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Creutzfeldt Jakob Disease Delaware UPDATE

Posted Feb 08 2008 12:56pm
Creutzfeldt Jakob Disease Delaware


Greetings et al,


confusious is confused again. if you remember correctly, in December 2007, the state of Delaware and the sporadic CJD cases, several at dupont. i have enclosed the final results to those cases in pdf, and will summarize. but what confusious is confused about is the continued diagnostic criteria differentiating the different strains, routes, sources i.e. the UKBSEnvCJD only theory. ...


in this report (attached pdf file) Gambetti et al reported 4 confirmed prion disease of which one was sCJDVV2, the second most common type sCJD, and 3 were sCJDMM1, the most common type of sCJD. and then state that no evidence that any of these four cases had acquired the prion disease from contaminated food, surgical instruments or drugs.


_documented_ TSEs. they have already conceded that they are missing cases ;



THE PATHOLOGICAL PROTEIN

Hardcover, 304 pages plus photos and illustrations. ISBN 0-387-95508-9

June 2003

BY Philip Yam


CHAPTER 14 LAYING ODDS

Answering critics like Terry Singeltary, who feels that the U.S. under-
counts CJD, Schonberger conceded that the current surveillance system
has errors but stated that most of the errors will be confined to the older
population.

http://www.thepathologicalprotein.com/


Diagnosis and Reporting of Creutzfeldt-Jakob Disease

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

http://jama.ama-assn.org/


http://www.neurology.org/cgi/eletters/60/2/176#535


AND no evidence showed that these four cases did _not_ come from contaminated food, surgical instruments or drugs. they very well could have with the present diagnostic criteria.
you just dont know about these atypical TSE yet, and Collinge et al have
shown that BSE transmission to the 129-methionine genotype can lead to an alternate
phenotype that is indistinguishable from type 2 PrPSc, the commonest sporadic CJD. ...


http://www.neurology.org/cgi/eletters/60/2/176#535



iCJD is all sporadic until a proven route or source is established. so you
cannot rule out iCJD by simply stating it aint so because of no known route and source. they simply do not know, and with these new atypical TSEs i.e. h-BASE and l-BASE in the bovine, and the Nor-98 atypical scrapie in sheep, both of which are more virulent to humans, and DOES show a similarity with some sub-types of the sporadic CJD, and h-base atypical BSE and the atypical Nor-98 scrapie have now been documented in the USA, what about consumption or friendly fire i.e. iCJD, will that look the same pathologically or not? by stating there is no evidence, is simply misleading, in my opinion, and could help in the spreading of the TSE agent. ...


also, Gambetti et al state that the sCJDMM1 duration of illness is 3.9 months.


in the paper below 'MM1-type sCJD with unusually prolonged disease with panencephalopathic-type pathology'' of 58 months would seem to be another factor disputing Gambetti et al diagnostic criteria differentiating the strains, route, sources, by simply lumping them all in the sCJD category, along with the UKBSEnvCJD theory i.e. only one strain of TSE in only one species, will only transmit TSE agent to only one age group, in only one geographical location on this planet. in fact, Gambetti et al complete classification brake down of the 6 different phenotypes/strains of the sporadic CJD and the sub-types, and atypicals there of, are getting to be ridiculous, and in my opinion, wrong in regards with ''no evidence that any of these four cases had acquired the prion disease from contaminated food, surgical instruments or drugs''. ...


then, Gambetti et al state that Fatal Familial Insomnia i.e. FFi is of inherited form, but yet if i
understand this correctly, Gambetti et al have now classified a sporadic FFi, which is classified
under the sporadic CJD. what's that all about? how can an inherited disease i.e. FFi, be listed as
sFFi, under sporadic CJD's?


A subtype of sporadic prion disease mimicking fatal familial insomnia

http://www.neurology.org/cgi/content/abstract/52/9/1757


Gambetti et al's diagnostic criteria for the different human TSEs is getting more and more
complicated it seems, and with all the different atypical TSE showing up in the USA and
abroad, sCJD's increasing, and there is no denying that, they can continue to blame it on
better surveillance, but i disagree, this excuse has been used for 15 years or so. i think it's
time to look at it is for what it is. ...


A look At Gametti et al's brake down of the Human TSE ;


HUMAN PRION DISEASE : CLASSIFICATION


Form (Etiology) Phenotype


Inherited Creutzfeldt-Jakob disease (CJD)

Fatal Familial Insomnia (FFi)

Gerstmann-Straussler-Scheinker (GSS)

Mixed or undefined



Sporadic CJD

Typical M/M (M/V) 1

Early V/V1

Long M/M2

Kuru plaques M/V 2h

Ataxic V/V 2

FI

PrPDs

V/V

M/V


Acquired by infection


Kuru

Iatrogenic CJD (iCJD)

Variant of CJD (vCJD)




SPORADIC PRION DISEASES SUBTYPES


Phenotype Variant


Creutzfeldt Jakob Disease (CJD)

M/M and M/V 1 Onset (>63yr), classical, short duration (<4>15mo.), cortical pathology

M/M 2 cort. Onset (60yr), coarse spongiosis, long duration (>15mo.), cortical pathology

M/V 2 Onset (60yr), ataxia, kuru plaques, long duration (>17 mo.), subcortical pathology

V/V 2 Onset (>60yr), ataxia, plaque-like short duration (<7mo.), subcortical pathology


CJD is reportable in Delaware, however, DOES the state of Delaware and the Prion Unit ONLY
consider a case of any human TSE confirmed only by having a final autopsy ??


SO the victims that do not have autopsy do not count ??


WHY, IN 2008, still, there is no extensive WRITTEN, CJD QUESTIONNAIRE,
asking real questions pertaining to route and source of the TSE agent, going to every
victim and the family of these victims, why is this ??


WHY did the CJD Foundation INC. fight this at ever turn of the way, and apparently,
still do not issue a Written CJD questionnaire ??


I only ponder if those families in Delaware got one of those extensive WRITTEN CJD
questionnaire, or just the usual phone call cjd questionnaire, where no end results, and
or links of any route and source would be obvious to the public ??


DOES clinical diagnosis without autopsy of TSE count in statistics ??


IT seems out of the cases in Delaware that were diagnosed by either 14-3-3
and Tau, out of the 5 cases, only 2 were diagnosed as Probable CJD, the other
3 cases, even though 14-3-3 and Tau were positive, the Clinical diagnosis was
listed as NOT AVAILABLE ??


THE Prion disease cases in Delaware that were from Tissue Examination
3 cases were typical sCJDMM1, and 1 case, SCJDVV2, was atypical positive EEG,
WB T2, Histo typical, 129VV no Mut., duration 7 months, onset 78 yrs, with risks of
multiple orthopedic surgeries.


WHAT about the rest of the victims and families there of, are they all getting one of these
extensive CJD questionnaires, or just the usual courtesy call from the CJD Foundation INC.,
with a few questions only pertaining to whom, what, when, where and how was this diagnosis
made ??


WHY IS CJD still not reportable in every state, of every age group ??


WHOM has filled out one of these extensive WRITTEN CJD questionnaire's ??


