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"MAD
COWS", ENGLISHMEN AND THE PRION HYPOTHESIS
by Dorothy
B. Preslar, ProMED/AHEAD Program Officer
Reviewed by
John P. Woodall and J. Ralph Blanchfield
Introduction
In March 1996 the public was startled by a statement made to the British
Parliament that ten recent cases of a rare brain disease in the UK might be
linked to a similar disease in cattle. The human disease found in the cases is a
variant form of Creutzfeldt-Jakob Disease (CJD), which was recognized before the
turn of the 20th Century and kills one person out of a million world
wide per year. The cattle disease is Bovine Spongiform Encephalopathy (BSE),
which was first diagnosed in the UK in 1986 and subsequently in other countries,
and was initially believed to have resulted from feeding healthy cattle the
remains of sheep killed by a related disease called Scrapie.
For at least a decade, the UK and other countries have taken a number of
actions to reduce the incidence, or prevent the occurrence, of BSE.
Notwithstanding the similarities of the disease in animals and humans, the
possibility that it could be transmitted from cow or sheep to man, by any means,
is generally accepted as close to zero; the principal reason being the natural
barrier to such cross-infectivity between animals and man. Although a recent
article by evolutionary biologist David Krakauer a nd others, hypothesizes that
the barrier may be less than total (Nature, 25 April, 1996, p. 675), proof that
BSE has crossed the barrier will, according to Dr. Tom Pringle, reporting to
ProMED-Mail on 2 May, involve a demonstration "by immunofluorescence that
traces of rogue cow protein is present in human victims."
This survey of the ProMED-Mail discussion on the Internet (supplemented
by other information in the public domain) includes reports and requests for
information on several forms of spongiform encephalopathy. In animals other than
cattle, sheep and goa ts, the disease is usually referred to as Transmissible
Spongiform Encephalopathy (TSE) and includes Chronic Wasting Disease that
affects mule deer and elk. The feline type (FSE) affects domestic cats and TME
(transmissible mink encephalopathy) affects.. ...mink, of course. TSE has been
found in zoological specimens: in Great Britain, for example, confirmed cases
include six kudus, five eland, a nyala and a gemsbok, one Arabian oryx, one
puma, one scimitar-horned onyx, one ocelot and four cheetah; in Germany there
were 3 ostriches. Infection in all cases is believed to have resulted from
cattlefeed containing by-products of BSE-infected cattle remains.
There are five known human forms of the disease -- CJD, the recent
varient of CJD (V-CJD), kuru, Gerstmann- traussler Syndrome (GSS) and Fatal
familial insomnia. There are three forms of Classic CJD -- sporadic, inherited
and infective. Sporadic CJD is the most prevalent. Until the current appearance
in the UK of a CJD-type disease in 10 persons whose average age is 26.5, it was
considered a disease of men and women dying over the age of 45 and was, thus,
thought to be a result of genetics or age ing, or both. The inherited form
represents 10-15 percent of confirmed cases; 100 families have thus far been
identified. The infective form is rare -- about 80 cases, all of them unintended
results of medical procedures.
Kuru (from a Pacific Islander word meaning "tremble") was,
about a quarter of a century ago, traced to a tribal custom of eating the brains
of a deceased relative; since 1957 about 2,600 cases have been identified, but
less than 10 cases last year. The current variant of CJD in the UK resembles
kuru, both pathologically and clinically, more than it does Creutzfeldt-Jakob.
Gerstmann-Straussler, with few cases reported in recent decades, is inherited,
some 50 extended families identified. Fatal familial insomnia (FFI) is likewise
considered to be caused by a mutated gene in about 9 families.
Common to all types of the disease -- both human and animal -- is the
progressive deterioration of the brain. The overt symptoms are loss of
coordination (insomnia in FFI) followed by dementia, although in some CJD cases
the sequence is reversed.
Under
the microscope, tissue specimens appear as if holes have been randomly drilled
through on a horizontal plane -- like Swiss cheese or, in a more subtle
analogy,like a sponge. Hence the name spongiform encephalopathy. Once the
disease is overt, the patient can expect to live about one year; the span is one
month to more than 10 years.
