Human prion diseases are fatal neurodegenerative disorders that are characterized neuropathologically by the abnormal accumulation of a misfolded prion protein (PrP) in the central nervous system. The mechanism by which the cellular PrP (PrPC) is converted into the pathogenic scrapie‐type PrP (PrPSc) appears to involve a post‐translational change in PrPC conformation, from a predominantly α‐helical into a predominantly β‐sheet structure.1 PrPSc is the major, if not the sole, component of the transmissible agent in prion diseases. PrPSc is relatively insoluble and aggregates extracellularly, possibly inducing adjacent tissue malfunction, although the exact pathological mechanism is still unclear. Human prion diseases differ not only in their clinical and neuropathological features, but also in the biochemical features (differential glycosylation and relatively resistance to proteinase digestion) of PrPSc in the brain, making prionopathies a much more heterogeneous group of disorders than initially considered.
''It is well known that prionopathies, VPSPr included, are transmissible neurodegenerative diseases that pose potential health and safety risks.''
''Although extra health and safety measurements may be advised in suspected prionopathies, it is believed that the standard but rigorous health and safety measures in neuropathology laboratories and brain banks are sufficient to prevent accidental disease transmission.''
FRIDAY, JANUARY 10, 2014
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what if ???
Greetings Friends, Neighbors, and Colleagues,
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what if ???
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.
the US National Library of Medicine National Institutes of Health pub-med site, a quick search of the word SPORADIC will give you a hit of 40,747. of those, there are a plethora of disease listed under sporadic. sporadic simply means (UNKNOWN).
the US National Library of Medicine National Institutes of Health pub-med site, a quick search of the word FAMILIAL will give you a hit of 921,815. of those, there are a plethora of disease listed under familial.
again, sporadic and familial is a red herring, in my opinion.
also, in my opinion, when you start have disease such as sporadic Fatal Familial Insomnia, (and or sporadic GSS, or the VPSPr type prion disease), and there is NO familial genetic linkage to the family of the diseased, I have serious questions there as to a familial type disease, and thus, being defined as such.
*UPDATE*
NOVEMBER 16, 2014
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what if ??? Friday, January 10, 2014
Greetings again Friends, Neighbors, and Colleagues,
I would kindly like to follow up on ‘vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what if ???’ ran across an old paper from 1984, that some might find interest in, and I will update the link with this old science paper from 1984, a 2010 paper from Japan, and some information on scrapie transmission. The paper from Japan first, then the 1984 paper, and then the scrapie transmission studies.
***The occurrence of contact cases raises the possibility that transmission in families may be effected by an unusually virulent strain of the agent.
From: Terry S. Singeltary Sr.
Sent: Saturday, November 15, 2014 9:29 PM
To: Terry S. Singeltary Sr.
Subject: THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE R. G. WILL 1984
THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE
R. G. WILL
1984
snip...
D. Occupation
The possibility of case-to-case transmission of C.J.D. has led to anxiety among hospital personnel and laboratory staff regarding the possible risks of transmission by direct contact with patients suffering from the condition (Mayer, 1979). During the prospective study reluctance to perform post mortem or carry out electrophysiological studies was regularly encountered. In the past, epidemiological evidence has consistently failed to reveal any increased risk related to particular professions (Bobowick et al., 1973; Matthews, 1975a; Brown et al., 1979b; Galvez et al., 1980; Kondo and Kuroiwa, 1982) and, with the exception of the review by Masters et al. (1979a), no increased risk to medical or paramedical personnel. In the latter study 18 out of 308 cases were described as health professionals, although as Brown (1980) has pointed out, this may have been due to case selection. One neurosurgeon has been reported to have died of pathologically confirmed C.J.D. (Schoene et al., 1981), but although he had contact with a case of C.J.D. seven years prior to death, no operative procedure was carried out.
In the retrospective section of this study no occupational bias was discovered, there was no over-representation of health care personnel and only one patient, a nurse, was likely to have had direct contact with patients. In the prospective study, in which details of occupation throughout life were obtained, there was again no occupational bias. Possible contact between a dentist dying of confirmed C.J.D. and other patients is discussed below, but the putative transmission in these cases would have required direct implantation of the agent during dental procedures.
