No evidence of transfusion transmitted sporadic Creutzfeldt‐Jakob disease: results from a bi‐national cohort study
TRANSFUSION MEDICINE
No evidence of transfusion transmitted sporadic Creutzfeldt‐Jakob disease: results from a bi‐national cohort study
First published:18 March 2020
First published:18 March 2020
Abstract
BACKGROUND
Creutzfeldt‐Jakob disease (CJD) is an uncommon, invariably fatal, neurodegenerative disorder that presents as progressive dementia with concurrent motor symptoms and myoclonia. The pathophysiology involves prion protein misfolding and spreading in a self‐catalyzed manner. It has been shown to be transmissible through tissue transplants. Variant CJD (vCJD), a subtype of the disease is also transmissible through transfusion of blood products. This study aims to corroborate the scarce data that suggest that sporadic CJD (sCJD) is not transmitted via blood transfusion.
METHODS AND STUDY DESIGN
A retrospective cohort study was performed, using data from the bi‐national Scandinavian Donations and Transfusions (SCANDAT2) database containing data on blood donors, donations, transfusions, and transfused patients in Sweden and Denmark since 1968 and 1982, respectively. Mortality and medical data were collected from nationwide health care and population registries. Donors with subsequent CJD were identified, as well as recipients of blood products from these donors. A second analysis was performed, screening for clustering of CJD cases from donors without a CJD diagnosis.
RESULTS
We identified 39 donors with a subsequent diagnosis of sCJD. No cases of CJD occurred among the 883 recipients of blood products from these donors. A total of 89 CJD cases were identified among recipients of transfusions. No clustering of cases from the same donor occurred.
DISCUSSION
Using data from a large, bi‐national database of transfused patients, we find no evidence of sCJD transmission. Our data adds to the growing body of evidence indicating that sCJD is not transfusion transmitted.
Is sporadic Creutzfeldt‐Jakob disease transfusion‐transmissible?
First published:04 April 2020
Transmissible spongiform encephalopathies (TSEs), or prion diseases, are a heterogeneous group of invariably fatal neurodegenerative diseases. Creutzfeldt‐Jakob disease (CJD) is the most common human form. TSEs are caused by the accumulation of prions (PrPTSE), improperly folded conformers of a cell membrane protein of undefined function (PrPC), in the central nervous system (CNS).1 PrPTSE propagates in a self‐catalytic way by imprinting its aberrant conformation onto new molecules of PrPC in a seed‐mediated polymerization process.2 CJD cases can be subclassified as sporadic (sCJD; idiopathic), familial (fCJD; characterized by autosomal dominant mutations in the prion gene, PRNP), or iatrogenic (iCJD). The iatrogenic forms of CJD include infections caused by human growth hormone, dura mater transplants, or CNS electrodes contaminated with prions, as well as the variant form of CJD (vCJD), linked to consuming bovine spongiform encephalopathy (BSE)‐contaminated beef.3, 4
Although the highest level of expression of PrPC is found in the CNS, PrPC is expressed in all tissues. In blood, PrPC is primarily found in plasma, but it is also present in white blood cells and platelets.5, 6 Based on the ubiquitous expression of PrPC and observations in animal models, investigators raised concerns about the potential transfusion transmissibility of prion diseases. Blood from experimentally infected animals transmitted the disease to naïve animals, including blood collected during the pre‐symptomatic phase.7 It was inferred from these studies that the level of infectivity in blood is several orders of magnitude lower than in brain.8 PrPTSE accumulation and infectivity can also be found in non‐neuronal tissues, especially in patients with vCJD.9, 10 In these patients, PrPTSE can be detected in lymphoreticular tissues during the preclinical and clinical phases of the disease.11, 12 These findings led investigators to speculate that PrPTSE can circulate at sufficient levels in asymptomatic blood donors to allow transfusion‐transmission to recipients. A survey of de‐identified archival appendix tissue samples in the UK revealed an estimated prevalence of abnormal PrP accumulation of 1 per 2000. This finding was thought due to exposure of the community to beef contaminated with BSE prions and to indicate a vCJD carrier status in the general population.12 While these observations suggested that further cases of transfusion‐transmitted vCJD (TT‐vCJD) might occur, only four confirmed cases13, 14 and a probable fifth case in a hemophilia patient15 have been reported in the UK so far. Interestingly, one of these four cases was confirmed in an asymptomatic transfusion recipient who died of an unrelated medical condition but whose autopsy revealed accumulation of PrPTSE in the spleen.14 This individual was heterozygous, methionine/valine (MV) at codon 129 of the PRNP gene, in contrast to all previous definite and probable cases of vCJD who have been methionine homozygotes (MM). Of note, the spleen from this recipient was found to harbor infectivity when injected into wild‐type and humanized transgenic mice.16 The genotype at codon 129 of the PRNP gene plays an important role in disease phenotype, incubation, and progression.17 It is therefore possible that individuals who are either VV homozygous or MV heterozygous present with a longer pre‐symptomatic phase, which may explain a delay in the identification of additional cases of TT‐vCJD.
Albeit less frequently, PrPTSE and/or infectivity can also be found in non‐neuronal tissues from sCJD patients, including the spleen, muscle18 and bone marrow.19 Blood and plasma from sCJD and iCJD patients have been demonstrated to harbor infectivity and cause disease following intracerebral inoculation into animals.20, 21 Although previously contested,22 these findings have been supported by a recent study demonstrating infectivity following intracranial injection of plasma from two sCJD patients into humanized transgenic mice and by the detection of infectivity in the bone marrow from sCJD patients.19, 23 Attempts have been made to detect PrPTSE in soluble and cellular blood fractions from clinical sCJD patients by biochemical methods following amplification or concentration protocols, but these have yielded either unsuccessful5 or inconsistent results.24, 25 This is notable, considering that one of these techniques, protein misfolding cyclic amplification (PMCA), has reliably detected PrPTSE in blood from different experimental models of prion disease as well as vCJD patients.24, 26-28 One plausible explanation for the inconsistent detection of PrPTSE in blood from sCJD patients by PMCA relies on differences in conformation of the various prion strains and their specific requirements for in vitro conversion, which may result in ineffective amplification of sCJD prions by this technique (Saá et al., unpublished observations).28, 29 This is supported by the contrasting results obtained when an independent in vitro method, real‐time quaking‐induced conversion (RT‐QuIC), is used to detect prions in tissue samples from CJD patients. RT‐QuIC results in efficient amplification and detection of sCJD but not vCJD prions.30 Despite the enhanced performance of RT‐QuIC over PMCA to amplify sCJD prions, RT‐QuIC has failed detect prions in the blood of sCJD patients, leading to the alternate possibility that PrPTSE is not present in the blood of sCJD patients, and the sporadic detection of PrPTSE by PMCA in the experiments above is a stochastic event.
While experimental evidence indicates that blood from some sCJD patients harbors infectivity, epidemiological data from several case‐control31, 32 and look‐back studies conducted in the UK33 and US34 show no evidence of transfusion‐transmission of sCJD. Data from 94 donors who subsequently developed sCJD and recipients of blood products from these donors who, combined, have contributed over 5128 person‐years of follow‐up, have revealed no evidence of sCJD transmission. In this issue of TRANSFUSION, Holmqvist et al. contribute additional compelling data to the growing evidence that sCJD is not a transfusion‐transmissible disease. Using the Scandinavian Donations and Transfusion (SCANDAT2) database, the authors identified 39 blood donors with a subsequent diagnosis of sCJD and 883 recipients of blood products from these donors. SCANDAT2 collects data on blood donation and transfusions as well as donor‐recipient linkage. SCANDAT2 also connects with nationwide health and death registers from Denmark and Sweden, providing a complete donor/recipient data set for look‐back studies. Similar to previous investigations, the authors first compared the occurrence of sCJD among recipients of blood products from donors who subsequently developed sCJD to that of recipients of blood from donors without sCJD. They found no evidence of transfusion‐transmission of sCJD. But the strength and novelty of this study resides in the second analysis performed. Here, the authors counted the number of sCJD cases among all recipients of blood products from each individual donor to identify potential clusters of sCJD cases that could be attributed to a single donor, even if that donor was never diagnosed with sCJD. This second analysis is relevant because TSEs continue to be underdiagnosed and underreported. This is due in part to the late age of onset of sCJD, which increases the likelihood that sCJD will be confused with more common neurological disorders affecting older people. Additionally, it is difficult to obtain a definitive diagnosis of TSE from autopsy or brain biopsy. sCJD cases present with an annual incidence of one to two cases per million people globally. Although some reports suggest a steady rise in the incidence of sCJD, this is not found in other forms of TSE, supporting the notion that it is due to an aging population effect rather than increased awareness among medical professionals and improvements in diagnostic techniques.35 Thus, finding no aggregation of sCJD cases among blood recipients that could be attributed to individual donors overcomes the limitations of sCJD underreporting.