Until recently, it was not thought that human CJD could be diagnosed
before death. Now there are claims for a test using cerebrospinal fluid that not
only diagnoses CJD but also distinguishes it from Alzheimers, which has similar
symptoms. However, validating such a test requires carrying it out in a
substantial number of clinically suspected CJD cases and comparing the results
with those of subsequent postmortem histopathological examination of brains, and
finding a very high degree of correlation . The test has apparently not yet been
validated.
In the past three decades research has focused on the "prion
hypothesis" -- a naturally occurring protein that has "gone bad",
changing a normally harmless "prion protein" into a dangerous,
protease-resistant form. Probably the best explanation of pr ions for laypersons
appeared in the January 1995 issue of Scientific American, in an article written
by Stanley B. Prusiner, the leading proponent of the prion hypothesis who is
associated with the University of California School of Medicine in San
Francisco. However, recent reports published in Nature,Science and New Scientist
are most helpful, as is the elementary explanation contributed by Ralph
Blanchfield to these pages.
The Story from ProMED-Mail
1994
Note: The reports
to ProMED Mail included here are but a handful of the total number dealing with
spongiform encephalopathy.
The ProMED-Mail discussion of BSE began shortly after the electronic
network was launched with a report based on a newspaper article. In light of
recent events, it is a curious report. Taken from the Financial Times of London
[and posted 9 Nov 1994] , it read "A British-government funded study
release in October 1994 shows a statistical association between meat eating
(particularly veal, which could contain BSE) and CJD. The number of CJD cases in
the UK rose for 3 years, peaking at 55 in 1993 before falling to 40 in 1993. But
analysts say this is due to recall bias by the relatives who were questioned,
since the same association was found for suspected CJD cases who were later
diagnosed with Alzheimer's or other forms dementia."
What is curious is that, in late 1994, this report states that meat from
milk-fed calves (far under 30 months of age) was more likely to contain BSE than
cattle over the age of 30 months. In early 1996 it was officially suggested that
cattle over 30 months old were more likely to be infected with BSE, whereupon
the UK beef industry and government representatives volunteered to slaughter
varying numbers of cattle over that age in exchange for the dropping of bans
imposed by various countries, and in hopes of reassuring the public that UK beef
is safe to eat.
1995
The next report(3 Mar 1995)detailed the number of BSE cases reported by
eleven countries, as tallied by the Animal and Plant Health Inspection Service
(APHIS) of the US Department of Agriculture. Of the eleven, Oman and the
Falkland Islands had last reported in 1989. Cases in native cattle were reported
by only five countries -- Northern Ireland (1,385), Republic of
Ireland
(94), Switzerland(116), France (9) and Portugal (17). Cases in other countries
were found only in imported cattle. Great Britain (England, Scotland, Wales),
taken as a separate entity in the report, had a total 140,009 confirmed cases as
of 2 Dec 1994, with 52% of the herds affected.
All cases of BSE are not necessarily reported. For example, in response
to a request for information by a ProMED-Mail subscriber in the UK, a report was
posted (27 Mar 1995) by a Canadian microbiologist who said he had been told by a
Russian colleague several years prior that BSE had been confirmed in areas of
the then Soviet Union.
At the end of March, there was a brief exchange on ProMED-Mail between
veterinarians in the U.S. and Canada on the correct nomenclature for confirmed
cases in animals other than cattle and whether the other forms (mink, feline,
transmissible) in the cases mentioned could have been caused by feed containing
the remains of BSE-infected cattle or scrapie-infected sheep.
While
no one responded with respect to the zoological specimens that had died from
TSE, Dr. Clarence Gibbs of the National Institute s of Health said "I am of
the opinion that BSE has occurred in the past in the USA based on the two
outbreaks of transmissible mink encephalopathy, one in the early 1960s and the
other in the late 1980s. In both outbreaks the mink had been fed food prepa red
from "downer cattle" and horses."
In the first wave of reports of recent CJD deaths in Great Britain, a 28
Sept report based on two letters to the British medical journal The Lancet was
posted: "A third British dairy farmer has died of Creutzfeldt-Jakob
disease... . The 54- year-old man worked on a farm where three cows died of mad
cow disease [BSE]... . The other two farmers died within the past five years.
