Saturday, May 20, 2017

Sporadic Creutzfeldt-Jakob Disease in 2 Plasma Product Recipients, United Kingdom

Sporadic Creutzfeldt-Jakob Disease in 2 Plasma Product Recipients, United Kingdom 

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. 

Patrick Urwin, Kumar Thanigaikumar, James W. Ironside, Anna Molesworth, Richard S. Knight, Patricia E. Hewitt, Charlotte Llewelyn, Jan Mackenzie, and Robert G. Will

Comments to Author Author affiliations: University of Edinburgh Western General Hospital, Edinburgh, Scotland, UK (P. Urwin, J.W. Ironside, A. Molesworth, R.S. Knight, J. Mackenzie, R.G. Will); University Hospital Lewisham, London, UK (K. Thanigaikumar); National Health Service Blood and Transplant, London (P.E. Hewitt); National Health Service Blood and Transplant/Public Health England Epidemiology Unit, Cambridge, UK (C. Llewelyn) Cite This Article

Introduction

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Learning Objectives Upon completion of this activity, participants will be able to:

• Recognize the clinical features of 2 cases of sporadic Creutzfeldt-Jakob disease (sCJD) reported in patients with clotting disorders treated with fractionated plasma products.

• Identify the laboratory and pathology findings of 2 cases of sCJD reported in patients with clotting disorders treated with fractionated plasma product.

• Determine the clinical implications of 2 cases of sCJD reported in patients with clotting disorders treated with fractionated plasma products.

CME Editor Jude Rutledge, BA, Technical Writer/Editor, Emerging Infectious Diseases. Disclosure: Jude Rutledge has disclosed no relevant financial relationships.

CME Author Laurie Barclay, MD, freelance writer and reviewer, Medscape, LLC. Disclosure: Laurie Barclay, MD, has disclosed the following relevant financial relationships: owns stock, stock options, or bonds from Alnylam; Biogen; Pfizer.

Authors Disclosures: Patrick Urwin, MBBS, MA (CANTAB); Kumar Thanigaikumar, MBBS, MRCP, FRCPATH; James W. Ironside, MD; Anna Molesworth, PhD; Patricia E. Hewitt, MD, FRCPATH; Charlotte A. Llewelyn, PhD; and Jan Mackenzie, PG Cert Epidemiology, have disclosed no relevant financial relationships. Richard S. Knight, BMBCh, FRCP (E), has disclosed the following relevant financial relationships: served as a speaker or a member of a speakers bureau for Pfizer Inc. Robert G. Will, MD, has disclosed the following relevant financial relationships: served as an advisor or consultant for LFB (Paris); Ferring Pharmaceuticals.

Abstract

Sporadic Creutzfeldt-Jakob disease (sCJD) has not been previously reported in patients with clotting disorders treated with fractionated plasma products. We report 2 cases of sCJD identified in the United Kingdom in patients with a history of extended treatment for clotting disorders; 1 patient had hemophilia B and the other von Willebrand disease. Both patients had been informed previously that they were at increased risk for variant CJD because of past treatment with fractionated plasma products sourced in the United Kingdom. However, both cases had clinical and investigative features suggestive of sCJD. This diagnosis was confirmed in both cases on neuropathologic and biochemical analysis of the brain. A causal link between the treatment with plasma products and the development of sCJD has not been established, and the occurrence of these cases may simply reflect a chance event in the context of systematic surveillance for CJD in large populations.

Discussion This report describes 2 cases of sCJD in patients with a history of treatment with UK-sourced plasma products, 1 with a history of hemophilia B and 1 with von Willebrand’s disease. To our knowledge, no previous case of sCJD in a person with a history of extended exposure to plasma products has been reported. It is clearly of concern that there have been 2 such cases in a relatively short period in the UK, where many plasma product recipients have been informed that they are at increased risk for vCJD. However, a causal link between the treatment with plasma products and the onset of sCJD has not been established, and the occurrence of these cases may simply reflect a chance event in the context of systematic surveillance of CJD in large populations.

Both patients had been informed that they were at increased risk for vCJD, and considering the evidence for the type of CJD in the 2 cases is important. Both patients had a clinical phenotype suggestive of sCJD, including a short duration of illness, typical early symptoms, a suggestive MRI scan, and, in 1 patient, a typical EEG. Notably, both patients had a positive real-time quaking-induced conversion test result for PrPSc in CSF; previously this test had not been positive in any case of vCJD evaluated in our laboratory (Table 2) (9). However, neuropathological examination was critical; it showed appearances typical of sCJD in both patients and no evidence of peripheral pathogenesis on immunostaining of lymphoreticular tissues, a feature that is observed in all tested specimens of vCJD patients to date (10). Furthermore, both patients had a type 1A isoform PrPSc on Western blot consistent with a diagnosis of sCJD subtype MM1 (11). Neither patient had a history of potential iatrogenic exposure or a family history of CJD, and for the case for which sequencing of the PRNP was performed, no mutations were detected. In both cases, an MM genotype occurred at codon 129 of PRNP, which does not distinguish between sCJD and vCJD. Laboratory transmission studies to provide evidence of agent strain in the cases have not been possible.

