Iatrogenic CJD due to pituitary-derived growth hormone with genetically determined incubation times of up to 40 years
Iatrogenic CJD due to pituitary-derived growth hormone with genetically
determined incubation times of up to 40 years
Peter Rudge, Zane Jaumuktane, Peter Adlard, Nina Bjurstrom, Diana Caine,
Jessica Lowe, Penny Norsworthy, Holger Hummerich, Ron Druyeh, Jonathan D. F.
Wadsworth, Sebastian Brandner, Harpreet Hyare, Simon Mead, and John Collinge
Brain published 11 August 2015, 10.1093/brain/awv235
Iatrogenic CJD due to pituitary-derived growth hormone with genetically
determined incubation times of up to 40 years
(CC) Peter Rudge, Zane Jaumuktane, Peter Adlard, Nina Bjurstrom, Diana
Caine, Jessica Lowe, Penny Norsworthy, Holger Hummerich, Ron Druyeh, Jonathan D.
F. Wadsworth, Sebastian Brandner, Harpreet Hyare, Simon Mead, John Collinge DOI:
http://dx.doi.org/10.1093/brain/awv235
First published online: 12 August 2015 Summary Patients with iatrogenic
Creutzfeldt-Jakob disease due to administration of cadaver-sourced growth
hormone during childhood are still being seen in the UK 30 years after cessation
of this treatment. Of the 77 patients who have developed iatrogenic
Creutzfeldt-Jakob disease, 56 have been genotyped. There has been a marked
change in genotype profile at polymorphic codon 129 of the prion protein gene
(PRNP) from predominantly valine homozygous to a mixed picture of methionine
homozygous and methionine-valine heterozygous over time. The incubation period
of iatrogenic Creutzfeldt-Jakob disease is significantly different between all
three genotypes. This experience is a striking contrast with that in France and
the USA, which may relate to contamination of different growth hormone batches
with different strains of human prions. We describe the clinical, imaging,
molecular and autopsy features in 22 of 24 patients who have developed
iatrogenic Creutzfeldt-Jakob disease in the UK since 2008. Mean age at onset of
symptoms was 42.7 years. Gait ataxia and lower limb dysaesthesiae were the most
frequent presenting symptoms. All had cerebellar signs, and the majority had
myoclonus and lower limb pyramidal signs, with relatively preserved cognitive
function, when first seen. There was a progressive decline in neurological and
cognitive function leading to death after 5–32 (mean 14) months. Despite
incubation periods approaching 40 years, the clinical duration in methionine
homozygote patients appeared to be shorter than that seen in heterozygote
patients. MRI showed restricted diffusion in the basal ganglia, thalamus,
hippocampus, frontal and the paracentral motor cortex and cerebellar vermis. The
electroencephalogram was abnormal in 15 patients and cerebrospinal fluid 14-3-3
protein was positive in half the patients. Neuropathological examination was
conducted in nine patients. All but one showed synaptic prion deposition with
numerous kuru type plaques in the basal ganglia, anterior frontal and parietal
cortex, thalamus, basal ganglia and cerebellum. The patient with the shortest
clinical duration had an atypical synaptic deposition of abnormal prion protein
and no kuru plaques. Taken together, these data provide a remarkable example of
the interplay between the strain of the pathogen and host prion protein
genotype. Based on extensive modelling of human prion transmission barriers in
transgenic mice expressing human prion protein on a mouse prion protein null
background, the temporal distribution of codon 129 genotypes within the cohort
of patients with iatrogenic Creutzfeldt-Jakob disease in the UK suggests that
there was a point source of infecting prion contamination of growth hormone
derived from a patient with Creutzfeldt-Jakob disease expressing prion protein
valine 129.
snip...
Discussion
This study, covering the period from 2000–14, shows that iatrogenic CJD due
to cadaver-sourced pituitary growth hormone, a treatment that was discontinued
in 1985 in the UK, continues to occur in the UK at a frequency of 0–6 cases per
annum. Incubation periods are now extraordinarily long, with estimates ranging
from 18–40 years, the uncertainty based on clinical onsets and lengths of
treatment with potentially infected batches. In this paper we have reviewed the
clinical features, progression, imaging abnormalities, prion protein genotype,
PrPSc type by western blot and preliminary neuropathology data.
Clinical features and imaging correlations Typically patients with growth
hormone induced iatrogenic CJD present with gait ataxia, cerebellar dysarthria
and lower limb pain with cognitive function much less affected. Later sleep
disturbance, cognitive decline and pyramidal signs with weakness in the lower
limbs develops. Ultimately, the patient enters an akinetic mute state typical of
all types of CJD with death at 4–32 (mean 16.0) months after the initial
presentation. There are several points of special interest in this clinical
presentation.
First, gait ataxia, with much less limb ataxia, especially in the upper
limbs, is typical of superior cerebellar vermis damage. The MRI and pathological
examination of the cerebellum demonstrated extensive damage of the vermis with
lesser involvement of the cerebellar hemispheres consistent with these clinical
findings. Interestingly, in addition to gait ataxia, two of the patients
presented with abnormal visual input imbalance characterized by unsteadiness
induced by moving stimuli (waves when paddling and looking at moving water)
suggesting abnormal visual vestibular interaction partly dependent on cerebellar
pathways.
Second, pain in the lower limbs was of a quality suggesting abnormal
spino-thalamic function and MRI confirmed a diffuse abnormality of the thalamus
which, although maximal medially, did extend laterally to the ventro-posterior
components, part of the pain and thermal pathways. Of note is the similarity of
this pain to that experienced by many patients with variant CJD and kuru, which
are also acquired prion diseases associated with peripheral infection with
prions where thalamic involvement, especially posteriorly, occurs. However, a
contribution of the more peripheral components of the spino-thalamic system
cannot be excluded.
Third, later in the course of the disease cognitive dysfunction with
prominent memory decline emerged. The extensive involvement of many areas of the
deep nuclei, thalamus and cortex could explain this, but of note is the
prominent involvement of the hippocampus on MRI and pathologically. This,
together with the thalamic changes, is an adequate explanation of the amnesia.
Thalamic involvement would also explain the sleep disturbance similar to that
occurring in fatal familial insomnia (FFI) and frequently seen in sporadic CJD.
Finally, weakness in the lower limbs due to pyramidal involvement
correlated with cortical ribboning involving the dorsal and medial motor strip
demonstrated on MRI in most patients. Such involvement of the motor cortex is
rare in other forms of prion disease. More pronounced involvement of the motor
cortex and parietal lobe when compared with the anterior frontal or occipital
cortex was also confirmed morphologically with extensive micro-vacuolar change
and intense deposition of synaptic abnormal prion protein.
Neuropathology A detailed quantitative analysis of the pathology in the
nine autopsied cases will be the subject of a separate communication. However, a
striking feature was the presence of PrP plaques in all but one case. This
latter non-plaque case suggests that the different pathological appearances
might be caused by different prion strains. Similarly, iatrogenic CJD due to
dural grafts, a condition particularly prevalent in Japan, may show two distinct
pathologies, plaque-type and non-plaque-type, which have been linked with
differing transmission properties in transgenic mice (Kobayashi et al., 2014).
It is possible that future studies using material from the original batches of
pituitary-derived growth hormone and transgenic mice could clarify the
pathogenesis of the disease in our cases and comparison with the literature on
dural graft iatrogenic CJD.
PRNP codon 129 polymorphism determines incubation time A remarkable feature
of iatrogenic CJD cases in the UK is the distribution of the codon 129
polymorphism. An excess of VV homozygotes was reported in early UK cases and
then thought to be a marker of susceptibility (Collinge et al., 1991). MV
heterozygosity was reported to confer relative resistance to sporadic CJD
(Palmer et al., 1991). In the initial study of 27 UK patients 52% were
homozygous for valine and only 4% (one case) was homozygous for methionine; the
remainder were heterozygotes. This contrasts with the French experience in 77
patients where 48% were homozygous for methionine and 22% homozygous for valine
(Brandel et al., 2003). Similar proportions were also found in the few cases
reported from the USA (Brown et al., 2012). Furthermore in sporadic CJD, kuru
and variant CJD, methionine homozygosity predominates. This is thought to result
from the relative resistance afforded by heterozygosity at polymorphic PrP
residue 129 and from conformational selection whereby different prion strains
are preferentially propagated by prion proteins of different primary sequence
(Collinge, 1999; Collinge and Clarke, 2007). For example the bovine spongiform
encephalopathy-related prion strain causing variant CJD appears only to be
compatible with methionine 129 human PrP (Wadsworth et al., 2004).