The mad cow disease epidemic, which peaked in 1989, sparked fears tha t those
who ate beef or worked closely with cattle could catch a fatal brain disease.
"A second letter in The Lancet reported that the incidence of
Creutzfeldt-Jakob disease in Britain is similar to that in other countries that
have not suffered the cattle disease. That survey reportedly did not find any
other cases...among other workers exposed
to mad cows,such as veterinarians or butchers. It also appears that British
farmers are no more likely to get the disease than farmers in other European
countries who have not dealt with sick cows.
"Creutzfeldt-Jakob disease strikes about one in a million people
each year. It is not known what causes the disease or whether
the same agent triggers both the human and animal forms. Since 1986, 153,215
cattle have been destroyed in Britain afte r showing symptoms of the disease.
British beef imports have been banned by 23 nations."
Close behind this report came one based on a story of 6 Nov in the
Manchester Guardian "Doctors reported two cases ... in a girl of 16 and a
boy of 18, both of whom died, but say there is no obvious link to BSE... . Three
farmers have died f rom the disease and a fourth is seriously ill. A farmer's
wife and a businessman are the latest suspected victims."
In late November 1995, in a series of letters to the British Medical
Journal, doctors in Britain, the U.S. and Europe called for extensive new
research to determine whether or not humans can contract CJD by eating beef from
BSE-infected cattle. Jeffrey Almond of the School of Animal and Microbial
Science, a department of the University of Reading, wrote that there was
evidence that BSE-type disease jumped between species. Sheila Gore of the
Biostatistics Unit of the Medical Research Counci l wrote "Taken together,
cases of Creutzfeldt-Jakob disease in farmers and young adults are more than
happenstance."
At that point in the disease history, 53 percent of British dairy herds
were confirmed infected by BSE. Some researchers claimed that 34 million
beef-eating humans may have been exposed. The German parliament was trying to
ban British beef imports. On 7 Dec news reports published the results on a poll
in Britain: 9 out 10 said they did not believe their government'statements that
beef is safe to eat. And beef was eliminated from menus in hundreds of British
schools.
The British public thus aroused, the debate on the safety of eating beef
from British cattle became furious with retail beef sales dropping 25 percent
and even a threat of legal action by the maker of Bovril, a popular beef drink,
after a radio hel p line advised callers worried about catching "mad cow
disease" to stop consuming beef products. Government officials scurried to
reassure the public. Agriculture Minister Douglas Hogg said "I am
absolutely sure that British beef is wholly safe", while conceding
that there was no conclusive proof that BSE could not be transmitted to humans
through beef offal. Food Minister Angela Browning said she "of course"
ate beef.
Among those on the other side of the argument were leading brain expert
and former government health adviser Sir Bernard Tomlinson, who said he had
stopped eating hamburgers and anything else that contained beef offal, and
Leicester University resear cher Shaun Heaphy, who said "There is a grand
experiment going on in Britain with BSE with us as the laboratory animals."
Clearly, the incubation period for CJD -- up to 30 years -- made the public even
more wary than it would be if there were only a spa n of days or weeks from
exposure to symptoms.
Five days before Christmas, when one holiday meal in a typical home is
likely to be roast beef and Yorkshire pudding, British scientists from the
Imperial College School of Medicine said in a report to Nature magazine that
their experiments w ith mice had found no connection between BSE and CJD. The
experiment included two types of transgenic mice. The first type expressed both
mouse prion protein and human prion protein; the second type expressed only
human prion protein. When a group of the first type (mous e and human protein)
was challenged with CJD material by intracerebral innoculation, both the mouse
and the human protein succumbed. Another group of the first type was challenged
with BSE material, also introduced by intracerebral innoculation, the mous e
protein succumbed but the human protein did not.
Two groups of the second type, expressing only human prion protein, were
then challenged. The first group was intracerebrally innoculated with CJD
material, the second group with BSE material. The first group duly developed CJD
in 200 days. The secon d did not develop BSE and was still fit and well after
264 days.