One limitation of look‐back studies is the early mortality of recipients of blood transfusions related to the comorbidities that led to blood transfusion in the first place. In this study, 38.5% and 17.2% of exposed recipients were alive and undiagnosed with sCJD 10 and 20 years following transfusion, respectively. Analyses of spleen and muscle tissue from patients with sCJD indicate that PrPTSE levels in extra‐neuronal tissues are approximately four orders of magnitude lower than those found in the CNS of sCJD patients, and significantly lower than those found in lymphoid organs of patients with vCJD.18 These findings suggest that the infectivity of blood from sCJD patients, if present, may be lower than that of blood from vCJD patients. This may result in longer incubation times for sCJD than have been reported for TT‐vCJD cases. Thus, survival of 10 or 20 years following transfusion with blood from donors who subsequently developed sCJD may not be long enough to result in the clinical manifestation of TT‐sCJD. A further complication may be the recipientʼs polymorphism at codon 129 of the PRNP gene, which is not determined in any of these studies for ethical considerations but plays a significant role in the phenotype and incubation length of TSEs. Additionally, no post‐mortem examination has been performed in any recipient to assess the presence of PrPTSE in brain or lymphoid organs in these patients, which would definitely confirm sCJD transmission.
The study by Holmqvist et al. comes just after release of a new US Food and Drug Administration (FDA) draft guidance providing “Recommendations to Reduce the Possible Risk of Transmission of Creutzfeldt‐Jakob Disease by Blood and Blood Components.”36 The draft guidance takes into consideration the most recent experimental findings highlighted above, epidemiological data collected as part of the UK and US look‐back studies, and data collected using FDA risk assessment models to update recommendations for deferring donors at risk of CJD that were first introduced in 1987. The updated guidance was received with great enthusiasm by the blood industry, which applauded the agencyʼs recommendation to remove unnecessary donor deferrals that were not supported by current data. The main revisions involve changes to deferral recommendations for geographical risk of exposure to BSE prions, including potential exposure to UK‐sourced beef on US military bases; removal of human‐derived Growth Hormone from the medication deferral list; and removal of the recommendation for the deferral of donors who have a blood relative with CJD. These changes will reduce donor loss while maintaining the same levels of blood safety achieved with the original policy.
Despite their limitations, the solid epidemiological data from this study and UK33 and US34 look‐back studies, which collectively contributed 133 donors and more than 12,754 person‐years of follow up, strongly indicate that the transfusion‐transmissibility of sCJD remains theoretical. If sCJD is transmissible via blood, it is undoubtedly less infectious than vCJD. Of the 177 UK cases of vCJD, only 18 individuals had donated blood components that were subsequently used clinically and traced to identified recipients. Four recipients of components from three donors died of TT‐vCJD versus none of the 1920 recipients in the sCJD group combined from the UK, US, and Scandinavian studies. In aggregate, the data summarized above highlight the relevance of look‐back studies to inform policy changes and the importance of continuing surveillance of human prion diseases to ensure the safety of the blood supply.
ACKNOWLEDGMENTS
I would like to thank my colleagues of the American Red Cross, Dr. Roger Dodd for insightful discussions and his leadership of the US Creutzfeldt‐Jakob disease look back study for over 21 years, which has contributed so much to our current knowledge on the absence of transfusion transmissibility risk of sCJD, and Dr. Susan Stramer for her support and critical review of this editorial.
CONFLICT OF INTEREST
The authors have disclosed no conflicts of interest.
Brief Definitive Report
Infectivity in bone marrow from sporadic CJD patients
Authors
Accepted manuscript online: 9 August 2017 DOI: 10.1002/path.4954
Abstract
Prion infectivity was recently identified in the blood of both sporadic and variant Creutzfeldt-Jakob disease (CJD) patients. In variant CJD (vCJD) the widespread distribution of prions in peripheral tissues of both asymptomatic and symptomatic patients is likely to explain the occurrence of the observed prionaemia. However, in sporadic CJD (sCJD) prion infectivity is described to be located principally in the central nervous system. In this study, we investigated the presence of prion infectivity in bone marrow collected after death in patients affected with different sCJD agents. Bioassays in transgenic mice expressing the human prion protein revealed the presence of unexpectedly high levels of infectivity in the bone marrow from seven out of eight sCJD cases. These findings may explain the presence of blood-borne infectivity in sCJD patients. They also suggest that the distribution of prion infectivity in peripheral tissues in sCJD patients could be wider than currently believed, with potential implications for the iatrogenic transmission risk of this disease.
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Results and discussion
We first performed endpoint titrations of one MM1 and one VV2 reference sCJD brain homogenate (10% frontal cortex) in tgMet and tgVal (20 µL intracerebral inoculation) (Table 2). The MM1 and VV2 isolates transmitted in both mouse models. However, both the final end-point dilution and incubation periods indicated that the tgMet mice displayed a higher efficiency than tgVal for the propagation of prion in the MM1 sample. Conversely, the VV2 sample propagated with greater efficiency in tgVal than in tgMet. Based on these results, 10% w/v bone marrow and temporal cortex homogenates from eight different sCJD patients were inoculated (20 µl intracerebral) into tgMet or tgVal according to their PRNP genotype at codon 129 and PrPres type (Table 1).
The inoculation of the brain homogenate from all eight sCJD cases resulted in a 100% transmission rate in the tgHu mice (Table 3). The incubation periods, PrPres western blot patterns (Figure 1) and the lesion profile (Figure 2) in tgMet inoculated with the MM1 sCJD samples were identical to those observed in tgMet inoculated with the MM1 reference sample. Similar observations were made in tgVal mice inoculated with MV/VV2 sCJD samples and the reference VV2 sample. These data strongly support the contention that the prion strains in the brains of MM1 (sCJD 1 to 4) and MV/VV2 (sCJD 5 to 8) patients were similar to those in the MM1 and VV2 reference isolates, respectively.
The inoculation into tgHu mice of all but one (sCJD 8) of the bone marrow homogenates from the sCJD patients resulted in a clinical disease in tgHu mice (Table 3). Bone marrow from a control non-sCJD patient failed to transmit a clinical disease or to cause abnormal PrP accumulation in inoculated tgHu mice.
On first passage, bone marrow-inoculated mice displayed a longer incubation period (and in some instances a lower attack rate) than mice inoculated with the corresponding brain homogenate. However, identical abnormal PrP western blot profiles were seen in brain tissue of mice inoculated with brain or bone marrow from the same single patient. On second passage, incubation periods in groups of tgHu mice inoculated with brain or bone marrow from the same patient mice were similar (Table 3). Moreover, the lesion profiles in the brains of animals that were inoculated with the bone marrow or the brain homogenate from the same patient were identical (Figure 2). These results are consistent with the presence of the same prion strain in the bone marrow and in the brain of the sCJD patients.
Finally, the titres of infectivity in bone marrow and brain homogenates were estimated using the method developed by Arnold et al. [10]. The relationship between the titre of inoculum and the probability of infection and the length of the incubation period were derived from data corresponding to endpoint titration of the MM1 and VV2 reference isolates in tgMet and tgVal mice respectively (Table 2). A normal distribution for the relationship between dose and incubation period was assumed, and the probability of infection versus dose was assumed to follow a logistic regression curve (supplementary material, Figure S1). According to this model, the infectious titre in the positive bone marrow samples was estimated to range between 102.6 and 105.4 ID50 per gram of tissue in tgMet for MM1 patients and from 102.5 to 102.6 per gram in tgVal for the MV/VV2 patients (Table 3).
Together, these results unequivocally demonstrate the presence of prion infectivity in the bone marrow of patients affected by different subtypes of sCJD. These findings contradict the view that in sCJD patients the distribution of prion infectivity in the peripheral tissues is quite limited, and indicate that tissues other than CNS can contain high amount of infectivity [14]. The brain to bone marrow infectivity ratios indicated that in some patients (sCJD 3 and 7) the prion load in one gram of bone marrow was equivalent to the infectivity in up to 10–20 mg of temporal cortex. These values are three to four orders of magnitude higher than those previously observed in the plasma of MM1 sCJD patients [6]. They were also greatly in excess of the level of infectivity measured in the blood of various animal models of transmissible spongiform encephalopathies [15,16]. It is therefore very unlikely that residual blood that might be in bone marrow could explain the levels of infectivity found.
