Thursday, April 27, 2017

Creutzfeldt-Jakob disease lookback study: 21 years of surveillance for transfusion transmission risk

Subject: Creutzfeldt-Jakob disease lookback study: 21 years of surveillance for transfusion transmission risk

Creutzfeldt-Jakob disease lookback study: 21 years of surveillance for transfusion transmission risk 

Authors Lauren A. Crowder, Lawrence B. Schonberger, Roger Y. Dodd, Whitney R. Steele First published: 25 April 2017Full publication history DOI: 10.1111/trf.14145 View/save citation Cited by (CrossRef): 0 articles Check for updates Citation tools Funding Information 

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. 

This work has been funded by Grant 2 U01 CK000360-03 from the US Centers for Disease Control and Prevention. 



Transfusion transmission of human prion diseases has been observed for variant Creutzfeldt-Jakob disease (vCJD), but not for the classic forms of prion disease (CJD: sporadic, genetic, and iatrogenic). Although the presence of prions or misfolded prion proteins in blood has been documented in some patients with the most common form of CJD, sporadic CJD, no transfusion-transmitted cases of CJD have been recognized. Since 1995, the American Red Cross has conducted a lookback study of the recipients of blood products from donors who develop CJD to assess the risk of blood-borne CJD transmission in the United States. 


Blood donors subsequently diagnosed with confirmed or probable CJD were enrolled and the consignees were asked to identify the recipients of their blood products. These donors' transfusion recipients are traced annually with the National Death Index to see if they subsequently die of CJD. 


To date, 65 CJD donors have been enrolled along with 826 of their blood recipients. These recipients have contributed 3934 person-years of follow-up and no transfusion-transmitted cases of CJD have been recognized. 


From this study, as well as other epidemiologic studies, there is no evidence of CJD transfusion transmission; this risk remains theoretical.

with the USA CJD TSE Prion surveillance efforts to date, the efforts of trace back there from, the fact now that sporadic cjd has now been linked to typical and atypical BSE, typical and atypical Scrapie, and now scientist sounding the alarm of a threat of zoonosis from Chronic Wasting Disease CWD TSE Prion of cervid, the recent oral transmission of CWD to Pigs, this study is extremely flawed in my opinion, words on paper. sporadic CJD is not a single entity, but a name for many strains of CJD TSE Prion, that does not match the infamous nvCJD strain, that they have no clue as to what the routes and source of these CJDs strains are. ...kind regards, terry

SUNDAY, MARCH 09, 2014

A Creutzfeldt-Jakob Disease (CJD) Lookback Study: Assessing the Risk of Blood Borne Transmission of Classic Forms of Creutzfeldt-Jakob Disease


Transfusion Transmission of Human Prion Diseases

Tuesday, November 29, 2016

Transmissibility of Gerstmann–Sträussler–Scheinker syndrome in rodent models: new insights into the molecular underpinnings of prion infectivity

2017, please note concern, a few recent studies...kindest regards, terry

In summary, PrPsc was detectable at high levels in organs and tissues of the LRS only in BSE/vCJD infected animals (0.1% to 10% of the amounts found in the brains of the same animals). We interpreted these results as the BSE prion being highly lymphotropic in primates. These findings correlated indeed with the tonsils, spleens and appendices of vCJD patients being found positive for PrPsc18,19,20). We therefore proposed that LRS tissues be considered ‘high-risk’ in vCJD patients only.

However, lower amounts of PrPsc were detected in adrenals, muscles and intestinal tissue of macaques infected with BSE/vCJD as well as sCJD and iCJD, associated with peripheral nerves. 

Levels were less than 10,000 times lower than brain PrPres levels (<0 .001="" nbsp="" span="">

*** We therefore proposed that these tissues be considered “low-risk” for all CJD patients.

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Review Modeling Variant Creutzfeldt-Jakob Disease and Its Pathogenesis in Non-human Primates Corinne Lasmézas1)

1) Scripps Florida, 130 Scripps Way, Jupiter FL 33458, USA

 Released 20170330 Received 20170123 Accepted 20170209 

Keywords: prions, variant Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, non-human primates, transmission, pathogenesis, blood Full Text PDF [7720K] Corresponding author: Corinne Lasmézas, Scripps Florida, 130 Scripps Way, Jupiter FL 33458, USA (E-mail: lasmezas (at) The contents of this article reflect solely the view of the author(s).

Conflict of interest statement: The authors had no conflicts of interest to declare in this article.

This paper was presented at the Animal Prion Diseases Workshop “Updated Diagnosis and Epidemiology of Animal Prion Diseases for Food Safety and Security” supported by the OECD Co-operative Research Programme. (See “Food Safety” Vol.4 (2016), No.4, 103-4.)

Abbreviations: BSE: Bovine Spongiform Encephalopathy; CNS: central nervous system; iCJD: iatrogenic Creutzfeldt-Jakob disease; IV: intravenous; LN: lymph nodes; LRS: lymphoreticular system; PrPsc: disease-associated prion protein; RBCs: red blood cells; sCJD: sporadic Creutzfeldt-Jakob disease; TSEs: transmissible spongiform encephalopathies; vCJD: variant Creutzfeldt-Jakob disease


Abstract 1. Transmission of Bovine Spongiform Encephalopathy (BSE) to CynomolgusMacaques Reproduces vCJD: Establishment of a non-human Primate Model for vCJD 1.1. BSE, a New Disease in Cattle 1.2. vCJD in Humans and Transmission of BSE to Non-human Primates 1.3. Determination of the Minimal Infectious BSE Dose in Non-human Primates 1.4. Adaptation of the BSE Agent to Non-human Primates: Consequences for Human Health 2. The Cynomolgus Macaque as a model to Understand the Pathogenesis of Variant Creutzfeldt-Jakob Disease (vCJD) and Model Risk of Interhuman Transmission 2. 1. Distribution of Prions in Tissues and Organs of BSE/vCJD Macaques after Oral or Intravenous (IV) Inoculation 2. 2. Distribution of Prions in Tissues and Organs of vCJD, Sporadic and Iatrogenic CJD Infected Macaques 2.2. Blood Infectivity Studies in the Macaque vCJD Model Acknowledgments References Abstract In the early 90s’, Europe was shaken by the fear that the prions from “mad cow disease” (bovine spongiform encephalopathy) would transmit the disease to humans via beef products. In 1996, the first variant Creutzfeldt-Jakob (vCJD) patients were described, and the same year our Bovine Spongiform Encephalopathy (BSE) transmission studies to cynomolgus macaques demonstrated that the BSE prion was highly infectious for primates, inducing brain lesions identical to those observed in vCJD patients. These studies provided the first experimental evidence that vCJD was BSE in humans. Subsequent studies established the BSE/vCJD-infected cynomolgus macaque as a robust model to study the pathogenesis of vCJD. We showed rapid adaptation of BSE prions to primates upon subsequent passage, and their distribution in peripheral tissues and blood. Some key studies are summarized in the present paper.