Ralph Blanchfield, Chair of the Institute of Food Science and Technology
(IFST) Member Relations and Services Committee, reported to ProMED-Mail on 22
Dec and 29 Dec that the number of confirmed new BSE cases in the UK had fallen
sharply from 1992 ( a peak of 37,057 cases) to the end of November 1995 (11,031
cases reported to that date) and, further, that the number of cases in cattle
less than 5 years old (in late 1994) showed a "particularly sharp
decline"as stated in the Progress Report of the Spo ngiform Encephalopathy
Advisory Committee (SEAC) released in November 1994.
This would indicate that the Financial Times report of 9 Nov 1994 (quoted
at the beginning of this narrative) was either in error, or that the report that
plotted the confirmed cases by month of birth of cattle also contained
statistics indica ting an increase in cases in cattle less than 12 weeks old.
According to beef marketing regulations, this is the oldest a calf can be when
slaughtered as "milk-fed" veal, although calves as old as 24 weeks are
often slaughtered and sold as veal in superm arkets. But, in any case, there was
a decline in cases, and it chronologically reflected the 1989 ban on ruminant
feed for cattle.
1996
In the first week of January ProMED-Mail carried postings from a Canadian
and a Danish subscriber, both of whom had been following press reports on the
CJD-BSE situation in Britain. Taken together, they described a 52-year old man,
Leonard Franklin, who was being treated at York District Hospital with symptoms
of CJD. Franklin had worked in an abattoir from 1989 to 1991 and was first
diagnosed as having Alzheimers. Staff from the government's CJD Surveillance
Unit in Edinburgh visited the patient. It is presumed that Franklin died, but he
is not among the 10 cases of the disease in persons younger than 42 that are at
the heart of the current controversy. [It has been reported that CJD claimed 29
lives in Britain in 1995 and was suspect in 65 other deaths.]
On 20 March 1996 Stephen Dorrell, British Secretary of State for Health,
delivered a statement in Parliament based on advice
from SEAC, which, established in April 1990, is a committee of independent
scientists. Its task is to advise the UK govern ment on all scientific aspects
of BSE. Dorrell said "There remains no scientific proof that BSE can be
transmitted to man by beef, but the Committee [members] have concluded that the
most likely explanation at present is that these cases are linked to exposure to
BSE before the introduction of the specified bovine offal ban in 1989. Against
the background of this new finding, the committee has today agreed [on] the
series of recommendations which the Government is making public this
afternoon."
In the afternoon, the recommendations were made public: There should be
continued surveillance of the disease; current measures to protect the public
health should be properly enforced; and the complete removal of the spinal cord
in slaughtered cattle should be constantly supervised. Further, the Committee
recommended:
1."that carcasses from cattle aged over 30 months must be deboned in
licensed plants supervised by the Meat Hygiene Service
and the trimmings must be classified as SBOs" [Specified Bovine Offals];
2."a prohibition on the use of mammalian meat and bonemeal in feed
for all farm animals";
3."that HSE [Health and Safety Executive] and ACPP [Advisory
Committee on Dangerous Pathogens -- the acronym is incorrect], in consultation
with SEAC, should urgently review their advice in the light of these
findings"; and
4."that the Committee urgently consider what further research is
necessary."
"The Committee's previous advice that drinking milk is safe was
allowed to stand. If the recommendations set out above are carried out, the
committee concluded that the risk from eating beef is now likely to be extremely
small."
Immediately the British Government was accused in the press and in
Parliament of ties to the agriculture industry that prevented it from protecting
public health, and was roundly criticized by a number of scientists for allowing
the SEAC report to be made public before releasing data that would hopefully
mitigate the public panic. Nations not already imposing bans on imports of
British beef considered their options. Doctors and scientists began trying to
make sense of what data existed. Reports to ProMED-AHEAD rushed in.
THE
PRION HYPOTHESIS
[Note: This is an attempt at an explanation intended to be understandable
by non-scientists as well as scientists.
The
latter will recognize that some of the matters briefly described are more
complex than it is possible to indicate here, and that research is continually
bringing new knowledge in this field.]
