Monday, September 30, 2019

Spatial Epidemiology of Sporadic Creutzfeldt-Jakob Disease in Apulia, Italy

Spatial Epidemiology of Sporadic Creutzfeldt-Jakob Disease in Apulia, Italy


Puopolo M.a · Catelan D.b · Capellari S.c,d · Ladogana A.a · Sanguedolce A.e · Fedele A.f · Aprile V.f · Turco G.L.f · Colaizzo E.a · Tiple D.a · Vaianella L.a · Parchi P.d,g · Biggeri A.b · Pocchiari M.a







Background: Sporadic Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative disease caused by prions that is randomly distributed in all countries, with an overall yearly mortality rate of about 1–2 cases per million people. On a few occasions, however, sporadic CJD occurred with higher than expected rates, but further investigations failed to recognize any convincing causal link. In Italy, cluster analyses of sporadic CJD cases have not been performed previously. 
Objective: To investigate the geographical distribution of sporadic CJD using municipality geographical data of Apulia with the aim of detecting spatial clusters of disease. 
Patients and Methods: Patients included in this study were diagnosed as probable or definite sporadic CJD and were residents of the Apulia Region (Italy). Bayesian hierarchical models with spatially structured and unstructured random components were used to describe the spatial pattern of the disease and to assess the extent of heterogeneity among municipalities. The Kulldorff-Nagarwalla scan test and the flexible spatial scan statistic were used for detecting spatial clusters. 
Results: Smoothed Bayesian relative risks above the null value were observed in a few adjacent municipalities in the north and middle areas of Apulia. However, both the circular scanning method and the flexible spatial scan statistic identified only a single cluster in the central part of the region. 
Conclusion: Geographical analyses and tests for spatial randomness identified a restricted area with an unusually high number of sporadic CJD cases in the Apulia region of Italy. Environmental and genetic risk factors other than mutations in the prion protein gene however, need to be investigated.
© 2019 S. Karger AG, Basel


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CASE REPORT ARTICLE 

Front. Neurol., 05 September 2018 | https://doi.org/10.3389/fneur.2018.00739 

Sporadic MM-1 Type Creutzfeldt-Jakob Disease With Hemiballic Presentation and No Cognitive Impairment Until 
Death: How New NCJDRSU Diagnostic Criteria May Allow Early Diagnosis

 Comments - Terry Singeltary.

Terry Singeltary re-Sporadic MM-1 Type Creutzfeldt-Jakob Disease With Hemiballic Presentation and No Cognitive Impairment Until Death: How New NCJDRSU Diagnostic Criteria May Allow Early Diagnosis


Heidenhain Variant Creutzfeldt Jakob Disease ???

Greetings Authors and Frontiers et al,

wow, this case in some way brings back memories of my mom, who died from hvCJD i.e. the Heidenhain Variant of CJD.

i believe that hvcjd is mm1.

a few thinks that i posted way back in 1997 or 98. understanding that her clinical symptoms to death were a bit longer than what i wrote back then, thinking back....mom, hvCJD.

so, i kindly wish to run this by you all, i hope you don't mind...'notes from a peon'...warmest regards, terry

MOM 1997

SYMPTOMS:

VISION - BLIND IN ABOUT 10 TO 14 DAYS

COORDINATION AND MUSCLE CONTROL

SWALLOWING DIFFICULTY

CONFUSION AND DEMENTIA

SPEECH PROBLEMS

HALLUCINATIONS

TREMBLES TOO SEVERE

JERKING

LOSS OF WEIGHT

HANDS AND FEET GREW INWARD

UPPER TRUNK STIFFNESS, SHOULDER, UPPER ARM


Diagnosis and Reporting of Creutzfeldt-Jakob Disease

Singeltary, Sr et al. JAMA.2001; 285: 733-734.





see moms autopsy;


2018

WEDNESDAY, SEPTEMBER 26, 2018

JAVMA In Short Update USDA announces detection of atypical BSE


THURSDAY, OCTOBER 04, 2018

Cervid to human prion transmission 5R01NS088604-04 Update


TUESDAY, SEPTEMBER 4, 2018

USA CJD, BSE, SCRAPIE, CWD, TSE PRION END OF YEAR REPORTS September 4, 2018


WEDNESDAY, SEPTEMBER 26, 2018

A new variant of Creutzfeldt-Jakob disease in the UK 1995 revisited 2018 a review of science




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

>>> 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 ?

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

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

snip...see full Singeltary Nature comment here;

Alzheimer's disease

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





12:20 PM, 08 October 2018


May 10, 2005; 64 (9) ARTICLES

High incidence of genetic human transmissible spongiform encephalopathies in Italy

A. Ladogana, M. Puopolo, A. Poleggi, S. Almonti, V. Mellina, M. Equestre, M. Pocchiari First published May 9, 2005, DOI: https://doi.org/10.1212/01.WNL.0000160118.26865.11 Article Figures & Data Info & Disclosures

Abstract

Objective: To assess the incidence and mortality rates of genetic transmissible spongiform encephalopathy (TSE) diseases in Italy.

Methods: The authors have sequenced the prion protein gene (PRNP) in 643 patients referred to the Italian Registry of Creutzfeldt-Jakob disease (CJD) and related disorders between 1993 and 2002. Crude age- and sex-specific incidence and mortality rates were calculated. Differences in morbidity from genetic TSE diseases in the 20 Italian regions were assessed by the standardized morbidity ratio (SMR).

