Sporadic Creutzfeldt-Jakob Disease in a Woman Married Into a Gerstmann-Sträussler-Scheinker Family: An Investigation of Prions Transmission via Microchimerism
Aušrinė Areškevičiūtė, MSc Linea Cecilie Melchior, PhD Helle Broholm, MD Lars-Henrik Krarup, MD, PhD Suzanne Granhøj Lindquist, MD, PhD Peter Johansen, PhD Neil McKenzie, PhD Alison Green, PhD Jørgen Erik Nielsen, MD, PhD Henning Laursen, Dr.Med ... Show more Journal of Neuropathology & Experimental Neurology, Volume 77, Issue 8, 1 August 2018, Pages 673–684, https://doi.org/10.1093/jnen/nly043
Published: 07 June 2018
Abstract
This is the first report of presumed sporadic Creutzfeldt-Jakob disease (sCJD) and Gerstmann-Sträussler-Scheinker disease (GSS) with the prion protein gene c.305C>T mutation (p.P102L) occurring in one family. The father and son were affected with GSS and the mother had a rapidly progressive form of CJD. Diagnosis of genetic, variant, and iatrogenic CJD was ruled out based on the mother’s clinical history, genetic tests, and biochemical investigations, all of which supported the diagnosis of sCJD. However, given the low incidence of sCJD and GSS, their co-occurrence in one family is extraordinary and challenging. Thus, a hypothesis for the transmission of infectious prion proteins (PrPSc) via microchimerism was proposed and investigated. DNA from 15 different brain regions and plasma samples of the CJD patient was subjected to PCR and shallow sequencing for detection of a male sex-determining chromosome Y (chr. Y). However, no trace of chr. Y was found. A long CJD incubation period or presumed small concentrations of chr. Y may explain the obtained results. Further studies of CJD and GSS animal models with controlled genetic and proteomic features are needed to determine whether maternal CJD triggered via microchimerism by a GSS fetus might present a new PrPSc transmission route.
snip...
DISCUSSION
This is the first report of presumed sporadic CJD occurring in a person who married into a GSS family. The estimated prevalence of GSS is in the range of 2–5 per 100 million people worldwide, and the annual mortality rate for sCJD in Denmark is 1.46 per 1 million people (31). The population of Denmark consists of 5 740 185 individuals, and there are 2 registered GSS cases that belong to the same family. The Danish GSS family is only the thirty-fourth known GSS family in the world (32). One could assume that the risk for a Danish man with GSS to have a wife or a mother who would develop CJD in her seventies is as high as for any other man. On the basis of the mortality rate for sCJD, and assuming that the incidence of sCJD is the same among married and unmarried people, we could state that 1 man out of 684 932 men has a risk of marrying a woman who would develop CJD. However, in this case, the man a priori had GSS, which means that it would take 1 man out of 684 932 men with GSS for such a pairing to occur. Considering the worldwide rarity of GSS cases, the likelihood for co-occurrence of GSS and sCJD in one family is hence very low and warrants an investigation for the possible transmission of prions routes.
Four cases of a random co-occurrence of prion diseases in the same family were reported before (12–15). In 3 of those reports, evaluation of the likelihood of prion diseases cooccurrence by chance implies a considerably low probability. For example, the occurrence of sCJD in a husband and wife has been reported in the United States in 1998. In the 15-year surveillance period, the evaluation of the statistical likelihood for a couple in the United States to develop sporadic CJD within 5 years from each other was presented as a 2.1% risk, given the size of the population and its assumed structure at the time (13). In a case study from Switzerland, the estimated probability for a sibling of an iCJD patient to develop any kind of CJD was 1.4 10 3 , and the probability that one patient with sporadic fatal insomnia occurs by chance in a fatal familial insomnia family in Italy ranged from 0.78–1.56 10 4 (14, 15).
In the current study, a thorough neuropathological investigation of the CJD patient’s and GSS proband’s brain was performed and revealed a classic sCJD type V2 and GSS, respectively (33). In the CJD patient, the main histopathological findings were a characteristic diffuse synaptic and perineuronal PrPSc distribution throughout the brain, spongiosis, and neuronal loss, whereas in the GSS proband, the major finding was the presence of uni and multicentric PrPSc plaques, especially in the cerebellum.
To ensure that the CJD patient was not exposed to known routes of PrPSc transmission and did not carry pathogenic mutations, her clinical history was studied, the PrPSc type was defined, and the coding region of her PRNP was sequenced. Neither the clinical history nor the biochemical findings of the CJD patient’s tissues provided evidence of iCJD or variant CJD.
No established pathogenic mutations were found in the CJD patient’s PRNP coding region. However, she had a silent A117A mutation, which is present in only 5%–10% of the population in Western countries and is considered nonpathogenic because the evidence for its impact on prion diseases pathogenesis is lacking (34). Yet alanine-to-valine replacement at the same codon position (p.A117V) is known to cause GSS (35, 36). Whether or not the CJD patient’s possession of a silent A117A mutation in PRNP could have favored the CJD susceptibility in the given GSS family case remains to be elucidated, but if its presence was a cofactor, this could explain the rarity of CJD cases in GSS families.
Given the unusual circumstances, we hypothesized that the cells of the fetus, which carried the P102L mutation in PRNP and PrPSc, might be transmitted to the mother’s brain via acquired microchimerism, thus triggering the conversion of maternal PrPC into PrPSc. The microchimerism would have marked the start of the CJD incubation period. Although more than a 50-year incubation period seems lengthy for sCJD, there were cases of iCJD and Kuru incubation lasting up to 40 and 56 years, respectively, underlining the possible variability of the incubation period of prion diseases (37, 38).
During pregnancy, both the fetus’ and mother’s bloodbrain barriers exhibit increased permeability, allowing the exchange of DNA and cells (16). Microchimerism in female brains has been reported in 63% of all women who carried a male fetus, and it was detectable when measured 2 decades after the pregnancy (16).
We know that the CJD patient who married into the Danish GSS family was pregnant with the male fetus with GSS 52 years before her death. Therefore, her DNA samples from 15 different brain regions and blood plasma was extracted to search for the male sex-determining chr.Y. However, no male SRY was detected in the maternal brain. Besides, the number of high-quality chr.Y reads in the maternal plasma was too small to conclusively prove the presence of genuine male fetus’ cells (30, 39).
Different factors may have influenced the negative results: 1) the fetus cells might have vanished from the mother’s body because of the 52-year period since the putative microchimerism; 2) the sensitivity of the chr.Y detection methods might not have been high enough for the presumed low level of the target Y-sequence; and 3) although the samples were taken from 15 brain regions, it could be possible that the fetal cells were missed (16, 20). Even though no fetal cells were detected, according to the hypothesis, it is likely that PrPSc from the fetal cells acted as seeds and started the process of maternal PrPC misfolding and, once triggered, this process could go on for many years, even after the microchimeric fetal cells were lost again.
It is known that CJD susceptibility and phenotypes can differ greatly because of a person’s polymorphism at codon 129 in PRNP (40–42). In this case, the CJD patient was homozygous for V at codon 129 and had PrPSc type 2, which is the second most common sporadic CJD type, suggesting that V homozygosity may have favored PrPC misfolding and CJD pathogenesis (35, 43).
The PrPSc biochemical and histological picture of the V homozygote CJD patient is very different from that of GSS although, hypothetically, the initial PrPSc seed was from the P102L-129M GSS fetus. This could be explained by the host PrPSc strain mutation and/or a strain selection phenomenon, which also might have contributed to the lengthy CJD incubation period.
Strain mutation means that a distinct PrPSc strain can be propagated on the passage to a new host, even in the same species, if the PrPC primary sequence differs from that of the host. In humans, the propagation of certain PrPSc strains is thought to be influenced by variations in the host’s PRNP and likely in other genes that shape the microenvironment of the brain too (44, 45). For example, M at codon 129 is associated with the production of type 1 PrPSc and V with the production of type 2 PrPSc (46).
