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From: TSS (
Subject: Other animal prion diseases FULL TEXT
Date: January 25, 2005 at 1:45 pm PST

-------- Original Message --------
Subject: Other animal prion diseases FULL TEXT
Date: Tue, 25 Jan 2005 15:35:03 -0600
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy

##################### Bovine Spongiform Encephalopathy #####################

British Medical Bulletin 66:199-212 (2003)
© 2003 The British Council

Other animal prion diseases

Christina J Sigurdson* and Michael W Miller{dagger}

*Department of Microbiology, Immunology, and Pathology, Colorado State
University, Fort Collins, Colorado, USA
{dagger} Colorado Division of Wildlife, Wildlife Research Center, Fort
Collins, Colorado, USA

In addition to bovine spongiform encephalopathy (BSE) of cattle and
scrapie of sheep and goats, a few other animal prion diseases have been
reported. These include feline spongiform encephalopathy of zoological
and domestic cats (FSE) and transmissible spongiform encephalopathy
(TSE) of zoological ruminants and non-human primates, as well as chronic
wasting disease of deer and elk (CWD) and transmissible mink
encephalopathy of farmed mink (TME). The origins of TSE in cats, zoo
bovids, and non-human primates are clearly linked to the BSE epidemic;
however, the origins of CWD and TME are less clear, but are not
epidemiologically linked to the BSE epidemic. Here we review the
epidemiology, transmission, clinical features and pathology of these
other animal prion diseases.

Other animal prion diseases FULL TEXT

Christina J Sigurdson* and Michael W Miller

*Department of Microbiology, Immunology, and Pathology, Colorado State
University, Fort Collins,
Colorado, USA and Colorado Division of Wildlife, Wildlife Research
Center, Fort Collins,
Colorado, USA

In addition to bovine spongiform encephalopathy (BSE) of cattle and
scrapie of
sheep and goats, a few other animal prion diseases have been reported. These
include feline spongiform encephalopathy of zoological and domestic cats
and transmissible spongiform encephalopathy (TSE) of zoological
ruminants and
non-human primates, as well as chronic wasting disease of deer and elk
(CWD) and
transmissible mink encephalopathy of farmed mink (TME). The origins of
TSE in
cats, zoo bovids, and non-human primates are clearly linked to the BSE
however, the origins of CWD and TME are less clear, but are not
linked to the BSE epidemic. Here we review the epidemiology,
transmission, clinical
features and pathology of these other animal prion diseases.

Spongiform encephalopathy in zoo ruminants, cats, and nonhuman

BSE transmits to non-domestic bovids, felids, and non-human primates
Parallel to the BSE epidemic in cattle beginning in the 1980s, 15
additional species have contracted a spongiform encephalopathy,
virtually tripling the number of animal species known world-wide to
develop a TSE naturally. Seven bovid, 4 felid, and 4 primate species were
afflicted with a TSE, primarily in zoological collections in Great Britain
but also in France (Table 1)15. At the time of their diagnoses, the
geographic and temporal association with BSE suggested possible links
to the epidemic, and further epidemiological and experimental evidence
has bolstered this premise. Affected animals had either consumed
protein supplements or were in contact with prion-infected
individuals1,6. Additionally, mice inoculated with brain homogenates
from TSE-infected kudu, nyala, or domestic cats developed a spongiform
encephalopathy with profiles of histological lesions and incubation
periods virtually identical to those seen with BSE in mice7,8. Moreover,
the similar biochemical profiles of the protease-resistant prion protein,
PrPres, in experimental murine BSE, FSE, and experimental BSE in a
macaque supported the hypothesis that these apparently novel TSEs had
the same origin  BSE9. Thus, the assemblage of epidemiological and
biochemical clues has provided compelling evidence that these newly
described TSEs arose from BSE that had crossed species barriers.

Although a multitude of zoo species were exposed to BSE-contaminated
meat and bone meal, only a small group of animals developed
disease. The exotic zoo ruminants that died of TSE include greater kudu,
eland, nyala, gemsbok, Arabian oryx, a scimitar-horned oryx, and a
bison1,5; all are members of the family Bovidae. Most affected animals
had consumed diets that included ruminant-derived meat and bone
meal. The possible exception was greater kudu. Epidemiological studies
initially suggested that kudu developed TSE from exposure to foodborne
BSE, but then maintained the infection by horizontal spread
among animals in a manner similar to scrapie and CWD6; however, the
apparently prolonged epidemic may have been the product of sustained
exposure to BSE-contaminated feed5.