Page top 1. Transmission of Bovine Spongiform Encephalopathy (BSE) to Cynomolgus Macaques Reproduces vCJD: Establishment of a non-human Primate Model for vCJD 1.1. BSE, a New Disease in Cattle In 1987, a new prion disease affecting dairy cattle was described in the United Kindom1). Affected cows presented signs of aggressiveness, anxiety, ataxia and were finally found recumbent. The disease was rapidly classified in the group of “transmissible spongiform encephalopathies”, or TSEs, due to the transmissibility of the disease2), as well as the similarities of the neuropathological lesions and molecular hallmark with those found in sheep scrapie and human CJD: neuronal death, spongiform changes, and accumulation of misfolded and aggregated prion protein (termed PrPsc)3). PrPsc is the infectious form of the host prion protein PrP. It is also called a prion (for “proteinaceaous infectious particle4)) or TSE agent. The number of affected cows increased rapidly to top at a 37,280 diagnosed animals in the year of 1992 (OIE data). Thankfully, British epidemiologists recognized that BSE was due to the consumption of prion-tainted meat and bone meal (MBM)5), and the first feed-ban was implemented in 1988, prohibiting the feeding of ruminants with ruminant-derived MBM.

1.2. vCJD in Humans and Transmission of BSE to Non-human Primates In 1991, BSE was reported in a domestic cat that presumably was contaminated via pet food6). Transmission of scrapie from small ruminants to cats had never been described, raising concern that BSE might be more pathogenic than scrapie not only for cats, but also for humans. In order to probe the cow-to-primates species barrier of the BSE agent, we inoculated cynomolgus macaques (Macaca fascicularis) with BSE-infected cow brains at the French Atomic Energy Commision (CEA).

In 1996, 10 young individuals were described in the UK and one in France, harboring an unusual form of CJD that was coined variant CJD (vCJD)7,8). Besides patients being exceptionally young (adolescents and young adults, while sporadic CJD (sCJD) affects people over the age of 60), they exhibited unusual symptoms. Early symptoms were dysaesthesia, behavioral symptoms, depression, ataxia, with myoclonus appearing later on, contrasting with the cognitive course of the disease (memory impairment, dementia) preceding motor impairment, which is most frequently observed in sCJD. Moreover, vCJD patients presented specific neuropathological features with spongiosis and neuronal loss most evident in the basal ganglia and thalamus, and the presence of PrP amyloid plaques (abundant in the cerebral cortex and cerebellum) that were surrounded by vacuoles, giving them a flower-like appearance. These peculiar plaques were called florid plaques7).

At the same time as the first vCJD patients were being described, we were examining the brains of our 3 macaques that had all come down with disease 3 years after intracerebral (IC) inoculation with BSE-infected cow brain. Clinical signs were characterized by behavioral signs such as depression or edginess, as well as truncal ataxia (broad-based gait, tremors) and myoclonus. Neuropathological examination of the brains of the BSE-macaques revealed the presence of florid plaques and other neuropathological features similar to those observed in vCJD patients (Fig. 1). Florid plaques were not present in the brains of macaques inoculated with Kuru or sCJD, and thus were considered specific for infection by the BSE prion. Moreover, PrPsc in BSE-infected macaques and vCJD patients exhibited a similar electrophoretic pattern by western blot (Fig. 1).

In summary, macaques infected by BSE reproduced the behavioral and motor symptoms, the neuropathology and the biochemical signature of vCJD in humans. This study provided the first experimental evidence supporting that vCJD was due to human infection by the BSE agent9), and an experimental model to study the new disease.

1.3. Determination of the Minimal Infectious BSE Dose in Non-human Primates 

In a concerted European effort involving 5 laboratories including ours, the BSE-macaque model was then used to evaluate the minimal amount of BSE-infected material necessary to induce vCJD in primates. Results so far show that 5g of infectious BSE cattle brain is sufficient to induce the disease in all recipient animals by the oral route, with 500 mg yielding an incomplete attack rate10,11). The ID50 of BSE cattle brain is 200 mg for cattle12). These results suggest a low species barrier between cattle and non-human primates.

1.4. Adaptation of the BSE Agent to Non-human Primates: Consequences for Human Health 

The macaque BSE model provided an opportunity to evaluate the possible risk for humans of secondary inter-human transmission of the BSE/vCJD prion. Accidental human-to-human transmissions of sCJD, resulting in iatrogenic CJD (iCJD) has occurred in several unfortunate circumstances (described in ref.13). One of them was the infection of children with CJD-contaminated human growth hormone (hGH) extracted from cadaveric hypophyses. These iCJD patients had been treated for short stature by injection of hGH in childhood, and 226 of them died of iCJD as young adults, mainly in France and the USA13). Other dramatic iCJD cases had been linked to the surgical implantation of dura-mater grafts, resulting in 228 deaths13). A few cases were also due to corneal grafts and intracranial electrodes. Although all known iCJD cases prior to 2004 had been linked to contamination with central nervous system (CNS) tissue, the possibility existed that the BSE agent would harbor a different distribution in primates than the sCJD agent, thus representing a higher risk of transmission via organ/tissue grafts, contamination of surgical instruments or even blood transfusion.

As a first step for risk assessment, we transmitted the BSE prion from macaque to macaque via different routes. We also established a dose-response (incubation time) for the IC route to provide a baseline for subsequent infectivity measurement studies. This experiment showed that the BSE agent adapts rapidly to primates, as incubation periods shortened from 3 to 1.5 years upon secondary passage at the highest dose14). It also showed that, for a given amount of BSE material (40 mg BSE brain homogenate), the incubation period was the same whether inoculation was done by the IC or the intravenous (IV) route.

2. The Cynomolgus Macaque as a model to Understand the Pathogenesis of Variant Creutzfeldt-Jakob Disease (vCJD) and Model Risk of Interhuman Transmission 

2. 1. Distribution of Prions in Tissues and Organs of BSE/vCJD Macaques after Oral or Intravenous (IV) Inoculation 

We compared second passage macaques inoculated with BSE prions by the oral or IV routes15). PrPsc was detected by immunohistochemistry and by ELISA after “scrapie associated fibril” (SAF) purification15). In addition to the brain, we detected PrPsc in spleen, tonsils, intestine and sciatic nerve in amounts that did not depend on the inoculation route, with the exceptions of the spleen where PrPsc amounts were up to 4% the amounts found in the brain after IV inoculation, and up to 0.2% those of the brain after oral dosing15).

2. 2. Distribution of Prions in Tissues and Organs of vCJD, Sporadic and Iatrogenic CJD Infected Macaques 

We also infected macaques with vCJD, sCJD, iCJD16). As determined earlier, BSE and vCJD prions correspond to the same prion strain, and one or the other denomination is used depending on the species of origin for the brain tissue used as inoculum. All prion strains were inoculated in the same manner (intracerebral and intratonsillar combined), in order to be able to directly compare tissue distribution of PrPsc between strains.

