26th ANNUAL REPORT 2017 CREUTZFELDT-JAKOB DISEASE SURVEILLANCE IN THE UK
SUMMARY
The national surveillance programme for Creutzfeldt-Jakob disease (CJD) in the UK was initiated in May 1990. In 1999, the National CJD Research & Surveillance Unit (NCJDRSU) became a WHO Collaborative Centre on the surveillance, diagnosis and epidemiology of human transmissible spongiform encephalopathies (TSEs). In September 2001, the National Care Team was formed in response to concerns regarding the care of CJD patients. The team currently comprises two care coordinators (who are senior nurses) with secretarial and clinical neurological support from within the NCJDRSU where it is based.
The annual mortality rate for sporadic CJD (sCJD) was 1.83 cases/million in 2017. Although the data for 2017 may still be incomplete, detailed clinical and epidemiological information has been obtained for the great majority of patients. Although the autopsy rate in cases of suspected CJD has decreased in recent years, it remains relatively high in comparison to the general autopsy rate in the UK. The number of brain tissue specimens examined for sCJD in the neuropathology laboratory in 2017 was 33 cases (compared with 36 cases in 2016).
Over the period 1990-2017 average annual mortality rates from sCJD in England, Wales, Scotland and Northern Ireland were, respectively, 1.16, 1.46, 1.19 and 0.85/million/year. The differences between these rates are not statistically significant (p=0.3). The mortality rates of sCJD in the UK are comparable to those observed in most other European countries and elsewhere in the world, including countries that are free of BSE.
Up to 31st December 2017, 178 cases of definite or probable variant CJD (vCJD) had been identified in the UK (123 definite and 55 probable cases who did not undergo post mortem). All 178 cases have died. The clinical, neuropathological and epidemiological features of the cases of vCJD are remarkably uniform and consistent with previous descriptions. Risk factors for the development of vCJD include age, residence in the UK and methionine homozygosity at codon 129 of the prion protein gene – of 161 clinically affected definite and probable cases of vCJD with available genetic analysis, 160 have been methionine homozygotes and one methionine-valine heterozygous at codon 129 of the PRNP gene. Analysis of vCJD diagnoses and deaths from January 1994 to December 2011 continues to indicate that the peak has passed. While this is an encouraging finding, the incidence of vCJD may increase again, particularly if further cases in different genetic subgroups with longer incubation periods exist. The identification of an individual of the PRNP-129 MV genotype as a confirmed case of vCJD (in addition to the possible case of vCJD reported in the NCJDRSU 17th Annual Report, 2008) and the finding of disease-related prion protein in the spleen of a clinically unaffected blood recipient (reported in 2004) is consistent with such a hypothesis. These cases, along with the results of large-scale surveys of the prevalence of abnormal prion protein in appendix and tonsil tissues suggest the possibility of a greater number of asymptomatic infections (either preclinical or subclinical) in the population than might be indicated by the present numbers of confirmed clinical cases.
Section 1 T 26 th Annual Report 2017 4
To help prevent any possible spread of CJD between people, we continue to ask clinicians to refer all new suspect CJD cases to their local infection control and health protection teams. This is important as a local response may be required with respect to limiting potential secondary transmission and other issues that may arise over time concerning the protection of the wider community. The NCJDRSU continues to assist local health protection teams in local audit and investigations of cases in response to local concerns. The NCJDRSU also continues to collaborate with health departments and public health authorities throughout the UK in relation to a range of activities in relation to the follow up of those identified as at increased risk of CJD.
The activities of the NCJDRSU are strengthened by collaboration with other surveillance projects, including the Transfusion Medicine Epidemiology Review, Prion Surveillance in Primary Immunodeficiency Patients and the study of Progressive Intellectual and Neurological Deterioration in Children. The collaboration of our colleagues in these projects is greatly appreciated; the effectiveness of this collaboration allowed the identification in 2003 of a case of vCJD associated with blood transfusion and the identification in 2004 of disease-related PrP in the spleen of a recipient of blood donated by someone incubating vCJD. A patient was also identified in 2010 who had evidence of vCJD infection in the spleen (but no evidence of clinical vCJD), considered probably due to blood products (treatment for haemophilia).
The relatively recently described form of prion disease originally termed Protease Sensitive Prionopathy and renamed Variably Protease Sensitive Prionopathy (VPSPr), is of uncertain nosological significance but is presently considered a form of sporadic prion disease, alongside sCJD. The NCJDRSU has so far identified at total of 13 such cases in the UK and is continuing to monitor this form of disease.
The data concerning CSF RT-QuIC are given in Section 3.5; the sensitivity of CSF RT-QuIC for a diagnosis of sCJD is comparable with that of CSF 14-3-3. The specificity is superior to that of CSF 14-3-3 with no positives in cases with a confirmed alternate diagnosis.
The success of the National CJD Research & Surveillance Unit continues to depend on the extraordinary level of co-operation from the neurology and neuropathology communities and other medical and paramedical staff throughout the UK. Ongoing support is provided by the Infectious Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine. We are also particularly grateful to the relatives of patients for their collaboration.
Providing information to the public is an important aspect of the NCJDRSU’s activities. We held an Open Family Day in 2014 and plan to repeat this in the near future. We liaise closely with the CJD Support Network, providing articles for their Newsletter, updating their information booklets and giving presentations to their Annual Family Day Meetings. Professor Knight is the current Chair of the Network’s Management Committee. Professors Knight and Will are also members of the CJD International Alliance of CJD support organisations.
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2.6 Study of Progressive Intellectual & Neurological Deterioration (PIND)
The aim of this project is to use the mechanism of the British Paediatric Surveillance Unit to identify all cases of progressive intellectual and neurological deterioration in children in the UK, particularly those with features suggestive of vCJD. All cases are discussed and allocated to a diagnostic category by an Expert Neurological Advisory Group made up of consultants who have specialised knowledge of paediatric neurology, neurogenetics and metabolic disease, together with representation from the
National CJD Research & Surveillance Unit.9 , 10, 11
As of 31st December 2017, after nearly 21 years of surveillance, 4137 patients with suspected PIND had been reported and the Expert Group had discussed 2718 of these. 1752 cases had a confirmed underlying cause other than vCJD, being categorised into over 190 known neurodegenerative diseases. There have been six cases of vCJD: four definite and two probable. Three were reported in 1999, one in 2000 and two in mid-2001. One girl was aged 12 at onset - the youngest UK case of vCJD identified to date.
(Collaborators on this project: Dr C Verity, Prof A Nicoll, Dr A Powell, Ms AM Winstone)
5 Llewelyn CA, Hewitt PA, Knight RSG, Amar K, Cousens S, Mackenzie J, Will RG. Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 2004; 363: 417-421. 6 Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 2004 364: 527-529. 7 Wroe SJ, Pal S, Siddique D, Hyare H, Macfarlane R, Joiner S, Linehan JM, Brandner S, Wadsworth JD, Hewitt P, Collinge J. Clinical presentation and pre-mortem diagnosis of variant Creutzfeldt-Jakob disease associated with blood transfusion: a case report. Lancet 2006; 368: 2061-2067. 8 Health Protection Agency. Fourth case of transfusion-associated variant-CJD. Health Protection Report 2007;1(3): 9 Verity CM, Nicoll A, Will RG, Devereux G, Stellitano L. Variant Creutzfeldt-Jakob disease in UK children: a national surveillance study. Lancet 2000; 356: 1224-1227. 10 Devereux G, Stellitano L, Verity CM, Nicoll A, Will RG, Rogers P. Variations in neurodegenerative disease across the UK: findings from the national study of Progressive Intellectual and Neurological Deterioration (PIND). Arch Dis Child 2004; 89: 8-12. 11 Verity C, Winstone AM, Stellitano L, Will R, Nicoll, A. The epidemiology of progressive intellectual and neurological deterioration in childhood. Arch Dis Child 2010; 95:361-364 deterioration in childhood. Arch Dis Child 2010; 95:361-364.
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SUNDAY, OCTOBER 21, 2018
Surveillance for variant CJD: should more children with neurodegenerative diseases have autopsies? Singeltary Review
vCJD Appendix III study UPDATE
A further study was designed
– Appendix III – looking at two further population groups: appendices removed from individuals during surgery performed before 1980 and appendices removed from individuals born after 1996. These two groups being unexposed to dietary BSE risk, as discussed above. The expectation was, therefore, that no positive results would be found in either group.
***> However, positive results were found in both and the numerical analysis found no statistically significant difference in the rate of abnormal appendices in the three time groups: pre1980, 1980-1996 and post-1996.
There are two broad explanations for this unexpected finding:
1.That abnormal prion protein in the appendix is not always an indication of BSE infection. However, if this is so, it is not clear as to what it would indicate.
2.That the dietary exposure period in the UK was more extensive than supposed – beginning before 1980 and extending after 1996. However, from what is known about the BSE epidemic, it is not straightforwardly obvious as to how this could be.
The full details of the Appendix III study are not yet published. Discussions are ongoing as to how to interpret the results as they stand and further research is planned to see if the questions raised can be answered. However, at the moment, uncertainty surrounds some of the assumptions that have been made about BSE and vCJD in the UK.
The Appendix III study looked at samples outside of the presumed BSE exposure period: those removed before 1980, and from young people born after 1996.
The results of the Appendix III study have not yet been reported in detail, but a preliminary report [67] revealed that positive samples were found in both groups examined, but not in any appendix removed before 1976 or in any individual born after 2000. It could be that there is a low background prevalence of abnormal prion protein in appendices, unrelated to the intensity of exposure to BSE, or that it is related to BSE exposure and that human exposure began in the late 1970s and continued until the mid-1990s, although at a lower rate than in the central years in the mid-1980s.
Infection report
Volume 10 Number 26 Published on: 12 August 2016
Summary results of the third national survey of abnormal prion prevalence in archived appendix specimens
In July 2012, the Transmissible Spongiform Encephalopathies (TSE) Risk Assessment SubGroup of the Advisory Committee on Dangerous Pathogens (the successor national advisory committee to the Spongiform Encephalopathy Advisory Committee (SEAC)), considered the results of the second unlinked anonymous national survey of the prevalence of abnormal prion protein in human appendix samples (Appendix-II [1]), and concluded that a further similar survey should be conducted on tissues from population groups considered unexposed to BSE [2]. This third national survey (Appendix-III) of appendix specimens removed at operations prior to the BSE epizootic and appendix specimens from those born in 1996 or later, by which time measures had been put in place to protect the food chain, has now been concluded. This report provides a summary of the results of the Appendix-III survey prior to publication in due course of the complete data.
The Appendix-III survey examined by immunohistochemistry (IHC) appendices removed at operation and collected from 44 hospitals throughout England. Abnormal prion accumulation was detected within the follicular dendritic cells of seven appendices out of 29,516 suitable samples examined. Indirect comparison of available data showed that none of the positive appendices could have come from the 178 known vCJD cases in the UK.
Two of the seven positive samples were from the 14,692 appendices removed at operations conducted in 1962 through 1979: both these positive samples were from the 5,865 appendices removed in 1977 through 1979. The other five positive samples were found in the 14,824 appendices from subjects born in 1996 or later and removed at operation in 2000 through 2014: all five were in the sub-group of 10,074 born in 1996 through 2000. Therefore, none of the seven positive appendices were in specimens removed before 1977 or in patients born in 2001 or later.
The planned statistical analysis found no difference between the prevalence observed in the Appendix-II survey of 493 per million (95% Confidence Interval (CI): 282 to 801 per million) and the Appendix-III prevalence in appendices removed between 1962 through 1979 of 136 per
Health Protection Report Vol. 10 No. 26 – 12 August 2016
million (95%CI: 16 to 492 per million; exact p=0.08), nor with the Appendix-III prevalence in appendices from those born in 1996 through 2000 of 337 per million (95%CI: 110 to 787 per million; exact p=0.64). Test accuracy calculations using the Appendix-III data suggest the IHC technique specificity is in the range of 99.975% to over 99.99%. Although specificity of this magnitude (99.99%) implies few false positives, if the true prevalence is very low, then the positive predictive value of the IHC technique will diminish. At the one in 7,000 prevalence observed in the Appendix-III survey of specimens removed in 1979 or earlier, the positive predictive value (PPV) will be 56%, for a specificity of 99.99% and a sensitivity of 90%, compared to a PPV of 82% at the one in 2,000 prevalence observed in the Appendix-II survey. The Appendix-II and -III surveys were conducted by a collaboration of PHE, the Department of Neurodegenerative Diseases at the UCL Institute of Neurology, the Animal and Plant Health Agency, the National Creutzfeldt-Jakob Disease Research and Surveillance Unit, the Histopathology Department of Derriford Hospital in Plymouth, and the MRC Prion Unit.
In summary, the Appendix-III survey data have not produced a clear answer to the question of whether abnormal prions detected by IHC in the British population is limited to those exposed to the BSE epizootic, and various interpretations are possible. The survey results have been considered by the ACDP TSE Sub-Group and a position paper detailing the conclusions of the committee has been published online, simultaneously with this summary report [3].
References
1. Gill ON, Spencer Y, Richard-Loendt, A, Kelly C, Dabaghian R, Boyes L, et al (2013). Prevalent abnormal prion protein in human appendixes after bovine spongiform encephalopathy epizootic: large scale survey. BMJ 347: f5675, http://www.bmj.com/content/347/bmj.f5675.
2. Advisory Committee on Dangerous Pathogens TSE Risk Assessment Subgroup (July 2012). Position Statement on occurrence of vCJD and prevalence of infection in the UK population. Available from: ACDP TSE subgroup minutes, agendas and papers, https://app.box.com/s/hhhhg857fjpu2bnxhv6e.
3. Advisory Committee on Dangerous Pathogens TSE Risk Assessment Subgroup (August 2016). “Appendix-III” position statement. Available from: ACDP TSE subgroup minutes, agendas and papers, https://app.box.com/s/hhhhg857fjpu2bnxhv6e
some history...TSS
Transmissible Spongiform Encephalopathy Agents: Safe Working and the Prevention of Infection: Annex A1 ANNEX A1
Distribution of TSE infectivity in human tissues and body fluids
A1.1 There is evidence that the distribution of the disease-specific partially protease-resistant form of prion protein (PrPTSE) in tissues is more widespread in the body in variant CJD (vCJD) patients than in patients affected by sporadic CJD (1, 2, 3). In sporadic CJD, the presence of abnormal prion protein in patients with clinical disease appears to be restricted to the central nervous system (CNS). However, abnormal prion protein has been detected in various lymphoid tissues, including tonsils, spleen, gastrointestinal lymphoid tissue (appendix and rectum), lymph nodes, thymus and adrenal gland of patients with clinical vCJD. Abnormal prion protein has also been detected in lymphoid tissues within the appendix removed from 2 patients some 8 and 24 months before they developed vCJD (4, 5) suggesting that abnormal prion protein could be present in the lymphoid tissue of people incubating vCJD for some time before the onset of clinical disease. In similar tests, abnormal prion protein has not been detected in these tissues from sporadic CJD patients. Infectivity has been demonstrated in tonsil and spleen in vCJD by experimental transmission (6).