One patient had received multiple transfusions of blood components over an extended period, and the other had received 6 units of FFP 19 years before clinical onset, raising the possibility that these cases could have resulted from secondary transmission through blood components. In the case of the patient with von Willebrand disease, 107 donors have been traced, and none appear in the register of cases of CJD kept at the National CJD Research and Surveillance Unit. However, it has not been possible to obtain information on blood transfusions for this patient before 2001 nor on the FFP transfusions for the patient with hemophilia B. Lookback studies in the United States and United Kingdom have provided no evidence of transfusion-transmission of sCJD (2,3), and although 1 study suggested an increase in risk after a lag period of 10 years (12), this finding was not confirmed in another study (13). The balance of evidence indicates that, if sCJD is transmitted by blood transfusion, it must be a rare event, if it happens at all, and transfusion transmission is probably not the explanation for the 2 cases we describe.

Systematic surveillance for CJD, including a coordinated study in Europe (14), has been carried out in many countries over the past 25 years and is continuing. Many of these studies obtain information on potential risk factors, including details of past medical history. To date, no case of sCJD has been reported in a person who has received treatment for a clotting disorder. In fact, the absence of such a case has been used to argue against the possibility that plasma-derived products pose a risk for sCJD transmission (6). CJD surveillance centers are aware of the relevance of this issue, and sCJD patients with a history of treatment with plasma products probably would have been identified and reported if they occurred. Although it is surprising that 2 cases of sCJD have been identified among a population of 4,000–5,000 patients in the UK who have been treated for clotting disorders with fractionated plasma products, the total population under surveillance for CJD in Europe and internationally exceeds 500 million. Assuming an annual incidence rate of sCJD of 1.5–2.0 per million population (15), the occurrence of 2 cases of sCJD in this total population may not imply a causal link between the treatment and the occurrence of the disease. The 2 cases were identified over a period of months, and no further cases have been found since 2014; however, continuing to search for such cases through CJD surveillance programs is essential.

Dr. Urwin worked as a research registrar at the National CJD Research and Surveillance Unit and is currently training in neurology. His primary research interests include human prion diseases.


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.


''A causal link between the treatment with plasma products and the development of sCJD has not been established, and the occurrence of these cases may simply reflect a chance event in the context of systematic surveillance for CJD in large populations.'' 

???

>>>They found infectivity in the red and white blood cells and plasma of a variant CJD patient and in the plasma of two of four sporadic CJD patients tested. These findings indicate the need to continue assessing the possible risk for CJD transmission via transfusion of blood products.<<< 

>>>In tgBov inoculated with vCJD and tgHu inoculated with sCJD, the PrPres banding patterns observed by Western blot in animals challenged with brain homogenate and blood components were identical (Figure, panels C, D). These results support the contention that the TSE agent propagated in tgBov mice and tgHu were vCJD and sCJD agents, respectively.<<< 


Wednesday, December 11, 2013

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


-----Original Message----- 

From: Terry Singeltary <flounder9@verizon.net

To: bse-l l@lists.aegee.org


Sent: Thu, Apr 27, 2017 11:11 am 

Subject: 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. 

Abstract

BACKGROUND

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. 

STUDY DESIGN AND METHODS

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. 

RESULTS

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. 

CONCLUSION

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


SATURDAY, DECEMBER 08, 2007 

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="" all="" be="" cjd="" considered="" div="" for="" low-risk="" patients.="" proposed="" that="" therefore="" these="" tissues="" we="">

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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) scripps.edu) 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

Index

Abstract 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 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="" all="" be="" cjd="" considered="" div="" for="" low-risk="" patients.="" proposed="" that="" therefore="" these="" tissues="" we="">

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).

Acknowledgments 

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

Research

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

Abstract

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.

snip...

Discussion

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.

Acknowledgment

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).


FRIDAY, APRIL 21, 2017 

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


 MONDAY, NOVEMBER 23, 2015 

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

Issue

Cover image for Vol. 55 Issue 11

Transfusion

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

Abstract

BACKGROUND

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.

STUDY DESIGN AND METHODS

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.

RESULTS

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.

CONCLUSION

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


2015 PRION CONFERENCE

*** 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.

Subject: THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE R. G. WILL 1984

THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE R. G. WILL

1984

snip...


THE BAXTER STUDY...SEE MORE HERE ;



Saturday, May 30, 2015

PRION 2015 ORAL AND POSTER CONGRESSIONAL ABSTRACTS


Wednesday, December 11, 2013

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


THE BAXTER STUDY...SEE MORE HERE ;


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


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

Authors

Authors and affiliations

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

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

2.University College London Institute of Child HealthLondonUK

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

First Online: 03 November 2016

DOI: 10.1007/s00401-016-1638-x Cite this article as: Ritchie, D.L., Barria, M.A., Peden, A.H. et al. Acta Neuropathol (2016). doi:10.1007/s00401-016-1638-x 40 Downloads 

Abstract

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

Keywords

Creutzfeldt–Jakob diseasePrionIatrogenicGrowth hormoneDisease phenotypeAgent strain

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

Electronic supplementary material

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

SNIP...

