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PRION DISEASE UPDATE 2009 (01)
******************************
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 other prion-related diseases. Data on
vCJD cases and other forms of CJD: sporadic,
iatrogenic, familial, and GSS (Gerstmann-
Straussler-Scheinker disease) are included also
when they 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 5 Jan 2009
[2] France: Institut de Veille Sanitaire - as of 30 Dec 2008
[3] US National Prion Disease Pathology Surveillance Center - as of 30 Nov 2008
[4] and [5] Prion protein function
[6] CJD Update
*******
[1] UK: National CJD Surveillance Unit - monthly statistics as of 5 Jan 2009
Date: Mon 5 Jan 2009
Source: UK National CJD Surveillance Unit, monthly statistics [edited]
<http://www.cjd.ed.ac.uk/figures.htm>
The number of suspect cases of vCJD referred to
the CJD surveillance unit in Edinburgh and the
number of deaths of definite and probable variant
Creutzfeldt-Jakob disease [abbreviated in
ProMED-mail as CJD (new var.) or vCJD], the form
of the disease thought to be linked to BSE
(bovine spongiform encephalopathy), remain
unchanged since the previous monthly report; that
is, the number of definite or probable vCJD cases (dead and alive) remains 167.
This situation is consistent with the view that
the vCJD outbreak in the UK is in decline. 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, and
only one so far (up to the end of 2008).
Totals for all types of CJD cases in the year 2008
--------------------------------------------------
As of 31 Dec 2008 in the UK, so far there have
been 140 referrals, 73 deaths from sporadic CJD,
5 deaths from iatrogenic CJD, 3 from GSS, 2 from
familial CJD, and one from vCJD.
--
Communicated by:
ProMED-mail
<promed@promedmail.org>
******
[2] France: Institut de Veille Sanitaire - as of 30 Dec 2008
Date: 30 Dec 2008
Source: IVS - Maladie de Creutzfeldt-Jakob et
maladies apparentees [French, trans. & summ. Mod.CP, edited]
<http://www.invs.sante.fr/display/?doc=publications/mcj/donnees_mcj.html>
During the period 1992 to 2008, there were 23
cases of vCJD, all now deceased. They occurred
between 1996 and 2007: one case in 1996, one in
2000, one in 2001, 3 in 2002, none in 2003, 2 in
2004, 6 in 2005, 6 in 2006, 3 in 2007, and none
so far in 2008. There were 12 male and 11 female patients.
Their ages at time of death ranged from 19 to 58
years (mean 39); 6 of the patients resided in the
Ile-de-France [Paris area] and 17 in the
provinces. All the cases were met-met homozygotes
for codon 129 of the prion protein gene. No
special risk factors were evident, which
distinguished these patients from those with
other forms of CJD (sporadic, genetic,
iatrogenic). However, one patient had visited the UK at regular intervals.
Totals for all types of CJD cases in the year 2008
--------------------------------------------------
As of 30 Dec 2008 in France, during the course of
2008 there have been 1438 referrals, 76 deaths
from sporadic CJD, 3 deaths from iatrogenic CJD,
8 from familial CJD, none from GSS, and none from vCJD.
--
Communicated by:
ProMED-mail
<promed@promedmail.org>
******
[3] US National Prion Disease Pathology Surveillance Center - as of 30 Nov 2008
Date: 30 Nov 2008
Source: US National Prion Disease Pathology Surveillance Center [edited]
<http://www.cjdsurveillance.com/resources-casereport.html>
Cases examined - as of 30 Nov 2008
----------------------------------
During the period 1997 to 30 Nov 2008, 2 cases of
vCJD were reported, both contracted overseas. The
1st case was recorded in 2004, disease contracted
in the UK, and the 2nd in 2006, disease contracted in Saudi Arabia.
Totals for all types of CJD cases in the year 2008 as of 30 Nov 2008
--------------------------------------------------------------------
So far in 2008 there have been 332 referrals, 199
cases of prion disease, including 151 cases of
sporadic CJD, 21 cases of familial CJD, no cases
of atrogenic CJD and no indigenous cases of vCJD.
Overall during the period 1997 to 2008, there
have been 3018 referrals, 1745 cases of prion
disease, 1456 cases of sporadic CJD, 252 cases of
familial CJD, 4 cases of iatrogenic CJD and no indigenous cases of vCJD.