A1.2 PrPTSE has been identified in posterior spinal nerve roots in only an occasional case of sporadic CJD and GSS (7), but not in peripheral nerve in vCJD (3, 8). Transmission studies on peripheral nerve samples from cases of sporadic CJD by intracerebral inoculation into primates have shown no evidence of infectivity (9). PrPTSE has been detected in spinal dorsal root ganglia and trigeminal ganglia in vCJD (8), and in trigeminal ganglia in sporadic CJD (10). PrPTSE has also been detected in olfactory epithelium in sporadic CJD patients at post mortem (11), and in the olfactory tract in vCJD (12). Infectivity and PrPTSE have not been detected in dental pulp in a series of sporadic CJD cases (13), and PrPTSE was not detected in the alveolar nerve, dental pulp, gingiva, salivary gland, tongue in a small series of vCJD cases (14).
A1.3 Table A1 presents current information on the distribution of infectivity in tissues and body fluids in CJD other than vCJD, and in vCJD, based on data from experimental studies, where available, and on information from other studies of natural TSE disease in humans and animals. It also shows where PrPTSE has been detected in tissues. Published: 2 June 2003 1
Updated: December 2010 Transmissible Spongiform Encephalopathy Agents: Safe Working and the Prevention of Infection: Annex A1
A1.4 The precise relationship between the presence of PrPTSE and infectivity is not certain – for example, the absence of detectable PrPTSE does not necessarily mean absence of infectivity. Conversely, detection of small amounts of PrPTSE in a tissue does not necessarily mean that it will transmit disease in all circumstances. This guidance has been formulated on the basis of likelihood of the presence of infectivity using the identification of PrPTSE as a specific marker. In general terms, there is thought to be a broad correlation between PrPTSE load in a given tissue and the likelihood that the given tissue might present a risk of infection. The relative levels of PrPTSE in different tissues provide useful information for the assessment of relative risks of different procedures.
A1.5 In Table A1, tissue infectivity is classified as high, medium or low, on the basis of infectivity assays in experimental animals. Although such studies are limited in CJD and vCJD tissues, the preliminary data that are available support the findings in tissues from other natural and experimental TSE models. Therefore the relative levels of PrPTSE in different tissues provide useful information for the assessment of relative risks of different surgical and endoscopic procedures.
A1.6 The information given in this Annex describes the position at the time of publication. This will be kept under review and is subject to change as further information becomes available.
Table A1 – Distribution of TSE infectivity in human tissues and body fluids
Key: +ve = tested positive -ve = tested negative
NT = not tested P = infectivity proven in experimental transmission studies
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1Spinal ganglia have a high assumed level of infectivity in the WHO Guidelines. However, unpublished results on the infectivity of spinal ganglia indicate that this tissue is of medium infectivity.
Published: 2 June 2003 3 Updated: December 2010 Transmissible Spongiform Encephalopathy Agents: Safe Working and the Prevention of Infection: Annex A1 2Dura mater is designated low infectivity as virtually no detectable abnormal prion protein has been found in cases of CJD; however, as grafts of these tissues are associated with CJD transmission, probably as a result of contamination by brain and because of the lengthy period of implantation in the CNS, procedures conducted on intradural tissues (i.e. brain , spinal cord and intracranial sections of cranial nerves) or procedures in which human dura mater was implanted in a patient prior to 1992, remain high risk.
3Although PrPTSE has not been detected in the CSF in either sporadic or variant CJD (15), experimental transmission of infectivity has been achieved from CSF in sporadic CJD in 4 of 27 primates by intracerebral inoculation (9) indicating that levels of infectivity are likely to be much lower than in the central nervous system.
4PrPTSE has been detected in dura mater, skin, kidney, liver, pancreas, ovary and uterus in a case of vCJD in USA with a lengthy duration of illness (16). Earlier studies of these tissues in UK vCJD cases gave negative results (2,8,17).
References
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TUESDAY, NOVEMBER 11, 2008
SaBTO Summary of 1st Public Meeting – variant CJD and blood Tuesday 21st October 2008, 2pm-4pm Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO)
Summary of 1st Public Meeting – variant CJD and blood
Tuesday 21st October 2008, 2pm-4pm
New King’s Beam House, London SE1
Introduction
Mr John Forsythe – University of Edinburgh/SaBTO Chair
Mr Forsythe welcomed the audience, and outlined the background of SaBTO and the work of the committee. He explained that the committee feels that it is vital to share information used to make decisions and to invite comments from interested parties and the public. This explains the committee’s decision to hold an annual public meeting on selected topic.
1st Presentation: Introduction to variant CJD
Dr Hester Ward – National CJD Surveillance Unit/SaBTO vCJD expert
Dr Ward gave an introductory talk on the cause and epidemiology of variant CJD.
1. There are several different types of prion diseases in humans, which can be divided into idiopathic (e.g. sporadic CJD), acquired (e.g. variant CJD) and genetic (e.g. familial CJD). There is no evidence that sporadic CJD can be transmitted via transfusion.
2. Variant CJD emerged in 1996 with features distinct from those seen in sporadic CJD. It affects younger people, who survive longer, and there are also distinct clinical and neuropathological features.
3. 18 of those affected by vCJD are known to have been blood donors. 66 recipients of their blood have been identified, of whom 23 survive.
4. vCJD is infective in blood but there remain a large number of uncertainties. A self-sustaining secondary epidemic through blood transfusion may be possible.
5. Key to determining the size of a secondary epidemic is measuring how may people in the population may be carriers of vCJD (the ‘population prevalence’).
6. A study on stored appendix samples and one on tonsils have given estimates for carriers of between 1 in 1, 500 and 1 in 20, 000 of the UK population.
7. Possible further studies of this type could involve more appendix samples, a post-mortem archive or blood tests, which are not yet available but are in development.
2nd Presentation: Variant CJD and Blood: current safety measures and future options
Professor Marc Turner – University of Edinburgh and Scottish National Blood Transfusion Service/SaBTO Haematologist
Professor Turner gave a presentation on the issues around variant CJD and blood, the current safety measures in place, and options that may be considered in the future.
1. The prevalence of sub-clinical infection amongst the population of blood donors was discussed. The best estimate for incidence of further clinical cases is 70 .
2. This represents a discrepancy with the retrospective tonsil and appendix study data which indicates that the prevalence of sub-clinical infection of vCJD is 1/4000 (range 1/1000 to 1/20000). This suggests that up to 3,000 members of the UK population may be infected but remain sub clinical (symptom free) in the longer term.
3. It is known that in rodent models the potential level of peripheral infection is around 10 infectious doses per ml of blood (range 1-300 ID / ml).
4. These data taken together with the known transmission of variant CJD by blood suggest the possibility of an ongoing risk of transmission of variant CJD through blood, tissues and organs.
5. In the face of uncertainty, the best risk management approaches are those that give at least some control of risk over a wide range of plausible scenarios. In the context of variant CJD and blood, there are four potential approaches; donor selection, donor screening, component processing and minimising exposure.
6. Although a number of donor deferral criteria have been introduced both in the UK and internationally, they represent a relatively blunt risk management approach and can undermine the supply of blood and tissues.
7. A future test for vCJD may detect the presence of the abnormal protein in blood which would help to control the risk of secondary transmission , but will not give definitive information on the likelihood of development of clinical disease and will pose problems around sensitivity and specificity, validation and the management of those who have tested positive. There are particular concerns around the impact of a ‘poor’ test on donors and the blood supply.
8. Blood component processing is used to further reduce risk from transfusion. Red cells are re-suspended in optimal additive solution rather than plasma, and all red blood cells undergo leucodepletion. Using prion reduction filters to filter out prions from leucodepleted red blood cells may further reduce infectivity and these are currently under evaluation.
9. Risk reduction by reducing exposure to blood represents an immediately available, low cost measure that is relatively straightforward to implement.
3rd Presentation – A Patient’s Perspective
Mr Elwyn Nicol – SaBTO Patient Representative
Mr Nicol, explained that some 5 years ago he underwent a heart transplant, hence his interest in becoming the SaBTO patient representative.With no family connections or experience in, or background of, the medical profession. Mr Nicol represents the patient. He emphasised that his views are independent and well placed to express an opinion, based on his own experience.To lay members in this audience he confirmed that the well-being of patients, on this committee, seems paramount.There are 2.4m blood donors in the UK and it is claimed that the vCJD testing programmes being developed may be 99% effective. Mr Nicol said he considers that to be very good, but it could mean 1%, i.e. 24,000 donations or donors would be falsely told that they had tested positive for vCJD.
Until testing for vCJD in blood is 100% reliable, potentially 24000 blood donors, who 'do something special' without reward could be falsely told they have the disease every year. They could not know if they are truly threatened, not know if they will ever be able to get a life insurance policy, ever be able to get a mortgage or ever be able to buy a pension. As a heavily transfused patient, Mr Nicol was and remains, content with the range of precautionary measures that exist. Until a 100% test exists Mr Nicol would prefer to rely on those existing measures rather than see potential distress and harm being caused to individual blood donors.
Those who will make the final decision have a very difficult choice to make – Nr Nicol said that we ask a lot from donors and asked if we can ask a society that their generosity be extended to submit to an unreliable test that could result in such anguish for so many?
Statements from family members of those affected by variant CJD
Two relatives of individuals affected by vCJD spoke.
Mr Peter Buckland spoke on behalf of his family. His son died after contracting vCJD from contaminated blood. Mr Buckland made the following points:
• The devastating effect of vCJD on the families of those affected was huge.
• The tragic consequences of the disease have been made more acute by a lack of information available to his family at the time from government institutions.
• The processes around management of vCJD should be open and honest, and those responsible should be prepared to explain their decisions.
• Delays in notifying those at risk of the disease did those who went on to develop vCJD a great disservice. Lives would have been led differently if the future implications had been made clear.
• An earlier notification would at the very least have allowed families to explore potential treatments for the disease in the early stages.
• Any test for vCJD should be made available. It is not acceptable that “at-risk” individuals be kept in the dark, however low that risk may be.
Ms Christine Lord is the mother of Andrew Black, who died from vCJD in 2007 aged 24, and made the following points:
• Those making the decisions around management of vCJD should be supervised by independent sources that are not government funded or backed.
• The terrible risk and legacy of vCJD that the UK population now face should lay clearly at the door of those who Ms Lord considers responsible for her son’s death. Ms Lord believes that if those ministers and officials in the 1980s and 1990s had not put profit before lives vCJD would have never existed and SaBTO would not be faced with the terrible dilemmas it now has to wrestle with.
• Testing should be made available as soon as it is developed. Ms Lord believes that it may not be in the Government’s best interest to make such a test available. The doubts about prevalence mean that the likely number of positives is not known; ministers may be reluctant to allow the wider public to be made aware of the true prevalence of vCJD in the population, particularly if the situation was worse than is currently forecast.
• Testing for vCJD should be a personal choice allowing people to live their lives accordingly. Ms Lord believes that officials in the 1980s and 1990s played god with the UK populations lives resulting in vCJD and too many innocent people dying needlessly and she is mindful that government may very well be playing god again by refusing the UK population the choice to test or not.
• As a mother who has lost her son to vCJD Ms Lord would take a test tomorrow and would like the opportunity to be able to do this in the near future.
• The devastation vCJD has wrecked on families, careers, futures and relationships cannot be described in mere words. As a bereaved mother, a qualified journalist and psychological counsellor Ms Lord is acutely aware of the huge impact and life scarring event that nursing a child through the most horrific disease has had on hundreds of family members and thousands of colleagues and friends. Ms Lord’s website is www.justice4andy.com.
Summary of questions/open forum
Q. What developments have there been since 2004 aimed at reducing the risk of vCJD transmission by blood transfusion?
SaBTO is considering other potential options for mitigating the risk of vCJD, including importation of red cells for the children, double-dose red cell collection, extension of platelet apheresis and importation of plasma for all recipients.Several manufacturers are developing filters aiming to remove prion protein from red cells for transfusion. One of these filters is CE marked which means that it can legally be used in the UK. This filter is under active assessment by the UK and Irish Blood Services. It is important that any new technology used to produce blood components is assessed to make sure that it is effective and will not cause any harm to patients. A pathway for assessing prion removal filters has been established by the UK Blood Services and endorsed by SaBTO. The Spongiform Encephalopathy Advisory Committee (SEAC) have advised that the UK Blood Services should obtain an independent assessment of the ability of these filters to remove prion protein. The first of these studies is well underway with early results expected to be reported in 2009. The UK Blood Services are also undertaking a clinical study of prion-filtered red cells in surgical patients and then transfusion dependent patients, designed to assess whether the filter results in an increase in adverse events to patients. These clinical studies were endorsed by SaBTO’s predecessor, the Advisory Committee on the Microbiological Safety of Blood, Tissues and Organs (MSBTO). SaBTO will review this subject further in spring/summer 2009 when data from the independent evaluation and clinical studies of prion-filters are likely to become available.
Q. What are the panel’s views on the potential for embryonic stem cells to be used to produce blood components for transfusion?
Although there has been considerable progress in this area, we still have a lot to learn about how the growth of stem cells is controlled, and also how to produce specific cell types from stem cells. There are significant challenges in being able to produce sufficient amounts of cells for transfusion or transplantation from stem cells and it is likely to be some years before such cells can be used clinically.
Q. How long is the incubation period for vCJD transmitted by blood transfusion?
We do not know, but in the 4 cases where vCJD infection is thought to have been transmitted by blood transfusion, the incubation period between receiving the implicated transfusion and development of symptoms of disease was 6-8 years in the 3 symptomatic cases. In animals, the incubation period following infection can be influenced by genetic factors and in other human prion diseases, such as Kuru, the incubation period can be up to 40 years. It is possible, therefore, that some people have been infected but have not yet (and maybe will never) develop clinical disease.
Q. When is a test for vCJD in blood likely to be available?
There is currently no validated diagnostic test that can be used to determine whether blood is infected with vCJD. Several companies are developing tests for vCJD in blood and are making good progress. As for prion removal filters the UK Blood Services have developed a pathway for assessing tests that may be applied to blood donors. We currently do not know how accurate these tests will prove to be. There are concerns around telling asymptomatic people, for example blood donors, that they may be infected with vCJD when the significance of the test result is uncertain, when it is unknown whether infection would necessarily result in disease, and when there is no proven treatment.The impact of a screening test on the blood and tissue supply could be profound depending on how accurate the test is due to the direct loss of donations due to false positive results and the indirect impact in deterring people from donating., In addition there would be a need to carry out lookback studies and both donors and past recipients may need to be designated as “at risk of vCJD for public health purposes” leading to significant impact on the wider NHS.It was noted that the development of a diagnostic test for vCJD was highly desirable for groups of patients who have been identified as ‘at risk from vCJD for public health purposes’. However, SaBTO’s remit is restricted to consideration of tests in the context of blood, tissue and organ donation.
Q. With regards to screening tests for vCJD in blood, what level of specificity and sensitivity do SaBTO regard as acceptable?
Currently the UK Blood Services screen blood for several viruses. Donors that have a positive result then undergo further testing with one or more confirmatory tests before being informed that they are positive. The acceptable performance of a vCJD screening test would depend, in part therefore, on whether a secondary screening test or confirmatory test was available.
Q. Why is blood labelled "Risk of adverse reaction/infection, including vCJD" but other infectious agents such as HIV not included on the label? Why is plasma that is imported not labelled the same way?
The labelling of blood components has been changed to bring it in line with labelling of tissue products. Other infectious agents such as HIV do not appear on the label as blood donations are currently tested for these; there is no screening test for vCJD available. Plasma is imported from a country with low risk of vCJD and therefore not labelled in the same way as blood components from the UK. SaBTO are currently examining the possibility of recommending full written informed consent for transfusion, which would include information on the risks involved and whether there are any suitable alternatives.
Q. Why aren’t platelets imported? Is importation of red cells feasible?
Plasma components have a 2 year shelf-life and can be transported frozen. Platelets have a shelf-life of 5 days and must also be transported and stored in a very specific way to preserve them. It would therefore be highly unlikely that sufficient platelets could be imported from outside the UK with these limitations. NHS Blood & Transplant are currently conducting a feasibility study to assess options for importing red cells. Importing red cells for all patients in the UK will not be possible (over 2 million units of red cells per year are required). It may be possible to import red cells for selected patient groups, for example for children. Importation of special red cell products with a short-shelf life of 5 days or less is not likely to be feasible however. It is important to also consider other risks that may be increased in possible source countries, such as viral risk, since systems are not available to treat red cells to kill viruses. Q. If a test for vCJD is available, should it be used to screen egg and sperm donors?
So far SaBTO have only considered the possible use of a vCJD screening test for blood donors. In due course the committee will also have to consider the application of such a test to donors of tissues, organs and gametes.
Q. Would prion filtration prevent the need to import red cells? And unlike screening for vCJD, prion-filtration would not have any negative impact on the donor.
Prion-filtration or importation of red cells would reduce the cost-effectiveness of the other. SaBTO are considering a number of possible options to reduce the risk of vCJD transmission by blood. The cost-effectiveness and advantages/disadvantages of each option have been considered at the April and July 2008 meetings of SaBTO. The committee will be considering these measures further in 2009 when further data on prion filtration and testing are available.
Q. Has there been a case of vCJD transmission by blood transfusion of leucocyte depleted blood?
No. So far all 4 possible transmissions of infected prion protein have all been from non-leucocyte depleted red cells and there have been no known infections from blood since this time. Leucocyte depletion was implemented in the UK in 1998/1999. Animal studies suggest that leucocyte depletion only removes about 40-50% of infectivity in blood. We also do not know what the maximum period of incubation between transfusion of infected blood and development of vCJD could be, and therefore leucocyte-depleted blood could be capable of transmitting infection but there may not have been sufficient time for any of the recipients to develop clinical disease as yet.
Q. Have SaBTO sought advice from the Association of British Insurers regarding vCJD tests? The Association of British Insurers have been consulted previously with regard to patients who have developed CJD following treatment with growth hormones. Their response indicated that such recipients would not have any issues relating to insurance policies. SaBTO will obtain further information from the Association of British Insurers when more information is available on the performance of vCJD screening tests.
Q. SaBTO requested a feasibility study on the use of double-dose red cells at their July meeting. When will this be available?
NHS Blood & Transplant have been asked to perform a feasibility study on the use of double dose red cells for selected patient groups. This will be presented to the committee in Spring 2009 along side other options for risk-reduction of vCJD by transfusion.
Q. Why does SaBTO still use estimates of prevalence from the Hilton study published in 2004 and not the later National Anonymised Tonsil Archive (NATA) study?
This has been reviewed by the Spongiform Encephalopathy Advisory Committee (SEAC) not SaBTO. The Hilton study was on both appendices and tonsils (but mainly appendices). There are differences between the studies in terms of the tissue studied, the period in time the study was performed since the initial BSE epidemic and the sensitivity of test methods used. SEAC therefore do not consider it to be appropriate to combine data from the two studies. The estimates of prevalence from the two studies are currently consistent with each other, and the confidence intervals of the NATA study are within those of the Hilton study.
At the end of the meeting it was generally agreed that this exercise had been very useful – both to spread important information on this issue and also to open dialogue with all those involved. SaBTO intend to hold a similar public meeting next year.
***> PRION 2018 CONFERENCE <***
O19 Experimental transfusion of variant CJD-infected blood reveals novel class of prion disorders
Comoy EE (1), Mikol J (1), Rontard J (1), Delmotte J (1) & Deslys JP (1) 1) CEA, Institut François Jacob, Université Paris-Saclay, 18 Route du Panorama, 92265, Fontenayaux-Roses, France.
The recently reevaluated high prevalence of healthy carriers (1/2000 in UK) of variant of CreutzfeldtJakob Disease (v-CJD), whose blood might be infectious, suggests that the evolution of this prion disease might not be under control as expected and enforces the necessity to assess the corresponding transfusional risk.
After experimental transfusion of macaques and conventional mice with blood derived from v-CJD exposed individuals, we confirmed in these both models the transfusional transmissibility of v-CJD in optimal conditions, corresponding to non-deleukocyted, whole blood samples derived from donors (of same species) with high levels of peripheral replication and sampled during the clinical phase. However, we also observed unexpected neurological syndromes transmissible by transfusion in a higher proportion of recipients, which occurred under less optimal conditions for prion transmission, which included deleukocyted samples, donors with low levels of peripheral replication, inter-specific (human to macaque or macaque to mice) transfusion and notably in two recipients transfused with blood derived from healthy carriers. Despite their prion etiology confirmed through transmission experiments, these original cases would escape classical prion diagnosis, notably in the quasi-absence of detectable abnormal PrP with current techniques. In conventional mice, incomplete vCJD phenotypes with spinal involvement were observed, whereas macaques developed an original, yet undescribed myelopathic syndrome associating demyelination and pseudo-necrotic lesions of spinal cord, brainstem and demyelination of the optical tract without affecting encephalon, which is rather evocative of spinal cord diseases than prion diseases.
These atypical profiles, that were also observed after intravenous exposure to soluble fractions of infected brains, were associated to an absence of detectable accumulation of abnormal PrP in follicles of lymphoid organs. Optimized techniques of immunohistochemistry identified an ectopic accumulation of abnormal PrP around splenic vessels in both primates developing vCJD or myelopathy. In parallel, those atypical syndromes were transmissible to immunocompromised mice through the intravenous route. Taken altogether, these results suggest that some prion variants, mostly associated to soluble prions, may follow distinct pathophysiological pathways that would be independent of the immune system. In parallel to the obvious consequences in terms of public health if such a situation should exist in humans, these observations questioned the possibility that the spectrum of prion diseases may extend the current field restricted to the phenotypes associated to proteaseresistant PrP.
Unexpected prion phenotypes in experimentally transfused animals: predictive models for humans?
Emmanuel E. Comoy, Jacqueline Mikol & Jean-Philippe Deslys
Pages 162-169 | Received 06 Jul 2018, Accepted 24 Jul 2018, Accepted author version posted online: 06 Aug 2018, Published online: 16 Aug 2018
ABSTRACT
The recently reevaluated high prevalence of healthy carriers (1/2,000 in UK) of variant Creutzfeldt-Jakob Disease (v-CJD), whose blood might be infectious, suggests that the evolution of this prion disease might not be under full control as expected.
After experimental transfusion of macaques and conventional mice with blood derived from v-CJD exposed (human and animal) individuals, we confirmed in these both models the transmissibility of v-CJD, but we also observed unexpected neurological syndromes transmissible by transfusion: despite their prion etiology confirmed through transmission experiments, these original cases would escape classical prion diagnosis, notably in the absence of detectable abnormal PrP with current techniques.
It is noteworthy that macaques developed an original, yet undescribed myelopathic syndrome associating demyelination and pseudo-necrotic lesions of spinal cord, brainstem and optical tract without affecting encephalon, which is rather evocative of spinal cord disease than prion disease in human medicine.
These observations strongly suggest that the spectrum of human prion diseases may extend the current field restricted to the phenotypes associated to protease-resistant PrP, and may notably include spinal cord diseases.
KEYWORDS: (5-10): prion, vCJD, macaque, mouse, spinal cord disease, myelopathy, transfusion, abnormal PrP, demyelination, spongiform change
This article refers to:
Additional information
Funding
The original laboratory work was funded by European Commission [Fifth Framework Programme, QLK1-CT-2002-01096], French Research Funding Agency (Agence Nationale de la Recherche, ANR) [ANR-10-BLAN-1330 01], Health Canada [4500216567] and MacoPharma.
***> It is noteworthy that macaques developed an original, yet undescribed myelopathic syndrome associating demyelination and pseudo-necrotic lesions of spinal cord, brainstem and optical tract without affecting encephalon, which is rather evocative of spinal cord disease than prion disease in human medicine.
***> These observations strongly suggest that the spectrum of human prion diseases may extend the current field restricted to the phenotypes associated to protease-resistant PrP, and may notably include spinal cord diseases.
TUESDAY, AUGUST 7, 2018
Unexpected prion phenotypes in experimentally transfused animals: predictive models for humans?
MONDAY, NOVEMBER 06, 2017
Experimental transfusion of variant CJD-infected blood reveals previously uncharacterised prion disorder in mice and macaque
FRIDAY, OCTOBER 05, 2018
More Politicians and Very Young People Struck Down With Creutzfeldt Jakob Disease CJD mad cow type TSE Prion USA
Sunday, September 16, 2018
Mother to Offspring Transmission of TSE PRION DISEASE and risk factors there from
WEDNESDAY, SEPTEMBER 05, 2018
Edmonton woman one of the youngest diagnosed with CJD at 35 years old and pregnant
Volume 2: Science
4. The link between BSE and vCJD
4.29 The evidence discussed above that vCJD is caused by BSE seems overwhelming. Uncertainties exist about the cause of CJD in farmers, their wives and in several abattoir workers. It seems that farmers at least might be at higher risk than others in the general population. 1 Increased ascertainment (ie, increased identification of cases as a result of greater awareness of the condition) seems unlikely, as other groups exposed to risk, such as butchers and veterinarians, do not appear to have been affected.
***The CJD in farmers seems to be similar to other sporadic CJD in age of onset, in respect to glycosylation patterns, and in strain-typing in experimental mice.
***Some farmers are heterozygous for the methionine/valine variant at codon 129, and their lymphoreticular system (LRS) does not contain the high levels of PrPSc found in vCJD.
*** It remains a remote possibility that when older people contract CJD from BSE the resulting phenotype is like sporadic CJD and is distinct from the vCJD phenotype in younger people.
BSEINQUIRY
***>Some farmers are heterozygous for the methionine/valine variant at codon 129, and their lymphoreticular system (LRS) does not contain the high levels of PrPSc found in vCJD.<***
SATURDAY, JUNE 23, 2018
***> Diagnosis of Methionine/Valine Variant Creutzfeldt-Jakob Disease by Protein Misfolding Cyclic Amplification
Volume 24, Number 7—July 2018
SATURDAY, OCTOBER 06, 2018
Evaluation of iatrogenic risk of CJD transmission associated with corneal transplantation
SATURDAY, SEPTEMBER 22, 2018
Emerging Diseases, Infection Control & California Dental Practice Act
THURSDAY, OCTOBER 04, 2018
Case Western Reserve researchers to examine skin prions in fatal neurodegenerative disease $2.9 million NIH grant focuses on transmission and diagnostic testing
WEDNESDAY, JULY 04, 2018
CREUTZFELDT-JAKOB DISEASE: GUIDELINES FOR SOCIAL WORKERS IN ENGLAND June 2018
MONDAY, JUNE 18, 2018
Ecuador Six Case series of Creutzfeldt-Jakob disease in a third-level hospital in Quito
THURSDAY, OCTOBER 04, 2018
Cervid to human prion transmission 5R01NS088604-04 Update
WEDNESDAY, SEPTEMBER 26, 2018
JAVMA In Short Update USDA announces detection of atypical BSE
MONDAY, OCTOBER 01, 2018
Update on Classical and Atypical Scrapie in Sheep and Goats: Review 2018
HUMAN MAD COW DISEASE nvCJD TEXAS CASE NOT LINKED TO EUROPEAN TRAVEL CDC
Sunday, November 23, 2014
Confirmed Variant Creutzfeldt-Jakob Disease (variant CJD) Case in Texas
Updated: October 7, 2014
CDC and the Texas Department of State Health Services (DSHS) have completed the investigation of the recently reported fourth vCJD case in the United States. It confirmed that the case was in a US citizen born outside the Americas and indicated that the patient's exposure to the BSE/vCJD agent most likely occurred before he moved to the United States; the patient had resided in Kuwait, Russia and Lebanon. The completed investigation did not support the patient's having had extended travel to European countries, including the United Kingdom, or travel to Saudi Arabia. The specific overseas country where this patient’s infection occurred is less clear largely because the investigation did not definitely link him to a country where other known vCJD cases likely had been infected.
https://www.cdc.gov/ncidod/dvrd/vcjd/other/confirmed-case-in-texas.htm
https://vcjd.blogspot.com/2014/11/confirmed-variant-creutzfeldt-jakob.html
WEDNESDAY, SEPTEMBER 26, 2018
A new variant of Creutzfeldt-Jakob disease in the UK 1995 revisited 2018 a review of science
THURSDAY, OCTOBER 04, 2018
National Prion Disease Pathology Surveillance Center Cases Examined¹ (September 18, 2018)
THURSDAY, SEPTEMBER 27, 2018
Amydis Awarded Prion Disease Grant from NIH
TUESDAY, SEPTEMBER 4, 2018
USA CJD, BSE, SCRAPIE, CWD, TSE PRION END OF YEAR REPORTS September 4, 2018
prepare for the storm...
Tuesday, March 20, 2018
Variably protease-sensitive prionopathy (VPSPr), sporadic creutzfeldt jakob disease sCJD, the same disease, what if?
O3 Experimental studies on prion transmission barrier and TSE pathogenesis in large animals
Rosa Bolea(1), Acín C(1)Marín B(1), Hedman C(1), Raksa H(1), Barrio T(1), Otero A(1), LópezPérez O(1), Monleón E(1),Martín-Burriel(1), Monzón M(1), Garza MC(1), Filali H(1),Pitarch JL(1), Garcés M(1), Betancor M(1), GuijarroIM(1), GarcíaM(1), Moreno B(1),Vargas A(1), Vidal E(2), Pumarola M(2), Castilla J(3), Andréoletti O(4), Espinosa JC(5), Torres JM(5), Badiola JJ(1).
1Centro de Investigación en Encefalopatías y Enfermedades Transmisibles Emergentes, VeterinaryFaculty, Universidad de Zaragoza; Zaragoza,Spain.2 RTA, Centre de Recerca en Sanitat Animal (CReSA, IRTA-UAB) 3 4 INRA, ÉcoleVétérinaire, Toulouse, France.5CIC bioGUNE, Prion researchlab, Derio, Spain CISA- INIA, Valdeolmos, Madrid 28130, Spain.
Experimental transmission of Transmissible Spongiform Encephalopathies (TSE) has been understood and related with several factors that could modify the natural development of these diseases. In fact, the behaviour of the natural disease does not match exactly in each animal, being modified by parameters such as the age at infection, the genotype, the breed or the causative strain. Moreover, different TSE strains can target different animal species or tissues, what complicate the prediction of its transmissibility when is tested in a different species of the origin source. The aim of the experimental studies in large animals is to homogenize all those factors, trying to minimize as much as possible variations between individuals. These effects can be flattened by experimental transmission in mice, in which a specific strain can be selected after several passages. With this objective, several experimental studies in large animals have been developed by the presenter research team.
Classical scrapie agent has been inoculated in cow, with the aim of demonstrate the resistance or susceptibility of this species to the first well known TSE; Atypical scrapie has been inoculated in sheep (using several routes of infection), cow and pig, with the objective of evaluating the potential pathogenicity of this strain; Classical Bovine Spongiform Encephalopathy (BSE) has been inoculated in goats aiming to demonstrate if the genetic background of this species could protect against this strain; goat BSE and sheep BSE have been inoculated in goats and pigs respectively to evaluate the effect of species barrier; and finally atypical BSE has been inoculated in cattle to assess the transmissibility properties of this newly introduced strain.
Once the experiments have been carried out on large animal species, a collection of samples from animals studied were inoculated in different types of tg mice overexpressing PrPcin order to study the infectivity of the tissues, and also were studied using PMCA.
In summary, the parameters that have been controlled are the species, the strain, the route of inoculation, the time at infection, the genotype, the age, and the environmental conditions.
To date,
***> eleven of the atypical scrapie intracerebrally inoculated sheep have succumbed to atypical scrapie disease;
***> six pigs to sheep BSE;
***> one cow to classical scrapie;
***> nine goats to goat BSE and
***> five goats to classical BSE.
***> PrPSC has been demonstrated in all cases by immunohistochemistry and western blot.
=====> PRION CONFERENCE 2018
WITH the recent findings that Scrapie will transmit to Macaque by or route, that Scrapie and CWD TSE Prion will transit to pigs orally, recent outbreak documented of TSE Prion Disease in Dromedary Camels, Algeria, atypical TSE Prion still being documented, and again just recently in the USA, of another atypical BSE case, and this discovery was only documented by testing 20k head of cattle from some 100M head of cattle in any given year in the USA, the continued denial that atypical BSE and atypical Scrapie are a transmissible disease (science has shown otherwise) this is concerning to me. Science and scientific policy makers have forgotten what Gibbs, Gajdusek, Hadlow, Alper, Zigas, even Gordon with the infamous Scrapie vaccine blunder, a discovery of valuable importance, and so many others i am failing to remember now, what some found long ago, like Dr. Gibbs, he tried to warn us about scrapie zoonosis potential, yet that went ignored for decades and decades. we/scientist/officials/the world, knows the USA FDA PART 589 TSE PRION FEED ban has failed terribly, the BSE testing has failed terribly, and the surveillance there from has failed, SRM removal breaches, all proven by the OIG or the GAO, and others. But yet, we find ourselves now debating the issue of these same risk factors for scrapie, the same risk factors that we all knew were there, with science staring us in the face, we still deny scientific facts all in the name of corporate interest. let's not continue to make these same mistakes. human and animal life is at stake here. we must remove corporate/government/lobbyist interest from the scientific policy making and regulations there from for the TSE Prion, all of them. ...Terry S. Singeltary SR.
ZOONOSIS OF SCRAPIE TSE PRION
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.
============== https://prion2015.files.wordpress.com/2015/05/prion2015abstracts.pdf
***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. http://www.tandfonline.com/doi/abs/10.1080/19336896.2016.1163048?journalCode=kprn20
PRION 2016 TOKYO
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. http://www.tandfonline.com/doi/abs/10.1080/19336896.2016.1163048?journalCode=kprn20
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. BRADLEYhttps://web.archive.org/web/20170126051158/http://collections.europarchive.org/tna/20080102222950/http://www.bseinquiry.gov.uk/files/yb/1990/09/23001001.pdf
Title: Transmission of scrapie prions to primate after an extended silent incubation period)
*** 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. http://www.ars.usda.gov/research/publications/publications.htm?SEQ_NO_115=313160
***> Moreover, sporadic disease has never been observed in breeding colonies or primate research laboratories, most notably among hundreds of animals over several decades of study at the National Institutes of Health25, and in nearly twenty older animals continuously housed in our own facility. <***
Transmission of scrapie prions to primate after an extended silent incubation period
Emmanuel E. Comoy, Jacqueline Mikol, Sophie Luccantoni-Freire, Evelyne Correia, Nathalie Lescoutra-Etchegaray, Valérie Durand, Capucine Dehen, Olivier Andreoletti, Cristina Casalone, Juergen A. Richt, Justin J. Greenlee, Thierry Baron, Sylvie L. Benestad, Paul Brown & Jean-Philippe Deslys Scientific Reports volume 5, Article number: 11573 (2015) | Download Citation
Abstract
Classical bovine spongiform encephalopathy (c-BSE) is the only animal prion disease reputed to be zoonotic, causing variant Creutzfeldt-Jakob disease (vCJD) in humans and having guided protective measures for animal and human health against animal prion diseases. Recently, partial transmissions to humanized mice showed that the zoonotic potential of scrapie might be similar to c-BSE. We here report the direct transmission of a natural classical scrapie isolate to cynomolgus macaque, a highly relevant model for human prion diseases, after a 10-year silent incubation period, with features similar to those reported for human cases of sporadic CJD. Scrapie is thus actually transmissible to primates with incubation periods compatible with their life expectancy, although fourfold longer than BSE. Long-term experimental transmission studies are necessary to better assess the zoonotic potential of other prion diseases with high prevalence, notably Chronic Wasting Disease of deer and elk and atypical/Nor98 scrapie.
SNIP...
Discussion We describe the transmission of spongiform encephalopathy in a non-human primate inoculated 10 years earlier with a strain of sheep c-scrapie. Because of this extended incubation period in a facility in which other prion diseases are under study, we are obliged to consider two alternative possibilities that might explain its occurrence. We first considered the possibility of a sporadic origin (like CJD in humans). Such an event is extremely improbable because the inoculated animal was 14 years old when the clinical signs appeared, i.e. about 40% through the expected natural lifetime of this species, compared to a peak age incidence of 60–65 years in human sporadic CJD, or about 80% through their expected lifetimes. Moreover, sporadic disease has never been observed in breeding colonies or primate research laboratories, most notably among hundreds of animals over several decades of study at the National Institutes of Health25, and in nearly twenty older animals continuously housed in our own facility.
The second possibility is a laboratory cross-contamination. Three facts make this possibility equally unlikely. First, handling of specimens in our laboratory is performed with fastidious attention to the avoidance of any such cross-contamination. Second, no laboratory cross-contamination has ever been documented in other primate laboratories, including the NIH, even between infected and uninfected animals housed in the same or adjacent cages with daily intimate contact (P. Brown, personal communication). Third, the cerebral lesion profile is different from all the other prion diseases we have studied in this model19, with a correlation between cerebellar lesions (massive spongiform change of Purkinje cells, intense PrPres staining and reactive gliosis26) and ataxia. The iron deposits present in the globus pallidus are a non specific finding that have been reported previously in neurodegenerative diseases and aging27. Conversely, the thalamic lesion was reminiscent of a metabolic disease due to thiamine deficiency28 but blood thiamine levels were within normal limits (data not shown). The preferential distribution of spongiform change in cortex associated with a limited distribution in the brainstem is reminiscent of the lesion profile in MM2c and VV1 sCJD patients29, but interspecies comparison of lesion profiles should be interpreted with caution. It is of note that the same classical scrapie isolate induced TSE in C57Bl/6 mice with similar incubation periods and lesional profiles as a sample derived from a MM1 sCJD patient30.
We are therefore confident that the illness in this cynomolgus macaque represents a true transmission of a sheep c-scrapie isolate directly to an old-world monkey, which taxonomically resides in the primate subdivision (parvorder of catarrhini) that includes humans. With an homology of its PrP protein with humans of 96.4%31, cynomolgus macaque constitutes a highly relevant model for assessing zoonotic risk of prion diseases. Since our initial aim was to show the absence of transmission of scrapie to macaques in the worst-case scenario, we obtained materials from a flock of naturally-infected sheep, affecting animals with different genotypes32. This c-scrapie isolate exhibited complete transmission in ARQ/ARQ sheep (332 ± 56 days) and Tg338 transgenic mice expressing ovine VRQ/VRQ prion protein (220 ± 5 days) (O. Andreoletti, personal communication). From the standpoint of zoonotic risk, it is important to note that sheep with c-scrapie (including the isolate used in our study) have demonstrable infectivity throughout their lymphoreticular system early in the incubation period of the disease (3 months-old for all the lymphoid organs, and as early as 2 months-old in gut-associated lymph nodes)33. In addition, scrapie infectivity has been identified in blood34, milk35 and skeletal muscle36 from asymptomatic but scrapie infected small ruminants which implies a potential dietary exposure for consumers.
Two earlier studies have reported the occurrence of clinical TSE in cynomolgus macaques after exposures to scrapie isolates. In the first study, the “Compton” scrapie isolate (derived from an English sheep) and serially propagated for 9 passages in goats did not transmit TSE in cynomolgus macaque, rhesus macaque or chimpanzee within 7 years following intracerebral challenge1; conversely, after 8 supplementary passages in conventional mice, this “Compton” isolate induced TSE in a cynomolgus macaque 5 years after intracerebral challenge, but rhesus macaques and chimpanzee remained asymptomatic 8.5 years post-exposure8. However, multiple successive passages that are classically used to select laboratory-adapted prion strains can significantly modify the initial properties of a scrapie isolate, thus questioning the relevance of zoonotic potential for the initial sheep-derived isolate. The same isolate had also induced disease into squirrel monkeys (new-world monkey)9. A second historical observation reported that a cynomolgus macaque developed TSE 6 years post-inoculation with brain homogenate from a scrapie-infected Suffolk ewe (derived from USA), whereas a rhesus macaque and a chimpanzee exposed to the same inoculum remained healthy 9 years post-exposure1. This inoculum also induced TSE in squirrel monkeys after 4 passages in mice. Other scrapie transmission attempts in macaque failed but had more shorter periods of observation in comparison to the current study. Further, it is possible that there are differences in the zoonotic potential of different scrapie strains.
The most striking observation in our study is the extended incubation period of scrapie in the macaque model, which has several implications. Firstly, our observations constitute experimental evidence in favor of the zoonotic potential of c-scrapie, at least for this isolate that has been extensively studied32,33,34,35,36. The cross-species zoonotic ability of this isolate should be confirmed by performing duplicate intracerebral exposures and assessing the transmissibility by the oral route (a successful transmission of prion strains through the intracerebral route may not necessarily indicate the potential for oral transmission37). However, such confirmatory experiments may require more than one decade, which is hardly compatible with current general management and support of scientific projects; thus this study should be rather considered as a case report.
Secondly, transmission of c-BSE to primates occurred within 8 years post exposure for the lowest doses able to transmit the disease (the survival period after inoculation is inversely proportional to the initial amount of infectious inoculum). The occurrence of scrapie 10 years after exposure to a high dose (25 mg) of scrapie-infected sheep brain suggests that the macaque has a higher species barrier for sheep c-scrapie than c-BSE, although it is notable that previous studies based on in vitro conversion of PrP suggested that BSE and scrapie prions would have a similar conversion potential for human PrP38.
Thirdly, prion diseases typically have longer incubation periods after oral exposure than after intracerebral inoculations: since humans can develop Kuru 47 years after oral exposure39, an incubation time of several decades after oral exposure to scrapie would therefore be expected, leading the disease to occur in older adults, i.e. the peak age for cases considered to be sporadic disease, and making a distinction between scrapie-associated and truly sporadic disease extremely difficult to appreciate.
Fourthly, epidemiologic evidence is necessary to confirm the zoonotic potential of an animal disease suggested by experimental studies. A relatively short incubation period and a peculiar epidemiological situation (e.g., all the first vCJD cases occurring in the country with the most important ongoing c-BSE epizootic) led to a high degree of suspicion that c-BSE was the cause of vCJD. Sporadic CJD are considered spontaneous diseases with an almost stable and constant worldwide prevalence (0.5–2 cases per million inhabitants per year), and previous epidemiological studies were unable to draw a link between sCJD and classical scrapie6,7,40,41, even though external causes were hypothesized to explain the occurrence of some sCJD clusters42,43,44. However, extended incubation periods exceeding several decades would impair the predictive values of epidemiological surveillance for prion diseases, already weakened by a limited prevalence of prion diseases and the multiplicity of isolates gathered under the phenotypes of “scrapie” and “sporadic CJD”.
Fifthly, considering this 10 year-long incubation period, together with both laboratory and epidemiological evidence of decade or longer intervals between infection and clinical onset of disease, no premature conclusions should be drawn from negative transmission studies in cynomolgus macaques with less than a decade of observation, as in the aforementioned historical transmission studies of scrapie to primates1,8,9. Our observations and those of others45,46 to date are unable to provide definitive evidence regarding the zoonotic potential of CWD, atypical/Nor98 scrapie or H-type BSE. The extended incubation period of the scrapie-affected macaque in the current study also underscores the limitations of rodent models expressing human PrP for assessing the zoonotic potential of some prion diseases since their lifespan remains limited to approximately two years21,47,48. This point is illustrated by the fact that the recently reported transmission of scrapie to humanized mice was not associated with clinical signs for up to 750 days and occurred in an extreme minority of mice with only a marginal increase in attack rate upon second passage13. The low attack rate in these studies is certainly linked to the limited lifespan of mice compared to the very long periods of observation necessary to demonstrate the development of scrapie. Alternatively, one could estimate that a successful second passage is the result of strain adaptation to the species barrier, thus poorly relevant of the real zoonotic potential of the original scrapie isolate of sheep origin49. The development of scrapie in this primate after an incubation period compatible with its lifespan complements the study conducted in transgenic (humanized) mice; taken together these studies suggest that some isolates of sheep scrapie can promote misfolding of the human prion protein and that scrapie can develop within the lifespan of some primate species.
In addition to previous studies on scrapie transmission to primate1,8,9 and the recently published study on transgenic humanized mice13, our results constitute new evidence for recommending that the potential risk of scrapie for human health should not be dismissed. Indeed, human PrP transgenic mice and primates are the most relevant models for investigating the human transmission barrier. To what extent such models are informative for measuring the zoonotic potential of an animal TSE under field exposure conditions is unknown. During the past decades, many protective measures have been successfully implemented to protect cattle from the spread of c-BSE, and some of these measures have been extended to sheep and goats to protect from scrapie according to the principle of precaution. Since cases of c-BSE have greatly reduced in number, those protective measures are currently being challenged and relaxed in the absence of other known zoonotic animal prion disease. We recommend that risk managers should be aware of the long term potential risk to human health of at least certain scrapie isolates, notably for lymphotropic strains like the classical scrapie strain used in the current study. Relatively high amounts of infectivity in peripheral lymphoid organs in animals infected with these strains could lead to contamination of food products produced for human consumption. Efforts should also be maintained to further assess the zoonotic potential of other animal prion strains in long-term studies, notably lymphotropic strains with high prevalence like CWD, which is spreading across North America, and atypical/Nor98 scrapie (Nor98)50 that was first detected in the past two decades and now represents approximately half of all reported cases of prion diseases in small ruminants worldwide, including territories previously considered as scrapie free.. Even if the prevailing view is that sporadic CJD is due to the spontaneous formation of CJD prions, it remains possible that its apparent sporadic nature may, at least in part, result from our limited capacity to identify an environmental origin.
Singeltary on Scrapie and human transmission way back, see;
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.
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R. BRADLEY
BSE INQUIRY
1979
SILENCE ON CJD AND SCRAPIE
1980
SILENCE ON CJD AND SCRAPIE
*** 1981 NOVEMBER
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.
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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
12/10/76
AGRICULTURAL RESEARCH COUNCIL REPORT OF THE ADVISORY COMMITTE ON SCRAPIE
Office Note CHAIRMAN: PROFESSOR PETER WILDY
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A The Present Position with respect to Scrapie A] The Problem Scrapie is a natural disease of sheep and goats. It is a slow and inexorably progressive degenerative disorder of the nervous system and it ia fatal. It is enzootic in the United Kingdom but not in all countries. The field problem has been reviewed by a MAFF working group (ARC 35/77). It is difficult to assess the incidence in Britain for a variety of reasons but the disease causes serious financial loss; it is estimated that it cost Swaledale breeders alone $l.7 M during the five years 1971-1975. A further inestimable loss arises from the closure of certain export markets, in particular those of the United States, to British sheep. It is clear that scrapie in sheep is important commercially and for that reason alone effective measures to control it should be devised as quickly as possible. 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 emphasised by the finding that some strains of scrapie produce lesions identical to the once which characterise 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 acrapie problem urgent if the sheep industry is not to suffer grievously.
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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).
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).
why do we not want to do TSE transmission studies on chimpanzees $
IN CONFIDENCE
TRANSMISSION TO CHIMPANZEES
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5. A positive result from a chimpanzee challenged severely 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.
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R. BRADLEY
full text ;
RB3.20
IN CONFIDENCE
TRANSMISSION TO CHIMPANZEE
1. Kuru and CJD have been successfully transmitted to chimpanzees but scrapie and TME have not.
2. We cannot say that scrapie will not transmit to chimpanzees. There are several scrapie strains and I am not aware that all have been tried (that would have to be from mouse passaged material). Nor has a wide enough range of field isolates subsequently strain typed in mice been inoculated by the appropriate routes (i/c, i/p and i v);
3. I believe the proposed experiment to determine transmissibility, if conducted, would only show the susceptibility or resistance of the chimpanzee to infection/disease by the routes used and the result could not be interpreted for the predictability of the susceptibility for man. Proposals for prolonged oral exposure of chimpanzees to milk from cattle were suggested a long while ago and rejected.
4. In view of Dr Gibbs‘ probable use of Chimpazees Mr Wells‘ comments (enclosed) are pertinent. I have yet to receive a direct communication from Dr Schellekers but before any collaboration or provision of material we should identify the Gibbs' proposals and objectives.
5. A positive result from a chimpanzee challenged severely 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.
A negative result would take a lifetime to determine but that would be a shorter period than might be available for human exposure and it would still not answer the question regarding mans' susceptibility. In the meantime no doubt the negativity would be used defensively. It would however be counterproductive if the experiment finally became positive- We may learn more about public reactions following next Monday‘s meeting. CVO (+ Mr. Wells’ comments)
Dr. T W A Little
Dr. B J Shreeve
R Bradley September 1990
90/9.23/1/1
Wednesday, February 16, 2011
IN CONFIDENCE
SCRAPIE TRANSMISSION TO CHIMPANZEES
IN CONFIDENCE
Cervid to human prion transmission
Kong, Qingzhong
Case Western Reserve University, Cleveland, OH, United States
Abstract
Prion disease is transmissible and invariably fatal. Chronic wasting disease (CWD) is the prion disease affecting deer, elk and moose, and it is a widespread and expanding epidemic affecting 22 US States and 2 Canadian provinces so far. CWD poses the most serious zoonotic prion transmission risks in North America because of huge venison consumption (>6 million deer/elk hunted and consumed annually in the USA alone), significant prion infectivity in muscles and other tissues/fluids from CWD-affected cervids, and usually high levels of individual exposure to CWD resulting from consumption of the affected animal among often just family and friends. However, we still do not know whether CWD prions can infect humans in the brain or peripheral tissues or whether clinical/asymptomatic CWD zoonosis has already occurred, and we have no essays to reliably detect CWD infection in humans.
We hypothesize that:
(1) The classic CWD prion strain can infect humans at low levels in the brain and peripheral lymphoid tissues;
(2) The cervid-to-human transmission barrier is dependent on the cervid prion strain and influenced by the host (human) prion protein (PrP) primary sequence;
(3) Reliable essays can be established to detect CWD infection in humans; and
(4) CWD transmission to humans has already occurred. We will test these hypotheses in 4 Aims using transgenic (Tg) mouse models and complementary in vitro approaches.
Aim 1 will prove that the classical CWD strain may infect humans in brain or peripheral lymphoid tissues at low levels by conducting systemic bioassays in a set of humanized Tg mouse lines expressing common human PrP variants using a number of CWD isolates at varying doses and routes. Experimental human CWD samples will also be generated for Aim 3.
Aim 2 will test the hypothesis that the cervid-to-human prion transmission barrier is dependent on prion strain and influenced by the host (human) PrP sequence by examining and comparing the transmission efficiency and phenotypes of several atypical/unusual CWD isolates/strains as well as a few prion strains from other species that have adapted to cervid PrP sequence, utilizing the same panel of humanized Tg mouse lines as in Aim 1.
Aim 3 will establish reliable essays for detection and surveillance of CWD infection in humans by examining in details the clinical, pathological, biochemical and in vitro seeding properties of existing and future experimental human CWD samples generated from Aims 1-2 and compare them with those of common sporadic human Creutzfeldt-Jakob disease (sCJD) prions.
Aim 4 will attempt to detect clinical CWD-affected human cases by examining a significant number of brain samples from prion-affected human subjects in the USA and Canada who have consumed venison from CWD-endemic areas utilizing the criteria and essays established in Aim 3. The findings from this proposal will greatly advance our understandings on the potential and characteristics of cervid prion transmission in humans, establish reliable essays for CWD zoonosis and potentially discover the first case(s) of CWD infection in humans.
Public Health Relevance
There are significant and increasing human exposure to cervid prions because chronic wasting disease (CWD, a widespread and highly infectious prion disease among deer and elk in North America) continues spreading and consumption of venison remains popular, but our understanding on cervid-to-human prion transmission is still very limited, raising public health concerns. This proposal aims to define the zoonotic risks of cervid prions and set up and apply essays to detect CWD zoonosis using mouse models and in vitro methods. The findings will greatly expand our knowledge on the potentials and characteristics of cervid prion transmission in humans, establish reliable essays for such infections and may discover the first case(s) of CWD infection in humans.
Funding Agency
Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS088604-04
Application #
9517118
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer Wong, May
Project Start 2015-09-30 Project End 2019-07-31 Budget Start 2018-08-01 Budget End 2019-07-31 Support Year 4 Fiscal Year 2018 Total Cost Indirect Cost Institution Name Case Western Reserve University Department Pathology Type Schools of Medicine DUNS # 077758407 City Cleveland State OH Country United States Zip Code 44106
Related projects
NIH 2018 R01 NS Cervid to human prion transmission Kong, Qingzhong / Case Western Reserve University
NIH 2017 R01 NS Cervid to human prion transmission Kong, Qingzhong / Case Western Reserve University
NIH 2016 R01 NS Cervid to human prion transmission Kong, Qingzhong / Case Western Reserve University
NIH 2015 R01 NS Cervid to human prion transmission Kong, Qingzhong / Case Western Reserve University $337,507
ZOONOTIC CHRONIC WASTING DISEASE CWD TSE PRION UPDATE
here is the latest;
PRION 2018 CONFERENCE
Oral transmission of CWD into Cynomolgus macaques: signs of atypical disease, prion conversion and infectivity in macaques and bio-assayed transgenic mice
Hermann M. Schatzl, Samia Hannaoui, Yo-Ching Cheng, Sabine Gilch (Calgary Prion Research Unit, University of Calgary, Calgary, Canada) Michael Beekes (RKI Berlin), Walter Schulz-Schaeffer (University of Homburg/Saar, Germany), Christiane Stahl-Hennig (German Primate Center) & Stefanie Czub (CFIA Lethbridge).
To date, BSE is the only example of interspecies transmission of an animal prion disease into humans. The potential zoonotic transmission of CWD is an alarming issue and was addressed by many groups using a variety of in vitro and in vivo experimental systems. Evidence from these studies indicated a substantial, if not absolute, species barrier, aligning with the absence of epidemiological evidence suggesting transmission into humans. Studies in non-human primates were not conclusive so far, with oral transmission into new-world monkeys and no transmission into old-world monkeys.
Our consortium has challenged 18 Cynomolgus macaques with characterized CWD material, focusing on oral transmission with muscle tissue. Some macaques have orally received a total of 5 kg of muscle material over a period of 2 years. After 5-7 years of incubation time some animals showed clinical symptoms indicative of prion disease, and prion neuropathology and PrPSc deposition were detected in spinal cord and brain of some euthanized animals. PrPSc in immunoblot was weakly detected in some spinal cord materials and various tissues tested positive in RT-QuIC, including lymph node and spleen homogenates. To prove prion infectivity in the macaque tissues, we have intracerebrally inoculated 2 lines of transgenic mice, expressing either elk or human PrP. At least 3 TgElk mice, receiving tissues from 2 different macaques, showed clinical signs of a progressive prion disease and brains were positive in immunoblot and RT-QuIC. Tissues (brain, spinal cord and spleen) from these and pre-clinical mice are currently tested using various read-outs and by second passage in mice. Transgenic mice expressing human PrP were so far negative for clear clinical prion disease (some mice >300 days p.i.). In parallel, the same macaque materials are inoculated into bank voles.
Taken together, there is strong evidence of transmissibility of CWD orally into macaques and from macaque tissues into transgenic mouse models, although with an incomplete attack rate. The clinical and pathological presentation in macaques was mostly atypical, with a strong emphasis on spinal cord pathology. Our ongoing studies will show whether the transmission of CWD into macaques and passage in transgenic mice represents a form of non-adaptive prion amplification, and whether macaque-adapted prions have the potential to infect mice expressing human PrP. The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD.
***> The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD. <***
READING OVER THE PRION 2018 ABSTRACT BOOK, LOOKS LIKE THEY FOUND THAT from this study ;
P190 Human prion disease mortality rates by occurrence of chronic wasting disease in freeranging cervids, United States
Abrams JY (1), Maddox RA (1), Schonberger LB (1), Person MK (1), Appleby BS (2), Belay ED (1) (1) Centers for Disease Control and Prevention (CDC), National Center for Emerging and Zoonotic Infectious Diseases, Atlanta, GA, USA (2) Case Western Reserve University, National Prion Disease Pathology Surveillance Center (NPDPSC), Cleveland, OH, USA.
SEEMS THAT THEY FOUND Highly endemic states had a higher rate of prion disease mortality compared to non-CWD states.
AND ANOTHER STUDY;
P172 Peripheral Neuropathy in Patients with Prion Disease
Wang H(1), Cohen M(1), Appleby BS(1,2) (1) University Hospitals Cleveland Medical Center, Cleveland, Ohio (2) National Prion Disease Pathology Surveillance Center, Cleveland, Ohio..
IN THIS STUDY, THERE WERE autopsy-proven prion cases from the National Prion Disease Pathology Surveillance Center that were diagnosed between September 2016 to March 2017, AND included 104 patients.
SEEMS THEY FOUND THAT The most common sCJD subtype was MV1-2 (30%), followed by MM1-2 (20%), AND THAT The Majority of cases were male (60%), AND half of them had exposure to wild game.
snip...see more on Prion 2017 Macaque study from Prion 2017 Conference and other updated science on cwd tse prion zoonosis below...terry
Prion 2017
Conference Abstracts CWD 2017 PRION CONFERENCE
First evidence of intracranial and peroral transmission of Chronic Wasting Disease (CWD) into Cynomolgus macaques: a work in progress
Stefanie Czub1, Walter Schulz-Schaeffer2, Christiane Stahl-Hennig3, Michael Beekes4, Hermann Schaetzl5 and Dirk Motzkus6 1
University of Calgary Faculty of Veterinary Medicine/Canadian Food Inspection Agency; 2Universitatsklinikum des Saarlandes und Medizinische Fakultat der Universitat des Saarlandes; 3 Deutsches Primaten Zentrum/Goettingen; 4 Robert-Koch-Institut Berlin; 5 University of Calgary Faculty of Veterinary Medicine; 6 presently: Boehringer Ingelheim Veterinary Research Center; previously: Deutsches Primaten Zentrum/Goettingen
This is a progress report of a project which started in 2009. 21 cynomolgus macaques were challenged with characterized CWD material from white-tailed deer (WTD) or elk by intracerebral (ic), oral, and skin exposure routes. Additional blood transfusion experiments are supposed to assess the CWD contamination risk of human blood product. Challenge materials originated from symptomatic cervids for ic, skin scarification and partially per oral routes (WTD brain). Challenge material for feeding of muscle derived from preclinical WTD and from preclinical macaques for blood transfusion experiments. We have confirmed that the CWD challenge material contained at least two different CWD agents (brain material) as well as CWD prions in muscle-associated nerves. Here we present first data on a group of animals either challenged ic with steel wires or per orally and sacrificed with incubation times ranging from 4.5 to 6.9 years at postmortem. Three animals displayed signs of mild clinical disease, including anxiety, apathy, ataxia and/or tremor. In four animals wasting was observed, two of those had confirmed diabetes. All animals have variable signs of prion neuropathology in spinal cords and brains and by supersensitive IHC, reaction was detected in spinal cord segments of all animals. Protein misfolding cyclic amplification (PMCA), real-time quaking-induced conversion (RT-QuiC) and PET-blot assays to further substantiate these findings are on the way, as well as bioassays in bank voles and transgenic mice. At present, a total of 10 animals are sacrificed and read-outs are ongoing. Preclinical incubation of the remaining macaques covers a range from 6.4 to 7.10 years. Based on the species barrier and an incubation time of > 5 years for BSE in macaques and about 10 years for scrapie in macaques, we expected an onset of clinical disease beyond 6 years post inoculation.
PRION 2017
DECIPHERING NEURODEGENERATIVE DISORDERS
Subject: PRION 2017 CONFERENCE DECIPHERING NEURODEGENERATIVE DISORDERS VIDEO
PRION 2017
CONFERENCE DECIPHERING NEURODEGENERATIVE DISORDERS
*** PRION 2017 CONFERENCE VIDEO
TUESDAY, JUNE 13, 2017
PRION 2017 CONFERENCE ABSTRACT
First evidence of intracranial and peroral transmission of Chronic Wasting Disease (CWD) into Cynomolgus macaques: a work in progress
SATURDAY, JULY 29, 2017
Risk Advisory Opinion: Potential Human Health Risks from Chronic Wasting Disease CFIA, PHAC, HC (HPFB and FNIHB), INAC, Parks Canada, ECCC and AAFC
just out CDC...see;
Volume 24, Number 8—August 2018
Research
Susceptibility of Human Prion Protein to Conversion by Chronic Wasting Disease Prions
Marcelo A. BarriaComments to Author , Adriana Libori, Gordon Mitchell, and Mark W. Head Author affiliations: National CJD Research and Surveillance Unit, University of Edinburgh, Edinburgh, Scotland, UK (M.A. Barria, A. Libori, M.W. Head); National and OIE Reference Laboratory for Scrapie and CWD, Canadian Food Inspection Agency, Ottawa, Ontario, Canada (G. Mitchell)
M. A. Barria et al.
ABSTRACT
Chronic wasting disease (CWD) is a contagious and fatal neurodegenerative disease and a serious animal health issue for deer and elk in North America. The identification of the first cases of CWD among free-ranging reindeer and moose in Europe brings back into focus the unresolved issue of whether CWD can be zoonotic like bovine spongiform encephalopathy. We used a cell-free seeded protein misfolding assay to determine whether CWD prions from elk, white-tailed deer, and reindeer in North America can convert the human prion protein to the disease-associated form. We found that prions can convert, but the efficiency of conversion is affected by polymorphic variation in the cervid and human prion protein genes. In view of the similarity of reindeer, elk, and white-tailed deer in North America to reindeer, red deer, and roe deer, respectively, in Europe, a more comprehensive and thorough assessment of the zoonotic potential of CWD might be warranted.
snip...
Discussion
Characterization of the transmission properties of CWD and evaluation of their zoonotic potential are important for public health purposes. Given that CWD affects several members of the family Cervidae, it seems reasonable to consider whether the zoonotic potential of CWD prions could be affected by factors such as CWD strain, cervid species, geographic location, and Prnp–PRNP polymorphic variation. We have previously used an in vitro conversion assay (PMCA) to investigate the susceptibility of the human PrP to conversion to its disease-associated form by several animal prion diseases, including CWD (15,16,22). The sensitivity of our molecular model for the detection of zoonotic conversion depends on the combination of 1) the action of proteinase K to degrade the abundant human PrPC that constitutes the substrate while only N terminally truncating any human PrPres produced and 2) the presence of the 3F4 epitope on human but not cervid PrP. In effect, this degree of sensitivity means that any human PrPres formed during the PMCA reaction can be detected down to the limit of Western blot sensitivity. In contrast, if other antibodies that detect both cervid and human PrP are used, such as 6H4, then newly formed human PrPres must be detected as a measurable increase in PrPres over the amount remaining in the reaction product from the cervid seed. Although best known for the efficient amplification of prions in research and diagnostic contexts, the variation of the PMCA method employed in our study is optimized for the definitive detection of zoonotic reaction products of inherently inefficient conversion reactions conducted across species barriers. By using this system, we previously made and reported the novel observation that elk CWD prions could convert human PrPC from human brain and could also convert recombinant human PrPC expressed in transgenic mice and eukaryotic cell cultures (15).
A previous publication suggested that mule deer PrPSc was unable to convert humanized transgenic substrate in PMCA assays (23) and required a further step of in vitro conditioning in deer substrate PMCA before it was able to cross the deer–human molecular barrier (24). However, prions from other species, such as elk (15) and reindeer affected by CWD, appear to be compatible with the human protein in a single round of amplification (as shown in our study). These observations suggest that different deer species affected by CWD could present differing degrees of the olecular compatibility with the normal form of human PrP.
The contribution of the polymorphism at codon 129 of the human PrP gene has been extensively studied and is recognized as a risk factor for Creutzfeldt-Jakob disease (4). In cervids, the equivalent codon corresponds to the position 132 encoding methionine or leucine. This polymorphism in the elk gene has been shown to play an important role in CWD susceptibility (25,26). We have investigated the effect of this cervid Prnp polymorphism on the conversion of the humanized transgenic substrate according to the variation in the equivalent PRNP codon 129 polymorphism. Interestingly, only the homologs methionine homozygous seed–substrate reactions could readily convert the human PrP, whereas the heterozygous elk PrPSc was unable to do so, even though comparable amounts of PrPres were used to seed the reaction. In addition, we observed only low levels of human PrPres formation in the reactions seeded with the homozygous methionine (132 MM) and the heterozygous (132 ML) seeds incubated with the other 2 human polymorphic substrates (129 MV and 129 VV). The presence of the amino acid leucine at position 132 of the elk Prnp gene has been attributed to a lower degree of prion conversion compared with methionine on the basis of experiments in mice made transgenic for these polymorphic variants (26). Considering the differences observed for the amplification of the homozygous human methionine substrate by the 2 polymorphic elk seeds (MM and ML), reappraisal of the susceptibility of human PrPC by the full range of cervid polymorphic variants affected by CWD would be warranted.
In light of the recent identification of the first cases of CWD in Europe in a free-ranging reindeer (R. tarandus) in Norway (2), we also decided to evaluate the in vitro conversion potential of CWD in 2 experimentally infected reindeer (18). Formation of human PrPres was readily detectable after a single round of PMCA, and in all 3 humanized polymorphic substrates (MM, MV, and VV). This finding suggests that CWD prions from reindeer could be more compatible with human PrPC generally and might therefore present a greater risk for zoonosis than, for example, CWD prions from white-tailed deer. A more comprehensive comparison of CWD in the affected species, coupled with the polymorphic variations in the human and deer PRNP–Prnp genes, in vivo and in vitro, will be required before firm conclusions can be drawn. Analysis of the Prnp sequence of the CWD reindeer in Norway was reported to be identical to the specimens used in our study (2). This finding raises the possibility of a direct comparison of zoonotic potential between CWD acquired in the wild and that produced in a controlled laboratory setting. (Table).
The prion hypothesis proposes that direct molecular interaction between PrPSc and PrPC is necessary for conversion and prion replication. Accordingly, polymorphic variants of the PrP of host and agent might play a role in determining compatibility and potential zoonotic risk. In this study, we have examined the capacity of the human PrPC to support in vitro conversion by elk, white-tailed deer, and reindeer CWD PrPSc. Our data confirm that elk CWD prions can convert the human PrPC, at least in vitro, and show that the homologous PRNP polymorphisms at codon 129 and 132 in humans and cervids affect conversion efficiency. Other species affected by CWD, particularly caribou or reindeer, also seem able to convert the human PrP. It will be important to determine whether other polymorphic variants found in other CWD-affected Cervidae or perhaps other factors (17) exert similar effects on the ability to convert human PrP and thus affect their zoonotic potential.
Dr. Barria is a research scientist working at the National CJD Research and Surveillance Unit, University of Edinburgh. His research has focused on understanding the molecular basis of a group of fatal neurologic disorders called prion diseases.
Acknowledgments
snip...see;
Molecular Barriers to Zoonotic Transmission of Prions
Marcelo A. Barria, Aru Balachandran, Masanori Morita, Tetsuyuki Kitamoto, Rona Barron, Jean Manson, Richard Knight, James W. Ironside, and Mark W. Headcorresponding author
snip...
The conversion of human PrPC by CWD brain homogenate in PMCA reactions was less efficient when the amino acid at position 129 was valine rather than methionine.
***Furthermore, the form of human PrPres produced in this in vitro assay when seeded with CWD, resembles that found in the most common human prion disease, namely sCJD of the MM1 subtype.
snip...
However, we can say with confidence that under the conditions used here, none of the animal isolates tested were as efficient as C-type BSE in converting human PrPC, which is reassuring.
***Less reassuring is the finding that there is no absolute barrier to the conversion of human PrPC by CWD prions in a protocol using a single round of PMCA and an entirely human substrate prepared from the target organ of prion diseases, the brain.
ZOONOTIC, ZOONOSIS, CHRONIC WASTING DISEASE CWD TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY TSE PRION
10. ZOONOTIC, ZOONOSIS, CHRONIC WASTING DISEASE CWD TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY TSE PRION AKA MAD DEER ELK DISEASE IN HUMANS, has it already happened, that should be the question...
''In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids.'' Scientific opinion on chronic wasting disease (II)
EFSA Panel on Biological Hazards (BIOHAZ) Antonia Ricci Ana Allende Declan Bolton Marianne Chemaly Robert Davies Pablo Salvador Fernández Escámez ... See all authors
First published: 17 January 2018 https://doi.org/10.2903/j.efsa.2018.5132 ;
also, see;
8. Even though human TSE‐exposure risk through consumption of game from European cervids can be assumed to be minor, if at all existing, no final conclusion can be drawn due to the overall lack of scientific data. In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids. It might be prudent considering appropriate measures to reduce such a risk, e.g. excluding tissues such as CNS and lymphoid tissues from the human food chain, which would greatly reduce any potential risk for consumers. However, it is stressed that currently, no data regarding a risk of TSE infections from cervid products are available.
snip...
The tissue distribution of infectivity in CWD‐infected cervids is now known to extend beyond CNS and lymphoid tissues. While the removal of these specific tissues from the food chain would reduce human dietary exposure to infectivity, exclusion from the food chain of the whole carcass of any infected animal would be required to eliminate human dietary exposure.
https://efsa.onlinelibrary..wiley.com/doi/full/10.2903/j.efsa.2018.5132
zoonosis zoonotic cervid tse prion cwd to humans, preparing for the storm
***An alternative to modeling the species barrier is the cell-free conversion assay which points to CWD as the animal prion disease with the greatest zoonotic potential, after (and very much less than) BSE.116*** https://www.tandfonline.com/doi/pdf/10.4161/pri.29237
To date there is no direct evidence that CWD has been or can be transmitted from animals to humans.
However, initial findings from a laboratory research project funded by the Alberta Prion Research Institute (APRI) and Alberta Livestock Meat Agency (ALMA), and led by a Canadian Food Inspection Agency (CFIA) scientist indicate that CWD has been transmitted to cynomolgus macaques (the non-human primate species most closely related to humans that may be used in research), through both the intracranial and oral routes of exposure.
Both infected brain and muscle tissues were found to transmit disease.
Health Canada’s Health Products and Food Branch (HPFB) was asked to consider the impact of these findings on the Branch’s current position on CWD in health products and foods.
Summary and Recommendation:
snip...
Health Portfolio partners were recently made aware of initial findings from a research project led by a CFIA scientist that have demonstrated that cynomolgus macaques can be infected via intracranial exposure and oral gavage with CWD infected muscle.
These findings suggest that CWD, under specific experimental conditions, has the potential to cross the human species barrier, including by enteral feeding of CWD infected muscle. https://www.thetyee.ca/Documents/2017/06/24/Risk-Advisory-Opinion-CWD-2017.pdf
*** WDA 2016 NEW YORK ***
We found that CWD adapts to a new host more readily than BSE and that human PrP was unexpectedly prone to misfolding by CWD prions.
In addition, we investigated the role of specific regions of the bovine, deer and human PrP protein in resistance to conversion by prions from another species.
***We have concluded that the human protein has a region that confers unusual susceptibility to conversion by CWD prions.
Student Presentations Session 2
The species barriers and public health threat of CWD and BSE prions
Ms. Kristen Davenport1, Dr. Davin Henderson1, Dr. Candace Mathiason1, Dr. Edward Hoover1 1Colorado State University
Chronic wasting disease (CWD) is spreading rapidly through cervid populations in the USA. Bovine spongiform encephalopathy (BSE, mad cow disease) arose in the 1980s because cattle were fed recycled animal protein.
These and other prion diseases are caused by abnormal folding of the normal prion protein (PrP) into a disease causing form (PrPd), which is pathogenic to nervous system cells and can cause subsequent PrP to misfold. CWD spreads among cervids very efficiently, but it has not yet infected humans. On the other hand, BSE was spread only when cattle consumed infected bovine or ovine tissue, but did infect humans and other species.
The objective of this research is to understand the role of PrP structure in cross-species infection by CWD and BSE. To study the propensity of each species’ PrP to be induced to misfold by the presence of PrPd from verious species, we have used an in vitro system that permits detection of PrPd in real-time.
We measured the conversion efficiency of various combinations of PrPd seeds and PrP substrate combinations.
We observed the cross-species behavior of CWD and BSE, in addition to feline-adapted CWD and BSE. We found that CWD adapts to a new host more readily than BSE and that human PrP was unexpectedly prone to misfolding by CWD prions. In addition, we investigated the role of specific regions of the bovine, deer and human PrP protein in resistance to conversion by prions from another species.
***We have concluded that the human protein has a region that confers unusual susceptibility to conversion by CWD prions. CWD is unique among prion diseases in its rapid spread in natural populations. BSE prions are essentially unaltered upon passage to a new species, while CWD adapts to the new species. This adaptation has consequences for surveillance of humans exposed to CWD. Wildlife Disease Risk Communication Research Contributes to Wildlife Trust Administration Exploring perceptions about chronic wasting disease risks among wildlife and agriculture professionals and stakeholdershttp://www.wda2016.org/uploads/5/8/6/1/58613359/wda_2016_conference_proceedings_low_res.pdf
We found that CWD adapts to a new host more readily than BSE and that human PrP was unexpectedly prone to misfolding by CWD prions.
In addition, we investigated the role of specific regions of the bovine, deer and human PrP protein in resistance to conversion by prions from another species.
***We have concluded that the human protein has a region that confers unusual susceptibility to conversion by CWD prions.
Student Presentations Session 2
The species barriers and public health threat of CWD and BSE prions
Ms. Kristen Davenport1, Dr. Davin Henderson1, Dr. Candace Mathiason1, Dr. Edward Hoover1 1Colorado State University
Chronic wasting disease (CWD) is spreading rapidly through cervid populations in the USA. Bovine spongiform encephalopathy (BSE, mad cow disease) arose in the 1980s because cattle were fed recycled animal protein.
These and other prion diseases are caused by abnormal folding of the normal prion protein (PrP) into a disease causing form (PrPd), which is pathogenic to nervous system cells and can cause subsequent PrP to misfold. CWD spreads among cervids very efficiently, but it has not yet infected humans. On the other hand, BSE was spread only when cattle consumed infected bovine or ovine tissue, but did infect humans and other species.