Disease-associated PrP deposits were detected by immunocytochemistry in various organs. They were found in the Peyer’s patches of the gut and other lymphoreticular system (LRS) tissue of BSE/vCJD infected animals (Fig. 2). By PET-blot, we showed that these deposits corresponded to proteinase K-resistant PrP, a biochemical subset of PrPsc. Interestingly, not all Peyer’s patches of a single animal were PrPsc positive (Fig. 2), showing that PrPsc-negative LRS tissue biopsies may lead to false negative diagnostic results.

Pathological PrP deposits were also detected in the enteric nervous system in macaques infected with all prion strains. Fig. 3 shows the localization of pathological PrP in the pericarya of neurons of the myenteric plexus, as well as in small nerve fibers of the inner muscular layer of the intestine.

Pathological PrP deposits were also found in peripheral nerves and in muscle for all CJD strains (Table 1). In the peripheral nerves, they were found mostly at the surface of Schwann cells (Fig. 4). In muscle, they were localized to specific foci in the vicinity of nerve fibers (Fig. 5). Our results suggest that the heterogeneous, patchy distribution of pathological PrP deposits in muscles corresponds to the distribution zones of motor end plates. This study provides a possible explanation for the variably positive detection of pathological PrP in muscle samples of sCJD patients17).

PrPsc amounts were also measured semi-quantitatively using a sensitive biochemical detection method including phosphotungstic acid precipitation as a concentration method, and western blot or ELISA detection16). This method revealed the presence of PrPsc in the spleen of the sCJD infected macaque and tonsils of the iCJD infected macaque, but no PrPsc could be detected in lymph nodes and Peyer’s patches of these animals, a result most likely due to the presence of PrPsc amounts at the threshold of detection in the LRS of sCJD and iCJD macaques, and sampling variations. These results are summarized in Table 1.

In summary, PrPsc was detectable at high levels in organs and tissues of the LRS only in BSE/vCJD infected animals (0.1% to 10% of the amounts found in the brains of the same animals). We interpreted these results as the BSE prion being highly lymphotropic in primates. These findings correlated indeed with the tonsils, spleens and appendices of vCJD patients being found positive for PrPsc18,19,20). We therefore proposed that LRS tissues be considered ‘high-risk’ in vCJD patients only.

However, lower amounts of PrPsc were detected in adrenals, muscles and intestinal tissue of macaques infected with BSE/vCJD as well as sCJD and iCJD, associated with peripheral nerves. 

Levels were less than 10,000 times lower than brain PrPres levels (<0 .001="" nbsp="" span="">

*** We therefore proposed that these tissues be considered “low-risk” for all CJD patients.

Our results expanded upon observations made in vCJD patients that PrPsc is detectable in tonsils, emphasizing that BSE prions are largely lymphotropic in primates, and may replicate in lymph notes, tonsils, spleen and Peyer’s patches before the symptomatic phase. Our subsequent studies confirmed that lymph node biopsies of BSE-inoculated macaques were positive for PrPsc prior to the onset of clinical signs (see below). In another study, gut-associated lymphoid tissue and gut-draining lymph nodes were found positive for PrPsc within one year of oral infection of macaques with cattle BSE21). On the other hand, distribution of PrPsc in muscle of macaques inoculated with vCJD, sCJD and iCJD suggests a centrifugal spread of prions from the CNS to muscle motor plates via motor nerves, occurring after CNS invasion by prions. In addition, it is probable that centripetal spread of prions via peripheral nerves also occurs in earlier stages of infection stochastically from various points of entry, even in the absence of prior LRS replication. We demonstrated this paradigm earlier in severely immunodeficient (SCID) mice infected with mouse-adapted scrapie22). Moreover, spread from the gut to the CNS via autonomic nerve fibers has been shown in experimental scrapie and BSE23,24,25). Fig. 6 illustrates the distribution and proposed propagation of prions in our non-human primate model.

2.2. Blood Infectivity Studies in the Macaque vCJD Model The lymphotropic properties of BSE prions raised the important question of the presence of infectivity in blood of vCJD patients.

We initiated a large blood transfusion study where whole blood, white blood cells or plasma from either vCJD patients or BSE/vCJD macaques was injected by IV or IC to recipient macaques. This experiment led to most macaques surviving over prolonged periods of time (>10 years), and few coming down with BSE/vCJD or intercurrent illnesses. These studies continued after the author of this manuscript left the CEA. Interim transmission results are shown in Fig. 7, and some important observations were as follows. Blood depleted for red blood cells (RBC) from a vCJD patient (7.5 mL) injected intravenously did not result in any clinical disease in the recipient macaque after 10 years, yet this animal harbored positive IHC staining in the inguinal lymph nodes (LNs). Another macaque, who had received 25 mL of RBC-depleted blood intravenously from another vCJD patient, died suddenly at 42 months after inoculation, and harbored PrPsc positive inguinal LNs. Two other animals, that received 500 µL of buffy coat (BC) from vCJD patients by IC, were still alive 10 years after inoculation (with PrPsc positive LNs, Fig. 7A). A whole blood transfusion of 40 mL from a vCJD macaque (who died 3 years after intracerebral + intratonsillar inoculation of human vCJD brain homogenate) induced clinical signs of vCJD in the recipient macaque 66 months after the transfusion. Inguinal lymph nodes biopsies had been positive since 45 months, i.e. 75% of the incubation period (Fig. 7B). Other macaques transfused with blood from BSE-macaques survived more than 10 years, but some had positive LNs (Fig. 7C). Another notable result was the transmission of BSE infection by the plasma from a macaque that had been dosed orally with cattle BSE 27.5 months earlier. The donor macaque died with a behavioral syndrome of self-injury 117 months after challenge with a diagnosis of probable BSE, hence infectivity was present in its blood at a quarter of the incubation period (Fig. 7D).

In 2004, the first transfusion-related case of vCJD was described in a patient who had been transfused with non-leucoreduced red blood cells from a donor who developed vCJD 3.5 years after the donation26). A total of four transfusion-related vCJD transmissions have been reported to date27).


I thank the many people who supported and participated in this work at the CEA: Dominique Dormont, Jean-Philippe Deslys, Christian Herzog, Nathalie Lescoutra, Nicole Salès, Emmanuel Comoy, René Rioux. I also thank Ray Bradley and Michael Dawson for providing BSE-infected cattle brain homogenates. I am thankful to Robert Will and Nicolas Kopp for providing vCJD samples, and to James Ironside for his collaboration on the neuropathology of BSE-infected macaques. I am grateful to my European collaborators Maurizio Pocchiari, Gerhard Hunsmann, Johannes Löwer, Pär Bierke, Loredana Ingrosso, Uwe Hahmann, Dirk Motzkus, Edgar Holznagel, for their friendship and for embarking on this challenging project.

Volume 23, Number 6—June 2017 Synopsis

Sporadic Creutzfeldt-Jakob Disease in 2 Plasma Product Recipients, United Kingdom, P. Urwin et al.

View Summary

Two cases of sporadic CJD with clotting disorders have been identified, but this may represent a chance event.