Cases of PrPSc type 1 and type 2 co-occurring in the same patients prove that several PrPSc conformations defining the PrPSc types or strains can be found in a brain affected by prion disease (28, 35, 46). Moreover, it has been demonstrated that several rodents inoculated with the same human P102L GSS brain homogenate developed distinct pathologies and 2 different PrPSc strains corresponding to 8 and 21 kDa fragments (47, 48). Strain selection phenomenon refers to the propagation of one PrPSc strain over another that is selected by preferential “templating” against the host’s PrPC sequence and genetic background (44, 47). Studies on the transmissibility and conformation of synthetic PrPSc strains propose that when the host is introduced to a mixture of different PrPSc strains, those that are the most compatible with the host’s PrPC propagate the fastest and dominate the clinical symptoms (49).
Detailed investigation of the CJD and GSS patients’ genomes and proteomes would perhaps reveal more possible explanations for CJD and GSS co-occurrence in one family. However, this would require fresh brain tissues from the GSS proband and the son. Studies of transgenic animal models with genotypes and PrPSc types corresponding to the Danish GSS and CJD family model could be the next step in resolving the possibility of PrPSc transmission via microchimerism. Moreover, knowing that the CJD patient’s husband was a PrPSc carrier too, the possibility of other new PrPSc transmission routes, such as body fluids exchange during sexual relations, should be considered.
In conclusion, the current study is the first report of presumed sCJD and GSS presenting in the same family. We analyzed the clinical, neuropathological, and genetic findings of the affected family members; however, the co-occurrence of such rare diseases in the same family could not be explained by these findings. Thus, we have proposed and investigated a novel possible PrPSc transmission route in humans. We suggested that via acquired microchimerism, PrPSc could be freely transmitted from the fetus to the mother and possibly vice versa. Despite the data we have obtained, the time of sampling since the PrPSc seeding and the overall sensitivity of the genetic measurements necessarily limit the support for our novel transmission hypothesis in this extremely rare Danish case. However, the hypothesis should not be disregarded without further investigation. Exploring new possible prion infection routes and the biological mechanisms favoring them in animal models with controlled genetic and proteomic characteristics would help in elucidating the co-occurrence of CJD and GSS in one family.
The family case presented in the current study, and the 4 other previously reported family cases of rare prion diseases co-occurrence foster the necessity to explore the complexity of possible routes for prions transmission, as well as the biological and environmental factors contributing to the susceptibility of prion diseases. An in-depth comprehension of these aspects of prion diseases is essential for their prevention and for the proper genetic counseling of affected families.
ACKNOWLEDGMENTS
snip...
DISCUSSION
This is the first report of presumed sporadic CJD occurring in a person who married into a GSS family. The estimated prevalence of GSS is in the range of 2–5 per 100 million people worldwide, and the annual mortality rate for sCJD in Denmark is 1.46 per 1 million people (31). The population of Denmark consists of 5 740 185 individuals, and there are 2 registered GSS cases that belong to the same family. The Danish GSS family is only the thirty-fourth known GSS family in the world (32). One could assume that the risk for a Danish man with GSS to have a wife or a mother who would develop CJD in her seventies is as high as for any other man. On the basis of the mortality rate for sCJD, and assuming that the incidence of sCJD is the same among married and unmarried people, we could state that 1 man out of 684 932 men has a risk of marrying a woman who would develop CJD. However, in this case, the man a priori had GSS, which means that it would take 1 man out of 684 932 men with GSS for such a pairing to occur. Considering the worldwide rarity of GSS cases, the likelihood for co-occurrence of GSS and sCJD in one family is hence very low and warrants an investigation for the possible transmission of prions routes.
Four cases of a random co-occurrence of prion diseases in the same family were reported before (12–15). In 3 of those reports, evaluation of the likelihood of prion diseases cooccurrence by chance implies a considerably low probability. For example, the occurrence of sCJD in a husband and wife has been reported in the United States in 1998. In the 15-year surveillance period, the evaluation of the statistical likelihood for a couple in the United States to develop sporadic CJD within 5 years from each other was presented as a 2.1% risk, given the size of the population and its assumed structure at the time (13). In a case study from Switzerland, the estimated probability for a sibling of an iCJD patient to develop any kind of CJD was 1.4 10 3 , and the probability that one patient with sporadic fatal insomnia occurs by chance in a fatal familial insomnia family in Italy ranged from 0.78–1.56 10 4 (14, 15).
In the current study, a thorough neuropathological investigation of the CJD patient’s and GSS proband’s brain was performed and revealed a classic sCJD type V2 and GSS, respectively (33). In the CJD patient, the main histopathological findings were a characteristic diffuse synaptic and perineuronal PrPSc distribution throughout the brain, spongiosis, and neuronal loss, whereas in the GSS proband, the major finding was the presence of uni and multicentric PrPSc plaques, especially in the cerebellum.
To ensure that the CJD patient was not exposed to known routes of PrPSc transmission and did not carry pathogenic mutations, her clinical history was studied, the PrPSc type was defined, and the coding region of her PRNP was sequenced. Neither the clinical history nor the biochemical findings of the CJD patient’s tissues provided evidence of iCJD or variant CJD.
No established pathogenic mutations were found in the CJD patient’s PRNP coding region. However, she had a silent A117A mutation, which is present in only 5%–10% of the population in Western countries and is considered nonpathogenic because the evidence for its impact on prion diseases pathogenesis is lacking (34). Yet alanine-to-valine replacement at the same codon position (p.A117V) is known to cause GSS (35, 36). Whether or not the CJD patient’s possession of a silent A117A mutation in PRNP could have favored the CJD susceptibility in the given GSS family case remains to be elucidated, but if its presence was a cofactor, this could explain the rarity of CJD cases in GSS families.
Given the unusual circumstances, we hypothesized that the cells of the fetus, which carried the P102L mutation in PRNP and PrPSc, might be transmitted to the mother’s brain via acquired microchimerism, thus triggering the conversion of maternal PrPC into PrPSc. The microchimerism would have marked the start of the CJD incubation period. Although more than a 50-year incubation period seems lengthy for sCJD, there were cases of iCJD and Kuru incubation lasting up to 40 and 56 years, respectively, underlining the possible variability of the incubation period of prion diseases (37, 38).
During pregnancy, both the fetus’ and mother’s bloodbrain barriers exhibit increased permeability, allowing the exchange of DNA and cells (16). Microchimerism in female brains has been reported in 63% of all women who carried a male fetus, and it was detectable when measured 2 decades after the pregnancy (16).
We know that the CJD patient who married into the Danish GSS family was pregnant with the male fetus with GSS 52 years before her death. Therefore, her DNA samples from 15 different brain regions and blood plasma was extracted to search for the male sex-determining chr.Y. However, no male SRY was detected in the maternal brain. Besides, the number of high-quality chr.Y reads in the maternal plasma was too small to conclusively prove the presence of genuine male fetus’ cells (30, 39).
Different factors may have influenced the negative results: 1) the fetus cells might have vanished from the mother’s body because of the 52-year period since the putative microchimerism; 2) the sensitivity of the chr.Y detection methods might not have been high enough for the presumed low level of the target Y-sequence; and 3) although the samples were taken from 15 brain regions, it could be possible that the fetal cells were missed (16, 20). Even though no fetal cells were detected, according to the hypothesis, it is likely that PrPSc from the fetal cells acted as seeds and started the process of maternal PrPC misfolding and, once triggered, this process could go on for many years, even after the microchimeric fetal cells were lost again.
It is known that CJD susceptibility and phenotypes can differ greatly because of a person’s polymorphism at codon 129 in PRNP (40–42). In this case, the CJD patient was homozygous for V at codon 129 and had PrPSc type 2, which is the second most common sporadic CJD type, suggesting that V homozygosity may have favored PrPC misfolding and CJD pathogenesis (35, 43).
The PrPSc biochemical and histological picture of the V homozygote CJD patient is very different from that of GSS although, hypothetically, the initial PrPSc seed was from the P102L-129M GSS fetus. This could be explained by the host PrPSc strain mutation and/or a strain selection phenomenon, which also might have contributed to the lengthy CJD incubation period.
