Tuesday, November 29, 2016

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


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



Romolo Nonno, Michele Angelo Di Bari, Umberto Agrimi & Laura Pirisinu Page 00 | Received 10 Aug 2016, Accepted 19 Sep 2016, Accepted author version posted online: 28 Nov 2016 Download citation http://dx.doi.org/10.1080/19336896.2016.1239686 Crossmark Select Language​ Translator disclaimer Accepted author version



Abstract



Prion diseases, or transmissible spongiform encephalopathies, have revealed the bewildering phenomenon of transmissibility in neurodegenerative diseases. Hence, the experimental transmissibility of prion-like neurodegenerative diseases via template directed misfolding has become the focus of intense research. Gerstmann-Sträussler-Scheinker disease (GSS) is an inherited prion disease associated with mutations in the prion protein gene. However, with the exception of a few GSS cases with P102L mutation characterized by co-accumulation of protease-resistant PrP core (PrPres) of 21 kDa, attempts to transmit to rodents GSS associated to atypical misfolded prion protein with 8 kDa PrPres have been unsuccessful. As a result, these GSS subtypes have often been considered as non-transmissible proteinopathies rather than true prion diseases. In a recent study we inoculated bank voles with GSS cases associated with P102L, A117V and F198S mutations and found that they transmitted efficiently and produced distinct pathological phenotypes, irrespective of the presence of 21 kDa PrPres in the inoculum. This study demonstrates that GSS is a genuine prion disease characterized by both transmissibility and strain variation. We discuss the implications of these findings for the understanding of the heterogeneous clinic-pathological phenotypes of GSS and of the molecular underpinnings of prion infectivity.



Keywords: Gerstmann-Straussler-Scheinker disease, PrPC, PrPSc, prion infectivity, strain, protein misfolding, neurodegenerative diseases







Monday, June 27, 2011


Comparison of Sheep Nor98 with Human Variably Protease-Sensitive Prionopathy and Gerstmann-Sträussler-Scheinker Disease


http://prionopathy.blogspot.com/2011/06/comparison-of-sheep-nor98-with-human.html



http://prionopathy.blogspot.com/2011/09/variably-protease-sensitive-prionopathy.html



 Greetings,


IT could also be that this sFFI is just another case of iCJD (via friendly fire from the surgery for a colloid cyst of the third ventricle, and two ventricular shunts were placed, one correctly in the left ventricle, while the second ended in the right thalamus), some 20 years before the onset of symptoms of this so called sFFI case, from some sub-type of sporadic CJD, now called sporadic FFI ???


I believe it was Gambetti et al that coined this term sporadic FFI, from some conspicuous sub-type of sporadic CJD possibly? seems they could not tie it to a true FFI by diagnostic standards to date, so it was then termed a sFFI, confusing matters even worse ;


A subtype of sporadic prion disease mimicking fatal familial insomnia





THIS seems to raise more questions than answers, confusing the TSEs even worse.


WHAT is sporadic CJD, and how many sub-types and atypical strains, phenotypes etc. will there be, arising from nothing. a spontaneous happening of sorts???


i think not. ...tss









UPDATE* NOVEMBER 16, 2014



vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???



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 it ???’ 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.



snip...see ;



Friday, January 10, 2014



vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???






From: Terry S. Singeltary Sr.



Sent: Saturday, November 15, 2014 9:29 PM



To: Terry S. Singeltary Sr.



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



THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE



R. G. WILL



1984



snip...



 ***The 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;




Monday, November 23, 2015


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


ORIGINAL RESEARCH


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


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


Article first published online: 23 NOV 2015


DOI: 10.1111/trf.13422


© 2015 AABB


Issue


Cover image for Vol. 55 Issue 11


Transfusion


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


Abstract


BACKGROUND


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


STUDY DESIGN AND METHODS


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


RESULTS


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


CONCLUSION


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


http://onlinelibrary.wiley.com/doi/10.1111/trf.13422/abstract


2015 PRION CONFERENCE


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


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


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


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


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


https://prion2015.files.wordpress.com/2015/05/prion2015abstracts.pdf


ran across an old paper from 1984 ;

***The occurrence of contact cases raises the possibility that transmission in families may be effected by an unusually virulent strain of the agent. ***

http://transmissiblespongiformencephalopathy.blogspot.com/2014/01/vpspr-sgss-sffi-tse-iatrogenic-by.html

snip...see full text ;

http://transmissiblespongiformencephalopathy.blogspot.com/2015/11/blood-transmission-studies-of-prion.html




















Alzheimer's, what if ?


SWISS MEDICAL WEEKLY

Alzheimer-type brain pathology may be transmitted by grafts of dura mater 26/01/2016 Singeltary comment ;





Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy


07 02:27 AM


Terry S. Singeltary Sr. said:


re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy


2015-12-07 02:27 AM


Terry S. Singeltary Sr. said: re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy


Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015)





I would kindly like to comment on the Nature Paper, the Lancet reply, and the newspaper articles.