At what disease stage prions accumulate in bone marrow in sCJD is unknown, and the nature of the cells that accumulate or propagate infectivity in this tissue remains to be clarified. Primary cell cultures established from post-mortem bone marrow samples collected from two sCJD affected patients indicated that mesenchymal bone marrow cells could accumulate and replicate prions [17]. Moreover the expression of cellular PrP in haematopoietic stem cells, T and B lymphocyte, monocyte and granulocyte lineages indicates that most haematopoietic cells have the potential capacity to replicate prions [18-20]. Additional experiments are ongoing to determine the role that these different cell lineages could play in the pathobiology of prion diseases. ***Whatever the outcome of these new investigations, the presence of prions in bone marrow supports the view that this tissue might contribute to the prionaemia observed in some sCJD patients.
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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• 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.
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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.
WEDNESDAY, DECEMBER 11, 2013
Detection of Infectivity in Blood of Persons with Variant and Sporadic Creutzfeldt-Jakob Disease >>>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.<<<
>>>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.<<<
3. Detection of Infectivity in Blood of Persons with Variant and Sporadic Creutzfeldt-Jakob Disease, Jean Yves Douet, et al. Creutzfeldt-Jakob disease (CJD) is a rare but fatal brain disease of humans. Over the past 60 years, this disease has developed in several hundred patients who had received tissue (mainly growth hormone or nervous tissue grafts) from infected cadaver donors. A variant form of CJD, primarily occurring in Europe, has been causally linked with bovine spongiform encephalopathy (commonly known as mad cow disease). Recent research, which used a relatively new type of highly sensitive laboratory mice, enabled researchers to measure infectivity in blood. 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.
Contact: Press Relations INRA News Office – Jeremy Zuber +33 1 42 75 91 69 presse@inra.fr Olivier Andreoletti Joint Research Unit “Interactions Hosts-Pathogens” (INRA/ENVT) o.andreoletti@envt.fr
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Volume 20, Number 1—January 2014
Dispatch
Detection of Infectivity in Blood of Persons with Variant and Sporadic Creutzfeldt-Jakob Disease
Figure
Table 1
Table 2
Technical Appendix Adobe PDF file [31 KB - 3 pages]
Suggested Citation
Jean Yves Douet, Saima Zafar, Armand Perret-Liaudet, Caroline Lacroux, Séverine Lugan, Naima Aron, Herve Cassard, Claudia Ponto, Fabien Corbière, Juan Maria Torres, Inga Zerr, and Olivier AndreolettiComments to Author
Author affiliations: Ecole Nationale Vétérinaire Toulouse, France (J.Y. Douet, C. Lacroux, S. Lugan, N. Aron, H. Cassard, F. Corbière, O. Andréoletti); National Reference Center for Transmissible Spongiform Encephalopathy, Georg August University, Göttingen, Germany (S. Zafar, C. Ponto, I. Zerr); Hospices Civils de Lyon, France (A. Perret-Liaudet); BioRan, Bron, France (A. Perret-Liaudet); Centro de Investigación en Sanidad Animal, Madrid, Spain (J.M. Torres)
Abstract
We report the presence of infectivity in erythrocytes, leukocytes, and plasma of 1 person with variant Creutzfeldt-Jakob disease and in the plasma of 2 in 4 persons whose tests were positive for sporadic Creutzfeldt-Jakob disease. The measured infectivity levels were comparable to those reported in various animals with transmissible spongiform encephalopathies. Among humans, Creutzfeldt-Jakob disease (CJD) is a low incidence disease (≈1 case per million per year) that occurs as either a sporadic (sCJD) or a familial/genetic (fCJD) form. Whereas familial disease forms are linked to a mutation in the prion protein gene (Prnp), no clear epidemiologic risk factors have been identified for sporadic disease forms. sCJD is not a uniform disorder in terms of clinical and neuropathological phenotype. sCJD cases are classified as type 1 or 2 according to the polymorphism at codon 129 of the protease-resistant prion protein (PrP) sequence (methionine/valine) and to the electromobility of the proteinase K–resistant core of the abnormal PrP (PrPres) (1). Type 1 and type 2 isoforms in sCJD are believed to correspond to different transmissible spongiform encephalopathy (TSE) agents Despite their relative rarity, several hundred iatrogenically transmitted CJD cases were identified during the past 60 years (2). Some data supporting the presence of infectivity in the blood of sCJD-affected patients were reported following the intracerebral inoculation of blood fractions from affected patients into rodents. These observations remain ambiguous because other studies did not confirm them (3,4). In 1996, a new form of CJD, named variant CJD (vCJD), was identified in humans. Variant CJD was demonstrated to be caused by the agent that causes bovine spongiform encephalopathy in cattle (5). In the United Kingdom, 4 vCJD transmissions (3 clinical cases and 1 asymptomatic infection) were probably caused by the transfusion of non–leuco-depleted erythrocyte concentrates prepared from donors who later had positive test results for vCJD (6). More recently, a presumed additional case of vCJD infection was reported in the United Kingdom in a hemophilic patient who had received fractionated plasma products, including some units linked to a donor who later was diagnosed with vCJD (7). Despite the epidemiologic evidence of bloodborne transmission in vCJD, bioassays performed on conventional rodent models failed to demonstrate the presence of infectivity in the blood (8). The lack of TSE transmission in conventional rodent models could be a consequence of a low infectivity level in blood from vCJD- and sCJD-affected patients (as described in sheep and rodent TSE models) (9) or of the existence of the species barrier phenomenon that limits the transmission of human prions to these animal models. The development during the last decade of transgenic mice models expressing PrP from others species that abrogate the species barrier now offers the potential to detect low level of infectivity (10).
In this study, we used 2 transgenic mouse models that displayed a high sensitivity to the vCJD or sCJD TSE agents to estimate the infectious titer in certain blood fractions from vCJD- and sCJD-affected patients. According to legislation of the United Kingdom, Germany, and France, the experimental protocol, including the use of human samples, was approved by UK National CJD Research & Surveillance Unit tissue bank: REC reference number 2000/4/157-German TSE reference center: Ref Nr 11/11/93, PHRC ref 2004-D50-353 for patient from France.
The Study
Previous studies reported a high sensitivity in transgenic mice overexpressing bovine PrP (tgBov) for the detection of the bovine spongiform encephalopathy agent. To demonstrate that tgBov also displays a high sensitivity to vCJD infection, we titrated to endpoint a vCJD isolate (10% brain homogenate) by intracerebral inoculation in this model (Tg110) (11). Considering the potential diversity of TSE agents that may cause sCJD, we decided to focus only on type 1 homozygous for methionine at codon 129 of the PRP gene (MM1) sCJD cases. An endpoint titration of a MM1 sCJD 10% brain homogenate was performed in a mouse model that express the methionine 129 variant of the human PrP gene (tgHu:Tg340) (12). This enabled confirmation of the capacity of the tgBov and tgHu models to detect the vCJD and sCJD MM1 agent, respectively, up to a 10−6 dilution of the reference brain homogenates (Table 1; 13). This value was within the range of the brain/blood relative infectivity reported in various TSE animal models (9,14).
Figure
Thumbnail of Abnormal prion protein (PrPres) detection by using Western blot (WB) and paraffin-embedded tissue (PET) blot in the brain of transgenic mice expressing the methionine 129 variant of the human prion protein (PrP) (tgHu) or bovine PrP (tgBov). A, B) PET blot PrPres distribution in coronal section (thalamus level) of tgHu mice inoculated with sporadic Creutzfeldt-Jakob disease (sCJD) MM1 isolates (10% brain homogenate): A) reference isolate used for the endpoint titration in Table 1; B Figure. [[caption]]
In the next step of our experiment, blood fractions (erythrocytes, plasma, and leukocytes) from 1 vCJD-confirmed patient were injected intracerebrally in tgBov mice. Similarly, plasma samples from 4 sCJD MM1 patients were inoculated with tgHu (Table 2). The blood fraction preparation was performed by using laboratory scale hematologic protocols (Technical Appendix Adobe PDF file [PDF - 31 KB - 3 pages]), not by following the procedure applied by blood banking services. This method implies that the leucodepletion that is applied to blood labile products in most countries to reduce the vCJD bloodborne transmission risk was not performed. Brain tissue samples from each of the 4 sCJD cases were also inoculated with tgHu. On the basis of the incubation period (Table 2) and PrPres distribution pattern in the brain as assessed by using paraffin-embedded tissue blot, the TSE agents in those isolates were indistinguishable from those in the MM1 sCJD case that was used for endpoint titration (Figure, panel A).
No TSE clinical signs or PrPres accumulation were observed in the tgBov or tgHu mice inoculated with phosphate-buffered saline or brain and plasma from healthy human controls. The 3 blood fractions from the vCJD-affected patient caused a positive result but low attack rate among tgBov mice (Table 2). On the basis of these results, infectivity in erythrocytes and plasma was estimated to be 2.12 infectious dose (ID)/mL of inoculum. In leukocytes, the infectious titer was estimated to be 2.23 ID/mL of whole blood. According to these values and the hematocrit of the sample (Technical Appendix Adobe PDF file [PDF - 31 KB - 3 pages]), the global infectious titer whole blood in the tested patient would be ≈4.45 ID/mL. Such infectious level is approximately equivalent to 1.4 µg of the reference vCJD brain sample that was endpoint-titrated (Table 1).
