P177 PrP plaques in methionine homozygous Creutzfeldt-Jakob disease patients as a potential marker of iatrogenic transmission
Abrams JY (1), Schonberger LB (1), Cali I (2), Cohen Y (2), Blevins JE (2), Maddox RA (1), Belay ED (1), Appleby BS (2), Cohen ML (2) (1) Centers for Disease Control and Prevention (CDC), National Center for Emerging and Zoonotic Infectious Diseases, Atlanta, GA, USA (2) Case Western Reserve University, National Prion Disease Pathology Surveillance Center (NPDPSC), Cleveland, OH, USA.
Background Sporadic Creutzfeldt-Jakob disease (CJD) is widely believed to originate from de novo spontaneous conversion of normal prion protein (PrP) to its pathogenic form, but concern remains that some reported sporadic CJD cases may actually be caused by disease transmission via iatrogenic processes. For cases with methionine homozygosity (CJD-MM) at codon 129 of the PRNP gene, recent research has pointed to plaque-like PrP deposition as a potential marker of iatrogenic transmission for a subset of cases. This phenotype is theorized to originate from specific iatrogenic source CJD types that comprise roughly a quarter of known CJD cases.
Methods We reviewed scientific literature for studies which described PrP plaques among CJD patients with known epidemiological links to iatrogenic transmission (receipt of cadaveric human grown hormone or dura mater), as well as in cases of reported sporadic CJD. The presence and description of plaques, along with CJD classification type and other contextual factors, were used to summarize the current evidence regarding plaques as a potential marker of iatrogenic transmission. In addition, 523 cases of reported sporadic CJD cases in the US from January 2013 through September 2017 were assessed for presence of PrP plaques.
Results We identified four studies describing 52 total cases of CJD-MM among either dura mater recipients or growth hormone recipients, of which 30 were identified as having PrP plaques. While sporadic cases were not generally described as having plaques, we did identify case reports which described plaques among sporadic MM2 cases as well as case reports of plaques exclusively in white matter among sporadic MM1 cases. Among the 523 reported sporadic CJD cases, 0 of 366 MM1 cases had plaques, 2 of 48 MM2 cases had kuru plaques, and 4 of 109 MM1+2 cases had either kuru plaques or both kuru and florid plaques. Medical chart review of the six reported sporadic CJD cases with plaques did not reveal clinical histories suggestive of potential iatrogenic transmission.
Conclusions PrP plaques occur much more frequently for iatrogenic CJD-MM cases compared to sporadic CJD-MM cases. Plaques may indicate iatrogenic transmission for CJD-MM cases without a type 2 Western blot fragment. The study results suggest the absence of significant misclassifications of iatrogenic CJD as sporadic. To our knowledge, this study is the first to describe grey matter kuru plaques in apparently sporadic CJD-MM patients with a type 2 Western blot fragment.
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P186 Sporadic Creutzfeldt-Jakob Disease in a Woman Married into a GerstmannSträussler-Scheinker Family: An Investigation of Prions’ Transmission via Microchimerism
Areskeviciute A (1), Melchior LC(1), Broholm H(1), Krarup LH(2), Lindquist SG(3,4), Johansen P(4), Mckenzie N(5), Green A(5), Nielsen JE (3), Laursen H(1), Loebner EL(1)
(1) Department of Pathology, Copenhagen University Hospital - Rigshospitalet, Denmark. (2) Department of Neurology, Copenhagen University Hospital - Rigshospitalet, Denmark. (3) Danish Dementia Research Centre, Copenhagen University Hospital - Rigshospitalet, Denmark. (4) Department of Clinical Genetics, Copenhagen University Hospital - Rigshospitalet, Denmark. (5) National CJD Research and Surveillance Unit, the University of Edinburgh, United Kingdom.
This is the first report of presumed sporadic Creutzfeldt-Jakob disease (sCJD) and GerstmannSträussler-Scheinker disease (GSS) with the prion protein gene (PRNP) c.305C>T mutation (p.P102L) occurring in one family, which had the father and son with GSS and the mother with 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 cooccurrence 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 conclude whether maternal CJD triggered via microchimerism by a GSS fetus might present a new PrPSc transmission route.
This research has been accepted for publication in the Journal of Neuropathology and Experimental Neurology,published by Oxford University Press.
Source Prion Conference 2018 Abstracts
PLEASE NOTE! I remember back in the early days of BSE Inquiry;
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.
***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;
http://web.archive.org/web/20050425210551/http://www.bseinquiry.gov.uk/files/mb/m26/tab01.pdf
http://transmissiblespongiformencephalopathy.blogspot.com/2014/01/vpspr-sgss-sffi-tse-iatrogenic-by.html
Journal of the Neurological Sciences, 1983, 59:139-147 139
Elsevier Biomedical Press
FAMILIAL CREUTZFELDT-JAKOB DISEASE IN CHILE
SERGIO G,~.LVEZ j, LUIS CARTIER 2, MILENA MONARI l and GONZALO ARAYA 3 llnstituto de Neurocirugia e lnvestigaeiones Cerebrales, Santiago de Chile, 2Departmento de Neuropatologia del Servicio de Neurologia, Hospital Salvador, Santiago de Chile and 3Hospital Herminda Martin, Chill(m (Chile)
(Received 13 July, 1982)
(Revised, received 28 October, 1982)
(Accepted 3 November, 1982)
SUMMARY
Of the 87 cases of Creutzfeldt-Jakob disease (CJD) ascertained in Chile since 1931, 39 are familial accounting for 45% of all cases, and 25% of the 51 definite cases. There are 11 affected families with an average of 3.5 affected members per family, and a rate of occurrence consistent with autosomal dominant transmission. There is no evidence for maternal lineage, and age at death is not significantly different from that of sporadic cases. About half of the cases died around the same age, suggesting some form of vertical transmission. Three pairs of affected members in 3 different families died at the same time, possibly indicating common exposure to CJD agent. The study of absolute death intervals and temporal and spatial separations between affected members suggests minimum incubation periods ranging from 2 to 37 years, assuming case-to-case transmission. CJD occurring in a woman related by marriage to one of the affected families strongly argues for horizontal transmission. The high proportion of familial CJD observed in Chile is probably the result of both a genetically determined susceptibility to the CJD virus, and a high degree of case ascertainment. However, the present study leaves unanswered the mode of transmission of the agent within the affected families.
snip...
In contrast, in the group of 38 definite sporadic CJD the past medical and surgical histories were ascertained in 30 cases. In 10 patients a surgical procedure had been performed between 20 years and few days before the onset of CJD, in one instance cataract operation. Of particular interest is 1 patient in whom an herniated lumbar disc was removed 18 years before developing mental deterioration, visual hallucinations and neurological signs. The operation was done in the same surgical room where few months before a brain biopsy had been obtained from a definite sporadic CJD. Significant past medical illnesses were diabetes mellitus and arterial hypertension (6 cases), chronic alcoholism (5 cases), pulmonary tuberculosis (3 cases), acute head injury (3 cases), syphilis (1 case), and chronic osteomyelitis (1 case). In 2 patients the onset of CJD was coincident with propylthiouracil therapy and roentgentherapy for cervical spondylosis, respectively. In another patient CJD developed following an uncomplicated acute head injury. Three patients used to eat uncooked sheep blood and sheep brain, and 1 of them worked 18 years transporting, sheep between Chile and Argentina. As in the group of familial CJD, health-related professions were not reported. The clinical and neuropathological characteristics of our familial CJD were not substantially different from those of the sporadic cases.