Strain mutation means that a distinct PrPSc strain can be propagated on the passage to a new host, even in the same species, if the PrPC primary sequence differs from that of the host. In humans, the propagation of certain PrPSc strains is thought to be influenced by variations in the host’s PRNP and likely in other genes that shape the microenvironment of the brain too (44, 45). For example, M at codon 129 is associated with the production of type 1 PrPSc and V with the production of type 2 PrPSc (46).
Cases of PrPSc type 1 and type 2 co-occurring in the same patients prove that several PrPSc conformations defining the PrPSc types or strains can be found in a brain affected by prion disease (28, 35, 46). Moreover, it has been demonstrated that several rodents inoculated with the same human P102L GSS brain homogenate developed distinct pathologies and 2 different PrPSc strains corresponding to 8 and 21 kDa fragments (47, 48). Strain selection phenomenon refers to the propagation of one PrPSc strain over another that is selected by preferential “templating” against the host’s PrPC sequence and genetic background (44, 47). Studies on the transmissibility and conformation of synthetic PrPSc strains propose that when the host is introduced to a mixture of different PrPSc strains, those that are the most compatible with the host’s PrPC propagate the fastest and dominate the clinical symptoms (49).
Detailed investigation of the CJD and GSS patients’ genomes and proteomes would perhaps reveal more possible explanations for CJD and GSS co-occurrence in one family. However, this would require fresh brain tissues from the GSS proband and the son. Studies of transgenic animal models with genotypes and PrPSc types corresponding to the Danish GSS and CJD family model could be the next step in resolving the possibility of PrPSc transmission via microchimerism. Moreover, knowing that the CJD patient’s husband was a PrPSc carrier too, the possibility of other new PrPSc transmission routes, such as body fluids exchange during sexual relations, should be considered.
In conclusion, the current study is the first report of presumed sCJD and GSS presenting in the same family. We analyzed the clinical, neuropathological, and genetic findings of the affected family members; however, the co-occurrence of such rare diseases in the same family could not be explained by these findings. Thus, we have proposed and investigated a novel possible PrPSc transmission route in humans. We suggested that via acquired microchimerism, PrPSc could be freely transmitted from the fetus to the mother and possibly vice versa. Despite the data we have obtained, the time of sampling since the PrPSc seeding and the overall sensitivity of the genetic measurements necessarily limit the support for our novel transmission hypothesis in this extremely rare Danish case. However, the hypothesis should not be disregarded without further investigation. Exploring new possible prion infection routes and the biological mechanisms favoring them in animal models with controlled genetic and proteomic characteristics would help in elucidating the co-occurrence of CJD and GSS in one family.
The family case presented in the current study, and the 4 other previously reported family cases of rare prion diseases co-occurrence foster the necessity to explore the complexity of possible routes for prions transmission, as well as the biological and environmental factors contributing to the susceptibility of prion diseases. An in-depth comprehension of these aspects of prion diseases is essential for their prevention and for the proper genetic counseling of affected families.
ACKNOWLEDGMENTS
Chromosome Y, Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, Microchimerism, PRNP, Prions, Transmission Topic: mutation creutzfeldt-jakob disease dna gerstmann-straussler-scheinker disease prions y chromosomes brain prnp gene microchimerism Issue Section: Original Articles
© 2018 American Association of Neuropathologists, Inc. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
now don't get mad Roland Heynkes ;-) this is terrible if true, and confusing, so i am going to run this by everyone, a chance that all three wife, father, son, contracted sporadic cjd via consumption of some sorts, or was it casual contact from a most virulent mutated strain of sporadic cjd, i.e. transmission like cwd tse prion in cervid? our worst nightmare if true...terry
Subject: Woman dies from rare dementia contracted from baby while pregnant
Woman dies from rare dementia contracted from baby while pregnant
27 Nov, 2018 9:02am
Doctors believe the son inherited the mutated gene responsible for the disease from his father, before passing it back to his mother while in the womb. Photo / Getty ImagesDoctors
Daily Mail
By: Alexandra Thompson
A woman has died from a rare form of dementia decades after she is thought to have caught the disease from her own baby while pregnant.
Her husband died of sporadic Creutzfeldt-Jakob disease two decades ago - but her own genes were previously shown to be clear of the responsible mutation, reports the Daily Mail.
However, the unidentified woman, from Denmark, died of the same crippling disease as her late husband while in her seventies.
Her son, whose identity has also been withheld but is known to be 53 and a father himself, is now "showing symptoms" of sporadic CJD.
Doctors now believe the son inherited the mutated gene responsible for the disease from his father, before passing it back to his mother while in the womb.
Cells from the foetus that contained the toxic proteins are thought to have traveled across the placenta into her bloodstream, before lodging in her brain.
The fatal condition causes irreversible brain damage, triggered by abnormal proteins known as prions, which gradually destroy brain cells.
The rare case was uncovered by a team of medics at the Danish Reference Centre for Prion Diseases in Copenhagen University Hospital.
The woman was diagnosed with sporadic CJD before the disorder was linked to her late husband or son.
CJD occurs due to abnormal proteins known as prions, which cause nerve-cell damage.
Prions can occur spontaneously, be inherited or transmitted on contaminated surgical equipment.
There is no cure.
Treatment focuses on relieving symptoms and making sufferers comfortable via painkillers and antidepressants.
Ausrine Areskeviciute, one of the medics who stumbled across the case, told The Times that it is a "very sad story".
She said: "We already know that when a woman is pregnant cells from the baby travel across the placenta and travel around her body, lodging in various organs.
"However, in this case the foetus carried the mutation for the misfolded proteins, and its cells may also have had misfolded proteins when they got into the mother's body."
Ms Areskeviciute added this may have triggered the process that led to her death years later.
The case of CJD, which is considered to be a type of dementia, was published in the Journal of Neuropathology & Experimental Neurology.
CJD, of which there are four main types, is a prion disease, which derives its name from "protein" and "infectious".
It is defined by proteins in the nervous system taking on an unusual shape, which then spread in a domino-like effect to cause lesions in the brain.
Some 85 per cent of cases occur randomly, while 10-15 per cent are inherited. In less than one per cent of incidences, CJD is acquired.
Mad cow disease is also a prion condition, which occurs when a person eats meat from cattle affected by a similar disease.
Sporadic CJD affects as little as one in a million people each year in the UK, NHS figures state.
This comes after research released earlier this year suggested prion diseases can be spread during operations via poorly-cleaned surgical equipment.
*UPDATE* NOVEMBER 16, 2014
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???
Friday, January 10, 2014
Greetings again Friends, Neighbors, and Colleagues,
I would kindly like to follow up on ‘vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???’ ran across an old paper from 1984, that some might find interest in, and I will update the link with this old science paper from 1984, a 2010 paper from Japan, and some information on scrapie transmission. The paper from Japan first, then the 1984 paper, and then the scrapie transmission studies.
***The occurrence of contact cases raises the possibility that transmission in families may be effected by an unusually virulent strain of the agent.
From: Terry S. Singeltary Sr.
Sent: Saturday, November 15, 2014 9:29 PM
To: Terry S. Singeltary Sr.
Subject: THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE R. G. WILL 1984
THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE
R. G. WILL
1984
snip...
D. Occupation
The possibility of case-to-case transmission of C.J.D. has led to anxiety among hospital personnel and laboratory staff regarding the possible risks of transmission by direct contact with patients suffering from the condition (Mayer, 1979). During the prospective study reluctance to perform post mortem or carry out electrophysiological studies was regularly encountered. In the past, epidemiological evidence has consistently failed to reveal any increased risk related to particular professions (Bobowick et al., 1973; Matthews, 1975a; Brown et al., 1979b; Galvez et al., 1980; Kondo and Kuroiwa, 1982) and, with the exception of the review by Masters et al. (1979a), no increased risk to medical or paramedical personnel. In the latter study 18 out of 308 cases were described as health professionals, although as Brown (1980) has pointed out, this may have been due to case selection. One neurosurgeon has been reported to have died of pathologically confirmed C.J.D. (Schoene et al., 1981), but although he had contact with a case of C.J.D. seven years prior to death, no operative procedure was carried out.
