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From: TSS ()
Subject: MONTHLY CJD FIGURES MONDAY 9 JANUARY 2006
Date: January 9, 2006 at 8:59 am PST

Monthly Creutzfeldt Jakob disease statistics
Published:
Monday 9 January 2006
Reference number:
2006/0009

The Department of Health is today issuing the latest information about the numbers of known cases of Creutzfeldt Jakob disease. This includes cases of variant Creutzfeldt Jakob disease (vCJD) - the form of the disease thought to be linked to BSE. The position is as follows:

Definite and probable CJD cases in the UK:

As at 6 January 2006

Summary of vCJD cases

Deaths

Deaths from definite vCJD (confirmed): 109

Deaths from probable vCJD (without neuropathological confirmation): 43

Deaths from probable vCJD (neuropathological confirmation pending): 1

Number of deaths from definite or probable vCJD (as above): 153

Alive

Number of probable vCJD cases still alive: 6

Total number of definite or probable vCJD (dead and alive): 159

The next table will be published on Monday 6th February 2006

Referrals: a simple count of all the cases which have been referred to the National CJD Surveillance Unit for further investigation in the year in question. CJD may be no more than suspected; about half the cases referred in the past have turned out not to be CJD. Cases are notified to the Unit from a variety of sources including neurologists, neuropathologists, neurophysiologists, general physicians, psychiatrists, electroencephalogram (EEG) departments etc. As a safety net, death certificates coded under the specific rubrics 046.1 and 331.9 in the 9th ICD Revisions are obtained from the Office for National Statistics in England and Wales, the General Register Office for Scotland and the General Register Office for Northern Ireland.

Deaths: All columns show the number of deaths that have occurred in definite and probable cases of all types of CJD and GSS in the year shown. The figures include both cases referred to the Unit for investigation while the patient was still alive and those where CJD was only discovered post mortem (including a few cases picked up by the Unit from death certificates). There is therefore no read across from these columns to the referrals column. The figures will be subject to retrospective adjustment as diagnoses are confirmed.

Definite cases: this refers to the diagnostic status of cases. In definite cases the diagnosis will have been pathologically confirmed, in most cases by post mortem examination of brain tissue (rarely it may be possible to establish a definite diagnosis by brain biopsy while the patient is still alive).

Probable vCJD cases: are those who fulfil the ‘probable’ criteria set out in the Annex and are either still alive, or have died and await post mortem pathological confirmation. Those still alive will always be shown within the current year's figures.

Sporadic: Classic CJD cases with typical EEG and brain pathology. Sporadic cases appear to occur spontaneously with no identifiable cause and account for 85% of all cases.

Probable sporadic: Cases with a history of rapidly progressive dementia, typical EEG and at least two of the following clinical features; myoclonus, visual or cerebellar signs, pyramidal/extrapyramidalsigns or akinetic mutism.

Iatrogenic: where infection with classic CJD has occurred accidentally as the result of a medical procedure. All UK cases have resulted from treatment with human derived pituitary growth hormones or from grafts using dura mater (a membrane lining the skull).

Familial: cases occurring in families associated with mutations in the PrP gene (10 - 15% of cases).

GSS: Gerstmann-Straussler-Scheinker syndrome - an exceedingly rare inherited autosomal dominant disease, typified by chronic progressive ataxia and terminal dementia. The clinical duration is from 2 to 10 years, much longer than for CJD.

vCJD: Variant CJD, the hitherto unrecognised variant of CJD discovered by the National CJD Surveillance Unit and reported in The Lancet on 6 April 1996. This is characterised clinically by a progressive neuropsychiatric disorder leading to ataxia, dementia and myoclonus (or chorea) without the typical EEG appearance of CJD. Neuropathology shows marked spongiform change and extensive florid plaques throughout the brain.

Definite vCJD cases still alive: These will be cases where the diagnosis has been pathologically confirmed (by brain biopsy).


Related links
Download CJD statistics January 2006 (PDF, 12K)
Notes to editor
ANNEX

DIAGNOSTIC CRITERIA FOR VARIANT CJD

I A) PROGRESSIVE NEUROPSYCHIATRIC DISORDER

B) DURATION OF ILLNESS > 6 MONTHS

C) ROUTINE INVESTIGATIONS DO NOT SUGGEST AN ALTERNATIVE

DIAGNOSIS

D) NO HISTORY OF POTENTIAL IATROGENIC EXPOSURE

II A) EARLY PSYCHIATRIC SYMPTOMS *

B) PERSISTENT PAINFUL SENSORY SYMPTOMS **

C) ATAXIA

D) MYOCLONUS OR CHOREA OR DYSTONIA

E) DEMENTIA

III A) EEG DOES NOT SHOW THE TYPICAL APPEARANCE OF SPORADIC

CJD *** (OR NO EEG PERFORMED)

B) BILATERAL PULVINAR HIGH SIGNAL ON MRI SCAN

IV A) POSITIVE TONSIL BIOPSY

DEFINITE: IA (PROGRESSIVE NEUROPSYCHIATRIC DISORDER) and

NEUROPATHOLOGICAL CONFIRMATION OF vCJD ****

PROBABLE: I and 4/5 OF II and III A and III B

or I and IV A

* depression, anxiety, apathy, withdrawal, delusions.

