human-cadaver-derived pituitary growth hormone.28 As shown here, maximum incubation periods in kuru can exceed 50 years. The transmission barrier of BSE between cattle and human beings is unknown and cannot be directly measured. However, the cattle-to-mouse barrier for BSE has been well characterised experimentally by comparative endpoint titration. BSE prions transmit readily to laboratory mice, including after oral dosing.29 The murine LD50 (lethal dose causing 50% mortality) in C57Bl/6 mice is about 500-fold higher than that in cattle;30 this barrier also results in a three-fold to four-fold increase in mean incubation period.27 Mean incubation periods of human BSE infection of 30 years or more should therefore be regarded as possible, if not probable,27 with the longest incubation periods approaching (and perhaps exceeding) the typical human lifespan. The shortest incubation periods in kuru were estimated from the age of the youngest patients—suggesting that the shortest incubation period was Articles Vol 367 June 24, 2006 2073 4–5 years. Similarly in vCJD, although the total clinical caseload so far has been small, the youngest onsets of vCJD have been at age 12 years or above, providing an early estimate of a minimum incubation period. Furthermore, prion disease in mice follows a well-defined course with a highly distinctive and repeatable incubation time for a specific prion strain in a defined inbred mouse line. In addition to the PrP gene, a few additional genetic loci with a major effect on incubation period have been mapped.4,31,32 Human homologues of such loci could be important in human susceptibility to prion disease, both after accidental human prion exposure and after exposure to the BSE agent. By definition, patients identified so far with vCJD are those with the shortest incubation periods for BSE. These patients could have received an especially high dose of BSE prions. However, no unusual history of dietary, occupational, or other exposure to BSE has been reported from case-control studies. Because of the powerful genetic effects on incubation period in laboratory animals, vCJD patients identified could represent a distinct genetic subpopulation with unusually short incubation periods to BSE prions, with vCJD so far occurring predominantly in those individuals with short incubation time alleles at these multiple genetic loci, in addition to having the homozygous PRNP genotype of codon 129 methionine. Therefore, a human BSE epidemic may be multiphasic, and recent estimates of the size of the vCJD epidemic based on uniform genetic susceptibility could be substantial underestimations.33,34 Genes implicated in species-barrier effects, which would further increase both the mean and range of human BSE incubation periods, are also probably relevant. In this context, a human epidemic will be difficult to accurately model until such modifier loci are identified and their gene frequencies in the population can be measured.4Heterozygosity at PRNP codon 129 is a major determinant of susceptibility to and incubation time of human prion diseases.5,7,9,35 As expected, most of these recent kuru cases with extended incubation periods (eight of ten) were heterozygotes. We have reported previously that most elderly survivors of exposure to traditional mortuary feasts are heterozygous.9 Although the study included a small number of patients with kuru with long incubation periods, we saw no evidence of association with PRNP haplotype,10 HLA-DQ7,18 APOE,36 or PRND alleles.13


J Whitfield led the field patrol team throughout the study and investigated all suspect cases; E McKintosh provided assistance during this time. J Beck and S Mead undertook the molecular genetic studies. J Collinge, M P Alpers, E McKintosh, and D J Thomas did field neurological examinations. J Collinge and M P Alpers supervised the study and drafted the manuscript. All authors contributed to and approved the final version of the manuscript. .........


Posted by: Terry S. Singeltary Sr. July 25, 2006 07:05 PM


Tuesday, July 28, 2009

The kuru infectious agent is a unique geographic isolate distinct from Creutzfeldt–Jakob disease and scrapie agents

The kuru infectious agent is a unique geographic isolate distinct from Creutzfeldt–Jakob disease and scrapie agents

Laura Manuelidis1, Trisha Chakrabarty, Kohtaro Miyazawa, Nana-Aba Nduom, and Kaitlin Emmerling Section of Neuropathology, Yale University Medical School, 333 Cedar Street, New Haven, CT 06510 Communicated by Sheldon Penman, Massachusetts Institute of Technology, Brookline, MA, May 27, 2009 (received for review March 27, 2009)

