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PRION DISEASE UPDATE 2009 (10)
******************************
A ProMED-mail post
<http://www.promedmail.org>
ProMED-mail is a program of the
International Society for Infectious Diseases
<http://www.isid.org>
[With the continuing decline in the number of cases in the human population
of variant Creutzfeldt-Jakob disease -- abbreviated previously as vCJD or
CJD (new var.) in ProMED-mail -- it has been decided to broaden the scope
of the occasional ProMED-mail updates to include some other prion-related
diseases. In addition to vCJD, data on other forms of CJD, sporadic,
iatrogenic, familial, and GSS (Gerstmann-Straussler-Scheinker disease), are
included also since they may have some relevance to the incidence and
etiology of vCJD. - Mod.CP]
In this update:
[1] UK: National CJD Surveillance Unit - monthly statistics as of 2 Nov
2009 - new vCJD case
[2] France: Institut de Veille Sanitaire - monthly statistics as of 2 Nov 2009
[3] US National Prion Disease Center - not updated (quarterly statistics as
of 15 May 2009)
[4] Prion molecular structure
[5] Role of FDC cells
[6] Cattle import error (UK ex Czech Republic)
******
[1] UK: National CJD Surveillance Unit - monthly statistics as of 2 Nov 2009
Date: Mon 2 Nov 2009
Source: UK National CJD Surveillance Unit, monthly statistics [edited]
<http://www.cjd.ed.ac.uk/figures.htm>
The number of deaths due to definite or probable vCJD cases has risen by
one to 166. A total of 4 definite/probable patients are still alive, so
that the total number of definite or probable vCJD cases has increased to 170.
Although 2 new cases vCJE has been recorded this year [2009], the overall
picture is still consistent with the view that the vCJD outbreak in the UK
is in decline, albeit with a pronounced tail. The 1st cases were observed
in 1995, and the peak number of deaths was 28 in the year 2000, followed by
20 in 2001, 17 in 2002, 18 in 2003, 9 in 2004, 5 in 2005, 5 in 2006, 5 in
2007, one in 2008, and so far 2 in 2009.
Totals for all types of CJD cases in the UK in the year 2009
-----
As of Mon 2 Nov 2009 in the UK so far this year [2009], there have been 122
referrals, 51 cases of sporadic CJD, one case of familial CJD, one case of
iatrogenic CJD, 3 cases of GSS, and 2 case of vCJD.
--
communicated by:
ProMED-mail <promed@promedmail.org>
******
[2] France: Institut de Veille Sanitaire - monthly statistics as of Mon 2
Nov 2009
Date: Mon 2 Nov 2009
Source: IVS - Maladie de Creutzfeldt-Jakob et maladies apparentees [in
French, trans. & summ. Mod.CP]
<http://www.invs.sante.fr/display/?doc=publications/mcj/donnees_mcj.html>
So far in the 1st 9 months of 2009 there have been 1202 referrals, 63 cases
of sporadic CJD, 9 cases of familial CJD 3 cases of iatrogenic CJD, and 2
confirmed cases of vCJD.
A total of 25 cases of confirmed or probable vCJD have now been recorded in
France since 1997. The 25 confirmed cases comprise 13 females and 12 males.
All 25 are now deceased. Their median age was 37 (range 19 to 58). Seven
were resident in the Ile-de-France and 18 in the provinces. All the
identified cases have been Met-Met homozygotes. No risk factor has been
identified. One of the 25 had made frequent visits to the United Kingdom.
--
communicated by:
ProMED-mail <promed@promedmail.org>
******
[3] US National Prion Disease Center - not updated (quarterly statistics as
of 15 May 2009)
Date: Thu 6 Aug 2009
Source: US National Prion Disease Pathology Surveillance Center [edited]
<http://www.cjdsurveillance.com/pdf/case-table.pdf>
Not updated since 15 May 2009: During the period 1 Jan 2009 to 15 May 2009
there were 116 referrals, of which 66 were classified as prion disease,
comprising 37 cases of sporadic CJD, 14 of familial CJD, and no cases of
iatrogenic CJD or vCJD. (NB: The prion disease category includes cases
where the type determination is pending, but where vCJD has been excluded).