Most cases in the present series occurred within a single generation (4 families) or in one generation above that of the propositus (6 families). Only 1 family showed affected members in 3 successive generations. The proportional incidence or "rate of occurrence" calculated on the bases of the number of affected and nonaffected siblings and cousins aged 40 years or more within any generation was 58%, consistent with a pattern of autosomal dominant transmission. In our 11 families there were 5 affected fathers and 2 affected mothers of affected children. In the group of 7 families showing affected members in 2 or 3 succeeding generations a tendency for anticipation was observed, since there were 10 instances where the age at death of the offspring was equal or less than the parental age at death. In only 3 cases did the offspring's age at death exceed that of the respective parent. The restriction of cases to a single generation in 4 of the affected families, and the observation of 1 instance of skipped generation in family ECoM (Fig. 1) is difficult to interpret, although it may be attributed to insufficient information on the cause of death of apparently unaffected family members.
If person-to-person transmission of the CJD virus is assumed to occur within the affected families, the temporal and geographic separations between the affected members prior to the clinical onset might provide an important clue to the length of the minimum incubation period (Haltia et al. 1979; Masters et al. 1981). In our 11 families with CJD there are only 2 with a clear-cut history of temporal and spatial separation between the affected members. In family AAnC originated in Los Angeles, Chile (Galvez and Cartier 1979), 3 members were affected in 2 successive generations (Fig. 2). The propositus (111-3) was a woman who died in 1979 at 49 years of age. She had left home 21 years before onset of CJD and subsequently had no close physical contact with her relatives living in Los Angeles. The clinical onset of illness in II-10 and 111-3 occurred at the same time and at ages 40 and 49, respectively. This argues for a common exposure to a source of CJD agent 21 years before the clinical onset, and against some form of vertical transmission from the affected father 11-4 who died at the age of 61 years of possible CJD of 2 years duration. Another instance of simultaneous occurrence of CJD was observed in family AGoA, where a pair of cousins developed CJD at ages 57 and 63, respectively (Fig. 3). In the above generation an additional pair of siblings had already died of CJD 13 and 5 years before, at ages 55 and 73, respectively. These first affected siblings could be the source of infection of the last affected cousins, and since no physical contact existed between both pairs of affected family members for 5 years prior to onset, a minimum incubation period of 5 years can be postulated. In family FLaL, affected in a single generation, the mechanism involved in the occurrence of CJD is difficult to evaluate, since the 2 affected sisters died at the same time and about the same age, after living all the time in close physical relationship.
The rare occurrence of conjugal CJD (Jellinger et al. 1972) is not observed in the present series. However, a woman related by marriage to family ECoM developed CJD 13 years later, strongly suggesting horizontal transmission.
Within our 11 families with CJD 4 pairs of affected parent and affected first child with known death intervals were ascertained. The mean death interval was 14.5 years, with a range of 5-37 years. Thus, minimum incubation periods of between 5 and 37 years are determined if person-to-person transmission were occurring within the affected families. If the intervals between the death of sibling pairs are considered, a mean of 9.3 years, with a range of 2-23 years is obtained. In the total of 11 affected pairs of siblings with known age at the time of death, the mean difference in age at death was 8 years, with a range of 0-21 years. About half of the total affected siblings tended to die at the same age and only 2 pairs of siblings died at the same time.
snip...
DISCUSSION
The unusually high proportion of familial CJD determined in Chile largely exceeds that found in the worldwide survey (Masters et al. 1981) and is only comparable with the familial clustering of CJD observed among Israeli Libyan Jews (Neugut et al. 1979). This may be related either to a genetic: mechanism or to the better degree of case ascertainment and diagnosis in a relatively isolated geographic area with a small and well-defined population. The recent detection of a second affected branch in family AGoA, originally identified in 1977 (Fig. 3), and the discovery of 2 recently affected brothers of a woman with a definite "sporadic" CJD diagnosed in 1974 (Fig. 4) are consistent with a high level of cases ascertainment. In spite of the fact that there is no evidence for vertical transmission of naturally occurring kuru (Gajdusek 1977) and that vertical transmission of experimental kuru, CJD and scrapie has not been observed (Amyx et al. 1981), extensive epidemiological data on familial CJD suggest underlying genetic mechanisms involved in the familial occurrence of the illness. Since vertical transmission seems remote, an inherited susceptibility to the causative agent has boen postulated. Such a genetic control over expression of disease has been conclusively demonstrated in natural and experimental scrapie (Dickinson and Fraser 1979), and might also operate in familial CJD, where genetically susceptible individuals would be infected early in life either from an affected relative or from other natural source of CJD agent.
In the present series the occurrence of familial CJD suggesting an autosomal dominant transmission, and the absence of maternal lineage which excludes maternal vertical passage and transplacental or breast milk routes of infection agree with similar findings reported elsewhere (Haltia et al. 1979; Cathala et al. 1980; Masters et al. 1981). The average age at death (54.45 years) and minimum incubation periods ranging from 2 to 37 years are also closely similar to the corresponding figures of Masters' worldwide survey. However, the lack of statistical differences between age at death of familial and sporadic CJD, and the female preponderance observed in our 11 families are discrepant findings.
Although in 3 pairs of affected members from different families the clinical onset of CJD occurred at the same time, thus suggesting common exposure to a source of infection, the study of available occupational and past medical and surgical histories of our familial CJD patients has so far been unsuccessful in distinguishing some environmental causative factor. By contrast, in the group of patients with sporadic CJD the increase of previous surgical procedures, including 1 neurosurgical operation performed in a surgical room where a CJD patient had had surgery, and 1 instance of ocular surgery, points to the possible iatrogenic acquisition of illness. In regard to other possible risk factors presumptively involved in the pathogenesis of CJD, the questionable zoonotic origin from scrapie virus has no reasonable support in the present series.
The results of this study indicate that it is likely, but impossible to state with certainty, that the familial occurrence of CJD is of genetic origin. The documentation of CJD in a woman related by marriage to 1 of our affected families and other similarly related cases occurred in France (Brown et al. 1979) and in Great Britain (Will and Matthews 1982) are strong evidence for lateral transmission resulting from the high intrafamilial concentration of cases or from an unusually virulent virus strain.
FRIDAY, JANUARY 10, 2014
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???
Greetings Friends, Neighbors, and Colleagues,
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???
Confucius is confused again.
I was just sitting and thinking about why there is no genetic link to some of these TSE prion sGSS, sFFi, and it’s really been working on my brain, and then it hit me today.
what if, vpspr, sgss, sffi, TSE prion disease, was a by-product from iatrogenic gss, ffi, familial type prion disease ???
it could explain the cases of no genetic link to the gss, ffi, familial type prion disease, to the family.
sporadic and familial is a red herring, in my opinion, and underestimation is spot on, due to the crude prehistoric diagnostic procedures and criteria and definition of a prion disease.
I say again, what if, iatrogenic, what if, with all these neurological disorders, with a common denominator that is increasingly showing up in the picture, called the prion.
