Greetings,
I think something is terribly wrong here with this prionpathy debate vs prion debate i.e. Ironside first 10 nvCJD in 1996, compared to Gambetti's first 10+ prionpathy here in the USA in 2010.
what does this tell us ???
let's compare Gambetti's first 10 in 2010, to Ironside's first 10 in 1996, to a few other cases of this prionpathy in other countries. let' compare clinical and pathological features.
we know that the UKBSEnvCJD theory was born from the theory of sheep scrapie, to BSE in cows via feed, to nvCJD to humans via the infectious mad cows that were fed this tainted feed. but we now know that these different strains, cause different symptoms, length of illness from onset of symptoms to death, psychotic vs dementia, kuru type plaques vs no kuru plaques. but yet in 2010, this does not matter.
so why did it matter with the first 10 of Ironside?
How can we overlook some of the exact same clinical and pathological features from nvCJD (Ironside's first 10) to (Gambetti's first 10), and how can they conclude that in 1996 they meant one thing, but yet in 2010 they mean something else?
so how can there be so much change in science from then to now?
how can the big pond be such a factor in prion science $
why is it that only the UK and other EU countries can have mad cows, and have humans with mad cow disease there from, but here in the USA, where we have the most documented prion disease in different species on the planet, it's all spontaneous, or generic, with no related gene mutation, but a sporadic genetic prion disease, now called prionpathy ?
I don't believe it. I believe that it's just more of the same, just different strains.
I now call this new prionpathy, 'Prionbaloney'.
they cannot have their cake, and eat it too. which is it ? who is right ? Ironside or Gambetti ?
Does the USA really have a prion cloaking devise that protects us no matter how much banned mad cow protein is in commerce?
WHY is it so hard to believe that these atypical BSE strains were a cause of feed, same as with the c-BSE?
This theory was proven by the EU mad cow feed ban and the dramatic drop in mad cow cases across the EU, there from.
WHY is it that no one will assess this scientifically with transmission studies $ i.e. will atypical BSE transmit via feed as does/did c-BSE?
The only cow documented in the world to date with a Genetic mutation g-h-BSEalabama, the same as Gambetti's first 10+ in humans, and this cow had access to TONS of banned mad cow protein in Alabama during that same time period, and there is no link there, it's all just generic, spontaneous, but there is no related mutation to the humans, only to the cow in Alabama ???
something just does not compute here $
O.K. let's compare some recent cases of this prionpathy in other countries besides Gambetti's first 10 recently, that he claims is a spontaneous event, from a genetic disorder, that is not genetic, but sporadic, that is related to no animal TSE in North America, or the world. ...
J Neurol Neurosurg Psychiatry doi:10.1136/jnnp.2009.175646
Short report
The first case of protease-sensitive prionopathy (PSPr) in The Netherlands: a patient with an unusual GSS-like clinical phenotype
C Jansen1, M W Head2, W A van Gool3, F Baas4, H Yull2, J W Ironside2, A J M Rozemuller1,5 + Author Affiliations
1Department of Pathology, Dutch Surveillance Centre for Prion Diseases, University Medical Centre Utrecht, Utrecht, The Netherlands 2National Creutzfeldt-Jakob Disease Surveillance Unit, University of Edinburgh, Edinburgh, UK 3Department of Neurology, Academic Medical Centre, Amsterdam, The Netherlands 4Department of Neurogenetics, Academic Medical Centre, Amsterdam, The Netherlands 5Netherlands Brain Bank and Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands Correspondence to Dr C Jansen, Department of Pathology, Dutch Surveillance Centre for Prion Diseases, University Medical Centre Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands; c.jansen@umcutrecht.nl Received 16 February 2009 Revised 28 May 2009 Accepted 31 May 2009 Published Online First 14 June 2010
Abstract
An atypical case of prion disease is described in a 54-year-old Dutch man, homozygous for valine at codon 129 of the prion protein gene (PRNP). The clinical phenotype was characterised by progressive dementia, spastic paraplegia and sensorimotor polyneuropathy. The disease duration was 20 months. Genetic analysis of PRNP did not reveal any abnormalities. Neuropathologically, only mild spongiform change and a coarse granular immunohistochemical staining for the abnormal prion protein, PrPSc, was observed, with poorly formed plaques in the molecular layer of the cerebellar cortex. However, Western blotting showed low but detectable levels of proteinase K(PK)-resistant PrPSc occurring in an unusual ladder-like profile. These features define a phenotype that corresponds to the recently described protease-sensitive prionopathy (PSPr). Our report on the first Dutch patient with PSPr further expands the spectrum of prionopathies and exemplifies the need to re-evaluate cases of atypical prion disease.
http://jnnp.bmj.com/content/early/2010/06/12/jnnp.2009.175646.abstract
A case of protease sensitive prionopathy in a patient in the UK
M. W. Head1, R. Knight1, M. Zeidler2, H. Yull1, A. Barlow3, J. W. Ironside1Article first published online: 7 AUG 2009
DOI: 10.1111/j.1365-2990.2009.01040.x
Scientific correspondence
A case of protease sensitive prlonopathy in a patient in the UK
In 2008 the USA National Prion Disease Pathology Surveillance Centre reported a novel human prion disease, whlch they termed protease sensitive prionopathy (PSPr), based on a cohort of 11 patients [I]. The clinical features Included behavioural and psychiatric presenting symptoms in addition to dementia and ataxia. The patients had a mean age at onset or 62 years and mean duruuon of illness of 20 months. Neuropathological assessment showed minimal spongiform change, minimal gliosis, microplaques in the cerebellum and abnormal prion protein accumulation in the form of coarse aggregates, granules and microplaques. The patients had no known risk factors for prion exposure: no mutations in the prton protein gene (PRNP) coding sequence were found. but each patient was homozygous for valine (VV) at codon 129 or PRNP, and a family history or dementia was reported in the majority or the patterns. The most striking and perhaps defining feature or the PSPr phenotype was the presence or abnormal prion protein (PrpSc) in a form that was markedly less protease-resistant than that found in other known human prion diseases, thus making it difficult to detect using conconventional western blot analysts for PrPSc, and resulting in a faint ladder or prion protein fragments extending from the low molecular weight range to the size of the N-terminally truncated PrP, characteristic of most forms of Creutzfeldt-Jakob disese (CJD) [2].
Although the family history or dementia might be taken to suggest a genetic aetiology, an acquired or sporadic/spontaneous aetiology could NOT be ruled out. An International epidemiological evidence base is lacking for PSPr. In particular, it is important to determine the true prevalence or PSPr, whether It is a new disease or a newly described entity, and whether such cases have been referred to surveillance systems outside the USA [3]. Here we report a case of human prion disease referred to the UK National CJD Surveillance Unit that shares many features with PSPr.
A 56-year woman presented with forgetfulness and unusual behaviour in January 2005. Four months later she became tearful, with odd speech patterns and difficulty finding her way around. She developed increasing difficulties in recognizing and using common objects and started to confusing fictional with real life. These difficulties progressed very rapidly, plateaued for a few weeks and then progressed again. Eight months after onset, she had features of a rapidly progressing dementia with frontal lobe features (Mini Mental State Examination 8, Addenbrooke's Cognitive Examination 29), but without any other specific neurological features. At 12 months she was significantly cognitively impaired. At 16 months, she was unable to name objects, was doubly incontinent, but mobile. Myoclonus was noted on two occaslons. At 25 months, she was nearly mute, but still able to eat; by 27 months, she was in an akinetic mute state, dying in June 2008, after a total illness duration or 42 months. In the early stages of the illness. she was tearful at times. prone to become agitated and exhibited some obsessional behaviour, but these were in the context of significant cognitive decline and no specifically psychiatric features were noted.
Routine blood tests were normal (save for a positive anti-thyroid peroxidase). EEGs were undertaken on five occasions between 8 and 13 months and were normal, with nonspecific generalized slowing present at 23 months. Cerebral MRI was performed on three occasions showing generalized cerebral atrophy (8 and 10 months) and increased atrophy and periventricular white matter signal Change (23 months]. No basal ganglia or cortical changes typical of CJD were seen. A lumbar puncture performed at 10 months yielded acellular CSF with a weak positive 14-3-3 and an Sl00b of 0.65 ng/ml. A weak positive 14-3-3 result is not considered to be of diagnostic significance and as such is not included in our diagnostic criteria for sporadic CJD. Analysis of the PRNP gene showed no pathogenic mutations with valine homozygosity at codon 129. In life, she did not fullfill the current clinical diagnostic criteria for either probable or possible sporadic CJD. ...
full text ;
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2990.2009.01040.xlabstract
let's go back to 1995-96 now and compare ;
Lancet 1996; 347: 921- 25
A new variant of Creutzfeldt-Jakob disease in the UK
R G Will, J W Ironside, M Zeidler, S N Cousens, K Estibeiro, A Alperovitch, S Poser, M Pocchiari, A Hofman, P G Smith
Summary
Background Epidemiological surveillance of Creutzfeldt-Jakob disease (CJD) was reinstituted in the UK in 1990 to identify any changes in the occurrence of this disease after the epidemic of bovine spongiform encephalopathy (BSE) in cattle.