On the basis of the evidence from this and previous epidemiological studies, there appears to be no increased risk of transmission by direct contact with patients. Bodily secretions and excreta do not contain the agent (Masters et al., 1980) and although viraemia has been described in experimental transmission in guinea pigs (Manuelidis et al., 1978b, Gajdusek et al. (1978) suggest that human blood, if ever infective, must contain a very low titre of the agent. Despite a large number of transmission experiments no staff at Bethesda have ever contracted the condition (Gajdusek et al., 1978). Prior to the discovery that C.J.D. was trans- missible no special precautions were taken during post mortem and indeed the pathology technician in Dr. Nevin's cases has described eating food off the post mortem table immediately after necropsy of one of these patients. Despite the lack of precautions in the past no pathology technicians are known to have developed C.J.D.
In conclusion, sensible precautions as advised by both Gajdusek et al. (1977) and the Advisory Group on the Management of Patients with Spongiform Encephalopathy (1981) are sufficient. Patients do not require barrier nursing, blood and cerebrospinal fluid specimens should be treated in the same way as other 'high risk' specimens, and more stringent precautions should be observed at post mortem. The risk of case-to-case transmission at neurosurgery is established (as discussed below) and all instruments should be discarded after use.
E. Past Medical History
An increased incidence of surgical procedures and neurological and psychiatric illness in C.J.D. has been described by Masters et ale (1979a). Cases in this series were ascertained from a variety of sources, including direct referral and a review of the literature and selection bias cannot be excluded. It is also uncertain whether such an incidence of past medical or surgical illness differs from the incidence in this age group in the general population. Other retrospective epidemiological studies of C.J.D. (Bobowick et al. t 1973; Matthews, 1975a; Brown et al., 1979b; Kondo and Kuroiwa, 1982) have failed to show an increased incidence of past medical or surgical illness and combining the results of the Chilean (Galvez et al., 1980) and Hungarian (Majtenyi, 1978) studies only four patients out of a total of 67 had a significant past surgical history. In the study in France (Brown et al., 1979b) 8% of patients had some form of surgical procedure in the five years prior to developing C.J.D., but the rationale for limiting enquiry to the preceding five years is unclear in view of the possible incubation period in C.J.D. of over four decades (Masters et al., 1981a). In the retrospective survey in this study, which was without temporal limits, 28% of patients had a past history of some form of major surgery. Without a comparison with the incidence of major surgery in a matched population the significance of this figure is uncertain, and it is of note that in 40 patients no past illness was described.
In the prospective study a more detailed medical history was obtained and there was no specific factor in the past medical history common to all patients. As with other proposed risk factors, only a properly conducted case control study can assess the significance of putative risk factors discovered in descriptive epidemiological surveys.
The transmission of C.J.D. by corneal transplantation has been established (Duffy et al., 1974) and it is disturbing that in one case in this series corneas were removed for transplantation from a patient dying of C.J.D. and in a further case potentially contaminated corneal transplants had to be removed when the risks were realised. The recommendation that corneas must not be taken for transplantation from demented patients, from patients dying in psychiatric hospitals, nor from patients dying of undiagnosed neurological disease (Advisory Group on the Management of Patients with Spongiform Encephalopathy, 1981) should be reinforced.
F. Familial Associations
The overall familial incidence of 6% in the retrospective section of this study contrasts with the estimated familial incidence of 15% in a review of the world wide epidemiology of C.J.D. (Masters et al., 1979a). In individual series higher figures are quoted with, for example, a familial incidence of 47% in Chile (Galvez et al., 1980) and 35% in Libyan born Israelis (Neugut et al., 1979). In a comprehensive retrospective survey of C.J.D. in France (Brown et al., 1979b), however, a 9% familial incidence was discovered, a figure comparable with this series. The low familial incidence may reflect either the difficulties of retrospectively obtaining an accurate family history or an artificially high familial incidence in relatively selected series due to extensive investigation of individual families.
