Sunday, November 06, 2016

UK Iatrogenic Creutzfeldt–Jakob disease: investigating human prion transmission across genotypic barriers using human tissue-based and molecular approaches

UK Iatrogenic Creutzfeldt–Jakob disease: investigating human prion transmission across genotypic barriers using human tissue-based and molecular approaches


Authors and affiliations

Diane L. Ritchie Marcelo A. Barria Alexander H. Peden Helen M. Yull James Kirkpatrick Peter
Adlard James W. Ironside Mark W. Head
Email author
Diane L. Ritchie1
Marcelo A. Barria1
Alexander H. Peden1
Helen M. Yull1
James Kirkpatrick1
Peter Adlard2
James W. Ironside1
Mark W. Head13
Email author
View author's OrcID profile

1.National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, Deanery of Clinical SciencesThe University of Edinburgh Edinburgh UK

2.University College London Institute of Child HealthLondonUK

3.National CJD Research & Surveillance UnitUniversity of EdinburghEdinburghUK
Open AccessOriginal Paper

First Online: 03 November 2016

DOI: 10.1007/s00401-016-1638-x
Cite this article as:
Ritchie, D.L., Barria, M.A., Peden, A.H. et al. Acta Neuropathol (2016). doi:10.1007/s00401-016-1638-x


Creutzfeldt–Jakob disease (CJD) is the prototypic human prion disease that occurs most commonly in sporadic and genetic forms, but it is also transmissible and can be acquired through medical procedures, resulting in iatrogenic CJD (iCJD). The largest numbers of iCJD cases that have occurred worldwide have resulted from contaminated cadaveric pituitary-derived human growth hormone (hGH) and its use to treat primary and secondary growth hormone deficiency. We report a comprehensive, tissue-based and molecular genetic analysis of the largest series of UK hGH-iCJD cases reported to date, including in vitro kinetic molecular modelling of genotypic factors influencing prion transmission. The results show the interplay of prion strain and host genotype in governing the molecular, pathological and temporal characteristics of the UK hGH-iCJD epidemic and provide insights into the adaptive mechanisms involved when prions cross genotypic barriers. We conclude that all of the available evidence is consistent with the hypothesis that the UK hGH-iCJD epidemic resulted from transmission of the V2 human prion strain, which is associated with the second most common form of sporadic CJD.


Creutzfeldt–Jakob diseasePrionIatrogenicGrowth hormoneDisease phenotypeAgent strain

D. L. Ritchie and M. A. Barria contributed equally to this work.

Electronic supplementary material

The online version of this article (doi:10.1007/s00401-016-1638-x) contains supplementary material, which is available to authorized users.


Implications for person-to-person transmission

The RT-QuIC and PMCA comparisons performed here did not support the hypothesis that human-to-human transmission of CJD results in acquired replicative efficiency [36]. Indeed, the RT-QuIC assay showed reduced rather than enhanced seeding activity in hGH-iCJD compared to the matched subtypes of sCJD suggesting that hGH-iCJD is not markedly more of a public health concern than its presumed source, sCJD. However, CJD surveillance systems in countries where contaminated batches of growth hormone were used should remain vigilant for further cases of hGH-iCJD. Some of these cases may be identifiable by the presence of kuru plaques and the presence of PrPres type i. However, others cases may appear closely similar to the most common form of sCJD (MM1), and the only indication of an iatrogenic aetiology may be in their medical history. The overriding message from the UK experience with hGH-iCJD and perhaps human prion diseases, more generally, is that poorly assessed risks can continue to have ramifications for patients years to decades after the risk source is itself recognised and removed. This point is underscored by a further case of hGH-iCJD being identified during the writing of this report in 2016, some 30 years after treatment with pituitary-derived hGH was abandoned in the UK.

snip...see full text ;

*** Transmission of Creutzfeldt-Jakob disease to a chimpanzee by electrodes contaminated during neurosurgery ***

Gibbs CJ Jr, Asher DM, Kobrine A, Amyx HL, Sulima MP, Gajdusek DC. Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.