Methods Case ascertainment of CJD was mostly by direct referral from neurologists and neuropathologists. Death certificates on which CJD was mentioned were also obtained. Clinical details were obtained for all referred cases, and information on potential risk factors for CJD was obtained by a standard questionnaire administered to patients' relatives. Neuropathological examination was carried out on approximately 70% of suspect cases. Epidemiological studies of CJD using similar methodology to the UK study have been carried out in France, Germany, Italy, and the Netherlands between 1993 and 1995.
Findings Ten cases of CJD have been identified in the UK in recent months with a new neuropathological profile.
Other consistent features that are unusual include the young age of the cases,
clinical findings,
and the absence of the electroencephalogram features typical for CJD.
Similar cases have not been identified in other countries in the European surveillance system.
Interpretatlon These cases appear to represent a new variant of CJD, which may be unique to the UK. This raises the possibility that they are causally linked to BSE. Although this may be the most plausible explanation for this cluster of cases, a link with BSE cannot be confirmed on the basis of this evidence alone. It is essential to obtain further information on the current and past clinical and neuropathological profiles of CJD in the UK and elsewhere.
National CJD Surveillance Unit, Western General Hospital, Edinburgh EH4 2XU, UK (R G Will FRCP, J W lronside MRCPath, M Zeidler MRCP, K Estibeiro BSc); Department of Epidemiology and Population Science, London School of Hyglene and Tropical Medicine, London, UK (S N Cousens Dip Math Stat, Prof P G Smith DSC); INSEAM, Hopital de la Salpetrlere, Paris, France (A Alperovitch MD); Klinik und Poliklinik fur Neurologie, GeorgAugust- Universitat, Gottingen, Germany (S Poser MD); Laboratorio di Virologia, Istituto Superiore di Sanita, Rome, Italy (M Pocchiari MD); Erasmus University, Rotterdam, The Netherlands (Prof A Hofman MD) Correspondence to: Dr R G Will
snip...
Table 1: Known cases of sporadic CJD* in the UK, **1970-96, dying aged less than 45 years
These ten cases (four male) had disease onset from February, 1994, to October, 1995. One came to the attention of the CJD Surveillance Unit in March, 1995, and the other nine between October, 1995, and January, 1996. The ages at death of the eight patients who have died range from 19 to 41 years (median 29). Two patients remain alive at ages 18 and 31 years. Intervals between disease onsets and death range from 7.5 to 22.5 months (median 12). Surviving patients in March, 1996, have disease durations of 6 and 22 months. These patients are relatively young compared with most patients with CJD and their disease duration is relatively long. Among 185 cases of sporadic CJD identified since May, 1990, average age at onset was 65 years and median duration of disease four months; for half of these patients, duration was 2.5 to 6.5 months. Since May, 1990, only two other sporadic cases of CJD with age less than 45 years have been identified, both aged 44 years. These cases had disease onsets in 1993 and 1994; neither showed the neuropathological changes described.
snip...
Clinical course
The clinical course of disease in the ten patients was distinct from that usually seen in sporadic CJD (table 2). Nine had behavioural changes as an early clinical feature and were referred to a psychiatrist. In four patients, an early symptom was dysaesthesiae and in another, pain in the feet persisted throughout the illness. Nine patients developed ataxia early in the course of the disease. While all patients developed progressive dementia, in only two was memory impairment part of initial clinical presentation. Seven of the patients developed myoclonus, often late in the course of the disease, and three had choreoathetosis. None of the cases had the electroencephalographic (EEG) features usually associated with CJD.
With established diagnostic criteria for CJD[6] none of these cases would have been classified as "probable" cases of CJD on clinical grounds. At the time of initial referral to the CJD Surveillance Unit, two patients were classified as definite cases (after brain biopsy) and another as a possible case, while the remaining seven did not fulfil the criteria for even "possible" CJD.
Information on PrP genotype is available for eight cases. All were methionine homozygotes at codon 129 of the PrP gene and none of the known mutations associated with the inherited forms of CJD was identified. In a study of codon 129 genotypes in sporadic CJD in the UK, 1990- 93, 83% of cases (n=111) were methionine homozygotes.
Neuropathological features
Neuropathological examination in all ten cases showed spongiform change and PrP plaques confirming the diagnosis of CJD[6]. In two cases investigated by cerebral biopsy and in the eight necropsy cases, neuropathological features were uniform, with spongiform change in a relatively sparse distribution throughout the cerebral cortex (although all areas were involved to a variable extent in each case who came to necropsy). Spongiform change, neuronal loss, and astrocytosis were most evident in the basal ganglia and thalamus, and were present focally in the cerebrum and cerebellum, most evidently in areas with confluent spongiform change.
The most striking and consistent neuropathological abnormality in all cases was PrP plaques. In the eight necropsy cases, plaques were extensively distributed throughout the cerebrum and cerebellum, with smaller numbers in the basal ganglia, thalamus, and hypothalamus. Many of these plaques resembled kuru-type plaques with a dense eosinophilic centre and pale periphery and, unusually for this type of lesion, were surrounded by a zone of spongiform change (figures 1 and 2). This unusual feature was not seen in any of the other 175 sporadic CJD cases investigated. Similar lesions have, however, been described in scrapie, where they have been referred to as "florid" plaques[7]. Immunocytochemistry for PrP showed strong staining of these plaque-like lesions, but also showed many other smaller plaques, which appeared both as single and multicentric deposits. PrP deposition was also seen in a pericellular distribution in the cerebral cortex and in the molecular layer of the cerebellum, the pattern of which suggested deposition around small neurons (figure 3). Plaque and pericellular PrP deposits occurred throughout the cerebrum and cerebellum, and were clearly visible in the absence of confluent spongiform change in the surrounding neuropil. In the basal ganglia and thalamus, a perivacuolar pattern of PrP staining was also seen, with linear tract- like deposits within the grey matter. PrP plaques were also noted in these regions although there were fewer than in the cerebrum and cerebellum (figure 4).
snip...
PLEASE SEE FULL TEXT ;
http://www.cjd.ed.ac.uk/lancet.htm
and now Gambetti's first 10, that seems to be growing ;
Original Article
Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein
Wen-Quan Zou, MD, PhD 1 *, Gianfranco Puoti, MD, PhD 1, Xiangzhu Xiao, PhD 1, Jue Yuan, BA 1, Liuting Qing, PhD 1, Ignazio Cali, MSc 1, Miyuki Shimoji, PhD 1, Jan P.M. Langeveld, PhD 2, Rudy Castellani, MD 3, Silvio Notari, PhD 1, Barbara Crain, MD 4, Robert E. Schmidt, MD 5, Michael Geschwind, MD 6, Stephen J. DeArmond, MD, PhD 6, Nigel J. Cairns, MD 7, Dennis Dickson, MD 8, Lawrence Honig, MD 9, Juan Maria Torres, PhD 10, James Mastrianni, MD, PhD 11, Sabina Capellari, MD 12, Giorgio Giaccone, MD 13, Ermias D. Belay, MD 14, Lawrence B. Schonberger, MD, MPH 14, Mark Cohen, MD 1, George Perry, PhD 15, Qingzhong Kong, PhD 1, Piero Parchi, MD, PhD 12, Fabrizio Tagliavini, MD 13, Pierluigi Gambetti, MD 1 * 1Department of Pathology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH 2Central Veterinary Institute of Wageningen, Lelystad, the Netherlands 3Department of Neuropathology, University of Maryland Medical Center, Baltimore, MD 4Department of Neuropathology, Johns Hopkins University, Baltimore, MD 5Department of Neuropathology, Washington University, St. Louis, MO 6Department of Pathology, University of California at San Francisco, San Francisco, CA 7Departments of Neurology, Pathology, and Immunology, Washington University, St. Louis, MO 8Department of Neuropathology, Mayo Clinic-Jacksonville, Jacksonville, FL 9New York Presbyterian Hospital, Columbia University, New York, NY 10Centro de Investigación en Sanidad Animal, Madrid, Spain 11Department of Neurology, University of Chicago, Chicago, IL 12Department of Neurological Sciences, University of Bologna, Dipartimento di Scienze Neurologiche, Università di Bologna, Bologna, Italy 13IRCCS Foundation, National Neurological Institute, Instituto Nazionale Neurologico Carlo Besta, Milan, Italy 14Center of Investigation on Animal Health, Centers for Disease Control and Prevention, Atlanta, GA 15College of Science, University of Texas at San Antonio, San Antonio, TX
email: Wen-Quan Zou (wenquan.zou@case.edu) Pierluigi Gambetti (pierluigi.gambetti@case.edu)
*Correspondence to Wen-Quan Zou, Department of Pathology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH
*Correspondence to Pierluigi Gambetti, Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106
Potential Conflicts of Interest Nothing to report.
