Subject: On the Question of Sporadic or Atypical Bovine Spongiform Encephalopathy and Creutzfeldt-Jakob Disease
Date: November 7, 2006 at 1:57 pm PST
PERSPECTIVE
On the Question of Sporadic or Atypical Bovine Spongiform Encephalopathy and Creutzfeldt-Jakob Disease
Paul Brown,* Lisa M. McShane,† Gianluigi Zanusso,‡ and Linda Detwiler§
Strategies to investigate the possible existence of sporadic
bovine spongiform encephalopathy (BSE) require
systematic testing programs to identify cases in countries
considered to have little or no risk for orally acquired disease,
or to detect a stable occurrence of atypical cases in
countries in which orally acquired disease is disappearing.
To achieve 95% statistical confidence that the prevalence
of sporadic BSE is no greater than 1 per million (i.e., the
annual incidence of sporadic Creutzfeldt-Jakob disease
[CJD] in humans) would require negative tests in 3 million
randomly selected older cattle. A link between BSE and
sporadic CJD has been suggested on the basis of laboratory
studies but is unsupported by epidemiologic observation.
Such a link might yet be established by the discovery
of a specific molecular marker or of particular combinations
of trends over time of typical and atypical BSE and various
subtypes of sporadic CJD, as their numbers are influenced
by a continuation of current public health measures that
exclude high-risk bovine tissues from the animal and
human food chains.
Bovine spongiform encephalopathy (BSE) was first recognized
in 1986 in the United Kingdom and quickly
reached epidemic proportions, affecting >30,000 cattle per
year by 1992. Because of continuing exportation of both
live cattle and meat and bone meal rendered from the carcasses
of slaughtered cattle, the disease spread throughout
most of Europe and a few non-European countries. By
2006, 20 years after its first appearance in the United
Kingdom, the disease had been reported in an additional
24 countries (1).
Beginning toward the end of the 1980s in the United
Kingdom, and in the 1990s in other countries, numerous
regulations were enacted to minimize the entry of contaminated
tissues into both the animal and human food chains
and to eliminate the international spread of disease. These
measures have been extraordinarily successful, to the
extent that no new countries have been added to the list
during the past year and the number of new cases has dramatically
diminished in most countries in which BSE has
appeared (the situation in some countries with insufficient
surveillance remains unclear).
Although the origin of the epidemic is thought to have
been caused by a species-crossing contamination by sheep
scrapie during the course of rendering and recycling carcass
meat and bone meal as cattle feed, an alternative
hypothesis suggested an origin in a similarly recycled case
of spontaneously occurring disease in cattle. The pros and
cons of these competing ideas have been argued elsewhere
(2,3), and neither will ever be convincingly proved or disproved.
Thus, the phenomenon of spontaneous disease
remained in limbo until the recent discovery of “atypical”
strains of BSE reopened the question. In this article we
consider the importance of atypical BSE within the overall
concept of sporadic (spontaneous) disease and whether
such cases, if they exist, could account for at least some
cases of apparently sporadic Creutzfeldt-Jakob (CJD) in
humans.
Sporadic BSE
Obviously, the ideal country in which to examine the
question of sporadic BSE would have a large national herd
that was guaranteed never to have been exposed to environmental
sources of infection. Such an ideal will never be
realized. Until recently, the United States appeared to have
at least approached the ideal by having a large national
*Bethesda, Maryland, USA; †National Institutes of Health,
Bethesda, Maryland, USA; ‡University of Verona, Verona, Italy;
and §Virginia-Maryland Regional College of Veterinary Medicine,
College Park, Maryland, USA
1816 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 12, December 2006
herd, an adequate testing program, and an apparently small
risk for contamination by imported cattle or cattle feed.
That position was made vulnerable in late 2003 by the discovery
of a case of BSE imported from Canada and was
eliminated altogether by the subsequent discovery of 2
indigenously infected animals in widely separate regions
of the country. Although the 2 indigenous cases might represent
sporadic disease, the continuing identification of
cases in western Canada, coupled with a history of substantial
numbers of cattle imported from Canada into the
United States (both indigenous US animals had the same
molecular “signature” as the most recent Canadian case),
makes it difficult to ignore the possibility of undetected
instances of feed contamination from imported and recycled
infectious carcasses.
At present, the 2 best countries in which to undertake
testing programs would be Argentina and Australia; both
have large national herds (≈50 million and 30 million animals,
respectively), and both are considered to be free of
orally acquired BSE infections, on the basis of importation
history, nutritional practices, and adequacy of surveillance
(4). Even in these countries, however, the discovery of a
case of BSE could not be guaranteed to be spontaneous
because of the widespread global distribution of potentially
infected cattle and cattle feed and the vagaries of international
trade: imperfect record keeping, lack of
compliance, and just plain deception.
By way of illustration, an incident occurred many years
ago that involved a particularly bulky shipment labeled as
a pesticide. The large quantity seemed unusual to the customs
inspector, who opened it and discovered that the shipment
contained meat and bone meal destined to be spread
on fields to inhibit grazing by deer, a serious agricultural
pest. Thus, a study of sporadic BSE would only be truly
convincing if no cases were identified.
Moreover, the criteria for answering the question of
sporadic BSE are different than for orally acquired BSE.
Most importantly, we do not know at what age sporadic
cases of BSE might occur, but they are unlikely to be in the
3- to 5-year-old age group in which orally acquired BSE is
most prevalent. If the age distribution of sporadic disease
in cattle were to mimic that of sporadic CJD in humans, it
would not peak until 14–20 years of age (the last third of
the ≈20-year natural life span of a cow). Substantial numbers
of such older cattle do not exist, and thus it may never
be possible to state with assurance that spontaneous BSE
does not occur.
Even if we accept this practical constraint, we can still
take advantage of the fact that in many countries a proportion
of the total slaughter population consists of breeding
stock and dairy cows that are culled at >7 years of age, and
animals that go directly to rendering plants or die “on
farm” further increase this number. Argentina, for example,
with a national herd of ≈50 million cattle, in 2005
recorded nearly 1.4 million deaths from slaughter and natural
causes in animals >7 years (L. Mascitelli, pers.
comm.).
Approximately 10% of cases of sporadic CJD occur in
patients 25–50 years of age; this age in humans corresponds
to the middle third of a cow’s normal life span, or
7–13 years of age (Figure 1). If the age distribution of sporadic
BSE followed the same pattern, negative test results
in a total of ≈3 million animals randomly selected from
this group would allow us to be 95% confident that sporadic
BSE is not present at a prevalence >1 per million,
and ≈4.5 million negative animals would raise the level of
confidence to 99%. Larger numbers of BSE-negative animals
would be required to achieve these levels of confidence
for a maximum prevalence <1 per 10 million cattle
(Table 1, Figure 2).
Even the least rigorous negative result—a prevalence
not greater than that of sporadic CJD in humans, or 1 per
million—would require several years to achieve, and it is
perhaps unrealistic to suppose that the motivation to prolong
the testing program will endure much beyond the
global disappearance of orally acquired BSE and variant
CJD. Nevertheless, to the degree that testing older as well
as younger adult animals approached these numbers, both
statistical and consumer confidence would increase, and at
the very least provide reassurance that the occurrence of
sporadic disease must be exceedingly rare, with little likelihood
of posing a risk to either human or animal nutrition.
Atypical BSE
Because of its contemporary nature, the study of atypical
BSE is very much a work in progress, with comparatively
little published data and many unknowns. The first 2
cases to be identified were a serendipitous discovery made
in the course of an unrelated experimental study that
required a detailed neuropathologic and immunochemical
Figure 2. Maximum prevalence according to number of negative
cattle at 95% (solid line) and 99% (dashed line) confidence levels.