First, I applaud Nature, the Scientist and Authors of the Nature paper, for bringing this important finding to the attention of the public domain, and the media for printing said findings.


Secondly, it seems once again, politics is getting in the way possibly of more important Transmissible Spongiform Encephalopathy TSE Prion scientific findings. findings that could have great implications for human health, and great implications for the medical surgical arena. but apparently, the government peer review process, of the peer review science, tries to intervene again to water down said disturbing findings.


where have we all heard this before? it’s been well documented via the BSE Inquiry. have they not learned a lesson from the last time?


we have seen this time and time again in England (and other Country’s) with the BSE mad cow TSE Prion debacle.


That ‘anonymous' Lancet editorial was disgraceful. The editor, Dick Horton is not a scientist.


The pituitary cadavers were very likely elderly and among them some were on their way to CJD or Alzheimer's. Not a bit unusual. Then the recipients who got pooled extracts injected from thousands of cadavers were 100% certain to have been injected with both seeds. No surprise that they got both diseases going after thirty year incubations.


That the UK has a "system in place to assist science journalists" to squash embargoed science reports they find ‘alarming’ is pathetic.


Sounds like the journalists had it right in the first place: ‘Alzheimer’s may be a transmissible infection’ in The Independent to ’You can catch Alzheimer’s’ in The Daily Mirror or ‘Alzheimer’s bombshell" in The Daily Express.


if not for the journalist, the layperson would not know about these important findings.


where would we be today with sound science, from where we were 30 years ago, if not for the cloak of secrecy and save the industry at all cost mentality?


when you have a peer review system for science, from which a government constantly circumvents, then you have a problem with science, and humans die.


to date, as far as documented body bag count, with all TSE prion named to date, that count is still relatively low (one was too many in my case, Mom hvCJD), however that changes drastically once the TSE Prion link is made with Alzheimer’s, the price of poker goes up drastically.


so, who makes that final decision, and how many more decades do we have to wait?


the iatrogenic mode of transmission of TSE prion, the many routes there from, load factor, threshold from said load factor to sub-clinical disease, to clinical disease, to death, much time is there to spread a TSE Prion to anywhere, but whom, by whom, and when, do we make that final decision to do something about it globally? how many documented body bags does it take? how many more decades do we wait? how many names can we make up for one disease, TSE prion?


Professor Collinge et al, and others, have had troubles in the past with the Government meddling in scientific findings, that might in some way involve industry, never mind human and or animal health.


FOR any government to continue to circumvent science for monetary gain, fear factor, or any reason, shame, shame on you.


in my opinion, it’s one of the reasons we are at where we are at to date, with regards to the TSE Prion disease science i.e. money, industry, politics, then comes science, in that order.


greed, corporate, lobbyist there from, and government, must be removed from the peer review process of sound science, it’s bad enough having them in the pharmaceutical aspect of healthcare policy making, in my opinion.


my mother died from confirmed hvCJD, and her brother (my uncle) Alzheimer’s of some type (no autopsy?). just made a promise, never forget, and never let them forget, before I do.


I kindly wish to remind the public of the past, and a possible future we all hopes never happens again. ...


[9. Whilst this matter is not at the moment directly concerned with the iatrogenic CJD cases from hgH, there remains a possibility of litigation here, and this presents an added complication. There are also results to be made available shortly (1) concerning a farmer with CJD who had BSE animals, (2) on the possible transmissibility of Alzheimer’s and (3) a CMO letter on prevention of iatrogenic CJD transmission in neurosurgery, all of which will serve to increase media interest.]








snip...see full Singeltary Nature comment here;






see Singeltary comments to Plos ;



Subject: 1992 IN CONFIDENCE TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES POSSIBILITY ON A TRANSMISSIBLE PRION REMAINS OPEN



BSE101/1 0136



IN CONFIDENCE



CMO



From: . Dr J S Metiers DCMO



4 November 1992



TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES



1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have recognised the public sensitivity of these findings and intend to report them in their proper context. 'This hopefully will avoid misunderstanding and possible distortion by the media to portray the results as having more greater significance than the findings so far justify.



2. Using a highly unusual route of transmission (intra-cerebral injection) the researchers have demonstrated the transmission of a pathological process from two cases one of severe Alzheimer's disease the other of Gerstmann-Straussler disease to marmosets. However they have not demonstrated the transmission of either clinical condition as the "animals were behaving normally when killed". As the report emphasises the unanswered question is whether the disease condition would have revealed itself if the marmosets had lived longer. They are planning further research to see if the conditions, as opposed to the partial pathological process, is transmissible.



what are the implications for public health?



3. The route 'of transmission is very specific and in the natural state of things highly unusual. However it could be argued that the results reveal a potential risk, in that brain tissue from these two patients has been shown to transmit a pathological process. Should therefore brain tissue from such cases be regarded as potentially infective? Pathologists, morticians, neuro surgeons and those assisting at neuro surgical procedures and others coming into contact with "raw" human brain tissue could in theory be at risk. However, on a priori grounds given the highly specific route of transmission in these experiments that risk must be negligible if the usual precautions for handling brain tissue are observed.