Volume 23, Number 6—June 2017


Distribution and Quantitative Estimates of Variant Creutzfeldt-Jakob Disease Prions in Tissues of Clinical and Asymptomatic Patients

Jean Y. Douet, Caroline Lacroux, Naima Aron, Mark W. Head, Séverine Lugan, Cécile Tillier, Alvina Huor, Hervé Cassard, Mark Arnold, Vincent Beringue, James W. Ironside, and Olivier Andréoletti

Comments to Author Author affiliations: Institut National de la Recherche Agronomique, Toulouse, France (J.Y. Douet, C. Lacroux, N. Aron, S. Lugan, C. Tillier, A. Huor, H. Cassard, O. Andréoletti); University of Edinburgh, Edinburgh, Scotland, UK (M.W. Head, J.W. Ironside); Animal and Plant Health Agency, Loughborough, UK (M. Arnold); Institut National de la Recherche Agronomique, Jouy-en-Josas, France (V. Beringue) Suggested citation for this article


In the United-Kingdom, ≈1 of 2,000 persons could be infected with variant Creutzfeldt-Jakob disease (vCJD). Therefore, risk of transmission of vCJD by medical procedures remains a major concern for public health authorities. In this study, we used in vitro amplification of prions by protein misfolding cyclic amplification (PMCA) to estimate distribution and level of the vCJD agent in 21 tissues from 4 patients who died of clinical vCJD and from 1 asymptomatic person with vCJD. PMCA identified major levels of vCJD prions in a range of tissues, including liver, salivary gland, kidney, lung, and bone marrow. Bioassays confirmed that the quantitative estimate of levels of vCJD prion accumulation provided by PMCA are indicative of vCJD infectivity levels in tissues. Findings provide critical data for the design of measures to minimize risk for iatrogenic transmission of vCJD.



Most previous studies with tissue from vCJD patients have failed to identify consistent accumulation of the vCJD agent outside the nervous and lymphoreticular systems. However, data obtained in this study clearly demonstrate the presence of vCJD prions in a wide and unexpected variety of peripheral tissues.

Natural scrapie and experimental BSE in sheep are 2 models of orally transmitted prion diseases (24,25). In both diseases, the agent accumulates in the lymphoreticular system and the enteric nervous system during the early preclinical phase of the incubation period. Moreover, an early and persistent prionemia is observed in asymptomatic infected animals (26,27). These features were also observed in vCJD in humans and in view of the likely origin of vCJD (oral exposure to BSE agent), these similarities have led to a consensus that BSE and scrapie in sheep and vCJD in human have a common pathogenesis (28).

Although vCJD prions in a variety tissues, such as bone marrow, kidney, salivary gland, skeletal muscle, pancreas, liver, or heart, might be surprising, each of these tissue has already been demonstrated to accumulate prion infectivity or abnormal prion protein in TSE-infected sheep (29–33). Because low levels of infectivity have been reported in blood fractions from a vCJD-affected patient, such widespread tissue positivity might be derived from residual blood, rather than from the solid tissue in these samples (16). However, this proposal seems unlikely because in whole blood PMCA amplification inhibitors preclude detection of endogenous vCJD agent by this method (11,34–36).

The patient in our study who was infected with a prion containing PRNP gene codon 129 Met/Val is 1 of only 2 identified vCJD agent–infected persons known to have died of other causes before onset clinical symptoms of vCJD, and the only person who provided consent to sample autopsy tissues for research. For this patient, all previous investigations did not detect abnormal prion protein or infectivity in the brain (12,37). The negative PMCA results we obtained for cerebral cortex, dorsal root ganglia, and trigeminal ganglia tissue from this patient are consistent with a lack of central nervous system involvement at the time of death. However, PMCA seeding activity in the pituitary gland was surprising in this instance.

The presence of abnormal prion protein accumulation in the pituitary gland and other circumventricular organs before deposition of PrPres in surrounding brain has been reported in TSE-infected sheep (38). However, this phenomenon in animals does not represent the main route for neuroinvasion and is a probable consequence of hematogenous dissemination of the TSE agent through the fenestrated capillary system of the circumventricular organs, which is substantially more permeable than the other capillaries in the brain (blood–brain barrier). Therefore, this finding might be a consequence of the hematogenous route of secondary vCJD in this person (by transfusion of packed erythrocytes from a vCJD-infected donor), in contrast to the oral route of infection in primary clinical vCJD cases (12).

vCJD prions were detected in certain peripheral tissues from the patients infected with a prion containing the PRNP gene codon 129 Met/Val. Although distribution of vCJD seeding activity in lymphoreticular tissues was similar to that observed for symptomatic vCJD patients, several tissues that were positive in clinically affected patients were negative in this heterozygous asymptomatic person. These findings suggest that involvement of some peripheral tissues might occur at a later stage in the incubation period than others, or that they could involve recirculation of the agent from the central nervous system (i.e., centrifugal spread in a late state). However, we cannot discount the possibility that that these differences in tissue distribution are caused by the hematogenous route of infection in this person (as opposed to the probable oral route in patients with clinical vCJD) or the difference between the PRNP gene codon 129 genotype of the asymptomatic vCJD–affected person (PRNP gene codon 129 Met/Val) and persons with clinical vCJD (PRNP gene codon 129 Met/Met).

Irrespective of the actual explanation for these differences, the presence of vCJD agent in peripheral tissues of patients during preclinical and clinical stage of the disease indicates the potential for iatrogenic transmission of this fatal neurologic condition by surgical procedures. Furthermore, this finding shows that, for certain peripheral tissues, a level of infectivity equivalent to an end stage titer (and attendant risk) is reached at a preclinical stage.

Several hundred cases of iatrogenic CJD have been reported worldwide. These cases appear to result from transmission of sporadic CJD, and most cases have occurred in recipients of human dura mater grafts or after administration of human growth hormone extracted from cadaveric pituitaries (39). Although in sporadic CJD the distribution of the agent is largely restricted to the nervous system (central and peripheral), the wide distribution of the vCJD agent in the asymptomatic infected patient we report might serve to increase the range of medical procedures, including dentistry, organ transplant, and surgery involving nondisposable equipment, that might result in iatrogenic transmission of vCJD (40–43).

Nevertheless, >20 years after identification of the first vCJD patients, only 5 cases that are a probable consequence of iatrogenic vCJD transmission are known, all in the United Kingdom and associated with blood and blood products. These cases were caused by transfusion of non–leukocyte-depleted erythrocyte concentrates or by treatment involving large amounts of pooled plasma from the United Kingdom that were known to include donations from persons who later showed development of vCJD (12,44–46).