In tgHu mice, positive transmission was observed among mice inoculated with 2 of 4 plasma samples (Table 2). The infectious titers in both positive plasma samples were estimated to be 2.12 and 3.7 ID/mL of plasma, which is equivalent to 0.3–0.5 µg of the reference sCJD MM1 brain sample that was endpoint titrated (Table 1). However, because of the limited number of mice inoculated (n = 24) and the overall sensitivity of the assay (upper CI limit 6.24 ID/mL), the absence of transmission in mice inoculated with the 2 other plasma samples cannot be interpreted conclusively
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.
Conclusions
The data reported here confirm the presence of infectivity in erythrocytes, leukocytes, and plasma from vCJD-affected patients and demonstrate unambiguously the presence of infectivity in the plasma of some, but not all, sCJD-affected patients. The infectivity levels that we measured in the tested vCJD and sCJD blood components were comparable to those reported in various TSE animal models. The number of cases included in our study was limited; a new experiment that would include a larger number of cases and different blood fractions from sCJD cases will be necessary to refine the data. However, these results represent a substantial input for assessing the risk for interindividual bloodborne transmission of sCJD and vCJD.
Mr Douet is assistant lecturer in ophthalmology at the National Veterinary School of Toulouse and a PhD student in the TSE group in the UMR INRA ENVT 1225 unit. His primary research interests are the pathogenesis of the prion disease with special emphasis on the iatrogenic risk of transmission.
Acknowledgment
The authors are greatly indebted to the National Creutzfeldt-Jakob Disease Surveillance Unit (UK-Edinburgh) for providing variant CJD brain samples.
This work was supported by a grant from the European Commission: Protecting the food chain from prions: shaping European priorities through basic and applied research (PRIORITY, N°222887; project no. FP7-KBBE-2007-2A) and by grants from the JPND program (DEMTEST: Biomarker based diagnosis of rapid progressive dementias-optimization of diagnostic protocols, 01ED1201A). The study in Germany was funded by the Robert Koch-Institute through funds of the Federal Ministry of Health (grant no. 1369-341).
References
snip...
Detection of Infectivity in Blood of Persons with Variant and Sporadic Creutzfeldt-Jakob Disease
Technical Appendix
Biochemical Typing and PrP ORF Sequencing of Sporadic and Variant Creutzfeldt-Jakob Disease Genes Confirmation of the disease diagnosis, PrPres WB typing and PrnP gene sequencing in the patients were performed by the national CJD reference center of the country of origin of each patient. All patients were Methionine/Methionine at codon 129 and no other mutation was observed. sCJD cases were all originating from Germany. The vCJD case whose blood was tested by bioassay was originating from France. The vCJD case that was used in the endpoint titration experiment was provided by the UK CJD reference center in Edinburgh.
Blood Collection and Fractionation
sCJD blood samples were collected by using S-Monovette® Coagulation Sodium Citrate 1 in 3 mL tubes according to manufacturer instruction (SARSTEDT AG & Co. · www.sarstedt.com) . Tubes were centrifuged for 20 minutes at 2000 rpm, plasma was then collected and cell-free fraction underwent another centrifugation step at 13000 rpm for 10 minutes. Supernatant was collected and stored frozen. The hematocrit values corresponding to the different samples were: sCJD case 1: 37.6%, sCJD case 2: 39.7%, sCJD case 3: 43%, sCJD case 4: 43.7%.
vCJD blood sample on EDTA and fractionated by a 10 minutes 3000 g centrifugation at 12°C . Plasma was collected and directly frozen stored. The buffy coat was collected and washed twice in NaCl 0.9% (2 min, RT) before being pelleted at 3000 g 10 min and frozen.
The sample was submitted to standard biochemical analyze and the blood formula was red cells 5.21 1012/L, hemoglobin 149 g/L, hematocrit: 48%, total white cells 17.1 109/L, lymphocytes: 27.1%, monocytes 9.3%, neutrophils: 60%, eosinophil: 1.8%, Basophils: 1.8%, Platelets:356 109/L.
Page 2 of 3
Brain and Blood Samples Handling and Bioassay
Blood was collected during the diagnostic procedures when patients were evaluated for CJD diagnosis at notifying hospital. The time between blood sampling and patients’ decease are reported in Technical Appendix Table 1.
For sCJD patients, blood was processed at the CSF reference laboratory of the National TSE Reference Center at the Department of Neurology Göttingen, Germany. Autopsy was performed by the Department of Pathology of the notifying hospital and reference material was sent to the Department of Neuropathology, Göttingen, Germany. Blood and brain samples were stored in separate department and handled by different staff in the Gottingen University hospital.
The vCJD blood sample was collected and fractionated in the Bron Hospital (France). In this hospital the department handling CSF and blood samples and the pathology department (post mortem sampling) are distinct. The vCJD reference brain sample was obtained from the UK CJD reference laboratory in Edinburgh.
All the samples were dispatched to the laboratory that performed the bioassays (UMR INRA ENVT 1225) in separated sealed containers. Samples were kept untouched and prepared only a few hours before their inoculation in mice.
The sCJD endpoint titration in tgHu mice was performed 1 year before the reception of sCJD plasma samples.
Plasma and Brain samples from the four sCJD affected patients were prepared and inoculated separately; Brain from the affected patients (text Table 2) were inoculated after the first positive transmission occurred in mice inoculated with sCJD plasma.
Similarly the vCJD endpoint titration experiment and the inoculation of the vCJD blood samples in tg Bov were performed at different dates (9 months interval).
Negative control (phosphate-buffered saline and healthy blood samples) were inoculated during the same inoculation session than the inoculation of the blood fractions from the vCJD and sCJD patients. Healthy brain controls (human and bovine) were inoculated during the same session than the endpoint titration of sCJD and vCJD brain material. Page 3 of 3
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in
the United States 2003 revisited 2009
August 10, 2009
Greetings,
I would like to submit a review of past CJD surveillance in the USA, and the
urgent need to make all human TSE in the USA a reportable disease, in every
state, of every age group, and to make this mandatory immediately without
further delay. The ramifications of not doing so will only allow this agent
to spread further in the medical, dental, surgical arena's. North America
seems to have the most species with documented Transmissible Spongiform
Encephalopathy's, most all of which have been rendered and fed back to food
producing animals and to humans for years. If you look at the statistics,
sporadic CJD seems to be rising in the USA, and has been, with atypical
cases of the sCJD. I find deeply disturbing in the year of 2009, that Human
Transmissible Spongiform Encephalopathy of any strain and or phenotype, of
all age groups, and I stress all age groups, because human TSE's do not know
age, and they do not know borders. someone 56 years old, that has a human
TSE, that has surgery, can pass this TSE agent on i.e. friendly fire, and or
passing it forward, and there have been documented nvCJD in a 74 year old.
Remembering also that only sporadic CJD has been documented to transmit via
iatrogenic routes, until recently with the 4 cases of blood related
transmission, of which the origin is thought to be nvCJD donors. However
most Iatrogenic CJD cases are nothing more than sporadic CJD, until the
source is proven, then it becomes Iatrogenic. An oxymoron of sorts, because
all sporadic CJD is, are multiple forms, or strains, or phenotypes of
Creutzfeldt Jakob Disease, that the route and source and species have not
been confirmed and or documented. When will the myth of the UKBSEnvCJD only
theory be put to bed for good. This theory in my opinion, and the following
there from, as the GOLD STANDARD, has done nothing more than help spread
this agent around the globe. Politics and money have caused the terrible
consequences to date, and the fact that TSEs are a slow incubating death,
but a death that is 100% certain for those that are exposed and live long
enough to go clinical. once clinical, there is no recourse, to date. But,
while sub-clinical, how many can one exposed human infect? Can humans
exposed to CWD and scrapie strains pass it forward as some form of sporadic
CJD in the surgical and medical arenas? why must we wait decades and decades
to prove this point, only to expose millions needlessly, only for the sake
of the industries involved? would it not have been prudent from the
beginning to just include all TSE's, and rule them out from there with
transmission studies and change policies there from, as opposed to doing
just the opposite? The science of TSE's have been nothing more than a
political circus since the beginning, and for anyone to still believe in
this one strain, one group of bovines, in one geographical location, with
only one age group of human TSE i.e. nvCJD myth, for anyone to believe this
today only enhances to spreading of these human and animal TSE's. This is
exactly why we have been in this quagmire.