In the retrospective section of this study no occupational bias was discovered, there was no over-representation of health care personnel and only one patient, a nurse, was likely to have had direct contact with patients. In the prospective study, in which details of occupation throughout life were obtained, there was again no occupational bias. Possible contact between a dentist dying of confirmed C.J.D. and other patients is discussed below, but the putative transmission in these cases would have required direct implantation of the agent during dental procedures.
On the basis of the evidence from this and previous epidemiological studies, there appears to be no increased risk of transmission by direct contact with patients. Bodily secretions and excreta do not contain the agent (Masters et al., 1980) and although viraemia has been described in experimental transmission in guinea pigs (Manuelidis et al., 1978b, Gajdusek et al. (1978) suggest that human blood, if ever infective, must contain a very low titre of the agent. Despite a large number of transmission experiments no staff at Bethesda have ever contracted the condition (Gajdusek et al., 1978). Prior to the discovery that C.J.D. was trans- missible no special precautions were taken during post mortem and indeed the pathology technician in Dr. Nevin's cases has described eating food off the post mortem table immediately after necropsy of one of these patients. Despite the lack of precautions in the past no pathology technicians are known to have developed C.J.D.
In conclusion, sensible precautions as advised by both Gajdusek et al. (1977) and the Advisory Group on the Management of Patients with Spongiform Encephalopathy (1981) are sufficient. Patients do not require barrier nursing, blood and cerebrospinal fluid specimens should be treated in the same way as other 'high risk' specimens, and more stringent precautions should be observed at post mortem. The risk of case-to-case transmission at neurosurgery is established (as discussed below) and all instruments should be discarded after use.
E. Past Medical History
An increased incidence of surgical procedures and neurological and psychiatric illness in C.J.D. has been described by Masters et ale (1979a). Cases in this series were ascertained from a variety of sources, including direct referral and a review of the literature and selection bias cannot be excluded. It is also uncertain whether such an incidence of past medical or surgical illness differs from the incidence in this age group in the general population. Other retrospective epidemiological studies of C.J.D. (Bobowick et al. t 1973; Matthews, 1975a; Brown et al., 1979b; Kondo and Kuroiwa, 1982) have failed to show an increased incidence of past medical or surgical illness and combining the results of the Chilean (Galvez et al., 1980) and Hungarian (Majtenyi, 1978) studies only four patients out of a total of 67 had a significant past surgical history. In the study in France (Brown et al., 1979b) 8% of patients had some form of surgical procedure in the five years prior to developing C.J.D., but the rationale for limiting enquiry to the preceding five years is unclear in view of the possible incubation period in C.J.D. of over four decades (Masters et al., 1981a). In the retrospective survey in this study, which was without temporal limits, 28% of patients had a past history of some form of major surgery. Without a comparison with the incidence of major surgery in a matched population the significance of this figure is uncertain, and it is of note that in 40 patients no past illness was described.
In the prospective study a more detailed medical history was obtained and there was no specific factor in the past medical history common to all patients. As with other proposed risk factors, only a properly conducted case control study can assess the significance of putative risk factors discovered in descriptive epidemiological surveys.
The transmission of C.J.D. by corneal transplantation has been established (Duffy et al., 1974) and it is disturbing that in one case in this series corneas were removed for transplantation from a patient dying of C.J.D. and in a further case potentially contaminated corneal transplants had to be removed when the risks were realised. The recommendation that corneas must not be taken for transplantation from demented patients, from patients dying in psychiatric hospitals, nor from patients dying of undiagnosed neurological disease (Advisory Group on the Management of Patients with Spongiform Encephalopathy, 1981) should be reinforced.
F. Familial Associations
The overall familial incidence of 6% in the retrospective section of this study contrasts with the estimated familial incidence of 15% in a review of the world wide epidemiology of C.J.D. (Masters et al., 1979a). In individual series higher figures are quoted with, for example, a familial incidence of 47% in Chile (Galvez et al., 1980) and 35% in Libyan born Israelis (Neugut et al., 1979). In a comprehensive retrospective survey of C.J.D. in France (Brown et al., 1979b), however, a 9% familial incidence was discovered, a figure comparable with this series. The low familial incidence may reflect either the difficulties of retrospectively obtaining an accurate family history or an artificially high familial incidence in relatively selected series due to extensive investigation of individual families.
The paradox of an apparently dominantly inherited condition (Masters et al., 1981a) which is yet transmissible is unresolved. Detailed investigation of individual families suggests that, if case to case transmission occurs, the incubation period must extend to decades (Masters et al., 1981a). Although this is compatible with the suspected incubation period of kuru (Gajdusek, 1979), the tendency for siblings to die at the same age rather than the same time (Masters et al., 1981a) supports the presence of a genetic influence. ***The discovery of a discordant identical twin pair in the present study suggests that even if there is an inherited susceptibility an environmental factor is necessary for the development of the condition. It further suggests that genetic integration of the agent is unlikely, in accordance with experimental evidence in which nuclear fractions are non-infectious (Millson et al., 1971) and vertical trans- mission has not been found in the laboratory (Amyx et al., 1981).
An unexpected but interesting finding in the context of familial associations is the group of nine patients with a first degree relative dying of a different 'degenerative' neurological condition. The extraordinary family with apparently dominantly inherited Alzheimer's disease and carcinoma of the colon is under investigation at another centre.
In other systematic studies of the epidemiology of C.J.D. an association with other neurological conditions has not been described but Masters (1981a) has reported four cases of C.J.D. occurring within four pedigrees of familial Alzheimer's disease. Adam et ale (1982) have described a family with a dominantly inherited neurological disorder sharing features of cerebral amyloidosis, spongiform encephalopathy and Alzheimer's disease. ***The relationship of C.J.D. to other degenerative neurological disorders may be a fruitful avenue of further epidemiological research.
CASE CONTROL STUDY
The objective of the case control study was to obtain quantitative data on putative risk factors and to identify potential common exposure to an environmental source of infection. The difficulties of such a study have been described by Bobowick et al. (1973) and Kondo and Kuroiwa (1982) in the only previous case control studies of C.J.D. In a rare condition such as C.J.D. it is difficult to obtain sufficient patient numbers to achieve statistically valid results. In this study 22 patients were included in the first 18 months, a number sufficient to exclude any ubiquitous risk factor but inadequate to distinguish relative risk. The case control study has, however, continued beyond the time limits of this analysis and to date over a hundred patients have been included.
The necessity of obtaining information at second hand introduces a potential source of error in the study of C.J.D. In this study the level of co-operation and detail of information was clearly enhanced by interviewing relatives prospectively and for this reason cases ascertained after death were not included in the prospective study. The checking of information given by relatives of control cases with the patients themselves suggested that the quality of information given at second hand was remarkably accurate.
The selection of controls is critical to the potential significance of a case control study. In this study age- and sex-matched controls were obtained from concurrent inpatients. Although in some cases the discovery of a suitable control proved both difficult and time-consuming, and in a few cases impossible, it was felt essential to persevere with the stated protocol in order to avoid the introduction of bias. Both previous case control studies were carried out retro- spectively and used 'healthy' and potentially over-matched controls.
Despite the differences between previous studies and the present case control study, the results were, almost without exception, both concordant and negative. No difference between patients and controls was discovered in past surgical or medical history, occupational history, educational history, eating habits or exposure to animals. Kondo and Kuroiwa (1982) discovered a correlation between physical injuries and the development of C.J.D. but could not exclude a methodological bias. No such correlation was discovered in this study and the subject was not examined in the study by Bobowick et ale (1973).
In the latter study the consumption of hog brains by patients was stressed but did not differ from the control group and in both this study and the study in Japan (Kondo and Kuroiwa, 1982) no dietary factory was related to increased risk of developing C.J.D.