I urge all scientist to come together here, with this as the utmost of importance about all these neurological disease that are increasingly showing up as a prion mechanism, to put on the front burners, the IATROGENIC aspect and the potential of transmission there from, with diseases/disease??? in question, by definition, could they be a Transmissible Spongiform Encephalopathy TSE prion type disease, and if so, what are the iatrogenic chances of transmission?
this is very important, and should be at the forefront of research, and if proven, could be a monumental breakthrough in science and battle against the spreading of these disease/diseases.
http://transmissiblespongiformencephalopathy.blogspot.com/2014/01/vpspr-sgss-sffi-tse-iatrogenic-by.html
sporadic CJD, along with new TSE prion disease in humans, of which the young are dying, of which long duration of illness from onset of symptoms to death have been documented, only to have a new name added to the pot of prion disease i.e. sporadic GSS, sporadic FFI, and or VPSPR. I only ponder how a familial type disease could be sporadic with no genetic link to any family member? when the USA is the only documented Country in the world to have documented two different cases of atypical H-type BSE, with one case being called atypical H-G BSE with the G meaning Genetic, with new science now showing that indeed atypical H-type BSE is very possible transmitted to cattle via oral transmission (Prion2014). sporadic CJD and VPSPR have been rising in Canada, USA, and the UK, with the same old excuse, better surveillance. You can only use that excuse for so many years, for so many decades, until one must conclude that CJD TSE prion cases are rising. a 48% incease in CJD in Canada is not just a blip or a reason of better surveillance, it is a mathematical rise in numbers. More and more we are seeing more humans exposed in various circumstance in the Hospital, Medical, Surgical arenas to the TSE Prion disease, and at the same time in North America, more and more humans are becoming exposed to the TSE prion disease via consumption of the TSE prion via deer and elk, cattle, sheep and goats, and for those that are exposed via or consumption, go on to further expose many others via the iatrogenic modes of transmission of the TSE prion disease i.e. friendly fire. I pondered this mode of transmission via the victims of sporadic FFI, sporadic GSS, could this be a iatrogenic event from someone sub-clinical with sFFI or sGSS ? what if?
http://vpspr.blogspot.com/2014/11/transmission-characteristics-of.html
http://vpspr.blogspot.com/
8. Even though human TSE‐exposure risk through consumption of game from European cervids can be assumed to be minor, if at all existing, no final conclusion can be drawn due to the overall lack of scientific data.
***> In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison.
The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids. It might be prudent considering appropriate measures to reduce such a risk, e.g. excluding tissues such as CNS and lymphoid tissues from the human food chain, which would greatly reduce any potential risk for consumers.. However, it is stressed that currently, no data regarding a risk of TSE infections from cervid products are available.
snip...
The tissue distribution of infectivity in CWD‐infected cervids is now known to extend beyond CNS and lymphoid tissues. While the removal of these specific tissues from the food chain would reduce human dietary exposure to infectivity, exclusion from the food chain of the whole carcass of any infected animal would be required to eliminate human dietary exposure.
https://efsa.onlinelibrary.wiley.com/doi/full/10.2903/j.efsa.2018.5132
end…TSS
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Monday, January 29, 2024
iatrogenic Alzheimer’s disease, Alzheimer’s disease should now be recognized as a potentially transmissible disorder
''The clinical syndrome developed by these individuals can, therefore, be termed iatrogenic Alzheimer’s disease, and Alzheimer’s disease should now be recognized as a potentially transmissible disorder.''
Published: 29 January 2024
Iatrogenic Alzheimer’s disease in recipients of cadaveric pituitary-derived growth hormone
Gargi Banerjee, Simon F. Farmer, Harpreet Hyare, Zane Jaunmuktane, Simon Mead, Natalie S. Ryan, Jonathan M. Schott, David J. Werring, Peter Rudge & John Collinge Nature Medicine (2024)Cite this article
Abstract
Alzheimer’s disease (AD) is characterized pathologically by amyloid-beta (Aβ) deposition in brain parenchyma and blood vessels (as cerebral amyloid angiopathy (CAA)) and by neurofibrillary tangles of hyperphosphorylated tau. Compelling genetic and biomarker evidence supports Aβ as the root cause of AD. We previously reported human transmission of Aβ pathology and CAA in relatively young adults who had died of iatrogenic Creutzfeldt–Jakob disease (iCJD) after childhood treatment with cadaver-derived pituitary growth hormone (c-hGH) contaminated with both CJD prions and Aβ seeds. This raised the possibility that c-hGH recipients who did not die from iCJD may eventually develop AD. Here we describe recipients who developed dementia and biomarker changes within the phenotypic spectrum of AD, suggesting that AD, like CJD, has environmentally acquired (iatrogenic) forms as well as late-onset sporadic and early-onset inherited forms. Although iatrogenic AD may be rare, and there is no suggestion that Aβ can be transmitted between individuals in activities of daily life, its recognition emphasizes the need to review measures to prevent accidental transmissions via other medical and surgical procedures. As propagating Aβ assemblies may exhibit structural diversity akin to conventional prions, it is possible that therapeutic strategies targeting disease-related assemblies may lead to selection of minor components and development of resistance.
Snip…see full text;
https://www.nature.com/articles/s41591-023-02729-2
https://www.nature.com/articles/s41591-023-02729-2.pdf
Alzheimer’s disease acquired from historic medical treatments 30 January 2024
Five cases of Alzheimer’s disease are believed to have arisen as a result of medical treatments decades earlier, reports a team of UCL and UCLH researchers.
Alzheimer’s disease is caused by the amyloid-beta protein, and is usually a sporadic condition of late adult life, or more rarely an inherited condition that occurs due to a faulty gene. The new Nature Medicine paper provides the first evidence of Alzheimer’s disease in living people that appears to have been medically acquired and due to transmission of the amyloid-beta protein.
The people described in the paper had all been treated as children with a type of human growth hormone extracted from pituitary glands from deceased individuals (cadaver-derived human growth hormone or c-hGH). This was used to treat at least 1,848 people in the UK between 1959 and 1985, and used for various causes of short stature. It was withdrawn in 1985 after it was recognised that some c-hGH batches were contaminated with prions (infectious proteins) which had caused Creutzfeldt-Jakob disease (CJD) in some people. c-hGH was then replaced with synthetic growth hormone that did not carry the risk of transmitting CJD.
These researchers previously reported that some patients with CJD due to c-hGH treatment (called iatrogenic CJD) also had prematurely developed deposits of the amyloid-beta protein in their brains.* The scientists went on to show in a 2018 paper that archived samples of c-hGH were contaminated with amyloid-beta protein and, despite having been stored for decades, transmitted amyloid-beta pathology to laboratory mice when it was injected.** They suggested that individuals exposed to contaminated c-hGH, who did not succumb to CJD and lived longer, might eventually develop Alzheimer’s disease.
This latest paper reports on eight people referred to UCLH’s National Prion Clinic at the National Hospital for Neurology and Neurosurgery in London, who had all been treated with c-hGH in childhood, often over several years.
Five of these people had symptoms of dementia, and either had already been diagnosed with Alzheimer’s disease or would otherwise meet the diagnostic criteria for this condition; another person met criteria for mild cognitive impairment. These people were between 38 and 55 years old when they started having neurological symptoms. Biomarker analyses supported the diagnoses of Alzheimer’s disease in two patients with the diagnosis, and was suggestive of Alzheimer’s in one other person; an autopsy analysis showed Alzheimer’s pathology in another patient.
The unusually young age at which these patients developed symptoms suggests they did not have the usual sporadic Alzheimer’s which is associated with old age. In the five patients in whom samples were available for genetic testing, the team ruled out inherited Alzheimer’s disease.
As c-hGH treatment is no longer used, there is no risk of any new transmission via this route. There have been no reported cases of Alzheimer’s acquired from any other medical or surgical procedures. There is no suggestion that amyloid-beta can be passed on in day-to-day life or during routine medical or social care.
However, the researchers caution that their findings highlight the importance of reviewing measures to ensure there is no risk of accidental transmission of amyloid-beta via other medical or surgical procedures which have been implicated in accidental transmission of CJD.
The lead author of the research, Professor John Collinge, Director of the UCL Institute of Prion Diseases and a consultant neurologist at UCLH, said: “There is no suggestion whatsoever that Alzheimer’s disease can be transmitted between individuals during activities of daily life or routine medical care. The patients we have described were given a specific and long-discontinued medical treatment which involved injecting patients with material now known to have been contaminated with disease-related proteins.
“However, the recognition of transmission of amyloid-beta pathology in these rare situations should lead us to review measures to prevent accidental transmission via other medical or surgical procedures, in order to prevent such cases occurring in future.
“Importantly, our findings also suggest that Alzheimer's and some other neurological conditions share similar disease processes to CJD, and this may have important implications for understanding and treating Alzheimer’s disease in the future.”