IN NOT, why not $$$


CJD QUESTIONNAIRE


http://cjdquestionnaire.blogspot.com/



seems there are families of CJD victims in Delaware that are very unhappy with the
outcome of the recent meeting between the Prion Unit, and state officials. sadly, all
i can say is, join the crowd. ...


confusious says, "If it doesn't fit, you must acquit." ...TSS


Case Report

MM1-type sporadic Creutzfeldt-Jakob disease with unusually prolonged disease
duration presenting with panencephalopathic-type pathology

Akira Hoshino,11Department of Neurology, Aichi Medical University School of
Medicine, Aichi, Yasushi Iwasaki,22Department of Neurology, Nagoya
University Graduate School of Medicine, Nagoya, Yasushi Iwasaki, MD,
Department of Neurology, Nagoya University Graduate School of Medicine, 65
Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Emailiwasaki@sc4.so-net.ne.jp Masayuki Izumi,11Department of Neurology, Aichi
Medical University School of Medicine, Aichi, Shinya Kimura,33Department of
Rehabilitation Medicine, Aichi Medical University School of Medicine, Aichi,
Tohru Ibi,11Department of Neurology, Aichi Medical University School of
Medicine, Aichi, Tetsuyuki Kitamoto,44Division of CJD Science and
Technology, Department of Prion Research, Center for Translational and
Advanced Animal Research on Human Diseases, Tohoku University Graduate
School of Medicine, Sendai, and Mari Yoshida,55Department of Neuropathology,
Institute for Medical Science of Aging, Aichi Medical University, Aichi,
Japan Yoshio Hashizume55Department of Neuropathology, Institute for Medical
Science of Aging, Aichi Medical University, Aichi, Japan and Ko
Sahashi11Department of Neurology, Aichi Medical University School of
Medicine, Aichi, 1Department of Neurology, Aichi Medical University School
of Medicine, Aichi, 2Department of Neurology, Nagoya University Graduate
School of Medicine, Nagoya, 3Department of Rehabilitation Medicine, Aichi
Medical University School of Medicine, Aichi, 4Division of CJD Science and
Technology, Department of Prion Research, Center for Translational and
Advanced Animal Research on Human Diseases, Tohoku University Graduate
School of Medicine, Sendai, and 5Department of Neuropathology, Institute for
Medical Science of Aging, Aichi Medical University, Aichi, Japan

Yasushi Iwasaki, MD, Department of Neurology, Nagoya University Graduate
School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Email: iwasaki@sc4.so-net.ne.jp

Abstract

We report an autopsy case of MM1-type sporadic Creutzfeldt-Jakob disease
(sCJD) with an unusually prolonged disease duration of 58 months. The
initial symptom was progressive mental disorder followed by advanced
cognitive impairment. Clinical progression was generally slow; myoclonus
appeared at 17 months and periodic sharp-wave complexes on
electroencephalogram at 21 months. A state of akinetic mutism occurred 29
months after the onset of symptoms. MRI showed gradually progressive
cerebral atrophy. Neuropathologic examination showed widespread severe brain
involvement. In the cerebral neocortex, widespread severe tissue
rarefaction, hypertrophic astrocytosis and neuron loss (so-called status
spongiosus) were observed. The cerebral white matter showed diffuse myelin
pallor with intense hypertrophic astrocytosis, numerous foamy macrophages
and emperipolesis, indicating panencephalopathic-type sCJD pathology. The
brainstem was relatively preserved from sCJD pathology, with the exception
of the pontine nucleus and pyramidal tract. This may explain the prolonged
disease duration without respiratory insufficiency until the terminal stage.
Immunohistochemistry for prion protein (PrP) showed widespread synaptic-type
PrP deposits in the cerebral neocortex, hippocampus and thalamus. The
striatum and cerebellar cortex showed faint synaptic-type PrP deposition
with some areas of small plaque-like PrP deposition. Sparse PrP deposition
was also observed in the brainstem. Analysis of the PrP gene showed no
mutation but methionine homozygosity at polymorphic codon 129. Western blot
analysis of protease-resistant PrP indicated type 1 PrP. To our knowledge,
this is the longest reported disease duration of MM1-type sCJD.


http://www.blackwell-synergy.com/doi/abs/10.1111/j.1440-1789.2007.00854.x


The MM2-cortical form of sporadic Creutzfeldt–Jakob disease presenting with
visual disturbance



Abstract—A subclass of sporadic Creutzfeldt–Jakob disease (sCJD) characterized
by onset with visual symptoms (Heidenhain variant) has been reported to
belong to the MM1 or MV1 type according to Parchi’s classification. The authors
report a 65-year-old woman with MM2-cortical sCJD with slowly progressive
visual disturbance as the initial symptom. Diffusion-weighted MRIs
revealed hyperintensity in both occipital cortices at an early stage.

NEUROLOGY 2006;67:531–533



I. Nozaki, MD; T. Hamaguchi, MD, PhD; M. Noguchi-Shinohara, MD; K. Ono, MD,
PhD; H. Shirasaki, MD;
K. Komai, MD, PhD; T. Kitamoto, MD, PhD; and M. Yamada, MD, PhD



snip...


Discussion. This case was classified as MM2-
cortical sCJD for the following reasons: no history of
dural grafting; spongiform changes and PrP deposits
with a perivacuolar pattern in the cerebral cortices,
but no thalamic or inferior olivary degeneration as
found in the thalamic form; no mutation and MM at
polymorphic codon 129 in the PrP gene; and a Type
2A pattern (Parchi) of PrPres. Although it has been
reported that Type 1 and Type 2 PrPres coexist in a


third of patients with sCJD,7 Type 1 PrPres was not
found in our case as far as we examined.
sCJD was not diagnosed on the basis of clinical
diagnostic criteria8 before death because of few neurologic
manifestations and the absence of PSDs on
EEG and of CSF 14-3-3 protein; however, we suspected
sCJD because of areas of hyperintensity on
DW images of the brain. We have previously reported
that cortical hyperintensity on DW images is
useful for the diagnosis of MM2-cortical sCJD.9

In a recent report, 22 (3.7%) of 594 patients in the
United Kingdom with pathologically proven sCJD
had isolated visual symptoms at onset (Heidenhain
variant).4 The Heidenhain variant of sCJD is commonly
associated with rapid progression of various
neuropsychiatric manifestations and presents with
the MM1 or MV1 PrP in all examined cases.1,3,4 Although
a case of the Heidenhain variant with a long
clinical course (23 months) has been reported, molecular
analysis of PrP was not performed.10
On the other hand, in the MM2-cortical sCJD,
dementia is the most common manifestation at onset,
and the clinical course is relatively slow, while
ataxia and PSDs on EEG are typically absent.1 Visual
disturbance has never been reported throughout
the clinical course of MM2 sCJD.1 In our patient, it is
consistent with the visual disturbance at onset that
the early and most severe involvement of the occipital
cortex was proven with MR and pathologic examination.
We emphasize that visual disturbance at
onset (Heidenhain variant) in sCJD can be found not
only in the MM1 and MV1 types, but also in MM2-
cortical type associated with relatively slow progression
of visual symptoms. In such cases, occipital
cortical hyperintensity on DW images helps to establish
the clinical diagnosis of sCJD, even if neurologic
manifestations, EEG, and CSF 14-3-3 protein do not
satisfy the diagnostic criteria for sCJD.8


Acknowledgment


The authors thank Dr. Minoru Tobiume (Department of Pathology,
National Institute of Infectious Disease) for the measurements
of 14-3-3 protein, and Drs. Eisuke Furui, Ayumi Shibata,
Akiyoshi Morinaga, Tomohiko Machiya, Takahiro Maruta, and
Kazuo Iwasa for technical support at autopsy.


References...snip...end


http://www.neurology.org/cgi/content/abstract/67/3/531


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.