None of the 220 other vCJD cases identified worldwide have been linked to any other medical or dental procedure. Whereas this fact is reassuring, it would be unwise to disregard the threat that vCJD still poses for public health. Despite the relatively low number (n = 178) of vCJD clinical cases observed in the United Kingdom, the most recent epidemiologic studies indicate that ≈1 of 2,000 persons in the United Kingdom could be infected with the vCJD agent (as indicated by the presence of abnormal prion protein detected by immunohistochemical analysis of lymphoid follicles in the appendix). Each asymptomatic vCJD-infected person represents a potential source of secondary infection. The data in our report offer an opportunity for refining measures that were implemented in many countries to limit the risk for vCJD iatrogenic transmission. The apparent concordance between PMCA biochemical and infectivity bioassay data, and the higher analytical sensitivity of PMCA, suggest that future research need not rely exclusively on time-consuming and costly animal bioassay.

Our results indicate the need for vCJD screening assays. After more than a decade of effort, several vCJD blood detection tests have reached a stage in their development that could enable their evaluation as screening or confirmatory assays (11,47,48). In particular, there is now a strong case for use of PMCA in a highly sensitive and specific blood test for vCJD, as indicated by our previous studies (11,16) and studies by Bougard et al. (35) and Concha-Marambio et al. (36). The relationship shown here between PrPres amplification by PMCA and detection of infectivity by bioassay indicates that PMCA seeding activity is a good surrogate marker of infectivity and could provide a sound basis for a vCJD blood test for use with blood or tissue donors.

Dr. Douet is a research scientist and assistant lecturer in ophthalmology at the National Veterinary School of Toulouse, Toulouse, France. His primary research interests are the pathogenesis of the prion disease with special emphasis on the iatrogenic risk of transmission.


This study was supported in part by the Department of Health Policy Research Programme and the Scottish Government. The National CJD Research and Surveillance Unit is supported by the Policy Research Program of the Department of Health and the Scottish Government (DH121/5061). The Edinburgh Brain Bank is supported by the Medical Research Council (MRC grant G0900580). The Unité Mixte de Recherche 1225, Ecole Nationale Vétérinaire de Toulouse was supported by the European Union FEDER/INTERREG (EFA282/13 TRANSPRION), the Institut National de la Recherche Agronomique Institut Carnot en Santé Animale, and an Agence Nationale Recherche grant (Unmasking Blood Prions; ANR-15-CE18-0028).


Blood transmission studies of prion infectivity in the squirrel monkey (Saimiri sciureus): the Baxter study ORIGINAL RESEARCH 

Blood transmission studies of prion infectivity in the squirrel monkey (Saimiri sciureus): the Baxter study

Diane L. Ritchie1,*, Susan V. Gibson2,†, Christian R. Abee3, Thomas R. Kreil4, James W. Ironside1 and Paul Brown5

Article first published online: 23 NOV 2015

DOI: 10.1111/trf.13422

© 2015 AABB


Cover image for Vol. 55 Issue 11


Early View (Online Version of Record published before inclusion in an issue)



Four secondary transmissions of variant Creutzfeldt-Jakob disease (vCJD) infectivity have been associated with the transfusion of nonleukoreduced red blood cells collected from vCJD patients during the asymptomatic phase of the disease. Establishing efficient experimental models for assessing the risk of future transmissions of vCJD infectivity via blood transfusion is of paramount importance in view of a study of archived appendix samples in which the prevalence of asymptomatic vCJD infection in the United Kingdom was estimated at approximately 1 in 2000 of the population. In this study, we investigated transmission of vCJD and sporadic CJD (sCJD) infectivity from blood using the squirrel monkey, which is highly susceptible to experimental challenge with human prion disease.


Whole blood collected from vCJD- and sCJD-infected squirrel monkeys was transfused at multiple time points into recipient squirrel monkeys. Blood recipients were euthanized approximately 7 years after their first blood transfusion.


No clinical or pathologic signs of a prion disease were observed in either the sCJD- or the vCJD-transfused monkeys, and immunohistochemistry and biochemical investigations showed no PrPTSE in central nervous system or lymphoreticular tissues. Similarly, monkeys inoculated intracerebrally (IC) and intravenously (IV) with either buffy coat or plasma from vCJD and sCJD patients failed to develop disease. However, white blood cells from a chimpanzee-passaged strain of human Gerstmann-Sträussler-Scheinker (GSS) disease transmitted autopsy-proven disease to two IC-inoculated monkeys after incubation periods of 34 and 39 months.


Blood transmits GSS but not sCJD or vCJD infectivity to IC- or IV-inoculated squirrel monkeys within a 7-year observation period.


*** RE-P.164: Blood transmission of prion infectivity in the squirrel monkey: The Baxter study

***suggest that blood donations from cases of GSS (and perhaps other familial forms of TSE) carry more risk than from vCJD cases, and that little or no risk is associated with sCJD. ***

P.164: Blood transmission of prion infectivity in the squirrel monkey: The Baxter study

Paul Brown1, Diane Ritchie2, James Ironside2, Christian Abee3, Thomas Kreil4, and Susan Gibson5 1NIH (retired); Bethesda, MD USA; 2University of Edinburgh; Edinburgh, UK; 3University of Texas; Bastrop, TX USA; 4Baxter Bioscience; Vienna, Austria; 5University of South Alabama; Mobile, AL USA 

Five vCJD disease transmissions and an estimated 1 in 2000 ‘silent’ infections in UK residents emphasize the continued need for information about disease risk in humans. A large study of blood component infectivity in a non-human primate model has now been completed and analyzed. Among 1 GSS, 4 sCJD, and 3 vCJD cases, only GSS leukocytes transmitted disease within a 5–6 year surveillance period. A transmission study in recipients of multiple whole blood transfusions during the incubation and clinical stages of sCJD and vCJD in ic-infected donor animals was uniformly negative. These results, together with other laboratory studies in rodents and nonhuman primates and epidemiological observations in humans, suggest that blood donations from cases of GSS (and perhaps other familial forms of TSE) carry more risk than from vCJD cases, and that little or no risk is associated with sCJD. The issue of decades-long incubation periods in ‘silent’ vCJD carriers remains open. 

ran across an old paper from 1984 ;

***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.






Saturday, May 30, 2015


Wednesday, December 11, 2013

*** Detection of Infectivity in Blood of Persons with Variant and Sporadic Creutzfeldt-Jakob Disease ***


Thursday, November 12, 2015

Evaluation of the protection of primates transfused with variant Creutzfeldt-Jakob disease–infected blood products filtered with prion removal devices: a 5-year update

Primate Biol., 3, 47–50, 2016 doi:10.5194/pb-3-47-2016 © Author(s) 2016. CC
Attribution 3.0 License.
Walter Bodemer German Primate Center, Kellnerweg 4, 37077 Göttingen, Germany Correspondence to: Walter Bodemer (
Received: 15 June 2016 – Revised: 24 August 2016 – Accepted: 30 August 2016 – Published: 7 September 2016
 3 Conclusion
Most importantly, early signs of an altered circadian rhythm, sleep–wake cycle, and activity and body temperature were recorded in prion-infected animals. This experimental approach would have never been feasible in studies with human CJD cases. After 4–6 years animals developed clinical symptoms highly similar to those typical for CJD. Clinicians confirmed how close the animal model and the human disease matched. Non-neuronal tissue like cardiac muscle and peripheral blood with abnormal, disease-related prion protein were detected in rhesus monkey tissues.
Molecular changes in RNA from repetitive Alu and BC200 DNA elements were identified and found to be targets of epigenetic editing mechanisms active in prion disease. To conclude, our results with the rhesus monkey model for prion disease proved to be a valid model and increased our knowledge of pathogenic processes that are distinctive to prion disease.