The ones that believe that there is a spontaneous CJD in 85%+ of all cases
of human TSE, and the ones that do not believe that cattle can have this
same phenomenon, are two of the same, the industry, and so goes the
political science aspect of this tobacco and or asbestos scenario i.e.
follow the money. I could go into all angles of this man made nightmare, the
real facts and science, for instance, the continuing rendering technology
and slow cooking with low temps that brewed this stew up, and the fact that
THE USA HAD THIS TECHNOLOGY FIRST AND SHIPPED IT TO THE U.K. SOME 5 YEARS
BEFORE THE U.S. STARTED USING THE SAME TECHNOLOGY, to save on fuel cost.
This is what supposedly amplified the TSE agent via sheep scrapie, and
spread via feed in the U.K. bovine, and other countries exporting the
tainted product. BUT most everyone ignores this fact, and the fact that the
U.S. has been recycling more TSE, from more species with TSEs, than any
other country documented, but yet, it's all spontaneous, and the rise in
sporadic CJD in the U.S. is a happenstance of bad luck ??? I respectfully
disagree. To top that all off, the infamous BSE-FIREWALL that the USDA
always brags about was nothing more than ink on paper, and I can prove this.
YOU can ignore it, but this is FACT (see source, as late as 2007, in one
recall alone, some 10,000,000 MILLION POUNDS OF BANNED MAD COW FEED WENT OUT
INTO COMMERCE TO BE FED OUT, and most was never recovered. This was banned
blood laced, meat and bone meal. 2006 was a banner year for banned mad cow
protein going into commerce in the U.S. (see source of FDA feed ban warning
letter below). I stress that the August 4, 1997 USA mad cow feed ban and
this infamous BSE firewall, was nothing more than ink on paper, it was never
enforceable.
Greetings,
I would like to submit a review of past CJD surveillance in the USA, and the
urgent need to make all human TSE in the USA a reportable disease, in every
state, of every age group, and to make this mandatory immediately without
further delay. The ramifications of not doing so will only allow this agent
to spread further in the medical, dental, surgical arena's. North America
seems to have the most species with documented Transmissible Spongiform
Encephalopathy's, most all of which have been rendered and fed back to food
producing animals and to humans for years. If you look at the statistics,
sporadic CJD seems to be rising in the USA, and has been, with atypical
cases of the sCJD. I find deeply disturbing in the year of 2009, that Human
Transmissible Spongiform Encephalopathy of any strain and or phenotype, of
all age groups, and I stress all age groups, because human TSE's do not know
age, and they do not know borders. someone 56 years old, that has a human
TSE, that has surgery, can pass this TSE agent on i.e. friendly fire, and or
passing it forward, and there have been documented nvCJD in a 74 year old.
Remembering also that only sporadic CJD has been documented to transmit via
iatrogenic routes, until recently with the 4 cases of blood related
transmission, of which the origin is thought to be nvCJD donors. However
most Iatrogenic CJD cases are nothing more than sporadic CJD, until the
source is proven, then it becomes Iatrogenic. An oxymoron of sorts, because
all sporadic CJD is, are multiple forms, or strains, or phenotypes of
Creutzfeldt Jakob Disease, that the route and source and species have not
been confirmed and or documented. When will the myth of the UKBSEnvCJD only
theory be put to bed for good. This theory in my opinion, and the following
there from, as the GOLD STANDARD, has done nothing more than help spread
this agent around the globe. Politics and money have caused the terrible
consequences to date, and the fact that TSEs are a slow incubating death,
but a death that is 100% certain for those that are exposed and live long
enough to go clinical. once clinical, there is no recourse, to date. But,
while sub-clinical, how many can one exposed human infect? Can humans
exposed to CWD and scrapie strains pass it forward as some form of sporadic
CJD in the surgical and medical arenas? why must we wait decades and decades
to prove this point, only to expose millions needlessly, only for the sake
of the industries involved? would it not have been prudent from the
beginning to just include all TSE's, and rule them out from there with
transmission studies and change policies there from, as opposed to doing
just the opposite? The science of TSE's have been nothing more than a
political circus since the beginning, and for anyone to still believe in
this one strain, one group of bovines, in one geographical location, with
only one age group of human TSE i.e. nvCJD myth, for anyone to believe this
today only enhances to spreading of these human and animal TSE's. This is
exactly why we have been in this quagmire.
The ones that believe that there is a spontaneous CJD in 85%+ of all cases
of human TSE, and the ones that do not believe that cattle can have this
same phenomenon, are two of the same, the industry, and so goes the
political science aspect of this tobacco and or asbestos scenario i.e.
follow the money. I could go into all angles of this man made nightmare, the
real facts and science, for instance, the continuing rendering technology
and slow cooking with low temps that brewed this stew up, and the fact that
THE USA HAD THIS TECHNOLOGY FIRST AND SHIPPED IT TO THE U.K. SOME 5 YEARS
BEFORE THE U.S. STARTED USING THE SAME TECHNOLOGY, to save on fuel cost.
This is what supposedly amplified the TSE agent via sheep scrapie, and
spread via feed in the U.K. bovine, and other countries exporting the
tainted product. BUT most everyone ignores this fact, and the fact that the
U.S. has been recycling more TSE, from more species with TSEs, than any
other country documented, but yet, it's all spontaneous, and the rise in
sporadic CJD in the U.S. is a happenstance of bad luck ??? I respectfully
disagree. To top that all off, the infamous BSE-FIREWALL that the USDA
always brags about was nothing more than ink on paper, and I can prove this.
YOU can ignore it, but this is FACT (see source, as late as 2007, in one
recall alone, some 10,000,000 MILLION POUNDS OF BANNED MAD COW FEED WENT OUT
INTO COMMERCE TO BE FED OUT, and most was never recovered. This was banned
blood laced, meat and bone meal. 2006 was a banner year for banned mad cow
protein going into commerce in the U.S. (see source of FDA feed ban warning
letter below). I stress that the August 4, 1997 USA mad cow feed ban and
this infamous BSE firewall, was nothing more than ink on paper, it was never
enforceable.
I propose that the current diagnostic criteria for human TSEs only enhances
and helps the spreading of human TSE from the continued belief of the
UKBSEnvCJD only theory in 2009. With all the science to date refuting it, to
continue to validate this old myth, will only spread this TSE agent through
a multitude of potential routes and sources i.e. consumption, medical i.e.,
surgical, blood, dental, endoscopy, optical, nutritional supplements,
cosmetics etc. I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys,
Dormont, Gibbs, Gajdusek, Ironside, Manuelidis, Marsh, et al and many more,
that the world of TSE Transmissible Spongiform Encephalopathy is far from an
exact science, but there is enough proven science to date that this myth
should be put to rest once and for all, and that we move forward with a new
classification for human and animal TSE that would properly identify the
infected species, the source species, and then the route. This would further
have to be broken down to strain of species and then the route of
transmission would further have to be broken down. Accumulation and
Transmission are key to the threshold from sub- clinical to clinical
disease, and key to all this, is to stop the amplification and transmission
of this agent, the spreading of, no matter what strain. In my opinion, to
continue with this myth that the U.K. strain of BSE one strain TSE in cows,
and the nv/v CJD one strain TSE humans, and the one geographical location
source i.e. U.K., and that all the rest of human TSE are just one single
strain i.e. sporadic CJD, a happenstance of bad luck that just happens due
to a twisted protein that just twisted the wrong way, IN 85%+ OF ALL HUMAN
TSEs, when to date there are 6 different phenotypes of sCJD, and growing per
Gambetti et al, and that no other animal TSE transmits to humans ??? With
all due respect to all Scientist that believe this, I beg to differ. To
continue with this masquerade will only continue to spread, expose, and
kill, who knows how many more in the years and decades to come. ONE was
enough for me, My Mom, hvCJD i.e. Heidenhain Variant CJD, DOD 12/14/97
confirmed, which is nothing more than another mans name added to CJD, like
CJD itself, Jakob and Creutzfeldt, or Gerstmann-Straussler-Scheinker
syndrome, just another CJD or human TSE, named after another human. WE are
only kidding ourselves with the current diagnostic criteria for human and
animal TSE, especially differentiating between the nvCJD vs the sporadic CJD
strains and then the GSS strains and also the FFI fatal familial insomnia
strains or the ones that mimics one or the other of those TSE? Tissue
infectivity and strain typing of the many variants of the human and animal
TSEs are paramount in all variants of all TSE. There must be a proper
classification that will differentiate between all these human TSE in order
to do this. With the CDI and other more sensitive testing coming about, I
only hope that my proposal will some day be taken seriously. ...