Implications for person-to-person transmission

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

snip...see full text ;


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

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

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


THURSDAY, MARCH 30, 2017

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


Primate Biol., 3, 47–50, 2016 www.primate-biol.net/3/47/2016/ doi:10.5194/pb-3-47-2016 © Author(s) 2016. CC Attribution 3.0 License. 

Prions 

Walter Bodemer German Primate Center, Kellnerweg 4, 37077 Göttingen, Germany Correspondence to: Walter Bodemer (wbodemer@dpz.eu) Received: 15 June 2016 – Revised: 24 August 2016 – Accepted: 30 August 2016 – Published: 7 September 2016 

SNIP... 

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. 

SEE FULL TEXT ; 


WEDNESDAY, MAY 03, 2017 

First evidence of intracranial and peroral transmission of Chronic Wasting Disease (CWD) into Cynomolgus macaques


*** 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 

Abstracts 

WS-01: Prion diseases in animals and zoonotic potential 

Juan Maria Torres a, Olivier Andreoletti b, J uan-Carlos Espinosa a. Vincent Beringue c. Patricia Aguilar a, Natalia Fernandez-Borges a. and Alba Marin-Moreno a "Centro de Investigacion en Sanidad Animal ( CISA-INIA ). Valdeolmos, Madrid. Spain; b UMR INRA -ENVT 1225 Interactions Holes Agents Pathogenes. ENVT. Toulouse. France: "UR892. Virologie lmmunologie MolécuIaires, Jouy-en-Josas. France 

Dietary exposure to bovine spongiform encephalopathy (BSE) contaminated bovine tissues is considered as the origin of variant Creutzfeldt Jakob (vCJD) disease in human. To date, BSE agent is the only recognized zoonotic prion. Despite the variety of Transmissible Spongiform Encephalopathy (TSE) agents that have been circulating for centuries in farmed ruminants there is no apparent epidemiological link between exposure to ruminant products and the occurrence of other form of TSE in human like sporadic Creutzfeldt Jakob Disease (sCJD). However, the zoonotic potential of the diversity of circulating TSE agents has never been systematically assessed. The major issue in experimental assessment of TSEs zoonotic potential lies in the modeling of the ‘species barrier‘, the biological phenomenon that limits TSE agents’ propagation from a species to another. In the last decade, mice genetically engineered to express normal forms of the human prion protein has proved essential in studying human prions pathogenesis and modeling the capacity of TSEs to cross the human species barrier. To assess the zoonotic potential of prions circulating in farmed ruminants, we study their transmission ability in transgenic mice expressing human PrPC (HuPrP-Tg). Two lines of mice expressing different forms of the human PrPC (129Met or 129Val) are used to determine the role of the Met129Val dimorphism in susceptibility/resistance to the different agents. These transmission experiments confirm the ability of BSE prions to propagate in 129M- HuPrP-Tg mice and demonstrate that Met129 homozygotes may be susceptible to BSE in sheep or goat to a greater degree than the BSE agent in cattle and that these agents can convey molecular properties and neuropathological indistinguishable from vCJD. However homozygous 129V mice are resistant to all tested BSE derived prions independently of the originating species suggesting a higher transmission barrier for 129V-PrP variant. Transmission data also revealed that several scrapie prions propagate in HuPrP-Tg mice with efficiency comparable to that of cattle BSE. While the efficiency of transmission at primary passage was low, subsequent passages resulted in a highly virulent prion disease in both Met129 and Val129 mice. Transmission of the different scrapie isolates in these mice leads to the emergence of prion strain phenotypes that showed similar characteristics to those displayed by MM1 or VV2 sCJD prion. 

***These results demonstrate that scrapie prions have a zoonotic potential and raise new questions about the possible link between animal and human prions.


why do we not want to do TSE transmission studies on chimpanzees $ 

5. A positive result from a chimpanzee challenged severly would likely create alarm in some circles even if the result could not be interpreted for man. I have a view that all these agents could be transmitted provided a large enough dose by appropriate routes was given and the animals kept long enough. Until the mechanisms of the species barrier are more clearly understood it might be best to retain that hypothesis. 

snip... 

R. BRADLEY 


Title: Transmission of scrapie prions to primate after an extended silent incubation period) *** 

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

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

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


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. 


LOOKING FOR CWD IN HUMANS AS nvCJD or as an ATYPICAL CJD, LOOKING IN ALL THE WRONG PLACES $$$ 

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


*** 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 

Research Project: TRANSMISSION, DIFFERENTIATION, AND PATHOBIOLOGY OF TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES

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.