See Table 1 for exact numbers and statistical method.
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 12, December 2006 1817
examination of the entire brain (5). The absence of clinical
signs in these older animals, the unusual distribution of
PrPTSE, together with amyloid plaques, and a Western blot
pattern that differed from the stereotypic pattern seen in
typical BSE left little doubt about the probability that a
new “atypical strain” had been identified (bovine amyloidotic
spongiform encephalopathy[BASE]).
Although no further cases were found in nearly 200 cattle
examined in Italy, the initiation of Western blot studies
of animals in other countries with screening test programs
began to yield additional atypical patterns (Table 2, Figure
3) (6–14; P. Lind, pers. comm.). Two major patterns have
been described, named L (resembling the original Italian
case pattern with a lower molecular weight than typical
BSE) and H (for a distinct pattern first seen in France with
a higher molecular weight than typical BSE). It is not yet
clear whether other mixed patterns result from technical
procedures in different laboratories or whether a more
complicated scheme of classification will evolve as more
atypical patterns are discovered.
In addition, Western blots of PrPTSE are a fragile basis
on which to define a BSE phenotype. Little or no information
is available about either the clinical status or neuropathologic
features of these animals. We know that cases
have occurred in different breeds and PrP genotypes, and
we also know that very few of the animals have had the
typical clinical picture of BSE (behavioral disturbances,
sensory signs, ataxia, and tremors), but a cloud of ambiguity
surrounds the clinical picture even in those animals for
which an extensive post-hoc investigation was undertaken.
The fact that few detailed neuropathologic results are
available is explained by the need to preserve at least a full
half brain for examination, which is presently not done in
any of the various countries that have screening test programs.
In the future, the brain as well as the carcass must
be retained in cold storage until the test results are known.
The frequency of atypical cases is another unknown.
Published (7,12) and unpublished (11,13) observations
indicate that in some countries it might be as high as
5%–10% of the total number of older animals diagnosed
by rapid screening tests (e.g., 2/27 in Germany, and 1/9 in
Canada), which would seem to be a surprisingly high proportion
of spontaneously occurring cases. However, data
are not yet sufficient to estimate the overall prevalence of
atypical BSE, i.e., cases per million tested animals of all
ages.
In this context, a word is in order about the US testing
program. After the discovery of the first (imported) cow in
2003, the magnitude of testing was much increased, reaching
a level of >400,000 tests in 2005 (Figure 4). Neither of
the 2 more recently indigenously infected older animals,
with ambiguous or no clinical features, would have been
detected without such testing, and neither would have been
identified as atypical without confirmatory Western blots.
Despite these facts, surveillance has now been decimated
to 40,000 annual tests (USDA news release no. 0255.06,
July 20, 2006) and invites the accusation that the United
1818 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 12, December 2006
States will never know the true status of its involvement
with BSE.
In short, a great deal of further work will need to be
done before the phenotypic features and prevalence of
atypical BSE are understood. More than a single strain
may have been present from the beginning of the epidemic,
but this possibility has been overlooked by virtue of the
absence of widespread Western blot confirmatory testing
of positive screening test results. These new phenotypes
may be found, at least in part, to result from infections at
an older age by a typical BSE agent, rather than neonatal
infections with new “strains” of BSE. Neither alternative
has yet been investigated.
Sporadic CJD
The possibility that at least some cases of apparently
sporadic CJD might be due to infection by sporadic cases
of BSE cannot be dismissed outright. Screening programs
needed to identify sporadic BSE have yet to be implemented,
and we know from already extant testing programs that
at least a proportion of infected animals have no symptoms
and thus would never be identified in the absence of systematic
testing. Thus, sporadic BSE (or for that matter,
sporadic disease in any mammalian species) might be
occurring on a regular basis at perhaps the same annual
frequency as sporadic CJD in humans, that is, in the range
of 1 case per million animals.
Whether humans might be more susceptible to atypical
forms of BSE cannot be answered at this time.
Experimentally transmitted BASE shows shorter incubation
periods than BSE in at least 1 breed of cattle,
bovinized transgenic mice, and Cynomolgus monkeys
(12,13). In humanized transgenic mice, BASE transmitted,
whereas typical BSE did not transmit (13). Paradoxically,
the other major phenotype (H) showed an unusually long
incubation period in bovinized transgenic mice (12).
The limited experimental evidence bearing on a possible
relationship between BSE and sporadic CJD is difficult
to interpret. The original atypical BASE strain of BSE had
a molecular protein signature very similar to that of 1 subtype
(type 2 M/V) of sporadic CJD in humans (5).
In another study, a strain of typical BSE injected into
humanized mice encoding valine at codon 129 showed a
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 12, December 2006 1819
glycopattern indistinguishable from the same subtype of
sporadic CJD (15). In a third study, the glycopatterns of
both the H and L strains of atypical BSE evidently did not
resemble any of the known sporadic CJD subtypes (12).
To these molecular biology observations can be added
the epidemiologic data accumulated during the past 30
years. The hypothesis that at least some cases of apparently
sporadic CJD are due to unrecognized BSE infections
cannot be formally refuted, but if correct, we might expect
by now to have some epidemiologic evidence linking BSE
to at least 1 cluster of apparently sporadic cases of CJD.
Although only a few clusters have been found (and still
fewer published), every proposed cluster that has been
investigated has failed to show any common exposure to
bovines. For that matter, no common exposure has been
shown to any environmental vehicles of infection, including
the consumption of foodstuffs from bovine, ovine, and
porcine sources, the 3 livestock species known to be susceptible
to transmissible spongiform encephalopathies.
Additional negative evidence comes from several large
case-control studies in which no statistically significant
dietary differences were observed between patients with
sporadic CJD and controls (16,17).
On the other hand, the difficulty of establishing a link
between BSE and CJD may be compounded by our ignorance
of the infectious parameters of a sporadic form of
BSE (e.g., host range, tissue distribution of infectivity,
route of transmission, minimum infectious dose for
humans, whether single or multiple). Presumably, these
parameters would resemble those of variant CJD' that is,
high infectivity central nervous system and lymphoreticular
tissues of an infected cow find their way into products
consumed by humans. Transmissions that might have
occurred in the past would be difficult to detect because
meat products are generally not distributed in a way that
results in detectable geographic clusters.
Barring the discovery of a specific molecular signature
(as in variant CJD), the most convincing clue to an association
will come from the observation of trends over time of
the incidence of typical and atypical BSE and of sporadic
and variant CJD. With 4 diseases, each of which could
have increasing, unchanging, or decreasing trends, there
could be 81 (34) possible different combinations. However,
it is highly likely that the trends for typical BSE and variant
CJD will both decrease in parallel as feed bans continue
to interrupt recycled contamination. The remaining
combinations are thus reduced to 9 (32), and some of them
could be highly informative.
For example, if the incidence of atypical BSE declines
in parallel with that of typical BSE, its candidacy as a sporadic
form of disease would be eliminated (because sporadic
disease would not be influenced by current measures
to prevent oral infection). If, on the other hand, atypical
BSE continues to occur as typical BSE disappears, this
would be a strong indication that it is indeed sporadic, and
if in addition at least 1 form of what is presently considered
as sporadic CJD (such as the type 2 M/V subtype
shown to have a Western blot signature like BASE) were
to increase, this would suggest (although not prove) a
causal relationship (Figure 5).