--
communicated by:
ProMED-mail <promed@promedmail.org>
******
[4] Prion molecular structure
Date: Wed 7 Oct 2009
Source: Vanderbilt University News Network [edited]
<http://sitemason.vanderbilt.edu/news/releases/2009/10/05/first-direct-information-about-the-prions-molecular-structure-reported.93044>
A collaboration between scientists at Vanderbilt University and the
University of California, San Francisco has led to the 1st direct
information about the molecular structure of prions. In addition, the study
has revealed surprisingly large structural differences between natural
prions and the closest synthetic analogs that scientists have created in
the lab.
Prions are the infectious proteins responsible for human Creutzfeldt-Jakob
disease, bovine spongiform encephalopathy ["mad cow" disease], scrapie in
sheep, and several other related nervous system disorders in mammals. For a
number of years, scientists have been using the tools of genetic
engineering to create synthetic versions of these particles so they could
study them more easily. Although researchers have made particles [by
molecular genetics] that appear identical to natural prions, they have had
trouble duplicating their infectious behavior.
"We expected to find subtle differences, but we found major differences
instead," said Gerald Stubbs, professor of biological sciences at
Vanderbilt University. "Although we cannot say for certain that the
differences we've seen can explain why natural prions are so infectious,
there is a good chance that they are closely related."
The study, which was published online in the Proceedings of the National
Academy of Sciences last week [abstract reproduced below], was a joint
effort of the Stubbs laboratory and that of Stanley Prusiner at the
University of California, San Francisco (UCSF), who received the Nobel
Prize for the discovery of prions. "Our results will aid in attempts to
create the infectious synthetic prions that are needed to figure out how
prions work and ultimately to find cures for the diseases that they cause,"
said the lead author of the study, Holger Wille, assistant adjunct
professor of neurology in the Institute for Neurodegenerative Diseases,
which is based at UCSF and directed by Prusiner.
Prusiner's group was the 1st one that succeeded in making infectious prions
in the test tube. However, they are not nearly as infectious as the real
thing. 6 years ago, Prusiner contacted Stubbs, who is a world authority on
determining the molecular structures of fibrous materials, and asked if he
was interested in collaborating on an effort to characterize the detailed
structure of prions. It didn't take much convincing. "I've always been
interested in prions, so I readily agreed," said Stubbs.
Prions, because of their association with mad cow disease, are the most
notorious of the amyloids, which are insoluble clumps of fibrous protein
that play a role in a number of neurodegenerative diseases, including
Alzheimer's, Parkinson's and Lou Gehrig disease, as well as some other
common illnesses, including type II diabetes. "It is particularly difficult
to determine the molecular structure of fibrous materials like these
because they have an intrinsically high level of disorder," Stubbs explained.
When viewed with an electron microscope, which can magnify images up to one
million times, the natural and synthetic prions look nearly identical. They
both clump together to form microscopic filaments. At a magnification of
approximately 100 000 times, the only visible difference is the width of
the filaments: the synthetic material shows a wider distribution of widths
than the natural material.
[Electron micrographs of normal and synthetic prions can be seen in the
Science Daily version of this article at:
<http://www.sciencedaily.com/releases/2009/10/091005161324.htm> - Mod.CP]
The Stubbs lab used unconventional X-ray diffraction methods to get the 1st
details of the molecular structures of natural prions and Prusiner's
synthetic prions. The researchers found that the synthetic prions were
shaped something like a ladder. Based on electron microscopic images, the
Prusiner lab had proposed that the natural prions have a more complex,
3-sided cylindrical shape, and the X-ray experiments supported this proposal.