The paradox of an apparently dominantly inherited condition (Masters et al., 1981a) which is yet transmissible is unresolved. Detailed investigation of individual families suggests that, if case to case transmission occurs, the incubation period must extend to decades (Masters et al., 1981a). Although this is compatible with the suspected incubation period of kuru (Gajdusek, 1979), the tendency for siblings to die at the same age rather than the same time (Masters et al., 1981a) supports the presence of a genetic influence. ***The discovery of a discordant identical twin pair in the present study suggests that even if there is an inherited susceptibility an environmental factor is necessary for the development of the condition. It further suggests that genetic integration of the agent is unlikely, in accordance with experimental evidence in which nuclear fractions are non-infectious (Millson et al., 1971) and vertical trans- mission has not been found in the laboratory (Amyx et al., 1981).
An unexpected but interesting finding in the context of familial associations is the group of nine patients with a first degree relative dying of a different 'degenerative' neurological condition. The extraordinary family with apparently dominantly inherited Alzheimer's disease and carcinoma of the colon is under investigation at another centre.
In other systematic studies of the epidemiology of C.J.D. an association with other neurological conditions has not been described but Masters (1981a) has reported four cases of C.J.D. occurring within four pedigrees of familial Alzheimer's disease. Adam et ale (1982) have described a family with a dominantly inherited neurological disorder sharing features of cerebral amyloidosis, spongiform encephalopathy and Alzheimer's disease. ***The relationship of C.J.D. to other degenerative neurological disorders may be a fruitful avenue of further epidemiological research.
CASE CONTROL STUDY
The objective of the case control study was to obtain quantitative data on putative risk factors and to identify potential common exposure to an environmental source of infection. The difficulties of such a study have been described by Bobowick et al. (1973) and Kondo and Kuroiwa (1982) in the only previous case control studies of C.J.D. In a rare condition such as C.J.D. it is difficult to obtain sufficient patient numbers to achieve statistically valid results. In this study 22 patients were included in the first 18 months, a number sufficient to exclude any ubiquitous risk factor but inadequate to distinguish relative risk. The case control study has, however, continued beyond the time limits of this analysis and to date over a hundred patients have been included.
The necessity of obtaining information at second hand introduces a potential source of error in the study of C.J.D. In this study the level of co-operation and detail of information was clearly enhanced by interviewing relatives prospectively and for this reason cases ascertained after death were not included in the prospective study. The checking of information given by relatives of control cases with the patients themselves suggested that the quality of information given at second hand was remarkably accurate.
The selection of controls is critical to the potential significance of a case control study. In this study age- and sex-matched controls were obtained from concurrent inpatients. Although in some cases the discovery of a suitable control proved both difficult and time-consuming, and in a few cases impossible, it was felt essential to persevere with the stated protocol in order to avoid the introduction of bias. Both previous case control studies were carried out retro- spectively and used 'healthy' and potentially over-matched controls.
Despite the differences between previous studies and the present case control study, the results were, almost without exception, both concordant and negative. No difference between patients and controls was discovered in past surgical or medical history, occupational history, educational history, eating habits or exposure to animals. Kondo and Kuroiwa (1982) discovered a correlation between physical injuries and the development of C.J.D. but could not exclude a methodological bias. No such correlation was discovered in this study and the subject was not examined in the study by Bobowick et ale (1973).
In the latter study the consumption of hog brains by patients was stressed but did not differ from the control group and in both this study and the study in Japan (Kondo and Kuroiwa, 1982) no dietary factory was related to increased risk of developing C.J.D.
***The successful oral transmission of C.J.D. and scrapie to primates (Gibbs et al., 1980) and the close resemblance between the properties of the transmissible agent in the two conditions (Gibbs and Gajdusek, 1976) has raised the possibility that the human disease is contracted from sheep. No direct evidence is available and the concept is based on inference and interesting but unconvincing anecdotes
(Alter et al., 1971; Lo Russo et al., 1980; Kamin and Patten, 1984). The patient discovered in this study who had never been known to eat meat suggests that eating scrapie infected meat cannot be the only source of C.J.D. in man. C.J.D. occurs in countries in which natural scrapie has not been observed (Galvez et al., 1980; Kondo and Kuroiwa, 1982) and no relationship was discovered in France (Chatelain et al., 1981) between the geographic distribution of scrapie and the incidence of C.J.D. A similar investigation could not be carried out in England and Wales as notification of scrapie to the Ministry of Agriculture is inconsistent and sheep farmers often destroy affected animals without seeking veterinary advice for fear of financial loss.