FC5.5.1 BASE Transmitted to Primates and MV2 sCJD Subtype Share PrP27-30 and PrPSc C-terminal Truncated Fragments

Zanusso, G1; Commoy, E2; Fasoli, E3; Fiorini, M3; Lescoutra, N4; Ruchoux, MM4; Casalone, C5; Caramelli, M5; Ferrari, S3; Lasmezas, C6; Deslys, J-P4; Monaco, S3 1University of Verona, of Neurological and Visual Sciences, Italy; 2CEA, IMETI/SEPIA, France; 3University of Verona, Neurological and Visual Sciences, Italy; 4IMETI/SEPIA, France; 5IZSPLVA, Italy; 6The Scripps Research Insitute, USA

The etiology of sporadic Creutzfeldt-Jakob disease (sCJD), the most frequent human prion disease, remains still unknown. The marked disease phenotype heterogeneity observed in sCJD is thought to be influenced by the type of proteinase K- resistant prion protein, or PrPSc (type 1 or type 2 according to the electrophoretic mobility of the unglycosylated backbone), and by the host polymorphic Methionine/Valine (M/V) codon 129 of the PRNP. By using a two-dimensional gel electrophoresis (2D-PAGE) and imunoblotting we previously showed that in sCJD, in addition to the PrPSc type, distinct PrPSc C-terminal truncated fragments (CTFs) correlated with different sCJD subtypes. Based on the combination of CTFs and PrPSc type, we distinguished three PrPSc patterns: (i) the first was observed in sCJD with PrPSc type 1 of all genotypes,;

(ii) the second was found in M/M-2 (cortical form); (iii) the third in amyloidogenic M/V- 2 and V/V-2 subtypes (Zanusso et al., JBC 2004) . Recently, we showed that sCJD subtype M/V-2 shared molecular and pathological features with an atypical form of BSE, named BASE, thus suggesting a potential link between the two conditions. This connection was further confirmed after 2D-PAGE analysis, which showed an identical PrPSc signature, including the biochemical pattern of CTFs. To pursue this issue, we obtained brain homogenates from Cynomolgus macaques intracerebrally inoculated with brain homogenates from BASE. Samples were separated by using a twodimensional electrophoresis (2D-PAGE) followed by immunoblotting. We here show that the PrPSc pattern obtained in infected primates is identical to BASE and sCJD MV-2 subtype. *** These data strongly support the link, or at least a common ancestry, between a sCJD subtype and BASE. This work was supported by Neuroprion (FOOD-CT-2004-506579)


*******************************************************


USA MAD COW CASES IN ALABAMA AND TEXAS

***PLEASE NOTE***

USA BASE CASE, (ATYPICAL BSE), AND OR TSE (whatever they are calling it today), please note that both the ALABAMA COW, AND THE TEXAS COW,
both were ''H-TYPE'', personal communication Detwiler et al Wednesday, August 22, 2007 11:52 PM. ...TSS


http://lists.ifas.ufl.edu/cgi-bin/wa.exe?A2=ind0708&L=sanet-mg&T=0&P=19779


*******************************************************

FC5.5.2 Transmission of Italian BSE and BASE Isolates in Cattle Results into a Typical BSE Phenotype and a Muscle Wasting Disease

Zanusso, G1; Lombardi, G2; Casalone, C3; D’Angelo, A4; Gelmetti, D2; Torcoli, G2; Barbieri, I2; Corona, C3; Fasoli, E1; Farinazzo, A1; Fiorini, M1; Gelati, M1; Iulini, B3; Tagliavini, F5; Ferrari, S1; Monaco, S1; Caramelli, M3; Capucci, L2 1University of Verona, Neurological and Visual Sciences, Italy; 2IZSLER, Italy; 3IZSPLVA, Italy; 4University of Turin, Animal Pathology, Italy; 5Isituto Carlo Besta, Italy

The clinical phenotype of bovine spongiform encephalopathy has been extensively reported in early accounts of the disorder. Following the introduction of statutory active surveillance, almost all BSE cases have been diagnosed on a pathological/molecular basis, in a pre-symptomatic clinical stage. In recent years, the active surveillance system has uncovered atypical BSE cases, which are characterized by distinct conformers of the PrPSc, named high-type (BSE-H) and low-type (BSE-L), whose clinicopathological phenotypes remain unknown. We recently reported two Italian atypical cases with a PrPSc type similar to BSE-L, pathologically characterized by PrP amyloid plaques. Experimental transmission to TgBov mice has recently disclosed that BASE is caused by a distinct prion strain which is extremely virulent. A major limitation of transmission studies to mice is the lack of reliable information on clinical phenotype of BASE in its natural host. In the present study, we experimentally infected Fresian/Holstein and Alpine/Brown cattle with Italian BSE and BASE isolates by i.c. route. BASE infected cattle showed survival times significantly shorter than BSE, a finding more readily evident in Fresian/Holstein, and in keeping with previous observations in TgBov mice. Clinically, BSE-infected cattle developed a disease phenotype highly comparable with that described in field BSE cases and in experimentally challenged cattle. On the contrary, BASE-inoculated cattle developed an amyotrophic disorder accompanied by mental dullness. The molecular and neuropathological profiles, including PrP deposition pattern, closely matched those observed in the original cases. This study further confirms that BASE is caused by a distinct prion isolate and discloses a novel disease phenotype in cattle, closely resembling the phenotype previous reported in scrapie-inoculated cattle *** and in some subtypes of inherited and sporadic Creutzfeldt-Jakob disease. Oral Abstracts 14

P04.49

Case Report of Variant Creutzfeldt-Jakob Disease in a Macaque after Blood Transfusion

Lescoutra-Etchegaray, N1; Ruchoux, MM1; Correia, E1; Jolit, A1; Freire, S1; Lasmezas, CI2; Deslys, JP1; Comoy, E1 1CEA/DSV/IMETI/SEPIA, France; 2Scripps Florida, USA

A fourth human case of probable transmission of vCJD through transfusion has now been reported but a number of features affecting transfusion-related infection remain imprecise, including infectious dose, length of incubation period and critical infectious window of blood donors.

We report here the first case of experimental transmission of vCJD in primates by blood transfusion. Experimental infection of Cynomolgus macaque has been demonstrated to be a sensitive model for the investigation of human prion diseases, inducing similar distribution of infectivity in peripheral lymphoid tissues and equivalent brain pathology. In our study, transfusion was performed with 40 ml of whole blood drawn from a vCJD-infected macaque at the terminal stage of the disease. Clinical symptoms of vCJD appeared in the recipient animal after five years of incubation. The total amount of infectivity in the transfused blood was approximately 106 fold lower than in the brain (titration still in progress). In several animals infected intravenously with brain homogenate, the presence of PrPres in serial lymph nodes biopsies and in other organs at autopsy was examined and results will be presented.

http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf


P04.51

Atypical Presentation of Variant Creutzfeldt-Jakob Disease in a 73 Year Old Blood Transfusion Recipient

Wroe, S1; Pal, S1; Webb, T1; Alner, K2; Hewitt, P3; Brander, S4; Wadsworth, JD5; Collinge, J1 1National Hospital for Neurology and Neurosurgery, National Prion Clinic, UK; 2National Hospital for Neurology and Neurosurgery, Department of Neuropsychology, UK; 3Health Protection Agency, UK; 4National Hospital for Neurology and Neurosurgery, Department of Neuropathology, UK; 5Institute of Neurology, UCL, UK

We report atypical presentation of variant Creutzfeldt-Jakob Disease (vCJD) identified ante-mortem in a 73 year-old recipient of blood products. This patient was transfused following orthopaedic surgery in December 1997. Tracing of blood products identified a single unit of non-leucodepleted red cells from an individual who developed neuropathologically confirmed vCJD eleven months after donation. Nine years post transfusion, this individual was referred to the National Prion Clinic for specialist investigation. Six years post transfusion the recipient complained of fluctuating fatigue and impaired concentration. At this time neurological examination and MRI brain (T1/T2 weighted/DWI) were normal. Progressive symptoms emerged six months later with imbalance and deteriorating cognition. Examination two months after onset of neurological symptoms demonstrated cognitive deficits, dyspraxia or visuospatial dysfunction and normal motor, sensory and gait examination. Six weeks later cognitive impairment was identified alongside tremulousness, impaired manual dexterity and limb ataxia. Serological investigations were normal. MRI (T1/T2 weighted/FLAIR/DWI) demonstrated prominent signal change throughout the dorsal thalamus, consistent with vCJD. PRNP genotyping revealed no mutations and homozygosity for methionine at codon 129. The prolonged incubation period of vCJD and possibility of asymptomatic carrier states pose major public health concerns. This case highlights the significant risk encountered by recipients of contaminated blood products and the necessity for their specialist monitoring.