CONFIDENTIAL

EXPERIMENTAL PORCINE SPONGIFORM ENCEPHALOPATHY

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 ;

WEDNESDAY, APRIL 05, 2017 

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


WEDNESDAY, MAY 17, 2017 

SHIC FUNDED STUDY SUGGESTS POTENTIAL FOR PATHOGEN TRANSMISSION VIA FEED


FRIDAY, MARCH 31, 2017 

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


FRIDAY, JANUARY 27, 2017 

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


WEDNESDAY, MARCH 15, 2017 

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. 


SPONTANEOUS ATYPICAL BOVINE SPONGIFORM ENCEPHALOPATHY

***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 

TRANSMISSION, DIFFERENTIATION, AND PATHOBIOLOGY OF TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES 2016 ANNUAL REPORT ARS RESEARCH 


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

BOVINE SPONGIFORM ENCEPHALOPATHY BSE TSE PRION SURVEILLANCE, TESTING, AND SRM REMOVAL UNITED STATE OF AMERICA UPDATE JULY 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

4th MAD COW DISEASE U.S.A. CALIFORNIA ATYPICAL L-TYPE BSE 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


MONDAY, JANUARY 16, 2017

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



ONE DECADE POST MAD COW FEED BAN OF AUGUST 1997...

2007 

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. 

2007 Date: March 21, 2007 at 2:27 pm PST 

RECALLS AND FIELD CORRECTIONS: VETERINARY MEDICINES -- CLASS II PRODUCT 

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. 

VOLUME OF PRODUCT IN COMMERCE 42,090 lbs. DISTRIBUTION WI 

___________________________________ 

PRODUCT Custom dairy premix products: MNM ALL PURPOSE Pellet, HILLSIDE/CDL Prot- Buffer Meal, LEE, M.-CLOSE UP PX Pellet, HIGH DESERT/ GHC LACT Meal, TATARKA, M CUST PROT Meal, SUNRIDGE/CDL PROTEIN Blend, LOURENZO, K PVM DAIRY Meal, DOUBLE B DAIRY/GHC LAC Mineral, WEST PIONT/GHC CLOSEUP Mineral, WEST POINT/GHC LACT Meal, JENKS, J/COMPASS PROTEIN Meal, COPPINI - 8# SPECIAL DAIRY Mix, GULICK, L-LACT Meal (Bulk), TRIPLE J - PROTEIN/LACTATION, ROCK CREEK/GHC MILK Mineral, BETTENCOURT/GHC S.SIDE MK-MN, BETTENCOURT #1/GHC MILK MINR, V&C DAIRY/GHC LACT Meal, VEENSTRA, F/GHC LACT Meal, SMUTNY, A- BYPASS ML W/SMARTA, Recall # V-025-2007 

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. 

VOLUME OF PRODUCT IN COMMERCE 9,997,976 lbs. 

DISTRIBUTION ID and NV END OF ENFORCEMENT REPORT FOR MARCH 21, 2007 


NEW URL LINK; 

http://www.fda.gov/Safety/Recalls/EnforcementReports/ucm120446.htm

another NEWER LINK;


TUESDAY, JANUARY 17, 2017 

FDA PART 589 -- SUBSTANCES PROHIBITED FROM USE IN ANIMAL FOOD OR FEEDVIOLATIONS OFFICIAL ACTION INDICATED OAI UPDATE 2016 to 2017 BSE TSE PRION 



TUESDAY, APRIL 18, 2017 

*** EXTREME USA FDA PART 589 TSE PRION FEED LOOP HOLE STILL EXIST, AND PRICE OF POKER GOES UP ***


WEDNESDAY, MAY 17, 2017 

SHIC FUNDED STUDY SUGGESTS POTENTIAL FOR PATHOGEN TRANSMISSION VIA FEED


SUNDAY, APRIL 16, 2017

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


WEDNESDAY, APRIL 12, 2017 

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


TUESDAY, SEPTEMBER 13, 2016

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


SUNDAY, DECEMBER 04, 2016

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


SUNDAY, JANUARY 17, 2016

Of Grave Concern Heidenhain Variant Creutzfeldt Jakob Disease


TUESDAY, APRIL 04, 2017

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; 


Terry S. Singeltary Sr. [flounder@wt.net]

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...

snip... 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


THURSDAY, JANUARY 19, 2017 

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


THURSDAY, MARCH 30, 2017

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

URGENT GLOBAL UPDATE BLOOD, TISSUE, CJD, nvCJD, GSS, BSE, CWD, SCRAPIE, TSE, PRION


SUNDAY, DECEMBER 04, 2016 

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 


THURSDAY, APRIL 27, 2017

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


SATURDAY, MAY 20, 2017

Missouri CWD CJD TSE PRION Surveillance and Monitoring


WEDNESDAY, MAY 17, 2017 

SHIC FUNDED STUDY SUGGESTS POTENTIAL FOR PATHOGEN TRANSMISSION VIA FEED


MONDAY, MAY 15, 2017 

TEXAS New CWD TSE PRION Case Discovered at Fifth Captive Deer Breeding Facility


SUNDAY, MAY 14, 2017 

85th Legislative Session 2017 AND THE TEXAS TWO STEP Chronic Wasting Disease CWD TSE Prion, and paying to play, a lesson on how political and corporate science helps spread a deadly disease