Funded by: NIH; Grant Number: NIA AG14359, AG08702 NINDS; Grant Number: R01NS062787 Centers for Disease Control and Prevention; Grant Number: CCU 515004 Britton Fund CJD Foundation Alliance BioSecure University Center on Aging and Health with the support of the McGregor Foundation and President's Discretionary Fund (Case Western Reserve University) National Institute on Aging; Grant Number: AG05681
Abstract
Objective: The objective of the study is to report 2 new genotypic forms of protease-sensitive prionopathy (PSPr), a novel prion disease described in 2008, in 11 subjects all homozygous for valine at codon 129 of the prion protein (PrP) gene (129VV). The 2 new PSPr forms affect individuals who are either homozygous for methionine (129MM) or heterozygous for methionine/valine (129MV).
Methods: Fifteen affected subjects with 129MM, 129MV, and 129VV underwent comparative evaluation at the National Prion Disease Pathology Surveillance Center for clinical, histopathologic, immunohistochemical, genotypical, and PrP characteristics.
Results: Disease duration (between 22 and 45 months) was significantly different in the 129VV and 129MV subjects. Most other phenotypic features along with the PrP electrophoretic profile were similar but distinguishable in the 3 129 genotypes. A major difference laid in the sensitivity to protease digestion of the disease-associated PrP, which was high in 129VV but much lower, or altogether lacking, in 129MV and 129MM. This difference prompted the substitution of the original designation with variably protease-sensitive prionopathy (VPSPr). None of the subjects had mutations in the PrP gene coding region.
Interpretation: Because all 3 129 genotypes are involved, and are associated with distinguishable phenotypes, VPSPr becomes the second sporadic prion protein disease with this feature after Creutzfeldt-Jakob disease, originally reported in 1920. However, the characteristics of the abnormal prion protein suggest that VPSPr is different from typical prion diseases, and perhaps more akin to subtypes of Gerstmann-Sträussler-Scheinker disease. ANN NEUROL 2010;68:162-172
--------------------------------------------------------------------------------
Received: 9 March 2010; Revised: 5 May 2010; Accepted: 19 May 2010
Digital Object Identifier (DOI)
10.1002/ana.22094 About DOI
http://www3.interscience.wiley.com/journal/123598302/abstract?CRETRY=1&SRETRY=0
>>> Because 8 out of 10 patients had a positive family history of dementia in the original study, a genetic cause was suspected. Although all cases were homozygous for valine at codon 129 of the PrP gene, NO mutations were detected. <<<
http://creutzfeldt-jakob-disease.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.html
NOW, does this all not look similar to you ? NOW, let's go back further and see some of the political issues ;
2. The Collinge/Will dispute appears to rumble on. Dr. Collinge had told Dr. Tyrrell that Dr. Will's response to his criticism about sharing material had been ''quite unacceptable'' (in spite of it's apparently conciliatory tone). Apparently Professor Allen was now going to try and arrange a meeting to resolve the dispute. No action here for MAFF, although Mr. Murray may be interested.
3. Dr. Tyrrell regretted that the Committee had not seen the article on BBD. However he felt that for the time being NO specific action was called for. The most important need was to consider the possibility that the condition might be transmissible. As we have discussed, I suggested that we might circulate a paper to the members of the committee giving our appreciation of this condition (and perhaps of other non-BSE neurological conditions that had been identified in negative cases) and of any necessary follow up action. IF any Committee member felt strongly about this, or if the issue CAME TO A HEAD, we would call an interim meeting. He was happy with this approach. I would be grateful if Mr. Maslin could, in discussion with CVL and veterinary colleagues draft such a note, which will presumably very largely follow what Mr. Bradley's briefing paper has already said, taking account of DOH comments, We can then clear a final version with DOH before circulating it to Committee members.
http://web.archive.org/web/20030714222309/www.bseinquiry.gov.uk/files/yb/1992/10/29005001.pdf
IN CONFIDENCE
This is a highly competitive field and it really will be a pity if we allow many of the key findings to be published by overseas groups while we are unable to pursue our research findings because of this disagreement, which I hope we can make every effort to solve.
http://web.archive.org/web/20030714222309/www.bseinquiry.gov.uk/files/yb/1992/10/26002001.pdf
COLLINGE THREATENS TO GO TO MEDIA
http://web.archive.org/web/20030714222309/www.bseinquiry.gov.uk/files/yb/1992/12/16005001.pdf
Wednesday, August 20, 2008
Bovine Spongiform Encephalopathy Mad Cow Disease typical and atypical strains, was there a cover-up ? August 20, 2008
http://bse-atypical.blogspot.com/2008/08/bovine-spongiform-encephalopathy-mad.html
Thursday, July 08, 2010
Nosocomial transmission of sporadic Creutzfeldt-Jakob disease: results from a risk-based assessment of surgical interventions Public release date: 8-Jul-2010
http://creutzfeldt-jakob-disease.blogspot.com/2010/07/nosocomial-transmission-of-sporadic.html
Thursday, July 08, 2010
GLOBAL CLUSTERS OF CREUTZFELDT JAKOB DISEASE - A REVIEW 2010
http://creutzfeldt-jakob-disease.blogspot.com/2010/07/global-clusters-of-creutzfeldt-jakob.html
Saturday, July 17, 2010
Variant Creutzfeldt-Jakob disease Ironside JW., Haemophilia. 2010 Jul;16 Suppl 5:175-80 REVIEW ARTICLE
http://vcjdtransfusion.blogspot.com/2010/07/variant-creutzfeldtjakob-disease.html
Sunday, August 09, 2009
CJD...Straight talk with...James Ironside...and...Terry Singeltary... 2009
http://creutzfeldt-jakob-disease.blogspot.com/2009/08/cjdstraight-talk-withjames.html
Tuesday, August 18, 2009
BSE-The Untold Story - joe gibbs and singeltary 1999 - 2009
http://madcowusda.blogspot.com/2009/08/bse-untold-story-joe-gibbs-and.html
****************PLEASE READ THE FOLLOWING CAREFULLY************
To date the OIE/WAHO assumes that the human and animal health standards set out in the BSE chapter for classical BSE (C-Type) applies to all forms of BSE which include the H-type and L-type atypical forms. This assumption is scientifically not completely justified and accumulating evidence suggests that this may in fact not be the case. Molecular characterization and the spatial distribution pattern of histopathologic lesions and immunohistochemistry (IHC) signals are used to identify and characterize atypical BSE. Both the L-type and H-type atypical cases display significant differences in the conformation and spatial accumulation of the disease associated prion protein (PrPSc) in brains of afflicted cattle. Transmission studies in bovine transgenic and wild type mouse models support that the atypical BSE types might be unique strains because they have different incubation times and lesion profiles when compared to C-type BSE. When L-type BSE was inoculated into ovine transgenic mice and Syrian hamster the resulting molecular fingerprint had changed, either in the first or a subsequent passage, from L-type into C-type BSE. In addition, non-human primates are specifically susceptible for atypical BSE as demonstrated by an approximately 50% shortened incubation time for L-type BSE as compared to C-type. Considering the current scientific information available, it cannot be assumed that these different BSE types pose the same human health risks as C-type BSE or that these risks are mitigated by the same protective measures.
http://www.prionetcanada.ca/detail.aspx?menu=5&dt=293380&app=93&cat1=387&tp=20&lk=no&cat2
14th International Congress on Infectious Diseases
H-type and L-type Atypical BSE January 2010 (special pre-congress edition) 18.173 page 189
Experimental Challenge of Cattle with H-type and L-type Atypical BSE
A. Buschmann1, U. Ziegler1, M. Keller1, R. Rogers2, B. Hills3, M.H. Groschup1. 1Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany, 2Health Canada, Bureau of Microbial Hazards, Health Products & Food Branch, Ottawa, Canada, 3Health Canada, Transmissible Spongiform Encephalopathy Secretariat, Ottawa, Canada
Background: After the detection of two novel BSE forms designated H-type and L-type atypical BSE the question of the pathogenesis and the agent distribution of these two types in cattle was fully open. From initial studies of the brain pathology, it was already known that the anatomical distribution of L-type BSE differs from that of the classical type where the obex region in the brainstem always displays the highest PrPSc concentrations. In contrast in L-type BSE cases, the thalamus and frontal cortex regions showed the highest levels of the pathological prion protein, while the obex region was only weakly involved.
Methods:We performed intracranial inoculations of cattle (five and six per group) using 10%brainstemhomogenates of the two German H- and L-type atypical BSE isolates. The animals were inoculated under narcosis and then kept in a free-ranging stable under appropriate biosafety conditions.At least one animal per group was killed and sectioned in the preclinical stage and the remaining animals were kept until they developed clinical symptoms. The animals were examined for behavioural changes every four weeks throughout the experiment following a protocol that had been established during earlier BSE pathogenesis studies with classical BSE.
Results and Discussion: All animals of both groups developed clinical symptoms and had to be euthanized within 16 months. The clinical picture differed from that of classical BSE, as the earliest signs of illness were loss of body weight and depression. However, the animals later developed hind limb ataxia and hyperesthesia predominantly and the head. Analysis of brain samples from these animals confirmed the BSE infection and the atypical Western blot profile was maintained in all animals. Samples from these animals are now being examined in order to be able to describe the pathogenesis and agent distribution for these novel BSE types.