Increasingly, research is confirming the hypothesis of Stanley Prusiner
and his colleagues, that in transmissible spongiform encephalopathies (such as
BSE in cattle and CJD in humans) the infective agents are abnormal, distorted
PRIONS. A prion (PrP) is a small protein molecule found in the brain cell
membrane. It is not "live" -- it has no associated DNA.
"Prion" is a generic term. Different species have brain cell proteins
of different compositions. For example, the human prion differs by 30 d ifferent
amino acids from the cattle prion.
Protein molecules have three-dimensional folded shapes. An infective
prion (PrPsc) is one whose shape has become distorted (misshapen). [The PrPsc
designation originally referred to sheep scrapie prions, but is now used as a
generic designation for a ll kinds of infective prions .] The distorted shape is
protease-resistant, i.e. it is not broken down into amino acids in the digestive
system. It is also highly resistant to normal heating and to normal sterilants.
When a distorted prion molecule reaches (by whatever route) the prions in
the brain cell membrane of a "host" individual, that molecule is able
to act as a three-dimensional "template" to cause a normal prion
molecule to adopt a similar distorted shap e; and that in turn is able to act as
a template to do the same to another normal prion molecule; and so on.
One familiar example of a template is the three-dimensional Jello (or
jelly) mold, which causes the surface of the jelly in contact to set in exactly
the same shape as the mold. Another, two-dimensional, example is the
dressmaker's paper patterns t hat enable the cloth to be cut to their exact
sizes and shapes.
Distorted and infective BSE prions probably first arose from the
inclusion of scrapie-infected sheep offals in feed for cattle, and probably also
from inclusion of offals from cattle suffering from previously unrecorded cases
of BSE at low incidence l evel, amplified by subsequent "re-cycling"
of infected cattle offals in cattle feed.
CJD prions are likewise misshapen human brain prions. They may arise from
a genetic predisposition of an individual; or by transfer from a person with (or
incubating) CJD, via neurosurgery;or via injection of human pituitary gland
extract from corpse pituitary glands including persons who had died from CJD (as
happened before synthetic material became available); or possibly via
transfusion of CJD-infected blood. Other as yet unexplored possibilities might
be via the use of CJD-infected dental or opthalmological instruments previously
used of a person incubating CJD.
There is no scientific evidence that CJD prions can be caused by BSE
prions; i.e. no scientific evidence that BSE-infective prions can act as a shape
template to cause distortion in normal human prions.
NEW
QUESTIONS ON THE CAUSATIVE AGENT
During April, a month during which several papers and letters supporting
the prion pathogenesis of spongiform encephalitis appeared in Nature and Science
magazines, a most arresting question was put before ProMED-Mail: Is it in fact
po ssible that, popular hypotheses aside, BSE really is caused by a virus?
The question came from David A. Watson, a professor at the University of Texas
Medical Branch on 3 Apr:
"With all the discussion concerning BSE pathogenesis and
transmissibility, I am surprised that a very recent paper seems to have been
virtually ignored: Manuelidis L, Sklaviadis T, Akowitz A, Fritch W 1995. 'Viral
particles are required for infection in neurodegenerative Creutzfeldt-Jacob
disease.' Proc. Nat. Acad. Sci. 92:5124-5128.
"Quoting only the last 3 sentences of the abstract: `These data
strongly implicate a classical viral structure, possibly with no intrinsic PrP,
as the CJD infectious agent. CJD-spe cific protective nucleic acid-binding
protein(s) have already been identified in 120S preparations, and preliminary
subtraction studies have revealed several CJD-specific nucleic acids. Such viral
candidates deserve more attention, as they may be of use in preventing
iatrogenic CJD and in solving a fundamental mystery .'"
The next day, Gerhard Krexner, professor of experimental physics at the
University of Vienna, Austria, wrote:
"In the January 1995 edition of the Scientific American, Stanley B.
Prusiner has published a paper titled `The Prion Diseases.' In this article he
presents a survey on the subject for the non-specialist which is indeed highly
interesting and readable.