A detailed residential history was obtained in cases and controls. Although over-representation of cases was discovered in certain areas, similar but distinct areas of previous residence common to an apparent excess of controls was discovered. If C.J.D. does have a prolonged incubation period extending to decades the detailed study of residential history may, however, establish potential contact between individual cases which would be otherwise undetectable. The detailed study of individual cases in the prospective study has revealed the possibility of tenuous but extraordinarily coincidental contact between patients.
This may only be a reflection of intensive investigation, but if C.J.D. is transmitted by relatively minor surgical or dental procedures many years prior to death it is only by the systematic study of individual cases that potential cross-contamination may be discovered.
EVIDENCE FOR CASE-TO-CASE TRANSMISSION OF C.J.D.
The possible iatrogenic transmission of C.J.D. by neurosurgery, corneal transplantation and stereotactic electrodes has been suggested in the past (Duffy et al., 1974: Bernouilli et al., 1977; Masters et al., 1979a). In this series the close temporal relationship of neurosurgical procedures on two affected patients and three patients, unaffected at the time but who subsequently developed the disease is described. This provides strong circumstantial evidence of iatrogenic transmission by neurosurgery. Although sterilisation procedures have improved since the cases described, the unusual resistance of the agent and the recent description of probable neurosurgical transmission in France (Foncin et al., 1980) suggests that there is a continued risk of accidental transmission. However, brain biopsy to confirm the diagnosis of C.J.D. is now an unusual event and computed tomography has obviated the need for ventriculography.
The depth electrodes putatively responsible for one case of iatrogenic transmission in this series were inadequately sterilised in formalin and were subsequently used in over 200 patients. The neurosurgical instruments used in the cases of presumed neurosurgical transmission were sterilised using autoclaving procedures which were inadequate according to current advice (Gajdusek et al., 1978). However, despite detailed investigation, no cases other than those described above are known to have developed C.J.D. Thus, despite the possible implantation of the agent directly into the central nervous system, a large number of patients failed to develop the disease. This provides circumstantial evidence of an inherited susceptibility to the agent and suggests that cases of iatrogenic transmission may have occurred due to the unfortunate temporal proximity of susceptible individuals exposed to the agent.
In the close geographic group of three cases possible nodes of transmission can be suggested, either iatrogenic or through dental procedures, but these must remain conjectural. It is known, however, that the similar scrapie agent can be transmitted from the gums of animals (Adams and Edgar, 1978). Such close spatial clustering of cases is extremely unusual, being previously reported in England (Matthews, 1975a), Czechoslovakia (Mayer et al., 1977) and Hungary (Majtenyi, 1978), but not detected in the study of the epidemiology of C.J.D. in urban Paris (Cathala et al., 1978) where the incidence was found to be relatively high.
The occurrence of the disease in a patient who had contact with cases of familial C.J.D., but was not genetically related, has been described in Chile (Galvez et al., 1980) and in France (Brown et al., 1979b). In Chile the patient was related by marriage, but with no consanguinity, and had social contact with subsequently affected family members for 13 years before developing the disease. The contact case in France also married into a family in which C.J.D. was prevalent and had close contact with an affected member. In neither instance did the spouse of the non-familial case have the disease. The case described in this report was similarly related to affected family members and social contact had occurred for 20 years prior to developing C.J.D. If contact transmission had occurred, the minimum transmission period would be 11 years. Contact between sporadic cases has not been described and it is remarkable that possible contact transmissions have all been with familial cases. No method of transmission by casual social contact has been suggested.
***The occurrence of contact cases raises the possibility that transmission in families may be effected by an unusually virulent strain of the agent.
snip...see full text here;
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Abstract
Prion disease
Hidehiro Mizusawa, M.D., Ph.D.
Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences
Human prion diseases are classified into 3 categories according to etiologies: idiopathic of unknown cause, ac- quired of infectious origin, and genetic by PRNP mutation. The surveillance committee have analyzed 2,494 cases and identified 1,402 as prion diseases. Most of them are idiopathic, namely sporadic CJD (77%) with less genetic and acquired prion diseases (17% and 5%, respectively). The number of patients identified by the surveillance committee in these years is about 120 which are less than the number of annual death of prion disease. The differ- ence might be due to partly the fact our surveillance need the consent from patients' family and is not complete. The mean age at onset of prion disease is late 60s while the range is fairly wide. Brain MRIs and increase of CSF 14-3-3 and tau protein levels are very characteristic. Classical sporadic CJD could show completely normal T1 WI with patchy high signals in the cerebral cortex and basal ganglia on DWI. In Japan, classical sporadic CJD (MM1) is most popular but there are some rare atypical subtypes. Among them, MM2-thalamic C]D is hardest to diag- nose because it shows no high intensity signals on DWI, in addition to frequent absence of CSF and EEG charac- teristics. In this case, CBF decrease in the thalamus on SPECT is very helpful. Genetic prion diseases in Japan are quite distinct from those in Europe. V180I and M232R mutations are unique to Japan and show sporadic CJD phe- notype. Dura graft-associated CJD (dCJD) are composed of 67% of classical sporadic CJD phenotype and 33% of atypical phenotype showing slower progression with amyloid plaques. Trace-back experiments suggested the PrPsc of the atypical dCJD was likely to be modified from infection of abnormal VV2 protein. Although there are some atypical forms of prion diseases as mentioned above, almost all prion cases could be diagnosed with EEG, MRI, genetic test, CSF test and SPECT. We also have some incidents in which brain surgery was done before the diagnosis of prion disease and many other patients were operated using the same operating instruments before their sterilization against prion disease had been done. The explanation of possibility of prion disease infection to the patients and their follow-up was started by the incident committee. It is very important for all the nations to cooperate with each other in order to overcome this intractable disease.
(Clin NeuroI 2010;50:797-802)
Key words: prion disease, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome (GSS), fatal famil- ial insomnia (FFI), transmissible spongiform encephalopathy (TSE), 14-3-3 protein, tau protein, MRI-DWI
=============
Neurology. 1987 Jun;37(6):895-904.
The epidemiology of Creutzfeldt-Jakob disease: conclusion of a 15-year investigation in France and review of the world literature.
Brown P, Cathala F, Raubertas RF, Gajdusek DC, Castaigne P.
Abstract
During the 15-year period 1968-1982, a total of 329 patients dying of Creutzfeldt-Jakob disease (CJD) were identified in continental France. Annual mortality rates stabilized at 0.5 to 0.6 cases per million (1.1 to 1.2 cases per million in Paris). Six percent of cases were familial. Although the frequency of CJD was related to population density, no contacts could be established among the great majority of patients. No association with socioeconomic factors, preceding trauma or surgery (excepting one iatrogenic neurosurgical case), or exposure to animal sources of infection was identified. Evidence from this and other epidemiologic studies suggests that CJD is a minimally contagious disease that may be principally acquired in early life from presymptomatic patients, asymptomatic carriers, or chance contamination by environmental sources. It is possible that CJD could also occur sporadically as a noncontagious disease by a mechanism akin to oncogenes in carcinogenesis.
PMID: 3295589 [PubMed - indexed for MEDLINE]
why do we not want to do TSE transmission studies on chimpanzees $
5. A positive result from a chimpanzee challenged severly would likely create alarm in some circles even if the result could not be interpreted for man. I have a view that all these agents could be transmitted provided a large enough dose by appropriate routes was given and the animals kept long enough. Until the mechanisms of the species barrier are more clearly understood it might be best to retain that hypothesis.
snip...
R. BRADLEY
1: J Infect Dis 1980 Aug;142(2):205-8
Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.
Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.
Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation.
snip...
The successful transmission of kuru, Creutzfeldt-Jakob disease, and scrapie by natural feeding to squirrel monkeys that we have reported provides further grounds for concern that scrapie-infected meat may occasionally give rise in humans to Creutzfeldt-Jakob disease.
PMID: 6997404
Recently the question has again been brought up as to whether scrapie is transmissible to man. This has followed reports that the disease has been transmitted to primates. One particularly lurid speculation (Gajdusek 1977) conjectures that the agents of scrapie, kuru, Creutzfeldt-Jakob disease and transmissible encephalopathy of mink are varieties of a single "virus". The U.S. Department of Agriculture concluded that it could "no longer justify or permit scrapie-blood line and scrapie-exposed sheep and goats to be processed for human or animal food at slaughter or rendering plants" (ARC 84/77)" The problem is emphasised by the finding that some strains of scrapie produce lesions identical to the once which characterise the human dementias"
Whether true or not. the hypothesis that these agents might be transmissible to man raises two considerations. First, the safety of laboratory personnel requires prompt attention. Second, action such as the "scorched meat" policy of USDA makes the solution of the acrapie problem urgent if the sheep industry is not to suffer grievously.
snip...