1


92/11.4/1.1



BSE101/1 0137



4. The other dimension to consider is the public reaction. To some extent the GSS case demonstrates little more than the transmission of BSE to a pig by intra-cerebral injection. If other prion diseases can be transmitted in this way it is little surprise that some pathological findings observed in GSS were also transmissible to a marmoset. But the transmission of features of Alzheimer's pathology is a different matter, given the much greater frequency of this disease and raises the unanswered question whether some cases are the result of a transmissible prion. The only tenable public line will be that "more research is required’’ before that hypothesis could be evaluated. The possibility on a transmissible prion remains open. In the meantime MRC needs carefully to consider the range and sequence of studies needed to follow through from the preliminary observations in these two cases. Not a particularly comfortable message, but until we know more about the causation of Alzheimer's disease the total reassurance is not practical.



J S METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832 llllYc!eS 2 92/11.4/1.2






>>> The only tenable public line will be that "more research is required’’ <<<



>>> possibility on a transmissible prion remains open<<<



O.K., so it’s about 23 years later, so somebody please tell me, when is "more research is required’’ enough time for evaluation ?



Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease



*** Singeltary comment PLoS ***



Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic,
what if ?



Posted by flounder on 05 Nov 2014 at 21:27 GMT






Sunday, November 22, 2015


*** Effect of heating on the stability of amyloid A (AA) fibrils and the intra- and cross-species transmission of AA amyloidosis Abstract


Amyloid A (AA) amyloidosis is a protein misfolding disease characterized by extracellular deposition of AA fibrils. AA fibrils are found in several tissues from food animals with AA amyloidosis. For hygienic purposes, heating is widely used to inactivate microbes in food, but it is uncertain whether heating is sufficient to inactivate AA fibrils and prevent intra- or cross-species transmission. We examined the effect of heating (at 60 °C or 100 °C) and autoclaving (at 121 °C or 135 °C) on murine and bovine AA fibrils using Western blot analysis, transmission electron microscopy (TEM), and mouse model transmission experiments. TEM revealed that a mixture of AA fibrils and amorphous aggregates appeared after heating at 100 °C, whereas autoclaving at 135 °C produced large amorphous aggregates. AA fibrils retained antigen specificity in Western blot analysis when heated at 100 °C or autoclaved at 121 °C, but not when autoclaved at 135 °C. Transmissible pathogenicity of murine and bovine AA fibrils subjected to heating (at 60 °C or 100 °C) was significantly stimulated and resulted in amyloid deposition in mice. Autoclaving of murine AA fibrils at 121 °C or 135 °C significantly decreased amyloid deposition. Moreover, amyloid deposition in mice injected with murine AA fibrils was more severe than that in mice injected with bovine AA fibrils. Bovine AA fibrils autoclaved at 121 °C or 135 °C did not induce amyloid deposition in mice. These results suggest that AA fibrils are relatively heat stable and that similar to prions, autoclaving at 135 °C is required to destroy the pathogenicity of AA fibrils. These findings may contribute to the prevention of AA fibril transmission through food materials to different animals and especially to humans.


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


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


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




 the warning shots fired over the bow of the boat that were never heard ;


PITUITARY EXTRACT


This was used to help cows super ovulate. This tissue was considered to be of greatest risk of containing BSE and consequently transmitting the disease...





NON-LICENSED HUMAN TISSUE DEVICES WERE NOT COMMERCIALLY AVAILABLE


snip...


I was quite prepared to believe in unofficial pituitary hormones, also in the 1970's, whether as described by Dr. Little, or in other circumstances, for animal use.


snip...


The fact that there were jars of pituitaries (or extract) around on shelves is attested by the still potent 1943 pituitaries, described in Stockell Hartree et al. (J/RF/17/291) which had come from the lab. at Mill Hill. Having taken the trouble to collect them, they were not lightly thrown out...





3. The extraction is from a pool of pituitary glands collected from abbatoirs and the process used is unlikely to have any effect on the BSE agent. Hormones extracted from human pituitary glands have been responsible for a small number of Creutzfeldt Jacob disease in man.




 SEE LOOPHOLE ;





SEE LOOPHOLE SHOULD BE CLOSED ;








2012 Singeltary on CJD and Alzheimer’s and iatrogenic threat

 Proposal ID: 29403

 Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?

 Background

 Alzheimer’s disease and Transmissible Spongiform Encephalopathy disease have both been around a long time, and was discovered in or around the same time frame, early 1900’s. Both disease, and it’s variants, in many cases are merely names of the people that first discovered them. Both diseases are incurable and debilitating brain disease, that are in the end, 100% fatal, with the incubation/clinical period of the Alzheimer’s disease being longer than the TSE prion disease. Symptoms are very similar, and pathology is very similar. I propose that Alzheimer’s is a TSE disease of low dose, slow, and long incubation disease, and that Alzheimer’s is Transmissible, and is a threat to the public via the many Iatrogenic routes and sources. It was said long ago that the only thing that disputes this, is Alzheimer’s disease transmissibility, or the lack of. today, there is enough documented science (some confidential), that shows that indeed Alzheimer’s is transmissible. The risk factor for friendly fire, and or the pass-it-forward mode i.e. Iatrogenic transmission is a real threat, and one that needs to be addressed immediately.