"The natural, infectious prions are folded into a much more complicated
shape," said Stubbs. Proteins are molecules that are folded into shapes
that determine their biological properties. Prions and the other amyloids
are cases in which proteins are misfolded into shapes that interfere with
normal biological processes. "Normally, the cellular systems deal with
misfolded proteins but, for some reason, these slip through the cracks," he
said.
Prions don't have any DNA in their make-up so they don't reproduce in a
normal fashion. Instead, they spread by transforming proteins they come
into contact with into prions by causing them to misfold. "Our data on
prion structure is an important step toward understanding prion infection,"
said Stubbs, "and understanding the process is essential before people can
design drugs that restrict or prevent it."
--
communicated by:
ProMED-mail <promed@promedmail.org>
[It is not entirely clear whether the structural difference between the
recombinant synthetic prions and natural prions relates to greater
transmissibility of natural prions, or represents a more
replication-competent conformation in the case of natural prions.
Alternatively inhibitory forms of recombinant prion amyloid may interfere
with replication subsequent to transmission.
For the benefit of readers the abstract of the publication referred to in
the communication from Vanderbilt University is reproduced below. - Mod.CP
Wille H, Bian W, McDonald M, Kendall A, Colby DW, Bloch L, et al. Natural
and synthetic prion structure from X-ray fiber diffraction. Proc Natl Acad
Sci USA 2009 Sep 28. Epub ahead of print
<http://www.pnas.org/content/106/40/16990.abstract >
"A conformational isoform of the mammalian prion protein (PrP(Sc)) is the
sole component of the infectious pathogen that causes the prion diseases.
We have obtained X-ray fiber diffraction patterns from infectious prions
that show cross-beta diffraction: meridional intensity at 4.8 A resolution,
indicating the presence of beta strands running approximately at right
angles to the filament axis and characteristic of amyloid structure. Some
of the patterns also indicated the presence of a repeating unit along the
fiber axis, corresponding to 4 beta-strands. We found that recombinant
(rec) PrP amyloid differs substantially from highly infectious
brain-derived prions, both in structure as demonstrated by the diffraction
data, and in heterogeneity as shown by electron microscopy. In addition to
the strong 4.8 A meridional reflection, the recPrP amyloid diffraction is
characterized by strong equatorial intensity at approximately 10.5 A,
absent from brain-derived prions, and indicating the presence of stacked
beta-sheets. Synthetic prions recovered from transgenic mice inoculated
with recPrP amyloid displayed structural characteristics and homogeneity
similar to those of naturally occurring prions. The relationship between
the structural differences and prion infectivity is uncertain, but might be
explained by any of several hypotheses: only a minority of recPrP amyloid
possesses a replication-competent conformation, the majority of recPrP
amyloid has to undergo a conformational maturation to acquire replication
competency, or inhibitory forms of recPrP amyloid interfere with
replication during the initial transmission."]
******
[5] Role of FDC cells
Date: Thu 15 Oct 2009
Source: Science Daily [edited]
<http://www.sciencedaily.com/releases/2009/10/091014102032.htm>
Specific cells within the immune system could help explain why younger
people are more susceptible to variant Creutzfeldt-Jakob disease (vCJD),
scientists believe. Patients diagnosed with variant CJD are, on average, 28
years old but it has been unclear why older people are not as affected by
the disease. Variant CJD is a rare, degenerative, fatal brain disorder in
humans, according to the US Centers for Disease Control and Prevention.
Research at The Roslin Institute of the University of Edinburgh has
identified specific cells within the immune system that attract corrupted
proteins -- known as prions -- linked to variant CJD and encourage them to
multiply and spread.
The study, published in the Journal of Immunology, looked at how these
cells behaved in mice and found that the cells were impaired in older mice.
As a result, they were unable to trap and replicate the prions and the mice
did not develop clinical disease.
Neil Mabbott, of The Roslin Institute, said: "It has always been unclear
why younger people were more susceptible to variant CJD and the assumption
that they were more likely to eat cheap meat products is far too
simplistic. Understanding what happens to these cells, which are important
for the body's immune responses, could help us develop better ways of
diagnosing variant CJD or even find ways of preventing prions from
spreading to the brain. It could also help to create a vaccine."