THURSDAY, MAY 18, 2017

Minnesota Four more farmed white-tailed deer test positive for Chronic Wasting Disease CWD TSE Prion


MONDAY, MAY 15, 2017 

Pennsylvania 25 more deer test positive for CWD TSE PRION in the wild


WEDNESDAY, MAY 17, 2017

CWD, TSE, PRION, Cattle, Pigs, Sheep, and Humans aka Mad Cow Disease


WEDNESDAY, MAY 03, 2017 

*** First evidence of intracranial and peroral transmission of Chronic Wasting Disease (CWD) into Cynomolgus macaques ***


WEDNESDAY, DECEMBER 04, 2013

Chronic Wasting Disease CWD and Land Value concerns?



FRIDAY, APRIL 21, 2017

URGENT GLOBAL UPDATE BLOOD, TISSUE, CJD, nvCJD, GSS, BSE, CWD, SCRAPIE, TSE, PRION


*** OLD HISTORY ON BLOOD AND CJD

Transmission of Creutzfeldt-Jakob Disease from Blood and Urine Into Mice 

The Lancet, November 9, 1985 

Sir,--Professor Manuelidis and his colleagues (Oct 19, p896) report transmission to animals of Creutzfeldt-Jakob disease (CJD) from the buffy coat from two patients. We also transmitted the disease from whole blood samples of a patient (and of mice) infected with CJD.1 Brain, Cornea, and urine from this patient were also infectious, and the clinicopathological findings2 are summarised as follows. 

A 70-year-old man was noted to have a slowing of speech and writing and some disorientation, all of which progressed rapidly. Decorticate rigidity, forced grasping, positive snout reflex, and myoclonus appeared within 2 months. Electroencephalogram revealed typical periodic synchronous discharge, and he died of pneumonia and upper gastrointestinal haemorrhage, about 3 months after onset of the symptoms. The Brain weighed 1290g and showed severe histological changes diagnostic of CJD, including spongiform change, loss of nerve cells, and diffuse proliferation of astrocytes. There were no inflammatory cells, microglia, neurofibrillary tangles, and amyloid plaques, although virus-like particles were detected by electron microscopy. 

Results of innoculation in Mice 

Inocula NO* Incubation period (days)+ Brain 7/10 (4) 789 (+ or - 112) Cornea 1/6 (0) 1037 Blood 2/13 (0) 1080 (+ or - 69) Urine 5/10 (1) 880 (+ or - 55) CSF 0/10 

* Number of mice with CJD change/number examined histologically. Number with amyloid plaques shown in parentheses. 

+ means + or - SD 

Samples were taken aseptically at necropsy. 10% crude homogenates of brain and cornea in saline, whole blood (after crushing a clot), and untreated CSF and urine were innoculated intracerebrally into CF1 strain mice (20 ul per animal). Some mice showed emaciation, bradykinesia, rigidity of the body and tail, and sometimes tremor after long incubation periods. Tissues obtained after the animal died (or was killed) were studied histologically (table). Animals infected by various inocula showed common pathological changes, consisting of severe spongiform changes, glial proliferation, and a moderate loss of nerve cells. A few mice inoculated with brain tissue or urine had the same amyloid plaques found in patients and animals with CJD.3 

In our long-term experiments, inoculating materials taken from twenty patients with CJD or Gerstmann-Straussler-Scheinker's disease (GSS) into rodents, positive results were obtained in seventeen cases, including this patient. Brain tissue transmitted the disease most frequently within the shortes incubation period, except for one case where the lymph node was the most infectious. Transmission through the cornea has been noted in man4 and in guineapigs.5 Whole blood samples taken from three patients were inoculated and a positive transmission occured only in the case recorded here. Mouse-to-mouse transmission through blood inoculation was successful after a mean incubation period of 365 days.1 Transmission through urine was positive in this patient only, and negative in one other patient and in many infected animals. Transmission through the CSF from eight patients was negative, yet transmission via the CSF of infected rats was positive.1 

As viraemia has been proved in guineapigs,6 mice,1,7 and lately in patients with CJD, blood for transfusion or blood products for medical use must be tested for unconventional pathogens. For this purpose, we inoculated blood products inot rodents.8 The CJD pathogen was not found in the products examined. However, this approach takes too long to be of practical value. More efficient methods must be developed to detect pathogens and to eliminate them from blood. One proposal9 is to apply membrane filtration to the pruification protocol of human growth hormone suspected of being contaminated with CJD. Similar methods are needed for blood contamination. 

Department of Neuropathology, Neurological Institute, Faculty of Medicine, Kyushu University, Fukuoka812, Japan 

JUN TATEISHI 

1. Tateishi J, Sato Y, Kaga M. Doi H, Ohta M. Experimental transmission of human subacute spongiform encephalopathy to small rodents 1: Clinical and histological observations. Acta Neuropathol (Berl) 1980; 51: 127. 