[During 2008 so far the USA with approximately
2.5x the combine populations of the UK and France
have reported a similar number of cases of
sporadic CJD (149 versus 151). Whether this is
due ot a difference in surveillance procedure or
actual disease incidence is unclear at the present time. - Mod.CP]
--
Communicated by:
ProMED-mail
<promed@promedmail.org>
******
[4] Prion protein function
Date: Sun 21 Dec 2008
Source: BBC News online [edited]
<http://news.bbc.co.uk/1/hi/health/7788444.stm>
Scientists sniff out prion secret
---------------------------------
The brain protein which has a hand, when
defective, in the lethal disease CJD may also be
involved in aiding our sense of smell. Mice bred
to lack the prion protein could not find buried
food or choose between smells. Columbia
University scientists said some symptoms of prion
disease might be due to the loss of the protein's
original role. The study was published in the
journal Nature Neuroscience [see below].
The prion protein has historically received
something of a bad press, being blamed in its
misshapen form for degenerative brain diseases in
humans and other animals. However, many
scientists have been trying to uncover what it
actually does when it is behaving correctly. Dr
Stuart Firestein's team believe that one of these
roles is to help us smell. While his
prion-protein free mice were still able to detect
scents, they had lost some higher functions which
required that smell information to be analysed
and processed by the brain. The scientists found
changes in the communication between neurons in
the nerve cells of the olfactory bulb, part of
the forebrain which deals with odours. When the
protein was restored to this part of the brain,
the ability to discriminate between odours came back.
The scientists said that while the discovery had
no direct link to the diseases caused by faulty
prion proteins, it might help account for some of
the symptoms experienced by patients, which might
be due to the failure of the proteins to do their
normal job properly, rather than the damage
caused by accumulation of defective prions.
This is not the 1st suggested role for the prion
protein -- in 2007, Leeds University scientist
Professor Nigel Hooper said that it might help
reduce the formation of "plaques" linked to the
onset of Alzheimer Disease. He said of the
newly-reported research: "It's likely that these
proteins have a number of roles in various
different body systems, including the olfactory
system, as suggested here. "I don't think you can
say that it is so mysterious any more, or that we
do not understand what it does."
[Reference: Nature Neuroscience, Published
online: 21 December 2008 doi:10.1038/nn.2238
<http://www.nature.com/neuro/journal/v12/n1/abs/nn.2238.html>
Title: Olfactory behavior and physiology are
disrupted in prion protein knockout mice
Authors: Claire E Le Pichon1, Matthew T Valley1,
Magdalini Polymenidou2,3, Alexander T Chesler1,
Botir T Sagdullaev1,3, Adriano Aguzzi2 & Stuart Firestein1
Affiliations: Department of Biological Sciences,
Columbia University, 1212 Amsterdam Avenue, New
York, New York 10027, USA. Institute of
Neuropathology, University Hospital Zurich,
Schmelzbergstrasse 12, 8091 Zurich, Switzerland.
Abstract: The prion protein PrPC is infamous for
its role in disease, but its normal physiological
function remains unknown. Here we found a
previously unknown behavioral phenotype of
Prnp-/- mice in an odor-guided task. This
phenotype was manifest in three Prnp knockout
lines on different genetic backgrounds, which
provides strong evidence that the phenotype is
caused by a lack of PrPC rather than by other
genetic factors. Prnp-/- mice also showed altered
behavior in a 2nd olfactory task, suggesting that
the phenotype is olfactory specific. Furthermore,
PrPC deficiency affected oscillatory activity in
the deep layers of the main olfactory bulb, as
well as dendrodendritic synaptic transmission
between olfactory bulb granule and mitral cells.
Notably, both the behavioral and
electrophysiological alterations found in Prnp-/-
mice were rescued by transgenic neuronal-specific
expression of PrPC. These data suggest that PrPC
is important in the normal processing of sensory
information by the olfactory system.]
[And from the same issue of Nature Neuroscience. See below - Mod.CP]
******
[5] Prion protein function
Date: Sun 21 Dec 2008
Source: Nature Neuroscience 12, 7 - 8 (2009) [edited]
<http://www.nature.com/neuro/journal/v12/n1/full/nn0109-7.htm>
Title: Sniffing out a function for prion proteins
-------------------------------------------------
Abstract
--------
When prion proteins go wrong, they can do serious
damage, but little is known about their normal
function, despite their ubiquitous expression in
the brain. A new report in this issue [see above]
suggests a critical role for prions in olfactory discrimination.