Conclusions: A pilot study using a commercially avaialble BSE rapid test ELISA revealed an essential restriction of PrPSc to the central nervous system for both atypical BSE forms. A much more detailed analysis for PrPSc and infectivity is still ongoing.
http://www.isid.org/14th_icid/
http://ww2.isid.org/Downloads/IMED2009_AbstrAuth.pdf
http://www.isid.org/publications/ICID_Archive.shtml
14th ICID International Scientific Exchange Brochure - Final
Abstract Number: ISE.114
Session: International Scientific Exchange
Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009
T. Singeltary Bacliff, TX, USA
Background: An update on atypical BSE and other TSE in North America. Please remember, the typical U.K. c-BSE, the atypical l-BSE (BASE), and h-BSE have all been documented in North America, along with the typical scrapie's, and atypical Nor-98 Scrapie, and to date, 2 different strains of CWD, and also TME. All these TSE in different species have been rendered and fed to food producing animals for humans and animals in North America (TSE in cats and dogs ?), and that the trading of these TSEs via animals and products via the USA and Canada has been immense over the years, decades.
Methods: 12 years independent research of available data
Results: I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2009. With all the science to date refuting it, to continue to validate this old myth, will only spread this TSE agent through a multitude of potential routes and sources i.e. consumption, medical i.e., surgical, blood, dental, endoscopy, optical, nutritional supplements, cosmetics etc.
Conclusion: I would like to submit a review of past CJD surveillance in the USA, and the urgent need to make all human TSE in the USA a reportable disease, in every state, of every age group, and to make this mandatory immediately without further delay. The ramifications of not doing so will only allow this agent to spread further in the medical, dental, surgical arena's. Restricting the reporting of CJD and or any human TSE is NOT scientific. Iatrogenic CJD knows NO age group, TSE knows no boundaries. I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Gajdusek, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route.
see page 114 ;
http://ww2.isid.org/Downloads/14th_ICID_ISE_Abstracts.pdf
International Society for Infectious Diseases Web:
http://www.isid.org/
I ask Professor Kong ;
Thursday, December 04, 2008 3:37 PM
Subject: RE: re--Chronic Wating Disease (CWD) and Bovine Spongiform Encephalopathies (BSE): Public Health Risk Assessment
''IS the h-BSE more virulent than typical BSE as well, or the same as cBSE, or less virulent than cBSE? just curious.....''
Professor Kong reply ;
.....snip
''As to the H-BSE, we do not have sufficient data to say one way or another, but we have found that H-BSE can infect humans. I hope we could publish these data once the study is complete. Thanks for your interest.''
Best regards,
Qingzhong Kong, PhD Associate Professor Department of Pathology Case Western Reserve University Cleveland, OH 44106 USA
END...TSS
P.4.23
Transmission of atypical BSE in humanized mouse models
Liuting Qing1, Wenquan Zou1, Cristina Casalone2, Martin Groschup3, Miroslaw Polak4, Maria Caramelli2, Pierluigi Gambetti1, Juergen Richt5, Qingzhong Kong1 1Case Western Reserve University, USA; 2Instituto Zooprofilattico Sperimentale, Italy; 3Friedrich-Loeffler-Institut, Germany; 4National Veterinary Research Institute, Poland; 5Kansas State University (Previously at USDA National Animal Disease Center), USA
Background: Classical BSE is a world-wide prion disease in cattle, and the classical BSE strain (BSE-C) has led to over 200 cases of clinical human infection (variant CJD). Atypical BSE cases have been discovered in three continents since 2004; they include the L-type (also named BASE), the H-type, and the first reported case of naturally occurring BSE with mutated bovine PRNP (termed BSE-M). The public health risks posed by atypical BSE were largely undefined.
Objectives: To investigate these atypical BSE types in terms of their transmissibility and phenotypes in humanized mice. Methods: Transgenic mice expressing human PrP were inoculated with several classical (C-type) and atypical (L-, H-, or Mtype) BSE isolates, and the transmission rate, incubation time, characteristics and distribution of PrPSc, symptoms, and histopathology were or will be examined and compared.
Results: Sixty percent of BASE-inoculated humanized mice became infected with minimal spongiosis and an average incubation time of 20-22 months, whereas only one of the C-type BSE-inoculated mice developed prion disease after more than 2 years. Protease-resistant PrPSc in BASE-infected humanized Tg mouse brains was biochemically different from bovine BASE or sCJD. PrPSc was also detected in the spleen of 22% of BASE-infected humanized mice, but not in those infected with sCJD. Secondary transmission of BASE in the humanized mice led to a small reduction in incubation time. The atypical BSE-H strain is also transmissible with distinct phenotypes in the humanized mice, but no BSE-M transmission has been observed so far.
Discussion: Our results demonstrate that BASE is more virulent than classical BSE, has a lymphotropic phenotype, and displays a modest transmission barrier in our humanized mice. BSE-H is also transmissible in our humanized Tg mice. The possibility of more than two atypical BSE strains will be discussed.
Supported by NINDS NS052319, NIA AG14359, and NIH AI 77774.
http://www.prion2009.com/sites/default/files/Prion2009_Book_of_Abstracts.pdf
P02.35
Molecular Features of the Protease-resistant Prion Protein (PrPres) in H-type BSE
Biacabe, A-G1; Jacobs, JG2; Gavier-Widén, D3; Vulin, J1; Langeveld, JPM2; Baron, TGM1 1AFSSA, France; 2CIDC-Lelystad, Netherlands; 3SVA, Sweden
Western blot analyses of PrPres accumulating in the brain of BSE-infected cattle have demonstrated 3 different molecular phenotypes regarding to the apparent molecular masses and glycoform ratios of PrPres bands. We initially described isolates (H-type BSE) essentially characterized by higher PrPres molecular mass and decreased levels of the diglycosylated PrPres band, in contrast to the classical type of BSE. This type is also distinct from another BSE phenotype named L-type BSE, or also BASE (for Bovine Amyloid Spongiform Encephalopathy), mainly characterized by a low representation of the diglycosylated PrPres band as well as a lower PrPres molecular mass. Retrospective molecular studies in France of all available BSE cases older than 8 years old and of part of the other cases identified since the beginning of the exhaustive surveillance of the disease in 20001 allowed to identify 7 H-type BSE cases, among 594 BSE cases that could be classified as classical, L- or H-type BSE. By Western blot analysis of H-type PrPres, we described a remarkable specific feature with antibodies raised against the C-terminal region of PrP that demonstrated the existence of a more C-terminal cleaved form of PrPres (named PrPres#2 ), in addition to the usual PrPres form (PrPres #1). In the unglycosylated form, PrPres #2 migrates at about 14 kDa, compared to 20 kDa for PrPres #1. The proportion of the PrPres#2 in cattle seems to by higher compared to the PrPres#1. Furthermore another PK–resistant fragment at about 7 kDa was detected by some more N-terminal antibodies and presumed to be the result of cleavages of both N- and C-terminal parts of PrP. These singular features were maintained after transmission of the disease to C57Bl/6 mice. The identification of these two additional PrPres fragments (PrPres #2 and 7kDa band) reminds features reported respectively in sporadic Creutzfeldt-Jakob disease and in Gerstmann-Sträussler-Scheinker (GSS) syndrome in humans.
http://www.neuroprion.com/pdf_docs/conferences/prion2007/abstract_book.pdf
Wednesday, March 31, 2010
Atypical BSE in Cattle
http://bse-atypical.blogspot.com/2010/03/atypical-bse-in-cattle-position-post.html
Thursday, June 24, 2010
Accumulation of L-type Bovine Prions in Peripheral Nerve Tissues
Volume 16, Number 7–July 2010
http://bse-atypical.blogspot.com/2010/06/accumulation-of-l-type-bovine-prions-in.html
******$$$$$$******
Saturday, June 12, 2010 PUBLICATION REQUEST AND FOIA REQUEST Project Number: 3625-32000-086-05 Study of Atypical Bse
http://bse-atypical.blogspot.com/2010/06/publication-request-and-foia-request.html
*******$$$$$$*********
Archive Number 20100405.1091 Published Date 05-APR-2010 Subject PRO/AH/EDR> Prion disease update 1010 (04)
snip...