Results: A total of 130 cases were classified as genetic TSE diseases with a mean yearly incidence rate of 0.28 cases per million people. Genetic TSE diseases represent 17.7% of all TSE diseases, including sporadic, iatrogenic, and variant CJD. The most frequent mutation was the V210I (n = 54), and the second most common the E200K (n = 42). Mortality rates for genetic TSE diseases did not increase in any of the age groups under examination over the 10 years of surveillance. The analysis of regional distribution of genetic cases by place of birth revealed that in Campania and Calabria regions the number of genetic TSE cases was higher than in other regions.

Conclusions: In Italy the incidence of genetic transmissible spongiform encephalopathy (TSE) diseases is the second highest among European countries. Genetic analysis is important for a correct classification of patients with TSE.

View Full Text


MONDAY, SEPTEMBER 07, 2015 

ITALY REPORTING INCREASE IN CASES OF MAD COW TYPE TSE PRION DISEASE IN HUMANS CJD


Thursday, January 06, 2011
Italy: 'Mad cow disease' claims second Italian victim
1ST CASE NVCJD ITALY 2002
Eurosurveillance, Volume 6, Issue 6, 07 February 2002 Articles S Salmaso1
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Citation style for this article: Salmaso S.
First case of vCJD reported in Italy.
Euro Surveill. 2002;6(6):pii=2022.
Available online:
Date of submission:
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First case of vCJD reported in Italy
The first case of variant Creutzfeld-Jakob Disease (vCJD) has been reported in Italy (1). The case from Sicily was diagnosed in Italy and Great Britain on the basis of clinical and instrumental tests and tonsillar biopsy. The Istituto Superiore di Sanità (ISS) has classified the case as probable, but since the patient is still alive, the ISS has not released any additional information. The surveillance and reporting of CJD has been mandatory in Italy since the beginning of 2002. A ban on feeding mammalian protein to ruminants was approved on 28 July 1984, and enforced from 15 September that year. The prevalence of indigenous cases of bovine spongiform encephalopathy per 10 000 tests was 1.03 for the year 2001 (2).
References :
1.Ministero della Salute. Segnalato caso variante malattia Creutzfeldt-Jakob. Press release 05/02/2002 N° 40, 5 February 2002.
2.Centro per lo Studio e le Ricerche sulle Encefalopatie Animali e Neuropatologie Comparate. Focolai BSE in Italia: 2001/2002.
Reported by Stefania Salmaso
(salmaso@iss.it), Istituto Superiore di Sanità, Italy.
Eurosurveillance, Volume 6, Issue 40, 03 October 2002
Articles
A M Molesworth1
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Citation style for this article: Molesworth AM.
First case of variant Creutzfeldt-Jakob disease reported in Italy - update. Euro Surveill. 2002;6(40):pii=1891.
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First case of variant Creutzfeldt-Jakob disease reported in Italy - update
A paper published in the Lancet this week describes the first case of variant Creutzfeldt-Jakob disease (vCJD) in Italy (1). The patient, a 25 year old Sicilian woman, developed clinical symptoms in 2001 and was first reported in February this year (2). Although definitive diagnosis of vCJD requires neuropathological confirmation, the woman’s illness fulfils the diagnostic criteria for probable vCJD (3), a brain scan was characteristic of vCJD and the abnormal protein associated with vCJD has been detected in a tonsil biopsy.
The patient had never undergone neurosurgery, or received a blood transfusion or any other treatment that might be associated with transmission of a prion disease. Scientific evidence suggests that vCJD is, however, caused by transmission of the bovine spongiform encephalopathy agent (BSE) to humans. The woman is likely to have acquired her infection within Italy, having never travelled to the United Kingdom (UK) or any other country with reported BSE. Cases of indigenous BSE were first reported in Italy following the implementation, in 2001, of mandatory testing of cattle older than 30 months destined for slaughter (4). By the end of September 2002 70 indigenous cases and two British imported cases had been identified (5).
To date, in addition to the Italian case, single cases of definite or probable vCJD have been diagnosed with onset in each of the Republic of Ireland, Canada and the United States, a further six in France and 127 in the UK (see EUROCJD, http://www.eurocjd.ed.ac.uk/). The occurrence of cases both within and outside the UK remains a concern, supporting the need for continuous surveillance programmes of transmissible spongiform encephalopathies in humans and animals in the UK and other countries.
References :
La Bella V, Collinge J, Pocchiari M, Piccoli F. Variant Creutzfeldt-Jakob disease in an Italian woman. Lancet 2002; 360: 997-8. (http://pdf.thelancet.com/pdfdownload?uid=llan.360.9338.original_research.22571.1&x=x.pdf).
Salmaso S. First case of vCJD reported in Italy. Eurosurveillance Weekly 2002; 6: 020207. (http://www.eurosurveillance.org/ew/2002/020207.asp).
Will RG, Zeidler M, Stewart GE, Macleod MA, Ironside JW, Cousens SN, et al. Diagnosis of new variant Creutzfeldt-Jakob disease. Ann Neurol 2000;47: 575-82.
European Commission. Regulation (EC) No 999/2001 of the European Parliament and of the Council of 22 May 2001 (http://europa.eu.int/comm/food/fs/bse/bse36_en.pdf)
Centro per lo Studio e le Ricerche sulle Encefalopatie Animali e Neuropatologie Comparate. Focolai BSE in Italia [BSE Outbreaks in Italy]: 2001/2002 (http://www.to.izs.it)
Reported by Anna Molesworth (amolesworth@phls.org.uk) and Peter Horby, Public Health Laboratory Service Communicable Disease Surveillance Centre, London, England.
In October 1998 the simultaneous occurrence of spongiform encephalopathy in a man and his pet cat was reported.
The report from Italy noted that the cat did not display the same clinical features as FSE cases previously seen. Indeed, the presence of a new type of FSE was suggested. The man was diagnosed as having sporadic CJD, and neither case (man nor cat) appeared to be affected by a BSE-related condition.
Image] Research letters Volume 352, Number 9134 [Image] 3 October1998[Previous] [Next] [Image][Image]
Simultaneous occurrence of spongiform encephalopathy in a manand his cat in Italy
[Image] Gianluigi Zanusso, Ettore Nardelli, Anna Rosati, GianMaria Fabrizi, SergioFerrari, Antonella Carteri, Franco De Simone, Nicola Rizzuto, SalvatoreMonaco
Transmissible spongiform encephalopathies (TSE) encompass inherited,acquired, and sporadic mammalian neurological disorders, and are characterised by the conversion of the cellular prion protein (PrP) in an insoluble and protease-resistant isoform (PrPres). In human TSE, four types of PrPres have been identified according to size and glycoform ratios, which may represent different prion strains. Type-1 and type-2 PrPres are associated with sporadic Creutzfeldt-Jakob disease (CJD), type 3 with iatrogenic CJD, and type 4 with variant CJD.1,2 There is evidence that variant CJD is caused by the bovine spongiform encephalopathy (BSE)-prion strain.2-4 The BSE strain has been identified in three cats with feline spongiform encephalopathy (FSE), a prion disease which appeared in 1990 inthe UK.5
We report the simultaneous occurrence of sporadic CJD in a man and a new variety of FSE in his cat.
snip...
Evidence of a new type of FSE was further provided by the detection of a type-1 PrPres, other than the BSE-associated type 4.2
snip...end
Subject: ITALY: Two More Cases BSE Confirmed after some 54,500 tests since Jan. 1, 2001 (U.S.A. only 12,000 tests in 12 YEARS ???) Date: Tue, 27 Mar 2001 10:13:48 -0800 From: "Terry S. Singeltary Sr." Reply-To: Bovine Spongiform Encephalopathy To: BSE-L@uni-karlsruhe.de
######### Bovine Spongiform Encephalopathy #########
Italy: Two More Cases BSE Confirmed
ROME (AP) - Italy confirmed two more cases of mad cow disease Tuesday, bringing the total number of infected animals to nine.
Another suspected case in central Italy awaits final results.
The infected cows were found in two separate farms in the northern Lombardy region, said the Health Ministry.
Final analyses of the brain tissue were conducted in a Turin-based zoological institute.
Italy has tested more than 54,500 animals since the beginning of the year, when the European Union began requiring tests on cattle older than 30 months destined for slaughter. About 1,000 tests await final results, the Health Ministry said.
Many experts believe that bovine spongiform encephalopathy, the formal name for mad cow disease, can be transmitted to people who eat meat from infected animals.
So far, Italy has had no human cases.
Article Copyright 2001 Associated Press.
amazing, a Country the size Italy testing this many animals, but yet the U.S. still standing with finger in ?????????? ear....
i would be curious to know the total cattle population of Italy compared to U.S. ???
kind regards, Terry S. Singeltary Sr., Bacliff, Texas USA
New cases in Italy (+2), Belgium (+2), France (+1), Great Britain (+23)
BSE in EUROPE INCIDENCE OF BOVINE SPONGIFORM ENCEPHALOPATHY BSE-statistics http://ourworld.cs.com/_ht_a/j1braakman/BSE.htm or http://go.to/mad-cow
TSS
SEE FRANCE INCREASE OF SPORADIC CJD ;
nvCJD worldwide statistics that have been documented
see increased sporadic cjd cases in different BSE countries here ;
ITALY BSE
Italye   BSE
1994-2b
2001-48
2002-38
2003-29
2004-7
2005-8
2006-7
2007-2
2008-1
2009-2
e
Italy:
Year 2002 - Includes 2 imported cases.