One of the new findings of our study of UK patients is that there has been
a change in the distribution of the 129 polymorphism in the past 12 years. The
VV genotype has now greatly decreased and MM genotype increased while the
frequency of heterozygotes has remained relatively constant. There are
similarities and differences from the studies of kuru (Cervenakova et al., 1999;
Collinge et al., 2006; Mead et al., 2009b). In kuru both homozygous genotypes
predominated in young cases with presumably a shorter incubation time, but in
later and older cases heterozygotes occurred more frequently.
A possible explanation for these superficially contradictory distributions
of codon 129 in different outbreaks could be the compatibility of host genotype
and strain of the infecting prion, in keeping with the conformational selection
model of prion transmission (Collinge, 1999; Collinge and Clarke, 2007). This
model suggests that transmission is facilitated, with shorter incubation times,
if the host prion protein can readily adopt the preferred conformation
associated with the strain of the infecting prion. In the case of the UK, it is
likely that one particular preparation (Hartree modified Wilhelmi preparation)
was responsible for the outbreak as all patients to date received this
preparation.
Swerdlow et al. (2003) estimated that ∼400 000 pituitaries were harvested
for growth hormone production, but even this may be an underestimate. Attempts
were made to exclude patients who had neurological diseases but protocols for
harvesting were not strictly monitored (Swerdlow et al., 2003). It is likely
that some of these pituitary glands were sourced from cases with CJD; in the
1970s, the time when the majority of pituitary sourced growth hormone was
obtained, it is estimated from UK mortality data that 1 in 7000 deaths would
have been due to sporadic CJD. Two-thirds of cases of sporadic CJD worldwide are
of the 129MM genotype and therefore it is not surprising that most cases of
iatrogenic CJD outside the UK were of this genotype. However, in the present
series, the pattern was different with the early patients, which were
predominantly of the VV genotype. As only ∼24% of cases of sporadic CJD are
129VV the question arises as to why the UK patients differ from the rest of the
world in this regard.
One possibility is that the screening of donors was more successful than
suggested above and by chance only one or two cases of sporadic CJD were the
source of the growth hormone and these had an atypical phenotype that occured
more frequently in VV or MV cases. Alternatively many donors were included,
however, a single VV or MV case had a particularly high titre of infective
material in the pituitary. The profound influence of codon 129 in controlling
human prion transmission barriers has been extensively modelled in transgenic
mice expressing human PrP on a mouse PrP null background (Wadsworth et al.,
2010). These studies have shown that transmission barriers to infection with
classical CJD prions are asymmetric, dependent upon the codon 129 genotype of
the prion source and the recipient (Wadsworth et al., 2010). Whereas, transgenic
mice expressing human PrP 129 valine are highly susceptible to classical CJD
prions regardless of the PrPSc type or codon 129 genotype of the inoculum
(Collinge et al., 1995, 1996; Telling et al., 1995; Hill et al., 1997; Korth et
al., 2003; Kobayashi et al., 2007; Wadsworth et al., 2008b), the absence of a
transmission barrier to classical CJD prions is not uniformly observed in mice
expressing human PrP 129 methionine in the absence of mouse PrP. Here, mismatch
at residue 129 between the inoculum and host can significantly affect
transmission. Thus while there appears to be no barrier to transmission of
classical CJD prions from codon 129 methionine homozygous patients (Asante et
al., 2002; Korth et al., 2003; Beringue et al., 2008; Kong et al., 2008),
transmission of classical CJD prions from valine homozygous patients is often
associated with more prolonged and variable incubation periods and reduced
attack rates (Asante et al., 2002; Korth et al., 2003; Kobayashi et al., 2007,
2015). In the case of classical CJD prions from codon 129 heterozygous patients
the transmission efficiency in transgenic mice expressing human PrP 129
methionine varies dependent upon PrPSc type and whether prions are propagated on
human PrP with methionine or valine at residue 129 (Asante et al., 2002; Korth
et al., 2003; Bishop et al., 2010; Kobayashi et al., 2015). These data provide
an experimental background with which to interpret the temporal distribution of
codon 129 genotypes within the cohort of iatrogenic CJD patients in the UK and
suggest that the infecting prion contamination of growth hormone was from a VV
or MV individual.
Finally, the significance of the polymorphism in RRP9 found on exome
sequencing is unclear. The sample is small and the finding requires replication
in an independent cohort. Any association could be related to either the initial
condition for which the patients were treated or iatrogenic disease or both.
Mismatch of incubation period and rapidity of symptomatic progression A
further seemingly paradoxical observation is that those recent clinical cases
with particularly long incubation times have had the shortest clinical durations
once symptomatic. Rates of clinical decline in our series of iatrogenic CJD have
been most in keeping with observations of sporadic CJD with the MM genotype
being more rapid than MV (Pocchiari et al., 2004). A plausible explanation for
these observations is that the generation of a host prion strain compatible with
host genotype occurs in the periphery during the prolonged incubation time;
however, following CNS invasion the rapidity of disease progression [which is
thought to be determined by the rates of production of toxic PrP species
(designated PrPL for lethal); Hill et al., 2000; Collinge and Clarke, 2007;
Sandberg et al., 2011, 2014] is more rapid in MM versus MV individuals owing to
higher levels of homotypic substrate PrP available for conversion.
Conclusion
This study is the first to clearly define the clinical, imaging and
neuro-pathological characteristics of patients with iatrogenic CJD due to
cadaver-sourced growth hormone. It demonstrates that cases continue to occur at
a low but steady rate in the UK and that the incubation period can be up to four
decades. We have shown that all three common genotypes at PRNP are susceptible
albeit with markedly different incubation periods, a phenomenon also seen in
kuru. Whether similar susceptibility, with differing mean incubation times, will
be seen in the UK related to the transmission of bovine spongiform
encephalopathy prions remains to be seen. Further, we have demonstrated a
dissociation between the incubation period and the rapidity of decline once a
person develops symptoms.
Funding This work was funded by the UK Medical Research Council. The Cohort
study was initially funded by the Department of Health (England) and has been
funded since 2012 by the National Institute of Health Research’s Biomedical
Research Centre at University College London Hospitals NHS Foundation Trust.
Conflict of interest J.C. is a Director and J.C. and J.D.F.W. are
shareholders of D-Gen Limited which owns one of the antibodies used in this
study.
Supplementary material Supplementary material is available at Brain online.
Acknowledgements We thank the National Prion Disease Monitoring Cohort
steering committee- C Kennard, P Mills, V Farewell, P Chinnery, A Mackay, E
Riboli, R Knight. We thank all the patients, their carers and families, who took
part in the Cohort study and UK neurologists and the National CJD Surveillance
Unit for referring patients. We thank officials at the Department of Health,
Medical Research Council Research Management Group staff, co-chairs of the
PRION-1 and Cohort trial steering committee, and our colleagues at the National
CJD Research Surveillance Unit for establishing the National CJD referral and
data sharing arrangements, without which these studies would not have been
possible. We particularly acknowledge the contribution of J. Ironside and M.
Bishop for providing genotypes at PRNP codon 129 in six cases previously
unpublished. We thank all past and present colleagues at the National Prion
Clinic (formerly at St Mary’s Hospital, London and now at the National Hospital
for Neurology and Neurosurgery, Queen Square, London) in particular Kizzy Alner,
Sylvia Gamazo- Navarro, Durre Siddique, Suvankar Pal, Thomas Webb, Diego Kaski,
Dillip Gallujipali, Kathryn Prout, Nora Heard, Clare Morris, Rita Wilkinson,
Chris Rhymes, Suzanne Hampson, Claire Petersen, Chris Carswell, Joanna Field,
Elisabeth Morgan, Imogen Eastwood, Liz Ford, Jane Owen, Veronica O’Donnell,
Michele Gorham, Ekaterina Kassidi, and Colm Treacy and at the Medical Research
Council Clinical Trials Unit, in particular Michael Ranopa, Geraldine Keogh,
Moira Spyer, Debbie Johnson, Liz Brodnicki, and Patrick Kelleher.
iatrogenic Creutzfeldt-Jakob disease growth hormone prion disease RRP9PRNP
P.69: Distinct pathological phenotypes of Creutzfeldt-Jakob disease in
recipients of prion-contaminated growth hormone
Ignazio Cali1,2, Cathleen Miller3, Tetsuyuky Kitamoto4, Joseph Parisi5,
Michael Geschwind6, Pierluigi Gambetti1, and Lawrence Schonberger7 1National
Prion Disease Pathology Surveillance Center (NPDPSC); Department of Pathology;
Case Western Reserve University; School of Medicine; Cleveland, OH USA;
2Department of Clinical and Experimental Medicine; Second University of Naples;
Naples, Italy; 3Kaiser Permanente Vancouver Medical Center; Vancouver, WA USA;
4Graduate School of Medicine; Tohoku University; Sendai, Japan; 5Departments of
Laboratory Medicine & Pathology and Neurology; Mayo Clinic; Rochester,
MN USA; 6Department of Neurology; Memory and Aging Center; University of
California; San Francisco, CA USA; 7National Center for Emerging and Zoonotic
Infectious Diseases; Centers for Disease Control and Prevention; Atlanta, GA USA
The peripheral administration of growth hormone (GH) from
prion-contaminated cadaveric pituitary glands is believed to be causative of
iatrogenic Creutzfeldt-Jakob disease (iCJD) in more than 225 subjects worldwide.