** this includes both frank pain and/ or unpleasant dysaesthesia

*** generalised triphasic periodic complexes at approximately one per second

****spongiform change and extensive PrP deposition with florid plaques, throughout

the cerebrum and cerebellum.

http://www.dh.gov.uk/PublicationsAndStatistics/PressReleases/PressReleasesNotices/fs/en?CONTENT_ID=4126119&chk=joOCEs

SEE SPORADIC CJD CASES HERE;

http://www.eurocjd.ed.ac.uk/sporadic.htm

TOTAL CASES OF FAMILIAL/GENETIC CJD AND IATROGENIC CJD
DEATHS TO 30 SEPTEMBER 2005

http://www.eurocjd.ed.ac.uk/genetic.htm


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

In the apparent absence of a foreign nucleic acid genome

associated with the agents responsible for transmissible

spongiform encephalopathies or prion diseases,

efforts to provide a molecular definition of agent strain

have focused on biochemical differences in the abnormal,

disease-associated form of the prion protein, termed

PrPSc. Differences in PrPSc conformation and glycosylation

have been proposed to underlie disease phenotype

and form the biochemical basis of agent strain. This

proposal has found support in the observation that the

major phenotypic subtypes of sCJD appear to correlate

with the presence of either type 1 or type 2 PrPSc in

combination with the presence of either methionine or

valine at codon 129 of the prion protein gene.2 Similarly,

the PrPSc type associated with vCJD correlates with the

presence of type 2 PrPSc and is distinct from that found in

sCJD because of a characteristically high occupancy of

both N-linked glycosylation sites (type 2B).6,11 The

means by which such conformational difference is detected

is somewhat indirect; relying on the action of proteases,

primarily proteinase K, to degrade the normal

Figure 6. Type 1 PrPSc is a stable minority component of PrPSc from the vCJD

brain. Western blot analysis of PrP in a sample of cerebral cortex from a case

of vCJD during digestion with proteinase K is shown. Time points assayed

are indicated in minutes (T0, 5, 10, 30, 60, 120, 180). Duplicate blots were

probed with 3F4, which detects both type 1 and type 2 PrPSc, and with 12B2,

which detects type 1. The insert shows a shorter exposure of the same time

course study from a separate experiment also probed with 3F4. Both blots

included samples of cerebral cortex from a case of sporadic CJD MM1 (Type

1) and molecular weight markers (Markers) indicate weights in kd.

Figure 7. A minority type 1-like PrPSc is found in vCJD tonsil, vCJD transmitted

to mice and in BSE. Western blot analysis of PrPSc in a concentrated

sample of tonsil from a case of vCJD (Tonsil), in a concentrated brain sample

of a wild-type mouse (C57BL) infected with vCJD and in a sample of cattle

BSE brain (BSE) is shown. Tissue extracts were digested with proteinase K.

Duplicate blots were probed with either 3F4 or 6H4, both of which detect

type 1 and type 2 PrPSc, and with 12B2, which detects type 1. The blots

included samples of cerebral cortex from a case of sporadic CJD MM1 (Type

1) and molecular weight markers (Markers) indicate weights in kd.

Type 1 PrPSc in Variant Creutzfeldt-Jakob Disease 155

AJP January 2006, Vol. 168, No. 1

cellular form of PrP and produce a protease-resistant

core fragment of PrPSc that differs in the extent of its

N-terminal truncation according to the original

conformation.

A complication has recently arisen with the finding that

both type 1 and type 2 can co-exist in the brains of

patients with sCJD.2,5-8 More recently this same phenomenon

has been demonstrated in patients with iatrogenically

acquired and familial forms of human prion disease.

9,10 The existence of this phenomenon is now

beyond doubt but its prevalence and its biological significance

remain a matter of debate.

Conventional Western blot analysis using antibodies

that detect type 1 and type 2 PrPSc has severe quantitative

limitations for the co-detection of type 1 and type 2

PrPSc in individual samples, suggesting that the prevalence

of co-occurrence of the two types might be underestimated.

We have sought to circumvent this problem by

using an antibody that is type 1-specific and applied this

to the sole remaining human prion disease where the

phenomenon of mixed PrPSc types has not yet been

shown, namely vCJD.