[Terry S. Singeltary Sr. has added the following comment:
"According to the World Health Organisation, the future public health threat of vCJD in the UK and Europe and potentially the rest of the world is of concern and currently unquantifiable. However, the possibility of a significant and geographically diverse vCJD epidemic occurring over the next few decades cannot be dismissed
The key word here is diverse. What does diverse mean? If USA scrapie transmitted to USA bovine does not produce pathology as the UK c-BSE, then why would CJD from there look like UK vCJD?"
http://www.promedmail.org/pls/apex/f?p=2400:1001:568933508083034::NO::F2400_P1001_BACK_PAGE,F2400_P1001_PUB_MAIL_ID:1000,82101
> Up until about 6 years ago, the pt worked at Tyson foods where she
> worked on the assembly line, slaughtering cattle and preparing them for
> packaging. She was exposed to brain and spinal cord matter when she
> would euthanize the cattle.
http://www.recordandoalinda.com/index.php?option=com_content&view=article&id=19:cjd-english-info&catid=9:cjd-ingles&Itemid=8
CJD TEXAS 38 YEAR OLD FEMALE WORKED SLAUGHTERING CATTLE EXPOSED TO BRAIN AND SPINAL CORD MATTER
http://cjdtexas.blogspot.com/2010/03/cjd-texas-38-year-old-female-worked.html
Monday, April 5, 2010
UPDATE - CJD TEXAS 38 YEAR OLD FEMALE WORKED SLAUGHTERING CATTLE EXPOSED TO BRAIN AND SPINAL CORD MATTER
http://prionunitusaupdate2008.blogspot.com/2010/04/update-cjd-texas-38-year-old-female.html
re-National Prion Disease Pathology Surveillance Center Cases Examined1 (July 31, 2010)
i never saw this posted on the CJD Foundation site, or Gambetti's USA prion unit site ???
please see video at _bottom_ of this link that i added this morning (turn it up).
a damning and disturbing video.
its an old video about Scjd, and the possibility of BSE being relating to sporadic CJD. Jeff Schwann and his Mother (Terry), is also in this video, and listen to Aguzzi and how he admits that sporadic CJD might very well be caused by BSE. then an Italian Scientist is talking about atypical BSE, and the fact that this atypical BSE is exactly like sporadic CJD. a shocking find. ...atypical BSE has the exact same pathological and molecular similarities as sporadic CJD. Dr. Aguzzi says the USA is not trying to find BSE. the USA, and North America, refused for many years to put any kind of surveillance for BSE, this is a huge problem, a disgrace, particularly cries to Heaven, USA HAD TO ADMIT A HOME GROWN CASE OF MAD COW IN TEXAS. sCJD under estimated, no mechanisim to find cases, we ARE missing lots of cases. ...WE WANT ANSWERS. ...(Thanks Terry Schwann !)
National Prion Disease Pathology Surveillance Center Cases Examined1 (July 31, 2010)
TURN IT UP, and click on the video at the bottom of this link ;
http://prionunitusaupdate.blogspot.com/2010/08/national-prion-disease-pathology.html
Tuesday, June 1, 2010
USA cases of dpCJD rising with 24 cases so far in 2010
http://cjdtexas.blogspot.com/2010/06/usa-cases-of-dpcjd-rising-with-24-cases.html
Sunday, July 11, 2010
CJD or prion disease 2 CASES McLennan County Texas population 230,213 both cases in their 40s
http://creutzfeldt-jakob-disease.blogspot.com/2010/07/cjd-2-cases-mclennan-county-texas.html
Friday, February 05, 2010
New Variant Creutzfelt Jakob Disease case reports United States 2010 A Review
http://vcjd.blogspot.com/2010/02/new-variant-creutzfelt-jakob-disease.html
Manuscript Draft Manuscript Number: Title: HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory Article Type: Personal View Corresponding Author: Mr. Terry S. Singeltary, Corresponding Author's Institution: na First Author: Terry S Singeltary, none Order of Authors: Terry S Singeltary, none; Terry S. Singeltary
Abstract: TSEs have been rampant in the USA for decades in many species, and they all have been rendered and fed back to animals for human/animal consumption. I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2007.
http://www.regulations.gov/fdmspublic/ContentViewer?objectId=090000648027c28e&disposition=attachment&contentType=pdf
Saturday, June 13, 2009
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States 2003 revisited 2009
http://cjdusa.blogspot.com/2009/06/monitoring-occurrence-of-emerging-forms.html
Saturday, January 2, 2010
Human Prion Diseases in the United States January 1, 2010 ***FINAL***
http://prionunitusaupdate.blogspot.com/2010/01/human-prion-diseases-in-united-states.html
my comments to PLosone here ;
http://www.plosone.org/annotation/listThread.action?inReplyTo=info%3Adoi%2F10.1371%2Fannotation%2F04ce2b24-613d-46e6-9802-4131e2bfa6fd&root=info%3Adoi%2F10.1371%2Fannotation%2F04ce2b24-613d-46e6-9802-4131e2bfa6fd
HOW many of you recieved a written CJD Questionnaire asking real questions pertaining to route and source (and there are many here in North America) ?
IS every case getting a cjd questionnaire asking real questions ???
Friday, November 30, 2007
CJD QUESTIONNAIRE USA CWRU AND CJD FOUNDATION USA PRION UNIT
http://cjdquestionnaire.blogspot.com/
nope, they cannot have there cake and eat it too. the big pond just does not change science that much. either Ironside was wrong, or Gambetti is wrong. i do NOT believe this mad cow cloaking devise the USA apparently has $$$
Tuesday, August 03, 2010
Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein
http://creutzfeldt-jakob-disease.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.html
WHAT about the enfamous partial and voluntary mad cow feed ban in the USA of August 4, 1997, the one that was nothing more than ink on paper, and ramifications there from? what about all that mad cow feed in commerce in the USA to 2010 ;
10,000,000+ LBS. of PROHIBITED BANNED MAD COW FEED I.E. BLOOD LACED MBM IN COMMERCE USA 2007
Date: March 21, 2007 at 2:27 pm PST
RECALLS AND FIELD CORRECTIONS: VETERINARY MEDICINES -- CLASS II
___________________________________
PRODUCT
Bulk cattle feed made with recalled Darling's 85% Blood Meal, Flash Dried, Recall # V-024-2007
CODE
Cattle feed delivered between 01/12/2007 and 01/26/2007
RECALLING FIRM/MANUFACTURER
Pfeiffer, Arno, Inc, Greenbush, WI. by conversation on February 5, 2007.
Firm initiated recall is ongoing.
REASON
Blood meal used to make cattle feed was recalled because it was cross- contaminated with prohibited bovine meat and bone meal that had been manufactured on common equipment and labeling did not bear cautionary BSE statement.
VOLUME OF PRODUCT IN COMMERCE
42,090 lbs.
DISTRIBUTION
WI
___________________________________
PRODUCT
Custom dairy premix products: MNM ALL PURPOSE Pellet, HILLSIDE/CDL Prot- Buffer Meal, LEE, M.-CLOSE UP PX Pellet, HIGH DESERT/ GHC LACT Meal, TATARKA, M CUST PROT Meal, SUNRIDGE/CDL PROTEIN Blend, LOURENZO, K PVM DAIRY Meal, DOUBLE B DAIRY/GHC LAC Mineral, WEST PIONT/GHC CLOSEUP Mineral, WEST POINT/GHC LACT Meal, JENKS, J/COMPASS PROTEIN Meal, COPPINI - 8# SPECIAL DAIRY Mix, GULICK, L-LACT Meal (Bulk), TRIPLE J - PROTEIN/LACTATION, ROCK CREEK/GHC MILK Mineral, BETTENCOURT/GHC S.SIDE MK-MN, BETTENCOURT #1/GHC MILK MINR, V&C DAIRY/GHC LACT Meal, VEENSTRA, F/GHC LACT Meal, SMUTNY, A- BYPASS ML W/SMARTA, Recall # V-025-2007
CODE
The firm does not utilize a code - only shipping documentation with commodity and weights identified.
RECALLING FIRM/MANUFACTURER
Rangen, Inc, Buhl, ID, by letters on February 13 and 14, 2007. Firm initiated recall is complete.
REASON
Products manufactured from bulk feed containing blood meal that was cross contaminated with prohibited meat and bone meal and the labeling did not bear cautionary BSE statement.
VOLUME OF PRODUCT IN COMMERCE
9,997,976 lbs.
DISTRIBUTION
ID and NV
END OF ENFORCEMENT REPORT FOR MARCH 21, 2007
http://www.fda.gov/Safety/Recalls/EnforcementReports/2007/ucm120446.htm
Tuesday, March 2, 2010
Animal Proteins Prohibited in Ruminant Feed/Adulterated/Misbranded Rangen Inc 2/11/10 USA
http://madcowfeed.blogspot.com/2010/03/animal-proteins-prohibited-in-ruminant.html
Monday, March 1, 2010
ANIMAL PROTEIN I.E. MAD COW FEED IN COMMERCE A REVIEW 2010
http://madcowfeed.blogspot.com/2010/03/animal-protien-ie-mad-cow-feed-in.html
Terry S. Singeltary Sr. (Submitted question): Monday, April 5, 2010
Update on Feed Enforcement Activities to Limit the Spread of BSE April 5, 2010
http://madcowfeed.blogspot.com/2010/04/update-on-feed-enforcement-activities.html
Friday, April 23, 2010
Upcoming BSE Webinar on Thursday, April 22, 2010 a review
http://bseusa.blogspot.com/2010/04/upcoming-bse-webinar-on-thursday-april.html
Sunday, January 17, 2010
BSE USA feed inspection violations 01/01/2009 to 01/17/2010 FDA BSE/Ruminant Feed Inspections Firms Inventory Report
http://madcowfeed.blogspot.com/2010/01/bse-usa-feed-inspection-violations.html
Friday, January 15, 2010
New York Firm Recalls Beef Carcass That Contains Prohibited Materials (BSE)
http://bse-atypical.blogspot.com/2010/01/new-york-firm-recalls-beef-carcass-that.html
Friday, September 4, 2009
FOIA REQUEST ON FEED RECALL PRODUCT 429,128 lbs. feed for ruminant animals may have been contaminated with prohibited material Recall # V-258-2009
http://madcowfeed.blogspot.com/2009/09/foia-request-on-feed-recall-product.html
Saturday, August 29, 2009
FOIA REQUEST FEED RECALL 2009 Product may have contained prohibited materials Bulk Whole Barley, Recall # V-256-2009
http://madcowfeed.blogspot.com/2009/08/foia-request-feed-recall-2009-product.html
C O N F I R M E D
----- Original Message -----
From: "Terry S. Singeltary Sr."