The present study describes the neuropathology and molecular features of 3 of
the 30 identified iCJD cases among the approximately 7,700 recipients of
cadaveric pituitary hormone in the US National Hormone and Pituitary Program
(NHPP). All three cases were methionine (M) homozygous at codon 129 of the prion
protein (PrP) gene (GH-CJDMM) and all received NHPP hormone produced before 1977
when a new hormone purification protocol was introduced that reduced the risk of
prion contamination. Neuropathological examination revealed divergent
phenotypes. The first phenotype, observed in the most recent US NHPP GH-CJD
case, was characterized by the presence of amyloid plaques and reminiscent of
sCJDMV2-K and, to some extent, variant CJD (vCJD). The second phenotype showed
no plaques and shared several, but not all, characteristics with the sCJDMM(MV)1
subtype. However, PKresistant PrPSc (resPrPSc) from GH-CJDMM co-migrated with
resPrPSc type 1 (GHCJDMM1) of sCJDMM1, but not with type 2 of sCJDMV2-K.
Histopathological phenotypes with or without plaques also have been described in
2 groups of Japanese dura mater (d) graft-associated CJD (dCJD) with the same
129MM genotype but apparently different gel mobility of resPrPSc type 1. ***Our
study suggests that phenotypic diversity in these iatrogenic diseases reflects
adaptation of different exogenous prion strains to the 129MM host and/or to
different locations of the initial PrPC to PrPSc conversion.
J Neurol Neurosurg Psychiatry 2002;72:792-793 doi:10.1136/jnnp.72.6.792
Short report
Creutzfeldt-Jakob disease 38 years after diagnostic use of human growth
hormone
E A Croes1, G Roks1,*, G H Jansen3, P C G Nijssen2, C M van Duijn1
+ Author Affiliations 1Genetic Epidemiology Unit, Department of
Epidemiology and Biostatistics, Erasmus University Medical Centre Rotterdam, PO
Box 1738, 3000 DR Rotterdam, Netherlands 2Department of Neurology, St Elisabeth
Hospital, PO Box 90151, 5000 LC Tilburg, Netherlands 3Department of Pathology,
University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht,
Netherlands
Correspondence to: Professor C M van Duijn, Genetic Epidemiology Unit,
Department of Epidemiology and Biostatistics, Erasmus University Medical Centre
Rotterdam, PO Box 1738, 3000 DR Rotterdam, Netherlands; vanduijn@epib.fgg.eur.nl
Received 27 December 2001 Accepted 12 March 2002 Revised 1 March 2002
Abstract
A 47 year old man is described who developed pathology proven
Creutzfeldt-Jakob disease (CJD) 38 years after receiving a low dose of human
derived growth hormone (hGH) as part of a diagnostic procedure. The patient
presented with a cerebellar syndrome, which is compatible with iatrogenic CJD.
This is the longest incubation period described so far for iatrogenic CJD.
Furthermore, this is the first report of CJD after diagnostic use of hGH. Since
the patient was one of the first in the world to receive hGH, other cases of
iatrogenic CJD can be expected in the coming years.
snip...
An incubation period as long as 38 years had never been reported for
iatrogenic CJD. Huillard d'Aignaux et al7 studied the incubation period in 55
patients with hGH related CJD in a cohort of 1361 French hGH recipients. The
median incubation period was between 9 and 10 years. Under the most pessimistic
model, the upper limit of the 95% confidence interval varied between 17 and 20
years. Although the infecting dose cannot be quantified, it can be speculated
that the long incubation period in our patient is partly explained by the
administration of a limited amount of hGH. This hypothesis is supported by
experimental models, in which higher infecting doses usually produce shorter
incubation periods.6 Since our patient was one of the first in the world to
receive hGH, this case indicates that still more patients with iatrogenic CJD
can be expected in the coming years. Another implication of our study is that
CJD can develop even after a low dose of hGH. This case once more testifies that
worldwide close monitoring of any form of iatrogenic CJD is mandatory.
SHORT REPORT
Creutzfeldt-Jakob disease 38 years after diagnostic use of human growth
hormone
the warning shots fired over the bow of the boat that were never heard ;
PITUITARY EXTRACT
This was used to help cows super ovulate. This tissue was considered to be
of greatest risk of containing BSE and consequently transmitting the disease...
NON-LICENSED HUMAN TISSUE DEVICES WERE NOT COMMERCIALLY AVAILABLE
snip...
I was quite prepared to believe in unofficial pituitary hormones, also in
the 1970's, whether as described by Dr. Little, or in other circumstances, for
animal use.
snip...
The fact that there were jars of pituitaries (or extract) around on shelves
is attested by the still potent 1943 pituitaries, described in Stockell Hartree
et al. (J/RF/17/291) which had come from the lab. at Mill Hill. Having taken the
trouble to collect them, they were not lightly thrown out...
3. The extraction is from a pool of pituitary glands collected from
abbatoirs and the process used is unlikely to have any effect on the BSE agent.
Hormones extracted from human pituitary glands have been responsible for a small
number of Creutzfeldt Jacob disease in man.
SEE LOOPHOLE ;
SEE LOOPHOLE SHOULD BE CLOSED ;
Superovulation and embryo recovery in Red deer (Cervus elaphus ) hinds.
Fennessy PF1, Fisher MW, Shackell GH, Mackintosh CG. Author information
1Invermay Agricultural Centre Private Bag Mosgiel New Zealand.
Abstract
In two experiments, Red deer hinds were synchronized with intravaginal
progesterone and were given 4 d of treatment (3 d before progesterone withdrawal
and 1 d after) with an ovine follicle stimulating hormone (FSH) preparation
which had a claimed low level of luteinizing hormone (LH) contamination. In
Experiment 1, 12 hinds received one of four FSH levels by osmotic minipump.
Hinds were run with fertile stags, and laparotomy and embryo recovery were
performed 9 d after progesterone withdrawal. The ovulation rates (mean of three
hinds per dosage) were 1.0, 2.0, 4.3 and 15.3 (number of corpora lutea counted)
for estimated daily dosages rates of 0.036, 0.071, 0.11 and 0.14 units FSH
preparation/day; the response to the increasing dosage was exponential
...snip...end
ovine follicle stimulating hormone (FSH)
F8174 Sigma Follicle Stimulating Hormone from sheep pituitary Synonym: FSH
Sunday, August 02, 2015
*** TEXAS CWD, Have you been ThunderStruck, deer semen, straw bred bucks,
super ovulation, and the potential TSE Prion connection, what if? ***
************
‘’I shall not forget the profound effect on my emotions when I visited
these farms and was warmly welcomed because of the great benefits resulting from
the application of louping-ill vaccine, wheras the chief purpose of my visit was
to determine if scrapie was appearing in the inoculated sheep. The enquiry made
the position clear. Scrapie was developing in the sheep vaccinated in 1935 and
it was only in a few instances that the owner was associating the occurrence
with louping-ill vaccination. The disease was affecting all breeds and it was
confined to the animals vaccinated with batch 2.’’