ZOONOSIS OF SCRAPIE TSE PRION

O.05: Transmission of prions to primates after extended silent incubation periods: Implications for BSE and scrapie risk assessment in human populations 

Emmanuel Comoy, Jacqueline Mikol, Valerie Durand, Sophie Luccantoni, Evelyne Correia, Nathalie Lescoutra, Capucine Dehen, and Jean-Philippe Deslys Atomic Energy Commission; Fontenay-aux-Roses, France 

Prion diseases (PD) are the unique neurodegenerative proteinopathies reputed to be transmissible under field conditions since decades. The transmission of Bovine Spongiform Encephalopathy (BSE) to humans evidenced that an animal PD might be zoonotic under appropriate conditions. Contrarily, in the absence of obvious (epidemiological or experimental) elements supporting a transmission or genetic predispositions, PD, like the other proteinopathies, are reputed to occur spontaneously (atpical animal prion strains, sporadic CJD summing 80% of human prion cases). 

Non-human primate models provided the first evidences supporting the transmissibiity of human prion strains and the zoonotic potential of BSE. Among them, cynomolgus macaques brought major information for BSE risk assessment for human health (Chen, 2014), according to their phylogenetic proximity to humans and extended lifetime. We used this model to assess the zoonotic potential of other animal PD from bovine, ovine and cervid origins even after very long silent incubation periods. 