Feline spongiform encephalopathy
The prion diseases of non-domestic cats were likely due to ingestion of
BSE-infected cattle carcasses. Feline spongiform encephalopathy has
been described in a captive cheetah, puma, an ocelot, and a tiger from
zoological collections in Great Britain1,5.
In addition to the non-domestic felids, 87 domestic cats in Great Britain
and sporadic cases in Norway, Northern Ireland and Liechtenstein have
been diagnosed with FSE10. All cats were > 2 years old. Clinically, affected
cats initially demonstrated behaviour changes (more timid or
aggressive), with subsequent ataxia, hypermetria, and hyperesthesia to
sound and touch11,12. Histopathology revealed spongiform degeneration
in the neuropil of the brain and spinal cord with the most severe lesions
localized to the medial geniculate nucleus of the thalamus and the basal
nuclei10. A ban on bovine spleen and CNS tissue in pet foods was
initiated in 1990, and all but one of the FSE cases to date occurred in
cats born prior to the ban13.

Prions for physicians
British Medical Bulletin 2003;66
Table 1 Zoo animals diagnosed with transmissible spongiform
encephalopathy between
1985 and 19981,35
Species Number affected
Greater kudu (Tragelaphus strepsiceros) 6
Eland (Taurotragus oryx) 5
Gemsbok (Oryx gazella) 1
Nyala (Tragelaphus angasi) 1
Arabian oryx (Oryx leucoryx) 1
Scimitar-horned oryx (Oryx dammah) 1
Bison (Bison bison) 1
Cheetah (Acinonyx jubatus) 7
Puma (Felis concolor) 3
Ocelot (Felis pardalis) 2
Tiger (Panthera tigris) 1
Mayotte brown lemur (Eulemur fulvus mayottensis) 2
White fronted brown lemur (Eulemur fulvus albifrons) 1
Mongoose lemur (Eulemur mongoz) 1
Rhesus macaque (Macaca mulatta) 1

Spongiform encephalopathy in non-human primates

Lemurs and a rhesus macaque from a zoo and three primate facilities in
France naturally developed TSE in the 1990s. Primate diets had included
meat-meal supplements that were likely contaminated by British beef4.
Indeed, lemurs experimentally infected with BSE developed brain lesions
that were similar to those seen in naturally infected lemurs. Additionally,
the immunohistochemical staining patterns in natural and experimental
cases were similar and revealed PrPres in tonsil, Peyers patches, lymph
nodes and spleen4.

Chronic wasting disease: a prion disease in North American
deer and elk

Transmission and epidemiology
Chronic wasting disease (CWD) is the only prion disease known to
affect free-ranging wild-life. First recognized as a clinical syndrome of
captive mule deer (Odocoileus hemionus) in Colorado in the 1960s,
CWD was not diagnosed as a TSE until 1978, and was diagnosed in
captive research deer and captive Rocky Mountain elk (Cervus elaphus
nelsoni) in southeastern Wyoming soon thereafter14,15. Beginning in
1981, cases of CWD were diagnosed in free-ranging mule deer, whitetailed
deer (O. virginanus) and Rocky Mountain elk (cervids) on the
eastern slope of the Rocky Mountains and extending out on the plains
following river valleys within Colorado and Wyoming16,17. The origin of
CWD in captive or free-ranging deer remains enigmatic17,18.
CWD was first diagnosed in Canadas farmed elk industry in 1996,
and in the US elk industry in 1997. More recently, CWD-infected
ranched elk have been discovered in several other states and in Canada
and South Korea; these discoveries have heightened international
awareness and concern regarding CWD and other animal TSEs. Prior to
2000, CWD in free-ranging deer was believed to be limited to a focal
geographic region of the US. Unfortunately, in the last two years, CWD
has been detected in free-ranging deer in Wisconsin, Nebraska, South
Dakota, New Mexico, and western Colorado, and in Saskatchewan,
Canada (Fig. 1); the origins of these recent outbreaks remain under
investigation, but in most cases spill-over from infected game farms
seems the most plausible explanation. The appearance of CWD in wild
deer presents significant challenges to disease control or eradication due
to the extensive geographic range of North American deer and elk, lack
of ante-mortem diagnostic tests, as well as an inability to rid the
environment of potential prion-contaminated excreta18.

