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further into this study;
Discussion
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
http://www.thelancet.com 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
Contributors
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. .........
snip...end...TSS
----- Original Message -----
From: "Terry S. Singeltary Sr." <
[email protected]>
To: <
[email protected]>
Sent: Thursday, June 22, 2006 7:48 PM
Subject: Kuru in the 21st century—an acquired human prion disea se
##################### Bovine Spongiform Encephalopathy
#####################
CJD WATCH MESSAGE BOARD
TSS
Kuru in the 21st century—an acquired human prion disease
Thu Jun 22, 2006 19:44
70.110.82.186
The Lancet 2006; 367:2068-2074
DOI:10.1016/S0140-6736(06)68930-7
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.
Affiliations
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
http://www.thelancet.com/journals/lance ... 7/abstract
TSS
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. >>
http://www.thelancet.com/webfiles/image ... ne2006.mp3
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Human mad cow infection could hide for 50 years
Jennifer Cooke
June 24, 2006
INFECTION with the lethal prions that cause the human form of "mad cow" disease could last more than 50 years before symptoms appear, research based on an old cannibal disease from Papua New Guinea shows.
During that time, victims with silent infection could pass on the prions via blood transfusions, organ or tissue donations or insufficiently sterilised metal surgical instruments.
In a unique piece of research which continues the meticulous records that have tracked the epidemic of kuru - the "shivering" disease - since 1957, Australian, British and PNG researchers tracked a group of 11 former cannibals dying from the always fatal prion disease between 1996 and 2004.
Forming the tail-end of the epidemic, they were all born before 1950 and took part in endocannibalism, a ritual in which the whole body of deceased relatives was consumed as a sign of love and respect. The ritual was eradicated by Australian authorities by 1960.
The data gathered on these victims and published today in The Lancet have provided a model using actual cases instead of the usual mathematical modelling for future predictions for those infected after eating beef products contaminated with bovine spongiform encephalopathy (BSE). The human equivalent of BSE is variant Creutzfeldt-Jakob disease (vCJD).
Apart from the emerging epidemic of vCJD, in which 192 people have died since 1995 - mainly in Britain, but also in France, Ireland, Canada, the US, Saudi Arabia, Japan, Italy, Hong Kong and the Netherlands - kuru is the only other major human epidemic of prion disease with an oral transmission route.
British prion experts, including Professor John Collinge from University College London, and Professor Michael Alpers from Curtin University - the Australian kuru expert who has followed the disease since arriving in PNG in 1962 - calculated the minimum incubation period for kuru starting at 1960 to the birth year of the last recorded patient.
That minimum incubation time ranged from 34 to 41 years but in men it was calculated to be between 39 and 56 years - and possibly up to seven years longer.
For vCJD it might be even longer, because the infection was transmitted between species, from cows to humans, which usually takes longer than infection within the same species.
Australian prion experts have closely monitored the decade-old vCJD epidemic, and have long recognised from continuing kuru cases that incubation periods could top 50 years.
A professor of pathology and a CJD expert at the University of Melbourne, Colin Masters, commented yesterday: "These new data reinforce our need to maintain vigilance over potential risks to the safety of Australia's blood supply, since it has now been demonstrated that vCJD can be transmitted by blood transfusions."
In an accompanying editorial, The Lancet stated: "Any belief that vCJD incidence has peaked and that we are through the worst of this sinister disease must now be treated with extreme scepticism."
http://www.smh.com.au/news/world/human- ... 78945.html
TSS
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