************
SOME OTHER HISTORY HERE PITUITARY HORMONES AND TSE PRION ;
In 1993 the Allar’s inquiry into the use of cadaver-derived pituitary
hormones under The Australian Human Pituitary Hormone Program and the
association with four medically acquired (iatrogenic) Creutzfeldt-Jakob disease
(CJD) deaths recommended the formation of an Australian surveillance unit to
monitor further cases of iatrogenic CJD in Australia.1 The Australian National
Creutzfeldt-Jakob disease Registry (ANCJDR) was established in October 1993 at
the Department of Pathology at the University of Melbourne. The monitoring of
further Australian iatrogenic CJD cases related to pituitary hormone treatment
for infertility or short stature and contaminated dura mater grafts remains one
of the core objectives of the ANCJDR. However, the ANCJDR’s activities have
changed to encompass the surveillance of all types of CJD including sporadic,
genetic and variant CJD and other transmissible spongiform encephalopathies
(TSEs) such as Gerstmann Sträussler-Sheinker Syndrome (GSS) and fatal familial
insomnia (FFI).
see more here ;
Saturday, November 09, 2013
Surveillance for creutzfeldt-Jakob disease in Australia: update to December
2012
Background of Australian Human Pituitary Hormone Program From 1967 until
1985 2,100 Australians were treated with human pituitary hormones under the
Australian Human Pituitary Hormone Program (AHPHP).
In similar programs in overseas countries the majority of recipients of
human pituitary hormones (hPH) were treated with human growth hormone (hGH) for
short statue. In Australia the Australian Human Pituitary Hormone Program
(AHPHP) treated approximately 1570 woman and about 60 men for infertility using
human pituitary gonadotrophin (hPG). Approximately 660 Australian children were
treated for short statue with human growth hormone (hGH).
Five Australians may so far have developed and died from health-care
associated (iatrogenic) Creutzfeldt-Jakob disease (CJD) after hPH treatment .
The program was suspended in 1985 following CJD deaths of recipients of hGH in
the United States and England.
All those treated with hPH are at low risk of developing CJD. There is no
way of knowing if batches received by recipients were contaminated. To date
there is no test to show if recipients are incubating CJD.
The AHPHP was run under the auspices of the Commonwealth Department of
Health. The hormones were manufactured by the then government-owned Commonwealth
Serum Laboratories in Melbourne.
The AHPHP was conceived and operated by the Human Pituitary Advisory
Committee (HPAC) until its activities ceased in 1985 and the committee was
disbanded.
From 1992 intense media and political pressure followed news of the first
two deaths from iatrogenic CJD as the families demanded an explanation. The then
Minister for Health, Senator Graham Richardson, ordered an independent inquiry.
Associate Professor Margaret Allars, an administrative law expert from the
University of Sydney conducted the inquiry into the use of Pituitary Derived
Hormones in Australia and Creutzfeldt-Jakob Disease, which reported in June
1994.
The inquiry report made a number of recommendations concerning the care of
recipients, the establishment of support services and the formation of a
ministerial advisory council.
Recipients of hPH now live with a health status of being at “low risk” of
CJD. Current infection control guidelines refer to “low risk” patients.
Recipients and their families also live with anxiety linked to the threat of
contracting a disease which can lie dormant for decades and for which there is
no test, treatment or cure.
Tuesday, November 23, 2010
Prosecutors call for prison terms for CJD growth hormone doctors
Tuesday, May 04, 2010
Review of the Human Pituitary Trust Account and CJD Issue 20 January 2010
Creutzfeldt-Jakob Disease, CJD Support Group for short statured children of
the 1970's and 1980's. Recommendations for Unapproved/Unregistered recipients
wonder how Michael is doing today ??? hope is all well...
Mr. Michael O'Meara
Senator Bernardi Senator for South Australia Michael O’Meara 120 Port Road
P.O. Box 250 Hindmarsh SA 5007 Kinglake 3763 24th February 24, 2009
Dear Senator Bernardi
Re; Senate Committee Inquiry on Men’s Health
It is with regret that the 60 page submission I was preparing for this
inquiry was lost in the recent Kinglake Bushfire, along with all other property
and possessions of mine, and I now submit an abbreviated submission. Under such
personal adversity, I believe this submission falls within the Terms of
Reference.
Its is with pleasure that this submission be accepted in accordance with
your Notice Of Motion (276) published in November 2008, some 5 months after a
Private Member Motion was read in the House of Representatives. The Member for
McEwen (Ms Fran Bailey) read a very emotional speech in the House (Committee
Room) on 16th June 2008, supported by the Member for Moore, (Dr Mal Washer) and
further with bipartisan support by the Rudd Government - expressed by the
Members of Page, (Ms Janelle Saffin) and Dobell, (Mr. Craig Thomson)
It is with my pleasure that I submit the following Submission on behalf of
myself and all other (then) boys and men treated with Human Pituitary Hormones,
unofficially, and not recorded, under the Australian Human Pituitary Hormone
Program, and who have suffered, with both short term and long term side effects
to the male endocrine system as a result of such Human Experimentation, and with
such side effects that are irreversible.
Approved Recipients of Human Growth Hormone or Human Pituitary
Gonadotrohpin were subjected to a Senate Inquiry in 1993, known as “The Allars
Inquiry”, however – unapproved and/or “Off Program” recipients who were not
included in the Allars Inquiry, and whom were not disclosed to the Department of
Health and Aging, who are at the same risk of CJD, and were never advised of
their risk, particularly unrecorded recipients of hPG at Prince Henry’s Hospital
in Melbourne – hundreds of males. The Senate now records (1998) the “Allars
Inquiry” was misled.
It is these Males who were “overtreated” with Human Pituitary
Gonadotrophin1, who were “overstimulated” through invivo experimentation, with
batches varying2 and causing dire consequences to physical, mental and
reproductive health - those who were exposed to anabolic steroids (a
carcinogenic) as a Growth Promotant with severe side effects. Particular
Recommendations were presented and submitted to The Minister for Heath by
Professor Margaret Allars in 1994, and further explored by the Senate Affairs
Reference Committee in 1998. Of these numerous recommendations, I draw
particular reference to Recommendation 5 m stating
That the settlement offer should not preclude a plaintiff making any future
claim in relation to: (a) Other physical illnesses contracted by recipients
which may be related to long term side effects of HPH treatment3 This submission
is dedicated to the Infant boys, Toddlers boys, Prepubescent boys, Teenage boys,
Young, Middle Aged and Elderly Men aged 2 to 101 – who were treated under such
experimental Programs, exposed to Endocrine Disruptors during the 1970’s,
particularly those whom were castrated and sterilized by the Australian
Government and/or representatives engaged under the Health Act 1958. Such
Section with the Act has since been repealed so that the “experimental nature”
of “The Program” cannot happen again - following the “Allars Inquiry”. This does
not repeal or repair the ongoing side effects. In particular, I dedicate this
submission to the memory of the child who lost his life under these experimental
programs at Prince Henry’s Hospital during the 1970’s4.
Please accept my gratitude with appreciation with your efforts in this
forthcoming Inquiry.
Yours Faithfully
Michael O’Meara
PDF 159KB
see also ;
Michael was recruited into the growth hormone clinic at Prince Henry's
Hospital in 1972 when he was just 10 years old. He was subjected to deep sleep
therapy in April 1972. At this time he was administered the human growth hormone
using products from cadavers. It has since been found that some of this material
was contaminated, with a number of young recipients subsequently contracting and
dying of the deadly Creutzfeldt-Jakob disease, or CJD.
SNIP...SEE MORE HERE ;
BSE INQUIRY DFAs
Sunday, May 18, 2008
BSE Inquiry DRAFT FACTUAL ACCOUNTS DFA's
Sunday, May 18, 2008
BSE, CJD, and Baby foods (the great debate 1999 to 2005)
Sunday, May 18, 2008
MAD COW DISEASE BSE CJD CHILDREN VACCINES
http://web.archive.org/web/20060517075135/http://www.bseinquiry.gov.uk/files/mb/m11g/tab04.pdf
http://bseinquiry.blogspot.com/2008/05/mad-cow-disease-bse-cjd-children.html
‘’I shall not forget the profound effect on my emotions when I visited
these farms and was warmly welcomed because of the great benefits resulting from
the application of louping-ill vaccine, wheras the chief purpose of my visit was
to determine if scrapie was appearing in the inoculated sheep. The enquiry made
the position clear. Scrapie was developing in the sheep vaccinated in 1935 and
it was only in a few instances that the owner was associating the occurrence
with louping-ill vaccination. The disease was affecting all breeds and it was
confined to the animals vaccinated with batch 2.’’