To:
Sent: Thursday, November 05, 2009 9:25 PM
Subject: [BSE-L] re-FOIA REQUEST ON FEED RECALL PRODUCT contaminated with prohibited material Recall # V-258-2009 and Recall # V-256-2009
http://madcowfeed.blogspot.com/2009/11/re-foia-request-on-feed-recall-product.html
Thursday, November 12, 2009
BSE FEED RECALL Misbranding of product by partial label removal to hide original source of materials 2009
http://madcowfeed.blogspot.com/2009/11/bse-feed-recall-misbranding-of-product.html
Thursday, March 19, 2009
MILLIONS AND MILLIONS OF POUNDS OF MAD COW FEED IN COMMERCE USA WITH ONGOING 12 YEARS OF DENIAL
http://madcowfeed.blogspot.com/2009/03/millions-and-millions-of-pounds-of-mad.html
CVM Annual Report Fiscal Year 2008: October 1, 2007-September 30, 2008
PUTTING LIPSTICK ON A PIG AND TAKING HER TO A DANCE...TSS
BSE Feed Rule Enforcement: A Decade of Success OFF TO A FAST START
http://madcowfeed.blogspot.com/2008/06/texas-firm-recalls-cattle-heads-that.html
Thursday, April 9, 2009
Docket No. FDA2002N0031 (formerly Docket No. 2002N0273) RIN 0910AF46 Substances Prohibited From Use in Animal Food or Feed; Final Rule: Proposed
http://madcowfeed.blogspot.com/2009/04/docket-no-fda2002n0031-formerly-docket.html
P03.137
Transmission of BSE to Cynomolgus Macaque, a Non-human Primate; Development of Clinical Symptoms and Tissue Distribution of PrPSC
Yamakawa, Y1; Ono, F2; Tase, N3; Terao, K3; Tannno, J3; Wada, N4; Tobiume, M5; Sato, Y5; Okemoto-Nakamura, Y1; Hagiwara, K1; Sata, T5 1National Institure of Infectious diseases, Cell biology and Biochemistry, Japan; 2Corporation for Production and Research Laboratory Primates., Japan; 3National Institure of Biomedical Innovation, Tsukuba Primate Reserch Center, Japan; 4Yamauchi Univ., Veterinary Medicine, Japan; 5National Institure of Infectious diseases, Pathology, Japan
Two of three cynomolgus monkeys developed abnormal neuronal behavioral signs at 30-(#7) and 28-(#10) months after intracerebral inoculation of 200ul of 10% brain homogenates of BSE affected cattle (BSE/JP6). Around 30 months post inoculation (mpi), they developed sporadic anorexia and hyperekplexia with squeal against environmental stimulations such as light and sound. Tremor, myoclonic jerk and paralysis became conspicuous during 32 to 33-mpi, and symptoms become worsened according to the disease progression. Finally, one monkey (#7) fell into total paralysis at 36-mpi. This monkey was sacrificed at 10 days after intensive veterinary care including infusion and per oral supply of liquid food. The other monkey (#10) had to grasp the cage bars to keep an upright posture caused by the sever ataxia. This monkey was sacrificed at 35-mpi. EEG of both monkeys showed diffuse slowing. PSD characteristic for sporadic CJD was not observed in both monkeys. The result of forearm movement test showed the hypofunction that was observed at onset of clinical symptoms. Their cognitive function determined by finger maze test was maintained at the early stage of sideration. However, it was rapidly impaired followed by the disease progression. Their autopsied tissues were immunochemically investigated for the tissue distribution of PrPSc. Severe spongiform change in the brain together with heavy accumulation of PrPSc having the type 2B/4 glycoform profile confirmed successful transmission of BSE to Cynomolgus macaques. Granular and linear deposition of PrPSC was detected by IHC in the CNS of both monkeys. At cerebral cortex, PrPSC was prominently accumulated in the large plaques. Sparse accumulation of PrPSc was detected in several peripheral nerves of #7 but not in #10 monkey, upon the WB analysis. Neither #7 nor #10 monkey accumulated detectable amounts of PrPSc in their lymphatic organs such as tonsil, spleen, adrenal grands and thymus although PrPSc was barely detected in the submandibular lymph node of #7 monkey. Such confined tissue distribution of PrPSc after intracerebral infection with BSE agent is not compatible to that reported on the Cynomolgus macaques infected with BSE by oral or intra-venous (intra-peritoneal) routs, in which PrPSc was accumulated at not only CNS but also widely distributed lymphatic tissues.
P03.138
Clustering of PrPres in Central Brain Regions of BSE-infected Macaques (M. Fascicularis)
Motzkus, D1; Montag, J1; Hunsmann, G1; Schulz-Schaeffer, W2 1German Primate Center, Dept. Virology and Immunology, Germany; 2University of Göttingen, Dept. Neuropathology, Germany
According to biochemical and epidemiological findings bovine spongiform encephalopathy (BSE) was transmitted to humans causing variant Creutzfeldt Jakob disease (vCJD). Previous studies have shown intracerebral (i.c.) transmission of BSE affected brain from cattle can cause TSEs in cynomolgus macaques (M. fascicularis). The lesion profile resembles that of vCJD. Recently, oral infection of M. fascicularis with macaque-adapted BSE material was reported. In cooperation with five European partners a quantitative study for the transmission of the BSE agent to M. fascicularis was initiated to assess the risk of vCJD infection in humans through contaminated food products (EU study QLK1-CT-2002-01096). Titration was performed orally and intracerebrally to determine the minimal infectious dose for cynomolgus monkeys. Here we report the outcome of the intracerebral infection with 50 mg BSE brain homogenate in six non-human primates. All animals showed clinical symptoms of TSE after an average of 1100 days. Using immunohistological and biochemical methods prion protein (PrP) deposits were confirmed in the brains of all animals. Using Western blot analysis the glycosylation pattern was compared to the inoculum and to the pattern of different CJD subtypes. Simian PrPres was detected with the monoclonal anti prion antibody 11C6, which revealed a higher sensitivity in comparison to 12F10 and 3F4. We found that the PrP glycopattern in BSE-infected cynomolgus macaques resembles human CJD type 2. We further analysed the distribution of PrPres by microdissection of seven different brain regions of all infected macaques. High concentrations of PrPres were detected in central brain regions, as gyrus cinguli, nucleus caudatus, vermis cerebelli and basis pontis. In contrast, in the peripheral regions gyrus frontalis, gyrus parietalis and gyrus occipitalis PrPres was hardly detectable.
Thus, the incubation period related to the life expectancy, the PrPres glycosylation pattern as well as the distribution in certain brain regions resemble those in vCJD patients. The relative abundance of PrPres in macaques will be compared to that of orally infected animals.
P04.27
Experimental BSE Infection of Non-human Primates: Efficacy of the Oral Route
Holznagel, E1; Yutzy, B1; Deslys, J-P2; Lasmézas, C2; Pocchiari, M3; Ingrosso, L3; Bierke, P4; Schulz-Schaeffer, W5; Motzkus, D6; Hunsmann, G6; Löwer, J1 1Paul-Ehrlich-Institut, Germany; 2Commissariat à l´Energie Atomique, France; 3Instituto Superiore di Sanità, Italy; 4Swedish Institute for Infectious Disease control, Sweden; 5Georg August University, Germany; 6German Primate Center, Germany
Background: In 2001, a study was initiated in primates to assess the risk for humans to contract BSE through contaminated food. For this purpose, BSE brain was titrated in cynomolgus monkeys.
Aims: The primary objective is the determination of the minimal infectious dose (MID50) for oral exposure to BSE in a simian model, and, by in doing this, to assess the risk for humans. Secondly, we aimed at examining the course of the disease to identify possible biomarkers.
Methods: Groups with six monkeys each were orally dosed with lowering amounts of BSE brain: 16g, 5g, 0.5g, 0.05g, and 0.005g. In a second titration study, animals were intracerebrally (i.c.) dosed (50, 5, 0.5, 0.05, and 0.005 mg).
Results: In an ongoing study, a considerable number of high-dosed macaques already developed simian vCJD upon oral or intracerebral exposure or are at the onset of the clinical phase. However, there are differences in the clinical course between orally and intracerebrally infected animals that may influence the detection of biomarkers.
Conclusions: Simian vCJD can be easily triggered in cynomolgus monkeys on the oral route using less than 5 g BSE brain homogenate. The difference in the incubation period between 5 g oral and 5 mg i.c. is only 1 year (5 years versus 4 years). However, there are rapid progressors among orally dosed monkeys that develop simian vCJD as fast as intracerebrally inoculated animals.