Human sporadic Creutzfeldt–Jakob disease (sCJD), endemic sheep scrapie, and epidemic bovine spongiform encephalopathy (BSE) are caused by a related group of infectious agents. The new U.K. BSE agent spread to many species, including humans, and clarifying the origin, specificity, virulence, and diversity of these agents is critical, particularly because infected humans do not develop disease for many years. As with viruses, transmissible spongiform encephalopathy (TSE) agents can adapt to new species and become more virulent yet maintain fundamentally unique and stable identities. To make agent differences manifest, one must keep the host genotype constant. Many TSE agents have revealed their independent identities in normal mice. We transmitted primate kuru, a TSE once epidemic in New Guinea, to mice expressing normal and 8-fold higher levels of murine prion protein (PrP). High levels of murine PrP did not prevent infection but instead shortened incubation time, as would be expected for a viral receptor. Sporadic CJD and BSE agents and representative scrapie agents were clearly different from kuru in incubation time, brain neuropathology, and lymphoreticular involvement. Many TSE agents can infect monotypic cultured GT1 cells, and unlike sporadic CJD isolates, kuru rapidly and stably infected these cells. The geographic independence of the kuru agent provides additional reasons to explore causal environmental pathogens in these infectious neurodegenerative diseases.


Discussion The kuru agent stands out from the other CJD and scrapie agents here on the basis of incubation times, behavior, and neuropathology in 2 mouse genotypes. There was no evidence that it resembles or derives from sCJD. The clearly unique behavioral changes documented with each different agent in mice are compatible with the vastly different regional neuropathological changes that they induce. Additionally, whereas 15 independent sCJD isolates readily transmitted to hamsters (8), the kCJD sample did not. Remarkably, even after several prolonged 350-day serial passages in mice, the sCJD agent retained its capacity to reinfect hamsters with a short 150-day incubation and provoked the original widespread hamster lesions (8). The stability of sCJD agents, regardless of whether first passaged in multiple or in no other species, is also evident in the invariant scratching behavior and the highly restricted thalamic lesions produced in mice. The GT1 culture experiments recapitulated major kCJD and sCJD differences. Whereas sCJD produced negligible PrP-res, kCJD brain homogenates reproducibly infected and stably induced large amounts of PrP-res in GT1 cells. As in brain, kCJD did not provoke any unique agent-specific PrP-res band pattern that bred true. Rather, it showed only the standard GT1 pattern. On the basis of previous results, the GT1 PrP-res pattern confers no demonstrable change in the fundamental identity and behavior of TSE infectious agents (9, 16, 34).

Spleen studies further separated kuru and sCJD agents. The kCJD agent induced major accumulations of abnormal PrP in FDCs of the lymphoreticular system, whereas sCJD isolates provoked very few. Although different species infected with a single agent can show different levels of infectivity and pathological PrP deposits in the spleen, abnormal PrP in the spleen has important biological consequences, given the person-to-person transmission of vCJD by transfusion (11). The observation of abundant deposits in kCJD-infected mouse spleen, in addition to the infectivity of kCJD in primate spleens (31), supports transmission of kuru not only through ingestion but also via the bloodstream from wounds incurred during ritual cannibalism (1). The bloodstream is an excellent conduit for rapid and effective infection of many tissues, including the gastrointestinal tract (12, 35).

We have shown 100% transmission of the infectious kuru agent to both normal and Tg mice with WT murine PrP. Recently, kuru was transmitted to Tg mice overexpressing human PrP sequences (22) but not to normal mice. High numbers of PrP copies can enhance the development of rapid murine models, and the kCJD model here, like the vCJD model previously (11), yielded shorter incubation times than humanized PrP mice. Thus, the TSE infec- tious particle rather than the host’s PrP sequence defines crossspecies virulence. The sCJD agent is also relatively incapable of adaptive evolution in mice. Even after 8 passages, it has a very prolonged incubation time of 300 days, in contrast to kCJD and vCJD. Current and previous data do not support a conversion of homologous PrP to an infectious form, but are in accord with the proposal that host PrP is a required agent receptor that can modulate disease expression. Host receptor differences often modulate viral infection and disease progression. The kCJD and other TSE agents here maintain their fundamental identity, despite their adaptation to a new species and to monotypic cells with disparate cell-type-specific PrP bands.