***The successful oral transmission of C.J.D. and scrapie to primates (Gibbs et al., 1980) and the close resemblance between the properties of the transmissible agent in the two conditions (Gibbs and Gajdusek, 1976) has raised the possibility that the human disease is contracted from sheep. No direct evidence is available and the concept is based on inference and interesting but unconvincing anecdotes
(Alter et al., 1971; Lo Russo et al., 1980; Kamin and Patten, 1984). The patient discovered in this study who had never been known to eat meat suggests that eating scrapie infected meat cannot be the only source of C.J.D. in man. C.J.D. occurs in countries in which natural scrapie has not been observed (Galvez et al., 1980; Kondo and Kuroiwa, 1982) and no relationship was discovered in France (Chatelain et al., 1981) between the geographic distribution of scrapie and the incidence of C.J.D. A similar investigation could not be carried out in England and Wales as notification of scrapie to the Ministry of Agriculture is inconsistent and sheep farmers often destroy affected animals without seeking veterinary advice for fear of financial loss.
A detailed residential history was obtained in cases and controls. Although over-representation of cases was discovered in certain areas, similar but distinct areas of previous residence common to an apparent excess of controls was discovered. If C.J.D. does have a prolonged incubation period extending to decades the detailed study of residential history may, however, establish potential contact between individual cases which would be otherwise undetectable. The detailed study of individual cases in the prospective study has revealed the possibility of tenuous but extraordinarily coincidental contact between patients.
This may only be a reflection of intensive investigation, but if C.J.D. is transmitted by relatively minor surgical or dental procedures many years prior to death it is only by the systematic study of individual cases that potential cross-contamination may be discovered.
EVIDENCE FOR CASE-TO-CASE TRANSMISSION OF C.J.D.
The possible iatrogenic transmission of C.J.D. by neurosurgery, corneal transplantation and stereotactic electrodes has been suggested in the past (Duffy et al., 1974: Bernouilli et al., 1977; Masters et al., 1979a). In this series the close temporal relationship of neurosurgical procedures on two affected patients and three patients, unaffected at the time but who subsequently developed the disease is described. This provides strong circumstantial evidence of iatrogenic transmission by neurosurgery. Although sterilisation procedures have improved since the cases described, the unusual resistance of the agent and the recent description of probable neurosurgical transmission in France (Foncin et al., 1980) suggests that there is a continued risk of accidental transmission. However, brain biopsy to confirm the diagnosis of C.J.D. is now an unusual event and computed tomography has obviated the need for ventriculography.
The depth electrodes putatively responsible for one case of iatrogenic transmission in this series were inadequately sterilised in formalin and were subsequently used in over 200 patients. The neurosurgical instruments used in the cases of presumed neurosurgical transmission were sterilised using autoclaving procedures which were inadequate according to current advice (Gajdusek et al., 1978). However, despite detailed investigation, no cases other than those described above are known to have developed C.J.D. Thus, despite the possible implantation of the agent directly into the central nervous system, a large number of patients failed to develop the disease. This provides circumstantial evidence of an inherited susceptibility to the agent and suggests that cases of iatrogenic transmission may have occurred due to the unfortunate temporal proximity of susceptible individuals exposed to the agent.
In the close geographic group of three cases possible nodes of transmission can be suggested, either iatrogenic or through dental procedures, but these must remain conjectural. It is known, however, that the similar scrapie agent can be transmitted from the gums of animals (Adams and Edgar, 1978). Such close spatial clustering of cases is extremely unusual, being previously reported in England (Matthews, 1975a), Czechoslovakia (Mayer et al., 1977) and Hungary (Majtenyi, 1978), but not detected in the study of the epidemiology of C.J.D. in urban Paris (Cathala et al., 1978) where the incidence was found to be relatively high.
The occurrence of the disease in a patient who had contact with cases of familial C.J.D., but was not genetically related, has been described in Chile (Galvez et al., 1980) and in France (Brown et al., 1979b). In Chile the patient was related by marriage, but with no consanguinity, and had social contact with subsequently affected family members for 13 years before developing the disease. The contact case in France also married into a family in which C.J.D. was prevalent and had close contact with an affected member. In neither instance did the spouse of the non-familial case have the disease. The case described in this report was similarly related to affected family members and social contact had occurred for 20 years prior to developing C.J.D. If contact transmission had occurred, the minimum transmission period would be 11 years. Contact between sporadic cases has not been described and it is remarkable that possible contact transmissions have all been with familial cases. No method of transmission by casual social contact has been suggested.
***The occurrence of contact cases raises the possibility that transmission in families may be effected by an unusually virulent strain of the agent.
snip...see full text here;
Sunday, October 27, 2013
A Kiss of a Prion: New Implications for Oral Transmissibility
MONDAY, NOVEMBER 19, 2018
Benefit cuts hit mad cow disease sufferer A girl born severely disabled from vCJD may lose her home under universal credit
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, OCTOBER 17, 2018
PRICE OF TSE PRION POKER GOES UP spectrum of human prion diseases may extend the current field and may notably include spinal cord diseases
MONDAY, NOVEMBER 26, 2018
The agent of chronic wasting disease from pigs is infectious in transgenic mice expressing human PRNP
JUST OUT CDC;
Tuesday, November 20, 2018
Eyes of CJD patients show evidence of prions Finding could help early diagnosis, raise concern for eye exams and transplants.
Singeltary 1999
***> THE EYES HAVE IT, CJD, AND THEY COULD BE STEALING THEM FROM YOUR LOVED ONE!...year 1999
i said that 20 years ago about this very thing. but did anyone listen...no!
prepare for the storm...terry
year 1999 to 2000
Subject: RE-The Eyes Have It (cjd) and they could be stealing them from your loved one... "pay back time"
Date: Sat, 16 Sep 2000 10:04:26 -0700
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy
To: BSE-L@uni-karlsruhe.de
######### Bovine Spongiform Encephalopathy #########
Greetings List Members,
I hate to keep kicking a madcow, but this still is very disturbing to me. Not only for the recipient of the cornea's, but as well, for the people whom would be operated on, using the same tools that were used to put those stolen cornea's in the recipient with. No history of this donor or his family (re-ffi), or anything would be known, using stolen organs and or tissue's. I just think this is not only wrong, but very dangerous to a great many other people, as this is one of the most infectious tissues of TSE's. It seems that this practice of stealing organ/tissue happens more than we think. Anyway, the family of the victim which had their cornea's stolen, are now suing. In the example I used with my Mother, if 3 months before, she would have been in a catastrophic accident (car wreck, whatever), no autopsy (for whatever reason), no family (for whatever reason), she lay in the morgue, and after 4 hours, they come steal the cornea's, lot of people could have been infected, just because of lack of medical history of donor/family. It may be hypothetical, but very real. We need to stop the spread of this disease.
kind regards, Terry S. Singeltary Sr., Bacliff, Texas USA
===========================================
Previous story--
Cadaver corneal transplants -- without family permission...
Cadaver corneal transplants -- without family permission Houston, Texas channel 11 news 28 Nov 99
Reported by Terry S. Singeltary Sr.son of CJD victim
"It was a story about how the Lions eye bank were harvesting corneas from victims in the Morgue, without their consent. Under Texas law, this appears to be legal (remember Texas has the Veggie liable law). Even if Family says no, this appears to happen, from what the news story said.
They said the only way to prevent this, is to fill out a form, stating not to have this done. So if you don't fill out the form, they can do this. How many people don't know about the form?
This is not only disgusting and appalling, it could be highly infectious. Without proper background checking of the donors, on their physical history, checking on past dementia, and/or family history, some of these unfortunate victims, could be passing a human TSE.
Response Jill Spitler Clevelland Eye Bank:
"No, we are not stealing.........Yes, you do have such a law in the state of Texas, but not all your state Eye Banks utilize the law. The Eye Bank that you're speaking of is only one of 43 certified Eye Bank throughout the USA.
And there are measure taken per the Medical Standards of the Eye Bank Association of America, the certifying body for eye banks and per FDA regulations to address those concerns that you speak of.