The work referenced was performed in partial fulfilment of the study “BSE in primates“ supported by the EU (QLK1-2002-01096).
http://www.neuroprion.org/resources/pdf_docs/conferences/prion2007/abstract_book.pdf
PRION 2009 CONGRESS BOOK OF ABSTRACTS
O.4.3
Spread of BSE prions in cynomolgus monkeys (Macaca fascicularis) after oral transmission
Edgar Holznagel1, Walter Schulz-Schaeffer2, Barbara Yutzy1, Gerhard Hunsmann3, Johannes Loewer1 1Paul-Ehrlich-Institut, Federal Institute for Sera and Vaccines, Germany; 2Department of Neuropathology, Georg-August University, Göttingen, Germany, 3Department of Virology and Immunology, German Primate Centre, Göttingen, Germany
Background: BSE-infected cynomolgus monkeys represent a relevant animal model to study the pathogenesis of variant Creutzfeldt-Jacob disease (vCJD).
Objectives: To study the spread of BSE prions during the asymptomatic phase of infection in a simian animal model.
Methods: Orally BSE-dosed macaques (n=10) were sacrificed at defined time points during the incubation period and 7 orally BSE-dosed macaques were sacrificed after the onset of clinical signs. Neuronal and non-neuronal tissues were tested for the presence of proteinase-K-resistant prion protein (PrPres) by western immunoblot and by paraffin-embedded tissue (PET) blot technique.
Results: In clinically diseased macaques (5 years p.i. + 6 mo.), PrPres deposits were widely spread in neuronal tissues (including the peripheral sympathetic and parasympathetic nervous system) and in lymphoid tissues including tonsils. In asymptomatic disease carriers, PrPres deposits could be detected in intestinal lymph nodes as early as 1 year p.i., but CNS tissues were negative until 3 – 4 years p.i. Lumbal/sacral segments of the spinal cord and medulla oblongata were PrPres positive as early as 4.1 years p.i., whereas sympathetic trunk and all thoracic/cervical segments of the spinal cord were still negative for PrPres. However, tonsil samples were negative in all asymptomatic cases.
Discussion: There is evidence for an early spread of BSE to the CNS via autonomic fibres of the splanchnic and vagus nerves indicating that trans-synaptical spread may be a time-limiting factor for neuroinvasion. Tonsils were predominantly negative during the main part of the incubation period indicating that epidemiological vCJD screening results based on the detection of PrPres in tonsil biopsies may mostly tend to underestimate the prevalence of vCJD among humans.
O.4.4
PrPSc distribution pattern in cattle experimentally challenged with H-type and L-type atypical BSE
Anne Buschmann1, Ute Ziegler1, Leila McIntyre2, Markus Keller1, Ron Rogers3, Bob Hills3, Martin H. Groschup1 1Friedrich-Loeffler-Institut, INEID, Germany; 2Faculty of Veterinary Medicine, University of Calgary, Canada; 3Health Canada, Ottawa, Canada
Background: After the detection of two novel BSE forms designated H-type and L-type BSE, the question of the pathogenesis and the agent distribution in cattle affected with these forms was fully open. From initial studies, it was already known that the PrPSc distribution in L-type BSE affected cattle differed from that known for classical BSE (C-type) where the obex region always displays the highest PrPSc concentrations. In contrast in L-type BSE cases, the thalamus and frontal cortex regions showed the highest levels of the pathological prion protein, while the obex region was only weakly involved. No information was available on the distribution pattern in H-type BSE.
Objectives: To analyse the PrPSc and infectivity distribution in cattle experimentally challenged with H-type and L-type BSE.
Methods: We analysed CNS and peripheral tissue samples collected from cattle that were intracranially challenged with Htype (five animals) and L-type (six animals) using a commercial BSE rapid test (IDEXX HerdChek), immunohistochemistry (IHC) and a highly sensitive Western blot protocol including a phosphotungstic acid precipitation of PrPSc (PTA-WB). Samples collected during the preclinical and the clinical stages of the disease were examined. For the detection of BSE infectivity, selected samples were also inoculated into highly sensitive Tgbov XV mice overexpressing bovine prion protein (PrPC).
Results: Analysis of a collection of fifty samples from the peripheral nervous, lymphoreticular, digestive, reproductive, respiratory and musculo-skeletal systems by PTA-WB, IDEXXHerdChek BSE EIA and IHC revealed a general restriction of the PrPSc accumulation to the central nervous system.
Discussion: Our results on the PrPSc distribution in peripheral tissues of cattle affected with H-type and L-type BSE are generally in accordance with what has been known for C-type BSE. Bioassays are ongoing in highly sensitive transgenic mice in order to reveal infectivity.
O.11.3
Infectivity in skeletal muscle of BASE-infected cattle
Silvia Suardi1, Chiara Vimercati1, Fabio Moda1, Ruggerone Margherita1, Ilaria Campagnani1, Guerino Lombardi2, Daniela Gelmetti2, Martin H. Groschup3, Anne Buschmann3, Cristina Casalone4, Maria Caramelli4, Salvatore Monaco5, Gianluigi Zanusso5, Fabrizio Tagliavini1 1Carlo Besta” Neurological Institute,Italy; 2IZS Brescia, Italy; 33FLI Insel Riems, D, Germany; 4CEA-IZS Torino, Italy; 5University of Verona, Italy
Background: BASE is an atypical form of bovine spongiform encephalopathy caused by a prion strain distinct from that of BSE. Upon experimental transmission to cattle, BASE induces a previously unrecognized disease phenotype marked by mental dullness and progressive atrophy of hind limb musculature. Whether affected muscles contain infectivity is unknown. This is a critical issue since the BASE strain is readily transmissible to a variety of hosts including primates, suggesting that humans may be susceptible.
Objectives: To investigate the distribution of infectivity in peripheral tissues of cattle experimentally infected with BASE. Methods: Groups of Tg mice expressing bovine PrP (Tgbov XV, n= 7-15/group) were inoculated both i.c. and i.p. with 10% homogenates of a variety of tissues including brain, spleen, cervical lymph node, kidney and skeletal muscle (m. longissimus dorsi) from cattle intracerebrally infected with BASE. No PrPres was detectable in the peripheral tissues used for inoculation either by immunohistochemistry or Western blot.
Results: Mice inoculated with BASE-brain homogenates showed clinical signs of disease with incubation and survival times of 175±15 and 207±12 days. Five out of seven mice challenged with skeletal muscle developed a similar neurological disorder, with incubation and survival times of 380±11 and 410±12 days. At present (700 days after inoculation) mice challenged with the other peripheral tissues are still healthy. The neuropathological phenotype and PrPres type of the affected mice inoculated either with brain or muscle were indistinguishable and matched those of Tgbov XV mice infected with natural BASE.
Discussion: Our data indicate that the skeletal muscle of cattle experimentally infected with BASE contains significant amount of infectivity, at variance with BSE-affected cattle, raising the issue of intraspecies transmission and the potential risk for humans. Experiments are in progress to assess the presence of infectivity in skeletal muscles of natural BASE.
P.5.3
Differences in the expression levels of selected genes in the brain tissue of cattle naturally infected with classical and atypical BSE.
Magdalena Larska1, Miroslaw P. Polak1, Jan F. Zmudzinski1, Juan M. Torres2 1National Veterinary Institute, Poland; 2CISA/INIA
Background: Recently cases of BSE in older cattle named BSE type L and type H were distinguished on the basis of atypical glycoprofiles of PrPres. The nature of those strains is still not fully understood but it is suspected that the atypical BSE cases are sporadic. Hitherto most BSE cases were studied in respect to the features of PrPSc. Here we propose gene expression profiling as a method to characterize and distinguish BSE strains.
Objectives: The aim of the study was to compare the activities of some factors which are known to play a role in TSE’s pathogenesis in order to distinguish the differences/similarities between all BSE types.
Methods: 10 % homogenate of brain stem tissue collected from obex region of medulla oblongata from 20 naturally infected BSE cows (8 assigned as classical BSE, other 8 and 4 infected with atypical BSE L type and H type respectively) was used in the study. As negative control animals we’ve used 8 animals in the age between 2.5 and 13 years. The genes were relatively quantified using SYBR Green real time RT-PCR. Raw data of Ct values was transformed into normalized relative quantities using Qbase Plus®. Results and
Discussion: In most of the tested genes significant differences in the expression levels between the brain stem of healthy cattle and animals infected with different BSE types were observed. In c-type BSE in comparison to healthy and atypical BSE the overexpression of the gene of bcl-2, caspase 3, 14-3-3 and tylosine kinase Fyn was significant.
Simultaneously in atypical BSEs type-L and type-H the levels of prion protein, Bax and LPR gene was elevated in comparison to c-BSE. Additionally L-BSE was characterized by the overexpression of STI1 and SOD genes compared to the other of BSE types. The downregulation of the gene encoding NCAM1 was observed in all BSE types in comparison to healthy cows. Different gene expression profiles of bovine brains infected with classical and atypical BSE indicates possible different pathogenesis or source of the disease.