The PrP-res band patterns often are presumed to encode agentspecific information, yet they are a relatively poor indicator of the biological diversity and stability of TSE agents. In the present studies, only the vCJD agent elicited a consistent PrP-res marker in different species and cell types that bred true. Eleven other independent isolates did not (11, 32). In contrast, incubation times are clearly distinctive for each agent group and nonoverlapping when both CD-1 and Tga20 values are considered. The extreme precision of incubation time with each type of agent is really quite remarkable and remains unexplained by prion theory. It also begs the question of what type of viral (nucleic acid) sequence could lead to this diversity, and this further underscores both complex and subversive interactions between these TSE agents and their hosts. The differential susceptibility of neuronal subtypes with the same PrP to the various TSE agents presents yet another conundrum for prion theory.

There are many aspects of TSE agent biology and structure that remain unresolved, but these agents clearly encode individual virus-like properties. None of these diverse biological properties can be explained parsimoniously by the prion hypothesis or by actual PrP observations. The many distinct geographic TSE agents, the local outbreak of epidemic kuru and BSE, the rare but sudden mutation or progressive selection of new virulent strains (14, 15), and the endemic perpetuation of infection only in exposed hosts (as in sheep scrapie) strongly implicate a viral structure in the environment (10). On a structural level, the presence of nucleic acid in all infectious preparations and the consistent observation of virus-like ultrastructural particles support this hypothesis. Although host PrP as well as other factors may modulate susceptibility to infection and disease phenotype, there is also no simple genetic inheritance pattern, nor evidence for a spontaneous conversion of PrP into an infectious form.

The clear distinction of kuru from western sCJD, its occurrence only in New Guinea, and the observation that Japanese CJD is limited to Asia make one suspect that additional geographic TSE isolates in the environment may be uncovered. The U.S. stopped its scrapie eradication program years ago, before comparative rodent and culture models were introduced. Since then, scrapie agents with new properties may have evolved, possibly facilitating their spread to deer in the U.S. Geographic French scrapie agents are different (31), and Europe appears to be free of U.S. cervid TSE. An understanding of the origin, relative virulence, individual properties, and molecular structure of TSE agents remains a fundamental problem and a public health issue. The distinctive biology of a wide variety of TSE agents revealed in mice and in monotypic cultures already has defined intrinsic agent properties, and simplified cultures may allow one to follow and develop ways to limit the spread of different environmental TSE agents.


snip...see full text ;

Sent: Monday, July 27, 2009 10:31 PM




Tuesday, July 21, 2009

Transmissible mink encephalopathy - review of the etiology

Saturday, June 13, 2009

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

Monday, May 11, 2009

Rare BSE mutation raises concerns over risks to public health

Monday, June 01, 2009

Biochemical typing of pathological prion protein in aging cattle with BSE

Sunday, June 07, 2009


Sunday, May 10, 2009

Identification and characterization of bovine spongiform encephalopathy cases diagnosed and not diagnosed in the United States

Sunday, May 17, 2009


Saturday, April 04, 2009

An unusually presenting case of sCJD-The VV1 subtype Volume 111, Issue 3, Pages 282-291 (April 2009)

IT seems we have come full circle from the 'ORIGINAL 10' i.e. the 1st 10 adolescents in the UKBSEnvCJD only theory. and now we find us at the 1st 10 in USA, or is it the first 10, or the tip of the iceburg, many that went undocumented ???

lets look at the full circle, to date ;

Sunday, August 10, 2008 A New Prionopathy OR more of the same old BSe and sporadic CJD

HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory JUNE 2008


Tissue infectivity and strain typing of the many variants Manuscript of the human and animal TSEs are paramount in all variants of all TSE. There must be a proper classification that will differentiate between all these human TSE in order to do this. With the CDI and other more sensitive testing coming about, I only hope that my proposal will some day be taken seriously. ...


Elsevier Editorial System(tm) for The Lancet Infectious Diseases Manuscript Draft Manuscript Number: Title: HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory Article Type: Personal View Corresponding Author: Mr. Terry S. Singeltary, Corresponding Author's Institution: na First Author: Terry S Singeltary, none Order of Authors: Terry S Singeltary, none; Terry S. Singeltary


TSEs have been rampant in the USA for decades in many species, and they all have been rendered and fed back to animals for human/animal consumption. I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2007. snip...

see full text 31 pages ;

Friday, November 30, 2007


Friday, May 29, 2009

Characterization of a U.S. Sheep Scrapie Isolate with Short Incubation Time

Wednesday, July 1, 2009

Nor98 scrapie identified in the United States J Vet Diagn Invest 21:454-463 (2009)