Recognition of the different forms of BSE and CJD
depends upon continuing systematic testing for both
bovines and humans, but bovine testing will be vulnerable
Figure 5. Diagram of 2 possible informative trends in the incidence
of bovine spongiform encephalopathy (BSE) and Creutzfeld-Jakob
disease (CJD). The left panel shows the likely trends of typical
BSE and variant CJD (vCJD). The right upper panel shows 1 possible
pair of trends of atypical BSE and sporadic CJD (sCJD)
that might occur in conjunction with the typical BSE/vCJD trends,
and would be consistent with the interpretation that atypical BSE
is not sporadic and not related to sCJD. The right lower panel
shows a second possible associated pair of trends consistent with
the interpretation that atypical BSE is sporadic and might also be
related to the type 2 M/V subset of apparently sCJD.
1820 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 12, December 2006
to heavy pressure from industry to dismantle the program
as the commercial impact of declining BSE cases ceases to
be an issue. Industry should be aware, however, of the
implications of sporadic BSE. Its occurrence would necessitate
the indefinite retention of all of the public health
measures that exclude high-risk bovine tissues from the
animal and human food chains, whereas its nonoccurrence
would permit tissues that are now destroyed to be used as
before, once orally acquired BSE has disappeared.
Acknowledgments
We thank Victoria E. Bridges and Chris Kopral for providing
data about annual cattle slaughter numbers from the Food
Safety and Inspection Service of the US Department of
Agriculture (USDA) and for estimates of cattle dying on farms
from data supplied by the National Animal Health Monitoring
System, Animal and Plant Inspection Services, Veterinary
Service, USDA.
This study was funded in part by grant # 4AN/F10 “Studio
dei meccanismi patogenetici delle malattie neurodegenerative per
la diagnosi e lo sviluppo di approcci terapeutici” from the Istituto
Superiore di Sanità, Rome, Italy
Dr Brown has recently retired after a 41-year career in the
Laboratory of CNS Studies at the National Institutes of Health,
where he focused on studying transmissible spongiform
encephalopathies.
References
1. World Organization for Animal Health. Bovine spongiform
encephalopathy. Geographical distribution of countries that reported
BSE confirmed cases since 1989 [cited 2006 Oct 24]. Available
from http://www.oie.int/eng/info/en_esb.htm
2. Brown P, Bradley R, Detwiler L, Dormont D, Hunter N, Wells GAH,
et al. Transmissible spongiform encephalopathy as a zoonotic disease.
International Life Sciences Institute (ILSI) Europe Report
Series. Brussels: ILSI Press; 2003.
3. Horn GM, Bobrow ME, Bruce M, Goedert M, McLean A, Webster J.
Review of the origin of BSE 2001, London: Stationery Office; 2001.
4. World Organization for Animal Health. Bovine spongiform
encephalopathy. Recognition of the bovine spongiform encephalopathy
status of member countries [cited 2006 Oct 24]. Available
from http://www.oie.int/eng/info/en_statesb.htm
5. Casalone C, Zanusso G, Acutis P, Ferrari S, Capucci L, Tagliavini F,
et al. Identification of a second bovine amyloidotic spongiform
encephalopathy: molecular similarities with sporadic Creutzfeldt-
Jakob disease. Proc Natl Acad Sci U S A. 2004;101:3065–70.
6. Danish Institute for Food and Veterinary Research [cited 2006 Oct.
24]. Available from http://www.dfvf.dk/Default.asp?ID=8147&M=
News&PID=89507&NewsID=792
7. Polak M, Rozek W, Rola J, Zmudzinski JF. Prion protein glycoforms
from BSE cases in Poland. Bulletin of the Veterinary Institute of
Pulawy. 2004;48:201–5.
8. De Bosschere H, Roels S, Vanopdenbosch E. Atypical case of bovine
spongiform encephalopathy in an East-Flemish cow in Belgium. Int
J Appl Res Vet Med. 2004;2:52–4. Available from http://www.jarvm.
com/articles/Vol2Iss1/DEBOSSCHERE.htm
9. Yamakawa Y, Hagiwara K, Nohtomi K, Nakamurua Y, Nishijima M,
Higuchi Y, et al. Atypical proteinase K-resistant prion protein
(PrPrres) observed in an apparently healthy 23-month-old Holstein
steer. Jpn J Infect Dis. 2003;56:221–2.
10. Biacabe AG, Laplanche JL, Ryder S, Baron T. Distinct molecular phenotypes
in bovine prion diseases. EMBO Rep. 2004;5:110–4.
11. Canadian Food Inspection Agency. Report on the investigation of the
sixth case of bovine spongiformencephalopathy (BSE) in Canada
[cited 2006 Oct]. Available from http://www.inspection.gc.ca/english/
anima/heasan/disemala/bseesb/mb2006/6investe.shtml
12. Buschmann A, Gretzshel A, Biacabe AG, Schiebel K, Corona C,
Hoffmann C, et al. Atypical BSE in Germany—proof of transmissibility
and biochemical characterization. Vet Microbiol. 2006;
117:103–16.
13. Book of abstracts. Prion 2006, International Conference on Prion
Diseases of NeuroPrion, Network of Excellence, Turin, Italy, 2006
Oct 3–6 [cited 2006 Oct 24]. Available from http://www.
neuroprion.com/en/ev_prion2006.html
14. Seuberlich T, Botteron C, Wenker C, Café-Marçal V, Oevermann A,
Haase B, et al. Spongiform encephalopathy in a miniature zebu.
Emerg Infect Dis. 2006;12:xxx–xxx. [THIS ISSUE]
15. Wadsworth JDF, Asante EA, Desbruslais M, Linehan JM, Joiner S,
Gowland I, et al. Human prion protein with valine 129 prevents
expression of variant CJD phenotype. Science. 2004;306:1793–6.
16. Wientjens DP, Davanipour Z, Hofman A, Kondo K, Matthews WB,
Will RG, et al. Risk factors for Creutzfeldt-Jakob disease: a reanalysis
of case control studies. Neurology. 1996;46:1267–91.
17. Van Duijn CM, Delasnerie-Lauprêtre N, Masullo C, Zerr I, de Silva
R, Wientjens DPWM, et al. Case-control study of risk factors of
Creutzfeldt-Jakob disease in Europe during 1993–1995. Lancet.
1998;351:1081–5.
Address for correspondence: Paul Brown, 7815 Exeter Rd, Bethesda, MD
20814, USA; email: [email protected]
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 12, December 2006 1821
Case 1:06-cv-00544-JR Document 14-9 Filed 11/03/2006 Page 47 of 47
P.S. some of the charts, graphs, tables etc. i was not able to forward in plain text. ...TSS
SEE STEADY INCREASE IN SPORADIC CJD IN THE USA FROM
1997 TO 2006. SPORADIC CJD CASES TRIPLED, with phenotype
of 'UNKNOWN' strain growing. ...
http://www.cjdsurveillance.com/resources-casereport.html
There is a growing number of human CJD cases, and they were presented last week in San Francisco by Luigi Gambatti(?) from his CJD surveillance collection.
He estimates that it may be up to 14 or 15 persons which display selectively SPRPSC and practically no detected RPRPSC proteins.
http://www.fda.gov/ohrms/dockets/ac/06/transcripts/1006-4240t1.htm
http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4240t1.pdf
CJD (NEW VARIANT) UPDATE 2006 (11)
**********************************
A ProMED-mail post
ProMED-mail is a program of the
International Society for Infectious Diseases
[The definition of the designations deaths, definite cases, probable
vCJD cases, and the case definitions can be found by accessing the
Department of Health website or by reference to a previous
ProMED-mail post in this thread (for example, CJD (new var.) - UK:
update March 2002 20020305.3693).
Data on vCJD cases from other parts of the world are now included in
these updates whenever available.