76/10.12/4.6
Nature. 1972 Mar 10;236(5341):73-4.
Transmission of scrapie to the cynomolgus monkey (Macaca fascicularis).
Gibbs CJ Jr, Gajdusek DC.
Nature 236, 73 - 74 (10 March 1972); doi:10.1038/236073a0
Transmission of Scrapie to the Cynomolgus Monkey (Macaca fascicularis)
C. J. GIBBS jun. & D. C. GAJDUSEK
National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland
SCRAPIE has been transmitted to the cynomolgus, or crab-eating, monkey (Macaca fascicularis) with an incubation period of more than 5 yr from the time of intracerebral inoculation of scrapie-infected mouse brain. The animal developed a chronic central nervous system degeneration, with ataxia, tremor and myoclonus with associated severe scrapie-like pathology of intensive astroglial hypertrophy and proliferation, neuronal vacuolation and status spongiosus of grey matter. The strain of scrapie virus used was the eighth passage in Swiss mice (NIH) of a Compton strain of scrapie obtained as ninth intracerebral passage of the agent in goat brain, from Dr R. L. Chandler (ARC, Compton, Berkshire).
Wednesday, February 16, 2011
IN CONFIDENCE
SCRAPIE TRANSMISSION TO CHIMPANZEES
IN CONFIDENCE
A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes
Annick Le Dur*,?, Vincent Béringue*,?, Olivier Andréoletti?, Fabienne Reine*, Thanh Lan Laï*, Thierry Baron§, Bjørn Bratberg¶, Jean-Luc Vilotte?, Pierre Sarradin**, Sylvie L. Benestad¶, and Hubert Laude*,?? +Author Affiliations
*Virologie Immunologie Moléculaires and ?Génétique Biochimique et Cytogénétique, Institut National de la Recherche Agronomique, 78350 Jouy-en-Josas, France; ?Unité Mixte de Recherche, Institut National de la Recherche Agronomique-Ecole Nationale Vétérinaire de Toulouse, Interactions Hôte Agent Pathogène, 31066 Toulouse, France; §Agence Française de Sécurité Sanitaire des Aliments, Unité Agents Transmissibles Non Conventionnels, 69364 Lyon, France; **Pathologie Infectieuse et Immunologie, Institut National de la Recherche Agronomique, 37380 Nouzilly, France; and ¶Department of Pathology, National Veterinary Institute, 0033 Oslo, Norway
***Edited by Stanley B. Prusiner, University of California, San Francisco, CA (received for review March 21, 2005)
Abstract
Scrapie in small ruminants belongs to transmissible spongiform encephalopathies (TSEs), or prion diseases, a family of fatal neurodegenerative disorders that affect humans and animals and can transmit within and between species by ingestion or inoculation. Conversion of the host-encoded prion protein (PrP), normal cellular PrP (PrPc), into a misfolded form, abnormal PrP (PrPSc), plays a key role in TSE transmission and pathogenesis. The intensified surveillance of scrapie in the European Union, together with the improvement of PrPSc detection techniques, has led to the discovery of a growing number of so-called atypical scrapie cases. These include clinical Nor98 cases first identified in Norwegian sheep on the basis of unusual pathological and PrPSc molecular features and "cases" that produced discordant responses in the rapid tests currently applied to the large-scale random screening of slaughtered or fallen animals. Worryingly, a substantial proportion of such cases involved sheep with PrP genotypes known until now to confer natural resistance to conventional scrapie. Here we report that both Nor98 and discordant cases, including three sheep homozygous for the resistant PrPARR allele (A136R154R171), efficiently transmitted the disease to transgenic mice expressing ovine PrP, and that they shared unique biological and biochemical features upon propagation in mice.
*** These observations support the view that a truly infectious TSE agent, unrecognized until recently, infects sheep and goat flocks and may have important implications in terms of scrapie control and public health.