http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf


P04.36

Enhanced Surveillance of Persons Identified as at Increased Risk of CJD Due to Blood Transfusion or Healthcare Procedures

Brookes, D1; Chow, Y1; Ward, HJT2; Will, RG2; Hewitt, P3; Gill, ON1 1HPA, CJD, UK; 2National CJD Surveillance Unit, UK; 3Colindale, NHS Blood and Tissue, UK

Introduction
Reports of four iatrogenic transmissions of variant-CJD (vCJD) infection in the UK (all due to transfusion of blood from donors who later developed vCJD), evidence from iatrogenic transmissions of sporadic CJD and experimental work on CJD infectivity in tissues and on healthcare instruments have given rise to concern about the risks of iatrogenic transmission of CJD. This risk warrants a) certain public health precautions, and b) follow-up of individuals with identified risks in order to gain evidence about their risks and ensure appropriate management of these risks. Evidence of transmission via iatrogenic routes is important to inform public health measures and so prevent ongoing transmission of CJD.

Methods
The Health Protection Agency and Health Protection Scotland holds details of persons identified as ‘at-risk’ of vCJD due to blood transfusion and of persons identified as ‘at-risk’ of CJD (of any type) from other healthcare procedures. The GPs/clinicians of all persons identified as ‘at-risk’ for public health purposes are provided with: information; risk assessment updates; advice on public health precautions and advice on referral to specialist care. Procedures are being established to obtain enhanced surveillance data on these individuals, including: clinical status updates, date and cause of death, surplus tissue and blood specimens, and postmortem investigations.

Results
Persons ‘at-risk’ of CJD have experienced a range of exposures. Estimated risks are uncertain and overlapping. Some individuals - recipients of vCJD implicated blood components - are considered to be at a clearly higher risk of infection: active follow-up is currently conducted for these individuals. In time, the enhanced surveillance of persons at increased risk of CJD will provide estimates of transmission risks and of the impact of iatrogenic exposures on mortality. Conclusion: Knowledge about iatrogenic transmission of CJD is being gained by the follow-up of individuals who have been identified as ‘at-risk’ of CJD in the UK. This enhanced surveillance may need to be sustained for many years.

http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf


Prions in Plasma of Patients with Sporadic Creutzfeldt-Jakob Disease

Safar, J.G1,3, Geschwindm M.D2,3, Letessier, F1, Kuo, A1, Pomeroy, K1, Deering, C1, Serban, A1, Groth, D1, Miller, B.L2,3, DeArmond, S.J1,4, Prusiner, S.B1,3,5 1Institute for Neurodegenerative Diseases, 2Memory and Aging Center, Departments of 3Neurology, 4Pathology, and 5Biochemistry and Biophysics, University of California, San Francisco, California 94143

http://www.prion2007.com/pdf/Prion%20Friday.pdf

http://www.prion2007.com/pdf/Prion%20Thursday.pdf

http://www.prion2007.com/pdf/Prion%20Wednesday.pdf


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 v CJD 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.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf


Subject: Aspects of the Cerebellar Neuropathology in Nor98

Date: September 26, 2007 at 4:06 pm PST

P03.141

Aspects of the Cerebellar Neuropathology in Nor98

Gavier-Widén, D1; Benestad, SL2; Ottander, L1; Westergren, E1 1National Veterinary Insitute, Sweden; 2National Veterinary Institute, Norway

Nor98 is a prion disease of old sheep and goats. This atypical form of scrapie was first described in Norway in 1998. Several features of Nor98 were shown to be different from classical scrapie including the distribution of disease associated prion protein (PrPd) accumulation in the brain. The cerebellum is generally the most affected brain area in Nor98. The study here presented aimed at adding information on the neuropathology in the cerebellum of Nor98 naturally affected sheep of various genotypes in Sweden and Norway. A panel of histochemical and immunohistochemical (IHC) stainings such as IHC for PrPd, synaptophysin, glial fibrillary acidic protein, amyloid, and cell markers for phagocytic cells were conducted. The type of histological lesions and tissue reactions were evaluated. The types of PrPd deposition were characterized. The cerebellar cortex was regularly affected, even though there was a variation in the severity of the lesions from case to case. Neuropil vacuolation was more marked in the molecular layer, but affected also the granular cell layer. There was a loss of granule cells. Punctate deposition of PrPd was characteristic. It was morphologically and in distribution identical with that of synaptophysin, suggesting that PrPd accumulates in the synaptic structures. PrPd was also observed in the granule cell layer and in the white matter. *** The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.


http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf


Coexistence of multiple PrPSc types in individuals with Creutzfeldt-Jakob disease


Magdalini Polymenidou, Katharina Stoeck, Markus
Glatzel, Martin Vey, Anne Bellon, and Adriano Aguzzi


Summary


Background

The molecular typing of sporadic
Creutzfeldt-Jakob disease (CJD) is based on the size
and glycoform ratio of protease-resistant prion protein (PrPSc), and
on PRNP haplotype. On digestion with proteinase K, type1 and
type 2 PrPSc display unglycosylated core fragments of
21 kDa and 19 kDa, resulting from cleavage around amino
acids 82 and 97, respectively.

Methods

We generated anti-PrP monoclonal antibodies to
epitopes immediately preceding the differential proteinase
K cleavage sites. These antibodies, which were
designated POM2 and POM12, recognise type 1, but not
type 2, PrPSc.

Findings

We studied 114 brain samples from 70 patients
with sporadic CJD and three patients with variant CJD.
Every patient classified as CJD type 2, and all variant
CJD patients, showed POM2/POM12 reactivity in the
cerebellum and other PrPSc-rich brain areas, with a
typical PrPSc type 1 migration pattern.

Interpretation

The regular coexistence of multiple
PrPSc types in patients with CJD casts doubts on the
validity of electrophoretic PrPSc mobilities as surrogates for
prion strains, and *** questions the rational basis of
current CJD classifications.


snip...


The above results set the existing CJD classifications

into debate and introduce interesting questions about

human CJD types. For example, do human prion types

exist in a dynamic equilibrium in the brains of affected

individuals? Do they coexist in most or even all CJD

cases? Is the biochemically identified PrPSc type simply

the dominant type, and not the only PrPSc species?


Published online October 31, 2005


http://neurology.thelancet.com


Detection of Type 1 Prion Protein in Variant Creutzfeldt-Jakob Disease

Helen M. Yull,* Diane L. Ritchie,*

Jan P.M. Langeveld,? Fred G. van Zijderveld,?

Moira E. Bruce,? James W. Ironside,* and

Mark W. Head*

From the National CJD Surveillance Unit,* School of Molecular
and Clinical Medicine, University of Edinburgh, Edinburgh,
United Kingdom; Central Institute for Animal Disease Control

(CIDC)-Lelystad, ? Lelystad, The Netherlands; Institute for Animal
Health, Neuropathogenesis Unit, ? Edinburgh, United Kingdom


Molecular typing of the abnormal form of the prion
protein (PrPSc) has come to be regarded as a powerful
tool in the investigation of the prion diseases. All evidence
thus far presented indicates a single PrPSc molecular
type in variant Creutzfeldt-Jakob disease (termed
type 2B), presumably resulting from infection with a
single strain of the agent (bovine spongiform
encephalopathy).