I would suggest that those interested/concern with transplant contact their local agencies. The Eye Bank Association of America has a web. site . Further if anyone has problems contacting or finding out about their local organization(s), call me or e-mail me I would be glad to help. My e-mail address is jill@clevelandeyebank.org"
Terry Singeltary responds:
"Explain this to the family in Houston who went to their loved ones funeral, only to find out that the loved one that was in the casket, had their corneas removed without their permission, without the consent of the victim or it's family. They would not have known it, only for the funny look the victim had. So, they questioned, only to find out, the corneas, had in fact, been removed without consent.
I call that stealing, regardless what the law states. This type of legal grave robbing is not a logical thing to do without knowing any type of background of the victims medical past, which really will not prove anything due to the incubation period. Eye tissue being potentially a highly infective source, there are risks here.
Should they not at least know of the potential ramifications of TSE's (the person receiving the corneas)?
Should there not be some sort of screening?
Should there be some sort of moral issue here?
If this is the case, and in fact, they can come take your corneas, without your consent, then what will they start taking next, without your consent?
Lets look at a hypothetical situation:
What would happen if my Mom (DOD 12-14-97 hvCJD) would have gotten into a car wreck and died, before the symptoms of CJD appeared. Not much money, so there was no autopsy. What would have happened to that recipient of those infecting corneas?"
Comment (webmaster): Actual transmission of CJD by means of corneal transplant may or may not be rare. The incidence of infectivity in older people could be fairly high; this is not to be confused with the lower incidence of symptomatic (clinical) CJD. It is very unlikely that familial CJD would have been diagnosed in earlier generations; however, without interviewing the family even known kindreds would not be excluded.
In blood donation, a much stricter policy is followed, even though corneal transplant may be far more dangerous (being a direct link to the brain and not going through purification steps).
Since highly sensitive tests for pre-clinical CJD are now available, it would make sense to screen corneas for CJD, just as they are screened for AIDS, hepatitus, and a host of other conditions.
Eye procedure raises CJD concerns
BySTEVE MITCHELL, Medical Correspondent
WASHINGTON, Nov. 18 (UPI) -- A New York man who died from a rare brain disorder similar to mad cow disease in May underwent an eye procedure prior to his death that raises concerns about the possibility of transmitting the fatal disease to others, United Press International has learned.
The development comes on the heels of the announcement Thursday by U.S. Department of Agriculture officials of a possible second case of mad cow disease in U.S. herds.
Richard Da Silva, 58, of Orange County, N.Y., died from Creutzfeldt Jakob disease, an incurable brain-wasting illness that strikes about one person per million.
Richard's wife Ann Marie Da Silva told UPI he underwent a check for the eye disease glaucoma in 2003, approximately a year before his death. The procedure involves the use of a tonometer, which contacts the cornea -- an eye tissue that can contain prions, the infectious agent thought to cause CJD.
Ann Marie's concern is that others who had the tonometer used on them could have gotten infected.
A 2003 study by British researchers suggests her concerns may be justified. A team led by J.W. Ironside from the National Creutzfeldt-Jakob Disease Surveillance Unit at the University of Edinburgh examined tonometer heads and found they can retain cornea tissue that could infect other people -- even after cleaning and decontaminating the instrument.
"Retained corneal epithelial cells, following the standard decontamination routine of tonometer prisms, may represent potential prion infectivity," the researchers wrote in the British Journal of Ophthalmology last year. "Once the infectious agent is on the cornea, it could theoretically infect the brain."
Prions, misfolded proteins thought to be the cause of mad cow, CJD and similar diseases, are notoriously difficult to destroy and are capable of withstanding most sterilization procedures.
Laura Manuelidis, an expert on these diseases and section chief of surgery in the neuropathology department at Yale University, agreed with the British researchers that tonometers represent a potential risk of passing CJD to other people.
Manuelidis told UPI she has been voicing her concern about the risks of corneas since 1977 when her own study, published in the New England Journal of Medicine, showed the eye tissue, if infected, could transmit CJD.
At the time the procedure was done on Richard Da Silva, about a year before he died, she said it was "absolutely" possible he was infectious.
The CJD Incidents Panel, a body of experts set up by the U.K. Department of Health, noted in a 2001 report that procedures involving the cornea are considered medium risk for transmitting CJD. The first two patients who have a contaminated eye instrument used on them have the highest risk of contracting the disease, the panel said.
In 1999, the U.K. Department of Health banned opticians from reusing equipment that came in contact with patients' eyes out of concern it could result in the transmission of variant CJD, the form of the disease humans can contract from consuming infected beef products.
Richard Da Silva was associated with a cluster of five other cases of CJD in southern New York that raised concerns about vCJD.
None of the cases have been determined to stem from mad cow disease, but concerns about the cattle illness in the United States could increase in light of the USDA announcement Thursday that a cow tested positive on initial tests for the disease. If confirmed, this would be the second U.S. case of the illness; the first was detected in a Washington cow last December. The USDA said the suspect animal disclosed Thursday did not enter the food chain. The USDA did not release further details about the cow, but said results from further lab tests to confirm the initial tests were expected within seven days.
Ann Marie Da Silva said she informed the New York Health Department and later the eye doctor who performed the procedure about her husband's illness and her concerns about the risk of transmitting CJD via the tonometer.
The optometrist -- whom she declined to name because she did not want to jeopardize his career -- "didn't even know what this disease was," she said.
"He said the health department never called him and I called them (the health department) back and they didn't seem concerned about it," she added. "I just kept getting angrier and angrier when I felt I was being dismissed."
She said the state health department "seems to have an attitude of don't ask, don't tell" about CJD.
"There's a stigma attached to it," she said. "Is it because they're so afraid the public will panic? I don't know, but I don't think that the answer is to push things under the rug."
New York State Department of Health spokeswoman Claire Pospisil told UPI she would look into whether the agency was concerned about the possibility of transmitting CJD via tonometers, but she had not called back prior to story publication.
Disposable tonometers are readily available and could avoid the risk of transmitting the disease, Ironside and colleagues noted in their study. Ann Marie Da Silva said she asked the optometrist whether he used disposable tonometers and "he said 'No, it's a reusable one.'"
Ironside's team also noted other ophthalmic instruments come into contact with the cornea and could represent a source of infection as they are either difficult to decontaminate or cannot withstand the harsh procedures necessary to inactivate prions. These include corneal burrs, diagnostic and therapeutic contact lenses and other coated lenses.
Terry Singletary, whose mother died from a type of CJD called Heidenhain Variant, told UPI health officials were not doing enough to prevent people from being infected by contaminated medical equipment.
"They've got to start taking this disease seriously and they simply aren't doing it," said Singletary, who is a member of CJD Watch and CJD Voice -- advocacy groups for CJD patients and their families.
U.S. Centers for Disease Control and Prevention spokeswoman Christine Pearson did not return a phone call from UPI seeking comment. The agency's Web site states the eye is one of three tissues, along with the brain and spinal cord, that are considered to have "high infectivity."
The Web site said more than 250 people worldwide have contracted CJD through contaminated surgical instruments and tissue transplants. This includes as many as four who were infected by corneal grafts. The agency noted no such cases have been reported since 1976, when sterilization procedures were instituted in healthcare facilities.
Ironside and colleagues noted in their study, however, many disinfection procedures used on optical instruments, such as tonometers, fail. They wrote their finding of cornea tissue on tonometers indicates that "no current cleaning and disinfection strategy is fully effective."
Singletary said CDC's assertion that no CJD cases from infected equipment or tissues have been detected since 1976 is misleading.
"They have absolutely no idea" whether any cases have occurred in this manner, he said, because CJD cases often aren't investigated and the agency has not required physicians nationwide report all cases of CJD.
"There's no national surveillance unit for CJD in the United States; people are dying who aren't autopsied, the CDC has no way of knowing" whether people have been infected via infected equipment or tissues, he said.
Ann Marie Da Silva said she has contacted several members of her state's congressional delegation about her concerns, including Rep. Sue Kelly, R-N.Y., and Sen. Charles Schumer, D-N.Y.