OR
***The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.
OR
*** Intriguingly, these conclusions suggest that some pathological features of Nor98 are reminiscent of Gerstmann-Sträussler-Scheinker disease.
OR here;
*** The discovery of previously unrecognized prion diseases in both humans and animals (i.e., Nor98 in small ruminants) demonstrates that the range of prion diseases might be wider than expected and raises crucial questions about the epidemiology and strain properties of these new forms. We are investigating this latter issue by molecular and biological comparison of VPSPr, GSS and Nor98.
VARIABLY PROTEASE-SENSITVE PRIONOPATHY IS TRANSMISSIBLE ...price of prion poker goes up again $
OR-10: Variably protease-sensitive prionopathy is transmissible in bank voles
Romolo Nonno,1 Michele Di Bari,1 Laura Pirisinu,1 Claudia D’Agostino,1 Stefano Marcon,1 Geraldina Riccardi,1 Gabriele Vaccari,1 Piero Parchi,2 Wenquan Zou,3 Pierluigi Gambetti,3 Umberto Agrimi1 1Istituto Superiore di Sanità; Rome, Italy; 2Dipartimento di Scienze Neurologiche, Università di Bologna; Bologna, Italy; 3Case Western Reserve University; Cleveland, OH USA
Background. Variably protease-sensitive prionopathy (VPSPr) is a recently described “sporadic”neurodegenerative disease involving prion protein aggregation, which has clinical similarities with non-Alzheimer dementias, such as fronto-temporal dementia. Currently, 30 cases of VPSPr have been reported in Europe and USA, of which 19 cases were homozygous for valine at codon 129 of the prion protein (VV), 8 were MV and 3 were MM. A distinctive feature of VPSPr is the electrophoretic pattern of PrPSc after digestion with proteinase K (PK). After PK-treatment, PrP from VPSPr forms a ladder-like electrophoretic pattern similar to that described in GSS cases. The clinical and pathological features of VPSPr raised the question of the correct classification of VPSPr among prion diseases or other forms of neurodegenerative disorders. Here we report preliminary data on the transmissibility and pathological features of VPSPr cases in bank voles.
Materials and Methods. Seven VPSPr cases were inoculated in two genetic lines of bank voles, carrying either methionine or isoleucine at codon 109 of the prion protein (named BvM109 and BvI109, respectively). Among the VPSPr cases selected, 2 were VV at PrP codon 129, 3 were MV and 2 were MM. Clinical diagnosis in voles was confirmed by brain pathological assessment and western blot for PK-resistant PrPSc (PrPres) with mAbs SAF32, SAF84, 12B2 and 9A2.
Results. To date, 2 VPSPr cases (1 MV and 1 MM) gave positive transmission in BvM109. Overall, 3 voles were positive with survival time between 290 and 588 d post inoculation (d.p.i.). All positive voles accumulated PrPres in the form of the typical PrP27–30, which was indistinguishable to that previously observed in BvM109 inoculated with sCJDMM1 cases.
In BvI109, 3 VPSPr cases (2 VV and 1 MM) showed positive transmission until now. Overall, 5 voles were positive with survival time between 281 and 596 d.p.i.. In contrast to what observed in BvM109, all BvI109 showed a GSS-like PrPSc electrophoretic pattern, characterized by low molecular weight PrPres. These PrPres fragments were positive with mAb 9A2 and 12B2, while being negative with SAF32 and SAF84, suggesting that they are cleaved at both the C-terminus and the N-terminus. Second passages are in progress from these first successful transmissions.
Conclusions. Preliminary results from transmission studies in bank voles strongly support the notion that VPSPr is a transmissible prion disease. Interestingly, VPSPr undergoes divergent evolution in the two genetic lines of voles, with sCJD-like features in BvM109 and GSS-like properties in BvI109.
The discovery of previously unrecognized prion diseases in both humans and animals (i.e., Nor98 in small ruminants) demonstrates that the range of prion diseases might be wider than expected and raises crucial questions about the epidemiology and strain properties of these new forms. We are investigating this latter issue by molecular and biological comparison of VPSPr, GSS and Nor98.
WEDNESDAY, NOVEMBER 09, 2011
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