2. Shibayama Y, Sakaguchi Y, Nakata K, et al, Creutzfeldt-Jakob disease with demonstration of virus-like particles. Acta pathol Jpn 1982;32: 695. 

3. Tateishi J, Nagara H, Hikita K, Sato Y. Amyloid plaques in the brains of mice with Creutzfeldt-Jakob disease. Ann Neurol 1984; 15: 278. 

4. Duffy P, Wolf J, Colings G, DeVoe AG, Streeten B, Cowen D. Possible person-to-person transmission of Creutzfeldt-Jakob disease. N Engl J Med 1974; 290: 692. 

5. Manuelidis EE, Angelo JN, Gorgacz EJ, Kim JH, Manuelidis L. Experimental Creutzfeldt-Jakob disease transmitted via the eye with infected cornea. N Engl J Med 1977; 296: 1334. 

6. Manuelidis EE, Gorgacz EJ, Manuelidis L. Viremia in experimental Creutzfeldt-Jakob disease. Science 1978: 200: 1069. 

7. Kuroda Y, Gibbs CJ Jr, Amyx HL, Gajdusek DC. Creutzfeldt-Jakob disease in mice. Persistent viremiam and preferential replication of virus in low-density lymphocytes. Infect Immun 1983; 41: 154. 

8. Tateishi J, Tsuji S. Unconventional pathogens causing spongiform encephalopathis absent in blood products. J Med Virol 1985; 15: 11. 

9. Tateishi J, Kitamoto T, Hiratani H. Creutzfeldt-Jakob disease pathogen in growth hormone preparations is eliminatable. Lancet (in press). 


Subject: Transmission of BSE by blood transfusion in sheep... 

Date: Thu, 14 Sep 2000 18:19:06 -0700 

From: "Terry S. Singeltary Sr." 

Reply-To: Bovine Spongiform Encephalopathy 

To: BSE-L@uni-karlsruhe.de

######### Bovine Spongiform Encephalopathy #########

Greetings List Members,

More Dredful news, but predictable...

kind regards, Terry S. Singeltary Sr., Bacliff, Texas USA 

===========================================

It is possible to transmit BSE to a sheep by transfusion with whole blood taken from another sheep during the symptom-free phase of an experimental BSE infection'

It is well known that variant Creutzfeldt-Jakob disease (vCJD) is caused by the same strain of agent that causes bovine spongiform encephalopathy (BSE) in cattle. F Houston and colleagues report the preliminary findings of transfusing blood from 19 UK Cheviot sheep fed with 5 g BSE-affected cattle brain into Cheviot sheep from scrapie-free flock of New Zealand-derived animals. The investigators found BSE clinical signs and pathology in one recipient of blood taken from a BSE infected animal. Immunocytochemistry on tissues taken from the transfused sheep showed widespread PrPSC deposition throughout the brain and the periphery. This finding suggests that blood donated by symptom-free vCJD-infected human beings could transmit infection to recipients of blood transfusions. In a Commentary, Paul Brown states that these observations are consistent with previous reports in experimentally infected rodents.

==================

Research letters Volume 356, Number 9234 16 September 2000

Transmission of BSE by blood transfusion in sheep 

Lancet 2000; 356: 999 - 1000 Download PDF (1 Mb) 

F Houston, J D Foster, Angela Chong, N Hunter, C J Bostock

See Commentary

We have shown that it is possible to transmit bovine spongiform encephalopathy (BSE) to a sheep by transfusion with whole blood taken from another sheep during the symptom-free phase of an experimental BSE infection. BSE and variant Creutzfeldt-Jakob disease (vCJD) in human beings are caused by the same infectious agent, and the sheep-BSE experimental model has a similar pathogenesis to that of human vCJD. Although UK blood transfusions are leucodepleted--a possible protective measure against any risk from blood transmission--this report suggests that blood donated by symptom-free vCJD-infected human beings may represent a risk of spread of vCJD infection among the human population of the UK.

The demonstration that the new variant of Creutzfeldt-Jakob disease (vCJD) is caused by the same agent that causes bovine spongiform encephalopathy (BSE) in cattle1 has raised concerns that blood from human beings in the symptom-free stages of vCJD could transmit infection to recipients of blood transfusions. There is no evidence that iatrogenic CJD has ever occurred as a result of the use of blood or blood products, but vCJD has a different pathogenesis and could present different risks. CJD is one of the transmissible spongiform encephalopathies (TSEs) characterised by the deposition of an abnormal form of a host protein, PrPSc; the normal isoform (PrPC) is expressed in many body tissues. Available evidence, based on detection of infectivity in blood in rodent models, and absence of infectivity in naturally occurring TSEs, adds to the uncertainty in risk assessments of the safety of human blood. PrPSc has been reported in blood taken from preclinical TSE-infected sheep,2 but it does not follow that blood is infectious. Bioassays of human blood can only be carried out in non-human species, limiting the sensitivity of the test. One way of avoiding such a species barrier is to transfer blood by transfusion in an appropriate animal TSE model. BSE-infected sheep harbour infection in peripheral tissues3 and are thus similar to humans infected with vCJD.4 BSE infectivity in cattle does not have widespread tissue distribution.