Here we show for the first time that the PrPSc
that accumulates in the brain in variant Creutzfeldt-
Jakob disease also contains a minority type 1 component.
This minority type 1 PrPSc was found in all 21
cases of variant Creutzfeldt-Jakob disease tested,
irrespective of brain region examined, and was also
present in the variant Creutzfeldt-Jakob disease tonsil.

The quantitative balance between PrPSc types was maintained
when variant Creutzfeldt-Jakob disease was
transmitted to wild-type mice and was also found in
bovine spongiform encephalopathy cattle brain, indicating
that the agent rather than the host specifies their
relative representation. These results indicate that PrPSc
molecular typing is based on quantitative rather than
qualitative phenomena and point to a complex relationship
between prion protein biochemistry, disease phenotype
and agent strain.

(Am J Pathol 2006, 168:151-157;
DOI: 10.2353/ajpath.2006.050766)


snip...


Discussion

snip...


These results show that even in vCJD where susceptible
individuals have been infected supposedly by a
single strain of agent, both PrPSc types co-exist: a
situation reminiscent of that seen when similarly discriminant
antibodies were used to analyze experimental BSE in
sheep.14,17 In sporadic and familial CJD, individual
brains can show a wide range of relative amounts of the
two types in samples from different regions, but where
brains have been thoroughly investigated a predominant
type is usually evident.2,6,10 This differs from this
report on vCJD, where type 1 is present in all samples
investigated but always as a minor component that never
reaches a level at which it is detectable without a type
1-specific antibody. It would appear that the relative
balance between type 1 and type 2 is controlled within
certain limits in the vCJD brain. A minority type-1-like
band is also detected by 12B2 in vCJD tonsil, in BSE
brain and in the brains of mice experimentally infected
with vCJD, suggesting that this balance of types is agent,
rather than host or tissue, specific. Interestingly the "glycoform
signature" of the type 2 PrPSc found in vCJD (type
2B) is also seen in the type 1 PrPSc components, suggesting
that it could legitimately be termed type 1B.
PrPSc isotype analysis has proven to be extremely
useful in the differential diagnosis of CJD and is likely to
continue to have a major role in the investigation of human
prion diseases. However, it is clear, on the basis of
these findings, that molecular typing has quantitative
limitations and that any mechanistic explanation of prion
replication and the molecular basis of agent strain
variation must accommodate the co-existence of multiple
prion protein conformers. Whether or not the different
conformers we describe here correlate in a simple and
direct way with agent strain remains to be determined. In
principle two interpretations present themselves: either
the two conformers can be produced by a single strain of
agent or vCJD (and, therefore, presumably BSE) results
from a mixture of strains, one of which generally
predominates.

Evidence for the isolation in mice of more than one
strain from individual isolates of BSE has been presented
previously.18,19

One practical consequence of our findings is that the
correct interpretation of transmission studies will depend
on a full examination of the balance of molecular types
present in the inoculum used to transmit disease, in
addition to a thorough analysis of the molecular types that
arise in the recipients. Another consequence relates to
the diagnostic certainty of relying on PrPSc molecular
type alone when considering the possibility of BSE
infection or secondary transmission in humans who have a
genotype other than methionine at codon 129 of the
PRNP gene. In this context it is interesting to note that this
minority type 1B component resembles the type 5 PrPSc
described previously to characterize vCJD transmission
into certain humanized PRNP129VV transgenic mouse
models.12,20 This apparently abrupt change in molecular
phenotype might represent a selection process imposed
by this particular transgenic mouse model. Irrespective of
whether this proves to be the case, the results shown
here point to further complexities in the relationship between
the physico-chemical properties of the prion protein,
human disease phenotype, and prion agent strain.

Acknowledgments



snip...



Type 1 PrPSc in Variant Creutzfeldt-Jakob Disease 157

AJP January 2006, Vol. 168, No. 1 ...TSS



http://ajp.amjpathol.org/cgi/content/abstract/168/1/151maxtoshow=&HITS=10&hits=10&RESULTFORMAT=
&fulltext=prion&searchid=1136646133963_237&FIRSTINDEX=0&volume=168&issue=1&journalcode=amjpathol



Neuropathology and Applied Neurobiology

© 2005 Blackwell Publishing Ltd

565

Blackwell Science, LtdOxford, UKNANNeuropathology and
Applied Neurobiology0305-1846Blackwell Publishing Ltd, 2005

316565579

Review article

Phenotypic variability in human prion diseases

J. W. Ironside, D. L. Ritchie and M. W. Head

National Creutzfeldt-Jakob Disease Surveillance Unit,
Division of Pathology, University of Edinburgh,
Edinburgh, UK

J. W. Ironside, D. L. Ritchie and M. W. Head (2005)

Neuropathology and Applied Neurobiology

31,

565-579

Phenotypic variability in human prion diseases


Human prion diseases are rare neurodegenerative disorders
that can occur as sporadic, familial or acquired disorders.
Within each of these categories there is a wide range
of phenotypic variation that is not encountered in other
neurodegenerative disorders. The identification of the
prion protein and its key role in the pathogenesis of this
diverse group of diseases has allowed a fuller understanding
of factors that influence disease phenotype. In particular,
the naturally occurring polymorphism at codon 129
in the prion protein gene has a major influence on the
disease phenotype in sporadic, familial and acquired prion
diseases, although the underlying mechanisms remain
unclear. Recent technical advances have improved our
ability to study the isoforms of the abnormal prion protein
in the brain and in other tissues. This has lead to the concept
of molecular strain typing, in which different isoforms
of the prion protein are proposed to correspond to
individual strains of the transmissible agent, each with
specific biological properties. In sporadic Creutzfeldt-Jakob
disease there are at least six major combinations of codon
129 genotype and prion protein isotype, which appear to
relate to distinctive clinical subgroups of this disease.
However, these relationships are proving to be more complex
than first considered, particularly in cases with more
than a single prion protein isotype in the brain. Further
work is required to clarify these relationships and to
explain the mechanism of neuropathological targeting of
specific brain regions, which accounts for the diversity of
clinical features within human prion diseases.



© 2005 Blackwell Publishing Ltd, Neuropathology and
Applied Neurobiology, 31, 565-579


BSE prions propagate as either variant CJD-like or

sporadic CJD-like prion strains in transgenic mice

expressing human prion protein



The EMBO Journal Vol. 21 No. 23 pp. 6358±6366, 2002



Emmanuel A.Asante, Jacqueline M.Linehan,

Melanie Desbruslais, Susan Joiner,

Ian Gowland, Andrew L.Wood, Julie Welch,

Andrew F.Hill, Sarah E.Lloyd,

Jonathan D.F.Wadsworth and

John Collinge1

MRC Prion Unit and Department of Neurodegenerative Disease,

Institute of Neurology, University College, Queen Square,

London WC1N 3BG, UK

1Corresponding author

e-mail: j.collinge@prion.ucl.ac.uk



Variant Creutzfeldt±Jakob disease (vCJD) has been

recognized to date only in individuals homozygous for

methionine at PRNP codon 129. Here we show that

transgenic mice expressing human PrP methionine

129, inoculated with either bovine spongiform

encephalopathy (BSE) or variant CJD prions, may

develop the neuropathological and molecular phenotype

of vCJD, consistent with these diseases being

caused by the same prion strain. Surprisingly, however,

BSE transmission to these transgenic mice, in

addition to producing a vCJD-like phenotype, can also

result in a distinct molecular phenotype that is
indistinguishable

from that of sporadic CJD with PrPSc

type 2. These data suggest that more than one BSEderived

prion strain might infect humans; it is therefore

possible that some patients with a phenotype consistent

with sporadic CJD may have a disease arising

from BSE exposure.



snip...