*** WDA 2016 NEW YORK 

*** We found that CWD adapts to a new host more readily than BSE and that human PrP was unexpectedly prone to misfolding by CWD prions. 

*** In addition, we investigated the role of specific regions of the bovine, deer and human PrP protein in resistance to conversion by prions from another species. 

*** We have concluded that the human protein has a region that confers unusual susceptibility to conversion by CWD prions. 

Student Presentations Session 2 

The species barriers and public health threat of CWD and BSE prions Ms. Kristen Davenport1, Dr. Davin Henderson1, Dr. Candace Mathiason1, Dr. Edward Hoover1 1Colorado State University 

Chronic wasting disease (CWD) is spreading rapidly through cervid populations in the USA. Bovine spongiform encephalopathy (BSE, mad cow disease) arose in the 1980s because cattle were fed recycled animal protein. These and other prion diseases are caused by abnormal folding of the normal prion protein (PrP) into a disease causing form (PrPd), which is pathogenic to nervous system cells and can cause subsequent PrP to misfold. CWD spreads among cervids very efficiently, but it has not yet infected humans. On the other hand, BSE was spread only when cattle consumed infected bovine or ovine tissue, but did infect humans and other species. The objective of this research is to understand the role of PrP structure in cross-species infection by CWD and BSE. To study the propensity of each species’ PrP to be induced to misfold by the presence of PrPd from verious species, we have used an in vitro system that permits detection of PrPd in real-time. 

We measured the conversion efficiency of various combinations of PrPd seeds and PrP substrate combinations. 

We observed the cross-species behavior of CWD and BSE, in addition to feline-adapted CWD and BSE. 

We found that CWD adapts to a new host more readily than BSE and that human PrP was unexpectedly prone to misfolding by CWD prions. 

In addition, we investigated the role of specific regions of the bovine, deer and human PrP protein in resistance to conversion by prions from another species. 

We have concluded that the human protein has a region that confers unusual susceptibility to conversion by CWD prions. 

CWD is unique among prion diseases in its rapid spread in natural populations. BSE prions are essentially unaltered upon passage to a new species, while CWD adapts to the new species. 

This adaptation has consequences for surveillance of humans exposed to CWD. Wildlife Disease Risk Communication Research Contributes to Wildlife Trust Administration Exploring perceptions about chronic wasting disease risks among wildlife and agriculture professionals and stakeholders 

PRION 2016 TOKYO Zoonotic Potential of CWD Prions: An Update 

Ignazio Cali1, Liuting Qing1, Jue Yuan1, Shenghai Huang2, Diane Kofskey1,3, Nicholas Maurer1, Debbie McKenzie4, Jiri Safar1,3,5, Wenquan Zou1,3,5,6, Pierluigi Gambetti1, Qingzhong Kong1,5,6 1Department of Pathology, 3National Prion Disease Pathology Surveillance Center, 5Department of Neurology, 6National Center for Regenerative Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. 4Department of Biological Sciences and Center for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada, 2Encore Health Resources, 1331 Lamar St, Houston, TX 77010 

Chronic wasting disease (CWD) is a widespread and highly transmissible prion disease in free-ranging and captive cervid species in North America. The zoonotic potential of CWD prions is a serious public health concern, but the susceptibility of human CNS and peripheral organs to CWD prions remains largely unresolved. We reported earlier that peripheral and CNS infections were detected in transgenic mice expressing human PrP129M or PrP129V. Here we will present an update on this project, including evidence for strain dependence and influence of cervid PrP polymorphisms on CWD zoonosis as well as the characteristics of experimental human CWD prions. 

PRION 2016 TOKYO In Conjunction with Asia Pacific Prion Symposium 2016 PRION 2016 Tokyo Prion 2016 

Monday, May 02, 2016 

*** Zoonotic Potential of CWD Prions: An Update Prion 2016 Tokyo *** 

Saturday, April 23, 2016 

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 


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. 



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. 

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

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

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. 


*** These results would seem to suggest that CWD does indeed have zoonotic potential, at least as judged by the compatibility of CWD prions and their human PrPC target. Furthermore, extrapolation from this simple in vitro assay suggests that if zoonotic CWD occurred, it would most likely effect those of the PRNP codon 129-MM genotype and that the PrPres type would be similar to that found in the most common subtype of sCJD (MM1).*** 

*** The potential impact of prion diseases on human health was greatly magnified by the recognition that interspecies transfer of BSE to humans by beef ingestion resulted in vCJD. While changes in animal feed constituents and slaughter practices appear to have curtailed vCJD, there is concern that CWD of free-ranging deer and elk in the U.S. might also cross the species barrier. Thus, consuming venison could be a source of human prion disease. Whether BSE and CWD represent interspecies scrapie transfer or are newly arisen prion diseases is unknown. Therefore, the possibility of transmission of prion disease through other food animals cannot be ruled out. There is evidence that vCJD can be transmitted through blood transfusion. There is likely a pool of unknown size of asymptomatic individuals infected with vCJD, ***

*** and there may be asymptomatic individuals infected with the CWD equivalent. 

*** These circumstances represent a potential threat to blood, blood products, and plasma supplies. 

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

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

 TUESDAY, MARCH 28, 2017 

Passage of scrapie to deer results in a new phenotype upon return passage to sheep

Disease-associated prion protein detected in lymphoid tissues from pigs challenged with the agent of chronic wasting disease 


Location: Virus and Prion Research

Title: Disease-associated prion protein detected in lymphoid tissues from pigs challenged with the agent of chronic wasting disease

Author item Moore, Sarah item Kunkle, Robert item Kondru, Naveen item Manne, Sireesha item Smith, Jodi item Kanthasamy, Anumantha item West Greenlee, M item Greenlee, Justin

Submitted to: Prion Publication Type: Abstract Only Publication Acceptance Date: 3/15/2017 Publication Date: N/A Citation: N/A Interpretive Summary:

Technical Abstract: Aims: Chronic wasting disease (CWD) is a naturally-occurring, fatal neurodegenerative disease of cervids. We previously demonstrated that disease-associated prion protein (PrPSc) can be detected in the brain and retina from pigs challenged intracranially or orally with the CWD agent. In that study, neurological signs consistent with prion disease were observed only in one pig: an intracranially challenged pig that was euthanized at 64 months post-challenge. The purpose of this study was to use an antigen-capture immunoassay (EIA) and real-time quaking-induced conversion (QuIC) to determine whether PrPSc is present in lymphoid tissues from pigs challenged with the CWD agent. Methods: At two months of age, crossbred pigs were challenged by the intracranial route (n=20), oral route (n=19), or were left unchallenged (n=9). At approximately 6 months of age, the time at which commercial pigs reach market weight, half of the pigs in each group were culled (<6 challenge="" groups="" month="" pigs="" remaining="" the="">6 month challenge groups) were allowed to incubate for up to 73 months post challenge (mpc). The retropharyngeal lymph node (RPLN) was screened for the presence of PrPSc by EIA and immunohistochemistry (IHC). The RPLN, palatine tonsil, and mesenteric lymph node (MLN) from 6-7 pigs per challenge group were also tested using EIA and QuIC. Results: PrPSc was not detected by EIA and IHC in any RPLNs. All tonsils and MLNs were negative by IHC, though the MLN from one pig in the oral <6 5="" 6="" at="" by="" detected="" eia.="" examined="" group="" in="" intracranial="" least="" lymphoid="" month="" months="" of="" one="" pigs="" positive="" prpsc="" quic="" the="" tissues="" was="">6 months group, 5/6 pigs in the oral <6 4="" and="" group="" months="" oral="">6 months group. Overall, the MLN was positive in 14/19 (74%) of samples examined, the RPLN in 8/18 (44%), and the tonsil in 10/25 (40%). 

Conclusions: This study demonstrates that PrPSc accumulates in lymphoid tissues from pigs challenged intracranially or orally with the CWD agent, and can be detected as early as 4 months after challenge. CWD-infected pigs rarely develop clinical disease and if they do, they do so after a long incubation period. This raises the possibility that CWD-infected pigs could shed prions into their environment long before they develop clinical disease. Furthermore, lymphoid tissues from CWD-infected pigs could present a potential source of CWD infectivity in the animal and human food chains.



While this clearly is a cause for concern we should not jump to the conclusion that this means that pigs will necessarily be infected by bone and meat meal fed by the oral route as is the case with cattle. ...

we cannot rule out the possibility that unrecognised subclinical spongiform encephalopathy could be present in British pigs though there is no evidence for this: only with parenteral/implantable pharmaceuticals/devices is the theoretical risk to humans of sufficient concern to consider any action.

May I, at the outset, reiterate that we should avoid dissemination of papers relating to this experimental finding to prevent premature release of the information. ...

3. It is particularly important that this information is not passed outside the Department, until Ministers have decided how they wish it to be handled. ...

But it would be easier for us if pharmaceuticals/devices are not directly mentioned at all. ...

Our records show that while some use is made of porcine materials in medicinal products, the only products which would appear to be in a hypothetically ''higher risk'' area are the adrenocorticotrophic hormone for which the source material comes from outside the United Kingdom, namely America China Sweden France and Germany. The products are manufactured by Ferring and Armour. A further product, ''Zenoderm Corium implant'' manufactured by Ethicon, makes use of porcine skin - which is not considered to be a ''high risk'' tissue, but one of its uses is described in the data sheet as ''in dural replacement''. This product is sourced from the United Kingdom.....

snip... see much more here ;


Disease-associated prion protein detected in lymphoid tissues from pigs challenged with the agent of chronic wasting disease

FRIDAY, MARCH 31, 2017 

TPWD UPDATE CWD TSE Prion 49 confirmed cases and unwanted firsts for Texas 


TEXAS, Politicians, TAHC, TPWD, and the spread of CWD TSE Prion in Texas 


In vitro amplification of H-type atypical bovine spongiform encephalopathy by protein misfolding cyclic amplification 

"When considering the atypical L-BSE and H-BSE diseases of cattle, they have been assessed in both non-human primate and transgenic mouse bioassays (with mice transgenic for human PRNP) and both model systems indicate that H-BSE and L-BSE may have increased zoonotic potential compare with C-BSE. The detection of all types of BSE is therefore of significant importance." 

Monday, January 09, 2017 

Oral Transmission of L-Type Bovine Spongiform Encephalopathy Agent among Cattle CDC Volume 23, Number 2—February 2017 

Consumption of L-BSE–contaminated feed may pose a risk for oral transmission of the disease agent to cattle. 


***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.***

Wednesday, December 21, 2016 


Tuesday, September 06, 2016

A comparison of classical and H-type bovine spongiform encephalopathy associated with E211K prion protein polymorphism in wild type and EK211 cattle following intracranial inoculation

Saturday, July 23, 2016


Tuesday, July 26, 2016

Atypical Bovine Spongiform Encephalopathy BSE TSE Prion UPDATE JULY 2016

Monday, June 20, 2016

Specified Risk Materials SRMs BSE TSE Prion Program

Thursday, December 08, 2016 

USDA APHIS National Scrapie Eradication Program October 2016 Monthly Report Fiscal Year 2017 atypical NOR-98 Scrapie 

Saturday, December 01, 2007

Phenotypic Similarity of Transmissible Mink Encephalopathy in Cattle and L-type Bovine Spongiform Encephalopathy in a Mouse Model

Sunday, December 10, 2006

Transmissible Mink Encephalopathy TME

Saturday, June 25, 2011

Transmissibility of BSE-L and Cattle-Adapted TME Prion Strain to Cynomolgus Macaque

"BSE-L in North America may have existed for decades"

Wednesday, April 25, 2012


Discussion: The C, L and H type BSE cases in Canada exhibit molecular characteristics similar to those described for classical and atypical BSE cases from Europe and Japan.

*** This supports the theory that the importation of BSE contaminated feedstuff is the source of C-type BSE in Canada.

*** It also suggests a similar cause or source for atypical BSE in these countries. ***

see page 176 of 201 pages...tss

*** Singeltary reply ; Molecular, Biochemical and Genetic Characteristics of BSE in Canada Singeltary reply;

Wednesday, July 15, 2015

Additional BSE TSE prion testing detects pathologic lesion in unusual brain location and PrPsc by PMCA only, how many cases have we missed?

***however in 1 C-type challenged animal, Prion 2015 Poster Abstracts S67 PrPsc was not detected using rapid tests for BSE.

***Subsequent testing resulted in the detection of pathologic lesion in unusual brain location and PrPsc detection by PMCA only.

*** IBNC Tauopathy or TSE Prion disease, it appears, no one is sure ***

Posted by Terry S. Singeltary Sr. on 03 Jul 2015 at 16:53 GMT


APHIS Bovine Spongiform Encephalopathy (BSE): Ongoing Surveillance Program Last Modified: Jan 5, 2017

10,000,000 POUNDS REASON Products manufactured from bulk feed containing blood meal that was cross contaminated with prohibited meat and bone meal and the labeling did not bear cautionary BSE statement.
Date: March 21, 2007 at 2:27 pm PST
Bulk cattle feed made with recalled Darling's 85% Blood Meal, Flash Dried, Recall # V-024-2007 CODE Cattle feed delivered between 01/12/2007 and 01/26/2007 RECALLING FIRM/MANUFACTURER Pfeiffer, Arno, Inc, Greenbush,
WI. by conversation on February 5, 2007.
Firm initiated recall is ongoing.
REASON Blood meal used to make cattle feed was recalled because it was cross- contaminated with prohibited bovine meat and bone meal that had been manufactured on common equipment and labeling did not bear cautionary BSE statement.
CODE The firm does not utilize a code - only shipping documentation with commodity and weights identified.
RECALLING FIRM/MANUFACTURER Rangen, Inc, Buhl, ID, by letters on February 13 and 14, 2007.
Firm initiated recall is complete.
REASON Products manufactured from bulk feed containing blood meal that was cross contaminated with prohibited meat and bone meal and the labeling did not bear cautionary BSE statement.