 Methods

 Through years of research, as a layperson, of peer review journals, transmission studies, and observations of loved ones and friends that have died from both Alzheimer’s and the TSE prion disease i.e. Heidenhain Variant Creutzfelt Jakob Disease CJD.

 Results

 The likelihood of many victims of Alzheimer’s disease from the many different Iatrogenic routes and modes of transmission as with the TSE prion disease. TSE prion disease survives ashing to 600 degrees celsius, that’s around 1112 degrees farenheit. you cannot cook the TSE prion disease out of meat. you can take the ash and mix it with saline and inject that ash into a mouse, and the mouse will go down with TSE. Prion Infected Meat-and-Bone Meal Is Still Infectious after Biodiesel Production as well. the TSE prion agent also survives Simulated Wastewater Treatment Processes. IN fact, you should also know that the TSE Prion agent will survive in the environment for years, if not decades. you can bury it and it will not go away. TSE prion agent is capable of infected your water table i.e. Detection of protease-resistant cervid prion protein in water from a CWD-endemic area. it’s not your ordinary pathogen you can just cook it out and be done with. that’s what’s so worrisome about Iatrogenic mode of transmission, a simple autoclave will not kill this TSE prion agent.

 Conclusions

 There should be a Global Congressional Science round table event (one of scientist and doctors et al only, NO CORPORATE, POLITICIANS ALLOWED) set up immediately to address these concerns from the many potential routes and sources of the TSE prion disease, including Alzheimer’s disease, and a emergency global doctrine put into effect to help combat the spread of Alzheimer’s disease via the medical, surgical, dental, tissue, and blood arena’s. All human and animal TSE prion disease, including Alzheimer’s should be made reportable in every state, and Internationally, WITH NO age restrictions. Until a proven method of decontamination and autoclaving is proven, and put forth in use universally, in all hospitals and medical, surgical arena’s, or the TSE prion agent will continue to spread. IF we wait until science and corporate politicians wait until politics let science _prove_ this once and for all, and set forth regulations there from, we will all be exposed to the TSE Prion agents, if that has not happened already. what’s the use of science progressing human life to the century mark, if your brain does not work?



 combined cannot exceed 350 Words

 shortened to proper word count ;

 Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?

 Background

 Alzheimer’s disease and Transmissible Spongiform Encephalopathy disease have both been around a long time, and was discovered in or around the same time frame, early 1900’s. Both diseases are incurable and debilitating brain disease, that are in the end, 100% fatal, with the incubation/clinical period of the Alzheimer’s disease being longer (most of the time) than the TSE prion disease. Symptoms are very similar, and pathology is very similar.

 Methods

 Through years of research, as a layperson, of peer review journals, transmission studies, and observations of loved ones and friends that have died from both Alzheimer’s and the TSE prion disease i.e. Heidenhain Variant Creutzfelt Jakob Disease CJD.

 Results

 I propose that Alzheimer’s is a TSE disease of low dose, slow, and long incubation disease, and that Alzheimer’s is Transmissible, and is a threat to the public via the many Iatrogenic routes and sources. It was said long ago that the only thing that disputes this, is Alzheimer’s disease transmissibility, or the lack of. The likelihood of many victims of Alzheimer’s disease from the many different Iatrogenic routes and modes of transmission as with the TSE prion disease.

 Conclusions

 There should be a Global Congressional Science round table event set up immediately to address these concerns from the many potential routes and sources of the TSE prion disease, including Alzheimer’s disease, and a emergency global doctrine put into effect to help combat the spread of Alzheimer’s disease via the medical, surgical, dental, tissue, and blood arena’s. All human and animal TSE prion disease, including Alzheimer’s should be made reportable in every state, and Internationally, WITH NO age restrictions. Until a proven method of decontamination and autoclaving is proven, and put forth in use universally, in all hospitals and medical, surgical arena’s, or the TSE prion agent will continue to spread. IF we wait until science and corporate politicians wait until politics lets science _prove_ this once and for all, and set forth regulations there from, we will all be exposed to the TSE Prion agents, if that has not happened already.

 end...tss

Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?


















Friday, January 29, 2016

Synucleinopathies: Past, Present and Future, iatrogenic, what if?