These studies further strengthen the evidence that vCJD

is caused by a BSE-like prion strain. Also, remarkably, the

key neuropathological hallmark of vCJD, the presence of

abundant ¯orid PrP plaques, can be recapitulated on BSE

or vCJD transmission to these mice. However, the most

surprising aspect of the studies was the ®nding that an

alternate pattern of disease can be induced in 129MM

Tg35 mice from primary transmission of BSE, with a

molecular phenotype indistinguishable from that of a
subtype

of sporadic CJD. This ®nding has important potential

implications as it raises the possibility that some humans

infected with BSE prions may develop a clinical disease

indistinguishable from classical CJD associated with type 2

PrPSc. This is, in our experience, the commonest molecular

sub-type of sporadic CJD. In this regard, it is of interest

that the reported incidence of sporadic CJD has risen
in the

UK since the 1970s (Cousens et al., 1997). This has been

attributed to improved case ascertainment, particularly as

much of the rise is reported from elderly patients and

similar rises in incidence were noted in other European

countries without reported BSE (Will et al., 1998).

However, it is now clear that BSE is present in many

European countries, albeit at a much lower incidence than

was seen in the UK. While improved ascertainment is

likely to be a major factor in this rise, that some of
these

additional cases may be related to BSE exposure cannot be

ruled out. It is of interest in this regard that a 2-fold

increase in the reported incidence of sporadic CJD in 2001

has recently been reported for Switzerland, a country that

had the highest incidence of cattle BSE in continental

Europe between 1990 and 2002 (Glatzel et al., 2002). No

epidemiological case±control studies with strati®cation of

CJD cases by molecular sub-type have yet been reported.

It will be important to review the incidence of sporadic

CJD associated with PrPSc type 2 and other molecular
subtypes

in both BSE-affected and unaffected countries in the

light of these findings. If human BSE prion infection can

result in propagation of type 2 PrPSc, it would be expected

that such cases would be indistinguishable on clinical,

pathological and molecular criteria from classical CJD. It

may also be expected that such prions would behave

biologically like those isolated from humans with sporadic

CJD with type 2 PrPSc. The transmission properties of

prions associated with type 2 PrPSc from BSE-inoculated

129MM Tg35 mice are being investigated by serial

passage.

We consider these data inconsistent with contamination

of some of the 129MM Tg35 mice with sporadic CJD

prions. These transmission studies were performed according

to rigorous biosafety protocols for preparation of

inocula and both the inoculation and care of mice, which

are all uniquely identi®ed by sub-cutaneous transponders.

However, crucially, the same BSE inocula have been used

on 129VV Tg152 and 129MM Tg45 mice, which are

highly sensitive to sporadic CJD but in which such

transmissions producing type 2 PrPSc were not observed.

Furthermore, in an independent experiment, separate

inbred lines of wild-type mice, which are highly resistant

to sporadic CJD prions, also propagated two distinctive

PrPSc types on challenge with either BSE or vCJD. No

evidence of spontaneous prion disease or PrPSc has been

seen in groups of uninoculated or mock-inoculated aged

129MM Tg35 mice.

While distinctive prion isolates have been derived from

BSE passage in mice previously (designated 301C and

301V), these, in contrast to the data presented here, are

propagated in mice expressing different prion proteins

(Bruce et al., 1994). It is unclear whether our ®ndings

indicate the existence of more than one prion strain in

individual cattle with BSE, with selection and preferential

replication of distinct strains by different hosts, or that

`mutation' of a unitary BSE strain occurs in some types of

host. Western blot analysis of single BSE isolates has not

shown evidence of the presence of a proportion of

monoglycosylated dominant PrPSc type in addition to the

diglycosylated dominant pattern (data not shown).

Extensive strain typing of large numbers of individual

BSE-infected cattle either by biological or molecular

methods has not been reported.

Presumably, the different genetic background of the

different inbred mouse lines is crucial in determining

which prion strain propagates on BSE inoculation. The

transgenic mice described here have a mixed genetic

background with contributions from FVB/N, C57BL/6 and

129Sv inbred lines; each mouse will therefore have a

different genetic background. This may explain the

differing response of individual 129MM Tg35 mice, and

the difference between 129MM Tg35 and 129MM Tg45

mice, which are, like all transgenic lines, populations

derived from single founders. Indeed, the consistent

distinctive strain propagation in FVB and C57BL/6 versus

SJL and RIIIS lines may allow mapping of genes relevant

to strain selection and propagation, and these studies

are in progress.

That different prion strains can be consistently isolated

in different inbred mouse lines challenged with BSE

prions argues that other species exposed to BSE may

develop prion diseases that are not recognizable as being

caused by the BSE strain by either biological or molecular

strain typing methods. As with 129MM Tg35 mice, the

prions replicating in such transmissions may be

indistinguishable

from naturally occurring prion strains. It

remains of considerable concern whether BSE has transmitted

to, and is being maintained in, European sheep

flocks. Given the diversity of sheep breeds affected by

scrapie, it has to be considered that some sheep might have

become infected with BSE, but propagated a distinctive

strain type indistinguishable from those of natural sheep

scrapie. ...



The EMBO Journal Vol. 21 No. 23 pp. 6358±6366, 2002

6358 ãEuropean Molecular Biology Organization


http://embojournal.npgjournals.com/cgi/reprint/21/23/6358


J Neuropsychiatry Clin Neurosci 17:489-495, November 2005
doi: 10.1176/appi.neuropsych.17.4.489
© 2005 American Psychiatric Publishing, Inc.


Psychiatric Manifestations of Creutzfeldt-Jakob Disease: A 25-Year Analysis


Christopher A. Wall, M.D., Teresa A. Rummans, M.D.,
Allen J. Aksamit, M.D.,
Lois E. Krahn, M.D. and V. Shane Pankratz, Ph.D.
Received April 20, 2004; revised September 9, 2004;
accepted September 13,
2004. From the Mayo Clinic, Department of Psychiatry
and Psychology,
Rochester, Minnesota; Mayo Clinic, Department of
Neurology, Rochester,
Minnesota. Address correspondence to Dr. Wall, Mayo
Clinic, Department of
Psychiatry and Psychology, Mayo Building-W11A, 200
First St., SW, Rochester,
MN 55905; wall.chris@mayo.edu (E-mail).

This study characterizes the type and timing of psychiatric manifestations
in sporadic Creutzfeldt-Jakob disease (sCJD). Historically, sCJD has been
characterized by prominent neurological symptoms, while the variant form
(vCJD) is described as primarily psychiatric in presentation and course: A
retrospective review of 126 sCJD patients evaluated at the Mayo Clinic from
1976-2001 was conducted. Cases were reviewed for symptoms of depression,
anxiety, psychosis, behavior dyscontrol, sleep disturbances, and
neurological signs during the disease course. Eighty percent of the cases
demonstrated psychiatric symptoms within the first 100 days of illness, with
26% occurring at presentation. The most commonly reported symptoms in this
population included sleep disturbances, psychotic symptoms, and depression.
Psychiatric manifestations are an early and prominent feature of sporadic
CJD, often occurring prior to formal diagnosis.


snip...