Co-author Professor Jonathan Schott (UCL Queen Square Institute of Neurology, honorary consultant neurologist at UCLH, and Chief Medical Officer at Alzheimer’s Research UK) said: “It is important to stress that the circumstances through which we believe these individuals tragically developed Alzheimer’s are highly unusual, and to reinforce that there is no risk that the disease can be spread between individuals or in routine medical care. These findings do, however, provide potentially valuable insights into disease mechanisms, and pave the way for further research which we hope will further our understanding of the causes of more typical, late onset Alzheimer’s disease.”
First author Dr Gargi Banerjee (UCL Institute of Prion Diseases) said: “We have found that it is possible for amyloid-beta pathology to be transmitted and contribute to the development of Alzheimer’s disease. This transmission occurred following treatment with a now obsolete form of growth hormone, and involved repeated treatments with contaminated material, often over several years. There is no indication that Alzheimer’s disease can be acquired from close contact, or during the provision of routine care.”
The study was supported by the Medical Research Council, the National Institute for Health and Care Research (NIHR), the NIHR UCLH Biomedical Research Centre, Alzheimer’s Research UK, and the Stroke Association.
If you were treated with the growth hormone (c-hGH) in the UK between 1959 and 1985 and would like further information about this research, please contact the National Prion Clinic via email (uclh.prion.help@nhs.net) or by telephone (020 7679 5142 or 020 7679 5036).
https://www.ucl.ac.uk/prion/news/2024/jan/alzheimers-disease-acquired-historic-medical-treatments
Professor John Collinge on tackling prion diseases
Professor John Collinge is Director of the MRC Prion Unit and also directs the NHS National Prion Clinic at the adjacent National Hospital for Neurology and Neurosurgery.
What are prions, why are they important, and how might they help us develop treatments for neurodegenerative conditions like dementia? Prions are lethal pathogens that cause neurodegenerative diseases of humans and other mammals.
The best-known human prion disease is sporadic Creutzfeldt-Jakob disease (sCJD), a rapidly progressive dementia which accounts for around 1 in 5000 deaths worldwide. In sharp distinction to all other infectious agents, prions lack their own DNA or RNA genome and consist of polymers of a misfolded form of a normal cellular protein (the prion protein or PrP) which form amyloid fibrils.
These fibres grow by addition of PrP molecules at their ends and they eventually fragment producing more prion particles which continue this process and spread throughout the brain. The final proof of the once controversial “protein-only hypothesis” of prions came with the determination of the structure of infectious prions at near atomic resolution by cryogenic electron microscopy by ourselves and US colleagues in the last few years.
The normal cellular prion proteins are very similar between different species of mammals and therefore a prion infection from one species can sometimes infect another species. This is what happened with the prion disease of cattle, bovine spongiform encephalopathy (BSE) in the 1990’s which caused a new human prion disease known as variant Creutzfeldt-Jakob disease (vCJD) and led to the BSE crisis in the UK, EU and other countries.
While human prion diseases are thankfully rare, there are common prion diseases of other species, for example scrapie in sheep and goats worldwide and chronic wasting disease in deer in North America. While prions were first thought to be unique to these rare neurological diseases, it became clear that the molecular process was of far wider relevance with for example the recognition of several different proteins in yeast that could form prions.
Most importantly with respect to neurodegeneration and dementia in humans, it has been established that similar so-called “prion-like” mechanisms are involved in much commoner conditions including Alzheimer’s and Parkinson’s diseases. In Alzheimer’s disease (AD) for example, two proteins in the brain, amyloid-beta and tau can form self-propagating assemblies which spread in the brain. Indeed, we reported in two articles in Nature that the amyloid-beta pathology seen in AD can be transmissible between humans in rare circumstances causing the newly recognised condition iatrogenic cerebral amyloid angiopathy.
There is accumulating evidence also for iatrogenic AD. Understanding prion biology, and in particular how propagation of prions leads to neurodegeneration, is therefore of central research importance in medicine. Many years ago, we demonstrated that targeting the production of the normal cellular prion protein completely halted the progression of neurodegeneration (and indeed even reversed early pathological changes) in laboratory mice. This work has underpinned multiple efforts to develop rational treatments for prion and other neurodegenerative diseases.
What first attracted you to the area of prion diseases? I first became involved in this field while working as a graduate student applying early molecular genetic methods to study neuropsychiatric diseases and was involved in the first description of mutations in the prion protein gene in the late 1980s in what are now known as the inherited prion diseases.
As it was already known that brain tissue from patients who died from some of these genetic conditions could transmit disease when inoculated into laboratory animals, it seemed to me highly likely that some version of the then intensely controversial “protein-only hypothesis” was likely to be correct: this had major implications in pathobiology.
I went on to show that being heterozygous for a common human prion protein polymorphism had a profound effect on susceptibility to CJD; I considered this entirely consistent with a protein-only agent and this led to further work studying the genetics of prion disease.
It seemed to me at the time that these early genetic insights, albeit in a rare disease, provided a powerful way in to study the fundamental basis of neurodegeneration. Of course, the evolving concerns about BSE in the early 1990’s also focussed my mind on the specific public and animal health risks posed by prions.
You led the UK’s first clinical trial in CJD, the largest yet conducted internationally. Can you tell us about this? I was asked in 1997 by Medical Research Council (MRC) at the request of UK Government to establish and lead an MRC Unit to focus on understanding prion diseases and to ultimately develop treatments for them.
At the time it was unknown how many people would develop vCJD following the widespread dietary exposure of the UK population to BSE prions and the possibility that this may eventually affect hundreds of thousands could not then be excluded.
An early proposal (by Dr Prusiner at UCSF) for a treatment for CJD was the anti-malarial drug quinacrine based on early work in prion-infected cell cultures. We were asked by the Chief Medical Officer to establish a clinical trial and did so in collaboration with the MRC Clinical Trials Unit also based at UCL.
While the MRC PRION-1 trial, as is was called, did not show any benefit of quinacrine, we did learn a great deal about how best to conduct a clinical trial in CJD in conjunction with patients and families affected by these terrible conditions.
This lead on to the formation of the National Prion Monitoring Cohort (NPMC) to study the natural history of prion diseases and to develop better clinical scales and biomarkers, and earlier diagnosis, to facilitate future clinical trials. In particular, we reasoned that having a large longitudinal data set would allow us to conduct adequately powered efficacy trials by comparison of treated patients with historical controls rather that using a more classical placebo-controlled study which was understandably unacceptable to patients and their families given the rapid and invariably fatal progression of these diseases.
The NPMC has been extremely successful with the strong support of the patient community and has recruited over 1100 patients to date, by far the largest dataset worldwide, and has enabled development and validation of multiple clinical scales and blood and CSF biomarkers.
What in your opinion have been some of the most important findings of your research to date? Our early work established and characterised the inherited prion diseases and genetic susceptibility to acquired and sporadic prion disease, and pioneered diagnostic and presymptomatic genetic testing of neurodegenerative disease.
Many further genetic advances followed. Prions exist in multiple strain types and we developed molecular strain typing of prions which we applied in 1996 to first demonstrate that vCJD was caused by the same prion strain as cattle BSE, a finding of critical public and animal health significance at the time.
We characterised the pathogenesis of vCJD to inform public health risk assessments, developed the first blood test for vCJD and effective means to prion sterilise surgical instruments. We proposed the now widely accepted “conformational selection hypothesis” to explain the relationship between prion strains and intermammalian transmission barriers and proposed that prion strains constitute a “cloud” under host selection rather than a molecular clone.
Importantly, we described subclinical prion infections in which animals lived a normal lifespan despite harbouring high levels of prions and went on to study the kinetics of prion propagation in vivo and showed that propagation and neurotoxicity occur in two distinct mechanistic phases with pathology only developing after prion levels had plateaued in the brain.
We subsequently confirmed that prions themselves are not directly neurotoxic. These insights may be fundamental to understanding other diseases involving propagation and spread of assemblies of misfolded proteins, notably amyloid-beta and tau in AD.
Our discovery of human transmission of amyloid-beta pathology, mentioned above, in individuals treated many years earlier in childhood with human cadaver-derived pituitary growth hormone (c-hGH) accidentally contaminated with amyloid-beta seeds (prions) has wide implications for understanding, preventing and treating neurodegenerative diseases.
We defined iatrogenic cerebral amyloid angiopathy as a new disease, with relevance to Alzheimer’s disease and public health. Iatrogenic AD is likely to be recognised in the cohort of c-hGH recipients as they age further. Our demonstration that reducing prion expression during neuroinvasive prion disease in laboratory mice prevented onset, and reverses early pathology, produced a proof of principle of therapeutically targeting prion protein.
This led to our development of a biopharmaceutical which we have used to treat CJD. Recently, we have described the elusive structural basis of prion strain diversity: how prions can encode information in a non-Mendelian manner by determination of near atomic resolution structures of multiple prion stains by cryogenic electron microscopy.
In addition, we are proud of our long term field studies on the epidemic human prion disease kuru in the Eastern Highlands of Province of Papua New Guinea (PNG), in collaboration with the PNG Institute for Medical Research and the affected communities, which led to major insights including establishing the range of possible incubation periods of human prion infections (documenting cases with incubations over 50 years) and discovery of a novel prion protein variant selected by the epidemic which we demonstrated provides complete protection against prion infection and disease and the molecular structural basis of which we have recently characterised.
To what extent do you think we are entering a new era when it comes to developing drugs that could be used to prevent, or even reverse, neurodegenerative diseases? Thankfully we are entering a time when disease-modifying treatments for neurodegenerative diseases are becoming feasible and indeed first-generation agents have arrived, but we cannot yet prevent, halt or reverse neurodegeneration.
Our own work validating cellular prion protein as a therapeutic target led us to develop a humanised monoclonal antibody with high affinity for cellular PrP and this has been used to treat six patients with CJD at UCLH. We consider the encouraging results justify a formal clinical trial and are seeking funding support for this at present.
Our therapeutic strategy has been to target normal cellular PrP itself, the substrate for prion propagation, and not the disease-related assemblies of misfolded PrP that accumulate during disease. We reasoned, given the diversity of these species, that drugs binding prions themselves would lead to the rapid development of resistance and indeed this has been shown to be the case with drugs developed elsewhere.
There may be important lessons here for other neurodegenerative diseases. For example, this may be critical in determining whether monoclonal antibody drugs targeting amyloid-beta fibrils or other assemblies, which also exist as structural polymorphs, have a sustained therapeutic effect or result in strain selection and evolution of resistant sub-strains as in prion diseases.
A number of pharmaceutical and biotech companies are however developing gene targeting methods, conceptually analogous to those we demonstrated many years ago block prion pathogenesis, to reduce expression of proteins implicated in various neurodegenerative diseases. Given the complexity and diversity of AD, in which multiple proteinopathies are involved, it is likely that effective treatments are going to require a cocktail of drugs hitting multiple targets.
Another key consideration is the importance of accurate diagnosis and early treatment, not only for the obvious need to intervene before irreversible brain cell loss has occurred, but because at the stage where significant cell death (with release of toxic materials) is occurring, these secondary non-specific neurodegenerative processes may dominate and be unresponsive to the specific targeted therapies. The ultimate aim must be to identify these pathogenic processes very early (ideally pre-clinically) and intervene to delay, and eventually prevent, clinical progression or onset.
https://www.ucl.ac.uk/brain-sciences/dementia-ucl-priority/professor-john-collinge-tackling-prion-diseases
MONDAY, SEPTEMBER 11, 2023
Professor John Collinge on tackling prion diseases
“The best-known human prion disease is sporadic Creutzfeldt-Jakob disease (sCJD), a rapidly progressive dementia which accounts for around 1 in 5000 deaths worldwide.”
There is accumulating evidence also for iatrogenic AD. Understanding prion biology, and in particular how propagation of prions leads to neurodegeneration, is therefore of central research importance in medicine.
https://www.ucl.ac.uk/brain-sciences/dementia-ucl-priority/professor-john-collinge-tackling-prion-diseases
https://creutzfeldt-jakob-disease.blogspot.com/2023/09/professor-john-collinge-on-tackling.html
***> Singeltary Reply
Published: 09 September 2015
Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
https://www.nature.com/articles/nature15369#article-comments
https://www.nature.com/articles/nature15369
Singeltary Comment at very bottom of this Nature publishing;
re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
I would kindly like to comment on the Nature Paper, the Lancet reply, and the newspaper articles.
First, I applaud Nature, the Scientist and Authors of the Nature paper, for bringing this important finding to the attention of the public domain, and the media for printing said findings.
Secondly, it seems once again, politics is getting in the way possibly of more important Transmissible Spongiform Encephalopathy TSE Prion scientific findings. findings that could have great implications for human health, and great implications for the medical surgical arena. but apparently, the government peer review process, of the peer review science, tries to intervene again to water down said disturbing findings.
where have we all heard this before? it's been well documented via the BSE Inquiry. have they not learned a lesson from the last time?
we have seen this time and time again in England (and other Country's) with the BSE mad cow TSE Prion debacle.
That 'anonymous' Lancet editorial was disgraceful. The editor, Dick Horton is not a scientist.
The pituitary cadavers were very likely elderly and among them some were on their way to CJD or Alzheimer's. Not a bit unusual. Then the recipients ?
who got pooled extracts injected from thousands of cadavers ? were 100% certain to have been injected with both seeds. No surprise that they got both diseases going after thirty year incubations.
That the UK has a "system in place to assist science journalists" to squash embargoed science reports they find 'alarming' is pathetic.
Sounds like the journalists had it right in the first place: 'Alzheimer's may be a transmissible infection' in The Independent to 'You can catch Alzheimer's' in The Daily Mirror or 'Alzheimer's bombshell' in The Daily Express
if not for the journalist, the layperson would not know about these important findings.
where would we be today with sound science, from where we were 30 years ago, if not for the cloak of secrecy and save the industry at all cost mentality?
when you have a peer review system for science, from which a government constantly circumvents, then you have a problem with science, and humans die.
to date, as far as documented body bag count, with all TSE prion named to date, that count is still relatively low (one was too many in my case, Mom hvCJD), however that changes drastically once the TSE Prion link is made with Alzheimer's, the price of poker goes up drastically.
so, who makes that final decision, and how many more decades do we have to wait?
the iatrogenic mode of transmission of TSE prion, the many routes there from, load factor, threshold from said load factor to sub-clinical disease, to clinical disease, to death, much time is there to spread a TSE Prion to anywhere, but whom, by whom, and when, do we make that final decision to do something about it globally? how many documented body bags does it take? how many more decades do we wait? how many names can we make up for one disease, TSE prion?
Professor Collinge et al, and others, have had troubles in the past with the Government meddling in scientific findings, that might in some way involve industry, never mind human and or animal health.
FOR any government to continue to circumvent science for monetary gain, fear factor, or any reason, shame, shame on you.
in my opinion, it's one of the reasons we are at where we are at to date, with regards to the TSE Prion disease science i.e. money, industry, politics, then comes science, in that order.
greed, corporate, lobbyist there from, and government, must be removed from the peer review process of sound science, it's bad enough having them in the pharmaceutical aspect of healthcare policy making, in my opinion.
my mother died from confirmed hvCJD, and her brother (my uncle) Alzheimer's of some type (no autopsy?). just made a promise, never forget, and never let them forget, before I do.
I kindly wish to remind the public of the past, and a possible future we all hopes never happens again. ...