Introduction
---------------
Although the word prion was coined by Stanley
Prusiner to describe the "proteinaceous
infectious particle" that causes a family of
fatal neurodegenerative diseases known as
transmissible spongiform encephalopathies more
than 20 years ago, little is known about the
normal function of prion proteins. Most of what
is known about them comes from studies of their
involvement in these devastating diseases, which
include Creutzfeld-Jakob disease, bovine
spongiform encephalopathy ('mad-cow disease') and
chronic wasting disease in elk and deer. These
diseases are distinguished by rapidly progressive
neurological deterioration and a pattern of
neurodegeneration that is characterized by
prominent vacuolization of neuronal cytoplasm,
which gives the brain a sponge-like histological
appearance. The key pathogenic event in these
diseases is the conversion of an endogenous
cell-surface glycoprotein, the prion protein
(PrPc), to a pathological isoform (PrPsc) that
has an abnormal conformation and an unusual
resistance to proteolytic degradation. PrPsc
accumulates in cells and plaque-like
extracellular deposits, converting more PrPc into
the pathogenic form and triggering
neurodegeneration by mechanisms that are still
not fully understood. Conversion of PrPc can be a
result of inherited mutations, infection of the
host with a prion-infected tissue or rare
sporadic events. Although the formation of PrPsc
is believed to result in a gain of toxic
function, a loss of function of PrPc has not been
excluded as being involved in prion disease PrPc
is most abundantly expressed in the brain and it
would be expected that the loss of this protein
would result in substantial neurobehavioral
modifications. However, the specific role of PrPc
in neural function and behavior is far from
clear. In fact, previous work suggests that the
most robust phenotype of PrPc loss in transgenic
mice is protection from prion diseases. Although
changes in PrPc expression influence a variety of
critical cellular processes in neurons, including
cell survival, synaptic maintenance and
plasticity, and axonal maintenance, data on these
issues have occasionally been contradictory.
Thus, 'elusive' remains one of the descriptors
most commonly attached to this protein in papers
and reviews on PrPc. Fortunately, a clue to the
elusive prion function may lie right under, in,
our noses. Le Pichon and colleagues have begun
this investigation in this issue [see proceeding report].
There are several major hurdles to learning about
the function of a particular protein. One of
these is knowing where the protein resides in
cells. This localization can help narrow down the
potential functions of the protein. Earlier this
year [2008], it was demonstrated, using new
highly specific antibodies, that PrPc in the
olfactory system is localized to the axons of
both peripheral olfactory sensory receptor
neurons and central neurons such as the mitral
cells of the olfactory bulb. Glia or support
cells in the olfactory bulb or olfactory
epithelium were not detectably labeled. In
addition to axons, PrPc was also observed in the
dendritic spines of axonless olfactory bulb
granule cells. These spines are both pre- and
postsynaptic to mitral cells, forming reciprocal
synapses. Combined with the axon staining, this
suggests a potential role for PrPc in presynaptic
function. However, given how widely expressed
PrPc is throughout the brain, simply showing its
presence in the olfactory system was only
circumstantial; further tests were required to
determine whether it has a functional role in olfaction.
The observation that PrPc is expressed in
olfactory sensory neurons, mitral cells and
granule cells raises the possibility that it is
important for the local circuit function of the
olfactory bulb. Olfactory sensory neurons in the
nose send axons directly into the brain,
terminating on mitral cells, which send their
axons directly to olfactory cortex. In the
olfactory bulb, local circuits, which include
granule cells, refine spatiotemporal patterns of
sensory neuron input, and this local circuit
function can be monitored electrophysiologically
through oscillations in local field potentials.
Previous work in a variety of laboratories has
demonstrated that manipulation of local circuit
function in the olfactory bulb can modulate
various aspects of odor perception, 7). Thus, the
stage was set to ask whether loss of PrPc affects
normal olfaction. Le Pichon and colleagues
provide a convincing affirmative answer and with
it a clue to PrPc function. Specifically, the
loss of PrPc in neurons of the olfactory system
of transgenic mice impairs odor-guided behaviors
such as finding buried food and simple odor
discrimination. The deficit was expressed
regardless of the genetic background of the mice
and was not a simple anosmia but was rather an
apparent impairment in odor discrimination per
se. Although PrPc is found in olfactory sensory
neurons, the behavioral deficits were not
associated with detectable changes in receptor
function. In fact, the sense of smell could be
rescued by selectively replacing PrPc in
olfactory bulb neurons alone, suggesting a central brain site of action.
Given that PrPc deletion disrupted odor-guided
behavior, the final question is raised of whether
or not there are neural correlates of this
behavioral change in the olfactory bulb. Using
electrophysiological recordings, Le Pichon et al.
demonstrated specific changes in local circuit
function in the olfactory bulb in the PrPc
knockouts. For example, using in vivo electrical
stimulation to assay local circuit interneuron
function, the authors found a decrease in
inhibition of mitral cells by granule cell
interneurons. This mitral cellgranule cell
reciprocal interaction has been hypothesized to
be important for everything from lateral
inhibition to odor memory to state-dependent
modulation of olfactory bulb function.
Physiologically, activity in this local feedback
circuit underlies high-frequency oscillations in
olfactory bulb activity in response to odor
stimulation. These olfactory bulb local field
potential oscillations may facilitate temporal
coding and/or binding of disparate odor features
by target neurons in the olfactory cortex. Le
Pichon et al. found that these odor-evoked
high-frequency oscillations were abnormal in PrPc knockout mice.
The results suggest that PrPc may be important in
local circuit function in the olfactory system
and may in turn influence odor perception. There
has been some debate over whether neural damage
done by prion diseases is solely caused by the
buildup of PrPsc or whether the concomitant loss
of PrPc may also be involved. By demonstrating a
systems-level effect of PrPc loss, Le Pichon et
al. suggest that both may be important.
[Byline: Donald A Wilson1 and Ralph A Nixon2
1 Donald A Wilson is at the Emotional Brain
Institute, Nathan Kline Institute for Psychiatric
Research, 140 Old Orangeburg Road, Orangeburg,
New York 10962, USA, and the Department of Child
and Adolescent Psychiatry, New York University
School of Medicine, 215 Lexington Avenue, New York, New York 10016, USA.
2 Ralph A Nixon is at the Center for Dementia
Research, Nathan Kline Institute for Psychiatric
Research, 140 Old Orangeburg Road, Orangeburg,
New York 10962, USA, and the Departments of
Psychiatry and Cell Biology, New York University
School of Medicine, 550 1st Ave, New York, New
York 10016, USA. <dwilson@nki.rfmh.org>]
--
Communicated by:
ProMED-mail
<promed@promedmail.org>
[The references cited in the text can be found by
accessing the original text of tis report in
Naute Neuroscinece using the URL at the beginining of the report. - Mod.CP]
******
[6] CJD Update
Date 12 Dec 2008
Source: Health Protection Agency Report, Emerging
Infections/CJD [abbreviated and edited]
<http://www.hpa.org.uk/hpr/infections/ei_cjd>.htm>
Creutzfeldt-Jakob disease (CJD) update report
---------------------------------------------
This 6-monthly report provides an update on
reports of incidents of potential iatrogenic
(healthcare-acquired) exposure to CJD via
surgery, and on the National Anonymous Tonsil
Archive. Data are correct as of 5 Dec 2008. For
numbers of CJD case reports, readers should
consult data provided by the national CJD
Surveillance Unit (NCJDSU), Edinburgh [1], and
the ProMED-mail monthly Prion Disease Updates].
The latest yearly analysis of vCJD reports
(onsets and deaths) is also available from
the NCJDSU Web site [2], and the ProMED-mail monthly Prion Disease Update.
Reports of incidents of potential iatrogenic
exposure to CJD via surgery: 1 Jan 2000 to 30 Jun 2008
---------------------------------------------------------------------------------------------------
There were a total of 350 incidents reported
during this period (tabulated in the original
text). 12 surgical incidents were reported
between 1 Jan and 30 Jun 2008. A surgical
incident occurs when a patient undergoes surgery
but is only identified as having CJD or being at
risk of CJD at a later date. (This means that the
ACDP TSE Working Group infection control
guidelines would not have been followed). The
surgery carried out on an index patient with, or
at risk of CJD, may result in contamination of
the instruments with abnormal prion protein. (A
table in the original text gives the number of
CJD surgical incidents reported to the CJD
Incidents Panel from January 2000 to June 2008 by
the diagnosis of the index patient.)