Stereotactic multicontact electrodes used to probe the cerebral cortex of a middle aged woman with progressive dementia were previously implicated in the accidental transmission of Creutzfeldt-Jakob disease (CJD) to two younger patients. The diagnoses of CJD have been confirmed for all three cases. More than two years after their last use in humans, after three cleanings and repeated sterilisation in ethanol and formaldehyde vapour, the electrodes were implanted in the cortex of a chimpanzee. Eighteen months later the animal became ill with CJD. This finding serves to re-emphasise the potential danger posed by reuse of instruments contaminated with the agents of spongiform encephalopathies, even after scrupulous attempts to clean them.

the warning shots fired over the bow of the boat that were never heard ;


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...



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.


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.



We have demonstrated that conventional mice inoculated with Sc237 prions harbor high levels of PrPSc and high prion titers in their brains without developing clinical signs of prion disease within their normal lifespan. These results imply the existence of subclinical prion infections that can be induced by challenge with prions from another species. However, whether or not this infectivity is classified as preclinical or subclinical, it has important public health implications. Iatrogenic transmission could occur from apparently healthy humans who may harbor high prion titers and many animal species (including sheep, pigs, and poultry) were exposed to BSE prions via contaminated feed and could have developed subclinical prion infection. It is known that BSE


Page 4 of 17

prions retain their distinctive strain characteristics after passage in a number of other species including humans (4, 13), arguing that such BSE passaged in species other than cattle also may be pathogenic to humans. The possibility that subclinical BSE might be present in other species and thereby present a threat to human health has been raised (30) but not yet rigorously investigated. Furthermore, these data argue in favor of screening apparently healthy cattle after slaughter to investigate whether significant levels of subclinical or preclinical BSE are present.


Thursday, April 12, 2012

Health professions and risk of sporadic Creutzfeldt–Jakob disease, 1965 to 2010

Saturday, April 23, 2016


Saturday, April 23, 2016

SCRAPIE WS-01: Prion diseases in animals and zoonotic potential 2016

Prion. 10:S15-S21. 2016 ISSN: 1933-6896 printl 1933-690X online

Taylor & Francis

Prion 2016 Animal Prion Disease Workshop Abstracts

WS-01: Prion diseases in animals and zoonotic potential

Juan Maria Torres a, Olivier Andreoletti b, J uan-Carlos Espinosa a. Vincent Beringue c. Patricia Aguilar a,

Natalia Fernandez-Borges a. and Alba Marin-Moreno a

"Centro de Investigacion en Sanidad Animal ( CISA-INIA ). Valdeolmos, Madrid. Spain; b UMR INRA -ENVT 1225 Interactions Holes Agents Pathogenes. ENVT. Toulouse. France: "UR892. Virologie lmmunologie MolécuIaires, Jouy-en-Josas. France

Dietary exposure to bovine spongiform encephalopathy (BSE) contaminated bovine tissues is considered as the origin of variant Creutzfeldt Jakob (vCJD) disease in human. To date, BSE agent is the only recognized zoonotic prion. Despite the variety of Transmissible Spongiform Encephalopathy (TSE) agents that have been circulating for centuries in farmed ruminants there is no apparent epidemiological link between exposure to ruminant products and the occurrence of other form of TSE in human like sporadic Creutzfeldt Jakob Disease (sCJD). However, the zoonotic potential of the diversity of circulating TSE agents has never been systematically assessed. The major issue in experimental assessment of TSEs zoonotic potential lies in the modeling of the ‘species barrier‘, the biological phenomenon that limits TSE agents’ propagation from a species to another. In the last decade, mice genetically engineered to express normal forms of the human prion protein has proved essential in studying human prions pathogenesis and modeling the capacity of TSEs to cross the human species barrier.

To assess the zoonotic potential of prions circulating in farmed ruminants, we study their transmission ability in transgenic mice expressing human PrPC (HuPrP-Tg). Two lines of mice expressing different forms of the human PrPC (129Met or 129Val) are used to determine the role of the Met129Val dimorphism in susceptibility/resistance to the different agents.