and helps the spreading of human TSE from the continued belief of the
UKBSEnvCJD only theory in 2009. With all the science to date refuting it, to
continue to validate this old myth, will only spread this TSE agent through
a multitude of potential routes and sources i.e. consumption, medical i.e.,
surgical, blood, dental, endoscopy, optical, nutritional supplements,
cosmetics etc. I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys,
Dormont, Gibbs, Gajdusek, Ironside, Manuelidis, Marsh, et al and many more,
that the world of TSE Transmissible Spongiform Encephalopathy is far from an
exact science, but there is enough proven science to date that this myth
should be put to rest once and for all, and that we move forward with a new
classification for human and animal TSE that would properly identify the
infected species, the source species, and then the route. This would further
have to be broken down to strain of species and then the route of
transmission would further have to be broken down. Accumulation and
Transmission are key to the threshold from sub- clinical to clinical
disease, and key to all this, is to stop the amplification and transmission
of this agent, the spreading of, no matter what strain. In my opinion, to
continue with this myth that the U.K. strain of BSE one strain TSE in cows,
and the nv/v CJD one strain TSE humans, and the one geographical location
source i.e. U.K., and that all the rest of human TSE are just one single
strain i.e. sporadic CJD, a happenstance of bad luck that just happens due
to a twisted protein that just twisted the wrong way, IN 85%+ OF ALL HUMAN
TSEs, when to date there are 6 different phenotypes of sCJD, and growing per
Gambetti et al, and that no other animal TSE transmits to humans ??? With
all due respect to all Scientist that believe this, I beg to differ. To
continue with this masquerade will only continue to spread, expose, and
kill, who knows how many more in the years and decades to come. ONE was
enough for me, My Mom, hvCJD i.e. Heidenhain Variant CJD, DOD 12/14/97
confirmed, which is nothing more than another mans name added to CJD, like
CJD itself, Jakob and Creutzfeldt, or Gerstmann-Straussler-Scheinker
syndrome, just another CJD or human TSE, named after another human. WE are
only kidding ourselves with the current diagnostic criteria for human and
animal TSE, especially differentiating between the nvCJD vs the sporadic CJD
strains and then the GSS strains and also the FFI fatal familial insomnia
strains or the ones that mimics one or the other of those TSE? Tissue
infectivity and strain typing of the many variants of the human and animal
TSEs are paramount in all variants of all TSE. There must be a proper
classification that will differentiate between all these human TSE in order
to do this. With the CDI and other more sensitive testing coming about, I
only hope that my proposal will some day be taken seriously. ...
Like lambs to the slaughter
* 31 March 2001
* Debora MacKenzie
* Magazine issue 2284
Suspect symptoms
What if you can catch old-fashioned CJD by eating meat from a sheep infected with scrapie?
Exclusive from New Scientist magazine
Four years ago, Terry Singeltary watched his mother die horribly from a degenerative brain disease. Doctors told him it was Alzheimer's, but Singeltary was suspicious. The diagnosis didn't fit her violent symptoms, and he demanded an autopsy. It showed she had died of sporadic Creutzfeldt-Jakob disease.
Photo: Murdo McLeod
Most doctors believe that sCJD is caused by a prion protein deforming by chance into a killer. But Singeltary thinks otherwise.
He is one of a number of campaigners who say that some sCJD, like the variant CJD related to BSE, is caused by eating meat from infected animals. Their suspicions have focused on sheep carrying scrapie, a BSE-like disease that is widespread in flocks across Europe and North America.
Now scientists in France have stumbled across new evidence that adds weight to the campaigners' fears. To their complete surprise, the researchers found that one strain of scrapie causes the same brain damage in mice as sCJD.
"This means we cannot rule out that at least some sCJD may be caused by some strains of scrapie," says team member Jean-Philippe Deslys of the French Atomic Energy Commission's medical research laboratory in Fontenay-aux-Roses, south-west of Paris.
Hans Kretschmar of the University of Göttingen, who coordinates CJD surveillance in Germany, is so concerned by the findings that he now wants to trawl back through past sCJD cases to see if any might have been caused by eating infected mutton or lamb.
Brain damage
Scrapie has been around for centuries and until now there has been no evidence that it poses a risk to human health. But if the French finding means that scrapie can cause sCJD in people, countries around the world may have overlooked a CJD crisis to rival that caused by BSE.
Deslys and colleagues were originally studying vCJD, not sCJD. They injected the brains of macaque monkeys with brain from BSE cattle, and from French and British vCJD patients. The brain damage and clinical symptoms in the monkeys were the same for all three. Mice injected with the original sets of brain tissue or with infected monkey brain also developed the same symptoms.
As a control experiment, the team also injected mice with brain tissue from people and animals with other prion diseases: a French case of sCJD; a French patient who caught sCJD from human-derived growth hormone; sheep with a French strain of scrapie; and mice carrying a prion derived from an American scrapie strain.
As expected, they all affected the brain in a different way from BSE and vCJD. But while the American strain of scrapie caused different damage from sCJD, the French strain produced exactly the same pathology.
Multiple strains
"The main evidence that scrapie does not affect humans has been epidemiology," says Moira Bruce of the neuropathogenesis unit of the Institute for Animal Health in Edinburgh, who was a member of the same team as Deslys.
"You see about the same incidence of the disease everywhere, whether or not there are many sheep, and in countries such as New Zealand with no scrapie," she says. In the only previous comparisons of sCJD and scrapie in mice, Bruce found they were dissimilar.
But there are more than 20 strains of scrapie, and six of sCJD. "You would not necessarily see a relationship between the two with epidemiology if only some strains affect only some people," says Deslys. Bruce is cautious about the mouse results, but agrees they require further investigation. Other trials of scrapie and sCJD in mice, she says, are in progress.
Deformed proteins
People can have three different genetic variations of the human prion protein, and each type of protein can fold up two different ways. Kretschmar has found that these six combinations correspond to six clinical types of sCJD: each type of normal prion produces a particular pathology when it spontaneously deforms to produce sCJD.
But if these proteins deform because of infection with a disease-causing prion, the relationship between pathology and prion type should be different, as it is in vCJD. "If we look at brain samples from sporadic CJD cases and find some that do not fit the pattern," says Kretschmar, "that could mean they were caused by infection."
There are 250 deaths per year from sCJD in the US, and a similar incidence elsewhere. Singeltary and other US activists think that some of these people died after eating contaminated meat or "nutritional" pills containing dried animal brain.
Governments will have a hard time facing activists like Singeltary if it turns out that some sCJD isn't as spontaneous as doctors have insisted.
Deslys's work on macaques also provides further proof that the human disease vCJD is caused by BSE. And the experiments showed that vCJD is much more virulent to primates than BSE, even when injected into the bloodstream rather than the brain. This, says Deslys, means that there is an even bigger risk than we thought that vCJD can be passed from one patient to another through contaminated blood transfusions and surgical instruments.
More at: Proceedings of the National Academy of Sciences (vol 98, p 4142)
Correspondence about this story should be directed to letters@newscientist.com
1900 GMT, 28 March 2001
* New Scientist
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.
ZOONOSIS OF SCRAPIE TSE PRION
O.05: Transmission of prions to primates after extended silent incubation periods: Implications for BSE and scrapie risk assessment in human populations
Emmanuel Comoy, Jacqueline Mikol, Valerie Durand, Sophie Luccantoni, Evelyne Correia, Nathalie Lescoutra, Capucine Dehen, and Jean-Philippe Deslys Atomic Energy Commission; Fontenay-aux-Roses, France
Prion diseases (PD) are the unique neurodegenerative proteinopathies reputed to be transmissible under field conditions since decades. The transmission of Bovine Spongiform Encephalopathy (BSE) to humans evidenced that an animal PD might be zoonotic under appropriate conditions. Contrarily, in the absence of obvious (epidemiological or experimental) elements supporting a transmission or genetic predispositions, PD, like the other proteinopathies, are reputed to occur spontaneously (atpical animal prion strains, sporadic CJD summing 80% of human prion cases).
Non-human primate models provided the first evidences supporting the transmissibiity of human prion strains and the zoonotic potential of BSE. Among them, cynomolgus macaques brought major information for BSE risk assessment for human health (Chen, 2014), according to their phylogenetic proximity to humans and extended lifetime. We used this model to assess the zoonotic potential of other animal PD from bovine, ovine and cervid origins even after very long silent incubation periods.
*** We recently observed the direct transmission of a natural classical scrapie isolate to macaque after a 10-year silent incubation period,
***with features similar to some reported for human cases of sporadic CJD, albeit requiring fourfold long incubation than BSE. Scrapie, as recently evoked in humanized mice (Cassard, 2014),
***is the third potentially zoonotic PD (with BSE and L-type BSE),
***thus questioning the origin of human sporadic cases.
We will present an updated panorama of our different transmission studies and discuss the implications of such extended incubation periods on risk assessment of animal PD for human health.