Sunday, February 08, 2015
FDA SCIENCE BOARD TO THE FOOD AND DRUG ADMINISTRATION BOVINE HEPARIN BSE
CJD TSE PRION Wednesday, June 4, 2014
KURU Transmissible Spongiform Encephalopthy TSE Prion Disease
*** Kuru Video ***
Kuru: The Science and The Sorcery
*** Scrapie Video
*** Human Mad Cow Video
*** USA sporadic CJD MAD COW DISEASE HAS HUGE PROBLEM Video
PRION 2015 CONFERENCE FT. COLLINS CWD RISK FACTORS TO HUMANS
*** LATE-BREAKING ABSTRACTS PRION 2015 CONFERENCE ***
O18
Zoonotic Potential of CWD Prions
Liuting Qing1, Ignazio Cali1,2, Jue Yuan1, Shenghai Huang3, Diane Kofskey1,
Pierluigi Gambetti1, Wenquan Zou1, Qingzhong Kong1 1Case Western Reserve
University, Cleveland, Ohio, USA, 2Second University of Naples, Naples, Italy,
3Encore Health Resources, Houston, Texas, USA
Chronic wasting disease (CWD) is a widespread and expanding prion disease
in free-ranging and captive cervid species in North America. The zoonotic
potential of CWD prions is a serious public health concern. Current literature
generated with in vitro methods and in vivo animal models (transgenic mice,
macaques and squirrel monkeys) reports conflicting results. The susceptibility
of human CNS and peripheral organs to CWD prions remains largely unresolved. In
our earlier bioassay experiments using several humanized transgenic mouse lines,
we detected protease-resistant PrPSc in the spleen of two out of 140 mice that
were intracerebrally inoculated with natural CWD isolates, but PrPSc was not
detected in the brain of the same mice. Secondary passages with such
PrPSc-positive CWD-inoculated humanized mouse spleen tissues led to efficient
prion transmission with clear clinical and pathological signs in both humanized
and cervidized transgenic mice. Furthermore, a recent bioassay with natural CWD
isolates in a new humanized transgenic mouse line led to clinical prion
infection in 2 out of 20 mice. These results indicate that the CWD prion has the
potential to infect human CNS and peripheral lymphoid tissues and that there
might be asymptomatic human carriers of CWD infection.
==================
***These results indicate that the CWD prion has the potential to infect
human CNS and peripheral lymphoid tissues and that there might be asymptomatic
human carriers of CWD infection.***
==================
P.105: RT-QuIC models trans-species prion transmission
Kristen Davenport, Davin Henderson, Candace Mathiason, and Edward Hoover
Prion Research Center; Colorado State University; Fort Collins, CO USA
The propensity for trans-species prion transmission is related to the
structural characteristics of the enciphering and heterologous PrP, but the
exact mechanism remains mostly mysterious. Studies of the effects of primary or
tertiary prion protein structures on trans-species prion transmission have
relied primarily upon animal bioassays, making the influence of prion protein
structure vs. host co-factors (e.g. cellular constituents, trafficking, and
innate immune interactions) difficult to dissect. As an alternative strategy, we
used real-time quakinginduced conversion (RT-QuIC) to investigate trans-species
prion conversion.
To assess trans-species conversion in the RT-QuIC system, we compared
chronic wasting disease (CWD) and bovine spongiform encephalopathy (BSE) prions,
as well as feline CWD (fCWD) and feline spongiform encephalopathy (FSE). Each
prion was seeded into each host recombinant PrP (full-length rPrP of
white-tailed deer, bovine or feline). We demonstrated that fCWD is a more
efficient seed for feline rPrP than for white-tailed deer rPrP, which suggests
adaptation to the new host.
Conversely, FSE maintained sufficient BSE characteristics to more
efficiently convert bovine rPrP than feline rPrP. Additionally, human rPrP was
competent for conversion by CWD and fCWD. ***This insinuates that, at the level
of protein:protein interactions, the barrier preventing transmission of CWD to
humans is less robust than previously estimated.
================
***This insinuates that, at the level of protein:protein interactions, the
barrier preventing transmission of CWD to humans is less robust than previously
estimated.***
================
HUMANS CWD ?
In conclusion, an analysis of dietary histories revealed statistical
associations between various meats/animal products and INCREASED RISK OF CJD.
When some account was taken of possible confounding, the association between
VEAL EATING AND RISK OF CJD EMERGED AS THE STRONGEST OF THESE ASSOCIATIONS
STATISTICALLY. ...
snip...
In the study in the USA, a range of foodstuffs were associated with an
increased risk of CJD, including liver consumption which was associated with an
apparent SIX-FOLD INCREASE IN THE RISK OF CJD. By comparing the data from 3
studies in relation to this particular dietary factor, the risk of liver
consumption became non-significant with an odds ratio of 1.2 (PERSONAL
COMMUNICATION, PROFESSOR A. HOFMAN. ERASMUS UNIVERSITY, ROTTERDAM). (???...TSS)
snip...see full report ;
Thursday, October 10, 2013
*************CJD REPORT 1994 increased risk for consumption of veal and
venison and lamb**************
CJD9/10022
October 1994
Mr R.N. Elmhirst Chairman British Deer Farmers Association Holly Lodge
Spencers Lane BerksWell Coventry CV7 7BZ
Dear Mr Elmhirst,
CREUTZFELDT-JAKOB DISEASE (CJD) SURVEILLANCE UNIT REPORT
Thank you for your recent letter concerning the publication of the third
annual report from the CJD Surveillance Unit. I am sorry that you are
dissatisfied with the way in which this report was published.
The Surveillance Unit is a completely independant outside body and the
Department of Health is committed to publishing their reports as soon as they
become available. In the circumstances it is not the practice to circulate the
report for comment since the findings of the report would not be amended. In
future we can ensure that the British Deer Farmers Association receives a copy
of the report in advance of publication.
The Chief Medical Officer has undertaken to keep the public fully informed
of the results of any research in respect of CJD. This report was entirely the
work of the unit and was produced completely independantly of the the
Department.
The statistical results reqarding the consumption of venison was put into
perspective in the body of the report and was not mentioned at all in the press
release. Media attention regarding this report was low key but gave a realistic
presentation of the statistical findings of the Unit. This approach to
publication was successful in that consumption of venison was highlighted only
once by the media ie. in the News at one television proqramme.
I believe that a further statement about the report, or indeed statistical
links between CJD and consumption of venison, would increase, and quite possibly
give damaging credence, to the whole issue. From the low key media reports of
which I am aware it seems unlikely that venison consumption will suffer
adversely, if at all.
http://web.archive.org/web/20030511010117/http://www.bseinquiry.gov.uk/files/yb/1994/10/00003001.pdf
Thursday, October 10, 2013
*** CJD REPORT 1994 increased risk for consumption of veal and venison and
lamb
PLUS, THE CDC DID NOT PUT THIS WARNING OUT FOR THE WELL BEING OF THE DEER
AND ELK ;
Thursday, May 26, 2011
Travel History, Hunting, and Venison Consumption Related to Prion Disease
Exposure, 2006-2007
FoodNet Population Survey Journal of the American Dietetic Association
Volume 111, Issue 6 , Pages 858-863, June 2011.
NOR IS THE FDA recalling this CWD positive elk meat for the well being of
the dead elk ;
Wednesday, March 18, 2009
Noah's Ark Holding, LLC, Dawson, MN RECALL Elk products contain meat
derived from an elk confirmed to have CWD NV, CA, TX, CO, NY, UT, FL, OK RECALLS
AND FIELD CORRECTIONS: FOODS CLASS II
now, let’s see what the authors said about this casual link, personal
communications years ago. see where it is stated NO STRONG evidence. so, does
this mean there IS casual evidence ???? “Our conclusion stating that we found no
strong evidence of CWD transmission to humans”
From: TSS (216-119-163-189.ipset45.wt.net)
Subject: CWD aka MAD DEER/ELK TO HUMANS ???
Date: September 30, 2002 at 7:06 am PST From: "Belay, Ermias"
To: Cc: "Race, Richard (NIH)" ; ; "Belay, Ermias"
Sent: Monday, September 30, 2002 9:22 AM
Subject: RE: TO CDC AND NIH - PUB MED- 3 MORE DEATHS - CWD - YOUNG HUNTERS
Dear Sir/Madam,
In the Archives of Neurology you quoted (the abstract of which was attached
to your email), we did not say CWD in humans will present like variant CJD. That
assumption would be wrong. I encourage you to read the whole article and call me
if you have questions or need more clarification (phone: 404-639-3091). Also, we
do not claim that "no-one has ever been infected with prion disease from eating
venison." Our conclusion stating that we found no strong evidence of CWD
transmission to humans in the article you quoted or in any other forum is
limited to the patients we investigated.
Ermias Belay, M.D. Centers for Disease Control and Prevention
-----Original Message-----
From:
Sent: Sunday, September 29, 2002 10:15 AM
To: rr26k@nih.gov; rrace@niaid.nih.gov; ebb8@CDC.GOV
Subject: TO CDC AND NIH - PUB MED- 3 MORE DEATHS - CWD - YOUNG HUNTERS
Sunday, November 10, 2002 6:26 PM ......snip........end..............TSS
Thursday, April 03, 2008
A prion disease of cervids: Chronic wasting disease
2008 1: Vet Res. 2008 Apr 3;39(4):41 A prion disease of cervids: Chronic
wasting disease Sigurdson CJ.
snip...
*** twenty-seven CJD patients who regularly consumed venison were reported
to the Surveillance Center***,
snip... full text ;
*** These results would seem to suggest that CWD does indeed have zoonotic
potential, at least as judged by the compatibility of CWD prions and their human
PrPC target. Furthermore, extrapolation from this simple in vitro assay suggests
that if zoonotic CWD occurred, it would most likely effect those of the PRNP
codon 129-MM genotype and that the PrPres type would be similar to that found in
the most common subtype of sCJD (MM1).
*** The potential impact of prion diseases on human health was greatly
magnified by the recognition that interspecies transfer of BSE to humans by beef
ingestion resulted in vCJD. While changes in animal feed constituents and
slaughter practices appear to have curtailed vCJD, there is concern that CWD of
free-ranging deer and elk in the U.S. might also cross the species barrier.
Thus, consuming venison could be a source of human prion disease. Whether BSE
and CWD represent interspecies scrapie transfer or are newly arisen prion
diseases is unknown. Therefore, the possibility of transmission of prion disease
through other food animals cannot be ruled out. There is evidence that vCJD can
be transmitted through blood transfusion. There is likely a pool of unknown size
of asymptomatic individuals infected with vCJD, and there may be asymptomatic
individuals infected with the CWD equivalent. These circumstances represent a
potential threat to blood, blood products, and plasma supplies.
From: Terry S. Singeltary Sr.
Sent: Saturday, November 15, 2014 9:29 PM
To: Terry S. Singeltary Sr.
Subject: THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE R. G. WILL 1984
THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE
R. G. WILL
1984
*** The association between venison eating and risk of CJD shows similar
pattern, with regular venison eating associated with a 9 FOLD INCREASE IN RISK
OF CJD (p = 0.04). (SEE LINK IN REPORT HERE...TSS) PLUS, THE CDC DID NOT PUT
THIS WARNING OUT FOR THE WELL BEING OF THE DEER AND ELK ;
snip...
http://web.archive.org/web/20050425210551/http://www.bseinquiry.gov.uk/files/mb/m26/tab01.pdf
human cwd will NOT look like nvCJD. in fact, see ;
*** These results would seem to suggest that CWD does indeed have zoonotic
potential, at least as judged by the compatibility of CWD prions and their human
PrPC target. Furthermore, extrapolation from this simple in vitro assay suggests
that if zoonotic CWD occurred, it would most likely effect those of the PRNP
codon 129-MM genotype and that the PrPres type would be similar to that found in
the most common subtype of sCJD (MM1).***
O.05: Transmission of prions to primates after extended silent incubation
periods: Implications for BSE and scrapie risk assessment in human populations
Emmanuel Comoy, Jacqueline Mikol, Val erie Durand, Sophie Luccantoni,
Evelyne Correia, Nathalie Lescoutra, Capucine Dehen, and Jean-Philippe Deslys
Atomic Energy Commission; Fontenay-aux-Roses, France
Prion diseases (PD) are the unique neurodegenerative proteinopathies
reputed to be transmissible under field conditions since decades. The
transmission of Bovine Spongiform Encephalopathy (BSE) to humans evidenced that
an animal PD might be zoonotic under appropriate conditions. Contrarily, in the
absence of obvious (epidemiological or experimental) elements supporting a
transmission or genetic predispositions, PD, like the other proteinopathies, are
reputed to occur spontaneously (atpical animal prion strains, sporadic CJD
summing 80% of human prion cases). Non-human primate models provided the first
evidences supporting the transmissibiity of human prion strains and the zoonotic
potential of BSE. Among them, cynomolgus macaques brought major information for
BSE risk assessment for human health (Chen, 2014), according to their
phylogenetic proximity to humans and extended lifetime. We used this model to
assess the zoonotic potential of other animal PD from bovine, ovine and cervid
origins even after very long silent incubation periods. *** We recently observed
the direct transmission of a natural classical scrapie isolate to macaque after
a 10-year silent incubation period, ***with features similar to some reported
for human cases of sporadic CJD, albeit requiring fourfold longe incubation than
BSE. Scrapie, as recently evoked in humanized mice (Cassard, 2014), ***is the
third potentially zoonotic PD (with BSE and L-type BSE), ***thus questioning the
origin of human sporadic cases. We will present an updated panorama of our
different transmission studies and discuss the implications of such extended
incubation periods on risk assessment of animal PD for human health.
===============
***thus questioning the origin of human sporadic cases...TSS
===============
2014
***Moreover, L-BSE has been transmitted more easily to transgenic mice
overexpressing a human PrP [13,14] or to primates [15,16] than C-BSE.
***It has been suggested that some sporadic CJD subtypes in humans may
result from an exposure to the L-BSE agent.
*** Lending support to this hypothesis, pathological and biochemical
similarities have been observed between L-BSE and an sCJD subtype (MV genotype
at codon 129 of PRNP) [17], and between L-BSE infected non-human primate and
another sCJD subtype (MM genotype) [15].
snip...
ttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4213560/pdf/viruses-06-03766.pdf
Monday, October 10, 2011
EFSA Journal 2011 The European Response to BSE: A Success Story
snip...
EFSA and the European Centre for Disease Prevention and Control (ECDC)
recently delivered a scientific opinion on any possible epidemiological or
molecular association between TSEs in animals and humans (EFSA Panel on
Biological Hazards (BIOHAZ) and ECDC, 2011). This opinion confirmed Classical
BSE prions as the only TSE agents demonstrated to be zoonotic so far
*** but the possibility that a small proportion of human cases so far
classified as "sporadic" CJD are of zoonotic origin could not be excluded.
*** Moreover, transmission experiments to non-human primates suggest that
some TSE agents in addition to Classical BSE prions in cattle (namely L-type
Atypical BSE, Classical BSE in sheep, transmissible mink encephalopathy (TME)
and chronic wasting disease (CWD) agents) might have zoonotic potential.
snip...
Thursday, August 12, 2010
Seven main threats for the future linked to prions
First threat
The TSE road map defining the evolution of European policy for protection
against prion diseases is based on a certain numbers of hypotheses some of which
may turn out to be erroneous. In particular, a form of BSE (called atypical
Bovine Spongiform Encephalopathy), recently identified by systematic testing in
aged cattle without clinical signs, may be the origin of classical BSE and thus
potentially constitute a reservoir, which may be impossible to eradicate if a
sporadic origin is confirmed.
*** Also, a link is suspected between atypical BSE and some apparently
sporadic cases of Creutzfeldt-Jakob disease in humans.
*** These atypical BSE cases constitute an unforeseen first threat that
could sharply modify the European approach to prion diseases.
Second threat
snip...
Thursday, July 30, 2015
*** Professor Lacey believes sporadic CJD itself originates from a cattle
infection number of cattle farmers falling victim to Creutzfeld-Jakob Disease is
much too high to be mere chance ***
O35
J. Mikol1, S. Luccantoni-Freire1, E. Correia1, N. Lescoutra-Etchegaray1, V.
Durand1, C. Dehen1, J.P. Deslys1, E. Comoy1
1Institute of Emerging Diseases and Innovative Therapies, Service of Prion
Diseases, Atomic Energy Commission, 18 Route du Panorama 92265 Fontenayaux-
Roses, France
E-mail: jacqueline.mikol@wanadoo.fr
Uncommon prion disease induced in macaque ten years after scrapie
inoculation
Introduction: Bovine Spongiform Encephalopathy (BSE) is the single animal
prion disease reputed to be zoonotic, inducing variant of Creutzfeldt-Jakob
Disease (vCJD) in man, and therefore strongly conditioned the protective
measures. Among different sources of animal prion diseases, we show here that
after more than ten years of incubation, intracerebral injection of a sheep
scrapie isolate can induce a prion disease in cynomolgus macaque, a relevant
model of human situation towards several prion strains. Neuropathological
studies showed classical and uncommon data.
Material and method: The cynomolgus macaque was intracerebrally exposed to
a classical scrapie isolate issued from a naturally infected sheep flock. Upon
onset of clinical signs, euthanasia was performed for ethical reasons. Classical
methods of biochemistry and neuropathology were used.