CONCLUSIONS

Historically, psychiatric manifestations have been described as a relatively
infrequent occurrence in the sporadic form of creutzfeldt-Jakob disease.
However, our findings suggest otherwise. In this study, a vast majority of
the cases were noted to have at least one psychiatric symptom during the
course of illness, with nearly one-quarter occurring in the prodromal or
presenting phase of the illness. After comparing the frequency of
neuropsychiatric symptoms in sporadic CJD to studies describing the variant
form of CJD, we found that there are fewer clinical differences than
previously reported.5-7 While the age of patients with vCJD presentation
is significantly younger and the course of illness is longer, the type and
timing of psychiatric manifestations appear similar between these two
diseases. ...snip...end



http://neuro.psychiatryonline.org/cgi/content/abstract/17/4/489


Polish Journal of Neurology and Neurosurgery 6/2005

abstract

CASE REPORT
Mental disorders in a female patient with probable Creutzfeldt-Jakob disease

Neurol Neurochirur Pol 2005; 39, 6: 520–523


authors: Marek Gronkowski, Bozena Spila, Alina Nowicka, Piotr Machala, Grzegorz Przywara,


The paper presents an overview of the current knowledge about the etiology, classification of
Creutzfeldt-Jakob disease, abnormalities in the results of the EEG, MR and laboratory examinations in patients with this disease. The diagnostic value of the CSF examination for presence of protein 14-3-3 is underlined. The article is based on both Polish and foreign literature, describing mainly the diagnostics of CJD. The case of a female patient with dementia, mental disorders and neurological symptoms in the course of probable CJD, who was hospitalized at the Psychogeriatric Department of the Neuropsychiatric Hospital in Lublin is described.


Polish Journal of Neurology and Neurosurgery 6/2005


full text of the article

http://www.termedia.pl/showpdf.php?article_id=4105&filename=Zaburzenia%20psych.pdf&priority=1


2 January 2000

British Medical Journal

U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well

http://www.bmj.com/cgi/eletters/320/7226/8/b#6117


15 November 1999

British Medical Journal

vCJD in the USA * BSE in U.S.


http://www.bmj.com/cgi/eletters/319/7220/1312/b#5406


i am reminded of a few things deep throat told me years ago ;

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

2000 - 2001

The most frightening thing I have read all day is the report of Gambetti's
finding of a new strain of sporadic cjd in young people......... Dear God,
what in the name of all that is holy is that!!! If the US has different
strains of scrapie.....why?? than the UK... then would the same mechanisms
that make different strains of scrapie here make different strains of BSE...
if the patterns are different in sheep and mice for scrapie..... could not
the BSE be different in the cattle, in the mink, in the humans....... I
really think the slides or tissues and everything from these young people
with the new strain of sporadic cjd should be put up to be analyzed by many,
many experts in cjd........ bse..... scrapie Scrape the damn slide and put
it into mice..... wait..... chop up the mouse brain and and spinal
cord........ put into some more mice..... dammit amplify the thing and start
the damned research..... This is NOT rocket science... we need to use what
we know and get off our butts and move.... the whining about how long
everything takes..... well it takes a whole lot longer if you whine for a
year and then start the research!!! Not sure where I read this but it was a
recent press release or something like that: I thought I would fall out of
my chair when I read about how there was no worry about infectivity from a
histopath slide or tissues because they are preserved in formic acid, or
formalin or formaldehyde..... for God's sake........ Ask any pathologist in
the UK what the brain tissues in the formalin looks like after a year.......
it is a big fat sponge... the agent continues to eat the brain ...... you
can't make slides anymore because the agent has never stopped........ and
the old slides that are stained with Hemolysin and Eosin...... they get
holier and holier and degenerate and continue... what you looked at 6 months
ago is not there........ Gambetti better be photographing every damned thing
he is looking at.....

Okay, you need to know. You don't need to pass it on as nothing will come of
it and there is not a damned thing anyone can do about it. Don't even hint
at it as it will be denied and laughed at.......... USDA is gonna do as
little as possible until there is actually a human case in the USA of the
nvcjd........ if you want to move this thing along and shake the earth....
then we gotta get the victims families to make sure whoever is doing the
autopsy is credible, trustworthy, and a saint with the courage of Joan of
Arc........ I am not kidding!!!! so, unless we get a human death from
EXACTLY the same form with EXACTLY the same histopath lesions as seen in the
UK nvcjd........ forget any action........ it is ALL gonna be sporadic!!!

And, if there is a case....... there is gonna be every effort to link it to
international travel, international food, etc. etc. etc. etc. etc. They will
go so far as to find out if a sex partner had ever traveled to the
UK/europe, etc. etc. .... It is gonna be a long, lonely, dangerous twisted
journey to the truth. They have all the cards, all the money, and are
willing to threaten and carry out those threats.... and this may be their
biggest downfall...

Thanks as always for your help. (Recently had a very startling revelation
from a rather senior person in government here.......... knocked me out of
my chair........ you must keep pushing. If I was a power person.... I would
be demanding that there be a least a million bovine tested as soon as
possible and agressively seeking this disease. The big players are coming
out of the woodwork as there is money to be made!!! In short: "FIRE AT
WILL"!!! for the very dumb.... who's "will"! " Will be the burden to bare if
there is any coverup!"

again it was said years ago and it should be taken seriously.... BSE will
NEVER be found in theUS! As for the BSE conference call... I think you did
agreat service to freedom of information and making some people feign
integrity... I find it scary to see that most of the "experts" are employed
by the federal government or are supported on the "teat" of federal funds. A
scary picture! I hope there is a confidential panel organized by the new
government to really investigate this thing.

You need to watch your back........ but keep picking at them....... like a
buzzard to the bone... you just may get to the truth!!! (You probably have
more support than you know. Too many people are afraid to show you or let
anyone else know. I have heard a few things myself... you ask the questions
that everyone else is too afraid to ask.)

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

CJD QUESTIONNAIRE

http://cjdquestionnaire.blogspot.com/


USDA CERTIFIED H-BASE MAD COW SCHOOL LUNCH PROGRAM


http://cjdmadcowbaseoct2007.blogspot.com/2008/02/usda-certified-h-base-mad-cow-school.html


Thursday, January 31, 2008

Evaluation of the Human Transmission Risk of an Atypical Bovine Spongiform
Encephalopathy Prion Strain

J. Virol. doi:10.1128/JVI.02561-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed
Authors/Institutions. All Rights Reserved.

Evaluation of the Human Transmission Risk of an Atypical Bovine Spongiform
Encephalopathy Prion Strain

Qingzhong Kong*, Mengjie Zheng, Cristina Casalone, Liuting Qing, Shenghai
Huang, Bikram Chakraborty, Ping Wang, Fusong Chen, Ignazio Cali, Cristiano
Corona, Francesca Martucci, Barbara Iulini, Pierluigi Acutis, Lan Wang,
Jingjing Liang, Meiling Wang, Xinyi Li, Salvatore Monaco, Gianluigi Zanusso,
Wen-Quan Zou, Maria Caramelli, and Pierluigi Gambetti*
Department of Pathology, Case Western Reserve University, Cleveland, OH
44106, USA; CEA, Istituto Zooprofilattico Sperimentale, 10154 Torino, Italy;
Department of Neurological and Visual Sciences, University of Verona, 37134
Verona, Italy



* To whom correspondence should be addressed. Email: qxk2@case.edu.
pxg13@case.edu.


Abstract


snip...

These results suggest that, in humans, BASE is a more virulent BSE strain
and likely lymphotropic.

snip...


SEE FULL TEXT ;


http://jvi.asm.org/cgi/content/abstract/JVI.02561-07v1?papetoc


http://cjdmadcowbaseoct2007.blogspot.com/2008/01/evaluation-of-human-transmission-risk.html


http://cjdmadcowbaseoct2007.blogspot.com/



Thursday, January 31, 2008

SPONGIFORM ENCEPHALOPATHY ADVISORY COMMITTEE Draft minutes of the 99th
meeting held on 14th December 2007


snip...