[9. Whilst this matter is not at the moment directly concerned with the iatrogenic CJD cases from hgH, there remains a possibility of litigation here, and this presents an added complication. There are also results to be made available shortly (1) concerning a farmer with CJD who had BSE animals, (2) on the possible transmissibility of Alzheimer's and (3) a CMO letter on prevention of iatrogenic CJD transmission in neurosurgery, all of which will serve to increase media interest.]
https://www.nature.com/articles/nature15369
Singeltary Comment at very bottom of this Nature publishing, takes a while to load...terry
https://www.nature.com/articles/nature15369#article-comments
Re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
>>> The only tenable public line will be that "more research is required’’ <<<
>>> possibility on a transmissible prion remains open<<<
O.K., so it’s about 23 years later, so somebody please tell me, when is "more research is required’’ enough time for evaluation ?
Re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015)
snip...see full Singeltary Nature comment here;
Alzheimer's disease
let's not forget the elephant in the room. curing Alzheimer's would be a great and wonderful thing, but for starters, why not start with the obvious, lets prove the cause or causes, and then start to stop that. think iatrogenic, friendly fire, or the pass it forward mode of transmission. think medical, surgical, dental, tissue, blood, related transmission. think transmissible spongiform encephalopathy aka tse prion disease aka mad cow type disease...
Commentary: Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
Posted by flounder on 05 Nov 2014 at 21:27 GMT
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
Background
Alzheimer’s disease and Transmissible Spongiform Encephalopathy disease have both been around a long time, and was discovered in or around the same time frame, early 1900’s. Both diseases are incurable and debilitating brain disease, that are in the end, 100% fatal, with the incubation/clinical period of the Alzheimer’s disease being longer (most of the time) than the TSE prion disease. Symptoms are very similar, and pathology is very similar.
Methods
Through years of research, as a layperson, of peer review journals, transmission studies, and observations of loved ones and friends that have died from both Alzheimer’s and the TSE prion disease i.e. Heidenhain Variant Creutzfelt Jakob Disease CJD.
Results
I propose that Alzheimer’s is a TSE disease of low dose, slow, and long incubation disease, and that Alzheimer’s is Transmissible, and is a threat to the public via the many Iatrogenic routes and sources. It was said long ago that the only thing that disputes this, is Alzheimer’s disease transmissibility, or the lack of. The likelihood of many victims of Alzheimer’s disease from the many different Iatrogenic routes and modes of transmission as with the TSE prion disease.
Conclusions
There should be a Global Congressional Science round table event set up immediately to address these concerns from the many potential routes and sources of the TSE prion disease, including Alzheimer’s disease, and a emergency global doctrine put into effect to help combat the spread of Alzheimer’s disease via the medical, surgical, dental, tissue, and blood arena’s. All human and animal TSE prion disease, including Alzheimer’s should be made reportable in every state, and Internationally, WITH NO age restrictions. Until a proven method of decontamination and autoclaving is proven, and put forth in use universally, in all hospitals and medical, surgical arena’s, or the TSE prion agent will continue to spread. IF we wait until science and corporate politicians wait until politics lets science _prove_ this once and for all, and set forth regulations there from, we will all be exposed to the TSE Prion agents, if that has not happened already.
end...tss
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
Posted by flounder on 05 Nov 2014 at 21:27 GMT
https://journals.plos.org/plosone/article/comment?id=10.1371/annotation/933cc83a-a384-45c3-b3b2-336882c30f9d
Ann N Y Acad Sci. 1982;396:131-43.
Alzheimer's disease and transmissible virus dementia (Creutzfeldt-Jakob disease).
Brown P, Salazar AM, Gibbs CJ Jr, Gajdusek DC.
Abstract
Ample justification exists on clinical, pathologic, and biologic grounds for considering a similar pathogenesis for AD and the spongiform virus encephalopathies. However, the crux of the comparison rests squarely on results of attempts to transmit AD to experimental animals, and these results have not as yet validated a common etiology. Investigations of the biologic similarities between AD and the spongiform virus encephalopathies proceed in several laboratories, and our own observation of inoculated animals will be continued in the hope that incubation periods for AD may be even longer than those of CJD.
https://pubmed.ncbi.nlm.nih.gov/6758661/
CJD1/9 0185 Ref: 1M51A
IN STRICT CONFIDENCE
Dr McGovern From: Dr A Wight Date: 5 January 1993 Copies: Dr Metters Dr Skinner Dr Pickles Dr Morris Mr Murray
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
1. CMO will wish to be aware that a meeting was held at DH yesterday, 4 January, to discuss the above findings. It was chaired by Professor Murray (Chairman of the MRC Co-ordinating Committee on Research in the Spongiform Encephalopathies in Man), and attended by relevant experts in the fields of Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the spongiform encephalopathies, and by representatives of the MRC and AFRC. 2. Briefly, the meeting agreed that:
i) Dr Ridley et als findings of experimental induction of p amyloid in primates were valid, interesting and a significant advance in the understanding of neurodegenerative disorders;
ii) there were no immediate implications for the public health, and no further safeguards were thought to be necessary at present; and
iii) additional research was desirable, both epidemiological and at the molecular level. Possible avenues are being followed up by DH and the MRC, but the details will require further discussion. 93/01.05/4.1
http://web.archive.org/web/20090506012455/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
BSE101/1 0136
IN CONFIDENCE
5 NOV 1992 CMO From: Dr J S Metters DCMO 4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have recognized the public sensitivity of these findings and intend to report them in their proper context. This hopefully will avoid misunderstanding and possible distortion by the media to portray the results as having more greater significance than the findings so far justify.
2. Using a highly unusual route of transmission (intra-cerebral injection) the researchers have demonstrated the transmission of a pathological process from two cases one of severe Alzheimer's disease the other of Gerstmann-Straussler disease to marmosets. However they have not demonstrated the transmission of either clinical condition as the "animals were behaving normally when killed'. As the report emphasizes the unanswered question is whether the disease condition would have revealed itself if the marmosets had lived longer. They are planning further research to see if the conditions, as opposed to the partial pathological process, is transmissible. What are the implications for public health?
3. The route of transmission is very specific and in the natural state of things highly unusual. However it could be argued that the results reveal a potential risk, in that brain tissue from these two patients has been shown to transmit a pathological process. Should therefore brain tissue from such cases be regarded as potentially infective? Pathologists, morticians, neuro surgeons and those assisting at neuro surgical procedures and others coming into contact with "raw" human brain tissue could in theory be at risk. However, on a priori grounds given the highly specific route of transmission in these experiments that risk must be negligible if the usual precautions for handling brain tissue are observed.
92/11.4/1-1 BSE101/1 0137
4. The other dimension to consider is the public reaction. To some extent the GSS case demonstrates little more than the transmission of BSE to a pig by intra-cerebral injection. If other prion diseases can be transmitted in this way it is little surprise that some pathological findings observed in GSS were also transmissible to a marmoset. But the transmission of features of Alzheimer's pathology is a different matter, given the much greater frequency of this disease and raises the unanswered question whether some cases are the result of a transmissible prion. The only tenable public line will be that "more research is required" before that hypothesis could be evaluated. The possibility on a transmissible prion remains open. In the meantime MRC needs carefully to consider the range and sequence of studies needed to follow through from the preliminary observations in these two cases. Not a particularly comfortable message, but until we know more about the causation of Alzheimer's disease the total reassurance is not practical.