Results: The three elements of the triad were present:
spongiosis was predominant in the cortex, the striatum, the cerebellum.
Neuronal loss and gliosis were moderate.
The notable data were the following
(i) the brain was small, the atrophy involved mostly the temporal lobe in
which axonal loss was histologically demonstrated
(ii) the spongiosis of the Purkinje cells was so intense that most of them
were destroyed
(iii) there was a neuronal loss and a massive gliosis of the dorsomedialis
nucleus of the thalamus
(iv) iron deposits were present in the lenticular nucleus. PrPres heavily
distributed in the cortex, the basal ganglia and the cerebellum consisted in
synaptic deposits and aggregates. Western Blot exhibited a type 1 PrPres in all
parts of the brain.
Conclusion: We described here the successful transmission of a scrapie
prion disease to a non-human primate after an extended incubation period,
leading to a fatal, non-relapsing neurological disease with all the features of
a prion disease. The cerebral lesional profile we observed was original in
comparison to other animal prion diseases (c-BSE, L-type BSE, TME) we previously
experimentally transmitted in this model.
Tuesday, December 16, 2014
Evidence for zoonotic potential of ovine scrapie prions
Hervé Cassard,1, n1 Juan-Maria Torres,2, n1 Caroline Lacroux,1, Jean-Yves
Douet,1, Sylvie L. Benestad,3, Frédéric Lantier,4, Séverine Lugan,1, Isabelle
Lantier,4, Pierrette Costes,1, Naima Aron,1, Fabienne Reine,5, Laetitia
Herzog,5, Juan-Carlos Espinosa,2, Vincent Beringue5, & Olivier
Andréoletti1, Affiliations Contributions Corresponding author Journal name:
Nature Communications Volume: 5, Article number: 5821 DOI:
doi:10.1038/ncomms6821 Received 07 August 2014 Accepted 10 November 2014
Published 16 December 2014 Article tools Citation Reprints Rights &
permissions Article metrics
Abstract
Although Bovine Spongiform Encephalopathy (BSE) is the cause of variant
Creutzfeldt Jakob disease (vCJD) in humans, the zoonotic potential of scrapie
prions remains unknown. Mice genetically engineered to overexpress the human
prion protein (tgHu) have emerged as highly relevant models for gauging the
capacity of prions to transmit to humans. These models can propagate human
prions without any apparent transmission barrier and have been used used to
confirm the zoonotic ability of BSE. Here we show that a panel of sheep scrapie
prions transmit to several tgHu mice models with an efficiency comparable to
that of cattle BSE.
***The serial transmission of different scrapie isolates in these mice led
to the propagation of prions that are phenotypically identical to those causing
sporadic CJD (sCJD) in humans.
***These results demonstrate that scrapie prions have a zoonotic potential
and raise new questions about the possible link between animal and human prions.
Subject terms: Biological sciences• Medical research At a glance
why do we not want to do TSE transmission studies on chimpanzees $
5. A positive result from a chimpanzee challenged severly would likely
create alarm in some circles even if the result could not be interpreted for
man. I have a view that all these agents could be transmitted provided a large
enough dose by appropriate routes was given and the animals kept long enough.
Until the mechanisms of the species barrier are more clearly understood it might
be best to retain that hypothesis.
snip...
R. BRADLEY
1: J Infect Dis 1980 Aug;142(2):205-8
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.
snip...
The successful transmission of kuru, Creutzfeldt-Jakob disease, and scrapie
by natural feeding to squirrel monkeys that we have reported provides further
grounds for concern that scrapie-infected meat may occasionally give rise in
humans to Creutzfeldt-Jakob disease.
PMID: 6997404
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
Recently the question has again been brought up as to whether scrapie is
transmissible to man. This has followed reports that the disease has been
transmitted to primates. One particularly lurid speculation (Gajdusek 1977)
conjectures that the agents of scrapie, kuru, Creutzfeldt-Jakob disease and
transmissible encephalopathy of mink are varieties of a single "virus". The U.S.
Department of Agriculture concluded that it could "no longer justify or permit
scrapie-blood line and scrapie-exposed sheep and goats to be processed for human
or animal food at slaughter or rendering plants" (ARC 84/77)" The problem is
emphasized by the finding that some strains of scrapie produce lesions identical
to the once which characterize the human dementias"
Whether true or not. the hypothesis that these agents might be
transmissible to man raises two considerations. First, the safety of laboratory
personnel requires prompt attention. Second, action such as the "scorched meat"
policy of USDA makes the solution of the scrapie problem urgent if the sheep
industry is not to suffer grievously.
snip...
76/10.12/4.6
Nature. 1972 Mar 10;236(5341):73-4.
Transmission of scrapie to the cynomolgus monkey (Macaca fascicularis).
Gibbs CJ Jr, Gajdusek DC.
Nature 236, 73 - 74 (10 March 1972); doi:10.1038/236073a0
Transmission of Scrapie to the Cynomolgus Monkey (Macaca fascicularis)
C. J. GIBBS jun. & D. C. GAJDUSEK
National Institute of Neurological Diseases and Stroke, National Institutes
of Health, Bethesda, Maryland
SCRAPIE has been transmitted to the cynomolgus, or crab-eating, monkey
(Macaca fascicularis) with an incubation period of more than 5 yr from the time
of intracerebral inoculation of scrapie-infected mouse brain. The animal
developed a chronic central nervous system degeneration, with ataxia, tremor and
myoclonus with associated severe scrapie-like pathology of intensive astroglial
hypertrophy and proliferation, neuronal vacuolation and status spongiosus of
grey matter. The strain of scrapie virus used was the eighth passage in Swiss
mice (NIH) of a Compton strain of scrapie obtained as ninth intracerebral
passage of the agent in goat brain, from Dr R. L. Chandler (ARC, Compton,
Berkshire).
Friday, January 30, 2015
*** Scrapie: a particularly persistent pathogen ***
Thursday, March 26, 2015
Increased Infectivity of Anchorless Mouse Scrapie Prions in Transgenic Mice
Overexpressing Human Prion Protein
Increased susceptibility of human-PrP transgenic mice to bovine spongiform
encephalopathy following passage in sheep
J. Virol. doi:10.1128/JVI.01578-10 Copyright (c) 2010, American Society for
Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.
Increased susceptibility of human-PrP transgenic mice to bovine spongiform
encephalopathy following passage in sheep.
Chris Plinston, Patricia Hart, Angela Chong, Nora Hunter, James Foster,
Pedro Piccardo, Jean C. Manson, and Rona M Barron* Neuropathogenesis Division,
The Roslin Institute and R(D)SVS, University of Edinburgh, Roslin, Midlothian,
UK; Laboratory of Bacterial and TSE Agents, Food and Drug Administration,
Rockville, MD, USA * To whom correspondence should be addressed. Email:
rona.barron@roslin.ed.ac.uk .
Abstract
The risk of transmission of ruminant transmissible spongiform
encephalopathy (TSE) to humans was thought to be low due to the lack of
association between sheep scrapie and incidence of human TSE. However a single
TSE agent strain has been shown to cause both bovine spongiform encephalopathy
(BSE) and human vCJD, indicating that some ruminant TSEs may be transmissible to
humans. While the transmission of cattle BSE to humans in transgenic mouse
models has been inefficient, indicating the presence of a significant
transmission barrier between cattle and humans, BSE has been transmitted to a
number of other species. Here we aimed to further investigate the human
transmission barrier following passage of BSE in a sheep. Following inoculation
with cattle BSE, gene targeted transgenic mice expressing human PrP showed no
clinical or pathological signs of TSE disease. However following inoculation
with an isolate of BSE that had been passaged through a sheep, TSE associated
vacuolation and proteinase-K resistant PrP deposition were observed in mice
homozygous for the codon 129-methionine PRNP gene. This observation may be due
to higher titres of the BSE agent in sheep, or an increased susceptibility of
humans to BSE prions following passage through a sheep. ***However these data
confirm that, contrary to previous predictions, it is possible that a sheep
prion may be transmissible to humans and that BSE from other species may be a
public health risk.
Suspect symptoms
What if you can catch old-fashioned CJD by eating meat from a sheep
infected with scrapie?
28 Mar 01
Most doctors believe that sCJD is caused by a prion protein deforming by
chance into a killer. But Singeltary thinks otherwise. He is one of a number of
campaigners who say that some sCJD, like the variant CJD related to BSE, is
caused by eating meat from infected animals. Their suspicions have focused on
sheep carrying scrapie, a BSE-like disease that is widespread in flocks across
Europe and North America.