 Horizontal Transmission of Chronic Wasting Disease in Reindeer CDC Volume 22, Number 12—December 2016






Sunday, November 13, 2016


Horizontal Transmission of Chronic Wasting Disease in Reindeer CDC Volume 22, Number 12—December 2016





CHRONIC WASTING DISEASE CWD AND SCRAPIE TSE PRION ZOONOSIS UPDATE



*** WDA 2016 NEW YORK ***



We found that CWD adapts to a new host more readily than BSE and that human PrP was unexpectedly prone to misfolding by CWD prions. In addition, we investigated the role of specific regions of the bovine, deer and human PrP protein in resistance to conversion by prions from another species. We have concluded that the human protein has a region that confers unusual susceptibility to conversion by CWD prions. Student Presentations Session 2 The species barriers and public health threat of CWD and BSE prions Ms. Kristen Davenport1, Dr. Davin Henderson1, Dr. Candace Mathiason1, Dr. Edward Hoover1 1Colorado State University Chronic wasting disease (CWD) is spreading rapidly through cervid populations in the USA. Bovine spongiform encephalopathy (BSE, mad cow disease) arose in the 1980s because cattle were fed recycled animal protein. These and other prion diseases are caused by abnormal folding of the normal prion protein (PrP) into a disease causing form (PrPd), which is pathogenic to nervous system cells and can cause subsequent PrP to misfold. CWD spreads among cervids very efficiently, but it has not yet infected humans. On the other hand, BSE was spread only when cattle consumed infected bovine or ovine tissue, but did infect humans and other species.



The objective of this research is to understand the role of PrP structure in cross-species infection by CWD and BSE. To study the propensity of each species’ PrP to be induced to misfold by the presence of PrPd from verious species, we have used an in vitro system that permits detection of PrPd in real-time. We measured the conversion efficiency of various combinations of PrPd seeds and PrP substrate combinations. We observed the cross-species behavior of CWD and BSE, in addition to feline-adapted CWD and BSE.



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



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



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



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



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





PRION 2016 TOKYO


Zoonotic Potential of CWD Prions: An Update


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


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


PRION 2016 TOKYO


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




Cervid to human prion transmission


Kong, Qingzhong Case Western Reserve University, Cleveland, OH, United States



Abstract



Prion disease is transmissible and invariably fatal. Chronic wasting disease (CWD) is the prion disease affecting deer, elk and moose, and it is a widespread and expanding epidemic affecting 22 US States and 2 Canadian provinces so far. CWD poses the most serious zoonotic prion transmission risks in North America because of huge venison consumption (>6 million deer/elk hunted and consumed annually in the USA alone), significant prion infectivity in muscles and other tissues/fluids from CWD-affected cervids, and usually high levels of individual exposure to CWD resulting from consumption of the affected animal among often just family and friends. However, we still do not know whether CWD prions can infect humans in the brain or peripheral tissues or whether clinical/asymptomatic CWD zoonosis has already occurred, and we have no essays to reliably detect CWD infection in humans. We hypothesize that: (1) The classic CWD prion strain can infect humans at low levels in the brain and peripheral lymphoid tissues; (2) The cervid-to-human transmission barrier is dependent on the cervid prion strain and influenced by the host (human) prion protein (PrP) primary sequence; (3) Reliable essays can be established to detect CWD infection in humans;and (4) CWD transmission to humans has already occurred. We will test these hypotheses in 4 Aims using transgenic (Tg) mouse models and complementary in vitro approaches. Aim 1 will prove that the classical CWD strain may infect humans in brain or peripheral lymphoid tissues at low levels by conducting systemic bioassays in a set of "humanized" Tg mouse lines expressing common human PrP variants using a number of CWD isolates at varying doses and routes. Experimental "human CWD" samples will also be generated for Aim 3. Aim 2 will test the hypothesis that the cervid-to-human prion transmission barrier is dependent on prion strain and influenced by the host (human) PrP sequence by examining and comparing the transmission efficiency and phenotypes of several atypical/unusual CWD isolates/strains as well as a few prion strains from other species that have adapted to cervid PrP sequence, utilizing the same panel of humanized Tg mouse lines as in Aim 1. Aim 3 will establish reliable essays for detection and surveillance of CWD infection in humans by examining in details the clinical, pathological, biochemical and in vitro seeding properties of existing and future experimental "human CWD" samples generated from Aims 1-2 and compare them with those of common sporadic human Creutzfeldt-Jakob disease (sCJD) prions. Aim 4 will attempt to detect clinical CWD-affected human cases by examining a significant number of brain samples from prion-affected human subjects in the USA and Canada who have consumed venison from CWD-endemic areas utilizing the criteria and essays established in Aim 3. The findings from this proposal will greatly advance our understandings on the potential and characteristics of cervid prion transmission in humans, establish reliable essays for CWD zoonosis and potentially discover the first case(s) of CWD infection in humans. Public Health Relevance There are significant and increasing human exposure to cervid prions because chronic wasting disease (CWD, a widespread and highly infectious prion disease among deer and elk in North America) continues spreading and consumption of venison remains popular, but our understanding on cervid-to-human prion transmission is still very limited, raising public health concerns. This proposal aims to define the zoonotic risks of cervid prions and set up and apply essays to detect CWD zoonosis using mouse models and in vitro methods. The findings will greatly expand our knowledge on the potentials and characteristics of cervid prion transmission in humans, establish reliable essays for such infections and may discover the first case(s) of CWD infection in humans.