CWD is naturally transmitted with remarkable efficiency. Estimates of
CWD-infected deer revealed a prevalence of 115% within a defined
endemic region in northeastern Colorado and southeastern Wyoming17.
The efficiency of CWD transmission was also evident in a captive mule
deer herd, wherein ~90% of animals (n = 60) resident for 2 years or
longer developed CWD between 1970 and 198114. The original source
of infection was not determined, but these animals had not been fed
meat and bone meal19. The mechanism of CWD agent shedding and
natural transmission among free-ranging herbivores is unknown.
Epidemiological studies of natural disease suggest horizontal spread
potentially via the ingestion of forage or water contaminated by
infectious secretions, excretions, or other tissue source (e.g. placenta or
decomposed carcasses), although vertical transmission has not been
excluded1720. The abundant presence of the pathogenic prion protein,
PrPCWD, in alimentary mucosal-associated lymphoid tissues may favour
prion shedding into the environment via faeces or saliva5,18,21.
CWD surveillance within and around the endemic areas of northeastern
Colorado and southeastern Wyoming from 1997 to present has
been extensive. Brain samples have been acquired from over 12,000 deer
and elk sampled via geographically-focused random surveys and were
tested by immunohistochemistry using anti-PrP monoclonal
antibodies17,22. Brain and lymphoid tissue sections have been examined
for PrPCWD. Results of the surveys within the suspected endemic area
have revealed that ~5% of mule deer, 2% of white-tailed deer, and < 1%
of elk are infected, with wide variation within a species sampled from
different subpopulations17. Over a 3-year period of sampling, CWD
prevalence appeared stable17; however, more recent trend analyses
suggest prevalence is slowly increasing (MW Miller, unpublished
findings). Population models predict that if epidemics continue
unmanaged, then mule deer populations would be expected to decline
dramatically over a 3050-year period17,23. It is not known whether
multiple strains exist.

National surveillance efforts

National programmes for CWD surveillance and management are
currently under development in both the US and Canada. The United
States Department of Agriculture (USDA) currently encourages CWD
screening of all captive ranched elk and deer mortalities. In the absence of
national programmes, many states and provinces have developed their
own surveillance and certification programmes and have restricted
movement of deer or elk across state boundaries18. Due to lack of an
diagnostic assay in elk and deer, captive cervid herds with a
documented CWD-positive animal are typically eliminated. Thus far, there
have been 25 CWD-positive deer and elk herds detected in the US, 40 in
Canada, and at least one in South Korea. The USDA has depopulated 11
known-infected herds, plus additional herds in the endemic areas of
Colorado and Nebraska (L Creekmore, USDA, personal communication).
Surveillance for CWD in free-ranging cervids, conducted largely by
state and provincial wild-life management agencies, employs a
combination of symptomatically-targeted surveillance and random
surveys of harvested animals17,18. Surveillance data from free-ranging
cervids outside endemic portions of Colorado and Wyoming have been
assembled annually by the Southeastern Cooperative Wildlife Disease
Study (SCWDS). From 1998 to mid-2002, SCWDS received reports
indicating that 14,181 deer and elk had been tested for CWD24. In 2002,
Wisconsin wild-life officials reported CWD-positive deer had been
detected in hunter-harvested animals; shortly thereafter, officials in New
Mexico reported a confirmed case in a clinical suspect. Discovery of
these wild CWD-infected deer in states far from the original endemic
area raised several questions. How had CWD spread to these deer
populations? Had scrapie repeatedly jumped the species barrier to cause
CWD in geographically distant locations? Is CWD a spontaneously
arising disease, caused by a potentially enhanced susceptibility of cervids
for prion protein conversion? Is CWD spread by infected ranched deer
or elk? Or had CWD-infected deer and elk been illegally translocated
from Colorado into other states? Hopefully, on-going experimental and
epidemiological investigations will answer some, if not all, of these

Clinical signs

Early signs of CWD in clinically affected deer and elk are extremely
subtle and include weight loss, behavioural alterations (such as loss of
fear of humans), a lowered head and drooping ears. As clinical disease
progresses, more noticeable signs like flaccid hypotonic facial muscles,
excessive salivation, regurgitation of ruminal fluid, ruminal atony, and
polyuria and polydipsia arise. Individuals may develop aspiration
pneumonia in late stage disease14. Affected animals are typically > 2
years old (average, 35 years), with an equal prevalence seen among
males and females (Fig 2). Deer may survive up to 78 months after
onset of clinical signs14; elk may survive even longer20.