JS METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832 121/YdeS 92/11.4/1.2
https://web.archive.org/web/20170126060344/http://collections.europarchive.org/tna/20080102232842/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf
CJD1/9 0185
Ref: 1M51A
IN STRICT CONFIDENCE
From: Dr. A Wight Date: 5 January 1993
Copies:
Dr Metters Dr Skinner Dr Pickles Dr Morris Mr Murray
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
''on the possible transmissibility of Alzheimer's''
9. Whilst this matter is not at the moment directly concerned with the iatrogenic CJD cases from hgH, there remains a possibility of litigation here, and this presents an added complication. There are also results to be made available shortly
(1) concerning a farmer with CJD who had BSE animals,
(2) on the possible transmissibility of Alzheimer's and
(3) a CMO letter on prevention of iatrogenic CJD transmission in neurosurgery, all of which will serve to increase media interest.
https://web.archive.org/web/20040315075058/http://www.bseinquiry.gov.uk/files/yb/1992/12/16005001.pdf
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
Posted by flounder on 05 Nov 2014 at 21:27 GMT
https://journals.plos.org/plosone/article/comment?id=10.1371/annotation/933cc83a-a384-45c3-b3b2-336882c30f9d
http://journals.plos.org/plosone/article/comments?id=10.1371/journal.pone.0111492
https://www.frontiersin.org/articles/10.3389/fnagi.2016.00005/full
THURSDAY, FEBRUARY 7, 2019
In Alzheimer's Mice, Decades-Old Human Cadaveric Pituitary Growth Hormone Samples Can Transmit and Seed Amyloid-Beta Pathology
https://betaamyloidcjd.blogspot.com/2019/02/in-alzheimers-mice-decades-old-human.html
Subject: CWD GSS TSE PRION SPINAL CORD, Confucius Ponders, What if?
REVIEW
***> In conclusion, sensory symptoms and loss of reflexes in Gerstmann-Sträussler-Scheinker syndrome can be explained by neuropathological changes in the spinal cord. We conclude that the sensory symptoms and loss of lower limb reflexes in Gerstmann-Sträussler-Scheinker syndrome is due to pathology in the caudal spinal cord. <***
***> The clinical and pathological presentation in macaques was mostly atypical, with a strong emphasis on spinal cord pathology.<***
***> The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD. <***
***> All animals have variable signs of prion neuropathology in spinal cords and brains and by supersensitive IHC, reaction was detected in spinal cord segments of all animals.<***
***> In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids.'' Scientific opinion on chronic wasting disease (II) <***
Saturday, February 2, 2019
CWD GSS TSE PRION SPINAL CORD, Confucius Ponders, What if?
https://familialcjdtseprion.blogspot.com/2019/02/cwd-gss-tse-prion-spinal-cord-confucius.html
Friday, January 29, 2016
Synucleinopathies: Past, Present and Future, iatrogenic, what if?
http://synucleinopathies.blogspot.com/2016/01/synucleinopathies-past-present-and.html
http://synucleinopathies.blogspot.com/
all iatrogenic cjd is, is sporadic cjd, before the iatrogenic event is discovered, traced back, proven, documented, put into the academic domain, and then finally the public domain, this very seldom happens, thus problem solved, it's all sporadic cjd, PLUS, SPORADIC CJD HAS NOW BEEN LINKED TO ATYPICAL AND TYPICAL BSE, SCRAPIE, AND NOW CWD. ...terry
MONDAY, JANUARY 29, 2024
Iatrogenic Alzheimer’s disease in recipients of cadaveric pituitary-derived growth hormone
''The clinical syndrome developed by these individuals can, therefore, be termed iatrogenic Alzheimer’s disease, and Alzheimer’s disease should now be recognized as a potentially transmissible disorder.''
https://betaamyloidcjd.blogspot.com/2024/01/iatrogenic-alzheimers-disease-in.html
Monday, January 29, 2024
iatrogenic Alzheimer’s disease, Alzheimer’s disease should now be recognized as a potentially transmissible disorder
Iatrogenic Alzheimer’s disease in recipients of cadaveric pituitary-derived growth hormone
https://itseprion.blogspot.com/2024/01/iatrogenic-alzheimers-disease.html
WEDNESDAY, JANUARY 31, 2024
Creutzfeldt Jakob Disease, CJD Support Group for short statured children of the 1970's and 1980's And 2024 Alzheimer’s iatrogenic Transmission
https://creutzfeldt-jakob-disease.blogspot.com/2024/01/creutzfeldt-jakob-disease-cjd-support.html
SATURDAY, MARCH 10, 2018
Dura Mater Graft–Associated Creutzfeldt-Jakob Disease — Japan, 1975–2017 Update
https://cjdmadcowbaseoct2007.blogspot.com/2018/03/dura-mater-graftassociated-creutzfeldt.html
Friday, February 16, 2024
The Eyes are the windows to Our Souls, and a Potential Pathway for the TSE Prion disease, what if?
TUESDAY, NOVEMBER 20, 2018
CDC Eyes of CJD patients show evidence of prions concerns for iatrogenic transmission
MONDAY, DECEMBER 03, 2018
Prion Seeds Distribute throughout the Eyes of Sporadic Creutzfeldt-Jakob Disease Patients
Friday, December 04, 2009
New guidance on decontamination of trial contact lenses and other contact devices has been revealed for CJD AND vCJD
Eye procedure raises CJD concerns
By STEVE 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.
TUESDAY, NOVEMBER 20, 2018
CDC Eyes of CJD patients show evidence of prions concerns for iatrogenic transmission
SUNDAY, JANUARY 17, 2016
Of Grave Concern Heidenhain Variant Creutzfeldt Jakob Disease
Disinfection of Multi-Use Ocular Equipment for Ophthalmological Procedures: A Review of Clinical Effectiveness, Cost-Effectiveness, and Guidelines
CADTH Rapid Response Report: Summary with Critical Appraisal
Shirley S. T. Yeung and Mary-Doug Wright.
Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2019 Feb 19. Copyright and Permissions
Context and Policy Issues In ophthalmology, there are certain equipment that are used and reused across different patients within a medical practice that resulting in indirect contact between multiple patients.1 This could pose a risk of cross infection between patients, especially with viruses and bacteria.1 One example of such equipment would be the tonometer, a device to measure the intraocular pressure in patients to determine risk of glaucoma.1 The tonometer tip is in direct contact with the patient’s eye and studies have demonstrated the transmission of hepatitis B virus, hepatitis C virus, human immunodeficiency virus (HIV), and Creutzfeldt-Jakob disease can occur between patients.1 Therefore, equipment cleanliness is critical.
The Canadian Optometrists Association has a general infection control guideline; however, in general, among available guidelines, there is little consistency and guidance in what the best approach would be to reduce transmission of diseases between patients.2 In vitro studies compared various sterilization techniques to determine whether or not viral particles are removed from the ophthalmic equipment but it is important to evaluate the impact of these cleanliness techniques on clinically relevant outcomes, such as infection transmission.1 Various guidelines and recommendations exist but it is unclear if there is any association between these techniques and disease transmission between patients.
The objective of this review is to evaluate the comparative clinical and cost-effectiveness of various disinfection techniques and/or procedures for multi-use ocular equipment in ophthalmology patients, as well as the guidelines for its use.
Go to: Research Questions
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Summary of Findings Comparative clinical effectiveness No relevant evidence regarding the clinical effectiveness of various disinfection techniques and procedures for multi-use ocular equipment in ophthalmology patients was identified; therefore, no summary can be provided.
Cost-effectiveness One cost-effectiveness analysis was identified comparing Canadian patients from the hospital perspective which compared the cost-effectiveness between the use of alcohol swabs and peroxide bleach for cleaning of tonometry trips.6 Alcohol swabs are more cost-effective compared to peroxide bleach as the incremental cost-effectiveness ratio was $12,152 for each EKC case averted.6
Evidence-based guidelines Recommendations from the guidelines are summarized below and details are presented in Appendix 4.