*** We recently observed the direct transmission of a natural classical scrapie isolate to macaque after a 10-year silent incubation period, 

***with features similar to some reported for human cases of sporadic CJD, albeit requiring fourfold long incubation than BSE. Scrapie, as recently evoked in humanized mice (Cassard, 2014), 

***is the third potentially zoonotic PD (with BSE and L-type BSE), 

***thus questioning the origin of human sporadic cases. 

We will present an updated panorama of our different transmission studies and discuss the implications of such extended incubation periods on risk assessment of animal PD for human health. 

=============== 

***thus questioning the origin of human sporadic cases*** 

=============== 

***our findings suggest that possible transmission risk of H-type BSE to sheep and human. Bioassay will be required to determine whether the PMCA products are infectious to these animals. 

============== 


***Transmission data also revealed that several scrapie prions propagate in HuPrP-Tg mice with efficiency comparable to that of cattle BSE. While the efficiency of transmission at primary passage was low, subsequent passages resulted in a highly virulent prion disease in both Met129 and Val129 mice. 

***Transmission of the different scrapie isolates in these mice leads to the emergence of prion strain phenotypes that showed similar characteristics to those displayed by MM1 or VV2 sCJD prion. 

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

PRION 2016 TOKYO

Saturday, April 23, 2016

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

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

Taylor & Francis

Prion 2016 Animal Prion Disease Workshop Abstracts

WS-01: Prion diseases in animals and zoonotic potential

Juan Maria Torres a, Olivier Andreoletti b, J uan-Carlos Espinosa a. Vincent Beringue c. Patricia Aguilar a,

Natalia Fernandez-Borges a. and Alba Marin-Moreno a

"Centro de Investigacion en Sanidad Animal ( CISA-INIA ). Valdeolmos, Madrid. Spain; b UMR INRA -ENVT 1225 Interactions Holes Agents Pathogenes. ENVT. Toulouse. France: "UR892. Virologie lmmunologie MolécuIaires, Jouy-en-Josas. France

Dietary exposure to bovine spongiform encephalopathy (BSE) contaminated bovine tissues is considered as the origin of variant Creutzfeldt Jakob (vCJD) disease in human. To date, BSE agent is the only recognized zoonotic prion... Despite the variety of Transmissible Spongiform Encephalopathy (TSE) agents that have been circulating for centuries in farmed ruminants there is no apparent epidemiological link between exposure to ruminant products and the occurrence of other form of TSE in human like sporadic Creutzfeldt Jakob Disease (sCJD). However, the zoonotic potential of the diversity of circulating TSE agents has never been systematically assessed. The major issue in experimental assessment of TSEs zoonotic potential lies in the modeling of the ‘species barrier‘, the biological phenomenon that limits TSE agents’ propagation from a species to another. In the last decade, mice genetically engineered to express normal forms of the human prion protein has proved essential in studying human prions pathogenesis and modeling the capacity of TSEs to cross the human species barrier.

To assess the zoonotic potential of prions circulating in farmed ruminants, we study their transmission ability in transgenic mice expressing human PrPC (HuPrP-Tg). Two lines of mice expressing different forms of the human PrPC (129Met or 129Val) are used to determine the role of the Met129Val dimorphism in susceptibility/resistance to the different agents.

These transmission experiments confirm the ability of BSE prions to propagate in 129M- HuPrP-Tg mice and demonstrate that Met129 homozygotes may be susceptible to BSE in sheep or goat to a greater degree than the BSE agent in cattle and that these agents can convey molecular properties and neuropathological indistinguishable from vCJD. However homozygous 129V mice are resistant to all tested BSE derived prions independently of the originating species suggesting a higher transmission barrier for 129V-PrP variant.

Transmission data also revealed that several scrapie prions propagate in HuPrP-Tg mice with efficiency comparable to that of cattle BSE. While the efficiency of transmission at primary passage was low, subsequent passages resulted in a highly virulent prion disease in both Met129 and Val129 mice. 

Transmission of the different scrapie isolates in these mice leads to the emergence of prion strain phenotypes that showed similar characteristics to those displayed by MM1 or VV2 sCJD prion. 

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

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

5. A positive result from a chimpanzee challenged severly would likely create alarm in some circles even if the result could not be interpreted for man. 

***> I have a view that all these agents could be transmitted provided a large enough dose by appropriate routes was given and the animals kept long enough. 

***> Until the mechanisms of the species barrier are more clearly understood it might be best to retain that hypothesis.

snip...

R. BRADLEY



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

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

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

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


***> 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. <***

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

Emmanuel E. Comoy, Jacqueline Mikol, Sophie Luccantoni-Freire, Evelyne Correia, Nathalie Lescoutra-Etchegaray, Valérie Durand, Capucine Dehen, Olivier Andreoletti, Cristina Casalone, Juergen A. Richt, Justin J. Greenlee, Thierry Baron, Sylvie L. Benestad, Paul Brown & Jean-Philippe Deslys Scientific Reports volume 5, Article number: 11573 (2015) | Download Citation

Abstract 

Classical bovine spongiform encephalopathy (c-BSE) is the only animal prion disease reputed to be zoonotic, causing variant Creutzfeldt-Jakob disease (vCJD) in humans and having guided protective measures for animal and human health against animal prion diseases. Recently, partial transmissions to humanized mice showed that the zoonotic potential of scrapie might be similar to c-BSE. We here report the direct transmission of a natural classical scrapie isolate to cynomolgus macaque, a highly relevant model for human prion diseases, after a 10-year silent incubation period, with features similar to those reported for human cases of sporadic CJD. Scrapie is thus actually transmissible to primates with incubation periods compatible with their life expectancy, although fourfold longer than BSE. Long-term experimental transmission studies are necessary to better assess the zoonotic potential of other prion diseases with high prevalence, notably Chronic Wasting Disease of deer and elk and atypical/Nor98 scrapie.