Gross and histological pathology

On gross necropsy examination, end-stage clinical CWD cervids are
consistently emaciated with serious atrophy of fat; frothy rumen
contents, abomasal ulcers, and aspiration pneumonia are observed with
less consistency14,16. Characteristic histological lesions are confined to
the central nervous system and are similar to the other TSEs, namely:
intraneuronal vacuolation, neuronal degeneration and loss, extensive
neuropil spongiosis, astrocytic hypertrophy and hyperplasia, and
occasional amyloid plaques14,16,19,25. Spongiform lesions predominate
within the thalamus, hypothalamus, midbrain, pons and medulla
oblongata as well as in the olfactory tubercle and cortex14,16. Severe
lesions in the supra-optic and paraventricular nuclei, where anti-diuretic
hormone is produced, may be responsible for the clinical signs of
polyuria and polydipsia and the low urine specific gravity in clinically
dehydrated animals14.

Interestingly, the distribution of lesions in deer and elk is similar to
lesions of BSE in cattle or scrapie in sheep25 and differs from the lesion
distribution of TME, which predominates in the cerebral cortex and
basal nuclei26. The most consistent histological lesion and PrPCWD
immunohistochemical stain of brain is within the dorsal motor nucleus
of the vagus nerve21, which is notably the first site of PrPCWD
accumulation (ES Williams and MW Miller, unpublished findings).

Transmission experiments

In the 1980s, Williams and Young demonstrated that CWD was transmissible
by intracerebral (IC) inoculation of CWD brain homogenate
into deer with an incubation period of 1721 months19. Recently,
experiments demonstrated that oral exposure of mule deer fawns to
CWD using brain homogenate results in detection of PrPCWD in
lymphoid tissues (retropharyngeal lymph node, tonsil, Peyers patches,
ileocaecal lymph node) within 6 weeks postexposure27 and clinical
disease with an incubation period of 1525 months (ES Williams and
MW Miller, unpublished findings). PrPCWD accumulates within the
lymphoid germinal centres in a manner similar to vCJD and scrapie.
Phenotyping studies have revealed that within germinal centres, PrPCWD
accumulates on cell membranes of follicular dendritic cells and/or B cells
and within the cytoplasm of tangible body macrophages28. In advanced
cases of CWD in naturally infected deer, PrPCWD accumulates in tonsil,
spleen, Peyers patches, and lymph nodes throughout the body, as well
as nerves and ganglia, pancreatic islets, and adrenal medulla21,29.

Fig. 2 Deer with clinical CWD; signs are emaciation, depression,
weakness, drooping ears, and vacant stare (a). Brain
histopathology (b) is characterized by neuronal vacuoles and spongiform
degeneration of the neuropil.

Abundance of PrPCWD in lymphoid tissues: implications for diagnosis and

Large accumulations of PrPCWD are detectable by immunohistochemistry
in tonsil and other lymphoid tissues of animals affected with CWD21.
Similar accumulations are also seen in mule deer prior to onset of
clinical CWD22. Therefore, immunohistochemistry on tonsil biopsies has
recently been investigated as a means for ante-mortem diagnosis of
CWD in deer30,31. Interestingly, Kimberlin and others have associated
infection of the lymphoreticular system with the transmissibility of
scrapie among sheep32. It is plausible that the abundant PrPres in
alimentary mucosa-associated lymphoid tissues may promote the
shedding and efficient transmission of CWD (and scrapie) prions.