These transmission experiments confirm the ability of BSE prions to propagate in 129M- HuPrP-Tg mice and demonstrate that Met129 homozygotes may be susceptible to BSE in sheep or goat to a greater degree than the BSE agent in cattle and that these agents can convey molecular properties and neuropathological indistinguishable from vCJD. However homozygous 129V mice are resistant to all tested BSE derived prions independently of the originating species suggesting a higher transmission barrier for 129V-PrP variant.

Transmission data also revealed that several scrapie prions propagate in HuPrP-Tg mice with efficiency comparable to that of cattle BSE. While the efficiency of transmission at primary passage was low, subsequent passages resulted in a highly virulent prion disease in both Met129 and Val129 mice. Transmission of the different scrapie isolates in these mice leads to the emergence of prion strain phenotypes that showed similar characteristics to those displayed by MM1 or VV2 sCJD prion. These results demonstrate that scrapie prions have a zoonotic potential and raise new questions about the possible link between animal and human prions.
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.



*** In complement to the recent demonstration that humanized mice are susceptible to scrapie, we report here the first observation of direct transmission of a natural classical scrapie isolate to a macaque after a 10-year incubation period. Neuropathologic examination revealed all of the features of a prion disease: spongiform change, neuronal loss, and accumulation of PrPres throughout the CNS.

*** This observation strengthens the questioning of the harmlessness of scrapie to humans, at a time when protective measures for human and animal health are being dismantled and reduced as c-BSE is considered controlled and being eradicated.

*** Our results underscore the importance of precautionary and protective measures and the necessity for long-term experimental transmission studies to assess the zoonotic potential of other animal prion strains.

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, Valerie 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 long 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***


***our findings suggest that possible transmission risk of H-type BSE to sheep and human. Bioassay will be required to determine whether the PMCA products are infectious to these animals.


SCRAPIE WS-01: Prion diseases in animals and zoonotic potential 2016

Prion. 10:S15-S21. 2016 ISSN: 1933-6896 printl 1933-690X online

Monday, May 02, 2016

*** Zoonotic Potential of CWD Prions: An Update Prion 2016 Tokyo ***
Thursday, August 13, 2015

Iatrogenic CJD due to pituitary-derived growth hormone with genetically determined incubation times of up to 40 years

Friday, January 10, 2014

vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???

Greetings Friends, Neighbors, and Colleagues,

Thursday, January 14, 2016

*** Preventable Tragedies: Superbugs and How Ineffective Monitoring of Medical Device Safety Fails Patients REPORT ***

how can it be, HOW CAN IT BE $$$ not a word about CJD GSS FFI VPSPR TSE Prions that I saw...absolutely crazy, WE ARE MISSING THE BIGGER PICTURE!

how many victims that will never be reported ???

Sunday, January 17, 2016

*** Of Grave Concern Heidenhain Variant Creutzfeldt Jakob Disease ***

Saturday, February 6, 2016

*** Secretary's Advisory Committee on Animal Health; Meeting [Docket No. APHIS-2016-0007] Singeltary Submission ***

Saturday, April 16, 2016

*** APHIS [Docket No. APHIS-2016-0029] Secretary's Advisory Committee on Animal Health; Meeting May 2, 2016, and June 16, 2016 Singeltary Submission ***

Transmissible Spongiform Encephalopathy TSE PRION UPDATE

Saturday, July 23, 2016


Tuesday, July 26, 2016

Atypical Bovine Spongiform Encephalopathy BSE TSE Prion UPDATE JULY 2016

Sunday, July 17, 2016

Saturday, April 23, 2016

v-CJD prion distribution in the tissues of patients at preclinical and clinical stage of the disease

Tuesday, May 10, 2016

2015 PDA Virus & TSE Safety Forum Meeting Report

>>> Recently transmission of prions from blood of patients with sporadic CJD to humanized mice could be demonstrated.<<<

>>> Further-on, urine samples of a control population (normal and neurological population) showed no signal in the study; *** however, in samples from patients with sporadic CJD and vCJD, a signal was detected in both patient populations.<<<

Meeting Report: 2015 PDA Virus & TSE Safety Forum
Thursday, April 14, 2016

Arizona 22 year old diagnosed with Creutzfeldt Jakob Disease CJD
Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease

*** Singeltary comment PLoS ***

Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?