SNIP...

Discussion We describe the transmission of spongiform encephalopathy in a non-human primate inoculated 10 years earlier with a strain of sheep c-scrapie. Because of this extended incubation period in a facility in which other prion diseases are under study, we are obliged to consider two alternative possibilities that might explain its occurrence. We first considered the possibility of a sporadic origin (like CJD in humans). Such an event is extremely improbable because the inoculated animal was 14 years old when the clinical signs appeared, i.e. about 40% through the expected natural lifetime of this species, compared to a peak age incidence of 60–65 years in human sporadic CJD, or about 80% through their expected lifetimes. 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.

The second possibility is a laboratory cross-contamination. Three facts make this possibility equally unlikely. First, handling of specimens in our laboratory is performed with fastidious attention to the avoidance of any such cross-contamination. Second, no laboratory cross-contamination has ever been documented in other primate laboratories, including the NIH, even between infected and uninfected animals housed in the same or adjacent cages with daily intimate contact (P. Brown, personal communication). Third, the cerebral lesion profile is different from all the other prion diseases we have studied in this model19, with a correlation between cerebellar lesions (massive spongiform change of Purkinje cells, intense PrPres staining and reactive gliosis26) and ataxia. The iron deposits present in the globus pallidus are a non specific finding that have been reported previously in neurodegenerative diseases and aging27. Conversely, the thalamic lesion was reminiscent of a metabolic disease due to thiamine deficiency28 but blood thiamine levels were within normal limits (data not shown). The preferential distribution of spongiform change in cortex associated with a limited distribution in the brainstem is reminiscent of the lesion profile in MM2c and VV1 sCJD patients29, but interspecies comparison of lesion profiles should be interpreted with caution. It is of note that the same classical scrapie isolate induced TSE in C57Bl/6 mice with similar incubation periods and lesional profiles as a sample derived from a MM1 sCJD patient30.

We are therefore confident that the illness in this cynomolgus macaque represents a true transmission of a sheep c-scrapie isolate directly to an old-world monkey, which taxonomically resides in the primate subdivision (parvorder of catarrhini) that includes humans. With an homology of its PrP protein with humans of 96.4%31, cynomolgus macaque constitutes a highly relevant model for assessing zoonotic risk of prion diseases. Since our initial aim was to show the absence of transmission of scrapie to macaques in the worst-case scenario, we obtained materials from a flock of naturally-infected sheep, affecting animals with different genotypes32. This c-scrapie isolate exhibited complete transmission in ARQ/ARQ sheep (332 ± 56 days) and Tg338 transgenic mice expressing ovine VRQ/VRQ prion protein (220 ± 5 days) (O. Andreoletti, personal communication). From the standpoint of zoonotic risk, it is important to note that sheep with c-scrapie (including the isolate used in our study) have demonstrable infectivity throughout their lymphoreticular system early in the incubation period of the disease (3 months-old for all the lymphoid organs, and as early as 2 months-old in gut-associated lymph nodes)33. In addition, scrapie infectivity has been identified in blood34, milk35 and skeletal muscle36 from asymptomatic but scrapie infected small ruminants which implies a potential dietary exposure for consumers.

Two earlier studies have reported the occurrence of clinical TSE in cynomolgus macaques after exposures to scrapie isolates. In the first study, the “Compton” scrapie isolate (derived from an English sheep) and serially propagated for 9 passages in goats did not transmit TSE in cynomolgus macaque, rhesus macaque or chimpanzee within 7 years following intracerebral challenge1; conversely, after 8 supplementary passages in conventional mice, this “Compton” isolate induced TSE in a cynomolgus macaque 5 years after intracerebral challenge, but rhesus macaques and chimpanzee remained asymptomatic 8.5 years post-exposure8. However, multiple successive passages that are classically used to select laboratory-adapted prion strains can significantly modify the initial properties of a scrapie isolate, thus questioning the relevance of zoonotic potential for the initial sheep-derived isolate. The same isolate had also induced disease into squirrel monkeys (new-world monkey)9. A second historical observation reported that a cynomolgus macaque developed TSE 6 years post-inoculation with brain homogenate from a scrapie-infected Suffolk ewe (derived from USA), whereas a rhesus macaque and a chimpanzee exposed to the same inoculum remained healthy 9 years post-exposure1. This inoculum also induced TSE in squirrel monkeys after 4 passages in mice. Other scrapie transmission attempts in macaque failed but had more shorter periods of observation in comparison to the current study. Further, it is possible that there are differences in the zoonotic potential of different scrapie strains.

The most striking observation in our study is the extended incubation period of scrapie in the macaque model, which has several implications. Firstly, our observations constitute experimental evidence in favor of the zoonotic potential of c-scrapie, at least for this isolate that has been extensively studied32,33,34,35,36. The cross-species zoonotic ability of this isolate should be confirmed by performing duplicate intracerebral exposures and assessing the transmissibility by the oral route (a successful transmission of prion strains through the intracerebral route may not necessarily indicate the potential for oral transmission37). However, such confirmatory experiments may require more than one decade, which is hardly compatible with current general management and support of scientific projects; thus this study should be rather considered as a case report.