Experimental intra- and inter-species transmission of CWD

The natural host range of CWD appears limited to deer (Odocoileus spp.)
and elk. As with other prion diseases, however, the range of species
susceptible to experimental inoculation is somewhat broader. Studies by
Marsh and Williams in the mid 1980s demonstrated that the CWD agent
could be transmitted to ferrets, mink, squirrel monkeys, and a goat19. Bruce
and colleagues found mice relatively resistant to CWD infection such that
strain typing was problematic33. More recently, Bartz and colleagues
demonstrated the susceptibility of ferrets to intracerebral inoculation of
CWD with an incubation period of 1721 months34. Racoons were
reported to be susceptible to scrapie and TME, but not CWD, after
challenge35. As with other TSEs, the susceptibility of other wild-life
or domestic species to CWD prions has yet to be studied comprehensively.

Transmission to humans or domestic livestock

Investigations of unusual CJD cases in the US over the last decade have
identified no causal relationship with CWD exposure36, but these
investigations, as well as other retrospective and prospective studies of
CJD risk factors, are on-going. No higher incidence or unusual clusters
of CJD cases have been observed in northeastern Colorado or
southeastern Wyoming (J Pape, Colorado Department of Public Health
and Environment, personal communication). Hunting continues as a
population management tool within the CWD endemic regions, but
public health officials recommend that CWD-infected carcasses not be
consumed. The actual risk of CWD jumping the species barrier and
causing human disease is unknown. A recent study by Raymond et al37
examined the ability of PrPCWD to convert human PrPC in vitro and
determined that the conversion was inefficient, but similar to the
efficiency of PrPBSE or ovine PrPSc to convert human PrPC. Because BSE
is apparently infectious to humans, at least at a low level, it would seem
prudent to limit exposure of humans to CWD:

Could CWD also cross species barriers and infect cattle and sheep
sharing grazing areas with CWD-infected deer? CWD transmission to
cattle causing a new BSE strain would be economically devastating for
the US beef industry. There are several studies, both completed and ongoing,
to determine whether cattle might be susceptible to CWD:

1 Conversion of bovine PrPC by PrPCWD was relatively inefficient37 compared
to conversions by PrPBSE or ovine PrPSc.
2 Cattle have been exposed to CWD-infected brain homogenates by the
most extreme and unnatural route, intracerebral inoculation. Thus far, at
27 months post-inoculation (p.i.), 3 of 13 cattle have developed
detectable PrPres in brain by Western blot and immunohistochemistry38.
3 Cattle have been orally inoculated with CWD brain homogenate and
show no clinical signs at 62 months p.i. (ES Williams and MW Miller,
unpublished findings).
4 Cattle are living in research facilities among a deer population with a
historically high prevalence of CWD and are in close association with
deer showing clinical signs of CWD. None of these animals have
developed signs of TSE after 63 months exposure (MW Miller and ES
Williams, unpublished findings).
5 A histological and immunohistochemical surveillance of brainstem from
262 cattle over 4 years old grazing in CWD endemic areas has not
revealed any suspect lesions of TSE39.

Thus far, data from these studies indicate that CWD will not readily
transmit to cattle.


Within the PrP gene of mule deer, white-tailed deer and Rocky
Mountain elk, there are three known polymorphisms. Mule deer and
white-tailed deer have residues G/S at position 96 and S/N at position
but no apparent relationship between genotype and CWD susceptibility has
been demonstrated to date in either species. In contrast, the PrP
polymorphism in elk occurs at position 132 (M/L), and to date only elk
with 132 M/M or M/L have developed disease. In a study by ORourke et
al, elk expressing M/M at residue 132 were significantly over represented
among CWD-infected individuals from both free-ranging and captive
populations40, suggesting that the 132 PrP polymorphism (M/L) may
influence susceptibility in this species. Evidence of genetic
susceptibility to
CWD in elk resembles observations in two other host species: Human 129
PrP polymorphism (M/V) has been linked to susceptibility to vCJD and
some forms of CJD41. Similarly, sheep 136 (V/A) PrP polymorphism has
been linked to scrapie susceptibility, as has a second at 171 (Q/R).
In contrast to intensely bred domestic ruminant populations, the PrP
genetics of free-ranging cervid populations of different species,
subspecies, or breeding populations will require large-scale surveys.
Further, since the prevalence of CWD is so low in most populations,
estimating relative genetic susceptibility based on field exposure is not
likely to be useful, and experimental oral inoculations of animals of
various genotypes using an inocula of different genotypes will be
necessary (K ORourke, personal communication).