Also, data on other forms of CJD (sporadic, iatrogenic, familial and
GSS) are now included when they have some relevance to the incidence
and etiology of vCJD. - Mod.CP]
In this update:
[1] UK: Department of Health monthly CJD statistics, Mon 6 Nov 2006
[2] EUROCJD data as of 31 Oct 2006
[3] France: novel prion strain
******
[1] UK: Department of Health monthly CJD statistics, Mon 6 Nov 2006
Date: Mon 6 Nov 2006
From: ProMED-mail
Source: UK Department of Health, Monthly Creutzfeldt-Jakob Disease
Statistics [edited]
The Department of Health is today [Mon 6 Nov 2006] issuing the latest
information about the numbers of known cases of Creutzfeldt-Jakob
disease. This includes cases of 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).
Definite and probable CJD cases in the UK, as of Fri 3 Nov 2006:
-----------------------------------------------
Summary of vCJD cases - deaths
-----------------------------
Deaths from definite vCJD (confirmed): 112
Deaths from probable vCJD (without neuropathological confirmation): 46
Deaths from probable vCJD (neuropathological confirmation pending): 0
Number of deaths from definite or probable vCJD (as above): 158
Summary of vCJD cases - alive
-----------------------------
Number of probable vCJD cases still alive: 6
Total
-----
Number of definite or probable vCJD (dead and alive): 164
(The next table will be published on Mon 4 Dec 2006).
Since the previous monthly statistics were released on Mon 6 Nov
2006, the total number of deaths from definite vCJD has increased by
2 and stands at 158, and the overall total number of definite or
probable vCJD cases (dead and alive) has increased by 2, making the
overall total 164.
These data are consistent with the view that the vCJD outbreak in the
UK is in decline. The total number of deaths due to vCJD in the UK is
now 158. The peak number of deaths was 28 in the year 2000, followed
by 20 in 2001, 17 in 2002, 18 in 2003, and 9 in 2004, 5 in 2005. The
number of deaths due to definite or probable vCJD in the UK during
the 1st 10 months of 2006 has risen to 5.
Totals for all types of CJD cases in the UK in 2005 and 2006
-----------------------------------------------
As of 3 Nov 2006, in the UK in the year 2005, there were 122
referrals of suspected CJD, and there were 65 deaths from sporadic
CJD, 6 from familial CJD, 3 from iatrogenic CJD, 6 GSS
(Gerstmann-Straussler-Scheinker) syndrome cases, and 5 deaths from vCJD.
The corresponding figures so far for the 1st 10 months of 2006 are:
87 referrals, 48 deaths from sporadic CJD, 5 from vCJD, 4 from
familial CJD, 3 from GSS and one from iatrogenic CJD.
During the period 1995, when vCJD was 1st diagnosed, up to the
present, there have been 946 deaths from all forms of CJD, including
the 158 deaths attributable to definite or probable vCJD.
[These data are accessible via
.]
--
ProMED-mail
******
[2] EUROCJD data as of 31 Oct 2006
Date: Tue 31 Oct 2006
From: ProMED-mail
Source: EUROCJD [edited]
The European And Allied Countries Collaborative Study Group of CJD (EUCJD)
-----------------------------------------------
This web-site includes information from 2 projects funded by the
European Commission. The EUROCJD project started in 1993 and compares
data from national registries in Australia, Austria, Canada, France,
Germany, Italy, the Netherlands, Slovakia, Spain, Switzerland and the
UK. The NEUROCJD project started in 1998 after the European Union
Council recommended that epidemiological surveillance of CJD should
be extended to all member states. The member states involved in this
project are Belgium, Denmark, Finland, Greece, Iceland, Ireland,
Israel, Norway and Portugal. Both projects are coordinated from the
National CJD Surveillance Unit based in Edinburgh.
Current data as of October 2006
-------------------------------
Country / Total No. of Primary cases (No. alive) / Cumulative
residence in UK (>6 months) / Secondary transmission by blood transfusion
United Kingdom / 162 (6) / 164 / 2 (0)
France / 21 (2) / 1 / 0
Republic of Ireland / 4 (1) / 2 / 0
Italy / 1 (0) / 0 / 0
USA / 2 (0) / 2 / 0
Canada / 1 (0) / 1 / 0
Saudi Arabia / 1 (1) / 0 / 0
Japan / 1* (0) / 0 / 0
Portugal / 1 (1) / 0 / 0
Spain / 1 (0) / 0 / 0
Total / 197 (12) / - / 2
Footnote:
---------
* Residence in the UK for 24 days
--
ProMED-mail
******
[3] France: novel prion strain
Date: Thu 12 Oct 2006
From: Terry Singeltary
Source: PLoS Pathogens 2(10); published ahead of print [edited]
Terry S. Singeltary Sr. has drawn ProMED-mail's attention to the
following paper published ahead of print in PLoS Pathogens, which
although not directly featuring vCJD, he considers is relevant to
understanding the origin of the BSE outbreak in cattle and vCJD in
humans. He comments that this research indicates that different prion
disease phenotypes result from inoculation of cattle with 2
temporally separated sources of sheep scrapie from Great Britain.
The paper is entitled "Isolation from Cattle of a Prion Strain
Distinct from That Causing Bovine Spongiform Encephalopathy" and is
authored by Vincent Beringue and 10 others. The abstract reads as follows:
"To date, bovine spongiform encephalopathy (BSE) and its human
counterpart, variant Creutzfeldt-Jakob disease, have been associated
with a single prion strain. This strain is characterized by a unique
and remarkably stable biochemical profile of abnormal
protease-resistant prion protein (PrP(res)) isolated from brains of
affected animals or humans. However, alternate PrP(res) signatures in
cattle have recently been discovered through large-scale screening.
To test whether these also represent separate prion strains, we
inoculated French cattle isolates characterized by a PrP(res) of
higher apparent molecular mass, called H-type, into transgenic mice
expressing bovine or ovine PrP. All mice developed neurological
symptoms and succumbed to these isolates, showing that these
represent a novel strain of infectious prions. Importantly, this
agent exhibited strain-specific features clearly distinct from that
of BSE agent inoculated to the same mice, which were retained on
further passage. Moreover, it also differed from all sheep scrapie
isolates passaged so far in ovine PrP-expressing mice. Our findings
therefore raise the possibility that either various prion strains may
exist in cattle, or that the BSE agent has undergone divergent
evolution in some animals."
The authors' synopsis of their paper reads as follows: Prions are
unconventional agents of proteic nature that are formed of abnormal
conformations of the host-encoded prion protein (PrP). They cause
fatal neurodegenerative diseases in both animals and humans and can
be transmitted between species, as exemplified in humans by the
emergence of variant Creutzfeldt-Jakob disease following the epidemic
of bovine spongiform encephalopathy (BSE) in the United Kingdom.
Since diagnosis of prion infection is only possible once the central
nervous system has been invaded, brains of slaughtered or fallen
cattle are routinely screened in Europe to protect the consumers from
BSE. This has unexpectedly led to the discovery of unprecedented PrP
conformations that were distinct from the single one associated so
far with BSE or BSE-related diseases. To precisely determine their
etiology, the authors have studied the transmissibility of these new
conformations, termed H-type, to transgenic mice expressing either
bovine or ovine PrP. They show that these cases are highly pathogenic
for these mice. The authors also demonstrate that they are not
directly related to the agent involved in the BSE epidemic,
supporting the view for isolation of a new prion strain from cattle,
whose prevalence and associated zoonotic risk should be carefully
monitored in the future."