The objective of this research is to understand the role of PrP structure in cross-species infection by CWD and BSE. To study the propensity of each species’ PrP to be induced to misfold by the presence of PrPd from verious species, we have used an in vitro system that permits detection of PrPd in real-time.
We measured the conversion efficiency of various combinations of PrPd seeds and PrP substrate combinations.
We observed the cross-species behavior of CWD and BSE, in addition to feline-adapted CWD and BSE. We found that CWD adapts to a new host more readily than BSE and that human PrP was unexpectedly prone to misfolding by CWD prions. In addition, we investigated the role of specific regions of the bovine, deer and human PrP protein in resistance to conversion by prions from another species.
***We have concluded that the human protein has a region that confers unusual susceptibility to conversion by CWD prions. CWD is unique among prion diseases in its rapid spread in natural populations. BSE prions are essentially unaltered upon passage to a new species, while CWD adapts to the new species. This adaptation has consequences for surveillance of humans exposed to CWD. Wildlife Disease Risk Communication Research Contributes to Wildlife Trust Administration Exploring perceptions about chronic wasting disease risks among wildlife and agriculture professionals and stakeholdershttp://www.wda2016.org/uploads/5/8/6/1/58613359/wda_2016_conference_proceedings_low_res.pdf
CDC CWD 2018 TRANSMISSIONhttps://www.cdc.gov/prions/cwd/transmission.html
TUESDAY, SEPTEMBER 12, 2017
CDC Now Recommends Strongly consider having the deer or elk tested for CWD before you eat the meat http://chronic-wasting-disease.blogspot.com/2017/09/cdc-now-recommends-strongly-consider.html
CDC Now Recommends Strongly consider having the deer or elk tested for CWD before you eat the meat http://chronic-wasting-disease.blogspot.com/2017/09/cdc-now-recommends-strongly-consider.html
SATURDAY, JANUARY 27, 2018
CDC CHRONIC WASTING DISEASE CWD TSE PRION UPDATE REPORT USA JANUARY 2018http://chronic-wasting-disease.blogspot.com/2018/01/cdc-chronic-wasting-disease-cwd-tse.html
Subject: CDC CHRONIC WASTING DISEASE CWD TSE PRION UPDATE REPORT USA JANUARY 2018
CHRONIC WASTING DISEASE CWD TSE PRION IS THE USA AND NORTH AMERICA'S MAD COW DISEASE.
THE USDA INC ET AL WORKED VERY HARD CONCEALING BSE TSE PRION IN CATTLE. they almost succeeded $$$
BUT CWD TSE PRION IN CERVIDS IS A DIFFERENT BEAST, THE COVER UP THERE, USDA INC COULD NOT CONTAIN.
SPORADIC CJD IS 85%+ OF ALL HUMAN TSE PRION DISEASE.
SPORADIC CJD HAS NOW BEEN LINKED TO TYPICAL AND ATYPICAL BSE, SCRAPIE, AND CWD.
SPORADIC/SPONTANEOUS TSE HAS NEVER BEEN PROVEN.
***Moreover, sporadic disease has never been observed in breeding colonies or primate research laboratories, most notably among hundreds of animals over several decades of study at the National Institutes of Health25, and in nearly twenty older animals continuously housed in our own facility.***https://www.nature.com/articles/srep11573
CHRONIC WASTING DISEASE CWD TSE PRION IS THE USA AND NORTH AMERICA'S MAD COW DISEASE.
THE USDA INC ET AL WORKED VERY HARD CONCEALING BSE TSE PRION IN CATTLE. they almost succeeded $$$
BUT CWD TSE PRION IN CERVIDS IS A DIFFERENT BEAST, THE COVER UP THERE, USDA INC COULD NOT CONTAIN.
SPORADIC CJD IS 85%+ OF ALL HUMAN TSE PRION DISEASE.
SPORADIC CJD HAS NOW BEEN LINKED TO TYPICAL AND ATYPICAL BSE, SCRAPIE, AND CWD.
SPORADIC/SPONTANEOUS TSE HAS NEVER BEEN PROVEN.
***Moreover, sporadic disease has never been observed in breeding colonies or primate research laboratories, most notably among hundreds of animals over several decades of study at the National Institutes of Health25, and in nearly twenty older animals continuously housed in our own facility.***https://www.nature.com/articles/srep11573
CDC CWD TSE PRION UPDATE USA JANUARY 2018
As of January 2018, CWD in free-ranging deer, elk and/or moose has been reported in at least 22 states in the continental United States, as well as two provinces in Canada. In addition, CWD has been reported in reindeer and moose in Norway, and a small number of imported cases have been reported in South Korea. The disease has also been found in farmed deer and elk. CWD was first identified in captive deer in the late 1960s in Colorado and in wild deer in 1981. By the 1990s, it had been reported in surrounding areas in northern Colorado and southern Wyoming. Since 2000, the area known to be affected by CWD in free-ranging animals has increased to at least 22 states, including states in the Midwest, Southwest, and limited areas on the East Coast.. It is possible that CWD may also occur in other states without strong animal surveillance systems, but that cases haven’t been detected yet. Once CWD is established in an area, the risk can remain for a long time in the environment. The affected areas are likely to continue to expand. Nationwide, the overall occurrence of CWD in free-ranging deer and elk is relatively low. However, in several locations where the disease is established, infection rates may exceed 10 percent (1 in 10), and localized infection rates of more than 25 percent (1 in 4) have been reported. The infection rates among some captive deer can be much higher, with a rate of 79% (nearly 4 in 5) reported from at least one captive herd. As of January 2018, there were 186 counties in 22 states with reported CWD in free-ranging cervids...
Chronic Wasting Disease Among Free-Ranging Cervids by County, United States, January 2018
snip.... https://www.cdc.gov/prions/cwd/occurrence.html
*** 2017-2018 CWD TSE Prion UPDATEhttps://www.cdc.gov/prions/cwd/occurrence.html
*** 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. http://cdmrp.army.mil/prevfunded/nprp/NPRP_Summit_Final_Report.pdf
Transmission Studies
Mule deer transmissions of CWD were by intracerebral inoculation and compared with natural cases {the following was written but with a single line marked through it ''first passage (by this route)}....TSS
resulted in a more rapidly progressive clinical disease with repeated episodes of synocopy ending in coma. One control animal became affected, it is believed through contamination of inoculum (?saline). Further CWD transmissions were carried out by Dick Marsh into ferret, mink and squirrel monkey. Transmission occurred in ALL of these species with the shortest incubation period in the ferret.
snip...https://web.archive.org/web/20090506002237/http://www.bseinquiry.gov.uk/files/mb/m11b/tab01.pdf
http://www.fsis.usda.gov/OPPDE/Comments/03-025IFA/03-025IFA-2.pdf
Prion Infectivity in Fat of Deer with Chronic Wasting Disease▿
Brent Race#, Kimberly Meade-White#, Richard Race and Bruce Chesebro* + Author Affiliations
In mice, prion infectivity was recently detected in fat. Since ruminant fat is consumed by humans and fed to animals, we determined infectivity titers in fat from two CWD-infected deer. Deer fat devoid of muscle contained low levels of CWD infectivity and might be a risk factor for prion infection of other species.http://jvi.asm.org/content/83/18/9608.full
Prions in Skeletal Muscles of Deer with Chronic Wasting Disease
Here bioassays in transgenic mice expressing cervid prion protein revealed the presence of infectious prions in skeletal muscles of CWD-infected deer, demonstrating that humans consuming or handling meat from CWD-infected deer are at risk to prion exposure.http://science.sciencemag.org/content/311/5764/1117.long
*** now, let’s see what the authors said about this casual link, personal communications years ago, and then the latest on the zoonotic potential from CWD to humans from the TOKYO PRION 2016 CONFERENCE.
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 ;http://chronic-wasting-disease.blogspot.com/2008/04/prion-disease-of-cervids-chronic.html
> However, to date, no CWD infections have been reported in people.
key word here is 'reported'. science has shown that CWD in humans will look like sporadic CJD. SO, how can one assume that CWD has not already transmitted to humans? they can't, and it's as simple as that. from all recorded science to date, CWD has already transmitted to humans, and it's being misdiagnosed as sporadic CJD. ...terry
*** LOOKING FOR CWD IN HUMANS AS nvCJD or as an ATYPICAL CJD, LOOKING IN ALL THE WRONG PLACES $$$ ***
*** 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).*** http://www.tandfonline.com/doi/full/10.4161/pri.28124?src=recsys
http://www.tandfonline.com/doi/pdf/10.4161/pri.28124?needAccess=true
https://wwwnc.cdc.gov/eid/article/20/1/13-0858_article
SEE; Travel History, Hunting, and Venison Consumption Related to Prion Disease Exposure, 2006-2007 FoodNet Population Survey
Monday, May 23, 2011
CDC Assesses Potential Human Exposure to Prion Diseases Travel Warning
Public release date: 23-May-2011
Contact: Francesca Costanzo adajmedia@elsevier.com 215-239-3249 Elsevier Health Sciences
CDC assesses potential human exposure to prion diseases Study results reported in the Journal of the American Dietetic Association Philadelphia, PA, May 23, 2011 – Researchers from the Centers for Disease Control and Prevention (CDC) have examined the potential for human exposure to prion diseases, looking at hunting, venison consumption, and travel to areas in which prion diseases have been reported in animals. Three prion diseases in particular – bovine spongiform encephalopathy (BSE or “Mad Cow Disease”), variant Creutzfeldt-Jakob disease (vCJD), and chronic wasting disease (CWD) – were specified in the investigation. The results of this investigation are published in the June issue of the Journal of the American Dietetic Association.
“While prion diseases are rare, they are generally fatal for anyone who becomes infected. More than anything else, the results of this study support the need for continued surveillance of prion diseases,” commented lead investigator Joseph Y. Abrams, MPH, National Center for Emerging and Zoonotic Infectious Diseases, CDC, Atlanta.”But it’s also important that people know the facts about these diseases, especially since this study shows that a good number of people have participated in activities that may expose them to infection-causing agents.”
Although rare, human prion diseases such as CJD may be related to BSE. Prion (proteinaceous infectious particles) diseases are a group of rare brain diseases that affect humans and animals. When a person gets a prion disease, brain function is impaired. This causes memory and personality changes, dementia, and problems with movement. All of these worsen over time. These diseases are invariably fatal. Since these diseases may take years to manifest, knowing the extent of human exposure to possible prion diseases could become important in the event of an outbreak.
CDC investigators evaluated the results of the 2006-2007 population survey conducted by the Foodborne Diseases Active Surveillance Network (FoodNet). This survey collects information on food consumption practices, health outcomes, and demographic characteristics of residents of the participating Emerging Infections Program sites. The survey was conducted in Connecticut, Georgia, Maryland, Minnesota, New Mexico, Oregon, and Tennessee, as well as five counties in the San Francisco Bay area, seven counties in the Greater Denver area, and 34 counties in western and northeastern New York.
Survey participants were asked about behaviors that could be associated with exposure to the agents causing BSE and CWD, including travel to the nine countries considered to be BSE-endemic (United Kingdom, Republic of Ireland, France, Portugal, Switzerland, Italy, the Netherlands, Germany, Spain) and the cumulative length of stay in each of those countries. Respondents were asked if they ever had hunted for deer or elk, and if that hunting had taken place in areas considered to be CWD-endemic (northeastern Colorado, southeastern Wyoming or southwestern Nebraska). They were also asked if they had ever consumed venison, the frequency of consumption, and whether the meat came from the wild.
The proportion of survey respondents who reported travel to at least one of the nine BSE endemic countries since 1980 was 29.5%. Travel to the United Kingdom was reported by 19.4% of respondents, higher than to any other BSE-endemic country. Among those who traveled, the median duration of travel to the United Kingdom (14 days) was longer than that of any other BSE-endemic country. Travelers to the UK were more likely to have spent at least 30 days in the country (24.9%) compared to travelers to any other BSE endemic country. The prevalence and extent of travel to the UK indicate that health concerns in the UK may also become issues for US residents.
The proportion of survey respondents reporting having hunted for deer or elk was 18.5% and 1.2% reported having hunted for deer or elk in CWD-endemic areas. Venison consumption was reported by 67.4% of FoodNet respondents, and 88.6% of those reporting venison consumption had obtained all of their meat from the wild. These findings reinforce the importance of CWD surveillance and control programs for wild deer and elk to reduce human exposure to the CWD agent. Hunters in CWD-endemic areas are advised to take simple precautions such as: avoiding consuming meat from sickly deer or elk, avoiding consuming brain or spinal cord tissues, minimizing the handling of brain and spinal cord tissues, and wearing gloves when field-dressing carcasses.
According to Abrams, “The 2006-2007 FoodNet population survey provides useful information should foodborne prion infection become an increasing public health concern in the future. The data presented describe the prevalence of important behaviors and their associations with demographic characteristics. Surveillance of BSE, CWD, and human prion diseases are critical aspects of addressing the burden of these diseases in animal populations and how that may relate to human health.”
###
The article is “Travel history, hunting, and venison consumption related to prion disease exposure, 2006-2007 FoodNet population survey” by Joseph Y. Abrams, MPH; Ryan A. Maddox, MPH; Alexis R Harvey, MPH; Lawrence B. Schonberger, MD; and Ermias D. Belay, MD. It appears in the Journal of the American Dietetic Association, Volume 111, Issue 6 (June 2011) published by Elsevier.
In an accompanying podcast CDC’s Joseph Y. Abrams discusses travel, hunting, and eating venison in relation to prion diseases. It is available at http://adajournal.org/content/podcast.
http://www.eurekalert.org/pub_releases/2011-05/ehs-cap051811.php
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.
Travel History, Hunting, and Venison Consumption Related to Prion Disease Exposure, 2006-2007 FoodNet Population Survey
Joseph Y. Abrams, MPH, Ryan A. Maddox, MPH , Alexis R. Harvey, MPH , Lawrence B. Schonberger, MD , Ermias D. Belay, MD
Accepted 15 November 2010. Abstract Full Text PDF References .