Transmissible mink encephalopathy

Epidemiology and transmission  a controversial arena
Transmissible mink encephalopathy (TME), initially recognized in
Wisconsin and Minnesota in 1947, has sporadically appeared in farmed
mink in several countries where farmed mink are raised, including the
US, Canada, Finland, Russia, and East Germany42. Nonetheless, TME
outbreaks are rare; the most recent occurrence in the US was in 1985.
Epidemiological studies of outbreaks indicate that the disease is causally
linked to the ingestion of prion-contaminated meat, potentially scrapie
sheep43. However, in the 1985 TME outbreak in Stetsonville, Wisconsin,
the mink rancher stated with certainty that sheep were not fed to mink.
Instead, downer (ill) cattle were the primary source of mink food  a
discovery which has led to much speculation on a potentially
unrecognized BSE-like disease of American cattle43. Despite such
speculation, the ultimate origins of TME epidemics remain uncertain.
To further investigate potential food-borne sources of TME, mink
were intracerebrally (IC) exposed to UK- and North American-derived
sheep scrapie brain homogenates. Mink were highly susceptible to the
Suffolk sheep scrapie from the US, but only after IC inoculation44. Mink
did not develop disease from ingesting scrapie brain45. These studies
suggested, at minimum, that mink are susceptible to scrapie. However,
further experiments demonstrated that TME could pass into cattle and,
moreover, that brain from these cattle could transmit the TME agent
efficiently to mink by either the IC or the oral route, with an incubation
period of only 4 and 7 months, respectively. This indicates that TSEs can
be transmitted efficiently between cattle and mink46, although the
epidemiological significance of these findings are less clear.
Extensive studies of TME performed at the University of Wisconsin,
Madison have demonstrated experimental transmission to sheep, goats,
striped skunk, squirrel monkey, stump-tailed and rhesus monkey, and
hamster as reviewed by Rhein et al47. TME in hamsters presents as two
different clinical pictures with unique incubation periods, histological
lesions, and biochemical profiles. The two strains are referred to as
hyper and drowsy, and reflect the manifestations of clinical disease48.

Clinical signs

The incubation period of natural TME has been estimated at 712
months, based on observations following epizootics. Initially, infected
mink display behavioural changes including increased aggressiveness
and hyperesthesia which progresses to ataxia, occasionally tremors or
circling, and compulsive biting of self or objects (Fig. 3)47. Clinical
usually progress over weeks but can range from 1 week to several
months prior to death42.


The most salient histological feature in the TME brain is the extensive
neuropil vacuolation. Additionally, there is neuronal degeneration and
astrocytosis characteristic of TSEs. Lesions are well developed in the
cerebral cortex, particularly in the frontal cortex, as well as the corpus
striatum, thalamus and hypothalamus, and are less severe in the midbrain,
pons and medulla. Spongiform change is not usually evident in the
cerebellum and spinal cord47.

In contrast to CWD, little evidence of prion infection can be detected
in extraneural tissues of TME-infected mink. However, low concentrations
of infectivity have been demonstrated in spleen, intestine, and
mesenteric lymph node by bioassay49.

Fig. 3 TME in a mink. Clinical signs of TME include a rough hair coat,
extended tail, and ataxia (a). Brain from a
mink with TME depicting severe spongiform degeneration in the
hippocampus (b). Images were generously
provided by Dr Jason Bartz, Creighton University, Nebraska, USA.

Prevention of TME

Similar to FSE, TME apparently has arisen from exposure to a foodborne
prion agent, likely scrapie or a BSE-like agent in downer cattle.
The heightened awareness of TME by mink ranchers has likely led to the
exclusion of sheep or cattle as a food source. Therefore, future TME
infections are expected to be exceedingly rare.


We thank our colleagues for their contributions and helpful discussions: D
Gould, C Mathiason, J Bartz, J Fischer, R Allison, M Perrott, E Hoover, T
Spraker, E Williams, L Creekmore, and Katherine ORourke. This work
was supported, in part, by a grant from the National Institutes of Health.


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Prions for physicians

British Medical Bulletin 2003; 66: 199212
DOI 10.1093/bmb/dg66.199
The British Council 2003
Correspondence to:
Prof. Christina Sigurdson,
Research Fellow,
Institute of Neuropathology,
Hospital of Zürich,
Schmelzbergstrasse 12,
Zürich CH 8091,

British Medical Bulletin 2003;66TSS

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