The recommendations from the AORN guidelines are general and apply to all multi-use ophthalmic equipment in a surgical setting.7 The guideline indicates there is strong evidence to support the immediate cleaning of ophthalmic equipment according to the manufacturer’s instruction for use.7 There is moderate evidence to ensure the cleaning process is done in an adequate manner, including allowing enough time and personnel to ensure thorough cleaning and sterilization.7
Limitations Since no systematic reviews or primary studies were identified for this report, it is difficult to conclude the comparative clinical effectiveness for various cleaning and sterilization techniques for multi-use ocular equipment in ophthalmic patients. Of note, there were studies that were identified that included in vitro outcomes for various cleaning techniques, these are included in Appendix 5. There remains a research gap in identify the most clinically effective cleaning and sterilizing method for reducing transmission of potential diseases between patients in this setting.
One study examining the cost-effectiveness of various cleaning techniques was included and although it was a based on a Canadian population, the effectiveness outcomes were extrapolated from in vitro outcomes.6 This ultimately reduces the validity of these results as it may over or underestimate the magnitude of effect of the cleaning techniques. Additionally, little detail was provided on the exact cleaning procedures within this study, making it difficult for decision makers to determine what the cost-effective disinfection method may be.6
One guideline from the United States was identified and the recommendations are non-specific and do not provide much insight for policy makers as it was intended for a broad setting.6 Although there are a number of guidelines available in this particular area, many of them do not document rigorous methods or guideline development; therefore, are not included in this report but are listed in Appendix 5.
There remains a paucity of studies with patient relevant outcomes, ultimately making it difficult to inform clinical decisions.
Go to: Conclusions and Implications for Decision or Policy Making One cost-effectiveness study and one guideline were identified regarding cleaning techniques for the disinfection of multi-use ocular equipment.6,7
The identified cost-effective study indicated that the use of alcohol swabs was a more cost-effective technique compared to peroxide bleach as a cleaning method of tonometers for reducing epidemic keratoconjunctivitis in a Canadian population.6 However, no details on the cleaning procedures were provided.
One guideline recommends the importance of following the manufacturer’s instructions for use when cleaning and sterilizing ophthalmic equipment.7 It also stresses the importance of thorough and adequate cleaning and sterilization by ensuring the required conditions.7
No systematic reviews or primary studies were identified to answer the comparative clinical effectiveness between various cleaning techniques. Further research addressing various cleaning and sterilization techniques for multi-use ocular equipment, specifically for clinical outcomes in patients undergoing ophthalmology screening or treatment, would help to reduce uncertainty.
References
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Thank you kindly for this, i have been concerned and warning about this for 21 years.
yep, 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
===========================================
Houston, Texas channel 11 news 28 Nov 99
The eyes have it, cjd, and they could be stealing them from your loved one
TSE Prion and Endoscopy Equipment Singeltary Tue, 12 Oct 1999
TSE Prion and Endoscopy Equipment
Subject: Re: CJD * Olympus Endoscope
Date: Tue, 12 Oct 1999 15:57:03 –0500
From: "Terry S. Singeltary Sr."
To: GOLDSS@...
References: 1
Dear Mr. Goldstine, Hello again, I hope the CDC has not changed your mind, since our phone call, about sending me the information, in which we spoke of. I am still waiting for the information, re-fax. Someone had told me, you would not send me the information, but I told them you would, due to the importance of it pertaining to public safety, and the fact, you are a Doctor. I hope you don't disappoint me, and the rest of the public, and hide the facts, as the CDC and NIH have for years. Olympus can be part of the Truth, or you can be part of the cover-up. We are going to find out, sooner or later.
I already know, as do many more.
Still waiting,
Kind Regards,
Terry S. Singeltary Sr.
Wednesday, March 02, 2016
Endoscope Maker Olympus Agrees To $646 Million Settlement Over Kickbacks, while still ignoring the elephant in the room, CJD TSE PRIONS Health Inc.
*** Evidence For CJD TSE Transmission Via Endoscopes 1-24-3 re-Singeltary to Bramble et al ***
Evidence For CJD/TSE Transmission Via Endoscopes
From Terry S. Singletary
see full text;
Evidence For CJD/TSE Transmission Via Endoscopes
From Terry S. Singletary, Sr flounder@wt.net 1-24-3
I have researched human/animal TSEs now for over 5 years due to the death of my Mother from the Heidenhain Variant Creutzfeldt Jakob disease, one of six - known - variants of the infamous 'sporadic' CJD.
I did a little survey several years ago about CJD and ENDOSCOPY in 2001, and then went there again when another article was released recently. However, they seemed to only be concerned with the vCJD strain and risk from endoscopy equipment.
My concerns are if vCJD can be transmitted by blood, and there are now 6 variants of the infamous sporadic CJDs that they are documenting to date, how do they know that none of these 6 variants will not transmit the agent (prion) via blood?...especially since the sporadic CJDs are the only ones documented to date to transmit via the surgical arena and now that the CWD is spreading more and more, who knows about the cattle?
I would always read this study and it would bring me back to reality as to how serious/dangerous this agent is in the surgical/medical arena. You might want to read this short abstract from the late, great Dr. Gibbs twice, and let it really sink in. And please remember while reading some of these transmission studies, that most all, if not ALL these agents transmit freely to primates. Humans, of course, are primates.
Regarding claims that:
'Well, it has never been documented to transmit to humans."
There are two critical factors to think about:
A. CJD/TSEs in the USA are NOT reportable in most states and there is NO CJD/TSE questionnaire for most victims and their families, and the one they are now issuing asks absolutely nothing about route and source of the (prion) agent, only how the disease was diagnosed. Furthermore, the elderly are only very rarely autopsied, ie looking for Alzheimer's or 'FAST Alzheimer's' OR prion disease-related factors and phenomena, such as heart failure caused by disease.
B. It is unethical and against the law to do transmission studies of TSEs to humans, they are 100% FATAL.
I suggest you read these case studies about medical arena CJD transmission very carefully:
1: J Neurol Neurosurg Psychiatry 1994 Jun;57(6):757-8
Transmission of Creutzfeldt-Jakob disease to a chimpanzee by electrodes contaminated during neurosurgery.
Gibbs CJ Jr, Asher DM, Kobrine A, Amyx HL, Sulima MP, Gajdusek DC.
Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Stereotactic multicontact electrodes used to probe the cerebral cortex of a middle aged woman with progressive dementia were previously implicated in the accidental transmission of Creutzfeldt-Jakob disease (CJD) to two younger patients. The diagnoses of CJD have been confirmed for all three cases. More than two years after their last use in humans, after three cleanings and repeated sterilisation in ethanol and formaldehyde vapour, the electrodes were implanted in the cortex of a chimpanzee. Eighteen months later the animal became ill with CJD. This finding serves to re-emphasise the potential danger posed by reuse of instruments contaminated with the agents of spongiform encephalopathies, even after scrupulous attempts to clean them.
Thursday, November 14, 2013
Prion diseases in humans: Oral and dental implications
Subject: CJD: update for dental staff
Date: November 12, 2006 at 3:25 pm PST
1: Dent Update. 2006 Oct;33(8):454-6, 458-60. CJD: update for dental staff.
2001 Singeltary on CJD
February 14, 2001
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Terry S. Singeltary, Sr
Author Affiliations
JAMA. 2001;285(6):733-734. doi:10-1001/pubs.JAMA-ISSN-0098-7484-285-6-jlt0214
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.
26 MARCH 2003
RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States
Terry S. Singeltary, retired (medically)
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?
all iatrogenic CJD TSE PRION is, is sporadic CJD TSE PRION, before the iatrogenic event is discovered, traced back, proven, documented, put into the academic domain, and then finally the public domain, this very seldom happens, thus problem solved, it's all sporadic. with the many different human and animal TSE prion disease evolving into many different strains, exposure there from, immediate actions are urgently needed to stop friendly fire, iatrogenic TSE Prion from spreading across the medical and surgical theaters, across the globe...
Terry S. Singeltary Sr.