===============
***thus questioning the origin of human sporadic cases***
===============
***our findings suggest that possible transmission risk of H-type BSE to sheep and human. Bioassay will be required to determine whether the PMCA products are infectious to these animals.
==============
***Transmission data also revealed that several scrapie prions propagate in HuPrP-Tg mice with efficiency comparable to that of cattle BSE. While the efficiency of transmission at primary passage was low, subsequent passages resulted in a highly virulent prion disease in both Met129 and Val129 mice.
***Transmission of the different scrapie isolates in these mice leads to the emergence of prion strain phenotypes that showed similar characteristics to those displayed by MM1 or VV2 sCJD prion.
***These results demonstrate that scrapie prions have a zoonotic potential and raise new questions about the possible link between animal and human prions.
***> 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. <***
SATURDAY, JUNE 23, 2018
CDC
***> Diagnosis of Methionine/Valine Variant Creutzfeldt-Jakob Disease by Protein Misfolding Cyclic Amplification
Volume 24, Number 7—July 2018 Dispatch
Volume 2: Science
4. The link between BSE and vCJD
Summary
4.29 The evidence discussed above that vCJD is caused by BSE seems overwhelming. Uncertainties exist about the cause of CJD in farmers, their wives and in several abattoir workers. It seems that farmers at least might be at higher risk than others in the general population. 1 Increased ascertainment (ie, increased identification of cases as a result of greater awareness of the condition) seems unlikely, as other groups exposed to risk, such as butchers and veterinarians, do not appear to have been affected. The CJD in farmers seems to be similar to other sporadic CJD in age of onset, in respect to glycosylation patterns, and in strain-typing in experimental mice. Some farmers are heterozygous for the methionine/valine variant at codon 129, and their lymphoreticular system (LRS) does not contain the high levels of PrPSc found in vCJD. It remains a remote possibility that when older people contract CJD from BSE the resulting phenotype is like sporadic CJD and is distinct from the vCJD phenotype in younger people...end...BSE INQUIRY
> However, to date, no CWD infections have been reported in people.
sporadic, spontaneous CJD, 85%+ of all human TSE, just not just happen. never in scientific literature has this been proven.
if one looks up the word sporadic or spontaneous at pubmed, you will get a laundry list of disease that are classified in such a way;
sporadic = 54,983 hits https://www.ncbi.nlm.nih.gov/pubmed/?term=sporadic
spontaneous = 325,650 hits https://www.ncbi.nlm.nih.gov/pubmed/?term=spontaneous
key word here is 'reported'. science has shown that CWD in humans will look like sporadic CJD. SO, how can one assume that CWD has not already transmitted to humans? they can't, and it's as simple as that. from all recorded science to date, CWD has already transmitted to humans, and it's being misdiagnosed as sporadic CJD. ...terry
ALL iatrogenic CJD is, is sporadic CJD, until the iatrogenic event is discovered, traced back, proven, documented in the academic domain, and finally the public domain, which very seldom happens due to lack of trace back efforts, thus, all iatrogeic events stay as sporadic cjd.
THERE should be a mandatory trace out of these patients, and all patients should know, and if they choose not to, so be it, but the victim, patient, and Doctors of all involved must be made aware, and the hospital, this information should be put in some sort of confidential registry (WHERE INSURANCE COMPANIES CANNOT GAIN ACCESS OF SAID PATIENT/VICTIM), where hospitals and doctors can assess and be made aware of iatrogenic TSE Prion event, so that further iatrogenic transmission can hopefully be avoided. IF not, it's all pointless imo. ...terry
CJD TSE Prion Blood Products, iatrogenic transmission, Confucius is confused again, WHAT IF?
FRIDAY, JANUARY 31, 2020
CJD TSE Prion Blood Products, iatrogenic transmission, Confucius is confused again, WHAT IF? Docket Number: FDA-2012-D-0307
Confucius is confused again?
''The rare genetic forms of CJD (e.g., fCJD, GSS, FFI) share pathophysiological features with sCJD, and the transmission risk by blood components remains theoretical. Consequently, we recommend that establishments may stop asking prospective donors about having blood relatives with CJD.''
YET, vpspr, sporadic FFI, sporadic GSS, or the pending cases that can't be identified, are all now listed as sporadic CJD.
WHAT IF, sGSS, sFFI, are of an iatrogenic event from iatrogenic donor being from GSS or FFI?
what if vpspr is another strain of a different sporadic CJD, or familial? see;
7Includes 21 (21 from 2019) cases with type determination pending in which the diagnosis of vCJD has been excluded.
8The sporadic cases include 3831 cases of sporadic Creutzfeldt-Jakob disease (sCJD), 67 cases of Variably Protease-Sensitive Prionopathy (VPSPr) and 35 cases of sporadic Fatal Insomnia (sFI).
9Total does not include 264 Familial cases diagnosed by blood test only.
under new proposed guidelines ''we recommend that establishments may stop asking prospective donors about having blood relatives with CJD'' (of which i strongly oppose due to the fact sporadic cjd is not a single entity or a spontaneous event, never which have been proven), but under these guidelines, you will miss the vpspr, sgss, and sffi, because they are under sporadic cjd terminology, would you not?
The occurrence of the disease in a patient who had contact with cases of familial C.J.D., but was not genetically related, has been described in Chile (Galvez et al., 1980) and in France (Brown et al., 1979b). In Chile the patient was related by marriage, but with no consanguinity, and had social contact with subsequently affected family members for 13 years before developing the disease. The contact case in France also married into a family in which C.J.D. was prevalent and had close contact with an affected member. In neither instance did the spouse of the non-familial case have the disease. The case described in this report was similarly related to affected family members and social contact had occurred for 20 years prior to developing C.J.D. If contact transmission had occurred, the minimum transmission period would be 11 years. Contact between sporadic cases has not been described and it is remarkable that possible contact transmissions have all been with familial cases. No method of transmission by casual social contact has been suggested.
WHAT IF?
***The occurrence of contact cases raises the possibility that transmission in families may be effected by an unusually virulent strain of the agent.
snip...see full text here;
Sporadic Creutzfeldt-Jakob Disease in a Woman Married Into a Gerstmann-Sträussler-Scheinker Family: An Investigation of Prions Transmission via Microchimerism
Aušrinė Areškevičiūtė, MSc, Linea Cecilie Melchior, PhD, Helle Broholm, MD, Lars-Henrik Krarup, MD, PhD, Suzanne Granhøj Lindquist, MD, PhD, Peter Johansen, PhD, Neil McKenzie, PhD, Alison Green, PhD, Jørgen Erik Nielsen, MD, PhD, Henning Laursen, Dr.Med, Eva Løbner Lund, MD, PhD Journal of Neuropathology & Experimental Neurology, Volume 77, Issue 8, August 2018, Pages 673–684, https://doi.org/10.1093/jnen/nly043 Published: 07 June 2018
DISCUSSION
This is the first report of presumed sporadic CJD occurring in a person who married into a GSS family. The estimated prevalence of GSS is in the range of 2–5 per 100 million people worldwide, and the annual mortality rate for sCJD in Denmark is 1.46 per 1 million people (31). The population of Denmark consists of 5 740 185 individuals, and there are 2 registered GSS cases that belong to the same family. The Danish GSS family is only the thirty-fourth known GSS family in the world (32). One could assume that the risk for a Danish man with GSS to have a wife or a mother who would develop CJD in her seventies is as high as for any other man. On the basis of the mortality rate for sCJD, and assuming that the incidence of sCJD is the same among married and unmarried people, we could state that 1 man out of 684 932 men has a risk of marrying a woman who would develop CJD. However, in this case, the man a priori had GSS, which means that it would take 1 man out of 684 932 men with GSS for such a pairing to occur. Considering the worldwide rarity of GSS cases, the likelihood for co-occurrence of GSS and sCJD in one family is hence very low and warrants an investigation for the possible transmission of prions routes.
Volume 25, Number 1—January 2019
Research
Variable Protease-Sensitive Prionopathy Transmission to Bank Vol
Romolo Nonno1, Silvio Notari1, Michele Angelo Di Bari, Ignazio Cali, Laura Pirisinu, Claudia d’Agostino, Laura Cracco, Diane Kofskey, Ilaria Vanni, Jody Lavrich, Piero Parchi, Umberto Agrimi, and Pierluigi GambettiComments to Author
Author affiliations: Istituto Superiore di Sanità, Rome, Italy (R. Nonno, M.A. Di Bari, L. Pirisinu, C. d’Agostino, I. Vanni, U. Agrimi); Case Western Reserve University, Cleveland, Ohio, USA (S. Notari, I. Cali, L. Cracco, D. Kofskey, J. Lavrich, P. Gambetti); University of Bologna, Bologna, Italy (P. Parchi); Istituto delle Scienze Neurologiche di Bologna, Bologna (P. Parchi)
***> However, the VPSPr prion shares the multiplicity of the resPrPD electrophoretic bands with prions from a subset of inherited prion diseases referred to as Gerstmann-Sträussler-Scheinker disease (GSS), prompting the suggestion that VPSPr is the sporadic form of GSS (7,10). Furthermore, the presence of small amounts of sCJD-like 3-band resPrPD has also been signaled in VPSPr (6,11,12).