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://neurology.thelancet.com Published online October 31, 2005


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, type 1 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?


http://neurology.thelancet.com Published online October 31, 2005


HUMAN TSE USA 2005


Animal Prion Diseases Relevant to Humans (unknown types?)
Thu Oct 27, 2005 12:05
71.248.128.109


About Human Prion Diseases /
Animal Prion Diseases Relevant to Humans

Bovine Spongiform Encephalopathy (BSE) is a prion disease of cattle. Since 1986, when BSE was recognized, over 180,000 cattle in the UK have developed the disease, and approximately one to three million are likely to have been infected with the BSE agent, most of which were slaughtered for human consumption before developing signs of the disease. The origin of the first case of BSE is unknown, but the epidemic was caused by the recycling of processed waste parts of cattle, some of which were infected with the BSE agent and given to other cattle in feed. Control measures have resulted in the consistent decline of the epidemic in the UK since 1992. Infected cattle and feed exported from the UK have resulted in smaller epidemics in other European countries, where control measures were applied later.

Compelling evidence indicates that BSE can be transmitted to humans through the consumption of prion contaminated meat. BSE-infected individuals eventually develop vCJD with an incubation time believed to be on average 10 years. As of November 2004, three cases of BSE have been reported in North America. One had been imported to Canada from the UK, one was grown in Canada, and one discovered in the USA but of Canadian origin. There has been only one case of vCJD reported in the USA, but the patient most likely acquired the disease in the United Kingdom. If current control measures intended to protect public and animal health are well enforced, the cattle epidemic should be largely under control and any remaining risk to humans through beef consumption should be very small. (For more details see Smith et al. British Medical Bulletin, 66: 185. 2003.)

Chronic Wasting Disease (CWD) is a prion disease of elk and deer, both free range and in captivity. CWD is endemic in areas of Colorado, Wyoming, and Nebraska, but new foci of this disease have been detected in Nebraska, South Dakota, New Mexico, Wisconsin, Mississippi Kansas, Oklahoma, Minnesota, Montana, and Canada. Since there are an estimated 22 million elk and deer in the USA and a large number of hunters who consume elk and deer meat, there is the possibility that CWD can be transmitted from elk and deer to humans. As of November 2004, the NPDPSC has examined 26 hunters with a suspected prion disease. However, all of them appeared to have either typical sporadic or familial forms of the disease. The NPDPSC coordinates with the Centers for Disease Control and state health departments to monitor cases from CWD-endemic areas. Furthermore, it is doing experimental research on CWD transmissibility using animal models. (For details see Sigurdson et al. British Medical Bulletin. 66: 199. 2003 and Belay et al. Emerging Infectious Diseases. 10(6): 977. 2004.)


http://www.cjdsurveillance.com/abouthpd-animal.html


SEE STEADY INCREASE IN SPORADIC CJD IN THE USA FROM 1997 TO 2004. SPORADIC CJD CASES TRIPLED, and that is with a human TSE surveillance system that is terrible flawed. in 1997 cases of the _reported_ cases of cjd were at 54, to 163 _reported_ cases in 2004. see stats here;

p.s. please note the 47 PENDING CASES to Sept. 2005

p.s. please note the 2005 Prion D. total 120(8) 8=includes 51 type pending, 1 TYPE UNKNOWN ???

p.s. please note sporadic CJD 2002(1) 1=3 TYPE UNKNOWN???

p.s. please note 2004 prion disease (6) 6=7 TYPE UNKNOWN???


http://www.cjdsurveillance.com/resources-casereport.html


CWD TO HUMANS = sCJD ???


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://www.bseinquiry.gov.uk/files/yb/1991/01/04004001.pdf


ATYPICAL TSEs in USA CATTLE AND SHEEP ?


http://www.bseinquiry.gov.uk/files/sc/seac17/tab03.pdf


Infected and Source Flocks

As of August 31, 2005, there were 115 scrapie infected and source flocks (figure 3). There were 3 new infected and source flocks reported in August (Figure 4) with a total of 148 flocks reported for FY 2005 (Figure 5). The total infected and source flocks that have been released in FY 2005 are 102 (Figure 6), with 5 flocks released in August. The ratio of infected and source flocks released to newly infected and source flocks for FY 2005 = 0.69 :
1. In addition, as of August 31, 2005, 574 scrapie cases have been confirmed and reported by the National Veterinary Services Laboratories (NVSL), of which 122 were RSSS cases (Figure 7). This includes 55 newly confirmed cases in August 2005 (Figure 8). Fifteen cases of scrapie in goats have been reported since 1990 (Figure 9). The last goat case was reported in May 2005.

snip...

full text ;

http://www.aphis.usda.gov/vs/nahps/scrapie/monthly_report/monthly-report.html


TSS



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