--
Terry S. Singeltary Sr
[see also:
CJD (new var.) update 2006 (10) 20061002.2820
CJD (new var.) update 2006 (09) 20060904.2519
CJD (new var.) update 2006 (08) 20060807.2207
CJD (new var.) update 2006 (07) 20060703.1831
CJD (new var.) - Netherlands: 2nd case 20060623.1741
CJD (new var.) update 2006 (06) 20060605.1566
CJD (new var.) update 2006 (05) 20060508.1332
CJD (new var.) update 2006 (04) 20060404.1005
CJD (new var.) update 2006 (03) 20060306.0728
CJD (new var.) - UK: 3rd transfusion-related case 20060209.0432
CJD (new var.) update 2006 (02) 20060206.0386
CJD (new var.) update 2006 (01) 20060111.0101
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 (05) 20050505.1243
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 (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/jw
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[Docket No. FSIS-2006-0011] FSIS Harvard Risk Assessment of Bovine
Spongiform Encephalopathy (BSE)
http://www.fsis.usda.gov/OPPDE/Comments/2006-0011/2006-0011-1.pdf
[Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk Materials for Human Food and Requirement for the Disposition of Non-Ambulatory Disabled Cattle
03-025IFA
03-025IFA-2
http://www.fsis.usda.gov/OPPDE/Comments/03-025IFA/03-025IFA-2.pdf
THE SEVEN SCIENTIST REPORT ***
http://www.fda.gov/ohrms/dockets/dockets/02n0273/02n-0273-EC244-Attach-1.pdf
Full Text
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Singeltary, Sr et al. JAMA.2001; 285: 733-734.
http://jama.ama-assn.org/cgi/content/full/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=dignosing+and+reporting+creutzfeldt+jakob+disease&searchid=1048865596978_1528&stored_search=&FIRSTINDEX=0&journalcode=jama
http://www.neurology.org/cgi/eletters/60/2/176#535
BRITISH MEDICAL JOURNAL
BMJ
http://www.bmj.com/cgi/eletters/319/7220/1312/b#EL2
BMJ
http://www.bmj.com/cgi/eletters/320/7226/8/b#EL1
Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518
Date: November 7, 2006 at 1:57 pm PST
PERSPECTIVE
On the Question of Sporadic or Atypical Bovine Spongiform Encephalopathy and Creutzfeldt-Jakob Disease
Paul Brown,* Lisa M. McShane,† Gianluigi Zanusso,‡ and Linda Detwiler§
Strategies to investigate the possible existence of sporadic
bovine spongiform encephalopathy (BSE) require
systematic testing programs to identify cases in countries
considered to have little or no risk for orally acquired disease,
or to detect a stable occurrence of atypical cases in
countries in which orally acquired disease is disappearing.
To achieve 95% statistical confidence that the prevalence
of sporadic BSE is no greater than 1 per million (i.e., the
annual incidence of sporadic Creutzfeldt-Jakob disease
[CJD] in humans) would require negative tests in 3 million
randomly selected older cattle. A link between BSE and
sporadic CJD has been suggested on the basis of laboratory
studies but is unsupported by epidemiologic observation.
Such a link might yet be established by the discovery
of a specific molecular marker or of particular combinations
of trends over time of typical and atypical BSE and various
subtypes of sporadic CJD, as their numbers are influenced
by a continuation of current public health measures that
exclude high-risk bovine tissues from the animal and
human food chains.
Bovine spongiform encephalopathy (BSE) was first recognized
in 1986 in the United Kingdom and quickly
reached epidemic proportions, affecting >30,000 cattle per
year by 1992. Because of continuing exportation of both
live cattle and meat and bone meal rendered from the carcasses
of slaughtered cattle, the disease spread throughout
most of Europe and a few non-European countries. By
2006, 20 years after its first appearance in the United
Kingdom, the disease had been reported in an additional
24 countries (1).
Beginning toward the end of the 1980s in the United
Kingdom, and in the 1990s in other countries, numerous
regulations were enacted to minimize the entry of contaminated
tissues into both the animal and human food chains
and to eliminate the international spread of disease. These
measures have been extraordinarily successful, to the
extent that no new countries have been added to the list
during the past year and the number of new cases has dramatically
diminished in most countries in which BSE has
appeared (the situation in some countries with insufficient
surveillance remains unclear).
Although the origin of the epidemic is thought to have
been caused by a species-crossing contamination by sheep
scrapie during the course of rendering and recycling carcass
meat and bone meal as cattle feed, an alternative
hypothesis suggested an origin in a similarly recycled case
of spontaneously occurring disease in cattle. The pros and
cons of these competing ideas have been argued elsewhere
(2,3), and neither will ever be convincingly proved or disproved.
Thus, the phenomenon of spontaneous disease
remained in limbo until the recent discovery of “atypical”
strains of BSE reopened the question. In this article we
consider the importance of atypical BSE within the overall
concept of sporadic (spontaneous) disease and whether
such cases, if they exist, could account for at least some
cases of apparently sporadic Creutzfeldt-Jakob (CJD) in
humans.
Sporadic BSE
Obviously, the ideal country in which to examine the
question of sporadic BSE would have a large national herd
that was guaranteed never to have been exposed to environmental
sources of infection. Such an ideal will never be
realized. Until recently, the United States appeared to have
at least approached the ideal by having a large national
*Bethesda, Maryland, USA; †National Institutes of Health,
Bethesda, Maryland, USA; ‡University of Verona, Verona, Italy;
and §Virginia-Maryland Regional College of Veterinary Medicine,
College Park, Maryland, USA
1816 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 12, December 2006
herd, an adequate testing program, and an apparently small
risk for contamination by imported cattle or cattle feed.
That position was made vulnerable in late 2003 by the discovery
of a case of BSE imported from Canada and was
eliminated altogether by the subsequent discovery of 2
indigenously infected animals in widely separate regions
of the country. Although the 2 indigenous cases might represent
sporadic disease, the continuing identification of
cases in western Canada, coupled with a history of substantial
numbers of cattle imported from Canada into the
United States (both indigenous US animals had the same
molecular “signature” as the most recent Canadian case),
makes it difficult to ignore the possibility of undetected
instances of feed contamination from imported and recycled
infectious carcasses.
At present, the 2 best countries in which to undertake
testing programs would be Argentina and Australia; both
have large national herds (≈50 million and 30 million animals,
respectively), and both are considered to be free of
orally acquired BSE infections, on the basis of importation
history, nutritional practices, and adequacy of surveillance
(4). Even in these countries, however, the discovery of a
case of BSE could not be guaranteed to be spontaneous
because of the widespread global distribution of potentially
infected cattle and cattle feed and the vagaries of international
trade: imperfect record keeping, lack of
compliance, and just plain deception.
By way of illustration, an incident occurred many years
ago that involved a particularly bulky shipment labeled as
a pesticide. The large quantity seemed unusual to the customs
inspector, who opened it and discovered that the shipment
contained meat and bone meal destined to be spread
on fields to inhibit grazing by deer, a serious agricultural
pest. Thus, a study of sporadic BSE would only be truly
convincing if no cases were identified.
Moreover, the criteria for answering the question of
sporadic BSE are different than for orally acquired BSE.
Most importantly, we do not know at what age sporadic
cases of BSE might occur, but they are unlikely to be in the
3- to 5-year-old age group in which orally acquired BSE is
most prevalent. If the age distribution of sporadic disease
in cattle were to mimic that of sporadic CJD in humans, it
would not peak until 14–20 years of age (the last third of
the ≈20-year natural life span of a cow). Substantial numbers
of such older cattle do not exist, and thus it may never
be possible to state with assurance that spontaneous BSE
does not occur.
Even if we accept this practical constraint, we can still
take advantage of the fact that in many countries a proportion
of the total slaughter population consists of breeding
stock and dairy cows that are culled at >7 years of age, and
animals that go directly to rendering plants or die “on
farm” further increase this number. Argentina, for example,
with a national herd of ≈50 million cattle, in 2005
recorded nearly 1.4 million deaths from slaughter and natural
causes in animals >7 years (L. Mascitelli, pers.
comm.).
Approximately 10% of cases of sporadic CJD occur in
patients 25–50 years of age; this age in humans corresponds
to the middle third of a cow’s normal life span, or
7–13 years of age (Figure 1). If the age distribution of sporadic
BSE followed the same pattern, negative test results
in a total of ≈3 million animals randomly selected from
this group would allow us to be 95% confident that sporadic
BSE is not present at a prevalence >1 per million,
and ≈4.5 million negative animals would raise the level of
confidence to 99%. Larger numbers of BSE-negative animals
would be required to achieve these levels of confidence
for a maximum prevalence <1 per 10 million cattle
(Table 1, Figure 2).
Even the least rigorous negative result—a prevalence
not greater than that of sporadic CJD in humans, or 1 per
million—would require several years to achieve, and it is
perhaps unrealistic to suppose that the motivation to prolong
the testing program will endure much beyond the
global disappearance of orally acquired BSE and variant
CJD. Nevertheless, to the degree that testing older as well
as younger adult animals approached these numbers, both
statistical and consumer confidence would increase, and at
the very least provide reassurance that the occurrence of
sporadic disease must be exceedingly rare, with little likelihood
of posing a risk to either human or animal nutrition.
Atypical BSE
Because of its contemporary nature, the study of atypical
BSE is very much a work in progress, with comparatively
little published data and many unknowns. The first 2
cases to be identified were a serendipitous discovery made
in the course of an unrelated experimental study that
required a detailed neuropathologic and immunochemical
Figure 2. Maximum prevalence according to number of negative
cattle at 95% (solid line) and 99% (dashed line) confidence levels.
See Table 1 for exact numbers and statistical method.
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 12, December 2006 1817
examination of the entire brain (5). The absence of clinical
signs in these older animals, the unusual distribution of
PrPTSE, together with amyloid plaques, and a Western blot
pattern that differed from the stereotypic pattern seen in
typical BSE left little doubt about the probability that a
new “atypical strain” had been identified (bovine amyloidotic
spongiform encephalopathy[BASE]).
Although no further cases were found in nearly 200 cattle
examined in Italy, the initiation of Western blot studies
of animals in other countries with screening test programs
began to yield additional atypical patterns (Table 2, Figure
3) (6–14; P. Lind, pers. comm.). Two major patterns have
been described, named L (resembling the original Italian
case pattern with a lower molecular weight than typical
BSE) and H (for a distinct pattern first seen in France with
a higher molecular weight than typical BSE). It is not yet
clear whether other mixed patterns result from technical
procedures in different laboratories or whether a more
complicated scheme of classification will evolve as more
atypical patterns are discovered.
In addition, Western blots of PrPTSE are a fragile basis
on which to define a BSE phenotype. Little or no information
is available about either the clinical status or neuropathologic
features of these animals. We know that cases
have occurred in different breeds and PrP genotypes, and
we also know that very few of the animals have had the
typical clinical picture of BSE (behavioral disturbances,
sensory signs, ataxia, and tremors), but a cloud of ambiguity
surrounds the clinical picture even in those animals for
which an extensive post-hoc investigation was undertaken.
The fact that few detailed neuropathologic results are
available is explained by the need to preserve at least a full
half brain for examination, which is presently not done in
any of the various countries that have screening test programs.
In the future, the brain as well as the carcass must
be retained in cold storage until the test results are known.
The frequency of atypical cases is another unknown.
Published (7,12) and unpublished (11,13) observations
indicate that in some countries it might be as high as
5%–10% of the total number of older animals diagnosed
by rapid screening tests (e.g., 2/27 in Germany, and 1/9 in
Canada), which would seem to be a surprisingly high proportion
of spontaneously occurring cases. However, data
are not yet sufficient to estimate the overall prevalence of
atypical BSE, i.e., cases per million tested animals of all
ages.
In this context, a word is in order about the US testing
program. After the discovery of the first (imported) cow in
2003, the magnitude of testing was much increased, reaching
a level of >400,000 tests in 2005 (Figure 4). Neither of
the 2 more recently indigenously infected older animals,
with ambiguous or no clinical features, would have been
detected without such testing, and neither would have been
identified as atypical without confirmatory Western blots.
Despite these facts, surveillance has now been decimated
to 40,000 annual tests (USDA news release no. 0255.06,
July 20, 2006) and invites the accusation that the United
1818 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 12, December 2006
States will never know the true status of its involvement
with BSE.
In short, a great deal of further work will need to be
done before the phenotypic features and prevalence of
atypical BSE are understood. More than a single strain
may have been present from the beginning of the epidemic,
but this possibility has been overlooked by virtue of the
absence of widespread Western blot confirmatory testing
of positive screening test results. These new phenotypes
may be found, at least in part, to result from infections at
an older age by a typical BSE agent, rather than neonatal
infections with new “strains” of BSE. Neither alternative
has yet been investigated.
Sporadic CJD
The possibility that at least some cases of apparently
sporadic CJD might be due to infection by sporadic cases
of BSE cannot be dismissed outright. Screening programs
needed to identify sporadic BSE have yet to be implemented,
and we know from already extant testing programs that
at least a proportion of infected animals have no symptoms
and thus would never be identified in the absence of systematic
testing. Thus, sporadic BSE (or for that matter,
sporadic disease in any mammalian species) might be
occurring on a regular basis at perhaps the same annual
frequency as sporadic CJD in humans, that is, in the range
of 1 case per million animals.
Whether humans might be more susceptible to atypical
forms of BSE cannot be answered at this time.
Experimentally transmitted BASE shows shorter incubation
periods than BSE in at least 1 breed of cattle,
bovinized transgenic mice, and Cynomolgus monkeys
(12,13). In humanized transgenic mice, BASE transmitted,
whereas typical BSE did not transmit (13). Paradoxically,
the other major phenotype (H) showed an unusually long
incubation period in bovinized transgenic mice (12).
The limited experimental evidence bearing on a possible
relationship between BSE and sporadic CJD is difficult
to interpret. The original atypical BASE strain of BSE had
a molecular protein signature very similar to that of 1 subtype
(type 2 M/V) of sporadic CJD in humans (5).
In another study, a strain of typical BSE injected into
humanized mice encoding valine at codon 129 showed a
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 12, December 2006 1819
glycopattern indistinguishable from the same subtype of
sporadic CJD (15). In a third study, the glycopatterns of
both the H and L strains of atypical BSE evidently did not
resemble any of the known sporadic CJD subtypes (12).
To these molecular biology observations can be added
the epidemiologic data accumulated during the past 30
years. The hypothesis that at least some cases of apparently
sporadic CJD are due to unrecognized BSE infections
cannot be formally refuted, but if correct, we might expect
by now to have some epidemiologic evidence linking BSE
to at least 1 cluster of apparently sporadic cases of CJD.
Although only a few clusters have been found (and still
fewer published), every proposed cluster that has been
investigated has failed to show any common exposure to
bovines. For that matter, no common exposure has been
shown to any environmental vehicles of infection, including
the consumption of foodstuffs from bovine, ovine, and
porcine sources, the 3 livestock species known to be susceptible
to transmissible spongiform encephalopathies.
Additional negative evidence comes from several large
case-control studies in which no statistically significant
dietary differences were observed between patients with
sporadic CJD and controls (16,17).
On the other hand, the difficulty of establishing a link
between BSE and CJD may be compounded by our ignorance
of the infectious parameters of a sporadic form of
BSE (e.g., host range, tissue distribution of infectivity,
route of transmission, minimum infectious dose for
humans, whether single or multiple). Presumably, these
parameters would resemble those of variant CJD' that is,
high infectivity central nervous system and lymphoreticular
tissues of an infected cow find their way into products
consumed by humans. Transmissions that might have
occurred in the past would be difficult to detect because
meat products are generally not distributed in a way that
results in detectable geographic clusters.
Barring the discovery of a specific molecular signature
(as in variant CJD), the most convincing clue to an association
will come from the observation of trends over time of
the incidence of typical and atypical BSE and of sporadic
and variant CJD. With 4 diseases, each of which could
have increasing, unchanging, or decreasing trends, there
could be 81 (34) possible different combinations. However,
it is highly likely that the trends for typical BSE and variant
CJD will both decrease in parallel as feed bans continue
to interrupt recycled contamination. The remaining
combinations are thus reduced to 9 (32), and some of them
could be highly informative.
For example, if the incidence of atypical BSE declines
in parallel with that of typical BSE, its candidacy as a sporadic
form of disease would be eliminated (because sporadic
disease would not be influenced by current measures
to prevent oral infection). If, on the other hand, atypical
BSE continues to occur as typical BSE disappears, this
would be a strong indication that it is indeed sporadic, and
if in addition at least 1 form of what is presently considered
as sporadic CJD (such as the type 2 M/V subtype
shown to have a Western blot signature like BASE) were
to increase, this would suggest (although not prove) a
causal relationship (Figure 5).
Recognition of the different forms of BSE and CJD
depends upon continuing systematic testing for both
bovines and humans, but bovine testing will be vulnerable
Figure 5. Diagram of 2 possible informative trends in the incidence
of bovine spongiform encephalopathy (BSE) and Creutzfeld-Jakob
disease (CJD). The left panel shows the likely trends of typical
BSE and variant CJD (vCJD). The right upper panel shows 1 possible
pair of trends of atypical BSE and sporadic CJD (sCJD)
that might occur in conjunction with the typical BSE/vCJD trends,
and would be consistent with the interpretation that atypical BSE
is not sporadic and not related to sCJD. The right lower panel
shows a second possible associated pair of trends consistent with
the interpretation that atypical BSE is sporadic and might also be
related to the type 2 M/V subset of apparently sCJD.
1820 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 12, December 2006
to heavy pressure from industry to dismantle the program
as the commercial impact of declining BSE cases ceases to
be an issue. Industry should be aware, however, of the
implications of sporadic BSE. Its occurrence would necessitate
the indefinite retention of all of the public health
measures that exclude high-risk bovine tissues from the
animal and human food chains, whereas its nonoccurrence
would permit tissues that are now destroyed to be used as
before, once orally acquired BSE has disappeared.
Acknowledgments
We thank Victoria E. Bridges and Chris Kopral for providing
data about annual cattle slaughter numbers from the Food
Safety and Inspection Service of the US Department of
Agriculture (USDA) and for estimates of cattle dying on farms
from data supplied by the National Animal Health Monitoring
System, Animal and Plant Inspection Services, Veterinary
Service, USDA.
This study was funded in part by grant # 4AN/F10 “Studio
dei meccanismi patogenetici delle malattie neurodegenerative per
la diagnosi e lo sviluppo di approcci terapeutici” from the Istituto
Superiore di Sanità, Rome, Italy
Dr Brown has recently retired after a 41-year career in the
Laboratory of CNS Studies at the National Institutes of Health,
where he focused on studying transmissible spongiform
encephalopathies.
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Gowland I, et al. Human prion protein with valine 129 prevents
expression of variant CJD phenotype. Science. 2004;306:1793–6.
16. Wientjens DP, Davanipour Z, Hofman A, Kondo K, Matthews WB,
Will RG, et al. Risk factors for Creutzfeldt-Jakob disease: a reanalysis
of case control studies. Neurology. 1996;46:1267–91.
17. Van Duijn CM, Delasnerie-Lauprêtre N, Masullo C, Zerr I, de Silva
R, Wientjens DPWM, et al. Case-control study of risk factors of
Creutzfeldt-Jakob disease in Europe during 1993–1995. Lancet.
1998;351:1081–5.
Address for correspondence: Paul Brown, 7815 Exeter Rd, Bethesda, MD
20814, USA; email: [email protected]
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 12, December 2006 1821
Case 1:06-cv-00544-JR Document 14-9 Filed 11/03/2006 Page 47 of 47
P.S. some of the charts, graphs, tables etc. i was not able to forward in plain text. ...TSS
SEE STEADY INCREASE IN SPORADIC CJD IN THE USA FROM
1997 TO 2006. SPORADIC CJD CASES TRIPLED, with phenotype
of 'UNKNOWN' strain growing. ...
http://www.cjdsurveillance.com/resources-casereport.html
There is a growing number of human CJD cases, and they were presented last week in San Francisco by Luigi Gambatti(?) from his CJD surveillance collection.
He estimates that it may be up to 14 or 15 persons which display selectively SPRPSC and practically no detected RPRPSC proteins.
http://www.fda.gov/ohrms/dockets/ac/06/transcripts/1006-4240t1.htm
http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4240t1.pdf
CJD (NEW VARIANT) UPDATE 2006 (11)
**********************************
A ProMED-mail post
ProMED-mail is a program of the
International Society for Infectious Diseases
[The definition of the designations deaths, definite cases, probable
vCJD cases, and the case definitions can be found by accessing the
Department of Health website or by reference to a previous
ProMED-mail post in this thread (for example, CJD (new var.) - UK:
update March 2002 20020305.3693).
Data on vCJD cases from other parts of the world are now included in
these updates whenever available.
Also, data on other forms of CJD (sporadic, iatrogenic, familial and
GSS) are now included when they have some relevance to the incidence
and etiology of vCJD. - Mod.CP]
In this update:
[1] UK: Department of Health monthly CJD statistics, Mon 6 Nov 2006
[2] EUROCJD data as of 31 Oct 2006
[3] France: novel prion strain
******
[1] UK: Department of Health monthly CJD statistics, Mon 6 Nov 2006
Date: Mon 6 Nov 2006
From: ProMED-mail
Source: UK Department of Health, Monthly Creutzfeldt-Jakob Disease
Statistics [edited]
The Department of Health is today [Mon 6 Nov 2006] issuing the latest
information about the numbers of known cases of Creutzfeldt-Jakob
disease. This includes cases of 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).
Definite and probable CJD cases in the UK, as of Fri 3 Nov 2006:
-----------------------------------------------
Summary of vCJD cases - deaths
-----------------------------
Deaths from definite vCJD (confirmed): 112
Deaths from probable vCJD (without neuropathological confirmation): 46
Deaths from probable vCJD (neuropathological confirmation pending): 0
Number of deaths from definite or probable vCJD (as above): 158
Summary of vCJD cases - alive
-----------------------------
Number of probable vCJD cases still alive: 6
Total
-----
Number of definite or probable vCJD (dead and alive): 164
(The next table will be published on Mon 4 Dec 2006).
Since the previous monthly statistics were released on Mon 6 Nov
2006, the total number of deaths from definite vCJD has increased by
2 and stands at 158, and the overall total number of definite or
probable vCJD cases (dead and alive) has increased by 2, making the
overall total 164.
These data are consistent with the view that the vCJD outbreak in the
UK is in decline. The total number of deaths due to vCJD in the UK is
now 158. The peak number of deaths was 28 in the year 2000, followed
by 20 in 2001, 17 in 2002, 18 in 2003, and 9 in 2004, 5 in 2005. The
number of deaths due to definite or probable vCJD in the UK during
the 1st 10 months of 2006 has risen to 5.
Totals for all types of CJD cases in the UK in 2005 and 2006
-----------------------------------------------
As of 3 Nov 2006, in the UK in the year 2005, there were 122
referrals of suspected CJD, and there were 65 deaths from sporadic
CJD, 6 from familial CJD, 3 from iatrogenic CJD, 6 GSS
(Gerstmann-Straussler-Scheinker) syndrome cases, and 5 deaths from vCJD.
The corresponding figures so far for the 1st 10 months of 2006 are:
87 referrals, 48 deaths from sporadic CJD, 5 from vCJD, 4 from
familial CJD, 3 from GSS and one from iatrogenic CJD.
During the period 1995, when vCJD was 1st diagnosed, up to the
present, there have been 946 deaths from all forms of CJD, including
the 158 deaths attributable to definite or probable vCJD.
[These data are accessible via
.]
--
ProMED-mail
******
[2] EUROCJD data as of 31 Oct 2006
Date: Tue 31 Oct 2006
From: ProMED-mail
Source: EUROCJD [edited]
The European And Allied Countries Collaborative Study Group of CJD (EUCJD)
-----------------------------------------------
This web-site includes information from 2 projects funded by the
European Commission. The EUROCJD project started in 1993 and compares
data from national registries in Australia, Austria, Canada, France,
Germany, Italy, the Netherlands, Slovakia, Spain, Switzerland and the
UK. The NEUROCJD project started in 1998 after the European Union
Council recommended that epidemiological surveillance of CJD should
be extended to all member states. The member states involved in this
project are Belgium, Denmark, Finland, Greece, Iceland, Ireland,
Israel, Norway and Portugal. Both projects are coordinated from the
National CJD Surveillance Unit based in Edinburgh.
Current data as of October 2006
-------------------------------
Country / Total No. of Primary cases (No. alive) / Cumulative
residence in UK (>6 months) / Secondary transmission by blood transfusion
United Kingdom / 162 (6) / 164 / 2 (0)
France / 21 (2) / 1 / 0
Republic of Ireland / 4 (1) / 2 / 0
Italy / 1 (0) / 0 / 0
USA / 2 (0) / 2 / 0
Canada / 1 (0) / 1 / 0
Saudi Arabia / 1 (1) / 0 / 0
Japan / 1* (0) / 0 / 0
Portugal / 1 (1) / 0 / 0
Spain / 1 (0) / 0 / 0
Total / 197 (12) / - / 2
Footnote:
---------
* Residence in the UK for 24 days
--
ProMED-mail
******
[3] France: novel prion strain
Date: Thu 12 Oct 2006
From: Terry Singeltary
Source: PLoS Pathogens 2(10); published ahead of print [edited]
Terry S. Singeltary Sr. has drawn ProMED-mail's attention to the
following paper published ahead of print in PLoS Pathogens, which
although not directly featuring vCJD, he considers is relevant to
understanding the origin of the BSE outbreak in cattle and vCJD in
humans. He comments that this research indicates that different prion
disease phenotypes result from inoculation of cattle with 2
temporally separated sources of sheep scrapie from Great Britain.
The paper is entitled "Isolation from Cattle of a Prion Strain
Distinct from That Causing Bovine Spongiform Encephalopathy" and is
authored by Vincent Beringue and 10 others. The abstract reads as follows:
"To date, bovine spongiform encephalopathy (BSE) and its human
counterpart, variant Creutzfeldt-Jakob disease, have been associated
with a single prion strain. This strain is characterized by a unique
and remarkably stable biochemical profile of abnormal
protease-resistant prion protein (PrP(res)) isolated from brains of
affected animals or humans. However, alternate PrP(res) signatures in
cattle have recently been discovered through large-scale screening.
To test whether these also represent separate prion strains, we
inoculated French cattle isolates characterized by a PrP(res) of
higher apparent molecular mass, called H-type, into transgenic mice
expressing bovine or ovine PrP. All mice developed neurological
symptoms and succumbed to these isolates, showing that these
represent a novel strain of infectious prions. Importantly, this
agent exhibited strain-specific features clearly distinct from that
of BSE agent inoculated to the same mice, which were retained on
further passage. Moreover, it also differed from all sheep scrapie
isolates passaged so far in ovine PrP-expressing mice. Our findings
therefore raise the possibility that either various prion strains may
exist in cattle, or that the BSE agent has undergone divergent
evolution in some animals."
The authors' synopsis of their paper reads as follows: Prions are
unconventional agents of proteic nature that are formed of abnormal
conformations of the host-encoded prion protein (PrP). They cause
fatal neurodegenerative diseases in both animals and humans and can
be transmitted between species, as exemplified in humans by the
emergence of variant Creutzfeldt-Jakob disease following the epidemic
of bovine spongiform encephalopathy (BSE) in the United Kingdom.
Since diagnosis of prion infection is only possible once the central
nervous system has been invaded, brains of slaughtered or fallen
cattle are routinely screened in Europe to protect the consumers from
BSE. This has unexpectedly led to the discovery of unprecedented PrP
conformations that were distinct from the single one associated so
far with BSE or BSE-related diseases. To precisely determine their
etiology, the authors have studied the transmissibility of these new
conformations, termed H-type, to transgenic mice expressing either
bovine or ovine PrP. They show that these cases are highly pathogenic
for these mice. The authors also demonstrate that they are not
directly related to the agent involved in the BSE epidemic,
supporting the view for isolation of a new prion strain from cattle,
whose prevalence and associated zoonotic risk should be carefully
monitored in the future."
--
Terry S. Singeltary Sr
[see also:
CJD (new var.) update 2006 (10) 20061002.2820
CJD (new var.) update 2006 (09) 20060904.2519
CJD (new var.) update 2006 (08) 20060807.2207
CJD (new var.) update 2006 (07) 20060703.1831
CJD (new var.) - Netherlands: 2nd case 20060623.1741
CJD (new var.) update 2006 (06) 20060605.1566
CJD (new var.) update 2006 (05) 20060508.1332
CJD (new var.) update 2006 (04) 20060404.1005
CJD (new var.) update 2006 (03) 20060306.0728
CJD (new var.) - UK: 3rd transfusion-related case 20060209.0432
CJD (new var.) update 2006 (02) 20060206.0386
CJD (new var.) update 2006 (01) 20060111.0101
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 (05) 20050505.1243
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 (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/jw
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[Docket No. FSIS-2006-0011] FSIS Harvard Risk Assessment of Bovine
Spongiform Encephalopathy (BSE)
http://www.fsis.usda.gov/OPPDE/Comments/2006-0011/2006-0011-1.pdf
[Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk Materials for Human Food and Requirement for the Disposition of Non-Ambulatory Disabled Cattle
03-025IFA
03-025IFA-2
http://www.fsis.usda.gov/OPPDE/Comments/03-025IFA/03-025IFA-2.pdf
THE SEVEN SCIENTIST REPORT ***
http://www.fda.gov/ohrms/dockets/dockets/02n0273/02n-0273-EC244-Attach-1.pdf
Full Text
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Singeltary, Sr et al. JAMA.2001; 285: 733-734.
http://jama.ama-assn.org/cgi/content/full/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=dignosing+and+reporting+creutzfeldt+jakob+disease&searchid=1048865596978_1528&stored_search=&FIRSTINDEX=0&journalcode=jama
http://www.neurology.org/cgi/eletters/60/2/176#535
BRITISH MEDICAL JOURNAL
BMJ
http://www.bmj.com/cgi/eletters/319/7220/1312/b#EL2
BMJ
http://www.bmj.com/cgi/eletters/320/7226/8/b#EL1
Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518