Posted by flounder on 05 Nov 2014 at 21:27 GMT

Sunday, November 22, 2015

*** Effect of heating on the stability of amyloid A (AA) fibrils and the intra- and cross-species transmission of AA amyloidosis Abstract

Amyloid A (AA) amyloidosis is a protein misfolding disease characterized by extracellular deposition of AA fibrils. AA fibrils are found in several tissues from food animals with AA amyloidosis. For hygienic purposes, heating is widely used to inactivate microbes in food, but it is uncertain whether heating is sufficient to inactivate AA fibrils and prevent intra- or cross-species transmission. We examined the effect of heating (at 60 °C or 100 °C) and autoclaving (at 121 °C or 135 °C) on murine and bovine AA fibrils using Western blot analysis, transmission electron microscopy (TEM), and mouse model transmission experiments. TEM revealed that a mixture of AA fibrils and amorphous aggregates appeared after heating at 100 °C, whereas autoclaving at 135 °C produced large amorphous aggregates. AA fibrils retained antigen specificity in Western blot analysis when heated at 100 °C or autoclaved at 121 °C, but not when autoclaved at 135 °C. Transmissible pathogenicity of murine and bovine AA fibrils subjected to heating (at 60 °C or 100 °C) was significantly stimulated and resulted in amyloid deposition in mice. Autoclaving of murine AA fibrils at 121 °C or 135 °C significantly decreased amyloid deposition. Moreover, amyloid deposition in mice injected with murine AA fibrils was more severe than that in mice injected with bovine AA fibrils. Bovine AA fibrils autoclaved at 121 °C or 135 °C did not induce amyloid deposition in mice. These results suggest that AA fibrils are relatively heat stable and that similar to prions, autoclaving at 135 °C is required to destroy the pathogenicity of AA fibrils. These findings may contribute to the prevention of AA fibril transmission through food materials to different animals and especially to humans.

Purchase options Price * Issue Purchase USD 511.00 Article Purchase USD 54.00

Alzheimer-type brain pathology may be transmitted by grafts of dura mater 26/01/2016 Singeltary comment ;

re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy

Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015)

snip...see full Singeltary Nature comment here;

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

Singeltary, Sr et al. JAMA.2001; 285: 733-734. Vol. 285 No. 6, February 14, 2001 JAMA

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

To the Editor: In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.

Terry S. Singeltary, Sr Bacliff, Tex

1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323.

26 March 2003

Terry S. Singeltary, retired (medically) CJD WATCH

I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to comment on the CDC's attempts to monitor the occurrence of emerging forms of CJD. Asante, Collinge et al [1] have reported that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype that is indistinguishable from type 2 PrPSc, the commonest sporadic CJD. However, CJD and all human TSEs are not reportable nationally. CJD and all human TSEs must be made reportable in every state and internationally. I hope that the CDC does not continue to expect us to still believe that the 85%+ of all CJD cases which are sporadic are all spontaneous, without route/source. We have many TSEs in the USA in both animal and man. CWD in deer/elk is spreading rapidly and CWD does transmit to mink, ferret, cattle, and squirrel monkey by intracerebral inoculation. With the known incubation periods in other TSEs, oral transmission studies of CWD may take much longer. Every victim/family of CJD/TSEs should be asked about route and source of this agent. To prolong this will only spread the agent and needlessly expose others. In light of the findings of Asante and Collinge et al, there should be drastic measures to safeguard the medical and surgical arena from sporadic CJDs and all human TSEs. I only ponder how many sporadic CJDs in the USA are type 2 PrPSc?

Sent: Monday, January 08,2001 3:03 PM

TO: freas@CBS5055530.CBER.FDA.GOV

FDA CJD BSE TSE Prion Scientific Advisors and Consultants Staff January 2001 Meeting Singeltary Submission

2001 FDA CJD TSE Prion Singeltary Submission

2 January 2000

British Medical Journal

U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well

15 November 1999

British Medical Journal

vCJD in the USA * BSE in U.S. ;

Terry S. Singeltary Sr.

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