Funding Agency Agency National Institute of Health (NIH) Institute National Institute of Neurological Disorders and Stroke (NINDS) Type Research Project (R01) Project # 1R01NS088604-01A1 Application # 9037884 Study Section Cellular and Molecular Biology of Neurodegeneration Study Section (CMND) Program Officer Wong, May Project Start 2015-09-30 Project End 2019-07-31 Budget Start 2015-09-30 Budget End 2016-07-31 Support Year 1 Fiscal Year 2015 Total Cost $337,507 Indirect Cost $118,756 Institution Name Case Western Reserve University Department Pathology Type Schools of Medicine DUNS # 077758407 City Cleveland State OH Country United States Zip Code 44106







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



We hypothesize that:



(1) The classic CWD prion strain can infect humans at low levels in the brain and peripheral lymphoid tissues;



(2) The cervid-to-human transmission barrier is dependent on the cervid prion strain and influenced by the host (human) prion protein (PrP) primary sequence;



(3) Reliable essays can be established to detect CWD infection in humans;and



(4) *** CWD transmission to humans has already occurred. *** We will test these hypotheses in 4 Aims using transgenic (Tg) mouse models and complementary in vitro approaches.



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




Key Molecular Mechanisms of TSEs



Zabel, Mark D. Colorado State University-Fort Collins, Fort Collins, CO, United States



Abstract



Prion diseases, or transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative diseases affecting humans, cervids, bovids, and ovids. The absolute requirement of PrPC expression to generate prion diseases and the lack of instructional nucleic acid define prions as unique infectious agents. Prions exhibit species-specific tropism, inferring that unique prion strains exist that preferentially infct certain host species and confront transmission barriers to heterologous host species. However, transmission barriers are not absolute. Scientific consensus agrees that the sheep TSE scrapie probably breached the transmission barrier to cattle causing bovine spongiform encephalopathy that subsequently breached the human transmission barrier and likely caused several hundred deaths by a new-variant form of the human TSE Creutzfeldt-Jakob disease in the UK and Europe. The impact to human health, emotion and economies can still be felt in areas like farming, blood and organ donations and the threat of a latent TSE epidemic. This precedent raises the real possibility of other TSEs, like chronic wasting disease of cervids, overcoming similar human transmission barriers. A groundbreaking discovery made last year revealed that mice infected with heterologous prion strains facing significant transmission barriers replicated prions far more readily in spleens than brains6. Furthermore, these splenic prions exhibited weakened transmission barriers and expanded host ranges compared to neurogenic prions. These data question conventional wisdom of avoiding neural tissue to avoid prion xenotransmission, when more promiscuous prions may lurk in extraneural tissues. Data derived from work previously funded by NIH demonstrate that Complement receptors CD21/35 bind prions and high density PrPC and differentially impact prion disease depending on the prion isolate or strain used. Recent advances in live animal and whole organ imaging have led us to generate preliminary data to support novel, innovative approaches to assessing prion capture and transport. We plan to test our unifying hypothesis for this proposal that CD21/35 control the processes of peripheral prion capture, transport, strain selection and xenotransmission in the following specific aims.


1.       Assess the role of CD21/35 in splenic prion strain selection and host range expansion.



2. Determine whether CD21/35 and C1q differentially bind distinct prion strains



3. Monitor the effects of CD21/35 on prion trafficking in real time and space



4. Assess the role of CD21/35 in incunabular prion trafficking



Public Health Relevance



Transmissible spongiform encephalopathies, or prion diseases, are devastating illnesses that greatly impact public health, agriculture and wildlife in North America and around the world. The impact to human health, emotion and economies can still be felt in areas like farming, blood and organ donations and the threat of a latent TSE epidemic. This precedent raises the real possibility of other TSEs, like chronic wasting disease (CWD) of cervids, overcoming similar human transmission barriers. Early this year Canada reported its first case of BSE in over a decade audits first case of CWD in farmed elk in three years, underscoring the need for continued vigilance and research. Identifying mechanisms of transmission and zoonoses remains an extremely important and intense area of research that will benefit human and other animal populations.



Funding Agency Agency National Institute of Health (NIH) Institute National Institute of Allergy and Infectious Diseases (NIAID) Type High Priority, Short Term Project Award (R56) Project # 1R56AI122273-01A1 Application # 9211114 Study Section Cellular and Molecular Biology of Neurodegeneration Study Section (CMND) Program Officer Beisel, Christopher E Project Start 2016-02-16 Project End 2017-01-31 Budget Start 2016-02-16 Budget End 2017-01-31 Support Year 1 Fiscal Year 2016 Total Cost Indirect Cost Institution Name Colorado State University-Fort Collins Department Microbiology/Immun/Virology Type Schools of Veterinary Medicine DUNS # 785979618 City Fort Collins State CO Country United States Zip Code 80523







PMCA Detection of CWD Infection in Cervid and Non-Cervid Species



Hoover, Edward Arthur Colorado State University-Fort Collins, Fort Collins, CO, United States Abstract Chronic wasting disease (CWD) of deer and elk is an emerging highly transmissible prion disease now recognized in 18 States, 2 Canadian provinces, and Korea.