Investigation of surgical incidents may result in
advice to remove surgical instruments from
clinical use (to quarantine, destroy, or donate
for research). Such advice is generally only
given for instruments considered to be
potentially contaminated with the CJD agent that
have not undergone a certain number of cycles of
use and decontamination since their use on an
index patient. Hospitals are asked to consider
sending any instruments to be permanently removed
from use to the Surgical Instrument Store (held
by the Health Protection Agency, Porton Down) for
research. In the 2nd half of 2007, there were no
incidents in which instruments were permanently removed from use.
The Panel may advise contacting and informing
some patients of their possible exposure to CJD
in a surgical incident. Such advice is generally
only given for patients who have definitely been
exposed to potentially contaminated instruments
which have been used on risk tissues in certain
index patients. The Panel may advise that some of
these patients should be considered "at-risk of
CJD for public health purposes" and asked to take
certain precautions (i.e., not to donate blood or
other tissues and to inform their medical and
dental carers prior to any invasive procedures)
in order to reduce the risk of transmitting the
CJD agent further. Since 2000, 20 incidents have
given rise to such advice (tabulated in the
original text). One of these incidents was
reported in the 1st half of 2008. The Panel has
so far categorised 64 patients as "at-risk"; 13
of whom died before notification. 3 patients have
not been notified due to local, clinical
decisions. (One index patient undergoing a
cataract operation was a blood component
recipient with evidence of vCJD infection.)
National anonymous tonsil archive for studies of
detectable abnormal prion protein
----------------------------------------------------------------------------------
The National Anonymous Tonsil Archive (NATA)
continues to receive approximately 400 tonsil
pairs per week. The archive had received a total
of 67 696 tonsil pairs up to the end of October
2008 from hospitals in England and Scotland. A
further 3000 tonsil pairs have been received from
the Medical Research Council Prion Unit.
Therefore the total number of tonsil pairs in the archive was 70 696.
Testing of homogenates of the tonsil tissue from
the archive began at the end of January 2007. 2
enzyme immunoassays (EIAs) are being used for the
initial screening of the homogenates for the
presence of abnormal prion protein. These EIAs
allow the identification of any tonsils that need
to be investigated further by the more specific
tests of Western blotting (WB) and immunohistochemistry (IHC) [4].
References:
-----------
[1] The National Creutzfeldt-Jakob Disease
Surveillance Unit, The University of Edinburgh.
CJD statistics. CJD figures. Edinburgh: NCJDSU, 3 May 2005. Available at
<http://www.cjd.ed.ac.uk/figures.htm>.
[2] The National Creutzfeldt-Jakob Disease
Surveillance Unit, The University of Edinburgh.
Incidence of variant Creutzfeldt-Jakob Disease
Onsets and Deaths in the UK January 1994 - March
2005.Edinburgh: NCJDSU, 14 Apr 2005. Available at
<http://www.cjd.ed.ac.uk/vcjdqdec06.htm>.
[3] HPA CJD Incidents Panel [online]. London: HPA. Available at
<http://www.hpa.org.uk/web/HPAweb&Page&HPAwebAutoListName/Page/1204031511121>
[4] Spongiform Encephalopathy Advisory
Committee. Combining evidence from tissue surveys
to estimate the prevalence of subclinical vCJD. SEAC, 2008. Available at
<http://www.seac.gov.uk/papers/paper100-2.pdf>.
--
Communicated by:
Terry S. Singeltary Sr.
<flounder9@verizon.net>
[see also:
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
Prion disease update 2008 (09) 20080805.2402
Prion disease update 2008 (08) 20080707.2058
Prion disease update 2008 (07) 20080604.1793
Prion disease update 2008 (06) 20080506.1555
vCJD - Spain: susp. 20080410.1311
Prion disease update 2008 (05) 20080408.1285
Prion disease update 2008 (04) 20080303.0878
Prion disease update 2008 (03) 20080204.0455
Prion disease update 2008 (02) 20080107.0087
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 (07) 20071105.3602
Prion disease update 2007 (06) 20071003.3269
Prion disease update 2007 (05) 20070901.2879
Prion disease update 2007 (04) 20070806.2560
Prion disease update 2007 (03) 20070702.2112
Prion disease update 2007 (02) 20070604.1812
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/ejp/dk
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