The
way in which the material is exposed leaves the reader inevitably with the
impression that available evidence is overwhelmingly in favor of the prion
hypothesis and that the scientific debate of the question is more or less
closed. Yet, on e has to bear in mind that, as far as I understand, Prusiner was
at the origin of the prion hypothesis and that today he and his group continue
to belong to its most prominent exponents. Therefore, there might be some bias
in his presentation.
"There is a German translation of the Scientific American called
Spektrum der Wissenschaft presenting, essentially, translations of the original
manuscripts with a delay of two months. Apart from some editing...these
translations somet imes are complemented by additional material which is thought
to be, and indeed frequently is, of particular interest to the German-speaking
audience....
"In the March 1995 edition ...the translation of Prusiner's article
is followed by a 3-page paper by Heino Direinger and Mushin Oezel...from the
Robert-Koch-Institut in Berlin where these two authors work on unconventional
virus diseases.
In their paper
they strongly advocate the virus hypothesis and even present electron
microscopic images of what they call 'virus-like particles' found in brains of
scrapie-infected hamsters.
"Since the journals where the above work has been published are, as
I was told, in high repute it appears to me that the debate prion vs. virus is
still going on and that the matter has not yet been settled.
"I would very much appreciate, and in fact believe that most of the
participants in this board would do [sic], if experts and scientists actively
working in the field could comment on this issue.
"To my opinion there are at least two arguments pleading for a
broader discussion.
"Firstly, the question of whether there really exists an entirely
new class of infectious agents (namely: prions) that is of a fundamental nature
in itself.
"Secondly (and even more importantly in the present context), the
measures to be taken in order to prevent further spreading of BSE and its
possible communication to humans obviously will depend to some extent on the
underlying assumptions concerning the origin of the disease."
A
ROLE FOR PESTICIDES?
While the virus vs prion debate may, in the face of recently published research,
be running out of steam, the proposition that organophosphates (OP) in
insecticides may be implicated appears to be gathering interest. Responding
to a request for information about proponents of the OP hypothesis, Ralph
Blanchfield wrote on 5 Apr:
"The most vigorous argument for the possible involvement of
organophosphorus (OP)compounds in BSE is made by Dr.Douglas Latto, Chairman of
the British Safety Council. ... He argues that the role of OP is not directly in
interacting with prions, but in weakening the immune system, making the cow's
central nervous system more susceptible to the action of prions, and he has
called for their use to be discontinued."
And in answer to the question 'Does chemistry suggest that an interaction
between PrP and organophosphates is likely, perhaps...act
as a catalyst?', Torsten Brinch in Denmark says"Yes, chemistry does suggest
that such an interaction is likely. The surface of acetylcholinesterase has
enough properties in common with the PrP molecule, to make both molecules react
with anti-PrP antisera. The organophosphates are used precisely because they are
able to react irreversibly with acetylcholinesterase, th us killing the affected
insects.
"And the 'tombstone' products comprised partly of PrPSc, which are
found in diseased brains, have very strong acetylcholinesterase activity. So it
is definitely a possibility that the organophosphates can react with PrP."
Further, Brinch says "...O P does affect the same regions of the brain
which are affected by BSE, and there are similarities pathologically and
symptomatically between BSE and chronic OP poisoning."
According to Robert Trybis, a ProMED-Mail subscriber, the organophosphate
hypothesis was advanced by Mark Purdey, a UK farmer, who theorized that the
chemicals in the pesticides acted directly on bovine PrP to cause BSE which
could then be passed on to other cattle as a result of bovine to bovine feeding.
Trybis wrote "He [Purdey] speculated that humans might accumulate
organophosphate residues and so also be vulnerable to a BSE like disease."
In 1994 Purdey published an article in the Journal of Nutritional Medicine.