Secondly, transmission of c-BSE to primates occurred within 8 years post exposure for the lowest doses able to transmit the disease (the survival period after inoculation is inversely proportional to the initial amount of infectious inoculum). The occurrence of scrapie 10 years after exposure to a high dose (25 mg) of scrapie-infected sheep brain suggests that the macaque has a higher species barrier for sheep c-scrapie than c-BSE, although it is notable that previous studies based on in vitro conversion of PrP suggested that BSE and scrapie prions would have a similar conversion potential for human PrP38.

Thirdly, prion diseases typically have longer incubation periods after oral exposure than after intracerebral inoculations: since humans can develop Kuru 47 years after oral exposure39, an incubation time of several decades after oral exposure to scrapie would therefore be expected, leading the disease to occur in older adults, i.e. the peak age for cases considered to be sporadic disease, and making a distinction between scrapie-associated and truly sporadic disease extremely difficult to appreciate.

Fourthly, epidemiologic evidence is necessary to confirm the zoonotic potential of an animal disease suggested by experimental studies. A relatively short incubation period and a peculiar epidemiological situation (e.g., all the first vCJD cases occurring in the country with the most important ongoing c-BSE epizootic) led to a high degree of suspicion that c-BSE was the cause of vCJD. Sporadic CJD are considered spontaneous diseases with an almost stable and constant worldwide prevalence (0.5–2 cases per million inhabitants per year), and previous epidemiological studies were unable to draw a link between sCJD and classical scrapie6,7,40,41, even though external causes were hypothesized to explain the occurrence of some sCJD clusters42,43,44. However, extended incubation periods exceeding several decades would impair the predictive values of epidemiological surveillance for prion diseases, already weakened by a limited prevalence of prion diseases and the multiplicity of isolates gathered under the phenotypes of “scrapie” and “sporadic CJD”.

Fifthly, considering this 10 year-long incubation period, together with both laboratory and epidemiological evidence of decade or longer intervals between infection and clinical onset of disease, no premature conclusions should be drawn from negative transmission studies in cynomolgus macaques with less than a decade of observation, as in the aforementioned historical transmission studies of scrapie to primates1,8,9. Our observations and those of others45,46 to date are unable to provide definitive evidence regarding the zoonotic potential of CWD, atypical/Nor98 scrapie or H-type BSE. The extended incubation period of the scrapie-affected macaque in the current study also underscores the limitations of rodent models expressing human PrP for assessing the zoonotic potential of some prion diseases since their lifespan remains limited to approximately two years21,47,48. This point is illustrated by the fact that the recently reported transmission of scrapie to humanized mice was not associated with clinical signs for up to 750 days and occurred in an extreme minority of mice with only a marginal increase in attack rate upon second passage13. The low attack rate in these studies is certainly linked to the limited lifespan of mice compared to the very long periods of observation necessary to demonstrate the development of scrapie. Alternatively, one could estimate that a successful second passage is the result of strain adaptation to the species barrier, thus poorly relevant of the real zoonotic potential of the original scrapie isolate of sheep origin49. The development of scrapie in this primate after an incubation period compatible with its lifespan complements the study conducted in transgenic (humanized) mice; taken together these studies suggest that some isolates of sheep scrapie can promote misfolding of the human prion protein and that scrapie can develop within the lifespan of some primate species.

In addition to previous studies on scrapie transmission to primate1,8,9 and the recently published study on transgenic humanized mice13, our results constitute new evidence for recommending that the potential risk of scrapie for human health should not be dismissed. Indeed, human PrP transgenic mice and primates are the most relevant models for investigating the human transmission barrier. To what extent such models are informative for measuring the zoonotic potential of an animal TSE under field exposure conditions is unknown. During the past decades, many protective measures have been successfully implemented to protect cattle from the spread of c-BSE, and some of these measures have been extended to sheep and goats to protect from scrapie according to the principle of precaution. Since cases of c-BSE have greatly reduced in number, those protective measures are currently being challenged and relaxed in the absence of other known zoonotic animal prion disease. We recommend that risk managers should be aware of the long term potential risk to human health of at least certain scrapie isolates, notably for lymphotropic strains like the classical scrapie strain used in the current study. Relatively high amounts of infectivity in peripheral lymphoid organs in animals infected with these strains could lead to contamination of food products produced for human consumption. Efforts should also be maintained to further assess the zoonotic potential of other animal prion strains in long-term studies, notably lymphotropic strains with high prevalence like CWD, which is spreading across North America, and atypical/Nor98 scrapie (Nor98)50 that was first detected in the past two decades and now represents approximately half of all reported cases of prion diseases in small ruminants worldwide, including territories previously considered as scrapie free... Even if the prevailing view is that sporadic CJD is due to the spontaneous formation of CJD prions, it remains possible that its apparent sporadic nature may, at least in part, result from our limited capacity to identify an environmental origin.



Chronic Wasting Disease CWD TSE Prion

Cervid to human prion transmission 

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

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. 


ZOONOTIC CHRONIC WASTING DISEASE CWD TSE PRION UPDATE

here is the latest;

PRION 2018 CONFERENCE 

Oral transmission of CWD into Cynomolgus macaques: signs of atypical disease, prion conversion and infectivity in macaques and bio-assayed transgenic mice 

Hermann M. Schatzl, Samia Hannaoui, Yo-Ching Cheng, Sabine Gilch (Calgary Prion Research Unit, University of Calgary, Calgary, Canada) Michael Beekes (RKI Berlin), Walter Schulz-Schaeffer (University of Homburg/Saar, Germany), Christiane Stahl-Hennig (German Primate Center) & Stefanie Czub (CFIA Lethbridge). 