Now scientists in France have stumbled across new evidence that adds weight
to the campaigners' fears. To their complete surprise, the researchers found
that one strain of scrapie causes the same brain damage in mice as sCJD.
"This means we cannot rule out that at least some sCJD may be caused by
some strains of scrapie," says team member Jean-Philippe Deslys of the French
Atomic Energy Commission's medical research laboratory in Fontenay-aux-Roses,
south-west of Paris. Hans Kretschmar of the University of Göttingen, who
coordinates CJD surveillance in Germany, is so concerned by the findings that he
now wants to trawl back through past sCJD cases to see if any might have been
caused by eating infected mutton or lamb...
2001
Suspect symptoms
What if you can catch old-fashioned CJD by eating meat from a sheep
infected with scrapie?
28 Mar 01
Like lambs to the slaughter
31 March 2001
by Debora MacKenzie Magazine issue 2284.
FOUR years ago, Terry Singeltary watched his mother die horribly from a
degenerative brain disease. Doctors told him it was Alzheimer's, but Singeltary
was suspicious. The diagnosis didn't fit her violent symptoms, and he demanded
an autopsy. It showed she had died of sporadic Creutzfeldt-Jakob disease.
Most doctors believe that sCJD is caused by a prion protein deforming by
chance into a killer. But Singeltary thinks otherwise. He is one of a number of
campaigners who say that some sCJD, like the variant CJD related to BSE, is
caused by eating meat from infected animals. Their suspicions have focused on
sheep carrying scrapie, a BSE-like disease that is widespread in flocks across
Europe and North America.
Now scientists in France have stumbled across new evidence that adds weight
to the campaigners' fears. To their complete surprise, the researchers found
that one strain of scrapie causes the same brain damage in mice as sCJD.
"This means we cannot rule out that at least some sCJD may be caused by
some strains of scrapie," says team member Jean-Philippe Deslys of the French
Atomic Energy Commission's medical research laboratory in Fontenay-aux-Roses,
south-west of Paris. Hans Kretschmar of the University of Göttingen, who
coordinates CJD surveillance in Germany, is so concerned by the findings that he
now wants to trawl back through past sCJD cases to see if any might have been
caused by eating infected mutton or lamb.
Scrapie has been around for centuries and until now there has been no
evidence that it poses a risk to human health. But if the French finding means
that scrapie can cause sCJD in people, countries around the world may have
overlooked a CJD crisis to rival that caused by BSE.
Deslys and colleagues were originally studying vCJD, not sCJD. They
injected the brains of macaque monkeys with brain from BSE cattle, and from
French and British vCJD patients. The brain damage and clinical symptoms in the
monkeys were the same for all three. Mice injected with the original sets of
brain tissue or with infected monkey brain also developed the same symptoms.
As a control experiment, the team also injected mice with brain tissue from
people and animals with other prion diseases: a French case of sCJD; a French
patient who caught sCJD from human-derived growth hormone; sheep with a French
strain of scrapie; and mice carrying a prion derived from an American scrapie
strain. As expected, they all affected the brain in a different way from BSE and
vCJD. But while the American strain of scrapie caused different damage from
sCJD, the French strain produced exactly the same pathology.
"The main evidence that scrapie does not affect humans has been
epidemiology," says Moira Bruce of the neuropathogenesis unit of the Institute
for Animal Health in Edinburgh, who was a member of the same team as Deslys.
"You see about the same incidence of the disease everywhere, whether or not
there are many sheep, and in countries such as New Zealand with no scrapie." In
the only previous comparisons of sCJD and scrapie in mice, Bruce found they were
dissimilar.
But there are more than 20 strains of scrapie, and six of sCJD. "You would
not necessarily see a relationship between the two with epidemiology if only
some strains affect only some people," says Deslys. Bruce is cautious about the
mouse results, but agrees they require further investigation. Other trials of
scrapie and sCJD in mice, she says, are in progress.
People can have three different genetic variations of the human prion
protein, and each type of protein can fold up two different ways. Kretschmar has
found that these six combinations correspond to six clinical types of sCJD: each
type of normal prion produces a particular pathology when it spontaneously
deforms to produce sCJD.
But if these proteins deform because of infection with a disease-causing
prion, the relationship between pathology and prion type should be different, as
it is in vCJD. "If we look at brain samples from sporadic CJD cases and find
some that do not fit the pattern," says Kretschmar, "that could mean they were
caused by infection."
There are 250 deaths per year from sCJD in the US, and a similar incidence
elsewhere. Singeltary and other US activists think that some of these people
died after eating contaminated meat or "nutritional" pills containing dried
animal brain. Governments will have a hard time facing activists like Singeltary
if it turns out that some sCJD isn't as spontaneous as doctors have insisted.
Deslys's work on macaques also provides further proof that the human
disease vCJD is caused by BSE. And the experiments showed that vCJD is much more
virulent to primates than BSE, even when injected into the bloodstream rather
than the brain. This, says Deslys, means that there is an even bigger risk than
we thought that vCJD can be passed from one patient to another through
contaminated blood transfusions and surgical instruments.
Like lambs to the slaughter
Thursday, December 20, 2012
OIE GROUP RECOMMENDS THAT SCRAPE PRION DISEASE BE DELISTED AND SAME OLD BSe
WITH BOVINE MAD COW DISEASE
Monday, November 30, 2009
USDA AND OIE COLLABORATE TO EXCLUDE ATYPICAL SCRAPIE NOR-98 ANIMAL HEALTH
CODE
Monday, April 25, 2011
Experimental Oral Transmission of Atypical Scrapie to Sheep Volume 17,
Number 5-May 2011
Friday, February 11, 2011
Atypical/Nor98 Scrapie Infectivity in Sheep Peripheral Tissues
Monday, June 27, 2011
Comparison of Sheep Nor98 with Human Variably Protease-Sensitive
Prionopathy and Gerstmann-Sträussler-Scheinker Disease
BSE: TIME TO TAKE H.B. PARRY SERIOUSLY
If the scrapie agent is generated from ovine DNA and thence causes disease
in other species, then perhaps, bearing in mind the possible role of scrapie in
CJD of humans (Davinpour et al, 1985), scrapie and not BSE should be the
notifiable disease. ...
Thursday, January 15, 2015
41-year-old Navy Commander with sporadic Creutzfeldt–Jakob disease CJD TSE
Prion: Case Report
Subject: *** Becky Lockhart 46, Utah’s first female House speaker, dies
diagnosed with the extremely rare Creutzfeldt-Jakob disease aka mad cow type
disease
what is CJD ? just ask USDA inc., and the OIE, they are still feeding the
public and the media industry fed junk science that is 30 years old.
why doesn’t some of you try reading the facts, instead of rubber stamping
everything the USDA inc says.
sporadic CJD has now been linked to BSE aka mad cow disease, Scrapie, and
there is much concern now for CWD and risk factor for humans.
My sincere condolences to the family and friends of the House Speaker Becky
Lockhart. I am deeply saddened hear this.
with that said, with great respect, I must ask each and every one of you
Politicians that are so deeply saddened to hear of this needless death of the
Honorable House Speaker Becky Lockhart, really, cry me a friggen river. I am
seriously going to ask you all this...I have been diplomatic for about 17 years
and it has got no where. people are still dying. so, are you all stupid or
what??? how many more need to die ??? how much is global trade of beef and other
meat products that are not tested for the TSE prion disease, how much and how
many bodies is this market worth?
Saturday, January 17, 2015
*** Becky Lockhart 46, Utah’s first female House speaker, dies diagnosed
with the extremely rare Creutzfeldt-Jakob disease
*** ALERT new variant Creutzfeldt Jakob Disease nvCJD or vCJD, sporadic CJD
strains, TSE prion aka Mad Cow Disease United States of America Update December
14, 2014 Report ***
*** Creutzfeldt-Jakob Disease Public Health Crisis VIDEO
Alzheimer’s, iatrogenic, what if ?
Friday, January 10, 2014
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type
prion disease, what it ???
==================================
Tuesday, August 4, 2015
*** FDA U.S. Measures to Protect Against BSE ***
==================================
*** now, from all the consumption and exposure above, now think iatrogenic
cjd tse prion at a hospital near you, what if?
TSS
Thursday, August 13, 2015
Iatrogenic CJD due to pituitary-derived growth hormone with genetically
determined incubation times of up to 40 years
posted by Terry S. Singeltary Sr. at
10:43 AM