We report preliminary data from a study involving blood taken from UK Cheviot sheep challenged orally with 5 g BSE-affected cattle brain and transfused into Cheviot sheep from a scrapie-free flock of New Zealand-derived animals (MAFF/SF flock). MAFF/SF sheep do not develop spontaneous TSE and the transfused animals are housed separately from other sheep. All sheep in the study have the PrP genotype AA136QQ171 which has the shortest incubation period of experimental BSE in sheep.5 19 transfusions from BSE-challenged sheep have been done, mostly with whole blood. Sheep have complex blood groups and only simple cross-matching can be done by mixing recipient serum and donor erythrocytes and vice versa. Therefore single transfusions only were made between sedated cross-matched animals to minimise the risk of severe reactions. Negative controls were MAFF/SF sheep transfused with blood from uninfected UK Cheviot sheep. As a positive control, MAFF/SF sheep were intravenously injected with homogenised BSE-affected cattle brain.

We have seen BSE clinical signs and pathological changes in one recipient of blood from a BSE-infected animal, and we regard this finding as sufficiently important to report now rather than after the study is completed, several years hence. The blood donation resulting in transmission of BSE to the recipient was 400 mL of whole blood taken from a healthy sheep 318 days after oral challenge with BSE. BSE subsequently developed in this donor animal 629 days after challenge, indicating that blood was taken roughly half way through the incubation period. 610 days after transfusion, the transfused sheep (D505) itself developed typical TSE signs: weight loss, moderate pruritus, trembling and licking of the lips, hind-limb ataxia, and proprioceptive abnormalities. This is the first experimental transmission of BSE from sheep to sheep and so we have nothing with which to compare this incubation period directly. In cross-species transmissions, bovine BSE injected intracerebrally gives incubation periods of about 450 days in these sheep,5 and the donor animal had an oral BSE incubation period of 629 days (see above). There are no similar data available on other infection routes. Immunocytochemistry with the antibody BG4 on tissues taken from sheep D505 showed widespread PrPSc deposition throughout the brain and periphery. Western blot analysis of brain tissue with the antibody 6H4 showed that the PrPSc protein had a glycoform pattern similar to that of experimental BSE in sheep and unlike that of UK natural scrapie (figure), indicating that the TSE signs resulted from transmission of the BSE agent. All other recipients of transfusions and positive and negative controls are alive and healthy. The positive controls, which involve a species barrier, are expected to have lengthy incubation periods. With one exception, all transfused animals are at earlier stages post-transfusion than was D505. The exception is a sheep which is healthy 635 days after transfusion with BSE-blood donated at less than 30% of the BSE incubation period of the donor sheep.

PrPSc (proteinase K treated) analysed by SDS-PAGE, immunoblotted with 6H4, and visualised with a chemiluminescent substrate

All lanes are from the same gel with different exposure times. Size markers are to the left of lane 1. Lane1: natural scrapie sheep brain, 3 min exposure. Lane 2: as lane 1, 10 min exposure. Lane 3: sheep D505, blood-transfusion recipient, 10 min exposure. Lane 4: experimental BSE-affected sheep brain, 30 s exposure. Lane 5: as lane 4, 10 min exposure. Each lane loaded with amount of protein extracted from 0·1 g wet weight of brain, except lane 3 which was extracted from 0·2 g brain. 

Although this result was in only one animal, it indicates that BSE can be transmitted between individuals of the same species by whole-blood transfusion. We have no data on blood fractions or on levels of infectivity in blood of preclinical vCJD cases, but whole blood is not now used in UK transfusions. The presence of BSE infectivity in sheep blood at an early stage in the incubation period suggests that it should be possible to identify which cells are infected, to test the effectiveness of leucodepletion, and to develop a diagnostic test based on a blood sample.

We thank Karen Brown, Moira Bruce, Calum McKenzie, David Parnham, Diane Ritchie, and the Scottish Blood Transfusion Service. The project is funded by the Department of Health.

1 Bruce ME, Will RG, Ironside JW, et al. Transmissions to mice indicate that 'new variant' CJD is caused by the BSE agent. Nature 1997; 389: 488-501 [PubMed].

2 Schmerr MJ, Jenny A, Cutlip RC. Use of capillary sodium dodecyl sulfate gel electrophoresis to detect the prion protein extracted from scrapie-infected sheep. J Chromatogr B Biomed Appl 1997; 697: 223-29 [PubMed].

3 Foster JD, Bruce M, McConnell I, Chree A, Fraser H. Detection of BSE infectivity in brain and spleen of experimentally infected sheep. Vet Rec 1996; 138: 546-48 [PubMed].

4 Hill AF, Zeidler M, Ironside J, Collinge J. Diagnosis of new variant Creutzfeldt-Jakob disease by tonsil biopsy. Lancet 1997; 349: 99-100.