To date, BSE is the only example of interspecies transmission of an animal prion disease into humans. The potential zoonotic transmission of CWD is an alarming issue and was addressed by many groups using a variety of in vitro and in vivo experimental systems. Evidence from these studies indicated a substantial, if not absolute, species barrier, aligning with the absence of epidemiological evidence suggesting transmission into humans. Studies in non-human primates were not conclusive so far, with oral transmission into new-world monkeys and no transmission into old-world monkeys. Our consortium has challenged 18 Cynomolgus macaques with characterized CWD material, focusing on oral transmission with muscle tissue. Some macaques have orally received a total of 5 kg of muscle material over a period of 2 years. 

After 5-7 years of incubation time some animals showed clinical symptoms indicative of prion disease, and prion neuropathology and PrPSc deposition were detected in spinal cord and brain of some euthanized animals. PrPSc in immunoblot was weakly detected in some spinal cord materials and various tissues tested positive in RT-QuIC, including lymph node and spleen homogenates. To prove prion infectivity in the macaque tissues, we have intracerebrally inoculated 2 lines of transgenic mice, expressing either elk or human PrP. At least 3 TgElk mice, receiving tissues from 2 different macaques, showed clinical signs of a progressive prion disease and brains were positive in immunoblot and RT-QuIC. Tissues (brain, spinal cord and spleen) from these and pre-clinical mice are currently tested using various read-outs and by second passage in mice. Transgenic mice expressing human PrP were so far negative for clear clinical prion disease (some mice >300 days p.i.). In parallel, the same macaque materials are inoculated into bank voles. 

Taken together, there is strong evidence of transmissibility of CWD orally into macaques and from macaque tissues into transgenic mouse models, although with an incomplete attack rate. 

The clinical and pathological presentation in macaques was mostly atypical, with a strong emphasis on spinal cord pathology. 
Our ongoing studies will show whether the transmission of CWD into macaques and passage in transgenic mice represents a form of non-adaptive prion amplification, and whether macaque-adapted prions have the potential to infect mice expressing human PrP. 

The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD.. 

***> The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD. <*** 

https://prion2018.org/

READING OVER THE PRION 2018 ABSTRACT BOOK, LOOKS LIKE THEY FOUND THAT from this study ; 

P190 Human prion disease mortality rates by occurrence of chronic wasting disease in freeranging cervids, United States 

Abrams JY (1), Maddox RA (1), Schonberger LB (1), Person MK (1), Appleby BS (2), Belay ED (1) (1) Centers for Disease Control and Prevention (CDC), National Center for Emerging and Zoonotic Infectious Diseases, Atlanta, GA, USA (2) Case Western Reserve University, National Prion Disease Pathology Surveillance Center (NPDPSC), Cleveland, OH, USA.. 

SEEMS THAT THEY FOUND Highly endemic states had a higher rate of prion disease mortality compared to non-CWD 
states. 

AND ANOTHER STUDY; 

P172 Peripheral Neuropathy in Patients with Prion Disease 

Wang H(1), Cohen M(1), Appleby BS(1,2) (1) University Hospitals Cleveland Medical Center, Cleveland, Ohio (2) National Prion Disease Pathology Surveillance Center, Cleveland, Ohio.. 

IN THIS STUDY, THERE WERE autopsy-proven prion cases from the National Prion Disease Pathology Surveillance Center that were diagnosed between September 2016 to March 2017, 

AND 

included 104 patients. SEEMS THEY FOUND THAT The most common sCJD subtype was MV1-2 (30%), followed by MM1-2 (20%), 

AND 

THAT The Majority of cases were male (60%), AND half of them had exposure to wild game. 

snip...

see more on Prion 2017 Macaque study from Prion 2017 Conference and other updated science on cwd tse prion zoonosis below...terry 

https://prion2018.org/wp-content/uploads/2018/05/program.pdf 

https://prion2018.org/

THURSDAY, OCTOBER 04, 2018 

Cervid to human prion transmission 5R01NS088604-04 Update 

http://grantome.com/grant/NIH/R01-NS088604-04 

http://chronic-wasting-disease.blogspot.com/2018/10/cervid-to-human-prion-transmission.html

snip...full text;

SATURDAY, FEBRUARY 09, 2019 

Experts: Yes, chronic wasting disease in deer is a public health issue — for people


FRIDAY, JULY 26, 2019 

***> Chronic Wasting Disease in Cervids: Implications for Prion Transmission to Humans and Other Animal Species


THURSDAY, SEPTEMBER 26, 2019 

Sweden The third case of CWD in moose in Arjeplog is now established


friendly fire, pass it forward, they call it iatrogenic cjd, or what i call 'tse prion poker', are you all in $$$


all iatrogenic cjd is, is sporadic cjd, before the iatrogenic event is discovered, traced back, provern, documented, put into the academic domain, and then finally the public domain, this very seldom happens, thus problem solved, it's all sporadic cjd, PLUS, SPORADIC CJD HAS NOW BEEN LINKED TO ATYPICAL AND TYPICAL BSE, SCRAPIE, AND NOW CWD. ...terry

THURSDAY, AUGUST 10, 2017 

Minimise transmission risk of CJD and vCJD in healthcare settings Updated 10 August 2017



SATURDAY, MARCH 16, 2019 

Medical Devices Containing Materials Derived from Animal Sources (Except for In Vitro Diagnostic Devices) Guidance for Industry and Food and Drug Administration Staff Document issued on March 15, 2019 Singeltary Submission