Prions accumulate in lymphoid tissues -- part of the body's immune system
that include the spleen, lymph nodes, and tonsils -- before spreading to
the central nervous system where they kill off brain cells and cause
neurological disease. Attempts to estimate the number of people carrying
variant CJD have relied upon identifying the presence of prions in tonsil
and appendix samples collected during routine operations.
The latest study, funded by the Biotechnology and Biological Sciences
Research Council, suggests that even more people may be infected than
previously thought as researchers also found prions present in brain tissue
from older mice, which had not developed clinical disease.
Even when prions were present in the brains of older mice, however, they
were not always found in lymphoid tissues, suggesting that the prediction
of cases may be underestimated. It is thought the prions may have spread to
the brain before they died off in the lymphoid tissues. (Adapted from
materials provided by University of Edinburgh, via EurekAlert!, a service
of AAAS).
--
communicated by:
Terry S Singeltary Sr <flounder9@verizon.net>
[It is important to note that these experiments featured transmission of
the scrapie agent (originating from sheep) in an adult laboratory mouse
model. It is a large step to extrapolate these findings to explain features
of the the human situation, although they they are potentially significant.
The details and abstract of the Journal of Immunology paper are reproduced
below:
KL Brown, GJ Wathne, J Sales, ME Bruce, NA Mabbot. The effects of host age
on follicular dendritic cell status dramatically impair scrapie agent
neuroinvasion in aged mice. J Immunol 2009; 183: 5199-207. Published online
28 Sep <http://www.jimmunol.org/cgi/content/abstract/183/8/5199 >.
Abstract: "Following peripheral exposure, many transmissible spongiform
encephalopathy (TSE) agents accumulate 1st in lymphoid tissues before
spreading to the CNS (termed neuroinvasion) where they cause
neurodegeneration. Early TSE agent accumulation upon follicular dendritic
cells (FDCs) in lymphoid follicles appears critical for efficient
neuroinvasion. Most clinical cases of variant Creutzfeldt-Jakob disease
have occurred in young adults, although the reasons behind this apparent
age-related susceptibility are uncertain. Host age has a significant
influence on immune function. As FDC status and immune complex trapping is
reduced in aged mice (600 days old), we hypothesized that this
aging-related decline in FDC function might impair TSE pathogenesis. We
show that coincident with the effects of host age on FDC status, the early
TSE agent accumulation in the spleens of aged mice was significantly
impaired. Furthermore, following peripheral exposure, none of the aged mice
developed clinical TSE disease during their life spans, although most mice
displayed histopathological signs of TSE disease in their brains. Our data
imply that the reduced status of FDCs in aged mice significantly impairs
the early TSE agent accumulation in lymphoid tissues and subsequent
neuroinvasion. Furthermore, the inefficient neuroinvasion in aged
individuals may lead to significant levels of subclinical TSE disease in
the population." - Mod.CP]
******
[6] Cattle import error (UK ex Czech Republic)
Date: Thu 29 Oct 2009
Source: Food Standards Agency [edited]
<http://www.food.gov.uk/news/newsarchive/2009/oct/cowover30>
The [Food Standards] Agency has been notified that a cow aged over 30
months and imported from the Czech Republic had not been tested for bovine
spongiform encephalopathy (BSE). The cow was slaughtered on Thu 1 Oct 2009
at Alec Jarrett Ltd's abattoir in Oldland Common, Bristol, aged one day
short of 33 months. The cow was born in the Czech Republic and was imported
earlier this year [2009]. BSE testing is mandatory for cattle born there if
slaughtered for human consumption at over 30 months of age.
On Thu 8 Oct 2009, Alec Jarrett Ltd realised there had been an error and
acted quickly, preventing the carcass leaving the premises and recalling
all associated material that had left the premises. All the recalled
product and material still on site has since been disposed of under
official supervision. None of the affected product has reached the UK food
supply. A small amount of product has been exported to France and the
authorities there have been informed.