TUESDAY, APRIL 18, 2017 


SUNDAY, APRIL 16, 2017

MM1-type sporadic Creutzfeldt-Jakob disease with 1-month total disease duration and early pathologic indicators


Case-control study on the use of pituitary-derived hormones from sheep as a potential risk factor for the occurrence of atypical scrapie in Great Britain


Prion-Seeding Activity Is widely Distributed in Tissues of Sporadic Creutzfeldt-Jakob Disease Patients

MONDAY, APRIL 03, 2017

Accessing transmissibility and diagnostic marker of skin prions


Heidenhain variant of Creutzfeldt–Jakob disease in a patient who had bovine bioprosthetic valve implantation


Of Grave Concern Heidenhain Variant Creutzfeldt Jakob Disease


Please Support Funding for CDC and NPDPSC's Prion Disease Programs

Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Singeltary, Sr et al. JAMA.2001; 285: 733-734. Vol. 285 No. 6, February 14, 2001 JAMA
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
To the Editor: In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.
Terry S. Singeltary, Sr Bacliff, Tex
1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323.

26 March 2003 

Terry S. Singeltary, retired (medically) CJD WATCH 

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

The Lancet Infectious Diseases, Volume 3, Issue 8, Page 463, August 2003 doi:10.1016/S1473-3099(03)00715-1Cite or Link Using DOI 

Tracking spongiform encephalopathies in North America 

Original Xavier Bosch 

“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.” 49-year—old Singeltary is one of a number of people who have remained largely unsatisfied after being told that a close relative died from a rapidly progressive dementia compatible with spontaneous Creutzfeldt—Jakob ... 

RE: re-Human Prion Diseases in the United States part 2 flounder replied to flounder on 02 Jan 2010 at 21:26 GMT No competing interests declared. 

see full text ; 

*** Needless conflict ***

 Nature 485, 279–280 (17 May 2012) doi:10.1038/485279b

 Published online 16 May 2012

 Terry S. Singeltary Sr. said:

 I kindly wish to submit the following please ; 

 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;
Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease
*** Singeltary comment PLoS ***
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
Posted by flounder on 05 Nov 2014 at 21:27 GMT
Sunday, November 22, 2015
*** Effect of heating on the stability of amyloid A (AA) fibrils and the intra- and cross-species transmission of AA amyloidosis Abstract
Amyloid A (AA) amyloidosis is a protein misfolding disease characterized by extracellular deposition of AA fibrils. AA fibrils are found in several tissues from food animals with AA amyloidosis. For hygienic purposes, heating is widely used to inactivate microbes in food, but it is uncertain whether heating is sufficient to inactivate AA fibrils and prevent intra- or cross-species transmission. We examined the effect of heating (at 60 °C or 100 °C) and autoclaving (at 121 °C or 135 °C) on murine and bovine AA fibrils using Western blot analysis, transmission electron microscopy (TEM), and mouse model transmission experiments. TEM revealed that a mixture of AA fibrils and amorphous aggregates appeared after heating at 100 °C, whereas autoclaving at 135 °C produced large amorphous aggregates. AA fibrils retained antigen specificity in Western blot analysis when heated at 100 °C or autoclaved at 121 °C, but not when autoclaved at 135 °C. Transmissible pathogenicity of murine and bovine AA fibrils subjected to heating (at 60 °C or 100 °C) was significantly stimulated and resulted in amyloid deposition in mice. Autoclaving of murine AA fibrils at 121 °C or 135 °C significantly decreased amyloid deposition. Moreover, amyloid deposition in mice injected with murine AA fibrils was more severe than that in mice injected with bovine AA fibrils. Bovine AA fibrils autoclaved at 121 °C or 135 °C did not induce amyloid deposition in mice. These results suggest that AA fibrils are relatively heat stable and that similar to prions, autoclaving at 135 °C is required to destroy the pathogenicity of AA fibrils. These findings may contribute to the prevention of AA fibril transmission through food materials to different animals and especially to humans.
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*** 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.

Terry S. Singeltary Sr. []

Monday, January 08, 2001 3:03 PM

CJD/BSE (aka madcow) Human/Animal TSE’s--U.S.--Submission To Scientific Advisors and Consultants Staff January 2001 Meeting (short version)

Greetings again Dr. Freas and Committee Members,

I wish to submit the following information to the Scientific Advisors and Consultants Staff 2001 Advisory Committee...

I think you are all aware of CJD vs vCJD, but i don't think you all know the facts of human/animal TSE's as a whole, they are all very very similar, and are all tied to the same thing, GREED and MAN.

I am beginning to think that the endless attempt to track down and ban, potential victims from known BSE Countries from giving blood will be futile. You would have to ban everyone on the Globe eventually? AS well, I think we MUST ACT SWIFTLY to find blood test for TSE's, whether it be blood test, urine test, eyelid test, anything at whatever cost, we need a test FAST.

DO NOT let the incubation time period of these TSEs fool you. To think of Scrapie as the prime agent to compare CJD, but yet overlook the Louping-ill vaccine event in 1930's of which 1000's of sheep where infected by scrapie from a vaccine made of scrapie infected sheep brains, would be foolish. I acquired this full text version of the event which was recorded in the Annual Congress of 1946 National Vet. Med. Ass. of Great Britain and Ireland.

From the BVA and the URL is posted in my (long version).

U.S.A. should make all human/animal TSE's notifiable at all ages, with requirements for a thorough surveillance and post-mortem examinations free of charge, if you are serious about eradicating this horrible disease in man and animal. ...

snip...see full text ;

SUNDAY, APRIL 23, 2017 

FDA Sec. 589.1 589.2 Substances prohibited from use in animal food or feed Animal, proteins prohibited in ruminant feed current of April 1 2016


Variant Creutzfeldt–Jakob Disease in a Patient with Heterozygosity at PRNP Codon 129


Amyloid‑β accumulation in the CNS in human growth hormone recipients in the UK

SUNDAY, APRIL 16, 2017

MM1-type sporadic Creutzfeldt-Jakob disease with 1-month total disease duration and early pathologic indicators

FRIDAY, APRIL 21, 2017



Heidenhain variant of Creutzfeldt–Jakob disease in a patient who had bovine bioprosthetic valve implantation

Year : 2016 | Volume : 64 | Issue : 10 | Page : 767-769 

Tuesday, November 29, 2016 

Transmissibility of Gerstmann–Sträussler–Scheinker syndrome in rodent models: new insights into the molecular underpinnings of prion infectivity 

Sunday, November 06, 2016 

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

Terry S. Singeltary Sr.