Purdey summarized his theory in the introduction to the article:
"In utero exposure of the bovine fetus to chronic `low' doses of
neuroactive mutagenic pesticides of the anticholinesterase organophosphate (OP)
type that would target thea cetylcholinesterase-like surface of the PrP
molecule, and disrupt the chaperone-mediated folding of PrP production and RNA
translation process, may play a key non-viral role as the primary initiator of
the disease, inducing both the initial misfolding of the PrP, and the hitherto
disregarded serotonergic deficit which is fundamental to the 'stress'-invoked
secondary 'switch-on' of the PrPsc disease pathogenesis in post-natal life. Once
the PrP genetic process is mutated, the products become undegradable PrPsc,
infectious isoforms that invariably possess the property to being both
vertically and horizontally transmissible. The PrPsc agent, capable of
initiating chain reactions of multireplication, is transmitted into succeeding
generations that become co ntaminated via placental transmission or ingestion of
PrPsc-contaminated brain tissue feedstuff."
Paul Epstein of Harvard's School of Public Health asked on 29 April
"Might the OPs be working at the DNA level, and
through
m-RNA, build faulty, unstable surface proteins? The implications for relating
chemical toxins to prion disease – either actin g directly on cell membranes
or through mutations of structural and/or regulatory genes -- are
profound."
DIAGNOSTIC
TESTS
At the time the ProMED discussion began it was believed by laypersons (as
well as by those scientists who had not followed all the research in recent
years) that CJD could not be definitively diagnosed before death. This is
probably because such was true before research programs geared up after the late
1980s outbreak in Britain, because SE could be diagnosed in animals only by
microscopic examination of necopsied brain tissue, and because pre-mortem tests
appear not to have been validated by acc eptable methodology.
On 17 Nov 1995, Dr. Clarence Gibbs of the NIH refuted this belief:
"...we at the NIH are now able to support a clinical diagnosis of CJD and
certainly separate this from Alzheimers disease by use of a laboratory test on
cerebrospinal fluid. Should so meone want this test performed they need only
send frozen CSF to me at the NIH." and "...for cases that may be
associated with familial forms of CJD/GSS we can provide DNS [DNA ?] testing to
elucidate point mutations in the PrP gene. Moreover, Professor Collinge in
London is using transgenic mice to diagnose CJD/GSS."
Later in the discussion it was reported that in 1986 and 1990 a
pre-mortem test for CJD was described in articles in the New England Journal of
Medicine and Journal of Neurological Science. A joint effort by scientists from
NIH and CalT ech, the test uses cerebrospinal fluid.
In a report of 22 April 1996, Stuart Neilson of the UK said "The two
references I have to the ... test are old (1986, 1990), but I have seen many
claims that Harrington has published something recently... . For those that
haven't heard of this, two proteins (not PrP, and not related structurally to
PrP) were found in the spinal fluid of CJD pa tients. The presence is a highly
sensitive indicator of CJD, but non-specific. The other medical conditions in
which the pair of proteins occur can be discounted by clinical history. In
principle, a similar test could be applied to cattle, dependent up on the
sensitivity, specificity and particality [practicality?] of a commercially
available test ... ."
On 3 May, Peter Cowen of North Carolina State University wrote
"While the CJD [test] may be impressive in terms of sensitivity..., there
should be some serious pause before using the test. It may be the wrong test for
the wrong disease. The problem is the prevalence of CJD is too low. At one in a
million prevalence the numbers of false positives will be high, very high.
In
fact the positive predictive value of the test will be only 0.000048 in a
country of 100 million at-risk individuals....
"To make matters worse, this CSF [cerebrospinal fluid] test, when
positive, carries a rather ominous conclusion, i.e., a neurodegenerative
syndrome leading to death-type prognosis with the positive test result, which
can only be confirmed upon post mortem and with a fairly long incubation period.
Life after a positive test will not be pleasant for the thousands of false
positives while they are waiting for symptoms to develop. This test without a
confirmatory, antemortem test seems ill founded.Testing animals for BSE also
took a new turn in news that a field test using cattle urine had been developed
by Dr. Harash Narang in the UK. Dr. Neilson also wrote on 26 April 1996
"The latest I heard of Harash Narang's BSE urine test was last Wedn esday,
in evidence to Parliament. Guessing, (bravely or foolishly) I think this might
be a redox-potential test, rather than the presence of protein or viral
particles'. It is said (by Narang) to be quick and cheap. ...." [The
specifics of Dr. Narang's test have not yet been made public, pending resolution
of the intellectual property rights question. When details are available, they
will be summarized on the ProMED page.]
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