Background to BSE testing
[Bovine spongiform encephalopathy (BSE), commonly known as mad cow disease
(MCD), is a fatal, neurodegenerative disease in cattle, that causes a
spongy degeneration in the brain and spinal cord. BSE has a long incubation
period, about 4 years, usually affecting adult cattle at a peak age onset
of 4 to 5 years, all breeds being equally susceptible. In the United
Kingdom, the country worst affected, more than 179 000 cattle have been
infected and 4.4 million slaughtered during the eradication programme. -
Mod.CP]
Cattle aged over 48 months must be BSE tested before entering the food
supply if born in one of the following countries: Austria, Belgium,
Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg,
Netherlands, Portugal, Slovenia, Spain, Sweden, and United Kingdom.
Cattle aged over 30 months and born in any other country, including the
Czech Republic [because 28 cases of BSE were reported between 2001 and 2007
- Mod.CP], are only allowed to enter the food supply if they have 1st
tested negative for BSE. If there is no BSE test, all parts of the carcass
must be condemned.
BSE controls explained
The Community TSE Regulation 999/2001 (as amended) lays down rules for the
prevention, control and eradication of certain transmissible spongiform
encephalopathies [TSEs]. The Regulation is directly applicable in all
member states and sets out the requirements for TSE monitoring, animal
feeding and the removal of specified risk material. The arrangements for
its interpretation and enforcement within the UK are set out in the
following legislation:
England - The Transmissible Spongiform Encephalopathies (England)
Regulations 2008 (SI No. 2008/1881) (as amended by SI 2008/2269 and SI
2008/3295)
Wales - The Transmissible Spongiform Encephalopathies (Wales) Regulations
2008 (SI No. 2008/3154(W.252) (as amended by SI 2008/3266(W.288))
Scotland - The Transmissible Spongiform Encephalopathies (Scotland)
Regulations 2006 (SSI 2006/530) (as amended by SSI 2007/357, SSI 2008/166
and SSI 2008/417)
Northern Ireland - Transmissible Spongiform Encephalopathy Regulations
(Northern Ireland) 2008 (SR 2008 No. 508)
How is BSE being controlled in the UK?
Since the late 1980s, the Government has introduced and strengthened
controls to reduce the risk of people eating beef or meat products that
might be infected with BSE. The controls are based on current scientific
knowledge and are designed to reduce the risk to an extremely low level,
although the risk to consumers from BSE cannot be removed completely.
BSE testing and the removal of SRM [specific risk materials] are the 2
controls that keep potentially infected material out of the human food
chain. The ban on feeding animal protein to farm animals prevents them from
being exposed to BSE and therefore reduces the incidence or number of new
cases. Cattle born or reared in the UK before August 1996, when a
reinforced feed ban was introduced, are permanently excluded from the food
chain. In addition to these controls, cattle with BSE or suspected of
having BSE and the offspring and cohorts of BSE cases are removed from the
food chain.
(SRM is the parts of cattle, and sheep and goats most likely to carry BSE.
SRM must be removed when an animal is slaughtered. SRM must be disposed of
and does not go into our food or animal feed. In cattle, the SRM controls
are estimated to remove almost all potential infectivity in the unlikely
event of an animal infected with BSE but not yet showing any clinical signs
being slaughtered for human consumption.)