"Basically, what I want is to be a positive force in this, but I also want more of a dialogue going on with the public and the health department," she said.
Friday, December 04, 2009
New guidance on decontamination of trial contact lenses and other contact devices has been revealed for CJD AND vCJD
SUNDAY, JANUARY 17, 2016
Of Grave Concern Heidenhain Variant Creutzfeldt Jakob Disease
TUESDAY, NOVEMBER 20, 2018
CDC Eyes of CJD patients show evidence of prions concerns for iatrogenic transmission
MONDAY, NOVEMBER 26, 2018
Woman dies from rare dementia contracted from baby while pregnant?
WITH the recent findings that Scrapie will transmit to Macaque by oral 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.
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
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...
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.
==============
***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.
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.
why do we not want to do TSE transmission studies on chimpanzees $
5. A positive result from a chimpanzee challenged severly would likely create alarm in some circles even if the result could not be interpreted for man.
***> I have a view that all these agents could be transmitted provided a large enough dose by appropriate routes was given and the animals kept long enough.
***> Until the mechanisms of the species barrier are more clearly understood it might be best to retain that hypothesis.
snip...
R. BRADLEY
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.
***> 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;
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.
snip...
***> The successful transmission of kuru, Creutzfeldt-Jakob disease, and scrapie by natural feeding to squirrel monkeys that we have reported provides further grounds for concern that scrapie-infected meat may occasionally give rise in humans to Creutzfeldt-Jakob disease.
PMID: 6997404
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
12/10/76
AGRICULTURAL RESEARCH COUNCIL REPORT OF THE ADVISORY COMMITTE ON SCRAPIE
Office Note CHAIRMAN: PROFESSOR PETER WILDY
snip...
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 emphasized 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 Scrapie problem urgent if the sheep industry is not to suffer grievously.
snip... 76/10.12/4.6
Nature. 1972 Mar 10;236(5341):73-4.
Transmission of scrapie to the cynomolgus monkey (Macaca fascicularis).
Gibbs CJ Jr, Gajdusek DC. Nature 236, 73 - 74 (10 March 1972); doi:10.1038/236073a0
Transmission of Scrapie to the Cynomolgus Monkey (Macaca fascicularis)
C. J. GIBBS jun. & D. C. GAJDUSEK National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland
SCRAPIE has been transmitted to the cynomolgus, or crab-eating, monkey (Macaca fascicularis) with an incubation period of more than 5 yr from the time of intracerebral inoculation of scrapie-infected mouse brain. The animal developed a chronic central nervous system degeneration, with ataxia, tremor and myoclonus with associated severe scrapie-like pathology of intensive astroglial hypertrophy and proliferation, neuronal vacuolation and status spongiosus of grey matter. The strain of scrapie virus used was the eighth passage in Swiss mice (NIH) of a Compton strain of scrapie obtained as ninth intracerebral passage of the agent in goat brain, from Dr R. L. Chandler (ARC, Compton, Berkshire).
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).
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
why do we not want to do TSE transmission studies on chimpanzees $
5. A positive result from a chimpanzee challenged severly would likely create alarm in some circles even if the result could not be interpreted for man.
***> I have a view that all these agents could be transmitted provided a large enough dose by appropriate routes was given and the animals kept long enough. Until the mechanisms of the species barrier are more clearly understood it might be best to retain that hypothesis.
snip...
R. BRADLEY
Wednesday, February 16, 2011
IN CONFIDENCE SCRAPIE TRANSMISSION TO CHIMPANZEES IN CONFIDENCE
2018
***> 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
Summary
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.
***>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
THURSDAY, OCTOBER 04, 2018
Cervid to human prion transmission 5R01NS088604-04 Update
SATURDAY, NOVEMBER 10, 2018
cwd, bse, scrapie, cjd, tse prion updated November 10 2018
THURSDAY, OCTOBER 25, 2018
***> Norway New additional requirements for imports of hay and straw for animal feed from countries outside the EEA due to CWD TSE Prion
JUST OUT CDC;
Tuesday, November 20, 2018
Eyes of CJD patients show evidence of prions Finding could help early diagnosis, raise concern for eye exams and transplants.
Singeltary 1999
***> THE EYES HAVE IT, CJD, AND THEY COULD BE STEALING THEM FROM YOUR LOVED ONE!...year 1999
i said that 20 years ago about this very thing. but did anyone listen...no!
prepare for the storm...terry
year 1999 to 2000
Subject: RE-The Eyes Have It (cjd) and they could be stealing them from your loved one... "pay back time"
Date: Sat, 16 Sep 2000 10:04:26 -0700
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy
To: BSE-L@uni-karlsruhe.de
######### Bovine Spongiform Encephalopathy #########
Greetings List Members,
I hate to keep kicking a madcow, but this still is very disturbing to me. Not only for the recipient of the cornea's, but as well, for the people whom would be operated on, using the same tools that were used to put those stolen cornea's in the recipient with. No history of this donor or his family (re-ffi), or anything would be known, using stolen organs and or tissue's. I just think this is not only wrong, but very dangerous to a great many other people, as this is one of the most infectious tissues of TSE's. It seems that this practice of stealing organ/tissue happens more than we think. Anyway, the family of the victim which had their cornea's stolen, are now suing. In the example I used with my Mother, if 3 months before, she would have been in a catastrophic accident (car wreck, whatever), no autopsy (for whatever reason), no family (for whatever reason), she lay in the morgue, and after 4 hours, they come steal the cornea's, lot of people could have been infected, just because of lack of medical history of donor/family. It may be hypothetical, but very real. We need to stop the spread of this disease.
kind regards, Terry S. Singeltary Sr., Bacliff, Texas USA
===========================================
Previous story--
Cadaver corneal transplants -- without family permission...
Cadaver corneal transplants -- without family permission Houston, Texas channel 11 news 28 Nov 99
Reported by Terry S. Singeltary Sr.son of CJD victim
"It was a story about how the Lions eye bank were harvesting corneas from victims in the Morgue, without their consent. Under Texas law, this appears to be legal (remember Texas has the Veggie liable law). Even if Family says no, this appears to happen, from what the news story said.
They said the only way to prevent this, is to fill out a form, stating not to have this done. So if you don't fill out the form, they can do this. How many people don't know about the form?
This is not only disgusting and appalling, it could be highly infectious. Without proper background checking of the donors, on their physical history, checking on past dementia, and/or family history, some of these unfortunate victims, could be passing a human TSE.
Response Jill Spitler Clevelland Eye Bank:
"No, we are not stealing.........Yes, you do have such a law in the state of Texas, but not all your state Eye Banks utilize the law. The Eye Bank that you're speaking of is only one of 43 certified Eye Bank throughout the USA.
And there are measure taken per the Medical Standards of the Eye Bank Association of America, the certifying body for eye banks and per FDA regulations to address those concerns that you speak of.
I would suggest that those interested/concern with transplant contact their local agencies. The Eye Bank Association of America has a web. site . Further if anyone has problems contacting or finding out about their local organization(s), call me or e-mail me I would be glad to help. My e-mail address is jill@clevelandeyebank.org"
Terry Singeltary responds:
"Explain this to the family in Houston who went to their loved ones funeral, only to find out that the loved one that was in the casket, had their corneas removed without their permission, without the consent of the victim or it's family. They would not have known it, only for the funny look the victim had. So, they questioned, only to find out, the corneas, had in fact, been removed without consent.
I call that stealing, regardless what the law states. This type of legal grave robbing is not a logical thing to do without knowing any type of background of the victims medical past, which really will not prove anything due to the incubation period. Eye tissue being potentially a highly infective source, there are risks here.
Should they not at least know of the potential ramifications of TSE's (the person receiving the corneas)?
Should there not be some sort of screening?
Should there be some sort of moral issue here?
If this is the case, and in fact, they can come take your corneas, without your consent, then what will they start taking next, without your consent?
Lets look at a hypothetical situation:
What would happen if my Mom (DOD 12-14-97 hvCJD) would have gotten into a car wreck and died, before the symptoms of CJD appeared. Not much money, so there was no autopsy. What would have happened to that recipient of those infecting corneas?"