Monday, June 01, 2009 Biochemical typing of pathological prion protein in aging cattle with BSE


O.K. confusious asks, IF all these new atypical BSEs i.e. new strains of mad cow disease is just an 'OLD COW PRION DISEASE', why then can not the 'old human prion disease' such as the sporadic CJD, be from an 'old cow prion disease', same as the nvCJD 'young people mad cow disease' (which also happens in 74 year old), but why cannot the 'old cow prion diseases', i.e. l-BSE, h-BSE, and ibncBSE, cause the 'old people prion disease', which looks like sporadic CJD. seems that is what some of the pathology is showing ???

OH, that probably makes too much sense, and that the only answer could be that it's all just a happenstance of bad luck and or a spontaneous event, that just happens out of the clear blue sky $$$


Sunday, April 12, 2009

CWD UPDATE Infection Studies in Two Species of Non-Human Primates and one Environmental reservoir infectivity study and evidence of two strains

Thursday, April 03, 2008

A prion disease of cervids: Chronic wasting disease

2008 1: Vet Res. 2008 Apr 3;39(4):41

A prion disease of cervids: Chronic wasting disease

Sigurdson CJ.


*** twenty-seven CJD patients who regularly consumed venison were reported to the Surveillance Center***,


full text ;

From: TSS (


Date: September 30, 2002 at 7:06 am PST

From: "Belay, Ermias"


Cc: "Race, Richard (NIH)" ; ; "Belay,


Sent: Monday, September 30, 2002 9:22 AM


Dear Sir/Madam,

In the Archives of Neurology you quoted (the abstract of which was

attached to your email), we did not say CWD in humans will present like

variant CJD.

That assumption would be wrong. I encourage you to read the whole

article and call me if you have questions or need more clarification

(phone: 404-639-3091). Also, we do not claim that "no-one has ever been

infected with prion disease from eating venison." Our conclusion stating

that we found no strong evidence of CWD transmission to humans in the

article you quoted or in any other forum is limited to the patients we


Ermias Belay, M.D.

Centers for Disease Control and Prevention

-----Original Message-----


Sent: Sunday, September 29, 2002 10:15 AM

To: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000146/!; mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000146/!; mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000146/!x-usc:mailto:ebb8@CDC.GOV



Sunday, November 10, 2002 6:26 PM ......snip........end..............TSS


A. Aguzzi - Chronic Wasting Disease (CWD) also needs to be addressed. Most

serious because of rapid horizontal spread and higher prevalence than BSE in

UK, up to 15% in some populations. Also may be a risk to humans - evidence

that it is not dangerous to humans is thin.


Chronic Wasting Disease and Potential Transmission to Humans

Ermias D. Belay,* Ryan A. Maddox,* Elizabeth S. Williams,? Michael W. Miller,? Pierluigi Gambetti,§ and Lawrence B. Schonberger*

*Centers for Disease Control and Prevention, Atlanta, Georgia, USA; ?University of Wyoming, Laramie, Wyoming, USA; ?Colorado Division of Wildlife, Fort Collins, Colorado, USA; and §Case Western Reserve University, Cleveland, Ohio, USA

Suggested citation for this article: Belay ED, Maddox RA, Williams ES, Miller MW, Gambetti P, Schonberger LB. Chronic wasting disease and potential transmission to humans. Emerg Infect Dis [serial on the Internet]. 2004 Jun [date cited]. Available from:

Chronic wasting disease (CWD) of deer and elk is endemic in a tri-corner area of Colorado, Wyoming, and Nebraska, and new foci of CWD have been detected in other parts of the United States. Although detection in some areas may be related to increased surveillance, introduction of CWD due to translocation or natural migration of animals may account for some new foci of infection. Increasing spread of CWD has raised concerns about the potential for increasing human exposure to the CWD agent. The foodborne transmission of bovine spongiform encephalopathy to humans indicates that the species barrier may not completely protect humans from animal prion diseases. Conversion of human prion protein by CWD-associated prions has been demonstrated in an in vitro cell-free experiment, but limited investigations have not identified strong evidence for CWD transmission to humans. More epidemiologic and laboratory studies are needed to monitor the possibility of such transmissions.

snip...full text ;

please see ;

Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518