5 Goldmann W, Hunter N, Smith G, Foster J, Hope J. PrP genotype and agent effects in scrapie: change in allelic interaction with different isolates of agent in sheep, a natural host of scrapie. J Gen Virol 1994; 75: 989-95 [PubMed]. 

Institute for Animal Health, Compton, Newbury, UK (F Houston PhD, CJ Bostock PhD); and Institute for Animal Health, Neuropathogenesis Unit, Edinburgh, EH9 3JF, UK (N Hunter PhD, JD Foster BSc, Angela Chong BSc) 

Correspondence to: Dr N Hunter

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Commentary Volume 356, Number 9234 16 September 2000

BSE and transmission through blood 

Lancet 2000; 356: 955 - 956 Download PDF (55 Kb) Wether the outbreak of variant Creutzfeldt-Jakob disease (vCJD) in the UK will ultimately affect hundreds, or tens of thousands of people, cannot yet be predicted.1 If large numbers of apparently healthy people are now silently incubating infections with bovine spongiform encephalopathy (BSE), the implications for public health include the possiblity that blood from such individuals may be infectious. Established facts about infectivity in the blood of human beings and animals with transmissible spongiform encephalopathies (TSEs) are as follows:2-4

Blood, especially the buffy-coat component, from animals experimentally infected with scrapie or CJD and from either a clinical or preclinical incubation phase, is consistently infectious when bioassayed by intracerebral or intraperitoneal inoculation into the same species;

In naturally infected animals (sheep and goats with scrapie, mink with transmissible mink encephalopathy, and cows with BSE), all attempts to transmit disease through the inoculation of blood have failed;

Blood from four of 37 human beings with clinically evident sporadic CJD has been reported to transmit the disease after intracerebral inoculation into guineapigs, mice, or hamsters. But each success has been questioned on technical grounds and has not been reproducible; and

Epidemiological data have not revealed a single case of CJD that could be attributed to the administration of blood or blood products among patients with CJD, or among patients with haemophilia and other congenital clotting or immune deficiencies who receive repeated doses of plasma concentrates.

No comparable information about vCJD is available. However, since lymphoreticular organs, such as tonsils have been shown to contain the prion protein (which is an excellent index of infectivity), whereas it is not detectable in patients with sporadic CJD, there is some reason to worry that blood from individuals incubating vCJD might be infectious.5 Data from studies into the ability of blood from experimentally infected rodents and primates with vCJD to transmit the disease will not be available for months or years.

In this issue of The Lancet, F Houston and co-workers report convincing evidence that blood from a seemingly healthy sheep incubating BSE (infected by the oral route with brain from a diseased cow) was able to cause the disease when transfused into another sheep. This observation is entirely consistent with past experience in experimentally infected rodents. It extends current knowledge about blood infectivity in experimental models to a host/TSE strain pair that is closer to the human vCJD situation than the earlier rodent studies. It is also the first successful transfusion of BSE from blood taken during the all-important incubation period of infection. This result is part of a larger study (n=19) that includes both positive and negative control animals, all still healthy and in various early stages of the incubation period.

Is it appropriate to publish an experimental result from a single animal in a study that is not far enough along even to have validated its positive controls? Especially a result that does not in any fundamental way change our current thinking about BSE and vCJD and which would not seem to have any practical consequences for public health? The UK National Blood Transfusion Service has already implemented leucodepletion of donated blood, and imports all plasma and plasma derivatives from BSE-free countries. No further measures would seem possible--short of a draconian decision to shut down the whole UK blood-donor system. What, therefore, is the rationale for this publishing urgency? The answer, evidently, is a perceived need to "defuse", by an immediate and accurate scientific report, public reaction to possibly inaccurate media accounts. The full study, when it appears, will be an important addition to our knowledge of TSEs, but science should not be driven to what in certain medical quarters might be termed a premature emission through fear of media misrepresentation.

Paul Brown 

Laboratory of Central Nervous System Studies, National Institutes of Health, Bethesda, MD 20892, USA

1 Ghani AC, Ferguson NM, Donnelly CA, Anderson RM. Predicted vCJD mortality in Great Britain. Nature 2000; 406: 583-84 [PubMed].

2 Brown P. Can Creutzfeldt-Jakob disease be transmitted by transfusion? Curr Opin Hematol 1995; 2: 472-77 [PubMed].

3 Brown P, Cervenáková L, McShane LM, Barber P, Rubenstein R, Drohan WN. Further studies of blood infectivity in an experimental model of transmissible spongiform encephalopathy, with an explanation of why blood components do not transmit Creutzfeldt-Jakob disease in humans. Transfusion 1999; 39: 1169-78 [PubMed].

4 Rohwer RG. Titer, distribution, and transmissibility of blood-borne TSE infectivity. Presented at Cambridge Healthtech Institute 6th Annual Meeting "Blood Product Safety: TSE, Perception versus Reality", MacLean, VA, USA, Feb 13-15, 2000.

5 Hill AF, Butterworth RJ, Joiner S, et al. Investigation of variant Creutzfeldt-Jakob disease and other human prion diseases with tonsil biopsy samples. Lancet 1999; 353: 183-89.


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