ITEM 8 - PUBLIC QUESTION AND ANSWER SESSION


40. The Chair explained that the purpose of the question and answer
session was to give members of the public an opportunity to ask
questions related to the work of SEAC. Mr Terry Singeltary
(Texas, USA) had submitted a question prior to the meeting,
asking: "With the Nor-98 now documented in five different states so
far in the USA in 2007, and with the two atypical BSE H-base


13
© SEAC 2007


cases in Texas and Alabama, with both scrapie and chronic
wasting disease (CWD) running rampant in the USA, is there any
concern from SEAC with the rise of sporadic CJD in the USA from
''unknown phenotype'', and what concerns if any, in relations to
blood donations, surgery, optical, and dental treatment, do you
have with these unknown atypical phenotypes in both humans and
animals in the USA? Does it concern SEAC, or is it of no concern
to SEAC? Should it concern USA animal and human health
officials?"


41. A member considered that this question ............


snip... please see full text, sources, and comments here ;


http://seac992007.blogspot.com/2008/01/spongiform-encephalopathy-advisory.html


CJD TEXAS

http://cjdtexas.blogspot.com/


Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in
the United States

http://cjdusa.blogspot.com/


Creutzfeldt Jakob Disease

http://creutzfeldt-jakob-disease.blogspot.com/


Creutzfeldt-Jakob Disease, Prion Protein Gene Codon 129VV, and a Novel PrPSc
Type in a Young British Woman


http://creutzfeldt-jakob-disease.blogspot.com/2008/01/creutzfeldt-jakob-disease-prion-protein.html


CJD QUESTIONNAIRE

http://cjdquestionnaire.blogspot.com/


ANIMAL HEALTH REPORT 2006 (BSE h-BASE EVENT IN ALABAMA, Scrapie, and CWD)

http://animalhealthreport2006.blogspot.com/


CREUTZFELDT JAKOB DISEASE MAD COW BASE UPDATE USA

http://cjdmadcowbaseoct2007.blogspot.com/


Friday, January 11, 2008

CJD HUMAN TSE REPORT UK, USA, CANADA, and Mexico JANUARY 2008


http://cjdmadcowbaseoct2007.blogspot.com/2008/01/cjd-human-tse-report-uk-usa-canada-and.html


Friday, January 25, 2008

January 2008 Update on Feed Enforcement Activities to Limit the Spread of BSE

http://madcowspontaneousnot.blogspot.com/2008/01/january-2008-update-on-feed-enforcement.html


http://madcowspontaneousnot.blogspot.com/


BSE BASE MAD COW TESTING TEXAS, USA, AND CANADA

http://madcowtesting.blogspot.com/


NOR-98 ATYPICAL SCRAPIE USA UPDATE AS AT OCT 2007

http://nor-98.blogspot.com/


Scrapie

http://scrapie-usa.blogspot.com/



Diagnosis and Reporting of Creutzfeldt-Jakob Disease

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


Diagnosis and Reporting of Creutzfeldt-Jakob Disease

Since this article does not have an abstract, we have provided the first 150
words of the full text and any section headings.


To the Editor
In their Research Letter, Dr Gibbons and colleagues1 reported that the
annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable
since 1985. These estimates, however, are based only on reported cases, and
do not include misdiagnosed or preclinical cases. It seems to me that
misdiagnosis alone would drastically change these figures. An unknown number
of persons with a diagnosis of Alzheimer disease in fact may have CJD,
although only a small number of these patients receive the postmortem
examination necessary to make this diagnosis. Furthermore, only a few states
have made CJD reportable. Human and animal transmissible spongiform
encephalopathies should be reportable nationwide and internationally.

Terry S. Singeltary, Sr
Bacliff, Tex



1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob
disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323. FREE FULL
TEXT


http://jama.ama-assn.org/cgi/content/extract/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=singeltary&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

PDF]Freas, William TSS SUBMISSION
File Format: PDF/Adobe Acrobat -Page 1. J Freas, William From: SentToSubjectTerry S. SingeltarySr. [flounder@wt.net]
Monday, January 08,200l 3:03 PM freas ...

http://www.fda.gov/ohrms/dockets/ac/01/slides/3681s2_09.pdf


Asante/Collinge et al, that BSE transmission to the 129-methionine genotype
can lead to an alternate phenotype that is indistinguishable from type 2
PrPSc, the commonest _sporadic_ CJD;

http://www.fda.gov/ohrms/dockets/ac/03/slides/3923s1_OPH.htm


2001

DER SPIEGEL (9/2001) - 24.02.2001 (9397 Zeichen)USA: Loch in der MauerDie
BSE-Angst erreicht Amerika: Trotz strikter Auflagen gelangte in Texas
verbotenes Tiermehl ins Rinderfutter - die Kontrollen der
Aufsichtsbehördensind lax.Link auf diesen Artikel im
Archiv:http://service.spiegel.de/digas/find?DID=18578755


"Its as full of holes as Swiss Cheese" says Terry Singeltary of the FDA
regulations. ...


http://service.spiegel.de/digas/servlet/find/DID=18578755


Thu Dec 6, 2007 11:38

FDA IN CRISIS MODE, AMERICAN LIVES AT RISK


http://www.cidrap.umn.edu/cidrap/content/fs/food-disease/news/dec0407fda.html


FDA SCIENCE AND MISSION AT RISK

http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4329b_02_01_FDA%20Report%20on%20Science%20and%20Technology.pdf\



HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory

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 theUKBSEnvCJD only theory in 2007. With all the science to date refuting it, to continue to validate this myth, will only spread this TSE agent through a multitude of potential and proven routes and sources i.e. consumption, surgical, blood, medical, cosmetics etc. I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route.

This would further have to be broken down to strain of species and then the route of transmission would further have to be broken down. Accumulation and Transmission are key to the threshold from sub-clinical to clinical disease, and key to all this, is to stop the amplification and transmission of the TSE agent, the spreading of, no matter what strain. In my opinion, to continue with this myth that the U.K. strain of BSE (one strain TSE in cows), and the nv/v CJD (one strain TSE humans) and that all the rest of human TSE are just one single strain i.e. sporadic CJD (when to date there are 6 different phenotypes of sCJD, and growing per Gambetti et al), and that no other animal TSE transmits to humans, to continue with this masquerade will only continue to spread, expose, and kill, who knows how many more in the years and decades to come. ONE was enough for me, My Mom, hvCJD i.e. HeidenhainVariant CJD, DOD 12/14/97 confirmed, which is nothing more than another mans name added to CJD, like CJD itself, Jakob and Creutzfeldt, or Gerstmann-Straussler-Scheinker syndrome, just another CJD or human TSE, named after another human.

With the H-BASE atypical BSE strain, and the Nor-98 atypical Scrapie strain, BOTH now documented in the USA, and BOTH more closely related pathologically to the sporadic CJD, rather than the BSE strain, I once again urge you to make all human TSE strains in the USA reportable in every state, and Internationally, with a written mandatory CJD/TSE questionnaire asking real questions pertaining to route and source of the TSE agent. This is paramount for iCJD i.e. friendly fire, and secondary transmissions via the medical, dental, and surgical arena alone.

WE are only kidding ourselves with the current diagnostic criteria for human and animal TSE, especially differentiating between the nvCJD vs the sporadic CJD strains and then the GSS strains and also the FFI fatal familial insomnia strains or the ones that mimics one or the other of those TSE? Tissue infectivity and strain typing of the many variants of the human and animal TSEs are paramount in all variants of all TSE. There must be a proper classification that will differentiate between all these human TSE in order to do this. With the CDI and other more sensitive testing coming about, I only hope that my proposal will some day be taken seriously. ...


flounder9@verizon.net


Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518
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