TUESDAY, APRIL 09, 2019 

Horizon Health Network Moncton Hospital notified more than 700 patients after two cases of CJD were diagnosed both patients had undergone cataracts surgery before being diagnosed


SUNDAY, MARCH 10, 2019 

National Prion Disease Pathology Surveillance Center Cases Examined¹ Updated Feb 1, 2019 Variably protease-sensitive prionopathy VPSPr


MONDAY, AUGUST 26, 2019 

Creutzfeldt Jakob Disease CJD, TSE, Prion, Surveillance Update August 2019



Subject: Prion 2019 Conference

Thursday, May 23, 2019 

Prion 2019 Emerging Concepts CWD, BSE, SCRAPIE, CJD, SCIENTIFIC PROGRAM Schedule and Abstracts


see full Prion 2019 Conference Abstracts


MONDAY, FEBRUARY 25, 2019

MAD DOGS AND ENGLISHMEN BSE, SCRAPIE, CWD, CJD, TSE PRION A REVIEW 2019



Tuesday, September 10, 2019 

FSIS [Docket No. FSIS–2019–0021] Notice of Request To Renew an Approved Information Collection: Specified Risk Materials Singeltary Submission


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...


(It was noted with concern that hormone extracts could be manufactured by a veterinary surgeon for administration to animals under his care without any Medicines Act Control.)

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.

BEEF BRAIN AND BRAIN INFUSION BROTHS

Considered to be of great risk.


COMMERCIAL IN CONFIDENCE

MEDICINES ACT - VETERINARY PRODUCTS COMMITTEE

5 BLANK PAGES. ...TSS

7. Any Other Business


snip...see full text ;


snip...

THURSDAY, SEPTEMBER 26, 2019 

Veterinary Biologics Guideline 3.32E: Guideline for minimising the risk of introducing transmissible spongiform encephalopathy prions and other infectious agents through veterinary biologics


2019

friendly fire, pass it forward, they call it iatrogenic cjd, or what i call 'tse prion poker', are you all in $$$

all iatrogenic cjd is, is sporadic cjd, before the iatrogenic event is discovered, traced back, proven, documented, put into the academic domain, and then finally the public domain, this very seldom happens, thus problem solved, it's all sporadic cjd, PLUS, SPORADIC CJD HAS NOW BEEN LINKED TO ATYPICAL AND TYPICAL BSE, SCRAPIE, AND NOW CWD. ...terry

FRIDAY, SEPTEMBER 06, 2019 

Disinfection of Multi-Use Ocular Equipment for Ophthalmological Procedures: A Review of Clinical Effectiveness, Cost-Effectiveness, and Guidelines


Wednesday, September 11, 2019 

Is the re-use of sterilized implant abutments safe enough? (Implant abutment safety) iatrogenic TSE Prion


SUNDAY, SEPTEMBER 08, 2019 

Wisconsin Laboratory Testing Options for Prion Diseases, Wisconsin Neurologists, Clinical Laboratory Directors, and Infection Preventionists, Please Distribute Widely

Preparing for the Storm


TUESDAY, SEPTEMBER 10, 2019 

vCJD permanent deferral policy set to be reversed next month Irish Eye Bank to collect corneas from deceased Irish donors again

counting your chickens again before they have all hatched out $$$


SATURDAY, MARCH 16, 2019 

Medical Devices Containing Materials Derived from Animal Sources (Except for In Vitro Diagnostic Devices) Guidance for Industry and Food and Drug Administration Staff Document issued on March 15, 2019 Singeltary Submission


TUESDAY, APRIL 09, 2019 

Horizon Health Network Moncton Hospital notified more than 700 patients after two cases of CJD were diagnosed both patients had undergone cataracts surgery before being diagnosed


2019

SATURDAY, SEPTEMBER 21, 2019 

National Variability in Prion Disease–Related Safety Policies for Neurologic Procedures


A detailed perusal of document content in selected languages showed that risk assessment for patients or individuals was available in France, Germany, Ireland, Italy, the Netherlands, Spain and the United Kingdom. Patient risk categories differed among countries but were generally built on criteria for the presence of specific symptoms, well-defined associated risk factors, such as family history, or potential risk factors, such as exposure to dura mater grafts, donor blood or potentially contaminated instruments, etc. Decision trees, based on patient risk category and the infectivity level of tissue with which the procedure was to come into contact, were described in documents from France, Italy and the United Kingdom. In general, documents focused on patients facing exposure to surgical procedures or endoscopy. Specific content varied considerably among countries, with regard to information about specific technologies or procedures, i.e., type of endoscope (fibroscope, gastroscope or arthroscope) and approach route (endonasal, oral, etc.).


Friday, September 27, 2019


Prion disease and recommended procedures for flexible endoscope reprocessing – a review of policies worldwide and proposal for a simplified approach


THURSDAY, JULY 08, 2010 
GLOBAL CLUSTERS OF CREUTZFELDT JAKOB DISEASE - A REVIEW 2010

SUNDAY, MAY 26, 2019 

Arguments for Alzheimer’s and Parkinson’s diseases caused by prions Stanley B. Prusiner 

''From a large array of bioassays, we conclude that AD, PD, MSA, and the frontotemporal dementias, including PSP and CBD, are all prion diseases''



Here's another nice mess you've gotten me into - Stan Laurel ... 

Wasted Days and Wasted Nights - Freddy Fender ...

stupid is, as stupid does, and sometimes, you can't fix stupid - Terry S. Singeltary Sr. ...

Terry S. Singeltary Sr., Bacliff, TX., Galveston Bay, on the bottom...flounder9@verizon.net