FRIDAY, JANUARY 10, 2014
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???
Greetings Friends, Neighbors, and Colleagues,
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???
Confucius is confused again.
I was just sitting and thinking about why there is no genetic link to some of these TSE prion sGSS, sFFi, and it’s really been working on my brain, and then it hit me today.
what if, vpspr, sgss, sffi, TSE prion disease, was a by-product from iatrogenic gss, ffi, familial type prion disease ???
it could explain the cases of no genetic link to the gss, ffi, familial type prion disease, to the family.
sporadic and familial is a red herring, in my opinion, and underestimation is spot on, due to the crude prehistoric diagnostic procedures and criteria and definition of a prion disease.
I say again, what if, iatrogenic, what if, with all these neurological disorders, with a common denominator that is increasingly showing up in the picture, called the prion.
I urge all scientist to come together here, with this as the utmost of importance about all these neurological disease that are increasingly showing up as a prion mechanism, to put on the front burners, the IATROGENIC aspect and the potential of transmission there from, with diseases/disease??? in question.
by definition, could they be a Transmissible Spongiform Encephalopathy TSE prion type disease, and if so, what are the iatrogenic chances of transmission?
this is very important, and should be at the forefront of research, and if proven, could be a monumental breakthrough in science and battle against the spreading of these disease/diseases.
sporadic CJD, along with new TSE prion disease in humans, of which the young are dying, of which long duration of illness from onset of symptoms to death have been documented, only to have a new name added to the pot of prion disease i.e. sporadic GSS, sporadic FFI, and or VPSPR. I only ponder how a familial type disease could be sporadic with no genetic link to any family member? when the USA is the only documented Country in the world to have documented two different cases of atypical H-type BSE, with one case being called atypical H-G BSE with the G meaning Genetic, with new science now showing that indeed atypical H-type BSE is very possible transmitted to cattle via oral transmission (Prion2014). sporadic CJD and VPSPR have been rising in Canada, USA, and the UK, with the same old excuse, better surveillance. You can only use that excuse for so many years, for so many decades, until one must conclude that CJD TSE prion cases are rising. a 48% incease in CJD in Canada is not just a blip or a reason of better surveillance, it is a mathematical rise in numbers. More and more we are seeing more humans exposed in various circumstance in the Hospital, Medical, Surgical arenas to the TSE Prion disease, and at the same time in North America, more and more humans are becoming exposed to the TSE prion disease via consumption of the TSE prion via deer and elk, cattle, sheep and goats, and for those that are exposed via or consumption, go on to further expose many others via the iatrogenic modes of transmission of the TSE prion disease i.e. friendly fire. I pondered this mode of transmission via the victims of sporadic FFI, sporadic GSS, could this be a iatrogenic event from someone sub-clinical with sFFI or sGSS ? what if?
Thursday, March 8, 2018
Familial human prion diseases associated with prion protein mutations Y226X and G131V are transmissible to transgenic mice expressing human prion protein
Furthermore, GSS A117V infected vole brains were able to induce the same disease phenotype in recipient voles within 3–4 months after challenge, proving that a prion agent propagated in the brains of infected animals. These findings imply that brains of GSS patients harbor infectious prions with transmissibility features similar to those found in other human and animal TSEs.
*** 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.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8006664&dopt=Abstract
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.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8006664&dopt=Abstract
*** 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).***
PLOS ONE Journal
IBNC Tauopathy or TSE Prion disease, it appears, no one is sure
Terry S. Singeltary Sr., 03 Jul 2015 at 16:53 GMT
***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 ***
http://www.plosone.org/annotation/listThread.action?root=86610
***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 ***
http://www.plosone.org/annotation/listThread.action?root=86610
*** Singeltary reply ; Molecular, Biochemical and Genetic Characteristics of BSE in Canada Singeltary reply
Friday, September 27, 2019
Prion disease and recommended procedures for flexible endoscope reprocessing – a review of policies worldwide and proposal for a simplified approach Singeltary, GUT journal and Bramble et al
THURSDAY, SEPTEMBER 26, 2019
Veterinary Biologics Guideline 3.32E: Guideline for minimising the risk of introducing transmissible spongiform encephalopathy prions and other infectious agents through veterinary biologics
U.S.A. 50 STATE BSE MAD COW CONFERENCE CALL Jan. 9, 2001 Singeltary et al
SATURDAY, SEPTEMBER 21, 2019
National Variability in Prion Disease–Related Safety Policies for Neurologic Procedures
Wednesday, September 11, 2019
Is the re-use of sterilized implant abutments safe enough? (Implant abutment safety) iatrogenic TSE Prion
FRIDAY, SEPTEMBER 06, 2019
Disinfection of Multi-Use Ocular Equipment for Ophthalmological Procedures: A Review of Clinical Effectiveness, Cost-Effectiveness, and Guidelines
MONDAY, AUGUST 26, 2019
Creutzfeldt Jakob Disease CJD, TSE, Prion, Surveillance Update August 2019
SUNDAY, MARCH 10, 2019
National Prion Disease Pathology Surveillance Center Cases Examined¹ Updated Feb 1, 2019 Variably protease-sensitive prionopathy VPSPr
***> In conclusion, sensory symptoms and loss of reflexes in Gerstmann-Sträussler-Scheinker syndrome can be explained by neuropathological changes in the spinal cord. We conclude that the sensory symptoms and loss of lower limb reflexes in Gerstmann-Sträussler-Scheinker syndrome is due to pathology in the caudal spinal cord. <***
***> The clinical and pathological presentation in macaques was mostly atypical, with a strong emphasis on spinal cord pathology.<***
***> The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD. <***
***> All animals have variable signs of prion neuropathology in spinal cords and brains and by supersensitive IHC, reaction was detected in spinal cord segments of all animals.<***
***> In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids.'' Scientific opinion on chronic wasting disease (II) <***
THURSDAY, JANUARY 30, 2020
Docket Number: FDA-2012-D-0307 Recommendations to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Components; Draft Guidance for Industry Draft Guidance for Industry Singeltary Submission
FRIDAY, JANUARY 31, 2020
CJD TSE Prion Blood Products, iatrogenic transmission, Confucius is confused again, WHAT IF? Docket Number: FDA-2012-D-0307
Tables of Cases Examined
National Prion Disease Pathology Surveillance Center Cases Examined¹ Updated December 9, 2019
Year Total Referrals² Prion Disease Sporadic Familial Iatrogenic vCJD
1999 & earlier 380 230 200 27 3 0
2000 145 102 90 12 0 0
2001 209 118 110 8 0 0
2002 241 144 124 18 2 0
2003 259 160 137 21 2 0
2004 316 181 164 16 0 1³
2005 327 178 156 21 1 0
2006 365 179 159 17 1 2⁴
2007 374 210 191 19 0 0
2008 384 221 205 16 0 0
2009 398 232 210 21 1 0
2010 401 246 218 28 0 0
2011 392 238 214 24 0 0
2012 413 244 221 23 0 0
2013 416 258 223 34 1 0
2014 355 208 185 21 1 1⁵
2015 402 264 244 20 0 0
2016 396 277 248 29 0 0
2017 375 266 247 19 0 0
2018 309 223 204 18 1 0
2019 351 220 183 16 0 0
TOTAL 72086 4399⁷ 3933⁸ 428⁹ 13 4
1Listed based on the year of death or, if not available, on year of referral;
2Cases with suspected prion disease for which brain tissue was submitted;
3Disease acquired in the United Kingdom;
4Disease acquired in the United Kingdom in one case and in Saudi Arabia in the other;
5Disease possibly acquired in a Middle Eastern or Eastern European country;
6Includes 20 cases in which the diagnosis is pending, and 19 inconclusive cases;
7Includes 21 (21 from 2019) cases with type determination pending in which the diagnosis of vCJD has been excluded.
8The sporadic cases include 3831 cases of sporadic Creutzfeldt-Jakob disease (sCJD), 67 cases of Variably Protease-Sensitive Prionopathy (VPSPr) and 35 cases of sporadic Fatal Insomnia (sFI).
9Total does not include 264 Familial cases diagnosed by blood test only.
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.
Terry S. Singeltary Sr.
posted by Terry S. Singeltary Sr. at
12:52 PM
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