We have shown that Infected deer harbor and shed high levels of infectious prions in saliva, blood, urine, and feces, and in the tissues generating those body fluids and excreta, thereby leading to facile transmission by direct contact and environmental contamination. We have also shown that CWD can infect some non-cervid species, thus the potential risk CWD represents to domestic animal species and to humans remains unknown. Whether prions borne in blood, saliva, nasal fluids, milk, or excreta are generated or modified in the proximate peripheral tissue sites, may differ in subtle ways from those generated in brain, or may be adapted for mucosal infection remain open questions. The increasing parallels in the pathogenesis between prion diseases and human neurodegenerative conditions, such as Alzheimer's and Parkinson's diseases, add relevance to CWD as a transmissible protein misfolding disease. The overall goal of this work is to elucidate the process of CWD prion transmission from mucosal secretory and excretory tissue sites by addressing these questions:



(a) What are the kinetics and magnitude of CWD prion shedding post-exposure?



(b) Are excreted prions biochemically distinct, or not, from those in the CNS?



(c) Are peripheral epithelial or CNS tissues, or both, the source of excreted prions? and



(d) Are excreted prions adapted for horizontal transmission via natural/trans-mucosal routes?



The specific aims of this proposal are:



(1) To determine the onset and consistency of CWD prion shedding in deer and cervidized mice;



(2); To compare the biochemical and biophysical properties of excretory vs. CNS prions;



(3) To determine the capacity of peripheral tissues to support replication of CWD prions;



(4) To determine the protease- sensitive infectious fraction of excreted vs. CNS prions; and



(5) To compare the mucosal infectivity of excretory vs. CNS prions.



Understanding the mechanisms that enable efficient prion dissemination and shedding will help elucidate how horizontally transmissible prions evolve and succeed, and is the basis of this proposal. Understanding how infectious misfolded proteins (prions) are generated, trafficked, shed, and transmitted will aid in preventing, treating, and managing the risks associated with these agents and the diseases they cause.



Public Health Relevance



Chronic wasting disease (CWD) of deer and elk is an emergent highly transmissible prion disease now recognized throughout the USA as well as in Canada and Korea. We have shown that infected deer harbor and shed high levels of infectious prions in saliva, blood, urine, and feces thereby leading to transmission by direct contact and environmental contamination. In that our studies have also shown that CWD can infect some non-cervid species, the potential risk CWD may represents to domestic animal species and humans remains unknown. The increasing parallels in the development of major human neurodegenerative conditions, such as Alzheimer's and Parkinson's diseases, and prion diseases add relevance to CWD as a model of a transmissible protein misfolding disease. Understanding how infectious misfolded proteins (prions) are generated and transmitted will aid in interrupting, treating, and managing the risks associated with these agents and the diseases they cause.



Funding Agency Agency National Institute of Health (NIH) Institute National Institute of Neurological Disorders and Stroke (NINDS) Type Research Project (R01) Project # 4R01NS061902-07 Application # 9010980 Study Section Cellular and Molecular Biology of Neurodegeneration Study Section (CMND) Program Officer Wong, May Project Start 2009-09-30 Project End 2018-02-28 Budget Start 2016-03-01 Budget End 2017-02-28 Support Year 7 Fiscal Year 2016 Total Cost $409,868 Indirect Cost $134,234 Institution Name Colorado State University-Fort Collins Department Microbiology/Immun/Virology Type Schools of Veterinary Medicine DUNS # 785979618 City Fort Collins State CO Country United States Zip Code 80523






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).***




Monday, May 02, 2016


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




 Saturday, April 23, 2016


PRION 2016 TOKYO


Saturday, April 23, 2016

SCRAPIE WS-01: Prion diseases in animals and zoonotic potential 2016 Prion. 10:S15-S21. 2016 ISSN: 1933-6896 printl 1933-690X online



Taylor & Francis



Prion 2016 Animal Prion Disease Workshop Abstracts



WS-01: Prion diseases in animals and zoonotic potential



Juan Maria Torres a, Olivier Andreoletti b, J uan-Carlos Espinosa a. Vincent Beringue c. Patricia Aguilar a, Natalia Fernandez-Borges a. and Alba Marin-Moreno a "Centro de Investigacion en Sanidad Animal ( CISA-INIA ). Valdeolmos, Madrid. Spain; b UMR INRA -ENVT 1225 Interactions Holes Agents Pathogenes. ENVT. Toulouse. France: "UR892. Virologie lmmunologie MolécuIaires, Jouy-en-Josas. France Dietary exposure to bovine spongiform encephalopathy (BSE) contaminated bovine tissues is considered as the origin of variant Creutzfeldt Jakob (vCJD) disease in human. To date, BSE agent is the only recognized zoonotic prion. Despite the variety of Transmissible Spongiform Encephalopathy (TSE) agents that have been circulating for centuries in farmed ruminants there is no apparent epidemiological link between exposure to ruminant products and the occurrence of other form of TSE in human like sporadic Creutzfeldt Jakob Disease (sCJD). However, the zoonotic potential of the diversity of circulating TSE agents has never been systematically assessed. The major issue in experimental assessment of TSEs zoonotic potential lies in the modeling of the ‘species barrier‘, the biological phenomenon that limits TSE agents’ propagation from a species to another. In the last decade, mice genetically engineered to express normal forms of the human prion protein has proved essential in studying human prions pathogenesis and modeling the capacity of TSEs to cross the human species barrier. To assess the zoonotic potential of prions circulating in farmed ruminants, we study their transmission ability in transgenic mice expressing human PrPC (HuPrP-Tg). Two lines of mice expressing different forms of the human PrPC (129Met or 129Val) are used to determine the role of the Met129Val dimorphism in susceptibility/resistance to the different agents.



These transmission experiments confirm the ability of BSE prions to propagate in 129M- HuPrP-Tg mice and demonstrate that Met129 homozygotes may be susceptible to BSE in sheep or goat to a greater degree than the BSE agent in cattle and that these agents can convey molecular properties and neuropathological indistinguishable from vCJD. However homozygous 129V mice are resistant to all tested BSE derived prions independently of the originating species suggesting a higher transmission barrier for 129V-PrP variant. Transmission data also revealed that several scrapie prions propagate in HuPrP-Tg mice with ef?ciency comparable to that of cattle BSE. While the ef?ciency of transmission at primary passage was low, subsequent passages resulted in a highly virulent prion disease in both Met129 and Val129 mice. Transmission of the different scrapie isolates in these mice leads to the emergence of prion strain phenotypes that showed similar characteristics to those displayed by MM1 or VV2 sCJD prion. These results demonstrate that scrapie prions have a zoonotic potential and raise new questions about the possible link between animal and human prions.






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



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







 *** 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.








 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.



https://prion2015.files.wordpress.com/2015/05/prion2015abstracts.pdf SCRAPIE WS-01: Prion diseases in animals and zoonotic potential 2016



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






Monday, May 09, 2016



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







Monday, August 22, 2016



*** CREUTZFELDT JAKOB DISEASE USA 2015 SPORADIC CJD TOTAL FIGURES REACHES HIGHEST ANNUAL COUNT TO DATE AT 239 CONFIRMED CASES ***






Transmission of scrapie prions to primate after an extended silent incubation period



***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.***






Thursday, August 18, 2016



*** PROCEEDINGS ONE HUNDRED AND Nineteenth ANNUAL MEETING of the USAHA BSE, CWD, SCRAPIE, PORCINE TSE PRION October 22 28, 2015 ***






Tuesday, August 9, 2016



*** Concurrence with OIE Risk Designations for Bovine Spongiform Encephalopathy [Docket No. APHIS-2015-0055]






Saturday, July 23, 2016



*** BOVINE SPONGIFORM ENCEPHALOPATHY BSE TSE PRION SURVEILLANCE, TESTING, AND SRM REMOVAL UNITED STATE OF AMERICA UPDATE JULY 2016






Tuesday, July 26, 2016



*** Atypical Bovine Spongiform Encephalopathy BSE TSE Prion UPDATE JULY 2016






Saturday, July 16, 2016



*** Importation of Sheep, Goats, and Certain Other Ruminants [Docket No. APHIS-2009-0095]RIN 0579-AD10



WITH great disgust and concern, I report to you that the OIE, USDA, APHIS, are working to further legalize the trading of Transmissible Spongiform Encephalopathy TSE Pion disease around the globe. THIS is absolutely insane. it’s USDA INC.






Thursday, October 22, 2015



*** Former Ag Secretary Ann Veneman talks women in agriculture and we talk mad cow disease USDA and what really happened those mad cows in Texas ***






Monday, June 20, 2016



*** Specified Risk Materials SRMs BSE TSE Prion Program ***






Thursday, April 14, 2016



Arizona 22 year old diagnosed with Creutzfeldt Jakob Disease CJD






Thursday, January 15, 2015



41-year-old Navy Commander with sporadic Creutzfeldt–Jakob disease CJD TSE Prion: Case Report






Saturday, January 17, 2015



*** Becky Lockhart 46, Utah’s first female House speaker, dies diagnosed with the extremely rare Creutzfeldt-Jakob disease






Saturday, December 12, 2015



CREUTZFELDT JAKOB DISEASE CJD TSE PRION REPORT DECEMBER 14, 2015






Sunday, August 21, 2016



Kay Ellen Roedl Schwister Deceased August 7, 2016 at the age of 53 with Creutzfeldt-Jakob disease CJD TSE Prion spontaneous sporadic, zoonosis, or iatrogenic?






Monday, August 22, 2016



*** CREUTZFELDT JAKOB DISEASE USA 2015 SPORADIC CJD TOTAL FIGURES REACHES HIGHEST ANNUAL COUNT TO DATE AT 239 CONFIRMED CASES ***






Tuesday, November 22, 2016



AGFC finds 28 new cases of CWD in north Arkansas






Friday, November 11, 2016



Canada Transmissible Spongiform Encephalopathy TSE Prion Report Update







Terry S. Singeltary Sr.

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