Comment (webmaster): Actual transmission of CJD by means of corneal transplant may or may not be rare. The incidence of infectivity in older people could be fairly high; this is not to be confused with the lower incidence of symptomatic (clinical) CJD. It is very unlikely that familial CJD would have been diagnosed in earlier generations; however, without interviewing the family even known kindreds would not be excluded.
In blood donation, a much stricter policy is followed, even though corneal transplant may be far more dangerous (being a direct link to the brain and not going through purification steps).
Since highly sensitive tests for pre-clinical CJD are now available, it would make sense to screen corneas for CJD, just as they are screened for AIDS, hepatitus, and a host of other conditions.
Eye procedure raises CJD concerns
BySTEVE MITCHELL, Medical Correspondent
WASHINGTON, Nov. 18 (UPI) -- A New York man who died from a rare brain disorder similar to mad cow disease in May underwent an eye procedure prior to his death that raises concerns about the possibility of transmitting the fatal disease to others, United Press International has learned.
The development comes on the heels of the announcement Thursday by U.S. Department of Agriculture officials of a possible second case of mad cow disease in U.S. herds.
Richard Da Silva, 58, of Orange County, N.Y., died from Creutzfeldt Jakob disease, an incurable brain-wasting illness that strikes about one person per million.
Richard's wife Ann Marie Da Silva told UPI he underwent a check for the eye disease glaucoma in 2003, approximately a year before his death. The procedure involves the use of a tonometer, which contacts the cornea -- an eye tissue that can contain prions, the infectious agent thought to cause CJD.
Ann Marie's concern is that others who had the tonometer used on them could have gotten infected.
A 2003 study by British researchers suggests her concerns may be justified. A team led by J.W. Ironside from the National Creutzfeldt-Jakob Disease Surveillance Unit at the University of Edinburgh examined tonometer heads and found they can retain cornea tissue that could infect other people -- even after cleaning and decontaminating the instrument.
"Retained corneal epithelial cells, following the standard decontamination routine of tonometer prisms, may represent potential prion infectivity," the researchers wrote in the British Journal of Ophthalmology last year. "Once the infectious agent is on the cornea, it could theoretically infect the brain."
Prions, misfolded proteins thought to be the cause of mad cow, CJD and similar diseases, are notoriously difficult to destroy and are capable of withstanding most sterilization procedures.
Laura Manuelidis, an expert on these diseases and section chief of surgery in the neuropathology department at Yale University, agreed with the British researchers that tonometers represent a potential risk of passing CJD to other people.
Manuelidis told UPI she has been voicing her concern about the risks of corneas since 1977 when her own study, published in the New England Journal of Medicine, showed the eye tissue, if infected, could transmit CJD.
At the time the procedure was done on Richard Da Silva, about a year before he died, she said it was "absolutely" possible he was infectious.
The CJD Incidents Panel, a body of experts set up by the U.K. Department of Health, noted in a 2001 report that procedures involving the cornea are considered medium risk for transmitting CJD. The first two patients who have a contaminated eye instrument used on them have the highest risk of contracting the disease, the panel said.
In 1999, the U.K. Department of Health banned opticians from reusing equipment that came in contact with patients' eyes out of concern it could result in the transmission of variant CJD, the form of the disease humans can contract from consuming infected beef products.
Richard Da Silva was associated with a cluster of five other cases of CJD in southern New York that raised concerns about vCJD.
None of the cases have been determined to stem from mad cow disease, but concerns about the cattle illness in the United States could increase in light of the USDA announcement Thursday that a cow tested positive on initial tests for the disease. If confirmed, this would be the second U.S. case of the illness; the first was detected in a Washington cow last December. The USDA said the suspect animal disclosed Thursday did not enter the food chain. The USDA did not release further details about the cow, but said results from further lab tests to confirm the initial tests were expected within seven days.
Ann Marie Da Silva said she informed the New York Health Department and later the eye doctor who performed the procedure about her husband's illness and her concerns about the risk of transmitting CJD via the tonometer.
The optometrist -- whom she declined to name because she did not want to jeopardize his career -- "didn't even know what this disease was," she said.
"He said the health department never called him and I called them (the health department) back and they didn't seem concerned about it," she added. "I just kept getting angrier and angrier when I felt I was being dismissed."
She said the state health department "seems to have an attitude of don't ask, don't tell" about CJD.
"There's a stigma attached to it," she said. "Is it because they're so afraid the public will panic? I don't know, but I don't think that the answer is to push things under the rug."
New York State Department of Health spokeswoman Claire Pospisil told UPI she would look into whether the agency was concerned about the possibility of transmitting CJD via tonometers, but she had not called back prior to story publication.
Disposable tonometers are readily available and could avoid the risk of transmitting the disease, Ironside and colleagues noted in their study. Ann Marie Da Silva said she asked the optometrist whether he used disposable tonometers and "he said 'No, it's a reusable one.'"
Ironside's team also noted other ophthalmic instruments come into contact with the cornea and could represent a source of infection as they are either difficult to decontaminate or cannot withstand the harsh procedures necessary to inactivate prions. These include corneal burrs, diagnostic and therapeutic contact lenses and other coated lenses.
Terry Singletary, whose mother died from a type of CJD called Heidenhain Variant, told UPI health officials were not doing enough to prevent people from being infected by contaminated medical equipment.
"They've got to start taking this disease seriously and they simply aren't doing it," said Singletary, who is a member of CJD Watch and CJD Voice -- advocacy groups for CJD patients and their families.
U.S. Centers for Disease Control and Prevention spokeswoman Christine Pearson did not return a phone call from UPI seeking comment. The agency's Web site states the eye is one of three tissues, along with the brain and spinal cord, that are considered to have "high infectivity."
The Web site said more than 250 people worldwide have contracted CJD through contaminated surgical instruments and tissue transplants. This includes as many as four who were infected by corneal grafts. The agency noted no such cases have been reported since 1976, when sterilization procedures were instituted in healthcare facilities.
Ironside and colleagues noted in their study, however, many disinfection procedures used on optical instruments, such as tonometers, fail. They wrote their finding of cornea tissue on tonometers indicates that "no current cleaning and disinfection strategy is fully effective."
Singletary said CDC's assertion that no CJD cases from infected equipment or tissues have been detected since 1976 is misleading.
"They have absolutely no idea" whether any cases have occurred in this manner, he said, because CJD cases often aren't investigated and the agency has not required physicians nationwide report all cases of CJD.
"There's no national surveillance unit for CJD in the United States; people are dying who aren't autopsied, the CDC has no way of knowing" whether people have been infected via infected equipment or tissues, he said.
Ann Marie Da Silva said she has contacted several members of her state's congressional delegation about her concerns, including Rep. Sue Kelly, R-N.Y., and Sen. Charles Schumer, D-N.Y.
"Basically, what I want is to be a positive force in this, but I also want more of a dialogue going on with the public and the health department," she said.
Friday, December 04, 2009
New guidance on decontamination of trial contact lenses and other contact devices has been revealed for CJD AND vCJD
SUNDAY, JANUARY 17, 2016
Of Grave Concern Heidenhain Variant Creutzfeldt Jakob Disease
TUESDAY, NOVEMBER 20, 2018
CDC Eyes of CJD patients show evidence of prions concerns for iatrogenic transmission
MONDAY, NOVEMBER 19, 2018
Benefit cuts hit mad cow disease sufferer A girl born severely disabled from vCJD may lose her home under universal credit
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..” ............................
why do we not want to do TSE transmission studies on chimpanzees $
5. A positive result from a chimpanzee challenged severly would likely create alarm in some circles even if the result could not be interpreted for man.
***> I have a view that all these agents could be transmitted provided a large enough dose by appropriate routes was given and the animals kept long enough.
***> Until the mechanisms of the species barrier are more clearly understood it might be best to retain that hypothesis.
snip...
R. BRADLEY
Terry S. Singeltary Sr.