--
communicated by:
Terry S Singeltary Sr <flounder9@verizon.net>
[No case of BSE in cattle has been reported in the Czech Republic since
2007. This together with the destruction of the carcass, though delayed,
has virtually eliminated any danger of introduction of any BSE agent into
the human food chain in the UK. Unfortunately a small amount of material
was exported to France before disposal of the carcass, so risk has not been
entirely eliminated. Hopefully the French authorities will be able to
locate and destroy this material. - Mod.CP]
[see also:
vCJD - Italy: susp. 20091024.3671
Prion disease update 2009 (09) 20091005.3461
Prion disease update 2009 (08) 20090908.3170
Prion disease update 2009 (07) 20090806.2783
Prion disease update 2009 (06) 20090706.2433
Prion disease update 2009 (05) 20090602.2054
Prion disease update 2009 (04) 20090406.1337
vCJD, 5th death - Spain (Cantabria) 20090307.0953
Prion disease update 2009 (03) 20090305.0918
Prion disease update 2009 (02) 20090202.0463
Prion disease update 2009 (01) 20090108.0076
2008
---
Prion disease update 2008 (14): new vCJD wave imminent? 20081218.3980
Prion disease update 2008 (13) 20081201.3780
Prion disease update 2008 (12) 20081103.345
Prion disease update 2008 (11) 20081006.3159
vCJD, mother & son - Spain: (Leon) 20080926.3051
Prion disease update 2008 (10) 20080902.2742
vCJD - Spain: susp. 20080410.1311
Prion disease update 2008 (05) 20080408.1285
Prion disease update 2008 (01): correction 20080104.0046
Prion disease update 2008 (01) 20080102.0014
2007
---
Prion disease update 2007 (08) 20071205.3923
Prion disease update 2007 20070514.1542
CJD (new var.) update 2007 (05) 20070403.1130
CJD (new var.) update 2007 (04) 20070305.0780
CJD (new var.) update 2007 (03) 20070205.0455
CJD (new var.) update 2007 (02): South Korea, susp 20070115.0199
2006
---
CJD (new var.), blood transfusion risk 20061208.3468
CJD, transmission risk - Canada (ON) 20061207.3457
CJD (new var.) update 2006 (12) 20061205.3431
CJD (new var.) update 2006 (11) 20061106.3190
CJD (new var.) update 2006 (10) 20061002.2820
CJD (new var.) - Netherlands: 2nd case 20060623.1741
CJD (new var.) - UK: 3rd transfusion-related case 20060209.0432
CJD (new var.) update 2006 (02) 20060206.0386
CJD (new var.) update 2006 20060111.0101
2005
---
CJD (new var.) update 2005 (12) 20051209.3547
CJD (new var.) update 2005 (11) 20051108.3270
CJD (new var.) update 2005 (10) 20051006.2916
CJD (new var.) update 2005 (02) 20050211.0467
CJD (new var.) - UK: update 2005 (01) 20050111.0095
2004
---
CJD, genetic susceptibility 20041112.3064
CJD (new var.) - UK: update 2004 (14) 20041206.3242
CJD (new var.) - UK: update 2004 (10) 20040909.2518
CJD (new var.) - UK: update 2004 (02) 20040202.0400
CJD (new var.) - UK: update 2004 (01) 20040106.0064
CJD (new var.) - France: 8th case 20041022.2864
CJD (new var.) - France: 9th case 20041123.3138
CJD (new var.), blood supply - UK 20040318.0758
CJD (new var.), carrier frequency study - UK 20040521.1365
2003
---
CJD (new var.) - UK: update 2003 (13) 20031216.3072
CJD (new var.) - UK: update 2003 (01) 20030108.0057
2002
---
CJD (new var.) - UK: update Dec 2002 20021207.5997
CJD (new var.) - UK: update Jan 2002 20020111.3223
2001
---
CJD (new var.), incidence & trends - UK (02) 20011124.2875
CJD (new var.), incidence & trends - UK 20011115.2816
CJD (new var.) - UK: reassessment 20011029.2671
CJD (new var.) - UK: update Oct 2001 20011005.2419
CJD (new var.) - UK: regional variation (02) 20010907.2145
CJD (new var.) - UK: update Sep 2001 20010906.2134
CJD (new var.) - UK: update Aug 2001 20010808.1872
CJD (new var.) - UK: 9th Annual Report 20010628.1231
CJD (new var.) - UK: update June 2001 20010622.1188
CJD (new var.) - UK: update 3 Jan 2001 20010104.0025]
...................cp/msp/sh
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