Abstract
The transmission of bovine spongiform encephalopathy (BSE) to human beings and the spread of chronic wasting disease (CWD) among cervids have prompted concerns about zoonotic transmission of prion diseases. Travel to the United Kingdom and other European countries, hunting for deer or elk, and venison consumption could result in the exposure of US residents to the agents that cause BSE and CWD. The Foodborne Diseases Active Surveillance Network 2006-2007 population survey was used to assess the prevalence of these behaviors among residents of 10 catchment areas across the United States. Of 17,372 survey respondents, 19.4% reported travel to the United Kingdom since 1980, and 29.5% reported travel to any of the nine European countries considered to be BSE-endemic since 1980. The proportion of respondents who had ever hunted deer or elk was 18.5%, and 1.2% had hunted deer or elk in a CWD–endemic area. More than two thirds (67.4%) reported having ever eaten deer or elk meat. Respondents who traveled spent more time in the United Kingdom (median 14 days) than in any other BSE-endemic country. Of the 11,635 respondents who had consumed venison, 59.8% ate venison at most one to two times during their year of highest consumption, and 88.6% had obtained all of their meat from the wild. The survey results were useful in determining the prevalence and frequency of behaviors that could be important factors for foodborne prion transmission.http://www.adajournal.org/article/S0002-8223(11)00278-1/abstract
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.http://transmissiblespongiformencephalopathy.blogspot.com/2011/05/travel-history-hunting-and-venison.html
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 IIhttp://chronic-wasting-disease.blogspot.com/2009/03/noahs-ark-holding-llc-dawson-mn-recall.html
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 IIhttp://chronic-wasting-disease.blogspot.com/2009/03/noahs-ark-holding-llc-dawson-mn-recall.html
Transmissible Spongiform Encephalopathies
Spongiform Encephalopathy in Captive Wild ZOO BSE INQUIRYhttps://web.archive.org/web/20090506001201/http://www.bseinquiry.gov.uk/files/mb/m09a/tab03.pdf
BSE INQUIRY
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
*** 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). ***
*** 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). ***
*** 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). ***
There is some evidence that risk of CJD INCREASES WITH INCREASING FREQUENCY OF LAMB EATING (p = 0.02).
The evidence for such an association between beef eating and CJD is weaker (p = 0.14). When only controls for whom a relative was interviewed are included, this evidence becomes a little STRONGER (p = 0.08).
snip...
It was found that when veal was included in the model with another exposure, the association between veal and CJD remained statistically significant (p = < 0.05 for all exposures), while the other exposures ceased to be statistically significant (p = > 0.05).
snip...
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 ;
*** 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). ***
*** 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). ***
There is some evidence that risk of CJD INCREASES WITH INCREASING FREQUENCY OF LAMB EATING (p = 0.02).
The evidence for such an association between beef eating and CJD is weaker (p = 0.14). When only controls for whom a relative was interviewed are included, this evidence becomes a little STRONGER (p = 0.08).
snip...
It was found that when veal was included in the model with another exposure, the association between veal and CJD remained statistically significant (p = < 0.05 for all exposures), while the other exposures ceased to be statistically significant (p = > 0.05).
snip...
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 04, 2018
Cervid to human prion transmission 5R01NS088604-04 Update
WEDNESDAY, SEPTEMBER 26, 2018
JAVMA In Short Update USDA announces detection of atypical BSE
MONDAY, OCTOBER 01, 2018
Update on Classical and Atypical Scrapie in Sheep and Goats: Review 2018
SATURDAY, OCTOBER 06, 2018
Evaluation of iatrogenic risk of CJD transmission associated with corneal transplantation
SATURDAY, SEPTEMBER 22, 2018
Emerging Diseases, Infection Control & California Dental Practice Act
THURSDAY, OCTOBER 04, 2018
Case Western Reserve researchers to examine skin prions in fatal neurodegenerative disease $2.9 million NIH grant focuses on transmission and diagnostic testing
WEDNESDAY, JULY 04, 2018
CREUTZFELDT-JAKOB DISEASE: GUIDELINES FOR SOCIAL WORKERS IN ENGLAND June 2018
MONDAY, JUNE 18, 2018
Ecuador Six Case series of Creutzfeldt-Jakob disease in a third-level hospital in Quito
THURSDAY, OCTOBER 04, 2018
National Prion Disease Pathology Surveillance Center Cases Examined¹ (September 18, 2018)
2006-2007
HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory
TSEs have been rampant in the USA for decades in many species, and they all have been rendered and fed back to animals for human/animal consumption. I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2007. With all the science to date refuting it, to continue to validate this myth, will only spread this TSE agent through a multitude of potential routes and sources i.e. consumption, surgical, blood, medical, cosmetics etc. I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route. This would further have to be broken down to strain of species and then the route of transmission would further have to be broken down. Accumulation and Transmission are key to the threshold from subclinical to clinical disease, and of that, I even believe that physical and or blunt trauma may play a role of onset of clinical symptoms in some cases, but key to all this, is to stop the amplification and transmission of this agent, the spreading of, no matter what strain. BUT, to continue with this myth that the U.K. strain of BSE one strain in cows, and the nv/v CJD, one strain in humans, and that all the rest of human TSE is one single strain i.e. sporadic CJD (when to date there are 6 different phenotypes of sCJD), and that no other animal TSE transmits to humans, to continue with this masquerade will only continue to spread, expose, and kill, who knows how many more in the years and decades to come. ONE was enough for me, My Mom, hvCJD, DOD 12/14/97 confirmed, which is nothing more than another mans name added to CJD, like CJD itself, Jakob and Creutzfeldt, or Gerstmann-Straussler-Scheinker syndrome, just another CJD or human TSE, named after another human. WE are only kidding ourselves with the current diagnostic criteria for human and animal TSE, especially differentiating between the nvCJD vs the sporadic CJD strains and then the GSS strains and also the FFI fatal familial insomnia strains or the ones that mimics one or the other of those TSE? Tissue infectivity and strain typing of the many variants of the human and animal TSEs are paramount in all variants of all TSE. There must be a proper classification that will differentiate between all these human TSE in order to do this. With the CDI and other more sensitive testing coming about, I only hope that my proposal will some day be taken seriously.
My name is Terry S. Singeltary Sr. and I am no scientist, no doctor and have no PhDs, but have been independently researching human and animal TSEs since the death of my Mother to the Heidenhain Variant of Creutzfeldt Jakob Disease on December 14, 1997 'confirmed'. ...END
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.
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Singeltary, Sr et al. JAMA.2001; 285: 733-734.
BRITISH MEDICAL JOURNAL
BMJ
U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well...
02 January 2000
Terry S Singeltary
retired
US scientists develop a possible test for BSE
BMJ 1999; 319 doi: https://doi.org/10.1136/bmj.319.7220.1312b (Published 13 November 1999) Cite this as: BMJ 1999;319:1312
Rapid responses Response
Re: vCJD in the USA * BSE in U.S.
15 November 1999
Terry S Singeltary
NA
medically retired
January 28, 2003; 60 (2) VIEWS & REVIEWS
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States
Ermias D. Belay, Ryan A. Maddox, Pierluigi Gambetti, Lawrence B. Schonberger
First published January 28, 2003, DOI: https://doi.org/10.1212/01.WNL.0000036913.87823.D6
Abstract
Transmissible spongiform encephalopathies (TSEs) attracted increased attention in the mid-1980s because of the emergence among UK cattle of bovine spongiform encephalopathy (BSE), which has been shown to be transmitted to humans, causing a variant form of Creutzfeldt-Jakob disease (vCJD). The BSE outbreak has been reported in 19 European countries, Israel, and Japan, and human cases have so far been identified in four European countries, and more recently in a Canadian resident and a US resident who each lived in Britain during the BSE outbreak. To monitor the occurrence of emerging forms of CJD, such as vCJD, in the United States, the Centers for Disease Control and Prevention has been conducting surveillance for human TSEs through several mechanisms, including the establishment of the National Prion Disease Pathology Surveillance Center. Physicians are encouraged to maintain a high index of suspicion for vCJD and use the free services of the pathology center to assess the neuropathology of clinically diagnosed and suspected cases of CJD or other TSEs.
Received May 7, 2002. Accepted August 28, 2002.
RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States
Terry S. Singeltary, retired (medically)
Published March 26, 2003
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?
Reply to Singletary Ryan A. Maddox, MPH Other Contributors: Published March 26, 2003
Mr. Singletary raises several issues related to current Creutzfeldt- Jakob disease (CJD) surveillance activities. Although CJD is not a notifiable disease in most states, its unique characteristics, particularly its invariably fatal outcome within usually a year of onset, make routine mortality surveillance a useful surrogate for ongoing CJD surveillance.[1] In addition, because CJD is least accurately diagnosed early in the course of illness, notifiable-disease surveillance could be less accurate than, if not duplicative of, current mortality surveillance.[1] However, in states where making CJD officially notifiable would meaningfully facilitate the collection of data to monitor for variant CJD (vCJD) or other emerging prion diseases, CDC encourages the designation of CJD as a notifiable disease.[1] Moreover, CDC encourages physicians to report any diagnosed or suspected CJD cases that may be of special public health importance (e.g., vCJD, iatrogenic CJD, unusual CJD clusters).
As noted in our article, strong evidence is lacking for a causal link between chronic wasting disease (CWD) of deer and elk and human disease,[2] but only limited data seeking such evidence exist. Overall, the previously published case-control studies that have evaluated environmental sources of infection for sporadic CJD have not consistently identified strong evidence for a common risk factor.[3] However, the power of a case-control study to detect a rare cause of CJD is limited, particularly given the relatively small number of subjects generally involved and its long incubation period, which may last for decades. Because only a very small proportion of the US population has been exposed to CWD, a targeted surveillance and investigation of unusual cases or case clusters of prion diseases among persons at increased risk of exposure to CWD is a more efficient approach to detecting the possible transmission of CWD to humans. In collaboration with appropriate local and state health departments and the National Prion Disease Pathology Surveillance Center, CDC is facilitating or conducting such surveillance and case- investigations, including related laboratory studies to characterize CJD and CWD prions.
Mr. Singletary also expresses concern over a recent publication by Asante and colleagues indicating the possibility that some sporadic CJD cases may be attributable to bovine spongiform encephalopathy (BSE).[4] The authors reported that transgenic mice expressing human prion protein homozygous for methionine at codon 129, when inoculated with BSE prions, developed a molecular phenotype consistent with a subtype of sporadic CJD. Although the authors implied that BSE might cause a sporadic CJD-like illness among persons homozygous for methionine, the results of their research with mice do not necessarily directly apply to the transmission of BSE to humans. If BSE causes a sporadic CJD-like illness in humans, an increase in sporadic CJD cases would be expected to first occur in the United Kingdom, where the vast majority of vCJD cases have been reported. In the United Kingdom during 1997 through 2002, however, the overall average annual mortality rate for sporadic CJD was not elevated; it was about 1 case per million population per year. In addition, during this most recent 6-year period following the first published description of vCJD in 1996, there was no increasing trend in the reported annual number of UK sporadic CJD deaths.[3, 5] Furthermore, surveillance in the UK has shown no increase in the proportion of sporadic CJD cases that are homozygous for methionine (Will RG, National CJD Surveillance Unit, United Kingdom, 2003; personal communication).
References
1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Diagnosis and reporting of Creutzfeldt-Jakob disease. JAMA 2001;285:733-734.
2. Belay ED, Maddox RA, Gambetti P, Schonberger LB. Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States. Neurology 2003;60:176-181.
3. Belay ED. Transmissible spongiform encephalopathies in humans. Annu Rev Microbiol 1999;53:283-314.
4. Asante EA, Linehan JM, Desbruslais M, et al. BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein. EMBO J 2002;21:6358-6366.
5. The UK Creutzfeldt-Jakob Disease Surveillance Unit. CJD statistics. Available at: http://www.cjd.ed.ac.uk/figures.htm. Accessed February 18, 2003.
Competing Interests: None declared.
doi:10.1016/S1473-3099(03)00715-1 Copyright © 2003 Published by Elsevier Ltd. Newsdesk
Tracking spongiform encephalopathies in North America
Xavier Bosch
Available online 29 July 2003.
Volume 3, Issue 8, August 2003, Page 463
“My name is Terry S Singeltary Sr, and I live in Bacliff, Texas. I lost my mom to hvCJD (Heidenhain variant CJD) and have been searching for answers ever since. What I have found is that we have not been told the truth. CWD in deer and elk is a small portion of a much bigger problem.” ............................
FRIDAY, JUNE 29, 2018
Vaccines, TSE, Prion, risk factors?
***> see HISTORY great debate here <***
BSE, CJD, and Baby foods (the great debate 1999 to 2005)
see moms autopsy;
WEDNESDAY, SEPTEMBER 26, 2018
A new variant of Creutzfeldt-Jakob disease in the UK 1995 revisited 2018 a review of science
***> 2001 FDA CJD TSE Prion Singeltary Submission
http://www.fda.gov/ohrms/dockets/ac/01/slides/3681s2_09.pdf
Sent: Monday, January 08,2001 3:03 PM
WOW, my submission held up on the www for 17 years, and was proven to be true, and now, it has been removed from the www, the same url does not work anymore and it was just working this year. nothing like the FDA et al cleaning up any evidence of truth with their mad cow debacle and sporadic cjd cover up contineus...so sad$$$
let's review the truth about sporadic cjd shall we;
http://tseac.blogspot.com/2018/06/prion-scientific-advisors-and.html
***> U.S.A. 50 STATE BSE MAD COW CONFERENCE CALL Jan. 9, 2001
[host Richard Barns] and now a question from Terry S. Singeltary of CJD Watch.
[TSS] yes, thank you, U.S. cattle, what kind of guarantee can you give for serum or tissue donor herds?
[no answer, you could hear in the back ground, mumbling and 'we can't. have him ask the question again.]
[host Richard] could you repeat the question?
[TSS] U.S. cattle, what kind of guarantee can you give for serum or tissue donor herds?
[not sure whom ask this] what group are you with?
[TSS] CJD Watch, my Mom died from hvCJD and we are tracking CJD world-wide.
[not sure who is speaking] could you please disconnect Mr. Singeltary
[TSS] you are not going to answer my question?
[not sure whom speaking] NO
http://tseac.blogspot.com/2011/02/usa-50-state-bse-mad-cow-conference.html
http://www.fda.gov/ohrms/dockets/ac/01/slides/3681s2_09.pdf
Sent: Monday, January 08,2001 3:03 PM
WOW, my submission held up on the www for 17 years, and was proven to be true, and now, it has been removed from the www, the same url does not work anymore and it was just working this year. nothing like the FDA et al cleaning up any evidence of truth with their mad cow debacle and sporadic cjd cover up contineus...so sad$$$
let's review the truth about sporadic cjd shall we;
http://tseac.blogspot.com/2018/06/prion-scientific-advisors-and.html
***> U.S.A. 50 STATE BSE MAD COW CONFERENCE CALL Jan. 9, 2001
[host Richard Barns] and now a question from Terry S. Singeltary of CJD Watch.
[TSS] yes, thank you, U.S. cattle, what kind of guarantee can you give for serum or tissue donor herds?
[no answer, you could hear in the back ground, mumbling and 'we can't. have him ask the question again.]
[host Richard] could you repeat the question?
[TSS] U.S. cattle, what kind of guarantee can you give for serum or tissue donor herds?
[not sure whom ask this] what group are you with?
[TSS] CJD Watch, my Mom died from hvCJD and we are tracking CJD world-wide.
[not sure who is speaking] could you please disconnect Mr. Singeltary
[TSS] you are not going to answer my question?
[not sure whom speaking] NO
http://tseac.blogspot.com/2011/02/usa-50-state-bse-mad-cow-conference.html
FRIDAY, OCTOBER 05, 2018
More Politicians and Very Young People Struck Down With Creutzfeldt Jakob Disease CJD mad cow type TSE Prion USA
Terry S. Singeltary Sr.