O.10.1
Transmission of uncommon forms of bovine prions to transgenic mice expressing human PrP: questions and progress
Vincent Béringue, Hubert Laude INRA, UR 892, Virologie Immunologie Moléculaires, France
The active, large-scale testing of livestock nervous tissues for the presence of protease-resistant prion protein (PrPres) has led to the recognition of 2 uncommon PrPres molecular signatures, termed H-type and L-type BSE. Their experimental transmission to various transgenic and inbred mouse lines unambiguously demonstrated the infectious nature of such cases and the existence of distinct prion strains in cattle. Like the classical BSE agent, H- and L-type (or BASE) prions can propagate in heterologous species. In addition L-type prions acquire molecular and neuropathologic phenotypic traits undistinguishable from BSE or BSE-related agents upon transmission to transgenic mice expressing ovine PrP (VRQ allele) or wild-type mice. An understanding of the transmission properties of these newly recognized prions when confronted with human PrP sequence was therefore needed. Toward this end, we inoculated mice expressing human PrP Met129 with several field isolates. Unlike classical BSE agent, L-type prions appeared to propagate in these mice with no obvious transmission barrier. In contrast, we repeatedly failed to infect them with Htype prions. Ongoing investigations aim to extend the knowledge on these uncommon strains: are these agents able to colonize lymphoid tissue, a potential key factor for successful transmission by peripheral route; is there any relationship between these assumedly sporadic forms of TSE in cattle and some sporadic forms of human CJD are among the issues that need to be addressed for a careful assessment of the risk for cattle-to-human transmission of H- and L-type prions.
P.4.23
Transmission of atypical BSE in humanized mouse models
Liuting Qing1, Wenquan Zou1, Cristina Casalone2, Martin Groschup3, Miroslaw Polak4, Maria Caramelli2, Pierluigi Gambetti1, Juergen Richt5, Qingzhong Kong1 1Case Western Reserve University, USA; 2Instituto Zooprofilattico Sperimentale, Italy; 3Friedrich-Loeffler-Institut, Germany; 4National Veterinary Research Institute, Poland; 5Kansas State University (Previously at USDA National Animal Disease Center), USA
Background: Classical BSE is a world-wide prion disease in cattle, and the classical BSE strain (BSE-C) has led to over 200 cases of clinical human infection (variant CJD). Atypical BSE cases have been discovered in three continents since 2004; they include the L-type (also named BASE), the H-type, and the first reported case of naturally occurring BSE with mutated bovine PRNP (termed BSE-M). The public health risks posed by atypical BSE were largely undefined.
Objectives: To investigate these atypical BSE types in terms of their transmissibility and phenotypes in humanized mice. Methods: Transgenic mice expressing human PrP were inoculated with several classical (C-type) and atypical (L-, H-, or Mtype) BSE isolates, and the transmission rate, incubation time, characteristics and distribution of PrPSc, symptoms, and histopathology were or will be examined and compared.
Results: Sixty percent of BASE-inoculated humanized mice became infected with minimal spongiosis and an average incubation time of 20-22 months, whereas only one of the C-type BSE-inoculated mice developed prion disease after more than 2 years. Protease-resistant PrPSc in BASE-infected humanized Tg mouse brains was biochemically different from bovine BASE or sCJD. PrPSc was also detected in the spleen of 22% of BASE-infected humanized mice, but not in those infected with sCJD. Secondary transmission of BASE in the humanized mice led to a small reduction in incubation time. The atypical BSE-H strain is also transmissible with distinct phenotypes in the humanized mice, but no BSE-M transmission has been observed so far.
Discussion: Our results demonstrate that BASE is more virulent than classical BSE, has a lymphotropic phenotype, and displays a modest transmission barrier in our humanized mice.
BSE-H is also transmissible in our humanized Tg mice.
The possibility of more than two atypical BSE strains will be discussed.
Supported by NINDS NS052319, NIA AG14359, and NIH AI 77774.
http://www.prion2009.com/sites/default/files/Prion2009_Book_of_Abstracts.pdf
Simian vCJD can be easily triggered in cynomolgus monkeys on the oral route using less than 5 g BSE brain homogenate.
http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf
WE know now, and we knew decades ago, that 5.5 grams of suspect feed in TEXAS was enough to kill 100 cows.
look at the table and you'll see that as little as 1 mg (or 0.001 gm) caused 7% (1 of 14) of the cows to come down with BSE;
Risk of oral infection with bovine spongiform encephalopathy agent in primates
Corinne Ida Lasmézas, Emmanuel Comoy, Stephen Hawkins, Christian Herzog, Franck Mouthon, Timm Konold, Frédéric Auvré, Evelyne Correia, Nathalie Lescoutra-Etchegaray, Nicole Salès, Gerald Wells, Paul Brown, Jean-Philippe Deslys Summary The uncertain extent of human exposure to bovine spongiform encephalopathy (BSE)--which can lead to variant Creutzfeldt-Jakob disease (vCJD)--is compounded by incomplete knowledge about the efficiency of oral infection and the magnitude of any bovine-to-human biological barrier to transmission. We therefore investigated oral transmission of BSE to non-human primates. We gave two macaques a 5 g oral dose of brain homogenate from a BSE-infected cow. One macaque developed vCJD-like neurological disease 60 months after exposure, whereas the other remained free of disease at 76 months. On the basis of these findings and data from other studies, we made a preliminary estimate of the food exposure risk for man, which provides additional assurance that existing public health measures can prevent transmission of BSE to man.
snip...
BSE bovine brain inoculum
100 g 10 g 5 g 1 g 100 mg 10 mg 1 mg 0·1 mg 0·01 mg
Primate (oral route)* 1/2 (50%)
Cattle (oral route)* 10/10 (100%) 7/9 (78%) 7/10 (70%) 3/15 (20%) 1/15 (7%) 1/15 (7%)
RIII mice (ic ip route)* 17/18 (94%) 15/17 (88%) 1/14 (7%)
PrPres biochemical detection
The comparison is made on the basis of calibration of the bovine inoculum used in our study with primates against a bovine brain inoculum with a similar PrPres concentration that was inoculated into mice and cattle.8 *Data are number of animals positive/number of animals surviving at the time of clinical onset of disease in the first positive animal (%). The accuracy of bioassays is generally judged to be about plus or minus 1 log. ic ip=intracerebral and intraperitoneal.
Table 1: Comparison of transmission rates in primates and cattle infected orally with similar BSE brain inocula
Published online January 27, 2005
http://www.thelancet.com/journal/journal.isa
It is clear that the designing scientists must also have shared Mr Bradleys surprise at the results because all the dose levels right down to 1 gram triggered infection.
http://web.archive.org/web/20040523230128/www.bseinquiry.gov.uk/files/ws/s145d.pdf
it is clear that the designing scientists must have also shared Mr Bradleys surprise at the results because all the dose levels right down to 1 gram triggered infection.
http://web.archive.org/web/20030526212610/http://www.bseinquiry.gov.uk/files/ws/s147f.pdf
just food for thought here, but read and understand just what this sentence says here ;
IN CONFIDENCE
AS implied in the Inset 25 we must not _ASSUME_ that transmission of BSE to other species will invariably present pathology typical of a scrapie-like disease.
snip...
http://collections.europarchive.org/tna/20080102185948/http://www.bseinquiry.gov.uk/files/yb/1991/01/04004001.pdf
and ;
In Confidence
Perceptions of unconventional slow virus diseases of animals in the USA - APRIL-MAY 1989 - G A H Wells
3. Prof. A Robertson gave a brief account of BSE. The US approach was to accord it a very low profile indeed. Dr. A Thiermann showed the picture in the ''Independent'' with cattle being incinerated and thought this was a fanatical incident to be avoided in the US at all costs. BSE was not reported in the USA.
http://collections.europarchive.org/tna/20080102193705/http://www.bseinquiry.gov.uk/files/mb/m11b/tab01.pdf
seems the USA PRION unit has been working hard to change the science since those atypical mad cow and human TSE cases started showing up around 2005-2006 ;
Thursday, July 10, 2008
A Novel Human Disease with Abnormal Prion Protein Sensitive to Protease update July 10, 2008 Friday, June 20, 2008
http://cjdmadcowbaseoct2007.blogspot.com/2008/07/novel-human-disease-with-abnormal-prion.html
Thursday, July 10, 2008
A New Prionopathy update July 10, 2008
http://cjdmadcowbaseoct2007.blogspot.com/2008/07/new-prionopathy-update-july-10-2008.html
Original Article
Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein
http://www3.interscience.wiley.com/journal/123598302/abstract?CRETRY=1&SRETRY=0
>>> Because 8 out of 10 patients had a positive family history of dementia in the original study, a genetic cause was suspected. Although all cases were homozygous for valine at codon 129 of the PrP gene, NO mutations were detected. <<<
http://creutzfeldt-jakob-disease.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.html
OR JUST MORE PRIONBALONEY $$$
anything but a home grown mad cow in the USA, and or a human case there from, it's all genetic, sporadic, spontaneous, with no genetic link to any human, just a genetic link to the mad cow in Alabama.
i did not fall off a shrimp boat yesterday. ...
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA
